Dr. Adri Kok: Welcome colleagues. My name is Adri Kok. I am the president of the International Society of Internal Medicine. And it is a great pleasure to welcome you to this question and answer session on infectious diseases. I speak on behalf of myself and Dr. Zain Chagla from McMaster University. And [I’d like] to thank our organizers, McMaster University, the Polish Institute for Evidence-Based Medicine, the International Society of Internal Medicine, the European Federation for Internal Medicine, and the Jagiellonian University, who have all supported this informative session. And then, also with endorsement by the American College of Physicians. So, as some of the questions were posed to me, I will ask Dr. Zain Chagla to take over those questions. And we will then take turns to just cover the questions that have been posted to us before [the session]. Please, feel free to also post questions in the chat box which is at the bottom of your screen. We would like to just have as much participation and communication as possible and we would love to see as much interaction and debate as we can. So, I will hand over to Dr. Chagla. Professor Chagla, sorry.
Professor Zain Chagla: Hi, good afternoon or good evening everyone. I’m glad to be here. I will just take a moment quickly to introduce our esteemed panel. You’ve met Dr. Kok from South Africa. I would like to introduce as well Dr. Brian Garibaldi from Johns Hopkins, Dr. Mark Loeb – who is also from McMaster University – Dr. Pal – who is from R. G. Kar Medical College in India …, Dr. Somia Iqtadar from Pakistan, and we will have some feedback by Dr. Bram Rochwerg – also from McMaster University – who will actually be part of the next session, but given that there is a lot of critical care overlap here, we will also be able to incorporate him into this session as well. So I will be glad to use some of the questions for Dr. Kok. There are also questions for everyone on the board. And then, [to] our panelists – if they have something to add – please feel free to jump in, to help with the discussion here. So [the] first question [is] for Dr. Kok. Could you tell us if you [have reached] the threshold limiting access to ICU beds and, you know, if there were any changes with that, who is communicating those limitations to patients and families and to the general community?
Adri Kok: I think it was a challenge really throughout the world, as to ensure that we would assign the critical care support to the appropriate patients. So we did have patients waiting in cars outside hospitals at the height of the surge, which I think is really something that was experienced everywhere where this COVID-19 pandemic hit us. And one actually [had to] make real triage decisions as to who would get the appropriate level of care. And this often had to be managed very rapidly by an ethics committee in some incidences, if you had time. Otherwise, it was really thinking on your feet. So it did occur – luckily not many patients, but there were circumstances, especially with the very elderly or those with severe comorbidities – [where patients] had to make space for younger patients with a better prognosis. So I think that was really, essentially the experience everywhere. We tried to coordinate the care and also transfer patients to other units. If our unit was full, we even had tents put up outside the hospitals in the parking area with supplemental oxygen. So that you could – even if you could just give oxygen infusions, cortisone, and at least get the patient on some form of support, it was better than nothing. We had many patients at home on oxygen machines with support from their general practitioners as well.
Zain Chagla: Yes, it’s a very interesting scenario I think for all of us to the wave, but obviously in resource-limiting settings there are just so many challenges and the ethics of it are quite difficult, for sure.
Adri Kok: Yes.
Zain Chagla: So the next question… go ahead, Dr. Kok.
Adri Kok: I will just mention about the communication – sorry, I forgot about that. That was often difficult to coordinate. We did have, at some of the hospitals, social workers that tried to keep the patients’ families aware of what was happening. Often it was a lift to the treating physician to meet up with the families or speak to them. We often did video calls, and this is one situation where, you know, video calls were actually a godsend because we could at least see the person and have some discussion, even if they were on a ventilator, they could still gesture. We obviously tried to keep the patients as comfortable as possible, but that made a big difference. And in more recent times, we actually allowed family members in, with PPE and the whole set-up if we saw that the situation was deteriorating; but also for some situations, that actually helped the patients. So we tried to just be sensible about prohibiting people, but also keeping staff and doctors safe at the same time.
Zain Chagla: Excellent. Yes, again, I think some of the struggles that we’ve seen in much of the world is balancing the loneliness, especially with people’s last days in hospital. Again, a unique situation there for sure. There was a question, I think from one of your sessions, that talked about the 37% of South Africa’s population [who are] HIV-positive. I think we were just chatting about that prior to starting. And the question also says, “Does this exclude or include children?” So maybe just a little bit about the context of the childhood seroprevalence.
Adri Kok: Yes. So unfortunately, this is [a] statistic we’re not proud of. It occurred as a result of a previous health minister who didn’t believe that HIV and AIDS was actually anything to worry about. And [she] didn’t roll out antiretrovirals at the time. And she was at the time supported by the president of the country, [who] also was made to believe this disastrous attitude. Luckily, since then the program has been rolled out, the HIV management programs and really a major focus on treating patients have made a massive difference. And the mortality rate has improved by 20 years, just purely because HIV has been managed better. It did create a hiatus, though, of no treatment during which time unfortunately the prevalence increased, but hopefully with time, this can be curtailed. Then interestingly enough, we thought that this would be a major factor for COVID-19. We were very scared that this would be a disastrous cause of mortality in our population areas, where in our one township area, for example, it’s even more densely populated than the favellas in Rio, for example. But this didn’t occur. So luckily it wasn’t as bad as we expected at the time.
Zain Chagla: Yes. It’s fascinating. I think that actually leads into, I guess, the next question. It is: “What measures were being put in place in South Africa, particularly with B.1.351, the variant that also combines [the] 501 mutation with the 484 mutation, with amino escape and potentially increased transmission?” What is the story? Because it seems like South Africa dealt with the surge, but then somehow seemed to come out of it with some sort of measures in place.
Adri Kok: I think there was a delay in stopping international travel. So this, we even have 5 cases now of the Indian variant, despite the restriction on travel. And I think it was just a missed opportunity to contain what was in the country that this trend developed. And I think, unfortunately, it has come into the second surge that we saw a different pattern of presentation, that patients maybe presented much more ill. We had a higher mortality rate in the second surge and the second surge was also much more severe. The third surge now seems to be, at the moment, still attenuated because there is still this restriction on travel. I think we’re one of the countries that did early identification of the different strains and I think that did help us a lot. And somebody asked earlier, you know, “why is there a lower prevalence of COVID-19 in Africa?” I think it’s simply because there weren’t tests available always in some countries to actually pick up patients and some people just, there were mortalities that were never registered as being COVID-19-related. So I do not think for a minute that Africa has escaped this at all.
Zain Chagla: Yes, absolutely. And just, I think we were talking prior to this, there were a couple of publications, out of Zambia, that looked at community transmission seroprevalence and PCR-based studies and suggested about a half a million reported cases and about 5000 deaths. And [in] another morgue study from Zambia, there is a select number of individuals that had about 20% testing positive for COVID-19. So again, probably… And many of those were attributed to TB and HIV. So again, you know, many cases, that probably were misdiagnosed as part of registration. Just to follow up, you know, for that second surge that we saw, that ended, you know, knowing that there are extreme housing issues, much of South Africa lives in townships – what public health measures were put in place to prevent transmission, outside of international travel?
Adri Kok: Yes, it was attempted and still ignored to a large degree – especially by younger people – to adhere to, for example, just face masks, hand-washing, and keeping social distance. So unfortunately, it’s almost a challenge sometimes to not wear a face mask and to try and have these meetings, especially when there have been mass gatherings that [the authorities] have tried to prevent. So there have been limitations on funerals, for example, numbers of people attending weddings, etc. So trying to just curtail as much as possible: [at] any sports events, there is no audience; they’ve stopped all, for example, cinemas; … limitations at shopping centers, for example, the number of people in the shop. So all of those have been done. They also stopped at one stage the sale of alcohol and tobacco. That wasn’t such a bright idea because the black market unfortunately exploded. But yes, it was an attempt to… and I must say, interesting enough, during the winter season, here we saw almost no influenza or pneumonia. It was really quite amazing what a difference it made during that time. But yes, so, some measures have been successful, but many have not been able to curtail this. There are still non-believers. There are still people who think this is all a hoax, especially with the vaccine rollout. We’ve had major issues to try and convince people that this is actually an intervention that could make us go back to some kind of normality. So yes, some measures worked, some definitely didn’t.
Zain Chagla: Yes. It’s fascinating for sure, and that’s one of the environments I’ve been very intrigued about. It’s the way it seemed to end in December, as quickly as it started, and again, you know, with such vulnerability in the population it was a bit questionable in terms of what happened. They still can’t figure that out, in chatting with some of your colleagues. A couple of questions. One on discharging people in South Africa and DOACs and heparin and practice. And probably anyone else on the panel who wants to chime in too – for patients who required them, have they been aggressive about discharging patients on anticoagulation as part of their COVID-19 stay?
Adri Kok: We just… what sort of generated the idea to do this is that we had massively elevated D-dimers in many patients. Obviously, also with the inflammatory response. Low-molecular-weight heparin in South Africa is quite expensive and the DOACs were much more affordable. And of course, in some patients, there were actual pulmonary emboli, which of course would then necessitate much longer [treatment]. But for patients where the emboli were not proven – it was just purely COVID-19-related elevated D-dimers – we did continue for 14 days. I mean, there is no data to show that that’s a definite yes or no, but we had very few patients return with complications so far, in my experience. So I mean, it’s anecdotal, but we’ve developed an ICU group where we communicate with one another and give advice. And this is sort of being experienced on that site. So very interesting to hear what other people have found.
Zain Chagla: Does anyone else on the panel have any thoughts around anticoagulation and moderate to severe COVID-19 patients being discharged back to the community?
Adri Kok: These are definitely moderate to severe patients. So, they were on supplemental oxygen, sometimes in intensive care, and at times even discharged home on oxygen, if we needed beds for more ill patients. So we really… mild patients never actually got to hospital.
Zain Chagla: Yes, does anyone have any discussion? In our local practice I think it has been much more, if people are discharged, then the anticoagulation stops a discharge. But you know, it does give us pause there are a lot of people that probably are being discharged for healthcare capacity reasons that would probably stay in hospital a little bit longer relative to you know, pre-pandemic, in that sense. Dr. Garibaldi, I think you are about to chime in, it looks like?
Professor Brian Garibaldi: Yes, so you know, I think this is a difficult issue. We have not been by and large continuing anticoagulation post-hospital-stay for all patients, but it really is context-dependent, right? So if someone is going home to a situation where we know that they are not going to be very mobile, they had high inflammatory markers, they are really sick, [then] there have been some cases where we will extend [an] anticoagulation course for them for a couple of weeks, but that has not by and large been the practice for most patients once they are discharged.
Zain Chagla: Yes, fair enough. It seems like that’s much more the local context for sure. But again, one of these areas where it’s still very undefined and I think we are going to hear a little bit about thrombosis anticoagulation with the next set of speakers from what I recall. OK, I will turn it over to you, Dr. Kok, for the next set.
Adri Kok: That would be great, thank you. So, Dr. Garibaldi, you are next with questions for you, but I also thank you very much for a very interesting presentation from Johns Hopkins. The question is: “Do you think that the use of tocilizumab, if it’s used too early, could actually cause a risk of increased mortality?” Is that something that you experience at all?
Brian Garibaldi: Well, I think that’s what we worry about, right? I mean, we worry about the balance of you know, trying to go after antiviral therapies early and then trying to thread the needle on when to start anti-inflammatory therapies, with the hope that you can tamp down inflammation, but you don’t impair viral clearance. Unfortunately, we really just don’t know the answer to this question. I think this gets back to the broader issue of, you know, when is the right time to start tocilizumab, who is the right patient to start tocilizumab and, you know, the evidence has been a little bit all over the map, right? We have several different studies that have shown no benefit. More recently we’ve had some high-quality studies that seem to show a benefit in a select sub-set of patients. You know, early on, before we recognized the benefits of dexamethasone as an anti-inflammatory, we had very strict criteria for tocilizumab. You had to be on oxygen [and] you had to have elevated inflammatory markers. We had a home-grown IL-6 acid that we could send. So you had to have IL-6 greater than 100 or you could sub in a CRP or [erythrocyte sedimentation] rate or other, you know, elevated inflammatory markers. And when we looked backward, when we did a retrospective study of those patients who got tocilizumab, who met those criteria, there was a signal from mortality benefit. So we, you know, that was about 100 patients that had used tocilizumab early on. I think knowing when to use it when you are already on dexamethasone becomes a little bit more challenging. And so, we are no longer using strict IL-6 cut-offs. You know, you can sub in a mildly elevated CRP. And we’ve been using tocilizumab more for patients who are on [remdesivir] – most of our patients get remdesivir if they come to the hospital within 10 days of illness onset; most patients who are heading towards the ICU will get dexamethasone. It’s really a judgement call, if you think the clinical trajectory is rapidly accelerating or within 24 hours of them ending up in the intensive care unit, that’s sort of the window on which we talk about using tocilizumab, but I think we’ve been using a little bit more since RECOVERY and REMAP-CAP have come out, suggesting that those might be the patients who benefit. We also have a pretty large solid organ transplant patient population, where our transplant infectious disease doctors have been more aggressive in using tocilizumab in those patients, even if they are not yet in the intensive care unit. We have not clearly seen a signal of increased infection rates in those patients, which, you know, I think, has been borne out in all of the large studies that have looked at toci[lizumab], even if it hasn’t shown a benefit. So I worry less about the secondary infections and more about [whether it’s] too early in the process, is this someone who we really think is going to get better without it. So I think it’s really sort of pace of progression and those people who are sort of sky-rocketing towards the ICU – that’s when we’re using it.
Adri Kok: And I think we used sort of a combination; we used ferritin LTH, we had an IL-6 that was easily and quickly available. CRP temperature was useless. We didn’t find that many people that had a high temperature. So we used those almost like in combination, we had to make a decision because it wasn’t as easily available in South Africa, for example. We used the steroids quite early on, even before international opinion sort of said that this is the way to go. And then also, we used anticoagulation quite aggressively. So we tried to target and in fact a  level of up to 1, 0.81, to sort of see that the patient was adequately anticoagulated. So that’s sort of the kind of person that we used as a possible tocilizumab patient, but we also used remdesivir in combination. I’m sure again, as you did, you know, we learned as we went along what would work best in most patients. The other interesting point, because you mentioned about ebola and your experience when you had interventions in West Africa. Do you think that we are going to have future epidemiological challenges of these infectious diseases? Maybe COVID-19 variants, maybe other coronaviruses? Do you think there is any way we could predict this for the future?
Brian Garibaldi: Well, yes, obviously it’s hard to predict, but I think the answer is almost certainly “yes.” There is a paper that came out of a group at Duke that’s been studying coronaviruses in Malaysia and they found, they looked at people hospitalized with pneumonia in Sarawak, which is a region in Malaysian Borneo. And they found novel coronaviruses that previously had not been reported as infecting humans. And you know, not like 2% of the cases, right? So they didn’t document human-to-human transmission, but I think, as we continue to expand our footprint and our sort of interaction with the environment, a lot of these zoonotic infections are going to have the opportunity to jump into human hosts, probably from agricultural and farm-related industries. And then I think, by chance, one of them is going to have a mutation that allows it to spread. So you know, I think we need to work together on a global standpoint; just as we recognize [that] this current pandemic is not over until it’s over throughout the entire world, I think we really need to think about how to set up better surveillance globally so that we could have a little bit of a warning sign. We know that we can move fast with some of these new vaccine platforms. I think we’re a little bit lucky that this is a coronavirus, and that was one clear epitope that would be very immunogenic and so we are able to very quickly turn on vaccine production, but I think we need to think about what the surveillance networks look like internationally, so that we can be prepared, [can] have a sense of where there might be a risk of something jumping. And actually be proactive about getting diagnostic testing right and also getting future therapeutics right.
Adri Kok: And I think the limitation in travel was really one of the learnings from this whole pandemic. You know, and again, [in] some countries … the pandemic hit them later than others, depending on how the different patterns of spread occurred. So the one other question was: what about – you spoke about budesonide – was there any specific dose that you used and were the benefits mainly with systemic effects? Or do you think it was more local in the lung itself?
Brian Garibaldi: Yes, we have not been using budesonide here. I mean, I know there is interest and thought that perhaps it can reduce [the] duration of symptoms; there are some studies coming out suggesting it may have a role. You know, I would imagine it’s probably a local topical effect. … There have been studies done on many BALs of patients who have SARS-COV-2. We know that the inflammatory environment is different in those patients locally in the alveolus, it’s just from the BAL samples. There is a group at Northwestern that’s been doing a lot of work on this. So I suspect it’s probably altering the inflammatory unit in the alveolus itself, as opposed to having systemic effects, if it’s effective. We have not by and large been using that as a therapy here in our center. And I think if it has a role, it’s probably more in the out-patient [setting], you know, early on, as opposed to someone who is already on the ventilator and has, you know, full-blown ARDS. But certainly, a therapy of interest and you know, as things are really out of control in a lot of places in the world right now, things that could potentially be inexpensive, relatively safe, and impact people in the early stage of the disease, I think it would be an incredible way to decrease the load on the healthcare system. I’m just not sure if the evidence is there yet saying that it’s truly effective.
Adri Kok: We tend to find that the patients had a very  type of sputum, almost jelly-like; it was difficult to clear even with physiotherapy. So we did use in some patients hypertonic saline nebulization to clear the phlegm and then obviously also bronchoscopy to try and improve. And we tended to do early tracheostomy in these patients. I don’t know if that’s something that other panelists maybe have done as well?
Brian Garibaldi: I think early on, we had a lot of experience with ET tubes clotting with  mucus and having to do tube exchanges, which is pretty rare, unless there is a mechanical problem with the balloon, right? That we don’t usually just hand out ET tubes. Looking back, I think a lot of that was related to infection control policies that we instituted initially to try to reduce aerosolization. So we actually moved away from using humidification in the vent circuits for a very short period of time. And once we went back to saying, “you know what, we need to do this,” once we went back to the humidified circuits, we had not seen that issue. So I’m not sure if that’s something… we have not needed – in more select cases, yes – but that has not been something we’ve done commonly.
Adri Kok: OK, that’s great. Thank you very much. And then over to you, Zain. There were some questions specifically at your presentation, but please, if other panelists feel that they can contribute please do so. There were just the questions specifically about the use of tocilizumab, and I think this is one of the open questions. Do you use specific criteria in your unit to use this agent? Do you use, for example, your inflammatory markers or how do you make a decision [on] when to use this agent?
Zain Chagla: Yes, absolutely. So first of all, I just want to go back to the budesonide question, as I think it was in my presentation. So the 2 trials, DOAC and PRINCIPLE, used the dose of 400 per puff, 2 puffs b.i.d. And the durations were a little bit off: some were 40 days, some were just until symptom resolution. It was OK data to, you know, start the question, but it wasn’t necessarily [that] I think the data changed the standard of care. That being said, in resource-limited settings it might be a nice adjunct to keep people away from hospital for something that’s actually relatively simple. And there is a large ongoing clinical trial across Canada and the United States for other inhaled steroids, it’s placebo-controlled. So that will hopefully answer that question a bit more. For the tocilizumab question, our practice has been kind of a combination of the criteria that were used in RECOVERY and RE-MAP CAP. So we have prioritized anyone who is on oxygen, definitely prioritized people that are early critically ill patients, that are going to the ICU, needing organ support, or [needing] respiratory or cardiac support. And using at least for the ward-based cut-off CRP [value] of 75 – we don’t have IL-6 levels reasonably well – or you know, discretion amongst patients who might not make as much of a CRP response because they are transplant [patients] or heavily immunosuppressed; they may still be very pro-inflammatory despite that. And in the ICU, anyone with early respiratory deterioration essentially meet [the] criteria at that point. The other couple of things that we’ve done differently – number 1 is because of resource scarcity – we’ve actually halved the dose of tocilizumab. This is based on the fact that the 800 dose was largely based on CAR-T data for cytokine storm syndrome. When you look at IL-6 inhibition in patients with things like rheumatoid arthritis and COVID-19, it actually is much lower levels relative to CAR-T and cytokine storm. And so you know, that’s where that 400 rather than 800 or a weight-based dose kind of came together. Also, that just doubled our supply. And then the other part of RE-MAP CAP and RECOVERY that is a bit hard, [which] we’ve never actually used [is] the ability to give a second dose of tocilizumab to people in 12 to 24 hours if their first dose wasn’t great, or they didn’t show improvement. And again, given resource scarcity, we wouldn’t… we aren’t doing it for the sake of, you know… It’s hard to say patients will improve remarkably in 12 or 24 hours when you are resuscitating them and again, [so] to use another dose on someone just because they are still in the resuscitation period is a little hard in that sense. Actually, I’d love to hear from you guys, though, Dr. Garibaldi, Dr. Kok, maybe your experience with tocilizumab and how you dealt with resource scarcity as well?
Adri Kok: Yes, I think we – maybe just from our side – answer, that it was reserved for the patients in an intensive care setting that were on supplemental oxygen with a deteriorating picture but high inflammatory markers. As I said, we have an interleukin-6 level that’s available quite quickly. And I mean, throughout, these patients presented with excess of 100, we had levels up to 5000, 10 000 even, and in that situation it was easy. They also had worsening clinical symptoms and deteriorating gases. So you know, that was really the case where we tried to use it and we used it with remdesivir at the same time. And then of course, the steroids, low-molecular-weight heparin, etc. I don’t know, Brian, was there anything [else] from your side?
Brian Garibaldi: Yes, I would say, you know, this is still a case for tocilizumab; it was definitely very scarce early on and we had to make sure that we reserved enough doses for patients who were already scheduled to get CAR-T therapy early. It’s still run through a central committee, so you can’t just order it. You actually have to meet certain criteria and then present your case to a centralized committee who actually are aware of how much dosing we have in the hospital [and] what the current needs are for other patients. So we have more of it available now than we did previously, but that’s still a fairly tightly regulated drug. You can’t just decide I’m going to give it without, you know, going through a process, which I think is made us more thoughtful about using it and has probably helped us make sure that the patients who – as best as we can tell – are likely to benefit are the ones who are going to be getting it.
Adri Kok: Thank you.
Zain Chagla: Sorry. I think Dr. Iqtadar wanted to come in on this conversation, too.
Adri Kok: OK, that’s why there was a question. Yes, thank you.
Dr. Somia Iqtadar: Yes, thank you very much. I just wanted to add that I also see a lot of COVID-19 patients, so we do use tocilizumab in our clinical setting here in Pakistan. And we have a central committee who assesses every patient for the cytokine storm. So we have these criteria that if there is the aspirated deterioration requiring increased oxygen demand – more than 10 liters of oxygen – if there are increasing infiltrates or if the inflammatory markers are high, then we assess this [in] every patient. Tocilizumab is provided free of cost in all government hospitals to the right patients, but it has to go through a central committee for infectious diseases [consisting] of specialists and pulmonologists. So, they see [whether] they fulfill the criteria, then we do give tocilizumab in our critical patients. And we have seen some good results if given in a timely way, in [the] very small window which, you know, the cytokine storm is. And we do have IL-6 levels in our country and we go for them, but it’s not readily available. So if the patient is fulfilling the clinical criteria, we just go for it, but if we are in suspicion, we go for IL-6 markers and we make sure that the patient is not in sepsis by doing a procalcitonin level along with it. And obviously, if the patient is in sepsis we do not give it because there are chances of deterioration of those patients. But we have seen some really good results with decreasing oxygen demand and clearing of the infiltrates with the use of tocilizumab. And this is [turning] out to be one of [the useful] interventions in the management of COVID-19.
Adri Kok: And we also just asked, I mean, we didn’t see – and I don’t know if anybody else has the same experience – we really didn’t see any secondary infection or sepsis as the result of using tocilizumab in this setting. We tended to avoid antibiotics early on, even if the  was high, we did blood cultures and sputum cultures to see if there was any secondary infection and even if the CRP was high, you know, this was part of the inflammatory process. Did you also see that it was seldom a problem to use it in these patients? You didn’t cause sepsis with it?
Somia Iqtadar: Yes, well it didn’t cause sepsis with patients who are borderline and who already have a high TLC and are on high-dose steroids. They sometimes into a state of shock, and the infection prevention control measures are really not up to the mark in the government set-up hospitals in our country. So we do keep in mind that we have a close follow-up and we do the blood culture and sputum cultures in these patients before we initiate any such treatment which can likely make them to go into sepsis.
Adri Kok: Is there anybody else who wants to comment?
Professor Jyotirmoy Pal: May I make a comment? I’m Dr. Pal from India.
Adri Kok: Thank you, Dr. Pal.
Jyotirmoy Pal: Yes. In India, we are very seldom using tocilizumab, but usually in India, we recommend single dose because [with the] double dose, there is a [high] chance of secondary bacterial infection, we have observed in India, and that is why patients deteriorate. And now we are observing a lot of nuclear mycosis – it’s a fungal infection in the post-COVID-19 period – those patients are receiving tocilizumab [in] 2 doses or long-setting diuretics or patients get steroids but for a prolonged period. Now [they are] getting lot of nuclear mycosis from India. And most of the cases come from India . So in India they are getting tocilizumab [00:36:03].
Adri Kok: Thank you very much.
Somia Iqtadar: Regarding the nuclear mycosis, we haven’t seen much nuclear mycosis, 2 cases of aspergilloma in the initial phase, in the first and second waves of COVID-19 that we had in our country.
Jyotirmoy Pal: Madam, in which country?
Somia Iqtadar: I’m from Pakistan. And at present, I have 179 patients admitted to the COVID-19 unit in my hospital and we have 2 cases of nuclear mycosis. And 1 of them is a newly diagnosed diabetic, the other is a known diabetic. So, we do not see a lot of nuclear mycosis, but there were hardly any cases in the first and second waves, but in the third wave, currently, we have 2 patients admitted with the nuclear mycosis.
Jyotirmoy Pal: Madam, it is possible to see [this] in Pakistan because nuclear mycosis is mostly in the western part of India. That is the border region with Pakistan, so probably in that region –  Rajasthan, Punjab and that area – is probably getting more nuclear mycosis.
Adri Kok: Thank you. And then, just to get back to Zain, you know, there are a lot of conflicting results from the RECOVERY trial. I think part of the problem, as we’ve all shown in each of our settings, is that we sometimes have to make a decision on using these agents – and that goes for other agents as well – on the best evidence that we have. Do you think the RECOVERY trial is sort of the final answer, although there were previously some contradictory results where it didn’t show that it necessarily made such a difference? Do you think it was just a different cohort of patients and that’s why it didn’t show the benefit, that maybe as we’ve done the same as in Pakistan and as Dr. Garibaldi and yourself have done, these have been the more severe patients we’ve been successful using it with?
Zain Chagla: Yes, I mean, you know, I can say from 2 standpoints: one is being involved with one of the early tocilizumab clinical trials, in COVACTA, which was, you know, a lot of moderate to severe patients. We didn’t use biomarkers. It was placebo-controlled, but we really just gave it to pretty much everyone who was hospitalized, and saw what happened. You know, I think, number 1, the sheer numbers in RECOVERY kind of give you a bit of pause to say [that] if there is a signal, it’s going to show up there. And it seems to. And then, number 2, I think you know, that again, using a cut-off of inflammation, even if it’s a bit blunt of a tool, does give you a certain patient profile, right? There are patients that are admitted to hospital for complications of COVID-19 that are mainly thromboembolic and not particularly hyper-inflammatory. There are patients that are admitted for COVID-19 with, you know, organ dysfunction that isn’t particularly inflammatory. And so again, those patients probably won’t benefit from tocilizumab. The RE-MAP CAP criteria similarly looked at patients who were in early deterioration, likely as a surrogate for really impactful cytokine storm. And again, you’re starting to identify the subset of patients that seem to be there. But the one thing that gives pause is [that] there were still some issues in RECOVERY; it’s not a perfect trial. There was about 16% of people that were assigned to tocilizumab that never received it. So again, we don’t know exactly what their outcomes were. And you know, we have negative trials and so you, in the meta-analysis even that was included in RECOVERY, they were a lot of negative trials and what was fueling the use of tocilizumab was RE-MAP CAP and RECOVERY in that context, right? So as more trials come out, I think we might see again more conflicting data. It’s going to be ever weirder to try to consolidate all of this together.
Adri Kok: That’s on the chat, but because something that caused great confusion in South Africa was ivermectin. And [do you think] there is any sort of evidence… We just really ignored that, but some people went and actually had a stash at home of ivermectin. And then the other one is convalescent serum. I’ll just put the 2 questions to you at the same time or anybody on the panel that want to comment.
Zain Chagla: Yes, I think Brian: we were just trying to get on the last point there, but I’ll take it from there, yes.
Brian Garibaldi: Well, I was going to say [something] about the tocilizumab question. I think the right, where it’s kind of narrowing down, getting closer to who might be the patient who is the most likely to benefit. One of the challenges I think we’ve had with recovery in general is that – you know, it was a great study, it’s provided a ton of information about a number of different therapeutics, but it’s also in a health system that’s different than most other countries health systems, right? And so when you just kind of look at the baseline mortality rate in patients with COVID-19, it’s pretty high. I mean, if you look at the mortality of patients who met the criteria for RECOVERY, you know, the placebo mortality rate was 35%. And that’s higher than what we’ve seen in our patients who’ve met similar criteria. So how do you apply – you know, there is clearly a mortality benefit in their study and there might be in our study, but how do you then apply that same mortality benefit to a different health system, a different context, and know if that same benefit is really going to apply to the patients that you are seeing in your own health system. I think that applies in both directions, right? Going to the US, going to India, going to Pakistan, going to Canada. There are so many other factors that have changed over time that affect outcome. Just I think we’re narrowing down to a subgroup of patients who likely benefit from the drug, but it’s probably narrower than the inclusion criteria for RECOVERY, right? There are probably some patients who are not benefitting from tocilizumab [but] who are getting it right now because we still haven’t quite narrowed it down.
Adri Kok: Perfect.
Zain Chagla: Sorry, go ahead, Dr. Pal.
Jyotirmoy Pal: Yes, yes. For the ivermectin, there are many conflicting results. And the WHO had put a question mark over the use of ivermectin, but in India also there are several studies conducted practically more on the healthcare worker. In Calcutta, what we have done on the healthcare worker in the pre-vaccine era, the group that have taken the ivermectin usually suffers less mortality and milder disease. Similarly, we have observed for Bangladesh, our neighboring country – their data has been published – they got a better result from the use of ivermectin on healthcare workers. So, the eastern part of our subcontinent, [has] almost a similar result. So another result we published from our part. Still in the Indian guideline we have kept ivermectin till now because of the benefit of doubt. And we have least weapon, apart from vaccination to fight COVID-19 and to protect the healthcare worker.
Zain Chagla: Yes, I mean, the international data for ivermectin has been really conflicting. There have been studies in Brazil and elsewhere in the world, even mild to moderate to severe COVID-19, where there hasn’t been effects. You know, the question that still is on the table is very, very early kind of post-diagnosis treatment – whether or not that could be linked through McMaster and I think even through collaboration between McMaster, South Africa, and Brazil, there is the together trial, which is looking at ivermectin, fluvoxamine, and metformin, actually, as early therapies for people that are diagnosed. And I think, I was reading today actually, a group out of the University of Minnesota is going to spearhead an arm in the United States as well to mimic this. You know, that is one area of concern. I will say though that there is a large amount of alternative and low-yield information on ivermectin that really has driven some of the agenda around this drug. And I think Dr. Kok’s experience probably in South Africa – you know, certainly our experience in Canada and you know, a large clinical care group in the United States I know – have really kind of driven a bit of the agenda-based misinformation of the drug. Does it have benefits in vitro? Yes, but again, the time to administer, the dose to administer – which is the biggest part – the in vitro data really is not that convincing that you could actually get to an in vivo dose that would not be toxic, which is again, just the other part of this in that context, in that sense. I will also invite Dr. Rochwerg, who is joining us, to just maybe from the World Health Organization’s [view], as Dr. Rochwerg is part of the rapid review from the BMJ [British Medical Journal], the WHO, I believe, and in terms of his perspective and then maybe we will just toss around convalescent plasma as well.
Professor Bram Rochwerg: I appreciate it, Dr. Chagla. Thanks for the opportunity. Yes, I did work with the WHO as methods chair for recommendations we previously established on a number of drugs, but ivermectin was one of them. And you may be familiar with the recommendation that was published at the end of March: it was a recommendation against ivermectin except in the context of clinical trials. And this really was driven by the quality of the RCTs that are out there. And no doubt if you look at the point estimate, it looks quite convincing. But when you sit down and do a careful risk of bias assessment, looking at a comparison of published protocol versus the outcomes that were reported, looking at blinding, looking at how well randomization was done, this sort of thing, there are a number of issues around the risk of bias with a number of the trials. And certainly, that signal for a dramatic benefit is not as strong when you focus more on the low-risk-of-bias trials. And you know, the group of experts with the WHO ended up saying, further research [was] certainly warranted, but [they were] strongly against for the time being. [Another] very compelling [thing] was [that] we had expert pharmacologic input that sort of got to that point you just mentioned [that] the anti-inflammatory and anti-viral effects of ivermectin are a bit of a stretch from a pharmacologic principles perspective. And certainly, everyone talks about the safety of ivermectin, but the doses that were used in a lot of these studies were much, much larger than what we use for strongyloides and anti-parasitic infections. And there have been reports in widespread use in Peru and other jurisdictions of liver failure and complications from such high doses of ivermectin. So I think until we have better reports and hopefully – you know, you look at trial registries [and] there are 70 RCTs ongoing at the moment, looking at ivermectin for COVID-19 – so I’m hopeful that we will have more data informing this soon. I listened a little bit to the end of the tocilizumab discussion and I do think it’s interesting and we have a living network meta-analysis that informs the WHO guidelines. And I won’t let the cat out of the bag – we’ve just made a recommendation which will be released in the next couple of weeks – but suffice it to say that when we did a careful subgroup assessment, looking at severity of illness, timing of administration, dose, and linking to inflammatory markers, we did not find credible subgroup effects for any of these. And hence, you know, my sense is that the relative effect of tocilizumab is probably fairly consistent across the severity of groups and across inflammatory markers, though the key is that the absolute effect is going to vary, right? So if you get that patient that’s just been admitted to the hospital, the absolute bang for your buck of giving tocilizumab is probably going to be smaller as compared to that patient with a CRP of 150 that’s escalating in FIO2 and respiratory requirements, on their way to the ICU. So I think using some of these principles around clinical deterioration and elevated inflammatory markers are maybe more triage principles rather than, you know, effectiveness. It’s probably still, I think, relatively effective to give to that patient sitting on 1 or 2 liters, but given this context of not having widespread availability of tocilizumab, if we’re going to triage, probably focusing on this group that has the highest absolute benefits, i.e. the clinical deteriorating patient, is best. I will stop there. I appreciate the opportunity to provide input.
Zain Chagla: Yes. I could continue the conversation along on convalescent plasma, because it’s the other kind of major thing that’s come up. Again, the RECOVERY trial is a fairly negative trial, but it’s in the context of actually multiple negative trials. RE-MAP CAP again was a negative trial. The C3PO trial which was done at, I think, the University of Minnesota, again, had to be paused due to essentially the DSMB [Data and Safety Monitoring Board] showing … essentially futility in continuing. And that was in very early COVID-19 and even our local Canadian trial, CONCOR-1, which was paused and stopped because of again DSMB saying there is going to be no statistical way that you can actually show benefit here. You know, there are still questions about RECOVERY: there is a very potential, minor subgroup that might benefit from convalescent plasma and, you know, even looking at the subgroup analysis, which again, has caveats, but potentially people with low titers getting high-titer serum – you know, it’s a hypothesis-generating question, as compared to anything else, but in the grand context, a practicality of actually establishing that very quickly amongst patients in the setting – might make it just incredibly ineffective to actually use it; and the number of patients that you actually give this to who probably don’t meet that criteria is going to be very much an issue. And I think, again, you know, from a global standpoint and certainly from some of my collaborations with India, there is a black market for convalescent plasma that is fairly aggressive and may actually detract from you know, much more evidence-based therapies as compared to what is thought to be a very significant therapy, which likely does not have the effect. I am actually going to toss it to Dr. Loeb and just if there is any comment from the global standpoint in the collaborating center for this.
Jyotirmoy Pal: Yes. In India, we’ve conducted 4 studies on convalescent plasma in 4 major cities: north, east, west, and south. In all studies, it was uniformly disproved that convalescent plasma has no benefit in terms of mortality and morbidity, even though it does not decrease the duration of illness or duration of severity or other time period, in the typical care setup. So recently, the Indian Council of Medical Research has given the advice that convalescent plasma not be used in India in therapy. And another point, [00:51:40], because we are discussing the ivermectin in all Indian studies, it has been shown uniformly that in situ it has no prophylactic or therapeutic role in COVID-19 management. But still, ivermectin has a doubt for, some conflicting role, but in situ in all studies [it] is rejected. I don’t know what the other results [are] in the other countries, [but] that is in India.
Adri Kok: Professor Loeb? From your side?
Professor Mark Loeb: In terms of convalescent plasma? Is that the question?
Adri Kok: Yes, yes.
Mark Loeb: Yes. I think if you look at the totality of evidence, it seems like if you have healthcare dollars to pursue randomized controlled trials, that’s not where I would be putting my resources right now, given the evidence. Some could argue about the timing etc., but I just don’t think it’s the way to go in terms of what’s been seen so far.
Adri Kok: And maybe I could just ask on your lecture, on community-acquired pneumonia. Obviously, in some instances people did jump to antibiotics, it was patients with COVID-19 who would present with a high CRP. And I mean, we’ve been very conservative in South Africa [and] we’ve actually advised against using any antibiotics, rather focusing on the inflammatory markers. Do you think it’s always imperative to use an antibiotic in COVID-19? Or would you also agree with limiting antibiotic exposure?
Mark Loeb: Yes. Well, I would agree with limiting antibiotic exposure. I mean, the bottom line, it’s not always easy to say, right? So there are obviously a lot of overlaps between clinical symptoms and signs for community-acquired pneumonia and COVID-19. So I think you have to… you know, if you look at the context or the evidence, there were early studies that had suggested maybe a 25% event rate of co-infection between COVID-19, pneumonia, and bacterial super-infection. But as the pandemic was rolling out, it appeared that the entirety of the evidence is that it occurs in less than 10% of individuals. So you know, I think that you’re not going to have randomized controlled data for this sort of questions. So you have to use a pragmatic approach. If you have someone with relatively mild or moderate disease, you know, good contact, in terms of COVID-19 and exposure, and they’re coming in, there is no reason why – you know, all of these patients need empiric antibiotic therapy to cover them for the potential of co-infection – however, if you have for some reason you suspect bacterial infection, you have someone who is clinically unstable going to critically ill, then it’s hard to say well, you know, risk to benefit it might be worthwhile in those circumstances to treat empirically then to watch carefully over 72 hours. So I think the real issue is you make a decision, if you feel you have to re-assess it soon, rather than just, you know, just continuing on.
Adri Kok: One of the questions that came through was whether in a person that had been exposed to a previous hospitalization and now presents with community-acquired pneumonia, if you looking at the reason for hospitalization, how recent must it be to influence your choice of empiric antibiotics? Is there sort of a cut-off or a guideline on that side?
Mark Loeb: Yes, so it’s an interesting question. I would reframe the question, rephrase it a little bit in terms of recent hospitalizations. I would say recent antibiotic exposure, because that’s really what’s important, right? And in the studies that have looked at this have looked at exposure of pneumococcus and the effect is class-specific. So the studies haven’t gone back beyond 3 months; we’re talking about 3 months and more recent. So if you look at 3 months, there is a class effect that within 3 months’ macrolide exposure, you might not well be back at baseline in terms of your risk of resistance. So if someone has had a macrolide within 3 months, it would be worthwhile to change the class. But interestingly, it changes by the type of exposure. If you look at quinolones, within about 2 months they are back to baseline. So there, within a 2-month period, [and with] penicillin [or] cyclosporine, somewhere between 2 and 3 months. So, let’s say – again, it really depends on the class of antibiotic. But that’s sort of a ballpark way of thinking about this.
Adri Kok: Zain, any questions from your side for Professor Loeb?
Zain Chagla: Yes. I mean, Mark, the pneumonia in out-patients and particularly in settings with high levels of resistant gram-negative organisms, so many international partners, would you consider a change for things like beta-lactam-based therapy in the face of high levels of you know, colonization with ESBLs, particularly in out-patients at higher risk of gram-negative pneumonia, as compared to the typical community-acquired pneumonia.
Mark Loeb: Yes. Well, Zain, I would say first of all, if you look at the entirety of the evidence on – you know, community-acquired pneumonia that is treated as an out-patient… almost anything works, right? So these are not… there is some systematic review I’ve ever seen, as you could go throw anything at it and it resolves. So I think it’s a little bit different if we’re talking about someone who is coming into the hospital and they are pretty ill. I would say that again, [in] an out-patient, I would not be throwing cholestene and multiple drugs at someone because of previous history of some sort of multi-resistant gram-negative. Again, I would go the current guidelines. Again, because you’re talking about colonization, again, you know, from endonasal ferrics, right? And gram-negative pneumonia generally – particularly for those who are so mild to be treated as out-patients – it’s relatively rare to begin.
Zain Chagla: And I think the last question I think I have for you is: Does milder asymptomatic influenza infection often precede community-acquired bacterial pneumonia? And does it influence the choice of antibiotics? Do you think influenza vaccine may actually reduce the rate of the community-acquired pneumonia, bacterial pneumonia? And I’ll actually caveat that: there was actually, I think a study that came out in South Africa, just yesterday or the day before, looking at the rate of asymptomatic influenza infections amongst populations and suggesting up to 40% of their samples were asymptomatic influenzas. And potentially is it more that there is a synergy here, that they’re often the hallmark of developing pneumonia or is there anything to be done with that?
Mark Loeb: Yes, OK. So we can break this down. First of all, pneumonia occurring after any upper-respiratory viral infection is well documented – not only for influenza, [but] for RSV, for a number of viruses, number 1. Number 2, the bacteria is usually pneumococcus or Staphylococcus aureus. So it’s well established. Number 3, the evidence base is not the greatest, because there is no inception cohorts, right? So all of these studies usually start at the wrong end. They start instead of following people who have influenza and saying, “OK, how many of these individuals are going to get, you know, a pneumococcal or staph aureus infection?” They don’t do that. They start at the hospital level and they say, “aha, let’s look at people we’ve admitted with community-acquired pneumonia and let’s do some swabs on them and let’s see.” So it’s the wrong end. Probably because it’s very hard to do, you know, in such weak cohorts. So we’ve been doing flu randomized control trials in adults and children for about 15 years. In a typical season we would have a thousand individuals that we followed. Some people are vaccinated, some people that are not vaccinated. And you know, we get 100 to 150 cases of flu, but we will only get 5 or 6 cases of lower respiratory tract infection of pneumonia. So not nearly enough to answer the question. So the answer, really carefully, I’d say it’s very, very difficult. So there is no reason why qualitatively you would assume that there would be a different type of organism, you know, it’s going to be more commonly pneumococcus or staph aureus. So I don’t think it changes the management at all. A good question is “does influenza vaccine reduced pneumonia,” right? I think that’s a sort of related question. And that’s also very interesting because if you look at Cochrane reviews that looked at randomized control trials, they’ve looked at vaccinated, let’s say, high-risk older people and compared them to placebo and they found hey, there is no evidence that the flu vaccine does anything for the complications of influenza like hospitalization [or] pneumonia. Those are the key ones, which is sort of interesting. But they didn’t include the sort of high dose versus standard dose influenza vaccines. So if you look at those, there is a bit better evidence that it runs towards reducing complications. In other words, there is some evidence that I’d say high dose, not the greatest, because often it’s a trend towards it. But it doesn’t rule it out. It’s suggestive of a reduction in the complications, which are pneumonia and hospitalization. The other thing is there have been cluster randomized control trials in nursing home residents where they didn’t actually look at influenza infection, but they looked at the heart outcomes – cardiopulmonary hospitalization – where they found a difference. So it depends on what you look at. And the newer or the more novel findings are the core questions, whether flu vaccines… there are observation studies that suggest that influenza increases cardiovascular adverse events, right? So the question is, “is there randomized control trial data that does anything for adverse vascular events.” And there are a bunch of little studies that when you do a meta-analysis, you find a sizeable effect. The one randomized control trial now that was published in JAMA in December compared high dose influenza vaccine to regular dose. It didn’t find any effect. The study was stopped for futility. Now, we’ve been doing a study, we’ve got 5000 individuals enrolled and within 6 months we will see, we’re comparing influenza, inactivated influenza vaccine to no vaccine in probably about 12 countries. So that’s the second study that will come out and we’ll see if there is an effect of influenza vaccine on adverse vascular events.
Adri Kok: Thank you very, very much for that contribution. Dr. Pal, just to come to you quickly. We’ve only got a few minutes left. Just on the TB: there was a question about extrapulmonary TB. Do you still have to treat these body fluids as infectious when these fluids are submitted for assessment in MDR-TB?
Jyotirmoy Pal: No, no. Body fluids are not infectious. TB spreads by aerosol; that is [01:03:41] close contact only. So basically, TB does not spread by the fluid. So even in India, when we aspirate the fluid, we hardly see, we do not quite need that because it is not infectious.
Adri Kok: Right. And just a question to Dr. Iqtadar about dengue fever. Do you think that, you know, in bacterial sepsis we found that starches were harmful. You seem to suggest that this would be a good fluid to use to resuscitate patients with dengue fever. Why do you think there would be a difference between these two experiences?
Somia Iqtadar: In septic shock the mechanism of development of shock is entirely different from the shock that we see in dengue. Actually, in dengue hemorrhagic fever, in dengue shock syndrome, there is a transition of fluid in  spaces because of the phenomena of [01:04:43] leakage. And we need volume expanders to maintain the intra-circulatory volume. So that’s why we start with hyperoncotic solutions like dextran-40. They are used in dengue because they keep the fluid in the intravascular volume for a longer time. On the other hand, in septic shock, we have [01:05:04] vasoconstriction and therefore, we usually use norepinephrine for treating [this] shock, and the volume expanders and the fluids are not of much help in these patients.
Jyotirmoy Pal: And I have one comment on this. In dengue shock, we do not use dextran because it increases the probability. So basically in dengue shock we use the human albumin. We do not the dextran, because [01:05:35] profile and dengue is very prone to alter the  profile.
Somia Iqtadar: There are a lot of documents available from the World Health Organization and the local recommendations as well that [say] the best treatment for the shock is actually a volume expander like a start solution, and hemorrhagic fever patients do benefit from the dexran; it has been proven to be the best solution in many of the trials that had been conducted worldwide. I think one of them is from the collaborating center in Bangkok, which is the biggest center for dengue worldwide, and which they have documented that the best solution for treatment of dengue hemorrhagic fever with plasma liquid is actually dextran, partly, and there is a minimal role of albumin or plasma in these patients. If the patient is bleeding at the same time, we do have to replace the blood. But there is no role for Haemaccel or albumin in the management of dengue shock syndrome.
Adri Kok: Did you find at all with COVID-19 and the limitation of movement of people in the country, that it affected the prevalence of dengue at all?
Somia Iqtadar: Actually, it’s quite surprising that we did not have many cases of dengue last year, although dengue is prevalent in Pakistan and we had a huge epidemic in 2019. But 2020 was a less dengue-affected time because we did not have many cases. It could be because the whole of the focus of the health system was on COVID-19 and the reporting of dengue was not [very high], but in the hospitals, we had fewer patients of dengue fever. We are also looking at a project in which we are seeing that maybe there is some protective rule of [existing] dengue antibodies because we have not seen much of dengue this year. So you know that it’s a societal disease and if we have an epidemic one year, then the subsequent years we can have fewer cases, if the serotype switch is not there. So we are looking at it but this year, in the initial to the advanced data that we have collected, there is a rising trend of dengue cases and we are also trying to establish a correlation between COVID-19 infection and dengue infection if they co-exist, because there are [a] few case reports from the world in which there is a co-infection of dengue and COVID-19 at the same time. Although the mechanism of infection and the presentation of infections are entirely different, a person who is suffering from COVID-19 can be bitten by a mosquito who is infected by dengue, and then they can co-exist as well, because there were a lot of cases previously of dengue and malaria co-infections of COVID-19, and dengue co-infection is the new thing that we are working on.
Adri Kok: Yes, we also of course had malaria with COVID-19 in South Africa as well. I think, if there were some other questions, I don’t know that we have time. I don’t want to impose on the next session. I will hand over to Roman Jaeschke. He just wanted to make a comment, but just to thank all the panelists for your presentations and also for participating in this session. Roman, your final comments?
Professor Roman Jaeschke: Well, thank you very much. I’m talking on behalf of the organizers. If our panelists could look at the question and answer part. There are some questions which hopefully will be able to answer by writing rather than talking about them. And number two, I’m blown away by the quality of discussion. It was fascinating and it applies to my practice. I clearly benefited from it for myself. I want to invite people who are participating now to the next session which is on critical care and really overlaps to some degree with our discussion over the last hour. And finally, I want to comment that I’m quite happy that dextrans and albumin are used differently in the same disease in India and Pakistan, because we clearly are experiencing the same anxieties about the use of tocilizumab, dexamethasone, remdesivir, convalescent plasma, and ivermectin in our parts of the world, so to speak. I want to make a comment that the differences [in] how we practice medicine are both eye-opening and stimulating to [ask] ourselves on what basis we do certain things. And that’s where McMaster hopefully leads the field in asking the question: What is your evidence? I thank both moderators and I truly invite everybody to the next session. And this one exceeded all of my expectations. Thank you.