Tetanus;

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?

FA Manian MD, MPH, , , , , , , , , , , , , , , 1 Comment

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. 3 

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?

Why might convalescent sera or plasma transfusion therapy be effective in the treatment of patients with Covid-19?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , Leave a comment

Of the myriad therapeutic approaches currently under consideration in our fight against Covid-19, convalescent sera/plasma therapy (CSPT) is particularly promising. The principle behind CSPT is to provide immediate immunity to susceptible people by administering the serum or plasma—therefore antibodies—of individuals who have successfully recovered from Covid-19.1

The theory behind using antibody-containing blood products to treat infections is by no means new and goes back to the 1890s when serum from exposed animals who recovered from disease was used to protect healthy animals against tetanus and diphtheria.2

Historically, CSPT has been used against poliomyelitis, measles, mumps, and influenza, and more recently in a smaller number of patients with SARS, H5N1 and H7N9 avian influenza and Ebola.1,3-8 A 2015 systematic review and exploratory meta-analysis of 32 studies involving severe acute respiratory infections of viral etiology (including influenza and SARS) found a reduction in mortality (odds ratio, 0.25, 95% C.I. 0.14-0.45), particularly when CSPT was administered early into the illness.3

Experience with 1918 Spanish influenza pandemic: A meta-analysis of 1703 hospitalized patients (Yes, scientists performed wonderful studies back then too despite a pandemic!) during the 1918 Spanish influenza pandemic demonstrated decreased mortality with administration of convalescent blood products with crude case-fatality rates dropping by one-half (16% vs 37% in controls)! Notably, patients who were treated within 4 days of pneumonia had one-third the case-fatality rate compared to those treated later.3

Experience with 2002-2004 SARS epidemic: A retrospective study from Hong Kong involving 80 patients with SARS (caused by another coronavirus, SARS-CoV-1) not responding to antibiotics/steroids/interferon but receiving CSPT reported a lower mortality rate with near significant (P=0.08) improvement in outcome and reduced mortality in the group that received CSPT before day 14 of the illness (6.3% vs 21.9%).4

What about Covid-19? A very preliminary report out of China involving 5 mechanically-ventilated patients with ARDS and rapid progression despite corticosteroids and antivirals found clinical improvement in all 5 patients. More specifically, body temperature normalized within 3 days in 4 of 5 patients and ARDS resolved in 4 patients at 12 days following transfusion, 2 patients were in stable condition and 3 patients were eventually discharged from the hospital.9

Of course, we should be mindful of potential adverse reactions due to CSP as well, such as allergic reactions, infections, transfusion-related acute lung injury (TRALI), and theoretical risk of antibody-dependent enhancement of infection (ADE).1 Only properly designed clinical studies can shed light on the safety and efficacy of CSPT in Covid-19.

Nevertheless, the historical data on the use of CSPT in serious viral infections is encouraging. In fact, the first US studies of CSPT in Covid-19 have already been approved by the FDA!10 Stay tuned!

Bonus pearl: Did you know that serum and plasma both refer to the noncellular fluid part of blood, but serum is collected after coagulation factors (fibrinogen) have been removed. Fortunately, both contain antibodies!

 

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Contributed by Bruce Tiu, Harvard Medical Student, Boston, MA.

References:

  1. Casadevall A, Pirofski L. The convalescent sera for containing COVID-19. J Clin Invest. 2020;130(4):1545-1548. doi: 10.1172/JCI138003 https://www.jci.org/articles/view/138003
  2. Eibl MM. History of immunoglobulin replacement. Immunol Allergy Clin North Am. 2008;28(4):737–viii. doi:10.1016/j.iac.2008.06.004 https://www.sciencedirect.com/science/article/abs/pii/S0889856108000702
  3. Mair-Jenkins J, Saavedra-Campos M, Baillie K, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. J Infect Dis 2015; 211: 80-90. https://academic.oup.com/jid/article/211/1/80/799341
  4. Luke TC, Kilbane EM, Jackson JL, et al. Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?. Ann Intern Med. 2006;145:599–609. doi: 10.7326/0003-4819-145-8-200610170-00139 https://annals.org/aim/article-abstract/729754/meta-analysis-convalescent-blood-products-spanish-influenza-pneumonia-future-h5n1
  5. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44–46. doi:10.1007/s10096-004-1271-9 https://link.springer.com/article/10.1007/s10096-004-1271-9
  6. Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007;357:1450–1. doi: 10.1056/NEJMc070359 https://www.nejm.org/doi/full/10.1056/NEJMc070359
  7. Chen L, Xiong J, Bao L, et al. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis 2020;20: 398-400. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30141-9/fulltext
  8. Wu XX, Gao HN, Wu HB, Peng XM, Ou HL, Li LJ. Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma. Int J Infect Dis. 2015;41:3–5. doi: 10.1016/j.ijid.2015.10.009 https://www.ncbi.nlm.nih.gov/pubmed/26482389
  9. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783 https://jamanetwork.com/journals/jama/fullarticle/2763983
  10. https://thehill.com/regulation/healthcare/490768-first-us-coronavirus-patients-being-treated-with-plasma-therapy.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic 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!

 

 

 

 

Why might convalescent sera or plasma transfusion therapy be effective in the treatment of patients with Covid-19?