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Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy
J Infect Chemother xxx (2014) 1e4
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy Yutaka Mukai a, Shin-ichi Nureki a, *, Masahiro Hata b, Takehiko Shigenaga b, Issei Tokimatsu a, Eishi Miyazaki c, Jun-ichi Kadota a, Kyoko Yarita d, Katsuhiko Kamei d a Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan b Department of Respiratory Medicine, Oita Red Cross Hospital, 3-2-37, Chiyo-machi, Oita 870-0033, Japan c Center for Community Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan d Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 November 2013 Received in revised form 22 February 2014 Accepted 27 February 2014
Exophiala dermatitidis pneumonia is extremely rare. Here we report a case of E. dermatitidis pneumonia successfully treated with long-term itraconazole therapy. A 63-year-old woman without a remarkable medical history developed a dry and chest pain. Chest radiographs revealed consolidation in the middle lobe of the lung. Cytologic examination by bronchoscopy showed filamentous fungi and E. dermatitidis was detected in the bronchoalveolar lavage fluid. After 5 months of itraconazole therapy, her symptoms improved and the area of consolidation diminished. Two weeks after discontinuing the itraconazole therapy, the area of consolidation reappeared. Itraconazole therapy was restarted and continued for 7 months. The abnormal shadow observed on the chest X-ray gradually diminished. Over a 27-month follow-up with periodic examination, there was no relapse and the patient had a favorable clinical course. Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Bronchoalveolar lavage Bronchoscope Brushing cytology Exophiala dermatitidis Itraconazole Pneumonia
1. Introduction
2. Case report
Exophiala dermatitidis (E. dermatitidis) is considered a rare pathogen of cutaneous and superficial infection [1]. E. dermatitidis, however, is being identified with increasing frequency as a cause of human disease, especially in immunocompromised patients [2]. Although it occasionally colonizes to the lesions of cystic fibrosis [3], E. dermatitidis pneumonia is very rare and only six cases are reported in the literature [4e9]. Herein we present a case of E. dermatitidis pneumonia without underlying disease. Long-term itraconazole (ITCZ) therapy led to resolution of the symptoms and diminished consolidation on radiologic images.
In August 2009, a 63-year-old woman was admitted to our hospital for dry and chest pain that began 2 months earlier. She was a housewife and enjoyed gardening every day. She was a nonsmoker and had no dust exposure history and no particular medical history, including respiratory disease, chronic sinusitis, diabetes mellitus, or cancer. On admission, her temperature was 36.4 C, pulse rate 74 beats min1, and respiratory rate 18 breaths min1. No crackles were heard in either lung field. Laboratory data on admission included a white blood cell count of 6000 cells mm3 with 63.0% neutrophils, and C-reactive protein of 0.34 mg dL1. Serum levels of anti-Aspergillus antibody, b-D glucan, and tumor markers were within normal limits. The test for hepatitis B surface antigen, and anti-hepatitis C virus antibody, human immunodeficiency virus antibody, human T-lymphotropic virus Type 1 antibody, and autoimmune antibodies of collagen diseases were negative. Serologic test for syphilis and Treponema pallidum hemagglutination were also negative. Serum values of
* Corresponding author. Tel.: þ81 97 586 5804; fax: þ81 97 549 4245. E-mail address: [email protected] (S.-i. Nureki).
http://dx.doi.org/10.1016/j.jiac.2014.02.006 1341-321X/Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
2
Y. Mukai et al. / J Infect Chemother xxx (2014) 1e4
fasting blood sugar and hemoglobin A1c were within normal range. A chest X-ray showed an infiltrative shadow in the right lower lung (Fig. 1(a)). Chest computed tomography scans revealed consolidation in the middle lobe (S5) (Fig. 1(b)). We performed a bronchoscopy to investigate the possibility of malignant or infectious disease. Cytologic examination by bronchoscopy showed filamentous fungi (Fig. 2(a)). Black fungi were detected in the bronchoalveolar lavage fluid (BALF) culture using Sabouraud agar at 30 C for 1 week. Initially, the fungus was suspected to be Hortaea werneckii based on its characteristic morphology of twocell conidia with a relatively thick septum (Fig. 2(b)). In a recent analysis using stocked fungi, we identified this fungus as E. dermatitidis by analysis of nucleic acid sequences against the internal transcribed spacer 1, 5.8S, and internal transcribed spacer 2 of the nuclear ribosomal RNA gene. Minimum inhibitory concentrations for the stocked fungi were as follows; amphotericine B (AMPH-B) 0.5 mg/mL, 5-flucytosine (5-FC) 1.0 mg/mL, fluconazole (FLCZ) 8 mg/mL, ITCZ 0.25 mg/mL, voriconazole (VRCZ) 0.12 mg/mL,
miconazole (MCZ) 0.12 mg/mL, micafungin (MCFG) >16 mg/mL. BALF culture could not detect any pathogenic bacterium including Mycobacterium and BALF polymerase chain reaction analysis for Mycobacterium tuberculosis or Mycobacterium avium complex were negative. Sputum culture examination could not be done because the patient did not complain of sputum. Malignant cells were not observed in the BALF, brushing cytology, or transbronchial lung biopsy. One week after the bronchoscope examination, oral ITCZ therapy (200 mg day1) was introduced and maintained on an outpatient basis. We did not introduce antibacterial drug other than ITCZ. The patient’s symptoms gradually improved, with chest images demonstrating gradual shrinkage of the area of consolidation. After 5 months, the area of consolidation had almost disappeared with slight ground-glass opacity (Fig. 1(c)) and oral ITCZ therapy was discontinued. Two weeks after discontinuing ITCZ therapy, however, consolidation reappeared at the same site (Fig. 1(d)). Oral ITCZ therapy was restarted and continued for 7 months. The abnormal shadow in the chest computed tomography
Fig. 1. (a) Posteroanterior chest radiography on admission showing infiltrative shadow (arrow) in the right lower lung. (b) Chest computed tomography on admission showing consolidation (arrow) in the right middle lobe (S5). (c) Five months after the first itraconazole therapy, consolidation disappeared with slight ground-glass opacity (arrow). (d) Two weeks after the first itraconazole therapy, consolidation reappeared at the same site (arrow). (e) Seven months after second itraconazole therapy, the area of consolidation was diminished (arrow).
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
Y. Mukai et al. / J Infect Chemother xxx (2014) 1e4
3
3. Discussion
Fig. 2. (a) A Papanicolaou stain of brushing cytology showing filamentous fungus. (b) A microphotograph of the black filamentous fungus obtained by bronchoalveolar lavage fluid culture showing two-cell conidia with a relatively thick septum.
again had almost disappeared (Fig. 1(e)) and ITCZ therapy was discontinued. Since then, the patient has been in good health and there has been no worsening of the radiologic findings during the 27-month follow-up period.
The most common manifestations of E. dermatitidis are infections of skin, subcutaneous tissue, and the central nervous system (CNS) [10]. Other, less commonly reported sites of infection include the eyes, lymph nodes, nails, peritoneum, and internal organs [1,11]. Only six cases of pneumonia caused by E. dermatitidis are reported in the literature (Table 1) [4e9]. E. dermatitidis has been isolated from sawdust, soil, decaying timber, humidifiers, and moss; humans are considered to be accidental hosts [12]. About half of the patients with E. dermatitidis infection had no underlying disease [11]. Subcutaneous infections are believed to arise from traumatic implantation of the fungus, such as when a contaminated wood particle penetrates the skin. In our case, we suspected an airborne route of infection by the inhalation of particles from sawdust, soil, or decaying timber in the process of daily gardening. Due to the rarity of E. dermatitidis pneumonia, definite risk factors have yet to be established. Five patients had underlying respiratory disease, such as cystic fibrosis and bronchiectasis. Recently, E. dermatitidis has become recognized as a colonization agent in patients with cystic fibrosis [3]. In these cases, colonized E. dermatitidis may develop into pneumonia when the patient’s general condition worsens. Including our case, all previous cases of E. dermatitidis pneumonia occurred in women. Female sex could be a risk factor for Pseudomonas aeruginosa infection in patients with cystic fibrosis [13]. There is sufficient evidence to suggest that chronic airway infection, most notably non-cystic fibrosis bronchiectasis, is a more common and more virulent disease in women [14]. We suspect that cystic fibrosis or bronchiectasis and female sex are also risk factors for E. dermatitidis pneumonia. Although our case had no particular medical history including respiratory disease, the exposure of particles from sawdust, soil, or decaying timber in the process of daily gardening could be the risk factor for the development of E. dermatitidis pneumonia. An antifungal chemotherapy for E. dermatitidis pneumonia has not been established. Most of the previous cases were treated with combination or switch therapy with ITCZ, VRCZ, AMPH-B, 5-FC, ketoconazole, FLCZ, or MCZ. The susceptibility of the organisms to antifungal agents is an important factor affecting the development and outcome of E. dermatitidis infection. VRCZ, ITCZ, AMPH-B, posaconazole, and terbinafine have good activity against clinically isolated E. dermatitidis [15,16]. VRCZ and posaconazole are the most
Table 1 Clinical profiles from patients with Exophiala dermatitidis pneumonia. Age
Sex
Underlining disease
Symptoms
Chest radiographic findings
Extrapulmonary lesions
Therapy
Outcome
Reference no.
21
F
Chronic granulomatous disease
Fever, chills, shortness of breath, pleuritic chest pain
Right lower lobe infiltrate, pleural-based mass in the left upper lobe
Brain abscess
Alive
[4]
29
F
Cystic fibrosis
Hemoptysis
Cavity in the left lower lobe
None
Alive
[5]
79
F
Bronchiectasis
Infiltrate in the left lower lobe and lingula
None
Alive
[6]
7
F
Cystic fibrosis
Hemoptysis, cough, progressive weakness, weight loss Tachypnea at rest, cough
Left thoracotomy, subsegmental resection of right upper lobe, amphotericine Bþ5flucytosine / ketoconazole / fluconazole Amphotericine B / itraconazole / amphotericine B / voriconazole Amphotericine Bþ5-flucytosine
Large round parahilar radiodensities
None
86
F
Mild dementia
54
F
Bronchiectasis
63
F
None
Consolidation and nodules in the right lower lobe Infiltrate in the right middle lobe Consolidation in the middle lobe
Scant, non-productive cough Cough, sputum production Dry cough, chest pain
Alive
[7]
None
Amphotericine Bþ5flucytosine / amphotericine B inhalation / itraconazole Voriconazole
Alive
[8]
None
Miconazole inhalation þ amphotericine B
Alive
[9]
None
Itraconazole
Alive
Our case
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
4
Y. Mukai et al. / J Infect Chemother xxx (2014) 1e4
active drugs against the E. dermatitidis strains associated with cystic fibrosis patients [3]. We administered oral ITCZ therapy to treat our patient on an outpatient basis. Although we initially suspected that the black fungus was H. werneckii that could be susceptible to ITCZ, we finally identified the fungus as E. dermatitidis that could be also susceptible to ITCZ by the drug susceptibility test. In cases of E. dermatitidis pneumonia without underlying disease, a good clinical course may be obtained by antifungal monotherapy. Successful VRCZ monotherapy was also reported in a patient with E. dermatitidis pneumonia without underlying respiratory disease [8]. They suggest that a minimum 3e4 months of VRCZ monotherapy is necessary to effectively treat E. dermatitidis pneumonia. In our case, five month of ITCZ therapy resulted in the recurrence of pneumonia. We suspected that the duration of ITCZ monotherapy would not be enough for the remission and restarted ITCZ monotherapy for another seven months. Finally, our patients resulted in the remission with total one year of ITCZ monotherapy. Based on our experience, more than 1 year may be needed to treat E. dermatitidis pneumonia with ITCZ monotherapy. In three cases of E. dermatitidis pneumonia, combination therapy with AMPH-B and 5-FC was administered. The combinations of caspofungin with VRCZ, AMPH-B or ITCZ, or AMPH-B with 5-FC or ITCZ have synergic activity against E. dermatitidis [15,17]. In recurrent or refractory cases, antifungal combination therapy should be considered as a possible therapy choice. We restarted ITCZ monotherapy at the time of recurrence because we suspected that the recurrence would be due to the short duration of therapy rather than the ITCZ resistance in our case. The fatality rate of E. dermatitidis infection was reported to be 48% in a review of 33 cases [11]. In cases of systemic infection, the prognosis is usually grave [18]. Several reports of CNS involvement underline the importance of hematogenous spread of E. dermatitidis. Hohl et al. reported that the mortality associated with E. dermatitidis infection is high, rising to almost 100% in cases of CNS involvement [19]. Although the prognosis of E. dermatitidis pneumonia is unknown, the six previously reported cases and our case all survived. In five cases, the infection was limited to the lung. Disseminated disease was observed in only one case with CNS involvement and the patient was successfully treated with a surgical lung excision and long-term antifungal therapy. The prognosis of E. dermatitidis pneumonia may be favorable when patients are treated with appropriate antifungal drugs for the appropriate period of time before developing into a systemic infection. We report a case of E. dermatitidis pneumonia without underlying disease that was successfully treated with long-term ITCZ therapy. Early detection of black filamentous fungus was facilitated by a Papanicolaou stain of brushing cytology and BALF culture using Sabouraud agar. A good clinical course may be obtained by early introduction of antifungal therapy before the infection becomes systemic. This fungus should be considered in cases of pneumonia, and effective antifungal chemotherapy should be planned accordingly.
Conflict of interest None.
Acknowledgments We thank to Ms. Naho Sato and Mr. Akihiro Goto for their technical assistances to detect E. dermatitidis.
References [1] Zeng JS, Sutton DA, Fothergill AW, Rinaldi MG, Harrak MJ, de Hoog GS. Spectrum of clinically relevant Exophiala species in the United States. J Clin Microbiol 2007;45:3713e20. [2] Liou JM, Wang JT, Wang MH, Wang SS, Hsueh PR. Phaeohyphomycosis caused by Exophiala species in immunocompromised hosts. J Formos Med Assoc 2002;101:523e6. [3] Kondori N, Gilljam M, Lindblad A, Jonsson B, Moore ER, Wenneras C. High rate of Exophiala dermatitidis recovery in the airways of patients with cystic fibrosis is associated with pancreatic insufficiency. J Clin Microbiol 2011;49: 1004e9. [4] Kenney RT, Kwon-Chung KJ, Waytes AT, Melnick DA, Pass HI, Merino MJ, et al. Successful treatment of systemic Exophiala dermatitidis infection in a patient with chronic granulomatous disease. Clin Infect Dis 1992;14:235e42. [5] Diemert D, Kunimoto D, Sand C, Rennie R. Sputum isolation of Wangiella dermatitidis in patients with cystic fibrosis. Scand J Infect Dis 2001;33:777e9. [6] Barenfanger J, Ramirez F, Tewari RP, Eagleton L. Pulmonary phaeohyphomycosis in a patient with hemoptysis. Chest 1989;95:1158e60. [7] Kusenbach G, Skopnik H, Haase G, Friedrichs F, Dohmen H. Exophiala dermatitidis pneumonia in cystic fibrosis. Eur J Pediatr 1992;151:344e6. [8] Bulloch MN. The treatment of pulmonary Wangiella dermatitidis infection with oral voriconazole. J Clin Pharm Ther 2010;36:433e6. [9] Mukaino T, Koga T, Oshita Y, Narita Y, Obata S, Aizawa H. Exophiala dermatitidis infection in non-cystic fibrosis bronchiectasis. Respir Med 2006;100: 2069e71. [10] Chakrabarti A. Epidemiology of central nervous system mycoses. Neurol India 2007;55:191e7. [11] Matsumoto T, Matsuda T, Padhye AA, Standard PG, Ajello L. Fungal melanonychia: ungual phaeohyphomycosis caused by Wangiella dermatitidis. Clin Exp Dermatol 1992;17:83e6. [12] Nishimura K, Miyaji M. Studies on a saprophyte of Exophiala dermatitidis isolated from a humidifier. Mycopathologia 1982;77:173e81. [13] Levy H, Kalish LA, Cannon CL, Garcia KC, Gerard C, Goldmann D, et al. Predictors of mucoid Pseudomonas colonization in cystic fibrosis patients. Pediatr Pulmonol 2008;43:463e71. [14] Morrissey BM, Harper RW. Bronchiectasis: sex and gender considerations. Clin Chest Med 2004;25:361e72. [15] Sun Y, Liu W, Wan Z, Wang X, Li R. Antifungal activity of antifungal drugs, as well as drug combinations against Exophiala dermatitidis. Mycopathologia 2011;171:111e7. [16] Badali H, de Hoog GS, Sudhadham M, Meis JF. Microdilution in vitro antifungal susceptibility of Exophiala dermatitidis, a systemic opportunist. Med Mycol e Off Publ Int Soc Hum Animal Mycol 2011;49:819e24. [17] Taj-Aldeen SJ, El Shafie S, Alsoub H, Eldeeb Y, de Hoog GS. Isolation of Exophiala dermatitidis from endotracheal aspirate of a cancer patient. Mycoses 2006;49:504e9. [18] Hiruma M, Kawada A, Ohata H, Ohnishi Y, Takahashi H, Yamazaki M, et al. Systemic phaeohyphomycosis caused by Exophiala dermatitidis. Mycoses 1993;36:1e7. [19] Hohl PE, Holley Jr HP, Prevost E, Ajello L, Padhye AA. Infections due to Wangiella dermatitidis in humans: report of the first documented case from the United States and a review of the literature. Rev Infect Dis 1983;5:854e64.
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy Yutaka Mukai a, Shin-ichi Nureki a, *, Masahiro Hata b, Takehiko Shigenaga b, Issei Tokimatsu a, Eishi Miyazaki c, Jun-ichi Kadota a, Kyoko Yarita d, Katsuhiko Kamei d a Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan b Department of Respiratory Medicine, Oita Red Cross Hospital, 3-2-37, Chiyo-machi, Oita 870-0033, Japan c Center for Community Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan d Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 November 2013 Received in revised form 22 February 2014 Accepted 27 February 2014
Exophiala dermatitidis pneumonia is extremely rare. Here we report a case of E. dermatitidis pneumonia successfully treated with long-term itraconazole therapy. A 63-year-old woman without a remarkable medical history developed a dry and chest pain. Chest radiographs revealed consolidation in the middle lobe of the lung. Cytologic examination by bronchoscopy showed filamentous fungi and E. dermatitidis was detected in the bronchoalveolar lavage fluid. After 5 months of itraconazole therapy, her symptoms improved and the area of consolidation diminished. Two weeks after discontinuing the itraconazole therapy, the area of consolidation reappeared. Itraconazole therapy was restarted and continued for 7 months. The abnormal shadow observed on the chest X-ray gradually diminished. Over a 27-month follow-up with periodic examination, there was no relapse and the patient had a favorable clinical course. Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Bronchoalveolar lavage Bronchoscope Brushing cytology Exophiala dermatitidis Itraconazole Pneumonia
1. Introduction
2. Case report
Exophiala dermatitidis (E. dermatitidis) is considered a rare pathogen of cutaneous and superficial infection [1]. E. dermatitidis, however, is being identified with increasing frequency as a cause of human disease, especially in immunocompromised patients [2]. Although it occasionally colonizes to the lesions of cystic fibrosis [3], E. dermatitidis pneumonia is very rare and only six cases are reported in the literature [4e9]. Herein we present a case of E. dermatitidis pneumonia without underlying disease. Long-term itraconazole (ITCZ) therapy led to resolution of the symptoms and diminished consolidation on radiologic images.
In August 2009, a 63-year-old woman was admitted to our hospital for dry and chest pain that began 2 months earlier. She was a housewife and enjoyed gardening every day. She was a nonsmoker and had no dust exposure history and no particular medical history, including respiratory disease, chronic sinusitis, diabetes mellitus, or cancer. On admission, her temperature was 36.4 C, pulse rate 74 beats min1, and respiratory rate 18 breaths min1. No crackles were heard in either lung field. Laboratory data on admission included a white blood cell count of 6000 cells mm3 with 63.0% neutrophils, and C-reactive protein of 0.34 mg dL1. Serum levels of anti-Aspergillus antibody, b-D glucan, and tumor markers were within normal limits. The test for hepatitis B surface antigen, and anti-hepatitis C virus antibody, human immunodeficiency virus antibody, human T-lymphotropic virus Type 1 antibody, and autoimmune antibodies of collagen diseases were negative. Serologic test for syphilis and Treponema pallidum hemagglutination were also negative. Serum values of
* Corresponding author. Tel.: þ81 97 586 5804; fax: þ81 97 549 4245. E-mail address: [email protected] (S.-i. Nureki).
http://dx.doi.org/10.1016/j.jiac.2014.02.006 1341-321X/Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
2
Y. Mukai et al. / J Infect Chemother xxx (2014) 1e4
fasting blood sugar and hemoglobin A1c were within normal range. A chest X-ray showed an infiltrative shadow in the right lower lung (Fig. 1(a)). Chest computed tomography scans revealed consolidation in the middle lobe (S5) (Fig. 1(b)). We performed a bronchoscopy to investigate the possibility of malignant or infectious disease. Cytologic examination by bronchoscopy showed filamentous fungi (Fig. 2(a)). Black fungi were detected in the bronchoalveolar lavage fluid (BALF) culture using Sabouraud agar at 30 C for 1 week. Initially, the fungus was suspected to be Hortaea werneckii based on its characteristic morphology of twocell conidia with a relatively thick septum (Fig. 2(b)). In a recent analysis using stocked fungi, we identified this fungus as E. dermatitidis by analysis of nucleic acid sequences against the internal transcribed spacer 1, 5.8S, and internal transcribed spacer 2 of the nuclear ribosomal RNA gene. Minimum inhibitory concentrations for the stocked fungi were as follows; amphotericine B (AMPH-B) 0.5 mg/mL, 5-flucytosine (5-FC) 1.0 mg/mL, fluconazole (FLCZ) 8 mg/mL, ITCZ 0.25 mg/mL, voriconazole (VRCZ) 0.12 mg/mL,
miconazole (MCZ) 0.12 mg/mL, micafungin (MCFG) >16 mg/mL. BALF culture could not detect any pathogenic bacterium including Mycobacterium and BALF polymerase chain reaction analysis for Mycobacterium tuberculosis or Mycobacterium avium complex were negative. Sputum culture examination could not be done because the patient did not complain of sputum. Malignant cells were not observed in the BALF, brushing cytology, or transbronchial lung biopsy. One week after the bronchoscope examination, oral ITCZ therapy (200 mg day1) was introduced and maintained on an outpatient basis. We did not introduce antibacterial drug other than ITCZ. The patient’s symptoms gradually improved, with chest images demonstrating gradual shrinkage of the area of consolidation. After 5 months, the area of consolidation had almost disappeared with slight ground-glass opacity (Fig. 1(c)) and oral ITCZ therapy was discontinued. Two weeks after discontinuing ITCZ therapy, however, consolidation reappeared at the same site (Fig. 1(d)). Oral ITCZ therapy was restarted and continued for 7 months. The abnormal shadow in the chest computed tomography
Fig. 1. (a) Posteroanterior chest radiography on admission showing infiltrative shadow (arrow) in the right lower lung. (b) Chest computed tomography on admission showing consolidation (arrow) in the right middle lobe (S5). (c) Five months after the first itraconazole therapy, consolidation disappeared with slight ground-glass opacity (arrow). (d) Two weeks after the first itraconazole therapy, consolidation reappeared at the same site (arrow). (e) Seven months after second itraconazole therapy, the area of consolidation was diminished (arrow).
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
Y. Mukai et al. / J Infect Chemother xxx (2014) 1e4
3
3. Discussion
Fig. 2. (a) A Papanicolaou stain of brushing cytology showing filamentous fungus. (b) A microphotograph of the black filamentous fungus obtained by bronchoalveolar lavage fluid culture showing two-cell conidia with a relatively thick septum.
again had almost disappeared (Fig. 1(e)) and ITCZ therapy was discontinued. Since then, the patient has been in good health and there has been no worsening of the radiologic findings during the 27-month follow-up period.
The most common manifestations of E. dermatitidis are infections of skin, subcutaneous tissue, and the central nervous system (CNS) [10]. Other, less commonly reported sites of infection include the eyes, lymph nodes, nails, peritoneum, and internal organs [1,11]. Only six cases of pneumonia caused by E. dermatitidis are reported in the literature (Table 1) [4e9]. E. dermatitidis has been isolated from sawdust, soil, decaying timber, humidifiers, and moss; humans are considered to be accidental hosts [12]. About half of the patients with E. dermatitidis infection had no underlying disease [11]. Subcutaneous infections are believed to arise from traumatic implantation of the fungus, such as when a contaminated wood particle penetrates the skin. In our case, we suspected an airborne route of infection by the inhalation of particles from sawdust, soil, or decaying timber in the process of daily gardening. Due to the rarity of E. dermatitidis pneumonia, definite risk factors have yet to be established. Five patients had underlying respiratory disease, such as cystic fibrosis and bronchiectasis. Recently, E. dermatitidis has become recognized as a colonization agent in patients with cystic fibrosis [3]. In these cases, colonized E. dermatitidis may develop into pneumonia when the patient’s general condition worsens. Including our case, all previous cases of E. dermatitidis pneumonia occurred in women. Female sex could be a risk factor for Pseudomonas aeruginosa infection in patients with cystic fibrosis [13]. There is sufficient evidence to suggest that chronic airway infection, most notably non-cystic fibrosis bronchiectasis, is a more common and more virulent disease in women [14]. We suspect that cystic fibrosis or bronchiectasis and female sex are also risk factors for E. dermatitidis pneumonia. Although our case had no particular medical history including respiratory disease, the exposure of particles from sawdust, soil, or decaying timber in the process of daily gardening could be the risk factor for the development of E. dermatitidis pneumonia. An antifungal chemotherapy for E. dermatitidis pneumonia has not been established. Most of the previous cases were treated with combination or switch therapy with ITCZ, VRCZ, AMPH-B, 5-FC, ketoconazole, FLCZ, or MCZ. The susceptibility of the organisms to antifungal agents is an important factor affecting the development and outcome of E. dermatitidis infection. VRCZ, ITCZ, AMPH-B, posaconazole, and terbinafine have good activity against clinically isolated E. dermatitidis [15,16]. VRCZ and posaconazole are the most
Table 1 Clinical profiles from patients with Exophiala dermatitidis pneumonia. Age
Sex
Underlining disease
Symptoms
Chest radiographic findings
Extrapulmonary lesions
Therapy
Outcome
Reference no.
21
F
Chronic granulomatous disease
Fever, chills, shortness of breath, pleuritic chest pain
Right lower lobe infiltrate, pleural-based mass in the left upper lobe
Brain abscess
Alive
[4]
29
F
Cystic fibrosis
Hemoptysis
Cavity in the left lower lobe
None
Alive
[5]
79
F
Bronchiectasis
Infiltrate in the left lower lobe and lingula
None
Alive
[6]
7
F
Cystic fibrosis
Hemoptysis, cough, progressive weakness, weight loss Tachypnea at rest, cough
Left thoracotomy, subsegmental resection of right upper lobe, amphotericine Bþ5flucytosine / ketoconazole / fluconazole Amphotericine B / itraconazole / amphotericine B / voriconazole Amphotericine Bþ5-flucytosine
Large round parahilar radiodensities
None
86
F
Mild dementia
54
F
Bronchiectasis
63
F
None
Consolidation and nodules in the right lower lobe Infiltrate in the right middle lobe Consolidation in the middle lobe
Scant, non-productive cough Cough, sputum production Dry cough, chest pain
Alive
[7]
None
Amphotericine Bþ5flucytosine / amphotericine B inhalation / itraconazole Voriconazole
Alive
[8]
None
Miconazole inhalation þ amphotericine B
Alive
[9]
None
Itraconazole
Alive
Our case
Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006
4
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active drugs against the E. dermatitidis strains associated with cystic fibrosis patients [3]. We administered oral ITCZ therapy to treat our patient on an outpatient basis. Although we initially suspected that the black fungus was H. werneckii that could be susceptible to ITCZ, we finally identified the fungus as E. dermatitidis that could be also susceptible to ITCZ by the drug susceptibility test. In cases of E. dermatitidis pneumonia without underlying disease, a good clinical course may be obtained by antifungal monotherapy. Successful VRCZ monotherapy was also reported in a patient with E. dermatitidis pneumonia without underlying respiratory disease [8]. They suggest that a minimum 3e4 months of VRCZ monotherapy is necessary to effectively treat E. dermatitidis pneumonia. In our case, five month of ITCZ therapy resulted in the recurrence of pneumonia. We suspected that the duration of ITCZ monotherapy would not be enough for the remission and restarted ITCZ monotherapy for another seven months. Finally, our patients resulted in the remission with total one year of ITCZ monotherapy. Based on our experience, more than 1 year may be needed to treat E. dermatitidis pneumonia with ITCZ monotherapy. In three cases of E. dermatitidis pneumonia, combination therapy with AMPH-B and 5-FC was administered. The combinations of caspofungin with VRCZ, AMPH-B or ITCZ, or AMPH-B with 5-FC or ITCZ have synergic activity against E. dermatitidis [15,17]. In recurrent or refractory cases, antifungal combination therapy should be considered as a possible therapy choice. We restarted ITCZ monotherapy at the time of recurrence because we suspected that the recurrence would be due to the short duration of therapy rather than the ITCZ resistance in our case. The fatality rate of E. dermatitidis infection was reported to be 48% in a review of 33 cases [11]. In cases of systemic infection, the prognosis is usually grave [18]. Several reports of CNS involvement underline the importance of hematogenous spread of E. dermatitidis. Hohl et al. reported that the mortality associated with E. dermatitidis infection is high, rising to almost 100% in cases of CNS involvement [19]. Although the prognosis of E. dermatitidis pneumonia is unknown, the six previously reported cases and our case all survived. In five cases, the infection was limited to the lung. Disseminated disease was observed in only one case with CNS involvement and the patient was successfully treated with a surgical lung excision and long-term antifungal therapy. The prognosis of E. dermatitidis pneumonia may be favorable when patients are treated with appropriate antifungal drugs for the appropriate period of time before developing into a systemic infection. We report a case of E. dermatitidis pneumonia without underlying disease that was successfully treated with long-term ITCZ therapy. Early detection of black filamentous fungus was facilitated by a Papanicolaou stain of brushing cytology and BALF culture using Sabouraud agar. A good clinical course may be obtained by early introduction of antifungal therapy before the infection becomes systemic. This fungus should be considered in cases of pneumonia, and effective antifungal chemotherapy should be planned accordingly.
Conflict of interest None.
Acknowledgments We thank to Ms. Naho Sato and Mr. Akihiro Goto for their technical assistances to detect E. dermatitidis.
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Please cite this article in press as: Mukai Y, et al., Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.02.006