Concomitant occurrence of advanced fibrocavitary pulmonary sarcoidosis and chronic pulmonary aspergillosis

Abstract

An African American man in his 30s presented with haemoptysis associated with chronic productive cough, exertional dyspnoea, weight loss and skin lesions. Physical examination was notable for multiple cutaneous plaques over upper extremities and face. CT chest showed bilateral upper lobes cavitations and left upper lobe mass like consolidation. Further workup revealed positive serum aspergillus IgG, respiratory culture grew Aspergillus fumigatus, skin biopsy showed non-caseating granuloma. A final diagnosis of concomitant chronic pulmonary aspergillosis and advanced fibrocavitary pulmonary sarcoidosis with cutaneous involvement was made. The patient was initiated on antifungal therapy without steroids due to the concern of worsening the fungal infection. However, he presented later with worsening haemoptysis requiring bronchial artery embolisation. Surgical intervention was recommended but the patient eventually declined. The patient continued to be followed up closely in the clinic and repeated chest imaging showed stable findings 3 months after initial presentation.

Background

The combination of aspergilloma and sarcoidosis was first reported by Fougner et al.¹ Sarcoidosis is a major predisposing factor for development of chronic pulmonary aspergillosis.² On the other hand, chronic pulmonary aspergillosis complicates almost exclusively in patients with sarcoidosis with advanced fibrocavitary disease.^{3 4} This unique clinical entity is associated with poor prognosis and high mortality. Sarcoidosis associated chronic pulmonary aspergillosis not only presents a diagnostic challenge to clinician but also treatment dilemma. Unfortunately, there is no consensus treatment guidelines on this disease due to the lack of studies and trials performed on this particular subgroup of patients. Hereby, we present a case of undiagnosed advanced pulmonary sarcoidosis presenting with chronic pulmonary aspergillosis along with a brief discussion of currently available literature on this topic.

Case presentation

An African American man in his 30s with no significant medical history presented with haemoptysis for 3 days. The patient had been experiencing chronic productive cough with whitish sputum as well as worsening exertional dyspnoea and unintentional weight loss for over a year prior to presentation. He also noticed development of non-painful and non-pruritic skin lesions over his face and upper extremities which had been persisted for over a year. Three days prior to presentation, he started coughing up dark coloured blood and blood clots which amounted to a teaspoonful for every episode and associated with pleuritic chest pain. Otherwise, he denied any fever, chills, night sweats, loss of appetite or recent history of travel out of the country.

On presentation, vital signs were stable with blood pressure 116/74 mmHg, heart rate 93 beats/min, respiratory rate 16 breaths/min, SpO₂ 97% on room air and temperature of 37°C. Physical examination revealed multiple violaceous plaque over his face (figure 1) and bilateral upper arms (figure 2); reduced breath sounds over bilateral upper zones on lung auscultation. Other examination findings were unremarkable.

Figure 1.

Violaceous skin plaque on the face.

Figure 2.

Violaceous skin plaque over left forearm.

Investigations

Initial blood work on admission showed haemoglobin 11.6 g/L (reference range: 12.6–16.5 g/L), white blood cell count 5.6×10⁹/L (reference range: 4.0–12.0×10⁹//L), absolute lymphocytes 0.50×10⁹/L (reference range: 0.56–4.92×10⁹/L), platelet count 229×10⁹/L (reference range: 150–400×10⁹/L), alkaline phosphatase 199 U/L (reference range: 45–115 U/L), erythrocyte sedimentation rate 43 mm/hour (reference range 0–20 mm/hour). Chest X-ray revealed bilateral upper lobe infiltrates and lung volume loss (figure 3). Subsequent CT chest with contrast showed bilateral upper lobes bullous and fibrotic changes with cavitations along with left upper lobe mass like consolidation measuring 1.9×2.8 cm with air crescent sign (figure 4A, B).

Figure 3.

Chest X-ray showing bilateral upper lobe infiltrates and lung volume loss.

Figure 4.

(A) CT chest with contrast (axial view) showing bilateral upper lobes bullous and fibrotic changes with cavitations; left upper lobe mass like consolidation measuring 1.9×2.8 cm with air crescent sign (black arrow). (B) CT chest with contrast (coronal view) showing bilateral upper lobes bullous and fibrotic changes with cavitations; left upper lobe mass like consolidation measuring 1.9×2.8 cm with air crescent sign (black arrow).

Subsequent workup showed elevated serum aspergillus antigen 0.6 (reference range <0.5), positive aspergillus IgG antibody and elevated serum angiotensin converting enzyme (ACE) 178 U/L (reference range 16–85 U/L). Otherwise, sputum acid-fast smear and culture, HIV Ag-Ab, hepatitis panel, QuantiFERON tuberculosis, antineutrophil cytoplastic antibodies (ANCA) panel, serum (1,3) beta-D-glucan were unremarkable.

In order to confirm the diagnosis of chronic pulmonary aspergillosis, we proceeded with endobronchial ultrasound guided bronchial alveolar lavage. Bronchial alveolar lavage smear of the left upper lobe with Grocott Methenamine Silver stain was notable for numerous fungal organisms (figure 5). Respiratory culture from bronchoalveolar lavage of left upper lobe subsequently grew Aspergillus fumigatus sp. Fine needle aspiration cytology of subcarinal lymph node revealed granulomatous inflammation with epithelioid histiocytes in a background of lymphocytes, without apparent necrosis or caseation (figure 6).

Figure 5.

Bronchial alveolar lavage smear of left upper lobe with Grocott Methenamine Silver stain showing numerous fungal organisms.

Figure 6.

Fine needle aspiration cytology of subcarinal lymph node revealed granulomatous inflammation with epithelioid histiocytes in a background of lymphocytes, without apparent necrosis or caseation.

Lastly, due to the high suspicion of possible underlying undiagnosed sarcoidosis, skin biopsy of the left upper arm skin lesion was done which showed non-caseating granuloma without evidence of microorganisms seen on Grocott Methenamine Silver stain, Fite’s stain and Acid-Fast Bacillus stain (figure 7), further confirming the final diagnosis of cutaneous sarcoidosis.

Figure 7.

Skin biopsy of left upper arm skin lesion showing non-caseating granuloma.

Differential diagnosis

Initial differential diagnosis included pulmonary tuberculosis, pulmonary aspergillosis, ANCA-associated small vessel vasculitis and sarcoidosis. Pulmonary tuberculosis was ruled out as sputum acid-fast smear and culture as well as QuantiFERON tuberculosis were negative. ANCA-associated vasculitis was unlikely given negative serum ANCA panel. With elevated serum aspergillus antigen, positive aspergillus IgG antibody and A. fumigatus species in respiratory culture, a final diagnosis of chronic pulmonary aspergillosis with aspergilloma was made. However, with the young age of presentation and non-immunocompromised state, we had high suspicion that our patient might have an underlying undiagnosed medical condition which may have predisposed him to aspergillus infection. Eventually, we established the concomitant diagnosis of sarcoidosis with skin biopsy showing non-caseating granulomas supported with elevated serum ACE level. We speculated that our patient may have developed sarcoidosis initially leading to cavitation of his lungs which eventually predisposed him to pulmonary aspergillosis leading up to his initial presentation. Our final diagnosis was fibrocavitary pulmonary sarcoidosis with cutaneous involvement complicated with an aspergilloma.

Treatment

Our patient was initially started on broad spectrum antibiotics and treated with nebulised tranexamic acid for intermittent haemoptysis. After establishing the diagnosis of chronic pulmonary aspergillosis, antibiotics were discontinued and the patient was started on oral voriconazole. However, he experienced gastrointestinal symptoms following treatment with oral voriconazole and thus was switched to oral isavuconazole for 6 months duration to treat chronic pulmonary aspergillosis. Steroid therapy was not initiated for treatment of sarcoidosis due to concern of aggravating the underlying active aspergillus infection.

Outcome and follow-up

The patient was readmitted to the hospital 3 months later with massive haemoptysis, requiring multiple blood transfusions. He underwent embolisation of left inferior bronchial artery, left internal mammary artery and the side branches supplying the left upper lobe mass which temporarily improved his haemoptysis. Unfortunately, he presented again with massive haemoptysis a week later and was transferred to a tertiary hospital for further evaluation. The patient was advised for lobectomy which he subsequently declined. Fortunately, his haemoptysis improved with conservative management and he was later discharged home.

He was followed up as outpatient and reported only intermittent small volume haemoptysis. Repeat CT chest with contrast 6 months from initial presentation showed stable findings without interval changes. The patient was subsequently started on oral prednisone 20 mg daily for treatment of sarcoidosis and the treatment duration of oral isavuconazole was extended indefinitely due to concern of worsening aspergillus infection after the initiation of steroid therapy.

Discussion

Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology characterised by non-caseating granulomatous inflammation. The incidence and prevalence of sarcoidosis vary greatly depending on geographical regions and ethnicities which makes it extremely challenging to estimate the burden of the disease. The prevalence is estimated to be between 2 and 160 per 100 000 and the incidence ranges between 0.3 and 11.5 per 100 000 per year.⁵ Although sarcoidosis can affect any organ system, it is known to primarily affect the lungs, with pulmonary involvement accounted for majority of the morbidity and mortality associated with sarcoidosis.⁶ The natural history of pulmonary sarcoidosis is unpredictable and variable, ranging from asymptomatic cases and spontaneous resolution to chronic progressive disease and advanced fibrocystic disease in approximately 5% of patients.⁷ Fibrotic cysts, bullae and paracicatricial emphysema are manifestations of advanced stage pulmonary sarcoidosis.⁸ These fibrocystic lesions classically affect the upper and middle lung zones and typically follow the large airways in a perihilar distribution.⁸ Cavitation of lung parenchyma is an unusual finding in sarcoidosis and is reported in only 10% of patients with end-stage pulmonary sarcoidosis.⁹ Primary cavitary pulmonary sarcoidosis with central necrosis secondary to confluent granuloma is extremely rare and this entity is estimated to be reported in less than 0.8% of sarcoidosis cases.¹⁰ In fact, most lung cavitations seen on chest imagings are due to the development of blebs, bullae and cysts in advanced fibrocystic stage of sarcoidosis.¹¹ These lesions are known as pseudocavities and are lined by dense fibrous tissue and not by granulomas because these cavitations frequently occur in areas of advanced fibrosis.¹¹ Our patient presented with an initial CT chest which showed bilateral upper lobe cavitations with bullous and fibrotic changes which strongly suggested that he most likely had an undiagnosed advanced stage pulmonary sarcoidosis.

Chronic pulmonary aspergillosis includes a spectrum of disease manifestations that have considerable overlap and variation in severity. They consist of aspergilloma, aspergillus nodule, chronic cavitary pulmonary aspergillosis and chronic fibrosing pulmonary aspergillosis.¹² Majority of affected individuals have some forms of underlying pulmonary disease that results in cavities or bullae formations. The most common predisposing factor for chronic pulmonary aspergillosis is previously treated pulmonary tuberculosis.¹³ Other risk factors include non-tuberculous mycobacterial infection, chronic obstructive pulmonary disease, bronchiectasis, previously treated lung cancer, prior pneumothorax with bullae formation and fibrocavitary sarcoidosis.¹³ Patients with chronic pulmonary aspergillosis typically present with weight loss, chronic cough, shortness of breath and occasionally haemoptysis.¹⁴ Notable characteristic radiographic findings include lung cavitations which are typically localised within the upper lobes, with or without aspergilloma, infiltrates or pulmonary fibrosis.¹⁴ The cardinal diagnostic test for chronic pulmonary aspergillosis is a positive serum aspergillus IgG and this is usually supported by presence of aspergillus in sputum culture, aspiration or biopsy.¹⁵ We came to a final diagnosis of chronic pulmonary aspergillosis with aspergilloma in our patient with a positive confirmatory serum aspergillus IgG supported by evidence of A. fumigatus in respiratory culture from bronchoalveolar lavage and the characteristic CT chest findings.

The combination of aspergilloma and sarcoidosis was first reported by Fougner et al.¹ Sarcoidosis is a major risk factor for developing chronic pulmonary aspergillosis as it represents about 7–17% of chronic pulmonary aspergillosis cases.² On the other hand, chronic pulmonary aspergillosis complicates approximately 2% of sarcoidosis cases, mostly in patients with advanced fibrocavitary sarcoidosis.^{3 4} Interestingly, cavitary alveolar sarcoidosis which is an extremely rare distinct form of sarcoidosis also has been reported to be complicated by aspergilloma formation by Gera et al. This highlights pulmonary sarcoidosis as a major predisposing factor for the development of chronic pulmonary aspergillosis once cavitations have formed.¹⁶ Similar to the unpredictable natural history of sarcoidosis, it is currently not possible to predict which patients with sarcoidosis will develop aspergillosis.¹⁷ Majority of chronic pulmonary aspergillosis are caused by A. fumigatus while Aspergillus niger, Aspergillus flavus and Aspergillus nidulans have been described on rare occasions.² As fibrocavitary sarcoidosis has the characteristic pulmonary cavitations similar to chronic cavitary pulmonary aspergillosis, making a new diagnosis can be extremely challenging. The diagnosis of chronic pulmonary aspergillosis is determined by the presence of a fungal ball and/or serum aspergillus IgG. A retrospective cohort study by Uzunhan et al which included 3137 patients with sarcoidosis reported chronic pulmonary aspergillosis in 80 patients (2.6%), 41 patients (68%) were identified with the presence of aspergilloma, 60 patients (92%) had positive aspergillus IgG and 48 patients (81%) reported to grow Aspergillus spp from respiratory cultures.¹⁸ Chronic pulmonary aspergillosis was found to be present at the diagnosis of sarcoidosis in only 10 patients (15%), showing that most patients with sarcoidosis developed chronic pulmonary aspergillosis after they have been established to have a formal diagnosis of sarcoidosis.¹⁸

Our patient was first diagnosed with chronic pulmonary aspergillosis without any identified risk factors initially. This had raised the suspicion of a possible underlying undiagnosed condition which may have predisposed him to the development of chronic pulmonary aspergillosis. The presence of skin lesions which appeared to be cutaneous plaque sarcoidosis or more commonly known as lupus pernio ultimately lead us to the diagnosis of sarcoidosis after confirmation of non-caseating granuloma on skin biopsy with the absence of fungal organisms. This highlights the importance of clinical examination as the presence of lupus pernio was the most important clue in diagnosing sarcoidosis in this case and it should not be overlooked on initial assessment. So, we proposed that our patient may have an undiagnosed advanced stage pulmonary sarcoidosis with cutaneous involvement which subsequently complicated by chronic pulmonary aspergillosis leading to his initial presentation to our hospital.

To date, there is no definitive treatment guidelines for sarcoidosis associated chronic pulmonary aspergillosis. Unfortunately, the subset of patients with sarcoidosis associated aspergillosis have not been studied in the literature thus most recommendations were extrapolated from trials from chronic pulmonary aspergillosis alone. Itraconazole is the preferred first line antifungal followed by voriconazole; available third line agents include posaconazole and isavuconazole.¹⁹ Currently, there is no common treatment endpoints defined for chronic pulmonary aspergillosis due to the high disease relapse rate. Use of intracavitary instillation of amphotericin B has been reported by Kravitz et al who suggested that it is an effective short-term treatment for aspergilloma induced haemoptysis but the long-term benefit is unknown.²⁰ In cases with massive haemoptysis, bronchial artery embolisation is the recommended intervention. Surgical resection is a feasible treatment option for localised aspergillomas. However, the benefit and outcomes for patients with advanced diseases are controversial due to the poor pulmonary function and high disease recurrence.²¹ The mainstay treatment for sarcoidosis is corticosteroids with the goal of controlling the granulomatous inflammatory processes. This raises treatment dilemma as initiation of steroids may potentially cause progression of chronic pulmonary aspergillosis to invasive aspergillosis. Uzunhan et al reported the use of lower doses of corticosteroids and antifungals which resulted in lower mortality compared with previous studies.¹⁸

Patients with sarcoidosis complicated by chronic pulmonary aspergillosis have poor prognosis and experienced frequent relapses despite treatment. This clinical entity is associated with high mortality related to massive haemoptysis and underlying advanced stage pulmonary sarcoidosis. Tomlinson and Sahn reported mortality of 58% at 2 years in their cohort.²² Uzunhan et al reported survival rate of 73.7% and 61% for 5 years and 10 years, respectively.¹⁸ While Lowes et al reported survival rate of 62% at 5 years and 47% at 10 years.²³

In conclusion, clinicians should be aware of sarcoidosis related aspergillosis given the poor prognosis and high mortality associated with this clinical entity. Besides, screening patients with sarcoidosis with fibrocystic disease for chronic pulmonary aspergillosis with serum aspergillus IgG may be beneficial for early detection and initiation of antifungal therapy but this needs to be further studied. Due to the scarcity of trials and studies involving patients with sarcoidosis associated aspergillosis, larger studies are called for to study this particular subgroup of patients.

Learning points.

• Sarcoidosis is a major risk for development of chronic pulmonary aspergillosis.

• Chronic pulmonary aspergillosis complicates most commonly patients with advanced fibrocavitary pulmonary sarcoidosis.

• The cardinal diagnostic test for chronic pulmonary aspergillosis is a positive serum aspergillus IgG antibody.

• Although corticosteroids are the mainstay therapy for sarcoidosis, initiating treatment may risk the progression of localised aspergillus infection into invasive disease.

• The duration of antifungal therapy for sarcoidosis related aspergillus infection is unknown due to the lack of studies and high relapse rate of the disease entity.

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