Treatment options have been limited in the ongoing coronavirus disease 2019 (COVID-19) pandemic. Earlier optimism regarding immunomodulatory drugs such as azithromycin (AZM) and hydroxychloroquine (HCQ) seemed to be undermined by results of large interventional trials.
However, a fascinating new study posted to the medRxiv* preprint server (not peer-reviewed*), suggests that such disappointment may have been both premature and unwarranted, based on a re-analysis of over 250 patients on invasive mechanical ventilation (IMV) during the first two months of the pandemic.
Using computational modeling, the use of weight-adjusted HCQ and AZM appears to be associated with a more than 100% reduction in mortality, without a clear correlation with ECG abnormalities.
Study: Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic. Image Credit: Terelyuk / Shutterstock Study: Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic. Image Credit: Terelyuk / Shutterstock Study details In this study, based on a subset of critically ill COVID-19 patients, consisting of patients who required intubation and IMV, data from the medical records were analyzed using several novel methods. This included not only the vital signs and laboratory values but the therapeutic methods.
The study was carried out on patients at Saint Barnabas Medical Center, New Jersey, with just over 1% having been clinically diagnosed to have COVID-19. Of the 255 patients, almost 80% died during the study period. Seven patients were transferred to another hospital on the ventilator, mostly after day 40 of hospitalization.
Parameters were broadly comparable between survivors and non-survivors, except that all patients with an active malignancy, dementia, chronic obstructive pulmonary disease, and stroke failed to survive. However, sex, race, presentation severity, and blood type had no association with survival chances.
A pre-print version of the research paper is available on the medRxiv* server. A preprint is a version of a scholarly or scientific paper that precedes formal peer review and publication in a peer-reviewed scholarly or scientific journal.
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Laboratory markers Laboratory markers of inflammation, such as Ferritin, D-dimer, Lactate Dehydrogenase (LDH), and C-reactive protein (CRP), were above average in almost every patient (96%). While all parameters, except the LDH, were equivalent in survivors and non-survivors, three patients had D-dimer values above 69,000 ng/mL. LDH values were higher in non-survivors by almost 30%.
The increase in these parameters over time was characteristically steeper in patients who did not survive.
Clinical complications More than three in four non-survivors developed acute kidney injury (AKI), of which a tenth received renal replacement therapy (RRT). Of this latter group, a fifth survived.
Almost 60% of patients were intubated within three days of hospitalization. The time to intubation did not predict survival, but intubation beyond day 15 was associated with survival in only 1 of 16 patients.
More than 90% of the patients in this cohort had high blood glucose levels above 140 mg/dL, peak at >200 mg/dL, without corticosteroid therapy. Although none were known to be diabetics, most probably had impaired glucose tolerance before they acquired SARS-CoV-2.
This prevalence is higher than in most other studies, probably because the researchers looked actively for hyperglycemia
Obesity While half of the patients were obese, and 30% were overweight, the older patients were significantly heavier. That is, 74% of those above 60 were obese, vs 37% of those below this age.
The mean body weight was approximately 90 kg, but unlike most antibiotic clinical trials, the range of body weight was extensive. The heaviest patient thus weighed approximately seven times more than the lightest.
Notably, blood glucose levels or obesity did not predict a good clinical outcome.
Therapeutic drugs The chief therapeutic classes included steroids, tocilizumab, convalescent plasma, hydroxychloroquine, and azithromycin.
Corticosteroids, when given at 6 mg or more, reduced the mortality risk 1.4 times. Meanwhile, the interleukin-6 receptor blocker) tocilizumab had two-fold lower mortality.
Convalescent plasma (CP) was used only from week 4, in a fifth of the patients, mostly younger than those who did not receive it. The survival of the group which received CP was almost doubled from CP non-users.
HCQ was used in 94% of patients within 48 hours of emergency room arrival, while >55% received 2,000-3,000 mg, cumulatively. Of this number, approximately 63% also received AZM. This combination fell out of favor over the study period based on external recommendations.
Effect of HCQ/AZM on mortality With every log increase in the cumulative dose of HCQ, the mortality rate fell by 1.12 times, such that at 3 g HCQ, survival odds rose by 2.5 times.
When given together with AZM, the benefit was still more significant. Chances of survival increased further. Among those who received both > 3g HCQ and >1g AZM, almost half survived, compared to one in seven (16%) among patients who received one of these drugs at the same dosages.
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