Recurrent respiratory infections

A child or young adult with recurrent sinopulmonary infections, bronchiectasis, chronic productive cough, or unexplained Pseudomonas/aspergillus disease. The bedside question is which of three mechanisms is failing: mucociliary clearance, host immunity, or structural lung.

Three mechanistic buckets, each with its own discriminator at the bedside.

• Mucociliary clearance defects (cystic fibrosis, primary ciliary dyskinesia): chronic productive cough from childhood, sinusitis, classic colonizers (Pseudomonas, Staph), bronchiectasis on imaging.
• Primary immunodeficiency: pattern of infection localizes the defect (encapsulated bacteria for B-cell defects; opportunistic and viral pathogens for T-cell defects; catalase-positive organisms for phagocyte defects).
• Structural lung disease: alpha-1 antitrypsin emphysema, surfactant disorders, congenital malformations.

Mucociliary

• Cystic fibrosis: CFTR. Chronic pulmonary infections (especially Pseudomonas, Staph aureus), pancreatic exocrine insufficiency, failure to thrive, congenital bilateral absence of the vas deferens (male infertility). Sweat chloride greater than 60 mEq/L confirms. CFTR modulators are transformative for eligible genotypes.
• Primary ciliary dyskinesia: DNAH5, DNAI1, others. Chronic sinusitis, bronchiectasis, situs inversus (Kartagener) in roughly 50%, male infertility, neonatal respiratory distress at term gestation (an underused early clue). Nasal nitric oxide is low; ciliary biopsy or genetic panel confirms.

Primary immunodeficiency

• X-linked agammaglobulinemia: BTK. Recurrent encapsulated bacterial infections starting around 6 months as maternal IgG wanes. Absent B cells, all immunoglobulin classes low. IVIG is treatment.
• CVID: adult-onset hypogammaglobulinemia with normal B-cell numbers but defective antibody production. Autoimmunity and lymphoma risk.
• Severe combined immunodeficiency: infants with Pneumocystis pneumonia, chronic thrush, failure to thrive. Newborn screening via TREC catches it; hematopoietic stem cell transplant in early infancy is curative.
• IgA deficiency: usually mild, occasionally recurrent sinopulmonary infections plus autoimmune disease.
• Chronic granulomatous disease: CYBB (X-linked, most common), autosomal forms. Recurrent abscesses with catalase-positive organisms (Staph, Burkholderia, Serratia, Nocardia), Aspergillus pneumonia, granulomatous colitis. Dihydrorhodamine flow assay is diagnostic.
• Hyper-IgE syndrome (Job syndrome): STAT3 dominant negative. Staphylococcal "cold" abscesses, eczema, retained primary teeth, scoliosis, characteristic facies (broad nose, prognathism), pneumatoceles. IgE levels in the thousands.

Structural and parenchymal

• Alpha-1 antitrypsin deficiency: SERPINA1 PiZZ. Early-onset (third to fifth decade) panacinar lower-lobe emphysema, neonatal cholestasis or later cirrhosis. Augmentation therapy for lung disease.
• Surfactant protein disorders: SFTPB, SFTPC, ABCA3, NKX2-1 (brain-thyroid-lung). Present in neonates with refractory respiratory distress or in older children with ILD.

Other

• Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis or asthma; not heritable but worth flagging in the workup.

• Sweat chloride for any GI plus respiratory presentation, or newborn screening review.
• Quantitative immunoglobulins (IgG, IgA, IgM, IgE), lymphocyte subsets, vaccine response titers (tetanus, pneumococcal).
• Nasal nitric oxide and ciliary biopsy or PCD gene panel for chronic sinusitis plus situs or term neonatal RDS.
• Dihydrorhodamine flow assay if abscesses or Aspergillus.
• Alpha-1 antitrypsin level and Pi-typing in adults with emphysema before age 50 or with liver disease.