Complications of chronic necrotizing pulmonary aspergillosis: review of published case reports

Aleksandra Barac Tatjana Adzic Vukicevic Aleksandra Dudvarski Ilic Salvatore Rubino Vladimir Zugic Goran Stevanovic About the authors

ABSTRACT

Chronic necrotizing pulmonary aspergillosis (CNPA), a form of chronic pulmonary aspergillosis (CPA), affects immunocompetent or mildly immunocompromised persons with underlying pulmonary disease. These conditions are associated with high morbidity and mortality and often require long-term antifungal treatment. The long-term prognosis for patients with CNPA and the potential complications of CNPA have not been well documented. The aim of this study was to review published papers that report cases of CNPA complications and to highlight risk factors for development of CNPA. The complications in conjunction associated with CNPA are as follows: pseudomembranous necrotizing tracheobronchial aspergillosis, ankylosing spondylarthritis, pulmonary silicosis, acute respiratory distress syndrome, pulmonary Mycobacterium avium complex (MAC) disease, superinfection with Mycobacterium tuberculosis, and and pneumothorax. The diagnosis of CNPA is still a challenge. Culture and histologic examinations of bronchoscopically identified tracheobronchial mucus plugs and necrotic material should be performed in all immunocompromised individuals, even when the radiographic findings are unchanged. Early detection of intraluminal growth of Aspergillus and prompt antifungal therapy may facilitate the management of these patients and prevent development of complications.

Chronic necrotizing pulmonary aspergillosis; Complications; Aspergillus

INTRODUCTION

Aspergillus infection of the lung manifests in a wide spectrum of conditions ranging from saprophytic colonization to hypersensitivity reactions to necrotizing pneumonia with angioinvasion11. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47:45-68.. In the saprophytic form of the disease, aspergillomas establish themselves in pre-existing cavities. The chronic cavitary form of aspergillosis, which produces a slowly progressive infiltrate that may include mycetoma, was proposed in 1981 as a new category of semi-invasive pulmonary22. Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. “Semi-invasive” pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. Radiology. 1981;140:313-21. or chronic necrotizing pulmonary aspergillosis (CNPA)33. Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine (Baltimore). 1982;61:109-24.. CNPA is a form of chronic pulmonary aspergillosis (CPA), often presenting with rapid progressive infection (< 3 months) in moderately immunocompromised patients, which should be managed as invasive aspergillosis11. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47:45-68.. Aspergillus has a propensity to invade pulmonary blood vessels, resulting in pulmonary infarction and subsequent development of necrotic cavities and bronchus dilatation44. Pittet D, Huguenin T, Dharan S, Sztajzel-Boissard J, Ducel G, Thorens JB, et al. Unusual cause of lethal pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;154:541-4.. Lung conditions affecting the pulmonary defense system, such as previous surgical resection, ionizing radiation therapy, or chronic obstructive pulmonary disease (COPD), allow Aspergillus to penetrate the lung through enzyme secretion despite the absence of cavities55. Kibbler CC, Milkins SR, Bhamra A, Spiteri MA, Noone P, Prentice HG. Apparent pulmonary mycetoma following invasive aspergillosis in neutropenic patients. Thorax 1988;43:108–12.. In addition to COPD, other conditions commonly associated with CNPA include previous pulmonary tuberculosis (TB), atypical Mycobacterium tuberculosis infection, cystic fibrosis, pulmonary infarction, pulmonary fibrosis, previous surgery, and pneumoconiosis66. Attaway AH, Jacono F, Gilkeson R, Faress JA. Subacute invasive pulmonary aspergillosis associated with ankylosing spondylitis. Am J Respir Crit Care Med. 2016;193:572-3.

7. Peghin M, Ruiz-Camps I, Garcia-Vidal C, Cervera C, Andreu J, Martin M, et al. Unusual forms of subacute invasive pulmonary aspergillosis in patients with solid tumors. J Infect. 2014;69:387-95.
-88. Gupta PP, Fotedar S, Agarwal D, Magu S, Saini K. Pneumothorax: a rare presentation of pulmonary mycetoma. Ann Thorac Med. 2007;2:171-2.. Other conditions that may be associated with the development of CNPA include lung cancer, stage III or IV fibrocystic pulmonary sarcoidosis, and silicosis66. Attaway AH, Jacono F, Gilkeson R, Faress JA. Subacute invasive pulmonary aspergillosis associated with ankylosing spondylitis. Am J Respir Crit Care Med. 2016;193:572-3.

7. Peghin M, Ruiz-Camps I, Garcia-Vidal C, Cervera C, Andreu J, Martin M, et al. Unusual forms of subacute invasive pulmonary aspergillosis in patients with solid tumors. J Infect. 2014;69:387-95.
-88. Gupta PP, Fotedar S, Agarwal D, Magu S, Saini K. Pneumothorax: a rare presentation of pulmonary mycetoma. Ann Thorac Med. 2007;2:171-2.. Other immunosuppression conditions such as diabetes mellitus, malnutrition, alcoholism, connective tissue diseases, and prolonged corticosteroid therapy also increase the risk for development of CNPA11. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47:45-68.,22. Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. “Semi-invasive” pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. Radiology. 1981;140:313-21.. Complications of CNPA usually occur because of leakage of air from an air-filled lung cavity into the pleural space. These conditions are associated with high morbidity and mortality and often require long-term antifungal treatment99. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Disease Society of America. Clin Infect Dis. 2008;46:327-60.. The long-term prognosis for patients with CNPA and potential complications of CNPA have not been well documented. The aim of this study was to review published papers reporting cases of CNPA complications and to highlight risk factors for development of CNPA.

Pseudomembranous necrotizing tracheobronchial aspergillosis and CNPA

The Oh et al.1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82. reported a case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. They reported a rare case of Aspergillus pseudomembranous tracheobronchitis without an invasion of the pulmonary parenchyma that developed in an immunocompetent patient1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82.. Aspergillus tracheobronchitis was confined, at least initially, to the airways with only a superficial mucosal invasion, and the diagnosis was delayed because of non-specific signs, symptoms, and lack of radiographic abnormalities1111. Sayiner A, Kursat S, Toz H, Duman S, Onal B, Tumbay E. Pseudomembranous necrotizing bronchial aspergillosis in a renal transplant recipient. Nephrol Dial Transplant. 1999;14:1784-5.. Pseudomembranous necrotizing tracheobronchial aspergillosis has been reported recently as an uncommon form of airway invasive aspergillosis in immunocompromised patients1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82.,1212. Ahn MI, Park SH, Kim JA, Kwon MS, Park YH. Pseudomembranous necrotizing bronchial aspergillosis. Br J Radiol. 2000;73:73-5.

13. Silveira F, Paterson DL. Pulmonary fungal infections. Curr Opin Pulm Med. 2005;11:242-6.

14. Kim JS, Rhee Y, Kang SM, Ko WK, Kim YS, Lee JG, et al. A case of endobronchial aspergilloma. Yonsei Med J. 2000;41: 422-5.
-1515. Clarke A, Skeleton J, Fraser RS. Fungal tracheobronchitis: report of 9 cases and review of the literature. Medicine (Baltimore). 1991;70:1-14.. In a review of the literature on Aspergillus tracheobronchitis, including all forms of tracheobronchial involvement, reports indicated that the disease was progressive and fatal in about 40% of cases1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82.,1313. Silveira F, Paterson DL. Pulmonary fungal infections. Curr Opin Pulm Med. 2005;11:242-6.

14. Kim JS, Rhee Y, Kang SM, Ko WK, Kim YS, Lee JG, et al. A case of endobronchial aspergilloma. Yonsei Med J. 2000;41: 422-5.
-1515. Clarke A, Skeleton J, Fraser RS. Fungal tracheobronchitis: report of 9 cases and review of the literature. Medicine (Baltimore). 1991;70:1-14.. This was apparently a lethal variant of tracheobronchial aspergillosis with a markedly higher mortality rate and more parenchymal lung involvement (65%) compared with all cases of Aspergillus tracheobronchitis (45%)1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82.,1515. Clarke A, Skeleton J, Fraser RS. Fungal tracheobronchitis: report of 9 cases and review of the literature. Medicine (Baltimore). 1991;70:1-14.. It presents an extensive transmural necrotizing bronchitis with pseudomembrane formation that develops in immunocompromised patients, and it is usually characterized by a limited extension of inflammation and hyphae into the peribronchial tissue, without an invasion of the pulmonary parenchyma1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82.,1212. Ahn MI, Park SH, Kim JA, Kwon MS, Park YH. Pseudomembranous necrotizing bronchial aspergillosis. Br J Radiol. 2000;73:73-5.. Involvement of the bronchial tree can be invasive, leading to a pseudomembranous tracheobronchitis with extensive bronchial hemorrhage and invasion of the bronchial walls and vessels. In the literature review, we found reports of 22 cases with this variant of tracheobronchial involvement by Aspergillus1212. Ahn MI, Park SH, Kim JA, Kwon MS, Park YH. Pseudomembranous necrotizing bronchial aspergillosis. Br J Radiol. 2000;73:73-5.

13. Silveira F, Paterson DL. Pulmonary fungal infections. Curr Opin Pulm Med. 2005;11:242-6.

14. Kim JS, Rhee Y, Kang SM, Ko WK, Kim YS, Lee JG, et al. A case of endobronchial aspergilloma. Yonsei Med J. 2000;41: 422-5.
-1515. Clarke A, Skeleton J, Fraser RS. Fungal tracheobronchitis: report of 9 cases and review of the literature. Medicine (Baltimore). 1991;70:1-14.. There are published only five reports of this disease developing in an immunocompetent or mildly immunocompromised patient. The first case revealed cutaneous anergy and lymphopenia involving T cells and NK cells, related to a recent influenza A infection1616. Boots RJ, Paterson DL, Allworth AM, Faoagali JL. Successful treatment of post-influenza pseudomembranous necrotizing bronchial aspergillosis with liposomal amphotericin, inhaled amphotericin B, gamma interferon and GM-CSF. Thorax. 1999;54:1047-9.. In the second case, there were “grayish” mucus plugs in several segmental bronchi on autopsy and focally limited extension into the adjacent lung parenchyma1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. The third case revealed the presence of fungal invasion through the bronchial wall into the adjacent lung parenchyma and pulmonary arteries1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. The fourth case was a 70-year-old man with many risk factors, including corticosteroid use. The fifth case was a 66-year-old with underlying COPD1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. This patient had no risk factors associated with an immunocompromised state, and had no invasion of the parenchyma, or atelectasis, but his condition rapidly progressed to severe CO2 retention and respiratory failure. Pseudomembranous necrotizing tracheobronchial aspergillosis should be considered as potential complication of CNPA even in an immunocompetent host1010. Oh HJ, Kim HR, Hwang KE, Kim SY, Ahn SH, Yang SH, et al. Case of pseudomembranous necrotizing tracheobronchial aspergillosis in an immunocompetent host. Korean J Intern Med. 2006;21:279-82.,1515. Clarke A, Skeleton J, Fraser RS. Fungal tracheobronchitis: report of 9 cases and review of the literature. Medicine (Baltimore). 1991;70:1-14.,1616. Boots RJ, Paterson DL, Allworth AM, Faoagali JL. Successful treatment of post-influenza pseudomembranous necrotizing bronchial aspergillosis with liposomal amphotericin, inhaled amphotericin B, gamma interferon and GM-CSF. Thorax. 1999;54:1047-9..

Ankylosing spondylarthritis and CNPA

Fibro-bullous disease is a late complication of ankylosing spondylarthritis1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.,1818. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600.. Its radiologic features frequently mimics tuberculosis or excavated neoplasm. About 50 to 65% of patients with ankylosing spondylarthritis have chronic Aspergillus colonization of their airways1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. Pulmonary aspergillosis infection occurs in 10 to 30% during evolution. Pontier et al. reported two cases of patients with spondylarthritis who developed chronic necrotizing pulmonary aspergillosis1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. Diagnosis was based on serology, mycologic examination of expectoration and in one case, on histology obtain by transbronchial biopsies. Pulmonary complications due to Aspergillus species frequently reveal associated fibro-bullous disease in patients with ankylosing spondylarthritis. The fibroblastic disease is often asymptomatic and, as in the reported cases, its clinical revelation is often linked to a complication (bacterial or fungal infections, tuberculosis, pneumothorax, etc.). In one case, it was associated with unilateral, pseudo-tuberculosis, with a preferential apical location and pleural involvement. In cases with ankylosing spondylarthritis and CNPA, there is usually bilateral and asymmetric pachypleuritis1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.

18. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600.
-1919. Bourgeois P. Manifestations systémiques de la spondylarthrite ankylosante. In: Kahn MF, Peltier AP, Meyer O, Piette JC, éditeurs. Les maladies systémiques. 3eme ed. Paris: Médecine-Sciences Flammarion; 1991. p.839-55.. This is a rare complication of spondylitis in about 1.3% of patients1818. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600., with male predominance and it is estimated that it is revealed on average 17 years after the spinal signs. There is no specific predictive factor (HLA B27 antigen positive in 50% of cases)1818. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600.. The two patients reported by Pontier et al.1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6., had no previously known pulmonary pathology1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. At the anatomo-pathologic level, lesions of inter-alveolar fibrosis with hyaline fibrosis and non-specific lymphocytic and macrophage infiltrates were found1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. The origin of this fibrosis is currently unknown but several hypotheses have been suggested: an inflammatory fibrosis aggravated or caused by repeated infectious episodes, a hypoventilation of the apexes favored by the restrictive syndrome and systemic inflammatory attack comparable with the involvement of other organs1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.

18. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600.
-1919. Bourgeois P. Manifestations systémiques de la spondylarthrite ankylosante. In: Kahn MF, Peltier AP, Meyer O, Piette JC, éditeurs. Les maladies systémiques. 3eme ed. Paris: Médecine-Sciences Flammarion; 1991. p.839-55.. The evolution can be towards chronic respiratory insufficiency.

Semi-invasive pulmonary aspergillosis or CNPA occurs in 10-30% of cases of fibroblastic disease. It is a frequent mode of revelation1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.

18. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600.
-1919. Bourgeois P. Manifestations systémiques de la spondylarthrite ankylosante. In: Kahn MF, Peltier AP, Meyer O, Piette JC, éditeurs. Les maladies systémiques. 3eme ed. Paris: Médecine-Sciences Flammarion; 1991. p.839-55.. Unlike aspergilloma, there is no pre-existing cavity, and no walls are built. It is probably favored by hypoventilation of the vertices during spondylitis. It may develop into fibroblastic sequelae. The question arises as to whether fibroblastic disease is a sequela of semi-invasive pulmonary aspergillosis or pre-existing in asymptomatic form. In both cases, semi-invasive aspergillosis is manifested as severe broncho-pneumonia, resistant to antibiotics, and potentially fatal1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.. The general clinical sign predominates and distinguishes it from aspergilloma. Pontier et al.1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6. describe the acute form, evolving in a few weeks towards pneumonic block and signs of suppuration, and sub-acute form, with a pseudo-tuberculous picture evolving towards necrosis. In the cases presented by Pontier et al.1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6., a radio-clinical picture of intra-cavitary aspergillosis was demonstrated after favorable response to antifungal treatment. Although cases of isolated aspergilloma have been described in patients with ankylosing spondylitis with fibroblastic lesions1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6.

18. Peltier P, Germaud P, Martin M, Barrier J, Cottin S, Grolleau JY. Fibrose pulmonaire et pelvi-spondylite rhumatismale: à propos de 5 cas. Sem Hop. 1982;58:596-600.
-1919. Bourgeois P. Manifestations systémiques de la spondylarthrite ankylosante. In: Kahn MF, Peltier AP, Meyer O, Piette JC, éditeurs. Les maladies systémiques. 3eme ed. Paris: Médecine-Sciences Flammarion; 1991. p.839-55., in the two cases published by Pontier et al.1717. Pontier S, Bigay L, Doussau S, Recco P, Lacassagne L, Didier A. Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante. Rev Mal Respir. 2000;17:683-6., were probably a result of low-lying progression of semi-invasive aspergillosis previously incompletely controlled by medical treatment.

Pulmonary silicosis and CNPA

Blanco et al.2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14. reported three cases with a long history of exposure to silica dust with pulmonary aspergillosis complicated bu progressive massive fibrosis (PMF)2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14.. Pneumoconiosis, which causes deterioration of local immunity, is less frequent, limited to 2% and 3% of cases2121. Hohl TM, Feldmesser M. Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell. 2007;6: 1953-63.,2222. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37 Suppl 3:S265-80.. The three cases presented by Blanco et al.2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14. presented had a history of tuberculosis, which was variably described in the literature (between 11% and 93%)2121. Hohl TM, Feldmesser M. Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell. 2007;6: 1953-63.,2222. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37 Suppl 3:S265-80.. Frequent treatment with steroids in the first patient and a history of alcoholism in the second patient probably contributed to the predisposition for CNPA2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14.. On the other hand, all three had been active smokers2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14., a history referred to in 53% of the patients reported by Nam et al.2323. Nam HS, Jeon K, Um SW, Suh GY, Chung NP, Kim H, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14:e479-82. but not mentioned in the other series. Compared with Nam et al.2323. Nam HS, Jeon K, Um SW, Suh GY, Chung NP, Kim H, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14:e479-82. reports, in which the youngest patient was 48 years old and only 20% had large opacities, patients reported by Blanco et al.2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14. were younger and PMF was observed in all three cases. These patients usually present with fever, cough and weight loss, and less frequently dyspnea or chest pain. The three patients reported by Blanco et al.2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14. had hemoptysis and mycetoma2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14., which is reported in 49% and 90% of cases in the literature2121. Hohl TM, Feldmesser M. Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell. 2007;6: 1953-63.

22. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37 Suppl 3:S265-80.
-2323. Nam HS, Jeon K, Um SW, Suh GY, Chung NP, Kim H, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14:e479-82.. Radiologically, the presence of infiltrates in the upper lobes, cavitation, nodular opacities, and pleural thickening are the most common findings that coincide with silicosis in patients with CNPA2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14.

21. Hohl TM, Feldmesser M. Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell. 2007;6: 1953-63.

22. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37 Suppl 3:S265-80.
-2323. Nam HS, Jeon K, Um SW, Suh GY, Chung NP, Kim H, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14:e479-82..

CNPA can be serious, fatal if untreated, and may be accompanied by acute respiratory distress syndrome2323. Nam HS, Jeon K, Um SW, Suh GY, Chung NP, Kim H, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14:e479-82.-2424. Yano S. Acute respiratory distress syndrome due to chronic necrotizing pulmonary aspergillosis. Intern Med. 2007;46:889-91.. CNPA can also play a relevant role in the mortality of patients with silicosis. The study by Iossifova et al.2525. Iossifova Y, Bailey R, Wood J, Kreiss K. Concurrent silicosis and pulmonary mycosis at death. Emerg Infect Dis. 2010;16:318-20. showed that people with CNPA and silicosis are almost 10 times more likely to die than people without silicosis. In addition, in young patients, lung transplantation could be contraindicated, as shown in the first case reported by Blanco et al.2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14..

Given the high mortality, the diagnosis of CNPA in patients with silicosis should be considered as soon as possible, especially if there are any signs of new infiltrates, mycetomas, and anamnestic data of active smoking or a history of TB2020. Blanco JJ, Barcala FJ, Moure MA, Mao MC. Aspergilosis pulmonar necrotizante crónica como complicación de silicosis. An Sist Sanit Navar. 2011;34:109-14.

21. Hohl TM, Feldmesser M. Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell. 2007;6: 1953-63.

22. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37 Suppl 3:S265-80.

23. Nam HS, Jeon K, Um SW, Suh GY, Chung NP, Kim H, et al. Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases. Int J Infect Dis. 2010;14:e479-82.
-2424. Yano S. Acute respiratory distress syndrome due to chronic necrotizing pulmonary aspergillosis. Intern Med. 2007;46:889-91..

Acute respiratory distress syndrome and CNPA

Yano2424. Yano S. Acute respiratory distress syndrome due to chronic necrotizing pulmonary aspergillosis. Intern Med. 2007;46:889-91. published a report of a patient with acute respiratory distress syndrome (ARDS) who died because of CNPA. This patient had pulmonary fibrosis of unknown cause with a right upper bulla. Mycetoma in the bulla, invaded the tissue adjacent to the bulla, as the wall of the right upper bulla became thicker with surrounding lung infiltration2424. Yano S. Acute respiratory distress syndrome due to chronic necrotizing pulmonary aspergillosis. Intern Med. 2007;46:889-91.. This patient developed ARDS because of CNPA after Aspergillus invaded these tissues leading to fatal respiratory failure. The patient had a cerebral accident 6 days after respiratory failure, probably as a result of septic emboli accompanied with CNPA. Depending on the size of the emboli, nuclear magnet resonance (NMR) findings may vary from major arterial branch infarction to multiple small abscesses located at the gray-white matter junction, secondary to occlusion of small arteries and arterioles2525. Iossifova Y, Bailey R, Wood J, Kreiss K. Concurrent silicosis and pulmonary mycosis at death. Emerg Infect Dis. 2010;16:318-20.,2626. Parker JC Jr, Dyer MC. Neurologic infections due to bacteria, fungi, and parasites. In: Davis RL, Robertson DM, editors. Textbook of neuropathology. Baltimore: Williams & Wilkins; 1985. p. 632-703.. Small abscesses are accompanied by surrounding oedema and mass effect, which is well demonstrated on NMR11. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47:45-68.. One day before the first cerebral accident in case reported by Yano2424. Yano S. Acute respiratory distress syndrome due to chronic necrotizing pulmonary aspergillosis. Intern Med. 2007;46:889-91., the percentage of serum eosinophils increased to 13%; after the first cerebral attack, the increased percentage of eosinophils persisted at around 13-22%. This peripheral eosinophilia may reflect activation of the lung aspergillus lesion. It is important to consider that ARDS may occur in cases of CNPA and that peripheral eosinophilia might forebode worsening of CNPA2424. Yano S. Acute respiratory distress syndrome due to chronic necrotizing pulmonary aspergillosis. Intern Med. 2007;46:889-91.

25. Iossifova Y, Bailey R, Wood J, Kreiss K. Concurrent silicosis and pulmonary mycosis at death. Emerg Infect Dis. 2010;16:318-20.

26. Parker JC Jr, Dyer MC. Neurologic infections due to bacteria, fungi, and parasites. In: Davis RL, Robertson DM, editors. Textbook of neuropathology. Baltimore: Williams & Wilkins; 1985. p. 632-703.

27. Whiteman ML, Boman BC, Post MJ, Bell MD. Intracranial infection. In: Atlas SW, editor. Magnetic resonance imaging of the brain and spine. 2nd ed. New York: Raven; 1996. p.729-32.
-2828. Alan MS, Elizabeth AO. Aspergillus syndrome, mucormycosis and pulmonary candidiasis. In: Fishman AP, editor. Fishman’s pulmonary diseases and disorders. 3rd ed. New York: McGraw-Hill; 1998. p.2265-8..

Pulmonary Mycobacterium avium complex disease and CNPA

Pulmonary aspergilloma is an important complication occurring in cavities remaining after pulmonary TB, and it has been reported as a complication in 15% of patients with sequelae of pulmonary TB2828. Alan MS, Elizabeth AO. Aspergillus syndrome, mucormycosis and pulmonary candidiasis. In: Fishman AP, editor. Fishman’s pulmonary diseases and disorders. 3rd ed. New York: McGraw-Hill; 1998. p.2265-8.

29. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.
-3030. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50.. Although the most frequent underlying disease with pulmonary aspergillosis was pulmonary TB2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12., there are no detailed reports regarding the formation of pulmonary aspergilloma including CNPA with a fungus ball in a cavity formed by pulmonary Mycobacterium avium intracellular complex (MAC). Kobashi et al.3030. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50. reported a case of CNPA in which a fungus ball appeared in a growing cavity transitionally formed by pulmonary MAC, during a follow-up period after treatment3030. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50.. The most frequently reported underlying disease in cases of pulmonary aspergilloma including CNPA is sequela of pulmonary TB (25-72%), secondary to a pre-existing intrapulmonary cavity such as a pulmonary cyst2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.,3131. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6.,3232. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.. There have been a few reports of superinfection by Aspergillus spp. of pulmonary lesions caused by Mycobacterium xenopi3333. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.,3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.. However, the frequency of nontuberculous mycobacteria (MAC, etc.) has recently increased among patients with pulmonary mycobacterial diseases, especially in industrialized nations2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.. In addition, there are many cases in previous reports in which the underlying disease of pulmonary aspergilloma including CNPA was a cavity formed by a pulmonary nontuberculous mycobacterial, rather than a cavity formed by pulmonary TB2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.

30. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50.

31. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6.

32. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.

33. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.
-3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.. The clinical symptoms caused by pulmonary aspergilloma vary in accordance with the severity of the underlying pre-existing pulmonary disease, but a common characteristic has been hemosputum or haemoptysis2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.

30. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50.

31. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6.

32. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.

33. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.
-3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.. The chief complaint in the case presented by Kobashi et al.3030. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50. was continuous fever, which suggests that the patient probably developed the condition, which suddenly destroyed the lung, as semi-invasive pulmonary aspergillosis or CNPA, rather than pulmonary aspergilloma. Denning3131. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6. also reported that patients with pulmonary aspergilloma with clinical symptoms such as fever and cachexia usually have undiscovered CNPA, rather than pulmonary aspergilloma. The patient presented by Denning3131. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6. had a mixed infection caused by A. niger and M. avium, although it has been commonly mentioned that A. fumigatus is the most frequent isolate from patients with CNPA. Kawamura et al.3030. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50. and Perfect et al.3232. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33. reported isolation rates of A. fumigatus of 75% and 80%, respectively; the rates for A. niger were 9% and 10%, respectively.

With regard to the laboratory findings, it has been reported3232. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.

33. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.

34. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.
-3535. Vukicevic TA, Dudvarski-Ilic A, Zugic V, Stevanovic G, Rubino S, Barac A. Subacute invasive pulmonary aspergillosis as a rare cause of pneumothorax in immunocompetent patient: brief report. Infection. In Press 2017. that tumor markers (carcinoembryonic antigen, squamous cell carcinoma antigen, carbohydrate antigens sialyl Lewis, and sialyl SSEA-1) are often increased in several benign diseases such as pulmonary mycobacterial diseases, and the percentage increase of these tumor marker is 15-62%. Histologically, these tumor markers were expressed in mucous cells of the bronchial gland and the surface of bronchiolar surface epithelium cells2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.,3131. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6.

32. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.
-3333. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.. Consequently, it is suspected that serum tumor markers are increased in cases of hyperplasia of bronchiolar epithelium cells or mucous cells of bronchial gland, because of the existing chronic respiratory infection with bronchiectasis caused by pulmonary MAC2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.,3131. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6.

32. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.
-3333. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.. The case presented by Kobashi et al.3030. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50. serves as a reminder that pulmonary nontuberculous mycobacterial disease has become one of the underlying pulmonary diseases complicated by CNPA. In order to detect fast CNPA with a fungus ball as a complication, it is important to perform periodic radiological examinations (chest computed tomography [CT]), serological examinations (anti-Aspergillus antibody) and sputum culture examinations during the follow-up period of an underlying respiratory disease2929. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–12.

30. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Matsushima T. Chronic necrotizing pulmonary aspergillosis complicated by a cavitary lesion caused by Pulmonary Mycobacterium-avium complex disease. Intern Med 2005; 44(3):246-50.

31. Denning DW, Pleuvry A, Cole DC. Global burden of chronic pulmonary aspergillosis complicating sarcoidosis. Eur Respir J. 2013;41:621-6.

32. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infec Dis. 2001;33:1824-33.

33. Johnston ID. Mycobacterium xenopi infection and aspergilloma. Tubercle. 1988;69:139-143.
-3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4..

Superinfection by Mycobacterium tuberculosis and CNPA

Although aspergillosis is commonly found in old tuberculous cavities, pulmonary aspergillosis is rarely complicated by active pulmonary TB3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.,3535. Vukicevic TA, Dudvarski-Ilic A, Zugic V, Stevanovic G, Rubino S, Barac A. Subacute invasive pulmonary aspergillosis as a rare cause of pneumothorax in immunocompetent patient: brief report. Infection. In Press 2017.. Kohno et al.3636. Kohno S, Hatano T, Yamada H, Maesaki S, Yasuoka A, Kaku M, et al. Superinfection of chronic necrotizing pulmonary aspergillosis by Mycobacterium tuberculosis. Intern Med. 1992;31:540-3. presented a rare case of CNPA complicated by active pulmonary TB. The case is unusual because the necrotic granuloma of aspergillosis contained a few acid-fast bacilli in the necrotic foci. Colonization of pre-existing TB pulmonary lesions by Aspergillus species is well known; however, superinfection by Aspergillus of a cavity already infected by Mycobacterium is rare3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.. Binder et al.33. Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine (Baltimore). 1982;61:109-24. reported a case of CNPA with a moderate number of acid-fast bacilli, but commented that this might have been colonization by non-tuberculosis mycobacteria. Because the necrotic granuloma consisted mainly of Aspergillus hyphae, it is more likely that aspergillosis was the main lesion with M. tuberculosis superinfection. It is impossible to completely rule out the possibility that this case was an instance of aspergillosis invading a healed tuberculous lesion, but the pathologic features of CNPA are unique and characteristic3434. Choudat D, Horreard P, Pretet S, Grosset J, Toty L. Superinfection by Aspergillus fumigatus of a pulmonary lesion caused by Mycobacterium xenopi. Tubercle. 1986;67:71-4.. Superinfection of CNPA with Xanthomonas maltophilia has also been reported, but it is rare33. Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine (Baltimore). 1982;61:109-24..

Pneumothorax and CNPA

Adzic-Vukovic et al. reported a rare and unusual case of pneumothorax in an immunocompetent patient with CNPA3535. Vukicevic TA, Dudvarski-Ilic A, Zugic V, Stevanovic G, Rubino S, Barac A. Subacute invasive pulmonary aspergillosis as a rare cause of pneumothorax in immunocompetent patient: brief report. Infection. In Press 2017.. To our knowledge, this is the first reported case in Europe. A 40-year old woman, with body mass index less than 15 kg/m22. Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. “Semi-invasive” pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. Radiology. 1981;140:313-21. and high-grade fever developed symptoms of acute onset of breathlessness, dry cough, and chest pain on the left side. The left side of the chest was hyper-resonant and breath sounds were weak. Laboratory results excluded common variable immune deficiencies, but on the other hand, the patient could not be considered as clinically immunocompetent because she had end-stage COPD and cachexia. Radiography showed a left-sided pneumothorax with contralateral cavitation and an intercostal drainage underwater seal was applied (Figure 1). Four days later, CT scan of the thorax indicated the presence of possible necrotizing lesions bilaterally (Figure 1). Fiber-optic bronchoscopy was done and a tissue sample was taken. Serological analyses revealed a positive galactomannan index (2.19) in bronchoalveolar lavage (BAL), as well as a positive value for anti-Aspergillus IgG Ab in serum (280 UI/mL). Patho-histologic analyses of the tissue sample confirmed the presence of fungal hyphae, and culture was positive for A. fumigatus (Figure 1). The patient responded positively to antifungal therapy; her general condition improved with rapid radiographic improvement in 2 weeks. During a follow-up period of 1 year, there was no disease regression3535. Vukicevic TA, Dudvarski-Ilic A, Zugic V, Stevanovic G, Rubino S, Barac A. Subacute invasive pulmonary aspergillosis as a rare cause of pneumothorax in immunocompetent patient: brief report. Infection. In Press 2017..

Figure 1
1A) Left sided pneumothorax with a contralateral cavitation; 1B) Bilateral cavity lesions; 1C) Computed tomography scan showed bilateral necrotising pulmonary lesions; 1D) Radiographic regression after two weeks of voriconazole treatment.

Pneumothorax as a result of rupture of aspergilloma into the pleural space in non-immunocompromised patients is extremely rare88. Gupta PP, Fotedar S, Agarwal D, Magu S, Saini K. Pneumothorax: a rare presentation of pulmonary mycetoma. Ann Thorac Med. 2007;2:171-2.. Pneumothorax has been reported in granulocytopenic patients undergoing intensive cytotoxic therapy for hematologic malignancies88. Gupta PP, Fotedar S, Agarwal D, Magu S, Saini K. Pneumothorax: a rare presentation of pulmonary mycetoma. Ann Thorac Med. 2007;2:171-2.. In this case, the patient was immunocompetent according to the laboratory parameters, but clinically she was immunocompromised with end-stage COPD and cachexia3535. Vukicevic TA, Dudvarski-Ilic A, Zugic V, Stevanovic G, Rubino S, Barac A. Subacute invasive pulmonary aspergillosis as a rare cause of pneumothorax in immunocompetent patient: brief report. Infection. In Press 2017.. Surprisingly, the patient developed pneumothorax as a complication of the rupture of aspergilloma into the pleural space. Long-term weight loss, low body mass index and untreatable end-stage COPD should be considered as possible cause of spontaneous pneumothorax in this patient. Pneumothorax increases both short-and long-term morbidity and mortality in patients with CNPA and causes significant deterioration of their quality of life. This case highlights that a diagnosis of CNPA should be considered in patients with end-stage COPD, a low body mass index, or patients who develop pneumothorax.

CONCLUSION

Diagnosis of CNPA is still a challenge. A chest radiograph is not helpful to the diagnosis for several reasons: (1) usually because of normal radiologic findings, intraluminal mycetomas may not be readily detectable, (2) Aspergillus may enlarge so rapidly that recent chest radiographs may not reveal atelectasis, and (3) the lung parenchyma is usually unaffected3737. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.. A chest CT scan is much more helpful in the early diagnosis and aids further diagnostic studies, such as bronchoscopies and open-lung biopsies. Although a CT scan is helpful in the diagnosis of airway aspergillosis, diagnosis of this specific disease cannot be made based on imaging features alone. Bronchoscopy, apart from providing specimens for microbiological examination, is a useful method for detecting infections with endobronchial manifestations3737. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.. It should be recommended as early as possible for diagnosis and to maintain airway patency, at a time when it is most feasible3737. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.

38. Cadranel J, Philippe B, Hennequin C, Bergeron A, Bergot E, Bourdin A, et al. Voriconazole for chronic pulmonary aspergillosis: a prospective multicenter trial. Eur J Clin Microbiol Infect Dis. 2012;31:3231–9.
-3939. Kono Y, Tsushima K, Yamaguchi K, Kurita N, Soeda S, Fujiwara A, Sugiyama S, et al. The utility of galactomannan antigen in the bronchial washing and serum for diagnosing pulmonary aspergillosis. Respir Med. 2013;107:1094-100.. A presumptive diagnosis is made when the fungus is isolated from bronchial aspirates or BAL cultures, and a definitive diagnosis is made when there is histologic demonstration of invasion of the mucosa by hyphae3737. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1-e60.

38. Cadranel J, Philippe B, Hennequin C, Bergeron A, Bergot E, Bourdin A, et al. Voriconazole for chronic pulmonary aspergillosis: a prospective multicenter trial. Eur J Clin Microbiol Infect Dis. 2012;31:3231–9.
-3939. Kono Y, Tsushima K, Yamaguchi K, Kurita N, Soeda S, Fujiwara A, Sugiyama S, et al. The utility of galactomannan antigen in the bronchial washing and serum for diagnosing pulmonary aspergillosis. Respir Med. 2013;107:1094-100.. Therefore, culture and histologic examinations of bronchoscopically identified tracheobronchial mucus plugs and necrotic material should be performed in all immunocompromised individuals, even when the radiographic finding are unchanged. Early detection of intraluminal growth of Aspergillus and prompt antifungal therapy may facilitate the management of these patients and prevent development of complications.

ACKNOWLEDGEMENT

The paper has been published with the support of the Ministry of Education, Science and Technology of the Republic of Serbia (Project No. III45005).

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Publication Dates

  • Publication in this collection
    2017

History

  • Received
    6 Nov 2016
  • Accepted
    9 Mar 2017
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