Cytokine biomarkers for the diagnosis of tuberculosis infection and disease in adults in a low prevalence setting.

OBJECTIVE: Accurate and timely diagnosis of tuberculosis (TB) is essential to control the global pandemic. Currently available immunodiagnostic tests cannot discriminate between latent tuberculosis infection (LTBI) and active tuberculosis. This study aimed to determine whether candidate mycobacterial antigen-stimulated cytokine biomarkers can discriminate between TB-uninfected and TB-infected adults, and additionally between LTBI and active TB disease. METHODS: 193 adults were recruited, and categorised into four unambiguous diagnostic groups: microbiologically-proven active TB, LTBI, sick controls (non-TB lower respiratory tract infections) and healthy controls. Whole blood assays were used to determine mycobacterial antigen (CFP-10, ESAT-6, PPD)-stimulated cytokine (IL-1ra, IL-2, IL-10, IL-13, TNF-α, IFN-γ, IP-10 and MIP-1ß) responses, measured by Luminex multiplex immunoassay. RESULTS: The background-corrected mycobacterial antigen-stimulated cytokine responses of all eight cytokines were significantly higher in TB-infected participants compared with TB-uninfected individuals, with IL-2 showing the best performance characteristics. In addition, mycobacterial antigen-stimulated responses with IL-1ra, IL-10 and TNF-α were higher in participants with active TB compared those with LTBI, reaching statistical significance with PPD stimulation, although there was a degree of overlap between the two groups. CONCLUSION: Mycobacterial antigen-stimulated cytokine responses may prove useful in future immunodiagnostic tests to discriminate between tuberculosis-infected and tuberculosis-uninfected individual, and potentially between LTBI and active tuberculosis.

SIRCLE: a randomised controlled cost comparison of self-administered short-course isoniazid and rifapentine for cost-effective latent tuberculosis eradication.

BACKGROUND: Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of isoniazid (9H). A 3-month course of weekly isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain. AIM: Cost-analysis of standard and short-course therapy for LTBI in an Australian context. METHODS: Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily isoniazid or a 12-week course of weekly isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine. RESULTS: Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01). CONCLUSIONS: This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia.

The incidence of HBV and HCV infection in Australian travelers to Asia.

We analyzed paired pre- and post-travel sera in a cohort of Australian travelers to Asia and demonstrated the acquisition of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. The incidence density in nonimmune travelers for HCV infection was calculated as 1.8 infections per 10,000 traveler-days and for HBV infection 2.19 per 10,000 traveler-days.

Low risk of Japanese encephalitis in short-term Australian travelers to Asia.

The risk of Japanese encephalitis (JE) in travelers is unknown. In this prospective study, we investigated the incidence of JE in 387 short-term Australian travelers visiting Asia over a 32-month period from August 2007 to February 2010 by performing pre- and post-travel antibody testing. No travelers were infected with JE virus during travel, indicating a low risk of infection for short-term travelers.

Incidence and risk factors for acute respiratory illnesses and influenza virus infections in Australian travellers to Asia.

BACKGROUND: Respiratory infections including influenza are a common cause of acute short-term morbidity in travellers and yet the risk of these infections is poorly defined. OBJECTIVES: To estimate the incidence density of and risk factors for acute respiratory infections (ARIs) and influenza in Australian travellers to Asia. STUDY DESIGN: Travel-clinic attendees were prospectively identified and completed questionnaires (demographic data, travel itinerary, health and vaccination history) and also provided pre and post-travel serological samples for Influenza A and B (complement fixation test). Returned travellers with an ARI provided nasopharyngeal specimens for RT-PCR identification of respiratory viruses. RESULTS: In this cohort (n = 387) of predominantly (72%) short-term travellers, 58% were female, the median age was 37 years and 69% were tourists. ARIs occurred in 109 travellers (28%) translating to an incidence of 106.4 ARIs per 10,000 traveller days (95% confidence interval CI 88.6-126.7). The traveller type of missionary or aid worker was a risk factor for acquiring an ARI (p = 0.03) and ARIs occurred early (< 30 days) in the travel period (p = 0.001). Four travellers (1%) acquired influenza A during travel translating to an incidence density of 3.4 infections per 10,000 days of travel (95% CI 1.4-8.6). Influenza vaccination was reported in 49% of travellers with a 3.5-fold higher incidence of influenza in unvaccinated travellers compared to vaccinated travellers (p = 0.883). CONCLUSIONS: This is one of the largest prospective studies estimating the incidence of respiratory infections in travellers. These findings have important implications for practitioners advising prospective travellers and for public health authorities.

Development and validation of an instrument to assess the risk of developing viral infections in Australian travelers during international travel.

BACKGROUND: Questionnaires are widely used for data collection in travel medicine studies, but there are no validated instruments that are available to researchers in this field. Our objective was to develop and validate a questionnaire to be used in a prospective study designed to estimate the risk of three viral infections in Australian travelers to Asia. METHODS: Qualitative nonexperimental cognitive methods, including cognitive review, task analysis, and cognitive interviews, were selected. A pilot study was performed to assess the instrument in the target population. RESULTS: Recalling dates related to travel or health events was observed and reported to be the most difficult task for travelers. The use of cues embedded into items and provision of memory prompts such as calendars improves the recall of dates during travel. There is a wide spectrum of accommodation, activities, and travel experiences, and item responses that were constructed as lists were useful as memory triggers, particularly for travelers with long and complicated itineraries. Cognitive interviews provided a valuable insight into how travelers used inferential and direct memory to recall travel events and their confidence in the accuracy of these processes. CONCLUSIONS: The development and validation of questionnaires improve the accuracy of the data collected and should be considered an integral part of the methodology of travel-related studies.

Animal-associated injuries and related diseases among returned travellers: a review of the GeoSentinel Surveillance Network.

BACKGROUND: Increased travel to exotic destinations around the world is escalating the risk of exposure to animal-associated injuries with a risk of acquiring rabies. METHODS: We have examined data reported to GeoSentinel Surveillance Network to highlight characteristics of animal-associated injuries in travellers. RESULTS: A total of 320 cases were reported from 1998 to 2005. Travellers were predominantly tourists from developed countries with median travel duration of 23 days. A pre-travel encounter was recorded in 45.0% of the cases. A significantly greater proportion of patients with animal-related injuries were female compared to other travel associated diagnosis (54.7% versus 47.4%) and were most likely patients aged <15 years (6.2% versus 2.6%). The proportionate morbidity for sustaining an animal bite was higher among travellers visiting Southeast Asia (3.9%) and the rest of Asia (2.2%) compared to Australia-New Zealand (1.9%), Africa (1.0%), Latin America (0.8%), North America (0.9%) and Europe (1.2%). Seventy-five percent of cases occurred in countries endemic for rabies. Dogs were involved in 51.3% of cases, monkeys in 21.2%, cats in 8.2%, bats in 0.7% and humans in 0.7%. The higher likelihood for animal-related injuries among female travellers was dependant on the animal species involved, with monkeys accounting for the majority of injuries. In contrast, males were more likely to be injured by dogs. Only 66.1% of all patients reported with animal-related injury received rabies post-exposure prophylaxis. CONCLUSIONS: This data shows that animal-associated injuries are not uncommon among returned travellers presenting to GeoSentinel sites. The highest proportion of injuries was recorded in travellers to Asia, mostly in regions, which are endemic for rabies, and this had led to a requirement for PEP.

Illness in returned travelers and immigrants/refugees: the 6-year experience of two Australian infectious diseases units.

BACKGROUND: Data comparing returned travelers and immigrants/refugees managed in a hospital setting is lacking. METHODS: We prospectively collected data on 1,106 patients with an illness likely acquired overseas who presented to two hospital-based Australian infectious diseases units over a 6-year period. RESULTS: Eighty-three percent of patients were travelers and 17% immigrants/refugees. In travelers, malaria (19%), gastroenteritis/diarrhea (15%), and upper respiratory tract infection (URTI) (7%) were the most common diagnoses. When compared with immigrants/refugees, travelers were significantly more likely to be diagnosed with gastroenteritis/diarrhea [odds ratio (OR) 8], malaria (OR 7), pneumonia (OR 6), URTI (OR 3), skin infection, dengue fever, typhoid/paratyphoid fever, influenza, and rickettsial disease. They were significantly less likely to be diagnosed with leprosy (OR 0.03), chronic hepatitis (OR 0.04), tuberculosis (OR 0.05), schistosomiasis (OR 0.3), and helminthic infection (OR 0.3). In addition, travelers were more likely to present within 1 month of entry into Australia (OR 96), and have fever (OR 8), skin (OR 6), gastrointestinal (OR 5), or neurological symptoms (OR 5) but were less likely to be asymptomatic (OR 0.1) or have anaemia (OR 0.4) or eosinophilia (OR 0.3). Diseases in travelers were more likely to have been acquired via a vector (OR 13) or food and water (OR 4), and less likely to have been acquired via the respiratory (OR 0.2) or skin (OR 0.6) routes. We also found that travel destination and classification of traveler can significantly influence the likelihood of a specific diagnosis in travelers. Six percent of travelers developed a potentially vaccine-preventable disease, with failure to vaccinate occurring in 31% of these cases in the pretravel medical consultation. CONCLUSIONS: There are important differences in the spectrum of illness, clinical features, and mode of disease transmission between returned travelers and immigrants/refugees presenting to hospital-based Australian infectious diseases units with an illness acquired overseas.

Dengue Fever in travelers returning from southeast Asia.

BACKGROUND: Dengue fever is an important illness facing travelers from nonendemic to endemic countries. METHODS: We reviewed 696 consecutive returned travelers managed at an Australian tertiary-care hospital for an illness acquired overseas. Patients with dengue fever were compared to those with a dengue-like illness, malaria, typhoid fever and rickettsial infections. RESULTS: In total, 19 cases of dengue fever and 20 cases of dengue-like illness were diagnosed, with 85% of cases acquired in Asia. The most common presenting features of dengue were fever (100%), myalgia (79%), rash (74%), headache (68%), nausea (37%), and diarrhea (37%). Compared to those with malaria, typhoid fever and rickettsial infections, patients with dengue were significantly more likely to have myalgia and a temperature <39 degrees C. Compared to all other illnesses in our returned travelers, dengue fever was 18 times more likely if fever and leukopenia were present, 71 times if fever and rash were present, and 230 times if fever, rash and leukopenia were present. All patients with dengue recovered completely. CONCLUSIONS: Dengue fever is an important health problem for travelers not only to Southeast Asia but to all endemic countries. The prevalence appears to be increasing in travelers, and health care professionals need to be familiar with its presentation in travelers. The clinical presenting features provide important guides to establishing the diagnosis.