September 2023 Medical Image of the Month: Aspergillus Presenting as a Pulmonary Nodule in an Immunocompetent Patient

Figure 1. Chest CT showing 11 x10 mm nodule in the anterior segment of the left upper lobe in the background of emphysematous and basal sub segmental atelectatic changes.

Figure 2. Lung biopsy low power (A) showing chronic inflammatory infiltrate in the interstitium along with a collection of fungus (arrow) (H&E: x40). Fungus with an area of necrosis (B) (H&E: x100). Numerous thin, narrow-angle, and branching hyphae with septa morphologically consistent with Aspergillus (C) (H&E: x400). Collection of Aspergillus (D). (Periodic acid–Schiff stain: x400).

A 32-year-old nonsmoking woman presented with complaints of recurrent hemoptysis for 5 months and dyspnea on exertion for 1 month. She denied any history of fever, cough, or COVID infection. She has hypothyroidism controlled on thyroxine 25mcg. During the evaluation, she was found to have an enhancing solitary pulmonary nodule (11 x 10 x 9mm) in the anterior segment of the left upper lobe (Figure 1). The patient was given a course of oral antibiotics (amoxicillin /clavulanic acid) and supportive treatment for hemoptysis. Sputum for Ziehl–Neelsen stain and cartridge based nucleic acid amplification test (CBNAAT) was negative. CT- guided biopsy of the nodule was performed. Histopathology showed fungal organisms which were thin, septate with acute angle branching and focal necrotic areas, morphologically consistent with Aspergillus (Figure 2). Serum-specific IgG against aspergillus antigen was normal. The patient was started on oral itraconazole 200mg BID. Follow-up after 1 month showed both symptomatic and radiological improvement. Repeat chest CT showed a significant decrease in size of the nodule.

There is a large spectrum of pulmonary aspergillosis. From this spectrum, pulmonary nodules are a less common manifestation of chronic pulmonary aspergillosis (CPA), especially in immunocompetent individuals. Aspergillus nodules are defined as small, round, discrete, and focal opacities on chest imaging. It can be further classified on basis of internal cavitation (i.e., non-cavitary nodules and cavitary nodules). Differentiating these nodules from other lung pathology may be difficult on CT findings alone and may demand further investigation like image-guided needle aspiration cytology or biopsy, blood investigations like serum Aspergillus precipitin IgG antibody and/or serum Aspergillus galactomannan. Delay in diagnoses may lead to persistence of pulmonary symptoms, and cavitation of the nodule. This entity has a favorable prognosis if managed accordingly. Although there is data regarding surgical management of aspergillus nodules, but data regarding the benefits of anti-fungal therapy in the same is limited.

Diagnosing aspergillus nodules in an immunocompetent individual is a challenge to all pulmonologists. Literature shows limited case reports and small case series on CPA presenting as non-cavitating SPN on radiology. Usually, in such cases, the diagnosis is made following removal or biopsy of the nodule(s), presuming it to be malignant. Patients diagnosed with Aspergillus nodules can’t be differentiated from lung malignant conditions based on demographics, which are usually similar. In the largest case series of Aspergillus nodules done by Muldoon EG et al. (6), 33 patients were reviewed constituting less than 10 % of the cohort of patients with CPA.  In a study done by Kang et al. (4) 77% of patients with aspergillus nodules were symptomatic and the most common symptom reported was hemoptysis. Similarly in our case hemoptysis was the chief complaint of the patient. Our patient is a woman and non-smoker similar to previous case reports and series.

In the current guidelines, the detection of serum Aspergillus precipitin IgG antibody is a key diagnostic criterion for CPA. Literature is unclear if the presence of Aspergillus IgG antibody could be considered a supportive finding in the making the diagnosis of Aspergillus nodules. Similarly, in our case also serum specific IgG against Aspergillus fumigatus was negative. Azoles are the primary treatment option in all subtypes of CPA including aspergillus nodule. Our patient also showed disease regression during itraconazole treatment. Another option for management is surgical, though it is associated with significant postoperative complications and recurrence of disease at other sites and must be reserved for selected patients.

Dr. Deependra Kumar Rai, Dr. Priya Sharma, Dr. Vatsal Bhushan Gupta

Department of Pulmonary, Critical Care, and Sleep Medicine

AIIMS Patna, Bihar, India

References

1. Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax. 2015 Mar;70(3):270-7. [CrossRef] [PubMed]
2. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008 Mar;246(3):697-722. [CrossRef] [PubMed]
3. Lee SH, Lee BJ, Jung DY, Kim JH, Sohn DS, Shin JW, Kim JY, Park IW, Choi BW. Clinical manifestations and treatment outcomes of pulmonary aspergilloma. Korean J Intern Med. 2004 Mar;19(1):38-42. [CrossRef] [PubMed]
4. Kang N, Park J, Jhun BW. Clinical Characteristics and Treatment Outcomes of Pathologically Confirmed Aspergillus Nodules. J Clin Med. 2020 Jul 10;9(7):2185. [CrossRef] [PubMed]
5. Yasuda M, Nagashima A, Haro A, Saitoh G. Aspergilloma mimicking a lung cancer. Int J Surg Case Rep. 2013;4(8):690-2. [CrossRef] [PubMed]
6. Muldoon EG, Sharman A, Page I, Bishop P, Denning DW. Aspergillus nodules; another presentation of Chronic Pulmonary Aspergillosis. BMC Pulm Med. 2016 Aug 18;16(1):123. [CrossRef] [PubMed]
7. Denning DW, Cadranel J, Beigelman-Aubry C, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016 Jan;47(1):45-68. [CrossRef] [PubMed]
8. Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128. [CrossRef] [PubMed]
9. Godet C, Philippe B, Laurent F, Cadranel J. Chronic pulmonary aspergillosis: an update on diagnosis and treatment. Respiration. 2014;88(2):162-74. [CrossRef] [PubMed]
10. Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011 Sep 1;20(121):156-74. [CrossRef] [PubMed]

Cite as: Rai DK, Sharma P, Gupta VB. September 2023 Medical Image of the Month: Aspergillus Presenting as a Pulmonary Nodule in an Immunocompetent Patient. Southwest J Pulm Crit Care Sleep;27(3):30-32. doi: https://doi.org/10.13175/swjpccs035-23 PDF

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: Finger in Glove

Figure 1. PA (Panel A) and lateral (Panel B) chest x-ray showing finger in glove (arrow) in the right upper lung with other scattered areas of consolidation.

Figure 2. Repeat chest x-ray about a month later showing generalized clearing.

A 45-year old man with a history of asthma presented with increasing shortness of breath, and cough productive of dark firm plugs, sometimes branching. His chest x-ray (Figure 1) shows finger in glove (arrow) in the right upper lung with other scattered areas of consolidation. His serum IgE was elevated at 750 IU/ml (normal < 380 IU/ml).  His eosinophil count was 12%.   Aspergillus IgE was 6.69 (normal< 0.35). A diagnosis of probable allergic bronchopulmonary aspergillosis (ABPA) was made. He was given oral corticosteroids. Follow up about a month later showed dramatic clinical improvement and a repeat chest x-ray (Figure 2) showed generalized clearing.

The initial chest x-ray shows a “finger in glove” pattern in the right upper lobe (Figure 1, arrow), which is due to mucoid impaction within the larger bronchi (1). The same appearance has also been referred to as the rabbit ear appearance, Mickey Mouse appearance, toothpaste-shaped opacities, Y-shaped opacities, V-shaped opacities and the Churchill sign because it resembles the “V” gesture often associated with Winston Churchill.

ABPA is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and central bronchiectasis (2). Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and optimized asthma therapy. Uncertainties surround the prevention and management of bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, concurrent rhinosinusitis, environmental control and long-term management.

Gerald F. Schwartzberg, MD

Phoenix, AZ

References

1. Weerakkody Y, Jones J. Finger in glove sign. Available at: http://radiopaedia.org/articles/finger-in-glove-sign (accessed 11/22/13).
2. Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, Moss R, Denning DW; ABPA complicating asthma ISHAM working group. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 2013;43(8):850-73. [CrossRef] [PubMed]

Reference as: Schwartzberg GF. Medical image of the week: finger in glove. Southwest J Pulm Crit Care. 2014:8(1):64-5. doi: http://dx.doi.org/10.13175/swjpcc169-13 PDF