COVID-19 in solid organ transplantation patients: A systematic review

Nacif, Lucas Souto; Zanini, Leonardo Y.; Waisberg, Daniel R.; Pinheiro, Rafael S.; Galvão, Flávio; Andraus, Wellington; D'Albuquerque, Luiz Carneiro

doi:10.6061/clinics/2020/e1983

Lucas Souto Nacif ^**Corresponding author. E-mail: lucasnacif@usp.br

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

http://orcid.org/0000-0002-7059-3978

Leonardo Y. Zanini

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

Daniel R. Waisberg

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

Rafael S. Pinheiro

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

Flávio Galvão

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

http://orcid.org/0000-0003-1924-3208

Wellington Andraus

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

http://orcid.org/0000-0002-5162-138X

Luiz Carneiro D'Albuquerque

Divisao de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

http://orcid.org/0000-0001-7607-7168

*Corresponding author. E-mail: lucasnacif@usp.br

No potential conflict of interest was reported.

All authors have approved the final draft of the submitted manuscript. Nacif LS was responsible for the study conception and design, data collection, analysis and interpretation, manuscript writing, and literature search. Zanini LY, Waisberg DR and Pinheiro RS were responsible for the study conception and design, data collection, analysis and interpretation, and critical revisions. Galvão F, Andraus W and D'Albuquerque LC were responsible for the study conception, interpretation and critical revisions.

Article	Patients	Clinical manifestation	Laboratorial exams	Treatment	Outcome
Zhong et al. (16) and Qin et al. (14) (Case report)	37 years old Male VHB+HCC 9 days after LT FK+MPA	-Fever (38.6°C) -SpO₂ 94% -Weakness -Abdominal discomfort -Sleep disorders	-WBC 2.46×10⁹/L -Platelets 74×10⁹/L -Lymphs 0.48×10⁹/L -ALT 240 U/L -TBIL 38.9 μmol/L -RT-PCR positive for SARS-CoV-2 -CT scan showed bilateral glass density lesions	-UCI -Tacrolimus use was suspended -Administrated intravenous methylprednisolone (40 mg; 12/12h) -Oseltamivir -Cefoperazone -Sulbactam sodium	-After 2 days in UCI, satisfactory evolution -However, after 14 days of FK suspension, presented with possible graft dysfunction -Patient underwent MPA pulse therapy with satisfactory evolution
Huang et al. (17) (Case report)	59 years old Male VHB+HCC 3 years after LT FK+MMF	Three days of fever (40°C), cough, chills, fatigue, and diarrhea. HR of 112 beats/min, jaundice, splenomegaly, and ascites	-WBC 3.2×10⁹/L, -Lymphs 0.7×109/L -CRP 35.1 mg/L, -TBIL 83.9 μmol/L, -ALT 60 U/L -GGT 1087 U/L -RT-PCR positive for SARS-CoV-2 -CT scan showed bilateral glass density lesions	-UCI -Nebulized α- interferon -Umifenovir -Lopinavir/ritonavir -Piperacillin and tazobactam (empirical) -Required invasive ventilation (day 4)	-On the 12^th day of hospitalization, patient had positive cultures of Candida albicans and Pseudomonas aeruginosa -Worsening of hepatic and renal function -Plasma, immunoglobulin, blood transfusion, and hemodialysis were used -On the 33rd hospitalization day, RT-PCR was negative for SARS-CoV-2, but the patient evolved to death on the 47th day
Bin et al. (18) (Case report)	50 years old Male VHB 3 years after LT FK	-Fever (39.6°C) but initially low fever -Progressive dyspnea	-WBC 5.9×10⁹/L -CRP 32.1 mg/L -RT-PCR positive for SARS-CoV-2 -CT scan showed bilateral glass density lesions	-Discontinued FK and received systemic MPA -Cefoperazone (prophylactic) -Umifenovir -Lopinavir/ritonavir -Immunoglobulin -Nebulized α- interferon	-Patient had a satisfactory clinical evolution, with no complications and no liver dysfunction
Bhoori et al. (8) (Correspondence)	3 patients, >65 years old All male >10 years of LT Two patients receiving ciclosporin and one FK	Hospital admission with community-acquired pneumonia and quickly developed severe respiratory distress syndrome	Positive nasopharyngeal swab test for SARS-CoV-2	-UCI -Required invasive ventilation	All three patients evolved to death 3-12 days after the first pneumonia symptoms manifested
D’Antiga L (9) (Correspondence)	3 liver transplant children (From 700 LT)	None of the three patients had a clinical manifestation	Positive nasopharyngeal swab test for SARS-CoV-2	None	The three transplanted children did not develop any symptoms of COVID-19
Lagana S. et al. (15) (Case report)	6 female months children Biliary atresia LDLT COVID-19 infection manifestation 2 days after LT	-Fever -Dyspnea (employed CPAP) -Diarrhea	-RT-PCR positive for SARS-CoV-2 -Liver biopsy: mixed inflammatory infiltrate (lymphs) -Interlobular bile ducts with lymphocytic cholangitis	-Hydroxychloroquine	Patient still hospitalized, but with mild respiratory symptoms
Fernández-Ruiz et al. (7) (Case series)	Case 1 -63 years old -Male -COVID-19 infection manifestation 7.9 years after LT HBV+HCV+HCC -Everolimus	-Fever -SpO₂ 96% -Dyspnea -Cough -Diarrhea -Myalgia -Diarrhea	-Unifocal consolidation on chest X-Ray -Positive nasopharyngeal swab test for SARS-CoV-2	-Hydroxychloroquine -Lopinavir/ritonavir -Suspension of everolimus and substitution to FK +MMF	-Patient had a satisfactory clinical evolution, with no complications
	Case 2 -72 years old -Male -COVID-19 infection manifestation 5.5 years after LT Cryptogenic cirrhosis Everolimus+MMF	-Fever -SpO₂ 95% -Dyspnea -Cough	-Multifocal consolidation on chest X-Ray -Positive nasopharyngeal swab test for SARS-CoV-2	-Hydroxychloroquine -Lopinavir/ritonavir -Interferon-β -Substitution of Everolimus+MMF to FK	-Patient had worsening respiratory function and renal failure. Evolved to death after 7 days
	Case 3 -79 years old -Female -COVID-19 infection manifestation 15.3 years after LT -HCV+HCC -Prednisone+AZA+ Everolimus	-SpO₂ 96% -Dyspnea -Cough -Malaise -Diarrhea	-Bilateral consolidation on chest X-Ray -Positive nasopharyngeal swab test for SARS-CoV-2	-Hydroxychloroquine -Interferon-β -Immunosuppressive drugs maintained	-Patient had a satisfactory clinical evolution, with no complications
	Case 4 -73 years old -Male -COVID-19 infection manifestation 16.4 years after LT -HBV -MMF	-Fever -SpO₂ 76% -Dyspnea -Cough -Malaise	-Multifocal consolidation on chest X-Ray -Positive nasopharyngeal swab test for SARS-CoV-2	-ICU -Mechanical ventilation -Suspended MMF	-Patient had severe respiratory dysfunction and evolved to death in 24 days
	Case 5 -76 years old -Female -COVID-19 infection manifestation 26.5 years after LT -HCV -FK	-Fever -SpO₂ 98% -Thoracic pain	-Positive nasopharyngeal swab test for SARS-CoV-2	-Hydroxychloroquine -FK maintained	-Patient had a satisfactory clinical evolution, with no complications
	Case 6 -46 years old -Female -COVID-19 infection manifestation 6.4 years after LT -Acute liver failure -FK	-SpO₂ 100% -Diarrhea	-Positive nasopharyngeal swab test for SARS-CoV-2	-FK maintained	-Patient had a satisfactory clinical evolution, with no complications

Article	Patients	Clinical manifestation	Laboratory examination	Treatment	Outcome
Bussalino et al. (22) (Case report)	-32 years old -Male -3 years KT -Deceased donor -ESRD etiology was unknown -FK+MMF+Prednisone	-Three days of fever (38°C) -SpO2 97% -Dyspnea -Non-productive cough	-CRP 47.9 mg/L -PCT 0.33 μg/L -Creatinine 2.6 mg/dl -GFR 31 ml/min/1.73m² -RT-PCR positive for SARS-CoV-2	-Prednisone dose was increased to 15 mg/day -FK+MMF maintained -hydroxychloroquine -Oseltamivir -Ceftaroline -Oxygen administration by nasal catheters	-Patient had a satisfactory clinical evolution -Renal function remained similar to that at admission
Marx et al. (28) (Correspondence)	-58 years old -Male -3 years KT -Renal vein thrombosis -Balatacept+MMF+Prednisone	-Fever (38°C) -Dyspnea -Cough -History of contact with a person who received a COVID-19 diagnosis	-RT-PCR positive for SARS-CoV-2 -Pulmonary ground-glass opacities on CT	-Belatacept and MMF suspended at hospital admission	-Patient had a satisfactory evolution, without the necessity of mechanical ventilation or supplementary oxygen -Introduced cyclosporine on the 7^th hospitalization day
Bartiromo et al. (23) (Case report)	-36 years old -Female -First KT in 1993 -Second KT in 1995 (Cadaveric donor) -Senior-Loken syndrome -FK+Corticoesteroids	-Afebrile (36.3°C) -SpO2 97% -Fatigue -Dry cough -Coryza -History of contact with her mother who received a COVID-19 diagnosis	-CRP 67 mg/L -Creatinine 2.29 mg/dl -GFR 27 ml/min -RT-PCR positive for SARS-CoV-2	-Lopinavir/ritonavir* -Hydroxychloroquine -Ceftriaxone *On the 2^nd hospitalization day, patient presented with nausea and diarrhea, so the therapy with lopinavir/ritonavir was replaced with darunavir/cobicistat	- On the 4th hospitalization day, the patient presented with abdominal pain, nausea, and diarrhea. -Had a good clinical evolution -Medical release on the 9th hospitalization day
Ning et al. (24) (Case report)	-29 years old -Male -2 years KT (Living donor) -Cyclosporine+MMF+methylprednisolone	-Fever (37.7°C) -Without other symptoms in admission -During hospitalization (2^nd day), patient presented with nasal stuffiness, hyporexia, nausea, and vomiting	-First test RT-PCR negative for SARS-CoV-2 -Pulmonary ground-glass opacities on CT -Second test RT-PCR positive for SARS-CoV-2 (3rd hospitalization day)	-TMP-SMX (admission) -Immunosuppressive treatment was maintained -Lopinavir/ritonavir (after RT-PCR test was positive) -Probiotics	-On the 3^rd hospitalization day, patient presented with dizziness, nausea, vomit, oliguria, and hematuria -Laboratory tests revealed elevated creatinine levels and hyponatremia -Patient received fluids and had better renal function -Medical release on the 12th hospitalization day
Wang et al. (10) (Correspondence)	-49 years old -Male -2 years KT -Cyclosporine+MMF+ Prednisone	-Fever for six days -Without other symptoms in admission	-WBC 7.18×10⁹/L, -Lymphs 0.59×10⁹/L -CRP 22.73 mg/L -PCT 0.36 μg/L -Creatinine 1.44 mg/dl -RT-PCR positive for SARS-CoV-2 -Pulmonary ground-glass opacities on CT	-Nebulized α- interferon -Immunosuppressive treatment was maintained -Ribavirin -Lopinavir/ritonavir -Methylprednisolone -Oxygen administration by nasal catheters	-Patient had a good clinical evolution, without an impact on renal function
	Case 1 -38 years old -Male -3 months KT (Deceased donor)	-Fever (38.9°C) -SpO2 99% -Cough	-WBC 4.73×10⁹/L, -Lymphs 0.59×10⁹/L -CRP 6.68 mg/L -Creatinine 1.10 mg/dl -RT-PCR positive for SARS-CoV-2	-Antiviral therapy (oseltamivir or arbidol)	-Patient had a good clinical evolution, without the necessity of mechanical ventilation
	Case 2 -64 years old -Male -4 years KT (Deceased donor)	-Fever (38.3°C) -SpO2 96% -Cough -Sputum -Fatigue	-WBC 17.67×10⁹/L, -Lymphs 0.55×10⁹/L -CRP 337.11 mg/L -Creatinine 4.65 mg/dl -RT-PCR positive for SARS-CoV-2	-Antiviral therapy (oseltamivir or arbidol) -Cefixime	-Patient had anuria, persistent fever, normal CT chest, and an elevation of creatinine levels - Realized methylprednisolone pulse therapy, due rejection suspect -Had a good clinical evolution
Zhang et al. (25) (Case Series)	Case 3 -37 years old -Female -5 months KT (Deceased donor)	-Fever (39°C) -SpO2 99% -Cough	-WBC 5.67×10⁹/L, -Lymphs 0.31×10⁹/L -CRP 9.77 mg/L -Creatinine 1.54 mg/dl -RT-PCR positive for SARS-CoV-2	-Antiviral therapy (oseltamivir or arbidol) -IV immunoglobulin	-Patient had a good clinical evolution, without the necessity of mechanical ventilation
	Case 4 -47 years old -Male -11 months KT (Deceased donor)	-Fever (39.8°C) -SpO2 98% -Cough -Sputum -Fatigue	-WBC 3.99×10⁹/L, -Lymphs 0.51×10⁹/L -CRP 13.38 mg/L -Creatinine 1.66 mg/dl -RT-PCR positive for SARS-CoV-2	-Antiviral therapy (oseltamivir or arbidol)	-Patient had a good clinical evolution, without the necessity of mechanical ventilation
	Case 5 -38 years old -Male -3 years KT (Deceased donor)	-Fever (39.1°C) -SpO2 97% -Cough -Sputum -Fatigue	-WBC 6.44×10⁹/L, -Lymphs 0.91×10⁹/L -CRP 33.72 mg/L -Creatinine 1.53 mg/dl -RT-PCR positive for SARS-CoV-2	-Antiviral therapy (oseltamivir or arbidol)	-Patient had a good clinical evolution, without the necessity of mechanical ventilation
Chen et al. (26) (Case report)	-49 years old -Male -6 years KT (Deceased donor) -FK+MMF -Prednisolone	-Fever (38.6°C) -Hyporexia -Dry cough	-WBC 3.44×10⁹/L, -Lymphs 0.43×10⁹/L -CRP 74.34 mg/L -Creatinine 1.84 mg/dl -RT-PCR positive for SARS-CoV-2 -Pulmonary ground-glass opacities on CT	-MMF and prednisolone were suspended -Methylprednisolone -Ribavirin -Immunoglobin -Moxifloxacin	-Patient had worsening blood oxygen saturation, and oxygen inhalation was initiated. -Had a satisfactory clinical evaluation
Seminari et al. (27) (Case report)	-50 years old -Male -First KT 1993, failure 2008 -Second KT 2016 (4 years) -IgA nephropathy -FK+MMF	-Fever (37.3°C) -Cough	-WBC 3.2×10⁹/μL -Lymphs 0.6×10⁹/μL -RT-PCR positive SARS-CoV-2 -Chest x-ray showed interstitial lesions	-Immunosuppressive treatment was maintained -Lopinavir/ritonavir -Ceftriaxone	-Patient had a good clinical evolution, without the necessity of mechanical ventilation
Gandolfini et al. (29) (Correspondence)	Case 1 -75 years old -Male -10 years KT (Deceased donor) -FK+MMF -Prednisolone	-Fever (38-39°C) -Cough -Myalgia -Dyspnea	-WBC 6.56×10⁹/L, -Lymphs 0.80×10⁹/L -CRP 180 mg/L -PCT 1.29 ng/ml -Creatinine 2.2 mg/dl -RT-PCR positive for SARS-CoV-2 -Pulmonary ground-glass opacities on CT	-FK+MMF was discontinued -Lopinavir/ritonavir -Hydroxychloroquine	-Patients presented with significant worsening of respiratory function and evolved to death
Gandolfini et al. (29) (Correspondence)	Case 2 -52 years old -Female -8 months KT (Deceased donor) -FK+MMF -Prednisolone	-Fever (38-39°C) -Cough -Fatigue -Dyspnea -Diarrhea	-WBC 2.54×10⁹/L, -Lymphs 0.11×10⁹/L -CRP 158 mg/L -PCT 0.98 ng/ml -Creatinine 2.4 mg/dL -RT-PCR positive for SARS-CoV-2 -Pulmonary ground-glass opacities on CT	-FK+MMF was discontinued -Dorunavir/cobicistat -Hydroxychloroquine	-Patient received non-invasive oxygen therapy -Had a good clinical evaluation
Guillen et al. (30) (Case report)	-50 years old -Male -3^rd KT (4 years ago) -IgA nephropathy -FK+everolimus+ prednisone	1^st day -Fever (38.2°C) -Vomiting -Signs of dehydration 5^th day -Fever (37.4°C) -Crackles in the right lower lung -Conjunctivitis of the left eye	1^st day -WBC 8.58×10⁹/L -CRP<0.50 mg/dL -Creatinine 1.6 mg/dL, -GFR 50 mL/min 5^th day -WBC 10.15×10⁹/L -CRP 13.2 mg/dL -Creatinine 1.6 mg/dL, -GFR 50 mL/min -RT-PCR positive for SARS-CoV-2	-FK+Everolimus was discontinued -Lopinavir/ritonavir -Hydroxychloroquine -Ceftaroline+meropenem	-Patient had worsening respiratory function, and mechanical ventilation was initiated. -Until the publication of this article, the patient remains in intensive respiratory support
Fernández-Ruiz et al. (7) (Case series)	Case 1 -78 years old -Male -8.3 years of KT -Polycystic kidney disease -Prednisone+FK	-Fever -SpO₂ 89% -Dyspnea	-Unilateral consolidation on chest X-ray -RT-PCR positive for SARS-CoV-2	-Lopiravir/ritonavir -Reduction of FK doses	-Patient had respiratory failure and atrial fibrillation -Evolved to death after 5 days
	Case 2 -73 years old -Male -1.8 years of KT -Hypertensive nephropathy -Prednisone+FK+MPA	-Fever -SpO₂ 94% -Dyspnea -Cough	-Unilateral consolidation on chest X-ray -RT-PCR positive for SARS-CoV-2	-Lopinavir/ritonavir -Reduction of FK doses -Suspended prednisone+MPA	-Patient had myopericarditis -Had a satisfactory clinical evolution
	Case 3 -80 years old -Male -3.8 years of KT -Hypertensive nephropathy -Prednisone+FK+MPA	-SpO₂ 90% -Dyspnea -Cough -Hyporexia -Myalgia	-RT-PCR positive for SARS-CoV-2	-Lopinavir/ritonavir -Hydroxychloroquine -Reduction of FK doses -Suspended MPA	-Patient had worsening respiratory function -Evolved to death after 16 days
	Case 4 -71 years old -Female -6 years of KT -Unknown cause of renal failure -Prednisone+FK+MPA	-Fever -SpO₂ 97% -Dyspnea -Cough -Sore throat	-Bilateral interstitial pneumonia -RT-PCR positive for SARS-CoV-2	-Lopinavir/ritonavir -Hydroxychloroquine -Suspended MPA+prednisone	-Patient evolved to death after 16 days
	Case 5 -71 years old -Male -30.1 years of KT -Polycystic kidney disease -FK	-Fever -SpO₂ 100% -Epigastric pain	-RT-PCR positive for SARS-CoV-2	-Hydroxychloroquine -Intravenous immunoglobulin -Reduction of FK doses	-Patient showed an improvement in abdominal pain and was discharged home but returned to the hospital due to clinical worsening
	Case 6 -76 years old -Male -14.8 years of KT -IgA nephropathy -Prednisone+MMF+rapamycin	-Fever -SpO₂ 96% -Rhinorrhea	-Bilateral interstitial pneumonia -RT-PCR positive for SARS- CoV-2	-Hydroxychloroquine -Suspended MMF	-Patient had a good clinical evolution, without the necessity of mechanical ventilation
	Case 7 -39 years old -Male -16.8 years of KT -Polycystic kidney disease -Prednisone+FK+ Everolimus	-Fever -SpO₂ 100% -Myalgia	-RT-PCR positive for SARS- CoV-2	-Hydroxychloroquine -Suspended FK+everolimus	Patient had worsening respiratory function but showed mild radiological improvement
	Case 8 -65 years old -Male -6.5 years of KT -Chronic interstitial nephritis - Prednisone+FK+MPA	-Fever -SpO₂ 93% -Myalgia -Dyspnea -Cough	-Unilateral focal consolidation on chest X-ray -RT-PCR positive for SARS- CoV-2	-Lopinavir/ritonavir -Hydroxychloroquine -Reduced doses of MPA and FK	-Patient had a positive clinical evolution

	OVERALL PARAMETERS
Parameters	Liver transplant	Kidney transplant	Overall SOT	p-value
Cases (N)	16	23	39	-
Age (years)	55.25 (±23.8)	54.65 (±16.42)	54.65 (±16.42)	0.603
	61 (0.5-79)	50 (29-80)	52 (0.5-80)
Time after transplant to COVID-19 (years)	8.40 (±8.50)	6.79 (±7.84)	7.28 (±7.95)	0.686
	5.95 (0.01-26.5)	4 (0.25-30.1)	4 (0.01-30.10)
Death (N)	6	4	10	0.157
Fatality rate (%) (death/total)	37.5%	17.39%	25.64%	0.157
Fatality rate ≥60 years old (%)	62.5%	44.44%	52.94%	0.457

	PREVALENCE AND FATALITY RATE (%) (≥60 years old vs <60 years old)
	Age ≥60 years old	Age <60 years old	p-value
Liver transplant
Prevalence rate (%)	8 (50%)	8 (50%)	0.501
Fatality rate (%)	62.5%	12.5%	0.006
Kidney transplant
Prevalence rate (%)	9 (39.13%)	14 (60.87%)	0.501
Fatality rate (%)	44.44%	0%	0.039
Solid organ transplant
Prevalence rate (%)	17 (43.58%)	22 (56.42%)	0.501
Fatality rate (%)	52.94%	4.54%	0.001

[1] *Corresponding author. E-mail: lucasnacif@usp.br

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COVID-19 in solid organ transplantation patients: A systematic review