Epidemiology of Visceral Mycoses in Patients with Acute Leukemia and Myelodysplastic Syndrome: Analyzing the National Autopsy Database in Japan
Authors: Togano Tomiteru , Suzuki Yuhko , Tse William , Kume Hikaru 
Published: October 2019

Abstract
【Introduction】
Visceral mycoses (VM) are deadly infection and commonly occur in the severely immunocompromised hosts such as in patients with acute leukemia and myelodysplastic syndrome (MDS). To investigate the prevalence of visceral mycoses, we retrospectively analyze the data reported to the "Annual Report of Autopsy Cases in Japan" that includes nationwide autopsy cases published yearly by the Japanese Society of Pathology.
【Method】
We analyzed all the autopsy data from patients with acute leukemia and MDS included adult T-cell leukemia (ATL) reported in the "Annual Report of Autopsy Cases in Japan" between 1989 to 2015. These data also include patients received hematopoietic stem cell transplantation (SCT). Cases involved stillborn babies or inconclusive in diagnoses are excluded in current analysis. Severe cases were defined as follows: (1) direct cause of death, (2) severe pulmonary infection involving both lobes of the lung, (3) severe visceral infections of 2 or more organ systems, including those involving the central nervous system, (4) multiorgan systemic infection of 3 or more, or (5) a case described as fungemia.
【Result】
There are total of 175,615 autopsy cases in the data bank and about 7183 cases (4.1%) are acute leukemia and MDS patients. While visceral mycoses were only found in 7756 cases (4.4%) in total cases, there are 1,562 cases (21.7 %) in acute leukemia and MDS, nearly 6-fold higher in prevalence compared with none acute leukemia and MDS cases.
Among cases confirmed by single infected pathogen, Aspergillus spp. is the most predominant causative agent (45.0%), while Candida spp. is the second (22.7%). The prevalence of Aspergillus spp. was increased and peaked around 54.0% between 2001 and 2005, then gradually decreased since with more significantly in recent years. Candida spp. was also steadily decreased yearly and bottomed out in 2013. Overall, prevalence is half in Candida spp. and doubled in Mucor spp. compare with 30years ago.
Complicated infections cases were founded in 6.5% of patients with acute leukemia and MDS. The most frequent combination is Candida spp. plus Aspergillus spp. (59.8%), while next Mucor spp. plus another spp. (27.0%) and such combination has a trend of gradually increasing since 1997.
Most of the severe cases are patients with acute leukemia and MDS presented as visceral mycoses (62.2%). Among them the frequency was 55-67% in Aspergillus spp., Candida spp. and Cryptococcus spp. in severe cases. Otherwise, it was 70-75% in Mucor spp. and complicated cases. After reached the peak of incidence in 2005, the prevalence of Aspergillus spp. has been decreased since 2009.
Moreover, we also analyzed the 1098 autopsy cases on patients received stem cell transplantation. 294 cases are found to have visceral mycoses (26.8%). It was 378 cases with GVHD, and visceral mycoses were 23.3% with GVHD group. Prevalence is not decrease in total of SCT cases. Otherwise, it has been decreased in GVHD cases. Aspergillus spp. is the most common (51.6%) and Candida spp.was 19.4% in SCT cases. Interestingly, Candida spp.was more popular than before and the same frequency as Aspergillus spp. with GVHD cases in 2015.
【Discussion】
A limitation of this study is a retrospective epidemiology from the national archived autopsied cases that may bias towards the severely fatal fungal infection spectrum. Nonetheless, we believe this epidemiological analysis of the autopsied cases with fungal infection provides a strong evidence and incentive to intensify efforts in diagnosing and treating visceral mycosis. Comprehensive prophylaxis or pre-emetic treatment for visceral mycoses may be necessary for selective patients who are undergoing long-term immunosuppressive agent for acute or chronic GVHD, especially the emergence of the non-Candidaalbicans spp. recently as a breakthrough infection that is due to decades of widely use of fluconazole in these patient populations.
【Conclusion】
Our study is a long-term nationwide study of endemics of visceral mycoses among significant immunosuppressive patients. More recently frequent agents were Mucor spp. in leukemia and MDS, and especially Candida spp. with GVHD. Our data provide valuable evidence that antifungal treatment is one of the most important treatments for leukemia and MDS, and SCT.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.