Nocardiosis in renal transplant patients
========================================

* Maya Gibson
* Nianlan Yang
* Jennifer L Waller
* Lufei Young
* Wendy B Bollag
* Mufaddal Kheda
* Azeem Mohammed
* Stephanie L Baer

## Abstract

Renal transplant patients are immunosuppressed and are at increased risk of opportunistic infections, including *Nocardia* infection. In renal transplant patients, information on the incidence and risk factors associated with nocardiosis is limited. To address the incidence and risk factors associated with nocardiosis in a large renal transplant population, we used the US Renal Data System (USRDS). Sequelae of allograft failure or rejection after infection were also examined. Demographics, clinical risk factors, *Nocardia* diagnosis, and allograft failure following *Nocardia* infection were queried in USRDS renal transplant patients using International Classification of Diseases, Ninth Revision (ICD-9) codes in billing claims and Centers for Medicare and Medicaid Services Form 2728. Generalized linear models were used to determine the risk factors associated with nocardiosis, and Cox proportional hazards models were used to examine the association of risk factors with graft failure among patients with *Nocardia* infection. Of 203,233 renal transplant recipients identified from 2001 to 2011, 657 (0.32%) were diagnosed with *Nocardia* infection. Pneumonia was the most frequent presentation (15.2%), followed by brain abscess (8.4%). Numerous factors associated with increased *Nocardia* infection included age >65 years (OR=2.10, 95% CI 1.71 to 2.59), history of transplant failure (OR=1.28, CI 1.02 to 1.60) or history of rejection (OR=4.83, CI 4.08 to 5.72), receipt of a deceased donor transplant (OR=1.23, CI 1.03 to 1.46), and treatment with basiliximab (OR=1.25, CI 1.00 to 1.55), cyclosporine (OR=1.30, CI 1.03 to 1.65), tacrolimus (OR=2.45, CI 2.00 to 3.00), or thymoglobulin (OR=1.89, CI 1.59 to 2.25). In patients with nocardiosis administration of antithymocyte globulin (HR=2.76), chronic obstructive pulmonary disease (HR=2.47), and presentation of *Nocardia* infection with brain abscess (HR=1.85) were associated with an increased risk of graft failure. This study provides new information to enhance early recognition and targeted treatment of nocardiosis in renal transplant patients.

*   kidney transplantation
*   immunosuppression

### Significance of this study

#### What is already known about this subject?

*   The reported incidence of *Nocardia* infection in solid transplant recipients is 0.4%–3.6%.

*   Risk factors associated with nocardial infection include cytomegalovirus viremia, steroid use, and calcineurin inhibitors.

*   Pulmonary infection presentation is the most common manifestation of nocardiosis in renal transplant patients.

#### What are the new findings?

*   Of renal transplant recipients from 2001 to 2011, there is 0.32% incidence of nocardiosis within the United States.

*   The most common presentations of *Nocardia* infection in this cohort were pneumonia (14%) and brain abscess (8%).

*   Administration of basiliximab, cyclosporine, tacrolimus, or thymoglobulin was associated with an increased risk of nocardial infection.

*   Administration of antithymocyte globulin and presentation of *Nocardia* infection with brain abscess were associated with an increased risk of graft failure.

#### How might these results change the focus of research or clinical practice?

*   Nocardial infection is a rare infection in renal transplant patients which may present as pneumonia and/or brain abscess.

*   Many of the common immunosuppressants are associated with an increased risk of this opportunistic infection as are age 65+ at initial transplant, history of transplant failure, history of transplant rejection, or receipt of a transplant from a deceased donor.

## Introduction

Renal transplant recipients are by necessity immunosuppressed and are at a significantly increased risk of opportunistic infections, such as *Nocardia* infection. This bacterium is a Gram-positive filamentous rod which is rarely known to cause infection, with a reported incidence of 0.4%–3.6% in solid organ transplant recipients.1–3 A retrospective cohort study in 1989 of 94 renal transplant patients with *Nocardia* infection at a single center described various presentations: pulmonary (88%), cutaneous (20%), central nervous system (7%), and septic arthritis (7%).4 Nocardiosis may mimic the presentation of other opportunistic pathogens such as fungi. Infection occurs around 2 months to 2 years after renal transplant.1 5 Previously reported comorbidities or medications associated with *Nocardia* infection include cytomegalovirus viremia, steroid use, and calcineurin inhibitors.6–8 

Diagnosis of *Nocardia* infection often requires an invasive procedure such as bronchoscopy or biopsy to obtain a stainable specimen or culture. Misdiagnosis may arise due to structural similarities to *Actinomyces*. However, unlike *Actinomyces*, *Nocardia* will appear as a partially acid-fast filamentous rod on Kinyoun stain. Common sites of *Actinomyces* infection include the oral cavity, digestive tract, female reproductive tract, thoracic cavity, or musculoskeletal system. A study by Rousseau *et al* 9 estimates the prevalence of actinomycosis in renal transplant patients to be 0.02%.

Mortality among renal transplant recipients with non-disseminated nocardiosis ranges between 15% and 20%, while it is considerably higher, at 50%–60%, for disseminated infection.1 5 Retrospective studies suggest that early diagnosis of nocardiosis and timely treatment with antibiotics may significantly reduce mortality among renal transplant patients.5 However, several antibiotics used to treat *Nocardia* infection either affect the pharmacokinetics of immunosuppressive medicines or are nephrotoxic. *Nocardia* is not often covered by empiric antibiotics for undifferentiated fever, pneumonia, or rash. Therefore, understanding the risk factors associated with nocardiosis following renal transplant may help clinicians determine the best strategy for more expedient diagnosis and treatment.

Currently there is no reported study of nocardiosis within the United States renal transplant population. This study aims to examine the overall frequency of *Nocardia* diagnosis, the different presentations of this infection, and the associated immunosuppressive regimens, comorbidities, and risk factors associated with a diagnosis of *Nocardia* infection. Allograft failure or rejection after nocardiosis was also investigated.

## Methods

### Study cohort

A retrospective cohort study design was used to examine the incidence, time to infection, demographic, and clinical risk factors associated with individuals diagnosed with *Nocardia* infection among the renal transplant cohort in the United States Renal Data System (USRDS).10 The USRDS is a large federal data set containing demographic data, hospital, and physician/supplier claims on all Medicare-funded patients with end-stage renal disease (ESRD) in the United States on their initiation of dialysis. The database contains demographic characteristics, dialysis claims, transplant and treatment history, hospitalization events, physical/supplier services, comorbidity condition, and mortality data. All ESRD transplant patients aged 18 or older without missing data on sex, race, ethnicity, or hospital claims data were considered for inclusion in the study sample. Patients who received a pre-emptive transplant prior to dialysis were excluded as they are not in the database. This study examined the incidence of *Nocardia* infection, risk factors associated with *Nocardia* infection, presentations of *Nocardia* infection, and time to graft failure following a *Nocardia* infection.

### *Nocardia* infection

To determine whether ESRD transplant patients had a *Nocardia* infection, International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes for nocardiosis (039.1, 039.8, and 039.9) were used. All *Nocardia* infections after an initial transplant were included. *Nocardia* and *Actinomyces* share the same ICD-9 code, so the presentation of *Nocardia* infection was analyzed using clinical presentation ICD-9 codes for pneumonia, brain abscess, bacteremia, cellulitis/abscess, cutaneous nodules, and nodular pneumonia. Diagnoses with codes for lumpy jaw (039.2), Madura foot (039.4), and cutaneous infection (039.0) were excluded as these presentations are usually associated with *Actinomyces* infection. To account for time at risk of infection, the number of person-years at risk was determined from the time of the first transplant to the time of first *Nocardia* diagnosis, or to the last known follow-up date for subjects without a *Nocardia* diagnosis. The person-years at risk were then used in the statistical modeling.

### Risk factors associated with *Nocardia* infection

Demographic variables including race, ethnicity, mode of dialysis, and access type at initiation of dialysis were obtained from the Centers for Medicare and Medicaid Services (CMS) Form 2728, which is completed on initiation of dialysis. Transplant-related comorbidities and clinical risk factors were determined using procedure (current procedural terminology, CPT) and diagnosis (ICD-9) codes, and documentation of prescription of immunosuppression regimen medications was available in the transplant database. All CPT and ICD-9 codes used in this study are listed in online supplemental table 2. Transplant-related risk factors included age at transplant, donor type, history of rejection requiring at least one kidney transplant, and history of transplant failure. No limitation was placed on the number of previous kidney transplants. Immunosuppressive medications were evaluated within the database; however, the time of initiation and dosage are not made available. The medications reviewed included prescriptions for steroids, mycophenolate, cyclosporine, tacrolimus, sirolimus, prednisone, antithymocyte globulin (Atgam, Pfizer), azathioprine, everolimus, muromonab, basiliximab, rabbit antithymocyte globulin (thymoglobulin), rituximab, and infliximab. Comorbidities included the diagnosis code for cytomegalovirus, HIV, diabetes, hepatitis B, hepatitis C, granulomatous disease, chronic obstructive pulmonary disease (COPD), asthma, and tobacco use occurring after the initiation of dialysis but prior to *Nocardia* infection. Diagnosis of cytomegalovirus was defined as a diagnosis code after transplant and before the *Nocardia* diagnosis (or last follow-up date for controls). The risk factors are listed in online supplemental table 1.

### Supplementary data

[[jim-2021-001783supp001.pdf]](pending:yes) 

The number of person-years at risk was calculated from the time of initial transplant to the time of the first *Nocardia* diagnosis (for those with a diagnosis), or to the last known follow-up date (date of death or last claim date) for controls.

### Risk factors associated with increased graft failure in transplant patients with *Nocardia* infection

Among patients with nocardial infection, graft failure was defined as a diagnosis code occurring in patients who experienced a graft failure within 6 months from the time of *Nocardia* infection diagnosis. The reason 6 months was chosen for follow-up was to attempt to isolate the association of the infection or any adverse effect of its treatment on graft failure. Subjects with premature graft failure, defined as having graft failure occur within 14 days of transplant, were excluded (n=105). Time to graft failure was calculated as the number of days between the *Nocardia* infection diagnosis and the graft failure diagnosis code, or 183 days (or 6 months) for those who did not have a graft failure or whose failure occurred after 183 days. In the cohort with *Nocardia* infection, mortality was low enough the data is not reportable due to the data privacy constraints of the database.

### Statistical analysis

All statistical analyses were performed using SAS V.9.4 and statistical significance was assessed using an alpha level of 0.05. Descriptive statistics for demographic, transplant-related risk factors, and clinical diagnoses were determined overall and by *Nocardia* diagnosis. χ2 or t-tests were used to examine preliminary differences between those with and without *Nocardia* infection. To examine the association of risk factors with *Nocardia* infection, a generalized linear model (GLIM) was used incorporating person-years at risk. Each GLIM assumed a binomial distribution of the outcome measure, logit link, and used the natural log of the number of person-years at risk as an offset parameter to estimate the OR for *Nocardia* infection. Each risk factor was examined in a simple model and the crude OR was estimated along with 95% CI. All risk factors were then entered into a comprehensive full GLIM, and a backward model building strategy was used to arrive at the comprehensive final model. Starting with the full model, the most non-significant variable was removed from the model. The Akaike’s information criterion (AIC) and −2Log likelihood (−2LL) test were used to determine whether the reduced model fit is as good as the previous model. A lower AIC and non-statistically significant −2LL test indicated whether the reduced model was as good as the previous model. If the reduced model was not as good as the previous model, the variable was re-entered in the model and the next most non-significant variable was examined for removal. The final model included any variable that was statistically significant and/or needed in the model using the model building criteria. Adjusted OR and the corresponding 95% CI are presented for the final models.

For graft failure within 6 months after *Nocardia* infection, a Cox proportional hazards (CPH) analysis was used to investigate the effect of various demographic, transplant-related, or clinical risk factor variables on the time from transplant to graft failure using a similar model building strategy as before. Adjusted HR and 95% CI were determined for the final model.

Before multivariable modeling for both *Nocardia* infection as an outcome and for graft failure as an outcome, variance inflation factors between all potential risk factors were examined. All variance inflation factors were <5, indicating no multicollinearity between risk factors.

## Results

### Descriptive statistics

Of the 203,233 patients with ESRD with data available for evaluation in the USRDS transplant population between 2001 and 2011, 657 (0.32%) were diagnosed with *Nocardia* infection. Table 1 shows the descriptive statistics for ESRD transplant patients. Of all the transplant patients, 60% were male, nearly 70% were white and 25% black, 13% were Hispanic, and 13% were aged 65 or older at the time of initial transplant. About 70% received their transplant from a deceased donor and 42% had a history of graft failure.

View this table:
[Table 1](/content/70/1/36/T1)

Table 1 
Descriptive statistics, n (%), overall and by *Nocardia* infection in 203,233 ESRD transplant patients

### Risk factors associated with *Nocardia* infection

Table 2 and figure 1 show the final adjusted OR for risk factors associated with *Nocardia* infection.

View this table:
[Table 2](/content/70/1/36/T2)

Table 2 
Simple and final adjusted relative risk from GLIM of risk factors for *Nocardia* infection in 203,233 ESRD transplant patients

![Figure 1](/https://d3hme472k3gd2d.cloudfront.net/content/jim/70/1/36/F1.medium.gif)

[Figure 1](/content/70/1/36/F1)

Figure 1 
aRR and 95% CI from the final adjusted model for *Nocardia* infection among patients with end-stage renal disease. *Statistical significance. COPD, chronic obstructive pulmonary disease.

Age 65+ at initial transplant (OR=2.10, CI 1.59 to 2.25), history of transplant failure (OR=1.28), history of transplant rejection (OR=4.83), receipt of a transplant from a deceased donor (OR=1.23), or receipt of various immunosuppressant drug therapies including tacrolimus (OR=2.45, CI 2.00 to 3.00) and thymoglobulin (OR=1.89, CI 1.59 to 2.25) were associated with increased risk of *Nocardia* infection. Immunosuppressants with weaker association with increased risk included basiliximab (OR=1.25, CI 1.00 to 1.55) and cyclosporine (OR=1.30, CI 1.03 to 1.65). Receipt of azathioprine (OR=0.73) or receipt of sirolimus (OR=0.65), or a diagnosis of COPD (OR=0.78), diabetes (OR=0.86), or hepatitis C (OR=0.56), and tobacco use (OR=0.74) were associated with a decreased risk of *Nocardia* infection.

### Risk factors associated with graft failure within 6 months after *Nocardia* infection

Of all the transplant patients, 87,034 (42.82%) experienced graft failure. Patients with a diagnosis of *Nocardia* infection showed a higher percentage of graft failure at any time (67.28% vs 42.75% with and without *Nocardia*, respectively) as well as a history of kidney rejection (60.58% vs 27.25% with and without *Nocardia*, respectively).

A subcohort was used to study the presentation of *Nocardia* infection and the possible associated risk of graft failure within 183 days (roughly 6 months) to account for appropriate post-transplant follow-up; patients with graft failure occurring after 183 days were excluded and 552 patients with *Nocardia* infection were included. Among those with *Nocardia* infection, nearly 16% experienced graft failure. Demographic statistics of this cohort were comparable with patients with risk factors for *Nocardia* infection, as mentioned above (table 3).

View this table:
[Table 3](/content/70/1/36/T3)

Table 3 
Descriptive statistics, n (%), overall and by graft failure in 552 patients with *Nocardia* infection

Pneumonia was the most frequent presentation of *Nocardia* infection (n=78/552, 14.13%), followed by brain abscess (n=43/552, 7.79%). A few patients presented with infections in more than one system. Table 4 and figure 2 show the final adjusted HR from the CPH model of risk factors associated with graft failure.

View this table:
[Table 4](/content/70/1/36/T4)

Table 4 
Simple and final adjusted HR from CPH of risk factors for graft failure in 552 patients with *Nocardia* infection

![Figure 2](/https://d3hme472k3gd2d.cloudfront.net/content/jim/70/1/36/F2.medium.gif)

[Figure 2](/content/70/1/36/F2)

Figure 2 
HR and 95% CI from the final adjusted model for graft failure among patients with *Nocardia* diagnosis. *Statistical significance. CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease.

Antithymocyte globulin (HR=2.76), COPD (HR=2.47), and presentation of *Nocardia* infection with brain abscess (HR=1.85) were significantly associated with increased risk of graft failure. A history of graft failure (HR=0.41) and a history of kidney rejection (HR=0.52) were significantly associated with a decreased risk of graft failure.

## Discussion

To date, there has been no cumulative study that evaluated the risk factors for nocardiosis in renal transplant patients within the USUnited States. Our study used the USRDS, which encompasses all patients with ESRD and thus qualify for Medicare, providing a large sample size to analyze our clinical question. Our investigation confirms that older age, transplantation of deceased donor kidney, and/or therapy with tacrolimus, corticosteroids, and thymoglobulin are associated with increased risk of infection. It is important to note that trimethoprim-sulfamethoxazole is used as prophylaxis against *Nocardia*. However, it has not been proven to provide reliable protection against nocardiosis.11 

Prior to our study, no study to our knowledge has evaluated the risk factors for graft failure in patients who have been infected with *Nocardia*. The cohort of patients who were diagnosed with *Nocardia* infection showed a higher percentage of graft failure at any time and in addition had more previous diagnoses of kidney rejection when compared with transplant patients without *Nocardia* diagnosis. After the *Nocardia* diagnosis, patients with prescriptions for antithymocyte globulin or with a diagnosis of COPD were associated with an increased risk of graft failure. This is similar to existing evidence that suggests patients with ESRD with a diagnosis of COPD or after a renal transplant carry a greater risk of infection, death, and repeated hospitalization, which increase the risk for graft failure.12 Additionally, if nocardial infection presented as a brain abscess, there was an association with an increased risk for graft failure. The association with graft failure could be due to the severity of the infection, the nature of the therapy required, or the emphasis on decreasing immunosuppression due to severe infection.

Surprisingly, having a history of graft failure or a history of kidney rejection, which was 40%–60% prevalent in the cohort with nocardiosis, was associated with a decreased risk of graft failure. We speculate that the explanation might be due to increased physician and/or patient attention to their immunosuppressive regimen in patients with past graft failure. It could also be a result of other confounding variables not accounted for in the database, confounders in the multivariate model which when adjusted for had a stronger association than *Nocardia*, or a limitation introduced by limiting the cohort to only patients with *Nocardia* infection or limiting the follow-up to 6 months.

Our study demonstrates a lower occurrence of *Nocardia* infection (0.3%) than the values reported in previous studies,1–3 5 despite the fact that the ICD-9 codes used do not necessarily discriminate between a diagnosis of *Nocardia* or *Actinomyces* infection. Thus, limitations of this study include the nature of the USRDS data set, with all diagnoses inferred from billing codes submitted to Medicare or taken from CMS Form 2728, and the fact that *Nocardia* and *Actinomyces* share the same diagnostic ICD-9 code. To improve diagnostic reliability, an ICD-9 code for lumpy jaw, Madura foot, and cutaneous infection were excluded as these presentations are usually associated with *Actinomyces* infection. Another limitation is the lack of clinical-level data in the USRDS necessary to confirm an infection of *Nocardia*. Also part of the limitation of using an administrative database, the medication data queried did not include the details of timing, medication use as induction or maintenance therapy, and no patient compliance data were available. Due to the USRDS being a database of dialysis patients, those patients who received a pre-emptive transplant prior to initiation of dialysis were not available in the data set for this analysis. Although this study had its limitations, it used the largest available database of renal transplant patients in the United States, thereby providing a large cohort of patients and increasing the strength of the study.

The results from this data set provide evidence that encourages clinicians to suspect *Nocardia* infection, particularly in the presence of certain risk factors, in the assessment of pneumonia or brain abscesses in renal transplant patients. However, additional studies are required to further evaluate the timing of infection after renal transplant and to identify appropriate prophylaxis regimens to prevent nocardiosis and/or transplant failure after infection.

## Data availability statement

Data are available upon reasonable request.

## Ethics statements

### Patient consent for publication

Not required.

### Ethics approval

The Augusta University Institutional Review Board has determined that this research qualifies as non-human subjects research as the data set includes no identifiable data. The data reported here have been supplied by the US Renal Data System (USRDS).

## Acknowledgments

This work was supported with resources provided by the Charlie Norwood VA medical center.

## Footnotes

*   Twitter @StephanieBaerMD

*   Contributors All authors have contributed to the preparation of this manuscript.

*   Funding The study is supported by the Augusta University Medical Scholars Program (MG), a grant from Dialysis Clinic (MK, JLW, and AM), and the Translational Research Program of the Department of Medicine, Augusta University.

*   Disclaimer The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US Government. The contents do not represent the views of the Department of Veterans Affairs or the US Government.

*   Competing interests None declared.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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