Review question
We reviewed the evidence about the effects of prophylactic antibiotic regimens for preventing pneumococcal infection in children with sickle cell disease (SCD). This is an updated version of a previously published Cochrane Review.
Background
People living with SCD are especially prone to respiratory and blood infections. These infections are often caused by a germ (bacteria) known as Streptococcus pneumoniae, otherwise known as pneumococcus, which can cause many types of serious illnesses. Individuals with SCD can acquire infections more easily than unaffected persons because their spleen (an organ in the body that filters blood and is vital for the proper functioning of the immune system) does not work correctly, and also because damaged tissue and bone resulting from SCD can harbour bacteria. Infection prevention is therefore one of the major ways to improve the health of persons living with SCD and reduce the risk of death. The highest risk of infection occurs in children under three years of age, but the special vaccines that help to prevent illnesses with S pneumoniae are of limited use in this young population. Therefore, regular antibiotics in addition to these special vaccines are needed to prevent infection. As risk of infection decreases with age, there might be a time when preventative antibiotic treatment can be discontinued. The aim of the review was to determine the effects of antibiotic prophylaxis against pneumococcus in children with SCD.
Search date
The evidence is current to 25 January 2021.
Study characteristics
We gathered evidence for this Cochrane Review by examining three clinical trials with over 800 children included.
Key results and quality of the evidence
All three clinical trials showed a reduced rate of pneumococcal infection in children with SCD receiving penicillin preventatively. Two of these trials looked at whether treatment was effective. The third trial followed on from one of the early trials and looked at when it was safe to stop treatment. Adverse drug effects were rare and minor. However, there were problems with children keeping to the treatment schedule and with the development of antibiotic resistance. The quality of the evidence for both primary and secondary outcomes (end result) was judged to be low.
We conclude that penicillin given to preventatively reduces the rate of pneumococcal infections in children with SCD under five years of age. The risk of infection in older children is lower, and the follow-on trial did not show a significant increase in risk when regular penicillin was halted at five years old. Further research is needed to look at how commonly bacteria develop that are resistant to treatment and how clinically important this is.
The evidence examined was determined to be of low certainty and suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.
Sickle cell disease (SCD) is a group of inherited disorders that result in haemoglobin abnormalities and other complications. Injury to the spleen, among other factors, contribute to persons with SCD being particularly susceptible to infection. Infants and very young children are especially vulnerable. The 'Co-operative Study of Sickle Cell Disease' observed an incidence rate for pneumococcal septicaemia of 10 per 100 person-years in children under the age of three years. Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population. This is an update of a Cochrane Review which was first published in 2002, and previously updated, most recently in 2017.
To compare the effects of antibiotic prophylaxis against pneumococcus in children with SCD receiving antibiotic prophylaxis compared to those without in relation to:
1. incidence of Streptococcus pneumoniae infection;
2. mortality (as reported in the included studies);
3. drug-related adverse events (as reported in the included studies) to the individual and the community;
4. the impact of discontinuing at various ages on incidence of infection and mortality.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and also two clinical trials registries: ClinicalTrials.gov and the WHO International Registry Platform (not in 2020 given access issues relating to Covid-19 pandemic). Additionally, we carried out hand searching of relevant journals and abstract books of conference proceedings.
Date of the most recent search: 25 January 2021.
All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with SCD with placebo, no treatment or a comparator drug.
The standard methodological procedures expected by Cochrane were used. Both authors independently extracted data and assessed trial quality. The authors used the GRADE criteria to assess the certainty of the evidence.
Six trials were identified by the searches, of which three trials were eligible for inclusion. A total of 880 children, who were between three months to five years of age at randomization were included. The included studies were conducted in centres in the USA and in Kingston, Jamaica. In trials that investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-certainty evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-certainty evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five years.
Overall, the certainty of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias).