Aspergillus tracheobronchitis after allogeneic bone marrow ...

Bone Marrow Transplantation, (1999) 24, 1145–1149  1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt

Case report Aspergillus tracheobronchitis after allogeneic bone marrow transplantation U Machida1, M Kami1, Y Kanda1, K Takeuchi2, M Akahane3, I Yamaguchi4, C Kakiuchi2, N Takeda1, Y Tanaka1, S Chiba1, H Honda1 and H Hirai1 The Departments of 1Hematology and Oncology, 2Pathology, 3Radiology and 4Traumatology and Critical Care, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Summary: We describe a patient who developed Aspergillus tracheobronchitis after BMT. She complained of progressive dyspnea on day +165 and her respiratory function deteriorated rapidly. Although neither early chest Xrays nor CT scans were negative, bronchoscopy revealed formation of a pseudomembrane around the bronchial walls. Based upon pathological and microbiological examinations, she was diagnosed as having invasive Aspergillus tracheobronchitis. Retrospectively analyzed, the Aspergillus circulating antigen detection tests became positive before clinical symptoms developed, and may be beneficial for early diagnosis of Aspergillus tracheobronchitis. This form of aspergillosis should be regarded as one of the serious complications after BMT. Keywords: bone marrow transplantation; aspergillus; tracheobronchitis; steroid; pseudomembrane

Aspergillus infection is a potentially fatal complication in bone marrow transplant recipients. Despite the improvement in prophylaxis and treatment, it is still associated with a high morbidity and mortality.1 Invasive pulmonary aspergillosis (IPA), the most common form of Aspergillus infection in bone marrow transplant recipients, usually affects the lung parenchyma and occasionally disseminates to a variety of organs. A small number of patients, however, develop invasive tracheobronchitis as a local manifestation. Clinical characteristics of this disease are quite different from those of IPA. To improve the prognosis of Aspergillus infection, early diagnosis and prompt initiation of intensive antifungal treatment are requisites, but both the optimal diagnostic methods and treatments remain to be established. Because of its low incidence, we have little information on this type of Aspergillus infection. To our knowledge, there have been only four case reports published concerning this type of Aspergillus infection after bone marrow transplanCorrespondence: Dr U Machida, Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Received 4 March 1999; accepted 15 June 1999

Figure 1 CT scan of the chest shows marked central bronchial wall thickening and multiple patchy densities along the bronchovascular bundles surrounded by ground glass opacity. The left lower lobe is atelectatic with positive mass effect. The peripheral lung fields are relatively spared.

Figure 2 Bronchoscopy reveals the airway stenosis by the yellow-white pseudomembrane of necrotic tissues.

tation.2–5 Here we report a patient with Aspergillus tracheobronchitis who deteriorated rapidly despite intensive antifungal therapy. This report exemplifies the difficulties in early diagnosis and instigation of appropriate treatment for patients with Aspergillus tracheobronchitis after stem cell transplantation.

Aspergillus tracheobronchitis after BMT U Machida et al

1146 1000 mg Steroid mPSL

125 mg

Antifungal treatment

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AMPH-B 1.0 mg/kg

fluconazole 200 mg

Dyspnea

Symptoms

OD of EIA 2000

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EIA

1000 1.0 Serum BDG levels (pg/ml) 154

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Days post-BMT Figure 3 Clinical course of this patient: Aspergillus tracheobronchitis rapidly deteriorated after the initiation of the steroid-pulse treatment. mPSL = methyl-predonisolone; AMPH-B = amphotericin B; BDG = (1 → 3)-␤-d-glucan and EIA as enzyme-linked immunosorbent assay.

Case report A 44-year-old woman diagnosed with chronic myelocytic leukemia in accelerated phase underwent bone marrow transplantation from her HLA-identical sister in August 1998. Conditioning therapy was modified BAC6 which consisted of busulfan (4 mg/kg days −9 to −6), Ara-C (4 g/m2 days −5 to −4), cyclophosphamide (60 mg/kg days −3 to −2) and G-CSF (filgrastim 5 ␮g/kg days −6 to −4). GVHD prophylaxis was a combination of cyclosporine and shortterm methotrexate. Inhalation of aerosolized AMPH-B and oral administration fluconazole 200 mg were initiated from day −14 as antifungal prophylaxis. She developed stage II acute GVHD of the skin on day 42, which was followed by gradual impairment of renal function. The appearance of fragmented erythrocytes in the peripheral blood and elevation of serum LDH levels strongly suggested development of thrombotic microangiopathy (TMA). We therefore discontinued cyclosporine and started 2.5 mg/kg/day of methylpredonisolone on day 63. Both acute GVHD of the skin and TMA improved thereafter, but cholestatic liver injury appeared during the tapering of the steroids. On day 165, serum levels of total bilirubin reached 3.9 g/dl and we initiated steroid pulse therapy consisting of 1 g/day of methylpredonisolone for 3 days. On the same day, she complained of cough and fever and antibiotics were started. Although both chest X-rays and CT scan were normal, the fever did not respond to the antibacterial antibiotics and we empirically started 0.5 mg/kg of AMPH-B on day 172. Surveillance fungal cultures remained negative through her clinical course except for Candida grablata which was positive in stool cultures on day 165 and day 172. We had administered 200 mg of fluconazole orally until starting the intravenous AMPH-B. Dyspnea and wheezing progressed rapidly despite the antifungal treatment and chest X-ray showed bilateral pulmonary infiltrates the day following AMPH-B initiation. CT

scans of the chest showed marked central wall thickening and multiple patchy densities along the bronchovascular bundles. The left lower lobe was atelectatic with a positive mass effect, which suggested the airway stenosis or occlusion caused by the extensive infiltration. The peripheral lung fields were relatively spared (Figure 1). A few hours later, she was intubated because of rapid deterioration in respiratory function and transferred to the intensive care unit. Bronchoscopy was performed which showed the airway stenosis by a yellow-white pseudomembrane of necrotic tissues (Figure 2). Pathological and microbiological examination of the necrotic debris identified diffuse invasion with Aspergillus septate hyphae and she was diagnosed as having tracheobronchitis caused by Aspergillus. AMPH-B was increased to 1 mg/kg/day and we attempted removal of the necrotic debris occluding the trachea and bronchus under bronchoscopy. However, respiratory failure similar to the obstructive lung disease rapidly progressed and she died on day 175. Autopsy was not permitted. We retrospectively determined the serum (1 → 3)-␤-dglucan levels (BDG) (Fungi-Tec; Seikagaku Corp, Tokyo, Japan) and presence of circulating galactomannan antigen using an enzyme-linked immunosorbent assay (EIA) (Platelia Aspergillus; Sanofi, Diagnostic Pasteur, Paris, France) in serum specimens which had been stored at −20°C until the blood testing drawn from this patient. The cut-off levels of EIA and BDG are 0.372 of optimal density (OD) and 20 pg/ml, respectively.7,8 EIA and BDG became positive on day 154 and 166, respectively. These assays rapidly increased (Figure 3) and their maximal levels reached 2.9 of OD on day 173 and 2378 pg/ml on day 174, respectively. Discussion Aspergillus infection localized to the tracheobronchial tree has been recognized as a less common pattern of intrathor-

M/30

F/15

M/37

M/20

F/45

1

2

3

4

5

CML

SAA

MDS

ALL

CML

Disease

5 mo

5w

5 mo

29 d

not mentioned

Day postBMT

Steroid

+

+ +

+

+

GVHDb

+

+ +

−

+

Chest X-ray

5000

5000

350

1900

bilateral infiltrates

negative

bilateral infiltrates

elevated left diaphragm

not mentioned not mentioned

Neutrophil counts (/␮l)

destruction of the right mainstem bronchial wall and invasion of pulmonary artery thickening of the bronchial wall, atelectasis, multiple patchy densities

not mentioned

not mentioned

not mentioned

CT

stenosis of the trachea by the yellow-white pseudomembrane

thick green secretions covering diffusely friable mucosa aspergilloma obstructing the distal trachea

nearly totally obstructing rubbery mass in the trachea not donea

Bronchoscopy

cough, fever

night sweat, SOB, throat tightness

fever

fever

cough, SOB

Symptoms

dead, respiratory failure

dead, fatal hemorrhage



dead

Outcome

our case

5

4

3

2

Ref.

a Autopsy revealed that many segmental and subsegmental bronchi of all lung lobes were completely occluded by gelatinous, grayish material loosely adherent to the underlying bronchial walls. b Grading of acute GVHD was not mentioned in any patients. CML = chronic myeloid leukemia; ALL = acute lymphoblastic leukemia; MDS = myelodysplastic syndrome; SAA = severe aplastic anemia; SOB = shortness of breath.

Sex/Age

Reports on tracheobronchitis after BMT including our patient

No.

Table 1


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acic aspergillosis and there have been few reports concerning this type of aspergillus infection. Young et al9 reviewed 98 cases of histologically documented aspergillosis, of which eight had fungal infection of the tracheal and/or bronchial wall; in five individuals the infection was apparently limited to this site.9 The antemortem diagnosis was difficult in these patients because of the low yield of sputum cultures and fulminant nature of the disease. Although there were large numbers of hyphae in the trachea of this patient, aspergillus was not detected by sputumn culture. Therefore, the result of culture is not useful for early diagnosis of filamentous fungal infections. Clinical features of Aspergillus tracheobronchitis are entirely different from those of invasive pulmonary aspergillosis (IPA), the most common type of Aspergillus infection in BMT recipients. Patients with Aspergillus tracheobronchitis are usually less immunocompromized than those with IPA. Aspergillus tracheobronchitis mainly involves the respiratory tract and causes either respiratory failure due to obstructive lung disease or fatal hemorrhage from the pulmonary vessels adjacent to the respiratory ducts. It is a rare complication in BMT recipients and there have been only four cases reported who developed Aspergillus tracheobronchitis after BMT (Table 1). Because of its rarity, its clinical features in BMT patients have not been fully understood and early diagnosis and optimal management have not been possible. This patient with Aspergillus tracheobronchitis after BMT had a clinical course similar to those previously described in non-transplant patients.3 The first clinical symptoms were cough, dyspnea and wheezing and the CT scan at that time failed to demonstrate any obvious abnormalities in the lung. Her neutrophil counts remained normal, but dyspnea rapidly progressed and was followed by respiratory failure. These were typical features of Aspergillus tracheobronchitis, but all of them are nonspecific. We were not able to make a correct diagnosis of Aspergillus tracheobronchitis in this patient until the bronchoscopy revealed tracheal obstruction with yellow-white pseudomembranes from the part of the trachea distal to the main bronchus. Although we succeeded in making an antemortem diagnosis of Aspergillus tracheobronchitis using bronchoscopy, it was too late to successfully treat this patient. It is important to clarify the risk factors for Aspergillus tracheobronchitis in order to make an early diagnosis and to improve the prognosis. Underlying airway disease, prolonged use of endotracheal tubes and decreased mucociliary production are reported to be the risk factors in non-BMT patients,3 but this has not been confirmed in BMT recipients. We suspect that prolonged administration of corticosteroids and steroid-pulse therapy might have been associated with the development of Aspergillus tracheobronchitis in this patient. The former might mask pyrexia episodes and lead to delay in achieving the correct diagnosis and the latter might aggravate Aspergillus tracheobronchitis. It is to be noted that all the four patients with Aspergillus tracheobronchitis after BMT previously reported was receiving corticosteroids prior to the onset of this disease (Table 1). Administration of corticosteroids may be regarded as a risk factor for Aspergillus tracheobronchitis in BMT recipients. We should have considered changing from fluconazole to

intravenous low-dose AMPH-B for antifungal prophylaxis when we initiated corticosteroids for the treatment of GVHD. To evaluate the benefit of blood tests in making an early diagnosis of Aspergillus tracheobronchitis, we retrospectively determined serum BDG levels and presence of circulating galactomannan antigen in this patient using EIA. EIA became positive before initiation of steroid pulse therapy and both increased rapidly after the development of tracheobronchitis (Figure 3). These findings suggest that this disease may progress rapidly and that a massive fungal burden may be a prerequisite for the development of clinical symptoms. Thus, the EIA might become positive before a clinical diagnosis is established. We do not know the cause of the disparity between the BDG assay and the EIA, but EIA may be beneficial for the early diagnosis of Aspergillus tracheobronchitis in contrast to IPA.10 In conclusion, Aspergillus tracheobronchitis occurring in bone marrow transplant recipients follows a highly aggressive clinical course with a poor prognosis. Thus, this type of Aspergillus infection should be regarded as one of the serious complications after BMT. If this disease is suspected, bronchoscopy should be performed as early as possible even in the presence of normal chest X-rays and CT scans.

Acknowledgements Special thanks to Mr H Ban (BML Corporation, Tokyo, Japan) for determination of serum (1 → 3)-␤-d-glucan concentration and Miss T Suzuki (Fuji Revio, Tokyo, Japan) for Aspergillus EIA assay.

References 1 Denning DW, Evans EG, Kibbler CC et al. Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation. British Society for Medical Mycology. Eur J Clin Microbiol Infect Dis 1997; 16: 424–436. 2 Berlinger NT, Freeman TJ. Acute airway obstruction due to necrotizing tracheobronchial aspergillosis in immunocompromised patients: a new clinical entity. Ann Otol Rhinol Laryngol 1989; 98: 718–720. 3 Clarke A, Skelton J, Fraser RS. Fungal tracheobronchitis. Report of nine cases and review of the literature. Medicine 1991; 70: 1–14. 4 Hines DW, Haber MH, Yaremko L et al Pseudomembranous tracheobronchitis caused by Aspergillus. Am Rev Respir Dis 1991; 143: 1408–1411. 5 Putnam JB Jr, Dignani C, Mehra RC. Acute airway obstruction and necrotizing tracheobronchitis from invasive mycosis. Chest 1994; 106: 1265–1267. 6 Ratanatharathorn V, Karanes C, Lum LG et al. Allogeneic bone marrow transplantation in high-risk myeloid disorders using busulfan, cytosine arabinoside and cyclophosphamide (BAC). Bone Marrow Transplant 1992; 9: 49–55. 7 Stynen D, Goris A, Sarfati J, Latge JP. A new sensitive sandwich enzyme-linked immunosorbent assay to detect galactofuran in patients with invasive aspergillosis. J Clin Microbiol 1995; 33: 497–500.


8 Obayashi T, Yoshida M, Mori T et al. Plasma (1 → 3)-betad-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995; 345: 17–20. 9 Young RC, Bennett JE, Vogel CL et al. Aspergillosis. The spectrum of the disease in 98 patients. Medicine 1970; 49: 147–173.

10 Kami M, Tanaka Y, Ogawa S et al. The limitation of circulating Aspergillus antigen detection methods for BMT recipients. Bone Marrow Transplant 1998; 22: 832–833.

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