Exophiala dermatitidis is a saprophytic fungus that is usually present in decaying plants and soil. It can also be found in high-temperature and high-humidity areas, such as dishwashers, bathrooms or sauna facilities, in anthropogenic environments. It has also been isolated from railroad sleepers in subtropical areas. It is a rare conditional pathogen that often causes phaeohyphomycosis . It can colonize lung transplantation wounds and cause rapidly progressing invasive dermatitis , which has been reported in cystic fibrosis (CF) patients. A prospective study by Lebecque et al. found that 5.8% of CF patients had at least one sputum culture positive for this common respiratory tract-colonizing fungus. This fungus is considered a potential marker for atypical CF in patients with chronic respiratory diseases and recurrent lung infections . Central nervous system infections due to this fungus have also been reported in Asian populations with normal immunity .
In summary, in our case report, the patient had no clear underlying lung disease or immunosuppressive status; however, he was a middle-aged male with weight loss and long-term heavy smoking. Unfortunately, pulmonary function testing could not be performed because of multiple hemoptysis events, and it was impossible to assess whether there was chronic airway inflammation.
Although we did not obtain definitive evidence to confirm whether the patient was immunocompromised, T-cell subpopulation testing one month after illness onset showed that T-cell levels were decreased, and soon after treatment, related indices gradually returned to normal. Therefore, we speculated that he might have experienced a relatively significant reduction in CD4 cell levels in the early stage, which provided an opportunity for Exophiala dermatitidis infection.
A standardized diagnostic tool for the detection of Exophiala spp. is still lacking. Specific IgG detection tools have not yet been commercialized or widely applied. In addition, slow growth, large differences in morphological structures within the same species, and a lack of species-specific morphology all impose substantial challenges. Although matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry has been proven to be the best method for the rapid identification of pathogenic yeast from cultures , the databases used in routine clinical practice may not include Exophiala spp. . Currently, molecular methods are increasingly replacing morphological methods for the identification of fungi. Species-specific PCR was introduced by Nagano et al. in 2008 and was the first successful sequencing method, which is based on sequencing of the ribosomal DNA (rDNA) operon and its region . Most researchers believe that sequencing based on rDNA transcription spacers can obtain accurate species identification [7, 11]. A revision and update of the consensus definitions of invasive fungal disease by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) (2019) added tissue nucleic acid diagnosis as a criterion for proven invasive fungal disease . However, tissue nucleic acid diagnosis data is based mostly on Aspergillus infection, and its value in the diagnosis of other rare pulmonary fungal diseases needs additional research. In our case, multiple pathologies suggested inflammation, one of which suggested TB infection, but combined with the clinical characteristics, we were skeptical of TB infection and finally diagnosed the patient with Exophiala dermatitidis infection using tissue nucleic acid testing combined with treatment response data.
Regarding treatment, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/European Confederation of Medical Mycology (ECMM) guidelines recommend the use of azoles, such as voriconazole and posaconazole. Several antifungal susceptibility test results for Exophiala dermatitidis have been reported. Nweze et al. analyzed 16 isolates and found that almost all strains were sensitive to amphotericin B, 5-fluorocytosine, itraconazole, fluconazole and voriconazole . Another study showed that amphotericin B was active against all tested species except Exophiala mesophila, with minimum inhibitory concentration (MIC) values of 1 μg/mL . Gao et al. reported that voriconazole, itraconazole and posaconazole were active against Exophiala dermatitidis. Triazole combined with flucytosine, amphotericin B combined with flucytosine, amphotericin B combined with terbinafine, and posaconazole combined with amphotericin B all showed synergistic activity [15,16,17,18]. In contrast, echinocandins have weak antifungal activity. It is worth noting that a breakthrough infection during prevention and treatment with micafungin has also been reported .
After re-examining our case, we diagnosed Exophiala dermatitidis infection based on the mNGS results and continued the oral administration of voriconazole. After 2.5 months, most of the lesions had been significantly absorbed, but the dorsal lesion had progressed, and indications of drug-induced liver damage were observed. Considering a possible decrease in drug sensitivity, we adjusted the treatment to amphotericin B combined with posaconazole. Because of the cost involved, amphotericin B was finally administered. After 3 months, the lesion had been significantly absorbed. We adjusted the treatment to posaconazole for half a month in the later period. There was no evidence of recurrence at follow-up after treatment withdrawal. Although there is currently no established targeted PCR method for the detection of Exophiala dermatitidis from formalin-fixed paraffin-embedded (FFPE) tissue DNA, we believe a definitive diagnosis of pulmonary Exophiala dermatitidis infection can be established based on the current guidelines and during the treatment process.
Due to the limited culture technology available for the detection of this rare fungus, we failed to obtain drug sensitivity results; previous studies found that susceptibility test results for clinical isolates of Exophiala dermatitidis showed some differences. Therefore, if our patient had experienced a poor therapeutic effect, it would have been very difficult to select an appropriate antifungal drug therapy. Additionally, we discussed the positive antacid fluorescence and antacid 2 test results with the pathologist. Subsequently, the pathologist examined the pathological sections and performed staining of the same tissue again, which revealed negative antacid fluorescence results, and no acid-fast bacteria were observed. Considering the treatment course and the mNGS results, we are sure that the original results were false positives and considered the samples to have been contaminated. Due to the high incidence of TB in China and the fact that the respiratory pathology center of our hospital receives and processes a large number of clinical specimens from patients with complex infections that show a high acid-fast bacilli positivity rate, we speculate that the most likely source of the contamination was from the water bath for the paraffin sections.
Finally, some insights from our case are as follows: (1) the importance of symptoms at follow-up, follow-up chest CT, and efficacy and safety assessments, should be emphasized; and (2) the importance of molecular techniques, such as mNGS, for the identification of rare fungi should be emphasized. This will improve the pathogen diagnosis rate when combined with other clinical microbiological tests.