Patients
A nationwide mass vaccination using the Pfizer–BioNTech BNT162b2 mRNA Covid-19 vaccine against Covid-19 has been initiated in Israel on December 20, 2020 [2]. As of February 17, 2021, a total of 4,157,220 Israeli people received the first dose of the vaccine, and 2,777,825 the booster dose as well, numbers that translate into 44.9% and 30% of the total Israeli population, respectively [19].
After receiving the consent of the institutional ethical committee, all patients over 16 years of age referred for whole-body [18F]FDG PET-CT between December 27, 2020, and February 17, 2021, were interviewed regarding the date of the first and booster vaccine doses and the site of injections. Of all [18F]FDG PET-CT studies done in the mentioned period, 99 studies were excluded from analysis: 42 due to missing vaccination data, 34 were brain-only studies, 20 studies were of patients younger than 16 years old, and 3 studies were of patients vaccinated in their thigh or buttocks. All Other 951 consecutive patients were interviewed, consisting of the study cohort: 728 vaccinated patients (All-Vac group) and 223 patients that were not vaccinated (control group). Of the vaccinated patients, 346 received the first vaccine only (Vac-1 group), and 382 received both the first and booster vaccine doses (Vac-2 group). Table 1 summarizes the diseases and indications for PET-CT of the study cohort.
Table 1 Study population characteristics Detection, categorization, and interpretation of regional lymphadenopathy
[18F]FDG PET-CT studies were performed on PET-CT scanners (GE Healthcare; DISCOVERY 690 and DISCOVERY MI; 7 to 8 frames; frame time 1.5–3 min) according to our standard protocol with the administration of dilute oral contrast agent, injection of 3.7 MBq/kg [18F]FDG approximately 60 min prior to the study. Final PET-CT interpretation was carried out by at least one nuclear medicine specialist with PET-CT experience of at least 8 years.
HLN was recorded when at least one [18F]FDG-positive ASLN was identified and reported. HLN was categorized in our data as either tumor nodal involvement (malignant HLN – MHL), benign nodes associated with the vaccine (vaccine-associated HLN – VAHL), or equivocal (equivocal HLN – EqHL). Primary tumor type and site; stage of disease; the presence and location of other abnormal imaging findings, mainly malignant lymphadenopathy in other nodal stations; and findings on previous imaging studies were data assisting in interpreting the nature of the HLN, separating MHL and VAHL. However, if such differentiation could not be obtained, the regional lymphadenopathy ipsilateral to the vaccine injection site was interpreted as EqHL. If no “hot” ASLN was detected, the case was categorized as no-HLN.
In all VAHL identified, the locations of the “hot” nodes identified in the axilla were recorded as axillary level 1, 2, 3 or interpectoral nodes. [18F]FDG-uptake intensity was measured in the “hottest” node, using maximal standardized uptake value (SUVmax) calculated as [18F]FDG uptake (kBq/mL) divided with the injected dose (MBq) and multiplied with the lean body weight (kg). The size of the largest “hot” node was recorded using short-axis diameter measurement. Enlarged LN were defined as >8 mm for oval and > 10 mm for round LN.
Based on [18F]FDG-uptake intensity and nodal size, VAHL was graded on a 4 grades scale: grade 1, mild [18F]FDG-uptake intensity (SUVmax <2.2); grade 2, moderate [18F]FDG-uptake intensity (2.2 ≤ SUVmax <4); grade 3, high [18F]FDG-uptake intensity (SUVmax ≥4) in normal-size nodes; and grade 4, high [18F]FDG-uptake intensity (SUVmax ≥4) in enlarged nodes. Figure 1 illustrates the four different VAHL grades.
Statistical analysis
Categorical variables were reported as frequency and percentage. Continuous variables were evaluated for normal distribution and reported as median and interquartile range (IQR). Chi-square test and Fisher’s exact test were applied to compare proportions between groups. Independent samples Kruskal–Wallis test and Mann–Whitney test were used to compare continuous variables. Chi-square automatic interaction detection (CHAID) was used to identify a subgroup of patients with similar rates of VAHL grades. All statistical tests were performed using SPSS Statistics Version 27 (IBM, Armonk, NY, USA) and were two-sided, and p < 0.05 was considered statistically significant.