Abstract

Incidences of and risk factors for Streptococcus pneumoniaesepsis (SPS) after hematopoietic stem cell transplantation were analyzed in 1329 patients treated at a single center between 1973 and 1997. SPS developed in 31 patients a median of 10 months after transplantation (range, 3 to 187 months). The infection was fatal in 7 patients. The probability of SPS developing at 5 and 10 years was 4% and 6%, respectively. Age, sex, diagnosis, and graft versus host disease (GVHD) prophylaxis did not influence the development of SPS. Allogeneic transplantation (10-year probability, 7% vs 3% for nonallogeneic transplants; P = .03) and chronic GVHD (10-year probability, 14% vs 4%; P = .002) were associated with significantly higher risk for SPS. All the episodes of SPS were seen in patients who had undergone allograft or total body irradiation (TBI) (31 of 1202 vs 0 of 127;P = .07). Eight patients were taking regular penicillin prophylaxis at the time of SPS, whereas 23 were not taking any prophylaxis. None of the 7 patients with fatal infections was taking prophylaxis for Pneumococcus. Pneumococcal bacteremia was associated with higher incidences of mortality (6 of 15 vs 1 of 16;P = .04). We conclude that there is a significant long-term risk for pneumococcal infection in patients who have undergone allograft transplantation, especially those with chronic GVHD. Patients who have undergone autograft transplantation after TBI-containing regimens also appear to be at increased risk. These patients should receive lifelong pneumococcus prophylaxis. Consistent with increasing resistance to penicillin, penicillin prophylaxis does not universally prevent SPS, though it may protect against fatal infections. Further studies are required to determine the optimum prophylactic strategy in patients at risk.

Bone marrow transplantation for leukemia results in long-term survival in approximately 50% of patients who undergo it.1-4 These long-term survivors, otherwise cured of their disease, are at risk for complications that include infections.3-6 Immunodeficiency caused by chronic graft versus host disease (GVHD),7 functional hyposplenism induced by the conditioning regimen,8 and gradual loss of acquired immunity in the absence of reimmunization9 increase a patient's susceptibility to infection. This is particularly true of infections with encapsulated organisms because of the patient's impaired reactivity to polysaccharide antigens and IgG2 deficiency.9-12 

Streptococcus pneumoniae is a common cause of community-acquired pneumonia; it accounts for up to 30% of all such infections.13 The numerous reports of pneumococcal infections in recipients of marrow3-6,14-22 and solid organ23,24 transplants raise the important issue of long-term prophylactic measures either with antimicrobial therapy or vaccination. Although the desirability of using prophylactic measures in asplenic patients has been emphasized,25 the duration of risk for S pneumoniae sepsis (SPS) and the need for pneumococcal prophylaxis have not been determined in recipients of blood and marrow transplants. This retrospective analysis was undertaken to determine the long-term risk for SPS in those who undergo bone marrow transplantation (BMT).

Patients and methods

The database26,27 of the Leukaemia Unit of the Royal Marsden Hospital was searched to identify 1329 consecutive patients who underwent autologous, syngeneic, or allogeneic BMT for leukemia or allogeneic BMT for any malignant disease between 1973 and 1997. Patients who underwent autograft transplantation for multiple myeloma, lymphoma, or solid tumors were not included. Patient characteristics are shown in Table 1. Details of conditioning regimens and GVHD prophylaxis have been published earlier.28-31 

Table 1.

Patient characteristics

All patients (n = 1329) Patients with S pneumoniae sepsis (n = 31)
Median age (y) at BMT (range, y)  25 (1-61)  22 (2-49)  
Sex (M/F) 800/529  19/12  
Diagnosis  
 Acute myeloid leukemia  615  18  
 Acute lymphoblastic leukemia 339   7  
 Chronic myeloid leukemia  143   2 
 Other  232   3  
Median time (mo) from BMT (range, mo) 10 (3-187)  
Type of BMT  
 Allograft  918  26 
  Donor  
   Matched sibling  754  24 
   Mismatched family  91   0  
   Matched unrelated 73   2  
  Total-body irradiation  
   Yes 755  22  
   No  163   4  
  GVHD prophylaxis  
   Cyclosporine alone  525  21 
   Methotrexate ± cyclosporine  393   5 
 Autograft  411   5  
  Total-body irradiation 
   Yes  284   5  
   No  127   0 
Conditioning regimen  
 Total-body irradiation  1039 27  
 Chemotherapy only  290   4 
All patients (n = 1329) Patients with S pneumoniae sepsis (n = 31)
Median age (y) at BMT (range, y)  25 (1-61)  22 (2-49)  
Sex (M/F) 800/529  19/12  
Diagnosis  
 Acute myeloid leukemia  615  18  
 Acute lymphoblastic leukemia 339   7  
 Chronic myeloid leukemia  143   2 
 Other  232   3  
Median time (mo) from BMT (range, mo) 10 (3-187)  
Type of BMT  
 Allograft  918  26 
  Donor  
   Matched sibling  754  24 
   Mismatched family  91   0  
   Matched unrelated 73   2  
  Total-body irradiation  
   Yes 755  22  
   No  163   4  
  GVHD prophylaxis  
   Cyclosporine alone  525  21 
   Methotrexate ± cyclosporine  393   5 
 Autograft  411   5  
  Total-body irradiation 
   Yes  284   5  
   No  127   0 
Conditioning regimen  
 Total-body irradiation  1039 27  
 Chemotherapy only  290   4 

The autograft group included 19 recipients of syngeneic transplants, 1 of whom had pneumococcal sepsis.

Streptococcus pneumoniae prophylaxis

Patients were not routinely administered pneumococcal vaccine.9 Recipients of allogeneic transplants were recommended indefinite pneumococcal pharmaco-prophylaxis with penicillin or erythromycin from the late 1980s. After our initial analysis of SPS in transplant recipients in 1993,19 it was thought this should be extended to all patients who undergo transplantation.32 However, all patients were not receiving prophylaxis regularly, primarily because of compliance issues.21 Although details of drug prophylaxis were available for patients in whom SPS developed, these were not available in most patients in whom SPS did not develop.

Streptococcus pneumoniae sepsis

From the main group of 1329 patients, those who had a growth ofS pneumoniae in blood, sputum, upper respiratory tract, or normally sterile body fluids and who had symptoms of infection beyond 3 months after transplantation were identified. Serum immunoglobulin levels were unavailable after transplantation in most of the patients, including those with SPS. Patients in whom SPS developed were not always treated at our center, and they received the best available standard of care in terms of antimicrobial therapy and supportive therapy.

Statistical methods

The data were analyzed in September 1998. The probability for pneumococcal infection was estimated using the method of Kaplan and Meier.32 The following factors were analyzed in univariate and multivariate fashion to examine their influence on the probability for SPS: age at transplantation, sex, diagnosis, type of transplant (allograft vs autograft; syngeneic transplants included in the autograft group), conditioning regimen (TBI or no TBI), type of GVHD prophylaxis, acute GVHD, and chronic GVHD.

Results

Thirty patients had 31 episodes of clinically and microbiologically documented SPS for a median of 10 months (range, 3 to 187 months) after transplantation. One patient had 2 episodes of SPS in 4 years (pneumonia followed by meningitis). Table2 shows clinical presentations and outcomes; Figure 1 shows the probability of developing SPS.

Table 2.

Clinical presentation and outcome (31 episodes in 30 patients)

Clinical picture n Death (%)
Pneumonia  16 1 (6)* 
Bacteremia  15  6 (40)* 
Bacteremia alone 9  6 (67)  
With meningitis  3  0 (0)  
With pneumonia  3  0 (0) 
Clinical picture n Death (%)
Pneumonia  16 1 (6)* 
Bacteremia  15  6 (40)* 
Bacteremia alone 9  6 (67)  
With meningitis  3  0 (0)  
With pneumonia  3  0 (0) 
*

P = .04 (Fisher exact test).

Fig. 1.

Occurrence of pneumococcal infection after blood or marrow stem cell transplantation.

Fig. 1.

Occurrence of pneumococcal infection after blood or marrow stem cell transplantation.

Eight episodes of SPS occurred while the patients were regularly taking penicillin, and 23 occurred when patients were not receiving any prophylaxis. All the patients were admitted to the hospital and received parenteral broad-spectrum antibiotics, including penicillin (n = 29), cephalosporin (n = 1), or clarithromycin (n = 1).

Seven (23%) patients died as a direct consequence of SPS; 6 received allografts and 1 received an autograft. Six of 15 (40%) patients with bacteremia died compared with 1 of 16 (6.3%) without bacteremia (P = .04; Fisher exact test). All the deaths occurred in patients not receiving pneumococcal prophylaxis (7 of 23 vs 0 of 8 on prophylaxis; P = .09; Fisher exact test). Age, sex, diagnosis, type of transplant, conditioning regimen, GVHD prophylaxis, prior acute GVHD, or chronic GVHD did not have any impact on mortality. Of the 3 patients with meningitis, 2 have neurologic sequelae—seizures requiring anticonvulsants (n = 1) and partial deafness (n = 2).

Factors influencing the risk for pneumococcal sepsis

Age, sex, diagnosis, conditioning regimen, GVHD prophylaxis, or prior acute GVHD did not influence the risk for SPS. The risk was significantly higher in allograft recipients (7% vs 3% at 10 years;P = .03; Figure 2). Similarly, allograft recipients who had chronic GVHD were at higher risk (14% vs 4% for other allograft recipients at 10 years; P = .002; Figure 3). It was interesting that SPS was seen only in patients who had undergone allograft transplantation or received TBI (6% vs 0% at 10 years; P = .07; Figure4), even though this difference was not statistically significant. As stated earlier, it was difficult to ascertain prophylaxis compliance among patients who did not have SPS; therefore, the influence of prophylaxis on the incidence of SPS could not be assessed.

Fig. 2.

Significantly higher probability of pneumococcal infection among allograft recipients.

Fig. 2.

Significantly higher probability of pneumococcal infection among allograft recipients.

Fig. 3.

Significantly higher risk for pneumococcal sepsis among allograft recipients with chronic graft versus host disease.

Fig. 3.

Significantly higher risk for pneumococcal sepsis among allograft recipients with chronic graft versus host disease.

Fig. 4.

Combined effect of the type of transplant and TBI.

All instances of pneumococcal sepsis were seen in patients who had undergone allograft transplantation or TBI.

Fig. 4.

Combined effect of the type of transplant and TBI.

All instances of pneumococcal sepsis were seen in patients who had undergone allograft transplantation or TBI.

In multivariate analysis, the only factor independently associated with an increased risk for SPS was chronic GVHD (RR, 3.7;P = .001). The adverse influence of chronic GVHD persisted whether the whole group (all patients alive at day 100) or the allograft subpopulation (allograft recipients alive at day 100) were considered.

Discussion

The reported crude annual incidence of SPS in the general population varies between 1 and 100 per 100 000.33 In our series of BMT recipients, we identified 31 episodes in 1329 patients. Although a direct comparison with the general population is difficult, SPS seems to be a more noticeable problem in BMT recipients. Penicillin prophylaxis does not seem to be universally effective, but it may attenuate the severity of the infection and help prevent a fatal outcome.

The portal of entry for pneumococci is the respiratory tract, where the mucociliary lining facilitates their removal. Leukocyte margination and phagocytosis is important in containing the infection when the organism reaches the alveoli. Local appearance of antibody to capsular polysaccharide enhances phagocytosis and precedes the appearance of the antibody in the circulation. Failure of the local defense mechanisms allows spread of the organism to the hilar nodes, through the thoracic duct, and into the circulation, resulting in bacteremia. One or more of these mechanisms are defective in hematopoietic stem cell transplant recipients at some stage after transplantation, predisposing them to SPS.7-12,34 

Hypogammaglobulinemia and the inability to react to polysaccharide antigens are common in allograft recipients, especially in those with chronic GVHD.7 These defects are less pronounced in autograft recipients. Almost all patients who have autografts retain protective levels of antipneumococcal antibodies after transplantation, whereas only 25% of those who have allografts do.11 Why then are autograft recipients also at risk for SPS? TBI-induced functional hyposplenism can contribute to defective opsonization and leukocyte margination. Consistent with this explantation, SPS was seen only in autograft recipients who had undergone TBI.

It is noteworthy that SPS developed in 8 patients while they were on regular penicillin prophylaxis. This raises the possibility of emerging penicillin resistance.33 Despite resistance, it is possible that penicillin may protect against fatal SPS, and it is still probably the agent of choice for prophylaxis. Patients in whom SPS develops despite penicillin prophylaxis ought to be switched to an alternative agent, such as a macrolide or a quinolone.

The mortality rate of community-acquired SPS in older patients is in the range of 20%. The 23% mortality rate seen by us is consistent and suggests that transplantation increases susceptibility without altering mortality. Mortality rates were significantly higher in patients with bacteremia than in those with other sites of infection. This is not surprising because hematogenous dissemination occurs when the infection is advanced and the defense mechanisms of the body have failed to confine the infection.

Pneumococcal vaccination in transplant recipients has been shown to be relatively ineffective early after transplantation and in the presence of chronic GVHD.9,35 Even in patients who do respond to the 23-valent vaccine, the IgG2 response is often poor.11,36The 23-valent polysaccharide vaccine, apart from being poorly immunogenic, also does not cover 20% of the commonly encountered pathogenic pneumococcal strains, and immunized persons remain susceptible to them.9,37 

In conclusion, recipients of hematopoietic stem cell allografts, especially those with chronic GVHD, are at significant long-term risk for SPS and should receive lifelong penicillin prophylaxis. Autograft recipients who have undergone TBI also appear to be at risk and should receive lifelong prophylaxis. Prospective studies would help define the optimum duration of prophylaxis and would evaluate drugs other than penicillin, but they may have to be on a scale that is logistically difficult to manage. Autograft recipients (excluding patients with myeloma) who have not undergone TBI do not require lifelong prophylaxis.

Reprints:Ray Powles, Leukaemia and Myeloma Units, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, UK; e-mail:leukemia@clara.net.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

References

References
1
Frassoni
F
Labopin
M
Gluckman
E
et al
Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey.
Leukemia.
8
1994
924
2
Socie
G
Stone
JV
Wingard
JR
et al
Long-term survival and late deaths after allogeneic bone marrow transplantation.
N Engl J Med.
341
1999
14
3
Singhal
S
Powles
R
Treleaven
J
et al
Long-term outcome of adult acute leukemia patients who are alive and well two years after allogeneic bone marrow transplantation from an HLA-identical sibling.
Leuk Lymphoma.
34
1999
287
4
Singhal
S
Powles
R
Treleaven
J
Kulkarni
S
Horton
C
Mehta
J
Long-term outcome of adult acute leukemia patients who are alive and well 2 years after autologous blood or marrow transplantation.
Bone Marrow Transplant.
23
1999
875
5
Atkinson
K
Storb
R
Prentice
RL
et al
Analysis of late infections in 89 long-term survivors of bone marrow transplantation.
Blood.
53
1979
720
6
Hoyle
C
Goldman
JM
Life-threatening infections occurring more than 3 months after BMT.
Bone Marrow Transplant.
14
1994
247
7
Witherspoon
RP
Storb
R
Ochs
HD
et al
Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment.
Blood.
58
1981
360
8
Knecht
H
Jost
R
Gmur
J
Burger
J
Fehr
J
Functional hyposplenia after allogeneic bone marrow transplantation is detected by epinephrine stimulation test and splenic ultrasonography.
Eur J Haematol.
41
1988
382
9
Singhal
S
Mehta
J
Reimmunization after blood or marrow stem cell transplantation.
Bone Marrow Transplant.
23
1999
637
10
Sheridan
JF
Tutschka
PJ
Sedmak
DD
Copelan
EA
Immunoglobulin G subclass deficiency and pneumococcal infection after allogeneic bone marrow transplantation.
Blood.
75
1990
1583
11
Hammarström
V
Pauksen
K
Azinge
J
Oberg
G
Ljungman
P
Pneumococcal immunity and response to immunization with pneumococcal vaccine in bone marrow transplant patients: the influence of graft versus host reaction.
Support Care Cancer.
1
1993
195
12
Ekdahl
K
Braconier
JH
Svanborg
C
Impaired antibody response to pneumococcal capsular polysaccharides and phosphorylcholine in adult patients with a history of bacteremic pneumococcal infection.
Clin Infect Dis.
25
1997
654
13
Macfarlane
JT
Colville
A
Guion
A
Macfarlane
RM
Rose
DH
Prospective study of etiology and outcome of adult lower respiratory tract infections in the community.
Lancet.
341
1993
511
14
Winston
DJ
Schiffman
G
Wang
DC
et al
Pneumococcal infections after human bone-marrow transplantation.
Ann Intern Med.
91
1979
835
15
Boice
JL
Pneumococcal infection in bone marrow transplant recipients.
Ann Intern Med.
92
1980
571
16
Markman
M
Mannisi
J
Dick
JD
Filburn
B
Santos
GW
Saral
R
Sulfamethoxazole–trimethoprim-resistant pneumococcal sepsis.
JAMA.
248
1982
3011
17
Julia
A
Acebedo
G
Jornet
J
Zuazu
J
Spontaneous pneumococcal peritonitis: late infection after bone-marrow transplantation.
N Engl J Med.
312
1985
587
18
Schwella
N
Schwerdtfeger
R
Schmidt–Wolf
I
Schmid
H
Siegert
W
Pneumococcal arthritis after allogeneic bone marrow transplantation.
Bone Marrow Transplant.
12
1993
165
19
Rege
K
Mehta
J
Treleaven
J
et al
Fatal pneumococcal infections following allogeneic bone marrow transplantation.
Bone Marrow Transplant.
4
1994
903
20
Gomez–Casares
MT
Naranjo
A
Campo
C
et al
Another case of pneumococcal arthritis after allogeneic bone marrow transplantation.
Bone Marrow Transplant.
15
1995
650
21
Singhal
S
Powles
R
Treleaven
J
Lumley
H
Pollard
C
Mehta
J
Allogeneic bone marrow transplantation for primary myelofibrosis.
Bone Marrow Transplant.
16
1995
743
22
Perez–Retortillo
JA
Marco
F
Richard
C
et al
Pneumococcal pericarditis with cardiac tamponade in a patient with chronic graft-versus-host disease.
Bone Marrow Transplant.
21
1998
299
23
Bourgault
AM
Van Scoy
RE
Wilkowske
CJ
Sterioff
S
Severe infection due to Streptococcus pneumoniae in asplenic renal transplant patients.
Mayo Clin Proc.
54
1979
123
24
Amber
IJ
Gilbert
EM
Schiffman
G
Jacobson
JA
Increased risk of pneumococcal infections in cardiac transplant recipients.
Transplantation.
49
1990
122
25
Working Party of the British Committee for Standards in Hematology
Clinical Hematology Task Force: Guidelines for the prevention and treatment of infection in patients with absent or dysfunctional spleens.
BMJ.
312
1996
430
26
Powles
R
Milan
S
Horton
C
Singhal
S
Treleaven
J
Mehta
J
A prospective haemato-oncology patient database: structure and description.
Bone Marrow Transplant.
17(suppl 1)
1996
S140
27
Powles
R
Milan
S
Horton
C
Singhal
S
Treleaven
J
Mehta
J
A prospective haemato-oncology patient database for use in routine care and clinical research.
Bone Marrow Transplant.
17(suppl 1)
1996
S55
28
Mehta
J
Powles
RL
Mitchell
P
Rege
K
De Lord
C
Treleaven
J
Graft failure after bone marrow transplantation from unrelated donors using busulphan and cyclophosphamide for conditioning.
Bone Marrow Transplant.
13
1994
583
29
Mehta
J
Powles
R
Singhal
S
et al
Autologous bone marrow transplantation for acute myeloid leukemia in first remission: identification of modifiable prognostic factors.
Bone Marrow Transplant.
16
1995
499
30
Mehta
J
Powles
R
Treleaven
J
et al
Long-term follow-up of patients undergoing allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission after cyclophosphamide-total body irradiation and cyclosporine.
Bone Marrow Transplant.
18
1996
741
31
Powles
R
Singhal
S
Treleaven
J
Kulkarni
S
Horton
C
Mehta
J
Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation.
Blood.
91
1998
3481
32
Mehta
J
Powles
R
Singhal
S
Riley
U
Treleaven
J
Catovsky
D
Antimicrobial prophylaxis to prevent opportunistic infections in patients with chronic lymphocytic leukemia after allogeneic blood or marrow transplantation.
Leuk Lymphoma.
26
1997
83
88
33
Crook
D
Spratt
B
Multiple antibiotic resistance in Streptococcus pneumoniae.
Br Med Bull.
54
1998
595
34
Cordonnier
C
Gilain
L
Ricolfi
F
et al
Acquired ciliary abnormalities of nasal mucosa in marrow recipients.
Bone Marrow Transplant.
17
1996
611
35
Avanzini
MA
Carra
AM
Maccario
R
et al
Antibody response to pneumococcal vaccine in children receiving bone marrow transplantation.
J Clin Immunol.
15
1995
137
36
Lortan
JE
Vellodi
A
Jurges
ES
Hugh-Jones
K
Class- and subclass-specific pneumococcal antibody levels and response to immunization after bone marrow transplantation.
Clin Exp Immunol.
88
1992
512
37
Austrian
R
Pneumococcal infections.
Harrison's Principles of Internal Medicine.
13th ed.
Isselbacher
KJ
Braunwald
E
Wilson
JD
Martin
JB
Fauci
AS
Kasper
DL
1994
607
611
McGraw-Hill
New York