Our aim was to determine the risk of specific acute events in patients with sickle cell disease based on early or late initiation of intervention. We found that the risk of ACS and VOC were substantially and significantly lower among children for whom care was initiated prior to age five months. However, the risk of ASS and infection did not differ significantly between groups. A comparison of morbidity in children with early and late treatment initiation was only found in one previous study by Vichinsky, carried out in Oakland, California, United States of America. [17] The findings of this study differed to ours; in the former study no differences were found in in the number of life-threatening events in patients who were identified in the NBS program compared to those diagnosed after three months. Differences in the method between studies included the fact that the time chosen as the cut point between groups was earlier than that selected in our study. Additionally, while in our study the milder genotype of haemoglobin SC was not included, this genotype was included in the group identified by newborn screening in the study being compared. Patients with Haemoglobin SC were not considered to have the same baseline risk as patients with HbSS of developing the outcomes of interest and therefore would make comparison between early and late groups difficult.
We also found that VOC and ACS accounted for the vast majority of events and occurred with high rates in our study. The incidence rate of VOC in both early and late presenters in event per person- years that was found in our study was very similar to that found in a larger study, where the incidence rates of VOC was 0.8 episode per patient-year in HBSS and 1.0 episode per patient-year in sickle beta 0-thalassemia in a group of patients ranging from newborn to 66 years of age [18]. This study found additionally, that the number of pain episodes per year was associated with early deaths in patients over 20 years of age who have sickle cell disease. This suggests that a high degree of morbidity can be averted with early initiation of care. These rates concur with VOC being the most common event experienced by children with SCD in other settings [19, 20].
Acute chest syndrome was the second most common event in both groups. The longitudinal Jamaican Cohort Study found ACS to be a major cause of death in persons with sickle cell disease in all age groups [7]. Reducing the incidence of both of these events by early interventions offered at a specialist center may therefore reduce substantial morbidity and mortality in Jamaica and other regions of the world with high prevalence of SCD even in populations without access to chronic transfusion therapy or hydroxyurea.
There was no difference in the severity of these events as evidenced by morbidity indicators such as frequency of admissions, ACS requiring oxygen, number of events that require strong opioids and the proportion of ASS requiring transfusion. This could indicate that while the incidence of events were significantly different between groups the severity were similar.
The number of episodes of ASS, though relatively less frequent was far more frequent in our study compared to a previous study in California where there was only 10 episodes over a longer study period [17]. Even though there was no significant reduction in the incidence of ASS in the early group, previous studies have shown that educating parents to palpate for the spleen daily has reduced mortality [5].
The number of confirmed cases of infections in both groups was small and similar to that seen in the study referred to previously [17]. Specifically, there were no cases of haemophilus influenza type B and the only case of Pneumococcus was not from the early group. It was possible that some patients may have received antibiotics before presentation to hospital which may have led to negative cultures being obtained.
Our study also highlights the finding that nearly two-thirds of the patients who presented late were actually screened for sickle cell disease (SCD) as newborns. Of 290 patients included in the study most were screened for SCD at birth including 64% of the “late” group. This indicates that even though children were identified as having SCD at birth via NBS and referred to SCU, they did not report for the first visit. This may have been due to challenges with contact tracing which reduced early enrolment of infants for example incorrect or indecipherable addresses and telephone numbers, or the family’s reluctance to follow-up when contacted, hence the reason for “late” entry into care at a specialist center. Despite resource constraints during the study period, the SCU attempted to trace infants who had a positive screening result. However, there is now a robust national newborn screening programme in Jamaica since 2015 of all births. Additionally the ability to trace patients has increased considerably through a national network. Newborn screening coverage in Jamaica increased to 98% of births after 2015, but it is reportedly as low as 45% in other Caribbean countries [21] and still non-existent in others.
There is need for more aggressive efforts to trace infants diagnosed with SCD and enroll them into care in a timely manner. The study demonstrates that early enrolment and subsequent early initiation of care may be an additional benefit and can only be successful if affected newborn babies are identified and parents present to and remain under the care of medical facilities with the capacity to offer lifesaving interventions. Implementation and expansion of NBS therefore needs to be accompanied by stronger linkage and retention programs for parents and their children if the demonstrated benefits of NBS [5] are to be fully realized. There is on-going work to improve linkage and retention programs for parents and their children such as training of health care workers across the island to assist in early enrolment of infants who are positive at NBS screening. Additionally, a status card will be added shortly to the health passport that is given to each infant at birth.
In spite of these challenges, survival estimates with SCD have improved over recent years [5]. In fact, mortality in children less than 5 years of age with SCD diagnosed at birth and managed at specialist care center in Jamaica is no worse than that of the general population [15]. Our retrospective cohort data provide part of the evidence for how this has been achieved, and how incremental improvements can be made and monitored. The risk of acute events in children with sickle cell disease exposed to early intervention was found to be significantly less. Therefore, widespread screening with rapid referral to a specialist center stands to reduce substantial morbidity in Jamaica and other regions with high prevalence of sickle cell disease. The authors suggest that this may be because physicians at specialist centers are able to monitor patients regularly and intervene with preventive and management options early and also because the physician can communicate with the parents/family on a regular basis and is able to encourage them to monitor the child and to seek care immediately.
Limitations
Of note, approximately, 20% of hospital notes were not accessed for reasons which included unavailability at the time of data entry and lack of resources to retrieve further data. These omissions would more likely under count incidences of events, thus the results presented here are conservative. In some settings radiographical support was not easily accessed and microbial culture reports were not available to confirm ACS or infections. The number of ASS events and infection cases were low which may have impacted the power of the statistical analyses.