Rare Mycobacterial Infections in Kidney Transplant Recipients – Case Reports

Abstract

To study the clinical profile and outcomes of rare mycobacterial infections such as nontuberculous mycobacteria (NTM) and Mycobacterium leprae kidney transplant recipients. This is a retrospective analysis of clinical outcomes of the uncommon infections in renal allograft recipients over 22 years during 2000–2022 from a tertiary care center in southern India; the clinical data were obtained from electronic medical records of nephrology and clinical microbiology departments. Institutional review board approved this study vide minute number 13641 dated 02.12.2020. A total of 1970 patients underwent renal transplantation at our institute, from January 1, 2000, to December 31, 2022. During this period, five patients were diagnosed with mycobacterial infections, three of whom had NTM infections and two with Mycobacterium leprae infections. The patients were all diagnosed by isolating organism in blood and/or pus cultures. All patients were similarly managed initially with a reduction of immunosuppressive drugs and appropriate antibiotics as per protocol. At present, there is no standard serodiagnostic test available to reliably detect patients with rare infections. Initial cultures may yield negative results due to slow growth and inconsistent colony appearance. Our research revealed that the majority of patients had negative sputum cultures and negative Gram stains. Therefore, it is essential to maintain a high level of suspicion and conduct thorough investigations in postrenal transplant recipients to achieve early diagnosis, administer appropriate treatment, and prevent disease spread.

Introduction

Kidney transplantation remains a critical therapeutic intervention for patients with end-stage renal disease, offering a significant improvement in quality of life and survival. However, recipients of kidney transplants face increased susceptibility to a variety of infections due to the immunosuppressive therapies. Among these infections, non-tuberculous mycobacterial (NTM) infections and leprosy less commonly discussed complications.

Non-tuberculous mycobacteria, also known as environmental mycobacteria, are a diverse group of mycobacterial species that are widely distributed in soil, water, and dust. These organisms typically cause opportunistic infections in immunocompromised individuals. The clinical presentation of NTM infections can be insidious and challenging to diagnose, often leading to delayed treatment and poorer outcomes.

Leprosy, caused by Mycobacterium leprae, is another rare but significant infectious concern in kidney transplant recipients. Though it is predominantly found in endemic regions and has a low incidence in the general population, leprosy can present with atypical features and challenges in the immunocompromised host. The immunosuppressive environment of kidney transplant recipients may alter the natural history of the disease, complicating both diagnosis and management.

This article aims to review the current understanding of non-tuberculous mycobacterial infections and leprosy in the context of kidney transplantation. By exploring the pathogenesis, clinical manifestations, diagnostic challenges, and management strategies, we hope to enhance awareness and improve outcomes for transplant recipients at risk of these rare but significant infections.

Nontuberculous Nycobacterial Infections

Nontuberculous mycobacteria (NTM) encompass more than 140 distinct species of common environmental organisms typically found in soil and water. While NTMs are generally considered rare causes of clinical illness in the general population, their incidence postsolid organ transplantation (SOT) is perceived to be rising in recent years, attributable to increased exposure, longer survival rates, and enhanced diagnostic techniques.^[1] Among SOT recipients, kidney transplant recipients have the highest incidence of NTM infections, likely due to the greater number of kidney transplants performed compared to other types of SOT. Among renal transplant recipients, the estimated incidence of NTM infection ranges from 0.16% to 0.55%.^[2–6] This study presents three cases of kidney transplant recipients diagnosed with NTM infection.

Case 1

A 55-year-old female underwent live-related, ABO-compatible kidney transplantation in 2002, with basiliximab as induction agent followed by maintenance immunosuppression with prednislone, tacrolimus, and mycophenolate mofetil. She had no history of rejections or other posttransplant complications. Ten years after kidney transplantation, she presented with an abscess over anterior abdominal wall. She had stable graft function with serum creatinine of 1.3 mg/dl. The drained pus grew Mycobacterium fortuitum which was sensitive to amikacin, linezolid, ofloxacin, and imipenem. She was treated with sulfamethoxazole 800 mg-trimethoprim 160 mg (cotrimoxazole) double strength twice daily, levofloxacin (500 mg) and azithromycin (500 mg) in renal adjusted doses for 6 months. At 1 year, there was no recurrence of the abscess, either locally or systemically. Her graft function remained stable.

Case 2

A 35-year-old man underwent live-related ABO-compatible kidney transplantation in 2011. He had stable graft function with a serum creatinine of 1.4 mg/dl with no history of rejections. After 12 years of stable postkidney transplantation period, he presented with persistent right eye discharge and pain after cataract surgery. On evaluation, he was detected to have endophthalmitis. He underwent vitrectomy and removal of the exudative membrane. The vitreal aspirate grew Mycobaterium abscessus which is sensitive only to amikacin and imipenem. He was treated with intravenous imipenem 1 g twice daily with clarithromycin 500 mg twice daily and clofazmine 200 mg once daily for 1 month followed by linezolid 600 mg twice daily, clarithromycin 500 mg twice daily and clofazamine 200 mg once daily for 1 year in renal adjusted doses. The minimum inhibitory concentration (MIC) values were amikacin – 16 mg/L, moxifloxacin – >16 mg/L, clarithromycin – 64 mg/L, olinezolid – 64 mg/L, imipenem – 16 mg/L, minocycline – >32 mg/L, cotrimoxazole – >32 mg/L, and tetracycline – >32 mg/L. Most of the drugs were resistant but taking into account the various available options, linezolid has the closest MIC to the clinical and laboratory standard institute (CLSI) breakpoint. Hence, linezolid was added. At the end of 1 year, he had symptomatic improvement with no recurrence of infection and stable graft function.

Case 3

A 45-year-old man underwent a deceased donor kidney transplantation in 2016, which was his second kidney transplantation. There was persistent perigraft collection in the immediate postoperative period with stable graft function. The culture of aspirate from the collection grew Mycobacterium fortuitum which was sensitive to amikacin and linezolid. He was treated with intravenous amikacin 10 mg/kg once daily given for 1 month, moxifloxacin 400 mg once daily, minocycline 100 mg twice daily and linezolid 600 mg twice daily in renal adjusted doses for 6 months with close monitoring of graft function. At 6 months, he had complete resolution of perigraft collection. The clinical features, transplant details, organism isolated, and sensitivity patterns are detailed in Table 1.

Table 1. Clinical, transplant, and immunosuppression details of patients and sensitivity patterns of nontuberculus mycobacteria.

Age/sex	Live/Deceased	Induction	Maintenance IS	Onset of infection posttransplant	Clinical presentation	Specimen from which organism isolated	Organsim’s sensitivity pattern
							Am	Az	CT	Imipenem	Levoflox	TC
55/ female	Live ABO-compatible	Basiliximab	P/T/M	10 years	Abscess in anterior abdominal wall	Pus C/s M. fortuitum	Sensitive	Resistant	Resistant	Sensitive	Sensitive	Resistant
35/ male	Live ABO-compatible	Basiliximab	P/CsA/MPA	12 years	Right eye chronic endophthalmitis	Vitreous aspirate M. abscessus	Sensitive	Resistant	Resistant	Sensitive	Resistant	Resistant
45/ male	Deceased	ATG	P/AZA	Immediate postoperative period	Persistant perigraft collection	Pus C/s M. fortuitum	Sensitive	Resistant	Resistant	Resistant	Sensitive	Resistant

Am: Amikacin, Az: Azithromycin, ATG: Antithymocyte globulin, AZA: Azathiprine, C/s: Culture and sensitivity, CsA: Cyclosporine, IS: Immunosuppression, M: Mycobacterium, MPA: Mycophenolate, O: Ofloxcain, T: Tacrolimus, TC: Tetracycline, M. fortuitum: Mycobacterium fortuitum, M. abscessus: Mycobacterium abscessus

Discussion

Among SOT recipients, kidney transplant recipients exhibit the highest reported incidence of NTM infections, with the most prevalent being local cutaneous disease, including cases with secondary cutaneous dissemination, followed by osteoarticular disease.^[7] Risk factors for NTM disease encompass immunocompromised states, treatment with monoclonal antibody therapies, and genetic defects of the interferon-gamma receptors and signaling pathways.^[8] The overall state of immunosuppression may facilitate the progression to clinical disease among those with environmental exposures, particularly in patients undergoing anti-rejection therapy, thereby increasing the risk. The standard approach to treating NTM disease involves a combination antimycobacterial therapy administered for an extended duration.^[9] To prevent the development of resistance during therapy, multiple active agents are necessary, especially in patients with severe or disseminated disease and a high organism burden, for whom induction treatment with a minimum of three active drugs followed by maintenance therapy with dual drugs is recommended. Treatment often continues until multiple negative cultures are documented. The choice of antimycobacterial agents and treatment duration depends largely on the specific NTM isolate, considering the wide variability of in vitro susceptibility patterns. Alongside reducing immunosuppression, timely surgical resection, debridement of fluid collections or devitalized tissue, or removal of infected devices are advocated to decrease organism burden and diminish the risk of drug resistance. Anticipated interactions between medications for NTM and immunosuppressive agents should be considered. Rifamycins, such as rifabutin, are potent cytochrome P450 (CYP450) inducers and can lower blood levels of calcineurin and mammalian target of rapamycin inhibitors, while macrolide antibiotics like clarithromycin, potent CYP450 inhibitors, may have the opposite effect. Azithromycin, with minimal in vitro inhibitory effect on CYP450, is preferred in the transplant population. Treatment often necessitates a combination of a macrolide and rifamycin, thus requiring close monitoring of calcineurin inhibitor levels and adjustment of drug doses accordingly.

In this case series, three patients had varied clinical presentations of cutaneous abscess in the first patient, endophthalmitis in the second patient, and perigraft collection in the immediate posttransplant period in the third patient. None of our patients had received anti-rejection therapy within 6 months of NTM infection. In the first patient, the levels of the drug at the time of infection were tacrolimus level (C0) 5.8 ng/ml and mycophenolate area under the curve (MPA-AUC) level was 60.3 mg/h/L, which is on the higher side of the normal range. In the second patient, cyclosporine (Co) was 180.3 ng/ml and MPA-AUC was 62.6 mg/h/L,^[10] the latter being a bit higher than required. The third patient, had perigraft collection in the immediate postoperative period and methylprednisolone pulse intraoperative period and high dose of steroids in the early transplant period might contributed to the development of NTM infection. All the patients were managed with reduction of immunosuppression (50% reduction of antimetabolite agents such as MPA and azathioprine) and appropriate anti mycobacterial drugs as per culture and sensitivity. The therapeutic drug monitoring and graft function monitoring were done during the course of therapy as these patients required amikacin and clarithomycin. All three patients showed improvement and resolution of infection with stable graft function at the end of 6 months.

Hansen’S Disease

Leprosy is a chronic granulomatous disease caused by the acid-fast bacillus Mycobacterium leprae. It is rare in organ transplant patients; cases have been reported in three heart, one liver, and 12 renal transplantation patients worldwide.^[11,12] In 1997, Anand et al. have published nine cases of leprosy in postrenal transplant patients from our institute.^[13] With the Government’s National leprosy eradication program (NLEP) and active surveillance at field level, the incidence of leprosy has reduced considerably. However, the diagnosis cannot be ruled out in endemic countries where patients present with typical skin lesions.

Case 1

A 49-year-old female underwent live related ABO-compatible renal transplantation in 2001 with basiliximab as induction followed by maintenance immunosuppression with prednisolone and azathioprine. Tacrolimus was stopped in view of recurrent thrombotic microangiopathy in the early postoperative period. She had no rejections or other posttransplant complications like diabetes. She presented 12 years after transplant with complaints of erythematous patchy skin lesions associated with fever and myalgia. There was no family history or past history of Hansen’s disease. On examination, there were multiple well-defined erythematous plaques of size ranging from 1 × 1 cm to 3 × 3 cm all over the body involving the face, trunk, and both extremities. The motor and sensory nervous system examination was normal. Skin smears showed a Bacterial Index of 2.5%. She was diagnosed with subpolar lepromatous Hansen’s disease with type 2 reaction. She was started on multibacillary multi-drug treatment (MB-MDT) regimen for 12 months with clofazimine started at a dose of 300 mg once daily with decrease in dose by 100 mg every 3 months, followed by 50 mg once daily; minocycline 100 mg once daily, ofloxacin 400 mg once daily and thalidomide 50 mg once daily. The dosage of prednisolone was increased to 30 mg once daily, and the dose of azathioprine was reduced to 50 mg once daily. At the end of 12 months, she had a complete resolution of symptoms.

Case 2

A 46-year-old man underwent live-related ABO-compatible renal transplant in 2011 with basiliximab induction followed by maintenance immunosuppression with prednisolone, tacrolimus, and Mycophenolate mofetil. He had no rejections or other posttransplant complications like diabetes. He presented 9 years after transplantation with a history of erythematous rashes over the face, followed by spreading to the trunk and then extremities over 10 days. On examination, bilateral supraciliary madarosis was present. Also present were erythematous plaques in the periorbital region 6 cm × 5 cm with associated scaling and multiple erythematous plaques of varying sizes of about 2 cm × 1 cm on the forehead and face more on the left side, abdomen, arms and lower back. There was right ear lobe infiltration and there was erythematous plaque with scaling over the left ear lobe. His skin smear showed a bacterial index of 2+ in all the sites and a morphological index of 0. Histology of skin biopsy showed a borderline tuberculoid Hansen’s disease in type I reaction. In view of the Type 1 reaction with lesions around the eyes, he was treated with intravenous hydrocortisone 50 mg six hourly for 2 days followed by prednisolone 50 mg, which was tapered and stopped after 14 days. He was treated with MB-MDT for 12 months with supervised therapy of rifampicin 600 mg and clofazimine 300 mg once a month, which was administered on an empty stomach and self-administered therapy of dapsone 100 mg once daily and clofazamine 50 once daily. The clinical, transplant, and treatment details are detailed in Table 2.

Table 2. Clinical, transplant, and immunosuppression details, treatment details of patients with Hansen’s disease.

Age/sex	Live/deceased	Induction	Maintenance IS	Onset of infection posttransplant	Clinical presentation	Diagnosis	Treatment received (6 months)
49/female	Live ABO- compatible	Basiliximab	P/AZA	12 years	Erythematous patchy skin	Skin smears BI - 2.5% Subpolar LL with Type 2 reaction	Clofazamine-300 - → 100 mg OD Ofloxacin - 400 mg OD Minocycline 100 mg OD
46/male	Live ABO- compatible	Basiliximab	P/Tac/MPA	9 years	Erythematous patchy skin lesions	Skin smears BI - 2% Borderline TL with Type I reaction	Rifampicin 600 mg and Clofazimine 300 mg once a month for 6 months Dapsone 100 mg OD and Clofazimine 50 mg OD daily for 6 months

Aza: Azathioprine, BI: Bacteriological index, MPA: Mycophenolate, OD: Once a day, Tac: Tacrolimus, LL: Lepromatous leprosy, TL: Tuberculoid leprosy, IS: Immunosuppression

Discussion

Leprosy remains a significant public health concern in various regions globally. According to reports from the World Health Organization, in 2012, the global registered prevalence of leprosy was 0.34.^[14] In India, the NLEP serves as the centrally sponsored health initiative under the Ministry of Health and Family Welfare, Government of India. Over the years, there has been a notable decrease in the prevalence rate, from 57.8/10,000 in 1983 to achieving the status of “elimination as a public health problem” of <1/10,000 by December 2005, and further reducing to 0.66/10,000 in 2016, attributed to the implementation of multidrug therapy (MDT).^[15] A high level of suspicion is necessary when patients present with unusual skin rashes, even in the absence of sensory or motor neurological involvement. In our investigation, two patients exhibited skin rashes without sensory or motor neurological symptoms. Both patients positively responded to the MDT regimen, which can be safely administered to kidney transplant recipients undergoing immunosuppression. In addition, both patients maintained stable graft function.

Conclusion

Maintaining a high level of suspicion and conducting thorough investigations in postrenal transplant recipients can facilitate early diagnosis, ensuring prompt and effective treatment, and preventing disease dissemination. Initial cultures may yield negative results due to slow growth and variable colony morphology. In our study, the majority of patients exhibited negative sputum cultures, and Gram stains were also negative. Timely diagnosis, administration of appropriate antibiotics, and adherence to treatment duration are critical in managing this atypical disease. Regular therapeutic drug monitoring is essential to assess the net state of immunosuppression, which represents the most significant risk factor for opportunistic infections.