Genetic diagnosis of immune dysregulation can lead to targeted therapy for interstitial lung disease: A case series and single center approach

Abstract

In recent years, a growing number of monogenic disorders have been described that are characterized by immune dysregulation. A subset of these “primary immune regulatory disorders” can cause severe interstitial lung disease, often recognized in late childhood or adolescence. Patients presenting to pulmonary clinic may have long and complex medical histories, but lack a unifying genetic diagnosis. It is crucial for pulmonologists to recognize features suggestive of multisystem immune dysregulation and to initiate genetic workup, since targeted therapies based on underlying genetics may halt or even reverse pulmonary disease progression. Through such an approach, our center has been able to diagnose and treat a cohort of patients with interstitial lung disease from gene defects that affect immune regulation. Here we present representative cases related to pathogenic variants in three distinct pathways and summarize disease manifestations and treatment approaches. We conclude with a discussion of our perspective on the outstanding challenges for diagnosing and managing these complex life-threatening and chronic disorders.

1 |. INTRODUCTION

Over the past two decades, a growing number of monogenic disorders have been described that are characterized by systemic immune dysregulation. In these disorders, there are pathogenic variants in genes encoding proteins that play a critical role in orchestrating a robust, but self-limited, response to pathogens and environmental stressors. When this fine control is disrupted by a dysfunctional gene variant, there can be exaggerated inflammation, loss of tolerance, and decreased ability to fight infections. As a result, patients develop complex diseases with combined features of autoimmunity, autoinflammation, and immune deficiency. To capture the monogenic nature and broad immunologic sequelae of these conditions, they are referred to as primary immune regulatory disorders (PIRD).^1,2

While only a subset of primary immune regulatory disorders (PIRD) are strongly associated with pulmonary features, they comprise a large percentage of patients with childhood interstitial lung disease presenting outside of infancy.^3–5 Although respiratory symptoms may present severely and acutely, these symptoms often develop insidiously, presenting a diagnostic challenge for clinicians. The presence of extrapulmonary symptoms that evolve and progress over time serve as an important clue to underlying immune dysregulation. Recognition facilitates appropriate referral to additional specialists and genetic testing.

Identification of an underlying pathogenic gene variant can have critical implications for clinical management given that the affected molecular pathway may suggest a targeted therapy.⁶ We have observed multiple patients with identified PIRD experience dramatic improvements in their respiratory symptoms, pulmonary function testing, and radiographic disease burden following initiation of targeted therapies.

In our experience, PIRD associated with pulmonary manifestations are due to defects in cytokine signaling, nucleic acid sensing, and/or T cell activation. Such disorders are exemplified by gene variants in the Signal Transducer and Activator of Transcription (STAT), STimulator of Interferon Genes (STING), or Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) pathways, respectively. Below, we feature a representative case of a disease affecting each of these molecular pathways. Some of the patients with these pathogenic variants have been previously published in large summary cohorts; however, we will focus on the detailed course of the patients, the rationale behind their eventual genetic workup, and the outcomes of targeted therapy.^7–9 We provide a more comprehensive summary of PIRD involving these pathways in Table 1.^10–13 We conclude with our perspective on how to screen, diagnose, and manage patients with complex PIRD using a multidisciplinary team of specialists.

TABLE 1.

Characteristics of PIRD with features of interstitial lung disease

Syndrome	Inheritance	Median onset	Pulmonary features	Extrapulmonary features	Targeted therapy
STAT-related
STAT1 GOF	Autosomal dominant GOF variants in STAT1	CMC by age 1	Recurrent LRI Bronchiolar dilation; peribronchiolar inflammation Bronchiectasis	CMC, bacterial & viral infections, autoimmunity, growth failure, aneurysms, carcinoma	JAK inhibitor
STAT3 GOF	Autosomal dominant GOF variants in STAT3	Early childhood	Recurrent respiratory tract infection LIP GGO with interlobular septal thickening	CVID, autoimmune cytopenias, enteropathy, endocrinopathy, growth failure, lymphoproliferation, infections	JAK inhibitor IL-6 blockade
STING-related
COPA syndrome	Autosomal dominant negative variants in COPA Incomplete penetrance (possibly higher in women)	Hemorrhagic lung features may present in childhood ILD, renal and arthritic disease in adolescence	Diffuse alveolar hemorrhage and/or ILD LIP or follicular bronchitis GGO with cyst formation	Polyarthritis (RF + 50%), renal disease	Potentially JAK inhibitor
SAVI	Autosomal dominant GOF variants in TMEM173 (encodes STING)	Vascular skin findings may be present in first months of life	ILD Scattered lymphocytic inflammatory infiltrate, emphysema, & fibrosis GGO with cyst formation	Telangiectatic, blistering rashes on exposed areas, digital resorption, arthritis, myositis, CNS disease, kidney disease, thyroiditis	JAK inhibitor
CTLA-4-related
CTLA-4 haploinsufficiency	Autosomal dominant LOF variants in CTLA-4 Incomplete penetrance	Early childhood Clinical ILD in adolescence	Recurrent URI and LRI GL-ILD, fibrosis GGO	CVID, lymphoproliferation, enteropathy, autoimmune cytopenias, endocrinopathy, neuropathy, malignancy, infections	CTLA-4 Ig
LRBA deficiency	Autosomal recessive variants in LRBA Complete penetrance	Early childhood Clinical ILD in adolescence	Recurrent URI and LRI GL-ILD, fibrosis GGO, pulmonary nodules, mediastinal adenopathy	CVID, lymphoproliferation, enteropathy, autoimmune cytopenias, endocrinopathy, neuropathy, malignancy, infections	CTLA-4 Ig

Note: There are numerous STAT family proteins, not all of which are associated with defined syndromes; STAT2 GOF has recently been described in a single case report. Pulmonary features were present.

Abbreviations: CMC, chronic mucocutaneous candidiasis; CTLA, cytotoxic T‐lymphocyte associated; CVID, common variable immunodeficiency; GGO, ground glass opacities; GL‐ILD, granulomatous-lymphocytic ILD; GOF, gain of function; ILD, interstitial lung disease; LIP, lymphocytic interstitial pneumonia; LOF, loss of function; LRI, lower respiratory infection; PIRD, primary immune regulatory disorders; STAT, signal transducer and activator of transcription; URI, upper respiratory infection.

2 |. CLINICAL CASES

2.1 |. Case 1

Patient A is a 23-year-old female who presented at age 6 with a history of immune thrombocytopenic purpura (ITP) and lymphadenopathy. She was treated with intravenous immunoglobulin (IVIG) with good response and resolution of her ITP within 18 months of diagnosis. During her initial immune work-up, immunoglobulins, T/B/NK cell subsets, and vaccine titers were unremarkable. However, she later developed hypogammaglobulinemia and loss of protective vaccine titers, leading to a diagnosis of common variable immunodeficiency (CVID) and reinitiation of IVIG therapy.

By age 9, she developed diarrhea from microscopic colitis, a diagnosis shared by her sister. Her appetite was poor, and her weight dropped to <5th percentile. She was started on enteral budesonide and oral mesalamine, with improvement in her gastrointestinal symptoms and weight gain.

At age 14, she developed severe transfusion-dependent anemia and was diagnosed with pure red cell aplasia. There was no improvement with systemic corticosteroids or rituximab, but she responded well to cyclosporine. For the next several years, she continued subcutaneous immunoglobulin, enteral budesonide, mesalamine, and cyclosporine. She eventually developed renal toxicity and gingival hyperplasia from cyclosporine.

The patient presented to our pulmonary clinic at age 20 years for evaluation of 2 weeks of new, wet cough in the setting of chronic reticulonodular lung changes on chest computed tomography (CT) (lack of pulmonary follow-up in prior years). Bronchiolar lavage fluid grew Haemophilus influenzae. Repeat chest CT after a course of antibiotics showed bronchiectasis, worsening nodules, and tree-in-bud and ground glass opacification (GGO) in both lungs. Lung biopsy revealed follicular bronchiolitis, diffuse interstitial lymphoid hyperplasia, nonnecrotizing epithelioid granulomas, and alveolar septal fibrosis.

Given the progression of her disease, as well as her extrapulmonary inflammatory symptoms, an immune genetics panel was sent and revealed a suspected pathogenic gain-of-function (GOF) variant in STAT3 (c.307C > T; R103W), which was not found in the Genome Aggregation Database (gnomAD) that reports the frequencies of thousands of allele variants in the healthy population.¹⁴ The Combined Annotation Dependent Depletion score, a metric used to predict the likely pathogenicity of a mutation was markedly elevated at 33.¹⁵ STAT3 is a transcription factor downstream of multiple cytokines, including interleukin-6 (IL-6). She was started on the janus kinase (JAK) inhibitor, tofacitinib, at 5 mg daily, which led to clinical improvement in her respiratory symptoms. Baseline pulmonary function testing (PFTs) before initiation of tofacitinib demonstrated a severe diffusion defect, but no restrictive or obstructive airflow limitation (FVC 92%, FEV1 99%, RV/TLC 26%, TLC 97%, DLCO 48%, and KCO 52% predicted). Partial improvement was observed by 6 months of therapy and substantial improvement after 2 years of treatment (FVC 110%, FEV1 114%, RV/TLC 24%, TLC 117%, DLCO 76%, and KCO 72%). This was accompanied by interval improvement of the ground glass opacification and bronchiectasis (Figure 1). After JAK inhibitor therapy she was able to discontinue cyclosporine while maintaining stable blood counts. An attempt to wean her enteral budesonide resulted in rebound diarrhea, which resolved with an increase of her tofacitinib dose to 10 mg twice daily. She was subsequently able to wean down to 5 mg twice daily without recurrence of symptoms.

FIGURE 1.

Chest computed tomography (CT) imaging before and after starting tofacitinib treatment. (A) Bilateral pulmonary nodules and ground glass opacity (GGO) in all lobes with airway thickening and bronchiectasis. (B) Significantly improved GGO, nodular opacities, and airway abnormalities 6 months after treatment initiation.

Given the patient’s disease severity, the possibility of stem cell transplantation was discussed with the family at several points in her course. Ultimately, this was deferred after her STAT3 GOF diagnosis due to excellent clinical response to targeted therapy.

Patient A represents a classic case of STAT3 GOF disease, first recognized in 2014 and 2015.¹⁶ Gene variants in STAT3 can either lead to GOF or loss of function (LOF), with the latter resulting in an entirely different illness (hyper-IgE syndrome).¹⁷ Binding of IL-6 to its receptor results in recruitment and activation of JAK signal transduction factors, which subsequently induce STAT3 homodimerization and phosphorylation (Figure 2). In STAT3 GOF, there is constitutive pathway activation. While the molecular pathophysiology of these GOF variants is not fully understood, increased inflammatory cytokine signaling and reduced numbers and function of regulatory T cells are contributing factors.¹⁶ In a recent series describing 42 STAT3 GOF cases, the most common findings were autoimmune cytopenias (83%; 35/42), hypogammaglobulinemia (64%; 18/28 reported), lymphoproliferation (64%; 27/42), enteropathy (57%; 24/42), and endocrinopathy (50%; 21/42). Thirty-six percent of patients (15/42) had lymphocyte predominant interstitial lung disease.¹⁸ As seen with our patient, symptomatic pulmonary manifestations (most often lymphocytic interstitial pneumonitis) were delayed compared with other symptoms, with a median age of pulmonary symptom onset of 16 years. Therapies used have included hematopoietic stem cell transplantation, IL-6 blockade, and JAK inhibition. While IL-6 and JAK inhibitors are noncurative and have possible adverse effects,¹¹ in the aforementioned analysis of 42 patients, only 1/5 patients that received a stem cell transplant survived.¹⁸ Deaths were due to graft-vs-host-disease and adenovirus, systemic adenovirus infection, adenovirus and post-transplant hemophagocytic lymphohistiocytosis, and multiorgan failure. The one patient that survived is now reported to be disease free. Further data regarding genotype–phenotype correlations may help to triage who would most likely benefit from transplant versus long-term targeted therapy.

FIGURE 2.

Signal transducer and activator of transcription (STAT) gain of function (GOF). Under normal circumstances, the receptors for interferon gamma (IFN-γ) and interleukin-6 (IL-6) must bind to their respective cytokines for janus kinase (JAK) to phosphorylate STAT, which then travels to the nucleus to mediate a transcriptional program. In STAT1 and STAT3 GOF disease, however, there is constitutive signaling regardless of cytokine binding. JAK inhibitors directly inhibit this receptor complex. Image created on BioRender.com.

2.2 |. Case 2

Patient B is a 22-year-old male who presented to our rheumatology clinic at age 6 with a history of polyarticular arthritis, initially treated with methotrexate, and erythematous plaques on his knees. Exam showed swelling of multiple proximal interphalangeal joints of his hands and feet and reduced grip strength. Labs were notable for positive rheumatoid factor (RF) and cyclic citrullinated peptide antibodies with mildly elevated erythrocyte sedimentation rate and C-reactive protein. Remarkably, he had a family history of a father and paternal aunt with similar rashes and joint pain, who both later developed lung disease and were presumptively diagnosed with sarcoidosis. Both relatives passed away due to complications of their disease; details are largely unknown, although no biopsy confirmation of sarcoidosis was found. Given this history, specific gene testing for pathogenic variants in NOD2/CARD15 (observed in Blau syndrome, a familial form of sarcoidosis) was sent and was negative.

At age 12 years, he presented with eyelid erythema and scaling accompanied with persistent conjunctival injection. He was diagnosed with vernal conjunctivitis by an ophthalmologist, and he was treated with steroid eye drops. His skin findings, including eyelid lesions, were diagnosed as atopic dermatitis. He also had severe allergic rhinitis for which he received allergen immunotherapy. In the interim, his joint symptoms came under control with the addition of adalimumab (TNF-α inhibitor) to his methotrexate.

At age 14 years, he developed dyspnea with emphysematous and cystic changes on chest CT leading to pulmonary referral. His initial PFTs showed FVC 74%, FEV1 76%, TLC 74%, DLCO 49%, and KCO 56% predicted. Lung biopsy revealed chronic, marked lymphoplasmacytic inflammation. Adalimumab was discontinued to determine if there was a component of medication-induced interstitial lung disease, but this resulted in no improvement in pulmonary symptoms or function. He was started on azathioprine 75 mg daily and prednisone 40 mg daily with only modest improvement in respiratory symptoms. Meanwhile, he developed violaceous plaques and painful, punched-out ulcerations over the dorsal feet (Figure 3). Skin biopsy showed necrotizing vasculitis with neutrophilic and eosinophilic infiltrates and prominent leukocytoclasia.

FIGURE 3.

Development of digital ulceration that worsened in cold weather.

Given his multiple systemic inflammatory symptoms and unusual family history, whole exome sequencing was performed and revealed a heterozygous, previously published variant in the TMEM173 gene (c.463G > A; V155M¹⁹), encoding the cytosolic DNA sensor STING. This confirmed his disease as STING-associated vasculopathy with onset in infancy (SAVI). He was started on tofacitinib 5 mg twice daily and was able to slowly wean off systemic corticosteroids. Before initiation of tofacitinib, lung function demonstrated mild restrictive and obstructive airflow limitation, and a severe diffusion defect (FVC 67%, FEV1 63%, TLC 71%, DLCO 37%, and KCO 48% predicted). After 6 months of JAK inhibitor therapy, these restrictive, obstructive, and diffusion defects all improved (FVC 82%, FEV1 83%, TLC 87%, and DLCO 58%, and KCO 63% predicted). His inflammatory arthritis, cutaneous ulcerations, and eye symptoms improved, and, interestingly, so did his atopic features. He has since been able to discontinue all other systemic immunosuppression.

Patient B ultimately displayed all the features of SAVI, although the onset of vascular and pulmonary manifestations were not as prominent in infancy or childhood compared with the published description of SAVI patient cohorts.^20,21 Mechanistically, SAVI is due to GOF variants in TMEM173, the gene encoding STING, a vital part of the DNA-sensing antiviral response. Normally, in response to the detection of cytosolic DNA (e.g. from viruses) by the cytosolic enzyme cyclic-GMP-AMP-synthase (cGAS), cyclic GAMP (cGAMP) is synthesized from GTP and ATP. When cGAMP binds to STING, it traffics from the endoplasmic reticulum to the Golgi apparatus where it becomes activated and recruits interferon regulatory factor 3 (IRF3) to initiate an interferon response in addition to other pathways that participate in the antiviral response (e.g., autophagy, inflammasome activation²²). In SAVI, there is constitutive trafficking of STING, leading to chronic overproduction of interferons and immune dysregulation (Figure 4). Recently, another PIRD called COPA syndrome has been linked to this same pathway, whereby loss-of-function variants in COPA, which encodes COPα, a protein subunit of the COPI trafficking complex, prevent STING from returning to the endoplasmic reticulum.^23,24 The outcome is a similar downstream effect on type I interferon overproduction, dysregulated autophagy, as well as increased endoplasmic reticulum stress.²⁵ As with SAVI, pulmonary manifestations are a prominent feature of COPA syndrome. Due to the rarity and recent description of these conditions, literature on treatment modalities is limited. However, the largest case series for SAVI suggest that JAK inhibitors, which block interferon signaling, may be efficacious, as was seen in our patient.^21,26–28

FIGURE 4.

Stimulator of interferon genes (STING) pathway defects. Under normal circumstances, cytosolic DNA (such as from invading viruses) allosterically activates the cGAS enzyme (not shown) to generate cGAMP from GTP and ATP. cGAMP binds to STING, which then transports from the endoplasmic reticulum (ER) to the Golgi apparatus through the COPII transport complex. Activated STING leads to production of interferons (through IRF3) and enhanced autophagy. STING is subsequently recycled back to the ER through the COPI complex. In SAVI, gain of function (GOF) variants in TMEM173 (encoding STING) result in constitutive STING signaling. In COPA syndrome, STING is appropriately activated by cGAMP; however, STING becomes trapped in the Golgi apparatus due to variants in COPA that inactivate the COPI complex. In both scenarios, there is increased autophagy and type I interferon signaling. Janus kinase (JAK) inhibitors specifically target the IFN signaling. Image created on BioRender.com.

2.3 |. Case 3

Patient C presented to our hospital at 13 years of age after extensive workup and care in Saudi Arabia. He had an unremarkable childhood until age 7 years when he developed varicella infection despite vaccination. Over the next 2 years, he had several episodes of pneumonia. During an episode of fever and malaise, he was found to have marked hepatosplenomegaly (Figure 5A), which prompted an oncologic workup. Bone marrow analysis showed normal hematopoiesis without infiltration. Immunologic workup revealed hypogammaglobulinemia and absence of titers to childhood vaccines. He was diagnosed with CVID and started on IVIG therapy and trimethoprim-sulfamethoxazole prophylaxis.

FIGURE 5.

Baseline imaging after transfer to our center. (A) Massive hepatosplenomegaly with spleen measuring 22.6 cm. (B) Bilateral patchy ground glass opacification (GGO) and consolidation consistent with inflammatory/infectious process.

At 12 years of age, he developed recurrent upper respiratory infections, pneumonia, and ITP-associated epistaxis. He was diagnosed with cytomegalovirus (CMV) viremia and was treated with a course of ganciclovir. He developed worsening abdominal pain, diarrhea, and overall malaise. Concurrent to his clinical decline, there was an unsuccessful search for a stem cell donor, leading to transfer of care to our facility.

On initial evaluation in our immunology clinic, at age 13 years, the patient was acutely ill appearing. Chest CT showed diffuse GGO, nodularity, and extensive lymphadenopathy, as well as areas of active pneumonia in multiple lung lobes with H. influenzae growing from bronchiolar lavage sample (Figure 5B). Lung biopsy showed interstitial lymphoid hyperplasia and nonnecrotizing granulomatous inflammation, supportive of a diagnosis of granulomatous-lymphocytic interstitial lung disease (GL-ILD). Immune suppression was considered but deferred until his pulmonary infection was treated.

Subsequent whole exome sequencing revealed a heterozygous variant in CTLA-4 (c.361delG p.A121fs) leading to a frameshift and early stop codon. This led to a diagnosis of CTLA-4 haploinsufficiency. The CTLA-4 gene encodes the CTLA-4 protein, which is an inhibitory receptor analog for the T cell costimulatory molecule CD28. Treatment with abatacept, a chimeric protein of the extracellular domain of CLTA-4 and human IgG1, resulted in improved energy level, appetite, and respiratory function. His PFTs at treatment initiation (following resolution of his pneumonia) were FVC 62%, FEV1 63%, TLC 66%, DLCO 56%, and KCO 72% predicted. These improved to FVC 76%, FEV1 78%, TLC 81%, DLCO 74%, and KCO 83% predicted by 6 months of treatment.

Because of his recurrent infections, history of interstitial lung disease, and risk of further systemic manifestations, a bone marrow transplant was pursued. He underwent stem cell transplantation with a CMV+ 10/10 HLA-matched unrelated donor following reduced intensity conditioning (not myeloablative). His course was complicated by CMV reactivation, delayed engraftment, and poor graft function, with several episodes of virus-associated respiratory failure. He ultimately died on day +147 post-transplant from respiratory failure and pneumomediastinum.

Patient C demonstrated the most common findings of CTLA-4 haploinsufficiency, including hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenias, and respiratory disease (GL-ILD, bronchiectasis, and recurrent respiratory infections).⁹ CMV and Epstein–Barr virus infections can be particularly problematic, with the former holding true for our patient.⁹ Other common features include endocrinopathy, arthritis, and neurologic disease. Disease results from deficiency in CTLA-4, which serves to suppress T-cell activation. CTLA-4 is constitutively expressed on regulatory T cells, and its loss reduces their ability to promote peripheral tolerance. The overall clinical profile of CTLA-4 haploinsufficiency is similar to a syndrome caused by deficiency in lipopolysaccharide responsive beige-like anchor protein (LRBA). This protein is important for recycling of CTLA-4 to the cell surface (Figure 6).^29,30 While LRBA deficiency is autosomal recessive with complete penetrance, CLTA-4 haploinsufficiency is autosomal dominant with a penetrance of 67%. Our patient had no symptomatic family members although his father was found to have the same pathogenic variant.

FIGURE 6.

CTLA-4 pathway defects. Activation of T cells requires (1) binding of the T-cell receptor (TCR) to an antigen-loaded major histocompatability complex (MHC), and (2) binding of the costimulatory protein CD28 to CD80/86. CTLA-4 is an analog of CD28 that also binds CD80/86 but serves to inhibit T-cell activation. When CTLA-4 signaling is impaired, either by underproduction of CTLA-4 (CTLA-4 haploinsufficiency) or by enhanced CTLA-4 degradation/reduced recycling (LRBA deficiency), there is immune dysregulation from reduced peripheral tolerance. Treatment with CTLA-4-Ig (e.g., abatacept) can supply this missing signal. Image created on BioRender.com.

Best practices for treating CTLA-4 haploinsufficiency are still being developed. In a large study of 173 patients, investigators analyzed the response of various disease complications to treatment with abatacept versus other immune modulatory therapies.³¹ Gastrointestinal and pulmonary disease were very responsive to abatacept (100% and 70%, respectively), whereas neurological symptoms were refractory to most medications, and cytopenias required rituximab and/or systemic corticosteroids. In this same study, 18 patients underwent hematopoietic stem cell transplantation, most often for refractory cytopenias, lymphoproliferation, and/or severe enteropathy. Thirteen of the 18 are currently alive and off all medications (one still on immunoglobulin replacement). Death resulted from graft-versus-host-disease (two patients), respiratory failure, multiorgan failure, and diabetic ketoacidosis (transplant did not cure the diabetes). In a smaller series of eight patients who received 10/10 matched unrelated donor transplants with reduced intensity conditioning (like patient C), transplant-related mortality was 12.5%.³² Given the variable phenotype and severity of CTLA-4 haploinsufficiency, more data will be required to better prognosticate who is most likely to benefit from bone marrow transplantation as well as the optimal conditioning regimen.

3 |. DISCUSSION

Pulmonary disease can cause significant morbidity for patients with PIRD. However, it is often not the first presenting symptom, and as evident from our case vignettes, a patient’s diagnosis may evolve over time as additional organ systems become involved and/or standard therapies lose efficacy. Patient A was initially diagnosed with ITP and later CVID based on lab findings. However, CVID is not a distinct diagnosis but rather a laboratory feature of diverse syndromes, and, over time, a genetic diagnosis was sought to understand and manage the pulmonary, hematologic, and gastrointestinal symptoms. Indeed, in a series of 50 patients with CVID who also had early onset autoimmunity, B cell lymphopenia, or a positive family history of CVID, whole exome sequencing identified a pathogenic gene variant in 30% of cases.⁸ Patient B initially had features that fit with juvenile idiopathic arthritis; however, worsening respiratory and cutaneous symptoms could not be explained by this diagnosis. Patient C’s initial disease manifestations were all explainable by CVID; however, the disease progression despite immunoglobulin therapy and antibiotic prophylaxis was suspicious for immune dysregulation that was not being adequately addressed. As these cases demonstrate, features of immune dysregulation can evolve over time and often include pulmonary disease. Maintaining a high index of suspicion for PIRD in the right clinical context is important for the Pediatric Pulmonologist.

While the diseases outlined by our cases all have autosomal dominant inheritance, family history was only partially helpful for uncovering their diagnoses. This may reflect a selection bias in terms of the type of patients referred to our center. Additionally, many PIRD have only recently been described. Patient B’s strong family history was highly suspicious for an inherited disorder; however, limited records and the fact that his relatives were deceased made finding a genetic cause more challenging. Patient A had a sister with the same variant who had relatively mild gastrointestinal involvement and two other first-degree relatives that were asymptomatic, and Patient C’s father had the same variant but was asymptomatic. Incomplete penetrance and variable expressivity continue to challenge the interpretation of family history.

Given that a lack of symptomatic family members does not exclude an inherited disease, our center has taken the approach of early genetic testing for all patients presenting with features of immune dysregulation. To coordinate this effort, patients are followed by multidisciplinary teams of specialists in close communication with each other, as evidenced by our Multiple Autoimmunity and Immune Deficiency (MAID) Clinic³³ and Autoinflammatory Clinic. This team approach has been critical for both diagnosis and treatment of patients’ underlying conditions. For diagnosis, genetic testing can be sent once to avoid duplication of efforts. Whole exome sequencing is favored by many experts over targeted gene panels, which is supported by a recent cost-effectiveness analysis.^34,35

While patients with suspected immune dysregulation are often referred to our MAID clinic, for others, immune dysregulation has not yet been recognized, and these patients initially present to our general pulmonary clinic. Thus, it is critical for pulmonologists to recognize possible pulmonary and extrapulmonary evidence of immune dysregulation. Because these patients can have a history of recurrent respiratory tract infections and exacerbations as well as postinfectious and inflammatory airway and parenchymal disease, obtaining a detailed past respiratory history is important. Early onset disease that evolves over time and is resistant to standard therapies should prompt evaluation for PIRD. Increasingly, patients may also be identified as having immune dysregulation by other subspecialists and sent to pulmonary clinic for initial screening. While respiratory symptoms may not manifest until adolescence or later, often there are subclinical changes that can be identified by pulmonary function testing and/or high resolution chest CT. As earlier screening becomes more prevalent, this will enable a better sense of the spectrum and onset of pulmonary disease in these disorders.

When evaluating for pulmonary disease in patients with known or suspected immune dysregulation, we cannot stress enough the importance of a full pulmonary evaluation and the role of the Pulmonologist. As lung disease can evolve over time in PIRD, serial evaluation is needed. Pulmonary manifestations can include recurrent upper and lower respiratory tract infections, bronchiectasis or small airway disease, and ILD with pathologic patterns described including follicular bronchiolitis, lymphocytic interstitial pneumonia, granulomatous disease (sarcoid-like), GL ILD, vasculitis/capillaritis, non-specific interstitial pneumonia, and fibrosis. ILD manifestations may occur along a continuum, and there may be more than one pathologic entity present. Because of the broad pulmonary manifestations, pulmonary symptom screening and pulmonary function testing should include a full evaluation for infectious, airway, and interstitial lung disease complications. We recommend comprehensive PFTs including spirometry, lung volumes, diffusion capacity, and 6-min walk testing, as abnormalities may be seen even in those with no or minimal symptoms. If there are pulmonary symptoms, abnormal PFTs, or the presence of a disorder with high risk for pulmonary involvement, imaging is recommended. Often chest X-rays are not sensitive enough to detect the presence of small airway disease, bronchiectasis, or ILD, so chest CT may be necessary. Many patients with PIRD have susceptibility to persistent or unusual infections, so the need for respiratory infectious disease testing and bronchoscopy should be considered in patients with symptoms or findings compatible with infection. Bronchoscopy may also be needed to evaluate for pulmonary hemorrhage. Because there is a spectrum of lung pathologic processes described in these patients, we advocate for lung biopsy to help guide treatment decisions in most of patients with PIRD presenting with abnormal pulmonary findings. If the Pulmonologist is the first consultant seeing a patient suspected to have PIRD, then referral for immunologic evaluation and potential genetic testing should be facilitated.

At our center, we have found that a multidisciplinary team approach has been essential for decisions about initiation of and changes to immune modulatory therapies, since these therapies influence disease control in multiple organ systems. The pulmonologist is essential on this team to help (1) determine initial pulmonary evaluation and required monitoring, (2) define the spectrum and progression of lung disease, and (3) provide pulmonary specific input regarding treatment decisions. Targeted therapy has led to a reduction in immunosuppressive polypharmacy for many of our patients. We are hopeful that as more patients have genetic testing, and as an increased number of small molecule and biologic therapies become available, targeted therapies can be provided to patients earlier in their disease course to improve outcomes. In cases where we have not been able to identify a genetic explanation for clinically identified immune dysregulation, we have explored whether other testing, such as cytokine signatures or the cellular pathology of the disease, suggest specific medications.³⁶ Multidisciplinary discussion remains crucial for these patients.

Currently available targeted therapies are still limited in that that they do not provide a cure, and though they enable patients to be on fewer immunosuppressive agents, they still have associated risks. JAK inhibitors, for example, are known to increase the risk of multiple types of infection. There has also been a recent boxed warning for greater risk of cancer, cardiac events, and venous thromboembolism (seen in adult patients with rheumatoid arthritis). Hence, there are ongoing efforts to identify the best candidates for and approach to bone marrow transplantation. Transplant earlier in life (before significant disease burden) may have better outcomes, and yet, with incomplete penetrance and variable expressivity of many PIRD, it is not yet possible to know who will go on to have severe disease that would warrant the risk of transplant. Transplant related mortality for PIRD is higher than for primary immune deficiencies as there are more adverse graft-host interactions (immunodeficient patients lack robust immune systems, while PIRD patients have highly dysregulated immune systems).³⁷ For this reason, full donor T-cell chimerism may be required to prevent breakthrough symptoms of immune dysregulation from residual host cells, and this may require fully myeloablative regimens that have higher morbidity. Further research is needed to develop prognostic markers and disease-specific transplant protocols for patients with PIRD.^31,38

4 |. CONCLUSION

PIRD are a growing body of monogenic disorders that can cause significant pulmonary morbidity and mortality, usually becoming symptomatic in adolescence. Achieving an accurate diagnosis starts with recognizing features that may suggest immune dysregulation such as CVID, autoimmunity, a positive family history, and/or refractoriness to standard therapies. Once there is a high enough index of suspicion, patients can be referred to centers where multidisciplinary teams can coordinate genetic testing and, ideally, targeted disease management that may control and even reverse disease progression. The care of patients with PIRD will benefit from the development of future multi-institutional collaboration, clinical guidelines, and clinical trials to better understand optimal evaluation and treatment approaches for specific disorders.

Abbreviations:

CTLA-4

cytotoxic T-lymphocyte associated protein 4

CVID

common variable immune deficiency

GGO

ground glass opacity

GL-ILD

granulomatous-lymphocytic interstitial lung disease

GOF

gain of function

ILD

interstitial lung dis

LOF

loss of function

PIRD

primary immune regulatory disorder

STAT

signal transducer and activator of transcription

STING

stimulator of interferon genes

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.