Jovi Stuart
Good evening everyone and welcome to the second series for the New South Wales Covid Update. This webinar is on post-acute and antivirals. We are joined tonight by Professor Steven Faux, Dr Martina Gleeson, Associate Professor Anthony Byrne and RACGP facilitator, Professor Charlotte Hespe. My name is Jovi and I am the Project Officer for the New South Wales ACT at the RACGP. Before we get started, I would like to make an acknowledgement of Country. We recognise the traditional custodians of the land and sea in which we live and work, and we pay our respects to elders past, present and emerging. I would also like to acknowledge any Aboriginal and Torres Strait Islander colleagues that have joined us online tonight. I would like to now formally introduced to our speakers for this evening. Professor Steven Faux is the Director of Pain Medicine at St Vincent's Hospital in Sydney and a conjoint Professor of Medicine at the University of New South Wales and the University of Notre Dame. Steven is a clinical lead for New South Wales Health Rehabilitation Community of Practice and COVID 19 and sits in the New South Wales Clinic COVID Counsel and together with Associate Professor Byrne, has established one of the first long COVID clinics in New South Wales as St. Vincent's Hospital in Sydney. As such, Professor Anthony Byrne is an experienced respiratory physician at St. Vincent's and St. George's Hospitals in Sydney and Associate Professor of Medicine at the University of New South Wales and a respiratory and global health researcher as principal investigator on many national and international investigations. Professor Byrne co-leads the multidisciplinary Long COVID Service at St. Vincent's Hospital with Professor Steven Faux, and is also the lead of the Tuberculosis Service at the hospital. Dr Martina Gleeson is a General Practitioner in the Sutherland Shire of Sydney. Martina is also the Regional Clinical Advisor at the New South Wales Health Pathways, so welcome and Professor Charlotte Hespe works part time in clinical general practice in in a city Glebe as a Principal of a 16 doctor group practice. Charlotte also works as Head of General Practice and Primary Care Research for the University of Notre Dame in Australia, School of Medicine, Sydney. Charlotte has held numerous positions at the college including Vice President, National OSCE facilitator, Expert Committee Member and Examiner and is former chair of New South Wales State Faculty. Welcome to all of our speakers this evening. I would like to now hand over to Charlotte to go over the learning objectives.
Professor Charlotte Hespe
Thank you so much, Jovi. I would also like to start by acknowledging the traditional owners of the land. For me, it is the Gadigal people of the Eora nation, And I would like to pay respects to all elders past, present and any of you present tonight. So tonight, by the end of this activity, we would love to have everybody feel that we have updated you on the use of antivirals with the current guidelines for patients who present with COVID, that we will have a really good discussion about the management of patients with long COVID. Have a better understanding about how we can refer to the current evidence and recommendations for appropriate COVID antiviral prescribing, and looking at how do we identify patients who we really need to refer onward and how the use of health pathways will help with that. I will very rapidly hand over to Anthony Byrne, who is going to take us straight into the antivirals. Thank you so much, Anthony.
Associate Professor Anthony Byrne
Thanks Charlotte and thanks everyone for attending this evening. I will get straight into in the interest of time, so, I just wanted to start with an example. This is a pretty typical patient, and this is a 51-year-old female vaccinated schoolteacher. She has had a cough for two days and she has done a home rapid antigen test which tests positive for COVID. Her past medical history is pretty benign but significant for very mild childhood asthma. Her body mass index, which is important in many conditions, but particularly in COVID is 27 and she has had a creatinine on a blood test earlier in the year, which was just out of the normal range. The question that I have for everyone attending this webinar today is in regard to her management, should she receive antivirals? So we have got a poll here and if you could just with a yes or no answer, if you think she should get antivirals, and this is hopefully a really, really important question that many of your patients will be asking you, and it is not necessarily straightforward although it should be perhaps, but hopefully by the end of this it will be straightforward. I have got why or why not and we can go into that in terms of PBS or non-PBS and there are those sort of things to consider, but if we are just talking purely on PBS prescribing. We have got the majority that that have responded as no. There are three things at least to consider in addition to PBS prescribing practices and the PBS usually tries to incorporate these things when they are making decisions about whether they are funded or not funded, and a really important question is what is this lady's risk of hospitalisation? Just have a bit of a think about that. What do you think? Is she high risk or low risk? What is the risk of death for this lady that has had previous vaccination? She is 51. She is pretty well otherwise, and what is her risk of long COVID, post-acute COVID sequelae, which is not an insignificant question for reasons of having this webinar. They are really important questions and I would encourage you to consider those for each of the patients that comes to you with a similar scenario, and hopefully at the end of this short presentation, you will you will be able to answer those.
Next slide. COVID since 2020 has infected most of the world's population. This number from the WHO COVID dashboard is an under estimate of the number of people infected with COVID acutely and as is the number of deaths that have been attributed to COVID acutely, but nonetheless seven million deaths in four years is highly significant and in fact made COVID the number one cause of death from a single infectious disease for the past three or four years taking over the mantle from tuberculosis for those playing at home.
Next slide. Just one slide on our long COVID service. We accept patients that are over the age of 16 that have persistent symptoms beyond 12 weeks, and they require a referral from GPs with some investigations done previously. We would consider blood tests, chest x ray and a COVID-19 Yorkshire questionnaire available on the HOPE platform as a minimum standard, and they are triaged by our CNC and they are triaged into either the respiratory or rehab phenotype and in the respiratory arm of the clinic for important reasons that I will tell you about, we obviously like lung function testing and we do spirometry and Oscillometry on all the patients that we see. Long COVID can be considered immune dysregulation and you can see this in A here, there is ABCD and it is a very busy slide, but I will just draw your attention to A in the red and the blue that you see on that screen, and you can see with acute COVID, this is data from our DAPT study started in 2020, the longest running cohort study in the country, now having completed two year follow up, and you can see there that a lot of patients have an improvement in their symptoms after 28 days, but the persistence of those symptoms post 28 days is in the blue, and fatigue, cough, shortness of breath were highest among them in an unvaccinated 2020-2021 cohort. We have some good news I think in the data recently published by our group in National Communication and Nature Communications this year showing the at least significant improvement in many of the cytokines and inflammatory markers seen in long COVID patients by that two year follow up and also an improvement in symptoms but not complete resolution, it should be said in all patients. It does not just go away after two years and is an important take home.
Next slide. The respiratory sequelae of COVID are significant. This is a really nasty coronavirus that destroys pneumocytes through receptor bindings and replication and the release of cytokines causing a systemic inflammatory response and creating thrombosis, and that is why we commonly see raised D-dimers on blood tests and in these patients, and so they have a coagulopathies and they have airway injury, and that is really important in terms of symptoms such as cough and post-viral bronchitis and post-viral bronchospasm.
Next slide. Getting to the really the heart of this presentation is the antivirals for acute COVID SARS-CoV-2, and as I said the three important considerations here are mortality, hospitalisation and morbidity, including of course, long COVID, and to start off with people require a diagnosis and the earlier the better. We know there is limitation in testing for any test, but particularly the rapid antigen test which has been validated against earlier versions of the virus, but not necessarily updated with the RAT that is sitting on your shelf, the RAT being negative, someone should proceed to a PCR test, and as we know, you cannot just rock up for a PCR test. You need a GP referral or a doctor referral. I would really encourage you if you take home nothing except doing more GP referrals, doctor referrals for PCR tests and so giving instructions to patients. If you are unwell, you do a RAT and it is negative and you are still unwell, get a PCR test because you need a diagnosis, the earlier the better, and then the consideration is whether you have oral or intravenous antivirals and of course whether it is on the PBS or not on the PBS. There is an option, of course, for any medication to have a private script. There are implications of that, but some of those are worth considering.
Next slide. Paxlovid or combination of ritonavir and Nirmatrelvir has been used and is used for acute COVID, and this is an inhibitor of protease and it reduces viral replication and it is oral and the baby dose ritonavir, as we have seen HIV meds, is there to boost the levels of Nirmatrelvir, and there are a number of studies that have been published and demonstrating the efficacy in unvaccinated and then vaccinated individuals with acute COVID. Now, it is really important to consider the timing of these studies when interpreting them. Obviously, the earlier on that they were done, the more the severe phenotype. There were the people were unvaccinated in 2020 and 2021, and so it is perhaps no surprise then that the study that was published by Hammond in NEJM a couple of years ago as an RCT did show a significant 89% reduction to that primary outcome of hospitalisation and death, and if you look at the numbers there, the hospitalisation or death rate is 0.7% versus 6.8% in those that did not receive the treatment, and obviously that is a really highly significant P value. Now, more real world data, if you like, came from the COSMOS study published later in 2022, which was a retrospective national study of a large number of patients nearly two million in fact, adults that were prescribed Paxlovid within five days, similar to what we do here in terms of PBS prescribing. It included vaccinated patients at that time, and what you see is that there is a 51% reduction to hospitalisation, but look at the numbers there. There are a lot less. 0.47% were hospitalised versus 0.86%. There is a big drop in the number of people that end up in hospital even if they are not on treatment, but there is a significant reduction, and so it was off the back of this sort of data that the PBS allows, the TGA approved it and we now have it on the on the PBS for prescribing not in pregnancy and there is important CYP3A dependent interactions with other drugs that you need to consider. In terms of PBS prescribing, age over 70 years, regardless of comorbid conditions, age over 50 with two risk factors, age over 18 with prior hospitalisation because of COVID or moderate to severely immunocompromised, and there are definitions that we should become familiar with which risk factors and what immunosuppression means. For example, someone that is getting chemotherapy, transplant patient of course, anyone with HIV, but there are some ones that you might not consider and that includes obesity and diabetes and chronic kidney disease, relevant to the first example that I gave you. Respiratory conditions include asthma, but not mild asthma. They define it as moderate or severe asthma, so really important information there. The next antiviral to consider is Molnupiravir, which is also an oral agent for tablets twice a day for five days. It is a pro-drug that also inhibits viral replication, but it does it via a different way through gene mutations, potentially what is a different mechanism, and maybe that is one of the reasons for differences in efficacy seen in studies, but there are important differences in studies, and also important to say that there is no head-to-head trial of these medications, but if we look at some of the data, the move out trial was a reasonably large phase 3 RCT also in unvaccinated symptomatic high risk patients showing a 30% reduction in hospital admissions, and you see those numbers there, 6.8% versus nearly 10% hospitalisation, sort of typical of what we saw three years ago, but not what we see now in a general population. We had some systematic reviews and meta-analysis that were done by the WHO, and they looked at this medication and it showed a reduced hospitalisation rate with a confidence interval that was below one, and so it was largely on that basis that it was approved and listed on PBS funding. An important study was done in the UK called the PANORAMIC Trial and it was an open label adaptive RCT and it was including vaccinated patients for the most part, much like our population here, at least three vaccines, most of the people were aged over 50 and they looked at a primary outcome once again of death or hospitalisation at 28 days, and this was a negative study for that primary outcome, so 1% versus 1%, and so a confidence interval that crosses one, so not significant. However, there are a couple of important points here. One is that there was an improved time to recovery by about four days. There is a symptom improvement with oral Molnupiravir. Another important point is that usual care in the UK means that if people actually in the Molnupiravir or the usual care group were eligible for intravenous antivirals or other antivirals other than Molnupiravir such as Paxlovid, for example, then they could have got those and they would still have been analysed in this. Now that is probably a small number, but nonetheless important to consider when interpreting these results.
Next slide. Remdesivir is an intravenous medication. It is a nucleotide prodrug, and it also reduces viral replication and this is usually given intravenously once per day. The studies initially which I will show you on the next slide used it for five days typically but up to ten days intravenously, and so there are important practical implications for GPs prescribing this, obviously you need to have IV access and you need to have an ability to give an infusion once a day for at least three days, 200 initially and then 100 daily for the next two days, and it should not be in people with shortness of breath or reduced oxygen saturations in the community I mean because if you have got shortness of breath, chest pain or hypoxia, then you should not be getting this medication in the community, you should be in hospital.
Next slide. Some of the data from remdesivir. It shows that in the WHO solidarity trial that in a very large open label adaptive RCT that there was a reduced mortality in hospital, and just look at that mortality, I mean, 14.6% in-hospital mortality versus 16.3% confidence interval just below one, but not in those people that were mechanically ventilated, so really, really high mortality in the early stages of the pandemic. The discovery trial was an open label adaptive RCT in European hospitalised patients with hypoxia, and that showed that there was no difference in that acute mortality, so really hard outcome mortality in remdesivir, and then there are some other trials, most notably the PINETREE trial, which was a phase 2 randomised controlled study of people over the age of 12 from four countries including the States, and that was published in the NEJM early on, and the important thing here was that it was looking at high risk outpatients, and they actually showed that there was an 87% reduction in hospitalisation or death by day 28 and less than 1% versus 5% with a significant P value, so it is on that basis that that it is recommended for consideration of use, even in the ambulatory setting.
In summary then, in order to treat acute COVID, you need a diagnosis. It seems obvious, but believe me, it is not necessarily. You need to do a PCR if you are RAT negative. Please consider which pathology laboratories near you do PCR testing and get your patients a referral to have on standby as a COVID management plan. What happens when they get become unwell. Mitigation. We have not actually looked at this, but I have hinted at it that the effect in these studies is the primary outcomes are generally or almost exclusively hospitalisation and death with some secondary outcomes recovery, early recovery, but really none we are looking at long COVID beyond three months, but there is data that is now published last year in JAMA looking at Paxlovid and did show a reduction of 26% in those people that were prescribed Paxlovid versus those that were not so and that is to long COVID as an outcome. Important to mention inhaled steroids per the PRINCIPLE trial which was early on and that actually looked at hospitalisation and found that in that certain group of people over 50 that inhaled steroids actually reduced hospitalisation, so really cheap medication that we can use. Prevention, it is worth mentioning this study on metformin published in the NEJM looking at metformin acutely for 14 days and showing 6.3% at day 300 versus 10.4%. Once again, an inexpensive medication that can be considered in certain circumstances. The approach that we take and I know that Steve is going to present on this so I will not take his thunder, but just to mention this recently published systematic review that I participated in Respirology looking at this concept of treatable traits for long COVID. Treatable traits is a concept that we use for asthma and COPD and other complex conditions where we can identify a trait that is clinically relevant. It is able to be identified and measured and it is treatable, so the things we are talking about here are reactive airways disease, i.e. asthma, sleep disordered breathing, lots of different conditions that are overrepresented in this population, and we can do something about it. This treatable traits approach and phenotyping in long COVID is a really useful concept for clinicians such as yourself, so with that I will finish up and any questions, just put them in the chat and I will hand over to Steve.
Professor Steven Faux
Thanks, Anthony, and I am glad you gave a lot of detail about the antivirals because I am light on that, so thanks for that. I simply wanted to talk to you about approaches to patients coming in. The first thing I wanted to talk about was that I do not accept honoraria, but I have written a book on long COVID for patients, and that was funded by the Murdoch press, but they are not related to Rupert, you would be pleased to know.
Next slide. The question is, is it simply another post-viral symptom or is it a real thing and separate? And one of the reasons I talk about this is because there still are some thoughts out in the community that it is not quite real. If we have a look at the history of epilepsy that was thought to be actually a spiritual disorder brought about by devils and then in 1935 when we discovered electricity, it was found to actually have a cause. However, those people were still stigmatised by that history. The Spanish flu which is probably the largest pandemic prior to this one occurred at a time before we really had treatments for chronic illnesses or even social media, so if you were unwell, you generally did not make it. There were treatments to keep you surviving, and if we look at the other pandemics such as TB, polio and HIV, each of those epidemics had a chronic phase. TB had sanatoria. Polio has the late changes of polio or the post-polio syndrome and HIV still has a hand, which is a cognitive deficit that occurs in people who have HIV for prolonged periods. Some people like to lump all viruses together and others try to split them up. I think there is better value as a researcher and as a clinician to split them up because like epilepsy, the treatment of a petit mal is quite different to a grand mal, but they are all still epilepsy. There are a number of symptoms that other viruses have in common with coronavirus, but there are some that are different, so what we notice is the changes on CT scanning. We notice a lot of dysautonomia or abnormal functions of the autonomic nervous system as well as some cognitive impairments and the loss of smell, taste and the loss of hair, which is particular for COVID.
Next slide. We probably need to talk a little bit about the Queensland research because many of you probably read about that in the press. The group of Queensland researchers compared about 2000 people with COVID to around about 900 people with influenza, and they found that 3.6% of the COVID patients had long COVID, but 3% of the influenza patients had ongoing functional impairment for 12 months. What they did not tell you was that the COVID population were about 90% vaccinated and the influenza patients were about 40% vaccinated, and nobody who was ever hospitalised or in an ICU was allowed to be included in the study, which means you could not really use one of the major risk factors for long COVID. The volume of people need to be considered because 3% of three million Queenslanders are about 144,000 people, whereas it is only about 2500 people who suffered flu. There might be other factors that might be leading the Queensland Chief Medical Officer to say perhaps we should stop using the term long COVID, but it might not be the research.
Next slide. Is it different to other illnesses that can cause fatigue? Well, dyspnoea is a hallmark. There have been radiological changes, and the other thing is that the hospitalisation of patients often involves them using steroids and antivirals or with their own complications, and the mental health impact of this particular viral illness is quite different because many people face their own mortality or were in lockdowns, and so the mental impacts of this particular infection was a bit different, and if you have a look at SARS and MERS, also coronaviruses, they both had fatigue persisting for up to four years for SARS and MERS was 12 months, and actually after four years they stopped doing research, so we do not know if some of them still had that ongoing fatigue.
Next slide. I have talked about the context of chronic phases of epidemic and to imagine that we had a pandemic affecting the entire world and there will be no chronic phase to it, seems to fly in the face of what we know about viruses and history. Long COVID is likely to be around for a while, even though we are having less and less of it because we are vaccinated. More and more people are getting COVID and we are not registering them. In December 2023, in New South Wales, 100,000 people had positive PCRs, so if only 1% of them, there is an extra 1000 people with a chronic problem that month. It is not going to go away even though we might not want to call it by its name.
Next slide. For our clinic and also for any general practice, the first step is validation is to say, look, this is real. We do not know exactly what the causes are, but we need to work together to minimise the impact that this will have on your quality of life and your function, and dismissing symptoms or minimising them or saying this does not really occur is the thing that people remember most about their interactions with doctors. I would warn people about the importance of the validation.
Next slide. The next question is what causes it? Well, we do not know, but in nature late last year, there was a terrific article on the five main hypotheses. Anthony's already talked about the hypotheses of immune dysregulation, and what is interesting is that in monocytes and macrophages that often I call them the garbage trucks of the immune system, they clean up the rubbish. When the virus got into them, they actually did not kill them. They just paralysed them, which meant that the amount of cytokines being released was disordered and it meant that immune cells were often not sent to the right places to attack the infections or they were sent in the wrong order or they sent in the wrong numbers. This virus actually affects the immune system. The second hypothesis, which I really like, is the microbiota. What we found is people with long COVID tend to secrete particles of the COVID virus for a bit longer and it seems to upset the balance of germs or the microbiota in the gut, and we found that the absorption rate of L-tryptophan is decreased, and as you know, L-tryptophan is one of the basic building blocks of serotonin and might be responsible for why people have cognitive impairment or in fact worsening mental health issues. The other interesting theory is the production of extra autoantibodies, and we know that people who have long COVID tend to produce autoantibodies to their own epithelial cells, which changes the flow of blood in the small blood vessels, as well as that we have noted that people who normally have a certain immune profile to say the Epstein-Barr virus can have that changed as part of long COVID. The third one is that we found that blood clotting increases because of endothelial abnormalities. There seems to be an endotheliitis, and we know that amyloid fibrin seems to increase in the blood itself, which increases the risk of clotting, and we have seen that both in hospitalised patients and people outside the hospital. In fact, I note that Anthony's suspicion to run VQ scanning on patients with persistent shortness of breath is notable, and finally, we know that the virus tends to have predilection to the nervous system and we know that from autopsies where pathologists found that the trigeminal nerves of patients were teaming with the virus, those are the people who died, and we expect that this is probably happening all around the body, including on the in the autonomic system affecting the heart rate, so that is the Cook's tour of some of the modern hypotheses, and we will be probably finding out more and more of them as the research is revealed.
Next slide. There are about 200 symptoms, and the most common ones are fatigue, shortness of breath. Insomnia is quite marked in our population, difficulty walking, anxiety and depression as well as cough, and we are also seeing a quite a few people with palpitations, about 12%, and in a study in the UK, they found that about 10% of people coming to long COVID clinics were diagnosed as having POTS or postural orthostatic tachycardia syndrome. You are going to see a whole variety of symptoms. The phenotypes are currently just being described, but you will tend to have people with cognitive impairment some people with fatigue, some people with autonomic dysfunction or heart problems, and then you will have the respiratory phenotype. There will be quite a lot of different looking symptoms.
Next slide. This is a very valuable questionnaire. It is on the HOPE platform, New South Wales Health, but I think it can be available from anywhere in the country, and it's the Yorkshire C19. It is the only validated questionnaire. It takes a bit of time. The patients can do it by themselves and it gives you a score which you can use to monitor improvement, and it is very valuable. We have been using it quite a bit.
Next slide. The model of care is that mild COVID can probably be managed in the community through resources like websites and books and podcasts and things like that. Then the next step would be yourselves, General Practitioners, and we are advising people to go to their GPs to get a diagnosis because long COVID is a diagnosis of exclusion. You have to make sure they are not suffering from anything else, and then if you do need specialist referral, there are a number of integrated care services at the public hospitals that will give you access to specialists, but quite often what will happen is the specialist will say, I have examined the heart. There is nothing wrong here, and back to you. That often does not help a lot of general practitioners. We believe that there should be at least one or two long COVID clinics in each state to provide referral networks for yourselves, but also to provide a place where you can get information and also where we can support general practitioners to manage cases in the community. In New South Wales, there are at least two or three, not so in Victoria, I think there is none, in Queensland, they are all run in the private sector in those two states and there is one in South Australia, not one in Tasmania or Western Australia, and there is one in the AC2 which we understand is closing soon again through lack of support.
Next slide. One of the main things to help people manage is early multidisciplinary rehabilitation, and thankfully the Government has claimed that long COVID fits the diagnostic criteria as a chronic illness, which means that you can activate mental health management plans and extended care plans for these patients. It has been shown that if we start rehabilitation in any form of chronic illness, their outcomes are better, but in particular I can show some of the data on long COVID.
Next slide. Breathlessness, mobility, quality of life, muscle strength all seem to improve as well as kinesophobia or fear of movement, and there was a Norwegian study that showed that a three-day intensive rehab program with telephone follow up actually help people over three months. We also know that prolonged bed rest is not terrific. Early rehabilitation is important. Now, how do you do that.
Next slide. You will need to assemble a team. You need to get yourself a physical therapist, either an exercise physiologist or a physio, and sometimes a psychologist or an OT, and you need to develop a team and address particular symptoms. If it is an exercise intolerance, you can ask the physio to teach the patient an activity and movement program, but there is a caveat here. Getting them to exercise very heavily does not actually result in better outcomes and often causes crashes, so they need to have the exercise very carefully measured to their fatigue levels, and we also know that resistive exercises or weights seem to be better than aerobic activity. With psychological treatments or OT, the main focus is on teaching people how to pace. Now pacing makes a lot of sense and is easy to talk about, but there are some personality types that find it very difficult, particularly those who are high achievers or people burning the candle at both ends. They would find it difficult to have to slow themselves down. Sometimes OTs or psychologists or clinical nurses can help, and you need to set up a case review at about six to eight weeks to see if you are attaining goals and then to repeat it at 12 weeks. It is not without difficulty running that in general practice, but it is possible.
Next slide. The overall plan is to get your movement programs to the physio, some psychological treatments for pacing skills and if people are having trouble with work and we found in our clinic 25% of people have either stopped, worked, reduced worked or left work. You will often need communication with the workplace. Sometimes you can do that yourself, but if there is an occupational therapist, they are adept of doing that and also breaking down work tasks so that people can do them more easily.
Next slide. I am not going to go into the health pathways because I think Charlotte will be talking about that, but we have them available, and that I know is an enormous help for general practice.
Next slide. One of the things I want to tell you is some things do work and some things do not. TENS machines and TMS and virtual reality are being promoted, but there is not a lot of evidence. There are a lot of vitamins being suggested, but again, they are very little evidence but pretty low risk. Hyperbaric oxygen, there are currently no protocols available. It is very expensive and there is no great evidence for it, but off-label uses of medications are starting to take place and we are using that a lot. For instance, modafinil and L-dopa and even and metformin are examples of drugs that are tried off label. They have all got low evidence but they are accessible, so what you need to balance up is it worth the risk? So putting them on chemotherapy, which some people have been doing in the United States obviously is not worth the risk. Some drugs are incredibly expensive, and so sometimes the costs do not weigh up the benefits. You do need to get consent from your patient to try and off label drug, and you need to be aware that you are liable for any complications, But I would suggest you use an N on 1 trial to actually know whether you are getting somewhere with the drugs.
Next slide. N on 1 trials means that you are going to get the patient to use the medication for two weeks, then you are going to stop the medication for two weeks, and then you are going to restart the medication for two weeks. You need to decide on an outcome measure. For fatigue, I use the fatigue severity scale because it is very short, only seven questions, and you do it before they start on the drug when they have come off the drug and when they recommence on the drug and at the end of the second exposure, and if you are seeing good outcomes each time they are on the drug, well then I think you can feel that you have made a scientific approach to the use of an off label drug.
Next slide. Here is a case study and a question. Stephanie is a 59-year-old real estate agent who got COVID in January 2022. She had a past history of myasthenia gravis, which was treated with a thymectomy more than 20 years ago, and she had no drugs and she was completely fine. However, after COVID she developed fatigue, cough, breathlessness. She lost smell and developed brain fog. Now, she notices that she is slow at work. She is making errors, and she also reported some tingling in her face and occasional foot drop that comes on when she is fatigued and was a bit distressed. Her brain MRI was clear, but her MOCA was slightly reduced in short term memory and her fatigue was addressed with a slow resistance program which improves her exercise tolerance, but she still reported palpitations, particularly when fatigue, so my question to you is and I guess I am asking Jovi to help out here, would you, A, commence a rehabilitation program with a graded exercise program? B, exclude cardiomyopathy with an Echo and Holter and thyroid function tests. C, commence treatment for anxiety. D, check her antibodies for anticholinesterase inhibitor or Musk antibodies. E, commence a rehabilitation program with pacing and cognitive training and a tailored movement and activity program, or F, all of the above, except for A. It is a hard question, I am sorry. I made it difficult because I know that people in general practice are getting their heads around the simpler cases and are managing the simplest cases very easily.
Jovi Stuart
Just open it for another 15 more seconds and then we will share the results. Okay. Results are shared.
Professor Steven Faux
It looks like a lot of people would start rehab, which is good. Some people are worried about the heart, which is a good thing. A few people want to check the antibodies, and I think all of those are sort of okay, but if we go to the next slide, I will explain what we actually ended up doing. So, the answer was D, and one of the issues was that what had happened to this woman is that she developed new antibodies against myasthenia, and that was quite a shock to us. We had put her into a rehab program which was not actually working, and so when you are doing a rehab program and you are finding that you are not achieving your goals, you sometimes need to rethink it. She was admitted to hospital. She did have a cardiac MRI and echo, which excluded the myopathy, and she started tilt tabling for that postural impact on her heart rate. The Neurologist came and were surprised at the increased antibodies, but it is one of the possible hypotheses for long COVID, and she was commenced on Mastodon, which is the drug treatment for myasthenia gravis, and started a pacing program with a psychologist and activity program with a physio, and she returned to work within six weeks, part time initially, but then improved. I presented this case because it indicates that whilst rehabilitation is the right choice, you have got to monitor it and you need to have a look at it at six to eight weeks, and if you are not winning, you need to rethink it, and maybe review the diagnosis.
Next slide. Vaccination will decrease your risk of long COVID because it decreases your risk of going to hospital or getting severe COVID, but the question is if you have long COVID symptoms, should you have a vaccination? One of the studies showed that there was about a 15 to 20% improvement in long COVID symptoms for people who took a vaccine. Most people did not really change much and about 20% of people did get a bit worse following the vaccination for a short period of time of about two weeks. The question is, when you do get COVID, you have got immunity for around about six months, but not beyond that, and we will need to move on to the next slide.
Next slide. The use of the antivirals does prevent hospitalisation and risk of death and therefore would decrease the risk of long COVID, but I will not go into that because I think Anthony has explained it in much more detail, so thank you for that. Finally, I just want to say if anyone is around in Sydney for 1-6 June 2024, the World Rehab Congress is on and if you are interested in attending, there will be a lot of the international speakers on long COVID as well as many other really interesting talks on rehabilitation. Thank you very much.
Dr Martina Gleeson
I am just here to help you find out where to reinforce your learning from tonight and refresh your memories. I remind you that we have the same health pathways across most of the state of New South Wales for COVID and they have recently been updated. If you are looking for those PBS indications for the antivirals, how to work out, who should be receiving them and how to prescribe them, what precautions to take, contraindications, that sort of thing, then you go to the COVID-19 medications pathway. It has also got links to the pre-assessment action plan that you might want to do with your high risk patients so that you can get them all prepared and assess their interactions of medications so that they know which medication they should be getting when they get COVID. Links to the drug checker and also some autofill shortcuts for your clinical software to help you remember to cover all of the bits you need to do when you are prescribing, and including a dosage adjustment for renal impairment.
Next slide. There is also the post COVID-19 sequelae pathway which if you search for long COVID, you will find it as well, but it is called post COVID-19 sequelae because it also covers that period of time between when the COVID acute infection is finished and the 12 weeks when they officially can become long COVID, because there are a lot of people who have symptoms in that interval time, helps you to assess the severity, gives you the indications for escalation, gives you advice on specific symptoms and where to find your local support.
Next slide. That is what the health pathway looks like, and I chose the management section because it shows you that point number five, manage specific symptoms and you can just scroll down for the one that is most important for your patient and open up that drop box to find specific information to try and make it easier to find what you need. Thank you very much. Onto you Charlotte.
Professor Charlotte Hespe
Thank you so much. What we thought we would do next is just talk about a case, and hopefully we will have a bit of input from Steven along the way, Anthony, she was passed the antivirals thing. Debbie, 35-year-old, actually a full time university student, had acute COVID, actually did have a consultation with us around her COVID care, had no particular risk factors, however, I can admit that she was obese with a BMI of 33, but that was actually her only risk in for COVID. Four weeks later, saw me and presented with a lot of ongoing coughing. For her, the worst part, though, was actually the choking and vomiting that she reported with the coughing quite similar, I think to some of the symptoms that people report for pertussis, but no evidence of pertussis and in fact that was excluded. She reported muscle pain, fatigue a bit and denied any brain fog. We did look at the health pathways. We tried to figure out the role of Pulmicort, decided that at this point in time, there probably was not real evidence showing it, but we decided to that we would do an N equals 1 trial, and see whether the Pulmicort did actually assist her management of cough.
Next slide. She was reviewed again another four weeks later. The cough was persistent. She saw my colleague. This was not with me. She persisted ongoing fatigue. My colleague felt that she was probably worth keeping ongoing with the Pulmicort, but just for another three weeks and then for her to stop. She was reporting that she was pretty unable to continue with her current workload, so she was given a medical certificate for university, and we then reviewed her again another four weeks later. Interestingly, the persistent cough persist, but she did say that it was not nearly as frequent. It was the fatigue that really, really was hitting the agenda button, and this a new onset of dyspepsia, and so at that point I did look at the health pathways again around what was going to be the best management. We will not go there yet, Martina. We will do the next slide if I can. Because week 18, the persisting cough, still vomiting with the bouts of coffee, now reporting a foggy brain, and persistent nausea. Week 22, the cough was better, still vomiting though, really foggy brain, difficulty with word finding, short-term memory deficits and really very, very upset by the significant gastro symptoms and was also reporting myalgia and arthralgia thought at this point in time we might go and have a look at the health pathways and how we use that to help navigate these symptoms. So Martina, if you can share.
Dr Martina Gleeson
Hopefully I have got that sharing for you, Charlotte. Can everyone see it. I have got it at the management part of the long COVID pathway, so which one do you want to look at?
Professor Charlotte Hespe
I think we have not really talked much about the nausea or dyspepsia and I have had a number of patients who with their long COVID seemed to be developing some quite interesting symptoms, and I will not say what my long COVID people have decided. Steven, do you want to talk about that because it seems to me that it is common, but it is not really often talked about.
Professor Steven Faux
The nausea and dyspepsia.
Professor Charlotte Hespe
Then there is vomiting and that it just really being quite persistent.
Dr Martina Gleeson
Of course we do not have that symptom on the pathway, Charlotte. So that is awful.
Professor Steven Faux
What is interesting in terms of N on 1 trial is a lot of people have been using antihistamines, both type one and type two. Famotidine together with loratadine. People have been using loratadine during the day, and famotidine at night because there is this concept that people with persistent symptoms might have an oversupply of histamine, which Anthony can probably talk about a little bit more because it affects the lungs as well, and this patient might be somebody who would be worthwhile trailing on that combination.
Associate Professor Anthony Byrne
Sorry, I was just going to say, that is right. There is definitely an over-activation of mast cells, so there is a theoretical reason for why antihistamines might be of benefit. If you have got dyspepsia and you have got clinical reasons for looking at antihistamines, ranitidine, nizatidine, as treatment of dyspepsia then you have got two reasons to consider its use in this individual. The other things to say here is that this is a really classical patient. As a respiratory physician, we see a lot of post-viral bronchitis. We have got to consider secondary bacterial infection, haemophilus, strep really common. Collect some sputum, that is really important. Measure lung function. What are we treating with the budesonide, are we treating post-viral cough and airway inflammation or are we treating bronchospasm and asthma. The treatment of asthma is obviously quite different and that requires some investigations and lung function testing.
Professor Charlotte Hespe
Thank you. Effectively that is what happened with this girl and also the anxiety and the insomnia that was there, but she was not really sort of talking about it because she was more presenting with the physical symptoms. She was put on the double whacking antihistamine. She was also put on the moclobemide and she has been put on quite a number of things in terms of her long COVID, but what I do find fascinating is that and yes, she is better, but she is not better. That is the frustration when you have got a 35-year-old woman who really seemed to cope reasonably well at the start, but now is finding it harder and harder to cope with the ongoing and persistent symptoms, which is where we in general practice have to try and as you say validate their symptoms. Give them some hope that there is going to be some light at the end of the tunnel and continue to try these n = 1 trials of medicines, etc to what works.
Associate Professor Anthony Byrne
Psychological treatments might be of benefit too particularly with anxiety or the fear that it will never end which a lot of people have. That concept of seeing the whole person and understanding the anxiety is playing a role is really valuable.
Dr Martina Gleeson
It is a very common thing to need psychological support when you have got a new chronic disease that you are adjusting to and your expectations from your life are being challenged. It is like going through a grief process.
Associate Professor Anthony Byrne
Absolutely. The other couple of points on this case that I think are interesting are the distinction between fatigue and hypersomnolence. As a sleep physician, that is a point of a difference. Someone can be quite fatigued, but they are not necessarily sleepy. Talking, thinking about sleep hygiene, someone with like anxiety, PTSD, not sleeping, altered sleep-wake cycle, all that is really important to consider. The other thing in terms of the GI symptoms. We see in the research that a lot of these patients, the Chinese were doing this actually with PCR testing on stool samples and being more sensitive and positive for longer. We see a lot of replication of virus and shedding of virus in the GI tract, which may explain some of those GI predominant symptoms.
Dr Martina Gleeson
Charlotte, did you refer your patient at all?
Professor Charlotte Hespe
Yes, absolutely. She has been seen through the Royal North Shore. She lives on the North Shore of Sydney, although I am based in Glebe. She has been seen by a team. It is much better through the North Shore team. It has been much harder to find a place to be able to have her managed. We have been basically managing onward, as they say. She continues to struggle, but all of the things up above. Stephen, do you want through talk to that question?
Dr Martina Gleeson
Can I just take a minute to show people on the Health Pathway where to find that referral information. If you go down to Request and see this Refer to Integrated Care Teams. If indications for escalation are present and if you click on that Integrated Care Teams, it will take you to your Health Pathway region's information for how you can access some assistance with the health coaching and psychological support and whatever else is available through the teams. One of the other benefits of that referral is that if you refer to those teams, there is visibility to New South Wales Health that people do actually have long COVID. I will stop sharing, Anthony, and let you be the expert.
Professor Charlotte Hespe
We had a question there in terms of respiratory medication and what to use, and I would be quite interested, maybe Anthony, if you can also talk about role of the Pulmicort in the persisting cough and also the role of the ___.
Associate Professor Anthony Byrne
Thank you. I am not familiar with the medication that was in the question. I certainly do not have access to that, but Steve said antihistamines do have a role, studies that are ongoing in that. In terms of budesonide, we do as I mentioned, oscillometry and spirometry on everyone that comes through the clinic probably approaching something like 500 patients that we have done that on. When we presented this data at the European Respiratory Society last year, we found a significant number with essentially an asthma type syndrome. They have small airway dysfunction that is seen with more sensitivity on oscillometry, but there is a feel for it on spirometry post bronchodilator to the small airways, 25-75% but also obstruction. That responds pretty well to bronchodilators and to inhaled steroids.
Professor Charlotte Hespe
Thank you for that. Any last moment comments that you want to throw in because I know we are at the end of our time. Before you do your last comments, I will just say it has been fantastic. Thank you so much. All three of you. So much that is still to be learned, obviously but there was so much shared knowledge. That was fantastic. Thank you very much. Steven or Anthony, anything you want to throw in as a last minute comment before Jovi throws us all out?
Professor Steven Faux
All I want to say is this is likely to continue. It is not going to go away because people have decided not to call it that anymore. I am really buoyed by the fact that general practitioners are learning about this because I think this is going to walk into your rooms more and more and being comfortable with it and knowing how to refer and how to use the pathways is going to be a great service to patients. Keep going.
Associate Professor Anthony Byrne
It is all stuff that you guys know. These are these are treatable traits. They are conditions. Asthma, you know about, infection, bronchitis, sleep disorders. This is a really important condition for a number of reasons that you have outlined but also the health seeking. These patients seek healthcare. They go to emergency department with their chest pain and breathlessness. They seek specialist review from you guys. These are important symptoms that do require some sort of investigation and management.
Professor Charlotte Hespe
Thank you. Before we go, Steven or Anthony, is there any list anywhere of some of the medicines that people are trying that we can use as an n = 1 trial?
Professor Steven Faux
Great question. I have put a list of them in the book I wrote, but there is no real compendium of them. Essentially, there are some things that have been shown not to work but we do not have time to talk about all those. I think it will come down to each individual symptom and the cost/benefit and also the cost/risk for each of them.
Professor Charlotte Hespe
This is where we use our clinical appraisal skills and knowledge that we have about both our patients and the conditions that we treat and the medications that may treat that condition and have some measurable outcomes as we then give them a go of treating it. That is the skill of a GP. Thank you for that, Steven and Anthony.
Jovi Stuart
Perfect. Thanks, Charlotte. I would like to thank all our speakers, Charlotte, Steven, Martina and Anthony and everyone who have joined us online tonight. We do hope you enjoyed the presentation. Just a reminder that that as this is a CPD accredited activity and to be allocated your CPD hour, you must complete the survey following this webinar. Thank you and good night.
Professor Steven Faux
Thank you very much.
Associate Professor Anthony Byrne
Thanks everyone.