Hypersensitivity pneumonitis (HP)

Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is a delayed allergic response that affects the lung parenchyma, particularly the alveoli, terminal bronchioles, and alveolar interstitial space. Such a reaction is the result of a patient's frequent and protracted inhalation of various organic airborne particles or other substances to which he or she is hypersensitive and highly responsive, mainly organic dust of animal or vegetable source, with chemicals coming in a close second. Recurrent exposure to particles tiny enough (diameter 5 m) to enter the alveoli and activate an immunological response is required in this syndrome, which was initially described by Italian scientist Bernardino Ramazzini in different occupations.

Workers in workplaces or environments contaminated by organic dust of diverse origins, primarily gardeners or breeders, are the most at threat professional categories. Avian dust, fungus, paint catalysts, sugar cane dust, hay sand, mushrooms, rat or gerbil urine, tobacco, air-conditioning system water, maple bark dust, redwood bark sand, beer brewing, cork dust, plastic residues, epoxy matrix, enzyme detergents, wheat mold or dust are all possible causes. The intensity of symptoms, clinical manifestations, and prognosis of the syndrome vary widely based on the causative factor, length of exposure, host variables, and antigen features. Hypersensitivity pneumonitis can usually be corrected quickly by finding and eliminating the causative substances, which can be found in a variety of places, including the home, office, and recreational situations.

What is Hypersensitivity Pneumonitis?

Hypersensitivity pneumonitis is complicated immunological reactions of the lung parenchyma in response to repeated inhalation of a sensitized antigen, which is also classed as a diffuse parenchymal lung disease (previous known as interstitial lung disease). Because the inflammation affects not only the alveoli but also the bronchioles, the label hypersensitivity pneumonitis is a better fit than the prior term extrinsic allergic alveolitis. The disease burden and its clinical manifestations are affected by the amount and type of antigen breathed. The first thorough clinical reports of the disease were published in 1932, reporting manifestations in workers at a Michigan company who were subjected to a fungus on Maple bark and agricultural workers in England who were subjected to moldy hay. Since these first findings, numerous hypersensitivity pneumonitis-causing exposures have been reported from around the world.

Based on the time sequence and presentation, it has traditionally been divided into acute, sub-acute, and chronic types. However, based on clinical, radiographic, and pathologic features, it has lately been suggested to divide it into Acute or Inflammatory hypersensitivity pneumonitis (symptoms lasting less than six months) and Chronic or Fibrotic hypersensitivity pneumonitis (symptoms lasting more than six months).

Epidemiology

The lack of universally agreed diagnostic criteria, seasonal and regional diversity in antigen exposures, and other host variables all contribute to a wide range of incidence and prevalence. Non-specific symptoms can potentially lead to a misdiagnosis of mild hypersensitivity pneumonitis. According to the Swedish population register, the incidence of hypersensitivity pneumonitis among Swedish farmers is around 21 per 100,000 person-years. According to other European population databases, hypersensitivity pneumonitis accounts for 1.6 to 12 percent of all interstitial lung diseases. According to data from studies of high-risk occupations, exposed farmers and pigeon-breeders have a prevalence of 1.4 percent to 12 percent and 8 to 10 percent, respectively. Bird-related hypersensitivity pneumonitis is the most frequently reported type of hypersensitivity pneumonitis worldwide. Men in their forties and fifties are more likely to be diagnosed with hypersensitivity pneumonitis. Because of the unique exposures, hypersensitivity pneumonitis is more common in certain occupational groups and hobbies.

Pathophysiology

Inflammation of the parenchyma of the lungs in hypersensitivity pneumonitis is caused by a mix of type 3 and type 4 hypersensitivity reactions. After first sensitization, the irritating antigen or chemical agent causes an immune complex-mediated hypersensitive reaction. As a result, elevated titers of particular IgG antibodies (precipitins) might be identified in serum in cases of acute hypersensitivity pneumonitis. Prolonged antigen exposure causes a delayed (type 4) hypersensitivity reaction. This activates CD8 cytotoxic T cells, which release chemokines that cause macrophage activation and the formation of granulomas. An increased T-cell-mediated immune reaction is observed when the disease advances to subacute and chronic hypersensitivity pneumonitis. T-cell migration and proliferation rise as a result of this.

The mechanism that leads to the development of fibrosis is unknown. The elevated TH2 response, which stimulates collagen deposition and fibrosis, is considered to be the cause. Individual differences in hypersensitivity pneumonitis susceptibility point to a genetic relationship, most likely through MHC class II, which includes HLA-DR and HLA-DQ. Because nicotine inhibits macrophage activation and lymphocyte proliferation, cigarette smoking appears to prevent developing clinically severe hypersensitivity pneumonitis.

Hypersensitivity Pneumonitis Causes

Multiple factors, such as microorganisms, plants and animal’s proteins, organic and inorganic substances, can induce hypersensitivity pneumonitis in the workplace and home. The number of possible settings, situations, and causal agents is growing. Metal-workers subjected to inhaled metal-working fluids, which often contain mycobacteria, are a current example. When Canadian researchers investigated a metal fluid hypersensitivity pneumonitis epidemic in a vehicle manufacturing factory in Ontario, they discovered that once mycobacteria have set themselves in the fluid system's biofilms, eradicating them is extremely difficult, if not impossible. Hypersensitivity pneumonitis has also been found in wood processing facilities, peat moss packaging machines, and saxophone players, the latter of which is triggered by molds growing inside the instrument.

These isolated cases highlight the significance of taking a thorough environmental record when experiencing symptoms that point to the presence of hypersensitivity pneumonitis. On the other hand, even in the context of a single specific exposure, there can be a number of antigens that can cause an inflammatory pulmonary response. One example of this complexity is bird-breeder sickness, fancier's which has immunoglobulins, intestinal mucus found in bird poop, and blooms, a waxy substance that coats the feathers of birds as causal antigens. Another example is the complex ecology found in a contaminated humidification system, which includes bacteria from the Klebsiella genus and molds from the Pullularia, Aureobasidium, Penicillium, and Cephalosporium genera. In the summertime, little levels of these antigens can be found in lakes, soil, and outdoor air. Continuous causative agent investigation in occupational and non-occupational exposures is critical since a thorough understanding of these etiologic substances allows for better diagnosis and treatment, as well as a decrease in exposure.

Hypersensitivity Pneumonitis Types

Acute and Subacute Hypersensitivity Pneumonitis

Due to the inhalational character of the disease, the inflammation is focused around the airway. Bronchiolocentric, poorly-formed, non-caseating granulomas and inflammatory cell infiltrate, predominantly lymphocytes, are the most common findings. Smaller airways filled with fibroblastic plugs (Masson bodies) are common findings of organizing pneumonia.

When well-formed non-caseating granulomas are found along the bronchovascular bundle without signs of inflammatory cell infiltration, the key differential diagnosis to examine is sarcoidosis. With sarcoidosis, there are no signs of organizing pneumonia. With lymphoid hyperplasia, such as in lymphocytic interstitial pneumonia, poor-formed granulomas, giant cells, and lymphocytic infiltrates might be detected. Infections can also result in the creation of granulomas due to cellular infiltrates. As a result, specific stains for organisms are used.

Chronic Hypersensitivity Pneumonitis

Fibrosis develops as the condition progresses untreated (chronic hypersensitivity pneumonitis). Around the bronchioles, there are scattered poorly-formed non-caseating granulomas and chronic inflammation, as well as varying degrees of fibrosis. In terms of pathology, this can resemble either usual interstitial pneumonia or fibrotic nonspecific interstitial pneumonia. Hypersensitivity pneumonitis is preferred over the alternative diagnosis because of poorly developed granulomas and fibrosis focused around the smaller airways. Histologic alterations in advanced fibrosis might be difficult to differentiate from usual interstitial pneumonia, necessitating clinical and radiographic concordance.

Hypersensitivity Pneumonitis Symptoms

Within a few hours of heavy exposure to specific antigens, acute hypersensitivity pneumonitis causes fever, lethargy, cough, and breathlessness. Symptoms normally go away after 1 to 2 days of not being exposed. Subacute and chronic forms occur from long-term exposure to the susceptible antigen. Because of the airway-centered nature of inflammation, cough is a common symptom. Shortness of breath, lethargy, and weight loss are also reported by patients. To discover particular exposures in the patient's surroundings that may be causing disease, a complete history should be acquired, including activities and occupation. According to reports, a trigger is not found in up to 65% of cases. The physical exam is usually normal, although pulmonary evaluation may reveal inspiratory crackles or squeaks, which indicate small airway irritation. Crackles and clubbing may be more noticeable in chronic hypersensitivity pneumonitis.

Acute deterioration of the respiratory status in some people with chronic hypersensitivity pneumonitis can resemble acute exacerbations of idiopathic pulmonary fibrosis.

Hypersensitivity Pneumonitis Diagnosis

Hypersensitivity pneumonitis is difficult to diagnose and necessitates a combination of a thorough medical history, high-resolution CT findings, laboratory testing, and pathological investigation. There is no single test which can diagnose the condition. For a quick definite diagnosis, an interdisciplinary team of pulmonologists, radiologists, pathologists, and support workers is recommended.

Laboratory Testing

Normally, blood counts and metabolic panels are normal. Usually, inflammatory indicators including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are high.

Patients' serum can be tested for serum precipitins (IgG antibodies) against possible organic antigens such as molds, fungus, and grain dust. In order to diagnose hypersensitivity pneumonitis and recommend preventive actions, the problematic agent must be identified. Unfortunately, a positive IgG antibody just indicates that you've been exposed, not that you've been diagnosed. Furthermore, these tests have a high probability of false negatives, and the antigen of interest may not be included in the testing panel. As a result, a positive test does not guarantee a diagnosis of hypersensitivity pneumonitis, and a negative test does not exclude a diagnosis of hypersensitivity pneumonitis.

Environmental Sampling

If the suspected triggering factor isn't commercially available, a sample of settled dust from the home or office may be necessary. Specific IgG-inhibition tests with the patient's serum can be performed using dust preparations from these samples.

Inhalation Challenge

This would aid confirm the diagnosis if the patient experiences clinical symptoms after being exposed to the suspected antigen, such as a decline in spirometry values and radiographic alterations. Only specialized facilities can conduct this, and standard antigen preparations are rarely accessible.

Pulmonary Function Testing

Due to small airway involvement, spirometry frequently reveals a restrictive pattern with a markedly reduced forced expiratory flow. A restrictive ventilatory pattern is revealed by lung volume measurements. Diffusion capacity is also significantly reduced. Pulmonary function testing that is obstructive or mixed has also been described. Pulmonary function testing help define illness severity, track disease progression, and predict prognosis.

Plain Radiograph of the Chest

Chest radiographs are frequently normal in patients. Streaky or diffuse airway opacities are found, with occasional consolidations sparing the apex and base. When fibrosis progresses to the chronic stage, an upper area predominant reticular interstitial appearance with volume loss may appear.

High-Resolution CT Scan (HRCT)

The characteristic high-resolution CT finding is scattered ground-glass or nodular opacities in a bronchovascular distribution with signs of air trapping in the upper and middle lobes. Mosaic attenuation suggestive of air trapping is more visible on exhalation images. The "head cheese sign" refers to the heterogeneous appearance of subacute hypersensitivity pneumonitis on CT scan, which includes patches of ground glass or nodular opacities, air trapping, and normal parenchyma. The cut surface of head cheese, which is formed from chunks of meat from various parts of different animals, has a similar appearance. The accuracy of a diagnosis made with a high-resolution CT scan can reach 93 percent.

Significant reticulation suggestive of fibrosis and traction bronchiectasis is noted as the condition advances. Chronic hypersensitivity pneumonitis can also cause thin-walled cystic alterations, parenchymal deformation, and mediastinal lymphadenopathy. The appearance of reticulation and honeycombing can make distinguishing usual interstitial pneumonia from nonspecific interstitial pneumonia challenging. Hypersensitivity pneumonitis is preferable to usual interstitial pneumonia or nonspecific interstitial pneumonia due to the lack of bases and the presence of air trapping. In chronic hypersensitivity pneumonitis, the presence of honeycombing and traction bronchiectasis indicates a greater mortality rate.

Flexible Bronchoscopy

In hypersensitivity pneumonitis, flexible bronchoscopy with bronchoalveolar lavage frequently demonstrates lymphocytosis and a low CD4:CD8 ratio. This is simply supportive evidence for hypersensitivity pneumonitis, not a diagnosis. Normal cell counts, neutrophilia, and a high CD4:CD8 ratio are all signs of sarcoidosis. Although lymphocytosis is not always present in chronic hypersensitivity pneumonitis, it does help to distinguish it from usual interstitial pneumonia.

Lung Biopsy

A lung biopsy should be done if a correct diagnosis cannot be achieved after a thorough examination. Because it does not generate adequate tissue, transbronchial lung biopsy has a limited diagnostic role in hypersensitivity pneumonitis. Transbronchial lung biopsy should be sufficient to make the diagnosis in a small number of individuals with the characteristic clinical and radiological presentation. To achieve a definite diagnosis in subacute and chronic hypersensitivity pneumonitis, surgical lung biopsies are frequently required. The use of transbronchial biopsy to get large tissue samples is a new technique.

Differential Diagnosis

Acute and Subacute Hypersensitivity Pneumonitis

Infections of the respiratory tract are the most common differential diagnosis for acute hypersensitivity pneumonitis. Metal fume fever and organic dust toxic syndrome can both manifest in the same way. A thorough medical history, physical exam, and radiologic examination should be used to distinguish between the disorders.

Sarcoidosis can mimic subacute hypersensitivity pneumonitis in terms of clinical and radiologic manifestations. A diagnosis of hypersensitivity pneumonitis is supported by a history of exposure, the presence of serum precipitins, and lymphocytosis on bronchoalveolar lavage. In sarcoidosis, pathologic evaluation often shows well-formed non-caseating granulomas with no inflammatory cell infiltration along the bronchovascular bundle.

Organizing pneumonia and smoking-related interstitial lung disorders should be included in the differential, although a thorough history, high-resolution CT scan, and pathological investigation can help distinguish the two diseases.

Chronic Hypersensitivity Pneumonitis

Clinically, radiologically, and pathologically, chronic hypersensitivity pneumonitis might resemble usual interstitial pneumonia. A detailed history may reveal information about the exposure history that has contributed to hypersensitivity pneumonitis. The presence of lymphocytosis in the bronchoalveolar lavage confirms the diagnosis of hypersensitivity pneumonitis. In chronic hypersensitivity pneumonitis, the reticulation and honeycombing are largely upper and middle zone, as opposed to the usual interstitial pneumonia. Chronic hypersensitivity pneumonitis is further supported by patchy ground-glass opacification and areas of air trapping. Fibrosis of the upper zone, peribronchiolar fibrosis, the presence of granulomas, and lymphocytic interstitial inflammation are pathological characteristics that distinguish chronic hypersensitivity pneumonitis from usual interstitial pneumonia. Sub-pleural fibrosis and microscopic honeycombing with deformation of the lung parenchyma are common features of interstitial pneumonia.

Radiographic and pathologic appearances of fibrotic nonspecific interstitial pneumonia can be similar. The presence of granulomas and giant cells pathologically supports the diagnosis of chronic hypersensitivity pneumonitis.

Hypersensitivity Pneumonitis Treatment

Antigen Avoidance

The identification and removal of the causal agent from the patient's environment are the cornerstones of treatment. If detected early in the course of the disease, the condition is usually reversible, and total antigen avoidance can be attained. Due to social, financial, or vocational factors, this is frequently impossible. Although the use of respiratory protection equipment has been linked to a decrease in particular IgG antibodies, it has not been proven to be a successful method for preventing chronic hypersensitivity pneumonitis. To prevent disease and fibrosis advancement, complete antigen avoidance should be recommended by whatever means possible.

Glucocorticoid Medications

Although no controlled studies for the management of hypersensitivity pneumonitis have been conducted, glucocorticoids have been proven to speed up initial recovery in individuals with severe complaints, abnormal pulmonary function tests, or substantial radiographic abnormalities. Treatment with glucocorticoids has not been found to improve long-term outcomes. Inhaled steroids haven't been proved to be a good substitute for systemic glucocorticoids. Patients are usually given 0.5 to 1 mg/kg a day. Glucocorticoids are usually started at a higher dosage for 1–2 weeks and then tapered over 3 to 4 weeks with the goal of utilizing the lowest dose and shortest time possible.

Alternative Treatments

Adjunctive medications are utilized in patients with chronic hypersensitivity pneumonitis and in circumstances when the disease is progressing. Azathioprine and mycophenolate mofetil have been utilized as steroid-sparing drugs as well as in cases of steroid resistance. When administered in patients with chronic hypersensitivity pneumonitis who have persistent symptoms following antigen avoidance and glucocorticoid medication, they have been proven to improve pulmonary function testing. Rituximab and leflunomide have also been shown to be beneficial in limited studies. Antifibrotic medications have been indicated in patients of chronic hypersensitivity pneumonitis with progressive fibrosis.

Lung Transplantation

When compared to individuals with usual interstitial pneumonia, a lung transplant has been proven to have excellent medium-term survival in patients with significant lung disease owing to hypersensitivity pneumonitis. Patients with chronic hypersensitivity pneumonitis may be less prone to bronchiolitis obliterans syndrome, according to some research.

Hypersensitivity Pneumonitis Complications

Hypersensitivity pneumonitis can lead to pulmonary fibrosis and progressive respiratory failure if not identified and managed as described above. Fibrosis and honeycombing have been linked to a greater mortality rate.

Primary occupational prevention should aim to minimize agricultural employees' exposure to recognized organic allergens and provide safety awareness. Better engineering approaches, maintenance, the use of protective equipment, and health and safety education might all be part of this. When a case of hypersensitivity pneumonitis is discovered at work, a thorough examination of the environment and a survey of other employees should be conducted to diagnose more cases as soon as possible.

Hypersensitivity Pneumonitis Prognosis

In the majority of patients, correct detection and strict avoidance of the triggering antigen leads to complete recovery of lung function. Pulmonary fibrosis is associated with a poor prognosis, with a median survival rate of 4 to 5 years. Other characteristics that have been linked to poorer outcomes include advanced age, increased exposure, delayed treatment, cigarette smoking, the lack of lymphocytosis on bronchoalveolar lavage fluid, recurrent acute episodes, and pulmonary hypertension.

Conclusion

Hypersensitivity pneumonitis is now recognized as a complex dynamic clinical condition with a wide range of initial presentations and clinical outcomes. In epidemiological data, the incidence rates of hypersensitivity pneumonitis differ enormously and are dependent not only on exposure-related factors and host-related factors but also on the diagnostic criteria used. Current pathogenesis ideas identify the interaction of virtually all components of the immune system in this disease and highlight the evolution of the response over time and the significance of modulating variables that impact the interplay of antigenic stimulation and host immune response, either boosting or repressing the inflammatory reaction, reflecting the diverse and dynamic patterns of disease seen in clinical settings. The duration of antigen trigger exposure is a key component in the development of acute and subacute types of hypersensitivity pneumonitis. Even while many of the relationships between antigenic exposure and the patient characteristics and course of the disease remain unknown, lowering the level of exposure reduces the occurrence of hypersensitivity pneumonitis and is the most significant aspect in the management of the disease.