TORCH Profile – Part 2 – Cytomegalovirus (CMV)

The sample for the TORCH profile

1. Venous blood is collected to prepare the serum.
2. The other sample used is blood, urine, and spinal fluid for evidence of the infections for TORCH.
3. Diagnosis can be confirmed by the culture of one of the specific pathogens or by increased levels of IgM against the specific pathogen.

Purpose of the test (Indications)

1. TORCH profile is done to find the cause of premature birth or abortion.
2. TORCH is used to screen infants for infections such as toxoplasmosis, cytomegalovirus, herpes simplex, rubella, and syphilis.

Pathophysiology

1. TORCH profile includes the following tests:
   1. Toxoplasmosis antibody.
   2. Rubella antibody.
   3. Herpes Simplex.
   4. Cytomegalovirus
   5. some people include syphilis as well.
2. These infections may lead to birth defects, growth delay, brain, and nervous system problems in the baby.
3. If TORCH screening on infants is positive, more testing will be needed to confirm the diagnosis. The mother will also need to be checked.
4. The test is ordered when a pregnant woman is suspected of having any of the TORCH infections.
5. These infections can be serious if they occur during pregnancy because they can cross the placenta from the mother to the developing fetus and can cause congenital defects in the newborn.
6. The TORCH infections cause a syndrome characterized by:
   1. Microcephaly.
   2. Sensorineural deafness.
   3. Chorioretinitis.
   4. Hepatosplenomegaly.
   5. Thrombocytopenia.
7. TORCH infection sign/symptoms are:
   1. Fever and poor feeding.
   2. The newborn is often small for gestational age.
   3. A petechial rash on the skin may be present, with small reddish or purplish spots due to bleeding from capillaries under the skin.
   4. An enlarged liver and spleen (hepatosplenomegaly) are common, and jaundice.
   5. Hearing impairment, eye problems, mental retardation, autism, and death can be caused by TORCH infections.
   6. The mother often has a mild infection with few or no symptoms.
8. The examiner may test blood, urine, and spinal fluid for evidence of the infections for TORCH.
9. Diagnosis can be confirmed by the culture of one of the specific pathogens or by increased levels of IgM against the pathogen.

Cytomegalovirus (CMV)

Sample

1. Culture is the choice of method.
2. Blood of the patient to get the serum.
3. Urine.
4. Saliva.
5. Biopsy material.
6. White blood cells.

Pathology

1. 1904 first histologic changes characteristic of CMV was published.
   1. In 1966 the actual isolation of the virus following blood transfusion and raised antibody titer was noted.
   2. Human CMV is classified as a member of the herpes family of the viruses.
   3. There are five human herpesviruses:
      1. Herpes simplex 1.
      2. Herpes simplex 11.
      3. Varicella-zoster.
      4. Epstein- Barr virus.
      5. Cytomegalovirus.
   4. All these viruses are relatively large, enveloped DNA viruses.
      1. These DNA viruses undergo a replicative cycle involving DNA expression and nucleocapsid assembly within the nucleus.
      2. The viral structure gains an envelope when the virus buds through the nuclear membrane that is altered to contain specific viral proteins.
      3. All these viruses spread from cell to cell, most likely via intercellular bridges and there is the presence of antibodies in the extracellular phase.
      4. These viruses produce subclinical infections that can be reactivated under appropriate stimuli.

2. Epidemiology: CMV infection is endemic worldwide.
   1. CMV is considered the most important cause of congenital infection in the united states of America.
   2. Acquired CMV infection is usually is asymptomatic and can persist in the host as a chronic or latent disease.
   3. Dissemination of the virus may be:
      1. Oral.
      2. Respiratory.
      3. Venereal.
      4. By organ transplantation.
      5. By fresh Blood transfusion.
   4. CMV needs intimate contact with secretions or excretion of:
      1. Urine.
      2. Respiratory system.
      3. Genital secretion.
      4. Tears.
      5. Feces of an infected person.
   5. The most common is the venereal route through contact with infectious viruses in body secretion.
3. The seropositive population is 60 to 80% positivity in the western world, while it is much more in the developing countries.
   1. Seropositive cases increase with the age and in the lower socioeconomic group.
   2. The percentage is high for the people employed in the childcare facility.
4. (CMV) may have flu-like symptoms that are not easily differentiated from other illnesses.
5. This is seen in infants and is contracted in utero.
   1. CMV causes serious and life-threatening infections in the neonates and immunocompromised patients.
   2. Congenital infection is acquired in utero during passage through the infected birth canal.
6. CMV may be isolated from the throat.

7. The affected cells show typically nuclear and cytoplasmic inclusion.

8. Immunology:  CMV produces an increase in the absolute number of suppressor cells (CD8⁺) lymphocytes and a decrease in helper cell (CD4⁺) lymphocytes.
   1. This lymphocyte picture persists for months.
   2. Is there any role of CMV as an oncogenic virus?
      1. Viral antigens or nucleic acid have been found in human malignancies like adenocarcinoma of the colon, carcinoma of the cervix, Kaposi’s sarcoma, and cancer of the prostate.
      2. There is direct substantial evidence of CMV for Kaposi’s sarcoma. But a direct cause and effect relationship has not been established.

Disease pattern:

1. The pattern of the CMV disease is:
   1. Acquired infection. This is usually asymptomatic and can persist in the host as a chronic or latent infection.
   2. Latent infection. This is persistent infections characterized by the period of reactivation are called a latent infection.
   3. Congenital infection.
2. CMV infections are asymptomatic. After the infection, the virus may remain latent in the body.
3. The subclinical disease may be seen in early infants.
4. Disseminated or fulminant disease seen in infants and infection contracted in utero.
5. Late acute disseminated disease is seen in patients with leukemia and malignant diseases.
6. Liver disease is a chronic slow CMV infection occurs in children from 6 months to 8 years of age.
7. Post-natal infection may lead to hepatitis.
   1. In short, there are three groups:
      1. Perinatal disease (Congenital infection).
      2. In an immunocompetent person like mononucleosis syndrome.
      3. In immune-compromised patients are at risks like solid organs and bone marrow transplantation.

6. Antibody testing on the mother will help the physician to diagnose an infection that may be harmful to the unborn baby.
7. Congenitally infected infants: The test may be ordered on the newborn when the infant shows any signs suggestive of Congenital disease infections.
   1. The congenital infected babies show:
      1. The exceptionally small size was relative to the gestational age (low birth weight).
      2. Deafness.
      3. Mental retardation.
      4. Seizures.
      5. Heart defects.
      6. Cataracts.
      7. Enlarged liver or spleen (Hepatomegaly and splenomegaly).
      8. Low platelet level. leads to hemorrhagic pneumonitis and petechiae.
      9. Jaundice due to hemolytic anemia.
      10. Cerebral calcification.
      11. Micrencephaly.

Diagnosis:

1. A complete blood count shows leucocytosis.
   1. There is relative lymphocytosis.
   2. In infants there is thrombocytopenia.
2. Liver function tests are abnormal.
3. The virus is isolated from :
   1. Urine.
   2. Saliva.
   3. Leucocytes.
   4. Biopsy material.
4. The urine sample is diluted with an equal volume of alcohol (70 to 90%).
   1. Urine positive for CMV indicates:
      1. Acute infection.
      2. Asymptomatic patient.
      3. Active disease.
   2. The urine sample is the best sample for the recovery of CMV.
      1. There are inclusion bodies in leucocytes of urine sediments.
5. Washings, swab, and biopsy are kept in sorbitol diluent or keep the sample at -70 °C.
6. Serological tests:
   1. The antibody to early antigen undergoes a relatively rapid decline after the recovery but can persist up to 250 days.
      1. This antibody can detect recent and active infection.
      2. The presence of antibodies to the early antigen is strongly associated with viral shedding.
      3. The prevalence of CMV antibodies varies with age and geographical location but ranges from 40% to 100%.
   2. Detect antibody IgM for acute infection indicate primary infection.
      1. The serological test positive in the first three weeks of infants indicates congenital infection.
      2. Positive after the 4th-week indicates an infection of postpartum or intrapartum infection.
   3. IgG indicate convalescent stage.
      1. The increasing titer of IgG antibody indicates acute infection.
   4. The most common methods used are:
      1. Enzyme immunoassay (EIA).
      2. Indirect immunofluorescence (IIF).
      3. Complement fixation test.
      4. Anticomplement immunofluorescence.
      5. Indirect hemagglutination.
   5. Serological tests are positive in a population after the age of 30 years between 40 to 100%.
7. Policy for pregnant mothers:
   1. Test the pregnant mother in the first trimester.
      1. If positive then test viremia every three months.
      2. Congenital infection can be confirmed by the fetal blood or amniotic fluid for the IgM antibody.
      3. Amniocentesis is not helpful before 21 weeks of gestation because of inadequate urine released by the fetus.
      4. PCR may be advised on the newborn blood sample.

6. The biopsy is useful in diagnosing pneumonitis and gastrointestinal disease due to CMV.
   1. Biopsy shows typical intranuclear (owl eye) and intracytoplasmic inclusions.
7. False-positive serological tests are seen in patients with Rh-factor, heterophil antibodies, and varicella.

Treatment

1. For congenital CMV, treat with Ganciclovir or Valganciclovir for 6 months.
2. Treatment of other CMV conditions is treated Ganciclovir with Foscarnet.
3. Cidofovir is reserved for resistant cases.

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