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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 5  |  Page : 41-52

Expert group opinion for diagnosis and management of fungal infections in solid organ transplant recipients in South Asia


1 Department of Infectious Diseases, Jupiter Hospital; Department of Infectious Diseases, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
2 Department of Infectious Diseases, Bharati Hospital and Research Centre, Pune, Maharashtra, India
3 Department of Nephrology, Jupiter Hospital, Pune, Maharashtra, India
4 Department of Infectious Disease, Harvard Medical School, Brigham and Women's Hospital, Boston, USA
5 Department of Nephrology and Kidney Transplant, Medanta Hopsital, Gurgaon, Haryana, India

Date of Submission30-Aug-2021
Date of Acceptance17-Oct-2021
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Rajeev Soman
Department of Infectious Diseases, Jupiter Hospital Pune, Department of Infectious Diseases, Deenanath Mangeshkar Hospital, Pune
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_78_21

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  Abstract 


Fungal infections, are common in solid organ transplant (SOT) récipients in South Asia. Invasive fungal infections (IFI) are the third-most common cause of infections in SOT recipients in South Asia after urinary tract infection and tuberculosis and are a significant cause of morbidity and mortality in this population. There are multiple factors, which lead to poor outcomes of these patients, i.e., lack of awareness, inadequate training of physicians, poor laboratory support to diagnose these infections, and sometimes nonavailability of appropriate antifungal agents to treat these infections. Among the IFI in India, invasive candidiasis is the most common followed by mucormycosis, invasive aspergillosis, and cryptococcosis. There is an increasing prevalence of azole resistance and multi-drug resistance among candida infections in South Asia. There are drug interactions of azoles with tacrolimus, cyclosporine, and everolimus and this must be kept in mind when treating various fungal infections. Another challenge is, how to screen and treat the donors and recipients before accepting them for transplant and subsequent management of transplant recipients. The most common endemic mycoses in the Asia-Pacific region are histoplasmosis caused by Histoplasma capsulatum, talaromycosis caused by Talaromyces marneffei and sporotrichosis caused by Sporothrix schenckii. The endemic fungal infections should be kept in the differential diagnosis of pyrexia of unknown origin in transplant recipients. Finally, the outcomes of these patients can be improved by increasing awareness among transplant physicians, better and wider availability of diagnostic facilities, and appropriate use of antifungal agents to treat these infections.

Keywords: Aspergillosis, candidiasis, fungal infections, mucormycosis, transplant


How to cite this article:
Soman R, Rege S, Jeloka T, Jhaveri TA, Bansal SB. Expert group opinion for diagnosis and management of fungal infections in solid organ transplant recipients in South Asia. Indian J Transplant 2022;16, Suppl S1:41-52

How to cite this URL:
Soman R, Rege S, Jeloka T, Jhaveri TA, Bansal SB. Expert group opinion for diagnosis and management of fungal infections in solid organ transplant recipients in South Asia. Indian J Transplant [serial online] 2022 [cited 2022 Dec 9];16, Suppl S1:41-52. Available from: https://www.ijtonline.in/text.asp?2022/16/5/41/358663




  Introduction Top


There is a significant burden of invasive fungal infections (IFI) in organ transplant recipients in South Asia due to certain geographical and demographic features. However, data on the prevalence is scarce. There are significant challenges in diagnosing and treating IFI, with limited resources in most of the South Asian countries. Challenges include: (i) limited clinical awareness and diagnostic facilities outside of specialized units, (ii) lack of national surveillance systems and absence of obligatory or central reporting of IFIs, (iii) significant cost of treatment leading to undertreatment, and (iv) unregulated access to drugs leading to misuse of anti-fungal agents and antifungal resistance. Potential solutions include: (i) strengthen surveillance programs, (ii) enhanced widespread access of fungal diagnostic tests, (iii) make antifungal therapeutics more readily available, (iv) educate and increase awareness of all stakeholders including patients and families, and (v) explore alternative affordable diagnostic and therapeutic strategies.

Tan et al. conducted a web-based survey on management practices for IFI among clinicians from seven Asian countries.[1] They found that majority of Asian physicians were not formally trained in mycology, 80% of them did not consult Infectious disease physicians, and only 30% had an antifungal stewardship program in their hospital. Laboratory support was inadequate with only two-thirds having access to galactomannan assay and one-fourth having azole therapeutic drug monitoring. Providing optimal antifungal treatment was limited by significant cost, lack of insurance coverage, and nonavailability of the drug. In addition to these limitations found in the study, clinically, these patients are difficult to evaluate as therapeutic immunosuppression interferes with the inflammatory response. Nevertheless, there are certain clinical manifestations suggestive of the diagnosis of IFIs [Table 1]. This suspicion needs to be followed by standard microbiologic tests and molecular diagnosis [Table 2]. In selected cases, invasive procedures for direct detection of the pathogen may be needed. Sometimes, the isolation of the fungal organism from a nonsterile site needs careful interpretation to distinguish colonization from invasion.
Table 1: Clinical manifestations of invasive fungal infections

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Table 2: Microbiological diagnosis of invasive fungal infections

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  Yeasts Top


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.[3] 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.[4] 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.[5]

Another recent publication showed 67 (9.2%) of 725 renal transplant recipients had IFIs. Invasive candidiasis was the most common IFI followed by mucormycosis, invasive aspergillosis (IA), and cryptococcosis.[6]A study on intensive care unit (ICU)-candidemia noted the high rate of isolation of C. tropicalis (41.6%), with azole and multidrug resistance seen in 11.8 and 1.9% of isolates. The overall incidence of ICU-acquired candidemia in India was 6.51 cases/1000 ICU admission, of which 74 (5.3%) from 19 of 27 ICUs were due to C. auris.[7] C. auris has recently emerged as a multi-drug resistant pathogen globally, particularly in South Asia [Figure 1].[8]
Figure 1: A global map depiciting rapid emergence of multidrug resistant Candida auris strain in 5 continents

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It has been noted in up to 30% of candidemia episodes in certain centers in India.[9] C. parapsilosis was the leading non-albicans Candida species in Japan and Thailand and, in 7 of 10 hospitals in Turkey, 2 of 4 series in South Korea, and 1 of 3 series in China.[10] Unusual Candida species such as C. pelliculosa (Teleomorph Pichia anomala) was seen in up to 18% in pediatric patients and 5% in adults, following an outbreak in a teaching hospital in India.[11]

Risk factors

Most of the Candida prediction models developed to identify patients at high risk have a high negative predictive value but lack a useful positive predictive value. A multicenter retrospective cohort study from Korea in liver transplant recipients showed that history of antifungal agents, retransplantation, fungal colonization, and hyperalimentation are independent risk factors for IFI.[12] 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.[13] 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.[14]

Issues in solid organ transplant

Donor screening

Selecting a suitable donor is of paramount importance in reducing the risk of infectious morbidity and mortality from donor-transmitted infections.[15] Infections associated with Candida species may occur in the setting of positive preservation fluid cultures or possibly due to contamination at the time of organ procurement. Bowel perforation in the deceased donor is another common source of Candida contamination of the allograft.

Acceptance criteria

Infections with Candida species without systemic spread are not a contraindication for transplantation, with the exception of the involvement of the infected organ. Recipients who receive organs from bacteraemic or fungemic donors (often either at least partially treated or recognized in hindsight) should receive targeted antimicrobial therapy for at least 14 days.

Management

Echinocandins are now recommended as first-line agents for candidemia in all patients and fluconazole is considered as an acceptable alternative in some patients.[16] However, in resource-limited settings this recommendation is often impractical. Using azoles has an important problem of interactions and conventional amphotericin B has the problem of nephrotoxicity. With the increasing numbers of Candida auris infections in India, the best choice of therapy is severely restricted and is based on validated susceptibility tests.

Apart from appropriate antifungals in candidemic patients, the removal of central venous catheters when necessary, fundoscopy to evaluate for ophthalmic involvement (which would change management), echocardiography to rule out endocarditis, and additional blood cultures to document fungal clearance are of immense significance but have not been fully appreciated by the treating clinicians in developing countries. Invasive candidiasis should be treated for at least 2 weeks after documented clearance of bloodstream, source control, and resolution of signs and symptoms. Candida esophagitis should be treated with fluconazole for 14 days.

A lack of clear understanding about colonization versus invasion from respiratory and urinary tract leads to important therapeutic implications like over-diagnosis and over-treatment with antifungal agents.[17]

Renal transplant

Renal allografts from donors with candiduria can be used with appropriate treatment. 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 and can be used in most cases.[18] Therapy should be continued for up to 6 weeks depending upon whether there is organ involvement. Renal transplant recipients were previously considered to have a higher risk for ascending infection and candidemia following asymptomatic candiduria. However, recent studies reveal that although mortality is higher in these patients, it is not reduced with antifungal therapy and hence treatment of asymptomatic candiduria in these patients may no longer be warranted unless the patient is to undergo cystoscopy with stent removal where treatment with fluconazole (assuming susceptibility) for up to 7 days is recommended.[19]

Lung transplant

Lung allografts from donors with bronchial cultures positive for Candida species can also be used with appropriate treatment. Recipients of lung allograft from a donor with documented Candida colonization of the airways have shown to benefit from universal prophylaxis with an echinocandin for the prevention of early posttransplant infections including empyema.[20] After lung transplant, nebulized Amp-B should be continued until bronchoscopic evaluation confirms the integrity of the bronchial anastomosis. Except in lung transplant recipients with Candida tracheobronchitis, Candida isolated from the respiratory tract represents colonization and should not be treated.[15]

Post transplant prophylaxis

The requirements and duration of prophylaxis for candida is provided in [Table 3]A.
Table 3: Antifungal prophylaxis in solid-organ transplant recipients

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Infection control

Measures to reduce the incidence of these infections should include adequate hand hygiene, judicious use of antibiotics, and frequent assessments to determine the need for intravascular and urinary catheters.

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.[21] A systematic search showed the global incidence of cryptococcosis in SOT recipients appeared to have remain unchanged, but the mortality rate has significantly improved. It is typically a late-occurring infection; the median time to onset usually ranges from 16 to 21 months posttransplantation.[22] The time to onset is earlier for liver and lung (<12 months) compared to kidney transplant recipients, which may be due to a higher intensity of immunosuppression in the former subgroups.

Risk factors

Cryptococcal disease in SOT recipients is considered to represent reactivation of quiescent infection in majority of patients.[23] Risk factors for cryptococcosis include patients of older age, comorbidities such as diabetes and cirrhosis, and immunosuppressants such as corticosteroids and T-cell depleting monoclonal antibodies (alemtuzumab and anti-thymocyte globulin).[23],[24] 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.[25] 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.

Issues in solid organ transplant

Donor screening

Routine screening of transplant donors is not recommended.[26] Cryptococcosis should be considered in donors with undiagnosed meningoencephalitis and isolated pulmonary nodules in the presence of receipt of corticosteroids, iatrogenic immunosuppressants, sarcoidosis, end-stage liver or renal disease, and rheumatologic disorders. Serum cryptococcal antigen (CRAG) should be performed in donors with meningoencephalitis and in those with unexplained pulmonary lesions or fever of undetermined origin if they have underlying medical conditions predisposing to cryptococcosis. However, it has a lower yield for isolated pulmonary disease.[27],[28] Cerebrospinal fluid analysis for donors with meningoencephalitis of undetermined etiology and biopsy with histopathology for focal lesions are suggested. Many of these donors would already be declined for transplant, given meningoencephalitis of unclear etiology.

Acceptance criteria

Use of organs from untreated donors with documented systemic or central nervous system (CNS) cryptococcosis is not recommended. In donors with cryptococcal disease receiving antifungal therapy, the donation should be considered on an individual basis and preferably procured only upon documentation of mycologic eradication and with the consent of the recipient. If donor disease is detected posttransplant, the recipient must be treated preemptively.

Recipient

Routine screening of transplant recipients is not recommended. Donor-derived cryptococcosis should be considered in the following scenarios: An unexplained early meningitis within 30 days after transplantation; Cryptococcus demonstrated microbiologically or histologically at the surgical or graft site;[25] cryptococcosis documented at any site in the first 30 days after transplant, particularly at atypical sites outside the lungs and CNS; or cryptococcal disease is diagnosed in another recipient from the same donor.

Management

Comprises four key components:[21]

  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:


    1. 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
    2. 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.


Challenges

The overwhelming prevalence of TB in India, the strong association between TB and cryptococcosis, and the clinical resemblance to TB meningitis (TBM), lead to a very low suspicion of cryptococcal meningitis, especially in the non-HIV population.[25] The poor diagnostic yield in TBM often compels the physician to start empiric anti-tubercular treatment (ATT) without searching for an alternative diagnosis such as cryptococcal meningitis. This may change with better TB diagnostics even in resource-limited settings. In some instances, empiric ATT is continued even after cryptococcal meningitis has been diagnosed and as a result, rifampin may reduce the levels of fluconazole leading to cryptococcal relapse and/or resistance.[27]

Even after the diagnosis of cryptococcal meningitis is established, the cost and practical difficulties of providing treatment with amphotericin B and 5-flucytosine are considerable. The need for repeated cerebrospinal fluid drainage to reduce intracranial pressure and to document fungal clearance and the longer induction phase of treatment for non-HIV patients (SOT patients) is commonly missed, thus compromising the outcome of treatment. A clinician should also be aware of immune reconstitution syndrome (IRIS) that mimics recurrence; hence the exclusion of clinical failure with repeat cultures is warranted before initiating corticosteroid treatment for IRIS.

Posttransplant prophylaxis

Primary prophylaxis

No role.

Secondary prophylaxis

Should be considered on an individual basis in SOT recipients needing enhanced immunosuppression with previously treated cryptococcosis, as they are at risk for recurrent infection. Secondary fluconazole prophylaxis is advised for at least a year.

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.[17] Re-transplantation can be considered after 1 year of antifungal therapy.[24] 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.

  • Renal SOT with graft failure (bridging option with hemodialysis is available): At least several months of antifungal therapy, with a plan to continue antifungal therapy after transplant
  • Nonrenal SOT with graft failure (no bridging option is available): At least postinduction therapy, with a plan to continue antifungal therapy after transplant.



  Moulds Top


Aspergillosis

Epidemiology

IA is an important cause of morbidity and mortality in SOT patients in Asia. In an Indian tertiary care hospital-based study on aero-mycoflora, a high fungal spore burden (average 100 CFU/mm3) was demonstrated in hospital air with a predominance of Aspergillus species (A. fumigatus and A. flavus).[29] It has been noted that A. flavus has some degree of intrinsic resistance to amphotericin B.

The hot and humid climatic conditions in most Asian countries as well as construction activities, especially in the vicinity of hospitals, lead to very high environmental fungal colony counts. 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.[30]

Time from transplant to the diagnosis of IA is variable, but most cases present within the 1st-year posttransplant, with the shortest time to onset seen in liver and heart transplant recipients. The overall 12-week mortality of IA in SOT exceeds 20% and the prognosis is worse among those with CNS involvement or disseminated disease.

In transplant patients, data from India and other Asian countries are mostly either case reports or single-institution experience. IA is more commonly seen in HSCT rather than SOT. A tertiary-care hospital in South India noted a high incidence of IA in patients undergoing allogeneic HSCT. Of the 415 infection episodes, 15.9% were fungal and IA attributed to 69.7%.[31]Another multicenter study from Japan also found IA to be the most common invasive fungal disease (IFD) in their autologous HSCT patients.

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.[5] IA has been reported at a higher rate (2%–4%) in patients with renal transplantation in developing countries compared to <1% in developed countries.[28] IA occurred in 13% of patients with lung transplantation and is always associated with either acute rejection episodes or suture damage.[32]

Risk factors

Risk factors for IA can be determined based on the organ transplanted:

  • 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.


Issues in solid organ transplant

Donor screening

Donors with active invasive mold infections are not suitable for organ procurement. The slow growth of many filamentous fungi poses challenges to timely diagnosis. Nevertheless, awareness of situations where these infections are likely in the donor is important. Contaminated preservation fluid, infected donors, or breaches in aseptic techniques during organ procurement, transport, or implantation has been shown or suspected to be the mode of transmission of aspergillosis and mucormycosis associated with fungal arteritis, mycotic aneurysms, anastomotic infections, and graft site abscesses or fungus ball causing graft loss in kidney and liver transplant recipients.[33] The utilization of lungs with fungal infections is controversial since there is a high rate of transmission.

Recipient screening

Active infection should be ruled out before starting immunosuppression.

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.

Post transplant prophylaxis

The requirements and duration of prophylaxis is provided in [Table 3]B.

Therapeutic drug monitoring

Voriconazole decreases the metabolism of tacrolimus, cyclosporine, and everolimus, thereby increasing their serum levels, leading to potential over-immunosuppression. Hence, monitoring of serum trough levels for azole antifungal agents (voriconazole, posaconazole, itraconazole) and for potentially interacting drugs such as cyclosporine, tacrolimus, and sirolimus is recommended. It is specifically needed in the following conditions: concerns about gastrointestinal absorption; clinical or laboratory manifestations of toxicity; uncertain compliance with oral therapy; initiation or discontinuation of interacting drugs; cystic fibrosis; critically ill patients such as those with multi-organ failure or unstable hemodynamics requiring vasopressors or ECMO; before alteration in therapy to a second-line agent after the initial failure of therapy.

Therapeutic voriconazole serum concentrations (>1 mg/L) are predictive of clinical success. A trough level/MIC ratio (when the MIC is estimated using CLSI methodology) of 2–5 is associated with a near-maximal probability of response. Active dosage adjustment to keep serum concentrations <5.5 mg/L prevents voriconazole-related toxicity. In addition to drug monitoring, individuals receiving chronic azole therapy should also get the assessment of corrected QT interval with baseline and periodic electrocardiogram.

Challenges

The clinical and radiological manifestations of invasive pulmonary aspergillosis (IPA) overlap with tuberculosis and other common tropical respiratory infections. The latter are often treated empirically leading to a delay in the diagnosis of IPA. The restricted availability of CT scans and fungal biomarkers, the use of generic piperacillin-tazobactam, and the prevalence of other cross-reacting molds such as Talaromyces marneffei in Northeast India and Histoplasma capsulatum in different parts of the country add to difficulties in diagnosis. These diagnostic limitations coupled with the uncontrolled access to antifungal agents lead to the widespread empiric treatment of IA. Limited knowledge of the drugs, especially interactions with rifampin, anti-epileptic drugs, agents which prolonged QTc interval, immunosuppressants, and acid-suppressive agents may lead to inadequate AF drug exposures as well as serious toxicity. Another important challenge is the questionable quality and bioavailability of a wide range of generic agents that are freely available in many Asian countries. The limited availability and high cost of therapeutic drug monitoring preclude their use in most resource-limited settings. Polymorphisms in azole metabolizing enzymes need to be studied in developing countries to further refine the use of these drugs. Prolonged use of voriconazole for CNS aspergillosis has been associated with late complications such as periostitis and skin cancer. Awareness among physicians in developing countries about these toxicities is essential.

Infection control

Avoidance of areas and activities expected to result in high levels of mold spores (e.g., construction, gardening), strict infection control policies to prevent contamination, and use of specially designed units (protected environments) where additional standards (e.g., HEPA-filtered rooms) are in place can minimize mold exposure.

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.[34] A recent American and European series of fungal infections in SOT reported a frequency of mucormycosis lower than 3% among those with fungal infection.[5],[31] In renal transplant recipients, the incidence of mucormycosis has been reported at 1.2% in a single-center study in India.[35] 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.[36]

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.[37]

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.

Posttransplant prophylaxis

Posaconazole may be considered in recipients of donor lungs that are colonized with mucorales or in individuals requiring a very high level of immunosuppression.

Challenges

While the biopsy is the mainstay of diagnosis, IM is not suspected unless the physician has seen a “critical number” of such patients and recognizes the necrotic lesion or black-colored discharge as a hallmark of the disease. Failure of recognition leads to the use of inappropriate antibiotics and even steroids which aggravate the disease. In patients with conventional risk factors like profound neutropenia; hemodynamic instability, and thrombocytopenia often preclude invasive procedures and biopsy, thus leading to a delay in diagnosis. In addition, immediate and extensive surgical debridement may not be undertaken in these patients even after the diagnosis is established.

Distinguishing between mucormycosis and aspergillosis on biopsy requires expertise, especially when only scanty and disrupted hyphae are seen, but is needed in a timely fashion as treatment choices differ. The unavailability of all preparations of antifungals, the toxicity, and the cost in resource-limited settings often result in major treatment limitations. Lack of awareness, uncertain efficacy, expense, and potential for inadvertent harm often precludes the use of adjuvant therapy such as echinocandins, deferasirox, statins, and G-CSF.

Duration of treatment for IM is based on clinical and radiological resolution, adequate surgical debridement, and reversal of underlying risk factors. However, in reality, it is practically impossible to fulfill all these criteria in every patient, thus leading to prolonged, sometimes indefinite need of antifungals.

Finally, the successful outcome of IM requires a team approach involving the microbiologist, histopathologist, surgeon, ophthalmologist, and infectious disease physician. Apart from the multispecialty, tertiary care centers in large cities, the combined efforts of skilled specialists and laboratory expertise may be difficult to come by.


  Pneumocystis jiroveci Pneumonia Top


Epidemiology

Based on studies before the broad implementation of prophylaxis, the overall incidence of Pneumocystis jiroveci pneumonia (PJP) among solid organ transplant (SOT) recipients varied in the range of 5%–15%, depending on organ type, transplant center, and immunosuppressive regimens.[38] The incidence is highest in lung and combined heart-lung transplant recipients ranging from 10% to 40%, while the incidence in renal transplant recipients is 6% without prophylaxis. With the widespread use of prophylaxis, the incidence of PJP posttransplant appears to range from 0.3% to 2.5%.[39],[40],[41] As with most infections, the net state of immunosuppression is the main contributor to risk rather than any specific immunosuppressive agent. The risk is considered highest within the first 6 months posttransplant.

Risk factors

  1. Immunosuppressive therapy such as corticosteroids, chemotherapy, antibody therapies, mycophenolate mofetil, calcineurin inhibitors, and sirolimus
  2. CMV disease
  3. Allograft rejection
  4. GVHD
  5. Low CD4 T-cell counts
  6. Neutropenia.


Diagnosis

Immunofluorescence assay is the most sensitive microscopic diagnostic method. PCR testing of samples for PJP has increased diagnostic yield. However, it is important to differentiate between colonization and true pathogen based on clinical judgment. Serum Beta-D-glucan has a 95% sensitivity and 80% specificity and can be used concurrently for diagnosis and follow-up. Specimen from a lower respiratory tract (bronchoalveolar lavage, induced sputum, transbronchial biopsy, and open lung biopsy) is preferable to increase the yield.

Management

Trimethoprim-sulfamethoxazole (TMP-SMX): drug of choice. Adjunctive corticosteroids are best administered within 72 h of presentation in the setting of hypoxemia (pAO2 <70 mmHg). In cases of allergy or intolerance to TMP-SMX, intravenous pentamidine can be used; infusions should be given over 1–2-h period to ameliorate side-effects such as pancreatitis, hypo-and hyperglycemia, and electrolyte disturbances. Atovaquone or primaquine along with clindamycin can be used in mild-to-moderate infection as second-line agents.

Post transplant prophylaxis

The requirements and duration of prophylaxis is provided in [Table 3]C.[41]

Issues in solid organ transplant

Donor and recipient screening

No recommendations for screening pretransplant.

Infection control

Strict hospital segregation of transplant recipients with PJP with the use of face masks can reduce nosocomial transmission.


  Endemic Mycoses Top


Endemic mycoses are a frequent problem in the Asia-Pacific region but data are limited in SOT recipients. The most common endemic mycoses in the Asia-Pacific region are histoplasmosis caused by H. capsulatum, talaromycosis caused by T. marneffei and sporotrichosis caused by Sporothrix schenckii.[42]

Histoplasmosis

Epidemiology

H. capsulatum thrives in a warm and humid environment such as soil enriched with nitrogenous compounds and phosphates derived from avian excreta and bat guano.[43] Different studies from India have reported a prevalence ranging from 0% to 12.3% in various geographical areas. In India, the disease is endemic in the North-East region.[44] Despite the risk, posttransplant histoplasmosis is rare, with an estimated incidence of <1%, even in endemic areas. Transplant-associated infections surveillance network reported a 12-month cumulative incidence rate of histoplasmosis of 0.1%.[45] The median duration of presentation from the time of transplant in one series from India was 5 years (range, 1.5–5 years).[46] Most infections in western data occurred within 1–2 years posttransplant.[47]

Histoplasmosis in transplant recipients can occur either due to primary infection via inhalation causing pulmonary disease, or reactivation in the setting of immunosuppression. In these patients, due to impaired cell-mediated immunity, the organism remains viable within macrophages, posing increased risk of dissemination and clinical infection. Donor-derived infection from graft, though rare, has also been described.

Diagnosis

Direct visualization of morphologically consistent yeast on biopsy and/or growth of H. capsulatum on culture is the mainstay of diagnosis. Histoplasma antigen provides a rapid, noninvasive method for diagnosis and has good overall sensitivity, especially when combined from multiple sources (urine, serum, or BAL depending on resources available).

Management

Mild-to-moderate localized disease is treated with itraconazole. Severe disease is treated initially with Amphotericin B for 1–2 weeks, followed by itraconazole. The minimum duration of treatment of posttransplant histoplasmosis is 12 months. Based on the largest case series of histoplasmosis in renal transplant recipients from India, Rana et al. concluded that early suspicion, rapid diagnosis, and appropriate therapy promptly are likely to result in successful outcomes.[46] Urine and serum Histoplasma antigen levels can be used to follow treatment response and assess for relapse.

Issues in solid organ transplant

Donor screening

There are no uniform recommendations for screening of endemic mycoses in donors. If donor serology is positive, a lung transplant recipient should be treated for 3–6 months posttransplant.[48]

Recipient screening

Pretransplant screening for histoplasmosis is of limited value since latent histoplasmosis may be present with negative serology. Transplantation should be avoided during active disease until the treatment is completed. If urgently required, it may be considered once the disease is reasonably well controlled with the demonstration of clinical improvement and declining antigen levels. Awareness of the possibility of histoplasmosis is necessary when investigating a posttransplant febrile illness in a patient from an endemic area.

Acceptance criteria

Donors with active histoplasmosis are excluded from donating organs. Living donors may be reconsidered for donation after adequate treatment for at least 3–6 months with the resolution of signs and symptoms of active disease and clearance of histoplasma antigen.[49] Radiographic sequelae of old histoplasmosis are not considered a contraindication for transplant.

Prophylaxis

Primary prophylaxis for histoplasmosis in endemic areas is not recommended before organ transplant. Recipients with pretransplant histoplasmosis need to be monitored clinically. However, if they receive an organ transplant within 2 years of diagnosis, serial histoplasma antigen monitoring is indicated, and secondary prophylaxis with itraconazole may be considered. The shorter the interval between histoplasmosis diagnosis and transplant, the stronger the indication for prophylaxis. [Table 3]D shows indications for prophylaxis posttransplant.

Infection control

Since histoplasmosis is acquired from the environment, posttransplant patients should be advised to avoid construction areas, exposure to caves, and working on poultry farms. HSCT recipients, in particular, should wear HEPA filter masks during the early risk period.

Talaromycosis

Epidemiology

Talaromycosis (or penicilliosis) caused by the dimorphic fungus T. marneffei, is an endemic disease found in Southeast and Eastern Asia. Sethuraman et al. reported a series of five cases of Talaromyces, originating from nonendemic states of India, neighboring Manipur.[50]

Challenges

Differentiating talaromycosis from histoplasmosis is difficult in regions where both diseases are endemic, as both cause fever, weight loss, cough, anemia, lymphadenopathy, and hepatosplenomegaly. However, skin lesions are more frequently seen in T. marneffei infections.

Diagnosis

Although a presumptive diagnosis can be made based on its characteristic morphology on biopsy specimens, definitive diagnosis is made from tissue culture. Galactomannan testing can show cross-reactivity with T. marneffei.

Management

Transplant recipients with any form of talaromycosis should receive an induction regimen with a lipid formulation of amphotericin B for 2 and 4–6 weeks in case of CNS disease, followed by oral itraconazole (200 mg twice daily) for 10 weeks. Concomitant reduction in immunosuppression and/or discontinuation of biologics should be attempted.[12]

Issues in solid organ transplant

Pretransplant donor and recipient screening

It is not recommended in asymptomatic individuals.

Prophylaxis

Primary prophylaxis: No role.

Secondary prophylaxis

Itraconazole secondary prophylaxis can be given for a minimum of 6–12 months, with extended duration in patients on high-dose immunosuppression or with persistent impaired CMI.[49]

Sporotrichosis

Epidemiology

Sporotrichosis is a subacute or chronic subcutaneous, granulomatous mycosis. It is caused by intradermal inoculation of the dimorphic soil saprophyte S. Schenckii by minor local trauma. It is commonly seen in South-East Asia owing to ecological factors. Studies have shown that hay, corn stalks, and soil are possible sources of S. schenckii in the Asia-Pacific region.[37] The incidence of sporotrichosis in post-SOT recipients is unknown. However, there are case reports showing the presence of atypical features, severe disease, and osteoarticular disease in postliver and renal transplant recipients.

Diagnosis

Culture and histopathology are the mainstays for diagnosis.

Management

Mild infections can be treated with itraconazole. For severe clinical presentations, including pulmonary, CNS, and disseminated disease, an induction course of lipid formulation of amphotericin B is recommended (4–6 weeks), followed by step-down therapy with oral itraconazole for a minimum of 12 months. The duration of therapy and the need for secondary prophylaxis depends on clinical and radiological improvement.[12]

Issues in solid organ transplant

Pretransplant donor and recipient screening

Is not recommended in asymptomatic individuals. Only donors or recipients from endemic regions with the presence of chronic skin or lymphocutaneous lesions should be screened with histopathology and culture of tissue biopsy.[44]


  Conclusion Top


There are myriad of challenges and pitfalls in diagnosing and managing IFI in SOT recipients in resource-limited settings. However, solutions to these problems are difficult and elusive. Continuing education of clinicians across all specialties and implementation of clinical research to find acceptable, alternative diagnostic and therapeutic strategies are essential steps to achieve optimal outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

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Introduction
Yeasts
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