Abstract
Background:
Due to the ongoing opioid epidemic in the United States, deceased organ donors increasingly have a history of injection drug use (IDU), raising concerns about infectious risks to solid organ transplant (SOT) recipients. We sought to determine how recent IDU among deceased organ donors impacted donor culture results and recipient outcomes.
Methods:
A retrospective cohort study was performed at three transplant centers. Exposed donors were those with “recent IDU” (in the prior 12 months). Primary outcomes included (1) positive donor cultures for bacteria or Candida species, (2) recipient bacterial or Candida infection within 3 months posttransplant, and (3) recipient graft failure or death within 12 months posttransplant. Mixed effects multivariable regression models were used to evaluate the relationship between recent donor IDU and each outcome.
Results:
A total of 658 SOT recipients who received organs from 394 donors were included. Sixty-six (17%) donors had a history of recent IDU. Recent IDU in donors was associated with a significantly increased odds of donor culture positivity (aOR 3.65, 95% CI 1.06–12.60, p = .04) but was not associated with SOT recipient infection (aHR 0.98, 95% CI 0.71–1.36, p = .92) or graft failure or death (aHR 0.67, 95% CI 0.29–1.51, p = .33).
Conclusion:
Donors with recent IDU are more likely to have positive cultures, but their recipients’ outcomes are unaffected, suggesting organs from donors with recent IDU may be safely utilized.
Keywords: donor culture, donor-derived infection, injection drug use, solid organ transplantation
1 ∣. INTRODUCTION
The opioid epidemic in the United States has led to over 100 000 overdose deaths annually, and rates of overdose continue to increase.1 The main driver of overdose deaths is synthetic opioids, which are commonly injected.2 This has led to an increase in the proportion of deceased organ donors in the US who died due to drug overdose and who have a history of injection drug use (IDU).3 Indeed, the number of drug-related deaths among deceased donors has increased by 102% since 2009.4
Although the opioid epidemic and related overdose deaths have increased the number of potentially available organs, there have been concerns that donors with a history of recent IDU may impart additional infectious risks for solid organ transplant (SOT) recipients.5,6 More specifically, there is concern that donors with recent IDU may be more likely to be actively infected at the time of organ procurement (with, for example, viral hepatitis, HIV, or a disseminated bacterial or Candida infection) and may transmit that infection to the recipient via the allograft, causing a donor-derived infection (DDI).7-10 Donors with a history of IDU were previously classified as Public Health Services (PHS) “increased risk donors,” although this terminology was discontinued in the most recent 2020 PHS guidelines.11 This recommendation was due in part to prior studies showing that organs from donors classified as PHS “increased risk donors” were underutilized when compared to organs from donors not classified as “increased risk,”12,13 indicating a bias among transplant providers and recipients in accepting these organs. Organs remain exceedingly scarce, so utilization of organs from donors with recent IDU is critical to maintaining the donor pool.
Two prior observational studies have shown that use of organs procured from donors with drug-related deaths results in similar, or slightly better, rates of graft survival in the recipient,3,14 but no prior studies have systematically determined the impact of donor IDU on donor culture positivity or the risk of DDI in recipients. Therefore, in this study, we aimed to determine how recent donor IDU impacts donor bacterial culture positivity, and how these results influence recipient outcomes—including recipient infection, graft failure, and death. These data are critical in optimizing the safety of organ utilization practices.
2 ∣. MATERIALS AND METHODS
2.1 ∣. Study design and setting
A multicenter retrospective cohort study was conducted at three transplant centers in Philadelphia, PA: The Hospital of the University of Pennsylvania (725 inpatient beds), Temple University Hospital (722 inpatient beds), and Hahnemann University Hospital (496 inpatient beds).
2.2 ∣. Study population
The cohort included all adults who underwent SOT at one of the three included transplant centers and who received an organ from a deceased donor that was procured by the local organ procurement organization, the Gift of Life Donor Program (GLDP), between January 1, 2015 and June 30, 2016. Eligible recipients were identified by the GLDP.
2.3 ∣. Exposure groups
“Exposed” donors were those with “recent IDU,” defined as the use of injection drugs at any point in the 12 months preceding organ procurement. The exposure status was ascertained by manual review of donor charts maintained by the GLDP: the clinical history obtained from paramedics, hospital providers, and next-of-kin or donor informants were evaluated for report of IDU, and this information was cross-referenced with the results of toxicology screens performed on donors. We defined “recent IDU” as being present if any of the following criteria were met: (1) The donor was found with a needle injection at the time of death; (2) next-of-kin/donor informant reported a history of IDU in the prior 12 months; (3) next-of-kin/donor informant reported a history of IDU with an unknown timeframe, and the toxicology screen was positive for opiates; or (4) if the toxicology screen was positive for a substance that is typically injected (e.g., heroin) regardless of next-of-kin/donor informant report. If next-of-kin/donor informant reported a history of opioid use disorder but the route of administration of the substance was unknown, we did not classify that donor as having a confirmed IDU history. The GLDP routinely obtains information related to IDU in order to determine PHS-risk status.11 A 12-month window was used to define “recent IDU” in order to exclude those with only remote IDU but avoid excluding those for whom next-of-kin or donor informants were unaware of very recent IDU behaviors. “Unexposed” donors were those with no history of IDU in the 12 months preceding organ procurement.
The “exposed” SOT recipients were those who received an organ from a donor with recent IDU (as defined above). “Unexposed” recipients were those who received an organ from a donor with no history of recent IDU.
This study was approved by the Institutional Review Board at each of the participating transplant centers (see Supporting Information Section A).
2.4 ∣. Study outcomes
There were three primary outcomes. The first primary outcome was donor culture positivity, which was defined by growth of bacteria or Candida on routine cultures obtained at any point during the donor’s terminal hospitalization or at the time of organ procurement. The Gift of Life Donor Program collects a standardized set of bacterial cultures at procurement (including cultures of the blood, sputum, urine, ureter tips, and perfusate/transport solution), so each donor had the opportunity to be exposed. The only bacterial/Candida growth that was excluded from this outcome was “routine mouth flora” on respiratory cultures and “mixed flora” on urine cultures, since these are likely contaminants.
The second primary outcome was recipient bacterial or Candida infection within 3 months posttransplant, including DDIs. Infections were identified using Center for Disease Control (CDC)/National Healthcare Safety Network (NHSN) surveillance criteria15 and were determined via manual chart review by an infectious diseases-trained physician (JAA). Infections at any anatomical site, due to any organism, and due to any source (donor-derived or non-donor-derived) were included. Infections were evaluated through 3 months posttransplant as this is the typical timeframe in which bacterial/Candida donor-derived infections have been reported to occur,16 and this is the primary mechanism by which an effect on posttransplant infections was postulated to occur. A probable DDI was defined using criteria from the Organ Procurement and Transplantation Network Ad Hoc Disease Transmission Advisory Committee16 as: (a) a bacterial or Candida infection in the recipient, per CDC/NHSN criteria,15 within 3 months posttransplant, where (b) the infection was caused by an organism with the same species identification and susceptibility pattern as was identified on one of the donor’s hospital or organ procurement organization cultures. Probable DDI was determined independently by two transplant infectious diseases trained physicians (JAA and EAB), and discrepancies were resolved by a third transplant infectious diseases trained physician (DHL).
The third primary outcome was recipient graft failure or death within 12 months posttransplant. Graft failure was defined by re-listing for transplant for any organ recipient or return to dialysis for kidney transplant recipients.
2.5 ∣. Secondary outcomes
The following were evaluated as secondary outcomes: donor culture positivity with (1) Staphylococcus aureus (on any culture), (2) a multidrug resistant organism (MDRO) (on any culture), and (3) Candida on any nonrespiratory culture, as well as (4) donor blood culture positivity (with any organism). MDROs included: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species, extended-spectrum beta-lactamase-resistant Enterobacterales, carbapenem-resistant Enterobacterales (CRE), MDR-Pseudomonas, and MDR-Acinetobacter species. The CDC/NHSN definitions for each MDRO were used (see Supporting Information Section B).17
Finally, secondary outcomes also included recipient infection (per CDC/NHSN criteria15) due to (5) invasive candidiasis (which does not include oropharyngeal candidiasis [“thrush”] and Candida vulvo-vaginitis), (6) Staphylococcus aureus, (7) an MDRO (as defined above), and (8) a donor-derived organism (as defined above) within 3 months posttransplant.
2.6 ∣. Data collection
Data on donors were abstracted from the donor medical record maintained by the Gift of Life Donor Program. Data on SOT recipients were abstracted from the electronic medical record system at each hospital. (See Supporting Information Section C for a complete list of donor and recipient data elements that were collected). The standard peri-operative antimicrobial prophylaxis employed for each organ type at each center, as well as the typical approach to treating positive donor cultures, is provided in the Supporting Information Section D.
2.7 ∣. Statistical analysis
Exposed and unexposed SOT donors and recipients were characterized by baseline clinical factors, such as demographics and comorbidities. Continuous variables were compared using a two independent sample t-test or Wilcoxon rank-sum test, and categorical variables were compared using the χ2 or Fisher exact test.
For the analysis of donor culture positivity, we performed multivariable logistic regression. First, bivariable regression was used to examine the relationship between the primary exposure (recent IDU), as well as other baseline donor factors, and the outcome (donor culture positivity). Candidates for the multivariable model were those with a p value <.20 on bivariable analysis. Variables were retained in the final multivariable model if they were confounders of the primary association or had a p value of <.05 in the multivariable model. The strength of each association was measured using an odds ratio, and a 95% confidence interval (CI) was calculated for each effect estimate. Each donor was only included once in these analyses.
For the analyses of recipient infection and graft failure or death, survival analyses were performed. Time zero was defined as the day of transplantation, and the time at risk was measured in days. For the evaluation of posttransplant infection, the day on which the SOT recipient first met criteria for a bacterial or invasive Candida infection within 3 months posttransplant was the failure date, and subjects were censored at the time of death or at the end of 3 months of follow-up (whichever occurred first). If a recipient developed multiple infections within 3 months posttransplant, only the first infection was considered. For the evaluation of posttransplant graft and patient survival, the failure date was the day on which the SOT recipient met criteria for graft failure or died (whichever occurred first), and subjects were censored at 12 months of follow-up. For the unadjusted analyses, a Kaplan–Meier curve was plotted, stratified by exposure status, and a log rank test was performed. For the adjusted analyses, mixed effects multivariable frailty models using the Weibull distribution were developed for each outcome, with a random effect for donor. This random effect was included in order to account for possible clustering by donor, since several SOT recipients in the cohort received organs from the same donor. For each of the multivariable analyses, bivariable regression was used to examine the relationship between the primary exposure (recent donor IDU), as well as other baseline donor and recipient factors, and the outcome. Candidates for the multivariable model were those with a p value <.20 on bivariable analysis. Variables were retained in the final multivariable model if they were confounders of the primary association or had a p value of <.05 in the multivariable model. The strength of each association was measured using a hazard ratio, and a 95% CI was calculated for each effect estimate.
Of note, we did not adjust our analyses for antimicrobials administered to the donors or recipients peri- or posttransplant, since these antimicrobial administrations would have occurred after the exposure of interest (donor IDU) and would thus be on the causal pathway.
For all secondary outcomes, multivariable logistic regression was used (using the same procedure described above). All analyses were performed using StataSE v.15.1(StataCorp, College Station, Texas).
3 ∣. RESULTS
3.1 ∣. Study population
The cohort included 394 organ donors, 66 (17%) of whom were determined to have a history of recent IDU. Among donors with recent IDU, the median age was 30 years (interquartile range [IQR], 25–34), 24 (36%) were women, and 63 (95%) identified as White or Caucasian. (See Table 1a for further donor baseline characteristics).
TABLE 1.
Baseline characteristics of (a) deceased organ donors and (b) solid organ transplant recipients stratified by donor history of recent injection drug use (IDU)
| (a) Deceased organ donors (N = 394) | |||
|---|---|---|---|
| Baseline characteristica,b |
Donor with history of recent IDU(N = 66) |
Donor with no history of recent IDU (N = 328) |
p-Value |
| Demographics | |||
| Age (median, IQR), years | 30 (25-34) | 43 (27-54) | <.01 |
| Female gender | 24 (36%) | 140 (43%) | .34 |
| Race: Black | 1 (2%) | 53 (16%) | .01 |
| Race: White | 63 (95%) | 232 (71%) | <.01 |
| Ethnicity: Hispanic | 2 (3%) | 33 (10%) | .09 |
| Comorbidities | |||
| Diabetes mellitus | 1 (2%) | 43 (13%) | .01 |
| Hypertension | 1 (2%) | 43 (13%) | .01 |
| Active marijuana use | 16 (24%) | 56 (17%) | .17 |
| Death mechanism | |||
| Drug overdose | 48 (73%) | 31 (9%) | <.01 |
| Asphyxiation | 1 (2%) | 22 (7%) | .15 |
| Cardiovascular | 6 (9%) | 95 (29%) | .01 |
| Gunshot wound | 3 (5%) | 25 (8%) | .60 |
| Blunt injury | 4 (6%) | 51 (16%) | .05 |
| Intracranial hemorrhage | 4 (6%) | 96 (29%) | <.01 |
| Donor type | |||
| Donation after circulatory death | 4 (6%) | 96 (29%) | <.01 |
| Expanded criteria donor | 1 (2%) | 73 (22%) | <.01 |
| PHS-increased riskc,d | 65 (98%) | 66 (20%) | <.01 |
| Kidney donor profile index, median (IQR) | 24 (8-43) | 51 (23-79) | <.01 |
| Laboratory values | |||
| CMV seropositive | 24 (36%) | 178 (54%) | .01 |
| EBV seropositive | 66 (100%) | 297 (91%) | .01 |
| HCV seropositive | 14 (21%) | 9 (3%) | <.01 |
| HBsAg positive | 0 (0%) | 1 (0%) | >.99 |
| HBcAb positive | 0 (0%) | 15 (5%) | .09 |
| Donor management | |||
| Length of stay during terminal hospitalization (median, IQR), days | 4 (2-5) | 3 (2-5) | .18 |
| Antimicrobial administration during terminal hospitalization | 66 (100%) | 316 (97%) | .22 |
| (b) Solid organ transplant recipients (N=658) | |||
| Baseline characteristica,b |
Donor with history of recent IDU(N = 120) |
Donor with no history of recent IDU (N = 538) |
p-Value |
| Demographics | |||
| Age (median, IQR), years | 56 (45-63) | 60 (49-66) | .01 |
| Female gender | 35 (29%) | 196 (36%) | .13 |
| Race: White | 69 (58%) | 319 (59%) | .72 |
| Race: Black | 44 (37%) | 168 (31%) | .25 |
| Race: Asian | 4 (3%) | 17 (3%) | >.99 |
| Ethnicity: Hispanic | 12 (10%) | 36 (7%) | .21 |
| Organ transplant type | |||
| Kidney | 52 (43%) | 195 (36%) | .31 |
| Liver | 29 (24%) | 145 (27%) | .31 |
| Pancreas | 2 (2%) | 3 (1%) | .31 |
| Heart | 18 (15%) | 83 (15%) | .31 |
| Lung | 19 (16%) | 112 (21%) | .31 |
| Comorbidities | |||
| Uncomplicated diabetes mellitus | 14 (12%) | 91 (17%) | .16 |
| Complicated diabetes mellitus | 28 (23%) | 81 (15%) | .03 |
| Hypertension | 72 (60%) | 331 (62%) | .76 |
| Chronic kidney disease | 35 (29%) | 129 (24%) | .24 |
| Cirrhosis | 28 (23%) | 138 (26%) | .60 |
| Congestive heart failure | 29 (24%) | 114 (21%) | .48 |
| Prior solid organ Transplant | 10 (8%) | 18 (3%) | .01 |
| Charlson comorbidity index (median, IQR) | 4 (2–6) | 4 (2–6) | .57 |
| Pretransplant characteristics | |||
| Days on waitlist (median, IQR) | 187 (39–640) | 236 (51–783) | .55 |
| Intensive care unit pretransplantatione | 9 (8%) | 51 (9%) | .50 |
| Mechanical ventilation pretransplantatione | 2 (2%) | 16 (3%) | .55 |
| Renal replacement therapy pretransplantatione | 60 (50%) | 202 (38%) | .02 |
| Laboratory Values | |||
| CMV seropositive | 65 (54%) | 310 (58%) | .49 |
| EBV seropositive | 109 (91%) | 512 (95%) | .06 |
| HCV seropositive | 22 (23%) | 49 (13%) | .01 |
| HBsAg positive | 2 (2%) | 6 (1%) | .65 |
| HBcAb positive | 12 (10%) | 66 (12%) | .48 |
Abbreviations: CMV, cytomegalovirus; EBV, Epstein Barr virus; HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; HCV, hepatitis C virus; IDU, injection drug use; IQR, interquartile range; MDRO, multidrug-resistant organism; PHS, Public Health Service.
Data are presented as numbers (percentages) except where noted.
Only those variables with a p value <.20, those of notable biologic importance, and those included in the final multivariable models are shown in this table.
PHS has since adopted the use of “risk criteria” for infection transmission in place of the term “increased risk donor.” These data were collected prior to this terminology change.
One donor with a history of IDU in the prior 12 months was not classified as being an “increased risk donor,” likely because the history from next-of-kin/donor informant was ambiguous about exactly when the IDU ended and estimated it was “about a year ago.”
Assessed in the 24 h prior to transplantation.
These 394 donors provided organs to 658 SOT recipients at the study sites. Among the recipients, 120(18%) received organs from a donor with a history of recent IDU. Among the exposed recipients, the median age was 56 years (IQR 45–63), and 35 (29%) were women. (See Table 1b for further recipient baseline characteristics).
3.2 ∣. Association between recent IDU and donor culture positivity
A total of 343 (87%) donors had at least one positive culture obtained during their terminal hospitalization or at the time of organ procurement (see Table 2 for details of positive donor cultures). The most common sites of positive donor cultures were the respiratory tract (326, 83%) and genitourinary tract (75, 19%). The most common organisms isolated on donor cultures included S. aureus (167, 42%) and Candida species (112, 28%). MDROs were identified in 58 (15%) donors.
TABLE 2.
Donor culture results stratified by donor history of recent injection drug use (IDU)
| Donor culturea | Donor with recent history of IDU (N = 66) |
Donor with no history of recent IDU (N = 328) |
p-Value |
|---|---|---|---|
| Any positive cultureb | 63 (95%) | 280 (85%) | .03 |
| Any positive hospital culturec | 44 (67%) | 199 (61%) | .36 |
| Any positive OPO cultured | 236 (72%) | 55 (83%) | .06 |
| Sites of positive cultures | |||
| Positive blood culture | 6 (9%) | 37 (11%) | .60 |
| Positive respiratory culturee | 60 (91%) | 266 (81%) | .05 |
| Positive respiratory culture in lung recipient (positive allograft culture)e | 17 (89%) | 92 (82%) | .43 |
| Positive genitourinary culturef | 12 (18%) | 63 (19%) | .85 |
| Positive genitourinary culture in kidney recipient (positive allograft culture)f | 8 (13%) | 49 (23%) | .06 |
| Positive perfusate cultureg | 6 (9%) | 23 (7%) | .56 |
| Organism identified on donor cultures | |||
| Staphylococcus aureus | 32 (48%) | 135 (41%) | .27 |
| Candida spp. | 26 (39%) | 86 (26%) | .03 |
| Candida on respiratory culture | 21 (32%) | 76 (23%) | .14 |
| Candida on GU culture | 8 (12%) | 15 (5%) | .051 |
| Candida on perfusate culture | 2 (3%) | 3 (1%) | .20 |
| Candida on blood culture | 0 (0%) | 5 (2%) | .60 |
| Candida on abdominal culture | 0 (0%) | 1 (0.3%) | >.99 |
| Candida on pleural culture | 0 (0%) | 1 (0.3%) | >.99 |
| Coagulase-Negative Staphylococcus | 7 (11%) | 38 (12%) | .82 |
| Klebsiella pneumonia | 4 (6%) | 34 (10%) | .36 |
| Haemophilus influenza | 5 (8%) | 34 (10%) | .65 |
| Escherichia coli | 2 (3%) | 29 (9%) | .14 |
| Enterobacter spp. | 4 (6%) | 21 (6%) | >.99 |
| Enterococcus spp. | 2 (3%) | 20 (6%) | .55 |
| Non-Group A Beta-Hemolytic Streptococci | 3 (5%) | 18 (5%) | >.99 |
| Pseudomonas aeruginosa | 1 (2%) | 21 (6%) | .15 |
| MDROs identified on donor cultures | |||
| Any MDROh | 9 (14%) | 49 (15%) | .06 |
| MRSA | 8 (12%) | 28 (9%) | .36 |
| VRE | 0 (0%) | 3 (1%) | >.99 |
| ESBL-Enterobacterales | 1 (2%) | 19 (6%) | .22 |
| CRE | 0 (0.00%) | 1 (0%) | >.99 |
| MDR-Pseudomonas | 0 (0%) | 2 (1%) | >.99 |
Abbreviations: CRE, carbapenem-resistant Enterobacterales; ESBL, extended-spectrum beta-lactamases; IDU, injection drug use; MDR, multidrug-resistant; MDRO, multidrug-resistant organism; MRSA, methicillin-resistant Staphylococcus aureus; OPO, organ procurement organization; spp., species; VRE, vancomycin-resistant Enterococcus.
Data are presented as numbers (percentages) except where noted.
Routine mouth flora on respiratory cultures and mixed flora on urine cultures were excluded.
Hospital cultures were obtained during the donor’s terminal hospitalization, and results may have been known prior to organ procurement.
OPO cultures were collected at the time of organ procurement, and results would not have been known until after transplantation..
Respiratory cultures included sputum cultures, tracheal aspirate cultures, endotracheal tube aspirate cultures, bronchial cultures, and bronchoalveolar lavage cultures. A positive respiratory culture in a lung recipient is a “positive allograft culture.”
Genitourinary cultures included urine cultures and ureter swab cultures. A positive genitourinary culture in a kidney recipient is a “positive allograft culture.”
Perfusate cultures included perfusate fluid cultures, transport fluid cultures, and pump solution cultures.
MDROs included MRSA, ESBL-Enterobacterales, CRE, MDR-Pseudomonas, and VRE. MDR-Acinetobacter was also included, but there were no donors who had this MDRO identified on culture.
Among donors with recent IDU, 63 (95%) had at least one positive culture, compared to 280 (85%) of those with no recent IDU (p = .03). On multivariable analysis (Table 3), recent donor IDU was associated with significantly increased odds of at least one positive donor culture (aOR 3.65, 95% CI 1.06–12.60, p = .04).
TABLE 3.
Multivariable logistic regression model evaluating the association between recent donor injection drug use (IDU) and donor culture positivity
| Isolation of bacteria or Candida on donor culture | |||
|---|---|---|---|
| Variable | aOR | 95% CI | p-Value |
| History of recent IDU | 3.65 | 1.06–12.60 | .04 |
| Donor tobacco use | 6.38 | 0.83–48.90 | .07 |
| Donor immunomodulator usea | 0.16 | 0.07–0.37 | <.01 |
Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.
Immunomodulators included abatacept, anakinra, apremilast, azathioprine, cyclophosphamide, cyclosporine, denosumab, hydroxychloroquine, methotrexate, mycophenolate, rituximab, secukinumab, sulfasalazine, tocilizumab, tofacitinib, infliximab, adalimumab, certolizumab, golimumab, and etanercept (not including corticosteroids).
In evaluating the secondary outcomes (Table S1), we found that recent donor IDU was associated with a significantly increased odds of Candida growth on nonrespiratory cultures (aOR 2.59, 95% CI 1.07–6.24, p = .03) but was not significantly associated with MDRO growth (aOR 0.51, 95% CI 0.20–1.26, p = .14), S. aureus growth (aOR 1.20, 95% CI 0.67–2.13, p = .54), or growth of any organism on blood culture (OR 0.79, 95% CI 0.32–1.95, p = .60).
3.3 ∣. Association between recent donor IDU and recipient infection, graft failure, or death
Among 658 SOT recipients, 289 (44%) developed an infection within 3 months posttransplant. On unadjusted analysis (Figure 1A), there was no significant association between recent donor IDU and time to first recipient infection posttransplant (log rank p = .51). Similarly, on multivariable analysis (Table 4a), there was no significant association between recent donor IDU and time to first recipient bacterial or Candida infection posttransplant (aHR 0.98, 95% CI 0.71–1.36, p = .92).
FIGURE 1.
Kaplan–Meier curves depicting time to (A) first recipient bacterial or Candida infection within 3 months posttransplant and (B) recipient graft failure or death within 12 months posttransplant
TABLE 4.
Multivariable logistic regression model evaluating the association between recent donor injection drug use (IDU) and time to (a) first recipient bacterial or Candida infection within 3 months posttransplant and (b) recipient graft failure or death within 12 months posttransplant
| (a) First recipient bacterial or Candida infection | |||
|---|---|---|---|
| Variable | aHR | 95% CI | p-Value |
| History of recent IDU | 0.98 | 0.71–1.36 | .92 |
| Donor age (per year increase) | 0.99 | 0.98–1.00 | .02 |
| Donor alcohol usea | 1.65 | 1.08–2.52 | .02 |
| Recipient on hemodialysis pretransplantation | 2.18 | 1.31–3.62 | .01 |
| Recipient Charlson comorbidity index | 1.14 | 1.07–1.22 | <.01 |
| Organ type: kidney | ref | ||
| Organ type: liver | 1.37 | 0.78–2.41 | .28 |
| Organ type: pancreas | 1.19 | 0.22–6.38 | .84 |
| Organ type: heart | 3.28 | 1.90–5.65 | <.01 |
| Organ type: lung | 4.47 | 2.49–8.01 | <.01 |
| (b) Recipient graft failure or death within 12 months posttransplant | |||
| Variable | aHR | 95% CI | p-Value |
| History of recent IDU | 0.67 | 0.29–1.51 | .33 |
| Donor death due to blunt trauma | 2.45 | 1.36–4.43 | .01 |
| Recipient on hemodialysis pretransplant | 4.03 | 1.56–10.39 | .01 |
| Organ type: kidney | ref | ||
| Organ type: liver | 4.27 | 1.65–11.0 | .01 |
| Organ type: pancreas | 4.31 | 0.56–33.24 | .16 |
| Organ type: heart | 6.65 | 2.04–21.58 | .01 |
| Organ type: lung | 8.41 | 2.58–27.36 | <.01 |
Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; IDU, injection drug use.
Defined by alcohol detection on toxicology screen taken on admission to the donor’s terminal hospitalization.
Among 658 SOT recipients, 57 (9%) developed graft failure or death within 12 months posttransplant. On unadjusted analysis (Figure 1B), there was no significant association between recent donor IDU and time to graft failure or death (log rank p = .29). Similarly, on multivariable analysis (Table 4b), there remained no significant association between recent donor IDU and the hazard of graft failure or death (aHR 0.67, 95% CI 0.29–1.51, p = .33).
3.4 ∣. Association between recent donor IDU and specific recipient infections
Among the 659 SOT recipients, 25 (4%) developed invasive candidiasis, 48 (7%) developed S. aureus infection, and 58 (9%) developed infection with an MDRO within 3 months posttransplant. On multivariable logistic regression (adjusting for organ type) (Table S2), recent donor IDU was not significantly associated with invasive candidiasis (aOR 1.62, CI 0.63–4.18, p = .32), S. aureus infection (aOR 1.57, CI 0.69–3.56, p = .28), or MDRO infection in the recipient (aOR 1.27, CI 0.54–2.99, p = .59).
There were 31 (5%) SOT recipients with a probable DDI. There was no significant difference in the rate of DDI between those recipients with a donor with recent IDU (6, 5%) compared to recipients with a donor without recent IDU (25, 5%) (p = .87). On multivariable logistic regression (adjusting for organ type) (Table S2), there was no significant association between recent donor IDU and odds of a DDI (aOR 1.30, 95% CI 0.50–3.37, p = .60).
4 ∣. DISCUSSION
In this study, we found that donors with a recent history of IDU were more likely to have positive cultures, specifically Candida on nonrespiratory cultures, but this increase in donor culture positivity did not translate into an increased risk of infection, graft failure, or death among SOT recipients.
Donors with recent IDU did have significantly more positive donor cultures, perhaps due to increased exposure to skin and upper airway flora during injection and/or pulmonary aspiration in the setting of opioid-related somnolence.18 This hypothesis is supported by the finding that donor culture positivity was driven primarily by an increase in Candida, which commonly colonizes the skin and upper airway. This was a potentially concerning finding, since there are case reports of donor-derived Candida infections causing significant morbidity in SOT recipients, including vascular anastomotic disruption and pseudoaneurysm.19,20 However, the increased rate of positive donor cultures among donors with recent IDU did not lead to a significantly increased incidence of recipient infections, including invasive Candida infections or donor-derived infections. This lack of impact on recipient outcomes may be related to less pathogenic organisms colonizing/infecting donors, and/or the standardized treatment of recipients for positive donor cultures, including Candida on donor cultures. Therefore, although donors with recent IDU may have more organisms detected on culture, there was no clinically meaningful impact on infectious outcomes for their recipients.
Notably, there were few other significant differences in donor culture results between donors with and without recent IDU. The majority of donor infections that are associated with IDU and which are potentially worrisome for causing DDIs—including infections with S. aureus, MDROs, and bloodstream infections—were not observed at significantly higher rates among donors with recent IDU, nor were there higher rates of recipient infections due to these organisms. There remain some providers and transplant candidates who may be hesitant to accept organs from donors with a history of recent IDU given their previous designation as PHS “increased risk donors,” as shown by previous studies illustrating underutilization of these organs.12,13 The data from this study would thus suggest that organs from donors with a history of recent IDU do not confer an increased risk of serious infections, graft failure, or death to recipients, alleviating lingering fears surrounding the acceptance of these organs.
There are several limitations to this study. First, this was a retrospective observational study, and it is possible that there were unmeasured confounders that impacted the risk of donor IDU and the outcomes studied. However, assigning recipients to donors with or without recent IDU for the purposes of randomization would not be ethically feasible, and thus, an observational study is likely the only practical approach. Given our cohort was created prior to the COVID-19 pandemic, we were not able to explore whether COVID-19 infection is a possible confounder of the relationship between donor IDU and recipient outcomes. Second, it is possible that there was misclassification of the exposure, since a history of IDU among donors is typically gathered from interview of next-of-kin or donor informants, which is known to be an imperfect measure21; we attempted to mitigate this possible bias by supplementing the IDU history with toxicology screen results from the terminal hospitalization. Further, our use of the clinical information that is typically available to transplant centers about potential organ donors increases the generalizability of the study. Third, the outcomes described in this study occurred in the context of standardized management strategies for positive donor cultures (where recipients are given antimicrobials with activity against organisms that grow on donor blood cultures or donor cultures from the allograft that are not considered contaminants). It is possible that without such measures, organs from donors with recent IDU would be more likely to cause DDI in recipients, and that results from this study may not be generalizable to transplant centers that evaluate for and treat donor infection differently. Additionally, although the standard approach to positive donor cultures at the study centers is provided in this manuscript, we were not able to determine the consistency with which providers at each center followed these guidelines. Fourth, we acknowledge that it is difficult to differentiate between true infection and colonization when analyzing donor culture results. However, this issue is faced by all transplant providers when making decisions regarding organ acceptance, including those in our study. The transplant centers in this study routinely administer antibiotic prophylaxis based on donor culture results, regardless of whether there is evidence of true infection in the donor, in part due to the difficulty of determining true infection with the available donor data. Therefore, we believe our study reflects the current clinical situation faced by transplant providers, making it more generalizable. Lastly, this study focused on potential transmission of bacterial and Candida infections to recipients of donors with a history of recent IDU and did not evaluate for potential viral donor-derived infections such as HIV or hepatitis C virus.
In conclusion, donors with a history of recent IDU are more likely to have positive cultures compared to those donors without a history of recent IDU, but this does not translate into an increased risk of recipient infection, graft failure, or death. These results suggest that organs from donors with recent IDU do not pose significant novel infectious risks to recipients and therefore support the expansion of the donor pool to include donors with a history of recent IDU.
Supplementary Material
ACKNOWLEDGMENTS
This work was supported by the Transplant Foundation’s Innovative Research Grant Program, an affiliate of the Gift of Life Donor Program (donation and transplantation grant to J.A.A.); the Antibacterial Resistance Leadership Group (grant number: 5 UM 1AI104681-05 with a subaward fellowship grant to J.A.A.); the National Institutes of Health (grant numbers: K24-AI080942 to E.L. and K01-AI137317 to J.A.A.); and by a Centers for Disease Control and Prevention (CDC) Cooperative Agreement FOA#CK16-004-Epicenters for the Prevention of Healthcare Associated Infections (to E.L.).
Abbreviations:
- aHR
adjusted hazard ratio
- aOR
adjusted odds ratio
- CDC
Centers for Disease Control and Prevention
- CI
confidence interval
- DDI
donor-derived infection
- GLDP
Giftof Life Donor Program
- IDU
injection drug use
- MDR
multidrug-resistant
- MDRO
multidrug-resistant organism
- NHSN
National Healthcare Safety Network
- PHS
Public Health Service
- SOT
solid organ transplantation
Footnotes
CONFLICT OF INTEREST
Emily Blumberg receives research support from Merck, Takeda, and Hologic, is a member of a Data and Safety Monitoring Board (DSMB) for Amplyx, and is a member of Scientific Advisory Committees for Merck and Takeda. Jennifer Han was affiliated with the University of Pennsylvania during the conduct of this research and is now employed by, and holds shares in, the GlaxoSmithKline group of companies. Ebbing Lautenbach is a member of a DSMB for Merck and is a member of a scientific advisory committee for Paratek and Shionogi. None of these conflicts are relevant to this article. All other authors report no disclosures.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
REFERENCES
- 1.Drug overdose deaths in the U.S. top 100,000 annually. CDC. 2021. Accessed December 24, 2021. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2021/20211117.htm [Google Scholar]
- 2.Drug overdose deaths ∣ drug overdose ∣ CDC injury center. CDC. Accessed December 24, 2021. https://www.cdc.gov/drugoverdose/deaths/index.html [Google Scholar]
- 3.Durand CM, Bowring MG, Thomas AG, et al. The drug overdose epidemic and deceased-donor transplantation in the united states: a national registry study. Ann Intern Med. 2018;168(10):702–711. doi: 10.7326/M17-2451 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Goldberg D, Lynch R. Improvements in organ donation: riding the coattails of a national tragedy. Clin Transplant. 2020;34(1):e13755. doi: 10.1111/ctr.13755 [DOI] [PubMed] [Google Scholar]
- 5.Wolfe CR, Ison MG. Donor-derived infections: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13547. doi: 10.1111/ctr.13547 [DOI] [PubMed] [Google Scholar]
- 6.Fischer SA. Is this organ donor safe?: donor-derived infections in solid organ transplantation. Infect Dis Clin North Am. 2018;32(3):495–506. doi: 10.1016/j.idc.2018.04.001 [DOI] [PubMed] [Google Scholar]
- 7.Blasi M, Stadtler H, Chang J, et al. Detection of donor’s HIV strain in HIV-positive kidney-transplant recipient. N Engl J Med. 2020;382(2):195–197. doi: 10.1056/NEJMc1910189 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Suryaprasad A, Basavaraju SV, Hocevar SN, et al. Transmission of hepatitis C virus from organ donors despite nucleic acid test screening. Am J Transplant 2015;15(7):1827–1835. doi: 10.1111/ajt.13283 [DOI] [PubMed] [Google Scholar]
- 9.Kieslichova E, Protus M, Nemcova D, Uchytilova E. Single mutidrug resistant enterobacteriacae donor-derived infection in four solid organ transplant recipients: a case report. BMC Surg. 2019;19:111. doi: 10.1186/s12893-019-0574-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Azar MM, Turbett SE, Fishman JA, Pierce VM. Donor-derived transmission of candida auris during lung transplantation. Clin Infect Dis. 2017;65(6):1040–1042. doi: 10.1093/cid/cix460 [DOI] [PubMed] [Google Scholar]
- 11.Jones JM. Assessing solid organ donors and monitoring transplant recipients for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infection — U.S. public health service guideline, 2020. MMWR Recomm Rep. 2020;69:1–16. doi: 10.15585/mmwr.rr6904a1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Duan KI, Englesbe MJ, Volk ML. Centers for Disease Control ‘high-risk’ donors and kidney utilization. Am J Transplant. 2010;10(2):416–420. doi: 10.1111/j.1600-6143.2009.02931.x [DOI] [PubMed] [Google Scholar]
- 13.Volk ML, Wilk AR, Wolfe C, Kaul DR. The “PHS increased risk” label is associated with nonutilization of hundreds of organs per year. Transplantation. 2017;101(7):1666–1669. doi: 10.1097/TP.0000000000001673 [DOI] [PubMed] [Google Scholar]
- 14.Kim T, Chhabra N, Weech DM, Leikin JB. Short-term graft failure of organs procured from drug-related deaths compared with other causes of death. J Med Toxicol. 2020;17(1):37–41. doi: 10.1007/s13181-020-00801-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.CDC/NHSN surveillance definitions for specific types of infections. CDC. Accessed December 24, 2021. https://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf [Google Scholar]
- 16.Kaul DR, Vece G, Blumberg E, et al. Ten years of donor-derived disease: a report of the disease transmission advisory committee. Am J Transplant. 2021;21(2):689–702. doi: 10.1111/ajt.16178 [DOI] [PubMed] [Google Scholar]
- 17.2021 NHSN patient safety component manual. CDC. Accessed December 24, 2021. https://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf [Google Scholar]
- 18.Mégarbane B, Chevillard L. The large spectrum of pulmonary complications following illicit drug use: features and mechanisms. Chem Biol Interact. 2013;206(3):444–451. doi: 10.1016/j.cbi.2013.10.011 [DOI] [PubMed] [Google Scholar]
- 19.Yannam GR, Wrenshall L, Stevens RB. Loss of renal allografts secondary to candida vascular complications in two recipients from the same donor. Case Rep Transplant. 2012;2012:364735. doi: 10.1155/2012/364735 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.El-Bandar N, Kroy DC, Fuller TF, et al. Development of graft-site candidiasis in 3 solid organ transplant recipients from the same donor. Am J Case Rep. 2017;18:777–781. doi: 10.12659/AJCR.904119 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lehrmann E, Afanador ZR, Deep-Soboslay A, et al. Postmortem diagnosis and toxicological validation of illicit substance use. Addict Biol. 2008;13(1):105–117. doi: 10.1111/j.1369-1600.2007.00085.x [DOI] [PMC free article] [PubMed] [Google Scholar]
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