A case of allergic bronchopulmonary aspergillosis leading to pneumonia with unusual organisms.
Key Words: allergic bronchopulmonary aspergillosis, Aspergillus, Nocardia asteroides
First described in 1952 by Hinson et al, (1) the syndrome of allergic bronchopulmonary aspergillosis (ABPA) is characterized by bronchopulmonary aspergillosis, peripheral eosinophila, and asthma coupled with intermittent cough productive of mucous plugs containing Aspergillus. Despite the evolution of specific serologic tests and more definitive objective criteria, (2) diagnosis still requires a high degree of clinical suspicion. Here we present a case of ABPA coupled with an unusual pneumonia.
A 50-year-old white male with a history of severe asthma and seizure disorder presented with a 5-month history of increasing dyspnea. He had seen multiple physicians over this time period and had been treated for bronchopneumonia with ciprofloxacin, levofloxacin, and, most recently amoxicillin/clavulanic acid with little to no improvement. Approximately one month before admission, he had been seen by a pulmonologist who ordered a CT scan of the lungs, which revealed symmetrical bronchiectasis with mucoid impaction of the bronchi in the lingular segment of the left upper lobe and posterior segment of the right lower lobe. Subsequent bronchoscopic biopsy revealed enlarged mucous glands and longitudinal striations consistent with chronic bronchitis. Culture from bronchial washings eventually grew out Aspergillus fumigatus and Stenotrophomonas maltophilia. At admission, he complained of shortness of breath, both at rest and with exertion, fever and chills, minimally productive cough and generalized fatigue.
His past medical history included asthma treated with inhaled albuterol and fluticasone and a seizure disorder well controlled with phenytoin. On further questioning, he did recall a similar course of events approximately 10 years before admission during which he thought he had heard of Aspergillus and was treated with steroids. He also stated that he recalled the name "Sporanox." He had no known drug allergies. He denied chronic systemic corticosteroid use. He denied any family history of lung disease or allergies. There was no exposure history for animals, tuberculosis, or environmental irritants. He further denied tobacco, alcohol, high risk sexual behavior, or illicit drug use.
On physical examination, he was afebrile with stable vital signs. He had an oxygen saturation of 97% on room air. Lung examination showed bilateral inspiratory and expiratory wheezes and bibasilar crackles, but was otherwise unremarkable. Spirometry revealed the forced expiratory volume in 1 second to be 1.03 L (28% of predicted) with a forced vital capacity of 34% of expected. Flow volume loop was consistent with obstructive ventilatory defect. A CT angiogram done to rule out pulmonary embolus revealed a new pneumatocele in the left upper lobe with multiloculation, bronchiectasis in an upper lobe predominance, ground glass lung posteriorly in the right lung, and a three-pronged cluster of soft tissue mass in the superior aspect of the right lower lobe.
Allergic bronchopulmonary aspergillosis with concomitant community-acquired pneumonia was thus suspected and confirmed by immunoglobulin (Ig)E specific to Aspergillus fumigatus (although he did not have IgG specific to Aspergillus), a total IgE level of 3,589 IU/mL, and a high total eosinophil count of 880/[micro]L. Subsequent skin testing revealed an immediate cutaneous sensitivity to Aspergillus with a 5 mm wheal on puncture testing.
The patient was started on corticosteroids and voriconazole. Bronchoscopy revealed significant mucoid impaction of the endobronchial tree bilaterally with the most severe impaction in the left upper lobe. In this area, multiple bronchoscopies were required to remove the mucous plugging. Upon removal of this plugging, copious purulent discharge was noted from this lobe. Bronchoalveolar lavage cultures yielded colonies of Stenotrophomonas maltophilia and weakly acid-fast Gram positive branching rods that eventually proved to be Nocardia asteroides. He was treated with trimethoprim sulfamethoxazole and levofloxacin with an excellent initial clinical response. Voriconazole was discontinued.
Shortness of breath accompanied by pleuritic chest pain returned over the next several months. Repeat CT scan obtained approximately 10 weeks after discharge revealed multiple left upper lobe abscesses with complete destruction of this lobe. Bronchoscopy done at this time showed recurrence of the mucous plugging, marked inflammation, and pus in the endobronchial tree. Significant necrosis of the left upper lobe, presumably due to Nocardia pneumonia, was also seen. Surgical intervention was felt to be necessary and the patient underwent left upper lobectomy several days later.
Histologic examination revealed chronic inflammation and hyperplasia of the bronchial wall. Mucous and inflammatory exudates were present within the bronchi. Large granulomata with central necrosis were noted along with collections of multinucleated giant cells in lung sections. These sections also showed dilated airways consistent with bronchiectasis. There was peribronchiolar chronic inflammation. There were also areas of fibrosis with numerous pigmented macrophages. A relatively large lung nodule showed central cystic necrosis with eosinophilic material thought to be fungal hyphae in several areas but no bacteria. No cultures were obtained from this material.
Oral voriconazole was instituted. Prednisone was held during the perioperative period but restarted before discharge. At the one month follow-up visit, the patient reported complete resolution of symptoms. Follow-up chest x-ray was markedly improved and IgE levels had declined to 600 IU/mL.
Aspergillus fumigatus, the most common Aspergillus species causing disease in humans, is a common fungus that typically grows on decomposing matter and can be found both indoors and outside. (1-3) The hyphae are typically 10 [micro]m in length, septate, and branch at a 45[degrees] angle. Spores are small enough, at 2 [micro]m, to pass deep within the lung. (2) It is an organism that can cause distinct clinical syndromes either by direct invasion or immune response.
ABPA is characterized by the presence of asthma, immediate cutaneous reactivity to Aspergillus species, an elevated total serum IgE, and elevated serum IgG or IgE to Aspergillus fumigatus. (2) A diagnosis of seropositive ABPA (ABPA-S) can be made with the above criteria. Radiographic findings further categorize the disease. ABPA-S plus central bronchiectasis on computed tomography is necessary for a diagnosis of ABPA with central bronchiectasis (ABPA-CB). (2) A recent article designated a third variation of this process as ABPA with central bronchiectasis and other radiologic features (ABPA-CB-ORF) (4) These patients, in addition to satisfying criteria for ABPA-CB also had other radiologic features on CT such as pulmonary fibrosis, pneumothorax, blebs, scarring, bullae, ground glass appearance, and fibrocavitary lesions. Of note, with the progression from ABPA-S to ABPA-CB-ORF, the disease is usually increasingly severe. (4,5)
A similar pattern of disease exists in patients with asthma and peripheral eosinophilia who cough up mucous plugs and have fleeting infiltrates, yet have negative serologic workup for ABPA (with the exception of an elevated total IgE). These individuals are felt to have a similar reaction to a fungus other than Aspergillus, and the process is referred to as allergic bronchopulmonary mycosis. (6) In the case of our patient, all serologic criteria for ABPA were satisfied. Given his wide-spread bronchiectasis and other radiologic findings, he satisfied the criteria for proximal bronchiectasis as well as the ORF designation.
ABPA is usually categorized into one of five stages. (7) Stage I is the acute phase and is characterized by asthma, markedly elevated IgE level, peripheral eosinophila, pulmonary infiltrates and serum IgE and IgG to Aspergillus. Patients are rarely diagnosed at the time of this sentinel event, although in the case of our patient, we cannot rule out an earlier entity treated with steroids and itraconazole. Stage II is usually designated as remission, and these individuals may have largely normal radiologic studies and serology with the exception of a mildly elevated total IgE. Stage III is thought to be an exacerbation and is characterized by a doubling of the baseline IgE level. Stage IV is associated with steroid-dependent asthma and typically, bronchiectasis on chest x-ray. Stage V is characterized as end-stage lung disease. Patients are typically diagnosed at stage IV and few progress to stage V. This patient appears to be stage V, given his fibrosis and cystic cavitations on pathology.
It is not uncommon for pneumonia to be associated with ABPA, but this is typically caused by Staphylococcus aureus or Pseudomonas aeruginosa. (2) Our patient developed a necrotizing pneumonia associated with S maltophilia and N asteroides. A MEDLINE search citing ABPA with both of these microbes failed to produce any results. While relatively scarce
as pathogens in the general population, Nocardia species have been known to cause infection in patients with bronchiectasis. (8) While an asymptomatic carrier state may exist, (9) it seemed prudent to treat it as a pathogen in this individual. S maltophilia is usually encountered as an opportunistic infection in patients who have been given broad spectrum antibiotic coverage, as in our patient. (10)
This patient displayed two other entities occasionally associated with ABPA. The first process is mucoid impaction, which may be present with ABPA with or without asthma symptoms. This impaction can lead to atelectasis, or in this case, obstructive pneumonia, and therefore may be confused with malignancy. Our patient also appears to have had bronchocentric granulomatosis by pathology. This process is characterized by necrotizing granuloma as well as eosinophilic lung infiltrate and fibrosis. (3) Aspergillus is identified with granulomata about half of the time, and indeed fungal elements were identified on pathology.
Rarely, ABPA can convert to one of the other disease entities associated with Aspergillus species, such as invasive pulmonary aspergillosis (IPA) or chronic necrotizing aspergillosis (CNPA). (3) These entities can be difficult to differentiate from ABPA in that they may all present with fever, cough, sputum production, and weight loss. In addition, IPA may present with pleuritic chest pain and hemoptysis. Although the positive predictive value of respiratory tract cultures positive for Aspergillus in IPA has been reported to be as high as 63 to 78%, (11) patients typically have negative serology and the best diagnosis is made by showing local invasion of the lung on pathology. (3,12) Our patient did not have invasive disease histologically. Furthermore, the fungus does not appear to have disseminated to distant organs or to have invaded the vascular space. CNPA, in opposition to IPA, is characterized by minimal tissue invasion and a chronic indolent process over the course of time. (12)
In the differential diagnosis of ABPA, it is worth mentioning hyper-IgE syndrome. This rare neutrophil disorder is characterized by an elevated total serum IgE level, coupled with eczema, recurrent skin and pulmonary abscess. Patients also may present with facial and skeletal abnormalities. (13) No single dysfunction accounts for neutrophil ineffectiveness in these patients, so serologic diagnosis of this syndrome has been elusive. Hyper-IgE syndrome has been mistaken for ABPA, (14) and clinically these entities can be nearly impossible to separate. Patients with hyper IgE tend to do poorly on steroids and require constant antibiotic prophylaxis. (12) Our patient's initial positive response to steroid treatment, lack of characteristic facial features, and lack of cutaneous infections argued against his having this syndrome.
Treatment of ABPA with corticosteroids is well established and can often induce remission in individuals with mild cases. The recommended dosage is 0.5 to 1 mg/kg a day for two weeks, with conversion to alternate day therapy and a gradual taper for up to 6 months. (2,15) Total serum IgE levels and x-rays are used to monitor treatment. There have been multiple attempts to use antifungals as steroid-sparing agents, specifically with amphotericin B, ketoconazole, and itraconazole. These agents do appear to have some benefit, and until recently, itraconazole was felt to be the agent of choice due to its relatively benign side effect profile. (16) Voriconazole, while not specifically evaluated for use in ABPA, has been shown to be at least as efficacious as amphotericin B in IPA, (17) and may be an appropriate alternative here as well.
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Brown James McCallum, MD, David Amrol, MD, Joseph Horvath, MD, Nadeem Inayat, MD, and Rohit Talwani, MD
Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC.
Reprint requests to Brown James McCallum, MD, WJB Dorn VA Medical Center, 6439 Garners Ferry Rd, Columbia, SC 29209. Email: email@example.com
Accepted July 27, 2005.
The authors of this article have no commercial or financial interest in any drug, device or equipment mentioned in the article.
RELATED ARTICLE: Key Points
* Allergic bronchopulmonary aspergillosis requires a high degree of clinical suspicion for diagnosis.
* Allergic bronchopulmonary aspergillosis is characterized by the constellation of asthma, elevated total serum IgE, immediate cutaneous hypersensitivity to Aspergillus fumigatus, elevated IgG or IgE to Aspergillus fumigatus, and central bronchiectasis.
* Misdiagnosis or delayed diagnosis of ABPA can lead to significant morbidity or mortality.