Background
Sarcoidosis is a multisystem inflammatory disorder characterized by non-caseating granulomas with predominantly lung manifestations. Pulmonary function tests (PFTs) can show restrictive or, less commonly, obstructive lung disease. Rarely is pneumothorax a manifestation of sarcoidosis; it is noted in only 2%-4% of cases and is frequently seen as a late-presenting complication secondary to ruptured bullae, cysts, or pleural granulomas [1-4]. Still, pneumothorax has been reported as an early finding in sarcoidosis [5-7]. Here, we present a unique case of spontaneous pneumothorax attributed to biopsy-proven sarcoid disease in a patient with no prior history of pulmonary complications.
Case Report
A 60-year-old Black woman presented to the Emergency Department after a syncopal episode in which she sustained trauma to her left flank. She denied trauma to the head and no alteration in consciousness before or after the episode. A review of systems was only remarkable for shortness of breath associated with dull left-sided chest pain on exertion for several days. A week before the presentation, she underwent an uncomplicated ureteral stent placement for a ureterovesical stone and hydronephrosis of the right kidney. Her past medical history is remarkable for thyroid cancer treated with thyroidectomy. Her only medication is levothyroxine. She has no history of tobacco or inhaled substance use.
The patient’s presenting vitals were stable, and her initial oxygen saturation was 95% on room air. Her oxygen saturation briefly decreased to 92%, which subsequently improved to 98% with the administration of supplemental oxygen via nasal cannula at a rate of 2 l/minute flow. The initial physical examination was most notable for decreased breath sounds in the upper and lower lung fields relative to the right side. Neurological and musculoskeletal examinations demonstrated no abnormalities. No skin changes were noted over the left flank, and there was no tenderness to palpation over the ribs at the site of injury.
Initial studies included an electrocardiogram, which demonstrated normal sinus rhythm and rate. Her basic metabolic panel was significant for a calcium level elevated to 11.0 mg/dl (normal range: 8.4-10.4 mg/dl). Follow-up serum testing to assess the cause of hypercalcemia revealed an elevated Angiotensin-Converting Enzyme level, a normal Parathyroid Hormone level, and a 1,25-dihydroxy-Vitamin D/25-hydroxy-Vitamin D ratio greater than 4.0, suggesting active granulomatous disease. A venous blood gas revealed a mild respiratory acidosis with a normal lactate level. Diagnostic two-view chest radiographs demonstrated a novel moderate left-sided pneumothorax measuring up to 2.8 cm anteriorly and bilateral hilar prominence. These images did not show rib fractures or bullae, indicating that the pneumothorax was not caused by the puncturing of the pleura by a rib fragment at the time of her flank trauma. The hilar prominence noted on the radiograph prompted further exploration with computerized tomography (CT) of the chest, which additionally demonstrated diffuse pulmonary micronodules in a perilymphatic distribution (Figures 1 and 2).
CT image of the chest revealing moderate left pneumothorax measuring up to 2.8 cm anteriorly (contour of collapsed lung demarcated by red dashed line). Bilateral hilar lymphadenopathy is noted (red arrows). Diffuse bilateral pulmonary micronodules (white arrows) in a perilymphatic distribution are also noted.
Hematoxylin & eosin staining of transbronchial lung biopsy (low power). Non-necrotizing granulomas (black arrows) are formed by histiocytes, lymphocytes, and multinucleated giant cells with bronchial epithelial cells at the top.
The finding of a pneumothorax led to chest tube placement through the left chest wall to allow re-expansion of the left lung. Subsequently, the patient’s work of breathing improved, and her oxygen saturation eventually increased to 100% on room air. However, the patient’s abnormal calcium studies and imaging findings suggested a novel diagnosis of an underlying sarcoid disease which instigated the pneumothorax. To confirm this suspicion, an endobronchial ultrasound bronchoscopy was performed to garner biopsy-level evidence of sarcoidosis. Diffuse lymphadenopathy was visualized, and pathological analysis of the biopsies revealed non-caseating granulomas with no evidence of dysplasia (Figure 3), thus implicating sarcoidosis as the most likely etiology of her presentation rather than lymphoma or metastatic disease. Subsequent PFT demonstrated a forced expiratory volume/forced vital capacity equal to 34% of the predicted value and a diffusing capacity of the lungs for carbon monoxide equal to 64% of the predicted value, consistent with a severe obstructive ventilatory defect.
The combination of a spontaneous pneumothorax, hypercalcemia, and the recent history of a ureteral stone, in the setting of confirmed sarcoid disease, led us to initiate an oral prednisone course starting at 20 mg daily for 2 weeks, then 10 mg daily for 2 weeks. At the 1-month follow-up, the patient reported significant improvement in her shortness of breath and exercise tolerance. In addition, follow-up serum testing revealed an improvement in her serum calcium to 9.8 ng/dl. Her sarcoidosis remained in remission with no further complications at the time of procurement of the manuscript.
Discussion and Review
Our case involves the finding of a spontaneous pneumothorax in a 60-year-old Black woman with biopsy-proven sarcoidosis. Sarcoidosis is an inflammatory, multisystemic disorder of unknown etiology. In combination with genetic factors, it is thought that there is an environmental trigger of the disease in susceptible individuals that results in the characteristic non-caseating granulomatous inflammation with a predominance of T-helper cell lymphocytes [8]. Macrophages autonomously express the enzyme 1-alpha-hydroxylase, resulting in the overproduction of 1,25-OH-vitamin D, and thus leading to hypercalcemia and hypercalciuria [9]. Pulmonary manifestations are seen in more than 90% of cases, and typical symptoms include cough and dyspnea [10]. The disease can affect any area of the respiratory tract, from the oral mucosa and vocal cords to the terminal bronchioles and visceral pleura [11].
Diagnosis is made through a combination of findings from imaging, PFTs, and bronchoscopy with biopsy. Classic findings on chest CT are bilateral hilar lymphadenopathy and perilymphatic nodules along interlobular septa [12]. However, the results of these modalities can be discordant. The anatomic abnormalities (e.g., extrinsic compression, luminal stenosis, mucosal involvement, or airway distortion) caused by the granulomatous inflammation, even when severe on imaging, may or may not result in symptoms or PFT changes [13,14]. Also, renal involvement is likely underreported, and the specific manifestations are not elucidated [9].
Pneumothorax is a rare manifestation of sarcoidosis, thought to occur in 2% to 4% of patients [2-4]. The scant literature on this topic reports that pneumothorax is typically a manifestation of late sarcoid disease [2]. However, it can be the presenting sign of sarcoidosis or occur early in the disease course [5,6,15]. Recurrent or bilateral pneumothorax has also been reported [6,16,17].
The etiology of pneumothorax in sarcoidosis appears to be secondary to the rupture of a subpleural bulla or necrosis of a subpleural granuloma [2,3,5,18]. The exact mechanism of bullae development in sarcoidosis remains unclear but it is likely due to a combination of several proposed mechanisms. Bronchiolar obstruction by endobronchial lesion involvement leads to peripheral air-trapping and distension of airspaces which are prone to rupture [1,19,20]. Retraction mechanisms such as regression or fibrosis of the surrounding diseased pulmonary parenchyma may also lead to airspace enlargement and the formation of bullae [19,21]. It is also possible that cytokine release by granulomas drives alveolitis and air-trapping adjacent to diseased regions [19,22]. Bullae rupture is likely instigated by overdistension of the airspace or with increased exertional pressure, such as during exercise or with coughing.
The age of diagnosis of bullous sarcoidosis ranges from 21 to 67 years of age, and these changes in sarcoidosis are usually reported within 3-to-4 years of symptom presentation [22]. Our patient uniquely experienced a quick onset of pulmonary sarcoid disease leading to pneumothorax despite having no known prior history of such disease. A ruptured bulla may have caused the pneumothorax, but chest imaging did not reveal any other bulla in both lungs. The likelihood is higher that necrosis of a subpleural granuloma may have led to the development of the pneumothorax. Our patient’s presentation suggests that these pulmonary sequelae may occur early in the disease course and may lead to rapid deterioration of pulmonary function if the sarcoid disease is not appropriately treated.
Most authors agree that corticosteroid therapy for pulmonary sarcoidosis is indicated when severe functional impairment is present or significant deterioration is noted [1]. Oral prednisone improves pulmonary lesions and lung function and may even prevent recurrent pneumothorax [6]. Discontinuation of prednisone therapy may cause sarcoid disease remission, thus instigating recurrent pneumothorax [6]. However, Froudarakis et al. [2] did not observe a recurrence of pneumothorax in the absence of systemic therapy, concluding that steroids may be only helpful for patients with impaired lung function. The pneumothorax is managed with chest tube insertion until the afflicted lung demonstrates appropriate function.
Our patient’s PFT finding of severe obstructive ventilatory defect suggests a rare manifestation of pulmonary sarcoidosis. Sarcoidosis is generally regarded as a restrictive airway disease, but it can cause obstructive disease because it affects the entire respiratory tree [14,23]. According to one retrospective analysis of 164 patients presenting with newly diagnosed pulmonary sarcoidosis, the percentage of patients presenting with an obstructive lung defect was 23.2% [24]. Moreover, there were no differences in smoking status or diagnosis of asthma or chronic obstructive pulmonary disease between the obstructive and restrictive groups [24]. Patients with obstructive pulmonary sarcoid disease patterns were significantly older than those with restrictive patterns [24]. Obstructive airway disease is more common in African American patients with sarcoidosis than white European or American and Japanese patients [25].
It is essential to recognize that Black patients, especially Black females, have been found to have the worst prognosis and have been shown to have more rapidly progressing pulmonary disease [26]. They also historically tend to have obstructive findings on PFTs [25], though there is evidence suggesting this is not the case [24]. However, to the best of our knowledge, there is no literature reporting the difference in the prevalence of pneumothorax in sarcoid disease amongst different races. Given that Black patients may have more severe pulmonary disease, it can be postulated that they are more likely to experience pneumothoraxes, and further research is needed to explore this topic.
Conclusion
In summation, this interesting case suggests that patients with sarcoidosis may develop a pneumothorax early in the disease course. A pneumothorax may even be the first pulmonary sequela of sarcoidosis. A purely obstructive ventilatory defect without restriction does not preclude the development of pneumothorax. Chest tube placement in the afflicted lung(s) and prompt steroid therapy should be considered in patients with sarcoidosis presenting with pneumothorax.