A 23 year old male was first admitted to our hospital with a history of an itchy rash present for more than 7 months on the left side of his face and multiple neck masses for 1 month, without fever, cough, sputum, headache, dizziness, diarrhea, and any other discomfort. He was in prison for more than 3 years and had been released recently. He had a history of a scissors puncture on his face before the onset of the facial lesion. The parents are consanguineous. The dark red patches observed on his face (Figure 1A) were about the size of an egg, soft, and well defined, with no ulceration. Many enlarged, hard, and mobile lymph nodes ranging from the size of soybeans to quail eggs with no tenderness were noticed on the skin behind the left ear and neck. The complete blood cell count, acute-phase reactants (erythrocyte sedimentation rate, serum C-reactive protein, and procalcitonin), serum biochemistry tests including glucose, and liver function tests were normal. The serologic tests for viruses (HIV, syphilis, and hepatitis virus) were negative. The serum antibodies (anti-double-stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-ribonucleoprotein antibodies, and anti-Smith antibodies) were within the normal range. The cultures for blood bacteria and fungi were negative. The lymphocyte subsets showed no obvious abnormality. The titers of anti-nuclear antibodies were 1:100 (<1:100), anti-JO-1 antibodies were weakly positive, and blood IgE was 1693.10 IU/mL (normal 1-190 IU/mL). He did not present any symptoms of tuberculosis; however, the T-spot and purified protein derivative (PPD) skin tests were positive. He had a previous history of tuberculosis infection. Computed tomography (CT) of his lungs revealed a number of speckled shadows and nodules in both the lungs. The cranial CT showed no abnormality. Subsequently, cervical lymph node biopsy and culture of the neck lymphoid tissue was performed. The culture of the neck lymphoid tissue yielded a black yeast-like fungus (Figure 1B); the pathological report indicated fungal granulomatous inflammation with necrosis (Figures 1C,D), and the strain was later identified as E. dermatitidis by DNA sequencing of the ribosomal DNA ITS domains. A pair of primer was designed for the amplification and sequencing of the ribosomal DNA (ITS4: 5'-TCCTCCGCTTATTGATATGC-3' ITS1: 5'-TCCGTAGGTGAACCTGCGG-3'). The ITS sequence was found to be identical to that of Exophiala dermatitidis type strain CBS 207.35 (GenBank nr_121268.1). The patient was discharged and prescribed an anti-fungal medication, itraconazole, and his facial rash improved over time.
He was again admitted to our hospital 7 months later with headache, nausea, and vomiting persistent for a week, accompanied with no convulsions, unconsciousness, fever, and paralysis. A brain CT done in a local hospital suggested hydrocephalus and cerebral hernia. His vital signs at the time of admission were stable. Physical examination disclosed no obvious abnormality except neck stiffness. There was a slight decrease in the white and red blood cell counts and an insignificant increase in the percentage of monocytes. The serum biochemistry test revealed no significant abnormality. Compared with the previous results, the blood IgE was reduced to 938.20 IU/mL (normal 1-190 IU/mL). The thyroid function test indicated thyroid-stimulating hormone (TSH) levels at 0.1525 muIU/mL. B-ultrasonography of the thyroid showed heterogeneous cystic nodules. There was no evidence of pulmonary or any other local fungal infection. The brain MRI (Figures 2A,B) presented with noticeable meningeal thickening, large edema in the corpus callosum and white matter in both the hemispheres, and obvious ventricular expansion. In addition, MR hydrography of the cerebrospinal fluid indicated that the interventricular foramen of both the lateral ventricles was occluded, middle cerebral aqueduct was significantly narrowed, and the left lateral ventricle exhibited the most hydrocephalus in comparison with the other dilated ventricles. The lung CT (Figure 2C) showed no significant change as compared to the previous imaging. We began osmotherapy therapy after his admission. Mannitol and glycerol fructose were administered intravenously alternately every 6 h. However, the patient unexpectedly had a seizure 4 days after the admission. We treated him with diazepam and valproate in addition to the anti-fungal drug, liposomal amphotericin B. He was also treated with 20 % mannitol every 4 h. Nevertheless, he was imminently transferred to the neurosurgery department and a left lateral ventricle puncture and drainage surgery was performed. His CSF analysis demonstrated a normal white blood cell count (3/muL, normal < 8/muL) and sugar, protein, and chloride levels were also within the normal range. The percentages of polymorphonuclear cells, lymphocytes, and monocytes were not analyzed. The immunoglobulin analysis in the CSF revealed increased IgG levels (69.3 mg/L, normal range 4.80-58.60 mg/L), and decreased microalbumin levels (112 mg/L, normal range 139.0-246.0 mg/L). Additionally, CSF culture was performed, but no fungus and anaerobic bacteria were observed, and no acid-resistant bacilli were found in the smear. A few hyphae and spores were detected in the CSF under a fluorescence microscope with calcofluor white (CW) staining. A brain tissue specimen was collected during surgery for histopathological assessment, which showed mycelia and fungal granuloma (Figures 3C-E). We also sequenced CARD9 and found that the patient carried a novel homozygous mutation, which underlines life-threatening, invasive fungal infections in otherwise healthy individuals.
On the first day after the surgery, the head drainage tube and the catheter were both unobstructed, but condition of the patient deteriorated. The patient appeared to be in a coma with an accelerated heart rate of 120 beats per minute. The bilateral pupils were circular and equal in size, diameter of 2 mm, with no reflex. Moreover, his limbs were stiff and the Babinski's sign was positive, which indicated herniation of the brain. The blood gas analysis revealed respiratory alkalosis. Two days later, his CSF analysis showed an accelerated white blood cell count (17/muL, normal < 8/muL) and protein levels (1.62 g/L, normal 0.15-0.45 g/L), accompanied with normal sugar levels and chloride ions. The percentages of polymorphonuclear cells, lymphocytes, and monocytes were not analyzed. He was treated with liposomal amphotericin B and voriconazole. In the next few days, his blood routine examination indicated an elevated white blood cell count with mainly neutrophils. Furthermore, Pseudomonas aeruginosa, Enterobacter cloacae, and Streptococcus F group were cultured from his sputum. Serious pulmonary infection, pleural effusion and partial atelectasis (Figures 2D,E) resulted in repeated resuscitation from respiratory failure. However, deteriorating intracranial hypertension, ventricle enlargement, compression of brain stem, extensive intracranial infarction, and edema (Figures 2F,G) predicted a poor prognosis. Consequently, the patient's family decided to withdraw the therapy and transferred him to a local hospital. However, he eventually died, even with an active treatment at the subsequent hospitalization.