OTHER
The Clinical Respiratory Journal
Nondisseminated histoplasmosis of the trachea Nicholas Bhojwani1, Jason Brett Hartman2, David C. Taylor3, Mark Herbert4 and Michael Corriveau5 1 Department of Radiology, University Hospitals Case Medical Center, Cleveland, OH, USA 2 School of Medicine, Case Western Reserve University, Cleveland, OH, USA 3 Department of Pathology, Mount Carmel Health System, Columbus, OH, USA 4 Department of Infectious Disease, Mount Carmel Health System, Columbus, OH, USA 5 Department of Pulmonary and Critical Care Medicine, Mount Carmel Health System, Columbus, OH, USA
Abstract Histoplasma capsulatum can rarely affect the trachea. We report the case of a 68-year-old woman with rheumatoid arthritis on immunosuppressive therapy who presented with fevers, worsening shortness of breath, nonproductive cough and subjective throat hoarseness and fullness. Chest computed tomography demonstrated no tracheal findings. Bronchoscopy found mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending seven centimeters distal to the vocal cords. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Silver staining and culture and wash of the tracheal biopsy revealed Histoplasma capsulatum. She was treated with oral itraconazole then briefly on intravenous amphotericin for rising Histoplasma urinary antigen levels. She continued treatment 24 months following diagnosis with minimal dyspnea. Histoplasma tracheitis has been proposed as an indicator of disseminated infection. However, our patient did not demonstrate other organ manifestations. Histoplasma tracheitis should be considered in a differential diagnosis of tracheal lesions even in the absence of systemic involvement. Please cite as: as: Bhojwani N, Hartman JB, Taylor Herbert Corriveau Please citethis thispaper paper Bhojwani N, Hartman JB, DC, Taylor DC, M, Herbert M, M. Nondisseminated histoplasmosis of the trachea. Clin Respir J 2016; 10: Corriveau M. Nondisseminated histoplasmosis of the trachea. Clin Respir J 255–258. 2014; ••: DOI:10.1111/crj.12185. ••–••. DOI:10.1111/crj.12185.
Key words bronchoscopy – Histoplasma – immunosuppression – trachea Correspondence Nicholas Bhojwani, MD, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Ave, Mailstop BSH 5056, Cleveland 44106 OH, USA. Tel.: +1 216 844 1000 Fax: +1 888 340 4993 email: [email protected] Received: 23 July 2013 Revision requested: 27 May 2014 Accepted: 03 July 2014 DOI:10.1111/crj.12185 Authorship and contributorship Nicholas Bhojwani: Collected and analyzed data, composed manuscript. Jason Hartman: Analyzed data, composed manuscript. David C. Taylor: Designed study, reviewed manuscript. Mark Herbert: Designed study, reviewed manuscript. Michael Corriveau: Designed study, reviewed manuscript. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Presentations This material was presented at American College of Physicians Columbus, Ohio Chapter, October 2011.
Case report This report was exempted by the Mount Carmel Health System Institutional Review Board. A 68-year-
The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 The Clinical Clinical Respiratory
© 2014 John John Wiley Wiley && Sons Sons Ltd Ltd C 2014 V
old woman with a past medical history significant for rheumatoid arthritis on prednisone and methotrexate presented to an Ohio hospital in December 2008 with a 1-month history of worsening shortness of breath
1 255
Nondisseminated Nondisseminated histoplasmosis histoplasmosis of of the the trachea trachea
and nonproductive cough unresolved with oral courses of amoxicillin/clavulanate and levofloxacin. She admitted to some hoarseness, a feeling of fullness in her throat and low grade fevers. For several years, she had been on prednisone 5-mL oral tablet daily and methotrexate 25-mL injection weekly. She was a lifelong nonsmoker with no history of underlying lung disease. Her vitals on physical exam were an oral temperature of 98.4°F, pulse of 100 beats/min, respiratory rate 22 breaths/min, blood pressure 119/56 mmHg and oxygen saturation of 96% on 2-L nasal cannula. Stridor was heard on auscultation over the trachea. The rest of physical exam including cardiovascular, lower respiratory, gastrointestinal, neurological and integumentary systems was negative. The white blood cell count was 5.8K cells/μL. An arterial blood gas was within normal limits. A chest CT was performed that revealed minor atelectasis, but no pulmonary infiltrates or
Bhojwani Bhojwani et et al. al.
adenopathy. Bronchoscopy was then performed, which revealed mucosal irregularity, nodularity and vesicular lesions in the proximal trachea extending 7 cm distal to the vocal cords (see Fig. 1). Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion (see Fig. 1). Initial cultures from the bronchial wash and biopsy grew methicillinresistant Staphylococcus aureus, light Cryptococcus and light Histoplasma. Viral cultures were also sent, which were negative. Subsequent silver staining and culture of the tracheal biopsy and wash revealed Histoplasma capsulatum (see Fig. 2). Also seen on tracheal biopsy were acute and chronic inflammation, ulceration and inflammatory atypia (see Fig. 3). Oral itraconazole 100 mg twice daily was given for 9 months. After 4 months of itraconazole therapy, repeat bronchoscopy showed improving irregular inflammatory tracheal mucosa, granulation tissues on the true vocal cords
Figure 1. Upper images: at initial presentation, bronchoscopy demonstrates mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending 7 cm distally. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Lower images: following 4 months of treatment, there was moderate improvement.
256 2
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Bhojwani Bhojwani et et al. al.
Nondisseminated Nondisseminated histoplasmosis histoplasmosis of of the the trachea trachea
Figure 2. Silver staining of the tracheal biopsy on the right demonstrating Histoplasma capsulatum, 400× magnification. Hematoxylin and eosin staining of the tracheal biopsy on the left demonstrating necrotic/fibrinoinflammatory material, 400× magnification.
and mild narrowing of the trachea. After 9 months of oral itraconazole, the patient continued to have symptoms of hoarseness and some shortness of breath, presumably from chronic inflammation of the laryngeal structures. At this time, her Histoplasma urine antigen levels, a useful test to monitor the outcome of disseminated histoplasmosis, were found to be 11.21 ng/mL, consistent with poor treatment response. Liposomal Amphotericin B 5 mg/kg (400 mg) IV daily was initiated with good results; however, IV Amphotericin was stopped after 2 weeks due to the patient developing methicillin susceptible Staphylococcus aureus
Figure 3. Biopsy fragment of ulcerated/eroded bronchial mucosa with squamous metaplasia, 400× magnification.
The The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981
C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
bacteremia from her peripherally inserted central catheter. She was then started on posaconazole 400 mg oral twice daily. The Histoplasma antigen level came back to 6.3 ng/mL after amphotericin and then 2.1 ng/mL after 1 month of posaconazole. She continued treatment 24 months following diagnosis, with minimal dyspnea on exertion. Histoplasma capsulatum is an ascomycete that grows in soil as a dimorphic mold along the Ohio and Mississippi river valleys (1, 2). Exposure to microconidia from the affected soil leads to infection in fewer than 5% of those exposed to a low inoculum and typically results in symptoms similar to influenza with fever, chills, headache, myalgias and nonproductive cough (2, 3). Risk factors for infection are extremes of age, heavy exposure and immunosuppression (2, 4). Our patient meets the age risk and was on chronic corticosteroid and methotrexate therapy for rheumatoid arthritis. Chronic pulmonary histoplasmosis was once thought to primarily affect male smokers but more recent studies have found up to 48% of cases occur in females and 26% in nonsmokers (5). Histoplasma is well described as causing endobronchial stenosis as a consequence of fibrosing mediastinitis (6–8). In addition, a series of four cases was published with isolated endobronchial disease, all of whom presented with hemoptysis (9). However, there is little documentation of direct tracheal submucosal infection. The few cases that exist describe tracheal submucosal involvement in patients with disseminated histoplasmosis or cavitary disease, leading 2573
Nondisseminated Nondisseminated histoplasmosis histoplasmosis of of the the trachea trachea
to the proposal that Histoplasma tracheitis may be an indicator of disseminated infection (10). However, in this case the patient had no other organ manifestations. To the best of our knowledge, this particular presentation of localized histoplasmosis has not been previously reported. Histoplasma tracheitis should therefore be considered in a differential diagnosis of tracheal lesions, even in the absence of disseminated infection. Standard treatment guidelines do not address isolated endobronchial histoplasmosis. Our patient responded well to a 24-month course of antifungal therapy.
References 1. Bowman BH, Taylor JW, White TJ. Molecular evolution of the fungi: human pathogens. Mol Biol Evol. 1992;9: 893–904. 2. Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med. 2004;25: 129–44.
258 4
Bhojwani Bhojwani et et al. al.
3. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French ML, Biesecker JL. A large urban outbreak of histoplasmosis: clinical features. Ann Intern Med. 1981;94: 331–7. 4. Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine. 1980;59: 1–33. 5. Kennedy CC, Limper AH. Redefining the clinical spectrum of chronic pulmonary histoplasmosis: a retrospective case series of 46 patients. Medicine. 2007;86: 252–8. 6. Goodwin RA, Nickell JA, Des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and tuberculosis. Medicine. 1972;51: 227–46. 7. Davis AM, Pierson RN, Loyd JE. Mediastinal fibrosis. Semin Respir Infect. 2001;16: 119–30. 8. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine. 1981;60: 231–66. 9. Ross P Jr, Magro CM, King MA. Endobronchial histoplasmosis: a masquerade of primary endobronchial neoplasia – a clinical study of four cases. Ann Thorac Surg. 2004;78: 277–81. 10. Youness H, Michel RG, Pitha JV, Jones KR, Kinasewitz GT. Tracheal and endobronchial involvement in disseminated histoplasmosis: a case report. Chest. 2009;136: 1650–3.
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
The Clinical Respiratory Journal
Nondisseminated histoplasmosis of the trachea Nicholas Bhojwani1, Jason Brett Hartman2, David C. Taylor3, Mark Herbert4 and Michael Corriveau5 1 Department of Radiology, University Hospitals Case Medical Center, Cleveland, OH, USA 2 School of Medicine, Case Western Reserve University, Cleveland, OH, USA 3 Department of Pathology, Mount Carmel Health System, Columbus, OH, USA 4 Department of Infectious Disease, Mount Carmel Health System, Columbus, OH, USA 5 Department of Pulmonary and Critical Care Medicine, Mount Carmel Health System, Columbus, OH, USA
Abstract Histoplasma capsulatum can rarely affect the trachea. We report the case of a 68-year-old woman with rheumatoid arthritis on immunosuppressive therapy who presented with fevers, worsening shortness of breath, nonproductive cough and subjective throat hoarseness and fullness. Chest computed tomography demonstrated no tracheal findings. Bronchoscopy found mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending seven centimeters distal to the vocal cords. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Silver staining and culture and wash of the tracheal biopsy revealed Histoplasma capsulatum. She was treated with oral itraconazole then briefly on intravenous amphotericin for rising Histoplasma urinary antigen levels. She continued treatment 24 months following diagnosis with minimal dyspnea. Histoplasma tracheitis has been proposed as an indicator of disseminated infection. However, our patient did not demonstrate other organ manifestations. Histoplasma tracheitis should be considered in a differential diagnosis of tracheal lesions even in the absence of systemic involvement. Please cite as: as: Bhojwani N, Hartman JB, Taylor Herbert Corriveau Please citethis thispaper paper Bhojwani N, Hartman JB, DC, Taylor DC, M, Herbert M, M. Nondisseminated histoplasmosis of the trachea. Clin Respir J 2016; 10: Corriveau M. Nondisseminated histoplasmosis of the trachea. Clin Respir J 255–258. 2014; ••: DOI:10.1111/crj.12185. ••–••. DOI:10.1111/crj.12185.
Key words bronchoscopy – Histoplasma – immunosuppression – trachea Correspondence Nicholas Bhojwani, MD, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Ave, Mailstop BSH 5056, Cleveland 44106 OH, USA. Tel.: +1 216 844 1000 Fax: +1 888 340 4993 email: [email protected] Received: 23 July 2013 Revision requested: 27 May 2014 Accepted: 03 July 2014 DOI:10.1111/crj.12185 Authorship and contributorship Nicholas Bhojwani: Collected and analyzed data, composed manuscript. Jason Hartman: Analyzed data, composed manuscript. David C. Taylor: Designed study, reviewed manuscript. Mark Herbert: Designed study, reviewed manuscript. Michael Corriveau: Designed study, reviewed manuscript. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Presentations This material was presented at American College of Physicians Columbus, Ohio Chapter, October 2011.
Case report This report was exempted by the Mount Carmel Health System Institutional Review Board. A 68-year-
The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 The Clinical Clinical Respiratory
© 2014 John John Wiley Wiley && Sons Sons Ltd Ltd C 2014 V
old woman with a past medical history significant for rheumatoid arthritis on prednisone and methotrexate presented to an Ohio hospital in December 2008 with a 1-month history of worsening shortness of breath
1 255
Nondisseminated Nondisseminated histoplasmosis histoplasmosis of of the the trachea trachea
and nonproductive cough unresolved with oral courses of amoxicillin/clavulanate and levofloxacin. She admitted to some hoarseness, a feeling of fullness in her throat and low grade fevers. For several years, she had been on prednisone 5-mL oral tablet daily and methotrexate 25-mL injection weekly. She was a lifelong nonsmoker with no history of underlying lung disease. Her vitals on physical exam were an oral temperature of 98.4°F, pulse of 100 beats/min, respiratory rate 22 breaths/min, blood pressure 119/56 mmHg and oxygen saturation of 96% on 2-L nasal cannula. Stridor was heard on auscultation over the trachea. The rest of physical exam including cardiovascular, lower respiratory, gastrointestinal, neurological and integumentary systems was negative. The white blood cell count was 5.8K cells/μL. An arterial blood gas was within normal limits. A chest CT was performed that revealed minor atelectasis, but no pulmonary infiltrates or
Bhojwani Bhojwani et et al. al.
adenopathy. Bronchoscopy was then performed, which revealed mucosal irregularity, nodularity and vesicular lesions in the proximal trachea extending 7 cm distal to the vocal cords (see Fig. 1). Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion (see Fig. 1). Initial cultures from the bronchial wash and biopsy grew methicillinresistant Staphylococcus aureus, light Cryptococcus and light Histoplasma. Viral cultures were also sent, which were negative. Subsequent silver staining and culture of the tracheal biopsy and wash revealed Histoplasma capsulatum (see Fig. 2). Also seen on tracheal biopsy were acute and chronic inflammation, ulceration and inflammatory atypia (see Fig. 3). Oral itraconazole 100 mg twice daily was given for 9 months. After 4 months of itraconazole therapy, repeat bronchoscopy showed improving irregular inflammatory tracheal mucosa, granulation tissues on the true vocal cords
Figure 1. Upper images: at initial presentation, bronchoscopy demonstrates mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending 7 cm distally. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Lower images: following 4 months of treatment, there was moderate improvement.
256 2
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
Bhojwani Bhojwani et et al. al.
Nondisseminated Nondisseminated histoplasmosis histoplasmosis of of the the trachea trachea
Figure 2. Silver staining of the tracheal biopsy on the right demonstrating Histoplasma capsulatum, 400× magnification. Hematoxylin and eosin staining of the tracheal biopsy on the left demonstrating necrotic/fibrinoinflammatory material, 400× magnification.
and mild narrowing of the trachea. After 9 months of oral itraconazole, the patient continued to have symptoms of hoarseness and some shortness of breath, presumably from chronic inflammation of the laryngeal structures. At this time, her Histoplasma urine antigen levels, a useful test to monitor the outcome of disseminated histoplasmosis, were found to be 11.21 ng/mL, consistent with poor treatment response. Liposomal Amphotericin B 5 mg/kg (400 mg) IV daily was initiated with good results; however, IV Amphotericin was stopped after 2 weeks due to the patient developing methicillin susceptible Staphylococcus aureus
Figure 3. Biopsy fragment of ulcerated/eroded bronchial mucosa with squamous metaplasia, 400× magnification.
The The Clinical Clinical Respiratory Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981
C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
bacteremia from her peripherally inserted central catheter. She was then started on posaconazole 400 mg oral twice daily. The Histoplasma antigen level came back to 6.3 ng/mL after amphotericin and then 2.1 ng/mL after 1 month of posaconazole. She continued treatment 24 months following diagnosis, with minimal dyspnea on exertion. Histoplasma capsulatum is an ascomycete that grows in soil as a dimorphic mold along the Ohio and Mississippi river valleys (1, 2). Exposure to microconidia from the affected soil leads to infection in fewer than 5% of those exposed to a low inoculum and typically results in symptoms similar to influenza with fever, chills, headache, myalgias and nonproductive cough (2, 3). Risk factors for infection are extremes of age, heavy exposure and immunosuppression (2, 4). Our patient meets the age risk and was on chronic corticosteroid and methotrexate therapy for rheumatoid arthritis. Chronic pulmonary histoplasmosis was once thought to primarily affect male smokers but more recent studies have found up to 48% of cases occur in females and 26% in nonsmokers (5). Histoplasma is well described as causing endobronchial stenosis as a consequence of fibrosing mediastinitis (6–8). In addition, a series of four cases was published with isolated endobronchial disease, all of whom presented with hemoptysis (9). However, there is little documentation of direct tracheal submucosal infection. The few cases that exist describe tracheal submucosal involvement in patients with disseminated histoplasmosis or cavitary disease, leading 2573
Nondisseminated Nondisseminated histoplasmosis histoplasmosis of of the the trachea trachea
to the proposal that Histoplasma tracheitis may be an indicator of disseminated infection (10). However, in this case the patient had no other organ manifestations. To the best of our knowledge, this particular presentation of localized histoplasmosis has not been previously reported. Histoplasma tracheitis should therefore be considered in a differential diagnosis of tracheal lesions, even in the absence of disseminated infection. Standard treatment guidelines do not address isolated endobronchial histoplasmosis. Our patient responded well to a 24-month course of antifungal therapy.
References 1. Bowman BH, Taylor JW, White TJ. Molecular evolution of the fungi: human pathogens. Mol Biol Evol. 1992;9: 893–904. 2. Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med. 2004;25: 129–44.
258 4
Bhojwani Bhojwani et et al. al.
3. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French ML, Biesecker JL. A large urban outbreak of histoplasmosis: clinical features. Ann Intern Med. 1981;94: 331–7. 4. Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine. 1980;59: 1–33. 5. Kennedy CC, Limper AH. Redefining the clinical spectrum of chronic pulmonary histoplasmosis: a retrospective case series of 46 patients. Medicine. 2007;86: 252–8. 6. Goodwin RA, Nickell JA, Des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and tuberculosis. Medicine. 1972;51: 227–46. 7. Davis AM, Pierson RN, Loyd JE. Mediastinal fibrosis. Semin Respir Infect. 2001;16: 119–30. 8. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine. 1981;60: 231–66. 9. Ross P Jr, Magro CM, King MA. Endobronchial histoplasmosis: a masquerade of primary endobronchial neoplasia – a clinical study of four cases. Ann Thorac Surg. 2004;78: 277–81. 10. Youness H, Michel RG, Pitha JV, Jones KR, Kinasewitz GT. Tracheal and endobronchial involvement in disseminated histoplasmosis: a case report. Chest. 2009;136: 1650–3.
The Clinical Clinical Respiratory The Respiratory Journal Journal (2016) (2014) •• ISSN ISSN 1752-6981 1752-6981 C 2014 John Wiley & Sons Ltd V © 2014 John Wiley & Sons Ltd
