Mumbai: The number of COVID-19 cases and deaths are beginning to plateau in some parts of India, but continue to rise in others. There are two sets of numbers--documented and undocumented COVID-19 cases--and that distinction is quite clear now. But another serious issue that's emerged is the kind of after-effects being seen in COVID-19 patients who have been treated and who have recovered. It is known even to lay people that there are COVID-19 after-effects, but could these also be caused by some medicines, or by an overdose of those medicines? Which medicines, and what damage could these have done in the last year? Many of these medicines were administered due to panic among patients looking for a quicker response to treatment, therefore doctors had no choice but to administer them. Now, as India hopefully moves towards the end of the second wave, what lessons on medication could we take going forward as we prepare for a third wave?
To throw some light on the issue of COVID-19 medications and after effects, we speak to two well-known experts. Dr Rajani Bhat, a consultant pulmonologist based in Bengaluru, is an American Board of Medicine-certified doctor in pulmonary diseases and critical care from the Albert Einstein College of Medicine in New York. Dr Lancelot Pinto, a consultant pulmonologist and epidemiologist at Hinduja Hospital in Mumbai is an MBBS and Master of Science in epidemiology from McGill University, Montreal, Canada.
Dr Bhat, please explain to readers what steroids are, since these are among the medicines that have primarily been administered to COVID-19 patients and have led to some dangerous side-effects.
RB: Steroids are an external or artificial form of a certain kind of chemical which is produced in our body. Certain endogenous steroid-like chemicals like cortisol are produced in our body in response to stress. When COVID-19 infection happens, there is initially a phase where the virus is replicating and growing in our body. Then there is a very strong element of inflammation in the second week. Steroids are medications which are used for reducing inflammation. They come with the potential side effects of lowering immunity and raising blood sugar, so they are not medications that are given without any thought and caution. In the past, steroids had a really bad name, so even as pulmonologists, we sometimes have struggled with telling patients who need steroids that they actually need them. It was an issue of abuse several decades ago, followed by fear and caution in the general public, so that even the required use of steroids needs a lot more counselling from us.
What we have seen happen with COVID-19, especially with the publication of certain reports of the beneficial effect of steroids in moderate or severe cases of COVID-19 (those who require oxygen or ventilatory support), is a loosening of people's fears or cautions about the appropriate use of steroids. Of course, there's the problem of over-the-counter medications being available to people. So, steroids are those drugs which are wonderful if used judiciously at the right time for the right COVID-19 patient, and can be used without fear if under the advice of a physician. But definitely, they are drugs that need to be used with caution and should not be used without appropriate advice.
Dr Pinto, from your experience, have steroids been administered judiciously in the last year?
LP: Unfortunately, the answer to that is no, and we have seen the adverse effects of that happening quite rampantly. It is difficult to attribute or ascribe blame to this, but I think what typically happens is that an individual who has a high fever, which is a very common symptom of COVID-19 especially in the first week, finds it very worrisome in the atmosphere of paranoia all around. The individual realises his/her fever is not breaking in two or three days, so there's a lot of panic and anxiety. There's a pressure on the doctor to do something. If despite the standard medications like paracetamol, the fever doesn't settle, that kind of nudges the doctor towards trying to give steroids, because steroids work wonderfully at settling fever. The fever settles in a day or two and the patient is happy. Unfortunately, if it is done too early, that gives the virus a free hand in terms of multiplication, growing in the body. So the typical picture is one to two days of improvement, feeling great, feeling energetic, and then when people crash, unfortunately they crash really badly because that's the stage at which the virus comes back with a bang. Your body's immunity has been completely suppressed by the steroids so you don't have a natural immunity that you would normally mount, which would overcome the disease for a majority of individuals. Fever in the majority of individuals would persist for four or five days, but would settle on its own on day five or six. But if you don't wait for your body to take over, if you don't wait for that immunity to kick in and allow the infection to be controlled and therefore let the fever come down, if you start steroids in a haste, you suppress your own body's immunity and give the virus a free hand. Unfortunately, we are seeing this too often.
Dr Pinto, are you saying that steroids did not work in the first place? Are people accessing steroids over-the-counter, or are they getting these from doctors?
LP: Unfortunately, I'm seeing this in a lot of prescriptions, which on day three or four include steroids, so it's the doctor who is clearly prescribing these. That may be driven by immense pressure from the patients and their families saying that 'listen, we are really scared, there are no beds for us in case we deteriorate and this fever is not settling so please do something about it'. That may be driven by misunderstanding among doctors who have heard that steroids are wonder-drugs but have not realised there is a nuance to that argument. Steroids and oxygen are probably the only two drugs that save lives in COVID. But if you make a broad statement like that, and somebody just listens to that, they might just presume that at any stage of the illness, you give steroids and they are going to turn things around. And I think that's a genuine problem that needs to be addressed.
Dr Bhat, what are the steroids that are usually prescribed and administered in the early stage of COVID-19, when both of you have said these should not be? What are the normal practices in other countries like the US or the UK, at the point of three or four days of fever?
RB: In the largest trial, which was the Recovery Trial, they studied 2,000-plus patients who received steroids, and these were patients who were moderate or severely ill who required oxygen or ventilators. That steroid was dexamethasone and it was used in a dose of 6 milligrams for about 10 days and it did show improvement in these patients. It was actually the one drug which showed a mortality benefit in these patients. However, the same trial also showed that if it was given for patients who did not require respiratory support, who did not require oxygen, who were not severely ill, it had a detrimental effect. So, the trial was very clear in stating that there is an appropriate time and place for using the steroids, in a select group of patients who require oxygen or ventilators.
The other drugs of the same class of steroids that have been used are prednisone, methylprednisolone and hydrocortisone in equivalent doses, and this is part of standard treatment in many pulmonary and rheumatological diseases. We use equivalent doses of this class of medications, which is steroids. I think one of the main issues with steroids has been about using it appropriately in the right case. There is also a newer study that has come out--in a smaller number of patients, though--which is about inhaled steroids, inhale budesonide, which is the kind of medication that they've used in asthmatic patients and patients with chronic obstructive pulmonary disease (COPD). In the initial studies, they found that this group was underrepresented among severely ill [COVID-19] patients. Among people who were coming in severely ill [with COVID-19], there weren't so many asthmatics and so many COPD patients, so they started looking at whether their regular maintenance medicines were having a protective effect on them. So [inhaled steroids] is something that is emerging as maybe something that can help, again to be used judiciously and not without the advice of a doctor.
What's different in the practices in the UK, where a large part of recent studies were conducted, was that patients don't have access to over-the-counter medications. Steroids are accessible only to patients who are seeking hospital care, and not for those in home care, because they have a triage system, where it's only home care for patients who have oxygen saturations above 94. When this drops below 93 or 92 is when patients seek emergency care and that's when they receive the steroids. So you're not able to access the drug unless you have been evaluated for the right indication, which is a drop in your oxygen.
Do you think that's possible in India, to say that steroids would only be available to COVID-19 patients who are more serious and therefore make it available only in hospitals?
RB: I think it would have been possible had it not been for the fact that our healthcare system is overloaded. I know that there were similar attempts. When we were trying to figure out travel restrictions, certain states came up with restrictions on paracetamol and antihistamines being sold over-the-counter, that no chemist would give you paracetamol unless they were sure that you didn't have COVID-19. These things have been attempted. However, that works fine if you have adequate healthcare infrastructure for all these patients who have low oxygen. Right now, many of us are managing patients who require steroids, even patients who require oxygen, at home. So, I think the most important thing is to have a prescription.
Dr Pinto, a little over a year since the first wave and now into the second wave, what are the lessons we have learned about the way these medicines are administered. What have you seen in terms of the after-effects of the medicines being administered?
LP: What I've learned is that minimalism really works in a disease like COVID-19. Being watchful, monitoring carefully, hand-holding patients and keeping them calm when they get anxious is what doctors really need to do. Unfortunately, I see doctors completely overwhelmed and overburdened, and it is much easier to write a prescription with 10 drugs on it when the patient feels he/she is being served in some way, rather than tell them, 'you don't need anything'. They feel that the neighbour is getting so many [medicines] and their uncle and aunt are getting so many, but their doctor is giving them nothing. So, it has been unfortunate in a way. We have really had to work hard on convincing patients that they don't need anything for this disease. The lesson we have learned is far too much is being done for a disease that really doesn't need much to be done, other than monitoring for most of the disease process.
RB: In a discussion yesterday with my peers and colleagues, one of the things that came up is how can you send a patient with great anxiety away empty-handed? I don't think we are sending back patients empty-handed. We send them back with advice, with reassurance. What this needs is excellent communication and being there for the patient. This is part of our skills as doctors, to know when to do nothing but reassure, to know when watchful waiting is the most important thing for a patient. The other thing we have seen is that this misuse of medication is not just among the lay public, it is amongst doctors as well. I have treated my own mother and my husband and I have not misused these medications. But I have seen that fear takes over even the most scientific of minds. And at this point, we need to be governed by and follow the path of science rather than fear.
Dr Pinto, suppose I were to come to you and say 'I'm desperate, please give me some steroids because I read somewhere, or got a WhatsApp forward, that this steroid will curtail fever and I'll be okay in three or four days'? How would you warn me against that?
LP: I would tell you that I have over a year of experience now, unfortunately, in seeing the other side of the story. Most people in the community who prescribe these steroids will not see these individuals eventually when they get hospitalised. I've had the experience of receiving patients at the hospital who have been started on steroids too early, who have deteriorated very rapidly. What's also unfortunate is that the people who tend to mount the strongest fevers are often young and these are the individuals who we have seen come in a really bad shape to the hospital because they have been given steroids too early, because the fever was 102 degrees and that got somebody really anxious. I would tell them that with the experience that we have from the past year, that most countries across the world have, we know that fever by itself is not a cause for concern in the first week [of COVID-19 infection]. We know the real monitoring tool is the oxygen levels and we know that steroids work really well when given at the right time, when the oxygen levels do fall down. But as long as the oxygen levels are rock steady, as long as there are no really bad lower respiratory symptoms, if a person is not coughing too much, fever alone should definitely not be a reason to give somebody steroids early on in the disease.
Dr Bhat, what kind of after-effects of COVID-19 have you seen, if any, particularly long after the patient has recovered?
RB: After-effects just of COVID-19 in and of itself, especially what we're observing now, are these lingering fevers, a cough that persists. Patients who have been more severely affected with COVID-19 require hospitalisation longer, some of them may even require oxygen support a little longer. And there is a complex of symptoms which is called long COVID-19. So, a small percentage of people will experience symptoms going on much longer. That being said, there are some early indications that the use of inhaled medication might reduce the incidence of the annoying long effects, which is the persistent cough which causes a lot of anxiety and discomfort to patients. We are still waiting on data, whether that is really a true effect or not.
But long COVID-19 is not necessarily an outcome of overuse of steroid medication, right?
RB: No, long COVID-19 is not an outcome of steroid medication. What is a problem with excessive or injudicious use of steroids is secondary bacterial infections. Patients who will get other infections then have a much more prolonged recovery and the after-effects and sequelae of that extra infection.
Dr Pinto, black fungus seems to be one of those secondary bacterial infections. Everybody is quite worried about how it is spreading and it seems to be caused by medication or over-medication. Tell us about that.
LP: So, alluding to the same study again, the recovery study used 6 milligrams of dexamethasone for 10 days. That's pretty much all they used. Unfortunately, there is this misperception that the worse the disease, the higher the dose and longer the duration of steroids required, that it needs to be tapered over a longer period of time. So, there are two issues with steroids: one is that you start them too early and two is that when you do start them appropriately, you start them at too high a dose or for too long a period. And that's the second problem that leads to secondary bacterial/fungal infections that we have seen. We have lost a couple of patients who had come to us after being given really high doses of steroids at other hospitals. And then we realised that two weeks or three weeks down the road, because their immunity was suppressed to such an extent by those high doses of steroids, their lungs had become fertile ground for fungi and bacteria to grow. That is a real concern with using too high doses of steroids and for too long. I think that's more a dose and a duration-related effect rather than premature starting of steroids. There are two separate issues which really need to be addressed.
Did you also say that younger people were being administered steroids to a greater extent than older people?
LP: That's a personal observation that a lot of us have seen, that the younger you are, by virtue of the fact that your immune system is probably stronger, your immune reaction to the virus is more potent. So you tend to have higher fevers which last for a longer period of time. And a young person having a high fever getting anxious, therefore becomes a kind of a person who the doctor feels very pressured to start steroids on. And this is exactly the group which would have otherwise just mounted fever for probably 10 days, maybe a prolonged period, but would have settled down quietly. But now because they have been given steroids, they have a much more severe course of disease. A lot of people are talking about how younger people are being affected more severely this time round. It would be interesting to audit their prescriptions actually and see how many of them actually did worse because they were started on steroids too early. And I do hope somebody looks into that.
Dr Bhat, your views on younger people getting over-medicated, therefore ending up in a worse state?
RB: I do think there is truth to that, because younger people do have these robust responses where they're having these spiking fevers going up to 102-103 degrees, and they're worried about it. One of the other concerns early on in the pandemic was that we thought that the use of non-steroid anti-inflammatory drugs was not a good idea in COVID-19, looking at some of the actions of the virus on certain receptors in the lungs. One year into the illness, we have realised now that these drugs can also be used as an adjunct to paracetamol for the fevers. There was a time when we thought that those should be avoided as much as possible, because we were seeing patients coming in with kidney-related issues when they had severe COVID-19. We've gone past that. So we know that we have other drugs in our arsenal before we need to turn to steroids, so we can stay limited in our use of steroids for that specific indication of oxygen dropping down. We can be a little bit more liberal in terms of telling patients to walk around, see if your oxygen drops when your heart rate goes up a little bit. Then that may be an early indication to start steroids. There will always be a small group of patients who will benefit from early steroids or who will require prolonged steroids in severe COVID. But that's a much smaller number. The majority of them will require it only for that specific indication of low oxygen and for that specific duration of ten days.
LP: My prescription for steroids, based on the current knowledge of the literature, is inhaled steroids in the first week in a subset of individuals. It is one of those drugs which really doesn't have such a bad risk-benefit ratio, so even if you over-medicate, the likelihood of causing harm is quite small since you plan on giving it for a really short period in any case. It is not prolonged use of inhaled corticosteroids. So, the first week is paracetamol and inhaled corticosteroids. Towards the end of four or five days, if oxygen levels drop down at some point of time, that is the time you add corticosteroids. This is pretty much what you need to do if you're managing somebody at home.
Things like proning, sleeping on your belly at home is not a bad idea if your oxygen levels are borderline. We've created this simple infographic which is available on indiacovidsos.org in multiple languages now, which summarises what a person can do at home. We do realise that getting a bed in a hospital is not easy and we do realise that some of the things that we are doing at home may not have been things that we would have always done at home, had hospital beds been available easily. But I think you can still be very judicious, sensible and turn around a significant proportion of your patients while managing them with these simple measures--paracetamol, inhaled steroids, oral steroids if necessary in the stage where oxygen levels drop, proning as much as possible, and most individuals will turn around with this.
Dr Bhat, going forward, do you think some sort of regulatory intervention, or at least, a guideline, on when to use steroids is required? Maybe everyone knows this but need a reminder?
RB: I certainly think that having strong guideline statements from professional bodies will help a lot. As pulmonologists we speak to each other in an echo chamber--and since we are aware of the indications I don't see that kind of misuse--but we must understand that there's a very small number of pulmonologists for the kind of population that is facing this COVID-19 illness, and it has required the collaboration and cooperation of every other specialty. So it doesn't matter if you are an endocrinologist or cardiologist, you have patients who have COVID-19 who are approaching you for advice. Physicians, family physicians--everyone is treating patients with COVID-10. So, every professional association needs to send out guidelines to its members, that this is how you use [steroids] safely. I completely agree with what Dr. Pinto said about the best practices in the use of steroids and the simple things that we can advise patients about.
One more thing that I have noticed is that culturally we are not people who get annual health check-ups, even when we are in a certain middle age group. Very often, what we realise is that patients are diabetic and they have never known about it. So the questions we are asking them before we prescribe steroids in those patients where it is indicated is: 'do you know if you have any background diabetes or any other other illnesses?'. And they'll say 'not that I know of'. But we will check it out and tell them to monitor, and that's when you discover that there was an underlying illness, another risk factor. So, I think it's best practise also to check as patients may not always know what their background condition is.
As India may be seeing the second wave slow down and gearing up for a third wave, which we may hopefully not see, how do you think we could approach things differently, not just about the medicines being prescribed?
LP: The only thing that has consistently shown a change in terms of prevention, through the COVID-19 pandemic, is mass vaccination. Reaching people as quickly and as broadly as possible is our best bet at avoiding the next wave. Another thing that would be really useful is mass seroprevalence studies to direct the vaccination towards low prevalence areas and individuals, [then] I think we would definitely be able to prevent the next surge. If you look at the Mumbai sero prevalence study, the last one had 57% antibodies in the slums and 16% in the high-rises. Had we paid heed to that, we would have realised that this time around, about 80-90% of the infections are happening in high-rises. So, we [should] guide vaccinations towards these individuals who really need it the most, especially if there's a vaccine shortage. I think we need to be smart about that and that's our best bet at preventing the next wave.
RB: I think that for me, my pet peeve is inappropriate mask technique and social distancing. We tend to let our guard down with people that we know, that we are familiar with. I completely understand that it is uncomfortable and it is difficult to have a mask on for most of the time. We are familiar with it as pulmonologists. We have dealt with infectious diseases like tuberculosis and we accept the mask as a very simple thing that will protect us. So, I've seen that this time, we've seen infections spread amongst small groups of people who are familiar with each other, who trust each other's infection control practices. 'Oh, I know this person, they are a responsible person, they are not going to behave irresponsibly so I let my guard down in front of them'. I don't think we can let our guard down. We just have to, as much as we can, get the messaging out on the simplest of measures: masks and social distancing and hand hygiene. And, as Dr Pinto said, really approach vaccination on a massive scale. Those are the only two things that are really going to be protective for us.
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