On June 30, 2018, a 49-year-old woman was admitted to our hospital. Two weeks prior, she underwent functional endoscopic sinus surgery at an ear, nose, and throat (ENT) clinic due to sinusitis. The day after the surgery, she developed a headache, which continued to worsen and was accompanied by nausea and vomiting. She was then admitted to the hospital through the Neurology Emergency Department. Her headache was located frontally, parietally, and occipitally. The visual analogue scale (VAS) score was eight on admission. Neurological examination showed no focal deficits except neck stiffness. Body temperature was 37.4 °C. Ten years earlier, the patient had undergone resection for a pathologically confirmed type B1 thymoma that was accidentally found by chest computed tomography (CT) examination in the outpatient clinic due to cough symptoms.
Head CT showed no abnormality, but inflammation of the paranasal sinuses was observed in the whole bilateral group. Magnetic resonance imaging (MRI) demonstrated abnormal hyperintensity in the cerebral sulci of the bilateral frontal-parietal lobes on a fluid-attenuated inversion recovery sequence with gadolinium enhancement (Fig. 1).
The first lumbar puncture was completed on the day of admission, which revealed 24 mmHg opening pressure. Cerebrospinal fluid (CSF) examination revealed the following: reduced glucose (0.60 mmol/L) and chlorine (116 mmol/L), increased protein (1.01 g/L), and leukocytosis (740 × 106/L; multinucleate cells, 82%), which suggested an infectious aetiology. Routine CSF microbiological examinations (Gram stains, acid-fast stains, ink stains) were negative, and cultures for bacteria (i.e., aerobic bacteria: Escherichia coli, streptococci, staphylococci; anaerobes: Bacillus perfringens, Bacteroides fragilis) and fungi (i.e., Cryptococcus neoformans) were sterile. Leukopenia (white blood count, 1.93*109/L) and neutropenia (neutrophil count, 0.81*109/L) were noted. Serological testing for human immunodeficiency virus (HIV) was negative; anti-neutrophil antibodies (ANCAs) were undetectable. Tests for HIV and ANCA are administered routinely to patients who present with unexplained infection. Intravenous ganciclovir (300 mg i.v. twice a day [q12 h.]), fluconazole (200 mg i.v. once a day [q.d.]), levofloxacin (500 mg i.v. once a day [q.d.]), ceftriaxone (2000 mg i.v. once a day [q.d.]), and vancomycin (1000 mg i.v. twice a day [q12 h.]) were administered empirically but without improvement.
The second lumbar puncture was performed on July 8 and revealed a 23 mmHg opening pressure. CSF examination showed reduced glucose (0.91 mmol/L), increased protein (1.35 g/L), and leukocytosis (300 × 106/L; multinucleate cells, 74%). CSF was sent for next-generation sequencing (NGS). Five days later, UU DNA sequences were identified by NGS analysis; the number of identified sequence reads was 38,289. We added minocycline (100 mg p.o. twice a day [b.i.d.]) to the patient’s therapeutic regimen immediately, as minocycline is particularly efficacious against UU and accumulates at a high concentration in CSF. We retained levofloxacin (500 mg i.v. once a day [q.d.]) and stopped all the other anti-infective treatments (ganciclovir, fluconazole, ceftriaxone, and vancomycin). On July 14, to locate the source of infection, we took a small amount of paranasal sinus mucosa through nasal endoscopy for NGS, and UU was also found (reads were 98). Polymerase chain reaction (PCR) and Sanger sequencing confirmed the UU gene in both CSF and paranasal sinus mucosa samples. The patient's headache improved markedly. On July 19, a repeat lumbar puncture revealed decreased opening pressure (5 mmHg). On CSF examination, cell counts and protein levels were reduced to 46 × 106/L and 0.61 g/L, respectively, whereas glucose and chlorine levels were increased to 1.75 mmol/L and 122 mmol/L, respectively. Leukopenia was still notable on laboratory results (white blood count, 2.65*109/L; neutrophil count, 0.78*109/L). The patient had no neurological deficits and was discharged on July 23. Minocycline (100 mg p.o. twice a day [b.i.d.]) was continued for two weeks after discharge.
According to the severity and rarity of the case, secondary immunodeficiency was suspected. We measured serum immunoglobulin levels and found that all Ig classes were low: IgA, < 0.26 g/L (normal, 0.7–4 g/L); IgG 6.4 g/L (normal, 7–16 g/L); IgM < 0.174 g/L (normal, 0.4–2.3 g/L). Flow cytometry of the patient’s peripheral blood lymphocytes revealed undetectable levels of peripheral B cells (0.0%; reference, 5–18%), CD4-positive T-cell lymphopenia (22.5%; reference, 27–51%), a CD4-positive T-cell count of 754/μL, a CD8-positive T-cell count of 2134/μL, and an inverted CD4-positive/CD8-positive cell ratio (0.4; reference, 0.7–2.8). GS was eventually diagnosed based on thymoma history and the patient's susceptibility to opportunistic infections due to immune deficiency syndrome.
Follow-up evaluation of this GS patient two months after discharge demonstrated good status with normal CSF cell counts and negative findings on NGS of CSF. However, hypogammaglobulinaemia and leukopenia persisted. On August 13, 2021, we conducted a follow-up by telephone; the patient was in good condition except for occasional acute sinusitis and mild cough symptoms, which were relieved by anti-infective therapy every time. She had not acquired any common autoimmune phenomena and had never been treated with immunoglobulin replacement treatment.