What’s the effectiveness of Covid-19 vaccination in patients with multiple sclerosis (MS) treated with high-efficacy disease-modifying therapies?

The answer appears to be dependent on which high-efficacy disease-modifying agent is being used to treat MS.  Limited data suggest that cladribine treatment does not impair humoral response to Covid-19 vaccine in patients with MS, while ocrelizumab and fingolimod have a major negative impact on vaccine responsiveness based on humoral antibody measurements.1

A study involving 125 Covid-19 MS vaccine (mRNA, Pfizer BNT162b2) recipients  (58% females, 61% relapse-remitting, 19% primary-progressive, 14% secondary-progressive, 3% clinically isolated syndrome and 2% radiologically isolated syndrome), found high levels of SARS-CoV-2 anti-spike IgG in all subjects (n=23) receiving cladribine as early as 4.4 months from last treatment dose.1

In contrast only 4% of patients with MS treated with fingolimod had a post-vaccination humoral response (time-interval from last treatment dose to vaccination not reported).  Similarly, most patients under treatment with ocrelizumab failed to develop a post-vaccination humoral response, with only 23% demonstrating a protective antibody titer (time-interval from last treatment dose 3.1-8.9 months).

These results may not be totally surprising given the attenuated humoral response to several common vaccines in patients with MS treated with ocrelizumab or fingolimod.2,3

Given the potential suboptimal response to Covid-19 vaccine in patients with MS treated with fingolimod or ocrelizumab, until further data become available, it’s fair to state that patients treated with these agents should NOT depend on vaccination to protect them from Covid-19 and that they may need to still take extra precautions during the pandemic.   

 

Bonus Pearl: Did you know that fingolimod prevents lymphocyte egression from secondary lymphoid tissue and ocrelizumab is an anti-CD20 monoclonal antibody that depletes B lymphocytes?1

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Reference

  1. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Therapeutic Adances in Neurological Disorders 2021;14:1-8. https://journals.sagepub.com/doi/full/10.1177/17562864211012835
  2. Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis. Neurology 2020; 95:e1999-22008. https://pubmed.ncbi.nlm.nih.gov/32727835/
  3. Kappos L, Mehling M, Arroyo R, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology 2015;84:872-9. https://pubmed.ncbi.nlm.nih.gov/25636714/  

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the effectiveness of Covid-19 vaccination in patients with multiple sclerosis (MS) treated with high-efficacy disease-modifying therapies?

Why is the Delta variant of SARS-CoV-2 increasingly becoming a “variant of concern” in the current Covid-19 pandemic?

The Delta variant (B.1.617.2, formerly India variant) has become an increasingly prevalent strain of SARS-Cov-2 causing Covid-19 in many countries outside of India, including the United States and United Kingdom, particularly affecting younger unvaccinated persons.  Several features of the Delta variant are of particular concern. 1-7

  1. Delta virus appears to be more transmissible when compared to previously emerged variant viruses. Data from new Public Health England (PHE) research suggests that the Delta variant is associated with a 64% increased risk of household transmission compared with the Alpha variant (B.,1.1.7, UK variant) and 40% more transmissibility in outdoors. 1,8  
  2. Delta virus is also associated with a higher rate of severe disease, doubling the risk of hospitalization based on preliminary data from Scotland. In vitro, it replicates more efficiently than the Alpha variant with higher respiratory viral loads.5
  3. Delta virus may also be associated with reduced vaccine effectiveness with increased vaccine breakthroughs. One study found that Delta variant is 6.8-fold more resistant to neutralization by sera from Covid-19 convalescent and mRNA vaccinated individuals.5 Fortunately, a pre-print study released by PHE in May 2021 found that 2 doses of the Pfizer vaccine were still 88% effective against symptomatic infection with Delta variant  (vs 93% for the Alpha variant) and 96% effective against hospitalization; 1 dose was only 33% effective against symptomatic disease (vs 50% for the Alpha variant).  Two doses of Astra Zeneca vaccine were 60% effective against symptomatic disease from the Delta variant.8 
  4. Aside from its somewhat unique epidemiologic features, Covid-19 caused by Delta variant seems to be behaving differently (starting out as a “bad cold” or “off feeling”), with top symptoms of headache, followed by runny nose and sore throat with less frequent fever and cough; loss of sense of smell was not common at all based on reported data to date.1

What the Delta variant reminds us is, again, the importance of vaccination, masks and social distancing. The pandemic is still with us!

Bonus Pearl: Did you know that, on average, a Delta variant-infected person may transmit it to 6 other contacts (Ro~6.0) compared to 3 others (Ro~3) for the original SARS-CoV-2 strains found during the early part of the pandemic?1

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References

  1. https://www.bbc.com/news/health-57467051
  2. Knodell R. Health Advisory: Emergence of Delta variant of coronavirus causing Covid-19 in USA. Missouri Department of Health & Senior Services. 23 June, 2021. https://health.mo.gov/emergencies/ert/alertsadvisories/pdf/update62321.pdf
  3. Kupferschmidt K, Wadman M. Delta variant triggers new phase in the pandemic. Science 25 June 2021; 372:1375-76. https://science.sciencemag.org/content/sci/372/6549/1375.full.pdf
  4. Sheikh A, McMenamin J, Taylor B, et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet 2021; 397:2461-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201647/
  5. Mlcochova P, Kemp S, Dhar MS, et al. Sars-Cov-2 B.1.617.2 Delta variant emergence and vaccine breakthrough. In Review Nature portfolio, posted 22 June, 2021. https://www.researchsquare.com/article/rs-637724/v1
  6. Bernal JL, Andrews N, Gower C, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 variant. MedRxiv, posted May 24, 2021. https://www.medrxiv.org/content/10.1101/2021.05.22.21257658v1 vaccine efficacy
  7. Allen H, Vusirikala A, Flannagan J, et al. Increased household transmission of Covid-19 cases associatd with SARS-Cov-2 variant of concern B.1.617.2: a national case control study. Public Health England. 2021. https://khub.net/documents/135939561/405676950/Increased+Household+Transmission+of+COVID-19+Cases+-+national+case+study.pdf/7f7764fb-ecb0-da31-77b3-b1a8ef7be9aa  Accessed June 27, 2021.
  8. Callaway E. Delta coronavirus variant: scientists brace for impact. Nature. 22 June 2021. https://www.nature.com/articles/d41586-021-01696-3 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author.

Why is the Delta variant of SARS-CoV-2 increasingly becoming a “variant of concern” in the current Covid-19 pandemic?

My patient with Covid-19 and abdominal pain has an elevated lipase. Is there a connection between Covid-19 and acute pancreatitis?

Acute pancreatitis as a complication of Covid-19 is infrequent.1 Despite reports of elevated amylase/lipase and/or acute pancreatitis in some patients with Covid-19,2 the exact role that SARS-CoV-2 plays in causing acute pancreatitis is unclear at this time.

A retrospective study of over 11,000 hospitalized patients with Covid-19 in the U.S. found a point prevalence of acute pancreatitis of only 0.27%,3 while another retrospective study of Covid-19 patients seen in Spanish emergency rooms reported acute pancreatitis in only 0.07% of cases.4 Of interest, in the latter study, Covid-19 was associated with lower frequency of acute pancreatitis. Further adding to the controversy on the causative role of Covid-19 is lack of an observed increase in the incidence of acute pancreatitis during Covid-19 pandemic. 1

An earlier study from China reported mild elevation (<3x upper limits of normal) of amylase and/or lipase in 17% of patients with Covid-19 pneumonia, none of whom had abdominal pain. 5

The temporal relationship between Covid-19 and acute pancreatitis has varied from abdominal symptoms at the onset of Covid-19 symptoms to days after diagnosis of Covid-19? 1

Despite these disparate findings, Covid-19 related acute pancreatitis or pancreatic injury is plausible. Pancreatic ductal, acinar and islet cells express ACE2, an important receptor for SARS-CoV-2.1 Infection in the GI tract (virus can easily be found in the stool) may potentially spread from the duodenal epithelium to the pancreatic duct and the pancreatic parenchyma itself. Immune-mediated inflammatory response or endotheliitis caused by SARS-CoV-2 may also potentially explain reports of pancreatic injury in Covid-19. 1,2

Bonus Pearl: Did you know that SARS-CoV-2 has been found in pancreatic tissue of some patients who succumbed to Covid-19 and has been shown to infect human pancreatic beta cells in-vitro.6  Perhaps we should be on the lookout for diabetes as a consequence of Covid-19 as well!

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 References

  1. De-Madaria E, Capurso G. Covid-19 and acute pancreatitis: examining the causality. Nature Reviews Gastroenterol Hepatol 2021;18: 3-4. https://www.nature.com/articles/s41575-020-00389-y
  2. Kandasamy S. An unusual presentation of Covid-19: acute pancreatitis. Ann Hepatobiliary Pancreat Surg 2020;24:539-41. https://synapse.koreamed.org/upload/SynapseXML/2110ahbps/pdf/AHBPS-24-539.pdf
  3. Inamdar S, Benias PC, Liu Y, et al. Prevalence, risk factors, and outcomes of hospitalized patients with coronavirus disease 2019 presenting as acute pancreatitis. Gastroenterol 2020;159:2226-28. https://www.gastrojournal.org/article/S0016-5085(20)35115-5/pdf
  4. Miro O, Llorens P, Jimenez S, et al. Frequency of five unusual presentations in patients with Covid-19: results of the UMC-19-S. Epidemiol Infect 2020;148:e189. https://pubmed.ncbi.nlm.nih.gov/32843127/
  5. Wang F, Wang H, Fan J, et al. Pancreatic injury patterns in patients with coronavirus disease 19 pneumonia. Gastroenterology 2020;159:367-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118654/
  6. Wu C-T, Lidsky PV, Xiao Y, et al. SARS-CoV-2 infects human pancreatic beta cells and elicits beta cell impairment. Cell Metab 2021 May 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130512/

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My patient with Covid-19 and abdominal pain has an elevated lipase. Is there a connection between Covid-19 and acute pancreatitis?

Can Covid-19 exacerbate seizures in patients with epilepsy?

There have been several reports of seizure exacerbation in epileptic patients after Covid-19 infection. Seizure exacerbations have been observed in epileptic patients with uncontrolled epilepsy, as well as patients who were previously controlled with antiepileptic drugs (AEDs).1,2

In a survey of 362 epileptic patients in Wuhan, China, the site of the initial outbreak, 31 (8.6%) patients reported an increased number of seizures in the month after the public lockdown began; 16 (51.6%) of the 31 patients with seizure exacerbation had prior exposure to Covid-19.1

In a study of 439 patients with Covid-19 infection in Egypt, 19 (4.3%) patients presented with acute seizures.2  Two of the 19 seizure patients had a previous diagnosis of epilepsy, which had been controlled for up to 2 years. Interestingly, the other 17 patients had new onset seizures without a previous epilepsy diagnosis.

Covid-19 has been proposed to induce seizures by eliciting inflammatory cytokines in the central nervous system, leading to neuronal necrosis and increased glutamate levels in the cerebral cortex and hippocampus.3

Covid-19 infection may have also indirectly caused seizure exacerbations in a number of epileptic patients. Interestingly, stress related to worrying about the effect of the outbreak on a patient’s seizure activity was associated with seizure exacerbations (odds ratio: 2.5, 95% CI: 1.1-6.1)2. It is also possible that some seizure exacerbations may have been due to fear of visiting the hospital and AED withdrawal, as was demonstrated during the 2003 SARS outbreak.4

Bonus Pearl: Did you know that Guillain–Barré Syndrome has also been observed in patients with Covid-19 infection?5

Contributed by Luke Vest, Medical Student, St. Louis University Medical School

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References:

  1. Huang, S., Wu, C., Jia, Y., et al. (2020). COVID-19 outbreak: The impact of stress on seizures in patients with epilepsy. Epilepsia, 61(9), 1884-1893. https://doi.org/10.1111/epi.16635  
  2. Khedr, E. M., Shoyb, A., Mohammaden, M., & Saber, M. (2021). Acute symptomatic seizures and COVID-19: Hospital-based study. Epilepsy Res, 174, 106650. https://doi.org/10.1016/j.eplepsyres.2021.106650
  1. Nikbakht, F., Mohammadkhanizadeh, A., & Mohammadi, E. (2020). How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Multiple sclerosis and related disorders, 46, 102535. https://doi.org/10.1016/j.msard.2020.102535
  2. Lai, S. L., Hsu, M. T., & Chen, S. S. (2005). The impact of SARS on epilepsy: the experience of drug withdrawal in epileptic patients. Seizure, 14(8), 557–561. https://doi.org/10.1016/j.seizure.2005.08.010
  3.  Abu-Rumeileh, S., Abdelhak, A., Foschi, M., Tumani, H., & Otto, M. (2021). Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. Journal of neurology, 268(4), 1133–1170. https://doi.org/10.1007/s00415-020-10124-x   

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions, or St. Louis University Medical School. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Can Covid-19 exacerbate seizures in patients with epilepsy?

My elderly patient developed a flare-up of her gout few days after receiving Covid-19 vaccine. Is there a connection between immunization and gout flare?

Although the connection between Covid-19 vaccination and gout flare has yet to be established, higher rates of gout/gout flare following the administration of several other vaccines (eg, influenza, tetatnus, recombinant zoster) have been reported.1  Thus, it is conceivable that Covid-19 vaccine may also be associated with gout flare as more and more people are immunized.  

A 2019 prospective study of over 500 patients with gout found that vaccination was associated with 2-fold higher odds of gout flare (aO.R. 1.99; 95% ci 1.01-3.89) during the 2 day period following immunization; no information on the type of vaccines administered was provided, however.1  Similarly,  higher risk of gout (3.6-fold) has been reported in recipients of recombinant zoster vaccine following immunization.1

An intriguing mechanism explaining the association of vaccination and gout flare is the activation of the Nlrp3 inflammasome, a multiprotein complex produced in response to diverse stimuli such as uric acid crystals and ATP released from tissue injury/necrotic cells.2 Of interest, ~25% of patients with asymptomatic hyperuricemia have been found to have evidence of monosodium urate crystals in and around their joints by advanced imaging, such that vaccination may potentially bring out more inflammatory response and gout flare.

Although aluminum adjuvants intended to increase the immunogenicity of one-half of all routine adult vaccines (eg, tetanus, diphteria, pertussis) have been shown to activate the Nlrp3 inflammasome in vitro, neither currently available mRNA vaccines (Pfizer, Moderna) nor the Johnson&Johnson vaccine contains aluminum as an adjuvant. 4  

Despite the potential for gout flare following adult vaccination, it should be emphasized that the absolute risk is still low and pales compared to the overwhelming benefits of vaccination in general.1

Bonus Pearl: Did you know that, in addition to the usual uric acid lowering drugs, losartan, fenofibrate and some non-steroidal anti-inflammatory drugs, such as indomethacin, also lower serum uric acid levels? 5,6

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References

  1. Yokose C, McCormick N, Chen C, et al. Risk of gout flares after vaccination: a prospective case-crossoverstudy. Ann Rheum Dis 2019;78:1601-1604. https://ard.bmj.com/content/early/2019/07/31/annrheumdis-2019-215724.info?versioned=true
  2. Lyer SS, Pulskens WP, Sadler JJ, et al. Necrotic cells trigger a sterile inflammatory response throught the Nlrp3 inflammasome. PNAS 2009;106:20388-20393. https://pubmed.ncbi.nlm.nih.gov/19918053/
  3. Yokose C, Choi H. Response to “Clarification regarding the statement of the association between the recombinant zoster vaccine (RZV) and gout flares’ by Didierlaurent etal. Ann Rheum Dis Month, December 2019. https://ard.bmj.com/content/annrheumdis/early/2019/12/18/annrheumdis-2019-216670.full.pdf
  4. Covid-19 vaccine information. https://covidvaccine.mo.gov/ Accessed March 16, 2021.
  5. Daskalopoulou SS, Tzovaras V, Mikhailidis DP, et al. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Current Pharmaceutical Design 2005;11:4161-75. https://www.eurekaselect.com/60510/article
  6. Tiitinen S, Nissila M, Ruutsalo HM, et al. Effect of nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid. Clin Rheumatol 1983;2:233-6. https://pubmed.ncbi.nlm.nih.gov/6678696/#:~:text=The%20effect%20of%209%20nonsteroidal,studied%20had%20no%20significant%20influence.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My elderly patient developed a flare-up of her gout few days after receiving Covid-19 vaccine. Is there a connection between immunization and gout flare?

Is Covid-19 vaccine effective in immunocompromised patients?

The short answer is that we don’t have any solid data on the performance of Covid-19 among immunocompromised (IC) patients at this time because the large trials used to clear the available vaccines for FDA Emergency Use Authorization essentially excluded IC subjects (1,2). 

However, despite a potentially blunted response, the immunogenicity of the Covid-19 vaccine may be sufficient to reduce the risk of serious disease. The CDC and the American Society of Clinical Oncologists support Covid-19 vaccination of IC patients as long as there are no contraindications and patients are counseled about the uncertainty in vaccine efficacy and safety in this particular population (3,4).

 For patients undergoing treatment for cancer, the ASCO believes that Covid-19 vaccine may be offered in the absence of any contraindications.  To reduce the risk of Covid-19 while retaining vaccine efficacy, it recommends that the vaccine be given between cycles of therapy and after “appropriate waiting periods” for those receiving stem cell transplants and immunoglobulin therapy (4).

Previous experience with pneumococcal and influenza vaccine in IC patients have reported frequent suboptimal immunological response (2). Concomitant treatment with infliximab or other immunomodulatory drugs have had a negative impact on seroconversion after influenza vaccination. Similarly, in patients with Crohn’s on immunosuppressives, immune response to polysaccharide pneumococcal vaccine has been blunted (2). 

Nevertheless, the benefits of vaccination may still outweigh any risks of adverse events in this population. In fact, the CDC routine vaccination schedule for adults includes immunocompromised patients (5).  

At this time, given the seriousness of the Covid-19 pandemic and higher risk of severe disease among many IC patients, offering Covid-19 vaccine to these patients (with aforementioned caveats) seems prudent. 

 

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References

  1. Kumar A, Quraishi MN, Segal JP, et al. Covid-19 vaccinations in patients with inflammatory bowel disease. Lancet 2020;4:965-6. https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30295-8/fulltext
  2. Polack FP, Thomas SJ, Ktichin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020;383:2603-15. https://www.nejm.org/doi/full/10.1056/NEJMoa2034577
  3. Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. Accessed Feb 14, 2021.
  4. American Society of Clinical Oncologists. Covid-19 vaccine and patients with cancer.. https://www.asco.org/asco-coronavirus-resources/covid-19-patient-care-information/covid-19-vaccine-patients-cancer Accessed Feb 14, 2021
  5. CDC. Immunization schedules. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html Accessed Feb 14, 2021.  

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is Covid-19 vaccine effective in immunocompromised patients?

Should I treat my patient with Covid-19 with ivermectin?

Despite its potential antiviral activity,1 there is insufficient data at this time to recommend either for or against the use of ivermectin for the treatment of Covid-19, per NIH Covid-19 guidelines.2 This conclusion is based on lack of robust, adequately powered and designed clinical trials.The Infectious Diseases Society of America (IDSA) recommends against its use in ambulatory or hospitalized patients with Covid-19 (mild to moderate or severe, respectively) except in clinical trials.

Although some studies (published or preprint) have reported benefits of ivermectin (eg, shorter time to resolution of disease or viral clearance, greater reduction in inflammatory markers, and lower mortality rates) in Covid-19, others have found either no benefit or worsening of disease with ivermectin therapy.2-6

Unfortunately, methodological problems have plagued many of these studies.1 For example, a randomized-controlled preprint study from Egypt reported clinical improvement and decreased mortality in Covid-19 patients treated with ivermectin.  Noteworthy,  the ivermectin group also received hydroxychloroquine plus a “standard therapy”, defined in the study as azithromycin, vitamin C, zinc, lactoferrin and acetylcysteine.3

A retrospective study from Bangladesh involving hospitalized patients with Covid-19,  reported lower mortality in those receiving only 1 dose of ivermectin (12 mg) within 24 h of admission.  However, 60% of the non-ivermectin group also received antibiotics, often for undefined “secondary infection” (vs 15% of ivermectin group)4, making it difficult to interpret the results.

In contrast, a randomized double-blind trial in mild Covid-19 failed to find any improvement in time to resolution of symptoms  after a 5-day course of Ivermectin. In a retrospective preprint study from Peru found significantly higher rates of death and/or ICU transfer among hospitalized patients treated with ivermectin or hydroxychloroquine+azithromycin.7

The plausibility of studies supporting treatment of Covid-19 with ivermectin has been further questioned because, despite its apparent antiviral activity in vitro,1 pharmacokinetic and pharmacodynamic studies suggest that doses up to 100 times higher than those approved for use in humans would be needed to achieve potentially effective plasma concentrations.2,8

Bonus Pearl: Did you know that ivermectin enhances the activity of GABA receptors, resulting in paralysis of somatic muscles, poor pharyngeal function and starvation of parasites and worms? 9 Fortunately, ivermectin’s affinity for parasite is 100 times more than for brain of mammals because of the blood brain barrier.

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References

  1. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In vivo 2020;34:3023-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652439/pdf/in_vivo-34-3023.pdf
  2. NIH. The Covid-19 treatment guidelines panel’s statement on the use of ivermectin for the treatment of COVID-19. Last updated Jan 14, 2021. https://www.covid19treatmentguidelines.nih.gov/statement-on-ivermectin/. Accessed January 18, 2021.
  3. Elgazzar A, Hany B, Abo Youssef S, et al. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square Preprint 2020. https://assets.researchsquare.com/files/rs-100956/v2/39b225ad-5df4-4da7-9cbd-233bf26a0eb4.pdf
  4. Ahmed S, karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International J Infect Dis 2021;103:214-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709596/
  5. Soto-Becerra P, Culquichicon C, Hurtado-Roca Y, et al. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. MedRxive 2020. https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.full.pdf
  6. Chachar AZ, Khan KA, Asif M, et al. Effectiveness of ivermetctin in SARS-CoV-1/COVID-19 patients. International J Sciences 2020; 9:31-35. https://c19ivermectin.com/chachar.html
  7. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolutoin of symptoms among adults with mild COVID-19. JAMA 202;325:1426-35.  https://jamanetwork.com/journals/jama/fullarticle/2777389
  8. Chaccour C, hammann F, Ramon-Garcia S, et al. Ivermectin and COVID-19: Keeping rigor in times of urgency. Am J Trop med hyg 2020;102:1156-7. https://pubmed.ncbi.nlm.nih.gov/32314704/  
  9. Kaur H, Shekhar N, Sharma S, et al. Ivermectin as a potential drug for treatment of COVID-19:an in-sync review with clinical and computational attributes. Pharmacological Reports. Published online January 3, 2021. Great review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778723/pdf/43440_2020_Article_195.pdf

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should I treat my patient with Covid-19 with ivermectin?

Beyond masks and hand hygiene, what factors impact transmission of Covid-19 in indoor gatherings?

Aside from factors specific to the source individual (eg, viral load in exhaled air, “superspreader” features, etc…) and host characteristics (eg, older age, obesity, immunocompromised state), transmission of SARS-CoV-2 in indoor settings may be impacted by several factors, including social distancing, ventilation of rooms/ direction of airflow, room occupancy, exposure time and higher risk activities, such as eating, talking loud, heavy breathing during exercise, laughing, coughing and sneezing. 1-4

  1. Physical distance from infected individuals. Although a “safe” distance of 6 feet has often been cited, increasing evidence suggests that SARS-CoV-2 may be spread not only by larger droplets but also by airborne route (ie, beyond 6 feet or shortly after an infected person leaves the area). In fact, 8 of 10 studies on horizontal droplet distance have reported droplets traveling more than 6 feet (2 meters), some cases up to 26 feet (8 meters), and 1 study documented virus at 13 feet (4 meters). Transmission beyond 6 feet is not surprising since even as early as 1948 beta streptococci were found 9.5 feet from 10% of people who were infected!1
  2. Quality of ventilation and direction of airflow in the room. Poorly ventilated rooms would be expected to have more potentially infectious droplets in the air for longer periods of time, even after an infected person leaves the area.
  3. Room occupancy. The higher the occupancy the more likely to have exhaled contaminated air from 1 or more infected persons (symptomatic or asymptomatic) with exposure of susceptible hosts.
  4. Exposure time. Exposure to contaminated air in the room even for a relatively short period of time (ie, >5-15 minutes) is likely to increase the risk of transmission.
  5. Activity of infected individual. Many activities such as singing, speaking loudly, eating, laughing, breathing heavily during exercise, coughing and sneezing may increase risk of Covid-19 transmission in indoor settings.

Recall that over one-half of Covid-19 transmissions are due to asymptomatic individuals.5 In this setting and in the presence of factors discussed above, it’s easy to see how transmission of Covid-19 in indoor settings can occur readily, possibly explaining cases without apparent source.

Bonus Pearl: Did you know that the odds of Covid-19 transmission may be 18.7 times greater indoors compared to open-air environment and the odds of superspreading event in closed environments may be 32.6 times higher?4

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References

  1. Bahl P, Doolan C, de Silva C, et al. Airborne or droplet precautions for health workers treating coronavirus disease 2019? J Infect Dis 2020. Published online April 16, 2020. https://pubmed.ncbi.nlm.nih.gov/32301491/
  2. Jones NR, Quereshi Z, Temple RJ, et al. Two metres or one: what is the evidence for physical distancing in covid-19? BMJ 2020;370:m3223. https://www.bmj.com/content/370/bmj.m3223/rr-18
  3. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 transmission from people without COVID-19 symptoms. JAMA Network open. 2021;4():e2035057. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2774707?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=010721
  4. Nishiura H, Oshitani H, Kobayashi T, et al. Closed environments facilitate secondary transmission of coronavirus disease 2019 (COVID-19). MedRxiv 2020. https://www.medrxiv.org/content/10.1101/2020.02.28.20029272v2.full.pdf
  5. Leclerc QJ, Fuller NM, Knight LE,e tal. What settings have been linked to SARS-CoV-2 transmission clusters? Wellcome Open Research October, 2020. https://wellcomeopenresearch.org/articles/5-83    

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Beyond masks and hand hygiene, what factors impact transmission of Covid-19 in indoor gatherings?

Is the discovery of new variants of SARS-CoV-2 expected to impact the transmissibility, clinical course or vaccine efficacy in Covid-19?

To date, the discovery of new variants of SARS-CoV-2 has raised concerns primarily around their association with higher than expected transmission rates, not increased severity, risk of death or impairment in vaccine efficacy. 1-5

The new variants of SARS-CoV-2—first recognized in the U.K (strain B.1.1.7), then South Africa (B.1.351), and now many parts of the world, including US and Canada—seem to be associated with higher rates of transmission without any evidence for more severe disease or hospitalization.3 Based on mathematical models, it is suggested that the new variant may be up to 70% more transmissible than the original virus.1 However, it is important to point out that, to date, there are no published studies that corroborates this finding in laboratory animals and some have questioned whether these new strains are truly more transmissible.1

The B.1.1.7 strain has several mutations involving the spike protein (the surface  protein that attaches to host cells) at least 1 of which (N501Y) seems to improve the virus’s ability to bind to cells.1 Preliminary laboratory studies have also found higher viral replication rates in upper respiratory tract of hamsters when challenged with another SARS-CoV-2 variant with spike protein mutation (D614G) compared to the lungs.4  Both “stickiness” to cells and high replication rates in upper respiratory tract alone may explain more rapid spread of the virus without increased severity of disease.

Preliminary reports also suggest that that antibodies against the original strain  neutralize the B.1.1.7 strain, supporting the efficacy of the current Covid-19 vaccine in protecting against this strain.1

A theoretical concern, however, based on a preprint publication, is the suboptimal binding and neutralization of new strains by commercially available monoclonal antibodies.2

The potential increased transmissibility of new SARS-CoV-2 variants only underscores the importance of public health measure such as masks, social distancing and hand hygiene, now more than ever before!

Bonus Pearl: Did you know that despite lack of clear increase in the severity of disease associated with new variants of SARS-CoV-2, increased rate of transmission will lead to more people getting infected and therefore die from its complications. That’s why, more than ever before, we should double down our efforts to stick to public health measures to mask, social distance and exercise hand hygiene during this critical period of the pandemic. Please spread the word, again!

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References

  1. Reardon S. The U.K. coronavirus mutation is worrying but not terrifying. Scientific American. December 24, 2020. https://www.scientificamerican.com/article/the-u-k-coronavirus-mutation-is-worrying-but-not-terrifying/
  2. Starr TN, Greaney AJ, Addetia A, et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Bio Rxiv 2020. https://www.biorxiv.org/content/10.1101/2020.11.30.405472v1
  3. CDC. Interim: Implications of the emerging SARS-CoV-2 variant VOC 202012/01. Accessed Jan 12, 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-emerging-variant.html
  4. Plante JA, Liu Y, Liu J, et al. Spike mutation D614G alters SARS-CoV-2 fitness. Nature. Published online 26, 2020. https://pubmed.ncbi.nlm.nih.gov/33106671/
  5. Baric RS. Emergence of a highly fit SARS-CoV-2 variant. N Engl J Med 2020; 383;2684-2686. https://www.nejm.org/doi/full/10.1056/NEJMcibr2032888

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is the discovery of new variants of SARS-CoV-2 expected to impact the transmissibility, clinical course or vaccine efficacy in Covid-19?

What’s the connection between Covid-19 and persistent fatigue?

Fatigue is one of the most common symptoms in patients with Covid-19, both during the acute illness as well during the weeks or months that follows it. Depending on the study, fatigue has been reported in around 30%-80% of patients at 2-3 weeks to 6 months or longer after the onset of illness (1-4).

In a study of hospitalized patients with Covid-19, ~80% of patients complained of fatigue during the acute illness, with ~50% having persistent fatigue at a mean follow-up of 60 days following onset of illness (1). Persistent fatigue was the most common symptom during the post-Covid-19 period, followed by dyspnea, joint pain, chest pain and cough.

In another study, 52.3% of patients with Covid-19 complained of persistent debilitating fatigue at a median of 10 weeks after initial onset of symptoms, despite a negative test for the virus (2). Of interest, there was no association between severity of Covid-19 illness/need for hospitalization and post-covid fatigue.  No association was found between routine laboratory markers of inflammation, WBC profile, LDH, C-reactive protein or interleukin-6 levels and persistent fatigue.

A CDC survey of outpatients with Covid-19 patients at 14-21 days from test date found persistent fatigue in one-third of patients (3).   

A MedRxive study (pending peer review) of over 3700 patients with definite (27%) or probable diagnosis of Covid-19 from 56 countries (>90% not hospitalized) reported fatigue in 78% of patients after 6 months (4).

Although the true nature or course of persistent fatigue following Covid-19 has yet to be clearly defined, In some respects, it’s reminiscent of chronic fatigue syndrome associated with many acute viral infections, such as SARS, EBV, and enteroviruses (5-7).

Bonus pearl: Did you know that persistent fatigue following Covid-19 may be more frequent than that following influenza in which >90% of outpatients recover within about 2 weeks (3)?

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References

  1. Carfi A, Bernabei R, Landi. Persistent symptoms in patients after acute COVID-19.JAMA 2020;324:603-605. https://pubmed.ncbi.nlm.nih.gov/32644129/
  2. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLOS ONE 2020. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240784   
  3. Tenforde MW, Kim SS, Lindsell CJ, et al. Duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March—June 2020. MMWR 2020;69:993-98. https://www.cdc.gov/mmwr/volumes/69/wr/mm6930e1.htm
  4. Davis HE, Assaf GS, MCorkell L, et al. Characterizing long COVID in an international cohort:7 months of symptoms and their impact. MedRxive 2020. https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2.full.pdf
  5. Chia JKS, Chia AY. Chronic fatigue syndrome is associated with chronic infection of the stomach. Clin Pathol 2008;61:43-48. https://jcp.bmj.com/content/61/1/43
  6. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case control study. BMC Neurol 2011;11:37. https://pubmed.ncbi.nlm.nih.gov/21435231/
  7. Hickie I, Davenport T, Whitfield D, et al. Post-infective and chronic fatigue syndrome precipitated by pathogens: prospective cohort study. BMJ 2006;333:575. https://jcp.bmj.com/content/61/1/43

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the connection between Covid-19 and persistent fatigue?