New Delhi: From antiretrovirals to steroids, from focussing on ventilators to now looking for oxygen, a lot has changed in the standard of care for Covid-19 over the past five months in India.
On Saturday, the Ministry of Health and Family Welfare issued revised treatment guidelines including dexamethasone, the inexpensive and easily available steroid, in treatment protocols.
The revision, the fourth until date, comes nearly two weeks after the last one and after results of recovery trials in the United Kingdom, using dexamethasone, were made available on 18 June.
This is how fast the knowledge about the virus has been changing. By extension, so have strategies to manage patients ever since the first case of novel SARS CoV2 virus was detected at Wuhan in China in January.
“This is a pandemic, so the situation is dynamic. What is the standard of care today may not be so 15 days from now,” said Dr Kedar Toraskar, chest physician, Wockhardt Hospital, Mumbai, and a member of Covid-19 taskforce in Maharashtra. He, however, added that the knowledge of the last three months have made the medical community wiser about the disease.
The revised guidelines as well the one before it also include remdesivir, convalescent plasma therapy and tocilizumab for moderate patients under “investigational therapies”, which have limited available evidence.
From the first few weeks when it wasn’t clear on how to handle patients and what could be the possible progression of the disease and symptoms, there has been quite a bit of progress.
“Now, the medical fraternity will soon be able to find if therapies still under investigation — including remdesvir, favipiravir, stem cells, plasma therapy and tocilizumab — have any benefit or not,” said Dr Rashid Gouri, a senior resident at AIIMS, New Delhi, who treats Covid-19 patients.
Most patients show mild symptoms, get well at home
One of the biggest changes in the standard of care has been the fact that most Covid-19 positive cases have mild symptoms and do not need hospitalisation and can get better either in home isolation or institutional isolation centres.
According to the largest study of Covid-19 patients done in China and published in the Chinese Journal of Epidemiology, 95 per cent of patients suffer from mild symptoms, while 15 per cent need oxygen therapy and 4-5 per cent need ventilation.
Those with mild symptoms can be monitored for oxygen saturation with pulse oximetry and for temperature at the Covid Care centres. If the oxygen saturation drops below 80 per cent, patients are recommended to a higher centre.
The health ministry’s guidelines released in May also recommended that only the severe patients be shifted to dedicated Covid hospitals. It also allowed mild and moderate patients to be discharged in 10 days without a confirmation test if they had no symptoms for more than three days. Earlier patients needed two negative RT PCR tests before discharge.
The current policy makes sense as only the severe patients are occupying the beds, doctors told ThePrint.
Covid-19 infection has two parts, one part where the virus replicates and another part when there is inflammation that includes the cytokine part, said Dr Om Srivastav, infectious disease expert from Jaslok Hospital, Mumbai.
He said the virus replication happens in the first 10 days and the impact on heart or lung happens in the inflammation part of the infection after the 10 days.
“Now the treatment strategy has been evolved to identify which part of the infection the patient is in and address that part more aggressively,” said Srivastav. So the doctors prescribe antivirals during the first 10 days and anti-inflammatory drugs after the first seven or 10 days.
No HCQ and Azithromycin, Tamiflu, Vitamin C
The guidelines in March only recommended Hydroxychloroquine (HCQ) and Azithromycin for severe patients as no other antivirals were “proven to be effective”.
While Azithromycin has been dropped from current guidelines, HCQ is still included.
Many recent studies have shown HCQ is not effective in reducing mortality or outcomes in many trials, including RECOVERY trials. It has been dropped from the World Health Organisation’s ongoing Solidarity trial to find an effective treatment for Covid-19 that included four drugs.
The ministry’s current guidelines mention that “since these large observational studies had several limitations, HCQ is recommended in the early stage of the disease after an electrocardiogram is performed”.
Experts, however, said that the use of HCQ in hospitals has almost been stopped now. “After looking at the results of the studies, we have now stopped giving HCQ for more than two months now,” said Toraskar, who added that the combination of HCQ and Azithromycin is harmful and has also been stopped.
Also the use of zinc, vitamin C tablets has stopped as well as that of oseltamivir, which worked for H1N1 infection but hasn’t proven effective for Covid-19.
Next came the antiretroviral drug combination of lopinavir-ritonavir, which was also used to treat patients in Jaipur. After initial promise, however, the combination didn’t show promising outcomes in trials and was dropped.
“The role of antiretroviral drugs lopinavir and ritonavir may now go down with new experimental treatments like remdesivir and favipiravir coming in, but these anti-HIV drugs have played an important role until now,” Dr Gouri of AIIMS said.
New kids on the block: Remdesivir and favipiravir
Now the two antiviral drugs that have got much media attention are remdesivir and favipiravir.
Favipiravir, an oral antiviral drug first manufactured by Fuji Films and used for resistant influenza in 2014, has recently been licensed to be sold in India at a price of Rs 103 per pill.
The drug, however, is not a “magic bullet” and can reduce the recovery time but should only be used for mild patients. There are still no large trials that have proven its efficacy, said several doctors ThePrint spoke to.
“The problem with the drug is also that the pill burden is very high. You have to take nine pills the first day and four pills twice a day for 6-14 days,” said Dr Toraskar.
Remdesivir, an intravenous antiviral drug has shown good results and was first recommended by the US’ top public health authority, the National Institute of Allergy and Infectious Diseases (NIAID), in April. The drug reduced the recovery time but did not have a significant impact on mortality.
The drug is best used for moderate to severe patients and is used in the intensive care unit in the first 10 days of the infection, said Dr Toraskar.
In India, remedesivir was only available under compassionate use and will soon be available for “emergency restricted use” in hospitals after Cipla and Hetero got the licence for manufacture and sale.
“Remdesivir has shown good results on the 25 patients that we used the drugs for in the ICU,” said Dr Harsh Chafle, consultant intensivist and chest physician, Global Hospital, Mumbai.
Steroids have a role
Doctors were using steroids in the intensive care units but now have been validated by the UK RECOVERY trial, which has shown that dexamethasone can reduce mortality for severe patients and those who require ventilation.
The study used 6 mg of dexamethasone for 10 days on moderately ill patients and those who need oxygen supplementation.
“It is important to know that if you use it early or for mild patients, it is going to be harmful,” said Toraskar, who added that it should be used after the 10th day for patients who are moderately to severely ill and who require oxygen.
There is also a role for anticoagulants or blood-thinners since the Covid-19 has been known to cause inflammation and clot formation. These are recommended for moderate patients in the new guidelines.
Oxygenation and Proning
Earlier, the strategy was to use a ventilator early on but now the strategy is to delay using an invasive ventilator as much as possible, said Dr Chafle. Invasive ventilation is when a tube is inserted into the patient’s windpipe by a process called intubation.
Now, doctors prefer oxygenation through high flow nasal cannula (HFNC) and non-invasive ventilators.
Explaining how HFNC works, Chalfe said, “Oxygen can be given in central oxygen providing devices or cylinders. HFNC devices provide the same oxygen more effectively by giving it with high pressure and moisture.”
Patients who were intubated have reported higher mortality but that is because those patients are more serious, said Dr Toraskar. The idea to delay intubation is to reduce the inflammation with supportive oxygen and drugs.
However, the word of caution is to not delay intubation too much so that the patient deteriorates, said Dr Toraskar, adding that if the HFNC and non-oxygenation fails, patients should be ventilated.
He said doctors also use a procedure called proning, which is positioning the patient on his belly when the patient is intubated. He added that it is showing good results for patients with Acute Respiratory Distress Syndrome (ARDS). “We are proning very early and for a longer time compared to routine ARDS patients,” he added.
Proning has been recommended for moderate and severe patients in the guidelines.
‘Timing is critical’
While there is no magic bullet for the treatment of Covid-19, the only thing that doctors have learnt from experience is the “criticality of the time of changing the treatment and the right time of starting a particular therapy”, said Dr. Vikas Maurya, director and head of department, Respiratory Medicine & Interventional Pulmonologist, at Fortis Hospital, Shalimar.
Now, doctors know which therapy works at what stage, for example, plasma therapy won’t work in the later phase of the disease, Maurya said. “Toclizumab reduces the inflammation when the cytokine storm begins. Now we know that it begins from the second week of infection and the drug must be started from the eighth day,” he added.
Doctors, however, caution that even with the new drugs, evidence has been unreliable.
There have been over 30,000 studies published on Covid-19 from January to May 2020, many of them pre-prints that did not include a peer-review. Even reputed journals such as The Lancet and BMJ have had to retract their papers.
“The quality of research is very bad right now — anything and everything is getting published and one has to look at the trial very carefully to actually see if things are working or not,” said Dr. Sheetu Singh, assistant professor, Institute of Respiratory Medicine, SMS Medical College, Jaipur.
Srivasatav of Jaslok Hospital in Mumbai said that knowing the volume of papers published every day, a paper published on a small set of patients should not influence physicians. “They should be adopting practices that are scientifically based and that stand scientific scrutiny coming from a well structured trial,” he said.
Also, it is important to remember even with new drugs, there is no vaccine or drug that prevents or cures Covid-19 and doctors can just offer supportive treatment that supports the body as it fights the infection, he added.
While most patients who are getting serious are those above the age of 50 with co-morbidities, there are deaths in younger, seemingly healthy patients within days of hospitalisations as the cytokine storm has set in, said Singh.
“Even if the unlock period is on, do not step out unless it is necessary,” said Dr Chalfe. “Use masks, sanitisers and reach a doctor early if you have symptoms, like three or more days of high fever.”