A prolonged course most characterized the presented case of remote reactive lymphadenopathy after COVID-19 vaccination. The symptoms and signs were noticed 4 months after receiving the second dose of CoronaVac, after which the patient improved in 6 months and recovered in 8 months. To our knowledge, no cases of such a remote nature have been previously reported.

In CDC reports, lymphadenopathy occurred within 2 to 4 days after vaccination with Moderna and lasted for 1 to 2 days (11), and the duration in radiologic observational reports was longer (between 4 days and 10 weeks) (12–18). However, most of these cases were retrospective studies in the patients who recently received the COVID-19 vaccine and underwent positron emission tomography (PET). Therefore, there could be selection bias, short observational periods, and lack of reports involving other imaging modalities. This case may be an exception due to individual differences. Nonetheless, the existence of such a prolonged course challenged the current perception about the duration of this side effect.

Based on the abovementioned observations, current guidelines emphasize the timing for imaging after COVID-19 vaccination. A multidisciplinary expert panel recommended the postponement of imaging for at least 6 weeks after completion of the vaccination (19). The Breast Imaging Society also recommended a scheduling exam conducted at 4–6 weeks following the second dose for screening and a short-term follow-up examination at 4–12 weeks for ipsilateral axillary adenopathy patients who received the COVID-19 vaccine within 4 weeks (20). The recommended timing is practical; however, it cannot encompass exceptional situations, and a cautious approach is needed when facing lymphadenopathy potentially related to vaccines, even in unexpected situations.

This lymphadenopathy case was particularly unusual because the detection occurred outside of the expected time interval with the presence of other clinical findings, of which we were not aware. In hindsight, most of the diagnostic interventions were unnecessary, which resulted in physical and psychological burdens on the patient. Additionally, the misinterpretation of hypoperfusion on CEUS as “perfusion defect” supported the misdiagnosis, as it often suggests “necrosis” of tuberculous or malignant lymphadenopathy (21). Therefore, we must emphasize the importance of rational and subtle image interpretations to avoid both over- and underdiagnosis.

A limitation of this case was the lack of evidence of nucleic acid elements or SARS-CoV-2 antigen on PCR, western blot, or immunohistochemistry tests, which was mainly due to the misdiagnosis that resulted in all of the chosen tests being conducted to verify inflammation or tumors. We propose that biopsy of needle aspiration for PCR or western blot testing would be practical for future diagnostic quandaries that need genetic verification. Additionally, activated lymphocytes should also be examined as an important indicator.

An accurate diagnosis of lymphadenopathy after vaccination is important. In this case report, we discussed the diagnostic perplexity in an individual without combined medical conditions, whereas reports have also focused on cancer patients (12, 13, 15, 22). A modeling study suggested a large proportion of missed cancer diagnoses due to the pandemic (23). Therefore, subtle imaging interpretation is crucial in patient management.

Concerning imaging-detected reactive lymphadenopathy after COVID-19 vaccination, the majority of cases were identified on PET scans, mainly during cancer surveillance. This condition normally involved transient 18-fluorine-fluorodeoxyglucose (¹⁸F-FDG) uptake in ipsilateral lymph nodes, ranging from intense to gradually regressed after administration (13, 19, 22, 24–26). However, the maximal standardized uptake value (SUVmax) should not be solely used to differentiate between benign and malignant lymph nodes (14). There were attempts to improve the diagnostic rate by comparing the SUVmax of the ipsilateral lymph nodes to the contralateral lymph nodes (27) as well as the increased uptake in the deltoid muscle (28, 29) or using different tracers (30). PET is the most sensitive imaging modality for differentiating lymphadenopathy, whereas the radioactive nature and high cost are limitations.

Few of the cases were detected via magnetic resonance imaging (MRI) (31, 32), CT (15), and mammography (33). These techniques are common diagnostic workups that provide relevant information, especially in the case of breast or lung cancers which often involve axillary lymph node metastasis. They provide good overall observations but relatively few morphological details of abnormal lymph nodes compared to the US (34). Additionally, they cannot provide metabolic features compared to PET (35).

The US has a high diagnostic value in the screening, evaluation, and follow-up of lymphadenopathy (36); it presents high-resolution images of superficial lymph nodes with subtle morphological details that CT or MRI may not have been able to assess (37). We reviewed the full-text accessible literature on US-detected reactive lymphadenopathy after COVID-19 vaccination with a complete vaccination history and explicit image description. The US findings are shown in Table 1 (34, 38–46). In general, the size, shape, cortex-hilum structure, vascularity patterns, and stiffness of lymph node were essential signs to consider. Rational judgments should be made based on the combined information. It should be noted that there were “alarming” signs mentioned, such as spherical shape, thickened lymphatic cortex, hilum absence, and peripheral vascularity, which have often been observed in malignant or specifically infected lymph nodes (37).

In this case, the patient underwent 4 successive US examinations that demonstrated dynamic changes during progression and regression. Initially, the US showed increases in the number and size of abnormal lymph nodes, with notably thickened lymphatic cortex ( Figures 1A , 2A–C ). Regarding the progression of the largest lymph node, the second US showed an indistinctive decrease in cortical thickness, whereas the nodal size remained almost the same. Both size and cortical thickness markedly decreased and eventually resolved at the follow-up examination ( Figures 1A–D ). Based on these trends, we supposed that the thickened cortex might be related to nodal hyperplasia, and it began to subside in the early stage of nodal regression. The decrease in cortical thickness in the US may be an early imaging sign of improvement that should be considered.

To our knowledge, this case was the first to report the CEUS findings of reactive lymphadenopathy after COVID-19 vaccination. The patient underwent 3 successive CEUS scans that also demonstrated dynamic changes. Initially, CEUS demonstrated hypoperfusion in the deviated center of the largest lymph node. It was markedly narrowed in the second CEUS and became nearly invisible in the third exam ( Figures 1 α–γ). In hindsight, we noted that the initial hypoperfusion area overlapped with the most thickened cortex; moreover, it regressed even earlier than the cortex attenuation. A decrease of hypoperfusion may be an even earlier sign of improvement. We speculated that the COVID-19 vaccine might stimulate immune cells in the nodal cortex, which leads to excessive pressure on tissue microcirculation. The insufficiency of perfusion was represented as filling insufficiency on CEUS. However, this was merely a conjecture regarding pathogenesis without the support of systematic research, and further work is required to elucidate this mechanism.

In this case, accompanying manifestations interfered with the diagnosis, including transient fever, decreased white cell and lymphocyte counts, increased inflammatory markers (ESR, PCT, and SF), and abnormal coagulation function. A previous study reported a decrease in lymphocytes after COVID-19 vaccination (26), and elevated PCT and CRP were independent risk factors for death in patients with COVID-19 (47). As all tests for specific infections were negative, and the patient fully recovered without medical intervention, we retrospectively supposed that these manifestations were also vaccine reactions. However, local and systemic inflammatory reactions after COVID-19 vaccination should be transient, and further studies are needed to describe remote reactions after COVID-19 vaccination. Additionally, the patient presented with mild anemia in the second CBC, possibly due to malnutrition because of anxiety.

Concerning the type of COVID-19 vaccine that causes reactive lymphadenopathy, there have been more than 2,000 reported cases after mRNA vaccines and 14 reported cases after adenoviral vectored vaccines (12, 22), yet there have been no specific case reports related to protein subunit vaccines. In theory, regardless of the type, all COVID-19 vaccines might cause reactive lymphadenopathy, and this case can serve as a supplement to observational side effect studies.