Video Abstract

Video Abstract

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BACKGROUND:

Newborn screening provides early diagnosis for children with sickle cell disease (SCD), reducing disease-related mortality. We hypothesized that rapid point-of-care (POC) Sickle SCAN would be reliable in Haiti and would assist newborn screening.

METHODS:

Dried blood specimens were obtained from infant heel sticks and analyzed by isoelectric focusing (IEF) at a public hospital in Cap-Haïtien during a 1-year period. A total of 360 Guthrie cards were also analyzed for quality assurance by high-performance liquid chromatography at the Florida Newborn Screening Laboratory. In addition, two-thirds of the infants were also screened by the POC to assess differences with the IEF. The hemoglobinopathy incidence and the specificity and sensitivity of the POC scan were assessed.

RESULTS:

Overall, 1.48% of the children screened positive for SCD. The specificity and the sensitivity of POC Sickle SCAN were 0.97 (confidence interval 0.95–0.99) and 0.90 (confidence interval 0.55–1.00), respectively, relative to high-performance liquid chromatography gold standard. The confirmatory testing rate was 75% before POC and improved to 87% after POC was added for dual screening. Confirmatory testing revealed that 0.83% of children screened had SCD. Children who screened positive for SCD by POC started penicillin earlier, had their first pediatric follow-up a median of 38 days earlier, and received antipneumococcal vaccination on time when compared with those who screened positive for SCD by IEF alone.

CONCLUSIONS:

The observational study revealed a high incidence of SCD among Haitian newborns. Sickle SCAN had excellent specificity and sensitivity to detect SCD during newborn screening and shortened health care access for children positive for SCD.

What’s Known on This Subject:

Haiti lacks resources for newborn screening. There is limited but encouraging information about the utility of the rapid test Sickle SCAN in newborn screening.

What This Study Adds:

The 1-year observational study of >2100 newborns provides data about sickle cell incidence in Haiti and validates point-of-care Sickle SCAN in newborn screening. The rapid test shortens the time for children positive for sickle cell disease to receive care.

Newborn screening is 1 of the most important public health initiatives.1,2  In the United States, newborn screening provides a comprehensive testing battery for at least 35 core conditions.3  Sickle cell disease (SCD) is the most common condition diagnosed by newborn screening.

Globally, SCD is also the most common diagnosis identified by newborn screening. Although multiple countries have newborn screening programs, Haiti is not 1 of them. The prevalence of SCD in Haiti lacks large-scale data. However, it is postulated that Haiti has a high incidence of SCD from previous population screening conducted in 1995 at the Hôpital de l’Université d’Etat d’Haiti in Port-au-Prince, which detected SCD in 1.1% of the newborns tested.4  Furthermore, the incidence of SCD may be elevated because >95% of the Haitian population is of African ancestry.5 

Confirming results of children positive for SCD detected by newborn screening requires specific infrastructure, including tracking and notifying families. Because of known social barriers in Haiti such as unreliable addresses, we postulated that a point-of-care (POC) Sickle SCAN (BioMedomics, Inc, Morrisville, NC) would be advantageous because of the immediate screening results obtained at the bedside.

Sickle SCAN is a lateral flow immunoassay test, which detects the presence of normal hemoglobin (Hb) A and the abnormal Hbs S and C.6  In 2018, a French study of 104 newborns revealed that Sickle SCAN was reliable when compared to high-performance liquid chromatography (HPLC).7  Because this information is limited (1 study only with a relatively small sample size), we aimed to independently validate Sickle SCAN for newborn screening in a low-resource setting when compared to gold standard laboratory-based results.

In this observational study, we had 3 main objectives: (1) determine the current incidence of SCD in Haiti in a hospital setting, (2) examine the specificity and sensitivity of Sickle SCAN for newborn screening with a larger sample size than previously studied, and (3) evaluate the impact of the POC scan on health care delivery outcomes (number of days until confirmatory testing, days until first clinic visit and start of penicillin prophylaxis, age when child received first pneumococcal 13-valent conjugate vaccine [PCV13]).

The study was approved by the University of Miami and by the Hôpital Universitaire Justinien (HUJ) ethics committee. HUJ is located in Cap-Haïtien, Haiti’s second largest city. All children born at HUJ were eligible for screening after obtaining verbal consent from their mothers. Trained nurses performed the screening, and community health workers assisted in speaking to families about newborn screening and were available if there was a need to contact the families in the future. A laboratory technician received training in isoelectric focusing (IEF), with equipment obtained for the study. During the first 3 months (August–October 2017), designated here as period 1, we screened exclusively with IEF. Samples were processed according to standard method.8  Thereafter, during period 2, children were screened with both Sickle SCAN and IEF. A total of 360 unselected consecutive newborn screening cards were also reanalyzed at the Bureau of Public Health Laboratories in Jacksonville, Florida (which is the Florida Newborn Screening State Laboratory), to validate the POC results against an established laboratory test performed by experienced personnel. HPLC9  was the method used for quality control and POC validation.

The lateral heel of each infant was cleansed with alcohol solution and punctured to obtain blood drops, which were captured in Guthrie cards, according to well-established procedures.10  Five microliters of blood were then collected with a capillary tube and mixed with a hemolyzing buffer solution, shaking the bottle 3 times as previously described.6  Five drops of hemolysate were placed in the POC well. After 5 minutes, the results were available, detected as distinct Hb bands and a control band. The Sickle SCAN testing was performed at the bedside in the maternity ward. The screening nurse interpreted the POC result and immediately informed the mother. Children who tested positive for SCD were referred to the pediatrician (R.S.F.) for follow-up and were started on penicillin before leaving the hospital. Penicillin is indicated to begin within the first 2 months of life, not necessarily at birth, but we initiated it early to maximize health education as well as to prevent pneumococcal sepsis. In the meantime, the newborn screening cards were allowed to dry for 4 hours before being sent to the HUJ laboratory for analysis.

The possible results of Hb screening by IEF and HPLC were as follows: FA was normal Hb pattern; FAS, sickle cell trait; FAC, Hb C trait; FC, Hb C disease; FS, sickle cell anemia; FSA, sickle β thalassemia +; and FSC, combined heterozygote for Hbs S and C and Hb F for β thalassemia major. Other abnormal Hb variants could be identified, such as Oarab, D, E, and G. The POC results are limited to detect the presence of Hb A, C, and S. Therefore, the possible results were A for normal Hb, AS for sickle cell trait, AC for Hb C trait, C for C disease, S for sickle cell anemia, SC for combined heterozygote for Hbs S and C, and SA for sickle β thalassemia +. In contrast to sickle cell trait (AS), the S band in sickle β thalassemia + is stronger than the A band.

Children who were deemed to have sickle cell hemoglobinopathies (SS, SC, or SA) or Hb C disease were contacted to have confirmatory testing. Confirmatory testing was performed in parallel with both IEF and Sickle SCAN to get more information about the comparison between methods for confirmatory testing.

A clinical diagnosis was given to all children by the pediatric hematologist (O.A.A.) on the basis of the screening and confirmatory results. This doctor remained available for consultation if needed. All children who had SCD were managed by a pediatrician (R.S.F.) and the nurse coordinator (M.V.) and were placed on prophylactic penicillin and received PCV13. Children deemed to have SCD by POC result were placed on penicillin before confirmatory results. Both penicillin and PCV13 were provided free of charge throughout the study.

Demographic and laboratory result data were captured in Research Electronic Data Capture and analyzed by the statistical team from the University of Miami. Descriptive statistics were performed (frequencies, means, SDs). The incidence of SCD (sickle cell anemia or Hb SS, SC, and sickle β thalassemia +) were calculated from the screening frequencies. The hemoglobinopathy incidence was calculated from the IEF results during period 1, taking into consideration screening and confirmatory testing. The hemoglobinopathy incidence was calculated from POC and confirmatory testing during period 2 because the POC test was the best comparator against the HPLC. χ2 test, Fisher’s exact test, t test, and Wilcoxon rank test were used to compare variables between period 1 and period 2 when appropriate. P values <.05 were considered significant. The specificity and sensitivity of Sickle SCAN, using Florida HPLC as the gold standard, were calculated along with their 95% confidence intervals.11  The POC sensitivity is its ability to correctly identify those with SCD (true-positive rate). The POC specificity is its ability to correctly identify those without the disease (true-negative rate). A receiver operating characteristic curve was plotted versus HPLC, and the area under the curve was calculated.12 

We screened 2159 children during a 1-year period (August 2017–August 2018), including the first 734 newborns (one-third of the total) who were screened with the single method IEF. All mothers agreed to screen their children, resulting in 100% acceptability. Of those screened, 53% were boys and 47% were girls. All children were of black race. The mean chronological age at screening was 0.41 days (0–64 days of age). Two of the infants screened were >30 days of age, and they were screened after discharge from the nursery because of their mothers’ decision when they learned screening was being conducted. None of the infants were transfused before screening.

The incidence of hemoglobinopathies was a study objective. Figure 1 reveals the screening results with corresponding confirmatory testing. From the total 2159 infants, 19.8% had the presence of an abnormal Hb. Ten children did not have conclusive results because the POC and IEF gave different results that could not be repeated. Sickle cell trait (Hb AS) was detected in ∼14% of children screened. The other Hb traits were 2 Hb D trait and 1 Hb E trait detected by IEF. There were 6 children who screened positive for Hb C by IEF, but none proved to have Hb C by confirmatory testing. SCD was suspected in 1.48% of the children screened, including positive screening for Hb SS, Hb SC, and sickle β thalassemia +. Confirmatory testing revealed that 1 in 120 (0.83%) children had SCD, including sickle cell anemia (13 children [0.60%]) and Hb SC (5 children [0.23%]). All children who had positive screening for sickle β thalassemia + (n = 11) were found to have sickle cell trait on confirmatory testing. All 18 children with SCD (mean age 8 ± 0.8 months [range 4–15 months]) were managed in the program at the time of data analysis (December 2018).

FIGURE 1

Newborn screening flowchart. The total number of children in each category (n) and the percent of children from the total number screened are included.

FIGURE 1

Newborn screening flowchart. The total number of children in each category (n) and the percent of children from the total number screened are included.

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The POC and IEF were compared with each other at the time of screening and at the time of confirmatory testing. Each method was compared to HPLC as the gold standard. The positive predictive value and the negative predictive value of the POC were 0.47 (confidence interval [CI] 0.24–0.71) and 1.00 (CI 0.98–1.00), respectively. We could not achieve meaningful comparisons between IEF and POC because of IEF variability. When we compared the screening results of Sickle SCAN to HPLC, the specificity, sensitivity, and area under the curve of the receiver operating characteristic were 0.97 (CI 0.95–0.99), 0.90 (CI 0.55–1.00), and 0.936, respectively.

Minimizing delays in contacting families and how this impacted health care access were study outcomes. Thus, we introduced POC as a way to identify children faster and avoid delays notifying families. Table 1 shows the differences between the 2 periods (IEF alone and POC plus IEF) regarding health care access (number of positive results, time to obtain results, first visit to the pediatric clinic to establish care, and first PCV13 administered). The number of days it took to initiate penicillin prophylaxis is not included on the table. However, penicillin was started after knowledge of the positive results by POC scan and no later than the first day to attend the pediatric clinic in the case of children who were only tested by IEF.

TABLE 1

Differences in Test Results and Health Care Access With and Without POC Use

VariableIEF Only (N = 734)POC First (N = 1372)P
Children with positive SCD screening, n (%) 41 (5.6) 23 (1.7)a <.001b 
Children with confirmatory testing, n (% of the total who screened positive for SCD) 31 (75.6) 20 (86.9) .35c 
Children confirmed with SCD, n (%) 3 (9.7) 15 (75) <.001c 
Days to obtain screening results for children with positive screening, mean ± SD 60 ± 20 with IEF 35 ± 29 with IEF same day as POC screening <.001d 
Days from positive screening results to confirmatory results, mean ± SD 79 ± 37 with IEF 46 ± 37 with IEF same day as POC screening .001d 
Days from screening to first pediatric clinic visit, median (IQR) 39 (36.5–126.5) 1 (1–4) .02de 
Age when children with SCD received their first PCV13, median (IQR), mo 6 (5–7) 2 (2–3) — 
VariableIEF Only (N = 734)POC First (N = 1372)P
Children with positive SCD screening, n (%) 41 (5.6) 23 (1.7)a <.001b 
Children with confirmatory testing, n (% of the total who screened positive for SCD) 31 (75.6) 20 (86.9) .35c 
Children confirmed with SCD, n (%) 3 (9.7) 15 (75) <.001c 
Days to obtain screening results for children with positive screening, mean ± SD 60 ± 20 with IEF 35 ± 29 with IEF same day as POC screening <.001d 
Days from positive screening results to confirmatory results, mean ± SD 79 ± 37 with IEF 46 ± 37 with IEF same day as POC screening .001d 
Days from screening to first pediatric clinic visit, median (IQR) 39 (36.5–126.5) 1 (1–4) .02de 
Age when children with SCD received their first PCV13, median (IQR), mo 6 (5–7) 2 (2–3) — 

IQR, interquartile range; —, not applicable.

a

In addition, during the dual screening, there were another 9 children who had positive screening for SCD by IEF but not by POC scan. All were called except 1, and they were all negative for SCD.

b

χ2 test.

c

Fisher’s exact test.

d

t test.

e

Wilcoxon rank test.

During period 1, we had significant delays in contacting families. The first child who was identified with sickle cell anemia was actually started on penicillin at 7 months of age. The reasons contact with the family were delayed were multiple and included the need to repeat the IEF several times to get reliable results. Furthermore, the number of false positives was high when compared to the results obtained at the time of confirmatory testing. Before dual screening, 25% of children positive for SCD (28% of children if we add the children who screened positive for Hb C disease) could not be contacted for confirmatory testing. From a total of 41 children who were thought to have SCD, 31 came back and only 3 had positive confirmatory testing. In addition, 2 children were already dead when the nurse coordinator (M.V.) contacted the families: 1 screened positive for FS and the other child screened positive for FC.

During period 2, 1425 infants were eligible for screening using POC. However, POC was not available at the study site to screen 53 of those children. In total, 1372 infants were screened with POC and 23 had a positive screening for SCD. During period 2, the nurses provided immediate test results to the mothers because the POC results were available within 5 minutes. Once the children screened positive (FS, FSC, or FSA), they were referred to the pediatric clinic and, pending confirmatory results, started on penicillin V potassium 125 mg orally twice a day, given as crushed half tablets mixed with milk. After the dual testing was introduced, only 3 children (2 with FSA and 1 with FS) did not have confirmatory testing for SCD, reducing the percent of children not found or unable to return to 13%. Thus, the confirmatory testing rate (children returning for confirmatory testing) improved from 75% to 87% after the introduction of POC.

Pediatricians have an important role in global health with the purpose of reducing health disparities.13  In this spirit, we started an international collaboration with a Haitian team (R.S.F., M.V., and U.L.).

Our first objective was to establish the incidence of SCD in our sampled population. In our study, the incidence of SCD among infants tested in Cap-Haïtien was 0.83%. This incidence is higher than among children in the United States. Among African American children, the incidence is 1 in 365 births or 0.27% births.14  Previously, we (O.A.A., T.H.) studied the incidence of SCD among infants born in Florida from 2002 to 2007, finding an incidence of 1 of 226 (0.44%) among the people of color and African American category.15 

Previous studies conducted in Port-au-Prince, Haiti, revealed a higher incidence than in the United States. In 2010, 0.58% of the newborns screened positive for SCD at St. Damien Hospital in Port-au-Prince.16  It is important to underscore that in this latter study, the screening tests were not performed in Haiti but rather were performed in Italy by HPLC. Before, in 1995, Fleurival4  performed cellulose acetate electrophoresis to analyze newborn specimens, finding a 1.1% incidence among 1000 newborns screened at the Hôpital de l’Université d’Etat d’Haiti in Port-au-Prince. Cellulose acetate is not a sensitive test for newborn screening, and other methods like IEF, HPLC, or capillary electrophoresis are preferred. Therefore, ours is the first study performed with laboratory testing conducted in Haiti using sensitive tests for newborn screening and performed by Haitians.

Our second objective was to validate the POC Sickle SCAN for newborn screening in a large sample size. In the United States and other developed countries, newborn screening is an essential universal practice to detect many genetic conditions that need immediate medical attention to minimize morbidity and mortality. The laboratory equipment employed in newborn screening is expensive, and the result turnaround time is generally acceptable. There is also infrastructure in place to notify families of children with positive screening. These challenges in low-income settings could be circumvented, at least partially, with POC devices.

There are different sickle cell POC devices that are either based on an immune assay or are paper-based. The lateral flow immunoassay device Sickle SCAN was validated for children and adults.6  Moreover, children and adults were screened in Togo, Mali,17  and Tanzania18  with excellent results, making it an attractive method for rapid screening. Recently, authors of a French study sponsored by BioMedomics, the company that manufactures Sickle SCAN, validated this POC device in a small sample of 104 newborns.7  In the current study, we validated this device in a larger sample size in a low-resource country. The HemoTypeSC is another lateral flow immunochromatographic test strip, which was studied in the Caribbean and in the United States. In contrast to Sickle SCAN, the absence of bands indicates positive results, which, in our opinion, makes the results more difficult to interpret.19,20  The other type of sickle cell POC device is paper-based.21  The blood sample is hemolyzed, and the hemolysate is placed on chromatography paper. The characteristic bloodstain pattern, indicative of the presence or absence of Hb S in the blood sample, is formed by polymerized deoxy-Hb S, which gets trapped in the pores of the chromatography paper while the soluble Hb stays toward the periphery. The Hb red color is enough for visual evaluation of the bloodstain pattern. Otherwise, a scanner interprets the color intensity and provides a reading, differentiating normal Hb A from sickle cell trait or disease. The paper-based POC device was tested in a cohort of 159 newborns in Angola.22  The screening test detected the presence of Hb S. However, the test could not differentiate between sickle cell trait and SCD in newborns; thus, it requires a laboratory test for diagnosis.22 

Our third objective was to evaluate the impact of the rapid test on health care delivery outcomes. The POC achieved shorter time to obtain confirmatory testing, implement penicillin prophylaxis, engage children in health care, and receive PCV13; thus, the POC impacted health care delivery. All of these outcomes were considered meaningful to protect children with SCD from infection because of earlier parental education about SCD and the implementation of preventive interventions.

There were several barriers identified during the study: First, material procurement was difficult with some delays. The laboratory and newborn screening materials were shipped from the United States to Haiti, and occasionally there were delays and lack of materials between shipments. After paired screening testing was implemented, 1 of the methods was frequently missing (29.7% of the times, we had only Sickle SCAN but no IEF testing result, and only 3.7% of the time, we had IEF testing without Sickle SCAN rapid test). Nevertheless, a screening test was always available. The second barrier identified was malfunction of the IEF machine. There were several months when the machine was not functioning. This was attributed to equipment damage due to frequent power outages. Furthermore, some of the blood spots were exposed to excessive heat, and Hb could not be eluted out of the Guthrie cards.

This observational study has limitations, especially related to IEF results, underscoring the challenges encountered in low-resource settings. The time to perform IEF significantly improved between periods 1 (79 days) and 2 (46 days), although it was longer than generally expected in the United States (∼1 week). Although the IEF results were not as reliable as the POC results, we believe that a laboratory test is still necessary to identify other hemoglobinopathies that cannot be detected by the POC device. We learned from this experience and will implement several changes in the future: (1) installation of surge protection to prevent the IEF machine from malfunctioning, (2) strict retraining of laboratory personnel, and (3) quality assurance backup from another hemoglobinopathy laboratory. We also favor IEF over HPLC despite limitations because of the higher cost associated with HPLC in a low-resource setting.

Our results revealed high sensitivity and specificity for Sickle SCAN when used in newborn screening. Because of rapid results, the use of this POC device facilitates starting penicillin and providing immediate parental education. We conclude that Sickle SCAN is the preferred method for newborn screening in our study and that the reliability of this test is comparable to HPLC. Therefore, this method is ideally suited for low-resource settings.

We thank our sponsor Dr Larry Pierre, director of the Center for Haitian Studies in Miami, Florida, who believed in this work and generously supported us. We also thank Drs Jean Geto Dubé and Jean Gracia Coq, directors of HUJ, and Dr Robert Ernst Jasmin, director of the North Department Ministry of Health, for their willingness to accept this research at HUJ. We greatly appreciate the support received from the Florida Newborn Screening Program in providing the HPLC testing. We are indebted to our 2 newborn screening nurses Ms Myrline Blot and Ms Chantal Obas who performed the newborn screening. Finally, we owe inspiration for the newborn screening work to the former members of the Haiti Project Family Medicine Program at the University of Miami: Drs Arthur Fournier, Michel Dodard, and André Vulcain, who believed SCD was an important condition to explore in Haiti.

Dr Alvarez conceptualized and designed the study, supervised study procedures, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Saint Fleur supervised study procedures and collected data; Ms Hustace conceptualized the study, trained personnel, and reviewed the manuscript; Ms Voltaire and Mr Liberus collected data; Mr Mantero analyzed the data; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-1681.

FUNDING: Supported by a gift from the Center of Haitian Studies, Miami, Florida.

     
  • CI

    confidence intervals

  •  
  • Hb

    hemoglobin

  •  
  • HPLC

    high-performance liquid chromatography

  •  
  • HUJ

    Hôpital Universitaire Justinien

  •  
  • IEF

    isoelectric focusing

  •  
  • PCV13

    pneumococcal 13-valent conjugate vaccine

  •  
  • POC

    point-of-care

  •  
  • SCD

    sickle cell disease

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Alvarez has been an advisory board member for Novartis related to drugs tested or used in patients with sickle cell disease; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.