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.