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.
- cystic fibrosis
- pathogenic bacteria
- pneumonia infection
- pulmonary inflammation
- treatment guidelines
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.
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 . 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 .
Americans and Europeans are more susceptible to CF. One in 29 people of Caucasian ancestry is a healthy carrier of the CF gene mutation . 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 . Walaa et al.  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
2.2 CF respiratory pathogens
The two subtypes of
In some countries where CF lung disease is spreading, anti-staphylococcal agent is provided as a prophylaxis approach during childhood particularly when
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:
2.2.8 Fungi and viruses
A lot of fungi are isolated from CF patients, including yeasts such as
2.3 CF airway microbiome
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
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 . Many studies report that, bacterial infection and inflammation are leading to triggering of neutrophils . 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 .
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
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 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 . 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 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 . High level of neutrophil elastase in induced sputum indicates lung dysfunctions and bronchiectasis . The inflammation of the passage airways in sputum is reduced after detection and using of effective antibiotics for treatment of a CF-pulmonary diseases . Inflammatory proteins are considered potential biomarkers of disease in CF. For example, the blood plasma proteins are biomarkers of CF disease .
The common example of immune response in CF lung disease is the immune response to
4. Anti-inflammatory therapy of CF
Ibuprofen inhibits neutrophil migration and aggregation . 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 . 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 .
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 . Azithromycin may be used for a very long period (chronic azithromycin) either with or without chronic
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 . Inhaled corticosteroids do not have any efficacy in the treatment of CF . Therefore, the treatment of CF by systemic or inhaled corticosteroids is not recommended by the Cystic Fibrosis (CF) Foundation . 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 .
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 . 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 . 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.
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
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.
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.