Emerging Meningococcal B Meningitis in Japan: A Case Report of a 50-Year-Old Japanese Man with Diabetes

Introduction

Neisseria meningitidis (N. meningitis) is a gram-negative diplococcus with a diameter of 0.6 to 0.8 μm. Based on the structure of their capsular polysaccharides, there are 12 distinct serogroups of this organism, but it is mainly 6 serogroups – A, B, C, X, Y, and W – that are implicated in the development of invasive meningococcal disease (IMD) [1]. When an infection caused by N. meningitidis develops, it can rapidly progress within 24 to 48 hours, leading to meningitis or septicemia, and can be a severe disease with the potential to be fatal, with a mortality rate of about 10–15% [2]. The incubation period of meningococcal disease is typically 3 to 4 days, with a range of 1 to 10 days. N. meningitis colonizes the nasopharynx of healthy individuals and can be transmitted through droplets from carriers or patients. Explosive epidemics with incidence rates of up to 1000 cases per 100 000 inhabitants have been reported, particularly in sub-Saharan Africa. Meningococcal infections in Japan had more than 4000 reported cases annually around the time following World War II, then there was a significant decline in meningococcal cases, with fewer than 100 cases reported annually since 1970, and consistent reports of 30 to 40 cases of invasive meningococcal infections each year in Japan, where the meningococcal meningitis vaccine is not included in routine vaccination [3]. According to the National Epidemiological Surveillance of Infectious Diseases, meningococcal meningitis is rare in Japan; however, when outbreaks do occur, they predominantly involve domestically infected cases rather than those contracted overseas. However, as the vaccine for serogroup B is not approved in Japan, treatment strategies are needed. This report presents a case of serogroup B meningococcal infection in a healthy man in his 50s with no risk factors.

Case Report

A 55-year-old man with a history of diabetes mellitus was transferred to our emergency department from another hospital for suspected meningitis management. Four days before admission, he had close contact with a Japanese colleague who had complained of upper respiratory symptoms. Three days before admission, he developed a sore throat. Two days before admission, he experienced a fever of 38°C, without other symptoms. The day before admission, the patient collapsed at home and was taken to another hospital by ambulance. Given the suspicion of bacterial meningitis, he was then transferred to our facility for further management. His medical history included diabetes mellitus, with no known allergies or history of surgeries. The vaccination history of the patient was only the COVID-19 vaccine. Professionally, he works with stage props for events and only travels within the country. He did not have contact with foreigners. His current medications included metformin, canagliflozin, Semaglutide, and gliclazide. Upon arrival, vital signs were taken, revealing a Glasgow Coma Scale score of E3V1M5, temperature of 38.3°C, blood pressure of 159/108 mmHg, pulse of 116 bpm, SpO2 of 98%, and a respiratory rate of 28/min. Physical examination showed no obvious injury but did note neck stiffness, no Brudzinski and Kernig signs, no jaundice, no lymphadenopathy, normal breath sounds, and normal cardiac auscultation. Petechiae were observed on the right eyelid, bilateral ankles, and knees. Blood tests indicated a white blood cell count (WBC) of 23×103/μL [normal range: 33×103–86×103] (neutrophils 90%) [normal range: men 45.2–68.8, women 49.7–72.7], hemoglobin of 15.0 g/dL [normal range: man 13.7–16.8, woman 11.6–14.8], and platelets of 205×103/μL [normal range: 158×103–348×103/μL]. Biochemical tests showed total protein of 7.6 g/dL [normal range: 6.6–8.1], albumin of 3.8 g/dL [normal range: 4.1–5.1], blood urea nitrogen of 27.4 mg/dL [normal range: 8–20], creatinine of 1.58 mg/dL [normal range: man 0.65–1.07, woman 0.46–0.79], total bilirubin of 1.3 mg/dL [normal range: 0.4–1.5], alkaline phosphatase of 78 U/L [normal range: 106–322], lactate dehydrogenase of 202 U/L [normal range: 124–222], aspartate aminotransferase of 21 U/L [normal range: 13–30], alanine aminotransferase of 26 U/L [normal range: man 10–42, woman 7–23], gamma-glutamyl transferase of 33 U/L [normal range: men 13–64, women 9–32], creatine kinase of 100 U/L [normal range: men 59–248, women 41–153], sodium of 137 mEq/L [normal range: 138–145], and glucose of 440 mg/dL [normal range: 73–109]. C-reactive protein was 43.2 mg/dL [normal range: <0.14]. Cerebrospinal fluid (CSF) analysis revealed an opening pressure of 26 cmH2O [normal range: 7≤ CSF ≤18], a cloudy appearance, cell count of 5362 μL [normal range: ≤5] with a predominance of polymorphonuclear cells (94.8%), glucose of 4 mg/dL, and protein of 968 g/dL [normal range: ≤45]. CSF Gram stain showed gram-negative diplococci (Figure 1), while the latex agglutination test (Pastorex Meningitis®, Bio-Rad, California, U.S.) for serogroups A, B, C, and Y/W was negative. The multiplex polymerase-chain reaction (PCR) (BioFire® FilmArray® Meningitis/Encephalitis (ME) Panel, bioMérieux, Marcy-l’Etoile, France) returned positive results for N. meningitidis and parechovirus (PeV). The brain and chest computed tomography (CT) scans were normal. Brain magnetic resonance imaging (MRI) revealed high signal intensity in the meninges (Figure 2), leading to a diagnosis of meningococcal meningitis. The patient was treated with ceftriaxone (CTRX) 2 grams every 12 hours and underwent endotracheal intubation due to an altered mental status. On Day 5 of admission, the patient showed no signs of seizures, and his fever had subsided. An attempt at extubation was made; however, re-intubation was performed due to laryngeal edema and vocal cord dysfunction. On Day 8, spinal fluid culture turned negative, while N. meningitisdis was detected with serogroup B by the PCR and genetic type ST-2057 by the PCR followed by the sequencing at National Institute of Infectious Diseases. A tracheotomy was also conducted that day, and the patient was successfully weaned from the ventilator. Persistent fever warranted a contrast-enhanced CT scan on Day 13, which revealed multiple non-contrasting areas in both kidneys, indicative of potential abscess formation. On Day 20, an MRI scan showed no evidence of a brain abscess, which allowed for a reduction in the dosage of CTRX to once daily (Figure 3). On Day 27, a follow-up contrast-enhanced CT scan assessed the renal lesions, showing no significant change, thus CTRX treatment was discontinued. Once the patient’s breathing stabilized, the tracheostomy tube was removed and the stoma (tracheal opening) was allowed to close. At the time of discharge on Day 30, he had dizziness, headache, left hearing loss, and tinnitus, and 2 weeks after discharge, symptoms other than dizziness were still present. During the medical examination, the emergency department staff, due to the potential risk of COVID-19, donned N-95 masks and gowns. Moreover, they had been immunized with Menactra® (MenACWY meningococcal conjugate vaccine by Sanofi) during the 2020 Tokyo Olympics, which protects against serotypes A, C, Y, and W. However, taking into account N. menigitidis serogroup B, all staff at risk of exposure were also given prophylactic oral ciprofloxacin 300 mg 2 tablets, and none of them developed an infection.

Discussion

We experienced a case of meningococcal meningitis in a Japanese man with diabetes. Gram staining of the CSF revealed gram-negative diplococci, although cultures were negative. Subsequent identification by the National Institute of Infectious Diseases confirmed the presence of N. meningitidis, specifically serogroup B and genetic type 2057. In Japan, approximately 30 cases of meningococcal infections are reported annually, with serogroup B being the second most common after serogroup Y [4]. Over the past decade, N. meningitidis strains of clonal complex 2057 have become predominant among Japanese serogroup B cases and have not been identified in any other country [5]. Given the absence of any overseas travel history, the detection of a domestic strain of meningococcus in this patient was possible. The patient had been in contact with ill Japanese individuals who had not been tested for N. meningitidis colonization.

IMD can progress very rapidly, and in cases that follow a fulminant course, symptoms can include a sudden expansion of purpura, a decrease in blood pressure, and multi-organ failure. In the present case, blood cultures were negative, and no multiple organ dysfunctions were noted in this patient.

The sensitivity of CSF cultures for meningococci is known to be low, and the utility of PCR has been demonstrated [6]. In this case, although the CSF samples were not stored in a cold place and could be applied to the blood agar medium immediately after collection, the organism was not detected. The Infectious Diseases Society of America (IDSA) guidelines [7] recommend third-generation cephalosporins for bacterial meningitis caused by meningococci. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines also advocate the use of third-generation cephalosporins until susceptibility test results are available, especially in regions with expected penicillin resistance [8]. In vitro studies have shown that CTRX is effective [9–11]. Penicillin resistance is common in Japan [12], and susceptibility testing was not possible, so the administration of CTRX was continued. The patient did not experience any clinical worsening for over 7 days.

Multiplex PCR of the spinal fluid in this patient also detected PeV other than N. meningitidis. PeV are non-enveloped, single-stranded, ribonucleic acid viruses belonging to the Picornaviridae family, and are in the same taxonomic family as enteroviruses. There are 4 different species of this virus, but only PeV-A has been associated with disease in humans. PeV-A also has many different genotypes, including PeV-A3, which is the genotype most strongly associated with severe disease presentation [13]. In Japanese reports, Parechovirus infections are most commonly detected as types 1 (PeV-A1) and 3 (PeV-A3) [14]. PeV-A3 is known to cause gastroenteritis and respiratory infections in children older than 3 months, but it can lead to sepsis and meningoencephalitis in newborns and early infants under 3 months, sometimes with fatal outcomes [15]. In adults, it is known to cause epidemic myalgia [16]. However, central nervous system infections in adults are rare, and in a study of 6175 people in the Netherlands, there was only 1 reported case [17]. Cases have been reported in cancer patients [18]. In our case, the patient had a co-infection with bacterial meningitis, but no other case report was found on adult patients with only diabetes mellitus complications having PeV infection along with bacterial meningitis, which makes our case very valuable.

There are reports that the mortality rate of meningococcal meningitis in Japan is 15% [3], which is roughly the same as international reports [2]. The age distribution in Japan shows that two-thirds are below 50 years of age, similar to reports from other countries where the disease also affects younger populations [19]. Given the high risk of mortality across all age groups, there is a need for an effective meningococcal vaccination program. The Centers for Disease Control and Prevention (CDC) recommends 2 types of meningococcal vaccines: MenACWY and MenB [20]. While the MenACWY vaccine was approved in Japan in 2015, there is currently no approved MenB vaccine. In Japan, MenACWY vaccines are recommended for individuals with conditions such as asplenia, splenectomy, complement deficiency, HIV infection, and individuals receiving eculizumab for conditions like nocturnal hemoglobinuria, myasthenia gravis, neuromyelitis optica, and atypical hemolytic uremic syndrome. However, there have been reports of patients on eculizumab contracting serogroup B meningococcal disease [21], highlighting the urgent need for a MenB vaccine. Given the Food and Drug Administration (FDA)’s approval of the meningococcal groups A, B, C, W, and Y vaccine (PENBRAYA™; Pfizer), it is anticipated that this vaccine will also be expected in Japan. In our case, ciprofloxacin prophylaxis following exposure to N. meningitidis was administered as a precautionary measure. According to the CDC, antimicrobial prophylaxis should be administered to healthcare personnel who have been exposed to N. meningitidis, irrespective of vaccination status [22]. For prophylactic oral regimens, the CDC recommends Rifampin, Ceftriaxone, Ciprofloxacin, and Azithromycin. In Japan, all of these options exhibit a susceptibility greater than 90%, which is considered favorable. In our cases, no one developed the N. menigitidis infection. However, Amoxicillin and Rifampin, which can be administered orally, are preferred choices [12].

Conclusions

We encountered a case of meningococcal meningitis in Japan caused by the unique ST-2057 meningococci, without any history of overseas travel. Due to low culture sensitivity, the necessity for CSF multiplex PCR was considered. Given the rising incidence of serogroup B meningococcal meningitis in Japan, the introduction of the MenB vaccine or approval of a vaccine supporting the 5 serogroups is deemed necessary. For post-exposure prophylaxis, oral penicillin or Rifampin is considered suitable due to the susceptibility profile of meningococcus in Japan.