Echovirus Hepatic Failure in Infancy:Report of Four Cases with Speculation onthe PathogenesisJIANZHOU WANG,1,2 ROBERT W. ATCHISON,1,2 JANET WALPUSK,1,2 ANDRONALD JAFFE1,2*1Department of Pathology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213-2583, USA2Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
Received June 26, 2000; accepted February 22, 2001.
ABSTRACTDisseminated echovirus infection with fulminant he-patic failure occurs almost exclusively in newborns. Al-though a relatively uncommon condition, it is on occa-sion associated with neonatal death accompanied bydiffuse and extensive hemorrhagic necrosis of the liverand adrenals as the defining finding. We report fourcases of severe systemic neonatal echovirus infectionand present histologic and clinical evidence to demon-strate the two histologic patterns of liver involvement;intravascular coagulation in the early clinical course anda veno-occlusive component in later stages of the dis-ease. Viral damage to vascular endothelium and hepaticvenous endothelium by a “hit-and-run” process in theearly viremic phase rather than direct hepatocyte injuryis postulated to be a mechanism.
INTRODUCTIONThe human enteroviruses represent a family ofsmall, single-stranded RNA viruses that includepoliomyelitis viruses, coxsackieviruses A and B,and the echoviruses. Enteroviruses are known forcausing a wide spectrum of infections in adultsand in the pediatric population, especially in late
summer and fall, ranging from benign nonspecificfebrile illness, aseptic meningitis, or cardiomyop-athies to a life-threatening disseminated infection[1–3]. Severe disseminated enterovirus infection ismost commonly associated with echoviruses andoccurs almost exclusively in neonates [3–7]. Theclinical course is an initial nonspecific illness thatcan rapidly progress to a generalized multisysteminfection characterized by disseminated intravas-cular coagulation (DIC) and seizures. Jaundice,hepatosplenomegaly, and progressive hepatic fail-ure are invariably present at late stages of the dis-ease, and massive hemorrhagic hepatic and adre-nal necrosis is the usual pathologic finding inpostmortem examination in all reported cases[3,6,8–12].
We report four instances of severe systemicenteroviral infection and present histopathologic,electron microscopic, and molecular findings ofliver at early and late stages of the disease. Wedemonstrate that the hemorrhagic nature of liverinvolvement in the early phase of enteroviral sepsisis associated with DIC, while a veno-occlusivecomponent is the dominant picture in those pa-tients who have more prolonged survival. Viral-induced damage, direct or indirect, to hepatic ve-nous endothelium is postulated to be anunderlying mechanism.
*Corresponding author, at Department of Pathology, Children’sHospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213.
Pediatric and Developmental Pathology 4, 454–460, 2001
CLINICAL HISTORIESThe Human Rights Committee of Children’s Hos-pital exempted this protocol from review.
Case 1The patient was a male infant born to a 36-year-old mother by vaginal delivery at 37 weeks ofgestation, complicated by chorioamnionitis. Hisweight was 2860 g and Apgar scores were 8 and9. A septic work-up was negative. Five days afterbirth, the infant was admitted for irritability,poor feeding, and an apneic episode. On arrival,he was noted to be hypothermic and developedhypotension, ascites, and fulminant DIC, pre-sumed to be due to sepsis. Laboratory studiesshowed severe anemia, metabolic acidosis,markedly prolonged partial thromboplastin (PT)and activated partial thromboplastin time(aPTT), and abnormal liver function tests, withaspartate aminotransferase (AST) of 3242 IU/li-ter, alanine aminotransferase (ALT) of 3240 IU/liter ammonia of 393 mg/dl, and total bilirubin of5.7 mg/dl. No hepatosplenomegaly was noted.Ultrasound examination of the head showedgrade III intraventricular hemorrhage on day 7after birth; the patient died at 8 days. Reversetranscription–polymerase chain reaction (RT-PCR) analysis was performed as described, onpostmortem liver tissue [13]; and enteroviral ge-nome was detected (Fig. 1). Viral cultures per-formed on autopsy liver and lung tissue grew anenterovirus serotyped as echovirus type 11.
Case 2The patient was a male infant born to a 20-year-oldgravida 1 mother at 34 weeks of gestation, compli-cated by premature labor at 34 weeks and failedtocolysis. Four days after birth, the infant pre-sented with lethargy, poor feeding, and hypother-mia. Laboratory studies showed markedly pro-longed PT and aPTT, anemia, and severe metabolicacidosis. Bacterial cultures and viral culture forcytomegalovirus (CMV) were negative. Over thenext 4 days, the infant developed hypotension, re-nal failure, gastrointestinal bleeding, ascites, andgrade II–III intraventricular hemorrhage. Nohepatosplenomegaly was noted. The infant died9 days after birth. Viral cultures performed onpostmortem blood, liver, spleen, and lung tissue
demonstrated an enterovirus serotyped as echo-virus type 5.
Case 3The patient was a male infant born to a 26-year oldgravida 2, para 2 by vaginal delivery at 39 weeks ofgestation. During labor, the mother was found tohave a temperature of 101°F. The infant weighed3600 g and Apgar scores were 2 and 9 at 1 and 5min. The infant developed a “blue spell” in thenewborn nursery, and had a work-up for sepsis,with negative bacterial cultures. He developed pro-gressive hepatomegaly and tonic–clonic seizureover the next 3 days, and an ultrasound examina-tion revealed ascites on day 8 after birth. Clinicallaboratory findings showed thrombocytopenia,and prolonged PT and aPTT, and were marked byelevated hepatocellular enzymes, with an AST levelof 80,000 IU/liter and ALT of 75,000 IU/liter. Pe-ripheral blood smears showed schistocytes andcross-linked fibrin degradation products were 4-8mg/liter. Over the next 8 days, the infant becamejaundiced and increasingly lethargic. A computedtomography (CT) scan showed no cerebral abnor-malities. His liver enzyme levels decreased dramat-ically—AST to 46 IU/liter and ALT to 33 IU/liter,but total bilirubin and ammonia levels began torise to 17.4 mg/dl and 244 mg/dl, respectively, on
Figure 1. Reverse transcription–polymerase chain reac-tion (RT-PCR) analysis for enteroviral genome. Total RNAwas extracted from fresh liver tissue (cases 1, 3, and 4)and echovirus 11–infected primary rhesus kidney cell cul-tures (positive control), and RT-PCR was performed forenteroviral (EV) genome and b-actin (b-Ac) mRNA as aninternal control. The band representing enteroviral ge-nome was present in enterovirus-infected primary cellcultures and case 1, but not in cases 3 and 4, while b-actinPCR product was seen in all cases.
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day 15 after birth. Viral cultures for CMV, PCR forherpes simplex virus (HSV), and serological stud-ies for HSV, rubella, and toxoplasma were nega-tive. Viral cultures of blood, urine, and stool dem-onstrated an enterovirus serotyped as echovirustype 11. An open liver biopsy on day 27 after birthshowed extensive centrolobular necrosis involvingapproximately 70% of the tissue sampled. Viralculture of liver tissue was negative, and PCR anal-ysis was negative for enteroviral genome (Fig. 1).The baby subsequently underwent living-relatedorthotopic liver transplantation, which failed be-cause of occlusion of the arterial anastomosis, butreceived a second unrelated liver and was dis-charged 4 weeks later in good condition.
Case 4The patient was a male infant born to 19-year-oldgravida 2, para 1 by vaginal delivery at 39 weeks ofgestation. His body weight was 4200 g with Apgarscores of 9 and 10. Five days after birth, the infantpresented to a local hospital with lethargy, poorfeeding, and irritability. A work-up for sepsis thatincluded cultures for bacteria, CMV, and HSV wasnegative. Clinical laboratory findings of note in-cluded a thrombocytopenia, markedly elevatedhepatocellular enzyme levels, with ALT of 1849IU/liter and AST of 2045 IU/liter, and significantlyprolonged PT and aPTT. Over the next 6 days, theinfant became jaundiced and increasingly lethar-gic with hepatosplenomegaly and ascites. Viral cul-tures of blood, urine, and stool showed cytopathiceffects consistent with an enterovirus that waslater serotyped as echovirus type 11. By day 14after birth, total bilirubin rose from 2.6 mg/dl to26.2 mg/dl, hepatocellular enzyme levels decreasedmarkedly to ALT of 157 IU/liter and AST of 117IU/liter, and the ammonia level increased to 246mg/dl. A CT scan showed no evidence of intracra-nial bleeding. An open liver biopsy on day 25 afterbirth showed extensive centrolobular necrosis in-volving approximately 60% of the tissue sampled.Viral culture of the liver tissue was negative, andPCR analysis was negative for enteroviral genome(Fig. 1). The patient subsequently underwent suc-cessful living-related orthotopic liver transplanta-tion, and was discharged 3 weeks later in stablecondition.
PATHOLOGIC FINDINGSCases 1 and 2Autopsy findings from the postmortem examina-tion were remarkably similar in both cases, withenlarged hemorrhagic livers and adrenal glands,severe intraventricular hemorrhage, and otherfindings associated with DIC (Fig. 2A). The livershad diffuse, extensive sinusoidal congestion, hem-orrhage, and hepatocellular necrosis with slightaccentuation in zones II and III. Focal dystrophiccalcification and large areas of hemorrhagic infarc-tion were also present. Fibrin thrombi were seen inportal veins, central veins, and arteries of varyingcaliber with diffuse endothelial swelling, activa-tion, and necrosis (Fig. 2B). Fibrinoid necrosis andsubendothelial infiltration of eosinophils andmononuclear cells with nuclear debris were seen insome of the medium-sized hepatic arteries andsublobular veins (Fig. 2C,D). Extramedullary he-matopoiesis was present and the biliary tree wasuninvolved. There was little lobular inflammationand no viral inclusion. Trichome and reticulinstains showed an occasional central and sublobu-lar vein that contained a subintimal proliferationof loose fibrous tissue and reticulin fibers. Electronmicroscopic examination performed on liver tissuefrom case 1, hampered by the presence of extensivenecrosis, showed viral-like particles within rare,partially degenerated spindle-shaped cells adjacentto a central vein (Fig. 3). No evidence of viral-typeparticles was identified in hepatocytes or sinusoi-dal endothelial cells on this specimen.
Cases 3 and 4Biopsies at postpartum days 27 and 25 and hepa-tectomy specimens at postpartum days 29 and 27showed the resected livers to be red–tan with anirregular, finely granular capsular surface. Theweights and sizes of livers were within normallimits for age. The hepatic veins were identifiedand were patent. Portal veins and hepatic arteriesat the hilus were patent and the gallbladder wasunremarkable. Cut section of the livers showed afinely granular, dark red and hemorrhagic paren-chyma, speckled with islands of green, viable livertissue. The larger portal tracts were unremarkableand the major branches of hepatic veins were notobstructed. The lobular architecture was collapsed
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with diffuse and extensive centrilobular hemor-rhage, necrosis, and foci of dystrophic calcificationinvolving zone II and III hepatocytes (Fig. 2E). Theportal tracts had mild ductular proliferation withintact bile ducts, patent arteries, dilated veins, anda minimal mononuclear infiltrate (Fig. 2F). At theinterface of the viable hepatocytes and the zones ofhemorrhagic necrosis, moderate extramedullaryhematopoiesis was noted. The viable periportalhepatocytes were ballooned and there was markedhepatocellular and canalicular cholestasis. No viralinclusions, lobular inflammation, or vasculitis wasidentified. Trichrome and reticulin stains high-lighted central and sublobular veins marked con-centric/eccentric luminal narrowing or even com-
plete occlusion by a subintimal proliferation ofloose fibrous tissue and reticulin fibers with mac-rophages and entrapped red blood cells (Fig.2G,H). Electron microscopic examination showedno evidence of viral particles.
DISCUSSIONEnteroviral infections can occur in all age-groups,but they occur most frequently in neonates, typi-cally in the summer and fall [1,5,7]. Although theexact mechanism for this marked neonatal suscep-tibility is not known, it may be due at least in partto the naive immune system of the newborn. Po-tentially fatal systemic enteroviral infections occuralmost exclusively in early infancy, and the echo-
Figure 2. A–D: Autopsy liversections in case 1 showed hem-orrhagic central lobular necrosis(A, 325). Portal veins and arter-ies showed fibrin thrombi andreactive endothelial cells (B,3400). Fibrinoid necrosis andsubendothelial infiltration ofeosinophils and mononuclearcells with nuclear debris wereseen in some of the medium-sized sublobular veins (C, 3200)and hepatic arteries (D, 3480).E–H: Liver sections in case 3showed hemorrhagic centrallobular necrosis (E, 325). Portalveins, arteries, and bile ductsappeared intact (F, 3100). Ontrichrome and reticulin stains,the central veins and sublobularveins showed marked reductionto complete occlusion of lumi-nal space by a subintimal prolif-eration of loose fibrous tissueand reticulin fibers with macro-phages and entrapped redblood cells (G, 3250 and H,3250).
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viruses have generally been implicated. The echo-viruses have 31 genetically distinct serotypes. Al-though it is not known whether all types ofechoviruses can cause human diseases, severe neo-natal disseminated infections with fulminant liverdisease have been linked to echovirus types 6, 7, 9,10, 11, 12, 14, 19, and 20, and Coxsackievirus B5[1,5–12,14–17]. The clinical course and outcomemay vary depending on the type of echovirus; no-tably, echovirus type 11 is the most commonlymentioned serotype in fatal neonatal infections[1,3,9,12]. Transmission of the virus may occur inutero, at delivery, or postnatally through directcontact. Cases of intrauterine fetal death due toechovirus types 11, 20, 33, and 37 have been re-ported, with isolation of the virus from both pla-cental and fetal tissue in some [12,18–20]. Thedominant pathologic findings are diffuse extensivecentrilobular hemorrhagic necrosis and other find-ings are suggestive of DIC [6,11,18].
In this report, we describe four cases ofsevere disseminated neonatal echovirus infec-tion: three cases due to echovirus type 11, andone due to echovirus type 5. Cases 1 and 2 re-sulted in death relatively early in the course ofthe disease, while in cases 3 and 4, both infantssurvived following stabilization and liver trans-plantation. The first two infants died from liverfailure and DIC; the other two survived the acutephase, but developed progressive hepatic failure
with ascites and splenomegaly, subsequently re-quiring liver transplantation.
Examination of the livers at autopsy and theexplanted native livers showed two histopathologicpatterns in a background of diffuse, extensive,hemorrhagic necrosis with minimal inflammation.The first pattern was that of ongoing endothelialinjury, seen in the autopsied livers from cases 1and 2. Findings in these livers included focal dys-trophic calcifications, large areas of hemorrhagicinfarction, and numerous fibrin thrombi in portalveins, central veins, and arteries of varying caliber.In addition, the medium-sized hepatic arteries andsublobular veins showed evidence of a diffuse ac-tive endothelial injury, with endotheliitis and fi-brinoid necrosis. The second and later pattern wasthat that of veno-occlusive disease seen in the ex-planted livers from cases 3 and 4. In these cases,the architecture of the centrilobular region wasalso obscured by extensive hemorrhage. Interest-ingly, on trichrome and reticulin stains, the centralveins and sublobular veins showed marked lumi-nal narrowing, often with complete occlusion by asubintimal proliferation of loose fibrous tissue andreticulin fibers admixed with macrophages and en-trapped red blood cells. No evidence of thrombo-sis, fibrin thrombi, endotheliitis, or fibrinoid ne-crosis was present in the portal blood vessels, incontrast to the findings in the cases 1 and 2. On thebasis of the spectrum of vascular injury demon-
Figure 3. Electron micrograph ofpartially degenerated perivenularspindle-shaped cells from case 1(36200). An array of viral-like par-ticles was identified within thecytoplasm of the spindle-shapedcell, indicated by the arrow (inset,3105,000). Viral cores measured14–16 nm and the virions 28–30nm, confirmed on interparticledistance in the crystalline areas.CV, central vein.
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strated by these four cases, and the centrilobularhemorrhagic necrosis described in other reportedcases [6], we speculate that echoviral-related ful-minant hepatic failure in early infancy may havean underlying virally mediated endothelial mecha-nism of injury. The early viral insult to hepaticvascular endothelial cells could result in a subse-quent veno-occlusive disease, as illustrated in cases3 and 4.
Cytoplasmic and nuclear virus-like particlesin hepatocytes have been detected by means ofelectron microscopy in only rare reported casesof severe disseminated enterovirus infection[6,11,18,21]. The intranuclear virus-like particlesreported by Mostoufizadeh et al. [6] had irregularoutline and variable size, measuring up to 57 nm.Since Picornaviruses, as virions, are found only inthe cytoplasm, we interpret the putative nuclearparticles in their published figures to be nuclearaccumulation of glycogen, in a nonaggregated ormonoparticulate form. The report of Hughes et al.[11] also claims to demonstrate viral particles;their Figure 3 shows a hepatocyte, but the nuclearstructures said to measure 18–28 mm are too ir-regular in outline to be viral cores. Garcia et al.[18] provided only one picture of a purported he-patocyte; the illustrated features do not indicatethat this is a hepatocyte and not some other livercell. Phillips and colleagues [21] described “full andempty capsids” in the nuclei of infected hepatocytes,(Fig. V18b), but the accompanying illustration showsonly a portion of a nucleus, not recognizable hepa-tocyte cytoplasm, and the particulate aggregates areirregular in size and shape, measuring 23.3–46.5mm, and are most likely glycogen. Thus the pub-lished record to date is not convincing on the issue ofenterovirus particles in human hepatocytes. In ourcase 1, virus-like particles were identified within rare,partially degenerated spindle-shaped cells adjacentto a central vein lumen. These cells probably repre-sent perithelial or dendritic cells adjacent to a centralvein. Although the exact identity of these spindle-shaped cells could not be established by electronmicroscopy, this observation serves as evidence thatthe virus can infect cells other than hepatocytes.
The results of viral culture and molecularstudies suggest that echovirus may cause diffuseendothelial injury by a “hit-and-run” process in theearly viremic phase of infection. In cases 1 and 2,
all viral cultures were positive at days 8 and 9 afterbirth, and RT-PCR analysis of fresh liver tissue incase 1 was positive for the enteroviral genome.
Unfortunately, no fresh liver tissue wasavailable for RT-PCR study for case 2. In cases 3and 4, the virus was isolated only in the earlycourse of the infection at days 6 and 7, whilerepeated viral cultures on blood and urine werenegative at days 16 and 18. RT-PCR analysis offresh liver tissue obtained from the subsequentexplanted hepatectomy specimens at days 27 and29 was also negative for the viral genome. Inaddition, review of subsequent needle-core biop-sies from allografted livers of cases 3 and 4showed no recurrence of the pathologic findingsdescribed in the native organs. This temporalsequence, therefore, supports the hypothesis of ahit-and-run behavior of this enterovirus.
In the past decade, several potential receptorproteins have been implicated in echoviral attach-ment, such as decay-accelerating factor (DAF) andhuman very late antigen 2 (VLA-2) [22–27]: Thecellular expression of many of the potential viralreceptors is strongly influenced by the actions ofinflammatory mediators. It has been shown thatthe expression of DAF can be significantly up-reg-ulated by tumor necrosis factor alpha (TNF-a), anddown-regulated by plasminogen activator inhibitor2 (PAI-2) [28–30]: The presence of viral receptorproteins on the endothelial surface could play acrucial role in our proposed viral-mediated mech-anism of endothelial injury. Alternatively, Kupffercells may act as the source of the proinflammatorycytokines resulting in liver damage [31]. Furtherstudies of the expression of potential cellular re-ceptor proteins by hepatic venous endothelium,the profiles of cytokines and growth factors, andpotential influence of the presence of extramedul-lary hematopoiesis in neonatal livers may shedlight on the mechanism of vascular endothelialdamage caused by echovirus infection.
In summary, we report four cases of severeneonatal disseminated echovirus infection due totypes 11 (three cases) and type 5 (one case) thatpresented with progressive fulminant hepatic fail-ure and DIC. Two infants were successfully treatedwith orthotopic liver transplantation. Histologi-cally, livers examined early at autopsy (postpartumdays 8 and 9) showed diffuse hemorrhagic necrosis
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and ongoing endothelial injury characterized byfibrin thrombi, fibrinoid necrosis, and endotheliitisof hepatic arteries and veins. In two patients whoreceived orthotopic liver transplantation, the ex-planted native livers were seen later (postpartumdays 27 and 29), and had extensive centrilobularhemorrhagic necrosis with marked fibrous nar-rowing or occlusion of the hepatic venous system.We suggest that echoviral-related fulminant he-patic failure may be the result of echovirus-medi-ated endothelial injury by a hit-and-run process inthe early viremic phase, which in the setting ofprolonged survival, may result in a veno-occlusivephase.
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