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?

Is there an association between infections and falls?

Although the list of factors that lead to falls is long and varied, increasing number of reports have identified falls as a manifestation of infections, including Covid-19.1-4

A retrospective study involving over 1400 patients (mean age 72 years) admitted to the hospital for a fall or its complications found coexisting systemic infections (CSIs) in 21% of patients; 26% in those ≥75 years. Urinary tract infection accounted for 55% of CSIs, followed by pneumonia (36%), skin and soft tissue infections (7%), influenza/influenza-like illness (5%), bacteremia (5%), gastrointestinal infections (2%), and others. 1

Risk factors for CSI include preexisting symptoms (eg, weakness, dizziness), inability to get up on own, confusion, age ≥ 50 years and meeting the systemic inflammatory response syndrome (SIRS) criteria on presentation.1 Of note, CSI may not initially be suspected by providers in about one-third or more of the cases, with 15% of patients presenting with “mechanical fall” having a CSI.1,2  Fever or SIRS criteria (≥2) are absent in the majority of patients with CSI.1,2

More recently, reports of falls as a presenting feature of Covid-19 have also appeared in the lay press as well as the literature, with 1 study finding 24% of patients with Covid-19 seek care primarily because of syncope, near syncope, or a nonmechanical fall.3,4

Several factors may explain the association of infections with falls, including impairment of skeletal muscle function (eg, through cytokines, hypophosphatemia), poor oral intake and dehydration. 1 Perhaps that’s why inability to get up by one’s self from a fall in the absence of an obvious reason (eg, fracture) may be a clue to a CSI in patient presenting with a fall.

Bonus Pearl: Did you know that falls are a leading cause of injury and death, afflicting one-third of adults aged greater than 65 years each year?1

Disclosure: The author of this blog also was a coinvestigator in 2 cited studies (ref. 1 and 2)

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References

  1. Manian FA, Hsu F, Huang D, et al. Coexisting systemic infections in patients hospitalized because of a fall: prevalence and risk factors. J Emerg Med 2020;58:733-40. https://www.sciencedirect.com/science/article/abs/pii/S0736467920300214
  2. Blair A, Manian FA. Coexisting systemic infections in patients who present with a fall. Am J Med Sci 2017;353:22-26. https://pubmed.ncbi.nlm.nih.gov/28104099/
  3. Chen T, Hanna J, Walsh EE, et al. Syncope, near syncope, or nonmechanical falls as a presenting feature of COVID-19. Ann Emerg Med 2020 July;76:115-117. https://pubmed.ncbi.nlm.nih.gov/32591120/
  4. Norman RE, Stall NM, Sinha SK. Typically atypical: COVID-19 presenting as a fall in an older adult. J Am Geriatr Soc 2020 July;68:E36-37. DOI:10.1111/gs.16526 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267373/pdf/JGS-9999-na.pdf

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!

Is there an association between infections and falls?

What’s the evidence that people without symptoms can transmit Covid-19 to those around them?

Rapid spread of Covid-19 virus has been attributed in large part to its ease of transmission from person to person even before symptoms develop, particularly since an estimated 18% to 75% of patients testing positive for Covid-19 have no symptoms. 1-4

Transmission before onset of symptoms (presymptomatic): Modeled estimates for the percentage of transmissions that occur from presymptomatic patients range from 37% to as high as 62% based on studies of patients in the cities of Tianjin and Guangzhou in China, as well as Singapore.5-7 Infectiousness appears to begin within 1-3 days prior to symptoms.8-10

Transmission when symptoms never develop (asymptomatic): Asymptomatic transmission was invoked in a familial cluster in Anyang, China where 5 patients developed Covid-19 after a 6th asymptomatic family member returned home from Wuhan, China. The asymptomatic patient never developed symptoms—such as fever or respiratory symptom— and had a normal chest CT, but briefly tested positive for Covid-19 by RT-PCR before testing negative later.11

It’s important to point out that up to ~75% of patients who are initially “asymptomatic” later develop symptoms. 12-14 So what we often call “asymptomatic” may actually be “presymptomatic.”

Transmission of Covid-19 before onset of symptoms is in distinct contrast to SARS, another coronavirus disease, which was transmitted only when a person was symptomatic and was easier to control. This unique property among coronaviruses may be explained by the high tropism of Covid-19 virus not only for the lungs (as in case of SARS virus) but also for the upper respiratory tract.15,16 As such, Covid-19 behaves more like influenza viruses whose upper respiratory tract binding is thought to promote their rapid transmission even before symptoms develop.17  No wonder, Covid-19 spread like wild fire!

 

Coauthor, Bruce Tiu, Harvard Medical Student, Boston, MA

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References

 

  1. Mizumoto K, Kagaya K, Zarebski A, et al. Estimating the asymptomatic proportion of coronavirus diseae 2019 (COID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill.2020;25(10):pii=2000180 https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.10.2000180?ftag=MSF0951a18
  2. Kimaball, A, Hatfield KM, Arons M, et al. Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility—King County, Washington, March 2020. MMWR 2020;69:377-381. https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
  3. Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci 2020 Mar 4. https://www.ncbi.nlm.nih.gov/pubmed/32146694
  4. Day M. Covid-19: identifying and isolating asymptomatic people helped eliminate virus in Italian village. BMJ 2020;368 https://www.bmj.com/content/368/bmj.m1165
  5. He X, Lau E, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.15.20036707v2
  6. Ferretti L, Wymant C, Kendall M, et al. Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing [published online ahead of print, 2020 Mar 31]. Science. 2020; eabb6936. https://science.sciencemag.org/content/early/2020/03/30/science.abb6936
  7. Ganyani T, Kremer C, Chen D, et al. Estimating the generation interval for COVID-19 based on symptom onset data. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.05.20031815v1
  8. Wei WE, Li ZB, Chiew CJ, et al. Presymptomatic transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 1 April 2020. https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e1.htm
  9. He X, Lau E, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.15.20036707v2
  10. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med. 2020;382(10):970–971. https://www.nejm.org/doi/full/10.1056/NEJMc2001468
  11. Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19 [published online ahead of print, 2020 Feb 21]. JAMA. 2020;e202565. https://jamanetwork.com/journals/jama/fullarticle/2762028
  12. Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility — King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69:377–381 https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e1.htm
  13. Chen, C. “What We Need to Understand About Asymptomatic Carriers if We’re Going to Beat Coronavirus”. ProPublica. 2020. https://www.propublica.org/article/what-we-need-to-understand-about-asymptomatic-carriers-if-were-going-to-beat-coronavirus
  14. WHO. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 2020. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
  15. Woelfel R, Corman VM, Guggemos W, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. medRxiv. https://www.medrxiv.org/content/10.1101/2020.03.05.20030502v1
  16. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767–1772. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)13412-5/fulltext
  17. van Riel D, den Bakker MA, Leijten LM, et al. Seasonal and pandemic human influenza viruses attach better to human upper respiratory tract epithelium than avian influenza viruses. Am J Pathol. 2010;176(4):1614–1618. https://wwwnc.cdc.gov/eid/article/26/6/20-0357_article

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!

What’s the evidence that people without symptoms can transmit Covid-19 to those around them?

Key clinical pearls on the management of patients suspected of or diagnosed with Covid-19 in the outpatient setting

Here are some key points to remember when managing patients with Covid-19 symptoms in the outpatient setting.  These points are primarily based on the CDC guidelines and the current literature. They may be particularly useful to primary care providers (PCP) who do not have ready access to Covid-19 test kits or radiographic imaging in the diagnosis of patients suspected of or diagnosed with Covid-19.

  • Isolation precautions. 1,6-7 Minimize chances of exposure by placing a facemask on the patient and placing them in an examination room with the door closed. Use standard and transmission-based precautions including contact and airborne protocols when caring for the patient. Put on an isolation gown and N95 filtering facepiece respirator or higher. Use a facemask if a respirator is not available. Put on face shield or goggles if available. Adhere to strict hand hygiene practices with the use of alcohol-based hand rub with greater than 60% ethanol or 70% isopropanol before and after all patient contact. If there is no access to alcohol-based hand sanitizers, the CDC recommends hand washing with soap and water as the next best practice.

 

  • Risk Factors.2-3 Older patients and patients with severe underlying medical conditions seem to be at higher risk for developing more serious complications from Covid-19 illness. Known risk factors for severe Covid-19 include age over 60 years, hypertension, diabetes, cardiovascular disease, chronic respiratory disease, and immunosuppression.

 

  • Symptoms.2,4,8,9 Reported illnesses have ranged from mild symptoms to severe illness and death. These symptoms may appear after a 2- to 14-day incubation period.
    • Fever at any time 88-99%
    • Cough 59-79%
    • Dyspnea 19-55%
    • Fatigue 23-70%
    • Myalgias 15%-44%
    • Sputum production 23-34%
    • Nausea or vomiting 4%-10%
    • Diarrhea 3%-10%
    • Headache 6%-14%
    • Sore throat 14%
    • Rhinorrhea/nasal congestion (4.8%)
    • Anosmia (undocumented percentage)

 

  • Treatment for mild illness.5 Most patients have mild illness and are able to recover at home. Counsel patients suspected to have Covid-19 to begin a home quarantine staying in one room away from other people as much as possible. Patients should drink lots of fluids to stay hydrated and rest. Over the counter medicines may help with symptoms. There is controversy regarding the safety of NSAIDs in Covid-19 (See related P4P pearl). Generally, symptoms last a few days and  patients get better after a week. There is no official guidance from the CDC or other reliable sources on how often a PCP should check in with a patient confirmed with Covid-19 and in quarantine. Please use good judgement and utilize telehealth capabilities via phone call, video call, etc… if possible.

 

  • Treatment for severe illness.3 Patients should be transferred immediately to the nearest hospital. If there is no transfer service available, a family member with appropriate personal protective equipment (PPE) precautions, should drive patient to nearest hospital for critical care services.

 

  • Ending home isolation. 5
    • Without testing: Patients can stop isolation without access to a test result after 3 things have happened. 1) No fever for at least 72 hours. This is 3 full days of no fever and without the use of medication that reduces fever; 2) Respiratory symptoms have improved.; and 3) At least 7 days have passed since symptoms first appeared.
    • With testing. 5 Home isolation may be ended after all of the following 3 criteria have been met: 1) No fever for at least 72 hours. This is 3 full days of no fever and without the use of medication that reduces fever; 2) Respiratory symptoms have improved; and 3) Negative results from at least 2 consecutive nasopharyngeal swab specimens collected more than 24 hours apart.

To all the healthcare providers out there, please be safe and stay healthy!

 

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Contributed by Erica Barnett, Harvard Medical Student, Boston, MA.

 

References:

  1. CDC. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html
  2. CDC. Symptoms and Testing. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/index.html
  3. World Health Organization. Operational Considerations for case management for COVID-19 in health facility and community. https://apps.who.int/iris/bitstream/handle/10665/331492/WHO-2019-nCoV-HCF_operations-2020.1-eng.pdf
  4. Partners in Health. Resource Guide 1: Testing, Tracing, community management. https://www.pih.org/sites/default/files/2020-03/PIH_Guide_COVID_Part_I_Testing_Tracing_Community_Managment_3_28.pdf
  5. CDC. Caring for someone at home. https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/care-for-someone.html
  6. CDC. Using PPE. https://www.cdc.gov/coronavirus/2019-ncov/hcp/using-ppe.html
  7. CDC. Hand Washing. https://www.cdc.gov/coronavirus/2019-ncov/hcp/hand-hygiene.html
  8. Harvard Health Publishing. COVID-19 Basics. https://www.health.harvard.edu/diseases-and-conditions/covid-19-basics
  9. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020, March 6. DOI:10.1056/NEJM022002032 https://www.ncbi.nlm.nih.gov/pubmed/32109013

 

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!

Key clinical pearls on the management of patients suspected of or diagnosed with Covid-19 in the outpatient setting

How long are the symptoms of hospitalized patients with Covid-19 expected to last?

Although most patients with Covid-19 may have mild or no symptoms, those who are ill enough to be hospitalized often have fever, cough, or shortness of breath that lasts for 2 weeks or longer. 

Fever: A Chinese study 1 involving 137 successfully discharged hospitalized patients reported that fever (37.3° C or 99.1° F or higher) lasted a median of 12 days (range 8-13 days). It’s important to point out that nearly one-quarter of these patients were also placed on corticosteroids during their hospitalization which might have resulted in the resolution of fever sooner and therefore altered the “natural course” of Covid-19.  In a smaller study from Singapore2 involving generally less ill hospitalized patients, fever didn’t usually last as long (median 4 days, range 0-15 days). 

Cough/shortness of breath: Cough may last nearly 3 weeks (median 19 days) while shortness of breath can go on for about 2 weeks (median 13 days).1

All symptoms: Even among those who are less ill and do not require supplemental oxygen, it may take nearly 2 weeks (median 12 days, range 5-24 days) for all the Covid-19-related symptoms (defined as fever, cough, and shortness of breath, sore throat, diarrhea, and rhinorrhea) to resolve.2 

It goes without saying that recovery from Covid-19 among hospitalized patients may be slow. In a Seattle study3 involving hospitalized patients who were admitted to the ICU, the median duration on the ventilator was 10 days (IQR 7-12 days), and the median length of hospital stay was 17 days (IQR 16-23 days).

Hopefully, as we find effective anti-Covid-19 drugs, the duration of these symptoms and length of hospitalization can be significantly reduced. Stay tuned!

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References

  1. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COCID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
  2. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020; March 3, 2020 (corrected March 20). https://jamanetwork.com/journals/jama/fullarticle/2762688
  3. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in critically ill patients in the seattle region—Case series. N Engl J Med 2020; March 30. https://www.nejm.org/doi/full/10.1056/NEJMoa2004500

 

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!

How long are the symptoms of hospitalized patients with Covid-19 expected to last?

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)?

Catch these selected key clinical pearls on coronavirus disease (Covid-19)!

Although the Covid-19 pandemic is continuing to evolve and our knowledge of its epidemiology and pathophysiology is still far from complete, you may find the following pearls based on published literature to date useful when discussing this disease with your colleagues or the public. 1-11

  • Age group: Primarily an adult disease. Children (< 15-year-old) account for only a minority of symptomatic patients (<1%); ~50% of patients are between 15-49 years of age with 15% in the ≥ 65 year group. 1
  • Incubation period: A bit longer than seasonal flu. Median 4.0 days (IQR 2.0-7.0 days); an upper range up to 24 days has also been reported. In contrast, for seasonal flu the median incubation period is shorter (median 2.0 days, 1.0-7.0 days. 1,4,11
  • Transmission: Contact, droplet, and possibly airborne. On average each person may transmit Covid-19 virus to 2-3 other persons (vs <2 people for seasonal flu). Unlike SARS or MERS, but more akin to the seasonal flu, asymptomatic persons may also be able to transmit the disease. 4,5,11
  • Comorbid conditions (eg, diabetes, hypertension, COPD…): Present in about 1/3 of reported patients. 1
  • Symptoms 1,5
    • ~80% of patients may be either asymptomatic or have mild disease
    • Fever may be absent in ~50% of patients on presentation but will eventually develop in ~90% of hospitalized patients
    • Cough (2/3 dry) is present in majority (~80%) of cases
    • Rhinorrhea is uncommon (<10%), in contrast to the seasonal influenza
    • GI symptoms (nausea/vomiting/diarrhea) are uncommon by some reports(<10%), but not by others (>30.0%). 12
    • May take 9-12 days from onset of symptoms to severe disease
  • Labs 1
    • Lymphopenia is common (up to ~80%)
    • Abnormal liver function (AST and ALT) is found in about 1/3 of patients
    • C-reactive protein (CRP) is usually elevated (~80% of severe cases)
    • Procalcitonin is usually normal
  • Treatment: Supportive for now. Candidate drugs include remdesivir, lopinavir/ritonavir, chloroquine phosphate, ribavirin and several others.4
  • Mortality: Reported mortality among mostly symptomatic hospitalized cases is ~2.0% (0.9% without comorbidities, 5-10% in those with comorbidities, 50% among critically ill). Overall mortality rates will likely drop as more patients without symptoms or with mild disease are tested. In contrast, 2 other coronavirus diseases, SARS and MERS, have mortality rates of ~9.0% and 36.0%, respectively. 1,4,5

 

Bonus pearl: Did you know that, Covid-19-infected patients shed the virus in their nasopharyngeal secretions on the average for 12 days, some as long as 24 days?3

 

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020. First published Feb 28, 220, last updated March 6, 2020. https://www.nejm.org/doi/10.1056/NEJMoa2002032
  2. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel Coronavirus in the United States. N Engl J Med 2020; 382:929-36. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  3. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA. Doi:10.1001/jama.2020.3204. Published online March 3, 2020. https://jamanetwork.com/journals/jama/fullarticle/2762688
  4. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020. Doi: 10.1002/jmv.25748. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  5. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Eng J Med 2020. DOI:10.1056/NEJMe2002387. https://www.nejm.org/doi/full/10.1056/NEJMe2002387
  6. Del Rio C, Malani PN. 2019 novel coronavirus—important information for clinicians. JAMA 2020, Feb 5. https://www.ncbi.nlm.nih.gov/pubmed/32022836
  7. Lipsitch M, Swerdlow DL, Finelli L. Defining the epidemiology of Covid-19—studies needed. N Engl J Med 2020. Feb 19. DOI:10.1056/NEJMp2002125. https://www.ncbi.nlm.nih.gov/pubmed/32074416/
  8. Morens DM, Daszak P, Taubenberger JK. Escaping Pandora’s box—another novel coronavirus. N Eng J Med 2020. Feb 26. DOI:10.1056/NEJMp2002106. https://www.nejm.org/doi/full/10.1056/NEJMp2002106
  9. She J, Jiang J, Ye L, et al. 2019 novel coronavirus of pneumonia in Wuhan, China: merging attack and management strategies. Clin Trans Med 2020;9:19. https://clintransmed.springeropen.com/articles/10.1186/s40169-020-00271-z
  10. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
  11. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020. Feb 21. https://jamanetwork.com/journals/jama/fullarticle/2762028
  12. Pan L, Mu M, Yang P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am j Gastroenterol 2020. https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf
Catch these selected key clinical pearls on coronavirus disease (Covid-19)!

My patient with diverticular bleed has now developed signs of bowel ischemia with abdominal pain and sepsis after transcatheter colic artery embolization. Is bowel ischemia common after embolization of lower gastrointestinal (GI) arteries?

It may be more common than we think! Reported rates of bowel ischemia following lower GI artery embolization have been as high as 22% (1,2). For this reason, it is prudent to closely monitor for signs of bowel ischemia and infection in patients who undergo embolization to control lower GI bleeding.

In some cases, ischemia of the bowel appears to be mild enough to be treated conservatively, while in other cases bowel infarction with surgical intervention has been necessary (1).  One case report described signs of infection (including fever, abdominal tenderness and leukocytosis) 2 days after arterial embolization in a patient who was treated conservatively (3), while another described “sepsis” 6 days post procedure with bowel wall ischemia requiring surgical resection (1). 

Bowel injury leading to a septic picture following embolization of lower GI arteries should not be surprising given the expected capillary hypoperfusion and risk of tissue hypoxia.  Compared to embolization for upper GI bleed, lower GI embolization may place the patient at higher risk of bowel ischemia bowel ischemia due to lack of a rich collateral blood supply (1).  Older patients may also have mesenteric artery atherosclerotic disease or low cardiac output,  further compromising the collateral blood flow (3).  

At a more molecular level, hypoxia leads to the activation of hypoxia-inducible factor (HIF-1), which plays an important role in inducing gut injury. In fact, deletion of HIF-1a in mice prevented shock-induced intestinal permeability and bacterial translocation that ultimately led to bacteremia (4). 

As for preventing embolization-induced bacteremia, although antibiotics are used for liver and spleen embolization prophylaxis, their role in colic angioembolization is unclear (5).  

Bonus Pearl: Did you know that some of the earliest angioembolizations were performed during the Vietnam War to stop bleeding from bullet injuries? (6)

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References:

  1. Gady, J, Reynolds, H., & Blum, A. Selective arterial embolization for control of lower gastrointestinal bleeding: Recommendations for a clinical management pathway. Current Surg 2003; 60: 344-347. https://www.sciencedirect.com/science/article/abs/pii/S0149794402007493
  2. Rossetti A, Buchs NC, Breguet R, et al. Transarterial embolization in acute colonic bleeding: review of 11 years of experience and long-term results. Int J Colo Dis 2013;28:777-782. https://link.springer.com/article/10.1007/s00384-012-1621-5
  3. Shenoy, S, Satchidanand, S, & Wesp S. Colonic ischemic necrosis following therapeutic embolization. Gastrointest Radiol 1981, 6: 235-237. https://link.springer.com/article/10.1007/BF01890256
  4. Vollmar, B., & Menger, M. Intestinal ischemia/reperfusion: Microcirculatory pathology and functional consequences. Langenbeck Arch Surg 2011; 396: 13-29 https://link.springer.com/article/10.1007%2Fs00423-010-0727-x 
  5. Ryan, J. Mark, Ryan, Barbara M, & Smith, Tony P. Antibiotic prophylaxis in interventional radiology. JVIR 2004; 15: 547-556. https://www.sciencedirect.com/science/article/pii/S1051044307603248
  6. Nolan, T, Phan H, Hardy A, et al. Bullet embolization: Multidisciplinary approach by interventional radiology and surgery. Semin Interven Radiol 2012, 29: 192-6. https://www.ncbi.nlm.nih.gov/pubmed/23997411 

Contributed by Hannah Ananda Bougleux Gomes, Medical Student, Harvard Medical School, Boston, MA.

My patient with diverticular bleed has now developed signs of bowel ischemia with abdominal pain and sepsis after transcatheter colic artery embolization. Is bowel ischemia common after embolization of lower gastrointestinal (GI) arteries?

Is the average body temperature in adults lower than 98.6 ᵒF (37 ᵒC)?

Despite the widely-held belief that the normal body temperature is 98.6 ᵒF (37.0 ᵒC), it is becoming increasingly clear that the average body temperature among adults (at least in the U.S.) is actually lower than 98.6 ᵒF (37 ᵒC).

The concept of a single normal body temperature dates way back to the 1800’s, based on measuring axillary temperatures by mercury thermometers. 1 However, a 2001 systematic literature review of 20 studies (1935-1998) of normal body temperature measured in adults found the following mean temperatures: oral 97.5 ᵒF (36.4 ᵒC), rectal 98.4 ᵒF (36.9 ᵒC), tympanic 97.7 ᵒF (36.5 ᵒC), and axillary 97.3 ᵒF (36.3 ᵒC ).  A British study involving >35,000 patients also found a lower mean oral temperature of 97.9 ᵒF (36.6 ᵒC). 2 A 2020 US study of a cohort of >150,000 adults (2007-20017) found a mean oral temperature of 98.1 ᵒF (36.7 ᵒC) in men and 98.2 ᵒF (36.8 ᵒC) in women; these values were lower than that of an earlier cohort (1971-1975). 3

So is the discrepancy between the body temperature in 1800’s and the more recent era due to the differences in measurement techniques or the population? In other words, are we cooling off?

The weight of the evidence suggests that our bodies are cooling!3  The study of an 1860-1940 cohort—presumably using similar thermometer techniques —found a gradual drop in the mean temperature during that period alone. Since axillary temperature (accounting for some of the values in the earlier cohort) is about 1 ᵒC lower than that of oral temperature, the magnitude of the drop in mean temperatures over the past 150 years is likely higher that those reported. 3

Potential explanations for our cooling bodies over the past 2 centuries include reduction in the population level inflammation due to improved standard of living, sanitation, lower incidence of chronic infections. improved dental hygiene, and cooler ambient temperatures. 3

 

Fun Fact: Did you know that in 1851 Carl Wunderlich, a German physician, obtained millions of axillary temperatures from 25,000 patients in Leipzig and thereby established the standard body temperature of 98.6 ᵒF (37 ᵒC)? ᵒ

 

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References

  1. Sund-Levander M, Forsberg C, Wahren LK. Normal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review. Scan J Caring Sci 2002;16:122-128. https://www.ncbi.nlm.nih.gov/pubmed/12000664
  2. Obermeyer Z, Samra JK, Mullainathan S. Individual differences in normal body temperature: longitudinal big data analysis of patient records. BMJ 2017;359:j5468. https://www.ncbi.nlm.nih.gov/pubmed/29237616
  3. Protsiv M, Ley C, Lankester J, et al. Decreasing human body temperature in the United States since the industrial revolution. Human Biology and Medicine, Jan 7, 2020. DOI: 10.7554/eLife.49555. https://www.researchgate.net/publication/338433061_Decreasing_human_body_temperature_in_the_United_States_since_the_industrial_revolution
Is the average body temperature in adults lower than 98.6 ᵒF (37 ᵒC)?

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

Aside from the usual suspects associated with a painful extremity (eg, trauma, deep venous thrombosis and soft tissue infections), think of spontaneous diabetic myonecrosis (DMN), also known as diabetic muscle infarction (1-3).

DMN is characterized by abrupt onset of painful swelling of the affected muscle, most often of the lower extremities, but also occasionally upper extremities. DMN occurs in patients with longstanding DM whose blood glucose control has deteriorated over time, often with nephropathy, retinopathy and/or neuropathy (1-3).

Couple of things to remember when considering DMN in your differential of a painful extremity. First, except for localized edema and tenderness over the involved muscle, the exam may be unremarkable. Specifically, there is no erythema or signs of compartment syndrome and fever is absent in the great majority of patients (~90%) (2). Even white blood cell count and creatine kinase (CK) are usually normal. The reason for normal CK at presentation is not clear but CK might have already peaked by the time of patient presentation (3). In contrast, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated (>80%) (1).

MRI (without contrast in patients with renal insufficiency) is the imaging of choice with muscle enlargement and edema with hyperintense signal on T2-weighted images and other changes, including perifascial, perimuscular and or subcutaneous edema (1-3). Muscle biopsy is not currently recommended because of its adverse impact on time to symptomatic improvement. Non-surgical therapy, with rest, analgesia and glycemic control is usually recommended (1-3).

 
Though its exact cause is still unclear, atherosclerosis, diabetic microangiopathy, vasculitis with thrombosis and ischemia-reperfusion injury have been posited as potential precipitants for DMN. The role of anti-phospholipid syndrome, particularly in patients with type I DM, is unclear (1,2).

 
Bonus pearl: Did you know that symptoms of DMN may last for weeks with at least one-third of patients having a recurrence in the same muscle or elsewhere (1)?

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Reference
1. Horton WB, Taylor JS, Ragland TJ, et al. Diabetic muscle infarction: a systematic review. BMJ Open Diabetes Research and Care 2015;3:e000082.
2. Trujillo-Santos AJ. Diabetic muscle infarction. An underdiagnosed complication of long-standing diabetes. Diabetes Care 2003;26:211-15.
3. Diabetes muscle infarction in end-stage renal disease:A scoping review on epidemiology, diagnosis and treatment. World J Nephrol 2018;7:58-64.

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?