PRACA POGLĄDOWA

REVIEW ARTICLE

METHODS OF TRANSMISSION AND FEATURES OF THE COURSE OF HEPATITIS C VIRUS INFECTION IN CHILDREN: MEDICAL AND SOCIAL ASPECTS

Nataliia O. Iakovenko, Maksim Y. Zak, Mykola O. Klymenko, Svetlana V. Zhuk, Olena K. Nuzhna

PETRO MOHYLA BLACK SEA STATE UNIVERSITY, MYKOLAIV, UKRAINE

Abstract

Introduction: Hepatitis C virus (HCV) infection is a major global problem. According to WHO, 150-200 million people globally have hepatitis C infection. Even though HCV infection morbidity rate in children is relatively low in comparison with the adult population, approximately 5 million children in the world have active HCV. There is a number of differences between HCV infection in adults and in children. However, the data pertaining to this issue is controversial.

The aim: Research, analysis and synthesis of information from contemporary literature on transmission of infection and characteristics of the course of HCV infection in children.

Materials and methods: Analysis and synthesis of information from contemporary literature on transmission of infection and characteristics of the course of HCV infection in children were conducted.

Conclusions: Information from literature of the latest years on peculiarities of infection, disease course and complications of HCV infection in children was analyzed and summarized in this article.

KEY WORDS: hepatitis C virus infection, children, course of disease, medical and social aspects

Wiad Lek 2019, 72, 5 cz. I, 928-932

Introduction

Hepatitis C virus (HCV) infection is a major global problem. There has been a prominent increase in HCV morbidity rates in recent years, including the instances of chronic forms of disease. According to WHO, there is an estimated 150-200 million people suffering from HCV infection and 350,000 people per year die of complications – advanced liver failure, hepatic cirrhosis and hepatocellular carcinoma [1]. Already, the overall number of patients with hepatites in the world is 14-15 times more than the number of patients with HIV. Viral hepatites are 50-100 times more contagious, than HIV [2]. Even though viral hepatitis C morbidity rate in children is relatively low in comparison with the adult population, approximately 5 million children in the world have active HCV infection [3].
According to WHO, Ukraine has an average hepatitis C morbidity
rate – approximately 3% of citizens are infected, which amounts to approximately 1170,000 people. However, subsequent to the results of selective risk groups monitoring, HCV morbidity rates among some of them are significantly higher than the average, reaching 40-60%. In accordance with official statistics in Ukraine in recent years chronic HCV morbidity rates in children vary between 0.25 and 0.3 per 1000 and 1.04-0,55 per 100000 children under 17 years old [2].

It is worth mentioning that chronization frequency of diseases caused by hepatotrophic viruses in children is different from adults and depends on the child’s age when he was infected and reaches its maximum (up to 90%) during the first year of life, as well as in early childhood, which is caused by physiological aspects of a child’s organism and immaturity of the immune system [4].

The aim

Research, analysis and synthesis of information from contemporary literature on transmission of infection and characteristics of disease course of HCV infection in children.

Materials and methods

Analysis and synthesis of information from contemporary literature on transmission of infection and characteristics of the course of HCV infection in children were conducted.

Review and discussion

Hepatitis C virus (HCV) infection is an infectious disease induced by hepatitis C virus with bloodborne transmission mechanism and predominant injury of liver, as well as other internal organs.

Hepatitis C virus is a RNA virus and belongs to Flaviviridae family. Its main distinctive feature is incredibly variable – ability to make up the so called “quasispecies”, which makes it easy for the virus to avoid immune response, and the antibodies produced by the organism become “witnesses”, markers of infection and fail to resist HCV reinfection of homologous and other strains.

Today virus genotypes include 11 types, as well as more than 100 of its subtypes and a vast amount of so called quasispecies. Genotypes 1a, 1b, 2a, 2b, 2c and 3a constitute more than 90% of all virus isolates obtained in North and South America, Europe, Russia, China, Japan, Australia and New Zealand. Genotypes 4, 5a and 6 are found in Central and South Africa and in South-East Asia respectively. In Ukraine genotypes 1b (approximately 70%) and 3a prevail. Genotype does not affect the result of the disease, however it allows for predicting the effectiveness and duration of treatment. Poor response to interferon therapy is more often associated with types 1 and 4; hepatic steatosis is often associated with type 3.

The main site for HCV replication are liver hepatocytes, and other extrahepatic replication regions are lymphocytes and mononuclear cells of the peripheral blood (they account for about 3.1% of the viral load).

People’s natural susceptibility to the HCV is high. The source of infection are patients with acute or chronic HCV infection and carriers of the virus. The virus appears in the blood 1-3 weeks after infection.

Acute hepatitis C is an acute HCV infection in a patient who has not been diagnosed with hepatitis C and hepatitis symptoms 6 months prior. Acute HCV infection is often asymptomatic and does not manifest clinically. Acute HCV in newborns is defined by detection of HCV RNA in the newborn’s blood in the first 1-6 months of life, usually in the context of mother-to-child transmission of HCV. Newborns often have spontaneous regression of HCV. Neonatal HCV infection should be distinguished from perinatal transitory viremia when HCV RNA is detected in peripheral blood in the period of 0-5 days after birth.

In 20-30% of cases acute HCV infection can result in recovery with complete normalization of alanine aminotransferase (ALT) and the disappearance of HCV RNA for 6 to 12 months, but in the case of chronic hepatitis and progression of liver disease, there is a risk of developing liver cirrhosis and hepatocellular carcinoma. Fulminant forms of HCV in children are rare. Patients with immunosuppression (HIV infection, onco-hematologic pathology, diabetes mellitus, etc.) have a more severe course and more rapid progression of the disease. Hepatocellular carcinoma (HCC) is rarely found in children, and almost exclusively reported in children with cirrhosis. There are reports stating that children with chronic HCV infection and a history of leukemia may have an increased risk of HCC, but the data are limited [5]. To children with HCV infection and concomitant diseases such as obesity, non-alcoholic fatty liver disease and congenital heart defects with increased pressure in the right heart, and children receiving hepatotoxic drugs doctors should pay more attention and monitor the course of the disease and its progression [6].

The chronic HCV infection is diagnosed in cases where there are signs of active viral infection with detectable HCV RNA for a period of at least 6 months with progressive liver damage.

The spontaneous regression of HCV infection is diagnosed in case of disappearance of previously detectable HCV RNAs without any treatment, as evidenced by obtaining two consecutive negative tests for the presence of HCV RNA at intervals of at least 6 months.

The most common ways of infecting a child with HCV in developed countries is the vertical transmission of the virus from the RNA-positive HCV mother. The average risk of HCV transmission from mother to child is 4.7-6.7% [7]. According to Moskovska I.A. (2007), the genotype and maternal viral load (more than 1 million copies / ml) are attributed to the increased risk of perinatal HCV transmission [3]. The presence of a co-infection of the immune deficiency virus (HIV) / HCV virus with the mother increases the chances of mother-to-child transmission by 90% compared with HCV monoinfection; in such patients, the vertical transmission rate is 20% [8]. Internal fetal monitoring, prolonged rupture of fetal membranes and fetal hypoxia during delivery may increase the risk of infection.

In other cases, the infection results from contact with contaminated blood products, transplantation of infected organs, and in patients with prolonged dialysis of the kidneys. In addition, HCV infection occurs during using of personal hygiene products (toothbrushes, manicure scissors) with remains of blood infected with hepatitis C takes place, applying tattoos or piercings, injecting drugs [6].

In developing countries, the horizontal pathway of infection is prevalent – blood transfusion and infusion of blood components. This way of transmission of hepatitis C virus is widely studied in Egypt. According to the results of Egyptian doctors’ research, the highest risk factors for HCV infection were surgical interventions and blood transfusions. The highest risk factor for HCV persistence was the treatment of teeth and male sex, especially in those children who had high ALT levels and AST oscillations [9].

Concomitant diseases play a certain role in the infection and subsequent flow of HCV. As demonstrated in foreign research, comorbid conditions were present in 45.9% of HCV-positive children and included chronic blood diseases such as thalassemia and hemophilia (59%), insulin-dependent diabetes mellitus (12%), and other concomitant diseases (29%). Children with concomitant diseases had a lower body mass index and significantly higher incidence of such symptoms as abdominal pain, jaundice, hepatomegaly and splenomegaly [9].

It is important to note that hepatitis C is not transmitted through air, uninjured skin, accidental social contact and breastfeeding [3, 10]. But if the HCV-positive mother’s nipples and/or surrounding areola are cracked and bleeding, she should stop nursing temporarily. Once her nipples are no longer cracked or bleeding, she may fully resume breastfeeding.

It was established that there is a possibility of family-owned transmission of HCV infection. According to some authors, the risk of transmission of HCV does not exceed 2% in families where 1 person is infected [11], according to other authors – the risk of transmission of HCV from child to child in one family is 31%, from mother to child – 23%, from father to child – 12% [12]. There is no data on the transfer of HCV infection among children in kindergartens.

The risk of HCV infection during sexual intercourse in a stable sexual relationship is negligible, but this can not be a reason for sexually active adolescents to ignore the rules of safe sex.

There is a number of differences in HCV infection in adults and in children. But the data on this issue is ambiguous. It is believed that children have a higher incidence of spontaneous regression of chronic HCV and slower rate of disease progression compared to adults, a predominantly mild asymptomatic course with a slight increase in transaminases [5, 11]. Thus, as shown by studies of various authors, in infants infected as a result of vertical transmission the level of spontaneous regression of the disease reaches 25 – 40%. In most patients, spontaneous regression was observed at the age of up to 24 months [8, 13]. According to the results of Italian research, spontaneous regression for genotypes 1a, 1b, 2, 3 and 4 was observed respectively in 5%, 2.5%, 7%, 32% and 6% of asymptomatic HCV patients during the first 3 years of life [14]. According to another European study, among 155 children, the diagnosis of HCV which was put immediately after birth, spontaneous regression was observed in 17% of patients up to 2 years of life, 24% to 3 years and 30% to 5 years of life [15]. According to another study, only in 6 out of 332 (1.8%) of HCV infected children portal hypertension with ascites and varicose veins took place in the course of the disease. In two patients, these symptoms and signs appeared at an early age (2 and 5 years), while in 4 older ones – 11-15 years. In another European study, only in 0.5% (in one child out of 194 infected) the disease went into a stage of decompensation and required liver transplantation at the age of 19 years. All of these children were infected with the HCV genotype 1a [16].

According to other international studies, the risk of progression is higher in infants and early childhood than in adulthood, in almost 85% of patients infected with HCV infection in childhood the disease goes into chronic phase, 20-30% of them develop liver cirrhosis in 20 years [2]. This is confirmed by the results of a study conducted by prof. Uchaikin V.F. in the clinic of RAMS out of 204 children with chronic HCV infection liver tissue fibrosis was detected in 97% of them in 10-13 years, and in 10% of cases liver cirrhosis was formed in the first 5-8 years. Long spontaneous remission was observed only in 8% of children. In 82% of patients with chronic HCV infection the course of disease was low-symptomatic but with prolonged activity of the process (increased activity of ALT) and viral replication (detection of HCV RNA in PCR). In more than half of the children, subsequent biopsies of the liver revealed an increase in fibrosis, with the main factor determining the pace of this increase (in the absence of factors causing gapatotoxicity such as alcohol, drugs, concomitant severe diseases and metabolic disorders, drug load, stress and etc.) was the duration of infection, especially with present viral replication [4].

Similar data was obtained by other researchers. Retrospective analysis of 105 anti-HCV positive Egyptian children showed that HCV RNA was detected in more than half of the subjects. Sixty percent of RNA-positive children with HCV have undergone diagnostic liver biopsy, in which chronic hepatitis was detected in 73% of the subjects, cirrhosis – only one, and seven children (27%) had a normal histology of the liver [17].

Thus, we can assume that HCV is not always a nonmalignant illness in childhood.

The issue of the course of chronic HCV in children, the timing of the formation of liver cirrhosis, the conditions for progression of the disease and the incidence of liver cancer are still not fully understood.

Generally minimal clinical symptomatology impedes timely diagnosis of HCV infection in children. More than three quarters of children have no symptoms. Minimal nonspecific and short-term symptoms at the onset of the disease are found in approximately 15% of children (fever, lethargy, anorexia, nausea, vomiting and abdominal pain). These symptoms may be accompanied by dark urine coloration, arthralgia, and yellowness of the skin and sclera.

The rate of progression of chronic HCV infection in children, as well as in adults, is determined by the characteristics of fibrogenesis in the liver. In this regard, it is extremely important to timely diagnose the stages of fibrosis, which largely determines the need for antiviral therapy (AVT). The rates of progression of liver fibrosis are individual and are defined by the factors of the host (iron overload, steatosis, duration of infection, etc.) and the factors of the virus (the genotype of the virus, viral load) [18].

Staging of the disease in children can be accomplished by physical examination and estimation of usual laboratory parameters, including albumin, serum aminotransferase, total bilirubin, international normal ratio (INR) and platelet count every 6-12 months [6]. It should be noted that levels of serum aminotransferases do not always reflect the severity of the disease in children. In one study, almost 33% of children turned out to have normal levels of aminotransferase, despite severe inflammation and necrosis, as was established after a biopsy [12].

For children with progressing liver disease it is recommended to first visualize the liver to evaluate splenomegaly or venous colaterals using ultrasonography of the liver instead of CT or MRI because of its wide availability and the absence of ionizing radiation [6].

Liver biopsy still remains to be the “golden standard” for assessing the stage of liver fibrosis in both adults and children, however, its implementation is associated with the risk of serious complications and requires the availability of trained specialists. That is why the research of the informativity of non-invasive methods of diagnosing liver fibrosis is actively being conducted. Significance of direct (level of hyaluronic acid (HA), collagen type I and IV, procolagen type III, tissue inhibitor of metalloprotease I and II type, tissue type II and III type in the blood serum) and indirect (Fiber Test (FT), Fiber Meter, Fiber Max, etc.) methods for evaluating liver fibrosis have been studied mainly in adults [13, 19]. For children such data is insufficient and therefore needs further research.

The index of histological activity (HAI), which was first proposed by Knodel (1981), is widely used to determine the stage of the liver disease. The score is set in a gradation from 0 to 18 points. In the study of Italian and Spanish doctors, through the examination of children with hepatitis C it was found that in most patients the index of histological activity (HAI) was low, with an average of 3.6 (in the range of 0 to 11). Normal histology of the liver or minimal changes were detected in 14 of 80 cases, chronic hepatitis with low activity in 48 cases and a highly active form in 17 cases. Those children who were diagnosed with highly active chronic hepatitis were significantly older (12 years) than children with chronic hepatitis with low activity or minimal liver damage (8 years). Only one in 80 children (1.3%) had cirrhosis of the liver [16]. Fibrosis indicators firmly correlated with the duration of the disease and portal inflammation at the same time. In a later report, according to the results of this study, liver fibrosis was evaluated with a simpler system, the so-called METAVIR scale. According to this scale, histological activity is classified as light (A1), moderate (A2) or pronounced (A3). The study revealed a strong correlation between the stage of fibrosis, the age of children during biopsy and the duration of their infection. Using a linear progression analysis, the average rate of progression of fibrosis was calculated to be 0.227 ± 0.372 units of METAVIR per year with an average of 0.148, and thus the mean time to cirrhosis was 28 years.

In recent years there have been publications devoted to the role of genetic factors of the host in the course of chronic viral hepatitis. At the present stage, molecular genetic methods have found that changes in the cluster of cytokine genes located on the 19th human chromosome are the main factors that determine the features of antiviral protection of the organism. The greatest significance is polymorphism in the region adjacent to the gene of interleukin (IL) -28V [20]. It was established that the polymorphisms of the IL-28B gene determine the possibility of prognosis of self-mediated elimination of HCV, the effectiveness of antiviral therapy and affect the progression of fibrosis. Carriers of genotypes rs12979860 C/C and rs8099917 T/T are associated with spontaneous elimination of hepatitis C virus [21]. There are publications that confirm that the IL-28B genotype is the independent and most reliable predictive factor in the response to AVT in patients with CHC. The association with the frequency of early and sustained virologic response (SVR) with rs12979860 polymorphism also was established [22]. There are only a few literary publications devoted to studying the connection between the polymorphism variant of the IL-28B gene and the progression of fibrosis. The correlation between the polymorphism of the gene IL-28B, the level of gamaglutamyltransferase (GGT), activity and stage of liver fibrosis in patients with HCG has been established. [23].

Conclusions

According to the data acquired from literature, not all statements on the development of hepatitis C in children are explicit and a number of open issues still remain, which requires further study of this problem. Correct diagnostic tactic, timely diagnosis, distinguishing the form and stage of the process and appointment of adequate therapy are the exact factors that positively affect the course of the disease, give opportunity to avoid complications and preserve a patient’s chance to live a full life.

References

1. Messina JP, Humphreys I, Flaxman A et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61:77–87. DOI: 10.1002/hep.27259

2. Unіfіkovanij klіnіchnij protokol pervinnoї, vtorinnoї (specіalіzovanoї), tretinnoї (visokospecіalіzovanoї) medichnoї dopomogi dіtjam z vіrusnim gepatitom C. Nakaz Mіnіsterstva ohoroni zdorov’ja Ukraїni № 729 vіd 18.07.2016[Unified clinical protocol on primary, secondary (specialized), tertiary (highly specialized) medical treatment of children with viral hepatitis C. Order of the Ministry of Health of Ukraine No. 729 dated July 18, 2016]. https://zakon.rada.gov.ua/rada/show/v0729282-16 [UA]

3. Gower E, Estes C, Blach S, Razavi-Shearer K et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. Journal of Hepatology. 2014; 61(1): 45 – 57. DOI: 10.1016/j.jhep.2014.07.027

4. Uchajkin V. F., Nisevich N. I., Cherednichenko T. V. Virusnye gepatity ot A do TTV u detej [Viral hepatites from A to TTV in children]. Novaja volna. 2003: 432. [Ru]

5. Gonzalez-Peralta RP, Langham MR, Andres JM et al. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. Journal of Pediatric Gastroenterology and Nutrition. 2009; 48(5): 630 – 635. DOI: 10.1097/MPG.0b013e318170af04

6. American Association for the Study of Liver Diseases: HCV guidance: Recommendations for testing, managing, and treating hepatitis C [Internet]. Accessed on April 23, 2018. – Available at: https://www.hcvguidelines.org/unique-populations/children

7. Pawlowska M, Domagalski K, Pniewska A et al. What’s new in hepatitis C virus infections in children? World J Gastroenterol. 2015;21:10783–10789. DOI: 10.3748/wjg.v21.i38.10783

8. Polis CB, Shah SN, Johnson KE et al. Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis. 2007;44( 8): 1123-1131. DOI: 10.1086/512815

9. Esmat G, Hashem M, El-Raziky M et al. Risk factors for hepatitis C virus acquisition and predictors of persistence among Egyptian children. Liver Int. 2012; 32(3): 449-456. doi: 10.1111/j.1478-3231.2011.02643.x.

10. World Health Organization. Fact Sheet 2015, No 164. WHO Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection. Updated April 2016. – Available at: https://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2016/en/

11. Berezenko V. S. Klіnіko-patogenetichnі osoblivostі fіbrogenezu pechіnki pri hronіchnih gepatitah u dіtej ta shljahi jogo medikamentoznoї korekcії: avtoref. dis. na zdobuttja nauk. stupenja doktora med. nauk: spec. 14.01.10 «Pedіatrіja» [Clinical and pathogenetic aspects of hepatic fibrogenesis in children’s chronic hepatites and ways of its non-surgical correction] K. 2007; 37. [Ua]

12. Casiraghi MAntonietta, De Paschale M, Romanò L et al.. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Hepatology (Baltimore, Md.). 2004;39(1):90 – 96. DOI: 10.1002/hep.20030

13. Pirogova I. Ju., Pyshkin S.A. Algoritm differencial’noj diagnostiki hronicheskogo gepatita i cirroza pecheni u bol’nyh s hronicheskoj HCV- i HBV-infekciej [Algorithm for differential diagnosis of chronic hepatitis and liver cirrhosis in patients with chronic HCV- and HBV-infection] Klinicheskie perspektivy gastrojenterologii, gepatologii. 2011; 2: 19-26. [Ru]

14. Bortolotti F, Resti M, Marcellini M et al. Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: changing distribution and correlation with clinical features and outcome. Gut. 2005; 54 (6): 852–857.  DOI: 10.1136/gut.2004.053744

15. European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. Clin Infect Dis. 2005;41:45–51.   DOI: 10.1086/430601

16 Bortolotti F, Verucchi G, Cammà C et al. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology. 2008; 134: 1900–1907. DOI: 10.1053/j.gastro.2008.02.082

17. Raziky MS, Hawary M, Koofy N, et al. Hepatitis C virus infection in Egyptian. J Viral Hepat. 2004; 11: 471–476.  DOI: 10.1007/s00431-007-0472-5

18 Valva P, Casciato P, Carrasco J et al. The Role of Serum Biomarkers in Predicting Fibrosis Progression in Pediatric and Adult Hepatitis C Virus Chronic Infection. PLOS One. 2011; 6(8). DOI: 10.1371/journal.pone.0023218

19. Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology. 2012;142:1293-1302. DOI: 10.1053/j.gastro.2012.02.017

20. Ge D, Fellay J, Thompson A J et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262): 399-401. DOI: 10.1038/nature08309

21. Rauch A, Kutalik Z, Descombes P. et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138(4):1338-1347. DOI: 10.1053/j.gastro.2009.12.056

22. Li W, Jiang Y, Jin Q. et al.Expression and gene polymorphisms of interleukin 28B and hepatitis B virus infection in a Chinese Han population. Liver Int. 2011; 31( 8): P. 1118-1126. DOI: 10.1111/j.1478-3231.2011.02507.x

23. Fabris C., Falleti E, Cussigh A et al. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis role in the course of chronic viral hepatitis and the development of HCC. J. Hepatol. 2011;54(4): 716-722. OI: 10.1016/j.jhep.2010.07.019

Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Nataliia O. Iakovenko

Prospect Myru, bud. 30, kv. 38., 54034 Mykolaiv, Ukraine

tel: +380950544782

e-mail: kom75577@gmail.ru

Received: 18.03.2019

Accepted: 01.05.2019