DISCUSSION
Our study sought to identify the clinical predictors for COVID-19 that resulted in risk for worst outcomes and the effect of combined therapeutic on length of stay, ICU admission, need for MV and mortality. Our findings suggest that 1) the combination of AZM-Corticosteroid reduced the risk of ICU admission, need for MV and mortality; 2) AZM-Corticosteroid and therapeutic anticoagulation, when indicated, reduced the mean length of stay in ICU and MV; 3) the introduction of HCQ to the AZM-Corticosteroid combination increased the mean length hospital stay; 4) the use of HFNC prevented in one third the patient’s progression to MV and 5) Age >65 years, presence of up one comorbidity, pulmonary involvement ≥ 50%, saturation <93%, lymphopenia, D-dimers and CRP altered were admission clinical predictors associated with higher risk for mortality.
Observational and Randomized Clinical Trials (RCT) have been published, evaluating the effects of several drugs in terms of potency, efficiency or efficacy in clinical management3,5. Predictive factors and clinical characteristics that may influence COVID-19 severity have already been demonstrated in the literature and multivariable models have been used to identify high-risk individuals6,7.
Although some treatments are promising, it is thought to be early to clearly state that there is a definitive treatment. The Solidarity Trial Consortium8, funded by the World Health Organization showed that antiviral drugs including remdesivir, HCQ, lopinavir, and interferon regimens had little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Also, another promising intervention with convalescent plasma, validated in a RCT showed no significant differences in clinical status or overall mortality between patients treated or received placebo9.
Although controversial, the use of corticosteroid seems to have clinical potential on mortality reduction and need for intubation, provided it is adequate for the treatment regimen and individual clinical characteristics10-12. The Randomized Evaluation of COVID-19 Therapy (RECOVERY trial) showed that survival was significantly higher among patients treated with dexamethasone, especially for those requiring invasive intubation13. Our data reinforce these findings and highlight the corticosteroid therapeutic effectiveness, especially in reducing the risk of mortality, ICU admission and need for MV when combined with AZM. Also, we observed benefits related to reduced length of stay in ICU and MV in patients who used anticoagulant, findings additional to those reported by Nadkarni (2020)14, where therapeutic or prophylactic anticoagulation reduced intubation and mortality.
Some studies published at the beginning of the pandemic, with limited evidence, highlighted the benefits of using HCQ combined or not with AZM in reducing mortality and length of stay15-16. However, in an open-label, multicenter, randomized, controlled trial conducted by the Coalition COVID-19 Brazil I, among inpatients with mild-to-moderate COVID-19, the use of HCQ, alone or with AZM, did not improve clinical status at 15 days as compared with standard care17. Self et al.18 reported similar ineffectiveness in HCQ treatment on the 14th day of hospitalization.
Rosenberg (2020)19 and Magagnoli (2020)20 also performed a protocol using HCQ combined or not with AZM and found no reduction in mortality risk and need for MV. Also, they reported an increase in overall mortality for patients treated with HCQ alone. In the same direction, we observed that whenever HCQ was included in the model, the protective benefit of the association of AZM-Corticosteroids loses significance and becomes a risk factor for a worse prognosis. We showed that patients treated with HCQ have a longer hospitalization compared to patients not treated, a finding previously discussed by Kalligeros et al21. Interestingly also, when we analyzed the clinical predictors influence under the use of HCQ, there was no significant difference between those treated or not with HCQ. We assume that other factors, such drug interactions may be involved in these findings. Besides that, oseltamivir, convalescent plasma, vasopressor and tocilizumab when evaluated alone or combined with HCQ, AZM and corticosteroids showed no benefit.
The use of HFNC showed a trend toward reduction in the intubation rate and no difference in mortality, findings similar to those reviewed by Lin (2020)22. Geng (2020) presented HFNC as a favorable option to avoid intubation through adequate monitoring of the respiratory function of COVID patients23.
Clinical predictors at admission associated with higher risk for mortality include individuals older than >65 years, with up to one comorbidity, pulmonary involvement more than 50%, saturation <93%, lymphopenia, D-dimers and CRP elevated. We understand that if these clinical variables are considered upon patient arrival, management and treatment will be more effective. Oxygen requirement through BiPAP or HFNC, ICU admission and MV required during hospitalization were also risk markers. A recent publication showed that patients with leukocytosis and CRP altered on arrival were associated with poor prognosis and may predict the severity of COVID-1924.
The weakness of our study is related to the fact that it is observational, unicentric and retrospective however our results are in line with other RCTs that recommended the association of corticosteroids to the set of treatment and advise against HCQ use in patients with COVID-19. The reduced HCQ treatment efficiency when included to the set of drugs can be speculate through the pharmacological interaction with others drugs triggering for example an increase in its serum concentration, prolongation of the QT interval in the ECG and possibly triggering episodes of ventricular tachycardia25-28. It is known that longer QTc can cause life-threatening arrhythmias especially in critically ill patients, however monitoring of ECG and drug serum level was not uniformly standardized, given the retrospective nature of the study. Finally, the results of our study should be evaluated considering individual clinical characteristics in a real world and clinicians should carefully weigh the risks and benefits when considering any therapeutic scheme out of the randomized clinical trial setting.