Introduction:
Drug-induced pulmonary disease is not a single disorder but rather a common clinical problem. The affected patients present with various respiratory symptoms, deterioration of pulmonary function, histologic changes, or several of these findings associated with drug therapy. Depending on the drug, the syndromes can cause interstitial fibrosis, asthma, non-cardiogenic pulmonary edema, pulmonary eosinophilia, pleural effusions, or veno-occlusive disease.
What Are the Causes of Drug Induced Lung Disease?
Medicines cause many types of lung injury. It is usually impossible to predict who will develop lung disease from a medicine.
Types of lung problems that may be caused by medicines include:
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Alveolar Hemorrhage- Bleeding into the lung air sacs or alveoli (alveolar hemorrhage).
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Allergic Reactions - Asthma, hypersensitivity pneumonia, or eosinophilic pneumonia.
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Bronchitis - Swelling and inflamed tissue in the main passage that carries air into the lungs.
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Interstitial Fibrosis - Damage to the lung tissue.
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Lung Vasculitis - Inflammation of lung blood vessels.
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Lymph Node Swelling - Inflammation and swelling of the lymph nodes.
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Pneumonitis- Inflammation of the lung air sacs (pneumonitis).
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Granulomatous Lung Disease - A type of inflammation in the lungs.
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Mediastinitis - Swelling and irritation of the chest area between the lungs.
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Pulmonary Edema- An abnormal buildup of fluid in the lungs.
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Pleural Effusion - A buildup of fluid between the layers of tissue that line the lungs and chest cavity.
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Pulmonary Hypertension - Abnormal pressure of the arteries that bring blood to the lungs.
Many medicines and substances are known to cause lung disease in some people. These include:
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Antibiotics, such as Sulfa drugs and Nitrofurantoin.
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Chemotherapy drugs such as Methotrexate, Bleomycin, and Cyclophosphamide.
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Heart medicines such as Amiodarone.
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Cancer Therapy Drugs- The most common cancer drugs causing lung disease are Bleomycin, Gemcitabine, Methotrexate, epidermal growth factor receptor (EGFR)- directed therapies, mechanistic target of rapamycin protein inhibitors (mTOR) inhibitors, and immune checkpoint inhibitors.
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Bleomycin: Bleomycin, used most commonly to treat Hodgkin’s lymphoma and germ cell tumors, causes lung injury through immune-mediated and direct toxic effects. The clinical presentation of Bleomycin lung injury is highly variable but can be asymptomatic. Pulmonary physiology changes are common and include an early reduction in diffusing capacity of the lung for carbon monoxide followed by changes in forced vital capacity (FVC), which correlates with symptomatic deterioration. Idiosyncratic reactions at low doses early in the treatment course are also less commonly observed.
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Gemcitabine: Gemcitabine is used to treat a wide range of cancers, including non-small cell lung cancer (NSCLC), breast cancer, and pancreatic cancer. Mortality rates are generally low except in severe cases requiring hospitalization. In contrast to Bleomycin, the timing of onset and dose relationship are less consistent. The risk of drug-induced interstitial lung disease is highest when combined with other drugs, especially Erlotinib, Taxanes, and Bleomycin.
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Epidermal Growth Factor Receptor (EGFR) - Targeted Agents: Epidermal growth factor receptor-targeted agents include small molecular receptor tyrosine kinase inhibitors (RTKIs) and monoclonal antibodies for the treatment of non-small cell lung cancer, colorectal cancer, and breast cancer. The drug-induced interstitial lung disease caused due to epidermal growth factor receptor-targeted agents and receptor tyrosine kinase inhibitors appears to be an early event. But studies of Gefitinib and Erlotinib report the highest incidence within four weeks of starting treatment.
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Mechanistic Target of Rapamycin Protein (mTOR) Inhibitors: Mechanistic targets of Rapamycin protein inhibitors are used predominantly in the treatment of renal cell cancers and neuroendocrine tumors and also as anti-rejection agents in solid organ transplantation. Sirolimus, Temsirolimus, and Everolimus are associated with pulmonary toxicity.
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Immune Checkpoint Inhibitors: Checkpoint inhibitors of programmed cell death 1 (PD-1) and its ligands (PD-L1 and PD-L2) and cytotoxic lymphocyte antigen protein 4 (CTLA-4) are involved in the treatment of metastatic melanoma, Hodgkin’s lymphoma, and non-small cell lung cancer. The incidence rate, mortality, and severity of drug-induced interstitial lung disease are all higher for PD-1 inhibitors compared with PD-L1 inhibitors.
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Methotrexate: Methotrexate is a mainstay agent in rheumatology and for the treatment of lymphomas and sarcomas. The chance of recurrence is approximately one-third of re-challenged cases and carries a high mortality.
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Antibiotics: Nitrofurantoin is most commonly used in the treatment and prophylaxis of urinary tract infections. Reports state that drug-induced interstitial lung disease accounts for 16 to 48 % of Nitrofurantoin-related adverse events. The hospitalization rate was 75%, and mortality rates were 0.5 % and eight percent, respectively, for patients with acute lung reactions and chronic interstitial pneumonia. An acute reaction occurs within days or hours if there has been previous Nitrofurantoin exposure. The most common underlying mechanism is a hypersensitivity reaction which resolves quickly in most cases. Chronic interstitial pneumonia rarely occurs, mimicking pulmonary fibrosis. It is more commonly seen in patients on long-term prophylaxis.
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Amiodarone: Amiodarone is the most common cause observed in drug-induced interstitial lung disease patients. Patients most commonly present with a subacute form of drug-induced interstitial lung disease, whereas acute and fatal forms can also occur. Symptomatic recovery in survivors occurred over a median of 36 months, with improvement in radiological features of alveolitis but a high rate of fibrosis. Cumulative dose is an important risk factor for Amiodarone-related drug-induced interstitial lung disease, and the combination of high doses over longer periods is more strongly associated with drug-induced interstitial lung disease than dose or duration alone.
What Are the Symptoms of Drug Induced Lung Disease?
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Hemoptysis (coughing up blood or bloody mucus from the lungs and throat).
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Chest pain.
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Cough.
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Wheezing.
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Fever.
What Is the Risk Factor for the Development of Drug Induced Interstitial Lung Disease?
Risk factors for the development of drug-induced interstitial lung disease vary according to the disease, drug, and population being treated. Certain risk factors have featured prominently across drugs.
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Age: Increased age is identified as a significant risk factor for drug-induced interstitial lung disease for treatment with Bleomycin, Gemcitabine, Leflunomide, Methotrexate, Amiodarone, and Nitrofurantoin.
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Smoking: Smokers are at increased risk when treated with Gemcitabine and Methotrexate.
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Drug Dosage: A clear dose-dependent relationship is well recognized for Bleomycin, Amiodarone, and Nitrofurantoin.
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Other Risk Factors:
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Higher alcohol consumption.
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Genetic susceptibility.
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Renal dysfunction.
What Is the Treatment Approach for Drug Induced Interstitial Lung Disease?
The first step is to stop the medicine that is involved in causing the disease. Other treatments are provided based on the underlying symptoms present. Oxygen therapy is maintained until the drug-induced lung disease improves. Anti-inflammatory medicines called Corticosteroids are most often used to quickly reverse lung inflammation.
Conclusion:
A proper diagnostic approach and timely management aid in the prevention of the progression of the disease. The prognosis for acute and chronic forms of the disease varies depending on the condition and provides positive outcomes after the medicine has been stopped. Certain drug-induced lung diseases, such as pulmonary fibrosis, may never clear away and can worsen even after the medicine is stopped and can result in death.
