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Hydroxychloroquine + Azithromycin Therapy at a Higher Dose Improved Survival by Nearly 200% in Ventilated COVID Patients

AHA Publisher — Mon, 07 Jun 2021 07:00:14 +0000

Dr. Liji Thomas, MD via News-Medical – 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 However, a fascinating new study posted to the medRxiv* preprint server (not peer-reviewed*), suggests that such disappointment may have been both premature and unwarranted, based on a re-analysis of over 250 patients on invasive mechanical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 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. 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. To read the original article click here.

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Hospitalized COVID-19 Patients Fare Worse When They Have High Blood Sugar

AHA Publisher — Thu, 01 Apr 2021 07:00:16 +0000

Endocrine Society via Newswise – Patients hospitalized with COVID-19 have worse outcomes if they have high blood sugar, or hyperglycemia, regardless of whether they have diabetes, a new study finds. The researchers will present their results, of the first known study of the impact of hyperglycemia on a largely Black patient population with the novel coronavirus, at ENDO 2021, the Endocrine Society’s annual meeting. The investigators found that patients with COVID-19 who had hyperglycemia on admission to the hospital were more likely than those with normal glucose (sugar) to require a breathing machine or admission to the intensive care unit (ICU). These patients also were reportedly likelier to have kidney injury and to die in the hospital. “COVID-19 patients presenting to the hospital with hyperglycemia require closer observation, as they are likely to require more aggressive therapies,” said the study’s lead investigator, Samara Skwiersky, M.D., M.P.H., an internal medicine resident physician at the State University of New York (SUNY) Downstate Medical Center in Brooklyn, N.Y. Although a few prior studies have identified hyperglycemia or diabetes as an independent risk factor for worse COVID-19 outcomes, Skwiersky said they did not take place in a predominantly Black population. The virus has disproportionately affected Black people, including higher rates of hospitalization and death than in white people, she noted. Their study included 708 adults with COVID-19 admitted to SUNY Downstate Medical Center, 89 percent of whom were Black. About half were men, and 54 percent of patients had a history of either type 1 or type 2 diabetes on admission. The researchers studied patient outcomes by the presence or absence of diabetes and by their blood glucose values on admission. Because guidelines recommend that hospitalized patients with diabetes maintain blood glucose levels between 140 and 180 milligrams per deciliter (mg/dL), the investigators divided patients into groups by glucose levels less than 140 and less than 180 mg/dL. Patients with diabetes whose blood glucose values on admission exceeded 140 mg/dL had a 2.4-fold increased odds of ICU admission and intubation—needing a breathing machine—versus those whose glucose levels were lower, the researchers reported. Furthermore, patients with diabetes whose admission glucose levels were higher than 180 mg/dL had an approximately twofold increased odds of in-hospital death, their data showed. However, Skwiersky said the odds of death also were increased twofold for patients who did not have diabetes and whose glucose values exceeded 140 mg/dL. Additionally, these patients had a 3.5-fold raised odds of ICU admission and a 2.3-fold higher odds of intubation and of experiencing acute kidney injury. According to Skwiersky, patients without diabetes whose blood glucose levels topped 180 mg/dL had a fourfold greater death risk, a nearly threefold increased odds of ICU admission, and a 2.7-fold higher odds of intubation. “The results from our study,” she said, “reiterate the importance of regularly monitoring blood glucose in patients hospitalized with COVID-19, even without a prior diagnosis of diabetes.” It is unclear whether hyperglycemia is the result of or a cause of more severe COVID-19 illness, Skwiersky stated. Still, she said their results suggest the need for intensive glucose control in hospitalized COVID-19 patients with high blood sugar. This is consistent with the current Endocrine Society guidelines, which recommend that all patients with blood glucose above 140 mg/dL be monitored with point–of–care glucose testing and treated with appropriate therapies. “More frequent glucose monitoring and treatment with insulin therapy to a target glucose value less than 140 mg/dL could improve outcomes in these patients,” Skwiersky said. To read the original article click here.

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The Role of Nutrition in Recovery from COVID-19

AHA Publisher — Mon, 29 Jun 2020 07:00:54 +0000

By Emily Henderson, B.Sc. via News-Medical Net – Dr. Riccardo Caccialanza speaks to News-Medical about his research on the role of nutrition in recovering from COVID-19 and how implementing nutritional support early on can make a significant difference to patient recovery time. What has led you to explore the importance of nutrition in COVID-19 recovery? There is little practical clinical guidance for nutritional care during recovery of COVID-19, even though it can impact recovery time and people’s ability to return to doing the things that matter most to them. Nutrition is vital for maintaining skeletal muscle and avoiding metabolic disturbances and when patients are spending around two weeks in ICU, these can become very serious issues. Respiratory difficulties add an extra layer of complexity, preventing patients from eating effectively. A huge proportion of the patients we have treated required assisted ventilation, making it difficult to provide food and oral supplements. This has meant that nutrition has had to become an important part of COVID-19 patients’ recovery. What is the aim of your research? My research in Italy is being supported by a grant from Nutricia*. My research aims to better understand the fundamental role of nutritional status and medical nutrition on treatment and recovery outcomes. I hope the research outcomes will ultimately result in the adoption of practical guidelines on integrating nutritional care in the treatment and rehabilitation of patients. Why is there a lack of knowledge on appropriate rehabilitation after significant ICU stays, such as those of critically ill COVID-19 patients? The focus is often on helping patients whether it is through the acute phase of critical illness, for healthcare professionals like myself, as well as the patient and their family, it is a huge relief when they can be discharged. The long-term impact of their stay in intensive care is sometimes underestimated though, which might impact how well rehabilitation requirements are understood. What complications are being seen in COVID-19 patients that are leading to long recovery periods? The care for critically ill COVID 19 patients is similar to that for patients diagnosed with viral pneumonia-causing respiratory failure. What is different though, is that critically ill COVID-19 patients are often admitted to ICUs for a very long time, extending up to 2-3 weeks. We know from other patient groups in ICUs who require intubation, that oral nutrition intake can be inadequate after extubation. People might not be able to eat enough food to meet their nutritional needs during recovery, contributing to further loss of lean muscle – which could occur in ICU at the rate of up to 1kg per day. Muscle wasting is the most common complication of critical illness, occurring in up to 50% of patients, which can seriously lengthen recovery times, impaired immunity, increase infection risk and cause the development of wounds and pressure ulcers. For some, even mortality. In the early days of the pandemic, most of the patients quickly deteriorated, meaning they required immediate respiratory assistance. So, most stopped eating as soon as they were admitted to the hospital and they were also unable to tolerate oral nutrition support. As the pandemic has progressed, we are increasingly seeing very elderly patients and those suffering from underlying health conditions, like obesity and diabetes. For these patient groups, nutrition is extremely complex. It is difficult to keep these patients in a stable condition, and what makes the difference in this balance is appropriate and timely nutrition support. How could appropriate nutrition improve recovery? Being discharged from the ICU is only the start of a recovery, and medical nutrition when integrated in patient recovery programs can positively impact recovery outcomes, as well as the quality of life of patients. We already know that medical nutrition can positively contribute to clinical outcomes with a variety of conditions and diseases. Unfortunately, healthcare professional awareness of the role of medical nutrition is still low. There is little practical clinical guidance for nutritional care during recovery of COVID-19, even though it can impact recovery time and people’s ability to return to doing the things that matter most to them. I hope the research will contribute to the development of such guidance. How could your research be used to provide successful in-hospital rehabilitation programs? Challenges exist in integrating nutrition into treatment and recovery plans in most diseases. It might seem obvious, but unfortunately, nutrition is still widely overlooked in the hospital setting. Generally speaking, it is much easier to integrate nutrition into a recovery plan. In the experience of COVID-19, the virus is disproportionately affecting the fragile elderly and those who are overweight or obese with diabetes and hypertension. These are two very different population groups, but what links them is the need for nutritional intervention. For those who have spent a significant length of time in ICU and on ventilators, we can already see the positive results when nutrition is part of both a patient’s treatment and recovery plan. I think our experience can really help in making nutrition a greater medical priority, for both in-hospital rehabilitation and in post-discharge community recovery. What do you expect will be needed in terms of longer-term care for patients who have been critically ill from COVID? What we have been experiencing is that when nutritional support is implemented in the early stages of any pathological condition treatment, including COVID19, it can make a real difference to patient recovery time. Nutrition is vital for maintaining skeletal muscle and avoiding metabolic disturbances – when patients are spending around two weeks in ICU, these can become very serious issues. Respiratory difficulties add an extra layer of complexity, preventing patients from eating effectively. A huge proportion of the patients we treated required assisted ventilation, making it difficult to provide food and oral supplements. When thinking longer-term, what is needed is for nutrition to become more of a medical priority so that it is part of the treatment and recovery program, not just the latter. What is your advice for people recuperating from less serious COVID-19 cases for a quick and safe recovery? It is important people recovering from less severe COVID-19 infections take the time to recover, rest, and eat well, which means to be conscious that adequate eating is part of their recovery not to be overlooked. From a nutritional standpoint, how has this virus and its aftermath compared to other illnesses you work with? We know that for many other diseases and conditions nutrition plays a vital role in patient recovery and health. While the scale and impact of the COVID-19 pandemic has been unprecedented and our understanding of the disease is developing, there are many elements of how it affects patients that are similar to other conditions, like lung infections and, more generally inflammatory diseases. If nutritional care is integrated in their recovery programs it can certainly positively impact clinical outcomes as well as the quality of life of patients. Do you think your research will improve awareness of the importance of applying nutritional knowledge to dealing with viruses and their recovery in general? Nutrition is critical for reducing the burden of comorbidities. This is a burden we must have control over in general, but in the case of COVID-19, we are still not sure whether there will be a second wave of the virus. Our preliminary analysis clearly shows that the majority of patients admitted with COVID-19 have a vitamin D deficiency. It is of course too early to speculate whether this could be a reason why patients suffer particularly badly from the effects of the virus. But we do know that Vitamin D levels are important for general health. Biochemical and epidemiological background tells us that Vitamin D deficiency is associated with the incidence of some cancers and cardiovascular diseases, for example. So, I hope that COVID-19 and that research, such as my own and the other studies, are seen and taken as our chance to develop a well-designed preventive campaign that puts nutrition and tailored vitamin supplementation at the core of preventative medicine. Could your research be used to help deal with future pandemics effectively? Yes, definitely. Discharge from the intensive care unit is often only the start of patient recovery. The longer a patient has been required to remain in ICU the greater the need for medical nutrition in their recovery plan. If through the experience of COVID-19, we can implement practical clinical guidelines for nutritional care, then I am certain it will help us be more prepared for the full care journey from diagnosis to complete recovery (where possible) in future pandemics. The lessons we learn here will accelerate our ability to respond to future outbreaks of both known and novel diseases. What is the next step for your research? We are coordinating an Italian multicentre study to research the impact of nutritional status and in-hospital nutritional support on the outcomes of the two most impacted patient groups – the elderly and those who were overweight or obese at admission. It is a simple observational study in which we will collect nutritional information in about 11 hospitals across Italy. The study uses data collected in ‘normal’ clinical routine, such as blood tests, BMI, details of nutritional support provided as part of a treatment plan, and of course the clinical outcomes of each patient. We have already received early data from the study, and I am confident we will have a pretty good idea of medical nutrition’s impact on patient outcomes in a relatively short period. To read the original article click here.

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