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F CDC Classification System for HIV Infections INTRODUCTION Persons infected with the etiologic retrovirus of acquired immunodeficiency syndrome (AIDS) ( 1-4). may present with a variety of manifestations ranging from asymptomatic infec- tion to severe immunodeficiency and life-threatening secondary infectious diseases or can- cers. The rapid growth of knowledge about human T-lymphotropic virus type 111/ Iymphadenopathy-associated virus (HTLV-111/LAV) has resulted in an increasing need for a system of classifying patients within this spectrum of clinical and laboratory findings attri- butable to HTLV-111/LAV infection (5- 7). Various means are now used to describe and assess patients with manifestations of HTLV-111/LAV infection and to describe their signs, symptoms, and laboratory findings. The surveillance definition of AIDS has proven to be extremely valuable and quite reliable for some epidemiologic studies and clinical assessment of patients with the more severe manifestations of disease. However, more inclusive definitions and classifications of HTLV-111/LAV infection are needed for optimum patient care, health planning, and public health control strategies, as well as for epidemiologic studies and special surveys. A broadly applicable, easily understood classification system should also facilitate and clarify communication about this disease. In an attempt to formulate the most appropriate classification system, CDC has sought the advice of a panel of expert consultants" to assist in defining the manifestations of HTLV-111/ LAV infection. GOALS AND OBJECTIVES OF THE CLASSIFICATION SYSTEM The classification system presented in this report is primarily applicable to public health purposes, including disease reporting and surveillance, epidemiologic stud~s, prevention and control activities, and public health policy and planning. Immediate applications of such a system include the classification of infected persons for reporting of cases to state and local public health agencies, and use in various disease coding and recording systems, such as the forthcoming 1 0th revision of the International Classifica- t~n of Diseases. The AIDS virus has been variously termed human T-lymphotropic virus type 111 (HTLV-111), Iymphadenopathy-associated virus (LAV), AlDS-associated retrovirus (ARV), or human immunodeficien- cy virus (HIV). The designation human immunodeficiency virus (HIV) has recently been proposed by a subcommittee of the International Committee for the Taxonomy of Viruses as the appropriate name for the retrovirus that has been implicated as the causative agent of AIDS (4). tThe following persons served on the review panel: DS Burke, MD, RR Redfield, MD, Walter Reed Army Institute of Research, Washington, DC; J Chin, MD, State Epidemiologist, California Department of Health Services; LZ Cooper, MD, St Luke's-Roosevelt Hospital Center, New York City; JP Davis, MD, State Epidemiologist, Wisconsin Division of Health; MA Fischl, MD, University of Miami School of Medi- cine, Miami, Florida; G Friedland, MD, Albert Einstein College of Medicine, New York City; MA Johnson, MD, Dl Abrams, MD, San Francisco General Hospital; D Mildvan, MD, Beth Israel Medical Center, New York City; CU Tuezon, MD, George Washington University School.of Medicine, Washington, DC; RW Price, MD, Memorial Sloan-Kettering Cancer Center, New York City; C Konigsberg, MD, Broward County Public Health Unit, Fort Lauderdale, Florida; MS Gottlieb, MD, University of California-Los Angeles Medical Center; representatives of the National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institutes of Health; Center for Infectious Diseases, CDC. SOURCE: Repnnted from Morbidity and Mortality Weekly Report 35 (May 23, 1986):334-339. 320
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APPENDIX F 321 DEFINITION OF HTLV-111/LAV INFECTION The most specific diagnosis of HTLV-111/LAV infection is by direct identification of the virus in host tissues by virus isolation; however, the techniques for isolating HTLV-111/LAV cur- rently lack sensitivity for detecting infection and are not readily available. For public health purposes, patients with repeatedly reactive screening tests for HTLV-111/LAV antibody (e.g., enzyme-linked immunosorbent assay) in whom antibody is also identified by the use of sup- plemental tests (e.g., Western blot, immunofluorescence assay) should be considered both in- fected and infective (8-10). Although HTLV-111/LAV infection is identified by isolation of the virus or, indirectly, by the preser,ce of antibody to the virus, a presumptive clinical diagnosis of HTLV-111/LAV infection has been made in some situations in the absence of positive virologic or serologic test results. There is a very strong correlation between the clinical manifestations of AIDS as defined by CDC and the presence of HTLV-111/LAV antibody ( 1 1-14 ). Most persons whose clinical illness fulfills the CDC surveillance definition for AIDS will have been infected with the virus ( 12-14 ). CLASSIFICATION SYSTEM This system classifies the manifestations of HTLV-111/LAV infection into four mutually ex- clusive groups, designated by Roman numerals I through IV (Table 5). The classification system applies only to patients diagnosed as having HTLV-III/LAV infection (see previous sec- tion, DEFINITION OF HTLV-111/LAV INFECTION). Classification in a particular group is not explicitly intended to have prognostic significance, nor to designate severity of illness. Howev- er, classification in the four principal groups, I-IV, is hierarchical in that persons classified in a particular group should not be reclassified in a preceding group if clinical findings resolve, since clinical improvement may not accurately reflect changes in the severity of the underlying disease. Group I includes patients with transient signs and symptoms that appear at the time of, or shortly after, initial infection with HTLV-111/LAV as identified by laboratory studies. All patients in Group I will be reclassified in another group following resolution of this acute syndrome. TABLE 5. Summary of classification system for human T-lymphotropic virus type 111/ I ym phaden opath y-ass ociated vi rus Group I. Acute infection Group I I. Asymptomatic infection. Group lilt Persistent generalized Iymphadenopathy. Group IV. Other disease Subgroup A. Constitutional disease Subgroup B. Neurologic disease Subgroup C. Secondary infectious diseases Category C-1. Specified secondary infectious diseases listed in the CDC surveillance definition for AlDSt Category C-2. Other specified secondary infectious diseases Subgroup D. Secondary cancers" Subgroup E. Other conditions Patients in Groups II and lil may be subclassified on the basis of a laboratory evaluation. "includes those patients whose clinical presentation fulfills the definition of AIDS used by CDC for na- tional reporting.
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322 APPENDIX F Group 11 includes patients who have no signs or symptoms of HTLV-111/LAV infection. Pa- tients in this category may be subclassified based on whether hematologic and/or immuno- logic laboratory studies have been done and whether results are abnormal in a manner consis- tent with the effects of HTLV-IIVLAV infection. Group 111 includes patients with persistent generalized Iymphadenopathy, but without find- ings that would lead to classification in Group IV. Patients in this category may be subclassi- fied based on the results of laboratory studies in the same manner as patients in Group 11. Group IV includes patients with clinical symptoms and signs of HTLV-111/LAV infection other than or in addition to Iymphadenopathy. Patients in this group are assigned to one or more subgroups based on clinical findings. These subgroups are: A. constitutional disease; B. necrologic disease; C. secondary infectious diseases; D. secondary cancers; and E. other conditions resulting from HTLV-111/LAV infection. There is no a priori hierarchy of severity among subgroups A through E, and these subgroups are not mutually exclusive. Definitions of the groups and subgroups are as follows: Group 1. Acute HTLV-111/LAV Infection. Defined as a mononucleosis-like syndrome, with or without aseptic meningitis, associated with seroconversion for HTLV-111/LAV antibody ( 15 16). Antibody seroconversion is required as evidence of initial infection; current viral iso- lati~on procedures are not adequately sensitive to be relied on for demonstrating the onset of infection. Group 11. Asymptomatic HTLV-111/LAV Infection. Defined as the absence of signs or symptoms of HTLV-111/LAV infection. To be classified in Group 11, patients must have had no previous signs or symptoms that would have led to classification in Groups 111 or IV. Patients whose clinical findings caused them to be classified in Groups 111 or IV should not be reclassi- fied in Group 11 if those clinical findings resolve. Patients in this group may be subclassified on the basis of a laboratory evaluation. Labora- tory studies commonly indicated for patients with HTLV-111/LAV infection include, but are not limited to, a complete blood count (including differential white blood cell count) and a platelet count. Immunologic tests, especially T-lymphocyte helper and suppressor cell counts, are also an important part of the overall evaluation. Patients whose test results are within normal limits, as well as those for whom a laboratory evaluation has not yet been completed, should be differentiated from patients whose test results are consistent with defects associated with HTLV-111/LAV infection (em, Iymphopenia, thrombocytopenia, decreased number of helper _ . . [T4] T-lymphocytes). Group 111. Persistent Generalized Lymphadenopathy (PGL). Defined as palpable Iym- phadenopathy (Iymph node enlargement of 1 cm or greater) at two or more extra-inguinal sites persisting for more than 3 months in the absence of a concurrent illness or condition other than HTLV-111/LAV infection to explain the findings. Patients in this group may also be subclassified on the basis of a laboratory evaluation, as is done for asymptomatic patients in Group 11 (see above). Patients with PGL whose clinical findings caused them to be classified in Group IV should not be reclassified in Group 111 if those other clinical findings resolve. Group lift Other HTLV-111/LAV Diisease. The clinical manifestations of patients in this group may be designated by assignment to one or more subgroups (A-E) listed below. Within Group IV, subgroup classification is independent of the presence or absence of Iymphade- nopathy. Each subgroup may include patients who are minimally symptomatic, as well as pa- tients who are severely ill. Increased specificity for manifestations of HTLV-111/LAV infection, if needed for clinical purposes or research purposes or for disability determinations, may be achieved by creating additional divisions within each subgroup.
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APPENDIX F 323 Subgroup ~ Constitutional disease. Defined as one or more of the following: fever per- sisting more than 1 month, involuntary weight loss of greater than 10% of baseline, or diar- rhea persisting more than 1 month; and the absence of a concurrent illness or condition other than HTLV-111/LAV infection to explain the findings. Subgroup B. Neurologic disease. Defined as one or more of the following: dementia, myelopathy, or peripheral neuropathy; and the absence of a concurrent illness or condition other than HTLV-111/LAV infection to explain the findings. Subgroup C. Secondary infectious diseases. Defined as the diagnosis of an infectious disease associated with HTLV-111/LAV infection and/or at least moderately indicative of a defect in cell-mediated immunity. Patients in this subgroup are divided further into two categories: Category C-1. Includes patients with symptomatic or invasive disease due to one of 12 specified secondary infectious diseases listed in the surveillance definition of AIDS§: Pneumocystis carinii pneumonia, chronic cryptosporidiosis, toxoplasmosis, extra- intestinal strongyloidiasis, isosporiasis, candidiasis (esophageal, bronchial, or pulmo- nary), cryptococcosis, histoplasmosis, mycobacterial infection with Mycobacterium avium complex or M. kansasii, cytomegalovirus infection, chronic mucocutaneous or disseminated herpes simplex virus infection, and progressive multifocal leukoen- cephalopathy. Category C-2. Includes patients with symptomatic or invasive disease due to one of six other specified secondary infectious diseases: oral hairy leukoplakia, multidermatomal herpes poster, recurrent Salmonella bacteremia, nocardiosis, tuberculosis, or oral can- didiasis (thrush). Subgroup D. Secondary cancers. Defined as the diagnosis of one or more kinds of cancer known to be associated with HTLV-111/LAV infection as listed in the surveillance definition of AIDS and at least moderately indicative of a defect in cell-mediated immunity,: Kaposi's sarcoma, non-Hodgkin's Iymphoma (small, noncleaved Iymphoma or immunoblastic sarco- ma), or primary Iymphoma of the brain. Subgroup E. Other conditions in HTLV-111/LAV infection. Defined as the presence of other clinical findings or diseases, not classifiable above, that may be attributed to HTLV-111/ LAV infection and/or may be indicative of a defect in cell-mediated immunity. Included are patients with chronic Iymphoid interstitial pneumonitis. Also included are those patients whose signs or symptoms could be attributed either to HTLV-111/LAV infection or to another coexisting disease not classified elsewhere, and patients with other clinical illnesses, the course or management of which may be complicated or altered by HTLV-111/LAV infection. Examples include: patients with constitutional symptoms not meeting the criteria for sub- group IV-A; patients with infectious diseases not listed in subgroup IV-C; and patients with neoplasms not listed in subgroup IV-D. Reported by Center for Infectious Diseases, CD C. Editorial Note: The classification system is meant to provide a means of grouping patients infected with HTLV-111/LAV according to the clinical expression of disease. It will require periodic revision as warranted by new information about HTLV-111/LAV infection. The defini §This subgroup includes patients with one or more of the specified infectious diseases listed whose clinical presentation fulfills the definition of AIDS as used by CDC for national reporting. 1lThis subgroup includes those patients with one or more of the specified cancers listed whose clinical presentation fulfills the definition of AIDS as used by CDC for national reporting.
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324 APPENDIX F tion of particular syndromes will evolve with increasing knowledge of the significance of cer- tain clinical findings and laboratory tests. New diagnostic techniques, such as the detection of specific HTLV-111/LAV antigens or antibodies, may add specificity to the assessment of pa- tients infected with HTLV-111/LAV. The classification system defines a limited number of specified clinical presentations. Pa- tients whose signs and symptoms do not meet the criteria for other groups and subgroups, but whose findings are attributable to HTLV-111/LAV infection, should be classified in sub- group IV-E. As the classification system is revised and updated, certain subsets of patients in subgroup IV-E may be identified as having related groups of clinical findings that should be separately classified as distinct syndromes. This could be accomplished either by creating additional subgroups within Group IV or by broadening the definitions of the existing sub- groups. Persons currently using other classification systems (6-7) or nomenclatures (e.g., AIDS- related complex, Iymphadenopathy syndrome) can find equivalences with those systems and terminologies and the classification presented in this report. Because this classification system has only four principal groups based on chronology, presence or absence of signs and symptoms, and the type of clinical findings present, comparisons with other classifications based either on clinical findings or on laboratory assessment are easily accomplished. This classification system does not imply any change in the definition of AIDS used by CDC since 1981 for national reporting. Patients whose clinical presentations fulfill the surveil- lance definition of AIDS are classified in Group IV. However, not every case in Group IV will meet the surveillance definition. Persons wishing to comment on this material are encouraged to send comments in writing to the AIDS Program, Center for Infectious Diseases, CDC. References Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retrovi- ruses (HTLV-111) from patients with AIDS and at risk for AIDS. Science 1984;224:500-3. Barre-Sinoussi F. Chermann JC, Rey F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1383;220:868-71. Levy JA, Hoffman AD, Kramer SM, Landis JA, Shimabukuro JM, Oshiro LS. Isolation of Iymphocy- topathic retroviruses from San Francisco patients with AIDS. Science 1984;225:840-2. 4. Coffin J. Haase A, Levy JA, et al. Human immunodeficiency viruses [Letter]. Science 1986;232: 697. 5. CDC. Revision of the case definition of acquired immunodeficiency syndrome for national re- porting-United States. MMWR 1 985;34:373-5. 6. Haverkos HW, Gottlieb MS, Killen JY, Edelman R. Classification of HTLV-111/LAV-related diseases [Letter]. J Infect Dis 1 985; 1 52:1 095. 7. Redfield RR, Wright DC, Tramont EC. The Walter Reed staging classification for HTLV-111/LAV infec- tion. N Engl J Med 1986;314:131-2. 8. CDC. Antibodies to a retrovirus etiologically associated with acquired immunodeficiency syndrome (AIDS) in populations with increased incidences of the syndrome. MMWR 1984;33:377-9. 9. CDC. Update: Public Health Service Workshop on Human T-Lymphotropic Virus Type 111 Antibody Testing-United States. MMWR 1 985;34:477-8. 10. CDC. Additional recommendations to reduce sexual and drug abuse-related transmission of human T-lymphotropic virus type III/lymphadenopathy-associated virus. MMWR 1 986;35:1 52-5. 11. Selik RM, Haverkos HW, Curran JW. Acquired immune deficiency syndrome (AIDS) trends in the United States, 1978-1982. Am J Med 1984;76:493-500. 12. Sarngadharan MG, Popovic M, Bruch L, Schupbach J. Gallo RC. Antibodies reactive with human T- lymphotropic retroviruses (HTLV-111) in the serum of patients with AIDS. Science 1984;224:506-8. 13. Safai B. Sarngadharan MG, Groopman JE, et al~ Seroepidemiological studies of human T- lymphotropic retrovirus type 111 in acquired immunodeficiency syndrome. Lancet 1984;1:1438-40. 14. Laurence J. Brun-Vezinet F. Schutzer SE, et al. Lymphadenopathy associated viral antibody in AIDS. Immune correlations and definition of a carrier state. N Engl J Med 1984;31 1: 1269-73.
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APPENDIX F 325 15. Ho DO, Sarngadharan MG, Resnick L, Dimarzo-Veronese F. Rota TR, Hirsch MS. Primary human T- lymphotropic virus type 111 infection. Ann Intern Med 1 985; 1 03:880-3. 16. Cooper DA, Gold J. Maclean P. et al. Acute AIDS retrovirus infection. Definition of a clinical illness associated with seroconversion. Lancet 1985;1:537-40.
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