Fatal fulminant herpes simplex hepatitis following surgery in an adult

Table 1 Reported cases of herpes simplex virus hepatitis in patients underwent non-transplant surgical procedures

No. authors (year), (reference)	Age (yr), sex/ races or nationality	Surgical procedures (diseases)/transmission pathway	Manifestation (days after surgery )/herpetiform lesions	Laboratory data Leucocytes (/mm3), Platelets (× 104/mm3), AST/ALT (U/L), TB (mg/dL). Coagulopathy, encephalopathy	HSV serology (IgM/ IgG), HSV type, HSV PCR	Ante-mortem diagnosis/ methods	Treatment/outcome (survival time after surgery, time after onset of liver dysfunction)
1.Douglas (1977)[33]	17, M/ United States	Splenectomy, liver biopsy, Ln excision (remission of Hodgekin’s disease)/ND	Fever (day 3), vomiting and diarrhea (day 4), liver dysfunction (day 5)/ none	ND, ND, 8700/ND, ND	ND/ND, ND, ND	No/ autopsy	Supportive/died (11 d, 6 d)
2. Marrie (1982)[34],	28, M/ white, Canada	Drainage, steroids (Brain stem injury)/ ND	Fever(12 HD)/ tongue, palate (20HD, 6 pod)	ND, ND, 9000/7000, ND. Encepahopathy	ND/ND, HSV-1, ND	No/liver biopsy	Spontaneously improved
3. Williams (1985)[35]	57, M/ United States	Aorto-coronary bypass, PSL (postcardiotomy syndrome)/esophagitis	Nausea, weakness, epigastric discomfort, liver dysfunction (day 8)/ none	ND, ND, 10050/4905, ND. Coagulopathy	ND/ND, HSV, ND	No/ autopsy	Supportive/died (10 d, 2 d)
4. Fisher (1985)[36]	62, M/ United States	Transperitoneal ureteroithotomy and cholecystectomy (ureteral obstruction and cholelithiasis)/ ND	Fever (day 3), vomiting (day 6), diarrhea (day 9), liver dysfunction (day 9)/ none	5600, 8.1, > 500/ND, 1.2, Coagulopathy, Encephalopathy	ND/ND, HSV-1, ND	No/ autopsy	Supportive/died (14 d, 5 d)
5-7, Goodman (1986)[8]	81, F/ United States	Gastrectomy (stomach cancer)/ ND	Fever (day 8)/ ND	ND	ND/ND, ND, ND	No/ autopsy	Supportive/died (ND, 6 d)
	93, F/ United States	Biliary bypass (bile duct cancer)/ ND	ND/ ND	ND	ND/ND, ND, ND	No/ autopsy	Supportive/died (ND, 16 d)
	59, M/ United States	PD (bile duct cancer ) stormy course /ND	ND/ ND	ND	ND/ND, ND, ND	No/ autopsy	Supportive/died (ND, 30 d)2
8. Katz (1994)[37]	76, M/ United States	Hemimandibulectomy, radical neck, and tracheotomy (plasmacytoma)/ND	Fever (day 6), diarrhea (day 9), liver dysfunction (day 11)/ none	10100, ND, 7460/2970, ND. Coagulopathy, Encephalopathy	ND/ND, ND, ND	No/ autopsy	Supportive/died (15 d, 4 d)
9. Kaufman (1997)[38]	66, M/ United States	Tumor excision, intraoperative PSL (menigioma)/ ND	Fever (day 14), liver dysfunction (day 20), lethargic (day 20)/ mo	4800, 2, 10340/ND, 1.9. Coagulopathy, Encephalopathy	ND/ND, HSV-1, ND	No/autopsy	Supportive/died (21 d, 1 d)
10. Price (2001)[39]	Nulliparous/ United States	Laparoscopy, hysteroscopy (tubal infertility)/genital tract	Fever, nausea, abd pain, vaginal burning (day 3) /none	900, ND, ND/ND, ND. Coagulopathy	-/-, HSV-1, ND	No/autopsy	Supportive/died (9 days, 6 d)
11. Kohno (2001)[40]	58, M/ Japanese	Craniotomy (hypertensive cerebral hemorrhage)/ ND	Liver dysfunction (day 7)/none	11100, 9.3, 10956/5327, 3.5. Coagulopathy, Encephalopathy	ND/ND, HSV-2, ND	No/autopsy	Supportive/died (16 d, 9 d)
12. Ichai (2005)[20]	15 F/ France	Craniotomy (brain tumor) , PSL/ ND	Fever (day 9), Liver dysfunction (day 12)/ none	9000, ND, 5000/ 4500, ND	+/+, HSV-2, PCR positive	Yes/serology, explanted liver culture	LT/ died (CR l yr)
13. Biancofiore (2007)[41]	25, M/ Italy	Thymectomy (myasthenia gravis)/ND	Fever (day 2), liver dysfunction (day 10)/	7820, 3.8, 15000/6818, 2.1. Encephalopathy	-/-, HSV-1, PCR positive	Yes/PCR (urine, blood, cerebrospinal fluid)	ACV (day 10) , LT (d 12)/died (12 d, 9 d after LT)
14. Chaudhary (2017)[42]	48 F/ Hispanic, United States	Repair of vaginal cuff (Vaginal cuff dehiscence/ trans-vaginal	liver dysfunction (day 1)/ vaginal ulcers	ND, ND, 20692/63, 8.5. Encephalopathy	+/-, HSV-2, PCR (serum, cerebrospinal fuid)	Yes/ vaginal ulcers, serology, PCR	ACV (day 4), foscarnet (day 10)/ survived
15. Present case	72, M/ Japanese	cholecystectomy and choledocholithotomy (biliary stone)/ ND	Fever (day 5), diarrhea (day 5), liver dysfunction (day 5)/ none	1200, 4.3, 6557/2039, 2.0. Coagulopathy, Encephalopathy	-/-, HSV-1, ND	No/ autopsyr	ACV (day 8)/died (9 d, 4 d)
Summary	58 yr (15-93)/Male (n = 8), United States (n = 10), Japan (n = 2), Canada (n = 1), France (n = 1), Italy (n = 1)	Malignancy (n = 5), benign (n = 10), Immunosuppressive status or treatment (n = 5)/ surgical wound (n = 2), trans-esophagus (n = 1)	Fever: (n = 15), day 4.5 (day 1-14), Digestive symptoms (n = 6): day 7 (day 4-9), Liver dysfunction (n = 15) day 8.5 (day 1-20)/ Herpetiform lesions: present (3/11 cases)	Leukocytes: 3.905 (900-10100), Plts: 4.3 (2-8.1), AST/ALT: 10.340 (5000-20692)/5116 (2970-7000), TB: 2.1 (2-8.5). Coagulopathy (n = 8), Encephalopathy (n = 7)	IgM +/- (2/3 cases)/ IgG +/- (1/4 cases), HSV: type-1(n = 5), type-2 (n = 3), PCR (n = 3)	Yes/no: 3/12 cases, Autopsy (n = 12), biopsy (n = 1), PCR (n = 3), serology (n = 1),	Supportive (n = 10), ACV (n = 3), LT (n = 2)/ Outcome: survived (n = 2), died (n = 13), Survival time1 after surgery: 13 (6-30) d, Survival time after liver dysfunction: 5.5 (1-9) d

The continuous data were expressed as median values (minimum-maximum values).

¹Survival time: Data were excluded those of surviving patients;

²The patient was co-infected with multiple agents; bacteria and fungi in the abdominal abscess, cytomegalovirus in the pancreas and lungs, and HSV in the lung and liver. Abd: Abdominal; ACV: Acyclovir; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CR: Chronic rejection; HD: Hospital day; HSV: Herpes simplex virus; Ln: Lymph node; LT: Liver transplantation; ND: Not determined or described; PCR: Polymerase chain reaction; POD: Postoperative days; PSL: Predonisolone; TB: Total bilirubin.

Table 2 Clinico-laboratory findings of herpetic hepatitis in postsurgical and non-surgical immunocompetent patients

	Postsurgical patients (n = 15)	Non-surgical patients (n = 42)	P value
Gender (M/F) (n)	8/7	18/24	0.454
Age (yr)	58 (15-93) (n = 15)	44 (15-87) (n = 43)	0.060
Clinical manifestation
(present/absent or ND)
Fever (n)	14/1	42/0	0.263
Nausea, vomiting, diarrhea (n)	6/9 (17.5%)	10/32 (23.8%)	0.312
Herpetic lesion present/none (n)	3/8 (27.3%)	20/19 (51.2%)	0.308
Transmission route
Identified or suspected (n)	3 (20%)	10 (23.8%)	0.535
	Surgical wounds (Trans-genital tracts) (n = 2)	Sexually (n = 6)
	Tran-esophagus (n = 1)	Percutaneous (n = 1)
		Trans-esophagus (n = 2)
		Trans-rectum (n = 1)
Leukocyte count (/mm3)	3905 (900-10100) (n = 14)	2600 (1000-7300) (n = 39)	0.152
AST (U/L)	10,340 (5000-20692) (n = 10)	5664 (92-18937) (n = 39)	0.006
ALT	5116 (2970-7000) (n = 8)	3248 (141-13980) (n = 29)	0.048
Total bilirubin (mg/dL)	2.1 (2-8.5) (n = 6)	4.4 (0.1-35) (n = 25)	0.154
Serology
positive/negative (n)	2/3 (40%)	14/12 (53.8%)	0.654
PCR analyzed (yes/no) (n)	3/12 (20%)	5/39 (8.4%)	0.407
HSV type (1/2/1 and 2) (n)	5/3/0	14/14/3	1.0
Ante-mortem diagnosis
yes/no (n)	3/12 (20%)	24/18 (57.1%)	0.017
ACV treatment
Yes/ no (n)	3/12 (20%)	21 / 21 (50%)	0.041
Liver transplantation
Yes/no (n)	2/13	6/38	1.0
Outcome
Survived/ died (overall) (n)	2/13 (13.3%)	12/30 (28.6%)	0.312
Survival time12 (d)	13 (6-30) (n = 12)	10 (5-29) (n = 26)	0.729
Survival time2 after liver dysfunction emerged (d)	5.5 (1-9) (n = 11)	5 (1-16)) (n = 18)	0.821

Continuous data were presented as median with range from minimum and maximum values. For categorical variables and continuous measures, differences were compared using Fisher’s exact test or χ² test, and the Mann-Whitney U test, respectively.

¹Survival time: were expressed as the days after surgery or symptoms emerging;

²Survival time: Data were excluded from the surviving patients. ACV: Acyclovir; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HSV: Herpes simplex virus; LT: Liver transplantation; PCR: Polymerase chain reaction.

Table 3 Clinical features of herpetic hepatitis in surgical and non-surgical immunocompetent patients before 1985 and after 1986 (acyclovir era)

	Postsurgical patients (n = 15)	Non-surgical patients (n = 42)	P value (Postsurgical vs Non-surgical)
Ante-mortem diagnosis
Yes/ no (before 1985) (n)	0/4 (0%)	3/6 (33.3%)	0.497
Yes/ no (since 1986) (n)
	3/8 (27.3%)	21/12 (63.4%)	0.040
P values
(before1985 vs since 1986)
	0.363	0.166
ACV treatment
Yes/ no (before 1985) (n)	0/4 (0%)	0/9 (0%)	1.0
Yes/ no (since 1986) (n )
	3/8 (27.3%)	21/12 (63.4%)	0.040
P values
(before1985 vs since 1986)
	0.363	0.013
Outcome
Survived/ died (before 1985) (n)	1/3 (25%)	0/9 (0%)	0.308
Survived/ died (since 1986) (n)
	1/10 (9.2%)	12/21 (36.4%)	0.086
P values
(before1985 vs since 1986)
	0.476	0.0321
Timing of ACV treatment1	8 (4-10) (n = 3)	10 (6-15) (n = 16)	0.365
Outcome after ACV treatment
Survived/ died	1/3 (25%)	12/9 (57%)	0.322

Continuous data were presented as median with range from minimum and maximum values. For categorical variables and continuous measures, differences were compared using Fisher’s exact test or χ² test and the Mann-Whitney U test, respectively.

¹Timing of ACV treatment: Data were expressed as the days after liver dysfunction emerged. ACV: Acyclovir.