CMAAO Coronavirus Facts and Myth Buster: COVID Drugs Update

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With inputs from Dr Monica Vasudev

1002: Drug treatment – Remdesivir: The much sought-after results from the National Institute of Allergy and Infectious Diseases clinical trial of remdesivir, published in May, confirmed preliminary findings indicating that the drug reduces the disease course for hospitalized COVID-19 patients. The US Food and Drug Administration (FDA) issued an emergency use authorization for the drug. Drugmaker Gilead came out with results from the sponsored, randomized phase 3 SIMPLE trial, which suggested that a 5-day course of the drug led to improved outcomes among patients hospitalized with COVID-19 who did not require ventilation.

According to the National Institutes of Health, the most benefit was seen in patients on oxygen who did not require ventilation.

Dutch investigators; however, warned that the drug can be associated with rare but severe liver complications.

Take home message: Remdesivir is administered intravenously, thus restricting its use to hospitalized patients. Phase 1 trials of an inhaled nebulized version were started in late June 2020 to ascertain if remdesivir can be used on an outpatient basis and at earlier stages of disease.

The FDA has cautioned against use of the drug in combination with hydroxychloroquine (HCQ).

Dexamethasone

British researchers stated that the RECOVERY trial with more than 6000 patients had been stopped early owing to positive results. Dexamethasone was shown to reduce death rate by about one-third among severely ill hospitalized COVID-19 patients. There was a mixed reaction in the United States initially.

Some clinicians suggested that the results confirmed their own experience, while others were wary of embracing the study results prior to peer review.

The Infectious Diseases Society of America (IDSA) announced that the drug will be included in the COVID-19 treatment guidelines. Dexamethasone, or an equivalent steroid such as methylprednisolone or prednisone, is recommended for hospitalized patients requiring supplemental oxygen, mechanical ventilation, or extracorporeal mechanical oxygenation.

Take home message: Corticosteroids are not generally recommended for the treatment of COVID-19 or any viral pneumonia; however, the UK RECOVERY trial changed that. IDSA guidelines include low-dose dexamethasone (6 mg orally or intravenously daily for 10 days) in patients requiring respiratory support. The World Health Organization has warned clinicians to reserve the use for severely ill patients.

Hydroxychloroquine

As per, initial data, HCQ and chloroquine, sometimes in combination with azithromycin, had some level of efficacy in COVID-19 patients. However, newer data from observational trials soon followed, pointing that the drugs had no benefit and could also be dangerous for some patients. Following 2 months of controversy, the FDA revoked the emergency use authorization it had granted for use of these agents in inpatients.

In early July, the Henry Ford Hospital came out with the results of a retrospective, observational trial of HCQ with azithromycin that revealed that the combination, if given within the first 2 days of hospital admission, reduced COVID-19 mortality.

Trials of HCQ as preventive therapy are underway. A randomized trial published in early June noted that the drug was ineffective as prevention and the side effects were common.

Take home message: While some still promote its benefit, especially if given early in the course of infection, there is little evidence to support its use at any stage of illness.

Other Antimicrobials

Azithromycin. Some initial trials of azithromycin in combination with HCQ showed promise, but later results have not held up and major cardiology organizations have cautioned against the combination. There are no recommendations for use of azithromycin.

Antiviral agents. The UK-based RECOVERY trial looked into other drugs besides dexamethasone, and noted that the combination of lopinavir and ritonavir was not beneficial in hospitalized patients. A Japanese trial of favipiravir revealed that patients receiving the drug early in the trial had more improvement as compared to those given delayed doses; however, the results did not reach statistical significance.

Other Drugs

Convalescent plasma. A very small Chinese pilot study reported in April that its use in severely ill COVID-19 patients led to a rise in antibody titers, reduction in viral load, and improved the symptoms. Other studies have not yet shown it to be effective. The FDA has approved its use in patients with serious or immediately life-threatening infection.

Colchicine. An undergoing open-label, randomized trial in Greece has suggested that hospital course was slightly shorter and the time to clinical deterioration improved in patients treated with colchicine. There appeared to be no significant differences between treated and untreated groups in cardiac and inflammatory biomarkers.

Nitric oxide. In 2004, the role of inhaled nitric oxide was assessed as a supportive measure for patients with SARS-CoV-1. It reversed pulmonary hypertension, improved severe hypoxia, and decreased the length of ventilatory support. A phase 2 study is ongoing in patients with COVID-19, aimed at preventing disease progression in those with severe acute respiratory distress syndrome.

Zinc. Initial trials of HCQ often evaluated the drug in combination with azithromycin and zinc. Some studies pointed that zinc may be somewhat effective in treatment of upper respiratory infections, some of which are caused by coronaviruses; however, the National Academies of Sciences, Engineering, and Medicine warned that there is no evidence to suggest that it has a role in the treatment or prevention of COVID-19.

Monoclonal antibodies. Human antibodies are being investigated across the world. Eli Lilly has come out with positive interim results of its trials of monoclonal antibodies, and expects FDA review and possible approval by September. European trials of another antibody could begin soon. Trials of a third agent are expected to start in August in Singapore.

[Medscape Excerpts]

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA

Every Breath You Take…

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Reproduced from: India Legal, https://www.indialegallive.com/special-story/every-breath-you-takepublished July 6, 2020

The need of the hour during the Covid-19 pandemic is a medical oxygen plant that can replace oxygen cylinders. This will avert India’s oxygen shortage crisis and help those with lung problems

Covid-19 is here to stay. Even as it subsumes all countries, its insidious way of entering the body has set alarm bells ringing. However, new forms of supplying oxygen to patients have given a ray of hope.

One of the fallouts of the virus is silent hypoxia or walking dead—a condition where the person develops low blood oxygen levels but is conscious and has no confusion or altered consciousness. This silent hypoxia, if not treated in time, can end in cellular and organ hypoxia, leading to multi-organ failure. In some cases, hypoxia is associated with inflammation of the body, leading to a hyper-immune inflammatory condition. In others, it leads to clots in all the smaller and larger vessels of the body. In a few patients, it develops a massive cytokine storm, leading to pulmonary and multi-system failure at the same time. But some 80 percent of Covid-19 patients require no treatment and become alright just by simple observation.

Timely detection of silent ischaemia can save lives. Starting oxygen early, giving low molecular weight heparin, a blood thinner, and giving early antiviral drugs at the time of detecting low oxygen levels can save lives. It would be a good idea for every family to buy an oxygen monitor to detect early fall of oxygen, defined as a limit lower than 92. It is believed that India has the lowest Covid-19 mortality in the world and that is due to the early detection of silent hypoxia.

But the 15 percent who get affected, require timely oxygen and only 5 percent of them require ventilation. Out of these, 15 percent can be treated with simple oxygen. In young and healthy patients, oxygen treatment can be started at home or in smaller hospitals through oxygen cylinders or making oxygen available at home.

Portable oxygen concentrators is one option and another is a medical oxygen plant. Absstem, a company supplying oxygen generators, can replace oxygen cylinders with a self-generating oxygen plant. This is a revolutionary measure to avert India’s oxygen shortage crisis during Covid times and will go a long way in reshaping our healthcare industry.

This can give hospitals continuous, affordable and contactless supply of oxygen. Earlier, oxygen cylinders or liquid oxygen were used, which is expensive, time-consuming and requires physical contact. The medical oxygen generator uses electricity to produce oxygen from atmospheric air for the entire hospital. But an oxygen concentrator is a device that concentrates the oxygen from a gas supply (typically ambient air) by selectively removing nitrogen to supply an oxygen-enriched gas.

Most medical oxygen generators work on the principle of pressure swing adsorption, widely termed as PSA. This conventional gas separation technology is being used to separate oxygen from compressed air. The major components are a pair of adsorbent vessels, surge tank, switching valves, intelligent PLC, oxygen analyser and instruments. The adsorbent vessels, filled with Zeolite (crystalline structures made of silicon, aluminium and oxygen) adsorb nitrogen and carbon dioxide, whereas oxygen is not adsorbed due to its larger molecular size and passes through the adsorber to the surge tank.

Early oxygen therapy can save lives and serious patients may require oxygen for days together. Imagine a situation where a large number of people require oxygen and hospitals are overloaded. This is what happened in Italy. There were not enough oxygen cylinders for patients to have oxygen therapy at home or in the hospital.

It would be a good idea during the pandemic for everyone to buy an oxygen monitor. Every family should have an oxygen generator or concentrator which can give oxygen supply of at least five litres per minute at home and 10 litres per minute in hospital settings. All hospitals must have, apart from a central oxygen supply unit, an oxygen generation machine. In the long run, these plants will be cheaper, cost-effective and reduce the cost of treatment. With modern oxygen generators, entire hospitals can run on their supply.

Some patients require long-term oxygen therapy. The indications for this are chronic lung disease, including a pulse oxygen saturation (SpO2) less than or equal to 88 percent. Many patients can be cured by using oxygen concentrators and prone positioning. In two recent studies, self-proning was associated with improved oxygenation parameters in at least two-thirds of adults with Covid-19.

Even hospitalised patients with Covid-19 should spend as much time as is feasible and safe in the prone position while receiving oxygen or non-invasive modalities of support such as high-flow oxygen delivered via a nasal cannulae or non-invasive ventilation. The WHO suggests titrating oxygen to SpO2 greater than 90 percent. For most critically-ill patients, targeting an SpO2 between 90-96 is feasible. Higher flows of oxygen may be administered using a simple face mask, venturi face mask or non-rebreather mask, but as the flow increases, the risk of dispersion also increases, increasing contamination of surrounding environment and staff. All these situations can be handled by portable oxygen concentrators (POCs) or oxygen generators in hospitals.

Portable generators make use of improved battery technology and the size and power of pumps and motors provide lightweight, battery-powered oxygen concentration. POCs are smaller than oxygen concentrators designed for home use and are battery operated instead of being continuously plugged into an electrical socket. Battery lives range from 2.5 to 8 hours. Additional batteries can extend the time that a patient can de­pend on it for oxygen supply. POCs vary in oxygen flow.

The weight and size of oxygen concentrators is partly determined by the flow requirement of the patient. While a standard oxygen concentrator weighs 16 to 23 kg, several POCs have been developed that weigh between 2.3 and 8.2 kg. As they generally deliver oxygen via pulsing, there could be a lack of delivery during sleep if the patient resorts to mouth breathing and does not trigger the pulse.

Using an oxygen-conserving device in conjunction with the concentrator enables adequate oxygen delivery at lower flows. Most POCs have an integrated conserver, which may not be ideal for patients who require a higher flow rate. However, some larger units provide continuous oxygen delivery options. Investing in such devices may help save a stitch in time.

Dr KK Aggarwal

President CMAAO and Past National President IMA

CMAAO Coronavirus Facts and Myth Buster: Around the globe

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With inputs from Dr Monica Vasudev

986:  COVID-19 patients have been found to have 27 times higher likelihood than others to have lost their sense of smell. However, they had merely 2.6-fold higher odds of having fever or chills. So then, why are we measuring the temperature as a detection method for asymptomatic COVID-19? Why not measure the smell and taste as the screening method.

987: How Does Antigen Test Work: First category of COVID-19 tests includes RT-PCR, TrueNat, CBNAAT and Antigen test. These tests tend to detect the virus in the body. The second category, the serologic test, is meant to detect antibodies that are produced in the body to protect it against the virus.

Antigen is a substance, or a part of the virus, which triggers an immune response. Presence of an antigen in the nasal or throat swab indicates that the person is infected.

The RT-PCR test involves several steps and yields results within five to six hours. An antigen test, on the other hand, provides results within 30 minutes. An antigen test costs Rs 450 while an RT-PCR costs Rs 2,400.

Several companies have approached ICMR to obtain approval for their antigen test kit; however only one company, SD Biosensor, has received approval, which manufactures Standard Q COVID-19 Ag kit.

An ICMR study has revealed that Standard Q COVID-19 Ag kit can detect an uninfected person as negative in almost 100%. However, it can diagnose only 50% infected persons as positive.

What does it mean? It means that if out of 100 people, 90 are uninfected, and 10 are infected, the test can detect five as positive and rest all as negative. So, while 90 are truly negative, five are false negative.

Because of this, all 95 should undergo RT-PCR test according to experts. ICMR; however, is of the opinion that only those who have COVID-19 symptoms but are diagnosed as negative in antigen test should go for RT-PCR test.

It would be preferable to also identify asymptomatic false negatives as they can potentially spread the disease being unaware that they are positive. (Source: Outlook India)

988: ICMR has got the Tamil Nadu governments approval to investigate the efficacy of the Bacillus Calmette- Gurin (BCG) vaccine in senior citizens in the fight against COVID-19, at its National Institute for Research in Tuberculosis (NIRT).

989: A decreased lymphocyte count in people coming to the hospital with COVID-19 could assist physicians in identifying those at higher risk for intensive care unit (ICU) admission. Patients with lymphocytopenia were found to have a more than 3-times higher risk for requiring ICU care compared with people with normal lymphocyte counts at the time of admission. Acute kidney injury (AKI) also appeared to be more common among people with low absolute lymphocyte counts.

This study shows that an absolute lymphocyte count <1000 at admission is associated with ICU admission and organ damage. [July 10 International Journal of Laboratory Hematology]

990: Moderna Vaccine Produces Immune Response in Patients

Every person given Modernas COVID-19 vaccine, mRNA-1273, was found to develop an immune response to the virus that causes it. However, some side effects were reported in the 45 people in the phase I study, but there were no significant safety issues. The vaccine resulted in a robust immune response.

Testing of the vaccine is underway in a larger group of people in a phase II trial. Phase III trials are expected to begin in late July. Phase III trials will test the vaccine on an even larger group and are the final step before FDA approval.

The results from the study, led by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, are published in The New England Journal of Medicine.

Modernas vaccine uses messenger RNA, or the mRNA. It carries the instruction for making the spike protein. This is a key protein on the virus surface that allows it to enter the cells when a person is infected. After being injected, it goes to the immune cells and instructs them to make copies of the spike protein, acting as if the cells have been infected with the actual coronavirus. Other immune cells thus develop immunity.

The study divided the participants into three groups of 15 people each. All participants were given two vaccinations 28 days apart; however, each group received a different strength of the vaccine —25, 100, or 250 micrograms.

Every participant developed antibodies that have the potential to block the infection. Side effects following the second vaccination in the 100-microgram group included fatigue, chills, headache, and muscle pains, ranging from mild to moderately severe.

The phase II study includes 300 heathy adults 18-55 years of age, along with another 300 people aged 55 and older. The company says that it hopes to include nearly 30,000 participants at the 100-microgram dose level in the U.S. for the phase III trial. The estimated date of initiation is July 27. [N Engl J Med. July 14, 2020.]

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA

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