Are women at higher risk of Covid-19 vaccine-related adverse events?

Data to date shows a preponderance of Covid-19 vaccine-related adverse events (AEs) among women compared to men. This finding may be due to the generally more robust immunological response to infections and vaccines among women, increased reporting of AEs by women, genetic factors, microbiome differences as well as other factors.1-3

A CDC study involving mRNA vaccines (Pfizer and Moderna) during the 1st month of vaccination roll out in the US, found that nearly 80% of adverse events were reported by women.  The great majority (>90%) of these AEs were not serious and included symptoms such as headache, dizziness and fatigue.1

A JAMA study involving individuals receiving one of the mRNA vaccines found that 94% (Pfizer) and 100% (Moderna) of anaphylaxis events occurred among women. Of note, the median age was ~40 years  with the majority of anaphylaxis events were reported after the first dose. 2

Higher incidence of AEs following Covid-19 vaccination is not surprising and may be explained biologically. Women typically have a more robust immune response to infections and vaccination, both at the level of innate and adaptive immunity with higher antibody responses.  

These findings may be in part due to hormones such as estrogen which is known to enhance differentiation of dendritic cells and proinflammatory cytokine production. Other proposed mechanisms include differences in microbiome between sexes and sex-based genetic influences on humoral immune profile with the X chromosome expressing 10 times more genes than the Y chromosome, including genes that influence immunity.3

Bonus Pearl: Did you know that anaphylactic reaction to the mRNA Covid-19 vaccines is extremely rare, occurring in only 2-5 cases/ million!2

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References

  1. Gee J, Marquez P, Su J, et al. First month of Covid-19 vaccine safety monitoring—United States, December 14, 2020—January 13, 2021. MMWR 2021;70:283-88. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm
  2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA Covid-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA 20201;325:1101-1102. https://jamanetwork.com/journals/jama/fullarticle/2776557
  3. Fischinger S, Boudreau CM, Butler AL, et al. Sex differences in vaccine-induced humoral immunity. Semin Immunopath 2019;41:239-49. https://pubmed.ncbi.nlm.nih.gov/30547182/

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!

Are women at higher risk of Covid-19 vaccine-related adverse events?

How might categorizing severity of illness help in the management of my patient with Covid-19?

Although the criteria for Covid-19 severity of illness categories may overlap at times or vary across guidelines and clinical trials, I have found those published in the National Institute of Health (USA) Covid-19 Treatment Guidelines most useful and uptodate.1  Keep in mind that the primary basis for severity categories in Covid-19 is the degree by which it alters pulmonary anatomy and physiology and respiratory function (see my table below).

The first question to ask when dealing with Covid-19 patients is whether they have any signs or symptoms that can be attributed to the disease (eg, fever, cough, sore throat, malaise, headache, muscle pain, lack of sense of smell). In the absence of any attributable symptoms, your patient falls into “Asymptomatic” or “Presymptomatic” category.  These patients should be monitored for any new signs or symptoms of Covid-19 and should not require additional laboratory testing or treatment.

If symptoms of Covid-19 are present (see above), the next question to ask is whether the patient has any shortness of breath or abnormal chest imaging. If neither is present, the illness can be classified as “Mild” with no specific laboratory tests or treatment indicated in otherwise healthy patients. These patients may be safely managed in ambulatory settings or at home through telemedicine or remote visits. Those with risk factors for severe disease (eg, older age, obesity, cancer, immunocompromised state), 2 however, should be closely monitored as rapid clinical deterioration may occur.

Once lower respiratory tract disease based on clinical assessment or imaging develops, the illness is no longer considered mild. This is a good time to check a spot 02 on room air and if it’s 94% or greater at sea level, the illness qualifies for “Moderate” severity. In addition to close monitoring for signs of progression, treatment for possible bacterial pneumonia or sepsis should be considered when suspected. Corticosteroids are not recommended here and there are insufficient data to recommend either for or against the use of remdesivir in patients with mild/moderate Covid-19.

Once spot 02 on room air drops below 94%, Covid-19 illness is considered “Severe”; other parameters include respiratory rate >30, Pa02/Fi02 < 300 mmHg or lung infiltrates >50%. Here, patients require further evaluation, including pulmonary imaging, ECG, CBC with differential and a metabolic profile, including liver and renal function tests. C-reactive protein (CRP), D-dimer and ferritin are also often obtained for their prognostic value. These patients need close monitoring, preferably in a facility with airborne infection isolation rooms.  In addition to treatment of bacterial pneumonia or sepsis when suspected, consideration should also be given to treatment with corticosteroids. Remdesivir is recommended for patients who require supplemental oxygen but whether it’s effective in those with more severe hypoxemia (eg, those who require oxygen through a high-flow device, noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation-ECMO) is unclear. Prone ventilation may be helpful here in patients with refractory hypoxemia as long as it is not used to avoid intubation in those who otherwise require mechanical ventilation.

“Critical” illness category is the severest forms of Covid-19 and includes acute respiratory distress syndrome (ARDS), septic shock, cardiac dysfunction and cytokine storm. In addition to treatment for possible bacterial pneumonia or sepsis when suspected, corticosteroids and supportive treatment for hemodynamic instability and ARDS, including prone ventilation, are often required. The effectiveness of remdesivir in patients with severe hypoxemia (see above) is unclear at this time.

 

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 References

  1. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/. Accessed Aug 27, 2020.
  2. CDC. Covid-19.  https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html/. Accessed Aug 27, 2020.  

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 might categorizing severity of illness help in the management of my patient with Covid-19?

How common are neurological symptoms in patients with Covid-19 infection?

Although we usually think of it as primarily a respiratory tract disease, neurological manifestations with Covid-19 are not at all uncommon,1-6 occurring in over one-third of hospitalized patients with Covid-19 according to one medRxiv report.1

In a Chinese study1 involving 214 hospitalized patients with Covid-19, 36.4% had 1 or more neurological symptoms, with the majority involving the central nervous system (CNS) (25.0%), of which the most common complaints were dizziness (17%) and headache (13.0%). Some patients (9.0%) had cranial nerve/peripheral nerve complaints of which the most common were difficulty with taste (hypogeusia) (6.0%) and sense of smell (hyposmia) (5.0%).  A fewer number of patients had impaired consciousness, acute cerebrovascular disease (including ischemic stroke and cerebral hemorrhage). Although not strictly-speaking a neurological manifestation, the study also reported “muscle injury” in ~20.0% of patients     (defined as myalgia plus CK >200 IU/L).

Descriptions of Covid-19 encephalopathy, including one associated with acute hemorrhagic necrotizing process, are also beginning to appear in the literature.3-5 Reports of “Neuro-Covid-19 units” in Italy further underlines the common occurrence of neurological symptoms in these patients.6

More than one mechanism for neurological complications in Covid-19 are likely,  including:1-2

  1. Direct viral invasion into the CNS which could explain the associated headache, high fever, vomiting, convulsions, and consciousness disorders. Some have reported normal CSF parameters but a report of PCR positive CSF suggests direct injury from the virus itself.2 Covid-19 virus may gain access to the CNS through direct invasion of neuronal pathways (eg. olfactory nerve given recent reports of difficulty with sense of smell) or through blood circulation.
  2. Indirect CNS injury through extreme systemic derangements such as hypoxia, or immune/inflammatory response-related injury (eg, through cytokines, hypercoagulability related to infection). Some have also posited that binding of Covid-19 virus to ACE2 may cause abnormally elevated blood pressure and increase the risk of cerebral hemorrhage.2

The fact that Covid-19 is so versatile and affects the nervous system as well shouldn’t surprise us. Neurological complications have been reported with couple of other related respiratory Coronaviruses such as those of SARS and MERS.2

 

Bonus pearl: Did you know that as early 1970-80s some coronaviruses were shown to cause “nasoencephalopathy” when injected intranasally in mice with subsequent spread to the CNS through the olfactory nerve?7 Maybe we shouldn’t be too surprised that sense of smell is impaired in some Covid-19 patients. If we could only stop the virus at the nose!

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References

  1. Mao L, Wang M, Chen S, et al. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1
  2. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity 2020, March 30. https://www.sciencedirect.com/science/article/pii/S0889159120303573
  3. Xiang et al. 2020. First case of 2019 novel Coronavirus disease with encephalitis. ChinaXiv, T202003 (2020), p. 00015 (obtained from reference 2).
  4. Poyiadji N, Shain G, Noujaim D, et al. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020 https://pubs.rsna.org/doi/10.1148/radiol.2020201187
  5. Filatov A, Sharma P, Hindi F, et al. Neurological complications of coronavirus (COVID-19): encephalopathy. Cureus 12(3): e7352. DOI 10.7759/cureus.7352 https://www.cureus.com/articles/29414-neurological-complications-of-coronavirus-disease-covid-19-encephalopathy
  6. Talan J. COVID-19: Neurologists in Italy to Colleagues in US: Look for poorly-defined neurologic conditions in patients with the Coronavirus. Neurology Today 2020, March 27. https://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=920
  7. Perlman S, Jacobsen G, Afifi A. Spread of a neurotropic murine Coronavirus into the CNS via the trigeminal and olfactory nerves. Virology 1989;170:556-560 https://www.sciencedirect.com/science/article/pii/0042682289904467

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 common are neurological symptoms in patients with Covid-19 infection?

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