Blood lead testing to identify children with lead exposure and link them with recommended follow-up services is an essential component of a comprehensive lead poisoning prevention program.1 While blood lead testing is at the core of secondary prevention of childhood lead poisoning, it also has a clear role in primary prevention efforts to identify and remove sources of lead in homes and the environment before any exposure occurs.2 The collection of blood lead test results for surveillance activities helps public health agencies identify high-risk geographic areas and populations to effectively target scarce resources where needed most.
A blood lead test is recommended for initial screening purposes and, in the case of elevated screening blood lead levels, for confirmatory diagnostic evaluation and ongoing monitoring.3–5 Capillary blood lead measurements may be used for initial screening purposes, but generally venous blood is recommended for diagnostic evaluation.3–6 There are several laboratory analytical methods for the determination of lead in blood including anodic stripping voltammetry, graphite furnace atomic absorption spectroscopy, and inductively coupled plasma mass spectrometry, the latter 2 of which use laboratory-developed tests to conduct high-complexity diagnostic tests.7 , 8 The US Food and Drug Administration (FDA) categorizes diagnostic tests on the basis of 7 Clinical Laboratory Improvement Amendments (CLIA) criteria categorized by complexity—from the least to the most complex: waived tests, moderate complexity tests, and high complexity tests.9
A family of instruments for blood lead analysis using anodic stripping voltammetry methods, known as LeadCare Testing Systems (ie, LeadCare I, LeadCare II, LeadCare Plus, and LeadCare Ultra) manufactured by Magellan Diagnostics (North Billerica, Massachusetts), has been approved for marketing by the FDA. Both LeadCare Plus, designed to be used in small laboratories, and LeadCare Ultra, a high-throughput testing system designed for use in larger laboratories, are classified as a “moderate complexity” tests. The LeadCare II point-of-care (POC) instrument, a second-generation of LeadCare I (ESA Biosciences, Chelmsford, Massachusetts), has been approved for marketing by the FDA as a “CLIA-waived” device for use in nonlaboratory settings such as doctors' offices and clinics.10 Diagnostic tests are categorized by FDA as “waived” if they are simple to use and there is little chance that the test will provide wrong information or cause harm if it is done incorrectly.11
On May 17, 2017, the FDA issued a safety communication regarding a class I recall for all versions of the LeadCare Testing Systems devices following a review of the company's data-supporting information contained in Magellan's previously issued “customer notifications” about possible inaccurate results and suggested steps to mitigate the problem.12 , 13 The FDA defines a class I recall, the most serious type, as one in which there is a reasonable probability that use of the product “will cause serious adverse health consequences or death.”14 The FDA warned that LeadCare Testing Systems “may underestimate blood lead levels (BLLs) and give inaccurate results when processing venous blood samples.”
Concurrent with the FDA warning, the Centers for Disease Control and Prevention (CDC) issued an advisory aimed at public health officials, health care providers, and clinical laboratories through its Health Alert Network.15 The advisory provided recommendations for retesting potentially affected persons with a venous blood test result of less than 10 μg/dL analyzed using a LeadCare instrument. Children younger than 6 years at the time of the alert and women currently pregnant or lactating were identified by the CDC as the highest risk priority groups and thus, the focus of the retesting recommendations (Figure).
Most public health agencies have regulatory or statutory authority that requires reporting of blood lead test results for residents in their jurisdictions regardless of where the test was administered or analyzed. Childhood blood lead surveillance is typically the responsibility of state and local Childhood Lead Poisoning Prevention Programs (CLPPPs). Consequently, CLPPPs were at the forefront in responding to the FDA's safety recall and CDC's retesting recommendations. Thus, the CDC sought to understand how this extraordinary incident impacted state and local CLPPPs. For example, what challenges did programs face and what lessons were learned? To answer these questions, the CDC utilized a 2-pronged approach to collect information: case studies and semistructured phone interviews. Four case studies described herein provide both common and unique experiences of public health agencies in responding to the recall and recommendations. Additional information garnered from the interviews is provided in the study by Trinh and Mason16 in this issue.
The Connecticut Department of Public Health (CT DPH) became concerned about error rates and inconsistencies between LeadCare package inserts and the Advisory Committee on Childhood Lead Poisoning Prevention's (ACCLPP) POC recommendations for confirmatory tests. The CT DPH consulted with scientists who informed the ACCLPP about their concerns. In January 2016, the CT DPH notified pediatricians and hospital laboratories via a “circular letter” that venous results from LeadCare instruments were not an acceptable form of confirmation and briefly described the differentiation of moderate- and high-complexity testing for confirmation.17
As a result of its investigation, the CT DPH found that certain laboratories used as “reference labs” were, unbeknownst to pediatricians, using the moderate complexity LeadCare Ultra/Plus instruments for confirmatory analysis. Differences exist between the underlying analytic anodic stripping voltammetry method of the LeadCare II—intended for POC use—and the LeadCare Ultra/Plus instruments that were being used to confirm screening results.18 , 19 These differences include the number of channels and therefore the number of analyses that can be conducted at the same time, the freshness of sample matrix from time of draw, how samples are transferred to sensors, whether carbon particles are part of the analytical process, and the limits of detection. In addition, the CT DPH learned that due to the quick turnaround time, providers were basing clinical decisions on whether or not to chelate using results derived from LeadCare instruments that do not meet the ACCLPP recommendation for confirmatory test utilizing high-complexity analytic methods.6
On May 17, 2017, the CT DPH learned of the class I FDA recall through the CDC Health Advisory via the Association of State and Territorial Health Officials e-mail listserv. Following the recall of the LeadCare venous feature and the CDC's subsequent retesting recommendations, the CT DPH sent out a second circular letter that informed providers of the recall and recommendations and required all laboratories using LeadCare to inform referring pediatricians to determine whether the patients needed retesting. The CT DPH also worked diligently with the medical director of the department of children and families to determine which children needed retesting. In addition, the CT DPH worked with hospitals to gather paired data on venous samples analyzed using both LeadCare and high-complexity methods to further understand potential discrepancies. Analysis revealed differences for blood lead levels greater than 5 μg/dL (as measured by LeadCare II) ranging from −28 to +4.3 μg/dL between paired results for LeadCare II and high-complexity methods (unpublished data, Connecticut Department of Health, 2017). Therefore, differing medical courses of action may have been prescribed depending on which analytical method was used.
The CT DPH's prerecall action likely reduced the number of children who required retesting in Connecticut. To ensure that confirmatory testing is appropriately done, health departments may want to consider educating providers and laboratories, particularly hospital laboratories, of important differences, such as detection limits, between the various laboratory methods. In addition, by denoting the blood sample type and whether the sample is for screening or confirmatory purposes, health care providers can provide better information to the analyzing laboratory and health department responsible for collecting and following up on blood lead test results.
The New Jersey Department of Health (NJ DOH) identified 11 providers representing 24 user sites in New Jersey that reported blood lead test results on venous samples that were analyzed on either a LeadCare II or LeadCare Ultra instrument. Providers included local health departments, health care professional offices, hospitals, and independent laboratories. The NJ DOH took the following actions after receiving notification about the recall and retesting recommendations: (1) instructed the laboratory director at each site to cease analyzing venous samples on LeadCare instruments and informed them that further guidance would be forthcoming; (2) faxed a frequently asked question information sheet, the FDA notification, the retesting protocol, and a sample patient notification letter to each user site; and (3) used a Family Health Warm Line to address frequently asked questions from the public regarding the health advisory.
Fifteen thousand children were identified by the NJ DOH as meeting the CDC retesting criteria. Two local health departments were impacted by the warning, resulting in 4700 children requiring retesting according to the CDC recommendations. The NJ DOH provided a list of identified children to the impacted local health departments. In reviewing blood lead test results for the impacted providers, the NJ DOH noted an abnormally high quantity of identical results for an independent laboratory. Of 956 reports to the NJ DOH between May 2011 and June 2016, 944 (98.7%) were reported with a value of 3.0 μg/dL, which may have been the result of rounding of the LeadCare II limit of detection of 3.3 μg/dL. However, after some investigation and being unable to contact the laboratory, the NJ DOH discovered that the laboratory had been submitting falsified reports and the owners had pled guilty to fraud.
The warning and advisory provided an opportunity for the NJ DOH to update its LeadCare user contact list and to reinforce regulatory reporting requirements. The NJ DOH's childhood lead surveillance data management plan now has quality assurance and improvement protocols in place to identify anomalies. An important lesson learned is that intra- and interdepartmental communication can facilitate efficient communication with impacted providers and the public and to address other concerns that affect public health outcomes.
The Oklahoma Childhood Lead Poisoning Prevention Program (OCLPPP) was notified of the FDA advisory officially via e-mail notices through the CDC Health Alert Network. The OCLPPP participated on a CDC conference call on May 18th, describing the potential for falsely low venous test results and clarifying retesting recommendations.
Magellan Diagnostics mails the OCLPPP a monthly, updated list of organizations or providers who have purchased a LeadCare instrument in Oklahoma. The OCLPPP assists new users with reporting, onboarding, and following up with nonreporters to identify whether the instrument is still in use. Because these procedures were already in place, the OCLPPP had contact information for the LeadCare II users affected by the recall, as well as a large hospital laboratory that was using a LeadCare Ultra instrument. In OCLPPP's blood lead surveillance and case management system, blood lead test results analyzed using a LeadCare II instrument are identified by the laboratory name “In Office.” Therefore, OCLPPP was easily able to identify which patients were impacted by the FDA advisory and CDC's recommended retesting protocol by analyzing the “In Office” and the large hospital's data. Relevant data were imported into SAS to identify patients who (1) were born on or after May 17, 2011; (2) had a venous specimen tested on a LeadCare instrument; and (3) either had no further blood lead testing or subsequent testing was also conducted using a venous specimen on a LeadCare instrument.
The OCLPPP mailed letters to the parents or guardian of the 6442 children who met the retesting criteria. The letter detailed the advisory and potential for falsely low results in the child's previous blood lead test, recommended that the child receive a follow-up blood lead test, and provided contact information for the OCLPPP to answer any additional questions or provide assistance. The OCLPPP also mailed a letter to the 383 unique health care providers who ordered the original blood lead tests on the 6442 children asking them to contact the child's guardian to schedule a retest. If a “parent” letter was returned, the OCLPPP personnel queried additional databases to see whether a newer address was on file and, if so, mailed the letter to the new address. The OCLPPP has not tracked the proportion of children who received the recommended follow-up test because by querying the blood lead surveillance system for new blood lead testing data, the OCLPPP cannot definitively ascertain whether the retest was collected because of the recall or as part of standard Oklahoma screening requirements.
The CDC guidance was helpful in establishing the criteria for recommended retesting and allowed for standardization of how each state would handle the challenge and promoted uniformity of response from all states. At this time, the OCLPPP is not pursuing additional steps in its response and considers that the matter has been resolved satisfactorily. No changes will be made to the reporting methodology as the current system easily identified LeadCare II test results and could do so again if a similar situation should arise.
In response to the CDC-issued health alert, the Minnesota Department of Health (MDH) issued its own health advisory, developed frequently asked questions for health care providers and parents, and identified laboratories with LeadCare instruments. Laboratories and local public health agencies were sent lists of individuals meeting the CDC's retesting criteria and were encouraged to ensure that patients were retested. In addition, refugees aged 6 to 17 years were recommended for retesting. Retesting was prioritized for persons with previous elevated blood lead levels (EBLLs [defined as ≥5 μg/dL]). The MDH monitored retesting progress through routine blood lead surveillance and sent updated lists to partners.
The MDH identified 59 laboratories with LeadCare instruments that had analyzed 58 319 samples of venous blood or unknown sample type. Four of those laboratories were using LeadCare Ultra instruments. Of identified test results, 26 491 persons met retesting criteria, including 18 152 children, 7113 adults with unknown pregnancy status, and 1226 refugees; 1528 had an elevated result from a capillary sample in the 12 months before having a venous sample analyzed on a LeadCare instrument (prior EBLL). As of April 30, 2018, the MDH had received retests from 4867 (18.4%) persons, including 3994 (22.0%) children, 796 (11.2%) adult women, and 77 (6.3%) refugees. Of those with prior EBLLs, 502 (32.9%) received a retest.
The proportion of individuals who received a retest was associated with the year of their prerecall blood lead test (P < .01). Only 1.6% (16/1023) of individuals who had been tested during 2007 to 2011 received a retest, compared with 10.4% (1224/11 754) of individuals with a prerecall test during 2012 to 2015, and 26.4% (3627/13 714) of individuals with a prerecall test during 2016 to 2017. Of retested persons, 80 (1.6%) had at least 1 elevated blood lead test result following the recall. Of those, 39 (48.8%) had confirmed EBLLs; 7 (8.8%) had elevated capillary results and have not yet received confirmatory testing; and the remainder were found to be noncases.
Several factors were instrumental to this response. Purchase records from the manufacturer allowed identification of laboratories that used LeadCare instruments. However, the type of instrument used by each laboratory that submits data to MDH had to be validated because purchase records did not include instruments purchased prior to 2007 or laboratories that are located outside of Minnesota. Quality data in MDH's surveillance system facilitated generating lists of persons to retest. Voluntary cooperation from laboratories and local public health agencies was invaluable for contacting patients.
The MDH was contacted about several instances when a patient attempted to schedule a retesting appointment and experienced difficulty because its clinic schedules appointments using a centralized switchboard, and the operators were unaware of the recall. Several health care providers reportedly told their patients that they did not need to be retested. In addition, some patients received confusing or contradictory messages about who would pay for the retesting appointment. In each of these circumstances, the MDH staff attempted to intervene and educate health care providers and clinic staff on the importance of retesting. These difficulties highlight the importance of communicating with all levels of the health care delivery system, including local and tribal health departments, health care providers, staff who schedule appointments for clinics, and health insurance providers and managed care plans. The MDH continues to monitor test results received to ensure that laboratories utilizing LeadCare instruments do not test venous samples.
Discussion and Conclusions
Between January 1, 2014, and May 22, 2017, there were more than 8 million blood lead tests analyzed on LeadCare Testing Systems kits distributed in the United States.13 , 20 Based on the CDC reference value of 5 μg/dL, Magellan Diagnostics estimated that 2.5% of the 8 million tests, or 200 000 results, may have been affected by the potential for falsely low blood lead results.21 However, there is no way to estimate how many tests were actually affected. In May 2005, a voluntary recall of 8 specific lots of LeadCare testing kits identified defective sensors as the root cause of a negative bias that potentially affected 500 000 blood lead tests from kits distributed between September 2003 and April 2005.22 This recall also resulted in a recommendation to retest affected persons.23
The LeadCare II POC instrument, designed to be used with 2 drops of capillary blood from a finger stick, offers several benefits over more complex methods including rapid results, no specialized skill required for use, portability, and relative affordability.24 However, capillary blood specimens may provide falsely elevated lead levels that can be the result of inappropriate blood collection procedures (eg, finger stick collection from a lead-contaminated finger) or due to contaminated materials used to collect and transport the specimen.5 , 25 , 26 In 2013, the CDC ACCLPP recommended that blood lead levels of 5 μg/dL or greater analyzed on POC instruments on children younger than 6 years be confirmed using a venous blood sample analyzed by CLIA-certified high-complexity method.6 At that time, LeadCare II was (and still is) the only POC instrument approved for blood lead testing.6 The subsequent approval and marketing of the LeadCare Ultra and LeadCare Plus instruments increased the availability of moderate-complexity tests, which have been shown to compare well with high-complexity methods.18 , 19 However, given the low detection limits, precision, and high throughput capabilities of inductively coupled plasma mass spectrometry and graphite furnace atomic absorption spectroscopy, high-complexity tests from laboratories that meet CLIA proficiency standards of ±10% or ±4 μg/dL are recommended for confirmatory blood lead analysis.6 , 27–30
Falsely low blood lead tests from the use of LeadCare Testing Systems with venous blood may have resulted in persons with EBLLs not receiving appropriate follow-up care. Therefore, the CDC recommended that (1) children younger than 6 years with a venous blood lead test of less than 10 μg/dL be analyzed using a LeadCare instrument at an on-site (eg, health care facility) or at an off-site laboratory and (2) currently pregnant or lactating women who had a venous blood lead test performed using a LeadCare instrument be retested.15 Although the root cause of the most recent negative bias identified, that is, when LeadCare Testing Systems are used with venous blood, is still under investigation by FDA, it is possible that the use of certain blood collection tubes (BD Vacutainer plastic tubes with K2EDTA anticoagulant, Becton Dickinson [BD] & Company, Franklin Lakes, New Jersey) may be involved because of significant changes to the formulation of the rubber stoppers.31
The simultaneous US FDA LeadCare Testing Systems Recall and CDC Health Alert and subsequent response by state and local health departments highlight both strengths and weaknesses of the current public health and laboratory testing systems to identify and respond to those, particularly children, with lead exposure in need of follow-up services and coordinated care. Federal agencies such as the CDC and the FDA are at the forefront of providing timely and relevant information to public health agencies during times of emergency, as well as to inform their day-to-day activities. The CDC CLPPP is committed to serving local, state, and tribal CLPPPs that implement actions to protect the health and well-being of the nation from lead exposures and resulting adverse health outcomes.
Implications for Policy & Practice
- A well-functioning surveillance system is at the core of lead poisoning prevention program activities and not only enables public health agencies to perform their daily activities but is essential to their ability to respond to extraordinary or emergency events in a timely and efficient manner.
- Health care providers and laboratories could assist public health efforts to improve surveillance by better documenting and reporting important details including type of blood specimen obtained, laboratory methods used for blood lead analysis, and information on analytic methods such as precision, limits of detection, and rules used for rounding or truncating results.
- Developing and maintaining key relationships and understanding the role of each entity in the continuum of care necessary to identify and follow up on lead-exposed children, that is, health care provider, clinic, hospital laboratory, and/or independent laboratory, may help public health agencies improve their ability to respond to an emergency or other serious event.
- While POC instruments have increased the ability to reach high-risk populations, the ACCLPP recommended that these instruments be used for screening purposes only. Current ACCLPP recommendations suggest using a CLIA-categorized high-complexity test for confirmatory blood lead testing.
4. Centers for Disease Control and Prevention. CDC Response to Advisory Committee on Childhood Lead Poisoning Prevention Recommendations in “Low Level Lead Exposure Harms Children: A Renewed Call of Primary Prevention.” Atlanta, GA: US Department of Health & Human Services. https://www.cdc.gov/nceh/lead/acclpp/cdc_response_lead_exposure_recs.pdf
. Published June 2012. Accessed June 10, 2018.
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. Published May 17, 2017. Accessed May 7, 2018.
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25. Centers for Disease Control and Prevention. Preventing Lead Poisoning in Young Children: A Statement by the Centers for Disease Control (CDC). Atlanta, GA: US Department of Health & Human Services; Public Health Service. https://www.cdc.gov/nceh/lead/publications/plpyc1985.pdf
. Published January 1985. Accessed May 30, 2018.
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. Published February 28, 1992. Accessed May 12, 2018.