Invasive Fungal Disease in Transplantation: Prevention in a Shifting Landscape

For a patient recovering from a lifesaving transplant, an invasive fungal disease (IFD) can derail months of progress in just days. Depending on the transplant type, more than 1 in 12 patients may develop an IFD within the first year of transplantation.^1,2 Even with modern antifungals, IFDs still kill approximately 1 in 3 patients.^1,2

Despite the public health and clinical importance of IFDs, we still do not have a clear understanding of exactly which patients undergoing transplant will contract them and why. That is because surveillance for IFDs in transplant populations is limited or altogether lacking, leading to an unclear national and global picture. The most comprehensive study of IFDs in US patients undergoing transplant comes from the Transplant-Associated Infections Surveillance Network (TRANSNET), which conducted surveillance for IFDs among solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients at a network of 23 transplant centers from 2001 to 2006.^1,2 Since then, data on the epidemiology and risk factors for IFDs in transplant recipients have been limited to much smaller studies, primarily at single centers.^3-5

This is problematic because the types and rates of fungal infections in transplant recipients may vary widely among centers based on geography, climate, and local clinical practices.⁶ As a first step in addressing this data gap, we explored a large commercial health insurance claims database to provide updated benchmark data.⁶ Although our study had important limitations, especially with representativeness and its reliance on International Classification of Diseases, Tenth Revision codes, we gained insight into current IFD epidemiology. Classically, IFDs in patients undergoing transplant have been characterized by early Candida infections followed by later Aspergillus infections.^1,2,7,8

In our analysis, candidiasis still generally occurred earlier than invasive mold infections for both SOT and HSCT recipients. Notably, patients undergoing HSCT in our study experienced infections later (169 days for candidiasis and 172-349 days for other IFD types) than patients undergoing HSCT in the TRANSNET study (61 days for candidiasis and ~100-150 days for other IFD types).² We also found that a higher-than-anticipated percentage of IFDs were due to invasive mold infections compared with invasive candidiasis, particularly in patients undergoing SOT.⁶

IFDs caused by blastomycosis, coccidioidomycosis, and histoplasmosis were more frequent in both SOT (15.6%) and HSCT (4.1%) recipients than previously reported in the TRANSNET study, where these diseases made up 5% or less of IFDs in SOT recipients and less than 1% in HSCT recipients.⁶ This is a notable finding given that recent data have demonstrated a substantial expansion of the traditional geographic areas associated with these so-called endemic fungi.⁹ We also found that aspergillosis and mucormycosis were highest in the Northeast among SOT recipients, highest in the West among HSCT recipients, and lowest in the South for both groups, which merits further study and underscores the importance of understanding geographic epidemiologic trends.⁶ The epidemiology of IFDs is shifting, both in infection types and in species’ resistance profiles.¹⁰ Although studies specifically examining transplant populations are generally lacking, several major trends have emerged. Candida albicans has been declining as the main causative organism of candidemia, which is concerning, as non-albicans species can be associated with poorer outcomes and more frequent antifungal resistance.^11,12 Breakthrough invasive yeast infections on fluconazole prophylaxis and the rise of fluconazole-resistant Candida parapsilosis and echinocandin-resistant Candida glabrata have complicated treatment of many transplant recipients.¹³ Further, highly drug-resistant fungal pathogens such as Candida auris have recently emerged and rapidly spread globally, prompting concern about the potential impact on the transplant population.¹⁴ For mold infections, the rise of rare and difficult-to-treat molds such as Fusarium and Lomentospora has been noted in recent years among immunocompromised hosts despite the use of antifungal prophylaxis.¹⁵ The past few decades have also witnessed the devastating effects of health care–associated outbreaks of rare mold infections linked to environmental contamination of water sources, hospital construction, and even bed linens.^16-19

However, the transplantation care community has achieved notable success in preventing IFDs in transplant recipients. The use of fluconazole in patients undergoing HSCT has substantially reduced the incidence of early candidemia.²⁰ Moldactive azoles, such as voriconazole and posaconazole, have proven effective in decreasing the occurrence of invasive aspergillosis among patients with high-risk disease undergoing HSCT.²¹ Certain SOT populations, particularly lung and liver transplant recipients, also benefit from targeted antifungal prophylaxis strategies.²² Beyond antifungal prophylaxis, the transplantation care community has also made major strides in enhancing the safety of health care environments for patients. The implementation of high-efficiency particulate air (HEPA) filtration systems and positive pressure rooms has been an essential strategy for minimizing exposure to airborne fungal pathogens.²³

Increased awareness and proactive measures to prevent outbreaks related to construction activities and health care linens have further protected patients from health care–associated mold infections.^18,24 Infection prevention and control measures, including improved care for central lines, have also contributed to a reduction in Candida bloodstream infections.¹² With the successes of antifungal prophylaxis have come unanticipated new challenges and potential obstacles. Prophylaxis may contribute to increased incidence of breakthrough mold infections, particularly those involving Mucorales and Fusarium.^25,26 These infections may require treatment with different and often more toxic antifungals and have a high associated mortality.¹⁵ Selection pressure from fluconazole use may be driving a shift to non-albicans species.²⁷ Challenges with toxicity and drug interactions persist, such as difficulties in tolerating trimethoprim-sulfamethoxazole for Pneumocystis pneumonia prophylaxis and the myriad of toxicities associated with voriconazole and other triazoles.^28,29

In addition, new drugs for preventing graft-vs-host disease or cancer relapse after HSCT can lead to important drug-drug interactions with common antifungals.³⁰ Finally, these antifungal prophylaxis medications are often costly and challenges with insurance coverage frequently impede access.³¹ Thus, it is important to incorporate antifungal stewardship efforts at any transplant center to ensure that the right patient is receiving the right medication at the right time.³² Novel targeted and pan-fungal molecular tests represent real progress. However, these tests remain unavailable in many clinical settings and culture remains the gold standard.³³ Continued development of new diagnostic technologies in the field of mycology is critical especially for rapid detection of antifungal resistance given the rise of this phenomenon globally.³⁴

The application of diagnostic stewardship to guide clinicians in the optimal use of these new tests will be a valuable component of care moving forward.³⁵ We still have room for improvements in managing environmental conditions. HEPA filtration systems are important for keeping patients safe, but hospital surveillance for invasive mold diseases is variable among facilities and standardized approaches and evidence for effective environmental mold monitoring are lacking.³⁶

In addition, a shift toward performing HSCT procedures outside of the hospital setting may affect the risk for fungal infections in the future, and close monitoring of these patients is warranted.³⁷ Counseling patients about the potential risks of IFD in the community and how to avoid them is a critical part of transplant care.³⁸ To effectively prevent IFDs and assess the success of our prevention efforts, we need to understand disease epidemiology. Specifically, rigorous epidemiological studies that use standardized case definitions and integrate detailed information on environmental factors, electronic medical record data, and prophylaxis practices could greatly enhance our understanding of who is at risk and which prevention strategies are most effective.^39,40 These comprehensive data could help us continuously refine our strategies— both pharmacologic and nonpharmacologic— tailored to the evolving landscape of IFDs. As new drugs, an increasing number of patients undergoing transplant, innovative practices, and advanced technologies emerge, adapting our approaches accordingly could help ensure optimal IFD prevention and management.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

References

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