Figure 1 COVID-19

Q&A Series: Dr. Shikha Mittoo

 

Date: April 29, 2020

 

Featured Physician: Dr. Shikha Mittoo, Community-based Rheumatologist, University Health Network, Toronto.

 

Featured Topic: The COVID-19 pandemic has added an additional layer of complexity to the management of patients with rheumatic disease or those on immunosuppressive therapy. This has been compounded by the lack of specific data on SARS-CoV-2 infection in this population, as well as shortages of hydroxychloroquine.

Dr. Shikha Mittoo (@rheumatlarge) is a community-based rheumatologist appointed at University Health Network in Toronto, Canada, with a particular interest in inflammatory arthritis and the impact of lung disease on clinical outcomes in rheumatic disease. She served as the co-research director for the Interstitial Lung Disease Program at University Health Network, and as adjunct assistant professor at the University of Toronto.

Dr. Mittoo will be taking your questions on fever syndromes, hyperinflammation, and cytokine storms associated with COVID-19; clues to differentiating rheumatic disease, rheumatic flares, and COVID-19 infection with rheumatic features; and the management strategies she's using for her patients during the pandemic.

Discussion:

Q1: What's the best way to set up an outpatient infusion center to decrease the risk of exposure for patients receiving biologics? (Submitted by a Primary Care Physician)

A1: 1. Spacial distancing (6 feet 6 inch) and infection control guidelines (and College guidelines vis a vis COVID19) depending on who operates the space must be maintained (eg. pharmacy or physician college). 2. Surfaces including knobs to be disinfected after use. 3. Pre-screening patients before infusion (1-2 days prior) for COVID19 by phone and then on site (by temp). 3. Consider use of face masks (Dr. Mittoo)

Q2: Any benefits to using steroids at any stage of the disease? (Submitted by a Medical Officer)

A2: Yes there may be a place for steroids but little evidence supper. NIH released their guidance and stated there is no role. In defined cytokine storm, vascular leak, without concomitant bacterial pneumonia, in severe cases it can be considered. (Dr. Mittoo)

Q3: Any ideas on immunocompromised patients (RA, SLE, etc) who work essential jobs? Are you prophylactically reducing immunosuppressive medications to decrease their risk of infection? (Submitted by a Neurologist)

A3: Though I am concerned for that population, there is a lack of data to suggest RA/SLE patients fare worse vs other populations in COVID-19. A trend in higher mortality suggested in early COVID-19 Global Rheum registry (6% vs world rates ranging 1.4-9.7%). Reduce pred to <=10mg/day. Left untreated, high RA/SLE disease activity will increase risk of infection so no need to reduce the dose of DMARDs. I do consider reducing the interval of biologic therapy or stopping entirely in stable rheumatic patients with deep sustained remission. (Dr. Mittoo)

Q4: Are these patients at risk for opportunistic infections if on a mechanical vent? (Submitted by a Pharmacist)

A4: Yes, but the standard risk stratification to determine the probability of opportunistic infection is likely no different from other populations on a vent. (Dr. Mittoo)

Q5: What is the role of colchicine in treating COVID-19? (Submitted by a Neurologist)

A5: It is still to be determined (Montreal Heart Institute launching COLCORONA trial). Colchicine is used in diseases associated with inflammasome-dependent or mediated (gout, FMF) cytokine release (which can lead to storm--IL-1, TNFa, IL-6), but it also inhibits neutrophils and in turn could reduce neutrophil extracellular traps (NETs) which are thought to lead to more severe COVID19 manifestations. (Dr. Mittoo)

Q6: Healthy 55yo male, hx of gout currently controlled without meds, COVID19 positive. Minimal respiratory symptoms experienced. He has developed inflammatory joint pain- first presented in lumbar, moved to one then both shoulders, now right hip. He has experienced a 20lb weight loss in 3 weeks. Is this due to COVID19? Preferred treatment? (Submitted by a Pharmacist)

A6: This is inflammatory (cytokine-driven) until proven otherwise. Gout rarely leads to axial involvement and the migratory pattern suggests post-infectious inflammatory flare or active infection. Is he still having fevers? If not, then this is similar to post-infectious rheumatic syndromes (eg. post-strep). Consider NSAIDs or colchicine. (Dr. Mittoo)

Q7: Is the virus killing patients or is it primarily the profound inflammatory response severe cases display? Is it possible that a patient on certain biologics will have some protection and therefore better outcome if infected? (Submitted by a Respiratory Therapist)

A7: Around 15% have respiratory distress and 5% respiratory failure. Reports have shown even after negligible viral load, a profound inflammatory response presenting as 'cytokine storm,' 'sepsis,' 'vascular leak' explains many deaths, but there are concomitant bacterial infections (rare), and severe viral pneumonia and lung damage to explain rest. It is too early still to reach any conclusion. As for your second question, yes some biologic may serve an advantage but depending on when in the COVID19 trajectory they are. In the early phase and possibly late severe anakinra may be beneficial without risk of worsening viral infection and Anti-IL-6 inhibitors at later cytokine storm presentation. However, at first sign of infection on biologic, most biologics should be discontinued.  (Dr. Mittoo)

Q8: What’s your take on the BCG vaccine in COVID-19 infection? (Submitted by an Medical Officer)

A8: No benefit in COVID-19 during infection but interesting data showing that BCG may reduce risk of infections beyond tuberculosis including viral infection. The Netherlands are studying BCG as a way to prevent severe infection/incident COVID infection. Stay tuned! (Dr. Mittoo)

Q9: I am a health care worker working on the front line with RA. I am on plaquenil, Xeljanz and Methotrexate. I took a 4 week break from my Xeljanz but have recommenced as the curve has flattened in my state and I was starting to flare. Is there any data available on COVID acquisition in those with autoimmune disease on long term plaquenil? (Submitted by a Certified Nurse Midwife)

A9: Yes. COVID-19 Global Rheumatology Alliance, where I have contributed my data, supports the fact that patients treated with hydroxychloroquine can have presumed and/or confirmed COVID19 (86/334 patients). My patient who recovered was on long term therapy before COVID19+confirmed. The bigger question I think will be is how severe the COVID19+ HCQ cases will be (hospitalization, storm, or death). (Dr. Mittoo)

Q10: Have you seen arthritic flares in the hands of COVID-19 patients? I've seen several, as well as inflamed, painful toes and also post-infection rashes. (Submitted by an Advanced Practice Registered Nurse)

A10: Among my practice, of 5 strongly suspected COVID19+ rheumatic patients and one definite COVID19+ case, only one patient (suspected +) had increased joint pain. Myalgias were reported. Larger registries have not reported yet. Infections can lead to arthralgias, arthritis, inflammatory rashes; Chikungunya, Parvovirus b19 can lead to auto-antibody positive RA and SLE. (Dr. Mittoo)

Q11: Is it possible to differentiate a periodic fever syndrome flare-up (such as PFAPA) from COVID-19 without testing? (Submitted by a Physician Assistant Student) 

A11: PFAPA is usually in children between ages of 2-5 years and COVID19 does not have propensity for children. If you suspect adult form of PFAPA, a key cardinal sign includes cervical adenitis, apthous ulcerations, stomatitis. In contrast, COVID19 patients have sore throat, lymphadenopathy is rare in recent meta-analysis from China at 5% (mediastinal not even cervical) and fever pattern differs. (Dr. Mittoo)

Q12: How did the community think about hydroxychloroquine out of ALL the meds for treating COVID? There was no evidence and a high risk of QT prolongation with azithromycin. (Submitted by a Pharmacist)

A12: In rheumatic disease, approved dosing regimens allow for lower serum peaks, but higher doses have been used in COVID-19 treatment. Prolonged QTc is described in HCQ-treated patients and can lead to myocardial injury, including of conduction system. COVID19-VA study showed higher mortality in HCQ vs control and HCQ parent drug, chloroquine, had RCT in COVID19 stopped early due to cardiac toxicity. (Dr. Mittoo)

Q13: Is there an association between RA and more severe covid disease? (Submitted by an Emergency Medicine Physician)

A13: Not specific for COVID. High disease activity in RA leads to infection/serious infectious events. Also prednisone >= 10mg daily dose increases risk in a relevant way and meta-analysis in RA showing methotrexate increased pulmonary infections. The online RABBIT risk score for infection in RA also shows how comorbid conditions and age influence infection in RA. Being sedentary/disabled inc risk. (Dr. Mittoo)

Q14: Has anyone seen a relationship with respect to morbidity and mortality and jobs? If a "cytokine storm" is theorized then those people with lots of antibodies (teachers, pediatricians, GPs etc) would seem to be at higher risk. Children do well and it is generally unusual to see children with autoimmune diseases… Why? less antibodies? less disease experience? (Submitted by a Pediatrician)

A14: Certainly viral burden (from exposures) linked with bad outcomes in COVID19. The possible reasons for differential response in kids and adults is: 1. More co-morbidities (obesity etc) in adults 2. Immunosenescence in adults and age-dependent differences in host defense and RAS (which influences ARDS). 3. kids may not be able to mount cytokine storm,thus milder infections and not COVID tested. (Dr. Mittoo)

Q15: What are some of the basic principles of managing an ICU patient with cytokine storm? Thanks! (Submitted by a Critical Care Physician)

A15: Consider anti-IL-6 (tocilizumab, sarilumab) x1 (with repeat dosing only if responds and flares again)> Anakinra, colchicine (serositis dose), if d-dimer high, consider anticoagulation unless contraindication, if shock systemic steroids +-IVIG (if serum IgG low). Please get IL-6 levels or CRP levels pre- + post anti-IL-6; check thyroid function. Investigational: anti-IL-8, anti-VEGF. (Dr. Mittoo)

Q15a: I’ve never used colchicine for these patients, but I’d like to try it if I have the opportunity. Any words of caution? I also wanted to ask how high a d-dimer should be in order to consider empiric anticoagulation. (Submitted by the same Critical Care Physician as above)

A15a: Colchicine cautious use if renal dysfunction. A single centre study of 81 patients with COVID-19 requiring ICU admission suggested 1,500 ng/ml (sen/spec of 85/89 %, respectively) for DVT recurrence. Normal renal function and fibrinogen normal or high can choose low dose therapeutic heparin but if late stage COVID caution no anticoagulant given hemorrhagic phenotype. Timing of therapy key I think. (note: APLA Ab are reported thus can check). (Dr. Mittoo)

Q16: Tocilizumab is usually given for RA right? In that case, would natural herb treatments for RA be a potential helper for covid against cytokine storms too? (Submitted by an Emergency Medicine Resident)

A16: Theoretically, curcumin could increase histone deacetylase 2 and in turn decrease cytokine IL-1, TNF, IL-6, but how this plays out in real life not known and could even have deleterious effects by blunting early cytokine response necessary to fight infection. I can’t speak to other herbs. Supplemental IV Vit C being tried as adjunct. (Dr. Mittoo)

Q17: How exactly does it express dominantly on patients receiving immunosuppressive therapy? (Submitted by a Medical Student)

A17: Most patients independent of their immune status typically are presenting with dominant features (fever, cough, dyspnea) approximately 80%, but we are still learning that there are atypical presentations (vasculitis, renal failure, cardiac, CNS inflammatory states)and it is not clear how they are linked with patients having immunocompromised states at this time. (Dr. Mittoo)

Q18: What has the response been of these treatments with RA and Lupus patients? I have not found any reports, but have some concern over these. Especially those undiagnosed, or fall under mild stage criteria. What appropriate measures can we take aside from isolating these patients, and what treatment approaches can we consider with these ? Thank you! (Submitted by a Neurosurgery Resident)

A18: COVID19 Rheum registry still looking at that. It is too early. Stay attuned as I suspect there will be nuances as certain therapies (ie. JAK inhibitors, anti-IL-6, antimetabolites) are used (either removed or started) depending on the stage of the COVID19 presentation. (Dr. Mittoo)

Q19: Should one dose of tocilizumab be enough? How often to treat? Is a repeat dose effective? (Submitted by a Pharmacist)

A19: Hard to say at this point, but there is a trend in some centres to use as repeat dosing if a patient responds to the first dose in the setting of cytokine storm syndromes. Please reference clinicaltrial.gov or wait for final publication of recently reported findings from France's RCT showing positive results of tocilizumab. (Dr. Mittoo)

Q20: Would you consider recent hyperinflammation in an RA pt who is also a healthcare workers a sign of COVID-19? In such cases, would you suggest a change in their care plan? (Submitted by a Technologist)

A20: Yes, unless the patient has been in sustained moderate to high levels of inflammation and there is a sudden change in the inflammatory picture, I would test for COVID19 given the exposure and also expand testing for cytokine storm: CBC, ferritin, LDH, CRP, ESR, d-dimer as a first node of the decision tree for next steps of care. In high prob COVID19 waiting for results, stop anti-metabolite tx. (Dr. Mittoo)

 

Q21: Is there any data to come to any conclusion on the risk of fatality due to rheumatic co-morbidities as compared to someone who is otherwise well? (Submitted by a Physiotherapist)

A21: The theme of data from oncology-COVID19 dataset, historical RA-infection data/epi studies, and from New York COVID19 experience and recent UK COVID19 hospitalized patients (16, 749) showed older age and co-morbidities (chronic heart, lung), metastatic cancer, lung cancer, liquid tumours, obesity, and diabetes are risks for increased mortality. In RA, would reference answer in string above.

Q22: What is the role of colchicine in treating COVID-19? (Submitted a Neurologist)

A22: It is still to be determined (Montreal Heart Institute launching COLCORONA trial). Colchicine is used in diseases associated with inflammasome-dependent or mediated (gout, FMF) cytokine release (which can lead to storm--IL-1, TNFa, IL-6), but it also inhibits neutrophils and in turn could reduce neutrophil extracellular traps (NETs) which are thought to lead to more severe COVID19 manifestations. (Dr. Mittoo)

Q23: How can we prevent cytokinin storm before it actually happens in a sick patient? (Submitted by a General Surgeon)

A23: I think we need to start characterizing (with biomarkers) these subgroups of COVID19 into: hospitalized with viral pneumonia+ no systemic or serologic features or hospitalized with high risk serologic features (eg. inc d-dimer, lymphopenia, elevated CRP, inc ferritin) and clinical features (worsening oxygenation) and it is the later group to define and begin targeted Rx to avoid progression.

Q24: How likely is a person who has rheumatoid arthritis to get the corona virus?

A24: If the patient has high disease activity, there are more susceptible to COVID19. Other factors to this include steroid (and its dose in particular), other DMARD/advanced therapies, comorbidities, higher age, poor functional, and possibly (my bias) is type of occupational exposure (including night shifts or where there is breach in circadian rhythm by occupation/stress as this impacts immunity) (Dr. Mittoo)

Q25: What is the average time for a pt to present with cytokine storm? Is there any preventative or reduction techniques that can be done by a patient at home? (Submitted by an Occupational Therapy Assistant)

A25: It is not clear the "average time" but after 5-7 days average before symptom onset, the patients' condition can rapidly change (within hours) if storm develops. Unfortunately, no prevention known but lowering exposure to viral load (PPE) which is linked directly to storm and mortality, supportive (good sleep, mood stabilization) factors may be started but not likely to sign. impact trajectory. (Dr. Mittoo)

Q26: What has the recovery rate been like? And have there been any reinfections? If so, what are the characteristics of antibodies formed in terms of its duration in the system? (Submitted by a Medical Officer)

A26: Yes, there are reported reinfections (Korea, China) but it remains unclear if these are true reinfections or resurgence of their primary event. Also, testing with PCR tests may have changed during the duration of the response/center which makes a difference as some tests report high FN rates. (Dr. Mittoo)

Q27: What is the threshold for commencing Tocilizumab or Sarilumab in patients whose lab values are consistent with a cytokine release syndrome but clinically fever and ARS absent? As per the RCT RECOVERY trial in the UK, eligibility for Tocilizumab is elevated CRP & Sats <92% room air. Is there any risk for commencing early intervention in some cases? (Submitted by a Registered Nurse)

A27: It is not known but yes it could be risky particularly early on (pre-storm). (Dr. Mittoo)

Q28: For those of us that need Hydroxychloroquine for arthritis do you know what the likelihood of getting prescriptions filled in near future will be? My pharmacy tells me they can’t get it at all! Thank you. (Submitted by an Advanced Practice Registered Nurse)

A28: In Ontario, I am unaware of shortages at this point. Talk to your doctor about if there is a shortage whether chloroquine can be considered as an alternative. (Dr. Mittoo)

Q29: Is plasma transfer to a patient with COVID-19 from a patient cured of this disease effective? (Submitted by a Medical Student) 

A29: It's unknown if effective but being trialled to determine this. While it can be effective, the challenge with this approach is higher buden, cost, and scalability which is also why other therapies and ultimately a vaccine is the optimal cure and scalable. It is a good shorter term strategy as we wait for more options I think. (Dr. Mittoo)

Q30: Could dihroxychloroquine or steroid have a place in preventing cytokinestorm? (Submitted by a Family Medicine Physician)

A30: Though mechanistically, this drug can reduce cytokine and has anti-viral properties (reducing entry of virus in cell) and is attractive, it is not as powerful as other agents during a storm where overwhelming levels of IL-1, Il-6, TNFa require targeted approaches. I don't see a role as a prevention at this juncture, but I could see it being tried in high risk populations getting exposed. (Dr. Mittoo)

(Please note that as the information is changing so fast this Q&A was provided by the end of April 2020 ; therefore in order to reach updated information please refer to our resources page)

 

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