Introduction

Neisseria cinerea is a gram-negative, oxidase-positive organism classified as a nonpathogenic bacterium. It is considered a commensal bacterium capable of colonizing the oropharyngeal and upper respiratory tracts, and although it does not typically cause disease in humans [1, 2], it is a very infrequent cause of invasive disease, including lymphadenitis, peritonitis, proctitis, pneumonia, conjunctivitis, and ophthalmia neonatorum [2,3,4,5,6]. Cases of bacteremia involving this organism are quite uncommon, with only seven previously reported cases in the literature [7,8,9,10,11,12]. We present a case of Neisseria cinerea bacteremia in a patient with a history of atypical hemolytic uremic syndrome associated with end-stage renal disease and maintained on chronic eculizumab therapy. It is the eighth reported case of Neisseria cinerea bacteremia. To our knowledge, it represents the first case in a patient receiving eculizumab.

Case report

A 38-year-old Caucasian woman with a history of postpartum atypical hemolytic uremic syndrome (aHUS) resulting in end-stage renal disease and necessitating chronic hemodialysis (HD) presented to the Western Pennsylvania Hospital Emergency Department in January of 2017 with an abrupt onset of subjective fever, chills, and rigors while receiving HD. Upon arrival, her fevers and chills had abated. She denied acute respiratory, cardiovascular, or gastrointestinal symptoms. She denied new rashes and had no ear, nose, or pharyngeal complaints.

In addition to her diagnoses of aHUS and end-stage renal disease, she also had a past medical history significant for hepatitis C related to remote intravenous drug use. With respect to her diagnosis of aHUS, she presented in May 2015 complaining of severe abdominal pain. Laboratory investigation revealed a hemoglobin of 6.1 g/dL (reference range [ref] 12.3–15.3), a platelet count of 3200/mm3 (ref 145,000–445,000), an LDH of 1012 (ref 110–216), and a serum haptoglobin less than 10 mg/dL (ref 16–200). Three to five schistocytes per high-power field were noted on her peripheral blood smear. She was found to have acute kidney injury with a creatinine of 1.93 and a fractional excretion of sodium of 1.4. A renal ultrasound was unrevealing. A renal biopsy revealed the typical changes of glomerular thrombotic microangiopathy, confirming the diagnosis of aHUS. The diagnosis of aHUS was made within 30 days of an elective abortion, qualifying her for the designation of postpartum aHUS. Her renal function deteriorated further, necessitating the initiation of hemodialysis. She received her first infusion of eculizumab prior to hospital discharge and has remained continuously on biweekly eculizumab therapy since that time. She ultimately progressed to dialysis-dependent end-stage renal disease and underwent creation of a left brachio-basilic fistula with transposition of the basilic vein in October 2015.

She had no recent travel and denied recent sexual activity. She lived alone at home with her cats and dogs. One of the cats did scratch her on the shoulder area several weeks prior to the onset of symptoms, but she did not develop a rash or lymphadenopathy. She had no residual sequelae from this incident. She had previously received two doses of both the meningococcal serogroup B vaccine and the quadrivalent meningococcal vaccine following her aHUS diagnosis in preparation for complement-inhibitory therapy.

Her vital signs revealed a heart rate of 57 beats per minute, a respiratory rate of 18 breaths per minute, and a blood pressure of 112/82 mmHg. Her left upper extremity arteriovenous fistula (AVF) had minimal warmth and very mild tenderness to palpation. There was no significant swelling, fluctuance, or erythema. The remainder of an extensive physical examination was unremarkable. Her peripheral white blood cell count was 7290 cells/mm3 (ref, 4400–11,300) with a normal differential. Three sets of blood cultures were obtained via peripheral blood draw. She was evaluated by the general surgery as well as nephrology teams, and both services did not believe that her AVF was infected. As there was little clinical concern for an active, systemic bacterial infection, she was discharged to home; however, all three sets of blood cultures were subsequently flagged for growth by the VITEK 2 instrument. The first set revealed growth in 1.01 days in both the aerobic and anaerobic bottles. Gram staining revealed a gram-negative coccobacillus. She was instructed to return to the hospital for further evaluation and management and was placed empirically on cefepime 1 g every 24 h. The organism was identified by the VITEK 2 instrument as Neisseria cinerea with 99% probability. Repeat blood cultures performed 2 and 4 days after the initial sets were all without growth. The patient remained on cefepime, but the dosing was adjusted for ease of administration to 2 g after each HD session. Kirby–Bauer disk diffusion susceptibilities revealed zone of inhibition sizes of 31 mm for ampicillin–sulbactam, 38 mm for cefepime, 37 mm for gentamicin, and 35 mm for piperacillin–tazobactam. As there are no interpretive criteria from the Clinical and Laboratory Standards Institute (CLSI) for this organism, we extrapolated from the CLSI interpretive criteria for Neisseria gonorrhea, for which a zone of inhibition size of ≥ 31 mm for cefepime is considered susceptible.

An ultrasound with Doppler evaluation of the AVF in her left upper extremity did not reveal a drainable fluid collection. The patient continued to remain afebrile without a leukocytosis or other localizing complaints. She completed 2 weeks of therapy with cefepime without incident. At the completion of therapy, she was placed on indefinite oral penicillin VK 1000 mg twice daily as prophylaxis, which she has tolerated well.

Discussion

Eculizumab, a recombinant humanized monoclonal antibody, binds to the C5 complement protein with high affinity and blocks the generation of the pro-inflammatory and cytolytic proteins, C5a and C5b-9, respectively [13]. The drug is approved by the United States Food and Drug Administration (FDA) for the treatment of both paroxysmal nocturnal hemoglobinuria and aHUS [14, 15]. As a consequence of its inhibition of terminal complement, patients receiving eculizumab are at risk of infections caused by encapsulated organisms, including invasive Neisserial infections [16]. Patients who are treated with eculizumab have a 2000-fold increased risk of developing infection due to Neisseria meningiditis, and severe and fatal meningococcal infections have been reported in persons receiving the drug [16,17,18]. Thus, eculizumab carries an FDA black-box warning for the risk of infections due to Neisseria meningiditis [16]. Prescription of the agent is restricted to physicians who have enrolled in a risk evaluation and mitigation strategy required by the FDA [16]. When possible, meningococcal vaccination should be performed at least 2 weeks prior to the initiation of eculizumab therapy [17]. Patients being managed with eculizumab should receive a conjugated quadravalent meningococcal vaccine to protect against serogroups A, C, W, and Y, as well as a serogroup B meningococcal vaccine [16, 17].

Despite appropriate vaccination, recent reports demonstrate that patients may still develop invasive meningococcal disease, especially from non-groupable Neisseria meningiditis [18]. Neisseria cinerea is described as a nonpathogenic species [1, 2]. While it is able to colonize the upper respiratory tract of humans, development of invasive infection with this bacterium is quite rare. With the inclusion of our patient, only eight cases of Neisseria cinerea bacteremia have been reported (Table 1). Patients with complementopathies/hypocomplementemia are known to have an increased risk of infections with encapsulated organisms due to diminished capacity for complement-mediated eradication of circulating bacteria [17]. We suspect that the eculizumab-induced functional complement deficiency was the main factor responsible for the patient developing bacteremia with an organism that is typically considered nonpathogenic.

Table 1 Documented cases of Neisseria cinerea bacteremia
Full size table

Meningococcus expresses factor H binding protein (fHbp), a surface-exposed lipoprotein which recruits the inhibitory complement-regulatory protein factor H (CFH) to the microbial surface, thereby shielding the organism from complement-mediated opsonophagocytosis and bacteriolysis [19]. It has recently been demonstrated that Neisseria cinerea is also capable of expressing fHbp and thus binds CFH with a similar affinity as meningococcal fHbp [19]. This immune-escape mechanism of the organism, coupled with eculizumab-induced inhibition of opsonophagocytosis and cell lysis, provides biologic plausibility as to how a nonpathogenic commensal organism would be capable of causing a serious, invasive infection in a patient such as ours. Lavender and colleagues found that immunization with a serogroup B meningococcal vaccine is able to stimulate serum bactericidal activity against N. cinerea, which is directed against fHbp [19].

Despite appropriate vaccination, patients treated with eculizumab have developed breakthrough meningococcal infections [18]. A recent study by Konar and Granoff examined the effect of eculizumab on the killing of N. meningiditis by whole blood from patients who had been immunized with a quadrivalent meningococcal vaccine as well as a serogroup B vaccine [20]. They used an ex vivo whole-blood model which incorporated both serum bactericidal activity and opsonophagocytosis, mechanisms by which serum antibodies offer protection against invasive meningococcal disease. Impaired opsonophagocytic killing by serum from immunized patients was observed in the presence of eculizumab. In very elegant studies, the authors were able to attribute this to the inhibition of C5a, a complement factor critically involved in the upregulation of phagocytosis [20].

As prior receipt of serogroup B vaccination by our patient should have prevented the development of invasive N. cinerea infection, we postulate that it is this impaired opsonophagocytic killing due to eculizumab which allowed our patient to develop bacteremia with this commensal organism. Physicians should maintain a heightened awareness for Neisseria infections in patients receiving eculizumab despite having been vaccinated. A clear understanding of the key mechanisms responsible for vaccination failure will be necessary to better manage the overall risk of infection in these patients.