Infections Post Transplant Incidence, risk factors, and ... - Nature

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Infections Post Transplant Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation Chien-Shing Chen1, M Boeckh, K Seidel, JG Clark, E Kansu, DK Madtes, JL Wagner2, RP Witherspoon, C Anasetti, FR Appelbaum, WI Bensinger, HJ Deeg, PJ Martin, JE Sanders, R Storb, J Storek, J Wade3, M Siadak, MED Flowers and KM Sullivan Clinical Research Division, Fred Hutchinson Cancer Research Center and the University of Washington, School of Medicine Seattle, WA, USA

Summary: The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for o20 years, 1.2 for 440 years, P ¼ 0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P ¼ 0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P ¼ 0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.

Correspondence: Dr KM Sullivan, Division of Medical Oncology and Transplantation, Duke University Medical Center, Box 3476, Durham, NC 27710, USA. E-mail: [email protected] 1 Current address: Division of Hematology/Oncology and Stem Cell and Bone Marrow Transplant Program, Loma Linda University Medical Center, Loma Linda, CA 92350, USA 2 Current address: BMT Department, Thomas Jefferson University, 130 S 9th Street, Edison Bldg #400, Philadelphia, PA 19107, USA 3 Current address: Medical College of Wisconsin, 9200 W Wisconsin Ave., FEC 3963A, Milwaukee, WI 53226, USA Supported in part by grants from The National Heart, Lung, and Blood Institute (HL36444) and The National Cancer Institute (CA15704, CA18029, CA18221, CA15704) of the National Institutes of Health, DHHS. Received 1 July 2002; accepted 9 March 2003

Bone Marrow Transplantation (2003) 32, 515–522. doi:10.1038/sj.bmt.1704162 Keywords: pneumonia; blood stem cell transplantation; late complications

Despite improved outcome of blood and marrow stem cell transplantation (SCT), infection remains a serious complication after myeloablative conditioning. After engraftment, patients remain at risk for potentially fatal infection due to immunosuppression and chronic graft-versus-host disease (GVHD).1–5 Our previous report examining the incidence of first pneumonia following discharge from Seattle during 1985–1989 revealed a Kaplan–Meier probability of late pneumonia by 4 years post-transplant of 60 and 25%, respectively, in HLA-matched recipients with and without chronic GVHD.6 An increased risk for all types of late infection including pneumonia after SCT was observed among patients with HLA-mismatched related donors or active chronic GVHD.1–3 Two groups have further examined the incidence of late post transplant infections.4,5 From a survey among 18 UK centers, Hoyle et al4 reported that only 6% patients developed late life-threatening infections of any type requiring admission. In another report with 249 allograft transplant recipients from a single center, the incidence of any type or site of late infection up to 2 years post transplant was greater in unrelated donor recipients, advanced GVHD, and patients of older age. However, pneumonia only comprised about 10% of total single-site infection cases.5 The incidence rates of late infection could be higher and were acknowledged by both studies. The present study investigated the incidence, etiology, risk factors, and outcome of pneumonia developing late after autologous, HLA-identical, nonidentical, and unrelated SCT in order to further define methods to improve post transplant monitoring and infection control.

Material and methods Study population and follow-up A total of 1359 patients (63% of all transplanted cases (2164 patients)) given allogeneic, syngeneic, autologous,

Late pneumonia after BMT C-S Chen et al

516

and unrelated marrow or blood SCT at the Fred Hutchinson Cancer Research Center (FHCRC) between January 1992 and January 1997 were prospectively followed after discharge home (Table 1). These patients were followed after returning home a median of 95 (range 12–245), 99 (15–359), and 49 (11–268) days, respectively, after HLA-matched related (N ¼ 471), HLA-mismatched related/unrelated (N ¼ 466), and autologous/syngeneic (N ¼ 422) peripheral blood or marrow SCT. Criteria for discharge home included sustained hematopoietic engraftment without further need for transplant-specific intensive care or control of active infection or GVHD. However, exceptions exist as some patients returned to the care of their referring physicians without achieving the above criteria. Subsequent follow-up and tracking of medical events were conducted by several methods.7 On-site examination of returning patients was performed at the first and selected subsequent anniversaries of transplantation and included detailed medical, hematological, and immunological evaluations. Follow-up questionnaires were sent to referring physicians initially at 6 months and then at each anniversary of SCT. Medical events, including infection and pneumonia, were detailed and survival data reported to the date of last contact. Yearly questionnaires were also sent to each patient eliciting functional performance information, symptoms, and medical complications and infection. Coding and key entry of incoming information (questionnaire, office and telephone records, and return visits) were performed within 48 h of receipt, using modified codes of the Systemized Nomenclature of Medicine (SNOMED). With this broad-based approach to followup, current medical status information was available for 92% of surviving patients.7

Definitions of pulmonary infection Histological and microbiologic evaluations of bronchoalveolar lavage (BAL) or lung biopsy were provided by primary physicians or by the virology or microbiology laboratories at FHCRC. Patients were designated as having idiopathic pneumonia syndrome (IPS) if there were diffuse radiographic multilobar infiltrates and no viral or other pathogen identified by histology or tissue culture.8 If microbiologic or tissue samples were not obtained, the etiology was categorized as unknown (ie clinical pneumonia diagnosis). Pneumonia was classified as multiorganism if more than one pathogen was reported. Patients were considered to have had multiple distinct episodes of pneumonia if the isolates were recovered at least 2 weeks apart. Pneumonias developing at or after morphologic relapse of malignancy were excluded from analysis.

Table 1

Characteristics of patients discharged home (1992–1997) Total patients (n=1359)

Patient age (years) o20 20–40 40–60

246 (18%) 491 (36%) 622 (46%)

Donor gender-patient gender Male-male Female-male Autologous, male Male-female Female-female Autologous, female

320 231 144 211 196 256

Type of transplant HLA-matched related allogeneic Unrelated and mismatched related Autologous/syngeneic

471 (35%) 466 (34%) 422 (31%)

Day of discharge after Txp: median (range) HLA-matched related allogeneic Unrelated and mismatched related Autologous/syngeneic

(24%) (17%) (11%) (16%) (14%) (19%)

Pneumonia patients (n=341) 47 (14%) 130 (38%) 164 (48%)

97 86 24 48 48 38

(28%) (25%) (7%) (14%) (14%) (11%)

129 (38%) 149 (44%) 63 (18%)

95 (12, 245) 96 (31, 181) 99 (15, 359) 100 (15, 216) 49 (11, 268) 52 (18, 130)

Primary diagnosis Acute leukemia Chronic leukemia/CML Multiple myeloma Lymphoma Myelodysplastic syndrome (MDS) Aplastic anemia (AA) Breast cancer Other diseases

361 397 58 174 109 38 156 66

(27%) (29%) (4%) (13%) (8%) (3%) (11%) (5%)

85 124 16 36 39 7 20 14

(25%) (36%) (5%) (11%) (11%) (2%) (6%) (4%)

Total body irradiation (cGy) None p1000 (single fraction) 1200 (fractionated) >1200 (fractionated)

529 16 330 398

(42%) (1%) (26%) (31%)

119 4 81 119

(37%) (1%) (25%) (37%)

CMV pretransplant serology Donor pos or neg, recipient pos Donor pos, recipient neg Donor neg, recipient neg

677 (53%) 152 (12%) 459 (36%)

182 (55%) 39 (12%) 111 (33%)

Acute GVHD prophylaxis CSP+MTX Other Not applicable (autologous/syngeneic)

570 (48%) 197 (17%) 422 (35%)

170 (59%) 54 (19%) 63 (22%)

Acute GVHD (among allograft recipients)a Grade 0–I Grade II–IV

189 (24%) 615 (76%)

41 (17%) 203 (83%)

Chronic GVHD (among allograft recipients)a Clinical extensive (cumulative incidence) 474 (57%)

173 (67%)

Infection prophylaxis policies

CML=chronic myelogenous leukemia; CMV=cytomegalovirus; CSP= cyclosporine; GVHD=graft-versus-host disease; MTX=methotrexate; Neg=negative; Pos=positive; Txp=transplantation. a A total of 99 allograft recipients have missing acute GVHD data and 51 allograft recipients missing chronic GVHD data.

During the study period, Pneumocystis carinii pneumonia (PCP) prophylaxis in autologous/syngeneic transplantation was given until day 120 after transplant. In allograft recipients, PCP prophylaxis was given until 6 months after transplant or until discontinuation of immunosuppressive treatments for chronic GVHD, whichever occurred later.

The dose of trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis was one DS tablet p.o. twice daily on two consecutive days each week. In case of sulfa intolerance, desensitization for TMP/SMX was started post transplant

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Statistical methods The incidence of first episodes of pneumonia was summarized from the time of discharge home using cumulative incidence estimators. Potential risk factors for developing pneumonia were evaluated using univariable and multivariable Cox proportional hazards regression. Covariates included patient age, patient/donor gender combination, relationship of donor to patient, diagnosis, total body irradiation (TBI), GVHD prophylaxis regimen, patient/ donor CMV serostatus, and chronic GVHD. Chronic GVHD was treated as a time-dependent covariate. Since several risk factors for pneumonia were not relevant in the autologous or syngeneic transplant setting, separate multivariable regression models were developed for the allogeneic and autologous/syngeneic populations. For 33 pneumonia cases, follow-up ended at the time of pneumonia diagnosis. These patients were therefore not included in the survival analysis. Kaplan–Meier curves were used to summarize survival from the time of diagnosis of first pneumonia following discharge home.

Results Patient characteristics Demographics and cohort characteristics are described in Table 1. Of the 1359 patients discharged home between 1992 and 1997, 471 patients received allografts from HLAidentical siblings, 134 from mismatched related donors, 332 from unrelated donors, 23 from syngeneic donors, and 399

from autologous marrow or peripheral blood stem cell sources.

517

Incidence and etiologies of pneumonia With a median follow-up of 2 (range 0.01–5) years, 341 patients (25% of the cohort) developed at least one episode of pneumonia after discharge home. Among these patients, there were 478 episodes of pneumonia: 265 patients (78%) had a single episode, 64 (19%) had 2–3 episodes, and 12 (3%) had four or more episodes of late pneumonia. Since the incidence and survival of first pneumonia were similar for HLA-mismatched related and unrelated donor recipients, these two groups were combined in the analysis. The cumulative incidences of first pneumonia at 4 years after discharge home were 39, 34, and 18% among unrelated/ HLA-mismatched related, matched related, and autologous/syngeneic transplants, respectively (Figure 1). Although most first pneumonias occurred by 2 years after discharge home, some patients were still at risk of developing first pneumonia well beyond the second year. The median days after transplant of onset of each type of pneumonia are 165 days for viral, 222 days for fungal, 237 days for idiopathic, 278 days for PCP, 337 days for bacterial, and 316 days for clinical pneumonia. The cumulative incidences at 2 years after discharge were 33% in unrelated/HLA-mismatched related, 28% in HLA-matched related, and 15% in autologous/syngeneic recipients. At 4 years after discharge home, the cumulative incidence of all types of first pneumonia was 31%. The overall incidences for 4 years of specific etiologies included 19% clinical pneumonia, 3% bacterial, 3% viral, 2% multiple organism, 2% IPS, 1% fungal, and 1% Pneumocystis carinii. For etiologies of special interest, we evaluated all cases of late pneumonia regardless of episode number. The cumulative incidences of ever developing CMV pneumonia as a first or subsequent pneumonia at the first and fourth year were 2.4 and 2.7%, respectively, regardless of CMV serological status. The cumulative incidences of ever developing PCP at the first and fourth year were 1.8 and 2.2%, respectively. The etiologies of first pneumonia episodes are presented in Table 2. Etiologies of viral pneumonia included CMV (22 cases), respiratory syncytial virus (3), herpes simplex

1.00 Cumulative incidence of first late pneumonia

when the absolute neutrophil counts were greater than 500/ mm3 for 72 h or by day 30.9,10 Patients who could not tolerate TMP/SMX received dapsone 50 mg p.o. twice daily on 3 days per week.10 Cytomegalovirus (CMV) prophylaxis employed an antigenemia-guided pre-emptive treatment approach.11,12 CMV antigen (pp65) monitoring was performed weekly until discharge home. Starting in 1997, the monitoring in CMV seropositive individuals, seronegative patients with seropositive donors, or individuals receiving corticosteroid therapy for chronic GVHD continued until day 365. Ganciclovir was administered to patients with either CMV antigenemia (45 positive cells per slide) or viremia (detected by shell vial culture). All transplant recipients were given fluconazole 400 mg/day orally or intravenously from the start of conditioning through day 75. No antifungal prophylaxis was administered after day 75.13,14 Antibacterial and PCP infection prophylaxis was given after discharge home for those receiving chronic GVHD therapy.7 This consisted of intermittent TMP/SMX as described above and daily penicillin prophylaxis. If severe hypogammaglobulinemia (IgG o400 mg/dl) and documented infection developed, intravenous immunoglobulin (IVIg) was given at a dose of 500 mg/kg/month. Subsequent doses were adjusted based on serum IgG level and clinical status. The vaccination policy for SCT recipients generally starts 1 year after transplant.15

0.75 0.50

URD/mismatched related (n =466)

39% 34%

matched related (n =471) 18%

0.25

autologous/twin (n =422)

0.00 0

1

2

3

4

Years after discharge home Figure 1 Cumulative incidences of first late pneumonia at 4 years after transplant and discharge home. Bone Marrow Transplantation


518

virus (2), varicella (2) Epstein–Barr virus (1), and other virus (3). Bacterial etiologies were more heterogeneous: Gram-negative organisms included klebsiella (4), pseudomonas (2), and Serratia marcescens (1). Other bacterial organisms included S. pneumoniae (7), streptococcus (beta hemolytic or NOS) (5), staphylococcus (aureus or coagulase negative) (3), mycobacterium (avium or tuberculosis or acid-fast bacillus) (3), Nocardia asteroides (2), Hemophilus influenzae (1), legionella (1), moraxella (1), and Mycoplasma pneumoniae (1). Fungal infections were subclassified as molds or nonmolds. Invasive molds included aspergillus (14) while nonmold infections included Blastomyces dermatitidis (1), Candida albicans (1), or unspecified yeast (1). In two cases, fungal elements were observed but no further identification was made. More than one microbial isolate was identified in 20 individuals with first pneumonia (Table 2). Among them, 12 patients had fungal infection and other infection and eight had CMV pneumonia and other infection. Three patients with PCP had concomitant CMV pneumonia. Autologous transplant recipients rarely acquired either fungal or multiorganism infections (one case each). PCP was identified in 16 patients (Table 2). Six of the 16 patients received autologous transplants, where prolonged PCP prophylaxis was not routine and none of the six patients were receiving TMP/SMX when PCP developed. The underlying diseases of these six patients included leukemia (3), lymphoma (2), and neuroblastoma (1). Five of the six patients survived the PCP episodes. No patient with breast cancer developed PCP. Two autograft patients with PCP were receiving corticosteroids for either pseudoGVHD or chronic idiopathic thrombocytopenia purpura. Overall, incidences of PCP as the first pneumonia for the entire cohort of autograft recipients and autograft recipients with the primary diagnosis other than breast cancer were 1.5 and 2.5%, respectively. Of the 10 allogeneic recipients developing PCP, one individual was receiving TMP/SMX and four were receiving low-dose dapsone prophylaxis at the time of infection.10 Four patients with active chronic GVHD were receiving immunosuppressant therapy without PCP prophylaxis. The underlying diseases of these 10 allograft recipients included leukemia (8), myelodysplastic syndrome (1), and multiple myeloma (1).

Analyses of risk factors for first late pneumonia Multivariable regression models were constructed to assess whether covariates identified as significant in the singleTable 2

factor analyses represented independent risk factors for developing any pneumonia. There was no evidence that risks differed for HLA-matched related transplants vs mismatched/unrelated transplants; therefore, multivariable regressions were performed separately for allogeneic (related or unrelated) patients and for autologous patients. Among the allogeneic recipients, patient age, donor type, and chronic GVHD were significant independent risk factors for developing late pneumonia (Table 3). Patients under 20 years of age were at lower risk relative to patients in the 20 to 40-year age range (RR ¼ 0.5). The associations seen in the univariable analyses (primary disease diagnosis, donor/recipient sex, TBI dose, and prior acute GVHD) were no longer statistically significant after adjusting for other factors. Among autologous SCT recipients, no significant independent risk factor was identified.

Survival after pneumonia The overall survivals at 1 month and 1 year after the diagnosis of first late pneumonia were 80 and 63%, respectively. Survival according to type of pneumonia is illustrated in Figure 2. The number of deaths within 14 days after diagnosis of initial pneumonia episode are five patients for idiopathic, three for bacteria, six for viral, 11 for fungal, two for PCP, 11 for clinical, and six for multiple organism pneumonias. The survival rates at 1 year after diagnosis of pneumonia were lowest among patients with multiorganism (8%) or fungal (27%) etiologies. Survival rates after first pneumonia caused by viral or PCP cases were 41 and 51%, respectively. Patients diagnosed with idiopathic or bacterial etiologies had 1-year survivals of 60 and 71%, respectively. In 197 cases of clinical pneumonia, where patients were empirically treated without a microbiologic diagnosis, the 1-year survival was 76%.

Discussion This study demonstrates that patients remain at substantial and sustained risk of developing life-threatening pneumonia late after myeloablative SCT. The cumulative incidence of a first pneumonia episode at 4 years after discharge home was 18% for autologous/syngeneic, 34% for HLA-matched related, and 39% for mismatched/unrelated SCT. The true incidence of late pneumonia may be higher since some patients did not meet the home discharge criteria due to

First pneumonia episodes after discharge home

Type of pneumonia

Auto/syngeneic

HLA-matched related

Unrelated and mismatched related

Clinical diagnosis Viral Bacterial Idiopathic Multiple organism Fungal Pneumocystis carinii

44 4 2 5 1 1 6

79 9 13 10 7 6 5

74 20 16 10 12 12 5

Total

63

129

149

a

a

No tissue or microbiologic samples were obtained.


Total cases 197 33 31 25 20 19 16

(58%) (10%) (9%) (7%) (6%) (6%) (4%)

341


519 Multivariable models for risk of first late pneumonia

Covariate

Allogeneic Relative risk

Patient age (years) 0–20 20–40 >40 Donor sex-patient sex Male-male Female-male Male-female Female-female Donor type Related Unrelated Diagnosis category Acute leukemia Chronic leukemia Multiple myeloma Lymphoma Myelodysplastic syndrome Aplastic anemia Others Breast cancer Total body irradiation (cGy) None o1100 1200 >1300 Acute GVHD prophylaxis CSP and MTX Other regimen Acute GVHD grade 0–I II–IV Patient/donor CMV serostatus p/d p/d+ p+ Chronic GVHD None/limited Clinical extensive

1.00

Autologous

P-value

Relative risk

a

a

0.009 0.5 1.0 1.2

P-value 0.10

1.5 1.0 2.4 0.30a

1.0 1.1 0.8 0.8

0.07

unknown/clin dx only 0.75 bacterial 0.50

PCP

idiopathic viral fungal multiple organisms

0.25

1.0

0.00 0 1.9

1

2

3

4

Years after first pneumonia diagnosis

0.01 1.0 1.6

Figure 2 Survival rates according to types of pneumonia. 0.45a

1.0 1.1 2.1 1.4 1.3 0.7 0.7

0.49a 1.0 1.0 0.5

0.5 0.9 0.17a

1.5 1.2 1.0 1.5

0.58a 0.7 0.4 1.0

0.81 1.0 1.0 0.08 1.0 1.4 0.29a 1.0 0.7 1.0 1.0 1.5

Survival probability

Table 3

0.88 1.0 1.0

0.007

a

P-values were taken from likelihood ratio test for the significance of the entire set of subcategories for the factor.

ongoing transplant complications. Late pneumonia could be classified into six categories: (1) The largest cohort of late first pneumonias (197 cases, 58% of total) in this study was clinical pneumonia and these patients were empirically treated without establishing a tissue or microbial isolate diagnosis. The relatively favorable outcome in this group of patients suggests that the clinical presentation of these pneumonias may have been less severe. Similar empiric strategies have been employed in the management of community-acquired pneumonia wherein no specific cause was found in 25–50% of nontransplant pneumonia patients.16 (2) Next most common were bacterial pneumonias. The most frequent isolate was S. pneumoniae; however Gramnegative organisms (seven cases, 23% of all bacterial pneumonia) appeared to be more prevalent in the current study than in an immunocompetent population.16 Late bacterial pneumonias were often associated with chronic

GVHD in this and in earlier reports from our center.2,3 Recent studies indicate that pneumococcal infection can occur despite prophylactic antibiotics.5,17 Whether these cases occurred due to lack of compliance with prophylaxis or to resistance to TMP/SMX or penicillin could not be assessed in this study. (3) Fungal and multiple organism pneumonias had a very poor prognosis. Aspergillus represented a significant proportion of late infections in two large studies and has a known high mortality.4,5 With better control of other opportunistic infections, especially CMV, invasive fungal disease has become the leading infectious cause of death during the first 100 days after transplant.18,19 Late fungal infection is predominantly due to aspergillus, while late candidiasis appears to be less common since introduction of post transplant fluconazole prophylaxis in allograft recipients.14,20 (4) PCP was a relatively rare complication. In this study, all cases of PCP developed within 2 years of discharge home. Infections in the 10 allografts occurred either after PCP prophylaxis had been discontinued or during prophylaxis with low-dose dapsone. However, six autograft patients developed late PCP. While this relatively high incidence of late PCP was unexpected, it was similar to another series of 12 patients developing PCP in an European study where only two were taking TMP/SMX prophylaxis.4 In a retrospective study in Seattle, there was an 18-fold increased relative risk of PCP in patients receiving dapsone (50 mg p.o. b.i.d. 3 days a week) compared with standard TMP/SMX prophylaxis.10 Based on that study and other recent reports comparing dapsone to TMP/SMX, it appears that daily dosing of dapsone is required to provide protection comparable to TMP/SMX prophylaxis.21–25 (5) Late-onset CMV pneumonia has emerged as an important complication.26,27 In a prior study, one-third of late viral infections were caused by CMV, and CMV was responsible for 57% of late life-threatening viral infections.5 In the current study, two-thirds of late viral pneumonias were caused by CMV, and most of these first late episodes occurred within the first year after discharge home. (6) Idiopathic pneumonia was seen in 7% (25 cases) of this cohort and survival 1 year after diagnosis was 60%. Bone Marrow Transplantation


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Studies of late pneumonia report a 20–54% incidence of IPS.28,29 Early after transplant, IPS has a mortality rate of 60–75%.30–32 Thus, late IPS may have a somewhat better outcome than those developing earlier post transplant. Strategies to prevent late pneumonia can be developed based on the patient risk factors and infectious etiologies. Individuals with high risk features such as mismatched or unrelated donors, chronic GVHD, older age, or autologous patients with the diagnosis of hematological malignancies should be monitored closely for early signs or symptoms of lower respiratory tract infection or CMV antigenemia. As a result of the significant mortality rate associated with late pneumonia even as late as 3–4 years after transplant, tissue sampling by BAL should be obtained to identify specific pathogens in patients who develop pneumonia.33 To prevent PCP, TMP/SMX prophylaxis can be considered for at least 6 months after autologous SCT for treatment of hematologic malignancies. For autograft recipients, this is longer than previously recommended.15 Allogeneic SCT recipients should receive PCP prophylaxis until 6 months after immunosuppressive therapy has been discontinued. Daily dapsone is recommended as second-line prophylaxis. Aerosolized pentamidine appears associated with lower efficacy and higher 1-year mortality.34 For fungal prophylaxis, fluconazole significantly reduces the risk of systemic fungal infection early after SCT.35 When given until day 75, fluconazole also has a long-term protective effect against Candida albicans and C. tropicalis.14 Patients with high-risk features (unrelated donor recipients receiving immunosuppressive therapy for active chronic GVHD, or those with neutropenia) may benefit from prolonged antifungal prophylaxis.14,36,37 A prospective, randomized study is currently under way to test the efficacy of long-term prophylaxis. For prevention of CMV disease, early detection of CMV infection followed by ‘preemptive therapy’ appears to be effective.11,38–40 Alternatively, ganciclovir prophylaxis can be given early after transplant.11,41 Late CMV disease is now a complication that occurs with both early pre-emptive therapy and prophylaxis.26 Prevention strategies for late CMV disease such as continued surveillance and pre-emptive therapy or extended prophylaxis with oral anti-CMV drug (eg valganciclovir) are currently under study.26,42 For prevention of bacterial pneumonia, most transplant reports have been directed toward prevention of Grampositive encapsulated organisms. Patients with chronic GVHD have an increased risk for pneumococcal infections due to reduced levels of pneumonoccal antibody and due to poor immunologic response after polysaccharide pneumococcal vaccinations. Conjugate pneumococcal vaccines might offer greater protection from this infection, and guidelines for post transplant immunizations for both autograft and allograft recipients have been recently published.15 Hypogammaglobulinemia is also associated with recurrent pneumococcal infections in transplant recipients,43,44 and IVIG repletion is recommended to prevent recurrent disease. Individuals with pneumococcal infection should be placed in standard isolation.45 Patients receiving prednisone therapy for treatment of chronic GVHD or other reasons (including autograft recipients) should be receiving prophylactic TMP-SMX. For Gram-


negative organisms, prevention of disease with antibiotics, in particular fluoroquinolones, has been controversial because of concerns about the emergence of drug resistance.46,47 In both the early and late post transplant periods, routine use of IVIG prophylaxis has not consistently shown long-term survival benefit.48–50 In the absence of infection and severe hypogammaglobulinemia (serum IgG o400 mg/dl), routine use of IVIG is not indicated. In conclusion, we have found that pneumonia remains a significant cause of morbidity and mortality over an extended period of time after SCT and requires continued long-term monitoring. Infection control measures should be tailored to patient risk factors and improved methods to reduce GVHD and evolving guidelines and approaches to preventing late infection could potentially further decrease the mortality of myeloablative SCT.

Acknowledgements We express our appreciation to attending physicians and nursing staff caring for these patients and Janet Nims, RN, Judy Campbell, RN, and Carina Moravec, ARNP of the Long-Term Follow-Up program at FHCRC. We appreciate the critical review from Kieren A Marr, MD. We also thank Linda Wu, RN, MsN for secretarial assistance.

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