ASPLENIA AND INFECTION

1
ASPLENIA AND INFECTION

• Dr Gavin Spickett
• Royal Victoria Infirmary, Newcastle upon Tyne

2
Functions of the Spleen

• Spleen is non-vital
• Secondary lymphoid organ
• Reservoir for naïve T and B cells
• Removes antigen from the bloodstream
• Antigen processing and presentation by phagocytic
  cells
• Major defence against encapsulated bacteria

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

1 Sarangi J et al. Prevention of post
splenectomy sepsis a population based approach.
J Public Health Med. 1997 Jun19(2)208-12 2
Kyaw MH et al. Evaluation of severe infection and
survival after splenectomy. Am J Med. 2006
Mar119(3)276 e1-7.
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

3 Lutwick LI. Life threatening infections in
the asplenic or hyposplenic individual. Curr Clin
Top Infect Dis. 20022278-96, with modification.
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

4 Schilling RF. Estimating the risk for sepsis
after splenectomy in hereditary spherocytosis.
Ann Intern Med. 1995 Feb 1122(3)187-8.
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

4 Schilling RF. Estimating the risk for sepsis
after splenectomy in hereditary spherocytosis.
Ann Intern Med. 1995 Feb 1122(3)187-8.
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

4 Schilling RF. Estimating the risk for sepsis
after splenectomy in hereditary spherocytosis.
Ann Intern Med. 1995 Feb 1122(3)187-8.
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 lt16 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

5 Holdsworth RJ, Irving AD, Cuschieri A.
Postsplenectomy sepsis and its mortality rate
actual versus perceived risks. Br J Surg. 1991
Sep78(9)1031-8
14
Infection risk

• Severe infection after splenectomy for benign
  disease uncommon except infants (infection rate
  15.7) and children lt5 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

6 Bisharat N et al. Risk of infection and death
among post-splenectomy patients. J Infect. 2001
Oct43(3)182-6
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)

7 Kyaw MH et al. Evaluation of severe infection
and survival after splenectomy. Am J Med. 2006
Mar119(3)276 e1-7
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

7 Kyaw MH et al. Evaluation of severe infection
and survival after splenectomy. Am J Med. 2006
Mar119(3)276 e1-7
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
  

8 Cullingford GL et al. Severe late
post-splenectomy infection. Br J Surg. 1991
Jun78(6)716-21
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

9 Schutze GE et al. Invasive pneumococcal
infections in children with asplenia. Pediatr
Infect Dis J. 2002 Apr21(4)278-82
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 lt15 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

10 Brigden ML. Detection, education and
management of the asplenic or hyposplenic
patient. Am Fam Physician. 2001 Feb
163(3)499-506, 8
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

11 Foss Abrahamsen A et al. Systemic
pneumococcal disease after staging splenectomy
for Hodgkin's disease 1969-1980 without
pneumococcal vaccine protection a follow-up
study 1994. Eur J Haematol. 1997 Feb58(2)73-7.
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

10 Foss Abrahamsen A et al. Systemic
pneumococcal disease after staging splenectomy
for Hodgkin's disease 1969-1980 without
pneumococcal vaccine protection a follow-up
study 1994. Eur J Haematol. 1997 Feb58(2)73-7.
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

11 Hosea SW et al. Impaired immune response of
splenectomised patients to polyvalent
pneumococcal vaccine. Lancet. 1981 Apr
111(8224)804-7 12 Giebink GS et al. Serum
antibody responses of high-risk children and
adults to vaccination with capsular
polysaccharides of Streptococcus pneumoniae. Rev
Infect Dis. 1981 Mar-Apr3 SupplS168-78
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)

13 Landgren O et al. A prospective study on
antibody response to repeated vaccinations with
pneumococcal capsular polysaccharide in
splenectomised individuals with special reference
to Hodgkin's lymphoma. J Intern Med.
2004255(6)664-73.
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

14 Cherif H et al. Poor antibody response to
pneumococcal polysaccharide vaccination suggests
increased susceptibility to pneumococcal
infection in splenectomised patients with
hematological diseases. Vaccine. 2006 Jan
924(1)75-81
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 µg/ml and 60 had levels higher than 1 µg/ml

15 Konradsen HB et al. Antibody levels against
Streptococcus pneumoniae and Haemophilus
influenzae type b in a population of
splenectomised individuals with varying
vaccination status. Epidemiol Infect. 1997
Oct119(2)167-74.
32
Immunisation - Hib

• Role of anti-PRP
• Hib gt0.15 µg/ml short term protection
• Hibgt 1.0 µg/ml long term protection
• Conjugate vaccines
• 70 infants gt0.15 µg/ml
• 40 infants gt1 µg/ml
• 90 protection

Cimaz R et al. Safety and immunogenicity of a
conjugate vaccine against Haemophilus influenzae
type b in splenectomised and non-splenectomized
patients with Cooley anemia. J Infect Dis. 2001
Jun 15183(12)1819-21
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 lt0.15 µg/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

16 Heath PT et al. Antibody concentration and
clinical protection after Hib conjugate
vaccination in the United Kingdom. JAMA. 2000 Nov
8284(18)2334-40
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 (gt1 µg/mL)
  antibody levels
• Antibody titers declined after the initial
  post-vaccination increase, becoming undetectable
  in 4 pts and decreasing to 0.15-1 µg/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

17 Cimaz R et al. Safety and immunogenicity of
a conjugate vaccine against Haemophilus
influenzae type b in splenectomized and
non-splenectomized patients with Cooley anemia. J
Infect Dis. 2001 Jun 15183(12)1819-21
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

18 Ruben FL et al. Antibody responses to
meningococcal polysaccharide vaccine in adults
without a spleen. Am J Med. 1984 Jan76(1)115-21
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

18 Ruben FL et al. Antibody responses to
meningococcal polysaccharide vaccine in adults
without a spleen. Am J Med. 1984 Jan76(1)115-21
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

19 Balmer P et al. Immune response to
meningococcal serogroup C conjugate vaccine in
asplenic individuals. Infect Immun. 2004
Jan72(1)332-7
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

19 Balmer P et al. Immune response to
meningococcal serogroup C conjugate vaccine in
asplenic individuals. Infect Immun. 2004
Jan72(1)332-7
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

16 Gaston MH et al. Prophylaxis with oral
penicillin in children with sickle cell anemia. A
randomized trial. N Engl J Med. 1986 Jun
19314(25)1593-9
41
Absent or dysfunctional spleen in adults
Immunisation
Travel
Antibiotics
Influenza Annual Influenza vaccine
HiB Vaccine Previously non immunised adults
should receive a single dose of vaccine.
Meningitis C vaccine Previously non immunised
adults should receive a single dose of vaccine
Anti-malarials if travelling to endemic
areas Meningitis AC,W135,Y if
appropriate Antibiotics
Pneumococcal vaccine Polysaccharide vaccine
(Pneumovax). Avoid in pregnancy.
Antibiotic prophylaxis (adult dose) Penicillin V
500mg b.d. Amoxycillin 500mg bd (Erythromycin
250mg od if penicillin allergy)
Check antibodies 4/52 post vaccination
Good response recheck antibody titre in 1 year
Antibiotic cover 3 day supply of Amoxycillin
should be kept by the patient with instructions
to take 1gm at first sign of infection and 500mg
tds thereafter and to seek immediate medical
attention.
Poor response revaccinate and re-test at 4/52
If poor response give conjugate (Prevenar) if not
already given.
Discuss with Adult Infectious Disease team
Antibiotic prophylaxis may need altering
depending upon local resistance.
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 lt35 mg/l
• Hib lt1.5 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 AC, 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