R. de Groot

Streptococcus pneumoniae colonisation: the key to pneumococcal disease

Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. The burden of disease is highest in the youngest and oldest sections of the population in both more and less developed countries. The treatment of pneumococcal infections is complicated by the worldwide emergence in pneumococci of resistance to penicillin and other antibiotics. Pneumococcal disease is preceded by asymptomatic colonisation, which is especially high in children. The current seven-valent conjugate vaccine is highly effective against invasive disease caused by the vaccine-type strains. However, vaccine coverage is limited, and replacement by non-vaccine serotypes resulting in disease is a serious threat for the near future. Therefore, the search for new vaccine candidates that elicit protection against a broader range of pneumococcal strains is important. Several surface-associated protein vaccines are currently under investigation. Another important issue is whether the aim should be to prevent pneumococcal disease by eradication of nasopharyngeal colonisation, or to prevent bacterial invasion leaving colonisation relatively unaffected and hence preventing the occurrence of replacement colonisation and disease. To illustrate the importance of pneumococcal colonisation in relation to pneumococcal disease and prevention of disease, we discuss the mechanism and epidemiology of colonisation, the complexity of relations within and between species, and the consequences of the different preventive strategies for pneumococcal colonisation.

Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children

A trial with a 7-valent pneumococcal-conjugate vaccine in children with recurrent acute otitis media showed a shift in pneumococcal colonisation towards non-vaccine serotypes and an increase in Staphylococcus aureus-related acute otitis media after vaccination. We investigated prevalence and determinants of nasopharyngeal carriage of Streptococcus pneumoniae and S aureus in 3198 healthy children aged 1-19 years. Nasopharyngeal carriage of S pneumoniae was detected in 598 (19%) children, and was affected by age (peak incidence at 3 years) and day-care attendance (odds ratio [OR] 2.14, 95% CI 1.44-3.18). S aureus carriage was affected by age (peak incidence at 10 years) and male sex (OR 1.46, 1.25-1.70). Serotyping showed 42% vaccine type pneumococci. We noted a negative correlation for co-colonisation of S aureus and vaccine-type pneumococci (OR 0.68, 0.48-0.94), but not for S aureus and non-vaccine serotypes. These findings suggest a natural competition between colonisation with vaccine-type pneumococci and S aureus, which might explain the increase in S aureus-related otitis media after vaccination.

The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

Objective:To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. Design:A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Results:Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41–0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22–0.37) for less than 100 cells/μl, 0.33 (0.25–0.44) for 100 to less than 200 cells/μl, 0.38 (0.28–0.52) for 200 to less than 350 cells/μl, 0.55 (0.41–0.74) for 350 to less than 500 cells/μl, and 0.77 (0.58–1.01) for 500 cells/μl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49–0.67) for less than 1 year since initiation to 0.21 (0.14–0.31) for 5 years or more (P value for trend <0.001). Conclusion:We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Host genetic determinants of Neisseria meningitidis infections

The clinical presentation of infections caused by Neisseria meningitidis is highly diverse. Some patients develop meningitis, and others present with sepsis or even septic shock. After invasion of the bloodstream by the bacteria, three main cascade pathways are activated. These are the complement system, the inflammatory response, and the coagulation and fibrinolysis pathway. These pathways do not act independently but are able to interact with each other. Genetic polymorphisms among components of these pathways have been shown to be involved in the susceptibility, severity, and outcome of meningococcal disease. We review knowledge of genetic variations associated with susceptibility to and severity of meningococcal infection. Complement deficiencies and defects in sensing or opsonophagocytic pathways, such as the rare Toll-like receptor 4 single nucleotide polymorphisms (SNPs) and combinations of inefficient variants of Fcgamma-receptors, seem to have the most important role in genetically established susceptibility. Effect on severity has repeatedly been reported for FcgammaRIIa and plasminogen activator inhibitor type 1 (PAI1) polymorphisms. Outcome effects have been confirmed for SNPs in properdin deficiencies, PAI1 and combination of the -511C/T SNP in interleukin 1beta, and the +2018C/T SNP in interleukin RN. Conflicting results are reported for the effect of the -308G/A promoter polymorphism in tumour necrosis factor (TNF) alpha. These differences may reflect discrepancies in group definitions between studies or the influence of additional SNPs in the TNFalpha promoter, which can form haplotypes representing different cytokine production capacity. For several SNPs, the potential effect on susceptibility, severity, or outcome has not yet been confirmed in an independent study.

Long-term effects of respiratory syncytial virus (RSV) bronchiolitis in infants and young children: a quantitative review.

One of the major questions regarding long‐term side effects of bronchiolitis by respiratory syncytial virus (RSV) is whether or not it induces asthma in later life. In this quantitative review, the data of 10 controlled studies are analysed. Methods: Follow‐up studies of RSV bronchiolitis published between January 1978 and December 1998 were identified through a MEDLINE search. Studies were selected if (i) postnatal age at the time of the inital illness was below 12 mo, (ii) all children were hospitalized for RSV bronchiolitis, (iii) the diagnosis RSV was virologically confirmed in all cases, and (iv) a control group was used. Results: Six studies met all selection criteria. Up to 5 y of follow‐up after RSV bronchiolitis in infancy, 40% of children reported wheezing as compared to only 11% in the control group (p < 0.001). Between 5 and 10 y of follow‐up 22% of the bronchiolitis group reported wheezing against 10% of the control group (p= 0.19). The incidence of recurrent wheezing as defined by three or more wheezing episodes also decreased with increasing years of follow‐up: at 5 or more years of follow‐up the difference between the RSV group and the control group was no longer significant. Furthermore, the presence of either a personal and/or a family history of either atopy and/or asthma did not differ between the two groups.

Risk factors for respiratory syncytial virus associated apnoea

Abstract Respiratory syncytial virus (RSV) infections are characterized by upper or lower respiratory tract symptoms including bronchiolitis and pneumonia. Apnoea may be the first sign of disease in children with RSV infection. The aims of this study were the identification of independent risk factors for RSV associated apnoea and the prediction of the risk for mechanical ventilation in children with RSV associated apnoea. Medical records of children younger than 12 months of age admitted with RSV infection between 1992 and 1995 to the Sophia Childrens Hospital, were reviewed. Demographic parameters, clinical features and laboratory parameters (SaO2, pCO2 and pH) were obtained upon admission and during hospitalization. Children with and without apnoea were compared using univariate and multivariate logistic and linear regression analysis. One hundred and eighty-five patients with RSV infection were admitted of whom 38 (21%) presented with apnoea. Patients with apnoea were significantly younger, had a significantly lower temperature, higher pCO2 and lower pH and had on chest radiographs also more signs of atelectasis. The number of patients admitted to the ICU because of mechanical ventilation and oxygen administration was significantly higher in children with RSV associated apnoea. Apnoea at admission was a strong predictor for recurrent apnoea. The relative risk for mechanical ventilation increased with the number of episodes of apnoea: 2.4 (95% CI 0.8 – 6.6) in children with one episode of apnoea (at admission) versus 6.5 (95% CI 3.3 – 12.9) in children with recurrent episodes of apnoea. Conclusions Age below 2 months is the strongest independent risk factor for RSV associated apnoea. Apnoea at admission increases the risk for recurrent apnoea. The risk for mechanical ventilation significantly increases in children who suffer from recurrent apnoea.

Zanamivir Susceptibility Monitoring and Characterization of Influenza Virus Clinical Isolates Obtained during Phase II Clinical Efficacy Studies

ABSTRACT Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated clinical efficacy against influenza A and B virus infections. In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log1050% tissue culture infective doses compared to a placebo, with no reemergence of virus after the completion of therapy. Paired isolates (n = 41) obtained before and during therapy with zanamivir demonstrated no shifts in susceptibility to zanamivir when measured by NA assays, although for a few isolates NA activity was too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility of isolates to zanamivir was extremely variable even at baseline and did not correlate with the speed of resolution of virus shedding. Isolates with apparent limited susceptibility to zanamivir by plaque reduction proved highly susceptible in vivo in the ferret model. Further sequence analysis of paired isolates revealed no changes in the hemagglutinin and NA genes in the majority of isolates. The few changes observed were all natural variants. No amino acid changes that had previously been identified in vitro as being involved with reduced susceptibility to zanamivir were observed. These studies highlighted problems associated with monitoring susceptibility to NA inhibitors in the clinic, in that no reliable cell-based assay is available. At present the NA assay is the best available predictor of susceptibility to NA inhibitors in vivo, as measured in the validated ferret model of infection.

Relationship between clinical severity of respiratory syncytial virus infection and subtype.

The relationship between clinical severity of respiratory syncytial virus (RSV) infection and distribution of subtype A or B was investigated. The data of 232 children, who were admitted with RSV infection or diagnosed in the outpatient department of the Sophia Childrens Hospital, Rotterdam between 1992 and 1995, were studied. The diagnosis of RSV was confirmed by a direct immunofluorescence assay. Subtyping was performed by an indirect immunofluorescence assay using specific monoclonal antibodies. Gender, age at diagnosis, gestational age and birth weight, the presence of underlying diseases, feeding difficulties, the presence of wheezing and retractions, respiratory rate, temperature, clinical diagnosis at presentation, oxygen saturation (SaO2), carbon dioxide tension (PCO2), and pH, characteristics of hospitalisation, and the need for mechanical ventilation were observed. Analysis was performed on data from all patients diagnosed with RSV infection in the period between 1992 and 1995 spanning three RSV seasons, and separately on the RSV season 1993-4. The outcome of the three year analysis (150 (64.7%) subtype A v 82 (35.3%) subtype B) was compared with the outcome of the season 1993-4, a mixed epidemic with 37 (60.7%) subtype A and 24 (39.3%) subtype B isolates. None of the variables observed in the season 1993-4 differed significantly between RSV subtype A and B. Similar results were obtained from the analysis in the period 1992 until 1995, with the exception of PCO2 (a higher PCO2 was found in subtype A, p < 0.001) and retractions (more retractions were noted in patients with subtype A, p = 0.03). After correcting for possible confounders using regression analysis, these differences were not significant anymore. The data indicate that there is no relationship between clinical severity of RSV infection and subtype.

Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort.

Objective:We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART). Design:Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml). Methods:Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/&mgr;l (group A), 200–350 cells/&mgr;l (group B), 351–500 cells/&mgr;l (group C) or more than 500 cells/&mgr;l (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs). Results:Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.33–0.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.14–0.86)]. Conclusion:Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients.

Chlamydia trachomatis as a Cause of Neonatal Conjunctivitis in Dutch Infants

BACKGROUND. Chlamydia trachomatis is the most common sexually transmitted pathogen in adults, which at delivery may be transmitted from mother to child and cause conjunctivitis and pneumonia. In the Netherlands, prenatal chlamydial screening and treatment of pregnant women is not routine practice. The contribution of C trachomatis to neonatal ophthalmic disease has not been studied in the Netherlands and remains unclear. METHODS. At the Sophia Childrens Hospital and Rotterdam Eye Hospital, 2 cohorts of infants <3 months of age presenting with conjunctivitis were studied, 1 retrospectively (July 1996 to July 2001) and 1 prospectively (September 2001 to September 2002). Laboratory diagnosis was based on bacterial culture and polymerase chain reaction for C trachomatis. RESULTS. C trachomatis was detected in 27 (64%) of 42 retrospectively studied infants and 14 (61%) of 23 prospectively studied infants. Mucopurulent discharge was present in 35 (95%) of 37, swelling of the eyes in 27 (73%) of 37, conjunctival erythema in 24 (65%) of 37, respiratory symptoms in 14 (38%) of 37, and feeding problems in 5 (14%) of 37 infants respectively. Before microbiological diagnosis, general practitioners prescribed antichlamydial antibiotics locally to 5 (12%) of 41 and systemically to 4 (10%) of 41 infants who tested positive for chlamydia, and ophthalmologists prescribed to 21 (51%) of 41 and 7 (17%) of 41, respectively. CONCLUSIONS. C trachomatis was the major cause of bacterial conjunctivitis in this population. Clinically, differentiation from other pathogens was not possible. Many infants who tested positive for chlamydia did not receive appropriate antibiotic treatment.