**7.4. Pathophysiology**

exacerbations because of chronic immunosuppression and undesirable side-effect profiles

Cystic fibrosis (CF) results from a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial cell ion transporter. Although the resultant lung pathology is the main source of morbidity and mortality, there is multi-system dys‐ function due to the prevalence of the channel in several cell types. The myriad manifes‐ tations of CF include lung disease, pancreatic insufficiency (both endocrine and exocrine), male infertility, liver disease, meconium ileus, and distal intestinal obstruction. [43],[44] Among these, the primary cause of morbidity and mortality in cystic fibrosis is pulmonary disease. Pulmonary complications stem from impaired ion transport in the airways, which results in thick mucus, reduced ciliary beat frequency and pathogen clearance from the respiratory tract. These pathogens constantly bombard and eventually colonize the CF patient's airways, which leads to a state of persistent inflammation

CF predominately affects Caucasians, and has an estimated prevalence of roughly 80,000 people worldwide. When it was first described in 1938, CF virtually guaranteed death short‐ ly after diagnosis. However, advances in knowledge of the disease process and clinical man‐ agement of CF have led to improved life expectancy of 25 years in 1985 and currently approaching 40 years. Individuals diagnosed with CF today are expected to survive beyond

The cystic fibrosis gene is situated on the long arm of chromosome 7. CF mutations are transmitted in an autosomal recessive pattern [47] and over 1500 unique mutations of the CF gene have been identified. [48] Such a large number of different mutations, and the demon‐ strated influence of other genes (i.e. TGFΒ1) suggests the probability of considerable varia‐ bility in genotype, phenotype and disease severity. [49] Indeed, this is the case; symptoms, onset and severity vary widely across the CF population. CF patients are classified I-VI ac‐ cording to the type of defect the mutation causes in the resultant protein. Class I mutations are nonsense or stopgain mutations that cause the protein to be truncated. Class II are typi‐ cally missense mutations that affect the tertiary structure of the protein and prevent it from trafficking to the cell membrane (this is by far the most common type of mutation seen in CF). The most common of all CFTR mutations is termed ΔF508, a deletion of three nucleoti‐ des resulting in a deletion of phenylalanine at position 508, and is a class II mutation. In

from long-term daily use. [42]

106 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

marked by recurrent infections and exacerbations. [45]

**7.2. Epidemiology/prevalence/survival**

50 years of age. [46]

**7.3. Etiology**

**7. Cystic fibrosis**

**7.1. Disease overview**

As noted above, CF presents with numerous extra-pulmonary symptoms, but only pulmo‐ nary complications will be addressed herein. Pulmonary manifestations of CF can be under‐ stood as a stepwise melding of the following pathologic processes:


(1) The underlying genetic defect in CF results in either a dysfunctional or absent CFTR channel. The submucosal glands in the distal airways express CFTR, a protein that spans the membrane of epithelial cells. It employs a cAMP-mediated, PKA activated mechanism to conduct chloride ions across the lipid bilayer. Other functions of CFTR that have been de‐ scribed are affected with varying degrees based on the type of mutation (congenital bilateral absence of the vas deferens). How those secondary functions are altered may explain the phenotypic severity in CF, but dysregulation and dysfunction in chloride conductance is the primary pathology of the CFTR in CF.

(2) Ineffective secretion of chloride anions (and unregulated absorption of sodium ions) leads to a reduced volume of airway surface liquid (ASL) due to the diminished electro‐ lyte content in the airway and very little osmotic pull. In turn, this alters the consistency of airway mucus to a thick, desiccated, hyper-viscous layer that adheres to the airway epithelium. [53]

(3) The adherent mucus creates plaques that obstruct the airways and disrupt the mucocili‐ ary clearance mechanism. The detrimental effect of poor mucus clearance is two-fold. First, lung function, as measured by spirometry, declines due to the physical obstruction of the airways. Clogged with mucus plugs, the small airways conduct air less efficiently. Second, the adherent mucus becomes a nidus for infection. [54]

(4) The airways are thus persistently colonized by multiple species of bacteria, namely Pseu‐ damonas aeruginosa, Burkholderia cepacia, Hemophila influezae and Staphylococcus aur‐ eus. These organisms are difficult to eradicate in the CF patient, even with continuous prophylactic antibiotic treatment. Colonization is a doorway for infection, and CF is marked by periods of infection and significant decline in lung function known as exacerbations. The etiology of CF exacerbations is closely linked to fluctuations in the balance of bacterial flora in the airway. [55]

ing channelopathy. Current CF therapeutics are best understood in relation to how they ad‐ dress the five pathological processes described above. Efforts to address the underlying cause of CF, mutations of the CFTR gene, are underway in the form of gene therapy. The central problem surrounding gene therapy is the search for a suitable delivery mechanism. Viral vectors have been studied, but immune provocation remains to be an obstacle. [60] Re‐ duced ASL height has been successfully addressed with inhaled hypertonic saline and en‐ zymes, such as recombinant human DNAase (dornase alfa). In conjunction with the inhalation therapies noted above, techniques such as breathing exercises, positive expiratory pressure masks, and chest compression (both manual and automated) seek to disrupt the mucus plaques that line the CF airways. Aggressive antibiotic therapy is employed to com‐ bat both chronic colonization and acute infections. Although inhaled tobramycin and cipro‐ floxacin therapy have been effective, the wide array of bacteria in the CF airway precludes development of antibiotic therapy protocol. Finally, high dose ibuprofen and macrolide (typically Azithromycin) treatments stifle the persistent, PMN-dominated inflammation seen in CF. [46],[61],[62] There have been recent exciting discoveries regarding treatment of

New Frontiers in the Diagnosis and Treatment of Chronic Neutrophilic Lung Diseases

http://dx.doi.org/10.5772/53834

109

α1-Antitrypsin (A1AT) deficiency (A1AD) is a form of COPD that is an extreme form of the condition, with the potential to develop COPD without excessive smoking. Patients with A1AT deficiency comprise approximately 5% of the global COPD population and have a predicted life span more than 10 years less than those of a life-long smoke with COPD. A1AT is believed by many to be an underreported condition affecting up to 1:2000 people. [63] Although this may seem extremely prevalent, those with the condi‐ tion only begin to appear symptomatic with cigarette smoking. The underreporting of A1AD may also be due to clinicians giving a diagnosis of idiopathic COPD, or COPD

A1AD is a genetic disorder inherited in an autosomal recessive manner. Patients with A1AT have at least two mutations in a *trans* configuration in the A1AT gene. A1AD patients most often become symptomatic after cigarette smoking, although it is possible to present with emphysema in the third decade of life with no prior tobacco use. Patients present with

A1AT, an acute phase protein, is member of the serpin family of protease inhibitors. It is produced in the liver and serves to prevent activation and function of the neutrophil serine

wheezing, shortness of breath, rales, rhonci, and in some cases, liver failure. [65]

CF and these will be discussed in a later section.

**8. Alpha 1 AT**

**8.2. Etiology**

**8.3. Pathophysiology**

**8.1. Overview/epidemiology**

without a known underlying cause. [64]

(5) Airway obstruction, colonization and episodic exacerbations promote a state of chronic inflammation in CF. In fact, the clinical status of the CF patient, especially during an exacer‐ bation, is tied more closely to the inflammatory response than the quantity and types of or‐ ganisms responsible for the infection. That inflammatory response is dominated by neutrophils (PMNs) and is responsible for the bulk of tissue damage in the CF airways. Bronchoalveolar lavage and sputum specimens from patients during exacerbation reveal high concentrations of both PMNs and their effectors and signaling molecules, such as neu‐ trophil elastase and IL-8, respectively. [56] IL-8 is a powerful recruiter of PMNs, and excess levels of this signaling molecule likely explains the PMN dominated inflammation in CF. Excess PMN recruitment to the lungs results in the discharge of their destructive weapons (described above) and subsequent killing of pathogens, apoptosis and damage to lung and airway tissue. More often the extreme inflammatory state leads to an aggregation of dying PMNs that result in dysregulated cell lysis, or necrosis, instead of a controlled destruction that mitigates tissue damage. When PMNs undergo necrosis instead of apoptosis they re‐ lease all of the activated enzymes and molecules designed to destroy pathogen into the in‐ terstitial space, further damaging an already taxed pulmonary environment. This damage results in a collection of mucopurulent debris that further clogs airways and provides a breeding ground for further infection. [57]

## **7.5. Diagnosis of cystic fibrosis**

The accepted method for diagnosing CF is by quantitative analysis of the chloride ion con‐ tent of the sweat. This is based on the premise that the CFTR protein is expressed in sweat glands as well, leading to excessive chloride ion concentration in the sweat. DNA immunor‐ eactive trypsinogen screening techniques are available that detect the presence of many of the common CF mutations. [52],[58] Although not standard, newer diagnostic and screening techniques include genotyping and measurement of the nasal potential difference. No mat‐ ter what the sweat chloride results, diagnosis of CF remains incomplete without molecular analysis of CFTR gene. Identification of the mutations, and confirmation of their trans state is necessary to provide the patient with an accurate prognosis and clear counseling to pa‐ rents as to their future reproductive options. Nasal potential difference assesses ion conduc‐ tance in vivo by observing changes in the voltage potential difference across the nasal epithelium. [59]

#### **7.6. Current cystic fibrosis therapeutics**

Advancements in therapeutics in CF in recent decades are the foundation for the prolonged survival of individuals noted above. Unfortunately, almost all current therapies the clinician has at his or her disposal only address the symptoms of CF without correcting the underly‐ ing channelopathy. Current CF therapeutics are best understood in relation to how they ad‐ dress the five pathological processes described above. Efforts to address the underlying cause of CF, mutations of the CFTR gene, are underway in the form of gene therapy. The central problem surrounding gene therapy is the search for a suitable delivery mechanism. Viral vectors have been studied, but immune provocation remains to be an obstacle. [60] Re‐ duced ASL height has been successfully addressed with inhaled hypertonic saline and en‐ zymes, such as recombinant human DNAase (dornase alfa). In conjunction with the inhalation therapies noted above, techniques such as breathing exercises, positive expiratory pressure masks, and chest compression (both manual and automated) seek to disrupt the mucus plaques that line the CF airways. Aggressive antibiotic therapy is employed to com‐ bat both chronic colonization and acute infections. Although inhaled tobramycin and cipro‐ floxacin therapy have been effective, the wide array of bacteria in the CF airway precludes development of antibiotic therapy protocol. Finally, high dose ibuprofen and macrolide (typically Azithromycin) treatments stifle the persistent, PMN-dominated inflammation seen in CF. [46],[61],[62] There have been recent exciting discoveries regarding treatment of CF and these will be discussed in a later section.
