RESUMEN
BACKGROUND: Rapid diagnostic tests (RDTs) for coronavirus disease (COVID) are used in low- and middle-income countries (LMICs) to inform treatment decisions. However, to date, it is unclear when this use is cost-effective. Existing analyses are limited to a narrow set of countries and uses. The aim of this study is to assess the cost-effectiveness of COVID RDTs to inform the treatment of patients with severe illness in LMICs, considering real world practice. METHODS AND FINDINGS: We assessed the cost-effectiveness of COVID testing across LMICs using a decision tree model, differentiating results by country income level, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) prevalence, and testing scenario (none, RDTs, polymerase chain reaction tests-PCRs and combinations). LMIC experts defined realistic care pathways and treatment options. Using a healthcare provider perspective and net monetary benefit approach, we assessed both intended (COVID symptom alleviation) and unintended (treatment side effects) health and economic impacts for each testing scenario. We included the side effects of corticosteroids, which are often the only available treatment for COVID. Because side effects depend both on the treatment and the patient's underlying illness (COVID or COVID-like illnesses, such as influenza), we considered the prevalence of COVID-like illnesses in our analyses. We found that SARS-CoV-2 testing of patients with severe COVID-like illness can be cost-effective in all LMICs, though only in some circumstances. High influenza prevalence among suspected COVID cases improves cost-effectiveness, since incorrectly provided corticosteroids may worsen influenza outcomes. In low- and some lower-middle-income countries, only patients with a high index of suspicion for COVID should be tested with RDTs, while other patients should be presumed to not have COVID. In some lower-middle-income and upper-middle-income countries, suspected severe COVID cases should almost always be tested. Further, in these settings, negative test results in patients with a high initial index of suspicion should be confirmed through PCR and, during influenza outbreaks, positive results in patients with a low initial index of suspicion should also be confirmed with a PCR. The use of interleukin-6 receptor blockers, when supported by testing, may also be cost-effective in higher-income LMICs. The cost at which they would be cost-effective in low-income countries ($162 to $406 per treatment course) is below current prices. The primary limitation of our analysis is substantial uncertainty around some of the parameters in our model due to limited data, most notably on current COVID mortality with standard of care, and insufficient evidence on the impact of corticosteroids on patients with severe influenza. CONCLUSIONS: COVID testing can be cost-effective to inform treatment of LMIC patients with severe COVID-like disease. The optimal algorithm is driven by country income level and health budgets, the level of suspicion that the patient may have COVID, and influenza prevalence. Further research to better characterize the unintended effects of corticosteroids, particularly on influenza cases, could improve decision making around the treatment of those with COVID-like symptoms in LMICs.
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COVID-19 , Análisis Costo-Beneficio , Países en Desarrollo , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/economía , Enfermedad Crítica/economía , Prueba de COVID-19/economía , Prueba de COVID-19/métodos , Árboles de Decisión , Prueba de Diagnóstico RápidoRESUMEN
Vγ9Vδ2 T lymphocytes are programmed for broad antimicrobial responses with rapid production of Th1 cytokines even before birth, and thus thought to play key roles against pathogens in infants. The process regulating Vδ2 cell acquisition of cytotoxic potential shortly after birth remains understudied. We observed that perforin production in cord blood Vδ2 cells correlates with phenotypes defined by the concomitant assessment of PD-1 and CD56. Bulk RNA sequencing of sorted Vδ2 cell fractions indicated that transcripts related to cytotoxic activity and NK function are enriched in the subset with the highest proportion of perforin+ cells. Among differentially expressed transcripts, IRF8, previously linked to CD8 T cell effector differentiation and NK maturation, has the potential to mediate Vδ2 cell differentiation towards cytotoxic effectors. Our current and past results support the hypothesis that distinct mechanisms regulate Vδ2 cell cytotoxic function before and after birth, possibly linked to different levels of microbial exposure.
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Antígeno CD56 , Linfocitos T CD8-positivos , Citotoxicidad Inmunológica , Receptor de Muerte Celular Programada 1 , Receptores de Antígenos de Linfocitos T gamma-delta , Subgrupos de Linfocitos T , Humanos , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Sangre Fetal , Perforina/genética , Perforina/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Antígeno CD56/metabolismoRESUMEN
BACKGROUND: When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response. METHODS: Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson's Chi-squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR). RESULTS: 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008). CONCLUSION: Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.
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Antimaláricos , Artemisininas , Infecciones por VIH , Malaria Falciparum , Malaria , Humanos , Adulto , Antimaláricos/uso terapéutico , Malaui , Artemisininas/uso terapéutico , Arteméter/uso terapéutico , Combinación de Medicamentos , Combinación Arteméter y Lumefantrina/uso terapéutico , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/prevención & control , Lumefantrina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Resultado del Tratamiento , Etanolaminas/uso terapéutico , Fluorenos/uso terapéuticoRESUMEN
BACKGROUND: The prevalence of small for gestational age (SGA) may vary depending on the chosen weight-for-gestational-age reference chart. An individual participant data meta-analysis was conducted to assess the implications of using a local reference (STOPPAM) instead of a universal reference (Intergrowth-21) on the association between malaria in pregnancy and SGA. METHODS: Individual participant data of 6,236 newborns were pooled from seven conveniently identified studies conducted in Tanzania and Malawi from 2003-2018 with data on malaria in pregnancy, birthweight, and ultrasound estimated gestational age. Mixed-effects regression models were used to compare the association between malaria in pregnancy and SGA when using the STOPPAM and the Intergrowth-21 references, respectively. RESULTS: The 10th percentile for birthweights-for-gestational age was lower for STOPPAM than for Intergrowth-21, leading to a prevalence of SGASTOPPAM of 14.2% and SGAIG21 of 18.0%, p < 0.001. The association between malaria in pregnancy and SGA was stronger for STOPPAM (adjusted odds ratio (aOR) 1.30 [1.09-1.56], p < 0.01) than for Intergrowth-21 (aOR 1.19 [1.00-1.40], p = 0.04), particularly among paucigravidae (SGASTOPPAM aOR 1.36 [1.09-1.71], p < 0.01 vs SGAIG21 aOR 1.21 [0.97-1.50], p = 0.08). CONCLUSIONS: The prevalence of SGA may be overestimated and the impact of malaria in pregnancy underestimated when using Intergrowth-21. Comparing local reference charts to global references when assessing and interpreting the impact of malaria in pregnancy may be appropriate.
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Recién Nacido Pequeño para la Edad Gestacional , Malaria , Peso al Nacer , Femenino , Retardo del Crecimiento Fetal , Edad Gestacional , Humanos , Recién Nacido , Malaria/epidemiología , Embarazo , Tanzanía/epidemiologíaRESUMEN
BACKGROUND: Daily co-trimoxazole is recommended for African adults living with human immunodeficiency virus (HIV) irrespective of antiretroviral treatment, immune status, or disease stage. Benefits of continued prophylaxis and whether co-trimoxazole can be stopped following immune reconstitution are unknown. METHODS: We conducted a randomized controlled trial at 2 sites in Malawi that enrolled adults with HIV with undetectable viral load and CD4 count of >250/mm3 and randomized them to continue daily co-trimoxazole, discontinue daily co-trimoxazole and begin weekly chloroquine, or discontinue daily co-trimoxazole. The primary endpoint was the preventive effect of co-trimoxazole prophylaxis against death or World Health Organization (WHO) HIV/AIDS stage 3-4 events, using Cox proportional hazards modeling, in an intention-to-treat population. RESULTS: 1499 adults were enrolled. The preventive effect of co-trimoxazole on the primary endpoint was 22% (95% CI: -14%-47%; Pâ =â .20) versus no prophylaxis and 25% (-10%-48%; Pâ =â .14) versus chloroquine. When WHO HIV/AIDS stage 2 events were added to the primary endpoint, preventive effect increased to 31% (3-51%; Pâ =â .032) and 32% (4-51%; Pâ =â .026), respectively. Co-trimoxazole and chloroquine prophylaxis effectively prevented clinical malaria episodes (3.8 and 3.0, respectively, vs 28/100 person-years; Pâ <â .001). CONCLUSIONS: Malawian adults with HIV who immune reconstituted on ART and continued co-trimoxazole prophylaxis experienced fewer deaths and WHO HIV/AIDS stage 3-4 events compared with prophylaxis discontinuation, although statistical significance was not achieved. Co-trimoxazole prevented a composite of death plus WHO HIV/AIDS stage 2-4 events. Given poor healthcare access and lack of routine viral load monitoring, co-trimoxazole prophylaxis should continue in adults on ART after immune reconstitution in sub-Saharan Africa. Clinical Trials Registration. NCT01650558.
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Infecciones por VIH , Combinación Trimetoprim y Sulfametoxazol , Adulto , Antirretrovirales/uso terapéutico , Recuento de Linfocito CD4 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Malaui/epidemiología , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.
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COVID-19 , Tuberculosis , Control de Enfermedades Transmisibles , Femenino , Humanos , Malaui/epidemiología , Masculino , Pandemias , SARS-CoV-2 , Tuberculosis/diagnóstico , Tuberculosis/epidemiologíaRESUMEN
BACKGROUND: Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD). METHODS AND FINDINGS: In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon. CONCLUSIONS: DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment. TRIAL REGISTRATION: clinicaltrials.gov NCT03519425.
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Coinfección , Tos/diagnóstico , Diagnóstico por Computador , Infecciones por VIH/diagnóstico , Prueba de VIH , Radiografía Torácica , Tuberculosis/diagnóstico por imagen , Adulto , Fármacos Anti-VIH/uso terapéutico , Antituberculosos/uso terapéutico , Análisis Costo-Beneficio , Tos/microbiología , Diagnóstico por Computador/economía , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Prueba de VIH/economía , Costos de la Atención en Salud , Accesibilidad a los Servicios de Salud , Humanos , Malaui/epidemiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Atención Primaria de Salud , Radiografía Torácica/economía , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Tuberculosis/microbiología , Adulto JovenRESUMEN
Human Vγ9Vδ2 T cells respond to several diverse pathogens by sensing microbial cholesterol intermediates. Unlike CD4 T cells, they are poised for rapid Th1-like responses even before birth, which allows them to play a key role in the first line of defense against pathogens in early life. However, their regulation and functional maturation during infancy (in particular the acquisition of cytotoxic potential) remain understudied. We thus characterized their responses to cholesterol intermediates and Bacille Calmette-Guérin in a cohort of African neonates and 12-month-old infants. Infant Vδ2 lymphocytes exhibited intermediate or adult-like expression of markers associated with differentiation or function, intermediate proliferative responses, and adult-like cytotoxic potential. The enhancement of Vδ2 cell cytotoxic potential coincided with decreasing PD-1 and increasing NKG2A expression. Our results are consistent with the hypothesis that switching from a PD-1+ to a NKG2A+ phenotype during infancy indicates a shift in mechanisms regulating Vδ2 T cell function.
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Sangre Fetal/citología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Adulto , Factores de Edad , Diferenciación Celular/fisiología , Células Cultivadas , Cordocentesis , Femenino , Expresión Génica/genética , Humanos , Lactante , Recién Nacido , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Malaui/epidemiología , Masculino , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi. METHODS: A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression. RESULTS: Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02-5.06), increasing age (aOR:1.02, 95%CI:1.01-1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45-7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8-12/day). CONCLUSIONS: Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.
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Tamizaje Masivo/estadística & datos numéricos , Tuberculosis/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Instituciones de Atención Ambulatoria , Femenino , Humanos , Entrevistas como Asunto/estadística & datos numéricos , Modelos Logísticos , Malaui/epidemiología , Masculino , Tamizaje Masivo/métodos , Tamizaje Masivo/normas , Persona de Mediana Edad , Mycobacterium tuberculosis/aislamiento & purificación , Estudios Prospectivos , Esputo/microbiología , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Adulto JovenRESUMEN
OBJECTIVES: WHO recommends HIV viral load (VL) testing 6 months after antiretroviral therapy (ART) initiation and every 12 months thereafter, but cost prohibits routine, universal VL testing in many developing countries. We sought to devise a targeted approach to routine VL monitoring that could reduce cost and identify those at low risk for virologic failure (VF). METHODS: We analysed screening data from a clinical trial enrolling adults on ART in Malawi. We identified risk factors associated with VF and employed the Knill-Jones method to assign summary score identifying persons at lower risk for VF. RESULTS: Among 957 adults, prevalence of VF was 9.4%. Factors independently associated with VF included age <38 years (OR 3.44, 95% CI 2.01-5.89), ART duration >2.5 years (OR 2.98, 95% CI 1.79-4.96), ART adherence <95% (OR 1.76, 95% CI 1.06-2.94), CD4 count <200 cells/µl (OR 5.94, 95% CI 3.27-10.78), haemoglobin <13 g/dl (OR 2.76, 95% CI 1.70-4.50) and CD8 count >885 cells/µl (OR 2.10, 95% CI 1.28-3.44). Our VF prediction summary score included all factors above except CD8 count and was fairly accurate with validated area under receiver operating characteristic curve of 0.76. Implementation could reduce VL testing by 65%. CONCLUSION: A simple score incorporating age, ART duration and adherence, and CD4 count can accurately identify adults at low risk for VF in a sub-Saharan African setting. In areas with high ART utilisation and limited VL testing capacity, a targeted approach could optimise routine VL monitoring while identifying adults in need of alternate ART regimens.
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Fármacos Anti-VIH/uso terapéutico , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Carga Viral , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Pruebas Diagnósticas de Rutina/economía , Femenino , Humanos , Malaui , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A successful pregnancy depends on the maintenance of tolerance at the fetal-maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human Vδ2 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal Vδ2 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal-maternal interface. Neonatal Vδ2 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-α production and degranulation) by neonatal Vδ2 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal Vδ2 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control Vδ2 cell inflammatory responses during fetal life.
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Epigénesis Genética , Regulación de la Expresión Génica , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Antígeno B7-H1/inmunología , Metilación de ADN , Femenino , Desarrollo Fetal , Humanos , Tolerancia Inmunológica , Recién Nacido , Inflamación/inmunología , Activación de Linfocitos , Embarazo , Regiones Promotoras Genéticas , Células TH1/inmunología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial. METHODS: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373. FINDINGS: Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]). INTERPRETATION: Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes. FUNDING: Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development.
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Mycobacterium tuberculosis , Tuberculosis , Adulto , Humanos , Adolescente , Antibacterianos/uso terapéutico , Malaui , Azitromicina/uso terapéutico , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Amoxicilina/uso terapéuticoRESUMEN
BACKGROUND: Studies have shown that mobile health technologies (mHealth) enhance the use of maternal health services. However, there is limited evidence of the impact of mHealth use by community health workers (CHWs) on the use of maternal health services in sub-Saharan Africa. OBJECTIVE: This mixed method systematic review will explore the impact of mHealth use by CHWs on the use of the maternal health continuum of care (antenatal care, intrapartum care, and postnatal care [PNC]), as well as barriers and facilitators of mHealth use by CHWs when supporting maternal health services. METHODS: We will include studies that report the impact of mHealth by CHWs on the use of antenatal care, facility-based births, and PNC visits in sub-Saharan Africa. We will search 6 databases (MEDLINE, CINAHL, Web of Science, Embase, Scopus, and Africa Index Medicus), with additional articles identified from Google Scholar and manual screening of references of the included studies. The included studies will not be limited by language or year of publication. After study selection, 2 independent reviewers will perform title and abstract screening, followed by full-text screening to identify the final papers to be included. Data extraction and risk-of-bias assessment will be performed using Covidence software by 2 independent reviewers. We will use a Mixed Methods Appraisal Tool to perform risk-of-bias assessments on all included studies. Finally, we will perform a narrative synthesis of the outcomes, integrating information about the effect of mHealth on maternal health use and barriers and facilitators of mHealth use. This protocol follows the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines. RESULTS: In September 2022, we conducted an initial search in the eligible databases. After removing duplicates, we identified 1111 studies that were eligible for the title and abstract screening. We will finalize the full-text assessment for eligibility, data extraction, assessment of methodological quality, and narrative synthesis by June 2023. CONCLUSIONS: This systematic review will present new and up-to-date evidence on the use of mHealth by CHWs along the pregnancy, childbirth, and PNC continuum of care. We anticipate the results will inform program implementation and policy by highlighting the potential impacts of mHealth and presenting contextual factors that should be addressed to ensure the success of the programs. TRIAL REGISTRATION: PROSPERO CRD42022346364; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346364. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44066.
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BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.
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COVID-19 , Hepatitis , Preescolar , Femenino , Humanos , Masculino , Enfermedad Aguda , Estudios de Casos y Controles , SARS-CoV-2 , Reino Unido/epidemiologíaRESUMEN
OBJECTIVE: Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4 + cell count among adults on ART. DESIGN: We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4 + âcells/µl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ). METHODS: We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4-12âweeks). CD4 + cell count and viral load were measured every 24âweeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558. RESULTS: Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4 + cell count or viral load. CONCLUSION: In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.
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Antimaláricos , Infecciones por VIH , Malaria , Adulto , Antimaláricos/uso terapéutico , Recuento de Linfocito CD4 , Quimioprevención , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Malaria/epidemiología , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
Seasonal trends in tuberculosis (TB) notifications have been observed in several countries but are poorly understood. Explanatory factors may include weather, indoor crowding, seasonal respiratory infections and migration. Using enhanced citywide TB surveillance data collected over nine years in Blantyre, Malawi, we set out to investigate how weather and seasonality affect temporal trends in TB case notification rates (CNRs) across different demographic groups. We used data from prospective enhanced surveillance between April 2011 and December 2018, which systematically collected age, HIV status, sex and case notification dates for all registering TB cases in Blantyre. We retrieved temperature and rainfall data from the Global Surface Summary of the Day weather station database. We calculated weekly trends in TB CNRs, rainfall and temperature, and calculated 10-week moving averages. To investigate the associations between rainfall, temperature and TB CNRs, we fitted generalized linear models using a distributed lag nonlinear framework. The estimated Blantyre population increased from 1,068,151 in April 2011 to 1,264,304 in December 2018, with 15,908 TB cases recorded. Overall annual TB CNRs declined from 222 to 145 per 100,000 between 2012 and 2018, with the largest declines seen in HIV-positive people and adults aged over 20 years old. TB CNRs peaks occurred with increasing temperature in September and October before the onset of increased rainfall, and later in the rainy season during January-March, after sustained rainfall. When lag between a change in weather and TB case notifications was accounted for, higher average rainfall was associated with an equivalent six weeks of relatively lower TB notification rates, whereas there were no changes in TB CNR associated with change in average temperatures. TB CNRs in Blantyre have a seasonal pattern of two cyclical peaks per year, coinciding with the start and end of the rainy season. These trends may be explained by increased transmission at certain times of the year, by limited healthcare access, by patterns of seasonal respiratory infections precipitating cough and care-seeking, or by migratory patterns related to planting and harvesting during the rainy season.
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Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Notificación de Enfermedades/estadística & datos numéricos , Femenino , Infecciones por VIH/complicaciones , Humanos , Lactante , Malaui/epidemiología , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Vigilancia de la Población , Lluvia , Estaciones del Año , Factores Sexuales , Temperatura , Tuberculosis Pulmonar/etiología , Tiempo (Meteorología) , Adulto JovenRESUMEN
BACKGROUND: Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption-that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not-has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics. METHODS: In this systematic review and meta-analysis we searched the MEDLINE, Embase, and Global Health databases for studies published up to March 15, 2019, that investigated the sensitivity and specificity of the trial of antibiotics against mycobacteriology tests in adults (≥15 years) with tuberculosis symptoms. We used the QUADAS-2 tool to assess the risk of bias. We estimated pooled values for sensitivity and specificity of trial of antibiotics (as the index text) versus mycobacteriology tests (as the reference standard) using random-effects bivariate modelling, and we used the I2 statistic to assess heterogeneity between studies contributing to these estimates. This study is registered with PROSPERO, number CRD42017083915. FINDINGS: Of the 9410 articles identified by our search, eight studies were eligible for inclusion. The studies were from seven countries in Africa, South America, and Asia, and involved 2786 participants. Six studies used mycobacterial culture as the reference standard, and six used penicillins for the trial of antibiotics. The treatment duration, number of antimicrobial courses, and definition of what constituted response to treatment varied substantially between studies. The pooled sensitivity (67%, 95% CI 42-85) and specificity (73%, 58-85) of the trial of antibiotics versus mycobacteriology tests were below internationally defined minimum performance profiles for tuberculosis diagnostics and had substantial heterogeneity (I2 was 96% for sensitivity and 99% for specificity). Each included study failed on one or more domain of the QUADAS-2 tool. INTERPRETATION: Current policy and practice regarding the trial of antibiotics appear inappropriate, given the weak evidence base, poor diagnostic performance, potential contribution to the global antimicrobial resistance crisis, and adverse individual and public health consequences from the misclassification of tuberculosis status. Antibiotic strategies during tuberculosis investigations should instead optimise clinical outcomes, ideally guided by clinical trials in both inpatient and outpatient groups. FUNDING: Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.
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Antibacterianos , Mycobacterium tuberculosis , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Coinfección , Infecciones por VIH/virología , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Curva ROC , Sensibilidad y Especificidad , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
BACKGROUND: Antimicrobial resistance generates a huge health and economic burden and has the potential to become the leading cause of death globally, but its underlying drivers are yet to be fully described. The association between a microbe's exposure to antimicrobials and subsequent development of, or selection for, resistance is well documented, as are the exacerbating microbial and human factors. However, the nature and extent of this risk, and how it varies by antimicrobial class and duration of treatment, is poorly defined. The goal of our systematic review and network meta-analysis is to determine the relationship between the duration of antimicrobial exposure and selection for resistance. We will use macrolides as the antimicrobial class of interest and Streptococcus pneumoniae carriage as an indicator organism. Our secondary outcomes include duration of symptoms, risk of treatment failure and recurrence, and descriptions of resistance mechanisms. METHODS: We will conduct a systematic review, selecting studies if they are published randomised controlled trials (RCTs) which report the relationship between taking a macrolide for any indication and incidence of resistant Streptococcus pneumoniae in patients of any age group. We will use a predefined search strategy to identify studies meeting these eligibility criteria in MEDLINE, Embase, Global Health and the Cochrane Central Register of RCTs. Two authors will independently screen titles and abstracts, review the full texts and undertake data extraction. We will use the Cochrane Collaboration's tool to assess the quality of included RCTs. If feasible, we will perform pair-wise meta-analysis modelling to determine the relationship between the duration of macrolide treatment and development of macrolide resistant Streptococcus pneumoniae. If the identified studies meet the assumptions for a network meta-analysis (NMA), we will additionally model this relationship using indirect comparisons. Our protocol utilises reporting guidance by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the extensions for protocols (PRISMA-P) and network meta-analyses (PRISMA for NMA). Our review will also report to these standards. DISCUSSION: Establishing the relationship between the duration of antimicrobial exposure and development of, or selection for, resistance will inform the design of antimicrobial prescriptions, treatment guidelines and the behaviour of both physicians and patients. This work will therefore be a strong contribution towards the full realisation of current antimicrobial resistance stewardship strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018089275.
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Antibacterianos , Farmacorresistencia Bacteriana , Macrólidos , Metaanálisis en Red , Humanos , Antibacterianos/administración & dosificación , Farmacorresistencia Bacteriana/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Streptococcus pneumoniae/aislamiento & purificación , Factores de Tiempo , Insuficiencia del Tratamiento , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Suboptimal diagnostics for pulmonary tuberculosis (PTB) drives use of 'trial-of-antibiotics (non-tuberculosis)' in an attempt to distinguish PTB patients from those with bacterial lower respiratory tract infection (LRTI). The underlying assumption-that patients with LRTI will report 'response' to broad-spectrum antibiotics, while those with PTB will not-has minimal evidence base for such a widely used intervention. Numerous potential causes of misclassification include bacterial super-infection of active PTB, placebo effect, and antimicrobial resistance (AMR). The main aim of this systematic review is to collate available evidence on the performance of trial-of-antibiotics as a diagnostic test and to explore the timing, interpretation, and decision-making process. METHODS: We will search MEDLINE, Embase, and Global Health using the Ovid platform for published studies that recruited adults being investigated for PTB, performed trial-of-antibiotics accompanied by mycobacteriological investigations, and reported both diagnostic test outcomes at the individual level. Following article selection, two authors will independently review titles and abstracts against eligibility criteria then perform full-text screening and extraction into a spreadsheet. We will conduct a risk of bias assessment at the level of the study using QUADAS-2 (University of Bristol) tool that assesses diagnostic evaluation work in four domains: (1) patient selection, (2) the index test, (3) the reference standard, and (4) patient flow and timing of tests. We will perform a narrative synthesis and, where possible, meta-analyses addressing our primary outcome. Our protocol adheres to the standards recommended by the PRISMA-P. DISCUSSION: Pooling all available evidence on the accuracy, approach, and interpretation of results of trial-of-antibiotics in the context of PTB diagnosis will meet an urgent need, considering the widespread utilisation and potential for antimicrobial resistance. We therefore believe that our findings will have impact on policy and that they will inform the design of future detailed investigations into this important diagnostic approach. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017083915.