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Aspergillus felis in Patient with Chronic Granulomatous Disease.

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 [micro]g/L) 1 month before his hospital visit.

At admission, blood counts showed mild leukocytosis (leukocytes 9.6 x [10.sup.9] cells/L, reference range 4-10 x [10.sup.9] cells/L), with neutrophils at 6.1 x [10.sup.9] cells/L (reference range 1.5-7 x [10.sup.9] cells/L) and eosinophils at 2 x [10.sup.9] cells/L (reference <0.5 x [10.sup.9] cells/L). Computed tomography (CT) revealed an upper left lobe consolidation (Appendix Figure, https://wwwnc.cdc.gov/EID/article/25/12/19-1020App1.pdf). We administered broad-spectrum antimicrobial drugs (2 g meropenem 3x/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 x [10.sup.6] 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 CharcotLeyden 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 x [10.sup.9] 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 2x/d, followed by 200 mg 2x/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 [beta]-tubulin target gene enabled the identification of Aspergillus felis (109/109 bp; 100% similarity to the type strain, CBS DTO_131-E3 [beta]-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 [micro]g/L for voriconazole, 4 [micro]g/L for itraconazole, 0.25 [micro]g/L for posaconazole, 2 [micro]g/L for caspofungin, and 4 [micro]g/L for amphotericin B. Based on EUCAST MIC breakpoints for A. fumigatus (2), we switched treatment to oral posaconazole (loading dose of 300 mg 2x/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, and 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 (99). 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 spp. 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.

Acknowledgments

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

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.

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;14:982-4. https://doi.org/10.1111/j.1469-0691.2008.02086.x

(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;764:27-55. https://doi.org/10.1007/978-1-4614-4726-9_3

(4.) Greenberger PA, Bush RK, Demain JG, Luong A, Slavin RG, Knutsen AP. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract. 2014;2:703-8. https://doi.org/10.1016/j.jaip.2014.08.007

(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;104:1265-72. https://doi.org/10.1016/S0091-6749(99)70023-0

(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;102:684-91. https://doi.org/10.1093/ajcp/102.5.684

(7.) Beaute 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;30:57-62. https://doi.org/10.1097/INF.0b013e3181f13b23

(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. https://doi.org/10.1371/journal.pone.0064871

(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. https://doi.org/10.1093/ofid/ofy213

(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;49:102-11. https://doi.org/10.1086/599345

Address for correspondence: Fanny Lanternier, Hopital Necker-Enfants Malades, Service de Maladies Infectieuses et Tropicales, 149 Rue de Sevres, 75015 Paris, France; email: fanny.lanternier@aphp.fr

Olivier Paccoud, Romain Guery, Sylvain Poiree, Gregory Jouvion, Marie Elisabeth Bougnoux, Emilie Catherinot, Olivier Hermine, Olivier Lortholary, Fanny Lanternier

Author affiliations: Hopital Necker-Enfants Malades, Paris, France (O. Paccoud, R. Guery, S. Poiree, M.E. Bougnoux, O. Hermine, O. Lortholary, F. Lanternier); Institut Pasteur, Paris (G. Jouvion, O. Lortholary, F. Lanternier); Hopital Foch, Universite Versailles-Saint-Quentin-en-Yvelines, Versailles, France (E. Catherinot)

DOI: https://doi.org/10.3201/eid2512.191020
Table. Defining features of invasive pulmonary aspergillosis and
allergic bronchopulmonary aspergillosis in a 42-year-old man with X-
linked chronic granulomatous disease, Paris, France *

                                 Defining features

                                IPA (oncohematologic
Category                              setting)

Underlying disease                  Neutropenia

Mechanisms of disease              Angioinvasion

Course of infection                Acute, single
                                       event

Radiographic findings               Cavitation,
                                     pulmonary
                                  infarction, air
                                   crescent sign,
                                     halo sign

Galactomannan testing                 Positive

Total serum IgE                        Normal

Aspergillus species-specific          Negative
IgE or skin test reactivity

Aspergillus IgG                       Negative

Precipitating antibodies to           Negative
Aspergillus

Blood eosinophilia                     Absent

First-line treatment                 Antifungal
                                     treatment

                                    Defining features

Category                              IPA during CGD

Underlying disease                  CGD, particularly
                                       X-linked CGD

Mechanisms of disease           Tissue invasion, little or
                                     no angioinvasion

Course of infection                Subacute or chronic,
                                       single event

Radiographic findings           Single or multiple nodules
                                    and consolidations

Galactomannan testing              Positive or negative

Total serum IgE                           Normal

Aspergillus species-specific             Negative
IgE or skin test reactivity

Aspergillus IgG                          Negative

Precipitating antibodies to              Negative
Aspergillus

Blood eosinophilia                Absent; reported only
                                    during "fulminant
                                     mulch pneumonia"

First-line treatment               Antifungal treatment

                                    Defining features

Category                          Patient in this study

Underlying disease                     X-linked CGD

Mechanisms of disease                No angioinvasion

Course of infection                     Subacute,
                                       single event

Radiographic findings              Single consolidation

Galactomannan testing                    Negative

Total serum IgE                          Elevated
                                       (1,410 IU/L)

Aspergillus species-specific        Positive (7 IU/mL)
IgE or skin test reactivity

Aspergillus IgG                    Positive (54 IU/mL)

Precipitating antibodies to        Positive (2 arcs of
Aspergillus                           precipitation)

Blood eosinophilia                       Present
                                (2.2 x [10.sup.9] cells/L)

First-line treatment               Antifungal treatment

                                     Defining features

Category                                   ABPA

Underlying disease                Asthma, cystic fibrosis

Mechanisms of disease                   Exaggerated
                                   inflammatory response
                                      to Aspergillus

Course of infection                    Chronic with
                                       exacerbations

Radiographic findings             Central bronchiectasis,
                                  pulmonary infiltrates,
                                        mucus plugs

Galactomannan testing                    Negative

Total serum IgE
                                  Elevated (>1,000 IU/L)

Aspergillus species-specific       Positive (>0.1 IU/mL)
IgE or skin test reactivity

Aspergillus IgG                    Positive (>10 IU/mL)

Precipitating antibodies to         Positive (>1 arc of
Aspergillus                           precipitation)

Blood eosinophilia                        Present
                                (>0.5 x [10.sup.9] cells/L)

First-line treatment                Systemic or inhaled
                                      corticosteroids

* ABPA, allergic bronchopulmonary aspergillosis; CGD, chronic
granulomatous disease; IPA, invasive pulmonary aspergillosis.
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Title Annotation:RESEARCH LETTERS
Author:Paccoud, Olivier; Guery, Romain; Poiree, Sylvain; Jouvion, Gregory; Bougnoux, Marie Elisabeth; Cathe
Publication:Emerging Infectious Diseases
Geographic Code:4EUFR
Date:Dec 1, 2019
Words:1776
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