Infection
https://doi.org/10.1007/s15010-023-02089-6
RESEARCH
Real‑time, random‑access organ screening for carbapenem‑resistant
organisms (CRO) reduces CRO‑associated, donor‑derived infection
mortality in lung transplant recipients
Wen‑Yong Zhou1 · Lei Shen2,3 · Jian‑Xin Shi1 · Xing‑Hui Gao4 · Jun Yang1 · Shi‑Jie Fu1 · Xu‑Feng Pan1 · Min‑Fang Zhu5 ·
Shen Zhang5 · Chong Zhang5 · Feng Li6 · Hai Zhang6 · Feng Yao1 · Fred C. Tenover7 · Yi‑Wei Tang4 · Wen‑Tao Fang1
Received: 3 May 2023 / Accepted: 22 August 2023
© The Author(s) 2023
Abstract
Purpose Donor-derived infection (DDI) has become an important factor affecting the prognosis of lung transplantation
patients. The risks versus benefits of using donor organs infected with multidrug-resistant organisms (MDRO), especially
carbapenem-resistant organisms (CRO), are frequently debated. Traditional microbial culture and antimicrobial susceptibility testing at present fail to meet the needs of quick CRO determination for donor lungs before acquisition. In this study, we
explored a novel screening method by using Xpert® Carba-R assay for CRO in donor lungs in a real-time manner to reduce
CRO-associated DDI mortality.
Methods This study was registered on chictr.org.cn (ChiCTR2100053687) on November 2021. In the Xpert Carba-R screening group, donor lungs were screened for CRO infection by the Xpert Carba-R test on bronchoalveolar fluid (BALF) before
acquisition. If the result was negative, donor lung acquisition and subsequent lung transplantation were performed. In the
thirty-five potential donors, nine (25.71%) with positive Xpert Carba-R results in BALF were declined for lung transplantation. Twenty-six recipients and the matching CRO-negative donor lungs (74.29%) were included in the Xpert Carba-R
screening group. In the control group, nineteen recipients underwent lung transplants without Xpert Carba-R screening. The
incidence and mortality of CRO-associated DDI were collected and contrasted between the two groups.
Results Multivariate analysis showed that CRO-related death due to DDI within 60 days was significantly lower in the Xpert
Carba-R screening group than that in the control group (OR = 0.05, 95% CI 0.003–0.74, p = 0.03).
Conclusion Real-time CRO screening of donor lungs before transplantation at the point of care by the Xpert Carba-R helps
clinicians formulate lung transplantation strategies quickly and reduces the risk of subsequent CRO infection improving the
prognosis of lung transplantation.
Keywords Donor-derived infection · Carbapenem-resistant organisms · Lung transplantation · Point-of-care testing ·
Prognosis
Introduction
Lung transplantation is the only effective treatment option for
patients with end-stage lung disease. Lung donations come
mainly from patients who have suffered brain death (i.e., donation after brain death, DBD) and donation after cardiac death
(DCD) [1]. Infection is one of the leading causes of both shortterm and long-term death in lung transplantation recipients [1,
Wen-Yong Zhou, Lei Shen and Jian-Xin Shi contributed equally to
this work.
Extended author information available on the last page of the article
2]. Donor-derived infection (DDI) is an important infection
in lung transplant recipients [3]. Although the epidemiology
varies markedly among different geographical regions, risk
factors of prolonged (> 7 days) ICU stay, vasopressor support,
and cardiopulmonary resuscitation increases colonization with
multidrug-resistant organisms (MDRO) including extendedspectrum β-lactamase -producing Enterobacteriaceae (ESBLE) and carbapenem-resistant organisms (CRO) in donors [4].
The current study suggests that MDRO or CRO may significantly contribute to the burden of bacterial DDI [5, 6]. Lung
transplant recipients appear to be disproportionately affected,
potentially due to the high frequency of MDRO colonization
of the donor respiratory tract [7, 8]. MDRO-associated DDI
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or CRO-associated DDI may play a role in the development
of early posttransplant infections in transplant recipients [9],
leading to several complications, including stomal leak, bleeding, graft loss, and even death [7, 10, 11]. If donor colonization or infection with CRO is known before transplantation,
a risk–benefit evaluation should be made based on the organ
to be transplanted and the site of the positive donor cultures.
Clinicians suggest that acquiring the lung from a donor experiencing CRO bacteremia or respiratory colonization for transplantation should be avoided [3].
Traditionally, CRO screening of donor lungs is based on
bacterial culture followed by phenotypic antimicrobial susceptibility testing. However, there are two main problems with
culture-based screening: (i) the time to results, which requires at
least 72 h, is too slow to meet the needs of donor lung acquisition; and (ii) the requirements for trained personnel, equipment,
sites, etc., which are inconsistent with the organ procurement
organizations (OPOs) [12]. The culture method has a result
reporting time delay, which may lead to occult CRO infection
in the donor lungs during the period before culture and susceptibility test results are available. Therefore, a rapid, simple,
and accurate technique for CRO screening of donor organs
is urgently needed at the point of care. This could effectively
reduce latent donor CRO infection, reduce the incidence of
postoperative DDI and infection-related adverse events of lung
transplantation, and improve the prognosis of patients who
receive lung transplantation.
The Xpert® Carba-R assay (Cepheid, Sunnyvale, CA,
USA) is an on-demand PCR test specifically designed for
the qualitative detection and differentiation of five common
carbapenemase gene families, including blaKPC, blaNDM,
blaVIM, blaIMP, and blaOXA-48 with results available in less
than one hour [13]. Due to the portability of the instrument,
the donor lung acquisition team can test the donor lung for
CRO at the OPO and decide whether to acquire the lung and
perform the transplantation after obtaining the CRO results
in real time. This approach would help avoid the acquisition
of a CRO-infected donor lung and reduce the occurrence of
CRO-associated DDI and infection-related complications
after lung transplantation caused by using CRO-infected
lungs. This study used the GeneXpert II instrument combined with the Xpert Carba-R test on-site to detect CRO in
donor bronchoalveolar fluid (BALF) as an off-label specimen before donor lung acquisition.
Materials and methods
Patients and study design
This historically controlled prospective trial was approved by
the Ethics Committee of Shanghai Chest Hospital, Shanghai
Jiao Tong University (No. IS21101) and registered on chictr.
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org.cn (ChiCTR2100053687). Written informed consent was
obtained from the recipients. We obtained the authorization
of the donor's next of kin and the Ethics Committee to use
donor-derived biological samples for clinical and research
purposes. All recipients who enrolled in the study accepted
lung transplant treatment at Shanghai Chest Hospital. The
screening group included patients who underwent lung
transplantation from November 2021 to September 2022
with negative CRO results of the donor lung by the Xpert
Carba-R test. The historically controlled group included
patients who underwent lung transplantation from January
2016 to December 2020. All patients who were included in
the Xpert Carba-R screening group and control group met
the same inclusion criteria of this study.
The study design is shown in Fig. 1. From November
2021 to September 2022, twenty-nine consecutive recipients were observed in the study. Among them, three cases
died during the waiting period for donor lung supply, and
one of these cases had an MDRO infection in the lung.
The remaining twenty-six recipients eligible for inclusion
criteria were included in the Xpert Carba-R screening
group. During the same period, forty donor lungs were
available for transplant. Thirty-five donor lungs met the
inclusion criteria and five dropped out for various reasons.
The thirty-five donor lungs were defined as potential donor
lungs for Xpert Carba-R testing. If one or more carbapenemase gene (including blaKPC, blaNDM, blaVIM, blaIMP,
and blaOXA-48) was positive in BALF by Xpert Carba-R,
the potential donor lungs were not acquired and would
be declined for the subsequent lung transplantation. Only
the potential donor lungs of carbapenemase gene negative
were used as donor lungs in the Xpert Carba-R screening group. For the historic controls, twenty-three cases of
donor lungs and twenty-two recipients were consecutively
observed from January 2016 to December 2020. According to the inclusion criteria, nineteen recipients and the
matching donor lungs were included.
Donor inclusion criteria
Donor meeting the following criteria were considered for
inclusion in the study: legal and ethical instruments of organ
donation can be obtained; DBD; same blood type or different but compatible with recipient blood type; age ≥ 18
and ≤ 70 years; oxygenation index (P/F) > 230 mmHg
(FiO2 = 1.0, PEEP = 5 cm H2O); chest radiograph showing
a clear lung field or a mild to moderate exudation; appropriate size-match in lung donor and recipient, or a poor sizematch but with satisfactory matching after volume reduction
to donor lung; absence of chest trauma; absence of aspiration or slight aspiration improved after treatment; absence
or a small amount of purulent secretions in the airway; cold
Real‑time, random‑access organ screening for carbapenem‑resistant organisms (CRO) reduces…
Fig. 1 Study flowchart. MDRO, multidrug-resistant organisms
ischemia time < 8 h; and no evidence of MDRO or CRO
infection and colonization.
Recipient inclusion criteria
The patients who suffered non-neoplastic pulmonary disease accepted for lung transplantation showed: normal blood
sugar levels or fasting blood glucose of diabetic patients that
were controlled below 10 mmol/L; normal or mildly abnormal liver function (Child–Pugh grade A); normal or mildly
abnormal renal function (GFR > 59 ml/min); age ≤ 75 years;
a postoperative survival time was more than 1 week; no
evidence of MDRO (including CRO, methicillin-resistant
Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamases (ESBLs)producing bacteria, or multidrug-resistant tuberculosis
(MDR-TB)) infection or colonization were noted before
lung transplantation. For MDRO detection, BALF or sputum specimens of recipients were obtained every three days
for microbial culture and antimicrobial susceptibility testing
before lung transplantation.
BALF was recovered by aspiration. One ml of the BALF
suspension was added to a 5 mL Xpert Carba-R sample reagent vial and mixed for 10 s. Using the supplied pipette,
1.7 ml of sample reagent was transferred into the sample
chamber of the Xpert Carba-R cartridge, the lid was closed,
and the cartridge was placed in the Cepheid GeneXpert platform for testing.
Bacterial culture of BALF samples
10 µl of BALF from the donor lung was inoculated onto a
Columbia blood agar blood plate, a vancomycin-containing
chocolate agar plate, and a crystal violet-containing MacConkey agar plate, and incubated at 35 °C for 24–48 h.
When the BALF samples grew more than 104 CFU/mL,
colonies were selected and identified using matrix-assisted
laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF–MS). Antimicrobial susceptibility testing (AST) of these identified bacteria was performed by
using the disc diffusion method and the broth microdilution
method according to the 2022 Clinical Laboratory Standard
Institute (CLSI) guidelines [14].
Xpert Carba‑R CRO detection in donor lung
Clinical outcomes
For the BALF sample, we used the Xpert Carba-R test with
the off-label following procedure: approximately 15 ml of
sterile normal saline was injected into the left and right main
bronchus of the donor lung by bronchoscopy. At least 20 ml
DDI was defined as any infection present in the donor that is
transmitted to one or more recipients during or after transplantation [15]. At present, there is still a lack of effective
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W.-Y. Zhou et al.
methods for the identification of DDI in donor infections,
especially the lack of consensus on the identification of
DDI using molecular diagnostic tests. In this study, BALF
or sputum specimens from recipients were obtained every
three days for microbial culture and antimicrobial susceptibility testing before lung transplantation. Cultures growing
MDRO, especially those indicating CRO -infected or colonized- recipients, were used to exclude those patients from
the study cohort. Therefore, in this study, we defined CROassociated DDI as an infection in a recipient within 1 week
after lung transplantation, if the CRO-containing organism
recovered from the recipient is the same as the CRO-containing organism carried by the donor lung and the organisms
has the same antimicrobial susceptibility profile. Death of
recipients related by infection with any donor- or recipientderived pathogen within 60 days after lung transplant was
described as infection-related death within 60 days, which
includes CRO-associated DDI-related death within 60 days.
In this study, we collected the clinical characteristics of
the donors and recipients to compare the baselines between
the two groups. The outcomes and incidence of DDI, CROassociated DDI, and infection-or CRO-associated DDIrelated death within 60 days were mainly focused on the
effect of Xpert Carba-R donor lung screening on the prognosis of recipients.
Statistical analysis
We analyzed variable distribution by the D’Agostino-Pearson test. The continuous variables of normal distributions
were expressed as mean ± standard deviation, and the continuous variables of non-normal distribution were presented
as medians and quartiles. The classification variables were
presented as frequencies and percentages. The continuous
variables were compared by an independent sample t-test
or rank-sum test, and the comparison of classification variables was conducted by Fisher's exact test. Logistic regression was used for the univariate analysis and multivariate
analysis. Penalized likelihood logistic regression was used
when quasi-complete separation happened. A p-value < 0.05
was considered statistically significant. SPSS 26.0 software
(IBM, Chicago, USA) plus Normaltest software package and
Statistical Analysis System (SAS) statistical software package, version 9.4 were used for statistical analysis.
Results
In the thirty-five potential donors, nine (25.71%) with positive Xpert Carba-R results in BALF were declined for lung
transplantation before the acquisition. Finally, the twenty-six
recipients and matching CRO-negative donor lungs (74.29%)
were included in the Xpert Carba-R screening group.
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The baseline characteristics of donors and recipients
in both groups were summarized in Table 1. The factors
of donors, including age, sex, death mechanism, duration
of brain death declaration (BDD) to lung transplantation,
mechanical ventilation support time, and cold ischemia time
were not statistically significant between the screening and
control groups. In the Xpert Carba-R screening group, the
donor lungs of carbapenemase gene negative were used for
lung transplantation.
In this study, microbial culture and antimicrobial susceptibility testing of BALF specimens from donor lungs were
routinely cultured prior to lung transplantation regardless
of the Xpert Carba-R results. The BALF culture reports of
donors in the Xpert Carba-R screening group suggested that
in addition to one case of methicillin-resistant Staphylococcus epidermidis (MRSE) infection, there was one case of
carbapenem-resistant Klebsiella pneumoniae (CRKP) infection, and one case carbapenem-resistant Acinetobacter baumannii (CRAB) infection.
The rate of CRO isolation from donor lung specimens was
significantly lower in the Xpert Carba-R screening group
(2/26, 7.69%) compared with that in the control group (7/19,
36.84%) (p = 0.02) (Table 1). For specimens from recipients,
there was a significant difference between the two groups
in CRO positivity rate of postoperative lung grafts (9/26,
34.62% vs. 15/19, 78.94%, p < 0.01) (Table 1).
Whether the presence of CRO infection in the donor lung
has effects on DDI and outcomes of recipients is unclear. In
this study, compared with non-CRO infected-donor lungs,
the use of donor lungs with CRO infection significantly
increased DDI (p < 0.01) and infection-related death within
60 days (p < 0.01) in recipients after lung transplantation
(Table 2).
Among forty-five lung transplantation patients (twentysix in the Xpert Carba-R screening group and nineteen in
the control group), DDI and CRO-associated DDI occurred
in 19.23% and 7.69% in the screening group, and 36.84%
and 31.58% in the control group, respectively (Table 3). We
observed several infection-related deaths within 60 days.
There were two (7.69%) and seven (36.84%) deaths in the
two groups, respectively (OR = 0.14, 95% CI 0.03–0.80,
p = 0.02), including one CRO-related death due to DDI
(3.85%) in the screening group and six (31.58%) in the control group (OR = 0.09, 95% CI 0.01–0.80, p = 0.03) (Tables 3
and 4). Adjusted for the potential confounders of BMI and
diabetes mellitus in recipients suggested by the results of
univariate analysis, multivariate analysis showed that Xpert
Carba-R screening for donor lungs significantly reduced the
risk of CRO-associated DDI relating death within 60 days
in recipients (OR = 0.05, 95% CI 0.003–0.74, p = 0.03)
(Table 4). In this study, the Xpert Carba-R screening group
received a lower dose of therapeutic antibiotics than the control group (p = 0.02) (Table 3).
Real‑time, random‑access organ screening for carbapenem‑resistant organisms (CRO) reduces…
Table 1 Baseline characteristics of donors and recipients in the Xpert Carba-R screening group and control group
Donor baseline characteristics
Age (years; mean ± SD)
Male gender (n; %)
Death mechanism (n; %)
Intracranial hemorrhage
Trauma
Asphyxiation
Other
BDD to lung transplantation (hours; mean ± SD)
Duration of mechanical ventilation support (hours; mean ± SD)
Cold ischemia time of donor lungs (minutes; mean ± SD)
Pathogens isolation in donor lungs (n; %)
Pathogens isolation positive
CRO isolation positive
Type of MDRO isolation in donor lungs (n; %)
Staphylococcus epidermidis (MRSE)
Acinetobacter baumannii (CRAB)
Pseudomonas aeruginosa (CRPA)
Klebsiella pneumoniae (CRKP)
Recipient baseline characteristics
Age (years; mean ± SD)
Male gender (n; %)
Blood type (n; %)
A
B
O
AB
BMI (kg/m2;; mean ± SD)
Smoking (n; %)
Never smoker
Ex-smoker
Current smoker
Primary diseases (n; %)
COPD
ILD
LAM
Pneumonoconiosis
OB
Comorbidities (n; %)
Diabetes mellitus
Hypertension
Coronary heart disease
Connective tissue disease
Preoperative oxygen saturation (FiO2: 0.21) (%, mean ± SD)
Oxygen support pre-transplantation (n; %)
Nasal oxygen
OxyMask
High-flow oxygen
Mechanical ventilation
Xpert Carba-R screening
group (n = 26)
Control group (n = 19)
P value
42.00 ± 8.16
19/26 (73.08%)
40.26 ± 10.33
14/19 (73.68%)
0.53
1.00
0.96
12/26 (46.15%)
7/26 (267.92%)
3/26 (11.54%)
4/26 (15.38%)
45.42 ± 18.05
67.35 ± 19.39
381.65 ± 120.86
9/19 (47.37%)
6/19 (31.58%)
2/19 (10.53%)
2/19 (10.53%)
51.58 ± 18.48
65.79 ± 23.79
349.47 ± 123.94
0.27
0.81
0.39
14/26 (53.85%)
2/26 (7.69%)
9/19 (47.37%)
7/19 (36.84%)
0.77
0.02
1/26 (3.85%)
1/26 (3.85%)
N/A
1/26 (3.85%)
N/A
3/19 (15.79%)
1/19 (5.26%)
3/19 (15.79%)
64.35 ± 6.81
23/26 (88.46%)
56.90 ± 12.36
15/19 (78.95%)
9/26 (34.62%)
10/26 (38.46%)
4/26 (15.38%)
3/26 (11.54%)
21.76 ± 2.74
9/19 (47.37%)
4/19 (21.05%)
3/19 (15.79%)
3/19 (15.79%)
20.62 ± 2.95
5/26 (19.23%)
18/26 (69.23%)
3/26 (11.54%)
7/19 (36.84%)
9/19 (47.37%)
3/19 (15.79%)
7/26 (26.92%)
18/26 (69.23%)
N/A
1/26 (3.85%)
N/A
14/26 (53.85%)
6/26 (23.08%)
6/26 (23.08%)
2/26 (7.69%)
1/26 (3.85%)
89.00 ± 5.51
5/19 (26.32%)
11/19 (57.89%)
1/19 (5.26%)
N/A
2/19 (10.53%)
7/19 (36.84%)
3/19 (15.79%)
5/19 (26.32%)
N/A
N/A
87.21 ± 6.35
14/26 (53.85%)
5/26 (19.23%)
4/26 (15.38%)
3/26 (11.54%)
5/19 (26.32%)
8/19 (42.11%)
3/19 (15.79%)
3/19 (15.79%)
0.01
0.43
0.65
0.19
0.32
0.28
0.26
0.32
0.25
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W.-Y. Zhou et al.
Table 1 (continued)
Laboratory test results (mean ± SD)
Hemoglobin (g/L)
Albumin (g/L)
Total bilirubin (mol/L)
Serum creatinine (umol/L)
Days on waitlist (days; mean ± SD)
Types of lung transplantation (n; %)
Double lung
Single lung
Retransplant
Preoperative pathogens isolation positive in recipient lungs (n; %)
Postoperative pathogens isolation in recipient lung grafts (n; %)
Pathogens isolation positive
CRO isolation positive
Type of MDRO isolation in postoperative recipient lung grafts (n; %)
Klebsiella pneumoniae (ESBL-E)
Staphylococcus aureus (MRSA)
Acinetobacter baumannii (CRAB)
Pseudomonas aeruginosa (CRPA)
Klebsiella pneumoniae (CRKP)
Different classes of antibiotics used (mean ± SD)
Ceftazidime/avibactam used (n; %)
Xpert Carba-R screening
group (n = 26)
Control group (n = 19)
P value
139.54 ± 19.43
33.50 ± 6.43
13.56 ± 6.13
60.73 ± 10.27
26.58 ± 21.11
136.05 ± 23.32
34.00 ± 4.41
16.71 ± 10.43
55.89 ± 16.52
38.53 ± 35.64
0.59
0.77
0.21
0.23
0.17
0.23
14/26 (53.85%)
12/26 (46.15%)
N/A
3/26 (11.54%)
10/19 (52.63%)
7/19 (36.84%)
2/19 (10.53%)
2/19 (10.53%)
1.00
23/26 (88.46%)
9/26 (34.62%)
19/19 (100%)
15/19 (78.94%)
0.25
0.01
1/26 (4.55%)
N/A
4/26 (15.38%)
4/26 (15.38%)
4/26 (15.38%)
5.19 ± 2.58
4/26 (15.38%)
N/A
1/19 (5.26%)
8/19 (42.11%)
5/19 (26.32%)
6/19 (31.58%)
5.05 ± 2.12
3/19 (15.79%)
0.85
1.00
P value calculated with t-test or Chi-square test as appropriate. BDD duration of brain death declaration, COPD chronic obstructive pulmonary disease, ILD interstitial lung disease, LAM lymphangioleiomyomatosis, OB obliterative bronchiolitis, CRO carbapenem-resistant organisms, MDRO multi-drug resistant organisms, MRSE methicillin-resistant Staphylococcus epidermidis. ESBL-E extended-spectrum β-lactamaseproducing Enterobacteriaceae, MRSA methicillin-resistant Staphylococcus aureus, CRAB carbapenem-resistant Acinetobacter baumannii, CRPA
carbapenem-resistant Pseudomonas aeruginosa, CRKP carbapenem-resistant Klebsiella pneumoniae
Table 2 The effict of CRO isolation in preoperative donor lungs on outcomes in lung transplant recipients
Outcomes of recipients
CRO isolation positive in
donor lungs (n = 9)
Non-CRO isolation positive in
donor lungs (n = 36)
DDI (n; %)
Infection-related death within 60 days (n; %)
Duration of postoperative ICU treatment (days; mean ± SD)
Postoperative consumption of therapeutic antibiotics (cumulative
DDDs, mean ± SD)
8/9 (88.89%)
7/9 (77.78%)
36.89 ± 20.05
94.16 ± 58.80
4/36 (11.11%)
2/36 (5.56%)
27.86 ± 27.11
58.57 ± 60.63
P value
< 0.01
< 0.01
0.36
0.12
DDI donor-derived infection, CRO carbapenem-resistant organisms, cumulative DDDs the sum of the DDDs of each therapeutic antibiotic used
for postoperative lung transplant recipients, DDDs the mass of each antibiotic consumed/ defined daily dose (DDD)
Discussion
Donor-derived infections, especially those that are CROrelated, are an important risk factor leading to poor outcomes of lung transplantation. Occult CRO infections in
donor lungs often result in high mortality, which with
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carbapenem-resistant Klebsiella pneumoniae infection can
reach 72.7% [16]. Current CRO screening methods, mainly
based on bacterial culture followed by AST, are too slow
to provide information on infection in donor lungs before
transplantation. Thus, infected lungs may be transplanted,
leading to postoperative infections requiring antimicrobial
Real‑time, random‑access organ screening for carbapenem‑resistant organisms (CRO) reduces…
Table 3 The effect of Xpert Carba-R screening on outcomes in lung transplant recipients
Outcomes of recipients
Xpert Carba-R screening
group (n = 26)
Control group (n = 19)
P value
DDI (n; %)
CRO-associated DDI (n; %)
Infection-related death within 60 days (n; %)
CRO-associated DDI relates death within 60 days (n; %)
Duration of postoperative ICU treatment (days; mean ± SD)
Postoperative consumption of therapeutic antibiotics (cumulative
DDDs, mean ± SD)
5/26 (19.23%)
2/26 (7.69%)
2/26 (7.69%)
1/26 (3.85%)
24.65 ± 16.33
47.20 ± 44.21
7/19 (36.84%)
6/19 (31.58%)
7/19 (36.84%)
6/19 (31.58%)
36.53 ± 34.40
90.99 ± 72.86
0.31
0.06
0.02
0.03
0.13
0.02
DDI donor-derived infection, CRO carbapenem-resistant organisms, cumulative DDDs the sum of the DDDS of each therapeutic antibiotic used
for postoperative lung transplant recipients, DDDs the mass of each antibiotic consumed/ defined daily dose (DDD)
therapy. In addition, CRO-related infections, especially
those caused by metallo-β-lactamases (MBLs) producing organisms, are very difficult to treat, leading to higher
mortality rates after transplantation. The Xpert Carba-R
test, which provides qualitative detection and differentiation of five commonly encountered carbapenemase gene
families with a turnaround time of less than one hour, can
provide real-time screening for donor organs.
The Xpert Carba-R test has been reported to show
excellent performance detecting CRO in a variety of clinical specimens, including 95% sensitivity and 99% specificity for rectal swabs [17], 92.9% sensitivity, and 86.7%
specificity for sputum samples [18], and 95% sensitivity
and 95% specificity for bronchial aspirates [19], although
the latter two specimen types are considered off-label. In
this study, the lung acquisition team was able to bring the
GeneXpert II instrument and cartridges to the OPO site
to enable rapid, point-of-care testing for CRO in bronchoalveolar lavage specimens taken from the donors. This
enabled clinicians to recognize CRO infection in the donor
lung before acquisition and transplantation, improving the
postoperative prognosis of recipients.
In this study, cumulative DDDs were significantly different among patients in the Xpert Carba-R screening
group and those in the Control group. There may be a costeffect in the screening process using the Xpert Carba-R
test, although this will require additional studies for confirmation. CRO infections have become a major international
public health problem due to inadequate treatment options
and the historically slow pace of developing novel antimicrobial drugs. In China, there has been a sharp increase
in infections caused by CRO and the emergence of new
resistance genotypes in multiple bacterial species has been
observed. Some bacterial species have been documented to
carry two or more carbapenemase genes [13]. Due to the
poor outcome associated with transplanting CRO-positive
organs, it is critical to screen organs from DBD and DCD
before transplantation. The quick, on-demand, real-time
capacity of the Xpert Carba-R test provides enough time
for the acquisition team to screen potential donor lungs
before transplantation, which is not possible with traditional culture and AST methods. This enables the securing
of donor organs more cost-effectively.
To our knowledge, this is the first study demonstrating
that accurate screening for CRO in donor lungs in a realtime manner raises the potential to reduce CRO-associated
DDI mortality. However, there are several limitations to this
study. First, this study used a group of historical patients as
controls when the real-time molecular screening method was
not yet available. These historical controls may have given
results that could be biased by a variety of confounding factors. Such as the low average age of recipients in historical
controls. Second, the study was performed in a single center
with relatively small numbers of patients recruited. A larger,
multi-center clinical trial is being planned with a focus on
healthcare economics.
In conclusion, the capacity for quick and accurate detection
and characterization of CRO by Xpert Carba-R provides an
ideal screening tool in donor lungs before transplantation. This
enabled clinicians to know the CRO infection status of donor
lungs in a real-time manner and to formulate a more precise
plan for acquiring the lung from the donor for transplantation.
Acknowledgements We thank Ling Jiang, Hong Leng for technical
assistance, Mengran Li for data analysis assistance, and Sherry Dunbar
for reviewing the manuscript.
Authors contribution WYZ, YWT, and WTF conceived the project.
WYZ, LS, and JXS designed the study goals. WYZ, YJ, SJF, XFP,
MFZ, SZ, CZ, FL, HZ, and FY conducted the experiments. WYZ,
XHG, and FCT analyzed data. WYZ, XHG, and YWT wrote the paper.
WYZ, YWT and FCT offered scientific advice.
13
13
Table 4 Effect of Xpert Carba-R screening and other clinical characteristics on CRO-associated DDI relates death within 60 days in recipients, univariable and multivariable analyses
Variables
Sex of recipients
Age of recipients
Cold ischemia time (CIT) of donor lungs
CRO isolation positive in donor lungs
BMI (kg/m2) of recipients
Smoking status of recipients
Primary lung diseases in recipients
Types of lung transplantation
Diabetes mellitus in recipients
Xpert Carba-R screening for donor lungs
Level
Male
Female
≥ 60
< 60
Long CIT
Short CIT
Yes
No
≤ 18.5
> 18.5
Current smoker
Non-current smoker
COPD
Other
Double-lung transplant
Other
Yes
No
Control group
Xpert Carba-R screening group
CRO-associated DDI relates
death within 60 days
Yes
No
6 (16.22%)
1 (12.50%)
6 (20.00%)
1 (6.67%)
5 (20.83%)
2 (9.52%)
7 (77.78%)
0 (0.00%)
3 (30.00%)
4 (11.43%)
1 (16.67%)
6 (15.38%)
2 (18.18%)
5 (14.71%)
5 (21.74%)
2 (9.09%)
3 (33.33%)
4 (11.11%)
6 (31.58%)
1 (3.85%)
31 (83.78%)
7 (87.50%)
24 (80.00%)
14 (93.33%)
19 (79.17%)
19 (90.48%)
2 (22.22%)
36 (100.00%)
7 (70.00%)
31 (88.57%)
5 (83.33%)
33 (84.62%)
9 (81.82%)
29 (85.29%)
18 (78.26%)
20 (90.91%)
6 (66.67%)
32 (88.89%)
13 (68.42%)
25 (96.15%)
P value
(Fisher's exact
test)
Univariable analyses
Multivariable analyses
P value
P value
OR
95%CI
0.33
0.37
0.05–2.76
OR
95%CI
0.79
0.74
0.08–7.15
0.27
0.29
0.03–2.62
0.31
0.40
0.07–2.32
< 0.01
0.01
0.00–0.11
0.17
0.30
0.06–1.66
0.94
0.91
0.09–9.22
0.78
0.78
0.13–4.70
0.26
0.36
0.06–2.09
0.12
0.25
0.04–1.41
0.06
0.09
0.01–1.10
0.01
0.09
0.01–0.80
0.03
0.05
0.00–0.74
1.00
0.40
0.42
< 0.01
0.17
1.00
1.00
0.41
0.13
0.03
COPD chronic obstructive pulmonary disease, CRO carbapenem-resistant organisms, DDI donor-derived infection, BMI body mass index
1
Logistic analysis was used for univariate analysis of each factor. While penalized likelihood logistic regression was used for the factor of CRO isolation positive in donor lungs because quasicomplete separation happened
2
The factors with P value < 0.2 (univariate analysis) were added to the multivariate logistic model except the factor of CRO isolation positive in donor lungs for it is a mediator that lies on the
causal pathway between the exposure and outcome
Long cold ischemia time was defined as more than mean of cold ischemia time (368 min) in this study
4
All analyses in this table were conducted using the Statistical Analysis System (SAS) statistical software package, version 9.4
W.-Y. Zhou et al.
3
Real‑time, random‑access organ screening for carbapenem‑resistant organisms (CRO) reduces…
Funding The present study was supported in part by the National Natural Science Foundation of China (82170108, 81700092), the Clinical
Research Projects in Health industry of Shanghai Municipal Health
Commission, the Foundation of the Center for Medical and Engineering Interdisciplinary Innovation, University of Shanghai for Science
and Technology, the Basic Research Foundation of Shanghai Chest
Hospital (2020YNJCM05), the Interdisciplinary Program of Shanghai
Jiao Tong University (YG2019QNA51) and the Cepheid InvestigatorInitiated Study award (Cepheid-IIS-2020-0019).
Data availability Not applicable.
Declarations
Conflict of interest X.G., F.C.T., and Y.W.T. are employees of Cepheid, the commercial manufacturer of the Xpert® Carba-R test. The
other authors declare no competing interests.
Ethical Approval This historically controlled prospective trial was
approved by the Ethics Committee of Shanghai Chest Hospital, Shanghai Jiao Tong University (No. IS21101) and registered on chictr.org.cn
(ChiCTR2100053687). The study has been performed in accordance
with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Authors and Affiliations
Wen‑Yong Zhou1 · Lei Shen2,3 · Jian‑Xin Shi1 · Xing‑Hui Gao4 · Jun Yang1 · Shi‑Jie Fu1 · Xu‑Feng Pan1 · Min‑Fang Zhu5 ·
Shen Zhang5 · Chong Zhang5 · Feng Li6 · Hai Zhang6 · Feng Yao1 · Fred C. Tenover7 · Yi‑Wei Tang4 · Wen‑Tao Fang1
* Wen-Yong Zhou
zhou.wenyong@shsmu.edu.cn
* Yi-Wei Tang
yi-wei.tang@cepheid.com
1
2
Department of Thoracic Surgery, Shanghai Chest Hospital,
Shanghai Jiao Tong University School of Medicine,
Shanghai, China
Shanghai Institute of Immunology, Department
of Immunology and Microbiology, and Key Laboratory
of Cell Differentiation and Apoptosis of the Chinese Ministry
of Education, Shanghai Jiao Tong University School
of Medicine, Shanghai, China
13
3
Shanghai Key Laboratory of Tumor Microenvironment
and Inflammation, Shanghai Jiao Tong University School
of Medicine, Shanghai, China
4
Medical Affairs, Danaher Diagnostic Platform/Cepheid,
Shanghai, China
5
Department of Critical Care Medicine, Shanghai Chest
Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai, China
6
Department of Pulmonary Medicine, Shanghai Chest
Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai, China
7
Medical and Scientific Affairs, Cepheid, Sunnyvale, CA,
USA