A Case Report of Mass-Forming Aspergillus Tracheobronchitis Successfully Treated with Voriconazole.

Aspergillus tracheobronchitis (ATB) represents a rare disease entity accounting for 3.5% to 5.0% of cases of invasive aspergillosis. Particularly, mass-forming ATB is extremely rare, and clinical reports are limited. Given that the patency of the trachea and bronchi are essential for maintaining sufficient airflow, a central airway mass originating from an Aspergillus infection is likely to be associated with severe clinical manifestations and fatal outcomes. Although several therapeutic options for ATB have been suggested, including medication and airway interventions, the optimal choice of treatment in diverse clinical conditions remains under discussion.We report a case of ATB that initially manifested as severe dyspnea and total atelectasis of the left lung in a patient with newly detected diabetes.Radiographic study, bronchoscopy, and pathologic findings of the lesion revealed mass-forming type of ATB.Interestingly, our patient's symptoms dramatically resolved with voriconazole without further invasive intervention.This clinical experience highlights the beneficial role of voriconazole in the treatment of rare and potentially fatal cases of ATB.

INTRODUCTION

Aspergillus tracheobronchitis (ATB) refers to a unique type of Aspergillus-associated pulmonary disease in which the trachea and bronchi may be the main or even sole site of infection.[1] ATB represents a rare disease entity accounting for only 3.5% to 5.0% of all cases of invasive aspergillosis and is known to occur primarily in immunocompromised hosts.[1,2] Furthermore, 1 report indicated that ATB leads to devastating clinical outcomes with a mortality rate of up to 84% in severe immunocompromised hosts.[3]

To aid characterization and early diagnosis of ATB, there are several classification systems based on bronchoscopic findings with histologic data and depth of invasion (eg, obstructive, ulcerative, and pseudomembranous ATB by Denning;[4] superficial infiltration, full-layer involvement, occlusion, and mixed type by Wu et al).[5] However, it is difficult to characterize various types of tracheobronchial involvement into a uniform system. Moreover, diverse clinical manifestations and the rarity of ATB render its diagnosis quite difficult. In particular, mass-forming types of ATB may not fit clearly into the suggested ATB classification systems, and to the best of our knowledge only 2 cases of mass-forming ATB have been reported to date.[6,7] Given that the patency of the trachea and bronchi are essential for maintaining sufficient airflow, a central airway mass containing Aspergillus is likely to be associated with severe clinical manifestations and fatal outcomes. For example, symptoms in these patients involve severe dyspnea and/or wheezing.[6,7]

Herein, we report a case of ATB that initially manifested as severe dyspnea and total atelectasis of the left lung in a patient with newly detected diabetes. Radiographic study, bronchoscopy, and pathologic findings of the lesion led to a diagnosis of mass-forming ATB. Interestingly, the obstructing lesion dramatically resolved with voriconazole without further invasive interventions.

CASE PRESENTATION

A 31-year-old man with no past history of known medical illnesses was admitted to our emergency department because of severe dyspnea and accompanying tachypnea (30 breaths per minute). The patient had never smoked and had no previous history of allergic diseases. On physical examination, there was dullness over the left lung field, and decreased breath sounds on the left lung heard on auscultation. There were no enlarged lymph nodes in the body. Arterial blood gas analysis revealed PO2 80.3 mmHg, PCO2 33.1 mmHg, pH 7.46, and SaO2 96.5%. Laboratory data showed that platelets, white blood cells, and differential cell counts were within the normal range. The patient's erythrocyte sedimentation rate was 70 mm/hour (reference range: 0–9 mm/hour) and C-reactive protein was 27.75 mg/L (reference range: 0–5 mg/L), which together indicated an underlying inflammatory process. Notably, urine glucose was 4+ and HbA1c was 19.4%, confirming underlying diabetes mellitus.

On imaging studies, chest radiographs showed total opacification of the left lung (Figure 1A). Subsequently, chest computed tomography (CT) revealed total atelectasis of the left lung and a mass-forming lesion at the distal trachea (Figure 1B, white arrow). However, simultaneous mediastinal or hilar lymphadenopathy was not detected. Examination of the lesion with bronchoscopy revealed an erythematous, swollen, and soft mass approximately 4 cm above the carina (Figure 1C). We subsequently performed transtracheal biopsy of the lesion; however, we were unable to obtain enough tissue for culture due to the severe clinical condition of the patient during bronchoscopic examination. Bronchial washing culture revealed no microorganisms; however, upon histopathologic examination using Grocott-Gomori's methenamine silver staining (Figure 2A, black arrows), invasion of the tracheal cartilage by septate hyphae was observed (Figure 2B, black arrows). In addition, numerous inflammatory cells were recruited to the adjacent tracheal epithelium (Figure 2B, inset box). The invading hyphae exhibited acute angle branching patterns, indicating possible infection with an Aspergillus species. Based on these findings, a presumptive diagnosis of ATB was established.

FIGURE 1

(A) Chest X-ray demonstrating total opacity of the left lung. (B) Coronal view computed tomography (CT) scan showing a mass-forming lesion (white arrow) and total atelectasis of the left lung. (C) Bronchoscopic examination at the distal trachea revealed an erythematous, swollen, and soft mass. The initial attempt of bronchoscopic biopsy caused bleeding as shown in the figure.

FIGURE 2

(A) A transbronchial biopsy of the lesion showing Aspergillus species with acute angle branching and septate hyphae (black arrows) (GMS, ×400). (B) Biopsy showing deep invasion of Aspergillus hyphae into tracheal cartilage (black arrows) and various inflammatory cells infiltrations (H&E, ×100); inset shows a higher magnification of infiltration of inflammatory cells (H&E, ×200). (C, D) A follow-up bronchoscopic examination and CT scan on the 19th day of medication revealed successful resolution of the lesion. GMS = Grocott-Gomori's methenamine silver, H&E = hematoxylin and eosin.

During the bronchoscopic examination, we attempted to perform debridement of the lesion via bronchoscopy to maintain airway patency. However, the patient's clinical condition and respiratory symptoms worsened after bronchoscopy necessitating endotracheal intubation and mechanical ventilation (oxygen saturation was 74.8% in spite of maximal degree of supplementary oxygen). Moreover, the likelihood of procedure-associated adverse events (eg, bronchoesophageal fistula) was substantially high considering the severity of the pathologic findings including deep invasion of the Aspergillus species into the cartilage wall and the presence of uncontrolled diabetes. Thus, we decided to treat the patient with voriconazole. On the first day of treatment, 6 mg/kg of voriconazole was administered intravenously for every 12 hours as a loading dose, which was then switched to 400 mg/day of oral voriconazole as a maintenance dose according to the guidelines for treating invasive aspergillosis.[8]

After treatment with voriconazole, the respiratory symptoms of the patient gradually improved without additional invasive management. On the 19th day of medication, follow-up CT and bronchoscopy showed successful resolution of the lesion (Figure 2C, D). After a month of admission, the patient was discharged without any respiratory sequelae. The patient was treated with voriconazole for a total of 10 weeks, and there has been no evidence of recurrence of disease in this patient at the time of this publication.

DISCUSSION

Here, we report a rare and severe case of ATB that occurred in a young patient with newly detected diabetes but without severe immune suppression. The patient suffered from dyspnea owing to an obstructive mass in the distal trachea coinciding with total atelectasis of the left lung. Subsequent examinations revealed that the lesion was an extremely rare type of ATB, namely, mass-forming ATB. Although clinical symptoms of the patient required urgent therapeutic intervention, the possibility of intervention-associated complications was considerably high due to the extensive invasion of ATB into the tracheal cartilage and to the presence of uncontrolled diabetes. Therefore, we chose monotherapy with voriconazole. Interestingly, signs and symptoms of respiratory illness in the patient gradually improved, and the lesion successfully resolved based on follow-up images 19 days after treatment with voriconazole.

In general, immunocompromised patients are usually associated with poor prognoses. Several previous reports have suggested that the immune status of patients with mass-forming ATB is not uniform. For example, Routsi et al[6] reported a mass-forming type of ATB in an immunocompromised patient who took chemotherapy for erythroleukemia whereas another study reported that a relatively immunocompetent patient with well controlled diabetes mellitus experienced mass-forming ATB.[7]

The symptoms of the patient in this study were devastating with subsequent respiratory failure, but the patient's immune system was not severely impaired. The spectrum of the initial clinical manifestations and the underlying immune status of our patient made establishing an appropriate therapeutic strategy quite difficult. Interestingly, the patient showed dramatic therapeutic response to voriconazole after treatment for 19 days, with the ATB resolved completely thereafter. This outcome was in contrast to a previous report on ATB, where antifungal treatment lasting approximately 4 to 19 months was required to achieve complete resolution on chest CT.[9] Based on our experience, monotherapy with voriconazole appears to have a beneficial role even in treating rare and severe types of ATB.

Although the reason for mass formation in ATB is not clearly understood, intact immune responses in the host appear to influence mass development partly through the accumulation of various inflammatory cells as depicted in the pathologic examination of a previous case.[7] Similarly, the pathologic examination of our case also showed prominent infiltration of various inflammatory cells. Moreover, our patient had newly detected diabetes with a high level of HbA1c (19.4%) before the onset of evident metabolic decompensation. Considering the impact of hyperglycemia in the immune system (eg, impairment of transmigration and chemotaxis of neutrophils, decrease of their bactericidal activity, decrease of response to antigens of CD4+ cells, and unnecessary glycosylation of antibodies),[10] the gradual decrease in the competence of immune system likely affords sufficient time for mass formation following Aspergillus infection. In the same context, the relatively well preserved immune system in our patient may have played an important role in the dramatic response to voriconazole.

In this report, we describe a case of mass-forming ATB that presented with disastrous respiratory signs and symptoms that required immediate airway management. However, considering the significantly high possibilities of procedure-associated complications, we decided to treat with voriconazole without further interventions. Surprisingly, the patient's respiratory symptoms were successfully improved with voriconazole. This clinical experience suggests that medication with voriconazole may be an effective therapeutic option in rare and severe ATB patients who are not candidates for invasive airway procedures.

ETHICAL REVIEW AND PATIENT CONSENT

The Institutional Review Board of Chonbuk National University Hospital stated that it was not necessary to achieve IRB approval for this case report, but that patient consent was required as the study dealt only with retrospective use of the patient's medical record and related images. Written informed consent was obtained from the patient prior to the publication of this case report and accompanying images.