LETTERS distinguish between the species included in the subgroup Actinomyces bovis (3), which includes A. naeslundii. The diagnosis of pulmonary actinomycosis was consistent with the patient’s history and clinical status. The history of current severe periodontal disease reinforced the diagnosis probability, and the diagnosis of actinomycosis was thus established (4). Although only one case of A. naeslundii pulmonary infection has previously been reported (4), A. naeslundii is a pathogen that plays an important role in forming dental biofilms and causes gingival inflammation (5) and is thus likely to give aspiration pneumonia. An 8-month amoxicillin treatment was initiated, leading to a significant clinical and radiological improvement with gained weight, the disappearance of asthenia, and shrinkage of the nodules (Figures 1G–1I). Despite the microbiological analysis of several respiratory samples, including a lung biopsy, we could not diagnose A. naeslundii infection in our patient using conventional microbiological tools. Some recent studies have shown that PCR ESI mass spectrometry may significantly enhance the microbiological diagnostic yield in several clinical situations by allowing rapid identification of bacteria or fungi in different samples, such as blood samples, sputum, body fluids, or tissues (6–9). The PCR ESI mass spectrometry, particularly in cases of nonor slow-growing pathogens in culture, is a promising technology in the characterization of pulmonary pathologies with orphan diagnosis. In conclusion, the development of new molecular technologies gives new insights in the management of infectious diseases poorly diagnosed by conventional microbiology. Author disclosures are available with the text of this letter at www.atsjournals.org. Claire Hussenet, M.D. Jer ´ ome ˆ LeGoff, Pharm.D., Ph.D. Gwenael ¨ Lorillon, M.D. François Simon, M.D., Ph.D.
IgG4-Related Pulmonary and Salivary Disease Associated with Pulmonary Tuberculosis To the Editor: IgG4-related disease is a fibroinflammatory process first recognized as a systemic condition in 2003 (1). Traditionally associated with autoimmune pancreatitis, it has since been described in multiple organs including salivary glands, lymph nodes, lungs, aorta, kidneys, liver, and biliary tract. Clinical presentation is often subacute, and many patients do not have constitutional symptoms. Diagnosis is dependent on key pathological features: dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and eosinophilic infiltration (2). Patients are often treated successfully with corticosteroids. Known conditions reported to occur in association with IgG4-related disease may represent etiologic triggers for abnormal IgG4-related immunological reactions, although the role of tuberculosis in Author Contributions: All authors contributed to the submitted study.
Letters
Anne Bergeron, M.D., Ph.D. Hopital ˆ Saint Louis Paris, France
References 1 Yildiz O, Doganay M. Actinomycoses and Nocardia pulmonary infections. Curr Opin Pulm Med 2006;12:228–234. 2 Sampath R, Hall TA, Massire C, Li F, Blyn LB, Eshoo MW, Hofstadler SA, Ecker DJ. Rapid identification of emerging infectious agents using PCR and electrospray ionization mass spectrometry. Ann N Y Acad Sci 2007;1102:109–120. 3 Ramos CP, Foster G, Collins MD. Phylogenetic analysis of the genus Actinomyces based on 16S rRNA gene sequences: description of Arcanobacterium phocae sp. nov., Arcanobacterium bernardiae comb. nov., and Arcanobacterium pyogenes comb. nov. Int J Syst Bacteriol 1997;47:46–53. 4 Suzuki JB, Delisle AL. Pulmonary actinomycosis of periodontal origin. J Periodontol 1984;55:581–584. 5 Sato T, Watanabe K, Kumada H, Toyama T, Tani-Ishii N, Hamada N. Peptidoglycan of Actinomyces naeslundii induces inflammatory cytokine production and stimulates osteoclastogenesis in alveolar bone resorption. Arch Oral Biol 2012;57:1522–1528. 6 Laffler TG, Cummins LL, McClain CM, Quinn CD, Toro MA, Carolan HE, Toleno DM, Rounds MA, Eshoo MW, Stratton CW, et al. Enhanced diagnostic yields of bacteremia and candidemia in blood specimens by PCR-electrospray ionization mass spectrometry. J Clin Microbiol 2013;51:3535–3541. 7 Farrell JJ, Sampath R, Ecker DJ, Bonomo RA. “Salvage microbiology”: detection of bacteria directly from clinical specimens following initiation of antimicrobial treatment. PLoS ONE 2013;8:e66349. 8 Szewczyk R, Kowalski K, Janiszewska-Drobinska B, Druszczyńska M. Rapid method for Mycobacterium tuberculosis identification using electrospray ionization tandem mass spectrometry analysis of mycolic acids. Diagn Microbiol Infect Dis 2013;76:298–305. 9 Wu CJ, Chen YP, Wang HC, Su IJ, Ko WC, Chen JS, Cheng CN, Lee NY, Sun HS, Chi CY, et al. Identification of fungal pathogens from clinical specimens using multi-locus PCR coupled with electrospray ionization mass spectrometry. Diagn Microbiol Infect Dis 2014;78:141–143. Copyright © 2014 by the American Thoracic Society
this regard has not been established. We report a case that highlights concurrent diagnosis of IgG-related disease and recurrent pulmonary tuberculosis, thereby suggesting a possible link. A 68-year-old Vietnamese man presented with 1 year of progressive weight loss and fatigue. The patient had previously been treated in Vietnam for tuberculosis in the 1970s with a four-drug regimen. Details regarding treatment were unavailable. He was in stable health until he experienced persistent mild productive cough. As a result of chest computed tomography findings of chronic bilateral upper lobe fibrosis with volume loss and the new development of left apical masses (Figure 1), as well as nondiagnostic bronchoscopy, including negative biopsies and cultures for Mycobacterium tuberculosis, the patient underwent wedge resection by video-assisted thoracoscopic surgery. Pathology was notable for dense lymphoplasmacytic infiltrate with obliterative phlebitis, a whorled fibrotic pattern, and a high concentration of IgG4-positive plasma cells (up to 100 per high-power field). These findings were consistent with 1165
LETTERS
Figure 1. Chest computed tomography shows chronic bilateral upper lobe fibrosis with volume loss and new development of left apical masses. Reprinted by permission from Reference 7.
IgG4-related disease (Figure 2). In addition, necrotizing and nonnecrotizing granulomas were both seen. Fite special stain was positive for acid-fast bacilli. Mycobacterium tuberculosis was isolated from tissue culture. A submandibular mass had been resected several months prior, with pathology demonstrating chronic sialadenitis with nodular fibrosis. Given lung tissue findings consistent with IgG4related disease, the submandibular mass was reevaluated: IgG4 stain of this tissue demonstrated a marked increase in IgG4-positive plasma cells. Of note, the patient’s mother and sister both had submandibular masses resected as adults, with pathology reportedly being benign. Antinuclear antibody test, anti-Sj¨ogren’s syndrome A, anti-Sj¨ogren’s syndrome B, and rheumatoid factor were all negative. Serum IgG4 level was normal at 14 mg/dL (normal range, 7–89 mg/dL), although levels of IgG1, IgG2, and IgG3 were elevated, at 2,050 mg/dL (normal range, 240–1,118
mg/dL), 3,110 mg/dL (normal range, 124–549 mg/dL), and 230 mg/dL (normal range, 21–134 mg/dL), respectively. The patient was started on antituberculosis therapy with isoniazid, rifampin, ethambutol, and pyrazinamide. His clinical course was complicated by the presence of isoniazid resistance, herpes zoster, and nausea and early satiety contributing to continued weight loss. He completed therapy for tuberculosis with rifampin, ethambutol, and pyrazinamide. Steroid treatment for IgG4-related disease has thus far been deferred because of clinical improvement and a lack of evidence of disease recurrence. Case studies have described both parenchymal and pleural involvement of IgG4-related disease. Several pathophysiological mechanisms have been postulated, including an autoimmunemediated Th2 cell response that in turn activates IgG4 antibody production. We postulate that Mycobacterium tuberculosis activates a Th2 response that in turn leads to overexpression of interleukins 4, 5, 10, and 13 and transforming growth factor b. Collectively, these cytokines contribute to elevation in IgE and IgG4, eosinophilia, and fibrosis, which marks the development of IgG4-related disease (2–4). Very few case reports linking these two entities have been described. In one instance, a patient developed sclerosing sialadenitis and dacryoadenitis after treatment for cervical lymph node tuberculosis (5). In another, a patient developed IgG4-related systemic disease with submandibular and renal involvement after treatment for urinary tract tuberculosis (6). In our case, the immunologic response to tuberculosis either during initial exposure or recurrent active infection may have precipitated the development of IgG4-related lesions. This case highlights a possible association between pulmonary tuberculosis and IgG4-related pulmonary and salivary gland disease.
Figure 2. Pathological features of IgG4-related disease identified in this patient. (A) Lymphoplasmacytic infiltrate with fibrosis seen on submandibular mass hematoxylin and eosin (H&E). (B) IgG4 immunostain of submandibular mass shows numerous IgG4-positive plasma cells. (C) Bronchiolar wall infiltrated by plasma cells, H&E. (D) Elastic stain of residual vessel demonstrates obliterative phlebitis.
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AnnalsATS Volume 11 Number 7 | September 2014
LETTERS Author disclosures are available with the text of this letter at www.atsjournals.org. Acknowledgment: The authors thank Dr. John Heffner for his helpful input. Kristina L. Bajema, M.D. Jonathan C. Daniel, M.D. Sanaa Hussain, M.D. Ronald J. Dworkin, M.D. Providence Portland Medical Center Portland, Oregon
References 1 Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, Okamoto A, Egawa N, Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38: 982–984.
Letters
2 Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539–551. 3 Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010;34:1812–1819. 4 Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, Nakanuma Y. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 2007;45:1538–1546. 5 Kawano M, Yamada K, Kakuchi Y, Ito K, Hamano R, Fujii H, Inoue R, Matsumura M, Takahira M, Zen Y, et al. A case of immunoglobulin G4-related chronic sclerosing sialadenitis and dacryoadenitis associated with tuberculosis. Mod Rheumatol 2009;19:87–90. 6 Imai T, Yumura W, Takemoto F, Kotoda A, Imai R, Inoue M, Hironaka M, Muto S, Kusano E. A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis. Rheumatol Int 2013;33: 2141–2144. 7 Presented at the American College of Physicians Oregon Chapter Scientific Meeting. November 8, 2012, Eugene, OR. Copyright © 2014 by the American Thoracic Society
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IgG4-Related Pulmonary and Salivary Disease Associated with Pulmonary Tuberculosis To the Editor: IgG4-related disease is a fibroinflammatory process first recognized as a systemic condition in 2003 (1). Traditionally associated with autoimmune pancreatitis, it has since been described in multiple organs including salivary glands, lymph nodes, lungs, aorta, kidneys, liver, and biliary tract. Clinical presentation is often subacute, and many patients do not have constitutional symptoms. Diagnosis is dependent on key pathological features: dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and eosinophilic infiltration (2). Patients are often treated successfully with corticosteroids. Known conditions reported to occur in association with IgG4-related disease may represent etiologic triggers for abnormal IgG4-related immunological reactions, although the role of tuberculosis in Author Contributions: All authors contributed to the submitted study.
Letters
Anne Bergeron, M.D., Ph.D. Hopital ˆ Saint Louis Paris, France
References 1 Yildiz O, Doganay M. Actinomycoses and Nocardia pulmonary infections. Curr Opin Pulm Med 2006;12:228–234. 2 Sampath R, Hall TA, Massire C, Li F, Blyn LB, Eshoo MW, Hofstadler SA, Ecker DJ. Rapid identification of emerging infectious agents using PCR and electrospray ionization mass spectrometry. Ann N Y Acad Sci 2007;1102:109–120. 3 Ramos CP, Foster G, Collins MD. Phylogenetic analysis of the genus Actinomyces based on 16S rRNA gene sequences: description of Arcanobacterium phocae sp. nov., Arcanobacterium bernardiae comb. nov., and Arcanobacterium pyogenes comb. nov. Int J Syst Bacteriol 1997;47:46–53. 4 Suzuki JB, Delisle AL. Pulmonary actinomycosis of periodontal origin. J Periodontol 1984;55:581–584. 5 Sato T, Watanabe K, Kumada H, Toyama T, Tani-Ishii N, Hamada N. Peptidoglycan of Actinomyces naeslundii induces inflammatory cytokine production and stimulates osteoclastogenesis in alveolar bone resorption. Arch Oral Biol 2012;57:1522–1528. 6 Laffler TG, Cummins LL, McClain CM, Quinn CD, Toro MA, Carolan HE, Toleno DM, Rounds MA, Eshoo MW, Stratton CW, et al. Enhanced diagnostic yields of bacteremia and candidemia in blood specimens by PCR-electrospray ionization mass spectrometry. J Clin Microbiol 2013;51:3535–3541. 7 Farrell JJ, Sampath R, Ecker DJ, Bonomo RA. “Salvage microbiology”: detection of bacteria directly from clinical specimens following initiation of antimicrobial treatment. PLoS ONE 2013;8:e66349. 8 Szewczyk R, Kowalski K, Janiszewska-Drobinska B, Druszczyńska M. Rapid method for Mycobacterium tuberculosis identification using electrospray ionization tandem mass spectrometry analysis of mycolic acids. Diagn Microbiol Infect Dis 2013;76:298–305. 9 Wu CJ, Chen YP, Wang HC, Su IJ, Ko WC, Chen JS, Cheng CN, Lee NY, Sun HS, Chi CY, et al. Identification of fungal pathogens from clinical specimens using multi-locus PCR coupled with electrospray ionization mass spectrometry. Diagn Microbiol Infect Dis 2014;78:141–143. Copyright © 2014 by the American Thoracic Society
this regard has not been established. We report a case that highlights concurrent diagnosis of IgG-related disease and recurrent pulmonary tuberculosis, thereby suggesting a possible link. A 68-year-old Vietnamese man presented with 1 year of progressive weight loss and fatigue. The patient had previously been treated in Vietnam for tuberculosis in the 1970s with a four-drug regimen. Details regarding treatment were unavailable. He was in stable health until he experienced persistent mild productive cough. As a result of chest computed tomography findings of chronic bilateral upper lobe fibrosis with volume loss and the new development of left apical masses (Figure 1), as well as nondiagnostic bronchoscopy, including negative biopsies and cultures for Mycobacterium tuberculosis, the patient underwent wedge resection by video-assisted thoracoscopic surgery. Pathology was notable for dense lymphoplasmacytic infiltrate with obliterative phlebitis, a whorled fibrotic pattern, and a high concentration of IgG4-positive plasma cells (up to 100 per high-power field). These findings were consistent with 1165
LETTERS
Figure 1. Chest computed tomography shows chronic bilateral upper lobe fibrosis with volume loss and new development of left apical masses. Reprinted by permission from Reference 7.
IgG4-related disease (Figure 2). In addition, necrotizing and nonnecrotizing granulomas were both seen. Fite special stain was positive for acid-fast bacilli. Mycobacterium tuberculosis was isolated from tissue culture. A submandibular mass had been resected several months prior, with pathology demonstrating chronic sialadenitis with nodular fibrosis. Given lung tissue findings consistent with IgG4related disease, the submandibular mass was reevaluated: IgG4 stain of this tissue demonstrated a marked increase in IgG4-positive plasma cells. Of note, the patient’s mother and sister both had submandibular masses resected as adults, with pathology reportedly being benign. Antinuclear antibody test, anti-Sj¨ogren’s syndrome A, anti-Sj¨ogren’s syndrome B, and rheumatoid factor were all negative. Serum IgG4 level was normal at 14 mg/dL (normal range, 7–89 mg/dL), although levels of IgG1, IgG2, and IgG3 were elevated, at 2,050 mg/dL (normal range, 240–1,118
mg/dL), 3,110 mg/dL (normal range, 124–549 mg/dL), and 230 mg/dL (normal range, 21–134 mg/dL), respectively. The patient was started on antituberculosis therapy with isoniazid, rifampin, ethambutol, and pyrazinamide. His clinical course was complicated by the presence of isoniazid resistance, herpes zoster, and nausea and early satiety contributing to continued weight loss. He completed therapy for tuberculosis with rifampin, ethambutol, and pyrazinamide. Steroid treatment for IgG4-related disease has thus far been deferred because of clinical improvement and a lack of evidence of disease recurrence. Case studies have described both parenchymal and pleural involvement of IgG4-related disease. Several pathophysiological mechanisms have been postulated, including an autoimmunemediated Th2 cell response that in turn activates IgG4 antibody production. We postulate that Mycobacterium tuberculosis activates a Th2 response that in turn leads to overexpression of interleukins 4, 5, 10, and 13 and transforming growth factor b. Collectively, these cytokines contribute to elevation in IgE and IgG4, eosinophilia, and fibrosis, which marks the development of IgG4-related disease (2–4). Very few case reports linking these two entities have been described. In one instance, a patient developed sclerosing sialadenitis and dacryoadenitis after treatment for cervical lymph node tuberculosis (5). In another, a patient developed IgG4-related systemic disease with submandibular and renal involvement after treatment for urinary tract tuberculosis (6). In our case, the immunologic response to tuberculosis either during initial exposure or recurrent active infection may have precipitated the development of IgG4-related lesions. This case highlights a possible association between pulmonary tuberculosis and IgG4-related pulmonary and salivary gland disease.
Figure 2. Pathological features of IgG4-related disease identified in this patient. (A) Lymphoplasmacytic infiltrate with fibrosis seen on submandibular mass hematoxylin and eosin (H&E). (B) IgG4 immunostain of submandibular mass shows numerous IgG4-positive plasma cells. (C) Bronchiolar wall infiltrated by plasma cells, H&E. (D) Elastic stain of residual vessel demonstrates obliterative phlebitis.
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AnnalsATS Volume 11 Number 7 | September 2014
LETTERS Author disclosures are available with the text of this letter at www.atsjournals.org. Acknowledgment: The authors thank Dr. John Heffner for his helpful input. Kristina L. Bajema, M.D. Jonathan C. Daniel, M.D. Sanaa Hussain, M.D. Ronald J. Dworkin, M.D. Providence Portland Medical Center Portland, Oregon
References 1 Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, Okamoto A, Egawa N, Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38: 982–984.
Letters
2 Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539–551. 3 Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010;34:1812–1819. 4 Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, Nakanuma Y. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 2007;45:1538–1546. 5 Kawano M, Yamada K, Kakuchi Y, Ito K, Hamano R, Fujii H, Inoue R, Matsumura M, Takahira M, Zen Y, et al. A case of immunoglobulin G4-related chronic sclerosing sialadenitis and dacryoadenitis associated with tuberculosis. Mod Rheumatol 2009;19:87–90. 6 Imai T, Yumura W, Takemoto F, Kotoda A, Imai R, Inoue M, Hironaka M, Muto S, Kusano E. A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis. Rheumatol Int 2013;33: 2141–2144. 7 Presented at the American College of Physicians Oregon Chapter Scientific Meeting. November 8, 2012, Eugene, OR. Copyright © 2014 by the American Thoracic Society
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