key: cord-0789303-bnkkw1ym
authors: Tu, Wendy; Gierada, David S.; Joe, Bonnie N.
title: COVID-19 Vaccination-Related Lymphadenopathy: What To Be Aware Of
date: 2021-04-09
journal: Radiol Imaging Cancer
DOI: 10.1148/rycan.2021210038
sha: f294b62bcfbca29a0c28113ee868a2b41fe3cfaa
doc_id: 789303
cord_uid: bnkkw1ym

nan

The COVID-19 pandemic has changed the landscape of society since February of 2020 with a significant and tragic impact on morbidity and mortality with 2.77 million deaths across the world and 548,087 deaths in the United States as of March 26, 2021. Leading scientific minds have brought us a glimmer of hope with the development of multiple vaccines that are currently being distributed throughout the world. With the mass rollout of vaccination, both prevention of COVID-19 infection and reduction in morbidity and mortality can be achieved with hopes of ending the pandemic. Since With mass vaccination rollout, lymphadenopathy ipsilateral to the injected deltoid muscle has become an important manifestation of an immune response to be aware of as it may present as a diagnostic dilemma on cancer imaging studies. We write this editorial as a public service message at a time where other countries are starting mass vaccination programs with the goal of preventing unnecessary nodal biopsies and alleviating patient concern.

What are the side effects of COVID-19 vaccination?

The most common COVID-19 vaccine side effects include local injection site pain, fever, chills, myalgias, headache and fatigue, with resolution usually in a few days [1, 2] . However, palpable lymphadenopathy commonly involving the axilla as an immune response to vaccination may present a clinical diagnostic dilemma especially in persons with a history of malignancy. Patients may be concerned regarding lymphadenopathy as a sign of malignancy, especially persons with a prior oncologic history. This anxiety will only increase in patients with lymphadenopathy as widespread rollouts of vaccination continue. In addition, lymphadenopathy may be found incidentally on imaging examinations, such as routine screening or oncologic surveillance examinations, presenting a diagnostic dilemma for radiologists.

Although unilateral lymphadenopathy is a known side effect of vaccines, it is rarely reported with vaccines such as the Bacillus Calmette-Guérin, influenza, and human papillomavirus vaccines [3] [4] [5] . In a larger series examining 83 recipients of the influenza vaccine, four patients had unexpected fluorodeoxyglucose axillary node accumulations on imaging [5] . In addition, lymph node uptake on nuclear medicine studies after vaccination has been shown by multiple studies. This is in contrast with the two-dose approved COVID-19 vaccines in the United States, Pfizer-BioNTech and Moderna, which both have higher reported rates of axillary swelling compared to prior vaccines. This may be due to a higher immunogenic response to these mRNA vaccines, a type of vaccine that has not previously been approved for use. As a solicited adverse event in the Moderna clinical trials, axillary swelling or tenderness was reported in 11.6% of patients (5.0% placebo) after Dose 1 and 16.0% (4.3% placebo) after Dose 2 [1] . While not solicited as an adverse event in the Pfizer trials, reports of lymphadenopathy from Dose 1 through 30 days after Dose 2 were imbalanced with notably more cases in the Pfizer-BioNTech COVID-19 vaccine group (64) versus the placebo group (6) , which is plausibly related to vaccination [2] . The true incidence of post-vaccination lymphadenopathy may be higher given I n p r e s s axillary swelling was only reported as an unsolicited adverse event. Incidence of axillary lymphadenopathy visible at imaging is likely higher as not all patients have clinical symptoms.

As of March 2021, at least 20 articles have been published illustrating or discussing COVID-19 vaccine-related lymphadenopathy, with 18 of these articles published in imaging journals. The earliest publications occurred in the field of breast imaging, where vaccine-induced lymphadenopathy was cited as a cause of unilateral axillary lymphadenopathy. Other imaging subspecialities citing this side effect included nine articles in nuclear medicine, and one article in cardiothoracic imaging. In most publications so far, there has only been one or a very small number of patients reported on; one of the largest groups of patients reported on is 23 patients with axillary adenopathy who had undergone breast imaging [6] . What are the current imaging guidelines related to vaccine-induced axillary lymphadenopathy?

The Society of Breast Imaging (SBI) was the first imaging society to propose guidelines addressing axillary lymphadenopathy seen on imaging [7], with the Canadian Society of Breast Imaging (CSBI) endorsing the SBI recommendations. There have now been multiple publications suggesting guidelines for unilateral axillary lymphadenopathy with focus on different modalities or oncologic subspecialities. We summarize these below divided in terms of different phases of care.

Vaccination dates, injection site/laterality and vaccine type should be documented on patient intake forms or electronic medical record [7].

To mitigate the diagnostic dilemma of vaccine-induced lymphadenopathy, the SBI recommends that patients should "consider scheduling screening exams prior to the first dose of a COVID-19 vaccination or 4-6 weeks following the second dose of a COVID-19 vaccination" [7]. This recommendation has been followed by a similar guideline published in Radiology from a multidisciplinary panel from oncologic centers, recommending for non-urgent indications such as routine I n p r e s s surveillance, screening, or staging imaging to be scheduled prior to vaccination or to postpone imaging "at least 6 weeks after final vaccination dose" [8] . McIntosh et al also [9] suggested performing PET/CT "at least two weeks after vaccination in patients with a cancer for which interpretation is anticipated to be potentially impacted by the vaccination, though optimally 4-6 weeks after vaccination". However, like other imaging exams, if there is an urgent clinical indication such as treatment planning, active treatment monitoring, or assessment of new symptoms or potential complications, imaging should not be delayed, regardless of vaccination status.

An additional strategy to mitigate confounding findings would be to administer COVID-19 vaccinations "on the side contralateral to the primary cancer" [8] .

For subclinical unilateral lymphadenopathy detected on imaging, vaccination history including injection site and date is now a key piece of clinical information to obtain. In cases of unilateral axillary lymphadenopathy on screening mammography, the SBI recommends a BI-RADS 0 designation to bring the patient back for assessment of the ipsilateral breast and additional documentation of medical and vaccination history [7] . After an otherwise negative diagnostic workup, and if a COVID-19 vaccine was given on the ipsilateral side in the past 4 weeks, a BI-RADS 3 (Probably Benign) assessment is then assigned with consideration for a short term follow up in 4-12 weeks after the second vaccination dose. If lymphadenopathy persists at follow up, then consider a BI-RADS 4 (Suspicious) assessment with biopsy to exclude malignancy. As these recommendations were first announced in January 2021 based on very early experience with COVID-19 vaccinations, they are necessarily meant to be conservative. In an update (March 9, 2021), the SBI notes that individual practices may wish to establish their own guidelines based on local expertise and resources.

A different approach was suggested by a recent publication in JACR proposing use of "BI-RADS 2 Benign" assessment with clinical follow-up for isolated unilateral lymphadenopathy after recent COVID-19 vaccination in the ipsilateral arm [10] . This is consistent with the American College of Radiology BI-RADS recommendations for unilateral lymphadenopathy in the setting of a known inflammatory cause [10] . In comparison with the more conservative SBI recommendations, this "pragmatic" approach would result in fewer follow-up examinations.

In terms of management of clinically evident post-vaccination lymphadenopathy, the multidisciplinary panel recommended "observing for at least 6 weeks until resolution before referring for diagnostic imaging evaluation or biopsy of the nodes" [8] . The multidisciplinary panel also recommended "expectant management strategy without default follow-up imaging" in patients whom pre-test probability of adenopathy is much more likely to due to vaccination rather than malignancy. In higher-risk situations, either a short-term imaging follow up with ultrasound and/or tissue diagnosis can be considered, especially in patients with a high-risk oncologic history (e.g. ipsilateral breast or head/neck cancer, melanoma or lymphoma) [8] . The expected duration of post-vaccination lymphadenopathy is not yet determined.

Widespread patient education regarding vaccine-induced lymphadenopathy is needed, especially as this may be mistaken as a sign of malignancy. Imaging societies, clinicians, and news media outlets should spread awareness to educate the public regarding this side effect to minimize patient anxiety. When vaccines are administered, side effects such as axillary swelling should be highlighted and normalized as an immune response initiated by the vaccine. Patients should be aware of the best times to schedule routine imaging exams with more infographics such as the SBI mammography recommendations for women receiving the COVID-19 vaccine being widely distributed. In patients with palpable lymphadenopathy after vaccination, another suggestion may be to proceed with clinical followup by a clinician or the patient themselves rather than imaging, resulting in cost-savings to the system. Care should also be taken to ensure clinical and/or imaging follow-up for those with lymphadenopathy that does not resolve, those with potentially causative malignancies (such as breast or head/neck cancer, lymphoma, or melanoma), and those with additional sites of lymphadenopathy. 

Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events: Moderna COVID-19 Vaccine

Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events: Pfizer-BioNTech COVID-19 Vaccine

Development of unilateral cervical and supraclavicular lymphadenopathy after human papilloma virus vaccination

Axillary lymph node accumulation on FDG-PET/CT after influenza vaccination

Society of Breast Imaging, SBI Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination

Multidisciplinary Recommendations Regarding Post-Vaccine Adenopathy and Radiologic Imaging:. Radiology

COVID-19 Vaccination-Related Uptake on FDG PET/CT: An Emerging Dilemma and Suggestions for Management

Unilateral Lymphadenopathy Post COVID-19 Vaccination: A Practical Management Plan for Radiologists Across Specialties