Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide.

BACKGROUND: Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). METHODS: C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 µg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined. RESULTS: In comparison to mice challenged only with A. niger, addition of LPS (1 µg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies. CONCLUSIONS: In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Lung disorders induced by respirable organic chemicals.

Respirable organic chemicals were originally thought to cause allergic respiratory diseases, such as bronchial asthma and hypersensitivity pneumonitis, and believed not to cause lung disorders derived from inflammatory or fibrotic processes such as pulmonary fibrosis and interstitial pneumonitis. It has recently been reported, however, that exposure to organic chemicals can cause interstitial lung diseases. In this review, we discuss the clinical features of occupational asthma and hypersensitivity pneumonitis, as well as other lung disorders, including interstitial pneumonitis, caused by humidifier disinfectants in Korea and by a cross-linked acrylic acid-based polymer (CL-PAA) in Japan.

Chest CT Diagnosis and Clinical Management of Drug-Related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper From the Fleischner Society.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others.

Comparative safety of flavocoxid vs prescription NSAIDs among osteoarthritis patients.

OBJECTIVE: Flavocoxid is a prescription medical food used to manage osteoarthritis (OA) symptoms. Safety concerns based on case reports raised an association with acute liver injury and hypersensitivity pneumonitis. We determined incidence rates (IR) of these safety events in a cohort of new users of flavocoxid and prescription non-steroidal anti-inflammatory drugs (NSAIDs). METHOD: MarketScan® claims data (2006-2017) was used to identify patients initiating flavocoxid or NSAIDs. Propensity score matching (1:2 ratio) was used to balance patient characteristics. Outcomes included hospitalization for hypersensitivity pneumonitis, liver injury, gastrointestinal bleeding, myocardial infarction, and acute kidney injury. Poisson regression was used to calculate IRs and Cox regression for calculating adjusted hazard ratios (aHR). RESULTS: 3,337 flavocoxid and 6,674 NSAID users met eligibility criteria. Before matching, flavocoxid users were older (mean 57 vs 51 years), had more polypharmacy (68% vs 29% taking ≥11 medications). After matching, characteristics were well balanced. The rate of hypersensitivity pneumonitis was 1.1 (95% CI 0.0-5.9) per 1,000 PY for flavocoxid and 0.0 (95% CI 0.0-2.2) for NSAIDs. For hospitalized liver injury, it was 3.2 (95% CI 0.7-9.3) for flavocoxid and 2.4 (95% CI 0.7-6.1) for NSAIDs, aHR = 1.16, 95% CI 0.23-6.01. A lower rate of GI bleed was observed, IR: 5.3 (1.7-12.3) for flavocoxid and 10.2 (5.9-16.3) for NSAIDs, aHR 0.49 (0.18-1.68). There were no significant differences for MI or AKI. CONCLUSION: The rate of hypersensitivity pneumonitis and liver injury associated with flavocoxid was low and minimally elevated compared to NSAIDs. Flavocoxid users had a significantly lower risk for hospitalized GI bleeding. The risk-benefit profile of flavocoxid may warrant reevaluation in light of these findings.

Secondhand smoke from electronic cigarette resulting in hypersensitivity pneumonitis.

Cases of vaping-induced lung injury have increased in the USA, resulting in a heterogeneous collection of pneumonitis patterns in persons who used electronic cigarettes. Hypersensitivity pneumonitis has been documented in several cases of first-hand electronic cigarette use; however, secondhand smoke health-related consequences have not been fully understood. We present a case of the patient who developed hypersensitivity pneumonitis secondary to exposure to secondhand smoke from electronic cigarette. We summarise the presentation and diagnostic investigation, as well as the management of this case.

Analysis of bronchoalveolar lavage samples collected from 30 patients with drug-induced pneumonitis.

BACKGROUND: Drug-induced pneumonitis is a disease encountered by pulmonologists in the clinical setting. The diagnosis generally considers the patient's clinical course and the results of peripheral blood tests, radiological examinations, and often bronchoscopic examinations. However, few studies have reported the association between radiological patterns such as ground-glass opacity (GGO) or consolidation, and bronchoalveolar lavage fluid (BALF) cell fractions. This study aimed to clarify this association. METHODS: Patients with a Naranjo's score of probable or definite were enrolled, and all 30 patients were categorized under probable. Data such as patient background, blood examination results, radiological findings, and BALF cell fractions were retrospectively collected. The association between BALF cell fractions and other factors such as chest computed tomography (CT) findings was evaluated. RESULTS: The most common radiological finding in patients with lymphocyte-dominant BALF was GGO, with only one patient exhibiting consolidation. However, patients with eosinophil-dominant BALF were more likely to have consolidation; only three cases showed crazy paving and one showed GGO. In addition, patients with a GGO-dominant pattern on CT had an increased lymphocyte fraction of 41.0%; those with a consolidation-dominant pattern showed a relatively high eosinophil fraction of 5.2%; and those with a crazy paving pattern showed elevated eosinophil and neutrophil fractions of 19.1% and 9.9%, respectively. CONCLUSIONS: In this study, a remarkable difference in radiological findings was observed among different BALF patterns.

Eribulin-induced Interstitial Pneumonia: A Case Series and Retrospective Cohort Study.

Eribulin is a chemotherapeutic agent used for advanced breast cancer, but there are some reports of eribulin-induced lung injuries. Three of our patients experienced eribulin-related lung injuries. Radiology revealed organizing pneumonia in two cases and diffuse ground-glass shadows indicative of hypersensitivity pneumonitis in the third. A retrospective survey of patients treated with eribulin at our hospital identified no other cases of eribulin-induced lung injuries. Overall, drug-related lung injuries occurred in 2.8% of our eribulin-treated patients, which is similar to the rates reported for other anticancer drugs. The findings from these three cases provide guidance for the safe use of eribulin.

An Open-label Study With Pirfenidone on Chronic Hypersensitivity Pneumonitis.

BACKGROUND: Chronic hypersensitivity pneumonitis (cHP) represents a severe lung disease often evolving to fibrosis with the subsequent destruction of the lung parenchyma. There are no approved therapies with confirmed efficacy to deal with this disease. METHODS: We performed an open-label, proof of concept study, to evaluate the efficacy and safety of pirfenidone added to immunosuppressive drugs on the treatment of cHP. We included 22 patients assigned to two groups: Group 1, nine patients that received prednisone plus azathioprine and Group 2, thirteen patients, received prednisone plus azathioprine and pirfenidone (ClinicalTrials.gov identifier NCT02496182). There were no significant imbalances in clinically relevant baseline characteristics between two study groups. RESULTS: After 1 year of treatment, inclusion of pirfenidone was not associated with improved forced vital capacity (primary end-point). A not significant tendency to show higher improvement of diffusion capacity of the lung for carbon monoxide (DLCO) was observed in the group receiving pirfenidone (p=0.06). Likewise, a significant improvement in the total score on the SGRQ was found in the group 2 (p=0.02) without differences in other two questionnaires related to quality of life (ATAQ-IPF and EQ-5D-3L). HRCT showed a decrease of the ground glass attenuation without changes in the fibrotic lesions and without differences between both groups. CONCLUSIONS: These findings suggest that the addition of pirfenidone to the anti-inflammatory treatment in patients with chronic HP may improve the outcome with acceptable safety profile. However, prospective randomized double-blind, placebo-controlled trials in largest cohorts are needed to validate its efficacy.

Sertraline-induced hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a granulomatous, non-IgE-mediated hypersensitivity reaction of the alveoli and distal bronchioles presenting as an acute, subacute or chronic condition. It is most commonly associated with exposure to extrinsic allergens (eg, avian dust, mould and tobacco) and medications including antiarrhythmics (eg, amiodarone), cytotoxics (eg, methotrexate) and antiepileptics (eg, carbamazepine). Individuals diagnosed with this condition can present with severe hypoxia and respiratory failure. The fundamental principle of management is to remove the causative allergen. Evidence implicating selective serotonin reuptake inhibitors as a causative agent is limited, and this case report describes a rare clinical presentation of HP associated with sertraline, how it was diagnosed and subsequently treated. It is anticipated that raising awareness of this interaction will assist multidisciplinary teams, managing patients diagnosed with HP, to be more cognisant of sertraline as being an aetiological factor for this condition.

Immune Checkpoint Inhibitor Therapy-related Pneumonitis: Patterns and Management.

In recent years, the use of immune checkpoint inhibitor (ICI) therapy has rapidly grown, with increasing U.S. Food and Drug Administration approvals of a variety of agents used as first- and second-line treatments of various malignancies. ICIs act through a unique mechanism of action when compared with those of conventional chemotherapeutic agents. ICIs target the cell surface receptors cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, or programmed cell death ligand 1, which result in immune system-mediated destruction of tumor cells. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. ICI therapy-related pneumonitis is an uncommon but important complication of ICI therapy, with potential for significant morbidity and mortality. As the clinical manifestation is often nonspecific, CT plays an important role in diagnosis and triage. Several distinct radiographic patterns of pneumonitis have been observed: (a) organizing pneumonia, (b) nonspecific interstitial pneumonia, (c) hypersensitivity pneumonitis, (d) acute interstitial pneumonia-acute respiratory distress syndrome, (e) bronchiolitis, and (f) radiation recall pneumonitis. Published guidelines outline the treatment of ICI therapy-related pneumonitis based on the severity of symptoms. Treatment is often effective, although recurrence is possible. This article reviews the mechanism of ICIs and ICI therapy complications, with subsequent management techniques and illustrations of the various radiologic patterns of ICI-therapy related pneumonitis.©RSNA, 2019.

Fibrotic Lung Toxicity Induced by Hydroxycarbamide.

A patient treated for 4 months with hydroxycarbamide (hydroxyurea) for chronic myelomonocytic leukemia was admitted to hospital for recently developed severe dyspnea and acute respiratory failure. The computed tomographic scan of the chest showed diffuse ground glass opacities, some centrilobular low-density nodules (resembling hypersensitivity pneumonitis-like pattern), and minimal interstitial reticulation of the subpleural region. The analysis of bronchoalveolar lavage fluid excluded infection, as did serological examinations. The patient was started on oxygen therapy and with relief of thrombocytopenia and suspected hemolytic anemia, hydroxyurea treatment was discontinued. The patient underwent steroid therapy, with a rapid progressive improvement of clinical and radiological features. As hydroxyurea is increasingly used for a number of systemic disorders, physicians must be aware of its potential lung toxicity, requiring immediate cessation of the treatment and empiric corticosteroid therapy.

Methotrexate-induced Hypersensitivity Pneumonitis appearing after 30 years of use: a case report.

BACKGROUND: Methotrexate has been implicated in a variety of lung complications, one of which is hypersensitivity pneumonitis. Hypersensitivity pneumonitis most often occurs within the first year of starting low-dose orally administered methotrexate. We present a case of methotrexate-induced hypersensitivity pneumonitis after 30 years of methotrexate use, which is the first case to be reported so far. CASE PRESENTATION: A 77-year-old African American woman with a history of rheumatoid arthritis presented with progressively worsening shortness of breath and nonproductive cough. She was on a daily dose of 2.5 mg of methotrexate that had been orally administered for the last 30 years. A physical examination was significant for fever of 38.2 °C (100.8 °F), tachycardia, bilateral basal crackles, and oxygen saturation of 88% on room air. A laboratory work up was significant for normal white blood cell count, increased eosinophil count of 18.3%, and erythrocyte sedimentation rate of 111 mm/hour. Sputum cultures were negative for any bacterial pathogens including acid-fast bacilli. Influenza and respiratory syncytial viral infection were ruled out. A (1-3)-B-D-glucan assay (Fungitell®) was within normal limits. Pulmonary embolism was ruled out and echocardiography was normal. A chest X-ray showed hazy opacity with prominent reticulation within the upper lung fields bilaterally, right greater than the left with no pleural effusion. Lung computed tomography revealed nonspecific bilateral upper lung opacification. A pulmonary function test was significant for no obstruction, normal maximum voluntary ventilation, and no restriction, with mildly decreased diffusion. Methotrexate was stopped, and our patient was started on prednisone 60 mg orally administered daily with dramatic clinical and radiologic improvement. CONCLUSIONS: Methotrexate-induced hypersensitivity pneumonitis usually occurs in the initial few weeks to months of starting treatment with methotrexate; however, it can occur late during therapy too, and prompt diagnosis is crucial as it is a reversible condition when diagnosed early.

Aripiprazole-induced hypersensitivity pneumonitis.

Aripiprazole is an atypical antipsychotic agent commonly used in the management of schizophrenia. Aripiprazole has not been reported to have an association with interstitial lung disease. We describe a case of a 36-year-old woman who began to experience respiratory issues shortly after starting aripiprazole and presented to us 4 years later with progressive exertional shortness of breath. High-resolution CT of the chest showed a bilateral ground glass pattern. Video-assisted thoracoscopy with biopsy revealed alveolar septal thickening and an inflammatory infiltrate composed mainly of lymphocytes, suggestive of chronic hypersensitivity pneumonitis. After discontinuing aripiprazole and initiating prednisolone therapy, the patient's pulmonary symptoms improved. This case highlights that aripiprazole can cause hypersensitivity pneumonitis in susceptible individuals.

Pet Groomer's Lung: A novel occupation related hypersensitivity pneumonitis related to pyrethrin exposure in a pet groomer.

A 61-year-old man was evaluated for a 2 month history of cough and dyspnea without relevant exposures other than pyrethrin containing insecticidal sprays he used while grooming dogs almost daily. High Resolution Computed Tomography (HRCT) of the chest demonstrated a Non-Specific Interstitial Pneumonia (NSIP) pattern. Pulmonary function testing revealed an isolated mildly reduced diffusion capacity. Bronchoalveolar lavage (BAL) results confirmed the presence of foamy histiocytes, lymphocytes, and polymorphonuclear cells consistent with ongoing exposure. Open lung biopsy showed poorly formed granulomas and bronchiolitis. He was advised to avoid exposure to pyrethrin. While he declined to stop grooming dogs, on follow-up, his symptoms had improved with use of a P100 mask and better ventilation to protect himself when using the pet sprays. We conclude that sustained exposure to pyrethrin containing sprays in the pet grooming industry may be a risk factor for a novel occupation related hypersensitivity pneumonitis. ("Pet Groomer's Lung"). Am. J. Ind. Med. 60:141-145, 2017. © 2016 Wiley Periodicals, Inc.

Hypersensitivity Pneumonitis Due to Metalworking Fluid Aerosols.

PURPOSE OF REVIEW: This review summarises the clinical knowledge of hypersensitivity pneumonitis in workers exposed to aerosols of metalworking fluid, reviewing published outbreaks and clinical cases. RECENT FINDINGS: Metalworking fluid exposure has become the commonest recognised cause of occupational hypersensitivity pneumonitis, having been rare before 2000. There are many possible agents in the metalworking fluid which may be the cause of disease including bacteria, mycobacteria, fungae, biocides, emulsifiers, reodorants and dissolved chrome and cobalt. Causes are likely to be different in different outbreaks. Mycobacteria growing in the metalworking fluid have generated immune responses in some workers, but their role in disease causation is not yet established. Many outbreaks have been identified in large workplaces using common sumps. It is not possible to prevent microbial contamination of metalworking fluids in use. Disease prevention should focus on stopping inhalation of aerosols, particularly by re-engineering to remove recirculation.

Hypersensitivity pneumonitis associated with azathioprine therapy in a patient with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA), an autoimmune disease characterized by inflammatory granulomas and necrotizing small-vessel vasculitis, primarily affects the respiratory tract and kidneys. Azathioprine (AZA) is a purine analog that is commonly used for maintaining GPA remission after induction therapy with cyclophosphamide. While the dose-dependent side effects of AZA are common and well known, hypersensitivity reactions such as pulmonary toxicity are rare. Here, we describe a case involving a 38-year-old man with GPA-associated pauci-immune crescentic glomerulonephritis who developed subacute hypersensitivity pneumonitis (HP) during AZA maintenance therapy. Five months after the initiation of AZA administration (100 mg/day), the patient was admitted with a 7-day history of cough, dyspnea, and fever. High-resolution computed tomography of the chest showed ill-defined centrilobular nodules and diffuse ground-glass opacities in both lung fields. Bronchoscopy with bronchoalveolar lavage was negative for infectious etiologies. A transbronchial lung biopsy specimen revealed poorly formed non-necrotizing granulomas. A chest radiograph obtained at 2 weeks after discontinuation of AZA showed normal findings. The findings from this case suggest that AZA-induced HP should be considered as a differential diagnosis when a patient with GPA exhibits fresh pulmonary lesions accompanied by respiratory symptoms during AZA therapy.

Quincke's edema and hypersensitivity pneumonitis induced by lenalidomide for multiple myeloma.

A 64-year-old man with recurrent multiple myeloma (BJP-κ type) was treated with 15 mg of lenalidomide (LEN) and dexamethasone. He developed Quincke's edema on his eyelid on day 4. Since the edema improved after withdrawal of LEN, the drug was subsequently re-administered at a decreased dose. However, the edema developed again on day 4. After withdrawal of LEN, the drug was administered again with gradually dose escalation, while confirming the absence of eyelid edema. Although edema did not develop, eosinophils and basophils were increased, and the CRP level was elevated. During the third course of LEN administration, his chest CT showed bilateral ground-glass opacity, and LEN-induced hypersensitivity pneumonitis was diagnosed. The pneumonitis resolved after LEN withdrawal and prednisolone administration. These observations suggested that Quincke's edema, eosinophilia and basophilia, CRP elevation, and hypersensitivity pneumonitis might occur due to the immunological effects of LEN, which is classified as an immunomodulatory drug.

Chemical determinants of occupational hypersensitivity pneumonitis.

BACKGROUND: Workplace inhalational exposures to low molecular weight (LMW) chemicals cause hypersensitivity pneumonitis (HP) as well as the more common manifestation of respiratory hypersensitivity, occupational asthma (OA). AIMS: To explore whether chemical causation of HP is associated with different structural and physico-chemical determinants from OA. METHODS: Chemical causes of human cases of HP and OA were identified from searches of peer-reviewed literature up to the end of 2011. Each chemical was categorized according to whether or not it had been the attributed cause of at least one case of HP. The predicted asthma hazard was determined for each chemical using a previously developed quantitative structure-activity relationship (QSAR) model. The chemicals in both sets were independently and 'blindly' analysed by an expert in mech anistic chemistry for a qualitative prediction of protein cross-linking potential and determination of lipophilicity (log K ow). RESULTS: Ten HP-causing chemicals were identified and had a higher median QSAR predicted asthma hazard than the control group of 101 OA-causing chemicals (P < 0.01). Nine of 10 HP-causing chemicals were predicted to be protein cross-linkers compared with 24/92 controls (P < 0.001). The distributions of log K ow indicated higher values for the HP list (median 3.47) compared with controls (median 0.81) (P < 0.05). CONCLUSIONS: These findings suggest that chemicals capable of causing HP tend to have higher predicted asthma hazard, are more lipophilic and are more likely to be protein cross-linkers than those causing OA.