HIV-exposed infants with acute respiratory failure secondary to acute lower respiratory infections managed with and without mechanical ventilation

Objectives. The decision to provide mechanical ventilation (intermittent positive pressure ventilation (IPPV)) to HIV-exposed infants in resource-poor settings has remained difficult owing to problems in confirming HIV infection and the lack of data on outcome. We evaluated the predictive value of the HIV antibody test in confirming infection in infants requiring mechanical ventilation for acute lower respiratory infections (ALRis), and compared the outcome for children denied access with the outcome for similar subjects who were ventilated.Setting and design. This investigative study was conducted over a 12-month period at the paediatric intensive care unit (PICU) at King Edward VIII Hospital (KEH) in Durban, and at Ngwelezana Hospital in northern KwaZulu-Natal.Subjects. HIV-exposed patients with acute respiratory failure (ARF) secondary to ALRI entering the PICU at KEH were enrolled into the IPPV arm, while similar children who were refused such care at Ngwelezana Hospital were admitted into the non-IPPV arm. Standardised protocols for entry and management of enrolled subjects were utilised.Outcome measures. HIV DNA polymerase chain reaction (PCR) testing was performed to establish HIV status. Clinical and laboratory parameters were correlated with HIV status to determine predictors of infection and outcome (survival to discharge).Results. One hundred and sixteen HIV-exposed infants were enrolled, 49 into the IPPV arm and 67 into the non-IPPV arm. The median age of both groups was 3.0 months (0.5 - 11 months), and the male/female ratio and proportion of infants under 3 months of age were similar in both groups. The predictive values of the HIV antibody test in determining HIV infection in the IPPV and non-IPPV arms were 87.8% and 85.0% respectively. Splenomegaly and a serum globulin of >35 g/l increased the likelihood of being HIV PCR- positive (p = 0.006 and p = 0.04 respectively). Survival to discharge rates for HIV-infected children in the IPPV and non-IPPV arms were 41.9% and 24.6% respectively (p = 0.08). Age less than 3 months (p = 0.04) and very severe pneumonia (p = 0.007) were the only indicators of poor outcome.Conclusion. Mechanical ventilation provided little benefit in HIV-infected children with ARF from ALRI. An HIV antibody test in infants with ALRI and ARF is highly suggestive of HIV infection. Splenomegaly and a serumglobulin of greater than 35 g/l were the only useful markers in identifying HIV infection

The good, the bad and the twisted: a survey of ligand geometry in protein crystal structures

The protein databank now contains the structures of over 11,000 ligands bound to proteins. These structures are invaluable in applied areas such as structure-based drug design, but are also the substrate for understanding the energetics of intermolecular interactions with proteins. Despite their obvious importance, the careful analysis of ligands bound to protein structures lags behind the analysis of the protein structures themselves. We present an analysis of the geometry of ligands bound to proteins and highlight the role of small molecule crystal structures in enabling molecular modellers to critically evaluate a ligand model’s quality and investigate protein-induced strain

QuantiFERON®-TB gold in-tube performance for diagnosing active tuberculosis in children and adults in a high burden setting.

To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania. Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB. Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline. QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting

Challenges of Loss to Follow-up in Tuberculosis Research.

In studies evaluating methods for diagnosing tuberculosis (TB), follow-up to verify the presence or absence of active TB is crucial and high dropout rates may significantly affect the validity of the results. In a study assessing the diagnostic performance of the QuantiFERON®-TB Gold In-Tube test in TB suspect children in Tanzania, factors influencing patient adherence to attend follow-up examinations and reasons for not attending were examined. In 160 children who attended and 102 children who did not attend scheduled 2-month follow-up baseline health characteristics, demographic data and risk factors for not attending follow-up were determined. Qualitative interviews were used to understand patient and caretakers reasons for not returning for scheduled follow-up. Being treated for active tb in the dots program (OR: 4.14; 95% CI:1.99-8.62;p-value<0.001) and receiving money for the bus fare (OR:129; 95% CI 16->100;P-value<0.001) were positive predictors for attending follow-up at 2 months, and 21/85(25%) of children not attending scheduled follow-up had died. Interviews revealed that limited financial resources, i.e. lack of money for transportation and poor communication, were related to non-adherence. Patients lost to follow-up is a potential problem for TB research. Receiving money for transportation to the hospital and communication is crucial for adherence to follow-up conducted at a study facility. Strategies to ensure follow-up should be part of any study protocol

Advances in the Diagnosis of Pulmonary Tuberculosis in HIV-Infected and HIV-Uninfected Children

The identification of improved diagnostic tests for tuberculosis has been identified as a global research priority. Over the past decade, there has been renewed interest in the development and validation of novel diagnostic tools for pulmonary tuberculosis that are applicable to resource-poor settings. These techniques are aimed primarily at improving detection of the organism or a specific host immune response. Although most studies have focused on determining the accuracy of novel tests in adults, it is likely they will also have the capacity to significantly improve the diagnosis of childhood tuberculosis. Improving the quality of clinical samples obtained from children with suspected tuberculosis remains an important research priority while awaiting validation of novel diagnostic tests. This review will focus on a number of recent developments for the diagnosis of tuberculosis, with a specific emphasis on the application of these new tests to children in settings where tuberculosis is endemic

Whole Blood Interferon-Gamma Responses to Mycobacterium tuberculosis Antigens in Young Household Contacts of Persons with Tuberculosis in Uganda

Due to immunologic immaturity, IFN-gamma-producing T cell responses may be decreased in young children compared to adults, thus we hypothesized that IFN-gamma responses to mycobacterial antigens in household contacts exposed to Mycobacterium tuberculosis (Mtb) would be impaired in young children relative to adults. The objective of this study was to compare whole blood IFN-gamma production in response to mycobacterial antigens between children and adults in Uganda.We studied household contacts of persons with culture-positive pulmonary tuberculosis (TB) enrolled in a cohort study conducted in Kampala, Uganda. Whole blood IFN-gamma production in response to Mtb culture-filtrate antigens was measured by ELISA and compared between infants (<2 years old, n = 80), young children (2 <5 years old, n = 216), older children (5 <15 years old, n = 443) and adults (> or =15 years old, n = 528). We evaluated the relationship between IFN-gamma responses and the tuberculin skin test (TST), and between IFN-gamma responses and epidemiologic factors that reflect exposure to Mtb, and the effect of prior BCG vaccination on IFN-gamma responses. Young household contacts demonstrated robust IFN-gamma responses comparable to those of adults that were associated with TST and known risk factors for infection. There was no effect of prior BCG immunization on the IFN-gamma response.Young children in a TB endemic setting can mount robust IFN-gamma responses generally comparable to those of adults, and as in adults, these responses correlated with the TST and known epidemiologic risk factors for Mtb infection

Diagnosis of Tuberculosis by an Enzyme-Linked Immunospot Assay for Interferon-γ

*National Taiwan University Hospital, Taipei, Taiwan