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Acquired immunodeficiency syndrome and the emergency physician
COLLECTIVE REVIEW acquired immunodeficiency syndrome
Acquired Immunodeficiency Syndrome and the Emergency Physician [Skeen WF: Acquired immunodeficiency syndrome and the emergency physician. Ann Emerg Med March 1985;14:267-273.]
William F Skeen, MD, MPH Los Angeles, California
INTRODUCTION
From the Department of Emergency Medicine, University of Southern California, Los Angeles, California.
Like Legionnaires' disease and toxic Shock syndrome, acquired immUnodeficiency syndrome (AIDS) is a newly recognized public health threat that has received wide media coverage. Unlike the first two diseases, however, AIDS does not promise to be a short-lived epidemic. The Centers for Disease Control (CDC) defines AIDS as "a disease, at least moderately predictive of a defect in cell-mediated immunity, Occurring in a person with no known cause for diminished resistance to that disease. Such diseases include Kaposi's sarcoma (KS), pneumocystis carinii pneumonia (PCP), and serious other opportunistic infections."1 Some AIDS cases will present as true emergencies; the majority will be less urgent but will require appropriate treatment and referral.
Received for publication December 30, 1983. Revision received May 24, 1984. Accepted for publication August 13, 1984. Address for reprints: William F Skeen, MD, MPH, University of Southern California School of Medicine, Department of Emergency Medicine, 1200 North State Street, Los Angeles, California 90033.
EPIDEMIOLOGY As of November 1984, 6,993 AIDS cases in the United States had been reported and confirmed by the CDC. The current mortality rate is 48%, 2 but it will probably increase as patients classified as "survivors" succumb to the disease. Several groups at high risk for developing AIDS have been identified. These include h o m o s e x u a l men, 3-s intravenous (IV) drug abusers,I, 9 hemophiliacs, lo-14 and HaitiansjS-lS In addition, cases have been reported among male prisoners,19 female sexual partners of high-risk AIDS patients, 2o and infants born to high-risk mothers. 21-24 A number of cases of possible transfusion-related AIDS occurring in patients without other apparent risk factors have been reported.2S, 26 One was an infant who received mukiple transfusions after birth and later developed-severe cell-mediated immunodeficiency.2S,26 One of the donors, who had been healthy at the time of donation,2S was subsequently identified as a fatal AIDS case. KS accounts for 24% of AIDS cases; PCP accounts for 53%; and 6% of AIDS patients have both KS and PCP. Many AIDS patients have other opportunistic infections, and 17% have such infections without KS or PCP (Table 1).2 Most patients with AIDS fall into one or more of the high-risk categories: 73% are homosexual or bisexual men; 17% are IV drug abusers; 4% are Haitians living in the United States; and fewer than 1% are hemophiliacs. The remaining 5% do not have clearly defined risk factors (Table 2). Cases have been reported among all primary racial groups in the United States. 2 Women account for 7% of the totalY Geographic clustering has been noted, with New York reporting 42% of all cases; California, 23%; and Florida, 7%. Nonetheless, cases have been reported in 45 states, the District of Columbia, and Puerto Rico. 27
CLINICAL PRESENTATION A N D COURSE Kaposi's Sarcoma Moriz Kaposi originally described five cases of "idiopathic multiple pigmented sarcoma of the skin" in 1872. 28 Prior to the current epidemic, Ka-
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posi's sarcoma was uncommon in the United States, occurring primarily in elderly men of Jewish, Italian, or Mediterranean descent. Lesions typically were found on the lower extremities. The disease followed an indolent course and was responsive to radiotherapy or single-agent chemotherapy. In equatorial Africa, however, KS is endemic; it occurs frequently in children and young adults and accounts for 9% of all neoplasms in the region.3, 7,29 By contrast, almost all AIDS patients with KS are under the age of 50.3 In one series, patients presented with the following complaints: skin lesions (50%); skin lesions and lymphadenopathy (20%); weight loss and fever (10%); and weight loss, fever, and pneumonia (10%).3 Skin lesions may be macules, papules, nodules, or plaques that vary in size from a few millimeters to more than several centimeters (Figure 1). They may be reddish-pink in color, or have a characteristic violaceous to red-brown hue (Figure 2). Although lesions may be present on any region of the body, including mucous membranes, there is a predilection for the head and neck region. Over time, the lesions tend to increase in size and number. More than 50% of AIDS patients have gastrointestinal lesions, occurring anywhere from the mouth to the anus. Such lesions are redp raised, sessile, submucosal nodules ranging in size from several millimeters to more than a centimeter. They may present with chronic occult blood loss or rem a i n c l i n i c a l l y silent. Gastrointestinal lesions may antedate skin lesions in some cases. KS in AIDS patients may occur in virtually any body organ. 3° Compared to the classic form of KS, the disease in AIDS patients is far more fulminant. PCP frequently complicates the clinical course, as do a variety of other opportunistic infections. 3 The CDC reports a mortality rate of 24% for patients with KS alone, 47% for PeP alone, and 63% for patients with both KS and PCPJ Because KS in the setting of immunodeficiency does not respond to traditional therapy, 31 current treatment is largely experimental. Various antitumor regimens with such standard c h e m o t h e r a p e u t i c agents as vinblastine, adriamycin, and bleomycin have shown modest results. 3~ The 120/268
search for agents to correct the underlying immune defect has centered on lymphokines, which are immune mediators produced by T-lymphocytes.32 In one series, recombinant leukocyte A interferon produced clinical improvement in two-thirds of KS patients. 33 Preliminary studies have indicated that interleukin-2 and gamma interferon also may have therapeutic benefiti32,34
Pneurnocystis Carinii Pneumonia P e P is a u b i q u i t o u s p r o t o z o a n transmitted by inhalation. By four years of age, 80% of healthy individuals have significant antibody titers to the organism.35 Therefore, clinically apparent disease usually develops only in immunocompromised persons. 5 More than half of all AIDS patients develop PeP at some point in their illness. A prodrome of nonpulmonary symptoms, such as fever, weight loss, and diarrhea, may precede the onset of pneumonia by many months. Pulmonary complaints, such as cough and dyspnea, also m a y be present for months or may progress rapidly to respiratory failure within a few days. 36 Many patients will recover with treatment; however, recurrent episodes often are fatal. 3s In-hospital therapy consists of trimethoprim/sulfamethoxazole or pentamidine and ventilatory support. 37-39
Other Opportunistic Infections Other opportunistic infections have been described in AIDS patients (Figure 3). Cryptococcus neoformans, Mycobacterium avium-intracellulare, and cytomegalovirus (CMV) may cause diffuse pneumonitis. 31 Most AIDS patients have evidence of active CMV infection with positive throat, blood, or urine cultures. 40 Recurrent diarrhea often is noted in the prodromal period and in fully established AIDS cases. It may take the form of a few loose stools per day or profus e watery diarrhea. The homosexual population in general is subject to infection with multiple enteric pathogens, including Salmonella, Shige]la, and Campylobacter species,
Entamoeba histolytica, Giardia lamblia, and other parasites that may or may not be pathogenic. 31 Even in the absence of these organisms, however, AIDS patients may experience severe diarrhea. Some cases are due to disseminated gastrointestinal Annals of Emergency Medicine
TABLE 1. AIDS cases by primary
disease Primary Disease
% of Total
KS alone PeP alone Both KS and PeP Other opportunistic infections without KS or PCP
24 53 6
Total
17 100%
TABLE 2. AIDS cases among high-
risk groups Patient Group
% of Total
Homosexual/ bisexual men IV drug abusers Haitian immigrants Hemophiliacs Unknown risk factors
73 17 4 1 5
Total
100%
EMMa41, 42 and others may be caused by cryptosporiodiosis.3° The latter disease is acquired from animals and is usually self-limited in immunocompotent hosts. 31 In AIDS patients, however, symptoms are severe and refractory to treatment. In some patients with diarrhea, no pathogen can be isolated.31 Other gastrointestinal complaints include dysphagia and odynophagia due to invasive oral and esophageal candidiasis. 31 Herpes simplex virus can produce severe ulcerative oral, genital, and perineal lesions.30, 43 The central nervous system (CNS) frequently is affected by opportunistic infections in AIDS patients. Toxoplasma gondii abscesses present as mass lesions with headaches, seizures, or focal deficits.18,44 Haitian AIDS patients have a higher incidence of this complication, is Cryptococcal meningitis is not uncommon i n the syndrome. 31 A progressive encephalopathy that slowly leads to severe dementia and is possibly due to CMV has been described. 45 Chorioretinitis with decreasing visual acuity is also caused by CMV or, occasionally, T
gondiJ. 3t
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Persistent Generalized Lymphadenopathy Among persons at high risk for development of AIDS, a syndrome of persistent generalized lymphadenopathy has been described. 46 Such persons have l y m p h a d e n o p a t h y of at least three months duration involving two or more extrainguinal sites and c o n f i r m e d on e x a m i n a t i o n . This lymphadenopathy occurs in the absence of any illness or drug known to induce such changes, and biopsy, if done, shows reactive hyperplasia. Some patients in this category have such nonspecific symptoms as fever, night sweats, and weight loss, while others are asymptomatic. It is not yet known if this syndrome represents the forerunner of AIDS or, ahernatively, a group of persons who have come into contact with the AIDS agent and are resistant to the disease. 46
IMMUNE DEFECT Lymphocytes are broadly divided into two types. Thymus-derived or TlymphocYtes (T-cells) are directly involved with cellular immunity, while bursa-derived or B-lymphocytes (Bcells) are concerned with antibody production and humeral immunity. Tcells can be further differentiated into helper (Th), suppressor (Ts), and killer subp0pulations. These first two cell t y p e s help r e g u l a t e i m m u n e responses; the latter type is cytotoxic effector cells. Intact T-cell function is necessary to defend the body against 14:3 March 1985
certain viruses, fungi, mycobacteria, and other parasites. 47 Common to all AIDS patients is a severe deficit in cell-mediated immunity Peripheral lymphopenia is common, especially among the patients with opportunistic infections. The absolute n u m b e r of Th ceils is decreased, while the number of Ts cells is normal or increased, resulting in a decreased Th to Ts ratio. Anergy to skin tests is the rule. In addition, Tcell response to various mitogens is markedly reduced among AIDS patients.48-so Studies sl-s3 have shown similar but less pronounced defects among certain homosexual men and hemophiliacs who do not have AIDS, suggesting possible widespread exposure to the AIDS agent in these groups. Hemophiliacs who receive commercially prepared lyophilized factor VIII concentrate from pooled donor sources have lower Th to Ts ratios than do t h o s e w h o use o n l y f a c t o r VIII cryoprecipitate. The latter usually is obtained from a single donor.S4, ss Among homosexual men, the presence of AiDS and lower Th to Ts ratios has been correlated with a higher number of sexual partners.S, 6 The immunologic defect in AIDS may not be limited to the T-cell popu: lation. One study s6 reported decreased B-cell response to T-cell independent stimulation in homosexual AIDS patients. Spontaneous secretion of polyclonal immunoglobulin was increased Annals of Emergency Medicine
Fig. 1. Hyperpigmented nodular KS lesions. Fig. 2. Plaque-like violaceous KS lesions on a foot. ten times over control values, but no further increase was noted with stimulation. Such polyclonal activation has been seen in vivo in response to viral infections. An increased incidence of aut0immune thrombocytopenic purpura in homosexual men has been noted. 57 These patients did not have AIDS but did have significantly decreased Th to Ts ratioS. The occurrence of an autoimmune disease in a high-risk group with evidence of immunosuppression suggests that abnormalities of immune regulation eventually may be linked to AIDS. ETIOLOGY AIDS is a two-stage disease. Immunosuppression occurs, most likely as a result of exposure to a new Virus and/ or to multiple environmental and lifestyle factors. In this setting, malignancies or opportunistic infections develop. Increased promiscuity in the homosexual male c o m m u n i t y during the past decade was thought to have led to the bombardment and breakdown of the immune system by exposure to a wide variety of sexually transmitted viruses, parasites, and allogenic sperm.58, s9 This does not explain the 269/121
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occurrence of the disease among heterosexuals. Use of such recreational drugs as inhalant nitrites, or "poppers," has been implicated as a possible immunosuppressive factor.S Yet many AIDS patients deny use of these agents. 5 A CDC study found no immunosuppressive effects of inhaled nitrites in laboratory mice. 6o The epidemiologic evidence 61 favors the theory that AIDS is caused by a transmissible agent. This agent appear s to be spread by sexual contact or contaminated blood products, much like hepatitis B virus. A cluster of 16 homosexual male AIDS patients in Los Angeles and Orange counties, each of whom had had sexual contact with at least one other member of the group, has been reported. 62 The odds of 16 randomly selected homosexual men knowing each other in such a large metropolitan area are extremely small. Hemophiliacs exposed to blood products prepared f r o m a greater number of donors have lower Th to Ts ratios. 11 Intravenous drug abusers are at high risk presumably because they share contaminated needles. Recent investigation61 strongly implicates a newly discovered h u m a n retrovirus known as human T-cell leukemia virus (HTLV-III) as the cause of immunosuppression in AIDS. Human retroviruses came under suspicion for several reasons: 1) a feline variety causes immunosuppression in cats; 63 2) HTLV retroviruses are T-cell tropic; 63 3) they have a preference for Th cells; 63 4) in some cases they are cytotoxic for T-cells; 63 and 5) they may be transmitted by blood products or sexual contact. 63 One series 64 detected HTLV-III in 18 of 21 patients with prodromal AIDS symptoms; 13 of 43 adult KS patients; 10 of 21 AIDS patients with opportunistic infections; and none in 115 clinically healthy heterosexual volunteers. Of 22 clinically h e a l t h y h o m o s e x u a l s , one t e s t e d p o s i t i v e and d e v e l o p e d AIDS six m o n t h s later, Another study 65 reported that 43 of 49 AIDS patients (88%) and ll of 14 homosexual males with prodromai symptoms (79%)had sera that reacted to HTLV-III antigens. Only one of 186 heterosexual controls (0.5%) was positive. The role of CMV in AIDS also is under investigation. A higher prevalence of antibodies to CMV (93%) and active viral shedding (7%) was reported a m o n g h o m o s e x u a l men. 66 Among patients with KS, CMV anti122/270
Fig. 3. Other opportunistic infections common among AIDS patients. gens and CMV RNA were demonstrated in t u m o r tissue but not in healthy tissue. 4° Therefore, CMV may have a role in oncogenesis. Heredity also may contribute to the d e v e l o p m e n t of AIDS. One s t u d y found a high prevalence of the HLADR5 allele among both heterosexual and homosexual KS patients.7
PSYCHOSOCIAL ASPECTS The psychosocial aspects of AIDS are in some ways similar to those of cancer and other life-threatening illnesses. The AIDS patient faces such issues as fear of the unknown, the image of physical deterioration, the fear of dissolution of self, dread of pain and suffering, the struggle to maintain a sense of control, worry over loved ones who will survive, and the possibility of death earlier than anticipated. 67 Many psychosocial aspects of AIDS are unique. AIDS patients are prone to high levels of anxiety, guilt, anger, and depression. Many aspects of the medical illness itself contribute to these emotions. AIDS is a new disease with prolonged symptoms and no known cure. Fear of contagion or association with disadvantaged groups leads to social stigmatization: Treatment may be physically and emotionally difficult and e c o n o m i c a l l y devastating. The disease or treatment may lead to loss of vocational success, recreational activities, and social relationships. Homosexual men, who comprise about three-quarters of all reported AIDS cases, face special difficulties. Because their disease is associated with sexual activity, feelings of guilt a b o u t h o m o s e x u a l i t y m a y be rekindled. If a patient has not done so previously, he may need to tell his family and friends not only that he has a life-threatening illness but also that he is a homosexual. The latter process of "coming out" is usually quite stressful in itself.68 Because the syndrome has m a n y unknowns and because of wide media publicity, a group of patients known as the "worried well" has emerged. These are often, but not always, members of high-risk groups w i t h o u t apparent symptoms who are inordinately fearful of contracting AIDS. 67 This phenomenon is similar to cancer phobia. Annals of Emergency Medicine
Candida albicans Cryptococcus neoformans Cryptosporidium Cytomegalovirus Herpes simplex Mycobacteriurn avium - intracellulare Toxoplasma gondii The worried well may exhibit anxiety parallel in intensity to that of patients who actually have the disease. In general, patients with AIDS who seek psychiatric help are not looking for insight into psychological problems. Rather they seek help in trying to cope and adapt to the severe disruptions in their lives brought about by a medical problem. The approach to psychotherapy, then, is usually supportive rather than confrontational. An attempt is made to preseve the patient's defense mechanisms as an integral part of the coping effort. 67
EMERGENCY EVALUATION AND MANAGEMENT Although the underlying i m m u n e defect is c o m m o n to all AIDS patients, the manifestations of the disease are protean and nonspecific. A careful social and sexual history must b e elicited from all patients. Specifically patients should be questioned about sexual orientation, use of intravenous drugs, country of origin, exposure to known cases of AIDS, and history of transfusion of blood or blood products. If a patient is found to have any of the known risk factors, then AIDS must be considered in the differential diagnosis. Physical examination and laboratory studies should be guided by the patients' presenting complaints. Such nonspecffic c o m p l a i n t s as lowgrade fever, malaise, fatigue, or lymphadenopathy in a high-risk pat i e n t deserve a t h o r o u g h physical examination, limited laboratory workup, reassurance, and referral to a primary care physician for fi,trther evaluation and/or long-term follow-up. On physical examination, skin and mucous membrane lesions suggestive of KS should be sought, and the oral cavity s h o u l d be e x a m i n e d for candidiasis. Lymphadenopathy should be noted. In high-risk p a t i e n t s or k n o w n 14:3 March 1985
AIDS patients who present with pulmonary symptoms, PCP should be high on the list of differential diagnoses. Fulminant PCP may present with fever, cough, and severe dyspnea.35 Arterial blood gas reports may show marked hypoxemia, 36 and chest films typically show patchy or diffuse bilateral infiltratesi 69 however, biopsyproven PCP has been reported in a patient who presented with dyspnea but had a normal chest film and arterial oxygen tension. 70 Hospital admission is indicated for high-risk or known AIDS patients with significant dyspnea with or without abnormal chest films or arterial blood gas reports. Diarrhea is a common presenting complaint. 31 Homosexuals who do not have AIDS may have diarrhea caused by a variety of enteric pathogens. 31 Stool culture, ova and parasite examination, and a smear for fecal leukocytes may be useful diagnostic tests. If physical examination reveals significant dehydration, fluid and electrolyte replacement should be undertaken. High-risk and known AIDS patients may present with a variety of CNS symptoms. Focal deficits may result from T gondii abscesses, CNS lymphomas, or vascular complications such as cerebral hemorrhage in the setting of thrombocytopenia or nonbacterial thrombotic endocarditis. 4s Seizures may accompany focal lesions. Computed tomography brain scan and lumbar puncture may be diagnostic. Emergency therapy is primarily supportive, and emergency neurologic consultation should be obtained. Subtle changes in mental status may be early signs of progressive dementia. 4s Often these changes are attributed to depression and are not pursued. A high index of suspicion combined with a detailed mental status and neurologic examination may lead to the correct diagnosis. Some causes of organic brain syndrome in AIDS patients are treatable. 4s From a psychosocial standpoint, the most important task for the emergency physician is to neutralize whatever bias he may have toward AIDS patients who are homosexuals, drug addicts, or are from other disadvantaged groups. Compassion and sensitivity are essential for successful physicianpatient interaction. The physician should offer reassurance and accurate medical information. The diagnosis of 14:3 March 1985
AIDS cannot be confirmed in the emergency department (ED). The incidence of AIDS is low, even among high-risk groups. The incidence of homosexuality in the general male population is not known, but if estimated at 5%, 71 the percentage of homosexuals w i t h AIDS is approximately 0.05%. 71 Known AIDS patients or the worried well who exhibit high levels of anxiety, anger, depression, or other psychological impairment should be referred for consultation. The ED should have telephone numbers avail: able for referral to psychosocial comm u n i t y support groups located in most metropolitan areas. The Public Health Service maintains a toll-free AIDS hotline, 800/342-AIDS. The emergency physician should offer guidance on disease prevention to members of high-risk groups in a sensitive, nonjudgmental fashion. Homosexuals should be advised to avoid exchange of bodily fluids during sexual contact. Condoms are preferable to u n p r o t e c t e d anal intercourse and fecal-oral contact should be avoided. Reducing the number of sexual partners will decrease the risk of disease. 61 Hemophiliacs should consult their primary physicians for specific recommendations. Intravenous drug abusers should not share contaminated needles, and they should be encouraged to overcome their addiction. Health care personnel who may come into contact with AIDS patients also are concerned about contracting the disease. The CDC reported four cases of AIDS a m o n g health care workers, 72 but found no evidence that these workers acquired the disease from in-hospital contact with AIDS patients. The CDC has begun a prospective study of health care workers exposed via parenteral or m u c o u s membrane routes to blood and body fluids of AIDS patients. Thus far, none of 51 workers has contracted AIDS, but the follow-up period is less than 12 months for all but one ease. 73 Precautions for clinical and laboratory workers have been published.74J s These basically recommend hepatitis B-type precautions. There is no evidence for airborne spread or spread by casual contact with AIDS patients. 23 Specific recommendations include the following: 1) avoiding a c c i d e n t a l wounds from sharp instruments or needles contaminated with potentially infectious material; 2) wearing gloves when contacting body fluids; 3} Annals of Emergency Medicine
wearing a gown if exposure to body fluids is likely; 4) washing hands after contact with patient or body fluids; 5) using special labels for blood and other specimens; 6} using disposable needles and syringes; and 7) using a private room for patients too ill to practice good hygiene (eg, patients with profuse diarrhea). TM Ventilation devices for AIDS patients requiring cardiopulmonary resuscitation should be readily available to obviate the need for mouth-to-mouth contact. 76 There are anecdotal stories of health care personnel refusing to care for AIDS patients. This manifestation of so-called 'AIDS hysteria" is unwarranted in view of current knowledge. Such behavior is unprofessional and ethically unacceptable.
SUMMARY AIDS is a new public health disaster that is unlikely to be resolved quickly. It is manifested by a profound immune deficiency accompanied by the development of KS, PCP, and/or other opportunistic infections. A retrovirus, HTLV-III, is the probable cause of the immunosuppression, and it is transmitted in a manner similar to hepatitis B virus. Groups at highest risk inelude homosexual men, intravenous drug abusers, Haitians, and hemophiliacs. Therapy is largely experimental, and mortality is high. The emergency physician must be familiar with the signs, symptoms, and early management of AIDS. He should be able to offer guidance on disease prevention to both health care workers and members of high-risk groups. Allocation of major financial resources and intensive investigation are necessary to abort this cruel epidemic that affects primarily younger persons. Such investigation will undoubtedly produce new advances in virology, oncology, and immunology that will benefit medicine and society as a whole.
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67. Malyon AK, Pinka AT: Acquired immune deficiency syndrome: A challenge to psychology. The Professional Psychologist 1983;7:1-10.
58. Sonrabend J, Witkin SS, Purtilo DT: Acquired immunodeficiency syndrome, opportunistic infections, and malignancies in male homosexuals. A hypothesis of etiologic factors in pathogenesis. JAMA 1983;249:2370-2374.
68. Nichols SE: Psychiatric aspects of AIDS. Psychosomatics 1983;24:1083-1089.
59. Levy JA, Ziegler JL: Acquired immu-nodeficiency syndrome is an opportunistic infection and Kaposi's sarcoma results from secondary immune stimulation. Lancet 1983;2:78-81.
50. Schroff RW, Gottlieb MS, Prince HE, et ah Immunological studies of homosexual men with immunodeficiency and Kaposi's sarcoma. Clin Immunol Immunopathol 1983;27:300-314.
60. An evaluation of the immunotoxic potential of isobutyl nitrite. MMWR 1983;32:457-458, 464.
51. Komfield H, Vande Stouwe RA, Lange M, et ah T-Lymphocyte subpopulations in homosexual men. N Engl J Med 1982;307: 729-731.
61. Prevention of acquired immune deficiency syndrome {AIDS): Report of interagency recommendations. MMWR 1983; 32:101-103.
52. Pinching AJ, Jeffries DJ, Donaghy M, et ah Studies of cellular i m m u n i t y in male homosexuals in London. Lancet 1983;2:126-129.
62. A cluster of Kaposi's sarcoma and pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange counties, California. MMWR 1982;31:305-307.
53. de Shazo RD, Andes WA, Nordberg J, et ah An immunologic evaluation of hemophiliac patients and their wives. Relationships to the acquired immunodeficiency syndrome. A n n Intern Med 1983;99:159-164. 54. Lederman MM, Ratnoff OD, Scillian JJ, et ah Impaired cell-mediated immunity in patients with classic hemophilia. N Engl J Med 1983;308:79-83. 55. Menitove JE, Aster KH, Casper JT, et ah T-Lymphocyte subpopulations in patients with classic hemophilia treated with cryoprecipitate and lyophilized concentrates. N Engl J Med 1983;308:83-86. 56. Lane HC, Masur H, Edgar LC, et ah
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63. Popovic M, Sarngadharan MG, Read E, et al: Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 1984;224:497-500.
69. Hill CA, Harle TS, Mansell WA: The prodrome, Kaposi's sarcoma, and infections associated with acquired immunodeficiency syndrome: Radiologic findings in 39 patients. Radiology 1983;149: 393-399. 70. Goodman JL, Tashkin DP: Pneumocystis with normal chest x-ray film and arterial oxygen tension. Arch Intern Med 1983;143:1981-1982. 71. Kinsey AC: Sexual Behavior in the Human Male. Philadelphia, WB Saunders Co, 1948, p 617. 72. An evaluation of the acquired immunodeficiency syndrome (AIDS) reported in health-care personnel - - United States. MMWR 1983;32:358-360. 73. Prospective evaluation of health-care workers exposed via parenteral or mucusmembrane routes to blood and body fluids of patients with acquired immunodeficiency syndrome. MMWR 1984;33:181182. 74. Acquired i m m u n e deficiency syndrome IAIDS): Precautions for clinical and laboratory staffs. MMWR 1982;31: 577-580.
64. Gallo RC, Salahuddin SZ, Popovic M, et ah Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984;224:500-502.
75. Acquired immunodeficiency syndrome (AIDS): Precautions for health care workers and allied professionals. MMWR 1983;32:450-451.
65. Sarngadharan MG, Popovic M, Bruch L, et ah Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science 1984;224:506-508.
76. Conte JE, Hadley WK, Sande M: Infection-control guidelines for patients with the acquired imunodeficiency syndrome (AIDS). N Engl J Med 1983;309: 740-744.
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Acquired Immunodeficiency Syndrome and the Emergency Physician [Skeen WF: Acquired immunodeficiency syndrome and the emergency physician. Ann Emerg Med March 1985;14:267-273.]
William F Skeen, MD, MPH Los Angeles, California
INTRODUCTION
From the Department of Emergency Medicine, University of Southern California, Los Angeles, California.
Like Legionnaires' disease and toxic Shock syndrome, acquired immUnodeficiency syndrome (AIDS) is a newly recognized public health threat that has received wide media coverage. Unlike the first two diseases, however, AIDS does not promise to be a short-lived epidemic. The Centers for Disease Control (CDC) defines AIDS as "a disease, at least moderately predictive of a defect in cell-mediated immunity, Occurring in a person with no known cause for diminished resistance to that disease. Such diseases include Kaposi's sarcoma (KS), pneumocystis carinii pneumonia (PCP), and serious other opportunistic infections."1 Some AIDS cases will present as true emergencies; the majority will be less urgent but will require appropriate treatment and referral.
Received for publication December 30, 1983. Revision received May 24, 1984. Accepted for publication August 13, 1984. Address for reprints: William F Skeen, MD, MPH, University of Southern California School of Medicine, Department of Emergency Medicine, 1200 North State Street, Los Angeles, California 90033.
EPIDEMIOLOGY As of November 1984, 6,993 AIDS cases in the United States had been reported and confirmed by the CDC. The current mortality rate is 48%, 2 but it will probably increase as patients classified as "survivors" succumb to the disease. Several groups at high risk for developing AIDS have been identified. These include h o m o s e x u a l men, 3-s intravenous (IV) drug abusers,I, 9 hemophiliacs, lo-14 and HaitiansjS-lS In addition, cases have been reported among male prisoners,19 female sexual partners of high-risk AIDS patients, 2o and infants born to high-risk mothers. 21-24 A number of cases of possible transfusion-related AIDS occurring in patients without other apparent risk factors have been reported.2S, 26 One was an infant who received mukiple transfusions after birth and later developed-severe cell-mediated immunodeficiency.2S,26 One of the donors, who had been healthy at the time of donation,2S was subsequently identified as a fatal AIDS case. KS accounts for 24% of AIDS cases; PCP accounts for 53%; and 6% of AIDS patients have both KS and PCP. Many AIDS patients have other opportunistic infections, and 17% have such infections without KS or PCP (Table 1).2 Most patients with AIDS fall into one or more of the high-risk categories: 73% are homosexual or bisexual men; 17% are IV drug abusers; 4% are Haitians living in the United States; and fewer than 1% are hemophiliacs. The remaining 5% do not have clearly defined risk factors (Table 2). Cases have been reported among all primary racial groups in the United States. 2 Women account for 7% of the totalY Geographic clustering has been noted, with New York reporting 42% of all cases; California, 23%; and Florida, 7%. Nonetheless, cases have been reported in 45 states, the District of Columbia, and Puerto Rico. 27
CLINICAL PRESENTATION A N D COURSE Kaposi's Sarcoma Moriz Kaposi originally described five cases of "idiopathic multiple pigmented sarcoma of the skin" in 1872. 28 Prior to the current epidemic, Ka-
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posi's sarcoma was uncommon in the United States, occurring primarily in elderly men of Jewish, Italian, or Mediterranean descent. Lesions typically were found on the lower extremities. The disease followed an indolent course and was responsive to radiotherapy or single-agent chemotherapy. In equatorial Africa, however, KS is endemic; it occurs frequently in children and young adults and accounts for 9% of all neoplasms in the region.3, 7,29 By contrast, almost all AIDS patients with KS are under the age of 50.3 In one series, patients presented with the following complaints: skin lesions (50%); skin lesions and lymphadenopathy (20%); weight loss and fever (10%); and weight loss, fever, and pneumonia (10%).3 Skin lesions may be macules, papules, nodules, or plaques that vary in size from a few millimeters to more than several centimeters (Figure 1). They may be reddish-pink in color, or have a characteristic violaceous to red-brown hue (Figure 2). Although lesions may be present on any region of the body, including mucous membranes, there is a predilection for the head and neck region. Over time, the lesions tend to increase in size and number. More than 50% of AIDS patients have gastrointestinal lesions, occurring anywhere from the mouth to the anus. Such lesions are redp raised, sessile, submucosal nodules ranging in size from several millimeters to more than a centimeter. They may present with chronic occult blood loss or rem a i n c l i n i c a l l y silent. Gastrointestinal lesions may antedate skin lesions in some cases. KS in AIDS patients may occur in virtually any body organ. 3° Compared to the classic form of KS, the disease in AIDS patients is far more fulminant. PCP frequently complicates the clinical course, as do a variety of other opportunistic infections. 3 The CDC reports a mortality rate of 24% for patients with KS alone, 47% for PeP alone, and 63% for patients with both KS and PCPJ Because KS in the setting of immunodeficiency does not respond to traditional therapy, 31 current treatment is largely experimental. Various antitumor regimens with such standard c h e m o t h e r a p e u t i c agents as vinblastine, adriamycin, and bleomycin have shown modest results. 3~ The 120/268
search for agents to correct the underlying immune defect has centered on lymphokines, which are immune mediators produced by T-lymphocytes.32 In one series, recombinant leukocyte A interferon produced clinical improvement in two-thirds of KS patients. 33 Preliminary studies have indicated that interleukin-2 and gamma interferon also may have therapeutic benefiti32,34
Pneurnocystis Carinii Pneumonia P e P is a u b i q u i t o u s p r o t o z o a n transmitted by inhalation. By four years of age, 80% of healthy individuals have significant antibody titers to the organism.35 Therefore, clinically apparent disease usually develops only in immunocompromised persons. 5 More than half of all AIDS patients develop PeP at some point in their illness. A prodrome of nonpulmonary symptoms, such as fever, weight loss, and diarrhea, may precede the onset of pneumonia by many months. Pulmonary complaints, such as cough and dyspnea, also m a y be present for months or may progress rapidly to respiratory failure within a few days. 36 Many patients will recover with treatment; however, recurrent episodes often are fatal. 3s In-hospital therapy consists of trimethoprim/sulfamethoxazole or pentamidine and ventilatory support. 37-39
Other Opportunistic Infections Other opportunistic infections have been described in AIDS patients (Figure 3). Cryptococcus neoformans, Mycobacterium avium-intracellulare, and cytomegalovirus (CMV) may cause diffuse pneumonitis. 31 Most AIDS patients have evidence of active CMV infection with positive throat, blood, or urine cultures. 40 Recurrent diarrhea often is noted in the prodromal period and in fully established AIDS cases. It may take the form of a few loose stools per day or profus e watery diarrhea. The homosexual population in general is subject to infection with multiple enteric pathogens, including Salmonella, Shige]la, and Campylobacter species,
Entamoeba histolytica, Giardia lamblia, and other parasites that may or may not be pathogenic. 31 Even in the absence of these organisms, however, AIDS patients may experience severe diarrhea. Some cases are due to disseminated gastrointestinal Annals of Emergency Medicine
TABLE 1. AIDS cases by primary
disease Primary Disease
% of Total
KS alone PeP alone Both KS and PeP Other opportunistic infections without KS or PCP
24 53 6
Total
17 100%
TABLE 2. AIDS cases among high-
risk groups Patient Group
% of Total
Homosexual/ bisexual men IV drug abusers Haitian immigrants Hemophiliacs Unknown risk factors
73 17 4 1 5
Total
100%
EMMa41, 42 and others may be caused by cryptosporiodiosis.3° The latter disease is acquired from animals and is usually self-limited in immunocompotent hosts. 31 In AIDS patients, however, symptoms are severe and refractory to treatment. In some patients with diarrhea, no pathogen can be isolated.31 Other gastrointestinal complaints include dysphagia and odynophagia due to invasive oral and esophageal candidiasis. 31 Herpes simplex virus can produce severe ulcerative oral, genital, and perineal lesions.30, 43 The central nervous system (CNS) frequently is affected by opportunistic infections in AIDS patients. Toxoplasma gondii abscesses present as mass lesions with headaches, seizures, or focal deficits.18,44 Haitian AIDS patients have a higher incidence of this complication, is Cryptococcal meningitis is not uncommon i n the syndrome. 31 A progressive encephalopathy that slowly leads to severe dementia and is possibly due to CMV has been described. 45 Chorioretinitis with decreasing visual acuity is also caused by CMV or, occasionally, T
gondiJ. 3t
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Persistent Generalized Lymphadenopathy Among persons at high risk for development of AIDS, a syndrome of persistent generalized lymphadenopathy has been described. 46 Such persons have l y m p h a d e n o p a t h y of at least three months duration involving two or more extrainguinal sites and c o n f i r m e d on e x a m i n a t i o n . This lymphadenopathy occurs in the absence of any illness or drug known to induce such changes, and biopsy, if done, shows reactive hyperplasia. Some patients in this category have such nonspecific symptoms as fever, night sweats, and weight loss, while others are asymptomatic. It is not yet known if this syndrome represents the forerunner of AIDS or, ahernatively, a group of persons who have come into contact with the AIDS agent and are resistant to the disease. 46
IMMUNE DEFECT Lymphocytes are broadly divided into two types. Thymus-derived or TlymphocYtes (T-cells) are directly involved with cellular immunity, while bursa-derived or B-lymphocytes (Bcells) are concerned with antibody production and humeral immunity. Tcells can be further differentiated into helper (Th), suppressor (Ts), and killer subp0pulations. These first two cell t y p e s help r e g u l a t e i m m u n e responses; the latter type is cytotoxic effector cells. Intact T-cell function is necessary to defend the body against 14:3 March 1985
certain viruses, fungi, mycobacteria, and other parasites. 47 Common to all AIDS patients is a severe deficit in cell-mediated immunity Peripheral lymphopenia is common, especially among the patients with opportunistic infections. The absolute n u m b e r of Th ceils is decreased, while the number of Ts cells is normal or increased, resulting in a decreased Th to Ts ratio. Anergy to skin tests is the rule. In addition, Tcell response to various mitogens is markedly reduced among AIDS patients.48-so Studies sl-s3 have shown similar but less pronounced defects among certain homosexual men and hemophiliacs who do not have AIDS, suggesting possible widespread exposure to the AIDS agent in these groups. Hemophiliacs who receive commercially prepared lyophilized factor VIII concentrate from pooled donor sources have lower Th to Ts ratios than do t h o s e w h o use o n l y f a c t o r VIII cryoprecipitate. The latter usually is obtained from a single donor.S4, ss Among homosexual men, the presence of AiDS and lower Th to Ts ratios has been correlated with a higher number of sexual partners.S, 6 The immunologic defect in AIDS may not be limited to the T-cell popu: lation. One study s6 reported decreased B-cell response to T-cell independent stimulation in homosexual AIDS patients. Spontaneous secretion of polyclonal immunoglobulin was increased Annals of Emergency Medicine
Fig. 1. Hyperpigmented nodular KS lesions. Fig. 2. Plaque-like violaceous KS lesions on a foot. ten times over control values, but no further increase was noted with stimulation. Such polyclonal activation has been seen in vivo in response to viral infections. An increased incidence of aut0immune thrombocytopenic purpura in homosexual men has been noted. 57 These patients did not have AIDS but did have significantly decreased Th to Ts ratioS. The occurrence of an autoimmune disease in a high-risk group with evidence of immunosuppression suggests that abnormalities of immune regulation eventually may be linked to AIDS. ETIOLOGY AIDS is a two-stage disease. Immunosuppression occurs, most likely as a result of exposure to a new Virus and/ or to multiple environmental and lifestyle factors. In this setting, malignancies or opportunistic infections develop. Increased promiscuity in the homosexual male c o m m u n i t y during the past decade was thought to have led to the bombardment and breakdown of the immune system by exposure to a wide variety of sexually transmitted viruses, parasites, and allogenic sperm.58, s9 This does not explain the 269/121
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occurrence of the disease among heterosexuals. Use of such recreational drugs as inhalant nitrites, or "poppers," has been implicated as a possible immunosuppressive factor.S Yet many AIDS patients deny use of these agents. 5 A CDC study found no immunosuppressive effects of inhaled nitrites in laboratory mice. 6o The epidemiologic evidence 61 favors the theory that AIDS is caused by a transmissible agent. This agent appear s to be spread by sexual contact or contaminated blood products, much like hepatitis B virus. A cluster of 16 homosexual male AIDS patients in Los Angeles and Orange counties, each of whom had had sexual contact with at least one other member of the group, has been reported. 62 The odds of 16 randomly selected homosexual men knowing each other in such a large metropolitan area are extremely small. Hemophiliacs exposed to blood products prepared f r o m a greater number of donors have lower Th to Ts ratios. 11 Intravenous drug abusers are at high risk presumably because they share contaminated needles. Recent investigation61 strongly implicates a newly discovered h u m a n retrovirus known as human T-cell leukemia virus (HTLV-III) as the cause of immunosuppression in AIDS. Human retroviruses came under suspicion for several reasons: 1) a feline variety causes immunosuppression in cats; 63 2) HTLV retroviruses are T-cell tropic; 63 3) they have a preference for Th cells; 63 4) in some cases they are cytotoxic for T-cells; 63 and 5) they may be transmitted by blood products or sexual contact. 63 One series 64 detected HTLV-III in 18 of 21 patients with prodromal AIDS symptoms; 13 of 43 adult KS patients; 10 of 21 AIDS patients with opportunistic infections; and none in 115 clinically healthy heterosexual volunteers. Of 22 clinically h e a l t h y h o m o s e x u a l s , one t e s t e d p o s i t i v e and d e v e l o p e d AIDS six m o n t h s later, Another study 65 reported that 43 of 49 AIDS patients (88%) and ll of 14 homosexual males with prodromai symptoms (79%)had sera that reacted to HTLV-III antigens. Only one of 186 heterosexual controls (0.5%) was positive. The role of CMV in AIDS also is under investigation. A higher prevalence of antibodies to CMV (93%) and active viral shedding (7%) was reported a m o n g h o m o s e x u a l men. 66 Among patients with KS, CMV anti122/270
Fig. 3. Other opportunistic infections common among AIDS patients. gens and CMV RNA were demonstrated in t u m o r tissue but not in healthy tissue. 4° Therefore, CMV may have a role in oncogenesis. Heredity also may contribute to the d e v e l o p m e n t of AIDS. One s t u d y found a high prevalence of the HLADR5 allele among both heterosexual and homosexual KS patients.7
PSYCHOSOCIAL ASPECTS The psychosocial aspects of AIDS are in some ways similar to those of cancer and other life-threatening illnesses. The AIDS patient faces such issues as fear of the unknown, the image of physical deterioration, the fear of dissolution of self, dread of pain and suffering, the struggle to maintain a sense of control, worry over loved ones who will survive, and the possibility of death earlier than anticipated. 67 Many psychosocial aspects of AIDS are unique. AIDS patients are prone to high levels of anxiety, guilt, anger, and depression. Many aspects of the medical illness itself contribute to these emotions. AIDS is a new disease with prolonged symptoms and no known cure. Fear of contagion or association with disadvantaged groups leads to social stigmatization: Treatment may be physically and emotionally difficult and e c o n o m i c a l l y devastating. The disease or treatment may lead to loss of vocational success, recreational activities, and social relationships. Homosexual men, who comprise about three-quarters of all reported AIDS cases, face special difficulties. Because their disease is associated with sexual activity, feelings of guilt a b o u t h o m o s e x u a l i t y m a y be rekindled. If a patient has not done so previously, he may need to tell his family and friends not only that he has a life-threatening illness but also that he is a homosexual. The latter process of "coming out" is usually quite stressful in itself.68 Because the syndrome has m a n y unknowns and because of wide media publicity, a group of patients known as the "worried well" has emerged. These are often, but not always, members of high-risk groups w i t h o u t apparent symptoms who are inordinately fearful of contracting AIDS. 67 This phenomenon is similar to cancer phobia. Annals of Emergency Medicine
Candida albicans Cryptococcus neoformans Cryptosporidium Cytomegalovirus Herpes simplex Mycobacteriurn avium - intracellulare Toxoplasma gondii The worried well may exhibit anxiety parallel in intensity to that of patients who actually have the disease. In general, patients with AIDS who seek psychiatric help are not looking for insight into psychological problems. Rather they seek help in trying to cope and adapt to the severe disruptions in their lives brought about by a medical problem. The approach to psychotherapy, then, is usually supportive rather than confrontational. An attempt is made to preseve the patient's defense mechanisms as an integral part of the coping effort. 67
EMERGENCY EVALUATION AND MANAGEMENT Although the underlying i m m u n e defect is c o m m o n to all AIDS patients, the manifestations of the disease are protean and nonspecific. A careful social and sexual history must b e elicited from all patients. Specifically patients should be questioned about sexual orientation, use of intravenous drugs, country of origin, exposure to known cases of AIDS, and history of transfusion of blood or blood products. If a patient is found to have any of the known risk factors, then AIDS must be considered in the differential diagnosis. Physical examination and laboratory studies should be guided by the patients' presenting complaints. Such nonspecffic c o m p l a i n t s as lowgrade fever, malaise, fatigue, or lymphadenopathy in a high-risk pat i e n t deserve a t h o r o u g h physical examination, limited laboratory workup, reassurance, and referral to a primary care physician for fi,trther evaluation and/or long-term follow-up. On physical examination, skin and mucous membrane lesions suggestive of KS should be sought, and the oral cavity s h o u l d be e x a m i n e d for candidiasis. Lymphadenopathy should be noted. In high-risk p a t i e n t s or k n o w n 14:3 March 1985
AIDS patients who present with pulmonary symptoms, PCP should be high on the list of differential diagnoses. Fulminant PCP may present with fever, cough, and severe dyspnea.35 Arterial blood gas reports may show marked hypoxemia, 36 and chest films typically show patchy or diffuse bilateral infiltratesi 69 however, biopsyproven PCP has been reported in a patient who presented with dyspnea but had a normal chest film and arterial oxygen tension. 70 Hospital admission is indicated for high-risk or known AIDS patients with significant dyspnea with or without abnormal chest films or arterial blood gas reports. Diarrhea is a common presenting complaint. 31 Homosexuals who do not have AIDS may have diarrhea caused by a variety of enteric pathogens. 31 Stool culture, ova and parasite examination, and a smear for fecal leukocytes may be useful diagnostic tests. If physical examination reveals significant dehydration, fluid and electrolyte replacement should be undertaken. High-risk and known AIDS patients may present with a variety of CNS symptoms. Focal deficits may result from T gondii abscesses, CNS lymphomas, or vascular complications such as cerebral hemorrhage in the setting of thrombocytopenia or nonbacterial thrombotic endocarditis. 4s Seizures may accompany focal lesions. Computed tomography brain scan and lumbar puncture may be diagnostic. Emergency therapy is primarily supportive, and emergency neurologic consultation should be obtained. Subtle changes in mental status may be early signs of progressive dementia. 4s Often these changes are attributed to depression and are not pursued. A high index of suspicion combined with a detailed mental status and neurologic examination may lead to the correct diagnosis. Some causes of organic brain syndrome in AIDS patients are treatable. 4s From a psychosocial standpoint, the most important task for the emergency physician is to neutralize whatever bias he may have toward AIDS patients who are homosexuals, drug addicts, or are from other disadvantaged groups. Compassion and sensitivity are essential for successful physicianpatient interaction. The physician should offer reassurance and accurate medical information. The diagnosis of 14:3 March 1985
AIDS cannot be confirmed in the emergency department (ED). The incidence of AIDS is low, even among high-risk groups. The incidence of homosexuality in the general male population is not known, but if estimated at 5%, 71 the percentage of homosexuals w i t h AIDS is approximately 0.05%. 71 Known AIDS patients or the worried well who exhibit high levels of anxiety, anger, depression, or other psychological impairment should be referred for consultation. The ED should have telephone numbers avail: able for referral to psychosocial comm u n i t y support groups located in most metropolitan areas. The Public Health Service maintains a toll-free AIDS hotline, 800/342-AIDS. The emergency physician should offer guidance on disease prevention to members of high-risk groups in a sensitive, nonjudgmental fashion. Homosexuals should be advised to avoid exchange of bodily fluids during sexual contact. Condoms are preferable to u n p r o t e c t e d anal intercourse and fecal-oral contact should be avoided. Reducing the number of sexual partners will decrease the risk of disease. 61 Hemophiliacs should consult their primary physicians for specific recommendations. Intravenous drug abusers should not share contaminated needles, and they should be encouraged to overcome their addiction. Health care personnel who may come into contact with AIDS patients also are concerned about contracting the disease. The CDC reported four cases of AIDS a m o n g health care workers, 72 but found no evidence that these workers acquired the disease from in-hospital contact with AIDS patients. The CDC has begun a prospective study of health care workers exposed via parenteral or m u c o u s membrane routes to blood and body fluids of AIDS patients. Thus far, none of 51 workers has contracted AIDS, but the follow-up period is less than 12 months for all but one ease. 73 Precautions for clinical and laboratory workers have been published.74J s These basically recommend hepatitis B-type precautions. There is no evidence for airborne spread or spread by casual contact with AIDS patients. 23 Specific recommendations include the following: 1) avoiding a c c i d e n t a l wounds from sharp instruments or needles contaminated with potentially infectious material; 2) wearing gloves when contacting body fluids; 3} Annals of Emergency Medicine
wearing a gown if exposure to body fluids is likely; 4) washing hands after contact with patient or body fluids; 5) using special labels for blood and other specimens; 6} using disposable needles and syringes; and 7) using a private room for patients too ill to practice good hygiene (eg, patients with profuse diarrhea). TM Ventilation devices for AIDS patients requiring cardiopulmonary resuscitation should be readily available to obviate the need for mouth-to-mouth contact. 76 There are anecdotal stories of health care personnel refusing to care for AIDS patients. This manifestation of so-called 'AIDS hysteria" is unwarranted in view of current knowledge. Such behavior is unprofessional and ethically unacceptable.
SUMMARY AIDS is a new public health disaster that is unlikely to be resolved quickly. It is manifested by a profound immune deficiency accompanied by the development of KS, PCP, and/or other opportunistic infections. A retrovirus, HTLV-III, is the probable cause of the immunosuppression, and it is transmitted in a manner similar to hepatitis B virus. Groups at highest risk inelude homosexual men, intravenous drug abusers, Haitians, and hemophiliacs. Therapy is largely experimental, and mortality is high. The emergency physician must be familiar with the signs, symptoms, and early management of AIDS. He should be able to offer guidance on disease prevention to both health care workers and members of high-risk groups. Allocation of major financial resources and intensive investigation are necessary to abort this cruel epidemic that affects primarily younger persons. Such investigation will undoubtedly produce new advances in virology, oncology, and immunology that will benefit medicine and society as a whole.
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nodeficiency syndrome (AIDS) in Haiti. N Engl J Med 1983;309:945-950. 18. Pitchenik AE, Fischl MA, Dickinson GM, et al: Opportunistic infections and Kaposi's sarcoma among Haitians: Evidence of a new acquired immunodeficiency state. A n n I n t e r n M e d 1983;98: 277-283. 19. Wormser GP, Krupp LB, Hanrahan JP, et al: Acquired immunodeficiency syndrome in male prisoners. Ann Intern Med 1983;98:297-303.
32. Murray HW,, Rubin BY, Masur H: Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Eng] J Med 1984;310:883-889. 33. Krown SE, Real FX, CunninghamRundles S: Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with Kaposi's sarcoma. N Engl J Med 1983;308: 1071-1076.
6. Rogers MF, Morens DM, Steward JA, et al: National case-control study of Kaposi's sarcoma and pneumocystis carinii pneumonia in homosexual men: Part 2, laboratory results. A n n Intern Med 1983;99: 151-158.
20. Harris C, Small CB, Klein RS, et al: Immunodeficiency in female sexual partners of men with the acquired immunodeficiency syndrome. N Engl J Med 1983;308:1181-1184.
34. Rook AH, Masur H, Lane C, et al: Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. ] Clin Invest 1983;72: 398-403.
7. Friedman-Kien AE, Laubenstein LS, Rubenstein P, et al: Disseminated Kaposi's sarcoma in homosexual men. Ann Intern Med 1982;96:693-700.
21. Unexplained immunodeficiency and opportunistic infections in infants - N e w York, N ew Jersey, C a l i f o r n i a . M M W R 1982;31:665-667.
35. Golden J: Pneumocystis lung disease in homosexual men - - Medical staff conference, University of California, San Francisco. West J Med 1982;137:400-407.
8. Hymes KB, Green JB, Marcus A, et al: Kaposi's sarcoma in homosexual men - A report of eight cases. Lancet 1981;2: 598-600.
22. Joncas JH, Delage G, Chad Z, et al: Acquired (or congenital) immunodeficiency syndrome in infants born of Haitian mothers (letter). N Engl J Med 1983;308: 842.
36. Masur H, Michelis MA, Greene JB, et al: An outbreak of community acquired Pneumocystis earinii pneumonia. N Engl J Med 1981;305:1431-1438.
9. Masur H, Michelis MA, Wormser JP, et al: Opportunistic infection in previously healthy women. Initial manifestations of a community acquired cellular immunodeficiency. A n n Intern Med 1982;97: 533-539. 10. P n e u m o c y s t i s carinii p n e u m o n i a a mong persons w i t h h e m o p h i l i a A. M M W R 1982;31:365-367. 11. Acquired i m m u n o d e f i c i e n c y syndrome (AIDS} among patients with hemophilia - - United States. M M W R 1983; 32:613-615. 12. Davis KC, Horsburgh CR, Hasiba U, et al: Acquired immunodeficiency syndrome in a patient with hemophilia. Ann Intern Med 1983;93:284-286. 13. Poon MC, Landay A, Prasthofer EF, et al: Acquired immunodeficiency syndrome with Pneumocystis carinii pneumonia and Mycobacterium avium-intracellulare infection in a previously healthy patient with classic hemophilia. Ann Intern Med 1983;98:287-290. 14. Ragni M, Spero JA, Lewis JH, et al: Acquired immunodeficiency-like syndrome in two haemophiliacs. Lancet 1983;l:213-214. 15. Opportunistic infections and Kaposi's sarcoma among Haitians in the United States. M M W R 1982;31:353-354, 360-361. 16. Viera J, Frank E, Spira TJ, et al: Acquired immune deficiency in Haitians: Opportunistic infections in previously healthy Haitian immigrants. N Engl J Med 1983;308:1235-1239. 17. Pape JW, Liautaud B, Thomas F, et al: Characteristics of the acquired immu124/272
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67. Malyon AK, Pinka AT: Acquired immune deficiency syndrome: A challenge to psychology. The Professional Psychologist 1983;7:1-10.
58. Sonrabend J, Witkin SS, Purtilo DT: Acquired immunodeficiency syndrome, opportunistic infections, and malignancies in male homosexuals. A hypothesis of etiologic factors in pathogenesis. JAMA 1983;249:2370-2374.
68. Nichols SE: Psychiatric aspects of AIDS. Psychosomatics 1983;24:1083-1089.
59. Levy JA, Ziegler JL: Acquired immu-nodeficiency syndrome is an opportunistic infection and Kaposi's sarcoma results from secondary immune stimulation. Lancet 1983;2:78-81.
50. Schroff RW, Gottlieb MS, Prince HE, et ah Immunological studies of homosexual men with immunodeficiency and Kaposi's sarcoma. Clin Immunol Immunopathol 1983;27:300-314.
60. An evaluation of the immunotoxic potential of isobutyl nitrite. MMWR 1983;32:457-458, 464.
51. Komfield H, Vande Stouwe RA, Lange M, et ah T-Lymphocyte subpopulations in homosexual men. N Engl J Med 1982;307: 729-731.
61. Prevention of acquired immune deficiency syndrome {AIDS): Report of interagency recommendations. MMWR 1983; 32:101-103.
52. Pinching AJ, Jeffries DJ, Donaghy M, et ah Studies of cellular i m m u n i t y in male homosexuals in London. Lancet 1983;2:126-129.
62. A cluster of Kaposi's sarcoma and pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange counties, California. MMWR 1982;31:305-307.
53. de Shazo RD, Andes WA, Nordberg J, et ah An immunologic evaluation of hemophiliac patients and their wives. Relationships to the acquired immunodeficiency syndrome. A n n Intern Med 1983;99:159-164. 54. Lederman MM, Ratnoff OD, Scillian JJ, et ah Impaired cell-mediated immunity in patients with classic hemophilia. N Engl J Med 1983;308:79-83. 55. Menitove JE, Aster KH, Casper JT, et ah T-Lymphocyte subpopulations in patients with classic hemophilia treated with cryoprecipitate and lyophilized concentrates. N Engl J Med 1983;308:83-86. 56. Lane HC, Masur H, Edgar LC, et ah
14:3 March 1985
63. Popovic M, Sarngadharan MG, Read E, et al: Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 1984;224:497-500.
69. Hill CA, Harle TS, Mansell WA: The prodrome, Kaposi's sarcoma, and infections associated with acquired immunodeficiency syndrome: Radiologic findings in 39 patients. Radiology 1983;149: 393-399. 70. Goodman JL, Tashkin DP: Pneumocystis with normal chest x-ray film and arterial oxygen tension. Arch Intern Med 1983;143:1981-1982. 71. Kinsey AC: Sexual Behavior in the Human Male. Philadelphia, WB Saunders Co, 1948, p 617. 72. An evaluation of the acquired immunodeficiency syndrome (AIDS) reported in health-care personnel - - United States. MMWR 1983;32:358-360. 73. Prospective evaluation of health-care workers exposed via parenteral or mucusmembrane routes to blood and body fluids of patients with acquired immunodeficiency syndrome. MMWR 1984;33:181182. 74. Acquired i m m u n e deficiency syndrome IAIDS): Precautions for clinical and laboratory staffs. MMWR 1982;31: 577-580.
64. Gallo RC, Salahuddin SZ, Popovic M, et ah Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984;224:500-502.
75. Acquired immunodeficiency syndrome (AIDS): Precautions for health care workers and allied professionals. MMWR 1983;32:450-451.
65. Sarngadharan MG, Popovic M, Bruch L, et ah Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science 1984;224:506-508.
76. Conte JE, Hadley WK, Sande M: Infection-control guidelines for patients with the acquired imunodeficiency syndrome (AIDS). N Engl J Med 1983;309: 740-744.
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