Medicosnext
This is a summary of the webinar presentation by Dr. Daniel Griffin, MD, PhD, on April 10, 2021, hosted by Dr. Bishal Bhandari, Dr. Roshan Lal Shrestha, Dr. Digvijay Raja Mahat, and Dr. Sargam Raja Mahat in the USA. The presentation, Dr. Griffin says, offers a way of looking and understanding the stages of COVID-19 that was a collaboration of dozens of physicians, scientists, and clinicians through out the world.
Dr. Griffin is Chief of the Division of Infectious Diseases at ProHealth Care and President of Parasites Without Borders, and Associate Research Scientist in the Department of Biochemistry and Molecular Biophysics at Columbia University. He recently co-authored the America Society of Hematology ASH 2021 Guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19 and the importance of understanding the stages of COVID-19 in the treatment and trials that have tremendously helped clinicians worldwide.
In the presentation, he talks about the three periods and five phases comprising the stages of COVID-19 and the importance of using therapeutics in the appropriate phase for better management of patients.
Timing, Dr. Griffin says, is very critical in the treatment of COVID-19 and a lot of times when something didn’t work it might have been used at the wrong time and in the wrong patient.
The three periods of COVID-19, he says, are: 1) Pre-exposure period: a period before a person has been exposed to someone with SARS CoV-2, (2) Incubation period: a period from the time of exposure until the virus is detected, and 3) Detectable viral replication period: it starts at the time when the virus is detected, and it also kick-starts the clinical phase.
The clinical phases are: 1) Viral Symptom Phase, 2) Early Inflammatory Phase, 3) Secondary Infection Phase, 4) Multisystem Inflammatory Phase, and 5) Tail Phase.
The pre-exposure period, he says, is a good time for vaccination. The risk of spreading the infection is further minimized by wearing a properly fitted mask, maintaining physical distance, limiting the size of gatherings, and frequently washing hands. The first three feet gives us about 80 percent reduction of risks, and going up to six feet gives 90 percent protection, and meeting people outdoors is about 20 times safer, he informs. The highest significant risk is when you are within six feet of an individual for 15 minutes continuous or cumulative, and when people are not wearing masks and they are indoors.
In the incubation or post exposure period, he says he would want to reinforce that a test doesn’t predict the future. One can go on to develop symptoms and test positive at any time in the next 2 to 14 days, and not everyone who tests positive and spreads the virus ever has any symptoms. A negative test at day 2 doesn’t tell what will happen at day 13 or day 14, so the biggest thing one can do in this period is to avoid harm and have a plan about what if the person turns positive and goes into the next phase.
First Week: Period of detectable viral infection replication/ viral symptom phase
When one moves on from the detectable viral infection period, a person might first start to have symptoms, or they might get their first positive test. “In the US we are emphasizing a lot on educating the public and physicians about passive vaccination to treat people during the first week,” says Dr. Griffin.
“We are giving a couple of cocktails like bamlanivimab/etesevimab from Eli Lily that have really high concentration to patients. When given within the first 7-10 days, we saw progress in about 87 percent of people, who reported feeling better in about 36 to 48 hours,” he informs, adding that in the case of regeneron cocktail, “We are using casirivimab and imdevimab, which, too, benefited 70 percent of people when introduced in the first 10 days.” He says that they are using the cocktails because of the variants.
In the recent update, on April 16, 2021, the U.S. Food and Drug Administration (FDA), however, revoked bamlanivimab’s solo emergency use authorization for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg). It can now only be used in combination with etesevimab because they saw much-reduced efficacy against the variants with just bamlanivimab.
In places where these expensive monoclonals are not available, Dr. Griffin says studies are being conducted on serum or convalescent plasma. He says that patients fared better if they received the plasma in the first three days. The Brazilian Clinical Trial also showed that the treatment was safe if applied in the first 10 days after the onset of symptoms. There are, however, some quality and other challenges in these products, he adds.
Regarding anti-viral therapy, he says remdesivir is widely used in the US, but there is really only about one study that showed much benefit. “It’s not something your patients miraculously get better. There may be a subtle shortening of the hospital stay, but it is not as impressive an anti-viral therapy as we all were hoping it would be. There are other products that are coming up, and we are expecting to hear preliminary date on Merck’s products in the coming weeks.”
He suggests that using NSAIDs really helps us at this time. “Though when we first started having cases of COVID-19, there was a communication out of France suggesting the use of pain relievers or anything to help with fevers, such as acetaminophen, ibuprofen, and naproxen, particularly the non-steroidal non-inflammatory drugs, could do potential harm to patients.”
But, fortunately, there was a study on the use of NSAIDs and risk of death from COVID-19: an open SAFELY cohort analysis based on two cohorts. The study compared over half a million current NSAID users to almost a million non-users in the general population and found no evidence of difference in the risk of COVID-19 related death associated with the current use (HR 0.96, 95 % Cl 0 .80to 1.140). “So, I think it really helps us. It can be miserable to have COVID, particularly during the first week, and then it can make a huge difference to be able to offer these therapies to our patients.”
Second Week: Early Inflammatory Phase
Immune modulation
In the early inflammatory phase, he says, they are using steroids based upon certain criteria. They are using it in individuals who are hypoxic, or if the patient’s oxygen level starts to drop below 94 percent. He says that the study on dexamethasone in hospitalized patients with COVID-19 by the RECOVERY Collaborate Group, published in February on NEJM, is one of the most influential studies encouraging people to use steroids. According to the RECOVERY trial, treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days showed a decline in 28-day mortality in patients with COVID-19 who are receiving respiratory support.
But, it is not advisable to use steroid in the first week, as the evidence suggests it would actually do more harm than good, he informs. He also cautions against giving steroids to people if they seem to be doing fine and breathing well, even if they are in the second week. Steroids, he says, give only about two percent mortality benefit, and it should be given to the right patient at the right time. It usually makes the most difference in the mechanically ventilated and the sickest patients. But, it is just a subtle difference. One must also be wary about the steroid psychosis and other risk of infections. In the presence of other parasitic co-infections, we are talking about 10 days in the right person, he adds.
The other drug that they are using in the US is tocilizumab that targets the interlukin- 6(IL-6) pathway. “Adding this to the right patient at the right time can give you about four percent of additional mortality benefit. But, it’s not the majority of patients. They are the patients we are treating with steroids, who are on a low amount of oxygen, but now progressing to significant amount of oxygen support.”
This medicine costs thousands of dollars for a single dose, and only a very small group of patients benefit from this. Most patients are not going to fall into that window. And, giving this medicine to people who do not require oxygen, and without premeditating with steroids, you may be doing harm, not benefit, for your patients, he informs.
He says that there are a few major studies, including COVACTA trial and REMAP-CAP trial to settle some of the controversy related to tocilizumab and its usage was quite controversial in the United States too. “But we even finally have good data on it,” he says.
Anticoagulation
The current recommendation across the board in the American Society of Hematology suggests giving anticoagulation for all COVID-19 patients, either prophylactic or full dose. “Most of the patients, we believe, from some of the unpublished studies and data that we have reviewed, will benefit from full dose. But, in a lot of severely ill patients, the risk of bleeding can increase, and sometimes it’s better to use prophylactic doses.”
It is really important to look at your patients and gauge their risk before administering anticoagulation, he suggests. On whether using subcutaneous heparin or coumadin or aspirin or an anti-platelet agent, he says there is evidence supporting all those interventions, and it is definitely better than doing nothing.
A study published in the British Medical Journal for early initiation of prophylactic anticoagulation for prevention of coronavirus 2019 mortality in patients admitted to hospital in the US demonstrated about 27 percent decrease in 30 days mortality over no anticoagulation. “This really moved us from discussion about no anticoagulation vs. doing anticoagulation to the question of what level of anticoagulation.” But, we are still waiting for the data of the large studies on anticoagulation dosing in COVID-19 patients to be peer reviewed on how much dose we are doing and what agents we are using, so that we can incorporate into our updated guidelines, he informs.
The three large studies include 58 site candidates in USA, Brazil, and Mexico, 60 sites in USA and Spain, and 290 sites throughout the world, including Nepal. The studies have combined their analysis and the primary outcome of organ-free support days favored full dose anti coagulation for moderate COVID-19 and lower prophylactic dosing for people requiring ICU level care. He says that there are different intensities of anti-coagulation that benefit certain patients.
Pulmonary support
It is given when people start having increasing oxygen needs. But, Dr. Griffin says, if anything we have learned over time, keeping these people off mechanical ventilation is the key. We should use all the non-invasive ventilation (NIV) methods instead, including supplemental oxygen and laying them on their belly even though patients are reluctant about it. Proning is actually one of the most significant interventions we can do with a mortality benefit, he says, adding that “it is something we have been doing for many years and there is data to support it makes a difference.”
In a study (a retrospective multi-center observational study conducted in 27 hospitals in Mexico and Ecuador on 827 non-intubated patients with COVID-19 who were managed with prone vs. supine positioning), less patients (23.6 percent) in the prone group required endotracheal intubation mechanical ventilation than patients laying on their backs (40.4 percent). The mortality percent was 20 vs. 37.9 in the prone and supine positioning, respectively.
“We are seeing a mortality benefit just having people lay belly down before they end up on a mechanical ventilator. And, actually, we are keeping a bunch of people off mechanical ventilation. So, it’s a very low-tech approach that can make a lot of difference in COVID-19,” he explains.
Antiviral Rx
He further says that in this period, a lot of them receive remdesivir. And, one of the arguments for why it hasn’t done much is that the virus is already on the way down. So, the problem here is not the virus, but the immune response.
Third Week
After being exposed, infected and going through the inflammatory phase, some individuals are either still in the hospital or returning to the hospital in the third week. It is in this week, Dr. Griffin says, that there is an increased incidence of bacterial infections. According to him, 99 percent of the people who show up in the hospitals in the US are not secondarily infected; they have a viral illness that does not benefit from antibiotics.
“They are in the secondary infection phase, and we are also seeing fungal infections like candida, aspergillus, cryptococcus, and all the different kinds of fungal infections. Also, this is the time where, if an individual was not adequately anticoagulated or protected against clotting, this is when we can see a significant incidence of strokes from deep clots. At this point, it really takes a clinician to sort out what is going on, if it is a surge of inflammation or a infection or a clotting disorder.”
Fourth Week
This is the time when multisystem inflammatory phase starts. Initially, this was described in children in the UK. Now, it is reported in a lot of hospitals for children as well in adults in the states, Dr. Griffin informs.“But, we are not clear if we should treat them with IVIG or use steroids. We don’t know what will make the difference. We are sort of borrowing from other diseases when we treat this.”
Then we move on to the period that terrifies a lot of us throughout the world that people may not get better. “When we discharged patients from the hospital after they were all better we thought they had recovered, but more and more data are suggesting that people are not all better at all. We are seeing high readmission rates, and about 10 percent of these individuals are not even alive a month or two after discharge.”
Dr. Griffin says that they are discharging people on prolonged anti-coagulation, based up on their risk factors and resources. “I have to say here in the US a couple of these medicines like rivaroxaban and apixaban are actually quite expensive. We are sending them out, and we are seeing that some of their insurance plans are not covering these. So, a lot of time we are using daily aspirin in this patient population. I think that is really troubling when we are willing to spend the resources we have spent to get them through that hospital and now our coverage plans and health care system is dropping the ball here.”
He says they are seeing a lot of long-term care challenges, ongoing fatigue, and cognitive impairments in the COVID-patients. “I have nurses and professors who have trouble finishing sentences after their bout of COVID. They can’t even sign their names. A significant number of people are have pulmonary compromises and our cardiologists are quite busy with all the different cardiac issues that we are struggling with.”
So, timing really matters, and it is important to have the scheme of different stages when you are thinking about taking care of your COVID-19 patients, says Dr. Griffin.“Early on, ideally, we want to jump in with our vaccines before people are exposed, get them vaccinated with enough time to build those protective T-cells, B-cells, antibodies. During the first week after someone starts getting symptoms, there is not a lot that we can do that is helpful, but there is a lot that we can do that is harmful. In the second week, you can start looking at steroids, not that first week. I think it’s critical to know that giving steroids in the first week can actually do harm, and the anticoagulation is something again you can consider starting in that second week.”
