Pediatric hepatitis C virus infection

　　First, Etiology

　　Hepatitis C virus (HCV) belongs to the Flaviviridae family, with a single-stranded RNA genome, enveloped and nucleocapsid. There are mainly 5 genotypes, with a geographical distribution, and China is mainly type II and III. HCV is difficult to propagate in cell culture, and chimpanzees are currently the only ideal model animals. Heating at 100℃ for 10 minutes, ultraviolet light, 20% hypochlorous acid, and chloroform treatment can inactivate the virus.

　　Second, Pathogenesis

　　The pathogenic mechanism of hepatitis C (viral hepatitis C) is not fully understood. It is currently believed that HCV has a direct effect on cell lesions and can also induce immune injury. Specific CTLs are the main mechanism for the body to clear HCV, and they are also an important cause of direct or indirect destruction of infected liver cells. Apoptosis of infected liver cells mediated by Fas antigen also participates in the mechanism of liver cell necrosis.

　　The pathological changes of the liver show that fatty degeneration is common, lymphocytes accumulate in the portal area, bile ducts are damaged or disappear, and liver cell necrosis is relatively mild.

　　1. Biliary tract infection often occurs simultaneously with severe hepatitis or is seen in children with chronic hepatitis C,自觉症状 are not prominent, more common manifestations include persistent low fever or moderate fever. Or jaundice persists without regression, occasionally peripheral blood leukocyte count increases, local signs are rare. Diagnosis can be confirmed mainly through duodenal drainage, bile examination and culture, and ultrasound examination can assist in diagnosis.

　　2. Hemolytic jaundice in the early stage of acute hepatitis due to rapid onset of hemolytic crisis, the condition is relatively serious, children are accompanied by mental depression due to severe anemia. Jaundice rapidly worsens, serum bilirubin increases, mainly indirect bilirubin, peripheral blood red blood cells and hemoglobin decrease, reticulocytes increase.

　　3. Severe aplastic anemia, severe hepatitis or more severe acute jaundice, persistent jaundice and persistently elevated transaminases, more than a few weeks after onset or during the recovery period, anemia, abnormal blood counts, and bone marrow changes occur, often accompanied by severe infection. The clinical manifestation is often progressive decline in platelet count as an early sign. The probability of hepatitis combined with aplastic anemia is low, but once it occurs, it progresses rapidly, and most patients die. Patients with chronic hepatitis combined with aplastic anemia are usually mild and progress slowly.

　　4. Children with chronic hepatitis C or HBV carriers may develop nephritis associated with HBV antigens.

　　5. Vitamin A deficiency can cause bile stasis, children with malabsorption of fat-soluble vitamins are prone to ocular symptoms of vitamin A deficiency.

　　Incubation period of 2-26 weeks, with an average of 8 weeks, common clinical types and characteristics include the following:

　　One, Acute hepatitis C

　　Most cases have an insidious onset, mild symptoms, common symptoms include fatigue or decreased exercise tolerance, anorexia, abdominal discomfort, etc., about 25% present with jaundice, which is usually mild, the liver is slightly to moderately enlarged, splenomegaly is rare, ALT can show a single or multiple phase increase, the latter type predicts severe liver damage or a tendency to develop into chronic type, the course of the disease is about 3-6 months or longer, with a significant tendency to chronicize, about 40%-60% develop into chronic hepatitis.

　　Two, Chronic hepatitis C

　　Classification is the same as hepatitis B, viremia can be persistent or intermittent, the former is more common, the possibility of spontaneous recovery is extremely small, and some children may develop into hepatitis cirrhosis.

　　Three, Subclinical type of hepatitis C

　　A common clinical type in pediatrics, children with no symptoms of hepatitis are often found to have hepatitis during physical examination or when seeking medical treatment for other diseases. Further investigation of the etiology leads to diagnosis. Inquiring about relevant medical history may reveal that some children are still in the acute phase, while others have already entered the chronic stage.

　　Four, Viral carrier state

　　No symptoms of hepatitis, regular follow-up shows no abnormalities in liver size and texture, ALT is not elevated, and liver biopsy is basically normal or shows slight changes.

　　Five, Characteristics of HCV infection in infants

　　1. Overt infection: Jaundice is common, and splenomegaly is more common in older children.

　　2. Infection acquired through mother-to-child transmission: Infants may present with transient viremia, which disappears a few months after birth, and the anti-HCV titer often follows suit and decreases.

　　Six, Mixed infection with HCV and other viruses

　　1. Mixed infection with HIV: Studies on infants with mixed infection acquired through mother-to-child transmission show that the two viruses have a synergistic pathogenic effect: HIV infection progresses faster, and the level of HCV viremia significantly increases.

　　2. Mixed infection with HBV: It can exacerbate liver damage, increase the risk of severe hepatitis and hepatocellular carcinoma, and HCV replication often dominates.

　　1. The main transmission route of HCV is blood transmission, and HCV infected blood donors are one of the main sources of infection. Therefore, strengthen the management of blood donor teams, strengthen the management and quality control of the transportation process of blood cells and other blood components of single plasma collection institutions, and eliminate the source of cross-infection. Strictly control the screening of blood donors, seriously carry out anti-HCV and transaminase screening. Establish quality control for HCV diagnostic reagents, develop more sensitive HCV gene diagnostic methods, and improve the positive rate of screening. Vigorously promote voluntary blood donation and eliminate the system of paid professional blood donation. 2. Strengthen the management of blood products. All production units should strictly screen blood, supply safe blood products, and carry out product identification. Strengthen the supervision of blood screening and product quality of production units. Strictly control the indications for the application of blood and blood products, and medical units should strictly comply with them, opposing abuse to reduce HCV infection.

　　3. Promote the use of disposable syringes and infusion equipment, and strengthen the quality control of the production and sales of disposable syringes and infusion equipment. Strengthen the disinfection management of surgical instruments, endoscopes, and dialysis equipment. Separate rooms and equipment should be used for surgery, examination, and dialysis for HCV infected individuals to reduce the opportunity for cross-infection.

　　4. Strengthen the prevention of mother-to-child transmission, and list anti-HCV and HCVRNA as routine examination items in pregnant women's physical examinations. For pregnant women with positive anti-HCV and HCVRNA, all equipment in the delivery room should be strictly disinfected to minimize neonatal injury and maternal blood contamination.

　　5. Strengthen the research on hepatitis C vaccine. There are currently no active or passive immunization measures to prevent HCV infection. The hepatitis C vaccine is under active development.

　　Pathogenic diagnosis:

　　1. HCV: RNA (RT-PCR method) qualitative or quantitative detection of serum or liver tissue, the viral gene in serum can be detected within 1-2 weeks after infection, which can be used for early rapid diagnosis and is an effective indicator for evaluating antiviral efficacy.

　　2. Serum anti-HCV (including antibodies against structural and non-structural antigens): The anti-HCV IgG is commonly detected, a positive result indicates infection or ongoing infection with HCV; its IgM-type antibody can appear before, simultaneously, or even after the IgG, and those that persist for more than half a year without regression often develop into chronic hepatitis. In the active phase of chronic liver disease, it often presents as positive. HCV antigen testing can directly detect HCV antigens in serum, body fluids, or liver tissue for diagnosis. Immuno-PCR methods have been established to detect low-level expressed HCV antigens.

　　3. Perform abdominal ultrasound to understand the liver, spleen and other conditions.

　　1. Provide high-protein diet:When suffering from viral hepatitis, the liver is severely damaged, and it requires a sufficient amount of protein to enhance the regeneration and repair of liver cells, so a high-quality, high-protein diet should be provided, with a recommendation of 2 to 3 grams of protein per kilogram of body weight per day.

　　2, Provide an appropriate amount of fat:During the acute phase of liver disease, the secretion of bile汁 is reduced, and clinical symptoms such as anorexia, nausea, vomiting, and aversion to oil are observed. Children have poor digestion to begin with, and fats are not easily digested, so the diet should appropriately limit the intake of fat. The daily fat supply should be around 50 grams.

　　3, Appropriately control the supply of carbohydrates:Carbohydrates can synthesize glycogen, which has a protective effect on the damaged liver, so it is advisable to provide a high-carbohydrate diet during the acute phase, with carbohydrates accounting for more than 61% of the total daily calorie intake (about 70 grams or more). After passing the acute phase, the normal amount can be resumed.

　　4, It is necessary to supplement trace elements such as calcium, zinc, and iron:Children are in the period of growth and development, and they need a large amount of essential trace elements such as calcium, zinc, and iron. When children suffer from viral hepatitis, due to poor digestion and absorption, they are more prone to a lack of these minerals, so the diet should provide more foods rich in calcium, zinc, and iron.

　　5, Eat in small portions and more frequently:It is advisable to eat 4 to 5 meals a day. According to the calculation of food nutrients, it can be simplified to: 275 grams of staple food such as rice and flour, 250 grams of milk, a total of 150 grams of eggs, meat, poultry, fish, etc. in supplementary food, 300 to 350 grams of vegetables, 25 grams of peanut oil, 3 to 5 grams of salt, and 150 to 200 grams of fruit can meet the needs.

　　One, Treatment

　　1, The treatment of acute hepatitis C with cholestatic hepatitis is basically the same as that of hepatitis A. Since acute hepatitis C is prone to transform into chronic, antiviral treatment should be considered.

　　2, During the comprehensive treatment of chronic hepatitis C, it is necessary to pay attention to the elimination of hepatitis viruses. If children with chronic hepatitis C do not receive effective antiviral treatment, they are bound to suffer misfortune in their future life due to liver cirrhosis or liver cancer.

　　(1) Antiviral treatment:

　　①Interferon α: In the absence of ideal drugs that can completely eliminate hepatitis viruses, the application of interferon α (IFN-α) has already helped alleviate the condition of some chronic hepatitis patients, even leading to complete recovery. Just like the treatment of other infectious diseases, people are increasingly paying attention to the research on etiological treatment. Interferon α has a certain inhibitory effect on the replication of the virus, as well as on the inflammatory and fibrotic processes within the liver. The usage should refer to that of hepatitis B.

　　②HCV interferon therapy: The HCV genome varies greatly, and it is difficult for the host to produce a lasting protective immunity after infection with HCV. The self-limiting nature of acute hepatitis C is about 50%, and the chance of chronicity after HCV infection is as high as 40% to 60%. Literature reports that chronic active hepatitis C, with granulomatous necrosis and bridging necrosis observed in the tissue, approximately 50% of patients will develop liver cirrhosis after an average of 50 months. After cirrhosis of hepatitis C, approximately 1% will develop hepatocellular carcinoma (HCC), and the survival rate of severe hepatitis C is about 46.2%, so antiviral treatment is essential.

　　③ Adenosine: It is converted into adenosine triphosphate (ATP) in the body, which can inhibit DNA polymerase and nucleotide reductase, thereby inhibiting viral synthesis. The dosage of adenosine is 10-15mg/(kg·d), administered intravenously to maintain for 8 hours each time, for a course of 1-2 months.

　　④ Monophosphate Adenosine: The mechanism is the same as above. The dosage is: 10mg/(kg·d) for the first 5 days, administered intramuscularly or intravenously, and 5mg/(kg·d) for intramuscular injection from the 6th to the 30th day. The combined use of monophosphate adenosine with thymosin (thymic hormone) can improve the efficacy.

　　⑤ Acyclovir: It is converted into trisphosphorylated acyclovir in cells, which inhibits viral DNA polymerase. The dose of acyclovir is 15mg/(kg·d), administered intravenously in two divided doses, for a course of 1-2 months. Literature reports that after treating chronic hepatitis B patients, the negative conversion rate of HBV DNA is 44.4%, the negative conversion rate of DNAP is 62.5%, the negative conversion rate of anti-HBcIgM is 80.0%, the negative conversion rate of preS2 antigen is 30.0%, and the seroconversion rate of HBeAg/anti-HBe is 40.0%. Thirty-two units in East China have applied acyclovir alone or in combination with other drugs for the treatment of chronic hepatitis B, and the short-term efficacy shows that the negative conversion rate of HBV virus replication markers is 40% to 60%.

　　⑥ Polyinosinic acid-polycytidylic acid (PolyI:C): It is an interferon inducer with a low price. It is administered intramuscularly at a dose of 4-6mg per time, every other day, for a course of 3 months, which can be used for 2 courses. It can also be administered intravenously at a dose of 10mg/d for a course of 3 months. The drug generally has no adverse reactions, and occasionally transient low fever may occur after administration. If the dose is >1mg/kg, adverse reactions are significant.

　　⑦ Sodium Phosphate: A pyrophosphate analog, it is a broad-spectrum antiviral drug that not only inhibits DNA polymerases of cytomegalovirus, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, etc., but also has inhibitory effects on influenza virus RNA polymerase and HIV reverse transcriptase. In recent years, it has been found that the drug has inhibitory effects on the DNA polymerase of HBV. Research results from Harbin Medical University of China prove that the short-term efficacy of Sodium Phosphate in the treatment of chronic hepatitis B is not significantly different from that of interferon alpha. After intravenous infusion treatment for one month, the negative conversion rate of HBeAg is 42.86%, and the negative conversion rate of HBV DNA is 53.33%. When Sodium Phosphate is combined with interferon alpha, the former is used for one month and the latter for three months, the negative conversion rate of HBeAg is 52.63%, and the negative conversion rate of HBV DNA is 65.00%, both of which are significantly higher than when only Sodium Phosphate or interferon alpha is used. There are no significant side effects, only a few people have gastrointestinal reactions, and no significant nephrotoxicity has been observed.

　　(2) Treatment acting on the liver inflammation process:

　　① Compound Glycyrrhizin (Qianglixin, Qianglin, Ganlinxin): It is made by replicating glycyrrhizin with L-homocysteine and glycine. Glycyrrhizin can inhibit the over-activation of T cells by HBV-infected cells, inhibit the cytotoxic effect mediated by TNF, prevent liver cell damage mediated by Fas, and maintain a balance between Th1/Th2. Clinically, it has the effects of improving symptoms, reducing ALT, GGT, and bilirubin, and can also alleviate liver inflammation and fibrosis to a certain extent. The pediatric dosage is 40-60ml/d, added to 100ml of 10% glucose solution for intravenous infusion. The course should be long enough to 1-3 months, as early termination of medication may not achieve the effect of alleviating liver inflammation.

　　② Fructose Diphosphate: Promotes the synthesis of ATP in liver cells, improves cell function, promotes the exchange of K+ and Na+ in liver cells, reduces liver cell edema, reduces the phenomenon of bile duct compression and cholestasis, and makes jaundice disappear. For adults, 5g intravenous infusion per day, 3-4 weeks is one course of treatment. It can also be taken orally, 2 tablets per time, 3 times a day.

　　③ Glutathione (Reduced Glutathione, Gualuoding): Containing active SH bonds, it participates in various biochemical reactions in liver cells, has protective effects on the liver cell membrane, promotes the metabolism of enzymes and bile acids in liver cells, and has a significant detoxifying effect. For adults, 600mg, once a day, intramuscular injection or intravenous infusion, and 1-2 months is one course of treatment. There are no significant adverse reactions to this drug.

　　④ Orotic Acid Carnitine (Carnitine Orotate): Carnitine promotes the β-oxidation process of fatty acids, promotes the metabolism of free fatty acids in the liver cell mitochondria. Orotic acid is a precursor in the biosynthesis of DNA and RNA, which can promote the recovery of liver cell function and prevent necrosis of liver cells. South Korea has been using this drug to treat hepatitis for 15 years. The dosage is 4ml/d, intravenous infusion, and 1-2 months is one course of treatment.

　　⑤ Adenosine Methionine (Simeprevir): Adenosine methionine, as a methyl donor and precursor of physiological thiol compounds, participates in important biochemical reactions in the body. It can promote the detoxification of liver cells, regulate the fluidity of the liver cell membrane, and help prevent bile stasis in the liver. It is used in jaundice type hepatitis and cholestatic hepatitis, and can be taken orally, intramuscular injection, or intravenous infusion. For adults, 1000mg/d; for children, 20-40mg/kg intravenous infusion, once a day. For acute hepatitis, it is used for 2-4 weeks, and for chronic hepatitis, it is used for 4-6 weeks. Its efficacy in reducing jaundice and restoring liver function is superior to that of Kuxiang Injection. Adverse reactions are rare.

　　⑥ Thiopurine (2-mercaptoacetyl glycine, Ketsily): A drug containing thiol groups, it protects the structure of hepatic mitochondria, promotes the regeneration and activity of liver cells, and clears reactive oxygen species, improving liver function. Oral administration for 3 months is one course of treatment.

　　(3) Prevention or reduction of liver fibrosis: There is currently a lack of definitive and effective medications, and it is also difficult to expect to achieve therapeutic effects solely through antifibrotic drugs, as HBV is not eliminated and inflammation is not alleviated. Cordyceps sinensis mycelium and traditional Chinese herbs for activating blood and removing blood stasis (such as salvia miltiorrhiza) may have some effect.

　　3. The treatment principles for severe hepatitis are rare in children. Severe hepatitis falls into liver failure due to massive necrosis of liver cells. If there are sufficient numbers of surviving liver cells, liver function failure may be reversed, which requires early treatment to stop the continued destruction of liver cells, strengthen monitoring, and maintain the function of each organ, to allow time for liver cell regeneration and the recovery of liver function. The use of hepatocyte growth-promoting factors (hepatocyte growth-promoting factors) as an adjuvant therapy for severe viral hepatitis has some efficacy, with adult administration being 80 to 100 mg intravenous infusion, once a day, for a course of 4 to 6 weeks. It can also be administered intramuscularly at a dose of 40 mg, twice a day. Some patients may have low fever and rash, but no other adverse reactions. The application of artificial liver support systems (artificial liver support systems, ALSS) in the treatment of severe hepatitis has achieved significant efficacy, significantly reducing the mortality rate of severe hepatitis. The application of ALSS includes medicinal carbon perfusion devices, membrane-type plasma component separators, bilirubin adsorbers, and methods such as plasma exchange, hemoperfusion, hemofiltration, hemodialysis, and plasma adsorption are selected according to the condition, and are used singly or in combination.

　　(1) The first-line antiviral treatment is interferon (IFN-α), or the combined use of interferon (IFN-α) and ribavirin. The recommended oral dose of ribavirin for children is 10 to 15 mg/(kg·d), with a course of treatment of ≥6 months.

　　(2) There is currently no other medication that can achieve better results than interferon. The reports on the efficacy of treatment in children are significantly fewer than in adults, and interferon (IFN-α2b) is also used for chronic hepatitis C in children, generally at a dose of 50,000 to 100,000 U/(kg·time), three times a week, for 4 to 6 months. The clinical criteria for therapeutic response are mainly determined by the serum ALT level, with nearly 70% of patients' ALT levels returning to normal within the first 1 to 4 months of treatment. If the ALT level remains normal for 6 months, it is considered a complete response. After 6 months of treatment, some patients' ALT levels remain unstable, and only 25% achieve long-term stability. The serum HCVRNA levels generally decrease or become negative during the course of treatment, but more than 60% of patients have a recurrence of HCVRNA 6 months after discontinuation of medication, and there is also an increase or maintenance of normal ALT levels. Because interferon only inhibits HCV replication, thus reducing inflammation, it has far from achieving the goal of completely eliminating the virus. Therefore, the goal of antiviral treatment for hepatitis C is currently only to restore the serum ALT level to normal, and many patients will eventually relapse. The principles of treatment for acute hepatitis C are the same as for hepatitis A and B, and there is currently no consensus on the use of interferon treatment. Acute hepatitis C has a self-healing rate of about 40%, and whether the use of IFN can reduce chronicity remains to be confirmed by strict double-blind randomized controlled trials.

　　(3) A novel type of recombinant interferon α (CIFN) is a non-natural type I (α-type) interferon containing 166 amino acids produced by gene recombinant technology. Its amino acid sequence is the most frequent at the points of 11 known (α-type) interferon subtypes. The recombinant molecular structure significantly improves the biological activity of the protein per unit content. In vitro studies have confirmed its strong antiviral activity, so it may be the direction for developing a new generation of interferon therapy for hepatitis B and C. Jensen et al. compared the treatment of chronic hepatitis C between the CIFN9g group and the IFN-α2b3MU group; the HCVRNA negative conversion rate in the CIFN group (51%) was better than that in the IFN-α2b group (31%); the ALT normalization rate in the CIFN group (60%) was also better than that in the IFN-α2b group (7%). The short-term and long-term complete response rates of the multi-center study in China using 15g CIFN treatment were all shown to be better than the IFN-α2a3MU course of 24 weeks. 4. Regarding gene therapy issues, with the development and combination of molecular biology and gene engineering technology, and the continuous update of gene transfer technology in the past decade, gene therapy has made rapid progress. Hepatitis virus is a natural hepatotropic vector. Due to the lack of a suitable method to allow the virus particles to replicate in the body, and the extreme sensitivity of the hepatitis genome to changes in gene structure, the work of modifying hepatitis virus as a gene transfer vector has progressed slowly, but the ideal of gene therapy will eventually be realized.

　　Second, Prognosis

　　The probability of transforming into chronic hepatitis is high, it is easy to lead to cirrhosis of the liver and induce liver cancer, so the prognosis is poor.