Articles on Medical Diseases and Conditions

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  • Respiratory Syncytial Virus

    Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory illness of infants and young children, causing 5%-40% of pneumonias and 60%-90% of bronchiolitis episodes. Peak incidence is at 2-3 months of age. About 30%-50% of children have been infected by 12 months of age and about 95% by age 5 years. However, no significant clinical immunity is produced; repeat infections may occur, and persons of any age may develop acute infection. The most common clinical illness is upper respiratory tract infection similar to the common cold. The virus is spread through airborne droplets. The incubation period is 2-8 days. Diagnosis can be made by culture, by tests for antigen, and by tests for antibody. The best specimen for culture is nasal washings; the next best is nasopharyngeal swab. In either case, the specimen should include cells from the posterior nose and pharyngeal epithelium, since they contain the virus. Swab specimens should be placed immediately into a transport medium, and any specimen should be placed into wet ice. However, culture is expensive, and usually must be sent to a reference laboratory with wet ice. Standard culture methods take 4-14 days; and shell-vial methods, 2-3 days. The virus survives only about 4 days at 4°C and dies quickly at ordinary freezer temperatures or at high temperatures. Culture (under optimal conditions) is still considered the gold standard for diagnosis. However, some investigators report less than optimum results (69%-83% sensitivity), especially with mailed-in specimens. Antibody detection methods include immunofluorescence and ELISA. Antibody detection methods have several drawbacks: the fact that sensitivity is often less than 50% in infants less than 3 months old; the need for acute and convalescent specimens unless sufficiently elevated IgM titers are present; and the necessity in most cases to send the serum specimens to a reference laboratory. Methods for antigen detection in patient specimens are also available,including fluorescent antibody and ELISA, with same-day results. Nasopharyngeal aspirates are reported to provide the best specimens. Compared to culture, sensitivity of these methods are about 80%-90% (range, 41%-99%). Antigen detection methods may be positive on some specimens that are negative by culture, especially with mailed-in specimens. Antigen detection is rapidly replacing culture and antibody detection for diagnosis of RSV infection. However, the sensitivity of different manufacturers’ kits may differ considerably.

  • Mumps

    Mumps is a disseminated virus infection, although the main clinical feature is salivary gland enlargement. Evidence of nonsalivary gland involvement is most commonly seen in adults. In men, orchitis (usually unilateral) is reported in about 20% of cases. Adult women occasionally develop oophoritis. Persons of any age may be affected by meningoencephalitis, the most serious complication of mumps. This is reported in 0.5%-10% of patients. Many persons with CSF changes are asymptomatic. Females are affected five times more frequently than males. Complications of mumps may appear before, during, or after parotitis, sometimes even without clinical parotitis. Diagnosis is made by culture or serologic tests. Saliva is probably best for culture; mouth swabs or CSF can be used. Serologic tests require acute and convalescent serum specimens.

  • Measles

    Measles (rubeola) is still important, even though widespread vaccination has begun. Measles is spread by droplet inhalation. Incubation lasts about 9-11 days, followed by 3-4 days of fever, cough, and sometimes conjuctivitis. Koplik’s spots appear on the oral mucosa in 50%-90% of patients about 2-3 days after symptoms begin. These last about 6-7 days. The typical measles skin rash begins about 4-5 days after onset of upper respiratory tract symptoms. The two main complications are encephalitis and pneumonia. Fortunately, encephalitis is rare, the incidence being 0.01%-0.2%. Due to the great frequency of the disease, however, the total number of cases is appreciable. About one third of those with encephalitis die, one third recover completely, and the remainder survive but show moderate to severe residua. Measles encephalitis is considered postinfectious because it develops 4-21 days after the onset of rash. Measles involves lymphoid tissue and respiratory epithelium early in the illness. Therefore, bronchitis, bronchiolitis, and pneumonia are fairly frequent. Most cases of pneumonia are due to superimposed bacterial infection (staphylococci, pneumococci, streptococci), but some are caused directly by the rubeola virus. Secondary bacterial otitis media is also fairly frequent. For diagnosis, culture and serologic tests are available. Standard culture takes 7-10 days. Culture depends on the stage of disease. For a period of 1 week ending with the first appearance of the rash, blood, nasopharyngeal swabs, or urine provide adequate specimens. After appearance of the rash, urine culture is possible up to 4 days. Beyond this, culture is not useful, and serologic tests must be employed using acute and convalescent serum specimens. Measles HI-detectable antibodies appear about the end of the first week after appearance of the rash and peak about 2 weeks later. Measles IgM antibody appears about 2 days following rash onset, peaks about 10-14 days after rash onset, and becomes undetectable at about 30 days. Interpretation is similar to that of rubella tests. However, one report indicates about 30% false negative IgM results even 3 weeks after disease onset. IgG acute and convalescent serum specimens can also provide a diagnosis.

  • Parvovirus B19

    Parvovirus B19 belongs to a genus that infects both animals and humans. These are small DNA viruses without an outer envelope. Replication appears to take place in erythroid precursors of the bone marrow. The two most common diseases produced are erythema infectiosum (“fifth disease”), a condition somewhat resembling rubella, but with a rash that has a somewhat different body distribution; and transient aplastic crises. Both are more frequent in children. In both conditions, the incubation period is about 5-15 days, but may be as long as 20 days. In both conditions there may be a viral-type prodrome with fever, malaise, and other symptoms. Most patients with aplastic crises due to B19 already have some type of hemolytic anemia (such as sickle cell disease), either congenital or acquired. Immunocompromised patients (such as those with HIV-1 infection) can also have aplastic crises. It is thought that B19 infection is responsible for 90% of aplastic crises in patients with these conditions.

    IgM antibody becomes detectable in the second week after infection and IgG antibody during the third week. IgM antibody decreases to nondetectable levels at roughly 6 months but can persist longer. The most commonly used tests are EIA for IgM antibody and nucleic acid (DNA) probe methods for viral antigen in serum or body fluids during acute illness. These tests would usually have to be obtained at large reference laboratories or university centers.

  • Varicella-Zoster Virus (VZV)

    Varicella-zoster virus (VZV) is a member of the herpesvirus group. Infection is spread through direct contact with skin lesions or through droplet inhalation. The incubation period is about 14 days (range, 9-21 days). Primary infection is usually varicella (chickenpox). The period of skin rash lasts about 4-6 days. This may be preceded by a short prodromal period. The period of contagion is said to be from 2 days before the rash until no new skin lesions appear and all old ones become crusted. Usually there is lifelong immunity to new infection (although not always). Complications are not common but are not rare. They include pneumonia, encephalitis, and Reye’s syndrome (20%-30% of Reye’s syndrome follows varicella infection). Incidence and severity of complications are increased in immunocompromised persons. Twenty-three percent to 40% of bone marrow transplant patients develop primary VZV infection or reinfection. Varicella infection in pregnancy may affect the fetus in 5%-10% of cases.

    After the varicella syndrome is over, the virus begins a latent period in sensory nerve ganglion cells. Later on, it may reactivate in the form of zoster. Reactivation is more common in persons with malignancy or in those who are immunocompromised. It becomes more frequent with increasing age. About 10%-20% of the population is affected. Neuralgia is the most frequent symptom. A rash is also relatively frequent, often in the distribution of a dermatome. Encephalitis, sensory and motor neurologic abnormality, and ocular abnormality may occur.

    Laboratory tests include Tzanck test smears of varicella-zoster lesions. Sensitivity is said to be 50% or less in varicella and 80% or less in zoster. This procedure is described in the section on simplex and the microscopic appearance is the same. Culture of lesions can be done, but results in varicella are reported to be 34%-78% positive and in zoster to be 26%-64%. Serologic tests can be done using fluorescent antibody (FA), ELISA, and slide LA. EIA is said to be 50% sensitive (range, 36%-94%); FA, about 75% (range, 69%-93%); and LA, about 60% (52%-76%). It appears that antibody production (and, therefore, sensitivity) is greater in otherwise healthy children than in adults. IgM antibody rises in varicella about 5-6 days after the rash begins and peaks at about 14 days; it rises in zoster about 8-10 days after onset of the rash and peaks at about 18-19 days. Some patients with VZV infection who later are infected by herpesvirus type 1 experience an anamnestic rise in VZV antibody. Nucleic acid (DNA) probe methods have also been reported for skin lesions and for CSF specimens.

  • Human Herpesvirus 6 (HHV-6) and 7 (HHV-7)

    Human herpesvirus 6 (HHV-6) was first isolated and characterized in 1986. It infects predominately T-lymphocytes of the CD4 (helper) type, but also B-lymphocytes, megakaryocytes, and probably other cells. It is the sixth described member of the Herpesvirus family (the others being HSV-1, HSV-2, EBV, CMV, and varicella-zoster). Infection takes place mainly in the first 2-3 years of life, with antibodies detected in 52% to “almost all” (over 90%) of young children and up to 80% of adults. Similar to the other herpesviruses, a lifelong low-grade or latent infection is produced and reactivation may occur. HHV-6 is now well accepted as the cause of exanthema subitum (roseola infantum). Evidence has been presented for possible involvement in other conditions, such as heterophil-negative mononucleosis, transient febrile illnesses in children, and a type of chronic fatigue syndrome with CNS involvement centered in Nevada and California. One report suggests a role in idiopathic bone marrow transplant failure, seen in about 20% of bone marrow transplants. There is some reported serologic evidence of HHV-6 reactivation associated with CMV infection.

    Tests have been described to detect HHV-6 IgG antibody, mostly fluorescent immunoassay and ELISA. Tests for antigen in patient peripheral blood monocytes have also been described, both fluorescent immunoassay and nucleic acid probe with PCR amplification. These tests are currently available only in research laboratories or large reference laboratories.

    HHV-7 was identified in 1990. It is frequently found in saliva and apparently causes frequent subclinical infection similar to HHV-6. Also similar to HHV-6, HHV-7 has been reported to cause some cases of exanthema subitum in young children. Serologic testing for IgG antibody has been reported using indirect immunofluorescent methodology.

  • Herpes Simplex (HSV)

    HSV infection is characterized by a primary infection, often asymptomatic, after which the virus remains dormant in the dorsal root ganglia of peripheral nerves interrupted in some patients by one or more episodes of recurrent disease. Primary infection usually requires a person without preexisting HSV antibody. However, a person can have antibody against one strain of HSV (from previous infection) and become infected by a different strain (reinfection as opposed to reactivation or recurrence of preexisting disease). Primary infection or reinfection is usually acquired from close contact with an infected person: the mouth in cases of nongenital infection, and sexual intercourse in cases of genital infection. However, transmission can occur through body secretions. Immunocompromised persons are at increased risk of primary HSV infection and reactivation. There are two closely related but distinct types of HSV that share some antigens but not others. Herpes simplex virus type 1 (HSV-1) typically produces nongenital infections of various types such as lesions of the mouth, blisters on the mucous membrane border of the lips (“canker sores,” or “cold sores”), keratitis (corneal ulcers of the eye), focal lesions of the fingers (“Whitlow”), and encephalitis (most frequently involving the temporal lobes of the brain). Occasional immunocompromised patients develop disseminated HSV-1 disease. At one time about 90% of the population was found to have antibodies against HSV-1, but more recently this incidence is said to have fallen to about 25%-50%. About 20%-45% of patients with HSV-1 oral lesions eventually develop recurrence. Herpes simplex virus type 2 (HSV-2) produces blistering lesions (vesicles) on the genitalia of males and females and is considered a venereal disease. Reports indicate that HSV-2 causes 20%-50% of genital ulcerations in U.S. sexually transmitted disease clinics. About 5%-15% of patients with genital herpes have HSV-1 isolated rather than HSV-2, and one report indicates that up to 20% of labial or facial lesions are due to HSV-2 rather than HSV-1. About 85% of persons with HSV-2 with genital lesions have recurrences.

    In primary HSV-2 genital infection that is symptomatic, the incubation period is about 5-7 days (range, 1-45 days). About one half of the patients (range, 39%-68%) develop systemic symptoms (e.g., fever, malaise, myalgia, and headache), including a subset of about 25% (range, 13%-36%) of all patients who experience a mild self-limited episode of aseptic meningitis (which has a marked difference in severity and prognosis from the severe brain infection of HSV-1). Extragenital lesions on skin or mucous membranes occur in about 25% of patients (range, 10%-30%), most often in the general area of the groin. A few patients develop lesions on one or more fingers, and herpes ocular keratitis sometimes occurs. About 20% are reported to show evidence of pharyngeal involvement, and about 50% have urethral involvement. Herpes simplex virus can be cultured from the cervix in 80%-90% of female patients. About 80% of all patients develop tender inguinal adenopathy in the second or third week.

    Recurrent infection differs considerably from primary infection. Only about 5%-10% of patients experience systemic symptoms. Extragenital lesions appear in about 5%. Cervical culture is reported to detect HSV in less than 15%.

    Neonatal HSV infection is usually due to HSV-2 associated with active maternal HSV-2 genital infection and is usually (but not always) acquired during birth rather than by transmission through the placenta. About 1% of pregnant women are estimated to have either overt or nonapparent HSV-2 infection. However, asymptomatic cervical or vulvar infection has itself been reported in about 1% (range, 0.5%-8.0%) of women. In genital HSV-2 infection during pregnancy only about 40% of infected women have typical lesions, and about 40% do not have visible lesions. It is estimated that if primary maternal HSV infection is present at delivery, there is a 40%-60% chance of symptomatic neonatal HSV-2 infection. If this occurs, there is serious or even fatal disease in about 50% of those infants. Delivery-infected infants do not develop symptoms until several days to 4 weeks after delivery. Symptoms may suggest sepsis or meningitis. If recurrent maternal HSV is present, there is only about a 5%-8% chance of infant infection. It is also reported that 70%-80% of neonatally infected infants are born to mothers who are asymptomatic at the time of delivery.

    Diagnosis of herpes simplex infection culture.

    Culture is still considered the gold standard HSV diagnosis. Material for culture must be inoculated into special transport media. Although some authorities advocate freezing the specimen, others report that refrigerator temperature is better for virus in transport media. Culture sensitivity depends on several factors. Some types of cells used for culture give better results than others. Specimens taken from vesicular lesions are considerably (50%-100%) more sensitive than material taken from ulcerative lesions, which, in turn, provide better results than crusted lesions. The earlier a lesion is cultured after it appears, the more likely it will yield a positive result (in one study, culture was positive in 70% of lesions less than 24 hours old, 50% in those 24-48 hours old, and 35% in those over 5 days old). A lesion from a primary infection is more likely to be positive than a lesion due to reinfection or recurrence. When urine or other secretions are cultured, the results from patients with primary infections are much more likely to be positive, since they shed virus much longer than patients with reinfection or recurrent disease. Culture in asymptomatic patients is much less likely to be positive than in patients with lesions. In addition to problems with sensitivity, specimens (in most hospitals) must be sent to a reference laboratory.

    Antigen detection. Several methods are available to detect HSV antigen; most differentiate between HSV-1 and HSV-2 or claim to be specific for one or the other. Most have the advantage of same-day or overnight results. Some depend on abbreviated culture followed by use of specific antibody to HSV. Others (such as fluorescent immunoassay or latex agglutination) employ specific antibody on material from clinical specimens. To date, all methods have failed to consistently detect 95% or more patients who have positive results by standard culture and, in general, independent evaluations have not consistently upheld manufacturer’s claims. Some have achieved sensitivity in the 85%-95% range compared to culture; others have not. In general, whether the lesion is from primary or recurrent infection, the type of lesion and the number of days after the lesion appears before the specimen was obtained affects methods that detect HSV antigen similarly to culture. Sensitivity of direct antigen methods tends to be better in material from mucocutaneous vesicles than from genital lesions. Also, there have been problems in cross-reaction between HSV-1 and HSV-2, especially in fluorescent antibody methods. Some nucleic acid probe methods with PCR amplification have been reported to be equal to or better than culture in tissue or CSF.

    Direct smear methods. The most rapid diagnosis is made through stained smears from scrapings obtained from a lesion. A sterile scalpel blade is used to unroof a vesicle and material from gentle scraping of the base of the lesion is smeared gently on a slide. Giemsa, Wright’s, or Papanicolaou stains can be used. For Giemsa or Wright’s stain, the smear is air-dried or fixed in methanol. For Papanicolaou, the smear is immediately fixed in cytology fixative. The slide preparation is sometimes called a Tzanck test. The technologist looks for multi-nucleated epithelial cells with enlarged atypical nuclei. The same findings are seen in varicella-zoster lesions. Pap stain also can show intranuclear inclusions. Sensitivity of the Tzanck test is reported to be 30%-91%, with average sensitivity probably about 45%-50%. It is probably less with persons who are inexperienced in obtaining specimens and interpreting the smears. Sensitivity is higher from vesicle scrapings than from other specimens. Fluorescent antibody tests have been applied to the smears, which increases positive results to about two thirds of cases.

    Serologic tests for antibody. Most current methods are ELISA or fluorescent immunoassay plus a few LA kits. Antibody detection has also been somewhat disappointing. Acute and convalescent specimens must be obtained 2 weeks apart. A fourfold rise in titer is needed to prove recent onset of infection; this is most likely to be found in HSV-2 disease and during the time of primary infection (60%-70% of cases). Only about 5% of patients with recurrent HSV demonstrate a fourfold rise in titer. There may also be problems with interpretation due to the high rate of positive results in the general population and because of cross-reaction between HSV-1 and HSV-2 antibodies.

    Other tests. In culture-proved HSV-1 encephalitis, one study reported that radionuclide brain scan revealed a focal lesion or lesions in the temporal lobe in 50% of cases, computerized tomography scan displayed some type of abnormality in 59%, and electroencephalogram (EEG) was abnormal in 81%. However, these procedures or their results cannot prove that the etiology is herpes infection. Spinal fluid tests show elevated CSF protein levels in about 80% of cases, increased WBC count in 97% (with about 75% of all cases between 50 and 500 WBCs/mm3), and normal glucose levels in 95% of cases. Another study found a normal cell count and protein level in 10% of cases on first spinal tap. Increase in WBC count is predominantly lymphocytic, although segmented neutrophils may be present in varying percentage (occasionally substantial) in the early stages. CSF immunofluorescent IgG antibody tests are about 25% sensitive by 10 days after onset of symptoms and about 85% after 15 days. At present, brain biopsy with culture of the specimen is the most accurate method of diagnosis. However, there is controversy about biopsy of such a vital organ. Culture of brain biopsy specimens is said to detect up to 95% of patients with HSV–1 encephalitis. Microscopic examination of the biopsy specimens can demonstrate encephalitis in about 85% of cases, but detects the intranuclear inclusions necessary to diagnosis HSV in only about 50% of cases. Use of immunofluorescent staining methods increases diagnosis to about 70%. Nucleic acid probe with PCR amplification was reported to detect over 95% of patients with HSV encephalitis testing CSF. However, homemade reagents were used. Clinical assessment alone is not sufficiently accurate: in one series of patients who underwent brain biopsy for suspected herpes, about 45% did not disclose herpes and about 10% were found to have treatable diseases other than herpes. CSF culture was positive in only about 5% of patients whose brain biopsy results were culture positive. In one large series, serologic tests suggested that 30% of patients had primary HSV infection and 70% had recurrent infection.

  • Human T-Cell Lymphotropic Virus I and II (HTLV-I and HTLV-II)

    These are closely related retroviruses somewhat distantly related to HIV-1. Transmission is similar to that of HIV-1 (contaminated blood products, less frequently by sexual intercourse or breast feeding). HTLV-I is found predominantly in Southern Japan, some of the Caribbean islands, parts of Central and South America, and sub-Saharan Africa. HTLV-I has been detected in U.S. intravenous drug abusers (20%-25%; range 7%-49%) and female prostitutes (7%; range, 0-25%) and in Native Americans in the United States (1%-13%) and Central and South America (8%-33%). HTLV-I is associated with adult T-cell leukemia (also called T-cell leukemia/lymphoma), involving peripheral blood and lymph nodes with large malignant cells having a multilobated (monocyte-shaped) nucleus and having a short clinical course. HTLV-I is less frequently associated with a neurologic condition called tropical spastic paraparesis. HTLV-II currently has no definite disease association, although several have been suggested.

    Serologic tests for HTLV-I antibody are mostly ELISA methods based on whole virus antigen. In general, these tests also detect most patients with HTLV-II. However, some reports indicate a significant number of HTLV-II patients are missed. Western blot methods are used to confirm and differentiate positive test results, and these procedures also have shown inconsistent results. Several new ELISA tests are based on several recombinant viral proteins and are said to reliably detect and differentiate the two viruses. At present, nucleic acid probe with PCR enhancement is the most sensitive and reliable way to differentiate HTLV-I and II.

    Idiopathic CD4 T-cell lymphocytopenia (ICL)

    This syndrome is being defined as CD4 T-cell counts below 300/mm3 (µL) or less than 20% of the total number of lymphocytes, no serologic evidence of HIV or HTLV infection, and no other known cause for CD4 depression. The main clinical findings are infection and other conditions associated with immunosuppression. Only a few cases have been reported as of 1994. Thus far, there has not been any strong evidence of blood-borne or sexual transmission. Retrovirus etiology has been suspected but not proven (to date).

  • Human Immunodeficiency Virus 2 (HIV-2)

    HIV-2 is closely related to, but not identical, to HIV-1. HIV-2 is found predominantly in West Africa, where in some areas it is the predominant HIV infection. In other areas it may occur with less frequency than HIV-1. It has also been found in low frequency in Central, East, and Southern Africa. It is spread through sexual intercourse. A few cases have been reported in various Western countries, including the United States, thus far almost entirely in immigrants from West Africa or a few persons who traveled or lived temporarily in that region. Clinically, HIV-2 resembles HIV-1, although in general HIV-2 appears to be somewhat slower to progress to AIDS. Antibodies to HIV-2 cross-react to some extent with standard serologic tests for antibody to HIV-1; the frequency of cross-reaction has been variable (8%-91%). Also, cross-reactivity to HIV-1 tests decreases as severity of HIV-2 infection increases. The typical HIV-2 reaction pattern with HIV-1 tests is a reactive HIV-1 screening test result plus an “indeterminant” Western blot result.

    Specific ELISA tests for HIV-2 antibody are not available, and a Western blot technique can be used to verify HIV-2 infection. In addition, commercial tests are now available designed specifically to detect both HIV-1 and HIV-2. These tests are being used predominantly in blood banks.

  • Human Immunodeficiency Virus 1 (HIV-1)

    The HIVs are retroviruses; their genetic information (genome) is composed of RNA rather than the usual DNA. To reproduce, the virus uses an enzyme known as reverse transcriptase to produce a DNA copy of its genetic RNA and incorporates this material into the host cell genetic material. Some of the copied viral genome also exists in the host cell without being incorporated into host chromosomes. Thus, the host cell nucleus reproduces the virus as well as itself. The HIVs have an unusual property, similar to the herpesvirus group, that active viral reproduction and infection can coexist with presence of antibodies against the virus. In most other virus infections, appearance of specific antibody marks the end of the infection and confers partial or complete protection against subsequent infection by that virus. The HIVs attack a subgroup of T-lymphocytes known as helper (inducer) T-cells (CD4 cells). Helper T-cells are important in cell-mediated immunity (delayed hypersensitivity), which is the immunologic mechanism classically defending against chronic lower virulence infections such as tuberculosis, fungus, and parasites. Monocytes, macrophages, and possibly Langerhans cells also become infected.

    The first HIV to be discovered was isolated from patients with the acquired immunodeficiency syndrome (AIDS) by three different groups of investigators who each gave the virus a different name (human T-cell lymphotropic virus type III, or HTLV-III; lymphadenopathy-associated virus, or LAV; and AIDS-associated retrovirus, or ARV). The current terminology for this virus is human immunodeficiency virus type 1 (HIV-1). This virus is present endemically in Central Africa. A related virus that produces a syndrome similar to AIDS is found in West Africa and has been named HIV-2 (originally called HTLV-IV). The HIV viruses are related to a similar virus found in African green monkeys. They are also related, but less closely, to certain animal viruses called lenteviruses (“slow viruses”), of which the most well known is the visna virus of sheep. Besides the HIV virus group that injures or destroys helper T-cells, there is another group of viruses that affects T-cells but that causes excessive T-cell proliferation rather than destruction. This group has retained the name of HTLV and includes HTLV-I (which causes human T-cell leukemia) and HTLV-II (which may be associated with hairy cell leukemia). Similar to the HIV viruses, the HTLV virus group is related to a monkey T-cell leukemia virus and more distantly to a T-cell leukemia virus of cattle.

    Clinical findings

    HIV-1 can be isolated from many body fluids (including blood or blood products, semen, cervical secretions, saliva, tears, cerebrospinal fluid, breast milk, urine, and various tissues including the cornea). However, urine and saliva appear to have relatively little infectious capacity. HIV-1 is predominantly transmitted in three ways: by sexual intercourse (heterosexual or male homosexual), by transfusion or inoculation of infected blood or blood products, and by mother to fetus through the placenta. After exposure, there is an incubation period that typically lasts 2-6 weeks (range, 6 days-8 weeks, but sometimes lasting several months or years). In about 50% of patients (range, 4%-70%) this is followed by an acute viral type of illness (sometimes called the “acute seroconversion” or “acute HIV syndrome”) resembling infectious mononucleosis or CMV infection that usually lasts 2-3 weeks (range, 3 days-several weeks). Symptoms usually include fever, sore throat, and lymphadenopathy; often include skin rash, myalgias, diarrhea, vomiting, and aseptic meningitis; and sometimes thrombocytopenia. Some patients never develop the initial acute febrile illness or any clinical infection; they may recover completely from the initial exposure (although this is probably uncommon) or may become an asymptomatic carrier. Those who develop the initial acute illness exhibit a wide spectrum of possible outcomes. After recovery they may become asymptomatic carriers; may have defective immunologic responses without clinical disease; may develop persistent generalized lymphadenopathy (PGL); may develop a variety of non-life-threatening fungal, bacterial, or viral infections (e.g., oral Candida) as part of the so-called AIDS-related complex (ARC); or may develop the AIDS syndrome.

    AIDS is the most severe manifestation of HIV-1 infection, defined briefly as serologic evidence of HIV antigen or antibody plus certain opportunistic infections or Kaposi’s sarcoma (a malignant tumor of fibroblasts and capillary-sized blood vessels) in a patient who is immunocompromised without known cause. The most frequent opportunistic organism producing active infection in AIDS is pneumocystis carinii (about 60% of cases; range, 35%-80%); other common agents include Cryptococcus neoformans (4%-13% of cases), Candida albicans esophagitis (14%-25%), “atypical” mycobacteria of the Mycobacterium avium-intracellulare complex (22%-30%), and protozoans such as Toxoplasma(3%-12%) and Cryptosporidium (4%-13%). Other organisms with evidence of frequent past or recent infection include CMV (66%94%) and HSV (4%-98%, the lower figures being active infection). Incidence of Kaposi’s sarcoma varies according to risk group; in male homosexuals with AIDS the incidence is about 35% (range, 25%-50%) in clinical studies and 30%-75% in autopsy studies; but in drug abusers and hemophiliacs it is found in less than 5%. Some 50%-80% of patients with AIDS develop various types of neurologic disorders with or without dementia, which may precede other evidence of AIDS in 25% of patients. In one series, 66% of these patients had elevated CSF protein levels (42-189 mg/100 ml; 0.42-1.89g/L); 20% had a small degree of mononuclear cell count elevation (4-51 WBCs); and three of seven patients tested had oligoclonal bands detected in their CSF. Cerebral abnormalities were found in two thirds of the patients with AIDS who were autopsied. There is an increased incidence of B-cell lymphoma, especially primary CNS lymphoma (2%-6% of patients).

    In the United States as of 1992, about 58% of AIDS patients were male homosexuals, usually those who had multiple sex partners. About 23% were intravenous drug abusers; about 6% were persons infected heterosexually; and about 4% were of undetermined etiology. However, incidence of heterosexual infection (as opposed to current incidence of AIDS, a late-stage development of HIV-1 infection) is becoming more frequent. Infection has been reported after a single heterosexual encounter, although more commonly it takes more than one episode. After an infected person develops detectable antibody, the current approximate calculated progression to AIDS per year is about 2.5% for asymptomatic patients, 3.5% for PGL patients, and 8.5% for ARC patients. Progression to AIDS is highest among infected male homosexuals (4%-10%/year) and low among transfusion-infected hemophiliacs. About 20%-40% (range, 10%-73%) of infected mothers transmit the virus to the fetus during pregnancy. A few infants appear to become infected during delivery and some during breast feeding.

    Laboratory findings

    In the few small studies in AIDS patients that contain hematologic data, anemia was present in about 80% (range, 45%-95%), leukopenia in about 65% (range, 40%-76%), thrombocytopenia in about 25%-30% (range, 3%-59%; about 5%-10%, range 3%-15% in HIV-infected non-AIDS patients) and pancytopenia in 17%-41%. Lymphocytopenia was reported in about 70%-80% (range, 30%-83%).

    Diagnosis of HIV-1 infection

    Culture. HIV-1 can be isolated from concentrated peripheral blood lymphocytes and less frequently from body fluids. Isolation rates in already seropositive patients average about 50%-60% (range, 8%-100%; more likely positive just before or during the first half of the acute HIV syndrome). Culture is difficult, is expensive, takes several days, is available only at a relatively few laboratories, and is positive more often in early stages of infection than in later stages. Culture may be the only method that can confirm infection in the first 2-3 weeks after exposure. Culture detects only about 50% of neonates infected in utero in the newborn period up to the first month of life (range, 30%-50%) but a greater percentage at 3 and 6 months. Culture is positive in CSF from about 30% (range, 20%-65%) of seropositive adult patients whether or not CNS symptoms are present, but about 20% more often in more advanced states of disease.

    Antigen detection. Viral antigen may become detectable as soon as 2 weeks after infection (in one report it was detected 4 days after a transplant operation). Antigenemia (viremia) lasts roughly 3 months (range, 1 week-5 months). In several reports, antigen could be detected from a few days to as many as 6-9 months before first-generation ELISA antibody test results became positive. Several methods have been used, including RIA, fluorescent antibody, and ELISA. Until about 1990, sensitivity was usually less than 50% and varied considerably between kits of different manufacturers. It was discovered that varying amounts of the circulating p24 antigen were bound to immune complexes. Methods are now available that break up (dissociate) the bound complexes before testing. In one study this increased test sensitivity to 60%-65% in patients without symptoms and 80%-90% in patients with symptoms.

    Nucleic acid probe kits with PCR amplification (NA-PCR) have become available. These detect HIV antigen within infected peripheral blood lymphocytes. Sensitivity appears to be about 40%-60% in the first 1-2 weeks of life and up to 98% by age 3 months. NA-PCR detects about 96%-100% of seropositive pediatric patients over age 6 months or adult patients with CD4 counts over 800/mm3 and about 85%-97% of those with CD4 counts below 200/mm3. NA-PCR is more sensitive than culture in HIV-infected but seronegative patients and can detect HIV in CSF from about 60% of seropositive patients. As with all laboratory tests, all manufacturer’s NA-PCR probes are not identical in sensitivity.

    Antibody detection. Seroconversion occurs on the average about 6-10 weeks after infective exposure (range, 12 days-5 years), which corresponds to the last part of the acute HIV syndrome stage or up to several weeks afterward (in some degree depending on the sensitivity of the test). Two types of antibodies are produced, IgM and IgG. IgM antibodies are detectable first, and several studies report IgM antibody present in some patients 1-10 weeks before IgG antibody (using first-generation IgG ELISA methods). In general, IgM antibody becomes detectable about 1-2 weeks after onset of the “acute HIV syndrome” (about 5-6 weeks after infection), peaks about 2-3 weeks after first detection, and becomes nondetectable 2-4 months after first detection. IgG antibody becomes detectable 1-2 weeks after IgM antibody, peaks several weeks later, and persists for life (there is controversy over whether a few patients lose antibody shortly before death from AIDS). However, one recent study using a second-generation IgG ELISA found little difference. Commercial ELISA IgM, second-generation IgG, and rapid slide LA methods are now available. Many of these use antibody against one (sometimes more) selected protein components of HIV-1 obtained through recombinant DNA techniques (see Confirmatory Methods section). Test results in HIV-1 infection are shown in Fig. 17-10.

    Tests in HIV-1 infection

    Fig. 17-10 Tests in HIV-1 infection.

    The bulk of published test kit evaluations involve first-generation ELISA methods, which are based on crude extracts of the whole virus. There were a considerable number of such methods commercially available, but even the first was introduced in only mid-1985. These tests detect antibody in 94%-99.5% of patients with confirmed AIDS, depending on the particular assay and the investigator. Positive tests in random blood donors have averaged about 0.9% (range, 0.2%-2.56%). However, in some (not all) of these first-generation kits only about 25%-35% (range, 17%-44%) of initially positive ELISA test results on random blood donors remain reactive when retested with the same kit. Of those whose results were repeatedly positive, only about 20%-35% (range, 15%-62%) were positive on confirmatory tests. This means that only about 10%-15% (range, 3%-22%) of the initial positive results on random blood donors from these particular kits eventually were confirmed positive. Some manufacturer’s kits were shown to be more sensitive than others, and some produced more false positive results than others. Some of this discrepancy is explained on the basis of different appearance times or quantity present of different viral antigens being detected by the different kit antibodies being used. There is also controversy whether reactivity against only a single antigen or a certain type (e.g., the core proteins [“group-specific antigen” or gag] p24 and p55 or the envelope glycoproteins gp 120/160 and gp 41) is sufficient to consider the test truly reactive and thus indicative of HIV-1 infection in the absence of reactivity against any other important structural protein. When this happens, it is often considered a false positive or an “indeterminant” reaction, although its significance has not yet been definitely established. In addition to these controversies, definite false negative results and false positive results may occur. Previously mentioned have been false negative results due to variable time periods before antibody is produced and variation in sensitivity of different methods and different manufacturers kits. Also, in the late or terminal stages of AIDS, antibody may disappear from patient serum in about 2%-4% (range, 0%-7%) of those who previously had antibody.

    When HIV infection is acquired in utero, IgM (and IgA) antibody is slow to rise until 3-6 months after birth. In several reports, IgA was detectable in 6%-17% at one month of age, 57%-67% at 3 months, and 77%-94% at 6 months. IgG antibody was not helpful for the first 6 months of life (range, 3-18 months) because it may be acquired from the mother through the placenta. False negative and positive results can be due to technical and clerical errors. False positive results in some kits may be due to patient antibodies against certain HLA antigens (most often, DR4) in antigenic material from infected H9 cells used in the kits to capture the patient antibodies. Antigenic material from different cell lines or synthetic (recombinant) antigen does not have this problem. Some kits, but not others, have an increased incidence of false positive results in active alcoholic cirrhosis, renal failure, and autoimmune diseases. Gamma globulin used for HBV prophylaxis may contain antibody against HIV-1, although the gamma globulin is noninfectious due to certain steps in its manufacture. This passively transferred antibody may be detectable for as long as 3 months. Antibody detection methods for urine have been developed with sensitivity reported to be comparable to serum tests.

    Confirmatory antibody detection methods. Until 1988 these tests consisted of Western blot and immunofluorescent methods. Western blot is an immunochromatographic technique in which virus material from cell culture is separated into its major component proteins by electrophoresis, transferred (“blotted”) onto a chromatography support medium, and exposed to patient serum. Antibody in patient serum, if present, attaches to whatever virus component proteins it recognizes. Then the preparation is stained to display visually what protein areas had reacted. Not all the virus proteins are considered specific for HIV-1. There is some controversy as to what specific proteins must be present for the results to be considered definitely positive. This affects sensitivity of the test. The two most specific proteins are the virus envelope glycoprotein gp41 and the group-specific antigen (gag) core protein p24 (the numbers refer to molecular weight). However, other proteins, particularly a precursor envelope protein called gp160 (from which gp41 is derived), often appears before either of the more specific proteins. Western blot in general has been shown to detect antibody earlier than most of the first-generation ELISA tests but not as early as IgM or antigen-detection methods (or “second-generation” IgG tests). Unfortunately, Western blot is time consuming, takes 2 days to complete, and reliable results are considerably technique dependent. False negative and false positive results have been reported, although the exact incidence is currently unknown, due to lack of quality control surveys. The test is currently available only in large medical centers and reference laboratories. Immunofluorescence procedures are also available and are claimed to produce results equivalent to Western blot. Immunofluorescence is easier to perform and produces same-day results. However, a minority of investigators found Western blot to be more reliable. Both of these techniques are generally considered suitable to confirm screening test results. The Western blot, however, is currently considered the gold standard. There is also a radioimmunoprecipitation (RIPA) technique that has also been used as a confirmatory procedure. This method is slightly more sensitive than Western blot. However, it is technically difficult and currently is used only in research laboratories.

    Recently, tests have become available based on genetically engineered HIV proteins, most often gp160, gp120, gp41, and p24. One or more of these are used in “second-generation” ELISA or LA tests. In general, these tests are somewhat more sensitive and specific than the “first-generation” tests. One kit (HIVAGEN) consists of separate ELISA tests for antibody against several of these antigens, thus becoming, in effect, a sort of ELISA version of the Western blot.

    Tests for immunologic status. As noted previously, HIV-1 selectively infects T-lymphocyte CD4 cells (also called helper/inducer, Leu3, or OKT4 cells; CD means cluster designation), which eventually leads to defective immune function. CD8 T-cells (suppressor/cytotoxic or OKT8 cells) are normal or become increased. The 1993 CDC revised classification system for HIV infection considers 500 CD4 T-cells/mm3 or more to be normal; 200-499, moderately decreased; and less than 200, severely decreased. CD4 absolute or relative counts are considered to be the best index of HIV disease severity. Eighty percent to 95% of AIDS patients have a decreased absolute number of helper T-cells (<400/mm3) and a reversed (inverted) helper T-cell/suppressor T-cell ratio, with a T4/T8 ratio less than 1.0. One possible cause of false T4 decrease is the recent report that about 20% of African Americans have helper T-cells that fail to react with the OKT4 antibody but do react with the Leu3 and certain other helper T-cell antibodies. A lesser but substantial number of AIDS patients display more nonspecific immune system abnormalities, such as lymphocytopenia (<1,500/mm3) and nonreactivity to skin test challenge by standard delayed sensitivity antigens such as Candida, mumps, or Trichophyton. Tests of immune function usually do not become abnormal until relatively late stages of HIV-1 infection. These tests are not tests for HIV infection, nor are they diagnostic of AIDS. CD4 cell levels are currently considered the best overall indicator of HIV-1 disease severity and prognosis.

    Beta-2 microglobulin. Beta-2 microglobulin (B2M) is a small polypeptide that forms the light chain of the class I histocompatibility complex antigen (HLA) molecules present on the surface of many nucleated cells, including lymphocytes. It is released into serum by cell destruction or membrane turnover and is filtered by the renal glomerulus, after which it is more than 99% reabsorbed and metabolized by the proximal renal tubules. About 50% of serum B2M is derived from lymphocytes. Therefore, B2M levels have been used as a nonspecific marker for lymphocyte proliferation or turnover, as seen in immunologic stimulation or lymphoproliferative disorders. Since it is excreted by the kidney, it has been used to estimate renal function. Since CD4 (T-helper) lymphocytes are affected in HIV infection, B2M is reported to be elevated in about 85%-90% (range, 68%-100%) of patients with AIDS or ARC, 45% of patients with PGL, in smaller numbers of other persons with HIV infection but few or no symptoms, and in varying numbers of clinically healthy male homosexuals (20%-44% in two studies). Some investigators have used B2M as a marker for progression to AIDS, because in general the degree of B2M elevation corresponds roughly with degree of HIV illness severity and inversely with CD4 count. B2M can be assayed by RIA, EIA, or immunodiffusion.

    B2M may also become elevated in persons with poor renal function; in various lymphomas and leukemias, especially (but not exclusively) those of B-cell origin, in myeloma, in nonlymphoid malignancies, in sarcoidosis, in infectious mononucleosis and certain other viral infections, in various chronic inflammatory diseases including active liver disease, and in autoimmune disorders.

    Neopterin. Neopterin is an intermediate substance in the biopterin synthesis pathway. It is produced by macrophages when stimulated by gamma interferon released by activated T-cells (lymphocytes also produce neopterin but to a minor degree). Therefore, neopterin is an indirect indicator of increased T-cell activity. Neopterin is excreted by the kidney. Plasma or urine neopterin levels can be elevated in acute or active chronic infections or noninfectious inflammatory conditions, similar to B2M or C-reactive protein (CRP). The neopterin level is likely to be elevated in both viral and bacterial infection, whereas the CRP level is more likely to become elevated in bacterial than in viral infection. Also, the neopterin level is more likely than the CRP level to be elevated in immunologic graft rejection, whereas both become elevated in graft infection. In general, like B2M, the neopterin level becomes elevated in HIV infection; and the incidence and degree of elevation have a rough correlation to degree of HIV severity and inverse correlation to CD4 count. One reference states that the neopterin level is elevated in about 90% of seropositive but asymptomatic HIV-infected persons. Another found B2M elevated in 75% of these asymptomatic HIV patients and the neopterin level elevated in 60%; both were elevated in all ARC patients. B2M thus far seems to have aroused more interest than neopterin as a marker for severity in HIV infection.

    Summary of human immunodeficiency virus 1 tests. In summary, ELISA tests for HIV-1 antibody are used as a general screen to detect persons infected with HIV-1. Western blot (or equivalent) tests help establish presence of infection. Culture, tests for HIV-1 antigen, and possibly ELISA-IgM antibody tests, may detect infection earlier than the ELISA screening tests. Tests for decreased immunologic function (especially CD4 lymphocyte absolute counts) are useful to help confirm a clinical impression of advanced-stage HIV-1 and AIDS.