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Invasive Infections Caused by Nannizziopsis spp. Molds in Immunocompromised Patients.

Nannizziopsis spp. molds have been reported in extremely rare cerebral and disseminated infections (1,2), (Table). We describe 2 cases of Nannizziopsis infection diagnosed in France during the past 2 years. Both case-patients were immunocompromised and had recently returned from Africa.

The Cases

Case-patient 1 was a 63-year-old woman from France who had been treated for T-cell prolymphocytic leukemia diagnosed in December 2014. She initially received alemtuzumab, switching to bendamustine in March 2015 after tumor progression. That treatment failed, and idelalisib was started on July 11, 2015. The patient was hospitalized 2 days later for acute renal failure with mild fever. She became confused and drowsy, and cerebral computed tomography (CT) scan showed systematized subcortical hypodense areas. Lumbar puncture showed neoplastic cells in the cerebrospinal fluid (CSF) and glucose concentration within reference range. Bacteriological and fungal cultures were sterile. A large volume of ascites fluid remained, despite iterative punctures with negative bacteriological cultures. We initiated intrathecal chemotherapy with methotrexate/cytarabine/methylprednisolone. However, the patient's condition worsened, with heart failure and loss of consciousness. On July 18, we took new specimens of CSF, bronchial wash, ascites fluid, and blood cultures and sent them for bacteriological investigation. We started empiric treatment with imipenem/aminoglycosides, but the patient died on July 19 of septic shock. No autopsy was performed. Extended-spectrum [beta]-lactamase-producing Escherichia coli sensitive to imipenem grew quickly in 1 pair of blood cultures. A second pair was positive 4 days later, with the presence of large septate fungal hyphae and arthroconidia. White and thin cottony mold colonies grew on Sabouraud media incubated at 35[degrees]C (online Technical Appendix Figure 1, https://wwwnc.cdc.gov/EID/ article/24/3/17-0772-Techapp1.pdf). We performed best model determination and phylogenetic analyses in MEGA6 (http://www.megasoftware.net). We identified N. obscura by sequencing the 18S-internal transcribed spacer (ITS) 1-5.8S-ITS2 region (online Technical Appendix Figure 2). The strain had low MICs for antifungals as defined by the European Committee on Antimicrobial Susceptibility Testing (http://www.eucast.org/): amphotericin B 0.06 [micro]g/ mL, itraconazole 0.25 [micro]g/mL, voriconazole 0.03 [micro]g/mL, posaconazole 0.06 [micro]g/mL, caspofungin 0.5 [micro]g/mL, and micafungin 0.015 [micro]g/mL. We performed mycologic investigations of CSF and ascites fluid a posteriori on frozen aliquots and conducted PCR assays targeting the ITS region on CSF sampled on July 15 and July 19 and on ascites fluid sampled on July 19. We observed positive amplifications in all samples; subsequent sequencing confirmed the presence of DNA from N. obscura. We investigated the origin of the patient's contamination. She had made several trips to Senegal, the latest in January 2015, during which an ulcerative inflammatory lesion developed on her left little finger. However, Grocott stain and PCR on paraffin-embedded tissue of skin biopsy were negative, and we attributed the lesion to the hematological malignancy.

Case-patient 2 was a 52-year-old woman from France living in Mali, who was hospitalized in Bamako in November 2016 for cough, fever, alteration of general state, and headache. She tested seropositive for HIV (CD4 3/[micro]L; HIV-1 viral load 45.300 copies/mL). Chest radiograph showed bilateral pneumonia, and cerebral CT scan showed a single process on the left temporal lobe. Antiretroviral therapy was initiated with a combination of efavirenz/lamivudine/tenofovir associated with isoniazid, metronidazole, amoxicillin/clavulanate, and trimethoprime/sulfamethoxazole. Because of worsening of her neurologic status, she was repatriated to France. At hospital admission on January 12, 2017, she had a lesion on the left middle fingernail suggestive of onychomycosis, hemiparesis, and paralysis of the right side of the face associated with Broca's aphasia. A thoracic-abdominalpelvic scan revealed a nodular lesion in the right lung (Figure, panel A) and multiple partly calcified pleural lesions. Bacteriological assays, including investigation for mycobacteria on bronchoalveolar lavage (BAL) fluid, showed negative results. A Penicillium grew rapidly on mycological medium, and Pneumocystis jiroveci PCR results were slightly positive. Cranial tomodensitometry showed multiple gadolinium-enhancing nodules surrounded by edema (Figure, panel B). We initiated fluconazole and pyrimethamine/sulfadiazine and switched antiretroviral therapy to raltegravir/abacavir/lamivudine after the onset of acute renal insufficiency. Hemiplegia developed 15 days later. A new CT scan showed stable cerebral lesions but an increase in surrounding edema. We performed a lumbar puncture and started intravenous corticotherapy. CSF contained 127 leukocytes (61% lymphocytes) and showed hypoglycorrhachia. Investigations for toxoplasmosis, cryptococcosis, histoplasmosis, tuberculosis, and CMV showed negative results, but ITS-targeting PCR results were positive on CSF. The sequence was closely related to N. obscura, but mycological cultures were sterile (online Technical Appendix Figure 2). The results of a p-D-glucan assay of serum was positive (983 pg/mL; Fungitell, Associates of Cape Cod, Inc., http://www.acciusa. com/clinical/fungitell/index.html) and galactomannan antigen was negative. On February 6, we performed a cerebral biopsy. Histopathologic examination showed granuloma containing hyphae (Figure, panels C, D), and on the fourth day of incubation, white mold grew on Sabouraud media at 25[degrees]C and 35[degrees]C (online Technical Appendix Figure 1). The phylogenetic analyses of the 18S-ITS1-5.8S-ITS2 region confirmed that the fungus belonged to Nannizziopsis spp. Although the 18S region was closely related to N. obscura, the ITS1 region had a large insertion, suggesting the strain does not belong to the described Nannizziopsis species (online Technical Appendix Figure 2). Strain MICs as defined by the European Committee on Antimicrobial Susceptibility Testing were amphotericin B 0.25 [micro]g/mL, itraconazole 0.03 [micro]g/mL, voriconazole 0.125 [micro]g/ mL, posaconazole 0.25 [micro]g/mL, caspofungin 0.25 [micro]g/mL, and micafungin <0.008 [micro]g/mL. We initiated liposomal amphotericin B (5 mg/kg). On July 16, the patient became drowsy with a bilateral pyramidal syndrome and moderate reactive mydriasis. Cranial CT scan showed an increase in the abscesses and edema with brain displacement. We performed a craniotomy. One month after diagnosis, the patient's general status had improved, with regression of the lung lesions and cerebral abscesses; her [CD.sub.4] cell count was 50/[micro]L and HIV-1 load <40 copies/mL. We switched her antifungal treatment to voriconazole.

Conclusions

The molds of the N. vriesii complex (Chrysosporium-like anamorph, CANV) are members of the Nannizziopsis genus (Onygenales, Eurotiomycetidae, Eurotiomycetes, Ascomycota).

CANV includes the keratinophilic species, which causes skin and fatal disseminated infections in reptiles (3,4). There is no documented evidence of zoophilic species involvement in human infections, but 3 other CANV species have been recovered from human samples (Table). Of the 5 previous cases of Nannizziopsis infections, 3 involved HIV patients. One of our patients was seropositive for HIV and the other had T-cell prolymphocyte leukemia, which suggests that lymphopenia could be a key risk factor. All patients with reported N. obscura infection had recently traveled in Africa. Results for case-patient 1 showed that the fungus grows in blood cultures and thus has high potential for dissemination. Case-patient 2 had pulmonary lesions, but BAL cultures were rapidly invaded by a Penicillium fungus. Although we could not detect Nannizziopsis in BAL, the lesion evolved favorably after antifungal therapy. Because Nannizziopsis spp. are keratinophilic molds, we looked for cutaneous lesions. Both case-patients had recently developed cutaneous or nail lesions during their time in Africa, but we did not detect Nannizziopsis from these lesions. These molds have not been isolated in our laboratory in other kinds of samples (clinical or environmental).

CSF cultures from both our case-patients and ascites cultures from case-patient 1 were negative, but panfungal PCR successfully detected molds (6). Data on biomarkers are scarce. N. infrequens cross-reacts with the Histoplasma AccuProbe test and N. hominis with the Blastomyces AccuProbe test (Hologic, San Diego, CA, USA) (5). In case-patient 2, p-D-glucan was positive in CSF and serum but galactomannan antigen was not. N. obscura seems to be sensitive to most antifungal agents (2).

These observations show how difficult this infection is to detect, which could explain why so few cases of human infections have been reported. However, the diagnosis of these 2 cases since 2015 suggests that the prevalence of Nannizziopsis infections may be underestimated.

Acknowledgments

The authors thank all the members of the Centre National de Reference des Mycoses et Antifongiques (CNRMA, Institut Pasteur de Paris, France) for their invaluable help in the antifungal susceptibility testing.

Dr. Nourrisson is a medical mycologist and parasitologist at the university hospital of Clermont-Ferrand, France. Her research interests include medical fungi epidemiology and digestive protozoa.

References

(1.) Stillwell WT, Rubin BD, Axelrod JL. Chrysosporium, a new causative agent in osteomyelitis. A case report. Clin Orthop Relat Res. 1984; (184):190-2.

(2.) Steininger C, van Lunzen J, Tintelnot K, Sobottka I, Rohde H, Horstkotte MA, et al. Mycotic brain abscess caused by opportunistic reptile pathogen. Emerg Infect Dis. 2005;11:349-50. http://dx.doi.org/10.3201/eid1102.040915

(3.) Sigler L, Hambleton S, Pare JA. Molecular characterization of reptile pathogens currently known as members of the Chrysosporium anamorph of Nannizziopsis vriesii complex and relationship with some human-associated isolates. J Clin Microbiol. 2013;51:3338-57. http://dx.doi.org/10.1128/JCM.01465-13

(4.) Stchigel AM, Sutton DA, Cano-Lira JF, Cabanes FJ, Abarca L, Tintelnot K, et al. Phylogeny of chrysosporia infecting reptiles; proposal of the new family Nannizziopsiaceae and five new species. Persoonia. 2013;31:86-100. http://dx.doi.org/ 10.3767/003158513X669698

(5.) Brandt ME, Gaunt D, Iqbal N, McClinton S, Hambleton S, Sigler L. False-positive Histoplasma capsulatum Gen-Probe chemiluminescent test result caused by a Chrysosporium species. J Clin Microbiol. 2005;43:1456-8. http://dx.doi.org/10.1128/ JCM.43.3.1456-1458.2005

(6.) Ihrmark K, Bodeker ITM, Cruz-Martinez K, Friberg H, Kubartova A, Schenck J, et al. New primers to amplify the fungal ITS2 region--evaluation by 454-sequencing of artificial and natural communities. FEMS Microbiol Ecol. 2012;82:666-77. http://dx.doi.org/10.1111/j.1574-6941.2012.01437.x

Address for correspondence: Philippe Poirier, Laboratoire de Parasitologie-Mycologie, Centre de Biologie, CHU Gabriel Montpied, 58 rue Montalembert, 63000 Clermont-Ferrand, France; email: ppoirier@chu-clermontferrand.fr

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Celine Nourrisson, Magali Vidal-Roux, Sophie Cayot, Christine Jacomet, Charlotte Bothorel, Albane Ledoux-Pilon, Fanny Anthony-Moumouni, Olivier Lesens, [1] Philippe Poirier [1]

Author affiliations: Centre Hospitalier Universitaire Clermont-Ferrand, Clermont-Ferrand, France

DOI: https://doi.org/10.3201/eid2403.171562

[1] These authors were co-principal investigators for this article.

Caption: Figure. Diagnostic testing of a 52-year-old woman from France living in Mali who had Nannizziopsis spp. fungal infection. A) Thoracic-abdominal-pelvic scan shows pseudo-nodular lesions in the apex of the right lung, of which one is excavated.

B) Cerebral computed tomography scan shows contrast enhancement on several hemispheric nodules on the left and in frontal, parietal, and temporal regions, responsible for large surrounding edema and compression of the left lateral ventricle. The median line is deviated to the right with a subfalcorial herniation.

C) Hematoxylin-eosin-saffron stain of brain biopsy containing mononuclear inflammatory infiltrates; giant cell granulomas; histiocytes, sometimes with an epithelioid appearance; and neutrophils (original magnification x200). D) Grocott stain showing thick bulbous mycelial filaments in the cytoplasm of certain giant cells/histiocytes (original magnification x600). Round shapes correspond to cross? sections of bulbous territories.
Table. Characteristics of Nannizziopsis spp. infection in humans *

                                                Underlying
Year               Age,                        condition or
(reference)        y/sex        Country           context

2017 (this         52/F         France        HIV, living in
study)                                             Mali

2015 (this         63/F         France           Leukemia,
study)                                         recent travel
                                                to Senegal

2005 (2)           38/M         Germany       HIV, travel to
                                                  Nigeria

2005 (5)           40/M      United States          HIV

2000 (3,4)         32/M      United States       Travel to
                                                  Nigeria

1994 (3)           NA/M      United States          HIV

1982 (1)           24/M      United States       Travel to
                                                  Africa

Year                                                     Positive
(reference)           Species        Localization         samples

2017 (this         Nannizziopsis     Brain abscess       Cerebral
study)                  sp.                             biopsy, CSF

2015 (this          N. obscura       Brain abscess    Blood culture,
study)                                                 CSF, ascites
                                                           fluid

2005 (2)            N. obscura       Brain abscess        Needle
                                                       aspiration of
                                                       brain lesion

2005 (5)           N. infrequens         Lung            Bronchial
                                                          washing

2000 (3,4)          N. hominis       Lymph nodes,      3 lymph nodes
                                     heart, lungs,
                                    spleen, kidneys

1994 (3)            N. hominis        Right thigh       Deep muscle
                                         mass           mass on the
                                                       right thigh,
                                                       right groin,
                                                       buttock, and
                                                           lung

1982 (1)            N. obscura        Abscess in       2 biopsies of
                                     right ankle,       abscess in
                                     osteomyelitis         tibia

Year
(reference)          Treatment          Outcome

2017 (this        AmpB for 1 mo,     Recovery but
study)               then VCZ         neurologic
                                    sequela after 2
                                          mo

2015 (this          Not treated      Death before
study)             (death before       diagnosis
                    diagnosis)

2005 (2)                VCZ            Recovery
                                        without
                                    sequelae after
                                         4 mo

2005 (5)           Not treated,     Recovery after
                  considered as a    treatment of
                    contaminant      CMV infection

2000 (3,4)         ITRA for 2 y           NA

1994 (3)               ITRA          Death after 8
                                          mo

1982 (1)           AmpB for 4 mo    Recovery after
                                         4 mo

* AmpB, amphotericin B; CMV, cytomegalovirus; CSF, cerebrospinal
fluid; ITRA, itraconazole; NA, not available; VCZ, voriconazole.
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Article Details
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Title Annotation:DISPATCHES
Author:Nourrisson, Celine; Vidal-Roux, Magali; Cayot, Sophie; Jacomet, Christine; Bothorel, Charlotte; Ledo
Publication:Emerging Infectious Diseases
Geographic Code:6SOUT
Date:Mar 1, 2018
Words:2322
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