Anna P. Ralph

Group a streptococcal diseases and their global burden

Group A streptococcus (GAS) or Streptococcus pyogenes has been recognised as an important human pathogen since early days of modern microbiology, and it remains among the top ten causes of mortality from an infectious disease. Clinical manifestations attributable to this organism are perhaps the most diverse of any single human pathogen. These encompass invasive GAS infections, with high mortality rates despite effective antimicrobials, toxin-mediated diseases including scarlet fever and streptococcal toxic shock syndrome, the autoimmune sequelae of rheumatic fever and glomerulonephritis with potential for long-term disability, and nuisance manifestations of superficial skin and pharyngeal infection, which continue to consume a sizable proportion of healthcare resources. Although an historical perspective indicates major overall reductions in GAS infection rates in the modern era, chiefly as a result of widespread improvements in socioeconomic circumstances, this pathogen remains as a leading infectious cause of global morbidity and mortality. More than 18 million people globally are estimated to suffer from serious GAS disease. This burden disproportionally affects least affluent populations, and is a major cause of illness and death among children and young adults, including pregnant women, in low-resource settings. We review GAS transmission characteristics and prevention strategies, historical and geographical trends and report on the estimated global burden disease attributable to GAS. The lack of systematic reporting makes accurate estimation of rates difficult. This highlights the need to support improved surveillance and epidemiological research in low-resource settings, in order to enable better assessment of national and global disease burdens, target control strategies appropriately and assess the success of control interventions.

A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis

Background The grading of radiological severity in clinical trials in tuberculosis (TB) remains unstandardised. The aim of this study was to generate and validate a numerical score for grading chest x-ray (CXR) severity and predicting response to treatment in adults with smear-positive pulmonary TB. Methods At a TB clinic in Papua, Indonesia, serial CXRs were performed at diagnosis, 2 and 6 months in 115 adults with smear-positive pulmonary TB. Radiographic findings predictive of 2-month sputum microscopy status were used to generate a score. The validity of the score was then assessed in a second data set of 139 comparable adults with TB, recruited 4 years later at the same site. Relationships between the CXR score and other measures of TB severity were examined. Results The estimated proportion of lung affected and presence of cavitation, but not cavity size or other radiological findings, significantly predicted outcome and were combined to derive a score given by percentage of lung affected plus 40 if cavitation was present. As well as predicting 2-month outcome, scores were significantly associated with sputum smear grade at diagnosis (p<0.001), body mass index, lung function, haemoglobin, exercise tolerance and quality of life (p<0.02 for each). In the validation data set, baseline CXR score predicted 2-month smear status significantly more accurately than did the proportion of lung affected alone. In both data sets, CXR scores decreased over time (p<0.001). Conclusion This simple, validated method for grading CXR severity in adults with smear-positive pulmonary TB correlates with baseline clinical and microbiological severity and response to treatment, and is suitable for use in clinical trials.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial

Background Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). Methods In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. Results 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference −3%, 95% CI −19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI −9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. Conclusion Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. Registry ClinicalTrials.gov. Registry number: NCT00677339

Vitamin D and solar ultraviolet radiation in the risk and treatment of tuberculosis

Improved understanding of the association between tuberculosis and vitamin D is needed to inform clinical practice. Vitamin D has both immunostimulatory and immunosuppressive effects relevant to human antimycobacterial responses. Ultraviolet radiation, the main source of vitamin D, also induces immunomodulation and could affect the relation between vitamin D and tuberculosis. Clinical trials of vitamin D supplementation in patients with tuberculosis have produced largely negative results, prompting the review of dosing regimens-an explanation for low 25-hydroxyvitamin D status in patients with active tuberculosis is also needed. The reporting of vitamin D deficiency needs to address assay inaccuracies, rising thresholds to define sufficiency, and scarce knowledge of the concentrations needed for optimum immune responses. Future research to measure the effect of the inflammatory setting on serum concentrations of 25-hydroxyvitamin D, at tuberculosis diagnosis and during recovery, could help to account for 25-hydroxyvitamin D changes in these concentrations in patients with tuberculosis. Studies into the role of vitamin D supplementation in latent tuberculosis justify clinical trials in this population, but pose methodological challenges. Vitamin D trials in patients with active tuberculosis should be done in well selected populations using adequate vitamin D doses, although such doses remain undefined.

Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial

BACKGROUND In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal β-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. METHODS In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. RESULTS We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. CONCLUSIONS Combining an antistaphylococcal β-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).

L-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis

Worsening drug resistance and the need for prolonged treatment in tuberculosis (TB) require innovative solutions including investigation of inexpensive, safe adjunctive immunotherapies. L-arginine, the precursor of nitric oxide, and vitamin D recently have elucidated mycobactericidal and immunomodulatory actions against TB and are deficient in people with TB. We review the potential of these agents as adjunctive TB immunotherapies and explore how comparative clinical trials might help clarify their relative importance in the human TB immune response. By enhancing mycobacterial killing in macrophages, L-arginine and vitamin D might have the potential to enable shorter duration of treatment, reduced infectivity and improved response in drug-resistant TB.

Mortality attributable to Plasmodium vivax malaria: a clinical audit from Papua, Indonesia

BackgroundPlasmodium vivax causes almost half of all malaria cases in Asia and is recognised as a significant cause of morbidity. In recent years it has been associated with severe and fatal disease. The extent to which P. vivax contributes to death is not known.MethodsTo define the epidemiology of mortality attributable to vivax malaria in southern Papua, Indonesia, a retrospective clinical records-based audit was conducted of all deaths in patients with vivax malaria at a tertiary referral hospital.ResultsBetween January 2004 and September 2009, hospital surveillance identified 3,495 inpatients with P. vivax monoinfection and 65 (1.9%) patients who subsequently died. Charts for 54 of these 65 patients could be reviewed, 40 (74%) of whom had pure P. vivax infections on cross-checking. Using pre-defined conservative criteria, vivax malaria was the primary cause of death in 6 cases, a major contributor in 17 cases and a minor contributor in a further 13 cases. Extreme anaemia was the most common primary cause of death. Malnutrition, sepsis with respiratory and gastrointestinal manifestations, and chronic diseases were the commonest attributed causes of death for patients in the latter two categories. There were an estimated 293,763 cases of pure P. vivax infection in the community during the study period giving an overall minimum case fatality of 0.12 per 1,000 infections. The corresponding case fatality in hospitalised patients was 10.3 per 1,000 infections.ConclusionsAlthough uncommonly directly fatal, vivax malaria is an important indirect cause of death in southern Papua in patients with malnutrition, sepsis syndrome and chronic diseases, including HIV infection.

Diagnosing tuberculous meningitis – have we made any progress?

Tuberculous meningitis (TBM) comprises a significant proportion of TB cases globally and causes substantial morbidity and mortality, especially in children and HIV‐infected patients. It is a challenging condition to diagnose due to its non‐specific clinical presentation and the limited sensitivity of existing laboratory techniques. Smear microscopy and culture are the most widely available diagnostic tools yet are negative in a significant proportion of TBM cases. Simplified and more affordable nucleic acid amplification tests (NAATs) are increasing in use in resource‐limited settings but have not been optimised for cerebrospinal fluid (CSF) samples. Novel diagnostic methods such as CSF interferon‐gamma release assays and various biomarkers have been developed but require further evaluation to establish their utility as diagnostic tools. There is an urgent need for further research into optimal diagnostic strategies to decrease the morbidity and mortality as a result of delayed or missed diagnosis of TBM. In this review, we discuss current and novel diagnostic tests in TBM and areas where future research should be prioritised.

Improvement in rheumatic fever and rheumatic heart disease management and prevention using a health centre-based continuous quality improvement approach

BackgroundRheumatic heart disease (RHD) remains a major health concern for Aboriginal Australians. A key component of RHD control is prevention of recurrent acute rheumatic fever (ARF) using long-term secondary prophylaxis with intramuscular benzathine penicillin (BPG). This is the most important and cost-effective step in RHD control. However, there are significant challenges to effective implementation of secondary prophylaxis programs. This project aimed to increase understanding and improve quality of RHD care through development and implementation of a continuous quality improvement (CQI) strategy.MethodsWe used a CQI strategy to promote implementation of national best-practice ARF/RHD management guidelines at primary health care level in Indigenous communities of the Northern Territory (NT), Australia, 2008–2010. Participatory action research methods were employed to identify system barriers to delivery of high quality care. This entailed facilitated discussion with primary care staff aided by a system assessment tool (SAT). Participants were encouraged to develop and implement strategies to overcome identified barriers, including better record-keeping, triage systems and strategies for patient follow-up. To assess performance, clinical records were audited at baseline, then annually for two years. Key performance indicators included proportion of people receiving adequate secondary prophylaxis (≥80% of scheduled 4-weekly penicillin injections) and quality of documentation.ResultsSix health centres participated, servicing approximately 154 people with ARF/RHD. Improvements occurred in indicators of service delivery including proportion of people receiving ≥40% of their scheduled BPG (increasing from 81/116 [70%] at baseline to 84/103 [82%] in year three, p = 0.04), proportion of people reviewed by a doctor within the past two years (112/154 [73%] and 134/156 [86%], p = 0.003), and proportion of people who received influenza vaccination (57/154 [37%] to 86/156 [55%], p = 0.001). However, the proportion receiving ≥80% of scheduled BPG did not change. Documentation in medical files improved: ARF episode documentation increased from 31/55 (56%) to 50/62 (81%) (p = 0.004), and RHD risk category documentation from 87/154 (56%) to 103/145 (76%) (p < 0.001). Large differences in performance were noted between health centres, reflected to some extent in SAT scores.ConclusionsA CQI process using a systems approach and participatory action research methodology can significantly improve delivery of ARF/RHD care.

Tuberculosis into the 2010s: Is the Glass Half Full?

During the 16 years since the World Health Organization declared tuberculosis (TB) a global emergency, major new challenges have emerged-in particular the spread of extensively drug-resistant (XDR)-TB and its overlap with human immunodeficiency virus infection. However, during this period, we have also witnessed the creation of-and major commitments from-agencies dedicated to TB control, research, and funding, and tangible positive achievements have occurred; these include improvements in both new and existing TB diagnostics, a developmental pipeline of new candidate TB drugs, better treatment outcomes for multidrug-resistant TB and XDR-TB, heightened recognition of the importance of nosocomial transmission, and improved strategies to reduce mortality associated with concurrent human immunodeficiency virus infection and TB. We suggest updates to the 2006 International Standards of Tuberculosis Care to embrace these developments. The incorporation of these recent advances into optimized directly observed treatment, short course (DOTS), programs, in conjunction with more widespread deployment and enhanced political will, all provide grounds for improved control.