Invasive rhinosinusitis due to Penicillium chrysogenum in an adolescent man with new-onset leukaemia: a diagnostic dilemma

Abstract

An adolescent boy with newly diagnosed T-cell acute lymphoblastic leukaemia developed right eye and facial pain, and a 1 cm × 2 cm area of black eschar over his hard palate. Initial differential diagnosis included rhinocerebral mucormycosis and aspergillosis, and he was started on liposomal amphotericin B. Later, he underwent nine surgical debridements of his sinus cavities, resection of a third of his palate and right orbital exenteration. While histological specimens exhibited features of both Aspergillus and Mucor, a PCR assay detected Penicillium chrysogenum. He was successfully treated with amphotericin B and Posaconazole. P. chrysogenum has been reported in a rare case of endocarditis, a case of post-traumatic endophthalmitis, disseminated infection in a child with Henoch-Schonlein syndrome, and one fatal adult case of invasive rhinosinusitis. While infection from Penicillium species is rare, it should be considered as a cause of invasive rhinosinusitis in cases of unclear histopathology.

Background

Acute fungal rhinosinusitis may present with fever, facial pain, nasal congestion, changes in vision or facial numbness. Most cases of invasive fungal rhinosinusitis are caused by Aspergillus species and Zygomycetes species including Mucor and Rhizopus.¹ Infection by Penicillium species is rare and usually develops in immunocompromised hosts. To our knowledge, there has been one case report of fatal invasive rhinosinusitis due to unidentified Penicillium species in an immunocompromised adult patient.² This case provides an example of invasive fungal rhinosinusitis due to Penicillium chrysogenum in a paediatric patient.

Case presentation

An adolescent man with no significant medical history presented to his paediatrician with a 2-week history of fevers, fatigue and enlarged lymph nodes in the neck. During the same time period, he experienced excessive tearing of his right eye with no eye redness or pain. The initial white cell count was 45 x 10⁹/L, with 2% neutrophils, 30% lymphocytes and 68% blasts. A subsequent bone marrow biopsy performed at the haematology oncology centre confirmed the diagnosis of T-cell acute lymphoblastic leukaemia (ALL).

This patient was placed on induction chemotherapy consisting of peg asparaginase, vincristine, dexamethasone, intrathecal methotrexate and cytarabine. Three days into treatment, his right eye symptoms worsened with pronounced eye pain and he developed right-sided facial pain. He denied fevers, headaches, neck pain or visual changes. An ophthalmology exam including a slit lamp was normal. A CT scan of his sinuses showed right-sided frontal, maxillary and ethmoid sinusitis with no evidence of orbital cellulitis (figure 1). He was started empirically on levofloxacin for bacterial sinusitis. Four days later, he developed new-onset erythema over his right eyelid and right facial swelling. He was subsequently admitted to the hospital.

Figure 1.

A CT scan of the sinuses showed right-sided sinus disease with osteomeatal pattern of involvement. (A) Red arrow points to maxillary sinus involvement. (B) Yellow arrow points to an area of skin thickening and soft tissue oedema in the soft tissues overlying the right maxillary region.

On physical examination, he was well appearing and in no acute distress. His temperature was 37.9°C, his heart rate was 76 /minute, his respiratory rate was 17 /minute and his blood pressure was 126/67 mm/Hg. He was noted to have right periorbital oedema and erythema with mild palpebral conjunctival injection. There was no eye discharge or proptosis and he had normal extraocular movements. On examination of his oral cavity, he was noted to have a 1cm x 2cm area of black eschar over his hard palate (figure 2). His white cell count was 1.3 x10⁹/L) with 2% neutrophils, 92% lymphocytes. He was empirically started on vancomycin, imipenem and amphotericin B. However, the eschar over the hard palate continued to expand to 3 cm × 4cm.

Figure 2.

Black eschar over hard palate with surrounding erythema and erythematous right upper eyelid.

Investigations

The Ear, Nose and Throat (ENT) physician initially performed an endoscopic sinus wash-out procedure in which cultures and biopsies were obtained. He later underwent nine surgical debridements of his sinus cavities, including resection of a third of his palate and a right orbital exenteration.

Multiple cultures obtained from the procedures did not grow any organisms. On histopathology, the patient’s tissue specimens exhibited features of both Aspergillus and Mucor (figure 3). Tissue sample pathology showed some ribbon-like broad hyphae with broad-angle branching and rare septation consistent with Mucor, in addition to examples of narrow hyphae with acute-angle branching and occasional septation consistent with Aspergillus. A sample was sent to the New York State (NY State) Department of Health Wadsworth Center and a PCR assay detected P. chrysogenum in formalin-fixed tissue samples.

Figure 3.

Tissue specimens from the patient’s sinuses.

Treatment

Along with aggressive surgical debridement, the patient was treated with intensive antimicrobial therapy. He was initially started on vancomycin, imipenem and amphotericin B prior to his operative washouts. Given the lack of growth on bacterial cultures and the evidence of fungal infection on his pathology specimens, a combination of amphotericin B and caspofungin was continued for his 4-week inpatient admission while awaiting fungal culture results and further identification from the NY State Laboratory. After the identification of P. chrysogenum, caspofungin was discontinued. At that time, his chemotherapy was resumed and he was continued on amphotericin B throughout the induction phase for 8 weeks. He had biweekly ENT exams with no signs or symptoms of sinus infection. His antifungal regimen was changed to oral posaconazole at the time of transition to consolidation chemotherapy for an additional 4 months.

Outcome and follow-up

Our patient underwent aggressive surgical debridement including resection of part of his palate and a right orbital exenteration. He completed 7 months of antifungal treatment and continued chemotherapy for his underlying ALL. A sinus biopsy performed after his antifungal therapy did not show any presence of hyphae. There were no signs or symptoms of recurrence at his 12-month follow-up after stopping antifungal therapy. The patient has a future plan for facial reconstructive surgery.

Discussion

Acute invasive fungal rhinosinusitis is a disorder characterised by mycotic infiltration of the mucosa of the nasal cavity and paranasal sinuses. The disease occurs primarily in immunocompromised hosts and in the absence of treatment, is rapidly fatal in 50%–80% of patients secondary to an invasion of the orbit and intracranial cavity. The mainstay of treatment is a combination of antifungal antibiotics and aggressive surgical debridement.³ Most cases of invasive fungal rhinosinusitis are caused by Aspergillus species and Zygomycetes species including Mucor and Rhizopus. However, invasive rhinosinusitis from a Penicillium species is relatively rare.¹

The genus Penicillium comprises more than 200 species and they are found in soil, on decaying vegetation and in the air. Penicillium marneffei has been reported as a common cause of infection in the HIV population in the endemic areas of Southeast Asia, but infections by other Penicillium species are uncommon.⁴ P. chrysogenum has been reported in a rare case of endocarditis, invasive pulmonary disease in a patient with lung cancer, a case of post-traumatic endophthalmitis, oesophagitis in an HIV patient, central nervous system infection and disseminated infection in immunocompromised patients, including a paediatric patient with Henoch-Schonlein Purpura.^{5 6} In addition, in 2018, there was one documented case report of fatal Pencicillum rhinosinusitis in an immunocompromised adult patient with acute myelogenous leukaemia. Culture of tissue and aspirate from this patient grew unidentified species of Penicillium.² This present case further highlights the importance of the recognition and consideration of the Penicillium species as an aetiology of invasive rhinosinusitis in patients with cancer.

Aspergillus and Penicillium are closely related genera. Although invasive disease is more common with Aspergillus, Penicillium can produce the same spectrum of disease in immunocompromised hosts. Histological sections showing hyaline septate hyphae could be consistent with Aspergillus or Penicillium, in contrast to Mucor which has non-septated hyphae.^{4 5} Currently, there are no treatment guidelines for the management of Penicillium infections but case reports have shown successful treatment with amphotericin B, itraconazole or fluconazole.⁶ We initially used a combination of amphotericin B and caspofungin, followed by oral posaconazole.

Medical management of fungal rhinosinusitis recognised in a timely fashion includes preemptive treatment with antifungals and restoration of immune function through appropriate withdrawal of immunosuppression.² The preferred empiric agents are lipid formulations of amphotericin B, either liposomal amphotericin B or amphotericin B lipid complex. Surgical debridement depends on the extent of the affected tissue. Sinus debridement and marsupialisation decrease fungal burden, remove necrotic tissue, allow penetration of antifungal agents and allow endoscopic monitoring of disease.² In this case, the aggressive nature of the disease required multiple surgeries.

This case recognises P. chrysogenum as a cause of invasive fungal rhinosinusitis in an immunocompromised paediatric patient. The diagnosis in our case was initially a dilemma since the patient’s cultures did not grow an organism and the pathology results showed findings consistent with both Mucor and Aspergillus-like features. The PCR which returned 2 weeks later confirmed the diagnosis of P. chrysogenum. Our patient underwent aggressive surgical debridement, completed 7 months of antifungal treatment, and showed no signs of recurrence at his 1-year follow-up.

Learning points.

• Acute invasive fungal rhinosinusitis is a disorder characterised by mycotic infiltration of the mucosa of the nasal cavity and paranasal sinuses. Most cases of invasive fungal rhinosinusitis are caused by Aspergillus species and Zygomycetes species including Mucor and Rhizopus.

• While infection from Penicillium species is rare, it should be considered as a cause of invasive fungal rhinosinusitis in cases of unclear histopathology.

• Case reports have shown successful treatment with amphotericin B, itraconazole or fluconazole for Penicillium infections. This present case showed successful treatment of Penicillium chrysogenum invasive rhinosinusitis with surgical debridement, and 7 months of antifungal antibiotics including 1 month of combination amphotericin B and caspofungin, 2 months of only amphotericin B, and 4 months of oral posaconazole.

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