Combination therapy with itraconazole and terbinafine for phaeohyphomycosis caused by Exophiala spinifera: A case report and literature review.

Exophiala spinifera is a rare dematiaceous fungus causing cutaneous, subcutaneous and disseminated phaeohyphomycosis (PHM). Standard antifungal therapy for PHM is still uncertain. Here, we report a case of a Chinese male with PHM caused by E. spinifera, who received significant clinical improvement after the treatment with oral itraconazole and terbinafine. With the aim of evaluating the antifungal therapy for PHM caused by E. spinifera, a detailed review was performed.

Subcutaneous phaeohyphomycosis caused by Alternaria section Alternaria.

A woman presented with purulent infiltrating plaques on her hands and arms after a 7-year history of nephrotic syndrome. She was ultimately diagnosed with subcutaneous phaeohyphomycosis, which is caused by Alternaria section Alternaria. The lesions completely resolved after 2 months of antifungal treatment. Interestingly, spores (round-shaped cells) and hyphae were observed in the biopsy and pus specimens, respectively. This case report highlights that distinguishing subcutaneous phaeohyphomycosis from chromoblastomycosis may be difficult if the diagnosis is solely based on pathological findings. It also emphasizes that the parasitic forms of the dematiaceous fungi in immunosuppressed hosts may vary with the site and environment.

Pulmonary abscess caused by Cladosporium cladosporioides after receiving outpatient chemotherapy.

Cladosporium cladosporioides is one of the most ubiquitous dematiaceous fungi that seldomly occur human infection. Here, we demonstrate a rare case of pulmonary phaeohyphomycosis with a distinctive pulmonary lesion during the nadir period of outpatient chemotherapy against endometrial cancer. In addition to severe neutropenia, excessive exposure to C. cladosporioides at patient's residence was considered as dominant causative factor. More caution is considered necessary for pulmonary phaeohyphomycosis in patients who receive outpatient chemotherapy and are homebound during neutropenic status.

Clinical characteristics of central nervous system phaeohyphomycosis: A brief report of 20 years' experience.

Central nervous system (CNS) phaeohyphomycosis is a rare and often fatal fungal infection. Our study reported a case series of eight CNS phaeohyphomycosis cases at our institution over the past 20 years. We did not observe the common pattern of risk factors, abscess location, or number of abscesses among them. Most patients were immunocompetent without classic risk factors for fungal infection. Early diagnosis and aggressive management with surgical intervention and prolonged antifungal therapy can lead to a favorable outcome. The study highlights the need for further research to better understand the pathogenesis and optimal management of this challenging rare infection.

Mouse Models of Phaeohyphomycosis.

Infections by dematiaceous fungi especially phaeohyphomycosis are an emerging group of infectious diseases worldwide with a variety of clinical presentations. The mouse model is a useful tool for studying phaeohyphomycosis, which can mimic dematiaceous fungal infections in humans. Our laboratory has successfully constructed a mouse model of subcutaneous phaeohyphomycosis and found significant phenotypic differences between Card9 knockout and wild-type mice, mirroring the increased susceptibility to this infection observed in CARD9-deficient humans. Here we describe construction of the mouse model of subcutaneous phaeohyphomycosis and related experiments. We hope that this chapter can be beneficial for the study of phaeohyphomycosis and facilitate the development of new diagnostic and therapeutic approaches.

Phaeohyphomycosis: A study from tertiary health care center in North India.

Objectives: Phaeohyphomycosis refers to infections caused by phaeoid/dematiaceous or darkly pigmented fungi. This study was undertaken to further increase our knowledge about the incidence of phaeohyphomycosis and its causative agents. Materials and Methods: The present study was conducted over a period of one and a half years (January 2018-June 2019) on specimens received from patients with varied clinical manifestations ranging from superficial infections, subcutaneous cysts, pneumonia, brain abscess to a disseminated infection. These specimens were processed in the Department of Microbiology for potassium hydroxide (KOH) examination and culture and in Pathology for cytology/histopathological examination (HPE). All specimens positive on direct examination for dark grey, brown or black fungi were included in the study. Results: A total of 20 specimens were confirmed as phaeohyphomycosis. Most of the patients belonged to the age group of 41 to 50 years. Male: Female ratio was 2.3:1. Trauma was the most common risk factor. Spectra of the isolated fungal pathogens comprised of Bipolaris species, Exophiala species, Curvularia geniculata, Phialemonium species, Daldinia eschscholtzii, Hypoxylon anthochroum, Phaeoacremonium species, Leptosphaerulina australis, Medicopsis romeroi, Lasiodiplodia theobromae, Eutypella species, Chaetomium globosum, Alternaria species, Cladophialophora bantiana and 2 unidentified dematiaceous fungi. Recovery from phaeohyphomycosis was seen in 12 patients, 7 were lost to follow up and one patient succumbed to the illness. Conclusion: Infections caused by phaeoid fungi can no longer be viewed as rare. In fact, phaeohyphomycosis can have myriad of presentations spanning from mild cutaneous infections to fatal brain disease. Therefore, a high index of clinical suspicion is needed to diagnose such infections. The primary treatment modality remains surgical removal of the lesion in cutaneous or subcutaneous infections however disseminated disease with a guarded prognosis requires aggressive management.

Pulmonary phaeohyphomycosis due to Exophiala dermatitidis in a patient with pulmonary non-tuberculous mycobacterial infection.

A 65-year-old Japanese woman repeatedly withdrew and resumed antibiotics against pulmonary non-tuberculous mycobacterial infection caused by Mycobacterium intracellulare for more than 10 years. Although she continued to take medications, her respiratory symptoms and chest computed tomography indicated an enlarged infiltrative shadow in the lingular segment of the left lung that gradually worsened over the course of a year or more. Bronchoscopy was performed and mycobacterial culture of the bronchial lavage fluid was negative, whereas Exophiala dermatitidis was detected. After administration of oral voriconazole was initiated, the productive cough and infiltrative shadow resolved. There are no characteristic physical or imaging findings of E. dermatitidis, and it often mimics other chronic respiratory infections. Thus, when confronting refractory non-tuberculous mycobacterial cases, it might be better to assume other pathogenic microorganisms, including E. dermatitidis, and actively perform bronchoscopy.

A rare case of refractory facial phaeohyphomycosis caused by Cladosporium halotolerans successfully treated with aminolevulinic acid photodynamic therapy.

A 55-year-old female presented with a gradually enlarged red plaque and ulceration on the right side of her nose, face and suborbital region for ten years. The histopathologic features indicated infectious granuloma. The results of the fungal culture of the tissue and DNA sequencing identified as Cladosporium halotolerans infection. The patient was diagnosed with phaeohyphomycosis due to Cladosporium halotolerans. In this case, it was unsuitable for surgical treatment since the lesion was located periorbital. Furthermore, the patient had a poor response to oral itraconazole (400 mg/d) for 9 months. Therefore, ALA-PDT was added to the treatment regimen. The patient received ALA-PDT irradiation 5 times at 2-week intervals and achieved significant clinical remission. We believe that ALA-PDT may be an effective and safe adjuvant therapy.

Not all black fungus is mucormycosis: A challenging case of Medicopsis romeroi.

In this case of phaeohyphomycosis, fine needle aspiration cytology enabled a rapid diagnosis and prompt treatment. This infection is quite prevalent in immunocompromised individuals; however, the Medicopsis romeroi species is a rare causative agent. These cases are associated with inadequate response to standard antifungal therapy and require discussion.

Challenges towards management of CARD9-deficient patients with phaeohyphomycosis: A case report and case series study.

BACKGROUND: A number of recalcitrant phaeohyphomycosis cases with a life-threatening prognosis have been observed in CARD9-deficient patients, but little is known about the long-term management strategies that are effective for such intractable individuals. OBJECTIVES: To study the genetic and immunological mechanisms underlying recalcitrant phaeohyphomycosis and to share our clinical experiences regarding its treatment. PATIENTS/METHODS: Ten CARD9-deficient patients with recalcitrant phaeohyphomycosis admitted to our centre in the past two decades were followed-up, and their clinical presentations, laboratory findings, treatment and prognoses were analysed; one of them was a novel case of recalcitrant phaeohyphomycosis harbouring CARD9 mutations. Innate and adaptive immunological responses of patient-derived peripheral blood mononuclear cells were evaluated using ELISA and flow cytometry. RESULTS: We identified a total of seven CARD9 mutations in the ten analysed patients. Moreover, patient-derived cells exhibited a significant impairment of innate and adaptive immune responses upon fungus-specific stimulation. All the patients experienced recurrence and exacerbation; four of them died, two exhibited continued disease progress with unsatisfactory therapeutic efficacy, three showed obvious improvement under maintenance therapy, and only one achieved a clinical cure. CONCLUSIONS: Our study highlighted that otherwise healthy patients diagnosed with early-onset, unexplained and recalcitrant phaeohyphomycosis should be analysed for CARD9 mutations and immune deficiency. Thereafter, the length and choice of management remain challengeable and must be adjusted based on the clinical presentations and responses of patients over their lifetimes. Although continued posaconazole treatment may be the promising first-line therapy at present, novel strategies are worth exploring.

Pediatric Phaeohyphomycosis: A 44-Year Systematic Review of Reported Cases.

BACKGROUND: Phaeohyphomycosis is an infection caused by pigmented fungi, which can be life-threatening in immunocompromised hosts and in disseminated disease. In adults with disseminated disease, mortality is as high as 79%. Data in children are derived from case reports and series. We conducted this study to review the characteristics of phaeohyphomycoses in children. METHODS: We conducted this study following the PRISMA 2020 guideline for reporting systematic reviews. We performed a review of the reported cases of pediatric phaeohyphomycoses in core bibliographic databases published in the English and Spanish language, between June 1977 and October 2021. We included all eligible cases in patients <18 years to determine the clinical characteristics, diagnosis, treatment, and outcomes. RESULTS: A total of 130 cases were reviewed. The mean age was 8 years. The most common underlying conditions and risk factors included hematologic malignancies (32.5%), neutropenia (26.9%), steroid therapy (24.6%), trauma or surgery (23.1%), and children that received a transplant (14.6%). The most common presentation was localized infection (61.5%); skin and soft tissue infections were the most prevalent (25.4%). Exserohilum spp (20.8%) and Exophiala spp (17.7%) were the most common organisms isolated. Antifungal therapy remains as the most frequent treatment (87%). Overall mortality rate was 22.3% (localized 13.7% vs disseminated 37.3%). CONCLUSION: The findings of this review suggest that phaeohyphomycoses in children have a better outcome compared to adults. We report a lower mortality rate in children when compared with adults in disseminated infection (37.3% vs 79%) and CNS infection (50% vs 60-70%). However, there is a wide variation in mortality rates according to the infection site, treatment, and underlying conditions. Prospective studies are needed.

Subcutaneous Phaeohyphomycosis in a Renal Transplant Patient by a Rare Fungus Medicopsis romeroi.

Medicopsis romeroi is a dematiaceous fungus that rarely causes subcutaneous phaeohyphomycosis. Here, we report a subcutaneous phaeohyphomycosis caused by a rare dematiaceous fungus, M. romeroi, in a 56-year-old male renal transplant patient. The patient was admitted for graft dysfunction and was found to have painless swelling over the anterior aspect of the right knee, which was aspirated twice within 40 days. Broad septate hyphae (determined by microscopy) and growth of phaeoid in a culture were observed in both the specimens. No sporulation was observed in the slide culture. Swelling recurred even after treatment with voriconazole, so the lesion was surgically excised. Genotypically, the isolate was identified as M. romeroi in both specimens. He was discharged on voriconazole. During a 6-month follow-up, no relapse was noticed. Phaeohyphomycosis caused by M. romeroi is rare, with only a few cases reported in India. Laboratory diagnosis of Medicopsis by conventional methods is challenging. Medicopsis species should be considered one of the etiological agents for subcutaneous phaeohyphomycosis. Molecular methods should be used for the identification of unusual pathogens.

Atypical pulmonary phaeohyphomycosis due to Aureobasidium spp. - case report and brief literature review.

We report on a case of probable invasive Auerobasidium spp. pulmonary infection in a patient with myelodysplastic syndrome. The patient was successfully treated with liposomal amphotericin B monotherapy, with transition to orally administered isavuconazole. This case shows an atypical initial radiological presentation with diffuse ground-glass opacities, as previously demonstrated in cases of Aureobasidium spp. hypersensitivity pneumonitis. Moreover this case further highlights the difficulties associated with the diagnosis and complexity in the management of Aureobasidium spp. infections.

Subcutaneous phaeohyphomycosis caused by plant pathogenic Corynespora cassiicola: A case report.

Corynespora cassiicola is a common plant pathogen responsible for leaf-spotting diseases in the tropical and subtropical areas. C. cassiicola seldom causes human infections. Here we describe a case of subcutaneous phaeohyphomycosis caused by C. cassiicola in a 76-year-old Chinese man, who presented to our hospital with a purulent discharge and painful sensation on his right leg. Skin biopsy revealed an abscess, and culture confirmed C. cassiicola to be the causative agent. The result was further identified by sequence analysis of the internal transcribed spacer region. The patient was successfully treated with systemic voriconazole and wound debridement: the lesion disappeared after 20 days.

New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box® that present synergism with itraconazole.

BACKGROUND: Black fungi of the Herpotrichiellaceae family are agents of chromoblastomycosis and phaeohyphomycosis. There are few therapeutic options for these infections and it is common to associate antifungal drugs in their treatment. OBJECTIVES: To investigate the Medicines for Malaria Venture (MMV) Pathogen Box® for possible compounds presenting synergism with antifungal drugs used to treat black fungal infections. METHODS: An initial screening of the Pathogen Box® compounds was performed in combination with itraconazole or terbinafine at sub-inhibitory concentrations against Fonsecaea pedrosoi. Hits were further tested against eight Herpotrichiellaceae using the checkerboard method. FINDINGS: No synergism was observed with terbinafine. MMV687273 (SQ109) and MMV688415 showed synergism with itraconazole against F. pedrosoi. Synergism of these compounds was confirmed with some black fungi by the checkerboard method. SQ109 and itraconazole presented synergism for Exophiala dermatitidis, F. pedrosoi, F. monophora and F. nubica, with fungicidal activity for F. pedrosoi and F. monophora. MMV688415 presented synergism with itraconazole only for F. pedrosoi, with fungicidal activity. The synergic compounds had high selectivity index values when combined with itraconazole. MAIN CONCLUSIONS: These compounds in combination, particularly SQ109, are promising candidates to treat Fonsecaea spp. and E. dermatitidis infections, which account for most cases of chromoblastomycosis and phaeohyphomycosis.

Management of Extensive Central Nervous System Cladophialophora bantiana Infection in a 9-Year-Old Child.

BACKGROUND: Pediatric central nervous system (CNS) phaeohyphomycosis is a rare invasive fungal infection associated with high mortality. METHODS: We describe a child with progressive neurologic symptoms whose ultimate diagnosis was Cladophialophora bantiana -associated CNS phaeohyphomycosis. We discuss her clinical presentation, medical and surgical management and review the current literature. RESULTS: A 9-year-old female presented with acute onset of headaches, ophthalmoplegia and ataxia. Initial infectious work-up was negative, including serial fungal cerebrospinal fluid cultures. Over 2 months, she experienced progressive cognitive and motor declines, and imaging revealed worsening meningitis, ventriculitis and cerebritis. Ultimately, Cladophialophora was detected by plasma metagenomic next-generation sequencing (mNGS). Fourth ventricle fluid sampling confirmed the diagnosis of C. bantiana infection. Given the extent of her disease, complete surgical resection was not feasible. She required multiple surgical debridement procedures and prolonged antifungal therapy, including the instillation of intraventricular amphotericin B. With aggressive surgical and medical management, despite her continued neurologic deficits, she remains alive 3 years after her initial diagnosis. To our knowledge, this is one of a few published pediatric cases of CNS phaeohyphomycosis and the first with the causative pathogen identified by plasma mNGS. CONCLUSION: CNS phaeohyphomycosis is a serious, life-threatening infection. The preferred management includes a combination of surgical resection and antifungal therapy. In cases complicated by refractory ventriculitis, intraventricular antifungal therapy can be considered as adjuvant therapy. Direct sampling of the CNS for pathogen identification and susceptibility testing is the gold standard for diagnosis; however, the use of plasma mNGS may expedite the diagnosis.