Hypersensitivity pneumonitis: symptoms, diagnosis, treatment and prognosis

Hypersensitivity pneumonitis is an immune-mediated inflammatory interstitial lung disease that develops in susceptible individuals after repeated exposure to a causative antigen. The source of such an antigen may be mold fungi, bird proteins, contaminated water, organic dust, certain industrial chemicals, and other household or occupational factors. In modern pulmonology, this disease is not considered a "common lung allergy," but a complex syndrome in which exposure, individual susceptibility, the nature of the immune response, and the presence or absence of established pulmonary fibrosis all play a role. [1]

Historically, this condition was often referred to as exogenous allergic alveolitis. This term is now used less frequently, as modern classification emphasizes not only alveolar inflammation but also damage to the small airways, interstitium, and, in some patients, the development of pulmonary fibrosis. This is why current international guidelines primarily divide hypersensitivity pneumonitis into non-fibrotic and fibrotic variants, as the presence of fibrosis significantly alters the prognosis and treatment strategy. [2]

The disease can progress in a wide variety of ways. In some patients, symptoms appear within hours of intense exposure to the antigen and resemble an infection with fever, cough, and shortness of breath. In others, the disease develops over months or years, gradually leading to decreased exercise tolerance, chronic shortness of breath, cough, and the development of interstitial fibrosis. Because of this variability, hypersensitivity pneumonitis is often diagnosed late or mistaken for idiopathic pulmonary fibrosis, sarcoidosis, asthma, chronic bronchitis, or recurrent pneumonia. [3]

Two factors are particularly important for clinical practice. First, the disease is often reversible in the early stages if the causative antigen can be quickly identified and eliminated. Second, if it persists, especially in the fibrotic variant, it can behave like a progressive fibrosing interstitial lung disease with deteriorating respiratory function, exacerbations, and an increased risk of death. [4]

The key points of the introduction are summarized in the table. [5]

Parameter	Key feature
The nature of the disease	Immune-inflammatory interstitial lung disease
Trigger factor	Re-inhalation of the causative antigen
Main sources	Birds, mold, organic dust, contaminated water, chemical agents
Modern division	Non-fibrotic and fibrotic variants
Major clinical risk	Transition to progressive pulmonary fibrosis

Code according to ICD 10 and ICD 11

In the International Classification of Diseases, 10th revision, hypersensitivity pneumonitis is classified under the heading J67—hypersensitivity pneumonitis caused by organic dust. This is not a single narrow code, but a whole group of subheadings that includes individual forms associated with different types of organic exposure, such as bagassosis, poultry farmer's lung, suberosis, and other variants. This approach reflects clinical reality: the same syndrome can occur with different antigen sources, but shares a common pathogenetic mechanism. [6]

In practice, coding according to the International Classification of Diseases, 10th revision, depends on whether the source of exposure has been accurately identified. If the antigen is known, a more specific subcategory within J67 is selected. If the causative factor is unknown, the code for unspecified hypersensitivity pneumonitis due to organic dust is more often used. For the clinician, this is important not only for statistical reasons, but also because documenting a link to a specific household or occupational factor helps organize prevention of re-exposure. [7]

In the International Classification of Diseases, 11th revision, the morbidity and mortality coding system for hypersensitivity pneumonitis due to organic dust is classified as CA70 – hypersensitivity pneumonitis due to organic dust. At the same time, in the structure of the International Classification of Diseases, 11th revision, the disease is also associated with the section on allergic and hypersensitivity respiratory disorders, which emphasizes its immunological nature, but the respiratory category CA70 is used for statistical coding. [8]

It should be noted that the code does not replace a detailed diagnosis. It is advisable to include in the clinical record not only the code but also the clinical course, the presence or absence of fibrosis, the suspected antigen, the occupational or social connection, and the degree of respiratory failure, if any. This is especially important for patient routing, prognosis assessment, and decision-making regarding specialized antifibrotic therapy or referral for transplant consultation. [9]

The main codes are summarized in the table. [10]

Classification	Code	Name	Practical commentary
ICD 10	J67	Organic dust hypersensitivity pneumonitis	General section
ICD 10	J67.2	Poultry breeder's lung	Used when a bird exhibit is installed
ICD 10	J67.8	Hypersensitivity pneumonitis due to other organic dusts	For other established reasons
ICD 10	J67.9	Hypersensitivity pneumonitis due to unspecified organic dust	For unclear antigen
ICD 11	CA70	Hypersensitivity pneumonitis due to organic dust	Basic modern code in the International Classification of Diseases, 11th revision

Epidemiology

Hypersensitivity pneumonitis is considered a rare disease in the general population, but its prevalence is much higher among interstitial lung diseases. According to the American Thoracic Society, the annual prevalence in the United States was approximately 1.67 to 2.71 cases per 100,000 population, and the cumulative annual incidence was 1.28 to 1.94 cases per 100,000 between 2004 and 2013. In Europe, estimated incidence rates of approximately 0.12–0.9 cases per 100,000 per year have been reported.[11]

However, population figures do not reflect the actual risk distribution. In specialized registries of interstitial lung diseases, the proportion of hypersensitivity pneumonitis ranged from approximately 2% to 47%, which is related to geography, industrial and agricultural exposure profiles, differences in diagnostic approaches, and varying physician alertness. After idiopathic pulmonary fibrosis and interstitial lung diseases in systemic connective tissue diseases, hypersensitivity pneumonitis is often considered one of the most significant causes of chronic fibrosing interstitial lung disease. [12]

Age plays a significant role. In one analysis, prevalence increased from 1.48 per 100,000 among people aged 35–44 years to 11.2 per 100,000 among those aged 65 years and older. Furthermore, in the American sample, 56% to 68% of cases annually were classified as chronic forms, and 36% to 48% of chronic forms already had fibrosis. This explains why, in real-world practice, a pulmonologist more often sees not an acute “farmer’s” flare-up, but a patient with long-standing dyspnea and interstitial changes on CT scan. [13]

Epidemiology varies greatly depending on the environment. Worldwide, the most common forms include farmer's lung and avian variants. Occupational outbreaks have also been described in workers exposed to contaminated metalworking fluids, humidifiers, fungi, wood dust, and low-molecular-weight chemicals. Seasonality also plays a role: for example, agricultural variants are more frequently observed during livestock feeding periods and after harvest. [14]

Mortality from hypersensitivity pneumonitis also deserves attention. In the United States, an increase in age-standardized mortality from 0.12 to 0.68 per 1,000,000 population was reported between 1988 and 2016. This increase appears to be related not only to the actual disease burden but also to better recognition of chronic and fibrotic forms, which may previously have been miscoded as other interstitial lung diseases. [15]

The main epidemiological landmarks are summarized in the table. [16]

Indicator	Data
Annual prevalence in the United States	1.67-2.71 per 100,000
Annual incidence in the United States	1.28-1.94 per 100,000
Estimated incidence in Europe	0.12-0.9 per 100,000 per year
Share in interstitial lung disease registries	About 2-47%
The proportion of chronic forms in a number of samples	56-68%
The proportion of fibrotic forms among chronic	36-48%

Reasons

The cause of the disease is not a single universal microbe or toxin, but rather the repeated inhalation of a wide range of antigens. Current reviews and documents from the American Thoracic Society indicate that more than 200-300 potential causative antigens have already been identified. These can be microbial, plant, animal, or chemical, and exposure to them is possible at home, at work, or during hobbies. [17]

The most common causes are antigens associated with agriculture and poultry. Classic examples include farmer's lung from exposure to moldy hay, grain, or silage, and poultry farmer's lung from inhaling proteins from the feathers, whey, and droppings of domestic and ornamental birds. In many countries, these two groups remain the leading causes. [18]

The second important group is exposures to water and mold. These include humidifiers, hot tubs, saunas, contaminated water systems, air conditioners, moisture-damaged rooms, and organic dust in the home environment. These types of exposures are particularly difficult to diagnose, as the patient may not associate the household environment with respiratory symptoms for years. [19]

The third group includes occupational chemical and industrial factors. Among these, the most well-known are isocyanates, anhydrides, metalworking fluids, some pesticides, heated epoxy resins, wood dust, and fungal aerosols. These factors are particularly important for occupational health, because without eliminating exposure, even properly prescribed treatment will be ineffective. [20]

In some patients, the causative antigen cannot be identified. According to modern reviews, unidentified exposure occurs in approximately 20-50% of cases, especially in the fibrotic variant. This does not rule out the diagnosis, but is usually associated with more difficult prevention of re-exposure and a less favorable prognosis. [21]

The main reasons and typical situations are summarized in the table. [22]

Group of antigens	Typical sources	Examples of clinical variants
Mold fungi and thermophilic actinomycetes	Hay, silage, grain, compost	Farmer's lung, compost worker's lung
Bird squirrels	Poultry, pigeons, decorative feathers	Poultry breeder's lung
Contaminated water and aerosols	Hot baths, humidifiers, saunas	Easy hot baths, options for water systems
Wood and other organic dust	Woodworking, cork, flour	Carpenter's lung, suberose, baker's lung
Chemical agents	Isocyanates, anhydrides, epoxy resins	Professional chemical options

Risk factors

The main risk factor is significant and repeated exposure to the antigen itself, but this is not sufficient to develop the disease. Most people exposed never become ill. This means that hypersensitivity pneumonitis develops only in a subset of susceptible individuals who develop an abnormal immune response to the inhaled agent. [23]

Genetic factors play a significant role. Polymorphisms of the major histocompatibility complex genes, including HLA-DR and HLA-DQ, as well as other variants affecting antigen presentation and immune inflammation, have been associated with increased susceptibility. Links with genetic variants known to cause idiopathic pulmonary fibrosis, including MUC5B and telomere shortening, have also been described for the fibrotic variant. [24]

Risk is increased by age and the duration of undetected chronic exposure. The acute form most often occurs after intense contact in an already sensitized individual, while the chronic and fibrotic forms typically develop after months or years of exposure to low doses of the antigen. This is why poultry, poorly ventilated areas, and hidden sources of mold are particularly insidious: a person becomes accustomed to the environment and does not perceive it as dangerous for a long time. [25]

Interestingly, smoking has a mixed effect. Smokers are less likely to develop the non-fibrotic form of the disease, likely due to a modified immune response, but if fibrotic hypersensitivity pneumonitis does develop, the prognosis for smokers is worse. Therefore, smoking cannot be considered a practical protection and remains an unfavorable prognostic factor. [26]

In those already infected, poor prognostic factors include an unidentified antigen, ongoing exposure to the causative agent, male gender, older age, lower lung function tests, and the presence of fibrosis on CT scan. These are not so much factors in onset as indicators of a high risk of an unfavorable course after disease manifestation. [27]

The risk factors are summarized in the table. [28]

Factor	Meaning
Repeated exposure to the causative antigen	The basic condition for the development of the disease
Genetic susceptibility	Increases the likelihood of an abnormal immune response
Long-term latent exposure	Associated with chronic and fibrotic course
Older age	Associated with a more severe prognosis
Smoking	Less common is the non-fibrotic variant, but the prognosis is worse with fibrotic
Unidentified antigen	Complicates prevention and worsens outcomes
Continued contact after disease onset	Accelerates progression

Pathogenesis

The pathogenesis of hypersensitivity pneumonitis is based on repeated antigen inhalation and an excessive immune response in the lung tissue. Following sensitization, inflammation develops in the alveoli, interstitium, and small airways. Unlike atopic diseases, where the immediate immunoglobulin E-mediated reaction predominates, immune complexes, cellular immunity, and inflammation involving lymphocytes and macrophages play a key role here. [29]

In the early stages, bronchiolocentric inflammation develops. This is clearly visible on both computed tomography and morphology: small, poorly defined centrilobular nodules, ground-glass opacities, air traps, and mosaic changes in lung tissue density appear. Lymphocytic inflammation, foci of organizing pneumonia, and poorly formed noncaseating granulomas are typical morphologically. [30]

If exposure continues, the inflammatory process gradually restructures the lung architecture. Peribronchiolar and interstitial fibrosis, traction bronchiectasis, and a decrease in lung tissue volume appear, and in some cases, a picture very reminiscent of idiopathic pulmonary fibrosis develops. It is this transition from a predominantly inflammatory process to a fibrosing one that determines the modern division of the disease into non-fibrotic and fibrotic variants. [31]

Some patients develop progressive pulmonary fibrosis. Current consensus defines this disease behavior as the presence of at least two of three signs for one year without any other explanation: worsening respiratory symptoms, physiological progression, and radiological progression. This variant is particularly dangerous because it leads to a persistent decrease in vital capacity, increasing respiratory failure, and increased mortality. [32]

Progression depends not only on the severity of exposure but also on host characteristics. Associations with telomere shortening, MUC5B variants, and other genetic factors suggest that some patients develop a biological program similar to other fibrosing interstitial lung diseases. This partially explains why two people with seemingly similar exposures may exhibit completely different disease behaviors. [33]

The pathogenesis by stages is summarized in the table. [34]

Stage	What's happening
Sensitization	The immune system begins to recognize the inhaled antigen
Early inflammation	The alveoli, interstitium and small airways are affected
Bronchiolocentric lesion	Centrilobular nodules and air traps form
Granulomatous response	Poorly formed non-caseating granulomas appear
Fibrosis	Peribronchiolar and interstitial fibrosis develop
Progressive phenotype	Symptoms worsen, function and CT scans deteriorate

Symptoms

The clinical presentation depends on the intensity and duration of exposure to the antigen, as well as whether fibrosis is already present. In the acute form, symptoms typically appear 4-8 hours after massive exposure in a previously sensitized individual. Typical symptoms include fever, chills, cough, shortness of breath, chest tightness, and sometimes nausea and general malaise. This presentation often resembles a viral infection or bacterial pneumonia. [35]

The subacute form develops over days or weeks. Symptoms include cough, gradually increasing shortness of breath, fatigue, loss of appetite, and decreased exercise tolerance. This form is less dramatic than the acute form, but for this reason, it often remains underestimated and persists despite continued exposure. [36]

The chronic form, especially the fibrotic form, develops over months or years. Patients complain of shortness of breath during physical exertion, a dry or unproductive cough, fatigue, and weight loss. Fever is usually absent. Inspiratory wheezing and sometimes high-pitched inspiratory "squeaks" are often heard on auscultation. In advanced cases, clubbing, pulmonary hypertension, right ventricular failure, and respiratory failure may occur. [37]

Anamnestic clues are especially important for the physician. These include recurring " atypical pneumonias," worsening after staying in a particular house, on a farm, near birds, after contact with hot baths, humidifiers, or organic dust, and improvement with a change of environment. This relationship of symptoms to the environment is one of the most valuable clinical clues to diagnosis. [38]

Some patients experience mild symptoms, despite already noticeable changes on CT scans. This makes the disease particularly dangerous: despite relatively mild symptoms, irreversible fibrosis may already develop. Therefore, any unexplained shortness of breath and cough associated with typical household or occupational exposure should be considered for hypersensitivity pneumonitis. [39]

Symptoms according to the course of the disease are summarized in the table. [40]

Option	Typical terms	Main symptoms
Spicy	Hours after intense contact	Fever, chills, cough, shortness of breath, chest tightness
Subacute	Days and weeks	Cough, shortness of breath, weakness, loss of appetite
Chronic	Months and years	Shortness of breath on exertion, cough, fatigue, weight loss
Fibrotic	Long-term course	Persistent dyspnea, exercise limitation, signs of interstitial fibrosis

Classification, forms and stages

Previously, hypersensitivity pneumonitis was divided into acute, subacute, and chronic. This scheme remains useful for understanding the clinical picture, but current international guidelines consider a different division—non-fibrotic and fibrotic—more important. The reason is simple: the presence of fibrosis is best associated with prognosis, treatment choice, and risk of progression. [41]

The non-fibrotic variant is a predominantly inflammatory disease without convincing evidence of structural pulmonary fibrosis on CT or morphology. This form is most often characterized by centrilobular nodules, ground-glass opacities, mosaic ventilation, and air trapping. With timely antigen elimination and anti-inflammatory treatment, this form has the greatest potential for reversibility. [42]

The fibrotic variant includes cases in which reticular changes, traction bronchiectasis, loss of lung volume, sometimes honeycombing, and other signs of scarring are already present. Morphologically, peribronchiolar fibrosis, a picture resembling ordinary interstitial pneumonia, and poorly formed granulomas are possible. This variant more often leads to deterioration of respiratory function and early mortality. [43]

The progressive phenotype of fibrotic hypersensitivity pneumonitis is particularly relevant. According to current consensus criteria, progression is defined by a combination of at least two signs over 1 year: worsening symptoms, physiological deterioration, and radiological deterioration without another explanation. This is the most important stage in terms of transitioning to antifibrotic therapy and discussing the transplant route. [44]

Thus, in daily clinical work, it is reasonable to use two description systems simultaneously: a clinical one based on the rate of symptom development and a modern one based on the presence or absence of fibrosis. They do not contradict each other, but rather complement each other. [45]

The classification is summarized in the table. [46]

Approach	Options	Practical significance
By the rate of development	Acute, subacute, chronic	Helps to understand the clinical scenario
By the structure of lung tissue	Non-fibrotic, fibrotic	Determines the forecast and tactics
By the behavior of the disease	Stable, progressive	Important for the choice of antifibrotic therapy
By antigen source	Poultry, farm, water, chemical and others	Helps in eliminating exposure

Complications and consequences

The main complication is the development of irreversible pulmonary fibrosis. If the causative antigen is not eliminated or the diagnosis is late, the inflammatory process gradually gives way to scarring of the interstitium. This leads to a persistent decrease in lung compliance, decreased diffusion capacity, increasing dyspnea, and decreased physical activity. [47]

The second major complication is progressive pulmonary fibrosis with deterioration of respiratory function. In a large Spanish cohort of fibrotic hypersensitivity pneumonitis, signs of progression during the observation period were observed in 55.8% of patients. This emphasizes that the fibrotic variant cannot be considered a "quiet" form of chronic inflammation. [48]

Severe sequelae include acute decompensation of interstitial disease, respiratory failure, pulmonary hypertension, right ventricular failure, and the need for lung transplantation. In the same cohort, acute exacerbation during follow-up was an independent factor for higher mortality, and the in-hospital mortality for such episodes was estimated in the review to be approximately 44%.[49]

Even without catastrophic complications, the disease significantly reduces quality of life. Patients have poor exercise tolerance, tire more quickly, limit daily activities, and, in severe cases, require oxygen and long-term rehabilitation. Therefore, complications of hypersensitivity pneumonitis should be assessed not only by survival but also by the degree of functional loss. [50]

The main complications are summarized in the table. [51]

Complication	Clinical significance
Interstitial fibrosis	Irreversible remodeling of lung tissue
Progressive pulmonary fibrosis	Accelerated decline in lung function
Acute exacerbation	High risk of hospitalization and death
Respiratory failure	Oxygen demand and activity limitation
Pulmonary hypertension	Decreased load on the right side of the heart
The need for transplantation	A sign of an advanced disease

When to see a doctor

A doctor should be consulted if unexplained coughing and shortness of breath occur, especially if symptoms recur after exposure to birds, mold, hay, grain, hot baths, humidifiers, or occupational organic dust. The sooner a doctor recognizes a potential exposure, the better the chance of identifying the non-fibrotic form and stopping the disease before scarring occurs. [52]

Special attention should be given to situations where fever, cough, and shortness of breath develop several hours or the next day after work, cleaning a moldy area, or exposure to birds or agricultural materials. Such an episode can easily be mistaken for an infection, but if it recurs, it should raise concerns about hypersensitivity pneumonitis. [53]

Immediate evaluation is necessary for rapidly worsening shortness of breath, cyanosis, markedly decreased oxygen saturation, chest pain, confusion, high fever, and signs of respiratory failure. In a patient with a known fibrotic variant, such symptoms may indicate an acute exacerbation or other serious condition requiring hospitalization. [54]

If cough and shortness of breath persist for months, and CT scans already show interstitial changes, delaying a consultation at an interstitial lung disease center is especially dangerous. In this disease, not only the diagnosis itself is valuable, but also the quality of the multidisciplinary assessment, as it determines the accuracy of differentiation from idiopathic pulmonary fibrosis, sarcoidosis, and other interstitial diseases. [55]

The situations for appeal are summarized in the table. [56]

Situation	Tactics
Recurrent cough and shortness of breath after exposure to an antigen	Scheduled consultation with a pulmonologist
Fever and shortness of breath within a few hours of exposure	Quick in-person assessment
Chronic progressive dyspnea	Further examination for interstitial lung disease
A drop in saturation, severe respiratory failure	Urgent help
The fibrotic variant and increasing symptoms have already been established.	Urgent reassessment for progression or exacerbation

Diagnostics

The diagnosis of hypersensitivity pneumonitis is based not on a single test, but on a combination of a carefully collected exposure history, clinical presentation, high-resolution computed tomography (HRCT), bronchoalveolar lavage results, biopsy if necessary, and multidisciplinary discussion. Both the American Thoracic Society and Chest guidelines emphasize that diagnosis requires exclusion of alternative causes of interstitial lung disease. [57]

The first step is a detailed search for the causative antigen. The doctor asks not only about the patient's occupation but also about birds in the home, feather pillows and blankets, humidity and mold, hot baths, air conditioning, hobbies, woodworking, farm work, music with brass instruments, and other seemingly unexpected factors. Modern reviews specifically note that structured questionnaires increase the likelihood of identifying an exposure, although in approximately 20-50% of patients, the causative factor remains unidentified. [58]

The second step is a functional assessment of the lungs. A pulmonary function test is not a diagnostic test in itself, but it helps assess the severity of the disease and monitor its progression. Many patients exhibit restrictive ventilation disorders and reduced pulmonary diffusion capacity, although in the early stages the picture may be mixed or less pronounced. [59]

The third step is high-resolution computed tomography (CT ). The non-fibrotic variant is particularly characterized by poorly defined centrilobular nodules, ground-glass opacities, density mosaicism, and air trapping. The most specific CT feature is the so-called tripartite pattern, which simultaneously displays areas of normal density, ground-glass opacities, and hypodensity due to air trapping. The fibrotic variant is characterized by reticular changes, traction bronchiectasis, volume loss, and sometimes honeycombing. [60]

The fourth step involves laboratory and bronchoscopic methods. Serum immunoglobulins specific to suspected antigens are useful as markers of previous exposure, but do not prove the disease and do not differentiate simple sensitization from clinically significant pneumonitis. Bronchoalveolar lavage often reveals lymphocytosis. In some situations, lymphocyte levels greater than 30% can significantly increase the diagnostic probability, especially if the clinical picture and imaging do not fully match. However, the absence of significant lymphocytosis does not exclude fibrotic hypersensitivity pneumonitis. [61]

The fifth step is morphology if the diagnosis remains unclear. Biopsy can reveal bronchiolocentric inflammation, poorly formed noncaseating granulomas, peribronchiolar fibrosis, and other features that support the diagnosis. However, interpretation of the material is complex, as some patterns overlap with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, drug-induced lung injury, and connective tissue diseases. Therefore, a multidisciplinary team discussion involving a pulmonologist, radiologist, and pathologist with experience in interstitial lung diseases is considered optimal. [62]

The step-by-step diagnostic algorithm is summarized in the table. [63]

Step	What is being assessed?	What does this give?
1	Exposure history	Allows us to suspect the causative antigen
2	Respiratory function test	Determines the severity and dynamics
3	High-resolution computed tomography	Reveals the typical pattern and signs of fibrosis
4	Specific immunoglobulins to antigens	They confirm contact, but not the diagnosis itself.
5	Bronchoalveolar lavage	Helps to increase diagnostic confidence in lymphocytosis
6	Lung biopsy if necessary	Refines the morphological pattern
7	Multidisciplinary discussion	Increases the accuracy of the final diagnosis

Differential diagnosis

The greatest difficulty arises in distinguishing hypersensitivity pneumonitis from other interstitial lung diseases, particularly idiopathic pulmonary fibrosis. The fibrotic variant can have similar symptoms, similar restrictive disorders, and even a similar morphology to usual interstitial pneumonia. Therefore, simply seeing fibrosis on CT or biopsy is not enough to make a diagnosis. The exposure history and signs of bronchiolocentric involvement must be taken into account. [64]

The second major contender is sarcoidosis. Both diseases can be accompanied by granulomas and interstitial changes. However, in hypersensitivity pneumonitis, granulomas are usually poorly formed, there is a pronounced association with an inhaled antigen, and the bronchoalveolar lavage and CT patterns are often different. Furthermore, sarcoidosis is more often characterized by lymphocytosis with a predominance of certain cellular ratios, whereas in hypersensitivity pneumonitis, a different immune lavage profile is classically described. [65]

The third major group includes interstitial lung diseases associated with systemic connective tissue diseases and drug-induced interstitial lesions. Particularly challenging are cases where biopsy reveals granulomas and peribronchiolar fibrosis. In such situations, extrapulmonary signs of autoimmune disease, drug history, serology, and the nature of the inflammatory infiltrate are important. A document from the American Thoracic Society specifically notes that bronchiolocentric fibrosis is not absolutely specific for hypersensitivity pneumonitis. [66]

The fourth group includes organic dust toxic syndrome and other acute respiratory reactions to inhalation irritants. Organic dust toxic syndrome can cause fever, chills, and shortness of breath after extensive exposure, but does not require prior sensitization and has a different mechanism. This is especially important in agricultural practices, where symptoms after working in a dusty environment do not always indicate hypersensitivity pneumonitis. [67]

Differential diagnosis should be based not on a single symptom, but on a combination of data. In reality, five key elements play a key role: exposure history, high-resolution computed tomography, the presence or absence of lymphocytosis in bronchoalveolar lavage, morphology, and multidisciplinary discussion. [68]

The main differences are summarized in the table. [69]

Disease	What makes it similar	What helps to distinguish
Idiopathic pulmonary fibrosis	Fibrosis, shortness of breath, cough	Exposure, bronchiolocentricity, air trapping, granulomas
Sarcoidosis	Granulomas, interstitial changes	Different systemic context, different morphology and immune profile
Interstitial lung disease in systemic connective tissue disease	Fibrosis, inflammation	Autoimmune features, serology, inflammatory pattern
Drug-induced interstitial lung disease	Granulomas and fibrosis are possible.	Drug history, extrapulmonary signs, temporal relationship
Toxic organic dust syndrome	Acute symptoms after inhalation	No need for sensitization, different pathogenesis

Treatment

The basis of treatment is the earliest and most complete elimination of the causative antigen. This is not an additional measure, but a key therapeutic step, without which even potent anti-inflammatory therapy will be ineffective. If the antigen is identified, the patient is advised to eliminate it from the home or work environment, change ventilation, avoid contact with birds, eliminate the source of mold, or, if necessary, modify work conditions. The sooner contact is stopped, the higher the likelihood of stabilization or partial reversal of inflammatory changes. [70]

In the non-fibrotic variant and with severe symptoms, systemic glucocorticosteroids are often used. They can more quickly reduce inflammation and alleviate symptoms, especially in acute or subacute cases. However, an important caveat is that there is no convincing data on long-term survival improvement in the chronic fibrotic variant with this therapy. Therefore, steroids are not automatically used indiscriminately or indefinitely. [71]

In clinical practice, systemic glucocorticosteroids are most often prescribed for severe onset, acute respiratory deterioration, or signs of disease progression despite antigen elimination. The dose is then gradually tapered. Indefinite treatment is avoided due to the risk of diabetes, hypertension, cataracts, osteoporosis, infections, and other steroid complications. [72]

If long-term anti-inflammatory control is required or steroid tolerance is poor, steroid-sparing immunosuppressants are considered in practice. The most frequently mentioned are mycophenolate mofetil, mycophenolic acid, and azathioprine. Observational studies have shown that such drugs can improve gas exchange and reduce drug toxicity compared with long-term prednisolone therapy, but evidence from high-quality randomized trials is still insufficient. Therefore, these agents are used individually, usually in specialized centers. [73]

A special situation is the fibrotic variant, which continues to progress despite antigen elimination and basic therapy. For such patients, modern strategies increasingly include antifibrotic treatment. Nintedanib has been shown to slow the decline in forced vital capacity in patients with progressive fibrosing interstitial lung diseases, including hypersensitivity pneumonitis. This is why modern reviews and the American Thoracic Society recommend its consideration in patients with a progressive fibrotic phenotype. [74]

Pirfenidone is also considered a potential option for some patients with fibrotic hypersensitivity pneumonitis, but the evidence base for it is weaker. A randomized, double-blind study was underpowered but showed good tolerability and a signal of improvement in time to progression. Therefore, pirfenidone cannot yet be considered as confidently confirmed as nintedanib for the progressive fibrosing variant, but as a new approach, it deserves attention in specialized practice and research. [75]

For patients whose disease continues to worsen despite antigen elimination therapy, steroids, and standard immunosuppressants, newer approaches are emerging. In 2025, a prospective cohort of patients with refractory hypersensitivity pneumonitis showed that rituximab was associated with a significant slowing of the decline in forced vital capacity, a reduction in dyspnea, and an improvement in six-minute walk distance. However, these data cannot yet be considered a basis for routine use in all patients: this is an emerging approach for difficult-to-treat cases in expert centers. [76]

Non-pharmacological interventions are no less important than medications. Patients with hypoxemia are prescribed oxygen, and if exercise tolerance decreases, pulmonary rehabilitation is recommended. Vaccinations, smoking cessation, and treatment of concomitant gastroesophageal reflux disease, obesity, sleep apnea, cardiovascular disease, and pulmonary hypertension are essential. This comprehensive approach reduces the symptom burden and improves daily functioning, even if the disease can no longer be completely reversed. [77]

In advanced fibrotic disease, rapid progression, or repeated exacerbations, referral for transplant consultation should be discussed early. The American Thoracic Society emphasizes the importance of early consideration of transplantation in patients with severe fibrosis and a progressive course, and not only in the terminal stage, when the window of opportunity may already be closing. [78]

Finally, treatment should always be reassessed dynamically. At each visit, symptoms, respiratory function, oxygen requirements, risk of re-exposure, imaging data, and adverse effects of therapy are assessed. There is no "one-size-fits-all" treatment for hypersensitivity pneumonitis: in some patients, the disease stabilizes after antigen elimination and a short course of steroids, while others require a long, multi-stage regimen with immunosuppressants, antifibrotic therapy, rehabilitation, and preparation for transplantation. [79]

The main treatment methods are summarized in the table. [80]

Method	Where is it used?	Comment
Antigen elimination	To all patients	A basic and mandatory step
Systemic glucocorticosteroids	Acute, subacute, severe inflammatory variant	Fast anti-inflammatory effect, but not for long-term use
Mycophenolate mofetil, mycophenolic acid, azathioprine	If steroid-sparing tactics are necessary	The data are mostly observational.
Nintedanib	Progressive fibrotic variant	The most proven antifibrotic option
Pirfenidone	Selected fibrotic cases, research and specialized approach	Promising, but the evidence base is more limited
Rituximab	Refractory cases in expert centers	A new approach, not yet a first-line standard
Oxygen therapy	In case of hypoxemia	Symptomatic and supportive care
Pulmonary rehabilitation	When load tolerance decreases	Improves stamina and quality of life
Lung transplant	Severe progressive fibrosis	Considered early, not at the last minute

Prevention

The primary preventative strategy is environmental control. For at-risk groups, this means regularly assessing working and living conditions, controlling mold and dampness, ensuring proper ventilation, safely handling agricultural materials, monitoring humidifiers and water systems, and exercising caution when housing birds. Without eliminating exposure, no prevention will be complete. [81]

In occupational medicine and agriculture, engineering and organizational measures are important: ventilation, humidity control, timely replacement of contaminated materials, and protection when working with organic dust and chemical agents. Once a diagnosis has been established, repeated exposure to the antigen should be considered a risk factor for progression, rather than a harmless household detail. [82]

The second level of prevention is early recognition of symptoms. If a person regularly develops cough, fever, or shortness of breath after exposure to birds, hay, mold, or water aerosols, this is not a reason for endless self-medication, but for early evaluation. The most favorable outcomes are observed when diagnosis is made before widespread fibrosis develops. [83]

For patients with confirmed hypersensitivity pneumonitis, prevention of relapse includes environmental control, smoking cessation, vaccination, treatment of comorbidities, and routine monitoring with assessment of lung function and symptoms. This is particularly important because the disease can progress even after partial reduction in antigen exposure. [84]

Preventive measures are summarized in the table. [85]

Preventive measure	Target
Antigen Detection and Elimination	Avoid initial or repeated contact
Moisture and mold control	Reduce home inhalation load
Safety in production and agriculture	Reduce professional risk
Early screening for recurring symptoms	Catch the disease before fibrosis occurs
Quitting smoking	Improve overall respiratory prognosis
Routine monitoring of those already ill	Notice progression in time

Forecast

The prognosis is highly variable and depends primarily on the presence of fibrosis. In the non-fibrotic variant, especially if the antigen is quickly identified and eliminated, the course can be stable and relatively favorable. In the fibrotic variant, outcomes are significantly worse, and some patients develop progressive pulmonary fibrosis with high mortality. [86]

Adverse features include unidentified or persistent antigen, older age, male gender, decreased vital capacity and diffusing capacity, progressive deterioration of respiratory function, acute exacerbations, and a high prevalence of fibrosis on CT scan. The American Thoracic Society document specifically states that the presence and extent of fibrosis on CT scan are key predictors of mortality risk. [87]

In a large multicenter cohort of fibrotic hypersensitivity pneumonitis, more than half of the patients showed disease progression, and independent factors for worse outcome included older age, lower forced vital capacity, low percentage of lymphocytes in bronchoalveolar lavage, acute exacerbations, and, in the biopsy group, the presence of fibroblastic foci. This emphasizes that prognosis is determined not only by the "disease name" but also by the specific morphological and functional profile of the patient. [88]

In some patients, fibrotic hypersensitivity pneumonitis approaches idiopathic pulmonary fibrosis in severity and survival. In early cohorts of the chronic variant, five-year survival could drop to very low values, especially with an unfavorable morphological pattern. This explains why, in the case of progression, observation and short courses of steroids alone are not sufficient. [89]

A summary of prognostic factors is given in the table. [90]

Factor	Impact on prognosis
Presence of fibrosis	Significantly worsens the prognosis
Unidentified or persistent antigen	Associated with poorer survival
Older age	An unfavorable sign
Low vital capacity and diffusion capacity	Reflect a more severe disease
Acute exacerbation	Dramatically increases the risk of death
Fibroblastic foci in biopsy	Associated with worse outcomes
Lymphocytosis in bronchoalveolar lavage	Higher levels are associated with a better prognosis.

Frequently Asked Questions

Is hypersensitivity pneumonitis an allergy or an interstitial lung disease?
It is an interstitial lung disease of immune origin. It is associated with a hypersensitivity reaction to an inhaled antigen, but its clinical behavior and morphology are significantly more complex than those of a common respiratory allergy. [91]

Can the disease resolve simply by eliminating the antigen?
Yes, especially in the non-fibrotic stage. However, in the fibrotic stage, simply stopping contact is often insufficient, requiring medication and long-term observation. [92]

Is a lung biopsy necessary?
No. With a typical presentation, characteristic CT scan, and a coordinated multidisciplinary evaluation, the diagnosis can sometimes be established without a biopsy. A biopsy is necessary when serious diagnostic doubts remain. [93]

How does hypersensitivity pneumonitis differ from idiopathic pulmonary fibrosis?
The main difference is the presence of a causative antigen and a bronchiolocentric immune-inflammatory pattern. However, with the fibrotic variant, distinguishing between these diseases can be difficult, requiring a multidisciplinary discussion. [94]

Are antigen-specific immunoglobulins always elevated?
No. These tests reflect contact and sensitization, but do not prove the disease. A negative result does not rule out hypersensitivity pneumonitis. [95]

When is antifibrotic therapy considered?
When a patient has the fibrotic variant of the disease and signs of progressive pulmonary fibrosis despite antigen elimination and background therapy. Nintedanib is currently considered the most appropriate option. [96]

Is a complete cure possible?
In the early non-fibrotic stage, this is possible in the sense of complete clinical stabilization and regression of inflammation. In the fibrotic stage, the goal is often not a complete cure, but rather slowing progression and preserving lung function. [97]

Key points from experts

Ganesh Raghu, MD, professor of pulmonary and laboratory medicine at the University of Washington and director of the University of Washington Interstitial Lung Disease Center,
is a key thesis of his international working group: the diagnosis of hypersensitivity pneumonitis cannot be made based on a single finding. It requires the integration of an exposure history, high-resolution computed tomography (HRCT), bronchoalveolar lavage (BAL) data, and, when appropriate, morphology. In practice, this means that a good history is sometimes as important as high-tech imaging. [98]

Martina Koziar Vašáková, MD, PhD, Professor, Head of the Department of Pneumology at the First Faculty of Medicine, Charles University.
The second key thesis of the modern international approach, of which she is a co-author, is the division of the disease into non-fibrotic and fibrotic variants. This is not just new terminology, but a practical tool that immediately impacts prognosis, monitoring intensity, and the willingness to consider antifibrotic therapy. [99]

Kevin S. Wilson, MD, professor of medicine at Boston University and editor of the official documents of the American Thoracic Society,
emphasizes another principle: progressive pulmonary fibrosis is not a separate diagnosis, but a pattern of disease behavior. For a patient with hypersensitivity pneumonitis, this means that the physician must regularly evaluate the dynamics of symptoms, function, and CT scans and adjust management not based on the disease's name, but on its actual course. [100]