Allergy - 2021 - Barnes - Hypersensitivity pneumonitis Current concepts in pathogenesis diagnosis and treatment

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442  |  Allergy. 2022;77:442–453.wileyonlinelibrary.com/journal/all
1  |  INTRODUC TION
Hypersensitivity pneumonitis (HP) is an immune- mediated inter-
stitial lung disease (ILD) caused by an inhalational exposure to 
low- molecular weight compounds, which occurs in susceptible in-
dividuals. Hypersensitivity pneumonitis may present in two forms: 
acute, predominantly inflammatory HP (non- fibrotic HP), and 
chronic or fibrotic HP (fibrotic HP).1 Some patients will experience 
a self- limiting acute HP course, whereas others, given sufficient 
time and exposure, will progress from non- fibrotic to fibrotic dis-
ease, and still other patients may present with established fibrotic 
HP without a clear acute episode of exposure. This suggests that 
the pathophysiology of HP is contributed by complex pathways of 
antigen exposure, aberrant immunological mechanisms, and genetic 
predispositions.
1.1  |  Epidemiology
Reported estimates of the incidence of HP vary across popula-
tions, with 1– 3 per 100,000 people per year (including children) in 
Denmark,2 11.5 per 100,000 people over 65 years per year in the 
USA,3 and up to 30 per 100,000 people per year in New Mexico.4 
HP is the third most common ILD after idiopathic pulmonary fibro-
sis (IPF) and connective tissue disease- related interstitial lung dis-
ease (CTD- ILD).5 The estimated prevalence of HP is higher in at- risk 
Received: 5 June 2021  | Accepted: 21 July 2021
DOI: 10.1111/all.15017 
R E V I E W A R T I C L E
Hypersensitivity pneumonitis: Current concepts in 
pathogenesis, diagnosis, and treatment
Hayley Barnes1,2  | Lauren Troy3,4 | Cathryn T. Lee5 | Anne Sperling5 | Mary Strek5 | 
Ian Glaspole1,2
© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd
1Central Clinical School, Monash 
University, Melbourne, VIC, Australia
2Alfred Hospital, Melbourne, VIC, 
Australia
3Royal Prince Alfred Hospital, Sydney, 
NSW, Australia
4University of Sydney, Sydney, NSW, 
Australia
5Section of Pulmonary and Critical Care 
Medicine, The University of Chicago, 
Chicago, IL, USA
Correspondence
Hayley Barnes, Department of Respiratory 
Medicine, Alfred Health, 34 Commercial 
Rd, Melbourne, Australia.
Email: Hayley.Barnes@monash.edu
Abstract
Hypersensitivity pneumonitis is an immune- mediated interstitial lung disease 
caused by an aberrant response to an inhaled exposure, which results in mostly T 
cell– mediated inflammation, granuloma formation, and fibrosis in some cases. HP is 
diagnosed by exposure identification, HRCT findings of ground- glass opacities, cen-
trilobular nodules, and mosaic attenuation, with traction bronchiectasis and hon-
eycombing in fibrotic cases. Additional testing including serum IgG testing for the 
presence of antigen exposure, bronchoalveolar lavage lymphocytosis, and lung biopsy 
demonstrating granulomas, inflammation, and fibrosis, increases the diagnostic con-
fidence. Treatment for HP includes avoidance of the implicated exposure, immuno-
suppression, and anti- fibrotic therapy in select cases. This narrative review presents 
the recent literature in the understanding of the immunopathological mechanisms, 
diagnosis, and treatment of HP.
K E Y W O R D S
extrinsic allergic alveolitis, interstitial pneumonia, occupational lung disease
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    |  443BARNES Et Al.
populations, with cross- sectional studies estimating the prevalence 
of HP in farmers at 1.3– 12.9%,6,7 in bird breeders at 3.7– 10.4%,8,9 
and in mushroom workers at 3.5– 29%.10- 13
1.2  |  Exposures
Certain low- molecular weight compounds have a predilection for 
causing HP. The first reports of HP were in farmers working with 
hay containing Saccharomycetes spp. growth,14,15 followed by similar 
cases in those exposed to maple bark,16 pigeons,17 and mushrooms.18 
Since these reports, a multitude of exposures have been reported in 
association with HP (Table 1). The most commonly implicated expo-
sures are birds (up to 30% of HP cohorts) from feather dust (bloom), 
droppings, and serum, most commonly derived from pigeons, budg-
erigars (parakeets), cockatiels, parrots and canaries, and duck and 
goose down products. Mold due to water damage and microbial and 
bacterial contamination of air conditioning units and ventilation sys-
tems are also common.19 It is estimated that 12– 28% of HP cases are 
directly attributable to workplace exposures,20 the most common 
of which is farming. Exposure to other agricultural environments in-
cluding mushroom cultivation, organic waste, and greenhouses may 
also increase the risk of HP. Occupationally or recreationally derived 
low- molecular weight chemicals including isocyanates, although 
themselves not immunogenic, can combine with human proteins 
to form haptens and trigger HP.21 Over time, and due to evolving 
workplace practices, some exposures have become less frequently 
seen (paprika splitters, pituitary snuff), and some more frequently 
reported (metalworking fluids, musical instruments).19,22 Though a 
multitude of antigens have been reported in association with HP, 
many share similar properties; small (<3 µm) enough to be inhaled 
into the distal bronchi and alveoli, clearance via local lymphatic 
drainage inducing an IgG antibody response, capacity to activate 
complement pathways (eg, cell walls of molds containing β- (1– 3)- d- 
glucan) and high molecular weight glycoproteins resistant to degra-
dation (eg, pigeon intestinal mucin and Trichosporon cutaneum).23
Few studies have examined the exposure duration and intensity 
required to cause HP, which may vary depending on the implicated 
antigen. Greater intensity of exposure and persistent exposure may 
be more likely to lead to progression of disease.24 Few studies have 
TA B L E 1  HP exposures
Name Exposure source Antigen
Birds Pigeons, budgerigars, cockatiels, chickens Proteins from bloom, feather, droppings, serum, or 
down products
Mold Previous water damage, rising damp Aspergillus spp., cladosporium spp., Penicillium spp.
Farming Moldy hay or silage Saccharomycetes spp.,
Aspergillus spp.
Air conditioner/ humidifier/ swamp 
cooler
Contaminated water Thermoactinomyces spp., Aspergillus spp., Penicillium 
spp.
Hot tub Contaminated water Mycobacterium avium complex, Aspergillus fumigatus, 
Mycobacterium abscessus, Cladosporium spp.
Machine operators/ metalworking fluid Contaminated water- based metalworking 
fluid
Mycobacterium avium complex, Mycobacterium 
immunogenum
Summer- type HP Damp wooden structures
Common in Japan
Trichosporon spp.
Wood Moldy wood- cedar, mahogany, pine, 
redwood, spruce, cork (suberosis)
Alternaria spp., Bacillus subtilis, Mucor spp., Rhizopus 
spp.
Isocyanates Glue, polyurethane foam, paint, plastic, 
resins, varnishes
Isocyanate acid anhydrides
Mushroom worker's lung Moldy compost and mushrooms Shitake, bunashimeji, himeji, thermophilic 
Actinomycetes
Gardening/organic waste Soil/ organic waste Aspergillus fumigatus, Saccharopolyspora rectivirgula, 
thermophilic Actinomycetes
Musical instrument HP Wind instruments - saxophones, trombones, 
bagpipes
Mycobacterium chelonae/abscessus, Fusarium spp.
Salami workers/ chacineros’ lung Mold dust Aspergillus spp., Cladosporium spp., Penicillium spp.
Cheese- washer's lung Mold dust Penicillium spp.
Cane sugar (bagassosis) Moldy sugar cane Thermoactinomyces Sacchari
Dental products Dental technicians Methyl acrylates
Lifeguard lung Contaminated water jets and sprays – 
lifeguards, pool workers
Pseudomonas spp.
CPAP machine Contaminated water Molds and fungi
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444  |    BARNES Et Al.
considered the contribution of multiple exposures and polysensitiza-
tion in HP. Where reported, multiple exposures may be present in up 
to 8% of HP cases.25,26 The inhalational exposure in many HP cases 
comprises a mixture of antigens with inert dusts, other chemicals, 
etc., which although associated with an increased risk of fibrosis in 
other fibrotic lung diseases,27,28 their contribution in HP is poorly 
elucidated.
2  |  IMMUNOPATHOGENESIS
The immunological mechanisms resulting in the development of 
HP are incompletely understood, though believed to result from an 
aberrant immune response following inhalational exposure to low- 
molecular weight compounds in susceptible individuals, resulting 
in inflammation, granuloma formation, and in some cases perpetual 
damage and fibrosis (Figure 1).
Following inhalation of antigenic particles, antigen- presenting 
cells including activated macrophages and dendritic cells are stim-
ulated. The reasons for this are not completely known, but may be 
due to repeat exposure,21 genetically based differences in structures 
involved in antigen processing, and adjuvant modulatory factors. 
Pattern recognition receptors, including toll- like receptors (TLRs), 
are critical elements in initiating this immune response. TLR- 2 and −6 
recognize diacyl lipopeptides and lipoteichoic acid on bacterial cell 
walls and are upregulated in murine mouse models of HP.29 TLR- 6 is 
important in granuloma formation (macrophages which develop into 
epithelioid cells and formation of multinucleated giant cells).30 Other 
innate receptors including TLR- 9 and dectin- 1 have also been found 
to contribute to HP in murine models and promote Th17 differentia-
tion, which drives further inflammation and fibrosis.31 Dendritic cells 
are involved in the initiation of the adaptive immune response by mi-
grating to the lymph nodes and priming the T- cell immune response. 
Those with HP have increased levels of dendritic cells in their lung 
parenchyma after antigen challenge.32
In parallel, inhaled antigen also binds to IgG antibodies which ini-
tiates the complement cascade and produces byproducts including 
C5, which further stimulates macrophages.33 Serum IgG- specific an-
tibodies can be used as part of the diagnostic work- up for HP.
Activated macrophages, when presented with foreign antigen, 
release pro- inflammatory, and chemotactic factors, including CCL- 
18 which attracts lymphocytes, and IL- 18, MCP- 1, TNF- α, IL- 1, and 
IL- 6 which upregulates B7 expression and greatly enhances the 
antigen- presenting capacity of macrophages in response to inhaled 
antigens.34,35 Production of TNF- α and IL- 1 are responsible for the 
development of fever and other acute- phase symptoms present in 
acute HP.35,36
Presentation of foreign antigen by APCs to CD4+ T cells stimu-
lates a predominantly CD4+ Th1 immune response. Correspondingly, 
presence of lymphocytosis in bronchoalveolar lavage fluid is a useful 
tool in differentiating HP from other ILDs.37 This response, medi-
ated by IL- 12 and interferon- γ, produces CXCL10 to recruit T lym-
phocytes to the alveolar space, and promote granuloma formation 
by inducing the functional differentiation and survival of activated 
macrophages and dendritic cells.38 The immunologically mediated 
pathways leading to HP are shared with other granulomatous lung 
diseases, including chronic beryllium disease and sarcoidosis. These 
common mechanisms include a response to an inhaled antigen, lym-
phocytic alveolitis, granuloma formation, and fibrosis. Differences in 
the nature of the exposure and to the types of causative antigens, 
genetic predispositions, and signaling pathways within the inflam-
matory response may explain the subsequent histopathological and 
radiological differences in HP and other granulomatous diseases 
(characterized by poorly formed granulomas accompanied by cen-
trilobular, bronchiolocentric, and peribronchial interstitial inflam-
mation in HP, compared with well- formed granulomas involving the 
perilymphatic and peribronchovascular interstitium in sarcoidosis.39
The transition from an acute, inflammatory process to a chronic, 
fibrotic process in HP is modulated in part by a switch from a Th1 
to Th2 inflammatory response, inhibition of regulatory T cells, and 
upregulation of NKT cells. It also remains to be elucidated whether 
an inflammatory phase always precedes fibrosis, or whether sep-
arate pathways shared with other fibrotic lung diseases are more 
prominent in fibrotic HP. Regulatory T- cell inhibition contributes to 
both a proliferation of inflammation and a switch to a Th2 response 
via a loss of Foxp3 expression.40 Later in the course of the disease, 
IL- 6 produced by activated macrophages promotes differentiation 
of B cells to plasma cells and maturation of cytotoxic CD8+ T cells.41 
Although less prominent than CD4+ T cells, CD8+ T cells play an im-
portant role in cell lysis, and the development of CD8+CD56+ NKT 
cells, potent inducers of interferon- γ, promotes differentiation from 
a Th1 to Th2 response.42
Th2 cytokines including IL- 4, IL- 13, and an increase in CCR4 (a 
Th2 chemokine receptor) and reduction in CXCR3 (a Th1 chemokine 
receptor) induce fibroblast proliferation and collagen production. 
Such changes are found in BAL fluid analysis in those with HP.43 
Fibroblast proliferation is also induced by IL- 17, produced by Th17 
cells, neutrophils, and expression of CD103+ on dendritic cells.44 
Similar to other ILDs including IPF, fibrosis is also perpetuated by 
persistent inflammation in the interstitial and alveolar spaces, re-
sulting in epithelial damage and destruction of the alveolar- capillary 
basement membrane. Fibroblasts, activated by profibrotic cyto-
kines, differentiate into myofibroblasts, and migrate to the alveolar 
space, predominantly driven by TGF- β. Fibroblasts produce extra-
cellular matrix, leading to lung tissue remodeling, resulting in tissue 
stiffness and hypoxia which in turn upregulates profibrotic pathways 
and perpetuates fibrogenesis.45
2.1  |  Genetic risk factors
Common and rare genetic variants have been identified with greater 
frequency in those with HP and especially fibrotic HP, which aids 
in determining risk and increases understanding of disease patho-
genesis. Increased susceptibility to HP has been associated with 
gene variants located within the major histocompatibility complex, 
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    |  445BARNES Et Al.
including the TNF- gene promotor region, correlating with higher 
TNF production perpetuating inflammation, and HLA- DRB1- related 
increases in peptide affinity to the HLA- DR4 molecular and T- cell 
receptor recognition,46 HLA- DR3 (bird- related HP), HLA- DQ3 
(summer- type HP), and HLA- A, - B, and - C loci (farmer's lung).46 
Similar to IPF, MUC5B gain of function alleles have been detected 
with greater frequency in chronic HP compared to healthy con-
trols.47 Overexpression of MUC5B in the respiratory bronchioles re-
sults in mucociliary dysfunction and disruption of the normal repair 
mechanisms of the lung. Protein- altering telomere- related gene vari-
ants including TERT, RTEL, and PARN have been identified in genetic 
studies of those with HP.48 Telomere dysfunction promotes DNA 
damage pathways, cellular senescence, inappropriate apoptosis, and 
stimulation of lung remodeling and fibrosis.49
2.2  |  Other risk factors
Previous respiratory tract infections (Epstein- Barr virus, human her-
pesvirus7 and 8, cytomegalovirus, parvovirus 19)50 are associated 
with an increased risk of developing HP by increasing MHC II ex-
pression on alveolar macrophages, increasing production of TNF, 
IL- 1, 6, IFN- α, and RANTES, and may promote fibrosis through 
epithelial cell injury, upregulation of TGF- β, and promotion of 
epithelial- mesenchymal transition.51 Exposure to organochlorine 
and carbamate pesticides has been associated with farming- related 
HP, possibly due to their putative role in upregulation of pro- 
inflammatory cytokines TNF- α, IL- 2, and 4.6 Smoking paradoxically 
reduces the risk of developing HP (likely because nicotine attenuates 
the production of IL- 1, TNF, and macrophage phagocytosis); how-
ever, those who have HP who persistently smoke are more likely to 
develop worse outcomes.52 More recent studies have demonstrated 
an increase in bacterial burden and altered microbial composition 
in the lower airways of those with CHP compared to healthy sub-
jects,53 which in other fibrotic lung diseases have been found to be 
associated with risk of progression.54 Further research on the role of 
the lung microbiome in HP is imperative.
Our understanding of the immunopathogenesis of HP has been 
derived in part from animal models (initially rabbits, guinea pigs, 
and mice) and later murine knockout models, using intratracheal 
F I G U R E 1  Immunopathogenesis of HP 
in the lung. Inhaled antigens interact with 
antigen- presenting cells (macrophages, 
dendritic cells), via pattern recognition 
receptors including toll- like receptor 
2, 6, 9. APCs stimulate a Th1 response, 
enhanced by cytokine and chemokine 
production. Neutrophils are present in 
early disease. In parallel, stimulated B 
cells (plasma cells) produce IgG antibodies 
which initiates the complement cascade 
and further stimulates macrophages. 
Macrophages fuse to multinucleated 
giant cells and epithelioid cells to form 
granulomas, mediated by Th1 cytokine 
production. Chemotactic factors 
produced by granulomas, a greater Th2 
to Th1 response, a decrease in regulatory 
T- cell response, CD8+ T- cell production, 
and Th17 differentiation (partly induced 
by CD103+ on dendritic cells) promotes 
fibroblast proliferation. Fibroblasts 
differentiate into myofibroblasts, produce 
collagen and extracellular matrix
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446  |    BARNES Et Al.
distillation of antigen directly to the animal, or adoptive transfer of 
T cells to distinguish direct effects of the antigen from indirect ef-
fects of the immune response.55 Murine models are useful, however, 
have limited ability to induce granulomas and may not reflect the 
complexity of human disease behavior. Human BAL and lung biopsy 
analysis have confirmed and provided additional understanding of 
HP mechanisms. More recently, technological advances in genomics, 
next- generation sequencing, proteomics, and metabolomics56 have 
and will continue to provide a more nuanced and detailed under-
standing of HP immunopathogenesis.
3  |  DIAGNOSIS
The diagnosis of HP is made through a combination of clinical his-
tory (including exposure assessment), suggestive HRCT findings, 
and where required histopathological material, ideally presented at 
an interstitial lung disease multi- disciplinary discussion (MDD). The 
MDD should consider the variable contribution of different diagnos-
tic tests dependent on clinical phenotype (ie, BAL lymphocytosis 
may be less useful in fibrotic HP) and should not only consider what 
is required for a high confidence diagnosis of HP, but also aim to 
characterize an inflammatory, fibrotic, or mixed phenotype to aid 
treatment choices and prognostication.57
3.1  |  Clinical assessment
A thorough assessment for inhalational exposures is essential in the 
diagnosis of HP, both to identify an inciting antigen for diagnostic 
confidence and for exposure mitigation, as lack of exposure identi-
fication and ongoing exposure portends a poorer survival.58 A thor-
ough clinical history should be undertaken including assessment of 
known HP exposures. Several HP- specific exposure questionnaires 
have been proposed59,60; however, none have as yet been clinically 
validated and should be tailored to consider geographical differ-
ences in exposures and climate. For any potential exposure elicited, 
consideration should be given to the duration, extent, and frequency 
of exposure, and their relationship to symptoms.
Dyspnea and cough are the most common clinical symptoms of 
HP. Other symptoms include chest tightness, weight loss, and rhi-
nitis.8,61,62 Fever and malaise are common symptoms of acute HP. 
Physical examination most commonly reveals crackles, clubbing (7– 
50% patients) and occasionally squawks (inspiratory lung sounds 
with a mixture of musical and non- musical components), suggestive 
of small airways disease.63 Patients may also present with acute ex-
acerbations (acute respiratory deterioration with new ground- glass 
opacities on CT, not due to any other cause), with or without re- 
exposure to the inciting antigen. Similar to other fibrotic ILDs, HP 
exacerbations are more common in those with a UIP- like pattern and 
portend poor survival.64,65
Restriction (particularly a reduced forced vital capacity; FVC) is 
the most common physiological abnormality found on pulmonary 
lung function tests, followed by a reduction in diffusing capacity 
for carbon monoxide (DLCO).66- 68 Such parameters may be used to 
demonstrate response to treatment, or predict progressive fibrosing 
disease (>10% decline in FVC% predicted over 24 months or 5– 10% 
decline in FVC% predicted with worsening symptoms and/or pro-
gression on CT) which portends poor survival.69 Obstructive pat-
terns are also seen in cases with bronchiolitis or emphysema, and 
airway responsiveness may also be present.70
3.2  |  Additional antigen testing
Serum- specific IgG tests assess the presence of a specific IgG anti-
body which interacts with a pre- formed test antigen (eg, bird drop-
pings, specific molds), leading to the production of antigen- antibody 
complexes. Test performance variation may occur due to differences 
in the technique used (Ouchterlony or passive double immunodif-
fusion technique, electrosyneresis, or ELISA), and the methods by 
which the antigens are produced (bulk versus local antigen collec-
tion versus bespoke personalized antigen derivation).71 Commercial 
antigen tests (most commonly Aspergillus fumigatus, Aspergillus niger, 
Aspergillus flavus, Thermoactinomyces vulgaris, Micropolyspora faeni, 
and parrot, pigeon, parakeet serum) are available in some countries. 
The test performance characteristics also vary depending on the 
control population; serum IgG testing in HP patients compared to 
other ILD patients has a sensitivity of 83% and specificity of 68%; 
when HP is compared to exposed asymptomatic controls the sensi-
tivity is 90% and specificity 91%; and unexposed controls the sensi-
tivity is 93% and specificity 100%.72 Serum IgG testing can be most 
useful when a clinical history reveals more than one active exposure, 
or where no exposure is revealed73; however, a positive serum IgG 
does not confirm the diagnosis of HP, nor does a negative serum IgG 
exclude it.
Specific inhalational challenge involves the graded exposure 
to the causative antigen in a controlled laboratory setting, and a 
positive test results from a 15% reduction in DLCO% to 20% re-
duction in FVC%, relative hypoxemia (decline in oxygen satura-
tions by 3%), rise in temperature (by 0.5℃), or clinical symptoms 
(cough, dyspnea).74 Though few studies have been performed 
to assess its use, the sensitivityis estimated at 73% and specific-
ity 84%.71 Specific inhalational challenge is limited by set up bur-
den, lack of test standardization, and potential side effects and is 
therefore used in few centers. Skin patch testing is not routinely 
used in HP.
In select cases, occupational and environmental assessment may 
be employed. This involves more detailed history taking, and a home 
or job site visit to inspect ventilation, water damage, and specific 
elicited sources of exposure. Surface and air samples may be taken 
for testing, and bespoke antibody testing may be utilized.71 The ad-
ditive benefits are yet to be fully elucidated, though it may identify 
exposures in antigen- indeterminate disease or distinguish between 
several potential exposures (eg, bird in the home and hay in the 
workplace).73
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3.3  |  Radiology
High- resolution computed tomography (HRCT) with inspiratory and 
expiratory films form an essential component of HP diagnosis and 
prognosis.66 Compared to other ILDs, those with HP typically exhibit 
diffuse parenchymal ground- glass opacities, centrilobular nodules, 
mosaic attenuation, and air trapping on expiratory films, usually 
in a craniocaudal distribution (Figure 2).66 Airspace consolidation 
and lung cysts may also be present. In those with fibrotic HP, ad-
ditional features of coarse reticulation, traction bronchiectasis, and 
occasionally honeycombing may be present66 and suggest a poorer 
prognosis.47
3.4  |  Bronchoalveolar lavage (BAL)
Limitations in the specificity of HRCT findings and uncertain anti-
gen exposure will necessitate further diagnostic evaluation in many 
ILD patients. Bronchoalveolar lavage (BAL) is commonly performed 
as an adjunctive investigation to enhance diagnostic confidence.66 
Bronchoscopically obtained BAL fluid can be analyzed for nucle-
ated immune cells including alveolar macrophages, lymphocytes, 
neutrophils, and eosinophils. BAL fluid lymphocytosis, defined as 
lymphocyte percentage >15%, is common in HP.66,75 In non- fibrotic 
HP, lymphocyte counts may exceed 50%.75,76 In fibrotic HP, more 
modest BAL fluid lymphocyte elevations are observed and levels 
may even be normal, particularly in smoking or elderly patients.77,78 
In the recently published ATS/JRS/ALAT HP guidelines, an expert 
panel agreed that 30% BAL fluid lymphocytosis was a reasonable 
threshold for distinguishing between HP and IPF or sarcoidosis.66 In 
addition to cytological analysis, BAL is useful for ruling in or out in-
fectious pathology of the respiratory tract, including Mycobacterium 
species.
3.5  |  Lung biopsy
Histopathologic information may be required when diagnosis re-
mains uncertain, following baseline investigations. The three meth-
ods for obtaining lung tissue are transbronchial forceps lung biopsy 
(TBB), transbronchial lung cryobiopsy (TBLC), and surgical lung bi-
opsy (SLB). With a diagnostic yield of only 37% (95% CI 32– 42), TBB 
is less favored than other modalities.66 TBLC has greater diagnostic 
power than TBB, with an estimated diagnostic yield of 82% (95% CI 
78– 86%) for HP.79 TBLC carries increased risk of airway bleeding 
and pneumothorax compared with TBB, requiring procedural exper-
tise and careful patient selection.80,81 SLB is the reference standard 
for tissue sampling, with a diagnostic yield of 96% (95% CI 90– 100%) 
in HP, however, also carries a risk of airway bleeding, pneumotho-
rax, post- procedural exacerbations, and death.66 The risk is greater 
in those requiring in- patient biopsy for rapidly progressive disease, 
male sex, increasing age (over 65 years), multiple comorbidities in-
cluding pulmonary hypertension, and low baseline lung function 
(FVC% predicted <50% and/or DLCO% predicted <35%).66,82 The 
decision to proceed to biopsy and the choice of technique are neces-
sarily determined by available resources and patient suitability, and 
should be discussed in an MDD prior to undertaking the procedure.
3.6  |  Histopathology
Non- fibrotic HP is characterized by bronchiolocentric expansion 
of the interstitium with lymphocytes, occasional plasma cells and 
eosinophils, and scant lymphoid aggregates without germinal cent-
ers.66 Chronic cellular bronchiolitis and peribronchiolar granuloma-
tous inflammation are also key findings, the latter typified by loosely 
formed clusters of epithelioid and multinucleated macrophages, and 
isolated giant cells with non- specific inclusions such as cholesterol 
clefts as seen in other interstitial diseases affecting the distal air-
ways (Figure 3).83
In fibrotic HP similar features are also observed; however, the in-
filtrate is paucicellular and there is associated fibrosis. There is often 
significant overlap with the usual interstitial pneumonia pattern 
seen with IPF, including features such as fibroblast foci and subpleu-
ral honeycomb cysts.83 Occasionally, other disease patterns, such as 
F I G U R E 2  A, High- resolution CT expiratory image of 
inflammatory HP with ground- glass opacities and centrilobular 
nodules with marked air trapping. B, Fibrotic HP with traction 
bronchiectasis and reticulation, with mild mosaic attenuation and 
centrilobular ground- glass nodules
(A)
(B)
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448  |    BARNES Et Al.
non- specific interstitial pneumonia (NSIP) or organizing pneumonia, 
are observed in HP. Idiopathic forms of these diseases are important 
differential diagnoses for HP as are other types of granulomatous 
ILD such as sarcoidosis, common variable immune deficiency (CVID), 
and infections due to mycobacteria, fungi, and certain respiratory 
viruses.
4  |  TRE ATMENT
4.1  |  Exposure remediation
The initial management for those diagnosed with HP includes the 
identification and remediation of the implicated exposure. Ongoing 
exposure is associated with further decline in respiratory function, 
and improvement with exposure remediation may help confirm the 
diagnosis.69 No evidence- based guidelines specific to HP on how 
to mitigate exposures currently exist, though case reports suggest 
removal of the implicated exposure may not be sufficient to clear 
all antigenic particles from the environment without additional deep 
cleaning.84,85
4.2  |  Immunosuppression
While exposure remediation is the most important management 
strategy, in many patients with HP an antigen is not identified. 
Persistent respiratory symptoms, lung function decline, and/or ra-
diographic progression may occur even with antigen avoidance and 
prompt the consideration of therapy with anti- inflammatory or anti- 
fibrotic medications.1,86 The immunosuppressive agents used in HP 
include systemic corticosteroids (which inhibits the synthesis of 
inflammatory cytokines through blocking the function of nuclear 
factor kappa B (ηf- κβ) and activator protein 1 (AP- 1)),87 mycopheno-
late mofetil (which inhibits B- and T- cell proliferation and has some 
anti- fibrotic properties),88 azathioprine (which inhibits B- and T- cell 
proliferation and inhibits the costimulatory CD28 binding of T cells 
with APCs)89 and rituximab (which depletes CD 20+ B lymphocytes 
and inhibits T- cell co- stimulation).90 Demonstrated efficacy of these 
therapies in rigorous clinical trials, however, is lacking. The anti- 
fibrotic agent nintedanib(a tyrosine kinase inhibitor which targets 
multiple growth factor receptors, including vascular endothelial 
growth factor, fibroblast growth factor, and platelet- derived growth 
factor) has been shown to be efficacious in a randomized, placebo- 
controlled trial in patients with progressive fibrosing ILD including 
HP.91 Acute exacerbations in patients with HP are typically treated 
with intravenous corticosteroids based on anecdotal evidence of 
benefit in some cases.
Corticosteroids are considered the first- line medical therapy for 
those in whom the HP does not improve or resolve with successful 
antigen remediation. In one small randomized study in patients with 
acute farmer's lung,92 prednisolone compared to placebo resulted in 
improvement in DLCO at one month but not FVC or DLCO at five 
years with recurrent farmer's lung noted more commonly in the 
corticosteroid- treated group. A retrospective study of immunosup-
pressive therapy in patients with chronic HP showed that patients 
treated with prednisone alone had more frequent treatment- related 
adverse events than those who also received azathioprine or my-
cophenolate mofetil.93 This may have been due to the dose reduc-
tion in prednisone afforded by the use of these agents as was seen 
in a recent multicenter retrospective investigation.94 In this study, 
treatment with either azathioprine or mycophenolate mofetil also 
resulted in improvement in DLCO with stable FVC after one year 
of therapy. In patients with chronic HP treated with mycophenolate 
mofetil, an improved survival was noted in those with longer telo-
mere length compared to those with short telomeres.95 The benefit 
of rituximab in HP has been noted in a case report and uncontrolled 
studies.96- 98 A recent small retrospective study suggested that rit-
uximab was associated with stabilization to modest improvement in 
lung function in chronic HP.98 In patients with progressive fibros-
ing ILD, a subset of whom had HP (n=173), nintedanib was shown 
to slow the decline in FVC compared to placebo.91 This may be of 
particular benefit in those with HP and UIP type pulmonary fibro-
sis for whom anti- inflammatory therapy may result in little or no 
improvement.
Rigorous trials are urgently needed to confirm the efficacy re-
ported in retrospective studies, including when immunosuppression 
is beneficial and whether it might be harmful in the presence of fi-
brosis or known genetic variants. Further studies are also needed to 
determine the additive benefit of anti- fibrotic therapy and for novel 
therapies.
4.3  |  Non- pharmacological treatments
In HP patients, significant physical deconditioning can develop 
due to avoidance of activity and generalized sarcopenia due to 
chronic inflammation, altered hormonal profiles, and metabolic 
F I G U R E 3  High power surgical lung biopsy specimen 
demonstrating a small aggregate of histiocytes and giant cells, with 
some cholesterol crystals within the cytoplasm
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    |  449BARNES Et Al.
derangement.99 Furthermore, corticosteroid use can lead to proxi-
mal myopathy. Many patients will benefit from outpatient pul-
monary rehabilitation100,101; shown to improve six- minute walk 
distance (6MWD), dyspnea scores, and quality of life in mixed 
ILD populations.102 Supplemental oxygen can improve endur-
ance and is advised for all ILD patients with resting hypoxemia, 
and for those with exercise- induced hypoxemia during pulmonary 
rehabilitation.101,103
A select group of HP patients with progressive disease may be 
suitable for lung transplantation. Transplanted HP patients appear to 
have better outcomes than those with IPF, with lower rates of acute 
rejection in the HP group in one retrospective series.1,104 Notably, 
HP may recur in the allograft in a small proportion of patients if the 
exposure is not removed.104
For patients with progressive disease who are not transplant- 
eligible, palliative care is an important but currently underutilized 
service for management of complex needs.105,106 A large burden 
of respiratory symptoms can be reduced with timely introduction 
of palliative medications, behavioral strategies, specialist nursing, 
and psychological support delivered by community- based expert 
clinicians.107
5  |  NATUR AL HISTORY
The natural history of HP is dependent on the underlying disease 
phenotype. Markers of inflammatory HP including ground- glass 
opacities on HRCT are associated with a better prognosis (reduced 
hazard ratio for mortality of 0.31108). Conversely, those with fibro-
sis on CT have a poorer survival (7.95 years; honeycomb fibrosis 
2.76 years; no fibrosis >14.73 years).25,108-110
Similar findings have been demonstrated using automated CT 
analysis, as well as demonstrating in one study that pulmonary ves-
sel volume was a separate predictor of survival, and in another that 
automated analysis using CALIPER was a stronger predictor of mor-
tality than visual CT analysis.111,112 Older age, male gender, lower 
baseline pulmonary physiology, and a decline in FVC >10% are poor 
prognostic indicators.3,69 Pulmonary hypertension also portends a 
poorer survival (23 months when present compared to 98 months 
when absent).113
Patients with HP experience greater complexity of care than 
other forms of ILDs and are more likely than their ILD counter-
parts to undergo invasive surgical lung biopsy and other additional 
tests. Conversely, clinical trial access is less commonly available 
for HP than compared with IPF or other ILDs.114 Health- related 
quality of life is worse in those with HP, even when controlling for 
age and pulmonary impairment,115 found to be in part associated 
with the complex psychosocial problems associated with antigen 
identification and avoidance.116 Mood disorders may be present 
in up to 50% of those with HP, and depression in 28%.24 Degree 
of dyspnea and extent of comorbidities have been shown to con-
tribute to mood disorder, while dyspnea and fatigue impact on qual-
ity of life.102
6  |  BIOMARKERS FOR 
PROGNOSTIC ATION
A number of prognostically significant biomarkers have been de-
scribed for HP.117 In addition to CT features of fibrosis as described 
above, the next most frequently utilized biomarker is BAL lympho-
cyte counts, with higher % lymphocytosis being associated with 
more inflammatory forms of presentation and lower counts carrying 
a worse prognosis.24 Markers of epithelial and pneumocyte damage 
(KL- 6, SP- D), inflammatory mediators (CCL17), and protein deposi-
tion (periostin) are also associated with mortality.118- 121 CXCL13 
(promotes B lymphocyte migration and granuloma formation), ma-
trix metalloproteinase- 7 (responsible for extracellular matrix deg-
radation and processing of growth factors including FAS ligand, β4 
integrin, E- cadherin, plasminogen, transmembrane tumor necrosis 
factor α (pro- TNF- α), and osteopontin),122 and VCAM- 1 (known to 
stimulate fibroblast proliferation in IPF)123 are also associated with 
increased risk of fibrosis and mortality.
Genetic predictors of worse outcome include shorter telomere 
length and the MUC5B rs35705950 single nucleotide polymor-
phism being associated with more severe fibrosis on CT, and shorter 
telomere length with reduced survival.47 Differences in the trigger-
ing environmental antigen have not been shown to generally alter 
outlook, but where the antigen cannot be identified, prognosis is 
worse.58 Additionally, where ongoing environmental exposure is 
higher, progression appears more likely.124 A significant minority of 
those with HP have features or serologic markers consistent with 
autoimmune disease.These autoimmune features may increase the 
risk of mortality by fourfold in HP patients when adjusted for other 
known predictors of survival.125
7  |  CONCLUSIONS AND FUTURE 
RESE ARCH PERSPEC TIVES
Hypersensitivity pneumonitis is a commonly encountered ILD, and 
its recognition and prevalence have increased over time. Large, mul-
ticenter cohort registry- based studies have contributed to identi-
fying clinical, radiological, and pathological features leading to the 
development of common key diagnostic criteria, and to the evolution 
of more useful HP phenotypes (non- fibrotic and fibrotic, versus the 
previous classification of acute; subacute; chronic) which aid in prog-
nostication and treatment making decisions.
Our understanding of the complex immunological drivers of dis-
ease have been greatly enhanced by the new developments in tech-
nology (including RNA sequencing and SNP analysis) and revealed 
pathways unique to HP and shared pathways with other ILDs lead-
ing to fibrosis. In turn, non- invasive biomarkers of disease are being 
identified, with potential for enhanced diagnostic and prognostic 
accuracy in the future.
The disease trajectory for many patients with HP remains poor, 
despite treatment. Given that immunosuppression may be dele-
terious in certain types of ILDs,126 rigorous trials are needed to 
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450  |    BARNES Et Al.
determine the role of immunosuppression in treating the various 
phenotypes of HP. Anti- fibrotic therapy in HP appears likely to have 
a role for fibrotic HP, but further confirmation and studies of anti- 
fibrotics are needed. While antigen identification and remediation 
are vital, antigen identification remains poor,58 providing a further 
need for future research.
ACKNOWLEDG MENTS
We thank Dr Kirk Jones (UCSF) for the provision of histopathology 
slides, and Dr Brett Elicker (UCSF) for the provision of HRCT images.
CONFLIC T OF INTERE S T
Dr. Strek conducts clinical research studies for Boehringer- Ingelheim 
and Galapagos, and has received honoraria for consulting and medi-
cal writing from Boehringer- Ingelheim and honoraria for serving on 
an adjudication committee for FibroGen.
AUTHOR CONTRIBUTIONS
HB and IG conceived the article. HB, CL, LT, AS, MS, and IG contrib-
uted to the draft and approved the final manuscript.
ORCID
Hayley Barnes https://orcid.org/0000-0002-7615-4191 
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How to cite this article: Barnes H, Troy L, Lee CT, Sperling A, 
Strek M, Glaspole I. Hypersensitivity pneumonitis: Current 
concepts in pathogenesis, diagnosis, and treatment. Allergy. 
2022;77:442– 453. https://doi.org/10.1111/all.15017
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