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Miliary tuberculosis
CASE CONFERENCE
Miliary Tuberculosis Donald Levine, MD* Judith E. Tintinalli, MDt -editor Detroit, Michigan
Levine D, Tintinalli JE: Miliary tuberculosis. JACEP 8:485-489, November 1979.
tubercu/osis, mi/iary
INTRODUCTION The case for discussion today is t h a t of a y o u n g m a n with m i l i a r y tuberculosis (TB). The guest s p e a k e r is Donald Levine, MD, a s s i s t a n t professor of i n t e r n a l medicine and infectious disease at W a y n e S t a t e U n i v e r s i t y and D e t r o i t G e n e r a l Hospital. CASE REPORT J u d i t h T i n t i n a l l i , MD: The p a t i e n t is a 20-year-old m a n who came to t h e e m e r g e n c y d e p a r t m e n t b e c a u s e of a nosebleed of one day's d u r a t i o n . D a i l y episodes of epistaxis had occurred for two to t h r e e weeks. On f u r t h e r questioning, he complained of a chronic cough with production of yellow s p u t u m a n d occasional hemoptysis. S h o r t n e s s of b r e a t h at r e s t h a d been p r e s e n t for six months. There was a h i s t o r y of i n t e r m i t t e n t fever, anorexia, n a u s e a and vomiting, a n d a weight loss of 25 pounds in a year. He ingested about a p i n t of v o d k a a d a y for five or six years. H e took no medication and denied a h i s t o r y of d r u g abuse. His t e m p e r a t u r e was 39 C; pulse, 120 b e a t s / m i n and regular; r e s p i r a t i o n s , 24/min; and blood pressure, 130/80 m m Hg. H e ai~peared cachectic and malnourished. T h e r e were no cardiac m u r m u r s , rubs or gallops. Rales were p r e s e n t a t the left lung base with scattered rhonchi t h r o u g h o u t the chest. The a b d o m e n was soft without evidence of masses or organomegaly. T h e r e were no rectal m a s s e s and the stool g u a i a c was negative. His neck was supple, and m e n t a t i o n , coordination, motor, and sensory function were normal. There was no lymphadenopathy. The differential diagnosis a t this p o i n t was sepsis or p u l m o n a r y tuberculosiS. L a b o r a t o r y studies r e v e a l e d the following: hemoglobin, 14.8 gm/100 ml; white blood cell count, 4,800/cu ram; platelets, 22,000/cu ram; sodium, 132 mEq/ liter; potassium, 4.4 mEq/liter; chlorine, 96 mEq/liter; glucose, 102 rag/100 ml; blood u r e a nitrogen (BUN), 12 rag/100 ml; creatinine, 1.2 mg/100 ml; s e r u m g l u t a m i c o x a l a c e t i c t r a n s a m i n a s e e n z y m e (SGOT), 110 IU; a l k a l i n e phosp h a t a s e , 255 IU. The p r o t h r o m b i n t i m e was 15 seconds with a control of 12 seconds, and the p a r t i a l t h r o m b o p l a s t i n time was 23 seconds with a control of 20 seconds. A chest r a d i o g r a p h showed a diffuse r e t i c u l e - n o d u l a r infiltrate, and t h e s p u t u m was t e e m i n g with acid-fast organisms. The p a t i e n t was a d m i t t e d for t r e a t m e n t of tuberculosis w i t h isoniazid (INH), rifampin, and streptomycin. From the Department of Internal Medicine and Infectious Disease,* and the Section of Emergency Medicine,t Wayne State University School of Medicine, and the Emergency Department, Detroit General Hospital, Detroit, Michigan. Address for reprints: Judith E. Tintinalli, MD, Vice-chief, Emergency Department, Detroit General Hospital, 1326 St. Antoine, Detroit, Michigan 48226. 8:1 1 (November) 1979
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DISCUSSION D o n a l d Levine, MD: The complaints of chronic nosebleeds a n d cough, shortness of breath, weight loss, a n d i n t e r m i t t e n t f e v e r f o r m a c l a s s i c h i s t o r y for m i l i a r y or p u l m o n a r y TB. However, this h i s t o r y is also classic for a large n u m b e r of other diseases, which can m a k e tuberculosis difficult to diagnose. A p a t i e n t with o v e r w h e l m i n g m i l i a r y tuberculosis m a y not h a v e evidence of old TB on his chest radiograph. The pat i e n t with m i l i a r y TB will g e n e r a l l y have a history of tuberculosis, a l t h o u g h on occasion he m a y h a v e h a d p r i o r a s y m p t o m a t i c , u n d i a g n o s e d disease. I do not see a n y t h i n g on this p a t i e n t ' s x - r a y film (Figure) which w o u l d i n d i c a t e t h a t he h a d a p r e v i o u s p u l m o n a r y focus of TB, nor do I see a n y t h i n g in the history stating t h a t he h a d been t r e a t e d before for t h e disease. T h e r e are no a p p a r e n t cavities on the x-ray film. If a p a t i e n t p r e s e n t s with a history of previous TB, well t r e a t e d or not, the diagnosis of m i l i a r y tuberculosis cannot be excluded. This circumstance is less likely in the e r a of p a t i e n t s receiving isoniazid, b u t in p a t i e n t s who have received other modes of t h e r a p y it is q u i t e possible. The chest x-ray film shows a r e t i c u l o - n o d u l a r p u l m o n a r y i n f i l t r a t e t h a t is c o m p a t i b l e w i t h s a r coidosis, pneumoconiosis, and lymphoma, as well as p u l m o n a r y t u b e r c u l o s i s . T h e m e a n d u r a t i o n of s y m p t o m s in p a t i e n t s w i t h m i l i a r y TB is about 7 to 15 weeks. O u r p a t i e n t was sick for about six months (24 weeks), p e r h a p s i n d i c a t i n g a long incubation period. T h e n o s e b l e e d s w e r e p r o b a b l y d u e to t h r o m b o c y t o p e n i a a n d p o s s i b l y n a s a l t r a u m a . My f i r s t t h o u g h t was t h a t thrombocytopenia was due to tuberculosis i n v o l v e m e n t of t h e bone marrow. However, a 14 g m hemoglobin is too high to suggest m a r r o w involvement, even t h o u g h he was probably d e h y d r a t e d a n d this figure was falsely elevated. I suspect t h a t t h r o m b o c y t o p e n i a was due to alcohol, b e c a u s e t h e p l a t e l e t count s p o n t a n e o u s l y r e t u r n e d to n o r m a l during the first week of hospitalization. The word m i l i a r y refers to the m i l l e t seed sized lesions which h a v e s p r e a d from a focus t h r o u g h o u t t h e body, g e n e r a l l y affecting all organs. S p r e a d occurs from erosion of a pre-existing focus of p r i m a r y infection, which m a y not necessarily be in the lungs. T h e r e a r e a n u m b e r of routes by which t u b e r culosis can spread. The first, and commonest, is invasion by the o r g a n i s m from a visceral focus into the int i m a of vessels, followed by spread directly into the b l o o d s t r e a m . This g e n e r a l l y results in m a s s i v e and w i d e s p r e a d disease. A second p a t h is by erosion of a caseous l y m p h node directly into a blood vessel or into a l y m p h a t i c duct. F i n a l l y , a p u l m o n a r y focus m a y caseate and erode into a bronchial vessel, r e s u l t i n g in i n t e r b r o n c h i a l spread. M i l i a r y TB used to be a disease of the very young, but the age of those affected is g r a d u a l l y increasing. The a v e r a g e age in m e n now is around forty, a n d is going up. P r e g n a n t women, especially d u r i n g the imm e d i a t e p o s t p a r t u m or p r e p a r t u m periods, are also a h i g h r i s k group. Men a r e a b o u t twice as l i k e l y as w o m e n to g e t m i l i a r y TB. Blacks have a g r e a t l y inc r e a s e d s u s c e p t i b i l i t y to t h e disease. C h i l d r e n a r e more susceptible to m i l i a r y disease when convalescing from measles, whooping cough, or tonsillitis because t h e s e infections are well-known i m m u n e suppressants. Some o t h e r m a j o r t y p e s of i m m u n o - d e f i c i e n t s t a t e s t h a t predispose to any type of tuberculosis, including 72/486
F i g . Chest radiograph o f patient with miliary tuberculosis. There are no apparent cavities, but there is ~ evidence o f reticulo-nodular p u l m o n a r y infiltrate. m i l i a r y , are diabetes; previous gastrectomy; therapy w i t h i m m u n o s u p p r e s s a n t s , steroids, or antineoplastic agents; and neoplasia, especially l y m p h o r e t i c u l a r disorders. Alcoholism, chronic psychiatric disorders, and d r u g dependence are also common in a n y population w i t h tuberculosis. 1
Clinical Features There probably is no distinct p a t t e r n for m i l i a r y disease a n y more t h a n t h e r e is a distinct p a t t e r n for p u l m o n a r y tuberculosis. Classic textbooks m a y state t h a t m i l i a r y TB results in the death" of the p a t i e n t in from four to six weeks. I n t h e past, it was our opinion t h a t w i t h o u t t r e a t m e n t , a p a t i e n t would die within t h r e e m o n t h s from t h e t i m e of diagnosis. A wide range of d a t a indicate, however, t h a t m i l i a r y TB m a y actua l l y occur in two clinical forms: acute a n d chronic. The d a t a are difficult to i n t e r p r e t because h i s t o r i c a l l y it m a y be impossible to d e t e r m i n e w h e t h e r a p a t i e n t had slowly progressive p u l m o n a r y disease which resulted in h e m a t o g e n o u s d i s s e m i n a t i o n and t h e presentation of m i l i a r y TB, or w h e t h e r m i l i a r y disease was actually p r e s e n t all the t i m e in an indolent form. There is some evidence i n d i c a t i n g t h a t p a t i e n t s a d m i t t e d to t h e hosp i t a l with a n o r m a l chest r a d i o g r a p h who develop a m i l i a r y p a t t e r n on the x - r a y film w i t h i n two weeks h a v e a f u l m i n a n t course. As m a n y as 90% of patients with t r u e m i l i a r y TB will u l t i m a t e l y show t h e classic m i l i a r y p a t t e r n on chest x-ray, b u t only 50% will come into t h e hospital with t h a t p a t t e r n . The presence of a chronic tuberculosis focus, for i n s t a n c e in the kidney, lung, or epididymis, is g e n e r a l l y associated w i t h rapid onset and progression of disease. The commonest p r e s e n t i n g s y m p t o m , occurring in
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more than 90% of patients, is weakness followed by anorexia. Weight loss and fever are next in prominence; then cough, dyspnea, headache, a b d o m i n a l pain, and hemoptysis. 2-4 The presence of headache and abdominal pain is especially important. Almost all patients with headache have tuberculous meningitis, even when there is no nuchal rigidity, and abdominal pain often suggests TB peritonitis. 5-7 Two additional i m p o r t a n t signs a s s o c i a t e d w i t h m i l i a r y TB are tachycardia and tachypnea. G e n e r a l l y , the pulse r a t e is much f a s t e r t h a n would be expected for the degree of the fever. This patient had a temperature of 39 C, which is perhaps a little higher than is commonly seen in miliary disease. Generally, adventitious p u l m o n a r y sounds, u s u a l l y widespread rales, are present. The m a n n e r of sudden, u n e x p e c t e d d e a t h in miliary TB is often respiratory failure and arrest. Severe hypoxia may develop secondary to ventilationperfusion abnormalities and alveolar-capillary block. Hypocarbia may become hypercarbia as hypoventilation progresses. Consequently, the respiratory status must be monitored carefully. S p l e n o m e g a l y does not occur c o m m o n l y w i t h miliary disease, although when present it does not preclude the diagnosis. About 60% of patients have normal white counts. Of the other 40%, about half will have high white counts and, on occasion, a leukemoid reaction. In the old medical literature, many of these patients were thought to have acute leukemia. The other 20% have low white counts. 2 Anemia is present in at least half the patients, and in severe disease with marrow involvement, the complete blood count may even resemble t h a t of aplastic anemia. 2 The most outs t a n d i n g e x a m p l e of such a p a t i e n t was E l e a n o r Roosevelt, who was treated for aplastic anemia and at autopsy was found to have miliary TB. Q u e s t i o n : Do you often see TB pericarditis as a complication of miliary tuberculosis? Dr. L e v i n e : Interestingly enough, no. I suspect the reason is that the most common route of spread of disease into the pericardium in infectious pericarditis is through the pulmonary or endocardial lymphatics. M i l i a r y TB tends to s p r e a d by the h e m a t o g e n o u s route, s I was surprised to find when reviewing the literature on miliary TB t h a t pericarditis is not a commonly reported complication.9,1° Liver function studies, especially alkaline phosphatase, are abnormal in n e a r l y all patients. 2 The serum a l b u m i n g e n e r a l l y is only mildly decreased, while the prothrombin time is commonly increased. In a p a t i e n t who is also alcoholic, these liver abnormalities are more likely to be interpreted as alcohol related. H y p o n a t r e m i a due to inappropriate antidiuretic hormone (ADH) secretion is often seen in tuberculosis. 2 No one knows why this happens. It may occur because the lung sequesters antidiuretic hormone and then releases it with pulmonary damage; or because the lung secretes the hormone; or because the neurohypophysiS is involved. We have all probably heard that the PPD is usually negative in miliary disease. The PPD may indeed be initially negative, but more than 90% of patients with m i l i a r y TB will be positive at the second challenge, and 80% are positive within the first week.l~, TM Place a PPD as soon as you suspect the disease; if the first is negative, r e p e a t it. Somehow, a r e p e a t antigenic c h a l l e n g e can s t i m u l a t e t h e response. A1-
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though a positive PPD will never establish the diagnosis, it provides strong support. About 90% of patients develop the radiographic miliary pattern within two and a half weeks of diagnosis. 2 Sputum smear generally becomes positive about the third week. 2 The textbooks say that in classic miliary disease, the sputum smear is negative 'if pulmonary cavities are not present. That is probably true, but most commonly, prior pulmonary disease is present, so t h a t one t h i r d of cases will have positive sputums. Similarly, gastric washings are positive in about one third of cases. 13,14 If these simple procedures do not furnish the diagnosis, tissue biopsy is necessary. Generally, biopsy when you suspect clinical disease. For example, if the patient has ascites, TB peritonitis may be present, and peritoneal biopsy can be done. Spinal fluid and bone marrow culture, or lymph node or liver biopsy can be helpful. Liver biopsy probably has the highest yield. Bone marrow culture is not very helpful, although histology may be normal while cultures are still positive. Six weeks may be a long time to wait, though, to establish the diagnosis. Urine culture is positive in about a quarter of patients. 15 Cutaneous lesions occur with miliary TB and can serve as excellent sights for positive results on smear, biopsy, and culture, especially when they appear as chronic draining lesions. Skin lesions are vari a b l e , from a m a c u l a r r a s h to v e s i c u l a r lesions. Chronic draining skin lesions may develop secondary to an underlying abscess or osteomyelitis. The most common misdiagnosis is viral or bacterial pneumonia, followed by neoplastic diseases. Carcinomatosis, lymphosarcoma, lymphoma, pulmonary carcinoid, and l y m p h o m a with p u l m o n a r y involvem e n t are other common misdiagnoses. In p a t i e n t s with fever of unknown origin, about one third have infection, one third have carcinoma, and one t h i r d have collagen vascular diseases. Of those with an infection, about two thirds have tuberculosis. 2 There are several factors which may adversely affect the patient's outcome. Nonwhites have a worse prognosis t h a n whites. U n d e r l y i n g nontuberculous disease, such as lymphoma or diabetes, is a bad sign. A short s y m p t o m a t i c history, loss of bacteriologic diagnosis, minimal or absent temperature elevation on admission, or rapid defervescence are also poor prognostic factors. A hematocrit below 30%, indicating significant bone marrow involvement, is an adverse factor. Prompt bacteriologic response to chemotherapy without clinical evidence of improvement is also a poor prognostic factor. There are six factors which favorably affect the patient's outcome: three can be affected by the physician. Early patient presentation, a s y m p t o m a t i c meningitis, and lack of serious concomitant disease are factors one cannot change. Early and a c c u r a t e diagnosis, a d e q u a t e and a g g r e s s i v e c h e m o t h e r a p y , a n d good g e n e r a l s u p p o r t i v e care (primarily respiratory) are factors the physician can alter. This p a t i e n t was treated with INH, rifampin and streptomycin, a fairly standard regimen for miliary disease. INH and rifampin are probably more popular than INH and ethambutol for drug t r e a t m e n t of TB in general. 14 There are lots of theoretical reasons for this, but generally it has to do with the rapidity of conversion from an infectious to a noninfectious sputum. INH and rifampin are both bacteriocidal drugs, while ethambutol is a bacteriostatic agent. INH is a stand-
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p u l m o n a r y cavities? D r . L e v i n e : By t h e t i m e the p a t i e n t seeks treatment, he h a s probably been infectious for about six months. Since he has been infectious to his family, friends, and coworkers for this time, i t does not make sense to r u s h h i m into an isolation room. A t this point, he will be contagious to other p a t i e n t s a n d t h e hospital staff. Reliable people who h a v e been w o r k i n g can be m a n a g e d well a t h o m e until t h e y a r e no longer infectious. If t h e p a t i e n t is u n r e l i a b l e or a t r a n s i e n t who is c o n t i n u a l l y in contact with l a r g e a n d v a r y i n g numb e r s of people, h o s p i t a l i z a t i o n is necessary. Radiog. r a p h y , collection of u r i n e and s p u t u m samples, and g a s t r i c w a s h i n g s can all be performed on a n outpat i e n t basis. M a n y p a t i e n t s will no l o n g e r be infectious after two or t h r e e weeks of t r e a t m e n t . A t t h a t time, the s m e a r m a y be negative. E v e n w h e n positive , however, the p a t i e n t m a y not be infectious. The typical p a t i e n t m a y be off w o r k for a couple weeks, and if he feels and looks good, he can r e t u r n to work after only a b r i e f absence. Question: Should you t r e a t t h e p a t i e n t ' s family, even if t h e y have not converted from a n e g a t i v e to a positive skin test? Dr. L e v i n e : T h a t depends on t h e age. W i t h adults a n d older children, a PPD, if n e g a t i v e , should be rep e a t e d in t h r e e m o n t h s a n d n o t h i n g done in the meantime. If t h e y convert a t t h r e e months, work t h e m up for active disease. If t h e r e is no active disease, they should receive I N H prophylaxis. If t h e second PPD is negative, no t r e a t m e n t is necessary. If a child is six y e a r s old or younger, most would place a PPD and also begin prophylaxis. If t h e PPD is positive, investigate the child for active disease. If t h e r e is no active disease, continue the child on INH~for a year. If the PPD is negative, continue I N H and r e p e a t the PPD in three months. A t this time, if it is positive and t h e r e is no active disease, continue I N H so t h e child will receive a full y e a r of t r e a t m e n t . If the PPD is n e g a t i v e , the INH can be discontinued a t t h r e e months. 1~,ls-ls
a r d a g e n t unless t h e o r g a n i s m is r e s i s t a n t . A l l ant i t u b e r c u l o s i s drugs, except streptomycin, p e n e t r a t e t h e cerebrospinal fluid well, regardless of the presence or absence of m e n i n g e a l i n f l a m m a t i o n . Steroids proba b l y are of no benefit in the t r e a t m e n t of a s y m p t o m a t ic T B meningitis. In s y m p t o m a t i c m e n i n g i t i s t h e r e is some evidence t h a t steroids are beneficial. The use of a t h i r d drug, streptomycin, is r e c o m m e n d e d in most c u r r e n t reviews of t h e t r e a t m e n t of m i l i a r y TB. Generally, it is used for a period of two to t h r e e months. In t h e infectious disease division at D e t r o i t G e n e r a l Hosp i t a l we use a two- or t h r e e - d r u g regimen, depending on the clinical s t a t u s of the p a t i e n t and t h e n u m b e r of factors p r e s e n t which favor a good or b a d prognosis. W h i c h e v e r d r u g s a r e used, the t r e a t i n g p h y s i c i a n m u s t carefully m o n i t o r the p a t i e n t for signs of toxicity. I N H is associated with h e p a t o t o x i c i t y which usua l l y occurs d u r i n g t h e first 60 days of use, b u t can occur t h r o u g h o u t the course of t h e r a p y and m a y or m a y not be p r e c e d e d by symptoms. U n f o r t u n a t e l y , some p a t i e n t s develop extensive hepatic i n v o l v e m e n t from I N H and are a s y m p t o m a t i c . Most do not recomm e n d f r e q u e n t checking of t h e liver function studies as a routine, b u t leave t h a t issue to the discretion of the t r e a t i n g physician. 1s-is Certainly, it is n e c e s s a r y to a s k t h e p a t i e n t periodically if he has a n y s y m p t o m s of h e p a t i t i s , a n d you should specifically n a m e those s y m p t o m s : u n e x p l a i n e d anorexia, n a u s e a and vomiting, p e r s i s t e n t f a t i g u e or w e a k n e s s , d a r k u r i n e , icterus, or rash. Q u e s t i o n : How would you h a n d l e a p a t i e n t w i t h alcohol and liver disease who should receive I N H ? D r . L e O n e : E l e v a t i o n of s e r u m t r a n s a m i n a s e s occurs in 10% to 20% of p a t i e n t s on I N H . It can occur a n y t i m e , b u t is most common in the first four to six m o n t h s of t h e r a p y . T h e o l d e r t h e i n d i v i d u a l , t h e g r e a t e r t h e chance of I N H h e p a t i t i s , ls-19 Most a u t h o r i ties feel t h a t if the SGOT is less t h a n 3 times g r e a t e r t h a n t h e n o r m a l value, t r e a t m e n t of I N H can be init i a t e d or continued. I n i t i a t i o n of t h e r a p y m a y produce a t r a n s i e n t e l e v a t i o n of liver enzymes followed by a g r a d u a l decrease to normal. Mild enzyme e l e v a t i o n is g e n e r a l l y not a concern. If enzymes continue to rise, or if t h e SGOT is over 150, t h e n you are faced with a r e a l diagnostic d i l e m m a : alcoholic liver disease or INH. A t this point, most would stop the I N H and hope t h e enzyme levels decrease. If t h e y fall, t h e n you have to decide w h e t h e r to r e i n s t i t u t e t h e r a p y . P a t i e n t s who d e m o n s t r a t e i m p r o v e m e n t upon w i t h d r a w a l of t h e d r u g m a y , u p o n r e c h a l l e n g e , r e m a i n s t a b l e or det e r i o r a t e , some p a t i e n t s seriously. R e m e m b e r t h a t , in g e n e r a l , i t is t h e alcoholic p a t i e n t who gets TB. I don't fear the use of I N H in such a p a t i e n t . The developm e n t of h e p a t i t i s is uncommon, and t h e p a t i e n t is more l i k e l y to die of tuberculosis if left u n t r e a t e d . If t h e SGOT is only 50 or 100 IU, I would p r o b a b l y cont i n u e the I N H and r e p e a t enzymes weekly. If t h e y decrease, I relax; if t h e y continue to rise, I m o n i t o r the p a t i e n t m o r e closely a n d r e c o m m e n d t h a t he slow down his d r i n k i n g . Q u e s t i o n : W h a t are your c r i t e r i a for a d m i t t i n g a p a t i e n t with TB? Dr. L e v i n e : More a n d more p a t i e n t s are b e i n g t r e a t e d w h i l e a m b u l a t o r y . 13,1a The case t h a t n e e d s a d m i s s i o n is c l e a r l y t h e cachectic, febrile, s e v e r e l y s y m p t o m a t i c p a t i e n t , or one with a complication such as m e n i n g i t i s or peritonitis. Question: What about the patient with large
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REFERENCES 1. Reichman LB, Felton CP~ Edsall JR: Drug dependence, a possible new risk factor for tuberculosis disease. Arch Intern Med 139:337-339, 1979. 2. Munt PW: Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults. Medicine 50:139-155, 1971. 3. Gelb AF, Leffler C, Brewein A, et al: Miliary tuberculosis. A m Rev Respir Dis 408:1327-1333, 1973. 4. Castleman B (ed): Weekly CPC #51-1971, miliary tuberculosis. N E n g l J Med 285:1474-1480, 1971. 5. Borhanmanesh F, Hekmat K, Vaezzadeh K, et al: Tuberculous peritonitis. A n n Intern Med 76:567-572, 1972. 6. Cryer RE, Kissane J: Miliary tuberculosis. A m J Med 58:847-856, 1975. 7. Kennedy DH, Fallon RJ: Tuberculous meningitis. JAMA 241:264-268, 1979. 8. Ortbils DW, Avioli LV: Tuberculous pericarditis. Arch Intern Med 139:231-234, 1979. 9. Rooney JJ, Crocco JA, Lyons HA: Tuberculous pericarditis. A n n Intern Med 72:73-78, 1970. 10. Agner RC, Gallis HA: Pericarditis. Differential diagnostic considerations. Arch Intern Med 139:407-412, 1979. 11. Comstock GW, Furcolow ML, Greenberg RA, et al: The tuberculin skin test. A m Rev Respir Dis 104:769-775, 1971.
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12. Rooney J J , Crocco JA, K r a m e r S, et al: F u r t h e r observations on tuberculin reactions in active tuberculosis. A m J IVied 60:517-522, 1976. 13. Iseman MD, Bentz RR, Fraser RI, et ah Guidelines for the investigation and m a n a g e m e n t of tuberculosis contacts. A m Rev Respir Dis 114:459-463, 1976.
n a r y tuberculosis. A m J Med 63:410-420, 1977. 16. Center for Disease Control: Weekly Morbidity and Mortality Report. INH hepatitis. 23:97-98, 1974. 17. Barlow PB, Block M, B r u m m e r DL, et al: Preventive t h e r a p y of t u b e r c u l o u s i n f e c t i o n . A m Rev R e s p i r Dis 110:371-374, 1974.
14. J o h n s t o n RF, Wildrick KH: State of the a r t review. The impact of chemotherapy on the case of patients with tuberculosis. A m Rev Respir Dis 109:636-664, 1974.
18. Center for Disease Control: Weekly Morbidity and Mortality Report. Preventive therapy of tuberculosis infection. 24:71-78, 1975.
15. Simon HB, Weinstein AJ, P a s t e r n a k MS, et al: Genitouriinary tuberculosis. A m J Med 63:410-420, 1977.
19. Maddrey WC, Boitnott JK: Isoniazid hepatitis. Ann Intern Med 79:1-12, 1973.
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Miliary Tuberculosis Donald Levine, MD* Judith E. Tintinalli, MDt -editor Detroit, Michigan
Levine D, Tintinalli JE: Miliary tuberculosis. JACEP 8:485-489, November 1979.
tubercu/osis, mi/iary
INTRODUCTION The case for discussion today is t h a t of a y o u n g m a n with m i l i a r y tuberculosis (TB). The guest s p e a k e r is Donald Levine, MD, a s s i s t a n t professor of i n t e r n a l medicine and infectious disease at W a y n e S t a t e U n i v e r s i t y and D e t r o i t G e n e r a l Hospital. CASE REPORT J u d i t h T i n t i n a l l i , MD: The p a t i e n t is a 20-year-old m a n who came to t h e e m e r g e n c y d e p a r t m e n t b e c a u s e of a nosebleed of one day's d u r a t i o n . D a i l y episodes of epistaxis had occurred for two to t h r e e weeks. On f u r t h e r questioning, he complained of a chronic cough with production of yellow s p u t u m a n d occasional hemoptysis. S h o r t n e s s of b r e a t h at r e s t h a d been p r e s e n t for six months. There was a h i s t o r y of i n t e r m i t t e n t fever, anorexia, n a u s e a and vomiting, a n d a weight loss of 25 pounds in a year. He ingested about a p i n t of v o d k a a d a y for five or six years. H e took no medication and denied a h i s t o r y of d r u g abuse. His t e m p e r a t u r e was 39 C; pulse, 120 b e a t s / m i n and regular; r e s p i r a t i o n s , 24/min; and blood pressure, 130/80 m m Hg. H e ai~peared cachectic and malnourished. T h e r e were no cardiac m u r m u r s , rubs or gallops. Rales were p r e s e n t a t the left lung base with scattered rhonchi t h r o u g h o u t the chest. The a b d o m e n was soft without evidence of masses or organomegaly. T h e r e were no rectal m a s s e s and the stool g u a i a c was negative. His neck was supple, and m e n t a t i o n , coordination, motor, and sensory function were normal. There was no lymphadenopathy. The differential diagnosis a t this p o i n t was sepsis or p u l m o n a r y tuberculosiS. L a b o r a t o r y studies r e v e a l e d the following: hemoglobin, 14.8 gm/100 ml; white blood cell count, 4,800/cu ram; platelets, 22,000/cu ram; sodium, 132 mEq/ liter; potassium, 4.4 mEq/liter; chlorine, 96 mEq/liter; glucose, 102 rag/100 ml; blood u r e a nitrogen (BUN), 12 rag/100 ml; creatinine, 1.2 mg/100 ml; s e r u m g l u t a m i c o x a l a c e t i c t r a n s a m i n a s e e n z y m e (SGOT), 110 IU; a l k a l i n e phosp h a t a s e , 255 IU. The p r o t h r o m b i n t i m e was 15 seconds with a control of 12 seconds, and the p a r t i a l t h r o m b o p l a s t i n time was 23 seconds with a control of 20 seconds. A chest r a d i o g r a p h showed a diffuse r e t i c u l e - n o d u l a r infiltrate, and t h e s p u t u m was t e e m i n g with acid-fast organisms. The p a t i e n t was a d m i t t e d for t r e a t m e n t of tuberculosis w i t h isoniazid (INH), rifampin, and streptomycin. From the Department of Internal Medicine and Infectious Disease,* and the Section of Emergency Medicine,t Wayne State University School of Medicine, and the Emergency Department, Detroit General Hospital, Detroit, Michigan. Address for reprints: Judith E. Tintinalli, MD, Vice-chief, Emergency Department, Detroit General Hospital, 1326 St. Antoine, Detroit, Michigan 48226. 8:1 1 (November) 1979
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DISCUSSION D o n a l d Levine, MD: The complaints of chronic nosebleeds a n d cough, shortness of breath, weight loss, a n d i n t e r m i t t e n t f e v e r f o r m a c l a s s i c h i s t o r y for m i l i a r y or p u l m o n a r y TB. However, this h i s t o r y is also classic for a large n u m b e r of other diseases, which can m a k e tuberculosis difficult to diagnose. A p a t i e n t with o v e r w h e l m i n g m i l i a r y tuberculosis m a y not h a v e evidence of old TB on his chest radiograph. The pat i e n t with m i l i a r y TB will g e n e r a l l y have a history of tuberculosis, a l t h o u g h on occasion he m a y h a v e h a d p r i o r a s y m p t o m a t i c , u n d i a g n o s e d disease. I do not see a n y t h i n g on this p a t i e n t ' s x - r a y film (Figure) which w o u l d i n d i c a t e t h a t he h a d a p r e v i o u s p u l m o n a r y focus of TB, nor do I see a n y t h i n g in the history stating t h a t he h a d been t r e a t e d before for t h e disease. T h e r e are no a p p a r e n t cavities on the x-ray film. If a p a t i e n t p r e s e n t s with a history of previous TB, well t r e a t e d or not, the diagnosis of m i l i a r y tuberculosis cannot be excluded. This circumstance is less likely in the e r a of p a t i e n t s receiving isoniazid, b u t in p a t i e n t s who have received other modes of t h e r a p y it is q u i t e possible. The chest x-ray film shows a r e t i c u l o - n o d u l a r p u l m o n a r y i n f i l t r a t e t h a t is c o m p a t i b l e w i t h s a r coidosis, pneumoconiosis, and lymphoma, as well as p u l m o n a r y t u b e r c u l o s i s . T h e m e a n d u r a t i o n of s y m p t o m s in p a t i e n t s w i t h m i l i a r y TB is about 7 to 15 weeks. O u r p a t i e n t was sick for about six months (24 weeks), p e r h a p s i n d i c a t i n g a long incubation period. T h e n o s e b l e e d s w e r e p r o b a b l y d u e to t h r o m b o c y t o p e n i a a n d p o s s i b l y n a s a l t r a u m a . My f i r s t t h o u g h t was t h a t thrombocytopenia was due to tuberculosis i n v o l v e m e n t of t h e bone marrow. However, a 14 g m hemoglobin is too high to suggest m a r r o w involvement, even t h o u g h he was probably d e h y d r a t e d a n d this figure was falsely elevated. I suspect t h a t t h r o m b o c y t o p e n i a was due to alcohol, b e c a u s e t h e p l a t e l e t count s p o n t a n e o u s l y r e t u r n e d to n o r m a l during the first week of hospitalization. The word m i l i a r y refers to the m i l l e t seed sized lesions which h a v e s p r e a d from a focus t h r o u g h o u t t h e body, g e n e r a l l y affecting all organs. S p r e a d occurs from erosion of a pre-existing focus of p r i m a r y infection, which m a y not necessarily be in the lungs. T h e r e a r e a n u m b e r of routes by which t u b e r culosis can spread. The first, and commonest, is invasion by the o r g a n i s m from a visceral focus into the int i m a of vessels, followed by spread directly into the b l o o d s t r e a m . This g e n e r a l l y results in m a s s i v e and w i d e s p r e a d disease. A second p a t h is by erosion of a caseous l y m p h node directly into a blood vessel or into a l y m p h a t i c duct. F i n a l l y , a p u l m o n a r y focus m a y caseate and erode into a bronchial vessel, r e s u l t i n g in i n t e r b r o n c h i a l spread. M i l i a r y TB used to be a disease of the very young, but the age of those affected is g r a d u a l l y increasing. The a v e r a g e age in m e n now is around forty, a n d is going up. P r e g n a n t women, especially d u r i n g the imm e d i a t e p o s t p a r t u m or p r e p a r t u m periods, are also a h i g h r i s k group. Men a r e a b o u t twice as l i k e l y as w o m e n to g e t m i l i a r y TB. Blacks have a g r e a t l y inc r e a s e d s u s c e p t i b i l i t y to t h e disease. C h i l d r e n a r e more susceptible to m i l i a r y disease when convalescing from measles, whooping cough, or tonsillitis because t h e s e infections are well-known i m m u n e suppressants. Some o t h e r m a j o r t y p e s of i m m u n o - d e f i c i e n t s t a t e s t h a t predispose to any type of tuberculosis, including 72/486
F i g . Chest radiograph o f patient with miliary tuberculosis. There are no apparent cavities, but there is ~ evidence o f reticulo-nodular p u l m o n a r y infiltrate. m i l i a r y , are diabetes; previous gastrectomy; therapy w i t h i m m u n o s u p p r e s s a n t s , steroids, or antineoplastic agents; and neoplasia, especially l y m p h o r e t i c u l a r disorders. Alcoholism, chronic psychiatric disorders, and d r u g dependence are also common in a n y population w i t h tuberculosis. 1
Clinical Features There probably is no distinct p a t t e r n for m i l i a r y disease a n y more t h a n t h e r e is a distinct p a t t e r n for p u l m o n a r y tuberculosis. Classic textbooks m a y state t h a t m i l i a r y TB results in the death" of the p a t i e n t in from four to six weeks. I n t h e past, it was our opinion t h a t w i t h o u t t r e a t m e n t , a p a t i e n t would die within t h r e e m o n t h s from t h e t i m e of diagnosis. A wide range of d a t a indicate, however, t h a t m i l i a r y TB m a y actua l l y occur in two clinical forms: acute a n d chronic. The d a t a are difficult to i n t e r p r e t because h i s t o r i c a l l y it m a y be impossible to d e t e r m i n e w h e t h e r a p a t i e n t had slowly progressive p u l m o n a r y disease which resulted in h e m a t o g e n o u s d i s s e m i n a t i o n and t h e presentation of m i l i a r y TB, or w h e t h e r m i l i a r y disease was actually p r e s e n t all the t i m e in an indolent form. There is some evidence i n d i c a t i n g t h a t p a t i e n t s a d m i t t e d to t h e hosp i t a l with a n o r m a l chest r a d i o g r a p h who develop a m i l i a r y p a t t e r n on the x - r a y film w i t h i n two weeks h a v e a f u l m i n a n t course. As m a n y as 90% of patients with t r u e m i l i a r y TB will u l t i m a t e l y show t h e classic m i l i a r y p a t t e r n on chest x-ray, b u t only 50% will come into t h e hospital with t h a t p a t t e r n . The presence of a chronic tuberculosis focus, for i n s t a n c e in the kidney, lung, or epididymis, is g e n e r a l l y associated w i t h rapid onset and progression of disease. The commonest p r e s e n t i n g s y m p t o m , occurring in
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more than 90% of patients, is weakness followed by anorexia. Weight loss and fever are next in prominence; then cough, dyspnea, headache, a b d o m i n a l pain, and hemoptysis. 2-4 The presence of headache and abdominal pain is especially important. Almost all patients with headache have tuberculous meningitis, even when there is no nuchal rigidity, and abdominal pain often suggests TB peritonitis. 5-7 Two additional i m p o r t a n t signs a s s o c i a t e d w i t h m i l i a r y TB are tachycardia and tachypnea. G e n e r a l l y , the pulse r a t e is much f a s t e r t h a n would be expected for the degree of the fever. This patient had a temperature of 39 C, which is perhaps a little higher than is commonly seen in miliary disease. Generally, adventitious p u l m o n a r y sounds, u s u a l l y widespread rales, are present. The m a n n e r of sudden, u n e x p e c t e d d e a t h in miliary TB is often respiratory failure and arrest. Severe hypoxia may develop secondary to ventilationperfusion abnormalities and alveolar-capillary block. Hypocarbia may become hypercarbia as hypoventilation progresses. Consequently, the respiratory status must be monitored carefully. S p l e n o m e g a l y does not occur c o m m o n l y w i t h miliary disease, although when present it does not preclude the diagnosis. About 60% of patients have normal white counts. Of the other 40%, about half will have high white counts and, on occasion, a leukemoid reaction. In the old medical literature, many of these patients were thought to have acute leukemia. The other 20% have low white counts. 2 Anemia is present in at least half the patients, and in severe disease with marrow involvement, the complete blood count may even resemble t h a t of aplastic anemia. 2 The most outs t a n d i n g e x a m p l e of such a p a t i e n t was E l e a n o r Roosevelt, who was treated for aplastic anemia and at autopsy was found to have miliary TB. Q u e s t i o n : Do you often see TB pericarditis as a complication of miliary tuberculosis? Dr. L e v i n e : Interestingly enough, no. I suspect the reason is that the most common route of spread of disease into the pericardium in infectious pericarditis is through the pulmonary or endocardial lymphatics. M i l i a r y TB tends to s p r e a d by the h e m a t o g e n o u s route, s I was surprised to find when reviewing the literature on miliary TB t h a t pericarditis is not a commonly reported complication.9,1° Liver function studies, especially alkaline phosphatase, are abnormal in n e a r l y all patients. 2 The serum a l b u m i n g e n e r a l l y is only mildly decreased, while the prothrombin time is commonly increased. In a p a t i e n t who is also alcoholic, these liver abnormalities are more likely to be interpreted as alcohol related. H y p o n a t r e m i a due to inappropriate antidiuretic hormone (ADH) secretion is often seen in tuberculosis. 2 No one knows why this happens. It may occur because the lung sequesters antidiuretic hormone and then releases it with pulmonary damage; or because the lung secretes the hormone; or because the neurohypophysiS is involved. We have all probably heard that the PPD is usually negative in miliary disease. The PPD may indeed be initially negative, but more than 90% of patients with m i l i a r y TB will be positive at the second challenge, and 80% are positive within the first week.l~, TM Place a PPD as soon as you suspect the disease; if the first is negative, r e p e a t it. Somehow, a r e p e a t antigenic c h a l l e n g e can s t i m u l a t e t h e response. A1-
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though a positive PPD will never establish the diagnosis, it provides strong support. About 90% of patients develop the radiographic miliary pattern within two and a half weeks of diagnosis. 2 Sputum smear generally becomes positive about the third week. 2 The textbooks say that in classic miliary disease, the sputum smear is negative 'if pulmonary cavities are not present. That is probably true, but most commonly, prior pulmonary disease is present, so t h a t one t h i r d of cases will have positive sputums. Similarly, gastric washings are positive in about one third of cases. 13,14 If these simple procedures do not furnish the diagnosis, tissue biopsy is necessary. Generally, biopsy when you suspect clinical disease. For example, if the patient has ascites, TB peritonitis may be present, and peritoneal biopsy can be done. Spinal fluid and bone marrow culture, or lymph node or liver biopsy can be helpful. Liver biopsy probably has the highest yield. Bone marrow culture is not very helpful, although histology may be normal while cultures are still positive. Six weeks may be a long time to wait, though, to establish the diagnosis. Urine culture is positive in about a quarter of patients. 15 Cutaneous lesions occur with miliary TB and can serve as excellent sights for positive results on smear, biopsy, and culture, especially when they appear as chronic draining lesions. Skin lesions are vari a b l e , from a m a c u l a r r a s h to v e s i c u l a r lesions. Chronic draining skin lesions may develop secondary to an underlying abscess or osteomyelitis. The most common misdiagnosis is viral or bacterial pneumonia, followed by neoplastic diseases. Carcinomatosis, lymphosarcoma, lymphoma, pulmonary carcinoid, and l y m p h o m a with p u l m o n a r y involvem e n t are other common misdiagnoses. In p a t i e n t s with fever of unknown origin, about one third have infection, one third have carcinoma, and one t h i r d have collagen vascular diseases. Of those with an infection, about two thirds have tuberculosis. 2 There are several factors which may adversely affect the patient's outcome. Nonwhites have a worse prognosis t h a n whites. U n d e r l y i n g nontuberculous disease, such as lymphoma or diabetes, is a bad sign. A short s y m p t o m a t i c history, loss of bacteriologic diagnosis, minimal or absent temperature elevation on admission, or rapid defervescence are also poor prognostic factors. A hematocrit below 30%, indicating significant bone marrow involvement, is an adverse factor. Prompt bacteriologic response to chemotherapy without clinical evidence of improvement is also a poor prognostic factor. There are six factors which favorably affect the patient's outcome: three can be affected by the physician. Early patient presentation, a s y m p t o m a t i c meningitis, and lack of serious concomitant disease are factors one cannot change. Early and a c c u r a t e diagnosis, a d e q u a t e and a g g r e s s i v e c h e m o t h e r a p y , a n d good g e n e r a l s u p p o r t i v e care (primarily respiratory) are factors the physician can alter. This p a t i e n t was treated with INH, rifampin and streptomycin, a fairly standard regimen for miliary disease. INH and rifampin are probably more popular than INH and ethambutol for drug t r e a t m e n t of TB in general. 14 There are lots of theoretical reasons for this, but generally it has to do with the rapidity of conversion from an infectious to a noninfectious sputum. INH and rifampin are both bacteriocidal drugs, while ethambutol is a bacteriostatic agent. INH is a stand-
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p u l m o n a r y cavities? D r . L e v i n e : By t h e t i m e the p a t i e n t seeks treatment, he h a s probably been infectious for about six months. Since he has been infectious to his family, friends, and coworkers for this time, i t does not make sense to r u s h h i m into an isolation room. A t this point, he will be contagious to other p a t i e n t s a n d t h e hospital staff. Reliable people who h a v e been w o r k i n g can be m a n a g e d well a t h o m e until t h e y a r e no longer infectious. If t h e p a t i e n t is u n r e l i a b l e or a t r a n s i e n t who is c o n t i n u a l l y in contact with l a r g e a n d v a r y i n g numb e r s of people, h o s p i t a l i z a t i o n is necessary. Radiog. r a p h y , collection of u r i n e and s p u t u m samples, and g a s t r i c w a s h i n g s can all be performed on a n outpat i e n t basis. M a n y p a t i e n t s will no l o n g e r be infectious after two or t h r e e weeks of t r e a t m e n t . A t t h a t time, the s m e a r m a y be negative. E v e n w h e n positive , however, the p a t i e n t m a y not be infectious. The typical p a t i e n t m a y be off w o r k for a couple weeks, and if he feels and looks good, he can r e t u r n to work after only a b r i e f absence. Question: Should you t r e a t t h e p a t i e n t ' s family, even if t h e y have not converted from a n e g a t i v e to a positive skin test? Dr. L e v i n e : T h a t depends on t h e age. W i t h adults a n d older children, a PPD, if n e g a t i v e , should be rep e a t e d in t h r e e m o n t h s a n d n o t h i n g done in the meantime. If t h e y convert a t t h r e e months, work t h e m up for active disease. If t h e r e is no active disease, they should receive I N H prophylaxis. If t h e second PPD is negative, no t r e a t m e n t is necessary. If a child is six y e a r s old or younger, most would place a PPD and also begin prophylaxis. If t h e PPD is positive, investigate the child for active disease. If t h e r e is no active disease, continue the child on INH~for a year. If the PPD is negative, continue I N H and r e p e a t the PPD in three months. A t this time, if it is positive and t h e r e is no active disease, continue I N H so t h e child will receive a full y e a r of t r e a t m e n t . If the PPD is n e g a t i v e , the INH can be discontinued a t t h r e e months. 1~,ls-ls
a r d a g e n t unless t h e o r g a n i s m is r e s i s t a n t . A l l ant i t u b e r c u l o s i s drugs, except streptomycin, p e n e t r a t e t h e cerebrospinal fluid well, regardless of the presence or absence of m e n i n g e a l i n f l a m m a t i o n . Steroids proba b l y are of no benefit in the t r e a t m e n t of a s y m p t o m a t ic T B meningitis. In s y m p t o m a t i c m e n i n g i t i s t h e r e is some evidence t h a t steroids are beneficial. The use of a t h i r d drug, streptomycin, is r e c o m m e n d e d in most c u r r e n t reviews of t h e t r e a t m e n t of m i l i a r y TB. Generally, it is used for a period of two to t h r e e months. In t h e infectious disease division at D e t r o i t G e n e r a l Hosp i t a l we use a two- or t h r e e - d r u g regimen, depending on the clinical s t a t u s of the p a t i e n t and t h e n u m b e r of factors p r e s e n t which favor a good or b a d prognosis. W h i c h e v e r d r u g s a r e used, the t r e a t i n g p h y s i c i a n m u s t carefully m o n i t o r the p a t i e n t for signs of toxicity. I N H is associated with h e p a t o t o x i c i t y which usua l l y occurs d u r i n g t h e first 60 days of use, b u t can occur t h r o u g h o u t the course of t h e r a p y and m a y or m a y not be p r e c e d e d by symptoms. U n f o r t u n a t e l y , some p a t i e n t s develop extensive hepatic i n v o l v e m e n t from I N H and are a s y m p t o m a t i c . Most do not recomm e n d f r e q u e n t checking of t h e liver function studies as a routine, b u t leave t h a t issue to the discretion of the t r e a t i n g physician. 1s-is Certainly, it is n e c e s s a r y to a s k t h e p a t i e n t periodically if he has a n y s y m p t o m s of h e p a t i t i s , a n d you should specifically n a m e those s y m p t o m s : u n e x p l a i n e d anorexia, n a u s e a and vomiting, p e r s i s t e n t f a t i g u e or w e a k n e s s , d a r k u r i n e , icterus, or rash. Q u e s t i o n : How would you h a n d l e a p a t i e n t w i t h alcohol and liver disease who should receive I N H ? D r . L e O n e : E l e v a t i o n of s e r u m t r a n s a m i n a s e s occurs in 10% to 20% of p a t i e n t s on I N H . It can occur a n y t i m e , b u t is most common in the first four to six m o n t h s of t h e r a p y . T h e o l d e r t h e i n d i v i d u a l , t h e g r e a t e r t h e chance of I N H h e p a t i t i s , ls-19 Most a u t h o r i ties feel t h a t if the SGOT is less t h a n 3 times g r e a t e r t h a n t h e n o r m a l value, t r e a t m e n t of I N H can be init i a t e d or continued. I n i t i a t i o n of t h e r a p y m a y produce a t r a n s i e n t e l e v a t i o n of liver enzymes followed by a g r a d u a l decrease to normal. Mild enzyme e l e v a t i o n is g e n e r a l l y not a concern. If enzymes continue to rise, or if t h e SGOT is over 150, t h e n you are faced with a r e a l diagnostic d i l e m m a : alcoholic liver disease or INH. A t this point, most would stop the I N H and hope t h e enzyme levels decrease. If t h e y fall, t h e n you have to decide w h e t h e r to r e i n s t i t u t e t h e r a p y . P a t i e n t s who d e m o n s t r a t e i m p r o v e m e n t upon w i t h d r a w a l of t h e d r u g m a y , u p o n r e c h a l l e n g e , r e m a i n s t a b l e or det e r i o r a t e , some p a t i e n t s seriously. R e m e m b e r t h a t , in g e n e r a l , i t is t h e alcoholic p a t i e n t who gets TB. I don't fear the use of I N H in such a p a t i e n t . The developm e n t of h e p a t i t i s is uncommon, and t h e p a t i e n t is more l i k e l y to die of tuberculosis if left u n t r e a t e d . If t h e SGOT is only 50 or 100 IU, I would p r o b a b l y cont i n u e the I N H and r e p e a t enzymes weekly. If t h e y decrease, I relax; if t h e y continue to rise, I m o n i t o r the p a t i e n t m o r e closely a n d r e c o m m e n d t h a t he slow down his d r i n k i n g . Q u e s t i o n : W h a t are your c r i t e r i a for a d m i t t i n g a p a t i e n t with TB? Dr. L e v i n e : More a n d more p a t i e n t s are b e i n g t r e a t e d w h i l e a m b u l a t o r y . 13,1a The case t h a t n e e d s a d m i s s i o n is c l e a r l y t h e cachectic, febrile, s e v e r e l y s y m p t o m a t i c p a t i e n t , or one with a complication such as m e n i n g i t i s or peritonitis. Question: What about the patient with large
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12. Rooney J J , Crocco JA, K r a m e r S, et al: F u r t h e r observations on tuberculin reactions in active tuberculosis. A m J IVied 60:517-522, 1976. 13. Iseman MD, Bentz RR, Fraser RI, et ah Guidelines for the investigation and m a n a g e m e n t of tuberculosis contacts. A m Rev Respir Dis 114:459-463, 1976.
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14. J o h n s t o n RF, Wildrick KH: State of the a r t review. The impact of chemotherapy on the case of patients with tuberculosis. A m Rev Respir Dis 109:636-664, 1974.
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