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Diagnosis and management of fungal infections in solid organ transplant recipients in South Asia

Introduction

Solid organ transplant (SOT) recipients in South Asia frequently contract fungi infections. After urinary tract infections and tuberculosis, invasive fungal infections (IFI) are the third most frequent cause of infections in SOT recipients in South Asia. IFI are a substantial source of morbidity and mortality in this population. Numerous problems, including lack of knowledge, poor physician training, inadequate laboratory assistance for infection diagnosis, and occasionally an absence of suitable antifungal drugs to treat infections, contribute to the poor outcomes of these patients. In India, invasive candidiasis is the most prevalent IFI, followed by invasive aspergillosis, mucormycosis, and cryptococcosis. Azole resistance and multi-drug resistance are becoming more common among candida infections in South Asia. When treating various fungal infections, it is important to keep in mind that azoles and tacrolimus, cyclosporine, and everolimus have medication interactions. How to evaluate and care for donors and recipients before admitting them for transplants, as well as how to manage transplant patients afterward, present additional challenges. Finally, by raising awareness among transplant doctors, expanding access to better diagnostic tools, and using appropriate antifungal medications to treat these infections, the outcomes of these patients can be improved.

Candidiasis

Epidemiology

Data has shown that 50% of the global cases of candidemia have been reported from Asia.[2] The incidence of candidemia varies from 1 to 12/1000 admissions in India. An Indian case series of 64 postliving donor liver transplant patients showed that 38 (59.5%) patients had 103 infectious episodes – 10 patients had single infectious episode and 28 patients had two or more infectious episodes. Candida infections were seen in 7 (6.8%), of which C. albicans and C. tropicalis were the most common. A case series on infectious complications in renal transplant recipients in India showed that after urinary tract infection and tuberculosis, candidiasis was the next most found infection amounting to 15.6% of infections.

Risk factors

Candida infection is more frequently observed in abdominal transplant recipients (liver, kidney, and kidney-pancreas), likely a consequence of Candida colonization of the gastrointestinal tract. Established risk factors for invasive Candidiasis include older age, broad-spectrum antibiotic therapy, central venous catheters, parenteral nutrition, prolonged neutropenia, prolonged ICU stay, diabetes, renal replacement therapy, and Candida colonization.

Management

Renal Transplant

Treatment of renal allograft recipients from donors with candiduria should consist of a tailored antifungal agent for urinary tract involvement. Urinary levels of fluconazole exceed minimum inhibitory concentration values for most Candida species. Renal transplant recipients were previously considered to have a higher risk for ascending infection following asymptomatic candiduria.

Lung Transplant

Candida isolated from the respiratory tract represents colonization and should not be treated. Except in lung transplant recipients with Candida tracheobronchitis, nebulized Amp-B should be continued until bronchoscopic evaluation confirms the integrity of the bronchial anastomosis.

Cryptococcosis

Epidemiology

There is not much literature on cryptococcosis in SOT recipients in South Asia. Globally, approximately 8% of IFIs in SOT recipients are due to cryptococcosis.

Risk factors

Among SOTs, lung transplant recipients are at the highest risk for cryptococcosis. Increasing age, prior transplant failure or rejection, congestive heart failure, and liver disease are independent risk factors for in-hospital death. Calcineurin-inhibitors, the mainstay of immunosuppression in SOT recipients, alter the manifestations of cryptococcal disease, as patients are more likely to have pulmonary rather than disseminated cryptococcosis.

Management

Comprises four key components

1. Lumbar puncture (LP) to assist with evaluation and management of CNS involvement and increased intracranial pressure; sometimes serial LPs are needed

2. Antifungal therapy:
• CNS disease, disseminated disease, or moderate-severe pulmonary disease: Induction therapy with lipid amphotericin B plus 5-flucytosine followed by consolidation and maintenance therapy with fluconazole
• Asymptomatic or mild-to-moderate disease: Fluconazole

3. Adjunctive therapies – the role of dexamethasone currently unclear

4. Immunosuppression reduction – gradual tapering such that there is the eradication of infection with preservation of allograft function.

Timing of retransplantation for solid organ transplant recipients with graft failure post-crypotococcosis For SOT recipients with graft failure post-cryptococcosis, ideal timing of re-transplantation is unknown. Re-transplantation can be considered after 1 year of antifungal therapy. Individuals should have no signs or symptoms attributable to active cryptococcal disease and negative cultures from the original site of infection. There are no data to support monitoring cryptococcal antigen testing once induction therapy is completed.

Aspergillosis

Epidemiology

A study conducted in Bangladesh to estimate the burden of IFIs estimated a prevalence of 30,178 people with chronic pulmonary aspergillosis, 80% attributable to tuberculosis. The most common of SOTs in India and other Asian countries is renal transplant, mostly from living donors. A study from South India on 1476 renal transplant recipients observed 6.64% of IFD, with Aspergillosis being the predominant IMD. IA has been reported at a higher rate (2%–4%) in patients with renal transplantation in developing countries compared to <1% in developed countries. IA occurred in 13% of patients with lung transplantation and is always associated with either acute rejection episodes or suture damage.

Risk factors

• Liver – Re-transplantation, renal failure, fulminant hepatic failure, malnourishment, the requirement of hemodialysis, prolonged ICU stay, and cytomegalovirus infection (usually >3 months)
• Lung – Single-lung transplant, CMV infection, rejection and augmented immunosuppression, pretransplant Aspergillus colonization, posttransplant Aspergillus colonization within a year of transplant, and positive intraoperative Aspergillus cultures in patients with cystic fibrosis
• Heart – Aspergillus colonization, CMV disease, airborne Aspergillus spores in ICU, posttransplant hemodialysis, and reoperation (thoracic)
• Kidney – Pretransplant diagnosis of COPD, graft failure, acute rejection episode, high and prolonged corticosteroid use..

Management

Voriconazole is the drug of choice to treat all forms of IA. Depending on the availability in the institution, alternative agents include isavuconazole and lipid Amphotericin-B (L-AmB). Posaconazole can be considered for salvage therapy. Primary therapy with an echinocandin is not recommended. Duration of treatment should be guided by the clinical and radiological response and most cases will require at least 12 weeks if tolerated. Routine antifungal susceptibility is not recommended, but it can be considered for patients suspected to have an azole-resistant isolate.

Mucormycosis

Epidemiology

In India, the rise in the number of Mucorales cases has been tremendous, especially in patients with uncontrolled diabetes. It is also being recognized as a nosocomial disease. A review of several Indian studies has revealed a prevalence rate of 0.14 cases/1000 population, which is 70 times the worldwide rate. In renal transplant recipients, the incidence of mucormycosis has been reported at 1.2% in a single-center study in India. A multicenter study conducted in 11 Indian ICUs showed Mucorales were isolated in 14.4% of patients who had invasive mold infections; Mucorales was also found to be an independent predictor of mortality.

Risk factors

The heavy burden of fungal spores during construction, contaminated air filters, and health care-associated devices have been linked to nosocomial acquisition. Risk factors described in SOT recipients include renal failure, diabetes mellitus, and prior voriconazole and/or caspofungin use. Other notable risk factors include prolonged neutropenia and corticosteroid use. Cases typically develop within 3–6 months of transplant but may occur much later except in liver transplant recipients where disease frequently occurs in the 1st month after transplant.

Management

Surgical excision or debridement is the mainstay of treatment and is recommended for all extrapulmonary infections. LF-AmB is the antifungal agent of choice for induction therapy followed by posaconazole for maintenance therapy.

Conclusion

In settings with limited resources, detecting and controlling IFI in SOT recipients presents a variety of difficulties and dangers. However, finding answers to these issues is challenging and illusive. To attain the best results, it is crucial that practitioners from all disciplines continue their education and that clinical research is used to identify appropriate alternative diagnostic and therapeutic approaches.

Source:  Soman, Rajeev. and Rege, Sujata. and Jeloka, Tarun. and Jhaveri, Tulip. and Bansal, Shyam, Expert group opinion for diagnosis and management of fungal infections in solid organ transplant recipients in South Asia, Indian Journal of Transplantation, volume 16, pages 41-52, 2022.