A shot in the dark

By Danielle M. DeHoratius, MD
March 10, 2021
Vol. 3, No. 10

For the past few Mondays, I have been asked to see the following “emergency” patients who called in with the diagnosis of cellulitis after the COVID-19 vaccination. Typically, these patients were seen in urgent care centers over the weekend for a red, warm rash at the site of the vaccination. It usually appears at least a few days after the inoculation. Some patients have reported pruritus and most of the patients I have seen have been women. Through history, they have no additional systemic symptoms consistent with cellulitis. Almost all had been placed on antibiotics and told to follow up with their dermatologist. There seems to be slight waxing and waning of the erythema, but within days the reaction fades.

The above scenario has recently been reported through correspondence in the New England Journal of Medicine. (1) The authors of the letter describe a series of 12 patients with delayed large local reactions with a variable appearance to the COVID mRNA-1273 vaccine. The median onset was 8 days after the vaccine.

Over the past few weeks, I have asked colleagues if they have observed similar reactions and, if so, how are they treating it. All of my patients had this reaction following the first injection. To date I have not seen anyone presenting with “COVID arm” after the second vaccination. While I have only seen this reaction with the Moderna vaccine, agreeing with Weise (2), Gilbert has some anecdotal reports of this occurring with the Pfizer vaccine. (3)

There have been several publications classifying reactions to vaccines and their constituents. Vaccines are composed of immunogens, preservatives, adjuvants, antibiotics, and manufacturing by-products. (4) Any of these ingredients can cause adverse reactions. Reactions can be immediate-type (IgE mediated) or delayed-type (type 4) hypersensitivity reactions and each have different clinical manifestations. Overall, the rate of vaccine-induced adverse effects is low, ranging from 4.8 to 83 per 100,000 doses of the most frequently used vaccines. (5)

The first two approved COVID-19 vaccines represent a new class of mRNA vaccines which contain mRNA in lipid nanoparticles. Their goal is to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19). These vaccines, produced by Pfizer-BioNTech and Moderna, have been granted emergency use authorization. (6). The one dose Johnson and Johnson vaccine is first being administered on March 2, 2021, so I have not had any patients receive it yet.

The late local reactions we are seeing are in direct contrast to common injection site reactions typically observed within a day or two of the vaccination and present with redness, swelling, and pain. (7)

The “COVID arm” we are observing occurs about 1 week after vaccination and presents with a well-defined area of erythema. It may be tender or pruritic and there may be slight swelling. It is difficult to classify this as a delayed type hypersensitivity reaction since this is occurring on the first vaccination and there has been no prior exposure. On the other hand, while patients have never received an mRNA vaccines they may have been exposed to the components of the vaccine previously. The timing is of the reaction simply does not conform to standard humoral or cellular immunity (6) — maybe the reaction is as novel as the virus itself!

In the Moderna clinical trial with 15,181 participants injected with the vaccine there were delayed injection-site reactions (those with onset on or after day 8) noted in 244 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose. These reactions were characterized by erythema, induration, and tenderness that resolved in 4 to 5 days. (8)

Intrinsic host factors such as sex, age, genetics, and comorbidities and extrinsic factors such as preexisting immunity and infection affect immune responses. Additionally, environment, behavior, and nutrition are other factors found to impact immune responses. (9)

Age is an important variable in vaccine responses with diminished responses at both extremes. When people age there is a shift toward anti-inflammatory interleukin-10 (IL-10) which causes a decline in CD8 T-cells that are responsible for clearing viruses. (10) Gender can also be a factor in the immune response with females showing higher antibody responses to many vaccines. (9) Finally, genetics also influence the immune response to a vaccine. Polymorphisms in the major histocompatibility complex (MHC) genes, as well as different expression levels of genes involving early interferon signaling, antigen processing, and antigen presentation can impact the response. (11) There have been reports about blood types and susceptibility to COVID-19 infection. Blood group antigens likely influence the innate immune response to vaccination. (12)

Since these vaccinations are currently being administered to patients over 65, many in this patient population will have significant comorbidities which could also impact antibody responses. It is worthwhile to note that several diseases may affect immune responses to vaccines, such as celiac disease, diabetes mellitus, or renal or liver failure.

Stress can also impact immune reactions. One study found that in elderly people, a positive mood on the day of vaccination was associated with a higher antibody response to the influenza vaccine. (13) Elderly people who suffer from stress were found to have less antibody responses, less IL-2 and more IL-6 production. (14) More optimism in the elderly was associated with higher antibody production and more IL-10 production. (15) I have had the opportunity to volunteer at vaccine clinics and I must admit the elation of senior citizens receiving the vaccine is tremendous; everyone has been abundantly positive, which will hopefully translate into a robust immune response.

Finally, various studies have found that sleep can impact the antibody response around the time of vaccine administration. Typically, short sleep duration is associated with lower antibody responses. Some studies have found that sleep deprivation, even up to 1 week after vaccine administration, is associated with lower antibody responses. (9)

There has been significant discussion about vitamin D and COVID-19. Vitamin D plays an important role in innate, humoral, and cellular immune responses, however its role on vaccine responses is not clear. (16)

“COVID arm” typically resolves without treatment. Symptomatic relief can be prescribed: analgesics if painful or antihistamines if pruritic. Systemic steroids could be considered but they may impact the immune response to the vaccine. Topical steroids may be more helpful with less impact to the systemic response.

This is an evolving situation, and we can only learn more with continued observation and reporting. It has been recommended that patients with COVID receive the second vaccine however it may be wise (according to Weise, LOL!) to receive it in the opposite arm. (2) Patient reassurance is essential, although it will be easier to do this with greater experience. From a scientific perspective it would be interesting to analyze this reaction histopathologically. In the NEJM case series their suspicion of a delayed-type or T-cell-mediated hypersensitivity was supported by skin biopsies revealing superficial and perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells. Please consider using the registry to report COVID arm. Perhaps those with “COVID arm” will have a more robust immune response to the vaccine with more long-lasting antibodies. In the NEJM case series, only half of the patients had a recurrence of the delayed large local reaction and the median onset was earlier than the first occurrence. Only time will tell what the implications of COVID arm will be in the immune response and the infection risk to COVID-19.

Point to remember: In this ever-evolving world of living with COVID-19 the presentation of new cutaneous findings of both the disease and the vaccinations will continue to emerge. We need to continue the dialogue about our observations so we can learn, classify, and help our patients navigate living with the virus!

Our expert’s viewpoint

Christen Mowad, MD
Chair of Dermatology
Geisinger Medical Center
Danville, Pennsylvania

The COVID vaccine has been a huge boost to the quarantine and mask-wearing world we live in. Although the vaccine won't remove the masks or the social distancing, it has lifted the mood of our patients and provided some hope. One of my elderly patients dramatically stated that “getting the vaccine felt like a death sentence had been lifted.” Though all vaccines have side effects, the Pfizer and Moderna COVID vaccines seem to be well tolerated. The cutaneous reactions discussed in this article result predominantly from the Moderna vaccine. We have seen a presentation about 5-9 days after the first vaccination with what has been referred to in the media as COVID arm. It presents with significant redness, induration, and sometimes warmth, typically in a circular pattern at the injection site with some patients presenting to their doctors thinking it is cellulitis. It is often itchy. It appears to occur more frequently in women and does not have the same prevalence after the second dose as would be expected if it were a true delayed hypersensitivity reaction. This appears to be an exuberant local immune reaction and is harmless typically resolving in 24-72 hours and should not discourage anyone from getting the second vaccine. No treatment is needed but local topical steroids or antihistamines for itch can be used if needed. As we see more patients get vaccinated and more people receive the second dose we will be provided with more information on the immunology of this reaction. Patch testing with constituents of the vaccine and pathology of the reactions may provide us with more information. Further studies will be needed to fully identify and understand the immune process causing this reaction.

1. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. NEJM 2021. Accessed at https://www.nejm.org/doi/full/10.1056/NEJMc2102131 on 3/4/2021.

2. Weise E. ‘COVID arm” rash seen after Moderna vaccine annoying but harmless, doctors. USA Today. 1/27/2021 updated 1/29/2021.

3. Gilbert, C. What’s the New Phenomenon Called “COVID Vaccine Arm”? Psychology Today. 1/28/2021.

4. Leventhal JS, Berger EM, Brauer JA, & Cohen DE. Hypersensitivity Reactions to Vaccine Constituents: A Case Series and Review of the Literature. Dermatitis May/June 2012 23(3) 102-109.

5. Fritsche PJ, Helbling A, Ballmer-Weber BK. Vaccine hypersensitivity – update and overview. Swiss Med Wkly 2010;140:238-246.

6. Kelso JM. Allergic reactions to vaccines. UpToDate 2/25/2021

7. Rosenblatt AE & Stein SL. Cutaneous reactions to vaccinations. Clin in Dermatol 2015; 33:327-332.

8. https://www.idsociety.org/covid-19-real-time-learning-network/vaccines/moderna-covid-19-vaccine/

9. Zimmerman P & Curtis N. Factors That Influence the Immune Response to Vacccination. Clin Microbiology Reviews 2019;32:1-50.

10. McElhaney JE, Upshaw CM, Hooton JW, Lechelt KE, Meneilly GS. Responses to influenza vaccination in different T-call subsets: a comparison of healthy young and older adults. Vaccine (1998) 16:1742-1747.

11. Bucasas KL, Franco LM, Shaw CA, Bray MS, Wells JM, Nino D, Arden N, Quarles JM, Couch RB, Belmont JW. Early patterns of gene expression correlate with the humoral immune response to influenza vaccinationin humans. J Infect Dis 2011 203:921-929.

12. Cooling L. Blood groups in infection and host susceptibility. Clin Microbiol Rev 201528:801-870.

13. Ayling K, Fairclough L, Tighe P, Todd I, Halliday V, Garibaldi J, Royal S, Hamed A, Buchanan H, Vedhara K. Positive mood on the day of influenza vaccination predicts vaccine effectiveness: a prospective observational cohort study. Brain Behav Immun 2018 67:314-323.

14. Segerstrom SC, Schipper LJ, Greenberg RN. Caregiving, repetitive thought, and immune response to vaccination in older adults. Brain Behav Immun 2008 22:744-752.

15. Hayney MS, Coe CL, Muller D, Obasi CN, Backonja U, Ewers T, Barrett B. Age and psychological influences on immune responses to trivalent inactivated influenza vaccine in the meditation or exercise for preventing acute respiratory infection (MEPARI) trial. Hum Vaccin Immunother 2014 10:83-91.

16. Sadarangani SP, Whitaker JA, Poland GA. “Let there be light”: the role of vitamin D in the immune response to vaccines. Expert Rev Vaccines 2015 14:1427-1440.

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