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?

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?

Can my patient with Covid-19 get reinfected?

Patients with prior history of Covid-19 have been shown to get reinfected, sometimes less severe and sometimes more severe than the first bout.1-3 What we don’t really know is how often reinfection actually occurs, either with or without symptoms.

Symptomatic reinfection with genetically distinct SARS-CoV-2 following Covid-19 has been reported from several countries, including the USA. 1  A case series of 4 patients (age range of 33-51 y) found the severity of second infection ranging from asymptomatic to more severe disease requiring hospitalization.  First infection was mild in these cases with an intervening period of 48-142 days.1  BNO News, a Dutch website, lists many more “officially confirmed cases” as well as over a thousand “suspected reinfection cases”.4

Reinfection with Covid-19 in at least some people should not be too surprising. Some may have a suboptimal immune response to the first infection (eg with mild infection) that may be short-lasting, while others may have a better response.  Even in those with adequate response, SARS-CoV-2 antibodies may drop rapidly (half-life 36 days according to one study).3 Immunity to several other seasonal respiratory coronaviruses (cousins of SARS-CoV-2) also seems short lived (as short as 6 months).5 How much other arms of the immune system besides antibodies (eg, T cell immunity) play a role in conferring longer lasting immunity remains unclear.

These findings suggest that we cannot rely on natural infection to provide us individual or herd immunity.  Immunization is likely a better answer!

Bonus Pearl: Did you know that preliminary reports suggest that antibody loss with Covid-19 is more rapid than that found for SARS-CoV-1, the agent of SARS pandemic of 2003?3

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References

  1. Iwasaki A. What reinfections mean for COVID-19. Lancet Infect Dis 2020. Published online October 12, 2020. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30783-0/fulltext
  2. Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis 2020. Published online October 12, 2020. https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30764-7.pdf
  3. Ibarrondo J, Fulcher JA, Goodman-Meza D, et al. Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19. N Engl J Med 2020; September 10. https://www.nejm.org/doi/full/10.1056/nejmc2025179
  4. Kunzman K. Contagion Live. October 12, 2020. https://www.contagionlive.com/view/us-reports-first-confirmed-covid-19-reinfection-patient. Accessed Dec 23, 2020.
  5. Edridge AWD, Kaczorowska J, Hoste ACR, et al. Seasonal coronavirus protective immunity is short-lasting. Nature Medicine 2020;26:1691-93. https://pubmed.ncbi.nlm.nih.gov/32929268/

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!

 

 

Can my patient with Covid-19 get reinfected?

What is the significance of Howell-Jolly bodies in the peripheral smear of my patient with a spleen who presents with pneumonia?

Howell-Jolly bodies (HJBs, Figure) are often indicative of asplenia (either post-splenectomy or congenital absence) or hyposplenism associated with a variety of conditions, including  sickle cell disease, autoimmune disorders, celiac disease, inflammatory bowel disease (particularly ulcerative colitis), HIV, cirrhosis, primary pulmonary hypertension, splenic irradiation, amyloidosis, sarcoidosis, bone marrow transplantation, and high-dose corticosteroid therapy1-4.

Patients with pneumonia and HJBs on peripheral smear may be hyposplenic and at risk of potentially serious infections, predominantly caused by encapsulated bacteria eg, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis3.  Such patients should be immunized against these organisms, including sequential receipt of both conjugated and polysaccharide pneumococcal vaccines3,5.

HJBs are nuclear remnants in circulating mature red blood cells which are usually pitted by the spleen under normal physiological conditions. 

Final Fun Pearl:  Did you know that  HJBs were named after Henry Howell, an American physiologist who pioneered the use of heparin as an anti-coagulant and Justin Jolly, a French hematologist who was among the first to film mitotic activity in cells?

howelljollymgh

Figure. Howell-Jolly body in an RBC. Photo courtesy of Michael S. Abers, MD

Contributed by Katarzyna Orlewska, Medical Student, Warszawski Uniwersytet Medyczny, Poland

 

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References

  1. Di Sabatino, A, Carsetti R, Corazza G. Post-splenectomy and hyposplenic states. Lancet 2011;378:86–97. https://www.ncbi.nlm.nih.gov/pubmed/21474172
  2. Brousse, V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol 2014;166: 165–176. https://www.ncbi.nlm.nih.gov/pubmed/24862308
  3. Mathew H, Dittus C, Malek A, Negroiu A. Howell-Jolly bodies on peripheral smear leading to the diagnosis of congenital hyposplenism in a patient with septic shock. Clin Case Rep 2015;3:714-717. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551333
  4. Ryan FP, Smart RC, Holdsworth CD, et al. Hyposplenism in inflammatory bowel disease 1978;19:50-55. https://www.ncbi.nlm.nih.gov/pubmed/624506
  5. Kuchar E, Miśkiewicz K , Karlikowska M. A review of guidance on immunization in persons with defective or deficient splenic function. Br J Haematol 2015; 171:683-94.  http://onlinelibrary.wiley.com/doi/10.1111/bjh.13660/full

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 is the significance of Howell-Jolly bodies in the peripheral smear of my patient with a spleen who presents with pneumonia?

Is there a seasonal variation in the incidence of cardiovascular (CV) events or venous thromboembolism (VTE)?

Seasonal variation, primarily characterized by a winter peak, has been reported for acute CV events, such as acute myocardial infarction (AMI) and sudden death, aortic rupture or dissection, and ischemic or hemorrhagic stroke, and VTE (1). A meta-analysis involving patients with VTE, primarily with a diagnosis of pulmonary embolism, revealed a 20% absolute increase in the incidence of VTE during January (1).  

Potential physiological mechanisms for these observations include increased sympathetic activity, decreased loss of fluids and sodium, increase in LDL cholesterol, increase in serum fibrinogen levels and other coagulation markers and C-reactive protein, and lower vitamin D levels due to shorter daylight hours during winter months (1,2).  At least in the case of AMI in the U.S., the higher incidence in winter is not affected by climate (2).  

Respiratory virus infections as a cause of acute inflammation leading to  CV or VTE events is another intriguing explanation (3). Indeed, influenza vaccination has been associated with reduction in hospitalization for cardiac disease and stroke among the elderly (4) and, in patients with cardiovascular disease, a reduction in death due to combined cardiovascular disease events such as heart attacks and strokes (5).

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References

  1. Dentali F, Ageno W, Rancan E, et al. Seasonal and monthly variability in the incidence of venous thromboembolism. A systematic review and a meta-analysis of the literature. Thromb Haemost 2011;106:439-447. https://www.ncbi.nlm.nih.gov/pubmed/21725580
  2. Spencer FA, Goldberg RJ, Becker RC, et al. Seasonal distribution of acute myocardial infarction in the Second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998;31:1226-33.h ttps://www.ncbi.nlm.nih.gov/pubmed/9581712
  3. Woodhouse PR, Khaw KT, Plummer M, et al. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet 1994;343:435-39.  https://www.ncbi.nlm.nih.gov/pubmed/7508540
  4. Nichol KL, Nordin J, Mulloly J, et al. Influenza vaccination and reduction in hospitalization for cardiac disease and stroke among the elderly. N Engl J Med 2003; 348:1322-1332. http://www.nejm.org/doi/full/10.1056/NEJMoa025028
  5. Clar C, Oseni Z, Flowers N, et al. Cochrane Database of Systematic Reviews 2015. DOI: 10.1002/14651858.CD005050.pub3h ttp://www.cochrane.org/CD005050/VASC_flu-vaccines-for-preventing-cardiovascular-disease  

 

 

 

 

Is there a seasonal variation in the incidence of cardiovascular (CV) events or venous thromboembolism (VTE)?