Description of 3 , 180

Background: In 2010, Médecins Sans Frontières (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children #5 y of age with severe paediatric lead intoxication reported to date to our knowledge. Methods and Findings: In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children #5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL $ 45 mg/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL $ 80 mg/dl and $ 120 mg/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%–79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%–57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged #5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in ,2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for. Conclusions: Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and nonadherence may have influenced the impact of outpatient treatment. Please see later in the article for the Editors’ Summary. Citation: Thurtle N, Greig J, Cooney L, Amitai Y, Ariti C, et al. (2014) Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children #5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data. PLoS Med 11(10): pmed.1001739. doi:10.1371/journal.pmed.1001739 Academic Editor: Bruce P Lanphear, Simon Fraser University, Canada Received September 16, 2013; Accepted August 19, 2014; Published October 7, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Research data are accessible via the MSF open data policy for researchers who meet the criteria for access to confidential data (http://fieldresearch.msf.org/msf/handle/10144/306501). Funding: This study was funded as part of MSF operations. Lundbeck donated some DMSA, but had no role in the treatment programme or in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry and should not be construed to represent any agency determination or policy. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: ALT, alanine transaminase; BD, twice daily; CaNa2EDTA, calcium disodium versenate; CDC, US Centers for Disease Control and Prevention; DMSA, 2,3-dimercaptosuccinic acid; DOT, directly observed therapy; ICPMS, inductively coupled plasma mass spectrometry; IV, intravenous; ECP, end-course venous blood lead level as a percentage of pre-course venous blood lead level; MSF, Médecins Sans Frontières; TDS, thrice daily; VBLL, venous blood lead level. * Email: Jane.Greig@london.msf.org PLOS Medicine | www.plosmedicine.org 1 October 2014 | Volume 11 | Issue 10 | pmed.1001739

[1]  K. Caldwell,et al.  Analysis of a novel field dilution method for testing samples that exceed the analytic range of point-of-care blood lead analyzers , 2014, International journal of environmental health research.

[2]  P. Dargan,et al.  Association of Blood Lead Level with Neurological Features in 972 Children Affected by an Acute Severe Lead Poisoning Outbreak in Zamfara State, Northern Nigeria , 2014, PloS one.

[3]  Ord,et al.  Guidance on Selecting Age Groups for Monitoring and Assessing Childhood Exposures to Environmental Contaminants , 2013 .

[4]  Nasir Sani-Gwarzo,et al.  Outbreak of Fatal Childhood Lead Poisoning Related to Artisanal Gold Mining in Northwestern Nigeria, 2010 , 2011, Environmental health perspectives.

[5]  M. Kosnett Chelation for Heavy Metals (Arsenic, Lead, and Mercury): Protective or Perilous? , 2010, Clinical pharmacology and therapeutics.

[6]  Y. Amitai,et al.  Lead poisoning among internally displaced Roma, Ashkali and Egyptian children in the United Nations-Administered Province of Kosovo. , 2010, European journal of public health.

[7]  A. Vale,et al.  A comparison of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning , 2009, Clinical toxicology.

[8]  A. Vale,et al.  Use of oral dimercaptosuccinic acid (succimer) in adult patients with inorganic lead poisoning. , 2009, QJM : monthly journal of the Association of Physicians.

[9]  A. Vale,et al.  Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning , 2009, Clinical toxicology.

[10]  Shunqin Wang,et al.  Blood lead levels of children and its trend in China. , 2009, The Science of the total environment.

[11]  R. Bertollini,et al.  Mass Lead Intoxication from Informal Used Lead-Acid Battery Recycling in Dakar, Senegal , 2009, Environmental health perspectives.

[12]  S. Kales,et al.  Lead encephalopathy due to traditional medicines. , 2008, Current drug safety.

[13]  M. Brown,et al.  Evaluation and recommendations for preventing lead poisoning among the internally displaced Roma population in Kosovo from the Centers for Disease Control and Prevention , 2007 .

[14]  N. Horton Multilevel and Longitudinal Modeling Using Stata , 2006 .

[15]  Death of a child after ingestion of a metallic charm--Minnesota, 2006. , 2006, MMWR. Morbidity and mortality weekly report.

[16]  C. R. Harris CRITICAL CARE TOXICOLOGY: DIAGNOSIS AND MANAGEMENT OF THE CRITICALLY POISONED PATIENT , 2005 .

[17]  Monica Cheesbrough,et al.  District Laboratory Practice in Tropical Countries: Acknowledgements , 2005 .

[18]  J. Gibson,et al.  A Plea for Painted Railings and Painted Walls of Rooms as the Source of Lead Poisoning Amongst Queensland Children , 2005, Public health reports.

[19]  Catherine Anne Kelly,et al.  Comparison of consciousness level assessment in the poisoned patient using the alert/verbal/painful/unresponsive scale and the Glasgow Coma Scale. , 2004, Annals of emergency medicine.

[20]  J. Coresh,et al.  Blood lead and chronic kidney disease in the general United States population: results from NHANES III. , 2003, Kidney international.

[21]  Catherine J Staes,et al.  Deaths related to lead poisoning in the United States, 1979-1998. , 2003, Environmental research.

[22]  B. Harvey Managing elevated blood lead levels among young children : recommendations from the Advisory Committee on Childhood Lead Poisoning Prevention , 2002 .

[23]  Robert L. Jones,et al.  The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. , 2001, The New England journal of medicine.

[24]  A. Onalaja,et al.  Genetic susceptibility to lead poisoning. , 2000, Environmental health perspectives.

[25]  J. Chisolm,et al.  Safety and Efficacy of Meso-2,3-Dimercaptosuccinic Acid (DMSA) in Children with Elevated Blood Lead Concentrations , 2000, Journal of toxicology. Clinical toxicology.

[26]  K. White,et al.  A Comparison of Two Dosing Regimens of Succimer in Children with Chronic Lead Poisoning , 1999, Journal of clinical pharmacology.

[27]  I. Bergdahl,et al.  Lead concentrations in human plasma, urine and whole blood. , 1997, Scandinavian journal of work, environment & health.

[28]  P. Bijur,et al.  Relationships among blood lead levels, iron deficiency, and cognitive development in two-year-old children. , 1996, Environmental health perspectives.

[29]  J. Graziano,et al.  Metabolism of meso-2,3-dimercaptosuccinic acid in lead-poisoned children and normal adults. , 1995, Environmental health perspectives.

[30]  K. Hurlbut,et al.  Pharmacokinetics of meso-2,3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults. , 1994, The Journal of pediatrics.

[31]  M. Shannon,et al.  Efficacy of oral meso-2,3-dimercaptosuccinic acid therapy for low-level childhood plumbism. , 1994, The Journal of pediatrics.

[32]  B. Dean,et al.  Ceramic lead glaze ingestions in nursing home residents with dementia. , 1994, The American journal of emergency medicine.

[33]  V. Slavkovich,et al.  Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication. , 1992, The Journal of pediatrics.

[34]  J. Chisolm,et al.  Evaluation of the potential role of chelation therapy in treatment of low to moderate lead exposures. , 1990, Environmental health perspectives.

[35]  J. Graziano,et al.  Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations. , 1988, The Journal of pediatrics.

[36]  D. Moel,et al.  Slow, natural reduction in blood lead level after chelation therapy for lead poisoning in childhood. , 1986, American journal of diseases of children.

[37]  D. Altman,et al.  STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT , 1986, The Lancet.

[38]  J. Graziano,et al.  2,3‐Dimercaptosuccinic acid as an antidote for lead intoxication , 1985, Clinical pharmacology and therapeutics.

[39]  D. E. Carter,et al.  DMSA, DMPS, and DMPA--as arsenic antidotes. , 1984, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[40]  J. Chisolm The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. , 1968, The Journal of pediatrics.

[41]  W. Staples,et al.  Treatment of lead encephalopathy in children. , 1966, The Journal of pediatrics.

[42]  J. Greengard,et al.  ACUTE LEAD ENCEPHALOPATHY IN YOUNG CHILDREN. , 1965, The Journal of pediatrics.

[43]  S. C. Wang,et al.  Chelating therapy with Na-DMS in occupational lead and mercury intoxications. , 1965, Chinese medical journal.

[44]  J. Chisolm,et al.  The treatment of acute lead encephalopathy in children. , 1957, Pediatrics.

[45]  A. Merklen,et al.  [Lead poisoning]. , 1956, Revue medicale de Nancy.

[46]  F. Rieders,et al.  The efficacy of edathamil calcium disodium in the treatment of occupational lead poisoning. , 1955, Industrial medicine & surgery.

[47]  H. Harrison,et al.  Treatment of lead encephalopathy with PAL (2.3-dimercaptopropanol). , 1950, Pediatrics.

[48]  E. Kaplan,et al.  Incidence of Lead Poisoning in the City of Baltimore. , 1942 .