FormalPara Key Summary Points

Invasive meningococcal disease (IMD) is rare but life-threatening, posing substantial challenges for clinicians because of the diverse and often non-specific spectrum of presenting clinical features.

We reviewed IMD case reports published from 2011 to 2023 to describe real-life clinical presentations of IMD in newborns, infants, children, and adolescents to help clinicians manage IMD in routine clinical practice.

Approximately one-third of the reviewed cases were in adolescents, and atypical gastrointestinal presentations were observed with serogroup W infections.

Clinicians should at least consider the possibility of IMD in any unwell newborn, infant, child, or adolescent to enable early diagnosis, prompt treatment initiation, and, ultimately, protect these patients from this devastating disease.

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Introduction

Invasive meningococcal disease (IMD) can be devastating, with an overall case fatality rate of 8.3% (range 4.1–20.0%) [1] and long-term physical sequelae and/or neurological sequelae experienced by 10–20% of patients who do not die, including consequences as severe as amputation and hearing loss. The introduction of meningococcal vaccines in national immunization programs (NIPs) and for the immunization of high-risk individuals has enabled great progress in the control and prevention of IMD globally, encompassing protection of the unvaccinated and immunocompromised by passive immunity [2]. The increasing incidence of serogroups W and Y observed globally during the first two decades of the 21st century led to the introduction of multivalent vaccines simultaneously protecting against multiple serogroups [3,4,5]. Currently, the array of licensed meningococcal vaccines includes monovalent vaccines targeting serogroup C and serogroup A, quadrivalent vaccines simultaneously targeting serogroups A, C, W, and Y, and two protein-based vaccines protecting against serogroup B [5]. Inclusion in NIPs, vaccination strategies, and recommendations vary globally [5,6,7]. Although pediatricians’ experience with IMD may vary as a result, the severity of this disease highlights the importance of early diagnosis and prompt antibiotic treatment initiation.

The spectrum of clinical presentation of IMD is diverse, varying from a mild febrile illness to meningitis and sepsis, affecting 30–60% and 20–30% of infected individuals, respectively, with 12% having features of both meningitis and sepsis [8,9,10]. Focalized infections, such as conjunctivitis or septic arthritis, can accompany meningitis and/or sepsis, or present alone [8]. The clinical picture changes rapidly after an incubation period of 3–4 days (range 1–10 days) [9]. The onset of IMD is sudden and the disease can be fatal within 24–48 h after developing symptoms (e.g., fever, vomiting, headache, petechial, or purpuric rash) [8, 9]. Clinical presentation varies and can differ by age, and it is not uncommon for children to be initially misdiagnosed as a result of non-specific signs (e.g., irritability and/or lethargy) [10]. The importance of prompt clinical management in infants and children was highlighted by the substantial burden associated with Neisseria meningitidis infections observed in a large European prospective cohort study of 2844 individuals aged 1 month to 18 years old, where these infections were found to be the cause of 29.9% cases of meningitis, 17.1% cases of sepsis, 30.7% cases of septic shock, 33.8% cases of severe sepsis, and 22.8% of deaths [11].

Known risk factors for IMD include immunocompromised status (e.g., due to genetic complement deficiencies, asplenia, uncontrolled HIV infection, or treatment with eculizumab) [7, 12,13,14], and environmental risk factors, such as household crowding (e.g., college students living in on-campus residences and military recruits in barracks [7]) and routine exposure to N. meningitidis isolates (e.g., laboratory workers) [7, 15]. Carriage is high in adolescents and young adults, mostly as a result of their lifestyle [5]. Nonetheless, most cases of IMD occur in previously healthy individuals, without warning signs [16].

Given the rarity of the disease and the rapid but potentially fatal progression, it is paramount that clinicians maintain awareness of the diverse clinical spectrum of IMD in routine practice [1, 17]. While case reports and case series are limited by their descriptive nature and selection bias, they can be a particularly useful design for rare diseases [18]. Specifically, case reports can be used to highlight learnings from patients with IMD in the real-life clinical setting, including unusual observations, misdiagnoses, and treatment paradigms, with the potential to help clinicians promptly recognize IMD and improve outcomes for these patients [17]. The aim of this narrative review was to collate global case reports describing the diagnosis, clinical presentation, management, and outcomes of IMD cases reported in neonates, infants, children, and adolescents.

Methods

Search Strategy and Selection Criteria

Literature searches were conducted in PubMed and Embase using combinations of terms describing IMD (“Neisseria meningitidis”, “invasive meningococcal disease”) and terms describing pediatric and/or adolescent patients (“infant”, “children”, “paediatric”, “pediatric”, or “adolescent”) and study design (“case report” and “case series”) published between January 1, 2011, and March 9, 2023. The searches included both subject headings and free-text terms. The review included papers published in English, available as full-text electronic articles, and within the scope of this narrative review, that is, related to IMD, describing patients aged ≤ 19 years, and published as case reports or case series. Data were manually extracted (wherever available) on method of sample isolation, isolated serogroup, clinical presentation (defined as meningitis, sepsis, septic arthritis, shock, purpura fulminans, and/or pneumonia), presenting symptoms (e.g., fever, skin rash, lethargy), and clinical complications and outcomes (e.g., death, amputations, seizures); data extraction was documented on a spreadsheet. A study flowchart illustrating the criteria used to identify the reviewed cases is shown in Fig. 1.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Fig. 1
figure 1

Study flowchart. aSearch terms (“Neisseria meningitidis”, “invasive meningococcal disease”) and (“infant”, “children”, “paediatric”, “pediatric”, or “adolescent”) and (“case report” and “case series”). IMD invasive meningococcal disease

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Results

In total, 184 individual pediatric and adolescent patient cases were described in 97 case reports (Fig. 1), including 42.3% reports from Europe, 27.8% from Asia, 13.4% from North America, 10.3% from Oceania, and 3.1% each from South America and Africa (Supplementary Fig. S1).

Sex and Age

Overall, 54.9% of patients were male, 40.2% were female; sex was not clearly reported for 4.9% of patients. Among the 82.6% of patients with known age, 34.2% were adolescents aged 13–19 years (Supplementary Fig. S2A), 27.6% were children aged 1–5 years, 17.1% were children aged 6–12 years, 17.1% were infants aged 1–12 months, and 3.9% were newborns aged 0–28 days. Age was reported as a range for 24 patients in one case series (3 months to 14 years) [19], and eight patients in another series (5 to 46 months) [20].

Sample Isolation and Identification

The predominant sample sites for isolation of N. meningitidis were blood (60.3%) and cerebrospinal fluid (26.6%) (Supplementary Table S1). N. meningitidis was also isolated from synovial fluid (5.4%), aqueous or vitreous humor (1.6%), a conjunctival swab (1.6%), punch biopsy from a purpuric lesion of the skin (0.5%), and cerebral tissue (0.5%). A total of 5.4% reports did not document the clinical samples from which N. meningitidis was isolated.

Serogroup Distribution

Overall, serogroup was reported for 89.1% of patients, with the most common serogroups identified as being W (40.2%), B (31.7%), and C (10.4%) (Supplementary Fig. S2B). Where both age and serogroup were reported (66.3%), serogroup B was the most common among neonates (1.6%), infants (9.0%), children aged 1–5 years (11.5%), and children aged 6–12 years (4.9%); serogroup W was the most reported serogroup among adolescents (17.2%) (Supplementary Fig. S2C).

Clinical Presentation

One or more clinical presentations of IMD (i.e., meningitis, sepsis, septic arthritis, shock, purpura fulminans, pneumonia) were reported for 72.3% of patients. The most common clinical presentation was meningitis (46.6%), followed by sepsis (36.8%), septic arthritis (17.3%), shock (14.3%), and purpura fulminans (12.0%) (Fig. 2; citations provided in Supplementary Table S2). Among the 25 reported cases of septic arthritis, 60.9% were infected with serogroup W [19, 21,22,23,24,25]. Additionally, three patients (13.0%) had septic arthritis due to serogroup Y [26, 27].

Fig. 2
figure 2

Clinical presentations in 133 IMD cases. Multiple clinical presentations may be reported for each patient. The data represent the total number of occurrences of each clinical presentation, with each patient potentially included in multiple sections of the pie chart. IMD invasive meningococcal disease

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Overall, the most reported symptoms were fever (78.1%), vomiting (36.5%), rash (30.7%), and headache (24.1%), with other symptoms including lethargy, neck stiffness, diarrhea, decreased appetite, hypotension, tachycardia, and tachypnea; patients with N. meningitidis joint infections presented with joint swelling, joint pain, and/or a painful limp (citations provided in Table 1). Symptom data stratified by age are presented in Supplementary Table S3.

Table 1 Clinical symptoms in 137 IMD cases
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Atypical clinical presentations with gastrointestinal symptoms were reported in a case series of 15 previously healthy 15–19-year-olds with serogroup W infection identified in England between 2015 and 2016, with seven individuals presenting with a short history of nausea, vomiting, and/or diarrhea [23]. For example, one patient was initially sent home by the general practitioner with a gastroenteritis diagnosis, suddenly deteriorated the following day with rapid progression and death in the accident and emergency department (A&E), following presentation with diarrhea, vomiting, stomach cramps, lethargy, and no skin rash [23]. Another patient was initially sent home with a gastroenteritis diagnosis after presenting to A&E with vomiting, diarrhea, sore limbs, and no skin rash, and died in A&E later the same day [23]. In a larger case series that included 24 patients, 11 individuals had vomiting and/or diarrhea, although only two were thought to have gastroenteritis at their initial presentation [19]. Overall, vomiting and/or diarrhea were reported in 39.3% cases with serogroup W.

Among patients with IMD, 7.6% had immune dysfunction (Table 2). Of these, 78.6% had congenital complement deficiencies and 21.4% had acquired immune deficiencies (14.3% associated with eculizumab treatment; 7.1% had an uncontrolled HIV infection).

Table 2 IMD cases with immune dysfunction
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A total of 4.3% of patients had breakthrough infections, that is, they were infected with a serogroup against which they had previously been immunized (serogroup B, 50.0%; serogroup C, 37.5%; serogroup W, 12.5%) (Table 3). For example, a 16-month-old infant in Spain with serogroup B meningococcal infection had been vaccinated with three doses of the four-component meningococcal serogroup B vaccine (4CMenB), with the last dose 7 months before presentation [28]; a 12-year-old child in Spain with serogroup B meningococcal infection had been fully vaccinated against this serogroup, including two doses of 4CMenB at age 12 years and the second one 5 months before the meningitis episode [28]; an 18-year-old adolescent in the UK with serogroup W meningococcal infection had previously completed the full course of MenACWY vaccination [22].

Table 3 IMD cases who had previously received a vaccine against Neisseria meningitidis
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Among the 16 patients who had previously received a meningococcal vaccine, 37.5% had risk factors for meningococcal infection, including complement deficiency (6.3%), splenectomy (6.3%), treatment with eculizumab (12.5%), poorly controlled HIV infection (6.3%), and a history of recurrent meningococcal septicemia (6.3%).

Clinical Complications and Outcomes

Complications and outcomes of IMD were reported for 92.9% of patients (Table 4). Among these patients, 14.6% died, 5.3% underwent amputations, 3.5% had seizures, 1.2% underwent enucleation for fulminant endophthalmitis, 0.6% had severe neurological deficits, and 0.6% had residual motor weakness. Among the 25 patients who died, 12 (48.0%) were adolescents; serogroup W was identified in 75.0% of the adolescents who died. Two 15–19-year-olds, cases from the UK case series in 2015–2016 are described in more detail in the previous section (Clinical Presentation) [23]. Two adolescents (14 and 17 years old, respectively) who died following a serogroup W infection were identified in China in 2012–2013 and had no history of MenACWY vaccination [29]. Overall, IMD-associated complications in patients who died included acute petrified myocardium, disseminated intravascular coagulation, multiorgan failure, pneumonia, and Waterhouse–Friderichsen syndrome. The outcomes of patients with immune dysfunction are reported in Table 2.

Table 4 Clinical complications and outcomes in 171 IMD cases
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Treatment

Antibiotic treatment was reported for 75.0% of patients (Supplementary Table S4). Among these patients, the most prescribed antibiotic for suspected or confirmed N. meningitidis infection was a third-generation cephalosporin (ceftriaxone, 63.8%; cefotaxime, 19.6%; not specified, 0.7%). Other antibiotic regimens were described in 3.8% of patients, including piperacillin/tazobactam, meropenem, and penicillin (1.4% each), and amikacin (0.7%). The antibiotic administered was not identified for 10.9% of patients, and a further 2.9% of patients suddenly died before antibiotic therapy could be initiated (all because of sudden death before routine diagnosis procedures could be carried out). Regarding the 25 recorded deaths, eight patients died after receiving antibiotics, four did not receive antibiotics, and treatment was not recorded for the remaining 13 patients.

The results of antibiotic sensitivity testing were provided for 38 cases (22.2%). Reduced susceptibility to penicillin antibiotics (penicillin, amoxicillin, amoxicillin/clavulanate, and ampicillin) was reported for 33 isolates (serogroup W, 75.8%; serogroup Y, 9.1%; serogroup B, 9.1%; serogroup X, 3.0%; non-groupable, 3.0%). Reduced sensitivity to quinolone (nalidixic acid [30]) or fluoroquinolone (ciprofloxacin [31, 32]) antibiotics was reported for 7.9% isolates (serogroups B, C, and Y). A total of 10.3% of isolates were reported to be resistant to more than one antibiotic class, including 5.3% of isolates (serogroups B and X) resistant to both penicillin and ciprofloxacin and 2.6% of non-groupable isolates resistant to cotrimoxazole, nalidixic acid, and ciprofloxacin.

The details of additional non-antibiotic therapy were generally not provided, although one report described the first case of successful use of hemadsorption for cytokine removal therapy in a 10-year-old child with meningococcal septic shock and Waterhouse–Friderichsen syndrome [33]. In this patient, hemadsorption therapy was administered within 48 h of them presenting with septic shock, which resulted in a stabilization of hemodynamics and well-controlled hyperinflammation [33]. Other treatments described in reports included administration of vasopressors and/or inotropes (21.2%), mechanical ventilation (19.7%), corticosteroids (19.7%), fresh frozen plasma infusion (15.2%), platelet transfusion (10.6%), antiepileptics (2.1%), and immunoglobulins (2.1%) (Supplementary Table S4).

A total of 11.4% of patients required surgery. Various surgical procedures were described, including craniotomy (19.0%), joint drainage (19.0%), limb amputation (42.9%), insertion of a ventricular drain and decompression of the foramen magnum (4.8%), placement of a ventriculo-peritoneal shunt for hydrocephalus (4.8%), plastic surgery for cutaneous sequelae (4.8%), and ocular enucleation (5.3%).

Discussion

This review of IMD case reports published over the past decade highlights that, despite being rare, IMD continues to pose a threat to the health of children and adolescents. Although no epidemiological inferences can be drawn from the selected case reports, this review provides useful insights into real-life clinical presentations, treatment paradigms, diagnoses, and clinical outcomes, emphasizing the importance of remaining vigilant to the diverse clinical spectrum of IMD, including any atypical presentations.

The case reports reviewed here reflect the diverse clinical features of IMD observed throughout childhood and adolescence, ranging from mild febrile illness with rapid progression to severe systemic disease and potentially life-threatening complications. Across the reviewed case reports, 14.6% of patients died as a result of IMD; however, estimations of fatality rates based on case studies should be interpreted with caution because of limited sample sizes and publication and reporting bias. Previous studies have estimated case fatality ratios ranging from 4% to 20% [1], with mortality reaching up to 50% in patients who do not receive timely treatment [34]. This highlights the severity of IMD and the importance of initiating treatment promptly.

Although no epidemiological inferences can be drawn from the selected case reports, adolescents represented over one-third of the reviewed cases, followed by children aged 6–12 and 1–5 years, with the caveat that there may be some bias due to the age cutoffs. High infection rates have been previously reported in adolescents and infants, with adolescents often being asymptomatic carriers [35, 36]. Risk factors for carriage and transmission include living in college dormitories, having active social habits/participating in nightlife, smoking, and having intimate/sexual contact, emphasizing the importance of prevention by vaccination [37]. The findings that adolescents represented the largest group with IMD in this review, and that 48.0% of the patients who died were adolescents, emphasize the importance of performing large-scale epidemiological studies focusing on this age group to better understand the impact of IMD in adolescents and to inform vaccination policies.

The most reported serogroups in the reviewed cases with available data were serogroup W in adolescents and serogroup B in all other age groups, with serogroups A, C, E, X, and Y also reported. Serogroup E is rare and generally associated with infection in immunocompromised patients [38]. Accordingly, three of the four cases of serogroup E identified here were in patients with known immunocompromised status. Pentavalent vaccines are currently in development, which could offer broad protection against serogroups A, B, C, W, and Y, and serogroups A, C, W, Y, and X [39,40,41].

Clinicians should maintain awareness of the atypical extrameningeal presentations associated with serogroup W (e.g., gastrointestinal symptoms and focal infections), as failure to identify these signs could delay diagnosis and treatment initiation [42]. In a study of 65 cases of unusual meningococcal disease in France, serogroup W was significantly associated with arthritis and with meningococcal pneumonia in 54.5% of patients (particularly those aged > 70 years). Importantly, blood culture was central to identifying the underlying cause of disease [42]. In this review, we identified patients presenting with atypical gastrointestinal symptoms and joint infections; however, it is unclear whether these reports were the result of increased awareness of this association. Other atypical conditions included epiglottitis, Kawasaki disease complicated by macrophage activation syndrome, skeletal dysplasia, and conjunctivitis.

Reports of patients who previously received meningococcal vaccination and subsequently developed IMD were identified. One of the cases included in this review suggested that vaccination prevented severe disease in a patient who had previously received the MenC conjugate vaccine [43]. This 4.5-year-old child developed fulminant ophthalmitis attributed to serogroup C (detected by 16S ribosomal DNA analysis in aqueous humor) despite having bactericidal serum titers. The authors hypothesized that these antibodies prevented the development of meningococcemia and meningitis (microbiological cultures were negative), but did not prevent intraocular infection; however, they prevented severe or fatal consequences associated with IMD [43].

Eight patients (4.3%) who developed IMD were infected with a serogroup for which they had previously been immunized. These included a patient with a complement deficiency, a patient with HIV, a patient with recurrent IMD, and a patient treated with eculizumab. Patients with known immunodeficiencies (e.g., asplenia) remain a high-risk patient population, which should be considered in national vaccination programs and promptly managed by clinicians. Immunosuppressed cases were reported in multiple countries with different NIPs and vaccine recommendations. For example, in one case from Australia, a 5-year-old with complement C7 deficiency was infected with serogroup E [38]. In South Australia, the introduction of a 4CMenB vaccination program demonstrated coverage rates of 91.4% for two doses and 79.4% for three doses in infants, with a two-dose vaccine effectiveness against serogroup B IMD of 94.2% (95% confidence interval [CI] 36.6–99.5) or 94.7% (95% CI 40.3–99.5) in children (depending on the estimation method) [44]. Two-dose coverage rates among those aged approximately 16 years was 69.0%, with no IMD cases reported in adolescents and young adults after implementation of the program [44]. The first real-world evidence of 4CMenB was from the UK, with 87.9% coverage resulting in a 75% reduction in meningitis B in eligible age groups after 3 years in England [45, 46]. No IMD cases with serogroup B infection in immunocompromised patients were identified in the UK in this review.

Where details on antibiotic treatment were provided, patients generally received antibiotic therapy with a third-generation cephalosporin (ceftriaxone or cefotaxime), which is the recommended treatment for IMD [47]. These antibiotics were administered either empirically or following identification of N. meningitidis in clinical specimens. No evidence of resistance to third-generation cephalosporins was reported in the reviewed cases. However, reduced susceptibility to penicillin, ciprofloxacin, cotrimoxazole, nalidixic acid, and ciprofloxacin was observed. Antibiotic resistance has been reported in other studies; for example, in a UK study, out of 4122 IMD isolates, 113 were shown to be penicillin-resistant, five were ciprofloxacin-resistant, two were rifampicin-resistant, and one was cefotaxime-resistant [48]. A recent evaluation of IMD cases submitted to the US Centers for Disease Control and Prevention for whole-genome sequencing identified an emerging strain of ciprofloxacin-resistant β-lactamase-producing N. meningitidis in 33 of 2097 isolates [49]. Although outside the scope of this review, increased monitoring of resistant strains will be key to tailoring treatment.

Case series and case reviews involve a description of the characteristics and outcomes among a group of individuals with a disease over a period of time, without a control group or any randomization. By definition, the objective is to describe the population of interest, without statistically comparing risk across groups, making the case series design neither exhaustive nor comprehensive. Additionally, selection bias typically favors cases of clinical interest, such as those with an unusual underlying condition, unexpected disease course, or severe complications. Nonetheless, case reviews are particularly useful for rare diseases, as demonstrated by the case review highlighting the atypical gastrointestinal presentations in adolescents with serogroup W infections following anecdotal reports in the UK [23]. Limitations specific to this review are its non-systematic nature and the inclusion only of publications where the full text was available in English. The information available in each report was generally limited and, overall, a substantial amount of information regarding the treatment and the clinical course of IMD was missing. Publication bias is also evident in the paucity of cases from South America and Africa and the potential overrepresentation of Oceania.

This review of case reports provides insights into the diverse clinical spectrum of IMD in cases identified in routine practice. It highlights the need for increased surveillance in adolescents and for vaccination programs providing the broadest possible protection against the main disease-causing serogroups. Our findings also reinforce the need for the establishment of a multicenter/national registry system collating data for all IMD cases.

Conclusions

While IMD has become uncommon where vaccination programs have been introduced, infants, children, and adolescents still die from this disease every year. Many of the symptoms are non-specific and onset is rapid, making it advisable to at least consider the possibility of IMD in any unwell newborn, infant, child, or adolescent [17]. High-risk patients should be promptly identified, and treatment initiated immediately [17]. Clinicians should be particularly alert to any atypical extrameningeal presentations (e.g., gastrointestinal symptoms) potentially associated with serogroup W. Although this review highlighted the importance of monitoring the real-life clinical management of IMD, including reports of atypical presentations, large-scale epidemiological studies are required to inform vaccination policies and programs, at a time when meningococcal vaccines against the five most common disease-causing serogroups are available, and combination vaccines are in development.