| Abstract|| |
Introduction: Fungi are ubiquitous organisms and significantly alter the post-transplant course. They are a major cause of morbidity and mortality and more so in developing countries. Aims: To study the clinical profile, etiology, risk factors, treatment, and outcome of fungal infections in post-renal transplant recipients. Materials and Methods: This was a cross-sectional observational retrospective study from January 2014 to June 2017 wherein renal transplant recipients with invasive fungal infection were included and were followed. Results: Amongst 550 renal transplant recipients, 56 (10.2%) patients developed invasive fungal infection. Mean age of patients was 40.61 ± 10.06 (13-66) years and mean duration of acquiring infection post-transplant was 25.33 ± 23.65 (1-96) months. Male to female ratio was 3:1. Fever was the commonest presentation observed in 89.3% patients. Cough (76.8%), breathlessness (64.3%), sputum (55.3%), hypoxia (50%), and hemoptysis (10.7%) were other common clinical symptoms at presentation. Mean serum creatinine at presentation was 1.70 mg/dl. Most common invasive fungal infection isolated was Mucormycosis 15 (26.7%), foolwed by Aspergillosis 13 (23.2%), Pneumocystis jiroveci 12 (21.4%), Cryptococcus 6 (10.7%), Candida 4 (7.1%), Histoplasmosis 3 (5.3%), Phaeohypomycosis 2 (3.5%), and 5 (8.9%) patients had undetermined fungal etiology. Twenty (35.7%) patients had evidence of dual infection. Use of antithymocyte globulin 27 (48.2%), post-transplant diabetes mellitus 18 (32.1%), Cytomegalovirus (CMV) infection 16 (28.5%), anti-rejection therapy 9 (16%), and Hepatitis C infection 7 (12.5%) were some identified risk factors. Ten (17.8%) patients had graft loss and 12 (21.4%) patients died in the study period. Conclusions: Invasive fungal infection is a serious threat to renal transplant recipients. Patient and graft survival is significantly affected by fungal infection in developing world.
Keywords: Aspergillosis, cryptococcosis, invasive mycosis, mucormycosis, post-renal transplant
|How to cite this article:|
Gupta KL, Bagai S, Ramachandran R, Kumar V, Rathi M, Kohli HS, Sharma A, Chakrabarti A. Fungal infection in post-renal transplant patient: Single-center experience. Indian J Pathol Microbiol 2020;63:587-92
|How to cite this URL:|
Gupta KL, Bagai S, Ramachandran R, Kumar V, Rathi M, Kohli HS, Sharma A, Chakrabarti A. Fungal infection in post-renal transplant patient: Single-center experience. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Nov 24];63:587-92. Available from: https://www.ijpmonline.org/text.asp?2020/63/4/587/299306
| Introduction|| |
Renal transplantation offers the best cure for chronic kidney disease (CKD) end-stage renal disease (ESRD) patients. It ensures a better quality and longevity of life as compared to patients on waiting list for transplant. The refinements in immunosuppressive agents, graft preservation, and surgical techniques have all contributed to better graft survival; however, this has been accompanied by high incidence of opportunistic infections. Calcineurin inhibitor, which includes cyclosporine and tacrolimus, impairs calcineurin-induced upregulation of IL-2 expression, affecting T-lymphocyte functions resulting in increased susceptibility to invasive fungal diseases (IFI). The hot and humid climate, overcrowding, nonaffordability, malnutrition, and inaccessible healthcare facilities have made the developing nations more susceptible to these infections and is a serious cause of morbidity and mortality and also has a huge impact on the countries economy. As per one study post-transplant infections rank second as the cause of death in patients with allograft. The state of net immunosuppression seals the final fate of the transplant recipient. However, there is limited information on the etiology and course of post-transplant infections in tropical countries. An Indian study by Jha et al. estimated that infections complicate the course of 50–70% of transplant recipients in tropical countries; with mortality ranging from 20 to 60%. However, despite new antimicrobials infection rate following transplant have not come down. As per Rubin's timeline fungal infection can dominate right from immediate post-transplant period to any time after that. This is consistent with study by RK where fungal infections contributed to 55% of total opportunistic infections. Currently, overall mortality due to IFIs in solid organ transplant recipients ranges between 25% and 80%.
Not many studies are available from India which have comprehensively studied the fungal infection profile in the post-transplant patients. This article will provide an insight on the risk factors, clinical presentation, etiology, treatment and outcome of the patients.
| Materials and Methods|| |
This was a single-center, retrospective observational study of 550 RTR who underwent transplantation between 2014 and 2017. Medical records were studied. Diagnosis was based on clinical presentation, radiological findings, and unresponsiveness of infections to conventional antibiotics followed by microbiological findings. Response to antifungal treatment was recorded. Patient demographic details were noted. Time to onset of infection, clinical presentation, organ of involvement, risk factors, immunosuppression, and graft function at presentation in form of serum creatinine were noted. Etiological diagnosis was established by subjecting specimens like sputum, bronchoalveolar lavage (BAL), wound infections, tissue, and blood for culture sensitivity and susceptibility. CT-guided fine needle aspiration cytology (FNAC), transbronchial lung biopsy (TBLB), transbronchial needle aspiration (TBNA), stereotactic brain biopsy, and surgical excision were other invasive procedures done in individual cases to establish a confirm diagnosis. Special stains and culture were used to identify each fungus.
Statistical analysis: It was a descriptive study. Variables were expressed as mean, median and interquartile range (IQR) as per normal or otherwise distribution.
| Results|| |
IFI were diagnosed in 56 (10.2%) patients amongst 550 transplant recipients during the study period. Mean age of patients was 40.61 ± 10.06 (13-66) years. Male to female ratio was 3:1 (42 males and 14 females). Thirty nine (70%) patients had undiagnosed cause of CKD, 5 (9%) had chronic glomerulonephritis (CGN), Diabetic nephropathy each, 2 (3.5%) had congenital anomalies of kidney an durinary tract (CAKUT), chronic interstitial nephritis (CIN) and focal segmental glomerulosclerosis (FSGS) each and 1 (1.6%) had IgA nephropathy (IgAN) as cause of CKD. Twenty seven (48%) patients received ATG induction, 4 (7%) received basiliximab whereas 25 (44.6%) did not receive any induction. Majority of donors (n = 24) were unrelated and 10 patients were deceased donor transplants [Table 1].
Presentation and risk factors for IFI
The mean duration of diagnosis of infection post-transplant was 25.33 ± 23.65 (range:1-96) months. Amongst clinical symptoms fever was the most common and was seen in 89.3% of patients. Cough (76.8%), breathlessness (64.3%), sputum (55.3%), hypoxia (50%), hypotension (26.8%), and hemoptysis (10.7%) were other common clinical symptoms at presentation. Mean serum creatinine at presentation was 1.70 mg/dl. Most of the patients 52 (93%) were on triple immunosuppression with CNI, mycophenolate, and prednisolone. Use of antithymocyte globulin 27 (48.2%), post-transplant diabetes mellitus 18 (32.1%), CMV co-infection 16 (28.5%), anti-rejection therapy 9 (16%), hepatitis C infection 7 (12.5%), and hepatitis B 1 (1.6%) were risk factors identified [Table 2] and [Table 3].
Fungal etiology and site of IFI
Most common invasive fungal infection isolated was Mucormycosis 15 (26.7%). This was identified by presence of aseptate hyphae in tissues [Figure 1]. Pulmonary involvement in form of cavity, consolidation was the most common form of presentation (n = 11). Graft 2 (3.5%), rhinocerebral 1 (1.6%) and disseminated mucormycosis 1 (1.6%) were other pattern of involvement seen [Figure 1]. Out of 15 patients with mucormycosis, 2 (3.5%) had co-infection with mycobacteria and 1 (1.6%) was co-infected with aspergillus. Aspergillosis occurred in 13 (23.2%) patients of all transplant recipients. The fungus morphologically appears as septate hyphae and species identification was done as per culture. Majority (93%) of infection was localized in the lungs (n = 12) but 1 patient had graft aspergillosis for which culture came out to be positive for aspergillus flavus [Figure 2]. Out of 13 patients with aspergillosis 6 (10.7%) had dual infection, 2 patients had co-infection with mucormycosis and bacterial each, 1 patient had co-infection with scedosporium and mycobacteria each. Pneumocystis jiroveci infection was seen in 12 (21.4%) patients where 4 patients had co infection with CMV and 1 had co infection with Nocardia. All pneumocystis cases were localized to the lungs. Six 6 (10.7%) patients had a cryptococcal infection with 5 cases localized to CNS and 1 patient had evidence of dissemination involving lung and CNS. Candida was isolated in 4 (7.1%) patients with 3 cases localized to oral cavity and 1 case had candida related graft pyelonephritis. Histoplasmosis 3 (5.3%) was localized to the lung in 2 cases and 1 case had nasal mass. Phaeohypomycosis 2 (3.5%) and 5 (8.9%) patients with undetermined fungal etiology were other infection seen in our study. Demetacious fungi have morphological appearance similar to aspergillus but show grayish olivaceous colonies on lactophenol cotton blue staining. The detailed etiology with area of infestation with each fungus is listed in [Table 4].
|Figure 1: (a) CT chest showing a cavity in the right lower lobe of lung. (b) Trans-bronchial lung biopsy reveals fungal hyphae consistent with Zygomycosis/Mucormycosis (H and E, ×160). (c) Photomicrograph showing broad aseptate hyphae of Mucormycosis (PAS, ×640). (d) Calcofluor KOH mount showing broad aseptate hyphae of Mucormycosis under fluorescent microscope|
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|Figure 2: Sagittal section of brain showing two haemorrhagic infarcts in the right temporal lobe. (a) Dichotomous acute angle branching of Aspergillus hyphae (silver methenamine stain, ×640). (b) Confluent Aspergillus colony in the lung (PAS stain, ×160). (c) Typical microscopic morphology of Aspergillus flavus on lactophenol cotton blue mount showing the sporulating heads|
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|Table 4: Etiology and site of Invasive fungal infections in renal transplant recipients|
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Treatment and outcome
All patients with Mucormycosis, Histoplasmosis, Cryptococcosis were treated with conventional amphotericin-B at dose 1 mg/kg/day or liposomal amphotericin-B at a dose of 3–5 mg/kg with close observation for side effects for cumulative dose around 3.0 gm and 4.5 gm, respectively. Aspergillus and Phaeohypomycosis were treated with voriconazole and pneumocystis cases were given cotrimoxazole. For Mucormycosis cases, posaconazole was used as maintenance. Simultaneously, the dose of immunosuppressive drugs was reduced in all cases. Mycophenolate and calcineurin inhibitors (CNI's) were temporarily discontinued. Surgical intervention was done in all cases of mucrmycosis. Graft nephrectomy was done in cases of invasive fungal infection involving the graft.
Twelve (21.4%) patients died and rest showed clinical improvement. Around 37 (66%) patients had evidence of AKI but only 10 (17.8%) had graft loss.
| Discussion|| |
The incidence of invasive fungal infection varies with the type of organ transplant. Incidence of IFI have been maximum in Liver transplant patients and least with renal transplant recipients as per one study. The Incidence varies ranges from 5 to 42% following SOT. In our study, the incidence of IFI was 10.2% which is consistent with a previous study done at our center where Gupta et al. reported 9.8% post-transplant patients who had systemic mycoses with candidiasis (2.8%), aspergillosis (2.3%), mucormycosis (2%), and cryptococcosis (1.9%). In another study from our center IFI incidence was 6.1%. The incidence of IFI varies from institute to institute as the environmental condition varies and this is the difference between different incidence rates reported from various centers all across India.,,, Candida and Aspergillus dominated amongst the fungal infections in the past. However, Gupta et al. reported a recent rise in angio-invasive infections like aspergillosis and mucormycosis, which are associated with high mortality. Mean age of study participants was 40.61 ± 10.06 (13-66) years and male to female ratio was 3:1 (42 males and 14 females) which is similar to other studies.
Twenty seven (48%) patients received ATG induction, 4 (7%) received basiliximab whereas 25 (44.6%) did not receive any induction. Majority of donors (n = 24) were unrelated and 10 patients were deceased donor transplants.
The mean duration of diagnosis of infection post-transplant was 25.33 ± 23.65 (range:1-96) months. This varied range of presentation in our study is consistent with John et al. who had showed that fungal infections occur at all time points, crossing the 6-month milestone even in those who have no extra immunosuppression. Kumar A in their study also concluded that most infections in their study occurred 1 year after transplant. Amongst clinical symptoms fever was the most common and was seen in 89.3% of patients. Cough (76.8%), breathlessness (64.3%), sputum (55.3%), hypoxia (50%), hypotension (26.8%), and hemoptysis (10.7%) were other common clinical symptoms at presentation. This is similar to another studies in India where fever was the most common presentation seen., Mean serum creatinine at presentation was 1.70 mg/dl. Most of the patients 52 (93%) were on triple immunosuppression with CNI, mycophenolate, and prednisolone. Use of Antithymocyte globulin 27 (48.2%), post-transplant diabetes mellitus 18 (32.1%), CMV co-infection 16 (28.5%), anti-rejection therapy 9 (16%), hepatitis C infection 7 (12.5%), and hepatitis B 1 (1.6%) were risk factors identified. This is consistent with findings of study done in other centers.,,
Most common invasive fungal infection isolated in our study were Mucormycosis and Aspergillosis, which is consistent with previous study from our center. This is in contrast to many studies wherein, the incidence of invasive mycosis is not high as was seen in our study, which can be due to our being a referral center in North India. Mucormycosis is caused by saprophytic fungi belonging to the order Mucorales and genera Rhizopus, Absidia, and Mucor. In this study, most common fungi isolated was Mucormycosis 15 (26.7%). Pulmonary involvement in the form of the cavity, consolidation was the most common form of presentation (n = 11). Graft 2 (3.5%), rhinocerebral 1 (1.6%) and disseminated 1 (1.6%) were other pattern of involvement of mucormycosis. In a study Park BJ et al. showed that lung is most common site of mucormycosis in solid organ transplant patient. Out of 15 patients with mucormycosis, 2 (3.5%) had co-infection with mycobacteria and 1 (1.6%) was co-infected with aspergillus. Mucormycosis patients in our study had a high mortality of 53.3% (n = 8). This is consistent with other studies., Demonstration of aseptate hyphae in tissue proved/disproved the diagnosis.
Aspergillosis is a very common opportunistic infection in renal transplant recipients with a prevalence of 0.5-4%. The most common site of infection is lungs. In our study, Aspergillosis occurred in 13 (23.2%) patients with 93% of infection localized in the lungs (n = 12) and 1 patient had graft aspergillosis. Out of 13 patients with aspergillosis 6 (10.7%) had dual infection, 2 patients had co-infection with mucormycosis and bacterial each, 1 patient had co-infection with scedosporium and mycobacteria each. It is associated with mortality rates of 40-70%. In our study, low mortality was seen with aspergillosis 2 (15%).
Pneumocystis jiroveci is a quintessential opportunistic infection in immunocompromised patients. Its incidence was high before cotrimoxazole introduction. Overall incidence of infection among solid organ transplant recipients varied in the range of 5–15%. In our study incidence was a bit higher (21.4%) patients where 4 patients had co infection with CMV and 1 had co-infection with Nocardia. CMV co-infection has immunomodulatory effects, hence increases chances of post-transplant infections.
Cryptococcus is a common infection which usually occurs after 6 months of post-transplantation with symptoms usually localized to central nervous system (CNS). [17,22] It may be reinfection or reactivation of the infection. Overall incidence as per literature is around 0.5-5% and contributes about 8% to IFI's. CNS and lungs constitute for most of the cases. Around 50-70% cases have disseminated disease or are localized to CNS. Lack of exudative inflammation is a characteristic feature of CNS cryptococcosis, and signs of meningeal irritation are absent in most cases. Diagnosis is made by examination of the cerebrospinal fluid, including India ink staining and cryptococcal capsular polysaccharide antigen testing are required where index of suspicion is high. In our study, 6 (10.7%) patients had cryptococcal infection with 5 (83%) cases localized to CNS and 1 patient had evidence of dissemination involving lung and CNS.
Candida was isolated only in 4 (7.1%) patients with 3 cases localized to the oral cavity and 1 case had candida-related graft pyelonephritis. This is consistent with previous study from our center where incidence of candidiasis was 2.8% but another study previously showed 37% cases of candida infection.
Histoplasmosis is an endemic fungi with approximately 90% of these infections result in mild and clinically significant respiratory infections. The other 10% of the patients suffer serious pulmonary or disseminated infection. In this study, 3 (5.3%) was localized to lung in 2 cases and 1 case had nasal mass. Phaeohyphomycosis is caused by a large, heterogeneous group of darkly pigmented fungi. The presence of melanin in their cell walls is characteristic, and is likely an important virulence factor. Brain abscess and pneumonia can occur with these infections and is associated with high mortality of about 25-40% of patients. Phaeohypomycosis 2 (3.5%) and 5 (8.9%) patients with undetermined fungal etiology were other infection seen in our study.
CT guided FNAC, Bronchoalveolar lavage and transbronchial lung biopsy were used as invasive methods for diagnosing the etiology of the infection. Patients were treated with amphotericin B, voriconazole, and fluconazole. Posaconazole was given to mucormycosis patients as rescue treatment or added on treatment. Surgical intervention was combined with medical treatment for managing mucormycosis.
Twelve (21.4%) patients died and rest showed clinical improvement. This is consistent with other study where reported mortality was 30%. Around 37 (66%) patients had evidence of AKI but only 10 (17.8%) had graft loss.
| Conclusions|| |
IFI is a common complication following renal transplantation. IFI is associated with increased morbidity and mortality in RT patients. Triple immunosuppression, post-transplant diabetes mellitus, anti-rejection therapy, CMV and hepatitis co-infection are added risks for IFI. Zygomycosis and aspergillosis are important causes of IFI and meticulous workup is required for delineating exact etiology and for improving prognosis of the patients.
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Conflicts of interest
There are no conflicts of interest.
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Krishan L Gupta
Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]