Hypersensitivity Pneumonitis:

Diagnostic and Therapeutic Challenges

Prof SK Chhabra
Ex-Director-Prof, Vallabhbhai Patel Chest Institute

Currently

HOD
Dept. of Pulmonary, Sleep and Critical Care Medicine
Primus Superspeciality Hospital
Chanakyapuri, New Delhi

1
 HP: Introduction
• An ILD caused by hypersensitivity to a wide variety of
aerosolized antigens
• Earlier called “extrinsic allergic alveolitis”
• Common Antigens
– Avian
– microbial (environmental fungi or bacteria)
– chemical (usually organic compounds including
isocyanates)

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 Diagnostic Problems
• HP is suspected to be underrecognized
• Wide geographical variations because of role of environment
• Diagnostic difficulties arise due to
– the broad range of presenting symptoms
– wide spectrum of HRCT findings
– variations in histopathologic findings (often not available)
– lack of validated diagnostic criteria

• Question arises when features are not typical:

– Is it IPF? NSIP? Sarcoidosis? HP?
• Yet, distinction is important as therapy, natural history, and prognosis
• A substantial proportion of patients initially diagnosed with IPF were
later found to have HP
Morell et al Lancet Respir Med 2013;1:685–694
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 Interstitial Lung Disease in India
ILD registry
• Adult patients with new-onset ILD (n=1,084)
• 27 centers, 19 Indian cities, March 2012–June 2015
• Diagnosis mostly based on clinical features and HRCT
• Biopsy (by any method) only in 7.5%
• Highest prevalence:
– Hypersensitivity pneumonitis: 47.3%
– CTD-ILD: 13.9%
– Idiopathic pulmonary fibrosis: 13.7%
– Idiopathic NSIP: 8.5%
– Sarcoidosis: 7.8%
Singh et al AJRCCM 2017: 195: 801-813

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 Spectrum of Interstitial Lung Diseases
PGI Study
• 803 subjects (mean age, 50.6 years; 50.2% women) March
2015 to February 2017
• Histopathological specimen was obtained in 49.9% of the
subjects yielding a histologically confirmed diagnosis in
40.6%
• Most prevalent ILDs
– Sarcoidosis (42.2%)
– Idiopathic pulmonary fibrosis (IPF, 21.2%)
– Connective tissue disease (CTD)-related ILDs (12.7%)
– Hypersensitivity pneumonitis (10.7%)
– Non-IPF idiopathic interstitial pneumonias (9.2%)
Dhooria S, 2018 PLOS ONE 13(2): e0191938
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Spectrum of diffuse parenchymal lung diseases in Literature

Dhooria S, 2018 PLOS ONE 13(2): e0191938

 Clinical Presentation
• Manifestations of HP are variable
– intensity and duration of exposure
– nature of the antigen
– host factors
• Acute/subacute
– Prototype: Farmer’s lung
– episodic dyspnoea, with/without wheezing (like asthma)
– cough, usually dry
– systemic response with fevers and malaise (not invariable)
– lasting hours to weeks
– temporal relationship to antigen exposure
 Clinical Presentation
• Chronic
– Prototype: pigeon breeder’s lung or bird fancier’s lung
– insidiously developing dyspnoea on exertion over months to
years
– dry cough
– fever and malaise not prominent
– symptoms progress or remain unchanged for variable periods
– may be punctuated with acute increases in symptoms,
presumably related to exposures to the offending antigen
– May or may not have a clearly defined acute stage
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 Newer Classifications
• According to disease behavior
– acute nonprogressive and intermittent
– acute progressive/subacute
– chronic nonprogressive
– chronic progressive
• Clustering of features
• Based on clinical–radiologic–pathologic correlation
(Vasakova et al Am J Respir Crit Care Med 2017; 196, 680–689)
– acute/inflammatory HP
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– chronic/fibrotic HP
 Approach to Diagnosis of Chronic HP
• Standard Multidisciplinary ILD approach (Clinical,
Physiological, HRCT, Serology, Histopathology)
• Detailed clinical history to identify possible causes
– rheumatologic disease
– occupational exposures
– drug toxicity
• Clinical Features:
– Subtle differences from other ILDs (wheeze, variability,
association with exposures, fever, remissions)
– no clubbing
– crackles, rhonchi and squeaks 11

• Physiological: Evidence of small airways disease

 Approach to Diagnosis of Chronic HP
• Dedicated multidisciplinary case review (i.e., pulmonologist,
thoracic radiologist, and pathologist) is recommended
especially if classical UIP-IPF is ruled out

• However, agreement across multidisciplinary teams on an HP

diagnosis is only fair (k = 0.24)
– whereas agreement on IPF (k = 0.60) or connective tissue disease–
associated ILD (k = 0.64) is moderate to good

• Reasons include local practice variation and absence of

consensus guidelines for diagnosing HP
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• If multidisciplinary review is not possible (most centers),
clinical judgement of the pulmonologist is the key
 Imaging: Chest PA and HRCT
HRCT Chest
• Contrast? If looking for lymph nodes (sarcoidosis) or
blood vessels/mediastinum
• Reconstruct in 1mm
• Always ask for prone cuts in early disease
• Always ask for an expiratory CT
• Always get coronal reconstructions
• MIP and MinIP reconstructions are useful
• Always examine a CT on the console or large screen
on PACS
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 HRCT Chest in HP
• Fibrotic ILD features include septal thickening, traction
bronchiectasis, and honeycomb cysts
• Important differences from other fibrotic ILDs
– distribution in a patchy or geographic pattern usually upper
lung predominance
– ground-glass opacities
– centrilobular nodules
– mosaic attenuation
– air trapping
• Confident radiologic HP diagnosis is 88–92% specific and
44–61% sensitive
• In select patients, clinical-radiological diagnosis may be 14
sufficient
 HRCT Differential Diagnosis
• HRCT appearances of HP are because of mixed
interstitial and airway disease
• DD includes
– rheumatologic diseases
– chronic sarcoidosis
– ILD with concurrent small airway disease
(asthma or smoking-related chronic
obstructive pulmonary disease).
– ILD with pulmonary vascular disease (mosaic
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attenuation)
HP: Acute

• Ground glass opacities,

bilateral
• Around mid-zomes
• Like acute pulmonary
edema

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 HP: Subacute

ill-defined centrilobular
nodules of ground-glass opacity
(80% of cases)

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 HP: Subacute

ill-defined centrilobular Mosaic pattern of a combination of

nodules of ground- patchy ground-glass opacity due to
glass opacity (80% of lung infiltration and patchy lucency
cases) due to bronchiolitis with air trapping

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HP: Chronic
• Septal and intralobular reticular
thickening, in a mid zone
distribution indicating already
existing irreversible fibrosis

• Reticulation can be patchy,

subpleural or anywhere

• Minor honeycombing may be

present

• Distorted vessels and bronchi

(traction bronchiectasis) due to
fibrosis

• Mosaic pattern with areas of

ground-glass atenuation and areas
of low attenuation
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 Chronic HP: Head Cheese Sign
• Composed of
– ground glass opacities (high
attenuation)
– mosaic attenuation pattern
(low attenuation) (may only be
apparent on expiratory scans)
– normal lung tissue (normal
attenuation)
• Highly specific
• May be seen in other mixed
infiltrative and obstructive
processes such as sarcoidosis

Mosaic attenuation (MA) and air trapping (AT) predict better prognosis
Chung et al Ann Am Thorac Soc. 2017;14:1533-1538 20
 Chronic HP: Head Cheese Sign
•
• Mild reticulation and
extensive bilateral ground-
glass opacities
• Bilateral centrilobular
nodules
• Localized areas of
decreased attenuation and
vascularity

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 Chronic HP: BOOP-Like
• Patchy bilateral ground-
glass opacities

• Nodular areas of
consolidation (straight
arrows)
• Perilobular opacities
(curved arrows)

Isabela et al Am J Roentgenol 2007;188: 334-344

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 CHP: Like NSIP

• Bilateral reticulation, traction bronchiectasis (curved arrow), and traction

bronchiolectasis (straight arrows)
• Subpleural cysts consistent with mild honeycombing (arrowheads)
• Area of ground-glass opacity with superimposed reticulation is present in right
middle lobe
• Predominance of abnormalities in subpleural and basal regions (coronal cut) 23
CHP: Evolution from NSIP-like to Classical

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 CHP: Acute Exacerbation

• Left: Septal thickening, Traction Bronchiectasis

• Right: Acute exacerbation shows extensive bilateral ground-glass opacities

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 Indirect or Direct Histopathologic
Evaluation
• Bronchoscopy with bronchoalveolar lavage (BAL)
cellular analysis
• Transbronchial biopsy
• Transbronchial cryobiopsy
• Surgical lung biopsy
– VATS
– Open Lung biopsy

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 BAL in HP
• BAL lymphocytosis (mean BAL % lymphocytes, 29–
57%) supports
• Sensitivity and specificity limited
• BAL lymphocytosis is also reported in NSIP, organizing
pneumonia, and sarcoidosis
• CD4 cell:CD8 cell ratio is has no diagnostic value

• Useful when combined with clinical and HRCT

characteristics but no validated prediction rule

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 Histopathological Study
• Transbronchial biopsy has limited value
– less than 25% of individuals are confidently diagnosed
– Worthwhile especially if sarcoidosis is suspected
• Cryobiopsy is an emerging technique
• Surgical lung biopsy is the gold standard for ILDs

• A careful multidimensional assessment obviates the

need for a biopsy in most cases

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 HP: Subacute Pathology
• moderate, diffuse, bronchiolocentric chronic
lymphocytic inflammatory infiltrate
• Inset: poorly formed granuloma with chronic
interstitial inflammatory infiltrate
Patchy mild interstitial mononuclear
cell infiltrate
Classical triad: Bronchiolitis, bronchiolocentric
interstitial pneumonitis, ill-defined loose 29
granulomas
 Chronic HP Pathology

Left: Low power view: areas of subacute (curved arrows) and chronic (straight
arrows) changes of hypersensitivity pneumonitis
Right: High power view; chronic interstitial inflammatory infiltrate and interstitial
fibrosis. Also evident are giant cell (curved arrow) and fibroblast focus (straight
arrows).
The classical histopathological triad of subacute HP may also be present. 30
 Environmental evaluation
• Enquiry is important: home, workplace & occupational

• A questionnaire tailored to the practice locale may help

– no validated set of questions is available

• If identified, details about exposure duration and relationship to

pulmonary or systemic symptoms

• Specific inhalation challenge by nebulization with subsequent

monitoring of physiological parameters
– Not standardized
– Not recommended for clinical application

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 Specific Antibody Testing
• Unfortunately, history may be indeterminate (> 50%)
• Commercially available panels measure serum IgG against a
few microbial and avian antigens
– value of results is limited
– many antigens are unrepresented
– Far more unaffected and exposed individuals test positive than
affected subjects (marker of exposure)
 In clinical context, positive tests support diagnosis
 Negative results do not rule out

• A thoughtful search for an antigen should proceed, but given

current testing limitations, antigen identification is not
mandatory for HP diagnosis confirmation 32
 Diagnosis
• Various diagnostic criteria: none validated
• Diagnosis is multidimensional
– History of antigen exposure
– Precipitating antibodies to the offending antigen
– Clinical features (History/Examination/PFT)
– BAL (Lymphocytosis)
– HRCT abnormalities
– Pathologic abnormalities
• Response to treatment and disease behavior over
time helps
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Diagnosis: Clinical Prediction Model

If all 6 predictors in the model are present, the

probability of having HP is 98%
Lacasse et al Am J Respir Crit Care Med 2003;168:952-8 34
 Diagnostic Algorithm
Salisbury et al Am J Respir Crit Care Med 2017; 196, 690–699

• Evidence-supported minimum noninvasive criteria

for a confident HP diagnosis include
– presence of typical HRCT features
– BAL lymphocytosis (>20–30% of total Leukocytes)
Or
– typical HRCT features plus
– a plausible and temporally related exposure

• Patients not meeting these criteria may require a

surgical lung biopsy when feasible
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Evaluation of Lung Biopsy

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 Management
• No Guidelines
• Antigen avoidance
• Antigen not found: change of residence? Work?
• Drugs: steroids and/or cytotoxic drugs directed at
suppression of ongoing inflammation
– Mainly based on observational studies/expert
opinion

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 Principles of Drug Management
• Assess inflammation
– GGO
– centrilobular nodules
– BAL lymphocytosis
– Biopsy: cellular interstitial pneumonia or granulomatous inflammation
• A trial of immunosuppression may be reasonable in such patients
– Monitor with PFT and if required, HRCT
– Improvement in FVC and/or DLCO by 10% indicates response
– Is stability a failure or success?
– Deterioration in FVC and/or DLCO by 10% is a failure

• Caution advised in initiation or continuation of immunosuppression

– If not much inflammation
– treatment failures

• End-stage disease and non-responders: supportive management

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 Treatment Strategies in Hypersensitivity
Pneumonia: Inflammation Present
• Watchful waiting is also an option in stable and/or mild
disease, or if an antigen is identified and removed
• Corticosteroids (0.5–1 mg/kg daily prednisone equivalent) ±
cytotoxic agent (azathioprine, MMF)
– Taper prednisone to 20 mg daily in the first 3 mo
– FEV1, FVC, and DLCO (consider every 1–2 mo initially)
– Taper corticosteroid to <20 mg daily when PFT plateaus (presuming
initial improvement)
• PFT every 3–4 mo. Consider HRCT at 3–6 mo
• Worsening during steroid taper, consider cytotoxic agent (if
not already initiated).
• Evaluate for infection or reintroduction of antigen, as
indicated 40
 Treatment Strategies in Hypersensitivity
Pneumonia: Inflammation Absent
• Environmental evaluation and antigen remediation
• Trial of immunosuppression can be considered after review of
risks and expected benefits

• Advanced fibrosis and no sign of inflammation

– limit treatment trial to 3 mo of corticosteroids
– taper off if no improvement is observed.

• Addition of a cytotoxic agent may be of little benefit

– result in untoward side effects

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 Management
• Manage comorbidities: GERD
• General principles of chronic lung disease
– Vaccination
– Pulmonary rehabilitation
– Steroid complications
– Home oxygen
– Management of PH and cor pulmonale (diuretics,
maybe PDE inhibitors; Specific PH drugs: no role)
– Lung transplantation
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 Importance of fibrosis
• In HP, like in IPF, increasing fibroblastic foci
score is associated with
– extent of reticulation
– severity of traction bronchiectasis
• Walsh et al BMC Med. 2015 Sep 24;13:241
• Predictors of poor prognosis in HP
– Extensive traction bronchiectasis
– Macrocystic honeycombing
• Walsh et al. Eur Radiol. 2012;22:1672-9

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 Progressive Fibrosing ILDs (PF-ILDs)
ILD
Idiopathic Interstitial Hypersensitivity
Autoimmune ILDs Sarcoidosis† Other ILDs
Pneumonias (IIPs) Pneumonitis (HP)

Idiopathic Pulmonary Rheumatoid Arthritis • Lymphangioleiomyomatosis (LAM)

Fibrosis (IPF) Interstitial
Pneumonia with ILD (RA-ILD)
Autoimmune • Langerhans Cell Histiocytosis (LCH)
Idiopathic Non-Specific Features (IPAF)*
Interstitial Pneumonia
Sjögren’s Syndrome • Drug-Associated ILD
ILD
(iNSIP) • Other Exposure ILDs‡
Respiratory Systemic Lupus • Vasculitis/Granulomatosis ILDs
Bronchiolitis- Interstitial Erythematous ILD
Lung Disease • Other Rare ILDs
Idiopathic Lymphoid
Interstitial Pneumonia Polymyositis and
Desquamative Interstitial Dermatomyositis ILD
Pneumonia
Idiopathic
Pleuroparenchymal Mixed Connective
Fibroelastosis Tissue Disease ILD
Cryptogenic Organising
Pneumonia
Systemic Sclerosis
Unclassifiable IIPs ILD (SSc-ILD)
Acute Interstitial
Pneumonia Other Connective
Tissue Disease ILDs

*Not an established clinical diagnosis. †Stage IV sarcoidosis only. ‡e.g. asbestosis, silicosis.
 Progressive Fibrosing ILDs (PF-ILDs)

Progressive fibrosis was defined as fibrosis detected by HRCT (reticular abnormality with traction bronchiectasis with or without honeycombing) that was
progressive in terms of worsening of lung function (FVC and/or DLco) and/or respiratory symptoms and/or chest images
Based on online physician survey
Defining Progression in Patients with Fibrosing
ILDs
End-points in clinical trials
 an increase in fibrosis evident on HRCT

 a decline in forced vital capacity (FVC)

 a decline in gas exchange (i.e. diffusing capacity of the
lung for carbon monoxide (DLCO)
 worsening of symptoms and exercise capacity
 deterioration in health-related quality of life
No consensus on how progression should be defined
quantitatively
• In clinical trials, usually in terms of decline in FVC

change from baseline in mL
 as a categorical change (typically ≥10% predicted)
 Phase III INBUILD trial
Flaherty K, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases N Eng J Med.
Published 29 September, 2019. NEJM.org. DOI: 10.1056/NEJMoa1908681

• Evaluated the efficacy, safety, and tolerability of nintedanib in patients

with progressive fibrosing interstitial lung disease
• Chronic hypersensitivity pneumonitis (26.1%)
• Autoimmune ILDs such as rheumatoid arthritis-associated ILD,
systemic sclerosis-associated ILD (SSc-ILD), mixed connective tissues
disease-associated ILD (25.6%)
• Sarcoidosis
• Non-specific interstitial pneumonia
• Unclassified idiopathic interstitial pneumonia
• Criteria for ILD progression within 24 months despite treatment
• decline in FVC
• increased fibrotic changes on imaging
• worsening of symptoms
 Ninetedanib: Phase III INBUILD trial
• Randomised, double-blind, placebo-controlled, parallel group trial
 153 sites in 15 countries
 663 patients, of whom 412 (62.1%) had a UIP fibrotic pattern on HRCT
 Mean age was 65.8 years, the FVC 69% pred, DLCO 46.1%pred
 Oral nintedanib 150 mg twice daily or placebo

• Primary endpoint was the annual rate of decline in FVC (mL/year)

assessed over 52 weeks
• Nintedanib slowed lung function decline by 57% across the overall
study population
• This was independent of the fibrotic pattern seen on chest imaging
• Side effect profile :diarrhoea the most common adverse event
 Ninetedanib for Progressive Fibrosing
ILDs (PF-ILD)


October 10, 2019

 Breakthrough therapy designation from the US Food and

Drug Administration (FDA) for nintedanib in chronic
fibrosing interstitial lung diseases (ILDs) with a progressive
phenotype
 Conclusions
• Fibrotic hypersensitivity pneumonia remains difficult to
diagnose and treat
• Specific therapies remain unstudied
• Important unanswered questions
– whether immunosuppression is helpful (or harmful) in specific
subgroups of patients with fibrotic HP (based on inflammation and
fibrosis)?
– whether antifibrotic drug therapies may be beneficial?
– When and in whom should antifibrotic drugs be added?
• Absence of specific guidelines is a major limitation in adopting
a standardized approach

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Thank you for your kind attention