Sunday, June 20, 2021

Hydroxychloroquine and azithromycin as a treatment of COVID-19 4

Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic

Leon G. Smith, Nicolas Mendoza, David Dobesh, Stephen M. Smith


This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.


Introduction This observational study looked at 255 COVID19 patients who required invasive mechanical ventilation (IMV) during the first two months of the US pandemic. Through comprehensive, longitudinal evaluation and new consideration of all the data, we were able to better describe and understand factors affecting outcome after intubation. 

Methods All vital signs, laboratory values, and medication administrations (time, date, dose, and route) were collected and organized. Further, each patient’s prior medical records, including PBM data and available ECG, were reviewed by a physician. These data were incorporated into time-series database for statistical analysis. 

Results By discharge or Day 90, 78.2% of the cohort expired. The most common pre-existing conditions were hypertension, (63.5%), diabetes (59.2%) and obesity (50.4%). Age correlated with death. Comorbidities and clinical status on presentation were not predictive of outcome. Admission markers of inflammation were universally elevated (>96%). The cohort’s weight range was nearly 7-fold. Causal modeling establishes that weight-adjusted HCQ and AZM therapy improves survival by over 100%. QTc prolongation did not correlate with cumulative HCQ dose or HCQ serum levels. 

Discussion This detailed approach gives us better understanding of risk factors, prognostic indicators, and outcomes of Covid patients needing IMV. Few variables were related to outcome. By considering more factors and using new methods, we found that when increased doses of co-administered HCQ and AZM were associated with >100% increase in survival. Comparison of absolute with weight-adjusted cumulative doses proves administration ≥80 mg/kg of HCQ with > 1 gm AZM increases survival in IMV-requiring Covid patients by over 100%. According to our data, HCQ is not associated with prolongation. Studies, which reported QTc prolongation secondary to HCQ, need to be re-evaluated more stringently and with controls. 

The weight ranges of Covid patient cohorts are substantially greater than those of most antibiotic RCTs. Future clinical trials need to consider the weight variance of hospitalized Covid patients and need to study therapeutics more thoughtfully.

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% increase in survival, without a clear correlation with ECG abnormalities.

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.

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 


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. 

Number of patients by Date of Admission and breakdown by treatment with HCQ/AZM, HCQ alone or no HCQ therapy. Shown are the number of patients in the Cohort by admission date, from March 12 – May 1, 2020. HCQ therapy for each patient is demonstrated by use of color. Blue means the patient received HCQ and AZM therapy together, Gold, HCQ therapy without AZM, and Red, the patient did not receive HCQ.

Number of patients by Date of Admission and breakdown by treatment with HCQ/AZM, HCQ alone or no HCQ therapy. Shown are the number of patients in the Cohort by admission date, from March 12 – May 1, 2020. HCQ therapy for each patient is demonstrated by use of color. Blue means the patient received HCQ and AZM therapy together, Gold, HCQ therapy without AZM, and Red, the patient did not receive HCQ.

This means a 32% absolute difference in survival, or a relative improvement in survival odds of 200%, with the combination of HCQ/AZM at this dosage. This far exceeds the survival benefit cited in any study of any intervention so far. 

When HCQ/AZM was given at lower dosages, the risk of death was over three times higher relative to the above combination and dosage regimen. 

When the cohort was divided into patients who received >3g HCQ/>1g AZM and those who did not, overall, the absolute chances of survival were 23% higher for the first group. The 17% survival in the second group would have increased to 39% with the former treatment, predicted the researchers. 

This indicates that treatment with >3g HCQ/>1g AZM was associated with a more than 130% increase in survival rate compared to any other standard therapy. 

Weight-adjusted cumulative dosage

The researchers also found that when adjusted for weight, the cumulative dose would have a still greater effect. In fact, the average treatment effect (difference in mean survival, in this case) shows a steep increase between 40-50 mg/kg to peak at 46% for a dose of 82 mg/kg. 

Thus, patients receiving HCQ above 80 mg/kg of HCQ with >1g AZM had 14 times higher survival odds compared to those who did not. If HCQ dosage was fixed at >3g, the odds of survival were 7 times higher, or less than half of that achieved with the weight-adjusted cumulative dosage. 

“The fact that weight-adjusted cumulative dose has an even greater effect on survival than cumulative HCQ dose is strong confirmation of the causal relationship between this treatment and improvement in survival rate.” 

Age was another major factor since those older than 60 were five times more likely to succumb than younger patients. Hyperlipidemia was the single comorbidity linked to approximately four times higher odds of death. 

Interestingly, there was no correlation between the cumulative dose of HCQ (or AZM) and the occurrence of QTc prolongation. In fact, the QT interval began to fall during the period when the cumulative dose of HCQ increased. None of the patients showed torsades de pointes. 

What are the implications?

These findings indicate that a steeply rising ferritin, D-dimer and LDH over time predict poor survival, the rate of rise being several times greater for non-survivors. This should be validated to help provide a better prognosis for COVID-19 patients. 

The extensive range of obesity among critically ill patients indicates that weight-adjusted dosage is critical in achieving the correct therapeutic levels. Moreover, AZM is an independent contributor to improved survival. 

Most importantly, this is the first clinical study to demonstrate the remarkable benefit of using cumulative doses of HCQ>3g/AZM>1g, compared to those not treated with this combination. 

Why did such a large effect miss observation? For one thing, HCQ produces its benefit by cumulative effects on the target cells, which is weight-dependent. The failure to treat patients with weight-adjusted doses leads to ineffective treatment and outcomes biased towards lighter patients. 

HCQ is both safe and tolerable at higher doses, as shown in studies of rheumatoid arthritis or lupus. Such high doses for such long durations have not been used to treat COVID-19. 

The earlier studies claiming prolongation of the QTc duration with HCQ in COVID-19 treatment are shown to be flawed. Indeed, available data suggests that this finding is due to the underlying illness itself. 

The investigators also point out: “On April 24, 2020, the FDA issued a warning about the possible effects of low HCQ on QTc interval (47). Since 2010, the FDA has approved over 150 clinical trials, which include HCQ treatment. The FDA did and does not require monitoring for cardiotoxicity. In each of these trials, the total HCQ dose and expected tissue levels are markedly higher than used or seen in Covid patients. This discrepancy lacks logic or explanation.” 

In this startling study, the investigators carefully re-examined the data, showing that among critically ill COVID-19 patients on IMV, less than 4% “walk out of hospital.” In contrast, the survival benefit of combined HCQ/AZM at a cumulative dosage of >80 mg/kg and >1g, respectively, is shown to be both clear and significant. 

The safety at such doses is obvious, since survival is increased by almost 130% in this very high-risk population. Moreover, it appears that AZM is an important component of this therapy in terms of mortality reduction.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

1 comment:

  1. The malaria and arthritis drug much-touted by President Donald Trump, hydroxychloroquine, is getting its chance under the microscope now, with the beginning of a clinical trial by the National Institutes of Health to determine its potential as a COVID-19 therapy.

    Testers hope the drug could have potential with adults hospitalized by the pandemic. The trial’s first participants are being pulled from Tennessee, to be enrolled at the Vanderbilt University Medical Center in Nashville, Tennessee. For the more than 500 adults expected to be enrolled, the test will be blind, placebo-controlled and randomized. It will be run by the Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network.

    “Effective therapies for COVID-19 are urgently needed,” James Kiley, director of the Division of Lung Diseases at the National Heart, Lung and Blood Institute, said. “Hydroxychloroquine has showed promise in a lab setting against SARS-CoV-2, the virus that causes COVID-19 and preliminary reports suggest potential efficacy in small studies with patients. However, we really need clinical trial data to determine whether hydroxychloroquine is effective and safe in treating COVID-19.”

    The drug has the potential for severe side effects, even in its designated role for treating malaria and rheumatoid conditions. Even short use can lead to cardiac arrhythmias, seizures, dermatological reactions and hypoglycemia. Yet, in various studies, it has also shown antiviral potential, the capability to modify immune system activity and what the NIH labels an established safety profile at appropriate doses.

    “Many U.S. hospitals are currently using hydroxychloroquine as first-line therapy for hospitalized patients with COVID-19 despite extremely limited clinical data supporting its effectiveness,” Dr. Wesley Self, emergency medicine physician at Vanderbilt University Medical Center and PETAL Clinical Trials Network investigator leading the ORCHID trial, said. “Thus, data on hydroxychloroquine for the treatment of COVID-19 are urgently needed to inform clinical practice.”

    All participants in the study will continue to receive clinical care. ORCHID participants will be randomly assigned 400 mg of hydroxychloroquine twice per day for two doses on the first day, then 200 mg twice daily for the subsequent eight doses for up through day five, followed by a placebo twice daily for five days after.

    Those hardest hit by COVID-19 see it manifest as an acute respiratory infectious illness, capable of damaging multiple organ systems. Fever, coughing, fatigue, pneumonia and respiratory failure have all been associated with the disease, which has infected more than 1,619,000 people worldwide and killed more than 97,000, according to Johns Hopkins University as of Friday.

    Currently, no approved therapies for COVID-19 exist.