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A study of 42 episodes of overwhelming post-splenectomy infection: Is current guidance for asplenic individuals being followed?
Journalof Infection (1997) 35, 289-294
A Study of 42 Episodes of Overwhelming Post-splenectomy Infection: Is Current Guidance for Asplenic Individuals Being Followed? D. J. Waghorn .1 and R. T. Mayon-White 2 tWycombe General Hospital, Oueen Alexandra Road, High ½~combe, Bucks HPll 2TZ U.K. and 20xfordshire Health Authority, Old Road, Headington, Oxford OX3 7LG, U.K. Individuals without a spleen have an increased risk of overwhelming post-splenectomy infection (OPSI). Improved awareness in recent years has stimulated increased efforts to prevent OPSI. Published guidelines have described policies for immunization, chemoprophylaxis and other measures considered beneficial to asplenic patients, yet OPSI episodes continue to occur. In an attempt to investigate why serious infections are still being seen, we have conducted a nationally based survey of recent OPSI episodes, using mainly a network of medical microbiologists. Data including clinical background to both splenectomy and OPSI episode, immunization and chemoprophylaxis history have been collated. Forty-two cases of overwhelming infection were reported by June 1996. Patients of all ages were affected with OPSI occurring up to 59 years after splenectomy. A mortality rate of 45 % was seen. Pneumococcal infection caused at least 37 of 42 episodes, but only 12 patients had received pneumococcal vaccine. Four cases were possible vaccine failures. Only 22% of individuals had taken any chemoprophylaxis since spleneetomy, and only one carried a medical alert card. Much more needs to be done to ensure that asplenic patients are warned of the risks of infection, and given at least pneumococcal vaccine. The role of antibiotics for either continual prophylaxis or as a reserve supply for selfprescription at appropriate times also needs greater discussion. Further work on improving pneumococcal vaccine response together with suitable programmes for revaccination are required. Surveillance should continue until the incidence of OPSI reaches an irreducible minimum.
Introduction The risk of life-threatening infection in asplenic individuals h a s been recognized for m a n y years. ~ More recently, increased efforts h a v e been m a d e to i m p r o v e g e n e r a l a w a r e n e s s a n d advise on a p p r o p r i a t e p r e c a u t i o n s to p r e v e n t o v e r w h e l m i n g p o s t - s p l e n e c t o m y infection (OPSI). This raised profile has included leading editorialsz 3 s t i m u l a t i n g further m e d i c a l correspondence, < s mailshots a i m e d at e v e r y g e n e r a l practice, 6 w r i t t e n g u i d a n c e from the D e p a r t m e n t of H e a l t h 7 a n d n u m e r o u s articles in n a t i o n a l n e w s p a p e r s plus o t h e r m e d i a c a m p a i g n s . A few groups h a v e t a k e n their o w n local initiatives. 8'9 Guidelines h a v e r e c e n t l y been published for the m a n a g e m e n t of asplenic a n d f u n c t i o n a l l y hyposplenic individuals, m Despite all s u c h efforts, cases of OPSI c o n t i n u e to occur. Is this b e c a u s e the advice is wrong? Are c u r r e n t p r e v e n t i v e m e a s u r e s ineffective, or h a s t h e advice been unheeded.) One a p p r o a c h to i n v e s t i g a t i n g these issues is * Address correspondence to: D. J. Waghorn. Accepted for publication 11 April 1997. 0163-4453/97/060289 + 06 $12.00/0
to a n a l y s e d a t a from OPSI c a s e s ) A s t u d y h a s been u n d e r t a k e n to e x a m i n e episodes c u r r e n t l y t a k i n g place w i t h i n the U.K. This report describes the findings a n d is intended to stimulate further interest in the problem a n d its prevention.
Methods In A u g u s t 1 9 9 4 a passive surveillance p r o g r a m m e was initiated. A q u e s t i o n n a i r e was devised a n d distributed to all m e m b e r s of the Association of Medical Microbiologists (AMM), requesting cases of OPSI to be reported. A decision was m a d e t h a t clinical microbiologists were the most likely single g r o u p of specialists to e n c o u n t e r cases of OPSI, a n d the AMM m e m b e r s h i p e n c o m p a s s e s most districts w i t h i n the U.K. To reinforce a w a r e n e s s a n d inform o t h e r potential sources of cases, notices r e g a r d i n g the s u r v e y were also published by the C o m m u n i c a b l e Disease Surveillance Centre (CDSC) 1~ a n d the Scottish Centre for Infection a n d E n v i r o n m e n t a l H e a l t h (SCIEH). tz OPSI was defined as septicaernia and~or meningitis,
usually fulminant but not always fatal, occurring days to © 1997 The British Society for the Study of Infection
D.J. Waghorn and R. T. Mayon-White
290
Table Ill. Capsular types of pneumococcal isolates causing OPSI.
Table I. Ages of OPSI cases. Age group
No. of cases (total = 42)
<2 years 2-19 years 20-29 years 30-39 years 40-49 years 50-59 years 60-69 years 70-79 years 80-89 years
1 0 5 10 10 7 4 4 1
Bears after the removal of the spleen. Information asked for included data on the acute OPSI episode, background to the patient's asplenic state and information on immunization and antibiotic prophylaxis history. In a further attempt to maximize data for the study, CDSC asked individual clinicians who had recently reported to them cases of septicaemia and/or meningitis accompanied by asplenia to send a completed OPS[ questionnaire.
Results By June 1996 42 OPSI cases had been reported, one from 1992, two from 1993, 16 from 1994, i 7 from 1995 and six from the first half of 1996. There were 26 males and 16 females, with an age range from 18 months to 85 years (Table I). Two individuals had not undergone surgical splenectomy, These were a child with congenital asplenism found soon after birth and a w o m a n with dermatitis herpetiformis discovered to have severe splenic atrophy at autopsy following overwhelming infection. In the remaining 40 cases, the interval from splenectomy to OPSI varied from 24 days to 59 years (Table II).
Table II. Time interval from splenectomy to OPSI. Time interval
No. of cases
(total = 40)* <3 months 1-4 years 5-9 years i 0 - 1 9 years 20-29 years 30-39 years 40-49 years >50 years Unknown
2 2 3 15 8 6 1 2 1
* Child with congenital asplenia and adult with severe splenic atrophy not included.
Pneumococcal capsular type
No. of cases (total = 37)
4~
2
6A 6B~ 7A 7F~
1' 2 1 1
9v~
1
10" 12F~ 17F{ 18"
1 5 1 1
18C~ 20~
1 1
22F~ 23* 23F~ 29 34 38 Unknown
2 2 1 1 1 1 11
* Subtype not known. ~ Capsular types included in current pneumococcal vaccine.
The most common reason for splenectomy was t r a u m a (13 cases). Other causes were lymphoma including Hodgkins (eight cases), idiopathic thrombocytopenia (six cases), haemolytic anaemias (five cases), damage at abdominal surgery for nonmeoplastic disease (four cases) and one case each of chronic lymphocytic leukaemia, chronic granulomatous disease, myelofibrosis and thrombocytopenia associated with systemic lupus erythematosis. Nineteen patients died (45% mortality) as a direct result of their OPSI episode. Thirty-one patients had pneumococcal septicaemia; six of these cases were accompanied by meningitis, and in one case each by endocarditis and septic arthritis. Six further cases of pneumococcal meningitis without clinical septicaemia were reported; in one case pneumococcal infection was diagnosed by latex agglutination of cerebrospinal fluid rather t h a n by positive culture. Thus, 37 OPSI episodes (88%) were due to confirmed Streptococcus pneumoniae infection. Pneumococcal capsular types were available for 26 cases (Table III). Five other cases of septicaemia were reported. One infection was due to Klebsiella pneumoniae, another to Escherichia coli, and a third to Salmonella tHphimurium. In two episodes no specific organism was identified. Twelve of 40 patients for w h o m the information was available had received pneumococcal vaccine before their OPSI episode. Only one patient had post-immunization pneumococcal antibodies measured 1 m o n t h after vaccine administration. Ten of these 12 suffered pneumococcal infections and at least four could be considered
A Study of Overwhelming Post-splenectomy Infection
291
Table IV. Cases who received pneumococcalvaccine before OPSI. Case no.
Reasonfor splenectomy
Time i n t e r v a l between vaccination and OPSI
Pneumococcal type or other organism
Fatal episode
Possiblevaccine failure
6 12 16
Chronic granulomatous disease Myelofibrosis Surgery for non-neoplastic disease (portal hypertension) Surgery for non-neoplastic disease (partial pancreatectomy) Hodgkins lymphoma idiopathic thrombocytopenia Haemolytic anaemia Idiopathic thrombocytopenia Haemolytic anaemia Non-Hodgkins lymphoma Chronic lymphocytic leukaemia Systemic lupus erythematosis with thrombocytopenia
27 days 3 months 1 year
29 Organism not identified KIebsiellasp.
No No No
No Na* Na*
12F
Yes
Yes
15 months 7 years 11 years 2.5 y e a r s 2 months 2 years 2 years
22F Pneumococcus type unknown 9V Pnemnococcus type unknown 23F 6B Pneumococcus type unknown
Yes No Yes No No No Yes
Yes Unknown NoT Unknown Yes Yes Unknown
4 months
Pneumococcus type unknown
No
Unknown
17 22 24 31 32 33 35 37 41
5 years
* Not applicable. Although infecting pneumococcalserotype included in vaccine, patient had not received booster immunization.
possible vaccine failures (Table IV). Three individuals were given pneumococcal immunization following their OPS[ episode. The 18-month-old child (case 8) with congenital asplenism had suffered a septicaemia due to S. pneumoniae type 23, but immunization had been deferred because of the predicted poor antibody response under 2 years of age. Two individuals had been offered but refused pneumococcal vaccine. One case, a 29-year-old man (case 7) who had idiopathic thrombocytopenia as a child, died following his third attack of pneumococcal meningitis. He had been taking prophylactic penicillin regularly, but had not renewed his prescription when it expired 10 days before the fatal episode. The other refusal came from a 67-year-old m a n (case 21) who had undergone splenectomy aged 8; he survived his pneumococcal meningitis episode. Both these patients' capsular types would have been covered by the pneumococcal vaccine. Five patients had received Haemophilus influenzae type b (Hib) vaccine before OPSI, including the child who had been given Hib as part of his routine infant immunization programme. A further three patients were given Hib after their OPSI episode. Three patients had received meningococcal vaccine before OPSI, with another three cases immunized afterwards. Antibiotic prophylaxis information was available on 40 cases. Nine individuals had taken prophylaxis for variable periods before 0PSI, with six of these nine on
medication at the time of their episode (Table V). None of the patients not taking regular prophylaxis kept a stock of antibiotic at home to self-prescribe for early symptoms of infection. 0nly one patient possessed a medical alert card describing his asplenic condition.
Discussion This survey is unlikely to have included all OPSI episodes from the last 2-3 years within the U.K. The reliance on reporting mainly by clinical microbiologists may be open to inherent bias, such as declaring only those cases where an organism had been identified or infections caused only by S. pneumoniae. Allowing for these limitations, the study clearly demonstrates that life-threatening infections in asplenic individuals are continuing to occur despite the recent increased effort in professional and public education. A mortality rate of 45% is disturbing, particularly when a significant number of episodes are taking place in those aged under 50 who are in otherwise good health. One hopeful sign that guidance is beginning to be followed, at least for people who have recently had splenectomies, is the relatively few patients in this series who had undergone surgery in the previous 4 years. The highest risk of OPSI is said to exist within the first few years after surgery, 3 but this study confirms that the risk remains for life, with almost 60% of cases occurring
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D.J. Waghorn and R. T. Mayon-White
Table V. Details of nine cases who had taken chemoprophylaxis before sepsis. Case no. 6
Reason for splenectomy
Cause of infection
Fatal episode
Antibiotic history
Chronic granulomatous disease
S. pneumoniae
No
Took erythromycin for 7 days only after splenectomy; OPSI occurred 17 days later. Pneumococcus sensitive to penicillin and erythromycin. Took penicillin V for 14 years but stopped 10 days before OPSI because had not renewed prescription. Had refused pneumococcaI vaccine. Pneumococcus sensitive to penicillin. Infant took amoxycillin 62.5 mg twice daily since asplenia discovered soon after birth. Pneumococcus sensitive to penicillin. Took penicillin V 250 mg four times a day for 34 days between splenectomy and OPSI. Took penicillin V for 30 years between splenectomy and OPSI. Took penicillin V 250 mg twice a day for 10 years between splenectomy and OPSI. Pneumococcus sensitive to penicillin. Took penicillin V for 8 years from splenectomy till aged 16. OPSI occurred 4 years later. Took erythromycin 500 mg once a day for the 3 years prior to this OPSI episode, following an earlier episode. Pneumococcus resistant to erythromycin but sensitive to penicillin. 'rook penicillin V 500 mg twice daily for 2 years between splenectomy and OPSI. Pneumococcus sensitive to penicillin.
type 29 7
Idiopathic thrombocytopenia
S. pneumoniae
Yes
type 22F 8
Congenital asplenism
S. pneumoniae
No
type 23 12
Myelofibrosis
Unknown
No
16
Surgery for non-neoplastic disease (portal hypertension) Hodgkins lymphoma
Klebsiellasp.
No
S. pneumoniae
Yes
22
type 22F 31
Haemolytic anaemia
S. pneumoniae
Yes
type 9V 35
Non-Hodgkins lymphoma
S. pneumoniae
No
type 6B 37
Chronic lymphocytic leukaemia
S. pneumoniae type
unknown
1 0 - 3 0 y e a r s later a n d two individuals infected m o r e t h a n 50 y e a r s after splenectomy. The risk of sepsis also varies w i t h t h e i n d i c a t i o n for s p l e n e c t o m y a n d a n y u n d e r l y i n g disease. Neoplasia, especially h a e m a t o l o g i c a l , is r e p o r t e d to c a r r y the h i g h e s t risk, ~3 a n d in this series potentially severe u n d e r l y i n g i m m u n o s u p p r e s s i v e disease h a d b e e n p r e s e n t in 26%. Overall, t r a u m a w a s t h e leading cause for splenectomy, s t r e n g t h e n i n g the need to offer o p t i m a l p r o t e c t i o n for all asplenic individuals irrespective of aetiology. H y p o s p l e n i s m c a n result in i m p a i r e d i m m u n i t y a n d severe sepsis. ~4 A n association is found w i t h a n u m b e r of diseases i n c l u d i n g sickle cell disease, coeliac disease a n d d e r m a t i t i s herpetiformis, as seen in one fatal case from this series. Clinicians should be a w a r e of diseases associated w i t h h y p o s p l e n i s m so t h a t periodic blood films m a y be e x a m i n e d to aid diagnosis. If features of h y p o splenism are found, t h e p a t i e n t s h o u l d be m a n a g e d as a n asplenic individual. 1~ Despite t h e sparsity of d a t a s h o w i n g clear clinical efficacy in asplenic patients, ~6 p n e n m o c o c c a l imm u n i z a t i o n is accepted as a m a j o r p a r t of t h e p r e v e n t i v e s t r a t e g y a g a i n s t infection. A p p a r e n t vaccine failures were expected, b u t it w a s d i s a p p o i n t i n g to discover t h a t only 12 patients h a d received p n e u m o c o c c a l vaccine prior to their OPSI episode, especially as p n e u m o c o c c i were
Yes
responsible for at least 88% of infections, a figure in line w i t h earlier reports. 17 Of the 12 cases w h o h a d received i m m u n i z a t i o n , t e n suffered p r o v e n p n e u m o c o c c a l infection. Possible vaccine failure could be a t t r i b u t e d to at least four episodes. I n t h e r e m a i n i n g 27 cases of p n e u m o c o c c a l infection w h e r e i m m u n i z a t i o n h a d n o t been administered, t h e c u r r e n t 2 3 - v a l e n t p o l y s a c c h a r i d e vaccine w o u l d h a v e covered up to 85% of strains a n d therefore m a y h a v e offered some p r o t e c t i o n to those infected. In one reported series of asplenic h a e m a t o l o g y patients, o n l y four episodes o f p n e u m o c o c c a l s e p t i c a e m i a / meningitis were observed in over 2 0 0 v a c c i n a t e d individuals w i t h i n a 1 3 - y e a r period, ~s a n d in all four episodes the infecting c a p s u l a r type w a s n o t included in t h e vaccine. Only one of t h e 12 patients given p n e u m o c o c c a l vaccine h a d a n t i b o d y levels checked after i m m u n i z a t i o n . Up to 20% of asplenic individuals m a y s h o w poor a n t i b o d y responses to p n e u m o c o c c a l p o l y s a c c h a r i d e vaccines, a n d a n t i b o d y levels m a y decline m o r e rapidly t h a n in those still possessing a s p l e e n ] 9 The level of p n e u m o c o c c a l a n t i b o d y considered protective is undecided, b u t some a u t h o r s h a v e r e c o m m e n d e d t h a t t i m i n g of booster imm u n i z a t i o n s should be based on p n e u m o c o c c a l a n t i b o d y m e a s u r e m e n t . 2°'21 The o p t i m a l frequency of m e a s u r i n g antibodies is unclear, b u t a r e c o m m e n d a t i o n
A Study of Overwhelming Post-splenectomy Infection of preimmunization, 1 month after and subsequently at 3 and 5 years has been made. 22 Individuals with poor or absent responses could then be targeted for life-long chemoprophylaxis. Only 10% of patients had been given Hib and meningococcal vaccines before their OPSI episodes. Both H. influenzae and Neisseria meningitidis have been reported as important causes of septicaemia in asplenic individuals, ~3'24 leading to the recommendations for vaccination, 7'2s but the protective efficacy of either Hib or meningococcal vaccine in asplenic patients has not been proven. No cases of 14. influenzae or N. meningitidis infection were reported in this study, confirming that S. pneumoniae is the outstanding pathogen in relation to OPSI. The role of antibiotic prophylaxis remains controversial, and patient records in this series highlight the problem. Only 22% of individuals had received any chemoprophylaxis following splenectomy, whilst half of the infecting isolates, in those on medication at the time of OPSI, showed in vitro sensitivity to the prescribed agent. There are no data relating to the efficacy of chemoprophylaxis in asplenic patients, 26 yet recent guidelines have recommended life-long antibiotics, l° Concern over increasing resistance of, especially, pneumococci to the commonly used prophylactic agents, together with patient compliance difficulties, have influenced others to advise that a supply of antibiotic should be kept at home to serf-prescribe at the first signs of possible infection. 27'2s This option was not reported for any patient in this series. Based on two audits of asplenic patients in defined populations, ~'29 we estimate that there are 4 0 - 5 0 000 asplenic individuals within the U.K., and their increased risk of severe sepsis is now unquestioned. This study suggests that although cases of OPSI will continue to occur, current guidance for protection is only being partially implemented, i.e. on individuals who have undergone recent surgery. There needs to be a more active case finding search for patients who underwent splenectomy many years previously, so that they may be offered protection. It is likely that an irreducible minimum number of cases will persist due to vaccine failure and refusal to take chemoprophylaxis when appropriate. However, this should not deflect from continuing to offer the available vaccines and information about the infection risk to all asplenic patients. Development of vaccines is urgently required to improve the immune response, especially for pneumococcal vaccine. The protective efficacy of antibiotic prophylaxis will remain contentious unless a prospective nationally based study can be performed, but this may prove difficult. 3° Heightened patient awareness, by adopting an active education programme, can be achieved at a local
293
district level. In most circumstances the clinical microbiologist and/or infectious disease physician can contribute to the vital initial guidance given to patients immediately after splenectomy, especially if an automatic referral system, for example, can be introduced between the surgical wards and clinical microbiology/infectious disease service. Furthermore, they should identify who in their hospital/district is ensuring that guidance is applied locally. improvement in the overall management of the asplenic individual still requires further research, and the necessary data should be obtained from co-ordinated regional and national studies.
Acknowledgements We are grateful to the AMM, CDSC and to the following, who have reported OPSI cases: GE Bignardi, Sl Bourke, R Brindle, CR Catchpole, JS Cheesbrough, RA Cox, D Crook, J Cunniffe, K Daly, A Fife, L Fitch, AP Gillett, LR Griffiths, M Lockhart, DN Looker, JA Lowes, P McKay, B Marshall, MG Morgan, D Muir, I Muscat, S Parker, S Partridge, E Ridgway, T Riordan, T Roomaya, MH Snow, A Sohal, C Tremlett, PF Unsworth, M] Weinbren, N Williams. ED Wright, EP Wright, ML 'fee. We shall be grateful to receive reports on further cases of OPSI.
References 1 Jenks PJ, Jones E. Infections in asplenic patients. Clin Micro Infect 1996; 1: 266-272. 2 McMullin M, Johnston G. Long term management of patients after splenectomy. BMJ 1993; 307: 1372-1373. 3 Reid MM. Splenectomy, sepsis, immunisation, and guidelines. Lancet 1994; 344: 970-971. 4 Flegg PJ. National guidelines, please. BMJ 1994; 308: 131. 5 0 b a r o SK, Henderson DC, Monteil M. Immunity to pneumococcal infections. Lancet 1995; 345: 70-71. 6 Baddeley P, Boyer P, Mayon-White R. Fact sheets, posters, and protocol cards available. BMJ 1994; 308: 132. 7 Department of Health. Asplenic patients and immunisation. CMO's Update 1994; 1: 3. 8 MacInnes J, Waghorn DJ, Haworth E. Management of asplenic patients in South Buckinghamshire: an audit of local practice. Public Health Laboratory Service CDR Review 1995; 5:R173-R177. 9 Long SG, Smith AG, Perry BA, Leyland MJ, Milligan DW. Implementing a policy for pneumococcal prophylaxis in a haematology unit after splenectomy. QualitL d in Health Cam 1995; 4: 194-196. 10 Worldng Party of the British Committee for Standards in Haematology Clinical Haematology Task Force. Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. BM] 1996; 312: 430-434. l l Anonymous. Surveillance of overwhelming infection following splenectomy. Public Health Laboratorly Service CDR Week19 1994; 4: 169. 12 Anonymous. Overwhelming infection following splenectomy. Scottish Centre for Infection and Environmental Health SCIEH Week19 Report 1995; 29: I. 13 Shaw JH, Print CG. Postsplenectomy sepsis. Br J Surg 1989; 76: 1074-1081. 14 McKay PJ, Kennedy DH, Lucie NE Should hyposplenic patients receive prophylaxis against bacterial infection? Scot Med J 1993: 38: 51-52. 15 Muller AF, Toghill PJ. Hyposplenic patients need prophylactic penicillin. BM] 1994; 308: 132-133. 16 Fielding AK. Prophylaxis against late infection following splen-
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ectomy and bone marrow transplant. Blood Reviews 1994; 8: 179-191, Van Wyke DB. Overwhelming post-splenectomy infection (OPSI): the clinical syndrome. L~rnphology 1983; 16: 107-114. Abildgaard N, Nielsen JL. Pneumococcal septicaemia and meningitis in vaccinated splenectomised adult patients. ScandJ Infect Dis 1994; 26: 615-617. Hazlewood M, Kumararatne DS. The spleen. Who needs it anyway? Clin Exp Immunol 1992; 89: 327-329. Konradsen HB, Pedersen FK, Henrichsen ]. Pneumococcal revaccination of splenectomized children. Pediatr Infect Dis ] 1990; 9: 258-263. Konradsen HB. The need for revaccination 10 years after primary pneumococcal vaccination in splenectomized adults. Scand] Infect Dis 1991; 23: 397. Kassianos GC. Uncertainty exists over frequency of blood tests to test antipneumococcal immunity. BMJ 1996; 312: 1360-1361.
23 Anonymous. Splenectomy - a long-term risk of infection. Lancet 1985; ii: 928-929. 24 Holdsworth R], Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Sur~ 1991; 78: 1031-1038. 25 Spelman DW. Postsplenectomy overwhelming sepsis: reducing the risks. Med J Aust 1996; 164: 648. 26 Read RC, Finch RG. Prophylaxis after splenectomy. I Antimierob Chemother 1994; 33: 4-6. 27 Finch RG, Read R. Lifelong penicillin may be ineffective. BM] 1994; 308: 132. 28 Waghorn D]. Prevention of postsplenectomy sepsis. Lancet 1993; 341: 248. 29 Deodhar HA, Marshall RJ, Barnes JN. Increased risk of sepsis after splenectomy. BMJ 1993; 307: 1408-1409. 30 Makris M, Greaves M, Winfield DA, Preston FE, Lilleyman JS. Lifelong penicillin unproved in trials. BM] 1994; 308: 131-132.
A Study of 42 Episodes of Overwhelming Post-splenectomy Infection: Is Current Guidance for Asplenic Individuals Being Followed? D. J. Waghorn .1 and R. T. Mayon-White 2 tWycombe General Hospital, Oueen Alexandra Road, High ½~combe, Bucks HPll 2TZ U.K. and 20xfordshire Health Authority, Old Road, Headington, Oxford OX3 7LG, U.K. Individuals without a spleen have an increased risk of overwhelming post-splenectomy infection (OPSI). Improved awareness in recent years has stimulated increased efforts to prevent OPSI. Published guidelines have described policies for immunization, chemoprophylaxis and other measures considered beneficial to asplenic patients, yet OPSI episodes continue to occur. In an attempt to investigate why serious infections are still being seen, we have conducted a nationally based survey of recent OPSI episodes, using mainly a network of medical microbiologists. Data including clinical background to both splenectomy and OPSI episode, immunization and chemoprophylaxis history have been collated. Forty-two cases of overwhelming infection were reported by June 1996. Patients of all ages were affected with OPSI occurring up to 59 years after splenectomy. A mortality rate of 45 % was seen. Pneumococcal infection caused at least 37 of 42 episodes, but only 12 patients had received pneumococcal vaccine. Four cases were possible vaccine failures. Only 22% of individuals had taken any chemoprophylaxis since spleneetomy, and only one carried a medical alert card. Much more needs to be done to ensure that asplenic patients are warned of the risks of infection, and given at least pneumococcal vaccine. The role of antibiotics for either continual prophylaxis or as a reserve supply for selfprescription at appropriate times also needs greater discussion. Further work on improving pneumococcal vaccine response together with suitable programmes for revaccination are required. Surveillance should continue until the incidence of OPSI reaches an irreducible minimum.
Introduction The risk of life-threatening infection in asplenic individuals h a s been recognized for m a n y years. ~ More recently, increased efforts h a v e been m a d e to i m p r o v e g e n e r a l a w a r e n e s s a n d advise on a p p r o p r i a t e p r e c a u t i o n s to p r e v e n t o v e r w h e l m i n g p o s t - s p l e n e c t o m y infection (OPSI). This raised profile has included leading editorialsz 3 s t i m u l a t i n g further m e d i c a l correspondence, < s mailshots a i m e d at e v e r y g e n e r a l practice, 6 w r i t t e n g u i d a n c e from the D e p a r t m e n t of H e a l t h 7 a n d n u m e r o u s articles in n a t i o n a l n e w s p a p e r s plus o t h e r m e d i a c a m p a i g n s . A few groups h a v e t a k e n their o w n local initiatives. 8'9 Guidelines h a v e r e c e n t l y been published for the m a n a g e m e n t of asplenic a n d f u n c t i o n a l l y hyposplenic individuals, m Despite all s u c h efforts, cases of OPSI c o n t i n u e to occur. Is this b e c a u s e the advice is wrong? Are c u r r e n t p r e v e n t i v e m e a s u r e s ineffective, or h a s t h e advice been unheeded.) One a p p r o a c h to i n v e s t i g a t i n g these issues is * Address correspondence to: D. J. Waghorn. Accepted for publication 11 April 1997. 0163-4453/97/060289 + 06 $12.00/0
to a n a l y s e d a t a from OPSI c a s e s ) A s t u d y h a s been u n d e r t a k e n to e x a m i n e episodes c u r r e n t l y t a k i n g place w i t h i n the U.K. This report describes the findings a n d is intended to stimulate further interest in the problem a n d its prevention.
Methods In A u g u s t 1 9 9 4 a passive surveillance p r o g r a m m e was initiated. A q u e s t i o n n a i r e was devised a n d distributed to all m e m b e r s of the Association of Medical Microbiologists (AMM), requesting cases of OPSI to be reported. A decision was m a d e t h a t clinical microbiologists were the most likely single g r o u p of specialists to e n c o u n t e r cases of OPSI, a n d the AMM m e m b e r s h i p e n c o m p a s s e s most districts w i t h i n the U.K. To reinforce a w a r e n e s s a n d inform o t h e r potential sources of cases, notices r e g a r d i n g the s u r v e y were also published by the C o m m u n i c a b l e Disease Surveillance Centre (CDSC) 1~ a n d the Scottish Centre for Infection a n d E n v i r o n m e n t a l H e a l t h (SCIEH). tz OPSI was defined as septicaernia and~or meningitis,
usually fulminant but not always fatal, occurring days to © 1997 The British Society for the Study of Infection
D.J. Waghorn and R. T. Mayon-White
290
Table Ill. Capsular types of pneumococcal isolates causing OPSI.
Table I. Ages of OPSI cases. Age group
No. of cases (total = 42)
<2 years 2-19 years 20-29 years 30-39 years 40-49 years 50-59 years 60-69 years 70-79 years 80-89 years
1 0 5 10 10 7 4 4 1
Bears after the removal of the spleen. Information asked for included data on the acute OPSI episode, background to the patient's asplenic state and information on immunization and antibiotic prophylaxis history. In a further attempt to maximize data for the study, CDSC asked individual clinicians who had recently reported to them cases of septicaemia and/or meningitis accompanied by asplenia to send a completed OPS[ questionnaire.
Results By June 1996 42 OPSI cases had been reported, one from 1992, two from 1993, 16 from 1994, i 7 from 1995 and six from the first half of 1996. There were 26 males and 16 females, with an age range from 18 months to 85 years (Table I). Two individuals had not undergone surgical splenectomy, These were a child with congenital asplenism found soon after birth and a w o m a n with dermatitis herpetiformis discovered to have severe splenic atrophy at autopsy following overwhelming infection. In the remaining 40 cases, the interval from splenectomy to OPSI varied from 24 days to 59 years (Table II).
Table II. Time interval from splenectomy to OPSI. Time interval
No. of cases
(total = 40)* <3 months 1-4 years 5-9 years i 0 - 1 9 years 20-29 years 30-39 years 40-49 years >50 years Unknown
2 2 3 15 8 6 1 2 1
* Child with congenital asplenia and adult with severe splenic atrophy not included.
Pneumococcal capsular type
No. of cases (total = 37)
4~
2
6A 6B~ 7A 7F~
1' 2 1 1
9v~
1
10" 12F~ 17F{ 18"
1 5 1 1
18C~ 20~
1 1
22F~ 23* 23F~ 29 34 38 Unknown
2 2 1 1 1 1 11
* Subtype not known. ~ Capsular types included in current pneumococcal vaccine.
The most common reason for splenectomy was t r a u m a (13 cases). Other causes were lymphoma including Hodgkins (eight cases), idiopathic thrombocytopenia (six cases), haemolytic anaemias (five cases), damage at abdominal surgery for nonmeoplastic disease (four cases) and one case each of chronic lymphocytic leukaemia, chronic granulomatous disease, myelofibrosis and thrombocytopenia associated with systemic lupus erythematosis. Nineteen patients died (45% mortality) as a direct result of their OPSI episode. Thirty-one patients had pneumococcal septicaemia; six of these cases were accompanied by meningitis, and in one case each by endocarditis and septic arthritis. Six further cases of pneumococcal meningitis without clinical septicaemia were reported; in one case pneumococcal infection was diagnosed by latex agglutination of cerebrospinal fluid rather t h a n by positive culture. Thus, 37 OPSI episodes (88%) were due to confirmed Streptococcus pneumoniae infection. Pneumococcal capsular types were available for 26 cases (Table III). Five other cases of septicaemia were reported. One infection was due to Klebsiella pneumoniae, another to Escherichia coli, and a third to Salmonella tHphimurium. In two episodes no specific organism was identified. Twelve of 40 patients for w h o m the information was available had received pneumococcal vaccine before their OPSI episode. Only one patient had post-immunization pneumococcal antibodies measured 1 m o n t h after vaccine administration. Ten of these 12 suffered pneumococcal infections and at least four could be considered
A Study of Overwhelming Post-splenectomy Infection
291
Table IV. Cases who received pneumococcalvaccine before OPSI. Case no.
Reasonfor splenectomy
Time i n t e r v a l between vaccination and OPSI
Pneumococcal type or other organism
Fatal episode
Possiblevaccine failure
6 12 16
Chronic granulomatous disease Myelofibrosis Surgery for non-neoplastic disease (portal hypertension) Surgery for non-neoplastic disease (partial pancreatectomy) Hodgkins lymphoma idiopathic thrombocytopenia Haemolytic anaemia Idiopathic thrombocytopenia Haemolytic anaemia Non-Hodgkins lymphoma Chronic lymphocytic leukaemia Systemic lupus erythematosis with thrombocytopenia
27 days 3 months 1 year
29 Organism not identified KIebsiellasp.
No No No
No Na* Na*
12F
Yes
Yes
15 months 7 years 11 years 2.5 y e a r s 2 months 2 years 2 years
22F Pneumococcus type unknown 9V Pnemnococcus type unknown 23F 6B Pneumococcus type unknown
Yes No Yes No No No Yes
Yes Unknown NoT Unknown Yes Yes Unknown
4 months
Pneumococcus type unknown
No
Unknown
17 22 24 31 32 33 35 37 41
5 years
* Not applicable. Although infecting pneumococcalserotype included in vaccine, patient had not received booster immunization.
possible vaccine failures (Table IV). Three individuals were given pneumococcal immunization following their OPS[ episode. The 18-month-old child (case 8) with congenital asplenism had suffered a septicaemia due to S. pneumoniae type 23, but immunization had been deferred because of the predicted poor antibody response under 2 years of age. Two individuals had been offered but refused pneumococcal vaccine. One case, a 29-year-old man (case 7) who had idiopathic thrombocytopenia as a child, died following his third attack of pneumococcal meningitis. He had been taking prophylactic penicillin regularly, but had not renewed his prescription when it expired 10 days before the fatal episode. The other refusal came from a 67-year-old m a n (case 21) who had undergone splenectomy aged 8; he survived his pneumococcal meningitis episode. Both these patients' capsular types would have been covered by the pneumococcal vaccine. Five patients had received Haemophilus influenzae type b (Hib) vaccine before OPSI, including the child who had been given Hib as part of his routine infant immunization programme. A further three patients were given Hib after their OPSI episode. Three patients had received meningococcal vaccine before OPSI, with another three cases immunized afterwards. Antibiotic prophylaxis information was available on 40 cases. Nine individuals had taken prophylaxis for variable periods before 0PSI, with six of these nine on
medication at the time of their episode (Table V). None of the patients not taking regular prophylaxis kept a stock of antibiotic at home to self-prescribe for early symptoms of infection. 0nly one patient possessed a medical alert card describing his asplenic condition.
Discussion This survey is unlikely to have included all OPSI episodes from the last 2-3 years within the U.K. The reliance on reporting mainly by clinical microbiologists may be open to inherent bias, such as declaring only those cases where an organism had been identified or infections caused only by S. pneumoniae. Allowing for these limitations, the study clearly demonstrates that life-threatening infections in asplenic individuals are continuing to occur despite the recent increased effort in professional and public education. A mortality rate of 45% is disturbing, particularly when a significant number of episodes are taking place in those aged under 50 who are in otherwise good health. One hopeful sign that guidance is beginning to be followed, at least for people who have recently had splenectomies, is the relatively few patients in this series who had undergone surgery in the previous 4 years. The highest risk of OPSI is said to exist within the first few years after surgery, 3 but this study confirms that the risk remains for life, with almost 60% of cases occurring
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D.J. Waghorn and R. T. Mayon-White
Table V. Details of nine cases who had taken chemoprophylaxis before sepsis. Case no. 6
Reason for splenectomy
Cause of infection
Fatal episode
Antibiotic history
Chronic granulomatous disease
S. pneumoniae
No
Took erythromycin for 7 days only after splenectomy; OPSI occurred 17 days later. Pneumococcus sensitive to penicillin and erythromycin. Took penicillin V for 14 years but stopped 10 days before OPSI because had not renewed prescription. Had refused pneumococcaI vaccine. Pneumococcus sensitive to penicillin. Infant took amoxycillin 62.5 mg twice daily since asplenia discovered soon after birth. Pneumococcus sensitive to penicillin. Took penicillin V 250 mg four times a day for 34 days between splenectomy and OPSI. Took penicillin V for 30 years between splenectomy and OPSI. Took penicillin V 250 mg twice a day for 10 years between splenectomy and OPSI. Pneumococcus sensitive to penicillin. Took penicillin V for 8 years from splenectomy till aged 16. OPSI occurred 4 years later. Took erythromycin 500 mg once a day for the 3 years prior to this OPSI episode, following an earlier episode. Pneumococcus resistant to erythromycin but sensitive to penicillin. 'rook penicillin V 500 mg twice daily for 2 years between splenectomy and OPSI. Pneumococcus sensitive to penicillin.
type 29 7
Idiopathic thrombocytopenia
S. pneumoniae
Yes
type 22F 8
Congenital asplenism
S. pneumoniae
No
type 23 12
Myelofibrosis
Unknown
No
16
Surgery for non-neoplastic disease (portal hypertension) Hodgkins lymphoma
Klebsiellasp.
No
S. pneumoniae
Yes
22
type 22F 31
Haemolytic anaemia
S. pneumoniae
Yes
type 9V 35
Non-Hodgkins lymphoma
S. pneumoniae
No
type 6B 37
Chronic lymphocytic leukaemia
S. pneumoniae type
unknown
1 0 - 3 0 y e a r s later a n d two individuals infected m o r e t h a n 50 y e a r s after splenectomy. The risk of sepsis also varies w i t h t h e i n d i c a t i o n for s p l e n e c t o m y a n d a n y u n d e r l y i n g disease. Neoplasia, especially h a e m a t o l o g i c a l , is r e p o r t e d to c a r r y the h i g h e s t risk, ~3 a n d in this series potentially severe u n d e r l y i n g i m m u n o s u p p r e s s i v e disease h a d b e e n p r e s e n t in 26%. Overall, t r a u m a w a s t h e leading cause for splenectomy, s t r e n g t h e n i n g the need to offer o p t i m a l p r o t e c t i o n for all asplenic individuals irrespective of aetiology. H y p o s p l e n i s m c a n result in i m p a i r e d i m m u n i t y a n d severe sepsis. ~4 A n association is found w i t h a n u m b e r of diseases i n c l u d i n g sickle cell disease, coeliac disease a n d d e r m a t i t i s herpetiformis, as seen in one fatal case from this series. Clinicians should be a w a r e of diseases associated w i t h h y p o s p l e n i s m so t h a t periodic blood films m a y be e x a m i n e d to aid diagnosis. If features of h y p o splenism are found, t h e p a t i e n t s h o u l d be m a n a g e d as a n asplenic individual. 1~ Despite t h e sparsity of d a t a s h o w i n g clear clinical efficacy in asplenic patients, ~6 p n e n m o c o c c a l imm u n i z a t i o n is accepted as a m a j o r p a r t of t h e p r e v e n t i v e s t r a t e g y a g a i n s t infection. A p p a r e n t vaccine failures were expected, b u t it w a s d i s a p p o i n t i n g to discover t h a t only 12 patients h a d received p n e u m o c o c c a l vaccine prior to their OPSI episode, especially as p n e u m o c o c c i were
Yes
responsible for at least 88% of infections, a figure in line w i t h earlier reports. 17 Of the 12 cases w h o h a d received i m m u n i z a t i o n , t e n suffered p r o v e n p n e u m o c o c c a l infection. Possible vaccine failure could be a t t r i b u t e d to at least four episodes. I n t h e r e m a i n i n g 27 cases of p n e u m o c o c c a l infection w h e r e i m m u n i z a t i o n h a d n o t been administered, t h e c u r r e n t 2 3 - v a l e n t p o l y s a c c h a r i d e vaccine w o u l d h a v e covered up to 85% of strains a n d therefore m a y h a v e offered some p r o t e c t i o n to those infected. In one reported series of asplenic h a e m a t o l o g y patients, o n l y four episodes o f p n e u m o c o c c a l s e p t i c a e m i a / meningitis were observed in over 2 0 0 v a c c i n a t e d individuals w i t h i n a 1 3 - y e a r period, ~s a n d in all four episodes the infecting c a p s u l a r type w a s n o t included in t h e vaccine. Only one of t h e 12 patients given p n e u m o c o c c a l vaccine h a d a n t i b o d y levels checked after i m m u n i z a t i o n . Up to 20% of asplenic individuals m a y s h o w poor a n t i b o d y responses to p n e u m o c o c c a l p o l y s a c c h a r i d e vaccines, a n d a n t i b o d y levels m a y decline m o r e rapidly t h a n in those still possessing a s p l e e n ] 9 The level of p n e u m o c o c c a l a n t i b o d y considered protective is undecided, b u t some a u t h o r s h a v e r e c o m m e n d e d t h a t t i m i n g of booster imm u n i z a t i o n s should be based on p n e u m o c o c c a l a n t i b o d y m e a s u r e m e n t . 2°'21 The o p t i m a l frequency of m e a s u r i n g antibodies is unclear, b u t a r e c o m m e n d a t i o n
A Study of Overwhelming Post-splenectomy Infection of preimmunization, 1 month after and subsequently at 3 and 5 years has been made. 22 Individuals with poor or absent responses could then be targeted for life-long chemoprophylaxis. Only 10% of patients had been given Hib and meningococcal vaccines before their OPSI episodes. Both H. influenzae and Neisseria meningitidis have been reported as important causes of septicaemia in asplenic individuals, ~3'24 leading to the recommendations for vaccination, 7'2s but the protective efficacy of either Hib or meningococcal vaccine in asplenic patients has not been proven. No cases of 14. influenzae or N. meningitidis infection were reported in this study, confirming that S. pneumoniae is the outstanding pathogen in relation to OPSI. The role of antibiotic prophylaxis remains controversial, and patient records in this series highlight the problem. Only 22% of individuals had received any chemoprophylaxis following splenectomy, whilst half of the infecting isolates, in those on medication at the time of OPSI, showed in vitro sensitivity to the prescribed agent. There are no data relating to the efficacy of chemoprophylaxis in asplenic patients, 26 yet recent guidelines have recommended life-long antibiotics, l° Concern over increasing resistance of, especially, pneumococci to the commonly used prophylactic agents, together with patient compliance difficulties, have influenced others to advise that a supply of antibiotic should be kept at home to serf-prescribe at the first signs of possible infection. 27'2s This option was not reported for any patient in this series. Based on two audits of asplenic patients in defined populations, ~'29 we estimate that there are 4 0 - 5 0 000 asplenic individuals within the U.K., and their increased risk of severe sepsis is now unquestioned. This study suggests that although cases of OPSI will continue to occur, current guidance for protection is only being partially implemented, i.e. on individuals who have undergone recent surgery. There needs to be a more active case finding search for patients who underwent splenectomy many years previously, so that they may be offered protection. It is likely that an irreducible minimum number of cases will persist due to vaccine failure and refusal to take chemoprophylaxis when appropriate. However, this should not deflect from continuing to offer the available vaccines and information about the infection risk to all asplenic patients. Development of vaccines is urgently required to improve the immune response, especially for pneumococcal vaccine. The protective efficacy of antibiotic prophylaxis will remain contentious unless a prospective nationally based study can be performed, but this may prove difficult. 3° Heightened patient awareness, by adopting an active education programme, can be achieved at a local
293
district level. In most circumstances the clinical microbiologist and/or infectious disease physician can contribute to the vital initial guidance given to patients immediately after splenectomy, especially if an automatic referral system, for example, can be introduced between the surgical wards and clinical microbiology/infectious disease service. Furthermore, they should identify who in their hospital/district is ensuring that guidance is applied locally. improvement in the overall management of the asplenic individual still requires further research, and the necessary data should be obtained from co-ordinated regional and national studies.
Acknowledgements We are grateful to the AMM, CDSC and to the following, who have reported OPSI cases: GE Bignardi, Sl Bourke, R Brindle, CR Catchpole, JS Cheesbrough, RA Cox, D Crook, J Cunniffe, K Daly, A Fife, L Fitch, AP Gillett, LR Griffiths, M Lockhart, DN Looker, JA Lowes, P McKay, B Marshall, MG Morgan, D Muir, I Muscat, S Parker, S Partridge, E Ridgway, T Riordan, T Roomaya, MH Snow, A Sohal, C Tremlett, PF Unsworth, M] Weinbren, N Williams. ED Wright, EP Wright, ML 'fee. We shall be grateful to receive reports on further cases of OPSI.
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