Abstract
Background:
Nocardia is an opportunistic pathogen that primarily affects immunocompromised individuals, including solid organ transplant (SOT) recipients. Up to 2.65% of SOT recipients develop nocardiosis; however, few studies have examined risk factors and prophylaxis for nocardiosis.
Methods:
We performed a multicenter, matched nested case-control study of adult SOT recipients with culture-confirmed nocardiosis from 2000 through 2020. Controls were matched up to 2:1 by sex, first transplanted organ, year of transplant, transplant center, and adequate post-transplant follow-up. Multivariable conditional logistic regression was performed to analyze associations with nocardiosis. Cox proportional hazards regression compared 12-month mortality between infection and uninfected patients.
Results:
123 SOT recipients were matched to 245 uninfected controls. Elevated calcineurin inhibitor level, acute rejection, cytomegalovirus infection, lymphopenia, higher prednisone dose, and older age were significantly associated with nocardiosis while trimethoprim-sulfamethoxazole prophylaxis was protective (odds ratio [OR] 0.34; 95% confidence interval [CI] 0.13–0.84). The effect of prophylaxis was similar, though not always statistically significant, in sensitivity analyses that only included prophylaxis dosed more than twice-per-week (OR 0.30; 95% CI 0.11–0.80) or restricted to years 2015–2020 (OR 0.33, 95% CI 0.09–1.21). Nocardiosis was associated with increased 12-month mortality (hazard ratio 5.47; 95% confidence interval 2.42–12.35).
Conclusions:
Multiple measures of immunosuppression and lack of trimethoprim-sulfamethoxazole prophylaxis were associated with nocardiosis in SOT recipients. Effectiveness of prophylaxis may be related to trimethoprim-sulfamethoxazole dose or frequency. Trimethoprim-sulfamethoxazole should be preferentially utilized over alternative agents in SOT recipients with augmented immunosuppression or signs of heightened immunocompromise.
Keywords: Nocardia, organ transplantation, trimethoprim-sulfamethoxazole, calcineurin inhibitor, disseminated infection
Background
Nocardia is an opportunistic pathogen with a propensity for infecting immunocompromised individuals. Solid organ transplant (SOT) recipients have rates of Nocardia infection as high as 2.65%.1 Nocardiosis in the SOT population has been associated with poor outcomes, with several factors further increasing the risk of mortality.2,3 However, few studies have examined predisposing factors for development of nocardiosis. Reported associations have included steroid boluses, cytomegalovirus (CMV) disease, higher doses of maintenance immunosuppression, and older age.4,5 Several potential risk factors including subsequent transplant episodes and lymphopenia have not been evaluated in adjusted analyses.4
Identification of associations with nocardiosis in SOT recipients would support preventative interventions. However, studies examining trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for nocardiosis have yielded mixed results.6 Breakthrough Nocardia infection has been well-documented and two studies examining associations with nocardiosis in SOT recipients did not show reduced odds of nocardiosis in those receiving TMP-SMX.4,5 However, other studies of SOT recipients and non-SOT immunocompromised populations have suggested benefit from TMP-SMX prophylaxis.7–11
In this study, we aimed to evaluate proposed risk factors for development of nocardiosis in SOT recipients, including TMP-SMX prophylaxis, by examining a large, three site transplant center database. Additionally, we sought to evaluate and quantify the risk of 12-month mortality from nocardiosis as compared to uninfected, matched controls.
Methods
Study design and setting
We performed a multicenter, matched nested case-control study of SOT recipients with or without nocardiosis followed at three sites in Arizona, Florida, and Minnesota between the years 2000 and 2020. These sites share common transplantation protocols. Prophylaxis is not routinely administered for nocardiosis; however, Pneumocystis prophylaxis is standard. TMP-SMX is the preferred Pneumocystis prophylactic agent and is routinely administered for 6 months following kidney, kidney-pancreas, pancreas, and liver transplantation, 12 months following heart transplantation, and lifelong following lung and heart-lung transplantation. Standard prophylaxis is TMP-SMX 80–400 mg once daily, with dose adjustment for renal function. Patients with sulfa allergies are recommended to undergo a desensitization protocol. Those who cannot take TMP-SMX as prophylaxis are recommended to receive either atovaquone, dapsone, or nebulized pentamidine. Decisions regarding which alternative prophylactic agent to use are made on a case-by-case basis by the transplant team based on individual patient factors. An exception to this protocol is for heart or heart-lung transplant recipients who are Toxoplasma seronegative and receive a transplant from a seropositive donor, as these patients receive lifelong TMP-SMX prophylaxis dosed 160–800 mg once daily. Pneumocystis prophylaxis is also given for 1- or 3-months following treatment for acute rejection, depending on the use of lymphocyte-depleting agents. Our internal institutional review board reviewed the study protocol and granted it an exempt status and a waiver for informed consent (IRB# 21–002606).
Inclusion and exclusion criteria
The nocardiosis cases were ascertained as part of a previous study.3 These included adult SOT recipients who developed culture confirmed Nocardia infection following their first transplant episode. Controls were matched up to a 2:1 ratio on sex, first transplanted organ, transplant site, and transplant within 1 year of their associated case. In the event less than two adequate controls were available for a transplant recipient with nocardiosis, subsequent controls were screened if at least one transplanted organ was in common (Supplementary Table 1). Control patients were also required to have adequate follow-up with a functioning allograft at least to the same time from transplantation as their matched case patient. Further information regarding matching is detailed in the Supplementary Materials. Data including demographics, transplantation characteristics, maintenance immunosuppression, laboratory values, and transplant complications were manually abstracted from the electronic medical record as of their date of diagnosis or, for controls, the associated date of follow-up. Patients without research authorization, those who developed nocardiosis prior to first organ transplantation, or those without a functioning allograft at their index date were excluded. Study data were collected and managed using REDCap electronic data capture tools hosted at Mayo Clinic.12,13
Definitions
Nocardiosis was defined as culture growth of a Nocardia species with compatible signs, symptoms, and/or radiographic features consistent with infection. Control patients were defined as those without evidence of nocardiosis at the index date. The index date was the date of initial culture ascertainment for case patients or the same days from transplantation for control patients. Current TMP-SMX prophylaxis was defined as receipt of TMP-SMX at the time of presentation for evaluation of signs or symptoms that were ultimately attributed to nocardiosis. A subsequent transplant was defined as undergoing a transplantation surgery after first transplantation, regardless if it was a repeat transplantation or a different organ. CMV infection and invasive fungal infection were defined according to published guidelines and assessed in the 6 months prior to the index date.14,15 Acute rejection was defined as biopsy-proven or suspected cell-mediated or antibody-mediated rejection that prompted initiation of augmented immunosuppressive therapy and must have occurred within 6 months prior to the index date. Elevated calcineurin inhibitor (CNI) level was defined as a tacrolimus trough level ≥10 ng/mL or cyclosporine trough level ≥300 ng/mL within 30 days before the index date. Lymphopenia was defined as an absolute lymphocyte count <0.5 ×109/L. Absolute lymphocyte count was assessed at the most recent measurement prior to symptom onset. Chronic kidney disease was defined as a baseline estimated glomerular filtration rate of less than 60 mL/min/1.73 m2, measured by the 2021 CKD-EPI equation. Creatinine clearance calculated via the Cockroft-Gault equation was used to assess renal function for TMP-SMX prophylaxis dose adjustment. For those whose actual body weight was more than 120% of their ideal body weight, adjusted body weight was used when calculating creatinine clearance. Patients with a creatinine clearance less than 30 mL/min had their equivalent drug exposure adjusted according to Supplementary Table 2.
Statistical analysis
The primary outcome was development of nocardiosis at any point following first transplantation. The secondary outcome was mortality within 12 months after the index date. Continuous variables are presented as mean (standard deviation [SD]) or median (interquartile range [IQR]) and categorical variables as number (percentage). Multivariable conditional logistic regression was performed to analyze independent associations with development of nocardiosis. Inconsistent prophylaxis was defined as receipt of TMP-SMX weekly or twice-weekly, while consistent prophylaxis was receipt of TMP-SMX thrice-weekly or more frequently. A sensitivity analysis was performed where TMP-SMX prophylaxis was re-leveled as consistent prophylaxis, inconsistent prophylaxis, and no prophylaxis to assess if the effect of TMP-SMX prophylaxis changed with exclusion of weekly or twice-weekly from the prophylaxis definition. This was not performed again with equivalent TMP-SMX exposure as incorporating equivalent exposure based on creatinine clearance did not change the number with weekly or twice-weekly prophylaxis. A second sensitivity analysis was performed where the study period was restricted to 2015–2020 to analyze if the effect of TMP-SMX prophylaxis was affected by the long study period, specifically if the effect measure was similar to the overall estimate. Proposed associations or possible confounders of these variables were considered for inclusion in the multivariable models and defined a priori. A Kaplan-Meier curve was constructed and compared using the log-rank test for survival following the index date. A Cox proportional regression analysis was performed to calculate the effect measure of nocardiosis on 12-month mortality. In this analysis, patients were censored at last follow-up, death, or after 12 months, whichever occurred first. All analyses were performed using R Statistical Program, Version 3.6.2. (R Foundation for Statistical Computing, Vienna, Austria).
Results
Among 125 SOT recipients with nocardiosis, 123 were able to be matched to 245 control patients (Table 1). The most common transplanted organ was kidney (43.5%). Seven case patients were unable to be matched using exact transplanted organs and some controls were matched based on one of multiple organs (Supplementary Table 1). Most case patients (N=98/123; 79.7%) were diagnosed in 2011–2020, with 75 (61.0%) diagnosed in year 2015 or later (Supplementary Figure 1).
Table 1:
Baseline characteristics of 123 solid organ transplant recipients with nocardiosis and 245 matched solid organ transplant recipients without nocardiosis
| Case (N=123) | Control (N=245) | Total (N=368) | |
|---|---|---|---|
| Age, years, mean (SD) | 58.6 (11.2) | 55.2 (12.8) | 56.4 (12.4) |
| Sex | |||
| - Female | 40 (32.5) | 79 (32.2) | 119 (32.3) |
| - Male | 83 (67.5) | 166 (67.8) | 249 (67.7) |
| Race (N=367) | |||
| - American Indian or Alaska Native | 5 (4.1) | 8 (3.3) | 13 (3.5) |
| - Asian | 7 (5.7) | 14 (5.7) | 21 (5.7) |
| - Black or African American | 12 (9.8) | 32 (13.1) | 44 (12.0) |
| - Native Hawaiian or Other Pacific Islander | 0 (0.0) | 1 (0.4) | 1 (0.3) |
| - White | 98 (80.3) | 180 (73.5) | 278 (75.5) |
| - Other | 0 (0.0) | 10 (4.1) | 10 (2.7) |
| Ethnicity (N=349) | |||
| - Hispanic or Latino | 15 (13.0) | 29 (12.4) | 44 (12.6) |
| - Not Hispanic or Latino | 100 (87.0) | 205 (87.6) | 305 (87.4) |
| Body mass index, kg/m2, median (IQR) | 24.4 (21.8–27.6) | 27.4 (23.4–30.9) | 26.6 (22.9–30.3) |
| Transplant typea | |||
| - Heart | 23 (18.7) | 48 (19.6) | 71 (19.3) |
| - Kidney | 54 (43.9) | 106 (43.3) | 160 (43.5) |
| - Liver | 11 (8.9) | 22 (9.0) | 33 (9.0) |
| - Lung | 13 (10.6) | 28 (11.4) | 41 (11.1) |
| - Pancreas | 4 (3.3) | 6 (2.4) | 10 (2.7) |
| - Multiorganb | 18 (14.6) | 35 (14.3) | 53 (14.4) |
| Subsequent transplant | 15 (12.2) | 14 (5.7) | 29 (7.9) |
| Induction immunosuppression (N=362) | 107 (87.0) | 191 (79.9) | 298 (82.3) |
| Chronic pulmonary disease | 23 (18.7) | 32 (13.1) | 55 (14.9) |
| Diabetes mellitus | 60 (48.8) | 110 (44.9) | 170 (46.2) |
| Chronic kidney disease | 91 (74.0) | 126 (51.4) | 217 (59.0) |
| Dialysis requirement | 8 (6.5) | 2 (0.8) | 10 (2.7) |
| Charlson comorbidity index, median (IQR) | 3.0 (2.0–4.0) | 3.0 (2.0–4.0) | 3.0 (2.0–4.0) |
| Invasive fungal infection in last 6 monthsc | 13 (10.6) | 7 (2.9) | 20 (5.4) |
| Posttransplant lymphoproliferative disease | 2 (1.6) | 2 (0.8) | 4 (1.1) |
| Lymphopenia | 66 (53.7) | 49 (20.0) | 115 (31.2) |
| Acute rejection within 6 monthsd | 27 (22.0) | 9 (3.7) | 36 (9.8) |
| CMV infection within 6 monthse | 14 (11.4) | 11 (4.5) | 25 (6.8) |
| Maintenance immunosuppression | |||
| - Cyclosporine | 4 (3.3) | 9 (3.7) | 13 (3.5) |
| - Tacrolimus | 114 (92.7) | 221 (90.2) | 335 (91.0) |
| - Sirolimus | 1 (0.8) | 10 (4.1) | 11 (3.0) |
| - Mycophenolate | 104 (84.6) | 194 (79.2) | 298 (81.0) |
| - Azathioprine | 6 (4.9) | 17 (6.9) | 23 (6.2) |
| - Belatacept | 1 (0.8) | 1 (0.4) | 2 (0.5) |
| - Prednisone | 116 (94.3) | 178 (72.7) | 294 (79.9) |
| Daily prednisone dose, mg, mean (SD) | 8.8 (6.8) | 7.8 (4.4) | 8.2 (5.5) |
| Elevated CNI level within 30 days | 62 (50.4) | 37 (15.1) | 99 (26.9) |
| Current Pneumocystis prophylaxis | 69 (56.1) | 118 (48.2) | 187 (50.8) |
| - Atovaquone | 2 (2.9) | 0 (0.0) | 2 (1.1) |
| - Dapsone | 3 (4.3) | 6 (5.1) | 9 (4.8) |
| - Nebulized pentamidine | 31 (44.9) | 11 (9.3) | 42 (22.5) |
| - TMP-SMX | 33 (47.8) | 101 (85.6) | 134 (71.7) |
All data are N (%) unless otherwise specified.
Abbreviations: CMV, cytomegalovirus; CNI, calcineurin inhibitor; IQR, interquartile range; SD, standard deviation; TMP-SMX, trimethoprim-sulfamethoxazole.
Transplant type are transplanted organs before the index date. While patients were matched based on first transplant, some patients had subsequent transplantation episodes where they may have received a separate organ.
Multiorgan transplant includes pancreas-kidney (35), kidney-liver (10), heart-kidney (7), and heart-lung (1).
Fungal organisms include Aspergillus (12), Alternaria (2), and 1 each of Acrophialophora, Candida, Coccidioides, Cryptococcus, Fonsecaea, and Pneumocystis.
Includes 34 with cell-mediated rejection and 2 with antibody-mediated rejection. Eight were treated with a lymphocyte depleting agent and 28 received high-dose corticosteroids.
Includes 21 with DNAemia and 4 with tissue-invasive disease.
Case patients had a higher proportion of those with a subsequent transplant, chronic kidney disease, recent invasive fungal infection, acute rejection, CMV infection, or elevated CNI level. Control patients had a higher proportion of sirolimus use as maintenance immunosuppression and current TMP-SMX prophylaxis. However, despite a lower rate of TMP-SMX prophylaxis, a higher proportion of case patients were receiving Pneumocystis prophylaxis at their index date (56.1% versus 48.2%). Non-TMP-SMX prophylaxis was most commonly nebulized pentamidine, followed by dapsone and atovaquone. Patients received non-TMP-SMX prophylaxis due to pre-transplant allergy (N=13, 24.5%), hyperkalemia (N=12, 22.6%), leukopenia (N=9, 17.0%), renal failure (N=8, 15.1%), and other adverse effects (N=10, 18.9%). Avoidance of TMP-SMX prophylaxis for renal failure was slightly more common among case patients (16.7% versus 11.8%) while avoidance for leukopenia was similar (16.7% versus 17.6%). TMP-SMX prophylaxis doses and doses adjusted for creatinine clearance are shown in Table 2. Of 14 cases and 28 controls with lung or heart-lung transplants, 11 (78.6%) cases and 26 (92.9%) controls were receiving azithromycin as bronchiolitis obliterans prophylaxis (p=.178), most commonly dosed 250 mg thrice-weekly.
Table 2:
Trimethoprim-sulfamethoxazole doses and equivalent drug exposure based on creatinine clearance
| Case (N=123) | Control (N=245) | Total (N=368) | |
|---|---|---|---|
| CrCl, mL/min | 44.8 (31.3–61.8) | 58.6 (47.1–77.2) | 55.1 (41.1–72.8) |
| CrCl <30 mL/min | 29 (23.6) | 7 (2.9) | 36 (9.8) |
| - Current TMP-SMX prophylaxis among those with CrCl < 30 mL/min | 7 (24.1) | 2 (28.6) | 9 (25.0) |
| Current TMP-SMX prophylaxis | 33 (26.8) | 101 (41.2) | 134 (36.4) |
| - Actual TMP-SMX doses | |||
| 160–800 mg daily | 1 (3.0) | 7 (6.9) | 8 (6.0) |
| 160–800 mg thrice-weekly | 9 (27.3) | 13 (12.9) | 22 (16.4) |
| 160–800 mg twice-weekly | 0 (0.0) | 2 (2.0) | 2 (1.5) |
| 160–800 mg weekly | 7 (21.2) | 11 (10.9) | 18 (13.4) |
| 80–400 mg daily | 10 (30.3) | 40 (39.6) | 50 (37.3) |
| 80–400 mg thrice-weekly | 6 (18.2) | 28 (27.7) | 34 (25.4) |
| - Equivalent TMP-SMX drug exposure, adjusted for CrCl | |||
| 160–800 mg twice-daily | 1 (3.0) | 0 (0.0) | 1 (0.7) |
| 160–800 mg daily | 3 (9.1) | 7 (6.9) | 10 (7.5) |
| 160–800 mg thrice-weekly | 8 (24.2) | 13 (12.9) | 21 (15.7) |
| 160–800 mg twice-weekly | 1 (3.0) | 2 (2.0) | 3 (2.2) |
| 160–800 mg weekly | 6 (18.2) | 11 (10.9) | 17 (12.7) |
| 80–400 mg daily | 10 (30.3) | 42 (41.6) | 52 (38.8) |
| 80–400 mg thrice-weekly | 4 (12.1) | 26 (25.7) | 30 (22.4) |
All data are N (%) or median (interquartile range).
Abbreviations: CrCl, creatinine clearance; TMP-SMX, trimethoprim-sulfamethoxazole.
Among all patients, the case patients had a weekly sulfamethoxazole dose of 552.8 mg (SD 1060.2) compared to 930.6 mg (SD 1355.5) in the control patients (p<0.001, paired t-test). Of those receiving TMP-SMX prophylaxis, case patients had a weekly sulfamethoxazole dose of 2060.6 mg (SD 1039.8) and compared to 2257.4 mg (SD 1207.4) in the control patients (Figure 1). Control patients had a longer mean duration of TMP-SMX prophylaxis (537.7 versus 392.6 days; p<.001, paired t-test).
Figure 1:
Box plots showing weekly sulfamethoxazole dose for all patients (A) and only those receiving trimethoprim-sulfamethoxazole prophylaxis at their index date (B).
Among the 123 included case patients, time from transplant to diagnosis was median 399 (IQR 153.5–1471) days. Thirty-three (26.8%) were disseminated at diagnosis and 77 (62.6%) had localized pulmonary involvement. Of 119 case patients with available Nocardia susceptibility testing results, seven (5.9%) were resistant to TMP-SMX, two (N=2/32; 6.3%) of which were receiving TMP-SMX prophylaxis prior to diagnosis. Twenty-six patients were infected with N. farcinica, all of which were susceptible to TMP-SMX. Seventy-one (63.6%) of isolates were resistant to clarithromycin.
Risk factors for development of nocardiosis
Multivariable conditional logistic regression was performed, analyzing proposed associations with adjustment for confounders (Table 3). Current TMP-SMX prophylaxis, elevated CNI level, acute rejection within 6 months, CMV infection within 6 months, lymphopenia, higher daily prednisone dose, and older age were statistically significant. The effect measure of TMP-SMX prophylaxis did not significantly change after performing a sensitivity analysis where weekly or twice-weekly TMP-SMX dosing were removed from the consistent prophylaxis group. Similarly, the effect measure of TMP-SMX was similar after restricting our study period to 75 case patients and 149 control patients with index dates from 2015–2020, though this specific analysis was not statistically significant. (odds ratio 0.33, 95% confidence interval 0.09–1.21; p = 0.070).
Table 3:
Multivariable conditional logistic regression of associations with development of nocardiosis
| Variable | Odds ratio (95% confidence interval) |
P value |
|---|---|---|
| Current TMP-SMX prophylaxisa | 0.34 (0.13–0.84) | .020 |
| Elevated CNI level within 30 days | 5.74 (2.35–13.99) | <.001 |
| Acute rejection within 6 months | 7.46 (1.81–30.69) | .005 |
| CMV infection within 6 months | 5.11 (1.28–20.44) | .021 |
| Daily prednisone dose (per 5 mg) | 2.40 (1.40–4.16) | .002 |
| Lymphopeniab | 8.04 (3.33–19.41) | <.001 |
| Age (per 10 years) | 1.63 (1.19–2.24) | .002 |
| Subsequent transplant | 1.01 (0.29–3.60) | .983 |
| Chronic pulmonary disease | 2.78 (0.54–14.37) | .223 |
Bold values indicate p<.05.
Abbreviations: CNI, calcineurin inhibitor; CMV, cytomegalovirus; TMP-SMX, trimethoprim-sulfamethoxazole.
A sensitivity analysis was performed where patients receiving weekly or twice-weekly TMP-SMX were removed from the consistent prophylaxis group. This yielded similar results (odds ratio 0.30; 95% confidence interval 0.11–0.80). Using equivalent TMP-SMX exposure based on renal function did not change the number of patients with weekly or twice-weekly TMP-SMX prophylaxis.
Lymphopenia was defined as an absolute lymphocyte count <0.5 ×109/L.
After excluding patients with an elevated CNI level within 30 days, acute rejection within 6 months, CMV infection within 6 months, and lymphopenia, the number of cases decreased from 123 to 30. These 30 patients were diagnosed relatively distant from transplant (median 2.6 years).
Mortality following nocardiosis
Twenty-nine (7.9%) SOT recipients died within 12 months of their index date, 21 (17.1%) of which had nocardiosis (Figure 2). Patients started antibiotic therapy a median of 18.0 (IQR 9.0–27.5) and 3.0 (IQR 1.0–7.5) days from symptom onset and their index date, respectively. After stratifying by patient age, patients with nocardiosis had a hazard ratio of 5.47 (95% confidence interval 2.42–12.35; p <0.001) for 12-month post-diagnosis mortality.
Figure 2:
Kaplan-Meier curve comparing survival following nocardiosis diagnosis or associated index date for control patients. The vertical tick-marks represented censored patients. P value is calculated by the log-rank test.
Discussion
Our study found multiple associations with development of nocardiosis in SOT recipients. These were largely measures of immunosuppression, including heightened exposure to maintenance immunosuppression, recent augmentation of immunosuppression for acute rejection, and CMV infection. After accounting for these factors, TMP-SMX prophylaxis was shown to have a protective association against development of nocardiosis in the main analysis and a sensitivity analysis excluding infrequently dosed prophylaxis.
Few studies have examined risk factors for developing nocardiosis in SOT recipients. Previously described associations include elevated CNI level, use of tacrolimus, higher maintenance corticosteroid dose, augmented immunosuppression, CMV disease, older age, and longer intensive care unit stay during index transplantation.4,5,7 These are consistent with many of the findings in the present study, all being measures of immunosuppression or more complicated post-transplant courses. We have additionally identified lymphopenia as an association with nocardiosis after adjusting for potential confounders. Many of these risk factors are shared among several opportunistic pathogens in the SOT population, including Pneumocystis. Higher maintenance immunosuppression, augmented immunosuppression, CMV infection, and lymphopenia are described associations with Pneumocystis,16 and TMP-SMX prophylaxis is typically recommended during periods of increased risk.17 It is possible that these risk factors may compound on one another, and the presence of multiple such factors may increase the importance of using optimal prophylaxis. CMV infection is a notable finding. Current guidelines do suggest Pneumocystis prophylaxis in patients with CMV infection or disease, though this is not always done in clinical practice.17 However, CMV does have immunomodulatory properties, and CMV infection or disease after transplantation may be a marker for otherwise unappreciated over-immunosuppression. CMV should be considered in decision-making for prophylaxis use and selection. It is also important to note that 30 patients did not have apparent risk factors for nocardiosis other than organ transplantation. It is possible that the cumulative effect from other posttransplant complications, such as declining graft function, malignancies, and cumulative immunosuppression, played a role in its development, though this is speculative.
Our study highlights the potential to prevent nocardiosis with TMP-SMX prophylaxis. Studies examining TMP-SMX as Nocardia prophylaxis have reported inconsistent results.4,5,7–10,18 However, study of TMP-SMX prophylaxis is prone to confounding by indication, where patients at highest risk for nocardiosis will often also be those receiving prophylaxis. This is partially true in the present study, where patients with nocardiosis had higher rates of Pneumocystis prophylaxis, though less usage of TMP-SMX specifically. Additionally, due to the uncommon nature of Nocardia infection in the SOT population, most studies have insufficient numbers to account for all potential confounders. Furthermore, breakthrough Nocardia infections are well-established and TMP-SMX is known to at most provide only incomplete protection. This is consistent with our data, where the odds of nocardiosis in those receiving TMP-SMX was reduced by 66%, though 26.8% of our case patients were receiving TMP-SMX at diagnosis. Though commonly used as an alternative prophylaxis, nebulized pentamidine has not been considered a risk factor for nocardiosis.
The dose and frequency of TMP-SMX is also heterogeneous in the SOT population. In one study of SOT recipients where prophylaxis did not appear beneficial, half were receiving TMP-SMX prophylaxis dosed either once or twice weekly and the remainder were largely 80–400 mg thrice-weekly.4 Another study did not report specific dosage regimens, but noted those with nocardiosis were receiving lower weekly sulfamethoxazole doses and almost no patients received high-dose TMP-SMX prophylaxis.5 The most common dosages in our study were 80–400 mg daily and 160–800 mg thrice-weekly, and it is possible the effect of prophylaxis is greater with more frequently dosed prophylaxis to minimize periods with insufficient TMP-SMX levels.
The overlap between risk factors and prophylaxis for Nocardia and Pneumocystis is noteworthy. While Nocardia is relatively uncommon in SOT recipients1,4 and may not warrant routine prophylaxis on its own, the risk of Pneumocystis infection does warrant routine prophylaxis in the early post-transplant period and during periods of increased risk.17 These commonalities should heighten awareness of the advantages of TMP-SMX prophylaxis over alternative Pneumocystis prophylactic agents that are not expected to prevent nocardiosis. Furthermore, use of TMP-SMX as Pneumocystis prophylaxis has been shown to be effective in preventing urinary tract infections, toxoplasmosis, and infections by other TMP-SMX susceptible organisms.19–23 Despite these advantages, alternative prophylactic agents are utilized in a sizable proportion of SOT recipients.10 However, most patients with a reported allergy or prior adverse reaction to TMP-SMX can tolerate its use as a therapeutic agent for nocardiosis,24 despite this generally being at a higher dose. Transplant providers should be aware that TMP-SMX is preferred prophylaxis and efforts should be made to clarify reported TMP-SMX allergies or reactions and rechallenge or desensitize as appropriate. This is even more paramount given the high mortality associated with nocardiosis,2,25,26 and over 5-fold increased risk of mortality in the present study.
Notably, our study did not have data regarding potential exposures such as occupation, hobbies, or travel. Geography, particularly residence in an arid climate, has been posited to increase risk of nocardiosis due to greater organismal burden in the soil.27 While our study included patients in Arizona, we were unable to confirm this association as our analysis necessitated matching based on site of transplantation.
The number of Nocardia cases in SOT recipients appeared to increase over time during the study period. This may reflect improvements in diagnostic testing, as well as an increase in the number of transplantation procedures over time. This is particularly notable for the Arizona and Florida sites, whose transplant programs increased in volume substantially during the study period. However, there did not appear to be signs of clustering or outbreaks. Additionally, we performed a sensitivity analysis to examine if the effect of TMP-SMX prophylaxis was similar in a more modern subset as compared to the overall cohort. The effect estimate was similar after restricting our study period from 2015–2020 (odds ratio of 0.33 versus 0.34), indicating time does not seem to be significantly influencing these results and they are likely applicable to modern patients. While this was not statistically significant for the restricted sample period (p = 0.070), this is likely due to the reduction in sample size limiting the power of the sensitivity analysis.
Our study has several limitations of note. This was performed retrospectively and is subject to intrinsic sources of bias. We relied on culture to identify case patients. It is possible some patients were undiagnosed or diagnosed through non-culture-based methods, such as molecular diagnostics. We were unable to exactly match our multiorgan transplant recipients with controls based on first transplanted organ, though most were ultimately able to be matched to patients with a one common transplanted organ that follows similar immunosuppression and prophylaxis practices. Our patients also received variable doses of TMP-SMX prophylaxis. We performed a sensitivity analysis that excluded less frequent dosing schedules that are less likely to be impactful, but we were unable to determine the optimal prophylactic dosing strategy. Finally, these results may not necessarily apply to secondary prophylaxis, as recurrent infection may be reliant on different factors.
In conclusion, our study found several associations with nocardiosis in SOT recipients that largely represent measures of immunosuppression. TMP-SMX was associated with reduced odds of nocardiosis in most analyses, noting the time-period sensitivity analysis was similar in effect but non-significant. Given the overlap of risk factors for Nocardia and other preventable post-transplant infections, measures to increase use of TMP-SMX as the preferred prophylactic agent should be considered. Future studies should examine exposure-related characteristics and further identify which patients may benefit from Nocardia-directed prophylaxis.
Supplementary Material
Funding
This project was supported by Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Abbreviations
- CMV
Cytomegalovirus
- CNI
Calcineurin inhibitor
- CNS
Central nervous system
- IQR
Interquartile range
- SD
Standard deviation
- SOT
Solid organ transplant
- TMP-SMX
Trimethoprim-sulfamethoxazole
Footnotes
Potential conflicts of interest
All authors have no conflicts of interest to report.
References
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