Thursday, June 30, 2022

Covid Links

  • A few years ago my mother had a stroke and was in ICU. After discharge she went to a convalescent hospital for a few weeks. The food there was appalling. Sugar and cheap carbs everywhere. Imagine oatmeal with maple syrup and a glass of OJ for breakfast. So I requested a meeting with the lead dietitian. I told her that I wanted my mother to get bacon and eggs for breakfast, and none of that sugary stuff. Meat or eggs at every meal. She looked at me like I was from Mars, but ultimately she complied. Meanwhile, twice a day I brought my mother a whey protein drink I devised, giving her an extra 30-50 g/d protein, plus some NAC and magnesium and creatine. My mother is still alive today at 99, and probably would not be if she continued eating hospital style. It's within your power to change this stuff. Raise a big stink. The life of someone you love may depend on it. When my mother was in ICU in a prestigious, big-city hospital, the doctor in charge of her care called me on the phone. "What do you want to do if her heart or breathing stops?" We discussed this. My mother was in her mid 90s, but had been active and giving music lessons up until the week before. I knew she wasn't ready to leave this earth. I told him this. A few days later, another doctor called with the same question, evidently having failed to get the message. Now I was pissed off. I had the distinct impression that these doctors were more concerned about a "do not resuscitate" order than caring for my mother. Due to her age, it seemed they were ready to write her off. I told the doctor, "DO YOUR JOB. DON'T LET HER HEART STOP." Maybe I was unfair to the doctor, but someone had to say it. Don't take medical treatment of a loved one for granted. Don't be reluctant to get involved. No one cares as much for your family members as you do. [P.D. Mangan]
  • The research team, led by senior author Davey M. Smith, MD, chief of Infectious Diseases and Global Public Health at UC San Diego School of Medicine and infectious disease specialist at UC San Diego Health, set out to better understand the causes of COVID-19 rebound following Paxlovid treatment. They first isolated the SARS-CoV-2 BA.2 virus from a COVID-19 rebound patient and tested whether it had developed any drug resistance. They found that after Paxlovid treatment, the virus was still sensitive to the drug and showed no relevant mutations that would reduce the drug’s effectiveness. “Our main concern was that the coronavirus might be developing resistance to Paxlovid, so to find that was not the case was a huge relief,” said first author Aaron F. Carlin, MD, PhD, assistant professor at UC San Diego School of Medicine. The team next sampled the patient’s plasma to test their immunity against SARS-CoV-2. The patient’s antibodies were still effective at blocking the virus from entering and infecting new cells, suggesting that a lack of antibody-mediated immunity was also not the cause of the patient’s recurring symptoms. The authors said the rebound of COVID-19 symptoms following the end of Paxlovid treatment is likely due to insufficient drug exposure: not enough of the drug was getting to infected cells to stop all viral replication. They suggested this may be due to the drug being metabolized more quickly in some individuals or that the drug needs to be delivered over a longer treatment duration. [UCSD]
  • Melatonin has anti-inflammatory, antioxidant, immunomodulating and metabolic effects that are likely important in the mitigation of COVID-19 disease. Multiple studies have demonstrated the benefit of melatonin at various stages of the disease. A large retrospective study demonstrated that the use of melatonin in intubated patients with COVID-19 significantly reduced the risk of death (HR 0.1; p<0.0001). It is intriguing to recognize that bats, the natural reservoir of coronavirus, have exceptionally high levels of melatonin, which may protect these animals from developing symptomatic disease. Similarly, children have high levels of circulating melatonin approximating those of bats, while elderly people — particularly those over the age of 60 — have very low melatonin levels; this may partly explain the increased vulnerability of the elderly to COVID-19. [covid19criticalcare]
  • Six studies were identified which showed that curcumin supplementation led to a significant decrease in common symptoms, duration of hospitalization and deaths. In addition, all of these studies showed that the intervention led to amelioration of cytokine storm effects thought to be a driving force in severe COVID-19 cases. This was seen as a significant (p < 0.05) decrease in proinflammatory cytokines such as IL1β and IL6, with a concomitant significant (p < 0.05) increase in anti-inflammatory cytokines, including IL-10, IL-35 and TGF-α. Taken together, these findings suggested that curcumin exerts its beneficial effects through at least partial restoration of pro-inflammatory/anti-inflammatory balance. [NLM]
  • We reported the preliminary results of the DisCoVeRy trial regarding the efficacy and safety of remdesivir in hospitalised patients with COVID-19 in February, 2022. Remdesivir did not have a clinical or virological benefit in the studied population. Notably, the number of patients included was lower than initially expected, because inclusions in this trial group were prematurely stopped by the data and safety monitoring board. [The Lancet]
  • On Day 10, NAC therapy led to significant improvement in SpO2/FiO2 compared to the controls. Furthermore, NAC administration markedly decreased the values of CRP and NEWS2 scale in comparison to the control group. Duration of hospitalization was also significantly shorter in the NAC group (p = 0.01). All other clinical outcomes (transfer to ICU, need for non-invasive or invasive mechanical ventilation, and 28-day mortality) did not differ between the groups. There were no cases of adverse events leading to NAC discontinuation. [Journal of Infection]
  • Endogenous glutathione deficiency appears to be a crucial factor enhancing SARS-CoV-2-induced oxidative damage of the lung and, as a result, leads to serious manifestations, such as acute respiratory distress syndrome, multiorgan failure, and death in COVID-19 patients. When the antiviral activity of GSH is taken into account, individuals with glutathione deficiency seem to have a higher susceptibility for uncontrolled replication of SARS-CoV-2 virus and thereby suffer from an increasing viral load. The severity of clinical manifestations in COVID-19 patients is apparently determined by the degree of impaired redox homeostasis attributable to the deficiency of reduced glutathione and increased ROS production. This assumption can be supported by our findings. In particular, COVID-19 patients with moderate and severe illness had lower levels of glutathione, higher ROS levels, and greater redox status (ROS/GSH ratio) than COVID-19 patients with a mild illness. Long-term and severe manifestations of COVID-19 infection in one of our patients with marked glutathione deficiency suggest that the degree of glutathione decrease correlates negatively with viral replication rate and that an increasing viral load exacerbates oxidative damage of the lung. This finding suggests that the virus cannot actively replicate at higher levels of cellular glutathione, and therefore, milder clinical symptoms are observed with lower viral loads. Glutathione deficiency is an acquired condition attributable to decreased biosynthesis and/or increased depletion of the endogenous GSH pool influenced by risk factors such as aging, male sex, comorbidity, and smoking alone or in combinations. Glutathione deficiency in COVID-19 patients with serious illness may also be a result of decreased consumption of fresh vegetables and fruits (especially during winter and spring seasons), which contributes to over 50% of dietary glutathione intake.The hypothesis suggests that SARS-CoV-2 virus poses a danger only for people with endogenous glutathione deficiency, regardless which of the factors aging, chronic disease comorbidity, smoking or some others were responsible for this deficit. The hypothesis provides novel insights into the etiology and mechanisms responsible for serious manifestations of COVID-19 infection and justifies promising opportunities for effective treatment and prevention of the illness through glutathione recovering with N-acetylcysteine and reduced glutathione. Since the antiviral effect of glutathione is nonspecific, there is reason to believe that glutathione is also active against SARS-CoV-2. Therefore, restoration of glutathione levels in COVID-19 patients would be a promising approach for the management of the novel coronavirus SARS-CoV-2. Notably, long-term oral administration of N-acetylcysteine has already been tested as an effective preventive measure against respiratory viral infections. (1) N-Acetylcysteine is widely available, safe, and cheap and could be used in an “off-label” manner. Moreover, parenteral injection of NAC or reduced glutathione (GSH is more bioavailable than NAC) could be an efficient therapy for COVID-19 patients with serious illness. Horowitz et al. (18) just published a paper confirming this hypothesis: the authors reported the efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia. [ACS Infectious Diseases]
  • A major driver of hypoxemia in COVID-19 appears to be atelectasis. Once this begins happening, it may become a vicious spiral wherein lung architecture is distorted by collapsed alveoli – making it harder for neighboring alveoli to stay open. Lung recruitment may be achieved in one of two ways: Prone positioning or varying positions (e.g., from side to side) helps recruit the non-dependent lung tissue. Positive airway pressure (e.g., CPAP or BiPAP) directly promotes alveolar inflation. [Internet Book of Critical Care (IBCC) / Management of COVID-19 patients admitted to stepdown or ICU]
  • N-acetylcysteine (NAC), an analogue and precursor of reduced glutathione, has been in clinical use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% > or = 65 yrs, and 62% suffering from nonrespiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centres. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease. [NLM]


CP said...

We noted a numerical gap in oxygen saturation, which we have called the ‘sats gap’, between different levels of inspired oxygen. This is initially best illustrated through a single case study. A 73-year-old woman (patient C in Table 1), with reasonably controlled type 2 diabetes, hypertension and chronic kidney disease, was admitted to a district hospital with COVID pneumonia, requiring 15 L/min oxygen through a non-rebreather mask for 20 days. Thereafter she was transferred to the Mitchells Plain Hospital of Hope on nasal prongs oxygen, where she required <5 L/min oxygen for a further 33 days. She had no history of smoking, and was fully mobile prior to admission. In addition to her diabetes and hypertensive medications and routine enoxaparin sodium, she was given 40 mg prednisone daily for 4 weeks, followed by a short course of 60 mg daily for 5 days. She was discharged home with an oxygen saturation of 90% on room air, without home oxygen. The graph of the patient’s oxygen saturation readings in the first 2 weeks of her admission to intermediate care (Fig. 1) clearly shows the ‘sats gap 1’ between room air and low-flow oxygen, as well as the ‘sats gap 2’ between exertion and low-flow oxygen.

We present a series of 12 patients who conformed to the above definition (Table 1). They are ranked according to the total length of stay in hospital. The average age of the patients was 62 years, with 8 out of the 12 being female. One was an ex-smoker, 8 had hypertension, and half had diabetes. The longest total hospital stay was 69 days, 42 at intermediate-care level. The recovery period was on average longer than the acute stage of illness (24 v. 18 days, respectively). Five of the 12 had had high-flow nasal oxygen (HFNO). Two were discharged on home oxygen and the rest on room air, with 5 of the 12 having saturation levels <90%. All received steroids for various lengths of time, with 3 being given lengthy prescriptions on discharge.

We observed that the following patterns related to recovery occurred commonly:

• The sats gap between low-flow oxygen and room air often remained static for an extended period of time, sometimes several weeks, after the acute stage was over (i.e. after week 2).
• The sats gap between room air at rest and room air after exertion often showed the most variability, and seemed to be a sensitive indicator of recovery.
• The length of time that the patient required post-exertion for their sats to return to baseline on room air gave us a more sensitive indicator of recovery. It was often the only indicator that showed any change from day to day, while the sats gaps remained static.
• Indicators of the functional capacity of the patient, e.g. the distance that they were able to walk off oxygen, the activities they were able to do, and the length of time that they felt comfortable off oxygen, were slightly more subjective but also useful signs of recovery. The ‘40 step test’ was introduced as a means of standardising the level of exertion for the purposes of comparison, even though it has not been validated.
• After 2 weeks of static indicators, having excluded other causes, we accepted a new baseline of oxygen saturation, even <90%, and sent the patient home.

We often noted a persistent tachycardia of >100/min for which there was no obvious cause other than recovery from the pneumonia.

CP said...

When you are sick with a potentially fatal disease, it's hard to do research yourself because:

A. You are sick.
B. You never heard of this problem before.
C. Most of what you read is really depressing and makes you want to give up.

In a crisis it, can help to have competent assistance beyond the standard. For example, when I was diagnosed with non-Hodgkins lymphatic cancer in 1996, I hired a general purpose oncologist as a consultant to help me decide among the Chicago area's 3 NHL specialists. Because I happened to have high speed Internet at work more than a quarter of a century ago, I myself found the clinical trial soon opening up in the region for Rituxan, which turned out to be the first blockbuster monoclonal antibody, but my consultant then told me to do whatever it took to get into that trial. And my wife, who knows a lot about medicine, insisted upon getting a second and third radiologists' opinions on exactly what type of NHL had, which turned out to be life-saving.

Steve Sailer

CP said...

One recent trial studied 354 patients undergoing primary angioplasty for acute myocardial infarction. Patients were randomized to placebo, standard-dose N-acetylcysteine (600-mg bolus intravenously before angioplasty, followed by 600 mg orally twice daily for four days), or to double-dose N-acetylcysteine (1,200-mg bolus intravenously, followed by 1,200 mg orally twice daily for four days). Patients in the N-acetylcysteine groups had marked dose-dependent reductions of contrast-induced nephropathy (35 percent in the control group, 15 percent in the standard-dose N-acetylcysteine group, and 8 percent in the high-dose N-acetylcysteine group [ P < .0001]). In addition, in-hospital mortality was markedly reduced by N-acetylcysteine (P = .03), as was the combined end point of death, acute renal failure requiring dialysis, and the need for mechanical ventilation during the acute phase of myocardial infarction (P = .002).16 This protocol (Table 116) is the only one to date showing a mortality benefit.