Editor’s Note: Solid Organ Transplantation (SOT) is a crucial procedure for saving the lives of patients with end-stage organ failure. In recent years, the field of SOT has flourished in China, with significant improvements in the number of transplants and treatment outcomes. However, infections remain a critical factor affecting the survival and quality of life of SOT recipients. Among these, the incidence and mortality rates of invasive fungal diseases (IFD) are particularly high, especially among lung transplant recipients. At the recent 4th National Conference on Bacterial and Fungal Infections organized by the Chinese Medical Association (BISC 2024), the journal “Infection Medicine Today” had the opportunity to interview Professor Chunrong Ju from The First Affiliated Hospital of Guangzhou Medical University. Professor Ju shared her expert insights on the prevalence, current treatment landscape, and diagnostic challenges of IFD in SOT recipients, as well as discussed strategies for improving treatment outcomes through precision medicine.
Infectious disease frontier : As we know, IFD in SOT recipients is currently a disease with high infection and mortality rates, severely threatening the lives and health of lung transplant patients. Could you please discuss the current prevalence and treatment status of this disease in China?
Professor Chunrong Ju: China’s organ transplantation efforts are undergoing rapid development. With the widespread use of corticosteroids and immunosuppressants, the incidence of invasive fungal diseases (IFD) after solid organ transplantation (SOT) is gradually increasing. The incidence of IFD varies among different organ transplant recipients: it is higher among small intestine and lung transplant recipients, and relatively lower among pancreas and kidney transplant recipients. Globally, the average incidence of IFD among SOT recipients ranges from 4.6% to 7.5%, with significant variations depending on local epidemiological characteristics, diagnostic strategies, and antifungal prevention measures. Overall, the incidence of IFD in SOT recipients is on the rise, and the cumulative incidence increases over time after transplantation. Data specific to China is limited, but a study by the Guangzhou Respiratory Health Institute on thoracic organ transplant recipients in Southern China found that 36.3% of lung transplant recipients experienced at least one IFD during their lifetime.
Regarding the risk factors for the rising incidence of IFD in SOT recipients, besides the use of postoperative corticosteroids and other immunosuppressants, infections originating from donors are also significant, especially as China fully enters the era of organ donation. Changes in the high-risk population have led to shifts in the pathogen composition of IFD, with non-Candida species causing invasive candidiasis, invasive aspergillosis, mucormycosis, and other fungal infections increasingly on the rise. In light of the current situation, timely and accurate diagnosis and proactive, precise treatment are especially crucial.
Aspergillus is the most common pathogen in SOT recipients and the primary cause of IFD in lung transplant recipients. The median time to diagnose invasive aspergillosis is 168 days, but it can appear immediately after transplantation and last up to 720 days. Recent studies have shown that respiratory viral infections, particularly influenza and COVID-19, significantly increase the incidence of aspergillosis and mucormycosis, making both viral infections high-risk factors for IFD. SOT recipients are at high risk for respiratory viral infections and IFD, putting them at a significantly higher risk of developing IFD compared to the general population.
Mucormycosis and Cryptococcus also play significant roles in IFD among SOT recipients. In particular, mucormycosis infections have recently surpassed those caused by Cryptococcus. Over the past 3-4 years, COVID-19 has further increased the incidence of mucormycosis. A study in India among kidney transplant recipients indicates that mucormycosis has become a common IFD in this group, with an infection rate of up to 10.7%.
With changes in high-risk populations, the composition of IFD pathogens has also shifted, with increasing incidences of invasive diseases caused by non-Candida fungi, Aspergillus, and other molds. For SOT recipients, polymicrobial infections involving a combination of multiple bacteria, fungi, and viruses are common. It’s not uncommon to see patients with both aspergillosis and mucormycosis infections. However, the current clinical challenge remains the early diagnosis and preemptive treatment of IFD. Although advancements in molecular biology have significantly improved the diagnosis rates of IFD, there is still no diagnostic method that achieves high sensitivity and specificity in the early stages of the disease for a rapid, sensitive, and accurate diagnosis of IFD.
Infectious Disease Frontier: Given the need for precise diagnosis and preemptive treatment of IFD in SOT recipients, what unique insights can you provide regarding precision medicine in current clinical practice?
Professor Chunrong Ju: With continuous improvements in diagnostic and therapeutic levels and the introduction of new antifungal medications, the strategies for diagnosing and treating IFD in SOT recipients are constantly evolving. Precision medication for SOT recipients with IFD not only saves lives but also maximally enhances the quality of life and reduces healthcare costs. Key considerations include:
When SOT recipients develop IFD, most are in a state of immunosuppression and/or critical condition. The choice of treatment should be based on the characteristics of the transplanted organ, the severity of IFD, the presence of systemic dissemination, the patient’s age, time post-transplant, the body’s immune status, and the risk of rejection reactions, among other factors. Generally, a comprehensive assessment based on these factors is performed when IFD is clinically diagnosed, followed by adjustments to the patient’s immune status, aiming to prevent transplant rejection while minimizing the intensity of immunosuppressants.
The treatment of IFD in SOT recipients adopts a tiered approach, categorized from low to high level as empirical treatment, clinical diagnosis treatment, confirmed treatment, and intensified treatment. Among these, clinical diagnosis treatment involves continuous monitoring (both imaging and microbiological studies) of transplant recipients identified as high-risk due to host factors, environmental factors, or clinical characteristics. Antifungal treatment begins immediately upon positive results, preventing treatment delays due to immunosuppression and also avoiding the overuse and misuse of medications typically seen with empirical treatment. This has become a primary antifungal treatment strategy in clinical settings.
The selection of antifungal medications must meet three prerequisites: (1) choosing the appropriate type of antifungal that can cover the responsible pathogens; (2) ensuring the selected antifungal can reach the site of infection and achieve high tissue concentration there; (3) selecting the appropriate drug dosage and administration method to ensure good bioavailability, maintaining serum drug concentrations within the optimal therapeutic range.
New infections by Candida auris pose a significant risk to the SOT population, particularly due to its potential to cause bloodstream infections. Initial empirical treatment may involve echinocandin class drugs, but it is crucial to perform susceptibility testing and consider the results seriously. Although data supporting routine combination therapy is lacking, combination treatments may be beneficial for refractory cases.
SOT recipients often use long-term calcineurin inhibitors (CNI) such as tacrolimus or cyclosporine A, and other chronic disease medications like antihypertensives and antidiabetics. Therefore, when using antifungal medications, it is essential to monitor for drug interactions to minimize adverse reactions. For instance, voriconazole and posaconazole can significantly increase the levels of CNIs like tacrolimus, potentially leading to drug toxicity and various complications, including renal damage. Moreover, rifampin should be avoided if tuberculosis is suspected or confirmed because, as a potent hepatic enzyme inducer, it can reduce the levels of CNIs and azole drugs, leading to rejection or failure of antifungal treatment. Additionally, azoles should not be used concurrently with anticoagulants like rivaroxaban and statins like atorvastatin; if necessary, doses of the anticoagulant and lipid-lowering drugs should be adjusted to avoid bleeding events or rhabdomyolysis.
Alongside antifungal treatment, managing the underlying disease or removing high-risk factors is crucial. For instance, in cases of candidemia, it is vital to promptly remove or replace related central venous catheters. For invasive mucormycosis and aspergillosis, addressing the underlying conditions is key, including controlling blood sugar, correcting acidosis, increasing granulocyte levels, and reducing or discontinuing corticosteroids wherever possible. In treating mucormycosis, along with eliminating high-risk factors for aspergillosis, attention should be paid to iron overload and unnecessary long-term use of voriconazole, and consider early surgical intervention (including local debridement or resection of infected tissues or organs) where feasible.
Treatment doses and methods should be precisely tailored based on the patient’s condition and the drug’s side effects. When renal function is impaired, the use of amphotericin B formulations should be cautious, and injectable triazoles containing cyclodextrin (like voriconazole and posaconazole) should be avoided.
Professor Chunrong Ju
First Affiliated Hospital, Guangzhou Medical University
Professor, Chief Physician, PhD Supervisor, Postdoctoral Co-Supervisor
Vice Chair of the 4th Committee of the Guangdong Provincial Organ Transplantation Branch, Chinese Medical Association
Chair of the Immunodeficiency Committee, Guangdong Provincial Primary Medicine Association
Vice Chair of the Youth Committee of the Guangdong Branch of the Chinese Medical Association for Respiratory Diseases
Member of the Lung Transplantation Group, Organ Transplantation Branch, Chinese Medical Association
Member of the Perioperative Group, Organ Transplantation Branch, Chinese Medical Association
Quality Control Committee Member, National Health Commission’s China Lung Transplantation Quality Control Center
Deputy Head of the Pulmonary Medicine Quality Control Committee, National Health Commission
Member of the Organ Transplant Recipient Health Management Committee, China Organ Transplant Development Foundation
Standing Committee Member, Thoracic Transplantation Committee, Guangdong Thoracic Disease Society
Vice Chair of the Diffuse Parenchymal Lung Disease Committee, Guangdong Province
Member of the Critical Care and Infection Group, Guangdong Medical Doctor Association
Visiting Scholar, Organ Transplant Center, University of Toronto, Canada
Recognized as one of the first batch of young medical leaders in Guangdong Province.
