Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

Despite recent internet reports of the association of non-steroidal anti-inflammatory drugs (NSAIDs) with worsening symptoms among patients with Covid-19 (1), firm clinical evidence to support such claims is currently lacking. However, there are some theoretical reasons why it may still be best to avoid NSAIDs in this condition due to their potential adverse impact on the innate and adaptive immune responses as well as their antipyretic properties (2-9).

 
Blunting of the innate immune response: Certain NSAIDs (eg, ibuprofen, naproxen and celecoxib) inhibit cyclooxygenase enzyme-2 (COX-2) and impair production of several pro-inflammatory cytokines important in fighting infections, such as tumor necrosis factor, interleukin 1 and 6, as well as interferon, an antiviral cytokine (2,6,8). COX-2 has been shown to be important in controlling viral replication in influenza (4). Ibuprofen has been associated with inhibitory effects on a variety of polymorphonuclear functions, including chemotaxis (2).

 
Impact on adaptive immune response: COX-2 inhibition may be associated with impaired neutralizing antibody production (3,4,8). Potential mechanisms include modulation of cytokine expression, nitric-oxide production, and antigen processing/presentation and T lymphocyte activation (3,8).

 
Antipyretic effect: NSAIDs are often given for treatment of fever which is an evolutionary host response to infection. A meta-analysis of animal studies evaluating the impact of antipyretics (including aspirin, NSAIDs, and acetaminophen) in influenza found lower survival in animals treated with antipyretics (9). Longer duration of viral shedding has also been associated with the use of aspirin or acetaminophen in rhinovirus infection (9).

 
Formal epidemiologic and experimental studies are sorely needed to evaluate the safety of NSAIDS in Covid-19.  

 

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References
1. Kolata G. Is ibuprofen really risky for Coronavirus patients? NY Times, March 17, 2020. https://www.nytimes.com/2020/03/17/health/coronavirus-ibuprofen.html
2. Graham NMH, Burrell CJ, Douglas RM, et al. Adverse effects of aspirin, acetaminophen and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990;162:1277-1282. https://academic.oup.com/jid/article/162/6/1277/918184
3. Culbreth MJ, Biryunkov S, Shoe JL, et al. The use of analgesics during vaccination with a live attenuated Yersinia pestis vaccine alters the resulting immune response in mice. Vaccines 2019;7, 205; doi:10.3390/vaccines7040205 https://www.mdpi.com/2076-393X/7/4/205
4. Ramos I, Fernandez-Sesma A. Modulating the innate immune response to influenza A virus:potential therapeutic use of anti-inflammatory drugs. Frontiers in Immunology. July 2015. Volume 6. Article 361. https://www.ncbi.nlm.nih.gov/pubmed/26257731
5. Falup-Pecurariu O, Man SC, Neamtu ML, et al. Effects of prophylactic ibuprofen and paracetamol administration on the immunogenicity and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine(PHID-CV) co-administered with DTPa-combined vaccines in children:An open-label, randomized, controlled, non-inferiority trial. Human Vaccines & Immunotherapeutics 2017;13: 649-660. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360152/
6. Housby JN, Cahill CM, Chu B, et al. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 1999;11:347-58. https://www.ncbi.nlm.nih.gov/pubmed/30186359
7. Agarwal D, Schmader KE, Kossenkov AV, et al. Immune response to influenza vaccination in the elderly is altered by chronic medication use. Immunity & Ageing 2018;15:19. https://www.ncbi.nlm.nih.gov/pubmed/30186359
8. Bancos S, Bernard MP, Topham DJ, et al. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol 2009;258:18-28. https://www.ncbi.nlm.nih.gov/pubmed/19345936
9. Eyers S, Weatherall M, Shirtcliffe P, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med 2010;103:403-11. https://www.ncbi.nlm.nih.gov/pubmed/20929891

 

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!

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

Should I continue to vaccinate my 65 years or older patients with pneumococcal conjugate vaccine (PCV13)?

The 2020 U.S. Advisory Committee on Immunization Practices (ACIP) has revised its previous 2014 guidelines from routinely vaccinating all adults 65 years or older with PCV13 to a more selective vaccination approach based on shared clinical decision-making in the absence of immunocompromising conditions, cerebrospinal fluid leak or cochlear implant. 1

More specifically, ACIP recommends that we “regularly” offer PCV13 for patients 65 years or older who have not previously received PCV13 in the following settings:

  • Residents of nursing homes or other long-term care facilities
  • Residents of settings with low pediatric PCV13 uptake
  • Travelers to settings with no pediatric PCV13 program

ACIP also recommends that we consider offering the PCV13 to patients with chronic heart, lung, or liver disease, diabetes, or alcoholism, those who smoke cigarettes, or those with more than 1 chronic medical condition.

Why the change in recommendations? The primary reason is sharp declines in pneumococcal disease in unvaccinated children and adults due to the widespread use of PCV7 and PCV13 in children, resulting in prevention of transmission of vaccine-type strains.  

These recommendations do not apply to the pneumococcal 23-valent polysaccharide vaccine (PPSV23), however. All adults 65 years or older should continue to receive a dose of PPSV23. 

Bonus Pearl: If a decision is made to administer PCV13 to an adult 65 years old or older, PCV13 should be administered first, followed by PPSV23 at least 1 year later.

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References

  1. Freedman M, Kroger A, Hunter P, et al. Recommended adult immunization schedule, United States, 2020. Ann Intern Med 2020; [Epub ahead of print 4 February 2020]. Doi: https://doi.org/10.7326/M20-0046.
  2. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the advisory committee on immunization practices. MMWR 2019;68:1069-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871896/pdf/mm6846a5.pdf

 

Should I continue to vaccinate my 65 years or older patients with pneumococcal conjugate vaccine (PCV13)?

Should my hospitalized patient with ulcerative colitis flare-up receive pneumococcal vaccination?

There are at least 2 reasons for considering pneumococcal vaccination in hospitalized patients with ulcerative colitis flare.

First, these patients are often on immunosuppressants (eg, glucocorticoids) or biological agents (eg, infliximab) that qualifies them for both 13-valent conjugate (PCV13) and 23-valent polysaccharide (PPSV23) pneumococcal vaccines under the Advisory Committee on Immunization Practices (ACIP) Guidelines’ “Immunocompromised persons” risk group.1-4

Another reason is the possibility of  UC patients having coexisting hyposplenism, a major risk factor for pneumococcal disease. Although this association has been described several times in the literature since 1970s, it is relatively less well known.  In a study of patients with UC, hyposplenism (either by the presence of Howell-Jolly bodies in the peripheral blood smear or prolongation of clearance from blood of injected radioactively labelled heat-damaged red blood cells) was found in over one-third with some developing life-threatening septicemia in the early postcolectomy period.5

Another study found the majority of patients with UC having slow clearance of heat damaged RBCs despite absence of Howell-Jolly bodies in the peripheral smear.6 Fulminant and fatal pneumococcal sepsis has also been reported in patients with UC.7

Although the immunological response to pneumococcal vaccination may be lower among immunosuppressed patients in general, including those with UC, it should still be administered to this population given its potential benefit in reducing the risk of serious pneumococcal disease. 2,3  

References

  1. CDC. Intervals between PCV13 and PSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2015;64:944-47. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6434a4.htm
  2. Carrera E, Manzano r, Garrido. Efficacy of the vaccination in inflammatory bowel disease. World J Gastroenterol 2013;19:1349-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602493/
  3. Reich J, Wasan S, Farraye FA. Vaccinating patients with inflammatory bowel disease. Gastroenterol Hepatol 2016;12:540-46. http://www.gastroenterologyandhepatology.net/archives/september-2016/vaccinating-patients-with-inflammatory-bowel-disease/
  4. Chaudrey K, Salvaggio M, Ahmed A, et al. Updates in vaccination: recommendations for adult inflammatory bowel disease patients. World J Gastroenterol 2015;21:3184-96. https://www.ncbi.nlm.nih.gov/pubmed/25805924
  5. Ryan FP, Smart RC, Holdworth CD, et al. Hyposplenism in inflammatory bowel disease. Gut 1978;19:50-55. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1411782/
  6. Jewell DP, Berney JJ, Pettit JE. Splenic phagocytic function in patients with inflammatory bowel disease. Pathology 1981;13:717-23. https://www.ncbi.nlm.nih.gov/pubmed/7335378
  7. Van der Hoeven JG, de Koning J, Masclee AM et al. Fatal pneumococcal septic shock in a patient with ulcerative colitis. Clin Infec Dis 1996;22:860-1. https://www.ncbi.nlm.nih.gov/pubmed/8722951

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Should my hospitalized patient with ulcerative colitis flare-up receive pneumococcal vaccination?

How should I interpret a positive urine pneumococcal antigen when my suspicion for pneumococcal disease is very low?

The popular urine pneumococcal antigen (UPA) (based on the C-polysaccharide of Streptococcus pneumoniae cell wall) has been a valuable diagnostic tool in diagnosing invasive pneumococcal infections, but may be associated with up to nearly 10% rate of false-positivity in hospitalized patients1.  Three factors have often been cited as the  cause of false-positive UPA results: a. Nasopharyngeal carriage; b.Prior invasive pneumococcal infection and;  c. Pneumococcal vaccination.

Among adults with nasopharyngeal carriage of S. pneumoniae, particularly those with HIV infection, 12-17% of positive UPA tests may be false-positive1. In patients with recent invasive pneumococcal disease, UAP may remain positive in over 50% of patient at 1 month and about 5% at 6 months1,2.

Among persons receiving the 23-valent polysaccharide pneumococcal vaccine (PPV), over 20% may have a positive UPA up to 30 hours following immunization, some potentially longer1.  In fact, the manufacturer of UPA assay recommends that UPA not be obtained within 5 days of receiving PPV. There is reason to believe that conjugated pneumococcal vaccine may be associated with the same phenomenon3.

So in a hospitalized patient with low suspicion for pneumococcal disease but a positive UAP, it would be wise to first exclude the possibility of PPV administration earlier during hospitalization before the sample was obtained1,4.

 

References

  1. Ryscavage PA, Noskin GA, Bobb A, et al. Incidence and impact of false-positive urine pneumococcal antigen testing in hospitalized patients. S Med J 2011;104:293-97.
  2. Andre F, Prat C, Ruiz-Manzano J, et al. Persistence of Streptococcus pneumoniae urinary antigen excretion after pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 2009;28:197-201.
  3. Navarro D, Garcia-Maset Leonor, Gimeno C, et al. Performance of the Binax NOW Streptococcus pneumoniae urinary assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection. J Clin Microbiol 2004; 42: 4853-55.
  4. Song JY, Eun BW, Nahm MH. Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward. Infect Chemother 2013;45:351-66.

 

How should I interpret a positive urine pneumococcal antigen when my suspicion for pneumococcal disease is very low?

What’s the latest on vaccination of adults 65 years old or over with conjugated pneumococcal vaccine?

Since August, 2014, the Advisory Committee on Immunization Practices (ACIP) has recommended routine use of 13-valent pneumococcal conjugated vaccine (PCV13, Prevnar) in adults ≥ 65 years, in addition to the traditional 23-valent pneumococcal polysaccharide vaccine (PPSV23, Pneumovax) (1).   The approval of PCV13 was based on a large randomized, double-blind, placebo-controlled trial (CAPITA) that found PCV13 effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease (2).

Due to the potential  for mutual interference with immunogenecity, these 2 vaccines should be spaced apart. When PPSV23 is administered first, PCV13 should be held for 1 year or longer. On the other hand, when PCV13 is administered first, PPSV23 can be given within 6-12 months (minimum 8 weeks). So it makes sense to give PCV13 first in our older pneumococcal vaccine-naive patients.

 

1. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjuage vaccine and 23-valent penumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committe on Immunization Practices (ACIP). MMWR;2014:63: 822-25.

2. Bonten MJM, Huijts, M, Bolkenbaas C, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med 2015;372:1114-25.

 

What’s the latest on vaccination of adults 65 years old or over with conjugated pneumococcal vaccine?