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Laryngeal tuberculosis in renal allograft patients
Laryngeal Tuberculosis in Renal Allograft Patients Ana M. Tato, MD, Julio Pascual, MD, PhD, Luis Orofino, MD, PhD, Gema Ferna´ndez-Jua´rez, MD, Juan Martı´nez-San-Milla´n, MD, PhD, Luis Fogue´, MD, PhD, Fernando Lian˜o, MD, PhD, and Joaquı´n Ortun˜o, MD, PhD ● Laryngeal tuberculosis, although the most common granulomatous disease of the larynx, is a rare form of extrapulmonary tuberculosis, never reported in immunosuppressed allograft recipients. We present two cases of laryngeal tuberculosis in renal transplant patients and a review of the literature. Two women, a 29-year-old and a 60-year-old, each more than 9 years after their cadaveric renal allograft, presented with a 2-week febrile illness with hoarseness and dysphagia, and both were found to have laryngeal tuberculosis by direct laryngoscopy. Although both radiographs were unremarkable, both patients had sputum positive for acid-fast bacilli that subsequently grew Mycobacterium tuberculosis. Clinical response promptly followed institution of isoniazid, rifampicin, and pyrazinamide in each case, although both required threefold increases in daily cyclosporin A dosage to maintain therapeutic levels. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Laryngeal tuberculosis; kidney transplantation; cyclosporine.
T
HE INCREASED INCIDENCE of infection in the renal transplant population remains an important cause of morbidity and mortality. The use of immunosuppressive therapy results in major defects in host defense and an increased prevalence of opportunistic infections such as tuberculosis (TB).1 Although the importance of TB has been widely debated, to our knowledge, these are the first reported cases of laryngeal disease in renal transplant patients. CASE REPORTS
quent positive culture for Mycobacterium tuberculosis (Fig 2). Acid-fast bacilli were also present in sputum; however, chest radiograph was unremarkable. A three-drug regimen with isoniazid and rifampicin for 9 months and pyrazinamide for the first 2 months was prescribed. Because of enhanced metabolism and clearance of CyA, the patient needed a threefold increase in the daily dose of CyA. Otherwise, the treatment was well tolerated without presenting any other side effect. Renal function was preserved, with even a mild transient decrease in serum creatinine levels, possibly attributable to the lower CyA blood concentration. Symptomatic amelioration was observed 1 week after antituberculosis treatment was started, with complete recovery at the end of the 12 months.
Case 1
Case 2
A 29-year-old white woman had been on hemodialysis since 1985 for chronic renal failure caused by glomerulonephritis. In 1986, she underwent a cadaveric renal transplantation, which was immediately functioning. Chest radiograph was unremarkable at that moment. Basal immunosuppression consisted of prednisone 0.5 mg/kg/d tapered to 20 mg/d at 6 months and 10 mg/d at 1 year; cyclosporin A (CyA) was initially administered at a dose of 14 mg/kg/d, rapidly tapered to achieve levels of 150 to 250 ng/mL. Her posttransplantation course was uneventful, without acute rejection episodes. A year later, mild proteinuria with slowly progressive elevation of serum creatinine was observed. This clinical feature together with graft biopsy findings yielded the diagnosis of chronic allograft dysfunction, and she was put on azathioprine (1.5 mg/kg/d) in addition to CyA and prednisone.2 In May 1995, she presented with a 2-week history of progressive fever, dysphagia, hoarseness, and 3-kg weight loss. General physical examination was unremarkable. Indirect laryngoscopic examination showed an amorphous epiglottic mass. A computed tomography (CT) scan of the neck without intravenous contrast showed a lesion infiltrating the preepiglottic space and involving the valleculae, arytenoepiglottidean folds, and periglottic space. The lesion had lower density than muscles (Fig 1). She underwent a direct laryngoscopy with a biopsy that yielded epithelioid granulomata with acid-fast bacilli and subse-
A 60-year-old white woman with end-stage renal failure secondary to lupus nephritis on maintenance hemodialysis since 1984 received a cadaveric renal allograft in 1986. Basal immunosuppression was entirely similar to that prescribed in case 1. She was maintained for 9 years with a double regimen of CyA-prednisone. Chest radiograph was entirely normal. In 1996, she was admitted to this hospital with 2 months’ history of sore throat and dysphagia. She did not have fever until 15 days before admission. Physical examination was unremarkable. Laryngoscopic examination showed an exophytic ulcerated mass extending to the posterior epiglottis and the left sinus pyriformis. A CT scan showed the laryngeal mass apparently confined to the epiglottis (Fig 3). The dysphagia made nasoenteral feeding neces-
From the Servicio de Nefrologı´a, the Servicio de Radiologı´a, and the Servicio de Anatomı´a Patolo´gica, Hospital Ramo´n y Cajal, Madrid, Spain. Received July 8, 1997; accepted in revised form September 12, 1997. Address reprint requests to Julio Pascual, MD, PhD, Servicio de Nefrologı´a, Hospital Ramo´n y Cajal, Carretera de Colmenar Km. 9.100, Madrid 28034, Spain.
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3104-0020$3.00/0
American Journal of Kidney Diseases, Vol 31, No 4 (April), 1998: pp 701-705
701
702
TATO ET AL
Fig 1. Nonenhanced CT scan (case 1) showing (A) thickened epiglottic apex (white arrowhead) and (B) thickening of the ariepiglottic folds (white arrowheads) and infiltration of the preepiglottic fat (black asterisk).
sary. At that time, the patient’s clinical status made laryngeal biopsy not advisable. Although chest radiograph appeared normal, acid-fast bacilli were present in sputum, and antituberculosis therapy (three-drug regimen as in case 1) was started, with clinical improvement in 5 days. Total daily dose of CyA had to be increased threefold to achieve adequate blood levels. No other side effect was recorded. Two weeks later, a direct laryngoscopy with biopsy showed epithelioid granulomata in epiglottic lamina propria strongly suggestive of TB. Acid-fast bacilli were not observed in this sample. Currently the patient has completed 1 year of treatment, renal function is stable, and she is asymptomatic.
DISCUSSION
In renal transplant patients, TB presents differently than in the general population. Uremia and immunosuppressive drugs promote reactivation of latent TB as well as development of newly acquired disease.3 The role of immunosuppression has been widely debated. Although Higgins et al4 did not find any difference despite variations in the immunosuppressive protocol,4 other authors describe a higher TB incidence in the pre-CyA era, or associated with tacrolimus therapy, pulsed intravenous steroids, or with OKT3.5-8 In addition, TB occurs more often after renal transplantation than in the general population. The estimated prevalence for TB ranges from 0.5% to 4% in Northern Europe and North America, to 3.5% in Saudi Arabia or 11.5% in India.3,4,6 From November 1979 to December 1991, we reported a 1.8% incidence in our renal transplant population.5 The lung remains the most frequent site of involvement; however, disseminated and cutaneous TB are also frequent, as
well as atypical mycobacteriosis.9 These atypical presentations produce a delay in diagnosis and therefore increase morbidity and exposure of the patients’ contacts, with particular emphasis on nosocomial transmission.7-11 Laryngeal TB, although the most common granulomatous disease of the larynx, is a rare form of extrapulmonary TB. Its incidence has experienced a dramatic reduction in developed countries, from 35% to 40% in the immediate postwar period to a 0.5% incidence in the eighties.12 From 1977 to 1994, only 14 cases have been diagnosed in our center.13 It used to affect young patients with extensive lung disease in past decades. The typical localization was in the posterior larynx as a result of the passage of infected sputum in patients confined to bed. Nowadays, the mean age of presentation is in the fifth or sixth decades, patients have minimal pulmonary involvement, and the disease usually affects the vocal cords, suggesting a hematogenous or lymphatic spread.14-17 Clinical manifestations include hoarseness, cough, odynophagia, fever, and weight loss. Physical examination is often unremarkable. Although some papers describe previous lung disease as a universal finding,12,14,15,17 other authors report some cases of laryngeal TB without pulmonary involvement.13,18 Before antituberculous therapy was available, laryngeal manifestations of TB were frequent and were almost always accompanied by advanced cavitary pulmonary lesions. Studies in the past 15 years suggest that pulmonary disease and symptoms still precede the laryngeal lesions in approximately 80% of cases, but it is no longer ‘‘rare.’’15 CT scan appearance of laryngeal TB depends on the stage and extent of the disease. In the acute phase, bilateral and diffuse thickening of the vocal cords is usually seen. The chronic phase is characterized by a local thickening or a mass in the vocal cords, with diffuse asymmetric thickening of the contralateral vocal cord, epiglottis, and perilaryngeal tissue.11,17 The most important differential diagnosis is primary laryngeal carcinoma. A unilateral mass that causes sclerosis or destruction of the laryngeal structures and extends to the hypopharynx or subglottic areas favors laryngeal carcinoma.11,15,17 Other clinical conditions in the differential diagnosis include sarcoidosis, Wegener
LARYNGEAL TB IN TRANSPLANTATION
703
Fig 2. Laryngeal biopsy (case 1) showing (A) necrotizing epitelioid granulomatosis (H&E, original magnification ⴛ60) and (B) acid-fast bacilli (arrows) (Ziehl-Neelsen, original magnification ⴛ60).
granulomatosis, syphilis, histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis, amyloidosis, traumatic polypoid granulation, and laryngeal papilloma.15,16 Diagnostic confirmation usually requires laryngoscopy followed by biopsy. Histology yields granulomatous tissue with giant cell histiocytes and areas of caseous necrosis. Acid-fast bacilli are usually identified providing no previous treatment has been instituted.19 In our first patient, precocious biopsy was performed before specific
therapy allowed us to observe the responsible acid-fast bacilli. However, in our second patient, 2 weeks of antituberculous treatment cleared the bacilli from direct visualization in the laryngeal sample. The standard treatment instituted for extrapulmonary TB includes isoniazid, rifampicin, and pyrazinamide or ethambutol initially. Pyrazinamide or ethambutol are not necessary after the first 2 months. Total duration of therapy should not be any longer than that if the patient is
704
TATO ET AL
the differential diagnosis in the renal allograft recipient with hoarseness. Laryngeal masses are not always neoplasia. In our experience, prognosis is excellent and, providing adequate treatment, a complete recovery may be achieved. REFERENCES
Fig 3. Contrast-enhanced axial CT scan (case 2) showing (A) thickened epiglottic apex (white arrowhead) and (B) thickening of the epiglottic mucosa (white arrowheads) and normal piriform sinuses (black arrows).
profoundly immunocompromised or in the presence of HIV infection; 6-month regimens are probably effective for otherwise normal hosts, although all patients should be followed closely to show clearance of acid-fast bacilli from sputum. Difficulties are posed by rifampicin, a potent hepatic P450 cytochrome oxidase inducer that increases the clearance of CyA and favors acute rejection. Careful monitoring of CyA blood levels must be performed. It is often necessary to increase by threefold to fivefold the standard CyA dose or even to give it three times a day.4,10,20-22 In some cases, it is unavoidable to withdraw rifampicin from the drug regimen because of excessively low CyA levels despite great doses. Fortunately, in our two patients, we were able to proceed with adequate antituberculous treatment including rifampicin without acute rejection episodes, only increasing CyA doses. Chemoprophylaxis in renal transplant patients remains controversial. No adequate data exist as to whether its benefits outweigh the possible side effects.23 The use of isoniazid (200 mg/d for 12 months plus rifampicin before CyA was introduced and isoniazid thereafter) in high-risk patients has been reported.4 None of them developed TB, whereas 22% of high-risk patients who did not receive prophylaxis developed the disease. Conversely, a recent review quotes an 8.5% incidence of pulmonary TB despite patients with either previous history of TB or any old scarring on chest radiograph that were prescribed prophylactic isoniazid.24 In summary, laryngeal TB should be added to
1. Cohen J, Hopkin J, Kurtz J: Infectious complications after renal transplantation, in Morris PJ (ed): Kidney Transplantation (ed 4). Philadelphia, PA, Saunders, 1994, pp 364-389 2. Pascual J, Marce´n R, Orofino L, Quereda C, Mampaso F, Lian˜o F, Ortun˜o J: Evidence that addition of azathioprine improves renal function in cyclosporine-treated patients with allograft dysfunction. Transplantation 52:276-279, 1991 3. Qunibi WY, Al-Sibai B, Thaer S, Harder EJ, De Vol E, Al-Furayh O, Gin HE: Mycobacterial infection after renal transplantation: Report of 14 cases and review of the literature. Q J Med 77:1039-1060, 1990 4. Higgins RM, Cahn AP, Porter D, Richardson AJ, Mitchel RJ, Hopkin JM, Morris PJ: Mycobacterial infections after renal tranplantation. Q J Med 78:145-153, 1991 5. Gamez C, Marcen R, Orofino L, Rivera M, Quereda C, Fortun J, Serrano P, Teruel JL, Ortun˜o J: Tuberculosis disease in renal transplant recipients, in Andreucci, Del Canton (eds): Current Therapy in Nephrology. Witchig Editore, 1993, pp 589-591 6. Hall MC, Wilcox PA, Swanepoel CR, Kahn D, Van Zyl Smith R: Mycobacterial infection in renal transplant patients. Chest 106:435-439, 1994 7. Sunberg R, Shapiro R, Darras F, Jensen C, Scantlebury V, Jordan M, McCauley J, Kusne S, Edmon MB, Ho M, Medvick J, Pascoulle W, Hakala T, Simmons RL, Starzi TE: A tuberculosis outbreak in a renal transplant program. Transplant Proc 23:3091-3092, 1991 8. Oh CS, Stratta RJ, Fox BC, Sollinger HW, Belzer FO, Maki DG: Increased infections associated with the use of OKT3 for the treatment of steroid-resistant rejection in renal transplantation. Transplantation 45:68-73, 1988 9. Ortun˜o J, Teruel JL, Marcen R, Gil P, Berenguer A, Zubicoa S, Navarro-Berastegui V: Primary intestinal tuberculosis following renal transplantation. Nephron 31:59-60, 1982 10. Drobniewski FA, Ferguson J: Tuberculosis in renal transplant units. Nephrol Dial Transplant 11:768-770, 1996 11. Swallow CE, McAdams HP, Colon E: Tuberculosis manifested by laryngeal mass on CT scans. AJR 163:179180, 1994 12. Galietti F, Giorgis GE, Gandolfi G, Astesiano A, Miravalle C, Ardizzi A, Favata G, Miscioscia D: Examination of 41 cases of laryngeal tuberculosis observed between 1975-1985. Eur Respir J 2:731-732, 1989 13. Fortun J, Sierra C, Raboso E, Perez C, Plaza G, Navas E, Gomez-Mampaso E, Guerrero A: Tuberculosis del Area Otorrinolaringologica: Formas laringeas y extralaringeas. Enferm Infect Microbiol Clin 14:352-356, 1996
LARYNGEAL TB IN TRANSPLANTATION
14. Soda A, Rubio H, Salazar M, Ganem J, Berlanga D, Sanchez A: Tuberculosis of the larynx: Clinical aspects in 19 patients. Laryngoscope 99:1147-1150, 1989 15. Scully RE, Mark EJ, McNelly WF, McNelly BU: Case records of the Massachusetts General Hospital, Case 34-1994. N Engl J Med 331:728-734, 1994 16. Prieto de Paula JM, Villamandos Nicas V: Tuberculosis laringea. Descripcio´n de tres casos. Rev Clin Esp 195:279280, 1995 17. Moon WK, Han MH, Chang KH, Kim HJ, Im JG, Yeon KM, Han MC: Laryngeal tuberculosis: CT findings. AJR 166:445-449, 1996 18. Beg MHA, Marfani S: The larynx in pulmonary tuberculosis. J Laryngol Otol 99:201-203, 1985 19. Getson WR, Park YW: Pathologic quiz case. Arch Otolaryngol Head Neck Surg 118:878-881, 1992 20. Koselij M, Bren A, Kandus A, Kovac D: Drug interac-
705
tions between cyclosporine and rifampicin, erythromicin and azoles in kidney recipients with opportunistic infections. Transplant Proc 26:2823-2824, 1994 21. Al-Sulaiman MH, Dhar JM, Al-Khader AA: Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immunosuppressed with cyclosporine. Transplantation 50:597-598, 1990 22. Pescke B, Ernst W, Gossmann J, Kachel HG, Schoeppe W, Scheurmann EH: Antituberculous drugs in kidney transplant recipients treated with cyclosporine. Transplantation 56:236-238, 1993 23. Naqvi SA, Hussain M, Askari H, Hashmi A, Hussain Z, Hussain I, Hafiz S, Yazdani I, Rizvi SAH: Is there a place for prophylaxis against tuberculosis following renal transplantation? Transplant Proc 24:1912, 1992 24. Edeltein CL, Jacobs JC, Mooasa MR: Pulmonary complications in 110 consecutive renal transplant recipients. SAMJ 85:160-163, 1995
T
HE INCREASED INCIDENCE of infection in the renal transplant population remains an important cause of morbidity and mortality. The use of immunosuppressive therapy results in major defects in host defense and an increased prevalence of opportunistic infections such as tuberculosis (TB).1 Although the importance of TB has been widely debated, to our knowledge, these are the first reported cases of laryngeal disease in renal transplant patients. CASE REPORTS
quent positive culture for Mycobacterium tuberculosis (Fig 2). Acid-fast bacilli were also present in sputum; however, chest radiograph was unremarkable. A three-drug regimen with isoniazid and rifampicin for 9 months and pyrazinamide for the first 2 months was prescribed. Because of enhanced metabolism and clearance of CyA, the patient needed a threefold increase in the daily dose of CyA. Otherwise, the treatment was well tolerated without presenting any other side effect. Renal function was preserved, with even a mild transient decrease in serum creatinine levels, possibly attributable to the lower CyA blood concentration. Symptomatic amelioration was observed 1 week after antituberculosis treatment was started, with complete recovery at the end of the 12 months.
Case 1
Case 2
A 29-year-old white woman had been on hemodialysis since 1985 for chronic renal failure caused by glomerulonephritis. In 1986, she underwent a cadaveric renal transplantation, which was immediately functioning. Chest radiograph was unremarkable at that moment. Basal immunosuppression consisted of prednisone 0.5 mg/kg/d tapered to 20 mg/d at 6 months and 10 mg/d at 1 year; cyclosporin A (CyA) was initially administered at a dose of 14 mg/kg/d, rapidly tapered to achieve levels of 150 to 250 ng/mL. Her posttransplantation course was uneventful, without acute rejection episodes. A year later, mild proteinuria with slowly progressive elevation of serum creatinine was observed. This clinical feature together with graft biopsy findings yielded the diagnosis of chronic allograft dysfunction, and she was put on azathioprine (1.5 mg/kg/d) in addition to CyA and prednisone.2 In May 1995, she presented with a 2-week history of progressive fever, dysphagia, hoarseness, and 3-kg weight loss. General physical examination was unremarkable. Indirect laryngoscopic examination showed an amorphous epiglottic mass. A computed tomography (CT) scan of the neck without intravenous contrast showed a lesion infiltrating the preepiglottic space and involving the valleculae, arytenoepiglottidean folds, and periglottic space. The lesion had lower density than muscles (Fig 1). She underwent a direct laryngoscopy with a biopsy that yielded epithelioid granulomata with acid-fast bacilli and subse-
A 60-year-old white woman with end-stage renal failure secondary to lupus nephritis on maintenance hemodialysis since 1984 received a cadaveric renal allograft in 1986. Basal immunosuppression was entirely similar to that prescribed in case 1. She was maintained for 9 years with a double regimen of CyA-prednisone. Chest radiograph was entirely normal. In 1996, she was admitted to this hospital with 2 months’ history of sore throat and dysphagia. She did not have fever until 15 days before admission. Physical examination was unremarkable. Laryngoscopic examination showed an exophytic ulcerated mass extending to the posterior epiglottis and the left sinus pyriformis. A CT scan showed the laryngeal mass apparently confined to the epiglottis (Fig 3). The dysphagia made nasoenteral feeding neces-
From the Servicio de Nefrologı´a, the Servicio de Radiologı´a, and the Servicio de Anatomı´a Patolo´gica, Hospital Ramo´n y Cajal, Madrid, Spain. Received July 8, 1997; accepted in revised form September 12, 1997. Address reprint requests to Julio Pascual, MD, PhD, Servicio de Nefrologı´a, Hospital Ramo´n y Cajal, Carretera de Colmenar Km. 9.100, Madrid 28034, Spain.
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3104-0020$3.00/0
American Journal of Kidney Diseases, Vol 31, No 4 (April), 1998: pp 701-705
701
702
TATO ET AL
Fig 1. Nonenhanced CT scan (case 1) showing (A) thickened epiglottic apex (white arrowhead) and (B) thickening of the ariepiglottic folds (white arrowheads) and infiltration of the preepiglottic fat (black asterisk).
sary. At that time, the patient’s clinical status made laryngeal biopsy not advisable. Although chest radiograph appeared normal, acid-fast bacilli were present in sputum, and antituberculosis therapy (three-drug regimen as in case 1) was started, with clinical improvement in 5 days. Total daily dose of CyA had to be increased threefold to achieve adequate blood levels. No other side effect was recorded. Two weeks later, a direct laryngoscopy with biopsy showed epithelioid granulomata in epiglottic lamina propria strongly suggestive of TB. Acid-fast bacilli were not observed in this sample. Currently the patient has completed 1 year of treatment, renal function is stable, and she is asymptomatic.
DISCUSSION
In renal transplant patients, TB presents differently than in the general population. Uremia and immunosuppressive drugs promote reactivation of latent TB as well as development of newly acquired disease.3 The role of immunosuppression has been widely debated. Although Higgins et al4 did not find any difference despite variations in the immunosuppressive protocol,4 other authors describe a higher TB incidence in the pre-CyA era, or associated with tacrolimus therapy, pulsed intravenous steroids, or with OKT3.5-8 In addition, TB occurs more often after renal transplantation than in the general population. The estimated prevalence for TB ranges from 0.5% to 4% in Northern Europe and North America, to 3.5% in Saudi Arabia or 11.5% in India.3,4,6 From November 1979 to December 1991, we reported a 1.8% incidence in our renal transplant population.5 The lung remains the most frequent site of involvement; however, disseminated and cutaneous TB are also frequent, as
well as atypical mycobacteriosis.9 These atypical presentations produce a delay in diagnosis and therefore increase morbidity and exposure of the patients’ contacts, with particular emphasis on nosocomial transmission.7-11 Laryngeal TB, although the most common granulomatous disease of the larynx, is a rare form of extrapulmonary TB. Its incidence has experienced a dramatic reduction in developed countries, from 35% to 40% in the immediate postwar period to a 0.5% incidence in the eighties.12 From 1977 to 1994, only 14 cases have been diagnosed in our center.13 It used to affect young patients with extensive lung disease in past decades. The typical localization was in the posterior larynx as a result of the passage of infected sputum in patients confined to bed. Nowadays, the mean age of presentation is in the fifth or sixth decades, patients have minimal pulmonary involvement, and the disease usually affects the vocal cords, suggesting a hematogenous or lymphatic spread.14-17 Clinical manifestations include hoarseness, cough, odynophagia, fever, and weight loss. Physical examination is often unremarkable. Although some papers describe previous lung disease as a universal finding,12,14,15,17 other authors report some cases of laryngeal TB without pulmonary involvement.13,18 Before antituberculous therapy was available, laryngeal manifestations of TB were frequent and were almost always accompanied by advanced cavitary pulmonary lesions. Studies in the past 15 years suggest that pulmonary disease and symptoms still precede the laryngeal lesions in approximately 80% of cases, but it is no longer ‘‘rare.’’15 CT scan appearance of laryngeal TB depends on the stage and extent of the disease. In the acute phase, bilateral and diffuse thickening of the vocal cords is usually seen. The chronic phase is characterized by a local thickening or a mass in the vocal cords, with diffuse asymmetric thickening of the contralateral vocal cord, epiglottis, and perilaryngeal tissue.11,17 The most important differential diagnosis is primary laryngeal carcinoma. A unilateral mass that causes sclerosis or destruction of the laryngeal structures and extends to the hypopharynx or subglottic areas favors laryngeal carcinoma.11,15,17 Other clinical conditions in the differential diagnosis include sarcoidosis, Wegener
LARYNGEAL TB IN TRANSPLANTATION
703
Fig 2. Laryngeal biopsy (case 1) showing (A) necrotizing epitelioid granulomatosis (H&E, original magnification ⴛ60) and (B) acid-fast bacilli (arrows) (Ziehl-Neelsen, original magnification ⴛ60).
granulomatosis, syphilis, histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis, amyloidosis, traumatic polypoid granulation, and laryngeal papilloma.15,16 Diagnostic confirmation usually requires laryngoscopy followed by biopsy. Histology yields granulomatous tissue with giant cell histiocytes and areas of caseous necrosis. Acid-fast bacilli are usually identified providing no previous treatment has been instituted.19 In our first patient, precocious biopsy was performed before specific
therapy allowed us to observe the responsible acid-fast bacilli. However, in our second patient, 2 weeks of antituberculous treatment cleared the bacilli from direct visualization in the laryngeal sample. The standard treatment instituted for extrapulmonary TB includes isoniazid, rifampicin, and pyrazinamide or ethambutol initially. Pyrazinamide or ethambutol are not necessary after the first 2 months. Total duration of therapy should not be any longer than that if the patient is
704
TATO ET AL
the differential diagnosis in the renal allograft recipient with hoarseness. Laryngeal masses are not always neoplasia. In our experience, prognosis is excellent and, providing adequate treatment, a complete recovery may be achieved. REFERENCES
Fig 3. Contrast-enhanced axial CT scan (case 2) showing (A) thickened epiglottic apex (white arrowhead) and (B) thickening of the epiglottic mucosa (white arrowheads) and normal piriform sinuses (black arrows).
profoundly immunocompromised or in the presence of HIV infection; 6-month regimens are probably effective for otherwise normal hosts, although all patients should be followed closely to show clearance of acid-fast bacilli from sputum. Difficulties are posed by rifampicin, a potent hepatic P450 cytochrome oxidase inducer that increases the clearance of CyA and favors acute rejection. Careful monitoring of CyA blood levels must be performed. It is often necessary to increase by threefold to fivefold the standard CyA dose or even to give it three times a day.4,10,20-22 In some cases, it is unavoidable to withdraw rifampicin from the drug regimen because of excessively low CyA levels despite great doses. Fortunately, in our two patients, we were able to proceed with adequate antituberculous treatment including rifampicin without acute rejection episodes, only increasing CyA doses. Chemoprophylaxis in renal transplant patients remains controversial. No adequate data exist as to whether its benefits outweigh the possible side effects.23 The use of isoniazid (200 mg/d for 12 months plus rifampicin before CyA was introduced and isoniazid thereafter) in high-risk patients has been reported.4 None of them developed TB, whereas 22% of high-risk patients who did not receive prophylaxis developed the disease. Conversely, a recent review quotes an 8.5% incidence of pulmonary TB despite patients with either previous history of TB or any old scarring on chest radiograph that were prescribed prophylactic isoniazid.24 In summary, laryngeal TB should be added to
1. Cohen J, Hopkin J, Kurtz J: Infectious complications after renal transplantation, in Morris PJ (ed): Kidney Transplantation (ed 4). Philadelphia, PA, Saunders, 1994, pp 364-389 2. Pascual J, Marce´n R, Orofino L, Quereda C, Mampaso F, Lian˜o F, Ortun˜o J: Evidence that addition of azathioprine improves renal function in cyclosporine-treated patients with allograft dysfunction. Transplantation 52:276-279, 1991 3. Qunibi WY, Al-Sibai B, Thaer S, Harder EJ, De Vol E, Al-Furayh O, Gin HE: Mycobacterial infection after renal transplantation: Report of 14 cases and review of the literature. Q J Med 77:1039-1060, 1990 4. Higgins RM, Cahn AP, Porter D, Richardson AJ, Mitchel RJ, Hopkin JM, Morris PJ: Mycobacterial infections after renal tranplantation. Q J Med 78:145-153, 1991 5. Gamez C, Marcen R, Orofino L, Rivera M, Quereda C, Fortun J, Serrano P, Teruel JL, Ortun˜o J: Tuberculosis disease in renal transplant recipients, in Andreucci, Del Canton (eds): Current Therapy in Nephrology. Witchig Editore, 1993, pp 589-591 6. Hall MC, Wilcox PA, Swanepoel CR, Kahn D, Van Zyl Smith R: Mycobacterial infection in renal transplant patients. Chest 106:435-439, 1994 7. Sunberg R, Shapiro R, Darras F, Jensen C, Scantlebury V, Jordan M, McCauley J, Kusne S, Edmon MB, Ho M, Medvick J, Pascoulle W, Hakala T, Simmons RL, Starzi TE: A tuberculosis outbreak in a renal transplant program. Transplant Proc 23:3091-3092, 1991 8. Oh CS, Stratta RJ, Fox BC, Sollinger HW, Belzer FO, Maki DG: Increased infections associated with the use of OKT3 for the treatment of steroid-resistant rejection in renal transplantation. Transplantation 45:68-73, 1988 9. Ortun˜o J, Teruel JL, Marcen R, Gil P, Berenguer A, Zubicoa S, Navarro-Berastegui V: Primary intestinal tuberculosis following renal transplantation. Nephron 31:59-60, 1982 10. Drobniewski FA, Ferguson J: Tuberculosis in renal transplant units. Nephrol Dial Transplant 11:768-770, 1996 11. Swallow CE, McAdams HP, Colon E: Tuberculosis manifested by laryngeal mass on CT scans. AJR 163:179180, 1994 12. Galietti F, Giorgis GE, Gandolfi G, Astesiano A, Miravalle C, Ardizzi A, Favata G, Miscioscia D: Examination of 41 cases of laryngeal tuberculosis observed between 1975-1985. Eur Respir J 2:731-732, 1989 13. Fortun J, Sierra C, Raboso E, Perez C, Plaza G, Navas E, Gomez-Mampaso E, Guerrero A: Tuberculosis del Area Otorrinolaringologica: Formas laringeas y extralaringeas. Enferm Infect Microbiol Clin 14:352-356, 1996
LARYNGEAL TB IN TRANSPLANTATION
14. Soda A, Rubio H, Salazar M, Ganem J, Berlanga D, Sanchez A: Tuberculosis of the larynx: Clinical aspects in 19 patients. Laryngoscope 99:1147-1150, 1989 15. Scully RE, Mark EJ, McNelly WF, McNelly BU: Case records of the Massachusetts General Hospital, Case 34-1994. N Engl J Med 331:728-734, 1994 16. Prieto de Paula JM, Villamandos Nicas V: Tuberculosis laringea. Descripcio´n de tres casos. Rev Clin Esp 195:279280, 1995 17. Moon WK, Han MH, Chang KH, Kim HJ, Im JG, Yeon KM, Han MC: Laryngeal tuberculosis: CT findings. AJR 166:445-449, 1996 18. Beg MHA, Marfani S: The larynx in pulmonary tuberculosis. J Laryngol Otol 99:201-203, 1985 19. Getson WR, Park YW: Pathologic quiz case. Arch Otolaryngol Head Neck Surg 118:878-881, 1992 20. Koselij M, Bren A, Kandus A, Kovac D: Drug interac-
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