Pneumonitis Hipersensitif

01Pathophysiology

Hypersensitivity pneumonitis (HP) results from repeated inhalation of small organic particles that penetrate deep into the distal airways and alveoli. The antigens are typically less than 5 micrometers in diameter, which allows them to bypass the upper airway defenses. Common culprits include thermophilic actinomycetes found in moldy hay (Farmer's Lung), avian proteins from droppings and feathers (Bird Fancier's Lung), and Mycobacterium avium complex from contaminated water (Hot Tub Lung).

The immune response involves two concurrent hypersensitivity pathways. A Type III (immune complex-mediated) reaction dominates the acute phase: the inhaled antigen binds to preformed IgG antibodies in the alveolar interstitium, forming immune complexes that activate complement and recruit neutrophils. This explains the acute onset of fever, chills, and dyspnea 4 to 8 hours after antigen exposure, which mirrors the timeline of a classic Arthus reaction. Critically, this is NOT an IgE-mediated (Type I) process, which is why the patient does not present with wheezing or urticaria.

A Type IV (delayed-type, T-cell-mediated) response develops with continued or repeated exposure. Sensitized CD8+ T lymphocytes infiltrate the lung parenchyma and form non-caseating granulomas centered around the terminal bronchioles. This peribronchiolar granulomatous inflammation is the histologic hallmark of subacute HP and explains why HRCT findings are predominantly centrilobular. Over time, persistent antigenic stimulation overwhelms the lung's reparative capacity, leading to progressive interstitial fibrosis and irreversible architectural distortion in chronic HP.

The restrictive physiology on PFTs directly reflects this pathological process: granulomatous inflammation and fibrosis stiffen the lung parenchyma, reducing compliance and total lung capacity. The decreased $D_{LCO}D\_\{LCO\}$ reflects destruction of the alveolar-capillary membrane. Understanding this two-phase immune mechanism is essential because it explains why the same disease can present acutely (immune complexes) or insidiously (granulomas and fibrosis) depending on the duration and intensity of exposure.

02Classification and Clinical Manifestation

The 2020 ATS/JRS/ALAT guideline has introduced a simplified two-category system: non-fibrotic HP (encompassing acute and subacute) versus fibrotic HP (corresponding to chronic). This distinction matters clinically because fibrotic HP carries a worse prognosis and may warrant antifibrotic therapy, while non-fibrotic HP is generally reversible with antigen removal and short-term corticosteroids.

A notable clinical clue is the temporal relationship between symptoms and exposure. In acute HP, patients classically describe symptom onset 4 to 8 hours after returning to the offending environment (e.g., returning to the barn, cleaning the bird cage), with resolution within 24 to 48 hours after leaving. This pattern is sometimes called "Monday morning fever" in occupational settings: the worker feels well over the weekend, then develops symptoms upon returning to work.

03Diagnostic Workup

The diagnostic approach to HP begins with a thorough occupational and environmental history, which is arguably the single most important step. The vignette will often embed the critical clue as a seemingly casual detail: "a farmer who recently moved bales of old hay," "a woman who recently acquired pet parakeets," or "a man who uses his hot tub daily." This history is what separates HP from other interstitial lung diseases.

HRCT of the chest is the best initial imaging study once HP is suspected. The classic triad in subacute HP is centrilobular ground-glass nodules, mosaic attenuation (reflecting air trapping from bronchiolar inflammation), and areas of normal lung interspersed between affected zones (the "headcheese sign"). On expiratory images, areas of air trapping become more conspicuous. In chronic fibrotic HP, the pattern shifts to honeycombing and traction bronchiectasis, which can mimic usual interstitial pneumonia (UIP). However, unlike idiopathic pulmonary fibrosis, the fibrosis in HP tends to predominate in the upper and mid-lung zones rather than the bases.

Serum precipitating IgG antibodies (precipitins) against the suspected antigen are frequently tested but must be interpreted with caution. A positive result confirms immunologic sensitization (exposure), but does NOT confirm disease. Up to 40 to 50% of asymptomatic farmers have positive precipitins without clinical HP. Conversely, negative precipitins do not exclude the diagnosis. This is a common exam trap.

BAL with cell differential is a highly valuable diagnostic tool. A finding of lymphocytosis exceeding 20 to 30% strongly supports HP and helps differentiate it from idiopathic pulmonary fibrosis, where neutrophilia predominates. In HP, the lymphocytes are typically CD8+ predominant, yielding a low CD4:CD8 ratio, which contrasts with sarcoidosis where the ratio is characteristically elevated.

Lung biopsy remains the gold standard when clinical, radiographic, and BAL findings are inconclusive. The classic histopathologic triad includes: (1) peribronchiolar chronic inflammation, (2) poorly formed non-caseating granulomas, and (3) foci of organizing pneumonia. Transbronchial cryobiopsy has increasingly replaced surgical biopsy as a less invasive alternative with adequate tissue yield.

04Management and Treatment

Antigen avoidance is the single most important intervention and should always be the first answer on the exam. No pharmacologic therapy can substitute for removing the causative exposure. This may involve changing occupations, rehoming birds, remediating mold, or discontinuing hot tub use. In cases where complete avoidance is impossible (e.g., a farmer who cannot leave the profession), personal protective equipment such as powered air-purifying respirators can reduce antigen load but are inferior to complete avoidance.

For patients with acute HP and significant symptoms (hypoxia, severe dyspnea), systemic corticosteroids accelerate symptom resolution. The standard regimen is prednisone 0.5 to 1 mg/kg/day, typically capped at 60 mg/day, with a gradual taper over 4 to 6 weeks. Most patients with acute HP recover fully once the antigen is removed, and steroids primarily hasten recovery rather than alter long-term outcomes.

Subacute HP with persistent symptoms despite antigen removal warrants a longer course of corticosteroids, typically tapered over 3 to 6 months. Close monitoring with serial PFTs and HRCT is recommended to assess response.

Chronic fibrotic HP is the most challenging form to manage. If the disease continues to progress despite antigen avoidance and corticosteroids, steroid-sparing agents are introduced. Mycophenolate mofetil (1 to 1.5 g twice daily) is the most commonly used agent, with azathioprine (2 mg/kg/day) as an alternative. For patients who meet criteria for progressive fibrosing interstitial lung disease (defined as worsening symptoms, declining FVC, or progressive fibrosis on imaging despite standard therapy), nintedanib 150 mg twice daily is an option based on the INBUILD trial results.

Lung transplantation is reserved for patients with end-stage fibrotic HP who continue to deteriorate despite all medical interventions. It is important to note that fibrotic HP, unlike the non-fibrotic form, may continue to progress even after complete antigen removal because fibrosis becomes a self-perpetuating process independent of the original antigenic trigger.

A key contraindication to keep in mind: corticosteroids should be used cautiously in patients with diabetes mellitus, osteoporosis, or active infections. In such cases, earlier transition to steroid-sparing agents is preferred.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common mistake students make with HP is confusing it with an IgE-mediated allergic reaction (Type I hypersensitivity). Because the name contains "hypersensitivity," many students expect to see wheezing, eosinophilia, and elevated IgE. This is incorrect. HP is a Type III and Type IV reaction mediated by IgG immune complexes and T lymphocytes, which is why the patient has crackles (not wheezing), a restrictive pattern (not obstructive), and BAL lymphocytosis (not eosinophilia).

The second common trap involves serum precipitins. Students often select "positive serum precipitins" as the confirmatory test. However, precipitins only confirm antigen exposure and immunologic sensitization, not clinical disease. Many exposed but healthy individuals have positive precipitins. The precipitin test is supportive, not diagnostic, and the biopsy remains the gold standard.

A third pitfall is failing to identify the exposure in the vignette. The antigen is almost always embedded in the social or occupational history, sometimes disguised as background detail. If a patient presents with recurrent episodes of fever, cough, and dyspnea that resolve on weekends or during vacations, this temporal pattern is the strongest clue and should prompt you to search the stem for an environmental trigger.

Finally, students frequently select corticosteroids as the best initial management step. While steroids are important for symptomatic relief, the best initial step is always antigen avoidance. On the exam, if a question asks for the "most important" or "best initial" intervention, choose removal of the exposure over pharmacologic treatment. Corticosteroids accelerate resolution but cannot substitute for eliminating the antigenic source.

The core competency being tested in HP questions is the ability to integrate an occupational/environmental history with a restrictive lung disease presentation, distinguish it from obstructive and other granulomatous conditions, and prioritize antigen avoidance as the definitive management strategy.