CONCEPTS AIDS; HIV

The Management of HIV-Related Illness in the Emergency Department [Talan DA, Kennedy CA: The management of HIV-related illness in the emergency department. Ann Emerg Med December 1991;20:I355-1365.] INTRODUCTION Since the initial recognition of the acquired immunodeficiency syndrome (AIDS) in 1981 and subsequent serologic testing for human immunodeficiency virus (HIV) infection in 1985, AIDS has become a global pandemic. 1-3 The World Health Organization estimates that there have been more than 500,000 cases of AIDS and that eight to ten million adults and one million children worldwide are infected with HIV.4,s As of May 31, 1991, 179,136 AIDS cases had been reported to the United States Centers for Disease Control (CDC) and from 1981 through 1990, there were 100,777 deaths due to AIDS. 6,7 The United States Public Health Service estimates that approximately 1.0 to 1.5 million Americans are infected with HIV.8,9 The majority of HIVinfected individuals are asymptomatic; however, increasing numbers are developing advanced and symptomatic HIV-related illnesses. From studies of the natural history of HIV infection, approximately 50% of patlents will develop an AIDS-defining diagnosis within seven to ten years from the time of initial infection, lo-12 The annual increase in the incidence of reported AIDS cases rose from 9% in 1989 to 23% in 1990.13 As the epidemic continues, virtually every emergency department will care for both asymptomatic patients with unrecognized HIV infection as well as patients with clinical illness due to HIV. Seroprevalence studies conducted at one inner-city ED demonstrated that approximately 4% of patients (92 of 2,275) had unrecognized HIV infection; trauma patients were found te found to have a seroprevalence rate approximating 10%.14,15 Investigators from the same institution recently reported that the percentage of total ED patients with known HIV infection increased from 0.5% in 1986 to more than 2.2% in 1988.16 Other studies of ED populations have revealed prevalences of HIV-infected patients ranging from 0% to 8.9%.17-24 This article will focus on the common diagnoses and management issues that have arisen with the advent of AIDS epidemic and that are unique to the ED setting. To this end, the relevant recent literature will be reviewed. However, the reader should be aware that there are few areas of medicine in which there is as much ongoing research and current standards of care have and will continue to change.

David A Talan, MD, FACEP* Sylmar, California Charles A Kennedy, MDt San Diego, California From the Department of Emergency Medicine and Internal Medicine, Division of Infectious Diseases, ©live View/UCLA Medical Center, Sylmar, California;* and Department of Internal Medicine, Divisions of Infectious Diseases, and the Human Immunodeficiency Virus Evaluation Unit, Naval Hospital, San Diego, California.t Received for publication May 28, 1991. Revision received September 16, 1991. Accepted for publication September 20, 1991. The opinions expressed are those of the authors and do not reflect official policy of the US Government, US Navy, or the Department of Defense. Address for Reprints: David A. Talan, MD, FACER Department of Emergency Medicine, ©live View / UCLA Medical Center, Room 2A208, 14445 Olive View Drive, Sylmar, CA 91342.

RECOGNIZING THE PATIENT AT RISK FOR HIV INFECTION The first step in evaluating a patient for possible HIV-related disease is to determine the likelihood of HIV infection. This can be ascertained by asking patients if they have had an HIV antibody test and if they are aware of their serologic status. Standard testing uses an enzyme-linked immunosorbent assay (ELISA) with confirmatory Western Blot testing. Recently, HIV infection also has been tested for by detection of HIV DNA by polymerase chain reaction. 2s Though infrequent, patients recently found to be HIV antibody negative may in fact harbor HIV infection. 26-29 This may occur from recently acquired HIV infection (usually within two to 12 weeks) or because a small percentage of patients may not develop detect-

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TABLE. Staging of HIV disease* Stage

Clinical

CD4 Cell Count Normal > 400/mm3

Acute Early

Mononucleosis-like illness Asymptomatic or persistent generalized lymphadenopathy Aseptic meningitis Dermatologic manifestations

Middle

Asymptomatic or persistent generalized lymphadenopathy Thrush Hairy leukoplakia Idiopathic thrombocytopenic purpura, etc

200 400/mm3

Late

Opportunistic infections Malignancy Wasting Dementia

< 200/mms

*Adapled lrom Chaisson and Volberding.4z

able antibody by ELISA u n t i l several years after p r i m a r y infection. In these i n d i v i d u a l s , as w e l l as t h o s e w h o have not been previously tested, HIV risk activity m u s t be assessed. Epidemiologic data of adult and adolescent cases reported to the C D C in 1990 i n d i c a t e t h a t 88% of AIDS p a t i e n t s are m a l e and 88% are bet w e e n the ages of 20 and 39 years. 3o Of m e n w i t h AIDS, 66% are homosexual, 19% are IV drug users, 7% are both h o m o s e x u a l and W drug users, 3% have a coagulation disorder and/ or had received blood p r o d u c t s between 1977 and 1985, 2% had heterosexual contact w i t h an HIV-infected w o m a n , and 3% have o t h e r risk or no definable risk factor. A m o n g female AIDS patients, 51% are IV drug users, 33% had heterosexual contact w i t h H I V - i n f e c t e d m e n , 9% w e r e b l o o d p r o d u c t r e c i p i e n t s , a n d 7% have other risk or no definable risk a c t i v i t y . T h r o u g h 1990 t h e r e w e r e 2,786 pediatric (less than 13 years of age) AIDS cases in the U n i t e d States, of w h o m 84% were infected transplac e n t a l l y from s e r o p o s i t i v e m o t h e r s ; m o s t of the r e m a i n d e r had a coagulation disorder and/or had received c o n t a m i n a t e d blood products. 31-36 Despite a growing awareness of the HIV epidemic and r e c o m m e n d a t i o n s from the A m e r i c a n Medical Association that physicians r o u t i n e l y screen p a t i e n t s for r i s k b e h a v i o r , t h e r e is e v i d e n c e t h a t s c r e e n i n g r a r e l y occurs. 3z A survey of faculty, fellows, and r e s i d e n t s at a t e a c h i n g i n s t i t u tion in the M i d w e s t w i t h a low preva l e n c e of AIDS r e v e a l e d t h a t o n l y 11% of t h e s e p h y s i c i a n s r o u t i n e l y a s k e d p a t i e n t s a b o u t h i g h - r i s k activities. 3s Those physicians who had 10 6/1356

FIGURE. C D C surveillance case definition for A I D S . * received training in h u m a n sexuality and substance abuse were significantly m o r e comfortable in screening for these behaviors. In a t t e m p t i n g to assess the risk of HIV infection, a direct approach w i t h the p a t i e n t is critical. To a m a n ask, "Have you ever had sex with a m a n ? " W i t h regard to parenteral drug u s e i n q u i r e , " H a v e y o u ever u s e d needles to inject drugs?" While these w o u l d s e e m to be s e n s i t i v e issues, m o s t p a t i e n t s are n o t o f f e n d e d by q u e s t i o n s a b o u t H I V - r e l a t e d activities and realize that this is critical medical information. For patients in w h o m an accurate history is not obtainable, HIV risk m u s t be based on a n a s s e s s m e n t of g e n e r a l d e m o graphics and clues from the clinical e v a l u a t i o n as d e s c r i b e d f u r t h e r below. Based on this initial assessment, if a patient has k n o w n positive serology or risk factors for HIV infection, the physician must next consider w h e t h e r the patient's c o m p l a i n t s are p o t e n t i a l l y caused by an HIV-related process.

ASSESSING THE PROBABILITY O F OPPORTUNISTIC INFECTION IN THE HIV ANTIBODY-POSITIVE OR HIGH-RISK PATIENT W i t h the exception of an acute retroviral syndrome associated with HIV seroconversion (see below), m o s t patients are a s y m p t o m a t i c u n t i l late in the course of t h e i r disease. Over t i m e CD4 (T4 helper cells) lymphocytes are destroyed, and patients deAnnals of Emergency Medicine

Diseases diagnosed definitively without confirmation of HIV infection in patients without other causes of immunodeficiency Candidiasis of the esophagus, trachea, bronchi, or lungs Cryptococcosis, extrapulmonary Cryptosporidiosis > 1 mon duration CMV infection of any organ except the liver, spleen, or lymph nodes Herpes simplex infection, mucocutaneous (> 1 mon duration) or of the bronchi, lungs, or esophagus Kaposi sarcoma in patients < 60 yr old. Primary CNS lymphoma in patients < 60 yr old. Lymphoid interstitial pneumonitis (LIP) and/ or pulmonary lymphoid hyperplasia (PLH) in patients < 13 yr old Mycobacterium avium complex or M kansasii disseminated Pneumocystis carinii pneumonia Progressive multifocal leukoencephaiopathy Toxoplasmosis of the brain in patients > 1 mon old Diseases diagnosed definitively with confirmation of HIV infection Multiple or recurrent pyogenic bacterial infections in patients < 13 yr old Ooccidioidomycosis, disseminated Histoplasmosis, disseminated Isosporiasis > 1 mon duration Kaposi sarcoma, any age NonHodgkin's lymphoma (small, noncleaved lymphoma; Burkitt or nonBurkitt type; or immunoblastic sarcoma) Mycobacterial disease other than M tuberculosis, disseminated M tuberculosis, extrapulrnonary Salmonella septicemia, recurrent Diseases diagnosed presumptively with confirmation of HIV infection Candidiasis of the esophagus CMV retinitis Kaposi sarcoma LIP/PLH in patients < 13 yr old Disseminated mycobacterial disease (not cultured) Pneumocysfis carinii pneumonia Toxoplasmosis of the brain in patients > 1 men old HIV encephalopathy HIV wasting syndrome *From US Centers for Disease Control.46

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velop signs and symptoms of AIDSrelated complex (ARC) or an AIDSdefining opportunistic infection or neoplasm..~9 41 The term ARC was coined in 1984 to describe various s y m p t o m s and signs f r e q u e n t l y found in HIV-infected patients, including generalized l y m p h a d e n o pathy, oral candidiasis, herpes zoster, c o n s t i t u t i o n a l w a s t i n g , and idiopathic thrombocytopenia.42, 4.3 The ARC classification has largely been abandoned because some findings were not found to be prognostically r e l a t e d to t h e d e v e l o p m e n t of AIDS.44,45 The current CDC surveillance case definition for AIDS is listed (Figure). 46 We prefer to use the classification system from Chaisson and Volberding that stages disease progression based on clinical and prognostic parameters (Table). 47 This staging system allows for assessment of the magnitude of i m m u n o s u p p r e s s i o n and probability of serious opportunistic infection among symptomatic ED patients. The potential for opportunistic infection in HIV-seropositive patients is best predicted by the absolute CD4 lymphocyte count and the CD4 lymphocyte percentage.39-4~, 48-5° Early in the course of HIV infection the CD4 count remains normal (800 to 1,600 lymphocytes/mmg) or only slightly depressed (500 to 800 lymphocytes/ mind). CD4 counts of less than 200/ mm 3 are associated with a dramatic increase in the risk of various opportunistic infections, including Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV), Mycobacterium avium-intracellulare (MAI), and Crypt ococcus neoformans infections. Rarely, HIV-infected patients will develop opportunistic infections w i t h a b s o l u t e CD4 l y m p h o c y t e counts above 200/mm 3. Recent reports describe b i o p s y - d o c u m e n t e d PCP in patients with CD4 counts of 400/mm 3 or more; of note, virtually all these patients had CD4 lymphocyte percentages of 20% or less. 51-53 Overall assessment of opportunistic infection risk should be based on both the absolute CD4 count and the CD4 lymphocyte percentage if these data are available.48,sl, s4 The associations of the specific CD4 absolute and r e l a t i v e l y m p h o c y t e c o u n t s noted above do not apply for children less than 1 year old. 5° Although these test results are not available within 20:12 December 1991

the time frame of ED care, patients with known HIV infection who are followed closely by their primary p h y s i c i a n i n v a r i a b l y k n o w their most recent CD4 lymphocyte count. This datum also may be obtained from the hospital record or from the patient's physician. Knowledge of these values can be critical in determining whether a patient has a trivial illness or is at risk for a potentially serious opportunistic infection. The absolute CD4 l y m p h o c y t e count correlates with certain clinical manifestations. If the CD4 count is unknown, the clinical stage of HIV infection can be roughly estimated by the presence of certain historical and physical findings. A m o n g patients in whom the risk of HIV infection cannot be ascertained, the presence of these findings would strongly suggest HIV-related disease. A history of p r o f o u n d w e i g h t loss; an AIDS-associated opportunistic infection or Kaposi's sarcoma; and findings of cachexia, thrush, oral hairy leukoplakia, encephalopathy, lesions of Kaposi's sarcoma, or pancytopenia suggest advanced HIV disease. The p a t i e n t ' s m e d i c a t i o n s m a y provide a clue to the stage of HIV disease. The absolute CD4 lymphocyte count dictates the need for retroviral therapy and prophylaxis against PCP. Current recommendations for initiating retroviral therapy with zidovudine (AZT) are an absolute CD4 count of less than 500/mm3. ss,s6 In the recent past, patients were not given zidovudine unless they had a CD4 count of 200/mm 3 or less or an AIDS-defining opportunistic infection or malignancy. Two trials reported in 1990 showed that early administration of AZT to asymptoma t i c or m i l d l y s y m p t o m a t i c seropositive patients with 200 to 500 CD4 l y m p h o c y t e s / m m 3 slows progression to AIDS, reduces the risk of opportunistic infection, and prolongs survival.SS, 56 A recent report concluded that AZT therapy for asymptomatic HIV-infected patients was cost effective compared with other c o m m o n medical therapies. 57 PCP prophylaxis with trimethoprim/sulfamethoxazole or aerosolized pentamidine is initiated in patients with a prior episode of PCP or in those patients with CD4 counts of less than 250/mm 3 or CD4 lymphocyte percentages of 20% or less. 58 Finally, m a n y HIV-infected paAnnals of Emergency Medicine

tients have a close relationship with their primary physician, usually an internist or infectious disease specialist. One report from an inner-city public hospital by Kelen et al found that 70.9% of ED p a t i e n t s w i t h known HIV infection had a regular source of care; this occurred with greater frequency among homosexu a l / b i s e x u a l p a t i e n t s (81%) than among IV drug users (55%). 16 Seventy percent of HIV-infected patients presented at times when their regular source of care was unavailable. An attempt to c o m m u n i c a t e with the patient's primary physician is especially important in this patient population in order to determine the stage of HIV disease and to help separate acute from chronic symptoms. Kelen et al also noted that 51% of HIVinfected ED patient visits resulted in hospital admission compared with an admission rate of 21% in seronegarive controls. The fact that an HIVinfected patient seeks medical attention in the ED suggests that he may have a serious problem.

OVERVIEW OF PRESENTATIONS OF HI'VI N F E C T E D PATIENTS The most frequent and life-threatening problems for which HIV-infected patients present to the ED are opportunistic infections. Of these, by far the most common are pneumonia (often PCP, but also bacterial, mycobacterial, or fungal) and central nervous system (CNS) infection with either Toxoplasma gondii or C neoformans. HIV-infected patients also appear to be at increased risk for c o m m u n i t y - a c q u i r e d bacteremia, particularly with Staphylococcus aureus, Salmonella species, and encapsulated organisms. Bacteremia with endocarditis is a particular concern among IV drug users. Pneumonia, CNS infection, and bacteremia comprise the critical, treatable conditions that must be considered in any HIVinfected ED patient with symptoms suggestive of systemic infection. Constitutional symptoms are often the most frequent complaints from ED patients with known HIV infection. 16 Fever, chills, night sweats, and rigors are important complaints; however, these may be lacking and focal symptoms such as cough or headache may be the only clues to indicate the presence of serious underlying infection. Many patients 1357/107

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have chronic fever that may be due to HIV or disseminated infection with CMV or MAI. Any change in the magnitude or pattern of the fever may be important. Other c o m m o n presenting problems of HIV-infected patients include A Z T - i n d u c e d a n e m i a or granulocytopenia, allergic reactions or bone marrow toxicity from trimethoprim/ sulfamethoxazole, gastrointestinal disease such as esophagitis or diarrhea, wasting syndromes, dementia, and psychosocial problems. The relative risk of suicide in HIV-infected men has been found to be 36 times that of seronegative homosexual men and 66 times that of the general population. 59 Many HIV-infected patients lack access to health care and have limited financial resources; this may have a significant impact on the types of presentations and disposition considerations in the ED.

PULMONARY INFECTIONS PCP is the most frequent cause of pneumonia in HIV-infected patients, and, prior to effective prophylaxis programs, occurred in 70% to 80% of seropositive patients.l-3 Pulmonary symptoms were present in 40%, and PCP was the most frequent specific p r o v i s i o n a l diagnosis in p a t i e n t s with known HIV infection presenting to an inner-city ED. 16 Prior to the AIDS epidemic, PCP occurred most frequently in patients with lymphoproliferative malignancies and in those receiving corticosteroids or cytotoxic agents. 60-62 Solid organ or bone marrow transplantation also was associated with a significant incidence of PCp.63,64 PCP in HIV-infected patients usually has a subacute presentation characterized by nonproductive cough, exertional dyspnea, fever, and weight loss. Symptoms are often present for two to six weeks before patients seek medical attention. Tachypnea and tachycardia are usually present. A u s c u l t a t o r y findings vary from a normal chest examination to signs of dense lobar consolidation. Hypocapnia, room-air hypoxemia, and an increased arterialalveolar oxygenation gradient are usually present; CO 2 retention is distinctly unusual.65 The classic radiographic manifestations of PCP are bilateral interstitial infiltrates that begin in a perihilar distribution and progress to involve the lung periphery, with or without alveolar consol108~358

idation.66-68 A r e a d i l y available l a b o r a t o r y study in the ED that is reasonably sensitive and specific for the presence of PCP is an elevated serum lactate d e h y d r o g e n a s e (LDH). 69-73 A study of 279 ambulatory patients at risk of HIV and with respiratory symptoms determined that the sensit i v i t y and s p e c i f i c i t y of an LDH above 220 IU for the presence of PCP was 83% and 85%, respectively (positive predictive value, 57%; negative p r e d i c t i v e value, 95%). 69 O t h e r studies also have found that LDH is significantly elevated in AIDS pat i e n t s w i t h PCP c o m p a r e d w i t h those with nonPCP pneumonia including, specifically, pneumococcal p n e u m o n i a w i t h bacteremia.70, 71 Based on the cumulative evidence, we believe that an LDH should be considered in every ED patient suspected of PCP, particularly when the diagnosis is not obvious after clinical evaluation, chest radiograph, and arterial blood gas analysis. PCP m a y o c c a s i o n a l l y present with clinical and radiographic findings suggestive of other pulmonary i n f e c t i o u s processes. Lobar infiltrates, pleural effusions, hilar adenopathy, parenchymal nodules, and c a v i t a r y d i s e a s e are w e l l described. 74-77 Apical infiltrates, spontaneous pneumothoraces, and extrap u l m o n a r y PCP i n f e c t i o n appear to be associated with aerosolized p e n t a m i d i n e p r o p h y l a x i s and are r e p o r t e d w i t h i n c r e a s i n g freq u e n c y . 78-88 T h i s a s s o c i a t i o n is t h o u g h t to exist because pentamidine, when administered as an inhaled aerosol, has poor peripheral lung distribution and insignificant systemic levels. In patients with defined HIV risk factors and radiographic findings consistent with PCP, the clinical diagnosis is not difficult. Histologic confirmation will be subsequently obtained by sputum induction, bronchoalveolar lavage, or transbronchial biopsy. 89-91 O p e n lung b i o p s y is rarely necessary.92 The diagnostic yield is not significantly affected by s e v e r a l d a y s of e m p i r i c a n t i pneumocystis therapy. Once appropriate bacterial cultures are obtained in patients with presumed PCP, it is prudent to begin empiric antipneumocystis therapy. The antibiotic of choice in suspected cases of PCP is trimethoprim/sulfaAnnals of Emergency Medicine

methoxazole (15 to 20 mg trimethoprim/kg/day by IV infusion in divided doses every six hours). A safe and standard adult regimen is three a m p u l e s (80 mg trimethoprim/400 mg sulfamethoxazole per ampule) every six hours. More than 50% of AIDS patients may experience hypersensitivity reactions when receiving IV sulfonamides, although immediate h y p e r s e n s i t i v i t y reactions are r a r e . 93,94 An alternative drug to trimethoprim/sulfamethoxazole is IV pentamidine. This agent has a long half-life and significant toxicities with w h i c h physicians should be familiar prior to its use (see below).95 1oo The standard dosage of pentamidine is 4 mg/kg/day IV over 60 minutes. While trimethoprim/sulfamethoxazole and pentamidine are currently the drugs of choice for PCP, other therapeutic alternatives are available. There was initial e n t h u s i a s m for using aerosolized p e n t a m i d i n e for acute PCP; however, two recent trials indicate that aerosolized pentamidine is inadequate for the treatment of moderate-to-severe PCP and is associated with an unacceptable failure rate.lOl, 1°2 The combination of oral dapsone and trimethoprim was recently shown to be clinically equivalent to t r i m e t h o p r i m / s u l f a m e t h o x a z o l e and was associated with less overall drug toxicity (specifically, chemical hepatitis and neutropenia) than the former combination. lo3 Primaquine and clindamycin have been used in the treatment of some patients with PCP, but as yet this combination has not been compared in a randomized trial with more established agents.l°4, los A number of recent studies suggest that corticosteroid a d m i n i s t r a t i o n prevents respiratory deterioration in patients with moderate-to-severe PCp.lo6 lO8 The California Collaborative Treatment Group Study enrolled 251 patients with confirmed (225) or presumed (26) PCP. All patients received 40 mg prednisone twice daily with gradual tapering over 21 days during concomitant antipneumocystis therapy. Progression to respiratory failure, need for mechanical ventilation, and mortality were reduced in the steroid-treated cohort by 50%. lo8 There was a slight increase in the incidence of m u c o c u t a n e o u s herpes simplex infections and oral thrush in the steroid-treated group; however, 20:12 December 1991

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other opportunistic infections and Kaposi's sarcoma did not occur with increased frequency. Noninfectious complications of steroid use including psychosis, peptic ulcer disease, and m e t a b o l i c a b n o r m a l i t i e s occurred infrequently in steroid-treated patients with PCP. The National Institutes of HealthUniversity of California Expert Panel on C o r t i c o s t e r o i d s as A d j u n c t i v e Therapy for Pneumocystis recently r e c o m m e n d e d that p a t i e n t s w i t h "documented or suspected HIV infection and documented or suspected pneumocystis pneumonia be given corticosteroid therapy if they have moderate to severe pulmonary dysfunction defined by an arterial partial pressure of oxygen less than 70 m m Hg or an arterial-alveolar oxygen gradient of more than 35 m m Hg. ''1°9 Adjunctive corticosteroids should be started at the time of antipneumocystis therapy. Initially, the equivalent of 40 mg of oral prednison e should be administered twice daily. Of particular clinical importance is the predisposition of HIV-infected patients to develop life-threatening bacterial pneumonias that may mimic or coexist with PCP. Polsky et al reported 18 episodes of c o m m u n i t y acquired bacterial p n e u m o n i a in AIDS patients; six presented radiographically with diffuse infiltrates, six with patchy lobar infiltrates, and six w i t h lobar c o n s o l i d a t i o n . 110 Community-acquired pathogens such as Haemophilus in~luenzae and Streptococcus pneumoniae were frequently recovered. In an IV drug user, scattered p u l m o n a r y infiltrates or cavities should also suggest tricuspid valve endocarditis with septic pulmonary emboli. It is essential that bacterial pathogens be empirically treated in patients with presumed PCP until the latter diagnosis is histologically confirmed. Trimethoprim/sulfamethoxazole has activity against both PCP and most common bacterial pathogens. However, if p e n t a m i d i n e is used as initial therapy, an antibacterial agent such as a third-generation cephalosporin (eg, ceftriaxone or cefotaxime) or a f~-lactamase inhibitor antibiotic should be added to the initial empiric regimen. The occurrence of severe atypical pneumonia due to Mycoplasma, Legionella, or Chlamydia is infrequently observed in AIDS patients. Consequently, em20:12 December 1991

piric therapy with doxycycline or erythromycin is not routinely recommended. While PCP and bacterial pneumonia are the most frequent concerns in an HIV-infected patient with a defined pulmonary process, there is a broad differential diagnosis for pulmonary infiltrates in AIDS patients. This population is also at risk for m y c o b a c t e r i a l and f u n g a l p n e u monias, in particular Mycobacteria

tuberculosis, M avium-intracellulare, and C neoformans, ll 1-114 AIDS patients are at increased risk for acute or reactivation fungal disease associated with geographic exposure; in the United States, cocc i d i o m y c o s i s (southwest), histoplasmosis (central), and blastomycosis ( s o u t h e a s t e r n and s o u t h central). 11s-119 Viral pneumonia due to CMV tends to manifest as a systemic illness and often coexists with PCP in end-stage patients. Kaposi's sarcoma also may present with pulmonary infiltrates and is often associated with hilar adenopathy and largevolume pleural effusions, lz°,lzl Among the most difficult clinical decisions is the differentiation of early PCP from other mild respiratory syndromes. Ten to 20% of patients subsequently proven to have PCP lack fever, hypoxemia, or chest radiograph abnormalities at presentation.~22 ~24 The certainty that a patient has, or is at risk for HIV infect i o n , and the degree of i m m u nocompromise (as discussed above) must be taken into account. A recent study identified risk factors for the presence of PCP among 279 ambulatory patients seen at the University of California at San Francisco School of Medicine urgent care clinic. 69 There were four independent risk factors: diffuse or perihilar infiltrates on chest radiograph (sensitivity, 68%; specificity, 97%), the presence of thrush or hairy leukoplakia (63%, 93%), LDH above 220 IU (83%, 85%), and an erythrocyte sedimentation rate of 50 m m / h r or more (85%, 81%). In this cohort, in the absence of diffuse or perihilar infiltrates, the risk of PCP with two or three of these abnormal findings, one abnormal finding, or no abnormal findings was 47%, 9%, and 0%, respectively. The implications of this study may be limited by its unique population (eg, relatively low prevalence of IV Annals of Emergency Medicine

drug users), selective test ordering, and retrospectively defined cutoffs for laboratory value abnormalities. The value of arterial blood gas analysis was not studied. Further studies are needed to identify the key clinical and laboratory variables that will help discriminate early PCP from less serious diagnoses. In some larger institutions additional technical diagnostic tests may be available to help confirm or exclude the diagnosis of PCP. These include arterial desaturation during exercise, pulmonary diffusion capacity (DLCO), and direct examination of induced sputum specimens for P carinii trophozoites.125,1~6 Each of these diagnostic modalities requires trained personnel and technical support but may be available in some centers during routine working hours. In each case, abnormal results are helpful and would lead to subsequent hospitalization; however, negative findings will not definitively rule out PCP. Gallium scintigraphy may reveal diffuse p u l m o n a r y activity in 70% to 90% of patients with PCP. t 2z-129 Unfortunately, these results are not available within the time frame relevant to emergency care.

The disposition of patients with possible early PCP is dictated by the likelihood of severe disease and by the feasibility of close outpatient follow-up. Factors associated with decreased survival in AIDS patients with PCP have been studied previously.72,73,130, TM In the absence of these findings, which include a history of prior PCP, an elevated respiratory rate, an abnormal chest exami n a t i o n , l e u k o c y t o s i s (> 10,300 WBCs/mm3), elevated LDH, hypoxemia, hypoalbuminemia, or an abnormal radiograph, a good short-term prognosis is likely. Patients with favorable prognostic parameters may be discharged from the ED with close outpatient follow-up, ideally within two to three days. Due to the potential toxicity of trimethoprim/sulfamethoxazole, empiric treatment with this agent for well-appearing patients with a low probability of disease is discouraged. An empiric trial of oral erythromycin may be indicated for t r e a t m e n t of b r o n c h i t i s or pneum o n i a due to Mycoplasma pneumoniae or Chlamydia (TWAR strain)

pneumoniae. Any deterioration on outpatient 1359/109

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oral antibiotics should prompt admission for a more extensive diagnostic evaluation. While trimethoprim/sulfamethoxazole is given empirically as outpatient therapy for presumed early PCP by some clinicians, we prefer to observe these patients in the hospital pending diagnostic evaluation.

CENTRAL NERVOUS SYSTEM INFECTION Neuropsychiatric symptoms and diagnoses are second only to those related to the p u l m o n a r y system among HIV-infected patients who present to EDs.16,132-134 Any CNSrelated complaint such as headache, abnormal mentation, focal neurological deficits, seizures, or neck stiffness, should prompt immediate evaluation in any patient at risk for HIV infection. One report reviewed CNS complications encountered in 315 patients with AIDS or generalized lymphadenopathy. 133 The frequencies of various diagnoses were toxoplasmosis, 33%; progressive dementia, 17%; cryptococcal meningitis, 13%; CNS lymphoma, 9%> aseptic meningitis, 7%; Herpes simplex encephalitis, 3%; progressive multifocal leukoencephalopathy, 2%; and other, 16%. T gondii is the most common cause of intracranial mass lesions in HIV-infected patients and is the initial presentation of AIDS in approximately 2% of cases. 135,136 Headache (40% to 50%), lateralizing neurological deficits (60%), altered mentation (60%), generalized seizures (30%), and fever (10% to 74%) are the most frequent presenting findings of CNS toxoplasmosis

135,136

C o n t r a s t - e n h a n c e d CT typically demonstrates ring-enhancing lesions that are bilateral (60%), multiple and unilateral (10%), or single (19%), or atrophy (8%) or no detectable lesions (4%). A double dose of contrast gives maximal enhancement and may be preferred to single dose, provided that renal f u n c t i o n is first established to be normal. 137 Magnetic resonance imaging (MRI) is more sensitive than CT for demonstrating the lesions of cerebral toxoplasmosis.138 Any patient at risk for AIDS with s y m p t o m s referable to the CNS should be evaluated by contrast-enhanced CT or MRI. The standard antimicrobial regimen for toxoplasmosis is pyrimeth110/1360

amine and sulfadiazine, with clind a m y c i n as an alternative in sulf o n a m i d e allergic patients.139A 4° Empiric therapy for toxoplasmosis need not be initiated in the ED in most cases, however, measures to c o n t r o l seizures or reduce intracranial pressure m a y be required. C o r t i c o s t e r o i d t h e r a p y s h o u l d be considered in patients with significant intracranial edema or mass effect. Another frequent and important cause of CNS infection in HIV-seropositive patients is cryptococcal meningitis, which occurs in approximately 10% of AIDS patients. 141q43 Chuck and Sande reviewed 106 cases of cryptococcal infection seen at San Francisco General Hospital. TM Headache was the most common symptom (76%), followed by fever (65%). Of note, meningismus and photophobia occurred in only 22% and 18% of patients, respectively. Lumbar p u n c t u r e r e v e a l e d i n c r e a s e d opening pressure ( > 200 m m H20 ) in 66% of patients. Cerebrospinal fluid leukocyte counts ranged from 0 to 700, but only 21% of patients had more than 20 WBCs/mm 3. Protein elevation ( > 55 mg/dL) and hypoglycorrhachia (glucose < 40 mg/dL) were seen in 55% and 24% of patients,- respectively. India ink stains were positive in 75% of patients, and cryptococcal antigen was detected in 91%. In the absence of a marked pleocytosis or other CSF chemical abnormalities, one should be cautious in interpreting a spinal fluid specimen as normal without confirmatory cryptococcal testing. India ink stains can be performed immediately in most hospital or ED laboratories. A m p h o t e r i c i n B is the drug of choice for cryptococcal meningitis with or without synergistic doses of f l u c y t o s i n e . 144 A n e w i m i d a z o l e compound, fluconazole, has proven beneficial in the maintenance therapy of cryptococcal meningitis but does not appear to be as effective as amphotericin B to treat acute disease. t45 In m o s t cases a n t i f u n g a l therapy would not need to be initiated in the ED. Lumbar puncture is the necessary diagnostic procedure in patients suspected of having cryptococcal meningitis. Due to the frequency of intracranial mass lesions in AIDS patients and the potential risk of tentorial Annals of Emergency Medicine

herniation, it is our opinion that intracranial imaging is warranted prior to lumbar puncture even in the absence of focal neurological deficits, papilledema, or seizures. Although AIDS patients do not appear to be at increased risk for bacterial meningitis, if there are findings suggestive of meningitis of any etiology and the lumbar puncture is delayed in order to obtain intracranial imaging, antibiotics appropriate for treatment of bacterial meningitis should be initiated i m m e d i a t e l y following the procurement of blood cultures. 146 The syndrome of progressive dementia in HIV-infected patients, unrelated to other opportunistic processes, has been termed the AIDS dementia complex or HIV encephalopathy. 147-151 Up to two thirds of HIV-infected patients will eventually develop some degree of impaired cognitive function. The onset of dementia may precede other manifestations of AIDS; however, severe dementia commonly occurs late in the course of HIV disease. Initially there may be subtle cognitive changes and over weeks to months severe slowing of mental and motor function occurs. Profound weakness, neglect, ataxia, tremor, seizures, and psychosis may develop. Intracranial imaging generally demonstrates only cortical atrophy and ventricular enlargement; white matter hypodensities may be seen occasionally. The cerebrospinal fluid often reveals an elevated protein, the glucose is usually normal, and a minority of patients have a mononuclear pleocytosis. From the standpoint of emergency evaluation, the AIDS dementia complex is a diagnosis entertained only if other HIV-related CNS disorders have been excluded. Recent studies suggest that high-dose AZT is beneficial in the treatment of HIV-related dementia. ~s2 HIV-infected patients appear to be less responsive to standard therapeutic regimens for syphilis and therefore are at greater risk for rapid progression to later stage disease. Benzathine penicillin (2.4 million units) is likely to be inadequate for the treatment of primary, secondary, or early latent syphilis in HIV-infected patients. 153,154 Well-documented reports describe CNS relapse in patients who have been treated with a single p e n i c i l l i n i n j e c t i o n . 153-156 Three w e e k l y i n j e c t i o n s of ben20:12 December 1991

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zathine penicillin are thought to be superior therapy for primary and secondary syphilis in these patients. 157 Meningovascular syphilis should be considered in any HIV-infected patient presenting with an ischemic neurologic syndrome. 158,159

BACTEREMIA In addition to PCP, fungal, and mycobacterial infections, AIDS patients also appear to be at increased risk for serious bacterial disease, including pneumonia and spontaneous bacteremia. For example, pneumococcal bacteremia has been estimated to be approximately 100 times more common in HIV-infected patients than in the general community prior to the AIDS e p i d e m i c . 16o In one report, community-acquired bacteremia accounted for a p p r o x i m a t e l y 5% of hospital a d m i s s i o n s of AIDS patients. Of note, these patients often did not manifest typical signs of infection. 161 Among 38 patients with 44 episodes of bacteremia, on presentation 43% were afebrile and 59% had a peripheral WBC count between 3,000 and 14,000/mm< However, these patients in general appeared sufficiently ill to require hospitalization and b l o o d c u l t u r e s . U n f o r tunately, the factors that identify patients at risk of bacteremia in this population have not been identified. Several series have reported bacteremia due to S pneumoniae, S aureus, Escherichia coli, and H influe f l z a e . 161-163 S aureus bacteremia, although reported in h o m o s e x u a l HIV-infected patients, is a particular concern in IV drug users because of the risk of endocarditis. 164 With regard to IV users, signs of infection without a clear nonbacterial etiology, should always prompt consideration of endocarditis and the need for hospital admission.165 Relapsing bacteremia due to Salmonella species also appears to be more frequent in the HIV-infected population. 166,167 Preliminary studies suggest that suppressive therapy with oral ciprofloxacin may reduce the incidence of Salmonella bacteremia in some AIDS patients.168 Because of the risk of bacteremia, empiric treatment of seriously ill HIV-infected patients should include coverage for these bacteria, particularly if the source of sepsis is uncertain. T r i m e t h o p r i m / sulfamethoxazole, a third-generation cephalosporin, or a ~-lactamase in20:12 December 1991

hibitor agent provide reasonable empiric coverage.

GASTROINTESTINAL DISEASE The most common gastrointestinal problem in AIDS patients is profuse diarrhea. 169 Often the diarrhea is chronic, refractory to a n t i m o t i l i t y agents, and due to primary HIV ent e r o p a t h y , M A I e n t e r i t i s , Cryptosporidia, or Microsporidia (Enterocytozooan). 170,171 Male homosexual AIDS patients are also at risk for treatable gay-bowel associated pathogens such as Salmonella, Shigella, Entamoeba, and Giardia. I69,172,173 Isospora be]li is a frequent stool p a t h o g e n in HIV-infected p a t i e n t s and is amenable to treatment with trimethoprim/sulfamethoxazole. A frequent, serious, and treatable problem in AIDS patients is esophagitis. The most c o m m o n etiologies are Candida, CMV, and Herpes simplex. 174 Patients who present with odynophagia should be admitted for upper endoscopy and biopsy. Acalculous cholecystitis has been described in AIDS patients primarily due to biliary infection with CMV or Cryptosporidium.17s, 176 Hepatic inf l a m m a t i o n m a y be caused by the agents of hepatitis A, B, or C, CMV, Herpes simplex, toxoplasmosis, disseminated fungal infection, atypical m y c o b a c t e r i a , or e x t r a p u l m o n a r y pneumocystosis. Gastrointestinal hemorrhage may be a manifestation of invasive Kaposi's sarcoma, nonHodgkin's lymphoma, CMV enterocolitis, or a variety of enteroinvasive bacterial pathogens. CMV RETINITIS Any change in visual acuity is significant because of the risk of CMV r e t i n i t i s in H I V - s e r o p o s i t i v e patients. 177,178 This disease usually occurs in end-stage patients and is often diagnosed by fundoscopic examination. The retinal lesions have a "tomato and cheese pizza" appearance characterized by central pallor w i t h areas of surrounding hemorrhage. Early recognition is critical as m a c u l a r i n v o l v e m e n t is v i s i o n threatening and requires immediate i n d u c t i o n t h e r a p y w i t h ganciclovir. 179,180 THE ACUTE RETROVIRAL SYNDROME P r i m a r y i n f e c t i o n w i t h HIV, t e r m e d the a c u t e r e t r o v i r a l synAnnals of Emergency Medicine

drome, occurs one to six weeks following exposure to HIV. 181-186 This syndrome mimics mononucleosis and is characterized by fever, diffuse lymphadenopathy, sweats, malaise, myalgias, anorexia, nausea, diarrhea, and a n o n e x u d a t i v e p h a r y n g i t i s . Neck stiffness, headache, and photophobia occur frequently. One quarter of patients experience a truncal rash that m a y be maculopapular, morbilliform, or urticarial.187 Aseptic meningitis, characterized by a lymphocytic pleocytosis and an elevated protein level, accompanies HIV seroconversion in one third of patients. In this stage of the illness, p24 antigen levels are elevated. HIV antibody by ELISA does not appear until several weeks later. Other than supportive care, there is no specific therapy indicated for the acute retroviral syndrome.

METABOLIC A N D DRUG COMPLICATIONS In the HIV-infected patient presenting with hypotension refractory to volume resuscitation, underlying adrenal insufficiency should be considered. Hyponatremia, hyperkalemia, hypoglycemia, and a nonanion gap metabolic acidosis may be present. Disseminated tuberculosis or systemic fungal infection, atypical mycobacterial infection, CMV, or adrenal replacement by lymphoma or Kaposi's sarcoma m a y produce this clinical syndrome. 188 Patients receiving ketoconazole for fungal infection are also at risk for adrenal insufficiency as this drug inhibits the biosynthesis of mineralocorticoid hormones. 189 Side effects reported after IV pentamidine administration include hypotension, dysglycemias, acute renal failure, rhabdomyolysis, hyperkalemia, herxheimerlike reactions, ketoacidosis, and v e n t r i c u l a r dysrhythmias.96 lOl Dysglycemias following pentamidine infusion may be acute or delayed for days to weeks. 97 In HIV-seropositive individuals presenting with altered mental status, e m e r g e n c y glucose d e t e r m i n a t i o n should be performed, particularly if the patient has previously received IV pentamidine. Some patients with cryptococcal meningitis receive maintenance amphotericin infusions as outpatients through an indwelling central venous catheter. Hypokalemia and hypomag1361/111

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nesemia may result in cardiac dysrhythmias, m u s c u l a r weakness, intestinal ileus, or seizures in these patients. The primary adverse effects associated with AZT are hematologic; both a n e m i a and n e u t r o p e n i a are seen more frequently than in AIDS/ARC patients given placebo. 19o Nausea, myalgia, insomnia, and severe headaches are also significantly associated with the use of AZT. More recent investigations indicat~ that hematologic and most other side effects are associated primarily with higher dosages (1,500 mg per day) as opposed to the current standard dosage for AZT (approximately 500 mg per day), which appears to be as effective as the higher dosage and is rarely associated with side effects.191,192 Dideoxyinosine (DDI) is an investigational antiretroviral drug currently available on s t u d y protocol or by c o m p a s s i o n a t e plea. 193 D D I m a y cause profound hypokalemia and hypocalcemia resulting in ventricular dysrhythmias, tetany, or generalized seizures. Mild to life-threa[ening pancreatitis is a well-described side effect of this medication, and serum amylase determinations are indicated in any DDI-treated patient with abdominal complaints. DDI m a y also induce a profound sensory peripheral neuropathy characterized by "stocking-glove" paresthesias.

SUMMARY As the AIDS epidemic progresses, the number of ED patients with HIVrelated illness will continue to increase. As reviewed in this article, much of the existing clinical research in HIV-related illness has an impact on the diagnostic and m a n a g e m e n t issues that arise in the ED. Many of the patterns of disease, subtleties of diagnosis, and therapies unique to AIDS p a t i e n t s h a v e already b e e n greatly elucidated. However, as the recognition of this disease goes into only its second decade, m a n y questions remain. Further studies are needed, for example, to improve physician assessment of HIV risk, to further identify discriminators of PCP and b a c t e r e m i a , and to o p t i m i z e strategies for disposition and outpatient management. In the future, in the areas of research and clinical care, emergency medicine will play an increasing important role in the 112/1362

frontline attack on this m o d e m epidemic.

ADDENDUM Some of the recommendations expressed in this article are based on the experience of the authors. Dr Kennedy has practiced as an emergency physician and currently is an attending p h y s i c i a n at the N a v a l Hospital of San Diego in the Department of Medicine, Division of Infectious Diseases, and is Director of the HIV Evaluation Unit. Dr Talan is faculty of the Olive View/UCLA Dep a r t m e n t of E m e r g e n c y Medicine and the Department of Medicine, Division of Infectious Diseases. The authors have cared for HIV-infected patients since the disease was first recognized at UCLA Medical Center and at other institutions, including Olive View/UCLA Medical Center and the Naval Hospital of San Diego. The authors extend their appreciation to Ms Cecilia Cesefia and Mr Michael Reich for preparation of the manuscript, table, and figure.

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