Internal Medicine Journal 38 (2008) 349356

REVIEW

Guidelines for the prevention of sepsis in asplenic and hyposplenic patients

D. Spelman,1 J. Buttery,2 A. Daley,3 D. Isaacs,4,5 I. Jennens,6 A. Kakakios,5 R. Lawrence,7 S. Roberts,8 A. Torda,9 D. A. R. Watson,10 I. Woolley,11,12 T. Anderson13 and A. Street14 on behalf of the Australasian Society for Infectious Diseases
1

Microbiology and Infectious Diseases, 11Infectious Diseases Unit and 14Haematology Unit, Alfred Hospital, 2Infectious Diseases Unit, Murdoch Childrens Research Institute, 3Department of Microbiology and Infectious Diseases, Royal Childrens Hospital 6Infectious Diseases Unit, Royal Melbourne Hospital, and 12Infectious Diseases Unit, Monash Medical Centre, Melbourne, Victoria, 4University of Sydney, 5Childrens Hospital, 7 Sydney Adventist Hospital and 9Infectious Diseases Unit, University of NSW, Prince of Wales Hospital, Sydney, New South Wales, 10Infectious Diseases Unit, Canberra Hospital, Canberra, Australian Capital Territory and 13Department of lnfectious Diseases and Microbiology, Royal Hobart Hospital, Hobart, Tasmania, Australia and 8Department of Microbiology, Auckland City Hospital, Auckland, New Zealand

Key words asplenia, hyposplenia, spleen, immunization, antibiotics. Correspondence Denis Spelman, Microbiology and Infectious Diseases, Alfred Hospital, Commercial Road, Melbourne, Vic 3004, Australia. Email: d.spelman@alfred.org.au Received 13 June 2007; accepted 18 October 2007 doi:10.1111/j.1445-5994.2007.01579.x

Abstract
Asplenic or hyposplenic patients are at risk of fulminant sepsis. This entity has a mortality of up to 50%. The spectrum of causative organisms is evolving as are recommended preventive strategies, which include education, prophylactic and standby antibiotics, preventive immunizations, optimal antimalarial advice when visiting endemic countries and early management of animal bites. However, there is evidence that adherence to these strategies is poor. Consensusupdated guidelines have been developed to help Australian and New Zealand clinicians and patients in the prevention of sepsis in asplenic and hyposplenic patients.

Introduction
Fulminant sepsis is a risk in patients following splenectomy or in patients who are hyposplenic for other reasons such as congenital asplenia or coeliac disease or following bone marrow transplantation. The incidence of such infections can be reduced by preventive measures, although compliance with recommendations in the published works is poor.1,2 In this paper, we review current published works on preventive measures and their efcacy and based on that review make recommendations for the prevention of sepsis in asplenic and hyposplenic patients. For the majority of these recommended interventions, there are no randomized controlled studies. Therefore, we have not attempted to rate each

according to the quality of available evidence. These recommendations are also based on the consensus and opinion of the authors, who are active in the elds of infectious diseases, paediatrics, immunology and haematology. There are previously published recommendations from UK,3 which have been recently updated,4 Canada5 and Australia6 as well as specic postsplenectomy immunization guidelines included in USA7 and Canada8 and New Zealand9 immunization recommendations. We have examined these in constructing these guidelines. These present recommendations target Australian and New Zealand medical practitioners and include references published since the publication of previous recommendations.

Causative organisms
The commonest causative organisms are encapsulated bacteria especially Streptococcus pneumoniae, which has caused over 50% of cases in some series.2 Other
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Funding: None Potential conicts of interest: None

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encapsulated bacteria implicated include Neisseria meningitidis2 and Haemophilus inuenzae type b (Hib),10 especially before the era of routine Hib vaccination. Less commonly described bacterial causes include Gram-negative rods2 and Streptococcus suis.11 Importantly, the spleen also has a role in removing Babesia,12 plasmodia13 and Ehrlichia spp.14 and severe infections with these organisms have been reported in asplenic or hyposplenic patients. Most recently, a new organism, Bordetella holmesii15 has been described as a cause of sepsis in asplenic patients. The description of the clinical disease caused by this organism shows how asplenic and hyposplenic individuals may be a host group for emerging infectious diseases and how the pattern of disease may not be overwhelming sepsis.16 There are many infections, for example, viral respiratory tract infections and gastroenteritis, in which the incidence and frequency do not appear to be increased in this patient group, although no signicant study has been carried out.

Incidence of and mortality in sepsis in asplenic patients

The reported incidence varies with the patient group, duration of follow up, denitions used and whether the rate is calculated or estimated. In an Australian study, the reported incidence was 0.42 per 100 person years.27 Other estimates are 0.180.42 cases per 100 person years,2 7.16 per 100 person years28 and 2.3 per 100 person years at risk.29 Another way of presenting rates is the percentage of patients who develop sepsis postsplenectomy 3.2%,30 4.4% in children <16 years31and 0.9% in adults.31 The overall mortality of fulminant infection in this patient group of 4050% is far higher than the mortality from sepsis in the normal population.2 It is hoped that the frequency and severity of infections in those without a functioning spleen could be decreased with early diagnosis and treatment.

Duration of increased risk Patients at risk

The number of persons with asplenia or hyposplenia in Australia/New Zealand is unknown. It has been estimated that there are 50 000 such patients in the UK.2 In one UK district, it was estimated that the prevalence of persons following splenectomy was 9.75 per 10 000 population.17 Also a single laboratory study found 1 of 200 of the population (0.5%) were asplenic on the basis of the presence of HowellJolly bodies.18 The rmest recommendations on prophylaxis are for patients who have undergone surgical splenectomy. However, there are other patients who have functional asplenia/hyposplenia in whom the same preventive recommendations are indicated. These include some patients who underwent allogeneic bone marrow transplantation, especially in the presence of chronic graft versus host disease,19 those with coeliac disease,20 patients with haemoglobinopathies, for example, sickle cell anaemia,21 thalassaemia major and systemic lupus erythematosus22 and those with inammatory bowel disease.23 There is also a small number of patients with familial/congenital asplenia.24 The risk in patients who undergo subtotal splenectomy or signicant splenic trauma and in whom the spleen has been preserved is uncertain. The presence of HowellJolly bodies on a blood lm is accepted as the usual diagnostic marker of asplenia/hyposplenia, although this is a marker of the spleens ability to remove damaged cells rather than of immunological function.25 There is evidence that the absence of IgM memory B cells is a predictor of an individuals impaired immune response to encapsulated bacteria following splenectomy and this may become the basis for future assessment.26 It has been thought that the risk of fulminant sepsis in this patient group is mainly within the rst few years postsplenectomy.32 However, there are case series that suggest that the increased risk is lifelong. In a recent large series of overwhelming infection in asplenic patients, most of the reported 77 cases occurred 1030 years after splenectomy, with only 11% of cases occurring within 4 years of surgery.2 Other reports also included cases occurring decades after splenectomy.33 In the systematic review of 19 680 patients with a median follow up of 6.9 years, the average duration to rst invasive infection was 22.6 months.30 Minor infections including viral infections and postoperative infections were excluded in this study.

Recommendations
Education
All patients and their families should be educated about the risk of sepsis and strategies to minimize that risk. El-Alfy et al. have shown that those patients with asplenia who have the best knowledge concerning sepsis had the lowest incidence of this outcome.10 Patients and their families should be given written information concerning these recommendations. Ideally, they should carry a medical alert, for example, wallet-sized laminated card and/or MediAlert bracelet or medallion that can inform medical carers of the patients asplenia or hyposplenia. With the consent of the patient, his/her general practitioner should be informed and given written information. Up-to-date recommendations should be readily accessible to all general practitioners.
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Splenic salvage
Maximal efforts should be made to preserve splenic tissue and therefore splenic function. Salvage techniques that have been suggested include splenic repair, splenorrhaphy and the embedding of splenic tissue in the omentum. Patients at risk, for example, following splenic trauma or with a disease that predisposes them to asplenia/hyposplenia, may be monitored for the appearance of Howell Jolly bodies and by measurement of IgM memory B cells.

Antibiotic prophylaxis
Phenoxymethylpenicillin prophylaxis has most often been used. The Australian Therapeutic Guidelines: Antibiotic (2006) recommend, for adults, amoxycillin, 250 mg daily or phenoxymethylpenicillin, 250 mg, p.o., every 12 h, and for children under 2 years, amoxycillin, 20 mg/kg, p.o., daily or phenoxymethylpenicillin 125 mg, p.o., every 12 h.6 For patients hypersensitive to penicillins, roxithromycin (child 4 mg/kg up to) 150 mg, p.o. or erythromycin, 250 mg, p.o., daily (all ages) is recommended. Others recommend moxioxacin or cotrimoxazole, based on local rates of macrolide resistance.34 The duration of antibiotic prophylaxis is controversial. The most conservative guidelines3 at present recommend lifelong antibiotics and there is good evidence that the risk of sepsis is also lifelong. Nevertheless, recommendations do have to be rened to the needs and wishes of the individual patient who may be unwilling or incapable of taking prophylactic antibiotics for decades. In these patients, we would recommend at least 2 years of prophylactic antibiotics followed by the use of emergency or standby antibiotics and early presentation to medical care. Such an approach necessitates a rigorous education programme with ongoing reinforcement of the need to present early to medical care, the need to maintain vaccination status and the need to maintain a supply of up-to-date antibiotics as an emergency supply. Prophylactic phenoxymethylpenicillin or amoxycillin is often recommended lifelong for those patients with an underlying haematological condition and/or who have ongoing impaired immune function.35 The only randomized controlled studies of penicillin prophylaxis have been in children with sickle cell anaemia. The rst study was carried out in very young children aged less than 3 years, the age group with the highest incidence of sepsis. It found a 84% reduction in pneumococcal bacteraemia in children receiving penicillin V, occurring in 2 of 105, as compared to 13 of 110 children receiving placebo over a mean of 15 months (P = 0.0025).36 A second study randomized 400 children aged 5 years with sickle cell disease to penicillin or placebo
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and followed them for a mean of 3.2 years.37 There were four pneumococcal infections in the placebo group and two in the penicillin arm, although not statistically signicant. Their conclusion was that it is safe to stop penicillin prophylaxis at 5 years in sickle cell disease. However, the effect of the emergence of the drug-resistant S. pneumoniae on the effectiveness of antimicrobial prophylaxis is unknown. More recently, a follow-up study of 318 patients (age: median 18 years, range 1026) who underwent splenectomy between 1985 and 1997 showed a signicant difference in the occurrence of sepsis in those who took penicillin (2.7%) and those who did not (10%) (P < 0.01).10 Failures of antibiotic prophylaxis have been reported, so patients should be warned that prophylaxis reduces but does not abolish the risk of sepsis.38

Reserve standby antibiotic supply

These patients should have a reserve or standby antibiotic supply with instructions to take in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, especially when medical review is not readily accessible. Recommended options for adults include the following. 1 Amoxycillin, 3 g starting dose followed by 1 g, every 8 h.39 2 Amoxycillin/clavulanate, 500/125 mg, every 8 h.34 3 Cefuroxime, 250 mg, every 12 h.34 4 Moxioxacin in penicillin allergic patient.34

Immunizations
Pneumococcal immunization
There are currently two vaccines available in Australia and New Zealand: the 23-valent polysaccharide vaccine (23vPPV), approved for use in older children and adults, and the 7-valent pneumococcal conjugate vaccine (7vPCV) approved for use in children up to 9 years. The 7vPCV is more immunogenic in children, especially those less than 2 years old. Unlike the 23vPPV, it also provides T-cell-mediated immune memory, avidity maturation of elicited antibody, mucosal immunity and herd immunity.40,41 The use of pneumococcal vaccine has been followed by a decrease in pneumococcal infection in splenectomized patients when compared with historical controls.42 A follow-up study of 318 patients who had undergone splenectomy showed a signicant difference in the occurrence of sepsis between patients who had had pneumococcal polysaccharide vaccine (2.4%) and those who had not (7.8%), (P < 0.05).10 Failures of polysaccharide pneumococcal vaccine in this patient group have been reported.38

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The choice of vaccines is straightforward in young children in Australia, where 7vPCV is now recommended routinely for all children at 2, 4 and 6 months, with 23vPPV at 18 months.43 Funding for all Australian children up to the age of 2 years commenced from 1 January 2005. The 7vPCV will be included in the National Immunisation Schedule in New Zealand from 1 June 2008 for all babies born from 1 January 2008. It has been available since 2006 for children with specic conditions that put them at greater risk of invasive pneumococcal disease. These conditions include pre- and postsplenectomy and functional asplenia.9 The schedule for 7vPCV vaccine depends on the age of the child at the start of the course: children aged 6 weeks to 6 months should receive 3 doses, at least 68 weeks apart, plus a fourth dose at 15 months; children aged 711 months should receive 2 doses, at least 68 weeks apart, plus a third dose at 15 months; children aged 1259 months should receive two doses given 6 8 weeks apart. All should receive a dose of 23vPPV at the age of 2 years and a second dose when aged 45 years followed by every 5 year boosters. However, the optimal vaccine strategy in adults and older children is unclear. It has been suggested that using both vaccines in tandem or sequentially may increase the protection given by these vaccines.4 Additionally, serotypes not contained in the seven-valent conjugate vaccine have been described as causing up to 19% of sepsis in children, with the 23vPPV covering up to 96%.44 Currently, the Australian Immunisation handbook43 recommends the 23vPPV for individuals aged over 5 years with asplenia. The current recommendations in New Zealand for children aged 59 years with functional asplenia is to give one dose of 7vPCV, followed 68 weeks later by one dose of the 23vPPV.9 They should receive a booster of the 23vPPV every 5 years. Children aged 10 years or older may receive the 7vPCV if considered appropriate, otherwise they should receive one dose of 23vPPV followed by every 5 year boosters. There are few studies on the use of 7vPCV in normal adults let alone adults with asplenia/hyposplenia. The conjugate vaccine may have a role in non-responders to the 23vPPV but is not licensed for adult use.45 We, therefore, cannot recommend its use alone but it may be used as an adjunctive vaccine subject to the discretion of the individual medical practitioner. Patients ideally should receive vaccine at least 2 weeks before elective splenectomy. Optimal timing of receipt of vaccine following emergency splenectomy remains uncertain. There is evidence that vaccine response to 23vPPV is the same at day 14 and 28 following splenectomy as in healthy adults.46 However, functional antibody responses were signicantly higher when 23vPPV was given at 14 days following splenectomy compared with day 1 or

day 7.47 On occasions, vaccine may be given before hospital discharge, if there is a risk of loss of patient follow up. If a patient undergoes splenectomy and is receiving chemotherapy and/or radiotherapy, it has been suggested that immunization should be delayed for 6 months.48 Revaccination recommendations for 23vPPV vary: the British guidelines recommend revaccination every 5 10 years,3 whereas the Australian Guidelines recommend a further dose 5 years after the initial dose.43 An alternative approach is to revaccinate when antibody levels fall below a protective level. One difculty with this approach is the uncertainly as to what makes up a protective level. In the past, there also has been no standardized method for assessing vaccine-serotype-specic antibody responses. This is now being addressed by a World Health Organization working party, which has produced a protocol for a pneumococcal polysaccharide enzyme-linked immunosorbent assay method.49 A standardized method is available locally at the Royal Childrens Hospital, Melbourne, so antibody levels could be used to guide the need for revaccination. However, there is still no clear agreement on serologic correlate of protection for invasive pneumococcal disease. The safety and immune response after trauma splenectomy to 23vPPV revaccination has been studied. Revaccination is well tolerated and 48% of this patient group had a twofold increase in antibody titres.50

Meningococcal immunization
There are two vaccines available in Australia: quadrivalent (A,C,W135,Y) polysaccharide vaccine (4vMenPV) and the more recently available meningococcal C conjugate vaccine (MenCCV). The current recommendation in Australia but not in New Zealand is to give MenCCV to all babies at 12 months and catch up to all children and young adults up to the age of 19 years.43 There are three vaccines available in New Zealand: 4vMenPv, the conjugate MenCCV, and the Group B OMP vesicle vaccine (MeNZB). Other meningococcal vaccines are licensed in New Zealand but are not routinely available. The current recommendation in New Zealand is to give the MeNZB vaccine to children aged 6 weeks, 3, 5 and 10 months; adults and children pre- and postsplenectomy or with functional asplenia should receive 3 doses at 6 week intervals.9 The vaccine is funded for these purposes. The 4vMenPv vaccine is recommended and funded for adults and children pre- and postsplenectomy or with functional asplenia. It is recommended for use but not funded in other situations, as outlined in the Ministry of Health Immunisation Handbook 2006.9 The MenCCV vaccine is not routinely recommended in New Zealand but can be used in situations outlined in the Ministry of Health Immunisation Handbook 2006.9 The MeNZB is not a conjugate
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vaccine and immune responses are generally of low titre and wane relatively quickly. There are no data on immune responses to this vaccine in asplenic/hyposplenic patients. The evidence that meningococcal disease occurs more frequently in asplenic/hyposplenic patients is limited. Case series of sepsis in asplenic patients have included small numbers of cases caused by N. meningitidis.2 Patients with lymphoid tumours who underwent splenectomy and who had received chemotherapy or radiotherapy responded poorly to GpA and GpC meningococcal vaccines, whereas similar asplenic patients with nonlymphoid tumours had nearly as good a response as normal subjects.51 Antibody response to meningococcal serogroup C conjugate vaccine has also been studied after splenectomy. The geometric mean titre of bactericidal antibody was signicantly lower in the splenectomy group compared with controls.52 We recommend that for an asplenic/hyposplenic Australian patient over the age of 12 months and who has not previously received meningococcal vaccine, a single dose of MenCCV should be given, followed 68 weeks later by a single dose of 4vMenPv.43 Infants 06 months old require two doses of MenCCV, 12 months apart followed by a further dose at 12 months, and vaccination with 4vMenPV should occur at 2 years of age. Adults and children over the age of 2 years in New Zealand with asplenia/hyposplenia should receive a dose of the 4vMenPV.9 For adults and older children in Australia and New Zealand reimmunization with 4vMenPv is recommended after 35 years in those with ongoing risk. New Zealand patients (children) should be given three doses of MeNZB at intervals of 46 weeks.9,43 The need for revaccination at 2 years is unclear. It is not a current recommendation in New Zealand that children with asplenia/hyposplenia receive MenCCV. Asplenic and hyposplenic patients travelling to high-risk regions of the world should receive the 4vMenPv regardless of having received the MenCCV previously.4

Inuenza immunization
This is recommended annually for asplenic/hyposplenic patients over 6 months of age. This may be of benet in that prevention of inuenza may decrease the risk of secondary bacterial infection, including pneumococcal infection.4

Further strategies
Alerts
The medical history should be marked with an alert sticker and a checklist should be included in that history outlining date, type, dose of vaccines and when the next vaccination is due. Anatomical pathologists should include a comment on their histology reports on the risk of fulminant sepsis when a spleen is processed, as should a haematologist when HowellJolly bodies are seen.

Malaria
Due to the increased risk of severe malaria, asplenic and hyposplenic travellers to endemic areas should be warned of this risk, which should be considered when making their decision to go and planning their actual itinerary.55 Travellers should take optimal precautions to prevent infection by means of antimalarial prophylaxis, mosquito repellents and other barrier precautions. Advice from an infectious disease physician or expert travel advisor is recommended.

Babesiosis
This is an unusual infection transmitted by ticks and has not been described in Australia or New Zealand. The spleen is an important organ for removing Babesia spp., which has produced fatal infections in asplenic patients.56 Travellers to at risk regions should be warned of this risk.

Hib immunization
Hib vaccination is recommended for both children and adults. Children who have received all scheduled vaccine doses do not require a booster dose following splenectomy.43 Previously unvaccinated adults, especially those have who have close contact with young children, should receive a single dose of Hib vaccine.43 Hib vaccine has been shown to be immunogenic in patients following splenectomy,53 although the immune response was signicantly reduced compared with normal controls,54 and antibody levels declined more rapidly in splenectomized patients. The need for revaccination is uncertain.
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Meningococcal immunizations for travellers

Travellers with asplenia or hyposplenia should also consider the quadrivalent vaccine when travelling to high-risk areas, for example, sub-Saharan Africa, regardless of them previously receiving MenCCV.

Animal bites
There is an increased risk of severe sepsis in patients with asplenia or hyposplenia who are bitten by dogs and other animals. The common causative organism is

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Capnocytophaga canimorsus. Such patients should be warned of this risk and have adequate antibiotic cover following such bites, for example, amoxycillin/clavulanic acid for 5 days.

dose, followed by 1 g, every 8 h, or amoxycillin/clavulanate 500/125 mg, every 8 h.

Immunizations
Pneumococcal immunization. Children: pneumococcal conjugate vaccine (7vPCV) (number of doses according to age) followed by 23vPPV, 68 weeks later or once the child is 2 years old. Adults: 23vPPV. Reimmunization: at 5 years (23vPPV). l Meningococcal immunization. Australia: MenCCV, followed 68 weeks later by 4vMenPV. Reimmunization: at 35 years (4vMenPV). New Zealand: for the MeNZB vaccine, children who have not received the vaccine with the infant vaccination schedule should receive 3 doses at intervals of 46 weeks followed by the 4vMenPV. l Hib immunization. Single dose if >18 months and not previously vaccinated. Number of doses according to age for children. l Annual inuenza immunization
l

Asplenic registry
Registries of patients with asplenia and hyposplenia have been both reported and recommended.2,57 The potential role of such ongoing registries is to ensure that patients (and their carers) are given optimal and up-to-date preventive advice and that they receive long-term ongoing support, such as reminders when revaccinations are due. A registry will also collect important long-term data and may be the vehicle for studies on the efcacy of recommended interventions.

Summary of recommendations
Education
l All patients and their families should be educated about the potential risks of fulminant sepsis. l All should be given written information by their doctor and encouraged to carry a MediAlert. l Good communication is necessary with other medical carers, especially general practitioners. l Patients who are asplenic or hyposplenic should promptly report any unexplained fever, chills or constitutional symptoms to their doctor or hospital emergency department.

Travel advice
l Travellers should be educated and take optimal preventive measures for the prevention of malaria and babesiosis. l Travellers to high-risk areas, for example, sub-Saharan Africa, should have 4vMenPV, regardless of previous receipt of MenCCV.

Other advice Antibiotic prophylaxis

l Oral phenoxymethylpenicillin or amoxycillin. For children aged <2 years: amoxycillin 20 mg/kg daily, up to 250 mg, p.o., daily, or phenoxymethylpenicillin 125 mg, p.o., every 12 h. For older children, adults: amoxycillin 250 mg, daily or phenoxymethylpenicillin 250 mg, every 12 h. l If allergic to penicillin, roxithromycin 150 mg, p.o., daily (child: 4 mg/kg, up to 150 mg, daily) or erythromycin 250 mg, p.o., daily (all ages). l We recommend lifelong prophylaxis for patients with ongoing impaired immune function. For other patients, there should be individual reevaluation of the need for ongoing antibiotic prophylaxis at 2 years. l All persons with asplenia or hyposplenia should be warned of the risk of animal bites and have early and optimal treatment of such bites. l Medical histories should be marked with an alert or asplenia sticker

Splenic salvage and monitoring

Maximal efforts should be made to preserve splenic tissue, for example, with splenic embolization rather than removal of bleeding spleen. l Patients at risk of hyposplenia may be monitored using HowellJolly bodies and measurement of IgM memory B cells.
l

Acknowledgements
Standby antibiotic
Patients should have a reserve or standby supply of antibiotics, with instructions when to commence them, for example, at onset of fever or rigour, especially if early medical review is not possible, for amoxycillin, 3 g starting
l

We thank the members of the Australasian Society for Infectious Diseases, Dr John Andrew from the Royal College of Pathologists of Australasia and Mr George Kiroff from the Royal Australasian College of Surgeons for their helpful comments.
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