Description of the condition
Sickle cell disease (SCD) is a generic term for a group of inherited genetic disorders of haemoglobin, the oxygen-carrying protein contained in red blood cells. Under low oxygen tension the abnormal haemoglobin polymerises, distorting the red blood cells into a sickle shape. This sickling has two effects; firstly the sickled cells block small blood vessels resulting in tissue damage; and secondly the sickled cells are easily removed from circulation, resulting in anaemia. Common complications of SCD include increased severity of infections, pain episodes, stroke, kidney failure, chest infections and lung damage (acute sickle chest syndrome). In addition, growth and development may be delayed (Platt 1984).
Sickle cell disease was originally a disease of African, Indian, and Middle Eastern heritage because the carrier state affords protection against severe malaria; but migration has now made it a global problem (Davies 1989). The inheritance is in an autosomal recessive pattern, so individuals with SCD have inherited abnormal genes from both parents. The inheritance of the gene for sickle haemoglobin may be combined with those for other structurally abnormal haemoglobins, such as haemoglobin C, and also with abnormalities of haemoglobin production, such as beta thalassaemia.
Splenic sequestration occurs when red blood cells become entrapped in the spleen, which enlarges, pooling and then destroying the red blood cells. It is defined clinically as a fall of two grams per decilitre (g/dl) or more in blood haemoglobin concentration from the persons' normal levels, and an enlarging spleen (Topley 1981). Splenic sequestration crisis can be either acute or chronic. An acute splenic sequestration (ASS) is when splenic sequestration occurs rapidly. It manifests clinically as abdominal pain and distension, pallor, weakness, breathlessness, and rapid heart rate (Al-Salem 1999). Chronic sequestration (hypersplenism) has a gradual onset and can follow an attack of ASS (Topley 1981).
The incidence of ASS in homozygous SCD is highest in young children, ranging from 7% to 30% in children up to two years of age (Powell 1992; Topley 1981). After infection, ASS is the second most common cause of death in the first decade of life accounting for between 15% to 44% of deaths in this period (Emond 1985; Powell 1992; Topley 1981). The first attack can occur in infants as young as five weeks (Airede 1992), but attacks are uncommon after puberty. Most cases are seen in individuals with homozygous SS, but have also been reported in S beta thalassaemia and SC. Mortality can be reduced by the early detection of SCD by neonatal screening, followed by parental education (to detect splenic enlargement and pallor) and by early clinical intervention (Emond 1985; Powell 1992).
Acute splenic sequestration crisis is a medical emergency that requires the immediate restoration of blood volume, usually with red cell transfusions. ASS recurs in about 50% of survivors of the first attack with diminishing intervals between subsequent crises (Emond 1985). The mortality rate of the survivors who suffer a recurrence is approximately 20% (Topley 1981). Due to the frequency of recurrences, both long-term blood transfusion therapy and the surgical removal of the spleen (splenectomy) have been used as methods to prevent further ASS and death (Grover 1990).
Although transfusions have been used to reduce the frequency of attacks of ASS, they are expensive, time-consuming, and are associated with adverse effects including development of antibodies to red blood cells (alloimmunization), iron overload, transmission of blood-borne infections such as hepatitis and HIV, and allergic reactions (Rao 1985).
Description of the intervention
Splenectomy (full, partial, and embolisation) is also used to prevent ASS. The advantages of having a splenectomy include stopping blood transfusions and the absence of discomfort from mechanical pressure of the enlarged spleen (Al-Salem 1999). The main objection to performing a splenectomy in young children with SCD is the increased risk of infection. The risk of septicaemia after splenectomy is approximately 2% overall, 4% in children less than four years of age, and can be 30% or more in children in the first year of life (Idowu 1998). Current United Kingdom (UK) guidelines recommend that people who have had a splenectomy should receive lifelong prophylactic penicillin, and be given pneumococcal vaccine before surgery with boosters every three years after splenectomy. Haemophilus influenzae (H. influenzae) type b and meningococcal vaccines have also been recommended (WPBCSH 1996). There is also concern that children living in malaria endemic regions have an increased risk of malarial attacks following a splenectomy (Evans 1945). The fear of loss of the immune protection the spleen gives to the body and of having to undergo surgery are disincentives for splenectomy. Partial splenectomies are performed as an alternative in children in order to try and retain some immune competence, which would otherwise have been lost (Idowu 1998). Other problems associated with partial or full splenectomy include: the risk of having recurrences of ASS in the remnant spleen; and anaesthetic and surgical complications, such as left lower lung collapse.
Why it is important to do this review
As there is continuing debate over the risks and benefits of splenectomy compared to repeated exchange transfusion as strategies to avoid recurrent attacks of ASS, we have reviewed the advantages and disadvantages of both full and partial splenectomy to prevent recurrence of ASS in people with SCD.
To determine whether a full or partial splenectomy, by whatever means, performed to prevent acute splenic sequestration improved survival and decreased morbidity in people with SCD, as compared with regular blood transfusion.
Criteria for considering studies for this review
Types of studies
Randomized (RCT) or quasi-randomized trials. Trials in which quasi-randomized methods, such as alternation, were to be included if there was sufficient evidence that the treatment and control groups were similar at baseline.
Types of participants
All people with confirmed SCD (including SS, SC, SßO, Sß+ proven by haemoglobin electrophoresis) who had experienced at least one ASS crisis.
In this review we defined an ASS crisis as a fall in haemoglobin of at least 2 g/dl from steady-state levels, an acutely enlarging spleen, and evidence of reticulocytosis indicating an increased bone marrow response (Topley 1981).
Types of interventions
Full or partial splenectomy to prevent an ASS compared to conservative management (no treatment or a regimen of regular blood transfusions e.g. four-weekly) to prevent an ASS.
Types of outcome measures
- Episodes of ASS (in individuals who either had a partial splenectomy or conservative management)
- Pneumococcal infections
- Other infections including malaria
- Blood transfusions
- Number of days as a hospital inpatient
- People experiencing sickle-related events (pain episodes, stroke, kidney failure, and chest syndrome)
- People developing chronic hypersplenism
- Adverse effects of interventions including development of alloantibodies, blood-borne infections, iron overload, surgical complications, or any other adverse effects
Search methods for identification of studies
A comprehensive search strategy was formulated in an attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Relevant trials were identified from the Group's Haemoglobinopathies Trials Register using the terms: sickle cell AND (splenectomy OR pneumococcal).
The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.
In addition to the above, further subject specific electronic searches of MEDLINE (1966 to June 2003) and EMBASE (1988 to June 2003) were carried out. This was in combination with The Cochrane Collaboration's highly sensitive search strategy detailed in the Cochrane Reviewers' Handbook (Clarke 2001). For the full search strategy used, please see the appendix attached to this review (Appendix 1).
Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 06 December 2012.
Searching other resources
Additional trials were sought from the reference lists of the trials and reviews identified by the search strategy.
Data collection and analysis
Selection of studies
We did not apply the process described below, as we were not able to identify any trials eligible for inclusion. However, if we include any trials in future updates of this review, we will apply the following methods.
The two authors will independently identify potentially relevant trials from the results of the searches. Both authors will independently apply an eligibility form to potentially relevant trials. The form will take into account the inclusion criteria as described in the 'Criteria for considering studies for this review'. We will resolve disagreements by discussion, or if necessary by consulting a third party. The reasons for excluding trials will then be stated in the review.
Data extraction and management
Each author will independently extract data on trial information including methods, participants, interventions and outcomes. We will check any discrepancies that occur in data extraction by referring to the original paper. One author (SOO) will enter data into Review Manager software (Review Manager 2011).
We planned to group outcome data into those measured at one week and one, three, six and twelve months and annually thereafter. If outcome data were recorded at other time periods consideration would be given to examining those as well.
Assessment of risk of bias in included studies
Each review author will independently assess trials following the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.2 (Higgins 2011). The assessments will be compared and any inconsistencies between the review authors will be discussed and resolved.
Assessment will be made of the following domains, each will be assessed as having either a low, unclear or high risk of bias.
- Generation of the allocation sequence
- Concealment of allocation
- Blinding (of participants, personnel and outcome assessors)
- Incomplete outcome data
- Selective outcome reporting
Measures of treatment effect
Where appropriate, we will analyze data using Review Manager software (Review Manager 2011). We will combine binary data using the Mantel-Haenszel odds ratio or risk ratio where appropriate. We will use mean difference for continuous data, which has been reported using means and standard deviations. Any skewed data found, will be analyzed using the most appropriate method available, e.g. transforming data or summary statistics. We will present continuous data, reported using medians and ranges, in tables only. With event counts, though it would be preferable to state beforehand how data will be analyzed, we will analyze such data in one of several ways based on the format of the data available. We will decide to make the outcome being considered either dichotomous, continuous, time-to-event or a rate, and then extract counts accordingly.
Dealing with missing data
Where the trials have been published in abstract form, presented at meetings, or reported to the authors, we will seek full reports from the trial authors. We will contact the primary investigator if information is missing or unclear.
Assessment of heterogeneity
We will measure the degree of heterogeneity between trials using the I
Assessment of reporting biases
We will examine funnel plots for asymmetry. Selection biases e.g. publication and location biases, poor methodological quality of studies and heterogeneity may be some causes of funnel plot asymmetry.
In the absence of homogeneity of treatment effects, we will use a random-effect approach, otherwise, we will use the fixed-effect model.
Subgroup analysis and investigation of heterogeneity
If there are a sufficient number of trials, we will explore the following sources of heterogeneity:
- type of sickle cell disease;
- partial or complete splenectomy or embolisation;
- transfusion regimens i.e. either at four-weekly intervals or periods more than four-weekly intervals, top up transfusions or exchange, or transfusions when HbS mean less than 40% or more than 40%;
- developed versus developing countries.
Description of studies
No trials were found that were eligible for inclusion in the review.
Risk of bias in included studies
No trials were included in the review.
Effects of interventions
No trials were eligible for inclusion in the review.
There is a paucity of evidence to support splenectomy, by whatever means, performed to improve survival and decrease morbidity from acute splenic sequestration (ASS).
Common practice for the initial management of ASS is red cell transfusion to manage shock (hypovolaemia) and to alleviate symptoms of anaemia. After this, the long-term management options are a splenectomy; a transfusion programme; or careful observation for early signs of ASS until the spleen gradually becomes non-functional (splenic atrophy). In certain places, the choice of treatment depends on the severity of the initial episode of ASS and the age of individual. In developing countries, where the regular supply of 'zero-risk' blood may not be constant, chronic transfusion programmes are hardly considered as part of management of ASS. Chronic transfusions have been advocated by some, to protect susceptible children from recurrent attacks of ASS until splenic atrophy has occurred (Topley 1981).
Splenectomies have also been suggested for children with a variety of presentations (Grover 1990; Topley 1981; Wright 1999). The obvious advantage of having the spleen removed is that it prevents recurrent events, but the counter arguments are that splenectomy compromises their already impaired immune status and the operation being unnecessary in a condition in which the spleen is likely to become non-functional. Another debatable point is whether the spleen, after an attack of ASS, or in established hypersplenism (i.e. chronic enlargement of spleen with a persistent reduction in haemoglobin level), makes any contribution to the immune status of the individual. It is also prudent to bear in mind that the child with sickle cell anaemia after surgical splenectomy may have a similar risk as one in whom the natural phenomenon of 'autosplenectomy' (nature's own physiological spleen removal) has occurred.
Few people with SCD in developed countries, who are known to have received prophylactic penicillin and pneumococcal and H. influenzae vaccines after splenectomy, go on to suffer overwhelming infection (Emond 1984; Kinney 1990). In the UK, guidelines for the prevention and treatment of infection in people with an absent or dysfunctional spleen (asplenia) recommend pneumococcal and H. influenzae type b immunization, as well as life-long prophylactic antibiotics (WPBCSH 1996). The above prophylactic measures may reduce the risk of septicaemia but may not guarantee protection from penicillin-resistant organisms. Asplenic individuals are at risk of severe falciparum malaria and thus adherence to antimalarial prophylaxis in malaria endemic regions cannot be overemphasised (Evans 1945).
Different forms of splenectomy (such as partial splenectomy, splenic embolisation, and splenic irradiation) are employed in the management of chronic splenic enlargement in order to preserve splenic tissue and function (Idowu 1998; Pinca 1992). The advantages of less invasive procedures include avoidance of large scars, and the absence of high platelet counts normally resulting from splenectomy. Disadvantages such as infections and the reappearance of hypersplenism could result. Laparoscopic splenectomy is also another described alternative (Hendricks 2000).
Clinicians must, however, bear in mind that the risks of splenectomy should be compared with those of potential therapies such as blood transfusion and weighed against the dangers of their complications. It should also be considered that the natural history of ASS shows recurrence after the age of five years to be less likely.
Implications for practice
No RCTs of splenectomy for splenic sequestration were found for inclusion in this review. Therefore, the research evidence on which to base clinical decisions is limited to case series and other less robust trials.
We have not identified any relevant trials up to December 2012. We therefore do not plan to update this review until new trials are published.
Implications for research
This systematic review has identified the need for a well-designed, adequately-powered RCT to assess the benefits and risks of splenectomy compared to transfusion programmes, as a means of improving survival and decreasing mortality from ASS in people with SCD.
The protocol for this review was developed during the Mentorship Programme organized by the Cochrane Infectious Diseases Group, May to June 2001. The Department for International Development (UK) supports this Programme through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine.
We thank all our referees for their constructive criticism and suggestions.
Data and analyses
This review has no analyses.
Appendix 1. MEDLINE (1966 to June 2003) and EMBASE (1988 to June 2003)
Last assessed as up-to-date: 19 April 2013.
Protocol first published: Issue 1, 2002
Review first published: Issue 4, 2002
Contributions of authors
This review was conceived by the Cochrane Cystic Fibrosis and Genetic Disorders Group and designed by Dr Owusu-Ofori.
Dr Owusu-Ofori, Dr Riddington and the Cochrane Cystic Fibrosis and Genetic Disorders Group conducted searches for relevant trials.
Dr Owusu-Ofori and Dr Hirst planned to screen, appraise and abstract data for the review.
Dr Owusu-Ofori and Dr Hirst will seek additional information from authors, where necessary.
Dr Owusu-Ofori will perform data entry for future updates. Dr Owusu-Ofori and Dr Hirst will interpret the data with advice from the Cochrane Cystic Fibrosis and Genetic Disorders Group.
Dr Owusu-Ofori took the lead in the write up of the original review and the updated reviews.
Declarations of interest
Since completion of the review, Ceri Hirst has received funding from several pharmaceutical companies for contract research unrelated to the review topic.
Sources of support
- No sources of support supplied
- Department of Health - Research & Development Programme, UK.
Medical Subject Headings (MeSH)
MeSH check words