The European Hematology Association (EHA) Guideline Committee recently agreed to review
the Global Guideline for the Diagnosis and Management of Rare Mold Infection of the
European Confederation of Medical Mycology (ECMM) in cooperation with International
Society for Human and Animal Mycology (ISHAM) and American Society for Microbiology
(ASM).
1
External reviews from independent experts were obtained in a standardized review process
and the EHA decided to endorse the guideline.
With increasing numbers of immunosuppressed patients at risk for opportunistic infections,
mycoses caused by molds other than Aspergillus or Mucorales are on the rise.
2
Infections with rare molds possess several challenges for diagnosis and treatment
and require complex multidisciplinary management.
3
All invasive fungal diseases meet the definition of orphan diseases—an absolute frequency
in the population of less than 1 in 2000—and therefore, resources remain more limited
than in other areas of medicine. Guidance for optimal management is urgently needed.
On that background, the ECMM has set out an unprecedented orphan diseases guidance
initiative including all disciplines involved in diagnosis and treatment of invasive
fungal infections.
4,5
Previous guidelines on rare molds were limited to individual pathogens, focused on
specific groups of patients such as those with hematological malignancies, or were
missing altogether for infections caused by many of the very rare, but emerging pathogenic
molds. The current ECMM Guideline is therefore an ambitious and unprecedented effort,
as invasive mold infections caused by Fusarium spp., Lomentospora spp., Scedosporium
spp., dematiaceous molds causing phaeohyphomycosis, Rasamsonia spp., Scopulariopsis
spp., Penicillium spp., nonmarneffei Talaromyces spp., Paecilomyces spp., Purpureocillium
spp., and Schizophyllum spp. as well as other basidiomycetes have been covered in
detail.
1
The endorsement of the EHA is of particular importance as fungal infections significantly
contribute to morbidity and mortality in patients with hematological malignancies
or those undergoing hematopoietic stem cell transplantation.
6
Although numerically rare in the general population, frequencies of invasive fungal
infections are much higher in immunocompromised patients and with treatment advances
for underlying diseases as well as more common fungal infections such as invasive
aspergillosis, treating physicians are increasingly confronted with less common and
often multiresistant molds. The epidemiology of many of these rare and emerging infections
is still not well studied, as data on incidence and prevalence are scarce and show
high variability depending on geographical region and availability of diagnostic approaches.
However, the ubiquitous environmental distribution of filamentous fungi and expanding
patient populations with immunosuppression fosters the emergence of these infections,
changing the epidemiological landscape lately (Figure 1). Various other drivers, such
as new diagnostic utilities and the selective pressure caused by widespread antifungal
use, including antifungal prophylaxis, accelerate this process.
7
Figure 1.
Worldwide distribution of reported rare mold infections. Number of reported cases
of severe fungal infections caused by fungi of the genera Fusarium, Paecilomyces,
Penicillium, Phaeohyphomycetes, Purpureocillium, Rasamsonia, Scedosporium, Lomentospora,
Schizophyllum, Scopulariopsis, and Talaromyces in humans as provided for each pathogen
separately in the Rare Mold Global Guideline are presented in a concatenated format
for a general overview of the worldwide distribution. The map provides a current view
on published cases that is likely related to the medical infrastructure and economic
resources in some countries. Numbers are not supposed to predict incidences per country.
Most of the emerging molds cause severe disseminated disease in critically ill and
immunocompromised patients and possess multiple challenges in diagnosis and management.
Diagnosis requires a high index of clinical suspicion, mycological expertise, and
accurate diagnostic methods. Knowledge on epidemiology, risk factors, and clinical
characteristics can facilitate diagnosis. In hematological patients, fusariosis frequently
manifests systemically with positive blood cultures and disseminated disease characteristically
presents with necrotic erythematous skin lesions.
8
Hematological malignancy and its treatment are also major risk factors for infection
with Lomentospora spp. and Scedosporium spp. Dissemination of lomentosporiosis is
detected in more than 80% of hematological patients, and mortality is devastating,
mostly above 90%. Endocarditis and cerebral infection are frequently seen in disseminated
lomentosporiosis, while patient with scedosporiosis predominantly present with pulmonary
or cutaneous infections. Underlying malignancy predicts worse outcome for both lomentosporiosis
and scedosporiosis.
9
Infections caused by Rasamsonia spp. have been reported mainly in patients with chronic
granulomatous disease or underlying malignancy and predominantly affect the lungs
with high mortality rates.
10
These examples demonstrate the importance of rare molds as etiological agents of life-threatening
infections in a hematological setting. Appropriate prophylaxis and treatment in this
vulnerable group of patients are complicated by the fact that several rare molds are
intrinsically resistant against classes of antifungals. This includes Fusarium, Lomentospora,
and Scedosporium spp. as well as even less common emerging molds such as Rasamsonia,
Scopulariopsis, Paecilomyces, and Purpureocillium spp. Prompt and accurate classification
at species level is therefore indispensable to tailor treatment based on individual
susceptibility profiles. Optimization of the complex multidisciplinary management
of these infections has the potential to improve prognosis.
The present ECMM recommendations are part of the “One World – One Guideline” initiative
to incorporate regional differences in epidemiology and management.
4,5
Available diagnostic and therapeutic options differ across global regions and guidance
needs to reflect this to optimize patient management. Utilizing the global network
of the ECMM and together with the International Society for Human and Animal Mycology
and the American Society for Microbiology, medical professionals from around the world
contributed their expertise and analyzed published evidence to develop global guidance
for diagnosis and management of rare mold infections. Guidance is stratified for high-
and low-resource countries and therefore applicable worldwide.
Due to the rarity and heterogeneity of emerging molds, the field still lacks high
quality of evidence in several critical areas affecting the management of our patients.
Nevertheless, medical professionals representing the fields of dermatology, infectious
diseases, intensive care, hematology, microbiology, pathology, pediatrics, pharmacology,
radiology, and surgery, and have put maximum effort to generate a balanced and effective
tool to facilitate clinical decision-making. This guideline is therefore expected
to be of substantial help to clinicians dealing with rare mold infections worldwide.
Simultaneously, the guideline provides an overview of the areas of uncertainty for
invasive mold infections and new directions of future research. The endorsement of
the EHA is very encouraging and emphasizes the importance of rare mold infections
in patients with hematological malignancies.
Disclosures
The authors declare no conflicts of interest.