formal de nition of an acute exacerbation of ILD (AEILD) cites no speci c, identi able precipitating factor, infection, inhalational injury and drugs can certainly trigger acute deteriorations. Drugs implicated in AEILD include antimetabolites, chemo agents, TKI, ICI, TNF alpha antagonists, amiodarone, and infuenza vaccination [3, 4]. In 58 pathologically-­con rmed DAD cases (15 with underlying pulmonary brosis), the drugs bleomycin, aracytine, gemcitabine, cocaine, and amiodarone were thought to have precipitated the acute deterioration in six and radiation therapy in one [139]. In 42 rheumatoid arthritis patients, TNF-alpha inhibitors were thought have caused the exacerbation [133]. While rheumatoid arthritis-associated ILD was once considered a relevant risk factor for the development of acute methotrexate pneumonitis [140], this view has changed lately [130, 131, 141] and methotrexate no longer appears nowadays contraindicated in patients with a background of rheumatoid pulmonary brosis.

•\ Fatal deterioration of previously diagnosed indolent pulmonary brosis has been reported in lung cancer patients treated with chemotherapy drugs, TKI, and/or ICI [3, 4]. In addition, drugs known to cause pulmonary toxicity in patients without pretherapy pulmonary abnormalities (e.g., amiodarone, statins) are often given to patients with smoking-related or idiopathic pulmonary brosis owing to age-related comorbidities. Out of an abundance of caution, we recommend withdrawal of any nonessential pneumotoxic drug in patients with pulmonary brosis who presents with acute exacerbation of the underlying disease.

•\ Recent case reports implicated SARS CoV2 vaccination as a cause for severe ILD [3, 4] [142] and exacerbation of pulmonary brosis [103]. In a recent letter, out of 26 patients presenting with an acute exacerbation of pulmonary brosis, there was none of the classic precipitating causes in ten individuals. Four of these ten gave a history of recent SARS-COVID19 vaccination as the sole potential explanation [104]. Adequate cohort studies in pulmonary brosis are needed to shed light to these preliminary observations about COVID-19 or infuenza vaccination.

Anaphylaxis

Anaphylaxis is an explosive, potentially life-threatening allergic reaction that is primarily induced by food and drugs. Medications account for 25–36% of the cases [3, 4]. Insect stings and exercise are other signi cant eliciting factors. As of now, 222 drugs including antibiotics, NSAIDs, muscle relaxants, immunotherapy, oxaliplatin, biologicals (monoclonal antibodies used to treat rheumatoid arthritis (infiximab, etanercept)), and treatments for hematologic and solid malignancies including ICI, cetuximab, omalizumab, radiocontrast media, herbals, amino acids, and food supplements

[3, 4] have been identi ed as a cause for anaphylaxis. Incidence, time to onset, populations at risk, and the adverse effects of rechallenging the patient are not equal between drugs and monoclonal antibodies. Atopy and parenteral administration of drugs exposes to a greater risk, as compared to oral administration. A multicenter study of anaphylaxis due to drugs given during a hospital stay identi ed 184 cases for review [143]. Incidence of anaphylaxis was 5–15 cases per 100,000 exposed patients for orallyor parenterally-­ administered analgesics and antibiotics and 32 per 100,000 for parenteral penicillin. Incidence for blood, dextran, pentoxifylline, and both ionic and nonionic contrast media ranged from 35 to 95 per 100,000. The rates for streptokinase and plasma were highest at 378 and 284 per 100,000, respectively. Cetuximab poses interesting though potentially severe risks in residents of the southeastern United States, where tick bites predispose to the risk of cetuximab hypersensitivity and anaphylaxis via antigenic cross reaction. Signs and symptoms of anaphylaxis include the rapid onset (within seconds or minutes; with drugs demonstrating the shortest time to onset of all triggers) of malaise, impending doom, fainting, wheezing, bronchospasm, upper airway obstruction and laryngeal edema, and/or lower airway edema and obstruction, cardiovascular collapse or shock, cramping, loss of consciousness, seizures, and pulmonary edema. Drugs (mainly antibiotics, radiocontrast media, and NSAIDs) and foods account for the bulk of causes of fatal anaphylaxis. Time to potentially fatal cardiac or respiratory arrest is within 5–7 min of drug administration giving little time for the unprepared healthcare team to act [144]. Death (3.6%) or irreversible hypoxic brain damage can occur [144]. Epinephrine (adrenaline) is the life-saving drug of choice that should be administered or auto-administered in a timely fashion (0.01 mg/kg intramuscularly to be repeated every 1–5 min in most symptomatic patients, along with large amounts of fuids) [145]. Epinephrine is often not given early enough [146] or it is given with inappropriate dosage or insuf cient amounts before cardiopulmonary arrest develops [146, 147]. Epinephrine has its own risks, including acute systemic hypertension, pulmonary edema, and/or myocardial infarction [3, 4, 8]. Epinephrine autoinjection, supportive measures (fuids, oxygen, mechanical ventilation), avoidance of the sitting posture, elevation of the legs to help restore effective blood volume are paramount. All physicians and healthcare workers should be prepared to recognize, diagnose, and manage drug-induced anaphylaxis. Preemptive simulation practice is recommended [148] and can improve management skills [149]. Anaphylaxis is a common cause of litigation for malpractice [144].

Acute Vasculopathy

Acute vasculopathy with or without the development of ARDS may result from intravenous infusion of drugs or for-