Nocardiosis in Solid Organ Transplant Recipients: 10-Year Single Center Experience and Review of Literature

Solid organ transplant recipients (SOTRs) are at an increased risk of nocardiosis, a rare but life-threatening opportunistic infection. Universal PCP prophylaxis with trimethoprim–sulfamethoxazole (TMP-SMX) is used at our center, which is active in vitro against most species of the Nocardia genus and may have a role in preventing early infections. This is a single-center retrospective cohort study of nocardiosis in adult SOTRs at a large transplant center between January 2012 and June 2022, with comprehensive review of literature. Out of 6179 consecutive cases, 13 (0.2%) were diagnosed with nocardiosis. The patients were predominantly male (76.9%) and kidney transplant recipients (62%). Infection was diagnosed at median of 8.8 months (range, 3.7–98) after transplant. Patients were followed for a median of 457 days (range 8–3367). Overall mortality within one year after diagnosis was 46% (6/13), of which 17% (1/6) of deaths was attributable to Nocardia infection. No recurrence was reported. Nocardia infections were noted in a small proportion of our SOTRs and carried significant morbidity and mortality. TMP-SMX prophylaxis may be protective in some cases given low incidence of cases.


Introduction
Nocardiosis is an opportunistic infection caused by Nocardia spp., a ubiquitous actinomycete found in decaying vegetation, soil, and fresh and salty water.As inhalation is the main form of entry for Nocardia, lung involvement is frequent, and bacteria may subsequently disseminate to distant areas, such as the skin/soft tissue, brain, or another vital organ [1].
Solid organ transplant recipients (SOTRs) are uniquely predisposed to nocardiosis due to their iatrogenic cell-mediated immune deficit necessary to avoid rejection and to maintain allograft function.The overall incidence of Nocardia infection in SOTRs ranges from 0.1 to 3.5%.Rates of infection vary based on the transplanted organ, with higher rates reported among thoracic transplant recipients [2][3][4][5][6][7].Most cases of Nocardia infection occur at a median of 17.5 (range, 2-244) months after solid organ transplant (SOT) [4].Early nocardiosis can occur in the setting of acute rejection treatment.

Study Design and Patient Selection
This is a single-center, retrospective cohort of adult SOTRs with nocardiosis from 1 January 2012 to 30 June 2022 who underwent transplantation at the Miami Transplant Institute, Jackson Memorial Hospital (JMH), Miami, Florida, USA.Patient demographics, immunosuppressive regimen, use of PCP prophylaxis, rejection, concurrent opportunistic infections, clinical presentation, radiological findings, treatment, and outcomes were collected.

Definition
Nocardia infection was defined as culture growth of Nocardia species with compatible signs, symptoms, and/or radiographic features.Sampling sites included blood, sputum, bronchoalveolar lavage (BAL), lung biopsy, skin biopsy, or abscess drainage of collections.Disseminated infection was defined as involvement of at least 2 non-contiguous sites, or isolated central nervous system (CNS) involvement.Determination of infection cure or nocardiosis as the attributable cause of death was performed by physician review of the medical record.
Organisms were identified initially in the JMH microbiology laboratory using MALDI-TOF MS (Biomerieux, Marcy-l'Étoile, France).Specimens were then sent to the National Jewish Health Laboratories (Denver, CO, USA) for further identification by molecular methods if needed, and antimicrobial susceptibility testing.The institutional review board approved the study.

Statistical Analysis
Demographic data were analyzed using descriptive statistics.Categorical variables were reported as numbers and percentages.Continuous variables were reported as the median and interquartile range (IQR) or range.
The induction regimen varied according to the SOT type.Five out of thirteen patients were diagnosed with acute rejection at a median of 97 days (range: 59-149) before diagnosis of Nocardia infection and were treated with augmented immunosuppression as per institutional protocol.Most patients (10/13) received a T-cell-depleting antibody in the preceding 12 months as either part of the induction regimen or rejection treatment.Prednisone was part of the maintenance regimen at the time of Nocardia diagnosis in 12/13 patients (92%), with a median dose of 20 mg daily.An elevated calcineurin inhibitor level in the preceding month was present in only 1/13 patients (7.5%).
Nine out of thirteen patients were diagnosed with nocardiosis while receiving PCP prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX).Among patients on TMP-SMX prophylaxis, data on Nocardia susceptibility were available for 7/9 patients, and all isolates were susceptible to TMP-SMX.Compliance with TMP-SMX could not be evaluated.In addition, 2/13 patients were receiving PCP prophylaxis with dapsone, and 2/13 were not receiving any PCP prophylaxis due to remote history of transplantation.
Six out of thirteen patients (46%) had a concomitant opportunistic infection, particularly cytomegalovirus, invasive aspergillosis, and non-tuberculous mycobacteria.

Clinical and Radiographical Characteristics
Time from transplantation to nocardiosis diagnosis ranged from 3.7 to 98 months (median 8.8 months).Lungs were the sole site of infection in 55% of the patients (7/13).Radiographic findings included lung mass, pulmonary nodules, ground-glass opacities, cavitary lesions, and halo signs.Four out of thirteen patients (30%) had extrapulmonary involvement in addition to pneumonia, including skin abscesses, bacteremia, and brain lesions.Isolated skin infection was present in 1/13 patients (7.5%), and isolated CNS infection was observed in 1/13 patients (7.5%).Of the 12 patients with no neurological symptoms, 11 (91.6%)underwent routine brain computerized tomography or magnetic resonance imaging, and 3/11 (27%) were found to have Nocardia metastatic CNS infection.

Management
Antibiotic susceptibility testing was available for 11/13 isolates and is outlined in Table 2.All strains were susceptible to TMP-SMX, imipenem (IPM), and linezolid (LZD).Combination therapy was implemented in all patients.Intravenous therapy was the initial route in 11/13 cases (84%).The most common empiric regimen was IPM plus TMP-SMX in 5/13 cases (38%), followed by IPM plus LZD in 3/13 cases (23%).Among the patients with susceptibility available, 11/11 received at least one drug with in vitro activity against the Nocardia isolate during the first 2 weeks.Ten out of eleven patients (90%) received an association of two appropriate antibiotics during the first 2 weeks of treatment.The median duration of therapy was 12 months (range 6-19 months) among the patients who completed treatment.Side effects were reported in 6/13 cases (46%), with hyperkalemia due to TMP-SMX being the most common.Secondary prophylaxis was utilized in 7/8 patients (87.5%).

Outcomes
One-year all-cause mortality was 46% (6/13), with 1/6 (17%) deaths attributable to nocardiosis.Nocardia infection did not directly contribute to 5/6 deaths, as determined by physician review of the medical record.Five out of thirteen patients (38%) achieved cure, with no recurrence after a median follow-up of 47 months (range 13.5-112.2months).

Discussion
Nocardia infection was documented in 0.2% (13 of 6179) of our patients.The highest frequency corresponded to combined heart-kidney, followed by heart, lung, and kidney transplantation.Even though the overall rate of nocardiosis was lower than previously reported [2,3,6], it maintained the trend of higher rates among thoracic compared to abdominal transplant recipients.In our center, universal PCP prophylaxis with TMP-SMX is provided for a minimum of one year for non-lung transplant and lifelong for lung transplant recipients and is also active in vitro against most Nocardia species [5].Our institutional prophylaxis protocol recommends one TMP-SMX double strength (DS) tablet Monday/Wednesday/Friday (MWF) or one TMP-SMX SS tablet daily for one-year posttransplant for heart, liver, kidney, pancreas, intestinal, and multi-visceral transplant and lifelong for lung transplant recipients.Dapsone or atovaquone are reserved for patients with documented sulfa allergy.Even though the data on the use of TMP-SMX prophylaxis for Nocardia infection have been mixed [2,25], some studies indicate a partial protective effect related to TMP-SMX dose and frequency [4,24,26,27].We hypothesize that the low incidence of Nocardia infections in our series could be related to the use of universal TMP-SMX prophylaxis for a minimum of 12 months in our center.A comprehensive summary of existing literature is outlined in Table 1.
Time from transplantation to Nocardia diagnosis in our cohort ranged from 3 months to 8 years (median 8.8 months), occurring earlier than in previous reports [4] but in accordance with our review of the literature.Acute rejection treatment and a high rate of T-cell-depleting antibody use in the preceding 12 months could have favored the early development of nocardiosis in our series.
Guidelines for the treatment of nocardiosis in SOTRs have been published elsewhere [8].An optimal management protocol has not been well established for SOTRs.An initial empiric regimen is typically applied and subsequently tailored based on antimicrobial susceptibility testing.Combination therapy should be considered in severe and/or disseminated disease, and several months of therapy are usually required.Secondary prophylaxis and reinstitution of primary prophylaxis following acute rejection should be considered, even though the best TMP-SMX dose and frequency have not been determined [4,24,26,27].In our cohort, the median duration of therapy in 8/13 patients who completed treatment was 12 months, which is in accordance with the guidelines [8].Most patients (7/8) received secondary prophylaxis following treatment.No recurrences were reported after a prolonged follow-up period.Despite treatment, only 54 patients had a favorable outcome in our series.Nocardia caused 17% of deaths.
This study has several limitations of note.Firstly, it was retrospective and observational and is thus subject to intrinsic sources of bias.Secondly, we had a low number of events, which limited our analysis.The data on the duration of follow-up for the entire transplant cohort are not available, and loss of follow-up following transplantation could have contributed to the low incidence of cases.
In conclusion, nocardiosis is a rare but life-threatening opportunistic infection in immunocompromised hosts.Nocardia infection can lead to dissemination and death if untreated.A high index of suspicion is necessary even in the setting of TMP-SMX prophylaxis in SOTRs.

Table 1 .
Literature review and summary of nocardiosis in solid organ transplant recipients in the past 30 years.

Table 2 .
Clinical characteristics and outcomes.