key: cord-0843767-y1p8fg5p
authors: Ha, Su Min; Chu, A Jung; Lee, JungBok; Kim, Soo-Yeon; Lee, Su Hyun; Yoen, Heera; Cho, Nariya; Moon, Woo Kyung; Chang, Jung Min
title: US Evaluation of Axillary Lymphadenopathy Following COVID-19 Vaccination: A Prospective Longitudinal Study
date: 2022-04-26
journal: Radiology
DOI: 10.1148/radiol.220543
sha: 86feec4ac5a158420d3b40a15f527b173d365aa3
doc_id: 843767
cord_uid: y1p8fg5p

BACKGROUND: Both temporal changes in imaging characteristics of lymphadenopathy on US following COVID-19 vaccination and expected duration of radiologically evident lymphadenopathy remain uncertain. PURPOSE: To longitudinally evaluate COVID-19 vaccine-associated lymphadenopathy on axillary US at various time intervals, in both mRNA and vector vaccine recipients. MATERIALS AND METHODS: This prospective cohort study was conducted between March 2021 and January 2022. The participants were asymptomatic women without breast cancer who had received COVID-19 vaccination. Serial follow-up US was performed in women manifesting lymphadenopathy. Following variables were assessed: cortical thickness, number of lymph nodes, morphology, and Doppler signal. Temporal changes in cortical thickness and number of lymph nodes during follow-up were assessed using a linear mixed model. RESULTS: Ninety-one women with lymphadenopathy in the vaccinated arm had undergone a total of 215 serial US (mean age, 44 years ±13). Fifty-one participants had received vector vaccine (ChAdOx1 nCoV-19 vaccine) and 40 mRNA vaccines (BNT162b2 vaccine [n=37] and mRNA-1273 vaccine [n=3]). Except for three women with follow-up loss, eighty-eight women underwent serial US and complete resolution of axillary lymphadenopathy at median 6 weeks interval (range, 4-7 weeks) was observed in 26% (23 of 88) of women. Of 49 women with follow-up US at median 12 weeks interval (range, 8-14 weeks), persistent lymphadenopathy was observed in 51% (25 of 49). During the follow-up period, the cortical thickness gradually decreased (P < .001) over time regardless of vaccine type; however, values were higher in recipients of the mRNA vaccine than in recipients of the vector vaccine (P = .02). CONCLUSION: COVID-19 vaccine-associated axillary lymphadenopathy frequently persisted over 6 weeks on US. Lymphadenopathy should be interpreted considering vaccine type and time elapsed since vaccination. Follow-up US examination at least 12 weeks after vaccination may be reasonable, particularly for recipients of the mRNA vaccine. © RSNA, 2022 See also the editorial by Moy and Kim.

Vaccination-associated reactive lymphadenopathy is considered a local adverse reaction to vaccination, more commonly observed after receiving COVID-19 messenger RNA (mRNA) vaccines (1) (2) (3) (4) (5) . Similar to other vaccines, mRNA vaccines depend on the migration of antigen presenting cells to the regional lymph nodes to elicit cellular (T-cell) and humoral (B-cell) immune response.

Compared with protein-based vaccines, mRNA vaccines elicit more robust and rapid B-cell proliferation in the germinal center of lymph nodes, likely increasing the incidence of lymphadenopathy (6,7). Two representative mRNA COVID-19 vaccines, mRNA-1273 vaccine (Moderna) and BNT162b2 vaccine (Pfizer-BioNTech), induce host immune cells to produce antigens, whereas the attenuated viral vector ChAdOx1 nCoV-19 vaccine (AstraZeneca) induces an immune response mechanism (8). According to the Centers for Disease Control Prevention, axillary swelling or tenderness has been reported in up to 16% of recipients of the mRNA-1273 vaccine (9).

With increasing COVID-19 vaccine availability and wider vaccinated patient populations, we anticipate that more patients will demonstrate subclinical lymphadenopathy on imaging. Several reports have identified COVID-19 vaccine-associated lymphadenopathy via mammography (3% of recipients of COVID-19 vaccine) (4) or PET/CT (1-45% of recipients of the mRNA vaccine) (10).

Imaging findings of axillary lymphadenopathy following COVID-19 vaccination have been reported in up to 15% and 57% of recipients of the BNT162b2 vaccine and mRNA-1273 vaccine, respectively (11) . A recent study reported that 44% of patients who had received COVID-19 vaccination and underwent breast imaging revealed lymphadenopathy on at least one imaging modality, 9% identified on mammography alone, 61% on US alone, and 30% on both examinations (12) . However, there is still no information on the temporal changes of these imaging characteristics and the duration for which the enlarged nodes remain asymmetrically detectable, as well as the time to lymphadenopathy resolution following COVID-19 vaccination on US (1) . There is also a lack of consensus regarding the management recommendations for COVID-19 vaccine-associated lymphadenopathy observed on imaging, ranging from screening at least 6 weeks after (1, 2) or at least 12 weeks after (5,12,13) the second vaccination dose. This uncertainty causes diagnostic confusion for clinicians and radiologists resulting in unwarranted biopsies and follow-up examinations. Since US is the primary method for axillary lymph node evaluation that can be repeatedly performed without concerns of radiation or contrast agent, we hypothesized that serial follow-up axillary US examinations after COVID-19 vaccination would provide more information on the temporal imaging changes and the optimal timeline for resolution. Therefore, the purpose of our study was to prospectively and longitudinally evaluate COVID-19 vaccine-associated lymphadenopathy on axillary US at various time intervals, in both mRNA and vector vaccine recipients.

The institutional review board of the Seoul National University Hospital approved this prospective, observational, longitudinal single-center study, and written informed consent was obtained from all participants. The first COVID-19 vaccination was administered in the Republic of Korea on February 26, 2021, for high-risk groups, which included patients aged ≥ 65 years, disabled, and healthcare workers and the large-scale vaccination for the general population began in May (14) . Thus, between

March 2021 and January 2022, we prospectively recruited healthy recipients of the COVID-19 vaccine aged ≥18 years who were willing to screen bilateral breasts and axillae after COVID-19 vaccination or presented with axillary lymphadenopathy detected on screening or follow-up US examinations. All patients were required to have negative or benign findings within 6 months on the breast and axillary US examination. Recruitment was consecutive and was censored when participants nearly or completely resolved axillary lymphadenopathy on follow-up US examinations. The inclusion criteria were as follows: (a) women who had received COVID-19 vaccination, (b) no symptoms in both breasts, (c) no recent diagnosis of breast cancer, and (d) voluntary, written informed consent for follow-up examinations. We excluded women with known current malignancy, or those who were pregnant or lactating.

One of the two attending breast radiologists (J.M.C and S.M.H with 15 and 9 years of experience in breast imaging, respectively) performed axillary US using a 13-5 MHz linear transducer, Arietta 850 (Fujifilm Healthcare Corporation). Details on standard axillary US including B-mode and color Doppler images are described in Appendix E1 [Online].

The following criteria were used to identify suspicious lymph nodes: cortical abnormalities, including focal or diffuse thickening > 3 mm with partial or complete fatty hilum loss or rounded hypoechoic lymph node and non-hilar or diffuse flow (15) . At the first US examination after vaccination, the radiologists counted the number of lymph nodes, and identified the most suspicious lymph node among them. The maximal cortical thickness, morphology, and Doppler findings of the most suspicious lymph node were assessed and recorded. We recommended a follow-up US at 4-6 weeks interval from vaccination upon detecting suspicious lymph nodes. An additional US at a 10-12 weeks interval from vaccination was recommended for unresolved lymph nodes at the previous follow-up.

When the participant requested an earlier or later visit for follow-up examination, we allowed a minimum 1-2 weeks interval variability between the specified follow-ups. Thus, despite recommended follow-up examinations at 4-6 weeks and additional 10-12 weeks interval for unresolved lymph nodes, variability in time intervals from vaccination persisted. Hence, we calculated the time interval between follow-up US and vaccination and categorized the scheduled visits accordingly (≤ 2, > 2 and ≤ 4, > 4 and ≤ 6, > 6 and ≤ 10, > 10 and ≤ 12, and > 12 weeks). During the follow-up US examination, the radiologists reviewed the recent preceding US finding to identify the most suspicious lymph node that was detected previously and repeatedly assessed maximal cortical thickness, morphology, and Doppler findings of the predefined lymph node and the number of visible lymph nodes to evaluate temporal changes. The same imaging assessment was performed for lymph nodes in the contralateral axilla. The complete resolution of axillary lymphadenopathy was defined as normalization of cortical thickness showing difference less than 0.5 mm compared with the contralateral side or pre-vaccination state for previously available US images. Among variable imaging parameters we obtained during different time intervals, the maximal cortical thickness was selected as the main imaging feature for assessment of normalization of lymphadenopathy, since it is a quantitative feature that is less subject to observer variability, directly shows the temporal changes of its values, and is easily applicable in clinical practice.

We recorded the age, vaccine type (vector vaccine = ChAdOx1 nCoV-19 vaccine, mRNA vaccine = BNT162b2 vaccine and mRNA-1273 vaccine), time from vaccination (interval between US and vaccination), dose (first or second), injection site (left or right arm), and associated symptoms.

The temporal changes of axillary lymphadenopathy on US examinations acquired from recipients of vector vaccine and recipients of mRNA vaccine were analyzed. Due to variability in time intervals from vaccination and inconsistency in the number of follow-up examinations from participants, we used linear mixed model of our repeated measured data acquired from scheduled visits to estimate the interaction between vaccine and time effect, vaccine effect and time effect on cortical thickness and number of lymph nodes. We used the least squares mean with standard errors for comparison.

Differences between categorical and continuous variables of recipients of vector and mRNA vaccines were compared using the Chi-square or Fisher exact tests and Student t-test, respectively. Statistical analyses were performed using R statistical software (version 4.1.2; The R Foundation). Statistical significance was set at P < .05.

A total of 106 eligible women were screened using US to identify axillary lymphadenopathy at first visit. Of 106 women, 50 (47%) were women for screening purposes after COVID-19 vaccination, and 56 (53%) were women having axillary lymphadenopathy detected on screening or follow-up US examinations. Of the 50 women who volunteered for screening purposes, 35 women (70%) showed axillary lymphadenopathy within 1 week of vaccination. All 15 women who did not manifest lymphadenopathy had received the vector vaccine; thus, they did not undergo further US examination.

Ninety-one women exhibiting lymphadenopathy in the vaccinated arm were included and underwent 215 serial axillary US scans (median number of examinations, 3; interquartile range, 2-3). The mean interval between vaccination and the last follow-up image acquisition was 8.9 weeks ± 3.2 (range, 4- 

Of the 91 women, 88 underwent follow-up serial US examinations after vaccination, except three with non-evaluable temporal changes because of loss to follow-up. Of these 88 women, complete resolution of axillary lymphadenopathy was observed at median 6 weeks (range, 4-7 weeks) in 26% follow-up after 12 weeks, and complete resolution was observed in two and one vector and mRNA vaccine recipients at 13 and 16 weeks, respectively. There were no women in whom suspicious lymphadenopathy was aggravated or biopsy was performed. In our linear mixed model analysis, overall vaccine effect on cortical thickness was significantly higher in recipients of the mRNA vaccine than recipients of the vector vaccine (P = .02) and time effect on gradual decrease of cortical thickness was significant (P < .001), although interaction between vaccine type and time effect was not (P = .14). Regarding the number of lymph nodes, interaction between vaccine type and time effect on number of lymph nodes was significant (P = .002) along with higher numbers observed in recipients of the mRNA vaccine (P = .02) with a gradual decrease over time (P < .001) ( Table 2, Figures 2 and 3) .

All 91 women showed ipsilateral axillary lymph node with focal or diffuse cortical thickening > 3 mm and the cortical thickness was largest within 2 and 2-4 weeks following mRNA (5.3 ± 0.2 mm) and vector (4.3 ± 0.3 mm) vaccine administration, respectively ( Table 2) . At 2 weeks after vaccination in recipients of mRNA and vector vaccines, number of lymph nodes were 6.0±0.3 and 3.9±0.3, respectively. In most cases, fatty hilum of ipsilateral axillary lymph node was preserved. Suspicious morphology including fatty hilum loss (partial or complete) or rounded hypoechoic features was noted 

With increasing COVID-19 vaccine availability and wider vaccinated patient populations, we anticipate that more patients will demonstrate subclinical lymphadenopathy on imaging. However, the information on the temporal changes of lymphadenopathy following COVID-19 vaccination according to the vaccine types is still limited. We therefore prospectively and longitudinally evaluated COVID-19 vaccine-associated ipsilateral lymphadenopathy. Of 88 women who underwent serial US, complete resolution of axillary lymphadenopathy occurred at median 6 weeks in only 26% (23 of 88) of women. Of 49 women with follow-up US at median 12 weeks interval, persistent lymphadenopathy was observed in 51% (25 of 49) of women, which lasted up to 16 weeks after vaccination. The cortical thickness of the ipsilateral axillary lymph node was largest within 2 and 2-4 weeks following the messenger RNA vaccine (5.3 ± 0.2 mm) and vector vaccine (4.3 ± 0.3 mm) administration, respectively, with higher values in recipients of the messenger RNA vaccine than in recipients of the vector vaccine. Furthermore, suspicious morphology and Doppler signal, as well as increased numbers of lymph nodes were predominantly observed within 2 weeks with both vaccine types with higher values and incidence in recipients of messenger RNA vaccine.

Our study elucidated the temporal changes of COVID-19 vaccine-associated lymphadenopathy on axillary US and optimal follow-up timing. Although imaging follow-up is not recommended in healthy women for axillary adenopathy after vaccination, cautious interpretation may be needed in those with recently diagnosed breast cancer (3) or asymptomatic patients with a history of cancer undergoing monitoring for recurrence (16) . In patients with a new or active cancer diagnosis, reactive lymphadenopathy cannot be easily distinguished from metastatic disease by their morphology or location (3, 17) . Different time effects on complete resolution attributed to vaccine administration provide clues for deciding the time for follow-up examination or directly proceeding to biopsy in women with higher risk of metastatic lymphadenopathy, thus our findings can be especially helpful for determining optimal management for women who have recently diagnosed breast cancer or personal history of breast cancer. Indeed, the timing of the recommended follow-up imaging is debatable. The National Comprehensive Cancer Network recommends scheduling screening examinations prior to the first COVID-19 vaccination or 4-6 weeks after the second dose, postponing the short-interval follow-up for 4-6 weeks after the final dose (18) . A previous study reported that the incidence of COVID-19 vaccine-associated lymphadenopathy on mammography decreased over time, disappearing more than 28 days after vaccination (4), thereby supporting the recommendations from the Society of Breast Imaging (2) . However, the European Society of Breast Imaging recommends imaging in cases of axillary lymphadenopathy at least 12 weeks from the second vaccine dose in patients without a history of breast cancer (5), which was consistent with our study results. In a recent study, the time to resolution of reactive lymphadenopathy varied, with persistent axillary lymphadenopathy observed up to 43 weeks post-vaccination (12) , which led to the suggestion of no need for short-term follow-up imaging. Considering the extended time to resolution, short-term follow-up imaging examination within 6 weeks is not helpful in making a differential diagnosis of benign reactive lymphadenopathy regardless of vaccine type. Instead, follow-up imaging examination at least 12 weeks after vaccination may be reasonable, particularly for recipients of the mRNA vaccine. Similarly, our results showed a larger number of mRNA vaccine recipients with suspected axillary lymphadenopathy and longer duration of lymphadenopathy, with only 18% (7 of 39) of recipients displaying complete resolution at median 6 weeks (range, 4-7 weeks) after mRNA vaccination. In addition to cortical thickening, suspicious morphologic features of loss in fatty hilum, rounded shape, increased cortical flow, and increase in overall number of lymph nodes were more frequently observed in women receiving mRNA vaccines. Although no women needed biopsy in our study, these imaging findings may raise more concern for malignant lymphadenopathy (3, 12, 17, 20) , thus, cautious interpretation is needed.

Our study had some limitations. First, this is a single-center design with a small sample size. In this prospective observational study, we could only enroll a limited number of women owing to time, cost, and compliance issues related to serial US examination planned for each participant. However, we believe our study is distinct from other retrospective studies since we only included women with a clear antecedent relationship between COVID-19 vaccination and lymphadenopathy. Second, in our linear mixed model, the analysis was conducted on the premise of missing at random, and cortical thickness and number of lymph nodes were not evaluated at 10-12 weeks in participants who showed complete resolution within 6 weeks. This may influence our results, however, comparison between two groups was still possible with no significant difference in the number of objects measured at each time point. Third, fewer women received the mRNA-1273 vaccine in our country because the ChAdOx1 nCoV-19 vaccine had been initiated earlier. Last, we did not have information on the lymphadenopathy incidence, which was beyond our scope since we intended to evaluate the temporal changes of lymphadenopathy resolution on US. However, we can indirectly infer the incidence in our study population since 47% (50 of 106 eligible women) of the participants were part of the screening population, and 70% (35 of 50) of them showed axillary lymphadenopathy that was higher than other studies (4, (10) (11) (12) . This high incidence should be interpreted cautiously because our study population was enriched with women whom lymphadenopathy had been detected. The use of various types of vaccine and US examination performed within a short interval from vaccination could explain this high incidence; however, further larger studies are warranted.

In conclusion, COVID-19 vaccine-associated axillary lymphadenopathy as identified on US developed within the first 2 weeks of vaccination and frequently persisted over 6 weeks. Clinicians and radiologists should understand the different timelines for lymphadenopathy resolution according to the vaccine type and cautiously interpret lymphadenopathy considering the timeframe from vaccination and overall nodal metastatic risk of individual patients. Even in situations that require follow-up US examinations, short-term follow-up within 6 weeks is not helpful for identifying the resolution of lymphadenopathy; thus, follow-up US examination at least 12 weeks after vaccination may be reasonable, particularly for recipients of the messenger RNA vaccine. 

Note-Data are numbers with percentages in parentheses, unless otherwise specified. Cortical thickness of lymph node is presented as mean ± standard errors. LN = lymph node, mRNA = messenger RNA, SE = standard error.

We used linear mixed model of our repeated measured data acquired from scheduled visits to estimate the interaction between vaccine and time effect, vaccine effect and time effect on cortical thickness and number of lymph nodes. 

Multidisciplinary recommendations regarding post-vaccine adenopathy and radiologic imaging: radiology scientific expert panel

SBI Recommendations for the management of axillary adenopathy in patients with recent COVID-19 vaccination. Society of Breast Imaging Web site

Axillary lymphadenopathy after COVID-19 vaccination in a woman with breast cancer

Incidence of axillary adenopathy in breast imaging after COVID-19 vaccination

PET-CT and relevance to study interpretation

Association of COVID-19 mRNA vaccine with ipsilateral axillary lymph node reactivity on imaging

Axillary adenopathy after COVID-19 vaccine: No reason to delay screening mammogram

Prevalence of increased FDG PET/CT axillary lymph node uptake beyond 6 weeks after mRNA COVID-19 vaccination

Statistics and Research: Coronavirus (COVID-19) vaccinations

Utility of preoperative ultrasound for predicting pN2 or higher stage axillary lymph node involvement in patients with newly diagnosed breast cancer

US surveillance of regional lymph node recurrence after

The participants were placed in a supine oblique position with their arms abducted and externally rotated with the hands above the head. For standard axillary US, the ipsilateral I and II axilla levels to the injection site were scanned along with contralateral I and II axilla levels for reference. The radiologists obtained color Doppler images and evaluated the presence of diffuse or non-hilar abnormal flow. The images were acquired in two orthogonal planes (radial, anti-radial, transverse, and longitudinal planes) for the most suspicious lymph node, and the short axis of the cortex was used to measure the maximal cortical thickness of the lymph node in a cross-sectional plane ( Figure E1 [Online]) (15) . The number of lymph nodes seen on US was counted and recorded.