2 Clinical and immunological diagnosis of HIV infection

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2-1 What is the natural history of HIV infection in children?

  1. Once HIV enters the body at the time of infection, it starts to multiply rapidly in CD4 cells. These HIV-infected CD4 cells then release large amounts of virus into the bloodstream so that HIV can infect other CD4 cells. For a short while the number of CD4 cells may drop.
  2. The body responds after a few weeks by producing antibodies in an attempt to control the virus. As a result of this immune response, the amount of HIV in the body decreases and the number of CD4 cells increases after a few months.
  3. However, the CD4 cells continue to be infected and killed. The number of CD4 cells eventually starts to fall and the function of the immune system begins to fail. As a result, the rate of HIV multiplication rises again and the amount of virus in the blood slowly increases once more.

Therefore the amount of virus in the blood is high early and late in the course of HIV infection. The number of CD4 cells in the blood slowly falls as the HIV infection progresses and the body is no longer able to replace the killed CD4 cells. The infection progresses much more rapidly in children than in adults, especially in those children infected during pregnancy, delivery or soon after birth. The increase in HIV and decrease in CD4 cells result in the children becoming progressively more ill.

HIV infects CD4 cells and slowly damages the immune system.

Figure 2-1: The changes in viral load, CD4 count and clinical features of HIV infection in adults

Figure 2-1: The changes in viral load, CD4 count and clinical features of HIV infection in adults

2-2 Do children become ill as soon as they are infected with HIV?

No. They do not become ill at the time of HIV infection. However, they may develop acute seroconversion illness soon after infection. Acute seroconversion illness is relatively common in adolescents and adults but rarely diagnosed in infants and children.

Infection with HIV may cause acute seroconversion illness.

Acute seroconversion illness

2-3 What is acute seroconversion illness?

At the time that HIV antibodies appear in the blood (seroconversion) about 50% of infected people develop a flu-like illness which lasts a few days or weeks. This illness occurs two to four weeks after infection with HIV and is called acute seroconversion illness.

During acute seroconversion illness (acute retroviral syndrome or acute HIV disease) the amount of virus in the blood is very high but the amount of antibody still very low. Therefore, the screening tests for HIV (which depend on the presence of HIV antibodies) may still be negative at the time of acute seroconversion illness, i.e. may still be the ‘window period’ (the period of time from infection to when the HIV tests become positive).

Acute seroconversion illness is often the first clinical sign of HIV infection in adults and older children.

During acute seroconversion illness the CD4 count may be temporarily depressed.

2-4 What are the common clinical features of acute seroconversion illness?

The common clinical features of acute seroconversion illness are:

  1. Fever and sweating
  2. General tiredness
  3. Headache
  4. Cough or sore throat (pharyngitis)
  5. Muscle or joint pains
  6. Nausea, vomiting or diarrhoea
  7. Enlarged lymph nodes (generalised lymphadenopathy)
  8. A measles-like rash
  9. Oral or genital ulcers

The above symptoms and signs are similar to those found in glandular fever (infectious mononucleosis). Many people with acute seroconversion illness think they have severe flu. During infancy lymphadenopathy, rash and failure to thrive are common signs of acute seroconversion illness.

2-5 How are patients with acute seroconversion illness managed?

Patients with acute seroconversion illness are managed symptomatically with antipyretics (e.g. paracetamol) for fever. There is no role for antiretroviral treatment.

During the first few weeks of HIV infection, especially if the person develops seroconversion illness, large amounts of virus are present in the blood and other body fluids. As a result, the person is very infectious to others. It is therefore of particular importance in adults to abstain from sexual intercourse during this time. Unfortunately most are not aware that they have been recently infected with HIV.

2-6 What is the latent phase of HIV infection?

Following the primary HIV infection (and acute seroconversion illness) there is a latent phase before chronic HIV illness develops.

2-7 What are the clinical features of the latent phase of HIV infection?

HIV infection and seroconversion are followed by a latent period when the child looks and feels well. During this phase it is not obvious that the child has HIV infection. There may be no clinical signs at all or only persistent, painless, generalised lymphadenopathy during the latent phase.

During the latent phase the viral load is low and the CD4 count is normal or only mildly depressed.

Children in the latent phase of HIV infection appear well.

2-8 How long does the latent phase last?

In adults this silent, asymptomatic period usually lasts five to 10 years. However, in children it is much shorter. Owing to their immature immune system, HIV infection progresses much faster from the latent phase to the symptomatic phase.

2-9 Is the length of the latent phase of HIV infection the same in all children?

No. In some children the progression to symptomatic infection is much faster (‘fast progressors’) than in other children (‘slow progressors’). As a result the latent phase is shorter in ‘fast progressors’. The most important factor indicating how fast the HIV infection will progress is the timing of the infection:

  1. Children who are infected before, during or soon after delivery usually progress fast. In many the latent phase is only a few months long. Most infants with perinatal infection will have symptoms and signs of HIV infection by six months of age. Without appropriate management, including antiretroviral treatment, 35% of these children will die before one year of age and more than 50% will die by their second birthday.
  2. Children who are infected later, usually via breast milk, tend to progress much more slowly. Most will die by five years but some may survive beyond 10 years without treatment.

The earlier the HIV infection, the shorter the asymptomatic latent phase.

2-10 What is symptomatic HIV infection?

When patients who have been clinically well during the latent (asymptomatic) phase of HIV infection become ill, they are said to have symptomatic HIV infection (HIV disease). The symptoms and signs of symptomatic chronic HIV infection only present when the damaged immune system is no longer able to protect the person from serious infections.

2-11 What are the common clinical presentations of HIV infection in children?

Chronic HIV infection can present with a very wide range of clinical symptoms and signs. These are usually due to secondary viral, bacterial, fungal or parasitic infections.

Common ways that HIV infection can present include:

  1. Weight loss or failure to thrive
  2. Severe or persistent oral thrush beyond the first two months of life
  3. Enlarged lymph nodes, liver, spleen or parotid glands
  4. Severe rash
  5. Repeated or persistent bacterial infections such as pneumonia
  6. Severe forms of common viral infections which often respond slowly to treatment such as severe oral herpes
  7. Chronic diarrhoea
  8. Tuberculosis
  9. Infections which do not usually affect children with a healthy immune system, such as oesophageal candidiasis
  10. Delayed developmental milestones

Clinical staging of HIV infection

2-12 What are the clinical stages of HIV infection?

The WHO clinical criteria divide HIV infection into four stages: an asymptomatic, latent stage (stage 1) followed by three symptomatic stages (stages 2, 3 and 4). As the HIV infection progresses and the illness becomes more severe, the clinical stage progresses from 2 to 4.

HIV infection can be divided into four clinical stages.

2-13 What is the value of knowing the clinical stage?

Knowing the clinical stage is a valuable way of predicting what the prognosis will be, especially if the child is not given antiretroviral treatment. Therefore the clinical stage can be used to estimate how long the child is likely to survive without treatment.

The clinical stage helps to predict the likely course of the illness.

2-14 What is advanced HIV disease?

The World Health Organisation defines advanced HIV disease as stage 3 or 4 HIV infection. AIDS (acquired human immunodeficiency syndrome) refers to stage 4 disease. Infants with AIDS are at high risk of dying within weeks or months unless correctly treated. With antiretroviral treatment AIDS is a manageable chronic condition.

AIDS is the most advanced form of HIV infection.

The term AIDS is confusing to the public as it is often used incorrectly to describe any person with symptomatic HIV infection. Many experts regard both stage 3 and 4 as AIDS in children. Previously the Centre for Disease Control (CDC) in the USA defined AIDS as clinical category C disease. Therefore it is best not to use the term AIDS.

2-15 What are the features of stage 1 HIV infection?

These children are clinically well. However, they may have persistent, generalised lymphadenopathy on clinical examination.

Although acute seroconversion illness is part of the primary HIV infection, it is formally included in stage 1.

2-16 What are the clinical features of stage 2 HIV infection?

These children are moderately symptomatic and may present with any of the following clinical features:

  1. Unexplained persistent hepatosplenomegaly (enlarged liver and spleen)
  2. Unexplained chronically enlarged painless parotid glands
  3. Repeated or chronic upper respiratory tract infections (e.g. otitis media, tonsillitis, pharyngitis and sinusitis)
  4. Skin rashes (‘itchy bump disease’, warts, molluscum) and fungal nail infections
  5. Recurrent mouth ulcers (aphthous ulcers) and inflamed gums
  6. Herpes zoster

Stage 2 presents with many common mild childhood infections.

2-17 What are the clinical features of stage 3 HIV infection?

These children are more ill than children with stage 2 HIV infection. They have advanced signs and may present with any of the following:

  1. Unexplained moderate malnutrition
  2. Persistent fever (intermittently or persistently above 37.5 °C for longer than a month)
  3. Persistent diarrhoea (14 days or more)
  4. Oral candidiasis (thrush) after two months of age
  5. Oral hairy leucoplakia (white lines on the edge of the tongue)
  6. Severe ulceration and bleeding of the gums
  7. Pulmonary tuberculosis (TB) or lymph node TB
  8. Severe, recurrent bacterial pneumonia
  9. Symptomatic lymphoid interstitial pneumonitis (LIP)
  10. Chronic lung disease including bronchiectasis
  11. Unexplained anaemia, neutropenia (low white cells) or thrombocytopenia (low platelets)

Stage 3 presents with common severe infections.

2-18 What are the clinical features of stage 4 HIV infection?

These children are severely symptomatic and are seriously ill with any of the following:

  1. Unexplained severe malnutrition with wasting that does not respond to feeding
  2. Recurrent severe bacterial infections other than pneumonia, e.g. meningitis or osteitis
  3. Pneumocystis pneumonia
  4. Oesophageal candidiasis
  5. Severe chronic herpes simplex infection
  6. Extrapulmonary disseminated TB
  7. HIV-associated malignancies
  8. HIV encephalopathy
CMV retinitis, cryptococcal meningitis, disseminated fungal infections, disseminated non-tuberculous mycobacterial infection and chronic cryptosporidiosis or isosporiasis are also included as stage 4 conditions. However, these infections are not common in children with advanced HIV disease. HIV-associated cardiomyopathy, nephropathy and rectovaginal fistula are now also classified as stage 4 conditions.

Stage 4 presents with uncommon severe infections.

The new WHO classification defines moderate malnutrition as a z-score below 2 (2 SD below the mean weight for age) and severe malnutrition as a z-score below 3.

2-19 What rashes are common in children with stage 2 HIV infection?

  1. Pruritic papular eruption
  2. Seborrhoeic dermatitis
  3. Extensive molluscum contagiosum
  4. Extensive warts
  5. Herpes zoster (especially if widespread)
  6. Fungal nail infections
  7. Severe scabies

Other non-specific skin rashes are also common in children with HIV infection.

Skin rashes are common in children with HIV infection.

2-20 What is pruritic papular eruption?

This is very common in children with HIV infection and presents with a persistent severe itch and scattered pigmented papules, especially on the trunk and limbs (‘itchy bump disease’). It responds to topical steroids.

2-21 Which malignancies are common in HIV-infected infants?

  1. Lymphomas, which usually occur in the lung or brain. They are especially common in East Africa.
  2. Kaposi’s sarcoma, which usually presents with multiple painless purple or brown patches or nodules (bumps) on the skin, especially the face, trunk and legs. The mouth may also be involved, especially the hard palate. In advanced cases other organs such as the gut, lungs and lymph nodes can be affected. Kaposi’s sarcoma is usually not life threatening and the patches and nodules often improve with antiretroviral treatment.
Viral infections are associated with both lymphomas (Epstein-Barr virus) and Kaposi’s sarcoma (the Human Herpes 8 virus).

Confirmation of HIV infection

2-22 How is the clinical diagnosis of HIV infection confirmed?

By testing for the presence of antibodies to HIV (antibody tests) or the presence of HIV itself (viral tests). In adults the diagnosis of HIV infection is usually based on finding antibodies to HIV in the blood or other body fluids (e.g. saliva). However, in young children it is necessary to show that the virus (HIV) itself is present.

Screening for HIV infection should be done in all sick children in countries where AIDS is common, including South Africa.

Wherever possible, the HIV status of all children should be established.

2-23 When is antibody testing helpful in diagnosing HIV infection in children?

Only in older children (18 month of age or more) if the mother is HIV-positive. Mothers who are infected with HIV produce antibodies to HIV and these antibodies pass across the placenta to their fetus. Therefore, if the mother has antibodies to HIV, her newborn infant will also have HIV antibodies whether the infant is infected with HIV or not. These maternal antibodies slowly disappear from the infant’s blood during the months after birth but may remain up to the age of 18 months. As a result, positive antibody screening tests for HIV antibody (ELISA test and rapid test) cannot be used to diagnose HIV infection in children before the age of 18 months. However, if the antibody test is negative, the child has not been exposed to HIV.

Antibody testing for diagnosing HIV infection is only reliable in children of 18 months or older.

Many HIV-exposed but uninfected children will already have a negative HIV antibody screening test by nine months of age when the child attends clinic for the first measles immunisation. Most, but not all, uninfected children will have a negative antibody screening test by 12 months. With few exceptions, all uninfected children will get an HIV-negative result by 18 months.

An antibody screening HIV test is also useful if the mother’s HIV status is unknown or cannot be obtained, e.g. for orphans or abandoned children. If the infant’s antibody test is negative the mothers test must also be negative and therefore the infant has not been exposed to HIV.

2-24 What tests detect whether HIV is present?

  1. RNA (genetic material) from the HIV can be detected, using the polymerase chain reaction (or PCR) test. If the PCR test for HIV is positive, a confirmatory PCR test is performed before it can be concluded that the child is definitely infected with HIV. However, the PCR test takes up to six weeks to become positive after the child has been infected with HIV. Therefore, it can only be used with confidence to make or exclude a diagnosis of HIV infection in children who have never been breastfed once they reach the age of six weeks. In breastfed infants, a negative test result is only reliable if done six weeks after breastfeeding has been completely stopped.
  2. The ultra-sensitive p24 antigen test can be used to detect HIV proteins in children. A positive ultrasensitive p24 antigen test, therefore, confirms HIV infection even in children less than 18 months. The ultrasensitive p24 antigen tests are as reliable as PCR for diagnosing HIV infection in children.

The PCR test is used to diagnose HIV infection in children younger than 18 months.

The DNA-PCR test includes a reverse transcription step which allows for the detection of HIV RNA in lymphocytes. It is an extremely sensitive and specific test (approaching 100%). The Department of Health advocates its use to diagnose HIV infection in children younger than 18 months of age. The RNA-PCR test (currently used to measure the viral load) detects free virus and is equally sensitive. It is also used for confirming a positive DNA-PCR test in children.

2-25 What is the window period?

This is the time after infection with HIV when the blood tests may still be negative. For viral tests the window period ranges from 3 days to 6 weeks, and for antibody tests e.g. HIV ELISA, it ranges between 2 weeks and 12 weeks.

During the six-week window period the tests for HIV infection may be negative, even if the child is infected with HIV.

Immunological staging of HIV infection

2-26 How is HIV infection staged immunologically?

In addition to the clinical staging of HIV infection, patients should also be staged immunologically. This is based on the number of CD4 cells (helper or CD4+ T cells) in the blood. As HIV destroys more and more CD4 cells the body’s immune system becomes weaker and weaker. The number of CD4 cells in the blood is therefore a direct measure of the degree of damage to the immune system and the risk of HIV-associated infections.

The number of CD4 cells indicates whether the immune system has been damaged.

2-27 What is the CD4 count?

This is the number of CD4 cells in one µl of serum (i.e. a 1000th of a ml). In normal healthy adults who are HIV-negative, the CD4 count is above 500 cells/µl (usually about 1000 cells/µl). In children the normal range is higher, especially in younger children who have an immature immune system. As the CD4 count varies according to the child’s age, it is preferable to use the CD4 percentage rather than the absolute CD4 count in younger children (under the age of five years). The CD4 percentage is the percent of lymphocytes in the blood that are CD4 cells.

2-28 What is the normal percentage of CD4 cells in children?

In normal healthy children, more than 25% of the lymphocytes in their blood should be CD4 cells. This indicates that there is no immunosuppression (no damage to the immune system). If the immune system of children with HIV infection is suppressed, their percentage of CD4 cells will be less than 25%.

Normal children have a CD4 percentage of 25 or more.

2-29 How can the percentage of CD4 cells be used to grade the degree of immune suppression in children?

  1. A CD4 percentage between 15 and 24 indicates moderate immune suppression.
  2. A CD4 percentage of less that 15 indicates severe immune suppression.

A CD4 percentage below 15% indicates severe immunosuppression.

2-30 What is the value of knowing the CD4 percentage?

The lower the CD4 percentage, the greater the risk of severe illness and death.

The CD4 percentage is not as accurate a predictor of death as the CD4 count is in adults.

2-31 Should both the clinical and immunological staging be used together?

Yes. It is best if both systems of staging are used together when deciding whether a child needs to be fast-tracked onto antiretroviral treatment. While the immunological staging indicates the degree of immunosuppression, the clinical staging indicates the effect of the immunosuppression. Both are important.

Fast-tracking means that the child should be started on antiretroviral treatment within 7 days of HIV diagnosis. Those who qualify for fast-tracking include children less than 1 year of age, or with a CD4 count below 200 cells/μl or less than 15%, with WHO stage 4 disease or MDR or XDR TB.

Yes. It is very important that informed consent is always obtained before any form of HIV testing is done. This means that counselling must be provided before obtaining consent.

Consent must be obtained before testing a child for HIV.

When children need to be tested, consent is usually obtained from a responsible adult, such as the parent or guardian (caretaker). Adolescents of 12 years or more can give their own consent, although it is always preferable to get consent from a parent or legal guardian as well. Children who give consent must receive pretest counselling which they can understand. If a child is not able to give consent, the person providing consent must receive appropriate counselling.

The new South African Children’s Bill recognises certain rights of children, including the right to consent to medical treatment if they are 12 years old and are sufficiently mature and capable of understanding the benefits, risks and social implications of the test. Therefore, the age of consent is 12 years in the new bill.

Adolescents aged 12 years or more can give consent for HIV testing

Abandoned or orphaned children have the same legal rights as other children. Adoptive or foster parents are legal guardians and can give consent. If there is no available guardian, the provincial minister for social services should be approached for consent. This is often needed when abandoned children who are ill are admitted to hospital.

The High Court may also be approached for consent. However, this is seldom necessary as the option only arises if a dispute occurs between legal guardians and doctors when treatment is considered to be lifesaving.

2-35 Can children be tested without their parents knowing?

Confidentiality is important and children of 12 years or more can be tested and keep the result of their HIV test from their parents if they so wish. Consent for the clinic or hospital staff to disclose the result of the HIV test to the parents must first be obtained from these children. Therefore, older children should be tested without their parents knowledge or permission if this is their wish.

2-36 Should young children take part in their parents’ decision on HIV testing or treatment?

Yes. A child less than 12 years of age who is able to understand should, if possible, agree with and support the parent’s decision on HIV testing or treatment. This is called assent and allows the children to participate in the choice their parents make.

Agreeing with their parents’ decision helps with acceptability and treatment compliance.

2-37 What counselling is needed before HIV testing?

As a diagnosis of HIV infection in a child has important implications for the parents and whole family, the parents should be counselled before they give consent for the child to be tested. In most children a positive diagnosis in the child implies HIV infection in the mother and often the father. The parents need to understand what HIV infection is, how a child becomes infected with HIV and the clinical presentation and course of HIV infection.

Age-appropriate counselling should be given to children aged between 7 and 12 years before assent is obtained.

Case study 1

A 15-year-old adolescent presents with a fever, sore throat, headache and general feeling of tiredness. On examination she has pharyngitis and a measles-like rash. When questioned she gives a history of recent sexual relations with an older man.

1. What is the probable diagnosis?

Acute seroconversion illness. This presents in some people two to four weeks after infection with HIV. The symptoms and signs usually disappear after a few weeks. Acute seroconversion illness is uncommon in young children.

2. How can the diagnosis be confirmed?

Usually an HIV screening test (rapid test) is done. However, the test may still be negative even though the person is infected with HIV because they are still in the window period.

3. What is the latent period?

This is the time between infection and the first appearance of symptoms and signs due to chronic HIV infection (i.e. symptomatic HIV infection).

4. How long is the latent period in children?

It is shorter than in adults where the latent period is usually a number of years. In children who are infected around the time of birth, the latent period is usually weeks or months (‘fast progressors’). It is longer in children who are infected via breast milk (‘slow progressors’).

5. What is often the first clinical sign of chronic HIV infection?

Persistent, painless, generalised lymphadenopathy.

Yes. At the age of 15 years she can give consent for the test. However, it is always preferable to also obtain the parents’ consent.

Case study 2

A two-year-old child is brought to a clinic by a woman who was HIV-positive when screened during her pregnancy. The infant was never breastfed. She reports that the child has had an itchy skin rash for the past few days. On examination he also has an enlarged liver and spleen, as well as a chronic otitis media.

1. Do you think this child has HIV infection?

Yes. The hepatosplenomegaly, skin rash and chronic otitis media all suggest symptomatic HIV infection, especially if the mother is HIV-positive. A positive rapid test would confirm the HIV infection.

2. What rash do you think this child has?

Pruritic papular eruption or ‘itchy bump disease’. It responds to topical steroids.

3. What other itchy skin rash is common in HIV-positive children?

Severe scabies.

4. How would you stage the infection?

The child has some features of stage 2 infection (a typical rash, hepatosplenomegaly and chronic upper respiratory tract infection).

5. What other clinical signs may be present in a child with stage 2 HIV infection?

Enlarged painless parotid glands, other skin rashes such as warts and molluscum, fungal nail infections, mouth ulcers and inflamed gums, other upper respiratory tract infections and Herpes zoster.

Consent must always be obtained first before testing anyone for HIV infection.

Case study 3

A six-month-old child with known HIV infection presents at the outpatients department of the local hospital. His mother says that he has lost weight recently, has a sore mouth and a chronic cough. On examination the child has oral candidiasis (thrush).

1. How would you stage this child’s HIV infection?

Stage 3, as he has oral candidiasis. He is probably malnourished as well.

2. What is the likely cause of his cough?

Pulmonary tuberculosis. However, he should be fully investigated as there are many other causes of chronic cough and lung infection in children with HIV infection.

3. What other lung diseases are seen in children with stage 3 HIV infection?

Severe recurrent bacterial pneumonia, symptomatic lymphoid interstitial pneumonitis and chronic lung disease.

4. Is Kaposi’s sarcoma a feature of stage 3 HIV infection?

No. This is a feature of stage 4 HIV infection.

5. Can the CD4 percentage be used to stage the clinical progress of HIV infection?

No. The CD4 percentage is used to immunologically stage the illness. Both the clinical and the immunological staging are important as they are used to decide when to start antiretroviral treatment.

6. Does this child have advanced HIV disease?

Yes. Advanced HIV disease in children is defined as stage 3 or 4 HIV infection.

Case study 4

A woman with asymptomatic HIV infection delivers a preterm infant who is clinically healthy. She wants to know whether her infant is also infected with HIV. The mother has a normal CD4 count.

1. Can a rapid test be used to determine whether this infant is infected with HIV?

No. In an HIV-exposed infant, these tests can only be used to diagnose HIV infection after 18 months. The rapid test will be positive even if the infant is not infected with HIV.

2. What test can be used to decide whether this child has HIV infection?

A PCR test should be done on this infant at birth. If the test is positive a confirmatory PCR test is done to confirm the diagnosis of HIV infection. Once the diagnosis is confirmed the child should be fast-tracked for antiretroviral treatment.

If the test is negative, the PCR test should be repeated at 10 weeks of age. For infants who receive 12 weeks of NVP as prophylaxis the PCR test should be repeated at 18 weeks of age. Furthermore, if the mother breastfeeds, the PCR test should be repeated on her HIV-exposed infant again six weeks after she stops breastfeeding, and at any stage during breast feeding period if clinical features of HIV infection develop.

A positive PCR test should be confirmed with a second PCR test before HIV infection is diagnosed in a child less than 18 months of age. At 18 months of age all HIV-exposed infants should be tested with a rapid HIV antibody test.

3. What is a CD4 count?

This is a test to determine whether the immune system has been damaged. The CD4 percentage rather than the CD4 count is used in children.

4. What is a normal CD4 percentage in children?

More than 25%. A CD4 percentage of 15 to 24% indicates moderate immune suppression while a CD4 percentage below 15% indicates severe immunosuppression.

5. What is the value of knowing a child’s CD4 percentage?

It helps to predict how fast the HIV infection will progress. Children with a low CD4 percentage will reach stage 3 or 4 sooner than children with a higher CD4 percentage.