An 18 year old student has a three week history of worsening headache, myalgias and fever not responding to acetaminophen (Case scenario is adapted from reference 1). His primary care physician diagnosed him to have a "viral syndrome". He was noted to have oral thrush and was advised to undergo HIV testing (which he did 10 days ago) because he admitted to being bisexual and engaging in unprotected sex. He also had a truncal rash and arthralgias 5 days previously (currently resolved). He denies illicit drug use.
Exam: VS T 39, P 118, RR 24, BP 110/74. He is mildly ill appearing. His head, ear, heart and lung exams are normal. His oral exam is significant for thrush. His abdomen is nontender, liver edge palpable 3 cm below the right costal margin (liver span 11 cm), moderate splenomegaly is present. Skin without rash. Small, nontender anterior/posterior cervical and occipital lymphadenopathies are present. No focal neurologic findings are present, but he has some meningeal signs.
Lab: CBC: WBC: 11,500, 93% neutrophils, 3% lymphocytes, 1% monocytes, 3% atypical lymphocytes, Hct 45. Serum transaminases slightly elevated. Heterophil antibody (Monospot) negative. Serum RPR negative. HIV ELISA (performed 10 days earlier) was negative. A lumbar puncture is performed. CSF analysis shows 22 WBC, 95% lymphocytes and 5% PMNs. The CSF protein is mildly elevated. CSF VDRL is negative.
His symptoms gradually improve after initiation of treatment with several antiretroviral medications. You thought that this patient is recently infected with HIV and his symptoms are consistent with HIV aseptic meningitis and a mononucleosis like syndrome. This phenomenon is also called acute retroviral syndrome and occurs 2-8 weeks after exposure. The HIV ELISA tests can be initially negative as it was in this patient. The decrease in the absolute lymphocyte count and increase in serum transaminases are common. CSF lymphocytic pleocytosis can be seen at any stage of HIV disease. CSF pleocytosis diminishes and protein elevation persists as HIV disease advances. The finding of pleocytosis in advanced disease warrants exclusion of other etiologies.
Since AIDS was recognized as a distinct disease in 1981, over 50 million individuals worldwide have been infected by HIV-1 (2). An estimated 1.3 million children under 15 are living with HIV/AIDS. As of January 1, 2000, 8718 cases of AIDS in children <13 years old had been reported, and approximately 60% of these children have died (3).
HIV is transmitted by both homosexual and heterosexual contact, by blood and blood products, by infected mothers to infants either intrapartum, perinatally or via breast milk. Heterosexual transmission is the most common mode of infection worldwide. The presence of other sexually transmitted diseases in the partners increases the risk of transmission. The risk of HIV transmission following skin puncture from a needle that was contaminated with blood from a patient with HIV infection depends on multiple factors (such as the viral load of the patient, the amount of the blood on the needle, etc.) and without antiretroviral therapy, the transmission risk is about 0.3%.
Women, in whom HIV infection is most often acquired via heterosexual sex, now comprise the group in which HIV infection is increasing most rapidly in the United States. About 25% of the infants born to HIV-seropositive mothers who are not receiving antiretroviral therapy are infected by HIV-1 (4,5). Perinatal transmission can occur during pregnancy, during labor and delivery and after delivery through breast-feeding. In the absence of breast feeding, 60-75% of transmission occurs during labor and delivery. Among women who breast feed, breast feeding is responsible for 10-15% of transmission. Clinical factors that increase the likelihood of perinatal transmission include immunologically or clinically advanced HIV disease in the mother, high plasma viral load, maternal injection drug use during pregnancy, preterm delivery, non-receipt of antiretroviral treatment and breast-feeding. Obstetric factors are also important. Delivery >4 hours after the rupture of fetal membranes can double the risk of transmission. Chorioamnionitis and maternal infection with another sexually transmitted disease during pregnancy increase the risk. Most of these risk factors have been identified before the use of zidovudine chemoprophylaxis and their effects are unknown now, since most pregnant infected women are receiving treatment. Reducing the exposure of the infant to the maternal blood and secretions during the intrapartum period as in cesarean section can prevent HIV transmission. The birth of every perinatally HIV-infected infant signals either a missed prevention opportunity (no prenatal care, HIV testing is not offered or obtained, no prophylaxis) or, more rarely, a failure of prophylaxis.
The term HIV syndrome is used to describe the cellular and humoral immunodeficiency and the numerous complications that result from the HIV-1 and HIV-2 infections. Acquired immunodeficiency syndrome (AIDS) is the spectrum of disorders (HIV-wasting, opportunistic infections, certain malignancies) resulting from advanced HIV infection.
Also, any HIV-infected child with less than 15% of circulating lymphocytes as CD4+ T-lymphocytes (CD4 cell) has severe suppression regardless of the presence of symptoms or opportunistic infections. The CD4 cell counts may differ in children depending on their age and accordingly, the definitions for the immunosuppression level may differ between different age groups.
Etiology and establishment of infection
HIV is a RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. HIV belongs to the family of human retroviruses and the subfamily of the lentiviruses. The four recognized human retroviruses belong to two distinct groups as the human T-lymphotropic viruses (HTLV-1 and HTLV-II) and the human immunodeficiency viruses (HIV-1 and HIV-2). HIV-2 was originally confined to West Africa, but a number of cases have been recently identified in other parts of the world.
The HIV viral envelope proteins (such as gp120 protein) have a high affinity (tropism) for the CD4 lymphocytes. In order for HIV to fuse to and enter its target cell (mostly CD4 cells), it must also bind to one of a group of co-receptors. The two major co-receptors are CCR5 and CXCR4. Both of these receptors belong to the family of G protein-coupled cellular receptors, and the use of one or the other or both receptors by the virus is an important determinant of the cellular tropism of the virus.
After HIV binds to CD4 cells, the viral and cellular membranes fuse via the gp41 molecule and the HIV nucleoprotein complex enters the cytoplasm. The RNA viral genome then undergoes transcription by the virally encoded reverse transcriptase. The double stranded viral DNA enters into the nucleus, where integration of the DNA provirus into the host chromosome is catalyzed by the enzyme "integrase". This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression.
When a CD4 cell with the integrated provirus is activated, the viral particles are assembled and virions are released from the cell by budding. Productive viral replication is lytic to the infected T cells. Rapid production and turnover of CD4 cells occur throughout the course of HIV infection. Although a highly dynamic, complex equilibrium between HIV and CD4+ cells may be maintained for several years, eventually a decline in circulating CD4 cells occurs. A decrease in function as well as number of CD4 cells is central to the immune dysfunction in HIV infection.
The events associated with primary HIV infection are likely critical determinants of the subsequent course of HIV disease. In particular, the dissemination of the virus to lymphoid organs is a major factor in the establishment of a chronic and persistent infection. It is uncertain which cell in the blood or lymphoid tissue is the first to actually become infected; however, studies in animal models suggest that dendritic lineage cells may be the initial cells infected. These cells pass the virus on to CD4 cells in the draining lymph nodes of the animals. In humans this mechanism probably operates when the virus enters "locally" (such as vagina, rectum, upper gastrointestinal tract and breast milk) as opposed to directly into the blood.
In primary infection, virus replication in CD4 cells intensifies prior to the initiation of a virus specific immune response, leading to a burst of viremia and then to a rapid dissemination of the virus to other lymphoid organs, brain and other tissues. Two to eight weeks after initial exposure, up to 70% of the patients experience this immune response as a mononucleosis-like syndrome. These acute symptoms may last 3 days to 3 weeks and can include arthralgias, fever, headache, lymph node enlargement, maculopapular rash and sore throat. Ten percent to 20% of patients have neurologic involvement, usually presenting as aseptic meningitis with possible cerebrospinal fluid pleocytosis. The progression of diseases varies greatly among individuals and the route of HIV transmission does not influence the rate of progression. Generalized lymph node enlargement occurs in 35 to 60% of asymptomatic HIV-infected persons.
Despite the initial immune response, once infection is established, the virus is virtually never cleared from the body. A median of approximately 10 years passes before the patient becomes clinically ill. This period is shorter in perinatally infected children. HIV successfully evades elimination by the immune system in order to establish chronicity and the mechanisms of this evasion are not clear. This goes along with the establishment of a pool of latently infected, resting CD4 cells. These cells can remain in this state until an activation signal drives the expression of the replicating virus. This persistent pool of cells is a major obstacle to any goal of eradication of virus from the infected patients. Some degree of viremia is present in all untreated patients and the level of this "steady-state" viremia, called the "viral set point", at approximately 1 year has important prognostic implications. If the patients have a lower set point, it can be said that the disease progression will be much slower. Several genetic mutations can be responsible for this delay in the progression of the disease (as in certain deletions of the CCR5 co-receptor gene).
Diagnosis
In most centers, enzyme-linked immunosorbent assay (ELISA) is used as the primary screening test. If the test is reactive, it is repeated in duplicate and if either or both repeat tests are reactive, the sample is considered positive and a western blot or indirect immunofluorescence assay is done on the sample for confirmation. The western blot detects antibodies to specific denatured HIV-1 proteins. The absence of all bands in western blot is considered a negative test.
This protocol has a 3-4 week "window period" prior to seroconversion, during which results can be negative or indeterminate. Most experts suggest the use of plasma viral load (PVL) for patients that may be in the window period (as in the case scenario). In addition to PVL, very sensitive virological assays (RT-PCR, bDNA) are also used for diagnosis. However, one frequent consequence of using highly sensitive tests will be the loss of specificity, meaning that false-positive results will occur. For this reason, ELISA with a confirmatory western blot remains the "gold standard" for the diagnosis of infection in adults and older children. Rapid tests for expedited screening can be used in selected patients such as pregnant women.
The diagnosis of HIV infection in newborns and infants <18 months of age is different. Nearly all infants born to infected mothers passively acquire maternal antibodies and in some instances will test positive regardless of whether they are infected. Definitive diagnosis in this age group requires virological tests as PCR or viral culture. Two positive assays on two separate specimens are required for diagnosis. Infant HIV testing should be done as soon possible. The infant who has two negative virological tests, both of which are performed at 1 month of age or older and one of which is performed at 4 months of age or older, is considered to have had HIV infection reasonably excluded in the absence of any clinical illness.
T cell counts are important for the diagnosis and laboratory monitoring of the patients. Generally, along with a decrease in the CD4+ levels, an increase in CD8+ levels is observed. This decrease in CD4+ to CD8+ ratio can also occur with other viral infections, such as those caused by CMV or EBV. CD4 count is generally accepted as the best indicator of the immediate state of immunologic competence of the patient.
Response of T-lymphocytes to plant lectin mitogens (pokeweed) are decreased or absent and patients may be anergic to skin tests. Serum immunoglobulins, particularly IgG and IgA are frequently elevated during the early stages of HIV infection.
Clinical manifestations
The clinical manifestations can be due to HIV or its complications. The disease spectrum changes from primary infection with or without the acute syndrome to the asymptomatic stage and to advanced disease. Approximately 50% of untreated patients develop AIDS within 10 years. An additional 30% will have mild symptoms of immunodeficiency and fewer than 20% will be entirely asymptomatic.
The pediatric manifestations usually include generalized lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, oral candidiasis, recurrent diarrhea, parotitis, cardiomyopathy, hepatitis, nephropathy, CNS disease (including developmental delay), lymphoid interstitial pneumonia, recurrent invasive bacterial infections, opportunistic infections and malignancies. Fever is common and can be due to Mycobacterium avium complex, toxoplasmosis, CMV infection, tuberculosis, Pneumocystis carinii infection, salmonellosis, cryptococcosis, histoplasmosis, medications or malignancies. Acute bronchitis and sinusitis are more prevalent during all stages of disease. The most common causes of pneumonia are the bacterial infections and Pneumocystis carinii pneumonia (PCP). PCP occurs most frequently in infants between 3 and 6 months of age who acquire infection before at birth. In addition to these pulmonary manifestations, another important clinical feature in children is lymphoid interstitial pneumonitis (LIP). LIP is a benign lung infiltrate and is felt to be part of the polyclonal activation of lymphocytes. It is generally self-limited and no specific treatment is necessary. HIV infected patients appear to be particularly prone to infections with encapsulated microorganisms such as S. pneumoniae and H. influenzae type B.
Malignancies in pediatric HIV infection have been relatively uncommon, but leiomyosarcomas, CNS lymphomas, and Burkitt lymphomas occur much more frequently in children with HIV infection than in nonimmunocompromised children. The development of opportunistic infections, particularly PCP, progressive neurologic disease, and severe wasting is associated with a poor prognosis.
HIV pediatric findings have been revised into 4 categories (4):
Category N: Not symptomatic. These children may have only one of the conditions from category A. These patients have CD4 cells >25%.
Category A: Mildly symptomatic. They can have 2 or more of the following conditions: lymphadenopathy, hepatomegaly, splenomegaly, dermatitis, parotitis, recurrent or persistent upper respiratory tract infections.
Category B: Moderately symptomatic. Findings may include but are not limited to: anemia, neutropenia, single episode of meningitis, pneumonia, recurrent or chronic diarrhea, HSV infections, lymphoid interstitial pneumonitis, persistent fever (>1 month).
Category C: Any condition listed as "AIDS defining conditions" including serious multiple and recurrent bacterial infections, candidiasis, disseminated coccidioidomycosis and histoplasmosis, extrapulmonary cryptococcosis, cryptosporidiosis >1 month, CMV infection developing after 1 month of age. It also includes wasting syndrome (persistent weight loss >10% of baseline or downward crossing of at least 2 of the following percentile lines on the weight for age chart in a child >1 year of age or <5th percentile on weight for height chart on 2 consecutive measurements plus chronic diarrhea or documented fever), encephalopathy, Kaposi's sarcoma, lymphomas. These patients usually have circulating CD4 cells of <15%.
Treatment
Initiation of antiretroviral treatment (ART) depends upon virologic, immunologic and clinical criteria. The CD4+ lymphocyte count or percentage value is used in conjunction with viral load to guide treatment decisions and primary prophylaxis of PCP after age 1 year. Expert opinions and knowledge about diagnostic and therapeutic strategies are changing rapidly and these can be followed from several resources such as: www.hivatis.org (posts federally approved treatment guidelines), www.actis.org (information on federally funded and privately funded clinical trials), www.cdcnpin.org (updates on epidemiologic data from the CDC), www.cc.nih.gov/hiv-mgt (online images of HIV drugs and information regarding dosing). If enrollment into clinical trials is possible, enrollment of the HIV-infected child into an available clinical trial should be encouraged. There are several groups of drugs used in ART.
Nucleoside analog reverse transcriptase inhibitors (NRTIs): zidovudine (ZDV-Retrovir), didanosine (ddI-Videx), lamivudine (3TC, Epivir), stavudine (d4T, Zerit), zalcitabine (ddC, Hivid), abacavir (ABC, Ziagen).
Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs): nevirapine (NVP, Viramune), efavirenz (EFV, DMP-266, Sustiva).
Protease inhibitors (PIs): ritonavir (Norvir), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase, Fortovase), amprenavir (Agenerase), ABT-378/r (Kaletra).
Fusion inhibitors: T-20.
Antiretroviral therapy has provided substantial clinical benefits to HIV-infected children with immunologic or clinical symptoms of HIV infection. Studies have demonstrated substantial improvements in neurodevelopment, growth, and immunologic and/or virologic status with initiation of ZDV, ddI, 3TC, or stavudine monotherapy . More recent pediatric trials of symptomatic children who have not previously received antiretrovirals have demonstrated that combination therapy with either ZDV and 3TC or ZDV and ddI is clinically, immunologically, and virologically superior to monotherapy. When compared with monotherapy, combination therapy: a) slows disease progression and improves survival, b) results in a greater and more sustained virologic response and c) delays development of virus mutations resistant to the drugs being used. Data from clinical trials that address the effectiveness of antiretroviral therapy in asymptomatic infants and children with normal immune function are not available. However, initiation of therapy early in the course of HIV infection, including during the period of primary infection in the neonate, is theoretically advantageous. Antiretroviral treatment is definitely required in the presence of any AIDS-definitive infection (Category C), wasting or failure to thrive, HIV encephalopathy, AIDS-associated malignancy and two episodes of meningitis or sepsis. Several ART drugs are not approved for use in children. ART should be initiated by a pediatric infectious diseases specialist with expertise in HIV infection and its treatment. Generally, the combination of a protease inhibitor and two non-nucleoside RTIs is recommended for initial antiretroviral therapy. If the patients cannot swallow pills, the PIs nelfinavir or ritonavir can be used. If they can swallow pills, indinavir can also be used. Another recommended alternative to this treatment is nevirapine with two NRTIs or abacavir with ZDV and 3TC. Monotherapy, d4T/ZDV, ddC/ddI, ddC/d4T, ddC/3TC treatments are not generally recommended.
Adherence to treatment can be increased by use of suitable formulations, use of G-tubes, and directly observed therapy. Drug concentrations should be monitored. Viral assays can be done to assess resistance. ART may have serious side effects and patients should be carefully monitored. There are currently no data available that define the threshold at which a change in therapy should occur. If the PVL is above detectable limits on two determinations or if the PVL exceeds the arbitrary figure of 10,000 to 20,000 copies/mL, a change in therapy may be considered. PVL assays and CD4 cell counts should be repeated at 3 to 4 month intervals during therapy.
Early diagnosis and aggressive treatment of opportunistic infections may prolong survival. Four major opportunistic infections need to be considered for prophylactic treatment: bacteremia/sepsis, Pneumocystis carinii infection (PCP), tuberculosis and mycobacterium avium/m. intracellulare infection. For infants younger than 1 year of age with possible or proven HIV infection, PCP prophylaxis should be administered at 4 to 6 weeks of age and continued for the first year of life unless infection is excluded.
IVIG can be given in addition to ART to children with hypogammaglobulinemia, recurrent, serious bacterial infections, children who fail to develop antibodies to common antigens and to children living in areas where measles is highly prevalent who have not developed an antibody response after two doses of MMR.
Treatment of HIV-infected women with zidovudine during the second and third trimester of pregnancy and during delivery, followed by zidovudine treatment of the infant for 6 weeks is shown to decrease maternal-fetal transmission to 8%.
Following significant exposure of health care employees (needle-stick injuries) prompt administration of a combination regimen of indinavir, zidovudine, and lamivudine, significantly decreases the likelihood of HIV infection.
Immunizations
In general, live virus (OPV) vaccines and live bacterial (BCG) vaccines should not be given to patients with AIDS or other clinical manifestations of HIV infection indicative of significant immunosuppression. An exception is MMR vaccine which can be given to patients who are not severely immunocompromised. Other routinely recommended vaccines, should be given according to the usual immunization schedule. Pneumococcal vaccine and influenza vaccination are also recommended. Varicella vaccine can be administered to asymptomatic patients if the benefits of vaccination outweigh its risks.
Control measures
In addition to the measures for the reduction of perinatal HIV transmission and counseling of HIV-infected women to not breastfeed; education, counseling, behavior modification are the cornerstones of infection prevention. Another important point is that HIV infected children should not be excluded from day-care centers or schools for the protection of other children or personnel. The need for a more restricted environment should be evaluated on a case by case basis with consideration of conditions that may pose an increased risk to others, such as aggressive biting behavior or the presence of exudative, weeping skin lesions that cannot be covered. Only the child's parents, guardians, and physician have an absolute need to know that the child is HIV infected. The number of personnel aware of the child's condition should be kept to the minimum needed to ensure proper care of the child.
HIV vaccines using viral surface proteins, non-HIV live vector viruses, combination of several viral elements, naked DNA and HIV protein fragments are studied and in some instances clinical trials are being performed.
Questions
1. Which one of the following is not a finding in HIV wasting syndrome?
. . . . a. <5th percentile on weight-for-height chart on 2 consecutive measurements.
. . . . b. Chronic diarrhea.
. . . . c. Temperature of 38.5 °C, intermittently during the last 2 months.
. . . . d. Persistent weight loss.
. . . . e. Thrombocytopenia.
2. Which one of the following is used as a screening test in HIV infection diagnosis?
. . . . a. Enzyme immunoassay
. . . . b. Polymerase chain reaction
. . . . c. Western-blot
. . . . d. Immune fluorescence assay
. . . . e. Viral culture
3. Which of the following vaccines is not routinely recommended in HIV infected asymptomatic children?
. . . . a. IPV
. . . . b. MMR
. . . . c. Hib
. . . . d. Pneumococcal
. . . . e. Varicella
4. Which of the following is a definite indication to start antiretroviral treatment in HIV infected children?
. . . . a. CD4 cell counts >1500 in a 4 year old asymptomatic child.
. . . . b. Pneumocystis carinii pneumonia.
. . . . c. Recurrent otitis media but no other symptoms.
. . . . d. Bilateral anterior cervical lymphadenopathy.
5. Which one of the following is/are not shown to be a transmission route for HIV infection?
. . . . a. Vertical transmission
. . . . b. Breast feeding
. . . . c. Vectors
. . . . d. Blood transfusion
. . . . e. Heterosexual sex
6. Which of the following enzymes have critical importance in the establishment of HIV infection?
. . . . a. Neuraminidase
. . . . b. DNA polymerase
. . . . c. Protein kinase
. . . . d. RNA polymerase
. . . . e. Reverse transcriptase
References
1. Cunha BA (ed). Infectious Disease Pearls. 1999, Philadelphia: Hanley and Belfus, Inc., pp. 198-200.
2. HIV infection and AIDS. In: Gorbach SL, Falagas M (eds). The 5 minute infectious diseases consult. 2001, Philadelphia: Lippincott Williams and Wilkins, pp. 218-221.
3. Fauci AS, Lane HC. Human immunodeficiency virus (HIV) disease: AIDS and related disorders. In: Braunwald E, Fauci AS, Kasper DL, et al (eds). Harrison's Principles of Internal Medicine, 15th edition. 2001, New York: McGraw-Hill, pp. 1852-1913.
4. HIV infection. In: Pickering LK, et al (eds). 2000 Red Book: Report of the Diseases, 24th edition. 2000, Elk Grove Village, IL: American Academy of Pediatrics, pp. 325-350.
5. Centers for Disease Control and Prevention. Revised recommendations for HIV screening of pregnant women. MMWR 2001;50(RR19):59-86.
Answers to questions
1.e, 2.a, 3.e, 4.b, 5.c, 6.e