Effects of Coronavirus Disease 2019 on Solid Organ Transplantation.

BACKGROUND: As the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a viral pandemic, data on the clinical characteristics and outcomes of patients with SARS-CoV-2 infection undergoing solid organ transplant are emerging. The objective of this systematic review was to assess currently published literature relating to the management, clinical course, and outcome of SARS-CoV-2 infection in liver, kidney, and heart solid organ transplant recipients.
METHODS: We conducted a systematic review to assess currently published literature relating to the management, clinical course, and outcome of SARS-CoV-2 infection in liver, kidney, and heart solid organ transplant recipients. Articles published through June 2020 were searched in the MEDLINE, ClinicalTrials.gov, and PubMed databases. We identified 49 eligible studies comprising a total of 403 solid organ transplant recipients.
RESULTS: Older age, male sex, and preexisting comorbidities, including hypertension and/or diabetes, were the most common prevailing characteristics among the solid organ transplant recipients. Clinical presentation ranged from mild to severe disease, including multiorgan failure and death. We found an overall mortality rate of 21%.
CONCLUSION: Our analysis suggests no increase in overall mortality or worse outcome in solid organ transplant recipients receiving immunosuppressive therapy compared with mortality in the general surgical population with SARS-CoV-2. Our findings suggest that transplant surgery and its immunosuppressive effects should not be a deterrent to proper surgical care for patients in the SARS-CoV-2 era.

The World Health Organization (WHO) declared the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that causes coronavirus disease 2019 (COVID-19) a pandemic disease on March 11, 2020 [1], and as of September 5, 2020, the WHO reported 26,468,031 cases and 871,166 deaths related to SARS-CoV-2 infection globally [2]. Despite the extraordinary burden and stress the healthcare system is experiencing because of the disease, the vast majority of surgical care cannot be delayed or indefinitely withheld. Although current data on the clinical characteristics and outcomes of patients with SARS-CoV-2 infection undergoing surgery are sparse [3], it has been postulated that major surgery combined with SARS-CoV-2 infection may induce significant inflammatory stress, imparting an increased risk of postoperative complications and mortality [4,5].

Although many institutions are delaying elective surgeries, transplant surgeries are designated as tier 3b (“do not postpone”) by the Centers for Medicare and Medicaid Services [6]. Despite this designation, these solid organ transplant (SOT) recipients represent an extremely vulnerable surgical cohort: in frequent contact with healthcare personnel, chronically immunosuppressed, and having other concomitant medical conditions [7,8]. The surgical management and outcomes of SARS-CoV-2 in SOT recipients remain unclear [9], because published reports on SARS-CoV-2 positive SOT recipients and their outcomes are limited and largely unknown [[9], [10], [11]]. Case reports from Asia, Europe, and the United States suggest a wide range in severity of clinical symptoms from mild and nonspecific to severe respiratory distress and pneumonia [[11], [12], [13]]. Furthermore, reports of atypical presentations with an absence of respiratory symptoms may confound the diagnosis [[12], [13], [14]].

Although the American Society of Transplant Surgeons has recommended best practice guidelines for transplantation in the SARS-CoV-2 era, regional and institutional variation in transplant practice persists [15,16]. In addition, limitation and regional variance in testing pose a significant difficulty in the early identification of suspected SARS-CoV-2 cases in SOT recipients. A recent survey of 111 transplant centers in the United States found a marked reduction in transplant activity despite the tier 3b designation, a wide variation in SARS-CoV-2 testing practices, and substantial differences in the use of off-label and investigational therapies for treatment [17].

There is an urgent need to better understand the effects of SARS-CoV-2 on SOT recipients. We reviewed published literature in this rapidly evolving field to examine the current management practice; the clinical course of the disease; and the outcomes of SARS-CoV-2 infection in liver, kidney, and heart SOT recipients.

Materials and Methods

We conducted a review of SARS-CoV-2 infection in SOT recipients according to the recommended Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Study Search

Articles published through June 6, 2020, were searched in the MEDLINE, ClinicalTrials.gov, and PubMed databases. A combination of the following Medical Subject Heading terms was used to identify articles discussing SARS-CoV-2 infection in solid organ transplant recipients: “coronavirus,” “SarsCov,” “SarsCov2,” “SARS-Cov-2,” “Severe Acute Respiratory Syndrome,” “COVID,” “COVID-19,” “kidney,” “heart,” “liver,” “solid organ transplant,” “transplant,” “transplantation,” “outcome,” and “immunosuppressant.”

Inclusion and Exclusion Criteria

Only case reports, case series, and prospective and retrospective cohort studies published between 2019 and 2020 were included for final analysis and discussion. No restriction was placed on the publication status of the article. All non-English, investigational, animal, in vitro, and cadaveric studies were excluded. In addition, book chapters, conference abstracts, review articles, management guidelines, and any article that did not include discussion of clinical course, treatment, or outcomes of SARS-CoV-2 infection in SOT recipients were also excluded.

Data Collection and Analysis

Articles were screened independently by the authors. Any disagreements were reconciled through discussion between reviewers. Data extracted from each article included study type, year and month of publication, study country, number of patient cases, SOT type (heart, kidney, liver, or multiple), patient demographics, presence of comorbidities, immunosuppressant medications, time from transplant to initial presentation, initial presenting symptoms, treatment, clinical course, and outcomes (Table 1 ). Reporting of all of the above variables was not a requirement for article inclusion, and any unavailable variables were documented as “not reported.” Data were reported using the median and interquartile range (IQR) for non-normally distributed continuous variables and absolute counts and percentages for categorical variables.

Table 1

Summary of Clinical Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2–positive Solid Organ Transplant Recipients, by Study

SOT	Author [reference]	Location	No. of Cases (n)		Age and Sex	Comorbidities	ImmunosuppressiveRegimen	Time From Transplant	Initial Presentation (Symptoms)	Treatment	Clinical Course	Outcomes
Multiple SOT types	Tschopp et al [18]	Switzerland	21Kidney (48%)Liver (24%)>1 organ (14%)Pancreas (5%)Lung (5%)Heart (5%)		Median56 years71% male	HTN (67%)DM (43%)Obesity (24%)	Tac (86%)Prednisone (43%)MMF (17%)CSA (10%)Aza (10%)mTOR (5%)	Median47 months	Fever (76%), dry cough (57%), nausea (33%) and diarrhea(33%).	Immunosuppressant modified in 14 pts (67%); HCQ, azithromycinlopinavir/ritonavir	20 pts (95%) admitted5 pts (25%) to ICU	16 pts (80%) discharged3 pts (15%) remain hospitalized2 pts (10%) died
	Fernández-Ruiz et al [11]	Spain	18Kidney (44%)Liver (33%)Heart (22%)		Median71 years77% male	HTN (72%)DM (50%)Cirrhosis (28%)Obesity (11%)	Prednisone (67%)MMF/MPA (61%)Tac (56%)EVE (22%)CSA (17%)Aza (6%)mTOR (6%)	Median9.3 years	Fever (83%), gastrointestinal symptoms (28%), respiratory failure (28%)	Lopinavir/ritonavir ± HCQ (50%)HCQ monotherapy (28%)Interferon-β (17%)	2 pts (11%) required ICU and invasive mechanical ventilation4 pts (22%) developed progressive respiratory failure1 (6%) pt had improvement in condition	5 pts died (28%)5 pts (28%) remain hospitalized8 pts (44%) discharged
	Pereira et al [8]	United States	90Kidney (51%)Lung (19%)Liver (14%)Heart (10%)Heart-kidney (3%)Liver-kidney (1%)Kidney-pancreas (1%)		Median 57 years59% male	HTN (64%)DM (46%)CKD (63%)Chronic lung disease (19%)Dialysis (6%)Obesity (6%)Cancer (3%)HIV (1%)	CNI (86%)MMF (72%)Steroid (59%)Aza (4%)Belatacept (6%)IVIG ± pheresis (3%)mTOR (7%)	Median 6.64 years	Fever (70%), cough (59%), dyspnea (43%), fatigue (28%), myalgias (24%), diarrhea (31%)	Immunosuppressant held or reduced in majority of hospitalized ptsHCQ (91%)Azithromycin (66%)Remdesivir (3%)Tocilizumab (21%)Bolus steroid (24%)	22 (24%) required outpatient care68 pts (76%) admitted; of these, 27 (30%) had severe disease requiring intubation or admission to ICU	16 pts (18%) died37 pts (54%) discharged
	Travi et al [19]	Italy	13Liver (54%)Kidney (31%)Heart/kidney (15%)		Median59 years69% male	HTN (54%)DM (31%)	Tac (54%)CSA (38%)MMF (38%)Steroid (46%)Belatacept (8%)	Median 5.3 years	Respiratory symptoms	62% had reduction or change to immunosuppressant medicationHCQ (62%)HCQ + lopinavir/ritonavir (23%)Remdesivir (8%)High-dose steroids (23%)Tocilizumab (15%)	69% developed respiratory failure	1 pt died
	Fung et al [20]	United States	10Kidney (70%) 7Lung (10%)1Heart (10%)1Liver (10%)1		Median 56.5 years60% male6	HTN, DM, cardiovascular disease	Triple immunosuppression (70%)7	Median6.1 years	Fever (80%), cough (80%), dyspnea (80%), myalgia (60%), fatigue (50%)	Immunosuppressive medications decreased in 8 (80%)2 (20%) enrolled in RCT3 (30%) with either HCQ, azithromycin, lopinavir/ritonavir, 7 (70%) abx	70% hospitalized30% required ICU admission; all developed ARDS and shock	5 pts (50%) discharged2 pts (20%) remain hospitalized
	Hoek et al [21]	Netherlands	23Kidney (65%)15Heart (13%)3Lung (13%)3Liver (4%)1Kidney-heart (4%)1		Mean 59 years78% male18	HTN (83%) 19, DM (43%) 10, obese (22%) 5	CNI + MMF (61%) 14CNI, MMF + steroid (26%)6Steroid (4%)1EVE (4%)1	<1 year (4%)>1 year (96%)	Fever (81%) 19, cough (71%) 16, dyspnea (59%)14	57% remained on immunosuppressive medications13All hospitalized pts received abxHCQ (13%)3	83% required hospitalization1913% monitored at home without additional treatment32 pts (9%) admitted to ICU requiring ventilation	5 (22%) died14 (61%) recovered and discharged4 (17%) with clinical improvement
	Hsu et al [22]	Los Angeles, CA	1 heart/kidney		39 years, male	DM, HTN, obesity, chronic foot ulcer	Tac, MMF, prednisone	3 years	Fever, headache, sore throat, dry cough, dyspnea, fatigue, myalgias	HCQEnrolled in clinical trial	Tac, prednisone, continued for entirety of illness course, MMF held starting SD 4Presented to ED on SD 2; home quarantine SD 3; worsening symptoms and hospitalization SD 4, discharge SD 5; readmission SD 8; worsening hypoxia and transfer to ICU ID 9; transferred out of ICU; discharged SD 15	Alive, discharged
	Yi et al [23]	Houston, TX	21Kidney (57%)12Liver (14%)3Lung (10%)2Heart-lung (5%)1Liver-kidney (5%)1Heart-kidney (5%)1Kidney-pancreas (5%) 1		Mean 54.8 years62% male13	90% with either HTN, DM, obesity, chronic lung disease, CVD	Triple immunosuppression (81%)17	Median of 5.58 years	95% with fever, coughSOB2043% with diarrhea, vomiting, abdominal pain9	Immunosuppressive medications adjusted daily based on organ typeAzith ± HCQ, tolicuzimab remdesivir, ribavirin	33% treated as outpatients767% hospitalized1450% hospitalized pts admitted to the ICU, 36% of hospitalized requiring ventilatory support7 ICU, 5 vent	1 pt (5%) died (heart-kidney)4 (19%) remain in ICU6 (29%) discharged
Heart SOT	Holzhauser et al [24]	United States	2		Pt 1: 59 years/femalePt 2: 75 years/male	Pt 1: HTN, DM, CKDPt 2: HTN, DM, CKD, and CAV	Pt 1: Tac, MPAPt 2: CSA, MMF	Pt 1: 8 yearsPt 2: 20 years	Pt 1: Fever, myalgia, fatigue, diarrhea, productive coughPt 2: Fever, cough, diarrhea, fatigue, anorexia	Pt 1: Cefepime, vancomycin, oseltamivir, HCQ, tocilizumab, doxycycline, IVIG, lopinavir/ritonavir, micafungin, SMZ-TMP, tobramycin, linezolidImmunosuppressants heldPt 2: HCQ, tocilizumab, methylprednisoloneMMF held	Pt 1: Respiratory failure, renal failure, and ARDS requiring intubationPt 2: Required noninvasive respiratory support; clinical improvement over course of hospitalization	Pt 1: DiedPt 2: Alive, discharged
	Li et al [25]	China	2		Pt 1: 51 years/malePt 2: 43 years/male	Pt 1: HTNPt 2:Hyperlipidemia,IGT	Pt 1: Tac, MMFPt 2: Tac, MMF	Pt 1: 17 yearsPt 2: 3 years	Pt 1: Fever, chills, fatigue, anorexia, diarrheaPt 2: Fever	Pt 1: Levofloxacin ribavirin, moxifloxacin, ganciclovir, IVIG, methylprednisolone, UmifenovirPt 2: Ceftriaxone, ganciclovir, moxifloxacin, Umifenovir	Pt 1: Hospital admissionMMF and Tac held 5 daysPt 2: Home quarantine followed by hospitalization for 5 days	Pt 1: Alive, dischargedPt 2: Alive, discharged
	Russell et al [26]	United States	1		3 years/female	EBV	Tac	25 months	Productive cough, rhinorrhea, nasal congestion	IVIG	Hospital admission; remained clinically stable with mild clinical course	Alive, discharged
	Latif et al [27]	United States	28		Median 64 years79% male	HTN (71%)DM (61%),CAV (57%)Obesity (25%)	CNI (96%),MMF (68%)Steroid (68%)Sirolimus/EVE (18%)	Median 8.6 years	Fever (83%), dyspnea/cough (91%), gastrointestinal symptoms (48%)	22 pts (79%) had change in immunosuppressant medications on hospitalizationHCQ (78%),High-dose steroid (47%)IL-6-ra (26%)	6 pts (21%) managed outpatient22 pts (79%) hospitalized7 pts (25%) required mechanical ventilation	7 admitted pts (25%) died11 admitted pts (50%) discharged4 admitted pts (18%) remain hospitalized
Kidney SOT	Alberici et al [28]	Italy	20	Not reported		Not reported	Not reported	Not reported	Not reported	HCQ (95%)Dexamethasone (55%)Tocilizumab (30%)	4 pts (20%) admitted to ICU	5 pts (25%) died3 pts (15%) discharged
	Banerjee et al [29]	England	7	Median age 54 years (range, 45-69)Pt 1: 48/malePt 2: 67/femalePt 3: 54/femalePt 4: 65/malePt 5: 69/femalePt 6: 54/malePt 7: 45/male		Pt 1: HTNPt 2: DM, HTNPt 3: Post-transplant diabetes mellitus, CMVPt 4: HTN, wheelchair boundPt 5: DM, HTNPt 6: HTN, hemolytic anemiaPt 7: HTN	Pt 1: Aza, prednisolonePt 2: Tac, MMF, prednisolonePt 3: Tac, MMF, prednisolonePt 4: Tac, MMF, prednisolonePt 5: Tac, MMF, prednisolonePt 6: Tac, MMFPt 7: Tac, Aza, prednisolone	Pt 1: 31 yearsPt 2: 1 yearPt 3: 3 monthsPt 4: 2 yearsPt 5: 2 monthsPt 6: 7 yearsPt 7: 3 years (second transplant)	Respiratory symptoms (cough, shortness of breath) and feverPt 5 presented with respiratory symptoms, fever plus vomiting and diarrhea	Pt 1: Aza, prednisolone continuedPt 2: MMF stopped; Tx with broad-spectrum abx in ICU; Tac d/c 1 day before deathPt 3: Tac and MMF stopped; Tx with broad-spectrum abx, oseltamivir; Empiric tx for pneumocystis with high-dose cotrimoxazolePt 4: MMF stoppedPt 5: MMF stopped; Tx with doxycycline, piperacillin-tazobactam, paracetamol, furosemide, and blood transfusionPt 6: MMF stoppedPt 7: Aza stopped, Tac dose reduced, prednisolone dose increased	Pt 1: Remained at homePt 2: Hypoxic, transferred to ICU, required ventilation; developed AKI, severe metabolic acidosisPt 3: Hypoxic on presentation, started on CPAP; rapid deterioration of respiratory status requiring ventilationPt 4: Admitted to ICU; stepped down to medical wardPt 5: Brief ICU stay for respiratory support, not intubated; stepped down to wardPt 6: Developed AKI, continued to remain symptomatic, and MMF stoppedPt 7: Admitted, managed in the ward; developed severe AKI, required one hemodialysis session	Pt 1: Full recoveryPt 2: Died 12 days after hospitalizationPt 3: Alive, remains on ventilationPt 4: Alive, requires 4 to 6 L oxygen to maintain saturationPt 5: Alive, in inpatient wardPt 6: Stayed at home; alive with continued cough and some flulike symptomsPt 7: Alive, in inpatient ward
	Arpali et al [30]	Turkey	1	28 years/female		Not reported	Tac and prednisone	6 months	Fever, malaise, sore throat, rhinorrhea	Continued on Tac and prednisone; oseltamivir given at second ED visit	Initially presented to ED, treated with amoxicillin, no SARS-CoV-2 testing done; presented following day to ED with high fever, swabbed for SARS-CoV-2, sent home; 6 days later, testing result positive and returned to hospital to be monitored; discharged after 24 hours	Alive, at home, reports no symptoms
	Guillen et al [31]	Spain	1	50 years/male		HTN	Tac, EVE, prednisone	4 years (third deceased donor transplant)	Fever, vomiting	Ceftriaxone, azithromycin, ceftaroline, meropenem, lopinavir/ritonavir, HCQ, interferon-β, Tac and EVE held due to potential DDI	Presented to ED and discharged with presumptive viral gastroenteritis; presented to ED 5 days later with persistent fever and productive cough, dx with CAP; tested positive for SARS-CoV-2, was placed in isolation; respiratory status worsened, requiring intubation	Remains in ICU with respiratory support
	Zhu et al [32]	China	1	52 years/male		Not reported	Tac, MMF, prednisone	12 years	Fatigue, dyspnea, tightness and chest pain, nausea, loss of appetite, intermittent abdominal pain, occasional dry coughs, fever, headache	Tac, MMF, prednisone discontinued; restarted at full dose 3 days prior to dischargeUmifenovir, moxifloxacin, methylprednisolone, IVIG, interferon alpha, carbapenem, pantoprazole	Presented to fever clinic, laboratory findings and chest CT suggestive of SARS-CoV-2Symptoms worsened at home and admitted to hospital on SD 8; required oxygen via NC; symptoms improved over course of hospitalization; discharged on SD 21	Alive, discharged to home
	Marx et al [33]	France	1	58 years/male		Not reported	Belatacept, MMF, prednisone	3 years	Fever, mild dyspnea, cough	MMF and belatacept discontinued on admission to hospital; CSA started but plan to d/c this and restart MMF and belatacept at next date of infusion	Pt admitted to hospital; treated for possible bacterial superinfection but reported to have mild hospital course	Alive, resolution of fever and respiratory symptoms 5 days after discharge
	Gandolfini et al [34]	Italy	2	Pt 1: 75 years/malePt 2: 52 years/female		Pt 1: COPD, heart disease, HTN, obesityPt 2: HTN	Pt 1: Tac, MMF, steroidPt 2: Tac, MMF, steroid	Pt 1: 120 monthsPt 2: 8 months	Cough, myalgia, fever, dyspnea	MMF and Tac were discontinued on the day of admission; both patients received hydroxychloroquine and lopinavir/ritonavir or darunavir/cobicistatPt 2: Colchicine	Both patients required noninvasive ventilationPt 1: Abrupt worsening of respiratory conditions and died 5 days after admissionPt 2: Respiratory symptoms worsened and received colchicine; respiratory symptoms improved after drug initiation	Pt 1: DiedPt 2: Alive, remained on noninvasive ventilation
	Akalin et al [35]	United States	36	Median of 60 years72% males		HTN (94%), DM (70%)History of smoking tobacco or current smokers (36%)CVD (17%)	Tac (97%)Prednisone (94%)MMF (86%)	Not reported	Fever (58%), diarrhea (22%)	Of hospitalized pts:Antimetabolite held in 86%Tac held in 21%HCQ (86%)21% received leronlimab on a compassionate-use basis7% received tocilizumab	8 pts (22%) in stable condition were monitored at home28 pts (78%) were admitted to the hospital; 11 pts (39%) received mechanical ventilation, 6 pts (21%) received renal replacement therapy	10 (28%) pts died, including 2 pts who had been monitored as outpatients12 pts (43%) remained hospitalized10 pts (36%) hospitalized discharged to home
	Chen et al [36]	China	1	49 years/male		HTN	Tac, MMF, prednisone	7 years	Loss of appetite, fever	MMF, Tac, and prednisone heldUmifenovir, methylprednisolone, moxifloxacin, IVIG, ribavirin	Progressive worsening of cough, shortness of breath, hypoxic, fever; required inhaled oxygen and transferred to respiratory intensive care; symptoms gradually improved over course of hospitalization	Alive, discharged to home
	Fontana et al [37]	Italy	1	61 years/male		CKD, malignancy, coagulopathy, Parkinson disease	CSA, steroid	15 years	Fever/chills	CSA held, steroid increasedHCQ, tocilizumab, azithromycin, meropenem	Remained hemodynamically stable throughout hospitalization	Alive, discharged to home
	Zhang et al [38]	China	5	Mean 45 years80% male4		HTN (40%), 2DM (40%), 2Malignancy (20%), 1	MMF, CNI, and steroid (80%) 4	Range of 2 months to 4 years	Fever (100%), cough (100%), myalgia/fatigue (60%), 3Sputum (60%) 3	Oseltamivir or arbidol (100%)Abx (20%) 1IVIG (20%) 1	Immunosuppressant modified after symptom onsetAll pts hospitalized; resolution of symptoms in 4 (80%)None required intubation or ICU admission	2 (40%) discharged3 (60%) remain hospitalized
	Abrishami et al [39]	Iran	12	Mean 47.66 years75% male		HTN (17%)	All on triple therapy (steroid, CNI/sirolimus, MMF/Aza)	Not reported	Fever (75%), cough (75%), dyspnea (42%)	HCQ, lopinavir/ritonavir, abx (100%)IVIG given if pt hypoxic	Immunosuppressant modified for all100% pts hospitalized;10 (83%) admitted to ICU; 90% in ICU were intubated	8 (67%) died4 (33%) discharged
	Columbia University Kidney Transplant Program [40]	United States	15	Median 51 years65% male10		Not reported	Tac (93%)14MMF/MPA (80%)12Prednisone (67%)10Belatacept (13%)2Leflunomide (7%)1Aza (7%) 1	Median 49 months	Fever (87%),13Cough (60%),9Diarrhea (20%),3Myalgias (13%)2	93% had immunosuppressant regimen changed14HCQ ± azithromycin (87%)13Tocilizumab (7%)1	4 (27%) required intubation6 (40%) developed AKI	2 (13%) died8 (53%) discharged6 (40%) remain hospitalized
	Nair et al [41]	United States	10	Median 57 years60% male6		HTN (100%), majority also with DM	Tac + MMF/MPA (90%) 9Steroid (70%) 77	Median 7.7 years	Fever, cough, myalgia, fatigue, diarrhea	Hospitalized patients had antimetabolite agent stoppedHCQ + azithromycin (100%)Antibiotic (60%)	90% hospitalized95 (50%) admitted to ICU5 (50%) developed acute kidney injury.	3 (30%) died7 (70%) discharged
	Zhu et al [32]	China	10	Age between 24 and 65 years80% male		HTN, CAD, COPD, atrial fibrillation, HF (60%)	Tac (90%)MMF (90%)Steroid (70%)CSA (10%)Mizoribine (10%)	6 mo to 12 years	Fever (90%), cough (90%), shortness of breath (90%), fatigue (90%), diarrhea (30%)	Immunosuppressant medication modified in 90%Methylprednisolone (80%)IVIG (70%)Antiviral (100%)	Mild symptoms in 20%Severe symptoms in 50%Critical symptoms in 30%100% received NC30% required noninvasive mechanical ventilationNone underwent intubation	80% recovered1 (10%) remained hospitalized1 (10%) died
	Machado et al [42]	Brazil	1	69 years/male		HCV, DM, HTN	Tac, MMF, prednisone	6 years	Fever, fatigue, confusion, diarrhea, decreased urine output	MMF held, Tac decreased, prednisone increased on hospitalizationHCQ, nitazoxanide, ceftriaxone, azithromycin	Developed mild AKI and severe metabolic acidosis; did not require supplemental oxygen; improved over course of hospitalization	Alive, discharged
	Kim et al [43]	Korea	2	Pt 1: 37 years/malePt 2: 56 years/male		Not reported	Pt 1: Tac, MMF, prednisolonePt 2: Tac, MMF, prednisolone	Pt 1: 4 yearsPt 2: 8 years	Pt 1: Fever, cough, rhinorrhea, diarrhea, and decreased urine outputPt 2: Asymptomatic	Pt 1: MMF, tac held; Lopinavir/ritonavir and HCQPt 2: MMF held; HCQ with azithromycin	Pt 1: Improvement in clinical course and kidney function; did not require supplemental oxygenPt 2: Remained hemodynamically stable with mild symptoms (cough); did not require supplemental oxygen	Pt 1: RecoveredPt 2: Recovered
	Seminari et al [44]	Italy	1	50 years/male		HTN, DM	Tac, MMF	4 years	Fever, cough	Ceftriaxone	Improvement in clinical course	Alive, discharged
	Wang et al [45]	China	1	49 years/male		HTN, DM	CSA, MMF, prednisone	2 years	Fever, respiratory symptoms	Immunosuppressant medications continuedLopinavir/ritonavir, ribavirin, interferon-α2b, methylprednisolone	Required supplemental oxygen; respiratory status improved over course of admission	Recovered
	Billah et al [46]	United States	1	44years/M		Not reported	Tac, MMF, prednisone	7 years	Dyspnea	Immunosuppressant medications continuedMethylprednisolone	Developed AKI requiring dialysis; Intubated for respiratory failure	Remains both dialysis and ventilator dependent
	Cheng et al [47]	China	2	Pt 1: 48 years/malePt 2:65 years/female		Pt 1: Not reportedPt 2: Not reported	Pt 1: Tac, MMF, prednisonePt 2: Tac, MMF, prednisone	Pt 1: 11 yearsPt 2: 9 years	Pt 1: Fever, chest tightnessPt 2: Fever, cough, chest tightness, myalgia	Pt 1: Immunosuppressant medications held; methylprednisolonePt 2:Immunosuppressant medications held; moxifloxacin, Umifenovir, IVIG, methylprednisolone	Pt 1: Symptomatic supportive treatment with improvement in clinical coursePt 2: Respiratory symptoms initially deteriorated; required supplementary oxygen; gradual improvement in clinical course	Pt 1: Alive, dischargedPt 2: Alive, discharged
	Crespo et al [48]	Spain	16	Median73.6 years75% male12		HTN (88%) 14, DM (50%) 8, heart disease (50%) 8, obesity (44%) 7, malignancy (31%) 5, lung disease (19%) 3	CNI (88%) 14 prednisone (81%) 13, MMF (50%) 8, mTOR (31%) 5, TCDA (19%) 3	Not reported	Fever (100%), dyspnea (75%) 12 myalgia (50%) 8, diarrhea (25%) 4	Tac held in 70%, MMF and mTOR held in all 16Abx (88%), 14HCQ (81%) 13, steroid (38%)6 ritonavir-lopinavir/darunavir (31%), 5 tocilizumab (25%) 4	15 pts (94%) hospitalized6 pts (40%) required ICU admission	8 pts (53%) died
	Ning et al [49]	China	1	29 years/male		HTN	MMF, CSA, methylprednisolone	2 years	Fever/chills, fatigue	Immunosuppressant medications continuedSMZ-TMP, moxifloxacin, lopinavir/ritonavir	Developed oliguria and hyponatremia; clinical course improved over course of admission	Resolution and discharge
	Bush et al [50]	United States	1	13 years/male		Chronic severe constipation, rectal prolapse, cecostomy, colostomy with colonic resection	Sirolimus, MMF	6 years	Rhinorrhea, cough, fever	MMF and sirolimus reducedAntibiotics	Required NC; remained hemodynamically stable	Alive, discharged to home
	Kumar et al [51]	United States	1	50 years/male		HIV, HTN, asthma, steatohepatitis	Tac, MMF	14 months	Fever/chills, nasal congestion, cough	Not reported	Not admitted, enrolled in COVID home monitoring program	Health improved to baseline
Liver SOT	Maggi et al [52]	Italy	2		Pt 1: 61 years/malePt 2: 69 years/M	Pt 1: Not reportedPt 2: HIV	Basiliximab, prednisolone, and Tac	Pts developed SARS-CoV-2 infection during hospitalization for transplant	Pt 1: Fever POD 9Pt 2: Not reported	Not reported	Pt 1: Presented with fever POD 9 but with normal chest x-ray findingsPts 2: Tested positive for SARS-CoV-2 on POD 22	Pt 1: AlivePt 2: Died on POD 30
	Bhoori et al [53]	Italy	3		>65 years/male	HTN, hyperlipidemia, DM (100%)	CSA (67%)Tac (33%)	>10 years	Respiratory symptoms similar to CAP	Not reported	100% required supplementary oxygen at admission but rapidly developed severe respiratory distress syndrome that required mechanical ventilation	100% died between 3 and 12 days after the onset of pneumoniaAuthors report 3 recently (within last 2 years) transplanted patients with positive test result for SARS-CoV-2 (on full imuunosuppression); all experienceduneventful course of disease (no further details about this cohort provided)
	D’Antiga et al [54]	Italy	3		Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	None developed clinical pulmonary disease	Not reported
	Qin et al [55]	China	1		37 years/male	Not reported	Tac, glucocorticoid	Pt developed SARS-CoV-2 infection during hospitalization for transplant	Fever following chemoembolization on day 3 of hospitalization; persistent fever noted 2 days after transplant (transplant occurred on day 7 of hospitalization)	Osteltamivir, rh-GCSF, IVIG started after confirmation of infectionTac and glucocorticoids titrated to lower dose and then increased on day 40 of hospitalization given concerns for acute cellular rejection	Presented with fever following hepatic arterial chemoembolization; continued to have persistent fever 2 days following embolization; RT-PCR confirmed infection; fever subsided on day 33 of hospitalization	Alive, discharged to home
	Lagana et al [56]	United States	1		6 months/female	Not reported	Not reported	Pt developed SARS-CoV-2 infection during hospitalization for transplant	Respiratory distress, fever, diarrheaNotably, donor tested positive on POD 2 (symptoms not reported)	HCQ	Fever with increased work of breathing on POD 4; admitted to ICU	Pt remained in hospital with mild respiratory symptoms
	Huang et al [57]	China	1		59 years/male	Hepatitis B	Tac, MMF	3 years	Fever, cough, chills, fatigue, diarrhea, jaundice, ascites, splenomegaly	Nebulized α-interferon, umifenovir, lopinavir/ritonavir, methylprednisolone, albumin, blood, plasma, IVIG; multiple antimicrobials, including caspofungin, voriconazole, piperacillin tazobactam, cefoperazone -sulbactam, meropenemTac and MMF dosages halved due to DDI with lopinavir/ritonavir	Respiratory failure on day 4 of hospitalization, placed on NC; hypoxemia worsened requiring intubation; on day 12, blood cx positive for Candida, pleural fluid positive for Pseudomonas; ECMO on day 15 due to worsened respiratory status; condition deteriorated to multiorgan failure	Pt died on day 45 of admission
	Bin et al [58]	China	1		50 years/male	Not reported	Tac	3 years	Fever	Umifenovir, lopinavir/ritonavir, methylprednisolone, IVIG, alpha interferon, antibioticsTac held on admission to hospital; increased to full dose on discharge	Pt became progressively dyspneic requiring NC on day 5 of hospitalization; symptoms resolved on day 21; discharged after 4 weeks of hospitalization	Alive, at home
	Lee et al [59]	United States	38		Median 60 years	For hospitalized pts (n = 24):CKD (71%) 17HTN (71%), 17 DM (50%), 12 cardiovascular disease (42%), 10 obesity (42%),10	For hospitalized pts (n = 24):Tac (96%) 23CSA (4%) 1MPA (54%) 13Steroid (50%) 12	Not reported	Gastrointestinal symptoms (42%) 10	Immunosuppression was decreased in 79% of hospitalized patients 1918 (75%) received HCQ + azithromycin5 (21%) received glucocorticoid8 (33%) received anticoagulant	63% hospitalized18 (75%) required supplemental oxygen8 (33%) required mechanical ventilation	7 (29%) died3 (13%) remain hospitalized14 (58%) discharged
	Patrono et al [60]	Italy	10		Pt 1: 69 years/malePt 2: 59 years/malePt 3: 56 years/malePt 4: 58 years/malePt 5: 64 years/femalePt 6: 64 years/malePt 7: 64 years/malePt 8: 62 years/malePt 9: 75 years/malePt 10: 85 years/female	Pt 1: NonePt 2: ObesityPt 3 through Pt 10: Not reported	Pt 1: MMF, Tac, prednisonePt 2: Tac, EVEPt 3: Tac, EVEPt 4: MMF, Tac, prednisonePt 5: Tac, prednisonePt 6: MMF, TacPt 7: MMF, TacPt 8: MMF, TacPt 9: MPA, TacPt 10: Tac	Pt 1: 5 daysPt 2: 8 monthsPt 3: 3 yearsPt 4: 2 monthsPt 5: 4 yearsPt 6: 8 yearsPt 7: 9 yearsPt 8: 11 yearsPt 9: 11 yearsPt 10: 22 years	Pt 1: CoughPt 2: Fever, diarrhea, dyspneaPt 3: Fever, odonyphagia, coughPt 4: AsymptomaticPt 5: Fever, anorexia, diarrheaPt 6: FeverPt 7: FeverPt 8: FeverPt 9: Fever, diarrhea, myalgia, coughPt 10: Asymptomatic	6 patients were administered HCQ, 3 high-dose steroids, and 2 antivirals (lopinavir/ritonavir and darunavir/ritonavir)6 patients were administered HCQ, 3 high-dose steroids and 2 antivirals (lopinavir/ritonavir and darunavir/ritonavir)6 (60%) HCQ, 3 (30%) high dose steroids, 2 (20%) antivirals	Pt 1: AsymptomaticPt 2: Required supplemental oxygen; gradual symptom improvementPt 3: Mild symptoms followed by dyspnea requiring supplemental oxygen; clinical course improvedPt 4: Tested positive 2 months after discharge for transplantPt 8: Contracted infection during hospitalization for head traumaPt 10: Incidentally found to be positivePt 5-7, 9: Not reported	Pt 1: AlivePt 2: AlivePt 3: AlivePt 4: AlivePt 5: AlivePt 6: AlivePt 7: AlivePt 8: Died (unrelated to SARS-CoV-2)Pt 9: DiedPt 10: Alive
	Hammami et al [61]	United States	1		63 years/male	ESRD, DM, HTN, HF, PVD	Tac	10 years	Fever, dry cough, fatigue, headache	HCQ, ceftriaxone, azithromycin, cefepime, vancomycin, tocilizumab	Waxing and waning fever; day 10 of hospitalization developed pleuritic chest pain and severe periumbilical pain, with improvement after tocilizumab; remained afebrile thereafter	Alive
	Modi et al [62]	United States	1		32 years/male	HIV	Tac, MMF, prednisone	7 years	Fatigue, fever, headache, dry cough	MMF held, Tac reduce, prednisone continuedHCQ	Admitted with mild symptoms which gradually improved over course of hospitalization	Discharge home
	Morand et al [63]	France	1		4 years/female	EBV	Tac	5 months	Rhinitis, fever, cough	Tac dose reducedAntipyretic	Improvement in clinical symptoms during hospitalization	Recovered

Abbreviations: Abx, antibiotics; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; Aza, azathioprine; CAD, coronary artery disease; CAP, community-acquired pneumonia; CAV, cardiac allograft vasculopathy; CNI, calcineurin inhibitor; CMV, cytomegalovirus; CPAP, continuous positive airway pressure; CSA, cyclosporine; Cx, culture; CMV, cytomegalovirus; CVD, cardiovascular disease; Dx, diagnosis; d/c, discontinued; DDI, drug–drug interaction; DM, diabetes mellitus; EBV, Epstein-Barr virus; ED, emergency department; ESRD, end-stage renal disease; EVE, everolimus; HCQ, hydroxychloroquine; HCV, hepatitis C virus; HF, heart failure; HIV, human immunodeficiency virus; HTN, hypertension; ICU; intensive care unit; IGT, impaired glucose tolerance; IL-6-ra, interleukin 6 receptor antagonist; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MPA; mycophenolate acid; mTOR, mammalian target of rapamycin; NC, nasal cannula; Pt(s), patient(s); POD, postoperative day; PVD, peripheral vascular disease; RCT, randomized controlled trial; rh-GCSF, recombinant human granulocyte colony-stimulating factor; SD, symptom day; SMZ-TMP; sulfamethoxazole-trimethoprim; Tac, tacrolimus; TCDA, T-cell–depleting agents; Tx, treatment.

Results

Study Selection

A total of 1455 citations were identified in the initial search. After removing 211 duplicates, a total of 1244 studies were screened by title and abstract (Fig 1 ). Studies were excluded if they did not mention SOT, SARS-CoV-2 infection, or associated clinical course and outcomes or did not fulfill the inclusion criteria. After excluding 1164 studies, we completed a full-text assessment of the remaining 80 studies. Forty-nine studies were included in our final analysis after the exclusion of 31 studies after a full-text screen. Exclusion of these 31 studies at the full-text review included the following reasons: discussed management and recommendations (n = 10), review articles (n = 6), discussed impact of pandemic on transplant program volumes (n = 3), descriptive studies (n = 3), non-English (n = 1), discussed non-SOT transplant (n = 1), did not discuss SOT (n = 2), discussed SARS-CoV-2 infection in transplant surgeon or donor (n = 2), discussed investigational therapy (n = 1), discussed immunologic response (n = 1), or discussed non–transplant-related guideline (n = 1).

Fig 1

PRISMA flowchart.

Study Characteristics

Of the 49 studies included, 22 were case reports, 8 were case series, and 19 were cohort studies. Four studies discussed heart SOT, 25 discussed kidney SOT, 12 discussed liver SOT, and 8 included multiple SOTs. A total of 433 SOTs were reported among all studies (Table 2 ). The most common SOT was the kidney with 252 (58.2%), followed by liver with 89 (20.6%), heart with 51 (11.8%), lung with 24 (5.5%), and pancreas with 1 (0.2%). Seventeen individuals (3.9%) received more than one SOT. A majority were men (n = 264; 61%). The median age was 54 years (IQR, 45-64), and the median time from transplant was 48 months (IQR, 12-108). Overall mortality was reported as 21% (Table 3 ).

Table 2

Characteristics of Total Solid Organ Transplant Recipients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

	No.	%
Location
United States	249	57.51%
Italy	55	12.7%
China	26	6%
Organ transplanted
Kidney	252	58.2%
Liver	89	20.6%
Heart	51	11.8%
Other organ∗	42	9.6%
Sex
Male	264	61.0%
Comorbidity
HTN	249	57.5%
DM	159	36.7%
Obesity	44	10.2%
CKD	77	17.8%
Immunosuppressive
Tac	160	37.0%
CNI	122	28.2%
Prednisone or other steroid	217	50.1%
MMF/MPA	214	49.4%
Other immunosuppressive†	125	28.8%

Abbreviations: CKD, chronic kidney disease; CNI, calcineurin inhibitor; DM, diabetes mellitus; HTN, hypertension; MMF, mycophenolate mofetil; MPA, mycophenolic acid; Tac, tacrolimus.

Includes lung, pancreas, and multiple solid organ transplant.

Includes mammalian target of rapamycin, belatacept, leflunomide, mizoribine, cyclosporine, azathioprine, intravenous immunoglobulin/pheresis, basiliximab, T-cell–depleting agents, CNI + MMF, and triple therapy.

Table 3

Presentation, Clinical Course, and Outcome of Total Solid Organ Transplant Recipients

	No.	%
Initial presentation
Fever	291	67.2%
Cough	220	50.8%
Gastrointestinal symptoms	120	27.7%
Dyspnea	169	39.0%
Asymptomatic	3	0.7%
Treatment
Immunosuppressant modified	235	54.3%
Antibiotics	178	41.1%
HCQ	242	55.9%
Methylprednisolone or other steroid	78	18.0%
Clinical course
Hospitalized	283	65.4%
Outpatient	50	11.5%
Respiratory failure	18	4.2%
Transfer to ICU	78	18.0%
Outcome∗
Death (all studies)	91	21.0%
Kidney	39	26.0%
Heart	8	24.2%
Liver	14	26.4%

Abbreviations: HCQ, hydroxychloroquine; ICU, intensive care unit.

Death for all studies includes studies for multiple solid organ transplant (SOT) type, including those reporting lung, pancreas, and multiple SOT, whereas death for kidney, heart, and liver SOT recipients was determined solely from studies discussing each individual organ separately.

Characteristics, Clinical Course, and Outcomes by SOT Type

Kidney

Among the 25 studies reporting solely kidney SOT, 150 recipients with SARS-CoV-2 infection were identified. Ninety-five (63.3%) were male. The most common comorbidities were hypertension (55.3%) and diabetes mellitus (26.7%). Tacrolimus (52%), mycophenolate mofetil (MMF) (56%), and prednisone/steroid (64.7%) were the most commonly used maintenance immunosuppressants. Additional immunosuppressant regimens included unspecified calcineurin inhibitors (CNIs) (12%), mTOR inhibitors (4.6%), and belatacept (2%). Fever was the most common presenting symptom (71.3%), followed by cough (39.3%) and dyspnea (26%). Ninety-three individuals (62%) were hospitalized, and 10.7% developed acute kidney injury. Mechanical ventilation, supplemental oxygen, and transfer to an intensive care unit (ICU) for a higher level of care were required in 20%, 11.3%, and 19.3% of the individuals, respectively. Nearly half (46.7%) of those reported had their maintenance immunosuppressant reduced when the infection was suspected or confirmed. The most commonly used treatments were hydroxychloroquine (HCQ) (65.3%), antibiotics (43.3%), steroids (20.7%), and lopinavir/ritonavir (15.3%). Thirty-three patients were reported as alive (22%), discharged to home (n = 45; 30%), or remaining hospitalized (non-ICU, n = 27 [18%]; ICU, n = 3 [2%]), and 26% of individuals died (n = 39).

Liver

Fifty-three liver SOT recipients were identified from 12 studies reporting liver SOT, and males comprised 28.3% of the population (n = 15). Hypertension, chronic kidney disease, and diabetes were the most common comorbidities (39.6%, 32.1%, and 30.2%, respectively). Tacrolimus (79.2%), MMF/mycophenolic acid (MPA) (39.6%), and steroids (35.8%) were the most commonly used maintenance immunotherapies. Fever and gastrointestinal symptoms were the 2 most common initial presenting symptoms, followed by cough (28.3%, 28.3%, and 18.9%, respectively). Thirty-four individuals (64.2%) were hospitalized, and 45.3% subsequently had their maintenance immunosuppressant medication reduced. HCQ and antibiotics were used in 39.6% and 39.6%, respectively, for treatment of SARS-CoV-2 infection. In addition, 47.2% of individuals required supplemental oxygen during hospitalization, and 14 (26.4%) individuals died after the onset of illness.

Heart

Thirty-three individuals who underwent heart SOT were reported in 4 studies; 25 (75.8%) were male. The most common comorbidities were hypertension (69.7%), diabetes (57.6%), and cardiac allograft vasculopathy (48.5%). The most commonly used maintenance immunotherapies were CNI (81.8%) and MMF/MPA (69.7%). Fever (81.8%), cough (94.8%), dyspnea (75.8%), and gastrointestinal symptoms (48.5%) were the most common initial presenting symptoms. Twenty-seven (81.8%) patients were hospitalized, and intubation/mechanical ventilation was required in 24.2% of those individuals. Twenty-four (72.7%) patients received HCQ, and high-dose steroids were administered to 15 patients (45.5%). Maintenance immunotherapy was modified in 75.8% of the cases. Fifteen (45.5%) were reported as discharged, and 24.2% of the individuals died during their illness.

Discussion

As the number of SARS-CoV-2 infections continues to grow worldwide, clinical data in SOT recipients are emerging, and our study showed overall mortality of 21% with no substantial variations among the different types of SOT (Table 3). The mortality rate is in concordance with published data in terms of outcomes reported in patients undergoing acute care surgery and cancer surgery: Lei et al, Liang et al, and the COVIDSurg Collaborative group reported mortality in the general surgical population of 20.5%, 39%, and 23.8%, respectively [4,64,65].

Older age, male sex, and preexisting conditions such as hypertension and diabetes were the most common characteristics among the SOT recipients. As predicted, we saw a broad spectrum of clinical courses ranging from having only a few mild symptoms to multiorgan failure leading to death. Despite the concerns of atypical disease presentation in immunocompromised patients, the most common presenting symptoms were similar to general population symptoms [7,66,67]; however, there were some variations in the incidence of the initial presenting symptoms among the different SOT types (Table 1).

Modification of immunosuppressant therapy at confirmation or suspicion of SARS-CoV-2 infection was reported in 54.3% of the patients, reflecting individualized adjustment based on the severity of the disease, type of transplanted organ, interval time since transplant, and risk of rejection [8]. On a similar note, the American Association for the Study of Liver Diseases recently published management guidelines for liver transplant recipients in the COVID era [68]: continuing the routine immunosuppressive regimen in nonsymptomatic recipients and reducing the immunosuppression regimen, including prednisone, azathioprine, or MMF and CNI in symptomatic patients with COVID-19. Our study suggests that the current practice of reducing immunosuppression upon the diagnosis of SARS-CoV-2 infection appears to be an appropriate measure without causing significant short-term adverse effects on graft function while maintaining patient survival comparable to that of the general population.

The median time from transplant to infection was 48 months in our study; the majority of the studies focused on patients who had received SOTs many years ago. Although it is a small number, we identified 4 cases in which the SOT recipient contracted SARS-CoV-2 infection during the transplant perioperative period, and we found no significant difference in their initial presentation, clinical course, and outcome when compared with a cohort of patients who received a transplant more than 1 year ago.

Although our study provides a general overview of SOT recipients’ clinical course and outcomes with SARS-CoV-2 infection, we recognize several limitations of the study. First, the inclusion of early case reports may be biased toward those with increased severity of disease and worse outcome, leading to publication bias with overinterpretation. Second, the inclusion of a mixed transplant population and a wide heterogeneity in study inclusion criteria may not be a true representation of the study samples and therefore precluded the ability to derive causality. Furthermore, data were based on absolute counts and therefore can be used only for descriptive purposes. Last, a certain degree of reporting bias inevitably played a role because SOT recipients are trained to be more vigilant with their health conditions and have a low threshold for seeking medical attention. This reporting bias could have led to more disease diagnosis in our study group than in the general population.

In conclusion, SARS-CoV-2 infection in SOT recipients in general appears to have similar presentation, clinical course, and outcome as in the general non-SOT surgical population. We found that the patient demographics, preexisting risk factors, and outcomes were similar within each SOT type, and we saw no substantial differences in mortality rate among the different SOT types. Although our data show that the overall short-term survival is about the same, long-term patient survival and graft function data are needed to fully understand the impact of COVID in SOT patients.