key: cord-0798332-kwtni4ro authors: Keshavarz, Pedram; Yazdanpanah, Fereshteh; Rafiee, Faranak; Mizandari, Malkhaz title: Lymphadenopathy Following COVID-19 Vaccination: Imaging Findings Review date: 2021-05-01 journal: Acad Radiol DOI: 10.1016/j.acra.2021.04.007 sha: f15f31d6c2c3ea786d2b0f871b010479d596ad14 doc_id: 798332 cord_uid: kwtni4ro RATIONALE AND OBJECTIVES: : Despite all the benefits and effectiveness of the coronavirus disease 2019 (COVID-19) vaccines mentioned in recent clinical trials, some post-vaccination side effects such as lymphadenopathy (LAP) were observed. The present study reviewed all studies with imaging findings presentation of LAP after COVID-19 vaccination. MATERIALS AND METHODS: : We conducted a literature search in online databases, including Scopus, Medline (PubMed), Web of Science, Embase (Elsevier), Cochrane library, and Google Scholar. RESULTS: : A total of 19 studies (68 cases), including 60 (88.2%) females and 8 (11.8%) males with a presentation of LAP after COVID-19 vaccination, were reviewed. LAP was identified after first or second dosages of three types of COVID-19 vaccines, including Pfizer-BioNTech (n = 30, 44.1%), Moderna (n = 17, 25%), and Oxford-AstraZeneca (n = 1, 1.5%). In 20 (29.4%) cases, vaccine type was not reported or only reported as mRNA COVID-19 vaccine. The median days of LAP presentation after the first and second dosages of COVID-19 vaccination, were 12 and 5 days, respectively. Most of the LAP imaging findings related to COVID-19 vaccination (n = 66, 97%) were seen from first day to four weeks after vaccination. However, LAP remained after 5 and 6 weeks of the first and second dosages of COVID-19 vaccination with decreased lymph nodes’ size and residual cortical thickening in two cases. CONCLUSION: : This review study of cases with LAP-associated COVID-19 vaccination guides radiologists and physicians to rely on patient's clinical context and updated resources to prevent potential disease upstaging and change in therapy. Since December 2019, coronavirus disease 2019 (COVID-19) has faced the world with a considerable challenge affected many other items besides health (1) . According to the World Health Organization (WHO) statistics, as of March 27, 2021, more than 125 million people worldwide have been infected, and more than 2.700.000 have died (2) . After implementing various methods to deal with the destructive effects of the virus, efforts to develop an effective vaccine as the final solution accelerated (3, 4) . Since December 2020, various vaccines with mRNA, vector, and protein subunit mechanisms marketed over time. Pfizer-BioNTech and Moderna are among the first vaccines approved emergency use authorization (EUA) from the United States Food and Drug Administration (FDA) (5) (6) (7) . Vaccination began immediately in the United States, and until March 27, 2021, more than 91 million (27.6%) of the USA population have received one or more doses (8) . In the latest update, the FDA issued EUA for the Janssen vaccine on February 27, 2021 (9) . Despite all the vaccines' benefits and effectiveness, as mentioned above, mild and negligible side effects have been observed. Some of them include local pain at the injection site, fatigue, headache, muscle or joint pain, fever, and chills. Furthermore, some severe adverse effects were noted in physical exams, including lymphadenopathy (LAP), which was reported in 0.3% and 1.1% of Pfizer-BioNTech and Moderna vaccines, respectively (10) (11) (12) . Over time, with increasing vaccination rates in the general population, regional adenopathy on the same side of vaccination was frequently reported as an incidental finding in different imaging modalities (13) . Determining whether the adenopathy is benign or malignant has critical importance following detecting it in imaging examinations. It can affect some plans in the screening or follow-up of cancerous patients simultaneously (14) . Comprehensive clinical practice and analysis have confirmed that COVID-19 is a heterogeneous multisystem disorder; consequently, it can have various imaging features. Chest images such as CXR and CT illustrate characteristics that display lower lobe and peripheral ground-glass opacities in the lungs. These characteristics for the gastrointestinal system in COVID-19 patients are enteritis or mesenteric ischemia. Findings on imaging of pediatric patients are relatively similar to adults, particularly in the respiratory system. The notable CT findings are feeding vessel sign, halo sign, and pleural thickening (15) (16) (17) . Here, we reviewed the imaging findings of cases with the presentation of LAP after COVID-19 vaccination. We searched various online data sources, including Scopus, Medline (PubMed), Web of Science, The Cochrane Library, Embase (Elsevier), and Google Scholar from January 1, 2019, to February 28, 2021 , and updated on March 25, 2021. All types of studies, including original research studies, clinical perspective, case series/reports, editorials, and commentaries were assessed. Studies on COVID-19 vaccinated individuals (with any type of COVID-19 vaccine with the United States FDA approval) presented with LAP by various imaging modalities such as sonography, mammography, MRI, PET/CT scan, and PET/MRI were included. Duplicates, studies reported other adverse events of COVID-19 vaccines rather than adenopathy, and studies without available full text were excluded. Keywords of literature search included "COVID-19", "coronavirus disease," "SARS-CoV-19", "Vaccin*", and "Vaccination", "Immunization", "side effect*", "adenopath*", and "Lymphadenopathy". The details of the PubMed keywords search strategy are presented in appendix A. Two independent authors screened the reference lists of included studies to increase the sensitivity of our search process, and the corresponding author resolved any disagreements. The following data from each study were extracted: First author's name, country and region, study type, population characteristics, vaccine type, a dosage of vaccination, site and location of adenopathy, size of adenopathy, presence of cortical thickening and hilar fat, type of imaging modality, and imaging findings. Furthermore, we reported a series of imaging findings from two included studies after obtaining formal permissions (34, 36). (Figs. 2-4) We identified a total of 2043 records through the initial search in databases. Following the removal of duplicates, 1103 studies remained for a title and abstract screening, 56 studies were selected as the candidates for assessment according to our eligibility criteria. Finally, nineteen studies were identified to be eligible for this study. Figure 1 reveals the flow diagram of the study selection process. The present study reviewed 68 cases, including 60 (88.2%) females and 8 (11.8%) males with the age range of 32-76 years old. The majority of cases (n = 56, 82.3%) had previous or active history of malignancy, including breast cancer (BC) (n = 40; such as triple-negative, HER2 positive, invasive ductal, BRCA mutation carrier, breast focal lesion or had positive family history of BC), smoldering myeloma (n = 1), malignant melanoma (n = 3), oligometastatic myxoid liposarcoma (n = 1), oligosecretory myeloma (n = 1), mantle cell lymphoma (n = 1), lung cancer (n = 4, including, two squamous cell, one solitary pulmonary nodule, and one another type), cervical cancer (n = 1), diffuse large B-cell lymphoma (n = 1), cutaneous melanoma (n = 1), parotid malignancy (secretory carcinoma) (n =1), and oral cavity squamous cell carcinoma (n = 1). Five (7.4%) cases presented with left palpable painful/painless axillary or supraclavicular LAP. In seven (10.3%) cases, the accurate characteristics of cases were not reported. (Table 1 ) Among 68 cases, the most applied radiologic modality for evaluating the suspicious LNs was the US, which revealed LNs enlargement with diffuse or focal cortical thickening in 29 (42.6%) cases, preserved nodal hilar fat reported in one case. Six (8.8%) cases were screened only by mammography (18). Additionally, LNs demonstrated a necrotic pattern evidenced by homogenous hypo-echogenicity and absence of internal vascular flow in a single case (19). In two (2.9%) cases, abnormal LNs were detected in the chest CT scan performed due to other reasons (13, 20) . Abnormal axillary adenopathy was detected in 12 (17.6%) cases who underwent MR imaging for other reasons (such as BC screening or follow-up). Except for the LNs enlargement, the feature reported was nodal cortical thickening ranging from 3 to 7 mm in five cases, irregular nodal cortex in one case, and preserved hilar fat reported in two cases. Otherwise, no discriminative characteristic of LNs involved by the COVID-19 infection was detected in this modality. Another modality was 18 F-FDG-PET/CT that demonstrated abnormal LNs in 18 (26.4%) cases as increased FDG uptake with the mean SUV max of 6.8 ± 3.4 g/ml (range, 1.8-13). Moreover, associated increased FDG uptake at the injection site and in ipsilateral superficial soft tissue was detected in three cases with a mean SUV max of 7.6 ± 3.3 g/ml, and preserved nodal hilar fat was reported in one case. An incidental note was taken of abnormal FDG uptake in axillary nodes in the performed cardiac PET/MRI in one (1.5%) case (21) . The mean of maximum LNs dimension reported in all modalities was 20.9 ± 5.8 mm (range, [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] , with a mean short axis of 12 ± 2.9 mm, and cortical thickness of 6.2 ± 0.8 mm. A summary of the imaging findings is provided in Table 2 . LAP was reported after first or second dosages of three types of COVID-19 vaccines, including Pfizer-BioNTech (n = 30, 44.1%), Moderna (n = 17, 25%), and Oxford-AstraZeneca (n = 1, 1.5%). In 20 (29.4%) cases, vaccine type was not reported or only reported as mRNA COVID-19 vaccine. Location of LAP was reviewed, including axillary 82.3% (65/79), supraclavicular 11.4% (9/79), infraclavicular 1.2% (1/79), and subpectoral or neck regions 5.1% (4/79). (Table 3) LAP was observed in imaging examinations after the first and second dosages of Pfizer-BioNTech vaccine with median days of 10.5 (range, 5-18 days) and 5 (range, 1-7 days), respectively. About the Moderna vaccine, LAP was observed with median days of 11 (range, 3-26 days), 3 (range, 1-22 days), respectively. Overall, the median days of LAP presentation after the first and second dosages of COVID-19 vaccines were observed 12 (range, 3-26 days) and 5 (range, 1-22 days), respectively. This study is a first review study of LAP presentation followed by COVID-19 vaccination. Several radiologic findings are consistent with a reactive LAP, such as diffuse or focal cortical thickening and preserved hilar fat in the imaging modalities, reported in some cases of present study. Moreover, it was found that 97% of imaging findings of LAP after COVID-19 vaccination were seen from the first day to four weeks after vaccination. Although, LAP remained after 5 and 6 weeks of the first and second dosages of COVID-19 vaccination with decreased LNs size and residual cortical thickening in two cases (21, 22) . Fernandes et al. reported LAP in 20 cases after injection of both Pfizer-BioNTech and Moderna vaccines and observed the resolution of LAP after five days to more than four weeks (23). Thereby, most studies recommended routine imaging screening before or at least 4-6 weeks after the second dose of COVID-19 vaccines to prevent potential disease upstaging and change in therapy. vaccines, and around 10 and 1-2 days, in Pfizer-BioNTech and Moderna vaccines, respectively (11, 12) . Our results revealed that this duration was more than the CDC average, and in the recent studies, LAP was observed with the median days of 12 and 5 days after the first and second dosages of these COVID-19 vaccines, respectively. More than a year after the inception of the COVID-19 pandemic, various vaccines have been developed to boost immunity and human resistance to the virus with different mechanisms (24) . Global immunization has been started, with the first FDA-approved vaccines (Pfizer and Moderna) for EUA. It continues with other vaccines such as Sputnik V, Oxford-AstraZeneca, and Sinopharm in different countries (25) . LAP is one of the rare complications of immunization before COVID-19 vaccination. Thereby, new image interpretation conflicts appear due to LAPrelated vaccination (6, 7, 26) . This rate is lower with the Pfizer-BioNTech vaccine considering severe adverse reactions, including LAP, which was observed in 0.3% or 64 of participants occurred up to 4.6% of partners and were more frequent after the second dose and adults less than 55 years of age (6, 7, 34) . Different factors come to the radiologists' and physicians' aid to distinguish a malignant versus benign focal LAP in selected patients. Such factors include both the clinical and radiological findings. For instance, in physical examination, palpable focal axillary LAP ipsilateral to the injection site in a BC patient (of the contralateral side of vaccination) is more likely to be reactive in nature. However, since one case of necrotic LAP was reported in post-COVID19 vaccination (19), differentiation of the adenopathy caused solely by this feature should be cautioned. The other reported radiologic characteristic of abnormal LNs was cortical thickening, defined as more than 3 mm thickness of the affected node (35) . Although this feature does not help distinguish a reactive process from a neoplastic one, both diffuse and focal cortical thickenings were reported in approximately 25% of the present study. Furthermore, regarding the cases who underwent nuclear imaging, normal-sized LNs with normal cortical thickness also could be involved by the associated pathologic process (26). Among the modalities in use for abnormal LN detection, the FDG PET/CT could be one of the most confusing. We reviewed fourteen cases with known underlying malignancies presented with increased uptake in focal LNs draining the axillary territory. 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