Main content

Sickle-cell disease (SCD) is an auto­somal, recessive haemoglobinopathy and multisystem disorder character­ised by episodes of vaso-occlusion, ongoing haemolytic anaemia and progressive organ failure. It is the most common monogenetic dis­ease worldwide with an estimated 350.000 births annually affected and recognised as a global public health problem by the World Health Organization (WHO).[1] The global distribution of the sickle haemo­globin (HbS) allele is indicative of the protective effect of sickle cell trait (HbAS) against Plasmodium falciparum malaria, first described by Haldane in 1949.[2,3,4] However, migration from malaria-endemic regions to Northern America, West­ern Europe and Australia has led to spreading of the HbS allele far beyond its origin.[5] Roughly 2500 individuals in the Netherlands cur­rently have SCD, of which 1000 are children, and the carrier incidence is 0.4%.[6] Most of those affected are of Surinamese, Asian or African ancestry, with a minority being of Afro-Caribbean or Middle Eastern descent.[7]

Seventy five percent of the global burden of SCD occurs in sub-Saharan Africa, where the majority of children with the disease do not reach their fifth birthday.[1,8] In contrast, the life expectancy in well-resourced countries has signifi­cantly improved with almost all infants now expected to survive into adulthood because of comprehensive care pro­grams.[9,10] However, the average life ex­pectancy of patients with SCD is still 20 years less than that of healthy adults.[11]

This article aims to provide insight into the characteristics of routine compre­hensive care for patients with SCD in the Netherlands, with a special focus on paediatric aspects. It does not, however, provide a summary of the management of SCD, which is excellently reported in the guideline of the National Heart Lung and Blood Institute (NHLBI).[12]

Neonatal screening

Prompt diagnosis is the first step in improving treatment outcomes of individuals with SCD. Early diagno­sis, before clinical symptoms occur, allows for the enrolment in compre­hensive care programs and education of parents on the recognition of danger signs and importance of vaccina­tions and prophylactic antibiotics.

Increased migration from sickle-cell endemic countries to the Netherlands resulted in initiation of a universal newborn screening program for SCD in the Netherlands on 1 January 2007.[13] Diagnosis is established by high-­performance liquid chromatography (HPLC), which has a high sensitivity and specificity and a positive predictive value of 100%. In addition, only a small blood sample is required and other inherited blood disorders such as severe α- and β- thalassemia are concomi­tantly diagnosed by this method.[14]

When a carrier of HbS is identified, both parents and the general practitio­ner (GP) receive a letter explaining the test results, except for parents who have indicated that they do not want to be in­formed about the carrier status of their child (opting out). Parents are then invit­ed for an informative consultation about SCD and carriership. GPs are advised to emphasise the importance of testing both parents for haemoglobinopathies and to refer couples at-risk to a clinical geneticist. Knowledge of this risk allows for a range of options, including prena­tal diagnosis and limiting of family size.

Vaccination and anti-biotic prophylaxis

Children with SCD are particularly at increased risk of severe bacterial infections due to an impaired splenic function. Prior to the initiation of neonatal screening for SCD, infection by encapsulated organisms was the lead­ing cause of death in afflicted children.[16] In addition to routine courses of immunisations according to national schedules, yearly vaccinations against influenza from the age of 6 months are administered as well as repetitive pneu­mococcal vaccinations. Furthermore, all SCD patients receive twice-daily prophylactic penicillin from the age of 4 months until their twelfth birthday.

However, one-third of the children newly diagnosed with SCD are immigrants and not born in the Nether­lands.[5] Unfortunately, those children are not systematically screened for haemoglobinopathies and are therefore at high risk of life-threating complica­tions before the diagnosis SCD has been made. This is a disparity in healthcare and therefore the initiation of other screening programs is currently being considered (i.e., in health screening package offered to immigrants).

Specialised sickle- cell clinics

It is recommended that all patients diagnosed with SCD are referred to a (paediatric) haematologist with exper­tise in haemoglobinopathies to ensure good quality of care. Comprehensive medical care for SCD has significantly decreased morbidity and prolongs life expectancy for patients.[16] The Neth­erlands has specialised (paediatric) haematologists in all academic centres. Those centres are equipped with a dedicated sickle-cell care team consist­ing of a (paediatric) haematologist, sickle-cell nurse, clinical geneticist, social worker and psychologist, working closely with a variety of sub-specialisms with expertise in SCD (e.g. neurology, cardiology, pulmonology, nephrology, ophthalmology, orthopaedics). This multidisciplinary approach allows for comprehensive, family-centred care for children and adults with SCD. Unfor­tunately, an extensive analysis of Dutch paediatric SCD patients showed that not all children are provided with such care.[6] This could be due to insufficient access to the Dutch healthcare system by minorities or potential unaware­ness among health professionals of the importance of comprehensive care for ‘less severe’ SCD. Regarding the latter, it is of the utmost importance to identify patients and to establish col­laborations between paediatricians and haematologists with less expertise on the one hand and specialists in com­prehensive care centres on the other, in order to provide the best care possible given current scientific knowledge.

Multiple sickle cells in a blood smear

Comprehensive medical evaluations

In summary, all paediatric and adult SCD patients need at least half-yearly scheduled medical evaluations to document baseline physical findings, including blood pressure and peripheral oxygen saturation and the evaluation of growth and development, as well as yearly sampling of blood and urine to detect organ failure. In addition, patients are monitored for complications of SCD including transcranial Doppler (TCD) ultrasonography (due to the high incidence of cerebral infarction [17]) and dilated eye examination (to screen for proliferative retinopathy). If the course of disease is severe or symptoms of deterioration or organ failure occur, treatment is intensified (hydroxyurea, blood- or exchange transfusions) and patients are immediately referred to sub-­specialists with SCD expertise. Further­more, patients and their parents are also followed with regard to quality of life by using validated questionnaires. The results are then integrated in clinical practice to address psychosocial issues in an efficient and effective manner.

Sickle cell outcome research (score)

The Dutch SCORE consortium was founded in 2016 and is composed of (paediatric) haematologists from seven comprehensive sickle-cell centres (Amsterdam, Rotterdam, Leiden, The Hague, Utrecht, Nijmegen and Groningen). SCORE is designed as a multicentre, prospective cohort study which aims to include the majority of SCD patients in the Netherlands. The goal of the collaboration is to identify factors and biomarkers contributing to the morbidity and mortality of SCD by uniformly collecting data. The research focuses on combining doctor-reported outcome measures (measures assessed by physicians, also called clinical data) with outcome measures from the pa­tients’ perspective, also called PROMs (patient reported outcome measures) and PREMs (patient reported experi­ence measures). By incorporating the patients’ and families’ values, beliefs and cultural norms, the impact of treat­ment and care can be fully evaluated.

Conclusion

Comprehensive care for patients with SCD is a time-intensive endeavour that includes neonatal screening, vaccina­tion and antibiotic prophylaxis, periodic evaluations with screening for complica­tions, and ongoing education of patients and relatives in specialised sickle-cell centres. Nevertheless, even with the best care, many SCD patients still face a lifetime of complications. Method­ologically sound research is needed to address evidence gaps and improve our understanding of the best care for these patients. The SCORE initiative hopes to unravel the heterogeneity of the disease and to assess the impact of SCD on the wellbeing of patients and their families.
CORRESPONDING AUTHOR: M.HOUWING@ERASMUSMC.NL

References

  1. Piel FB, Hay SI, Gupta S, Weatherall DJ, Wil­liams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLOS Medicine 2013;10:7.
  2. Allison AC. Protection Afforded by Sickle-cell Trait Against Subtertian Ma­larial Infection. BMJ 1954;1:290-4.
  3. May J, Evans JA, Timmann C, Ehmen C, Busch W, Thye T, Aqbenyega T, Horstmann RD. He­moglobin variants and disease manifestations in severe falciparum malaria. JAMA 2007;297:20.
  4. Haldane, JBS. Disease and evolution. Supple­ment to La Ricerca Scientifica 1949;19.
  5. Piel FB, Tatem AJ, Huang Z, Gupta S, Wil­liams TN, Weatherall DJ. Global migration and the changing distribution of sickle haemoglo­bin: a quantitative study of temporal trends between 1960 and 2000. Lancet 2014;2:2.
  6. Peters M, Fijnvandraat CJ, van den Tweel XW, Garre FG, Giordano PC, van Wouwe JP, Rodriques Pereira R, Verkerk PH. One-third of the new paediatric patients with sickle cell disease in The Netherlands are immigrants and do not benefit from neonatal screening. Arch Dis Child 2010;95:10.
  7. Suijker MH, Roovers EA, Fijnvandraat CJ, Dors N, Rodriques Pereira R, Giordano PC, Verkerk PH, Peters M. Haemoglobinopathy in the 21st cen­tury: incidence, diagnosis and heel prick screen­ing. Ned Tijdschr Geneeskd 2014;158: A7365.
  8. McGann PT, Hernandez AG, Ware RE. Sickle cell anemia in sub-Saharan Africa: advanc­ing the clinical paradigm through partner­ships and research. Blood 2017;129:2.
  9. Quin CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood 2010;115:17.
  10. Van der Plas EM, Van den Tweel XW, Geskus RB, Heijboer H, Biemond BJ, Peters M, Fijnvandraat CJ. Mortality and causes of death in children with sickle cell disease in the Netherlands, before the introduc­tion of neonatal screening. Br J Haematol 2011;155:1.
  11. Gardner K, Douiri A, Drasar E, Allman M, Mwiriqi A, Awoqbade M, Thein SL. Surviv al in adults with sickle cell disease in a high-income setting. Blood 2016;128:10.
  12. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:10.
  13. Bolhuis PA, Page-Christiaens GC. The advisory report ‘Neonatal screening’ from the Health Council of the Netherlands. Ned Tijdschr Geneeskd 2005;149:2857-60.
  14. Giordano PC. Starting neonatal screen­ing for haemoglobinopathies in The Neth­erlands. J Clin Pathol 2009;62:18-21.
  15. Onwubalili JK. Sickle-cell anaemia: an ex­planation for the ancient myth of reincarna­tion in Nigeria. Lancet 1983;27:2.
  16. Vichinsky EP. Comprehensive care in sickle cell disease: its impact on morbidity and mortality. Sem Hematol 1991;28:3.
  17. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:1.