Histoplasmosis After Solid Organ Transplant
Histoplasmosis After Solid Organ Transplant
Maha Assi 18
Stanley Martin 16
L. Joseph Wheat 15
Chadi Hage 22
Alison Freifeld 21
Robin Avery 20
John W. Baddley 19
Paschalis Vergidis 24
Rachel Miller 23
David Andes 17
Jo-Anne H. Young 7
Kassem Hammoud 8
Shirish Huprikar 5
David McKinsey 6
Thein Myint 3
Julia Garcia-Diaz 4
Eden Esguerra 1
E. J. Kwak 2
Michele Morris 0
Kathleen M. Mullane 10
Vidhya Prakash 9
Steven D. Burdette 11
Mohammad Sandid 18
Jana Dickter 12
Darin Ostrander 13
Smyrna Abou Antoun 18
Daniel R. Kaul 14
0 Division of Infectious Diseases, University of Miami Miller School of Medicine , Florida
1 St John's Regional Medical Center , Joplin, Missouri
2 Division of Transplant Infectious Diseases, University of Pittsburgh , Pennsylvania
3 Division of Infectious Diseases, University of Kentucky , Lexington
4 Ochsner Medical Foundation , New Orleans, Louisiana
5 Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai , New York , New York
6 Infectious Disease Associates of Kansas City , Missouri
7 Department of Medicine, Division of Infectious Disease, University of Minnesota , Minneapolis
8 Division of Infectious Diseases, University of Kansas Medical Center , Kansas City
9 Infectious Disease Department, Wright-Patterson Medical Center
10 Department of Medicine, University of Chicago , Illinois
11 Division of Infectious Disease, Wright State University Boonshoft School of Medicine , Dayton, Ohio
12 Division of Infectious Diseases, Kaiser Permanente , Fontana, California
13 Transplant and Oncology Infectious Diseases Clinical Research Center, Division of Infectious Diseases, Johns Hopkins University School of Medicine , Baltimore, Maryland
14 Department of Internal Medicine, Division of Infectious Disease, University of Michigan Medical School , Ann Arbor
15 MiraVista Diagnostics
16 Division of Infectious Diseases, Ohio State University Medical Center , Columbus
17 Department of Medicine and Medical Microbiology and Immunology, University of Wisconsin , Madison
18 Department of Internal Medicine, University of Kansas School of Medicine , Wichita
19 Division of Infectious Diseases, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center
20 Division of Infectious Disease (Transplant Oncology), Johns Hopkins University of Medicine , Baltimore, Maryland
21 Department of Internal Medicine, Division of Infectious Diseases, University of Nebraska Medical Center , Omaha
22 Department of Internal Medicine, Pulmonary-Critical Care and Infectious Diseases, Indiana University , Indianapolis
23 Divison of Infectious Diseases, University of Iowa , Iowa City
24 Division of Clinical Microbiology, Mayo Clinic , Rochester, Minnesota
Background. To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT. Methods. All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected. Results. One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty-eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients. Conclusions. Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse.
histoplasmosis; fungal infection; solid organ transplant.
The dimorphic fungus Histoplasma capsulatum is most
common in the United States in the Ohio and
Mississippi River valleys. Sensitivity to Histoplasma antigens
among individuals living in these river valleys may
exceed 80% . Infection is often asymptomatic or
subclinical. Because of the relationship between an
individuals underlying immune function and histoplasmosis
severity, the early years of the AIDS epidemic resulted
in an increase in the incidence of symptomatic and severe
Histoplasma infection . Clinicians thus gained experience
regarding the diagnosis, treatment, and outcomes of this
lifethreatening infection in immunosuppressed populations.
In the field of solid organ transplantation (SOT), T-cell
immune dysfunction can also be significant, although the
incidence of clinical histoplasmosis is <0.5% in most studies .
Infection can be difficult to predict with variable clinical
presentation, response to therapy, and risk for complications.
Symptomatic infection among SOT recipients could occur via
primary infection, secondary infection in patients with prior
exposure who come in contact with a large inoculum in a now
immunosuppressed state, and reactivation of previous latent
infection. Rarely, transmission from the allograft itself has been
reported [9, 10].
Much of our present knowledge of histoplasmosis after SOT
comes from single-center studies from areas of variable
endemic rates [3, 5]. Specific data regarding diagnosis,
incidence, treatment, and outcomes of this infection are needed.
The present study attempts to improve our understanding by
performing a large multicenter evaluation of histoplasmosis
All cases of histoplasmosis in SOT recipients diagnosed
between 1 January 2003 and 31 December 2010 at 24
participating institutions were retrospectively identified. Multiple
transplant centers in the United States were approached and
data were collected by those interested in participating.
Diagnosis of histoplasmosis required positive culture, positive serum,
or urine Histoplasma antigen (Miravista Diagnostics,
Indianapolis, Indiana), histopathology demonstrating yeast-like
structures characteristic of H. capsulatum, the presence of H or M
precipitin bands by immunodiffusion, or complement fixation
titers 1:8. Progressive disseminated histoplasmosis was
defined as clinical, laboratory, or imaging evidence of
extrapulmonary involvement as previously suggested . The site of
extrapulmonary involvement was determined based on clinical
signs or laboratory evidence. Pulmonary histoplasmosis was
defined as respiratory symptoms and chest imaging (radiograph
or computed tomography) with infiltrates and/or mediastinal
lymphadenopathy in the absence of progressive disseminated
histoplasmosis. As has been done in previous studies, disease
was characterized as mild, moderate, or severe . Mild
disease was treated with outpatient therapy, moderate disease
required hospitalization but not critical care, and severe disease
was treated in an intensive care unit. Suppressive therapy was
defined as treatment continued >12 months after diagnosis
except if given for relapse. Death was directly attributed to
histoplasmosis if the patient had findings of active histoplasmosis
and no other cause of death was identified. Evidence of active
histoplasmosis included 1 of the following: treatment for <6
weeks, persistent signs and symptoms, failure of antigen to
decline, demonstration of organisms by cytology or pathology,
or positive culture. Histoplasmosis was considered to have
contributed to the death if a patient died of another condition but
the investigator felt that the patient had evidence for active
histoplasmosis. Clinical and demographic data were collected
from investigators. Patient management decisions were made
by treating clinicians. Institutional review board approval was
obtained by the investigator at each site. At some centers,
patients included in this series had been included in previously
published series [3, 5, 6, 13]. All patient data were collected
independently for this study; no data were extracted from
Baseline characteristics were compared using the 2-sample
independent t test for continuous variables and 2 test for
categorical variables. For variables with expected cell count of <5, Fisher
exact test was used. For variables that are not normally
distributed, Mann-Whitney and Wilcoxon rank-sum tests were used. To
determine risk factors for death and relapse, a multivariate
analysis was used. Initially univariate analysis was conducted based on
clinical grounds and available variables. Variables included age,
disease severity, fungemia, urine antigen results,
immunosuppression reduction, amphotericin treatment, type of transplant,
and organ involvement. Variables that were statistically
significant (P .05) were then entered into the multivariate analysis.
Appropriateness of the model was assessed using Hosmer and
Lemeshow goodness-of-fit test. Two way interactions were tested
when appropriate. Casewise diagnostics were performed to
detect any outliers. SPSS software version 19 was used.
Patient and Center Characteristics
From 24 SOT centers, we identified 152 cases of posttransplant
histoplasmosis. One center contributed 22 cases, 5 centers 10
20 cases, and the remaining centers had 10 cases. The location
of the centers and the rates of histoplasmin reactivity are in
Table 1. Baseline characteristics are described in Table 2. Most
patients were on maintenance immunosuppression with a
calcineurin inhibitor, mycophenolate mofetil, and a corticosteroid.
Ten percent of patients were treated for rejection in the 3
months preceding the diagnosis of histoplasmosis.
The median time from transplant to diagnosis with
histoplasmosis was 27 months, but 34% presented in the first year, with
2% presenting within 1 month of transplant. The longest
interval from transplant to diagnosis was 20 years (Figure 1). Most
patients had disseminated disease (81%). Table 3 describes
Table 1. Participating Centers and Rates of Histoplasmin Skin
Omaha, University of Nebraska
Indianapolis, Indiana University
Birmingham, University of Alabama
Cleveland, Ohio Cleveland Clinic
Columbus, Ohio Ohio State University
Iowa City, Iowa University of Iowa
Madison, University of Wisconsin
Minneapolis, University of Minnesota
Rochester, Mayo Clinic
Kansas City, University of Kansas
Ann Arbor, University of Michigan
Associates of Kansas
University of Kentucky
New York, Mount Sinai
Wichita, Kansas University of Kansas
Chicago, Illinois University of Chicago
Dayton, Ohio Wright-Patterson
Dayton, Ohio Wright State University
Joplin, Missouri St Johns Regional
Medical Center Johns Hopkins Baltimore, Maryland
Pennsylvania Fontana, California Miami, Florida
Ochsner Medical Foundation University of Pittsburgh Kaiser Permanente
University of Miami
specific organ involvement. Fungemia was present in 63% of
patients. Twenty-seven percent had severe disease, 63%
moderate disease, and 8% mild disease. In multivariate analysis, use of
mycophenolate preparation and the presence of fungemia were
risk factors for severe disease (Table 3).
Table 4 describes the overall yield of the diagnostic tests used.
Antigen detection provided the highest sensitivity for diagnosis,
African American Latino Asian Diabetes
93% for antigenuria and 86% for antigenemia. Detection of
antibody was the least sensitive diagnostic method, positive in
36% of cases. More than 1 diagnostic test was positive in 115
patients (76%), whereas a single test was positive in 37 (24%).
These included antigenuria in 27 (18%), pathology or cytology
in 6 (4%), culture in 3 (2%), and antibody detection in 1 (1%).
Combined visualization of the organism and detection of
antigen was the basis for diagnosis in 69 (45%), whereas
antigen was positive but pathology was negative in 20 (13%)
and pathology was positive but antigen was negative in 9
patients (6%). Culture provided the sole basis for diagnosis in 3
patients (2%) and antibody detection by complement fixation
in 1 patient (1%). In this case, a patient with meningitis
demonstrated complement fixation titer of 1:32 in serum and 1:8 in
cerebrospinal fluid; antigen was negative in serum using a less
sensitive version of the antigen assay as existed in 2003 ;
urine antigen, cultures, cytology, and pathology were not
performed. Antigen detection was more sensitive in patients with
disseminated disease compared to those with pulmonary
Organisms were visualized in the bone marrow in 12 of 17
patients (71%). In 5 patients, all diagnosed between 7 and 12
months after transplant, granuloma was observed on biopsy of
tissue in the transplanted organ.
Treatment and Outcome
The most common management strategy was an amphotericin
formulation followed by therapy with an azole (Table 5). For
patients with severe disease, 42 (98%) initially received an
amphotericin formulation and 1 (2%) initially received an azole.
Moderate disease was initially treated with amphotericin in
69% of cases, with 31% receiving initial therapy with an azole.
Ninety-two percent of patients with mild disease initially
received azole therapy. Seventeen patients (11%) died prior to
receiving step-down therapy. In the remaining cases, an azole was
given as step-down therapy for a median duration of 12
months (Table 5). Twenty-one percent of patients continued
chronic suppressive therapy. Immunosuppression was held or
decreased in the majority of patients (Table 5).
Nineteen percent of the patients in the cohort died;
histoplasmosis was the cause of death in 10% and 72% of deaths
occurred within the first month after diagnosis, resulting in a
median interval to death of 2 weeks. No histoplasmosis-related
deaths occurred within 2 months of transplant. In univariate
analysis, older age, severe disease, fungemia, and higher urine
antigen were associated with death from histoplasmosis. In
multivariate analysis, age and severe disease remained
statistically significant risk factors (Table 6).
Relapse occurred in 9 (6%) patients. Six occurred in the first
2 years following the original diagnosis; 1 patient relapsed 9
years later. Follow-up for >1 year after discontinuation of
therapy was available for 57 patients; 6 relapsed, 3 received 7
months of initial therapy, and 3 were treated for at least 1 year.
The other 3 relapses occurred among the 38 patients on
chronic maintenance therapy who were followed for at least 1
year (median, 34 months [range, 1274 months]). Relapse
occurred at 5, 14, and 48 months of chronic maintenance
antifungal therapy. Relapse occurred in 3 of 38 patients (8%) while
receiving therapy, and 6 of 57 (10%) who stopped therapy
(P = .67). Information on drug levels was not available. Of the 9
relapsed patients, 2 died of histoplasmosis after relapse. One
died 1 month and the other 4 months after beginning treatment
for relapse. The only risk factor significantly associated with
relapse was failure to reduce calcineurin inhibitor dosage (75%
vs 95%; P = .043).
This paper describes the largest series (152 cases) of
histoplasmosis after SOT. Histoplasma-related mortality was 10%, with
most deaths occurring soon after diagnosis. One-third of the
cases occurred within 1 year of transplant, and almost half
occurred in the first 2 years after transplant. The very early
development of disease and presence of granuloma in the
transplanted organ suggests that some of these cases were
donor-derived. Antigenuria was the most sensitive diagnostic
test. Patients were typically treated with polyenes followed by
azoles for a median of 1 year, and relapse was rare, suggesting
that chronic suppressive treatment is unnecessary in most
cases. Nonetheless, 2 deaths occurred after relapse, and clinical
and laboratory monitoring after discontinuation of therapy is
Previous single-center studies have demonstrated an
incidence of 0.48% of histoplasmosis among SOT recipients ,
with a significant proportion (34%) of cases occurring during
Table 3. Selected Risk Factors for Severe Disease
Abbreviations: CI, confidence interval; ng, nanograms; OR, odds ratio.
a Severity of 1 case could not be classified.
b One small bowel and 2 multiorgan nonrenal/pancreas transplants not included.
c No. of patients in whom results of the respective test were available.
the first year after transplant. A recent, large prospective
multicenter study of invasive fungal infection after SOT reported 48
cases of histoplasmosis with 43% occurring within 6 months of
transplant . These rates are disproportionate compared to
the proportion of living transplant patients who were
transplanted within the last year. For example, of all living patients
Lung, respiratory culture
Pathology or cytology
Lung, respiratory pathology or cytology
Culture, pathology, or cytology
Lung, respiratory culture, pathology or cytology
Univariate OR (95% CI)
OR (95% CI)
Table 5. Treatment and Immunosuppression Management
Amphotericin B lipid complex
Amphotericin B deoxycholate
Decrease or stop immunosuppression
in the United Network of Organ Sharing (UNOS) registry as of
31 December 2011, 9.3% were transplanted that year and 89.7%
in preceding years (e-mail communication; June 2012, Sarah
Taranto, Organ Procurement and Transplantation Network/
UNOS). Thus, about one-third of cases occur in approximately
10% of the patients at risk. More intense immunosuppression
likely plays a major factor in the increased first-year risk, as
could donor-derived infection.
Donor-derived histoplasmosis is rare, but confirmed
transmission has been reported [9, 10]. We noted 8 cases that
exhibited features suggestive of donor-derived histoplasmosis based
either on diagnosis in the first month after transplant or the
finding of granuloma in the transplanted organ combined with
diagnosis during the first year after transplant. Other possible
explanations for early disease include smoldering infection in
the recipient prior to transplant, and newly acquired disease in
the recipient. In either of these circumstances, granuloma
might be observed in the transplanted organ. As we do not
have clinical information on the donor or other recipients,
donor-derived infection cannot be proven. Our study supports
continued attention to the possibility of donor-derived
histoplasmosis when assessing donors in endemic areas .
The significant mortality associated with posttransplant
histoplasmosis and the nonspecific clinical presentation
emphasizes the importance of maintaining a low threshold for
consideration of histoplasmosis, and raises the question
whether screening before or during the first year following
transplant could identify cases earlier, perhaps reducing
mortality. The role of routine screening for antigenuria following
transplant has not been studied, but this approach was
addressed in patients receiving treatment with tumor necrosis
factor inhibitors in which results of a pilot project did not
support screening . More information is needed to
determine the benefit of screening.
Detection of antigenuria was the most sensitive diagnostic
method. Antigenuria was present in all of the cases in 2 other
reports [5, 6]. In another study, only 69% of patients exhibited
antigenuria, which was attributed to use of older, less sensitive
assays . Sensitivity of antigen testing is lower in patients who
do not have disseminated disease . Although not
demonstrated in this study, other studies and clinical experience show
that the highest sensitivity for diagnosis is achieved by testing
both urine and serum [18, 19]. Serologic tests for antibodies to
H. capsulatum were not sensitive, positive in about one-third of
patients, and the sole basis for diagnosis in only 1 patient.
As the majority of patients presented with disseminated
disease, treatment usually consisted of a lipid formulation of
amphotericin B followed by itraconazole, combined with a
Age, y, median (range)
Urine antigen, ng/mL,
Urine antigen >19 ng/mL
Reduced calcineurin inhibitor
Death due to
Histoplasmosis (n = 15)
(n = 128)
Abbreviations: CI, confidence interval; ng, nanograms; OR, odds ratio.
a Cannot be calculated with zero count cells.
Multivariate OR (95% CI)
reduction in immunosuppression. Despite aggressive
treatment, 10% of the patients died of histoplasmosis with most deaths
occurring within the first 3 weeks following diagnosis, including
2 who died prior to treatment. In the literature, death during
the first few weeks following diagnosis was reported in the 2
other fatal cases for which information was provided [4, 5].
Higher antigen concentration as well as older age and fungemia
were associated with higher death rates in univariate analysis.
Although most patients with disseminated disease should
initially be treated with an amphotericin formulation, patients
with these risk factors are particularly likely to require polyene
therapy even if renal function is impaired. Although it is
common practice and makes intuitive sense to reduce
maintenance immunosuppression in SOT recipients with severe
infections, we did not find a correlation between reduction of
immunosuppression and risk of death. Any benefit of reducing
immunosuppression, however, may have been masked by the
fact that immunosuppression was reduced in >90% of cases
and most deaths occurred soon after diagnosis.
The optimal duration of treatment for histoplasmosis after
SOT is unknown. In 2 other reports, suppressive therapy was
administered in 23%  and 50%  of patients; in a third report,
none received suppressive therapy with no relapses noted in
patients treated for 12 months . Combining the 4 series, 14 of
197 patients (7.1%) relapsed, 9 (64.3%) within the first 2 years,
12 (85.7%) within the first 4 years, and 1 patient each at 6 and 9
years following the original episode. Thus, the greatest risk is
during the first 2 years, but 36% occurred later, up to at least 9
years following the original episode. Overall, our findings
support the safety of discontinuing antifungal therapy following
a 12-month course of treatment. Heightened awareness of
findings consistent with relapse should be maintained during the
first 2 years following the initial episode, and continued
awareness of the risk of relapse for the remainder of the patients life.
Sequential antigen testing might be useful in determining if a
subset of patients is at risk for relapse if azole therapy is
discontinued. The Infectious Diseases Society of America guidelines
suggest that antigen concentration should be <2 ng/mL prior to
stopping therapy and monitored for at least 12 months after
treatment is stopped . As patients in our study did not all
have antigenuria monitored at routine intervals, our
conclusions regarding the utility of this practice are incomplete.
However, some observations can be made. Antigenuria
progressively declined during therapy. Relapse occurred in 2 of the
7 patients (29%) with antigenuria >2 ng/mL and 1 of 32
patients (3%) with antigen concentrations of 1.9 ng/mL
(undetectable in 17 of 32). One of the 2 patients who discontinued
therapy before the antigen concentration fell below 2 ng/mL
died following a relapse of histoplasmosis: the concentration at
discontinuation of therapy was 5.9 ng/mL in that patient. In
another report, antigenuria persisted in 3 of 9 patients at the
time treatment was stopped, and relapse did not occur .
Antigen levels in the urine and serum had declined from peak
at the time treatment was stopped, and the authors concluded
that antigen testing and clinical follow-up should be performed
for at least 1824 months. A significant increase in antigen
should prompt very careful clinical monitoring or reinstitution
Our study has several important limitations. Data were not
collected prospectively, and diagnostic and treatment strategies
varied over time and from center to center. The scope of the
study and the multicenter nature made a case-control series
impractical. Thus, risk factors for the development of
histoplasmosis could not be determined. Furthermore, because data
from each center providing the number of surviving
posttransplant patients stratified by time from transplant were not
available, precise incidence rates could not be calculated. A
standardized diagnostic protocol was not used at each center,
and comparison of performance of diagnostic methods was
thus imperfect. Determination of the cause of death by
retrospective review of medical records is difficult and impacts the
analysis of risk factors. Finally, conclusions regarding the safety
of discontinuing chronic maintenance therapy must be
tempered by the variable duration of follow-up.
This study describes a large, multicenter cohort of patients
with histoplasmosis after SOT. Although a significant number
of late cases occur, the first year after transplant is the period of
greatest risk. Some of these cases likely represent donor-derived
infection. Antigen detection in the serum or urine is the most
sensitive diagnostic test. As is true of many infections following
transplant, serological tests are of limited sensitivity. Although
early deaths occur, treatment with a polyene followed by 12
months of azole therapy is successful in most cases with only
rare relapses. Conducting prospective studies to refine the
optimal treatment of histoplasmosis would be very challenging.
Future prospective studies, however, could focus on universal
serological or antigen-based screening of donors and recipients
in endemic areas to better inform practices to reduce the
incidence of early donor- or recipient-derived disease.
Acknowledgments. The authors thank Dionissios Neofytos, MD, Jennifer
Cuellar-Rodriguez, MD, Steven Mawhorter, MD, Chris Ledtke, MD, and
David van Duin, MD, for their work abstracting, collecting, and reviewing data.
Financial support. This work was supported by the National Institutes
of Health (grant number K24 A1085118), which supplied funds for the
database from which the data were extracted (Johns Hopkins University).
Disclaimer. The views and opinions expressed in this article are those
of the authors and do not reflect official policy or position of the US Air
Force, Department of Defense, or US government.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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