Asthma

Heading the differential list is asthma, defined as reversible obstructive airway disease with a significant inflammatory component leading to increased edema and production of mucus. In the United States , asthma prevalence increased between 2001 and 2010 from 7.3% to 8.4%, with the highest reported prevalence of 9.5% in children between 0 and 17 years of age. Asthma can be distinguished from chronic bronchitis by pulmonary function evaluation documenting reversal of airway obstruction after delivery of pulmonary bronchodilators. Recurrent episodes of acute bronchitis often can be interpreted as chronic bronchitis, although the intermittent nature of these episodes and absence of a persistent cough usually distinguish this group of patients clinically.

Acute Infections

Specific viral infections (e.g., rhinovirus, respiratory syncytial virus, human metapneumovirus) in children with or without allergic rhinitis may provoke airway hyperreactivity and late onset of asthma, which may be confused symptomatically with chronic bronchitis. Persistent lower respiratory tract infections (i.e., Chlamydia spp., pertussis, Mycoplasma spp., and Mycobacterium spp.) frequently manifest with the complex of symptoms described or chronic wet cough and are evaluated best with chest radiographs in a search for enlarged hilar nodes or interstitial lung infiltrates. Respiratory tract secretions for appropriate bacterial and viral culture and serum for determinations of antibacterial antibodies should be obtained. In the case of tuberculosis, a delayed hypersensitivity skin test for Mycobacterium tuberculosis antigen should be applied or, in anergic individuals with blunted skin reactivity, interferon-γ release assays can measure immune reactivity of exposed/infected individuals’ white blood cells to M. tuberculosis . These types of assays, like the delayed hypersensitivity skin test, cannot differentiate past from active disease.

Cystic Fibrosis

Cystic fibrosis is a recessively inherited illness occurring in approximately 1 in 3700 live births, with clinical manifestations of failure to thrive, steatorrhea, nasal polyps, and recurrent lower respiratory tract symptoms. The disorder is associated with mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cystic fibrosis can be diagnosed by newborn screening, and all 50 U.S. states and the District of Columbia participate in screening but not all utilize the same methodologies. Immunoreactive trypsinogen (IRT) testing is often combined with a DNA test including identifying typical CFTR gene variant patterns in DNA extracted from collected blood specimens on Guthrie cards at or after birth or clinically by detecting abnormally elevated chloride levels (>60 mEq/L) as measured by the sweat iontophoresis test. In clinical practice, one or both modalities may be used for establishing the diagnosis, especially for patients with genetic variations of the CFTR gene not typical of the classic cystic fibrosis phenotype or for patients with uninterpretable sweat test outcomes.

Ciliary Dyskinesia

Primary ciliary dyskinesia encompasses the immotile cilia disorders and Kartagener syndrome (rhinosinusitis, bronchitis or bronchiectasis, situs inversus) and affects 1 in 16,000 births in the United States. Primary ciliary dyskinesia typically is inherited as an autosomal recessive disorder and is associated with defects in mucociliary transport in the respiratory tree. The symptom complex also has been associated with polycystic kidneys, hepatic disease, and central nervous system symptoms. Screening tests for primary ciliary dyskinesia include nasal nitric oxide and in vivo tests of ciliary motility, but these tests are not universally available, and standardization is problematic. Genetic testing is commercially available and can detect disease-causing mutations in autonomic genes coding for outer dynein arms (present in 60% of affected individuals), radial spoke, and cytoplasm proteins involved in dynein arm assembly.

Primary Immunodeficiency

The primary immune disorders associated most frequently with recurrent sinopulmonary infections include selective immunoglobulin (Ig) A deficiency, functional antibody deficiencies, hypogammaglobulinemia, and ataxia telangiectasia (AT). Selective IgA deficiency is the primary immune disorder encountered most commonly, with an incidence of 1/500. It may be asymptomatic or accompanied by a propensity for atopy and an increase in associated autoimmune disease (most often rheumatoid arthritis and systemic lupus erythematosus). The diagnosis is made readily by evaluation of quantitative serum immunoglobulins defining IgA levels of less than 10 mg/dL. IgA deficiency may be associated with IgG subclass deficiencies (IgG2 deficiency was identified in 85% in a series of >150) with or without clinical symptoms. Children with normal serum Ig levels may have recurrent infections associated with specific functional antibody defects. In particular, the inability to respond serologically to vaccination with polysaccharide antigens such as Streptococcus pneumoniae or Haemophilus influenzae type B has been reported in association with four separate immune phenotypes: severe (fewer than three protective titers to S. pneumoniae ), moderate (<70% of S. pneumoniae titers protective), and mild (loss of response within 6 months of vaccination). Clinical sinopulmonary disease has been associated with each immune phenotype, but the severe and moderate more often require clinical intervention.

Patients with hypogammaglobulinemia represent a diverse group having primary immune disorders that include but are not limited to X-linked agammaglobulinemia, common variable immune deficiency (CVID), and hyper-IgM syndrome. X-linked agammaglobulinemia typically affects boys who experience recurrent sinopulmonary infections, with onset occurring postnatally as maternal antibody wanes. X-linked agammaglobulinemia is associated with deficiency of a B-cell maturation enzyme, Bruton tyrosine kinase, and is characterized by the absence of circulating mature B lymphocytes. CVID is a disorder of young adults with immune findings of agammaglobulinemia and variable T-cell defects. Clinical classification systems for CVID have been proposed that vary by measure of B lymphocyte immune parameters and/or inclusion of autoimmune disease, but all include infections—specifically lower respiratory tract and sinus disease no matter the infectious etiology. Inherited CVID disorders have been described that include absence of B-cell markers (CD19 or CD20 ⁺ ) in peripheral blood, defects in B-cell activating factor of the tumor necrosis factor family receptor (BAFF), inducible T-cell costimulator gene and transmembrane activator, and calcium-modulator and cyclophilin ligand interactor (TACI), but, except for the latter, they represent a small population of affected individuals with CVID. Patients with TACI variant and CVID may lack circulating mature B lymphocytes. More often, patients with CVID normally express B-cell markers on circulating lymphocytes. Hyper-IgM syndrome is a rare disorder associated with elevated IgM and Ig class switch failure resulting in low IgG and IgA. The disorder can be caused by differing genetic defects with an X-linked form (CD40 ligand gene variant resulting in poor protein production) and autosomal recessive forms (CD40 antigen absence, activation-induced cytidine deaminase variant or uracil DNA glycosylase variant). Independent of genetic inheritance, all forms of hyper-IgM syndrome are associated with recurrent infections including sinopulmonary and hepatic infections.

Patients with AT have depressed serum IgA concentrations and progressive neurologic dysfunction, eventually impacting the swallowing mechanism and leading to recurrent lower respiratory tract infections probably secondary to recurrent aspiration. These patients are identified in childhood by telangiectasias of the skin and conjunctivae in association with aberrant and progressively deteriorating neurologic symptoms and immunodeficiency (depressed IgA and IgE and aberrant T-cell–mediated immunity). Some patients have depressed IgG subclasses (IgG2, IgG4) as well. The gene abnormality in AT has been identified as disruption of the ataxia telangiectasia molecules responsible for detection and implementation of DNA repair dependent on phosphatidylinositol-3-kinase signal transduction pathways.

Primary immune disorders with hypogammaglobulinemia can be diagnosed through evaluation of serum immunoglobulin levels. Further characterization includes assessment of antibody production after vaccine or neoantigen challenge, evaluation of circulating lymphocyte cell surface markers, and in vitro proliferative responses to plant lectins or specific antigens. Evaluation of associated gene variants is important for determining corrective interventions (e.g., transplantation, gene therapy) and genetic counseling. Whole exome sequencing and molecular diagnosis for patients with primary immunodeficiency disease are imperative to predict their morbidity to allow for family counseling for affected individuals or carriers and will likely impact development of therapeutic approaches.

Secondary Immunodeficiency (Including HIV Infection)

Secondary immune disorders (prematurity, pediatric human immunodeficiency virus [HIV] infection, designed medical immunosuppression) also may be associated with significant sinopulmonary infections. Premature infants with attendant severe respiratory distress syndrome requiring positive-pressure ventilation may develop bronchopulmonary dysplasia. Diagnostic criteria include hypoxia requiring oxygen supplementation, characteristic diffuse interstitial markings on chest radiograph, and clinical signs of pulmonary disease (i.e., tachypnea, intercostal retractions). In one series, more than 60% of surviving children with bronchopulmonary dysplasia were documented to have significant pulmonary disease and associated morbidity (i.e., increased hospitalizations). Continued improved care for premature infants and resultant decreased incidence of mortality may increase the population of infants with bronchopulmonary dysplasia.

Pediatric HIV infection has declined and is documented to affect approximately 2% of infants born to HIV-infected mothers in the United States and Europe. This reduced infection rate can be attributed to (1) universal prenatal HIV counseling and testing, (2) availability and use of highly active antiretroviral therapy (HAART) in pregnant women and their newborn infants, (3) practices that minimize exposure to breast milk, and (4) obstetric practices that encourage cesarean delivery or decrease time from membrane rupture to delivery. Continued maternal-to-child infection is associated with maternal lack of knowledge about her HIV status, breastfeeding, and lack of HAART therapy during pregnancy independent of CD4 cell count or HIV RNA levels.

HIV-infected infants report serious lower respiratory tract illness. Lymphoid interstitial pneumonitis/hyperplasia (LIP), reported in 25% of all U.S. children with acquired immunodeficiency syndrome pre-HAART was rare, with a reported incidence rate of less than 0.5 per 100 person-years in children in 2006. However, ongoing studies of HIV-infected youth in sub-Saharan Africa suggest chronic lung disease (LIP, bronchiectasis) is underrepresented and debilitating. With restoration of immunocompetence with antiretroviral therapy (ARV), lower respiratory tract infections (viral, bacterial, fungal) rates in the United States lowered as compared to pre-ARV reports; the incident rate for bacterial pneumonia is 11.1 versus 123.1 (pre-/post-ARV). An unexpected consequence of ARV in affected children may lead to increased risk for developing asthma through an immune reconstitution mechanism.

The diagnosis of HIV infection is established by viral diagnostic assays (nucleic acid tests [NAT]) in infancy when diagnostic sensitivity of the testing is enhanced, preferably during delivery of neonatal ARV prophylaxis and then 2 to 4 weeks after cessation of prophylaxis. Early diagnosis is important so that affected children may start ARV therapy early in their clinical course. HIV antibody testing (enzyme-linked immunosorbent assay and confirmation assays [Western blot analysis, indirect fluorescent antibody assay]) can confirm infection in infants presenting to care under special circumstances after 18 months or older with additional non-perinatal HIV risks. HIV serologic assays in children 18 months of age or younger with perinatal HIV exposure can confuse interpretation of such testing because passively acquired maternal HIV antibodies may persist for up to 24 months in some studies in such infants and delay diagnosis and institution of appropriate care.

Lower respiratory infections with chronic cough can be seen in individuals with autoimmune or inflammatory disorder and cancers or as a result of medical immunosuppression for the same disorders. Solid organ and stem cell transplant with immune suppression is also associated with infectious and inflammatory residual lung disease with chronic cough. Graft-versus-host disease affecting the lungs has been described in immunocompromised patients and particularly following transplantation. The lesion is caused by chronic pulmonary lymphocytic infiltrates and pulmonary fibrosis mimicking the symptom complex of chronic bronchitis and often is indistinguishable radiographically or clinically from infections that characteristically are pathogenic (i.e., Pneumocystis jiroveci , Candida albicans , Aspergillus spp.).

Airway Blockage

Anatomic lesions that lead to pulmonary obstructive airway disease can simulate the complex of chronic bronchitis. An infant with chronic cough, poor feeding habits, and failure to thrive should undergo evaluation for gastroesophageal reflux and tracheoesophageal fistula, which are identified most easily by upper gastrointestinal imaging studies, pH probe and impedance monitoring in older infants and adolescents, and nuclear scan. Mediastinal tumors can produce extrinsic obstruction, leading to recurrent cough and wheezing. Congenital heart disease should be considered in this patient group and can be evaluated with chest radiography, electrocardiography, and echocardiography.

Noxious Agents

Respiratory tract irritants have been implicated as a cause of chronic cough, as documented in adult populations of industrial European nations. An assessment of the public health impact of pollution in Austria, France, and Switzerland concluded that air pollution caused 6% of all mortality, or 40,000 attributable cases per year. Teasing out the impact of urbanization or biomass fuel smoke exposures from other noxious lung factors like smoking can be difficult in population-based studies. A recent study in Peru, a country with overall low prevalence of tobacco smoking, reported a distinct difference in the prevalence of chronic bronchitis in those living daily in urbanized communities as compared to more rural cities (8.3% vs. 1.3%, respectively). In this cohort, individuals with chronic bronchitis had higher prevalence rates (PR) when they reported daily urban living (PR, 3.34) and daily exposure to biomass fuel smoke (PR, 2.0). Nonindustrial, rural communities, such as the forest zone of Nigeria, report virtually no chronic bronchitis, whereas increased risk for development of respiratory disease (i.e., persistent cough, persistent phlegm, asthma) is noted in children residing in six cities in Northern China with the highest ambient air levels of particulate air pollution. After exposure to urban air particulate matter, animal models with induced chronic bronchitis (exposure to 200 ppm of sulfur dioxide for 6 weeks) have shown pathologic changes consistent with exacerbation of chronic bronchitis—changes in ventilatory capacity and marked pulmonary inflammation.

A correlation between tobacco smoking and reduced ventilatory capacity in adults has been reported by many investigators. Peat and associates described teenagers in Sydney, Australia, with recurrent episodes of bronchitis with worsened lung function when coupled with tobacco smoking. A meta-analysis of 21 relevant publications on relationships between exposure to environmental tobacco smoke and lower respiratory tract infection in infancy and early childhood concluded that exposure to environmental smoke resulted in adverse childhood respiratory outcomes (hospitalizations). In a study of approximately 65,000 nonsmoking Canadians 12 years or older, vehicular environmental tobacco smoke was associated with chronic bronchitis for children between 12 and 19 with odds ratios of 2.3 and 2.25 for children and older teens, respectively. Tashkin and colleagues further found in 300 individuals followed for 10 years that both tobacco and marijuana smoking appeared to be causally associated with the development of chronic bronchitis. These data suggest that it is not only imperative to prevent smoking in individual youth to prevent respiratory disease but also to gather a smoking history (tobacco and drugs) for household members and apprise them of the impact of their smoking on their children. Newer popular practices of e-cigarette (e-cig devices or e-liquid [nicotine in a glycerol/propylene glycol vehicle with flavorings]) use or vaping cannabis may diminish individual particulate lung exposure, but data addressing whether these practices diminish lung damage have not yet been published in large population-based studies over significant exposure intervals. These devices clearly do not reduce nicotine or cannabis exposure to the end user.

Other noxious agents associated with outdoor pollution have been associated with poor control of chronic cough complex diseases such as asthma. In Los Angeles, adults with asthma were more poorly controlled if they resided near areas of heavy traffic. Similar findings of poorly controlled lung disease associated with traffic pollution have been documented in adult and pediatric patients in Lima, Peru. Occupational exposures long have been cited for exacerbating pulmonary diseases and may be responsible for about 15% of chronic bronchitis and chronic obstructive pulmonary disease. Classic examples of occupational exposures leading to increased risk for developing chronic cough are described in coal dust for miners in Great Britain and recently in smoking and welding fumes in Northern European welders.