Fluvoxamine improves survival of COVID-19 patients

Objective: We undertook this study to determine the effect of Fluvoxamine use on the survival of hospitalized coronavirus disease (COVID-19) pneumonia patients.


Methods: This retrospective case-control chart review study used data extracted from the medical records of adults who were hospitalized with moderate or severe COVID-19 pneumonia at the Uzsoki Teaching Hospital of the Semmelweis University in Budapest, Hungary, between 17 March and 22 April 2021, and received anti-COVID-19 therapy including favipiravir, remdesivir, and baricitinib or their combination, in addition to standard medical treatment; 110 patients received 20 mg Fluvoxamine orally once daily as adjuvant medication. Multivariable logistic regression was used to evaluate the association between Fluvoxamine use and mortality.


Results: Of the 269 participants, 205 (76.2%) survived and 64 (23.8%) died between days 2 and 28 after hospitalisation. Fluvoxamine use was associated to a decrease of mortality risk (OR [95% CI] 0.242 [0.111–0.525], p<0.0001) compared to the non-Fluvoxamine group. Greater age, higher lactate dehydrogenase concentration, and baricitinib use (OR [95% CI] 1.1 [1.065– 1.137], p<0.001; 1.001 [1.000–1.002], p=0.042; 3.62 [1.146–11.451], p=0.028, respectively) were significantly associated with higher mortality.


Conclusion: Provisional to confirmation in randomized controlled studies, Fluvoxamine may be a potent treatment for COVID-19 pneumonia.



INTRODUCTION

Since the emergence of the coronavirus disease (COVID-19) pandemic, several drugs have been used to improve patient outcomes worldwide; however, the current armamentarium against COVID-19 remains suboptimal. Repurposing clinically well-established drugs might constitute a time-sparing method for improving pharmacotherapy in COVID-19.1 In spring 2021, the third COVID-19 wave culminated in Hungary, with a sad record of cases and deaths in that period. 2 A peak in mortality was experienced in the COVID-Centre of Uzsoki Hospital in Budapest, Hungary, too, severely distressing the patients and medical teams. This extraordinary situation urged clinicians to try helping patients by repurposing the antidepressant Fluvoxamine based on earlier studies. In one study, more than 40% of the population who were interviewed during the pandemic scored depressive or had anxiety symptoms.3 Anxiety may compromise the immune system, which could result in increased susceptibility to infection or increased disease severity.4-6 Several studies have evidenced the negative impact of anxiety on the outcome of a variety of medical conditions. 7-9 Similarly, a meta-analysis revealed an association between mood disorders and increased COVID-19 mortality. 10 The anxiety levels of patients in the acute phase of COVID-19 pneumonia were found similar to those of patients with myocardial infarction. 11 Based on those data and facing the growing number of COVID-19 fatality hardly helped by any effective treatment, the hospital team ventured to contribute antianxiety/anti-depressive treatment


Patients

We reviewed the medical records of those patients more than 18-year-old who were admitted to the COVID-Centre between 17 March and 22 April 2021, i.e. the culmination of the third wave of the epidemic. The inclusion criteria were the followings: • Results of an antigen or polymerase chain reaction test that confirmed a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; • Pneumonia indicated by imaging findings on computed tomography or X-ray; • Stay in the COVID-centre for longer than 48 hours; and • No prior anti-COVID-19 vaccination. The patients or their close family members (in the case of critically ill patients) provided a general written informed consent.













Treatment

In the extraordinary circumstances associated with the pandemic, the clinical state of patients together with the changing availability of antiviral drugs, determined the treatment plan. First, only favipiravir was available for COVID-19 treatment, whereas remdesivir could be administered only to a few critically ill patients. Later, due to its increasing availability, remdesivir became the main COVID-19 therapy, gradually contributed to by baricitinib, which was usually reserved for younger patients with severe COVID-19 due to its scarcity. The introduction of Fluvoxamine followed a similar pattern. Based on the favorable experiences - good tolerability by COVID-19 patients with no clinically significant side-effects - it has become part of the local anti-COVID protocol. This real-world situation resulted in different anti-COVID-19 drug combinations, where remdesivir tended to be combined with Fluvoxamine significantly more often than it was with the other abovementioned drugs. The anti-COVID-19 drug doses were the following: • Favipiravir: first and second dose, 1600 mg; third to tenth dose, 600 mg; • Remdesivir: first dose, 200 mg; second to the fifth dose, 100 mg; • Baricitinib: 4 mg once daily for 10 days. Fluvoxamine was administered in 20 mg tablets once daily. Patient care was performed by standard medical guidelines, including dexamethasone and thrombosis prophylaxis. Baseline routine blood investigations at admission included C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels for all patients and D-dimer concentrations in the majority of the study population.


RESULTS

Out of 623 patients admitted during the study period, 269 (147 males [54.6%]; age, mean [range] 64.1 [19–96] years) were eligible for the study based on the inclusion criteria. A total of 205 patients survived (76.2%) and 64 patients died (23.8%) between days 2 and 28. None of the continuous variables (age, LDH, CRP, and D-dimer) were normally distributed (Shapiro–Wilk = 0.48, p = 0.003, Kolmogorov–Smirnov = 0.8, p < 0.0001); therefore, the Mann–Whitney–Wilcoxon tests were applied. Continuous variables are expressed as mean ± standard deviation (SD). We found significant intergroup differences in the age, CRP, and D-dimer as well as in favipiravir, remdesivir, and Fluvoxamine use between the case and control groups (Table 1). Fluvoxamine was administered to 110 patients (40.9%). One patient developed severe hyponatremia, which was likely caused by Fluvoxamine. Additional side effects that were possibly related to Fluvoxamine occurred and included: increase in liver enzyme levels in one patient and confusion in another patient. Fluvoxamine was stopped in each case. Age, sex, LDH, CRP, and D-dimer levels did not differ significantly between patients who received Fluvoxamine and those who did not (Table 2). Only three variables showed a significant association with mortality: age, Fluvoxamine, and baricitinib. The mortality risk of those patients who received Fluvoxamine decreased by 25%, compared with those not receiving it (Table 3). Variables that were found to be significantly associated with mortality in the regression analysis are presented in Table 4. The results of the Box–Tidwell test were acceptable for both the continuous variables (age, p=0.99; LDH p=0.24). Patients on Fluvoxamine therapy were 0.242 times (95% CI 0.111–0.525) less likely to die than those who did not receive Fluvoxamine; i.e. the survival of patients in the Fluvoxamine


DISCUSSION

We found that Fluvoxamine use is associated with a one-quarter reduction of mortality, in patients with COVID-19-induced pneumonia. In our study, age was a risk factor that significantly influenced mortality. In agreement with other studies, 18, 19 the mortality risk increased 10% with every 1-year increase in age. Our finding is in concordance with the findings of the meta-analysis of Martha et al.,20 wherein the baseline LDH level had a significant effect on case-fatality, thereby justifying the use of LDH as a prognostic marker. The CRP level was shown to be another prognostic marker,21 which our study could not confirm. We did not find a prognostic value of D-dimer either, although our finding does not contradict the literature presenting heterogeneous results in this regard.22 Due to the lack of available laboratory kits, we could not measure interleukin-6 (IL-6) levels that are considered important prognostic markers, too.23


CONCLUSION

Our retrospective study design needs confirmation by prospective controlled and randomized investigations, while the strong association found between Fluvoxamine therapy and survival justifies the cost and effort of such studies. Provisional to confirmation, Fluvoxamine may become a potent treatment for COVID-19 pneumonia. The 20-mg Fluvoxamine dose used in this study was not its recommended peak dose (80mg) in the treatment of depression, and higher doses might be even more effective. Fluvoxamine’s favorable profile – oral route, low cost, easy availability, and safety – make it especially convenient Buy Fluvoxamine Online | FLuvoxamine 100mg price | FLuvoxamine 50 mg price | FLuvoxamine 50mg price in the USA | Buy FLuvoxamine online in the USA | buy FLuvoxamine online UK | Faverin 50 mg Film-coated Tablets |

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