Successful Management of Miliary Tuberculosis after Renal Transplantation Luda C. Rattazzl, MD,’ Minneapolis, Minnesota Rkhard L. Simmons, MD, Minneapolis, Minnesota Panayktls K. Spanos, MD,’ Minneapolis, Minnesota Davld S. Bradford, MD, Minneapolis, Minnesota John S. Najarlan, MD, Minneapolis, Minnesota

Transplantation patients are susceptible to infection by common and uncommon pathogens during immunosuppression; most deaths are due to infection [I-4), and most lethal infections originate in the lungs [5-S]. Surprisingly, pulmonary tuberculosis has rarely been encountered in patients after transplantation [3,5,7,8], and the successful management of miliary tuberculosis in these patients has not been described previously. Case Report The patient (DA), a forty-three year old white woman with polycystic renal disease, received a cadaveric kidney graft in May 1972. The kidneys and spleen had already been removed. The post-transplantation postoperative course was uncomplicated, and the patient was discharged with good renal function. She was admitted one month later because of a rejection episode that responded promptly to irradiation of the graft and increased prednisone dosage. She was seen again three months after transplantation because of sinusitis and bacterial pneumonia of the left lower lobe. Both conditions responded promptly to appropriate antibiotic treatment. She was then followed up through the outpatient department and was in excellent health with normal kidney function (serum creatinine level, 0.9 mg/lOO ml). Surgery and &thopadk &ugay, Udwdty Of Thb work was suppated by Grant #AM13083 from the Mted States Pubk Health Service. Reprint requests should be addressed to Rkhard I_. Simmons. MD. Departmentof Surgery. Sax 185. Mayo hhmc+ial BuikIng. Unhfedty of Mlnnasota Hos~ls. Minneawlls. Minnesota 55455. ’ address: D&a&t of Sugary. unker.9ity of Mieml. Et& cayne Annex, PO Box 875. Miami, Flcda 33152. +ReeBntaddress: Departmentof Surgery, Mayo Clink. Rochester, Minnesota 5590 1. From

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One year post transplantation, pain and swelling of the right knee developed without local or systemic signs of infection. Synovitis was diagnosed and treated symptomatically without improvement. Twice in the next two months, aspiration of the articular space was performed with immediate symptomatic relief. Cultures of the norma1 appearing synovial fluid were sterile. Daily dosage of maintenance drugs at this time included azathioprine (150 mg/kg), prednisone (20 mg/kg), sulfisoxaxole (8 gm), and hydrochlorothiazide (50 mg). One week after the second articular aspiration, the patient had a mild, nonproductive cough, fever in the range of 101 to 102”F, increased swelling and pain in the right knee, and a 3 mm area of erythema surrounding the puncture site of the previous articular aspiration. Because of persistent symptoms, the patient was rehospitalized fifteen months post-transplantation. On this admission, physical examination revealed only a diffusely swollen, tender right knee with minimal functional impairment associated with infrapatellar erythema and swelling. Laboratory studies on admission demonstrated normal findings on the hemogram, sedimentation rate of 112 mm at 60 minutes, normal results of coagulation studies, blood urea nitrogen level of 15 mg/lOO ml, and creatinine level of 1.0 mg/lOO ml. Urinalysis showed l+ protein and occasional white and red blood cells. Aspiration of the right knee was performed again, and at this time purulent material was obtained. Chest x-ray films (posteroanterior and lateral) revealed interstitial infiltrate of the right upper lobe and bilateral diffuse fihe nodular infiltrates. (Figure 1.) Because of this radiologic finding, diagnostic bronchoscopy was performed immediatelv and demonstrated generalized edema and erv_ thema with a moderate amount of exudate in the visualized bronchi. Acid-fast smear of both the bronchial and articular aspirates revealed acid-fast bacilli. Culture of

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Figure 1. Detail of chest x-ray film on admission, demonstrating fine diffuse nodular infiltrate present In all lung fields.

the same material demonstrated Mycobacterium tuberculosis var. hominis. Urine and spinal fluid contained no M tuberculosis. Therapy was begun with isoniazid (5 mglkglday), pyridoxine (50 mg/day, in three oral doses), streptomycin sulphate (0.75 gm/day, in four intramuscular doses), ethambutol (15 mg/kg/day), and rifampin (600 mg/day, in four oral doses). Azathioprine was discontinued for approximately three days and resumed, slowly increasing the dosage to 100 mg (1.5 mg/kg/day) in a period of twenty days. Prednisone dosage was slowly reduced from the previous level of 20 mg/day, in four oral doses (0.35 mg/kg/day), to 15 mg/day, in four oral doses (0.2 mg/kg/day). Strict isolation technics and bed rest because of the articular lesion were used. The patient rapidly became afebrile. Radiologic findings consistent with miliary tuberculosis remained unchanged for the next two weeks of therapy. Stain and culture of the sputum for acid-fast bacilli became sterile, after approximately ten days of therapy. The symptoms related to the articular lesion subsided in approximately fifteen days, allowing ambulation without any discomfort.

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After twenty days of hospitalization and after sputum stains and cultures for acid-fast bacilli were sterile on three separate occasions, the patient was discharged to receive quadruple therapy for tuberculosis (isoniazidpyridoxine, ethambutol, rifampin, and streptomycin) in the outpatient department. The dosage of streptomycin was reduced to 1 gm intramuscularly twice a week with the plan of discontinuing ethambutol when maximal clinical improvement had been achieved. The patient was asymptomatic for approximately three weeks and then noted stiffness and moderate swelling of the right knee again. On readmission, aspiration of the right knee joint was carried out and the aspirate, which previously had demonstrated no bacilli, again revealed acid-fast bacilli in the smear. The sputum contained no acid-fast bacilli. Renal function was stable. Chest x-ray films still demonstrated a very vague diffuse nodular infiltrate, and x-ray study of the right knee did not demonstrate any bony destruction. A cylinder cast was applied to the right lower limb. The patient was taught nonweightbearing technics and discharged soon after. The patient remained asymptomatic and the cylinder case was removed after approximately six weeks. Five months after the admission for miliary tuberculosis, the patient was rehospitalized for treatment of a rejection episode (serum creatinine level, 1.8 mg/lOO ml). Physical examination on admission was essentially noncontributory. Chest x-ray films reportedly revealed no abnormalities. Therapy consisted of an increase in prednisone dosage and irradiation of the graft. During this period, antitubercular therapy was increased to the dosage used during the active phase of the disease. Response to antirejection therapy was prompt, and there were no clinical nor radiologic signs of reactivation of tuberculosis. Maintenance antitubercular therapy was resumed when the prednisone dosage had reached values of less than 1 mg/kg/day. Seven months after the admission for miliary tuberculosis, another episode of acute rejection (serum creatinine level, 3.3 mg/lOO ml) occurred. Therapy again consisted of irradiation of the graft and increased prednisone dosage. Percutaneous needle biopsy of the graft confirmed the diagnosis. Cultures of the biopsy specimen and routine cultures of the sputum, blood, and urine revealed no mycobacteria. Readjustment of ethambutol and streptomycin dosage was necessary because of the renal malfunction. There has been no evidence of failure of antitubercular therapy at the present time. Comments Miliary tuberculosis is the most lethal form of tubercular disease. When tubercle bacilli are disseminated throughout the body in patients without immunosuppression as well as in those with immunosuppression [II], death is almost a certainty without therapy. The process may appear as part of the first infection with M tuberculosis or as reactivation of an

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old focus of disease. The symptoms are usually nonspecific, and the diagnosis is seldom made before the typical miliary pattern appears in the lungs and is recognized on roentgenography [12]. It is important to establish the etiologic organism as soon as possible, because the same radiologic picture can be presented by histoplasmosis, coccidioimycosis, blastomycosis, cryptococcosis, and aspergillosis; each of these infections, especially in patients receiving immunosuppressive therapy, may be rapidly lethal [1,5]. We have long advocated an aggressive diagnostic approach to pulmonary infection, stressing the early use of bronchoscopic washings and, occasionally, open lung biopsy [6]. The presence of a life-threatening infection in a patient with immunosuppression [13] indicated discontinuation of azathioprine for several days and the cautious resumption of administration when it appeared that the miliary spread had been arrested by antitubercular therapy. Furthermore, steroid dosage was gradually reduced, since the presence of infection strongly suggested an impaired immunologic response. This approach was only partially successful since rejection did occur several months later. The cornerstone of successful therapy in this case was the prompt institution of multiple drug therapy as soon as the diagnosis was confirmed by acid-fast staining. Para-aminosalicylic acid, because of its known action on the gastroenteric tract and on the kidney [14], was not utilized. Moreover, the known occurrence of streptomycin-resistant mycobacteria [15,16] prompted the use of the more recent powerful and safe antitubercular drugs [I7]. Summary Miliary tuberculosis is the most lethal form of tubercular disease. If dissemination of tubercle bacilli occurs without therapy, death is almost certain. The importance of establishing an etiologic diagnosis as promptly as possible in patients receiving immunosuppressive therapy is self-explanatory. The presence of a life-threatening infection in these patients requires aggressive antimicrobial therapy and discontinuation of the immunosuppressive drugs until the infectious process is under

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control; the presence of an impaired immunologic response is responsible for the life-threatening infection and the lack of an acute rejection reaction.

References 1. Rifkind D, Marchioro TL, Waddell WR, Starzl TE: infectious diseases associated with renal homotransplantation. 1. IncMence, types, and predisposing factors. il. Differential diagnosis and management. JAMA 189: 397, 1964. 2. Rifkind D, Marchioro TL, Schneck SA, Hill RB Jr: Systemic fungal infections complicating renal transplantation and immunosuppressive therapy. Am J A&d 43: 28, 1967. 3. Fulginlti VA, Schribner G, Groth CG, Putnam CW, BrettSchneider L, Gilbert S, Porter KA, Starzi TE: Infections in recipients of liver homografts. N Engl J Med 279: 619. 1968. 4. Hill RB Jr, Dahrling BE, Starzl RE. Rifkind D: Death after transplantation. An analysis of 60 cases. Am J Med 42: 327, 1967. 5. Hill RB Jr, Rowlands DT Jr, Rifkind D: Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation. N Engl J Med 271: 1021, 1964. 6. Simmons RL, Uranga VM. LaPlante ES, Buselmeier TJ, Kjellstrand CM, Najarian JS: Pulmonary complications in transplant recipients. Arch Surg 105: 260, 1972. 7. Duma RJ: Unusual infections in transplant patients. Transplant Proc IV: 711, 1972. 8. Burgos-Cakler R, Pankey GA, Figeuroa JE: Infection in kiiney transplantation. Surgery 70: 334, 197 1. 9. Moore TC, Hume DM: The period and nature of hazard in clinical renal transplantation. III. The hazard to transplant kklney survival. Ann Surg 170: 25, 1969. 10. Starzl RE: Experience in Renal Transplantation. Philadelphia, WB Saunders, 1964, p 225. 11. Simmons RL, Tailent MB, Kjellstrand CM, Najarian Js: I%vention of death after renal transplantation. I. Recognizable patterns leading to death in long-term survivors. Am J Surg 119: 553, 1970. 12. Berger HW, Samortin TG: Miiiiry tuberculosis: diagnostic methods with emphasis on the chest roentgenograms. Chest 58: 586, 1970. 13. Anderson RJ. Schafer LA, Olin DB, Eickhoff TC: Infectious risk factors in the immunosuowessed hosts. Am J Med .. 54: 453, 1973. 14. Weinstein L: Drugs used in the chemotherapy of leprosy and tuberculosis. D 13 11. The Pharmacological Basis of Therapeutics (G&man LS, Giiman A, ed).‘New York, Macmillan, 1971. 15. Hobby GL, Johnson PM, Crawford-Gagliirdi L, Boytar V, Johnson GE: Primary drug resistance: a continuing study of drug resistance in tuberculosis in a veteran population within the United States. V. September 1963 to September 1965. Am Rev Respir Dis 94: 703, 1966. 16. Hobby GL, Lenert TF, Maier J, O’Malley P: Primary drug resistance. II. A continuing study of tubercle bacilli in a veteran population within the United States. Am Rev Respir Dis 91: 30.1965. 17. Salinger PL. Dormer BA: Rifampicin, ethambutol, ethionam ide and hydronsan in advanced pulmonary tuberculosis. S Afr Med J 46: 354, 1972.

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Successful management of miliary tuberculosis after renal transplantation.

Miliary tuberculosis is the most lethal form of tubercular disease. If dissemination of tubercle bacilli occurs without therapy, death is almost certa...
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