Retrospective analysis of the etiology, clinical characteristics and outcomes of community-acquired bacterial meningitis in the University Infectious Diseases Centre in Lithuania

Community-acquired bacterial meningitis (CABM) is an impactful disease with substantial mortality and morbidity worldwide [1].

Today, CABM is usually caused by Streptococcus pneumoniae, Neisseria meningitidis and Listeria monocytogenes and appears with an estimated annual incidence of 0.6–4 cases per 100,000 adults. Despite substantial improvement in patient care, CABM remains a severe disease with a high risk of complications that may lead to death or severe sequelae [2‐6]. Consequently, the etiology, clinical characteristics, treatment, outcomes and predictors of poor prognosis must be assessed regularly.

The highest invasive meningococcal disease notification rates in Europe were observed over the last 5 years in Lithuania (1.8 to 2.6 notifications per 100,000 population), as defined by the European Centre for Disease Prevention and Control (ECDC) surveillance data report for 2017 [7]. This high notification rate led to routine infant vaccination for meningococcus B, with the four-component capsular group B meningococcal vaccine (4CMenB) introduced into the national routine immunization program in July 2018.

The aim of this study was to identify the distribution of etiological agents and their relationship with clinical characteristics, treatment and outcomes in a cohort of university hospital patients with CABM.

During the study period, 167 patients were diagnosed with CABM, 159 patients were included, 8 cases excluded due to missing medical records. Among included patients, all were white, 82 (51.6%) were male, and the median age was 36 years (IQR 24–56). Microbiologically confirmed causative agent was identified in 80 patients (51.3%). The etiology was predominated by N. meningitidis in 55 patients (34.6%), S. pneumoniae in 15 patients (9.4%), and L. monocytogenes in 5 patients (3.1%). Among 55 N. meningitidis strains, serotype B was identified in 47 (85%), serotype C was identified in 1 (2%), and for the remaining 7 (13%), the serotype was not identified (Table 1). No clusters of meningococcal disease were determined during the study period.

N. meningitidis was identified in 55 patients: only in the CSF in 28 (50.9%) and in both the CSF and the blood cultures of 27 (49.1%) patients. S. pneumoniae was identified in 15 patients: only in the CSF culture in 4 (26.7%) patients and in both the CSF and the blood cultures in 11 (73.3%) patients. L. monocytogenes was identified in 5 patients: only in the CSF culture in 2 (40.0%) patients and in both the CSF and the blood cultures in 3 (60.0%) patients. Other etiological agents were S. aureus in one patient (in CSF and blood cultures), S. pyogenes in one patient (in CSF and blood cultures) and H. influenzae in three patients (all identified only in CSF culture). We less frequently defined the cause of bacterial meningitis in patients who had received antibiotics prior to hospital presentation than in those who had not: no organism was cultured in 59 (75%) patients with prior antibacterial treatment compared to in 20 (25%) patients who had not received antibiotics out of 79 patients with meningitis of unknown origin, p = 0.009.

The sex of patients with CABM was similar according to the etiological agent (female/male ratio 28/27 in the N. meningitidis group vs. 7/8 in the S. pneumoniae group vs. 4/1 in the L. monocytogenes group; p = 0.155). Patients with N. meningitidis meningitis were significantly younger: median age 28 years (IQR 21–50) vs. 49 years (IQR 40–64) in the S. pneumoniae group vs. 54 years (IQR 37–81) in the L. monocytogenes group; p = 0.155. The most common clinical symptoms at presentation were headache, reported by 134 patients (84.3%), followed by neck stiffness in 128 patients (81.0%), fever ≥38 °C in 109 patients (68.6%) and nausea in 88 patients (55.3%). The clinical triad (neck stiffness, altered mental status and fever) was present in 94 (59.1%) patients. The presence of the clinical triad was not associated with the causative agent: 38/55 (69.1%) in the meningococcal meningitis group, 6/15 (40%) in the pneumococcal meningitis group, and 3/5 (60%) in the L. monocytogenes meningitis group; p = 0.1066. The presence of hemorrhagic rash was the most common symptom in the meningococcal meningitis group, 36 (65.5%) cases, with 31 (39.2%) cases among unknown-origin meningitides and no cases in the pneumococcal, L. monocytogenes and other meningitis groups, p < 0.001. Coexisting conditions and comorbidities were similar in all groups stratified by the causative agents: 30 (55%) in 55 episodes of meningococcal meningitis, 13 (87%) in 15 episodes of pneumococcal meningitis and 3 (60%) in five episodes of listerial meningitis (p = 0.0625). Two of 5 L. monocytogenes meningitis cases occurred in adults under 50 years without specific risk factors (Table 2).

We observed a median CSF white cell count of 1706.34 cells per μl (IQR 160.83–5120.0), a median CSF protein of 2.76 g/l (IQR 1.23–5.44) and a median CSF glucose of 2.1 mmol/l (IQR 0.30–3.20). The highest CSF white cell count was in the other (H. influenzae – 3 patients, S. aureus – 1 patient, S. pyogenes – 1 patient) meningitis group, and the lowest was in the L. monocytogenes meningitis group. The median CSF white cell count was 3968.16 cells per μl (IQR 1021.33–5290.75) in the other meningitis group, 1706.67 cells per μl (IQR 143.30–7381.33) in the N. meningitidis group, 2805.0 cells per μl (IQR 396.90–5333.33) in the S. pneumoniae group and 225.0 cells per μl (IQR 102.50–592) in the L. monocytogenes group, but no significant difference was found (p = 0.227). The highest CSF protein level was in the other meningitis group, and the lowest CSF glucose level was in the N. meningitidis and S. pneumoniae groups. The median CSF protein level and the median CSF glucose level were 6.55 g/l (IQR 3.48–89.50) and 1.80 mmol/l (IQR 0.30-NA) in the other meningitis group, 4.10 g/l (IQR 1.47–6.54) and 0.55 mmol/l (IQR 0.30–2.79) in the N. meningitidis group, 3.91 g/l (IQR 2.58–6.14) and 0.55 mmol/l (IQR 0.30–3.70) in the S. pneumoniae group, and 2.29 g/l (IQR 0.94–5.06) and 1.22 mmol/l (IQR 0.67–2.40) in the L. monocytogenes group; p = 0.013 and p = 0.007, respectively. The highest serum white blood cell (WBC) count was noted in the S. pneumoniae group. The median WBC count was 19.52 x10e9/l (IQR 14.06–25.48) in the S. pneumoniae group, 18.30x10e9/l (IQR 14.20–25.70) in the N. meningitidis group, and 8.40x10e9/l (IQR 6.89–8.49) in the L. monocytogenes group; p < 0.001. The lowest platelet (PLT) count and the highest level of C-reactive protein (CRP) were more commonly seen in the N. meningitidis group. The median PLT count and the median CRP level were 172.0 x10e9/l (IQR 129–227.0) and 175.32 g/l (IQR 125.24–217.0) in the N. meningitidis meningitis group, 204.0 x10e9/l (IQR 161.0–267.0) and 138.49 g/l (IQR 85.0–186.07) in the S. pneumoniae group, and 288.0 x10e9/l (IQR 198.0–298.50) and 65.29 g/l (IQR 21.07–73.70) in the L. monocytogenes group; p = 0.048 and p < 0.001, respectively. The level of blood glucose was significantly lower in patients with L. monocytogenes meningitis. The median blood glucose was 6.50 mmol/l (IQR 5.55–7.78) in the L. monocytogenes group, 7.49 mmol/l (IQR 6.65–9.87) in the N. meningitidis group, and 8.44 mmol/l (IQR 7.37–11.23) in the S. pneumoniae group; p = 0.023 (Table 3).

Initial antimicrobial treatment most frequently consisted of penicillin in 78 patients (49.1%) and ceftriaxone in 72 patients (45.3%). The median time in which antibiotic treatment was started was 40 min (IQR 30.0–90.0) and it did not differ significantly according to the causative agent of CABM: 30.0 min (IQR 15.0–60.0) in the meningococcal meningitis group, 50 min (IQR 30.0–100.0) in the pneumococcal meningitis group and 100.0 min (IQR 50.0–370.0) in the listerial meningitis group; p = 0.067. The median duration of antibiotic therapy was 14 days (IQR 11.0–16) and it was significantly longer in the L. monocytogenes group (median 26 days, IQR 21.0–29.0) than in the N. meningitidis group (13 days, IQR 10.0–16.0) and the S. pneumoniae group (17 days, IQR 12.0–22.0) (p = 0.004). Penicillin-resistant N. meningitidis was identified in 2 (3.6%) patients, and penicillin-resistant S. pneumoniae was identified in 5 (33.3%) patients. The patients with N. meningitidis meningitis more commonly needed hospitalization in the intensive care unit (ICU) (85.5% in the meningococcal meningitis group vs. 73.3% in the pneumococcal meningitis group vs. 60% in the L. monocytogenes meningitis group; p < 0.001). One hundred six (66.7%) patients with CABM were treated in the ICU. The duration of hospitalization in the ICU was significantly longer in the S. pneumoniae group (median 6.50 days, IQR 4.50–10.0) than in the N. meningitidis group (4 days, IQR 3–5) and the L. monocytogenes group (2 days, IQR 1.0-NA) (p = 0.017). The total duration of hospitalization was significantly longer in the L. monocytogenes group (median 28 days, IQR 21.0–30.5 vs. N. meningitidis group, 15 days, IQR 12.0–19.0 vs. S. pneumoniae group, 20 days, IQR 13.0–25.0; p = 0.007) (Table 4).

Among 159 patients with CABM, 150 (94.3%) patients survived, and 9 (5.7%) patients died. The mortality rate did not vary depending on the causative organism; it was 9.1% for meningococcal meningitis compared with 6.7% for pneumococcal meningitis and 3.8% for meningitis of unknown origin (p = 0.452) (Table 4). Neurological sequelae occurred in 9 (5.7%) patients, consisting of polyneuropathy in 6 (3.9%), paresis in 2 (1.2%) and plegia in 1 (0.6%) patient. The outcomes were scored by the Glasgow Outcome Scale (GOS) score: 9 (5.7%) cases were categorized as GOS 1, no cases as GOS 2, 16 (10.1%) cases as GOS 3, 36 (22.6%) cases as GOS 4 and 98 (61.6%) cases as GOS 5 at discharge. A univariate analysis was performed to explore unadjusted associations between the features at presentation and the outcome. The unfavorable outcome (GOS score of ≤3) did not differ significantly according to the causative agent. Characteristics associated with an unfavorable outcome included age > 65 years (OR, 5.71; 95% CI, 2.16–15.12; p < 0.001), cardiovascular disease (OR, 4.17; 95% CI, 1.50–11.61; p = 0.006), headache (OR, 0.31; 95% CI 0.12–0.82; p = 0.019), pneumonia (OR, 9.29; 95% CI 3.55–24.26; p < 0.001), PLT count < 150 x10e9/l (OR, 3.65; 95% CI 1.51–8.83; p = 0.004), and the level of CSF glucose > 2.48 mmol/l (OR, 0.25; 95% CI 0.08–0.83; p = 0.022) (Table 5). Time to antibiotic therapy was not associated with unfavorable outcome at discharge (Table 6). A multivariable model was further established to identify factors associated with an unfavorable outcome. Characteristics associated with a higher risk of unfavorable outcome by multivariate modeling included age > 65 years (OR, 6.50; 95% CI 1.54–27.39; p = 0.011), coexisting pneumonia (OR, 7.07; 95% CI 2.33–21.44; p = 0.001) and reduced PLT count < 150 x10e9/l at presentation (OR, 3.08; 95% CI 1.05–9.05; p = 0.041) (Table 7).

CABM remains an important public health problem, may lead to serious sequelae and has a high impact on patients’ quality of life [1]. The etiology, clinical characteristics, treatment outcomes and predictors of poor prognosis of CABM must be assessed regularly due to the substantial morbidity and mortality [2‐5]. Therefore, the aim of our study was to retrospectively identify the distribution of etiological agents and their relationship with clinical characteristics, treatment and outcomes in a cohort of patients with CABM.

The most common causative agent of CABM in our study was N. meningitidis (34.6%). Similarly, N. meningitidis was noted as the most frequent pathogen in just a few studies: Gjini et al. found that N. meningitidis was responsible for meningitis in 84% of cases in young adults in England and Wales and Sigurdardottir B. et al. study showed that N. meningitidis was a dominant causative agent in 56% of CABM in Iceland [12, 13]. However, this finding is in contrast with other studies in which S. pneumoniae was the major etiological agent of CABM in adults. S. pneumoniae is now the most common cause of CABM in all age groups (except neonatal meningitis, in which Streptococcus agalactiae and E. coli are the most common pathogens) and is diagnosed in 50–70% of cases despite the widespread availability of vaccines. Furthermore, N. meningitidis in other studies is the second-most common etiological agent in CABM and is important as a causative agent of outbreaks in Sub-Saharan Africa. Finally, it should be noted that meningococcal meningitis is an urgent condition in which early accurate diagnosis and rapid administration of appropriate antibacterial treatment are the key factors for the beneficial clinical outcome [3, 14‐16].

Serotype B is responsible for most cases of invasive meningococcal disease, especially in children under the age of five, and serotypes C, Y, and W are predominantly responsible for invasive meningococcal disease cases in older age groups [4, 7, 17‐19]. In our cohort, we observed that serotype B was responsible for the majority of meningococcal meningitis cases. Unlike most previously reported outbreaks of invasive meningococcal disease that were associated with serotype B [20], we found that all our cases of meningococcal meningitis were sporadic.

According to other studies, L. monocytogenes is the third most common causative agent of CABM and is associated with older age and immunodeficiency [15, 21‐24]. In our study, L. monocytogenes meningitis was the third most common etiological factor and 40% of L. monocytogenes meningitis in our study occurred in adults under the age of 50 without specific risk factors. Nevertheless, we cannot conclude about the risk factors of L. monocytogenes meningitis in our study due to a small number of cases.

CSF culture is the gold standard to diagnose bacterial meningitis [25]. However, a major proportion of CABM causative agents were not identified. We hypothesize that it could be associated with antibiotic therapy before admission to the hospital. Furthermore, bacterial meningitis cases caused by unidentified etiological agents could probably be N. meningitidis, and this finding emphasized the possible underestimation of the burden of meningococcal meningitis. Polymerase chain reaction becomes an important diagnostic tool for CABM and would be a useful tool for causative agent detection several days after the start of antibiotic treatment [26].

Considering the age of patients, the most common established etiological agents of CABM in adults are S. pneumoniae, N. meningitidis and L. monocytogenes; in children beyond the neonatal age, the most common are N. meningitidis and S. pneumoniae [15]. Unsurprisingly, younger age was significantly more common in patients with N. meningitidis meningitis in our cohort. We did not find associations between sex and causative factors.

The clinical presentation of CABM varies and depends on the patient’s age, coexisting conditions and comorbidities [15, 27‐31]. Our study revealed the most common signs of CABM – headache, fever ≥38 °C and nausea. Additionally, 59.1% of patients with CABM had the clinical triad, and it had no associations with the etiological factor. In a 20-year retrospective study conducted in Iceland, in which 51% of patients had the clinical triad, the most common pathogen was N. meningitidis, similar to our study [13]. Therefore, we consider that more patients with the clinical triad were found in our study due to the dominant etiological agent, N. meningitidis. However, multiple other studies have been performed on the clinical characteristics of adults with bacterial meningitis, showing that the clinical triad is reported in 41–51% of patients, less frequently than in our study [14]. Accordingly, the absence of the clinical triad cannot be used to exclude the possibility of bacterial meningitis. In our study, we were able to demonstrate only one etiological association between the presence of hemorrhagic rash and N. meningitidis. Previous studies also concluded that rashes occur more often in patients with N. meningitidis meningitis [31, 32]. Other researchers have also described that hyposplenism, chronic kidney or liver disease and alcoholism were more associated with S. pneumoniae meningitis and H. influenzae meningitis [21, 27]; acquired immunodeficiency (diabetes mellitus, cancer, the use of immunosuppressive therapy) was more associated with L. monocytogenes meningitis; and underlying conditions such as otitis, sinusitis or endocarditis were more associated with H. influenzae meningitis and S. aureus meningitis [33]. No associations between coexisting conditions, comorbidities and the causative agent were found in our study.

The patients in our study showed classical laboratory signs of bacterial meningitis [14]. Furthermore, we found that the highest CSF white cell count was in the other meningitis group, including H. influenzae, S. aureus and S. pyogenes; the lowest count was in the L. monocytogenes meningitis group, however, without a significant association. The highest CSF protein level was in the other meningitis group, and the lowest CSF glucose level was in the N. meningitidis and S. pneumoniae groups. A prospective cohort study of 62 patients with L. monocytogenes meningitis summarized that CSF abnormalities were not typical for bacterial meningitis in 26% of patients [33]. We found that the highest serum white blood cell count was identified more commonly in the S. pneumoniae group, and the lowest platelet count and the highest C-reactive protein level were more commonly seen in patients with N. meningitidis meningitis. Our study demonstrated that a lower level of blood glucose was significantly more common in patients with L. monocytogenes meningitis. However, a research study in an elderly population with L. monocytogenes meningitis revealed high levels of blood glucose [34]. We suggest that the results of our study could be associated with the younger age of patients with L. monocytogenes meningitis.

For the treatment of patients with CABM, the most common empiric antibiotic regimens were ceftriaxone and penicillin. During the study period, 96.4% of all N. meningitidis (n = 55) isolates were sensitive or intermediate to penicillin and 100% were sensitive to ceftriaxone. These results correspond to the national surveillance sensitivity data of invasive N. meningitidis issued by the National Public Health Surveillance laboratory: during the 5-year surveillance period from 2014 to 2018 in Lithuania, 93.8% (121/129) of N. meningitidis isolates were sensitive or intermediate to penicillin and 100% were sensitive to ceftriaxone [35]. S. pneumoniae in our study was sensitive to penicillin in 10 out of 15 patients (67%), and all of them were sensitive to ceftriaxone. The Lithuanian 5-year surveillance period showed that 82.6% (390/472) of invasive S. pneumoniae isolates were sensitive to penicillin and 94.5% (273/289) were sensitive to ceftriaxone. In our study, L. monocytogenes isolates were all sensitive to penicillin (n = 5), and H. influenzae isolates were all sensitive to ceftriaxone (n = 3).

The median duration of antibiotic therapy was 14 days (IQR 11.0–16). The median time in which antibiotic treatment was started was 40 min (IQR 30.0–90.0) and it did not differ significantly according to the causative agent. CABM is a life-threatening disease, and the timing of antibiotic therapy is crucial. Most scientific reports suggest that delay in antibiotic therapy has been associated with unfavorable outcomes [16, 36, 37]. The antibiotic therapy and duration in our study were as recommended by the European Society of Clinical Microbiology and Infectious Diseases guidelines [14]. Nevertheless, the time before the initiation of antibiotic therapy start was not sufficiently short in all cases. The possible reasons for delayed antibiotic treatment may include the following: 1) the retrospective analysis of medical records could result in an incorrect time of the first antibiotic dose being reported; 2) a transfer from another hospital might have prolonged the time to the first dose of antibiotic; 3) a wait in the diagnostic-treatment sequence (head CT followed by lumbar puncture for CSF study and antibiotics afterwards); and 4) an atypical clinical picture of CABM.

In our population, the majority of patients were treated with dexamethasone, and the mean duration was 6.5 ± 3.5 days. The dose, time of administration of corticosteroids and outcome associated with the implementation of adjunctive corticosteroids, however, differed between studies [4, 38].

Despite advances in diagnosis and treatment, CABM still has a high mortality rate, ranging from 17 to 28%; a requirement of treatment in the ICU; and long-term serious sequalae [1‐5, 39]. In our study, hospitalization in the ICU was a significant part of CABM management in many patients. The need for the hospitalization in the ICU was more common in the N. meningitidis group corresponding to the insidious course of meningococcal meningitis. Furthermore, the duration of hospitalization in the ICU was significantly longer in the S. pneumoniae group. This correlates with the course of pneumococcal meningitis as a risk for severe CNS complications along with hydrocephalus, brain edema, intracranial hemorrhage, cerebral venous and arterial complications and seizures, contributing to mortality and long-term disabilities and the need for a longer duration of hospitalization in the ICU [40].

In our study, death occurred in 5.7% of episodes, and the outcome was unfavorable in 15.7% of episodes and it did not vary significantly according to the etiological agent. The lower case fatality rate than that reported in other studies might have been related to N. meningitidis being the main etiological agent [12, 13]. Other studies found that meningitis caused by S. pneumoniae had the highest case fatality rates, 20 to 37% for high-income countries and up to 50% for low-income countries, while meningococcal meningitis fatality rates were much lower, between 3 and 10% for high- and low-income countries, respectively [19, 41, 42]. The strongest risk factors in our study for an unfavorable outcome were an older age, coexisting pneumonia and a low platelet count at presentation. According to other studies, impaired consciousness, low white-cell count, a delay in antibiotic therapy initiation and other comorbidities may also lead to a more severe course of meningitis [21, 22, 31, 43].

Our present study has several limitations to note. First, the retrospective nature of the study limited data on detailed medical information for our patients. Second, the number of patients was relatively small, and the study was conducted in just one center. Future prospective studies are necessary to explore diagnostic and therapeutic aspects of patients with CABM and the associations between genetic peculiarities and the increased susceptibility to meningococcal infection in Lithuania.