Association of COVID-19 mRNA Vaccine With Ipsilateral Axillary Lymph Node Reactivity on Imaging | Oncology | JAMA Oncology | JAMA Network
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Table 1.  Patient Characteristics Grouped According to Ipsilateral-to-Injection-Site Axillary Nodal Reactivitya
Patient Characteristics Grouped According to Ipsilateral-to-Injection-Site Axillary Nodal Reactivitya
Table 2.  Distribution of Deauville Scores for First and Second Dose of Moderna and Pfizer Vaccines
Distribution of Deauville Scores for First and Second Dose of Moderna and Pfizer Vaccines
1.
Gallamini  A, Barrington  SF, Biggi  A,  et al.  The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale.   Haematologica. 2014;99(6):1107-1113. doi:10.3324/haematol.2013.103218PubMedGoogle ScholarCrossref
2.
Coates  EE, Costner  PJ, Nason  MC,  et al; VRC 900 Study Team.  Lymph node activation by PET/CT following vaccination with licensed vaccines for human papillomaviruses.   Clin Nucl Med. 2017;42(5):329-334. doi:10.1097/RLU.0000000000001603PubMedGoogle ScholarCrossref
3.
Shirone  N, Shinkai  T, Yamane  T,  et al.  Axillary lymph node accumulation on FDG-PET/CT after influenza vaccination.   Ann Nucl Med. 2012;26(3):248-252. doi:10.1007/s12149-011-0568-xPubMedGoogle ScholarCrossref
4.
Özütemiz  C, Krystosek  LA, Church  AL,  et al.  Lymphadenopathy in COVID-19 vaccine recipients: Diagnostic dilemma in oncology patients.   Radiology. 2021;210275. doi:10.1148/radiol.2021210275PubMedGoogle Scholar
5.
CDC. Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events: Moderna COVID-19 Vaccine. Accessed April 7, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/reactogenicity.html
6.
SBI. Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination. Accessed Aptil 7, 2021. https://www.sbi-online.org/Portals/0/Position%20Statements/2021/SBI-recommendations-for-managing-axillary-adenopathy-post-COVID-vaccination.pdf
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    1 Comment for this article
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    Would the axillary lymphadenopathy be ameliorated by modifying the methodology of vaccine administration?
    John Leung, M.B.,B.S.,F.R.C.S.Ed. | St. Paul's Hospital
    We agree with Adin et al. that lymphadenopathy following intramuscular (i.m.) injection of the anti-COVID-19 vaccines may cause problems in the screening, investigation and follow up of ipsilateral cancer and some inflammatory lesions. We would like to propose to research centres to explore the feasibility of reducing such lymph node reactions by altering the route of injection and/or reduction of the vaccine dosage. E.g. in vaccination of children, it is well known than i.m. injections elicit much more reaction than subcutaneous injections. Other studies show a higher immune response with the intradermal injection with a much smaller dose. Therefore, the intradermal route may be a feasible alternative to the i.m. route.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    June 10, 2021

    Association of COVID-19 mRNA Vaccine With Ipsilateral Axillary Lymph Node Reactivity on Imaging

    Author Affiliations
    • 1Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
    JAMA Oncol. Published online June 10, 2021. doi:10.1001/jamaoncol.2021.1794

    Intramuscular coronavirus 2019 (COVID-19) vaccinations could induce ipsilateral axillary lymph node reactivity that may be falsely attributed to malignant abnormality, prompting unwarranted interventions, or it may be falsely attributed to vaccination rather than cancer, potentially delaying cancer care. We aimed to investigate Moderna and Pfizer COVID-19 vaccine-related nodal reactivity on 18F-flurodeoxyglocose (FDG) positron emission tomographic (PET)/computed tomographic (CT) scans.

    Methods

    All patients (n = 1290) who underwent FDG-PET/CT scans between December 11, 2020 and March 1, 2021 at the Yale New Haven Hospital were screened (eMethods in the Supplement) for COVID-19 vaccination. Sixty-eight patients who received at least 1 dose of COVID-19 vaccine were analyzed. Sixty-seven of 68 patients had PET/CT for oncologic indications, none of which was adenopathy ipsilateral to the vaccination site. Intensity of lymph node activity was graded by Deauville criteria1; activity more intense than mediastinal blood pool was considered reactive.

    Results

    Reactive ipsilateral axillary lymph nodes developed in 9 of these 68 patients (13%), 7 women and 2 men. After the first vaccine dose, in 2 of 41 patients (5%) and after the second vaccine dose, in 7 of 27 patients (26%) (Fisher exact P = .02; odds ratio [OR], 0.15; CI, 0.01-0.89), 3 (15%) for the Pfizer vaccine and 4 (57%) for the Moderna vaccine (Table 1). Median time from the second vaccine dose to the FDG-PET/CT scan was 10 days in patients with nodal reactivity and 12 days in those without nodal reactivity (Table 2). On CT scan, axillary lymph nodes were enlarged (≥10 mm short axis) in 1 of 59 patients (2%) with nonreactive nodes and in 5 of 9 patients (56%) with reactive nodes (Fisher exact P < .001; OR, 0.02; 95% CI, 0.01-0.19). Overall, FDG-activity was seen at the injection site in 6 of 51 patients (12%) for Pfizer and 2 of 17 patients (12%) for Moderna vaccines.

    Discussion

    Axillary lymphadenopathy following intramuscular vaccine has been observed with influenza and human papilloma virus vaccines, and recently with COVID-19 mRNA vaccines.2-4 We found that ipsilateral axillary nodal reactivity occurred after the first vaccine dose in 2 patients (5%) and after the second vaccine dose in 7 (26%); 4 patients (57%) after the second dose of the Moderna vaccine and 3 (15%) after the second dose of the Pfizer vaccine. In the Moderna trial, axillary swelling and tenderness on patient survey was reported in 1322 (11.6%) patients after the first dose (567 [5%] placebo) and in 1654 (16%) after the second dose (444 [4.3%] placebo) of vaccine; in the Pfizer trial, only unsolicited reactions were recorded.5

    18F-Flurodeoxyglocose–PET/CT is highly sensitive for detection of reactivity in nonenlarged or enlarged lymph nodes, explaining higher frequency of nodal reactivity in this study relative to the Moderna trial after the second dose. In the present study, only 5 patients (56%) with nodal reactivity on PET had nodal enlargement on CT findings. Increased nodal FDG uptake, presumably from an inflammatory immune response to the vaccine, was observed up to 32 days after vaccination in this cohort, harboring the potential risk of mimicking or masking malignant disease. Patients with cancer with a propensity for spread to ipsilateral axillary lymph nodes—breast cancer, melanoma, lymphomas—should have the COVID-19 vaccine in the axilla contralateral to the previously or potentially involved site. Nuclear medicine technologists should document vaccine site, date, type, and first vs second dose. In this cohort, ipsilateral axillary nodal activity was much less common after the first vaccine dose, and women were more likely to develop reactive nodes, an important implication for breast cancer imaging concordant with the statement issued by the Society of Breast Imaging.6

    Limitations

    This was a single institutional study with limited sample size and follow-up, comparing 2 COVID-19 vaccines available at Yale School of Medicine in early vaccination stage. However, the study was conducted by strict and reproducible PET and CT criteria, and provides a framework for the future studies in this field.

    Conclusions

    Ipsilateral axillary nodal reactivity is commonly seen after the intramuscular administration of the COVID-19 mRNA vaccines, more so after the second dose than after the first, and more commonly with the Moderna than the Pfizer vaccine.

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    Article Information

    Accepted for Publication: April 14, 2021.

    Published Online: June 10, 2021. doi:10.1001/jamaoncol.2021.1794

    Corresponding Author: Mehmet Emin Adin, MD, 20 York St, New Haven, CT 06510 (Emin.adin@gmail.com).

    Author Contributions: Drs Adin and Pucar had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Authors are guarantor of integrity of the data and manuscript.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Adin, Pucar.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Adin, Kulon, Pucar.

    Administrative, technical, or material support: Adin, Isufi, Pucar.

    Supervision: All authors.

    Conflict of Interest Disclosures: Dr Kulon is individual shareholder of pharmaceutical companies including Pfizer, Moderna, and Merck. No other conflicts are reported.

    Additional Contributions: The authors thank Dr Hadyn Williams (Department of Radiology & Imaging, Nuclear Medicine, Medical College of Georgia, Augusta University) for his editorial work and insightful suggestions, Dr Yulei Pang (Southern Connecticut State University, Department of Mathematics) for her help in statistical analyses, and Dr Slobodon Pucar (private practice Neuropsychiatrist from Belgrade, Serbia) and Dr Richard Bronen (Department of Radiology and Biomedical Imaging, Yale School of Medicine), for their helpful discussions on the matter. They were not compensated.

    References
    1.
    Gallamini  A, Barrington  SF, Biggi  A,  et al.  The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale.   Haematologica. 2014;99(6):1107-1113. doi:10.3324/haematol.2013.103218PubMedGoogle ScholarCrossref
    2.
    Coates  EE, Costner  PJ, Nason  MC,  et al; VRC 900 Study Team.  Lymph node activation by PET/CT following vaccination with licensed vaccines for human papillomaviruses.   Clin Nucl Med. 2017;42(5):329-334. doi:10.1097/RLU.0000000000001603PubMedGoogle ScholarCrossref
    3.
    Shirone  N, Shinkai  T, Yamane  T,  et al.  Axillary lymph node accumulation on FDG-PET/CT after influenza vaccination.   Ann Nucl Med. 2012;26(3):248-252. doi:10.1007/s12149-011-0568-xPubMedGoogle ScholarCrossref
    4.
    Özütemiz  C, Krystosek  LA, Church  AL,  et al.  Lymphadenopathy in COVID-19 vaccine recipients: Diagnostic dilemma in oncology patients.   Radiology. 2021;210275. doi:10.1148/radiol.2021210275PubMedGoogle Scholar
    5.
    CDC. Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events: Moderna COVID-19 Vaccine. Accessed April 7, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/reactogenicity.html
    6.
    SBI. Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination. Accessed Aptil 7, 2021. https://www.sbi-online.org/Portals/0/Position%20Statements/2021/SBI-recommendations-for-managing-axillary-adenopathy-post-COVID-vaccination.pdf
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