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Improved survival in homozygous sickle cell disease: lessons from a cohort study

^a MRC Laboratories (Jamaica), University of the West Indies, Kingston, Jamaica

Correspondence to: Professor G Serjeant.

Abstract

Objective: To examine whether simple interventions in a sickle cell clinic improve survival in sickle cell disease.
Design: Survival curve analysis and hazard ratios in a cohort study followed from birth.
Setting: MRC Laboratories (Jamaica) at the University of the West Indies, and Victoria Jubilee Hospital, Kingston, Jamaica.
Subjects: 315 patients with homozygous sickle cell disease detected during the screening of 100000 consecutive non-operative deliveries between June 1973 and December 1981 at the main government maternity hospital, Kingston, Jamaica.
Interventions: Prophylactic penicillin to prevent pneumococcal septicaemia, parental education in early diagnosis of acute splenic sequestration, close monitoring in sickle cell clinic.
Main outcome measures: Survival.
Results: Survival appeared to improve, the log rank test for trend comparing the first, second, and last third of the study reaching borderline significance (P=0.05). Combined deaths from acute splenic sequestration and pneumococcal septicaemia-meningitis declined significantly (test for trend, P=0.02).
Conclusion: Early diagnosis and simple prophylactic measures significantly reduce deaths associated with homozygous sickle cell disease.

Introduction

The debate on bone marrow transplantation in the treatment of homozygous sickle cell disease has highlighted the need for assessing alternative approaches.^{1 2 3} Bone marrow transplantation is an expensive, high technology procedure applicable only to the approximately 20% of patients with an identical HLA matched sibling⁴ and carries a short term mortality of around 10%. At a conservative cost of $100000 per patient it is unlikely to be applicable on a population basis especially in countries with limited resources where most sickle cell disease occurs. An alternative approach is the assessment of simple measures to prevent the high early mortality of the disease.⁵ These include prophylactic penicillin,^{6 7} parental education of acute splenic sequestration,⁸ better understanding of the pathogenesis and treatment of aplastic crisis,⁹ more effective treatment of the acute chest syndrome,^{10 11} earlier intervention after neonatal diagnosis, and coordinated management in dedicated sickle cell clinics. These measures are likely to diminish morbidity and improve survival, but their effects have not been documented until this assessment in the Jamaican cohort study of sickle cell disease.

Patients and methods

The patients attended the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica, and participated in a cohort study of all people with sickle cell disease born among 100000 consecutive non-operative deliveries at the government maternity hospital (Victoria Jubilee) between June 1973 and December 1981. Screening identified 315 babies with homozygous sickle cell disease, of whom eight failed to be admitted to the study. The 307 remaining patients were followed as described¹² and defaulting patients actively traced. Diagnostic criteria have been described previously.¹³

To assess changing survival the 315 children were divided into three equal groups of 105 children born between 25 June 1973 and 27 December 1975 (30 months), 28 December 1975 and 2 January 1979 (36 months), and 3 January 1979 and 28 December 1981 (36 months). Mortality was assessed with survival curve analysis by using the product limit method. Survival was examined from birth to the 15th birthday, and survival curves for each third were compared by using the log rank test for trend. Hazard ratios were calculated with Cox's proportional hazards model.

The cause of death was determined by necropsy in 54/61 deaths. Cases with multiple diagnoses were arbitrarily assigned to the perceived more serious event. Two cases with acute splenic sequestration and blood cultures that yielded positive results were attributed to septicaemia, and in one with the acute chest syndrome and acute splenic sequestration review suggested that the chest pathology led to death.

Results

There were 61 deaths before 15 years of age, 28 in the first third, 17 in the second third, and 16 in the last third; the log rank test for trend being of borderline significance (P=0.05). Table 1 summarises the probability of cumulative survival in the three groups, and the figure shows the survival curves. The hazard ratio (95% confidence interval) for adjacent thirds was 1.37 (1.00 to 1.88).

Table 1--Cumulative survival* in homozygous sickle cell
 disease according to date of birth. Figures are proportion
 surviving (95% confidence intervals)
---------------------------------------------------------------------------------
              First third           Second third              Last third
Age       (June 1973-December   (December 1975-January   (January 1979-December
(years)          1975)                 1979)                    1981)
---------------------------------------------------------------------------------
1         0.90 (0.85 to 0.96)    0.97 (0.94 to 1.00)      0.95 (0.91 to 0.99)
2         0.86 (0.80 to 0.93)    0.95 (0.91 to 0.99)      0.94 (0.90 to 0.99)
3         0.83 (0.75 to 0.90)    0.93 (0.88 to 0.98)      0.93 (0.88 to 0.98)
5         0.81 (0.73 to 0.88)    0.91 (0.86 to 0.97)      0.91 (0.86 to 0.97)
10        0.77 (0.68 to 0.85)    0.85 (0.78 to 0.92)      0.87 (0.80 to 0.93)
15        0.73 (0.64 to 0.81)    0.83 (0.75 to 0.90)      0.84 (0.77 to 0.91)
---------------------------------------------------------------------------------
*Total deaths were 28 in first third; 17 in second third; 16 in last
third.

The principle causes of death (table 2) in the first group were septicaemia-meningitis, the acute chest syndrome, and acute splenic sequestration. As acute splenic sequestration and pneumococcal septicaemiameningitis were the two common complications in which specific interventions were used, these were combined for analysis and together showed a significant decline in mortality during the study (test for trend, P=0.02; table 3). The hazard ratio (95% confidence interval) for adjacent thirds of the study was 2.40 (1.11 to 5.19). No change was observed in the numbers with the acute chest syndrome. In seven patients without necropsy the cause of death was unknown and could not be assumed from the history by family interview. One child died aged 7 years, three years after splenectomy for hypersplenism, having defaulted without pneumococcal prophylaxis; the history of fever and premonition of death was consistent with septicaemia. Two others died with high fever and four suddenly but without known cause.

Table 2--Causes of death according to date of birth
--------------------------------------------------------------------------------------------------
                                 First third           Second third               Last third
                             (June 1973-December   (December 1975-January   (January 1979-December
Diagnosis                          1975)                 1979)                     1981)
--------------------------------------------------------------------------------------------------
Acute splenic sequestration          5                     2                         1
Acute chest syndrome                 5                     5                         6
Gastroenteritis                      3                     0                         0
Septicaemia-meningitis:
  Pneumococcal                       4                     1                         1
  Salmonella                         2                     0                         1
  Haemophilus influenzae             0                     0                         3
  Unknown organism                   2                     0                         0
Stroke                               4                     2                         2
Aplastic crisis                      1                     0                         1
Portal vein thrombosis               0                     1                         0
Unknown                              2                     4                         1
Motor vehicle accident               0                     2                         0
--------------------------------------------------------------------------------------------------
Total                               28                    17                        16

Table 3--Cumulative survival in homozygous sickle cell
disease according to date of birth (deaths from acute
splenic sequestration and pneumococcal meningitis-septicaemia
only). Figures are proportion surviving (95%
confidence intervals)
--------------------------------------------------------------------------------
              First third           Second third              Last third
Age       (June 1973-December   (December 1975-January   (January 1979-December
(years)          1975)                 1979)                    1981)
--------------------------------------------------------------------------------
1         0.96 (0.92 to 1.00)    0.99 (0.97 to 1.00)      0.99 (0.97 to 1.00)
2         0.94 (0.89 to 0.99)    0.98 (0.95 to 1.00)      0.99 (0.97 to 1.00)
3         0.93 (0.88 to 0.98)    0.98 (0.95 to 1.00)      0.99 (0.97 to 1.00)
5         0.92 (0.86 to 0.97)    0.98 (0.95 to 1.00)      0.98 (0.95 to 1.00)
10        0.91 (0.85 to 0.97)    0.97 (0.93 to 1.00)      0.98 (0.95 to 1.00)
15        0.91 (0.85 to 0.97)    0.97 (0.93 to 1.00)      0.98 (0.95 to 1.00)

Discussion

There seems to be a trend of improved survival of cohort study children with sickle cell disease and, in particular, a significant trend of reduced mortality from acute splenic sequestration and pneumococcal septicaemia-meningitis combined. The decreased number of deaths from pneumococcal disease followed an apparently successful trial of pneumococcal prophylaxis,⁶ although mortality in the United States declined before widespread use of penicillin, possibly reflecting greater awareness, earlier diagnosis, and more prompt treatment.¹⁴ Latterly, Haemophilus influenzae was a more common agent consistent with a recognised susceptibility¹⁵ and suggesting the need for specific prophylaxis against this organism. Reduction in deaths from acute splenic sequestration probably resulted from both parental detection of the first episode⁸ and prophylactic splenectomy after two serious attacks, which together have reduced mortality from this complication by about 90%. The acute chest syndrome remains an important problem and, although aggressive transfusion treatment may reverse acute pulmonary sequestration in some cases,^{10 11} no decline in incidence was observed. Stroke has also shown no change and, although chronic transfusion may reduce the incidence of recurrence,¹⁶ nothing can yet be done to prevent the initial stroke. The aplastic crisis is a cause of death where reduced mortality might be expected as the epidemiology is well known, the clinical course benign and predictable if oxygen carriage is maintained by transfusion, and virtually all cases are caused by human parvovirus infection, auguring well for a vaccine, which is currently under development.

View larger version (13K): [in this window] [in a new window]   Survival of cohort with homozygous sickle cell disease followed up to 15th birthday by period of enrolment

In addition to the documented effects on acute splenic sequestration and pneumococcal septicaemiameningitis, dedicated clinics with specialist knowledge to which the patients have easy access are likely to encourage patients to present earlier, allowing more time for effective treatment. These observations from the Jamaican cohort study show that simple readily implementable measures may improve survival in sickle cell disease, but to avoid the high mortality in the first year of life neonatal detection of sickle cell disease is essential. Early detection of sickle cell disease and implementation of these preventive measures is the most realistic and feasible approach to improving survival in sickle cell disease.

We thank all the paediatricians, laboratory technologists, and nurses of the MRC Laboratories who have contributed to these data over the past 20 years.

Funding: None.

Conflict of interest: None.

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