INTRODUCTION
Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a novel member of human coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). It causes a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild, uncomplicated illness and severe cases, with or without pneumonia (2). Hospitalization and oxygen support, and admission to an intensive care unit are required in 14% and 5% of the patients, respectively (1). Gastrointestinal symptoms and positive viral nucleic acid testing on rectal swabs are considered as indicators of infection in digestive system and fecal-oral transmission of COVID-19 (3). Moreover, skin symptoms, including exanthems, may appear during the evolution of the disease leading to differential diagnosis with drug hypersensitivity reactions (DHRs) (4).
In critically ill patients, COVID-19 can be complicated by acute respiratory distress syndrome (ARDS), septic shock, and multi-organ dysfunction syndrome (1). In such patients, in response to viral infection, the excessive activation and expansion of T lymphocytes and macrophages lead to an overproduction of cytokines, which causes a cytokine storm and a hyperinflammatory state (5, 6). Acute hyperinflammation may activate coagulation cascade and inhibit fibrinolytic reaction, thus promoting thrombosis. Coagulopathy and thrombocytopenia are serious complications which increase the risk of haemorrhage and thrombosis and progress to disseminated intravascular coagulation (DIC) (7).
The periodically updated World Health Organisation interim guidance allows reliable comparison of investigational therapeutic interventions as part of randomized controlled trials, provides recommendations for the management and forms the basis of many institutional or national protocols (1). Unfortunately, none of the drugs used for COVID-19 have been proven to be truly effective yet; besides, no specific antiviral drugs have been approved for COVID-19 by health authorities (8,9). At the moment, there is no specific treatment for COVID-19, and standard practice of care focuses on treating the clinical symptoms with supportive care (1).
In this review, diagnosis and management of DHRs, which are expected to be caused by current or candidate repurposed and off-label drugs used for COVID-19 treatment mostly based on prior knowledge, are discussed (8,10,11). Drugs in this review are classified into four groups according to their potential roles in different phases of the disease as antiviral drugs, antiviral and/or immunomodulatory drugs used in viral pneumonia; anti-cytokine and anti-inflammatory drugs considered during macrophage activation syndrome (MAS) and cytokine storm; anti-inflammatory drugs in ARDS; and anti-aggregant and anti-coagulant drugs in coagulopathy (Figure 1). Information of DHRs due to the use of additional drugs for various purposes can be found in the relevant European Academy of Allergy and Clinical Immunology (EAACI) resources (12-20).
Since emerging recent findings are dynamically changing the clinical interventions, it is expected that the list of drugs determined according to current knowledge may change with upcoming recommendations in future.