Invasive Haemophilus influenzae Serotype a Infection in Children: Clinical Description of an Emerging Pathogen-Alaska, 2002-2014.

BACKGROUND: Invasive infections from Haemophilus influenzae serotype a (Hia) have been reported with increasing frequency, especially among indigenous populations. However, there are limited population-based studies of clinical severity. We studied invasive Hia infections in Alaska to determine clinical characteristics, mortality and sequelae. METHODS: We defined an invasive Hia infection as the first detection of Hia from a usually sterile site in a child <10 years of age from Alaska. We identified cases using the Alaska Invasive Bacterial Diseases Surveillance System and reviewed medical charts up to 2 years after reported illness. RESULTS: We identified invasive Hia infections in 36 children, 28 (78%) <1 year old, 34 (94%) living in an Alaskan village and 25 (69%) without documented underlying illness. Overlapping clinical presentations included meningitis in 15 children (42%); bacteremia and pneumonia in 10 children (28%); and bone, joint or soft tissue infections in 10 children (22%). In 4 other children, no source of invasive infection was identified. Intensive care was provided for 11 children (31%); 12 children (33%) required surgical intervention. One year after infection, 4 children (11%) had died from Hia, and 5 children (14%) had ongoing neurologic sequelae. CONCLUSIONS: Invasive Hia infections in Alaska occurred predominantly in Alaska Native infants in rural communities. Although one-third of children had preexisting conditions, most cases occurred without known comorbidity. Clinical syndromes were frequently severe. One year after infection, 1 in 4 children had either died or had neurologic sequelae. An effective vaccine would prevent significant morbidity and mortality in affected populations.

Pediatric invasive disease due to Haemophilus influenzae serogroup A in Riyadh, Saudi Arabia: case series.

UNLABELLED: We describe the first two cases of invasive disease caused by Haemophilus influenzae serotype A in Saudi Arabia. This is the first known reported invasive Haemophilus influenzae serotype A from Saudi Arabia. CASE PRESENTATION: A ten-month-old and three-month-old male not known to have any past history of any medical illness and who had received H. influenzae type b (Hib) vaccine presented to our hospital mainly with fever of few days' duration. A provisional diagnosis of meningitis with sepsis was made and laboratory tests were requested. The chest radiograph was normal. The laboratory results revealed leukocytosis, but leukopenia was noticed in the younger infant. Blood culture and cerebrospinal fluid specimens yielded a pure culture of Haemophilus influenzae and serotyping showed the isolates to be serogroup A. Both patients were started on vancomycin and third-generation cephalosporin. On receiving the blood culture result, vancomycin was stopped. Fever subsided after 48 hours, while in the second case, it continued for 12 days from the admission date. The repeat blood cultures were negative. Antibiotic therapy was given for 10 days for the first case with an unremarkable hospital course, while the second case was complicated by seizure and received a longer duration of antibiotics. Both infants were discharged home in good condition. CONCLUSIONS: Invasive non-typeable H. influenzae strains are emerging and there is a need for surveillance of this disease. This has implications in future vaccine development.

Histopathologic lesions in conventional pigs experimentally infected with Haemophilus parasuis serovar 5.

OBJECTIVE: In the present study various tissues of pigs were investigated for the presence of histopathologic lesions after an experimental infection with Haemophilus (H.) parasuis serovar 5. MATERIAL AND METHODS: Conventional pigs (n = 36) were divided into a control group B (n = 9) and a challenge group A (n = 27), which was infected intratracheally. Pigs that did not die prior to study termination were euthanized on day 14 post inoculation. Postmortem samples of the lung, heart, liver, kidney, spleen, left tarsal joint capsule and brain were collected. RESULTS: All but one pig with detectable histopathologic lesions (n = 11) showed typical macroscopic changes. Histopathologic examination of all tissue samples identified pyelitis (n = 10), synovitis (n = 7) and meningitis (n = 7) and all those animals were euthanized prior to study termination. No histopathologic lesions were found in pigs of the control group. The correlations between pyelitis and meningitis, pyelitis and synovitis and synovitis and meningitis were significant (p < 0.001). No significant correlation could be observed between the histopathologic and the clinical examination of the joints. The investigation of samples from the joints by PCR was not significantly correlated with the observed synovitis. The clinical observation of neurologic signs was significantly correlated with meningitis (p = 0.03). A significant correlation (p < 0.001) could be detected between meningitis and the detection of H. parasuis by PCR in brain samples. CONCLUSIONS: H. parasuis constantly causes clinical signs and pathologic lesions as soon as it infects the brain while it can infect the joints without causing histopathologic lesions. Pigs with histopathologic lesions do not always show typical clinical signs. Only few studies described the finding of kidney lesions in pigs with Glässer's disease and this is the first study to describe a pyelitis in pigs experimentally infected with H. parasuis. The observed pyelitis mainly occurred in acute cases.

Histophilus somni-induced infections in cattle from southern Brazil.

The sudden death of three calves, one diarrheic calf, and one aborted fetus from four farms in southern Brazil was investigated. Two Histophilus somni-associated syndromes were identified: systemic histophilosis (n = 4) and abortion (n = 1). The principal pathological findings included vasculitis, meningoencephalitis with thrombosis, necrotizing myocarditis, renal infarctions, hepatic abscesses, and bronchopneumonia. PCR assays were used to amplify specific amplicons of the ovine herpesvirus 2, bovine herpesvirus 1 and -5, Listeria monocytogenes, H. somni, and pestivirus; bovine group A rotavirus (BoRV-A) and bovine coronavirus (BCoV) were investigated in calves with diarrhea. H. somni DNA was amplified in tissues from all calves and the brain of the aborted fetus with pathological alterations consistent with histophilosis. All other PCR assays were negative; BoRV-A and BCoV were not identified. These findings confirm the participation of H. somni in the pathological alterations observed in this study and represent the first description of histophilosis in cattle from Brazil.

Complicated meningitis caused by a rare serotype of Haemophilus influenzae in Portugal.

We report a case of meningitis due to Haemophilus influenzae serotype d strain in an infant. As far as we know, this is the first report of a serotype d strain, responsible for childhood invasive disease in Europe, demonstrating an emerging of H. influenzae non-b serotype, in the post-vaccination era.

Haemophilus influenzae serotype a meningitis.

This work describes a case of Haemophilus influenzae serotype a meningitis in Brazil, after almost a decade since the introduction of Haemophilus influenzae serotype b conjugate vaccine. Uncertainty about the replacement of H. influenzae serotypes as a cause of invasive diseases justifies continuous surveillance, coupled with investigations of carriage rates and requirements of chemoprophylaxis in contact persons.

[Management strategy for pediatric presumptive bacterial meningitis (diagnosis, surveillance, follow-up)]. / Stratégie de prise en charge (diagnostic, surveillance, suivi) d'une méningite présumée bactérienne de l'enfant.

The epidemiology of bacterial meningitis has changed since the last French consensus in 1996, mainly because of more frequent Haemophilus influenzae B and pneumoccocus vaccination. A research PubMed and Cochrane databases was performed for articles published within the past 12 years, mentioning the diagnosis, surveillance, and follow-up of presumed bacterial meningitis in children. Sixty-one references were included among the 1606 on PubMed and 50 on the Cochrane databases. Additional articles (n=35) were identified using the references of selected articles. The definition of bacterial meningitis was reviewed, particularly when the causal agent was not identified. Clinical and biological criteria for the diagnosis and the place of brain imaging were updated. Guidelines available after the common use of Haemophilus influenzae vaccination were analyzed with their level of evidence. Initial surveillance data and risk factors associated with death or poor outcome were reviewed. The short and long-term follow-up was also analyzed to identify the proper follow-up for children.

Probable acute disseminated encephalomyelitis due to Haemophilus influenzae meningitis.

We report the case of a 17-year-old male on long-term steroid therapy for minimal lesion glomerulopathy who, after an upper respiratory infection, presented with Haemophilus influenzae type b meningitis. Twenty-four hours later he developed depression of consciousness which progressed to coma and left hemiparesis. Brain magnetic resonance imaging (MRI) revealed multiple lesions (hyperintense on T2 and slightly hypointense on Tl) involving mainly white matter suggestive of inflammation. MRI features were compatible with acute disseminated encephalomyelitis (ADEM), although a differential diagnosis included cerebritis or vasculitis, secondary to bacterial meningitis. The patient was treated with high-dose steroids which resulted in a gradual improvement followed by complete clinical recovery. We propose a diagnosis of ADEM was the best diagnosis because of the radiological features and response to steroids. The occurrence of ADEM associated with acute meningitis, however rare, represents an important diagnostic challenge for the clinician.

Long survival following bacterial meningitis-associated brain destruction.

This report describes the brain autopsy of a boy who at age 4(1/2) years experienced an episode of fulminant Haemophilus influenzae type b bacterial meningitis, resulting in massive brain destruction and the clinical signs of brain death. However, medical intervention maintained him for an additional two decades. Subsequent autopsy revealed a calcified intracranial spherical structure weighing 750 g and consisting of a calcified shell containing grumous material and cystic spaces with no recognizable neural elements grossly or microscopically. This case represents an example of long survival of brain death with a living body.

Kinetic Th1/Th2 responses of transgenic mice with bacterial meningitis induced by Haemophilus influenzae.

To investigate the kinetic Th1/Th2 immunopathogenic mechanisms of Haemophilus influenzae meningitis, we established a murine experimental model of meningitis and elucidated the Th1/Th2 immune responses in T1/T2 doubly transgenic mice based on a BALB/c background under the control of the IFN-gamma (interferon-gamma)/IL-4 (interleukin-4) promoters respectively. NTHi (non-typeable Haemophilus influenzae) meningitis was induced in these mice by inoculation with either a colonized (CNTHi) or invasive (INTHi) strain of NTHi. Mice inoculated with CNTHi displayed a less severe degree of disease in terms of clinical symptoms, mortality rate and brain histopathology. Conversely, INTHi-inoculated mice had more severe clinical symptoms. CNTHi-inoculated mice had a more significant Th1 response in terms of a higher percentage and longer maintenance of Th1 cells, and more production of IFN-gamma from strain-specific antigen-stimulated splenocytes than INTHi-inoculated mice. In contrast, INTHi-inoculated mice had a more significant Th2 response. This was due to a significant increase in IL-4-producing CD4(+) T-cells (Th2 cells) and more production of IL-4 from strain-specific antigen-stimulated splenocytes accompanied by a rapid decline of Th1 cells in INTHi-inoculated mice. In conclusion, the preferential Th1/Th2 trend in this murine model of NTHi meningitis is correlated with clinical severity as well as isolated characteristics of the pathogens themselves.

Kinetics of adaptive immunity to Haemophilus influenzae type b meningitis in transgenic mice: evidence from diverse expression of double T1/T2 transgenes and Th1/Th2-related cytokines.

To investigate the kinetic changes in adaptive immunity during experimental Haemophilus influenzae type b (Hib) meningitis, we established a murine meningitis model based on T1/T2 doubly transgenic mice. These mice carry two transgenes that express two distinct cell-surface markers: a human Thy1 transgene (hThy1) under the control of the murine IFN-gamma promoter, and a murine Thy1.1 transgene (mThy1.1) under the control of the murine IL-4 promoter, designated T1 and T2, respectively. Mice infected with Hib displayed severest symptoms and lowest total splenocyte counts on day 3 after infection. Simultaneously, we examined the significantly low percentage of CD19+ B cells, the relatively high level of CD4+ T cells and significantly high percentage of CD8+ T cells in Hib-infected mice. Furthermore, we observed the early induction of both Th1 and Th2 responses, in terms of the augmentation of Th1 cells (IFN-gamma-producing CD4+ T cells) and Th2 cells (IL-4-producing CD4+ T cells) in Hib-infected mice. On day 7 after infection, the Th1 response gradually declined and the Th2 response rather sustained. Two weeks after infection, both Th1 and Th2 cells were barely detectable. Moreover, we demonstrated using an antigen-specific re-stimulation test to analyze the effector function of lymphocyte subsets that CD8+ T cells contributed to more predominantly production of IFN-gamma than CD4+ T cells did; and CD4+ T cells partly contributed to the secretion of IL-4 from flowcytometry of intracellular cytokine staining. Our results support that these transgenic mice provide an available model to dissect the complex kinetic change of adaptive immunity in bacterial infectious diseases.

[Pathomorphology of meningitis caused by Haemophilus infection in children]. / Patomorfologiia meningitov, vyzvannykh gemofil'noi palochkoi, u detei.

Pathomorphological study of the brain of 14 children who died of Hemophilus bacillus infection shows that this disease is characterized by damage to microvessels with formation of microthrombi followed by development of necrosis foci in the brain matter. The maximal damage of the vessels was observed during two first days of the disease in the pia mater and foci of microinfarction were located in the subpial cortex zone only. With the disease progress microvessels of the brain cortex were affected and foci of damage blended together and were found in both cortex and white matter.

[Purulent meningitis in children: special considerations for developing countries]. / Méningites purulentes chez l'enfant: particularités dans les pays en développement.

Bacterial meningitis is frequent in tropical zones as a result of recurring epidemics, meningococcal meningitis and near-total absence of anti-haemophilus type b vaccination. Recently the situation has been further complicated by the unexplained appearance of meningococcal W135 epidemics in Burkina-Faso. With regard to pneumococcal meningitis, the appearance of antibiotic strains is a worldwide phenomenon that has greatly increased the cost of antimicrobial treatment. Hopefully in the future children in tropical areas will be able to benefit from immunization using a conjugate vaccine combining anti-haemophilus b, meningococcal type a and W135 vaccination. In this regard the currently available 7 valence pneumococcal vaccine is poorly suited to tropical epidemiology and that an additional 4 serotypes would be needed to achieve 85% coverage.

[Haemophilus influenzae bacterial meningitis: residual risk; case report]. / Méningite bactérienne à Haemophilus influenzae: le risque résiduel; à propos d'un cas.

UNLABELLED: Bacterial meningitis due to Haemophilus influenzae has become a rare, albeit not exceptional occurrence since generalized vaccination against that pathogen was instated, concerning as well incapsulated b and non-b Haemophilus influenzae strains, as non-incapsulated strains. CASE REPORT: A 19-month-old fully immunized infant was referred to our hospital for bacterial meningitis. CSF analysis elicited biotype III, non-incapsulated Haemophilus influenzae. CONCLUSION: Generalizing Haemophilus influenzae preventive inoculation has revolutionized the epidemiology of bacterial meningitis; however, a residual risk exists, which deserves to be taken into account.

Haemophilus influenzae and Streptococcus pneumoniae induce different intracerebral mRNA cytokine patterns during the course of experimental bacterial meningitis.

Using in situ hybridization with radiolabelled oligonucleotide probes, we studied the mRNA expression of IL-1beta, IL-4, IL-6, IL-10, IL-12, tumour necrosis factor-alpha (TNF-alpha), TNF-beta, interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) in the brain during the lethal course of experimental meningitis in a rat model inoculated intracisternally with Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae and in uninfected control rats inoculated with the same volume of PBS. The production of IL-1beta, IL-4, IL-6 and IFN-gamma was also evaluated by immunohistochemistry. In the brain of Hib-inoculated rats, there was marked mRNA expression of IL-1beta, IL-6, TNF-alpha, IL-12 and IFN-gamma. IL-1beta, IL-6 and TNF-alpha were up-regulated throughout the observation period at 2, 8 and 18 h post-inoculation (p.i.), with similar patterns of induction. The Th1 cytokines IFN-gamma and TNF-beta were up-regulated within 8 h p.i. IL-10 and TGF-beta were down-regulated at 18 h p.i., while IL-4 was not detected. In contrast, the brain of S. pneumoniae-inoculated rats showed lower levels of IL-1beta, IL-6 and TNF-alpha, but higher levels of TNF-beta and detectable mRNA expression of IL-4 when compared with Hib-inoculated rats. IL-12, IFN-gamma, IL-10 and TGF-beta exhibited similar patterns of induction in the brains of Hib- and S. pneumoniae-inoculated rats. At 18 h p.i., immunohistochemistry showed similar patterns of IL-1beta, IL-4, IL-6 and IFN-gamma as mRNA expression in the brains of Hib- and S. pneumoniae-inoculated rats. The differences of cytokine profiles induced by the two bacterial strains may imply that different immunomodulating approaches should be considered, depending on etiology.

Hemophilus influenzae type b meningitis: pediatric overview.

The authors valued the incidence and clinical therapeutic aspects of Haemophilus influenzae type b (Hib) meningitis in children. They report a retrospective study, in children, with diagnosis of acute purulent meningitis, from January 1982 to December 1994, aged between 1 month and 14 years. Particular attention was direct to Haemophilus influenzae type b meningitis (20 cases). The incidence rate of Hib meningitis in the overall cases (89) was 22.47% (20), while among children younger than 5 years Hib was the most frequently pathogen isolated (20/58-34.47%). In 1/4 of cases, particularly in children younger than 1 years, exordium was aspecific and unclear. At admission culture and examination of Cerebrospinal Fluid (CFS) have been done. CFS was cultured on blood agar and chocolate plates. A latex agglutination test was used for rapid detection of the bacterial antigens. In some cases we looked for bacterial antigens in urine. 20% of children had complications and 10% had sequelae (1 years of follow-up). We didn't have any dead. Antibiotic treatment was principally with Ampicillin, Cephalosporin and Chloramphenicol. The results of this study confirm the Hib gravity and suggest that the administration of conjugate vaccine against Hib to all living in Italy is justified.

Diffuse astrocytic swelling and increased second messenger activity following acute Haemophilus influenzae meningitis--evidence from a rat model.

Despite numerous epidemiological analyses of bacterial meningitis there is very little pathological data concerning the acute glial and neuronal responses to the disease. We have developed a safe, easily used rat model for Haemophilus influenzae type b meningitis. We measured cerebral blood flow, glucose utilisation and second messenger activity in this model, and carried out parallel light and ultrastructural analysis of glial and neuronal responses. Only protein kinase C activity was changed from control values. We obtained evidence for massive astrocytic swelling and neuronal degeneration. We posit that cytotoxic mechanisms may contribute to the pathology of meningitis.