2 курс / Микробиология 1 кафедра / Доп. материалы / Kartikeyan_HIV and AIDS-Basic Elements and Properties
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Ministry of Environment and Forests (MOEF), 1998, Biomedical Waste (Management and Handling) Rules (1998). New Delhi: Government of India, 27 July. Amended on 6th March and 2nd June 2000.
Mitchell D.H., Sorrell T.C., and McDonald P.J., 1997, HIV Control in Medical Practice. In: Managing HIV (G.J. Stewart, ed.). North Sydney: Australasian Medical Publishing, pp 149–153.
National AIDS Control Organisation (NACO). Training manual for doctors. New Delhi: Government of India.
Rhame F. and Mahi D., 1988, The case for wider use of testing HIV infection. N Engl J Med 320: 1248–1254.
Sathe P.V. and Sathe A.P., 1991, Epidemiology and management for health for all. Mumbai: Popular Prakashan.
Simpson R.A. and Slack R.C.B., 2006, Sterilisation and disinfection. In: Medical microbiology (D. Greenwood, R.C.B. Slack, and J.F. Peutherer, eds.). 16th edn. New Delhi: Elsevier, pp 73–82.
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SECTION TWO
DIAGNOSTIC ASPECTS
CHAPTER 8
CASE DEFINITIONS
Abstract
Several surveillance case definitions are used for HIV sentinel surveillance and surveillance reports should indicate which definition has been used. An appropriate national AIDS surveillance definition is recommended for systematic reporting of AIDS cases. Surveillance case definitions should not be used as a guide for clinical diagnosis or for other purposes and should not be confused with clinical staging systems for HIV infection, which are meant for clinical management of patients and clinical research purposes. Clinical case definitions are available for children and adults. A range of AIDS-defining clinical conditions have been described.
Key Words
AIDS-defining conditions, Bangui definition, Candidiasis, Caracas definition, Clinical case definitions, Cryptococcal meningitis, Cytomegalovirus retinitis, E/R/S tests, Herpes zoster, HIV sentinel surveillance, Kaposi’s sarcoma, Penicillium marneffei infection, Persistent generalised lymphadenopathy, Pneumocystis pneumonia, Surveillance case definitions, Toxoplasmosis.
8.1 – INTRODUCTION
Surveillance of HIV infection and AIDS cases is necessary for monitoring the course of the HIV pandemic and planning suitable public health interventions. The WHO recommends HIV sentinel surveillance for HIV infection and systematic reporting of AIDS cases (using an appropriate national AIDS surveillance definition) for their surveillance. HIV sentinel surveillance is a method for measuring the prevalence of HIV infection in specific populations. In this method, blood obtained in the health care setting for other purposes such as screening for syphilis in antenatal clinics is tested for antibody to HIV after all patient identifiers have been removed. Surveillance case definitions should not be used as a guide for clinical diagnosis or for other purposes and should not be confused with clinical staging systems of HIV infection, which are meant for clinical management of patients and clinical research purposes (WHO, 1994).
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8.1.1 – Various Case Definitions
WHO Surveillance Case Definition: is simple to use and inexpensive since it does not involve HIV serological testing. This is a modification of the provisional WHO clinical case definition (or “Bangui definition”). Its relatively low sensitivity and specificity is especially so because HIV-negative tuberculosis patients have similar clinical presentations.
Expanded WHO Surveillance Case Definition: has a higher specificity than the WHO case definition and is also simple to use. However, it requires HIV serological testing which may be expensive and logistically difficult.
1999 CDC Revised Case Definition for AIDS Surveillance: is available on the website of the Centers for Disease Control and Prevention: www.cdc.gov.
Pan American Health Organization (PAHO): also called “Caracas definition” is a case definition for AIDS surveillance.
European Case Definition for AIDS Surveillance: does not use immunological criteria. It includes recurrent pneumonia, pulmonary tuberculosis, or invasive cervical cancer as AIDS indicator conditions in persons with confirmed HIV infection (WHO, 1994).
One or more of the above-mentioned case definitions should adequately meet the AIDS surveillance requirements for most countries of the world. Case definitions that require HIV serology are suitable for use in settings with intermediate to high levels of diagnostic capabilities. The surveillance reports should indicate which definition has been used (WHO, 1994).
HIV infection and/or disease is suspected on clinical symptomatology and confirmed by serological tests. The case history should include past and present history of injecting drugs, multiple sexual contacts, history of genital ulcer or discharge, transfusion of blood and/or blood products, and scarification or tattooing (NACO). The difficulties in diagnosis are that the clinical signs and symptoms are not pathognomonic and may mimic those of many common illnesses.
The CDC case definition (CDC, 1993) is more rigorous and involves sophisticated diagnostic procedures. The surveillance case definition of the WHO (1986) is simplified and correlates well with CDC case definition (CDC, 1993).
8.2 – NACO CASE DEFINITION FOR CHILDREN (UP TO 12 YEARS OF AGE)
This case definition is given by NACO, Government of India. Two positive serological HIV tests in children older than 18 months, or confirmed maternal HIV infection in children younger than 18 months, and presence of at least two major and two minor signs in absence of known cause of immune suppression. Major signs: loss of body weight or failure to thrive, diarrhoea (intermittent or continuous) for more than 1 month, and fever (intermittent or continuous) for more
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than 1 month. Minor signs: repeated attacks of common infections such as pneumonitis, otitis and pharyngitis; PGL, oropharyngeal candidiasis, persistent cough for more than 1 month, and disseminated maculo-papular dermatosis.
8.3 – NACO CASE DEFINITION FOR ADULTS
Two positive serological tests for HIV by ELISA, rapid, or simple (E/R/S) tests and any one of the following criteria:
1.Weight loss (more than 10 per cent of body weight lost in 1 month), or HIVrelated cachexia and diarrhoea (intermittent or continuous) for more than 1 month, or fever (intermittent or continuous) for more than 1 month
2.Tuberculosis (extensive pulmonary, miliary, and extra-pulmonary)
3.HIV-related neurological impairment preventing independent daily activities
4.Candidiasis of oesophagus (diagnosable by oral candidiasis with odynophagia)
5.Clinically diagnosed life-threatening or recurrent episodes of pneumonia, with or without etiological confirmation
6.Kaposi’s sarcoma
7.Presence of other conditions – Cryptococcal meningitis, neuro-toxoplasmosis, cytomegalovirus retinitis, P. marneffei infection, disseminated molluscum, and recurrent or multidermatome herpes zoster
8.4 – WHO CLINICAL CASE DEFINITIONS
8.4.1 – Adults
AIDS in an adult is suspected by the presence of at least two major signs associated with at least one minor sign, in the absence of known causes of immune suppression such as cancer and severe malnutrition.
Major signs: weight loss (more than 10 per cent of body weight lost in previous 1 month), diarrhoea for more than 1 month, and prolonged fever for more than 1 month. Minor signs: persistent cough for more than 1 month, generalised pruritic dermatitis, recurrent herpes zoster, oropharyngeal candidiasis, chronic progressive and disseminated herpes simplex infection, and generalised lymphadenopathy.
8.4.2 – Children
AIDS is suspected in an infant or child presenting with at least two major signs associated with at least two minor signs, in the absence of known causes of immune suppression such as cancer and severe malnutrition.
Major signs: weight loss or abnormally slow growth (failure to thrive), diarrhoea for more than 1 month, and prolonged fever for more than 1 month. Minor signs: generalised lymphadenopathy, oropharyngeal candidiasis, repeated common infections such as otitis and pharyngitis, persistent cough for more than 1 month, generalised dermatitis, and confirmed maternal HIV infection.
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8.5 – AIDS-DEFINING CLINICAL CONDITIONS
The CDC has defined a range of AIDS-defining clinical conditions in adults and adolescents. This includes atypical mycobacterial infection (disseminated or extra-pulmonary), candidiasis of oesophagus and lower respiratory tract, cancer of uterine cervix, coccidioidomycosis, cryptococcosis, cryptosporidiasis (for more than 1 month), cytomegalovirus disease, herpes simplex virus infection (for more than 1 month), histoplasmosis, HIV-related encephalopathy, isosporiasis (for more than 1 month), Kaposi’s sarcoma, lymphomas (primary, Burkitt’s, immunoblastic), pneumocystis pneumonia, recurrent septicemia due to Salmonella, toxoplasmosis of brain, tuberculosis at any site, and wasting syndrome due to HIV (also called “slim disease”).
8.6 – SYSTEMIC MANIFESTATIONS
In addition to the clinical presentations mentioned below, patients may present with signs and symptoms pertaining to cardiac, renal, endocrine, reproductive, and haematological systems.
8.6.1 – Gastrointestinal System
Dysphagia may be seen in oral and oesophageal candidiasis, cytomegalovirus oesophagitis, oral hairy leukoplakia, gingivitis, ulcer. OHL seems to be unique to HIV-infected individuals. The margins of the tongue show white ridges of fronds on the epithelium. An association with EBV and papillomaviruses has been proposed (Simmonds & Peutherer, 2006). Persistent diarrhoea is a feature of infection with Salmonella, Shigella, Entamoeba histolytica, Giardia lamblia, Microspora, Cryptosporidia, and Isospora. Colitis is present in Kaposi’s sarcoma and cytomegalovirus infection. Individuals with proctitis or ulcers due to herpes virus may experience perianal discomfort.
8.6.2 – Respiratory System
Patients with tuberculosis may present with persistent cough, breathlessness, haemoptysis, and pleural effusion. Rapid breathing and cyanosis are seen in atypical mycobacterial infection, bacterial pneumonia, Legionella infection, cytomegalovirus pneumonia, PCP, interstitial pneumonia, candidiasis, and herpes simplex infection.
8.6.3 – Neurological System
When HIV-infected individuals complain of visual changes, it is important to rule out cytomegalovirus retinitis, microsporidiasis, toxoplasmosis, and keratoconjunctivitis. Headache and lethargy may be seen in HIV encephalopathy,
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though fatigue is commonly experienced as the disease progresses. Meningism or meningitis may be due to infection with crytococcus, M. tuberculosis, or other bacteria. Neurological deficits may occur as a consequence of lymphoma and abscesses caused by mycobacteria, cryptococcus, and toxoplasma. Lymphoma and HIV vasculitis are among the causes of peripheral neuropathy in HIVinfected persons. Ataxia, altered personality, convulsions, and incontinence are seen in lymphoma, AIDS dementia complex, cryptococcal meningitis, and herpes virus infection.
8.6.4 – Skin and Mucous Membranes
Infections of skin and mucous membranes include herpes zoster, herpes simplex, candidiasis, cryptococcosis, histoplasmosis, molluscum contagiosum, folliculitis, and hairy leukoplakia. Kaposi’s sarcoma, lymphoma, and basal cell carcinoma are cutaneous malignancies seen in HIV sero-positive individuals. Pruritic popular dermatitis, seborrhoeic dermatitis, drug eruptions, vasculitis, and gingivitis are among the other manifestations.
REFERENCES
Centers for Disease Control and Prevention (CDC), 1993, Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep 41(RR-17): 1–19.
National Aids Control Organisation (NACO), Training manual for doctors. New Delhi: NACO. Simmonds P. and Peutherer J.F., 2006, Retroviruses. In: Medical microbiology (D. Greenwood,
R.C.B. Slack, and J.F. Peutherer, eds.), 16th edn. New Delhi: Elsevier, pp 527–538.
WHO, 1986, Acquired immunodeficiency syndrome (AIDS). Wkly Epidemiol Rec 61: 69–73. WHO, 1994, WHO case definitions for AIDS surveillance in adults and adolescents. Wkly
Epidemiol Rec 69(37): 273–275.
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CHAPTER 9
LABORATORY DIAGNOSIS OF HIV INFECTION
Abstract
Tests for diagnosis of HIV infection include specific tests for HIV infection, detecting immune deficiency, and diagnosing opportunistic infections and malignancies. The specific tests for diagnosis of HIV infection are screening tests: Enzyme linked immunosorbent assay (ELISA), rapid assays, and simple agglutination assays, collectively known as “E/R/S”; confirmatory or supplemental assays: immunoblot or Western blot (WB), immuno-fluorescence assay (IFA), radio-immuno precipitation assay (RIPA), and radio-immuno assay (RIA); and tests for detecting HIV antigen, viral nucleic acids, viral components, or the virus itself: detection of p24 viral antigen, RT assay, virus culture, and detection of HIV nucleic acids. HIV-infected women tend to have higher CD4 cell counts as compared to their male counterparts, even when the viral loads are similar. HIV-infected women also tend to develop opportunistic infections at higher CD4 counts and this fact should be considered while initiating ARV treatment.
Key Words
ELISA, HIV testing policy, HIV testing protocols, Polymerase chain reaction, Rapid assays, Simple assays, Strategies for HIV testing, Supplemental assays, Western blot
9.1 – PURPOSE OF HIV TESTING
Mandatory Screening: All donated blood, blood products, semen, cells, tissues, cornea, bone marrow, kidney, and other organs are screened for the presence of HIV antibodies, as required by the law of the country. Antenatal screening may also be carried out. An individual found to be positive for HIV antibody should never donate blood or any body parts. Though HIV antibody tests may be negative during the early stage of infection, mandatory screening can eliminate large majority of HIV positive persons among potential donors. An individual who tests positive in early stage of infection is infectious to others.
Sero-Epidemiological Studies: Serological tests are useful in epidemiological studies to study incidence, prevalence, geographical, and demographical distribution of HIV infection.
Diagnosis: HIV antibody tests are used to determine when infection has occurred after accidental occupational exposure or in cases of rape. The antibody tests may be negative in acute illness (CDC Group I) and also in late stages when 129
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immune suppression has occurred. The test kits should be able to detect antibodies to both HIV-1 and HIV-2.
Prognosis: Absence of detectable anti-p24 antibodies indicates clinical deterioration. This is associated with increase in HIV antigens and viral load in peripheral blood. The following tests are used for monitoring the course of HIV infection:
(a) CD4 cell count: less than 500 cells per mm3 of peripheral blood indicates progression of disease and the need for ARV treatment; less than 200 cells per mm3 indicates risk of severe opportunistic infections; (b) viral load: measurement of HIV RNA by reverse transcriptase (RT)-PCR); and (c) measurement of beta-2-microglobin and neopterin in serum or urine: increasing levels indicate progression of HIV disease
9.2 – TYPES OF TESTS
9.2.1 – Laboratory tests for HIV infection and related conditions
1. Specific tests for the diagnosis of HIV infection are grouped as follows:
(a) screening (E/R/S) tests, (b) confirmatory or supplemental assays, and (c) tests for detecting HIV antigen, viral nucleic acids, viral components, or the virus itself – detection of p24 viral antigen, RT assay, virus culture, and detection of HIV nucleic acids.
2.Tests for detecting immune deficiency are not specific for detecting HIV infection alone. Abnormal results may also be obtained in other diseases and/or infections. They provide extra information about the health status of the patient. These comprise: (a) surrogate markers: serum prolactin (increased), dehydro epiandrosterone (decreased), anti-infectivity factor protein to HIV-1 (present), serum IgE (increased); and (b) indirect predictors: total leukocyte count (less than 400/mm3), CD4: CD8 ratio (normal = 2:1; AIDS = 0.5:1), CD4 cell count (decreased), thrombocyte (platelet) count (decreased), beta-2-microglobulin (increased), serum neopterin (increased), alpha-1-thymosin (increased), IgG and IgA levels (both raised), tuberculin and other skin tests (indicate reduced CMI).
3.Tests for diagnosing opportunistic infections and malignancies: most opportunistic infections are diagnosed by microscope and culture. Serology is unreliable due to immune suppression.
In most cases, the duration of viraemia is approximately less than 1 week before the appearance of anti-HIV antibodies. Anti-HIV antibodies are detectable by commonly employed tests within 4–6 weeks of infection and in virtually all infected individuals within 6 months and these antibodies persist for life. The level of viraemia is a predictive marker for progression of HIV disease (WHO, 2003).
9.2.2 – CD4 Cell Counts
The normal absolute count of CD4 cells is 950–1,700 per mm3 of peripheral blood. The percentage of CD4 and CD8 cells is 20–45 per cent and 30–60 per cent, respectively. These normal counts are based on Western literature. Studies
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conducted in Lucknow and Vellore show variations in these counts for the Indian population. Hence, a nationwide baseline study is necessary. 3 mL of blood is collected aseptically by venepuncture in a vaccutainer containing EDTA (an anticoagulant). The blood is collected after 10–12 hours of overnight fasting. Ideally, the sample should be processed immediately to prevent erroneous results due to disintegration of T-lymphocytes. CD4 and CD8 counts are usually determined by flow cytometry. This method measures the wavelength of light emitted by cells as they flow in a stream, to determine the type of cell. The percentage of cells of each type is multiplied by the total lymphocyte count per micro litre to calculate the absolute number of CD4 or CD8 cells per mL of blood. Manual count kits, enzyme immunoassays, and microsphere assays are also used for CD4 and CD8 cell counts. Though easier to perform and less expensive, these methods are less accurate, compared with flow cytometry. CD4 counts show considerable interassay variation.
As compared with adults, all counts of T-lymphocytes are higher in children. In women, the CD4 counts are influenced by the phase of the menstrual cycle. The CD4 cell counts are higher in the morning and day-to-day variations are also seen. It varies during stress, exercise, acute illness, and drug therapy. Therefore, any large unexpected change in the CD4 cell counts should be confirmed by repeat testing, few days later. The percentage of CD4 cells is less variable than the absolute count and may be more reliable in evaluating response to ARV therapy or progression of HIV disease. HIV-infected women tend to have higher CD4 cell counts as compared with their male counterparts, even when the viral loads are similar. HIV-infected women also tend to develop opportunistic infections at higher CD4 counts and this fact should be considered while initiating antiretroviral treatment.
9.2.3 – HIV Diagnosis in the New Born
Conventional antibody tests cannot establish the presence of HIV infection in babies born to HIV-infected mothers because presence of anti-HIV antibodies in newborns may be due to either primary infection or passive transfer of anti-HIV antibody from the mother to the uninfected baby. These anti-HIV antibodies may persist up to 18 months. Appropriate methods for diagnosing HIV infection in babies less than 18 months are by detection of viral DNA or RNA, viral culture, and detection of IgA antibodies to HIV. IgA does not cross the placenta (WHO, 2003).
9.3 – SPECIFIC TESTS
This is the simplest and most frequently used diagnostic technique. Antibodies to both core (p24) or envelope (gp120, gp41) proteins are detected. There are two types of serological tests: screening (E/R/S) tests and supplemental or confirmatory tests. Among the tests for detecting HIV infection, antibody