© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation A. Torda, Q. Chong, A. Lee, S. Chen, A. Dodds, M. Greenwood, S. Larsen, N. Gilroy. Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2014: 16: 751–759. All rights reserved Abstract: Background. Allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients are at high risk of invasive pneumococcal disease (IPD). We investigated the incidence and risk factors of IPD in alloHSCT recipients from 4 regional transplant centers over an 11-year period. This study aimed to inform future improvements in post-transplant care. Methods. We conducted a retrospective nested 1:2 case–control study in patients aged ≥18 years who underwent alloHSCT between 2001 and 2011 in 4 major allogeneic transplant centers. Controls were matched with IPD cases on the basis of conditioning intensity and donor relationship (related or unrelated). Demographics and clinical characteristics of cases and controls were summarized. Univariate analysis of risk factors in matched case–control sets, and multivariate conditional logistic regression to control for confounding, were performed. Results. In 23 alloHSCT recipients, 26 IPD episodes were identified. The cumulative incidence over 11 years was 2.3% (95% confidence interval [CI] 1.45–3.15) and the incidence density 956 per 100,000 transplant years of follow-up (95% CI 580–1321). Multivariate risk factor analysis and backwards elimination showed a significant positive association between mycophenolate mofetil (MMF), hyposplenism/asplenia, and IPD, whereas trimethoprimsulfamethoxazole (TMP/SMX) prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was associated with lower odds of IPD cases. Of alloHSCT recipients with IPD, 38.5% required intensive care, and, of deaths documented in cases over the period of review, 30% were attributable to IPD. Serotypes causing IPD matched currently available vaccines in 15/22 (68.1%) episodes. Conclusions. The incidence of IPD in alloHSCT recipients is an important cause of morbidity and mortality, with rates of disease being many fold higher than the general population. Patients with evidence of hyposplenism/asplenia define a high-risk group in the alloHSCT population for IPD, and the independent association with IPD and MMF in the adjusted model from this study requires further evaluation. The occurrence of post-transplant IPD may be reduced by measures such as vaccination with both 13-valent and 23valent pneumococcal vaccines. TMP/SMX prophylaxis for the prevention of PJP may offer incidental protection against IPD in alloHSCT recipients. Acquired deficiencies in circulating immunoglobulin (Ig)M and switched memory B cells after hematopoietic stem cell transplantation (HSCT) are associated with an increased risk of infection with encapsulated bacteria,
A. Torda1,2, Q. Chong1, A. Lee3, S. Chen4, A. Dodds5, M. Greenwood6, S. Larsen7, N. Gilroy8 1
Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia, 2Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia, 3Department of Microbiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, 4Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR – Pathology West, The University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia, 5 Department of Hematology, St Vincent’s Hospital, Darlinghurst, New South Wales, Australia, 6Department of Hematology, Royal North Shore Hospital, St Leonards, New South Wales, Australia, 7Department of Hematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, 8St Vincent’s Hospital Sydney and BMT Network, Agency for Clinical Innovation (ACI), Darlinghurst, New South Wales, Australia
Key words: invasive pneumococcal infection; HSCT; vaccination; incidence; serotype Correspondence to: Dr Adrienne Torda, Department of Infectious Diseases, Prince of Wales Hospital, Randwick, NSW 2031, Australia Tel: 02 93823405 Fax: 02 93823403 E-mail: [email protected]
Received 12 December 2013, revised 10 April 2014, 19 April 2014, accepted for publication 4 May 2014 DOI: 10.1111/tid.12268 Transpl Infect Dis 2014: 16: 751–759
such as Streptococcus pneumoniae (1). Allogeneic HSCT (alloHSCT) recipients are particularly susceptible to lifethreatening invasive pneumococcal disease (IPD) owing to risk factors that include functional hyposplenism,
751
Torda et al: Invasive pneumococcal infection following HSCT
hypogammaglobulinemia, immunosuppressive therapy, immunomodulatory effects of graft-versus-host disease (GVHD), and impaired responses to post-transplant pneumococcal vaccination (2–6). Previous multicenter surveys have found IPD incidence rates between 5.9 and 20.9 per 1000 in alloHSCT recipients, and 3.8–6.2 per 1000 in autologous transplant recipients (3–5). In one prospective populationbased study, the incidence density of IPD, adjusted for follow-up, was reported as 590 per 100,000 alloHSCTs per year, compared with 199 per 100,000 autologous transplants per year, and 11.5 per 100,000 per persons per year in the general population (5). These studies indicate that the risk of IPD in alloHSCT is 3- to 4-fold higher compared with autologous transplant recipients, and 50-fold higher than the general population. The risk of IPD in alloHSCT recipients is also increased in the late transplant phase (>day 100) (3, 5) and in those with chronic GVHD (6). After HSCT, immunization and antibiotic prophylaxis against pneumococcal infection are widely recommended. Various guidelines have been proposed in Europe, the United States, and Australia (2, 7–10). Two commonly used vaccines are 23-valent polysaccharide vaccine, and the protein conjugate vaccines including the 7-, 10-, and 13-valent vaccines. Antibiotic prophylaxis, usually with penicillin or a macrolide, is recommended in recipients with chronic GVHD (7, 10). In 2008, the reported population incidence of IPD in Australia was 7.6 per 100,000 persons (11). However, the incidence of IPD in alloHSCT recipients has not been determined in the Australian population, and risk factors for IPD in this population have not been evaluated. We undertook a retrospective nested case– control study to investigate the incidence and associated risk factors of IPD in recipients of alloHSCT in New South Wales (NSW) transplant centers over an 11-year period. The results of this study were intended to inform the development and implementation of improved vaccination and antibiotic prophylaxis protocols in the post-transplant setting.
Methods Study population This study was approved by Human Ethics Review Committees at each participating site. Patients for inclusion in this study were aged ≥18 years and had received an alloHSCT between January 1, 2001 and December 31, 2011 in 1 of the 4 adult allogeneic bone marrow transplant (BMT) centers in NSW, Australia.
752
These 4 centers accounted for all adult alloHSCT recipients in the state of NSW, and site-specific transplant databases provided transplant numbers and years of follow-up for incidence rate calculations over the period of review.
Case definitions A confirmed case of IPD was defined as a patient in whom S. pneumoniae was isolated from a normally sterile site (blood, cerebrospinal fluid [CSF], or joint aspirate), excluding the middle ear and pleural fluid. A probable case of IPD was defined as a patient with a positive pneumococcal urinary antigen, in the presence of a clinically compatible syndrome (sepsis, pneumonia, meningitis) (11). Early or late onset of IPD was defined as infection occurring ≤100 days or >100 days post first transplant, respectively.
Study design We performed a retrospective nested case–control study of adult alloHSCT recipients transplanted from 2001 to 2011. Each case of IPD was matched with 2 controls from the alloHSCT cohort. To minimize confounding, controls were matched with cases on the basis of conditioning intensity (myeloablative or non-myeloablative) and donor relationship (related or unrelated). Controls were required to have an overall survival that was at least as long as the case at the time of their IPD diagnosis. When several eligible controls matched these criteria, controls with a transplant date closest to the transplant date of the IPD case were selected. Transplant data, including underlying diagnosis, remission status, transplant date, donor type, conditioning regimen, and follow-up dates for cases and controls were identified from the site-specific transplant registers that contribute data to the Australian Bone Marrow Transplant Recipient Register. IPD cases were identified by cross-referencing the list of allogeneic transplant recipients with all sterile site isolates of S. pneumoniae (blood, urine, and joint fluids) and positive urinary antigen tests from the corresponding transplant center’s microbiology database. Hospital databases and medical records were used to obtain demographic and clinical information, including underlying disease and transplant indications, post-transplant care (antimicrobial prophylaxis, immunosuppression, vaccination), and comorbidities (GVHD, hyposplenism, hypogammaglobulinemia).
Transplant Infectious Disease 2014: 16: 751–759
Torda et al: Invasive pneumococcal infection following HSCT
IPD episodes Clinical information relating to IPD episodes, such as date of first positive culture, hospitalization dates with IPD, site of disease involvement (lung, blood, CSF, or other), treatment, and complications (requirement for intensive care, mortality), were sourced from medical records. Hospital microbiology databases provided information on the sterile site(s) from which S. pneumoniae was cultured and antibiotic susceptibilities. Pneumococcal serotype data were obtained from the Pneumococcal Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, NSW.
Statistical analysis Descriptive statistics including demographics (age, gender) and baseline clinical characteristics (disease, transplant factors, and post-transplant care) of cases and controls were summarized. Antimicrobial susceptibility, pneumococcal serotypes, and IPD outcomes were also summarized. Cumulative incidence rate over the 11 years of review was reported as number of IPD episodes occurring in the alloHSCT cohort. IPD incidence density was calculated as number of IPD episodes per 100,000 allogeneic transplant years of follow-up. Univariate risk factor analysis for a matched 1:2 case–control design involved matched odd ratios (mOR), 95% confidence intervals (CIs) using the Mantel Haenszel method for matched case–control sets, and Fisher’s exact test for P-values, with P < 0.05 being the level of significance. All variables included in the univariate analysis were fitted into a multivariable model (maximum model). Variables with the highest P-value were sequentially removed using the backward elimination approach (12). Variables in the final adjusted model with a 2-sided Pvalue 100 days). The details of IPD admission are summarized in Table 1. Eighty-eight percent of episodes had bacteremia, 73.1% pneumonia, and a single episode had meningitis. Almost 40% of cases required intensive care unit admission. A total of 10 deaths were reported, and 30% of these were directly attributable to IPD. Three cases had recurrent IPD infection; 1 of these secondary episodes was fatal.
Characteristics of cases and controls and risk factor analysis The median age of cases was 44 years (range 20– 68 years), and males accounted for 69.6% of cases. IPD episode details – Timing and outcome (n = 26) Timing Median age at IPD diagnosis, years (range) Median time post transplant to onset of IPD, days (range)
44 (21–73) 553 (6–3327)
Early onset (≤100 days)
2
Late onset (>100 days)
24
Site of disease involvement (%)
Results
Lung
19 (73.1)
Blood
23 (88.4)
Central nervous system
Incidence
ICU admission
A total of 1154 adult alloHSCT were performed in NSW during the review period with 2720 patient-years of follow-up. The median period of follow-up was 480 days (range 1–4148 days). We identified 26 IPD episodes
Median duration of hospitalization, days (range)
1 (3.8) 10 (38.5) 13 (0–98)
IPD, invasive pneumococcal disease; ICU, intensive care unit.
Table 1
Transplant Infectious Disease 2014: 16: 751–759
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Torda et al: Invasive pneumococcal infection following HSCT
Acute leukemia (AML/ALL) was the underlying diagnosis in 7 of 23 primary IPD cases. Stem cell source was peripheral blood in 87% of cases (others were bone marrow). The risk factors assessed in this study are summarized for cases and controls in Table 2. GVHD present at the time of IPD (both acute and chronic) of varying severity was documented in 91.3% and 80.4% of IPD cases and controls, respectively. Hyposplenism or asplenia was documented in 5/23 (21.7%) and hypogammaglobulinemia in 6/23 (26%) of IPD cases. At the time of IPD diagnosis, specific antibiotic prophylaxis (penicillin, erythromycin, or a cephalosporin) was documented in 43.5% of the cases. TMP/SMX prophylaxis for Pneumocystis jirovecii (PJP) was documented in 65.2% of cases and 71.7% controls. Cyclosporine and prednisolone were the most commonly used immunosuppressants in all centers. Of the 23 cases, 17.4% received 23-valent pneumococcal vaccine prior to IPD onset, compared to 26.1% in the control group (Table 2). The median time of receiving vaccination was approximately 2 years post HSCT. On univariate analysis of risk factors for IPD (Table 3), an increased association was observed in patients receiving mycophenolate mofetil (MMF) (mOR 5.0; P = 0.05) and a reduced association in those with an underlying diagnosis of acute leukemia (mOR 0.39; P = 0.05). Following backward stepwise elimination, the explanatory variables that were retained in the multivariable model, after adjusting for confounding, included hyposplenism/asplenia (aOR 12.67; P = 0.02), MMF immunosuppression (aOR 11.31; P = 0.02), receipt of TMP/SMX prophylaxis (aOR 0.14; P = 0.04), and relapse of underlying disease (aOR 12.28; P = 0.05) (Table 4).
Antimicrobial susceptibility Antibiotic susceptibility was available for 24 out of 26 isolates; 17 of 24 isolates (70.8%) were sensitive to penicillin, and 7 isolates (29.2%) had reduced sensitivity. Of the 7 isolates, 2 also had reduced sensitivity to third-generation cephalosporins.
Pneumococcal serotypes Serotype was determined in 22/26 IPD episodes (84.6%). The distribution of vaccine-containing serotypes is detailed in Table 5. Serotypes 6C, 23A, and 35F, not represented in any of the currently marketed pneumococcal vaccinations, accounted for 7/22 (30.4%) of serotyped IPD episodes. Twelve of 22
754
Characteristics of cases and controls Case (n = 23)
Control (n = 46)
Median age in years at transplantation (range)
44 (20–68)
44 (18–61)
100 days, evidence of chronic GVHD or unresolved acute GVHD predating IPD onset. 4 Refers to relapse of underlying disease without complete remission at time of IPD (or relapse at same time point post-transplant for controls). Relapsed disease included 2 leukemias and non-Hodgkin lymphoma in cases and a single case of myeloma relapse in a matched control. 5 fl of cases mismatched related allografts included 2 haploidentical related donors and an unrelated donor with single mismatch. Of controls, 2 unrelated allografts had a single HLA mismatch. 6 Of 3 cases, all non-peripheral stem cell grafts were sourced from bone marrow. Of 3 controls, non-PBSCT was sourced from cord blood (1) and bone marrow (2). 7 Hypogammaglobulinemia defined as documented total IgG levels
Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation A. Torda, Q. Chong, A. Lee, S. Chen, A. Dodds, M. Greenwood, S. Larsen, N. Gilroy. Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2014: 16: 751–759. All rights reserved Abstract: Background. Allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients are at high risk of invasive pneumococcal disease (IPD). We investigated the incidence and risk factors of IPD in alloHSCT recipients from 4 regional transplant centers over an 11-year period. This study aimed to inform future improvements in post-transplant care. Methods. We conducted a retrospective nested 1:2 case–control study in patients aged ≥18 years who underwent alloHSCT between 2001 and 2011 in 4 major allogeneic transplant centers. Controls were matched with IPD cases on the basis of conditioning intensity and donor relationship (related or unrelated). Demographics and clinical characteristics of cases and controls were summarized. Univariate analysis of risk factors in matched case–control sets, and multivariate conditional logistic regression to control for confounding, were performed. Results. In 23 alloHSCT recipients, 26 IPD episodes were identified. The cumulative incidence over 11 years was 2.3% (95% confidence interval [CI] 1.45–3.15) and the incidence density 956 per 100,000 transplant years of follow-up (95% CI 580–1321). Multivariate risk factor analysis and backwards elimination showed a significant positive association between mycophenolate mofetil (MMF), hyposplenism/asplenia, and IPD, whereas trimethoprimsulfamethoxazole (TMP/SMX) prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was associated with lower odds of IPD cases. Of alloHSCT recipients with IPD, 38.5% required intensive care, and, of deaths documented in cases over the period of review, 30% were attributable to IPD. Serotypes causing IPD matched currently available vaccines in 15/22 (68.1%) episodes. Conclusions. The incidence of IPD in alloHSCT recipients is an important cause of morbidity and mortality, with rates of disease being many fold higher than the general population. Patients with evidence of hyposplenism/asplenia define a high-risk group in the alloHSCT population for IPD, and the independent association with IPD and MMF in the adjusted model from this study requires further evaluation. The occurrence of post-transplant IPD may be reduced by measures such as vaccination with both 13-valent and 23valent pneumococcal vaccines. TMP/SMX prophylaxis for the prevention of PJP may offer incidental protection against IPD in alloHSCT recipients. Acquired deficiencies in circulating immunoglobulin (Ig)M and switched memory B cells after hematopoietic stem cell transplantation (HSCT) are associated with an increased risk of infection with encapsulated bacteria,
A. Torda1,2, Q. Chong1, A. Lee3, S. Chen4, A. Dodds5, M. Greenwood6, S. Larsen7, N. Gilroy8 1
Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia, 2Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia, 3Department of Microbiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, 4Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR – Pathology West, The University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia, 5 Department of Hematology, St Vincent’s Hospital, Darlinghurst, New South Wales, Australia, 6Department of Hematology, Royal North Shore Hospital, St Leonards, New South Wales, Australia, 7Department of Hematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, 8St Vincent’s Hospital Sydney and BMT Network, Agency for Clinical Innovation (ACI), Darlinghurst, New South Wales, Australia
Key words: invasive pneumococcal infection; HSCT; vaccination; incidence; serotype Correspondence to: Dr Adrienne Torda, Department of Infectious Diseases, Prince of Wales Hospital, Randwick, NSW 2031, Australia Tel: 02 93823405 Fax: 02 93823403 E-mail: [email protected]
Received 12 December 2013, revised 10 April 2014, 19 April 2014, accepted for publication 4 May 2014 DOI: 10.1111/tid.12268 Transpl Infect Dis 2014: 16: 751–759
such as Streptococcus pneumoniae (1). Allogeneic HSCT (alloHSCT) recipients are particularly susceptible to lifethreatening invasive pneumococcal disease (IPD) owing to risk factors that include functional hyposplenism,
751
Torda et al: Invasive pneumococcal infection following HSCT
hypogammaglobulinemia, immunosuppressive therapy, immunomodulatory effects of graft-versus-host disease (GVHD), and impaired responses to post-transplant pneumococcal vaccination (2–6). Previous multicenter surveys have found IPD incidence rates between 5.9 and 20.9 per 1000 in alloHSCT recipients, and 3.8–6.2 per 1000 in autologous transplant recipients (3–5). In one prospective populationbased study, the incidence density of IPD, adjusted for follow-up, was reported as 590 per 100,000 alloHSCTs per year, compared with 199 per 100,000 autologous transplants per year, and 11.5 per 100,000 per persons per year in the general population (5). These studies indicate that the risk of IPD in alloHSCT is 3- to 4-fold higher compared with autologous transplant recipients, and 50-fold higher than the general population. The risk of IPD in alloHSCT recipients is also increased in the late transplant phase (>day 100) (3, 5) and in those with chronic GVHD (6). After HSCT, immunization and antibiotic prophylaxis against pneumococcal infection are widely recommended. Various guidelines have been proposed in Europe, the United States, and Australia (2, 7–10). Two commonly used vaccines are 23-valent polysaccharide vaccine, and the protein conjugate vaccines including the 7-, 10-, and 13-valent vaccines. Antibiotic prophylaxis, usually with penicillin or a macrolide, is recommended in recipients with chronic GVHD (7, 10). In 2008, the reported population incidence of IPD in Australia was 7.6 per 100,000 persons (11). However, the incidence of IPD in alloHSCT recipients has not been determined in the Australian population, and risk factors for IPD in this population have not been evaluated. We undertook a retrospective nested case– control study to investigate the incidence and associated risk factors of IPD in recipients of alloHSCT in New South Wales (NSW) transplant centers over an 11-year period. The results of this study were intended to inform the development and implementation of improved vaccination and antibiotic prophylaxis protocols in the post-transplant setting.
Methods Study population This study was approved by Human Ethics Review Committees at each participating site. Patients for inclusion in this study were aged ≥18 years and had received an alloHSCT between January 1, 2001 and December 31, 2011 in 1 of the 4 adult allogeneic bone marrow transplant (BMT) centers in NSW, Australia.
752
These 4 centers accounted for all adult alloHSCT recipients in the state of NSW, and site-specific transplant databases provided transplant numbers and years of follow-up for incidence rate calculations over the period of review.
Case definitions A confirmed case of IPD was defined as a patient in whom S. pneumoniae was isolated from a normally sterile site (blood, cerebrospinal fluid [CSF], or joint aspirate), excluding the middle ear and pleural fluid. A probable case of IPD was defined as a patient with a positive pneumococcal urinary antigen, in the presence of a clinically compatible syndrome (sepsis, pneumonia, meningitis) (11). Early or late onset of IPD was defined as infection occurring ≤100 days or >100 days post first transplant, respectively.
Study design We performed a retrospective nested case–control study of adult alloHSCT recipients transplanted from 2001 to 2011. Each case of IPD was matched with 2 controls from the alloHSCT cohort. To minimize confounding, controls were matched with cases on the basis of conditioning intensity (myeloablative or non-myeloablative) and donor relationship (related or unrelated). Controls were required to have an overall survival that was at least as long as the case at the time of their IPD diagnosis. When several eligible controls matched these criteria, controls with a transplant date closest to the transplant date of the IPD case were selected. Transplant data, including underlying diagnosis, remission status, transplant date, donor type, conditioning regimen, and follow-up dates for cases and controls were identified from the site-specific transplant registers that contribute data to the Australian Bone Marrow Transplant Recipient Register. IPD cases were identified by cross-referencing the list of allogeneic transplant recipients with all sterile site isolates of S. pneumoniae (blood, urine, and joint fluids) and positive urinary antigen tests from the corresponding transplant center’s microbiology database. Hospital databases and medical records were used to obtain demographic and clinical information, including underlying disease and transplant indications, post-transplant care (antimicrobial prophylaxis, immunosuppression, vaccination), and comorbidities (GVHD, hyposplenism, hypogammaglobulinemia).
Transplant Infectious Disease 2014: 16: 751–759
Torda et al: Invasive pneumococcal infection following HSCT
IPD episodes Clinical information relating to IPD episodes, such as date of first positive culture, hospitalization dates with IPD, site of disease involvement (lung, blood, CSF, or other), treatment, and complications (requirement for intensive care, mortality), were sourced from medical records. Hospital microbiology databases provided information on the sterile site(s) from which S. pneumoniae was cultured and antibiotic susceptibilities. Pneumococcal serotype data were obtained from the Pneumococcal Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, NSW.
Statistical analysis Descriptive statistics including demographics (age, gender) and baseline clinical characteristics (disease, transplant factors, and post-transplant care) of cases and controls were summarized. Antimicrobial susceptibility, pneumococcal serotypes, and IPD outcomes were also summarized. Cumulative incidence rate over the 11 years of review was reported as number of IPD episodes occurring in the alloHSCT cohort. IPD incidence density was calculated as number of IPD episodes per 100,000 allogeneic transplant years of follow-up. Univariate risk factor analysis for a matched 1:2 case–control design involved matched odd ratios (mOR), 95% confidence intervals (CIs) using the Mantel Haenszel method for matched case–control sets, and Fisher’s exact test for P-values, with P < 0.05 being the level of significance. All variables included in the univariate analysis were fitted into a multivariable model (maximum model). Variables with the highest P-value were sequentially removed using the backward elimination approach (12). Variables in the final adjusted model with a 2-sided Pvalue 100 days). The details of IPD admission are summarized in Table 1. Eighty-eight percent of episodes had bacteremia, 73.1% pneumonia, and a single episode had meningitis. Almost 40% of cases required intensive care unit admission. A total of 10 deaths were reported, and 30% of these were directly attributable to IPD. Three cases had recurrent IPD infection; 1 of these secondary episodes was fatal.
Characteristics of cases and controls and risk factor analysis The median age of cases was 44 years (range 20– 68 years), and males accounted for 69.6% of cases. IPD episode details – Timing and outcome (n = 26) Timing Median age at IPD diagnosis, years (range) Median time post transplant to onset of IPD, days (range)
44 (21–73) 553 (6–3327)
Early onset (≤100 days)
2
Late onset (>100 days)
24
Site of disease involvement (%)
Results
Lung
19 (73.1)
Blood
23 (88.4)
Central nervous system
Incidence
ICU admission
A total of 1154 adult alloHSCT were performed in NSW during the review period with 2720 patient-years of follow-up. The median period of follow-up was 480 days (range 1–4148 days). We identified 26 IPD episodes
Median duration of hospitalization, days (range)
1 (3.8) 10 (38.5) 13 (0–98)
IPD, invasive pneumococcal disease; ICU, intensive care unit.
Table 1
Transplant Infectious Disease 2014: 16: 751–759
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Torda et al: Invasive pneumococcal infection following HSCT
Acute leukemia (AML/ALL) was the underlying diagnosis in 7 of 23 primary IPD cases. Stem cell source was peripheral blood in 87% of cases (others were bone marrow). The risk factors assessed in this study are summarized for cases and controls in Table 2. GVHD present at the time of IPD (both acute and chronic) of varying severity was documented in 91.3% and 80.4% of IPD cases and controls, respectively. Hyposplenism or asplenia was documented in 5/23 (21.7%) and hypogammaglobulinemia in 6/23 (26%) of IPD cases. At the time of IPD diagnosis, specific antibiotic prophylaxis (penicillin, erythromycin, or a cephalosporin) was documented in 43.5% of the cases. TMP/SMX prophylaxis for Pneumocystis jirovecii (PJP) was documented in 65.2% of cases and 71.7% controls. Cyclosporine and prednisolone were the most commonly used immunosuppressants in all centers. Of the 23 cases, 17.4% received 23-valent pneumococcal vaccine prior to IPD onset, compared to 26.1% in the control group (Table 2). The median time of receiving vaccination was approximately 2 years post HSCT. On univariate analysis of risk factors for IPD (Table 3), an increased association was observed in patients receiving mycophenolate mofetil (MMF) (mOR 5.0; P = 0.05) and a reduced association in those with an underlying diagnosis of acute leukemia (mOR 0.39; P = 0.05). Following backward stepwise elimination, the explanatory variables that were retained in the multivariable model, after adjusting for confounding, included hyposplenism/asplenia (aOR 12.67; P = 0.02), MMF immunosuppression (aOR 11.31; P = 0.02), receipt of TMP/SMX prophylaxis (aOR 0.14; P = 0.04), and relapse of underlying disease (aOR 12.28; P = 0.05) (Table 4).
Antimicrobial susceptibility Antibiotic susceptibility was available for 24 out of 26 isolates; 17 of 24 isolates (70.8%) were sensitive to penicillin, and 7 isolates (29.2%) had reduced sensitivity. Of the 7 isolates, 2 also had reduced sensitivity to third-generation cephalosporins.
Pneumococcal serotypes Serotype was determined in 22/26 IPD episodes (84.6%). The distribution of vaccine-containing serotypes is detailed in Table 5. Serotypes 6C, 23A, and 35F, not represented in any of the currently marketed pneumococcal vaccinations, accounted for 7/22 (30.4%) of serotyped IPD episodes. Twelve of 22
754
Characteristics of cases and controls Case (n = 23)
Control (n = 46)
Median age in years at transplantation (range)
44 (20–68)
44 (18–61)
100 days, evidence of chronic GVHD or unresolved acute GVHD predating IPD onset. 4 Refers to relapse of underlying disease without complete remission at time of IPD (or relapse at same time point post-transplant for controls). Relapsed disease included 2 leukemias and non-Hodgkin lymphoma in cases and a single case of myeloma relapse in a matched control. 5 fl of cases mismatched related allografts included 2 haploidentical related donors and an unrelated donor with single mismatch. Of controls, 2 unrelated allografts had a single HLA mismatch. 6 Of 3 cases, all non-peripheral stem cell grafts were sourced from bone marrow. Of 3 controls, non-PBSCT was sourced from cord blood (1) and bone marrow (2). 7 Hypogammaglobulinemia defined as documented total IgG levels
