We report the case of a 20-year old man who developed a transient febrile episode with chills and debilitating headaches accompanied by severe neutropenia, lymphopenia, and mild thrombocytopenia within 24 h after a tick-borne encephalitis (TBE) booster vaccine. The patient resides in Switzerland, which is an area endemic for TBE. Per the recommendations of local health authorities, he received a series of three TBE vaccinations at the age of ten. Ten years later, his general practitioner (GP) administered a TBE booster vaccination (FSME-Immun  CC, Lot. VNR1T04E). Nine hours later he started to feel feverish, experienced chills, joint pain, and severe headaches. Symptoms persisted after self-medication with a combination drug containing acetaminophen, pseudoephedrine, and dextromethorphan. The following day, he presented to his GP because of persistent symptoms. The GP recorded a fever of 39.0  C. Complete blood count (CBC) revealed leukopenia (0.90 x 109/L; range 3.50-10.00) and low platelet counts (99 x 109/L; range 150-450). The patient was referred to our walk-in clinic at the medical outpatient unit. Clinical examination was unremarkable; in particular, there was no injection site reaction, lymphadenopathy, rash, signs of localized infection, or neurological abnormalities. CBC performed 20 h after vaccination revealed mild leukopenia (3.01 x 109/L) as well as thrombocytopenia (115 x 109/L). Forty hours after vaccination, leukocytes were again substantially lower (1.11 x 109/L). In the initial blood draw in our clinic, neutrophils were normal, but with 37% bands (i.e., immature neutrophils; normal range 5.0-15.0) compared to only 52.5% segmented neutrophils (normal range 40.0-70.0). This suggests an increased neutrophil turn-over. The following day, differential blood counts showed severe neutropenia (0.22 x 109/L; range 1.30-6.70) with a left-shift of 6.4%. The patient was lymphopenic on both occasions (0.22 and 0.38 x 109/L, respectively; range 0.90-0.33) (Fig. 1). C-reactive protein (CRP) was only slightly elevated on the first day (11.0 mg/L; range <10), followed by a peak at 55.6 mg/L 48 h post-vaccination. Interleukin-6 (93.4 ng/L; range <7) and ferritin (581 microg/L; range 30-300) levels indicated an acute phase reaction. Tryptase was normal, and the clinical picture was not compatible with a hypersensitivity reaction.
Past medical history revealed exogenic allergic asthma and acne vulgaris, in addition to atopic dermatitis and shingles (single dermatome) at the age of 15 years. He was normal weight (71 kg). Until 4-5 weeks before the current event, the patient was taking low-dose isotretinoin (5 mg every other day) for acne treatment. Therapy was stopped due to good clinical response. Blood counts were regularly checked during the therapy and were always normal, including the most recent one taken 41 days earlier (Fig. 1).
Our initial differential diagnosis included a viral infection, a systemic reaction to vaccination, or transient bacteremia in the context of severe neutropenia. We found no clinical focus of infection. The TBE IgG level was high, with 844 VIEU/mL (positive; >=127) and TBE IgM negative. However, there was no clear evidence for an immune-complex-mediated type III reaction, as complement C3 and C4 serum levels were normal, and there was no relevant local injection site reaction. We recommended supportive treatment as an outpatient with high fluid intake, acetaminophen as needed, and close clinical follow-up. White blood cell (WBC) counts normalized spontaneously within just two days, followed by platelets by day ten. Because of a persistent headache, we performed a brain MRI that excluded meningoencephalitis. All symptoms resolved spontaneously during the following days. TBE-post-vaccination titers four weeks later showed a very high TBE IgG level (>1000 VIEU/mL) and elevated TBE IgM level (2.1 S/CO). Because of the patient's history of shingles at a young age and the current immune-dysregulated event, we completed the work-up with an immunophenotyping, which revealed normal immunoglobulin levels (IgG1-4, IgA, IgM) (Supplementary Table S1), lymphocyte subset counts (NK, CD4+ T cells, CD8+ T cells, B cells), and B cell subsets four weeks after the vaccination (Supplementary Table S2). The case was reported via the 'Regional Center of Pharmacovigilance' to the 'Swiss Agency for Therapeutic Products' (Swissmedic), the national authority of pharmacovigilance.