Patients’ characteristics
From 404 patients referred to our fast-track H&N clinics during the
study period, 88 patients had cervical lymphadenopathy. A total of 13
patients (14.8%) had cCVAL and were consecutively included in the study
(Figure 1 ). The mean age was 54.8 ± 16.1 years, and
interestingly most of the patients were females (N=11, 84.6%),Table 1. All patients had the Pfizer/BioNTech vaccine, and the
majority had the injection in the left deltoid (N=12, 92.3%). The study
period mostly covered the early phases of vaccination rollout in the UK,
and most patients (N=12) had only one dose by the time of presentation.
All patients experienced a feeling of a lump in the ipsilateral neck,
but pain was only reported in six patients (46.2%), Table 1 and
2. The swelling was first noticed by patients within a median of four
days (IQR 2-7) from vaccination, and in seven patients (53.9%) a
referral was made to the fast-track clinic within three weeks from the
onset of symptoms (Table 2 ).
Lymphadenopathy features on neck ultrasound scans
(USS)
All patients had USS, with median interval between the swelling onset
and the scan was 25 days (IQR 10-49). Table 3 summarises the
USS characteristics of the examined lymph nodes (LNs). Targeted USS
confirmed the presence of one or more LNs, all in level IV or V of the
neck. The average short axis diameter (SAD) of the most prominent nodes
was 5.5 ± 1.4 mm, but five patients (38.5%) had more rounded nodes with
short axis: long axis ratio (S:L) > 0.5. Scans performed ≤4
weeks from swelling onset showed significantly larger nodes (6.5 ± 1.4
mm) compared to scans performed >4 weeks (4.8 ± 0.8 mm),P =0.03. The overall scan impression was recorded as benign
reactive lymphadenopathy in all patients, but two cases had
increased vascularity on colour
doppler (Figure 2, Table 3 ). Moreover, two patients had mildly
hypoechoic LNs but none had fatty hilar abnormality. Two patients had
fine-needle aspiration biopsy, but cytology demonstrated features of
benign reactive lymphadenopathy. Moreover, two patients had follow-up
USS that showed reduction in CVAL size.
Lymphadenopathy outcomes
The outcomes of lymphadenopathy were subjectively reported by patients
during virtual follow-up (Table 2 ). Seven patients (53.9%)
reported full resolution (FR) of their palpable swelling within an
average of 3.1 ± 2.3 weeks from the onset of their symptoms. Five
patients (38.5%) reported partial reduction (PR) in the size of their
palpable lumps over an average period of 8.4 ± 3.1 weeks (Figure
1 ). When compared to the FR group, the PR group interestingly presented
to their general practitioner significantly later (35.6 vs. 9.0
days, P = 0.001 ), and had significantly smaller LNs on
USS (4.6 vs. 6.4 mm, P =0.024 ), Table 4.However, neither the patients’ age, nor the vaccination to
lymphadenopathy interval were found to be significantly Impacting the
clinical outcome.
Discussion
Post-vaccination lymphadenitis is an uncommon phenomenon that can be
triggered by intramuscular vaccine injections in the deltoid muscle. It
has been previously reported in adults following many viral vaccinations
especially for human papillomavirus (HPV)18 and H1N1
influenza19. More recently, cases with CVAL have been
described in reports from the United States, Spain, Israel and the
UK.8,12-14,20-22
The available evidence has suggested that mRNA-based vaccines are likely
more immunogenic than standard vaccines, and hence show higher incidence
of CVAL.7,21,22 In clinical trials on the
Pfizer/BioNTech mRNA vaccine, lymphadenopathy was only reported as an
unsolicited ADR, with incidence in the vaccine group as high as ten
times that in the placebo group (0.3% and 0.03%
respectively).1 As a solicited ADR, axillary
lymphadenopathy was the second most frequently reported reaction in the
Moderna vaccine trials, with incidence of 10.2% and 14% after the
first and second doses respectively.3 Reporting
lymphadenopathy in these trials was only based on physical examination,
and the true incidence rate was likely much
higher.1,3,7 Interestingly, clinical trials on the
Oxford/AstraZeneca adenovirus-vectored vaccine reported a lower
incidence of lymphadenopathy in the vaccination group (0.3%) compared
to the placebo group (0.4%).2 Our results show that
all patients referred to us with cervical CVAL (cCVAL) had the
Pfizer/BioNTech vaccine, and none had the Oxford/AstraZeneca vaccine
despite it accounting to almost 53% of the total UK vaccine doses given
during our study period.4 Moreover, real-life data
from the MHRA (reported using the yellow card scheme for ADRs) has shown
that the Pfizer/BioNTech vaccine had almost double the number of reports
for lymphatic system disorders compared to the Oxford/AstraZeneca
vaccine (22.4 vs . 11.7 per 100,000 doses given
respectively).4-6
Most of the COVID-19 vaccinations during our study period were
nationally prioritised to people ≥ 65 years old. The mean age of
patients with cCVAL in our study was 54.8 years, with only three
patients were 65 years or older. Data from the Pfizer/BioNTech trials
also demonstrated higher incidence and severity of ADRs in younger
participants, with lymphadenopathy reported five times more common in
the 16-55 years age group (0.5%) compared to the >55 years
age group (0.1%).1 Similarly, CVAL was more
frequently reported in younger individuals (18-64 years) following the
first and second doses of the Moderna vaccine (11.6% and 16%
respectively), compared to individuals aged ≥65 years (6.1% and 8.4%
respectively).3 In a case series of 20 female
healthcare workers with cCVAL, Fernández-Prada et
al. 12 reported that 75% of patients (N=15) had
full resolution within 16 days from symptoms onset. In our study, full
clinical resolution was reported within an average of 3.1 weeks from
symptoms onset in more than half of our cohort, and partial improvement
within an average of 8.4 weeks in 40% of patients. Interestingly, half
of our patients were directly referred to our fast-track H&N cancer
clinics within three weeks of symptoms onset.
USS features of COVID-19 vaccine-associated
lymphadenopathy
The role of ultrasonography in the assessment of supraclavicular (level
IV/V) lymphadenopathy is well established. All our patients had USS
within a median of 8 days from referral, and a median of 25 days from
onset of symptoms. There was a significant inverse association between
the timing of the scan and the size of the imaged nodes, possibly
highlighting a time-dependant reactive nature of the nodes. While the
overall impression was of benign nature, some nodes in our cohort showed
abnormal features. Large nodes with increased vascularity and a high S:L
ratio (more rounded) usually indicate abnormality.23Ying et al. recommended that the optimum cut-off value of SAD (S:L
ratio) in the lower neck should be 3-5 mm (0.4-0.5), with a high
specificty and moderate sensitivity.23 Our data
demonstrated that around half of our patients had nodes >5
mm and 40% had S:L ratio >0.5. These findings are in line
with previous reports that demonstrated that CVALs may show abnormal
morphology, and can appear enlarged, rounded, hypoechoeic and with loss
of echogenic fatty hila.8,9,13,20