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This study provides an update on invasive Haemophilus influenzae disease in Bellvitge University Hospital (2014-2019), reporting its evolution from a previous period (2008-2013) and analysing the non-typeable H. influenzae (NTHi) population structure using a clade-related classification. Clinical data, antimicrobial susceptibility and serotyping were studied and compared with those of the previous period. Population structure was assessed by multilocus sequence typing (MLST), SNP-based phylogenetic analysis and clade-related classification. The incidence of invasive H. influenzae disease remained constant between the two periods (average 2.07 cases per 100 000 population), while the 30 day mortality rate decreased (20.7-14.7 %, respectively). Immunosuppressive therapy (40 %) and malignancy (36 %) were the most frequent comorbidities. Ampicillin and fluoroquinolone resistance rates had increased between the two periods (10-17.6 % and 0-4.4 %, respectively). NTHi was the main cause of invasive disease in both periods (84.3 and 85.3 %), followed by serotype f (12.9 and 8.8 %). NTHi displayed high genetic diversity. However, two clusters of 13 ( n =20) and 5 sequence types (STs) ( n =10) associated with clade V included NTHi strains of the most prevalent STs (ST3 and ST103), many of which showed increased frequency over time. Moreover, ST103 and ST160 from clade V were associated with β-lactam resistance. Invasive H. influenzae disease is uncommon, but can be severe, especially in the elderly with comorbidities. NTHi remains the main cause of invasive disease, with ST103 and ST160 (clade V) responsible for increasing β-lactam resistance over time.

Introduction: Chronic infection is associated with adverse outcomes among people with bronchiectasis. However, it is not known which factors are associated with a bacterial infection, and with persistence of an infection after the first episode. We aimed to determine factors associated with a new infection and with chronicity of Pseudomonas aeruginosa (PA) and H. influenzae (HI), the most common organisms in bronchiectasis infection., Methods: Using an Israeli population database, we identified individuals diagnosed with bronchiectasis. Cox proportional hazard models were used to assess risk factors for first isolation and Logistic regression for chronicity of infection after a first isolation of PA and HI., Results: We included 1305 people with a median of 5 respiratory samples per individual. PA was initially isolated in 297 people, of whom 97 (33%) developed chronic PA infection. HI was newly identified in 169 people, of whom 39 (23%) developed chronic infection (p = 0.029). Factors associated with increased risk of a new infection with PA were COPD (HR 1.87 [1.52-2.28], previous isolation of HI (HR 1.38 [1.07-1.78]), and alcohol abuse (HR 2.22 [1.13-4.3]). Younger age was associated with increased risk of HI infection, while COPD was associated with a lower risk of HI infection. Prescription of an anti- PA antibiotic was associated with chronic PA after a new infection (OR = 1.8 [1.09-2.9], p = 0.02). A landmark analysis showed that survival was worse in people with chronic PA infection vs. single or intermittent infection (Log rank: p = 0.034) CONCLUSIONS: Younger age and presence of PCD are associated with a new isolation of HI. A new infection with PA is associated with previous HI infection, PCD, COPD, and alcohol abuse. Unexpectedly, treatment with appropriate anti-PA antimicrobials was not associated with a reduced risk of chronicity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The diagnosis of a concurrent infection of Avibacterium paragallinarum and fowl adenovirus (FAdV) in an infectious coryza-like outbreak in the outskirt of Beijing is reported. The primary signs of the infection were acute respiratory signs, a drop in egg production, and the presence of hydropericardium-hepatitis syndrome-like gross lesions. Laboratory examination confirmed the presence of A. paragallinarum by bacterial isolation and a species-specific PCR test. In addition, conventional serotyping identified the isolates as Page serovar A. Fowl adenovirus was isolated from chicken liver specimen and identified by hexon gene amplification. In addition, histopathologic analysis and transmission electron microscopy examination further confirmed the presence of the virus. Both hexon gene sequencing and phylogenetic analysis defined the viral isolate as FAdV-4. The pathogenic role of A. paragallinarum and FAdV was evaluated by experimental infection of specific-pathogen-free chickens. The challenge trial showed that combined A. paragallinarum and FAdV infection resulted in more severe clinical signs than that by FAdV infection alone. The concurrent infection caused 50% mortality compared with 40% mortality by FAdV infection alone and zero mortality by A. paragallinarum infection alone. To our knowledge, this is the first report of A. paragallinarum coinfection with FAdV. The case implies that concurrent infections with these 2 agents do occur and more attention should be given to the potential of multiple agents during disease diagnosis and treatment., (Copyright © 2020. Published by Elsevier Inc.)

Background: India accounts for a disproportionate burden of global childhood illnesses. To inform policies and measure progress towards achieving child health targets, we estimated the annual national and state-specific childhood mortality and morbidity attributable to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) between 2000 and 2015., Methods: In this modelling study, we used vaccine clinical trial data to estimate the proportion of pneumonia deaths attributable to pneumococcus and Hib. The proportion of meningitis deaths attributable to each pathogen was derived from pathogen-specific meningitis case fatality and bacterial meningitis case data from surveillance studies. We applied these proportions to modelled state-specific pneumonia and meningitis deaths from 2000 to 2015 prepared by the WHO Maternal and Child Epidemiology Estimation collaboration (WHO/MCEE) on the basis of verbal autopsy studies from India. The burden of clinical and severe pneumonia cases attributable to pneumococcus and Hib was ascertained with vaccine clinical trial data and state-specific all-cause pneumonia case estimates prepared by WHO/MCEE by use of risk factor prevalence data from India. Pathogen-specific meningitis cases were derived from state-level modelled pathogen-specific meningitis deaths and state-level meningitis case fatality estimates. Pneumococcal and Hib morbidity due to non-pneumonia, non-meningitis (NPNM) invasive syndromes were derived by applying the ratio of pathogen-specific NPNM cases to pathogen-specific meningitis cases to the state-level pathogen-specific meningitis cases. Mortality due to pathogen-specific NPNM was calculated with the ratio of pneumococcal and Hib meningitis case fatality to pneumococcal and Hib meningitis NPNM case fatality. Census data from India provided the population at risk., Findings: Between 2000 and 2015, estimates of pneumococcal deaths in Indian children aged 1-59 months fell from 166 000 (uncertainty range [UR] 110 000-198 000) to 68 700 (44 600-86 000), while Hib deaths fell from 82 600 (52 300-112 000) to 15 600 (9800-21 500), representing a 58% (UR 22-78) decline in pneumococcal deaths and an 81% (59-91) decline in Hib deaths. In 2015, national mortality rates in children aged 1-59 months were 56 (UR 37-71) per 100 000 for pneumococcal infection and 13 (UR 8-18) per 100 000 for Hib. Uttar Pradesh (18 900 [UR 12 300-23 600]) and Bihar (8600 [5600-10 700]) had the highest numbers of pneumococcal deaths in 2015. Uttar Pradesh (9300 [UR 5900-12 700]) and Odisha (1100 [700-1500]) had the highest numbers of Hib deaths in 2015. Less conservative assumptions related to the proportion of pneumonia deaths attributable to pneumococcus indicate that as many as 118 000 (UR 69 000-140 000) total pneumococcal deaths could have occurred in 2015 in India., Interpretation: Pneumococcal and Hib mortality have declined in children aged 1-59 months in India since 2000, even before nationwide implementation of conjugate vaccines. Introduction of the Hib vaccine in several states corresponded with a more rapid reduction in morbidity and mortality associated with Hib infection. Rapid scale-up and widespread use of the pneumococcal conjugate vaccine and sustained use of the Hib vaccine could help accelerate achievement of child survival targets in India., Funding: Bill & Melinda Gates Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

There is consensus that definitive therapy for infections with H. influenzae should include antimicrobial agents with clinical breakpoints against the bacterium. In Scandinavia, benzylpenicillin is the recommended empirical treatment for community-acquired pneumonia (CAP) except in very severe cases. However, the effect of benzylpenicillin on H. influenzae infections has been debated. The aim of this study was to compare the outcomes of patients given benzylpenicillin with patients given wide-spectrum beta-lactams (WSBL) as empirical treatment of lower respiratory tract H. influenzae infections requiring hospital care. We identified 481 adults hospitalized with lower respiratory tract infection by H. influenzae, bacteremic and non-bacteremic. Overall, 30-day mortality was 9% (42/481). Thirty-day mortality, 30-day readmission rates, and early clinical response rates were compared in patients receiving benzylpenicillin (n = 199) and a WSBL (n = 213) as empirical monotherapy. After adjusting for potential confounders, empirical benzylpenicillin treatment was not associated with higher 30-day mortality neither in a multivariate logistic regression (aOR 2.03 for WSBL compared to benzylpenicillin, 95% CI 0.91-4.50, p = 0.082), nor in a propensity score-matched analysis (aOR 2.14, 95% CI 0.93-4.92, p = 0.075). Readmission rates did not significantly differ between the study groups, but early clinical response rates were significantly higher in the WSBL group (aOR 2.28, 95% CI 1.21-4.31, p = 0.011), albeit still high in both groups (84 vs 81%). In conclusion, despite early clinical response rates being slightly lower for benzylpenicillin compared to WSBL, we found no support for increased mortality or readmission rates in patients empirically treated with benzylpenicillin for lower respiratory tract infections by H. influenzae.

Haemophilus influenzae type b (Hib) conjugate vaccines have led to dramatic reductions in Hib disease among young children worldwide. Nontypeable H. influenzae (NTHi) is now the major cause of invasive H. influenzae infections. We investigated the clinical characteristics of invasive NTHi diseases among children in Japan, to clarify the pathogenicity of isolated NTHi strains. The mortality rate was 10.7%, with deaths occurring mainly among children with underlying comorbidities. Biotypes II and III were the most common, and most strains (64.3%) had multiple amino acid substitutions at the Asp-350, Ser-357, Ser-385, and/or Met-377 sites of penicillin-binding protein 3. Two strains were β-lactamase positive and ampicillin-clavulanate resistant. Biofilm indices varied widely, and IS 1016 was detected in 10.7% of the strains tested. Moreover, there was wide variation in the characteristics of invasive NTHi strains. NTHi strains, showing great genetic diversity, are responsible for most invasive H. influenzae infections in children in the postvaccine era. Continuous monitoring of NTHi strains responsible for invasive diseases in children is important to detect changes in the epidemiology of invasive H. influenzae infections in the postvaccine era., (Copyright © 2018 American Society for Microbiology.)

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.

Introduction: The implementation of the Hib conjugate vaccine in the United Kingdom in 1992 resulted in a rapid decline in invasive Hib disease across all age groups. However, a resurgence in 2000-2002 prompted the introduction of additional control measures, including a routine 12-month booster in 2006. Here we describe results from a national serosurvey in children eligible for the 12-month booster and recent Haemophilus influenzae epidemiology in England and Wales., Methods: A national serosurvey was performed to determine the prevalence of anti-polyribosyl-phosphate (anti-PRP) IgG antibodies in 1000 residual samples from children up to 8 years of age in 2013-2014. Data were compared to previous national serosurveys performed by the same laboratory. Current epidemiology of invasive H. influenzae disease in England and Wales is also reported., Results: Median anti-PRP IgG concentrations were highest among 1 year olds at 4.4 µg/mL (IQR, 1.3-14.9; n = 99) and then declined rapidly but remained ≥1.0 µg/mL across the age-groups in the cohort eligible for the 12-month booster. Overall, 89% of children (719/817) had anti-PRP concentrations ≥0.15 µg/mL, the putative threshold for short-term protection against invasive Hib disease. During 2012-2016, annual Hib disease incidence remained below one case per million population, responsible for only 67 of 3523 laboratory-confirmed H. influenzae cases, including one case of Hib meningitis during the 5-year period. There were only two deaths within 30 days over the five-year period (case fatality rate, 3.0%)., Conclusions: Hib control in England and Wales is currently the best achieved since the vaccine was introduced more than two decades ago. However, Hib antibodies wane rapidly after the 12 months booster. Although most children remain protected against disease, antibody levels may not be high enough to prevent carriage among toddlers. Ongoing monitoring is essential to inform future vaccination policy., (Copyright © 2018 The British Infection Association. All rights reserved.)

Background: More than two decades after the implementation of the Hib conjugate vaccine in North America, Haemophilus influenzae serotype a (Hia) has emerged as a significant cause of invasive disease in Indigenous communities. However, little is known about the global presence of this pathogen., Methods: We interrogated the H. influenzae Multi-Locus Sequence Typing (MLST) website (https://pubmlst.org/hinfluenzae/) by selecting for serotype a records. We also updated our previous literature review on this subject matter., Results: Hia has been reported from at least 35 countries on six major continents. However, most Hia diseases were associated with Indigenous communities. Clonal analysis identified two clonal populations with one typified as ST-23 responsible for most invasive disease in North America and being the predominant clone described on the H. influenzae MLST website. Incidence of invasive Hia disease in Indigenous communities in North America are similar to the rates of Hib disease reported prior to the Hib conjugate vaccine era. Hia causes severe clinical diseases, such as meningitis, septicaemia, pneumonia, and septic arthritis with case-fatality rates between 5.6% and 33% depending on the age of the patient and the genetic makeup of the Hia strain., Conclusion: Although invasive Hia disease can be found globally, the current epidemiological data suggest that this infection predominantly affects Indigenous communities in North America. The clinical disease of Hia and the clonal nature of the bacteria resemble that of Hib. The high incidence of invasive Hia disease in Indigenous communities, along with potential fatality and severe sequelae causing long-term disability in survivors, may support the development of a new Hia conjugate vaccine for protection against this infection similar in design to the one introduced in the 1990s to control invasive Hib disease., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Although the incidence of ventilator-associated pneumonia (VAP) is very high, there are still many uncertainties about clinical course of VAP among tracheotomized patients. The goal of the present study was to determine the impact of tracheotomy on VAP incidence and etiology, as well as outcome of VAP patients with tracheotomy. The study was conducted in a 15-bed Surgical and Neurosurgical Intensive Care Unit (ICU), Sestre milosrdnice University Hospital Center in Zagreb, Croatia. The study included all patients undergoing only percutaneous tracheotomy during the study period. According to our data, the incidence of VAP among percutaneous tracheotomized patients was 42%, not considering the time between tracheotomy and VAP onset. However, when only patients developing VAP after tracheotomy were taken into account, the incidence of VAP among tracheotomized patients dropped to 8% only. The most commonly isolated bacterium was Staphylococcus aureus, accounting for 17 (37%) isolates, followed by Haemophilus influenzae, accounting for another 10 (22%) isolates. The development of VAP among percutaneously tracheotomized patients was associated with longer total ICU stay (regardless of whether VAP developed before or after tracheotomy), while total duration of mechanical ventilation and mortality rate remained unaffected.

Haemophilus parasuis is an important pathogen causing severe infections in pigs. However, the specific bacterial factors that participate in pathogenic process are poorly understood. VacJ protein is a recently discovered outer membrane lipoprotein that relates to virulence in several pathogens. To characterize the function of the vacJ gene in H. parasuis virulent strain HS49, a vacJ gene-deletion mutant ΔvacJ and its complemented strain were constructed. Our findings supported that VacJ is essential for maintenance of cellular integrity and stress tolerance of H. parasuis, by the demonstrations that the ΔvacJ mutant showed morphological change, increased NPN fluorescence and, and decreased resistance to SDS-EDTA, osmotic and oxidation pressure. The increased susceptibility to several antibiotics in the ΔvacJ mutant further suggested that the stability of the outer membrane was impaired as a result of the mutation in the vacJ gene. Compared to the wild-type strain, the ΔvacJ mutant strain caused a decreased survival ratio from the serum and complement killing, and exhibited a significant decrease ability to adhere to and invade PK-15 cell. In addition, the ΔvacJ mutant showed reduced biofilm formation compared to the wild-type strain. Furthermore, the ΔvacJ was attenuated in a murine (Balb/C) model of infection and its LD 50 value was approximately fifteen-fold higher than that of the wild-type or complementation strain. The data obtained in this study indicate that vacJ plays an essential role in maintaining outer membrane integrity, stress tolerance, biofilm formation, serum resistance, and adherence to and invasion of host cells related to H. parasuis and further suggest a putative role of VacJ lipoprotein in virulence regulation., (Copyright © 2016. Published by Elsevier B.V.)

Worldwide, pneumonia is the leading cause of death in infants and young children (aged <5 years). We provide an overview of the global pneumonia disease burden, as well as the aetiology and management practices in different parts of the world, with a specific focus on the WHO Western Pacific Region. In 2011, the Western Pacific region had an estimated 0.11 pneumonia episodes per child-year with 61,900 pneumonia-related deaths in children less than 5 years of age. The majority (>75%) of pneumonia deaths occurred in six countries; Cambodia, China, Laos, Papua New Guinea, the Philippines and Viet Nam. Historically Streptococcus pneumoniae and Haemophilus influenzae were the commonest causes of severe pneumonia and pneumonia-related deaths in young children, but this is changing with the introduction of highly effective conjugate vaccines and socio-economic development. The relative contribution of viruses and atypical bacteria appear to be increasing and traditional case management approaches may require revision to accommodate increased uptake of conjugated vaccines in the Western Pacific region. Careful consideration should be given to risk reduction strategies, enhanced vaccination coverage, improved management of hypoxaemia and antibiotic stewardship., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Non-typeable Haemophilus influenzae (NTHi) is a human restricted commensal and pathogen that elicits inflammation by adhering to and invading airway epithelia cells: transcytosis across these cells can result in systemic infection. NTHi strain R2866 was isolated from the blood of a normal 30-month old infant with meningitis, and is unusual for NTHi in that it is able to cause systemic infection. Strain R2866 is able to replicate in normal human serum due to expression of lgtC which mimics human blood group p(k). R2866 contains a phase-variable DNA methyltransferase, modA10 which switches ON and OFF randomly and reversibly due to polymerase slippage over a long tetrameric repeat tract located in its open reading frame. Random gain or loss of repeats during replication can results in expressed (ON), or not expressed (OFF) states, the latter due to a frameshift or transcriptional termination at a premature stop codon. We sought to determine if the unusual virulence of R2866 was modified by modA10 phase-variation. A modA10 knockout mutant was found to have increased adherence to, and invasion of, human ear and airway monolayers in culture, and increased invasion and transcytosis of polarized human bronchial epithelial cells. Intriguingly, the rate of bacteremia was lower in the infant rat model of infection than a wild-type R2866 strain, but the fatality rate was greater. Transcriptional analysis comparing the modA10 knockout to the R2866 wild-type parent strain showed increased expression of genes in the modA10 knockout whose products mediate cellular adherence. We conclude that loss of ModA10 function in strain R2866 enhances colonization and invasion by increasing expression of genes that allow for increased adherence, which can contribute to the increased virulence of this strain., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Nontypeable Haemophilus influenzae (NTHi) bacteraemia in pregnant women is strongly associated with pregnancy loss and preterm delivery. However, the clinical significance of isolation of NTHi from nonsterile sites is unknown., Aims: To examine the hypothesis that isolation of NTHi from any specimen is associated with adverse perinatal outcomes and to investigate the impression that NTHi is disproportionately isolated from indigenous women and their neonates., Materials and Methods: Cases where NTHi was isolated from maternal, fetal or neonatal specimens during the period from 1 July 1997 to 1 July 2009 were identified. Demographic and clinical data were extracted from case notes. Histopathological material was re-reviewed by a perinatal pathologist. Demographic and clinical features of the affected group were compared with the hospital obstetric population., Results: NTHi was isolated from maternal, fetal or neonatal specimens in 97 pregnancies. Two women had NTHi isolated during different pregnancies. Two mothers and 10 neonates were bacteraemic. Indigenous women comprised 28% of pregnancies where NTHi was isolated, compared with 6% of the hospital obstetric population (P < 0.001). Pregnancy loss occurred in six cases (6%). Median gestation at delivery was 33 weeks. Of 96 liveborn neonates, 88 (92%) required admission to a neonatal special care unit. Four liveborn neonates died (4%). Chorioamnionitis was confirmed by histology in 31/33 (93.9%) of placentas examined., Conclusions: Isolation of NTHi occurred more commonly in indigenous women and neonates. Isolation of NTHi from any obstetric or neonatal specimen is associated with chorioamnionitis, preterm birth, pregnancy loss, early-onset neonatal sepsis and neonatal death., (© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To characterize adverse events (AEs) after Haemophilus influenzae type b (Hib) vaccines reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system., Study Design: We searched VAERS for US reports after Hib vaccines among reports received from January 1, 1990, to December 1, 2013. We reviewed a random sample of reports and accompanying medical records for reports classified as serious. All reports of death were reviewed. Physicians assigned a primary clinical category to each reviewed report. We used empirical Bayesian data mining to identify AEs that were disproportionally reported after Hib vaccines., Results: VAERS received 29,747 reports after Hib vaccines; 5179 (17%) were serious, including 896 reports of deaths. Median age was 6 months (range 0-1022 months). Sudden infant death syndrome was the stated cause of death in 384 (51%) of 749 death reports with autopsy/death certificate records. The most common nondeath serious AE categories were neurologic (80; 37%), other noninfectious (46; 22%) (comprising mainly constitutional signs and symptoms); and gastrointestinal (39; 18%) conditions. No new safety concerns were identified after clinical review of reports of AEs that exceeded the data mining statistical threshold., Conclusion: Review of VAERS reports did not identify any new or unexpected safety concerns for Hib vaccines., (Published by Elsevier Inc.)

Purpose: Haemophilus influenzae type b bacteria has been responsible for recent increase in invasive disease in the adult population of the United States. This increase in H. influenzae infections is greatest in individuals above 65 years of age. A plausible explanation for this increase may be the changes observed in the epidemiology of invasive H. influenzae type b (Hib) disease and the susceptibility of aggregate hosts., Data Sources: A comprehensive literature review was conducted from multiple data sources, such as PubMed, MEDLINE, CDC, journal articles, reference texts, and Internet websites., Conclusions: The increase in infectious disease caused by H. influenzae type b bacteria is affecting individuals 65 years and older and is preventable. However, Hib vaccines are currently approved for the pediatric population and susceptible adults with certain immune deficiencies. New trends in this invasive disease require reevaluation of current guidelines to include individuals 65 years and older as target population for the polysaccharide Hib vaccine., Implications for Practice: The changing epidemiology of H. influenzae type b bacteria requires reevaluation of current immunization guidelines regarding Hib vaccination so that it is included in the immunization schedule for adults aged 65 and above., (©2014 American Association of Nurse Practitioners.)

Haemophilus parasuis is the cause of Glässer's disease in swine, which is characterized by systemic infection resulting in polyserositis, meningitis, and arthritis. Investigation of this animal disease is complicated by the enormous differences in the severity of disease caused by H. parasuis strains, ranging from lethal systemic disease to subclinical carriage. To identify differences in genotype that could account for virulence phenotypes, we established the virulence of, and performed whole genome sequence analysis on, 11 H. parasuis strains. Virulence was assessed by evaluating morbidity and mortality following intranasal challenge of Caesarean-derived, colostrum-deprived (CDCD) pigs. Genomic DNA from strains Nagasaki (serotype 5), 12939 (serotype 1), SW140 (serotype 2), 29755 (serotype 5), MN-H (serotype 13), 84-15995 (serotype 15), SW114 (serotype 3), H465 (serotype 11), D74 (serotype 9), and 174 (serotype 7) was used to generate Illumina paired-end libraries for genomic sequencing and de novo assembly. H. parasuis strains Nagasaki, 12939, SH0165 (serotype 5), SW140, 29755, and MN-H exhibited a high level of virulence. Despite minor differences in expression of disease among these groups, all pigs challenged with these strains developed clinical signs consistent with Glässer's disease between 1-7 days post-challenge. H. parasuis strains 84-15995 and SW114 were moderately virulent, in that approximately half of the pigs infected with each developed Glässer's disease. H. parasuis strains H465, D74, and 174 were minimally virulent or avirulent in the CDCD pig model. Comparative genomic analysis among strains identified several noteworthy differences in coding regions. These coding regions include predicted outer membrane, metabolism, and pilin or adhesin related genes, some of which likely contributed to the differences in virulence and systemic disease observed following challenge. These data will be useful for identifying H. parasuis virulence factors and vaccine targets.

Background: Many risks of death in childhood bacterial meningitis are well-identified, but factors influencing survival time have received less attention. Better understanding of this issue could help explain why adjuvant medications have performed unevenly in different trials., Methods: In a post hoc analysis of prospectively collected data from a large bacterial meningitis treatment trial in Luanda, Angola, we compared time to death after initiation of antimicrobial treatment among 206 children with etiology and other patient characteristics. The risks of dying very quickly (0-4 hours), quickly (4-8 hours) or after longer periods were analyzed by logistic regression., Results: Median time to death was 18.5 hours, half the time in Streptococcus pneumoniae (11.8 hours) compared with Haemophilus influenzae (26.8 hours) meningitis. Of all deaths caused by pneumococcal or H.influenzae meningitis, 42% versus 16%, respectively, occurred within the first 8 hours. In addition, patients who succumbed within 8 hours, unlike those dying later, had a short disease history, shock, hypoglycemia and poor cerebrospinal fluid white cell response., Conclusions: Time to death in Angola is so short that hardly anything, except perhaps modern intensive care, is likely to improve outcome in a patient with meningitis, especially the pneumococcal disease.

Haemophilus influenzae type b (Hib) vaccine was included in the Yemen immunization programme in 2005. This study compared the rates of very severe pneumonia and all-cause meningitis hospitalization and death, before and after introduction of conjugate Hib vaccine, and reports the results of the 2010 bacterial meningitis surveillance. A retrospective analysis was made of data collected for 2000-2010 for all children aged 2-60 months in the main children's hospital in Sana'a. Compared with the pre-Hib vaccination period, the post-Hib period showed significant and impressive reductions in the rates of hospitalization and death for all-cause meningitis. However, hospitalization and death for very severe pneumonia improved only modestly, and there was evidence of a decreasing but non-significant trend indicting that very severe pneumonia was a non-specific endpoint with multi-etiologies (both viral and bacterial). Very severe pneumonia remains the leading cause of severe morbidity and death for young children, particularly those aged < 12 months.

Background: The conjugated Haemophilus influenzae (Hi) type b vaccine caused a marked decrease in invasive Hi disease rates. Nonencapsulated Hi infection now constitutes most invasive Hi morbidity and mortality. This study examines invasive Hi infection incidence in Israel in the postvaccine era years, 2003-2012, and characterizes the epidemiology, clinical diagnosis and case fatality rates of invasive Hi disease in children <15 years of age., Methods: An ongoing, nationwide prospective surveillance program for invasive Hi infections in Israel. Epidemiologic and clinical data were collected. Diagnoses were classified as meningitis, pneumonia, bacteremia/sepsis and other clinical foci., Results: Overall, 389 cases of invasive Hi infections were identified; 242 (62%) nontypable Hi (NTHi), 103 (26%) Hi type b (Hib) and 41 (11%) encapsulated non-b Hi (enbHi). Children <1 year of age accounted for 51% of the overall disease. Invasive Hi disease incidence in children <15 years of age was stable with a mean annual incidence (per 100,000) of 2.0 ± 0.4. The highest incidence of invasive Hi infections was among infants <1 year with rates of 6.2, 4.9, 1.6 and 12.7 for NTHi, Hib, enbHi and total Hi, respectively. The clinical diagnoses of NTHi and enbHi were similar, but differed from Hib with the former presenting mostly as isolated sepsis/bacteremia and the latter primarily as meningitis. Among children with invasive Hib infection, 40% were classified as vaccine failure., Conclusions: In the post-Hib vaccination era, invasive Hi morbidity and mortality are largely attributed to NTHi sepsis. Still, with the changing epidemiology of invasive Hi, continued surveillance of all Hi strains is justified.

Haemophilus influenzae, particularly H influenzae serotype b (Hib), is an important pathogen that causes serious diseases like meningitis and septicaemia. Since the introduction of Hib conjugate vaccines in the 1990s, the epidemiology of invasive H influenzae disease has changed substantially, with most infections now caused by non-Hib strains. We discuss the importance of H influenzae serotype a (Hia) as a cause of serious morbidity and mortality and its global epidemiology, clinical presentation, microbiology, immunology, prevention, and control. Much like Hib, the capsule of Hia is an important virulence factor contributing to the development of invasive disease. Molecular typing of Hia has identified distinct clonal groups, with some linked to severe disease and high case-fatality rates. Similarities between Hia and Hib capsules, their clinical presentation, and immunology of infection suggest that a bivalent Hia-Hib capsular polysaccharide-protein conjugate vaccine could offer protection against these two important serotypes of H influenzae., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

To investigate the association between country incidence of type 1 diabetes and mortality from infectious disease and antibiotic susceptibility. An ecological study to explore the relationship at a country level of the reported incidence of type 1 diabetes (DiaMond) to infectious disease mortality (World Health Organisation) and to antibiotic susceptibility (Alexander Project). There were significant negative correlations between the incidence of type 1 diabetes and mortality for all infectious diseases studied. There were also significant positive correlations between the incidence of type 1 diabetes and antibiotic susceptibilities of Strep. pneumoniae, but not to those of Haem. influenzae. Since infectious disease mortality and antibiotic susceptibility are surrogate markers for bacterial exposure, our results provide support for a negative association between bacterial exposure in a community and its incidence of type 1 diabetes. The consistency of our results as well as the highly statistically significant results of most of the associations studied reinforces the validity of our findings.

Background: Optimal antibiotic treatment strategies of Haemophilus infections are still needed. Therefore, 30-day case fatality rate (CFR) of Haemophilus bacteremia and efficacy of various antibiotic treatment regimes were studied., Methods: All episodes of Haemophilus bacteremia in the former Copenhagen County during the period 2000-9 were included in the study. Clinical and biochemical findings and outcome were collected retrospectively from medical records., Results: 105 consecutive episodes were identified (median age: 69 years, with only 4 children <16 years), 72% were due to non-typeable -, 16% to typeable H. influenzae, and 11% to other Haemophilus species. Pneumonia was the most common primary focus (in 48%), and 58% of the patients had Charlson comorbidity index > 1. Definitive antibiotic therapy was in 26 cases benzylpenicillin, in 12 cases aminopenicillins, in 50 cases cefuroxime and in 16 cases broadspectrum antibiotics, whereas 1 palliative case died without start of therapy. Whereas the use of broadspectrum antibiotics was related to the severity of the disease (admittance to ICU, need for assisted ventilation or hemodialysis, septic shock), no significant difference in clinical features was demonstrated for therapy with benzylpenicillin, aminopenicillin or cefuroxime, except benzylpenicillin was rarely administered to immunosuppressed patients. The CFR was 22% (23/105). The choice of empiric antibiotic therapy was not significantly associated with mortality (adequate vs. inadequate treatment: 23% (21/93) vs. 17% (2/12), respectively, P > 0.05). In contrast, definite antibiotic therapy with cefuroxime or aminopenicillins resulted in a significantly lower CFR than treatment with benzylpenicillin (12% (6/50) or 0% (0/12) vs. 39% (10/26), respectively, Log rank test P < 0.02). When adjustments were made for other identified risk factors in bivariate logistic regression analysis, treatment with cefuroxime was still were found to be associated with a significantly lower CFR than for benzylpenicillin: OR: 0.21 (0.06-0.69), P = 0.01 (hospital-acquired bacteremia), OR: 0.27 (0.08-0.91), P = 0.04 (polymicrobial episodes), OR: 0.16 (0.04-0.59), P = 0.006 (admittance at intensive care unit), OR: 0.22 (0.06-0.82), P = 0.02 (alcohol abuse), OR: 0.15 (0.04-0.60), P = 0.008 (altered mental state), OR: 0.22 (0.07-0.71), P = 0.01 (temperature < 38 °C), OR: 0.23 (0.07-0.79), P = 0.02 (septic shock), OR: 0.21 (0.06-0.69), P = 0.01 (mechanical ventilation)., Conclusion: Our results suggest that, after susceptibility testing, cefuroxime or aminopenicillins are preferable to benzylpenicillins as definitive therapy for Haemophilus bacteremia.

Background: With the introduction of Haemophilus influenzae serotype b (Hib) conjugate vaccines, there has been a dramatic reduction of Hib disease in young children and the epidemiological trends of invasive H. influenzae have shifted., Methods: Data were collected from active surveillance for invasive H. influenzae disease conducted through Active Bacterial Core surveillance sites during 1989-2008., Results: During 1999-2008, the estimated mean annual incidence of H. influenzae infection was 1.62 cases per 100 000 population; 15.3% of cases were fatal. Incidence was higher among adults aged ≥65 years, compared with other age groups. The largest burden of disease among children aged <5 years was in infants aged <1 year; many of these cases occurred during the first month of life in preterm or low-birth weight infants. An estimated 10% of the total burden of disease among children aged <5 years occurred in American Indian and Alaska Native children. During 1989-2008, 7559 cases of H. influenzae disease were reported from Active Bacterial Core surveillance sites. Small increases in the incidence of serotypes a, e, and f were observed during 1989-2008. The largest of these increases was in serotype f and was primarily among adults aged ≥18 years., Conclusions: Since the introduction of Hib conjugate vaccines, the incidence of invasive disease caused by H. influenzae in the United States has decreased dramatically; however, a considerable burden of non-Hib disease is still present in the oldest and youngest age groups. There is no evidence of substantial replacement disease with non-b serotypes in young children in the United States.

Since the introduction of the Haemophilus influenzae type b vaccine, the incidence of invasive H. influenzae type b disease among children has fallen dramatically, but the effect on invasive H. influenzae disease among adults may be more complex. In this population-based study we examined the epidemiology and outcomes of invasive disease caused by typeable and nontypeable H. influenzae among Utah adults during 1998-2008. The overall incidence increased over the study period from 0.14/100,000 person-years in 1998 to 1.61/100,000 person-years in 2008. The average incidence in persons >65 years old was 2.74/100,000 person-years, accounting for 51% of cases and 67% of deaths. The incidence was highest for nontypeable H. influenzae (0.23/100,000 person-years), followed by H. influenzae type f (0.14/100,000 person-years). The case-fatality rate was 22%. The incidence of invasive H. influenzae in Utah adults appears to be increasing. Invasive H. influenzae infection disproportionately affected the elderly and was associated with a high mortality rate.

Haemophilus parasuis is the etiological agent of Glässer's disease in swine, characterized by fibrinous polyserositis, polyarthritis and meningitis. The lack of a vaccine against a broad spectrum of strains has limited the control of the disease. Recently, virulence associated trimeric autotransporters (VtaA) were described as antigenic proteins of H. parasuis. In this study 6 VtaA were produced as recombinant proteins and used to immunize snatch-farrowed, colostrum-deprived piglets. Immunized animals developed specific systemic and mucosal antibodies. The protective capacity of the anti-VtaA antibodies was evaluated by the inoculation of 3 × 10(8) or 6 × 10(6) colony forming units (CFU) of the highly virulent strain Nagasaki. Vaccinated animals had a delayed course of disease and 33 or 57%, respectively, of the animals survived the lethal challenge. The partial protection achieved with the recombinant VtaA supports their potential as candidates to be included in future vaccine formulations against H. parasuis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: Haemophilus influenzae is an important cause of invasive infection but contemporary data in non-selected populations is limited., Methods: Population-based surveillance for Haemophilus influenzae bacteremia was conducted in seven regions in Australia, Canada, and Denmark during 2000-2008., Results: The overall annual incidence rate was 1.31 per 100,000 population and type specific rates were 0.08 for H. influenzae serotype b (Hib), 0.22 for H. influenzae serotypes a, c-f (Hiac-f), and 0.98 per 100,000 for non-typeable H. influenzae (NTHi). Very young and old patients were at highest risk. The serotypes causing disease varied according to age with nearly all cases in the elderly due to NTHi. The presence of comorbid medical illness was common with 14%, 16%, and 29% patients having Charlson comorbidity scores of 1, 2, and ≥ 3, respectively. The 30-day all-cause case-fatality rate was 18%. Factors independently associated with death at 30-days in logistic regression analysis included male gender, hospital-onset disease, older age, and lower respiratory tract, central nervous system, or unknown focus of infection., Conclusions: Haemophilus influenzae is an important cause of morbidity and mortality particularly with NTHi in the elderly. These data serve as a baseline to assess the future effectiveness of new preventative interventions., (Copyright © 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Haemophilus parasuis is the agent responsible for causing Glässer's disease, which is characterized by fibrinous polyserositis, polyarthritis, and meningitis in pigs. In this study, we have characterized native outer membrane proteins with affinity to porcine transferrin (NPAPT) from H. parasuis serovar 5, Nagasaki strain. This pool of proteins was used as antigen to developed two vaccine formulations: one was adjuvanted with a mineral oil (Montanide IMS 2215 VG PR), while the other was potentiated with a bacterial neuraminidase from Clostridium perfringens. The potential protective effect conferred by these two vaccines was compared to that afforded by two other vaccines, consisting of recombinant transferrin-binding protein (rTbp) A or B fragments from H. parasuis, Nagasaki strain, and by a commercially available inactivated vaccine. Five groups of colostrum-deprived piglets immunized with the vaccines described above, one group per each vaccine, and a group of nonvaccinated control animals were challenged intratracheally with a lethal dose (3 × 10⁸ CFU) of H. parasuis, Nagasaki strain. The two vaccines containing rTbps yielded similar results with minimal protection against death, clinical signs, gross and microscopic lesions, and H. parasuis invasion. In contrast, the two vaccines composed of NPAPT antigen and commercial bacterin resulted in a strong protection against challenge (without deaths and clinical signs), mild histopathological changes, and no recovery of H. parasuis, thus suggesting their effectiveness in preventing Glässer's disease outbreaks caused by serovar 5.

Background: With the aim of populating the Lives Saved Tool (LiST) with parameters of effectiveness of existing interventions, we conducted a systematic review of the literature assessing the effect of Haemophilus influenzae type b (Hib) and pneumococcal (PC) conjugate vaccines on incidence, severe morbidity and mortality from childhood pneumonia., Methods: We summarized cluster randomized controlled trials (cRCTs) and case-control studies of Hib conjugate vaccines and RCTs of 9- and 11-valent PC conjugate vaccines conducted in developing countries across outcome measures using standard meta-analysis methods. We used a set of standardized rules developed for the purpose of populating the LiST tool with required parameters to promote comparability across reviews of interventions against the major causes of childhood mortality. The estimates could be adjusted further to account for factors such as PC vaccine serotype content, PC serotype distribution and human immunodeficiency virus prevalence but this was not included as part of the LiST model approach., Results: The available evidence from published data points to a summary effect of the Hib conjugate vaccine on clinical pneumonia of 4%, on clinical severe pneumonia of 6% and on radiologically confirmed pneumonia of 18%. Respective effectiveness estimates for PC vaccines (all valent) on clinical pneumonia is 7%, clinical severe pneumonia is 7% and radiologically confirmed pneumonia is 26%., Conclusions: The findings indicated that radiologically confirmed pneumonia, as a severe morbidity proxy for mortality, provided better estimates for the LiST model of effect of interventions on mortality reduction than did other outcomes evaluated. The LiST model will use this to estimate the pneumonia mortality reduction which might be observed when scaling up Hib and PC conjugate vaccination in the context of an overall package of child health interventions.

Secondary bacterial infections that follow infection with influenza virus result in considerable morbidity and mortality in young children, the elderly, and immunocompromised individuals and may also significantly increase mortality in normal healthy adults during influenza pandemics. We herein describe a mouse model for investigating the interaction between influenza virus and the bacterium Haemophilus influenzae. Sequential infection with sublethal doses of influenza and H. influenzae resulted in synergy between the two pathogens and caused mortality in immunocompetent adult wild-type mice. Lethality was dependent on the interval between administration of the bacteria and virus, and bacterial growth was prolonged in the lungs of dual-infected mice, although influenza virus titers were unaffected. Dual infection induced severe damage to the airway epithelium and confluent pneumonia, similar to that observed in victims of the 1918 global influenza pandemic. Increased bronchial epithelial cell death was observed as early as 1 day after bacterial inoculation in the dual-infected mice. Studies using knockout mice indicated that lethality occurs via a mechanism that is not dependent on Fas, CCR2, CXCR3, interleukin-6, tumor necrosis factor, or Toll-like receptor-4 and does not require T or B cells. This model suggests that infection with virulent strains of influenza may predispose even immunocompetent individuals to severe illness on secondary infection with H. influenzae by a mechanism that involves innate immunity, but does not require tumor necrosis factor, interleukin-6, or signaling via Toll-like receptor-4.

To analyze the role of Haemophilus influenzae type b in children's death resulting from severe pneumonia conventional PCR, Southern blotting and in situ PCR were evaluated for the detection of Hib in 202 paraffin-embedded lung tissue autopsy samples from children with fatal outcome of pneumonia in China during the period of 1953-2002. The results indicate that Hib was a cause of fatal pneumonia in 36 (17.8%) of 202 samples.

Background: Most of Asia, including Indonesia, does not use Haemophilus influenzae type b (Hib) conjugate vaccines. We estimated total vaccine-preventable disease burden and the cost-effectiveness of Hib conjugate vaccine in Indonesia., Methods: Hib pneumonia and meningitis incidences for children with access to health care were derived from a randomized vaccine probe study on Lombok Island, Indonesia during 1998-2002. Incidences were adjusted for limited access to care. Health system and patient out-of-pocket treatment cost data were collected concurrent with the probe study. For Hib vaccine in monovalent and combined (with DTP-HepB) presentations, we used 2007 UNICEF vaccine prices of US$3.30 and $3.75 per dose., Results: For the 2007 Indonesian birth cohort, Hib vaccine would prevent meningitis in 1 of every 179 children, pneumonia in 1 of every 18 children, and 4.9% of mortality among those younger than 5 years. The total incremental societal costs of introducing Hib vaccine in monovalent and pentavalent presentations were, respectively, US$11.74 and $8.93 per child vaccinated. Annual discounted treatment costs averted amounted to 20% of pentavalent vaccine costs. For the pentavalent vaccine, the incremental costs per discounted death and disability adjusted life-year averted amounted to US$3102 and $74, respectively, versus $4438 and $102 for monovalent vaccine., Conclusions: Routine infant Hib vaccination would prevent a large burden of pediatric illness and death in Indonesia. Even without external funding support, Hib vaccine will be a highly cost-effective intervention in either a monovalent or pentavalent presentation based on commonly used benchmarks.

In a case series of 152 children aged from 2 to 132 months will pleural emphema from a paediatric tertiary hospital in Luanda, Angola between September 2004 and March 2005, the authors found a high prevalence of anaemia and malnutrition. The most prevalent bacteria in pleural fluid were: D pneumoniae, Haemophyllus and S aureus. The median for hospital stay was 25 days. The lethality was 7.8% and was not statistically associated with malnutrition, although this variable was associated, in multivariate analysis, with prolonged hospitalization time.

Objective: To prospectively study the epidemiology and antibiotic resistance of Haemophilus infuenzae isolates from invasive infections in children., Methods: Children (<5years) with pneumonia, meningitis and septicemia from three hospitals in Dhaka, Bangladesh were enrolled (1999-2003); clinical and laboratory data, and blood for cultures were collected. Cerebrospinal fluid (CSF) of meningitis cases was analyzed (Gram stain, culture and biochemical tests). Hib antigen was detected by latex agglutination (LA) in culture-negative pyogenic CSF and PCR was done for bexA gene in culture- and LA-negative pyogenic CSF. Antibiotic susceptibility was determined by E-Tests and beta-lactamase by nitrocefin stick., Results: Seventy-three cases of H. influenzae infections (46 of 293 meningitis cases, 25 of 1493 pneumonia cases, 2 of 48 septicemia cases) were detected; 63%, 34% and 3% of them had meningitis, pneumonia and septicemia respectively. H. influenzae type b (Hib) caused infections in 80.8% of cases (60.3% meningitis, 20.5% pneumonia). Most (86%) infections clustered in 4-12month infants. The case-fatality in pneumonia was 8% compared to 19% in meningitis. H. influenzae isolates from pneumonia and meningitis children were equally resistant to antibiotics (46% vs 43%). Of 10 drugs tested, isolates were resistant to ampicillin (31%), chloramphenicol (42%), trimethoprim-sulfamethoxazole (44%) and azithromycin (1.4%). Multidrug-resistant (MDR) strains were equally prevalent in Hib (31%) and non-b-type (29%) isolates, and in pneumonia (31%) and meningitis (34%) cases. None was resistant to amoxicillin-clavulanate, ceftriaxone, ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin. Of all H. influenzae infections, 40%, 4.4% and 100% of pneumonia, meningitis and septicemia cases were caused by other serotypes or non-typeable strains. All ampicillin-resistant-strains produced beta-lactamase without detection of beta-lactamase-negative-ampicillin-resistant (BLNAR) strains., Conclusion: Hib is a leading cause of invasive bacterial infections in infants. Multidrug-resistant H. influenzae is common and requires amoxicillin-clavulanate, ceftriaxone or azithromycin as empirical therapy with specific recommendation for use of ceftriaxone for treatment of meningitis particularly MDR cases. New fluoroquinolines has potential utility. An effective national Hib vaccination programme is essential in Bangladesh although non-Hib infections will remain an issue.

Objective: This study had for aim to determine the etiology of Haemophilus b pediatric meningitis., Design: A retrospective study of 216 biologically confirmed cases was carried out during 6 years (January 1995- December 2000) on children 0 to 15 years of age, hospitalized at the Albert Royer Children Hospital Center., Results: Haemophilus influenzae b is the first cause of pediatric meningitis (19.7%) followed by Nesseria meningitidis (14.5%), and Streptococcus pneumoniae (13.6%). The Haemophilus influenzae b meningitis cases are distributed all year round with a peak between January and March, that is to say, during the dry and cool season. They affect children at an average age of 11.7 months, with a sex ratio of 1.1 for boys. Almost all of the patients live in the low-socio-economic areas of the Dakar suburbs (92.8%). More than 90% of the H. influenzae b isolates are sensitive to ceftriaxone (96%) chloramphenicol (93%), and to ampicillin (91%). Clinical evolution is marked by death (17.8%) and recovery with psychological, sensory, and motor sequels (19.9%)., Conclusion: This report should help to include the combined vaccine Antihaemophilus influenzae b in the Senegalese Broad Vaccination Program. The final aim is the reduction of morbidity and mortality of infections due to Haemophilus influenzae b.

We used Western Australian emergency department data linked to hospital morbidity, death and microbiology data to describe the bacteriology of pneumonia according to age. The 'atypical' organisms and viruses were not assessed. A total of 6908 patients over a 3-year period were given an emergency department diagnosis of pneumonia, 76.9% were admitted and 6.3% died in hospital. Blood was cultured from 52.9% of patients with 6.4% growing potential pathogens. Streptococcus pneumoniae was the most common organism isolated and accounted for 92% of pathogens in those aged <15 years. Isolation of Enterobacteriaceae species tended to increase with age and accounted for around 25% of isolates from the elderly. Sputum was cultured from 25.3% of patients and bacteria were isolated from 30.3% of samples, commonly Haemophilus influenzae and S. pneumoniae. Isolates from sputum showed no distinct trend across age groups. These patterns question the value of routine blood and sputum cultures and have implications for empiric therapy for the elderly.

Invasive Haemophilus influenzae type b (Hib) diseases are major causes of childhood morbidity and mortality. For the period from 1994 to 2003, we retrospectively identified 53 children with invasive Hib disease including 31 with meningitis, 14 with pneumonia, 2 with septic arthritis, 2 with epiglottitis, 1 with neutropenic sepsis, and 3 who were bacteraemic without a focus. Two children died and 22 had serious sequelae; significantly, survivors with sequelae had presented with meningitis (P-value<0.001) or sepsis (P-value=0.001). During the 11-year period, the annual incidence of invasive Hib disease was estimated to be 4.4/100,000 children <5 years old. With rising affluence, decreasing costs of vaccines, and increased costs in caring for survivors, universal infant immunization with Hib vaccine may need to be reconsidered in Singapore.

Due to a successful Haemophilus Influenzae (HIF) vaccination program, this pathogen is no longer a major contributor to childhood morbidity and mortality. The effect on adult acquisition of HIF is unknown. The purpose of this study was to determine HIF infection frequency in severely burned patients. In a 62-month period, there were 1486 admissions. Twenty-four of 1,486 (1.6%) burn patients had HIF pneumonia: 16 (1%) within 72 h after injury; 8 (0.5%) patients developed it after the seventh day of hospitalization; 74 of 1,486 (5.0%) burn patients had pneumonia due to other organisms. There was no statistically significant difference between patients with HIF pneumonia and those with other pathogens with respect to age, race, sex, percent total body surface area (TBSA), inhalation injury, ventilator days, intensive care days, sepsis, or mortality. Nineteen percent of patients with HIF were<14 years of age compared to 12% in the other pneumonia group, p<0.01. HIF contributed to both an early and late pneumonia in burn patients. The organism responded to treatment and did not affect mortality.

Background: Ventilator-associated pneumonia is a clear risk factor for acute lung injury which has been poorly described in trauma patients. This prospective study was undertaken to estimate the incidence of such ventilator-associated pneumonia leading to acute lung injury, the risk factors, and the associated morbidity and mortality in a group of multiple trauma patients., Methods: Trauma patients who were mechanically ventilated and survived at least 24 h were included. Ventilator-associated pneumonia was confirmed by a bacterial culture of a blind protected telescoping catheter with at least 10 colony-forming units/ml of at least one pathogen. Episodes of acute lung injury were prospectively recorded., Results: Ventilator-associated pneumonia was documented in 78 patients of the 175 included (44%) and led to the development of ventilator-associated pneumonia acute lung injury in 18 patients (23%). The sole independent risk factor for ventilator-associated pneumonia leading to acute lung injury was the presence of Haemophilus influenzae (hazard ratio, 8.8; 95% confidence interval, 2.7-28.6). Eleven (61%) of the 18 patients with ventilator-associated pneumonia leading to acute lung injury had development of a ventilator-associated pneumonia recurrence, as compared with 20 (33%) of the 60 patients with ventilator-associated pneumonia alone (P = 0.03). Seven (39%) of the 18 trauma patients with ventilator-associated pneumonia leading to acute lung injury died, as compared with 9 (15%) of the 60 trauma patients with ventilator-associated pneumonia alone (P = 0.04)., Conclusion: Acute lung injury complicated the course of 15% of ventilator-associated pneumonia in trauma patients. H. influenzae seemed to be one of the most frequent bacteria involved and the sole risk factor identified. Occurrence of ventilator-associated pneumonia leading to acute lung injury modified the prognosis of trauma patients.

Predictor variables of intra-hospital lethality among infants with pyogenic meningitis due to Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae were identified using data from a follow-up study of infants with bacterial meningitis. The infants who were admitted to Couto Maia Hospital from March 1, 1997 to December 31, 1997 presenting with symptoms of bacterial meningitis were identified and included in a database. An analysis of the clinical and laboratory information was performed using EPI info 6.01b and SPSS 6.1 statistical programs. The total mortality rate was 17.1%, and the majority of deaths occurred within 48 hours of hospitalization. Factors associated most frequently with poor outcome included absence of respiratory infection, high cerebrospinal fluid protein, and compromised cranial nerves. Early identification of major risk groups is important to adopt measures to improve prognosis.

The introduction of vaccination against Haemophilus influenzae serotype b (Hib) in the Swedish childhood vaccination programme in 1992 resulted in a rapid 90% decline in meningitis cases. A recent rise in incidence in the UK underlines the need for continuing surveillance also in Sweden. Descriptive analysis of surveillance data for all invasive Hib infection cases notified in 1997-2003 was performed, with respect to age, gender, seasonality, geography and death; 185 cases (children 0-4 y: 37 cases) of invasive Hib disease were reported for an average incidence rate of 0.3 per 100,000 (children 0-4 y; 1.1). One fifth of the cases were children below 5 y of age, but two- thirds were over 30 y; median age was 49.5 y of age. 61% were female and 39% male (p = 0.0026). The sharp downward trend in incidence seen in the period 1993-1998 appears to have halted. During 2002 and 2003 there was a slight increase for children aged 0-4 y. There was also a highly significant female dominance, which has not been described before. Together with a shift in age distribution towards adults this points to women aged +30 y as a potential new risk group. This may reflect an increased risk owing to women being the primary carers of young children.

Background: Injectable penicillin is the recommended treatment for WHO-defined severe pneumonia (lower chest indrawing). If oral amoxicillin proves equally effective, it could reduce referral, admission, and treatment costs. We aimed to determine whether oral amoxicillin and parenteral penicillin were equivalent in the treatment of severe pneumonia in children aged 3-59 months., Methods: This multicentre, randomised, open-label equivalency study was undertaken at tertiary-care centres in eight developing countries in Africa, Asia, and South America. Children aged 3-59 months with severe pneumonia were admitted for 48 h and, if symptoms improved, were discharged with a 5-day course of oral amoxicillin. 1702 children were randomly allocated to receive either oral amoxicillin (n=857) or parenteral penicillin (n=845) for 48 h. Follow-up assessments were done at 5 and 14 days after enrollment. Primary outcome was treatment failure (persistence of lower chest indrawing or new danger signs) at 48 h. Analyses were by intention-to-treat and per protocol., Findings: Treatment failure was 19% in each group (161 patients, pencillin; 167 amoxillin; risk difference -0.4%; 95% CI -4.2 to 3.3) at 48 h. Infancy (age 3-11 months; odds ratio 2.72, 95% CI 1.95 to 3.79), very fast breathing (1.94, 1.42 to 2.65), and hypoxia (1.95, 1.34 to 2.82) at baseline predicted treatment failure by multivariate analysis., Interpretation: Injectable penicillin and oral amoxicillin are equivalent for severe pneumonia treatment in controlled settings. Potential benefits of oral treatment include decreases in (1) risk of needle-borne infections; (2) need for referral or admission; (3) administration costs; and (4) costs to the family.

In the past 30 years, great strides have been made in immunizing infants and children routinely in developing countries under the Expanded Programme on Immunization. Despite this, the introduction of Haemophilus influenzae type b (Hib) vaccines has progressed rather slowly compared to previously-introduced vaccines for infant immunizations. This slower uptake has been attributed partly to the need for data on the burden of invasive Hib disease. To understand this need, conceptual underpinnings and prerequisites were explored for Hib disease-burden studies. Methodological approaches were also reviewed for conducting Hib disease-burden studies that may be considered in developing countries. Potential studies span a range of designs that provide varying levels of clinical, laboratory and epidemiologic evidence of the burden of invasive Hib disease. Carefully-conducted studies can lay the foundation for complementary studies of long-term disability due to invasive Hib disease, national economic analysis, and field evaluations of vaccine. Studies done in collaboration with national agencies and clinical investigators will maximize study value and provide critical data for national decision-makers who make choices regarding the introduction of Hib vaccines.

Vaccine trials, the most informative way of determining the efficacy of a vaccine, can also provide valuable information about the burden of disease. The burden of Haemophilus influenzae type b (Hib) remains a major barrier to the use of Hib vaccines, especially in Asia. Recent studies in Indonesia and Bangladesh have used vaccine-trial designs, with known effective vaccines, to estimate the vaccine-preventable burden of Hib disease in those communities. New vaccines against pneumonia and diarrhoeal diseases are usually directed at only one of various causes of the syndrome. In the case of pneumonia, it is very difficult to determine the aetiology in most cases, so the vaccine trial offers a means of determining the burden of vaccine-preventable diseases. This is particularly important for pneumococcal vaccines as serotype replacement may reduce the effectiveness of the vaccines in the field. This approach would underestimate disease burden if vaccines were found to have an impact on syndromes other than those against which they are directed, and might lead to errors in estimation if there were erroneous assumptions about the efficacy of the vaccine against the condition under investigation.

Background: In Paraguay, as in most Latin American countries, data on the epidemiology and clinical characteristics of Haemophilus influenzae type b (Hib) diseases are scarce and incomplete., Methods: To address this issue, we performed a retrospective analysis of 102 patients admitted to the Instituto de Medicina Tropical, a referral hospital in Asunción, Paraguay, between January 1991 and September 1995 with diagnosis of invasive Hib infection. This study included patients 15 years of age and under-identified with positive cultures for Hib in blood, cerebrospinal fluid, or other sterile body fluids., Results: Eighty three (81%) patients presented with meningitis as principal focus of infection with median age of 9 months. Forty five (54%) patients with Hib meningitis were <12 months of age and 20 (24% of total cases) were <6 months of age. Overall mortality rate of meningitis was 13%. Of 11 patients who died, 10 (91%) were <12 months of age (p <0.02). Risk for mortality was correlated with presence of coma during admission (p <0.007) and CSF glucose level of <10 mg/dL (p <0.05). Severe sequelae such as bilateral hearing loss, hydrocephalus, and mental retardation were observed in 39% (28/72) of surviving patients, of whom 18 (51%) patients were <12 months of age (p <0.02). Thirty percent of isolated strains of Hib were resistant to ampicillin, 20% were resistant to chloramphenicol, and 10% to both drugs., Conclusions: This information provides evidence concerning the importance of continued support for Hib vaccine supplies in immunization programs in countries with limited resources such as Paraguay.

We report 2 cases of Haemophilus parainfluenzae endocarditis and review 34 cases of HACEK endocarditis from the literature. HACEK organisms are the most common cause of Gram-negative endocarditis in children. They have a propensity to form friable vegetations (especially H. parainfluenzae) that break off and cause symptomatic emboli. HACEK endocarditis (from a review of the 36 published cases) may involve previously normal hearts (33%), may be complicated by embolization (31%) and may require vegetectomy or other surgery (31%). Mortality with HACEK endocarditis was 14%. HACEK organisms may be resistant to penicillins but are susceptible to third generation cephalosporins.

Aims: To estimate Haemophilus influenzae type b (Hib) disease burden in Fiji in children under the age of 5 years (under-5s) prior to vaccine introduction. To compare estimates from WHO's Hib rapid assessment tool (RAT), with that from decline in disease after vaccine introduction., Methods: Laboratory data (meningitis), hospitalization and mortality data (pneumonia and meningitis) before and after Hib vaccine introduction were collected. The RAT protocol provides two independent estimates of pre-vaccine disease burden (one based on meningitis incidence laboratory data and the other based on mortality statistics). A third estimate uses the decline in disease following vaccine introduction., Results: The decline in meningitis hospitalizations implies a pre-vaccine Hib meningitis incidence of 66 per 100,000 in under-5s. This compares with a pre-vaccine RAT estimate of Hib meningitis incidence of 84 per 100,000 (for 1992-1993). The RAT estimated the total annual pre-vaccine Hib burden (meningitis plus pneumonia) at 476 cases and 36 deaths per year ("meningitis incidence method") and 70 cases and 5 deaths ("child mortality method"). Hib vaccine led to declines of 32% (95% confidence interval (CI)=11-48%), and 78% (95% CI=22-94%) for all under-5s meningitis hospitalizations and deaths, respectively. There was no similar consistent decline in pneumonia hospitalizations or deaths after vaccine introduction, except for a statistically significant reduction in pneumonia mortality in children aged under 1 year., Conclusions: Hib disease constitutes an important burden on the health of Pacific children that can be rapidly reduced with Hib vaccine. In this setting, routine morbidity statistics (comparing pre-and post-vaccine) provided an estimate of Hib meningitis burden which is broadly similar to that of the Hib RAT, suggesting that both might be valid ways to estimate Hib meningitis incidence. However, Hib pneumonia burden could not be estimated from routine statistics.

We report a case of prosthetic, aortic valve, infective endocarditis caused by Haemophilus paraphrophilus. There are no other cases described in the available literature where this microorganism has caused prosthetic valve endocarditis and no other case reported involving only the aortic valve.

The relationship of the 76kDa immunoglobulin binding, surface antigen (p76) of Haemophilus somnus to the high molecular weight immunoglobulin binding proteins (HMW IgBPs) was investigated. The kanamycin resistance gene from pLS88 was used via homologous recombination with allelic exchange to replace a portion of the gene encoding IgBPs of H. somnus strain 8025. Recombinants were shown by Western immunoblotting to express and secrete truncated antigens of approximately 200kDa and not to produce p76. The truncated HMW IgBP variants retained the ability to bind bovine IgG2 by the Fc portion as demonstrated by Western immunoblotting against IgG2 anti-DNP. This data indicated that the deleted 1.8kb BglII fragment was not required for secretion or immunoglobulin Fc binding by the HMW IgBPs but was required for expression of the downstream p76 gene. Functional studies showed that, in addition to Fc binding of IgG2 to truncated HMW IgBPs, the mutant strain 8025 Kan1 was equally resistant to killing by mouse complement but less virulent than the wild type parent (8025) in a mouse septicemia model of H. somnus infection. However, mutant strain 8025 Kan1 did adhere less well than the wild type to bovine pulmonary artery endothelial cells. It is probable that p76 and the missing peptides of the HMW IgBPs play a role in this aspect of virulence and perhaps other aspects.