key: cord-0952707-vl9tnujw authors: Bshesh, Khalifa; Khan, Wafa; Vattoth, Ahamed Lazim; Janjua, Emmad; Nauman, Areej; Almasri, Muna; Mohamed Ali, Ateeque; Ramadorai, Vinutha; Mushannen, Beshr; AlSubaie, Mai; Mohammed, Ibrahim; Hammoud, Mais; Paul, Pradipta; Alkaabi, Haya; Haji, Aliyaa; Laws, Sa'ad; Zakaria, Dalia title: Lymphadenopathy post‐COVID‐19 vaccination with increased FDG uptake may be falsely attributed to oncological disorders: A systematic review date: 2022-02-07 journal: J Med Virol DOI: 10.1002/jmv.27599 sha: f0da18690611617338b8daa5e321522f80b5a830 doc_id: 952707 cord_uid: vl9tnujw Coronavirus disease 2019 (COVID‐19) has caused a global pandemic that continues to cause numerous deaths to date. Four vaccines have been approved by the Food and Drug Administration as of July 2021 to prevent the transmission of COVID‐19: Pfizer, Moderna, AstraZeneca, and Janssen. These vaccines have shown great efficacy and safety profile. One side effect that has been widely reported is post‐COVID‐19 vaccination lymphadenopathy. Due to the mimicry of the lymphadenopathy for metastases in some oncologic patients, there have been reports of patients who underwent biopsies that showed pathologic confirmation of benign reactive lymphadenopathy secondary to the COVID‐19 vaccine. Therefore, understanding the incidence of lymphadenopathy post‐COVID‐19 vaccinations will help guide radiologists and oncologists in their management of patients, both present oncologic patients, and patients with concerns over their newly presenting lymphadenopathy. A systematic literature search was performed using several databases to identify relevant studies that reported lymphadenopathy post‐COVID‐19 vaccination. Our results revealed that several cases have been detected in patients undergoing follow‐up fluorodeoxyglucose (FDG)‐positron emission tomography‐computerized tomography scans where lymph nodes ipsilateral to the vaccine injection site show increased uptake of FDG. Thus, knowledge of the incidence of lymphadenopathy may help avoid unnecessary biopsies, interventions, and changes in management for patients, especially oncologic patients who are at risk for malignancies. Coronavirus disease 2019 (COVID-19) is a respiratory disease caused by a newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. It was discovered in Wuhan city in China after documenting unknown etiology pneumonia cases by the end of December of 2019. 1 Afterward, the World Health Organization stated on 11th March 2020 that COVID-19 is a "public health emergency of international concern." 2 SARS-CoV-2 is a positive-sense single-stranded RNA virus, that can infect animals and humans. 3 Among positive-stranded RNA viruses, SARS-CoV-2 has the largest reported replicating RNA molecules. 4 CoV-2 invades the host cells by binding to angiotensin-converting enzyme 2 and mostly radiates through the respiratory tract. 5 SARS-CoV-2 may infect individuals of all age groups. However, there is a higher risk of infection in people aged above 60 years, as well as those with chronic diseases such as chronic respiratory disease, diabetes, and cardiovascular diseases. 6 Complications of the virus can lead to an uncontrolled inflammatory response, resulting in pneumonia and acute respiratory distress syndrome. In December 2020, Pfizer and BioNTech released the first messenger RNA (mRNA)-based vaccine targeted against COVID-19 for use in United Kingdom (UK) and United States (USA). Their vaccine BNT162b2 was authorized for emergency use only. 7 The vaccine consists of lipid nanoparticle (LNP)-formulation encapsulated mRNA, given through the intramuscular route, in 2 doses separated by 21 days. The vaccine works by stimulating CD4+ and CD8+ T cells' responses and high neutralizing antibody titers. 8 The European Medicines Agency recommended the vaccine for authorization in the EU on December 21, 2020. 9 Moderna's vaccine mRNA-1273 was authorized by the US Food and Drug Administration (FDA) for emergency use in December 2020. 10 Moderna's vaccine was the second COVID-19 vaccine recommended for emergency use in the EU by the European Medicines Agency. The vaccine is made of prefusion stabilized S protein mRNA encapsulated in LNP. It is given via the intramuscular route, in 2 doses separated by 28 days. It has been shown that repeated vaccine doses stimulate neutralizing antibodies and CD4+ and CD8+ T cell responses. 8 Oxford/AstraZeneca's COVID-19 vaccine AZD1222 is a Chimpanzee adenovirus vector expressing the spike protein on its surface. 8 It is given intramuscularly, in 2 doses 8-12 weeks apart. 11 It was approved in the UK for emergency use in December 2020 12 restrictions were made about the country, age, or gender. Any duplicated articles were removed. Any articles that did not include primary data, such as reviews were excluded from the study. Studies that were not in English were also excluded. Title and abstract as well as full-text screening were conducted by two different reviewers for each study using Covidence and disagreements were resolved by consensus. Demographic and clinical data of patients reported in each study (wherever data were available) were extracted independently by two different reviewers using Covidence and disagreements were resolved by consensus. Extracted data included age, sex, comorbidities, treatment/interventions and clinical progress. Categorical variables were expressed as percentages while continuous variables were expressed as mean standard deviation or range of results. Data were extracted from each study by two different reviewers. After removing the studies deemed irrelevant to our topic, 209 studies were selected for full-text screening with only 37 studies that met the inclusion criteria being included. A total of 172 studies were excluded as 115 studies were irrelevant to the data of interest, 34 had no primary data, 13 were duplicates, 6 were ongoing trials, 3 were not in English and 1 used animal models. Tables S1 and S2 summarize the types of the included studies. The results from our search yielded 24 case series/reports, 7 cohort studies without control (Table S1 ), 21-51 3 cohort studies with controls, and 3 randomized control trials (RCT) ( Table S2 ). [52] [53] [54] [55] [56] [57] Two of the cohort studies without control were conducted in the USA and two in Israel. The other three were conducted in Germany, South Korea, and the Czech Republic. As for the cohort studies with control, two were also conducted in the USA and one in Israel. Two of the RCTs were conducted mainly in the USA while the study conducted by Polack et al. 52 was a multinational study that had 152 total sites including Argentina (1), Brazil (2), South Africa (4), Germany (6), Turkey (9), USA (130). Out of the 24 case series/reports, 11 were from the USA, 4 from the UK, 2 from Israel, 2 from Italy, 2 from Canada, and 1 from each of Ireland, Germany, and Spain. Tables S1 and S2 summarize the demographic and clinical data extracted from the included studies. Table 1 Granata et al. 27 48 F 1 NR Hanneman et al. 28 Hiller et al. 21 Mehta et al. 29 Avner et al. 30 Finnegan et al. 32 Cellina et al. 33 Dominguez et al. 34 Edler et al. 35 Fernández RTCs. Summed data from 3 cohort studies without control showed a 24.5% incidence of lymphadenopathy in individuals taking the Pfizer vaccine (Table 1) . 25, 31, 36 Figure 4 separates the studies based on the type of subjects as 3 cohort studies included only oncologic patients. Two of the 3 compiled cohort studies had only subjects with malignancy and the individual rate of lymphadenopathy in such studies was 45% and 25.8% as reported by Eifer et al. 36 and Brenstine et al. 31 respectively. Riad et al. 25 reported that 16.2% of the cohort with a normal population (not specifically oncologic) that received Pfizer vaccine developed lymphadenopathy ( Figure 4A ). Approximately 4.2% of the individuals who took the Moderna vaccine developed lymphadenopathy in one cohort study. 41 In two cohort studies in which participants took either the Pfizer or Moderna vaccine (unspecified), 1.9% of the individuals developed lymphadenopathy. 43 Additionally, in another cohort 1.0% of the individuals who took the AstraZeneca vaccine developed lymphadenopathy 48 ( Figure 4A ). Table 2 reports the findings from cohort studies with control and RCTs ( Figure 4C ). The overall rate of lymphadenopathy in all the cohort studies with and without controls including the clinical trials is 13.51%. vaccinations. 53, 58, 59 Of those, lymphadenopathy was seen in the ipsilateral lymph nodes; specifically in axillary, supraclavicular, and infraclavicular lymph nodes. 21 The exact mechanism of how the COVID-19 vaccines may cause lymphadenopathy is still not clear. It is hypothesized that the increased immune response following vaccination causes a localized inflammatory response in the area surrounding the vaccination site. Immune cells in the nearby lymph nodes may proliferate as they become exposed to the vaccine antigen. This hyperplasia in response to the vaccine may cause lymphadenopathy to develop. Lymphadenopathy reactions have been reported after several other vaccines including measles, anthrax, smallpox, H1N1 and seasonal influenza, Bacille Calmette-Guerin, and human papillomavirus vaccines. [59] [60] [61] [62] [63] [64] [65] Lymphadenopathy seems to be a reaction common to most vaccines rather than specifically to those of COVID-19. Hence, the mechanism in which lymphadenopathy occurs may be similar in all vaccine types. Our results signify that lymphadenopathy may occur following COVID-19 after the 2nd dose as compared to 4.8% after the 1st dose and 3.9% after the 2nd dose in the control group. 54 Such rates are higher as compared to the rates of lymphadenopathy following Pfizer vaccination as reported by the safety trials. In the Pfizer vaccine safety trials, only 64 vaccine recipients (0.3%) as compared to 6 placebo recipients (<0.1%) reported lymphadenopathy. 52, 54 While there were reports of lymphadenopathy in the clinical trials, they were few specifically in the Pfizer ones. The AstraZeneca vaccine phase 3 clinical trials did not report any cases of lymphadenopathy. 18 Similarly, no cases of lymphadenopathy were reported in the Janssen safety trial. 66 Interestingly, however, some cases were described in case reports and cohort studies after each of these vaccines as well. [45] [46] [47] [48] 56 The unprecedented circumstances and emergent need for COVID-19 vaccines have led to fast approvals for widespread use. Although extensive and thorough clinical trials have been carried out, due to the rapid turnover, the emergence of some unexpected side effects that were not reported or underreported during the clinical trials may occur. The Janssen and AstraZeneca COVID-19 vaccines, however, did not report any case of lymphadenopathy in their phase 3 trials. 18, 66 It is unclear if the absence of any cases is due to none occurring or if participants were not examined for lymphadenopathy. Nevertheless, 14 cases in a cohort study and 3 case reports described lymphadenopathy occurring after the AstraZeneca vaccine. 45 Bernstine et al. 31 and Eifer et al. 36 which did not include control groups, Cohen et al., 53 conducted a cohort study that recruited vaccinated cancer patients and compared them with a control unvaccinated group. Statistical analysis revealed that the rate of occurrence of lymph nodes with benign metabolic hyperactivity was significantly higher in the Pfizer vaccinated group as compared to the control group. Furthermore, the rate was also significantly higher after the second dose as compared to the first dose. The same study reported that it was not always possible to differentiate between the benign and malignant nodal involvement especially when the vaccine was administrated on the same side as the tumor expected nodal drainage. The study, therefore, recommended that patients with breast cancer, axillary lymphoma, and malignancy of the upper limb should not be vaccinated in the arm next to the tumor expected nodal drainage. 53 4.6 | Are females more affected? One cross-sectional survey-based study found that lymphadenopathy as a side effect of the COVID-19 vaccine had a higher frequency among females in comparison to males. 25 However 88% of the subjects in this study were females, and thus the study population may not have had a wider scope on the male subjects. Although noting the prevalence of this side effect on females versus males was not the main objective for many of the included studies, one cohort study focused on investigating the female to male differences in adverse effects of the COVID-19 vaccine. 56 It was reported that females were more likely to experience a wider range of adverse effects than males such as nausea, fever, and vomiting. The difference was explained by the enhanced immune reactogenicity in females as shown by reviews of vaccine-induced hormonal immunity. This enhanced reaction results in more immunity to infectious diseases but also in a higher rate of adverse effects. 68 It was suggested that the interaction between the flu vaccine and estrogen may boost immunity which may apply to COVID-19 vaccines. 69 However, the same study reported that lymphadenopathy was more common in males than in females. 56 Therefore, further investigations are required to determine whether lymphadenopathy post-COVID-19 vaccination has a higher prevalence in either sex. Our results revealed that lymphadenopathy following COVID-19 vaccinations may be occurring more often than previously thought. However, the majority of cases have been benign with no major adverse effects occurring as a result of the lymphadenopathy. Therefore, it is important to recognize that postvaccination lymphadenopathy may not pose significant harm to the vaccinated individuals and is not a reason to withhold vaccinations. However, lymph node enlargements following COVID-19 vaccination is expected to be increasingly observed in the near future especially those that could be suspicious for malignancy during follow-up of tumor patients with imaging techniques. 67 It is, therefore, especially important to consider postvaccination lymphadenopathy in patients who undergo regular tests such as FDG-PET-CT or MRI as results may be misinterpreted. Clinicians must be aware of such possible transient detection of hypermetabolic regional lymph nodes following COVID-19 vaccination. 70 Several authors of the included studies recommend that vaccination information must be included in the medical history of patients who are being imaged. 39, 40 Patients are encouraged to always communicate their vaccination history to their oncologist, radiologist, and other medical staff treating them. 67 Other recommendations specific to patients with any kind of malignancy include taking the vaccine shots on the arm contralateral from the limb with expected lymphatic drainage of the malignancy if possible. 53 This may help minimize the need for repeated imaging and more invasive procedures such as biopsies due to inconclusive scans. 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Sexual dimorphism of humoral immunity with human vaccines COVID-19 mRNA vaccine-related adenopathy mimicking metastatic melanoma A B SBI Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination Society of Breast Imaging Patient Care and Delivery Committee We would like to thank Weill Cornell Medicine-Qatar for its continuous support. The authors declare that there are no conflict of interests. All authors whose names appear on the submission made substantial contributions to the conception or design of the work, screening of the studies, data extraction, and/or drafting the manuscript. All authors critically reviewed the manuscript and approved the version to be published. The data that supports the findings of this study are available in the supplementary material of this article. Dalia Zakaria https://orcid.org/0000-0001-9020-0038