**3. Microbial complications in patients with cystic fibrosis**

Airways of patients with CF are usually infected with various microorganisms. In infected airways of CF patients, microhabitats can develop owing to local differences in the inflammatory reaction between the different focal areas of infection and also as a result of the competing activities of the many co-colonizing microbial populations [16]. Several bacterial strains are major causes of mortality and morbidity and have therefore been studied intensely [12].

#### **3.1 Microbial infection in patients with cystic fibrosis**

Chronic infection is a characteristic of CF airway disease. So, conditions in the airways of patients with CF are conducive to forming colonization by different microorganisms such as bacterial, fungal, and viral pathogens. Molecular identification of microorganisms has emphasized and recorded the polymicrobial nature of microbial infections in the CF airway microenvironment. Additionally, changes in airway of CF physiology through the loss of CFTR functionality lead to a variety of immune dysfunctions that permit microbial pathogen colonization and microbial persistence [7].

The prognosis of patients with the hereditary disease CF is substantially dependent on chronic respiratory infection and inflammation [17]. CF lungs are often colonized or infected with a complex microbial species, mainly composed of bacteria, provoking acute and chronic infections [18]. Airway infection accounts for 90% of the morbidity and mortality observed in CF patients. These chronic infections are typically associated with a few bacterial pathogens such as *Pseudomonas aeruginosa*, *Staphylococcus aureus*, and *Burkholderia cepacia* complex [19].

High morbidity and mortality rates in cystic fibrosis patients are secondary to recurrent respiratory infections, which, when associated with this obstructive lung disease, lead to respiratory insufficiency, the main cause of death in these patients [5, 14].

CF lung disease is characterized by progressive colonization of respiratory tract infection by different bacterial strains leading to polymicrobial biofilms. Also, the emergence of nontuberculous mycobacteria (NTM) infections has caused additional challenges to patient management due to their multiresistance nature to antibiotics [20]. These are compounded by the impairment of mucociliary clearance and the inability to mobilize thick secretions within the airways. These result in mucus impaction, microorganism colonization, recurrent infections, persistent inflammation and death from respiratory failure. With improvement in CF prognosis, new challenges emerge, including the management of fungal colonization and infection [1].

#### **3.2 Host-microbe interactions with CF lung infection**

Bacterial and fungal infections are hallmarks of CF lung disease. In the era of long-term inhaled antibiotics and increasing CF patient survival, new "emerging" pathogens are detected in CF airways, yet their pathophysiological impact remains largely controversial and incompletely defined. As a consequence to chronic microbial triggers, innate immune cells, particularly neutrophils, are continuously recruited into CF airways where they combat pathogens but also lead to tissue injury through the release of oxidants and proteases. The coordinated interplay between host immune cell activation and pathogens is essential for the outcome of CF lung disease. A better understanding of this phenomena may enhance the survival in CF [21–23].

*Cystic Fibrosis - Heterogeneity and Personalized Treatment*

**2. Defining causes and history of cystic fibrosis**

failure causing death in over 90% of CF patients [3].

significantly improved quality of life and survival [2].

stresses and other environmental triggers [14, 15].

disease, and infertility [3].

asthma [11].

viral, and fungal pathogens [7].

variety of respiratory diseases, including CF [6]. Chronic infection is the defined characteristics of CF airway disease. Conditions within the airways of patients living with CF are conducive to colonization by a variety of opportunistic bacterial,

Also, bacterial strains that colonize the respiratory tract include *Haemophilus influenzae*, *Staphylococcus aureus*, *Pseudomonas aeruginosa* [8], and *Burkholderia cepacia*; these have been recorded as the main common CF pathogens. Traditionally, *Pseudomonas aeruginosa* has been regarded as the main pathogen in CF, and chronic infections have been linked to disease morbidity and mortality [9]. Little attention has been paid to the role of *Aspergillus* sp. and other filamentous fungi in CF. It has become more apparent, however, that *Aspergillus* sp. may play an important role in chronic lung disease in CF [10]. This chapter discusses the complications of microorganisms in patients with cystic fibrosis, including bacterial, fungal, and viral pathogens and their effects on this disease leading to an increased risk of mortality.

Cystic fibrosis is a multisystem genetic disease that affects children and young adults [11]. It is caused by mutations in CFTR gene leading to defective or insufficient amounts of functional CFTR protein and causes abnormalities in chloride (Cl), bicarbonate (HCO3), and sodium (Na) transport across cell membranes with serious consequences on multiple organs. The CF lung disease is characterized by infection and inflammation with eventual bronchiectasis and eventual respiratory

Cystic fibrosis is an autosomal recessively inherited disorder caused by the presence of one of more than 1500 possible mutations in CFTR gene with an occurrence of the clinical disease being 1 in 2500 live births. This mutation leads to the nonfunction or loss of function of CFTR (a cyclic AMP-regulated chloride ion channel) leading to defective chloride ion transport through epithelial cell surfaces [12]. Since its first description in 1938, study of the genetics, pathophysiology, and clinical manifestation of the disease has led to the creation of new therapies and

In CF, the biology and treatment strategies are important to understand for several reasons. Firstly, it is the most common cause of chronic respiratory failure in children and adults. Secondly, CF is a common reason for the dysfunction of pancreatic exocrine in children and adults. Thirdly, the majority also develop pansinusitis. Other potential consequences of CF include diabetes, liver disease, bone

Advances in research of CF have given a roadmap for the understanding of pathophysiology studies and treatment stages for other severe airway diseases, including chronic obstructive pulmonary disease, non-CF bronchiectasis, and

Survival of individuals with CF has improved significantly over the last half century from a median age of survival of 5 years in the 1970s to 40 years of age as of 2011. There are different reasons for improvement in clinical outcomes including the intense use of antibiotic therapy, advancement in chest physiotherapy, nutritional support, specialized CF units, and introduction of CFTR modulators; however, the majority of CF deaths still occurred in young adult especially in the ages between 21 and 30 years as a consequence of respiratory failure [13]. Recent research also suggests that even asymptomatic genetic carriers for CF may be at risk for subclinical physiological derangements, which can be exacerbated by external

**24**

#### **3.3 Nontuberculous mycobacteria species in patient with cystic fibrosis**

NTM are wide environmental microorganisms causing chronic pulmonary infection in lung diseases such as CF. Also, pulmonary disease caused by NTM has a major threat with CF and difficult to diagnose and problematic to treat according to the US Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS). Additionally, the most common NTM species identified in CF are the slow-growing *Mycobacterium avium* complex (MAC) including *M. intracellulare*, *M. avium*, and *M. chimaera* and the rapid-growing *M. abscessus* complex (MABSC) including subspecies of *M. a. abscessus*, *M. a. massiliense*, and *M. a. bolletii*. Other less common NTM species include *M. kansasii*, *M. simiae*, and *M. fortuitum* [24].

In addition, there are more than 100 types of NTM, and more are being found every year. The reported prevalence of NTM in CF varies widely from 45 to 40% with *Mycobacterium avium* complex and *Mycobacterium abscessus* complex being the most common [25, 26].

## **4. Airway colonization process in patients with cystic fibrosis**

Colonization of microorganisms in respiratory tract infection within young CF patient includes common pathogens such as *S. aureus* or *H. influenza* then succeeded by *P. aeruginosa* infection in the latter stages of CF.

It is well established that *Pseudomonas aeruginosa* is a frequent and virulent pulmonary pathogen in patients with CF [27]. After a period of intermittent colonization, the organism becomes permanently established and is difficult to eradicate. Most patients with CF become chronically infected with wild-type *P. aeruginosa* strains in early childhood [28]; prevalence increases with age, so that as many as 80% of patients with CF are infected by the time they reach 20 years [27]. During the years following initial colonization, the wild-type strains uniformly mutate into mucoid variants [28]. Conversion to the mucoid phenotype is thought to be driven by the unique CF microenvironment [29–31]. For patients with CF, this conversion results in a significant increase in morbidity and mortality accompanied by a measurable decline in pulmonary function [28]. The mucoid matrix is believed to allow the formation of protected biofilm microcolonies [30, 32] and provide increased resistance to opsonization, phagocytosis, and digestion [33]. Furthermore, resistance to various antibiotics is increased [27, 34].

The potentiality of pathogenic bacterial colony morphotypes in *P. aeruginosa* evolved to a non-swimming phenotype form. So, motility is considered as one of the first steps of *P. aeruginosa* in CF lungs that lead to adaptation steps including biofilm formation and progress to chronic infection. Also, impaired swimming motility seemed to be a candidate to disease marker of *P. aeruginosa* infection development. So far, the pathological changes in the lungs are best studied due to the high mortality rates linked to poorer lung function and recurrent development of infections [18].

Also, the lungs of people with cystic fibrosis are predominantly colonized with *Pseudomonas aeruginosa* using the following mechanism: firstly, reduced mucociliary clearance combined with the malfunction of antibacterial peptides; secondly, impaired defense of the lungs due to low levels of glutathione and nitrous oxide; thirdly, reduced ingestion of bacteria by lung cells; and finally, increased numbers of bacterial receptors [35].

On the other hand, earlier age of infection with *P. aeruginosa* in our population was strongly associated with greater likelihood of severe lung disease later in life, most particularly in those subjects who acquired *P. aeruginosa* before the age 5; the

**27**

*Recent Approach in Microbial Pathogen Complications in Patients with Cystic Fibrosis*

other processes determining lung function in children with CF [36].

**5. Fungal infection in patients with cystic fibrosis**

isolated from the respiratory secretions of CF patients [37].

factors access to the interstitial and vascular compartments [40].

*glabrata*, and *Candida dubliniensis* [1].

**6. Viral infection in patients with cystic fibrosis**

Also, exotic genera can be found in CF airway secretions, such as *Penicillium*, *Alternaria*, or *Scedosporium*. Some studies provide the first evidence that even healthy airways are not sterile and contain distinct fungi called "pulmonary mycobiome." The kinetics, dynamics, and disease relevance of the pulmonary mycobiome, however, are poorly understood [7]. The majority of yeasts in CF belong to *Candida* species and the most common species such as *Candida albicans* and other yeast strains recorded such as *Candida parapsilosis*, *Candida krusei*, *Candida* 

Progression of CF respiratory disease is influenced by viral infection. Respiratory viral infections include respiratory syncytial virus (RSV), rhinovirus,

observed association was stronger in females than in males. *P. aeruginosa* infection may be a cause of more severe CF lung disease but may also be a marker of some

Fungi are generally divided into molds or yeasts with the latter circumferentially

Yet, the relative contribution of other emerging pathogens, such as *S. maltophilia*,

shaped with a one-celled thallus. Molds also known as filamentous fungi grow as branching cylindrical hyphae [1]. Aspergillosis is the most well-characterized and well-recognized *Aspergillus* disease in CF, but reported prevalence varies significantly and is likely to be underdiagnosed. Aspergilli are saprophytic, sporeforming, filamentous fungi found ubiquitously in the environment. *A. fumigatus* is the most prevalent species causing human disease and is the species most frequently

*Aspergillus*, *Candida*, and *Scedosporium* species, remains less precisely defined. *Aspergillus fumigatus* is the only species that is associated with an increased risk for infection with *P. aeruginosa* [9]. *Candida* sp. is found in as many as 70% of patients with CF. The clinical significance of *Candida* in patients with CF is not clearly understood, but most clinicians discount these organisms as not significant [38]. Fungemia caused by *Trichosporon* has been reported in two patients with CF, who were double lung transplant recipients [39]. Some species such as *Exophiala dermatitidis* grow as unicellular fungi (yeast) at human body temperature but in the case of filamentous fungi at room temperature. *Trichosporon* species as of any *Candida* species may produce true mycelium in culture conditions or in host tissues. So, there are variations in isolation and purification of yeast and filamentous fungi. Additionally, some fungal strains are thermotolerant filamentous mycota such as *Aspergillus fumigatus* which are the most common, and others include *Scedosporium* species and *E. dermatitidis* [1]*. A. fumigatus* is frequently detected in respiratory secretions of both adults and children with CF. Once present in the airways, *Aspergillus* can exacerbate lung inflammation, establish infection, and trigger hypersensitivity responses [10]. In patients with CF, complications increased when exposed to *A. fumigatus* spores causing impaired mucociliary clearance and defective innate immune responses leading to accumulation and persistence of fungal spores within the smaller airways. Also, germination of spores leads to the formation of fungal hyphae and release of antigens, phospholipases, proteases, and other virulence factors which damage the airway of epithelial cells and allow a large dose of antigenic

*DOI: http://dx.doi.org/10.5772/intechopen.91635*

observed association was stronger in females than in males. *P. aeruginosa* infection may be a cause of more severe CF lung disease but may also be a marker of some other processes determining lung function in children with CF [36].
