Invasive Meningococcal Disease due to Nongroupable Neisseria meningitidis—Active Bacterial Core Surveillance Sites, 2011–2016 Open Access

Abstract

Neisseria meningitidis causes meningococcal disease, a serious illness with a 10%–15% case fatality rate. N. meningitidis is classified into serogroups based on its polysaccharide capsule; serogroups A, B, C, W, X, and Y cause most meningococcal disease cases worldwide.

Nongroupable, or unencapsulated, meningococci rarely cause invasive disease; most reports are among people with hereditary complement deficiencies or receiving the complement component inhibitor eculizumab [1, 2]. However, nongroupable cases have also been reported in apparently immunocompetent patients [1, 3, 4]. Reported nongroupable cases vary in severity but can be fatal [2, 3].

In the United States, nongroupable N. meningitidis caused ~8% of meningococcal disease cases reported during 2015–2016 [5, 6]. Risk factors for and characteristics of nongroupable meningococcal disease cases in the United States have not been well described. We therefore conducted a medical record review of nongroupable meningococcal disease cases identified in Active Bacterial Core surveillance (ABCs) sites in 2011–2016 and molecular analysis of isolates to characterize these cases and inform prevention and control strategies.

METHODS

Invasive, culture-confirmed meningococcal disease cases during 2011–2016 were identified through ABCs, an active population- and laboratory-based surveillance system for invasive bacterial infections within the Centers for Disease Control and Prevention’s (CDC’s) Emerging Infections Program. The ABCs surveillance area included California (3 counties), Colorado (5 counties), Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York (15 counties), Oregon, and Tennessee (20 counties).

Nongroupable meningococcal disease cases were defined as isolation of N. meningitidis from normally sterile sites in residents of the ABCs catchment area with isolates that were nongroupable by slide agglutination [7] at the CDC Bacterial Meningitis Laboratory (each nongroupable isolate was tested twice). Isolate capsule polysaccharide synthesis (cps) loci, clonal complex (CC), and sequence type (ST) were characterized by whole-genome sequencing (WGS) [8, 9]. CCs 11, 32, 41/44, and 269 were classified as hyperinvasive [10].

ABCs surveillance staff performed medical record reviews on all culture-confirmed meningococcal disease cases. For nongroupable cases, additional data were abstracted from a re-review of medical and public health records. Staff were not blinded to case serogroup results. Two ABCs sites (New Mexico and Tennessee) did not conduct additional record reviews, as no nongroupable meningococcal disease cases were reported from these sites in 2011–2016. For patients who survived infection and did not have eculizumab use or complement deficiency testing already documented, medical records up to 6 months after initial hospitalization were reviewed when available to identify potential complement testing after discharge. Data were analyzed using Microsoft Excel, SAS 9.4, and a Fisher’s exact test calculator (http://www.langsrud.com/stat/fisher.htm).

Both routine ABCs activities and the expanded medical record review were reviewed in accordance with human research protection procedures and determined to be nonresearch public health surveillance by the CDC and all participating ABCs surveillance sites except for Georgia, where the expanded medical record review was approved by the site institutional review board.

RESULTS

Demographics

Twenty-two nongroupable meningococcal disease cases were identified, representing 5% of meningococcal disease cases reported to ABCs in 2011–2016. The median patient age was 21 years, significantly lower than for other meningococcal disease cases reported through ABCs (all sites), whereas the sex, race, and ethnicity of nongroupable disease patients were comparable to those of other ABCs cases (Table 1).

Clinical Characteristics

All patients had meningitis (63%) and/or bacteremia (86%) (Table 1). Fever (91%), rash (68%), vomiting (68%), and headache (55%) were the most common symptoms; 36% of patients had diarrhea. Three cases were fatal, yielding a 14% case fatality rate, similar to among all other ABCs cases (Table 1). All patients were hospitalized except 1, who died in the emergency department. Among the 19 survivors, the mean hospitalization duration was 9 days; 12 patients were admitted to an intensive care unit. Two patients had sequelae: 1 had seizures, and 1 had finger and bilateral below-knee amputations (Table 1).

Molecular Characteristics

Isolate cps loci were characterized to understand the genetic basis of the nongroupable phenotype. One isolate had a capsule null locus (cnl); the remaining isolates were assigned to genogroups B, C, E, or Y based on serogroup-specific genes (Table 1). Four isolates had no cps locus mutations despite absent capsule expression. Two genogroup B isolates had a phase variable off capsule polymerase allele as the only detected cps mutation, 3 isolates had insertion element 1301 (IS1301) within the cps locus, 5 had internal stop codons and/or truncated cps genes, and 8 were missing 1 or more cps genes (Supplementary Table 1).

The 22 isolates belonged to 19 STs and 10 CCs; CC was unassigned for 1 isolate (Supplementary Table 1). Six (27%) isolates belonged to hyperinvasive CCs (2 CC11 and 4 CC41/44), significantly fewer than among all other ABCs cases (Table 1). Symptoms were not associated with isolate genogroup or CC.

Epidemiologic Characteristics

Three patients were taking eculizumab for PNH (2) or aHUS (1; 14%), significantly more than among all other ABCs cases (Table 1). No eculizumab recipients had documented receipt of antibiotic prophylaxis for meningococcal disease. Information on complement deficiency diagnosis or complement deficiency testing that included terminal complement components was available for 4 additional nongroupable cases. All complement deficiency testing was initiated after meningococcal disease onset. Three cases had physician-diagnosed C7 (1), C6 (1), or unspecified complement deficiency (1). The final patient had a CH50 level ~70% below the lower limit of the reference range, which has been observed in patients with complement C9 deficiency [11]; however, no diagnosis or additional complement testing results were identified. The C6-deficient patient also had HIV (viral load >10 million/mL). Both the C6- and C7-deficient patients reported previous episodes of bacterial meningitis (1 meningococcal, 1 unknown organism) within the past 3 years. Four additional patients had other underlying conditions, including 1 with asplenia and 1 with an intraoperative CSF leak (Table 1). Of the 3 patients who died, 1 had asthma; the others had no identified underlying conditions.

Three patients (14%) were attending college (Table 1); 1 lived off-campus and 2 on-campus. Another patient was a military barracks resident, and 2 additional patients, including the patient with HIV, were men who have sex with men (MSM). Two patients, 1 with unspecified complement deficiency and 1 without documented complement testing, had a family history of meningococcal disease. Thirteen (59%) patients had received quadrivalent serogroup A, C, W, Y meningococcal vaccine before disease onset; however, only the military barracks resident had documented receipt of serogroup B meningococcal vaccine (1 dose) (Table 1).

Six of 8 (75%) patients with isolates missing capsule genes had eculizumab use, complement deficiency, or another serious medical condition, compared with 4 of 14 (29%) of the remaining cases and 0 of 4 (0%) cases with no capsule operon mutations; however, these differences were not significant (P = .07 and .09, respectively, Fisher’s test). No other potential associations were observed when patient clinical or epidemiologic characteristics were stratified by isolate cps characteristics (data not shown). Two of the 3 fatal cases were caused by isolates with missing capsule genes; the third was caused by a phase variable off genogroup B isolate.

DISCUSSION

The nongroupable cases in this chart review had a case fatality rate, presentation, and risk of sequelae comparable to those for meningococcal disease caused by serogroupable strains (Table 1) [12]. Collectively, these cases demonstrate that although nongroupable meningococci are an uncommon cause of illness, they can cause serious invasive disease.

Although all nongroupable isolates were tested twice by slide agglutination to confirm nongroupable phenotype, 4 isolates had no cps locus mutations, and 5 had only phase variable off mutations or IS1301 insertion, both of which are potentially reversible [13]. It is possible that some of these strains may have expressed capsule while causing invasive disease or may have expressed capsule in vitro at a level undetectable by slide agglutination. However, 2 isolates with IS1301 insertions as the only cps locus mutations were genogroup E, which infrequently causes invasive disease even when expressing capsule. Furthermore, most cases were caused by strains with cps mutations unlikely to be readily reversible, including 8 isolates missing 1 or more capsule locus genes. Clinical and epidemiologic characteristics were similar among patients with disease caused by strains with reversible vs less reversible cps mutations, but the small number of cases limited power to detect differences.

All 4 patients with documented complement deficiency testing had either a diagnosed complement deficiency (3) or low CH50 results (1). Three additional patients were taking eculizumab. Terminal complement deficiency is a known risk factor for disease due to nongroupable meningococcal strains [1, 2]. Unfortunately, as most cases lacked complement testing results, it is unclear how many cases may be attributable to this risk factor. The prevalence of complement deficiency among groupable meningococcal disease cases in the United States is also unknown. The American Academy of Pediatrics suggests that physicians consider evaluating meningococcal disease patients for complement deficiency [12], but it is unclear how often such evaluation takes place. More routine complement testing for meningococcal disease patients, particularly those with nongroupable meningococcal disease, would both promote appropriate vaccination for patients and their families, who may be at risk of recurrent disease, and help define the contribution of this risk factor to meningococcal disease incidence in the United States.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Acknowledgments

We thank the CDC and site ABCs surveillance staff, including Kari Burzlaff, Susan Brooks, Christine Lees, Erin Parker, Jean Rainbow, Stephanie Thomas, Amy Tunali, Rachel Wester, and Daniel Wurm for assistance with medical record reviews and Brenda Barnes, Terresa Carter, Anise Elie, Caroline Graber, Gail Hughett, Carmen Marquez, Terri McMinn, Ashley Moore, Glenda Smith, and Nancy Spina for collection of routine ABCs surveillance data. We also thank the members of the CDC’s Bacterial Meningitis Laboratory for isolate testing.

Financial support. This work was supported by the United States Centers for Disease Control and Prevention Emerging Infections Program cooperative agreement (CK17-1701), which funded Active Bacterial Core surveillance system sites.

Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Potential conflicts of interest. Dr. Harrison has served as a consultant to Merck, Sanofi Pasteur, Pfizer, and GSK. The other authors have no conflicts of interest to report. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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