Liver-spleen axis dysfunction in COVID-19

Table 1 Main studies reporting liver involvement in patients without pre-existing liver disease

Ref.	Country	Patients	Liver involvement criteria	Patients with liver involvement, n (%)	Main findings
Fan et al[33]	China	148	ALT > 40 U/L or AST > 35 U/L	55 (37.2)	Abnormal liver function is common in COVID-19 inpatients, leading to a longer hospital stay
Goyal et al[17]	United States	375	ALT > 40 U/L	120 (32)	Mechanically ventilated patients more likely to have liver involvement.
Lenti et al[29]	Italy	100	ALT or GGT > 50 U/L	58/93 (62.4)	Liver involvement correlate to higher mortality and ICU need in those who develop ARDS
Medetalibeyoglu et al[32]	Turkey	554	ALT or AST > 40 U/L	153 (27.6)	Higher rate of moderate-to-severe pneumonia and ICU admission need in patients with liver involvement
Phipps et al[31]	United States	2273	ALT > 50 U/L	537 (24)	Severe liver involvement was rare (6.4%) and led to worse outcomes (ICU admission, higher mortality)
Ponziani et al[30]	Italy	515	AST > 45 U/I orALT > 45 U/I orGGT > 61	161 (31.3)	No cases of severe liver injury in this cohort. Liver involvement was generally mild and, although correlated to a higher need of ICU care, not associated to higher mortality
Richardson et al[7]	United States	5700	ALT > 60	2176 (39)	Acute liver injury occurred in 1% of the included patients and was associated with higher mortality
Schattenberg et al[28]	Germany	44	ALT >50 U/L	6/38 (15.8)	Severe liver involvement was rare (9%), with AST more commonly deranged than ALT

ALT: Alanine aminotransferase; ARDS: Acute severe respiratory distress syndrome; AST: Aspartate aminotransferase; COVID-19: Coronavirus disease 2019; GGT; Gamma-glutamyl transpeptidase; ICU: Intensive care unit.

Table 2 Main studies reporting outcomes in patients with pre-existing chronic liver disease

Ref.	Country	Patients	Patients with CLD, n (%)	Main findings
Bajaj et al[40]	United States	272	37 (13.6)	Higher mortality in cirrhotic COVID-19 positive patients
Hashemi et al[41]	United States	363	69 (19)	CLD patients had higher ICU admission and mechanical ventilation rate. CLD was a predictor of mortality
Iavarone et al[42]	Italy	50	50 (100)	COVID-19 infection led to liver function deterioration. CLD patients had increased mortality
Marjot et al[43]	International	1365	745 (54.6)	CLD correlate to higher mortality rate according to the CPT class. ALD was an independent risk factor for mortality
Qi et al[39]	China	21	21 (100)	Respiratory failure was the cause of death in most patients
Singh et al[37]	United States	250	60 (46.1)	Pre-existing CLD patients had higher hospitalisation and mortality rates
Sarin et al[38]	International	228	228 (100)	Decompensation of pre-existing CLD occurred in one fifth of cirrhotic patients

CLD: Chronic liver disease; COVID-19: Coronavirus disease 2019.

Table 3 Main studies reporting outcomes in liver transplant patients

Ref.	Country	Patients	Patients with LT	Main findings
Bhoori et al[45]	Italy	151 (COVID status unknown)	151 (100)	3 deaths recorded in long-term LT recipient on low immunosuppressant dose
Belli et al[47]	International	103	103 (100)	Mortality might correlate with age and longer time since LT
Donato et al[49]	Italy	640 (8 COVID positive)	640 (100)	Low prevalence of infection in LT patients who adhere to preventive measures
Lee et al[48]	United States	38	38 (100)	High mortality in LT patients regardless of time since transplant
Pereira et al[46]	United States	90	14 (15)	Solid organ transplant recipient had more severe outcomes
Webb et al[50]	International	778	151 (19.4)	LT patients did not have a higher mortality, ICU admission or hospitalisation rate; age and comorbidities correlated with outcomes

COVID: Coronavirus disease; ICU: Intensive care unit; LT: Liver transplant.

Table 4 Summary of the main studies reporting coronavirus disease 2019 related spleen dysfunction

Ref.	Country	Patients	Patients with spleen involvement, n (%)	Main findings
Feng et al[54]	China	6	6 (100)	ACE2 expression on tissue-resident CD169+ macrophages in spleen; viral NP antigen found in ACE2+ cells in spleen; direct damage of spleen tissue (lymph follicle depletion, splenic nodule atrophy, lymphocyte reduction, etc.)
Remmelink et al[55]	Belgium	17	11 (65)	SARS-CoV-2 RNA detected in spleen autopsy samples by RT-PCR assay
Sekulic et al[56]	United States	2	2 (100)	SARS-CoV-2 RNA detected at high level in spleen FFPE samples by RT-PCR assay
Han et al[58]	China	7356	NA	Expression of ACE2 in spleen tissue (lower than in other tissues), without difference according to sex
Li et al[59]	China	31	NA	Expression of ACE2 in spleen tissue (lower than in other tissues), without difference according to sex and age
Xu et al[60]	China	10	10 (100)	Decrease in spleen cell composition with decrease in lymphocyte components, white pulp atrophied, lymphoid follicles decreased or absent, increase in red pulp to white pulp ratio
Menter et al[61]	Switzerland	21	6 (29)	Acute splenitis and/or septic neutrophilic leucocytosis of the red pulp, suggesting vascular disfunction in patients with COVID-19
Lax et al[62]	Austria	11	10 (90)	White pulp atrophy due to lymphocyte depletion, areas of haemorrhage with acute or chronic congestion
Duarte-Neto et al[63]	Brazil	5	5 (100)	Lymphoid hypoplasia in 100%, red pulp haemorrhages in 60%, splenitis in 40%, extramedullary haematopoiesis in 50%, endothelial changes in 80%, vasculitis and arterial thrombus in 20%
Lenti et al[29]	Italy	63	55 (87.3)	IgM memory B cell depletion that correlates with increased mortality and superimposed infections
Kaneko et al[65]	United States	11	11 (100)	Loss of spleen germinal centres due to depletion of Bcl-6+ germinal centre B cells and Bcl-6+ germinal centre T follicular helper cells, resulting in a dysregulated humoral immune response

COVID-19: Coronavirus disease 2019; FFPE: Formalin-fixed paraffin-embedded; NA: Not available; NP: Nucleocapsid protein; RT-PCR: Real-time reverse-transcript polymerase chain reaction; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.