Epidemiology, Clinical Manifestations, and Outcome of Mucormycosis in Solid Organ Transplant Recipients: A Systematic Review of Reported Cases

Abstract

Mucormycosis is an emerging disease primarily affecting the immunocompromised host, but scarce evidence is available for solid organ transplant recipients (SOTR). We systematically reviewed 183 cases occurring in SOTR, exploring epidemiology, clinical characteristics, causative pathogens, therapeutic approaches, and outcomes. Kidney transplants accounted for half of the cases, followed by heart (18.6%), liver (16.9%) and lung (10.4%). Diagnosis showed a dichotomous distribution, with 63.7% of cases reported within 100 days of transplantation and 20.6% occurring at least one year after transplant. The 90-day and 1-year mortality rates were 36.3% and 63.4%, respectively. Disseminated disease had the highest mortality at both time points (75% and 93%). Treatment with more than three immunosuppressive drugs showed a significant impact on 90-day mortality (OR 2.33, 95%CI 1.02-5.66; p=0.0493), as did a disseminated disease manifestation (OR 8.23, 95%, CI 2.20-36.71; p=0.0027) and the presence of diabetes (OR 2.35, 95%, CI 1.01-5.65; p=0.0497). Notably, prophylaxis was administered to twelve cases with amphotericin B. Further investigations are needed to validate these findings and to evaluate the potential implementation of prophylactic regimens in high-risk SOTR.

Full text

Open Forum Infectious Diseases
REVIEW ARTICLE
DOI: 10.1093/ofid/ofae043 1
Epidemiology, clinical manifestations, and outcome of
mucormycosis in solid organ transplant recipients: a
systematic review of reported cases
Emanuele, EP, Palomba1,2, Marta, MC, Colaneri1,2, Cecilia, CA, Azzarà3, Marco, MF,
Fava3, Angelo, AM, Maccaro3, Giulia, GR, Renisi3, Giulia, GV, Viero3, Harsimran, HK,
Kaur4, Arunaloke, AC, Chakrabarti5, Andrea, AG, Gori1,2, Andrea, AL, Lombardi3,6✝
†
,
Alessandra, AB, Bandera3,6✝
1 Department of Infectious Diseases, Luigi Sacco Hospital, Milan, Italy; 2 Centre for
Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy; 3
Infectious Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan,
Italy; 4 Department of Medical Microbiology, Postgraduate Institute of Medical Institution and
Research, Chandigarh, India; 5 Doodhadhari Burfani Hospital and Research Institute, Haridwar,
India; 6 Department of Physiopathology and Transplantation, University of Milan, Milan, Italy
Mucormycosis is an emerging disease primarily affecting the immunocompromised host, but
scarce evidence is available for solid organ transplant recipients (SOTR). We systematically
reviewed 183 cases occurring in SOTR, exploring epidemiology, clinical characteristics,
causative pathogens, therapeutic approaches, and outcomes. Kidney transplants accounted for
half of the cases, followed by heart (18.6%), liver (16.9%) and lung (10.4%). Diagnosis showed
a dichotomous distribution, with 63.7% of cases reported within 100 days of transplantation and
————————————————————————————————————————
AL and AB shared last authorship
Correspondence: Andrea Lombardi, Department of Pathophysiology and Transplantation,
University of Milan, via Francesco Sforza 35, Milan, Italy. 0039-0255034767
andrea.lombardi@unimi.it
Alternate corresponding author: Emanuele Palomba, Department of Infectious Diseases, Luigi
Sacco Hospital, Milan, Italy. 0039-0239042975 palomba.emanuele@asst-fbf-sacco.it
© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of
America. This is an Open Access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial reproduction and distribution of the work, in any medium, provided the
original work is not altered or transformed in any way, and that the work is properly cited. For
commercial re-use, please contact journals.permissions@oup.com
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DOI: 10.1093/ofid/ofae043 2
20.6% occurring at least one year after transplant. The 90-day and 1-year mortality rates were
36.3% and 63.4%, respectively. Disseminated disease had the highest mortality at both time
points (75% and 93%). Treatment with more than three immunosuppressive drugs showed a
significant impact on 90-day mortality (OR 2.33, 95%CI 1.02-5.66; p=0.0493), as did a
disseminated disease manifestation (OR 8.23, 95%, CI 2.20-36.71; p=0.0027) and the presence
of diabetes (OR 2.35, 95%, CI 1.01-5.65; p=0.0497). Notably, prophylaxis was administered to
twelve cases with amphotericin B. Further investigations are needed to validate these findings
and to evaluate the potential implementation of prophylactic regimens in high-risk SOTR.
Keywords: mucormycosis; mortality; organ transplant; systematic review; epidemiology
Key points: Mucormycosis is a dreadful complication of solid organ transplantation, with the
intensity of immunosuppression having a significant impact on mortality. Disease onset shows
two peaks, within three months and after one year from transplantation. Infections may occur
despite antifungal prophylaxis.
BACKGROUND
In recent years, the global burden of invasive fungal disease caused by pathogens from the order
Mucorales (including Rhizopus, Rhizomucor, Mucor, Lichtheimia, Apophysomyces,
Cunninghamella, Saksenaea and other rarer species1) has grown to become the second most
common pathogens after Aspergillus spp. in patients with haematological malignancies,
haematopoietic stem cell transplantation and solid organ transplantation (SOT)2,3.
Mucorales primarily infect humans when spores are inhaled, with the lungs and sinuses being
common sites of initial infection. Additionally, infections can occur through skin breaks, burns,
or traumatic injuries involving soft tissues.
Invasive mucormycosis predominantly affects individuals with compromised immune systems,
such as those with uncontrolled diabetes mellitus, and patients with significant comorbidities,
especially when risk factors are present, such as trauma or indwelling of medical devices. In
immunocompromised hosts, the initial colonization can lead to severe conditions, spreading to
the eyes, central nervous system, and gastrointestinal tract. Mucormycosis is a severe condition,
with mortality rates ranging from 46% to over 90%, depending on disease localization, patients'
immune status and species identified1,4. The main therapeutic option is surgical debridement,
supported by antifungal treatment. Antimicrobial resistance is difficult to define, as clinical
breakpoints have not been established5. The diagnosis of mucormycosis is often complicated,
and recent advances in mycology have shown that the burden of the disease is more significant
than expected a few decades ago6. In addition, progress in transplantation medicine and onco-
haematology, along with the diffusion of immunomodulating therapy for patients with other
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diseases (such as autoimmune conditions), have undoubtedly widened the population at risk of
invasive fungal disease.
Currently, limited evidence on mucormycosis is derived from clinical studies, predominantly
case reports and case series. This is especially evident for individuals who have undergone solid
organ transplantation (SOT). Therefore, we performed a systematic review of cases of
mucormycosis in SOT recipients (SOTR) published between January 2002 and December 2022.
We aimed to explore the epidemiology, clinical and radiological characteristics, causative
pathogens, therapeutic approaches, and outcomes within this specific population.
METHODS
The study protocol of this systematic review was registered on PROSPERO
(CRD42023387356), and it was reported following the Preferred Reporting Items for Systematic
Review and Meta-Analyses (PRISMA) guidelines7. The electronic search was performed on
PubMed, Scopus, and Embase databases using keywords referring to mucormycosis and SOT.
Searches were limited to studies involving humans and those published in English from January
2002 to December 2022. Subsequently, a manual search of publications that the electronic search
might have missed was performed.
The details of this search are reported in the Supplementary Table 1.
Eligibility criteria
We reviewed the published case reports and case series of proven/probable mucormycosis8,9
occurring in adult patients who have undergone SOT.
Studies to be included had to describe a case(s) of mucormycosis occurring in adult SOTR; we
did not apply exclusion criteria regarding the availability of all the selected study variables.
Studies were excluded if (1) they were reported in congress abstracts, letters, or commentaries,
(2) they included only patients aged < 18 years old, and (3) they computed mortality excluding
early deaths. Mortality was considered at two time points, namely 90 days and one year after
mucormycosis diagnosis.
Screening of the articles and data extraction
The records identified through the electronic search were exported to a specifically developed
electronic spreadsheet.
Four separate authors independently screened the titles and abstracts of the records, assessing
them against predefined criteria for inclusion and exclusion.
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Following this initial screening, the full texts of the selected documents were obtained and
scrutinized against the same criteria. Consensus discussions involving a fifth reviewer resolved
any discrepancies during these two phases.
Four independent reviewers performed the data extraction, and disagreements regarding the
inclusion of studies were resolved through consensus.
In cases where we encountered missing data within a considered article, we reached out to the
authors to request undisclosed information or additional details.
Extracted variables were:
1) Characteristics of the studies, namely author and title, country, publication year, study design,
and total number of included patients.
2) Sociodemographic characteristics of the patients included in the studies, namely age, sex and
ethnicity.
3) Clinical characteristics of the patients included in the studies include underlying conditions at
the time of infection, namely diabetes mellitus, renal replacement therapy (RRT), major trauma,
CMV disease, liver disease or malignancies after SOT, neutropenia, and iron overload.
4) SOT characteristics of the patients included in the studies, such as SOT type (kidney, heart,
liver, lung, or other solid organs), time since SOT, SOT-related complications, and SOT-related
treatments, namely number and type of administered immunosuppressant drugs, and prophylactic
antifungal therapies.
5) Characteristics of the mucormycosis infection affecting the patients included in the study,
namely the identified microorganism, the disease's manifestations, the chest image results, and
the type of administered therapeutic antifungal agents.
Specifically, we categorized the clinical manifestations of mucormycosis, which can involve
rhino-orbital-cerebral, pulmonary, cutaneous, or disseminated forms, according to the primarily
affected body sites and the extent of infection at the point of diagnosis. We applied criteria
adapted from previous definitions for this categorisation1.
6) Data about the need for surgery, re-transplantation, 90-day and one-year mortality and
surgical sequelae.
Study outcomes
The study's primary outcome was describing clinical and microbiologic characteristics of SOTR
who developed mucormycosis.
The secondary aim was to assess those demographic and clinical characteristics associated with
90-day mortality of SOTR who developed mucormycosis.
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Summary of statistical analysis
Study characteristics were described using counts and percentages, or medians and interquartile
ranges (IQRs), as appropriate.
A descriptive summary was performed for patient characteristics, disease symptoms, and the
pathogens causing the disease. Categorial variables were evaluated using the chi-squared test or
Fischer's exact test. A multivariate logistic regression to assess the risk factors associated with
90-day mortality of mucormycosis was then performed, adjusting for demographic and clinical
features (age, sex, type of SOT, rejection, and therapy with more than three immunosuppressive
drugs).
A p-value of less than or equal to 0.05 was deemed to indicate statistical significance.
Analyses were performed using the R (version 4.2.1).
RESULTS
A total of 1,013 articles were identified through database search. After remotion of duplicates
and screening of titles and abstracts, 282 full-text articles were assessed for eligibility, with 130
studies included in the final analysis: 117 case reports of single patients10,11,20,110–119,21,120–125,22–
29,12,30–39,13,40–49,14,50–59,15,60–69,16,70–79,17,80–89,18,90–99,19,100–109, eight case reports of two patients126–133,
four case series describing three or more patients134–137, and a multicentre observational study of
30 patients138, accounting for a total of 183 cases of mucormycosis in SOTR (Figure 1).
Demographic characteristics and underlying conditions
The 183 patients with mucormycosis analyzed in our study were predominantly male (136,
74.3%), and their median (interquartile range) age was 40 (40-56.5) years. Half of cases (51.7%)
were reported from Asia, while Europe and North America accounted for 21.5% and 20.3% of
reports, respectively. The geographical distribution of cases is depicted in Figure 2.
Diabetes mellitus was the most common underlying condition (73/173, 42.2%), followed by
RRT (30/137, 21.9%) and major trauma (18/183, 9.8%), while other conditions such as severe
neutropenia (white blood cell count <500 cells/mm3) and iron overload were infrequent, reported
in 7.3% and 6% of cases, respectively. Patients' demographics and underlying conditions are
described in Table 1.
SOT characteristics
Half of the cases were represented by kidney transplant (KT) recipients (93/183, 50.8%),
followed by heart (34/183, 18.6%), liver (31/183, 16.9%), and lung (19/183, 10.4%).
Mucormycosis was diagnosed more frequently within the first 30 days post-SOT (58/165, 35%),
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and 63.7% of cases were reported within 100 days from transplantation. One-fifth of infections
(34/165, 20.6%) were diagnosed after at least one year from transplant. The most frequent SOT
complication described preceding mucormycosis was rejection (46/149, 30.9%), while one-
fourth of patients underwent reoperation or re-transplantation (45/178, 25.2%). Regarding the
immunosuppressive drugs used, 71.6% (131/183) of patients received more than three drugs,
with corticosteroids, tacrolimus and mycophenolic acid being the most common. One-third of
SOTRs (56/164, 34%) received antifungal prophylaxis, of which 22.6% (12/53) was potentially
effective against Mucorales (amphotericin B, AmB). Table 1 and Supplementary Table 2
summarise the main findings of this section.
Microbiological, clinical, and therapeutic characteristics
Rhizopus spp. was the most common species isolated from clinical specimens (52/124, 41.9%)
and, together with Mucor spp. and Lichteimia spp, accounted for 86.2% (107/124) of cases.
The two most common disease manifestations were pulmonary and rhino-orbital-cerebral, each
with 24.6% of reports, while 10% of cases (17/171) suffered from disseminated disease.
AmB was the most used antifungal agent (163/183, 89.1%) and was mainly administered as first-
line intravenous therapy with a median duration of 40 days. Posaconazole was given in a quarter
of all cases (49/183, 26.8%) and was mainly used as oral step-down therapy for an average of 93
days after intravenous AmB. When antifungal susceptibility essays were available, AmB and
posaconazole were active in less than a third of cases, 31% (9/29) and 30% (9/30), respectively.
Table 2 and Supplementary Table 3-4 describe the main findings of this section.
Outcomes by disease manifestation
Surgical debridement was performed in half of the cases (88/179, 49.2%), more frequently in
gastrointestinal (18/29, 62.1%), rhino-orbital-cerebral (25/42, 59.5%) and cutaneous (14/27,
51.9%) forms, and less frequently in disseminated disease, which accounted for 17.6% (3/17) of
cases.
The overall 90-day and 1-year mortality rates were 36.3% (62/171) and 63.4% (71/112),
respectively. Disseminated disease had the highest mortality at both time points, with 75%
(12/16) of patients dying at 90 days and 93% (14/15) of patients not surviving at one year.
When analyzing localized disease, pulmonary (16/37, 43.2%) and gastrointestinal (11/29, 37.9%)
involvement had the lowest survival rate at three months after disease onset, while cutaneous
forms had the lowest mortality (6/26, 23%). Two-thirds of patients affected by any form had died
in one year. A detailed description of outcomes is available in Table 3.
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Variables associated with 90-day mortality
Regarding the secondary outcome, after accounting for potential confounders (age, sex, SOT
type, rejection, diabetes mellitus, disseminated disease, presence of surgical treatment and
administration of more than three immunosuppressant drugs after SOT), the multivariate logistic
regression model showed that the disseminated form (OR 8.23, 95%, CI 2.20-36.71; p= 0.0027),
diabetes mellitus (OR 2.35, 95%, CI 1.01-5.65; p= 0.0497), and being treated with more than
three immunosuppressant drugs (OR 2.33, 95%, CI 1.02-5.66; p= 0.0493) have a significant
impact on 90-days mortality (Supplementary Table 5).
DISCUSSION
In this systematic review, we provided new insights into epidemiology, clinical and
microbiological characteristics, management approaches and outcomes of SOTR affected by
mucormycosis. Furthermore, our investigation confirmed the critical role of immunosuppression
in supporting disease development and influencing mortality rates within this vulnerable cohort.
Half of the reported cases originated from Asian countries, while North America and Europe
each contributed a fifth. This geographical distribution may be partly explained by the high
prevalence of type 2 diabetes in Asia, a well-known risk factor for mucormycosis, particularly
given that over 60% of the world's diabetic patients reside in this continent139. This factor likely
compounds with other risk factors among SOTR, further emphasizing the highlighted geographic
pattern. Moreover, countries undergoing rapid industrial and economic growth, such as China
and India, face social and environmental issues that significantly contribute to fungal diseases.
These issues, including air pollution, reduced biodiversity, and meteorological conditions, may
elevate host exposure to pathogens140. Finally, it should be noted that a substantial portion (16%)
of analyzed cases came from a large multicentre study in India138, which undeniably influenced
the overall geographical distribution of cases.
In line with previous studies4, mucormycosis was reported more frequently in KT recipients,
accounting for 51.8% of cases. This finding may be mainly attributed to the higher global
prevalence of KT, which accounts for 64% of SOT worldwide141. However, other factors may
also be at play. Firstly, diabetic nephropathy, accounting for more than 40% of KT142, persists as
a significant risk factor post-transplant due to ongoing impaired glucose metabolism and showed
a significant impact on 90-day mortality in our multivariate analysis. Secondly, KT candidates
are frequently hyperimmunized due to previous exposure to foreign antigens, particularly human
leukocyte antigens143. This poses a challenge because it increases the risk of hyperacute or acute
antibody-mediated post-transplant rejection, requiring specific immunosuppressive regimens or
strategies (e.g., plasmapheresis) that may increase the global "net-state of immunosuppression"
resulting in an enhanced infectious risk144. Finally, up to 30% of people who receive a KT will
experience some degree of rejection145, which exposes the patient to higher levels of
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immunosuppression and increases the risk of graft loss and the need for re-transplantation or
additional surgical procedures. Overall, it appears that immunosuppression, both iatrogenic and
related to the patient's underlying conditions, plays a pivotal role in driving the occurrence of
mucormycosis.
Concerning the transplant procedure, the onset of mucormycosis exhibited a dichotomous
distribution, with 63.7% of cases reported within 100 days of transplantation and 20.6%
diagnosed at least one year after SOT. These findings differ from the paradigmatic infection
timeline after SOT, which places the onset of invasive fungal disease at 6-12 months post-
transplant146. The prolonged state of immunosuppression undoubtedly contributes to developing
mucormycosis following SOT. Still, its onset appears to be influenced by the intensity rather
than the duration of the impairment of the immune system. Indeed, the reported cases were
characterized by a high prevalence of rejection (30%) and by the use of more than three
immunosuppressive drugs (71.6%). The latter significantly impacted 90-day mortality in the
multivariate logistic regression model (OR 2.33, 95%, CI 1.02-5.66; p= 0.0493).
Interestingly, we observed cases of infection in SOTR even when antifungal prophylaxis was
administered. While this observation is less relevant in instances where fluconazole or
voriconazole were used, since these agents are usually ineffective against Mucorales, it is
concerning to highlight that 12 cases were reported in patients receiving AmB, the first-line
agent for mucormycosis in patients without pre-existing renal disease147. Unfortunately, it was
impossible to verify the administration schedule or the dosage employed to understand the role
of sub-therapeutic drug concentration. Still, this data stresses the concept of possible
breakthrough mucormycosis despite ongoing prophylaxis with AmB, as already reported for
other invasive fungal infections, such as aspergillosis148,149. Where reported, antimicrobial
susceptibility testing (AST) showed a lack of activity for agents considered among the main
treatment options for mucormycosis. Particularly, AmB was inactive against the isolate in 30
reported cases, while posaconazole, the first-line agent (along with isavuconazole) for patients
with renal impairment, was inactive in 21 cases. These results highlight the importance of
obtaining the AST for the clinical management of patients with mucormycosis. They also
support the use of combination therapy as a first-line approach in cases where AST is
unavailable despite scarce evidence from available studies150.
Consistently with previous reviews of reported cases1,4, Rhizopus and Mucor spp. were the most
prevalent species. The landscape of mucormycosis aetiology will be shaped in the following
decades by climate change and mycology advances. The latter will allow the detection of cases
that would have been previously misdiagnosed or not identified. A recent study6 reported the
identification of a novel Apophysomyces species, highlighting the importance of collaboration
between clinicians, pathologists, and microbiologists to achieve timely diagnosis using a
combination of conventional culture, phenotypic and morphological analysis together with
molecular testing based on real-time PCR.
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The spectrum of manifestations in SOTR closely mirrors that reported in a recent systematic
review involving 851 patients, irrespective of underlying conditions. Pulmonary and rhino-
orbital-cerebral manifestations accounted for half of the cases (49.2%), whereas disseminated
disease was diagnosed in 10% of patients, compared to 54% and 13%, respectively, reported by
Jeong et al. Interestingly, we found a higher incidence of gastrointestinal manifestations (17%
versus 8%)4; this may be partially explained by the fact that abdominal surgery was performed in
most cases. Notably, the disseminated form showed a significant association with 90-day
mortality.
The predominant treatment approach involved combination therapy, with AmB as the backbone
followed by, or in combination with, an azole (most commonly posaconazole). The duration of
treatment exhibited heterogeneity, with initial intravenous therapy lasting a median of 40 days,
followed by oral step-down treatment for a median of 3 months. The optimal duration for
treating mucormycosis remains undefined and is often intricately linked with
immunosuppression management. Recent literature suggests a mean total duration of
approximately six months147, which is consistent with our findings. Shorter regimens in SOTR
are typically reserved for patients with relatively mild disease and in whom surgical debridement
has successfully achieved source control.
Surgery was indeed performed in half of the patients (49.2%). Analyzing the different
manifestations, patients with gastrointestinal, rhino-orbital-cerebral, and cutaneous forms
underwent surgery more frequently (62.1, 59.5 and 51.9%, respectively), while only 17.6% of
those with disseminated disease were treated surgically. As stated by recent international
guidelines, surgical treatment is the mainstay of mucormycosis management whenever viable,
leading to higher cure and survival rates147. Surgery can be separated into major groups:
debridement of the skin and soft tissue, debridement of rhino-orbital-cerebral mucormycosis,
orbital exenteration, lung resection, debridement of bone, and visceral resections in, for example,
liver, spleen, peritoneal structures, or transplanted organs. The surgical approach should be
timely and complete, requiring repeated resection or debridement.
In our analysis of reported cases, mucormycosis mortality rates at 3 and 12 months were
significant, as expected, particularly for pulmonary (43.2% and 69.2%) and disseminated (75%
and 93.3%) forms. However, with 63.4% of patients dying in one year, the overall mortality rate
for any manifestation of the disease was notable and higher than the 48% reported by Roden et
al. in the only available analysis that included details on SOTR1. These findings may be partly
explained by the predominance of reported cases from Asia, where the prognosis is reported to
be worse, and by changes in the characteristics of patients undergoing transplantation over the
last two decades.
Study limitations
Our study has some inherent limitations related to its design.
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Information was extrapolated from reports available in the literature, and missing data were
common, although attempts were made to obtain them by contacting the authors. In addition, our
study collects cases from all over the world and therefore presents a heterogeneity in terms of
epidemiology, risk factors and resources available for diagnosis and treatment.
Notably, up to 51.7% of cases come from Asia, predominantly India, where previous studies on
mucormycosis have shown a higher risk of infection with a worse prognosis, introducing a
potential bias.
Publication bias is also a limiting factor, as reports tend to describe rare or atypical disease
manifestations, potentially excluding more common findings. However, this issue may be
partially mitigated because we focused on SOTR, a specific population in which cases are more
likely to be reported, even if they have typical presentations.
Finally, despite the systematic search strategy, we have likely still missed cases aggregated in
more extensive larger series, including 35 SOT cases with COVID-19 associated mucormycosis
published as part of a larger metanalysis, for which at the time of literature search only a
published preprint was available which was missed by our manual search151.
CONCLUSIONS
In conclusion, our study represents the largest description of mucormycosis among SOTR
available in current literature. We have confirmed the severity of this condition and found a
significant association between its related mortality and the degree of immunosuppression
experienced by the recipient, along with better-known risk factors such as diabetes and
disseminated disease. Notably, we have brought attention to a previously overlooked peak in
occurrences during the early post-transplant period. It is incumbent upon the scientific
community to embark on further investigations to validate the robustness of these findings.
Specifically, there is an urgent call for comprehensive investigations, with mindful consideration
for potential antifungal prophylactic regimens tailored to combat agents responsible for
mucormycosis in carefully selected high-risk patients. This pursuit of additional empirical
evidence will strengthen our understanding of the ailment and contribute to refining preventive
measures, thereby advancing the overall care paradigm for SOTR.
ACKNOWLEDGMENTS
Author contributions: AL and EP conceived the research question and study design; AL, EP,
CA, MF, AM, GR and GV reviewed the articles and extracted the data; HK and AC provided
supplementary data on their cohort; MC performed the analysis; AL, EP and MC wrote the first
draft; AG and AB supervised the study; all authors contributed to and revised the submitted
version of the manuscript.
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Data availability: Data are available on reasonable request.
Patient consent: This study did not include factors requiring patient consent.
Financial support: This study was supported by the Italian Ministry of Health (Ricerca Corrente
Funds 2023 – Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico).
Potential conflicts of interest: The authors have no competing interests to declare.
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TABLES
Table 1. Epidemiological and clinical characteristics of solid organ transplant recipients with
mucormycosis.
Variable
Total (%)*
Sex
Male
136/183 (74.3)
Female
47/183 (25.7)
Age, IQR
Median
40.0, 40-56.5
Underlying condition at time of infection
Diabetes mellitus
73/173 (42.2)
Renal replacement therapy
30/137 (21.9)
Major trauma✝
18/183 (9.8)
CMV disease
10/183 (6.0)
Liver disease after SOT
10/137 (7.3)
WBC <500/mm3
3/183 (1.6)
Iron overload
2/165 (1.2)
Malignancies after SOT
2/137 (1.5)
SOT type
Kidney
93/183 (50.8)
Heart
34/183 (18.6)
Liver
31/183 (16.9)
Lung
19/183 (10.4)
Other§
6/183 (3.3)
Time since SOT
< 30 days
58/165 (35.2)
30-100 days
47/165 (28.5)
101-180 days
11/165 (6.7)
181-365 days
15/165 (9.1)
> 1 year
34/165 (20.6)
SOT complications
Rejection
46/149 (30.9)
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DOI: 10.1093/ofid/ofae043 23
Reoperation
27/178 (15.2)
Re-transplantation
18/178 (10.1)
Immunosuppressants, number of drugs
≤ 3 drugs
52/183 (28.4)
> 3 drugs
131/183 (71.6)
Antifungal prophylaxis
No
108/164 (65.9)
Yes
56/164 (34.1)
Antifungal agent used for prophylaxis#
Fluconazole
20/53 (37.8)
Amphotericin B
12/53 (22.6)
Terbinafine
6/53 (11.3)
Voriconazole
4/53 (7.5)
Anidulafungin
3/53 (5.7)
Flucytosine
3/53 (5.7)
Nystatin
3/53 (5.7)
Micafungin
2/53 (3.8)
CMV cytomegalovirus, SOT solid organ transplantation; IQR: interquartile range; WBC white blood cell
* percentage of the available records
✝ motor vehicle accident, surgery, natural disaster, open wound
§ Other: 2 multivisceral transplantations (stomach, liver, duodenum-pancreas, sma ll bowel, colon), 1 liver-pancreas,
1 liver-kidney, 1 kidney-heart, 1 kidney-pancreas
# 53 cases where antifungal agent used for prophylaxis wa s available
Table 2. Microbiological, clinical, and therapeutic characteristics of mucormycosis solid organ
transplant recipients.
Variable
Total (%)*
Organism identified
Rhizopus spp.
52/124 (41.9)
Mucor spp.
35/124 (28.2)
Lichtheimia spp. ✝
20/124 (16.1)
Cunninghamella spp.
6/124 (4.8)
Rhizomucor spp.
5/124 (4.0)
Apophysomyces spp.
4/124 (3.2)
Saksenaea complex
1/124 (0.8)
Other, unspecified
1/124 (0.8)
Disease manifestation
Pulmonary
42/171 (24.6)
Rhino-orbito-cerebral
42/171 (24.6)
Gastrointestinal
29/171 (17.0)
Cutaneous
27/171 (15.8)
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DOI: 10.1093/ofid/ofae043 24
Disseminated
17/171 (10.0)
Other#
14/171 (8.2)
Chest imaging
Lobular consolidation
28/80 (35.0)
Cavitary lesion
23/80 (28.8)
Disseminated
3/80 (3.8)
Solitary nodule
3/80 (3.8)
No lesion
2/80 (2.5)
Other
21/80 (26.2)
Antifungal agents administered
Amphotericin B
163/183 (89.1)
Posaconazole
49/183 (26.8)
Anidulafungin
4/183 (3.0)
Fluconazole
3/183 (1.6)
Isavuconazole
5/183 (2.7)
Ketaconazole
3/183 (1.6)
Micafungin
5/183 (2.7)
Nystatin
5/183 (2.7)
Voriconazole
9/183 (5.0)
Caspofungin
5/183 (2.7)
Itraconazole
2/183 (1.1)
Terbinafine
1/183 (0.5)
* Percentage of the available records
✝ Lichtheimia spp. formerly known as Absidia spp.
# Other disease localizations: 5 renal infections, 3 hepatic infections, 1 oral infection, 1 endovascular device
infection, 1 mediastinitis, 3 unspecified
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Table 3. Outcomes of 183 solid organ transplant recipients with mucormycosis.
Variable
Rhino-
orbito-
cerebral
(n=42)
Pulmonary
(n=42)
Cutaneous
(n=27)
Disseminated
(n=17)
Gastrointesti
nal (n=29)
Other
disease
localizati
on*
(n=14)
Total
(n=183)
Surgical
intervention
25/42
(59.5)
16/39
(41.0)
14/27 (51.9)
3/17 (17.6)
18/29 (62.1)
11/14
(78.6)
88/179
(49.2)
90-day
mortality
12/41
(29.3)
16/37
(43.2)
6/26 (23.1)
12/16 (75.0)
11/29 (37.9)
4/12
(33.3)
62/171
(36.3)
1-year
mortality
12/20
(60.0)
18/26
(69.2)
10/15 (66.7)
14/15 (93.3)
12/22 (54.5)
4/12
(33.3)
71/112
(63.4)
Need for
retransplant
0/18
(0.0)
2/23 (8.7)
0/14 (0.0)
1/14 (7.1)
2/20 (10.0)
1/12 (8.3)
6/102 (5.9)
Surgical
sequelae
2/18
(11.1)
0/22 (0.0)
2/13 (15.4)
1/12 (8.3)
3/20 (15.0)
1/12 (8.3)
9/98 (9.2)
* Other disease localizations: 5 rena l infections, 3 hepatic infections, 1 oral infection, 1 endovascular device
infection, 1 mediastinitis, 3 unspecified.
FIGURE LEGENDS
Figure 1. PRISMA diagram depicting the case selection process.
Records identified through
database search (n = 1013)
Titles and abstract screened
(n = 998)
Irrelevant records excluded
(n = 716)
Full-text articles assessed for
eligibility
(n = 282)
Full-text excluded (n = 151)
- Literature reviews or meta
analysis (n = 67)
- Not enough or irrelevant data
(n = 66)
- Full text unretrievable (n = 8)
- Articles not in English (n = 5)
- Paediatric patients (n = 5)
Studies included in final analysis
(n =130)
Identification
Screening
Included
Duplicates removed (n = 15)
Identification of studies via databases and registers
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DOI: 10.1093/ofid/ofae043 26
Figure 2. Geographical distributions of mucormycosis cases in solid organ transplant recipients
included in our review. The higher the colour intensity, the higher the number of patients
reported from the country.
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DOI: 10.1093/ofid/ofae043 27
Graphical abstract
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