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AWARD PAPERS IAPSCON
Year : 2023  |  Volume : 28  |  Issue : 1  |  Page : 5-8
 

Effect of cytomegalovirus infection on initial presentation and overall prognosis of biliary atresia patients


Department of Pediatric Surgery, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Date of Submission08-Jul-2022
Date of Decision24-Aug-2022
Date of Acceptance12-Sep-2022
Date of Web Publication10-Jan-2023

Correspondence Address:
Kirtikumar J Rathod
Department of Pediatric Surgery, All India Institute of Medical Sciences, Basni Phase 2 Industrial Area, Jodhpur - 342 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaps.jiaps_92_22

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   Abstract 


Background and Aim: Biliary atresia is known to have a multifactorial etiology and perinatal infection with hepatotropic viruses such as cytomegalovirus (CMV) is a probable trigger in a subset of patients. The aim of the current study is to evaluate the effects of CMV association of biliary atresia on the initial presentation of patients and their response to Kasai portoenterostomy.
Patients and Methods: We conducted a retrospective, single-center study on 20 patients of biliary atresia and classified them into two groups based on their CMV immunoglobulin M (IgM) positivity. We compared the age of initial presentation, the liver biochemistry at presentation, immediate and delayed follow-up, rate of jaundice clearance following Kasai portoenterostomy, and histopathology of liver between the two groups. Data were reported in terms of means, and P < 0.05 was considered significant.
Results: Out of 20 cases of biliary atresia, 60% (n = 12) were CMV IgM positive. Infants with CMV-positive status were noted to be older at presentation (88.5 days [65–150 days] vs. 83 days [45–160 days] P < 0.05) were more jaundiced at presentation (total bilirubin – 13.51 mg/dl [9.09–15.99 mg/dl] vs. 11.83 mg/dl [6.5–13.5 mg/dl] P < 0.05), had higher alkaline phosphatase (751.2 IU/L [387–1951 IU/L] vs. 621.75 IU/L [172–857 IU/L] P < 0.05), higher gamma-glutamyl transferase levels (505.58 IU/L [376–1127 IU/L] vs. 376.75 IU/L [186–624 IU/L] P < 0.05), and had higher incidence of splenomegaly. The rate of resolution of jaundice postKasai portoenterostomy was also evidently less in CMV-positive patients. Four out of 12 patients have bilirubin >2 mg/dl at a 6-month follow-up.
Conclusion: CMV-associated biliary atresia patients have delayed initial presentation and impaired jaundice clearance postKasai portoenterostomy. The role of antiviral therapy should be studied in this subset of patients.


Keywords: Biliary atresia, cytomegalovirus, prognosis


How to cite this article:
Vig A, Elhence P, Rathod KJ, Nayak S, Jadhav AS, Pathak M, Saxena R, Sinha A. Effect of cytomegalovirus infection on initial presentation and overall prognosis of biliary atresia patients. J Indian Assoc Pediatr Surg 2023;28:5-8

How to cite this URL:
Vig A, Elhence P, Rathod KJ, Nayak S, Jadhav AS, Pathak M, Saxena R, Sinha A. Effect of cytomegalovirus infection on initial presentation and overall prognosis of biliary atresia patients. J Indian Assoc Pediatr Surg [serial online] 2023 [cited 2023 Feb 1];28:5-8. Available from: https://www.jiaps.com/text.asp?2023/28/1/5/367394





   Introduction Top


Biliary atresia is characterized by progressive fibrosing and obliterative cholangiopathy of both intra- and extrahepatic biliary radicals.[1] Hepatotropic viruses such as cytomegalovirus (CMV) are assumed to be involved in the pathogenesis of this disease. According to current literature, 30%–40% of cases of biliary atresia have a positive association with CMV.[1] The causative role of CMV in the pathogenesis of biliary atresia is well accepted, but the prognostic role is still equivocal.[2] There is definite evidence of CMV association in murine models, however, human studies regarding this subject lack consistency.[3] Most of the studies are from Japan and China owing to the higher incidence of the disease in these regions and the literature from our subcontinent is limited to case reports or series. The aim of this study is to determine the role of CMV in patients with BA in terms of their presentation and prognosis postKasai portoenterostomy.


   Patients and Methods Top


We have reviewed a total of 20 cases of biliary atresia over the last 6 months at our institution and classified these infants into two groups based on their CMV immunoglobulin M (IgM)-positive status at presentation. We determined the CMV IgM-positive status using immunoenzymatic study in serum and urine samples of the affected infants. All infants underwent a thorough history taking and physical examination at presentation. Routine blood investigations such as liver function biochemistry, gamma-glutamyl transpeptidase levels, clotting profile, and complete blood counts were performed. Fasting and postprandial ultrasonography were performed to look for the status of gallbladder, liver echotexture, ascites, and splenomegaly. All babies were reviewed for the presence of any syndromic characteristics. According to the institute protocol, all cases of suspected biliary atresia underwent a hepatobiliary iminodiacetic acid scan and intraoperative cholangiography before proceeding for Kasai portoenterostomy. Portoenterostomy as well as wedge liver biopsy was performed by one of the five well-experienced surgeons at the institute. The liver biopsy was evaluated for fibrosis using Mason trichrome stain. Postoperatively, all patients received fat-soluble vitamin supplementation and ursodeoxycholic acid. Oral steroids were started after the stabilization of total leukocyte count and C-reactive protein.

Postoperatively, most patients were followed up with regular outpatient visits for a span of at least 6 months. On each visit, they were assessed for symptomatic improvement, the presence or absence of cholangitis episodes, clearing of jaundice, and age-appropriate weight gain.

Statistical analysis

Data were expressed as mean and median (with interquartile range). Categorical data were analyzed using Chi-square or Fischer exact test. Ordinal data were compared using nonparametric tests. All statistical analyses were performed using SPSS Version 23.0 (IBM Corp. Released 2015. Statistics for Windows, Version 23.0. Armonk, NY, USA, IBM Corp.)


   Results Top


During our study period (July 2021–June 2022), we included 20 patients of suspected biliary atresia. Out of these, 17 underwent Kasai portoenterostomy. The open procedure was performed for 16 cases, while the laparoscopic approach was adopted for 1 case. Three patients refused surgery and left against medical advice. The male-to-female ratio was 1:1. Out of 20 patients, 12 (60%) were CMV IgM positive at presentation. These babies were compared to the CMV IgM-negative group (n = 8, 40%). None of the patients had any features suggestive of congenital CMV infection such as microcephaly, generalized rashes, or chorioretinitis. Neither did any of the babies have any syndromic associations.

Age of development of symptoms

CMV-positive biliary atresia patients (mean: 88.5 days) presented later than CMV-negative cases (mean age – 83 days). The parent reported mean age of development of symptoms was 23 days (range: 7–30 days) in CMV-positive babies against 20 days (range: 3–45 days) in the latter group.

Liver biochemical analysis at presentation

On comparing the level of alkaline phosphatase (ALP) on presentation, a significant difference was noted-mean value of the study group was 751.2 IU/L as compared to the control group, in which it was 621.75 IU/L. This difference could also be appreciated in the more specific enzyme gamma-glutamyl transferase (GGT) the values of which were 505.58 IU/L versus 376.75 IU/L. The mean total and direct bilirubin values were also significantly higher in the study group (total bilirubin – 13.51 and direct bilirubin – 7.15) compared to the CMV-negative group (total bilirubin – 11.83 and direct bilirubin – 6.88) (P < 0.05).

Splenomegaly

Fifty-eight percent CMV-positive patients (n = 7) had splenomegaly, whereas only 12.5% of CMV-negative patients (n = 1) had enlarged spleen. Mean ultrasound measured spleen size was 7.5 cm (5.8–8.6 cm) in CMV-positive patients, whereas it was only 5.8 cm (5–6.4 cm) in CMV-negative patients; P < 0.005.

Immediate postoperative period

Fourteen patients required postoperative intensive care and six patients required blood transfusions postsurgery. The mean duration of abdominal drain placement was 9.2 days (range-2–27 days). No significant difference with respect to these parameters was noted in the two groups. One patient had repeated episodes of hematochezia in the postoperative period for which exploratory laparotomy was performed suspecting biliary-vascular fistula, however, none was found. One patient in the CMV-positive group died due to decompensated liver failure on the 7th postoperative day. The bilirubin levels of all eight patients in the CMV IgM-negative group were in declining trend in the immediate postoperative period and all these babies were noted to pass bilious stools at the time of discharge, as compared to the alternative group, in which only five patients were passing regular cholic stools at the time of discharge. However, no statistically significant difference was noted between the two groups in the immediate postoperative recovery period.

Cholangitis and signs of portal hypertension post Kasai portoenterostomy

No difference was noted in the rates of cholangitis between the two groups. Only one patient in the CMV-negative group had bile lake formation with microlithiasis and repeated episodes of cholangitis which was managed conservatively. The rates of development of new-onset ascites or variceal bleeding suggestive of worsening portal hypertension were similar in both groups (one in CMV-negative and two in the CMV-positive group).

Histopathological findings

The wedge liver biopsy sample was evaluated for degree of fibrosis after application of Masson's trichrome and Haematoxylin and Eosin stains. All patients in the CMV positive group and 3 patients in the CMV negative group had >Grade 2 fibrosis. Four patients in the CMV Positive group has worsened to the stage of Nodular cirrhosis. Thus, CMV positive Biliary atresia patients were noted to have higher grade of fibrosis at presentation. However, on correlation of the degree of fibrosis with the CMV positive status, the results did not prove to be statistically significant (P value – 0.50) [Image 1].



Resolution of jaundice

Six months after surgery, the mean total bilirubin values were also significantly lower in the CMV-negative group (0.96 mg/dl ± 0.66) as compared to the CMV-positive group (5.76 mg/dl ± 4.32). Moreover, there was a drastic discrepancy in the postoperative values of direct bilirubin. The mean direct bilirubin for the CMV-negative group was 0.47 mg/dl, whereas it was 3.42 mg/dl for the CMV-positive group. As per the definition of successful Kasai portoenterostomy (serum bilirubin at 6 months <2 mg/dl), all patients of the CMV-negative group fell under the category of successful Kasai. However, four of the CMV-positive babies had a total serum bilirubin value of >2 mg/dl at 6-month follow-up visit. One patient in the CMV-positive group died due to liver failure in the postoperative period. No significant difference was noted in the risk of cholangitis, developing features of portal hypertension such as ascites or bleeding manifestations in the two groups. Three patients in the CMV-positive group had ascites causing respiratory distress and decompensated liver failure at presentation. They refused for surgery and denied further treatment.


   Discussion Top


Hepatotropic virus-mediated damage has been implicated as a probable etiology for infantile cholestasis.[4] Numerous animal-based experimental studies have reported a cross-link between the immune response mounted by hepatotropic viruses and the progressive fibrosing and obliterative cholangitis noted in biliary atresia.[3] Davenport, in the year 2012, defined CMV-associated biliary atresia as a new subtype[1],[2] However, the clinical evidence of CMV association affecting the presentation and prognosis of biliary atresia infants is scarce. The data from the Indian subcontinent are limited to case reports and correspondence.[5]

The reported incidence of CMV association of biliary atresia in literature is 30%–40%, whereas it was 60% in our cohort. The mean age of presentation was 88 days in CMV-positive babies as compared to a mean of 83 days in CMV-negative babies, although this was statistically insignificant. Our results are similar to a study by Zani et al. where they reported a mean delay of 13 days in the presentation of CMV-positive biliary atresia, and attributed this to the postnatal acquisition of this infection.[2] Second, the levels of ALP and GGT at presentation were significantly higher than the noninfected infants. CMV inhabits in the hepatobiliary epithelium and this finding could be indicative of the greater degree of active inflammation and ongoing fibrosis in the biliary ductules.[3],[4] Five out of 12 patients of CMV-positive biliary atresia had gross ascites on the first presentation. Seven patients had splenomegaly on clinical examination and ultrasonography, indicative of impending liver decompensation and portal hypertension. These findings are suggestive that the CMV-positive infants are late presenters and their general condition is also worse than their seronegative counterparts. Similar results have been reported in literature where IgM-positive biliary atresia patients were reported to have higher bilirubin levels, raised liver enzymes, a higher APRi (AST-to-platelet ratio index) score, and more evident inflammation in liver biopsy as compared to the controls.[2]

No stark differences were noticed in the immediate postoperative recovery of patients from both groups. Conversely, on follow-up visits, the jaundice clearance was strikingly higher in the CMV-negative infants. Out of all the operated cases of biliary atresia, four patients had a serum bilirubin >2 mg/dl on the 6-month follow-up visit which corresponds to the failure of Kasai portoenterostomy. Interestingly, all of these patients belonged to the CMV-positive group. A study from China, conducted on 60 patients of biliary atresia reported CMV infection to be an independent risk factor of poor prognosis postKasai procedure.[6] Thus, it is evident that active CMV infection delays the jaundice clearance and recovery postKasai portoenterostomy. However, it is equally essential to assess the effect of CMV infection on native liver survival rate for which longer periods of follow-up are needed.

To prevent these detrimental effects of CMV infection in biliary atresia, few studies propose the administration of preoperative antiviral therapy in these patients. Mathur et al. reported that intravenous ganciclovir (6 mg/kg/dose twice a day) and followed by oral valacyclovir (16 mg/kg/dose twice a day for 3 weeks) in CMV IgM-positive biliary atresia patients have shown to improve postKasai jaundice clearance from 62% to 80%.[7] Back in 2014, Shah and Bhatnagar reported the use of ganciclovir in two cases of CMV-positive biliary atresia with significant liver damage. Although the treatment was started late, one of the patients had temporary jaundice clearance after starting ganciclovir.[8] Another publication by Parolini et al. studied a total of 36 patients of CMV-positive biliary atresia and divided them into two groups – the study group, who received antiviral therapy 5–7 days after Kasai procedure (n = 8) and the control group (n = 28) which did not receive it.[9] Nevertheless, this is an isolated experience in this regard and further evidence is indispensable to adopt this as a standard treatment.


   Conclusion Top


Association of biliary atresia with CMV infection leads to severe inflammation and aggravated hepatic fibrosis which adversely affects the initial presentation of patients and also hampers jaundice clearance postKasai portoenterostomy. Thus, the identification of CMV positivity is essential for risk stratification and prognosis prediction. Further studies are required to assess if adjuvant antiviral therapy has a role in reversing this damage and improving the overall prognosis of CMV-positive biliary atresia patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Zhao Y, Xu X, Liu G, Yang F, Zhan J. Prognosis of biliary atresia associated with cytomegalovirus: A meta-analysis. Front Pediatr 2021;9:710450.  Back to cited text no. 1
    
2.
Zani A, Quaglia A, Hadzic N, Zuckerman M, Davenport M. Cytomegalovirus-associated biliary atresia: An aetiological and prognostic subgroup. J Pediatr Surg 2015;50:1739-45.  Back to cited text no. 2
    
3.
Averbukh LD, Wu GY. Evidence for viral induction of biliary atresia: A review. J Clin Transl Hepatol 2018;6:410-9.  Back to cited text no. 3
    
4.
Rauschenfels S, Krassmann M, Al-Masri AN, Verhagen W, Leonhardt J, Kuebler JF, et al. Incidence of hepatotropic viruses in biliary atresia. Eur J Pediatr 2009;168:469-76.  Back to cited text no. 4
    
5.
Shah I, Bhatnagar S. Biliary atresia and cytomegalovirus and response to valganciclovir. Indian Pediatr 2012;49:484-6.  Back to cited text no. 5
    
6.
Shen C, Zheng S, Wang W, Xiao XM. Relationship between prognosis of biliary atresia and infection of cytomegalovirus. World J Pediatr 2008;4:123-6.  Back to cited text no. 6
    
7.
Mathur P, Udawat P, Mathur P, Ramrakhiani D, Mathur SK, Sitaraman S, et al. Antiviral therapy in cytomegalovirus-associated biliary atresia. Indian J Pediatr 2022;89:732.  Back to cited text no. 7
    
8.
Shah I, Bhatnagar S. Biliary atresia with cytomegalovirus infection and its response to ganciclovir. Trop Gastroenterol 2014;35:56-8.  Back to cited text no. 8
    
9.
Parolini F, Hadzic N, Davenport M. Adjuvant therapy of cytomegalovirus IgM + ve associated biliary atresia: Prima facie evidence of effect. J Pediatr Surg 2019;54:1941-5.  Back to cited text no. 9
    




 

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