We reviewed 242 allogeneic hematopoietic stem cell transplantation (HSCT) recipients retrospectively over a 2-year period (January 1998–December 1999) in order to analyze the characteristics and assess the outcomes of infectious complications in patients after HSCT in Korea. Bacteria were the major pathogens before engraftment, and viral and fungal infections predominated during the post-engraftment period. Varicella zoster virus was the most common viral pathogen after engraftment. Cytomegalovirus disease occurred mainly in the late-recovery phase. The frequency of mold infection was higher than that of yeast. There was a relatively high incidence of tuberculosis (3.0%) and Pneumocystis carinii pneumonia (6.5%). One case of death by measles confirmed by autopsy was also noted. Overall, cumulative mortality was 43% (104/242), and 59.6% of these deaths (62/104) were infection-related. Allogeneic HSCT recipents from unrelated donors were prone to infectious complication and higher mortality than those from matched sibling (17/39 (43.6%) vs 45/203 (22.2%), respectively; P<0.01; odd ratio 2.5; 95% confidence interval 1.2–5.1). As infection was the main post-HSCT complication in our data, more attention should be given to the management of infections in HSCT recipients.
Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for adult hematological malignancies. As infection is one of the main causes of morbidity and mortality after HSCT, the successful outcome of HSCT is largely affected by infectious complications as well as relapse or graft vs host effects.1, 2, 3, 4, 5, 6, 7, 8 As immunological recovery after HSCT progresses through different stages (ie the pre-engraftment, mid- and late-recovery phase), the relative frequencies of opportunistic pathogens vary at different periods of post-HSCT.1, 4 Therefore, it is important to define the pattern of infectious complications at different times after HSCT. Since 1983, when we performed the first successful HSCT operation in South Korea,9 we have carried out more than 2000 HSCT operations, as of August 2003. In 2003, we dealt with more than 250 HSCT cases, which represents more than half the annual HSCT cases in Korea. We periodically reported analyses of infectious complications after HSCT up to 1996.10, 11 In the present study, we have analyzed the recent trend of infectious complications and outcomes after allogeneic HSCT at our institution.
Patients and methods
We reviewed retrospectively the medical records of all consecutive 242 recipients of allogeneic HSCT who were admitted to our institution over a 2-year period (January 1998–December 1999). The end point of the study was set to September 2001 or time of death. The recipients received total body irradiation (TBI) and/or cyclophosphamide alone or in combination with other chemotherapeutic agents (busulfan, melphalan, cytosine arabinoside, thio-tepa, etc.) as a conditioning regimen. Prophylaxis of graft-versus-host disease (GvHD) was with cyclosporin A and methotrexate (cyclosporine 5 mg/kg i.v. on day −1; 3 mg/kg i.v. on days 0–20; 5 mg/kg p.o. twice daily; and 3 mg/kg p.o. twice daily after 23 days; methotrexate 10 mg/m2 on days 1, 3, 6 and 11).
Antimicrobial prophylaxis consisted of ciprofloxacin 500 mg, roxithromycin 300 mg, fluconazole 50 mg p.o. daily until engraftment. Antiviral prophylaxis was given with acyclovir 500 mg p.o. five times daily until engraftment. Cytomegalovirus (CMV) antigenemia assay for pp65 antigen in leukocytes was performed after engraftment. If CMV antigenemia was positive (>10 positive cells/200 000 leukocytes), pre-emptive ganciclovir was administered (5 mg/kg i.v. twice daily) until two consecutively negative assays. An empirical antibiotic regimen was given to febrile patients according to the guidelines of the Infectious Diseases Society of America (IDSA).12 If clinical, histopathological or radiological signs suggested invasive fungal infection (IFI), antifungal therapy consisting of intra-venous infusion of conventional or liposomal amphotericin B was initiated. The diagnosis of IFI was made on the basis of the definitions proposed by the consensus group of the European Organization for Research and Treatment of Cancer in conjunction with the Mycoses Study Group.13
All patients were managed in laminar airflow rooms until they recovered from neutropenia.
Definition of terms
Fever was defined as a single oral temperature of ⩾38.3°C or a temperature of ⩾38.0°C for ⩾1 h. Neutropenia was defined as a neutrophil count of less than 500/μl, or a count of less than 1000/μl with a predicted decrease to less than 500/μl.
The term microbiologically defined infection (MDI) was used if a clinically significant pathogen was identified from a normally sterile specimen or from an affected site by culture or biopsy, whereas the term clinically defined infection (CDI) was employed if fever was accompanied by appropriate clinical findings, for example, pulmonary infiltrates or inflammation of the skin or soft tissue. Fever was designated as being ‘unexplained’ when there was no clinical, radiological or microbiological evidence of infection.
CMV infection was defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen. We also used definitions of CMV end-organ diseases presented by Ljungman et al.14
Engraftment was established by bone marrow biopsy, or when the absolute neutrophil count was >500 cells/μl, Hb >10 g/dl and platelet count >20 000/μl for three consecutive days.
Data collection and analysis
Baseline information included age, sex, underlying diseases and type of allogeneic HSCT.
We reviewed and analyzed the clinical and microbiological features of recipients in the context of three phases after HSCT, that is, pre-engraftment phase (from the day of the transplant to engraftment, approximately day 30), mid-recovery phase (from engraftment until day 100) and late-recovery phase (>100 days after transplant).1 We also compared characteristics and outcomes of infections between matched sibling donor-HSCT (sHSCT) and unrelated donor-HSCT (uHSCT).
Statistical analyses were carried out with SPSS 10.0 (SPSS Korea, Seoul, Korea), and survival was assessed by survival analysis and log-rank test. We evaluated prognostic factors by univariate and multivariate logistic regression analysis. P-values <0.05 were considered statistically significant.
The median age of the 242 allogeneic recipients was 31 years (range: 15–54), and the ratio of male to female subjects was 146:96. Acute myelogenous leukemia (AML) was the most common underlying disease (n=69, 28.5%), followed by chronic myeloid leukemia (CML), severe aplastic anemia (SAA), acute lymphocytic leukemia (ALL), myelodysplastic syndrome, non-Hodgkin's lymphoma and others (Table 1). The source of the stem cells was bone marrow for all patients in this study. A total of 203 (83.9%) patients received hematopoietic stem cells from matched sibling donors while others (n=39; 16.1%) received from matched unrelated donors. A total of 145 (59.9%) patients received TBI.
Infections during the pre-engraftment phase
The mean duration of neutropenia was 16.4±8. 0 days. A total of 100 patients (41.3% of all recipients) had neutropenic fever and, in total, 106 febrile episodes developed (0.44 (106/242) febrile episodes per patient). Among 106 febrile episodes, 35 (33.0%) were MDI and 50 (47.2%) were CDI. The median time to fever 7 days after transplant (range: 2–18), and mean duration of therapeutic antibiotic use was 14.4±10.7 days.
A total of 35 organisms were identified during the pre-engraftment period. Bacterial pathogens accounted for 88.6% (31/35) of the major causative pathogens, and there were only two fungal (one Aspergillus fumigatus and one Candida albicans) and viral infections (one varicella zoster virus and one BK virus) each. Escherichia coli was the predominant pathogen (n=13, 37.1%), followed by Staphylococci (one S. aurues, two S. hominis, five S. epidermidis), Enterococci, Streptococci (one alpha-hemo-lytic, one group D, one nonhemolytic) and Klebsiella pneumoniae (Table 2). Overall, the proportion of Gram-positive cocci (GPC) was slightly higher than that of Gram-negative bacilli (45.7 vs 42.9%, respectively). The lower respiratory tract was the most common site of involvement (34.8%), followed by skin and soft tissue, blood and the gastrointestinal tract (Table 3).
Infections in the mid-recovery phase (from engraftment until day 100)
As 11 out of the initial 242 recipients died before engraftment, 235 patients in the mid-recovery phase were analyzed. In all, 37 patients (15.7% of 235 recipients) had fever and a total of 57 febrile episodes developed (0.24 (57/235) febrile episodes per patient). Among 57 febrile episodes, 35 (61.4%) were MDI, while 15 (26.3%) were CDI. In contrast to the pattern of infection before engraftment, viral infections were the major infectious complications during the mid-recovery phase. Herpes viruses (four herpes simplex virus type I, three CMV, three varicella zoster virus) and BK viruses, which were isolated from urine specimen of nine patients, were the predominant viruses (Table 2). Along with one case in the pre-engraftment period and one more case in the late-recovery phase, there were a total of 11 cases of hemorrhagic cystitis by BK virus. The median time of onset was 37 days (range 22–356) after transplant. Five out of 11 patients (45.5%) received busulfan as a conditioning regimen. Aspergillus species (5/36; 13.9%; 3 A. fumigatus, 2 A. flavus ) was the main fungal pathogen in the mid-recovery phase, while no Candida species was isolated. The lower respiratory tract and genitourinary tract were the most common sites of involvement (n=13; 37.1% each; Table 3).
Infections in the late-recovery phase (100 days–2 years after transplant)
Out of the initial 235 recipients (8.1%), 25 died within 100 days after transplant, and 230 patients remained in the late-recovery phase. A total of 141 patients (61.3% of 230 recipients) had fever and, in total, 305 febrile episodes developed (1.33 febrile episodes per patient).
Viral (n=95; 31.1%) and fungal (n=40; 13.1%) infections made up the major trend of infectious complications during the late-recovery period (Table 2). Although Candida species was isolated in seven cases (three C. albicans, one C. parapsilosis, four non-albicans), Aspergillus species (n=16; two A. fumigatus, one A. flavus, 13 other Aspergillus spp. not identified further) was the predominant fungal pathogen along with Pneumocystis carinii (n=15). There was only one case of mucormycosis.
About 33% (76/230) of recipients in the late-recovery phase experienced varicella zoster infection. The median time of onset was 210 days (range 104–895 days) after transplant. There was no disseminated case, and all patients with zoster survived.
There was a high rate of seropositivity for CMV before HSCT in both recipients (94.7%) and donors (96.7%). In total, 35% (86/246) were positive in the CMV antigenemia assay, and 16 of these CMV-positive patients progressed to CMV disease: 11 cases of CMV pneumonia, four cases of CMV colitis and one case of retinitis. The median time of onset was 172 days (range 37–530 days) after transplant and 81.3% (13/16) of CMV diseases occurred in the late-recovery phase. Of the 16 patients with CMV diseases, 15 (93.8%) had chronic GvHD. The mortality of CMV disease was 43.8% (7/16): four patients died of CMV pneumonia, while the other three patients died of causes not directly related with CMV (two chronic GvHD and one measles).
One case of influenza A was also noted. The patient was a 33-year old male with CML. He had limited chronic GvHD and relapse, and he got influenza from outside the hospital. His case was not complicated by pneumonia and he eventually survived.
There were relatively high occurrences of Mycobacterium tuberculosis (n=7; 3.0% of 230 recipients) and P. carinii (n=15; 6.5% of 230 recipients). The median time of onset was 452.5 days (range: 176–734 days) after transplant in tuberculosis, and that of P. carinii was 169 days (range: 106–271). Six out of seven tuberculosis patients (85.7%) had chronic GvHD. All patients with tuberculosis received 12-month schedule of quadriple regimen of anti-tuberculous medication (isoniazid, rifampicin, ethambutol and pyrazinamide). Until now, there has been no case of death in patients with tuberculosis. In 15 patients with P. carinii, 13 patients (86.7%) had chronic GvHD and eight (53.3%) had CMV diseases, too. Three (20%) patients died, all of these three who expired had chronic GvHD and one had CMV diseases.
Bacterial infection was identified in 26 cases, and there was only one case of encapsulated organism (one Streptococcus pneumoniae bacteremia). The pneumococcal bacteremic patient was a 17-year old female with ALL-relapse. She got bacteremia 691 days after HSCT. She had no chronic GvHD and was not vaccinated. Her case was complicated by pneumonia and she eventually died.
The lower respiratory tract remained the most common site of involvement (n=136, 48.9%), followed by skin (zoster lesion), upper respiratory tract and genitourinary tract (Table 3).
Clinical course and outcome
Seven patients failed to engaft, and all of them died. The median number of days after transplant to death was 26 (range: 14–78). Mortality during pre-engraftment period was 4.5% (11/242). Among 11 expired patients, six (54.5%) deaths were infection-related (Figure 1): three patients had pneumonia, two had sepsis, and one had bacterial meningitis.
Mortality during mid-recovery phase was 8.1% (19/235) and 10 out of 19 expired patients (52.6%) suffered infection-related death: eight patients had pneumonia and two had sepsis.
In the late-recovery phase, only 38.7% (89/230) were free of infection. Of the 230 patients, 74 (32.2%) died, and 62.2% (46/74) of these deaths were infection-related: 30 patients with pneumonia, 13 with sepsis, two with hemorrhagic cystitis and one with measles (Table 4). In two cases with hemorrhagic cystitis, one BK virus and one adenovirus were identified from urine by culture and PCR. Both of them were complicated with chronic GvHD, obstructive uropathy and renal failure. One case of measles was confirmed by autopsy on lung, which demonstrated multinucleated giant cells with intranuclear eosinophilic inclusion. The patient got measles on January 2001 (22 months after transplant) when the 2000–2001 epidemics of measles in Korea was in the peak status.
The overall cumulative mortality was 43% (104/242), and most of the deaths occurred in the late-recovery period. Among expired cases, infection-related death was 59.6% (62/104) for all time periods post-HSCT. In total, 27 out of 56 cases with infection-related death after engraftment (48.2%) had relapse, Univariate analysis showed that relapse (odd ratio (OR), 5.88; 95% confidence interval (CI), 2.98–11.63) and uHSCT (OR, 2.58; 95% CI, 1.23–5.43) were statistically significant risk factors for the infection-related mortality in the late-recovery phase. Multivariate logistic regression also revealed that relapse (OR, 6.80; 95% CI, 3.34–13.89) and receipt of uHSCT (OR, 3.47; 95% CI, 1.54–7.81) were statistically significant risk factors for infection-related death.
Comparison of infectious complications between matched sibling – and unrelated HSCT
After engraftment, major differences were noted in CMV infection and final outcome. uHSCT showed a significantly higher rate of positive CMV antigenemia (25/39, 64.1%) than that of sHSCT (58/203, 28.6%). In sHSCT patients, 4.9% (10/203) progressed to CMV diseases, while 15.3% (6/39) in uHSCT. The cumulative infection-related morta-lity was also significantly different between the two groups (45/203, 22.2% in sHSCT; 17/39, 43.6% in uHSCT; P<0.01; OR, 2.5; 95% CI, 1.2–5.1). As illustrated in Figure 2, patients undergoing sHSCT had about 9 months more infection-free survival than those with uHSCT (683.5±378.3 vs 406.3±360.7 days, respectively; log rank 12.20, P=0.0001).
In this study, we focused on the pattern and prognosis of infectious complications in 242 HSCT recipients from January 1998 to December 1999. Our previous study involved 264 patients between 1993 and 1996.11 We are thus currently dealing with many more patients annually (242 in 1998–1999 vs 264 in 993–1996), which means that the number of HSCT operations has increased considerably in Korea.
As a recipient of HSCT undergoes changes in immunological status during recovery,1, 4 it is important to understand the varying pattern of post-HSCT infection to improve the management of the patients. During the pre-engraftment phase, bacterial pathogens constituted major causative organisms. The proportion of GPC was higher than that of GNB, and this pattern was similar to that described in other previous reports.1, 2, 3, 4, 5, 6, 17 The relative frequency of GPC has been steadily increasing in our own data11 and we presume that the GPC predominance in the pre-engraftment phase is now established at our institution. Most infections manifested as pneumonia.
As patients remain functionally and quantitatively deficient in T and B lymphocytes even after full hematopoietic reconstitution during the post-engraftment period, the pattern of infection is quite different from that of the pre-engraftment period.1 In our data, viral infections were the main problem during the mid- and late-recovery phase, while bacterial infections were the primary cause of infection in the pre-engraftment period.
In the mid-recovery phase, the incidence of febrile episodes was relatively lower than that in the pre-engraftment phase. Most cases of hemorrhagic cystitis (9/11, 81.8%) occurred in this period. The incidence of hemorrhagic cystitis was 5% (12/242), which was much lower than that of other reports.18, 19, 20
Among the fungal infections, mold forms constituted the majority of pathogens, as in previous reports.21, 22 Considering our policy of the low-dose fluconazole (50 mg/day) prophylaxis since 1986, it was interesting that there was no yeast infection documented in the mid-recovery period. Although many studies have strongly recommended high-dose (400 mg/day) fluconazole prophylaxis,23, 24, 25 there are also several studies that have used lower dose (50–200 mg/day).26, 27, 28, 29, 30 The predominance of mold form and few yeast infections despite low-dose fluconazole prophylaxis at our institution was not clearly explainable. This should be elucidated further in the future study.
In the late-recovery phase, frequency of infectious episodes (total 305 episodes, 1.33 per patient) was highest compared with that of pre-engraftment (106, 0.44/patient) and of mid-recovery phase (57, 0.24/patient). Viral and fungal diseases were the major opportunistic infections. Among viral diseases, varicella zoster was the most common pathogen. The incidence (33%) was similar to other reports (up to 40%).31, 32
In view of the prevalence of high CMV seropositivity in the Korean population, reactivation rather than new or repeated infection should account for almost all the patients with CMV infections in our analysis.33 The median time of onset (172 days after transplant) was similar to other reports (169 days by Boeckh et al34; 188 days by Nguyen et al35). Prior to the establishment of ganciclovir prophylaxis or pre-emptive treatment, CMV disease used to develop during the first 3 months after transplant.36, 37, 38 However, recent reports have indicated that most of CMV diseases now develop in the late-recovery phase.34, 35, 39 All but one patient in our data had chronic GvHD, an established risk factor for the late CMV disease. We thought that continuous screening of antigenemia should be carried out on patients with a preceding episode of positive result and chronic GvHD.
The unique finding noted in the late phase was relatively high incidence of tuberculosis and P. carinii pneumonia (PCP). Tuberculosis after transplantation is a very rare infectious complication in the non-endemic area.40, 41, 42 However, in endemic countries, high incidence up to 5% has been reported.43, 44 Although prevalence of tuberculosis has dramatically decreased nowadays, Korea is still a tuberculosis-endemic country. According to the seventh nationwide tuberculosis survey in Korea, 1995, prevalence of active tuberculosis is 1032/100 000.45 A recent report of incidence of active TB after allogeneic HSCT from one center in Korea was 3.1%,46 which was similar to our result (3.0%). We have screened TB by previous history, radiologic finding and sputum AFB study. The positive AFB smear or a radiologic lesion suggesting active TB was an indication to postpone HSCT and anti-TB treatment, but the previous history of TB was not. As the incidence of TB in our data was relatively high, we are now considering INH propylaxis even on the patient with previous TB although the recent report in Korea showed little efficacy of INH prophylaxis to asymptomatic recipients.46
Lack of PCP prophylaxis in our patients was certainly contributable to the relatively high incidence of PCP (6.5%).47, 48, 49 Although PCP was not a major concern until this study, finding of high incidence of PCP has led us to add trimethoprim/sulfamethoxazole in the prophylaxis regimen at our institution now.
Measles after transplant is an extremely rare complication,50 and we had one expired case of measles during the nationwide epidemic in Korea.51 The patient suffered from chronic GvHD at that time, and died of giant cell pneumonia. This case will be presented in a separate case report.
The mortality was higher in the late-recovery phase than in the pre-engraftment or mid-recovery phase and infection occupied more than half the deaths. As the multivariate analysis indicated, relapse and type of allogeneic HSCT could independently affect the infection-related mortality in the late-recovery phase. Comparison between two types of allogeneic HSCT also showed that uHSCT was more prone to be complicated with infection-related death than sHSCT, which was similar to other studies.52, 53, 54, 55 According to the recent IBMTR data about causes of death after transplants done in 1996–2000,56 infection constituted 17% of death in allogeneic HSCT and 21% in uHSCT, which showed lower proportion than our data (57.6% (45/78 deaths) in sHSCT; 65.3% (17/26 deaths)). On the basis of these results, more attention should be given to prevention, early detection, and aggressive management of infections in HSCT recipients at our institution. In conclusion, infection was the main post-HSCT complication in Korea. Although the main trend of epidemiology during three recovery phases after transplant was grossly similar to that of other reports, relatively high incidence of tuberculosis and PCP, expired case of measles were unique findings in our data.
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We appreciate professor Julian Gross, Emeritus professor of Biochemistry, Oxford University, UK, for his careful editing and grammatical correction of this manuscript.
Part of this study was presented at the 29th World Congress of the International Society of Hematology (August-24–28, 2002), Seoul, South Korea.
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