Current Trends Classification System for Human Immunodeficiency Viru (HIV) Infection in Children Under 13 Years of Age

INTRODUCTION

With the identification of the causative agent of the acquired immuno- deficiency syndrome (AIDS), a broad spectrum of clinical manifestations has been attributed to infection with the human immunodeficiency virus (HIV). With the exception of the CDC surveillance definition for AIDS (1,2), no standard definitions for other manifestations of HIV infection have been developed for children. Classification systems published to date have been developed primarily to categorize clinical presentations in adult patients and may not be entirely applicable to infants and children (3-5).

Physicians from institutions caring for relatively large numbers of HIV-infected children report that only about half of their patients with symptomatic illness related to the infection fulfill the criteria of the CDC surveillance definition for AIDS (6,7).

To develop a classification system for HIV infection in children, CDC convened a panel of consultants * consisting of clinicians experienced in the diagnosis and management of children with HIV infection; public health physicians; representatives from the American Academy of Pediatrics, the Council of State and Territorial Epidemiologists, the Association for Maternal Child Health and Crippled Children's Programs, the National Institute on Drug Abuse/Alcohol, Drug Abuse and Mental Health Adminis- tration, the National Institute of Allergy and Infectious Diseases/National Institutes of Health, and the Division of Maternal and Child Health/Health Resources and Services Administration; and CDC.

GOALS AND OBJECTIVES OF THE CLASSIFICATION SYSTEM

The system was designed primarily for public health purposes, including epidemiologic studies, disease surveillance, prevention programs, and health-care planning and policy. The panel attempted to devise a simple scheme that could be subdivided as needed for different purposes.

DEFINITION OF HIV INFECTION IN CHILDREN (Table 1)

Ideally, HIV infection in children is identified by the presence of the virus in blood or tissues, confirmed by culture or other laboratory detection methods. However, current tests -- including culture -- for detecting the virus or its antigens are not standardized and are not readily available. Detection of specific antibody to the virus is a sensitive and specific indicator of HIV infection in adults, since the majority of adults with antibody have had culture evidence of infection (8-10). Similar studies involving children have not been reported. Also, the presence of passively transferred maternal antibody in infants limits the interpretation of a positive antibody test result in this age group. Most of the consultants believed that passively transferred maternal HIV antibody could sometimes persist for up to 15 months. For this reason, two definitions for infection in children are needed: one for infants and children up to 15 months of age who have been exposed to their infected mothers perinatally, and another for older children with perinatal infection and for infants and children of all ages acquiring the virus through other means.

Infants and children under 15 months of age with perinatal infection -- Infection in infants and children up to 15 months of age who were exposed to infected mothers in the perinatal period may be defined by one or more of the following: 1) the identification of the virus in blood or tissues, 2) the presence of HIV antibody as indicated by a repeatedly reactive screening test (e.g., enzyme immunoassay) plus a positive confirmatory test (e.g., Western blot, immunofluorescence assay) in an infant or child who has abnormal immunologic test results indicating both humoral and cellular immunodeficiency (increased immunoglobulin levels, depressed T4 (T-helper) absolute cell count, absolute lymphopenia, decreased T4/T8 ratio) and who meets the requirements of one or more of the subclasses listed under class P-2 (described below), or 3) the confirmation that a child's symptoms meet the previously published CDC case definition for pediatric AIDS (1,2).

The infection status of other perinatally exposed seropositive infants and children up to 15 months of age who lack one of the above immunologic or clinical criteria is indeterminate. These infants should be followed up for HIV-related illness, and they should be tested at regular intervals for persistence of antibody to HIV. Infants and children who become sero- negative, are virus-culture negative (if blood or tissue samples are cultured), and continue to have no clinical or laboratory-confirmed abnor- malities associated with HIV infection are unlikely to be infected.

Older children with perinatal infection and children with HIV infection acquired through other modes of transmission -- HIV infection in these children is defined by one or more of the following: 1) the identification of virus in blood or tissues, 2) the presence of HIV antibody (positive screening test plus confirmatory test) regardless of whether immunologic abnormalities or signs or symptoms are present, or 3) the confirmation that the child's symptoms meet the previously published CDC case definition for pediatric AIDS (1,2).

These definitions apply to children under 13 years of age. Persons 13 years of age and older should be classified according to the adult classi- fication system (3).

CLASSIFICATION SYSTEM (Table 2)

Children fulfilling the definition of HIV infection discussed above may be classified into one of two mutually exclusive classes based on the presence or absence of clinical signs and symptoms (Table 2). Class Pediatric-1 (P-1) is further subcategorized on the basis of the presence or absence of immunologic abnormalities, whereas Class P-2 is subdivided by specific disease patterns. Once a child has signs and symptoms and is therefore classified in P-2, he or she should not be reassigned to class P-1 if signs and symptoms resolve.

Perinatally exposed infants and children whose infection status is indeterminate are classified into class P-0.

Class P-0. Indeterminate infection. Includes perinatally exposed infants and children up to 15 months of age who cannot be classified as definitely infected according to the above definition but who have antibody to HIV, indicating exposure to a mother who is infected.

Class P-1. Asymptomatic infection. Includes patients who meet one of the above definitions for HIV infection but who have had no previous signs or symptoms that would have led to classification in Class P-2.

These children may be subclassified on the basis of immunologic testing. This testing should include quantitative immunoglobulins, complete blood count with differential, and T-lymphocyte subset quantitation. Results of functional testing of lymphocytes (mitogens, such as pokeweed) may also be abnormal in HIV-infected children, but it is less specific in comparison with immunoglobulin levels and lymphocyte subset analysis, and it may be impractical.

Subclass A - Normal immune function. Includes children with no immune abnormalities associated with HIV infection.

Subclass B - Abnormal immune function. Includes children with one or more of the commonly observed immune abnormalities associated with HIV infection, such as hypergammaglobulinemia, T-helper (T4) lymphopenia, decreased T-helper/T-suppressor (T4/T8) ratio, and absolute lymphopenia. Other causes of these abnormalities must be excluded.

Subclass C - Not tested. Includes children for whom no or incomplete (see above) immunologic testing has been done.

Class P-2. Symptomatic infection. Includes patients meeting the above definitions for HIV infection and having signs and symptoms of infection. Other causes of these signs and symptoms should be excluded. Subclasses are defined based on the type of signs and symptoms that are present. Patients may be classified in more than one subclass.

Subclass A - Nonspecific findings. Includes children with two or more unexplained nonspecific findings persisting for more than 2 months, including fever, failure-to-thrive or weight loss of more than 10% of baseline, hepatomegaly, splenomegaly, generalized lymphadenopathy (lymph nodes measuring at least 0.5 cm present in two or more sites, with bilateral lymph nodes counting as one site), parotitis, and diarrhea (three or more loose stools per day) that is either persistent or recurrent (defined as two or more episodes of diarrhea accompanied by dehydration within a 2-month period).

Subclass B - Progressive neurologic disease. Includes children with one or more of the following progressive findings: 1) loss of developmental milestones or intellectual ability, 2) impaired brain growth (acquired microcephaly and/or brain atrophy demonstrated on computerized tomographic scan or magnetic resonance imaging scan), or 3) progressive symmetrical motor deficits manifested by two or more of these findings: paresis, abnormal tone, pathologic reflexes, ataxia, or gait distur- bance.

Subclass C - Lymphoid interstitial pneumonitis. Includes children with a histologically confirmed pneumonitis characterized by diffuse inter- stitial and peribronchiolar infiltration of lymphocytes and plasma cells and without identifiable pathogens, or, in the absence of a histologic diagnosis, a chronic pneumonitis -- characterized by bilateral reticulonodular interstitial infiltrates with or without hilar lymphadenopathy -- present on chest X-ray for a period of at least 2 months and unresponsive to appropriate antimicrobial therapy. Other causes of interstitial infiltrates should be excluded, such as tuberculosis, Pneumocystis carinii pneumonia, cytomegalovirus infection, or other viral or parasitic infections.

Subclass D - Secondary Infectious diseases. Includes children with a diagnosis of an infectious disease that occurs as a result of immune deficiency caused by infection with HIV.

Category D-1. Includes patients with secondary infectious disease due to one of the specified infectious diseases listed in the CDC surveillance definition for AIDS: Pneumocystis carinii pneumonia; chronic cryptosporidiosis; disseminated toxoplasmosis with onset after 1 month of age; extra-intestinal strongyloidiasis; chronic isosporiasis; candidiasis (esophageal, bronchial, or pulmonary); extrapulmonary cryptococcosis; disseminated histoplasmosis; noncu- taneous, extrapulmonary, or disseminated mycobacterial infection (any species other than leprae); cytomegalovirus infection with onset after 1 month of age; chronic mucocutaneous or disseminated herpes simplex virus infection with onset after 1 month of age; extrapulmonary or disseminated coccidioidomycosis; nocardiosis; and progressive multifocal leukoencephalopathy.

Category D-2. Includes patients with unexplained, recurrent, serious bacterial infections (two or more within a 2-year period) including sepsis, meningitis, pneumonia, abscess of an internal organ, and bone/joint infections.

Category D-3. Includes patients with other infectious diseases, including oral candidiasis persisting for 2 months or more, two or more episodes of herpes stomatitis within a year, or multider- matomal or disseminated herpes zoster infection.

Subclass E - Secondary Cancers. Includes children with any cancer described below in categories E-1 and E-2.

Category E-1. Includes patients with the diagnosis of one or more kinds of cancer known to be associated with HIV infection as listed in the surveillance definition of AIDS and indicative of a defect in cell-mediated immunity: Kaposi's sarcoma, B-cell non-Hodgkin's lymphoma, or primary lymphoma of the brain.

Category E-2. Includes patients with the diagnosis of other malig- nancies possibly associated with HIV infection.

Subclass F - Other diseases. Includes children with other conditions possibly due to HIV infection not listed in the above subclasses, such as hepatitis, cardiopathy, nephropathy, hematologic disorders (anemia, thrombocytopenia), and dermatologic diseases.

Reported by: AIDS Program. Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: This classification system is based on present knowledge and understanding of pediatric HIV infection and may need to be revised as new information becomes available. New diagnostic tests, particularly antigen detection tests and HIV-specific IgM tests, may lead to a better definition of HIV infection in infants and children. Information from several natural history studies currently under way may necessitate changes in the subclasses based on clinical signs and symptoms.

A definitive diagnosis of HIV infection in perinatally exposed infants and children under 15 months of age can be difficult. The infection status of these HIV-seropositive infants and children who are asymptomatic without immune abnormalities cannot be determined unless virus culture or other antigen-detection tests are positive. Negative virus cultures do not necessarily mean the child is not infected, since the sensitivity of the culture may be low. Decreasing antibody titers have been helpful in diagnosing other perinatal infections, such as toxoplasmosis and cytomega- lovirus. However, the pattern of HIV-antibody production in infants is not well defined. At present, close follow-up of these children (Class P-0) for signs and symptoms indicative of HIV infection and/or persistence of HIV antibody is recommended.

The parents of children with HIV infection should be evaluated for HIV infection, particularly the mother. The child is often the first person in such families to become symptomatic. When HIV infection in a child is suspected, a careful history should be taken to elicit possible risk factors for the parents and the child. Appropriate laboratory tests, including HIV serology, should be offered. If the mother is seropositive, other children should be evaluated regarding their risk of perinatally acquired infection. Intrafamilial transmission, other than perinatal or sexual, is extremely unlikely. Identification of other infected family members allows for appropriate medical care and prevention of transmission to sexual partners and future children (11,12).

The nonspecific term AIDS-related complex has been widely used to describe symptomatic HIV-infected children who do not meet the CDC case definition for AIDS. This classification system categorizes these children more specifically under Class P-2.

The development and publication of this classification system does not imply any immediate change in the definition of pediatric AIDS used by CDC for reporting purposes (1,2). Changes in this definition require approval by state and local health departments. However, changes in the definition for reporting cases have been proposed by CDC and are awaiting state and local approval.

Written comments are encouraged. They should be mailed to the AIDS Program, Center for Infectious Diseases, Centers for Disease Control, Atlanta, GA 30333.

References

1. CDC. Update: acquired immunodeficiency syndrome (AIDS) -- United States. MMWR 1984;32:688-91.

2. CDC. Revision of the case definition of acquired immunodeficiency syndrome for national reporting -- United States. MMWR 1985;34:373-5.

3. CDC. Classification system for human T-lymphotropic virus type III/ lymphadenopathy-associated virus infections. MMWR 1986;35:334-9.

4. Redfield RR, Wright DC, Tramont EC. The Walter-Reed staging classi- fication for HTLV-III/LAV infection. N Engl J Med 1986;314:131-2.

5. Haverkos HW, Gotlieb MS, Killen JY, Edelman R. Classification of HTLV- III/LAV-related diseases {Letter}. J Infect Dis 1985;152:1095.

6. Pawha S, Kaplan M, Fikrig S, et al. Spectrum of human T-cell lympho- tropic virus type III infection in children. JAMA 1986;255:2299-305.

7. Scott GB, Anisman L, Zaldivar ML, Parks WP. Natural history of HTLV- III/LAV infections in children. Presented at the International Conference on AIDS, Paris, June 1986.

8. Ward JW, Grindon AJ, Feorino PM, Schable C, Parvin M, Allen JR. Labor- atory and epidemiologic evaluation of an enzyme immunoassay for antibodies to HTLV-III. JAMA 1986;256:357-61.

9. Peterman TA, Jaffe HW, Feorino PM, et al. Transfusion-associated acquired immunodeficiency syndrome in the United States. JAMA 1985;254:2913-7.

10. Jaffe HW, Feorino PM, Darrow WW, et al. Persistent infection with human T-lymphotropic virus type III/lymphadenopathy-associated virus in apparently healthy homosexual men. Ann Intern Med 1985;102:627-8.

11. CDC. Recommendations for assisting in the prevention of perinatal transmission of human T-lymphotropic virus type III/lymphadenopathy- associated virus and acquired immunodeficiency syndrome. MMWR 1985;34: 721-6,731-2.

12 CDC. Additional recommendations to reduce sexual and drug abuse-related

transmission of human T-lymphotropic virus type III/lymphadenopathy- associated virus. MMWR 1986;35:152-5.

• P Brunell, MD, R Daum, MD, American Academy of Pediatrics; J Chin, MD, State Epidemiologist, California Dept of Health Svcs; L Cooper, MD, St Luke's-Roosevelt Hospital Center, New York City; J Oleske, MD, MPH, L Epstein, MD, Univ of Medicine and Dentistry of New Jersey; N Luban, MD, Children's Hospital National Medical Center, Washington, DC; S Mailloux, MD, Assoc of Maternal Child Health and Crippled Children's Programs; S Pawha, MD, North Shore Univ Hospital, Cornell University Medical Center, Manhassett, NY; G Scott, MD, Univ of Miami School of Medicine; R Stiehm, MD, Univ of California, Los Angeles; P Thomas, MD, New York City Dept of Health; D Wara, MD, Univ of California, San Francisco; D Williams, MD, Los Angeles County Hospital: J Witte, MD, MPH, Florida Dept of Health and Rehabilitative Svcs.

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