Treatment-related mortality in children with cancer in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Approximately 90% of children with cancer live in low-income and middle-income countries (LMICs), where 5-year survival is lower than 20%. Treatment-related mortality in high-income countries is approximately 3-5%; however, in LMICs, treatment-related mortality has been reported in up to 45% of children with cancer. This study aimed to systematically explore the burden of treatment-related mortality in children with cancer in LMICs and to explore the association between country income level and treatment-related mortality. METHODS: For this systematic review and meta-analysis we identified articles published between Jan 1, 2010, and June 22, 2021, describing treatment-related mortality in paediatric patients (aged 0-21 years) with cancer in LMICs. We searched PubMed, Trip, Web of Science, Embase, and the WHO Global Metric Index databases. The search was limited to full-text articles and excluded case reports (<10 patients) and haematopoietic stem-cell transplantation recipients. Two reviewers independently screened studies for eligibility, extracted data from included publications, and evaluated data quality. Random and mixed-effects models were used to estimate treatment-related mortality burden and trends. The Cochran-Q statistic was used to assess heterogeneity between studies. This study is registered on PROSPERO (CRD42021264849). FINDINGS: Of 13 269 identified abstracts, 501 studies representing 68 351 paediatric patients with cancer were included. The treatment-related mortality estimate was 6·82% (95% CI 5·99-7·64), accounting for 30·9% of overall mortality (4437 of 14 358 deaths). Treatment-related mortality was inversely related to country income. Treatment-related mortality was 14·19% (95% CI 9·65-18·73) in low-income countries, 9·21% (7·93-10·49) in lower-middle-income countries, and 4·47% (3·42-5·53) in upper-middle-income countries (Cochran-Q 42·39, p<0·0001). In upper-middle-income countries, the incidence of treatment-related mortality decreased over time (slope -0·002, p=0·0028); however, outcomes remained unchanged in low-income (p=0·21) and lower-middle-income countries (p=0·16). INTERPRETATION: Approximately one in 15 children receiving cancer treatment in LMICs die from treatment-related complications. Although treatment-related mortality has decreased in upper-middle-income countries over time, it remains unchanged in LMICs. There is an urgent need for targeted supportive care interventions to reduce global disparities in childhood cancer survival. FUNDING: American Lebanese Syrian Associated Charities and National Cancer Institute.

Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

BACKGROUND: The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. PROCEDURE: The GRCCC is a deidentified web-based registry of patients less than 19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60 days post infection. RESULTS: The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30 days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p = .04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. CONCLUSION: In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

High morbidity and mortality associated with primary bloodstream infections among pediatric patients with cancer at a Guatemalan tertiary referral hospital.

Infectious complications remain major contributors to adverse outcomes in patients treated for non-communicable disease, particularly in resource limited settings. We performed a 5-year retrospective study of primary bloodstream infections at a dedicated pediatric oncology center in Guatemala. Two hundred and twelve episodes occurring in 194 unique patients qualified for inclusion. Patients required intensive care unit admission in 55% of episodes and death occurred in 24% of episodes. Despite subspecialty support in infectious diseases, poor outcomes, including prolonged hospitalization and mortality, were frequent. Our findings suggest that investments in laboratory and clinical data collection are critical to understanding the contributors to poor outcomes and therefore to improving the quality of bloodstream infection management in resource limited settings.

The PRINCIPAL Network: A Model to Optimize Infection Care and Prevention in Pediatric Oncology in the Latin American Region.

PURPOSE: Children with cancer are at high risk for poor outcomes, and health care providers are often unfamiliar with best practices in infection care and prevention (IC&P) in this small and fragile population. Graduates of training courses in IC&P in immunocompromised hosts identified a need for a community that would enable members to share health care experiences, provide resources for continuing medical education, and foster collaborative research and quality improvement opportunities. We developed a Latin American network, Prevencionistas e Infectólogos para Cáncer Pediátrico en América Latina, to grow and sustain the expertise of the clinical workforce in IC&P. Here, we describe the network, how we built it, and its early outcomes. METHODS: We began by codesigning the mission, vision, objectives, and values. We then established the structure for leadership and network management to provide a functional uniformity and sustainability. Virtual meetings with network members and strategic in-person gatherings optimized the use of the time and resources of the network. RESULTS: The network has seen good participation by members and candidates for membership, who have provided feedback on case-based learning. Members have attended training sessions on quality improvement, research in human subjects, and IC&P in pediatric oncology at national and regional meetings and workshops. Network members have presented their work at regional and global meetings, and publications are beginning to emerge from this community. A direct effect of the Prevencionistas e Infectólogos para Cáncer Pediátrico en América Latina network has been the creation of a similar network for the Asia Pacific region, and a third network is being planned. CONCLUSION: We have demonstrated the power of a discipline-specific network structure to facilitate sharing of evidence-based information that enhances the quality-of-care delivery in pediatric oncology.

Answers to common questions about COVID-19 vaccines in children with cancer.

BACKGROUND: The SARS-CoV-2 outbreak in 2020 evolved into a global pandemic, and COVID-19 vaccines became rapidly available, including for pediatric patients. However, questions emerged that challenged vaccine acceptance and use. We aimed to answer these questions and give recommendations applicable for use in pediatric patients with cancer by healthcare professionals and the public. METHODS: A 12-member global COVID-19 Vaccine in Pediatric Oncology Working Group made up of physicians and nurses from all world regions met weekly from March to July 2021. We used a modified Delphi method to select the top questions. The Working Group, in four-member subgroups, answered assigned questions by providing brief recommendations, followed by a discussion of the rationale for each answer. All Working Group members voted on each recommendation using a scale of 1 to 10, 10 being complete agreement. A "pass" recommendation corresponded to an agreement ≥7.5. RESULTS: We selected 15 questions from 173 suggested questions. Based on existing published information, we generated answers for each question as recommendations. The overall average agreement for the 24 recommendations was 9.5 (95% CI 9.4-9.6). CONCLUSION: Top COVID-19 vaccine-related questions could be answered using available information. Reports on COVID-19 vaccination and related topics have been published at record speed, aided by available technology and the priority imposed by the pandemic; however, all efforts were made to incorporate emerging information throughout our project. Recommendations will be periodically updated on a dedicated website.

Evidence-based surgical guidelines for treating children with Wilms tumor in low-resource settings.

BACKGROUND: Survival of Wilms tumor (WT) is > 90% in high-resource settings but < 30% in low-resource settings. Adapting a standardized surgical approach to WT is challenging in low-resource settings, but a local control strategy is crucial to improving outcomes. OBJECTIVE: Provide resource-sensitive recommendations for the surgical management of WT. METHODS: We performed a systematic review of PubMed and EMBASE through July 7, 2020, and used the GRADE approach to assess evidence and recommendations. RECOMMENDATIONS: Initiation of treatment should be expedited, and surgery should be done in a high-volume setting. Cross-sectional imaging should be done to optimize preoperative planning. For patients with typical clinical features of WT, biopsy should not be done before chemotherapy, and neoadjuvant chemotherapy should precede surgical resection. Also, resection should include a large transperitoneal laparotomy, adequate lymph node sampling, and documentation of staging findings. For WT with tumor thrombus in the inferior vena cava, neoadjuvant chemotherapy should be given before en bloc resection of the tumor and thrombus and evaluation for viable tumor thrombus. For those with bilateral WT, neoadjuvant chemotherapy should be given for 6-12 weeks. Neither routine use of complex hilar control techniques during nephron-sparing surgery nor nephron-sparing resection for unilateral WT with a normal contralateral kidney is recommended. When indicated, postoperative radiotherapy should be administered within 14 days of surgery. Post-chemotherapy pulmonary oligometastasis should be resected when feasible, if local protocols allow omission of whole-lung irradiation in patients with nonanaplastic histology stage IV WT with pulmonary metastasis without evidence of extrapulmonary metastasis. CONCLUSION: We provide evidence-based recommendations for the surgical management of WT, considering the benefits/risks associated with limited-resource settings.

Association of Cancer Diagnosis and Therapeutic Stage With Mortality in Pediatric Patients With COVID-19, Prospective Multicenter Cohort Study From Latin America.

Background: Children with cancer are at risk of critical disease and mortality from COVID-19 infection. In this study, we describe the clinical characteristics of pediatric patients with cancer and COVID-19 from multiple Latin American centers and risk factors associated with mortality in this population. Methods: This study is a multicenter, prospective cohort study conducted at 12 hospitals from 6 Latin American countries (Argentina, Bolivia, Colombia, Ecuador, Honduras and Peru) from April to November 2021. Patients younger than 14 years of age that had an oncological diagnosis and COVID-19 or multisystemic inflammatory syndrome in children (MIS-C) who were treated in the inpatient setting were included. The primary exposure was the diagnosis and treatment status, and the primary outcome was mortality. We defined "new diagnosis" as patients with no previous diagnosis of cancer, "established diagnosis" as patients with cancer and ongoing treatment and "relapse" as patients with cancer and ongoing treatment that had a prior cancer-free period. A frequentist analysis was performed including a multivariate logistic regression for mortality. Results: Two hundred and ten patients were included in the study; 30 (14%) died during the study period and 67% of patients who died were admitted to critical care. Demographics were similar in survivors and non-survivors. Patients with low weight for age (<-2SD) had higher mortality (28 vs. 3%, p = 0.019). There was statistically significant difference of mortality between patients with new diagnosis (36.7%), established diagnosis (1.4%) and relapse (60%), (p <0.001). Most patients had hematological cancers (69%) and they had higher mortality (18%) compared to solid tumors (6%, p= 0.032). Patients with concomitant bacterial infections had higher mortality (40%, p = 0.001). MIS-C, respiratory distress, cardiovascular symptoms, altered mental status and acute kidney injury on admission were associated with higher mortality. Acidosis, hypoxemia, lymphocytosis, severe neutropenia, anemia and thrombocytopenia on admission were also associated with mortality. A multivariate logistic regression showed risk factors associated with mortality: concomitant bacterial infection OR 3 95%CI (1.1-8.5), respiratory symptoms OR 5.7 95%CI (1.7-19.4), cardiovascular OR 5.2 95%CI (1.2-14.2), new cancer diagnosis OR 12 95%CI (1.3-102) and relapse OR 25 95%CI (2.9-214). Conclusion: Our study shows that pediatric patients with new onset diagnosis of cancer and patients with relapse have higher odds of all-cause mortality in the setting of COVID-19. This information would help develop an early identification of patients with cancer and COVID-19 with higher risk of mortality.

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study.

BACKGROUND: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. METHODS: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. FINDINGS: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p<0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8-3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3-2·4]; p=0·0001), and intensive treatment (1·8 [1·3-2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3-0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3-0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3-2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1-2·3]; p=0·020). INTERPRETATION: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. FUNDING: American Lebanese Syrian Associated Charities and the National Cancer Institute.

Global effect of the COVID-19 pandemic on paediatric cancer care: a cross-sectional study.

BACKGROUND: Although mortality due to COVID-19 has been reportedly low among children with cancer, changes in health-care services due to the pandemic have affected cancer care delivery. This study aimed to assess the effect of the COVID-19 pandemic on childhood cancer care worldwide. METHODS: A cross-sectional survey was distributed to paediatric oncology providers worldwide from June 22 to Aug 21, 2020, through the St Jude Global Alliance and International Society for Paediatric Oncology listservs and regional networks. The survey included 60 questions to assess institution characteristics, the number of patients diagnosed with COVID-19, disruptions to cancer care (eg, service closures and treatment abandonment), adaptations to care, and resources (including availability of clinical staff and personal protective equipment). Surveys were included for analysis if respondents answered at least two thirds of the items, and the responses were analysed at the institutional level. FINDINGS: Responses from 311 health-care professionals at 213 institutions in 79 countries from all WHO regions were included in the analysis. 187 (88%) of 213 centres had the capacity to test for SARS-CoV-2 and a median of two (range 0-350) infections per institutution were reported in children with cancer. 15 (7%) centres reported complete closure of paediatric haematology-oncology services (median 10 days, range 1-75 days). Overall, 2% (5 of 213) of centres were no longer evaluating new cases of suspected cancer, while 43% (90 of 208) of the remaining centers described a decrease in newly diagnosed paediatric cancer cases. 73 (34%) centres reported increased treatment abandonment (ie, failure to initiate cancer therapy or a delay in care of 4 weeks or longer). Changes to cancer care delivery included: reduced surgical care (153 [72%]), blood product shortages (127 [60%]), chemotherapy modifications (121 [57%]), and interruptions to radiotherapy (43 [28%] of 155 institutions that provided radiotherapy before the pandemic). The decreased number of new cancer diagnoses did not vary based on country income status (p=0·14). However, unavailability of chemotherapy agents (p=0·022), treatment abandonment (p<0·0001), and interruptions in radiotherapy (p<0·0001) were more frequent in low-income and middle-income countries than in high-income countries. These findings did not vary based on institutional or national numbers of COVID-19 cases. Hospitals reported using new or adapted checklists (146 [69%] of 213), processes for communication with patients and families (134 [63%]), and guidelines for essential services (119 [56%]) as a result of the pandemic. INTERPRETATION: The COVID-19 pandemic has considerably affected paediatric oncology services worldwide, posing substantial disruptions to cancer diagnosis and management, particularly in low-income and middle-income countries. This study emphasises the urgency of an equitably distributed robust global response to support paediatric oncology care during this pandemic and future public health emergencies. FUNDING: American Lebanese Syrian Associated Charities. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

The Global COVID-19 Observatory and Resource Center for Childhood Cancer: A response for the pediatric oncology community by SIOP and St. Jude Global.

The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community.

Guidance Statement for the Management of Febrile Neutropenia in Pediatric Patients Receiving Cancer-Directed Therapy in Central America and the Caribbean.

PURPOSE: Our objective was to provide regionally appropriate, resource-conscious recommendations for the diagnosis and treatment of pediatric patients with febrile neutropenia. METHODS: A multinational panel of Central American and Caribbean clinicians who deliver pediatric oncology care prioritized clinically important questions and then used the Grading of Recommendations Assessment, Development and Evaluation methodology to provide recommendations on the selected topics. RESULTS: Twenty-two questions and 2 definitions were included in the guideline, which was intended to establish minimum care standards for pediatric patients treated in regional centers. Of all the included studies, 6.9% were conducted in low- and middle-income countries, and no studies were performed in countries represented on the panel. CONCLUSION: The panel made recommendations on the basis of existing evidence but identified important gaps in knowledge from the region and from resource-limited settings that may affect the clinical applicability of these recommendations. These deficiencies suggest a research agenda that will enable future guidelines to be more responsive to the local context.

Evaluation of a fever-management algorithm in a pediatric cancer center in a low-resource setting.

BACKGROUND: In low- and middle-income countries (LMICs), inconsistent or delayed management of fever contributes to poor outcomes among pediatric patients with cancer. We hypothesized that standardizing practice with a clinical algorithm adapted to local resources would improve outcomes. Therefore, we developed a resource-specific algorithm for fever management in Davao City, Philippines. The primary objective of this study was to evaluate adherence to the algorithm. PROCEDURE: This was a prospective cohort study of algorithm adherence to assess the types of deviation, reasons for deviation, and pathogens isolated. All pediatric oncology patients who were admitted with fever (defined as an axillary temperature >37.7°C on one occasion or ≥37.4°C on two occasions 1 hr apart) or who developed fever within 48 hr of admission were included. Univariate and multiple linear regression analyses were used to determine the relation between clinical predictors and length of hospitalization. RESULTS: During the study, 93 patients had 141 qualifying febrile episodes. Even though the algorithm was designed locally, deviations occurred in 70 (50%) of 141 febrile episodes on day 0, reflecting implementation barriers at the patient, provider, and institutional levels. There were 259 deviations during the first 7 days of admission in 92 (65%) of 141 patient episodes. Failure to identify high-risk patients, missed antimicrobial doses, and pathogen isolation were associated with prolonged hospitalization. CONCLUSIONS: Monitoring algorithm adherence helps in assessing the quality of pediatric oncology care in LMICs and identifying opportunities for improvement. Measures that decrease high-frequency/high-impact algorithm deviations may shorten hospitalizations and improve healthcare use in LMICs.

Use of Fungal Diagnostics and Therapy in Pediatric Cancer Patients in Resource-Limited Settings.

Fungal diseases are an important cause of mortality in immunocompromised hosts, and their incidence in pediatric cancer patients in low- to middle-income countries is underestimated. In this review, we present relevant, up-to-date information about the most common opportunistic and endemic fungal diseases among children with cancer, their geographic distribution, and recommended diagnostics and treatment. Efforts to improve the care of children with cancer and fungal disease must address the urgent need for sustainable and cost-effective solutions that improve training, fungal disease testing capability, and the use of available resources. We hope that the collective information presented here will be used to advise healthcare providers, regional and country health leaders, and policymakers of the current challenges in diagnosing and treating fungal infections in children with cancer in low- to middle-income countries.

Infectious complications in children with acute lymphoblastic leukemia treated in low-middle-income countries.

Infections are the most important cause of morbidity and mortality in children treated for acute lymphoblastic leukemia (ALL). The rates of infection-associated mortality are up to 10-times higher in low- and middle-income countries (LMIC) than in high-income countries. The prevention, early recognition and management of infectious complications is especially challenging in LMIC because of disease and poverty-related factors, as well as the shortage of trained personnel, supplies, diagnostic tools and adequate organizational infrastructure. Children in LMIC with ALL, who are frequently underweight, are at increased risk of community-acquired pathogens, nosocomial multidrug-resistant pathogens and opportunistic microorganisms. This review summarizes the challenges of managing the major categories of infections in children receiving treatment for ALL and provides updated practical recommendations for preventing and managing these infections in LMIC.

Recognition of and Prompt Treatment for Tick-Borne Infections in Children.

Tick-borne infections create diagnostic challenges because they tend to present with nonspecific findings. Because clinicians often fail to recognize tick-borne illnesses in early stages, therapy is frequently delayed or omitted. This is especially problematic for rickettsial infections (Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis), because the risk of long-term morbidity and mortality increases with delayed treatment. We emphasize the need for clinicians to maintain a high index of suspicion for tick-borne infections; to diagnose these illnesses presumptively, without waiting for confirmatory laboratory test results; and to promptly start therapy with doxycycline, even in young children, when rickettsial infections are suspected.

Operational implementation of LED fluorescence microscopy in screening tuberculosis suspects in an urban HIV clinic in Uganda.

BACKGROUND: Light emitting diode (LED) fluorescence microscopy (FM) is an affordable, technology targeted for use in resource-limited settings and recommended for widespread roll-out by the World Health Organization (WHO). We sought to compare the operational performance of three LED FM methods compared to light microscopy in a cohort of HIV-positive tuberculosis (TB) suspects at an urban clinic in a high TB burden country. METHODS: Two spot specimens collected from TB suspects were included in the study. Smears were stained using auramine O method and read after blinding by three LED-based FM methods by trained laboratory technicians in the Infectious Diseases Institutelaboratory. Leftover portions of the refrigerated sputum specimens were transported to the FIND Tuberculosis Research Laboratory for Ziehl Neelsen (ZN) smear preparation and reading by experienced technologist as well as liquid and solid culture. RESULTS: 174 of 627 (27.8%) specimens collected yielded one or more positive mycobacterial cultures. 94.3% (164/174) were M. tuberculosis complex. LED FM was between 7.3-11.0% more sensitive compared to ZN microscopy. Of the 592 specimens examined by all microscopy methods, there was no significant difference in sensitivity between the three LED FM methods. The specificity of the LED FM methods was between 6.1% and 7.7% lower than ZN microscopy (P<0.001), although exclusion of the single poor reader resulted in over 98% specificity for all FM methods. CONCLUSIONS: Laboratory technicians in routine settings can be trained to use FM which is more sensitive than ZN microscopy. Despite rigorous proficiency testing, there were operator-dependent accuracy issues which highlight the critical need for intensive quality assurance procedures during LED FM implementation. The low sensitivity of FM for HIV-positive individuals particularly those with low CD4 T cell counts, will limit the number of additional patients found by LED FM in countries with high rates of HIV co-infection.