Hypersensitivity Pneumonitis

Type III (Immune Complex) Hypersensitivity Mechanism—Acute Phase Response

Type IV (Cell-Mediated) Hypersensitivity Mechanism—Delayed Phase Response

Antigen Clearance Defects and Persistent Sensitization

Granuloma Formation and Tissue Remodeling

Epithelial and Endothelial Barrier Dysfunction

Molecular Triggers and Pattern Recognition

Organic Antigens—Fungal Sources (Most Common Occupational HP)

• Thermophilic actinomycetes (Thermoactinomyces sacchari, Thermoactinomyces thalpophilus, Bacillus subtilis) found in moldy hay, grain, sugar cane bagasse → Bagassosis in sugar cane workers; Farmer's lung in grain workers and farmers with moldy hay exposure
• Aspergillus fumigatus and other Aspergillus species in moldy grain, compost, and stored agricultural products → occupational exposure in farmers and agricultural workers; also found in contaminated heating/ventilation systems
• Candida and other fungi in moldy wood chips, sawdust, cork dust → Wood worker's lung and cork worker's lung

Organic Antigens—Avian/Animal Protein Sources

• Avian serum proteins and fecal antigens (from pigeons, parakeets, budgerigies, chickens) → Pigeon breeder's lung and Bird fancier's lung (most common form of HP overall, affecting hobbyists and professionals); these antigens are exceptionally immunogenic
• Feather dust and down from pillows and bedding → potential non-occupational source
• Arthropod proteins from dust mite feces and insect debris

Occupational/Environmental Inorganic Exposures

• Metalworking fluids (water-soluble cutting fluids contaminated with bacteria and endotoxin) → HP in machinists and metalworkers; bacteria include Pseudomonas aeruginosa, Mycobacterium species, and environmental Gram-negative organisms
• Isocyanates and other organic chemicals (toluene diisocyanate, diphenylmethane diisocyanate) → can cause HP-like reactions in polyurethane foam workers and auto refinishers; distinguished from asthma by immune complex involvement

Domestic/Environmental Exposures

• Contaminated hot water systems and humidifiers containing thermophilic actinomycetes or Mycobacterium species → Summer-type HP in Japan (associated with home water systems); Humidifier lung in non-occupational settings; also sauna-taker's lung from sauna water contamination
• Moldy bedding, pillows, and home dust in sensitized individuals
• Contaminated heating, ventilation, and air conditioning (HVAC) systems in office buildings and homes → typically with thermophilic actinomycetes or Aspergillus

Healthcare-Associated Exposures

• Latex particles from gloves in sensitized healthcare workers
• Chronic grain exposure in hospital workers
• Contaminated respiratory equipment and nebulizer solutions

Exposures in Hobbyist/Recreational Settings

• Wine production (Botrytis spores and vineyard fungi)
• Hot tub use (Mycobacterium avium complex and thermophilic bacteria in aerosolized water)
• Composting and gardening with contaminated materials
• Exposure to moldy grain in home use (less common)

Risk Factors for Disease Development (Critical for Pathogenesis)

• Genetic susceptibility based on HLA haplotypes (HLA-DQ2, HLA-DQ8, HLA-DR3, HLA-DR4 associations reported in various populations); not absolute but increases disease risk substantially
• Repeated or continuous antigen exposure at high concentration; dose-response relationship exists (higher exposure intensity and frequency increase risk)
• Intensity and duration of exposure; occupational exposures are more intense than environmental, but hobby exposures can be substantial
• Smoking status is paradoxically protective (smokers have decreased incidence), possibly through altered immune response, but smokers may develop more severe fibrotic disease if HP develops
• Atopic phenotype (personal or family history of asthma, allergies) is NOT consistently associated, unlike in occupational asthma; HP represents a distinct immune mechanism
• Innate immune polymorphisms in pattern recognition receptors, inflammasome components, and interferon response genes
• Female predominance in certain settings (bird fanciers), suggesting hormonal influence on immune response
• Age factors: can develop at any age but more common in middle-aged workers with cumulative exposure; onset typically after repeated exposure rather than single exposure

Acute Hypersensitivity Pneumonitis (4-6 hours after exposure, typically high-dose exposure)

• Fever and constitutional symptoms: Temperature elevation to 101-103°F (38-39°C) with chills occurring 4-6 hours after antigen exposure; results from cytokine release (TNF-α, IL-1, IL-6) during immune complex deposition and complement activation; patients frequently report feeling feverish but may appear relatively well between fever spikes

• Acute dyspnea and tachypnea: Rapid-onset shortness of breath reflecting acute neutrophilic alveolitis with increased alveolar wall permeability and interstitial edema; sensation of "chest tightness" common; respiratory rate may reach 20-30 breaths/minute; dyspnea severity typically proportional to antigen concentration and inhalation duration

• Cough: Nonproductive or minimally productive cough developing within hours; lacks the wheeze characteristic of asthma; mechanical irritation from inflammatory exudate and epithelial damage rather than bronchospasm

• Malaise, myalgias, and arthralgias: Systemic inflammatory response with elevated TNF-α and IL-1β; patients often state they feel "influenza-like"; myalgias typically mild to moderate and generalized rather than focal

• Chest discomfort: Pleuritic or non-pleuritic chest pain in minority; suggests more extensive inflammation and possible pleural involvement (immune complex deposition also occurs in pleura)

• Physical examination in acute HP:
• Fine bibasilar crackles (end-inspiratory) most characteristic finding, representing alveolar filling from inflammatory exudate; typically bilateral and symmetric
• Tachypnea and tachycardia proportional to inflammation severity
• Wheezing absent (key distinguishing feature from asthma)—absence of bronchospasm
• Hypoxemia on pulse oximetry in moderate-to-severe cases; A-a gradient elevated (typically 15-30 mmHg)
• Fever palpable

• Timeline and resolution: Symptoms typically peak at 24-48 hours if patient is removed from antigen exposure and gradually resolve over 3-7 days as neutrophilic infiltration clears and complement is exhausted; complete resolution expected without sequelae in true acute cases with prompt exposure cessation

Subacute Hypersensitivity Pneumonitis (weeks of intermittent or low-level exposure)

• Progressive dyspnea and exercise limitation: Insidious worsening over weeks to months with continued low-level exposure; reflects progressive lymphocytic infiltration and granuloma formation replacing acute neutrophilic phase; patients often delay seeking care, attributing symptoms to poor fitness

• Persistent cough: Nonproductive or minimally productive, persistent throughout day; triggered or worsened by exposure days; less dramatic than acute but more persistent

• Fatigue and constitutional symptoms: Weight loss (sometimes substantial), fever (low-grade, often afternoon), night sweats; systemic manifestations reflect chronic inflammatory cytokine production

• Reduced exercise tolerance: Progressive limitation over weeks correlating with cumulative antigen exposure; patients notice they tire more easily with stairs or walking

• Physical examination in subacute HP:
• Fine to medium crackles (end-inspiratory) often more prominent than in acute phase and more widespread throughout lung fields
• Wheezing notably absent (continues to distinguish from asthma)
• Clubbing absent (important—distinguishes from idiopathic pulmonary fibrosis despite similar imaging in advanced cases)
• Cyanosis may develop in advanced cases with severe hypoxemia
• Hepatomegaly rare but reported with systemic inflammation

• Spirometry findings: FVC reduced (restrictive pattern) with FEV₁/FVC ratio preserved or elevated (truly restrictive, not obstructive); DLCO reduced more than expected from volume loss alone, reflecting diffuse alveolar inflammation; gas exchange deterioration

Chronic Hypersensitivity Pneumonitis (months to years of exposure)

• Progressive dyspnea on exertion: Insidious and progressive over months to years with continued exposure; reflects irreversible pulmonary fibrosis with architectural lung remodeling; eventually dyspnea at rest develops as FVC declines below 50% predicted

• Persistent cough: Often non-productive or productive of scant sputum; less dramatic than in acute/subacute but more debilitating due to chronicity; may worsen with exertion

• Constitutional symptoms less prominent: Unlike subacute disease, systemic symptoms (fever, malaise) often fade as chronic inflammation becomes localized despite progressive lung damage; patients may feel relatively well systemically while lungs deteriorate—dangerous misconception that symptoms improving means disease improving

• Marked exercise intolerance and dyspnea at rest: As FVC declines to <60% predicted, patients become significantly limited in daily activities; orthopnea may develop with severe restriction

• Physical examination in chronic HP:
• Fine inspiratory crackles throughout lung fields, often more pronounced at bases; basilar predominance reflects gravity-dependent fibrosis
• Absence of clubbing (key distinguishing feature from idiopathic pulmonary fibrosis, despite radiographic similarity)—presence of clubbing should prompt reconsideration of diagnosis
• Potential cor pulmonale findings with advanced disease: elevated JVP, right ventricular heave, prominent P2, peripheral edema (when PAP >40-50 mmHg for prolonged periods)
• Cyanosis common with advanced disease (SpO₂ <85-90% at rest)
• Tachypnea at rest in advanced cases

• Pulmonary function abnormalities:
• Restrictive pattern: FVC 40-70% predicted (or worse) with normal-to-high FE

Initial steps

• Structured exposure history: the single highest-yield "test" — birds, feather bedding, hot tubs, humidifiers/HVAC, moldy hay, metalworking fluid; ask about symptom improvement away from home or work.
• HRCT chest (inspiratory + expiratory): the required initial imaging. Nonfibrotic HP shows ground-glass opacity, ill-defined centrilobular nodules, and mosaic attenuation with expiratory air trapping from bronchiolocentric inflammation; the coexistence of ground glass, normal lung, and air trapping is the three-density (headcheese) sign. Fibrotic HP adds reticulation and traction bronchiectasis, classically upper/mid-lobe predominant with relative basal sparing — the mirror image of the basal, subpleural UIP of IPF.
• Pulmonary function testing: restriction with reduced DLCO; DLCO falls out of proportion to volume loss, and exercise desaturation on 6-minute walk marks physiologic severity. Concomitant bronchiolitis can add an obstructive component.
• Serum IgG (precipitins) to a candidate antigen panel: supports exposure and sensitization, not disease — many exposed, healthy people are positive. IgE and peripheral eosinophils are characteristically normal.

Confirmatory testing

• Bronchoalveolar lavage: marked lymphocytosis is the key supportive finding, with thresholds conventionally cited around 20–30% (higher in nonfibrotic disease); a reduced CD4:CD8 ratio is classic but neither sensitive nor specific.
• Lung biopsy (transbronchial forceps, cryobiopsy, or surgical) when confidence remains low: poorly formed, non-caseating peribronchiolar granulomas, cellular bronchiolocentric lymphocytic interstitial pneumonia, and multinucleated giant cells with cholesterol clefts or Schaumann bodies; fibrotic HP shows peribronchiolar and bridging fibrosis.
• Specific inhalation challenge exists at referral centers only and is not standardized for routine use.

Immediate/stabilizing measures

• Remove the patient from the antigen: the definitive intervention and the single best next step in any stem. Severe acute presentations may need hospitalization, supplemental oxygen, and rarely noninvasive ventilation for hypoxemic respiratory failure.
• Antigen remediation: rehome birds, decontaminate or remove hot tubs/humidifiers, remediate mold, change job tasks. The 2021 CHEST guideline stresses that respirators and air filtration are adjuncts, not substitutes, for eliminating exposure; some patients require occupational change.

First-line pharmacotherapy

• Systemic corticosteroids (representative agent: oral prednisone, tapered over weeks to months): reserved for symptomatic, hypoxemic, or physiologically significant disease. In farmer's lung, steroids accelerate recovery of lung function but have not been shown to alter long-term outcome — mild nonfibrotic disease often resolves with avoidance alone.

Escalation / steroid-sparing therapy

• Antimetabolite immunosuppressants: mycophenolate mofetil or azathioprine, used in progressive or steroid-dependent HP based largely on observational data; check TPMT/NUDT15 status before azathioprine.
• Rituximab or calcineurin inhibitors: salvage options in refractory inflammatory disease, low-quality evidence.
• Antifibrotic therapy: nintedanib, a tyrosine kinase inhibitor, is FDA-approved for chronic fibrosing ILD with a progressive phenotype, which includes fibrotic HP that progresses despite antigen avoidance and immunosuppression.

Definitive management

• Lung transplantation: refer early for progressive fibrotic HP with declining FVC, resting hypoxemia, or pulmonary hypertension, per ISHLT referral principles. Outcomes in HP are at least as good as in IPF, though recurrence can occur with re-exposure.
• Supportive care: pulmonary rehabilitation, ambulatory oxygen for resting or exertional hypoxemia, smoking cessation, and influenza/COVID-19/pneumococcal vaccination.

What to avoid

• Continued exposure — no drug compensates for it.
• Inhaled corticosteroids or bronchodilators as primary therapy: no evidence base; HP is not IgE-mediated bronchospasm.
• Indefinite empiric immunosuppression in UIP-like fibrotic HP: harm signals in fibrotic ILD argue for reassessment rather than open-ended therapy.

Disease-related

• Progressive pulmonary fibrosis: TGF-β–driven fibroblast activation converts reversible inflammation into fixed architectural distortion; signaled by falling FVC/DLCO on serial testing and expanding reticulation with traction bronchiectasis on HRCT. Fibrotic HP carries the worst prognosis of all HP phenotypes.
• Acute exacerbation of fibrotic HP: rapid worsening of dyspnea over days to weeks with new bilateral ground-glass opacity superimposed on fibrosis and no identified infection, heart failure, or PE. Emergency — high in-hospital mortality; requires ICU-level evaluation.
• Chronic hypoxemic respiratory failure: loss of alveolar–capillary surface area plus V/Q mismatch; exertional desaturation on 6-minute walk precedes resting hypoxemia.
• Pulmonary hypertension and cor pulmonale: hypoxic vasoconstriction plus capillary bed destruction; look for loud P2, right ventricular heave, elevated JVP, and peripheral edema. Acute right heart decompensation is an emergency.
• Secondary infection and pneumothorax: distorted, cystic lung and immunosuppression predispose; sudden pleuritic pain with unilateral absent breath sounds signals pneumothorax — emergency.

Treatment-related

• Corticosteroids: hyperglycemia, weight gain, osteoporosis and vertebral fracture, cataracts, HPA-axis suppression, and opportunistic infection. Prolonged high-dose therapy warrants Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole and bone protection per ACR glucocorticoid-induced osteoporosis guidance.
• Azathioprine: myelosuppression, magnified in TPMT/NUDT15-deficient patients — falling counts or febrile neutropenia is an emergency; also hepatotoxicity and long-term skin malignancy risk.
• Mycophenolate: cytopenias, diarrhea, infection; teratogenic and contraindicated in pregnancy.
• Nintedanib: diarrhea (dose-limiting), transaminitis requiring LFT monitoring, bleeding risk, and embryo-fetal toxicity.
• Lung transplantation: primary graft dysfunction, acute and chronic rejection (bronchiolitis obliterans syndrome), CMV disease, and post-transplant lymphoproliferative disorder; recurrent HP if the antigen is not eliminated from the home.

• The best next step is almost always the exposure history, then antigen removal — not a steroid, not a bronchodilator. Symptoms that abate on weekends or vacation and recur on return home/to work are the giveaway.
• Not IgE-mediated: HP is type III + type IV. Expect no wheezing, no peripheral eosinophilia, normal IgE, and negative skin prick testing. A stem with wheeze, eosinophilia, and high IgE plus central bronchiectasis is ABPA, not HP.
• Serum precipitins prove exposure, not disease: many asymptomatic bird keepers and farmers are positive. Do not let a positive panel alone make the diagnosis.
• HRCT triad: ground-glass, ill-defined centrilobular nodules, and expiratory air trapping — the headcheese sign is the classic buzzword.
• The examiners' favorite discriminator: fibrotic HP is upper/mid-lobe predominant with basal sparing, whereas IPF is basal and subpleural, and clubbing is absent in HP but common in IPF. (Separately, remember alpha-1 antitrypsin emphysema is basilar while smoking-related emphysema is upper-lobe.)
• BAL shows lymphocytosis, often with a low CD4:CD8 ratio — the opposite of sarcoidosis, which classically shows a high CD4:CD8 ratio, hilar adenopathy, and well-formed granulomas. HP granulomas are poorly formed, non-caseating, and peribronchiolar.
• Smoking is paradoxically protective against developing HP, though smokers who develop it may fare worse — a counterintuitive fact frequently tested.
• Know the named exposures: thermophilic actinomycetes in moldy hay (farmer's lung), avian proteins (bird fancier's lung), Mycobacterium avium complex in hot tub lung. Common distractor: silo filler's disease is nitrogen dioxide toxicity, a chemical pneumonitis — not HP.