CLINICAL REVIEW Medical Complications of Intravenous Drug Use MICHAEL D. STEIN, MD INTRAVENOUSDRUG USERS (IVDUs) have entered p u b l i c discourse as one of the groups most at risk for contracting and transmitting AIDS. The medical c o m m u n i t y has long e x p e r i e n c e w i t h p r o b l e m s particular to this p o p u lation. HIV infection is o n l y the current e p i d e m i c . In the 1940s falciparum malaria was frequently passed b e t w e e n addicts. In the 1950s, in N e w Y o r k City, 8.3% of deaths a m o n g addicts r e p o r t e d b y the city's c h i e f medical e x a m i n e r w e r e due to tetanus. In the late 1960s, acute hepatitis was the " f o r e m o s t cause of addict admissions . . . to m u n i c i p a l hospitals. ''1 By the 1970s, infections a c c o u n t e d for only 27.5 % of hospital admissions a m o n g addicts. 2 Over the past decade, novel noninfectious syndromes have b e e n identified a m o n g the estimated 1.3 million IVDUs in the United States. 3 Illicit drug injection continues to b e the second most c o m m o n risk behavior associated with AIDS. 4 HIV seroprevalence in drug users varies w i t h geography, but through January 2, 1989, 22,025 cases of AIDS a m o n g intravenous drug users, 27% of all adult cases, had b e e n r e p o r t e d to the Centers for Disease Control. ~ Although not the subject of this review, prevention, screening, and control of HIV infection in this p o p u l a tion remain major health p o l i c y issues. 6, 7 Up to 10% of all inner-city hospital admissions are addiction-related, s HIV infection has dramatically wid e n e d the s p e c t r u m of diseases seen a m o n g addicts. Indeed, d e t e r m i n i n g HIV-related illnesses in addicts can be difficult w i t h o u t a clear understanding of the pathophysiologic changes secondary to drug use itself.

DRUGS AND DILUENTS The drugs c o m m o n l y used b y addicts include heroin, cocaine, Demerol, Dilaudid, pentazocine, tripelennamine and barbiturates. These are used individually or mixed; " s p e e d b a l l s , " for instance, c o m b i n e heroin and cocaine. O t h e r p r e s c r i p t i o n drugs, not ordinarily given intravenously, have also b e e n a d o p t e d b y users. Opiates are sold as p o w d e r s and liquefied b y cooking in spoons or bottle caps before b e i n g filtered through cotton into syringes. Sold in " b a g s , " they arrive on the street w i t h a w i d e range of purity. A bag of 5% heroin is equivalent to 15 mg of m o r p h i n e . The user's lack of awareness a b o u t the exact concentration Received from the Division of General Internal Medicine, Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903. Address correspondence and reprint requests to Dr. Stein.

m a y be one cause of overdoses, estimated to kill 1% of addicts p e r year. 9 The possibilities of contamination b e t w e e n bag and b l o o d s t r e a m are manifold and are b o t h c h e m i c a l and microbial. Quinine is c o m m o n l y used as a diluent because it is similar in a p p e a r a n c e and taste to heroin. Alone, it can p r o d u c e abscesses on injection, and w i t h its high r e d o x potential, it may a l l o w anaerobic growth, fostering organisms such as Clostridium tetani. Quinine also is k n o w n to cause cardiac arrhythmias. 1° Sucrose, lactose, mannitol, m a g n e s i u m silicate, methpyrilene, baking soda, and procaine have also b e e n used as diluents. Ritalin tablets, adapted for intravenous use, contain talc. " B r o w n h e r o i n , " originally f r o m Mexico, is t h o u g h t to contain impurities of the o p i u m plant such as noscapine and p a p a v e r i n e that cause a particular musculoskeletal s y n d r o m e ) 1 Further, contamination m a y c o m e f r o m dissolving the solid drug in toilet or sink water, or in saliva. Pentazocine and t r i p e l e n n a m i n e do not n e e d to b e dissolved. Cotton, used as a filter, itself causes granulomatous p u l m o n a r y reactions. 12

INJECTION SITES AND COMPLICATIONS N e w users will inject first into a p p a r e n t superficial veins. After the c o m m o n l y used cephalic and basilic systems are sclerosed, large veins in the n e c k and groin are used and are often f o u n d to have b e e n used b y professionals w h o are paid to find hidden access. Arterial injection is done either accidentally or deliberately. 13 Involving the brachial system, this is called a "flash" or " h a n d trip," from the resulting paresthesia. "Skin p o p p i n g " into s u b c u t a n e o u s tissue and " p o c k e t shooting" into the supraclavicular fossa are not uncommon. Injected diluents can lead to vasospasm, norepin e p h r i n e release, intimal damage, thrombus, or particulate embolization, all of w h i c h contribute to vascular insufficiency.l~, 15After arterial injection, the combination of sepsis, local infection, and the n e e d for vascular reconstruction influence o u t c o m e , Is and early arteriography is r e c o m m e n d e d . With cocaine, t h r o m b u s distant f r o m the site of injection has b e e n found. 16 Myocardial infarction t e m p o r a l l y related to cocaine use in patients w i t h fixed coronary artery disease as w e l l as in those w i t h " n o r m a l " coronary arteries has b e e n described. 17 Cocaine, heroin and a m p h e t a m i n e s are potent s y m p a t h o m i m e t i c s and vasoconstrictors. 16 It is not unusual to find n e e d l e fragments subcutaZ49

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neously in addicts. Needles f r o m p e r i p h e r a l sites can migrate centrally. 18 Shooting into central veins can result in needle e m b o l i moving to the lungs. ~9 Hospital e x p e r i e n c e w i t h central vein catheterization d e m o n strates the significant m o r b i d i t y of this complication.18 Using the base of the n e c k to inject can lead to p n e u m o t h o r a x or h e m o t h o r a x . At one hospital, 20% of all p n e u m o t h o r a c e s seen over two years w e r e f o u n d in IVDUs. 16 Most addicts use 2 1- or 22-gauge needles, b u t small injuries can lead to c o m p l e t e or tension pneumothoraces.21 O t h e r c o m p l i c a t i o n s related to injection include pseudoaneurysm, which, if infected, presents as local tenderness, fever, and pulsatile mass22; d e e p v e n o u s thrombosis; endarteritis; and arteriovenous fistulas. Use o f the femoral triangle seems particularly dangerous. 23 Skin p o p p i n g regularly leads to l y m p h a t i c obstruction and edema. Drug overdose, the most c o m m o n cause of in-hospital death for addicts, accounts for 5% o f addict admissions. The acute response to a high concentration of a narcotic is variable, w i t h abrupt death seen in s o m e addicts and late reactions in others. The level o f free m o r p h i n e in the b l o o d has b e e n correlated w i t h survival. 24 The prevalent theory remains that lethal doses cause respiratory depression via hemorrhage, alveolar edema, and, in late reactions, interstitial fibrosis. Circulatory collapse can b e sudden, explaining w h y heroin metabolites ( d i a c e t y l m o r p h i n e ) are absent f r o m s o m e kidneys at autopsy. 24 Heroin-induced cardiac abnormalities that m a y contribute to fatalities include arrhythmias and acute cardiomyopathy. 2s-27 C o n c u r r e n t use of alcohol m a y e n h a n c e toxicity. 28 In addition, addicts have d e v e l o p e d their o w n forms of treatment, w h i c h m a y cause morbidity. 29

found to o c c u r in one patient after antibiotic therapy. 3o Lymphocytotoxic antibodies 32 m a y contribute to l o w T4 counts. It remains unclear w h e t h e r T-cell subsets in IVDUs generally correct after therapy, h o w these are influenced b y c o n c u r r e n t HIV infection, and w h a t prognostic significance they have. It also appears that heroin use itself, rather than a c c o m p a n y i n g infections or diluents, can affect total T-cells and alter their function in vivo as m e a s u r e d b y the ability to rosette s h e e p erythrocytes 33 or b y response to mitogens phytohemagglutinin, p o k e w e e d , or Con-conavilin A. 34 Indeed, l y m p h o c y t e s b i n d opiates stereospecifically. 33 Morphine has b e e n f o u n d to decrease the n u m b e r of T d y m p h o c y t e s in vitro, and naloxone (Narcan) can reverse this decrease. Evidence that cocaine abuse affects i m m u n o c o m p e t e n c e is lacking, as is evidence of the effects of non-opioids. The addict's " h y p e r i m m u n e " state and hypergamm a g l o b u l i n e m i a (most likely from r e p e a t e d antigenic stimulation) have b e e n used to explain the high rates of false-positive syphilis tests and atypical lymphocytosis seen in IVDUs. 1 O t h e r false positives r e p o r t e d in addicts include C o o m b s ' tests, s m o o t h m u s c l e antibodies, monospot, and r h e u m a t o i d factor, l, 32 Addicts w i t h t h r o m b o c y t o p e n i c p u r p u r a have circulating i m m u n e c o m p l e x e s c a p a b l e of reacting with platelets. 3s, 36 The a d e n o p a t h y and s p l e n o m e g a l y f o u n d in addicts m a y signal w i d e s p r e a d disturbances in the i m m u n e and reticuloendothelial systems. 3y These i m m u n o l o g i c abnormalities m a y h e l p explain the continuing rise in fatal "non-AIDS" o u t c o m e s for drug users infected w i t h HIV. 38

IMMUNOLOGY

Fever and b a c t e r e m i a c o m m o n l y result from intravenous drug use. Questions remain, however, as to w h e t h e r pyrogens originate from dirty syringes, contaminated drugs, or unsterile skin sites. Patterns of use, demographics, the use o f illicit antibiotics p u r c h a s e d f r o m dealers, and the user's recent hospitalizations det e r m i n e the infecting organisms. Cultured samples o f heroin have r e c o v e r e d bacillus species, coagulase-negative Staphylococcus, Clostridium perfringens, and aspergillus. 39'4° Alt h o u g h a large n u m b e r of samples w e r e gram-negative, limulus assays of the same materials tested negative, suggesting that p r e f o r m e d e n d o t o x i n was an unlikely cause of fever or sudden death. Hepatitis B has also never b e e n f o u n d in injected material. ~ Notably, the organisms isolated f r o m drug-use paraphernalia are rarely isolated f r o m the bloodstreams of infected users. This has led to the suggestion that the addict's skin flora are the likely source of infecting organisms. 4° The m i c r o b i o l o g y of addict soft tissue infections is m o r e consistent w i t h this theory. 42 Skin flora, however, m a y be e x p e c t e d to differ a m o n g insti-

Many i m m u n o l o g i c abnormalities have b e e n f o u n d in intravenous narcotic users, including decreased cutaneous sensitivity and mitogen responsiveness, as w e l l as changes in T-cell subsets and l y m p h o c y t e proliferation. Addicts, often malnourished, w i t h significant w e i g h t loss and chronic liver disease, have o t h e r reasons for i m m u n o r e g u l a t o r y cell alterations. The m o r e sophisticated analyses of the past several years, however, have b e e n c o n f o u n d e d b y the e m e r g e n c e of HIV infection, w h i c h has its o w n effects on i m m u n e competence. T - l y m p h o c y t e helper-to-suppressor ratios have b e e n studied twice in IVDUs hospitalized for nonopportunistic infections, b u t neither study tested for HIV seropositivity, and t h e y are therefore inadequate. In one g r o u p of 1 6 IVDUs, 3° 1 2 had inverted ratios, m o s t often due to increased suppressor cells (all viral titers other than HIV w e r e negative). In a second study o f 1 2 IVDUs, eight had inverted ratios, six due to l o w h e l p e r cell counts. 3! Normalization of the T-cell ratio was

BACTEREMIA

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tutions as well as injection sites. With a high rate of staphylococcal bacteremia ~3 and with the use of street antibiotics, addicts represent a growing reservoir of methicillin-resistant S. a u r e u s . 44 Although endocarditis is a c o m m o n cause o f persistent bacteremia, 3 5 - 60% of bacteremias are unrelated to endocarditis. 4, 45 Indeed, it has b e e n observed that " b a c t e r e m i c addicts with a recognized primary focus of infection seldom develop apparent endocarditis, ''46 possibly because they seek medical attention early, but concomitant endocarditis often remains a possibility if blood cultures remain positive. Among bacteremic addicts without classifiable endocarditis, an infection focus is found in 97% of cases. ~6 Origins o f hematogenous spread include soft tissue infections, mycotic aneurysms, thrombophlebitis, septic arthritis, lower respiratory tract infection, and osteomyelitis. Transient bacteremia with rapid clinical imp r o v e m e n t has also b e e n described. 47 Skin and soft tissue sites include cellulitis, abscesses, cutaneous ulcers, and necrotizing fasciitis. Noninfectious skin lesions are difficult to distinguish but include diluent-induced inflammation, skin infarction, sterile subcutaneous necrosis, and myonecrosis after crush injuries. 9, 48 Beta-hemolytic streptococci and S. a u r e u s account for the majority of unimicrobial cases of skin sites leading to septicemia. In the more c o m m o n examples of polymicrobial infections, enteric and oropharyngeal gram-negatives are also found. 43Anaerobes are predominant in some series, 49 and rarer anaerobic infections such as tetanus and w o u n d botulism have been found in chronic abusers, s°, 5t Necrotizing fasciitis may develop from contaminated IV injection sites, s2 and deep abscesses may be slow-growing, tender areas, often without systemic findings in the psoas, axilla, and chest wall regions, with gas present in 70% of cases, s3 Although osteomyelitis may result from contiguous soft tissue infection, s3 it more c o m m o n l y results from bacteremia. The pathway o f infections, via venous or arterial channels, has not b e e n established. Large reviews differ in the prevalent sites and organisms found in drug users. Roca found a high incidence of gram-negative infections and sternoarticular involvement, 54 while others ~5 have reported a p r e d o m i n a n c e of staphylococcal and streptococcal species in the extremities. Sacroiliac, p u b i c symphysis, vertebral, and rib sites are not unusual in this group. Positive b l o o d cultures are helpful at times, but identification of causative organisms often requires o p e n biopsy. The shortterm prognosis for addicts is excellent, but late complications are difficult to assess. Nonpyogenic osteomyelitis is well described. 56 Mycotic aneurysms may serve as sources of continuing bacteremia. The aorta, p u l m o n a r y artery, subclavian artery, and carotid artery have b e e n identified as foci.~7

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If bacteremia persists despite antibiotic therapy, splenic abscess is possible, especially if there is a history of abdominal trauma. 58 Splenectomy is often indicated due to the risk of rupture.~9 A distinct syndrome of disseminated candidiasis exists among heroin users. An initial phase that is clinically compatible with septicemia (with negative blood cultures) is followed by cutaneous signs one to ten days later. 6° Metastatic lesions include arthritis, costochondritis, hepatitis, skin lesions on the scalp, and ocular involvement, often resulting in loss o f vision. 61 High titers of serum antibodies to Candida are found. 62 Lemon juice, used to dissolve heroin, is the likely source of C a n d i d a a l b i c a n s . 61, 63

ENDOCARDITIS Some authors suggest that a history of IVDU implies "underlying heart disease ''45 by creating the endothelial valvular damage and platelet fibrin deposition thought necessary for bacterial endocarditis. 64 Persistently positive b l o o d cultures w i t h o u t an extracardiac source, pathologic and microbiologic evidence at surgery or autopsy, and echogenic masses on valves or contiguous structures are central to a definition of endocarditis. The sensitivity and specificity of echocardiography in addicts varies greatly b e t w e e n series, with recent sensitivities between 47 and 89%. 65.67 Echocardiograp h y is most helpful w h e n multiple infiltrates are seen o n chest x-ray. 67 Echogenic vegetations are predictive o f complications of endocarditis, e8 though the prognostic importance of valvular location requires further study. Patients without echogenic foci w h o are diagnosed as having bacterial endocarditis may develop life-threatening complications as well. The appearance of vegetations may persist after bacteriologic cure. 68 The incidence of bacterial endocarditis is estimated at 1.5 - 2 cases per 1,000 addicts peryear, w h i c h represents 5 - 20% of hospital admissions for IVDUs.4, 46, 69 Yet the classic signs and symptoms o f e n docarditis are often not predictive in febrile addicts. Physicians are able to correctly predict this diagnosis only approximately half the time.~5 An affinity b e t w e e n particular organisms and particular valves may exist. 7°, 71 S t a p h y l o c o c c u s a u r e u s remains the most frequent isolate in endocarditis, and the tricuspid is the valve most frequently involved. 72 S t a p h y l o c o c c u s a u r e u s infection of the tricuspid valve is medically cured 9 0 - 95% of the time, but large vegetations (more than 1 cm) may identify patients with a greater risk o f short-term right ventricular failure. 73 Streptococcus, the next most c o m m o n organism, is said to have a proclivity for left-sided valves, 74 but this may not be so. 7s In addicts, left-sided infections have a higher medical failure rate than do right-sided infections. 76 Pseudomonas infection may be biventricular more

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c o m m o n l y than infections with other bacteria, s but c o m b i n e d left- and right-sided endocarditis makes u p only 5 - 8% of all endocarditis 72 and characteristically has a p o o r prognosis. Other organisms that may be implicated include the enterobacteriaceae, rr bacilli, diphtheroids (possibly from paraphernalia), Neisseria, and Hemophilus. P n e u m o c o c c u s infection is rare. 46 Fungal endocarditis most often involves candidal species other than C. a l b i c a n s . 72 Aspergillus, a common bag contaminant in heroin, is rarely seen. Polymicrobial infections are not rare, 7s and response to routine antibiotic therapy is p o o r if Pseudomonas is involved. Directed antibiotic therapy remains of greatest importance. 79 Clinical prediction o f the infecting species is difficult, and pathogens change at individual hospitals over time, with methicillin-resistant and -tolerant staphylococcal species a growing problem. Uncomplicated infections with sensitive staphylococcal species may be successfully treated after four weeks s or even two weeks of combination therapy. 8° The need for surgery for IVDUs is based on criteria similar to those for other populations, 81, 82 but c o n t i n u e d IV drug use must be deterred.

LUNG DISEASE The acute p u l m o n a r y complications o f drug abuse include p u l m o n a r y edema, bronchospasm, septic emboll, and community-acquired pneumonias. Heroin overdose may be followed acutely by pulmonary edema, although there is no definite relationship b e t w e e n the time of injection and its onset, s3 and a delay of six to ten hours is not u n c o m m o n , u In the addict, the clinical findings of p u l m o n a r y edema may be absent, but chest x-rays typically reveal a widespread alveolar pattern with a normal-sized heart. Unilobar p u l m o n a r y edema has also b e e n described, s5 Fever and leukocytosis without evidence of infection are reported.9, s6 Patients follow two courses: a dramatic recovery two to 72 hours after administration of oxygen and Narcan, with clearing of the chest x-ray, or, in a small number, rapid death, s7 The mechanism of p u l m o n a r y edema is most likely alveolar capillary leak, as a high concentration of protein is found in edema fluid. ~ Although hypoventilation usually precedes p u l m o n a r y edema, finding only mild hypoxemia in most cases speaks against hypoventilation as the cause. 8° Reduced levels of serum IgM and c o m p l e m e n t are seen but remain unexplained. Other p r o p o s e d mechanisms include a central nervous system effect, 89 allergic reaction, 9° aspiration, 9t and opiate-induced histamine release. 9 The absence o f an experimental model precludes exact delineation. After the pulmonary edema o f overdose, vital capacity improves slowly but diffusing capacity remains unchanged for months, possibly indicating impaired diffusion prior to p u l m o n a r y edema.

Bronchospasm has b e e n reported to o c c u r after intravenous heroin use. 92 Symptoms can appear months after the first use of the narcotic and will respond to inhaled beta-agonists, methylxanthines, and steroids. Septic p u l m o n a r y embolism from endocarditis or thrombophlebitis may present as b r o n c h o p n e u m o n i a , round or wedge-shaped lesions w h i c h can excavate and form abscesses. 93 Pleural effusion and e m p y e m a may result. Most infarcts resolve with only minor pleural thickening, but p u l m o n a r y gangrene has b e e n reported.9~ Multiple septic emboli may cause p u l m o n a r y hypertension. Among febrile IVDUs, conventional p n e u m o n i a is the most c o m m o n diagnosis. 4s Most cases involve typical community-acquired organisms, although in some cities tuberculosis remains a concern. ~s' 86 The clinical, pathologic, hemodynamic, and roentgenographic complications of chronic intravenous drug abuse differ from those associated with acute drug use. Most can be ascribed to the injection of contaminants, with resultant foreign-particle emboli. There is no evidence that narcotics themselves cause chronic lung disease. Starch can cause mild, transient, pulmonary granuloma formation, 9s while cotton fibers from drug filters ~3 and talc (used as a filler in many oral preparations) can cause permanent intravascular and perivascular granulomas in pulmonary arteries and arterioles, as well as other organs. 96 By chest x-ray, "talc granulomatosis" appears as a micronodular pattern, and severity is dose-related. 96 Surrounding small vessels, angiothrombosis may lead to pulmonary hypertension, proven by cardiac catheterization, 97 and progressive loss of lung volume. Talc granulomatosis may be confirmed by bronchoalveolar lavage, w h e r e talc crystals may be found. 9s Overland et a1.,99 w i t h o u t providing details on the IV use of oral medications, found that 42% of drug abusers had a single-breath diffusing capacity (DLCO) less than 75% o f predicted, often with normal chest x-rays and few symptoms. ~ooAgain, this is thought to be due to repeated obliteration of capillaries by microemboll, which cause alveolar thickening and subsequent interstitial fibrosis. V e n t i l a t i o n - p e r f u s i o n (V/Q) scans in narcotic addicts are frequently abnormal. ~°~ Bullous disease, confined to the u p p e r lobes, has been r e p o r t e d ) °2 All patients had r e d u c e d vital capacities and DLCOs, as well as expiratory obstruction evident on p u l m o n a r y function testing. The authors speculate that emboli cause microbullae, w h i c h coalesce. Talc lung disease notably predominates in the u p p e r lobes. ~o3

RENAL DISEASE Acute renal diseases in IVDUs include myoglobinuria, necrotizing angiitis, and glomerulonephritis associated with endocarditis or hepatitis. Myoglobinuria can o c c u r hours after intravenous

JOURNALOFGENERALINTERNALMEDICINE,Volume 5 (May/June), 1990

injection of heroin. 1°4 Muscle tenderness, edema, elevated s e r u m m y o g l o b i n and elevated creatine phosphokinase, as well as muscle necrosis on biopsy, a p p e a r with renal dysfunction. Onset does not require immobilization or limb compression, w h i c h have also b e e n seen after overdose. 1°5 In acute focal and diffuse g l o m e r u l o n e p h r i t i s associated w i t h staphylococcal or streptococcal endocarditis, addicts present w i t h pyuria, mild proteinuria, and sterile urine cultures, thought secondary to circulating i m m u n e c o m p l e x e s . ~06 The chronicity of endocarditis m a y be important in i m m u n e c o m p l e x formation, and h y p o c o m p l e m e n t e m i a is c o m m o n . A return to normal renal function, usually within several months, is the rule.l°6 Bacterial emboli to the kidney m a y cause renal abscesses or infarction, and fungemia can lead to papillary infiltration and even fungus-ball f o r m a t i o n ) °7 Acute and chronic hepatitis B viral (HBV) infection is associated with a variety of g l o m e r u l a r l e s i o n s ) °s Asymptomatic HBV infection can b e evident years before renal disease, but renal dysfunction is also seen with chronic active, chronic persistent, and fulminant hepatitis, as well as in cirrhosis. Most patients will have either m e m b r a n o u s or m e m b r a n o p r o l i f e r a t i v e disease, but n e p h r o t i c synd r o m e w i t h minimal change and IgA n e p h r o p a t h y have also b e e n associated w i t h HBV) °s Serum c o m p l e m e n t is normal. 1°9 The prognosis of the renal lesion with acute hepatitis H° is better than that with chronic hepatitis. 108 Citron et al. described a necrotizing angiitis associated w i t h drug use. Indistinguishable f r o m polyarteritis nodosa, this angiitis may be associated w i t h cardiac, neurologic, and GI as w e l l as renal manifestations. 111 Diagnosis is confirmed b y angiography. Again, i m m u n e c o m p l e x activation and deposition, associated w i t h viral hepatitis, are considered necessary.

CHRONIC RENAL DISEASE A variety of chronic renal conditions exist in the addict. Addicts w h o have normal renal function often have abnormal urinalyses. Findings include m i l d to moderate proteinuria, m i c r o s c o p i c hematuria, and pyuria.112, 113 Biopsies of a s y m p t o m a t i c IVDUs usually reveal nonspecific mesangial c h a n g e s ) 12 N e p h r o t i c s y n d r o m e is well characterized, often occurring with m i c r o s c o p i c hematuria 114 and pyuria, 1ts w i t h or w i t h o u t renal insufficiency.1 ~s Focal and diffuse glomerulosclerosis (heroin-associated nep h r o p a t h y ) make u p the majority of r e p o r t e d cases, b u t other lesions include minimal-change, 116 focal m e m branoproliferative, 117 m e m b r a n o u s , 11° and amyloid (see b e l o w ) . Serologic tests are not helpful here as c o m p l e m e n t is normal and hepatitis antigen negative. t 14 Hypertension m a y play a role in progression to renal insufficiency, 113 but it is not frequent w i t h nephrotic syndrome. 1lO

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N e p h r o p a t h y progressing to end-stage renal disease seems to p r e d o m i n a t e in blacks. Ha Finding IgM and C 3 in g l o m e r u l a r lesions H5 suggests an i m m u n o logic basis. Drug adulterants are not k n o w n to b e n e p h r o t o x i c , nor does m o r p h i n e sulfate damage the glomeruli, t19 Uremia is the cause o f death in 3% 11a o f addicts and develops in a p p r o x i m a t e l y one addict p e r thousand p e r year. 12° There are obvious difficulties in establishing and maintaining vascular access in this population, and transplantation has b e e n used in f o r m e r addicts. 121 Renal amyloidosis occurs in addicts w h o skin p o p or have p r o n o u n c e d skin ulceration, abscesses, or muscle fibrosis f r o m intravenous drug use. I22124 The association b e t w e e n skin infections and renal amyloid has b e e n noted in p o s t m o r t e m series of addicts w i t h o u t k n o w n renal disease. 122, 123 Renal b i o p s y reveals AAprotein amyloid, similar to that found secondary to other chronic inflammatory states) 24 In the addict, amyloid has b e e n found in the skin, TM pleura, 125 and liver, t26 and amyloid fibrils can be discovered in urine. ~27 The average duration o f s u b c u t a n e o u s drug use is three years. Renal function at presentation is variable. It is most often reduced. Kidney size is normal or enlarged and hypertension is frequent. Reported tubular function defects include diabetes insipidus, glycosuria, phosphaturia, and renal tubular acidosis. Progression to renal failure occurs over months to years, and there is no evidence that halting drug use will alter this course, although regression in amyloid deposits in b u r n patients has occurred. 12s

HEPATITIS The parenteral drug abuser is serially e x p o s e d to hepatitis-causing viruses b y the sharing of contaminated e q u i p m e n t . Sexual transmission of hepatitides b e t w e e n addicts is also possible, t29 The acute and chronic liver diseases that follow have not b e e n attributed to opiates used or m e t h a d o n e taken, ~3° b u t m a y be e x a c e r b a t e d b y c o n c o m i t a n t alcohol abuse TM or unusual contaminants such as 3,4-methylene diamphetam i n e 132 or talc. 133 Hepatitis initially appears during the first year of needle use, 134 and a p p r o x i m a t e l y threequarters of addicts have s y m p t o m s within five years,135 although addicts are susceptible to m u l t i p l e acute icteric episodes, t36 Serologic surveys of m e t h a d o n e clinics demonstrate that 5 1 - 88% of a s y m p t o m a t i c addicts have b e e n e x p o s e d to HBV. 131' ~36 As a screening test, anti-HbC best estimates the p r e v a l e n c e of infection in this population,135 and 1 - 1 0% of addicts carry hepatitis B surface antigen (HBsAg))36 Hepatitis B with delta coinfection or superinfection carries a high risk for d e v e l o p i n g into fulminant hepatitis,~37, 13a as well as m o r e severe n o n f u l m i n a n t hepatitis. 139 The p r e v a l e n c e of delta infection rises over time within populations, 14°, 141 w i t h chronic HBV

~.$4

Stein, MEDICALCOMPLICATIONSOF INTRAVENOUSDRUGUSE

carriers more likely to have delta antibodies than acute HBV c a r r i e r s . This m a y b e p a r t l y e x p l a i n e d b y t h e effic a c y o f a l o w e r i n o c u l a t i n g d o s e for s u p e r i n f e c t i o n t h a n f o r a c u t e c o i n f e c t i o n , t42 A b i p h a s i c p a t t e r n o f illness, with clinical or biochemical relapse one to four weeks after t h e i n i t i a l f u l m i n a n t o r n o n f u l m i n a n t e p i s o d e , s h o u l d s u g g e s t t h e p o s s i b i l i t y o f d e l t a i n f e c t i o n . 142 D e l t a a n t i b o d y c o m m o n l y d o e s n o t a p p e a r u n t i l rel a p s e . 143 Non-A, non-B (NANB) h e p a t i t i s is g e n e r a l l y b e nign, but can be fulminant.t44 Only one-fourth of such c a s e s are i c t e r i c , 144 a n d c h r o n i c v i r e m i a is p o s s i b l e , t 4 5 s u g g e s t i n g that NANB h e p a t i t i s m a y b e c a p a b l e o f asymptomatic transmission. C l i n i c a l l y i m p o r t a n t c y t o m e g a l o v i r u s (CMV) o r Epstein-Barr v i r u s h e p a t i t i s is v e r y r a r e a m o n g add i c t s , t36 P l a u s i b l y , h e p a t i t i s A c o u l d b e t r a n s m i t t e d p a r e n t e r a l l y , t46 b u t t h e u s u a l t r a n s m i s s i o n o f t h i s a g e n t is n o t t h r o u g h b l o o d c o m p o n e n t s . T h e r e is l i t t l e e v i d e n c e t h a t h i s t o l o g i c r e s o l u t i o n o f l i v e r d i s e a s e o c c u r s w i t h h a l t i n g d r u g u s e , t34 o r t h a t HBsAg is lost. 147 O n e - t h i r d o f a d d i c t s r e m a i n HBsAgp o s i t i v e , ~36 a n d a p p r o x i m a t e l y 1% o f a d d i c t s w i t h a c u t e HBV g o o n t o d e v e l o p c h r o n i c a c t i v e h e p a t i t i s (CAH) o r cirrhosis. The progression from chronic persistent to c h r o n i c a c t i v e h e p a t i t i s is m o r e c o m m o n in IVDUs t h a n in t h o s e w h o d o n o t u s e d r u g s , t34, 142 O f a d d i c t s sel e c t e d for b i o p s y b e c a u s e o f p e r s i s t e n t l y a b n o r m a l t r a n s a m i n a s e s , 25% h a v e CAH o r c i r r h o s i s , t36 F i n d i n g c i r r h o s i s o f t e n s u g g e s t s c o n c o m i t a n t a l c o h o l u s e . 136 A d d i c t s w i t h NANB h e p a t i t i s a r e n o t w e l l s t u d i e d , but biochemical evidence of chronic hepatitis (more t h a n six m o n t h s ) c a n b e e x p e c t e d in a p p r o x i m a t e l y 50%, a n d o f t h e s e 60% w i l l h a v e CAH o r c i r r h o s i s . 144 A c u t e c o i n f e c t i o n w i t h HBV a n d d e l t a p o s e s a n u n k n o w n r i s k f o r c h r o n i c h e p a t i t i s , b u t t h o s e w h o survive delta superinfection and establish chronic delta i n f e c t i o n h a v e w o r s e p r o g n o s e s b y b i o p s y t h a n d o add i c t s w h o h a v e HBV a l o n e , 14s 97% in o n e s t u d y p r o g r e s s i n g t o CAH o r c i r r h o s i s . 142

NEUROLOGIC ENTITLES The neurologic complications of intravenous drug use can be divided into infectious and noninfectious.t49, 150 C e n t r a l n e r v o u s s y s t e m i n f e c t i o n s , w i t h a n d w i t h o u t e v i d e n c e o f e n d o c a r d i t i s , a r e s e e n i n addicts. Meningitis, brain abscess, subdural and epidural abscesses, and mycotic aneurysm are well described. Noninfectious complications other than seizures are uncommon. Seizures following drug overdose (usually cocaine and heroin) are most often grand mal, but m a y b e focal, e v e n w i t h o u t d e m o n s t r a b l e c e r e b r a l lesions. O v e r d o s e - r e l a t e d s e i z u r e s a r e m o s t c o m m o n l y due to centrally mediated respiratory depression and h y p o x i a , 1st a n d c e r e b r a l e d e m a is f o u n d at a u t o p s y . Cerebral infarction, both embolic and thrombotic, may

a l s o p r e s e n t as a s e i z u r e . C a u s e s i n c l u d e t a l c e m b o l i , v a s c u l i t i s , a n d d i s s e m i n a t e d i n f e c t i o n . 149 Transverse myelitis can present acutely, most often w i t h a n o r m a l m y e l o g r a m . S p i n a l c o r d n e c r o s i s has been found post mortem, suggesting that the lesions are d u e t o v a s c u l a r insufficiency. B r a c h i a l a n d l u m b o s a c r a l p l e x i t i s o c c u r m o r e s l o w l y . W e a k n e s s a n d s e n s o r y deftcits are a c c o m p a n i e d b y e l e c t r o m y o g r a p h i c e v i d e n c e o f d e n e r v a t i o n . P e r i p h e r a l n e r v e l e s i o n s m a y b e traum a t i c o r a t r a u m a t i c . 1so T r a u m a at an i n j e c t i o n site c a n c a u s e i m m e d i a t e p a i n a n d p a r e s t h e s i a , l e a d i n g to l o n g t e r m loss o f f u n c t i o n . A t r a u m a t i c m o n o n e u r o p a t h i e s h a v e b e e n r e p o r t e d at a d i s t a n c e f r o m t h e i n j e c t i o n site, and the proposed mechanisms of injury include hypersensitivity reactions and ischemia. Symmetrical polyn e u r o p a t h y r e s e m b l i n g G u i l l a i n - B a r r ~ s y n d r o m e ts2 m a y o c c u r a n d c a n a l s o b e c o n f u s e d w i t h b o t u l i s m , st Myopathies are associated with rhabdomyolysis and chronic intramuscular injections. C h a n g e s in m e n t a l status a r e c o m m o n as w e l l , a n d include delirium and hallucinations lasting hours to days.

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16. Cregler LL, Mark H. Medical complications of cocaine abuse. N EnglJ Med. 1986;315:1495-500. 17. IsnerJM, Estes NAM, Thompson PD, et al. Acute cardiac events temporally related to cocaine abuse. N Engl J Med. 1986;315:1438-43. 18. Galdun JP, Paris PM, Weiss LD, Heller MB. Central embolization of needle fragments: a complication of intravenous drug abuse. AmJ Emerg Med. 1987;5:379-82. 19. Angelos MG, Sheets CA, Zych PR. Needle emboli to lung following intravenous drug abuse. J Emerg Med. 1986;4:391-6. 20. Douglass RE, Levison MA. Pneumothorax in drug abusers: an urban epidemic? Am Surg. 1986;52:377-80. 21. Lewis JW, Groux N, ElliottJP,Jara FM, Obeid FN, Magilligan DJ. Complications of attempted central venous injections performed by drug abusers. Chest. 1980;78:613-7. 22. Geelhoed GW. The addict's angioaccess. Complications of exotic vascular injection sites. N Y State J Med. 1984;84:585-6. 23. Pace BW, Doscher W, Margolis IB. The femoral triangle: a potential death trap for the drug abuser. N Y State J Med. 1974;84:596-8. 24. Garriott JC, Sturner WQ. Morphine concentrations and survival periods in acute heroin fatalities. N Engl J Med. 1973; 289:1276-8. 25. Paranthaman SK, Khan F. Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdose. Chest. 1976;69:117-9. 26. Labi M. Paroxysmal atrial fibrillation in heroin intoxication. Ann Intern Med. 1969;71:951-9. 27. LipskiJ, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J. 1974; 86:663-8. 28. Huber DH. Heroin deaths--mystery or overdose? JAMA. 1974;229:689-90. 29. Kaufman RE, Levy SB. Overdose treatment: addict folklore and medical reality. JAMA. 1974;227:411-3. 30. Layon J, Idris A, Warzynski M, et al. Altered T-lymphocyte subsets in hospitalized intravenous drug abusers. Arch Intern Med. 1984;144:1376-80. 31. Hewlett D, Maayan S, Miller SN, et al. Reversal ofT cell helper/ suppressor ratios in intravenous drug abusers with nonopportunistic infections. J Infect Dis. 1985;15I:748-9. 32. Husby G, Pierce PE, Williams RC. Smooth muscle antibody in heroin addicts. Ann Intern Med. 1975;83:801-5. 33. McDonough RJ, MaddenJJ, FlaekA, et al. Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: in vivo evidence for opiate receptor sites on T lymphocytes. J Immunol. 1980;125:2539-43. 34. Brown SM, Stimmel B, Taub RN, Kochwa S, Rosenfield RE. Immunologic dysfunction in heroin addicts. Arch Intern Med. 1974;134:1001-6. 35. Savona S, Nardi MA, Lennette ET, Karpatkin S. Thrombocytopenic purpura in narcotics addicts. Ann Intern Med. 1985;102:737-41. 36. Ryan DH. heroin and thrombocytopenia. Ann Intern Med. 1979;90:852-3. 37. Geller SA, Stimmel B. Diagnostic confusion from lymphatic lesions in heroin addicts. Ann Intern Med. 1973;78:703-5. 38. DesJarlais DC, Friedman SR, Stoneburner RL. HIV infection and intravenous drug use: critical issues in transmission dynamics, infection outcomes, and prevention. Rev Infect Dis. 1988;10:151-8. 39. Tuazon CV, Hill R, Sheayren JN. Microbiologic study of street heroin and injection paraphernalia. J Infect Dis. 1974; 129:327-9. 40. Tuazon CU, Elin RJ. Endotoxin content of street heroin. Arch Intern Med. 1981;141:1385-6. 41. Spiro TE, Jaffe R, Holland PV, et al. A study of street heroin lots for the presence of the hepatitis B surface antigen. Drug Alcohol Dep. 1978;3:393-7. 42. Orangio GR, Della Latta P, Marino C, et al. Infections in parenteral drug abusers, further immunologic studies. Am J surg. 1983;146:738-41. 43. Orangio GR, Pitlick SD, Della Latta P, et al. Soft tissue infections in parenteral drug abusers. Ann Surg. 1984;199:97-100. 44. Saravolatz LD, Markowitz N, Arldng LM, Pohlod D, Fisher E.

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