Granulocytes in cerebrospinal fluid of adults suspected of a central nervous system infection: a prospective study of diagnostic accuracy.

PURPOSE: Cerebrospinal fluid (CSF) granulocytes are associated with bacterial meningitis, but information on its diagnostic value is limited and primarily based on retrospective studies. Therefore, we assessed the diagnostic accuracy of CSF granulocytes. METHODS: We analyzed CSF granulocytes (index test) from all consecutive patients in two prospective cohort studies in the Netherlands. Both studies included patients ≥ 16 years, suspected of a central nervous system (CNS) infection, who underwent a diagnostic lumbar puncture. All episodes with elevated CSF leukocytes (≥ 5 cells per mm3) were selected and categorized by clinical diagnosis (reference standard). RESULTS: Of 1261 episodes, 625 (50%) had elevated CSF leukocytes and 541 (87%) were included. 117 of 541 (22%) were diagnosed with bacterial meningitis, 144 (27%) with viral meningoencephalitis, 49 (9%) with other CNS infections, 76 (14%) with CNS autoimmune disorders, 93 (17%) with other neurological diseases and 62 (11%) with systemic diseases. The area under the curve to discriminate bacterial meningitis from other diagnoses was 0.97 (95% confidence interval [CI] 0.95-0.98) for CSF granulocyte count and 0.93 (95% CI 0.91-0.96) for CSF granulocyte percentage. CSF granulocyte predominance occurred in all diagnostic categories. A cutoff at 50% CSF granulocytes gave a sensitivity of 94% (95% CI 90-98), specificity of 80% (95% CI 76-84), negative predictive value of 98% (95% CI 97-99) and positive predictive value of 57% (95% CI 52-62). CONCLUSION: CSF granulocytes have a high diagnostic accuracy for bacterial meningitis in patients suspected of a CNS infection. CSF granulocyte predominance occurred in all diagnostic categories, limiting its value in clinical practice.

Diagnostic accuracy of inflammatory markers in adults with suspected central nervous system infections.

OBJECTIVES: We aimed to determine diagnostic accuracy of inflammatory markers in plasma and cerebrospinal fluid (CSF) for the diagnosis of central nervous system (CNS) infections and specifically bacterial meningitis. METHODS: We analyzed 12 cytokines, chemokines, and acute phase reactants in CSF and plasma of 738 patients with suspected neurological infection included in a multicenter prospective cohort. We determined diagnostic accuracy for predicting any CNS infection and bacterial meningitis. RESULTS: We included 738 episodes between 2017 and 2022, split into a derivation (n = 450) and validation cohort (n = 288). Of these patients, 224 (30%) were diagnosed with CNS infection, of which 81 (11%) with bacterial meningitis, 107 (14%) with viral meningitis or encephalitis, and 35 patients (5%) with another CNS infection. Diagnostic accuracy of CRP, IL-6, and Il-1ß in CSF was high, especially for diagnosing bacterial meningitis. Combining these biomarkers in a multivariable model increased accuracy and provided excellent discrimination between bacterial meningitis and all other disorders (AUC = 0.99), outperforming all individual biomarkers as well as CSF leukocytes (AUC = 0.97). When applied to the population of patients with a CSF leukocyte count of 5-1000 cells/mm3, accuracy of the model also provided a high diagnostic accuracy (AUC model = 0.97 vs. AUC CSF leukocytes = 0.80) with 100% sensitivity and 92% specificity. These results remained robust in a temporal validation cohort. CONCLUSIONS: Inflammatory biomarkers in CSF are able to differentiate CNS infections and especially bacterial meningitis from other disorders. When these biomarkers are combined, their diagnostic accuracy exceeds that of CSF leukocytes alone and as such these markers have added value to current clinical practice.

Predictors of unfavourable outcome in adults with suspected central nervous system infections: a prospective cohort study.

Suspected central nervous system (CNS) infections may pose a diagnostic challenge, and often concern severely ill patients. We aim to identify predictors of unfavourable outcome to prioritize diagnostics and treatment improvements. Unfavourable outcome was assessed on the Glasgow Outcome Scale at hospital discharge, defined by a score of 1 to 4. Of the 1152 episodes with suspected CNS infection, from two Dutch prospective cohorts, the median age was 54 (IQR 37-67), and 563 episodes (49%) occurred in women. The final diagnoses were categorized as CNS infection (N = 358 episodes, 31%), CNS inflammatory disease (N = 113, 10%), non-infectious non-inflammatory neurological disorder (N = 388, 34%), non-neurological infection (N = 252, 22%), and other systemic disorder (N = 41, 4%). Unfavourable outcome occurred in 412 of 1152 (36%), and 99 died (9%). Predictors for unfavourable outcomes included advanced age, absence of headache, tachycardia, altered mental state, focal cerebral deficits, cranial nerve palsies, low thrombocytes, high CSF protein, and the final diagnosis of CNS inflammatory disease (odds ratio 4.5 [95% confidence interval 1.5-12.6]). Episodes suspected of having a CNS infection face high risk of experiencing unfavourable outcome, stressing the urgent need for rapid and accurate diagnostics. Amongst the suspected CNS infection group, those diagnosed with CNS inflammatory disease have the highest risk.

Seizures in adults with suspected central nervous system infection.

BACKGROUND: Seizures can be part of the clinical presentation of central nervous system (CNS) infections. We describe patients suspected of a neurological infection who present with a seizure and study diagnostic accuracy of clinical and laboratory features predictive of CNS infection in this population. METHODS: We analyzed all consecutive patients presenting with a seizure from two prospective Dutch cohort studies, in which patients were included who underwent cerebrospinal fluid (CSF) examination because of the suspicion of a CNS infection. RESULTS: Of 900 episodes of suspected CNS infection, 124 (14%) presented with a seizure. The median age in these 124 episodes was 60 years (IQR 45-71) and 53% of patients was female. CSF examination showed a leukocyte count ≥ 5/mm3 in 41% of episodes. A CNS infection was diagnosed in 27 of 124 episodes (22%), a CNS inflammatory disorder in 8 (6%) episodes, a systemic infection in 10 (8%), other neurological disease in 77 (62%) and in 2 (2%) episodes another systemic disease was diagnosed. Diagnostic accuracy of clinical and laboratory characteristics for the diagnosis of CNS infection in this population was low. CSF leukocyte count was the best predictor for CNS infection in patients with suspected CNS infection presenting with a seizure (area under the curve 0.94, [95% CI 0.88 - 1.00]). CONCLUSIONS: Clinical and laboratory features fail to distinguish CNS infections from other causes of seizures in patients with a suspected CNS infection. CSF leukocyte count is the best predictor for the diagnosis of CNS infection in this population.

Neurofilament light chain in central nervous system infections: a prospective study of diagnostic accuracy.

Diagnosing central nervous system (CNS) infections quickly is often difficult. Neurofilament light chain (NfL) is a component of the axonal cytoskeleton and identified as marker of neuronal damage in several CNS diseases. We evaluated the diagnostic accuracy of NfL for diagnosing CNS infections. We included patients from a prospective cohort of consecutive patients in whom a lumbar puncture was performed for suspected CNS infection in an academic hospital in The Netherlands. The index test was NfL in cerebrospinal fluid (CSF) and reference standard the final clinical diagnosis. Diagnostic accuracy was determined using the area-under-the-curve (AUC) with 95% confidence intervals (CI). The association of CSF NfL with clinical characteristics, diagnosis and outcome was evaluated. Between 2012 and 2015, 273 episodes in adults of which sufficient CSF was available were included. CNS infection was diagnosed in 26%(n = 70), CNS inflammatory disease in 7%(n = 20), systemic infection in 32%(n = 87), and other neurological disorders in 33%(n = 90). Median CSF NfL level was 593 pg/ml (IQR 249-1569) and did not discriminate between diagnostic categories or CNS infection subcategories. AUC for diagnosing any CNS infection compared to patients without CNS infections was 0.50 (95% CI 0.42-0.59). Patients presenting with an altered mental status had higher NfL levels compared to other patients. We concluded that NfL cannot discriminate between causes in patients suspected of CNS infections. High concentrations of NfL are associated with severe neurological disease and the prognostic value of NfL in patients with CNS infections should be investigated in future research.

Pneumococcal Meningitis in Adults: A Prospective Nationwide Cohort Study Over a 20-year Period.

BACKGROUND: The epidemiology and treatment of pneumococcal meningitis has changed with the implementation of conjugate vaccines and the introduction of adjunctive dexamethasone therapy. METHODS: We analyzed episodes of community-acquired pneumococcal meningitis in adults (≥16 years) in the Netherlands, identified by the National Reference Laboratory for Bacterial Meningitis or treating physician between October 1, 1998, and April 1, 2002, and between January 1, 2006, and July 1, 2018. We studied incidence, pneumococcal serotypes, and clinical features. Predictors for unfavorable outcome (Glasgow Outcome Scale score 1-4) were identified in a multivariable logistic regression model. Two physicians independently categorized causes of death as neurological or systemic. RESULTS: There were 1816 episodes in 1783 patients. The incidence of 7- and 10-7-valent pneumococcal conjugate vaccine serotypes decreased (from 0.42 to 0.06, P = .001; from 0.12 to 0.03 episodes per 100 000 population per year, P = .014). Incidence of nonvaccine serotypes increased (from 0.45 to 0.68, P = .005). The use of adjunctive treatment with dexamethasone increased and was administered in 85% of patients in 2018. In-hospital death occurred in 363 episodes (20%) and unfavorable outcome in 772 episodes (43%). Delayed cerebral thrombosis occurred in 29 patients (2%), of whom 15 patients (52%) died. Adjunctive dexamethasone therapy was associated with favorable outcome (adjusted odds ratio 2.27, P < .001), individual pneumococcal serotypes were not. CONCLUSION: Implementation of conjugate vaccines and adjunctive dexamethasone therapy have changed the incidence and outcome of pneumococcal meningitis in adults over the last two decades. Despite recent advances pneumococcal meningitis remains associated with a residual high rate of mortality and morbidity.

Recurrent Community-Acquired Bacterial Meningitis in Adults.

BACKGROUND: Recurrent bacterial meningitis has been found to occur in about 5% of meningitis cases. METHODS: We analyzed adults with recurrent episodes in a prospective nationwide cohort study of community-acquired bacterial meningitis. RESULTS: Of 2264 episodes of community-acquired bacterial meningitis between 2006 and 2018, 143 (6%) were identified as recurrent episodes in 123 patients. The median age was 57 years (interquartile range [IQR], 43-66), and 57 episodes (46%) occurred in men. The median duration between the first and the current episode was 5 years (IQR, 1-15). For 82 of 123 patients (67%), it was the first recurrent episode, 31 patients had 2-5 previous episodes (25%), 2 had 6-10 episodes (2%), and 2 had >10 episodes (2%). Predisposing factors were identified in 87 of 118 patients (74%) and most commonly consisted of ear or sinus infections (43 of 120, 36%) and cerebrospinal fluid leakage (37 of 116, 32%). The most common pathogens were Streptococcus pneumoniae (93 of 143, 65%) and Haemophilus influenzae (19 of 143, 13%). The outcome was unfavorable (Glasgow outcome scale score, <5) in 24 episodes with recurrent meningitis (17%) vs 810 for nonrecurrent meningitis patients (39%, P < .001). Six of 143 died (4%) vs 362 of 2095 patients (17%, P < .001). CONCLUSIONS: Recurrent meningitis occurs mainly in patients with ear or sinus infections and cerebrospinal fluid leakage. Predominant causative pathogens are S. pneumoniae and H. influenzae. The disease course is less severe, resulting in lower case fatality compared with nonrecurrent meningitis patients.

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.

BACKGROUND: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. METHODS: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO2/FiO2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420). FINDINGS: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO2/FiO2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO2/FiO2 (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO2/FiO2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group. INTERPRETATION: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. FUNDING: InflaRx.

Community-acquired Bacterial Meningitis in Adults With Cerebrospinal Fluid Leakage.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is a risk factor for developing bacterial meningitis. METHODS: We analyzed episodes of community-acquired bacterial meningitis associated with CSF leakage from a prospective nationwide cohort study. RESULTS: CSF leakage was identified in 65 episodes of 2022 episodes (3%) in 53 patients. The cause of CSF leakage was identified in 49 of 65 episodes (75%), which most commonly consisted of ear-nose-throat surgery (19 of 49 episodes [29%]) and remote head trauma (15 of 49 episodes [23%]). The episode was a recurrent meningitis episode in 38 patients (59%). Of the recurrent episodes, 27 had known CSF leakage (71%) of whom 20 (53%) had previous surgery aiming to close the leak. Nine patients (38%) with known CSF leakage had been vaccinated (23-valent pneumococcal vaccine in 9 patients, meningococcal serogroup C vaccine in 2, meningococcal serogroup A and Haemophilus influenzae type b vaccine each in 1 patient). Streptococcus pneumoniae was cultured in 33 episodes (51%) and H. influenzae in 11 episodes (17%). The most common pneumococcal serotypes were 3 (4 episodes), 35B, 9N, 38, and 15C (each 2 episodes). Haemophilus influenzae was unencapsulated in all 10 episodes with known capsule type. The outcome was unfavorable in 8 episodes (12%) and no patient died. CONCLUSIONS: Bacterial meningitis in patients with CSF leakage has a high recurrence rate, despite surgical repair or vaccination, and outcome is generally favorable. CSF leakage should be suspected in patients with bacterial meningitis presenting with liquorrhea, recurrent meningitis, or with disease caused by H. influenzae.