J Infect Chemother 21 (2015) 479e481
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Note
Invasive pulmonary aspergillosis due to Aspergillus lentulus: Successful treatment of a liver transplant patient Hisao Yoshida a, 1, Masafumi Seki a, *, 1, Takashi Umeyama b, Makoto Urai b, Yuuki Kinjo b, Isao Nishi c, Masahiro Toyokawa c, Yukihiro Kaneko b, d, Hideaki Ohno b, e, Yoshitsugu Miyazaki b, Kazunori Tomono a a
Division of Infection Control and Prevention, Osaka University Hospital, Suita City, Osaka, Japan Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama, Tokyo, Japan Department of Laboratory Medicine, Osaka University Hospital, Suita City, Osaka, Japan d Department of Bacteriology, Osaka City University, Osaka, Japan e Division of Infectious Diseases, Saitama Medical University Kawagoe Hospital, Kawagoe, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 November 2014 Received in revised form 19 February 2015 Accepted 24 February 2015 Available online 6 March 2015
We report a patient with severe invasive pulmonary fungal infection caused by Aspergilllus lentulus, which was identified by genetic analysis, following liver transplantation. The patient was initially suspected to have Aspergilllus fumigatus infection, but worsened clinically despite antifungal therapy appropriate for that species. The patient survived after accurate diagnosis, and detailed drug susceptibility testing led to adequate therapy, demonstrating the importance of performing these investigations for severely immunocompromised patients, including organ transplant recipients. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Invasive pulmonary aspergillosis Aspergillus lentulus Voriconazole Liposomal amphotericin B Caspofungin Beta-tubulin
Early diagnosis of invasive aspergillosis and proper identification of the causative agent is crucial for guidance of therapy in immunocompromised patients [1]. Accurate diagnosis of Aspergillus lentulus, a filamentous fungus often misidentified as a typical Aspergillus fumigatus, is now of concern as there is a reduced susceptibility to multiple antifungal drugs [2]. Here we report a severe pulmonary invasive fungal infection caused by A. lentulus after liver transplantation. In November 2013, a 62-year-old man underwent liver transplantation for fulminant hepatitis virus type B infection; the organ donor was a 20-year-old male who had been declared brain death following an automobile accident. The patient was a current smoker, and COPD was suspected as one of the underlying
* Corresponding author. Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita City, Osaka 565-0871, Japan. Tel.: þ81 6 6879 5093; fax: þ81 6 6879 5094. E-mail address: [email protected] (M. Seki). 1 The first two authors contributed equally to this work.
diseases. Immunosuppressive therapy was consisted of steroids and tacrolimus, but neutrophil counts were normal or elevated, and neutropenia was never observed. After the transplantation, continuous hemodiafiltration followed by intermittent hemodialysis was performed to treat the abrupt onset of chronic renal failure. On post-transplantation day 5, chest X-ray revealed multiple consolidations, which suggested fungal infection (Fig. 1). We immediately started 5 mg/kg/day of liposomal amphotericin-B as pulmonary aspergillosis and mucormycosis were suspected, but on day 7 the b-D-glucan titer had increased (from 21.0 pg/mL to 78.2 pg/mL), and the aspergillus antigen titer had also increased (from 0.5 to 4.8). Therefore, we performed bronchoalveolar lavage (BAL); a filamentous fungus was cultured from BAL fluids and tracheal specimens (Fig. 2). The fungal isolates showed reduced sporulation after incubation at 30 C, and colonies were pale gray or whitish, rather than deep blue. Initially, atypical Aspergilllus fumigatus was suspected; this preliminary identification was confirmed as no growth was detected at 48 C, which
http://dx.doi.org/10.1016/j.jiac.2015.02.010 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
480
H. Yoshida et al. / J Infect Chemother 21 (2015) 479e481
Fig. 1. Clinical course of the patient after liver transplantation. L-Amph B: liposomal amphotericin B. CPFG: caspofungin. VRCZ: voriconazole.
is a marker for the presence of a sibling species of the section Fumigati [2,3]. Molecular analyses by the internal transcribed spacer (ITS) regions, domains 1 and 2 (D1/D2) of 26S rDNA, are not discriminative
enough within this group of species [4]; thus analyses of the betatubulin gene were performed. A BLAST search of partial betatubulin gene (409 bp) in GenBank revealed a sequence identity of 99.6% to the A. lentulus reference sequence (GenBank accession
Fig. 2. Morphological findings of Aspergillus lentulus isolated from bronchoaleveolar lavage fluid. (A) White, woolly colonies of A. lentulus inoculated onto SGA supplemented with benomyl after 5 days of incubation at 30 C. These findings are very different from the cottony, greenegray A. fumigatus colonies with aprons at margins. (B) Microscopic findings of cultured A. lentulus (400). (C) Lacto-phenol cotton blue staining of isolated A. lentulus in slide culture (400) was similar that of to A. fumigatus, except for poor sporulation.
H. Yoshida et al. / J Infect Chemother 21 (2015) 479e481 Table 1 Reported cases of pulmonary aspergillosis due to Aspergillus lentulus. Report # Authors (Year) 1.
Reference # Underlying diseases/conditions
2. 3. 4. 5.
de Azevedo Bastos VR et al. 1. Ref. [7] (2014) Gürcan S et al.et al. (2013) Ref. [6] Zbinden A et al. (2012) Ref. [8] Montenegro G et al. (2009) Ref. [9] Balajee SA et al. (2009) Ref. [11]
6.
Alhambra A et al. (2008)
Ref. [10]
Kidney transplantation Kidney transplantation Heart transplantation Kidney transplantation Hematopoietic stem cell transplantation Chronic obstructive pulmonary disease
number AY738520) with a demarcation of 4.1% to the next validated species (Neosartorya spinosa, AY879764), resulting in the final molecular identification of A. lentulus [5] We diagnosed a proven pulmonary invasive aspergillosis due to A. lentulus and empirically added caspofungin on posttransplantation day12 since b-D-glucan had elevated to 525.0 pg/ ml (Fig. 1). However, b-D-glucan peaked at 2382.8 pg/ml on day 19, suggesting poor therapeutic effects of liposomal amphotericin-B. Therefore, we changed the treatment regimen from liposomal amphotericin-B þ caspfungin to voriconazole þ caspofungin. Drug susceptibility tests revealed minimum inhibitory concentrations (MIC) of 0.5 mg/L for itraconazole, 2.0 mg/L for voriconazole, 4.0 mg/L for amphotericin B, and minimum effective concentrations (MEC) of
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Note
Invasive pulmonary aspergillosis due to Aspergillus lentulus: Successful treatment of a liver transplant patient Hisao Yoshida a, 1, Masafumi Seki a, *, 1, Takashi Umeyama b, Makoto Urai b, Yuuki Kinjo b, Isao Nishi c, Masahiro Toyokawa c, Yukihiro Kaneko b, d, Hideaki Ohno b, e, Yoshitsugu Miyazaki b, Kazunori Tomono a a
Division of Infection Control and Prevention, Osaka University Hospital, Suita City, Osaka, Japan Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Toyama, Tokyo, Japan Department of Laboratory Medicine, Osaka University Hospital, Suita City, Osaka, Japan d Department of Bacteriology, Osaka City University, Osaka, Japan e Division of Infectious Diseases, Saitama Medical University Kawagoe Hospital, Kawagoe, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 November 2014 Received in revised form 19 February 2015 Accepted 24 February 2015 Available online 6 March 2015
We report a patient with severe invasive pulmonary fungal infection caused by Aspergilllus lentulus, which was identified by genetic analysis, following liver transplantation. The patient was initially suspected to have Aspergilllus fumigatus infection, but worsened clinically despite antifungal therapy appropriate for that species. The patient survived after accurate diagnosis, and detailed drug susceptibility testing led to adequate therapy, demonstrating the importance of performing these investigations for severely immunocompromised patients, including organ transplant recipients. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Invasive pulmonary aspergillosis Aspergillus lentulus Voriconazole Liposomal amphotericin B Caspofungin Beta-tubulin
Early diagnosis of invasive aspergillosis and proper identification of the causative agent is crucial for guidance of therapy in immunocompromised patients [1]. Accurate diagnosis of Aspergillus lentulus, a filamentous fungus often misidentified as a typical Aspergillus fumigatus, is now of concern as there is a reduced susceptibility to multiple antifungal drugs [2]. Here we report a severe pulmonary invasive fungal infection caused by A. lentulus after liver transplantation. In November 2013, a 62-year-old man underwent liver transplantation for fulminant hepatitis virus type B infection; the organ donor was a 20-year-old male who had been declared brain death following an automobile accident. The patient was a current smoker, and COPD was suspected as one of the underlying
* Corresponding author. Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita City, Osaka 565-0871, Japan. Tel.: þ81 6 6879 5093; fax: þ81 6 6879 5094. E-mail address: [email protected] (M. Seki). 1 The first two authors contributed equally to this work.
diseases. Immunosuppressive therapy was consisted of steroids and tacrolimus, but neutrophil counts were normal or elevated, and neutropenia was never observed. After the transplantation, continuous hemodiafiltration followed by intermittent hemodialysis was performed to treat the abrupt onset of chronic renal failure. On post-transplantation day 5, chest X-ray revealed multiple consolidations, which suggested fungal infection (Fig. 1). We immediately started 5 mg/kg/day of liposomal amphotericin-B as pulmonary aspergillosis and mucormycosis were suspected, but on day 7 the b-D-glucan titer had increased (from 21.0 pg/mL to 78.2 pg/mL), and the aspergillus antigen titer had also increased (from 0.5 to 4.8). Therefore, we performed bronchoalveolar lavage (BAL); a filamentous fungus was cultured from BAL fluids and tracheal specimens (Fig. 2). The fungal isolates showed reduced sporulation after incubation at 30 C, and colonies were pale gray or whitish, rather than deep blue. Initially, atypical Aspergilllus fumigatus was suspected; this preliminary identification was confirmed as no growth was detected at 48 C, which
http://dx.doi.org/10.1016/j.jiac.2015.02.010 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
480
H. Yoshida et al. / J Infect Chemother 21 (2015) 479e481
Fig. 1. Clinical course of the patient after liver transplantation. L-Amph B: liposomal amphotericin B. CPFG: caspofungin. VRCZ: voriconazole.
is a marker for the presence of a sibling species of the section Fumigati [2,3]. Molecular analyses by the internal transcribed spacer (ITS) regions, domains 1 and 2 (D1/D2) of 26S rDNA, are not discriminative
enough within this group of species [4]; thus analyses of the betatubulin gene were performed. A BLAST search of partial betatubulin gene (409 bp) in GenBank revealed a sequence identity of 99.6% to the A. lentulus reference sequence (GenBank accession
Fig. 2. Morphological findings of Aspergillus lentulus isolated from bronchoaleveolar lavage fluid. (A) White, woolly colonies of A. lentulus inoculated onto SGA supplemented with benomyl after 5 days of incubation at 30 C. These findings are very different from the cottony, greenegray A. fumigatus colonies with aprons at margins. (B) Microscopic findings of cultured A. lentulus (400). (C) Lacto-phenol cotton blue staining of isolated A. lentulus in slide culture (400) was similar that of to A. fumigatus, except for poor sporulation.
H. Yoshida et al. / J Infect Chemother 21 (2015) 479e481 Table 1 Reported cases of pulmonary aspergillosis due to Aspergillus lentulus. Report # Authors (Year) 1.
Reference # Underlying diseases/conditions
2. 3. 4. 5.
de Azevedo Bastos VR et al. 1. Ref. [7] (2014) Gürcan S et al.et al. (2013) Ref. [6] Zbinden A et al. (2012) Ref. [8] Montenegro G et al. (2009) Ref. [9] Balajee SA et al. (2009) Ref. [11]
6.
Alhambra A et al. (2008)
Ref. [10]
Kidney transplantation Kidney transplantation Heart transplantation Kidney transplantation Hematopoietic stem cell transplantation Chronic obstructive pulmonary disease
number AY738520) with a demarcation of 4.1% to the next validated species (Neosartorya spinosa, AY879764), resulting in the final molecular identification of A. lentulus [5] We diagnosed a proven pulmonary invasive aspergillosis due to A. lentulus and empirically added caspofungin on posttransplantation day12 since b-D-glucan had elevated to 525.0 pg/ ml (Fig. 1). However, b-D-glucan peaked at 2382.8 pg/ml on day 19, suggesting poor therapeutic effects of liposomal amphotericin-B. Therefore, we changed the treatment regimen from liposomal amphotericin-B þ caspfungin to voriconazole þ caspofungin. Drug susceptibility tests revealed minimum inhibitory concentrations (MIC) of 0.5 mg/L for itraconazole, 2.0 mg/L for voriconazole, 4.0 mg/L for amphotericin B, and minimum effective concentrations (MEC) of
