2004 - A woman with an unresolving lung infiltrate
Drs Grace SM Lam, Arthur CW Lau, Loretta YC Yam; Department of Medicine, Pamela Youde Nethersole Eastern Hospital
Case History
A 53-year-old woman presented on 14thJune 2004 to the Accident and Emergency Department with left-sided pleuritic chest pain for one day, blood-stained sputum for two months, appetite and weight loss for two weeks, and malaise for one week. She had history of mild intermittent asthma not requiring medications for many years. She was a cleaner in a factory which processed herbal medicine, was neither a smoker nor drinker, and swam in a public pool every morning.
On admission she was afebrile with normal vital signs. White cell and differential counts, liver and renal functions were normal. She could not produce any sputum for culture. A lingular opacity was seen on chest radiograph (Fig. I). A course of oral amoxicllin-clavulanic acid and clarithromycin was prescribed for treatment of community-acquired pneumonia. Since her condition appeared to be stable and her pleuritic chest pain subsided after admission, she was discharged two days later.
When followed up at the out-patient department on 7thJuly 2004, she had no further respiratory complaints. However, the lingular opacity was still unresolved on the chest radiograph taken that day. The dense opacity was subsequently reported as a mass lesion on contrast CT thorax (Fig. 2). We performed bronchoscopy on 8thJuly 2004, which showed mucosal swellings at the lingular orifice, with greyish necrotic tissues at its opening that was partly removed by suction. Bronchoalveolar lavage yielded colonies of branching fungal hyphae suggestive of Aspergillus, but was negative for AFB smear and malignant cells. Only crush artefacts were seen in the lingular biopsy. Total IgE was slightly raised, but skin prick test, specific IgE and serum precipitins to Aspergillus fumigatus were all negative. Lung function test showed no airflow obstruction. She was not immunocompromised as evidenced by normal fasting blood glucose and immunoglobulin levels, negative anti-HIV antibody and autoimmune markers.
A repeat bronchoscopy was done on 13thJuly 2004 for confirmation of the diagnosis. Endobronchial findings were similar. Only one transbronchial biopsy sample could be obtained because the patient complained of severe pain when the forceps approached the swollen lingular bronchus a second time. Subsequent chest radiograph did not show any pneumothorax. The transbronchial biopsy sample (Fig. 3) was compatible with bronchocentric granulomatosis due to Aspergillus.
Although the histological features were compatible with aspergillosis, definitive diagnosis was only revealed by fungal culture of the bronchoalveolar lavage, which showed that another organism was responsible for the lesion.
What is the diagnosis?
Pulmonary pseudallescheriasis with features of bronchocentric granulomatosis and semi-invasion causing pneumonia and pleuritis.
Discussion
Pulmonary pseudallescheriasis is caused by the ubiquitous fungus Pseudallescheria boydii, which was first described as a human pathogen by Saccardo in 1911. The nomenclature for this fungus has been rather confusing. Pseudallescheria boydii is the name given to the sexual stage, which is capable of producing globose cleistothecium that releases asci when it matures and ruptures. The asexual stage is named Scedosporium apiospermum or Graphium, depending on conidial morphology. Petriellidium boydii and Allescheria boydii are obsolete names of the sexual stage, while Monosporium apiospermum was once used when the asexual stage was thought to be a different fungus.
This fungus has been isolated from soil, sewage, contaminated water and manure of farm animals. We postulate that our patient might have contracted the disease from working in close contact with decaying plants, or from public swimming pools which she visited daily. In 1997, Tekavec et al described a woman who cleaned swimming pools, who had both pulmonary tuberculosis and pneumonia caused by S.apiospermum . The authors concluded that infection by the asexual stage of P. boydii was the result of occupational exposure2.
P. boydii is an emerging opportunistic pathogen3,but infection in immunocompetent hosts, as in our patient, is not uncommon. Infection ranges from cutaneous mycetoma to disseminated disease. Reported cases included involvement of the central nervous system4-6, upper respiratory tract7, eyes8-9 and urinary tract10, native valve endocarditis 1I, continuous ambulatory peritoneal dialysis (CAPO) peritonitis 12, vertebral osteomyelitis13and arthritis14,in addition to pulmonary infections. The spectrum of pulmonary diseases caused by P. boydii is remarkably similar to that of Aspergillus, ranging from allergic bronchopulmonary pseudallescheriasisl5, to colonization of preformed cavities in pseudallescheriomal6, to pneumonial7 and intrabronchial growthl8, and finally to invasive infectionl9.
In addition to having a similar disease spectrum, P. boydii is notorious for causing diagnostic confusion with Aspergillus in histopathological specimens, because both form colourless, septated hyphae with dichotomous branching (hyalohyphomycoses). Other hyalohyphomycoses that are capable of causing similar diagnostic confusion include Fusarium, Paecilomyces and Acremonium. Hyphae that are haphazardly arranged, exhibit both 45° and 90° branching, with considerable variation in diameter (2-8 /-lm)will suggest an aetiological agent other than Aspergilluio. However, it is not possible to reliably differentiate between the two unless there is production of conidia. The conidia of P. boydii differ from those of Aspergillus in being oval and truncated at the base, and are produced singly at the end of conidiophores or short side-branches. The problem is that conidia may not be found in histopathological specimens, especially those obtained from closed lesions.
Ultimate differentiation relies on time-consuming cultures. Newer techniques using in-situ hybridization21 and PCR22 allow differentiation using histopathological specimens alone.
Differentiating the two fungi is important because P. boydii has an innate resistance to amphotericin B but is sensitive to azoles. According to a recently published Japanese stud/3, voriconazole has the lowest minimum inhibitory concentration (MIC) among other azoles, but MIC of various anti-fungal agents against the sexual and asexual stages are not different.
We treated our patient with itraconazole 100mg BD. Chest radiograph taken after six weeks of treatment showed resolution of the lingular opacity (Fig. 4). Optimal duration of treatment is not known, but the literature appears to favour treatment for more than four months even in immunocompetent subjects in order to reduce recurrences. Treatment duration may well be shortened if the lesion is resected, which is an acceptable option for localized disease failing medical treatment 16-17, 24-25
The diagnosis of bronchocentric granulomatosis was made in this case because granulomatous inflammation was centered upon an airway. In cases where there is total destruction of a bronchiole by a necrotizing granuloma, its bronchocentric distribution can be inferred by its location adjacent to a pulmonary artery. Elastic tissue stains, which have been used in our case, are also helpful in identifying the interrupted elastic layers of partially destroyed bronchioles.
Liebow26first described bronchocentric granulomatosis in 1973 as one of the five clinical syndromes of pulmonary angiitis and granulomatosis, the other four entities being Wegener's granulomatosis, lymphomatoid granulomatosis, necrotizing sarcoid granulomatosis and allergic angiitis and granulomatosis (Churg-Strauss syndrome). All these four entities have angiocentric granulomatous inflammation. Patients with bronchocentric granulomatosis can be divided into asthmatic and non-asthmatic. The former is considered to be a manifestation of allergic bronchopulmonary mycosis, most commonly representaed by allergic bronchopulmonary aspergillosis. Although our patient has mild intermittent asthma, we did not classify her under the asthmatic bronchocentric granulomatosis group because of the absence of peripheral eosinophilia and a polymorphonuclear predominant granulomatous inflammation instead of an eosinophilic one. The non-asthmatic group has been reported to be associated with a number of fungi including Aspergillus, Histoplasma and Blastomyces, and with the present case, Pseudallescheria boydii can be added to the list.
In conclusion, this patient is suffering from pulmonary pseudallescheriasis with features of bronchocentric granulomatosis and semi-invasion causing pneumonia and pleuritis. To our knowledge, this is the first reported case of pulmonary pseudallescheriasis causing bronchocentric granulomatosis.
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