Wegener's Granulomatosis Responding to Antituberculous Drugs
2001; Elsevier BV; Volume: 119; Issue: 2 Linguagem: Inglês
10.1378/chest.119.2.643
ISSN1931-3543
AutoresMikio Toyoshima, Kingo Chida, Takafumi Suda, Shiro Imokawa, Hirotoshi Nakamura,
Tópico(s)Mast cells and histamine
ResumoWe present a case of Wegener's granulomatosis (WG) that respondedto antituberculous drugs. A 44-year-old woman with multiple nodules onchest radiograph received a diagnosis of pulmonary tuberculosis becauseopen-lung biopsy specimens showed caseous granulomas. Her chest shadowsunderwent repeated resolution after the start of antituberculoustreatment, and relapse after the cessation of the drugs. Antineutrophilcytoplasmic antibody was positive (14 enzyme-linked immunosorbent assayunits), and the second lung biopsy specimens showed necrotizinggranulomas and vasculitis without pathogenic organisms. Thus, thepatient received a diagnosis of WG and was successfully treated withtrimethoprim/sulfamethoxazole 10 years after her initial evaluation. Antituberculous drugs were effective in this case of WG. We present a case of Wegener's granulomatosis (WG) that respondedto antituberculous drugs. A 44-year-old woman with multiple nodules onchest radiograph received a diagnosis of pulmonary tuberculosis becauseopen-lung biopsy specimens showed caseous granulomas. Her chest shadowsunderwent repeated resolution after the start of antituberculoustreatment, and relapse after the cessation of the drugs. Antineutrophilcytoplasmic antibody was positive (14 enzyme-linked immunosorbent assayunits), and the second lung biopsy specimens showed necrotizinggranulomas and vasculitis without pathogenic organisms. Thus, thepatient received a diagnosis of WG and was successfully treated withtrimethoprim/sulfamethoxazole 10 years after her initial evaluation. Antituberculous drugs were effective in this case of WG. Wegener'sgranulomatosis (WG) is a chronic systemic necrotizing vasculitis thatclassically affects the upper respiratory tract, lungs, and kidneys. Although the drugs used to treat this disease usually arecyclophosphamide and glucocorticoids, De Remee et al1DeRemee RA McDonald TJ Weiland LH Wegener's granulomatosis: observation on treatment with antimicrobial agents.Mayo Clin Proc. 1985; 60: 27-32Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholarreported cases of WG successfully treated withtrimethoprim/sulfamethoxazole (T/S). T/S is used alone or incombination with immunosuppressive agents in the treatment of WG and toprevent a relapse of WG.1DeRemee RA McDonald TJ Weiland LH Wegener's granulomatosis: observation on treatment with antimicrobial agents.Mayo Clin Proc. 1985; 60: 27-32Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar Although the mechanisms bywhich T/S exerts its effects in WG have not been clarified as yet, thepossible involvement of its antimicrobial effect has beensuggested.2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar Here, we describe a case of WG thatresponded to antituberculous drugs.Case ReportA 44-year-old woman presented with abnormal shadows on achest radiograph taken during a medical checkup in August 1987, and wasadmitted to our hospital on September 13, 1987, for further evaluation. She presented no symptoms, and findings on physical examination wereunremarkable. The chest radiograph revealed bilateral multiple nodularshadows (Fig 1, top, left). The leukocyte count was 4,800cells/μL with a normal differential count, and the erythrocytesedimentation rate was 13 mm/h. Urinalysis showed no abnormality. Skinreaction to purified protein derivative was positive. She had notreceived a bacille Calmette-Guérin vaccine, nor did shecome from an area with a high prevalence of tuberculosis. The patientunderwent right open-lung biopsy. Specimens obtained from two nodulesshowed granulomas with central necrosis; no vasculitis was observed. Although special stains and tissue culture for acid-fast bacilli, fungi, and bacteria yielded normal results, she received a diagnosis ofpulmonary tuberculosis, and was started on a regimen of isoniazid, 400mg; rifampicin, 450 mg; and ethambutol, 750 mg. This regimen wascontinued for 6 months and was followed by a regimen of isoniazid andrifampicin for 6 months. At the end of treatment, the multiple nodularshadows had almost disappeared (Fig 1, top,right). However, a follow-up chest radiograph taken on, September 12, 1995, revealed bilateral multiple nodular shadows (Fig 1,middle, left). Treatment was reinitiated with thesame regimen as the first time, and the shadows disappeared (Fig 1,middle, right). In November 1996, she began tocomplain of productive cough, nasal discharge, and arthralgia. A chestradiograph taken on December 6, 1997, disclosed bilateral multiplenodular shadows and infiltrates with or without cavities (Fig 1,bottom, left). Sputum and nasal cultures foracid-fast bacilli and bacteria were normal. Treatment with isoniazidand rifampicin was started, and the shadows began to resolve (Fig 1,bottom, right). However, antineutrophilcytoplasmic antibody directed against proteinase 3 measured byenzyme-linked immunosorbent assay (ELISA) was 14 ELISA units (normalrange, < 10 ELISA units). Since examination of a nasal biopsyspecimen produced unremarkable findings, she was subjected to open-lungbiopsy again. Specimens obtained from the right middle lobe showednecrotizing granulomas with vasculitis that were consistent with WG(Fig 2). Tissue cultures for acid-fast bacilli, fungi, and bacteria provednormal. Polymerase chain reaction for DNA of mycobacteria found in lungtissue was also normal. After the diagnosis of WG was established, T/S(400-mg tablet/80-mg tablet, four tablets daily) was substituted forantituberculous drugs. Her symptoms and the shadows observed on thechest radiograph resolved within a few weeks.Figure 2Photomicrograph of an open-lung biopsy specimentaken on the second admission showing necrotizing granulomas andvasculitis (hematoxylin-eosin, original × 100).View Large Image Figure ViewerDownload (PPT)DiscussionIn the present case, although the patient initially received adiagnosis of pulmonary TB during the course of the disease, based onher clinical and radiologic characteristics and the results of culturesof lung tissue specimens, it was established that she had WG. Surprisingly, the multiple nodular shadows observed on the chestradiograph began to disappear just after each time she was started onantituberculous drugs. Although the possibility of a coincidentalspontaneous resolution at the time of treatment cannot be excluded, webelieve that antituberculous drugs were effective against WG in ourcase, since the response was reproducible three times.It is not clear which antituberculous drug was effective, or themechanisms of its effects. However, as in case of T/S, it can bespeculated that antituberculous drugs eliminate causal or precipitatingagents in WG. Stegeman et al3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar reported the associationbetween nasal carriage of Staphylococcus aureus and anincreased risk of relapse of WG.3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar They postulated that T/Streatment reduced the frequency of relapses by eliminating or reducingS aureus in the upper airways.2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar van Putten etal4van Putten JWG van Haren EHJ Lammers JWJ Association between Wegener's granulomatosis and Staphylococcus aureus infection?.Eur Respir J. 1996; 9: 1955-1957Crossref PubMed Scopus (24) Google Scholar also described two cases of WG associated withS aureus infection in the lower respiratorytract.4van Putten JWG van Haren EHJ Lammers JWJ Association between Wegener's granulomatosis and Staphylococcus aureus infection?.Eur Respir J. 1996; 9: 1955-1957Crossref PubMed Scopus (24) Google Scholar From these reports, although S aureuswas not detected in nasal and tissue cultures in our case, wespeculated that elimination of S aureus by rifampicin mightinduce resolution of WG. Although we cannot provide direct evidencesupporting this hypothesis, it is possible that microorganismssensitive to antituberculous drugs are causal or precipitating agentsof WG. Wegener'sgranulomatosis (WG) is a chronic systemic necrotizing vasculitis thatclassically affects the upper respiratory tract, lungs, and kidneys. Although the drugs used to treat this disease usually arecyclophosphamide and glucocorticoids, De Remee et al1DeRemee RA McDonald TJ Weiland LH Wegener's granulomatosis: observation on treatment with antimicrobial agents.Mayo Clin Proc. 1985; 60: 27-32Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholarreported cases of WG successfully treated withtrimethoprim/sulfamethoxazole (T/S). T/S is used alone or incombination with immunosuppressive agents in the treatment of WG and toprevent a relapse of WG.1DeRemee RA McDonald TJ Weiland LH Wegener's granulomatosis: observation on treatment with antimicrobial agents.Mayo Clin Proc. 1985; 60: 27-32Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar Although the mechanisms bywhich T/S exerts its effects in WG have not been clarified as yet, thepossible involvement of its antimicrobial effect has beensuggested.2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar Here, we describe a case of WG thatresponded to antituberculous drugs. Case ReportA 44-year-old woman presented with abnormal shadows on achest radiograph taken during a medical checkup in August 1987, and wasadmitted to our hospital on September 13, 1987, for further evaluation. She presented no symptoms, and findings on physical examination wereunremarkable. The chest radiograph revealed bilateral multiple nodularshadows (Fig 1, top, left). The leukocyte count was 4,800cells/μL with a normal differential count, and the erythrocytesedimentation rate was 13 mm/h. Urinalysis showed no abnormality. Skinreaction to purified protein derivative was positive. She had notreceived a bacille Calmette-Guérin vaccine, nor did shecome from an area with a high prevalence of tuberculosis. The patientunderwent right open-lung biopsy. Specimens obtained from two nodulesshowed granulomas with central necrosis; no vasculitis was observed. Although special stains and tissue culture for acid-fast bacilli, fungi, and bacteria yielded normal results, she received a diagnosis ofpulmonary tuberculosis, and was started on a regimen of isoniazid, 400mg; rifampicin, 450 mg; and ethambutol, 750 mg. This regimen wascontinued for 6 months and was followed by a regimen of isoniazid andrifampicin for 6 months. At the end of treatment, the multiple nodularshadows had almost disappeared (Fig 1, top,right). However, a follow-up chest radiograph taken on, September 12, 1995, revealed bilateral multiple nodular shadows (Fig 1,middle, left). Treatment was reinitiated with thesame regimen as the first time, and the shadows disappeared (Fig 1,middle, right). In November 1996, she began tocomplain of productive cough, nasal discharge, and arthralgia. A chestradiograph taken on December 6, 1997, disclosed bilateral multiplenodular shadows and infiltrates with or without cavities (Fig 1,bottom, left). Sputum and nasal cultures foracid-fast bacilli and bacteria were normal. Treatment with isoniazidand rifampicin was started, and the shadows began to resolve (Fig 1,bottom, right). However, antineutrophilcytoplasmic antibody directed against proteinase 3 measured byenzyme-linked immunosorbent assay (ELISA) was 14 ELISA units (normalrange, < 10 ELISA units). Since examination of a nasal biopsyspecimen produced unremarkable findings, she was subjected to open-lungbiopsy again. Specimens obtained from the right middle lobe showednecrotizing granulomas with vasculitis that were consistent with WG(Fig 2). Tissue cultures for acid-fast bacilli, fungi, and bacteria provednormal. Polymerase chain reaction for DNA of mycobacteria found in lungtissue was also normal. After the diagnosis of WG was established, T/S(400-mg tablet/80-mg tablet, four tablets daily) was substituted forantituberculous drugs. Her symptoms and the shadows observed on thechest radiograph resolved within a few weeks. A 44-year-old woman presented with abnormal shadows on achest radiograph taken during a medical checkup in August 1987, and wasadmitted to our hospital on September 13, 1987, for further evaluation. She presented no symptoms, and findings on physical examination wereunremarkable. The chest radiograph revealed bilateral multiple nodularshadows (Fig 1, top, left). The leukocyte count was 4,800cells/μL with a normal differential count, and the erythrocytesedimentation rate was 13 mm/h. Urinalysis showed no abnormality. Skinreaction to purified protein derivative was positive. She had notreceived a bacille Calmette-Guérin vaccine, nor did shecome from an area with a high prevalence of tuberculosis. The patientunderwent right open-lung biopsy. Specimens obtained from two nodulesshowed granulomas with central necrosis; no vasculitis was observed. Although special stains and tissue culture for acid-fast bacilli, fungi, and bacteria yielded normal results, she received a diagnosis ofpulmonary tuberculosis, and was started on a regimen of isoniazid, 400mg; rifampicin, 450 mg; and ethambutol, 750 mg. This regimen wascontinued for 6 months and was followed by a regimen of isoniazid andrifampicin for 6 months. At the end of treatment, the multiple nodularshadows had almost disappeared (Fig 1, top,right). However, a follow-up chest radiograph taken on, September 12, 1995, revealed bilateral multiple nodular shadows (Fig 1,middle, left). Treatment was reinitiated with thesame regimen as the first time, and the shadows disappeared (Fig 1,middle, right). In November 1996, she began tocomplain of productive cough, nasal discharge, and arthralgia. A chestradiograph taken on December 6, 1997, disclosed bilateral multiplenodular shadows and infiltrates with or without cavities (Fig 1,bottom, left). Sputum and nasal cultures foracid-fast bacilli and bacteria were normal. Treatment with isoniazidand rifampicin was started, and the shadows began to resolve (Fig 1,bottom, right). However, antineutrophilcytoplasmic antibody directed against proteinase 3 measured byenzyme-linked immunosorbent assay (ELISA) was 14 ELISA units (normalrange, < 10 ELISA units). Since examination of a nasal biopsyspecimen produced unremarkable findings, she was subjected to open-lungbiopsy again. Specimens obtained from the right middle lobe showednecrotizing granulomas with vasculitis that were consistent with WG(Fig 2). Tissue cultures for acid-fast bacilli, fungi, and bacteria provednormal. Polymerase chain reaction for DNA of mycobacteria found in lungtissue was also normal. After the diagnosis of WG was established, T/S(400-mg tablet/80-mg tablet, four tablets daily) was substituted forantituberculous drugs. Her symptoms and the shadows observed on thechest radiograph resolved within a few weeks. DiscussionIn the present case, although the patient initially received adiagnosis of pulmonary TB during the course of the disease, based onher clinical and radiologic characteristics and the results of culturesof lung tissue specimens, it was established that she had WG. Surprisingly, the multiple nodular shadows observed on the chestradiograph began to disappear just after each time she was started onantituberculous drugs. Although the possibility of a coincidentalspontaneous resolution at the time of treatment cannot be excluded, webelieve that antituberculous drugs were effective against WG in ourcase, since the response was reproducible three times.It is not clear which antituberculous drug was effective, or themechanisms of its effects. However, as in case of T/S, it can bespeculated that antituberculous drugs eliminate causal or precipitatingagents in WG. Stegeman et al3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar reported the associationbetween nasal carriage of Staphylococcus aureus and anincreased risk of relapse of WG.3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar They postulated that T/Streatment reduced the frequency of relapses by eliminating or reducingS aureus in the upper airways.2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar van Putten etal4van Putten JWG van Haren EHJ Lammers JWJ Association between Wegener's granulomatosis and Staphylococcus aureus infection?.Eur Respir J. 1996; 9: 1955-1957Crossref PubMed Scopus (24) Google Scholar also described two cases of WG associated withS aureus infection in the lower respiratorytract.4van Putten JWG van Haren EHJ Lammers JWJ Association between Wegener's granulomatosis and Staphylococcus aureus infection?.Eur Respir J. 1996; 9: 1955-1957Crossref PubMed Scopus (24) Google Scholar From these reports, although S aureuswas not detected in nasal and tissue cultures in our case, wespeculated that elimination of S aureus by rifampicin mightinduce resolution of WG. Although we cannot provide direct evidencesupporting this hypothesis, it is possible that microorganismssensitive to antituberculous drugs are causal or precipitating agentsof WG. In the present case, although the patient initially received adiagnosis of pulmonary TB during the course of the disease, based onher clinical and radiologic characteristics and the results of culturesof lung tissue specimens, it was established that she had WG. Surprisingly, the multiple nodular shadows observed on the chestradiograph began to disappear just after each time she was started onantituberculous drugs. Although the possibility of a coincidentalspontaneous resolution at the time of treatment cannot be excluded, webelieve that antituberculous drugs were effective against WG in ourcase, since the response was reproducible three times. It is not clear which antituberculous drug was effective, or themechanisms of its effects. However, as in case of T/S, it can bespeculated that antituberculous drugs eliminate causal or precipitatingagents in WG. Stegeman et al3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar reported the associationbetween nasal carriage of Staphylococcus aureus and anincreased risk of relapse of WG.3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar They postulated that T/Streatment reduced the frequency of relapses by eliminating or reducingS aureus in the upper airways.2Stegeman CA Tervaert JWC de Jong PE et al.Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.N Engl J Med. 1996; 335: 16-20Crossref PubMed Scopus (734) Google Scholar3Stegeman CA Tervaert JWC Sluiter WJ et al.Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.Ann Intern Med. 1994; 120: 12-17Crossref PubMed Scopus (666) Google Scholar van Putten etal4van Putten JWG van Haren EHJ Lammers JWJ Association between Wegener's granulomatosis and Staphylococcus aureus infection?.Eur Respir J. 1996; 9: 1955-1957Crossref PubMed Scopus (24) Google Scholar also described two cases of WG associated withS aureus infection in the lower respiratorytract.4van Putten JWG van Haren EHJ Lammers JWJ Association between Wegener's granulomatosis and Staphylococcus aureus infection?.Eur Respir J. 1996; 9: 1955-1957Crossref PubMed Scopus (24) Google Scholar From these reports, although S aureuswas not detected in nasal and tissue cultures in our case, wespeculated that elimination of S aureus by rifampicin mightinduce resolution of WG. Although we cannot provide direct evidencesupporting this hypothesis, it is possible that microorganismssensitive to antituberculous drugs are causal or precipitating agentsof WG.
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