Liver transplant (LT) patients represent one of the largest immunosuppressed cohorts. However, outcomes of coronavirus disease (COVID-19) in this population remain poorly defined although liver injury has been reported in patients with COVID-19.1
We sought to examine the characteristics of LT patients infected with COVID-19 and study the rates of hospitalization, mortality, thrombosis, or intensive care unit (ICU) requirement in LT with COVID-19 in the United States.
Methods
We used a large health research network (TriNetX) to compile electronic medical records (EMRs) of adult (aged ≥18 years) LT recipients with confirmed severe acute respiratory syndrome coronavirus 2 infection (LT group) from 35 health care organizations in the United States, from January 1, 2020, to June 23, 2020. Within this same time period, we also identified COVID-19–positive patients with no history of LT (non-LT group). For both cohorts, we collected demographics, comorbidities, clinical symptoms, and laboratory findings at COVID-19 diagnosis and presentation. To address confounders, cohorts were balanced using 1:1 greedy nearest neighbor propensity score matching (PSM) based on age, race, and key comorbidities (Table 1 ).2 The 4 outcomes of interest were risk of hospitalization (defined as composite outcome of inpatient or critical care services), mortality, thrombosis (defined as composite outcome of deep vein thrombosis, acute pulmonary embolism, stroke, or myocardial infarction), and ICU requirement (requiring mechanical ventilation or extracorporeal membrane oxygenation) after a diagnosis of COVID-19. Further details on methodology are provided in the Supplementary Material.
Table 1.
Comparison of Medication Use Among Non-LT Patients With COVID-19 and LT Patients With COVID-19, Before 6 Months of Diagnosis of COVID-19
| Characteristics | Before matching |
After matching |
||||||
|---|---|---|---|---|---|---|---|---|
| LT | Non-LT | RR (95% CI) | P value | LT | Non-LT | RR (95% CI) | P value | |
| n | 126 | 43,508 | 125 | 125 | ||||
| Demographics | ||||||||
| Age, y, mean ± SD | 57.08 ± 13.28 | 50.06 ± 18.66 | <.0001 | 57.03 ± 13.32 | 59.83 ± 14.71 | .116 | ||
| Female, n (%) | 43 (34) | 23,844 (55) | <.0001 | 43 (34) | 40 (32) | .687 | ||
| Male, n (%) | 83 (66) | 19,576 (45) | <.0001 | 82 (66) | 85 (68) | .687 | ||
| Unknown sex, n (%) | 0 | 88 (<1) | .6133 | 0 | 0 | |||
| White, n (%) | 73 (58) | 19,901 (46) | .0061 | 73 (58) | 71 (57) | .798 | ||
| Black or African American, n (%) | 34 (27) | 11,157 (26) | .7308 | 34 (27) | 40 (32) | .4058 | ||
| American Indian or Alaska Native, n (%) | 10 (8)a | 142 (<1) | <.0001 | 10 (8) | 10 (8) | 1 | ||
| Asian, n (%) | 10 (8)a | 1207 (3) | .0004 | 10 (8) | 10 (8) | 1 | ||
| Native Hawaiian or Other Pacific Islander, n (%) | 10 (8)a | 88 (<1) | <.0001 | 0 | 0 | |||
| Unknown race, n (%) | 13 (10) | 11,013 (25) | .0001 | 13 (10) | 10 (8) | .5115 | ||
| Hispanic or Latino, n (%) | 14 (11) | 6064 (14) | .3602 | 14 (11) | 13 (10) | .8385 | ||
| Not Hispanic or Latino, n (%) | 78 (62) | 18,279 (42) | <.0001 | 77 (62) | 54 (43) | .0036 | ||
| Unknown ethnicity, n (%) | 34 (27) | 19,165 (44) | .0001 | 34 (27) | 58 (46) | .0016 | ||
| Comorbid conditions, n (%) | ||||||||
| Essential (primary) hypertension | 29 (23) | 4180 (10) | <.0001 | 29 (23) | 23 (18) | .3498 | ||
| Chronic kidney disease | 25 (20) | 1411 (3) | <.0001 | 24 (19) | 26 (21) | .7518 | ||
| Diabetes mellitus | 20 (16) | 3106 (7) | .0001 | 20 (16) | 20 (16) | 1 | ||
| Nicotine dependence | 10 (8)a | 673 (2) | <.0001 | 10 (8) | 0 | .0012 | ||
| Chronic lower respiratory diseases | 10 (8)a | 2346 (5) | .207 | 10 (8) | 10 (8) | 1 | ||
| Heart failure | 10 (8)a | 1131 (3) | .0002 | 10 (8) | 10 (8) | 1 | ||
| Cerebrovascular diseases | 10 (8)a | 485 (1) | <.0001 | 10 (8) | 10 (8%) | 1 | ||
| Alcohol-related disorders | 10 (8)a | 207 (<1) | <.0001 | 10 (8)a | 0 | .0012 | ||
| Dyspnea | 10 (8)a | 4632 (11) | .3246 | 10 (8)a | 11 (9) | .8196 | ||
| Ischemic heart diseases | 10 (8)a | 1438 (3) | .0038 | 10 (8)a | 10 (8)a | 1 | ||
| Presenting symptoms, n (%) | ||||||||
| Fever of other and unknown origin | 12 (10) | 4664 (11) | .6647 | 12 (10) | 18 (14) | .2429 | ||
| Cough | 10 (8)a | 6863 (16) | .0159 | 10 (8)a | 17 (14) | .1538 | ||
| Nausea and vomiting | 10 (8)a | 1122 (3) | .0002 | 10 (8)a | 10 (8)a | 1 | ||
| Malaise and fatigue | 10 (8)a | 1750 (4) | .0257 | 10 (8)a | 10 (8)a | 1 | ||
| Diarrhea, unspecified | 10 (8)a | 1493 (3) | .0056 | 10 (8)a | 10 (8)a | 1 | ||
| Abdominal and pelvic pain | 10 (8)a | 695 (2) | <.0001 | 10 (8)a | 10 (8)a | 1 | ||
| Acute pharyngitis | 10 (8)a | 1045 (2) | .0001 | 10 (8)a | 10 (8)a | 1 | ||
| Hypoxemia | 10 (8)a | 2139 (5) | .1177 | 10 (8)a | 10 (8)a | 1 | ||
| Laboratory test results, mean (SD) | ||||||||
| Sodium, mEq/L | 135.55 ± 5.03 | 136.58 ± 5.1 | .1262 | 135.67 ± 5 | 137.06 ± 6.09 | .2015 | ||
| Creatinine [mass/volume] in serum, plasma, or blood, | 2.03 ± 2.07 | 1.36 ± 1.65 | .0021 | 2.04 ± 2.09 | 3.14 ± 4.45 | .103 | ||
| Hemoglobin, g/dL | 10.88 ± 2.41 | 12.52 ± 2.48 | 0 | 10.88 ± 2.41 | 12.42 ± 2.38 | .0018 | ||
| Platelets, n/μL | 167.11 ± 103.94 | 220.64 ± 94.55 | 0 | 167.11 ± 103.94 | 199.18 ± 69.46 | .0797 | ||
| Leukocytes, n/μL | 6.56 ± 5.42 | 7.74 ± 5.55 | .1219 | 6.56 ± 5.42 | 6.76 ± 2.7 | .8378 | ||
| Alanine aminotransferase, U/L | 57.6 ± 154.56 | 41.59 ± 99.82 | .2507 | 57.6 ± 154.56 | 35.87 ± 37.27 | .3931 | ||
| Aspartate aminotransferase, U/L | 74.06 ± 245.79 | 55.22 ± 214.63 | .5284 | 74.06 ± 245.79 | 49 ± 54 | .5338 | ||
| Alkaline phosphatase, U/L | 152.15 ± 143 | 88.51 ± 58.23 | 0 | 152.15 ± 143 | 88 ± 74 | .0123 | ||
| Potassium, mEq/L | 4.28 ± 0.65 | 3.9 ± 0.58 | 0 | 4.29 ± 0.66 | 4.06 ± 0.8 | .1173 | ||
| Total bilirubin, mg/dL | 1.61 ± 3.39 | 0.63 ± 0.86 | 0 | 1.61 ± 3.39 | 0.59 ± 0.27 | .0655 | ||
| Albumin, g/dL | 3.29 ± 0.82 | 3.43 ± 0.76 | .205 | 3.29 ± 0.82 | 3.35 ± 0.68 | .7183 | ||
| Neutrophils, n/μL | 4.53 ± 5.1 | 7.51 ± 98.46 | .8642 | 4.53 ± 5.1 | 5.19 ± 1.86 | .512 | ||
| Body mass index, kg/m2 | 27.74 ± 5.42 | 30.14 ± 8.11 | .118 | 27.74 ± 5.42 | 30.45 ± 9.03 | .2246 | ||
| Prothrombin time, s | 14.94 ± 4.17 | 14.25 ± 6.76 | .6123 | 14.94 ± 4.17 | 14.3 ± 4.68 | .656 | ||
| C-reactive protein, mg/dL | 48.74 ± 63 | 76.44 ± 86.42 | .133 | 48.17 ± 64.49 | 102.94 ± 92.72 | .0242 | ||
| Lactate dehydrogenase, mmol/L | 244.9 ± 90.61 | 400.01 ± 315.65 | .0281 | 244.9 ± 90.61 | 394.88 ± 225.85 | .008 | ||
| Ferritin, ng/mL | 9333.93 ± 35,380.02 | 22,453.26 ± 76,506.63 | .493 | 93,33.93 ± 35,380.02 | 23,411.78 ± 89,271.63 | .5533 | ||
| Activated partial thromboplastin time, s | 34.31 ± 11.8 | 31.38 ± 10.61 | .3014 | 34.31 ± 11.8 | 32.9 ± 10.39 | .7445 | ||
| Creatine kinase, mg/dL | 105.92 ± 63.84 | 399.89 ± 2840.48 | .7091 | 105.92 ± 63.84 | 280.08 ± 288.57 | .0446 | ||
| Fibrin D-dimer FEU | 2.81 ± 5.97 | 196.24 ± 949.4 | .4995 | 2.81 ± 5.97 | 3.31 ± 2.22 | .8075 | ||
| Gamma glutamyl transferase, U/L | 42 ± 31.11 | 139.51 ± 174.46 | .0814 | 42 ± 31.11 | 44 ± 0 | .8412 | ||
| Erythrocyte sedimentation rate | 44 ± 31.57 | 45.44 ± 29.36 | .8772 | 44 ± 31.57 | 32.6 ± 17.26 | .3296 | ||
| Interleukin 6, pg/mL | 31.6 ± 0 | 120.58 ± 389.98 | .4711 | 31.6 ± 0 | 224.37 ± 277.5 | .0414 | ||
| Procalcitonin, ng/mL | 2.33 ± 6.39 | 22.07 ± 485.75 | .8978 | 2.33 ± 6.39 | 1.21 ± 1.08 | .5728 | ||
| Lymphocytes, n/μL | 0.79 ± 0.28 | 0.9 ± 3.14 | .9082 | 0.79 ± 0.28 | 0.41 ± 0.27 | .0058 | ||
| Outcomes | ||||||||
| Hospitalization | 50 (40) | 5510 (13) | 3.13 (2.52–3.89) | <.0001 | 50 (40) | 29 (23%) | 1.72 (1.17–2.53) | .0043 |
| Mortality | 10 (8)a | 1523 (4) | 2.27 (1.24–4.12) | .0069 | 10 (8)a | 10 (8)a | 1 (0.43–2.32) | 1 |
| Thrombosis | 10 (8)a | 972 (2) | 3.55 (1.95–6.46) | <.0001 | 10 (8)a | 10 (8)a | 1 (0.43–2.32) | 1 |
| Intensive care | 10 (8)a | 1310 (3) | 2.64 (1.45–4.79) | .0013 | 10 (8)a | 11 (9) | 0.91 (0.40–2.06) | .8196 |
NOTE. Comparison shown both before and after propensity score matching.
SD, standard deviation.
Results
Between January and June 2020, there were a total of 43,508 non-LT patients with COVID-19 and 126 LT patients with COVID-19 in the database (Table 1). LT patients were significantly older and predominately male and white, and they had a higher prevalence of comorbidities (Table 1). Thus, we performed (1:1) PSM for age, race, and comorbidities. The LT and non-LT groups were relatively balanced after PSM (n = 125 each group) (Table 1).
LT patients were more likely to have nausea and vomiting, malaise and fatigue, diarrhea, and abdominal and pelvic pain. LT patients were more likely to have higher mean levels of creatinine (Cr), total bilirubin, and alkaline phosphatase (Table 1). Within 6 months before diagnosis of COVID-19, 39% of LT patients were receiving prednisone, 9% hydrocortisone, 61% tacrolimus, 37% mycophenolate mofetil, and 8% each azathioprine, cyclosporine, sirolimus, everolimus, and basiliximab (Supplementary Table 1).
Patients in the LT group had a significantly higher risk of hospitalization compared to the non-LT group, both before and after PSM (Table 1). After PSM, in adjusted analysis, 40% of patients in the LT group required hospitalization compared to 23% of patients in the non-LT group (risk ratio [RR], 1.72; P < 0.0043). In unadjusted analyses, the risk of mortality (RR, 2.27; P = .0069), thrombosis (RR, 3.55; P < .0001), and ICU requirement (RR, 2.64; P = .0013) was higher in the LT group; however, after PSM, there was no difference in risk of mortality, thrombosis, and ICU requirement between LT and non-LT patients with COVID-19 (Table 1).
Discussion
We found LT patients with COVID-19 to have significantly higher risk of hospitalization but not a higher risk of mortality, thrombosis, or ICU requirement compared to patients without LT and COVID-19 upon adjusted analyses.
This is the largest study of LT patients with COVID-19 in the United States to date, to our knowledge. Yi et al3 reported 21 solid organ transplant recipients diagnosed with COVID-19, including 3 LT patients, at a US high-volume transplant center. In this study, 33% (1/3) of LT patients required hospitalization compared to 40% in our study, and 33% (7/21) of solid organ transplant patients required ICU care compared to 8% in our study.
Belli et al4 reported the European experience in 103 LT patients with COVID-19 from centers located in Italy, Spain, and France. Although they found fever, cough, and shortness of breath to be the most common presenting symptoms, we found LT patients to have a predominance of nausea and vomiting, malaise and fatigue, diarrhea, abdominal and pelvic pain. These differences in presenting symptoms might be due to differences in study design, methods of data collection, data analyses, and the size of source population. Although 40% of patients in our study were admitted to the hospital and 8% required ICU care, 81% of patients in their study required hospitalization, and 15% were admitted to the ICU. Importantly, 16% of LT patients died in their study compared to a mortality rate of 8% in our study.
Our lower rate of hospitalization and ICU care requirements compared to the European experience likely suggests earlier presentation and/or diagnosis in our patients. Furthermore, ICU requirement in our study was defined as requiring mechanical ventilation or extracorporeal membrane oxygenation, whereas in other studies, the definitions were more liberal, thereby leading to a lower estimate of ICU requirement in our study. Other factors such as increased accessibility to a multidisciplinary post-LT team and decreased threshold of admission for LT patients may also have played a role.
LT patients with COVID-19 had higher mean levels of Cr (2.03), suggestive of acute kidney injury compared to non-LT patients with COVID-19. Approximately 15% to 29%5 of patients with COVID-19 have been reported to have elevated Cr. Although a significant proportion of LT patients were on calcineurin inhibitors, ACE2 expression in kidney is known to be nearly100-fold higher than in respiratory organs and may increase the risk of acute kidney injury in patients with COVID-19.6
In a recent Dutch study7 of patients with COVID-19 pneumonia admitted to the ICU, 27% developed venous thromboembolism, and 3.7% developed arterial thrombotic events. In our study, the overall rate of thrombosis was 8%. The decreased rates of thrombosis in our study might be due to the differences in the study population because the Dutch study included only patients with COVID-19 pneumonia admitted to the ICU who had severe disease leading to increased inflammatory burden. Ours is one of the first studies in LT patients with COVID-19 to provide data on thrombosis, which appear to be reassuring.
This study is limited by its retrospective nature; the inability to access treatment regimens, if any, for patients with COVID-19; and other information unavailable in the TriNetX database, such as information about socioeconomic status, exposure history, and geographic data of the patient population. In addition, data from EMR-based databases is susceptible to coding errors during the translation of patient information into International Classification of Diseases, 10th Revision, codes. However, TriNetX aggregates data from EMRs in real time, which minimizes errors in data collection and analysis. Furthermore, patients with mild disease who were undiagnosed and did not present to health care organizations were not captured in our study, and thus, our cohort likely represents a relatively severe spectrum of COVID-19. However, compared to prior studies on LT and COVID-19, our estimate of hospitalization and mortality rates in LT might be more precise given our higher sample size in both the LT and non-LT groups with COVID-19.
In conclusion, in one of the largest multicenter network studies on LT and COVID-19 to date, we found LT patients with COVID-19 to have a significantly higher risk of hospitalization but not mortality, thrombosis, or ICU requirement compared to patients without LT and COVID-19 when matched for severity of illness. Given the limitations and retrospective nature of this study, further prospective studies are needed to evaluate the burden of care in LT patients and the long-term outcomes of LT patients with COVID-19.
Acknowledgments
Collaborators: Alexandra Mills, MBA,1 Kayla Schlick, MS,1 and Ahmad Khan, MD2
1Clinical Research Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio; and 2Department of Internal Medicine, West Virginia University–Charleston Division, West Virginia.
CRediT Authorship Contributions
Emad Mansoor, MD (Conceptualization: Lead; Investigation: Supporting; Methodology: Supporting; Project administration: Equal; Writing – original draft: Lead; Interpretation: Equal); Abe Perez, PhD (Data curation: Supporting; Formal analysis: Lead; Methodology: Lead); Mohannad Abou-Saleh, MD (Writing – review & editing: Supporting); Seth N. Sclair, MD (Writing – review & editing: Supporting); Stanley Cohen, MD (Writing – review & editing: Supporting); Gregory S. Cooper, MD (Conceptualization: Supporting; Investigation: Equal; Methodology: Supporting; Supervision: Lead; Writing – review & editing: Lead).
Footnotes
Conflicts of interest The authors disclose no conflicts.
Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/j.gastro.2020.09.033.
Supplementary Material
Supplementary Figure 1.
Patient selection protocol in COVID-19 Non-Liver transplant and Liver transplants groups. Patients with ICD-9 code 079.89 were excluded to reduce false positives (occasionally used as a “catch-all’ to describe more than 50 viral infections).
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