Hematologic system

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SECTION V

Hematologic system

A AIDS/HIV infection

Definition

Human immunodeficiency virus (HIV) is the most significant etiology of secondary immunosuppression that can result from infection that causes depletion of immune cells. The virus exists as two main types, HIV-1 and HIV-2. Of the two, HIV-1 is more prevalent and more pathogenic. The primary targets of HIV infection are CD4+ lymphocytes. A glycoprotein on the viral envelope binds to the CD4 antigen to allow the virus to enter the T cell. HIV is a retrovirus, that is, its genome contains 2 strands of single-stranded RNA. After the virus enters the host cell, its RNA undergoes reverse transcription to produce complementary DNA that is incorporated into the host cell DNA. Synthesis of new viral RNA then occurs in the host cell followed by formation of new virus particles and their release to infect other CD4+ cells. Infection with HIV alters T-cell function and causes cytotoxicity, leading to the characteristic decline in CD4+ cells. Exactly how HIV infection kills T cells, though, is not known and may involve several mechanisms. Ultimately, with a sufficient fall in CD4+ cells, individuals become susceptible to life-threatening opportunistic infections.

Pathophysiology

The epidemiologic basis for HIV infection begins with transmission of the virus through certain body fluids. Infection with HIV can progress to acquired immune deficiency syndrome (AIDS) and fatal disease. Although more than 25 million individuals have died as a result of AIDS complications since the first description of the disease, early detection, evaluation, and pharmacologic intervention have become very successful in controlling HIV infection in many individuals while preserving immune system integrity.

The potential sources of transmission of HIV are blood contact, sexual transmission, and perinatal exposure (see box below).

Routes of HIV Transmission

Absolute

Blood

Body fluids containing blood

Possible

Cerebrospinal fluid

Pericardial fluids

Amniotic fluids

Semen, vaginal secretions

Synovial fluid

Pleural fluid

Remote

Feces

Saliva

Sputum

Sweat

Tears

Urine

Wound drainage

Nasal secretions

Not implicated in health care settings

Human breast milk

Human immunodeficiency virus is transmitted through mucous membranes during anal, vaginal, and oral intercourse. Transmission of HIV also occurs through sharing injection equipment and needles. Vertical transmission occurs from mother to child. Blood, semen, vaginal fluid, breast milk, cerebrospinal fluid (CSF), amniotic fluid, and serosanguineous fluid can transmit HIV; saliva, tears, and sweat do not. The virus cannot survive outside the host, and 90% to 99% of infective HIV on dry surfaces is eliminated within hours. Insect bites and casual contact carry no risk.

As epidemic and scientific approaches to HIV infection evolved, the focus shifted from “risk groups” to “risky behaviors.” This distinction is important because risk groups can give a false sense of security by implying that certain groups of individuals are less vulnerable to infection. Risky behaviors is a more useful term, falling along a spectrum of “no risk” (e.g., complete sexual abstinence), “very low risk” (e.g., 100% use of latex condoms), to “very high risk” (e.g., unprotected receptive anal intercourse with ejaculation), with other behaviors in midspectrum. The physician serves as a source of accurate information to be provided in simple, nonjudgmental terms because ultimately the patient will decide the acceptable degree of risk.

Acute infection with HIV is characterized by a mononucleosis-like illness, in which release of inflammatory mediators, including interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α), causes symptoms such as malaise, fever, myalgias, and rash. At the same time, a transient decline in circulating CD4+ cells occurs. Over several weeks after the primary infection, antibodies directed against virus envelope proteins are produced, and cytotoxic T lymphocytes (CTLs) begin to kill infected T cells that display HIV peptides. These immune responses permit resolution of the symptoms of acute infection; however, anti-HIV antibodies and CTLs become overwhelmed by viral replication and mutation, and progression of HIV infection occurs.

Spontaneous resolution of the acute symptoms of HIV infection is followed by a variable period of asymptomatic infection. If the infection is not treated, a gradual, progressive fall in CD4+ cells occurs in conjunction with a gradual increase in the plasma viral load. Progression to AIDS in untreated individuals occurs in an average time of 10 years, although in some individuals, progression may occur much more rapidly or perhaps not at all. With respect to the latter possibility, there are reports of individuals who have not developed AIDS despite multiple exposures to HIV, suggesting that the adaptive immune system in some individuals may provide chronic protection by an as yet undefined mechanism. Clinically, AIDS is defined as a CD4+ cell count less than 200 cells/μL or by the presence of an AIDS-indicator condition.

About 33 million people worldwide are living with HIV/AIDS in 2007. Of these, 2.7 million have been newly infected, and 2 million people have died of HIV/AIDS. Developing countries account for more than 95% of these infections (UN AIDS, 2007). From 2004 to 2007, there has been an increase of 15% in the incidence of HIV/AIDS cases in the United States. This increase occurred mainly in persons age 40 to 44 years, who accounted for 15% of all HIV/AIDS cases, likely caused by both changes in reporting systems and increased HIV testing.

A disproportionate number of minorities and women are affected by HIV. Blacks constituted 45% of newly diagnosed cases in 2006, with a rate of infection of 83.7 per 100,000. Of these, 60% are women. Blacks living with HIV/AIDS constituted about 60% of the adult HIV-positive population in 2007, with a rate of 76.7 per 100,000. Similarly, Hispanics, although constituting 12% of the population, reflected 17% of persons newly infected with HIV in 2006 and 20% of those living with HIV/AIDS in 2007, with rates of 29.3 and 20 per 100,000, respectively. Year-end prevalence rates in 2007 were 185.1 per 100,000 population, with a range between 2.2 in Samoa and 1750 per 100,000 in the District of Columbia.

Acquired immunodeficiency syndrome was diagnosed within 12 months of diagnosis of HIV infection for a larger percentage of Hispanics and male intravenous drug users (IVDUs) and men with high-risk heterosexual contact. Survival after AIDS diagnosis has increased in those who were diagnosed between 1998 and 2000, among men who have sex with men, and those who have acquired HIV perinatally. More whites survive 48 months after a diagnosis of AIDS than minorities. Survival has declined in IVDUs and with each year of age at diagnosis after age 35 (HIV/AIDS Surveillance Report, 2007).

The three main modes of transmission of HIV are as follows:

1. Through the mucous membranes during anal, vaginal, or oral sexual intercourse with an HIV-infected person. The average risk of transmission in heterosexual exposure is one in 1000 and increases with commercial sex workers to about five to 10 in 100. Whereas co-infection with other sexually transmitted diseases (STDs), rough sex, and higher viral load increase risk, condom use and male circumcision reduce risk. Uncircumcised men a run risk similar to a woman, and circumcised men may transmit the virus to female partners four times as efficiently as uncircumcised men. Postmenopausal women are more susceptible because of thinning of the vaginal mucosa. Risk of infection per act has been suggested from cohort studies, so physicians should avoid discussing risks in numeric terms.

2. Through the veins while sharing needles or injection paraphernalia with an HIV-infected person

3. Vertically from an HIV-infected mother to an infant during pregnancy, delivery, or through breastfeeding. High viral load, prolonged time after rupture of membranes, and chorioamnionitis increase risk of transmission, and peripartum prophylactic antiretroviral therapy decreases risk. The overall risk of transmission by breastfeeding is about 15% to 25% in 18- to 24-month-old infants.

Occupational exposure occurs by needlestick injuries (risk, 3:1000), infected blood or fluid splashing into the mouth or nose, or exposure to infected blood through a cut or an open wound. Mucous membrane exposure carries a risk of infection of about nine in 10,000. Transmission of HIV through infected blood is extremely rare after routine screening of the blood supply was initiated in 1985. With risk of transmission as low as two per million, 16 annual infections are accounted for by infectious donations. Neither insect bites nor casual contact carry any risk.

Human immunodeficiency virus can be transmitted by blood, semen, vaginal fluid, breast milk, and serosanguineous body fluids. Contact with CSF, amniotic fluid, and synovial fluid can be a risk factor for HIV transmission. Importantly, although HIV can be present in small quantities in saliva, sweat and tears, contact with these fluids does not transmit HIV. The virus cannot survive outside the host, and the amount of infective virus dried on surfaces is reduced by 90% to 99% in a few hours.

The two classification systems currently in use to monitor the severity of HIV illness and assist with its management have been developed by the Centers for Disease Control and Prevention (CDC) (see table on pg. 115) and the World Health Organization (WHO) (see box below). The CDC classification, last modified in 1993, uses CD4+ counts and specific HIV-related conditions, but the WHO classification, developed in 1990 and revised in 2007, is guided by clinical observations and can be used in settings where access to CD4+ tests is unavailable. The CDC lists AIDS categories as A3, B3, C1, C2, and C3, with 23 AIDS-defining conditions. The WHO includes primary HIV infection and four clinical stages.

Centers for Disease Control and Prevention Classification System of HIV/AIDS

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PGL, Persistent generalized lymphadenopathy.

Data from US Centers for Disease Control and Prevention. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41(RR-17):1-19.

World Health Organization Clinical Staging of HIV/AIDS

Primary HIV infection

Asymptomatic

Acute retroviral syndrome

Clinical stage 1

Asymptomatic

Persistent generalized lymphadenopathy

Clinical stage 2

Moderate unexplained weight loss (<10% body weight)

Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, pharyngitis)

Herpes zoster

Angular cheilitis

Recurrent oral ulceration

Papular pruritic eruptions

Seborrheic dermatitis

Fungal nail infections

Clinical stage 3

Severe, unexplained weight loss (>10% body weight)

Unexplained diarrhea lasting >1 month

Unexplained, persistent, constant or intermittent fever >1 month (>37.6° C)

Persistent oral candidiasis

Oral hairy leukoplakia

Pulmonary tuberculosis

Severe presumed bacterial infections (pneumonia, empyema, pyomyositis, bone and joint infections, meningitis, bacteremia)

Acute necrotizing gingivitis, stomatitis, periodontitis

Unexplained anemia (hemoglobin <8 g/dL)

Neutropenia (<500 cells/mm3)

Chronic thrombocytopenia (<50,000 cells/mm3)

Clinical stage 4

All of the AIDS indicator conditions as defined by the CDC classification and

Atypical disseminated leishmaniasis

Symptomatic HIV-associated nephropathy

Symptomatic HIV-associated cardiomyopathy

Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis)

CDC, Centers for Disease Control and Prevention.

Modified from World Health Organization. Case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV related disease in adults and children. Geneva, WHO, 2007. www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf.

Category B: Symptomatic conditions

These conditions must indicate defective cell-mediated immunity caused by HIV infection, or their clinical course and management must be complicated by HIV. Category B conditions include the following:

• Constitutional symptoms (fever >38.5° C or diarrhea) lasting more than 1 month

• Candidiasis: oropharyngeal or persistent or recurrent vulvovaginal

• Pelvic inflammatory disease

• Moderate or severe cervical dysplasia or carcinoma in situ

• Oral hairy leukoplakia

• Idiopathic thrombocytopenic purpura

• Peripheral neuropathy

• More than two episodes of multidermatomal herpes zoster

• Bacillary angiomatosis

Category C: AIDS-defining illnesses

Including bacterial, viral, fungal infections, parasitic infestations, and some cancers

Bacterial:

• Mycobacterium tuberculosis infection at any site, pulmonary or extrapulmonary

• Mycobacterium avium complex disease; infection with Mycobacterium kansasii or other species, disseminated or extrapulmonary

• Mycobacterium, any species disseminated or extrapulmonary

• Bacterial pneumonia, recurrent (>2 episodes in 12 months)

• Nontyphoid Salmonella septicemia, recurrent

Viral:

• Cytomegalovirus disease (other than liver, spleen, or nodes) and retinitis with vision loss

• Herpes simplex virus (chronic ulcer persisting >1 month, bronchitis, pneumonitis, esophagitis)

• Progressive multifocal leukoencephalopathy

Fungal:

• Candidiasis of the esophagus, bronchi, trachea, or lungs

• Coccidioidomycosis, disseminated or extrapulmonary

• Cryptococcosis, extrapulmonary

• Histoplasmosis, disseminated or extrapulmonary

• Isosporiasis, chronic intestinal (persisting for >1 month)

• Pneumonia, recurrent (Pneumocystis jiroveci)

Parasitic:

• Cryptosporidiosis, chronic intestinal (persisting for >1 month)

• Toxoplasmosis of brain

• Isosporiasis, chronic intestinal (persisting for >1 month)

HIV-related conditions:

• Encephalopathy, HIV related

• Wasting syndrome, HIV related (weight loss >10% body weight with either chronic diarrhea of >2 stools/day for 1 month or chronic weakness and documented fever >1 month)

Cancers:

• Cervical cancer, invasive

• Kaposi sarcoma

• Lymphoma (Burkitt, immunoblastic, or primary lymphoma of the brain)

• Cancers and chronic renal failure associated with AIDS and lipodystrophy, insulin resistance, osteoporosis, and cardiovascular complications of HAART are being increasingly recognized and addressed.

The best defense is a good offense, and there is no substitute for strict adherence to universal precautions. If despite these efforts you or a coworker are exposed to HIV, postexposure prophylaxis is available. Because most occupational exposures do not result in HIV transmission, the guidelines for postexposure prophylaxis weigh the relative risk of infection against the potential toxicity of treatment. The relative risk of infection depends on both the type and amount of blood exposure. The risk of transmission is increased by (1) percutaneous exposure, (2) devices contaminated with visible blood, (3) hollow-bore needles, and (4) high viral titer (i.e., a patient late in the course of the disease). The three classes of antiretroviral agents recommended for prophylactic treatment include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. All are associated with a number of toxicities. A basic two-drug regimen is most often recommended, with an expanded three-drug regimen reserved for high-risk exposure (see table on pg. 118). The U.S. Public Health Service guidelines recommend that clinicians consider known drug resistance in their area or documented drug resistance in the source patient, or both, when selecting a prophylactic protocol. The duration of treatment is 4 weeks.

Recommended HIV Postexposure Prophylaxis (PEP) for Percutaneous Injuries

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