Asian Journal of Oral and Maxillofacial Surgery

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Asian Journal of Oral and Maxillofacial Surgery 23 (2011) 38–41

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Asian Journal of Oral and Maxillofacial Surgery

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / a j o m s

Case report

Invasive sinus aspergillosis with acute myeloid leukemia: A case report

Yoshinari Myoken

a,∗

, Tatsumi Sugata

a

, Yoshinori Fujita

a

, Hiromi Yuasa

b

, Somay Yamagata Murayama

c

aDepartment of Oral Surgery, Hiroshima Red Cross and Atomic Bomb Survivors Hospital, 1-9-6 Senda-machi, Naka-ku, Hiroshima 730-0052, Japan

bDepartment of Hematology, Hiroshima Red Cross and Atomic Bomb Survivors Hospital, Hiroshima, Japan

cLaboratory of Molecular Epidemiology for Infectious Agents, Graduate School of Infection Control Sciences & Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan

a r t i c l e i n f o

Article history:

Received 7 April 2010 Accepted 20 October 2010 Available online 7 January 2011

Keywords:

Invasive sinus aspergillosis Breakthrough

Hematological malignancy Antifungal treatment

a b s t r a c t

Invasive fungal sinusitis is still a life-threatening infection in immunocompromised patients. Its onset is rapid and leads to severe complications. We describe a neutropenic patient with acute myeloid leukemia who developed invasive sinus aspergillosis despite receiving prophylactic itraconazole and empirical micafungin. The patient demonstrated apparent clinical findings such as nasal discharge, nasal con- gestion, and skin and mucosal necrosis. Computer tomography scans strongly demonstrated invasive maxillary sinusitis. Serological examinations for (1-3)-␤-d-glucan and Aspergillus galactomannan antigen were positive, suggesting Aspergillus infection. The diagnosis of invasive sinus aspergillosis was confirmed by in situ hybridization using Aspergillus-specific probe in formalin-fixed, paraffin-embedded tissue sam- ples. The causative organism was identified as Aspergillus fumigatus by fungal culture. Despite surgical treatment with drainage and intensive antifungal administration of voriconazole and liposomal ampho- tericin B, the infection rapidly disseminated to the lungs, resulting in a fatal progression of the condition.

© 2010 Asian Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd.

All rights reserved.

1. Introduction

There is now growing evidence that invasive and systemic fungal infections are becoming major causes of morbidity and mor- tality among immunocompromised patients, such as patients with hematological malignancies and transplant recipients[1,2]. Fur- thermore, despite prophylactic and empirical antifungal treatment, the emergence of breakthrough invasive fungal infections caused by theoretically sensitive organisms as well as resistant organisms has raised serious concern in immunocompromised patients, who show a poor prognosis[3–5].

Invasive fungal sinusitis has increasingly been recognized as a life-threatening fungal infection in patients with hematological malignancies[6–10]. Although there is a wide range of causative pathogens, Aspergillus species account for most cases of invasive fungal sinusitis[6–10]. Cases of invasive sinus aspergillosis (ISA) in both adult and pediatric patients have been reported in the litera- ture (Table 1)[7–9]. The prognosis of patients with ISA depends on the underlying disease, the stage of infection, and anti-fungal man- agement, with the fatality rate ranging from 28.6% to 88.1%[9–11].

Early diagnosis and aggressive therapy are critical to achieve opti- mal therapeutic results [6–11]. In general, the early signs and

∗ Corresponding author. Tel.: +81 82 241 3111; fax: +81 82 246 0676.

E-mail address:myoken@do5.enjoy.ne.jp(Y. Myoken).

symptoms of ISA are subtle, and the disease must be distinguished from bacterial infection[6–9]. Although the definitive diagnosis of invasive aspergillosis is based on histological and cultural evidence of Aspergillus infection, fungal culture runs the risk of growth fail- ure and is time-consuming[9,10]. Serological tests for the detection of (1-3)-␤-d-glucan and Aspergillus galactomannan antigen have been developed for the early diagnosis of invasive aspergillosis [12,13]. In addition, a preliminary molecular diagnostic method based on in situ hybridization in tissue sections has been found to be more useful than culture-based diagnosis for the rapid and accurate diagnosis of invasive aspergillosis[14]. Treatment should include resection of the infected tissue in conjunction with inten- sive treatment with systemic antifungal agents[6–11]. However, even with such aggressive therapy, patients with ISA may not be curable when the infection is diagnosed at the advanced and late stages.

We describe a patient with acute myeloid leukemia (AML) who developed breakthrough ISA due to A. fumigatus at the advanced stage and disseminated pulmonary aspergillosis, underscoring the importance of early diagnosis in combination with surgical man- agement and systemic antifungal therapy.

2. Case report

On February 17, 2009, a 69-year-old man with relapse of AML was admitted for reinduction chemotherapy (enocitabine, idaru- 0915-6992/$ – see front matter © 2010 Asian Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd.All rights reserved.

doi:10.1016/j.ajoms.2010.10.008

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Y. Myoken et al. / Asian Journal of Oral and Maxillofacial Surgery 23 (2011) 38–41 39

Table 1

Summary of data for previously reported cases of ISA.

Reference (number of cases)

Signs and symptoms Serological examinations X-ray examination Biopsy Anti-fungal treatments Surgical treatments 7 (5) Nasal congestion Negative Aspergillus

galactomannan antigen

Positive findings including CT and MRI

Positive histology VRCZ and AMPH-B

Facial swelling Positive culture Surgery and drainage

Sinus pain Nasal necrosis

8 (3) Nasal congestion N.D. Positive findings including CT Positive histology

Positive culture

AMPH-B

Nasal discharge Surgery

Eyelid edema Headache

9 (12)a Nasal congestion N.D. Positive findings including CT Positive histology AMPH-B

Sinus pain Positive culture Surgery (9 of 12 cases)

Periorbital swelling Nose ulceration

Note: AMPH-B, amphotericin B; VORZ, voriconazole; N.D., not done.

aTwelve of 17 patients with invasive mold sinusitis developed ISA.

bicin, and etoposide). On day 13 after admission, the patient was placed on itraconazole (ITCZ; 200 mg po q.d.) for antifungal pro- phylaxis because of a dramatically decreased leukocyte count (100 cells/␮l: 0% neutrophil). On day 23, the patient was febrile

and unresponsive to antimicrobial treatment with panipenem and amikacin. Due to persistent fever and marked neutropenia, empir- ical antifungal treatment of micafungin (MCFG; 150 mg iv q.d.) was started combined with ITCZ. On day 29, the patient was referred

Fig. 1. Oro-facial and CT findings. (A) Photograph showing a black necrotic crust on the right root of the nose, facial swelling and nasal discharge. (B) CT scan of the face demonstrated a dense area within the right maxillary sinus and invasion of the ethmoidal sinus, eroding the bone. (C) Photograph of the right upper gingiva covered with a gray, necrotic pseudomembrane. (D) Post-surgical photograph showing the Penrose drain (arrowhead) in the surgical wound and some necrotic alveolar bone.

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40 Y. Myoken et al. / Asian Journal of Oral and Maxillofacial Surgery 23 (2011) 38–41

to the Department of Dermatology because he complained of right nasal pain and facial erythema. The skin lesion was biopsied and histopathological examination of HE-stained tissue sections demonstrated inclusion bodies in epidermal cells suggesting a viral infection of the skin. The serum level of (1-3)-␤-d-glucan was slightly elevated (12.8 pg/ml; normal value <11 pg/ml).

On day 39, the patient was referred to the Department of Oral Surgery because a black necrotic crust rapidly developed at the right root of the nose and caused facial swelling; in addi- tion, he complained of severe right buccal pain, nasal congestion, and nasal discharge (Fig. 1A). Computer tomography (CT) scans demonstrated a destructive lesion in the maxillary sinus that invaded the ethmoidal sinus, but there was no intracranial involve- ment (Fig. 1B). Oral examination demonstrated a wide destructive ulcer in the right maxillary mucogingiva, which was covered by a gray, necrotic pseudomembrane (Fig. 1C). His serum had a high concentration of (1-3)-␤-d-glucan (54.2 pg/ml) and was positive for Aspergillus galactomannan antigen (4.9 ng/ml; normal value <0.5 ng/ml), strongly suggesting ISA. His leukocyte count was 200 cells/␮l (10% neutrophils) and his platelet count was 22,000 cells/␮l. On day 41, antrotomy of the maxillary sinus and debridement of the necrotic gingiva were performed under local anesthesia with platelet infusion. The lateral portion of the sinus wall and soft tissue was necrotic. After the necrotic tissues were removed, a Penrose drain was placed for washing and instilling antifungal drugs into the surgical wound area (Fig. 1D). Fun- gal hyphae were found in a 10% KOH preparation of the tissue sample, supporting the diagnosis of ISA. Both MCFG and ITCZ

Fig. 2. Histopathological findings of necrotic sinus tissue. (A) Grocott staining show- ing the branching septate hyphae (magnification 100×). (B) In situ hybridization using an Aspergillus-specific DNA probe revealed Aspergillus hyphae in the same area (magnification 100×).

were discontinued and the patient was started on voriconazole (VRCZ; 200 mg po b.i.d.) combined with liposomal amphotericin B (l-AMPH-B; 150 mg iv q.d.) for ISA. The patient was also subjected to sinus rinses with AMPH-B (1 mg/ml diluted in distilled water) once a day as part of his post-surgical care. On day 43, histopatho- logically, Grocott-stained tissue sections showed organisms with dichotomously branched septate hyphae at acute angles, support- ing the diagnosis of ISA (Fig. 2A). On day 45, the hyphae in tissue sections were identified as Aspergillus species by in situ hybridiza- tion[14]using a highly specific DNA probe for Aspergillus species, thereby confirming the ISA (Fig. 2B). Tissue culture on Sabouraud’s dextrose agar yielded fungi that were morphologically identified as A. fumigatus on day 53.

On day 55, the patient was still febrile and complained of persis- tent cough. The level of (1-3)-␤-d-glucan dramatically increased to 364.1 pg/ml, and the serum was positive for Aspergillus galactoman- nan antigen. Thoracic high-resolution CT scans demonstrated several nodules (Fig. 3A) and a dense, cavitating infiltrate with halo sign in the lower lobes of both lungs (Fig. 3B), suggesting inva- sive pulmonary aspergillosis. On day 65, the oro-facial necrotic area showed gradual improvement due to daily systemic administration of VRCZ and l-AMPH-B in addition to sinus rinses with AMPH-B.

There were no symptoms suggestive of intracranial invasion. In addition, the level of (1-3)-␤-d-glucan decreased to 254.6 pg/ml.

Fig. 3. Pulmonary CT. CT scans of the chest demonstrated multiple nodules (A) and cavitating infiltrate (B) in the lower lobes of the lungs.

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Y. Myoken et al. / Asian Journal of Oral and Maxillofacial Surgery 23 (2011) 38–41 41

After receiving human recombinant G-CSF (2400␮g/total), the leukocyte count increased to 1000 cells/␮l (43% neutrophils). How- ever, on day 71, the patient with relapse of AML suddenly developed severe respiratory failure; his condition deteriorated and he died on day 79. An autopsy was not performed. In vitro susceptibil- ity testing showed that the causative A. fumigatus was sensitive to MCFG (MIC = 0.03125␮g/ml), ITCZ (MIC = 0.25 ␮g/ml), VRCZ (MIC = 0.125␮g/ml), and AMPH-B (MIC = 0.25 ␮g/ml).

3. Discussion

Despite advances in antifungal prophylaxis and treatment, invasive fungal infection remains the most common infectious cause of death among neutropenic patients undergoing induction chemotherapy for AML[1,2]. In particular, breakthrough invasive fungal infection including aspergillosis in patients receiving pro- phylactic or empirical treatment is a well-known problem and results in a high mortality rate[3–5]. In the present case, the patient developed ISA during prophylaxis with ITCZ and empirical therapy with MCFG, which have been shown to be effective against isolated A. fumigatus in vitro, suggesting the possibility that the plasma con- centrations of these agents were ineffective for a patient with deep neutropenia[4].

In general, ISA is characterized by rapid spread of the fungus from the sinus airspace into adjacent structures such as the brain and occasional dissemination to the lungs with a very high mortal- ity rate[9–11]. Therefore, early diagnosis and aggressive treatment of ISA are essential for patient survival[6–10]. The reported symp- toms of ISA include nasal congestion, nasal discharge, abnormal findings in the nasal cavity, buccal swelling with pain or numb- ness, gingival and skin necrosis, and high fever, but these symptoms are not always specific to ISA[6–10]. Although radiographs and CT scans demonstrated sinus involvement and spread of the lesion, suggesting the presence of fungal or bacterial infection, a defini- tive diagnosis requires histological and cultural confirmation based on surgical specimens [7–9,14]. Serological assay for (1-3)-␤-d- glucan is highly sensitive for fungal infections but not specific for aspergillosis, while the detection of Aspergillus galactomannan antigen is less sensitive but more specific[12,13]. In this patient, most of the clinical findings, such as nasal symptoms and oro- facial necrosis, were apparent. In addition, CT scans demonstrated sinus involvement and destruction of the bone. Furthermore, a high level of (1-3)-␤-d-glucan and positive Aspergillus galactomannan antigen indicated Aspergillus infection. Therefore, all these findings were strongly suggestive of ISA at the advanced stage. In addition to the usual histopathological examination and tissue culture, we per- formed in situ hybridization using an Aspergillus-specific DNA probe to confirm the diagnosis of aspergillosis[14]. Although the method is still preliminary, in situ hybridization is a promising technique for a more prompt diagnosis compared to culture-based methods, which are often time-consuming and carry the risk of growth failure due to incorrect handling of the tissue samples.

Aggressive systemic anti-fungal therapy is necessary to eradi- cate Aspergillus infection in immunocompromised patients[7–10].

Amphotericin B was long the standard treatment for ISA, but the current standard therapy is VRCZ, which has led to better responses and improved survival[12]. We treated our patient with VRCZ and

l-AMPH-B to enhance the anti-fugal activity against aspergillo- sis[5]. Furthermore, to help pharmacological therapy reach the infected area, immediate surgical debridement of the necrotic tis- sue is necessary, as demonstrated in our patient. Published case series strongly supports the need for surgical debridement plus antifungal agents to optimize the outcome, showing a 60% survival rate for patients with ISA that would otherwise be as low as 28.6%

[9]. We also adopted drainage and drug instillation of the sinus after surgical debridement to eradicate aspergillosis[7,8]. The oro-facial condition of ISA gradually improved in this patient after aggres- sive treatment including surgery, systemic antifungal therapy, and sinus irrigation. As ISA was thought to be the advanced stage when diagnosed, the infection resulted in fatal disseminated pulmonary aspergillosis despite treatments.

In conclusion, from our experience, fungal infection should be clinically diagnosed at an early stage and treated with surgery in combination with intensive antifungal administration to signifi- cantly reduce the mortality rate in neutropenic patients with AML.

4. Conflicts of interest

There are no conflicts of interest to be declared.

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