www.nature.

com/scientificreports

OPEN Incidence and risk factors

of opportunistic infections
after autologous stem cell
transplantation: a nationwide,
population‑based cohort study
in Korea
Da Jung Kim 1, Seri Jeong 2, Seom Gim Kong 3, Sangjin Lee 4, Sung‑Nam Lim 5, Sung Yong Oh 6,
Young Rok Do 7, Won Sik Lee 8, Mark Hong Lee 9, Sung Hwa Bae 10, Se Hyung Kim 11,
Min Kyoung Kim 12, Ho Sup Lee 1* & Consortium for Improving Survival of Lymphoma (CISL) *

Several guidelines classify autologous stem cell transplantation (ASCT) as a low to intermediate
risk group for infection. In a nationwide population-based study, using the Korean Health Insurance
Review and Assessment Service database, patients with lymphoma and multiple myeloma (MM)
who underwent ASCT from 2002 to 2016 were retrospectively analyzed. Cumulative incidence rates
(CIRs) and risk factors of opportunistic infections were investigated. CIRs of fungal, Varicella zoster
virus (VZV), cytomegalovirus (CMV), and Pneumocystis jirovecii infections in lymphoma were 7.9%,
16.0%, 7.4%, and 5.1%, respectively, and CIRs in MM were 6.3%, 19.1%, 4.2%, and 5.6%, respectively.
Fungal infection was significantly higher in patients with previous infection (Hazard ratio (HR) 2.003,
p = 0.005) in lymphoma. Incidence of CMV infection was significantly higher in patients with prior CMV
infection: HR 4.920, p < 0.001 (lymphoma); HR 3.022, p = 0.030 (MM). VZV infection was significantly
lower in patients receiving prophylaxis: HR 0.082, p < 0.001 (lymphoma); HR 0.096, p < 0.001 (MM). For
P. jirovecii infection, busulfex and melphalan conditioning (HR 1.875, p = 0.032) and previous P. jirovecii
infection (HR 4.810, p < 0.001) had a higher incidence in MM. Patients who underwent ASCT should
receive VZV prophylaxis and prophylaxis for fungal and P. jirovecii may be considered in patients with
previous same infection.

Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment option for hema-
tologic malignancies, especially malignant lymphoma and multiple myeloma (MM). With the advances in

1
Department of Internal Medicine, Kosin University College of Medicine, 34 Amnam‑Dong, Seo‑Gu, Busan 49267,
South Korea. 2Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College
of Medicine, Seoul 07441, South Korea. 3Department of Pediatrics, Kosin University College of Medicine,
Busan 49267, Korea. 4Graduate School, Department of Statistics, Pusan National University, Busan 46241,
Korea. 5Department of Internal Medicine, Haeundae Paik Hospital, College of Medicine Inje University,
Busan 48108, Korea. 6Department of Internal Medicine, Dong-A University College of Medicine, Busan 49201,
Korea. 7Division of Hematology‑Oncology, Department of Medicine, Dongsan Medical Center, Keimyung
University, Daegu 41931, Korea. 8Department of Internal Medicine, Busan Paik Hospital, College of Medicine
Inje University, Busan 47392, South Korea. 9Division of Hematology‑Oncology, Department of Internal Medicine,
Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, South Korea. 10Department
of Internal Medicine, Daegu Catholic University Medical Center, Daegu 42472, South Korea. 11Department of
Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea. 12Department
of Hematology‑Oncology, Yeungnam University Medical Center, Yeungnam University School of Medicine,
Daegu 42415, South Korea. *A list of authors and their affiliations appears at the end of the paper. *email:
[email protected]

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 1

Vol.:(0123456789)
 www.nature.com/scientificreports/

medicine, the success rate of ASCT has improved; however, infection is still an important complication related
to the prognosis of ASCT and can affect the quality of life and long-term survival in the early and late phases of
­transplantation1–3. Therefore, various prophylaxes have been used to reduce these infections. However, compared
with allogeneic hematopoietic stem cell transplantation, ASCT has a lower risk of infection; therefore, few studies
related to infection have been conducted.
According to the National Comprehensive Cancer Network (NCCN) guideline (version 1. 2021), ASCT is in
the intermediate-risk group for overall infections. Based on this risk, for fungal infections, when mucositis is pre-
sent, prophylaxis with fluconazole or echinocandin is recommended until recovery from neutropenia (category
1, for which there is a high level of evidence), and prophylaxis is not recommended without mucositis (category
2 B, where there is a lower level of evidence but no uniform consensus)4. Likewise, in the European Conference
on Infections in Leukemia (ECIL) guideline, patients undergoing ASCT, for whatever underlying condition, are
at a low risk of invasive fungal disease. Therefore primary antifungal propylaxis is not recommended, although
fluconazole should be considered to prevent mucosal Candida infection during the neutropenic p ­ hase5. For
Varicella zoster virus (VZV), it is recommended that acyclovir, famciclovir and valacyclovir be maintained for
6–12 months after the transplantation (category 2A, for which there is a lower level of evidence but uniform
consensus) in NCCN ­guideline4. In both guidelines, cytomegalovirus (CMV) prophylaxis is not recommended
as ASCT is not associated with the risk of CMV i­ nfection4,6. For Pneumocystis jirovecii (P. jirovecii), the NCCN
guideline recommends prophylaxis with trimethoprim/sulfamethoxazole (category 1) or atovaquone, pentami-
dine, dapsone (category 2A) for 3–6 months after transplantation (Category 2B)4, but the ECIL guideline does
not recommend p ­ rophylaxis7.
Even the two guidelines recommend differently for same infection, there are few reports on the incidence
rate of opportunistic infections after ASCT in the l­iterature8–11. In addition, most clinicians recognize the risk
of infection and perform prophylaxis before engraftment, but for post-engraftment infections, prophylaxis is
empirically conducted according to the opinion of the clinicians.
In this study, we investigated the incidence and risk factors of fungal and viral infections after ASCT in
patients with lymphoma and MM using big data especially in post-engraftment period. Based on these data,
we would like to consider the effectiveness of prophylactic antifungal and antiviral agents in clinical practice.

Methods
Data source. We used the nationwide and population-based Health Insurance Review and Assessment Ser-
vice database, which is based on data from the universal health insurance system run by the Korean government.
Since the National Health Insurance is the only public medical insurance system in Korea, the program covers
the entire Korean population. The database includes patient demographics, principal diagnoses, and comorbidi-
ties based on the International Classification of Diseases, 10th Revision, prescription codes, and special proce-
dures such as transplantation for both outpatients and inpatients. The National Health Insurance Service provide
these extensive data for use in research after the approval process. The independent Institutional Review Board
of Kosin University Gospel Hospital approved this study and granted a waiver of informed consent from the
study participants because anonymity of personal information was maintained (KUGH 2017-11-026). The data
acquisition number for the National Health Insurance Sharing Service was REQ0000016684. All methods were
carried out in accordance with relevant guidelines and regulations along with the approval.

Patient selection. From January 2002 to December 2016, of the patients registered with malignant lym-
phoma and MM who were over 18 years of age, those who underwent ASCT were enrolled. Patients who under-
went allogeneic hematopoietic stem cell transplantation after ASCT were excluded.
Infections were limited to cases that occurred at least 30 days after ASCT. Fungal infections were defined
as invasive candidiasis and aspergillosis, or cases in which antifungal agents such as intravenous (IV) ampho-
tericin B, IV liposomal amphotericin B, IV caspofungin, IV itraconazole, IV voriconazole, and IV fluconazole
were prescribed for more than 7 days. Patients with oral candidiasis were excluded from this study. Viral infec-
tion was defined as VZV reactivation, CMV viremia or disease, and was defined as IV acyclovir, per oral (po)
famciclovir for more than 5 days, and IV ganciclovir and valganciclovir for more than 7 days. Herpes simplex
virus and Epstein–Barr virus infections were excluded. P. jiroveciii infection was limited to cases in which IV
trimethoprim/sulfamethoxazole was administered for more than 7 days and when P. jiroveciii infection or pneu-
monia was diagnosed.
Prophylactic drugs were defined as drugs used in clinical practice, based on the National Comprehensive Can-
cer Network guidelines. The antifungal prophylactic agents were po fluconazole, and anti-P. jirovecii prophylaxis
was detected by po trimethoprim/sulfamethoxazole. In the case of antiviral therapy, VZV prophylaxis included
po acyclovir and po valaciclovir. However, prophylaxis for CMV infection was not analyzed because there was
no meaningful prophylactic therapy available at the time of analysis. Prophylaxis included cases in which each
prophylactic agent was administered for ≥ 30 days.

Statistical analysis. We evaluated the cumulative incidence and risk factors of opportunistic infections
after ASCT in patients with lymphoma and MM in Korea from 2002 to 2016. Because lymphoma and MM
are different diseases and the intensity of conditioning is different, the incidence and risk factors of both dis-
eases were analyzed. Incidence was calculated using the number of individuals with opportunistic infections
as the numerator, and the patients who underwent ASCT as the denominator. The cumulative incidence rate
(CIR) was reported at a specific time after transplantation (6 months, 12 months, and 5 years) using a landmark
approach. The cumulative incidence was estimated using the Kaplan–Meier method. The strength of the associa-
tion between the variables and opportunistic infections was assessed using Cox proportional hazards regression

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 2

Vol:.(1234567890)
www.nature.com/scientificreports/

analysis. We used maximally selected log-rank statistics in the maxstat function of R software (version 3.4.4)
to identify the optimal threshold to assess the cumulative incidence for age. We selected optimal age cutoffs of
45 years for lymphoma and 55 years for MM. Logistic regression analysis was used for multivariate analysis.
Statistical analyses were performed using the R statistical software (version 3.4.4; R Foundation for Statistical
Computing) and SAS statistical analysis software (version 9.4; SAS Institute Inc., Cary, NC, USA). Statistical
significance was set at P < 0.05.

Results
Patients characteristics. The characteristics of the 6516 patients who underwent ASCT for lymphoma
(n = 3236) and MM (n = 3280) are described in Table 1. The median age was 48 years (range 18–70) for lym-
phoma and 56 years (range 18–68) for myeloma at the time of transplantation, and 62.5% (n = 2022) and 55.9%
(n = 1834) of the patients were men with lymphoma and myeloma, respectively.
Of the patients with lymphoma, 51.7% of were diagnosed with diffuse large B-cell lymphoma or Burkitt
lymphoma. There were 141 (4.4%), 445 (13.8%), 35 (1.1%), and 60 (1.9%) patients with fungal, VZV, CMV,
and P. jirovecii infection prior to transplantation, respectively. The number of patients who received preventive
treatment for fungal, VZV, and P. jirovecii infections was 208 (6.4%), 375 (11.6%), and 187 (5.8%), respectively.

Value (%) Lymphoma (n = 3236) (%) Multiple myeloma (n = 3280) (%)

Age, years
Median (range) 48 (18–70) 56 (18–68)
Sex (%)
Male 2022 (62.5) 1834 (55.9)
Female 1214 (37.5) 1446 (44.1)
Diagnosis (%)
DLBCL/Burkitt lymphoma 1672 (51.7)
Indolent B cell lymphoma 479 (14.8)
T cell lymphoma 671 (20.7)
Others (Hodgkin’s disease, etc.) 414 (12.8)
Year of transplantation (%)
2002–2006 520 (16.1) 468 (14.3)
2007–2011 1100 (34.0) 1059 (32.3)
2012–2016 1616 (49.9) 1753 (53.4)
Conditioning regimen (%)
BuCyE 1084 (33.5) Melphalan only 2880 (87.8)
BuMelE 849 (26.2) BuMel 237 (7.2)
Others 1303 (40.3) Others 163 (5.0)
Comorbidity (%)
<2 2898 (89.6) 2701 (82.3)
≥2 338 (10.4) 579 (17.7)
Pre-transplantation infection (%)
Fungal 141 (4.4) 78 (2.4)
VZV 445 (13.8) 691 (21.1)
CMV 35 (1.1) 40 (1.2)
P. jiroveciii infection 60 (1.9) 31 (0.9)
Prophylaxis (%)
Fungal 208 (6.4) 205 (6.3)
VZV 375 (11.6) 540 (16.5)
P. jiroveciii 187 (5.8) 406 (12.4)
Post-transplantation infection (%)
Fungal 221 (6.8) 161 (4.9)
VZV 461 (14.2) 531 (16.2)
CMV 211 (6.5) 117 (3.6)
P. jiroveciii 143 (4.4) 143 (4.4)

Table 1.  Patient characteristics. DLBCL Diffuse large B cell lymphoma, BuCyE Busulfan and
Cyclophosphamide and Etoposide, BuMelE Busulfan and melphalan and Etoposide, P. jiroveciii Pneumocystitis
jiroveciii, VZV Varicella zoster virus, CMV cytomegalovirus.

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 3

Vol.:(0123456789)
 www.nature.com/scientificreports/

For MM, 78 (2.4%), 691 (21.1%), 40 (1.2%), and 31 (0.9%) patients had a history of fungal, VZV, CMV, and
P. jirovecii infections, respectively, prior to transplantation. A total of 205 (6.3%), 540 (16.5%), and 406 (12.4%)
patients received prophylaxis against fungal, VZV, and P. jirovecii infections, respectively.
Compared to 2002–2006, the number of transplantations increased from 520 to 1616 for lymphoma and from
468 to 1753 for MM, in 2012–2016.

Incidence of opportunistic infections. For lymphoma, 221 (6.8%), 461 (14.2%), 211 (6.5%), and 143
(4.4%) patients were infected with the fungi, VZV, CMV, and P. jirovecii pneumonia (PJP), respectively, and 161
(4.9%), 531 (16.2%), 117 (3.6%), and 143 (4.4%) patients with MM, respectively, after transplantation. (Table 1)
The CIRs at 6 months of fungal, VZV, CMV, and P. jiroveciii infection in lymphoma were 3.4%, 7.8%, 3.3% and
1.9%, respectively, and the CIRs in MM were 1.1%, 7.2%, 1.6% and 0.8%, respectively. The CIRs at 12 months
for fungal, VZV, CMV, and P. jirovecii infection in lymphoma were 4.9%, 11.3%, 4.7%, and 2.9%, respectively,
and the CIRs in MM were 2.0%, 10.6%, 2.2%, and 1.7%, respectively. The CIRs at 5 years for fungal, VZV, CMV,
and P. jirovecii infection in lymphoma were 7.9%, 16.0%, 7.4%, and 5.1%, respectively, and the CIRs in MM were
6.3%, 19.1%, 4.2%, and 5.6%, respectively (Fig. 1).

Analysis of risk factor for opportunistic infections. The results of the univariate and multivariate
analyses of the associations with opportunistic infections in lymphoma and MM are shown in Tables 2 and 3.
Multivariate analysis showed that the factors affecting fungal infection were the year of transplantation (hazard
ratio (HR) = 2.330 [95% confidence interval (95% CI) 1.485–3.658]; p < 0.001 in lymphoma patients, HR = 2.650
[95% CI 1.519–4.623]; p = 0.001 in MM patients) and previous fungal infection history (HR = 2.003 [95% CI
1.236–3.244]; p = 0.005 in lymphoma patients only). For patients with CMV infection, in the multivariate analy-
sis, the following factors showed a significantly higher incidence of infection: year of transplantation (HR = 2.752
[95% CI 1.689–4.484]; p < 0.001 in lymphoma patients only) and previous CMV infection history (HR = 4.920
[95% CI 2.552–9.600]; p < 0.001 in lymphoma patients and HR = 3.022 [95% CI 1.115–8.191]; p = 0.030 in MM
patients). Multivariate analysis showed that other conditioning regimens (HR = 1.349 [95% CI 1.081–1.682];
p = 0.008 in lymphoma patients only) and prophylaxis (HR = 0.082 [95% CI 0.034–0.197]; p < 0.001 in lymphoma
and HR = 0.096 [95% CI 0.053–0.175]; p < 0.001 in MM) were independent predictive factors for VZV reactiva-
tion. Based on multivariate analysis for P. jirovecii infection, the year of transplantation (HR = 2.552 [95% CI
1.439–4.526]; p = 0.001 in lymphoma and HR = 3.800 [95% CI 1.801–8.021]; p < 0.001 in MM) had a higher inci-
dence. For MM patients, busulfan and melphalan conditioning (HR = 1.875 [95% CI 1.055–3.333]; p = 0.032),
previous P. jirovecii infection (HR = 4.810 [95% CI 2.120–10.913]; p < 0.001) and prophylaxis (HR = 1.564 [95%
CI 1.040–2.352]; p = 0.032) had a higher incidence.

Figure 1.  Cumulative incidence rates (CIRs) of opportunistic infections. (A) Lymphoma. (B) Multiple
myeloma. (A) The CIRs at 6 months of fungal, Varicella zoster virus (VZV), Cytomegalovirus (CMV), and
Pneumocystis jirovecii (P. jiroveciii) infection was 3.4%, 7.8%, 3.3% and 1.9%, respectively. The CIRs at 12 months
was 4.9%, 11.3%, 4.7% and 2.9%. (B) The CIRs at 6 months of fungal, VZV, CMV, and P. jiroveciii infection was
1.1%, 7.2%, 1.6% and 0.8%, respectively. The CIRs at 12 months was 2.0%, 10.6%, 2.2% and 1.7%.

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 4

Vol:.(1234567890)
www.nature.com/scientificreports/

Fungal CMV VZV Pneumocystis jirovecii

Univariate Multivariate Univariate Multivariate Univariate Multivariate Univariate Multivariate

HR (95% HR (95% HR (95% HR (95% HR (95% HR (95% HR (95% HR (95%
Value CI) p value CI) p value CI) p value CI) p value CI) p value CI) p value CI) p value CI) p value

Age, years

≤ 45

1.017 (0.779– 0.956 (0.729– 1.147 (0.952– 0.804 (0.579–

> 45 0.901 0.747 0.149 0.192
1.328) 1.255) 1.383) 1.116)

Sex

Male

0.906 (0.688– 0.999 (0.756– 0.970 (0.803– 0.709 (0.496–

Female 0.485 0.992 0.751 0.060
1.194) 1.320) 1.172) 1.014)

Diagnosis

Indolent
B cell
lymphoma

DLBCL
1.176 (0.770– 1.223 (0.802– 1.079 (0.820– 1.063 (0.638–
/ Burkitt 0.453 0.350 0.586 0.815
1.796) 1.864) 1.421) 1.771)
lymphoma

T cell 1.649 (1.044– 1.361 1.557 (0.982– 1.275 (0.937– 1.716 (0.998–
0.032 0.044 0.060 0.122 0.051
lymphoma 2.604) (1.008–1.837) 2.467) 1.734) 2.951)

Others (HD, 1.403 (0.841– 0.912 (0.515– 0.991 (0.692– 0.995 (0.512–
0.195 0.750 0.959 0.988
etc.) 2.341) 1.612) 1.419) 1.934)

Year of transplantation

2002 ~ 2006

1.669 (1.050– 1.653 1.844 (1.113– 1.812 0.892 (0.695– 1.744 (0.966– 1.744
2007 ~ 2011 0.030 0.034 0.017 0.021 0.368 0.065 0.065
2.653) (1.040–2.629) 3.055) (1.093–3.002) 1.144) 3.151) (0.966–3.151)

2.342 (1.492– 2.330 2.815 (1.728– 2.752 0.778 (0.606– 2.552 (1.439– 2.552
2012 ~ 2016 < 0.001 < 0.001 < 0.001 < 0.001 0.048 0.001 0.001
3.676) (1.485–3.658) 4.585) (1.689–4.484) 0.998) 4.526) (1.439–4.526)

Conditioning regimen

BuCyE

1.177 (0.853– 1.292 (0.923– 1.225 (0.953– 1.194 1.571 (1.039– 1.295
BuMelE 0.321 0.136 0.113 0.166 0.032 0.160
1.624) 1.809) 1.575) (0.929–1.536) 2.375) (0.902–1.859)

0.732 (0.531– 0.878 (0.632– 1.443 (1.157– 1.349 1.004 (0.667–

Others 0.056 0.438 0.001 0.008 0.984
1.008) 1.219) 1.799) (1.081–1.682) 1.512)

Comorbidity

≥ 2 comor- 0.949 (0.616– 0.761 (0.469– 0.870 (0.637– 0.544 (0.277–

0.811 0.267 0.378 0.077
bidity 1.461) 1.233) 1.187) 1.068)

Previous
2.042 (1.261– 2.003 5.288 (2.712– 4.920 0.837 (0.629– 1.267 (0.404–
infection 0.003 0.005 < 0.001 < 0.001 0.222 0.685
3.307) (1.236–3.244) 10.314) (2.552–9.600) 1.114) 3.977)
history

0.743 (0.405– 0.079 (0.033– 0.082 0.678 (0.299–

Prophylaxis 0.336 < 0.001 < 0.001 0.351
1.362) 0.191) (0.034–0.197) 1.535)

Table 2.  Univariate and multivariate Cox analysis for atypical infection in lymphoma. CMV Cytomegalo
virus, VZV Varicella zoster virus, HR hazard ratio, CI confidence interval, DLBCL diffuse large B cell
lymphoma, HD Hodgkin’s disease, BuCyE Busulfan and Cyclophosphamide and Etoposide, BuMelE Busulfan
and Melphalan and Etoposide;

Discussion
ASCT is the standard treatment for malignant lymphoma and MM. Depending on the diagnosis, this procedure
is indicated as frontline treatment and in other cases as salvage t­ herapy12,13. Despite current improvements in
supportive care, mortality and complications after ASCT remain important concerns. Although the morbidity
and mortality of ASCT are lower than those of allogeneic transplantation, deaths still occur, mainly because of
infectious ­complications1,3. In ASCT, most infections occur during neutropenia, usually about a month after
transplantation. However, opportunistic infections occur after recovery from neutropenia, which affects the
quality of life and survival of patients.
This is because reconstitution of bone marrow (BM) includes functional recovery of cellular interaction as
well as simple numerical recovery of BM cellular ­elements14. Several studies have shown that immune modula-
tion occurs in ­ASCT14–16. Despite the heterogeneity of diseases, age, pre-transplant treatment and high-dose
conditioning regimens, lymphocyte subset analysis did not reveal any differences in immune reconstitution. All
patients had a low CD4(+)/CD8(+) ratio during at least the first year post-transplantation, which was caused by
a persistent increase in CD8(+) lymphocytes and reduction of CD4(+) lymphocytes, making the patients vul-
nerable to infections for a prolonged period time post-transplant16. Therefore, in the post-engraftment period,
patients often take antibiotics, antifungal, and antiviral agents for weeks to months.
However, few studies have evaluated the incidence of opportunistic infections and the impact of prophylaxis
on infections in ASCT, focusing on a large population, especially in the post-engraftment period. We conducted
a nationwide population-based study to provide information regarding the incidence and risk factors of oppor-
tunistic infections in patients with lymphoma and MM after ASCT in the Korean population. In particular, we
analyzed whether prophylactic therapy is effective and investigated infections after engraftment for a long-term
period of up to 5 years.

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 5

Vol.:(0123456789)
 www.nature.com/scientificreports/

Fungal CMV VZV Pneumocystis jirovecii

Univariate Multivariate Multivariate Multivariate Multivariate

HR (95% HR (95% Univariate HR (95% Univariate HR (95% Univariate HR (95%
Value CI) p value CI) p value HR (95% CI) p value CI) p value HR (95% CI) p value CI) p value HR (95% CI) p value CI) p value

Age, years

≤ 55

0.816 0.695 (0.480– 0.861 (0.726– 1.024 (0.738–

> 55 0.202 0.054 0.087 0.887
(0.598–1.115) 1.006) 1.022) 1.422)

Sex

Male

0.817 0.813 (0.561– 0.956 (0.805– 0.751 (0.536–

Female 0.209 0.275 0.611 0.098
(0.596–1.120) 1.178) 1.136) 1.054)

Year of transplantation

2002–2006

1.877 1.877 (1.069– 1.227 (0.704– 0.905 (0.713– 3.740 (1.795– 3.560 (1.706–
2007–2011 0.028 0.028 0.470 0.413 < 0.001 0.001
(1.069–3.297) 3.297) 2.136) 1.149) 7.789) 7.430)

2.650 2.650 (1.519– 1.163 (0.670– 0.793 (0.625– 4.210 (2.013– 3.800 (1.801–
2012–2016 0.001 0.001 0.591 0.056 < 0.001 < 0.001
(1.519–4.623) 4.623) 2.018) 1.006) 8.803) 8.021)

Conditioning regimen

Melphalan
only

1.659 0.872 (0.383– 0.897 (0.613– 2.142 (1.230– 1.875 (1.055–

BuMel 0.082 0.745 0.578 0.007 0.032
(0.938–2.933) 1.988) 1.314) 3.732) 3.333)

0.493 0.859 (0.316– 0.961 (0.607– 0.789 (0.291– 1.011 (0.372–

Others 0.225 0.765 0.863 0.640 0.984
(0.157–1.547) 2.331) 1.519) 2.135) 2.743)

Comorbidity

≥ 2 comor- 0.835 0.837 (0.512– 0.902 (0.720– 1.354 (0.925–

0.393 0.477 0.369 0.119
bidity (0.552–1.263) 1.368) 1.129) 1.983)

Previous
1.495 3.017 (1.113– 3.022 (1.115– 1.043 (0.850– 4.883 (2.156– 4.810 (2.120–
infection 0.334 0.030 0.030 0.686 < 0.001 < 0.001
(0.661–3.379) 8.177) 8.191) 1.281) 11.060) 10.913)
history

1.459 0.096 (0.053– 0.096 (0.053– 1.616 (1.075– 1.564 (1.040–

Prophylaxis 0.163 < 0.001 < 0.001 0.021 0.032
(0.858–2.483) 0.175) 0.175) 2.429) 2.352)

Table 3.  Univariate and multivariate Cox analysis for atypical infection in multiple myeloma. CMV
Cytomegalo virus, VZV Varicella zoster virus, HR hazard ratio, CI confidence interval, BuMel Busulfan and
Melphalan;

Among ASCT recipients, VZV reactivation occurred in 20–43% of the patients and extended through the first
y­ ear17–21. Erard et al. demonstrated the probability of reactivation of VZV in 8.2% of the patients who received
low prophylactic doses of acyclovir for one y­ ear22. In patients who did not receive acyclovir or who took it for a
shorter period (until the end of neutropenia), the rates increased to 21–25%17,22. In this study, VZV prophylaxis
was found to be a significant predictive factor for VZV reactivation. (HR = 0.082 [95% CI 0.034–0.197]; p < 0.001
in lymphoma and HR = 0.096 [95% CI 0.053–0.175]; p < 0.001 in MM) As seen in several studies, the efficacy and
safety of prophylaxis for VZV after SCT is well established, although there is poor consensus on the dose and
duration of prophylaxis after ­ASCT21. In our study, since the CIR of VZV reactivation increased steeply up to
1 year (Fig. 1), we think it would be better to provide prophylaxis for 1 year. This result supports the duration of
prophylaxis for VZV, according to the NCCN guideline. The cumulative dose of steroid was an independent risk
factor for VZV reactivation after chemotherapy in lymphoma performed at our institution (HR = 7.717 [95% CI
3.814–18.703]; p < 0.001)23, but there is a limitation in that it is not possible to check the dose of steroid using big
data. Previous VZV infection was also a significant risk f­ actor23. However, due to the nature of this study, since
the data were collected from the time of diagnosis of the disease, the infection before diagnosis of lymphoma or
myeloma was not identified, which is considered a limitation of big data.
In large studies involving more than 1000 patients with ASCT, the incidence of invasive fungal infection was
1.2–1.5%8–10. In our data, the incidence of invasive fungal infection was higher than that in large-scale studies
(6.8% in lymphoma, 4.9% in MM), because studies in other countries included only proven or probable cases.
Our data included cases with empirical therapy, and there was a limitation in the insurance system in that one
had to include a diagnostic code in order to prescribe antifungal agents. Therefore, the incidence in our study
may have been overestimated. Fungal infection occurred more frequently in T cell lymphoma (HR = 1.361 [95%
CI 1.008–1.837]; p = 0.044), probably because T cell lymphoma generally has a poorer prognosis than other type
of lymphoma, with more common relapse or refractory state requiring further chemotherapy or steroid admin-
istration. As the rate of prophylaxis is low in fungal infections (6.3%), it is difficult to analyze the effectiveness
of prophylaxis.
For CMV infection, the infection rate differs according to the diagnostic strategy. The incidence of CMV
infection ranged from 17 to 33%, when prospectively monitored by antigenemia and/or viremia by ­PCR24–27.
On the other hand, the frequencies were reported to range between 3 and 13% when applying a clinical-based
­strategy28–33. In our case, the diagnosis was based on clinical suspicion, and the results were similar to those
of previous studies. In Korea, most transplantation centers introduce pre-emptive therapy rather than routine
universal prevention because of the insurance coverage, cost–benefit ratio, and adverse drug r­ eactions34. There
is no effective prophylactic treatment for CMV in Korea; therefore, prophylaxis was not analyzed.

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 6

Vol:.(1234567890)
www.nature.com/scientificreports/

A large series in the 1990s reported an incidence rate for PJP of 1.4% in ASCT ­recipients35. Another study
using a large stem cell transplantation registry showed that the incidence of PJP was 0.28% (n = 52 cases of 18,525
total)11. In previous studies, the incidence rate may have been underestimated because those with a history of
PJP prior to transplantation were excluded. It is also possible that the incidence was overestimated in our study
because we included patients without a pathological diagnosis.
In our study, fungal, CMV, and P. jiroveciii infections showed an increased risk in 2012–2016 compared to
2002–2006, which is thought to be because the number of transplants increased and more high-risk patients
were transplanted. In fact, the median age of patients increases with the transplantation period. Compared to
2002–2006, in 2012–2016, it increased from 44 (range 18–65) to 50 (range 18–70) in lymphoma patients and
from 54 (range 25–65) to 56 (range 18–68) in MM. In MM, the induction regimen including bortezomib has been
available since October 2015, it is thought that bortezomib increased VZV infection in patients who underwent
ASCT after 2016. Prior to transplantation, the same type of infection was a risk factor for all infections except
VZV (Table 3). Therefore, we suggests that prophylaxis needs to be considered in patients with prior infection.
This study has several limitations. First, similar to other studies using big data, the results are based on
physicians’ diagnoses without additional microbiological confirmation, possibly resulting in overestimation
of the incidence. In particular, since the administration of a therapeutic agent is defined as infection, there is a
possibility that empirical treatment will be included. However, in order to exclude empirical treatment as much
as possible, the minimum duration of medication was defined, and considering Korean insurance system, it
is thought that clinically unlikely cases were not included. In addition, because we used data from the Health
Insurance Review and Assessment Service’s reimbursement system, we were unable to analyze drugs that were
not reimbursed, such as VZV vaccine, voriconazole, atovaquone, pentamidine, and dapsone. The lack of detailed
clinical information such as disease status (e.g., complete remission, partial remission or relapse etc.), laboratory
data (WBC, lymphocyte count, etc.), previous or post-transplantation chemotherapy (maintenance or salvage
chemotherapy) limits the analysis of various risk factors. Despite these limitations, it is a large-scale study
covering the entire national population over 14 years in Korea and meaningful in that it evaluated the incidence
of various opportunistic infections and the effectiveness of prophylactic therapy in the same disease group.
In conclusion, ASCT has a relatively low risk of infection compared to allogeneic hematopoietic stem cell
transplantation because it does not accompany graft-versus-host disease and does not take immunosuppressants.
However, since immune reconstitution is a process that occurs in both autologous and allogeneic stem cell
transplantation, it is thought to be related to opportunistic infections in ASCT after engraftment. Based on the
incidence and effectiveness of prophylaxis, patients undergoing ASCT should receive prophylaxis for VZV. In
addition, prophylaxis for fungal infections and PJP needs to be considered in patients who have previously had
an infection with the same organism. Further studies are required to determine the appropriate duration and
dose of prophylaxis.

Data availability
All data generated or analyzed during this study are included in this published article (Tables and Figures) and
available from the corresponding author on reasonable request. The additional raw data are available on request
to the National Health Insurance Service, Korea.

Received: 20 March 2022; Accepted: 2 January 2023

References
1. Jantunen, E. et al. Early treatment-related mortality in adult autologous stem cell transplant recipients: A nation-wide survey of
1482 transplanted patients. Eur. J. Haematol. 76, 245–250. https://​doi.​org/​10.​1111/j.​1600-​0609.​2005.​00605.x (2006).
2. Corciaalomo, Y., Knight Asorey, T., Espigado, I., Martin Villen, L. & Garnacho Montero, J. Mortality of oncohematological patients
undergoing hematopoietic stem cell transplantation admitted to the intensive care unit. Transplant. Proc. 47, 2665–2666. https://​
doi.​org/​10.​1016/j.​trans​proce​ed.​2015.​09.​033 (2015).
3. Suciu, S. et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years
with acute myeloid leukemia (AML) in first complete remission (CR1): An intention-to-treat analysis of the EORTC/GIME-
MAAML-10 trial. Blood 102, 1232–1240. https://​doi.​org/​10.​1182/​blood-​2002-​12-​3714 (2003).
4. Baden, L. R. et al. Prevention and treatment of cancer-related infections, Version 2.2016, NCCN clinical practice guidelines in
oncology. J. Natl. Comp. Cancer Netw. 14, 882–913. https://​doi.​org/​10.​6004/​jnccn.​2016.​0093 (2016).
5. Maertens, J. A. et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: Summary of the
updated recommendations from the European Conference on Infections in Leukaemia. J. Antimicrob. Chemother 73, 3221–3230.
https://​doi.​org/​10.​1093/​jac/​dky286 (2018).
6. Ljungman, P. et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies
and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect. Dis.
19, e260–e272. https://​doi.​org/​10.​1016/​S1473-​3099(19)​30107-0 (2019).
7. Maertens, J. et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies
and stem cell transplant recipients. J. Antimicrob. Chemother. 71, 2397–2404. https://​doi.​org/​10.​1093/​jac/​dkw157 (2016).
8. Jantunen, E. et al. Invasive fungal infections in autologous stem cell transplant recipients: A nation-wide study of 1188 transplanted
patients. Eur. J. Haematol. 73, 174–178. https://​doi.​org/​10.​1111/j.​1600-​0609.​2004.​00273.x (2004).
9. Pagano, L. et al. Fungal infections in recipients of hematopoietic stem cell transplants: Results of the SEIFEM B-2004 study—Sor-
veglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin. Infect. Dis. 45, 1161–1170. https://​doi.​org/​10.​1086/​
522189 (2007).
10. Kontoyiannis, D. P. et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients,
2001–2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin. Infect. Dis. 50,
1091–1100. https://​doi.​org/​10.​1086/​651263 (2010).
11. Williams, K. M. et al. The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplanta-
tion: A CIBMTR analysis. Bone Marrow Transplant. 51, 573–580. https://​doi.​org/​10.​1038/​bmt.​2015.​316 (2016).

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 7

Vol.:(0123456789)
 www.nature.com/scientificreports/

12. Gratwohl, A. et al. Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: Focus on increasing use
of unrelated donors. Bone Marrow Transplant. 39, 71–87. https://​doi.​org/​10.​1038/​sj.​bmt.​17055​55 (2007).
13. Sureda, A. et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: Current
practice in Europe, 2015. Bone Marrow Transplant. 50, 1037–1056. https://​doi.​org/​10.​1038/​bmt.​2015.6 (2015).
14. Guillaume, T., Rubinstein, D. B. & Symann, M. Immune reconstitution and immunotherapy after autologous hematopoietic stem
cell transplantation. Blood 92, 1471–1490 (1998).
15. Porrata, L. F., Litzow, M. R. & Markovic, S. N. Immune reconstitution after autologous hematopoietic stem cell transplantation.
Mayo Clin. Proc. 76, 407–412. https://​doi.​org/​10.​4065/​76.4.​407 (2001).
16. Steingrimsdottir, H., Gruber, A., Bjorkholm, M., Svensson, A. & Hansson, M. Immune reconstitution after autologous hemat-
opoietic stem cell transplantation in relation to underlying disease, type of high-dose therapy and infectious complications.
Haematologica 85, 832–838 (2000).
17. Schuchter, L. M. et al. Herpes zoster infection after autologous bone marrow transplantation. Blood 74, 1424–1427 (1989).
18. Vose, J. M., Kennedy, B. C., Bierman, P. J., Kessinger, A. & Armitage, J. O. Long-term sequelae of autologous bone marrow or
peripheral stem cell transplantation for lymphoid malignancies. Cancer 69, 784–789. https://​doi.​org/​10.​1002/​1097-​0142(19920​
201)​69:3%​3c784::​aid-​cncr2​82069​0328%​3e3.0.​co;2-m (1992).
19. Mawatari, M., Isoda, A., Miyazawa, Y., Sawamura, M. & Matsumoto, M. A Japanese single-hospital observational trial with a ret-
rospective case-control analysis of varicella zoster virus reactivation after autologous peripheral blood stem cell transplantation.
Transplant Infect. Dis. 17, 544–550. https://​doi.​org/​10.​1111/​tid.​12406 (2015).
20. Offidani, M. et al. A predictive model of varicella-zoster virus infection after autologous peripheral blood progenitor cell trans-
plantation. Transplant Infect. Dis. 32, 1414–1422. https://​doi.​org/​10.​1086/​320157 (2001).
21. Sahoo, F. et al. Herpes Zoster in autologous hematopoietic cell transplant recipients in the era of acyclovir or valacyclovir prophy-
laxis and novel treatment and maintenance therapies. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 23,
505–511. https://​doi.​org/​10.​1016/j.​bbmt.​2016.​12.​620 (2017).
22. Erard, V. et al. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplanta-
tion: No evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood J. Am. Soc. Hematol. 110, 3071–3077
(2007).
23. Lee, H. S. et al. Herpesviridae viral infections after chemotherapy without antiviral prophylaxis in patients with malignant lym-
phoma: Incidence and risk factors. Am. J. Clin. Oncol. 35, 146–150. https://​doi.​org/​10.​1097/​COC.​0b013​e3182​09aa41 (2012).
24. Al-Rawi, O. et al. Cytomegalovirus reactivation in adult recipients of autologous stem cell transplantation: A single center experi-
ence. Mediter. J. Hematol. Infect. Dis. 7, e2015049. https://​doi.​org/​10.​4084/​mjhid.​2015.​049 (2015).
25. Holmberg, L. A. et al. Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell
transplantation. Blood 94, 4029–4035 (1999).
26. Rossini, F. et al. Cytomegalovirus infection after autologous stem cell transplantation: Incidence and outcome in a group of patients
undergoing a surveillance program. Transplant Infect. Dis. 7, 122–125. https://​doi.​org/​10.​1111/j.​1399-​3062.​2005.​000111.x (2005).
27. Piukovics, K. et al. Cytomegalovirus infection in patients with haematological diseases and after autologous stem cell transplanta-
tion as consolidation: A single-centre study. Ann. Hematol. 96, 125–131. https://​doi.​org/​10.​1007/​s00277-​016-​2831-7 (2017).
28. Bilgrami, S. et al. Cytomegalovirus viremia, viruria and disease after autologous peripheral blood stem cell transplantation: no
need for surveillance. Bone Marrow Transplant. 24, 69–73. https://​doi.​org/​10.​1038/​sj.​bmt.​17018​27 (1999).
29. Marchesi, F., Pimpinelli, F., Ensoli, F. & Mengarelli, A. Cytomegalovirus infection in hematologic malignancy settings other than
the allogeneic transplant. Hematol. Oncol. 36, 381–391. https://​doi.​org/​10.​1002/​hon.​2453 (2018).
30. Mengarelli, A. et al. Prospective surveillance vs clinically driven approach for CMV reactivation after autologous stem cell trans-
plant. J. Infect. 72, 265–268. https://​doi.​org/​10.​1016/j.​jinf.​2015.​11.​005 (2016).
31. Ng, A. P. et al. Cytomegalovirus DNAemia and disease: Incidence, natural history and management in settings other than allogeneic
stem cell transplantation. Haematologica 90, 1672–1679 (2005).
32. Jain, T. et al. Cytomegalovirus infection in autologous stem cell transplant recipients in the era of rituximab. Ann. Hematol. 95,
1323–1327. https://​doi.​org/​10.​1007/​s00277-​016-​2700-4 (2016).
33. Han, X. Y. Epidemiologic analysis of reactivated cytomegalovirus antigenemia in patients with cancer. J. Clin. Microbiol. 45,
1126–1132. https://​doi.​org/​10.​1128/​jcm.​01670-​06 (2007).
34. Cho, S. Y., Lee, H. J. & Lee, D. G. Infectious complications after hematopoietic stem cell transplantation: Current status and future
perspectives in Korea. Korean J. Int. Med. 33, 256–276. https://​doi.​org/​10.​3904/​kjim.​2018.​036 (2018).
35. Chen, C. S. et al. Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplanta-
tion. Bone Marrow Transplant. 32, 515–522. https://​doi.​org/​10.​1038/​sj.​bmt.​17041​62 (2003).

Acknowledgements
This study was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea
Government (MSIT) (No. 2019R1G1A1010388 (D.J.K)).

Author contributions
D.J., H.S., S.R., and S.G. designed the study; S.J. contributed to data extraction and analyzed the data; S.R., S.G.,
S.N., S.Y., Y.R., W.S., M.H., S.H., S.H., S.H., and M.K. contributed to the conception of the study and reviewed
the manuscript; D.J. and H.S. wrote the manuscript, and all authors approved the manuscript.

Competing interests
The authors declare no competing interests.

Additional information
Correspondence and requests for materials should be addressed to H.S.L.
Reprints and permissions information is available at www.nature.com/reprints.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations.

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 8

Vol:.(1234567890)
www.nature.com/scientificreports/

Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons licence, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

© The Author(s) 2023

Consortium for Improving Survival of Lymphoma (CISL)

Da Jung Kim1, Sung‑Nam Lim5, Sung Yong Oh6, Young Rok Do7, Won Sik Lee8,
Mark Hong Lee9, Sung Hwa Bae10, Se Hyung Kim11, Min Kyoung Kim12 & Ho Sup Lee1* &

Scientific Reports | (2023) 13:2551 | https://doi.org/10.1038/s41598-023-27465-y 9

Vol.:(0123456789)