ORIGINAL ARTICLE

The Clinical Respiratory Journal

Intralobar pulmonary sequestration complicating with cryptococcal infection Chao Guan1, Hui Chen2, Changzhou Shao1, Lixian He1 and Yuanlin Song1 1 Shanghai Institute of Respiratory Diseases, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China 2 Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua, China

Abstract Introduction: Pulmonary sequestration is a rare congenital malformation characterized by accessory lung tissue supplied by an aberrant systemic artery. It often presents with recurrent infections. But fungus infection is exceptional. Objectives: To help other clinicians deal with patients with pulmonary sequestration complicating with cryptococcal infection. Methods: We reported a case of pulmonary sequestration complicating with pulmonary and eye cryptococcosis and did literature review. Results: A 20-year-old immunocompetent male patient suffered from eye pain and blurred vision, and received antibiotics and dexamethasone therapy with no improvement. Bacteriology inspection and computerized tomography scan indicated a diagnosis of cryptococcal infection in both eye and lung. Vitrectomy and antifungal agents were administered. Since symptoms fluctuations, lobectomy was operated. The surgery revealed the presence of pulmonary sequestration. Literature review showed that there is no report about pulmonary sequestration complicating with cryptococcal infection so far. Conclusions: Pulmonary sequestration is a very important but extremely negligent cause for pulmonary cryptococcal infection. Please cite this paper as: Guan C, Chen H, Shao C, He L and Song Y. Intralobar pulmonary sequestration complicating with cryptococcal infection. Clin Respir J 2015; 9: 22–26.

Key words cryptococcosis – endophthalmitis – lobectomy – pulmonary sequestration Correspondence Changzhou Shao, MD, 180 Fenglin Road, Shanghai, China. Tel: 086-21-64041990-2422 Fax: 086-21-64187165 email: [email protected] Received: 26 September 2013 Revision requested: 13 December 2013 Accepted: 04 January 2014 DOI:10.1111/crj.12099 Authorship and contributorship Chao Guan: performed study, collected data, analyzed data and wrote the paper. Hui Chen: performed study, collected data, analyzed data and wrote the paper. Changzhou Shao: designed study, performed study, collected data, analyzed data and wrote the paper. Lixian He: designed study, contributed important reagents and wrote the paper. Yuanlin Song: designed study, performed study, contributed important reagents and analyzed data. Ethics The study was approved by local ethics review committees and the patient gave informed consent. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.

Introduction Pulmonary sequestration (PS) is a rare congenital pulmonary malformation which exists separated nonfunctional lung tissue vascularized by a systemic artery. The abnormal lung structure may result in

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persistent pneumonia, which is mostly caused by pyogenic pathogens. PS is most often present with recurrent infections, respiratory distress or as an asymptomatic mass. Colonization by Cryptococcus has not been reported before. Here we report a case of PS complicating lung and eye infection with cryptococci.

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd

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Case presentation A 20-year-old male patient was admitted to our hospital for productive cough, fever and ophthalmalgia. Initially, he presented with blurred vision on his left eye and had extremely sore eyes for 1 month. Primarily been treated by antibiotics and dexamethasone for 4 days in the village hospital, he was referred to ophthalmology doctors in the city hospital where diagnosed left eye uveitis. But the smarting in the left eye and the decrease of visual acuity still persisted in spite of receiving treatments of dexamethasone 10 mg per day for about 2–3 days. Then he transferred to a superior hospital and continued antibiotics therapy for a 5-day period in which there was no clinical manifestations improvement. Ultimately, a vitrectomy and left eye intraocular laser surgery was operated. After the smooth operation, he maintained dexamethasone therapy to improve the symptoms. But 10 days later, left eye pain and blurred vision presented again, together with a repeated fever (maximum 38.9°C) and coughing yellow phlegm. There was no family history of respiratory illness. On admission, the patient’s body temperature was 38.6°C. Scattered rashes on his chest, a decrease in respiratory sounds and rhonchi in the lower lobe of right lung were found. The rest of the physical examination including pulmonary auscultation was normal. Complete blood count examinations showed WBC: 30 × 109/L, N%: 92%. His blood biochemistry results were normal. The patient’s T cell subpopulations were normal, and human immunodeficiency virus (HIV) antibody was negative. Chest X-ray showed a large dense shadow in the right lower lobe. After antibiotics therapy (including azithromycin, ofloxacin and ceftriaxone) for 3 days, his symptoms progressively worsened. Chest computerized tomography (CT) scan demonstrated a mass with several irregular cavitary lesions in the right lower lobe, right pleural effusion and multiple enlarged mediastinal lymph nodes, which suggested a possibility of empyema (Fig. 1A). Then fungus was found in bacterial smear of sputum and in his eye secretions. The patient underwent percutaneous lung biopsy guided by color Doppler ultrasound. Pathology showed granulomatous lesions and scattered spores. Moreover, periodic acid–Schiff (PAS) staining and Grocott’s methenamine silver (GMS) staining were positive, and negative for acid fast staining. Pathological diagnosis confirmed a fungal infection that inclined to Cryptococcus. Fluconazole was used for about 2 weeks. But the patient still had fever and cough, with no improvement on all symptoms, so combination antifungal therapy with itraconazole and

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd

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amphotericin B liposome was replaced for more than 1 month. The patient was discharged after a significant symptom improvement and the chest CT showed lesions obviously absorbed (Fig. 1B). Unfortunately, the patient had a fever again, and the mass in the right lower lobe grew bigger (Fig. 1C) 1 month later, although with continued application of amphotericin B liposome. A surgery was decided. In the operation, during isolation of pulmonary ligament, a 0.9-cm diameter of abnormal vascular malformation delivering from thoracic aorta was found. The vessel coursed into the right lower lobe. The diagnosis of intralobar PS was made, and a right lower lobectomy was performed. In gross specimen, a large cavitating lesion measuring 2.5 × 6 cm consistent with intralobar PS surrounded by fibrotic tissue was found. Postoperative pathology showed (right lung lobe) alveolar collapse, fibrosis and bronchial residual cavity expansion in the microscopic lesions area. Also many multinucleated giant cells and fungus spores with acid-fast stain (−), GMS (+), PAS (+) were found (Fig. 2). This confirmed chronic inflammation with mycosis, possibly cryptococcal infection. The patient continued treatment with amphotericin B liposome for another 3 months. The postoperative course was uneventful.

Discussion PS is characterized by the dysfunctional lung tissue with abnormal or absent communication with the bronchial tree and unusual arterial blood supplied from the systemic circulation. The incidence of this abnormality ranges from 0.4% to 1.8%. Sequestration is classified as extralobar sequestration (ELS) and intralobar sequestration (ILS). ILS accounts for 75% of PS cases. ELS is separated from normal lung tissue by its own visceral pleura, whereas ILS is contained within normal parenchyma and is connected with arbor bronchial (1). PS mostly involves the lower lobes, usually the medial and posterior basal segments, and occurs more frequently on the left side (60%) (2). Although it may present at any age, it typically presents in older children or young adults with recurrent pulmonary infection or, less frequently, hemoptysis. Several etiologies of PS have been proposed. No chromosomal abnormalities have been associated with PS (3). Radiographic studies are difficult to define PS only when angiography has been taken and abnormal vessels have been found. Most PS commonly appear as a solid mass, with or without cavitary lesions. A retrospective analysis including as many as 1106 cases of PS that were characterized by chest CT scan reported four 23

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Figure 1. Chest computerized tomography (CT) of pulmonary sequestration complicating with cryptococcal infection. (A) CT slice showing a mass and nodules lesion in the right lower lobe before antifungal treatment. (B) CT slice showing the lesion in the right lower lobe absorbed after 2-week antifungus treatment. (C) CT slice showing the lesion in the right lower lobe expands while the patient’s clinical symptom was worsen before the surgery. (D) CT slice showing a cavitating mass in the posterior basal segment of the right lower lobe, which is connected a cord-like image (aberrant systemic artery) with the hilum of lung.

categories: mass lesion (542 cases, 49.01%); cystic lesion (316 cases, 28.57%); cavitary lesion (128 cases, 11.57%); and pneumonic lesion (88 cases, 7.96%) (4). Some study on CT angiography for PS showed high accuracy (>95%) and sensitivity (>95%), considered it to be equivalent to the gold standard (5). The commonest clinical presentations of PS are chronic cough, sputum and recurrent attacks of pneumonia. These symptoms are usually secondary to superimposed infection, which is usually pyogenic. Some are exceptional as those due to Blastomycosis dermatitidis or to Exophiala. Superimposed infection of PS by fungal pathogens is extremely rare (6). Cryptococcosis is usually prevalent in immunocompromised patients (including those with acquired immune deficiency syndrome, treatment with glucocorticoids or immunosuppressors, and organ trans-

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plantation or malignancy) or in those who have a history of exposure to soil, dust or pigeon feces. But it is also an emerging pathogen of immunocompetent individuals. Cryptococcus neoformans var. neoformans (C. neoformans) is the species predominantly reported from immunocompromised patients, while Cryptococcus neoformans var. gattii (C. gattii) infection has been associated with immunocompetent patients (7). The lung is believed to be the portal of entry for Cryptococcus, and in fact, in HIV-negative patients, pulmonary involvement is more frequent (8). Patients with chronic lung diseases, such as bronchitis and bronchiectasis, may have positive cultures with Cryptococcus for many years without clinical manifestations, or they may go on to have symptoms of low-grade infection (cough and fever), or even progress to develop pneumonia (9). In the present case, we did not

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd

Guan et al.

Pulmonary sequestration with cryptococcosis

Figure 2. Postoperative pathology of pulmonary sequestration showing alveolar collapse, multinucleated giant cells and fungus spores with Grocott’s methenamine silver (GMS) staining (+) and periodic acid–Schiff (PAS) staining (+). (A: HE × 200; B: PAS × 200; C: GMS × 200).

find abnormality of the patient’s immunity through our tests. The patient has no hobby of raising pigeons or occupational exposure. On the basis of bacterial inspections of sputum and lung biopsy, we made an initial diagnosis of pneumonia caused by cryptococci, although there is no report about PS complicating with Cryptococcus as far as our information goes. Cryptococcus might reach the sequestrated lung through three ways: bloodstream, lymphatic system or from adjacent normal lung tissue via Kohn’s pores. In this case, endogenous endophthalmitis and pneumonia occurred on our patient about the same time. Endophthalmitis occurs when organisms disseminate through blood-borne spread and enter the internal ocular spaces through the blood–ocular barrier. We presume that there is the most probable way through hematogenous spread to the sequestration from a primary infection site of cryptococcosis. Abundant arterial blood flow from the systemic circulation makes the sequestration more susceptible to Cryptococcus.

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd

Lung could be the portal to the pathogen and pneumonia turned to be a risk factor complicating with endophthalmitis. A 10-year retrospective research at a referral center showed 64 samples taken from 64 patients, fungal isolates in 27 (65.9%) and C. neoformans in 1 case. Identifiable risk factors were present in 78.1% of patients and 3.7% of those with pulmonary fungal infection (10). According to the current guidelines of the Infectious Diseases Society of America, amphotericin B combined with fluconazole is recommended as primary therapy regimen, followed by fluconazole as consolidation therapy (11). The present patient was not relieved, although fluconazole and amphotericin B therapy was implemented. So several reasons should be considered. First, more than one organ has been involved. Because pulmonary cryptococcosis and endogenous fungal endophthalmitis was certain by the biology, disseminated cryptococcosis should been considered. Next, we presume antifungal resistance in this circumstance. 25

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However, the mechanism of drug resistance in C. neoformans has not been widely investigated. There were no reports showed Cryptococcus has primary resistance to amphotericin B. Mutations in genes were reported from an azole-resistant clinical strain. Apart from two genes (Erg11 and AFR1), Chr4 is another chromosome most frequently found to be disomic at drug concentrations higher than fluconazole (12, 13). In our case, with treatment of amphotericin B and azole, the symptoms improved and the mass reduced. So the possibility of resistance to these drugs is very small. This case is worth noticing because of the association PS with cryptococcal infection, and there were no similar cases in literature so far. We can learn some lessons from this case, which can help us avoid the delayed diagnosis and unnecessary treatment in the future. First, if a patient’s antifungal therapeutic effect is unsatisfactory, underlying reasons especially PS should be considered. The very important but extremely negligent possibility is that factors caused infection have not been removed. In our case, therapeutic efficacy was unsatisfactory in the condition of timely diagnose had been made. As PS acted as the reasonable factor causing persistent infection. Second, this case reminds us that if the CT scan shows persistent or recurrent consolidation in the same segment of the lung, especially the lower lobe near vertebral column, the possibility of PS should be suspected and the abnormal aberrant artery should be searched. In fact, review the CT slices of the present case, blood vessels governing the isolated sequestration have been revealed which have not been noticed before (Fig. 1D). If angelology is not available, enhanced CT scan could help us to drop the conclusion of PS earlier rather than in the operation. Third, to avoid the risk of recurrent infection and destruction of adjacent pulmonary parenchyma, resection of the malformation is advocated in cases where complications (e.g. persistent or recurrent infection, and hemoptysis) occur and antifungal agents are not effective. Last and the most painful, improper treatments of Cryptococcus endophthalmitis failing to give antifungal therapy as early as possible led to irreversible blindness of the patient.

Acknowledgments The work was supported by the National Natural Science Foundation of China (30772019), the Scientific Research Foundation for the Returned Overseas Chinese Scholars by State Education Ministry of

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China, Shanghai Natural Science Foundation (13ZR1406600) and Jinhua Municipal Science and Technology Bureau InFocus Programme on Social Development (2011-3-002).

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The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd

Intralobar pulmonary sequestration complicating with cryptococcal infection.

Pulmonary sequestration is a rare congenital malformation characterized by accessory lung tissue supplied by an aberrant systemic artery. It often pre...
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