Key words : Kidney transplantation, Nocardia

Introduction

For patients who have undergone solid-organ transplant, infection remains one of the most common and serious complications as a result of the regimens required to prevent rejection. Opportunistic infections, which are generally of lower virulence within a healthy host but cause more severe and frequent disease in immunosuppressed individuals, typically occur in the period from 1 month to 1 year after transplant. Risks of infection are influenced by many factors, including the epidemiologic exposures, the “net state of immunosuppression,” use of infection prophylaxis, and monitoring and time of infection relative to the time of transplant.¹ Perhaps the most critical factor in predicting the risk of opportunistic infection is the time of presentation of illness relative to the transplant procedure. Classically, infections occur during 3 time periods. During the first month posttransplant, almost all are due to typical postoperative nosocomial infections. Rarely do patients develop recipient origin infections or donor-derived infections. During the period of peak immunosuppression, typically months 1 to 12 posttransplant, most infections are classic opportunistic infections, including cytomegalovirus, aspergillus, Nocardia, and toxoplasmosis. The use of prophylaxis could result in the later development of opportunistic infections. Late infections, those occurring more than 1 year after transplant, are typically community-acquired infections, although opportunistic infections may rarely occur.²

Nocardia are aerobic actinomycetes, ubiquitous saprophytes in soil, decaying organic matter, and fresh and saltwater. Over 100 species of the genus Nocardia have been identified, and 50% have been described during the past 10 years. Under microscopic examination, Nocardia organisms are branching, beaded, filamentous, gram-positive bacteria.³

The clinical syndromes vary from pulmonary, disseminated, and cutaneous forms. The clinical manifestations may be subtle, with radiological findings mimicking other entities such as malignancy. The organism requires multiple days to grow in culture. Thus, detection and early treatment may be delayed. The lungs are presumed to be a primary site of infection (60% to 80% of cases), and brain abscess is the most common complication, conferring poor prognosis.⁴ Patients with impaired cell-mediated immunity are especially at high risk for infection, including those with lymphoma, other selected malignancies, human immunodeficiency virus infection, and solid-organ or hematopoietic stem cell transplants.⁵ Among solid-organ transplant recipients, the frequency of Nocardia infection has been shown to range from 0.6% to 3% and has been well described. In renal transplant patients, information on the incidence and risk factors associated with nocardiosis is restricted primarily to case reports and case series comprising a small number of patients.⁶

Irrespective of a patient’s immunologic status, the isolation of Nocardia from the respiratory tract or other body sources should not be regarded as a contaminant or commensal organism.5 The cutaneous, lymphocutaneous, and subcutaneous forms of nocardiosis arise from local traumatic inoculation. These infections are not necessarily associated with immunocompromised host states, but dissemination from these inoculation sites is more likely in immunocompromised hosts, particularly those with impaired cell-mediated immunity. Pleuropulmonary nocardiosis presumably arises from inhalation exposure. Disseminated nocardiosis results from hematogenous dissemination, usually from a pulmonary focus. Most individuals with disseminated nocardiosis have an underlying immunocompromising disease or are receiving immunosuppressive therapy. Nocardiosis produces suppurative necrosis with frequent abscess formation at sites of infection.

BK polyomavirus remains latent in uroepithelium cells after initial infection, which typically occurs in early childhood. Although asymptomatic shedding can occur in immunocompetent patients, it is more common among transplant recipients. The clinical disease can include hemorrhagic cystitis and BK virus nephropathy.⁷ Although BK virus nephropathy can rarely occur in nonrenal transplant patients, it causes BK virus nephropathy in up to 15% of kidney transplant recipients in the absence of routine screening.⁷ Because viruria and viremia predate the development of BK virus nephropathy in most patients, routine screening of renal transplant recipients coupled with modulation of immunosuppression is cost-effective. It decreases the risk of development of BK virus nephropathy. Current guidelines recommend monthly screening for viremia until month 9 followed by screening every 3 months until 2 years with prolonged screening in pediatric transplant patients. Persistent viremia of greater than 1000 copies/mL for 3 weeks or an increase to greater than 10 000 copies/mL should prompt a reduction of immunosuppression and more frequent monitoring in patients. No prospective study has demonstrated the optimal approach to reducing immunosuppression. Current guidelines suggest a 50% decrease of 1 agent first, with further decreases in immunosuppression if viremia persists or progresses.⁷

Here, we present a kidney transplant recipient who developed BK nephropathy and nocardiosis after kidney transplant.

Case Report
Our patient was a 54-year-old Kuwaiti man with type 2 diabetes mellitus for more than 10 years complicated by diabetic retinopathy, hypertension for more than 10 years, dyslipidemia, and end-stage kidney disease secondary to diabetic kidney disease.

In October 2017, the patient started renal replacement therapy with hemodialysis via a right internal jugular permanent venous catheter. He underwent a deceased donor kidney transplant in August 2019 with 2 mismatches, negative complement-dependant cytotoxicity, and flow cytometry crossmatch, with positive class II donor-specific antibodies with mean fluorescence intensity of 2697; for this, he received desensitization therapy with intravenous immunoglobulin (IVIg) and rituximab. He received induction with thymoglobulin and maintenance immunosuppression of prednisolone, tacrolimus, and mycophenolate mofetil (MMF). He was discharged 6 days posttransplant with a stable serum creatinine level of 90 ?mol/L. He received pneumocystis chemoprophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), cytomegalovirus prophylaxis with valganciclovir, and fungal prophylaxis with nystatin.

Unfortunately, he had persistent leukopenia/lymphopenia despite MMF holding and multiple filgrastim injections. The cytomegalovirus and Epstein-Barr virus polymerase chain reaction results were checked multiple times and were negative. In January 2020, he developed unexplained graft dysfunction with positive BK viremia (120?000 copies/mL) and viruria (6.4 billion copies/mL); thus, the provisional diagnosis was BK nephropathy. An ultrasonographic scan revealed no abnormality, and his panel reactive antibody test was negative. He refused to undergo graft biopsy, so 120 g IVIg over 5 days was given, MMF was switched to leflunomide, and corticosteroid dosage was tapered.

In June 2020, the patient had an accidental fall. He sought orthopedic consultation, which requested magnetic resonance imaging of the spine and pelvis. These scans revealed degenerative lumbar spondylosis, avascular necrosis of the femoral head, and obturator muscle abscess. In June 2020, he underwent an emergency surgical exploration by an orthopedic surgeon who did not find any abscesses. Meropenem was started empirically because the patient was febrile. A COVID-19 test was negative, and a septic profile was also obtained on admission. In July 2020, he discharged himself against medical advice with instructions for clindamycin 300 mg every 8 hours. Three days later, a blood culture showed Nocardia; therefore, the patient was admitted the next day to our center where he received dual antibiotic treatment (imipenem and linezolid) until the availability of the sensitivity report.

Computed tomography scans of his brain and chest ruled out any central nervous system or pulmonary involvement. Therefore, the treatment was planned for 6 months according to his culture and sensitivity. His bone scan revealed osteomyelitis of the right superior pubic ramus and prepubic swelling, likely an abscess in both obturator externus and internus, which was confirmed by a computed tomography scan (Figure 1).

The orthopedic surgeon evacuated the abscess. During this time, the patient had received more than 2 weeks of dual antibiotics, and he was still on the same planned antibiotic regimen. The cultured pus was negative for any growing organism. His serum creatinine stabilized around 155 ?mol/L, and his BK viruria and viremia improved after reduction of his immunosuppression. During his last follow-up in late August 2021, his graft function was stable, he showed negative panel reactive antibodies, and he had a normal leukocyte count and normal BK viremia (73 copies/mL). His maintenance immunosuppression included prednisolone 5 mg, tacrolimus with trough level 3.8 ng/mL, and MMF 500 mg twice per day.

Discussion
Nocardiosis is an uncommon gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia spp. can cause localized or systemic suppurative disease in humans and animals. Nocardiosis is typically regarded as an opportunistic infection; however, approximately one-third of infected patients are immunocompetent.⁸ Immunosuppressive therapy predisposes patients to Nocardia infection. In patients who are on these drugs because they have undergone organ transplant, immunosuppression cannot be stopped; however, the dose should be decreased as much as possible. In patients who are receiving immunosuppressive therapy for other reasons, it is ideal to discontinue the immunosuppressive agent if alternatives are available. Infection with Nocardia typically affects somewhere between 0.7% and 3.5% of solid-organ transplant recipients.⁹

Two characteristics of nocardiosis are its ability to disseminate to virtually any organ, particularly the central nervous system, and its tendency to relapse or progress despite appropriate therapy.

The lack of prospective controlled trials has so far hindered general treatment recommendations for nocardiosis. The optimal antimicrobial treatment regimens have not been firmly established. Nocardia displays variable in vitro antimicrobial susceptibility patterns, and management of Nocardia infections must be individualized.¹⁰ However, the Clinical and Laboratory Standards Institute has published their recommendations for antimicrobial susceptibility testing for Nocardia and other aerobic actinomycetes.¹¹ Despite their bacteriostatic activity, sulfonamides, including sulfadiazine and sulfisoxazole, have been the antimicrobials of choice to treat nocardiosis for the past 50 years. Divided doses of 5 to 10 mg/kg/day of the trimethoprim component (or 25 to 50 mg/kg/day of sulfamethoxazole) are recommended to produce sulfonamide serum concentrations between 100 and 150 g/mL. Adverse reactions to high-dose TMP-SMX therapy are frequent and include myelosuppression, hepatoxicity, and renal insufficiency. Trimethoprim-sulfamethoxazole is active against most Nocardia species; however, N. otitidiscaviarum is commonly resistant to TMP-SMX, and N. nova and N. farcinica are occasionally resistant.¹² Alternative antimicrobial agents with activity against Nocardia include amikacin, imipenem, meropenem, ceftriaxone, cefotaxime, minocycline, moxifloxacin, levofloxacin, linezolid, tigecycline, and amoxicillin/clavulanic acid. Combination therapy may provide enhanced activity.¹³

Some authorities have recommended prolonged oral maintenance therapy to prevent relapse of nocardiosis in patients who continue to be immunosuppressed due to their disease or treatment (eg, patients with HIV/AIDS, hematopoietic stem cell or solid-organ transplant recipients, and patients receiving high-dose glucocorticoids or cytotoxic therapy). A maintenance regimen of TMP-SMX at 1 single-strength tablet daily is advised provided that the Nocardia isolate is susceptible to TMP-SMX. Alternative maintenance regimens for patients unable to tolerate TMP-SMX have not been systematically evaluated. However, doxycycline 100 mg daily is a reasonable alternative.¹⁴

Regarding the treatment of BK viremia with or without nephropathy, reduction of immunosuppression is the mainstay of therapy. There is no good evidence to guide this, but many protocols start with reducing or withdrawing antiproliferative agents (MMF/azathioprine). Calcineurin inhibitor levels should be lowered (eg, a tacrolimus level of 3-6 ng/mL). The risk is precipitation of rejection; the treatment of this, with concomitant BK nephropathy, is highly challenging. Many clinicians continue with immunosuppression reduction and treat rejection with intravenous and oral steroids. An alternative is IVIg at 2 g/kg, for example, as it has the theoretical ability to “neutralize” the BK virus and has recognized anti-rejection efficacy. The anti-arthritis drug leflunomide has both immunosuppressive and antiviral properties (acts by inhibition of tyrosine kinase activity and depletion of pyrimidine). Its side effects include hemolytic anemia, thrombocytopenia, thrombotic microangiopathy, and hepatic impairment. Quinolones may have some benefits in treating BK viremia. No clear evidence has been shown to support the use of antivirals. Cidofovir for 1 to 4 doses every 2 weeks has been the most popular.¹⁵

Conclusions

In renal transplant recipients, successful management of combined BK nephropathy and nocardiosis was feasible with minimization of immunosuppression and proper antimicrobial therapy.

References:

1. Fishman JA. Infection in organ transplantation. Am J Transplant. 2017;17(4):856-879. doi:10.1111/ajt.14208
   CrossRef - PubMed
   
2. Helfrich M, Dorschner P, Thomas K, Stosor V, Ison MG. A retrospective study to describe the epidemiology and outcomes of opportunistic infections after abdominal organ transplantation. Transpl Infect Dis. 2017;19(3). doi:10.1111/tid.12691
   CrossRef - PubMed
   
3. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc. 2012;87(4):403-407. doi:10.1016/j.mayocp.2011.11.016
   CrossRef - PubMed
   
4. Kranick SM, Zerbe CS. Case report from the NIH Clinical Center: CNS nocardiosis. J Neurovirol. 2013;19(5):505-507. doi:10.1007/s13365-013-0193-7
   CrossRef - PubMed
   
5. Young LS, Rubin RH. Mycobacterial and nocardial diseases in the compromised host. In: Clinical Approach to Infection in the Compromised Host. Springer; 2002:249-264.
   CrossRef - PubMed
   
6. Gibson M, Yang N, Waller JL, et al. Nocardiosis in renal transplant patients. J Investig Med. 2021;jim-2021-001783. doi:10.1136/jim-2021-001783
   CrossRef - PubMed
   
7. Hirsch HH, Randhawa PS; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13528. doi:10.1111/ctr.13528
   CrossRef - PubMed
   
8. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore). 2004;83(5):300-313. doi:10.1097/01.md.0000141100.30871.39
   CrossRef - PubMed
   
9. Restrepo A, Clark NM; Infectious Diseases Community of Practice of the American Society of Transplantation. Nocardia infections in solid organ transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin Transplant. 2019;33(9):e13509. doi:10.1111/ctr.13509
   CrossRef - PubMed
   
10. Munoz J, Mirelis B, Aragon LM, et al. Clinical and microbiological features of nocardiosis 1997-2003. J Med Microbiol. 2007;56(Pt 4):545-550. doi:10.1099/jmm.0.46774-0
    CrossRef - PubMed
    
11. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes. NCCLS document M24-A, volume 23. Clinical and Laboratory Standards Institute (formerly NCCLS); 2011.
    CrossRef - PubMed
    
12. McNeil MM, Brown JM, Hutwagner LC, Schiff TA. Evaluation of therapy for Nocardia asteroides complex infection: CDN/NCID report. Infect Dis Clin Pract. 1995;4(4):287-292.
    CrossRef - PubMed
    
13. Cercenado E, Marin M, Sanchez-Martinez M, Cuevas O, Martinez-Alarcon J, Bouza E. In vitro activities of tigecycline and eight other antimicrobials against different Nocardia species identified by molecular methods. Antimicrob Agents Chemother. 2007;51(3):1102-1104. doi:10.1128/AAC.01102-06
    CrossRef - PubMed
    
14. Peleg AY, Husain S, Qureshi ZA, et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis. 2007;44(10):1307-1314. doi:10.1086/514340
    CrossRef - PubMed
    
15. Oxford Handbook of Nephrology and Hypertension. 2nd ed. Oxford University Press; 2014.
    CrossRef - PubMed