ChILD Associated with Inborn Errors of Immunity
Historically, single-gene or “monogenic” immune system disorders were referred to as primary immune deficiencies, implying susceptibility to infection as a main clinical feature. However, such genetic defects can also drive autoimmunity, lymphoproliferation, and autoinflammation. To capture the broader immune dysregulation associated with these disorders, the currently used term is “inborn errors of immunity” (IEI) [11-15]. There are ten groups of IEIs based on the International Union of Immunological Societies Expert Report, including “diseases of immune dysregulation” and “autoinflammatory disorders [11]. The immune dysregulation (often marked by polyautoimmunity) and autoinflammatory IEIs can predispose to pulmonary complications such as ILD [13-15].
[13]. With greater implementation of clinical genetic testing and confirmatory functional testing of new variants, variants in nearly 500 genes have been identified as causing IEIs [11].Due to strong genetic drivers, ILD secondary to IEIs may present earlier than ILD secondary to acquired systemic autoimmune and autoinflammatory diseases. In fact, pulmonary features may present as the earliest manifestation of an IEI. Thus, pulmonologists may be the first clinician to meet a patient with a yet undiagnosed IEI. Patients with known IEIs are also often referred to pulmonologists for screening or treatment of pulmonary complications. However, it is important to recognize that even monogenic disorders can have incomplete penetrance and variable expressivity based on environmental factors (toxins/infections), resulting in a spectrum of disease severity.
IEIs can present with infectious and non-infectious pulmonary complications. IEIs with predominant features of immune deficiency present most commonly with upper and lower infections, including bronchitis, pneumonia, and complicated pneumonia or with bronchiectasis secondary to recurrent infection [16]. Specific non-infectious pulmonary complications include structural changes (bronchiectasis, small airway disease, pneumatoceles and other parenchymal changes), inflammatory lung disease (interstitial lung disease and granulomatous lung disease), and tumors (lymphoreticular and solid lung tumors) [16]. The pathology of pulmonary complications of IEIs is characterized by patchy or diffuse inflammation, which can occur in multiple compartments of the lung, including the alveolar, interstitial, vascular, pleural or airway compartments [17], with most common patterns summarized in Table 1.
For non-infectious pulmonary complications, understanding the immune and genetic mechanisms underpinning these disorders can assist with diagnosis of ILD [17]. For example, some antibody and combined immunodeficiencies lead to immune dysregulation and ILD when there is some preserved T cell function but loss of T cell immune tolerance. Additionally, lack of B-cell regulation can lead to neutrophil accumulation and activation of lung myofibroblasts causing fibrosis [18]. Patients with congenital defects of phagocytosis, such as in chronic granulomatous disease (CGD) can develop non-infectious pulmonary granulomatous disease [19]. If alveolar macrophages are affected secondary to immune mediated macrophage dysfunction this can lead to pulmonary alveolar proteinosis [20]. In any of these disorders, the lung inflammation can eventually lead to fibrosis if left untreated.
Insight to pathophysiology can also assist with treatment. In patients with common variable immune deficiency (CVID), ILD can be the first sign of the presence of IEI. The ILD in CVID tends to have a pathologic pattern in the spectrum of GL-ILD, which includes granulomatous lymphocytic interstitial lung disease (GL-ILD), lymphocytic interstitial pneumonitis (LIP) and follicular bronchiolitis (FB) – or an overlap. ILD can be the first manifestation of CVID. CVID and GL-ILD may suggest more specific treatment approaches such as replacing immune globulin and treating with azathioprine and rituximab [21] unless a more specific IEI is identified.
For IEIs with broader immune dysregulation associated with ILD, we have found it helpful to group them into the following categories: STAT gain-of-function disorders (e.g., STAT1, STAT2, and STAT3 gain-of-function (GOF)), IPEX and IPEX-like syndromes (CTLA-4 Haploinsufficiency, LRBA deficiency), and those associated with autoinflammation driven vasculitis (COPA Syndrome, Sting-Associated Vasculopathy of Infancy (SAVI) [22-24], and Aicardi-Goutières Syndrome (AGS)). While this is not a comprehensive list, due to the mostly autosomal dominant or X-linked inheritance patterns, and wide recognition of these IEI in the literature, they may be relatively more commonly encountered/recognized. Importantly, these diseases often have systemic involvement – e.g. in LRBA deficiency, autoimmunity in any tissue is possible due to a defect in the CTLA-4 coinhibitory pathway. Abatacept can thus be used as a targeted therapy for both pulmonary and extra-pulmonary manifestations.
The above examples highlight a complementary approach to thinking about pulmonary disease associated with IEIs, which is to focus on the underlying mechanism of immune dysregulation driving lung disease, taking into consideration systemic involvement so that therapies chosen benefit more than one organ system.