May 2022 acute hepatitis outbreak, is there a role for COVID-19 and other viruses?

Table 1 Clinical data from various studies, n (%)

Ref.	Kelgeri et al[9], 2022	Cates et al[10], 2022	Marsh et al[11], 2022	Baker et al[12], 2022	Cumulative data
Demographic data
Country	UK	USA	Scotland, UK	Alabama, USA
Number of patients	44	296	13	9	362
Age (yr), median (range)	4 (1-7)	2.2 (0–9.7)	3.9 (3-5)	2 (1.66-5.7)	3 (0-9.7)
Male/female ratio	0.83:1	1.42:1	1.2:1	0.28:1	1.3:1
Clinical findings
Jaundice	41 (93)	71/123 (57.7)	8/9 (88.9)	8/9 (88.9)	128/185 (69)
Vomiting	24 (54)	76/123 (61.8)	4/4 (100)	7/9 (77.8)	113/180 (63)
Diarrhoea	14 (32)	61/123 (49.6)	4/4 (100)	6/9 (66.7)	85/180 (47.2)
Pale stools	13 (30)	/	/	/	13/44 (30)
Abdominal pain	12 (27)	48/123 (39.0)	7/9 (77.8)	/	69/176 (39)
Lethargy	10 (23)	15/123 (12.2)	4/4 (100)	1/9 (11.1)	30/180 (16.6)
Dark urine	6 (14)	44/123 (35.8)	/	/	50/167 (30.0)
Coryza	6 (14)	20/123 (16.3)	/	3/9 (33.3)	29/176 (16.5)
Pyrexia	4 (9)	51/123 (41.5)	0/4 (0)	5/9 (55.6)	60/180 (33.3)
Pruritus	1 (2)	/	/	/	1/44 (2.0)
Anorexia		65/123 (52.9)	/	/	65/123 (52.9)
Acute live failure	6 (14)	37/123 (30.1)	/	1/9 (11.1)	44/176 (25)

UK: The United Kingdom; USA: The United States of America.

Table 2 Suggested workup in the diagnosis of acute hepatitis of unknown aetiology

Item		Sample test
History		To be taken according to WHO for case definition, probable or confirmed case. History of traveling to high-risk areas endemic to hepatitis viruses, exposure to a local outbreak, household contact, sharing personal items with an infected person, attendance at day-cares, history of transfusion-dependent illness, or exposure to tattoos and/or body piercing using nonsterile techniques
Clinical examination		Low-grade fever, fatigue, anorexia, nausea, vomiting, enlarged and tender liver with/without splenomegaly, jaundice, abdominal pain, dark urine, pale or clay-coloured stool
Liver Functions		Total bilirubin, conjugated bilirubin, liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase), albumin, and prothrombin time
Liver biopsy		Staining with haematoxylin and eosin in selected cases
Imaging studies		Usually not required; may be needed to rule out biliary obstruction and other aetiologies for elevated liver enzymes and to exclude complications such as cirrhosis and hepatocellular carcinoma. Abdominal ultrasound: Shows enlarged liver with decreased (acute) or increased (chronic) echogenicity, brighter portal vein, periportal oedema, gallbladder wall thickening, and ascites. CT findings of acute hepatitis are nonspecific: Hepatomegaly, gallbladder wall thickening, periportal oedema, and ascites
Tests for autoimmune hepatitis		Autoantibodies such as ANAs and anti-SMAs
Detecting viral causes of hepatitis	Serology	Antibodies against Hepatitis A-E, Epstein-Barr virus, cytomegalovirus, HIV, varicella, adenovirus, SARS-CoV-2 (anti-S and anti-N antibodies)
	Culture	Blood: Adenovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, influenza viruses. Rectal Swab: Adenovirus, rotavirus, enteroviruses
	PCR	Blood: For hepatitis A, C, E, adenovirus, cytomegalovirus, enteroviruses, Epstein-Bar virus, Parechovirus, Herpes simplex virus, HHV 6 and 7. Throat Swab: Respiratory virus screening by multiplex assay (including Adenovirus, Influenza, Parainfluenza, Respiratory Syncytial Virus, Rhinovirus, Human bocavirus 1-3, Human metapneumovirus, Enteroviruses, SARS-CoV-2, etc.). Stool: For enteric viruses screening by multiplex assay (including Norovirus, Enteroviruses, Rotavirus, Astrovirus, Sapovirus)
Detecting bacterial causes of hepatitis	Serology	Antibodies against: Brucella spp., Bartonella henselae, Borrelia burgdorferi (when epidemiologically appropriate)
	Culture	Blood: Routine procedures for bacterial pathogens, when clinically applicable. Throat Swab: Streptococcus group A. Stool: Salmonella, Shigella, Campylobacter, E. coli 0157. Urine: Routine procedures for bacterial pathogens, when clinically applicable
	PCR	Stool or rectal swab: Enteric bacterial pathogens. Urine: Leptospira spp
Toxicological screening		Blood and urine by different methods, including mass spectrometry: Drugs (e.g., acetaminophen, antibiotics, antiepileptics, herbal medicines) or toxins (e.g., carbon tetrachloride)
Metabolic work-up		Ceruloplasmin; 24 h of urinary copper excretion; Celiac disease screening; Urine organic acid profile; Plasma amino acids; Plasma acylcarnitine; Whole exome and mitochondrial gene examination to rule out other inborn metabolic disorders that can cause liver injury; Other metabolic work-up according to the clinical scenario

ANA: Antinuclear antibody; CT: Computerized tomography; HIV: Human immunodeficiency virus; HHV: Human herpesvirus; PCR: Polymerase chain reaction; SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; SMA: Smooth muscle antibody; WHO: World Health Organization.