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COVID-19 AND POST COVID CONDITION Dr.Kathleen McCann Prof.Paddy Mallon and Dr.Stefano Savinelli Department of Infectious Diseases St.Vincent’s University Hospital • CEPHR • UCDteaching hospitals providing care across over 50 different medical specialities.Major referral centre for the region for patients with strokes and major trauma,and home 614 in-patient beds to National Centre for Cystic Fibrosis, National Cancer Control Programme, National Liver and PancreasTransplant Programmes. Serves population 1.5 175,000 outpatient million regionally,in attendance per annum addition to national programmes University College Dublin Centre for Experimental Pathogen Host Research (CEPHR) Established in 2019, CEPHR members comprise clinical, translational, statistical and biomedical researchers working interactively on aspects of host and pathogen research from the UCD School of Medicine, the UCD School of Biology and Biological Sciences, and the UCD School of Politics and International Relations. CEPHR research focuses on chronic viral infections, including areas such as diagnostic virology, pathogen discovery, HIV infection, viral hepatitis infection and long-term consequences of chronic viral infections including co-morbidities. How it Started • Post Covid Clinic started in May 2020,initially to care for patients who had been discharged after hospitalization with moderate to severe Covid-19.Initially,patients were seen in strict PPE/isolation guidelines • With in 2 – 3 months,it became evident that patients with initial mild Covid-19 were slow to recover from the infection,and were being referred to the service with symptoms such as tachycardia/palpitation,headaches,and shortness of breath. Primary care (GPs) and Occupational Health (for healthcare workers) began to refer patients. • A dedicated once-a-week clinic was established in anAssessment Hub,a pre-fab building purposely contructed outside of the main hospital. • It has since evolved into once a week in-person clinic and an additional weekly virtual/telephone clinic for triage/routine follow-up. • In the Irish health service,patients do not pay for their care in this clinic. Participation in research is fully voluntary,and does not affect care.SO, THAT’S WHO WE ARE … Now the patients May also be referred People with COVID- Patients may term it to as PACS or“post- 19 might have “long COVID”or acute sequelae of a sustained “long-haul COVID” SARS-CoV-2 postinfection sequelae. infection” POST-COVID CONDITIONPeople with COVID- Patients may term it to as PACS or“post-d 19 might have “long COVID”or acute sequelae of a sustained postinfection “long-haul COVID” SARS-CoV-2 sequelae. infection” It has been in ICD-10 classification as“post- COVID-19 condition” since September 2020. POST-COVID CONDITIONPeople with COVID- Patients may term it May also be referred to It has been in ICD-10 19 might have “long COVID”or as PACS or“post-acute classification as“post- sustainsequelae.fection “long-haul COVID” sCoV-2 infection”S- since September 2020. There is no globally standardised and agreed-upon definition. POST-COVID CONDITION The occurrence is Peop19 might have- Patients may term it as PACS or“post-acuteto Iclassification as“post- variable in its sustained postinfection “long COVID”or sequelae of a SARS- COVID-19 condition” sequelae. “long-haul COVID” CoV-2 infection” since September 2020. expression and its impact. There is no globally standardised and agreed-upon definition. POST-COVID CONDITION May also be referred It has been in ICD-10 People with COVID- Patients may term it to as PACS or“post- classification as“post- The occurrence is sustained postinfection “long COVID”or acute sequelae of a COVID-19 expression and its sequelae. “long-haul COVID” SARS-CoV-2 condition”since impact. infection” September 2020. There is no globally There is not yet an accepted standardised and agreed-upon characterisation of its definition. epidemiology . POST-COVID CONDITION What Causes PACS? Current Thought: There are likely multiple, potentially overlapping, causes of long COVID. Several hypotheses for its pathogenesis have been suggested: • persisting reservoirs of SARS-CoV-2 in tissues • immune dysregulationwith or without reactivation of underlying pathogens, including herpesviruses such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others • impacts of SARS-CoV-2 on the microbiota, including the virome , autoimmunity and priming of the immune system from molecular mimicry • microvascular blood clotting with endothelial dysfunction • dysfunctional signalling in the brainstem and/or vagus nerve Who Gets Long Covid? Post-Covid effects appear to occur irrespective of the initial severity of infection,but do seem to occur The only sure way to avoid long more frequently in: COVID is not to catch the virus • women in the first place. • middle age • in those with more symptoms initially“Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection,usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue,shortness of breath,cognitive dysfunction but also others (seeTable 3 andAnnex 2) which generally have an impact on everyday functioning.Symptoms may be new onset,following initial recovery from an acute COVID19 episode,or persist from the initial illness.Symptoms may also fluctuate or relapse over time.A separate definition may be applicable for children” Abdominal GI:diarrhoea, Tachycardia/ constipation, Menstrual and period palpitations problems reflux Tinnitus and other Altered smell/taste Headache hearing issues Post-Covid Anxiety Memory issues Condition Blurred vision Joint pain Chest pain Muscle pain/spasms Symptoms Cognitive Neuralgias dysfunction/brain fog New onset allergies Cough Parasthesiae Depression Post-exertional malaise Dizziness Shortness of breath Fatigue Sleep disorders Intermittent feverOver 200+ symptoms have been attributed to PACS! Post-COVID conditionS:not a single entity ➢ Different clusters of symptoms ➢ ? Different pathogenetic mechanisms ➢ Different functional impact ➢ Different therapeutic and rehabilitation approach Kenny G et al. OFID 2022 Incidence Lack of a definition and diagnostic criteria make accurate epidemiology difficult,but estimates are that between 8 – 20% of COVID-19 patients experience lingering symptoms for weeks to months following acute SARS- CoV -2 infectionIf we extrapolate that to Ireland In Ireland,we have had almost 1.5 million confirmed cases of Covid-19. If post- covid condition affects even 8%,that is over 100,000 people suffering with long term health effects from Covid 19. But we don’ t know: • How well do vaccines protect against developing long Covid if you have breakthrough infections? Early studies from UK,US,and Israel indicate there is some protection but that data is still out,especially on omicron. Interpretation of those numbers will include accounting for variables such as time since vaccination. • What causes post-Covid condition? Multiple proposed mechanisms,some supported by promising early research:mitochondrial dysfunction,serotonin,cortisol, immune dysfunction,viral reserve,autoimmune,autonomic system,microclots….(are we sure this is even one condition?!) • What is the most effective treatment for post-Covid condition? • Howlong will symptoms of post-covid condition last? W e do have patients who are getting better,but not enough data to make a prognosis for an individual patient. • What is the 5 year, 10 year outcome?• The All Ireland Infectious Disease cohort, led by Prof Paddy Mallon has been enrolling patients at a number of Irish Hospitals with infectious disease, including Covid-19. This study continues to collect samples from patients alongside clinical data and will allow investigators to determine the molecular contributors to the host pathogen interaction in patients who are ill with Covid-19. This national study involves collaborators from all over Ireland who are working together. • Started prospectively collecting data on Covid patients in March 2020 • Weekly Covid Clinic started in May 2020 and by mid-summer,we realised that we were seeing patients who had lingering covid symptoms and post-infectious complications had been reasonably excluded. APPROACH TO THE POST COVID PATIENT Or,how we do it Start with a Good History Past Medical History (before Covid) Medications (before and after Covid)We include asking about vitamins,herbals and supplements Social history – we specifically ask about ex-smoking,use of vape,use of cannaboids,alcohol use,.Occupation. If off-work post-Covid,how long? An idea of baseline/pre-morbid hobbies and activities can help put patient’s presentation into perspective SF -36: Psychological The Medical screening Outcomes Study includes GAD-2 36-Item Short and PHQ-2 Whole Person Form (SF-36) Approach. W e score disease De-Paul Mo19Yorkshired- impact using: Symptom Rehabilitiation Questionnaire: Screen PEM (C19-YRS) Date that they were diagnosed with Covid-19.W e Covid history separately record date of positive test and date of onset of symptoms. W e record all re-infections. Date that they were diagnosed with Covid-19.W e separately record date of positive test and date of onset of symptoms. Record all re-infections. Symptom lists: (W e cue patients from a Covid history set list of symptoms.) • Acute symptoms (started in first 14 days) • Persistent symptoms (the symptoms the patient is experiencing currently). MRC score for any patient with dyspnoea Date that they were diagnosed with Covid-19. W e separately record date of positive test and date of onset of symptoms. Record all re- infections. Symptom lists: (W e cue patients from a set list Covid history of symptoms.) • Acute symptoms (started in first 14 days) •currently).MRC score for any patient with dyspnoeaexperiencing Covid history: Hospitalised? Severity/treatments? ED visits? GP assessment/treatments? Date that they were diagnosed with Covid-19.We separately record date of positive test and date of onset of symptoms. Record all re-infections. Symptom lists: (We cue patients from a set list of symptoms.) Covid history • Acute symptoms (started in first 14 days) • Persistent symptoms (the symptoms the patient is experiencing currently).MRC score for any patient with dyspnoea Covid history: Hospitalised? Severity/treatments? ED visits? GP assessment/treatments? V accine status: dates/types of all covid vaccines, regardless of pre or post infection.Covid Social/Lifestyle History DoNOT skip this! • What can they not do now that they could do pre-Covid? • What is work like (anxious to return)? What specifically is holding them back from returning? • Living situation:homeless,domestic abuse • Alcohol,smoking,substance use • Ask about Sleep:Patients may complain about fatigue but many do not sleep.Consider STOP-BANG screen if risk factors for OSA. Signs found in our clinic: T argeted physical examination: Respiratory: Wheeze,cough,dysnpnoea,hoarseness,respiratory rate Due to the pandemic and Affect: flattened,anxious,tearful,tremor telemedicine,through 2020- Neuro:word finding difficulties,dysarthria,ataxia,nystagmus,dysmetria early 2022,we were often the first physicians to physically Rheum: nodules,swollen joints,tender points examine the patient Cardiovascular:tachycardia,arrhythmia,bilateral pedal pitting oedema Angular stomatitis Alopecia Goitre Acanthosis nigricans Height andWeight What next? Lying/Standing Obs – POTS,new hypertension ECG – post-viral sinus tachycardia, pericarditis Routine bloods (based on histo,exam, above): FBC,U&E,LFT’s and then targeted further bloods that might include TFTs,BNP ,HbA1c,autoimmune screen, HIV,syphilis,viral hepatis,ESR,D-dimer, fibrinogenSelf-Assessment Scores SF -36: The Medical Outcomes Study 36-Item Short Form (SF-36) health survey comprehensively evaluates patient perceived health status across broad physical and emotional health domains, and it is among the most commonly used generic HRQoL assessment tools worldwide. Psychological screening that incGAD-2 and PHQ-2 Pulmonary function tests (post-viral asthma cough) COPD presenting as SOB,wheeze, T argeted further Cardiac MRI,Echo investigation Holter (post-viral inappropriate sinus tachycardia,new arrhythmias presenting as tachy,palpitations) headaches)w hypertension,can present as W e don’t know: When or if we will have definitive guidelines about how/when it is safe to ignore worrying symptoms or signs in post-Covid patients without standard recommended investigation. Example: Laryngoscopy in new persistent/progressive hoarseness, especially in ex-smokers“I can’t believe it’ s • SLE (sometimes it is lupus)• Post-viral asthma, more • RheumatoidArthritis asthma, so much asthma not long Covid!” • Severe anxiety,agoraphobia, • Phaeochromocytoma and depression/suicidal • Hypothyroidism ideation • new Diabetes (often on • New diagnosis COPD background of risk factors) (often ex-smokers) • exacerbation of CCF • Fibromyalgia • Migraine • Obstructive SleepApnoea • Stimulant/cannabis/ • Myasthenia Gravis substance misuse • Menopause • MS (on background of strong family history) W e don’t know: Potential Role of Covid as an “Unmasker”? Patient with multiple risk factors (age, BMI,lifestyle,family history) but had no previous medical history presenting with new complaints. Many had not attended GP or reported previous borderline results. These include diabetes,asthma, hypertension,COPD,arthritis. Deconditioning Post- viral Post complications Covid Referred Condition to Long Covid Exunderlyings of Clinic conditions Unrelated new diagnoses Deconditioning Post- viral Post complications Covid Referred Condition to Long Covid Exunderlyings of Clinic conditions Unrelated new diagnoses WE DON’T KNOW: There is insufficient evidence to suggest optimal treatment for post-Covid Condition. What next? Multi-disciplinary approach to Medical management may rehabilitation does seem to help include amitryptilline (commonly some patients: used,no evidence),melatonin • Clinical psychology (sleep),SSRIs • Dietitian (anxiety/depression), • Physiotherapy procoralon/beta-blockers for • Energy management strategies tachycardias,inhalers for • Lifestyle medicine approaches,especially SOB/cough,NSAIDS for regarding sleep,smoking/substance joint/muscle pain. cessation,positive psychology 1.Thorough history and physical examination 2.Before diagnosing Post Covid Condition,we consider: • Post viral complications (myocarditis,thyroiditis, OurApproach to asthma,tachycardia) • New diagnoses (migraine,hypertension,diabetes, the Post-Covid COPD,GORD,Autoimmune) • Exacerbation of known underlying Conditions Patient (COPD,CCF ,arthritis) 3.Targeted Further Investigations 4. Appropriate referral for multi-disciplinary specialist opinion 5. Goal is to clear patient to participation in rehabilitation.What do results from a 6 week physical rehabilitation look like? GAD 7 Change -0.4 Pre Post PHQ Change -1.3 Working Full Working Full SGRQ Change -10.5 (MCID 4) Time 33% Time 56% Working Working MET Change +0.5 Reduced Reduced Capacity 11% Capacity 22% Estimated MET Change 1.1 Unable to Unable to Work 56% Work 22% 30 sec STS Change +1.4 The outcome measures reflected in the above data included submaximal exercise testing via Chester Step Test or 6MWT to determine MET and estimated MET, global assessment of George’s Respiratory Questionnaire (SGRQ). Source: InternalData from SVUH Depts of Phyiotherapyand Infectious Diseases, AIID Cohort to assess symptom burdenusing St.WE DON’T KNOW: THE IMPACT OF DECONDITIONING There is an element of deconditioning in many post-Covid patients. The incidence is unknown and the prognosis for a good response to a physical reconditioning programme is also unknown. There is insufficient evidence to suggest optimal treatment for post-COVID Condition. Fundamental role of MDT for recovery: • Clinical psychology for depression,anxiety ,insomnia,PTSD • OccupationalTherapy for cognition,pacing,fatigue management • Physiotherapy for physical re-conditioning,dysfunctional breathing • Other specialties as needed:neurology ,psychiatr,respiratory, cardiology,endocrinology ,rheumatology ,etc. W e don’t know: Prognosis The prognosis for recovery is unknown. Some of our patients do get better (sometimes weeks,sometimes months, sometimes almost 2 years) There is not yet enough evidence or data to help us predict who will recover or how long it will take or if there will be some patients who will have no recovery. Future directions What we don’t know What we know ➢ What causes long COVID ➢ Long COVID is not a single entity ➢ What is the most effective ➢ Need for personalised approach treatment for long COVID ➢ Need to exclude other medical ➢ One treatment for all? conditions ➢ Need to protect patients from: ➢ How long do symptoms last for without treatment ➢ Unnecessary and unjustified investigations ➢ Long-term health consequences ➢ Unproven and potentially harmful and expensive treatmentsW e Don’t Know • Pathophysiology • Diagnostic criteria • Actual Incidence • Risk Factors • OptimalTreatment • Overall Prognosis Long Covid Cures Patient are bombarded with misinformation, unethical practitioners, and predatory snake oil. • Does Hyperbaric OxygenTherapyWork? In short,we don’t know. Best advice: follow the HOT - LoCo trial at Karolinska who is trialling this. • Supplements: No evidence. unless a specific evidence-based indication or defiency (iron,B12,Vit D,folic acid etc.) • Does LDN work? No evidence. One to watch:RCT this year University of British Columbia,Canada focusing on fatigue. • Metformin? No RCT but area of interest:may have a role in patient in whom covid potentiated hyperinsulinaemia,pre-diabetes • Evidence-based symptom management: strategies such as P-P-P approach to fatigute management,CBT for anxiety,insominia,established chronic headache management guidelines • Be aware that patients are also marketed treatments/medical tourism for care that is not evidence-based/standard of care. These clinics often charge patients €€€ with risk of harm (example: plasmopharesis,high dose/prolonged anticoagulation in absence of diagnosed coagulation disorder orVTE) T akeAways • The most important thing is good medicine: history,examination,and investigation where necessary. • Remember that it is a diagnosis of exclusion.Identify and treat post-viral new diagnoses as per standard of care. • Educating patients on the expected recovery time of 12 weeks is important,but don’t dismiss problems that should be treated more acutely (asthma exacerbations, myocarditis) • Encourage patients do discuss their own research to help prevent potential harm, disappointment,exploitation but patients are free to make their own informed- decision to“try something,anything” • This is all really challenging for patients and healthcare professionals! Just a few of the more interesting future Directions toW atch • ReCOVer Studies (NIH,US): NEURO,VITAL,AUTONOMIC,SLEEP . NEURO andVITAL are underway at DUKE University. VITAL complex;NEURO has the most promise. • HOT-LoCo (Karolinska Institute): HOT RCT • LDN – double-blind,RCT looking at possible effect on post-Covid fatigue due to get underway soon University of British Columbia. • Preliminary Immunoprofiling as outlined in recent Nature may start to help understand pathophysiology: Klein, J., Wood, J., Jaycox, J. et al. Distinguishing features of Long COVID identifiedthrough immune profiling. Nature (2023). https://doi.org/10.1038/s41586-023-06651-yQUESTIONS?RESEARCH HIGHLIGHTS ROUND-UPNODAC – New Onset DiabetesAfter Covid More research needed This is on background that low HDL,insulin resistance and pre-existing T2DM increase risk of both severe Covid-19 as well as risk of long covid.The results support the hypothesis that a supervised multicomponent training program confers benefits on cardiovascular fitness and muscle strength,as well as on the recovery of the physical and mental health status of these patients. The concurrent training,regardless of the addition of inspiratory muscle training,was more effective in improving the primary outcomes as well as the two main symptoms (fatigue and dyspnea) muscle training alone or the issuance ofthan respiratory general nonindividualized exercise guidelines (i.e.,WHO recommendations) when these are not subject to supervision or monitoring,as in real life conditions.Rehab works. We know this. Figuring out the best approach is everything for patients. This is interesting. Pros:starts to look at healthcare burden long term Limitations: Inclusionof theseparticipantsin thecontrolgroupif they nevertestedfor Covid-19- mightresultin underestimationof risks.The VA populationcomprisesthosethataremostlyolderand male,no subgroups. all-causemortalityandall-causehospitalizationanddid not examinespecificcausesof mortalityor hospitalization. Temporal misclassification(thatis, misclassificationof thetimingof occurrenceof a sequela)mayalso be possible.We definedhealthburdencoefficients forDALYsbasedon theglobalburdenof disease(GBD)studydataand methodologies.Whena sequeladid not directlymatcha conditionin GBD,we applied.To obtainsufficientfollow-upfortheassessmentof 2- yearoutcomes,we enrolledparticipantsuntiltheend of year2020 (beforevaccinationbecamewidelyavailableand beforealpha,deltaor omicronbecamepredominantvariants).TakeAway - Vaccination of at least 2 doses does seem to reduce risk of long covid.TakeAway – • This is why long covid patients need in- person medical exams • Always check,especially if headache is a symptom • Don’t accept patients“white coat”reason – get the 24 ABPM • Are there other related risks – fasting lipids, glucose indicated? • Is it really new or just because attending GP at an age that they usually wouldn’t?This study really raises more questions about the role of metformin here,and the role of insulin resistance in these patients. The important thing to note here is that there is no proposed mechanism of action. It was also long covid prevention – not treatment.• >30 days post infection • associated with female gender,age and modifiable factors such as anxiety, depression and post-traumatic stress • overall rates of fatigue decreased by 6% per month.Both telerehabilitation exercise modalities are effective at improving stress symptoms and quality of life in patients with long COVID-19. For improving fatigue and functional performance,FE shows more promising resultsone-third of the study participants had clinically significant Cognitive Complaints, most commonly Memory CC were more likely to be under-reported Acute COVID-19 symptom severity, elevated depressive symptoms were risk factors Conclusions: Cognitive complaints after acute COVID-19 should be taken seriously. Patients with PASC may not accurately identify or characterize objective cognitive difficulties,