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Death Associated With Rifampin and Pyrazinamide 2-Month Treatment of Latent Mycobacterium Tuberculosis* Ann Medinger, MD, FCCP We present the case of an elderly patient who died of fulminant hepatic failure in the course of receiving 2 months of treatment with pyrazinamide and rifampin for his latent tuberculosis. This 2-month course of treatment for latent tuberculosis is one of four options recently recommended by the Centers for Disease Control and Prevention. We discuss the safety of using this two-drug regimen to treat latent tuberculosis in stable elderly patients. (CHEST 2002; 121:1710 –1712) Key words: drug toxicity; latent tuberculosis treatment; Mycobacterium tuberculosis; pyrazinamide; rifampin Abbreviation: CDC ⫽ Centers for Disease Control and Prevention his elderly patient with latent tuberculosis died of T fulminant hepatic failure in the course of receiving 2 months of treatment with pyrazinamide and rifampin. Case Report The patient was a 68-year-old, male, home health aid, who was admitted to the Washington, DC, Veterans Affairs Medical Center in June 2001 with a history of three days of nausea and malaise. His history included alcohol abuse, hepatic steatosis revealed by liver biopsy 5 years prior, diabetes mellitus, hypertension, gout, and a positive tuberculin skin test of long standing. Two months prior to hospital admission, the patient had requested antituberculous medication because he wanted to avoid the continuing requirement for an annual chest radiograph. His employer required positive tuberculin reactors to provide a physician’s certification of freedom from active tuberculosis. The common physician requirement that such patients have a normal current chest radiograph to be certified is usually waived after a course of antituberculous treatment. Urged by the patient and supported by the 2000 Centers for Disease Control and Prevention (CDC) guidelines1 for the treatment of latent tuberculosis, the physician agreed to prescribe preventive therapy. On March 29, treatment was initiated with pyrazinamide and rifampin, for a 2-month course. On April 13, the results of follow-up liver function testing were normal. On May 25, the patient reported feeling well at a clinical nutritionist appointment for the management of his diabetes. However, on May 28, he reported to the emergency department feeling ill. The patient had abstained from alcohol consumption for at least 5 years since *From the Department of Veterans Affairs Medical Center, Washington, DC. Manuscript received July 10, 2001; revision accepted October 4, 2001. Correspondence to: Ann Medinger, MD, FCCP, 5605 Park St, Chevy Chase, MD 20815-3404; e-mail: medingerbeeny@ erols.com receiving abnormal results from his liver biopsy specimen testing. His medications included the following: aspirin; colchicine; ibuprofen; lisinopril; metformin; pyrazinamide, 2 g qd; and rifampin, 600 mg qd. On physical examination, the following measurements were obtained: BP, 128/36 mm Hg; body temperature, 34.8°C; heart rate, 89 beats/min; respiratory rate, 26 breaths/min; and body weight, 101.8 kg. The patient was an obese, lethargic, elderly African-American man, who was confused and disoriented. He had icteric sclerae and asterixis but no stigmata of chronic liver disease. A chest examination revealed rales at the right base, and the findings of a cardiac examination were normal. His abdomen was protuberant and nontender, with normal bowel sounds. A rectal examination revealed brown heme-positive stool. The patient’s extremities had no edema, clubbing, bruises, muscle atrophy, or fasciculations. A neurologic examination showed encephalopathy and was otherwise nonfocal. His chest radiograph was clear. An abdominal sonogram showed ascites and a fatty liver, and was negative for biliary or urinary tract obstructions. Table 1 shows the sequential laboratory measurements for this patient. The patient received the following supportive care: IV fluids, including fluid containing 20% dextrose in water with additional fluid containing 50% dextrose in water, for recurrent hypoglycemia; blood products for GI bleeding; enteral lactulose plus neomycin for encephalopathy; IV dopamine first for renal perfusion and then for BP support. He received empiric broad-spectrum, renal-friendly antibiotics. On the second hospital day, he became comatose and anuric. He was intubated and required mechanical ventilation. He never regained consciousness, and his hepatic function continued to deteriorate. A liver transplantation was denied, and the patient died on the third hospital day. Discussion This elderly asymptomatic individual developed fulminant hepatic necrosis, rhabdomyolysis, and acute renal failure, and he died within 3 days of reporting symptoms of illness. One can infer from the fact that he had been stable prior to pyrazinamide and rifampin therapy, that the newly added medications probably caused or precipitated his demise. However, it is possible that his liver failure was due to another cause. Although his liver function measurements were within normal units, he had past biopsyproven hepatic steatosis. He was also taking other medications with potential hepatotoxicity, and, as an elderly gentleman living alone, he may have had an additional toxic exposure that was not reported or detected. His risk factors for complications of treatment (ie, history of liver disease, polypharmacy, and advanced age) may have enhanced the toxicity of the pyrazinamide and rifampin. The case underscores the importance of frequent monitoring of liver function in patients receiving this treatment. It also raises questions about the merits of treating asymptomatic elderly patients for latent tuberculosis. The CDC has reported two similar cases of severe hepatitis in individuals who were ⬎ 50 years of age and who were taking pyrazinamide and rifampin for latent tuberculosis.2 Reports within the last 5 years in the European and Japanese literature have noted an increase in the incidence of hepatotoxicity with the simultaneous 1710 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21977/ on 06/18/2017 Selected Reports Table 1—Sequential Laboratory Measurements in the Case Reported* Measurement Dates Tests 5/31/01 WBC, cells/L† HGB, g/dL MCV, mL PLT, cells/L† Glucose, mg/dL BUN, mg/dL Creatine, mg/dL NA, mmol/L Potassium, mmol/L CL, mmol/L CO2, mmol/L Protein, g/dL Albumin, g/dL AP, mU/mL‡ AST/GOT, mU/mL‡ ALA/GPT, mU/mL‡ T Bil, mg/dL D Bil, mg/dL NH3, mol/L Lactate, mmol/L CPK, U/L‡ INR 9.2 10.6 81.6 165 42 56 11 139 4.8 107 11 6.4 2 207 2,720 1,930 19.2 12.6 181 9.4 10.1 5/28/01 417 39 5.4 139 6.5 110 8 5.9 2.1 175 758 620 16.7 9.2 135 13.2 9,130 6 4/13/01 8.5 4.0 63 33 31 0.5 3/29/01 3/16/00 Reference Values 1.0 3.2–9.5 13.2–17.3 80.2–96.7 152–375 70–121 6–23 0.7–1.5 135–147 3.5–5.3 100–109 21–31 6–8.2 3.7–5 43–130 8–40 8–45 0.2–1.2 0–0.2 11–35 0.6–2.2 20–300 1.0 6.1 12.6 80 249 163 13 1.3 141 3.8 101 26 8.3 3.7 66 39 48 0.5 0.1 *Urine tests were positive for myoglobin without cells or casts. Urine tests were negative for eosinophils, blood acetaminophen, alcohol, viral hepatitis, and alphafetoprotein. HGB ⫽ hemoglobin; MCV ⫽ mean corpuscular volume; NA ⫽ sodium; AP ⫽ alkaline phosphatase; AST/ GOT ⫽ aspartate aminotransferase/glutamic-oxaloacetic transaminase; ALA/GPT ⫽ -aminolevulinic acid/glutamic-pyruvic transaminase; CPK ⫽ creatine phosphokinase; INR ⫽ international normalized ratio; PLT ⫽ platelet count; CL ⫽ chloride concentration; T Bil ⫽ total bilirubin; D Bil ⫽ direct bilirubin. †Cells signifies thousands of cells. ‡Measurement made at 37°C. administration of isoniazid, pyrazinamide, and rifampin. One Barcelona institution reported five cases in 1 year resulting in three deaths.3 The risk/benefit ratio of treating healthy patients for latent tuberculosis with potentially toxic drugs has been discussed in the past.4 Individuals who are not immunedeficient have a ⬍ 1 in 20 chance of developing active tuberculosis after the second year of stable latency. The risk of toxicity from antituberculous drugs increases with age and with the number of simultaneously administered hepatotoxic drugs.5 In the pre-AIDS era, cohort studies showed that treating patients with latent tuberculosis with 12 months of isoniazid therapy carried a greater risk from drug toxicity than from the risk of developing active tuberculosis in those patients who were ⬎ 50 years of age. Previous CDC guidelines have recommended that stable latent tuberculosis should not be treated in individuals over the age of 35 years with few exceptions, including those patients with immune deficiency. During the past 2 decades, progress in the use of combination antituberculous drugs and a heightened sense of danger from active tuberculosis have given us greater enthusiasm for treating patients with latent tuberculosis. The use of two or three powerful drugs simultaneously has permitted shorter treatment schedules for both active and latent tuberculosis, with higher rates of compliance. The increased concern about active tuberculosis has stemmed from the following events: a temporary resurgence in the incidence of active tuberculosis in the 1980s; an increased incidence of drugresistant tuberculosis; and the AIDS epidemic, with an increased prevalence of immunodeficiency. Mycobacterium tuberculosis infection hastens the progression of AIDS. In HIV-infected individuals, latent M tuberculosis infection may be undetectable by tuberculin test, yet it virtually always becomes active if untreated. Hence HIV-infected individuals have much to gain from eliminating active tuberculosis in the community. Administering antituberculous antibiotics to all individuals who have positive tuberculin test results reduces the incidence of active tuberculosis. In its 2000 revised guidelines for treating latent tuberculosis, the CDC has recommended 2 months of rifampin and pyrazinamide therapy as being the shortest of the four short-course options for treatment,1 based on laboratory results in mice and a multicenter trial in an HIV-infected population.6 The new guidelines also have dropped the age restriction for the treatment of patients with latent tuberculosis. Our case and the other reports raise questions about the safety of using rifampin and pyrazinamide therapy to treat latent tuberculosis in stable non-HIV patients who are over 50 years of age. These patients often have risk factors for hepatotoxicity in addition to age, as our case illustrates. If active tuberculosis develops in these www.chestjournal.org Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21977/ on 06/18/2017 CHEST / 121 / 5 / MAY, 2002 1711 people, drug treatment is highly effective, clearly worth the risk of toxicity, and the event precipitates aggressive follow-up by the public health system. As clinicians, we must take care that our eagerness to eliminate tuberculosis does no harm. therapy, and thoracic surgery.8 We report on a patient who suddenly developed pneumorrhachis several years after undergoing a thoracotomy and external beam radiation therapy for lung carcinoma. References Case Report 1 Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2000; 49(RR-6):1–51 2 Centers for Disease Control and Prevention. Fatal and severe hepatitis associated with rifampin, and pyrazinamide for the treatment of latent tuberculosis infection: New York, and Georgia, 2000. MMWR Morb Mortal Wkly Rep 2001; 50:289–291 3 Moitinho E, Salmeron JN, Mas A, et al. Severe hepatotoxicity of tuberculostatic agents: increase in incidence. Gastroenterol Hepatol 1996; 19:448 – 451 4 Miller B. Preventive therapy for tuberculosis. Med Clin North Am 1993; 77:1263–1275 5 Dutt AK, Stead WW. Tuberculosis in the elderly. Med Clin North Am 1993; 77:1353–1368 6 Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. JAMA 2000; 283:1445–1450 A 60-year-old man received a diagnosis of left upper-lobe, large cell, undifferentiated carcinoma with chest wall invasion. He underwent a left upper-lobe lobectomy, en bloc chest wall resection, and resection of ribs 3 to 5 followed by 500-cGy external beam radiation therapy through anteroposterior and posteroanterior ports. Three years later, after protracted severe coughing, this patient developed sudden-onset extensive subcutaneous emphysema in the head, neck, and chest. A chest radiograph and CT scan of the chest identified no pneumothorax. We chose conservative management because a chest tube could not be placed strategically, and we wished to avoid surgical intervention in view of the presence of COPD and the patient’s limited underlying pulmonary reserve. Subcutaneous emphysema of the neck and chest persisted for the following 8 months and then resolved abruptly. Several days later, the patients presented with excruciating pain in the back and left arm and leg. A spinal cord compression syndrome was suspected clinically, and an MRI scan revealed an epidural gas collection (5 to 10 mL) that extended from C3 through T4. A chest radiograph revealed a pneumomediastinum and subcutaneous emphysema (Fig 1). A CT scan of the chest revealed air in the epidural space, the mediastinum, and subcutaneous tissues (Fig 2). Air from the mediastinal and subcutaneous regions moved through the neural foramina into the epidural space. No definite pneumothorax was identified. The precise location of the presumed bronchopleural fistula could not be identified by MRI, CT scan, ventilation-perfusion scan, or fiberoptic bronchoscopy. The presence of an active infection at the time of presentation was not suspected. The patient did not respond to 2 weeks of conservative management, and at that time he underwent a modification of his prior thoracoplasty with resection of ribs 2 and 6 and a combined serratus anterior and intercostal muscle flap closure of the bronchopleural fistula. Multiple small air leaks were found emanating from the inflamed surfaces of the superior segment of the left lower lobe parenchyma. The bronchopleural fistula air leak returned 2 weeks after his muscle flap closure surgery. The failure of the surgery was not surprising since the muscle flap covered an area of the lung that was scarred and emphysematous. A chest tube was placed in the area of the presumed air leak and was left to open-air drainage. Persistent drainage of air continued through the chest tube, without recurrence of pneumorrhachis, for the next 2 years until his death due to end-stage COPD. An Unusual Case of Pneumorrhachis Following Resection of Lung Carcinoma* Ross L. Ristagno, MD, FCCP; Loren F. Hiratzka, MD, FCCP; and Raymond C. Rost, Jr., MD We report an unusual case of a patient with a bronchopleural-subcutaneous fistula that occurred 3 years following a lobectomy and en bloc chest wall resection for carcinoma. Following a sudden resolution of subcutaneous emphysema, an epidural air collection developed. Spontaneous pneumorrhachis is a previously unreported late complication after surgical or radiation therapy for lung carcinoma. (CHEST 2002; 121:1712–1714) Key words: bronchial fistula complications; CT; emphysema; emphysema complications; mediastinal emphysema; pneumocephalus; radiograph; spinal canal abnormalities; subcutaneous emphysema ir very rarely enters the spinal canal (pneumorrhachis). A Pneumorrhachis has been reported to occur following spontaneous pneumomediastinum,1– 4 traumatic pneumothorax,5 skull fracture,6 epidural anesthesia,7 radiation *From the Department of Pulmonary Medicine (Dr. Ristagno), and the Department of Diagnostic Radiology (Dr. Rost), The Christ Hospital, Cincinnati, OH; and the Department of Cardiac Surgery (Dr. Hiratzka), TriHealth, Cincinnati, OH. Manuscript received July 3, 2001; revision accepted November 27, 2001. Correspondence to: Ross L. Ristagno, MD, FCCP, 7960 Greylock Dr, Cincinnati, OH 45243; e-mail: [email protected] Discussion In general, pneumorrhachis may enter the epidural space or may penetrate further into the subarachnoid space. Air that enters the epidural space usually does not migrate significantly, and complete resorption occurs spontaneously. Epidural space pneumorrhachis causes no symptoms or local pain. When pulmonary air enters the subarachnoid space, a bronchopleural-subarachnoid fistula is present, and air easily travels cephalad to the cranium (ie, pneumocephalus). These patients experience severe headaches, or less often, focal neurologic symptoms similar to a stroke.9 Pneumorrhachis is best demonstrated on CT scanning but may be seen on MRI scanning or 1712 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21977/ on 06/18/2017 Selected Reports