Sickle cell patients are predisposed to infection by many different micro-organisms, but especially polysaccharide encapsulated organisms.1^–4 A number of immune mechanisms contribute to this: hyposplenism due to splenic atrophy, dysfunctional IgG and IgM antibody responses, defective fixation of complement via the alternative pathway, and poor opsonisation of organisms.5 Invasive pneumococcal disease is a major risk, and is clearly one of the most important causes of early mortality in sickle cell infants, even in developed countries in the 21st century.6 Pneumococcal sepsis was responsible for four deaths (out of 15 related to sickle cell disease) in the long-term cohort study of 771 sickle children in Dallas, USA.7 Data regarding Haemophilus influenzae type b (Hib) are more scarce, but this organism accounted for 19% of positive blood cultures in a 2001–2 study of sickle cell children in Uganda,8 and was responsible for one out of the 15 deaths in the Dallas cohort.7 No published data regarding the incidence of meningococcus group C (MenC) in sickle cell disease could be found. In the National Confidential Enquiry into Patient Outcome and Death report9 on the 48 deaths in sickle cell patients (adults and children) in England and Wales during 2005–6, there were seven deaths in sickle cell patients thought to involve infection as a factor (page 50 of the report). One was confirmed as pneumococcus, one was a streptococcus (species not identified), while in the others no organism was identified. It seems clear that protection against pneumococcus is the over-riding priority, while ensuring that cover for the other two organisms is not neglected. It should certainly be considered one of the raisons d’étre for the national neonatal haemoglobinopathy screening programme, so that patients can be given protection at the earliest possible opportunity. An effective immunisation schedule from infancy and throughout life is therefore essential. Long-term prophylaxis with penicillin (or erythromycin) is also indicated,10 11 but is not considered further in this paper.

The 7-valent pneumococcal conjugate vaccine (PCV) has been shown to produce a good antibody response12 13 and to decrease the incidence of invasive pneumococcal disease14^–16 in sickle cell patients. The use of the 23-valent pneumococcal polysaccharide vaccine (PPV) following immunisation with the 7-valent pneumococcal vaccine (as used in the UK immunisation schedule) enhances the antibody response, and the range of serotypes covered17^–19 To date, no studies looking specifically at the clinical effectiveness of Hib and MenC vaccines in sickle cell disease have been published. However, there has been a marked decrease in Hib infections in the general population following the widespread introduction of the vaccine20 (and see reference,21 page 128). Studies have demonstrated good antibody responses to the MenC conjugate vaccine in patients with sickle cell disease, and to the Hib conjugate vaccine in patients who were asplenic.22 23

Since 1992, the PPV Pneumovax has been recommended for at-risk groups, such as those with sickle cell disease. The PCV Prevenar was licensed for children under the age of 2 years in at-risk groups in 2002; this was extended to children under 5 years in 2004, and in 2006 was added to the routine childhood immunisation schedule. The Hib vaccine has been part of the routine UK childhood immunisation schedule since 1992, and the MenC conjugate vaccine since 2001.

The UK Department of Health publication Immunisation Against Infectious Disease is known as “The Green Book”.21 Its detailed guidance on immunisation for asplenic/hyposplenic individuals is summarised in table 1. Boosters are recommended for pneumococcus and MenC every 5 years, but no specific guidance is given regarding Hib boosters (interestingly the US equivalent—“The Pink Book”24—makes no mention of this either). We thus conclude that, until further evidence emerges, boosters against Hib (after the full childhood regimen or the primary adult regimen) are not required. Annual viral influenza immunisation is recommended.

SETTING FOR STUDY, AND METHODS

In view of the 2006 UK Guidance,21 we undertook an audit of the immunisation status of all known adult and paediatric patients with a sickling disorder (sickle cell anaemia (HbSS), or compound heterozygotes such as HbSC) in Coventry. Coventry is a city of just over 300 000 people situated in the British Midlands, with 16% of the population from non-white ethnic groups (mainly Indian subcontinent, but about 3% are of black African/Caribbean origin). There are two community-based haemoglobinopathy nurses (the first of whom started in post in 2005) who support patients with major haemoglobinopathies, and parents of newborn patients detected by the neonatal screening programme (operational in Coventry since 1998). Patients were identified from a locally held database maintained by the haemoglobinopathy nurses. Immunisation status was ascertained by questionnaire to local general practitioners (GPs), personal visits by the nurse specialists to the GP practices and by review of the hospital notes. The audit standards used were taken from the latest edition of The Green Book (2006)21 and are shown in table 1. The study was undertaken in April and May 2008. For pneumococcus and MenC, compliance was equated to evidence of primary immunisation or booster within the previous 5 years. For Hib, compliance was recorded if the person had ever had complete immunisation against this organism (either the childhood schedule or, for previously unvaccinated adults, the two dose primary regimen). For children, the audit took account of their dates of birth, and whether they would have been eligible for PCV immunisation (if they were under 2 years old in 2002, or less than 5 years in 2004; ie, any child born since 1 January 2000).

During our study, we discovered that one of our patients had, unbeknown to us, died of pneumococcal meningitis in August 2007. He was a 31-year-old Nigerian man with HbSC disease who had been in the UK for 6 years. He had been noted to have “protective” levels of anti-pneumococcal IgG (>20 U/ml) in 2005 but had not been immunised. This re-emphasised to us the futility of measuring antibody levels (it is no longer recommended in the Green Book even to aid decisions as to when to re-immunise), and the key importance of ensuring that all patients (including those with the “milder” sickling disorder, HbSC disease) are fully immunised.

RESULTS

A total number of 58 patients was identified from the database. The 33 adults were aged 17–63 years, and the 25 children were aged 4 months to 15 years. The genotypes were: 34 HbSS patients, 22 HbSC patients, one with HbSD-Punjab and one with HbSO-Arab.

Rates of compliance with UK guidance are shown in tables 2, 3, 4, 5 and 6. Four adult patients (12%) had complete up-to-date coverage against pneumococcus, Hib and MenC. Figures for the individual vaccines in adults are shown in Table 2.

Table 3 shows rates of compliance rates in children. Fourteen children (56%) had completed the childhood immunisation programme for the pneumococcal, Hib and MenC vaccines; eight (32%) had been incompletely vaccinated, and three (12%) had no record of vaccination. Further details of immunisation with PCV and booster doses are shown in tables 4 and 5.

Compliance with immunisation against influenza virus is shown in table 6. Six (10%) of our population had received vaccination in the last year. A further two patients had previously been immunised but were not up to date.

DISCUSSION

Our results demonstrate that the rates of immunisation against encapsulated bacteria and influenza virus are poor among our sickle cell patients. Whereas newborn sickle cell patients are benefiting from the routine UK childhood immunisation scheme, which now includes cover for pneumococcus, Hib and MenC, it is clear that older children and adults are not receiving the required initiation regimens or boosters. This is not restricted to Coventry: a survey conducted by the UK Health Protection Agency (1999–2005) examined the uptake of PPV in groups at increased risk of invasive pneumococcal disease.25 That study, which did not differentiate between adults and children, found an uptake of 15.9% in people with sickle cell disease. This compared with our adult uptake of 21%, paediatric uptake of 72%, and an overall rate of 43%. In the National Confidential Enquiry into Patient Outcome and Death report,9 prior immunisation among sickle cell patients who had died (from any cause) was documented in only 32% (pneumococcus), 23% (Hib), 19% (MenC) and 6% (influenza). The up-to-date coverage for influenza in our survey was only 8% in children and 12% in adults, which is similar to that found more generally in UK. The Department of Health surveillance of the influenza vaccine programme records immunisation rates amongst vulnerable populations of: <10% for those under 2 years, 20% for those between 2 and 16 years, and 45% for those aged 16–65 years.26

The reasons for the low rate of compliance with immunisation were not specifically addressed by this audit. In general, the younger children had the best immunisation record: of the 20 children aged less than 9 years, 12 (60%) had complete pneumococcus/Hib/MenC immunisation, but of the five children who were 9 years or older only two were complete (40%). This may simply be because of changing routine immunisation schedules over the last few years, or because some of the older children had moved to this country after the age of 5 years. In either case, we have clearly failed to recognise the deficits in their immunisation status and to arrange catch-up vaccination. The situation is even worse in adults, with complete immunisation cover against encapsulated organisms of just 12% in our audit. It became clear to us while carrying out this audit that it is an ineffective strategy to tell a patient, or his/her parents, at an outpatient visit that they need to attend their GP to receive their vaccines. Even if this is also mentioned in a letter to the patient with a copy to their GP, it does not often result in the patient attending and receiving the vaccines. In addition, of course, clinic attendance is poor in this patient group,27 so even administration in the hospital clinic may not be the answer.

In response to this audit, we are seeking to follow-up all patients who lack evidence of complete and up-to-date immunisation. The approach will be a cooperative one, involving the GPs, the GP practice nurses, the haematologist and the paediatrician. But the key people are the community-based haemoglobinopathy nurse specialists who will maintain a database of all patients and their immunisation status. They will liaise with the GPs, and offer help in bringing the patient to the practice for the vaccine or offering to take it to the patient’s home. Constant vigilance will be required to ensure that older children and adults, and patients newly arrived from abroad, are fully up-to-date with all the recommended vaccines. The specialist nurses also have a key role, along with local patient support groups, in raising patients’ awareness of the importance of the immunisations, and their own responsibility to keep up-to-date with them. Although there are nurse specialists in most areas of the UK with a high prevalence of sickle cell disease, there are even greater challenges in areas of low prevalence where these nurses may not exist. The planned national database run by the UK Haemoglobinopathy Forum, with Department of Health funding, will provide a way of tracking (and, it is hoped, thereby improving) the immunisation status of all patients in the country, and not least all those detected by the neonatal screening programme.