1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of Age
MMWR Volume 43, RR 12, pages 1-10
Publication date: 09/30/1994
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September 30, 1994 / MMWR 43(RR-12);1-10
1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of AgeThe following CDC staff members prepared this report: M. Blake Caldwell, M.D., M.P.H. Division of HIV/AIDS CONSULTANTS Stephane Blanche, M.D. Savita Pahwa, M.D.
Necker Hospital Cornell Medical School
Paris, France New York Hospital
New York, NY
Mary Boland, R.N., M.S.N.
Children's Hospital of New Jersey Catherine Peckham, M.D.
Newark, NJ Institute of Child Health
London, England
William Borkowsky, M.D.
New York University Medical Center Merlin Robb, M.D.
New York, NY Walter Reed Army Medical Center
Washington, DC
Edward Connor, M.D.
Children's Hospital of New Jersey Gwendolyn Scott, M.D.
Newark, NJ University of Miami School of
Medicine
Louis Cooper, M.D. Miami, FL
St. Luke's Hospital
New York, NY William Shearer, M.D., Ph.D.
Baylor College of Medicine
Clemente Diaz, M.D. Houston, TX
University Medical Center
San Juan, PR Richard Stiehm, M.D.
University of California at Los
Leon Epstein, M.D. Angeles Medical Center
University of Rochester School Los Angeles, CA
of Medicine
Rochester, NY Rand Stoneburner, M.D.
World Health Organization
David Fleming, M.D. Geneva, Switzerland
Oregon Department of Human
Resources Rachel Strikof, M.P.H.
Portland, OR New York State Health Department
Albany, NY
Celine Hanson, M.D.
Baylor College of Medicine Pauline Thomas, M.D.
Houston, TX New York City Department of Health
New York, NY
Laurene Mascola, M.D.
Los Angeles County Health Department Pier Tovo, M.D.
Los Angeles, CA University of Turin
Turin, Italy
James Oleske, M.D.
Children's Hospital of New Jersey Catherine Wilfert, M.D.
Newark, NJ Duke University Medical Center
Durham, NC
Public Health Service Consultants
Centers for Disease Control National Institutes of Health and Prevention Ruth Berkelman, M.D. James Balsley, M.D., Ph.D. Blake Caldwell, M.D., M.P.H. Rodney Hoff, Ph.D. Kenneth Castro, M.D. Lynne Mofenson, M.D. Margaret Oxtoby, M.D. Philip Pizzo, M.D. Martha Rogers, M.D. John Ward, M.D. Health Resources Services Administration Beth RoyAcknowledgments We thank the following persons/projects for contributing data used to establish the CD4+ percent categories: Stephane Blanche, the French Colla- borative Study; Mary Glenn Fowler, the Women and Infants Transmission Study; Catherine Peckham, the European Collaborative Study; Margaret Heagarty, the New York City Perinatal HIV Transmission Collaborative Study; Savita Pahwa, North Shore University Hospital; and William Shearer and Celine Hanson, Baylor Medical Center. Summary This revised classification system for human immunodeficiency virus (HIV) infection in children replaces the pediatric HIV classification system published in 1987 (1). This revision was prompted by additional knowledge about the progression of HIV disease among children. In the new system, infected children are classified into mutually exclusive categories according to three parameters: a) infection status, b) clinical status, and c) immunologic status. The revised classification system reflects the stage of the child's disease, establishes mutually exclusive classification categories, and balances simplicity and medical accuracy in the classification process. This document also describes revised pediatric definitions for two acquired immunodeficiency syndrome-defining conditions. INTRODUCTION Following the initial report in 1982 of acquired immunodeficiency syndrome (AIDS) in children (2), it became evident that the clinical charac- teristics of AIDS in children were different from those in adults. In 1987, CDC published a classification system for children infected with human immunodeficiency virus (HIV) (1), the causative agent of AIDS. This classifi- cation system categorized clinical manifestations of HIV infection in children based on the limited data available early in the epidemic. New knowledge about the progression of HIV disease among children warranted revision of the 1987 classification system to better reflect the disease process. In 1991, CDC convened a working group of Public Health Service and other consultants to discuss revision of the pediatric HIV classification system. The 1994 revised classification system was developed through ongoing colla- borations with the consultants following the 1991 meeting. The goal of the working group was to construct a revised system that would:
In the new system (Table 1), HIV-infected children are classified into mutually exclusive categories according to three parameters: a) infection status, b) clinical status, and c) immunologic status. Once classified, an HIV-infected child cannot be reclassified in a less severe category even if the child's clinical or immunologic status improves. DIAGNOSING HIV INFECTION IN CHILDREN Diagnosis of HIV infection in children born to HIV-infected mothers (Box 1 Table B1) is complicated by the presence of maternal anti-HIV IgG antibody, which crosses the placenta to the fetus. Virtually all these children are HIV-antibody positive at birth, although only 15%-30% are actually infected. In uninfected children, this antibody usually becomes undetectable by 9 months of age but occasionally remains detectable until 18 months of age. Therefore, standard anti-HIV IgG antibody tests cannot be used to indicate reliably a child's infection status before 18 months of age (3). Polymerase chain reaction (PCR) and virus culture are probably the most sensitive and specific assays for detecting HIV infection in children born to infected mothers (4-6). Use of these assays can identify approximately 30%-50% of infected infants at birth and nearly 100% of infected infants by 3-6 months of age (7). The standard p24-antigen assay is less sensitive than either virus culture or PCR, especially when anti-HIV antibody levels are high, because it fails to detect immune-complexed p24 antigen (8). However, modification of the p24-antigen assay to dissociate immune complexes has increased its sensitivity in diagnosing HIV infection among children exposed to HIV (9). Other laboratory assays (e.g., anti-HIV IgA and ELISPOT/in vitro antibody production {IVAP}) have not been included in the algorithm for determining infection status because they are not commonly used. In addition, they are less sensitive than both PCR or virus culture. However, clinicians who determine a child's antiretroviral therapy on the basis of such assays may use them to classify the child as being infected. Some children develop severe clinical conditions resulting from HIV infection before their infection status has been sufficiently established. For the purposes of classification, a child meeting the criteria for AIDS in the 1987 case definition (10) should be considered HIV-infected -- even in the absence of definitive laboratory assays. Children born to mothers with HIV infection are defined as seroreverters (SRs) and are considered uninfected with HIV if they a) become HIV-antibody negative after 6 months of age, b) have no other laboratory evidence of HIV infection, and c) have not met the AIDS surveillance case definition criteria (Box 1 Table B1). Sufficient data are not available to conclusively define a child who is uninfected on the basis of viral detection tests. However, in certain situations (e.g., clinical trials), negative viral detection tests may be used presumptively to exclude infection. IMMUNOLOGIC CATEGORIES The three immunologic categories (Table 2) were established to categorize children by the severity of immunosuppression attributable to HIV infection. CD4+ T-lymphocyte depletion is a major consequence of HIV infection and is responsible for many of the severe manifestations of HIV infection in adults. For this reason, CD4+ counts are used in the adult HIV classification system (11). However, several findings complicate the use of CD4+ counts for assessing immunosuppression resulting from HIV infection in children. Normal CD4+ counts are higher in infants and young children than in adults and decline over the first few years of life (12-16). In addition, children may develop opportunistic infections at higher CD4+ levels than adults (17-19). Although insufficient data exist to correlate CD4+ levels with disease progression at all age groups, low age-specific CD4+ counts appear to correlate with conditions associated with immunosuppression in children (12,17,20,21). Therefore, despite these complications, classifi- cation based on age-specific CD4+ levels appears to be useful for describing the immunologic status of HIV-infected children. Fewer data are available on age-specific values for CD4+ T-lymphocyte percent of total lymphocytes than for absolute counts. However, the CD4+ T- lymphocyte percent has less measurement variability than the absolute count (22). To establish the age-specific values of CD4+ percent that correlate with the CD4+ count thresholds, CDC compiled data from selected clinical projects in the United States and Europe. The data included greater than 9,000 CD4+ counts, with the corresponding CD4+ percent determinations, from both HIV-infected and uninfected children less than 13 years of age. Nonparametric regression modeling was used to establish the CD4+ percent boundaries that best correlated with the CD4+ count boundaries in the classification system. The immunologic category classification (Table 2) is based on either the CD4+ T-lymphocyte count or the CD4+ percent of total lymphocytes. If both the CD4+ count and the CD4+ percent indicate different classification categories, the child should be classified into the more severe category. Repeated or follow-up CD4+ values that result in a change in classification should be confirmed by a second determination. Values thought to be in error should not be used. A child should not be reclassified to a less severe category regardless of subsequent CD4+ determinations. CLINICAL CATEGORIES Children infected with HIV or perinatally exposed to HIV may be classified into one of four mutually exclusive clinical categories based on signs, symptoms, or diagnoses related to HIV infection (Box 2 Table B2). As with the immunologic categories, the clinical categories have been defined to provide a staging classification (e.g., the prognosis for children in the second category would be less favorable than for those in the first category). Category N, not symptomatic, includes children with no signs or symptoms considered to be the result of HIV infection or with only one of the conditions listed in Category A, mildly symptomatic. Category N was separated from Category A partly because of the substantial amount of time that can elapse before a child manifests the signs or symptoms defined in Category B, moderately symptomatic. Also, more staging information can be obtained during this early stage of disease by separating Categories N and A. In addition, for children who have uncertain HIV-infection status (prefix E), Categories N and A may help to distinguish those children who are more likely to be infected with HIV (23) (i.e., children in Category EA may be more likely to be infected than children in Category EN). Category B includes all children with signs and symptoms thought to be caused by HIV infection but not specifically outlined under Category A or Category C, severely symptomatic. The conditions listed in Box 2 Table B2 are examples only; any other HIV-related condition not included in Category A or C should be included in Category B. Anemia, thrombocytopenia, and lymphopenia have defined thresholds in the new classification system (23). Category C includes all AIDS-defining conditions except lymphoid inter- stitial pneumonitis (LIP) (Box 3 Table B3). Several reports indicate that the prognosis for children with LIP is substantially better than that for children who have other AIDS-defining conditions (21,24,25). Thus, LIP has been separated from the other AIDS-defining conditions in Category C and placed in Category B. Signs and symptoms related to causes other than HIV infection (e.g., inflammatory or drug-related causes) should not be used to classify children. For example, a child with drug-related hepatitis or anemia should not be classified in Category B solely because these conditions may be associated with HIV infection. In contrast, a child with anemia or hepatitis should be classified in Category B when the condition is thought to be related to HIV infection. The criteria for diagnosing some conditions and determining whether a child's signs, symptoms, or diagnoses are related to HIV infection may not be clear in all cases, and therefore may require judgment of the clinicians and researchers using the classification system. Categories in the 1987 pediatric HIV classification system can be translated into categories in the 1994 system in most cases (Box 4 Table B4). Class P0 is now designated by the prefix "E," and Class P1 is now Class N. Children previously classified as P2A are now classified in more than one category, reflecting the different prognoses for children with different conditions included in the P2A category (e.g., children who have wasting syndrome have a worse prognosis than those who have lymphadenopathy). EFFECT ON THE AIDS SURVEILLANCE CASE DEFINITION FOR CHILDREN Because the classification system is used in conjunction with the AIDS case definition, the 1994 revision provided an opportunity to update certain features of the 1987 AIDS surveillance case definition for children less than 13 years of age (10). Although LIP is in Category B under the new pediatric HIV classification system, it will continue to be reportable to state and local health departments (along with the conditions in Category C) as an AIDS-defining condition in children. Two changes in the definitions for other conditions are summarized in the following bulletted text:
References
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Table 1
TABLE 1. Pediatric human immunodeficiency virus (HIV) classification *
======================================================================================================
Clinical categories
-----------------------------------------------------------
B: + Moderate C: + Severe
Immunologic N: No signs/ A: Mild signs/ signs/ signs/
categories symptoms symptoms symptoms symptoms
-------------------------------------------------------------------------------------
1: No evidence of
suppression N1 A1 B1 C1
2: Evidence of moderate
suppression N2 A2 B2 C2
3: Severe suppression N3 A3 B3 C3
-------------------------------------------------------------------------------------
* Children whose HIV infection status is not confirmed are classified by using the above grid
with a letter E (for perinatally exposed) placed before the appropriate classification code (e.g.,
EN2).
+ Both Category C and lymphoid interstitial pneumonitis in Category B are reportable to state
and local health departments as acquired immunodeficiency syndrome.
======================================================================================================
Table B1
BOX 1. Diagnosis of human immunodeficiency virus (HIV) infection in children *
DIAGNOSIS: HIV INFECTED
a) A child <18 months of age who is known to be HIV seropositive or born to an
HIV-infected mother and:
. has positive results on two separate determinations (excluding cord blood)
from one or more of the following HIV detection tests:
-- HIV culture,
-- HIV polymerase chain reaction,
-- HIV antigen (p24),
or
. meets criteria for acquired immunodeficiency syndrome (AIDS) diagnosis
based on the 1987 AIDS surveillance case definition (10).
b) A child >=18 months of age born to an HIV-infected mother or any child
infected by blood, blood products, or other known modes of transmission (e.g.,
sexual contact) who:
. is HIV-antibody positive by repeatedly reactive enzyme immunoassay (EIA)
and confirmatory test (e.g., Western blot or immunofluorescence assay
{IFA});
or
. meets any of the criteria in a) above.
DIAGNOSIS: PERINATALLY EXPOSED (PREFIX E)
A child who does not meet the criteria above who:
. is HIV seropositive by EIA and confirmatory test (e.g., Western blot or
IFA) and is <18 months of age at the time of test;
or
. has unknown antibody status, but was born to a mother known to be infected
with HIV.
DIAGNOSIS: SEROREVERTER (SR)
A child who is born to an HIV-infected mother and who:
. has been documented as HIV-antibody negative (i.e., two or more negative
EIA tests performed at 6-18 months of age or one negative EIA test after
18 months of age);
and
. has had no other laboratory evidence of infection (has not had two
positive viral detection tests, if performed);
and
. has not had an AIDS-defining condition.
* This definition of HIV infection replaces the definition published in the 1987
AIDS surveillance case definition (10).
Table 2
TABLE 2. Immunologic categories based on age-specific CD4+ T-lymphocyte counts
and percent of total lymphocytes
=======================================================================================
Age of child
------------------------------------------------------
<12 mos 1-5 yrs 6-12 yrs
---------------- ---------------- --------------
Immunologic category uL (%) uL (%) uL (%)
-------------------------------------------------------------------------------------
1: No evidence of suppression >=1,500 (>=25) >=1,000 (>=25) >=500 (>=25)
2: Evidence of moderate 750- 500- 200-
suppression 1,499 (15-24) 999 (15-24) 499 (15-24)
3: Severe suppression <750 (<15) <500 (<15) <200 (<15)
-------------------------------------------------------------------------------------
=======================================================================================
Table B2
BOX 2. Clinical categories for children with human immunodeficiency virus (HIV)
infection
CATEGORY N: NOT SYMPTOMATIC
Children who have no signs or symptoms considered to be the result of HIV
infection or who have only one of the conditions listed in Category A.
CATEGORY A: MILDLY SYMPTOMATIC
Children with two or more of the conditions listed below but none of the condi-
tions listed in Categories B and C.
-- Lymphadenopathy (>=0.5 cm at more than two sites; bilateral = one site)
-- Hepatomegaly
-- Splenomegaly
-- Dermatitis
-- Parotitis
-- Recurrent or persistent upper respiratory infection, sinusitis, or otitis
media
CATEGORY B: MODERATELY SYMPTOMATIC
Children who have symptomatic conditions other than those listed for Category
A or C that are attributed to HIV infection. Examples of conditions in clinical
Category B include but are not limited to:
-- Anemia (<8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia
(<100,000/mm3) persisting >=30 days
-- Bacterial meningitis, pneumonia, or sepsis (single episode)
-- Candidiasis, oropharyngeal (thrush), persisting (>2 months) in children
>6 months of age
-- Cardiomyopathy
-- Cytomegalovirus infection, with onset before 1 month of age
-- Diarrhea, recurrent or chronic
-- Hepatitis
-- Herpes simplex virus (HSV) stomatitis, recurrent (more than two episodes
within 1 year)
-- HSV bronchitis, pneumonitis, or esophagitis with onset before 1 month of
age
-- Herpes zoster (shingles) involving at least two distinct episodes or more
than one dermatome
-- Leiomyosarcoma
-- Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia
complex
-- Nephropathy
-- Nocardiosis
-- Persistent fever (lasting >1 month)
-- Toxoplasmosis, onset before 1 month of age
-- Varicella, disseminated (complicated chickenpox)
CATEGORY C: SEVERELY SYMPTOMATIC
Children who have any condition listed in the 1987 surveillance case definition
for acquired immunodeficiency syndrome (10), with the exception of LIP (Box 3).
Table B3
BOX 3. Conditions included in clinical Category C for children infected with human
immunodeficiency virus (HIV)
CATEGORY C: SEVERELY SYMPTOMATIC *
-- Serious bacterial infections, multiple or recurrent (i.e., any combination of
at least two culture-confirmed infections within a 2-year period), of the
following types: septicemia, pneumonia, meningitis, bone or joint infection,
or abscess of an internal organ or body cavity (excluding otitis media, super-
ficial skin or mucosal abscesses, and indwelling catheter-related infections)
-- Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
-- Coccidioidomycosis, disseminated (at site other than or in addition to lungs
or cervical or hilar lymph nodes)
-- Cryptococcosis, extrapulmonary
-- Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month
-- Cytomegalovirus disease with onset of symptoms at age >1 month (at a site
other than liver, spleen, or lymph nodes)
-- Encephalopathy (at least one of the following progressive findings present for
at least 2 months in the absence of a concurrent illness other than HIV
infection that could explain the findings): a) failure to attain or loss of
developmental milestones or loss of intellectual ability, verified by standard
developmental scale or neuropsychological tests; b) impaired brain growth or
acquired microcephaly demonstrated by head circumference measurements or brain
atrophy demonstrated by computerized tomography or magnetic resonance imaging
(serial imaging is required for children <2 years of age); c)acquired
symmetric motor deficit manifested by two or more of the following: paresis,
pathologic reflexes, ataxia, or gait disturbance
-- Herpes simplex virus infection causing a mucocutaneous ulcer that persists for
>1 month; or bronchitis, pneumonitis, or esophagitis for any duration
affecting a child >1 month of age
-- Histoplasmosis, disseminated (at a site other than or in addition to lungs or
cervical or hilar lymph nodes)
-- Kaposi's sarcoma
-- Lymphoma, primary, in brain
-- Lymphoma, small, noncleaved cell (Burkitt's), or immunoblastic or large cell
lymphoma of B-cell or unknown immunologic phenotype
-- Mycobacterium tuberculosis, disseminated or extrapulmonary
-- Mycobacterium, other species or unidentified species, disseminated (at a site
other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
-- Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site
other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
-- Pneumocystis carinii pneumonia
-- Progressive multifocal leukoencephalopathy
-- Salmonella (nontyphoid) septicemia, recurrent
-- Toxoplasmosis of the brain with onset at >1 month of age
-- Wasting syndrome in the absence of a concurrent illness other than HIV
infection that could explain the following findings: a) persistent weight loss
>10% of baseline OR b) downward crossing of at least two of the following
percantile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th,
5th) in a child >=1 year of age OR c) <5th percentile on weight-for-height
chart on two consecutive measurements, >=30 days apart PLUS a) chronic
diarrhea (i.e., at least two loose stools per day for >30 days) OR b)
documented fever (for >=30 days, intermittent or constant)
* See the 1987 AIDS surveillance case definition (10) for diagnosis criteria.
Table B4
BOX 4. Comparison of the 1987 and 1994 pediatric human immunodeficiency virus
classification systems
1987 Classification 1994 Classification
----------------------------------------------
P-0 Prefix "E"
P-1 N
P-2A A, B, and C
P-2B C
P-2C B
P-2D1 C
P-2D2 C
P-2D3 B
P-2E1 C
P-2E2 B
P-2F B
Source: http://wonder.cdc.gov/wonder/prevguid/m0032890/m0032890.asp accessed on January 26, 2006.