Timothy Barkham

Persistent Arthralgia Induced by Chikungunya Virus Infection is Associated with Interleukin-6 and Granulocyte Macrophage Colony-Stimulating Factor

Background. Chikungunya virus (CHIKV) infection induces arthralgia. The involvement of inflammatory cytokines and chemokines has been suggested, but very little is known about their secretion profile in CHIKV-infected patients. Methods. A case-control longitudinal study was performed that involved 30 adult patients with laboratory-confirmed Chikungunya fever. Their profiles of clinical disease, viral load, and immune mediators were investigated. Results. When patients were segregated into high viral load and low viral load groups during the acute phase, those with high viremia had lymphopenia, lower levels of monocytes, neutrophilia, and signs of inflammation. The high viral load group was also characterized by a higher production of pro-inflammatory cytokines, such as interferon-α and interleukin (IL)–6, during the acute phase. As the disease progressed to the chronic phase, IL-17 became detectable. However, persistent arthralgia was associated with higher levels of IL-6 and granulocyte macrophage colony-stimulating factor, whereas patients who recovered fully had high levels of Eotaxin and hepatocyte growth factor. Conclusions. The level of CHIKV viremia during the acute phase determined specific patterns of pro-inflammatory cytokines, which were associated with disease severity. At the chronic phase, levels of IL-6, and granulocyte macrophage colony-stimulating factor found to be associated with persistent arthralgia provide a possible explanation for the etiology of arthralgia that plagues numerous CHIKV-infected patients.

Hajj-Associated Outbreak Strain of Neisseria meningitidis Serogroup W135: Estimates of the Attack Rate in a Defined Population and the Risk of Invasive Disease Developing in Carriers

An outbreak of disease due to Neisseria meningitidis serogroup W135 (W135) occurred in 2000 and 2001 among pilgrims returning from the annual Islamic pilgrimage to Saudi Arabia (the Hajj) and in their contacts. For the Hajj in 2000, the attack rate of W135 disease was 25 cases per 100,000 pilgrims. After the introduction of quadrivalent meningococcal vaccine for the Hajj in 2001, no pilgrim developed W135 disease. The estimated attack rates for household contacts of returning pilgrims were 18 cases and 28 cases per 100,000 contacts for the years 2000 and 2001, respectively. On the basis of rates of transmission of W135 carriage and national epidemiological data, the risk that an unvaccinated household contact who had acquired W135 carriage would develop invasive meningococcal disease was estimated to be 1 case per 70 acquisitions. Public health policies to protect household contacts of Hajj pilgrims need to be implemented.

Comparison of Sensitivities of Two Commercial Gamma Interferon Release Assays for Pulmonary Tuberculosis

ABSTRACT There are few head-to-head comparisons of the commercial gamma interferon release assays (GIRAs). We compared the performance of the T-SPOT.TB and QuantiFERON-TB Gold In-Tube (QFT-IT) assays in patients with culture-proven pulmonary tuberculosis. Blood was drawn for both assays within 14 days of starting antituberculosis treatment. The QFT-IT indeterminate rate was 3.5%; the T-SPOT.TB failure rate was 1.4%. There was poor agreement between the GIRAs (κ = 0.257) among the 270 patients with valid results for both tests. The sensitivities of the T-SPOT.TB and QFT-IT assays were 94.1 and 83.0%, respectively, with a significant difference in the performance of the assays (P = 0.001 [McNemar test]). Factors independently associated with indeterminate QFT-IT results were an age of ≥60 years (odds ratio [OR] 11.18, 95% confidence interval [CI] = 1.841 to 67.823, P = 0.009), female sex (OR = 7.47, 95% CI = 1.517 to 36.733, P = 0.013) and non-Chinese (i.e., Indian or Malay) race (OR = 7.89, 95% CI = 1.585 to 39.267, P = 0.012). The QFT-IT assay was significantly less sensitive in patients ≥60 years old (OR = 0.41, 95% CI = 0.181 to 0.918, P = 0.030) and in Indian compared to Chinese patients (OR = 0.27, 95% CI = 0.073 to 0.990, P = 0.048). The T-SPOT.TB assay was significantly less sensitive in Malay (OR = 0.23, 95% CI = 0.063 to 0.815, P = 0.023) and Indian patients (OR = 0.09, 95% CI = 0.017 to 0.429, P = 0.003) compared to Chinese patients. The performance of both assays was not significantly altered in diabetics. The diminished sensitivity of the GIRAs in persons of Malay and Indian race merits further study.

Dengue Virus Surveillance for Early Warning, Singapore

In Singapore, after a major outbreak of dengue in 2005, another outbreak occurred in 2007. Laboratory-based surveillance detected a switch from dengue virus serotype 1 (DENV-1) to DENV-2. Phylogenetic analysis showed a clade replacement within DENV-2 cosmopolitan genotype, which accompanied the predominant serotype switch, and cocirculation of multiple genotypes of DENV-3.

Tuberculosis treatment effect on T-cell interferon-γ responses to Mycobacterium tuberculosis-specific antigens

The hypothesis that T-cell interferon-&ggr; responses to Mycobacterium tuberculosis-specific antigens decline as disease activity diminishes with tuberculosis (TB) treatment has generated interest in the interferon-&ggr; release assays (IGRAs) as treatment-monitoring tools. We studied the effect of TB treatment on these responses as measured by the QuantiFERON-TB® Gold In-tube (QFT-IT) and T-SPOT.TB® assays. 275 sputum culture-positive, HIV-uninfected pulmonary TB patients were tested with QFT-IT and T-SPOT.TB® at baseline, treatment completion and 6 months thereafter. The QFT-IT was also performed at the end of the intensive phase. The time-treatment effect on the qualitative and quantitative IGRA results was determined. There were significant declines in the positivity rates and quantitative results of both IGRAs with treatment. The QFT-IT positivity rate was significantly lower than the T-SPOT.TB®. The test reversion rate was significantly different for the two assays (13.9% for T-SPOT.TB® versus 39.2% for QFT-IT). 79% and 46% tested positive with T-SPOT.TB® and QFT-IT respectively at 6 months post-treatment completion. The kinetics of the quantitative responses was not significantly different between subjects with and without risk factors for disease relapse. That a substantial proportion of patients remained test-positive after TB treatment would suggest a limited role of IGRAs as treatment monitoring tools.

Establishment of ST30 as the Predominant Clonal Type among Community-Associated Methicillin-Resistant Staphylococcus aureus Isolates in Singapore

ABSTRACT The number of infections attributable to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in Singapore is progressively increasing. Most cases in the past 2 years were caused by Panton-Valentine leukocidin-positive isolates belonging to sequence type 30, according to multilocus sequence typing. This has clearly become the predominant sequence type among CA-MRSA isolates in Singapore.

Improving the Clinical Diagnosis of Influenza—a Comparative Analysis of New Influenza A (H1N1) Cases

Background The presentation of new influenza A(H1N1) is broad and evolving as it continues to affect different geographic locations and populations. To improve the accuracy of predicting influenza infection in an outpatient setting, we undertook a comparative analysis of H1N1(2009), seasonal influenza, and persons with acute respiratory illness (ARI) in an outpatient setting. Methodology/Principal Findings Comparative analyses of one hundred non-matched cases each of PCR confirmed H1N1(2009), seasonal influenza, and ARI cases. Multivariate analysis was performed to look for predictors of influenza infection. Receiver operating characteristic curves were constructed for various combinations of clinical and laboratory case definitions. The initial clinical and laboratory features of H1N1(2009) and seasonal influenza were similar. Among ARI cases, fever, cough, headache, rhinorrhea, the absence of leukocytosis, and a normal chest radiograph positively predict for both PCR-confirmed H1N1-2009 and seasonal influenza infection. The sensitivity and specificity of current WHO and CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. However, the combination of WHO ILI criteria with the absence of leukocytosis greatly improved the accuracy of diagnosing H1N1(2009) and seasonal influenza (positive LR of 7.8 (95%CI 3.5–17.5) and 9.2 (95%CI 4.1–20.3) respectively). Conclusions/Significance The clinical presentation of H1N1(2009) infection is largely indistinguishable from that of seasonal influenza. Among patients with acute respiratory illness, features such as a temperature greater than 38°C, rhinorrhea, a normal chest radiograph, and the absence of leukocytosis or significant gastrointestinal symptoms were all positively associated with H1N1(2009) and seasonal influenza infection. An enhanced ILI criteria that combines both a symptom complex with the absence of leukocytosis on testing can improve the accuracy of predicting both seasonal and H1N1-2009 influenza infection.

Epidemiology of travel-associated pandemic (H1N1) 2009 infection in 116 patients, Singapore.

During the containment phase, regions of exposure for imported infections changed rapidly.

The performance of RT-PCR compared with a rapid serological assay for acute dengue fever in a diagnostic laboratory.

Summary The laboratory diagnosis of dengue has largely relied on serological assays, although many different RT-PCR protocols have been reported. Owing to its limited use, the value of RT-PCR in the clinical laboratory has not been fully evaluated. During the outbreak of severe acute respiratory syndrome (SARS) in Singapore in 2003, RT-PCR to detect dengue viral RNA was used as a rapid diagnostic tool to differentiate dengue from SARS among patients who presented to a hospital designated to manage and quarantine SARS cases. A total of 343 results for RT-PCR and 439 results for serology were analysed and compared with the final discharge diagnosis. Our experience indicates that RT-PCR for dengue can be set up rapidly in a clinical laboratory, with very sensitive and specific results for the diagnosis of dengue, particularly in the first 5 days from onset of symptoms.

Persistence of W135 Neisseria meningitidis Carriage in Returning Hajj Pilgrims: Risk for Early and Late Transmission to Household Contacts

After an outbreak of meningococcal disease caused by Neisseria meningitidis W135, associated with the Hajj pilgrimage in 2001, 15% of returning vaccinated pilgrims carried a single W135 clone, and 55% were still carriers 6 months later. Transmission to 8% of their unvaccinated household contacts occurred within a few weeks, but no late transmission took place. Public health interventions are needed to protect household contacts.