Compiled by Dr. Nitin Shah
Hon. Treasurer, Indian Academy of Pediatrics, Hon. Pediatrician, Urban Health Center, Dharavi, Mumbai
for Pediatric HIV/AIDS, First National Conference (Held on 3^rd & 4^th November, 2001 at Delhi)

Introduction

Since its first description in 1981, AIDS has spread like wild fire to engulf all the continents of the world to assume proportions of a pandemic. Initially children were not identified as the principal victims of the AIDS epidemic. However, with more data becoming available, the gravity of the problem is being better understood and HIV infection in children and adolescents is being recognized as a major issue.

The children and adolescents acquire HIV infection through one of the following routes:

1. Perinatal transmission: From an infected mother to her fetus or newborn baby. This route is commonly referred to as the vertical transmission;
2. Through the receipt of infected blood or blood products or i. v. drug abuse or
3. Through sexual transmission.

The vertical transmission is the predominant route of transmission and accounts for over 85% of pediatric HIV infections. The transmission through the receipt of blood or blood products has been minimized, if not eliminated in the Western countries through the use of safe transfusion practices. Although, the Indian government, the state governments and the Blood Bank societies are making concerted efforts, much still needs to be done (1,2). Sexual transmission is a route by which adolescents can acquire the infection. Young children, as victims of sexual abuse, may acquire the infection through the sexual transmission route.

The clinical manifestations of HIV infection in children are different from those in adults. The reasons for this phenomenon could be:

1. The immune system of perinatally infected young children is immature. This may allow widespread seeding into various organs;
2. Some organs like the brain may be susceptible to the effects of the virus in a manner different from that observed in adults.
3. The pattern of opportunistic infections in children is different from those in adults.

Clinical Manifestations

Differences in the Manifestations of HIV Infection in Children & those in Adults

The clinical manifestations of HIV infection and AIDS are varied. The manifestations of pediatric HIV infection and AIDS are different from those of AIDS in adults. The features such as lymphocytic interstitial pneumonitits (LIP), chronic parotid swelling and HIV encephalopathy are encountered more frequently in young children than in adults. Kaposi's sarcoma that is so frequent in the HIV- infected adults is hardly ever reported in children. Opportunistic infections are the hallmark of HIV infection in both children and adults. But, the pattern could be quite different. Pneumocystis carinii pneumonia and recurrent bacterial infections are the common opportunistic infections encountered in children. Mycobacterium avium complex, histoplasma and cryptococcal infections are more frequent in HIV- infected adults than in HIV- infected children.

Patterns of Manifestations

Most infected infants do not have any abnormal findings on clinical examination at birth. The initial manifestations of the disease are mild and non- specific. These include lymphadenopathy, chronic or recurrent diarrhea, failure to thrive and oral thrush. The mean age of presentation in perinatally infected children is 17 months; however, there are occasions when the manifestations are not apparent even till late in the first decade. (3) On the basis of age of presentation, three patterns have been described:

1. Manifestations in the form of opportunistic infections and neurological manifestations are apparent within the first few months of life. The children demonstrating this pattern are considered "rapid progressors" as they tend to have a natural downhill course.
2. The second pattern consists of children who show a more gradual development of manifestations. These children tend to develop manifestations after the age of 1 year and they usually present with failure to thrive, recurrent bacterial infections and lymphoid interstitial pneumonitis.
3. The third group comprises of children who manifest later in childhood with minor manifestations and behave as "adult equivalents" ^{4, 5, 6, 7, 8}.

Children acquiring infection via transfusion of infected blood tend to have an incubation period ranging up to 4 years. The manifestations of HIV infection in these children are similar to those in perinatally infected children.

HIV infection affects growth. Diarrhea, opportunistic infections and lymphadenopathy are some of the commonly encountered manifestations. Hepatomegaly, splenomegaly, parotid swelling, LIP and skin manifestations are also common. Nephropathy and cardiomyopathy have been described, but they are unlikely to be isolated early manifestations of asymptomatic HIV infection.

Hepatomegaly

It is a common manifestation of pediatric HIV disease (9, 10). It is likely to be caused by the replication of the virus in the liver. Malnutrition, fatty liver, steatosis, CMV infection and malignancy can be some of the other causes for hepatomegaly in these children. In perinatally infected infants development of hepatomegaly by 3 months of age indicates a poor prognosis.

Lymphadenopathy

Lymphadenopathy is also a common clinical manifestation of HIV disease in children (10, 11). The replication of the virus in the lymphoid tissue is the primary cause of lymph node enlargement. Associated conditions such as tuberculosis, infections with other mycobacterial species and viruses and malignancies like lymphoma and lymphosarcoma could also be responsible for lymphadenopathy.

Parotid swelling

The painless parotid swelling develops gradually in patients with HIV disease. It may be due to the direct infection of the parotid gland by HIV or due to lymphocytic infiltration of the gland.

Lymphoid Interstitial Pneumonitis and Pulmonary Lymphoid Hyperplasia

These disorders usually have an insidious onset. Cough and tachypnea are early clinical features. Dyspnea and clubbing develop later. There are often no findings in the chest unless recurrent bacterial infections have led to bronchiectasis. Diffuse bilateral reticulondular or interstitial infiltrates and hilar lymphadenopathy are often noted on the chest radiograph or tomogram. A presumptive diagnosis is made on the basis of clinical and radiological findings. However, opportunistic bacterial, viral and mycobacterial infections that can present with similar clinical and radiological findings need to be excluded. Definitive diagnosis is made on lung biopsy.

Skin Manifestations^{9, 10, 12}

Several skin diseases and manifestations are seen in children infected with HIV. Viral, bacterial and fungal infections have been very frequently reported in HIV infected children. These usually tend to be severe and resistant to therapy. The common skin infections seen in HIV infected children are listed in Table 1. Seborrheic, atopic and generalized dermatitis, lesions due to nutritional deficiency, eczema, psoriasis, drug eruptions and alopecia are the common non- infectious skin lesions seen.

Manifestations due to hematological abnormalities

Pediatric HIV disease is associated with anemia presenting as pallor and thrombocytopenia, which can present with petechiae and ecchymoses is likely to bediagnosed as "immune thrombocytopenia".

Cardiac Manifestations

Perinatally infected children do not seem to be excessively prone to develop congenital cardiac malformations. But, cardiovascular diseases, although usually clinically silent, do develop in HIV infected children. Cardiomegaly, congestive cardiac failure, non- bacterial thrombotic endocarditis, cardiomyopathy, pericardial effusion, cardiac tamponade, conduction disturbances and sudden death are known to occur. Cardiomyopathy is frequently accompanies HIV encephalopathy (13).

Gastrointestinal Manifestations

Diarrhea is one of the commonest clinical manifestations in HIV- infected infants and children (9, 10, 11). It can be acute, recurrent or persistent. The mechanisms responsible for diarrhea include infection due to a variety of organisms, other inflammatory processes and malabsorption of carbohydrate and fats (14, 15). The common infectious agents responsible for pediatric diarrhea include viruses such Rotavirus and CMV; Bacteria like Shigella, Camylobacter, E. coli and atypical mycobacterial species and other organisms such as Cryptosporidium parvum, Giardia, Cryptococcus and Isospora belli. HIV, itself is presumed to be responsible for diarrhea if no organism is isolated. Other gastrointestinal manifestations seen in HIV infected children include dysphagia, retro- sternal pain, difficulty in drinking fluids and excessive salivation and are related to opportunistic infections.

Affection of Physical Growth

HIV infection has an adversely affects the growth of infected children. The parameters such as weight, length and head circumference show deviation from the normal. The retardation of growth can be seen as early as 4- 6 months of age in perinatally infected children (16). Factors such as low birth weight, decreased food intake, diarrhea, malabsorption, long- standing diseases of the heart, kidney and lungs, micronutrient deficiencies and repeated episodes of infection also contribute to growth retardation (17).

Neurological Manifestations

HIV encephalopathy can present with developmental delay or with regression of milestones (12). The developmental delay that begins in infancy could be due to congenital opportunistic infections such as toxoplasmosis or CMV or rubella infection rather than due to HIV infection, alone. HIV infected infants are exposed to additional risk factors (low birth weight, poor prenatal care, maternal illness, drug abuse and maternal death) that can also lead to developmental delay. HIV encephalopathy can present with loss of previously acquired milestones, cognitive impairment, neuropsychiatric problems, focal neurological deficits, spasticity, acquired microcephaly and abnormal extra- pyramidal and cerebellar signs. Emotional lability, hyperactivity and lethargy are late signs of encephalopathy. The presence of encephalopathy indicates a poor prognosis. It must be remembered that opportunistic infections like the tuberculous meningitis, cryptococcal meningitis, pyogenic meningitis and CNS toxoplasmosis can also give rise to neurological manifestations in HIV- infected children (18)

Malignancy

Children infected with HIV have a higher chance of developing malignancy than other children. The common malignancies associated with childhood AIDS are non- Hodgkin's lymphoma, leiomyomas, leukemias and leiomyosarcoma.

Nephropathy

The manifestations of renal disease associated with AIDS include proteinuria, hematuria, hypertension, renal tubular acidosis, acute renal failure and progression to end- stage renal disease. In the initial stages, the patient is asymptomatic and the evidence of nephropathy can only be found only on laboratory testing.

Other Manifestations

Prolonged or intermittent fever and persistent cough have been predominant symptoms noted in a study (18). CMV retinitis, anterior uveitis, retinal detachment and vitreous hemorrhage are some of the ocular lesions observed in HIV- infected children (19).

Opportunistic Infections

Opportunistic infections constitute one of the commonest features of symptomatic HIV infection in children. In any immunodeficient disorder, the type of organisms predominantly encountered depends upon the type of immune defect. HIV infection directly or indirectly affects the cellular as well as the humoral arms of the immune system. In addition, associated factors such as malnutrition, use of immunosuppressive drugs and presence of indwelling catheters add to the defective immunity. Hence, these children suffer from viral, bacterial, fungal, protozoan as well as mycobacterial opportunistic infections.

Unusual organisms cause infections in the immunosuppressed HIV- infected children. In addition, these infections are of unusual severity (e.g. progressive varicella syndrome caused by varicella virus or retinitis, colitis and pneumonitis caused by the cytomegalovirus); resistant to usual treatment (e.g. oral candidiasis resistant to topical clotrimazole) and occur at unusual sites (e.g. propensity of extra- pulmonary tuberculosis in HIV- infected children).

Classification and Grading of Clinical Manifestations

The CDC Classification

The Clinical classification provided by The Center for Disease Control (CDC) divides HIV- infected children with symptomatic HIV infection (20) into 4 categories depending upon the severity of symptoms (Table 2). It is used in conjunction with the degree of immunosuppression in an effort to provide information about the severity of manifestations and prognosis. The degree of immunosuppression is assessed by the degree of decline in the CD4 counts (Table 3).

Classification on the Basis of Manifestations in Countries with Limited Resources

Many countries do not have adequate facilities for undertaking laboratory studies for confirming the diagnosis of HIV infection in children. Therefore, the World Health Organization looked at the possibility of evolving criteria whereby symptomatic HIV infection could be diagnosed without the aid of laboratory testing. This classification consists of major (Weight loss or abnormally slow growth or failure to thrive, chronic diarrhea for over 1 month, prolonged fever for more than one month) and minor signs (Generalized lymph node enlargement, oropharyngeal candidiasis, recurrent common bacterial infections, persistent cough for more than one month, generalized dermatitis and confirmed HIV infection in the mother) (21). The presence of at least two major signs in association with at least two minor signs in the absence of any known cause of immunosuppression is considered to be sufficient evidence for the diagnosis of pediatric AIDS. Unfortunately, these diagnostic criteria demonstrated a sensitivity of 37% to 40%. (22, 23, 24).

The National AIDS Control Organization has devised a clinical case definition of AIDS in children aged below 12 years of age (25). It combines the results obtained by laboratory tests with clinical manifestations (Table 4). For diagnosing HIV infection with certainty, use of laboratory testing should be resorted to. However, the classification put forward by the WHO provides clues regarding suspecting HIV infection on clinical grounds.

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