Invasive aspergillosis after renal transplantation

Introduction
Renal transplantation (RT) is the treatment of choice for patients with end-stage renal failure as it improves the quality of life and survival time of the patient [Li et al 2017]. The world observes a rising number of renal transplantation procedures owing to modern advances in the transplant medicine [Seok, et al 2020]. It is considered the most common solid organ transplantation type as it reaches approximately two-thirds of all solid organ transplantations (SOT) [Mouloudi, et al 2012; Seok, et al 2020]. For instance, compared to 4300 lung, 5900 heart, and 23,000 liver transplantations, 77,000 renal transplantations were observed in the year 2012 [ López‐Medrano, et al 2016].
Successful renal transplantation is based on better control of rejection however immunosuppressive therapy used here paves the way to infections due to viruses, bacteria, and fungi [Vinod et al, 2009]. Fungi are responsible for around five percent of all infections in renal transplanted patients and Aspergillus species is second only to Candida spp. in this cohort [Balcan et al, 2018]. Invasive aspergillosis (IA) is a life-threatening opportunistic infection in immunocompromised patients including renal transplant recipients [Trabelsi et al, 2013]. It renders severe outcomes in the absence of timely diagnosis and appropriate antifungal management [Trabelsi et al, 2013].

Incidence
Historically, a low incidence of IA was observed among renal transplant recipients in comparison with other solid organ transplanted patients [Altiparmak et al, 2002; Seok et al, 2020]. For instance, a multicentre study in France found an incidence rate of IA of 0.4%, 1.3%, and 1.9% after renal, heart, and liver transplantation, respectively [López‐Medrano et al, 2016].
Although the incidence rates are low at 0.5% in most research, they range from 0.2% to 14% in different studies [Altiparmak et al, 2002; López‐Medrano, et al 2016; Trnacevic et al 2018; María Asunción et al, 2021]. It is also observed that the reported incidence of IA after renal transplantation varies from region to region across the globe. For example, the reported incidence was 2.3%, 0.4%, and less than 1% in India, France, and England, respectively [Trabelsi et al, 2013]. It seems that the incidence of IA after RT depends on the infection control measures practiced by the transplantation centres. [Altiparmak et al, 2002].

Disease burden (Mortality and Morbidity)
Despite its low incidence, it can be hypothesized that renal transplants have the highest burden of IA in SOT since the number of renal transplants surpasses the number of other SOT [López‐Medrano et al, 2016].

A high mortality rate has been observed in IA in renal transplants (40%–60%) [Li et al 2017] [Heylen et al 2015]. In some studies, it is as high as 67% to 92% [Balcan et al, 2018; Trnacevic et al, 2018; Solak et al, 2011]. Studies observed increased mortality in line with delay in diagnosis of IA and baseline high fever [Balcan et al, 2018]. In addition, some studies have observed a significantly higher mortality in the early IPA cohort compared to the late IPA cohort [Seok et al, 2020]. However, the true burden of IA seemed to be underestimated in this cohort [Trabelsi et al ,2013].

Fungal infections including IA in renal transplantations are also associated with a substantial degree of morbidity [Vinod et al, 2009]. Prolonged hospitalization is a major adverse outcome related to IA in this cohort and this was observed by Abbott et al [2001]. His retrospective evaluation of 33,420 renal transplant recipients of the United States between 1994 and 1997 revealed that the mean length of hospital stay of kidney transplanted patients with IA was associated independently with prolonged hospital stay compared to all other fungal infections [Abbott et al, 2001]. Moreover, prolonged hospital stay, the use of expensive antifungals and ICU care in patient management invariably contribute to increased health care cost [Kabir et al, 2019].
In addition, wide use of antifungals in the healthcare setting could lead to the development of antifungal resistance in the healthcare setting [Kabir et al, 2019].

The management of refractory IA frequently requires interruption or discontinuation of immunosuppressive drugs. However, this might lead to graft rejection or delayed graft function requiring a step down to dialysis again [Kunthara et al, 2021; Li et al, 2017]. For example, a study conducted among 51 renal transplanted patients with early invasive aspergillosis infection in 19 institutions from 2000 to 2013 observed graft loss among 25% of survivors [López‐Medrano et al, 2016].

Risk factors for IA in RT
Risk factors for IA among renal transplanted patients have been evaluated in different studies. A retrospective study conducted at a tertiary-care referral hospital in Korea evaluated patients with invasive pulmonary aspergillosis (IPA) after renal transplantation from February 1995 to March 2015 found that older age, diabetes mellitus, delayed graft function, and acute graft rejection were associated with the development of IPA [Seok et al, 2020]. A multinational case-control study conducted by López‐Medrano. et al further added chronic pulmonary obstructive disease and development of bloodstream infection as risk factors for IPA among RT [López‐Medrano et al, 2016]. In his later study López‐Medrano et al further concluded that underlying diabetic nephropathy is a risk factor [López-Medrano et al, 2018]. Altiparmak et al also concluded that older age, prolonged antibiotic course, anti-rejection therapy such as pulse steroids and antilymphocytic globulins, cytomegalovirus disease, and neutropenia are risk factors [Altiparmak et al, 2002]. Apart from that, ongoing construction or demolition activities in hospital premises or residential areas also increase risk [Jha et al, 2000].

Timing of infection
It is observed that IA risk is highest within the first 6 months of post-transplantation if patients did not experience allograft rejection and this is further evidenced by studies. Almost half (43%) of the cases of IPA were diagnosed within the first 6 months after transplantation in a multinational retrospective study conducted in Europe among 112 renal transplant recipients diagnosed with probable (75% of cases) or proven (25%) IPA between 2000 and 2013 [López‐Medrano et al, 2016]. A study that followed up 120 kidney recipients for one year in the Organ Transplant Center in Kuwait from March 2016 to October 2019 observed IA most frequently between 1 to 6 months after transplantation [Sadon et al, 2020]. In addition, the highest incidence of IA was observed in the first 3 months after transplantation in a single-center retrospective analysis of forty cases of IA after kidney transplantation [Heylen et al, 2015].

However, the risk is continuous if patients experience rejection episodes and some studies showed late IPA is as common as early IPA in RT recipients and suggest that IPA can occur in any period after RT [Seok et al, 2020]. A retrospective study conducted at a tertiary-care referral hospital in Korea evaluated patients with invasive pulmonary aspergillosis after renal transplantation from February 1995 to March 2015 [Seok et al, 2020]. They found that approximately half of IPA in KT recipients developed during the late posttransplant period (> 6 months) [Seok et al, 2020]. Moreover, a single-centre, retrospective observational study of 438 patients who underwent renal transplantation between 2010 and 2016 in Turley, observed most IPA infections after the first year of transplantation; the median time to onset of IPA was 32.4 months [Balcan et al, 2018].

Clinical picture
The lung and the sinuses are the foremost sites of infection, followed by dissemination to other organ systems, mainly to the central nervous system [Schelenz et al, 2003]. This was supported by a single centre retrospective analysis of 40 cases of IA after RT which observed 30 IPA, four invasive bronchial aspergilloses, one cerebral abscess, and 5 disseminated cases [Heylen et al, 2015]

IPA may cause necrotizing, rapidly progressive pneumonia along with cavitation, vascular invasion, and haemorrhagic infarcts [Vinod et al, 2009; Trabelsi et al 2013]. Patients with pulmonary aspergillosis may present with fever, dyspnoea, cough, and haemoptysis [Vinod et al, 2009]. However, sometimes IPA in renal transplant recipients may present with nonspecific symptoms. For example, a multinational retrospective study of Europe observed one-fifth of the IPA patients presented without typical symptoms of lung infection [López‐Medrano et al, 2016].

The hematogenous spread of Aspergillus into the brain resulting in haemorrhagic infarction and abscess have been observed after RT [Coates et al, 2001]. The clinical picture mimics any other type of space-occupying lesion and clinical diagnosis is difficult [Coates et al, 2001]. The presenting symptoms might be stroke-like symptoms or convulsions with or without fever [Coates et al, 2001]. However, it is worth remembering that other organs system can also be affected and several other clinical forms of invasive aspergillosis could be seen. For example, rare clinical forms of invasive aspergillosis including Aspergillus endophthalmitis, Aspergillus pseudoaneurysm in graft sites, Aspergillus spondylitis, Aspergillus prostatitis, Aspergillus thyroiditis, Aspergillus peritonitis, hepatic aspergillosis, Aspergillus tracheobronchitis, and Aspergillus endocarditis after dissemination have been reported.

Diagnosis
The diagnosis of IA is based on a combination of clinical, microbiological, and radiological data [Ullmann et al, 2018]. The diagnosis of IA in transplanted populations is difficult and often delayed leading to poor prognosis [Trabelsi et al, 2013]. A retrospective study conducted at a tertiary-care referral hospital in Korea among patients with IPA after renal transplantation from February 1995 to March 2015 found that the median time to diagnosis was 161 days [Seok, et al, 2020]. Delayed diagnosis of any invasive mould infection is associated with a high mortality rate [Von Eiff et al, 1995].

Histology, direct microscopic examination and culture
Isolation in culture, direct microscopic examination with potassium hydroxide and demonstration of Aspergillus fungal filaments on histology of respiratory samples and biopsy tissues from involved sites are important steps in diagnosing IA [Douglas et al 2021 ][Kabir et al 2019] [Jha et al 2000]. Examination of tissues treated with KOH allows rapid detection of the pathogen, however has less sensitivity than other methods [Ullmann et al 2018]. [Kabir et al 2019]. Cultures allow isolation of Aspergillus species and antifungal sensitivity testing which is a guidance to optimal antifungal management. However, cultures of respiratory origin show only moderate sensitivity and have a long turnaround time [Kabir et al, 2019]. According to the study of Brown et al, the specimens from lungs of infected liver and kidney transplant patients are frequently positive than body fluids [Brown et al, 1996]. The most commonly isolated Aspergillus spp. is A. fumigatus from this group of patients [Brown et al, 1996].

Open lung biopsy, CT guided transthoracic biopsy, transbronchial biopsy and, video-assisted thoracoscopic surgery provide specimens from sterile sites for culture and histopathology for the diagnosis of IA [Ullmann et al, 2018]. In addition, diagnosis of IPA can be facilitated by bronchoscopy along with bronchoalveolar lavage, and bronchial aspirate [Jha et al, 2000] [Muthu et al, 2021]. However, many of these patients are not suitable candidates for these diagnostic procedures owing to multiple comorbidities. Cerebrospinal fluid examination shows minimally abnormalities and CSF culture is rarely positive throwing a diagnostic challenge on CNS aspergillosis in this group [Coates et al, 2001], although Aspergillus antigen is usually positive.

Use of galactomannan assay
Galactomannan (GM) is a fungal cell wall carbohydrate that is released during tissue invasion and widely used in the diagnosis in invasive aspergillosis [Küpeli et al, 2012]. However, unsatisfactory performance of Aspergillus galactomannan assay in serum for the diagnosis of invasive aspergillosis in solid organ recipients has been observed [Patterson et al, 2016]. The sensitivity and specificity of serum GM in solid organ transplanted individuals are 22% and 84%, respectively [Kabir et al, 2019]. Pfeiffer CD, et al observed a slightly higher pooled sensitivity of 41% of the GM test in solid organ transplant recipients in his meta-analysis [Pfeiffer et al, 2006]. This finding was further supported by Heylen et al [2015] who observed positive GM assay only in one-third of invasive aspergillosis patients with a transplanted kidney in a single-centre case-control study on invasive aspergillosis after RT [Heylen et al, 2015]. López‐Medrano et al observed 60% of positive GM levels in a multinational cohort study of IPA in RT [López‐Medrano et al, 2016]. Moreover, there are instances of false-positive GM test results reported in renal transplanted patients with suspected IA leading to an incorrect diagnosis [Park et al, 2017].

Variable sensitivity of GM observed in different studies creates uncertainty in its use as a diagnostic tool in RT patients. However, certain studies have obtained promising results highlighting the prognostic significance of the GM test. For instances, Heylen [2015] observed that the magnitude of the GM index (optical density >2) mirrors the mortality of patients [Heylen et al, 2015]. López‐Medrano et al also found that the GM indices were significantly higher in non-survivors at 6 weeks (serum and BAL) compared to survivors [López‐Medrano et al, 2016]. Balcon et al also observed a propensity of high mortality along with increased BAL galactomannan level post renal transplanted patients with IA [Balcan et al 2018]. This is further supported by a retrospective study conducted at a tertiary-care referral hospital in Korea which evaluated patients with IPA after renal transplantation from 1995 to 2015 [Seok et al, 2020]. They observed that serum GM index of > 2 and bronchoalveolar (BAL) GM index > 5.0 were associated with a high 12-week mortality [Seok et al, 2020]. Seok et al concluded that serum GM level might be used as a predictor of prognosis in renal transplanted patients with IPA [Seok et al, 2020]. A study conducted among 1762 solid organ transplanted patients observed nine renal transplanted patients with IA (0.5%) and having a positive serum GM antigen was related to higher mortality [Hoyo et al, 2014]. Moreover, a single-centre, retrospective study on 438 renal transplanted patients from 2010 to 2016 in Turley, observed a tendency towards high mortality with a high GM level [Balcan et al, 2018].

Meanwhile, some authors have suggested testing for GM before transplantation in recipients who will require aggressive immunosuppression [Trnacevic et al, 2018]

(1, 3)-beta-D-glucan
(1, 3)-beta-D-glucan is a cell wall component of fungi and is considered a pan fungal marker for many fungal pathogens including Aspergillus species [Patterson et al, 2016]. The positive predictive value of beta –D-glucan for the diagnosis of invasive fungal infection among solid organ transplanted individuals seemed to be moderate [Mutschlechner et al, 2015]. Its usage in the diagnosis of invasive aspergillosis in renal transplantation has not been fully investigated. However, a high level of serum (1, 3)-beta-D-glucan has been observed in renal transplanted patients with invasive aspergillosis [Estrada et al, 2012].

Radiology
Imaging evidence of invasive aspergillosis in renal transplanted patients is often non-specific and may also overlap with other pathologies in the early stages. Radiological appearances vary from non-specific infiltration, nodular opacities, nodular opacity plus infiltrate, halo signs, and cavity formation [López‐Medrano et al, 2016; Balcan et al, 2018; Trabelsi et al 2013]. Macro nodule(s) (more than 1cm) along with a halo of ground glass attenuation is considered the classical sign of IA [Ullmann et al, 2018]. However, a multinational retrospective study of 112 renal transplant recipients in Europe between 2000 and 2013 found that well-circumscribed nodules were the most common radiological sign (70%) in IPA [López‐Medrano et al, 2016]. Moreover, bilateral lung involvement was an independent predictor of non-survival in this study [López‐Medrano et al, 2016]. In contrast, a single-center, retrospective observational study of 438 renal transplant recipients between 2010 and 2016 in Turley observed infiltration without nodular opacity as the most commonly observed CT image in IPA [Balcan et al, 2018]. However, the same study found more nodular opacities with or without infiltration in IPA compared to non-IPA cases in this cohort [Balcan et al, 2018]. These findings were in line with the findings of a retrospective analysis of cases of invasive fungal infections in renal transplant recipients in a university hospital from 1995 to 2013 [Trabelsi et al, 2013]. It revealed that renal transplanted individuals with the invasive fungal disease had micro-nodules and alveolar condensation [Trabelsi et al, 2013]. In addition to the above-mentioned features, pleural effusion is rarely observed in IPA [Ma et al, 2022].

Since IPA may followed by central nervous system (CNS) aspergillosis, radiological evaluation (CT or MRI) of IPA patients with neurological symptoms is important. Aspergillus brain abscesses could be seen as solitary or multiple ring-enhancing lesions and this was demonstrated by a retrospective study of brain CT and MRI studies of patients with neurological symptoms after liver or kidney transplantation [Rahatli et al, 2018]. They observed ring-enhancing lesions, especially in grey-white matter junction along with central diffusion restriction on brain MRI [Rahatli et al, 2018].

Apart from central nervous system dissemination, pulmonary aspergillosis may disseminate to several other body sites so radiological investigations should be conducted accordingly. For example, a rare case of Aspergillus spondylodiscitis has presented as discitis, epidural abscess and subchondral T2 hypointense band on lumbar MRI [Rahatli et al, 2018].

Management
The decisions of management are usually extrapolated from the other groups of immunocompromised groups because of the scarcity of large clinical trials that address the management of renal transplant recipients. The management of IA in renal transplant recipients requires a multidisciplinary approach and appropriate antifungal therapy, adjunctive immunotherapy, adjunctive surgical therapy and a substantial reduction of the immunosuppressive drugs used in post-transplantation.

A key early decision in managing IA in renal transplant recipients is whether to stop or greatly reduce immunosuppression, usually resulting in loss of the graft [Denning, 1996]. The risk of death is high, as the diagnosis is often made late, and so this critical early decision is difficult and complex [Fernando et al, 2018]. The use of adjuvant gamma interferon may allow both patient and graft survival [Armstrong-James et al, 2010], but is still not always successful and the data supporting this strategy limited.

Antifungals
Antifungal treatment should be started as soon as possible as delay in starting antifungal treatment is associated with worse prognosis [Balcan et al, 2018]. Voriconazole, lipid based amphotericin B, isavuconazole, micafungin, and caspofungin are the most frequently used antifungals in the management of IA in RT [Kabir et al, 2019]. Given the risk of drug-drug interactions and renal toxicity, the choice of antifungal therapy in renal transplant recipients requires meticulous guidance. Avoiding nephrotoxic medication is advisable during the management of IA in renal transplanted patients.

Azole drugs:
Among the azoles, voriconazole, isavuconazole and posaconazole are the most frequently used antifungals in the management of invasive aspergillosis [Vanhove et al, 2017]. Fluconazole should not be used for aspergillosis because it does not act on Aspergillus spp [Patterson et al, 2016].

Voriconazole
Voriconazole is the drug of choice in the management of IA and its superiority above other antifungals is well documented [Patterson et al, 2016; Kabir et al, 2019]. In a global Aspergillus study, voriconazole was ~20% more effective in terms of survival, treatment response, and drug interactions compared to conventional amphotericin B [Herbrecht et al, 2002]. Liposomal amphotericin B is equivalent to conventional amphotericin B invasive aspergillosis but less nephrotoxic and so would be preferred [Patterson et al, 2016] [Denning, 2007]

However, administration of voriconazole is not free from adverse effects. Approximately 30% of patients on voriconazole develop reversible visual disturbance and some patients experience an elevation of liver enzymes [Kabir et al, 2019]. The patient’s liver enzyme level should be monitored before commencing therapy and then every 2-4 weeks during therapy [Kabir et al 2019]. Since prolonged voriconazole therapy is associated with cutaneous squamous cell carcinoma, patients should be advised to avoid sun exposure [Kabir et al, 2019]. In addition, prolonged usage of voriconazole leads to the accumulation of fluoride and is linked to painful periostitis in solid organ transplant recipients [Kabir et al, 2019]. Apart from that, accumulation of cyclodextrin of intravenous voriconazole may cause renal damage, and its use in significant renal impairment is contraindicated. Moreover, ingestion of voriconazole with fatty meals is not recommended since it can reduce the bioavailability of voriconazole [Kabir et al, 2019].

Therapeutic drug monitoring (TDM) of voriconazole is an important therapeutic guide in the management of IA owing to its variable degree of first-pass metabolism [Vanstraelen et al, 2015]. The first-pass metabolism of voriconazole is mediated by cytochrome 450 enzymes (CYP2C19, -2C9, -3A4, and -3A5) which shows genetic heterogeneity and high serum concentrations are observed in CYP2C19 poor metabolizers [Vanhove et al, 2017]. About 3% of people of European ancestry and 15% of north Asian ancestry are slow metabolisers. Its significant variable pharmacokinetics is related to genetic variability, hepatic dysfunction, drug-drug interactions, and patient age [Vanhove et al, 2017]. Consequently, dose adjustment of voriconazole according to TDM is recommended and especially for patients who do not respond to therapy and for patients with possible toxic effects [Kabir et al, 2019].

Administration of voriconazole in renal transplanted patients requires appreciation of significant interactions between different immunosuppressive drugs (calcineurin inhibitors and mTOR inhibitors) [Fernando et al, 2018]. Since voriconazole is a potent inhibitor of CYP3A4, it has the potential to increase the blood level of calcineurin inhibitors (cyclosporin and tacrolimus) leading to toxicity [Vanhove et al, 2017] [Fernando et al, 2018]. Some drugs, such as sirolimus, are contraindicated with the use of voriconazole [Kabir et al, 2019]. Concomitant use of voriconazole and tacrolimus requires an immediate tacrolimus dose reduction by 66-75% and monitoring the trough level of tacrolimus [Vanhove et al, 2017]. In addition, voriconazole interacts with prednisolone and dose adjustment is needed.

Isavuconazole and posaconazole
Both isavuconazole and posaconazole are effective and safe azole antifungal agents for IPA [Küpeli et al, 2012]. Isavuconazole shows similar efficacy with less liver toxicity and fewer drug interactions compared to voriconazole as shown in a recent randomized, prospective, double-blind, double-dummy, controlled trial [Maertens et al, 2016.] Although, isavuconazole is only a moderate CYP3A4 inhibitor, there are some key drug interactions to be aware of, including tacrolimus and sirolimus.

Posaconazole is also non-inferior to voriconazole in terms of mortality of IA as shown in a recent randomized, prospective, double-blind, double-dummy, controlled trial [Maertens et al, 2021]. Moreover, patients had fewer side effects compared to voriconazole and posaconazole was better tolerated [Maertens et al, 2021]. However, posaconazole therapy also requires regular checking of electrolytes levels and liver function [Maertens et al, 2021].

Itraconazole
Itraconazole has been used in the management of invasive aspergillosis in certain case reports with variable results. IPA patients have been successfully treated with itraconazole with a 100% success rate in early case series [Denning, 1996]. However, itraconazole is regarded as third-line drug therapy due to its variable bioavailability and drug-drug interaction with immunosuppressive therapy. Retrospective evaluation of systemic fungal infections in 296 renal transplanted patients from 1986 to 1999 described three IPA patients treated with oral itraconazole who died [Altiparmak et al, 2002]. However, itraconazole prophylaxis of 400mg per day seems to reduce the risk of IA in solid organ transplanted recipients but is not strongly recommended in renal transplantation [Kabir et al, 2019]. Cyclosporin dose should be halved on the first day of itraconazole treatment and then measured frequently.

Polyenes
Amphotericin B is recommended as second line therapy of IA (amphotericin B lipid complex 5 mg/kg/day IV, liposomal amphotericin B 3mg/kg/day IV) [Kabir et al, 2019]. Retrospective evaluation of systemic fungal infections in 296 renal transplanted patients from 1986 to 1999 revealed a 50% favourable response among treated IPA patient cases [Altiparmak et al, 2002]. Liposomal or lipid-associated amphotericin B are preferred to minimise nephrotoxicity. Although conventional amphotericin B (0.5-1.0 mg/kg) has been used as salvage therapy in the absence of lipid-based amphotericin B, a successful therapeutic outcome usually requires the cessation of immunosuppressive therapy and resection of the transplanted kidney.

Echinocandins
Eechinocandins are partially effective and safe agents for refractory IPA [Küpeli et al, 2012]. Both micafungin and caspofungin are considered second-line therapy for IA [Kabir et al, 2019]. They usually demonstrate a safe therapeutic profile and minimum drug interactions. Echinocandins are frequently used as a combination therapy in refractory IA [Kabir et al, 2019], and have value in those infected with azole-resistant strains of Aspergillus. In addition, dose adjustment during renal insufficiency is not needed for echinocandins.

Combination of antifungals
Certain species like Aspergillus calidoustus and some A. fumigatus strains are azole-resistant. In these cases, a combination of drugs (e.g., liposomal amphotericin B and an echinocandin) may be considered [Ganesh et al, 2021].

Aspergillus terreus and Aspergillus nidulans are amphotericin B resistant. The combination of echinocandin with a triazole is promising, however requires further studies [Küpeli et al, 2012]. A combination of voriconazole and echinocandin should be reserved for salvage therapy in treatment-refractory cases, unless resistance is demonstrated [Kabir et al, 2019].

Duration of antifungals
The optimal duration of antifungal therapy for IA in renal transplanted recipients has yet not been established and it should be guided by the extent of the disease, response to therapy and whether immunosuppression is necessary [Kabir et al, 2019]. Some authors recommend 6–12 weeks of administration of antifungals [Kabir et al, 2019] while others recommend antifungals until two weeks after complete clinical improvement of IA. Some authors recommend 6 months duration of treatment with voriconazole after surgical treatment of IA [Trnacevic et al, 2018]. Monitoring of GM and direct smear and cultures could be used to direct the decision of therapy discontinuation [Kabir et al, 2019]. The American Society of transplantation guidelines recommend antifungals (voriconazole) up to complete clinical improvement followed by secondary lifelong prophylaxis [Ganesh et al, 2021].

Surgical treatment
Surgical therapy is an adjunctive therapy to antifungal therapy in the management of IPA in RT patients [Scanagatta et al, 2004; Alkhunaizi et al, 2005]. Early and thorough surgical intervention, along with the use of appropriate antifungals and a substantial reduction of the immunosuppressive drugs contributes to the prolonged survival of RT patients with IA [Alkhunaizi et al, 2005]. Surgical resection of necrotic tissue reduces the load of fungi and may allow early discontinuation of antifungal therapy [Alkhunaizi et al, 2005] [Jha, et al 2000]. If resection is done, it should be complete to avoid contamination of the healthy lung, if technically possible [Scanagatta et al, 2004].

Surgical therapy is advocated for localized pulmonary lesions without extra-pulmonary dissemination [Scanagatta et al, 2004] [Alkhunaizi et al, 2005]. It is also lifesaving in the treatment of patients with massive haemoptysis [Küpeli et al, 2012][Kabir et al 2019].

The value of adjunctive surgical therapy has been highlighted and linked to the survival of patients in several case reports [Parasuraman et al, 2000; Trnacevic et al, 2018; Alkhunaizi et al, 2005]. A retrospective study of invasive fungal infections among 296 renal transplanted individuals emphasizes successful outcome owing to surgical intervention, management of super-infection, nutritional and metabolic support adjunctive to appropriate antifungal therapy [Altiparmak et al, 2002]. In some cases, surgical removal of renal graft has been required due to graft failure [Trnacevic et al, 2018]. However, it is noteworthy remembering that this cohort of patients are poor surgical candidates and surgical intervention in this group is hesitant due to multiple reasons [Scanagatta et al, 2004].

Immunomodulation (GCSF/Gamma interferon)
Recent studies have observed the positive impact of adjunctive immunotherapy along with IFN-γ in invasive fungal infections through enhancing host defense mechanisms [Delsing et al, 2014]. Interferon (IFN-γ) has been trialled in renal transplant recipients with life-threatening, refractory invasive fungal infections with positive outcomes [Armstrong‐James et al, 2010]. In this case series, IFN-γ was not associated with renal allograft dysfunction, IFN-γ toxicity and IFI relapses during follow-up [Armstrong‐James et al, 2010]. A 6-week of combination of IFN-γ and antifungals cured infections and led to savings in healthcare cost [Armstrong‐James et al, 2010].

Prevention
Most of the preventive methods have been extrapolated from other similar settings because there are no obvious recommendations pertaining to renal transplanted individuals. Constructions in progress in hospital premises or residences pose the risk of getting invasive aspergillosis [Vinod et al, 2009]. Consequently, avoiding such risk areas could be advisable. In addition, restricting bringing dust and plant pots into patient rooms would be good practice because they could have Aspergillus spores [Vinod et al, 2009].
The prophylactic use of antifungals in renal transplant recipients remains controversial attributed to its low incidence, significant drug-drug interactions, inadequate solid evidence, risk of resistance, risk of breakthrough infection, and costs [Neofytos et al, 2021]. At the moment, there is no formal recommendation regarding antifungal prophylaxis in renal transplant recipients [López‐Medrano et al, 2016].
L. Shamithra M. Sigera, Department of Mycology, Medical Research Institute, Colombo, Sri Lanka. sshamithra@yahoo.com

David W. Denning, The University of Manchester, Manchester UK
ddenning@manchester.ac.uk
July 2022