Endotoxin concentrations in cerebrospinal fluid correlate with clinical severity and neurologic outcome of Haemophilus influenzae type B meningitis

Endotoxin concentrations were measured in paired samples of cerebrospinal fluid from 38 patients with Haemophilus influenzae type b meningitis. On admission, the median concentration of endotoxin in cerebrospinal fluid was 104 ng/mL and decreased rapidly in follow-up samples. From 17 to 48 hours after admission, 50% of the patients had concentrations of less than 1 ng/mL. Endotoxin concentrations correlated significantly with concentrations of interleukin 1 beta, protein, and glucose in cerebrospinal fluid, duration of secondary fever, and neurologic abnormalities during hospitalization and on follow-up examinations. Twenty-eight percent of patients with endotoxin concentrations of 100 ng/mL or more on admission had long-term complications, compared with none of those with lower endotoxin concentrations (relative risk, 2.31; 95% confidence interval, 1.53 to 3.48). These results indicate that quantitation of endotoxin in cerebrospinal fluid could be a valuable aid in identifying those children at increased risk of complications during Haemophilus influenzae type b meningitis and provide additional evidence that the Haemophilus influenzae type b meningitis lipo-oligosaccharide is important in the pathogenesis of meningitis.     

Sequelae of Haemophilus influenzae meningitis

Fourteen children who had had Haemophilus influenzae meningitis more than two years earlier have been compared with their siblings. WISC, Frostig and Bender psychological tests and neurological examination were performed so that subject/sibling differences could be analysed. On neurological examination, subjects overall performed worse than the controls, although no "hard" neurological signs were found. Prolonged fever during the meningitis was associated with poorer results in psychological tests. In the subjects, there was a significant increase in left lateral dominance which may have been due to brain damage by the meningitis. However, most subjects did not differ significantly from their siblings in the tests, suggesting that prompt and adequate treatment of bacterial meningitis can prevent sequelae.     

Pathogenesis of Haemophilus influenzae meningitis

The hypoxia induced by decreased cerebrocortical blood flow contributes to the neurologic deficits found in many survivors of Hib meningitis. Because reduced blood flow is measurable within 48 hours of acquisition of bacteria, the inability of antibiotic therapy to prevent sequelae is more easily understood insofar as damage has already occurred by the time treatment is initiated. Hydrocephalus is probably due to severe choroid plexus necrosis with aqueductal occlusion. These deficiencies, along with the neuronopathy, contribute to permanent cerebrocortical deficits, including impaired learning ability.     

Arthritis associated with Haemophilus influenzae meningitis: septic or reactive?

We reviewed 165 pediatric cases of Haemophilus influenzae type b meningitis and found 11 (6.7%) with associated arthritis. Synovial fluid culture and Gram stain suggested that only three of these 11 cases were caused by a septic process. In all three children with septic arthritis, joint symptoms were present on admission or within 24 hours. In contrast, of the eight who had reactive arthritis, arthritis did not appear in six until after 1 week of antibiotic therapy. Patients with septic arthritis were older than patients with reactive arthritis (mean 31 months vs 17 months), had a longer duration of symptoms before the start of antibiotic therapy (mean 6.0 days vs 2.5 days), and were more likely to have a positive blood culture (67% vs 18%). It is probable that the majority of episodes of synovitis occurring after H. influenzae meningitis occur as a result of a reactive rather than a septic process. Treatment of reactive arthritis should be with anti-inflammatory agents rather than with multiple joint aspirations and prolonged antibiotic therapy.     

Pathogenicity of a rifampin-resistant cerebrospinal fluid isolate of Haemophilus influenzae type b

Two children in a day care facility developed Haemophilus influenzae type b meningitis. The second child was enrolled in the facility after rifampin had been administered to the other attendees. The isolate from the first child was susceptible to rifampin, but the isolate from the second was resistant. Both isolates had identical outer membrane protein PAGE profiles. To investigate the virulence of these isolates, we inoculated infant rats intranasally with either the rifampin-resistant or rifampin-susceptible CSF isolate. The rates of nasal colonization (14 of 20 and eight of eight animals inoculated with the rifampin-resistant and rifampin-susceptible isolates, respectively) did not differ significantly. However, bacteremia occurred less frequently in pups inoculated with the rifampin-resistant strain than in animals inoculated with the susceptible strain (four of 20 vs eight of eight, P less than 0.0001). Nasal washings, blood, and CSF obtained from animals inoculated with the rifampin-resistant isolate were divided and plated on media containing rifampin (1 microgram/ml) or without rifampin. Except for those from one animal, organisms isolated from blood and CSF grew only on medium lacking rifampin, whereas H. influenzae type b growing from nasal washings was frequently found on both media. We conclude that mutation of H. influenzae to rifampin resistance is a hazard of rifampin chemoprophylaxis. Rifampin-resistant isolates have the potential to cause disease in patients and experimental animals, although they may be relatively less pathogenic than the parent, susceptible organism.     

Direct detection of the multidrug resistance genome of Haemophilus influenzae in cerebrospinal fluid of children: implications for treatment of meningitis

BACKGROUND: Multidrug resistance (MDR), specifically to ampicillin and chloramphenicol, has complicated the treatment of Haemophilus influenzae type b (Hib) meningitis. This is worsened by use of prior antibiotics, which limits identification of the causative agent by culture and increases reliance on antigen detection. OBJECTIVE: We aimed to develop a PCR assay for detecting the family of Haemophilus integrating and conjugative elements (ICEs) represented by ICEHin1056 among antibiotic resistant Hib, and then apply this directly to CSF to diagnose Hib meningitis and predict organism susceptibility, irrespective of culture results. STUDY DESIGN: Primers specific for orf 51 of ICEHin1056 were designed and multiplexed with Bex primers, specific for H. influenzae, and tested on culture positive and negative cases. RESULTS: Of 73 Hib isolates, orf 51 PCR amplicons, predicting the presence of ICEs, were found in all 33 MDR isolates while only in 1 of 33 sensitive strains. The remaining 7 ampicillin susceptible, chloramphenicol and tetracycline resistant strains did not produce a PCR product to orf 51. PCR amplification from CSF specimens of these culture positive cases produced identical results with 100% and 97% positive and negative predictive values, respectively. Multiplex PCR to detect Bex and orf 51 identified another 16 MDR Hib cases among 81 culture-negative CSF samples. CONCLUSIONS: Direct PCR for orf 51 in CSF identified resistance pattern of 51% more Hib strains than culture alone (110 versus 73). The ability to detect MDR, in culture negative Hib meningitis cases has significant implications for better directing antibiotic treatment of meningitis cases and thus for preventing disability and death.