Abstract
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.
1. 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.
The mainstay of Nocardia treatment is prolonged antibiotic therapy, although surgical debridement may also be required [8]. Despite treatment, the prognosis of nocardiosis in SOTRs is poor [9,10,11,12,13]. Here, we describe our experience at a tertiary transplant center.
2. Methods
2.1. 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.
2.2. 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.
2.3. 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.
2.4. Literature Review
We conducted a comprehensive literature database search on Ovid Medline, Embase, CINAHL, and Cochrane CENTRAL to find all relevant literature, published from 1 March 1993 through 1 March 2023. We limited the search to studies on adult humans, in English. We included all randomized controlled trials (RCTs), cohort studies, and case series that included targeted data on Nocardia infection and SOT. We excluded the publications involving population other than SOTRs and case series with less than five SOTRs. Reports where information could not be extracted in detail were excluded. We initially found 616 citations. We used Covidence web-based software (www.covidence.org, accessed on 12 March 2023) to remove duplicates, screen titles and abstracts, and read full articles. In total, 17 publications met the criteria, including 13 retrospective reviews, 2 matched case–control studies, and 2 RCTs with a total of 475 patients (Table 1). Causative organisms included the following: N. farcinica (103/475; 21.6%), N. asteroides (90/475; 18.9%), N. nova (87/475; 16.8%), other N. species (82/475; 17.2%), N. cyriacigeorgica (42/475; 8.8%), N. abscessus (18/475; 3.7%), N. brasiliensis (15/475; 3.2%), N. beijingensis (11/475; 2.3%), N. veterana (7/475; 1.5%), N. pseudobrasiliensis (5/475; 1.0%), N. wallacei (3/475; 0.6%), N. otitidiscaviarum (3/475; 0.6%), N. tranvalencis (3/475; 0.6%), N. flavorosea (2/475; 0.4%), N. brevicatena (2/475; 0.4%), N. paucivorans (1/475; 0.2%), and N. asiatica (1/475; 0.2%). Overall Nocardia incidence ranged between 0.4 and 45%. The median time from transplant to Nocardia diagnosis ranged between 0 and 244 months post-transplant. Median duration of therapy ranged between 3 and 12 months. The recurrence rate ranged between 0 and 11%. Overall mortality ranged between 8.3% and 77%, with death attributable to Nocardia between 0 and 40%.
Table 1.
Literature review and summary of nocardiosis in solid organ transplant recipients in the past 30 years.
3. Results
3.1. Patient Characteristics
Between 1 January 2012 and 30 June 2022, 6179 SOTs were performed at JMH, including 3845 kidney, 1421 liver, 122 pancreas, 227 kidney–pancreas, 230 heart, 159 lung, 6 heart–lung, and 169 intestine. Within the entire cohort, a total of 13 patients were diagnosed with nocardiosis including 7/13 kidney alone (54%), 4/13 heart (30%), 1/13 double lung (8%), and 1/13 combined heart–kidney transplant recipients (8%) (Table 2). The overall rate of infection by Nocardia was 0.2%, with the following distribution according to transplant type: kidney 0.18% (7/3845), heart 1.73% (4/230), lung 0.62% (1/159) and combined heart–kidney 16.6% (1/6). The patients were predominantly male (77%) and African American (77%), with a median age of 54 years (range 26–66). Only one patient had a history of chronic corticosteroid use prior to SOT due to sarcoidosis.
Table 2.
Clinical characteristics and outcomes.
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.
3.2. 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.
Most patients required invasive work-up for Nocardia diagnosis, including bronchoscopy (6/13, 46%), lung biopsy (2/13, 15%), and skin biopsy (2/13, 15%). Out of 13 cases, 2 (15%) were diagnosed by blood cultures, and 1 (7.5%) was diagnosed by the Karius test. The Karius test is a non-invasive blood test based on next-generation sequencing of microbial cell-free DNA, able to diagnose clinically relevant bacteria, DNA viruses, fungi, and parasites. BAL or tissue Nocardia polymerase chain reaction was not performed. Nocardia species included N. cyriacigeorgica in 23% (3/13), N. asteroides in 7.5% (1/13), N. nova in 7.5% (1/13), N. farcinica in 7.5% (1/13), N. abscessus in 7.5% (1/13), N. carnea in 7.5% (1/13), and N. niwae in 7.5% (1/13) of patients. In contrast to our review of literature documenting N. farcinica to be the predominant species in SOTRs, our cohort had N. cyriacigeorgica as the most common isolate. Species identification of 4/13 isolates was not available. Time from symptom initiation to nocardiosis diagnosis ranged from 7 to 90 days (median 22 days).
3.3. 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%).
3.4. 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 13.5–112.2 months).
4. 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 post-transplant 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.
Additionally, 4/13 isolates (30%) had no species identification, and 2/13 (15%) had no antimicrobial susceptibility testing available.
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.
Author Contributions
J.B.V. and S.A. conceived and designed the study. J.M.R. and J.B.V. performed a review of the literature. All the authors participated in the generation of the data and interpretation of results. J.B.V. and S.A. wrote the first version of the article. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors on request.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
| ALZ | alemtuzumab |
| AMC | amoxicillin–clavulanic acid |
| AMK | amikacin |
| ATG | thymoglobulin |
| AZA | azathioprine |
| AZM | azithromycin |
| BAL | bronchoalveolar lavage |
| BAS | basiliximab |
| CIP | ciprofloxacin |
| CLR | clarithromycin |
| CNS | central nervous system |
| CRO | ceftriaxone |
| DB | daclizumab |
| DDKT | deceased-donor kidney transplant |
| DLT | double lung transplant |
| ESRD | end-stage renal disease |
| CEP | cefepime |
| GGO | ground-glass opacity |
| IPA | invasive pulmonary aspergillosis |
| IPM | imipenem |
| JMH | Jackson Memorial Hospital |
| LZD | linezolid |
| MAC | mycobacterium avium complex |
| MIN | minocycline |
| MMF | mycophenolate mofetil |
| MP | methylprednisolone |
| MPA | mycophenolic acid |
| MXF | moxifloxacin |
| MWF | Monday–Wednesday–Friday |
| N/A | not applicable |
| NICM | non-ischemic cardiomyopathy |
| PCP | Pneumocystis pneumonia |
| RCT | randomized controlled trial |
| RIX | rituximab |
| SOT | solid organ transplant |
| SOTRs | solid organ transplant recipients |
| Tac | tacrolimus |
| TMP-SMX | trimethoprim–sulfamethoxazole |
| TOB | tobramycin |
| Wk | weeks |
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