key: cord-0719340-zknp56ym
authors: Galdiero, Massimiliano; Napoli, Claudio
title: COVID-19: Do not be phobic from fever
date: 2020-06-08
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2020.06.003
sha: a9be43ce57cc39462ba83806e301a99eda96f233
doc_id: 719340
cord_uid: zknp56ym

nan

COVID-19, a novel coronavirus disease, arose in Wuhan (China) in December 2019, but readily evolved into a pandemic. The virus enters cells through the mucous membranes (nasal and larynx mucosa, then it invades organs of the respiratory tract establishing the most common early symptoms of infection that are fever and cough [1] . Afterward, the virus may pass from the respiratory system to peripheral blood causing viremia which is followed by a possible infection of the organs expressing the main virus cellular receptor (i.e., angiotensin-converting enzyme 2). Clinical signs could begin with initial pneumonia which may progress to acute respiratory distress syndrome followed by multi-organ failure and death.

The virus has a high replication dynamic in the early phases of infection which decreases in recovering patients but remains high in patients with fatal outcomes [2] . A hallmark of high pathogenic coronavirus, including Sars-CoV and Mers-CoV, is the so-called "cytokine storm". SARS-CoV-2 activates the innate immune system, macrophages, and other innate immune cells through Toll-Like Receptors leading to the release of inflammatory cytokines, including IL-1ß and IL-6. Adaptive immunity is also activated by antigen-presenting cells. Both T and B cells not only play an antiviral role but also promote the secretion of inflammatory cytokines. The viral infection is a potent trigger of antiviral response which includes temperature rise, by an early production of interferons (INFs) and thereby limiting viral replication and "viral" sepsis. Clinically, it is clear that any delay in INF production and reduction of viral titers is deleterious and leads to a robust inflammatory monocyte-macrophage and neutrophil infiltration with the release of pro-inflammatory cytokines.

Current guidelines for the treatment of viral infection guarantees the best forecast if administered early during the course of the illness, but with a limited advantage in later stages. Another clinical option would be to enhance the host immune system or, at least, not interfere with the pathophysiological reaction of the body against the virus. This reaction is represented by the rise in body temperature which might protect patients against higher viral load and impaired antibody response. When treating a fever with antipyretics (any antipyretic regardless of the mechanism of action) we only drag our immune response's feet to the advantage of a subtle and high pathogenic virus, such as the Sars-CoV-2. Fever per se can be considered self-limiting and rarely a serious problem provided the proper fluid replacement. For example, most influenza A strains infecting humans are temperature sensitive with inhibition of replication at temperatures within the physiological febrile range of 38-41 • C. Some mutated strains growing at higher temperatures are linked to a more severe outcome of infection. During viral infections, the febrile response determines a survival advantage [3] . Overall, clinical data do not support the hypothesis that antipyresis has a clinically significant beneficial or detrimental impact on the course or severity of minor viral illnesses. The increased rate of death during COVID-19 has sparked a debate on the appropriateness of using nonsteroidal anti-inflammatory drugs (NSAIDs) in Covid-19 infection [4] [5] [6] , with a consensus of using acetaminophen over ibuprofen, but therapy should be individualized for hospitalized patients, taking into consideration kidney and liver function (https://www.hopkinsguides.com/hopkins/ ub?cmd=repview&type=4,791,124&name=4 538747 PDF) Major side effects of NSAIDs include gastrointestinal adverse effects including bleeding, allergic reactions liver or kidney problems, and high blood pressure. The point being that evidence for contraindicating the use of any NSAIDs is still missing, as well, evidence for a therapeutic benefit for their use, therefore the suggestion should be to stick to the use of NSAIDs only in case of chronic pain or epilepsy.

In conclusion, antipyretics should be considered harmful if not administered under continuous medical supervision. Immunosuppressive therapy could be useful for the later stage of the infectious cycle for the critically unwell patient, but for the infected relatively asymptomatic subject (fever less than 38.5 • C) one of the best options could be just letting the fever exerts its protective effect.

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