Nigel Curtis

Sick and tired: Does sleep have a vital role in the immune system?

It is a common belief that we are more susceptible to infections when deprived of sleep. Consistent with this, there is increasing evidence that sleep deprivation has detrimental effects on the immune response, indicating that sleep should be considered a vital part of the immune system and that there is a reciprocal relationship between sleep and immunity. This relationship is important because, over recent decades, there has been a documented decrease in the mean duration and quality of sleep in the population. The concept that lack of sleep might be compromising immunity in the population has far-reaching public-health implications for both individuals and society.

How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children's hospital.

OBJECTIVES. The primary aims of this study were to determine the volume of blood submitted for culture in routine clinical practice and to establish the proportion of blood cultures with a blood volume inadequate for reliable detection of bacteremia. METHODS. The volumes of blood samples submitted for culture from infants and children up to 18 years of age were measured over a 6-month period. Blood cultures were deemed adequate submissions if they contained an appropriate (age-related) volume of blood and were submitted in the correct blood culture bottle type. During the study, an educational intervention designed to increase the proportion of adequate blood culture submissions was undertaken. RESULTS. The volume of blood submitted in 1358 blood culture bottles from 783 patients was analyzed. Of the 1067 preintervention blood cultures, 491 (46.0%) contained an adequate blood volume and only 378 (35.4%) were adequate submissions on the basis of collection into the correct blood culture bottle type. After the intervention, there were significant increases in both the proportion of blood cultures containing an adequate blood volume (186 [63.9%] of 291 cultures) and the proportion of adequate submissions (149 [51.2%] of 291 cultures). Overall, blood cultures with an adequate blood volume were more likely than those with an inadequate blood volume to yield positive blood culture results (34 [5.2%] of 655 cultures vs 14 [2.1%] of 648 cultures). Similarly, adequate blood culture submissions were more likely than inadequate submissions to yield positive blood culture results (26 [5.1%] of 506 cultures vs 22 [2.8%] of 797 cultures). CONCLUSIONS. In routine clinical practice, a negative blood culture result is almost inevitable for a large proportion of blood cultures because of the submission of an inadequate volume of blood. Even after an educational intervention, nearly one half of blood cultures were inadequate submissions.

Chips with everything: DNA microarrays in infectious diseases

Two developments are set to revolutionise research in and clinical management of infectious diseases. First, the completion of the human genome project together with the sequencing of many pathogen genomes, and second, the development of microarray technology. This review explains the principles underlying DNA microarrays and highlights the uses to which they are being put to investigate the molecular basis of infectious diseases. Pathogen studies enable identification of both known and novel organisms, understanding of genetic evolution, and investigation of determinants of pathogenicity. Host studies show the complexities of development and activation of both innate and adaptive immunity. Host-pathogen studies allow global analysis of gene expression during pathogenesis. Microarray technology will accelerate our understanding of the complex genetic processes underlying the interaction between microorganisms and the host, with consequent improvements in the diagnosis, treatment, and prevention of infectious diseases.

Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children

Background: The diagnosis of latent Mycobacteriumtuberculosis (MTB) infection with a tuberculin skin test (TST) in children is complicated by the potential influence of prior exposure to Bacille Calmette Geurin (BCG) vaccination or environmental mycobacteria. A whole blood assay has recently been developed to quantitatively measure interferon gamma (IFN-γ) production by lymphocytes specific to the MTB antigens ESAT-6 and CFP-10, but its use and assessment in children has been limited. A study was undertaken to compare the performance of the whole blood IFN-γ assay with the TST in diagnosing latent tuberculosis (TB) infection or TB disease in children in routine clinical practice. Methods: One hundred and six children with a high risk of latent TB infection or TB disease were enrolled in the study. High risk was defined as contact with TB disease, clinical suspicion of TB disease, or recent arrival from an area of high TB prevalence. The whole blood IFN-γ assay was undertaken in 101 children. Results: Seventeen (17%) of the 101 assays yielded inconclusive results due to failure of positive or negative control assays. There was poor correlation between the whole blood IFN-γ assay and the TST (kappa statistic 0.3) with 26 (70%) of the 37 children defined as latent TB infection by TST having a negative whole blood IFN-γ assay. There were no instances of a positive whole blood IFN-γ assay with a negative TST. Mitogen (positive) control IFN-γ responses were significantly correlated with age (Spearman’s coefficient = 0.53, p<0.001) and, in children with latent TB infection identified by TST, those with a positive IFN-γ assay were older (median 12.9 v 6.92 years, respectively, p = 0.007). The whole blood IFN-γ assay was positive in all nine children with TB disease. Conclusion: There was poor agreement between the whole blood IFN-γ assay and TST for the diagnosis of latent TB. The whole blood IFN-γ assay may have lower sensitivity than the TST in diagnosing TB infection in children. A significant proportion of whole blood IFN-γ assays fail when used as a screening assay in routine practice.

A three-way comparison of tuberculin skin testing, QuantiFERON-TB gold and T-SPOT.TB in children.

Background There are limited data comparing the performance of the two commercially available interferon gamma (IFN-γ) release assays (IGRAs) for the diagnosis of tuberculosis (TB) in children. We compared QuantiFERON-TB gold In Tube (QFT-IT), T-SPOT.TB and the tuberculin skin test (TST) in children at risk for latent TB infection or TB disease. Methods and Findings The results of both IGRAs were compared with diagnosis assigned by TST-based criteria and assessed in relation to TB contact history. Results from the TST and at least one assay were available for 96 of 100 children. Agreement between QFT-IT and T-SPOT.TB was high (93% agreement, κ = 0.83). QFT-IT and T-SPOT.TB tests were positive in 8 (89%) and 9 (100%) children with suspected active TB disease. There was moderate agreement between TST and either QFT-IT (75%, κ = 0.50) or T-SPOT.TB (75%, κ = 0.51). Among 38 children with TST-defined latent TB infection, QFT-IT gold and T-SPOT.TB assays were positive in 47% and 39% respectively. Three TST-negative children were positive by at least one IGRA. Children with a TB contact were more likely than children without a TB contact to have a positive IGRA (QFT-IT LR 3.9; T-SPOT.TB LR 3.9) and a positive TST (LR 1.4). Multivariate linear regression analysis showed that the magnitude of both TST induration and IGRA IFN-γ responses was significantly influenced by TB contact history, but only the TST was influenced by age. Conclusions Although a high level of agreement between the IGRAs was observed, they are commonly discordant with the TST. The correct interpretation of a negative assay in a child with a positive skin test in clinical practice remains challenging and highlights the need for longitudinal studies to determine the negative predictive value of IGRAs.

Evidence for a superantigen mediated process in Kawasaki disease.

The clinical, pathological, and immunological similarities between Kawasaki disease and the staphylococcal and streptococcal toxic shock syndromes suggest that a superantigen toxin may be involved in the pathogenesis of the disease. The V beta repertoire of peripheral blood mononuclear cells from 21 children with Kawasaki disease, 28 children with other illnesses, and 22 healthy controls were examined using monoclonal antibodies to V beta 2, 5, 8, 12, and 19. The mean percentage of V beta 2 expressing T cells in the patients with Kawasaki disease was increased when compared with healthy controls or children with other illnesses. The mean percentages of V beta 5, 8, 12, and 19 expressing T cells were also increased in the patients with Kawasaki disease compared with healthy controls, but were not increased when compared with children with other illnesses. The selective use of V beta 2 supports the hypothesis that a superantigen is involved in the pathogenesis of Kawasaki disease.

A Systematic and Functional Classification of Streptococcus pyogenes That Serves as a New Tool for Molecular Typing and Vaccine Development

Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate for epidemiological typing is both a virulence factor and a vaccine antigen. Over 220 variants of this protein have been described, making comparisons between proteins difficult, and hindering M protein-based vaccine development. A functional classification based on 48 emm-clusters containing closely related M proteins that share binding and structural properties is proposed. The need for a paradigm shift from type-specific immunity against S. pyogenes to emm-cluster based immunity for this bacterium should be further investigated. Implementation of this emm-cluster-based system as a standard typing scheme for S. pyogenes will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development.

Influence of BCG vaccine strain on the immune response and protection against tuberculosis

The Bacille Calmette-Guérin (BCG) vaccine has been used for more than 80 years to protect against tuberculosis. Worldwide, over 90% of children are immunized with BCG, making it the most commonly administered vaccine, with more than 120 million doses used each year. Although new tuberculosis vaccines are under investigation, BCG will remain the cornerstone of the strategy to fight the worsening tuberculosis pandemic for the foreseeable future. The recent delineation of genetic differences between BCG vaccine strains has renewed interest in the influence of the vaccine strain on the protective efficacy against tuberculosis. This review critically examines the data from animal and human studies comparing BCG vaccine strains. Although there is good evidence to support the notion that the induced immune response and protection afforded against tuberculosis differs between BCG vaccine strains, currently, there are insufficient data to favour or recommend one particular strain. Identifying BCG strains with superior protection would have a dramatic effect on tuberculosis control at a population level: a small increment in protection provided by BCG immunization will prevent large numbers of cases of severe tuberculosis and deaths, particularly in children.

Invasive group a streptococcal disease: epidemiology, pathogenesis and management.

Invasive group A streptococcal infections are uncommon, although serious, infections with high case fatality rates. Periodic resurgences in invasive group A streptococcal infections in industrialized countries have been reported from the 1980s onwards, with current estimates of incidence in these countries of approximately 3–4 per 100000 population. Infants, pregnant women and the elderly are at increased risk of invasive group A streptococcal infection. The group A streptococcus has an array of virulence factors that underpin its invasive capacity and, in approximately 10% of cases, super-antigen toxins produced by the bacteria stimulate a large proportion of T cells, leading to streptococcal toxic shock syndrome. Given the rapid clinical progression, effective management of invasive group A streptococcal infections hinges on early recognition of the disease and prompt initiation of supportive care (often intensive care) together with antibacterial therapy. In cases of toxic shock syndrome, it is often difficult to distinguish between streptococcal and staphylococcal infection before cultures become available and so antibacterial choice must include coverage of both of these organisms. In addition, clindamycin is an important adjunctive antibacterial because of its anti-toxin effects and excellent tissue penetration. Early institution of intravenous immunoglobulin therapy should be considered in cases of toxic shock syndrome and severe invasive infection, including necrotizing fasciitis. Early surgical debridement of necrotic tissue is also an important part of management in cases of necrotizing fasciitis.

Effectiveness of Clindamycin and Intravenous Immunoglobulin, and Risk of Disease in Contacts, in Invasive Group A Streptococcal Infections

BACKGROUND The use of clindamycin and intravenous immunoglobulin (IVIG) in treatment of invasive group A streptococcal (iGAS) infection, and the need for prophylactic antibiotics in close contacts, remains contentious. Controlled trials are unlikely to be conducted, so prospective, observational studies provide the best data to inform practice. METHODS We conducted population-based, prospective, active surveillance of iGAS infections throughout the state of Victoria, Australia (population 4.9 million), from March 2002 through August 2004. RESULTS Eighty-four cases of severe iGAS infection (streptococcal toxic shock syndrome, necrotizing fasciitis, septic shock, or GAS cellulitis with shock) were identified. Clindamycin-treated patients had more severe disease than clindamycin-untreated patients but lower mortality (15% vs 39%; odds ratio [OR], 0.28; 95% confidence interval [CI], .10-.80). Among those who received concurrent IVIG, the fatality rate was lower still (7%). The adjusted point estimate of the OR for mortality was lower in clindamycin-treated patients (0.31; 95% CI, .09-1.12) and clindamycin plus IVIG-treated patients (0.12; 95% CI, .01-1.29) compared with clindamycin-untreated patients. Three confirmed cases of iGAS infection occurred in household contacts of index cases. The incidence rate of iGAS disease in contacts was 2011 (95% CI, 413-5929) times higher than the population incidence in Victoria. CONCLUSIONS Our data suggest that clindamycin treatment of patients with severe iGAS infections substantially reduces mortality and that this effect may be enhanced by concurrent treatment with IVIG. The dramatically increased risk of iGAS disease among household contacts within 1 month of the index case highlights a potential role for antibiotic prophylaxis.