Graeme Maguire

Pulmonary Manifestations of Uncomplicated Falciparum and Vivax Malaria: Cough, Small Airways Obstruction, Impaired Gas Transfer, and Increased Pulmonary Phagocytic Activity

Despite recognition of acute respiratory distress syndrome in both falciparum and vivax malaria, disease-related changes in pulmonary function have not been defined, and underlying mechanisms are not well understood. Respiratory symptoms, pulmonary function, pulmonary phagocytic cell activity, and longitudinal changes were examined in 26 adults with uncomplicated falciparum, vivax, and ovale malaria after treatment. Self-limiting cough occurred in both falciparum (36%) and vivax or ovale (53%) malaria. In infection with each malaria species, admission measures of airflow and gas transfer were lower than predicted, and mean lung (99m)technetium-sulfur-colloid uptake was significantly increased. Changes were most evident in falciparum malaria, with treatment resulting in initial worsening of airflow obstruction and gas transfer. Altered pulmonary function in malaria is common and includes airflow obstruction, impaired ventilation, impaired gas transfer, and increased pulmonary phagocytic activity, and its occurrence in both vivax and falciparum malaria suggests that there may be common underlying inflammatory mechanisms.

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.

Antibodies to Plasmodium falciparum glycosylphosphatidylinositols: inverse association with tolerance of parasitemia in Papua New Guinean children and adults

ABSTRACT Individuals living in regions of intense malaria transmission exhibit natural immunity that facilitates persistence of parasitemia at controlled densities for much of the time without symptoms. This aspect of immunity has been referred to as malarial “tolerance” and is thought to partly involve inhibition of the chain of events initiated by a parasite toxin(s) that may otherwise result in cytokine release and symptoms such as fever. Antibodies to the candidate Plasmodium falciparum glycosylphosphatidylinositol (GPI) toxin have been viewed as likely mediators of such tolerance. In this study, the relationship between antibodies to P. falciparum GPIs, age, and parasitemia was determined in asymptomatic children and adults living in Madang, Papua New Guinea. The prevalence and intensity of antibody responses increased with age and were lowest in children 1 to 4 years old with the highest-density parasitemias. In children of this age group who were tolerant of parasitemia during the study, only 8.3% had detectable immunoglobulin G (IgG) and none had IgM antibodies to GPI. This suggests that anti-GPI antibodies are unlikely to be the sole mediator of malarial tolerance, especially in children younger than 5 years. Following antimalarial treatment, clearance of parasitemia led to a fall in anti-GPI IgG response in children and adolescents within 6 weeks. As anti-GPI antibodies potentially play a role in protecting against disease progression, our results caution against the treatment of asymptomatic parasitemia and suggest that generation of a sustained antibody response in children poses a challenge to novel antitoxic vaccination strategies.

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

Echocardiographic Screening for Rheumatic Heart Disease in High and Low Risk Australian Children

Background— Echocardiographic screening for rheumatic heart disease (RHD) is becoming more widespread, but screening studies to date have used different echocardiographic definitions. The World Heart Federation has recently published new criteria for the echocardiographic diagnosis of RHD. We aimed to establish the prevalence of RHD in high-risk Indigenous Australian children using these criteria and to compare the findings with a group of Australian children at low risk for RHD. Methods and Results— Portable echocardiography was performed on high-risk Indigenous children aged 5 to15 years living in remote communities of northern Australia. A comparison group of low-risk, non-Indigenous children living in urban centers was also screened. Echocardiograms were reported in a standardized, blinded fashion. Of 3946 high-risk children, 34 met World Heart Federation criteria for definite RHD (prevalence, 8.6 per 1000 [95% confidence interval, 6.0–12.0]) and 66 for borderline RHD (prevalence, 16.7 per 1000 [95% confidence interval, 13.0–21.2]). Of 1053 low-risk children, none met the criteria for definite RHD, and 5 met the criteria for borderline RHD. High-risk children were more likely to have definite or borderline RHD than low-risk children (adjusted odds ratio, 5.7 [95% confidence interval, 2.3–14.1]; P<0.001). Conclusions— The prevalence of definite RHD in high-risk Indigenous Australian children approximates what we expected in our population, and no definite RHD was identified in the low-risk group. This study suggests that definite RHD, as defined by the World Heart Federation criteria, is likely to represent true disease. Borderline RHD was identified in children at both low and high risk, highlighting the need for longitudinal studies to evaluate the clinical significance of this finding.

Utility of auscultatory screening for detecting rheumatic heart disease in high-risk children in Australia's Northern Territory

Objectives: To evaluate the utility of auscultatory screening for detecting echocardiographically confirmed rheumatic heart disease (RHD) in high‐risk children in the Northern Territory, Australia.

Variability in disease burden and management of rheumatic fever and rheumatic heart disease in two regions of tropical Australia.

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) contribute to Aboriginal Australian and Torres Strait Islander health disadvantage. At the time of this study, specialist ARF/RHD care in the Kimberley region of Western Australia was delivered by a broad range of providers. In contrast, in Far North Queensland (FNQ), a single‐provider model was used as part of a coordinated RHD control programme.

New World cutaneous leishmaniasis imported into Australia

Summary A case of cutaneous leishmaniasis in a traveller from Belize, Central America is reported. Leishmaniasis presents rarely in Australia and delays in diagnosis and treatment often occur. A high index of suspicion in a patient who has returned from an endemic region is required. Subsequent confirmation of a diagnosis of cutaneous leishmaniasis is best achieved by demonstration of the organism on skin biopsy, aspiration or smear. The histology is variable and depends on geographic, parasite species and host factors. Speciation of New World disease as either Leishmania braziliensis or Leishmania mexicana is important to determine the risk of later development of mucosal disease, which normally only occurs with L. braziliensis infection, and for optimal treatment. Several different modes of treatment have been suggested, but antimonials, such as sodium stibogluconate, remain the treatment of choice in New World cutaneous leishmaniasis.

The future of acute rheumatic fever and rheumatic heart disease in Australia

[Extract] An 8-year-old Aboriginal girl presents with shortness of breath and severe mitral regurgitation, and requires urgent surgery; a young Torres Strait Islander mother has a disabling stroke related to mitral stenosis; and a middle-aged Aboriginal community leader dies from infective endocarditis associated with a mechanical valve. These are the realities of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in Australia.

High Morbidity during Treatment and Residual Pulmonary Disability in Pulmonary Tuberculosis: Under-Recognised Phenomena

Background In pulmonary tuberculosis (PTB), morbidity during treatment and residual pulmonary disability can be under-estimated. Methods Among adults with smear-positive PTB at an outpatient clinic in Papua, Indonesia, we assessed morbidity at baseline and during treatment, and 6-month residual disability, by measuring functional capacity (six-minute walk test [6MWT] and pulmonary function), quality of life (St George’s Respiratory Questionnaire [SGRQ]) and Adverse Events ([AE]: new symptoms not present at outset). Results were compared with findings in locally-recruited volunteers. Results 200 PTB patients and 40 volunteers were enrolled. 6WMT was 497m (interquartile range 460-529) in controls versus 408m (IQR 346-450) in PTB patients at baseline (p<0.0001) and 470m (IQR 418-515) in PTB patients after 6 months (p=0.02 versus controls). SGRQ total score was 0 units (IQR 0-2.9) in controls, versus 36.9 (27.4-52.8) in PTB patients at baseline (p<0.0001) and 4.3 (1.7-8.8) by 6 months (p<0.0001). Mean percentage of predicted FEV1 was 92% (standard deviation 19.9) in controls, versus 63% (19.4) in PTB patients at baseline (p<0.0001) and 71% (17.5) by 6 months (p<0.0001). After 6 months, 27% of TB patients still had at least moderate-severe pulmonary function impairment, and 57% still had respiratory symptoms, despite most achieving ‘successful’ treatment outcomes, and reporting good quality of life. More-advanced disease at baseline (longer illness duration, worse baseline X-ray) and HIV positivity predicted residual disability. AE at any time during treatment were common: itch 59%, arthralgia 58%, headache 40%, nausea 33%, vomiting 16%. Conclusion We found high 6-month residual pulmonary disability and high AE rates. Although PTB treatment is highly successful, the extent of morbidity during treatment and residual impairment could be overlooked if not specifically sought. Calculations of PTB-related burden of disease should acknowledge that TB-related morbidity does not stop at 6 months. Early case detection and treatment are key in minimising residual impairment.