Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link

Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 25, Number 12—December 2019
Research Letter

Aspergillus felis in Patient with Chronic Granulomatous Disease

Olivier Paccoud, Romain Guery, Sylvain Poirée, Grégory Jouvion, Marie Elisabeth Bougnoux, Emilie Catherinot, Olivier Hermine, Olivier Lortholary, and Fanny LanternierComments to Author 
Author affiliations: Hôpital Necker-Enfants Malades, Paris, France (O. Paccoud, R. Guery, S. Poirée, M.E. Bougnoux, O. Hermine, O. Lortholary, F. Lanternier); Institut Pasteur, Paris (G. Jouvion, O. Lortholary, F. Lanternier); Hôpital Foch, Université Versailles-Saint-Quentin-en-Yvelines, Versailles, France (E. Catherinot)

Suggested citation for this article

Abstract

We report a case of Aspergillus felis infection in a patient with chronic granulomatous disease who had overlapping features of invasive pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Identifying the species responsible for aspergillosis by molecular methods can be crucial for directing patient management and selection of appropriate antifungal agents.

A 42-year-old man with X-linked chronic granulomatous disease (CGD) sought care at a hospital in Paris, France, for a 2-week history of cough and night sweats. He had been receiving long-term prophylaxis with itraconazole (400 mg/d) and had normal trough levels (1,240 μg/L) 1 month before his hospital visit.

At admission, blood counts showed mild leukocytosis (leukocytes 9.6 × 109 cells/L, reference range 4–10 × 109 cells/L), with neutrophils at 6.1 × 109 cells/L (reference range 1.5–7 × 109 cells/L) and eosinophils at 2 × 109 cells/L (reference <0.5 × 109 cells/L). Computed tomography (CT) revealed an upper left lobe consolidation (Appendix Figure). We administered broad-spectrum antimicrobial drugs (2 g meropenem 3×/d and 20 mg/kg/d amikacin). Results of bacterial and mycological cultures from sputum were negative, as was serum galactomannan.

The patient’s condition did not improve, so we administered liposomal amphotericin B (5 mg/kg/d) and caspofungin (70 mg/d loading dose followed by 50 mg/d). Bronchoalveolar lavage demonstrated hypercellularity (1.22 × 106 cells/mL); manual differential showed 12% macrophages and 76% eosinophils. Results of bacterial, mycological, and mycobacterial cultures were negative. Pathology studies from a transbronchial biopsy revealed numerous eosinophilic granulomas alongside Charcot-Leyden crystals (Appendix Figure). Grocott methenamine silver staining revealed rare septated filamentous hyphae, but results of mycological cultures were negative. The patient had elevated total serum IgE (1,210 IU/mL, reference <114 IU/mL), elevated serum A. fumigatus IgE (7 IU/mL, reference <0.1 IU/mL) and A. fumigatus IgG (54 IU/mL, reference <5 IU/mL), and precipitating antibodies to A. fumigatus (2 arcs of precipitation in immunoelectrophoresis). Results of parasitologic examination of fecal samples and serologic testing for alternative causes of eosinophilia were negative.

Eosinophilia persisted (1.8–2 × 109 cells/L) despite antiparasitic treatment with ivermectin (5 mg/kg/d at days 1 and 7) and albendazole (400 mg/d for 7 d). Pathology findings from a transthoracic percutaneous biopsy revealed granulomas with Grocott-positive septated hyphae. Result of an Aspergillus section Fumigati PCR on a biopsy specimen were positive, and mycological cultures yielded a mold morphologically identified as Aspergillus. After 5 weeks of liposomal amphotericin B therapy (including 2 weeks of combination therapy with caspofungin), we switched treatment to oral voriconazole (loading dose of 400 mg 2×/d, followed by 200 mg 2×/d). Normalization of eosinophilia occurred at 6 weeks.

We sent mycological cultures from the biopsy specimens to the French National Center for Invasive Mycoses and Antifungals (Paris). Molecular identification based on the partial sequence of the internal transcribed spacer 2, 5.8S ribosomal RNA gene, and internal transcribed spacer 2 (525/526 bp; 99% similarity to the type strain, CBS 130245; GenBank accession no. KF558318.1) and the β-tubulin target gene enabled the identification of Aspergillus felis (109/109 bp; 100% similarity to the type strain, CBS DTO_131-E3 β-tubulin [benA] gene, partial cds; GenBank accession no. KY808576.1). The European Committee for Antimicrobial Susceptibility Testing (EUCAST) MICs with broth microdilution methods (1) were 4 μg/L for voriconazole, 4 μg/L for itraconazole, 0.25 μg/L for posaconazole, 2 μg/L for caspofungin, and 4 μg/L for amphotericin B. Based on EUCAST MIC breakpoints for A. fumigatus (2), we switched treatment to oral posaconazole (loading dose of 300 mg 2×/d, followed by 300 mg/d). Chest CT performed 12 months after treatment initiation showed noticeable improvement of pulmonary lesions.

Invasive pulmonary aspergillosis (IPA) remains a leading cause of death during CGD, IPA typically manifests as subacute pneumonia, with little or no angioinvasion (3). This patient had pulmonary infection caused by A. felis with overlapping features of IPA and allergic bronchopulmonary aspergillosis (ABPA) (4). Sensitization to Aspergillus spp. in patients with CGD (5) and tissue eosinophilia in lung pathology studies during invasive fungal infections (6) have been reported but do not seem to be common features of IPA in patients with CGD (3,7). There was some uncertainty about whether A. felis was responsible for this overlapping phenotype between IPA and ABPA (Table).

A. felis is a member of the A. viridinutans complex, a group of cryptic species belonging to Aspergillus section Fumigati (8). Such fumigati-mimetic molds are increasingly being recognized as sporadic causes of IPA (9). A. felis has been reported as a cause of sino-orbital aspergillosis in cats, but less frequently in humans (8). In one such case of IPA, and in the few reported cases in patients with CGD of IPA caused by the closely related A. pseudoviridinutans and A. udagawae, the course of infection was more protracted than for A. fumigatus infections, and dissemination occurred in a contiguous manner (10). Nonfumigatus Aspergillus exhibit decreased in vitro susceptibility to commonly used antifungal drugs. Most previously reported antifungal susceptibilities from A. felis isolates showed high MICs for voriconazole and itraconazole but lower MICs for posaconazole (8).

Because isolates may be misidentified as A. fumigatus, culture-based morphological identification of invasive fungal infections in CGD may sometimes be insufficient. In cases of breakthrough fungal infections, or when faced with an atypical or refractory course of infection, identification of the fungus at a species level by molecular methods appears to be critical to guiding proper patient management.

Dr. Paccoud is an infectious diseases resident at Necker Hospital, Paris, France. His primary interests include care for immunocompromised patients, fungal infections, and infectious disease epidemiology.

Top

Acknowledgment

The authors thank Dea Garcia-Hermoso for her invaluable assistance with the identification of Aspergillus felis.

Top

References

  1. Subcommittee on Antifungal Susceptibility Testing of the ESCMID European Committee for Antimicrobial Susceptibility Testing. EUCAST technical note on the method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia-forming moulds. Clin Microbiol Infect. 2008;14:9824. DOIPubMed
  2. EUCAST. Antifungal agents: breakpoint tables for interpretation of MICs. 2018 [cited 2019 Aug 24]. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/Antifungal_breakpoints_v_9.0_180212.pdf
  3. Henriet  S, Verweij  PE, Holland  SM, Warris  A. Invasive fungal infections in patients with chronic granulomatous disease. Adv Exp Med Biol. 2013;764:2755. DOIPubMed
  4. Greenberger  PA, Bush  RK, Demain  JG, Luong  A, Slavin  RG, Knutsen  AP. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract. 2014;2:7038. DOIPubMed
  5. Eppinger  TM, Greenberger  PA, White  DA, Brown  AE, Cunningham-Rundles  C. Sensitization to Aspergillus species in the congenital neutrophil disorders chronic granulomatous disease and hyper-IgE syndrome. J Allergy Clin Immunol. 1999;104:126572. DOIPubMed
  6. Moskaluk  CA, Pogrebniak  HW, Pass  HI, Gallin  JI, Travis  WD. Surgical pathology of the lung in chronic granulomatous disease. Am J Clin Pathol. 1994;102:68491. DOIPubMed
  7. Beauté  J, Obenga  G, Le Mignot  L, Mahlaoui  N, Bougnoux  M-E, Mouy  R, et al.; French PID Study Group CEREDIH. Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France. Pediatr Infect Dis J. 2011;30:5762. DOIPubMed
  8. Barrs  VR, van Doorn  TM, Houbraken  J, Kidd  SE, Martin  P, Pinheiro  MD, et al. Aspergillus felis sp. nov., an emerging agent of invasive aspergillosis in humans, cats, and dogs. PLoS One. 2013;8:e64871. DOIPubMed
  9. Seyedmousavi  S, Lionakis  MS, Parta  M, Peterson  SW, Kwon-Chung  KJ. Emerging Aspergillus species almost exclusively associated with primary immunodeficiencies. Open Forum Infect Dis. 2018;5:ofy213. DOIPubMed
  10. Vinh  DC, Shea  YR, Sugui  JA, Parrilla-Castellar  ER, Freeman  AF, Campbell  JW, et al. Invasive aspergillosis due to Neosartorya udagawae. Clin Infect Dis. 2009;49:10211. DOIPubMed

Top

Table

Top

Suggested citation for this article: Paccoud O, Guery R, Poirée S, Jouvion G, Bougnoux EM, Catherinot E, et al. Aspergillus felis in patient with chronic granulomatous disease. Emerg Infect Dis. 2019 Dec [date cited]. https://doi.org/10.3201/eid2512.191020

DOI: 10.3201/eid2512.191020

Original Publication Date: 11/7/2019

Table of Contents – Volume 25, Number 12—December 2019

Comments

Please use the form below to submit correspondence to the authors or contact them at the following address:

Fanny Lanternier, Hôpital Necker-Enfants Malades, Service de Maladies Infectieuses et Tropicales, 149 Rue de Sèvres, 75015 Paris, France

Send To

character(s) remaining.

Comment submitted successfully, thank you for your feedback.

Top

Page created: November 07, 2019
Page updated: November 07, 2019
Page reviewed: November 07, 2019
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external