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.