In This Case Study
- A 75-year-old woman was admitted for dyspnea and cachexia stemming from severe and progressive allergic bronchopulmonary aspergillosis (ABPA) and bronchiectasis
- The patient had a history of recurrent respiratory problems that did not improve despite multiple courses of itraconazole and steroids in the years leading up to her admission
- The Pathways Consult Service at Massachusetts General Hospital took up the case and sought to determine whether the heterogeneous anatomic nature of her lung damage might provide insight into the underlying mechanisms driving her disease
A 75 year-old woman was admitted for dyspnea and cachexia stemming from severe and progressive allergic bronchopulmonary aspergillosis (ABPA) and bronchiectasis. First diagnosed with asthma in her thirties, the patient was well until she developed recurrent respiratory symptoms in her 60s, leading to a diagnosis of ABPA and bronchiectasis at age 65. Despite multiple courses of itraconazole and steroids, her pulmonary disease progressed with recurrent respiratory infections that increased in frequency after she developed influenza six years ago. In the months prior to admission, she required six liters of oxygen by nasal cannula and her weight dropped to under 100 pounds. A chest CT demonstrated tree-in-bud nodules, bronchiectasis and bronchial wall thickening in the right middle lobe and lingula with relative preservation of other areas of the lung.
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- Why did she have such an aggressive and progressive course of ABPA?
- Can the heterogeneous anatomic nature of her lung damage provide insight into the underlying mechanisms driving her disease?
Background and Diagnosis
ABPA is defined by an allergic immune response to the presence of Aspergillus fumigatus in the lung, leading to parenchymal and bronchial inflammation and damage. The clinical course of ABPA is highly variable with some patients entering remission and others progressing to severe lung damage and respiratory failure, as reported in Proceedings of the American Thoracic Society. The risk of ABPA in patients with asthma is low and appears to be driven by underlying deficiencies in immune function, either in the immune cell barrier or in the function of primary immune cells, according to findings published in Chest. Patients with ABPA appear to have a pronounced imbalance of Th2 to Th1 response, which may lead to decreased clearance and downstream immune activation including IL4 release resulting in IgE production, mast cell activation and eosinophil recruitment as well as subsequent degranulation, as reported in Immunology and Allergy Clinics of North America. However, the relationship between these or other factors and the variable clinical course and anatomic distribution of ABPA remains poorly understood, raising the possibility that other processes may be contributing to this patient's presentation.
A primary driver of tissue destruction in bronchiectasis is thought to be neutrophil elastase, which degrades the elastin fibers that form much of the structure of the lung parenchyma (Respiratory Research). Elastase levels correlate clinically with bronchiectasis exacerbation and progression, according to findings published in Mediators of Inflammation and American Journal of Respiratory and Critical Care Medicine. At the same time, the oxidative burst produced by neutrophils that results in elastase release is one of the primary methods by which the immune system clears pathogenic organisms (Free Radical Biology and Medicine). If the patient has a defect in the ability of her neutrophils to destroy colonizing pathogens, her neutrophils may experience continued, unchecked stimulation in the continued presence of the pathogens, resulting in excess elastase release and subsequent tissue damage. This possibility could also explain why most of the patient's documented respiratory pathogens are either catalase-positive (Aspergillus, Pseudomonas, Nocardia, Pasteurella, Stenotrophomonas) or intracellular (Mycobacterium), suggesting some degree of inherent resistance to the reactive oxygen species (ROS) used in neutrophilic killing.
While a defect in neutrophil function could explain the patient's severe course and recurrent infections, the heterogeneous anatomic pattern of lung involvement is difficult to attribute to an underlying systemic immune defect. Such heterogeneity suggests, instead, that local mechanisms must also be at play. Exposure to inflammatory insults can lead to chromatin changes in skin epithelial stem cells, opening regulatory regions of pro-inflammatory genes and therefore increasing their transcription. As reported in Nature, this epigenetic change acts as a biological memory, making cells in the region of exposure more inclined towards inflammation in the presence of future insults. If an analogous response occurs in bronchial airway stem cells, this mechanism could theoretically lead subsections of the lung parenchyma to acquire epigenetic memory of previous insults, and become hypersensitive to future stimuli, resulting in localized hyper-inflammation and, ultimately, bronchiectatic destruction.
Furthermore, this alteration in chromatin configuration can be inherited by daughter cells, perpetuating the regional memory and inflammatory predisposition. Such a mechanism could explain both the heterogeneous involvement of the lung tissue and the downward spiral of respiratory function that the patient experienced. Thus, the Pathways Consult Service hypothesized that the patient's severe but heterogeneous course of ABPA could be attributed to an underlying neutrophil defect that led to ineffective clearance of bacteria and lung tissue damage, and consequent epigenetic changes in lung epithelial stem cells perpetuate a localized exaggerated inflammatory response to subsequent insults.
Summary and Future Steps
It is unknown why some patients develop progressive and sometimes localized lung destruction or fibrosis in the face of infectious or toxic exposures, while others heal. It is presumed in some cases to reflect attributes of immune susceptibility, here perhaps due to defective neutrophil action. In the skin, an innate immune response can amplify and perpetuate localized destruction via epigenetic memory of skin stem cells. We have no direct evidence that epithelial stem cells of the lung have the same epigenetic memory for inflammation as skin epithelial cells do, but this is a testable hypothesis using stem cells obtained from bronchoalveolar lavage of preserved and damaged lungs. In principle, such persistent localized gene regulation might be therapeutically targetable.
While this research is unlikely to result in new therapies in time to benefit this patient given the severity of her disease, limiting blood flow to the most affected lung areas and maximizing caloric intake may offer some limited clinical value.
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