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*The professional part involved in this article is only for medical professionals to read for reference.
How to determine congenital HCMV infection and congenital HCMV infectious diseases? 1 What are the pathogenic characteristics of giant cells (HCMV)? (1) HCMV belongs to the β subfamily of herpes virus, the largest DNA virus; HCMV is an unstable virus, easy to be fat solvent, low pH (<5), heat (37 ℃ 1 hour or 56 ℃ 0.
5 hour), Inactivation by ultraviolet radiation (5 minutes)
.
(2) Salivary glands and urinary tract are the most common detoxification and detoxification sites; because they can escape host immune attack, they persist after infection; HCMV is a weak pathogenic factor, immunosuppressed individuals are prone to disease, and most of the immune systems are normal The individual has asymptomatic infection
.
(3) Tissue tropism is related to the age and immune status of the host
.
In the fetus and neonatal period, nerve cells and salivary glands are most sensitive to HCMV, and the liver and spleen are often affected
.
In older children and adults, when the immune system is normal, viral infections are mostly confined to the salivary glands and kidneys, with a few involving lymphocytes
.
Immunosuppressed individuals: The lungs are most often invaded, often causing systemic disseminated infections
.
(4) Due to the protection of the blood-brain barrier and blood-eye barrier, intraocular and intracranial HCMV infection is mainly seen in patients with intrauterine infection and immunodeficiency
.
2 What is the difference between HCMV infection and HCMV disease? HCMV infection: There is laboratory evidence of HCMV infection
.
HCMV disease: evidence of active HCMV infection + related disease manifestations
.
3 Laboratory evidence of HCMV infection? Evidence of HCMV active infection: (1) Direct evidence: directly detect virus particles or virus proliferation products
.
Including: 1) Virus isolation (detection of viral IEA after short-term culture): viral particles or cytomegalovirus inclusion bodies (but the detection rate is low), viral antigens (IEA, EA, PP65, etc.
), viral genes (mRNA) 2) HCMV DNA quantification (urine, saliva, serum/plasma): ①serum or plasma viral DNA is positive; ②high DNA load in urine and saliva or a significant increase in dynamic monitoring indicates active infection; ③Newborn The detection of viral DNA in childhood is evidence of primary infection; ④Positive whole blood or mononuclear cells cannot rule out latent infection, but the high load of viral DNA supports active infection
.
(2) Indirect evidence: serological evidence
.
1) Primary infection: ①The anti-HCMV IgG antibody was observed to be positive; ②Anti-HCMV IgM positive + anti-HCMV IgG negative or low-affinity IgG positive; ③Anti-HCMV IgM positive in the neonatal period indicates primary infection
.
2) Recent active infections: ①The anti-HCMV IgG titer of double serum during the acute or recovery period is ≥4 times higher; ②The anti-HCMV IgM and IgG are double positive
.
04 What are the diagnostic criteria for HCMV disease? Clinical diagnosis: evidence of HCMV active infection + HCMV-related disease manifestations, excluding other common causes of current disease
.
(The main idea of diagnosis: people with high incidence of disease + clinical evidence + virological evidence + exclusion of other reasons that can explain the clinical manifestations of the disease) Confirm the diagnosis: HCMV is isolated from diseased tissue or special body fluids or virus markers (viral antigens and gene transcription products are detected) ) Is a strong evidence for the diagnosis of HCMV organ diseases
.
HCMV DNA detection in special parts has clinical diagnostic significance: 1) A positive CSF test in AIDS patients can diagnose CNS infection; 2) A positive CSF test in a newborn with congenital infection indicates a prognosis for neurodevelopmental dysplasia; 3) A positive test in vitreous humor is HCMV Evidence of retinitis; 4) The serum or plasma HCMV DNA load of neonates and immunosuppressed individuals is positively correlated with the severity of HCMV disease and the spread of the virus
.
Note: The HCMV DNA of the alveolar lavage fluid sample should be interpreted with caution (because it is easily mixed with saliva)
.
In addition, when confirming the diagnosis of HCMV disease clinically, attention should be paid to: 1) Assess the immune status: For immunosuppressed individuals, newborns and infants with HCMV-related manifestations, virological evidence should be actively sought, and the disease should be highly vigilant; 2) Elimination Other common causes of current diseases; 3) In the clinical diagnosis of HCMV disease, it is emphasized that due to the weak pathogenicity of HCMV, most children have asymptomatic infections
.
5 Classification of HCMV infection (1) Classification according to the source of infection: primary infection: initial infection with exogenous HCMV; reinfection: including endogenous latent virus activation or reinfection with different exogenous virus strains
.
(2) Classification according to the time of primary infection: Congenital infection: HCMV infection confirmed ≤14 days after birth; Perinatal infection: HCMV infection confirmed after birth >14 days to ≤12 weeks; Postnatal infection: greater than after birth HCV infection was confirmed at 12 weeks
.
Congenital infection is the most harmful and requires clinical evaluation and follow-up observation
.
(3) Classification according to clinical signs: symptomatic infection and asymptomatic infection
.
6How to determine congenital HCMV infection and congenital HCMV infectious disease? (1) Virological evidence of congenital HCMV infection: 1) Evidence of primary (or recurring) infection during pregnancy; 2) Evidence of fetal infection: 3) Evidence of amniotic fluid and within 2 or 3 weeks after birth
.
How to judge the primary/recurrent infection of pregnant women: When pregnant women are positive for anti-HCMV IgM, virus titers should be tested: DNA quantification, anti-HCMV gB, anti-HCMV IgG affinity
.
1) Primary infection: anti-HCMV gB negative (generally appear only 3-4 months after infection), anti-HCMV IgG low affinity
.
2) Re-infection: anti-HCMV gB positive or anti-HCMV IgG high affinity
.
People with congenital infection usually excrete large amounts of toxins in the urine (Urine HCMV separation is often ≥3+, or high DNA load); continuous excretion of toxins takes a long time (up to 2-3 years)
.
(2) Congenital HCMV infectious diseases: virological evidence + clinical evidence Clinical evidence: The clinical manifestations of children with congenital HCMV are jaundice (mainly elevated DB) and hepatosplenomegaly
.
Others such as: thrombocytopenic ecchymosis; CNS involvement: microcephaly, enlarged ventricles with peripheral calcification, sensorineural deafness, neuromuscular abnormalities, convulsions and mental retardation, etc.
; retinal choroiditis; increased liver enzymes; peripheral blood abnormalities lymphocytosis; cerebrospinal fluid protein increased; coombs negative poor solvent; pneumonia; deformity: the most common inguinal hernia; other: cleft palate, biliary atresia, cardiovascular malformations, such as polycystic kidney disease
.
7Under what circumstances need antiviral treatment? Dosage and course of treatment and attention to medication? How to evaluate the efficacy? (1) According to the "Recommendations on the Diagnosis and Prevention of Children's Cytomegalovirus Diseases", the indications for antiviral treatment are pointed out: 1) HCMV diseases that meet the clinical diagnosis or definite diagnostic criteria and have serious or easily disabling HCMV diseases such as pneumonia and jaundice Or cholestatic hepatitis, encephalitis, retinal choroiditis (which can accumulate the macula and cause blindness), etc.
; 2) Preventive medication after transplantation; 3) Congenital infections with CNS damage including hearing damage to prevent deterioration of hearing damage
.
In short: Antiviral treatment should only be considered when it is emphasized that people with more serious or easily disabling HCMV disease
.
(2) Drug selection: commonly used anti-HCMV drugs for children are: ganciclovir, valganciclovir, foscarnet sodium (generally not preferred due to its nephrotoxicity)
.
Ganciclovir treatment regimen: induction therapy: 5mg/kg (intravenous infusion> 1 hour), q12h, 2-3w
.
Maintenance treatment: 5mg/kg, qd, 5-7d
.
Total course of treatment: 3-4 weeks
.
Recommendations: If the disease is relieved during the induction phase or the viremia/urinesis is eliminated, the maintenance phase can be entered in advance; if the virological evaluation of the induction treatment is invalid for 3 weeks, consider the infection of drug-resistant strains or secondary resistance; if the disease progresses in the maintenance phase, it can be Consider re-induction therapy; if the immunosuppressive factors in the maintenance phase are not eliminated, the maintenance course should be extended
.
Common maintenance therapy: 1.
Continue 5mg/kg, qd; 2.
or 6mg/kg, use 5 days a week, stop 2 days
.
3.
Or sequential oral ganciclovir (30mg/kg q8h) or valganciclovir
.
(3) Pay attention to the main adverse reactions of ganciclovir during the medication: 1.
Bone marrow suppression: blood routine should be monitored, if the platelet decline is less than or equal to 25X109/L and neutrophils less than or equal to 0.
5X109/L or to 50% before medication The level should be discontinued (generally recovered within 5-7 days after stopping the drug, granulocyte colony stimulating factor can be used in severe cases), if re-treatment is required, the original dose or a reduced dose can still be used
.
2.
Liver and kidney damage: Emphasize that the duration of instillation should exceed 1 hour, and reduce the dose as appropriate when renal insufficiency
.
(4) Evaluation of antiviral efficacy: 1) Improvement of symptoms, signs and organ function of HCMV disease; 2) Virological evaluation: ①Quantitative analysis of virus-specific antigen and virus titer; ②Quantification of HCMV DNA in serum or plasma or whole blood Dynamic monitoring
.
Note: Urine/saliva virus genetic testing is not suitable for evaluating antiviral efficacy (because it continues to detoxify for several years)
.
8Whether to continue breastfeeding and under what circumstances need to detect the virus HCMV in breast milk? (1) Healthy full-term infants without HCMV disease can continue breast milk; infected infants can continue breastfeeding without treatment; premature babies, especially low birth weight infants, need to deal with virus-carrying breast milk
.
Treatment method of virus-carrying breast milk (two-step method): 1) Dissolve at room temperature after at least 1 day at -20°C, and the virus titer can be obviously instilled; 2) Short-term pasteurization treatment (62-72°C, 5 seconds) , Can completely eliminate virus infectivity
.
At the same time pay attention to hand hygiene + avoid infection of the secretions of the detoxifier
.
(2) It is recommended to detect HCMV in breast milk for preterm infants, especially very low birth weight infants
.
9 Follow-up For all children with congenital HCMV infection, follow-up should be strengthened and regularly assessed for hearing, intelligence, eye, and tooth damage until adulthood
.
References: 1.
Yin Yifei, Qi Ying.
Guidelines for screening and clinical intervention of congenital cytomegalovirus infection[J].
Chinese Journal of Practical Gynecology and Obstetrics, 2019,35(04):417-423.
2.
Fang Feng.
Children Recommendations for the diagnosis and prevention of cytomegalovirus disease[J].
Chinese Journal of Pediatrics, 2012(04):290-292.
3.
Jiang Zaifang, Shen Kunling, etc.
Zhu Futang Practical Pediatrics[M].
Beijing: People's Medical Publishing House.
2015 :910-915.
4.
Jiang Yi, Zhang Xiaojiao.
Interpretation of 2017 consensus on the prevention, diagnosis and treatment of cytomegalovirus infection in pregnant women and newborns[J].
Chinese Journal of Neonatology, 2018,33(03):161-164.
How to determine congenital HCMV infection and congenital HCMV infectious diseases? 1 What are the pathogenic characteristics of giant cells (HCMV)? (1) HCMV belongs to the β subfamily of herpes virus, the largest DNA virus; HCMV is an unstable virus, easy to be fat solvent, low pH (<5), heat (37 ℃ 1 hour or 56 ℃ 0.
5 hour), Inactivation by ultraviolet radiation (5 minutes)
.
(2) Salivary glands and urinary tract are the most common detoxification and detoxification sites; because they can escape host immune attack, they persist after infection; HCMV is a weak pathogenic factor, immunosuppressed individuals are prone to disease, and most of the immune systems are normal The individual has asymptomatic infection
.
(3) Tissue tropism is related to the age and immune status of the host
.
In the fetus and neonatal period, nerve cells and salivary glands are most sensitive to HCMV, and the liver and spleen are often affected
.
In older children and adults, when the immune system is normal, viral infections are mostly confined to the salivary glands and kidneys, with a few involving lymphocytes
.
Immunosuppressed individuals: The lungs are most often invaded, often causing systemic disseminated infections
.
(4) Due to the protection of the blood-brain barrier and blood-eye barrier, intraocular and intracranial HCMV infection is mainly seen in patients with intrauterine infection and immunodeficiency
.
2 What is the difference between HCMV infection and HCMV disease? HCMV infection: There is laboratory evidence of HCMV infection
.
HCMV disease: evidence of active HCMV infection + related disease manifestations
.
3 Laboratory evidence of HCMV infection? Evidence of HCMV active infection: (1) Direct evidence: directly detect virus particles or virus proliferation products
.
Including: 1) Virus isolation (detection of viral IEA after short-term culture): viral particles or cytomegalovirus inclusion bodies (but the detection rate is low), viral antigens (IEA, EA, PP65, etc.
), viral genes (mRNA) 2) HCMV DNA quantification (urine, saliva, serum/plasma): ①serum or plasma viral DNA is positive; ②high DNA load in urine and saliva or a significant increase in dynamic monitoring indicates active infection; ③Newborn The detection of viral DNA in childhood is evidence of primary infection; ④Positive whole blood or mononuclear cells cannot rule out latent infection, but the high load of viral DNA supports active infection
.
(2) Indirect evidence: serological evidence
.
1) Primary infection: ①The anti-HCMV IgG antibody was observed to be positive; ②Anti-HCMV IgM positive + anti-HCMV IgG negative or low-affinity IgG positive; ③Anti-HCMV IgM positive in the neonatal period indicates primary infection
.
2) Recent active infections: ①The anti-HCMV IgG titer of double serum during the acute or recovery period is ≥4 times higher; ②The anti-HCMV IgM and IgG are double positive
.
04 What are the diagnostic criteria for HCMV disease? Clinical diagnosis: evidence of HCMV active infection + HCMV-related disease manifestations, excluding other common causes of current disease
.
(The main idea of diagnosis: people with high incidence of disease + clinical evidence + virological evidence + exclusion of other reasons that can explain the clinical manifestations of the disease) Confirm the diagnosis: HCMV is isolated from diseased tissue or special body fluids or virus markers (viral antigens and gene transcription products are detected) ) Is a strong evidence for the diagnosis of HCMV organ diseases
.
HCMV DNA detection in special parts has clinical diagnostic significance: 1) A positive CSF test in AIDS patients can diagnose CNS infection; 2) A positive CSF test in a newborn with congenital infection indicates a prognosis for neurodevelopmental dysplasia; 3) A positive test in vitreous humor is HCMV Evidence of retinitis; 4) The serum or plasma HCMV DNA load of neonates and immunosuppressed individuals is positively correlated with the severity of HCMV disease and the spread of the virus
.
Note: The HCMV DNA of the alveolar lavage fluid sample should be interpreted with caution (because it is easily mixed with saliva)
.
In addition, when confirming the diagnosis of HCMV disease clinically, attention should be paid to: 1) Assess the immune status: For immunosuppressed individuals, newborns and infants with HCMV-related manifestations, virological evidence should be actively sought, and the disease should be highly vigilant; 2) Elimination Other common causes of current diseases; 3) In the clinical diagnosis of HCMV disease, it is emphasized that due to the weak pathogenicity of HCMV, most children have asymptomatic infections
.
5 Classification of HCMV infection (1) Classification according to the source of infection: primary infection: initial infection with exogenous HCMV; reinfection: including endogenous latent virus activation or reinfection with different exogenous virus strains
.
(2) Classification according to the time of primary infection: Congenital infection: HCMV infection confirmed ≤14 days after birth; Perinatal infection: HCMV infection confirmed after birth >14 days to ≤12 weeks; Postnatal infection: greater than after birth HCV infection was confirmed at 12 weeks
.
Congenital infection is the most harmful and requires clinical evaluation and follow-up observation
.
(3) Classification according to clinical signs: symptomatic infection and asymptomatic infection
.
6How to determine congenital HCMV infection and congenital HCMV infectious disease? (1) Virological evidence of congenital HCMV infection: 1) Evidence of primary (or recurring) infection during pregnancy; 2) Evidence of fetal infection: 3) Evidence of amniotic fluid and within 2 or 3 weeks after birth
.
How to judge the primary/recurrent infection of pregnant women: When pregnant women are positive for anti-HCMV IgM, virus titers should be tested: DNA quantification, anti-HCMV gB, anti-HCMV IgG affinity
.
1) Primary infection: anti-HCMV gB negative (generally appear only 3-4 months after infection), anti-HCMV IgG low affinity
.
2) Re-infection: anti-HCMV gB positive or anti-HCMV IgG high affinity
.
People with congenital infection usually excrete large amounts of toxins in the urine (Urine HCMV separation is often ≥3+, or high DNA load); continuous excretion of toxins takes a long time (up to 2-3 years)
.
(2) Congenital HCMV infectious diseases: virological evidence + clinical evidence Clinical evidence: The clinical manifestations of children with congenital HCMV are jaundice (mainly elevated DB) and hepatosplenomegaly
.
Others such as: thrombocytopenic ecchymosis; CNS involvement: microcephaly, enlarged ventricles with peripheral calcification, sensorineural deafness, neuromuscular abnormalities, convulsions and mental retardation, etc.
; retinal choroiditis; increased liver enzymes; peripheral blood abnormalities lymphocytosis; cerebrospinal fluid protein increased; coombs negative poor solvent; pneumonia; deformity: the most common inguinal hernia; other: cleft palate, biliary atresia, cardiovascular malformations, such as polycystic kidney disease
.
7Under what circumstances need antiviral treatment? Dosage and course of treatment and attention to medication? How to evaluate the efficacy? (1) According to the "Recommendations on the Diagnosis and Prevention of Children's Cytomegalovirus Diseases", the indications for antiviral treatment are pointed out: 1) HCMV diseases that meet the clinical diagnosis or definite diagnostic criteria and have serious or easily disabling HCMV diseases such as pneumonia and jaundice Or cholestatic hepatitis, encephalitis, retinal choroiditis (which can accumulate the macula and cause blindness), etc.
; 2) Preventive medication after transplantation; 3) Congenital infections with CNS damage including hearing damage to prevent deterioration of hearing damage
.
In short: Antiviral treatment should only be considered when it is emphasized that people with more serious or easily disabling HCMV disease
.
(2) Drug selection: commonly used anti-HCMV drugs for children are: ganciclovir, valganciclovir, foscarnet sodium (generally not preferred due to its nephrotoxicity)
.
Ganciclovir treatment regimen: induction therapy: 5mg/kg (intravenous infusion> 1 hour), q12h, 2-3w
.
Maintenance treatment: 5mg/kg, qd, 5-7d
.
Total course of treatment: 3-4 weeks
.
Recommendations: If the disease is relieved during the induction phase or the viremia/urinesis is eliminated, the maintenance phase can be entered in advance; if the virological evaluation of the induction treatment is invalid for 3 weeks, consider the infection of drug-resistant strains or secondary resistance; if the disease progresses in the maintenance phase, it can be Consider re-induction therapy; if the immunosuppressive factors in the maintenance phase are not eliminated, the maintenance course should be extended
.
Common maintenance therapy: 1.
Continue 5mg/kg, qd; 2.
or 6mg/kg, use 5 days a week, stop 2 days
.
3.
Or sequential oral ganciclovir (30mg/kg q8h) or valganciclovir
.
(3) Pay attention to the main adverse reactions of ganciclovir during the medication: 1.
Bone marrow suppression: blood routine should be monitored, if the platelet decline is less than or equal to 25X109/L and neutrophils less than or equal to 0.
5X109/L or to 50% before medication The level should be discontinued (generally recovered within 5-7 days after stopping the drug, granulocyte colony stimulating factor can be used in severe cases), if re-treatment is required, the original dose or a reduced dose can still be used
.
2.
Liver and kidney damage: Emphasize that the duration of instillation should exceed 1 hour, and reduce the dose as appropriate when renal insufficiency
.
(4) Evaluation of antiviral efficacy: 1) Improvement of symptoms, signs and organ function of HCMV disease; 2) Virological evaluation: ①Quantitative analysis of virus-specific antigen and virus titer; ②Quantification of HCMV DNA in serum or plasma or whole blood Dynamic monitoring
.
Note: Urine/saliva virus genetic testing is not suitable for evaluating antiviral efficacy (because it continues to detoxify for several years)
.
8Whether to continue breastfeeding and under what circumstances need to detect the virus HCMV in breast milk? (1) Healthy full-term infants without HCMV disease can continue breast milk; infected infants can continue breastfeeding without treatment; premature babies, especially low birth weight infants, need to deal with virus-carrying breast milk
.
Treatment method of virus-carrying breast milk (two-step method): 1) Dissolve at room temperature after at least 1 day at -20°C, and the virus titer can be obviously instilled; 2) Short-term pasteurization treatment (62-72°C, 5 seconds) , Can completely eliminate virus infectivity
.
At the same time pay attention to hand hygiene + avoid infection of the secretions of the detoxifier
.
(2) It is recommended to detect HCMV in breast milk for preterm infants, especially very low birth weight infants
.
9 Follow-up For all children with congenital HCMV infection, follow-up should be strengthened and regularly assessed for hearing, intelligence, eye, and tooth damage until adulthood
.
References: 1.
Yin Yifei, Qi Ying.
Guidelines for screening and clinical intervention of congenital cytomegalovirus infection[J].
Chinese Journal of Practical Gynecology and Obstetrics, 2019,35(04):417-423.
2.
Fang Feng.
Children Recommendations for the diagnosis and prevention of cytomegalovirus disease[J].
Chinese Journal of Pediatrics, 2012(04):290-292.
3.
Jiang Zaifang, Shen Kunling, etc.
Zhu Futang Practical Pediatrics[M].
Beijing: People's Medical Publishing House.
2015 :910-915.
4.
Jiang Yi, Zhang Xiaojiao.
Interpretation of 2017 consensus on the prevention, diagnosis and treatment of cytomegalovirus infection in pregnant women and newborns[J].
Chinese Journal of Neonatology, 2018,33(03):161-164.