New research shows that non-steroidal anti-inflammatory drugs (NSAIDs) reduced both antibody and inflammatory responses to SARS-CoV-2 infection in mice.
The study appears this week in the Journal of Virology, a publication of the American Society for Microbiology.
The research is important because “NSAIDs are arguably the most commonly used anti-inflammatory medications,” said principal investigator Craig B. Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.
In addition to taking NSAIDs for chronic conditions such as arthritis, people take them “for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise,” said Dr. Wilen. “Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection.”
The research also suggests that the consequences of NSAID use during natural infection and vaccination should be evaluated in humans, said Dr. Wilen. “This data likely exists, particularly in the clinical trials for the vaccines, so it should be mined to see if it produces antibody responses in people.”
The potent anti-inflammatory, dexamethasone (not an NSAID), is detrimental to COVID-19 sufferers when taken early in the infection, but beneficial when administered during later stages of COVID-19, said Dr. Wilen.
Similarly, NSAIDs’ anti-inflammatory activity might be detrimental early in SARS-CoV-2 infection, because at this stage, inflammation is usually helpful.
That changes at later stages of COVID-19, particularly if the patient undergoes an intense inflammation known as a cytokine storm. A cytokine storm is an immune response of inflammatory compounds that often occurs in COVID-19 patients, can lead to complications, need for the intensive care unit, and even death.
A reduction in neutralizing antibodies caused by NSAIDs might be benign, or it might blunt the immune system’s ability to fight the disease during the early stages of infection. It could also reduce the magnitude and/or length of protection from either natural infection or vaccination, said Dr. Wilen.
The initial motivation to investigate NSAIDs’ effect on COVID-19 “was a twitter thread, suggesting NSAIDs should not be used during COVID-19,” said Dr. Wilen. “This seemed suspicious to us, so we wanted to investigate.”
Dr. Wilen and his team expected that there would be little to no effect of NSAIDs on viral infection, which turned out to be correct.They also thought that NSAIDs would not significantly affect the antibody response to natural infection.
“In fact, we initially didn’t even carefully look at the antibody response, because we didn’t expect it to be altered by NSAIDs. This turned out to be wrong, said Dr. Wilen.
Corticosteroids, including glucocorticoids and mineralocorticoids, are produced by the adrenal cortex. They have been proved as immunosuppressive and anti-inflammatory drugs for the treatment of conditions such as asthma, allergy, septic shock, multiple sclerosis, and lung tissue disorders.
Corticosteroids alter gene transcription through binding to a particular receptor in target cells. However, their use is limited by their massive probable side effects as hyperglycemia, hypertension, infection, osteoporosis, growth retardation, skin atrophy, glaucoma, and cataract (Ramamoorthy and Cidlowski, 2016; Song et al., 2020; Wang et al., 2020d). Systemic inflammation is an adverse outcome caused by coronaviruses, which persists after viral clearance.
So, theoretically, corticosteroids can be potential candidates for suppressing lung inflammations. There are some reviews summarizing reports on SARS and MERS, revealing no benefits of corticosteroids. In general, the studies suggest associations between corticosteroid administrations and disease deterioration (worsening pulmonary conditions) and mechanical ventilation requirements, delayed viral clearance, avascular necrosis, and diabetes.
They have called it a double-edged sword (Nasim et al., 2020; Russell et al., 2020). Since the outbreak of COVID-19, new studies have been designed on Corticosteroids. In an in vitro study on VeroE6 cells, Ciclesonide has been introduced as a safe corticosteroid to reduce viral replication and host inflammation by EC90=6.3 μM (Matsuyama et al., 2020).
A clinical study reviewed 46 patients with severe COVID-19, in which 26 patients received 1-2 mg/kg/d methylprednisolone intravenously for 5-7 days. Results revealed faster improvement of oxygen saturation, better absorption degree of the focus in chest CT, and shorter time to overcome hyperthermia (Wang et al., 2020d).
Nevertheless, a report on 31 patients with 11 administrated corticosteroids indicated no statistically significant differences in treated patients and the non-treated. They investigated the virus clearance time, hospital length of stay, and duration of symptoms, and there was no improvement compared with the control patients (Zha et al., 2020). Moreover, an open-labeled, randomized controlled trial enrolled 48 cases from Chongqing Public Health Medical Center, China.
The subjects are assigned in two groups, the intervention group, which receives an intravenous injection of 1-2 mg/kg/day methylprednisolone for three days, and the control group. The study is examined the timing of clinical improvement, duration of mechanical ventilation and hospitalization, rate of adverse effects, and mortality.
The results have not yet been revealed (Zhou et al., 2020). As of now, the use of corticosteroids in patients with COVID-19 is controversial since the WHO and the Centers for Disease Control and Prevention (CDC) generally recommend that glucocorticoids not be used in COVID-19 pneumonia unless in specific comorbid clinical conditions, e.g., exacerbation of chronic obstructive pulmonary disease (Song et al., 2020).
The RECOVERY trial is an ongoing, open-label, controlled trial conducted on hospitalized patients with COVID 19 in the UK. The primary endpoint was mortality rate at 28 days. The study assigned 2104 patients to receive Dexamethasone, oral or intravenous, at the dose of 6 mg daily for ten days, plus standard care, and 4321 patients to receive usual care alone. According to the preliminary analysis report, of 6,425 patients, 22.9% of patients (n=482) in the dexamethasone group and 25.7% (n=1110) in the standard care group died within 28 days of randomization (P< 0.001).
Compared to the usual care group, the dexamethasone group had a lower incidence rate of mortality among patients who required invasive mechanical ventilation (29.3% vs. 41.4%) and oxygen supplement (23.3% vs. 26.2%). A significant survival benefit was not found in patients who did not receive respiratory support (Horby et al., 2020).
The World Health Organization (WHO) rapid evidence appraisal for COVID-19 therapies (REACT) assessed the association between corticosteroids and mortality rate in critically ill patients infected with COVID-19. This meta-analysis includes seven trials (DEXA-COVID 19, RECOVERY, REMAP-CAP, CoDEX, CAP COVID, COVID STEROID, and Steroids-SARI) pooled data.
Of 1703 patients who had participated in the analysis, 678 received corticosteroids (3 trials Dexamethasone, three trials Hydrocortisone, one trial Methylprednisolone) 1025 had received standard of care or placebo. 222 patients (32%) in the corticosteroid group and 425 patients (40%) in the standard care or placebo group died (p<0.001) within 28 days. Dexamethasone and hydrocortisone were the same in mortality rate reduction (Sterne et al., 2020).
At the same time, WHO released the guideline of corticosteroids for COVID-19 in which systemic administration of Dexamethasone 6 mg daily or Hydrocortisone 150 mg (e.g., 50 mg every 8 hours), or Prednisone 40 mg, or Methylprednisolone 32 mg (e.g., 8 mg every 6 hours or 16 mg every 12 hours) for 7-10 days has been recommended for patients with severe and critical COVID-19 (https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1).
Early administration of corticosteroids at a low dose for the short term has been evaluated in 475 hospitalized patients with non-severe COVID 19 related pneumonia. Methylprednisolone 20 mg per day or 40 mg per day for 3 to 5 days was prescribed intravenously for 50 patients, and five patients received prednisone 20 mg per day for three days. 420 patients did not receive corticosteroid therapy.
The length of fever, virus clearance, and hospital stay were significantly prolonged in the corticosteroid group. More patents in the corticosteroid group progressed to severe disease. Antimicrobial therapy was more remarkable in the corticosteroid group. So worse outcomes are expected from corticosteroid therapy in non-severe COVID-19 pneumonia (Li et al., 2020).
Another retrospective study evaluated the effect of early administration of corticosteroids on mortality rate and mechanical ventilation in 1806 hospitalized patients with COVID 19. Of 1806 patients, 140 received corticosteroids within the first 48 hours of admission.
Corticosteroid therapy in patients with initial C-reactive protein (CRP) 20 mg/dL or more significantly decreased mortality or mechanical ventilation. In contrast, mortality or mechanical ventilation became more significant in patients with a CRP level of less than 10 mg/dL (Keller et al., 2020).
Careful interpretation of these findings needs to perform further randomized clinical studies.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816644/
More information: Jennifer S. Chen et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection, Journal of Virology (2021). DOI: 10.1128/JVI.00014-21