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    1. ASPLENIA AND INFECTION Dr Gavin Spickett Royal Victoria Infirmary, Newcastle upon Tyne

    3. Functions of the spleen Filters blood stream Removes aged blood cells Removes Howell-Jolly bodies from red cells (residual nuclear material)

    4. Causes of Asplenia Congenital genetic predisposition Splenectomy surgical removal Trauma, malignancy, hypersplenism Seeding of accessory spleens Functional Asplenia spleen present, non-functional

    5. Functional asplenia

    6. Incidence Study in UK found a prevalence of post-surgical splenectomy of 9.75 pts per 10,000 population (7.87-11.64) 1 Prevalence of asplenic patients in UK 1.09 per 1000 registered patients in primary practice 2

    7. Infection risk Problems with analysis: Indication for splenectomy Age at splenectomy Variable recording of infection and causation Long term follow up in large studies lacking

    8. Infection risk Risk of OPSI can be stratified according to underlying disease 3

    9. Age Age at time of splenectomy important role The younger the patient at the time of splenectomy the shorter the interval to life-threatening infectious complications In patients splenectomised for spherocytosis incidence of life threatening infection 4.4% in patients younger than 16 years and 0.8% in adults 4

    10. Definition of OPSI OPSI OPSI may have a short prodrome with non-specific symptoms Evolve into septic shock and DIC Clinical course measured in hours rather than days Fever most common most report rigors 1 - 2 days prior to presentation In adults OPSI usually cryptic infection without primary source

    11. Definition of OPSI In children under 5 years focal infections such as meningitis are more common High levels of bacteria mean organisms may be seen on gram stain Blood cultures usually positive within 24 hours

    12. Overwhelming sepsis Rapid onset overwhelming sepsis Hypotension Purpura and vascular compromise Rapid death if treatment delayed

    13. Infection risk Review of literature 1952 - 1987 5 12,514 patients but only 5,902 reports were sufficiently detailed to allow analysis. The incidence of infection in children <16 yrs 4.4% with a mortality rate of 2.2% In adults incidence of infection 0.9 % with mortality of 0.8% respectively. Mortality rate overall was 55.3% (349 episodes) with 68% deaths occurring within 24 hrs and 80% within 48 hrs

    14. Infection risk Severe infection after splenectomy for benign disease uncommon except infants (infection rate 15.7%) and children <5 years (infection rate 10.4%) Children, predominantly meningitis which is less frequently fatal Adults, in contrast, develop a septicaemic type of illness associated with higher mortality rate Children more susceptible to pneumococcal sepsis than any other organism. No increase in infection in normal people but coexistent disorder, notably hepatic disease, significantly increased risk

    15. Infection risk Review of literature 1966-96 6 78 studies with total of 19,680 patients 3.2% suffered from invasive infection (septicaemia or meningitis) with 1.4% mortality Incidence of infection 3.3% in children and 3.2% in adults Mortality higher in children 1.7% than adults 1.3%

    16. Infection risk Scottish study of splenectomy patients between 198899 7 648 pts with mean follow up of 4.45 yrs 350 pts (21.2%) reported to have severe infection requiring hospitalization after splenectomy First severe infection 7.0 per 100 person yrs 50-80% of severe infection/deaths in1-3 yrs Highest risk in patients haematological malignancy pts (13.3 per 100 person yrs) Septicaemia or meningitis occurred in 3.0% (0.89 per 100 person yrs)

    17. Infection risk Susceptibility to infection greatest in older pts First severe infection 7.0 per 100 person yrs 44.9 per 100 person yrs and 109.3 per 100 person yrs for 2nd and 3rd infection episodes after the 1st episode

    18. Infection risk Australian study of 1490 patients during a 12 year period 8 Severe late post-splenectomy infection incidence 0.42 per 100 person yrs Mortality rates of 0.08 per 100 person yrs. OPSI 0.04 per 100 person yrs In the 628 patients undergoing splenectomy for trauma incidence of 0.21 per 100 person yrs with mortality rate of 0.03 per person yrs. OPSI 0.03 per 100 person yrs Splenectomy pts 12.6 RR of late septicaemia Splenectomy due to trauma 8.6 RR late septicaemia

    19. Infection risk US study from 1993 to 1999 from 8 Childrens Hospitals 9 22 asplenic patients with 26 episodes of invasive S. pneumoniae were identified. 1% of the 2581 episodes of invasive S. pneumoniae infections identified 6 pts died

    20. Microbiology Streptococcus pneumonia most common organism in OPSI causative agent in 50-90% of cases. No difference in serotype distribution compared to other manifestations of infection Haemophilus influenza type b is 2nd commonest. Accounts for 32% of mortality 86% occurring in patients <15 yrs

    21. Microbiology No data that meningococcal infections more frequent/severe but impression is of increased fulminant infection Capnocytophagia canimorsus can cause fulminant sepsis following dog bites. In 80% reported cases asplenia or hyposplenia appears to be predisposing factor

    22. Summary Risk of post splenectomy sepsis low but carries high risk of death (50-80%) If patients are educated to seek attention immediately may be reduced to about 10% More than 50% who die do so within 48 hours of admission 10

    23. Malaria Malaria Lack of splenic clearance of leads to high parasitaemia Increased risk of fulminant malaria

    24. Other infections Intra-erythrocytic infections Babesiosis Occurs in Scotland Bartonellosis Some strains only

    25. Management issues Antibiotic prophylaxis Very little trial data! Immunisations Which vaccines? Licensed? Appropriate? Antibody testing?

    26. Immunisation - Pneumococcal No randomised controlled trials Norwegian study of 325 pts underwent staging laparotomy and splenectomy for Hodgkin's disease 1969-80 11 162 pts (49.8%) died before 1994, 8 (2.4%) from pneumococcal septicaemia and 16 (6.2%) from all infections Of 163 patients (50.2%) still alive 158 traced

    27. Immunisation - Pneumococcal 22 hospitalized for serious infection; 2 with pneumococcal septicaemia, and 6 with pneumonia without microbiological diagnosis. Incidence rate of systemic pneumococcal disease of 226 per 100,000 patient-yrs or RR 20.5 compared to general population Septicaemia often had abrupt clinical start occurring from 2-17 yr post splenectomy (mean 10 yr) The risk of overwhelming pneumococcal septicaemia in asplenic patients seems to persist even after 15-20 yrs

    28. Immunisation - Pneumococcal The specific antibody response (IgM and IgG) in asplenic hosts is delayed with a magnitude lower than controls 11 One study during 1 year of follow up antibody responses declined linearly by 24-32% from peak antibody concentration12

    29. Immunisation - Pneumococcal Prospective study of 311 splenectomised pts (208 HL; 65 AIC; 28 Trauma) 13 Depending on antibody levels pts revaccinated with Pneumovax up to 4x For each vaccination antibodies done at vaccination, after 1 month 2 weeks (peak), and after 1 year 6 months (follow-up) A significant response was seen on primary vaccination as well as on revaccination occasions for all pts No factors predictive of antibody response No severe adverse events to revaccination were reported Recommend monitoring of antibodies and frequent revaccination (1-5 yrs)

    30. Immunisation - Pneumococcal 76 splenectomised patients (HL 26, NHL 19, AIC 28, others 3) with median age 52 yrs (range 18-82) vaccinated with Pneumovax 14 Pneumococcal antibodies determined before vaccination, peak and follow-up Poor response to vaccination was observed in 21 (28%) pts During the follow-up period of 7.5 yrs (range 3.5-10.5 yrs) after vaccination 5 episodes (in 3 pts) of pneumococcal infections All infections in the poor responder group Revaccination of poor responders did not improve antibody levels No factors predictive of a poor antibody response Antibody levels useful to identify poor responders

    31. Immunisation Pneumococcal and Hib Danish study of 149 splenectomised pts between 1984 and 1993 15 Though vaccine coverage among the 149 persons was 91% only 52% had 'protective' levels of pneumococcal antibodies. Despite recommendations for regular follow-up of pneumococcal antibody levels this was only done in 4% Splenectomised pts with low pneumococcal antibody levels significantly more likely to have received initial vaccination less than 14 days before or after splenectomy All persons had Hib antibody levels higher than 0.15 g/ml and 60% had levels higher than 1 g/ml

    32. Immunisation - Hib Role of anti-PRP Hib >0.15 g/ml short term protection Hib> 1.0 g/ml long term protection Conjugate vaccines 70% infants >0.15 g/ml 40% infants >1 g/ml 90% protection

    33. Immunisation - Hib UK study 1992 - 99 in which children developing invasive Hib disease despite 3 doses of Hib conjugate vaccine were reported 16 Separate antibody studies in 2 cohorts of children (n = 153 and n = 107) 96 true vaccine failures occurring after 3 vaccine doses detected for est. 4.3 million Failure rate 2.2 per 100,000 Vaccine effectiveness declined significantly after the 1st yr but remained high until the 6th yr of life (99.4% 5-11 months vs. 97.3% 12-71 months). Numbers with anti-PRP <0.15 g/mL increased between 12 and 72 months (6% at 12 months to 32% at 72 months) Anti-PRP antibody levels and clinical protection against Hib disease wane over time after Hib vaccination

    34. Immunisation - Hib Immunogenicity of a conjugate Hib vaccine was investigated in 57 pts with thalassemia, 32 of whom had undergone splenectomy 17 Anti-capsular antibodies to Hib measured before, 2, 6, 12, 24, and 36 months after vaccination Immunization was well tolerated All patients achieved protective (>1 g/mL) antibody levels Antibody titers declined after the initial post-vaccination increase, becoming undetectable in 4 pts and decreasing to 0.15-1 g/mL in 2 pts when tested 2-3 yrs after vaccination Additional studies are needed to assess the need and timing of booster vaccination to maintain long-term immunity

    35. Immunisation Men C 22 asplenic pts and healthy controls immunized with bivalent A and C meningococcal polysaccharide vaccine 18 No adverse reactions to the vaccine Antibody results compiled for both seroconversions and changes antibody titres Traumatic splenectomy pts and controls showed a polyclonal antibody response to both vaccine antigens

    36. Immunisation Men C Splenectomy for non-lymphoid tumors nearly as good a response as normal Splenectomy for lymphoid tumors (with prior chemotherapy and radiotherapy) had poor responses to both antigens Meningococcal vaccine is immunogenic in asplenic persons except patients with lymphoid tumours

    37. Immunisation Men C 130 asplenic and 48 controls given meningococcal serogroup C conjugate (MCC) vaccine 19 Asplenics significantly lower mean titre of bactericidal antibody in serum (SBA) than an age-matched controls 80% of asplenic individuals achieved the proposed protective SBA titer of =8. No differences in serogroup C-specific IgG mean concentration

    38. Immunisation Men C A significant reduction in titres if medical reason for splenectomy 29 pts who did not achieve protective titre were offered 2nd dose 61% (14 of 23) of the individuals who received a second dose achieved a protective titre 93% of asplenic individuals achieved a titer of =8 (1 or 2 doses) Recommended following vaccination of asplenics, either antibody level should be determined, with a second dose of MCC vaccine offered to non-responders, or 2 doses of MCC vaccine offered

    39. Current DH Guidance Pneumococcal vaccine every 5 years But significant patients will be below threshold after two years Value of conjugated vaccine not addressed Hib-MenC conjugate vaccine No trial data in adults! Not licensed in adults! Antibody testing not recommended

    40. Evidence for Prophylaxis Prophylactic antibiotics in children with sickle cell anaemia Children randomly assigned to penicillin V (105 children) or placebo (110 children) twice daily Trial terminated 8 months early, after an average of 15 months of follow-up due to 84 % reduction in the incidence of infection in the penicillin group vs. placebo (13 of 110 patients vs. 2 of 105) No deaths from pneumococcal septicemia occurred in penicillin group but 3 deaths in placebo group [16]. Little data for the use of prophylaxis in adults

    42. Acknowledgements Dr. Andrew McLean-Tooke Dr. Angela Galloway Drs. Mike Snow, Ed Ong, Matt Schmid, Ashley Price

    43. Antibiotic Prophylaxis 1. All patients, regardless of underlying condition, should be on lifelong antibiotic prophylaxis. This should be either Penicillin V or Amoxycillin, with a preference for Penicillin V. Adult doses: Penicillin V 500 mg b.d. Amoxycillin 500 mg o.d. 2. For penicillin allergic patients, Erythromycin 250 mg b.d. should be used. 3. Patients travelling to areas where penicillin-resistant pneumococci have been identified [e.g. Spain, Southern France, S.Africa, USA, SE Asia] should be switched from Penicillin V to Amoxycillin before travelling and for one week after return.

    44. Immunisation 4. Asplenia in itself is not a contraindication to routine immunisation. Normal inoculations, including live vaccines, can be given safely to adults with absent or dysfunctional spleens. 5. All splenectomised patients and those with functional hyposplenism should receive pneumococcal immunisation; Haemophilus influenzae type B [Hib] conjugate vaccine and conjugated meningococcal C vaccine [MenC] as soon as possible. For pneumococcal vaccination the 23-polyvalent pneumococcal vaccine [Pneumovax] should be used.

    45. Immunisation 6. Patients undergoing elective splenectomy should receive Pneumococcal, Hib and MenC at least two weeks before surgery. Even after splenectomy these three vaccines should be given (when patient clinically better/prior to discharge), as there may be some benefit. Immunisation, however, should be delayed at least six months after immunosuppressive chemotherapy (including steroids) or radiotherapy, during which time prophylactic antibiotics should be given

    46. Immunisation 7. Antibody titres to pneumococcus and Hib should be measured annually. Revaccination should be undertaken if the antibody levels are low. Some patients fail to respond to Pneumovax. Patients who fail to respond to 2 doses of Pneumovax should be test immunised with heptavalent conjugate vaccine [Prevnar]. Persistent non-responders should be discussed with Adult Immunology Teams [see below]. No satisfactory assay exists for determining protective levels of meningococcal antibodies and single dose of the MenC vaccine only should therefore be given. Thresholds for revaccination are: Pneumovax <35 mg/l Hib <1.5 mcg/ml

    47. Immunisation 8. All adults should receive an annual Influenza immunisation. 9. Patients travelling abroad to high risk areas, especially to the Middle East, should receive a dose of the Meningococcal A+C, W135 & Y vaccine

    48. Treatment of acute infection 110. For patients not allergic to penicillin a supply of amoxycillin should be kept at home (and taken on holiday) and used immediately (1gm) initially followed by 500mg t.d.s.) should infective symptoms of raised temperature, malaise, or shivering develop. In such a situation the patient should seek immediate medical help. Any asplenic/hyposplenic patient who develops a sudden febrile illness should be treated promptly with full dose antibiotics. The onset of overwhelming post-splenectomy sepsis may be extremely rapid and the speed of response may determine the outcome. In the community setting, intravenous benzylpenicillin, after a blood culture [if possible], should be started at once, if the clinical circumstances warrant it, and the patient referred to the nearest acute hospital. If the patient is allergic to penicillin, any available non-penicillin antibiotic can be used.

    49. Treatment of acute infection 11. For patients referred in to Hospital with overwhelming sepsis, commence a 3rd generation cephalosporin [cefotaxime or ceftriaxozone] in an appropriate dose for age and size. If the patient is shocked, consult ITU staff and discuss transfer to HDU.

    50. Treatment of acute infection 112. Patients travelling to malarial areas require specialist advice on prophylaxis, as malaria in splenectomised patients can lead to severe malaria with very high peripheral blood parasite counts. Contact Adult Infectious Disease teams for further advice 113. Human, dog or other animal bites in asplenic/hyposplenic may be fatal if untreated due to infection with Capnocytophaga canimorsus and other virulent organisms. Augmentin [Co-Amoxiclav] 625 mg [500/125] td.s. orally should be commenced immediately. Patients should be referred urgently to Adult Infectious Disease Team

    51. Treatment of acute infection 14. Babesiosis is a tick borne infection with sporadic cases worldwide and endemic areas predominately in United States (Massachusetts Islands, New York Islands, and Connecticut) but cases occur in Scotland. Peak transmission occurs between May to September with an incubation period of 5 to 33 days. This is associated with significant morbidity and mortality in asplenic patients. Patients suspected to have or be at risk of having Babesiosis should be referred urgently to Adult Infectious Disease Team