Medical Image of the Month: Pulmonary Aspergillus Overlap Syndrome Presenting with ABPA, Multiple Bilateral Aspergillomas

Figure 1. Representative images from thoracic CT scan in soft tissue windows showing multiple Aspergillomas (arrows).

Introduction

Aspergillus is a ubiquitous fungal organism that causes a variety of pulmonary manifestations, both in immune-competent and immune-compromised patients. It can vary from simple colonization, Aspergilloma, ABPA to Chronic Pulmonary Aspergillosis (CPA) and Invasive Pulmonary Aspergillosis (IPA) (1). ABPA is the most frequently recognized manifestation of allergic aspergillosis, caused by the immunological reactions mounted against Asp. fumigatus. Aspergillomas are rounded conglomerates of fungal hyphae, fibrin, mucus and cellular debris that arise in pulmonary cavities, as a late manifestation of CPA. Chronic pulmonary aspergillosis (CPA) is a long-term aspergillus infection of the lung. The most common form of CPA is chronic cavitary pulmonary aspergillosis (CCPA), which untreated may progress to chronic fibrosing pulmonary aspergillosis. Aspergillus overlap syndrome is defined as the occurrence of more than one form of aspergillus disease (e.g., ABPA with Aspergilloma, ABPA progressing to IPA etc.) in a single individual.

Case Report

A 58-year-old woman, resident of Bihar presented with a 4 years history of cough with expectoration, blood stained sputum on coughing, breathlessness on exertion associated with wheezing, frequent on and off episodes of fever and weight loss. She also gave history of repeated attacks of cold. She received anti-tuberculous therapy (ATT) for 9 months, prescribed on clinical and chest x-ray basis; but there was no improvement. Due to repeated attacks of haemoptysis, she was referred to our hospital for further management. She gave history of taking analgesics and steroids on and off for 20 years, for joint pains from local practitioners although Rheumatoid factor was negative. There was no other significant medical or surgical illness in the past. At the time of presentation, on clinical examination, bilateral wheeze was noted. Occasional crackles were heard on auscultation over chest bilaterally. Sputum direct smear and MGIT for Acid fast bacilli were negative. Chest X-ray showed patchy infiltrates, bronchiectatic changes, and cavities in both lungs. Sputum for AFB was negative. ELISA Test for HIV was negative. Blood examination in September 2015 showed leukocytosis with eosinophilia (TLC = 16220/mm³, DLC = N⁶⁶L²³M⁶E^4.7, AEC = 770/µL). Serum Total IgE was 393.31IU/mL (0-200 IU/mL). Specific IgE for Aspergillus fumigatus was negative but Serum precipitins for Aspergillus fumigatus were positive. Sputum fungal culture at the same time grew Aspergillus fumigatus. CECT Chest showed scattered cystic bronchiectatic lesions in bilateral lungs with mycetoma formation in few of them. Peripheral air crescent formation was also present [Figure 1-3]. Peripheral pruning of bronchovascular markings was seen suggestive of emphysematous changes. Subcutaneous skin prick test was also positive for A. fumigatus and A. tamari. PFT showed mild obstruction and restriction. A diagnosis of ABPA with chronic pulmonary aspergillosis with multiple aspergillomas was made fitting into Aspergillus Overlap Syndrome (AOS). She was treated symptomatically for haemoptysis and inhaled ICS was prescribed for breathlessness. Itraconazole 200mg BD was started and ICS was continued. Follow up sputum sample for fungal culture done after 2^nd and 4^th month showed growth of A. fumigatus. But after 6^th month, repeat sputum samples became sterile for fungal organisms indicating favorable response with azole therapy. Patient continued to have some episodes of fever and slight breathlessness and was treated symptomatically, but there was overall improvement in general condition. She gained weight and haemoptysis also abated. She was lost to follow up, but later revisited after a 10 month gap. She had continued the itraconazole. There was significant symptomatic improvement, and weight gain. Repeat blood counts showed normal TLC (8180/mm³) with DLC showing eosinophil 4.40% and AEC of 360/µL. Serum total IgE was 122 kUA/L. Repeat sputum cultures were negative for Aspergillus.

Discussion

Aspergillus is a ubiquitous fungal organism that causes a variety of pulmonary manifestations, both in immunocompetent and immunocompromised patients. It can vary from simple colonization, Aspergilloma, ABPA, to Chronic Pulmonary Aspergillosis (CPA) and Invasive Pulmonary Aspergillosis (IPA) (1).

Chronic Pulmonary Aspergillosis (CPA) was recognized as a clinical entity in 1842 (2). Several different terminologies and classifications have been proposed. Denning et al. (3) in 2003 proposed a classification dividing CPA into Chronic Necrotizing Pulmonary Aspergillosis (CNPA), Chronic Cavitary Pulmonary Aspergillosis (CCPA), and Chronic Fibrosing Pulmonary Aspergillosis (CFPA). The ERS and ESCMID now classify CPA into five entities: 1) Simple Aspergilloma, 2) CCPA, 3) CFPA, 4) Aspergillus nodule, and 5) Subacute Invasive Aspergillosis (previously CNPA) (4). 

The estimated global prevalence of CPA following pulmonary TB is 1.74 million, and ranges from 7 to 20% in ABPA cases (5). In India, the annual incidence of CPA is estimated to vary from 27, 000 cases to 1,70, 000 cases (6). 

The diagnostic criteria for CPA include a consistent appearance in thoracic imaging (preferably by CT), direct evidence of Aspergillus infection or an immunological response to Aspergillus spp., and exclusion of alternative diagnoses. In addition, the minimum duration of disease should be of 3 months and patients shouldn’t be immunocompromised. Immunological response usually indicates a positive Aspergillus IgG (4).

CCPA is the more common variety of CPA and is defined as one or more pulmonary cavities (with either a thin or/ thick wall) possibly containing one or more aspergillomas or irregular intraluminal material, with serological or microbiological evidence implicating Aspergillus spp., with significant pulmonary and/or systemic symptoms and overt radiological progression (new cavities, increasing peri-cavitary infiltrates or increasing fibrosis) over at least 3 months of observation (4).

The typical radiologic features of CCPA include unilateral or bilateral areas of consolidation associated with multiple expanding usually thick-walled cavities that may contain one or more aspergillomas. Cendrine et al. (7), in their study of 36 patients over 6 months found cavities in 32 (91.4%) patients which were unilateral in 21 (65.6%) and contained fungal ball in 20 (55.5%) patients. 

The term Pulmonary Aspergillus Overlap syndrome is used when two or three of the Aspergillus syndromes overlap (e.g., ABPA with Aspergilloma, ABPA progressing to IPA etc.). It has been reported in few case series and reports (8). Our patient had symptoms and radiological features suggestive of CCPA, along with positive serum precipitins for Aspergillus and Aspergillus fumigatus on sputum fungal cultures. Tuberculosis was ruled out with a negative culture. The presence of cystic bronchiectatic features and positive immediate skin prick test for A. fumigatus suggest ABPA. An Aspergillus overlap syndrome can be considered due to presence of features of ABPA with multiple aspergillomas and CCPA. The presence of multifocal pulmonary aspergillomas in CPA, seen in our patient, is a rare finding in itself (9). 

Various anti-fungals like itraconazole, voriconazole, posaconazole, micafungin, caspofungin and amphotericin B have all been employed in the treatment of CPA, with near similar outcomes (10). Itraconazole being cheap and easily available with fewer side effects, is commonly used. R. Aggarwal et al.^. (6) in their study on Indian patients with CCPA showed that itraconazole therapy was superior to conservative management. Oral triazole therapy is now considered the standard of care (4). 

In our patient, oral itraconazole therapy for 4 months rendered sputum sterile for Aspergillus. She did not require the use of oral long-term steroids. After 1 year of therapy patient showed significant clinical improvement and she remained stable for 2 years on follow-up.

Bharath Janapati DNB, Anil K Jain MD, and Priya Sharma DNB

Department of Respiratory Medicine

National Institute of Tuberculosis and Respiratory Diseases

New Delhi 110030, India

References

1. Grippi MA, Elias JA, Fishman J, Kotlof RM, Pack AI. (eds). Fishman’s Pulmonary Diseases and Disorders. 5th Edition. New York, NY: McGraw Hill. 2015.
2. Bennett J. On the parasitic vegetable structures found growing in living animals. Trans Royal Soc Edinburgh. 1842;15:277-9.
3. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003 Oct 1;37 Suppl 3:S265-80. [CrossRef] [PubMed]
4. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, Ullmann AJ, Dimopoulos G, Lange C; European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016 Jan;47(1):45-68. [CrossRef] [PubMed]
5. Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol. 2013 May;51(4):361-70. [CrossRef] [PubMed].
6. Agarwal R, Denning DW, Chakrabarti A. Estimation of the burden of chronic and allergic pulmonary aspergillosis in India. PLoS One. 2014 Dec 5;9(12):e114745. [CrossRef] [PubMed]
7. Godet C, Laurent F, Bergeron A, et al. CT Imaging Assessment of Response to Treatment in Chronic Pulmonary Aspergillosis. Chest. 2016 Jul;150(1):139-47. [CrossRef] [PubMed]
8. Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011 Sep 1;20(121):156-74. [CrossRef] [PubMed]
9. Pendleton M, Denning DW. Multifocal pulmonary aspergillomas: case series and review. Ann N Y Acad Sci. 2012 Dec;1272:58-67. [CrossRef]  [PubMed]
10. Agarwal R, Vishwanath G, Aggarwal AN, Garg M, Gupta D, Chakrabarti A. Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature. Mycoses. 2013 Sep;56(5):559-70. [CrossRef] [PubMed]

Cite as: Janapati B, Jain AK, Sharma P. Medical Image of the Month: Pulmonary Aspergillus Overlap Syndrome Presenting with ABPA, Multiple Bilateral Aspergillomas. Southwest J Pulm Crit Care. 2021;22(3):76-80. doi: https://doi.org/10.13175/swjpcc002-21 PDF

Medical Image of the Week: Valley Fever Cavity with Fungus Ball

Figure 1. Chest x-ray taken in 2004 showing pulmonary nodule (arrows).

Figure 2. A: Thoracic CT scan in lung windows from 2004 showing the pulmonary nodule with cavitation. B: CT scan from 2007 showing thin-walled cavity. C: CT scan from 2008 showing fungus ball inside the cavity.  D: CT scan from 2010 showing the continued presence of the fungus ball inside the cavity.

A 72-year-old man was seen in 2010 because of hemoptysis. In 2004 a routine chest x-ray discovered a new pulmonary nodule (Figure 1, Figure 2A). Coccioidomycosis by complement fixation and IgM were negative but IgG was elevated at 0.203 (upper limit of normal 0.150).  A transthoracic needle biopsy revealed a granuloma without malignancy and no growth of any organisms. He was followed because he was asymptomatic. He remained asymptomatic but developed a thin-walled cavity (Figure 2B). However, beginning in 2008 he developed a cough with occasional hemoptysis. His thoracic CT scan was repeated and was interpreted as showing findings consistent with a fungus ball (Figure 2C). He was treated with fluconazole for about 6 months but his hemoptysis persisted and therapy was switched to itraconazole. His hemoptysis persisted although it was somewhat improved. A repeat CT scan performed in 2010 (Figure 2D) continued to show the fungus ball. He was referred to pulmonary and bronchoscopy revealed no other source of the hemoptysis; stains and cultures were negative; and he was referred to thoracic surgery for resection.

Hemoptysis from coccioidomycosis is unusual and should prompt a search for other causes (1). These could include bronchitis, malignancy, or rarely, a fungus ball as in our case. When hemoptysis is present with a fungus ball, treatment with fluconazole, itraconazole or amphotericin B is often advised although descriptions are limited to case reports. When hemoptysis persists despite drug therapy, resection of the cavity has been performed (2).

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

Reference

1. Galgiani JN, Knox K, Rundbaken C, Siever J. Common mistakes in managing pulmonary coccidioidomycosis. Southwest J Pulm Crit Care. 2015;10(5):238-49. [CrossRef]
2. Thadepalli H, Salem FA, Mandal AK, Rambhatla K, Einstein HE.Pulmonary mycetoma due to Coccidioides immitis. Chest. 1977 Mar;71(3):429-30. [PubMed]

Cite as: Robbins RA. Medical image of the week: valley fever cavity with fungus ball. Southwest J Pulm Crit Care. 2018;16(5):281-2. doi: https://doi.org/10.13175/swjpcc064-18 PDF 

Medical Image of the Week: Pulmonary Mycetoma

Figure 1. Thoracic CT scan showing mycetoma (arrow) in cavitary lesion in right upper lobe.

A 59 year-old woman presented with right sided chest pain and worsening shortness of breath. On CT of the chest she was found to have cavitary lesions in her right lung with one of them having a distinct opacity within the lesion concerning for a pulmonary mycetoma (Figure 1, arrow). Most literature describes pulmonary mycetomas occurring due to Aspergillus species. However, in our patient, neither the bronchoscopy with bronchoalveolar lavage (BAL) nor serological studies tested positive for Aspergillus. Cultures did however grow Candida albicans in 2 of the samples from the BAL. Mycetoma due to Candida has been described in the urinary tract in immunocompromised patients and, uncommonly, in the lung (1-3). Our patient had been treated for Stage III ovarian cancer with chemotherapy and at presentation her absolute neutrophil count was reduced at 860. In the hospital, she was treated for her shortness of breath with albuterol-ipratropium nebulizations to which she responded well. She was discharged once stable to follow up as outpatient for further treatment of her Candida albicans mycetoma.

Saud Khan, MD and Huzaifa A. Jaliawala, MD

Internal Medicine

University of Oklahoma Health Sciences Center

Oklahoma City, OK USA

References

1. Praz V, Burruni R, Meid F, Wisard M, Jichlinski P, Tawadros T. Fungus ball in the urinary tract: A rare entity. Can Urol Assoc J. 2014 Jan-Feb;8(1-2):E118-20. [CrossRef] [PubMed]
2. Song Z, Papanicolaou N, Dean S, Bing Z. Localized candidiasis in kidney presented as a mass mimicking renal cell carcinoma. Case Rep Infect Dis. 2012;2012:953590. [CrossRef] [PubMed]
3. Bachh AA, Haq I, Gupta R, Varudkar H, Ram MB. Pulmonary candidiasis presenting as mycetoma. Lung India. 2008 Oct;25(4):165-7. [CrossRef] [PubMed]

Cite as: Khan S, Jaliawala HA. Medical image of the week: pulmonary mycetoma. Southwest J Pulm Crit Care. 2017;15(4):169-70. doi: https://doi.org/10.13175/swjpcc123-17 PDF

Medical Image of the Week: Fungus Ball

Figure 1. Panel A: Coronal view of thoracic CT scan shows a fungus ball (mycetoma) within a 4.7cm thin walled cavity, Panel B: Axial image of fungus ball and thin walled cavity.

Figure 2 Panel A. Prominent eosinophilic infiltration with epithelial-lined cavity containing fungus ball (orange arrow). Panel B: Higher magnification.

A 69 year-old Asian woman living in Arizona with a past medical history of nephrotic syndrome on high-dose steroids had worsening pulmonary symptoms. A computed tomography (CT) of the chest (Figure 1) showed a 4.7 cm thin walled cavitary lesion in the right middle lobe compatible with mycetoma. She underwent thoracotomy for mycetoma resection. Surgical pathology confirmed an epithelial-lined cavity containing dense mycelia (Figure 2). Given the patient lived in an endemic area; the cavity was thought to be likely due to coccidioidomycosis. However, the mycetoma was of unclear etiology. No spherules were noted on GMS stain and tissue culture was negative. While of unclear clinical significance which fungus colonizes a pre-existing cavity, a Coccidioides PCR was performed and no Coccidioides genes were amplified making a Coccidioides mycetoma very unlikely.

Pulmonary mycetoma or “fungus ball” consists of dense fungal elements and amorphous cellular material within a pre-existing pulmonary cavity. Classically presenting as an aspergilloma, other fungi can cause similar lesions. Patients with mycetoma rarely develop symptoms. When present, symptoms can include chest pain, cough, hemoptysis, fatigue, fever, or unintentional weight loss. If asymptomatic, no treatment is required. Surgical resection and/or embolization may be required in cases of severe symptoms including hemoptysis.

Scott Rosen MD, Bridget Barker PhD, Branden Larsen MD PhD, and Ishna Poojary MD

Department of Medicine and Pathology

University of Arizona Medical Center

Tucson, AZ

and

Tgen North

Flagstaff, AZ

References

1. Winn RE, Johnson R, Galgiani JN, Butler C, Pluss J. Cavitary coccidioidomycosis with fungus ball formation. Diagnosis by fiberoptic bronchoscopy with coexistence of hyphae and spherules. Chest. 1994;105(2):412-6. [CrossRef] [PubMed]
2. Sobonya RE, Yanes J, Klotz SA. Cavitary pulmonary coccidioidomycosis: pathologic and clinical correlates of disease. Hum Pathol. 2014;45(1):153-9. [CrossRef] [PubMed]
3. Sheff KW, York ER, Driebe EM, Barker BM, Rounsley SD, Waddell VG, Beckstrom-Sternberg SM, Beckstrom-Sternberg JS, Keim PS, Engelthaler DM. Development of a rapid, cost-effective TaqMan Real-Time PCR Assay for identification and differentiation of Coccidioides immitis and Coccidioides posadasii. Med Mycol. 2010;48(3):466-9. [CrossRef] [PubMed]

Reference as: Rosen S, Barker B, Larsen B, Poojary I. Medical image of the week: fungus ball. Southwest J Pulm Crit Care. 2015;10(4):182-3. doi: http://dx.doi.org/10.13175/swjpcc025-15 PDF

Medical Image of the Week: Aspergilloma

Figure 1.  Axial thoracic computed tomography (CT) image showing emphysematous disease throughout with prominent bullous disease in the upper lobes.  Areas of consolidation were concerning for infection.  Large cavitation with particulate matter (arrow) was seen in the left upper lobe. 

A 69-year-old woman, a current smoker, with very severe chronic obstructive pulmonary disease and prior atypical mycobacterium, was found unresponsive by her family and intubated in the field by emergency medical services for respiratory distress.  Her CT thorax showed severe emphysematous disease, apical bullous disease, and a large left upper lobe cavitation with debris (Figure 1).  She was treated with broad-spectrum antibiotics and anti-fungal medications.  Hemoptysis was never seen.  Sputum cultures over a span of two weeks repeatedly showed Aspergillus fumigatus and outside medical records confirmed the patient had a known history of stable aspergilloma not requiring therapy. 

Aspergillomas usually arises in cavitary areas of the lung damaged by previous infections.  The fungus ball is a combination of colonization by Aspergillus hyphae and cellular debris.  Individuals with aspergillomas are usually asymptomatic or have mild symptoms (chronic cough) and do not require treatment unless it begins to invade into the cavity wall.  When bleeding complications arise, surgical resection is curative but in high-risk patients, embolization may be considered as a stabilizing measure. 

Wendy Hsu, MD, Carmen Luraschi-Monjagatta, MD and Gordon Carr, MD

Division of Pulmonary and Critical Care Medicine

University of Arizona 

Tucson, AZ 

Reference 

Kousha M1, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121):156-74. [CrossRef] [PubMed]

Reference as: Hsu W, Luraschi-Monjagatta C, Carr G. Medical image of the week: aspergilloma. Southwest J Pulm Crit Care. 2014;8(5):282-3. doi: http://dx.doi.org/10.13175/swjpcc044-14 PDF