PREreview del Real burden of mucormycosis diagnosed over five years in a French medical center : a retrospective study

Summary 

This preprint presents a novel addition to clinical literature about mucormycosis, a rare but severe invasive mold related infection with a high mortality rate of up to 79%. This disease affects immunocompromised individuals, namely those with other underlying health conditions like diabetes, neutropenia, and those who have received solid organ transplantation (SOT) or allogenic hematopoietic system cell transplantation (BMT). This study sought to investigate the risk factors associated with the development of mucormycosis, and the methodology needed to improve diagnosis, prognosis, and treatment of mucormycosis for future individuals. 80 individuals from France were included in a retrospective study from 2017-2022, including only those who presented with at least one positive mucorales sample from the study’s lab. The authors then collected participant epidemiological and clinical background, including additional disease presence, length of hospitalization, delay of diagnosis, treatment type, and incidence of in-hospital death. Authors also identified risk factors associated with proven or probable mucormycosis over possible mucormycosis. Authors found that the risk factors relevant to death by mucormycosis include differences in ICU admission, length of hospital stay, and existence of neutropenia. This manuscript presents a study conducted of the often overlooked rare and fatal fungal infection, illuding to its novelty regarding disease prevention and diagnosis. Further research regarding PCR usage in diagnosis and the potential to lower in-hospital mortality rates makes this preprint a significant piece to be published, given that the offers clarify some issues seen in the methods and results section. Although small in size and some missing data, this preprint is a novel and necessary addition to the research of mucormycosis, and may aid in disease prevention and treatment. 

Major Issues 

Methods

• Case definitions need supplemental information. Two points of improvement:

  • The authors do a good job at explaining criteria for the different types of mucormycosis cases included in study: proven, probable, or putative. To round out definitions, I would add a definition for proven mucormycosis, as well as an explanation bout why possible cases were not included. I would touch on how you know that these “possible” individuals won’t test positive for mucormycosis later. 

  • I would also include additional information about the different types of mucormycosis, including pulmonary and disseminated mucormycosis. Are there any differences in extent of disease based on different stages/type of mucormycosis?

• I noticed some inconsistency under statistical methods paragraph of methods section, where the authors do mention possible cases of mucormycosis:

  • “Univariate analyses were conducted for the first two objectives to identify risk factors associated with a proven, probable or possible diagnosis of mucormycosis, and to assess risk factors for in-hospital mortality” 

  • Is possible diagnosis of mucormycosis being included in study? Perfectly acceptable if so, but I would suggest refining study criteria if so. Or, if possible diagnosis is not being included in overarching testing, explain why it is included in initial univariate analyses. 

• The “real burden of mucormysis” is not defined by end of paper. I would ask the authors to clarify what they believe the “burden” of the disease is, and include additional statistics such as DALYs, YLLs, QALYs, and other adjusted metrics to fully illustrate the burden of disease beyond mortality rates. 

  • I would recommend adding a reference or two to clarify the extent of the disease, and the burden that mucormycosis presents to study and/or global population. 

  • One possible reference for use: 

    • Cornely OA et al., Mucormycosis ECMM MSG Global Guideline Writing Group. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019 Dec;19(12):e405-e421. doi: 10.1016/S1473-3099(19)30312-3. Epub 2019 Nov 5. PMID: 31699664; PMCID: PMC8559573. 

Results

• Confidence intervals are very large (see Table 4). The authors do a good job of addressing the size of confidence intervals (e.g., 1.67–165.58) and suggest that this is due to missing data and logistic regression estimates. Tor further supplement this, I would suggest that the authors go further and question if their model is underpowered or affected by sparse data bias, and if they still believe that their findings are significant. 

  • Some food for thought: would simplifying the regression model or performing penalized logistic regression result in more stable estimates?

  • Or, providing univariate associations or sensitivity analyses could demonstrate that the observed relationships remain consistent despite uncertainty. It would also strengthen the discussion to emphasize that these estimates should be viewed as exploratory, rather than confirmatory, due to limited power.

  • No need to do any of these additional tasks, but suggesting this for future edits to help reaffirm results of current study

Minor Issues

Results

• The authors should add axis titles for Figure 2, as “Dim1” and “Dim2” are not clear.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they did not use generative AI to come up with new ideas for their review.