Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis

*Katerina Theocharous, Bernadette Prentice, Charles F. Verge, Adam Jaffé and Shihab Hameed*

## **Abstract**

With advances in technology, it is now possible to detect the emergence of glucose abnormalities in cystic fibrosis with improved sensitivity, and from a very early age. These abnormalities are increasingly recognized as predictors of clinical decline, raising the possibility that early intervention may slow or prevent this deterioration. In this chapter, we will review the available literature on methods of detecting glucose abnormalities in cystic fibrosis (random and fasting glucose, HbA1c, oral glucose tolerance testing, and continuous glucose monitoring), and detail their advantages and possible limitations in the interpretation of glycemic data. We will also discuss treatment outcomes of early intervention, prior to the diagnosis of diabetes as currently defined.

**Keywords:** cystic fibrosis-related diabetes, glucose, insulin, abnormal glucose tolerance, indeterminate glycaemia, impaired glucose tolerance, oral glucose tolerance test, continuous glucose monitoring

## **1. Introduction**

Historically, cystic fibrosis (CF) caused fatal respiratory failure in early childhood [1, 2], but proactive multidisciplinary care has increased life expectancy to ~44 years [3]. With longer survival, co-morbidities have become more prevalent, the commonest being cystic fibrosis-related diabetes (CFRD) [4, 5]. This is associated with poorer clinical status [6–21], quality of life [22, 23], and life expectancy [16, 24, 25] relative to non-diabetic CF patients.

CFRD is distinct from other diabetes mellitus etiologies, including type 1 (T1D) and type 2 (T2D) (see **Table 1**) [4, 5]. It is caused primarily by chronic pancreatitis [26–30] with progressive insulin deficiency [9, 11, 31], particularly during firstphase insulin secretion [8, 9, 11, 19, 32–40]. Variations in peripheral insulin sensitivity also contribute to CFRD [20, 41]; hyperglycemia progressively induces insulin resistance via downregulation of glucose transporters [42–44], and insulin sensitivity decreases with inflammation, use of exogenous glucocorticoids, and puberty [45–49]. In CF, the depleted and dysfunctional pancreatic β-cells may be unable to compensate for this, producing early intermittent hyperglycemia progressing to fasting hyperglycemia [35, 44, 50].


#### **Table 1.**

*Comparison of common etiologies of diabetes. Adapted from Moran et al. [4].*

CFRD is usually preceded by a spectrum of abnormal glucose tolerance (AGT) on oral glucose tolerance testing (OGTT), including impaired fasting glucose (IFG), indeterminate glucose tolerance (INDET), and impaired glucose tolerance (IGT) [4, 51]. There may be 'waxing and waning' of glucose tolerance between these categories [19, 52–55], probably due to variations in insulin sensitivity [35, 44]. Nevertheless, large prospective cohort studies report overall deterioration in CF patients' glucose tolerance over life [16, 20, 53, 54, 56]. The date of onset of CFRD is considered to be the first time a patient meets diagnostic criteria, even if glucose abnormalities subsequently resolve due to improvement in insulin sensitivity [4]. This is because studies utilizing this definition report correlations between CFRD duration, microvascular disease prevalence [57], and mortality [16, 56].

Taken together, these factors explain why CFRD becomes more common with age. Prevalence is ~1.5% in CF patients aged <10 years, but ~15% in those aged 11–17 and ~50% in those aged ≥18 [8, 16, 58]. The American Diabetes Association (ADA) recommends annual screening from age 10, using 2-h OGTT [59]. CFRD can also be diagnosed using clinical status, random blood glucose, fasting plasma

**27**

**Table 2.**

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis*

form of intermittent postprandial glucose excursions [63].

**Diagnostic criteria**

HbA1c ≤5.6% (38 mmol/

2-h OGTT *0 min:* <5.6 mmol/L

CGM Usually

*CGM = continuous glucose monitoring.*

mol)

<5.6 mmol/L (100 mg/dL)

(100 mg/dL) *2 h:* <7.8 mmol/L (140 mg/dL)

<7.8 mmol/L (140 mg/dL)

ties, supporting their detection and management in routine practice.

Clinical status Classical symptoms of hyperglycemia, including polyuria, polydipsia, and

**IFG:**

*2 h*: N/A **INDET:**

(200 mg/dL)

dL)

**IGT:**

dL)

*AGT = abnormal glucose tolerance. INDET = indeterminate glucose tolerance. IGT = impaired glucose tolerance.* 

*Diagnostic criteria of glucose measurement methods commonly used in CF. Diagnosis must occur during clinical stability, defined as no pulmonary exacerbations during the past 6 weeks and no current systemic glucocorticoids. It is also recommended that any positive fasting plasma glucose, HbA1c, or OGTT is repeated at a later date. Non-CGM diagnostic criteria are from the American Diabetes Association [59, 64]. CGM diagnostic criteria are from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group [65].*

*HbA1c = glycated hemoglobin. OGTT = oral glucose tolerance testing. IFG = impaired fasting glucose.* 

glucose, and glycated hemoglobin (HbA1c) [4, 60, 61]. In clinically-stable outpatients with CF, diagnostic criteria are identical to those used for other etiologies of diabetes mellitus [4], and are shown in **Table 2**. Recently, continuous glucose monitoring (CGM) has also been used to investigate glucose abnormalities in CF patients. This method is not yet widely recommended for diagnosis of diabetes, but it is often used to monitor glycemic control or assist insulin dosage [62]. Moreover, CGM often detects even earlier CF-related glucose abnormalities than OGTT, in the

This chapter compiles research on use of each glucose measurement method in CF patients, with special focus on pre-diabetic patients. The benefits and limitations of each method will be explored to help ascertain when their usage might be appropriate. In the process, we will examine correlations between early glucose abnormalities and clinical decline. Finally, we will review preliminary evidence of improved long-term outcomes with insulin treatment of early glucose abnormali-

**Normal ranges Pre-diabetic ranges Diabetic ranges**

hyperglycemic crisis, may assist diagnosis of diabetes when combined with other positive diagnostic tests. Some CF-specific definitions also consider unexplained decline in lung function & nutritional status to be classical symptoms.

— — ≥11.1 mmol/L (200

**IFG:** ≥5.6 mmol/L (100 mg/ dL), <7.0 mmol/L (126 mg/dL)

All categories constitute **AGT**

*0 min:* ≥5.6 mmol/L (100 mg/ dL), <7.0 mmol/L (126 mg/dL)

*0 min:* <7.0 mmol/L (126 mg/

*OGTT midpoints:* ≥11.1 mmol/L

*2 h:* <7.8 mmol/L (140 mg/dL)

*0 min:* <7.0 mmol/L (126 mg/

*2 h:* ≥7.8 mmol/L (140 mg/dL), <11.1 mmol/L (200 mg/dL)

correlating them with AGT or diabetes.

Elevations ≥7.8 mmol/L (140 mg/dL) are referred to as **glucose excursions**, but there are no standardized criteria

5.7–6.4% (39–46 mmol/mol) ≥6.5% (48 mmol/mol)

mg/dL)

dL)

≥7.0 mmol/L (126 mg/

*0 min:* ≥7.0 mmol/L (126 mg/dL) *AND/OR 2 h:* ≥11.1 mmol/L (200 mg/dL)

*DOI: http://dx.doi.org/10.5772/intechopen.92847*

**Glucose measurement method**

Random blood glucose

Fasting plasma glucose

#### *Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.92847*

glucose, and glycated hemoglobin (HbA1c) [4, 60, 61]. In clinically-stable outpatients with CF, diagnostic criteria are identical to those used for other etiologies of diabetes mellitus [4], and are shown in **Table 2**. Recently, continuous glucose monitoring (CGM) has also been used to investigate glucose abnormalities in CF patients. This method is not yet widely recommended for diagnosis of diabetes, but it is often used to monitor glycemic control or assist insulin dosage [62]. Moreover, CGM often detects even earlier CF-related glucose abnormalities than OGTT, in the form of intermittent postprandial glucose excursions [63].

This chapter compiles research on use of each glucose measurement method in CF patients, with special focus on pre-diabetic patients. The benefits and limitations of each method will be explored to help ascertain when their usage might be appropriate. In the process, we will examine correlations between early glucose abnormalities and clinical decline. Finally, we will review preliminary evidence of improved long-term outcomes with insulin treatment of early glucose abnormalities, supporting their detection and management in routine practice.


*HbA1c = glycated hemoglobin. OGTT = oral glucose tolerance testing. IFG = impaired fasting glucose. AGT = abnormal glucose tolerance. INDET = indeterminate glucose tolerance. IGT = impaired glucose tolerance. CGM = continuous glucose monitoring.*

#### **Table 2.**

*Cystic Fibrosis - Facts, Management and Advances*

Childhood or adulthood

β-cell dysfunction & destruction, primarily autoimmune with genetic & possible environmental causes

Peak age of onset

Usual body habitus

Likely pathophysiology

Insulin deficiency

Insulin resistance

Pharmacological & dietary therapy

Likeliest cause of death

**Table 1.**

CFRD is usually preceded by a spectrum of abnormal glucose tolerance (AGT)

disease

**Type 1 diabetes Type 2 diabetes CFRD** Prevalence 0.2% 11% 35% (likely underestimated due

Onset Usually acute Insidious Insidious

Ketoacidosis risk High Low Low

• Insulin

Complications Microvascular &

• Dietary monitoring to ensure appropriate insulin dosage

macrovascular disease

*Comparison of common etiologies of diabetes. Adapted from Moran et al. [4].*

to lack of testing)

sometimes overweight (due to CF therapy success)

β-cell destruction due to inspissated pancreatic secretions, inflammation, and replacement with fibrosis & amyloid, plus a component of

circumstances (e.g. glycemic control, pubertal stage, use of glucocorticoids, inflammation)

• Continuation of CF-specific diet, designed to prevent wasting: high-calorie, highcarbohydrate, high-fat

• Decline in nutritional status & lung function, associated with

early mortality • Microvascular disease

CF pulmonary disease

β-cell dysfunction

• Insulin

Adulthood Ages 18–24

Normal Overweight Underweight, normal, or

Peripheral insulin resistance & subsequent β-cell

Nearly complete Partial and variable Severe but not complete

Variable Severe Variable depending on

• Insulin or oral anti-hypoglycemics • Low-calorie, low-carbohydrate, low-fat diet

Microvascular & macrovascular disease

stress

on oral glucose tolerance testing (OGTT), including impaired fasting glucose (IFG), indeterminate glucose tolerance (INDET), and impaired glucose tolerance (IGT) [4, 51]. There may be 'waxing and waning' of glucose tolerance between these categories [19, 52–55], probably due to variations in insulin sensitivity [35, 44]. Nevertheless, large prospective cohort studies report overall deterioration in CF patients' glucose tolerance over life [16, 20, 53, 54, 56]. The date of onset of CFRD is considered to be the first time a patient meets diagnostic criteria, even if glucose abnormalities subsequently resolve due to improvement in insulin sensitivity [4]. This is because studies utilizing this definition report correlations between CFRD duration, microvascular disease prevalence [57], and mortality [16, 56]. Taken together, these factors explain why CFRD becomes more common with age. Prevalence is ~1.5% in CF patients aged <10 years, but ~15% in those aged 11–17 and ~50% in those aged ≥18 [8, 16, 58]. The American Diabetes Association (ADA) recommends annual screening from age 10, using 2-h OGTT [59]. CFRD can also be diagnosed using clinical status, random blood glucose, fasting plasma

Macrovascular disease Macrovascular

**26**

*Diagnostic criteria of glucose measurement methods commonly used in CF. Diagnosis must occur during clinical stability, defined as no pulmonary exacerbations during the past 6 weeks and no current systemic glucocorticoids. It is also recommended that any positive fasting plasma glucose, HbA1c, or OGTT is repeated at a later date. Non-CGM diagnostic criteria are from the American Diabetes Association [59, 64]. CGM diagnostic criteria are from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group [65].*

## **2. Benefits and limitations of conventional methods used to diagnose glucose abnormalities in CF**

#### **2.1 Clinical status and/or random blood glucose**

The ADA allows diagnosis of CFRD following one random blood glucose measurement ≥11.1 mmol/L, provided that it is combined with polyuria, polydipsia, or hyperglycemic crisis [59]. However, symptomatic hyperglycemia or hyperglycemic crisis is extremely rare in CFRD [4]. In Lanng et al.'s seminal 5-year prospective cohort study of 191 CF patients receiving annual OGTT, only 33% of those diagnosed with CFRD had polyuria or polydipsia [54]. Moreover, in a cross-sectional study of all 60 patients aged ≥10 years at a Brazilian CF center, age at diagnosis was significantly lower for patients diagnosed using OGTT as opposed to clinical criteria (13.5 years vs. 22.3 years), implying much earlier detection of disease [66].

Some centers compensate by accepting unexplained decline in lung function or nutritional status as classical symptoms of hyperglycemia (see Section 3) [67]. In one cross-sectional study of 91 CF patients not known to be diabetic, these modified clinical criteria detected OGTT-diagnosed CFRD with 58% sensitivity [68], which is an improvement over other studies but still suboptimal for a screening test.

### **2.2 HbA1c**

HbA1c, i.e. glycated hemoglobin as a percentage of total hemoglobin, is commonly used to monitor glycemic control in diabetes mellitus. It usually reflects average blood glucose over the life of an erythrocyte (~3 months) [64, 69]. However, CF patients with CFRD, INDET or IGT rarely have a significantly-higher HbA1c than those with normal glucose tolerance (NGT) [11, 70–73], and even statisticallysignificant differences tend to be of <1% magnitude [8, 34, 40, 74, 75]. Godbout et al.'s study of 13 CFRD patients also found that HbA1c did not correlate with mean plasma glucose, as calculated using fingerprick self-monitoring [76].

Numerous hypotheses have been espoused to explain HbA1c's relatively poor correlation with glucose tolerance in CF. These include insufficient duration of transient CF-related post-prandial hyperglycemia, which is often limited to the early phase of insulin secretion; alteration of hemoglobin glycation by hypoxia; iron deficiency, which is a common comorbidity of CF; and increased erythrocyte turnover in the context of chronic inflammation [1, 4, 5, 76, 77]. This implies that HbA1c may vary with degree of inflammation [78], and that *trends* in HbA1c may be more useful for predicting deterioration in glucose tolerance. Supporting this, Lanng et al.'s 5-year prospective cohort study found significant differences in median HbA1c between patients who consistently had NGT (5.2%), patients who varied between NGT and IGT (5.3%), patients who developed CFRD during the study (5.8%), and patients who entered the study with a diagnosis of CFRD (6.5%) [54].

It has also been hypothesized that poor correlation between mean plasma glucose and HbA1c may be confounded by use of fingerprick tests to measure glucose, since these can easily miss CF-related hyperglycaemic peaks due to their relative infrequency [76]. In two studies of CF and CFRD patients, mean plasma glucose was estimated using 2–7 days of CGM rather than fingerprick self-monitoring, and strongly correlated with HbA1c (*r* = 0.86–0.89) [75, 79].

These findings have regenerated interest in potentially using HbA1c to screen for CF-related glucose abnormalities, especially because it is much more convenient than OGTT. However, computing HbA1c thresholds suitable for CFRD screening has proved challenging. Some studies do report almost 100% sensitivity for OGTTdefined CFRD using HbA1c thresholds of 6.0–7.5% [40, 80–82], but all have small

**29**

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis*

sample sizes, and most either did not calculate sensitivity to CF-related AGT [81] or report low values, ~20–50% [80, 82]. Therefore, HbA1c may not detect CFRD and its complications until late. Moreover, most evidence suggests that the diagnostic threshold for CFRD, HbA1c ≥6.5%, has poor sensitivity compared to OGTT [54, 83–85]. Lowering the diagnostic threshold for HbA1c abnormalities does increase sensitivity to both CFRD and AGT, but the thresholds required to achieve sufficient sensitivity for screening generally have unacceptably low specificity [60]. There is also wide variation in the sensitivities and specificities reported by different studies using the same HbA1c threshold; this may be due to differences in type of HbA1c assay [74, 86] and timing of the studies relative to the institution's routine OGTT screening [87]. Yung et al., conducting a cross-sectional study of 91 CF patients not known to be diabetic, but also not previously routinely screened, found that HbA1c ≥6.1% had 83% sensitivity for OGTT-diagnosed CFRD [68]. However, more recent studies with similar designs report only 30–50% sensitivity [39, 82, 88, 89]. Given this uncertainty, the current advice from the ADA is that HbA1c should not

be used to screen for CF-related glucose abnormalities [59]. HbA1c is still recommended for monitoring glycemic control in CFRD, although normal results must be interpreted with caution [4, 78]. It has also been suggested that HbA1c might be a useful adjunct to OGTT in screening, as its results may fluctuate less and hence, may more accurately predict long-term risk of glucose abnormalities. In a recent 6-year retrospective cohort study of 50 NGT adults with CF followed up with annual OGTT, HbA1c ≥5.6% had OR 3.49 for development of IGT or CFRD [90].

In 2003, the ADA briefly sanctioned fasting plasma glucose as an alternative to OGTT in CFRD screening, because there were insufficient data supporting insulin therapy for CFRD without fasting hyperglycemia [91]. However, subsequent studies have demonstrated similar insulin-induced clinical improvements in patients with and without fasting hyperglycemia [16, 92], and treatment of CFRD without fasting hyperglycemia is now standard practice [4]. Only 16–25% of patients diagnosed

Use of fasting glucose to detect pre-diabetic stages on the glucose tolerance spectrum remains somewhat contentious in CF. Most studies report that fasting plasma glucose does not significantly differ between CF patients with NGT, INDET or IGT [39, 72, 93]. The ADA does use fasting glucose to define one pre-diabetic glucose tolerance category, IFG (5.6–6.9 mmol/L), and suggested in 2003 that screening OGTTs could be limited to IFG patients [94]. A prospective cohort study of 1128 CF patients aged 10–64 found that this approach would reduce number of OGTTs by 67%, but miss 17.8% of CFRD and IGT [94]. In a cross-sectional analysis of 73 children with CF, IFG had 100% sensitivity for CFRD, but only 25% sensitivity for IGT [11].

Finally, like HbA1c, there is debate regarding the utility of IFG as an adjunctive test for predicting long-term risk of CFRD. Frohnert et al. found no significant relationship [95], but Schmid et al. found that IFG generated OR 2.72 for CFRD [96].

As discussed above, other conventional diagnostic tests have <100% sensitivity for CFRD compared to OGTT. Therefore, OGTT remains the recommended screening test in CF. It is also the only test with standardized definitions of multiple pre-diabetic glucose abnormalities, all demonstrated to predict development of CFRD [96].

Nevertheless, there are several issues with the 2-h OGTT. It may be more inconvenient and resource-intensive than other glucose measurement methods, which is

with CFRD on OGTT have fasting hyperglycemia [8, 54, 68, 81].

*DOI: http://dx.doi.org/10.5772/intechopen.92847*

**2.3 Fasting glucose**

**2.4 Oral glucose tolerance testing**

#### *Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.92847*

sample sizes, and most either did not calculate sensitivity to CF-related AGT [81] or report low values, ~20–50% [80, 82]. Therefore, HbA1c may not detect CFRD and its complications until late. Moreover, most evidence suggests that the diagnostic threshold for CFRD, HbA1c ≥6.5%, has poor sensitivity compared to OGTT [54, 83–85].

Lowering the diagnostic threshold for HbA1c abnormalities does increase sensitivity to both CFRD and AGT, but the thresholds required to achieve sufficient sensitivity for screening generally have unacceptably low specificity [60]. There is also wide variation in the sensitivities and specificities reported by different studies using the same HbA1c threshold; this may be due to differences in type of HbA1c assay [74, 86] and timing of the studies relative to the institution's routine OGTT screening [87]. Yung et al., conducting a cross-sectional study of 91 CF patients not known to be diabetic, but also not previously routinely screened, found that HbA1c ≥6.1% had 83% sensitivity for OGTT-diagnosed CFRD [68]. However, more recent studies with similar designs report only 30–50% sensitivity [39, 82, 88, 89].

Given this uncertainty, the current advice from the ADA is that HbA1c should not be used to screen for CF-related glucose abnormalities [59]. HbA1c is still recommended for monitoring glycemic control in CFRD, although normal results must be interpreted with caution [4, 78]. It has also been suggested that HbA1c might be a useful adjunct to OGTT in screening, as its results may fluctuate less and hence, may more accurately predict long-term risk of glucose abnormalities. In a recent 6-year retrospective cohort study of 50 NGT adults with CF followed up with annual OGTT, HbA1c ≥5.6% had OR 3.49 for development of IGT or CFRD [90].

#### **2.3 Fasting glucose**

*Cystic Fibrosis - Facts, Management and Advances*

**2.1 Clinical status and/or random blood glucose**

**glucose abnormalities in CF**

**2. Benefits and limitations of conventional methods used to diagnose** 

The ADA allows diagnosis of CFRD following one random blood glucose measurement ≥11.1 mmol/L, provided that it is combined with polyuria, polydipsia, or hyperglycemic crisis [59]. However, symptomatic hyperglycemia or hyperglycemic crisis is extremely rare in CFRD [4]. In Lanng et al.'s seminal 5-year prospective cohort study of 191 CF patients receiving annual OGTT, only 33% of those diagnosed with CFRD had polyuria or polydipsia [54]. Moreover, in a cross-sectional study of all 60 patients aged ≥10 years at a Brazilian CF center, age at diagnosis was significantly lower for patients diagnosed using OGTT as opposed to clinical criteria

Some centers compensate by accepting unexplained decline in lung function or nutritional status as classical symptoms of hyperglycemia (see Section 3) [67]. In one cross-sectional study of 91 CF patients not known to be diabetic, these modified clinical criteria detected OGTT-diagnosed CFRD with 58% sensitivity [68], which is an improvement over other studies but still suboptimal for a screening test.

HbA1c, i.e. glycated hemoglobin as a percentage of total hemoglobin, is commonly used to monitor glycemic control in diabetes mellitus. It usually reflects average blood glucose over the life of an erythrocyte (~3 months) [64, 69]. However, CF patients with CFRD, INDET or IGT rarely have a significantly-higher HbA1c than those with normal glucose tolerance (NGT) [11, 70–73], and even statisticallysignificant differences tend to be of <1% magnitude [8, 34, 40, 74, 75]. Godbout et al.'s study of 13 CFRD patients also found that HbA1c did not correlate with mean

Numerous hypotheses have been espoused to explain HbA1c's relatively poor correlation with glucose tolerance in CF. These include insufficient duration of transient CF-related post-prandial hyperglycemia, which is often limited to the early phase of insulin secretion; alteration of hemoglobin glycation by hypoxia; iron deficiency, which is a common comorbidity of CF; and increased erythrocyte turnover in the context of chronic inflammation [1, 4, 5, 76, 77]. This implies that HbA1c may vary with degree of inflammation [78], and that *trends* in HbA1c may be more useful for predicting deterioration in glucose tolerance. Supporting this, Lanng et al.'s 5-year prospective cohort study found significant differences in median HbA1c between patients who consistently had NGT (5.2%), patients who varied between NGT and IGT (5.3%), patients who developed CFRD during the study (5.8%), and

plasma glucose, as calculated using fingerprick self-monitoring [76].

patients who entered the study with a diagnosis of CFRD (6.5%) [54].

strongly correlated with HbA1c (*r* = 0.86–0.89) [75, 79].

It has also been hypothesized that poor correlation between mean plasma glucose and HbA1c may be confounded by use of fingerprick tests to measure glucose, since these can easily miss CF-related hyperglycaemic peaks due to their relative infrequency [76]. In two studies of CF and CFRD patients, mean plasma glucose was estimated using 2–7 days of CGM rather than fingerprick self-monitoring, and

These findings have regenerated interest in potentially using HbA1c to screen for CF-related glucose abnormalities, especially because it is much more convenient than OGTT. However, computing HbA1c thresholds suitable for CFRD screening has proved challenging. Some studies do report almost 100% sensitivity for OGTTdefined CFRD using HbA1c thresholds of 6.0–7.5% [40, 80–82], but all have small

(13.5 years vs. 22.3 years), implying much earlier detection of disease [66].

**28**

**2.2 HbA1c**

In 2003, the ADA briefly sanctioned fasting plasma glucose as an alternative to OGTT in CFRD screening, because there were insufficient data supporting insulin therapy for CFRD without fasting hyperglycemia [91]. However, subsequent studies have demonstrated similar insulin-induced clinical improvements in patients with and without fasting hyperglycemia [16, 92], and treatment of CFRD without fasting hyperglycemia is now standard practice [4]. Only 16–25% of patients diagnosed with CFRD on OGTT have fasting hyperglycemia [8, 54, 68, 81].

Use of fasting glucose to detect pre-diabetic stages on the glucose tolerance spectrum remains somewhat contentious in CF. Most studies report that fasting plasma glucose does not significantly differ between CF patients with NGT, INDET or IGT [39, 72, 93]. The ADA does use fasting glucose to define one pre-diabetic glucose tolerance category, IFG (5.6–6.9 mmol/L), and suggested in 2003 that screening OGTTs could be limited to IFG patients [94]. A prospective cohort study of 1128 CF patients aged 10–64 found that this approach would reduce number of OGTTs by 67%, but miss 17.8% of CFRD and IGT [94]. In a cross-sectional analysis of 73 children with CF, IFG had 100% sensitivity for CFRD, but only 25% sensitivity for IGT [11].

Finally, like HbA1c, there is debate regarding the utility of IFG as an adjunctive test for predicting long-term risk of CFRD. Frohnert et al. found no significant relationship [95], but Schmid et al. found that IFG generated OR 2.72 for CFRD [96].

#### **2.4 Oral glucose tolerance testing**

As discussed above, other conventional diagnostic tests have <100% sensitivity for CFRD compared to OGTT. Therefore, OGTT remains the recommended screening test in CF. It is also the only test with standardized definitions of multiple pre-diabetic glucose abnormalities, all demonstrated to predict development of CFRD [96].

Nevertheless, there are several issues with the 2-h OGTT. It may be more inconvenient and resource-intensive than other glucose measurement methods, which is of particular concern in CF because patients and clinics already face a high treatment burden from other aspects of CF care [97]. It also requires patient co-operation, which can be difficult when assessing children [93]. Patients are expected to consume at least 150 g (600 kcal) of carbohydrates for 3 days before an OGTT, then fast for 8 h overnight and be tested early the next morning [59]. They must drink a solution containing a 1.75 g/kg glucose load, preferably within 5 min, then lie or sit quietly for 2 h [64]. In a standard OGTT, venous blood is sampled twice: immediately before ingestion of the load, and at 120 min (BG120). Many CF centers also take hourly or 30-minutely samples to detect post-prandial hyperglycemia that resolves before 2 h [59]. As described earlier, these transient post-prandial glucose excursions are very common in CF, due to selective impairment of early insulin secretion. Our group previously performed OGTT with 30-minutely sampling in 33 children with CF aged 10–19, and found that peak venous insulin concentration was delayed until 90–120 min, producing an early venous glucose peak at 60–90 min [9] (**Figure 1**).

The inconvenience of OGTT may contribute to poor patient uptake of CFRD screening [98–100]. In 2018, the Cystic Fibrosis Foundation Patient Registry reported that the average CF center was screening just 61.3% of adolescents and 32.8% of adults [100]. Rates of utilization of other glucose measurement methods, such as HbA1c and fasting glucose, were much higher (92.3% for adolescents and 89.6% for adults), suggesting that the main barrier to screening is the OGTT itself [100]. Suggested solutions include shortening the OGTT to 60 or 90 min [83] or replacing it with the 50-g non-fasting 1-h glucose challenge test [89, 101], which is currently used to screen for gestational diabetes mellitus in healthy women [101]. These modified OGTT protocols are not standard recommended practice [4].

There are also other issues with the OGTT that likely cannot be resolved by simply shortening it. Its diagnostic thresholds are not specific to CF and may be insensitive to CF-related clinical decline (see Section 3). OGTT results also frequently fluctuate in CF, with a large multicenter prospective cohort study finding a variability coefficient 1.5–1.8 times higher than in the general population [55]. Similarly, in two 4–5 year prospective cohort studies, 18–58% of AGT patients demonstrated overall improvement in glucose tolerance category, while only 14–22% demonstrated deterioration [19, 54].

Finally, even with venous sampling at additional timepoints, the peak blood glucose measurements recorded during OGTT may poorly reflect peak blood glucose achieved by CF patients in daily life [4, 60, 61]. After all, the OGTT's 1.75 g/kg load contains less glucose than most CF patients' everyday meals [61, 98]. This has prompted research into CF-related glucose abnormalities using CGM, a technology that can screen for glucose excursions over a longer interval of everyday life and high calorie CF diet.

#### **Figure 1.**

*Venous blood glucose (□) and insulin (▓ ) in 30-minutely samples over a 2-h oral glucose tolerance test, as measured in 33 children with CF aged 10–19. Boxes indicate interquartile range, horizontal lines indicate median, whiskers indicate 5th and 95th percentiles. Figure taken from Hameed et al. [9].*

**31**

**Figure 2.**

supervision [97].

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis*

Most CGM systems consist of two parts: a sterile sensor, worn subcutaneously for up to 14 days, and a transmitter attached to the sensor that measures interstitial fluid glucose every 30 s, recording an average every 5 min [97] (**Figure 2**). Some systems do not require a separate sensor, instead measuring interstitial fluid glucose via an electrical current applied across intact skin, but issues have been reported with skin reactions and inaccuracy [102]. Interstitial fluid glucose reflects capillary

CGM has been validated against OGTT in children with CF of all glucose tolerance categories [104] and non-diabetic adolescents and adults with CF [105]. A subsequent study of this latter group found that they differed significantly from healthy controls in mean CGM glucose (+14.1%) and presence of CGM peaks ≥11.1 mmol/L (+33%), but not in the conventional diagnostic measures of fasting glucose, BG120, and HbA1c [106]. Moreover, 70% of CF patients undertaking simultaneous CGM and OGTT had their CGM peak *outside* OGTT [106]. This was the beginning of a substantial body of evidence demonstrating the superior sensitivity of CGM to CF-related glucose excursions above OGTT diagnostic thresholds, with numerous studies finding CGM glucose peaks ≥7.8 or 11.1 mmol/L in 71–93% of patients classified as NGT on recent OGTT [14, 31, 85, 98, 107, 108]. In a 5-year prospective cohort study of 21 adults with CF, 83% had their CGM peak and BG120 fall in different diagnostic categories, and for 93% the CGM-identified category was

worse. Again, this suggests the superior sensitivity of CGM over OGTT [98].

CGM does have one major disadvantage compared to OGTT. The clinical significance of the mild glucose excursions that it detects are still being determined; consequently, there is no standardized system for recognizing and describing clinically relevant CGM findings, and no universally accepted threshold for initiation

*Continuous glucose monitor sensor, before and after attachment of the transmitter. 'CGM set' and 'Continuous* 

*Glucose Monitor' by Sara Bassett are licensed under CC BY-NC-SA 2.0.*

Most of this evidence, particularly in children, is limited by small sample sizes [14, 85, 98, 107, 108] and lack of non-CF controls [14, 85, 98, 108]. However, it is logical that the increased duration and frequency of glucose monitoring facilitated by CGM, and the opportunity to incorporate the patient's usual diet and physical activity, facilitates more sensitive detection of glucose excursions [109]. CGM is also generally easier and better tolerated than OGTT [78]. While sensors and transmitters are expensive, and staff do require training on their usage, they have become more user-friendly, smaller and cheaper over time [73, 110]. The newest devices can be inserted rapidly during a clinic appointment, do not require calibration against fingerpricks, and can be removed by patients or carers without medical

*DOI: http://dx.doi.org/10.5772/intechopen.92847*

**2.5 Continuous glucose monitoring**

glucose with a 4–20 min delay [103].

## **2.5 Continuous glucose monitoring**

*Cystic Fibrosis - Facts, Management and Advances*

demonstrated deterioration [19, 54].

calorie CF diet.

of particular concern in CF because patients and clinics already face a high treatment burden from other aspects of CF care [97]. It also requires patient co-operation, which can be difficult when assessing children [93]. Patients are expected to consume at least 150 g (600 kcal) of carbohydrates for 3 days before an OGTT, then fast for 8 h overnight and be tested early the next morning [59]. They must drink a solution containing a 1.75 g/kg glucose load, preferably within 5 min, then lie or sit quietly for 2 h [64]. In a standard OGTT, venous blood is sampled twice: immediately before ingestion of the load, and at 120 min (BG120). Many CF centers also take hourly or 30-minutely samples to detect post-prandial hyperglycemia that resolves before 2 h [59]. As described earlier, these transient post-prandial glucose excursions are very common in CF, due to selective impairment of early insulin secretion. Our group previously performed OGTT with 30-minutely sampling in 33 children with CF aged 10–19, and found that peak venous insulin concentration was delayed until 90–120 min, producing an early venous glucose peak at 60–90 min [9] (**Figure 1**). The inconvenience of OGTT may contribute to poor patient uptake of CFRD screening [98–100]. In 2018, the Cystic Fibrosis Foundation Patient Registry reported that the average CF center was screening just 61.3% of adolescents and 32.8% of adults [100]. Rates of utilization of other glucose measurement methods, such as HbA1c and fasting glucose, were much higher (92.3% for adolescents and 89.6% for adults), suggesting that the main barrier to screening is the OGTT itself [100]. Suggested solutions include shortening the OGTT to 60 or 90 min [83] or replacing it with the 50-g non-fasting 1-h glucose challenge test [89, 101], which is currently used to screen for gestational diabetes mellitus in healthy women [101]. These modified OGTT protocols are not standard recommended practice [4]. There are also other issues with the OGTT that likely cannot be resolved by simply shortening it. Its diagnostic thresholds are not specific to CF and may be insensitive to CF-related clinical decline (see Section 3). OGTT results also frequently fluctuate in CF, with a large multicenter prospective cohort study finding a variability coefficient 1.5–1.8 times higher than in the general population [55]. Similarly, in two 4–5 year prospective cohort studies, 18–58% of AGT patients demonstrated overall improvement in glucose tolerance category, while only 14–22%

Finally, even with venous sampling at additional timepoints, the peak blood glucose measurements recorded during OGTT may poorly reflect peak blood glucose achieved by CF patients in daily life [4, 60, 61]. After all, the OGTT's 1.75 g/kg load contains less glucose than most CF patients' everyday meals [61, 98]. This has prompted research into CF-related glucose abnormalities using CGM, a technology that can screen for glucose excursions over a longer interval of everyday life and high

*Venous blood glucose (□) and insulin (▓ ) in 30-minutely samples over a 2-h oral glucose tolerance test, as measured in 33 children with CF aged 10–19. Boxes indicate interquartile range, horizontal lines indicate* 

*median, whiskers indicate 5th and 95th percentiles. Figure taken from Hameed et al. [9].*

**30**

**Figure 1.**

Most CGM systems consist of two parts: a sterile sensor, worn subcutaneously for up to 14 days, and a transmitter attached to the sensor that measures interstitial fluid glucose every 30 s, recording an average every 5 min [97] (**Figure 2**). Some systems do not require a separate sensor, instead measuring interstitial fluid glucose via an electrical current applied across intact skin, but issues have been reported with skin reactions and inaccuracy [102]. Interstitial fluid glucose reflects capillary glucose with a 4–20 min delay [103].

CGM has been validated against OGTT in children with CF of all glucose tolerance categories [104] and non-diabetic adolescents and adults with CF [105]. A subsequent study of this latter group found that they differed significantly from healthy controls in mean CGM glucose (+14.1%) and presence of CGM peaks ≥11.1 mmol/L (+33%), but not in the conventional diagnostic measures of fasting glucose, BG120, and HbA1c [106]. Moreover, 70% of CF patients undertaking simultaneous CGM and OGTT had their CGM peak *outside* OGTT [106]. This was the beginning of a substantial body of evidence demonstrating the superior sensitivity of CGM to CF-related glucose excursions above OGTT diagnostic thresholds, with numerous studies finding CGM glucose peaks ≥7.8 or 11.1 mmol/L in 71–93% of patients classified as NGT on recent OGTT [14, 31, 85, 98, 107, 108]. In a 5-year prospective cohort study of 21 adults with CF, 83% had their CGM peak and BG120 fall in different diagnostic categories, and for 93% the CGM-identified category was worse. Again, this suggests the superior sensitivity of CGM over OGTT [98].

Most of this evidence, particularly in children, is limited by small sample sizes [14, 85, 98, 107, 108] and lack of non-CF controls [14, 85, 98, 108]. However, it is logical that the increased duration and frequency of glucose monitoring facilitated by CGM, and the opportunity to incorporate the patient's usual diet and physical activity, facilitates more sensitive detection of glucose excursions [109]. CGM is also generally easier and better tolerated than OGTT [78]. While sensors and transmitters are expensive, and staff do require training on their usage, they have become more user-friendly, smaller and cheaper over time [73, 110]. The newest devices can be inserted rapidly during a clinic appointment, do not require calibration against fingerpricks, and can be removed by patients or carers without medical supervision [97].

CGM does have one major disadvantage compared to OGTT. The clinical significance of the mild glucose excursions that it detects are still being determined; consequently, there is no standardized system for recognizing and describing clinically relevant CGM findings, and no universally accepted threshold for initiation

#### **Figure 2.**

*Continuous glucose monitor sensor, before and after attachment of the transmitter. 'CGM set' and 'Continuous Glucose Monitor' by Sara Bassett are licensed under CC BY-NC-SA 2.0.*

of treatment [97]. Common variables computed by CGM software include average sensor glucose, maximum glucose, area under the curve of glucose per day (AUCglucose/day), percentage time spent above thresholds (e.g. 7.8 or 11.1 mmol/L), number of excursions ≥11.1 mmol/L, and measures of glycemic variability, such as standard deviation of average sensor glucose [103]. All these parameters have been correlated with HbA1c in CF patients [75], and many have been correlated with clinical outcomes. However, these studies report heterogeneous findings and rarely include substantial prospective follow-up (see Section 3) [84].

Given all these factors, CGM is not yet widely recommended for CFRD diagnosis or screening [4]. However, it is used in some centers for diagnosis and screening, follow-up of borderline diagnostic tests, and investigation of patients who cannot or refuse to undergo OGTT [31, 111, 112]. Like HbA1c, it may also be useful as an adjunctive test for predicting long-term risk of CF-related glucose abnormalities. In a prospective cohort study of 17 children with CF, all those who had glucose excursions ≥11.1 mmol/L on CGM developed either CFRD or IGT with INDET over a period of 2.5 years, irrespective of their glucose tolerance at baseline [107].

## **3. Clinical significance of early glucose abnormalities in CF, as detected using various glucose measurement techniques**

#### **3.1 Defining clinically significant sequelae of CFRD: the importance of lung function & nutritional status**

CFRD is well-understood to have a differing profile of sequelae as compared to T1D or T2D. Macrovascular disease is uncommon outside of case reports [1, 4, 5, 113], and although screening for microvascular disease should be routinely undertaken [59], microvascular complications are uncommon until at least 5–10 years of CFRD with fasting hyperglycemia [57, 114, 115]. Therefore they are substantially predated by declines in lung function [6–21, 116–118] and nutritional status [7, 9–12, 14, 117], both of which are significant predictors of early mortality in CF [10, 11, 16, 18, 25, 56, 119]. Four large cohort studies also report higher annual frequency in diabetic vs. non-diabetic CF patients of pulmonary exacerbations requiring intravenous antibiotics or hospitalization [10, 21, 39, 120], and it was recently demonstrated that diabetic CF patients have reduced recovery of baseline forced expiratory volume in 1 sec as a percentage of predicted (FEV1%) following pulmonary exacerbations [116].

A causative relationship between CFRD, impaired lung function, and poor nutritional status is implied by the clinical improvements seen following insulin therapy [13, 92, 120–122], and is also biologically plausible on several accounts. Insulin is a powerfully anabolic hormone, therefore insulin deficiency combined with CF's increased metabolic requirements promotes catabolism with nutritional decline [9, 93, 123, 124]. Regarding lung function and pulmonary exacerbations, hyperglycemia is known to promote respiratory tract infections (RTIs) both systemically, via pro-inflammatory and immunosuppressive effects [125, 126], and locally, via glucose leakage into airway secretions, which could promote pathogen growth [125, 127–130]. Several cohort studies report higher prevalence in diabetic vs. non-diabetic CF patients of certain RTIs, including *Pseudomonas aeruginosa* [10, 19, 117, 131], *Staphylococcus aureus* [132, 133], and *Burkholderia cepacia* [10, 117, 132].

Finally, hyperglycemia can also impair lung function through non-infective pathways. It has been associated with restrictive lung disease in T1D and T2D (via non-enzymatic glycation of collagen and elastin) [134], and with inflammatory and proteolytic lung destruction in CFRD [135–137]. Lung proteolysis may be exacerbated

**33**

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis*

**3.2 Decline in clinical status prior to diagnosis of CFRD**

by protein catabolism [19, 122], which can furthermore weaken respiratory muscles [138, 139] and impair immunoprotein synthesis during RTIs [61]. This may explain why lung function in CF also correlates with nutritional status [6, 7, 140–142].

Numerous cohort and case-control studies examining the 1–5 years before CFRD diagnosis report decline in lung function [19, 35, 38, 92, 143–146] and nutritional status [19, 35, 38, 92, 143, 144] in pre-diabetic patients, or significantly reduced values compared to non-diabetic CF controls [12, 17]. This suggests that prediabetic glucose abnormalities are clinically significant. Two case-control studies focusing specifically on pediatric populations also report that pre-diabetic children with CF have significantly lower height and weight velocities than non-diabetic CF controls [145, 146], with one study demonstrating differences up to 11 years before CFRD diagnosis [146]. These differing velocities produce steadily-widening gaps in height-for-age and weight-for-age, reaching statistically-significant sizes after CFRD diagnosis, usually around ages 15–19 [18, 146]. Importantly, this growing disparity seems to occur even if aggressive insulin therapy is commenced at diagnosis [144], and although it may narrow with prolonged therapy, it may not fully correct [18, 144, 147]. Therefore, optimizing clinical outcomes in CFRD may require treatment of pre-diabetic abnormalities, highlighting the importance of glucose measurement systems that can sensitively predict clinical decline.

**3.3 Clinically significant pre-diabetic markers detectable using OGTT**

find no significant relationship [19, 33, 34, 39, 53, 70–73, 150–152].

development of CFRD (OR 2.81 over ~3.5 years) [93, 96].

Traditional OGTT diagnostic thresholds are not specific to CF – in fact, they were originally designed to predict T2D-associated microvascular disease in Pima Native Americans [148]. This may explain their apparent insensitivity to CF clinical outcomes. A few studies do report poorer lung function or nutritional status in IGT vs. NGT CF patients [37, 72], and several more identify IGT as a significant risk factor for substantial decline in FEV1% over 4–5 years [19, 149]. However, most studies attempting to correlate IGT with contemporary lung function and nutritional status

A more successful non-conventional OGTT parameter is the additional glucose tolerance category of INDET, defined as blood glucose ≥11.1 mmol/L at an OGTT midpoint – most commonly 60 min (BG60) – as opposed to 0 or 120 min [4]. BG60 has been shown to inversely correlate with BMI in children with CF, and correlates with FEV1% and forced vital capacity as a percentage of predicted (FVC%) in both children [7] and adults [150]. In a subsequent study, INDET patients had mean FEV1% comparable to CFRD patients, representing a significant reduction compared to NGT and IGT patients [71]. INDET has also been confirmed to predict

Other OGTT parameters shown to predict FEV1% in non-diabetic CF patients include higher peak glucose (BGmax) [9, 33, 72, 153], higher AUCglucose [124, 153], and reduced insulin secretion [34, 35, 72, 124]. Finally, a few studies have correlated FEV1% with trajectories of deterioration in glucose tolerance [41, 154]. One prospective cohort study recruited 152 non-diabetic CF patients, and stratified them according to whether their glucose tolerance on OGTT improved, deteriorated or remained stable over 2 years [41]. While all patients experienced a decline in FEV1%, the extent of decline only reached statistical significance in patients of stable or deteriorating glucose tolerance, and those of deteriorating glucose tolerance also had a much larger drop than those of stable glucose tolerance (−6.1% vs. −1.6%) [41]. It is rarer for studies to report correlations between OGTT parameters and nutritional status [33–35, 41, 71, 72, 154], possibly because intensive dietician

*DOI: http://dx.doi.org/10.5772/intechopen.92847*

by protein catabolism [19, 122], which can furthermore weaken respiratory muscles [138, 139] and impair immunoprotein synthesis during RTIs [61]. This may explain why lung function in CF also correlates with nutritional status [6, 7, 140–142].

### **3.2 Decline in clinical status prior to diagnosis of CFRD**

*Cystic Fibrosis - Facts, Management and Advances*

of treatment [97]. Common variables computed by CGM software include average sensor glucose, maximum glucose, area under the curve of glucose per day (AUCglucose/day), percentage time spent above thresholds (e.g. 7.8 or 11.1 mmol/L), number of excursions ≥11.1 mmol/L, and measures of glycemic variability, such as standard deviation of average sensor glucose [103]. All these parameters have been correlated with HbA1c in CF patients [75], and many have been correlated with clinical outcomes. However, these studies report heterogeneous findings and rarely

Given all these factors, CGM is not yet widely recommended for CFRD diagnosis or screening [4]. However, it is used in some centers for diagnosis and screening, follow-up of borderline diagnostic tests, and investigation of patients who cannot or refuse to undergo OGTT [31, 111, 112]. Like HbA1c, it may also be useful as an adjunctive test for predicting long-term risk of CF-related glucose abnormalities. In a prospective cohort study of 17 children with CF, all those who had glucose excursions ≥11.1 mmol/L on CGM developed either CFRD or IGT with INDET over a period of 2.5 years, irrespective of their glucose tolerance at baseline [107].

**3. Clinical significance of early glucose abnormalities in CF, as detected** 

**3.1 Defining clinically significant sequelae of CFRD: the importance of lung** 

to T1D or T2D. Macrovascular disease is uncommon outside of case reports [1, 4, 5, 113], and although screening for microvascular disease should be routinely undertaken [59], microvascular complications are uncommon until at least 5–10 years of CFRD with fasting hyperglycemia [57, 114, 115]. Therefore they are substantially predated by declines in lung function [6–21, 116–118] and nutritional status [7, 9–12, 14, 117], both of which are significant predictors of early mortality in CF [10, 11, 16, 18, 25, 56, 119]. Four large cohort studies also report higher annual frequency in diabetic vs. non-diabetic CF patients of pulmonary exacerbations requiring intravenous antibiotics or hospitalization [10, 21, 39, 120], and it was recently demonstrated that diabetic CF patients have reduced recovery of baseline forced expiratory volume in 1 sec as a percentage of

CFRD is well-understood to have a differing profile of sequelae as compared

A causative relationship between CFRD, impaired lung function, and poor nutritional status is implied by the clinical improvements seen following insulin therapy [13, 92, 120–122], and is also biologically plausible on several accounts. Insulin is a powerfully anabolic hormone, therefore insulin deficiency combined with CF's increased metabolic requirements promotes catabolism with nutritional decline [9, 93, 123, 124]. Regarding lung function and pulmonary exacerbations, hyperglycemia is known to promote respiratory tract infections (RTIs) both systemically, via pro-inflammatory and immunosuppressive effects [125, 126], and locally, via glucose leakage into airway secretions, which could promote pathogen growth [125, 127–130]. Several cohort studies report higher prevalence in diabetic vs. non-diabetic CF patients of certain RTIs, including *Pseudomonas aeruginosa* [10, 19, 117, 131], *Staphylococcus aureus* [132, 133], and *Burkholderia* 

Finally, hyperglycemia can also impair lung function through non-infective pathways. It has been associated with restrictive lung disease in T1D and T2D (via non-enzymatic glycation of collagen and elastin) [134], and with inflammatory and proteolytic lung destruction in CFRD [135–137]. Lung proteolysis may be exacerbated

include substantial prospective follow-up (see Section 3) [84].

**using various glucose measurement techniques**

predicted (FEV1%) following pulmonary exacerbations [116].

**function & nutritional status**

**32**

*cepacia* [10, 117, 132].

Numerous cohort and case-control studies examining the 1–5 years before CFRD diagnosis report decline in lung function [19, 35, 38, 92, 143–146] and nutritional status [19, 35, 38, 92, 143, 144] in pre-diabetic patients, or significantly reduced values compared to non-diabetic CF controls [12, 17]. This suggests that prediabetic glucose abnormalities are clinically significant. Two case-control studies focusing specifically on pediatric populations also report that pre-diabetic children with CF have significantly lower height and weight velocities than non-diabetic CF controls [145, 146], with one study demonstrating differences up to 11 years before CFRD diagnosis [146]. These differing velocities produce steadily-widening gaps in height-for-age and weight-for-age, reaching statistically-significant sizes after CFRD diagnosis, usually around ages 15–19 [18, 146]. Importantly, this growing disparity seems to occur even if aggressive insulin therapy is commenced at diagnosis [144], and although it may narrow with prolonged therapy, it may not fully correct [18, 144, 147]. Therefore, optimizing clinical outcomes in CFRD may require treatment of pre-diabetic abnormalities, highlighting the importance of glucose measurement systems that can sensitively predict clinical decline.

#### **3.3 Clinically significant pre-diabetic markers detectable using OGTT**

Traditional OGTT diagnostic thresholds are not specific to CF – in fact, they were originally designed to predict T2D-associated microvascular disease in Pima Native Americans [148]. This may explain their apparent insensitivity to CF clinical outcomes. A few studies do report poorer lung function or nutritional status in IGT vs. NGT CF patients [37, 72], and several more identify IGT as a significant risk factor for substantial decline in FEV1% over 4–5 years [19, 149]. However, most studies attempting to correlate IGT with contemporary lung function and nutritional status find no significant relationship [19, 33, 34, 39, 53, 70–73, 150–152].

A more successful non-conventional OGTT parameter is the additional glucose tolerance category of INDET, defined as blood glucose ≥11.1 mmol/L at an OGTT midpoint – most commonly 60 min (BG60) – as opposed to 0 or 120 min [4]. BG60 has been shown to inversely correlate with BMI in children with CF, and correlates with FEV1% and forced vital capacity as a percentage of predicted (FVC%) in both children [7] and adults [150]. In a subsequent study, INDET patients had mean FEV1% comparable to CFRD patients, representing a significant reduction compared to NGT and IGT patients [71]. INDET has also been confirmed to predict development of CFRD (OR 2.81 over ~3.5 years) [93, 96].

Other OGTT parameters shown to predict FEV1% in non-diabetic CF patients include higher peak glucose (BGmax) [9, 33, 72, 153], higher AUCglucose [124, 153], and reduced insulin secretion [34, 35, 72, 124]. Finally, a few studies have correlated FEV1% with trajectories of deterioration in glucose tolerance [41, 154]. One prospective cohort study recruited 152 non-diabetic CF patients, and stratified them according to whether their glucose tolerance on OGTT improved, deteriorated or remained stable over 2 years [41]. While all patients experienced a decline in FEV1%, the extent of decline only reached statistical significance in patients of stable or deteriorating glucose tolerance, and those of deteriorating glucose tolerance also had a much larger drop than those of stable glucose tolerance (−6.1% vs. −1.6%) [41].

It is rarer for studies to report correlations between OGTT parameters and nutritional status [33–35, 41, 71, 72, 154], possibly because intensive dietician management of CF mitigates nutritional decline [133, 154]. Nevertheless, one seminal prospective cohort study inversely correlated age-adjusted height and BMI with AUCglucose [8], and a recent cross-sectional study found that lower-thanmedian insulin secretion at 60 min is independently associated with worse BMI [150]. In children, BMI (calculated as weight in kg divided by the square of height in meters) may be a less sensitive measure of nutritional status than weight-for-age, as poor linear growth may mask decline [146]. Nevertheless, Wooldridge et al. report a direct correlation between AUCinsulin and BMI z-score in 146 NGT children with CF aged 5–20 [123], and our group has found that AUCglucose inversely correlates with age-adjusted weight, height and BMI in children aged ≤10 years [153]. Furthermore, in an earlier cohort study of 33 children aged 10–19, we found that higher BGmax was associated with decline in weight z-score, FEV1% and FVC% over the past 12 months, and BGmax ≥8.2 mmol/L had 87% sensitivity and 70% specificity for a clinically significant decline in weight z-score [9]. By contrast, BG120 was no better than chance at detecting decline in weight z-score, and the conventional diagnostic threshold of 11.1 mmol/L had only 10% sensitivity [9]. These findings led us to propose an alternative system for classifying CF-related glucose abnormalities on OGTT, the Cystic Fibrosis Insulin Deficiency (CFID) stages (**Table 3**) [9].

### **3.4 Clinically significant pre-diabetic markers detectable using CGM**

Six main studies have explored the clinical significance of CGM-based measures of CF-related early glucose abnormalities [9, 98, 111, 152, 155, 156]. Their results are compelling but heterogeneous. Taylor-Cousar et al. conducted a 5-year prospective cohort study of 17 originally non-diabetic CF patients, 7 of whom developed CFRD during observation [98]. In this subgroup, there was significant inverse correlation between peak glucose and BMI, and a trend towards correlation with FEV1% [98]. Leclercq et al. also examined peak glucose, stratifying 38 NGT CF patients according to whether they had any peaks ≥11.1 mmol/L during 72-h CGM [155]. In the 'yes' group, there was significantly lower FEV1% and FVC%, and increased risk of colonization with *P. aeruginosa* [155].

In the aforementioned study undertaken by our research group in 33 children with CF aged 10–19, we also showed that percentage time ≥7.8 mmol/L on CGM predicted 12-month rate of decline in weight z-score, FVC%, and FEV1%. Similarly, on receiver operator characteristic (ROC) analysis, ≥4.5% time at ≥7.8 mmol/L on CGM was a sensitive and specific predictor of clinically significant decline in weight z-score and FVC% [9]. Frost et al. subsequently used these parameters to interpret the CGM results of 59 adults being investigated for CF-related glucose abnormalities [112]. They found that percentage time ≥7.8 mmol/L on CGM correlated with baseline FEV1% and 12-month rate of decline [112].

In Chan et al.'s study of 88 children with CF aged 10–18, 12-month decline in FEV1% and FVC% was predicted by multiple other CGM parameters: peak glucose, number of daily glucose excursions >11.1 mmol/L, mean amplitude of glycemic


**Table 3.**

*Cystic fibrosis insulin deficiency (CFID) classification system of CF-related glucose abnormalities, as proposed by Hameed et al. [9].*

**35**

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis*

excursions, and standard deviation [152]. Brugha et al. investigated another glycemic variability measure, glucose interquartile ranges, in a 7-year retrospective cohort study [111]. On ROC analysis, ranges >1.95 mmol/L predicted CFRD with 60% sensitivity and 98% specificity, but did not correlate with BMI or FEV1% [111]. Finally, our group recently conducted a cross-sectional study of 18 children with CF aged ≤5 years [156]. Even in this very young group, history of *P. aeruginosa* was predicted by mean glucose and percentage time at ≥7.8 mmol/L, and levels of inflammatory markers in bronchoalveolar lavage fluid were predicted by peak glucose, mean glucose, percentage time at ≥7.8 mmol/L, and standard deviation [156].

**3.5 Clinically significant pre-diabetic markers detectable using other glucose** 

Three studies report a weak inverse correlation between HbA1c and lung function in non-diabetic CF patients (*r* = −0.25–0.3) [72, 73, 88], and one of these also found a direct correlation with number of infective pulmonary exacerbations per year [73]. In two more studies, HbA1c ≥ 5.5–5.8% predicted poorer FVC% [74] or FEV1% [82]. Therefore HbA1c, despite its insensitivity to CF-related glucose abnor-

Several studies have also investigated fructosamine, glycated albumin, and 1,5-anhydroglucitol as alternatives to HbA1c in CF. These biomarkers are not dependent on the lifespan of erythrocytes, and have been shown to correlate with mean plasma glucose in CF as estimated using CGM [75]. However, evidence of their ability to predict glucose abnormalities and clinical decline in CF is currently mixed [11, 74, 157]. In one study, fractional serum fructosamine (FSF) ≥3.70 μmol/g predicted IGT and CFRD with 100% sensitivity and 67% specificity, and patients with elevated FSF also had significantly lower median FEV1% (47% vs. 90%) [157].

Early evidence suggests that fasting glucose, including IFG, does not correlate with clinical status in CF [53, 95]. In one case-control study, IFG actually predicted *better* lung function than normal fasting glucose in some patient subgroups,

particularly children with simultaneous IGT [95]. It was hypothesized that IFG may represent a physiological adaptation to CF, with hepatic glucose production upregu-

**4. Detection protocols for early glucose abnormalities and CFRD at the** 

Our institute, the Sydney Children's Hospital, provides one example of integrating multiple glucose measurement methods into routine practice. Children with CF are screened annually for glucose abnormalities from age 10, using OGTT with 30-minutely sampling. CGM is used to follow up borderline OGTTs, or to investigate children with clinically-suspected glucose abnormalities who have normal OGTTs or are unable to undergo OGTT. CGM excursions ≥11.1 mmol/L over 72 h of monitoring are considered severe abnormalities that warrant further investigation for possible insulin therapy. Moreover, some pre-diabetic children on OGTT are randomized to insulin therapy via the CF-IDEA trial (ClinicalTrials.

lated to meet increased baseline metabolic requirements [95].

**Sydney Children's Hospital, Randwick**

gov Identifier NCT01100892, see Section 5).

malities, may be a useful harbinger of clinical decline when elevated.

*DOI: http://dx.doi.org/10.5772/intechopen.92847*

**measurement techniques**

*3.5.2 Fasting glucose*

*3.5.1 HbA1c and alternative glycated proteins*

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.92847*

excursions, and standard deviation [152]. Brugha et al. investigated another glycemic variability measure, glucose interquartile ranges, in a 7-year retrospective cohort study [111]. On ROC analysis, ranges >1.95 mmol/L predicted CFRD with 60% sensitivity and 98% specificity, but did not correlate with BMI or FEV1% [111].

Finally, our group recently conducted a cross-sectional study of 18 children with CF aged ≤5 years [156]. Even in this very young group, history of *P. aeruginosa* was predicted by mean glucose and percentage time at ≥7.8 mmol/L, and levels of inflammatory markers in bronchoalveolar lavage fluid were predicted by peak glucose, mean glucose, percentage time at ≥7.8 mmol/L, and standard deviation [156].

#### **3.5 Clinically significant pre-diabetic markers detectable using other glucose measurement techniques**

## *3.5.1 HbA1c and alternative glycated proteins*

Three studies report a weak inverse correlation between HbA1c and lung function in non-diabetic CF patients (*r* = −0.25–0.3) [72, 73, 88], and one of these also found a direct correlation with number of infective pulmonary exacerbations per year [73]. In two more studies, HbA1c ≥ 5.5–5.8% predicted poorer FVC% [74] or FEV1% [82]. Therefore HbA1c, despite its insensitivity to CF-related glucose abnormalities, may be a useful harbinger of clinical decline when elevated.

Several studies have also investigated fructosamine, glycated albumin, and 1,5-anhydroglucitol as alternatives to HbA1c in CF. These biomarkers are not dependent on the lifespan of erythrocytes, and have been shown to correlate with mean plasma glucose in CF as estimated using CGM [75]. However, evidence of their ability to predict glucose abnormalities and clinical decline in CF is currently mixed [11, 74, 157]. In one study, fractional serum fructosamine (FSF) ≥3.70 μmol/g predicted IGT and CFRD with 100% sensitivity and 67% specificity, and patients with elevated FSF also had significantly lower median FEV1% (47% vs. 90%) [157].

#### *3.5.2 Fasting glucose*

*Cystic Fibrosis - Facts, Management and Advances*

colonization with *P. aeruginosa* [155].

baseline FEV1% and 12-month rate of decline [112].

management of CF mitigates nutritional decline [133, 154]. Nevertheless, one seminal prospective cohort study inversely correlated age-adjusted height and BMI with AUCglucose [8], and a recent cross-sectional study found that lower-thanmedian insulin secretion at 60 min is independently associated with worse BMI [150]. In children, BMI (calculated as weight in kg divided by the square of height in meters) may be a less sensitive measure of nutritional status than weight-for-age, as poor linear growth may mask decline [146]. Nevertheless, Wooldridge et al. report a direct correlation between AUCinsulin and BMI z-score in 146 NGT children with CF aged 5–20 [123], and our group has found that AUCglucose inversely correlates with age-adjusted weight, height and BMI in children aged ≤10 years [153]. Furthermore, in an earlier cohort study of 33 children aged 10–19, we found that higher BGmax was associated with decline in weight z-score, FEV1% and FVC% over the past 12 months, and BGmax ≥8.2 mmol/L had 87% sensitivity and 70% specificity for a clinically significant decline in weight z-score [9]. By contrast, BG120 was no better than chance at detecting decline in weight z-score, and the conventional diagnostic threshold of 11.1 mmol/L had only 10% sensitivity [9]. These findings led us to propose an alternative system for classifying CF-related glucose abnormalities on

OGTT, the Cystic Fibrosis Insulin Deficiency (CFID) stages (**Table 3**) [9].

**3.4 Clinically significant pre-diabetic markers detectable using CGM**

Six main studies have explored the clinical significance of CGM-based measures of CF-related early glucose abnormalities [9, 98, 111, 152, 155, 156]. Their results are compelling but heterogeneous. Taylor-Cousar et al. conducted a 5-year prospective cohort study of 17 originally non-diabetic CF patients, 7 of whom developed CFRD during observation [98]. In this subgroup, there was significant inverse correlation between peak glucose and BMI, and a trend towards correlation with FEV1% [98]. Leclercq et al. also examined peak glucose, stratifying 38 NGT CF patients according to whether they had any peaks ≥11.1 mmol/L during 72-h CGM [155]. In the 'yes' group, there was significantly lower FEV1% and FVC%, and increased risk of

In the aforementioned study undertaken by our research group in 33 children with CF aged 10–19, we also showed that percentage time ≥7.8 mmol/L on CGM predicted 12-month rate of decline in weight z-score, FVC%, and FEV1%. Similarly, on receiver operator characteristic (ROC) analysis, ≥4.5% time at ≥7.8 mmol/L on CGM was a sensitive and specific predictor of clinically significant decline in weight z-score and FVC% [9]. Frost et al. subsequently used these parameters to interpret the CGM results of 59 adults being investigated for CF-related glucose abnormalities [112]. They found that percentage time ≥7.8 mmol/L on CGM correlated with

In Chan et al.'s study of 88 children with CF aged 10–18, 12-month decline in FEV1% and FVC% was predicted by multiple other CGM parameters: peak glucose, number of daily glucose excursions >11.1 mmol/L, mean amplitude of glycemic

**Diagnostic category o-min OGTT glucose Max OGTT glucose 2-h OGTT glucose** CFID1 <7.0 mmol/L ≥8.2 mmol/L <11.1 mmol/L CFID2 <7.0 mmol/L ≥11.1 mmol/L <11.1 mmol/L CFID3 <7.0 mmol/L *N/A* ≥11.1 mmol/L CFID4 ≥7.0 mmol/L *N/A N/A*

*Cystic fibrosis insulin deficiency (CFID) classification system of CF-related glucose abnormalities, as proposed* 

**34**

**Table 3.**

*by Hameed et al. [9].*

Early evidence suggests that fasting glucose, including IFG, does not correlate with clinical status in CF [53, 95]. In one case-control study, IFG actually predicted *better* lung function than normal fasting glucose in some patient subgroups, particularly children with simultaneous IGT [95]. It was hypothesized that IFG may represent a physiological adaptation to CF, with hepatic glucose production upregulated to meet increased baseline metabolic requirements [95].

## **4. Detection protocols for early glucose abnormalities and CFRD at the Sydney Children's Hospital, Randwick**

Our institute, the Sydney Children's Hospital, provides one example of integrating multiple glucose measurement methods into routine practice. Children with CF are screened annually for glucose abnormalities from age 10, using OGTT with 30-minutely sampling. CGM is used to follow up borderline OGTTs, or to investigate children with clinically-suspected glucose abnormalities who have normal OGTTs or are unable to undergo OGTT. CGM excursions ≥11.1 mmol/L over 72 h of monitoring are considered severe abnormalities that warrant further investigation for possible insulin therapy. Moreover, some pre-diabetic children on OGTT are randomized to insulin therapy via the CF-IDEA trial (ClinicalTrials. gov Identifier NCT01100892, see Section 5).

## **5. Management of early glucose abnormalities in CF**

Ultimately, the most clinically relevant measures of CF-related early glucose abnormalities are those that alter patient management. Therefore the long-term effects of actively treating early abnormalities is an important research question. Most studies have focused on insulin therapy, as insulin is currently the only recommended pharmacotherapy for CFRD (in part because of its anabolic effects) [59]. Emerging research has also explored oral anti-hypoglycemics [158], incretin modifiers [159], and CFTR modulators [160, 161].

It is already known that earlier diagnosis and treatment of CFRD, via OGTT screening programs, improves life expectancy and resolves historical sex differences in clinical outcomes (females with CFRD previously did worse than males) [16, 24]. Seven studies were identified trialing insulin therapy for CF patients who were pre-diabetic on OGTT [92, 122, 143, 162–164]. Five report statistically-significant improvements in lung function [122, 163, 165], nutritional status [122, 143, 164, 165], or rate of decline in either variable [163, 164], either intra-individually or relative to untreated controls. Moreover, five out of six studies assessing tolerability found no significantly-increased incidence of symptomatic hypoglycemia [92, 122, 143, 162, 164, 165]. Finally, one additional study has assessed the efficacy of insulin therapy initiated based on CGM, via retrospective analysis of all non-diabetic adults at a British CF center who had a CGM ordered between 2013 and 2016 [112]. Insulin was initiated if patients spent >4.5% time at >7.8 mmol/L on CGM, and if they recorded no clear triggers for these glucose excursions in a contemporary food diary. Patients treated with insulin demonstrated statisticallysignificant improvements in FEV1% and weight within 3 months of treatment, and maintained an improvement in weight and annual rate of lung function decline at 12 months [112].

All this suggests that treatment of CF-related AGT may be beneficial. However, results are difficult to generalize, due to heterogeneity in studies' inclusions criteria, types of controls, and insulin regimens [166]. Studies are also limited by small sample sizes [92, 112, 122, 143, 162–165], short durations [92, 112, 122, 143, 162, 165], and mixed analysis of pre-diabetic and diabetic patients [92, 122], highlighting the need for large long-term randomized control trials. One such trial, CF-IDEA (ClinicalTrials.gov Identifier NCT01100892), is nearing completion. To date, CF-IDEA has recruited 86 participants aged ≥5 years at 5 participating sites, all non-diabetic on OGTT with BGmax 8.2 mmol/L to <11.1 mmol/L (CFID1) or ≥ 11.1 mmol/L (CFID2). Participants are randomized to observation only or to a once-daily insulin detemir (Levemir) for 12 months, with starting dose 0.1 units/kg/day, blood glucose self-monitoring intensively for 10 days and twice daily thereafter, and a blood glucose target range of 4–8 mmol/L. The main outcome factors are change in weight SDS, change in lung function, and frequency of hospitalization.

#### **6. Conclusions**

As patients with CF live longer, CFRD becomes an increasingly prevalent serious co-morbidity, associated with significant decline in lung function and nutritional status. Evidence suggests that this decline may begin years earlier, in the pre-diabetic phase. Currently, OGTT is the most sensitive licensed diagnostic tool for identifying pre-diabetic CF-related glucose abnormalities, but its utility is limited by inconvenience, high variability of results, and insensitivity of traditional diagnostic categories to CF-related glucose excursions and clinical decline.

**37**

**Author details**

of Australia.

Australia

Katerina Theocharous1

and Shihab Hameed1,3,4\*

Randwick, NSW, Australia

New South Wales, Sydney, NSW, Australia

provided the original work is properly cited.

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis*

Development of standardized interpretation systems for CGM may revolutionize detection of clinically relevant early glucose abnormalities. Results of randomized controlled trials of insulin treatment prior to onset of CFRD may alter the point at

SH, AJ and CFV have received funding from the National Health and Medical

Research Council of Australia, Australasian Cystic Fibrosis Research Trust, Regional Diabetes Support Scheme, Sydney Children's Hospital Foundation, and Australasian Pediatric Endocrine Care Grant from Pfizer, and industry support from Novo Nordisk, Medtronic, and Abbott Diagnostics. BP has been awarded a fellowship from the Thoracic Society of Australia and New Zealand and Vertex, and a postgraduate scholarship from the National Health and Medical Research Council

, Bernadette Prentice1,2, Charles F. Verge1,3, Adam Jaffé1,2

1 School of Women's and Children's Health, Faculty of Medicine, The University of

3 Department of Endocrinology, Sydney Children's Hospital, Randwick, NSW,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Respiratory Medicine, Sydney Children's Hospital,

4 Faculty of Medicine, University of Sydney, Sydney, NSW, Australia

\*Address all correspondence to: s.hameed@unsw.edu.au

*DOI: http://dx.doi.org/10.5772/intechopen.92847*

which insulin is offered.

**Acknowledgements**

*Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.92847*

Development of standardized interpretation systems for CGM may revolutionize detection of clinically relevant early glucose abnormalities. Results of randomized controlled trials of insulin treatment prior to onset of CFRD may alter the point at which insulin is offered.

## **Acknowledgements**

*Cystic Fibrosis - Facts, Management and Advances*

**5. Management of early glucose abnormalities in CF**

modifiers [159], and CFTR modulators [160, 161].

Ultimately, the most clinically relevant measures of CF-related early glucose abnormalities are those that alter patient management. Therefore the long-term effects of actively treating early abnormalities is an important research question. Most studies have focused on insulin therapy, as insulin is currently the only recommended pharmacotherapy for CFRD (in part because of its anabolic effects) [59]. Emerging research has also explored oral anti-hypoglycemics [158], incretin

It is already known that earlier diagnosis and treatment of CFRD, via OGTT screening programs, improves life expectancy and resolves historical sex differences in clinical outcomes (females with CFRD previously did worse than males) [16, 24]. Seven studies were identified trialing insulin therapy for CF patients who were pre-diabetic on OGTT [92, 122, 143, 162–164]. Five report statistically-significant improvements in lung function [122, 163, 165], nutritional status [122, 143, 164, 165], or rate of decline in either variable [163, 164], either intra-individually or relative to untreated controls. Moreover, five out of six studies assessing tolerability found no significantly-increased incidence of symptomatic hypoglycemia [92, 122, 143, 162, 164, 165]. Finally, one additional study has assessed the efficacy of insulin therapy initiated based on CGM, via retrospective analysis of all non-diabetic adults at a British CF center who had a CGM ordered between 2013 and 2016 [112]. Insulin was initiated if patients spent >4.5% time at >7.8 mmol/L on CGM, and if they recorded no clear triggers for these glucose excursions in a contemporary food diary. Patients treated with insulin demonstrated statisticallysignificant improvements in FEV1% and weight within 3 months of treatment, and maintained an improvement in weight and annual rate of lung function decline at

All this suggests that treatment of CF-related AGT may be beneficial. However, results are difficult to generalize, due to heterogeneity in studies' inclusions criteria, types of controls, and insulin regimens [166]. Studies are also limited by small sample sizes [92, 112, 122, 143, 162–165], short durations [92, 112, 122, 143, 162, 165], and mixed analysis of pre-diabetic and diabetic patients [92, 122], highlighting the need for large long-term randomized control trials. One such trial, CF-IDEA (ClinicalTrials.gov Identifier NCT01100892), is nearing completion. To date, CF-IDEA has recruited 86 participants aged ≥5 years at 5 participating sites, all non-diabetic on OGTT with BGmax 8.2 mmol/L to <11.1 mmol/L (CFID1) or ≥ 11.1 mmol/L (CFID2). Participants are randomized to observation only or to a once-daily insulin detemir (Levemir) for 12 months, with starting dose 0.1 units/kg/day, blood glucose self-monitoring intensively for 10 days and twice daily thereafter, and a blood glucose target range of

4–8 mmol/L. The main outcome factors are change in weight SDS, change in lung

As patients with CF live longer, CFRD becomes an increasingly prevalent serious co-morbidity, associated with significant decline in lung function and nutritional status. Evidence suggests that this decline may begin years earlier, in the pre-diabetic phase. Currently, OGTT is the most sensitive licensed diagnostic tool for identifying pre-diabetic CF-related glucose abnormalities, but its utility is limited by inconvenience, high variability of results, and insensitivity of traditional diagnostic categories to CF-related glucose excursions and clinical decline.

function, and frequency of hospitalization.

**36**

12 months [112].

**6. Conclusions**

SH, AJ and CFV have received funding from the National Health and Medical Research Council of Australia, Australasian Cystic Fibrosis Research Trust, Regional Diabetes Support Scheme, Sydney Children's Hospital Foundation, and Australasian Pediatric Endocrine Care Grant from Pfizer, and industry support from Novo Nordisk, Medtronic, and Abbott Diagnostics. BP has been awarded a fellowship from the Thoracic Society of Australia and New Zealand and Vertex, and a postgraduate scholarship from the National Health and Medical Research Council of Australia.

## **Author details**

Katerina Theocharous1 , Bernadette Prentice1,2, Charles F. Verge1,3, Adam Jaffé1,2 and Shihab Hameed1,3,4\*

1 School of Women's and Children's Health, Faculty of Medicine, The University of New South Wales, Sydney, NSW, Australia

2 Department of Respiratory Medicine, Sydney Children's Hospital, Randwick, NSW, Australia

3 Department of Endocrinology, Sydney Children's Hospital, Randwick, NSW, Australia

4 Faculty of Medicine, University of Sydney, Sydney, NSW, Australia

\*Address all correspondence to: s.hameed@unsw.edu.au

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[161] Kelly A, De Leon DD, Sheikh S, Camburn D, Kubrak C, Peleckis AJ, et al. Islet hormone and incretin secretion in cystic fibrosis after four

Poupon-Bourdy S, Iwaz J, Nove-

Fibrosis. 2018;**17**(3):400-406

2014;**13**(4):478-484

[147] White H, Pollard K, Etherington C, Clifton I, Morton AM, Owen D, et al. Nutritional decline in cystic fibrosis related diabetes: The effect of intensive nutritional intervention. Journal of Cystic Fibrosis. 2009;**8**(3):179-185

[148] Bennett P, Burch T, Miller M. Diabetes mellitus in American (Pima) Indians. The Lancet. 1971;**298**(7716):125-128

[149] Olszowiec-Chlebna M, Koniarek-Maniecka A, Stelmach W, Smejda K, Jerzyńska J, Majak P, et al. Predictors of deterioration of lung function in polish children with cystic fibrosis. Archives of

Medical Science. 2016;**2**:402-407

[150] Coriati A, Ziai S, Lavoie A, Berthiaume Y, Rabasa-Lhoret R. The 1-h oral glucose tolerance test glucose and insulin values are associated with markers of clinical deterioration in cystic fibrosis. Acta Diabetologica.

2016;**53**(3):359-366

Fibrosis. 2015;**14**:S103

2018;**17**(6):783-790

[151] Bourdy S, Rabilloud M,

[152] Chan CL, Vigers T, Pyle L, Zeitler PS, Sagel SD, Nadeau KJ. Continuous glucose monitoring abnormalities in cystic fibrosis youth correlate with pulmonary function decline. Journal of Cystic Fibrosis.

[153] Prentice BJ, Chelliah A, Ooi CY, Hameed S, Verge CF, Plush L, et al. Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis. Journal of Cystic

Fibrosis. 2020;**19**(2):305-309

Touzet S, Roche S, Drai J, Martin C, et al. 178 glucose tolerance in cystic fibrosis patients over a 3-year period (DIAMUCO study). Journal of Cystic

2017;**30**(8):815-821

**48**

[162] Minicucci L, Haupt M, Casciaro R, De Alessandri A, Bagnasco F, Lucidi V, et al. Slow-release insulin in cystic fibrosis patients with glucose intolerance: A randomized clinical trial. Pediatric Diabetes. 2012;**13**(2):197-202

[163] Kolouskova S, Zemkova D, Bartosova J, Skalicka V, Sumnik Z, Vavrova V, et al. Low-dose insulin therapy in patients with cystic fibrosis and early-stage insulinopenia prevents deterioration of lung function: A 3-year prospective study. Journal of Pediatric Endocrinology & Metabolism. 2011;**24**(7-8):449-454

[164] Drummond RS, Ross E, Bicknell S, Small M, Jones GC. Insulin therapy in patients with cystic fibrosis related diabetes mellitus: Benefit, timing of initiation and hypoglycaemia. Practical Diabetes International. 2011;**28**(4):177-182

[165] Hameed S, Morton JR, Field PI, Belessis Y, Yoong T, Katz T, et al. Once daily insulin detemir in cystic fibrosis with insulin deficiency. Archives of Disease in Childhood. 2012;**97**(5):464-467

[166] Pu MZMH, Christensen-Adad FC, Gonçalves AC, Minicucci WJ, Ribeiro JD, Ribeiro AF. Insulin therapy in patients with cystic fibrosis in the pre-diabetes stage: A systematic review. Revista Paulista de Pediatria. 2016;**34**(3):367-373

**51**

**Chapter 4**

**Abstract**

Microbial Cystic Fibrosis

Cystic fibrosis (CF) is the most common genetic disease in Caucasians that increases the mortality rate. This disease retards the passage of water and salt through the cells and therefore affects the vital functions of different organs. Pulmonary cystic fibrosis is the most common and responsible for the majority of symptoms, burden of care, and mortality. The gene that causes the disease has now been identified and sequenced. The lung diseases with CF are usually have three pathological elements; mucus obstruction, inflammation, and infection. In the last century, the relationship between CF, respiratory microbiology, and inflammation has been understood with increased longevity and development of new treatments and laboratory techniques. In this chapter, we will illustrate causes of CF lung

**Keywords:** cystic fibrosis, pathogenic bacteria, pneumonia infection, pulmonary

Cystic fibrosis (CF) arises due to recessive mutations in the CF transmembrane regulator (CFTR) gene. This genetic disorder is carried out when two carrier parents transport the mutant CFTR gene to their child. Although no symptoms appear in the carriers, CF can be detected by genetic testing. CF-pulmonary diseases are usually associated with three pathological aspects; airway obstruction, infection, and inflammation. According to previous studies, children are most frequently infected by this disease with high rate of mortality. *Staphylococcus aureus* is the main cause of bronchitis, bronchiectasis, and pulmonary abscesses arising in the bronchi, which are usually accompanied by tenacious greenish-gray mucopurulent material [1, 2]. The mutation that attacks CFTR gene leads to CF, and obstruction in the airways with abnormal mucus, infection, and inflammation is present. Although the current treatments cannot halt the disease progression, good nutrition, defective mucus clearance, and treatment of inflammation and infection greatly improve CF of the respiratory system and its complications [3]. There is a controversial relationship between infection and inflammation. Some scientists think that the infection should precede the inflammation of airways, while others suggest the opposite [4]. Americans and Europeans are more susceptible to CF. One in 29 people of Caucasian ancestry is a healthy carrier of the CF gene mutation [5]. Detection of CF in early phases is very useful due to symptom reduction, health improvement, and low cost. For example, since 2010s, all American newborns undergo screening for CF to provide a chance for recovery if the disease is diagnosed. Most patients of CF must take pancreatic enzymes to digest food effectively, and some require insulin

*Waleed Mohamed Abdulkhair and* 

*Mousa Abdullah Alghuthaymi*

diseases and modern therapeutic strategies.

inflammation, treatment guidelines

**1. Introduction**

## **Chapter 4** Microbial Cystic Fibrosis

*Waleed Mohamed Abdulkhair and Mousa Abdullah Alghuthaymi*

## **Abstract**

Cystic fibrosis (CF) is the most common genetic disease in Caucasians that increases the mortality rate. This disease retards the passage of water and salt through the cells and therefore affects the vital functions of different organs. Pulmonary cystic fibrosis is the most common and responsible for the majority of symptoms, burden of care, and mortality. The gene that causes the disease has now been identified and sequenced. The lung diseases with CF are usually have three pathological elements; mucus obstruction, inflammation, and infection. In the last century, the relationship between CF, respiratory microbiology, and inflammation has been understood with increased longevity and development of new treatments and laboratory techniques. In this chapter, we will illustrate causes of CF lung diseases and modern therapeutic strategies.

**Keywords:** cystic fibrosis, pathogenic bacteria, pneumonia infection, pulmonary inflammation, treatment guidelines

## **1. Introduction**

Cystic fibrosis (CF) arises due to recessive mutations in the CF transmembrane regulator (CFTR) gene. This genetic disorder is carried out when two carrier parents transport the mutant CFTR gene to their child. Although no symptoms appear in the carriers, CF can be detected by genetic testing. CF-pulmonary diseases are usually associated with three pathological aspects; airway obstruction, infection, and inflammation. According to previous studies, children are most frequently infected by this disease with high rate of mortality. *Staphylococcus aureus* is the main cause of bronchitis, bronchiectasis, and pulmonary abscesses arising in the bronchi, which are usually accompanied by tenacious greenish-gray mucopurulent material [1, 2].

The mutation that attacks CFTR gene leads to CF, and obstruction in the airways with abnormal mucus, infection, and inflammation is present. Although the current treatments cannot halt the disease progression, good nutrition, defective mucus clearance, and treatment of inflammation and infection greatly improve CF of the respiratory system and its complications [3]. There is a controversial relationship between infection and inflammation. Some scientists think that the infection should precede the inflammation of airways, while others suggest the opposite [4].

Americans and Europeans are more susceptible to CF. One in 29 people of Caucasian ancestry is a healthy carrier of the CF gene mutation [5]. Detection of CF in early phases is very useful due to symptom reduction, health improvement, and low cost. For example, since 2010s, all American newborns undergo screening for CF to provide a chance for recovery if the disease is diagnosed. Most patients of CF must take pancreatic enzymes to digest food effectively, and some require insulin

for diabetes mellitus. The treatment cost of CF is very high because the drugs which treat and prevent the pulmonary diseases are very expensive [6]. Walaa et al. [7] report that 60 Egyptian children are affected by CF (6 months to 14 years). Salty skin is the most common symptom in the children affected with CF, because they suffer from dehydration due to loss of exuberant salty sweat. The percentage of ill males is 63%, while the percentage of ill females is 37%. Positive consanguinity of patients is 57%. 23% of patients has a positive family history of CF; the most frequent clinical presentation is pulmonary disease (84%), followed by pancreatic insufficiency (56%). The scientific material of this chapter aims to clearly interpret the roles of infection and inflammation in CF lung disease pathogenesis. Also, we will shed light on the therapeutic approaches to both infection and inflammation.

## **2. Microbes: CF interaction**

#### **2.1 Microbiology of CF lung disease**

Severe and uncontrolled microbial infection may lead to CF. Microbes usually invade the airway luminal mucus, rather than tissues. Although *Staphylococcus aureus* is the main pathogenic agent for CF, many other bacteria are recorded with the development of both treatments and laboratory methods. The detection of pathogenic bacteria of CF depends on the cultivation of respiratory samples (e.g., sputum, bronchoalveolar lavage fluid, oropharyngeal swabs, or sinus samples) on the nutritive and selective media. Moreover, there are advanced techniques by which CF microbes are identified. Current methods mainly depend on cultivation of pathogenic bacteria on synthetic microbiological growth media and follow the incubation conditions to allow good growth and culture characteristics of pathogens [8]. Conventional techniques including microscopic and biochemical investigations revealed that the pathogenic microbes infecting CF airways usually exist in biofilms, which provide complete defense mechanism to the pathogens [9, 10].

#### **2.2 CF respiratory pathogens**

#### *2.2.1 Staphylococcus aureus*

*Staphylococcus aureus* is a Gram-positive bacterium and is the first CF respiratory pathogen. Children are more susceptible to CF lung diseases than adults, and they are usually affected by *S. aureus*, which has been associated with higher airway inflammation [11, 12] and lung dysfunctions [13, 14]. This infection can be lethal when associated with *Pseudomonas aeruginosa* [15]. This association may lead to worse outcomes, if *P. aeruginosa* is associated with specific subtypes of *S. aureus* such as methicillin-resistant *S. aureus* (MRSA) and small-colony variants of *S. aureus* (SCVs). *S. aureus* infection in adults is harmless than in children, because lung functions are better [16] and there are lower complications [17]. Accordingly, the pathogenicity of *S. aureus* has two levels: the first is high when the infection occurs in children or in the absence of *P. aeruginosa*, and the second is very high (extreme) when the host is infected by specific subtypes of *S. aureus* (such as MRSA or SCVs). On the other hand, *S. aureus* may be nonpathogenic, but just serves as a marker of early or mild disease as with children and adults, respectively [18].

The two subtypes of *S. aureus* which are mentioned above (MRSA and SCVs) as well as oxacillin-resistant *S. aureus* (ORSA) are usually identified either by their resistance to these β-lactams or by carriage of the *mec*A gene, which encodes this resistance. The subtypes of *S. aureus* SCVs are slow-growing, antibiotic-resistant variants

**53**

*Microbial Cystic Fibrosis*

*2.2.2 Pseudomonas aeruginosa*

for respiratory tract 31].

*DOI: http://dx.doi.org/10.5772/intechopen.91628*

that are difficult to detect with conventional cultures and require special laboratory methods. SCVs are associated with decreasing lung functions, and they may be treated with antibiotics including aminoglycosides and sulfonamides [19]. MRSA are tightly accompanied with CF lung disease especially in the last 20 years. A lot of people are infected with MRSA due to hospitalization and worse use of antibiotics [20–22]. Many studies reported that MRSA are associated with CF lung disease in particular decrease of lung functions [23]. Moreover, MRSA is an independent risk factor for decreasing lung functions and respiratory exacerbations [24] and for increased mortality [25]. There are some similarities between the two subtypes (MRSA and SCVs): antibiotic

In some countries where CF lung disease is spreading, anti-staphylococcal agent is provided as a prophylaxis approach during childhood particularly when *P. aeruginosa* is detected early [26]. Many of antibiotics are used to eradicate *S. aureus* and *P. aeruginosa* as co-infectious agents of CF lung disease, but the most commonly

After overcoming *S. aureus* by effective anti-staphylococcal agents, *P. aeruginosa* became the most common and important pathogen related to CF-pulmonary diseases [28]. *P. aeruginosa* infection is associated with decreasing lung functions, severe inflammation of the respiratory tract, a greater risk of respiratory exacerbations, and high rate of mortality [29]. Early detection of *P. aeruginosa* is a helpful factor for full eradication, while chronic infection cannot be eradicated. Also, eradication of *P. aeruginosa* can be carried out by using antipseudomonal bioagents [30]. In contrast with *S. aureus* infection, *P. aeruginosa* infection is higher in adults than in children. At the end-stage of CF-pulmonary disease, *P. aeruginosa* is only present as a main pathogen

Despite *P. aeruginosa* usually producing numerous toxins as virulence factors, it may loss these virulence factors or their regulatory genes during chronic CF infections [32]. After invasion of lungs with *P. aeruginosa*, the mucoid colonies are formed due to exuberant production of alginate as one of the phenotypic changes due to chronic infection of CF-pulmonary disease [33]. The mucoid texture provides high rates of persistence and resistance for many antimicrobial agents as well as full adaptation to the respiratory airways. *P. aeruginosa* may be epidemic or non-epidemic, but the former is associated with worse outcomes such as high rate

Although *P. aeruginosa* is a multidrug resistant pathogen and usually leads to severe pulmonary CF, it leads to worse outcomes when associated with MRSA and SCVs. Prophylaxis by using of antibiotics is not recommended in the recent approach of *P. aeruginosa* treatment due to severe adverse events of antibiotics, but if *P. aeruginosa* is early detected, the treatment course with antibiotics must begin for complete eradication and to decrease the risk of exacerbations. Recently, inhaled antibiotics such as tobramycin and aztreonam are sufficient for eradication without any additional oral antibiotics such as ciprofloxacin [35]. Although inhaled antibiotics are sufficient for *P. aeruginosa* treatment without oral antibiotics, the clinical reports are revealing that, the combination between two classes of antibiotics leads

*Burkholderia cepacia* complex (BCC) is a group of Gram-negative bacteria and is comprised of at least 18 species. Of these, two species are the most common and

treatment, antibiotic resistance, and higher lung disease severity.

used antibiotics are aminoglycosides and sulfonamides [27].

of mortality and requirement for lung transplantation [34].

to longer periods of clinical stability than does a single class [36].

*2.2.3 Burkholderia cepacia complex*

#### *Microbial Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91628*

*Cystic Fibrosis - Facts, Management and Advances*

**2. Microbes: CF interaction**

**2.2 CF respiratory pathogens**

*2.2.1 Staphylococcus aureus*

**2.1 Microbiology of CF lung disease**

for diabetes mellitus. The treatment cost of CF is very high because the drugs which treat and prevent the pulmonary diseases are very expensive [6]. Walaa et al. [7] report that 60 Egyptian children are affected by CF (6 months to 14 years). Salty skin is the most common symptom in the children affected with CF, because they suffer from dehydration due to loss of exuberant salty sweat. The percentage of ill males is 63%, while the percentage of ill females is 37%. Positive consanguinity of patients is 57%. 23% of patients has a positive family history of CF; the most frequent clinical presentation is pulmonary disease (84%), followed by pancreatic insufficiency (56%). The scientific material of this chapter aims to clearly interpret the roles of infection and inflammation in CF lung disease pathogenesis. Also, we will shed light on the therapeutic approaches to both infection and inflammation.

Severe and uncontrolled microbial infection may lead to CF. Microbes usually invade the airway luminal mucus, rather than tissues. Although *Staphylococcus aureus* is the main pathogenic agent for CF, many other bacteria are recorded with the development of both treatments and laboratory methods. The detection of pathogenic bacteria of CF depends on the cultivation of respiratory samples (e.g., sputum, bronchoalveolar lavage fluid, oropharyngeal swabs, or sinus samples) on the nutritive and selective media. Moreover, there are advanced techniques by which CF microbes are identified. Current methods mainly depend on cultivation of pathogenic bacteria on synthetic microbiological growth media and follow the incubation conditions to allow good growth and culture characteristics of pathogens [8]. Conventional techniques including microscopic and biochemical investigations revealed that the pathogenic microbes infecting CF airways usually exist in biofilms, which provide complete defense mechanism to the pathogens [9, 10].

*Staphylococcus aureus* is a Gram-positive bacterium and is the first CF respiratory pathogen. Children are more susceptible to CF lung diseases than adults, and they are usually affected by *S. aureus*, which has been associated with higher airway inflammation [11, 12] and lung dysfunctions [13, 14]. This infection can be lethal when associated with *Pseudomonas aeruginosa* [15]. This association may lead to worse outcomes, if *P. aeruginosa* is associated with specific subtypes of *S. aureus* such as methicillin-resistant *S. aureus* (MRSA) and small-colony variants of *S. aureus* (SCVs). *S. aureus* infection in adults is harmless than in children, because lung functions are better [16] and there are lower complications [17]. Accordingly, the pathogenicity of *S. aureus* has two levels: the first is high when the infection occurs in children or in the absence of *P. aeruginosa*, and the second is very high (extreme) when the host is infected by specific subtypes of *S. aureus* (such as MRSA or SCVs). On the other hand, *S. aureus* may be nonpathogenic, but just serves as a marker of early or mild disease as with children and adults, respectively [18]. The two subtypes of *S. aureus* which are mentioned above (MRSA and SCVs) as well as oxacillin-resistant *S. aureus* (ORSA) are usually identified either by their resistance to these β-lactams or by carriage of the *mec*A gene, which encodes this resistance. The subtypes of *S. aureus* SCVs are slow-growing, antibiotic-resistant variants

**52**

that are difficult to detect with conventional cultures and require special laboratory methods. SCVs are associated with decreasing lung functions, and they may be treated with antibiotics including aminoglycosides and sulfonamides [19]. MRSA are tightly accompanied with CF lung disease especially in the last 20 years. A lot of people are infected with MRSA due to hospitalization and worse use of antibiotics [20–22]. Many studies reported that MRSA are associated with CF lung disease in particular decrease of lung functions [23]. Moreover, MRSA is an independent risk factor for decreasing lung functions and respiratory exacerbations [24] and for increased mortality [25]. There are some similarities between the two subtypes (MRSA and SCVs): antibiotic treatment, antibiotic resistance, and higher lung disease severity.

In some countries where CF lung disease is spreading, anti-staphylococcal agent is provided as a prophylaxis approach during childhood particularly when *P. aeruginosa* is detected early [26]. Many of antibiotics are used to eradicate *S. aureus* and *P. aeruginosa* as co-infectious agents of CF lung disease, but the most commonly used antibiotics are aminoglycosides and sulfonamides [27].

#### *2.2.2 Pseudomonas aeruginosa*

After overcoming *S. aureus* by effective anti-staphylococcal agents, *P. aeruginosa* became the most common and important pathogen related to CF-pulmonary diseases [28]. *P. aeruginosa* infection is associated with decreasing lung functions, severe inflammation of the respiratory tract, a greater risk of respiratory exacerbations, and high rate of mortality [29]. Early detection of *P. aeruginosa* is a helpful factor for full eradication, while chronic infection cannot be eradicated. Also, eradication of *P. aeruginosa* can be carried out by using antipseudomonal bioagents [30]. In contrast with *S. aureus* infection, *P. aeruginosa* infection is higher in adults than in children. At the end-stage of CF-pulmonary disease, *P. aeruginosa* is only present as a main pathogen for respiratory tract 31].

Despite *P. aeruginosa* usually producing numerous toxins as virulence factors, it may loss these virulence factors or their regulatory genes during chronic CF infections [32]. After invasion of lungs with *P. aeruginosa*, the mucoid colonies are formed due to exuberant production of alginate as one of the phenotypic changes due to chronic infection of CF-pulmonary disease [33]. The mucoid texture provides high rates of persistence and resistance for many antimicrobial agents as well as full adaptation to the respiratory airways. *P. aeruginosa* may be epidemic or non-epidemic, but the former is associated with worse outcomes such as high rate of mortality and requirement for lung transplantation [34].

Although *P. aeruginosa* is a multidrug resistant pathogen and usually leads to severe pulmonary CF, it leads to worse outcomes when associated with MRSA and SCVs. Prophylaxis by using of antibiotics is not recommended in the recent approach of *P. aeruginosa* treatment due to severe adverse events of antibiotics, but if *P. aeruginosa* is early detected, the treatment course with antibiotics must begin for complete eradication and to decrease the risk of exacerbations. Recently, inhaled antibiotics such as tobramycin and aztreonam are sufficient for eradication without any additional oral antibiotics such as ciprofloxacin [35]. Although inhaled antibiotics are sufficient for *P. aeruginosa* treatment without oral antibiotics, the clinical reports are revealing that, the combination between two classes of antibiotics leads to longer periods of clinical stability than does a single class [36].

#### *2.2.3 Burkholderia cepacia complex*

*Burkholderia cepacia* complex (BCC) is a group of Gram-negative bacteria and is comprised of at least 18 species. Of these, two species are the most common and associated with CF lung infections and disease, *B. cenocepacia* and *B. multivorans*, but the latter is more distributed than the former. Nevertheless, *B. cenocepacia* is associated with more rapid lung function decline and mortality rate than *B. multivorans*. Other BCC species are less common, and their clinical associations are less well defined such as *B. gladioli* [37]. *Burkholderia* CF infections are notorious because they are associated with more severe lung disease, they are transmissible among persons with CF, they are resistant to multi-antibiotics, and epidemic strains can infect CF patients after internal contact at camps and clinics [38]. Associated outcomes often range from clinical quiescence to rapidly progressive, necrotizing pneumonia and fatal septic disease "cepacia syndrome" [39]. Therapy is usually limited to specific antibiotics as needed [40, 41].

#### *2.2.4 Stenotrophomonas maltophilia*

*Stenotrophomonas maltophilia* is a Gram-negative bacterium, which is widely spreading in the United States in recent years as CF pathogen especially among adolescents and young adults. This bacterium has intrinsic and acquired resistance to many antibiotics. No clear evidence for treatment of this pathogen so far [42].

#### *2.2.5 Haemophilus influenzae*

*Haemophilus influenzae* is a Gram-negative bacterium and is firstly detected in CF respiratory cultures. This bacterium is more prevalent in children and less common in adults. Although its association with CF complications is controversial, it is associated with non-CF bronchiectasis and chronic obstructive pulmonary disease. The cultivation of this bacterium is difficult and usually requires specific conditions for detection. The recent isolates of *H. influenzae* are non-typeable and unencapsulated since the vaccine of *H. influenzae* type B (HIB) has been discovered. This bacterium is well known as resistant to β-lactam antibiotics due to its production of β-lactamase; therefore, treatments usually include a β-lactamase inhibitor such as amoxicillin-clavulanate [43].

#### *2.2.6 Achromobacter xylosoxidans*

*Achromobacter xylosoxidans* is a Gram-negative bacterium that is similar to *P. aeruginosa*. Although this bacterium is widely spreading in the United States, it remains low in CF lung diseases (<10%). This bacterium is associated with worse radiographic and spirometric measures of lung disease. Similar to *P. aeruginosa* and BCC, *A. xylosoxidans* is the dominant, and occasionally, bacterium is isolated from CF patients at end-stage. Some microbes are notorious due to their resistance to many antibiotics, so their treatment is limited [44].

#### *2.2.7 Nontuberculous mycobacteria*

Nontuberculous mycobacteria represent 6–30% of CF prevalence. Two groups of mycobacteria, accounting for six species, are currently considered important CF pathogens: *Mycobacterium avium* and *Mycobacterium abscessus* complexes. The treatment of nontuberculous mycobacteria has two phases: multiple intravenous antibiotics for weeks to months or multiple inhaled and oral antibiotics for months to years. Side-effects and toxicities are common and can be troublesome [45].

#### *2.2.8 Fungi and viruses*

A lot of fungi are isolated from CF patients, including yeasts such as *Candida* spp. and filamentous fungi such as *Aspergillus* spp. There is a respiratory disease known as

**55**

*Microbial Cystic Fibrosis*

**2.3 CF airway microbiome**

*DOI: http://dx.doi.org/10.5772/intechopen.91628*

allergic bronchopulmonary aspergillosis (ABPA), in which the bronchia are affected by inflammation due to *Aspergillus* infection. Patients of CF and other chronic airway diseases can develop an IgE-mediated allergic airway disease known as ABPA. The treatment for which primarily involves steroids, although the addition of an antifungal such as itraconazole may allow for lower doses of steroids. Human respiratory viruses are not thought to chronically infect the CF airway, but they have been shown both to be important and common triggers of CF respiratory exacerbations [45].

Many studies which are concerned with identification of the microbiota of the respiratory system depend on DNA-sequencing techniques. The results of these techniques revealed that there is a wide diversity of microbiota inhabiting the respiratory system. This diversity of microbiota is high in young CF patients who have better lung functions and subsequently need fewer courses of antibiotics and vice versa in the case of adults. The most dominant microbiota in infected lungs of

Destruction of the respiratory airways may carry out due to the chronic CF infections. This damage is mediated by abnormal response of the host to airway infections, which in turn leads to irreversible bronchiectasis and lung function decline [47]. Many studies report that, bacterial infection and inflammation are leading to triggering of neutrophils [48]. Moreover, the dysfunction of CF-CFTR is a main cause of altered immune defense and disorders in the airway's environment.

Appearance of neutrophil elastase (NE) is a good biomarker of disease [49].

The mutant CFTR gene leads to production of an abnormal protein, resulting in abnormal transport of salt and water across lining cells of the respiratory system, digestive system, and genital tracts. Insufficient water transport to the lining cells of the airways leads to formation of more thick and viscous respiratory secretions which clog small airways. Due to water reduction, the mucus becomes stagnant and infected with bacteria such as *P. aeruginosa* that may be inhaled or brought into the lungs through the mouth. Due to stagnant mucus, infection and chronic inflammation are developed. The tenacity of stagnant mucus is increased because the inflammatory cells are trapped in it. Due to accumulation of stagnant and infected mucus inside the airways, the bronchi dilate, and subsequently their walls are weakened. This phenomenon is called bronchiectasis that results in further airflow obstruction. According to the previous case, the respiratory cycle can be called the viscous cycle in which airway obstruction, inflammation, and infection are present, which lead to decrease of lung functions, respiratory failure, and death. Decrease of lung functions especially in children can also be due to exposure to smoking and polluted

The defective CF gene leads to defective CFTR and thick viscous secretions, which in turn lead to bronchial obstruction then to an infection then inflammation and finally bronchiectasis. Infection, inflammation, and bronchiectasis can lead to bronchial obstruction (**Figure 1**). Infection amplifies defective CF gene, which in turn leads to defective CFTR, which activates the resident airway inflammatory cells, which stimulate neutrophils and neutrophil products such as neutrophil

The surface of epithelial lining cells of respiratory airways is dehydrated and acidified due to CFTR dysfunction, and abnormal mucociliary clearance is carried

elastase and monocytes, and finally bronchiectasis occurs (**Figure 2**).

CF patients are *P. aeruginosa*, BCC, and *A. xylosoxidans* [46].

**3. Immune response in CF lung disease**

air, which also leads to pulmonary exacerbations.

#### *Microbial Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91628*

allergic bronchopulmonary aspergillosis (ABPA), in which the bronchia are affected by inflammation due to *Aspergillus* infection. Patients of CF and other chronic airway diseases can develop an IgE-mediated allergic airway disease known as ABPA. The treatment for which primarily involves steroids, although the addition of an antifungal such as itraconazole may allow for lower doses of steroids. Human respiratory viruses are not thought to chronically infect the CF airway, but they have been shown both to be important and common triggers of CF respiratory exacerbations [45].

### **2.3 CF airway microbiome**

*Cystic Fibrosis - Facts, Management and Advances*

*2.2.4 Stenotrophomonas maltophilia*

*2.2.5 Haemophilus influenzae*

*2.2.6 Achromobacter xylosoxidans*

*2.2.7 Nontuberculous mycobacteria*

*2.2.8 Fungi and viruses*

many antibiotics, so their treatment is limited [44].

associated with CF lung infections and disease, *B. cenocepacia* and *B. multivorans*, but the latter is more distributed than the former. Nevertheless, *B. cenocepacia* is associated with more rapid lung function decline and mortality rate than *B. multivorans*. Other BCC species are less common, and their clinical associations are less well defined such as *B. gladioli* [37]. *Burkholderia* CF infections are notorious because they are associated with more severe lung disease, they are transmissible among persons with CF, they are resistant to multi-antibiotics, and epidemic strains can infect CF patients after internal contact at camps and clinics [38]. Associated outcomes often range from clinical quiescence to rapidly progressive, necrotizing pneumonia and fatal septic disease "cepacia syndrome" [39]. Therapy is usually limited to specific antibiotics as needed [40, 41].

*Stenotrophomonas maltophilia* is a Gram-negative bacterium, which is widely spreading in the United States in recent years as CF pathogen especially among adolescents and young adults. This bacterium has intrinsic and acquired resistance to many antibiotics. No clear evidence for treatment of this pathogen so far [42].

*Haemophilus influenzae* is a Gram-negative bacterium and is firstly detected in CF respiratory cultures. This bacterium is more prevalent in children and less common in adults. Although its association with CF complications is controversial, it is associated with non-CF bronchiectasis and chronic obstructive pulmonary disease. The cultivation of this bacterium is difficult and usually requires specific conditions for detection. The recent isolates of *H. influenzae* are non-typeable and unencapsulated since the vaccine of *H. influenzae* type B (HIB) has been discovered. This bacterium is well known as resistant to β-lactam antibiotics due to its production of β-lactamase; therefore, treatments usually include a β-lactamase inhibitor such as amoxicillin-clavulanate [43].

*Achromobacter xylosoxidans* is a Gram-negative bacterium that is similar to *P. aeruginosa*. Although this bacterium is widely spreading in the United States, it remains low in CF lung diseases (<10%). This bacterium is associated with worse radiographic and spirometric measures of lung disease. Similar to *P. aeruginosa* and BCC, *A. xylosoxidans* is the dominant, and occasionally, bacterium is isolated from CF patients at end-stage. Some microbes are notorious due to their resistance to

Nontuberculous mycobacteria represent 6–30% of CF prevalence. Two groups of mycobacteria, accounting for six species, are currently considered important CF pathogens: *Mycobacterium avium* and *Mycobacterium abscessus* complexes. The treatment of nontuberculous mycobacteria has two phases: multiple intravenous antibiotics for weeks to months or multiple inhaled and oral antibiotics for months to years.

A lot of fungi are isolated from CF patients, including yeasts such as *Candida* spp. and filamentous fungi such as *Aspergillus* spp. There is a respiratory disease known as

Side-effects and toxicities are common and can be troublesome [45].

**54**

Many studies which are concerned with identification of the microbiota of the respiratory system depend on DNA-sequencing techniques. The results of these techniques revealed that there is a wide diversity of microbiota inhabiting the respiratory system. This diversity of microbiota is high in young CF patients who have better lung functions and subsequently need fewer courses of antibiotics and vice versa in the case of adults. The most dominant microbiota in infected lungs of CF patients are *P. aeruginosa*, BCC, and *A. xylosoxidans* [46].

## **3. Immune response in CF lung disease**

Destruction of the respiratory airways may carry out due to the chronic CF infections. This damage is mediated by abnormal response of the host to airway infections, which in turn leads to irreversible bronchiectasis and lung function decline [47]. Many studies report that, bacterial infection and inflammation are leading to triggering of neutrophils [48]. Moreover, the dysfunction of CF-CFTR is a main cause of altered immune defense and disorders in the airway's environment. Appearance of neutrophil elastase (NE) is a good biomarker of disease [49].

The mutant CFTR gene leads to production of an abnormal protein, resulting in abnormal transport of salt and water across lining cells of the respiratory system, digestive system, and genital tracts. Insufficient water transport to the lining cells of the airways leads to formation of more thick and viscous respiratory secretions which clog small airways. Due to water reduction, the mucus becomes stagnant and infected with bacteria such as *P. aeruginosa* that may be inhaled or brought into the lungs through the mouth. Due to stagnant mucus, infection and chronic inflammation are developed. The tenacity of stagnant mucus is increased because the inflammatory cells are trapped in it. Due to accumulation of stagnant and infected mucus inside the airways, the bronchi dilate, and subsequently their walls are weakened. This phenomenon is called bronchiectasis that results in further airflow obstruction. According to the previous case, the respiratory cycle can be called the viscous cycle in which airway obstruction, inflammation, and infection are present, which lead to decrease of lung functions, respiratory failure, and death. Decrease of lung functions especially in children can also be due to exposure to smoking and polluted air, which also leads to pulmonary exacerbations.

The defective CF gene leads to defective CFTR and thick viscous secretions, which in turn lead to bronchial obstruction then to an infection then inflammation and finally bronchiectasis. Infection, inflammation, and bronchiectasis can lead to bronchial obstruction (**Figure 1**). Infection amplifies defective CF gene, which in turn leads to defective CFTR, which activates the resident airway inflammatory cells, which stimulate neutrophils and neutrophil products such as neutrophil elastase and monocytes, and finally bronchiectasis occurs (**Figure 2**).

The surface of epithelial lining cells of respiratory airways is dehydrated and acidified due to CFTR dysfunction, and abnormal mucociliary clearance is carried

**Figure 2.** *Potential alternative mechanism for airway inflammation in CF lung disease.*

out. Dehydration is carried out due to water loss, while acidification is carried out due to bicarbonate loss [50, 51]. The neutrophilic inflammatory response is higher in CF than in non-CF patients. However, the neutrophilic inflammatory response is reduced in neutrophil apoptosis. Neutrophils and their products are accumulated due to deficiency in mucociliary clearance and macrophage dysfunction [52]. The passage airways may destruct by the action of anti-proteases, such as alpha-1-antitrypsin, a serine protease inhibitor, and secretory leukocyte protease inhibitor. So, neutrophil

**57**

*Microbial Cystic Fibrosis*

response [59].

**4.1 Ibuprofen**

**4.2 Azithromycin**

*DOI: http://dx.doi.org/10.5772/intechopen.91628*

**4. Anti-inflammatory therapy of CF**

effects such as kidney failure and gastric bleeding [62].

**4.3 Corticosteroids and leukotriene receptor antagonists**

Corticosteroids, especially its systemic forms, or cortisones are powerful anti-inflammatory agents which are widely used in the treatment of CF. Although systemic corticosteroids can intensively improve lung functions, they have adverse

products such as proteases and elastases are released to react with anti-proteases and

Some substances act as mediators of immune response and serve as important biomarkers of disease progression, such as neutrophil elastase, which is abundant in induced sputum in children with CF compared to control children [55]. High level of neutrophil elastase in induced sputum indicates lung dysfunctions and bronchiectasis [13]. The inflammation of the passage airways in sputum is reduced after detection and using of effective antibiotics for treatment of a CF-pulmonary diseases [56]. Inflammatory proteins are considered potential biomarkers of disease in CF. For example, the blood plasma proteins are biomarkers of CF disease [57]. The common example of immune response in CF lung disease is the immune response to *P. aeruginosa* [58]. CFTR dysfunction predisposes the host to infection with *P. aeruginosa* and then allows for chronic infection and subsequent reduced opportunity for eradication. Moreover, *P. aeruginosa* interacts with other bacterial pathogens including *S. aureus* and *B. cepacia* complex to alter the inflammatory

Ibuprofen inhibits neutrophil migration and aggregation [60]. It improves the lung functions especially in patients younger than 13 years. Gastrointestinal bleeding may be associated with chronic therapy. Recent studies report that high-dose ibuprofen could slow the progression of lung disease in CF, particularly in children with mild disease [61]. Despite the efficacy of ibuprofen for CF lung disease therapy, its use is uncommon compared to other CF therapies due to severe adverse

Azithromycin is a broad-spectrum antibiotic belonging to macrolide group, and at the same time, it has immunomodulatory effects, so it has high effectiveness in the treatment of CF lung disease and other chronic inflammatory conditions [63]. Azithromycin may be used for a very long period (chronic azithromycin) either with or without chronic *P. aeruginosa* infection [64]. With chronic *P. aeruginosa* infection, azithromycin is taken thrice weekly for 6 months to improve forced expiratory volume (FEV) and subsequently decrease the risk of pulmonary exacerbations. On the other hand, without chronic *P. aeruginosa* infection, azithromycin could reduce 50% of pulmonary exacerbations and improve weight, but without improvement of lung functions [65]. Azithromycin is recommended for CF treatment in patients suffering from chronic *P. aeruginosa* infection and those without chronic infection aged 6 years and older [66]. Despite the high durability of azithromycin, resistant bacteria are emerging, so the treatment should be reassessed every 6–12 months. Azithromycin is prohibited for patients with nontuberculous mycobacteria (NTM) unless it is prescribed in combination with other anti-mycobacterial medications as part of NTM therapy.

therefore avoid their deleterious action toward the passage airways [53, 54].

**Figure 1.**

#### *Microbial Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91628*

products such as proteases and elastases are released to react with anti-proteases and therefore avoid their deleterious action toward the passage airways [53, 54].

Some substances act as mediators of immune response and serve as important biomarkers of disease progression, such as neutrophil elastase, which is abundant in induced sputum in children with CF compared to control children [55]. High level of neutrophil elastase in induced sputum indicates lung dysfunctions and bronchiectasis [13]. The inflammation of the passage airways in sputum is reduced after detection and using of effective antibiotics for treatment of a CF-pulmonary diseases [56]. Inflammatory proteins are considered potential biomarkers of disease in CF. For example, the blood plasma proteins are biomarkers of CF disease [57].

The common example of immune response in CF lung disease is the immune response to *P. aeruginosa* [58]. CFTR dysfunction predisposes the host to infection with *P. aeruginosa* and then allows for chronic infection and subsequent reduced opportunity for eradication. Moreover, *P. aeruginosa* interacts with other bacterial pathogens including *S. aureus* and *B. cepacia* complex to alter the inflammatory response [59].

## **4. Anti-inflammatory therapy of CF**

## **4.1 Ibuprofen**

*Cystic Fibrosis - Facts, Management and Advances*

**56**

**Figure 2.**

**Figure 1.**

*Traditional pathophysiology of CF lung disease.*

out. Dehydration is carried out due to water loss, while acidification is carried out due to bicarbonate loss [50, 51]. The neutrophilic inflammatory response is higher in CF than in non-CF patients. However, the neutrophilic inflammatory response is reduced in neutrophil apoptosis. Neutrophils and their products are accumulated due to deficiency in mucociliary clearance and macrophage dysfunction [52]. The passage airways may destruct by the action of anti-proteases, such as alpha-1-antitrypsin, a serine protease inhibitor, and secretory leukocyte protease inhibitor. So, neutrophil

*Potential alternative mechanism for airway inflammation in CF lung disease.*

Ibuprofen inhibits neutrophil migration and aggregation [60]. It improves the lung functions especially in patients younger than 13 years. Gastrointestinal bleeding may be associated with chronic therapy. Recent studies report that high-dose ibuprofen could slow the progression of lung disease in CF, particularly in children with mild disease [61]. Despite the efficacy of ibuprofen for CF lung disease therapy, its use is uncommon compared to other CF therapies due to severe adverse effects such as kidney failure and gastric bleeding [62].

### **4.2 Azithromycin**

Azithromycin is a broad-spectrum antibiotic belonging to macrolide group, and at the same time, it has immunomodulatory effects, so it has high effectiveness in the treatment of CF lung disease and other chronic inflammatory conditions [63]. Azithromycin may be used for a very long period (chronic azithromycin) either with or without chronic *P. aeruginosa* infection [64]. With chronic *P. aeruginosa* infection, azithromycin is taken thrice weekly for 6 months to improve forced expiratory volume (FEV) and subsequently decrease the risk of pulmonary exacerbations. On the other hand, without chronic *P. aeruginosa* infection, azithromycin could reduce 50% of pulmonary exacerbations and improve weight, but without improvement of lung functions [65]. Azithromycin is recommended for CF treatment in patients suffering from chronic *P. aeruginosa* infection and those without chronic infection aged 6 years and older [66]. Despite the high durability of azithromycin, resistant bacteria are emerging, so the treatment should be reassessed every 6–12 months. Azithromycin is prohibited for patients with nontuberculous mycobacteria (NTM) unless it is prescribed in combination with other anti-mycobacterial medications as part of NTM therapy.

#### **4.3 Corticosteroids and leukotriene receptor antagonists**

Corticosteroids, especially its systemic forms, or cortisones are powerful anti-inflammatory agents which are widely used in the treatment of CF. Although systemic corticosteroids can intensively improve lung functions, they have adverse effects that outweigh any benefit [67]. Inhaled corticosteroids do not have any efficacy in the treatment of CF [68]. Therefore, the treatment of CF by systemic or inhaled corticosteroids is not recommended by the Cystic Fibrosis (CF) Foundation [66]. On the other hand, leukotriene receptor antagonists (LTRAs) are nonsteroidal oral medications, which are used as anti-inflammatory bronchoconstriction preventors. LTRAs block a chemical reaction that leads to inflammation in the airways. LTRAs are effective as antihistamines, and they are better than placebo, but less effective than nasal corticosteroids in improving symptoms and quality of life in patients with seasonal allergic rhinitis [69].

#### **5. Treatment management of CF**

CF carrier testing is recommended for everybody especially for Caucasian women whether they are considering pregnancy or already pregnant. CF-carrier test must be made before marriage, because the marriage of the positive CF-carriers leads offspring affected with CF, and vice versa. So, the early diagnosis of CF either before birth or for newborns allows for earlier and faster treatment in CF centers and avoidance of serious complications including poor growth. CF centers must be accredited by the CF Foundation. CF centers have multidisciplinary teams of physicians, nurses, respiratory therapists, dietitians, and social workers who can care for both adult and pediatric patients [70]. Good nutrition for affected persons with CF increases lung functions and life expectancy. Once CF disease is diagnosed, the patient must follow a nutrition program that is including a high-calorie diet, pancreatic enzymes and a liberal-fat. Essential vitamins must be supplemented to reduce the risk of deficiency of certain fat-soluble vitamins.

Although ill infants and young children with CF have intermittent cough and wheezing, structural and functional abnormalities in the lung as early as the first few months of life are detected. CF treatments include physical methods to eliminate thick secretions from the chest. CF treatments with chemical methods include prescription of different medications, such as dornase alfa and hypertonic saline as thinners of sticky airway secretions, albuterol as bronchodilator, tobramycin as inhaled antibiotic, and ibuprofen and azithromycin as anti-inflammatory drugs [71]. Preventive measures against CF or its complications necessarily require frequent follow-up for nutrition, lung functions, and screening for complications in an accredited CF center.

#### **6. Conclusion**

CF lung disease is one of the many causes of morbidity and mortality worldwide. CF lung disease has indefinite symptoms including airway obstruction, infection, and inflammation. This disease is associated with different microorganisms such as *P. aeruginosa*, *S. aureus*, and *B. cepacia* complex. Several medications are used as antimicrobial treatment for these pathogens. The airway microbiota is influenced by several factors including the environment, host, disease progression, and antibiotic treatment. Immune response to microbes in the CF airways is high due to dysfunction of CFTR protein. Although the recent therapies for airway infections and immune-inflammatory response are effective, they cannot fully stop disease progression. Today, CF lung disease has less risk because anti-inflammatory and antimicrobial therapies are in continuous development. Eventually, the authors recommend that, CF-carrier test must be made in particular before the marriage, early treatment of respiratory diseases especially if CF disease is diagnosed, avoidance of

**59**

*Microbial Cystic Fibrosis*

**Acknowledgements**

this work as best as possible.

**Conflict of interest**

**Notes**

**Author details**

Saudi Arabia

Waleed Mohamed Abdulkhair1

*DOI: http://dx.doi.org/10.5772/intechopen.91628*

control by a physician due to its severe adverse effects.

The authors declare no conflict of interest.

relatives marriage because it enhances an emergence of genetic diseases including CF, and finally, the treatment with corticosteroids (cortisone) must be under full

Authors sincerely thank National Organization for Drug Control and Research (NODCAR), Egypt, and Faculty of Science and Humanities, Shaqra University, Saudi Arabia for their support. Authors thank everybody aids in the introducing of

This chapter is concerned with CF-pulmonary diseases rather than other diseases of CF, because it is more widespread around the world and a common cause of morbidity and mortality especially in Caucasian areas as reported by the WHO.

\* and Mousa Abdullah Alghuthaymi2

1 General Department of Basic Medical Sciences, Microbiology Department, National Organization for Drug Control and Research (NODCAR), Giza, Egypt

\*Address all correspondence to: waleed\_hamada@yahoo.com

provided the original work is properly cited.

2 Biology Department, Science and Humanities College, Shaqra University, Shaqra,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Microbial Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91628*

relatives marriage because it enhances an emergence of genetic diseases including CF, and finally, the treatment with corticosteroids (cortisone) must be under full control by a physician due to its severe adverse effects.

## **Acknowledgements**

Authors sincerely thank National Organization for Drug Control and Research (NODCAR), Egypt, and Faculty of Science and Humanities, Shaqra University, Saudi Arabia for their support. Authors thank everybody aids in the introducing of this work as best as possible.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Notes**

*Cystic Fibrosis - Facts, Management and Advances*

patients with seasonal allergic rhinitis [69].

**5. Treatment management of CF**

an accredited CF center.

**6. Conclusion**

effects that outweigh any benefit [67]. Inhaled corticosteroids do not have any efficacy in the treatment of CF [68]. Therefore, the treatment of CF by systemic or inhaled corticosteroids is not recommended by the Cystic Fibrosis (CF) Foundation [66]. On the other hand, leukotriene receptor antagonists (LTRAs) are nonsteroidal oral medications, which are used as anti-inflammatory bronchoconstriction preventors. LTRAs block a chemical reaction that leads to inflammation in the airways. LTRAs are effective as antihistamines, and they are better than placebo, but less effective than nasal corticosteroids in improving symptoms and quality of life in

CF carrier testing is recommended for everybody especially for Caucasian women whether they are considering pregnancy or already pregnant. CF-carrier test must be made before marriage, because the marriage of the positive CF-carriers leads offspring affected with CF, and vice versa. So, the early diagnosis of CF either before birth or for newborns allows for earlier and faster treatment in CF centers and avoidance of serious complications including poor growth. CF centers must be accredited by the CF Foundation. CF centers have multidisciplinary teams of physicians, nurses, respiratory therapists, dietitians, and social workers who can care for both adult and pediatric patients [70]. Good nutrition for affected persons with CF increases lung functions and life expectancy. Once CF disease is diagnosed, the patient must follow a nutrition program that is including a high-calorie diet, pancreatic enzymes and a liberal-fat. Essential vitamins must be supplemented to

Although ill infants and young children with CF have intermittent cough and wheezing, structural and functional abnormalities in the lung as early as the first few months of life are detected. CF treatments include physical methods to eliminate thick secretions from the chest. CF treatments with chemical methods include prescription of different medications, such as dornase alfa and hypertonic saline as thinners of sticky airway secretions, albuterol as bronchodilator, tobramycin as inhaled antibiotic, and ibuprofen and azithromycin as anti-inflammatory drugs [71]. Preventive measures against CF or its complications necessarily require frequent follow-up for nutrition, lung functions, and screening for complications in

CF lung disease is one of the many causes of morbidity and mortality worldwide. CF lung disease has indefinite symptoms including airway obstruction, infection, and inflammation. This disease is associated with different microorganisms such as *P. aeruginosa*, *S. aureus*, and *B. cepacia* complex. Several medications are used as antimicrobial treatment for these pathogens. The airway microbiota is influenced by several factors including the environment, host, disease progression, and antibiotic treatment. Immune response to microbes in the CF airways is high due to dysfunction of CFTR protein. Although the recent therapies for airway infections and immune-inflammatory response are effective, they cannot fully stop disease progression. Today, CF lung disease has less risk because anti-inflammatory and antimicrobial therapies are in continuous development. Eventually, the authors recommend that, CF-carrier test must be made in particular before the marriage, early treatment of respiratory diseases especially if CF disease is diagnosed, avoidance of

reduce the risk of deficiency of certain fat-soluble vitamins.

**58**

This chapter is concerned with CF-pulmonary diseases rather than other diseases of CF, because it is more widespread around the world and a common cause of morbidity and mortality especially in Caucasian areas as reported by the WHO.

## **Author details**

Waleed Mohamed Abdulkhair1 \* and Mousa Abdullah Alghuthaymi2

1 General Department of Basic Medical Sciences, Microbiology Department, National Organization for Drug Control and Research (NODCAR), Giza, Egypt

2 Biology Department, Science and Humanities College, Shaqra University, Shaqra, Saudi Arabia

\*Address all correspondence to: waleed\_hamada@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[15] Hudson VL, Wielinski CL,

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Risk factors for lung function decline in a large cohort of young cystic fibrosis patients. Pediatric Pulmonology. 2015;**50**:763-770. DOI: 10.1002/ ppul.23217

[15] Hudson VL, Wielinski CL, Regelmann WE. Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years. The Journal of Pediatrics. 1993;**122**:854-860. DOI: 10.1016/S0022-3476(09)90007-5

[16] Mayer-Hamblett N, Aitken ML, Accurso FJ, Kronmal RA, Konstan MW, Burns JL, et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2007;**175**:822-828. DOI: 10.1164/rccm.200609-1354OC

[17] Ahlgren HG, Andrea B, Jennifer SL, Joanie B, Elias M, Danuta R, et al. Clinical outcomes associated with *Staphylococcus aureus* and *Pseudomonas aeruginosa* airway infections in adult cystic fibrosis patients. BMC Pulmonary Medicine. 2015;**15**:67. DOI: 10.1186/ s12890-015-0062-7

[18] Goss CH, Muhlebach MS. Review: *Staphylococcus aureus* and MRSA in cystic fibrosis. Journal of Cystic Fibrosis. 2011;**10**:298-306. DOI: 10.1016/j. jcf.2011.06.002

[19] Hoffman LR, Déziel E, D'Argenio DA, Lépine F, Emerson J, McNamara S, et al. Selection for *Staphylococcus aureus* small-colony variants due to growth in the presence of *Pseudomonas aeruginosa*. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**:19890-19895. DOI: 10.1073/ pnas.0606756104

[20] Ren CL, Morgan WJ, Konstan MW, Schechter MS, Wagener JS, Fisher KA, et al. Presence of methicillin resistant *Staphylococcus aureus* in respiratory

cultures from cystic fibrosis patients is associated with lower lung function. Pediatric Pulmonology. 2007;**42**:513- 518. DOI: 10.1002/ppul.20604

[21] Sawicki GS, Rasouliyan L, Pasta DJ, Regelmann WE, Wagener JS, Waltz DA, et al. The impact of incident methicillin resistant *Staphylococcus aureus* detection on pulmonary function in cystic fibrosis. Pediatric Pulmonology. 2008;**43**:1117-1123. DOI: 10.1002/ ppul.20914

[22] Muhlebach MS, Sonya LH, Elena BP, Melissa BM, Valeria T, Margaret K, et al. Multicenter observational study on factors and outcomes associated with different MRSA types in children with cystic fibrosis. Annals of the American Thoracic Society. 2015;**12**:864-871. DOI: 10.1513/AnnalsATS.201412-596OC

[23] Dasenbrook EC, Merlo CA, Diener-West M, Lechtzin N, Boyle MP. Persistent methicillin-resistant *Staphylococcus aureus* and rate of FEV decline in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2008;**178**:814-821. DOI: 10.1164/rccm.200802-327OC

[24] Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. American Journal of Respiratory and Critical Care Medicine. 2010;**182**:627-632. DOI: 10.1164/rccm.200909-1421OC

[25] Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillinresistant *Staphylococcus aureus* and survival in cystic fibrosis. Journal of the American Medical Association. 2010;**303**:2386-2392. DOI: 10.1001/ jama.2010.791

[26] Smyth AR, Walters S. Prophylactic anti-staphylococcal antibiotics for

**60**

*Cystic Fibrosis - Facts, Management and Advances*

[1] Andersen D. Cystic fibrosis of the pancreas and its relation to celiac disease: A clinical and pathological study. The American Journal of Diseases of Children. 1938;**56**:344-399. DOI: 10.1001/archpedi.1938.01980140114013

et al. Infection prevention and control guideline for cystic fibrosis: 2013 update. Infection Control and Hospital Epidemiology. 2014;**35**(Suppl 1):S1-S67.

[9] Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, et al. Effects of reduced mucus oxygen concentration in airway *Pseudomonas* infections of cystic fibrosis patients. The Journal of Clinical Investigation. 2002;**109**:317-325. DOI: 10.1172/

DOI: 10.1086/676882

[10] Singh PK, Schaefer AL,

10.1038/35037627

cir399

Parsek MR, Moninger TO, Welsh MJ, Greenberg EP. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature. 2000;**407**:762-764. DOI:

[11] Sagel SD, Ronald LG, Julia E, Sharon M, Jane LB, Jeffrey SW, et al.

inflammation and clinical status in young children with cystic fibrosis. The Journal of Pediatrics. 2009;**154**:183-188. DOI: 10.1016/j.jpeds.2008.08.001

[13] Pillarisetti N, Williamson E, Linnane B, Skoric B, Robertson CF,

[14] Cogen J, Emerson J, Sanders DB, Ren C, Schechter MS, Gibson RL, et al.

Robinson P, et al. Infection, inflammation, and lung function decline in infants with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2011;**184**:75-81. DOI: 10.1164/rccm.201011-1892OC

[12] Gangell C, Gard S, Douglas T, Park J, de Klerk N, Keil T, et al. Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clinical Infectious Diseases. 2011;**53**:425-432. DOI: 10.1093/cid/

Impact of *Pseudomonas* and *Staphylococcus* infection on

JCI13870

[2] Di Sant'agnese PEA, Andersen DH. Celiac syndrome; chemotherapy in infections of the respiratory tract associated with cystic fibrosis of the pancreas; observations with penicillin and drugs of the sulfonamide group, with special reference to penicillin aerosol. American Journal of Diseases of

Children. 1946;**72**:17-61

cmr.15.2.194-222.2002

ajrccm/151.4.1075

ppul.21090

s40064-016-2338-7

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[8] Saiman L, Siegel JD, LiPuma JJ, Brown RF, Bryson EA, Chambers MJ,

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ajrccm.160.1.9808096

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[40] Regan KH, Bhatt J. Eradication therapy for *Burkholderia cepacia* complex in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2014;**24**:CD009876. DOI: 10.1002/14651858.CD009876.pub2

[41] Avgeri SG, Matthaiou DK, Dimopoulos G, Grammatikos AP, Falagas ME. Therapeutic options for *Burkholderia cepacia* infections beyond co-trimoxazole: A systematic review of the clinical evidence. International Journal of Antimicrobial Agents. 2009;**33**:394-404. DOI: 10.1016/j.

ijantimicag.2008.09.010

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resistant *Staphylococcus aureus*, gram-negative bacteria, and multiple infections. Annals of the American Thoracic Society. 2014;**11**:1120-1129. DOI: 10.1513/AnnalsATS.201402-050AS

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2005;**11**:528-533. DOI: 10.1097/01.

[39] Horsley A, Webb K, Bright-

mcp.0000181475.85187.ed

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2005;**11**:528-533. DOI: 10.1097/01. mcp.0000181475.85187.ed

*Cystic Fibrosis - Facts, Management and Advances*

American Journal of Respiratory and Critical Care Medicine. 2014;**190**:289- 297. DOI: 10.1164/rccm.201404-0681OC

[33] Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, et al. Longitudinal development of mucoid *Pseudomonas aeruginosa* infection and lung disease progression in children with cystic fibrosis. Journal of the American Medical Association. 2005;**293**:581-588. DOI: 10.1001/

[34] Oliver A, Mulet X, Lõpez-Causapé C, Juan C. The increasing threat of *Pseudomonas aeruginosa* high-risk clones. Drug Resistance Updates. 2015;**22**:41-59. DOI: 10.1016/j.

[35] Mogayzel PJ, Naureckas ET, Robinson KA, Brady C, Guill M,

approaches to prevention and eradication of initial *Pseudomonas aeruginosa* infection. Annals of the American Thoracic Society. 2014;**11**:1640-1650. DOI: 10.1513/ AnnalsATS.201404-166OC

[36] Merlo CA, Boyle MP,

10.1378/chest.06-2888

[37] Zlosnik JEA, Zhou G, Brant R, Henry DA, Hird TJ,

AnnalsATS.201408-395OC

[38] Lipuma JJ. Update on the

*Burkholderia cepacia* complex. Current Opinion in Pulmonary Medicine.

Lahiri T, et al. Cystic fibrosis foundation pulmonary guideline. Pharmacologic

Diener-West M, Marshall BC, Goss CH, Lechtzin N. Incidence and risk factors for multiple antibiotic-resistant *Pseudomonas aeruginosa* in cystic fibrosis. Chest. 2007;**132**:562-568. DOI:

Mahenthiralingam E, et al. *Burkholderia* species infections in patients with cystic fibrosis in British Columbia, Canada. 30 years' experience. Annals of the American Thoracic Society. 2015;**12**:70-78. DOI: 10.1513/

jama.293.5.581

drup.2015.08.002

cystic fibrosis. Cochrane Database of Systematic Reviews. 2014;**11**:CD001912. DOI: 10.1002/14651858.CD001912.pub2

Muhlebach MS, Smyth AR. Interventions

(MRSA) in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2015;**2**:CD009650. DOI: 10.1002/14651858.CD009650.pub2

for the eradication of methicillinresistant *Staphylococcus aureus*

[28] Gilligan PH. Microbiology of airway disease in patients with cystic fibrosis. Clinical Microbiology Reviews. 1991;**4**:35-51. DOI: 10.1128/cmr.4.1.35

Smyth AR. Antibiotic strategies for eradicating *Pseudomonas aeruginosa* in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2009;**7**:CD004197. DOI: 10.1002/14651858.CD004197.pub3

[30] Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum *Pseudomonas aeruginosa* density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. The American Review of Respiratory Disease. 1990;**141**:914-921. DOI: 10.1164/

ajrccm/141.4\_Pt\_1.914

Rosenfeld M, Gibson RL,

[32] Mayer-Hamblett N,

[31] Mayer-Hamblett N, Kloster M,

Retsch-Bogart GZ, Emerson J, et al. Impact of sustained eradication of new *Pseudomonas aeruginosa* infection on long-term outcomes in cystic fibrosis. Clinical Infectious Diseases. 2015;**61**:707-715. DOI: 10.1093/cid/

Rosenfeld M, Gibson RL, Ramsey BW, Kulasekara HD, Retsch-Bogart GZ, et al. *Pseudomonas aeruginosa in vitro* phenotypes distinguish cystic fibrosis infection stages and outcomes.

[29] Langton-Hewer SC,

[27] Lo DKH, Hurley MN,

**62**

civ377

[39] Horsley A, Webb K, Bright-Thomas R, Govan J, Jones A. Can early *Burkholderia cepacia* complex infection in cystic fibrosis be eradicated with antibiotic therapy? Frontiers in Cellular and Infection Microbiology. 2011;**1**:18. DOI: 10.3389/fcimb.2011.00018

[40] Regan KH, Bhatt J. Eradication therapy for *Burkholderia cepacia* complex in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2014;**24**:CD009876. DOI: 10.1002/14651858.CD009876.pub2

[41] Avgeri SG, Matthaiou DK, Dimopoulos G, Grammatikos AP, Falagas ME. Therapeutic options for *Burkholderia cepacia* infections beyond co-trimoxazole: A systematic review of the clinical evidence. International Journal of Antimicrobial Agents. 2009;**33**:394-404. DOI: 10.1016/j. ijantimicag.2008.09.010

[42] Parkins MD, Floto RA. Emerging bacterial pathogens and changing concepts of bacterial pathogenesis in cystic fibrosis. Journal of Cystic Fibrosis. 2015;**14**:293-304. DOI: 10.1016/j. jcf.2015.03.012

[43] Lipuma JJ. The changing microbial epidemiology in cystic fibrosis. Clinical Microbiology Reviews. 2010;**23**:299-323. DOI: 10.1128/CMR.00068-09

[44] Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS, LiPuma JJ, et al. Antibiotic management of lung infections in cystic fibrosis. I. the microbiome, methicillinresistant *Staphylococcus aureus*, gram-negative bacteria, and multiple infections. Annals of the American Thoracic Society. 2014;**11**:1120-1129. DOI: 10.1513/AnnalsATS.201402-050AS

[45] Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS, LiPuma JJ, et al. Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi. Annals of the American Thoracic Society. 2014;**11**:1298-1306. DOI: 10.1513/AnnalsATS.201405-203AS

[46] Caverly LJ, Zhao J, LiPuma JJ. Cystic fibrosis lung microbiome: Opportunities to reconsider management of airway infection: Cystic fibrosis lung microbiome. Pediatric Pulmonology. 2015;**50**:S31-S38. DOI: 10.1002/ ppul.23243

[47] Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2003;**168**:918- 951. DOI: 10.1164/rccm.200304-505SO

[48] Muhlebach MS, Stewart PW, Leigh MW, Noah TL. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. American Journal of Respiratory and Critical Care Medicine. 1999;**160**:186-191. DOI: 10.1164/ ajrccm.160.1.9808096

[49] Noah TL, Black HR, Cheng PW, Wood RE, Leigh MW. Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. The Journal of Infectious Diseases. 1997;**175**:638-647. DOI: 10.1093/infdis/175.3.638

[50] Boucher RC. Airway surface dehydration in cystic fibrosis: Pathogenesis and therapy. Annual Review of Medicine. 2007;**58**:157- 170. DOI: 10.1146/annurev. med.58.071905.105316

[51] Pezzulo AA, Tang XX, Hoegger MJ, Abou Alaiwa MH, Ramachandran S, Moninger TO, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012;**487**:109-113. DOI: 10.1038/ nature11130

[52] Alexis NE, Muhlebach MS, Peden DB, Noah TL. Attenuation of host defense function of lung phagocytes in young cystic fibrosis patients. Journal of Cystic Fibrosis. 2006;**5**:17-25. DOI: 10.1016/j.jcf.2005.11.001

[53] Birrer P, McElvaney NG, Rüdeberg A, Sommer CW, Liechti-Gallati S, Kraemer R, et al. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 1994;**150**:207- 213. DOI: 10.1164/ajrccm.150.1.7912987

[54] Weldon S, McNally P, McElvaney NG, Elborn JS, McAuley DF, Wartelle J, et al. Decreased levels of secretory leucoprotease inhibitor in the *Pseudomonas*-infected cystic fibrosis lung are due to neutrophil elastase degradation. Journal of Immunology. 2009;**183**:8148-8156. DOI: 10.4049/ jimmunol.0901716

[55] Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. American Journal of Respiratory and Critical Care Medicine. 2001;**164**:1425-1431. DOI: 10.1164/ rccm2104075

[56] Ordonez CL, Henig NR, Mayer-Hamblett N, Accurso FJ, Burns JL, Chmiel JF, et al. Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2003;**168**:1471-1475. DOI: 10.1164/ rccm.200306-731OC

[57] Sagel SD, Thompson V, Chmiel JF, Montgomery GS, Nasr SZ, Perkett E, et al. Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation. Annals of the American Thoracic Society. 2015;**12**:708-717. DOI: 10.1513/ AnnalsATS.201410-493OC

[58] Lovewell RR, Patankar YR, Berwin B. Mechanisms of phagocytosis and host clearance of *Pseudomonas aeruginosa*. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2014;**306**:L591-L603. DOI: 10.1152/ajplung.00335.2013

[59] Chattoraj SS, Murthy R, Ganesan S, Goldberg JB, Zhao Y, Hershenson MB, et al. *Pseudomonas aeruginosa* alginate promotes *Burkholderia cenocepacia* persistence in cystic fibrosis transmembrane conductance regulator knockout mice. Infection and Immunity. 2010;**78**:984-993. DOI: 10.1128/ IAI.01192-09

[60] Konstan MW, Vargo KM, Davis PB. Ibuprofen attenuates the inflammatory response to *Pseudomonas aeruginosa* in a rat model of chronic pulmonary infection. Implications for antiinflammatory therapy in cystic fibrosis. The American Review of Respiratory Disease. 1990;**141**:186-192. DOI: 10.1164/ajrccm/141.1.186

[61] Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database of Systematic Reviews. 2013;**6**:CD001505. DOI: 10.1002/14651858.CD001505. pub2

[62] Konstan MW, VanDevanter DR, Lawrence R, David JP, Ashley Y, Wayne JM, et al. Trends in the use of routine therapies in cystic fibrosis: 1995-2005. Pediatric Pulmonology. 2010;**45**:1167-1172. DOI: 10.1002/ ppul.21315

[63] Zarogoulidis P, Papanas N, Kioumis I, Chatzaki E, Maltezos E, Zarogoulidis K. Macrolides: From *in vitro* anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. European Journal of Clinical Pharmacology. 2012;**68**:479-503. DOI: 10.1007/s00228-011-1161-x

**65**

*Microbial Cystic Fibrosis*

[64] Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with *Pseudomonas aeruginosa*: A randomized controlled trial. Journal of the American Medical Association. 2003;**290**:1749- 1756. DOI: 10.1001/jama.290.13.1749

[65] Saiman L, Anstead M, Mayer-

Kloster M, Hocevar-Trnka J, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with *Pseudomonas aeruginosa*: A randomized controlled trial. Journal of the American Medical Association. 2010;**303**:1707-1715. DOI: 10.1001/

[66] Mogayzel PJ, Edward TN, Karen AR, Gary M, Denis H, Jeffrey BH, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. American Journal of Respiratory and Critical Care Medicine.

2013;**187**:680-689. DOI: 10.1164/

[68] Balfour-Lynn IM, Welch K. Inhaled corticosteroids for cystic fibrosis. Cochrane Database of Systematic Reviews. 2014;**10**:CD001915. DOI: 10.1002/14651858.CD001915.pub5

[69] Stelmach I, Korzeniewska A, Stelmach W, Majak P, Grzelewski T, Jerzynska J. Effects of montelukast treatment on clinical and inflammatory

variables in patients with cystic fibrosis. Annals of Allergy, Asthma & Immunology. 2005;**95**:372-380. DOI: 10.1016/S1081-1206(10)61156-8

[67] Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation prednisone trial group. The Journal of Pediatrics. 1995;**126**:515-523. DOI: 10.1016/s0022-3476(95)70343-8

rccm.201207-1160OE

Hamblett N, Lands LC,

jama.2010.563

*DOI: http://dx.doi.org/10.5772/intechopen.91628*

[70] Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. The Journal of Pediatrics. 2008;**153**:S4-S14. DOI: 10.1016/j.jpeds.2008.05.005

[71] Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: Chronic medications for maintenance of lung health. American Journal of Respiratory and Critical Care Medicine.

2007;**176**:957-969. DOI: 10.1164/

rccm.200705-664OC

*Microbial Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.91628*

*Cystic Fibrosis - Facts, Management and Advances*

Peden DB, Noah TL. Attenuation of host defense function of lung phagocytes in young cystic fibrosis patients. Journal of Cystic Fibrosis. 2006;**5**:17-25. DOI:

[58] Lovewell RR, Patankar YR,

10.1152/ajplung.00335.2013

Berwin B. Mechanisms of phagocytosis and host clearance of *Pseudomonas aeruginosa*. American Journal of

Physiology. Lung Cellular and Molecular Physiology. 2014;**306**:L591-L603. DOI:

[59] Chattoraj SS, Murthy R, Ganesan S, Goldberg JB, Zhao Y, Hershenson MB, et al. *Pseudomonas aeruginosa* alginate promotes *Burkholderia cenocepacia* persistence in cystic fibrosis

transmembrane conductance regulator knockout mice. Infection and Immunity.

2010;**78**:984-993. DOI: 10.1128/

[60] Konstan MW, Vargo KM, Davis PB. Ibuprofen attenuates the inflammatory response to *Pseudomonas aeruginosa* in a rat model of chronic pulmonary infection. Implications for antiinflammatory therapy in cystic fibrosis. The American Review of Respiratory Disease. 1990;**141**:186-192.

DOI: 10.1164/ajrccm/141.1.186

[61] Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database of Systematic Reviews. 2013;**6**:CD001505. DOI: 10.1002/14651858.CD001505.

[62] Konstan MW, VanDevanter DR, Lawrence R, David JP, Ashley Y, Wayne JM, et al. Trends in the use of routine therapies in cystic fibrosis: 1995-2005. Pediatric Pulmonology. 2010;**45**:1167-1172. DOI: 10.1002/

[63] Zarogoulidis P, Papanas N,

From *in vitro* anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. European Journal of Clinical Pharmacology. 2012;**68**:479-503. DOI:

10.1007/s00228-011-1161-x

Maltezos E, Zarogoulidis K. Macrolides:

Kioumis I, Chatzaki E,

IAI.01192-09

pub2

ppul.21315

[52] Alexis NE, Muhlebach MS,

10.1016/j.jcf.2005.11.001

[53] Birrer P, McElvaney NG, Rüdeberg A, Sommer CW,

[54] Weldon S, McNally P,

jimmunol.0901716

rccm2104075

Liechti-Gallati S, Kraemer R, et al. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 1994;**150**:207- 213. DOI: 10.1164/ajrccm.150.1.7912987

McElvaney NG, Elborn JS, McAuley DF, Wartelle J, et al. Decreased levels of secretory leucoprotease inhibitor in the *Pseudomonas*-infected cystic fibrosis lung are due to neutrophil elastase degradation. Journal of Immunology. 2009;**183**:8148-8156. DOI: 10.4049/

[55] Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. American Journal of Respiratory and Critical Care Medicine. 2001;**164**:1425-1431. DOI: 10.1164/

[56] Ordonez CL, Henig NR, Mayer-Hamblett N, Accurso FJ,

rccm.200306-731OC

[57] Sagel SD, Thompson V,

Chmiel JF, Montgomery GS, Nasr SZ, Perkett E, et al. Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation. Annals of the American Thoracic Society. 2015;**12**:708-717. DOI: 10.1513/ AnnalsATS.201410-493OC

Burns JL, Chmiel JF, et al. Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2003;**168**:1471-1475. DOI: 10.1164/

**64**

[64] Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with *Pseudomonas aeruginosa*: A randomized controlled trial. Journal of the American Medical Association. 2003;**290**:1749- 1756. DOI: 10.1001/jama.290.13.1749

[65] Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with *Pseudomonas aeruginosa*: A randomized controlled trial. Journal of the American Medical Association. 2010;**303**:1707-1715. DOI: 10.1001/ jama.2010.563

[66] Mogayzel PJ, Edward TN, Karen AR, Gary M, Denis H, Jeffrey BH, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. American Journal of Respiratory and Critical Care Medicine. 2013;**187**:680-689. DOI: 10.1164/ rccm.201207-1160OE

[67] Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation prednisone trial group. The Journal of Pediatrics. 1995;**126**:515-523. DOI: 10.1016/s0022-3476(95)70343-8

[68] Balfour-Lynn IM, Welch K. Inhaled corticosteroids for cystic fibrosis. Cochrane Database of Systematic Reviews. 2014;**10**:CD001915. DOI: 10.1002/14651858.CD001915.pub5

[69] Stelmach I, Korzeniewska A, Stelmach W, Majak P, Grzelewski T, Jerzynska J. Effects of montelukast treatment on clinical and inflammatory variables in patients with cystic fibrosis. Annals of Allergy, Asthma & Immunology. 2005;**95**:372-380. DOI: 10.1016/S1081-1206(10)61156-8

[70] Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. The Journal of Pediatrics. 2008;**153**:S4-S14. DOI: 10.1016/j.jpeds.2008.05.005

[71] Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: Chronic medications for maintenance of lung health. American Journal of Respiratory and Critical Care Medicine. 2007;**176**:957-969. DOI: 10.1164/ rccm.200705-664OC

**67**

**Chapter 5**

**Abstract**

Lung Transplantation in Patients

Cystic fibrosis (CF) is one of the most common indications for lung transplant (LTx) and nearly one-third of the LTx worldwide are performed in people with CF (PwCF). Due to vast developments in diagnostic modalities, antibiotic therapies, and management of associated comorbidities in dedicated and experienced centres, over the past few decades, more PwCF are reaching adulthood than ever before. This has increased the burden on transplant programs particularly in a universal donor shortage scenario. To improve the donor pool a diligent and proactive donor care management, acceptance of marginal organs and utilisation of ex-vivo lung perfusion systems for organ preservation, assessment, and improvement is being advocated widely. LTx is not a readily available therapy and the average waiting time is 18 months in the UK. Therefore, it is essential that PwCF are referred for LTx assessment when their disease is stable, before respiratory deterioration leads to overall deconditioning of the patients. Once listed for LTx, it is crucial to control waiting list mortality by prioritising rapidly deteriorating patients through schemes like the lung allocation score, national urgent and super-urgent waiting lists, and institutional highlighting of deteriorating patients that do not meet other urgent criteria. LTx in PwCF is challenging due to colonisation of the respiratory tract with multi-drug resistant organisms, associated comorbidities such as diabetes, liver disease, gastro-oesophageal reflux, and distal intestinal obstruction syndrome (DIOS) and CF-specific technical difficulties (adhesions due to prior pneumothoraces or pleurodesis, or bronchial collaterals that increase surgical time). Hilar lymphadenopathy and bronchial collaterals may increase surgical time, organ ischemia time, intra and post-operative bleeding, and blood transfusions. Advances in immunosuppression, prophylactic anti-viral and anti-fungal therapies, early ambulation and rigorous physiotherapy, and meticulous postoperative follow up with spirometry, x-rays, and bronchoscopies to detect rejection at the early stage followed by its efficient treatment have helped to improve post-LTx survival in the CF patients. Constant development in the surgical field with adoption of off-pump transplantation, sternal sparing bilateral thoracotomy approach, and utilisation of mechanical circulatory assist as a bridge to transplant and as a support for primary graft failure strives for better outcomes. However, chronic lung allograft dysfunction, chronic refractory infections, malignancies, and CF associated comorbidities remain major determinants of post-LTx long term survival. Despite this, CF patients are often good candidates for re-do LTx with improving survival outcomes. In this chapter, we are compiling the different aspects of LTx in PwCF emphasising the advances

with Cystic Fibrosis

*and André R. Simon*

*Prashant N. Mohite, Kavita Dave, Anna Reed* 

## **Chapter 5**

## Lung Transplantation in Patients with Cystic Fibrosis

*Prashant N. Mohite, Kavita Dave, Anna Reed and André R. Simon*

### **Abstract**

Cystic fibrosis (CF) is one of the most common indications for lung transplant (LTx) and nearly one-third of the LTx worldwide are performed in people with CF (PwCF). Due to vast developments in diagnostic modalities, antibiotic therapies, and management of associated comorbidities in dedicated and experienced centres, over the past few decades, more PwCF are reaching adulthood than ever before. This has increased the burden on transplant programs particularly in a universal donor shortage scenario. To improve the donor pool a diligent and proactive donor care management, acceptance of marginal organs and utilisation of ex-vivo lung perfusion systems for organ preservation, assessment, and improvement is being advocated widely. LTx is not a readily available therapy and the average waiting time is 18 months in the UK. Therefore, it is essential that PwCF are referred for LTx assessment when their disease is stable, before respiratory deterioration leads to overall deconditioning of the patients. Once listed for LTx, it is crucial to control waiting list mortality by prioritising rapidly deteriorating patients through schemes like the lung allocation score, national urgent and super-urgent waiting lists, and institutional highlighting of deteriorating patients that do not meet other urgent criteria. LTx in PwCF is challenging due to colonisation of the respiratory tract with multi-drug resistant organisms, associated comorbidities such as diabetes, liver disease, gastro-oesophageal reflux, and distal intestinal obstruction syndrome (DIOS) and CF-specific technical difficulties (adhesions due to prior pneumothoraces or pleurodesis, or bronchial collaterals that increase surgical time). Hilar lymphadenopathy and bronchial collaterals may increase surgical time, organ ischemia time, intra and post-operative bleeding, and blood transfusions. Advances in immunosuppression, prophylactic anti-viral and anti-fungal therapies, early ambulation and rigorous physiotherapy, and meticulous postoperative follow up with spirometry, x-rays, and bronchoscopies to detect rejection at the early stage followed by its efficient treatment have helped to improve post-LTx survival in the CF patients. Constant development in the surgical field with adoption of off-pump transplantation, sternal sparing bilateral thoracotomy approach, and utilisation of mechanical circulatory assist as a bridge to transplant and as a support for primary graft failure strives for better outcomes. However, chronic lung allograft dysfunction, chronic refractory infections, malignancies, and CF associated comorbidities remain major determinants of post-LTx long term survival. Despite this, CF patients are often good candidates for re-do LTx with improving survival outcomes. In this chapter, we are compiling the different aspects of LTx in PwCF emphasising the advances

in bridge to transplantation, the surgical approach, management of primary graft failure, and immunosuppression as well as complications post-transplant.

**Keywords:** cystic fibrosis, lung transplantation, advances, minimally invasive lung transplantation, off pump lung transplantation

## **1. Introduction**

While it took years following the first human LTx in 1963 for this procedure to become a gold standard therapy in the management of end-stage lung disease, the procedure took off in the 80s following the introduction of Cyclosporin in medical practice. The first transplant in a patient with CF was a heart-lung transplant performed by Magdi Yacoub in Harefield Hospital in the United Kingdom [1]. Since then, nearly ten thousand patients with CF have undergone LTx worldwide [2]. According to the 36th adult lung and heart-lung transplant report comprising more than 69000 adult LTx in the ISHLT registry, 15.2% of all adult LTx were performed in PwCF [2]. Although the number of transplants performed for each indication has increased ever since, the proportion of patients transplanted for CF continues to fall, now accounting for 13% of total adult lung transplants, compared with over 15% five years ago [2, 3]. With constant improvement in knowledge, better management of infective exacerbations, developments in the field of antimicrobials and breakthrough modulator therapy for PwCF, survival has improved in CF patients significantly [4–6]. However, this may have led not only to increasing numbers of PwCF meeting criteria for LTx but unfortunately, also to delayed referrals, referral of sicker patients with comorbidities, and patients with complex colonisations of multi-drug resistant organisms. Despite this, with 9.9 years of median survival and 12.4 years of conditional survival in patients that survive beyond the first year, PwCF demonstrate the best survival compared to any other indication for LTx [2]. Moreover, survival in ISHLT registry (1992 to 2017) stratified in 3 eras show a significant improvement in the survival of PwCF in the recent era when compared with other indications for LTx [2]. This is mainly due to the younger age and good other end-organ function of these patients at the time of transplantation. On the other hand, CF patients when compared to other indications for LTx pose a set of exclusive challenges. Familiarity, experience and expertise of the transplant team to deal with these problems make a significant difference in the outcomes.

## **2. Patient selection**

#### **2.1 Indications and contraindications of LTx in CF**

With a scarcity of donor organs and higher mortality in LTx recipients compared to other organs, health economics would support offering a limited supply of donor organs to recipients expected to benefit the most. However, the onus to identify such recipients falls upon timely referral and listing of the candidates for potential LTx. A clinical window where the patient is symptomatic enough to require LTx but strong enough to survive the operative trauma varies with the individual patient. Generally, when the FEV1 in PwCF drops below 30%, their expected median survival is around 2 years [7]. However, FEV1 is not a reliable indicator of survival as many with CF with longstanding low lung function may survive without transplantation. Currently though, in the absence of a better option, it remains the best available indicator for referral and listing purposes. Inadequacy of clinical parameters to sufficiently

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*Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

considering referral to a transplant centre.

**2.2 Criteria for referral and listing**

**2.3 Pre-operative work-up**

patient going to survive the transplant?

into the contraindications for LTx (**Table 1**) [12].

predict survival in CF patients raise a need for mortality prediction models. One of the first such comprehensive models recognised age, respiratory microbiology, height, FEV1, annual number of hospital admissions and courses of home intravenous antibiotics as the most important predictors of 2-year mortality [8]. However, the authors also admit that their model is no better than the widely used FEV1 < 30% predicted. Thus, referral of patients for transplant based either on their model probability of dying within 2 years or on an FEV1 of less than 30% predicted could result in a high rate of premature referral, as a substantial proportion of patients predicted to die within 2 years based on these criteria would survive this period. Therefore, it is wise to take into consideration risk factors associated with early mortality in PwCF when shortlisting them for LTx. One of the biggest CF databases, the UK CF Registry reviewed records from 2005 to 2015 on 6181 individuals, and acknowledged strong associations of *Burkholderia cepacia* infection, CF-related diabetes, and more hospital days on IV antibiotics with decreasing survival [9]. A Canadian CF registry analysis identified older age at diagnosis, diabetes, and deteriorating FEV1 as predictors of reduced survival [10] whilst a recent meta-analysis based upon 11 studies identified *Burkholderia cenocepacia* and ascending chronological year of LTx as predictors of post-LTx mortality [11]. Referring physicians whilst focusing on the FEV1, should also pay special attention to these risk factors for poor survival when

Contraindications of LTx in the CF are similar to other end-stage lung disease causes and are broadly divided into absolute and relative contraindications. A consensus document for the selection of LTx candidates offers a thorough review

Early or sometimes premature referral of PwCF to transplant centres offers patients a chance of early transplant assessment to maximise their window of opportunity for donor offers and a LTx. Additionally, early referral has the potential to identify modifiable contraindications to LTx or risk factors of transplant mortality allowing these to be treated and optimised before requiring listing. A delayed referral carries a risk of insufficient time to wait and less number of donor offers to the referred patients. Candidates may miss their window of opportunity and be removed from the waiting list due to clinical deterioration or worse. An ideal time of listing any candidate for LTx is when the benefits from the procedure balance its risk. It is not unusual practice at transplant centres to send patients back to the referring physicians for not meeting the criteria of listing post-assessment but identifying them as future candidates. A 2006 ISHLT update for selection of transplant candidates for the first time separated referral and listing criteria emphasising a timely referral of the end-stage lung disease candidate to transplantation centres

[13]. These were revised in a 2014 update as summarised in **Table 2** [14].

Transplant teams while assessing referred CF patients for LTx should ask two vital questions- (i) Is a transplant required- in other words, is the transplant going to improve survival and quality of life? (ii) Is the patient transplantable? – i.e. is the

Transplant evaluation requires a medical assessment, psychological assessment, and in some countries, financial assessment. The medical assessment requires an admission for 2–3 days so that a patient can have multiple investigations and be reviewed by the multi-disciplinary team (MDT) (**Table 3**) [15]. Additional investigations that may be

#### *Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

predict survival in CF patients raise a need for mortality prediction models. One of the first such comprehensive models recognised age, respiratory microbiology, height, FEV1, annual number of hospital admissions and courses of home intravenous antibiotics as the most important predictors of 2-year mortality [8]. However, the authors also admit that their model is no better than the widely used FEV1 < 30% predicted. Thus, referral of patients for transplant based either on their model probability of dying within 2 years or on an FEV1 of less than 30% predicted could result in a high rate of premature referral, as a substantial proportion of patients predicted to die within 2 years based on these criteria would survive this period. Therefore, it is wise to take into consideration risk factors associated with early mortality in PwCF when shortlisting them for LTx. One of the biggest CF databases, the UK CF Registry reviewed records from 2005 to 2015 on 6181 individuals, and acknowledged strong associations of *Burkholderia cepacia* infection, CF-related diabetes, and more hospital days on IV antibiotics with decreasing survival [9]. A Canadian CF registry analysis identified older age at diagnosis, diabetes, and deteriorating FEV1 as predictors of reduced survival [10] whilst a recent meta-analysis based upon 11 studies identified *Burkholderia cenocepacia* and ascending chronological year of LTx as predictors of post-LTx mortality [11]. Referring physicians whilst focusing on the FEV1, should also pay special attention to these risk factors for poor survival when considering referral to a transplant centre.

Contraindications of LTx in the CF are similar to other end-stage lung disease causes and are broadly divided into absolute and relative contraindications. A consensus document for the selection of LTx candidates offers a thorough review into the contraindications for LTx (**Table 1**) [12].

#### **2.2 Criteria for referral and listing**

Early or sometimes premature referral of PwCF to transplant centres offers patients a chance of early transplant assessment to maximise their window of opportunity for donor offers and a LTx. Additionally, early referral has the potential to identify modifiable contraindications to LTx or risk factors of transplant mortality allowing these to be treated and optimised before requiring listing. A delayed referral carries a risk of insufficient time to wait and less number of donor offers to the referred patients. Candidates may miss their window of opportunity and be removed from the waiting list due to clinical deterioration or worse. An ideal time of listing any candidate for LTx is when the benefits from the procedure balance its risk. It is not unusual practice at transplant centres to send patients back to the referring physicians for not meeting the criteria of listing post-assessment but identifying them as future candidates. A 2006 ISHLT update for selection of transplant candidates for the first time separated referral and listing criteria emphasising a timely referral of the end-stage lung disease candidate to transplantation centres [13]. These were revised in a 2014 update as summarised in **Table 2** [14].

#### **2.3 Pre-operative work-up**

Transplant teams while assessing referred CF patients for LTx should ask two vital questions- (i) Is a transplant required- in other words, is the transplant going to improve survival and quality of life? (ii) Is the patient transplantable? – i.e. is the patient going to survive the transplant?

Transplant evaluation requires a medical assessment, psychological assessment, and in some countries, financial assessment. The medical assessment requires an admission for 2–3 days so that a patient can have multiple investigations and be reviewed by the multi-disciplinary team (MDT) (**Table 3**) [15]. Additional investigations that may be


#### **Table 1.**

*Absolute and relative contraindications for LTx in CF.*

required include CT coronary angiogram (CTCA) in PwCF aged over 40 years or right heart catheterisation in severe pulmonary hypertension. All referrals require a dental assessment before listing, but PwCF may require assessment by ENT or gastroenterology doctors in addition. Psychology, palliative care and physiotherapy review during their assessment provides insight on a patient's suitability to undergo transplantation, and social support is also explored during this time. In some countries, financial evaluation is necessary to ensure a potential recipient can afford the immediate transplant care, lifelong aftercare and medications, and management of complications. Following this period of assessment, patients are subsequently discussed at MDT meetings, which include respiratory physicians, transplant surgeons, psychologists, immunologists, radiologists, dietitans and physiotherapists. After discussion, outcomes for each patient

**71**

or deferral as too well.

**2.4 Waiting list**

**Table 2.**

*Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

FEV1 < 30% pred or falling rapidly despite optimal therapy

Pulmonary hypertension in absence of hypoxic exacerbation

(iii) Worsening nutritional status despite supplementation

(v) Life threatening hemoptysis despite bronchial embolization

Chronic respiratory failure with hypoxia alone (PaO2 < 8 kPa) Chronic respiratory failure with hypercapnia (PaCO2 > 6.6 kPa)

*Timing of referral and timing of listing for LTx in CF patients.*

(ii) Increasing antibiotic resistance and poor clinical recovery from exacerbations

Clinical decline- increasing exacerbations with -

**Timing of referral**

(iv) Pneumothorax

**Timing of listing**

Long-term NIV

Pulmonary hypertension Frequent hospitalisation Rapid lung function decline WHO Functional Class IV

A 6-minute walk distance <400 m

(i) Acute resp. failure requiring NIV

include decision for active listing, further information required, rejection as unsuitable,

The time spent by potential recipients on the LTx waiting list depends on various factors including blood group, HLA antibody status and the size of pleural cavities. Whilst on the waiting list, patients are encouraged to exercise regularly, achieve or maintain a healthy BMI, avoid frequent infective exacerbations, and inform any changes in circumstances urgently. Transplant coordinators maintain contact with patients on the waiting list, update records, educate patients and communicate between all members of the transplant team. Traditionally, organ offering systems take into account time spent on the waiting list and the clinical status of the candidates, but influenced by the urgency of transplantation. With this freedom of recipient selection to the transplant centres, fairness in the distribution of the donor organs to the most worthy recipients may be jeopardised. A study looking into 2213 lung-only registrations into the UK Transplant Registry between 2004 and 2014 showed discrepancies between the risk profile and probability of LTx. The chance of LTx after listing differed by the combined effect of disease category and centre, height (taller patients having a greater chance of transplant) and blood group

The ideal recipient for any donor organ is the one with urgent need of transplantation along with the longest expected post-transplant survival. The Lung Allocation Score (LAS) system adopted in the US in 2005 incorporated estimated survival benefit offered by LTx by 1 year after surgery and medical urgency. Since its introduction, the number of deaths on the waiting list in the US has reduced

(blood group 'O' having highest waiting mortality) [16].


#### **Table 2.**

*Timing of referral and timing of listing for LTx in CF patients.*

include decision for active listing, further information required, rejection as unsuitable, or deferral as too well.

#### **2.4 Waiting list**

The time spent by potential recipients on the LTx waiting list depends on various factors including blood group, HLA antibody status and the size of pleural cavities. Whilst on the waiting list, patients are encouraged to exercise regularly, achieve or maintain a healthy BMI, avoid frequent infective exacerbations, and inform any changes in circumstances urgently. Transplant coordinators maintain contact with patients on the waiting list, update records, educate patients and communicate between all members of the transplant team. Traditionally, organ offering systems take into account time spent on the waiting list and the clinical status of the candidates, but influenced by the urgency of transplantation. With this freedom of recipient selection to the transplant centres, fairness in the distribution of the donor organs to the most worthy recipients may be jeopardised. A study looking into 2213 lung-only registrations into the UK Transplant Registry between 2004 and 2014 showed discrepancies between the risk profile and probability of LTx. The chance of LTx after listing differed by the combined effect of disease category and centre, height (taller patients having a greater chance of transplant) and blood group (blood group 'O' having highest waiting mortality) [16].

The ideal recipient for any donor organ is the one with urgent need of transplantation along with the longest expected post-transplant survival. The Lung Allocation Score (LAS) system adopted in the US in 2005 incorporated estimated survival benefit offered by LTx by 1 year after surgery and medical urgency. Since its introduction, the number of deaths on the waiting list in the US has reduced


#### **Table 3.**

*Assessment for LTx in CF patients.*

from 500/year to 300/year, the distribution of recipients has changed, and the number of LTx increased despite no substantial increase in organ donors with no decrease in 1-year survival after LTx, even though sicker patients were undergoing transplant [17]. With the introduction of the LAS, the number of LTx for PwCF

**73**

boundaries.

**3.1 Donors**

**3. Lung transplantation**

*Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

ultimately select a match.

increased by 25%, 70% of CF patients were transplanted within 1 year of being listed, and 1-year waiting-list mortality decreased from 15–10% [18]. The LAS was then adopted by Eurotransplant who distribute lungs between donor countries if they cannot be used within the donor's country of origin. After 3 years, the US results were imitated in Germany [19]. However, some reports have shown that the LAS increases the complexity of the post-transplant course and postoperative mortality [20, 21] and in some cases, reduced survival outcomes irrespective of risk profile [22]. Current allocation policy in the US initially utilises donor organ location and age to match with compatible wait-listed patients, followed by the LAS value, ABO blood type, thoracic cavity size and immunological compatibilities to

In the UK, between 2004 and 2014, 79.2% of patients with chronic obstructive pulmonary disease (COPD) received a transplant by 3 years of wait on the list versus 61.3% of PwCF and 48.9% of those with pulmonary fibrosis (PF). During the same period, patients with COPD had the lowest mortality on the list. In comparison, PwCF had a 230% higher chance of death on the list without LTx [16]. To optimise this disparity in organ allocation, in May 2017 the Cardiothoracic Advisory Group introduced an urgent and super-urgent lung allocation scheme in which patients at high risk of death without a LTx are prioritised at a national level [23]. In this scheme, patients supported with ECMO (extracorporeal membrane oxygenation) or iLA (interventional lung assist) as a bridge to transplant are prioritised on a national super-urgent waiting list, whilst severely unwell patients particularly in CF patient, worsening hypoxia and hypercapnia, persistently low pH, refractory right heart failure and ongoing massive hemoptysis can be recommended for the national urgent waiting list. Other policies in the UK include small adults (≥16 years of age and ≤ 155 cm of height) receiving offers of lungs from paediatric donors before other adults, (but after paediatric patients,) and priority is given to blood group identical recipients over blood group compatible recipients. In some cases, 'zonal centre' priority is given to patients at a centre if the donor is located within that centre's allocation zone [23]. However, the current system remain inefficient in prioritising patients depending upon the type of lung disease, and building individual risk profiles combining the factors such as urgency, height, and blood group. All current organ allocation systems strive to achieve the best post-transplant survival rates whilst reducing waiting list mortality, but remain far from ideal. Current systems should continue to undergo periodic evaluations, adopt practices from other systems, and remain dynamic to outcome-driven changes. The zonal allocation should depend on a distance rather than arbitrary geographical

Availability of donor organs remains the most important limiting factor for transplantation as lungs, in particular, have the lowest harvest rate. The Eurotransplant registry reports utilisation of lungs from only 698 donors out of 1192 registrants in the year 2019 which is significantly lower compared to abdominal organs [24]. Significant progress has been made in the last decade to improve the donor pool for lungs, but there remains a huge scope for further development. Donation after circulatory death (DCD) is becoming commonplace with a recent review of ISHLT data showing comparable five-year survival in recipients receiving lungs from donors after brain death (DBD) against DCD (63% vs. 61%) [25].

#### *Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

increased by 25%, 70% of CF patients were transplanted within 1 year of being listed, and 1-year waiting-list mortality decreased from 15–10% [18]. The LAS was then adopted by Eurotransplant who distribute lungs between donor countries if they cannot be used within the donor's country of origin. After 3 years, the US results were imitated in Germany [19]. However, some reports have shown that the LAS increases the complexity of the post-transplant course and postoperative mortality [20, 21] and in some cases, reduced survival outcomes irrespective of risk profile [22]. Current allocation policy in the US initially utilises donor organ location and age to match with compatible wait-listed patients, followed by the LAS value, ABO blood type, thoracic cavity size and immunological compatibilities to ultimately select a match.

In the UK, between 2004 and 2014, 79.2% of patients with chronic obstructive pulmonary disease (COPD) received a transplant by 3 years of wait on the list versus 61.3% of PwCF and 48.9% of those with pulmonary fibrosis (PF). During the same period, patients with COPD had the lowest mortality on the list. In comparison, PwCF had a 230% higher chance of death on the list without LTx [16]. To optimise this disparity in organ allocation, in May 2017 the Cardiothoracic Advisory Group introduced an urgent and super-urgent lung allocation scheme in which patients at high risk of death without a LTx are prioritised at a national level [23]. In this scheme, patients supported with ECMO (extracorporeal membrane oxygenation) or iLA (interventional lung assist) as a bridge to transplant are prioritised on a national super-urgent waiting list, whilst severely unwell patients particularly in CF patient, worsening hypoxia and hypercapnia, persistently low pH, refractory right heart failure and ongoing massive hemoptysis can be recommended for the national urgent waiting list. Other policies in the UK include small adults (≥16 years of age and ≤ 155 cm of height) receiving offers of lungs from paediatric donors before other adults, (but after paediatric patients,) and priority is given to blood group identical recipients over blood group compatible recipients. In some cases, 'zonal centre' priority is given to patients at a centre if the donor is located within that centre's allocation zone [23]. However, the current system remain inefficient in prioritising patients depending upon the type of lung disease, and building individual risk profiles combining the factors such as urgency, height, and blood group. All current organ allocation systems strive to achieve the best post-transplant survival rates whilst reducing waiting list mortality, but remain far from ideal. Current systems should continue to undergo periodic evaluations, adopt practices from other systems, and remain dynamic to outcome-driven changes. The zonal allocation should depend on a distance rather than arbitrary geographical boundaries.

## **3. Lung transplantation**

## **3.1 Donors**

Availability of donor organs remains the most important limiting factor for transplantation as lungs, in particular, have the lowest harvest rate. The Eurotransplant registry reports utilisation of lungs from only 698 donors out of 1192 registrants in the year 2019 which is significantly lower compared to abdominal organs [24]. Significant progress has been made in the last decade to improve the donor pool for lungs, but there remains a huge scope for further development. Donation after circulatory death (DCD) is becoming commonplace with a recent review of ISHLT data showing comparable five-year survival in recipients receiving lungs from donors after brain death (DBD) against DCD (63% vs. 61%) [25].

Metanalyses comparing LTx outcomes dependent on the type of donation have shown no difference in survival, primary graft dysfunction (PGD) or acute rejection [26, 27]. Protocol-based management of multiorgan brain dead donors with a focus on lung donation in recent years have significantly improved lung utilisation rates [28]. A ventilation strategy with a low tidal volume and higher PEEP, along with a neutral or negative fluid balance helps protect potential donor lungs [29].

Standard lung donor criteria have been liberalised in the last two decades with an increasing proportion of marginal donor lungs being utilised for LTx with equivalent outcomes. A review of the UNOS database showed reduced 1-year survival with the use of marginal donor lungs, especially in high-risk recipients [30]; however, the survival of these patients on the waiting list without transplantation is questionable. Moreover, it's the high-risk recipients and not marginal donors that are associated with poor outcomes [31]. A lung donor score (LDS) based upon past medical history, smoking history, age, arterial blood gases, chest X-ray, and bronchoscopy findings, that accurately predicts the likelihood of organ acceptance and recipient mortality may facilitate donor risk assessment and patient selection [32]. Ex-vivo lung perfusion (EVLP) is now an established therapy to repair and evaluate marginal lungs for transplantation with comparable post-transplant outcomes [33–35].

To expand the donor pool, more countries are embracing an 'opt-out' system for organ donation. In Europe, the 2018 figures of lung donor utilisation rate were significantly higher in Austria and Belgium (9.8 and 10.8 ppm) where they have opt-out systems for organ donation, compared to Germany and the Netherlands (3.8 and 4.7 ppm) where an opt-in system remains [36]. The waiting list mortality rates in countries with high donation rates are lower compared to those in countries with low donation rates (7% vs. 12% at 1 year), with higher quality donor lungs more often used in these countries with high donation rates, thus offering a chance of better outcomes in recipients [37].

#### **3.2 Challenges in LTx for CF**

#### *3.2.1 Preoperative procedures*

The average annual incidence of pneumothorax in PwCF is 1:167 patients per year and 3.4% of CF patients will experience a pneumothorax during their lifetime [38]. According to current CF Foundation practice guidelines, a chest drain is recommended for large pneumothoraces or small pneumothoraces with clinical instability, whilst surgical pleurodesis is recommended for recurrent, large pneumothoraces [39]. The incidence of CF patients with a history of pleural intervention undergoing LTx is increasing as patients are being offered alternative interventional therapies before resorting to LTx.

The inflammatory/chronic infective component of CF independently contributes to increased pleural adhesions [40]. Dense pleural adhesions encountered during LTx in such patients increases surgical time, bleeding, blood transfusion requirement (that may further increase the chance of primary graft failure (PGD)), renal injury, prolonged respiratory wean and early mortality [41, 42]. Some groups, however, report no difference in operative outcomes despite pleural adhesions in PwCF [40, 43, 44]. It is worth noting that the LAS nor the ISHLT Registry consider previous cardiothoracic procedures as a contraindication to LTx.

In a multicentre study of CT scan scoring in PwCF based on infection/inflammation, air trapping/hypoperfusion, normal/hyperperfusion, and bulla/cysts, infection/inflammation was found to have a significant predictive value for survival [45]. Careful and detailed studies of CTs for pleural thickening, irregularity and

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**3.3 Procedure of LTx**

therapeutic option [54, 55].

*Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

tion or lobar lung implantation.

*3.2.2 Preop ECMO and mechanical ventilation*

allow for ongoing physiotherapy rehabilitation.

calcification before listing for LTx is recommended to anticipate operative challenges and risk stratification. Avoidance of CPB, starting the procedure on the side of fewer adhesions, minimising blood loss by meticulous adhesiolysis and the presence of an experienced surgeon may prove helpful. PwCF may require lung resection for localised severe bronchiectasis, atelectasis, bronchopleural fistula refractory to medical management and severe hemoptysis refractory to conservative management [46, 47]. This not only causes pleural adhesions, but can also lead to loss of pleural cavity volume. At LTx evaluation, such patients require strategic planning while setting donor size parameters; they may require a donor lung reduc-

It is not uncommon for PwCF to suffer an infective exacerbation causing acute hypercapnic respiratory failure with worsening respiratory acidosis. Most exacerbations are managed with antibiotics and chest physiotherapy, but some require respiratory support with inhaled oxygen or escalation to non-invasive ventilation (NIV). Patients with deteriorating gas exchange despite NIV either require endotracheal intubation and invasive mechanical ventilation (IMV) or ECMO despite or to minimise IMV. Once an acceptable gas exchange is established with ECMO, sedation wean and extubation or tracheostomy should be performed in these patients to

Recent evidence from the UNOS database comprising 14,320 patients in the LAS era showed an association between pre-transplant ECMO and IMV with 30-day mortality as well as prolonged hospital length of stay after LTx [48, 49]. The Extracorporeal Life Support Organisation (ELSO) Registry showed 52% survival in CF patients supported on ECMO [50]. Fuehner et al. demonstrated improved survival in patients bridged to LTx with an "awake ECMO" strategy when compared with those managed with IMV (80% vs. 50% at 6 months), emphasising the potential advantages of minimising time sedated [51]. The key benefits of maintaining patients awake on ECMO is the avoidance of complications associated with sedation, intubation, IMV, and immobilisation. They can undertake active physiotherapy helping to reduce the rate of muscle wasting and preventing pressure sores. Patients are encouraged to eat and drink without enteral feed if possible. Meeting family and social media helps to maintain a positive mood, and suboptimal therapy or complications can be detected at an earlier stage as patients can identify

and communicate symptoms of dizziness, breathlessness, and pain [52].

Despite early success and advantages of heart-lung transplantation for CF (fewer anastomoses, shorter ischaemic times and re-utilisation of recipient's heart in a "domino" transplant), it has been superseded by LTx due to donor organ shortage and equivalent outcomes [53]. Bilateral sequential LTx in which unilateral pneumonectomy and donor lung implantation are performed in sequence is the standard operation for a suppurative disease like CF. However, single-LTx after synchronous or metachronous contralateral pneumonectomy for PwCF resulting in an asymmetric chest and lung volume mismatch may be an acceptable functional

The CF patient population consists of a large proportion of children and small adults that are not suitable recipients for most adult sized donors leading to an increase in the waiting list mortality. For a marginal size mismatch, peripheral lung resection, also known as 'lung shaving' may suffice, however, donor lung lobectomy

#### *Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

calcification before listing for LTx is recommended to anticipate operative challenges and risk stratification. Avoidance of CPB, starting the procedure on the side of fewer adhesions, minimising blood loss by meticulous adhesiolysis and the presence of an experienced surgeon may prove helpful. PwCF may require lung resection for localised severe bronchiectasis, atelectasis, bronchopleural fistula refractory to medical management and severe hemoptysis refractory to conservative management [46, 47]. This not only causes pleural adhesions, but can also lead to loss of pleural cavity volume. At LTx evaluation, such patients require strategic planning while setting donor size parameters; they may require a donor lung reduction or lobar lung implantation.

### *3.2.2 Preop ECMO and mechanical ventilation*

It is not uncommon for PwCF to suffer an infective exacerbation causing acute hypercapnic respiratory failure with worsening respiratory acidosis. Most exacerbations are managed with antibiotics and chest physiotherapy, but some require respiratory support with inhaled oxygen or escalation to non-invasive ventilation (NIV). Patients with deteriorating gas exchange despite NIV either require endotracheal intubation and invasive mechanical ventilation (IMV) or ECMO despite or to minimise IMV. Once an acceptable gas exchange is established with ECMO, sedation wean and extubation or tracheostomy should be performed in these patients to allow for ongoing physiotherapy rehabilitation.

Recent evidence from the UNOS database comprising 14,320 patients in the LAS era showed an association between pre-transplant ECMO and IMV with 30-day mortality as well as prolonged hospital length of stay after LTx [48, 49]. The Extracorporeal Life Support Organisation (ELSO) Registry showed 52% survival in CF patients supported on ECMO [50]. Fuehner et al. demonstrated improved survival in patients bridged to LTx with an "awake ECMO" strategy when compared with those managed with IMV (80% vs. 50% at 6 months), emphasising the potential advantages of minimising time sedated [51]. The key benefits of maintaining patients awake on ECMO is the avoidance of complications associated with sedation, intubation, IMV, and immobilisation. They can undertake active physiotherapy helping to reduce the rate of muscle wasting and preventing pressure sores. Patients are encouraged to eat and drink without enteral feed if possible. Meeting family and social media helps to maintain a positive mood, and suboptimal therapy or complications can be detected at an earlier stage as patients can identify and communicate symptoms of dizziness, breathlessness, and pain [52].

## **3.3 Procedure of LTx**

Despite early success and advantages of heart-lung transplantation for CF (fewer anastomoses, shorter ischaemic times and re-utilisation of recipient's heart in a "domino" transplant), it has been superseded by LTx due to donor organ shortage and equivalent outcomes [53]. Bilateral sequential LTx in which unilateral pneumonectomy and donor lung implantation are performed in sequence is the standard operation for a suppurative disease like CF. However, single-LTx after synchronous or metachronous contralateral pneumonectomy for PwCF resulting in an asymmetric chest and lung volume mismatch may be an acceptable functional therapeutic option [54, 55].

The CF patient population consists of a large proportion of children and small adults that are not suitable recipients for most adult sized donors leading to an increase in the waiting list mortality. For a marginal size mismatch, peripheral lung resection, also known as 'lung shaving' may suffice, however, donor lung lobectomy to utilise only the upper or lower (preferred option) lobe dependent on the recipient pleural cavity size may be required [56, 57]. Bi-partitioning lobar LTx is a bilateral lobar transplant from a single donor lung. This can be performed to maximise the donor pool, but is not a popular procedure due to technical challenges [58]. Livingdonor lobar LTx (LDLLT) is lifesaving in countries with low cadaveric donation and for patients deemed unable to await a cadaveric LTx [59]. Two lobes obtained from live donors can adequately support an adult CF patient and the morbidity from lobectomy to the healthy donor is minimal. A study where 84% of the cohort were CF patients undergoing LDLLT showed a survival of 70% and 45% at 1 and 5 years, which is comparable with double-lung cadaveric transplantation according to the ISHLT Registry (74% and 49.5% at 1 and 5 years) in in the same year [60].

#### **3.4 Advances in LTx surgery**

#### *3.4.1 Minimally invasive LTx*

For double LTx in CF, the clamshell is a conventional approach that offers a direct vision to the heart and lung hila, but can cause sternal dehiscence, malalignment, wound dehiscence and rarely mediastinitis. These complications are thought to be under-reported, but cause significant morbidity through readmissions, multiple surgical debridements and prolonged wound care. Infection can be difficult to treat in the presence of steroid-induced osteoporosis, breathing-induced mobility in healing sternal edges, and immunosuppression. Sternal sparing bilateral thoracotomy approach may be less painful and may support early extubation, ambulation, and rehabilitation [61]. This approach spares the internal mammary arteries, causing less blood loss, and is superior cosmetically to the clamshell incision. A requirement of long instruments and telescopic surgical skills for this approach is a myth. Utilisation of a modified rib spreader, with movable and adjustable blades provides optimum exposure without injuring the ribs. For emergency conversion to CPB, apart from peripheral access via the groin, one can cannulate via the thoracotomy.

#### *3.4.2 Role of mechanical circulatory support in LTx surgery*

Double LTx is conventionally performed with the aid of cardio-pulmonary bypass. As bilateral sequential LTx became commonplace, the use of CPB during the procedure declined. A comparative study of LTx in CF shows that the implantation of both lungs on CPB after bilateral pneumonectomy and airway decontamination does offer a protective effect against early graft infection [62]. CBP provides complete respiratory support and haemodynamic stability, ease of hilar dissection and retraction of the heart during the LTx, but can induce an inflammatory response, bleeding, (and thus increased requirement of blood transfusions), and a higher incidence of PGD [63]. Significantly lower survival was observed in CF patients undergoing LTx with the utilisation of extracorporeal circulation [64]. Offpump surgery may avoid complications caused by circulatory support but is susceptible to periods of hypotension, hypothermia, and hypoxia. It also exposes the new lung to the entire cardiac output potentially causing acute lung injury and PGD.

Off-pump LTx may require emergency conversion to CPB in case of inability to tolerate single lung ventilation, hemodynamic instability, or uncontrolled bleeding. Off-pump LTx requiring emergent conversion to CPB is by default a part of the onpump group in several reports comparing on-pump and off-pump procedures, which has found worse outcomes in the on-pump group [65, 66]. In the quest of a fair comparison, a further study segregated cases with unplanned CPB conversion and found that despite this segregation, patients with comparable preoperative demographic

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bleeding, irreversible arrhythmia or hemodynamic instability.

CF patients often become candidates for re-transplantation due to their young age at the time of their primary transplant. PwCF have overall good post-transplant survival but also suffer a higher incidence of bronchiolitis obliterans syndrome (BOS). BOS, primary graft failure (PGD) and irreversible airway complications (stenosis and dehiscence) are the main causes for lung re-transplantation. Pseudomonal airway colonisation before and after LTx is thought to be associated with the increased prevalence of BOS in CF patients [69]. CF recipients are at higher risk of acute cellular rejection and subsequent BOS due to the enhanced immune activation associated with CF, their younger age and higher prevalence of donor specific antibodies [70, 71]. Scarcity of donor organs and suboptimal outcomes have always raised doubts about the validity and ethics of re-transplantation, especially as historically, the survival post-re-transplantation has remained inferior compared to the primary transplantation. Interestingly though, rates of BOS has shown an improved trend with 1-year survival increasing from 47% in the 1990s to 72–78% in the last 15 years [73–75]. Re-transplantation in non-ambulatory, ventilated patients, with PGD, anastomotic dehiscence, or less than a year since primary transplantation is associated with higher mortality [72–75]. Careful recipient selection with preoperative optimization in terms of nutrition and functional status, along with end-organ function are vital for successful re-transplantation.

PwCF continue to demonstrate the best survival compared to other indications for LTx [76, 77], but suffer the same complications as those without CF to varying

*3.4.3 Re-transplantation*

**4. Complications of LTx in CF**

and risk profiles demonstrated better early postoperative outcomes including early survival with an off-pump strategy for LTx in comparison to an on-pump strategy. While a considerable proportion of high-risk patients require intraoperative conversion from off-pump to CPB with suboptimal outcomes, there is no significant benefit to employing an elective on-pump strategy in this high-risk group [67]. Although elective use of CPB for LTx has decreased in recent years, mechanical circulatory support of some form is still necessary during LTx in the presence of pulmonary hypertension, suboptimal cardiac function, severe respiratory disease, and marginal donor organs with an insufficient gas exchange when performing one-lung ventilation. Instead of CPB, ECMO that can potentially be continued post-operatively until the donor organs recover and pulmonary pressures alleviate is increasingly being utilised. ECMO offers cardiopulmonary support without cardiotomy suction, venous reservoir, a large amount of prime, and may avoid some complications associated with CPB. A meta-analysis of 7 studies comprising 785 patients comparing CPB and ECMO in LTx showed a lower rate of primary graft dysfunction, bleeding, renal failure requiring dialysis, tracheostomy, intraoperative transfusions, intubation time, and hospital stay along with a trend towards lower mortality in the ECMO group [68]. Elective use of mechanical circulatory support in LTx for CF is now limited to severe secondary pulmonary hypertension or if additional cardiac surgery is required, such as atrial septal defect closure. Optimisation with Milrinone and nitric oxide before a trial of pulmonary artery clamping can be helpful to assess if mechanical support may be required. If there is hemodynamic instability and inadequate gas exchange on single lung ventilation, the operation should continue under ECMO support, whilst emergency CPB can be ustilised in case of catastrophic

#### *Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

and risk profiles demonstrated better early postoperative outcomes including early survival with an off-pump strategy for LTx in comparison to an on-pump strategy. While a considerable proportion of high-risk patients require intraoperative conversion from off-pump to CPB with suboptimal outcomes, there is no significant benefit to employing an elective on-pump strategy in this high-risk group [67]. Although elective use of CPB for LTx has decreased in recent years, mechanical circulatory support of some form is still necessary during LTx in the presence of pulmonary hypertension, suboptimal cardiac function, severe respiratory disease, and marginal donor organs with an insufficient gas exchange when performing one-lung ventilation. Instead of CPB, ECMO that can potentially be continued post-operatively until the donor organs recover and pulmonary pressures alleviate is increasingly being utilised. ECMO offers cardiopulmonary support without cardiotomy suction, venous reservoir, a large amount of prime, and may avoid some complications associated with CPB. A meta-analysis of 7 studies comprising 785 patients comparing CPB and ECMO in LTx showed a lower rate of primary graft dysfunction, bleeding, renal failure requiring dialysis, tracheostomy, intraoperative transfusions, intubation time, and hospital stay along with a trend towards lower mortality in the ECMO group [68]. Elective use of mechanical circulatory support in LTx for CF is now limited to severe secondary pulmonary hypertension or if additional cardiac surgery is required, such as atrial septal defect closure. Optimisation with Milrinone and nitric oxide before a trial of pulmonary artery clamping can be helpful to assess if mechanical support may be required. If there is hemodynamic instability and inadequate gas exchange on single lung ventilation, the operation should continue under ECMO support, whilst emergency CPB can be ustilised in case of catastrophic bleeding, irreversible arrhythmia or hemodynamic instability.

## *3.4.3 Re-transplantation*

CF patients often become candidates for re-transplantation due to their young age at the time of their primary transplant. PwCF have overall good post-transplant survival but also suffer a higher incidence of bronchiolitis obliterans syndrome (BOS). BOS, primary graft failure (PGD) and irreversible airway complications (stenosis and dehiscence) are the main causes for lung re-transplantation. Pseudomonal airway colonisation before and after LTx is thought to be associated with the increased prevalence of BOS in CF patients [69]. CF recipients are at higher risk of acute cellular rejection and subsequent BOS due to the enhanced immune activation associated with CF, their younger age and higher prevalence of donor specific antibodies [70, 71]. Scarcity of donor organs and suboptimal outcomes have always raised doubts about the validity and ethics of re-transplantation, especially as historically, the survival post-re-transplantation has remained inferior compared to the primary transplantation. Interestingly though, rates of BOS has shown an improved trend with 1-year survival increasing from 47% in the 1990s to 72–78% in the last 15 years [73–75]. Re-transplantation in non-ambulatory, ventilated patients, with PGD, anastomotic dehiscence, or less than a year since primary transplantation is associated with higher mortality [72–75]. Careful recipient selection with preoperative optimization in terms of nutrition and functional status, along with end-organ function are vital for successful re-transplantation.

## **4. Complications of LTx in CF**

PwCF continue to demonstrate the best survival compared to other indications for LTx [76, 77], but suffer the same complications as those without CF to varying

extents. Within the first month, primary graft dysfunction, acute infections, and technical complications dominate the cause for admissions, transitioning to also include rejection in the first year. Rejection and infection remain complicating factors throughout a recipient's life, with malignancy an increasing risk the longer a recipient remains on immunosuppression [77, 78].

#### **4.1 PGD**

Primary graft dysfunction (PGD) is the main cause of death within the first 30 days post-operatively [78], and is a form of acute lung injury that involves a wide spectrum of signs and symptoms within the first 72 hours of transplantation. For this reason, it is also known as the "re-implantation response". PGD is the consequence of an inflammatory response triggered by injury to the donor, graft or recipient, ischaemia, and reperfusion, and can cause a decrease in oxygenation with minimal pulmonary infiltrates caused by oedema, through to complete graft failure and death or re-transplantation. PGD is caused by the activation of pulmonary macrophages and circulating leukocytes and is divided into two phases – a first acute phase of lung schaemia and reperfusion injury, which drives the second phase mediated by massive neutrophil recruitment which amplifies the initial innate immune reaction.

A number of risk factors for development of PGD have been identified; in general, donor factors tend to impact the initial 24 hours post-transplantation, whilst the recipient factors affect later outcomes. Donor-related risk factors include sex, age, smoking history, ischaemic time, and brain-death-associated lung injury [79, 80]. Given the underlying pathophysiology of PGD, the approach to management is based on the treatment of ARDS (acute respiratory distress syndrome) using protective IMV and maintaining a negative fluid balance. However, this treatment plan is complicated by patients who may not tolerate permissive hypercapnia cardiologically, and fragile renal function due to multiple insults in the operative and immediate post-operative period.

It has been shown that lung recipients who develop PGD have a marked graft and systemic inflammatory response, and that the timing and grade of PGD severity has implications to the risk of developing BOS (bronchiolitis obliterans) later [81, 82].

#### **4.2 Infections**

Post-transplant infections remain a significant source of morbidity and mortality in all recipients, but this is complicated by the nature of the multi-resistant organisms found in CF recipients due to repeated antibiotic courses. It has long been accepted that PwCF are chronically colonised with bacteria, and so finding positive microbiology in the sputum of transplanted PwCF does not necessitate an acute infection, but equally, transplanting the lungs does not eradicate individuals with CF of the bacteria which remain colonised in the upper airways and the sinuses. PwCF colonised with *Mycobacterium abscessus* or *Bulkholderia cenocepacia* cannot be transplanted in most centres due to the high morbidity and mortality rates associated with these conditions post-transplantation. Though there have been some success in transplanting PwCF who have negative sputum for *M. abscessus* pre-transplantation but remain on treatment [83–85].

It is just as important to consider the donor's microbiological profile. All donors are screened for obvious reasons for HIV, hepatitis B and hepatitis C, but where donors have died from undiagnosed infections, the risk of transmitting a potentially lethal infection into a recipient has to be considered. In addition, the longer

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*Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

the peri-operative and immediate post-operative period.

a potential donor is ventilated, the more likely they are to become colonised with antibiotic-resistant flora, complicating a future transplant. BAL before harvesting or implantation is useful to culture and therefore guide antibiotic management in

Like any major surgery, surgical site infection can also occur. Good peri-operative lavages of the donor lungs and the recipient's pleural cavity is important to reduce the presence of infected material. It is often difficult for antibiotics to penetrate the pleural cavity so although infections at a wound site are unusual, once present, they can be difficult to manage and treat. Again, PwCF are at higher risk of infections at anastomotic and surgical sites by the nature of the underlying disease. The antibiotics selected peri-operatively and post-operatively are guided by the patient's response to antibiotic combinations pre-operatively, as well as microbiological sensitivities. Just like other intensive-care patients, post-transplant patients are at high risk of ventilator-associated pneumonia (VAP), and so unless there are contraindications, it is important to work towards extubating the patient as expediently as possible. CMV (cytomegalovirus) disease used to be a significant concern post-transplant, but the routine use of prophylactic and treatment valgangiclovir combined with surveillance management has significantly reduced the risk of infection or reactivation [86]. A recent study looking at the incidence of CMV infection in heart transplant recipients has estimated the rate of early-onset (<100 days post-transplant) CMV disease at only 2%, compared with late-onset (>100 days post-transplant) at 7.5%, and this is largely thought to be due to the introduction of valganciclovir [87]. EBV (Epstein–Barr virus) mismatches where the donor is positive and the recipient negative, are rare as >95% of the population seroconvert by the time they are 20 years of age. Most recipients undergo a B-cell proliferation 1–3 months post-transplant, but occasionally this can proceed to a post-transplant lymphoproliferative disease (PTLD). Monitoring of EBV levels is generally used as a marker of over-immunosuppression rather than a way of looking for malignant disease. Similarly, with the widespread use of co-trimoxazole as first-line prophylaxis, PCP (pneumocystis pneumonia) – also known as PJP (*pneumocystis jiroveci pneumonia*) – is an unusual finding, with rates in solid organ transplant recipients reduced from 5 to 15% to 0.3–2.6% [88]. Other respiratory viruses that can have significant impact to a transplant recipient includes respiratory syncytial virus (RSV), metapneumovirus, influenza/parainfluenza, adenoviruses and rhinovirus. Any of these can cause a viral pneumonitis, which can in turn inflict permanent damage to the transplanted lungs, either through the inflammatory process of an infection, or by triggering acute rejection or chronic allograft dysfunction (CLAD) [89]. Most of these infections have no direct treatment, and so management remains supportive with the addition of IV methylprednisolone and/or IV immunoglobulin (IVIG) in an effort to prevent rejection which can be triggered by these viral infections [89]. Many PwCF are often sensitised to *Aspergillus fumigatus* and will often be on longterm oral antifungals that will need to continue following transplantation. For all causes, invasive aspergillosis is the most common cause of all invasive fungal infections in lung transplant recipients [90], but it can also be asymptomatic. Often however, it will lead to a more pathogenic process, including causing anastomotic dehiscence and lung function decline without obvious radiographic changes [91]. This process is still not fully understood, which often results in trials of treatment to find the most effective. *A. fumigatus* accounts for 44% of fungal infections in the post-lung transplant population, but other common fungal infections posttransplant include *Candida* (23%), *Scedosporium* (20%), *Mucorales* (3%) and *Cryptococcus* (2%) [92]. Throughout a recipient's lifetime, it is often difficult to tell the difference between rejection and infection as no reliable markers exist. Recipients are subjected to frequent invasive investigations (usually bronchoscopy)

#### *Lung Transplantation in Patients with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.94523*

a potential donor is ventilated, the more likely they are to become colonised with antibiotic-resistant flora, complicating a future transplant. BAL before harvesting or implantation is useful to culture and therefore guide antibiotic management in the peri-operative and immediate post-operative period.

Like any major surgery, surgical site infection can also occur. Good peri-operative lavages of the donor lungs and the recipient's pleural cavity is important to reduce the presence of infected material. It is often difficult for antibiotics to penetrate the pleural cavity so although infections at a wound site are unusual, once present, they can be difficult to manage and treat. Again, PwCF are at higher risk of infections at anastomotic and surgical sites by the nature of the underlying disease. The antibiotics selected peri-operatively and post-operatively are guided by the patient's response to antibiotic combinations pre-operatively, as well as microbiological sensitivities. Just like other intensive-care patients, post-transplant patients are at high risk of ventilator-associated pneumonia (VAP), and so unless there are contraindications, it is important to work towards extubating the patient as expediently as possible.

CMV (cytomegalovirus) disease used to be a significant concern post-transplant, but the routine use of prophylactic and treatment valgangiclovir combined with surveillance management has significantly reduced the risk of infection or reactivation [86]. A recent study looking at the incidence of CMV infection in heart transplant recipients has estimated the rate of early-onset (<100 days post-transplant) CMV disease at only 2%, compared with late-onset (>100 days post-transplant) at 7.5%, and this is largely thought to be due to the introduction of valganciclovir [87]. EBV (Epstein–Barr virus) mismatches where the donor is positive and the recipient negative, are rare as >95% of the population seroconvert by the time they are 20 years of age. Most recipients undergo a B-cell proliferation 1–3 months post-transplant, but occasionally this can proceed to a post-transplant lymphoproliferative disease (PTLD). Monitoring of EBV levels is generally used as a marker of over-immunosuppression rather than a way of looking for malignant disease. Similarly, with the widespread use of co-trimoxazole as first-line prophylaxis, PCP (pneumocystis pneumonia) – also known as PJP (*pneumocystis jiroveci pneumonia*) – is an unusual finding, with rates in solid organ transplant recipients reduced from 5 to 15% to 0.3–2.6% [88]. Other respiratory viruses that can have significant impact to a transplant recipient includes respiratory syncytial virus (RSV), metapneumovirus, influenza/parainfluenza, adenoviruses and rhinovirus. Any of these can cause a viral pneumonitis, which can in turn inflict permanent damage to the transplanted lungs, either through the inflammatory process of an infection, or by triggering acute rejection or chronic allograft dysfunction (CLAD) [89]. Most of these infections have no direct treatment, and so management remains supportive with the addition of IV methylprednisolone and/or IV immunoglobulin (IVIG) in an effort to prevent rejection which can be triggered by these viral infections [89].

Many PwCF are often sensitised to *Aspergillus fumigatus* and will often be on longterm oral antifungals that will need to continue following transplantation. For all causes, invasive aspergillosis is the most common cause of all invasive fungal infections in lung transplant recipients [90], but it can also be asymptomatic. Often however, it will lead to a more pathogenic process, including causing anastomotic dehiscence and lung function decline without obvious radiographic changes [91]. This process is still not fully understood, which often results in trials of treatment to find the most effective. *A. fumigatus* accounts for 44% of fungal infections in the post-lung transplant population, but other common fungal infections posttransplant include *Candida* (23%), *Scedosporium* (20%), *Mucorales* (3%) and *Cryptococcus* (2%) [92]. Throughout a recipient's lifetime, it is often difficult to tell the difference between rejection and infection as no reliable markers exist. Recipients are subjected to frequent invasive investigations (usually bronchoscopy)

especially in the early post-transplant period, requiring washings and biopsies to differentiate. Patients are encouraged to attend their transplant centres as their local referring centre which usually treat patients as having infections rather than consider or have the means to investigate for a diagnosis of rejection. This is especially true for PwCF as they are likely to remain positive for their primary pre-transplant pathogenic bacteria. It is important to keep in mind that they are also susceptible to the same atypical infections as all other lung transplant recipients are, and that even if a diagnosis of infection is correct, it may not be caused by the same causative organisms as per prior to transplantation.

Part of keeping transplant recipients well includes maintaining appropriate prophylactic antibiotic cover. In CF recipients, this often means continuing the oral anti-fungals or nebulised antibiotics they were on pre-transplant for a number of months at least. If these recipients remains well with no positive microbiology, an informed decision to reduce the prophylaxis burden could be considered. All recipients are advised to maintain annual vaccines such as the flu vaccine, but other vaccines should be discussed with transplant centres as not all vaccines are appropriate in the immunosuppressed population.

#### **4.3 Rejection**

The first 2 months post-transplant are high risk for acute rejection, as recipient lymphocytes encounter donor antibodies for the first time. However, the risk of death is low with acute cellular rejection (ACR), and this decreases even further with time [93]. Longer term, the risk is of bronchiolitis obliterans syndrome (for which ACR is a risk factor) and CLAD. Unlike most other solid organt transplants (SOT), lung transplantation has always required a fine balance between adequate immunosuppression and the risk of infection. Many patients end up with varying individualised immunosuppression based on the number of rejection episodes against the rate of infections each person has 28% of surviving lung transplant recipients between 2004 and 2015 required treatment for acute rejection in the first year post-discharge [3]. Most recipients will require treatment for acute rejection in the first year post-transplant, usually in the first 6 months [94]. Treatment is usually a short course of high dose IV methylprednisolone (IVMP) for 3–5 days, followed by a tapering course over 2–3 weeks. If a patient suffers from recurrent bouts of acute rejection and treatment adherence is confirmed, then immunosuppression may need to be increased if tolerated renally. Where acute cellular rejection is refractory to standard treatment, other modalities of treatment are available. RATG has variable success but is still used. Total lymphoid irradiation (TLI) and extracorporeal photophoresis are both used with a degree of success in slowing the rate of lung function decline, sometimes halting it altogether [95, 96].

Chronic lung allograft dysfunction (CLAD) remains a major barrier to longterm survival post lung transplantation. Until recently, CLAD and bronchiolitis obliterans syndrome (BOS) were used interchangeably. However, the heterogeneity of the clinical course of CLAD along with highly variable responses to treatment has caused clinicians to review radiology and histology and suggest two distinct phenotypes: BOS and restrictive allograft syndrome (RAS) (also known as restrictive CLAD (rCLAD)). BOS is characterised by an obstructive picture on pulmonary function tests, air trapping on CT imaging, and obliterative bronchiolitis (OB) on histology [97]. RAS is characterised by restrictive results on pulmonary function tests, pleuro-parenchymal infiltrates on CT and fibro-elastosis on biopsies [98]. It is important to differentiate between the two as patients with RAS have an average expected life expectancy of 6–18 months following diagnosis, compared to 3–5 years after diagnosis of BOS [97].

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With improved survival post-transplant, long term complications are increasingly common. Lung transplantation requires higher amounts of immunosuppression compared with most other solid organ transplants, which increases the risk of developing cancer due to impaired anti-tumour immune surveillance and anti-viral activity. Malignancies occur in 18% of patients reaching 5 years of survival, and 28.7% of patients reaching 10 years of survival [99]. Malignancies transmitted from the donor are rare due to the surveillance undertaken at the time of donation [100]. PTLD is diagnosed when EBV levels start to rise in association with an abnormal

white cell count, and is more common in lung transplant recipients than most other SOT recipients. It occurs in 2–9% of lung transplant recipients [101, 102]. Early cases (within 1 year of transplantation) typically involve the lungs and occur in recipients who have not previously been exposed to the virus, whereas cases presenting more than 1 year post-transplantation are more likely to involve the gastrointestinal (GI) tract [101]. Radiologically, lymphadenopathy and pulmonary nodules in the peripheral and basal zones are seen on CT [103]. Posttransplant immunosuppression impairs T-cell-specific immunity against EBV but EBV-negative PTLD has also been recognised. Early-onset PTLD is more likely to respond to a reduction in immunosuppression than late-onset as the pathogenesis of the latter is less well understood, but this in turn increases the risk of rejection and graft failure [104]. As a result, prognosis with late-onset PTLD is worse [102, 105]. If reduction in treatment is not the solution, the next option would be rituximab, which induces cell death of B-cells via CD20 which is on the surface of these cells. Non-melanoma skin cancers are the most common skin cancer for SOT recipients and this is also true in LTx [106, 107]. All lung transplant recipients are advised to monitor their skin for any suspicious changes, and regular review by their GP or a dermatologist is often recommended. They are also cautioned about time spent in the sun and advised to use high factor sun cream liberally. Squamous cell carcinomas (SCCs) are 100–200 times more likely to occur post-lung transplant compared to the general population [107], and they are usually more aggressive with high rates of recurrence [102]. All other forms of skin cancer are more common than the general population but not to the same extent. The increased risk of non-melanoma cancer in all SOT recipients is primarily due to immunosuppression which affects the usual cellular pathways that prevent cancerous growths. With LTx recipients receiving the highest levels of immunosuppression, it is unsurprising that this group of patients have the highest rates of skin cancer. There is also increasing evidence that voriconazole increases the risk of SCC [108] and so it is advised to reduce the length of treatment time if possible and otherwise switch to an alterna-

tive anti-fungal that appears to have less of an association with cancer.

immunosuppression and risk of graft rejection.

Treatment is identical to all other skin cancer treatments, aiming for local excision with complete clearance, but if possible, rates of immunosuppression should be reduced to reduce the risk of recurrence or further skin cancers. Radiotherapy is an alternative option for those who are high risk for surgery or whose cancers have progressed to being inoperable [109]. Monoclonal antibodies have had increasing success in the general population, however, these have not been tried to a great extent in post-transplant recipients due to concerns over their interaction with

Lung transplant recipients appear to have up to a 5-fold increased risk of lung cancer compared to the general population [110], but the risk is primarily related to pre-transplant risk factors and so there is a higher incidence in those transplanted for COPD or ILD. For PwCF, the risk of developing lung cancer is generally donorrelated risk factors or due to immunosuppression as described earlier. When lung

**4.4 Malignancy**

#### **4.4 Malignancy**

With improved survival post-transplant, long term complications are increasingly common. Lung transplantation requires higher amounts of immunosuppression compared with most other solid organ transplants, which increases the risk of developing cancer due to impaired anti-tumour immune surveillance and anti-viral activity. Malignancies occur in 18% of patients reaching 5 years of survival, and 28.7% of patients reaching 10 years of survival [99]. Malignancies transmitted from the donor are rare due to the surveillance undertaken at the time of donation [100].

PTLD is diagnosed when EBV levels start to rise in association with an abnormal white cell count, and is more common in lung transplant recipients than most other SOT recipients. It occurs in 2–9% of lung transplant recipients [101, 102]. Early cases (within 1 year of transplantation) typically involve the lungs and occur in recipients who have not previously been exposed to the virus, whereas cases presenting more than 1 year post-transplantation are more likely to involve the gastrointestinal (GI) tract [101]. Radiologically, lymphadenopathy and pulmonary nodules in the peripheral and basal zones are seen on CT [103]. Posttransplant immunosuppression impairs T-cell-specific immunity against EBV but EBV-negative PTLD has also been recognised. Early-onset PTLD is more likely to respond to a reduction in immunosuppression than late-onset as the pathogenesis of the latter is less well understood, but this in turn increases the risk of rejection and graft failure [104]. As a result, prognosis with late-onset PTLD is worse [102, 105]. If reduction in treatment is not the solution, the next option would be rituximab, which induces cell death of B-cells via CD20 which is on the surface of these cells.

Non-melanoma skin cancers are the most common skin cancer for SOT recipients and this is also true in LTx [106, 107]. All lung transplant recipients are advised to monitor their skin for any suspicious changes, and regular review by their GP or a dermatologist is often recommended. They are also cautioned about time spent in the sun and advised to use high factor sun cream liberally. Squamous cell carcinomas (SCCs) are 100–200 times more likely to occur post-lung transplant compared to the general population [107], and they are usually more aggressive with high rates of recurrence [102]. All other forms of skin cancer are more common than the general population but not to the same extent. The increased risk of non-melanoma cancer in all SOT recipients is primarily due to immunosuppression which affects the usual cellular pathways that prevent cancerous growths. With LTx recipients receiving the highest levels of immunosuppression, it is unsurprising that this group of patients have the highest rates of skin cancer. There is also increasing evidence that voriconazole increases the risk of SCC [108] and so it is advised to reduce the length of treatment time if possible and otherwise switch to an alternative anti-fungal that appears to have less of an association with cancer.

Treatment is identical to all other skin cancer treatments, aiming for local excision with complete clearance, but if possible, rates of immunosuppression should be reduced to reduce the risk of recurrence or further skin cancers. Radiotherapy is an alternative option for those who are high risk for surgery or whose cancers have progressed to being inoperable [109]. Monoclonal antibodies have had increasing success in the general population, however, these have not been tried to a great extent in post-transplant recipients due to concerns over their interaction with immunosuppression and risk of graft rejection.

Lung transplant recipients appear to have up to a 5-fold increased risk of lung cancer compared to the general population [110], but the risk is primarily related to pre-transplant risk factors and so there is a higher incidence in those transplanted for COPD or ILD. For PwCF, the risk of developing lung cancer is generally donorrelated risk factors or due to immunosuppression as described earlier. When lung

cancer does develop, treatment remains challenging as no treatment has been wellstudied alongside immunosuppression, and outcomes are often poor.

Although all SOT recipients are at increased risk of developing colorectal cancer, LTx recipients who have CF have a significantly higher incidence, even within the transplant population [111]. This is presumed to be due to the inherent risk of GI malignancy in all PwCF compounded with the increased incidence due to immunosuppression. The US-based CF Foundation have recently published Consensus guidelines for colorectal cancer screening in PwCF which should be followed posttransplant also [112]. Further information on colorectal cancer in CF can be found in the chapter entitled "Digestive System".

## **5. Conclusions**

Although lung transplantation in PwCF has achieved results once thought impossible, there remains substantial opportunity for progress. Avenues for these opportunities include better donor management and organ preservation, improved donor allocation systems to offer organs to those most in need who will also benefit most, optimization of recipients in terms of physiology, GERD management and CFRDM, and prevention of PGD, rejection, and infections. Preoperative pleurodesis and lung resections are not contraindications to lung transplantation, however, strategic planning with CT imaging and availability of experienced team members may reduce complications. While preoperative mechanical ventilation is potentially detrimental, patients should be bridged to lung transplantation with ECMO support, aiming to wake them as soon as is feasible. Bilateral thoracotomy approach is superior to the conventional clamshell cosmetically as well as in regards to wound complications. Elective use of mechanical circulatory support in LTx for CF is now limited to severe secondary pulmonary hypertension or additional cardiac surgery, and in the case of hemodynamic instability or inadequate gas exchange on single lung ventilation, the operation should be performed under ECMO support.

### **Author details**

Prashant N. Mohite\*, Kavita Dave, Anna Reed and André R. Simon Royal Brompton and Harefield NHS Foundation Trust, United Kingdom

\*Address all correspondence to: p.mohite@rbht.nhs.uk

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**91**

**Chapter 6**

**Abstract**

**1. Introduction**

domain (R domain) (**Figure 2**) [2].

Fibrosis

Recent Advances in Targeted

Genetic Medicines for Cystic

The cystic fibrosis transmembrane conductance regulator (*CFTR*) gene was discovered just over 30 years ago, and soon after, gene therapy for cystic fibrosis (CF) has been rapidly and continually developing. Recently, novel gene therapy strategies have been developed, including mRNA delivery, genome editing, and mRNA repair; all these strategies are collectively named "genetic medicines." The last quarter of the century showed a significant boost in the development of viral and nonviral vectors to deliver genetic treatment. This chapter will provide a brief overview of the *CFTR* gene and its different classes of mutations as well as a review of the different genetic therapeutic options that are under research. Later in this chapter, drugs that target different *CFTR* mutation classes and are currently

**Keywords:** cystic fibrosis, CFTR, gene therapy, CRISPR/Cas9, mRNA therapy, gene editing, gene delivery, viral vectors, nonviral vectors, CF animal models, CF drugs

CF is an autosomal recessive genetic disorder and is caused by mutations in both copies of *CFTR*. The *CFTR* gene is found on chromosome 7, on the long arm at position q31.2 from bp 116,907,253 to bp 117,095,955. *CFTR* consists of 27 exons, whereas the CFTR protein has 1480 amino acids with a molecular mass of 168,138 Da [1].

The *CFTR* gene encodes a protein that is an ATP-gated chloride and bicarbonate channel. It is located only on the apical membrane of the airway, intestinal, and exocrine glands epithelium. The CFTR protein undergoes different steps of posttranslational modifications and trafficking inside the epithelial cells (**Figure 1**). The CFTR protein structure consists of four main domains: an extracellular domain, a transmembrane domain, a nuclear binding domain (NBD), and the regulatory

1.**Extracellular domain**: It comprises of small loops that connect the transmem-

2.**Transmembrane domain**: It consists of two groups; each of them consists of six membrane-bound regions that are each connected to a nuclear binding

brane proteins, e.g., (M1 and M2), (M3 and M4), (M5 and M6), etc.

*Salsabil Elboraie, Konstantinos N. Kafetzis,* 

approved to treat CF patients will be briefly presented.

*Rajeev Shrivastava and Aristides D. Tagalakis*

## **Chapter 6**
