HIV Testing and Epidemiology in a Hospital-Based Surgical Cohort in Malawi

Despite the high prevalence of HIV in adults (11 %) in Malawi, testing among surgical patients is not routine. We examined the feasibility of universal opt-out HIV testing and counseling (HTC) on the surgical wards of Kamuzu Central Hospital in Lilongwe, Malawi, and sought to further delineate the role of HIV in surgical presentation and outcome

Use Of Xpert For The Diagnosis Of Pulmonary Tuberculosis In Severely Malnourished Hospitalized Malawian Children

Pulmonary tuberculosis contributes to increased morbidity and mortality in severely malnourished children in endemic settings. Despite high clinical suspicion, few tuberculosis prevalence estimates exist in malnourished African children. Diagnostics such as Xpert MTB/RIF may help to determine pulmonary tuberculosis prevalence, however its performance in severely malnourished children is largely unknown

Using a composite maternal-infant outcome measure in tuberculosis prevention studies among pregnant women

CITATION: Montepiedra, G. et al. 2021. Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women. Clinical infectious diseases, 73(3):587–e593. doi:10.1093/cid/ciaa1674The original publication is available at https://academic.oup.com/cid/Background: Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk-benefit of interventions. Methods: A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated. Results: The composite outcome scoring/ranking system categorized mother-infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4-26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, -3.2-6.2; P = .53). Conclusions: For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).https://academic.oup.com/cid/article/73/3/e587/5955952?login=truePublishers versio

Coronavirus disease 2019 (COVID-19) pharmacologic treatments for children : research priorities and approach to pediatric studies

CITATION: Garcia-Prats, A. J. et al. 2021. Coronavirus Disease 2019 (COVID-19) Pharmacologic Treatments for Children: Research Priorities and Approach to Pediatric Studies. Clinical infectious diseases, 72(6):1067–1073. doi:10.1093/cid/ciaa885The original publication is available at https://academic.oup.com/cid/Clinical trials of pharmacologic treatments of coronavirus disease 2019 (COVID-19) are being rapidly designed and implemented in adults. Children are often not considered during development of novel treatments for infectious diseases until very late. Although children appear to have a lower risk compared with adults of severe COVID-19 disease, a substantial number of children globally will benefit from pharmacologic treatments. It will be reasonable to extrapolate efficacy of most treatments from adult trials to children. Pediatric trials should focus on characterizing a treatment’s pharmacokinetics, optimal dose, and safety across the age spectrum. These trials should use an adaptive design to efficiently add or remove arms in what will be a rapidly evolving treatment landscape, and should involve a large number of sites across the globe in a collaborative effort to facilitate efficient implementation. All stakeholders must commit to equitable access to any effective, safe treatment for children everywhere.https://academic.oup.com/cid/article/72/6/1067/5864500?login=truePublishers versio

Development of a Clinical Prediction Score Including Monocyte-to-Lymphocyte Ratio to Inform Tuberculosis Treatment Among Children With HIV: A Multicountry Study

BACKGROUND: Clinical pediatric tuberculosis (TB) diagnosis may lead to overdiagnosis particularly among children with human immunodeficiency virus (CHIV). We assessed the performance of monocyte-lymphocyte ratio (MLR) as a diagnostic biomarker and constructed a clinical prediction score to improve specificity of TB diagnosis in CHIV with limited access to microbiologic testing. METHODS: We pooled data from cohorts of children aged ≤13 years from Vietnam, Cameroon, and South Africa to validate the use of MLR ≥0.378, previously found as a TB diagnostic marker among CHIV. Using multivariable logistic regression, we created an internally validated prediction score for diagnosis of TB disease in CHIV. RESULTS: The combined cohort had 601 children (median age, 1.9 [interquartile range, 0.9-5.3] years); 300 (50%) children were male, and 283 (47%) had HIV. Elevated MLR ≥0.378 had sensitivity of 36% (95% confidence interval [CI], 23%-51%) and specificity of 79% (95% CI, 71%-86%) among CHIV in the validation cohort. A model using MLR ≥0.28, age ≥4 years, tuberculin skin testing ≥5 mm, TB contact history, fever >2 weeks, and chest radiograph suggestive of TB predicted active TB disease in CHIV with an area under the receiver operating characteristic curve of 0.85. A prediction score of ≥5 points had a sensitivity of 94% and specificity of 48% to identify confirmed TB, and a sensitivity of 82% and specificity of 48% to identify confirmed and unconfirmed TB groups combined. CONCLUSIONS: Our score has comparable sensitivity and specificity to algorithms including microbiological testing and should enable clinicians to rapidly initiate TB treatment among CHIV when microbiological testing is unavailable

Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV

CITATION: Weinberg, A. et al. 2021. Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV. Clinical infectious diseases, 73(9): e3555–e3562. doi:10.1093/cid/ciaa1083The original publication is available at https://academic.oup.com/cid/Background Pregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity. Methods 944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results From entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum. Conclusions Decreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.https://academic.oup.com/cid/article/73/9/e3555/5877271?login=truePublishers versio

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BackgroundThe WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.MethodsIn this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.FindingsWe identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively.InterpretationC-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications.FundingWorld Health Organization

Tuberculosis case finding and performance of symptom screening and rapid diagnostic tests in HIV-infected pregnant women in western Kenya

Thesis (Master's)--University of Washington, 2015Background: Tuberculosis (TB) during pregnancy in HIV-infected women is associated with poor maternal and infant outcomes. There are limited data on TB prevalence, optimal TB screening, and performance of rapid diagnostics in pregnant HIV-infected women. Methods: We conducted a cross-sectional study among HIV-infected pregnant women seeking antenatal care in western Kenya. Following a standardized questionnaire, sputum smear microscopy for acid-fast bacilli (AFB), mycobacterial liquid culture, GeneXpert MTB/RIF (Xpert), urine lipoarabinomannan (LAM), and tuberculin skin testing (TST) were performed. We determined prevalence and correlates of culture-confirmed pulmonary TB, and compared diagnostic performance of World Health Organization (WHO) symptom screening and rapid diagnostic tests to sputum culture. Results: Between July 2013 and July 2014, we enrolled 306 women. Among 288 women with a valid sputum culture result, 54% were on antiretroviral treatment, median CD4 cell count was 437 cell/mm3 (IQR 342-565), and prevalence of culture-confirmed pulmonary TB was 2.4% (CI 1.0-4.9%). Cough >2 weeks (p=0.04) and positive TST (>5mm, p=0.03) were associated with pulmonary TB. Women with TB were 23-fold (95% CI 4.4-116.6) more likely to report a household member with TB symptoms (p=0.002). WHO symptom screen (43%), AFB smear (0%), Xpert (43%) and LAM (0%) had low sensitivity but high specificity (81%, 99%, 99% and 95%, respectively) for pulmonary TB. Conclusion: HIV-infected pregnant women had appreciable prevalence of pulmonary TB despite modest immunosuppression. Current TB screening and diagnostic tools perform poorly in pregnant HIV-infected women. Adapted TB screening tools that include household member TB symptoms may be useful in this population

Risk of Adverse Infant Outcomes Associated with Maternal Tuberculosis in a Low Burden Setting: A Population-Based Retrospective Cohort Study

Background. Maternal tuberculosis (TB) may be associated with increased risk of adverse infant outcomes. Study Design. We examined the risk of low birth weight (LBW), small for gestational age (SGA), and preterm birth (<37 weeks) associated with maternal TB in a retrospective population-based Washington State cohort using linked infant birth certificate and maternal delivery hospitalization discharge records. We identified 134 women with births between 1987 and 2012 with TB-associated ICD-9 diagnosis codes at hospital delivery discharge and 536 randomly selected women without TB, frequency matched 4 : 1 on delivery year. Multinomial logistic regression analyses were performed to compare the risk of LBW, SGA, and preterm birth between infants born to mothers with and without TB. Results. Infants born to women with TB were 3.74 (aRR 95% CI 1.40–10.00) times as likely to be LBW and 1.96 (aRR 95% CI 0.91–4.22) as likely to be SGA compared to infants born to mothers without TB. Risk of prematurity was similar (aRR 1.01 95% CI 0.39–2.58). Conclusion. Maternal TB is associated with poor infant outcomes even in a low burden setting. A better understanding of the adverse infant outcomes associated with maternal TB, reflecting recent trends in US TB epidemiology, may inform potential targeted interventions in other low prevalence settings

Symptom screening for active tuberculosis in pregnant women living with HIV

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To assess the accuracy of the four-symptom screen (cough, fever, night sweats, or weight loss) for identifying active TB in pregnant PLHIV who are screened in an outpatient or community setting. To investigate potential sources of heterogeneity of the accuracy of the four-symptom screen between studies including: ART status, CD4 cell count, gestational age, pregnancy stage (pregnancy vs. postpartum), screening test definition of cough (any cough vs. cough greater than 2 weeks). To describe the accuracy of single symptoms included within the four-symptom screen, additional symptoms or symptom combinations, for identifying active TB in pregnant PLHIV. For example, additional symptoms may include failure to gain weight or fatigu