Cystic Fibrosis (CF)


Cystic fibrosis (CF) is a rare, life-threatening disease of the exocrine glands in which thick, sticky mucus affects multiple organs, commonly the respiratory, digestive, and reproductive systems. Most children are diagnosed with CF by the age of 2 or 3 years. A small subgroup of individuals with milder forms of CF are diagnosed after 18 years of age, although this percentage (10%) of the CF population is diminishing due to the standardization of newborn screening, which allows for earlier diagnosis.1,2  

Many conditions share similar symptoms with CF, making CF difficult to diagnose without genetic testing.2

Acute sinusitis
Xray film of a skull of a patient (paranasal sinus) with acute left maxillary sinusitis (red circular shade) with haziness of the left maxillary air cells. Credit: Getty Images

Sinusitis

Acute sinusitis, characterized by inflammation of the mucosal lining of the sinus cavities, occurs simultaneously with rhinitis.3,4 Patients with CF experience symptoms of chronic, ongoing sinusitis, whereas acute sinusitis usually lasts a finite period, typically several weeks depending on how quickly antibiotics or the patient’s immune system can clear up bacterial or viral sinusitis, respectively. Bacterial sinus infections in CF differ from bacterial infections in non-CF sinusitis. 

In CF, common causes of bacterial sinusitis include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia, Achromobacter (also known as. Alcaligenes or Acinetobacter) xylosoxidans, and Stenotrophomonas maltophilia.5 Bacterial agents that typically cause acute sinusitis include Streptococcus pneumoniae, H influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.6

Bronchiolitis

Bronchiolitis is an acute inflammation of the bronchioles, commonly caused by viral infections such as respiratory syncytial virus and often severely affecting infants.7 Cystic fibrosis is chronic, whereas acute bronchiolitis lasts between 8 and 15 days. Determining the etiology aids in proper differentiation between bronchiolitis and CF. Respiratory syncytial virus usually causes bronchiolitis, while a CF transmembrane conductance regulator (CFTR) gene mutation causes CF.8 Scientists have recently questioned whether constrictive bronchiolitis was a proposed mechanism causing progressive CF lung disease.9

Pediatric Bronchiectasis

Pediatric bronchiectasis is the dilatation and gradual destruction of bronchi in the lungs of children, resulting from acute or chronic lung infections.10 Cystic fibrosis may cause bronchiectasis, but most cases of bronchiectasis are not due to CF.11 Cystic fibrosis requires genetic testing to assess the presence of a CFTR gene mutation and is often diagnosed following a single high-resolution computed tomography scan. Non-CF bronchiectasis requires multiple imaging sessions to identify the permanent abnormal dilatation of bronchi, and it may have the potential to resolve following treatment, whereas CF is progressive.12 

Pediatric Aspergillosis

The genus Aspergillus consists of saprophytic molds present on decaying material. More than 900 Aspergillus species exist. Aspergillus flavus accounts for around 10% of invasive diseases and is the most common cause of sinusitis.13 Airway infections due to Aspergillus species are prevalent in children under 5 years of age with CF and are potentially related to increased air trapping found in these patients.14 

Methods of differentiating pediatric aspergillosis from CF include serum total immunoglobulin (Ig) E, eosinophil count, sputum microbiology, Aspergillus radioallergosorbent testing (RAST), and Aspergillus precipitin testing to determine the presence of anti-Aspergillus antibodies in the blood.15 

Primary Ciliary Dyskinesia 

Primary ciliary dyskinesia is characterized by the lack of motion of cilia, leading to impaired mucociliary clearance. Kartagener syndrome is a form of primary ciliary dyskinesia characterized by the triad of chronic sinusitis, bronchiectasis, and situs inversus.16 In primary ciliary dyskinesia, mucus accumulates in the airways because the cilia are unable to sweep it away.2 In CF, the thick, sticky mucus adhere to normal cilia, affecting ciliary movement and subsequent proper airway clearance.17

In CF, lung disease predominantly impacts the upper lobes, whereas in primary ciliary dyskinesia, the middle and lower lobes are most affected. Sinus disease is common in both primary ciliary dyskinesia and CF; however, nasal polyps are characteristic of CF. Situs inversus is present in approximately 50% of patients with primary ciliary dyskinesia due to immotile cilia on the embryonic node leading to random lateral positioning of organs, while it is typically not associated with CF.17

Primary Immunodeficiency

In primary immunodeficiency, a weakened immune system is unable to fight infections, allowing them to occur more frequently.18 A recent study demonstrated that primary immunodeficiency disorders are common in children with non-CF bronchiectasis, with around 40% of affected children exhibiting them.19

CFTR mutations may directly impact immune cell function through the alteration of various leukocytes including T cells and may increase pulmonary hyperinflammation by altering the kinetics of polymorphonuclear neutrophil degradation; however, further research is required to explain the mechanisms of mucosal immunodeficiency in CF in greater detail.20 

Pediatric Asthma

Asthma in children indicates chronic inflammation of the airways obstructing airflow.21 Children with CF typically produce abundant sputum and have a chronic cough, symptoms which are atypical in severely asthmatic children. Children with CF also experience frequent respiratory tract infections from an early age, exhibiting symptoms similar to asthma, which may hinder proper diagnosis.22 

To add to the diagnostic difficulty, asthma is often a comorbidity in children and adults with CF. The North American Epidemiologic Study of Cystic Fibrosis reported that 19% of 18,411 patients with CF also had asthma at the time of their initial visit, while cumulative visits raised the prevalence to 31.5%. Similarly, the European Epidemiologic Registry of Cystic Fibrosis reported a 17% prevalence of comorbid asthma and CF in 6856 patients. While bronchodilator responsiveness strongly suggests asthma, CF patients with or without asthma may also respond to bronchodilators.15 

Scientists and clinicians are currently working to differentiate this CF-asthma overlap syndrome (CFAOS) from asthma, and they have published a comprehensive review for ways to differentially diagnose and treat CFAOS.23

Gastroesophageal Reflux Disease
Esophagram or Barium swallow oblique view showing esophagus for diagnosis GERD or Gastroesophageal reflux disease

Gastroesophageal Reflux Disease 

Gastroesophageal reflux disease (GERD) presents as a comorbidity in many patients with CF. Researchers believe that GERD contributes to the pathogenesis of progressive lung disease in CF, with patients who have both CF and GERD also demonstrating more severe lung disease, potentially due to reflux-induced aspiration.24 

Testing for GERD includes a 24-hour pH study.15 If GERD and CF are comorbid, then the 24-hour pH study and CF sweat test would either confirm these respective diagnoses or determine the presence of one and the absence of the other.15,25

Failure to Thrive/Short Stature 

Failure to thrive (FTT) characterizes neonatal growth insufficiency defined by a pattern of weight gain in infancy. Due to malabsorption problems and nutritional deficiencies, infants with CF typically exhibit FTT. In conventional FTT classifications, this exemplifies an organic failure to thrive, caused by acute or chronic diseases like CF that interfere with nutrient absorption. Organic FTTs comprise less than 5% of all FTT cases. If FTT is suspected, CF must be ruled out as a cause.26 

Many factors contribute to short stature, including CF. As a child with CF ages, nutritional deficiencies due to pancreatic insufficiency, chronic inflammation, decreased energy intake, and increased energy expenditure may result in stunted growth.27 Cystic fibrosis should be ruled out in children who fail to achieve a certain height-to-age percentile.  

Pediatric Celiac Disease

Celiac disease, an autoimmune disorder triggered by gluten ingestion, primarily affects the small intestine, damaging it over time. This impacts nutrient absorption in the small intestine. Consequently, celiac disease and CF have overlapping symptoms including fatigue, weight loss, constipation, and problems gaining weight and growing.28 

According to one study published in 2013, celiac disease and CF comorbidity is rare, affecting 1 in every 200,000 patients. The investigators assessed comorbidity of CF and celiac disease in a child, confirming CF through 3 positive sweat tests and pulmonary changes on imaging and confirming celiac disease through immunological tests like serological tests of anti-transglutaminase IgA antibodies, histological tests indicating changes in the duodenal mucosa, and an improvement in symptoms following a gluten-free diet.29 

A later study reflected on the ongoing difficulties of differentiating between celiac disease and CF, which were once thought to be the same disease because both cause malabsorption issues. These researchers described false-positive sweat tests in 2 patients who were initially diagnosed with CF but were later diagnosed only with celiac disease. Genetic testing to confirm a CFTR mutation may validate or negate positive sweat tests.30

Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome is another rare genetic disorder characterized by the malabsorption of fats and other nutrients due to pancreatic insufficiency and bone marrow dysfunction, causing serum blood cell deficiencies.2 Similarly, individuals with CF are more likely to develop iron deficiency anemia that progressively worsens with age and increased lung dysfunction.31 Exocrine pancreatic insufficiency is a common comorbidity in CF.

One method of differentiating CF from Shwachman-Diamond syndrome is the sweat test. Individuals with CF have abnormally high concentrations of sodium and chloride in their sweat, while individuals with Shwachman-Diamond syndrome have normal sweat electrolyte levels.32

References

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  4. Brook I. Acute sinusitis. Medscape. Updated February 23, 2021. Accessed January 17, 2022. 
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  12. Chalmers JD, Elborn JS. Reclaiming the name ‘bronchiectasis’. Thorax. 2015;70(5):399-400. doi:10.1136/thoraxjnl-2015-206956
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  22. Ullmann N, Mirra V, Di Marco A, et al. Asthma: differential diagnosis and comorbidities. Front Pediatr. 2018;6:276. doi:10.3389/fped.2018.00276
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Reviewed by Harshi Dhingra, MD, on 1/17/2022.

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