Identifying transmission routes of Streptococcus pneumoniae and sources of acquisitions in high transmission communities.

Identifying the transmission sources and reservoirs of Streptococcus pneumoniae (SP) is a long-standing question for pneumococcal epidemiology, transmission dynamics, and vaccine policy. Here we use serotype to identify SP transmission and examine acquisitions (in the same household, local community, and county, or of unidentified origin) in a longitudinal cohort of children and adults from the Navajo Nation and the White Mountain Apache American Indian Tribes. We found that adults acquire SP relatively more in the household than other age groups, and children 2-8 years old typically acquire in their own or surrounding communities. Age-specific transmission probability matrices show that transmissions within household were mostly seen from older to younger siblings. Outside the household, children most often transmit to other children in the same age group, showing age-assortative mixing behavior. We find toddlers and older children to be most involved in SP transmission and acquisition, indicating their role as key drivers of SP epidemiology. Although infants have high carriage prevalence, they do not play a central role in transmission of SP compared with toddlers and older children. Our results are relevant to inform alternative pneumococcal conjugate vaccine dosing strategies and analytic efforts to inform optimization of vaccine programs, as well as assessing the transmission dynamics of pathogens transmitted by close contact in general.

Variation at the capsule locus, cps, of mistyped and non-typable Streptococcus pneumoniae isolates.

The capsule polysaccharide locus (cps) is the site of the capsule biosynthesis gene cluster in encapsulated Streptococcus pneumoniae. A set of pneumococcal samples and non-pneumococcal streptococci from Denmark, the Gambia, the Netherlands, Thailand, the UK and the USA were sequenced at the cps locus to elucidate serologically mistyped or non-typable isolates. We identified a novel serotype 33B/33C mosaic capsule cluster and previously unseen serotype 22F capsule genes, disrupted and deleted cps clusters, the presence of aliB and nspA genes that are unrelated to capsule production, and similar genes in the non-pneumococcal samples. These data provide greater understanding of diversity at a locus which is crucial to the antigenic diversity of the pathogen and current vaccine strategies.

Use of serology and urine antigen detection to estimate the proportion of adult community-acquired pneumonia attributable to Streptococcus pneumoniae.

Streptococcus pneumoniae is a common cause of community-acquired pneumonia (CAP) but existing diagnostic tools have limited sensitivity and specificity. We enrolled adults undergoing chest radiography at three Indian Health Service clinics in the Southwestern United States and collected acute and convalescent serum for measurement of PsaA and PspA titres and urine for pneumococcal antigen detection. Blood and sputum cultures were obtained at the discretion of treating physicians. We compared findings in clinical and radiographic CAP patients to those in controls without CAP. Urine antigen testing showed the largest differential between CAP patients and controls (clinical CAP 13%, radiographic CAP 17%, control groups 2%). Serological results were mixed, with significant differences between CAP patients and controls for some, but not all changes in titre. Based on urine antigen and blood culture results, we estimated that 11% of clinical and 15% of radiographic CAP cases were due to pneumococcus in this population.

Measuring the incidence of adult community-acquired pneumonia in a Native American community.

Few population-based studies have investigated the epidemiology of adult community-acquired pneumonia (CAP). We aimed to determine the incidence of CAP in a population at high-risk for pneumococcal disease and to evaluate a standardized method for interpreting chest radiographs adapted from the World Health Organization paediatric chest radiograph interpretation guidelines. We reviewed radiology records at the two healthcare facilities serving the White Mountain Apache tribe to identify possible pneumonia cases > or =40 years of age. We categorized patients with clinical criteria and a physician diagnosis of pneumonia as clinical CAP and those with clinical criteria and an acute infiltrate as radiographic CAP. We identified 100 (27/1000 person-years) and 60 (16/1000 person-years) episodes of clinical and radiographic CAP, respectively. The incidence of CAP increased with age. Both radiographic and clinical CAP were serious illnesses with more than half of patients hospitalized. Our case definitions and methods may be useful for comparing data across studies and conducting vaccine trials.

Impact of the Hajj on pneumococcal transmission.

Over two million Muslim pilgrims assemble annually in Mecca and Medina, Saudi Arabia, to complete the Hajj. The large number of people in a crowded environment increases the potential for pneumococcal carriage amplification. We evaluated pneumococcal carriage prevalence with four cross-sectional studies conducted at beginning-Hajj (Mecca) and end-Hajj (Mina) during 2011 and 2012. A questionnaire was administered and a nasopharyngeal swab was collected. The swab was tested for pneumococcus, serotype and antibiotic resistance. A total of 3203 subjects (1590 at beginning-Hajj and 1613 at end-Hajj) originating from 18 countries in Africa or Asia were enrolled. The overall pneumococcal carriage prevalence was 6.0%. There was an increase in carriage between beginning-Hajj and end-Hajj cohorts for: overall carriage (4.4% versus 7.5%, prevalence ratio (PR) 1.7, 95% CI 1.3-2.3), and carriage of 23-valent pneumococcal polysaccharide vaccine serotypes (2.3% versus 4.1%, PR 1.8, 95% CI 1.2-2.7), 13-valent pneumococcal conjugate vaccine (PCV) serotypes (1.1% versus 3.6%, PR 3.2, 95% CI 1.9-5.6), 10-valent PCV serotypes (0.6% versus 1.6%, PR 2.6, 95% CI 1.2-5.3), antibiotic non-susceptible isolates (2.5% versus 6.1%, PR 2.5, 95% CI 1.7-3.6) and multiple non-susceptible isolates (0.6% versus 2.2%, PR 3.8, 95% CI 1.8-7.9). Fifty-two different serotypes were identified, most commonly serotypes 3 (17%), 19F (5%) and 34 (5%). These results suggest that the Hajj may increase pneumococcal carriage-particularly conjugate vaccine serotypes and antibiotic non-susceptible strains, although the exact mechanism remains unknown. The Hajj may therefore provide a mechanism for the global distribution of pneumococci.

Bacillus Calmette-Guérin complications in children born to HIV-1-infected women with a review of the literature.

OBJECTIVE: To compare the risk of complications following Bacillus Calmette-Guérin (BCG) vaccination among children by maternal and infant HIV-1 infection status as part of an investigation of an outbreak of BCG complications. METHODS: A nonconcurrent cohort study of BCG complications among 125 infants born to HIV-1 seropositive and 166 infants born to HIV-1 seronegative mothers was conducted in Cité Soleil, Haiti. Infants were examined at regular intervals until 15 months of age, and complications from BCG were documented. An investigation of BCG vaccination practices was conducted. RESULTS: Mild or moderate complications occurred among 16 of 166 (9.6%) infants born to HIV-1 seronegative mothers compared with 4 of 13 HIV-1-infected infants (30.8%, P = .04) and 10 of 75 (13.3%, P = .39) uninfected infants born to HIV-1-infected mothers. No serious complications were noted. The outbreak of complications was associated with administration of 2.0 to 2.5 times the recommended dose of BCG vaccine. CONCLUSIONS: This and five other cohort studies indicate that there may be a small increased risk of complications following BCG vaccination among HIV-1-infected children, but the reactions are usually mild and the risk does not outweigh the benefits of BCG vaccination in populations at high risk of tuberculosis during infancy and childhood.

Immunologic priming of young children by pneumococcal glycoprotein conjugate, but not polysaccharide, vaccines.

BACKGROUND: Streptococcus pneumoniae is the most common cause of invasive bacterial disease and otitis media in infants and young children. Licensed pneumococcal polysaccharide vaccines are not reliably immunogenic in children younger than 2 years of age; therefore pneumococcal glycoprotein conjugate vaccines are currently being evaluated for safety, immunogenicity and efficacy in various age groups. METHODS: During a 12-month period we determined the kinetics of pneumococcal IgG antibody in 60 children who received primary immunization with one dose of bivalent (serotypes 6A and 23F) pneumococcal polysaccharide-CRM197 vaccines at 18 to 30 months of age. To assess immunologic priming a subgroup of 20 subjects received secondary immunization with pneumococcal polysaccharide vaccine, including serotypes 6B and 23F, at 11 to 20 months after primary immunization. Pneumococcal-specific IgG subclass distributions were also evaluated in the subgroup. RESULTS: In the 12 months after primary immunization with glycoprotein conjugate vaccine, geometric mean pneumococcal IgG antibody concentrations to 6B and 23F serotypes remained stable. Pneumococcal polysaccharide vaccine induced a greater anamnestic response in children primed with glycoprotein conjugate vaccines (13- to 40-fold increases to geometric mean concentrations of 6 to 30 micrograms/ml for type 23F), than in those primed with polysaccharide (2- to 4-fold increases). A greater IgG response to pneumococcal serotype 23F than to 6B was observed with both primary and secondary immunization. The serotype-specific pneumococcal IgG antibody response was virtually restricted to the IgG1 subclass after primary immunization, but secondary immunization elicited antibodies of IgG1 and IgG2 subclasses. CONCLUSIONS: These glycoprotein conjugate vaccines appear to prime for anamnestic IgG antibody responses to subsequent immunization with polysaccharide vaccine, suggesting that the polysaccharide-CRM197 vaccine effectively induces a predominantly T cell-dependent immune response. The greater IgG response to 23F than to 6B indicates that pneumococcal serotype is a major determinant of immunogenicity of pneumococcal glycoprotein conjugate vaccines.

Impact of azithromycin on oropharyngeal carriage of group A Streptococcus and nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae.

BACKGROUND: Invasive group A streptococcal (GAS) infections are a cause of serious morbidity and high mortality. There is a need for a simple, effective antimicrobial regimen that could be used to prevent invasive GAS disease in high risk situations. To assess azithromycin as a chemoprophylactic agent, we evaluated its efficacy for eradication of oropharyngeal (OP) GAS and its impact on the nasopharyngeal (NP) colonization rate of macrolide-resistant Streptococcus pneumoniae. METHODS: We obtained OP and NP swabs for GAS and pneumococcus culture, respectively, from 300 schoolmates of a child with an invasive GAS infection. GAS culture-positive students were treated with daily azithromycin (12 mg/kg/day) for 5 days. We obtained follow-up OP and NP swabs at 9 (Day 17) and 24 (Day 32) days post-treatment from those students identified as GAS carriers on Day 0 and determined macrolide susceptibility of GAS and pneumococcal isolates. RESULTS: Of the 300 students swabbed 152 (50%) carried GAS in their oropharynx. On Day 17, efficacy of azithromycin for GAS eradication was 95% (140 of 147) for all students. NP colonization rates for pneumococci decreased from 46% (67 of 146) to 12% (17 of 144; P < 0.001) by Day 17 and to 20% (27 of 137; P < 0.001) by Day 32. The prevalence of erythromycin-resistant pneumococcal isolates increased from 2% (3 of 146) to 4% (6 of 144) by Day 17 and to 8% (11 of 137; P = 0.04) by Day 32. CONCLUSIONS: Azithromycin is an effective short course regimen for eradication of oropharyngeal GAS. However, azithromycin selected for macrolide-resistant strains of pneumococci. These findings highlight the importance of determining the appropriate circumstances for antimicrobial prophylaxis to prevent invasive GAS infections.

The prevalence and incidence of end-stage renal disease in Native American adults on the Navajo reservation.

Whereas members of the Navajo Nation are at high risk for diabetes mellitus, there are no recent published estimates of the burden of end-stage renal disease (ESRD), an important sequela of diabetes, on the Navajo Nation, a 16 million acre area in Arizona, New Mexico, and Utah with more than 200 000 tribal members. We used data from the US Renal Data System to estimate the prevalence and incidence of ESRD among Native American adults (>/=18 years) living on the Navajo Nation. For comparison, we estimated the prevalence and incidence of ESRD among all adults in the US, all Native American adults in the US, and Native American adults living in Arizona, New Mexico, Utah, and Colorado excluding those living on the Navajo Nation. The age-adjusted prevalence of ESRD in the Native American adults on the Navajo Nation was 0.63%, which was higher than in the US adults (0.19%, P<0.0001) and among the Native American adults in the US (0.36%, P<0.0001), but lower than among the other Native American adults in the Southwest (0.89%, P<0.0001). The age-adjusted incidence of ESRD in the Native American adults on the Navajo Nation was 0.11%, which was also higher than in the US adults (0.045%, P<0.0001) and among the Native American adults in the US (0.073%, P<0.0009), but lower than among the other Native American adults in the Southwest (0.17%, P<0.0003). The reasons behind these disparities merit further study.

Evaluation of the indirect effects of a pneumococcal vaccine in a community-randomized study.

When a sufficiently high proportion of a population is immunized with a vaccine, reduction in secondary transmission of disease can confer significant protection to unimmunized population members. We propose a straightforward method to estimate the degree of this indirect effect of vaccination in the context of a community-randomized vaccine trial. A conditional logistic regression model that accounts for within-randomization unit correlation over time is described, which models risk of disease as a function of community-level covariates. The approach is applied to an example data set from a pneumococcal conjugate vaccine study, with study arm and immunization levels forming the covariates of interest for the investigation of indirect effects.

Temperature dependence and mechanism of local anesthetic effects on mitochondrial adenosinetriphosphatase.

Chloroform-released ATPase prepared from beef heart mitochondria is inhibited by tetracaine and dibucaine over the entire temperature range in which the enzyme is active. The temperature of maximal activity is at 60 degrees C in the absence of anesthetic and is shifted upward by 2-3 degrees C by the addition of 0.3 mM dibucaine. Local anesthetics protect ATPase from irreversible cold inactivation. The kinetics of this protective effect are analyzed by a thermodynamic model in which the associated/dissociated subunit equilibrium is shifted toward the associated state by the preferential binding of anesthetic to the associated state. The accessibility of buried sulhydryl groups to reaction with 5,5'-dithiobis(2-nitrobenzoic acid) is increased by local anesthetics; this is interpreted to mean that the anesthetics increase the conformational flexibility of the protein. It is proposed that the hydrophobic moieties of local anesthetics and related compounds bind to numerous hydrophobic sites or crevices on ATPase; this binding induces a perturbation of the protein conformation, which in turn causes a decrease of enzyme activity. This model is sufficiently general to encompass the diversity of molecules which have similar anesthetic-like effects, and since it relates to common fundamental features of protein structure, it may also be the mechanism of the nonspecific effects of these molecules on other proteins.

Evaluation of inhA gene and catalase-peroxidase gene among isoniazid-sensitive and resistant Mycobacterium tuberculosis isolates.

The katG gene and the inhA gene of 30 INH-resistant (INH-R) and 28 INH-sensitive (INH-S) isolates of M. tuberculosis from Haiti and Maryland were analysed by PCR to establish the presence and frequency of two postulated mechanisms of INH-resistance, total katG gene deletion and inhA Ser94 to Ala94 amino acid substitution. Only two of 30 INH-R isolates (3%) appear to have total katG gene deletions. All 28 INH-S isolates (100%) produced a PCR product at both the 5' and the 3' ends of the katG gene. Gene deletion of katG is a rare mechanism of INH resistance. Allele specific oligonucleotide hybridisation analysis of the inhA PCR products from the same 58 isolates revealed no mutation at amino acid 94 or directly surrounding it. Other inhA gene mutations may be responsible for INH resistance in M. tuberculosis. Diagnostic strategies using katG gene deletion or inhA Ser94 mutations would fail to detect almost all INH-R isolates.

Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella.

OBJECTIONS: To test the hypothesis that nonsteroidal antiinflammatory drug use increases the risk of necrotizing soft tissue infections and, secondarily, all invasive group A streptococcal (GAS) infections in children with primary varicella infection. METHODS: We conducted a prospective, multicenter case-control study among children <19 years old. Cases were children hospitalized with primary varicella complicated by invasive GAS infection or necrotizing soft tissue infection identified by a network of 45 pediatric infectious disease specialists located throughout the United States. Controls were children with uncomplicated primary varicella residing in the same communities as the cases. Data on medical history, clinical features of the varicella infection, signs and symptoms of infectious complications, and medication use were collected by structured telephone interviews. Univariate and multivariate matched odds ratios were calculated using conditional logistic regression. RESULTS: Between June 1996 and September 1998, 52 cases of invasive GAS infection, including 21 with necrotizing soft tissue infection, and 172 controls with uncomplicated primary varicella were enrolled. Risk of invasive GAS infection was increased among children who were nonwhite (multivariate odds ratio [OR] 3.8, 95% confidence interval [CI]: 1.4-11), living in low-income households (OR 5.1, 95% CI: 1.7-15), exposed to varicella at home (OR 6.4, 95% CI: 2.6-16), or had a persistent high fever (OR 9.6, 95% CI: 2.8-33). Antipyretic regimen was associated with several measures of varicella illness severity among the controls. The risk of necrotizing soft tissue infection was not associated with the use of ibuprofen before the development of signs or symptoms of this complication (OR 1.3, 95% CI: 0.33-5.3). Risk of any invasive GAS infection was increased among children who had received ibuprofen (OR 3.9, 95% CI: 1.3-12), but not acetaminophen (OR 1.2, 95% CI: 0.50-3.0). However, there was no evidence of increasing risk with increasing duration of ibuprofen use. Subgroup analyses revealed that the risk of invasive GAS infection was increased only among children who had received both acetaminophen and ibuprofen. CONCLUSIONS: These data do not support the hypothesis that nonsteroidal antiinflammatory drugs, or ibuprofen in particular, increase the risk of necrotizing GAS infections. A statistically significant association was observed between nonnecrotizing invasive GAS infection and ibuprofen use; however, because of potential confounding, the meaning of this unexpected result is unclear. Nonetheless, these data suggest that parents use ibuprofen or ibuprofen together with acetaminophen to treat high fever and severe illness, which seems to identify children at high risk for invasive GAS infection.

Molecular epidemiology of a parainfluenza type 3 virus outbreak on a pediatric ward.

Parainfluenza type 3 virus (PIV-3), an important cause of acute lower respiratory illness in children, can be transmitted nosocomially. To differentiate between nosocomial transmission and community-acquired infection, a polymerase chain reaction-based sequencing assay was developed for the 5' noncoding region of the PIV-3 fusion protein gene and was applied to virus specimens from 10 children infected with PIV-3 during a hospital outbreak. Four strains of PIV-3 were identified among the 10 virus isolates. Six isolates, which appeared to belong to 1 strain, were obtained from a cluster of nosocomial cases in a pediatric intermediate care unit. In contrast, the remaining 4 isolates, which appeared to belong to 3 different strains, were obtained from children infected in the community or elsewhere in the hospital. These data indicate that multiple strains of PIV-3 can be found during a single epidemic and provide evidence that infections within the intermediate care unit were probably caused by transmission of 1 strain of virus within the unit rather than reintroduction of virus by new patients or staff.

Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection.

An outbreak of severe pneumococcal pneumonia among children occurred in Iowa from November 1995 through January 1996. An associated outbreak of influenza disease was predominantly caused by influenza A (H1N1) for the first time since 1989. We conducted a case-control study to determine whether preceding influenza infection was directly associated with pneumococcal illness. We identified 13 children with severe pneumococcal pneumonia. Patients were more likely than control subjects to report experiencing an influenza-like illness in the 7-28 days preceding admission (matched odds ratio [OR], 12.4; 95% confidence interval [CI], 1.7-306). Likewise, family members of patients were more likely than those of control subjects to report experiencing an influenza-like illness in the 28 days preceding their admission date (OR, 2.6; 95% CI, 1.0-6. 3). Patients were more likely than control subjects to have a positive influenza A (H1N1) convalescent serology (matched OR, 3.7; 95% CI, 1.0-18.1). This study provides direct and indirect evidence that influenza infection led to severe pneumococcal pneumonia among these children. Prevention of pneumococcal disease should be included among the potential benefits of influenza vaccination.

Early-onset neonatal sepsis in the era of group B streptococcal prevention.

OBJECTIVE: To determine whether intrapartum antibiotic prophylaxis for neonatal group B streptococcal (GBS) disease has resulted in an increased rate of non-GBS or antibiotic-resistant early-onset invasive neonatal disease. METHODS: Maternal and infant chart review of all infants with bacteria other than GBS isolated from blood or spinal fluid in 1996 through 1999 in 19 hospitals (representing 81% of in-state births to state residents) throughout Connecticut. Suspected cases were identified through clinical microbiology laboratory records or through International Classification of Diseases, Ninth Revision codes when microbiology records were incomplete. RESULTS: Ninety-four cases of non-GBS early-onset sepsis or meningitis were detected between 1996 and 1999. The rate of GBS-related early-onset infection (days 0-6 of life) dropped from 0.61/1000 to 0.23/1000 births, but the annual rate of non-GBS sepsis remained steady, ranging from 0.65 to 0.68/1000 during the surveillance period. There was an increase in the proportion of Escherichia coli infections that were ampicillin resistant between 1996 and 1998, but the proportion decreased. in 1999 CONCLUSION: There was no increase in the incidence of non-GBS early-onset neonatal infections between 1996 and 1999. Fluctuations in the annual incidence of E coli infections, including ampicillin-resistant infections, suggest the need for continuation of surveillance in Connecticut and expansion to monitor larger populations.