Lymphadenopathy post-COVID-19 vaccination with increased FDG uptake may be falsely attributed to oncological disorders

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Qatar Study Shows That Lymphadenopathy Due To COVID-19 Jabs With Increased FDG Uptake May Falsely Be Blamed On Oncological Issues.

The study team cautioned that care must be taken before suspecting lymph node metastasis or deciding for lymphadenectomy for patients following COVID-19 jabs.
 
Lymphadenopathy refers to lymph nodes that are abnormal in size (e.g., greater than 1 cm) or consistency. Palpable supraclavicular, popliteal, and iliac nodes, and epitrochlear nodes greater than 5 mm, are considered abnormal.
 
One side effect that has been widely reported is post-COVID-19 jabs is lymphadenopathy.  

https://pubmed.ncbi.nlm.nih.gov/33774684/
https://pubmed.ncbi.nlm.nih.gov/33378609/
https://pubmed.ncbi.nlm.nih.gov/33301246/
https://pubmed.ncbi.nlm.nih.gov/33707061/
https://pubmed.ncbi.nlm.nih.gov/33895650/
https://pubmed.ncbi.nlm.nih.gov/33782299/
The study team reports that 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 jabs.
 
Hence, 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.
 
The Lymphadenopathy-COVID-19-Jabs study team conducted a systematic literature search using several databases to identify relevant studies that reported lymphadenopathy post-COVID-19 jabs.
 
The study findings 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 jab 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.
 
The study findings were published in the peer reviewed Journal of Medical Virology. https://onlinelibrary.wiley.com/doi/10.1002/jmv.27599

COVID-19 reported postvaccination events

The US FDA Center for Biologics Evaluation and Research published a protocol on Background Rates of Adverse Events of Special Interest (AESIs) for COVID-19 vaccine safety monitoring. Many side effects were listed as the outcome for the general population including acute myocardial infarction, anaphylaxis, appendicitis, Bell’s palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and nonhemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis.19

In addition to the above adverse events, many studies reported the occurrence of lymphadenopathy post-COVID-19 vaccination.

Postvaccination lymphadenopathy

Lymphadenopathy can be defined as any type of inconsistency or abnormality in lymph nodes. The abnormality can lay within the firmness, size, or number of lymph nodes in a particular section of the body. Lymphadenopathies can result from a number of causes and can vary depending on the location, including bacterial, parasitic, and viral infections. Studies have shown that unilateral lymphadenopathy has been highly associated with vaccines such as the influenza vaccine, BCG vaccine, and HPV vaccine.20

Postvaccination lymphadenopathy may be falsely attributed to oncological disorders in patients who are diagnosed with cancer, in remission, or those who are at high risk for developing malignancies.

Therefore, it is necessary to be familiar with the possible post-COVID-19 vaccine lymphadenopathy to avoid unnecessary stressful diagnostic procedures including imaging and invasive biopsies.21 This review compiles data about the events of lymphadenopathy reported post-COVID-19 vaccination and the recommendations to avoid any clinical and/or diagnostic complications.

DISCUSSION

Lymphadenopathy as a side effect of vaccination is neither a new phenomenon nor isolated to COVID-19 vaccines. This presentation is considered common with the human papillomavirus vaccine, as well as H1N1 vaccinations.53, 58, 59 Of those, lymphadenopathy was seen in the ipsilateral lymph nodes; specifically in axillary, supraclavicular, and infraclavicular lymph nodes.21

How may vaccines cause lymphadenopathy?

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.59-65 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.

Lymphadenopathy following COVID-19 vaccination

Our results signify that lymphadenopathy may occur following COVID-19 vaccination. A total of 6022 individuals developed lymphadenopathy post-COVID-19 vaccination as reported by different types of studies including 24 case reports/series, 10 cohort studies, and 2 RCTs.

Although some of the studies reported higher rates of lymphadenopathy in the COVID-19 vaccinated groups compared to the control groups, only Cohen et al.,53 established a significant association between Pfizer vaccination and lymphadenopathy (45.6%) compared with the unvaccinated group (7.6%) (p value <0.01).

Furthermore, the rate of lymphadenopathy was significantly higher after the second dose as compared to the first dose. However, this cohort is not representative of the entire population as only patients with malignancies who may be more susceptible were included.

Baden et al.,54 Polack et al.,52 and Chu et al.55 reported a higher incidence of lymphadenopathy post-COVID-19 vaccine in comparison to placebo. However, the association has not been statically determined.52, 54, 55 Surprisingly, McMurry et al.,57 reported a significantly lower rate of lymphadenopathy in the vaccinated group as compared to the nonvaccinated control group.

This contradicts the findings of increased lymphadenopathy observed after vaccination in most other studies. This might be attributed to the selection process of the participants as anyone who visited the emergency department (ED) was used as a subject and was classified as either vaccinated or unvaccinated.

It was, therefore, suggested that those vaccinated may have been warned about the side effects and were less likely to present to the ED. Relatively high rates of lymphadenopathy were reported in 3 cohort studies 45.6% (Cohen et al.),53 45% (Eifer et al.),36 and 25.8% (Bernsite et al.).31 This could be attributed to the nature of the cohorts which had only subjects with malignancies. The overall rate of lymphadenopathy in the included cohort studies and RTCs is 13.15%. However, this overall rate is impacted by the high lymphadenopathy rate in the cohorts with oncologic subjects. The average rate of lymphadenopathy in the 3 studies with only oncologic patients is 38.8% which is higher than the average rate in the normal cohorts (6.65%).

Was lymphadenopathy reported following COVID-19 vaccination during the clinical trials?

It is common that some side effects do not become apparent until after the drug or vaccine is released to the public. Looking into the COVID-19 safety clinical trials, lymphadenopathy was reported as a side effect after taking the Moderna or Pfizer vaccines. The RCT reported by Chu et al.55 showed the development of lymphadenopathy in 11% of the participants after the first dose of the Moderna vaccine and 9% after the second dose in the 18–55-year-old cohort.

In the control group who had received saline instead, 4% developed lymphadenopathy after the first dose and 1% did after the second dose. Similarly, Baden et al.54 reported lymphadenopathy in 10.2% of the Moderna vaccinated group after the 1st dose and in 14.2% 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.45-48, 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.45-48

Lymphadenopathy in patients with malignancies post-COVID-19 vaccination

Hypermetabolic lymphadenopathy describes an abnormal lymph node that is metabolizing at an increased rate, which is demonstrated using an FDG-PET-CT scan. FDG-PET-CT scan is a medical imaging tool that uses radiotracers to detect metabolically active lesions within the body. Whole-body FDG-PET-CT is a standard practice to examine cancer patients to evaluate the progress of the disease.

However, FDG uptake can be also detected in inflammatory and infectious lesions which can also be caused by vaccination.31 Our included case reports and case series revealed the emergence of much post-COVID-19 vaccination lymphadenopathy especially in patients undergoing follow-up FDG-PET-CT where lymph nodes ipsilateral to the vaccine injection site show increased uptake of FDG.21, 23, 28

For example, Smith and Yang reported a case of benign hypermetabolic axillary lymph nodes following Pfizer/BioNTech vaccination near the injection site, most likely due to a vaccine-elicited immune response.26 Other resources refer to vaccine-related lymphadenopathy to be associated with sonographic and clinical features, such as being more common in oncological patients who may be experiencing an impact on the accuracy of their diagnostic tests.22 Out of the 6022 reported cases of lymphadenopathy in our included studies, 693 had confirmed malignancies as reported by several case reports/series or cohort studies with or without control.

All subjects in the studies conducted by Cohen et al.,53 Eifer et al.,36 and Bernstine et al.,31 had known malignancies and were assessed for lymphadenopathy using FDG-PET-CT or other PET-CT tracers. The studies reported relatively high rates of FDG-PET-CT positive results within the cohorts.

It was observed that cancer patients started to undergo FDG-PET-CT hypermetabolic axillary lymph nodes and a focal hypermetabolic region in the ipsilateral deltoid muscle following Pfizer vaccination especially after the second dose in the cohort study conducted by Bernstine et al.31 Similarly, Eifer et al.36 reported that a high proportion of cancer patients showed ipsilateral lymph node axillary uptake following Pfizer vaccination.

Unlike the studies conducted by 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 Furthermore, 18 cases who developed lymphadenopathy following COVID-19 vaccination conducted different tests such as FDG-PET-CT scan, MRI, US, and/or FNA biopsy without having any malignancies.21, 22, 28, 33, 34, 37, 49

In a recent study, Placke et al.,67 reported 8 patients (with melanoma or Merkel cell carcinoma) who were misdiagnosed with lymph nodes metastases and underwent lymph node excision following COVID-19 vaccination.68 Therefore, care must be taken before suspecting lymph node metastasis or deciding for lymphadenectomy following COVID-19 vaccination.

Awareness of 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.27

What is the outcome of the lymphadenopathy post-COVID-19 vaccination?

The studies reported the spontaneous resolution of lymphadenopathy post-COVID-19 vaccination. The reported duration until complete resolution varied among studies. Some studies reported a maximum duration of 10 days, with most resolutions occurring around the second day of symptoms.25, 52, 54, 55 However, durations of up to 32 days with a resolution still ongoing have been reported by some case reports and case series.21, 37

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.

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