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

Aspects of Tuberculosis and HIV Coinfection in Patients at Ethiopian Health Centers

HIV and tuberculosis (TB) remain the two most common infectious causes of death worldwide. During the recent decade antiretroviral treatment (ART) has become available for millions of people living with HIV (PLHIV) globally; yet more than half of PLHIV have not yet initiated ART. In order to achieve universal access, further decentralization of care is needed. This is a major challenge to health systems, since access to expertise and adapted diagnostic methods to diagnose and monitor patients on treatment in these areas are lacking. Most notably, two issues face clinicians treating PLHIV in high TB endemic areas; is this HIV-patient also infected with TB? and when should ART be started in patients with both HIV and TB? In two papers we developed clinical scoring algorithms to help answer these questions in areas with restricted access to laboratory facilities. In paper I, a clinical screening algorithm could increase the number of patients with low risk of TB, thereby limiting those in need of further investigations for TB as compared to only using the existing WHO-TB symptom screening algorithm. In paper II, a similar scoring algorithm was developed to assess the level of immunosuppression in patients with HIV and TB coinfection. For more than one third of these patients, severe immunosuppression could be excluded. According to current recommendations, this subset would therefore not be in need of immediate ART initiation during TB treatment providing time to prepare patients for life-long ART. In a second part of the thesis, we evaluated the impact of TB on the immune system, both on peripheral CD4 cells and neopterin as a marker of immune activation. In paper III, we found that 25% of HIV negative patients with TB had low CD4 cell count (below 500 cells/mm3). These levels increased until end of TB treatment but not to levels found in healthy controls, suggesting a sustained impact of TB on CD4 cell homeostasis. CD4 cell levels were associated with signs of severe TB (positive sputum smear microscopy, low mid upper arm circumference and bedridden status). In paper IV, neopterin levels were increased in TB patients (23.2 nmol/l) compared to controls (3.8nmol/l), particularly in HIV/TB coinfected patients (54nmol/l). Neopterin correlated to low CD4 cell count, and high neopterin levels were associated with increasing CD4 cell levels during treatment for TB. Yet, neopterin was not suitable as surrogate markers for CD4 cell count. In conclusion, this thesis shows that clinical evaluation of patients should be an integral part in the building of health care for HIV and TB in low-income settings, and that clinically based instruments may be helpful for triage and clinical decisions. Furthermore, we found that TB has an impact on both CD4 cell levels and immune activation. This further emphasizes the need to detect and treat TB in PLHIV

Severe diphtheria with neurologic and myocardial involvement in a Swedish patient : A case report

Background: Diphtheria is caused by Corynebacterium diphtheriae. Although waning in incidence diphtheria can cause severe disease as in this rare Swedish case with several complications. Case presentation: A 55-year old male presented to the emergency room with severe respiratory symptoms and greyish membranes in the airways, which turned positive for C. diphtheriae. He was put on ventilator support and remained hospitalized for three months. During care he developed myocarditis and severe neurological disease and he was also co-infected with tuberculosis. The patient was discharged with a favorable outcome. Conclusions: Diphtheria should be suspected in patients with life-threatening pneumonia especially if the patient has a history of travelling. Our patient was not treated with diphtheria anti-toxin (DAT) which may have contributed to the severity of the disease

Outcome of tuberculosis treatment in HIV-positive adults diagnosed through active versus passive case-finding

Background: The World Health Organization strongly recommends regular screening for tuberculosis (TB) in HIV-positive individuals. Objective: To compare the outcome of anti-tuberculosis treatment (ATT) in HIV-positive adults diagnosed with TB through active case-finding (ACF) or passive case-finding (PCF). Design: Antiretroviral therapy (ART)-naïve adults diagnosed with TB were included from two prospective cohort studies conducted in Ethiopia between September 2010 and March 2013. The PCF cohort was based at out-patient TB clinics, whereas participants in the ACF cohort were actively screened for TB by bacteriological sputum testing (smear microscopy, Xpert MTB/RIF assay, and liquid culture) without pre-selection on the basis of symptoms and signs. Outcomes of ATT were compared between participants in the two cohorts; characteristics at diagnosis and predictors of adverse outcomes were analysed. Results: Among 439 TB/HIV co-infected participants, 307 and 132 belonged to PCF and ACF cohorts, respectively. Compared with the ACF participants, hemoptysis, conjunctival pallor, bedridden status, and low mid upper-arm circumference (MUAC) were significantly more common in participants identified through PCF. Sputum smear-positivity rates among pulmonary TB cases were 44.2% and 21.1% in the PCF and ACF cohorts, respectively (p<0.001). Treatment success was ascertained in 247 (80.5%) of the participants in the PCF cohort and 102 (77.2%) of the participants in the ACF cohorts (p=0.223). Low MUAC (p=0.001) independently predicted mortality in the participants in both cohorts. Conclusion: Although patients identified through ACF had less advanced TB disease, ATT outcome was similar to the patients identified through PCF. To achieve a better outcome, case management in ACF strategy should be strengthened through enhanced patient-centred counselling and adherence support

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

Background: The 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. Methods: In 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. Findings: We 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 (<10 g/dL), body-mass index (<18·5 kg/m2), 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. Interpretation: C-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. Funding: World Health Organization. © 2021 World Health Organizatio

Kynurenine/tryptophan ratio for detection of active tuberculosis in adults with HIV prior to antiretroviral therapy

Objective: The aim of this study was to assess the performance of kynurenine/tryptophan ratio for tuberculosis (TB) case-finding among antiretroviral therapy (ART)-naive people with HIV (PWH), and to investigate other factors associated with kynurenine/tryptophan ratio in this population. Design: A nested case-control study based on a cohort of 812 ambulatory PWH in the Oromia region, Ethiopia. Methods: At enrolment, all participants submitted sputum samples for bacteriological TB investigations. Concentrations of kynurenine and tryptophan in plasma were quantified using liquid chromatography-mass spectrometry. Receiver operator characteristic curves were constructed to assess diagnostic performance (area under the curve; AUC) for kynurenine, tryptophan, and kynurenine/tryptophan ratio. Sensitivity, specificity, and predictive values were calculated. Kynurenine/tryptophan ratios were correlated to plasma levels of nine inflammation mediators, plasma HIV RNA levels, CD4+cell count, BMI, and mid-upper arm circumference (MUAC). Results: We included 124 individuals with HIV-TB coinfection (HIV+/TB+) and 125 with HIV mono-infection (HIV+/TB-). Tryptophan levels were lower in HIV+/TB+ than in HIV+/TB-(median 19.5 vs. 29.8 μmol/l, P < 0.01), while kynurenine levels were similar between these groups (median 2.95 vs. 2.94 μmol/l, P = 0.62). Median kynurenine/tryptophan ratio was 0.15 in HIV+/TB+, significantly higher compared with HIV+/TB-(0.11; P < 0.01), with AUC 0.70 for TB detection. Kynurenine/tryptophan ratio was positively correlated to plasma HIV RNA levels, IP-10, IL-18, and IL-27, and negatively correlated to CD4+cell count, BMI, and MUAC (all P < 0.01). Conclusion: Among ART-naive PWH, kynurenine/tryptophan ratio has modest potential for TB discrimination, limiting its utility for TB case-finding in this population

Plasma Levels of Neopterin and C-Reactive Protein (CRP) in Tuberculosis (TB) with and without HIV Coinfection in Relation to CD4 Cell Count

Background While the risk of TB is elevated in HIV-positive subjects with low CD4 cell counts, TB may in itself be associated with CD4 lymphocytopenia. We investigated markers of immune activation (neopterin) and inflammation (CRP) in TB patients with and without HIV coinfection and their association with CD4 cell levels, and determined their predictive capacity as alternative markers of advanced immunosuppression. Methods Participants selected from a cohort of adults with TB at Ethiopian health centers (195 HIV +/TB+, 170 HIV-/TB+) and 31 controls were tested for plasma levels of neopterin and CRP. Baseline levels of neopterin and CRP were correlated to CD4 cell count before and after anti-TB treatment (ATT). The performance to predict CD4 cell strata for both markers were investigated using receiver operating curves. Results Levels of both biomarkers were elevated in TB patients (neopterin: HIV+/TB+ 54 nmol/l, HIV-/TB+ 23 nmol/l, controls 3.8 nmol/l; CRP: HIV+/TB+ 36 mu g/ml, HIV-/TB+ 33 mu g/ml, controls 0.5 mu g/ml). Neopterin levels were inversely correlated (-0.53, p&amp;lt;0.001) to CD4 cell count, whereas this correlation was weaker for CRP (-0.25, p&amp;lt;0.001). Neither of the markers had adequate predictive value for identification of subjects with CD4 cell count &amp;lt;100 cells/mm(3) (area under the curve [AUC] 0.64 for neopterin, AUC 0.59 for CRP). Conclusion Neopterin levels were high in adults with TB, both with and without HIV coinfection, with inverse correlation to CD4 cell count. This suggests that immune activation may be involved in TB-related CD4 lymphocytopenia. However, neither neopterin nor CRP showed promise as alternative tests for immunosuppression in patients coinfected with HIV and TB.Funding Agencies|Swedish Civil Contingency Agency; Swedish International Development Cooperation Agency; Region Skane; Swedish Medical Association</p

Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care

Background: Early identification of virological failure (VF) limits occurrence and spread of drug-resistant viruses in patients receiving antiretroviral treatment (ART). Viral load (VL) monitoring is therefore recommended, but capacities to comply with this are insufficient in many low-income countries. Clinical algorithms might identify persons at higher likelihood of VF to allocate VL resources. Objectives: We aimed to construct a VF algorithm (the Viral Load Testing Criteria; VLTC) and compare its performance to the 2013 WHO treatment failure criteria. Methods: Subjects with VL results available 1 year after ART start (n = 494) were identified from a cohort of ART-naïve adults (n = 812), prospectively recruited and followed 2011-2015 at Ethiopian health centres. VF was defined as VL≥1000 copies/mL. Variables recorded at the time of sampling, with potential association with VF, were used to construct the algorithm based on multivariate logistic regression. Results: Fifty-seven individuals (12%) had VF, which was independently associated with CD4 count <350 cells/mm3, previous ART interruption, and short mid-upper arm circumference (<24cm and <23cm, for men and women, respectively). These variables were included in the VLTC. In derivation, the VLTC identified 52/57 with VF; sensitivity 91%, specificity 43%, positive predictive value (PPV) 17%, negative predictive value (NPV) 97%. In comparison, the WHO criteria identified 38/57 with VF (sensitivity 67%, specificity 74%, PPV 25%, NPV 94%). Conclusions: The VLTC identified subjects at greater likelihood of VF, with higher sensitivity and NPV than the WHO criteria. If external validation confirms this performance, these criteria could be used to allocate limited VL resources. Due to its limited specificity, it cannot be used to determine treatment failure in the absence of a confirmatory viral load

High rates of viral suppression in a cohort of HIV-positive adults receiving ART in Ethiopian health centers irrespective of concomitant tuberculosis.

INTRODUCTION: Antiretroviral therapy (ART) initiation during treatment for tuberculosis (TB) improves survival in HIV/TB co-infected patients. Data on ART outcome for HIV/TB co-infected patients managed in primary health care in low-income regions is limited. We compared virological suppression rates, mortality and retention in care in HIV-positive adults receiving care in five Ethiopian health centres with regard to TB co-infection. MATERIALS AND METHODS: HIV-positive ART-naïve adults eligible for ART initiation were prospectively recruited from October 2011 until March 2013. At inclusion, all patients submitted sputum for microbiological TB testing (smear microscopy, liquid culture and PCR). Virological suppression rates after six months of ART (VS; viral load <40 and <400 copies/mL) with regard to TB status was the primary outcome. The impact of HIV/TB co-infection on VS rates was determined by multivariate regression analysis. Mortality and retention in care were analyzed by proportional hazard models. RESULTS: Among 812 participants (TB 158; non-TB 654), 678 started ART during the follow-up period (TB 135; non-TB 543). Median CD4 cell counts at ART initiation were 161 cells/µL (interquartile range [IQR], 98–243) and 184 (IQR, 118–256) for TB and non-TB patients, respectively (p=0.05). No difference in retention in care between TB and non-TB patients was observed during follow-up; 25 (3.7%) patients died and 17 (2.5%) were lost to follow-up (p=0.30 and p=0.83, respectively). Overall rates of VS at six months were 72.1% (<40 copies/mL) and 88.7% (<400 copies/mL), with similar results for subjects with and without TB co-infection (<40 copies/mL: 65/92 (70.7%) vs. 304/420 (72.4%), p=0.74; <400 copies/mL: 77/92 (83.7%) vs. 377/420 (89.8%), p=0.10, respectively). CD4 cell count increase during treatment was 87 (IQR, 26–178) and 103 cells/µL (IQR, 38–173) for TB and non-TB patients, respectively, with no significant difference between the two groups (p=0.49). CONCLUSIONS: High rates of VS were achieved in adults receiving ART at Ethiopian health centres managed by non-physician clinicians, with no significant difference with regard to TB co-infection. These findings demonstrate the feasibility of combined ART and anti-TB treatment at primary health care level in low-income countries. This study is registered with clinicaltrial.gov, NCT01433796

Development of a clinical scoring system for assessment of immunosuppression in patients with tuberculosis and HIV infection without access to CD4 cell testing - results from a cross-sectional study in Ethiopia

Background: Currently, antiretroviral therapy (ART) is recommended for all HIV-positive patients with tuberculosis (TB). The timing of ART during the course of anti-TB treatment is based on CD4 cell counts. Access to CD4 cell testing is not universally available; this constitutes an obstacle for the provision of ART in low-income countries. Objective: To determine clinical variables associated with HIV co-infection in TB patients and to identify correlations between clinical variables and CD4 cell strata in HIV/TB co-infected subjects, with the aim of developing a clinical scoring system for the assessment of immunosuppression. Design: Cross-sectional study of adults with TB (with and without HIV co-infection) recruited in Ethiopian outpatient clinics. Clinical variables potentially associated with immunosuppression were recorded using a structured questionnaire, and they were correlated to CD4 cell strata used to determine timing of ART initiation. Variables found to be significant in multivariate analysis were used to construct a scoring system. Results: Among 1,116 participants, the following findings were significantly more frequent in 307 HIV-positive patients compared to 809 HIV-negative subjects: diarrhea, odynophagia, conjunctival pallor, herpes zoster, oral candidiasis, skin rash, and mid-upper arm circumference (MUAC) less than20 cm. Among HIV-positive patients, conjunctival pallor, MUAC less than20 cm, dyspnea, oral hairy leukoplakia (OHL), oral candidiasis, and gingivitis were significantly associated with less than350 CD4 cells/mm(3). A scoring system based on these variables had a negative predictive value of 87% for excluding subjects with CD4 cell counts less than100 cells/mm(3); however, the positive predictive value for identifying such individuals was low (47%). Conclusions: Clinical variables correlate with CD4 cell strata in HIV-positive patients with TB. The clinical scoring system had adequate negative predictive value for excluding severe immunosuppression. Clinical scoring systems could be of use to categorize TB/HIV co-infected patients with regard to the timing of ART initiation in settings with limited access to laboratory facilities