The authors have declared that no competing interests exist.
Conceived and designed the experiments: JG NT PID LS. Analyzed the data: JG CA. Wrote the paper: JG NT PID LS LC. Responsible for data management: JG NT LC AA CM. Contributed to the revision of the manuscript: JG NT LC CA AOA TA AA KC AC-P CG-R CM A. Neri DS NS-G A. Nasidi LS PID.
In 2010, Médecins Sans Frontières (MSF) investigated reports of high mortality in young children in Zamfara State, Nigeria, leading to confirmation of villages with widespread acute severe lead poisoning. In a retrospective analysis, we aimed to determine venous blood lead level (VBLL) thresholds and risk factors for encephalopathy using MSF programmatic data from the first year of the outbreak response.
We included children aged ≤5 years with VBLL ≥45 µg/dL before any chelation and recorded neurological status. Odds ratios (OR) for neurological features were estimated; the final model was adjusted for age and baseline VBLL, using random effects for village of residence. 972 children met inclusion criteria: 885 (91%) had no neurological features; 34 (4%) had severe features; 47 (5%) had reported recent seizures; and six (1%) had other neurological abnormalities. The geometric mean VBLLs for all groups with neurological features were >100 µg/dL vs 65.9 µg/dL for those without neurological features. The adjusted OR for neurological features increased with increasing VBLL: from 2.75, 95%CI 1.27–5.98 (80–99.9 µg/dL) to 22.95, 95%CI 10.54–49.96 (≥120 µg/dL). Neurological features were associated with younger age (OR 4.77 [95% CI 2.50–9.11] for 1–<2 years and 2.69 [95%CI 1.15–6.26] for 2–<3 years, both vs 3–5 years). Severe neurological features were seen at VBLL <105 µg/dL only in those with malaria.
Increasing VBLL (from ≥80 µg/dL) and age 1–<3 years were strongly associated with neurological features; in those tested for malaria, a positive test was also strongly associated. These factors will help clinicians managing children with lead poisoning in prioritising therapy and developing chelation protocols.
Lead poisoning is not a new phenomenon. Though debate continues as to whether it was described by Hippocrates
In resource-rich nations, deaths from lead encephalopathy are a largely historical phenomenon. Hundreds of children died from lead poisoning in the USA in the first half of the 20th Century when lead use was widespread
In March 2010, a Médecins Sans Frontières (MSF) disease surveillance team in Zamfara State, northern Nigeria, was contacted by leaders and health staff of a local village with reports of high mortality in young children following an unknown illness. MSF was invited to assist in investigating these reports by the state Ministry of Health. MSF carried out an initial assessment and rapidly assembled a dedicated response team and 24-hour care in the village clinic. Children presented with sudden onset of abdominal pain and/or vomiting, intractable seizures with or without fever, then sometimes rapid progression to death. Symptoms were unresponsive to initial treatment by the MSF team for common endemic diseases such as malaria and meningitis, and anti-convulsants had little effect. Over 2 months until 17 May 2010, nearly 300 children aged ≤5 years presented in four villages with these symptoms with a mortality of 48%. There were anecdotal reports of a recent increase in small-scale ore processing with dry-milling to extract gold. An outbreak of severe lead poisoning was confirmed
The focus of the MSF emergency medical response was clinical lead surveillance and chelation therapy. All children aged ≤5 years from the seven villages where remediation was taking place were offered screening by MSF as their villages were remediated. Treatment in the absence of environmental remediation has limited impact, so screening in unremediated villages was considered futile. Children with venous BLL (VBLL) ≥45 µg/dL (the MSF protocol and CDC recommended chelation threshold) from remediated villages
Although there has been some characterisation of the clinical pattern of lead toxicity
For the period June 2010 to the end of June 2011, we included all children aged ≤5 years with a first-ever VBLL ≥45 µg/dL recorded before chelation therapy and whose neurological status was recorded within 7 days of this VBLL. Screening and treatment were provided by MSF. Children were identified via an MSF door-to-door census that detailed children aged ≤5 years living in each residential compound. Screening for enrolment to the MSF chelation programme included a brief clinical history and examination, with particular attention to neurological status. Neurological assessment included history of seizures, change in behaviour, delay or loss of developmental milestones, peripheral neuropathies, gait, assessment of reflexes, and level of consciousness (alert/voice/pain/unresponsive [AVPU] assessment scale
Neurological status category | Definition | |
1 | Severe neurological features: | Seizures witnessed by medical staff; and/or altered consciousness (an AVPU of V or P or U). |
2 | Presumptive seizures: | A guardian's report of recent (within the past few days) seizure activity and an AVPU of A on presentation; but no seizures witnessed by medical staff. |
3 | Mild neurological features: | Any neurological signs or symptoms noted by medical staff but without reported history or witnessed seizure; and an AVPU of A on presentation. |
4 | No neurological features identified: | No significant neurological signs or symptoms identified on brief clinical examination by the initial treating doctor; and no history of recent seizures. |
*Noted abnormalities were hypo-reflexia, inconsolable crying, agitation, and decreased mobility.
“Any neurological features” = categories 1+2+3.
VBLL was measured using the Lead Care II point-of-care analyser (Magellan Biosciences, Chelmsford Massachusetts), using manufacturer-recommended protocols, with samples testing above the upper limit of 65 µg/dL retested using a dilution method developed with CDC and described elsewhere
Haematological and biochemical parameters were categorised
Selected clinical and laboratory data were routinely entered into an electronic database specifically designed (by JG) to support patient care and programme management. Data were analysed using STATA 10.1 (StataCorp, Texas, USA). Baseline characteristics were described as counts and percentages of patients in each category and compared with chi-squared or Fisher's exact tests unless a high proportion of data was missing. VBLL by neurological status category was calculated as geometric means with 95% confidence intervals (95% CI) due to non-normally distributed data, accommodating clustering by village of residence by using robust standard errors. Log VBLL values by neurological status categories were compared by Analysis of Variance with Scheffe test between groups. Odds ratios (OR) for any neurological features (compared to none) were estimated for the following variables based on review of descriptive data, completeness and plausibility, with random effects (for village of residence as a variable potentially incorporating various unmeasured factors such as level of environmental contamination): gender; age at time of VBLL; baseline VBLL category; nutritional status (MUAC); and haemoglobin. A multivariable multi-level logistic regression random effects model to estimate adjusted OR of the outcome of any neurological symptoms included factors significant at p<0.10 in the unadjusted analysis or with plausible epidemiological or biological association. Backward selection was used to choose prognostic variables for the final model, discarding those no longer associated (p>0.10) with the outcome after adjustment for other variables. P-values were calculated for the strength of association of each variable with the outcome using Wald tests, and the VBLL categorical variable assessed as continuous to test for trend. Interaction was not plausible with the retained variables. The sensitivity of the model was assessed for severity of neurological features. The role of malaria was assessed in patients who had been tested for malaria due to symptoms (33%), adjusting for age and VBLL.
This study met the standards set by the independent MSF Ethics Review Board for retrospective analyses of routinely collected programmatic data
Between 1 June 2010 and 30 June 2011 approximately 95% of children in the seven remediated villages were screened; 972 children met the inclusion criteria (
VBLL = venous blood lead level.
45–64.9 | 65–79.9 | 80–99.9 | 100–119.9 | 120–199.9 | 200+ | Total | ||
0–<6 months | 33 (65%) | 5 (10%) | 3 (6%) | 5 (10%) | 4 (8%) | 1 (2%) | 5% | |
6–<12 months | 52 (51%) | 5 (5%) | 20 (20%) | 14 (14%) | 7 (7%) | 4 (4%) | 10% | |
1–<2 years | 75 (47%) | 4 (3%) | 23 (14%) | 18 (11%) | 22 (14%) | 17 (11%) | 16% | |
2–<3 years | 53 (54%) | 8 (8%) | 14 (14%) | 11 (11%) | 11 (11%) | 1 (1%) | 10% | |
3–5 years | 363 (65%) | 34 (6%) | 88 (16%) | 44 (8%) | 29 (5%) | 4 (1%) | 58% | |
VBLL = venous blood lead level.
Most (885 [91%]) children had no neurological features, 34 (4%) had seizures witnessed by medical staff and/or reduced level of consciousness, 47 (5%) had a guardian-reported history of recent seizures but no altered consciousness on presentation, and six (1%) displayed some other signs of neurological abnormality (
VBLL tested from 1 June 2010 to 30 June 2011. VBLL = venous blood lead level.
No neurological features (n = 885) | Mild neurological features (n = 6) | Presumptive seizures (n = 47) | Severe neurological features (n = 34) | p-value |
All (n = 972) | |
Geometric mean VBLL (95% CI) (µg/dL) | 65.9 (59.7–72.7) | 157.6 (52.1–476.3) | 106.9 (76.1–150.3) | 170.1 (112.0–258.2) | <0.001 | 79.4 (62.6–100.7) |
VBLL range (µg/dL) | 45.0–345.1 | 49.2–708.0 | 46.9–531.0 | 50.6–459.9 | 45.0–708.0 | |
VBLL ≥80 µg/dL, n (%) | 276 (31%) | 5 (83%) | 32 (68%) | 27 (79%) | <0.001 | 340 (35%) |
Sex male, n (%) | 450 (51%) | 2 (33%) | 27 (57%) | 15 (44%) | 0.56 | 494 (51%) |
Age category, n (%) | <0.001 | |||||
0–<6 months | 48 (5%) | 0 | 2 (4%) | 1 (3%) | 51 (5%) | |
6–<12 months | 92 (10%) | 1 (17%) | 5 (11%) | 4 (12%) | 102 (10%) | |
1–<2 years | 119 (13%) | 3 (50%) | 17 (37%) | 20 (59%) | 159 (16%) | |
2–<3 years | 87 (10%) | 1 (17%) | 5 (11%) | 5 (15%) | 98 (10%) | |
3–5 years | 539 (61%) | 1 (17%) | 18 (38%) | 4 (12%) | 562 (58%) | |
Malaria RDT, n (%) | ||||||
Symptomatic; RDT negative | 80 (9%) | 1 (17%) | 4 (9%) | 7 (9%) | 92 (9%) | |
Symptomatic; RDT positive | 177 (20%) | 4 (67%) | 26 (55%) | 26 (76%) | 233 (24%) | |
Asymptomatic/missing |
628 (71%) | 1 (17%) | 17 (36%) | 1 (3%) | 647 (67%) | |
Nutritional status (MUAC), n (%) | 0.045 | |||||
Red (<110 mm) | 8 (1%) | 0 | 2 (4%) | 1 (3%) | 11 (1%) | |
Orange (≥110 <125 mm) | 23 (3%) | 0 | 5 (10%) | 1 (3%) | 29 (3%) | |
Yellow (≥125 <135 mm) | 56 (6%) | 1 (17%) | 3 (6%) | 5 (15%) | 65 (7%) | |
Green (≥135 mm) | 613 (69%) | 3 (05%) | 27 (57%) | 18 (53%) | 661 (68%) | |
Not applicable (<6 m old) | 48 (5%) | 0 | 2 (4%) | 1 (3%) | 51 (5%) | |
Missing (≥6 m old) | 137 (15%) | 2 (33%) | 8 (17%) | 8 (24%) | 155 (16%) | |
Laboratory tests at time of VBLL, n (%) | ||||||
Normal haemoglobin (g/dL) | 213 (24%) | 0 | 13 (28%) | 3 (9%) | 0.050 | 229 (24%) |
Low (<10 if <2 y; <11 if 2–5 y) | 664 (75%) | 6 (100%) | 33 (70%) | 30 (88%) | 733 (75%) | |
High (>13 if <2 y; >14 if 2–5 y) | 2 (0%) | 0 | 1 (2%) | 1 (3%) | 4 (0%) | |
Missing | 6 (1%) | 0 | 0 | 0 | 6 (1%) | |
Normal ALT, n (%) | 604 (68%) | 1 (17%) | 26 (55%) | 23 (68%) | 654 (67%) | |
Mildly elevated (>42–100 U/L) | 73 (8%) | 0 | 2 (4%) | 2 (6%) | 77 (8%) | |
Mod. elevated (>100–1000 U/L) | 11 (1%) | 0 | 0 | 1 (3%) | 12 (1%) | |
Severely elevated (>1000 U/L) | 0 | 0 | 0 | 0 | 0 | |
Missing | 197 (22%) | 5 (83%) | 19 (8%) | 8 (24%) | 229 (24%) |
*Malaria test performed only on symptomatic children, but no result in database not confirmation that asymptomatic.
p-values only given when <20% data missing. VBLL = venous blood lead level. RDT = rapid diagnostic test. MUAC = mid upper-arm circumference. Mod = moderately. m = months. y = years. ALT = alanine transaminase.
Within age groups, neurological features were most common in 1–<2 year olds (25% vs 6% for other ages; p<0.001). 233 (72%) of 325 children tested for malaria had a positive RDT result. A positive malaria test was more common in children with neurological features than in those without (82% [56/68] vs 69% [177/257], respectively; p = 0.034) (
In logistic regression (unadjusted OR, random effects for village of residence), presentation with any neurological features was not associated with gender (OR = 1.08, 95%CI 0.68–1.72; p = 0.73), or low haemoglobin (OR = 1.39, 95%CI 0.77–2.50; p = 0.27), but was associated with age (highest for 1–<2 years [OR = 9.42, 95%CI 5.23–16.96; p<0.001] compared with 3–5 years), increasing VBLL (test for trend p<0.001, starting from 80.0–99.9 µg/dL with OR = 3.06, 95%CI 1.43–6.53), and moderate-severe malnutrition (OR = 4.76, 95%CI 2.02–11.31; p<0.001). The final multivariate analysis retained only age and VBLL as strongly associated with any neurological features after adjustment for the other factors and random effects for village (both p<0.001). Children aged 1–<2 years had the highest odds of neurological features compared with children age 3–5 years (adjusted OR 4.77, 95%CI 2.50–9.11); age 2–<3 years was also associated with neurological features (adjusted OR 2.69, 95%CI 1.15–6.26) compared with children age 3–5 years. Increasing VBLL (compared with the reference category of 45–64.9 µg/dL) was strongly associated with increased odds of neurological features (test for trend p<0.001): adjusted OR 2.75, 95%CI 1.27–5.98 (VBLL 80–99.9 µg/dL); 3.84, 95%CI 1.62–9.09 (100–119.9 µg/dL); and 22.95, 95%CI 10.54–49.96 (≥120 µg/dL) (
Unadjusted OR (95% CI) | Adjusted OR (95% CI) | p-value |
|
Age at time of VBLL | <0.001 | ||
0–<6 months | 1.35 (0.36–5.04) | 1.66 (0.44–6.31) | |
6–<12 months | 2.07 (0.93–4.63) | 1.46 (0.61–3.51) | |
1–<2 years | 9.42 (5.23–16.96) | 4.77 (2.50–9.11) | |
2–<3 years | 3.54 (1.59–7.88) | 2.69 (1.15–6.26) | |
3–5 years | 1 | 1 | |
VBLL | <0.001 | ||
45–64.9 | 1 | 1 | |
65–79.9 | 1.21 (0.26–5.62) | 1.02 (0.21–4.87) | |
80–99.9 | 3.06 (1.43–6.53) | 2.75 (1.27–5.98) | |
100–119.9 | 4.87 (2.11–11.22) | 3.84 (1.62–9.09) | |
120+ | 38.77 (18.14–82.86) | 22.95 (10.54–49.96) |
*P-value from the Wald test of no association of the attribute with the outcome adjusted for the other variables in the model. VBLL = venous blood lead level. OR = odds ratio. (n = 972).
A sensitivity analysis using only the outcome of severe neurological features compared with all other patients gave similar overall results. The association with VBLL was stronger and the trend robust (test for trend p<0.001), but significant only from 100–119.9 µg/dL (adjusted OR 7.35, 95%CI 2.02–26.79; for VBLL≥120 µg/dL adjusted OR 23.96, 95%CI 7.33–78.31). The adjusted OR were also higher for all ages with the largest associations for children aged 1–<3 years (OR>6 for both 1–<2 y and 1–<3 y) compared with children aged 3–5 years.
Severe neurological features in children with a positive malaria RDT result were seen at VBLL as low as 50 µg/dL, while in those with a negative RDT the lowest VBLL with severe neurological features was 105 µg/dL, and in the one child with severe neurological features and no malaria test result the VBLL was 293 µg/dL. In the 325 children with a malaria RDT result, the unadjusted OR of a positive RDT with any neurological features was 2.04 (95% CI 0.96–4.35; p = 0.065). After adjustment for age and VBLL there was evidence of a strong association of malaria with neurological features (adjusted OR = 3.60, 95% CI 1.42–9.09; p = 0.007); after adjustment for malaria, age and VBLL showed a similar pattern of association with neurological features as in the entire cohort, that is, highest adjusted OR in 1–<2 year olds and increasing adjusted OR with increasing VBLL.
The MSF programmatic data collected during the response to the Zamfara lead poisoning disaster presents a cohort size and severity that is unprecedented. While lead poisoning was endemic in resource-rich countries in the early to mid-20th Century, an acute outbreak of this magnitude has not been reported in the literature. Chisolm
Children with severe neurological features of altered consciousness or seizures witnessed by clinical staff had significantly higher VBLL than those with only a guardian-reported recent history of seizures. Having any neurological feature was strongly associated with increasing initial VBLL, with evidence of an increased OR at a VBLL of 80–99.9 µg/dL, becoming stronger at 100–119.9 µg/dL and larger still from 120 µg/dL. This is consistent with previous ranges given for the threshold above which encephalopathy risk is increased
Severe neurological features were not seen below VBLL 50 µg/dL and in the absence of a positive malaria test, not below 105 µg/dL. Most children with neurological features at a lower VBLL (<80 µg/dL) also had a positive malaria test. In 325 children with symptoms suggestive of malaria who were tested by RDT, a positive result was independently associated with neurological features in addition to the trend associating increasing VBLL with neurological features. It is challenging to distinguish between features of cerebral malaria and lead encephalopathy clinically, and the presence of both lead and malaria were strongly associated with neurological features. We postulate that it is also possible that haemolysis associated with malaria increases the relative proportion of free plasma lead at a given (whole blood) VBLL, increasing the lead available to cause encephalopathy. The interaction between malaria infection and lead toxicity is still uncertain and is an area for future research.
Of children with no neurological features at the time of initial examination, 31% had VBLL ≥80 µg/dL, comparable to the United States National Academy of Sciences cohort
A larger proportion of children with neurological features were aged 1–3 years compared with those without neurological features. The greatest proportion of high VBLLs were seen in children aged 1–<2 years, and the strongest association with neurological features was in this age group after adjusting for VBLL. During the initial outbreak investigation (before lead poisoning was confirmed and before chelation therapy began) proportionally more children aged 1–<2 years died amongst children displaying probable or suspected neurological features. We hypothesise that this risk pattern for both high VBLL and stronger association with neurological features may reflect a number of factors: variation in bioavailability of ingested lead; variation in exposure due to behavioural (i.e., hand-mouth) and developmental factors; immaturity of the blood/brain barrier compared with older children and possibly other age-related influences on activities and movement around the contaminated villages and ore processing areas. Conversely, there are several reasons why children younger than 1 year may have been less at risk of raised VBLL and neurological effects: shorter duration of potential exposure by virtue of younger age; poorer mobility and less marked hand-mouth behaviour; and physiological variation in absorption. However, the neurological damage done by lead, beyond fatal lead encephalopathy, is long-term
Lead poisoning related to industrial activity is an ongoing problem, with a recent outbreak in Senegal secondary to used lead acid battery recycling linked to 18 child deaths and 81 additional cases of poisoning
Limitations to our data arise from the circumstance in which they were collected, namely an emergency humanitarian response to mass mortality and morbidity from lead poisoning. While screening was offered to all children in the seven villages remediated in the first year, tragically, hundreds of children had died before the excess mortality was notified and cause identified in these villages; these children were not included in this analysis. In the first 2 months of the response, 42 children did not have VBLL recorded immediately prior to starting chelation therapy (with an earlier screening BLL ≥65 µg/dL) due to logistical challenges, including three who had had witnessed seizures and three with presumptive seizures; these children were not included due to the likely effect of chelation on any VBLL taken after therapy was started. Blood for VBLLs from these children were taken 1–11 days after commencing chelation therapy; 70% were still ≥80 µg/dL (range 15–241 µg/dL). Thus potentially some of the most severely poisoned children were not included in this analysis. The neurological data collected may have missed subtle neurological abnormalities that would not have been identified with the simple tools used that focused on detecting life-threatening encephalopathy. The VBLLs in the first months may not be precise due to the unanticipated need to determine appropriate dilution methods for the portable testing equipment, and because the Lead Care II will not be as precise as ICPMS. However, quality control showed that Lead Care II values were on average only 4.0 µg/dL lower than those measured using ICPMS. In addition, the multivariable model was assessed for sensitivity to excluding VBLL tests in the first months and the pattern of associations were not substantially altered (data not shown). Children with inadequately recorded neurological status at time of VBLL had a lower geometric mean VBLL, which may indicate that these children were less likely to have exhibited neurological features. A sensitivity analysis of the model including all these patients as having had no neurological features did not alter the patterns of association (data not shown). The date of birth is often inaccurate or unknown in this remote, rural region, therefore most ages in this analysis are approximations, and thus age was categorised. In addition there was a substantial amount of missing data for some important variables such as the malaria RDT result. The fact that only symptomatic children were tested suggests that clinical malaria was present; however, as the RDT may be positive for weeks after treatment, microscopy would be needed to confirm acute infection. There is the potential that the neurological features seen may be related to comorbidities other than malaria or to permanent damage from previous high VBLLs. As with any large dataset, despite standardised forms, continuous use of data for clinical purposes, and regular data cleaning, it is possible that there was some misclassification, but this is considered unlikely to be differential. The strength of this dataset is its unequalled size, severity of lead exposure, and scope of routinely collected clinical data.
In this large cohort of 972 children exposed to environmental lead contamination, 35% of children ≤5 years with a VBLL requiring chelation therapy (≥45 µg/dL) had VBLLs ≥80 µg/dL. There was evidence that a VBLL ≥80 µg/dL was associated with neurological features and strengthened as VBLL increased, and neurological features were also more likely in children aged 1–<3 years compared to those 3–5 years. Severe neurological features were seen at VBLL <105 µg/dL only if there was a concurrent positive malaria test, and among children tested for malaria, a positive malaria RDT result was strongly associated with neurological features after adjustment for age and VBLL. These results will help clinicians managing children with lead poisoning to determine which individuals are likely to be at greatest risk of developing neurological features and therefore potentially life-threatening encephalopathy. This is particularly important when managing large outbreaks for determining urgency of therapy and to help guide chelation protocols.
There have been many staff dedicated to investigating and responding to this tragic outbreak, including Vicki Slinko, Andreas Häggström, Jenny Mackenzie, John Pringle, Dismus Adungo, Elshafie Mohamed Ahmed, Ellen Van Der Velden, Catrine Hoel, Jean Tiendrebiogo, Krystel Moussally, and particularly Samson Adewumi, data manager from the early stages of the project until his untimely death. We acknowledge the great work of all the other staff of the lead poisoning treatment project in Zamfara, and the endurance of the patients and their families, and the other organisations who have been involved in responding to this outbreak including TerraGraphics Environmental Engineering, the US Centers for Disease Control and Prevention, and the Nigerian Federal and Zamfara State Ministries of Health. We thank Sarah Venis at MSF UK for medical editing assistance.
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.