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Clinical microbiological case: poor radiologic evolution of pulmonary tuberculosis in a heart transplant patient
ANSWER S TO CONTINUING MEDICAL EDUCATION QUESTIONS
Clinical microbiological case: poor radiologic evolution of pulmonary tuberculosis in a heart transplant patient F. Gavila´n, J. Torre-Cisneros, M. A. Vizcaı´no, J. M. Arizo´n, R. Lama, F. Lo´pez-Rubio and P. Sa´nchez-Guijo
Please refer to the article on pages 367–368 of this issue to view the questions to which these answers refer. 1. After 21 days of anti-tuberculosis (TB) treatment, the patient agreed to an open lung biopsy, and a 2.5 cm lung tissue sample was duly obtained. The sample contained several yellow nodules 1–3 mm in diameter; intervening tissue was relatively normal. Examination of frozen sections revealed granulomatous inflammation centered entirely around terminal bronchioles and partially obliterated bronchiolar lumina (Figure 2). Neither acid-fast bacilli nor specific granulomas were observed. These findings were consistent with bronchiolitis obliterans organizing pneumonia (BOOP). Following diagnosis, treatment with corticosteroids (prednisone 1 mg/kg/day) was added to anti-TB drugs. Two weeks later, the patient was asymptomatic and chest X-rays were normal (Figure 1b). Anti-TB treatment was continued for
18 months, but ethambutol was stopped after the first 2 months. Prednisone was given for 2 weeks, and thereafter gradually withdrawn. Today, the patient remains asymptomatic. BOOP, also called cryptogenic pneumonia, is a recognized clinicopathologic entity characterized by the presence of myxomatous connective tissue plugs in the bronchiolar lumen, extending into alveoli [1]. Diagnosis is largely histologic, and an open lung biopsy is often considered necessary. The disease may be idiopathic or may be associated with a number of lung conditions, including lung allograft rejection and pulmonary infections [2]. The term ‘bronchiolitis’ covers two distinct clinicopathologic entities, both of which affect the small airways: (1) constrictive bronchiolitis [1]; and (2) BOOP or cryptogenic pneumonia [3]. The main characteristics are presented in Table 1. BOOP did not become a fully recognized entity until it was described by Epler in 1985 [4]. Histologically, the most relevant feature is the presence of granulated tissue plugs in bronchiolar lumina, extending into alveoli, accompanied by fibrosis and predominantly mixed lymphoplasmocellular interstitial inflammation [1,5]. 2. BOOP may present as a primary disease of unknown etiology, or may be secondary to: collagen vascular diseases such
Figure 1b Chest X-ray after corticosteroid treatment.
ß 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
400 Clinical Microbiology and Infection, Volume 7 Number 7, July 2001
Figure 2 Histologic examination of lung biopsy.
as rheumatoid arthritis; inhalation of poisonous gases; drugs such as bleomycin, cephalosporin, busulfan or cocaine; irradiation; or infection [1,2]. The main microorganisms associated with this entity are listed in Table 2. Although BOOP has been associated with numerous microorganisms, a bibliographic search through MEDLINE from 1992 to August 2000 revealed no report of association with Mycobacterium tuberculosis.
The patient described here was an immunocompromised host from a country where TB is endemic. He may have had previous contact with M. tuberculosis prior to transplant, and immunosuppressive treatment may have favored the development of TB. The relationship between TB and bronchiolitis has not been fully confirmed, and the etiology of BOOP in this patient may involve some degree of interplay between the infectious agent (M. tuberculosis) and the transplant; however,
Table 1 Characteristics enabling differentiation between constrictive bronchiolitis and bronchiolitis obliterans organizing pneumonia
Constrictive bronchiolitis Histology
Radiographic findings Lung function
Concentric fibrosis of bronchioles that may completely obliterate the bronchiolar lumen Normal or hyperinflated lung Obstructive
Evolution
Pulmonary fibrosis
Bronchiolitis obliterans organizing pneumonia Bronchiolar interluminal granulation tissue plugs, extending into the alveoli Diffuse or focal infiltrate Restrictive or mixed obstructive^restrictive Favorable
ß 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7, 399–401
Answers to Continuing Medical Education Questions
Table 2 Major BOOP-related microorganisms Organism Mycoplasma pneumoniae Streptococcus pneumoniae Nocardia Asteroides Aspergillus fumigatus Burkholderia cepacia Cytomegalovirus Mycobacterium avium
the absence of graft rejection, coupled with histologic and microbiological findings, strongly suggests that BOOP was due to bronchial spread from initial TB. 3. Little information is available regarding TB in transplant patients, since few cases have been reported to date. According to the Spanish Group for the Study of Infections in Transplant Patients (GESITRA), the incidence of TB is 20 times greater in transplant patients than in the national population (50/100 000 inhabitants), even when preventive treatment with isoniazid is administered to PPD-positive patients [6]. Where prophylaxis cannot be performed, surveillance mycobacterial cultures are useful for the early diagnosis of TB [7]. Most patients develop TB during the first 9 months following transplant; however, in a smaller number of cases, the disease does not develop until 2 years after transplant, or even longer. Although scattered or extrapulmonary forms of TB are more frequent in transplant patients than in the general population, most transplant patients develop pulmonary forms. Of all the factors contributing to the occurrence of infections in transplant recipients, the most important is iatrogenic immunosuppression. It is well known that corticosteroids inhibit the immune response, cellular immunity and, to a lesser extent, antibody formation; in these circumstances, reactivation of latent M. tuberculosis may lead to spread of the disease [8]. Complications such as bronchocentric granulomatosis have been reported in association with M. tuberculosis [9,10], but there are no documented cases of BOOP caused by this agent. There are apparently no previous reports of either (a) bronchiolitis obliterans associated with heart transplantation (i.e. without heart–lung transplantation) or (b) bronchiolitis obliterans associated with pulmonary TB in inmunocompromised patients. There has, however, been one report of an immunocompetent patient suffering BOOP associated with M. avium [7].
401
In lung, heart–lung and 10% of bone marrow transplant patients, BOOP appears in association with acute graft rejection, in many cases involving cytomegalovirus disease [2,11– 14]. Nevertheless, it has not been reported in association with rejection in heart transplant patients. In conclusion, it is felt that BOOP may be a manifestation of TB, which should therefore be included in the differential diagnosis of infectious causes of BOOP, particularly in the immunocompromised patient. Given that once corticosteroid treatment is started the prognosis of BOOP is good, correct diagnosis—generally requiring open lung biopsy—is essential. Inappropriate treatment could lead to the systemic spread of TB. R EFER E NCE S 1. Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol 1998; 2: 321–34. 2. Chaparro C, Chamberlain D, Maurer J, Winton T, Dehoyos A, Kestar S. Bronchiolitis obliterans organizing pneumonia (BOOP) in lung transplant recipients. Chest 1996; 110: 1150–4. 3. Ferna´ndez J, Va´zquez M, Alvarez M, Ruı´z A. El espectro de las bronquiolitis. An Med Intern 1997; 14: 89–92. 4. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312: 152–8. 5. Colby T. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992; 102: 38s–43S. 6. Aguado JM, Herrero JA, Gavalda´ J et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Transplantation 1997; 63: 1278–86. 7. Torre Cisneros J, Mata M, Rufian S et al. Importance of surveillance mycobacterial cultures after liver transplantation. Transplantation 1995; 60: 1054–5. 8. Meuleman J, Katz P. The immunologic effects, kinetics, and use of glucocorticoids. Med Clin North Am 1985; 69: 805. 9. Scully RE, Mark EJ, McNeely WF, Ebeling SH. Case records of Massachusetts General Hospital. N Engl J Med 1996; 334: 521–6. 10. Maguire GP, Lee M, Rosen Y, Lyons HA. Pulmonary tuberculosis and bronchocentric granulomatosis. Chest 1986; 89: 606–8. 11. Keller CA, Cagle PT, Brown RW, Noon G, Frost AE. Bronchiolitis obliterans in recipients of single, double and heart– lung transplantation. Chest 1995; 107: 973–80. 12. Ross DJ, Moudgil A, Bagga A et al. Lung allograft dysfunction correlates with gamma-interferon gene expression in bronchoalveolar lavage. J Heart Lung Transplant 1999; 18: 627–36. 13. Baron FA, Hermanne JP, Dowlati A et al. Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogenic bone marrow transplantation. Bone Marrow Transplant 1998; 21: 951–4. 14. Geist LJ, Dai LY. Cytomegalovirus modulates interleukin-6 gene expression. Transplantation 1996; 62: 653–8.
ß 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7, 399–401
Clinical microbiological case: poor radiologic evolution of pulmonary tuberculosis in a heart transplant patient F. Gavila´n, J. Torre-Cisneros, M. A. Vizcaı´no, J. M. Arizo´n, R. Lama, F. Lo´pez-Rubio and P. Sa´nchez-Guijo
Please refer to the article on pages 367–368 of this issue to view the questions to which these answers refer. 1. After 21 days of anti-tuberculosis (TB) treatment, the patient agreed to an open lung biopsy, and a 2.5 cm lung tissue sample was duly obtained. The sample contained several yellow nodules 1–3 mm in diameter; intervening tissue was relatively normal. Examination of frozen sections revealed granulomatous inflammation centered entirely around terminal bronchioles and partially obliterated bronchiolar lumina (Figure 2). Neither acid-fast bacilli nor specific granulomas were observed. These findings were consistent with bronchiolitis obliterans organizing pneumonia (BOOP). Following diagnosis, treatment with corticosteroids (prednisone 1 mg/kg/day) was added to anti-TB drugs. Two weeks later, the patient was asymptomatic and chest X-rays were normal (Figure 1b). Anti-TB treatment was continued for
18 months, but ethambutol was stopped after the first 2 months. Prednisone was given for 2 weeks, and thereafter gradually withdrawn. Today, the patient remains asymptomatic. BOOP, also called cryptogenic pneumonia, is a recognized clinicopathologic entity characterized by the presence of myxomatous connective tissue plugs in the bronchiolar lumen, extending into alveoli [1]. Diagnosis is largely histologic, and an open lung biopsy is often considered necessary. The disease may be idiopathic or may be associated with a number of lung conditions, including lung allograft rejection and pulmonary infections [2]. The term ‘bronchiolitis’ covers two distinct clinicopathologic entities, both of which affect the small airways: (1) constrictive bronchiolitis [1]; and (2) BOOP or cryptogenic pneumonia [3]. The main characteristics are presented in Table 1. BOOP did not become a fully recognized entity until it was described by Epler in 1985 [4]. Histologically, the most relevant feature is the presence of granulated tissue plugs in bronchiolar lumina, extending into alveoli, accompanied by fibrosis and predominantly mixed lymphoplasmocellular interstitial inflammation [1,5]. 2. BOOP may present as a primary disease of unknown etiology, or may be secondary to: collagen vascular diseases such
Figure 1b Chest X-ray after corticosteroid treatment.
ß 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
400 Clinical Microbiology and Infection, Volume 7 Number 7, July 2001
Figure 2 Histologic examination of lung biopsy.
as rheumatoid arthritis; inhalation of poisonous gases; drugs such as bleomycin, cephalosporin, busulfan or cocaine; irradiation; or infection [1,2]. The main microorganisms associated with this entity are listed in Table 2. Although BOOP has been associated with numerous microorganisms, a bibliographic search through MEDLINE from 1992 to August 2000 revealed no report of association with Mycobacterium tuberculosis.
The patient described here was an immunocompromised host from a country where TB is endemic. He may have had previous contact with M. tuberculosis prior to transplant, and immunosuppressive treatment may have favored the development of TB. The relationship between TB and bronchiolitis has not been fully confirmed, and the etiology of BOOP in this patient may involve some degree of interplay between the infectious agent (M. tuberculosis) and the transplant; however,
Table 1 Characteristics enabling differentiation between constrictive bronchiolitis and bronchiolitis obliterans organizing pneumonia
Constrictive bronchiolitis Histology
Radiographic findings Lung function
Concentric fibrosis of bronchioles that may completely obliterate the bronchiolar lumen Normal or hyperinflated lung Obstructive
Evolution
Pulmonary fibrosis
Bronchiolitis obliterans organizing pneumonia Bronchiolar interluminal granulation tissue plugs, extending into the alveoli Diffuse or focal infiltrate Restrictive or mixed obstructive^restrictive Favorable
ß 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7, 399–401
Answers to Continuing Medical Education Questions
Table 2 Major BOOP-related microorganisms Organism Mycoplasma pneumoniae Streptococcus pneumoniae Nocardia Asteroides Aspergillus fumigatus Burkholderia cepacia Cytomegalovirus Mycobacterium avium
the absence of graft rejection, coupled with histologic and microbiological findings, strongly suggests that BOOP was due to bronchial spread from initial TB. 3. Little information is available regarding TB in transplant patients, since few cases have been reported to date. According to the Spanish Group for the Study of Infections in Transplant Patients (GESITRA), the incidence of TB is 20 times greater in transplant patients than in the national population (50/100 000 inhabitants), even when preventive treatment with isoniazid is administered to PPD-positive patients [6]. Where prophylaxis cannot be performed, surveillance mycobacterial cultures are useful for the early diagnosis of TB [7]. Most patients develop TB during the first 9 months following transplant; however, in a smaller number of cases, the disease does not develop until 2 years after transplant, or even longer. Although scattered or extrapulmonary forms of TB are more frequent in transplant patients than in the general population, most transplant patients develop pulmonary forms. Of all the factors contributing to the occurrence of infections in transplant recipients, the most important is iatrogenic immunosuppression. It is well known that corticosteroids inhibit the immune response, cellular immunity and, to a lesser extent, antibody formation; in these circumstances, reactivation of latent M. tuberculosis may lead to spread of the disease [8]. Complications such as bronchocentric granulomatosis have been reported in association with M. tuberculosis [9,10], but there are no documented cases of BOOP caused by this agent. There are apparently no previous reports of either (a) bronchiolitis obliterans associated with heart transplantation (i.e. without heart–lung transplantation) or (b) bronchiolitis obliterans associated with pulmonary TB in inmunocompromised patients. There has, however, been one report of an immunocompetent patient suffering BOOP associated with M. avium [7].
401
In lung, heart–lung and 10% of bone marrow transplant patients, BOOP appears in association with acute graft rejection, in many cases involving cytomegalovirus disease [2,11– 14]. Nevertheless, it has not been reported in association with rejection in heart transplant patients. In conclusion, it is felt that BOOP may be a manifestation of TB, which should therefore be included in the differential diagnosis of infectious causes of BOOP, particularly in the immunocompromised patient. Given that once corticosteroid treatment is started the prognosis of BOOP is good, correct diagnosis—generally requiring open lung biopsy—is essential. Inappropriate treatment could lead to the systemic spread of TB. R EFER E NCE S 1. Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol 1998; 2: 321–34. 2. Chaparro C, Chamberlain D, Maurer J, Winton T, Dehoyos A, Kestar S. Bronchiolitis obliterans organizing pneumonia (BOOP) in lung transplant recipients. Chest 1996; 110: 1150–4. 3. Ferna´ndez J, Va´zquez M, Alvarez M, Ruı´z A. El espectro de las bronquiolitis. An Med Intern 1997; 14: 89–92. 4. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312: 152–8. 5. Colby T. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992; 102: 38s–43S. 6. Aguado JM, Herrero JA, Gavalda´ J et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Transplantation 1997; 63: 1278–86. 7. Torre Cisneros J, Mata M, Rufian S et al. Importance of surveillance mycobacterial cultures after liver transplantation. Transplantation 1995; 60: 1054–5. 8. Meuleman J, Katz P. The immunologic effects, kinetics, and use of glucocorticoids. Med Clin North Am 1985; 69: 805. 9. Scully RE, Mark EJ, McNeely WF, Ebeling SH. Case records of Massachusetts General Hospital. N Engl J Med 1996; 334: 521–6. 10. Maguire GP, Lee M, Rosen Y, Lyons HA. Pulmonary tuberculosis and bronchocentric granulomatosis. Chest 1986; 89: 606–8. 11. Keller CA, Cagle PT, Brown RW, Noon G, Frost AE. Bronchiolitis obliterans in recipients of single, double and heart– lung transplantation. Chest 1995; 107: 973–80. 12. Ross DJ, Moudgil A, Bagga A et al. Lung allograft dysfunction correlates with gamma-interferon gene expression in bronchoalveolar lavage. J Heart Lung Transplant 1999; 18: 627–36. 13. Baron FA, Hermanne JP, Dowlati A et al. Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogenic bone marrow transplantation. Bone Marrow Transplant 1998; 21: 951–4. 14. Geist LJ, Dai LY. Cytomegalovirus modulates interleukin-6 gene expression. Transplantation 1996; 62: 653–8.
ß 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7, 399–401