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\begin{document}

\title{Innovations in the Care of chILD Associated with Connective Tissue
Disease and Immune Mediated Disorders}



\author[1]{Aaida Samad}%
\author[2]{Holly Wobma}%
\author[1]{Alicia Casey}%
\affil[1]{Boston Children's Hospital Department of Pediatrics}%
\affil[2]{Boston Children's Hospital Division of Immunology}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Childhood interstitial lung disease associated with connective tissue
disease and immune mediated is the second most common chILD diagnostic
category. As knowledge of the molecular and genetic underpinnings of
these rare disorders advances, the recognized clinical spectrum of
pulmonary manifestations that can be associated with them continues to
broaden. This review will focus on chILD and other pulmonary
complications associated with primary immune disorders, namely monogenic
inborn errors of immunity as well as acquired systemic autoimmune and
autoinflammatory diseases. Pulmonary complications, including ILD in
these diseases can confer increased risk for morbidity and mortality and
can be complex to manage due to the multiple organ systems that can be
impacted in these systemic disorders. Thankfully, pulmonologists do not
have to work alone. These diseases often have stereotypical patterns of
extra-pulmonary features which aid in their recognition. In
collaboration with a multidisciplinary team of subspecialists, the
pulmonary and other systemic manifestations can be managed effectively
together. The goal of this review is to familiarize the reader with the
distinct patterns of ILD and associated systemic/immunologic features
that are characteristic of monogenic inborn errors of immunity and
systemic autoimmune and autoinflammatory diseases. In addition, this
review will highlight current, emergent and innovative therapeutic
strategies and will underscore the important role of multidisciplinary
management to improving outcomes for these patients.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Childhood onset interstitial lung disease (chILD) due to connective
tissue or immune-mediated disorders comprises 16.5\% of patients in the
U.S. Children's Interstitial Lung Disease Research Network Registry
Cohort {[}1{]}---the second largest diagnostic category. This is likely
an underestimate, as some patients may have secondary immune-mediated
ILD in the ``alveolar hemorrhage'', ``other specific multisystemic
disorders'', and ``environmental/toxic/drug related'' categories (9.2\%,
7\%, and 2.2\% of the registry cohort, respectively).

The goal of this review is to familiarize the reader with the distinct
patterns of ILD associated with monogenic inborn errors of immunity and
systemic autoimmune and autoinflammatory diseases, and to highlight
current and emerging therapies. Through advances in our understanding of
cellular and genetic pathophysiology and improvements in
multidisciplinary management, the care of children with immune mediated
chILD is rapidly advancing.

\textbf{General Approach to Evaluation of the Patient Suspected to have
Immune Mediated ChILD---The Importance of a Multidisciplinary Approach}

Evaluation of ILD in patients with immunologic diseases ideally involves
a multi-Candisciplinary team given the complexity of these patients,
many of whom have multiple organ systems involved. Multi-disciplinary
discussions (MDDs) are the current gold standard in diagnosis of ILD in
adults. Prior studies show that clinicians working together have greater
diagnostic accuracy {[}2-6{]} and that MDDs often result in a change in
the diagnosis of ILD (over 50\% of cases discussed in one case series
{[}7{]}) with a significant reduction in disease categorized as
``unclassifiable'' {[}7, 8{]}.

Given that pulmonary involvement can sometimes be the first, most
prominent, most acutely life-threatening and/or most chronically
life-limiting manifestations of these diseases, the pediatric
pulmonologist is an essential member of the multi-disciplinary care team
{[}9{]}. Because respiratory complaints can be the first presenting
symptom, making a diagnosis of immune-mediated ILD requires a high index
of suspicion, as initial clinical presenting signs of ILD may be subtle
and frequently mistaken for more common respiratory conditions such as
asthma or recurrent pneumonia. A generalized approach to diagnosis of
suspected immune-mediated chILD {[}10{]} is outlined in Figure 1.

\textbf{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-Gouti\selectlanguage{ngerman}ères
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.

\textbf{ChILD Associated with Autoimmune and Autoinflammatory Disorders}

As with IEIs, pulmonary complications including ILD are among the most
severe and life-threatening complications of acquired autoimmune and
autoinflammatory disorders. This review will focus on disorders with the
most significant pulmonary involvement, including systemic sclerosis
(SSc), juvenile dermatomyositis (JDM), systemic lupus erythematosus
(SLE), mixed connective tissue disease (MCTD), Sjögren's syndrome,
sarcoidosis, anti-neutrophil cytoplasmic antibody (ANCA) associated
vasculitis (AAV), and systemic juvenile idiopathic arthritis (sJIA).
Pulmonary manifestations of these disorders and representative CT images
are summarized in figures 2 and 3 respectively. Through a collaborative
approach, rheumatologists and pulmonologists can work together to make
earlier diagnosis and improve clinical outcomes for patients with these
disorders.

Systemic Sclerosis

In SSc, autoimmune inflammation drives fibrosis of body tissues.
Juvenile onset SSc (jSSc) is rare, comprising \textless{}10\% of SSc
cases (incidence 0.27-1 per million children per year). Diagnosis of SSc
requires skin thickening {[}25{]}, with other organ involvement
including ILD, pulmonary arterial hypertension (PAH), Raynaud's
phenomenon, digital ulceration, myositis, arthritis, esophageal
dysmotility, and gastrointestinal reflux. All manifestations are not
typically present and needed to make the diagnosis. The average age of
onset is 8-11 years, with female predominance (4:1 ratio) {[}26{]}.

Pulmonary disease, are major causes of morbidity and mortality in SSc,
with ILD present in 1/3 of jSSc patients and PAH present in
\textasciitilde{}2-5\% {[}26{]}. There are three main subtypes of SSc:
limited cutaneous, diffuse cutaneous, and overlap. ILD can be a feature
in diffuse and overlap subtypes. In limited cutaneous SSc, vasculopathy,
including pulmonary hypertension, is more common {[}27-29{]}.

With the development of ILD in SSc, imaging abnormalities may precede
clinical symptoms. Thus, baseline studies at diagnosis include
high-resolution chest CT, PFTs, echocardiogram (to assess for PAH), and
esophageal dysmotility studies (to assess for aspiration) {[}30, 31{]}.
Children with esophageal involvement have been shown to have
significantly decreased forced expiratory volume in the first second
(FEV1), forced viral capacity (FVC), and vital capacity (VC) {[}32{]}.
PFTs can also demonstrate restriction and low DLCO {[}33, 34{]}, but
tight facial skin and reduced oral aperture may lead to technically
limited PFTs. PFTs have limited sensitivity and specificity in diagnosis
ILD in childhood SSc {[}35{]}. CT is more sensitive for diagnosis, with
findings including parenchymal/subpleural micronodules, ground glass,
linear and diffuse centrilobular opacities, honeycombing, and traction
bronchiectasis {[}36{]}. Lung biopsy is rarely indicated; however,
pathologic patterns described include bland interstitial fibrosis, usual
interstitial pneumonia (UIP), non-specific interstitial pneumonia
(NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD),
honeycomb remodeling, pulmonary hypertensive changes, findings
compatible with aspiration and rarely, alveolar hemorrhage with
capillaritis {[}37{]}.

There have been several randomized controlled trials for ILD-related
outcomes in adults with SSc, with multiple sets of consensus guidelines
outlining organ-specific therapeutic approaches. Based on adult trials
{[}38-40{]} first line therapies to treat alveolar inflammation include
cyclophosphamide, mycophenolate mofetil, and tocilizumab. Rituximab has
some prospective cohort data to suggest its use as a second line
therapy. For patients with fibrosis, nintenadib, an oral tyrosine kinase
inhibitor, has shown benefit {[}41{]} in adults. As a
3\textsuperscript{rd}/4\textsuperscript{th} line option, autologous
hematopoietic stem cell transplantation (HSCT) has been shown to improve
cutaneous and pulmonary features based on RCT in Europe {[}42{]} and the
United States {[}43{]} comparing HSCT to cyclophosphamide. Depending on
the extent of lung fibrosis, some patients may require lung
transplantation. For PAH, endothelin receptor antagonists, PDE5
inhibitors, and intravenous prostacyclins may be used and have
additional benefit for severe Raynaud's {[}29, 44{]}. In the pediatric
population there is one expert guideline for management {[}45{]}. In
this guideline for management of heart and lung involvement it is
recommended to first treat with mycophenolate mofetil and
cyclophosphamide and then if refractory move to biologic treatments. In
our practice given fertility considerations and the success of biologic
treatments we often add biologics before treating with cyclophosphamide.

Juvenile Dermatomyositis

JDM is a rare inflammatory myopathy and vasculopathy, with an incidence
of 0.2-0.4 per 100,000 children {[}46-48{]}. Peak incidence occurs from
5-10 years of age, with a female predominance {[}46, 48, 49{]}. Clinical
manifestations include inflammation of the muscle (proximal weakness)
and skin (ulcerations, calcifications, Gottron's rash, heliotrope rash,
nailfold capillary changes), with possible involvement of the lung,
gastrointestinal tract, and joints {[}50{]}. The incidence of pulmonary
involvement in JDM is unknown. Pulmonary manifestations in JDM include
respiratory muscle weakness, hypoventilation, impaired swallowing
leading to aspiration, impaired airway clearance with respiratory tract
infections, spontaneous pneumothorax/pneumomediastinum, pulmonary
vasculitis, and interstitial lung disease {[}51, 52{]}.

While the incidence of ILD in JDM is not clear, it represents a
significant source of morbidity and mortality {[}53, 54{]}. ILD can
present with cough and shortness of breath but can also be seen in
asymptomatic patients when identified early. ILD in JDM can be rapidly
progressive (progression within 3 months of symptom onset) and can occur
before or after myositis symptoms. Serum tests elevated in JDM-related
ILD include Krebs von den Lungen 6 (KL-6), molecule that is
predominantly expressed by damaged alveolar type II cells, and IL-18. In
addition, anti-melanoma differentiation-associated gene 5 (anti -MDA-5)
and anti-Ro52 antibodies may appear before signs of interstitial lung
disease {[}53, 55-60{]}.~ ILD in adult dermatomyositis has been
associated with anti-Jo-1 and anti-synthetase antibodies {[}61, 62{]},
but these antibodies are rarer in children. If any of these antibodies
are present, the patient needs to be followed closely by a pulmonologist
for the development of ILD.

PFTs and cross-sectional chest imaging are essential for evaluating for
pulmonary involvement in JDM. Patients with JDM can have a range of PFT
patterns, which may be due to the presence of ILD or other pulmonary
complications. Prior reports show abnormal lung function in a high
percentage of patients, including asymptomatic patients {[}63{]}. From
case series the following PFT abnormalities were reported in JDM:
obstructive lung disease,15\%, abnormal DLCO, 10 -- 49\%, reduced TLC,
24 -- 29\%, decreased maximal respiratory pressures, 30\% {[}51,
63-66{]}.

CT findings in ILD associated with JDM cannot distinguish between
rapidly progressive and chronic disease, but this is often apparent
based on rate of progressive symptoms. {[}67{]} Findings previously
reported include atelectasis, nodules/micronodules, ground glass
opacities, air trapping, bronchial wall thickening, traction
bronchiectasis, reticulation, consolidation, and fibrosis {[}51, 53,
54{]}. Biopsies are not necessary for diagnosis of ILD in JDM, but
reported pathology includes nonspecific interstitial pneumonia (NSIP),
cellular interstitial pneumonitis, bronchiolitis obliterans organizing
pneumonia (BOOP), usual interstitial pneumonia (UIP), acute interstitial
pneumonitis, diffuse alveolar damage (DAD) and fibrosis {[}68-76{]}.
Pneumothorax or pneumomediastinum may have a poorer prognosis and
complicate ILD in JDM {[}77{]}.

Early initiation or escalation of immune suppression is critical for ILD
given the possibility of severe deterioration. There are no randomized
controlled trials for treatment of ILD in JDM. Glucocorticoids and
methotrexate with or without immunomodulatory IVIG (1-2g/kg) are the
mainstay of treatment for JDM in general {[}78{]}. Patients with
anti-MDA5 antibody rapidly progressive ILD require rapid escalation of
therapy. Case reports/series of ILD associated with JDM have reported
efficacy in using calcineurin inhibitors (cyclosporine, tacrolimus)
{[}53, 54, 79{]}, cyclophosphamide, plasmapheresis {[}67, 80, 81{]},
rituximab {[}60{]}, and tofacitinib {[}82-84{]}. In the most severe
cases, some patients have been put on extracorporeal membrane
oxygenation (ECMO) as a bridge to lung transplant; however, the
mortality rate is still very high {[}67, 80, 81{]}.

Systemic Lupus Erythematosus

SLE is a multi-system autoimmune disorder characterized by generation of
autoantibodies against cellular components and tissue damage from immune
complex deposition. While SLE is more common in adults, approximately
20\% of individuals present prior to the age of 18 {[}85{]}, with female
predominance in both age groups. The incidence and prevalence of
childhood onset SLE (cSLE) varies between populations, with an incidence
range of 0.28-0.48/100,000 and a prevalence rate of 6.3-24.0/100,000
{[}86{]}. Fever, fatigue, lymphadenopathy, nephritis, neuropsychiatric
disease, cytopenia and mucocutaneous involvement (Malar, photosensitive,
purpuric vasculitic rashes and oral/nasal mucosal ulcers) are more
common in children at presentation than adults {[}85, 87{]}. Overall,
cSLE is reported to have a more severe course {[}85{]}.

\textbackslash{}sout

Pulmonary involvement in SLE can occur at onset of symptoms or any time
during disease course, ranging from asymptomatic to severe and acutely
life-threatening. Pulmonary complications in cSLE includes involvement
of the upper airway, lung parenchyma, pulmonary vasculature, pleura and
respiratory muscles, with prior reports of pneumonia (up to 90\%),
pleuritis (50-80\%), acute pneumonitis (\textless{}10\%), chronic ILD
(3\%), pulmonary hypertension (5-14\%), diffuse alveolar hemorrhage
(DAH) (\textless{}2\%), shrinking lung syndrome (\textless{}1\%) and
thrombotic disease {[}52, 88, 89{]}.

Pleuritis can be unilateral or bilateral and may be associated with a
pleural effusion. Patients can present asymptomatically or with
debilitating dyspnea, pain, and fever. Pleuritis can be treated with
NSAIDs, although may require escalation of immune suppression.

Diffuse alveolar hemorrhage (DAH) in SLE is associated with significant
morbidity and mortality. Patients may present with dyspnea, hemoptysis,
fatigue, anemia, and respiratory failure. It can be difficult to
distinguish DAH from infection as both can present with diffuse alveolar
opacities. Flexible bronchoscopy, and in some cases lung biopsy, may aid
in diagnosis. Infections have been identified at the onset of DAH, so
simultaneous treatment of both may be required. Two studies have
systematically examined DAH in pediatric SLE cohorts with an incidence
of 1.7-2.2\% of cSLE patients {[}90, 91{]}. Mortality varied widely in
these cohorts, close to 50\% in one cohort, whereas the second was 14\%.
In both cohorts, patients often required transfusions and mechanical
ventilation {[}90, 91{]}. While there are no controlled trials, for
critically ill patients, prompt initiation of high dose steroid with an
additional agent like cyclophosphamide is often pursued. Rituximab may
also be helpful but has a slower time to effect {[}92-94{]}.
Immunomodulatory dosing of intravenous immunoglobulin (IVIG) and
plasmapheresis can be considered in refractory cases.

ILD is a rare pulmonary manifestation in adult SLE, is rarer still in
cSLE, and can present as acute pneumonitis or chronic ILD. In a
twenty-year retrospective cohort of 157 cSLE patients, lupus
pneumonitis/ILD was diagnosed in 3.8\% at diagnosis and in 12.1\% during
disease course. Acute lupus pneumonitis is associated with significant
morbidity and mortality {[}95{]} and is characterized pathologically by
alveolitis, interstitial inflammation and edema. Findings associated
with capillaritis and pleuritis can also be seen concurrently {[}96,
97{]}. Chronic ILD in cSLE can occur following acute lupus pneumonitis
or develop in isolation, with pathologic findings including cellular
interstitial pneumonia, interstitial fibrosis, lymphocytic interstitial
pneumonitis, fibrinous pleuritis, organizing pneumonia, desquamative
interstitial pneumonitis, nonspecific interstitial pneumonitis,
bronchiolitis and peribronchiolitis {[}98, 99{]}. ILD with pathologic
findings consistent with organizing pneumonia has been described in
patients meeting criteria for SLE including a pediatric patient
{[}96{]}. ILD in SLE has been associated with \textgreater{}10 years
duration of disease, Raynaud phenomenon, anti-(U1) RNP anti-bodies,
sclerodactyly, and abnormal nailfold capillary loops {[}97, 100{]}.
Given the rarity of ILD in SLE, drug reaction and other rheumatologic
diagnoses such as mixed connective tissue disease should be considered.

Acute lupus pneumonitis warrants aggressive treatment given poor
prognosis. The ideal treatment of chronic ILD in pediatric patients with
SLE is unknown due to lack of controlled trials in children or adults.
As it can be very difficult to determine if it is lupus pneumonitis vs.
infection vs. DAH or co-existence of multiple complications, empiric
treatment with broad spectrum antimicrobials and extensive infectious
disease and DAH evaluation is warranted. Systemic steroids are often
employed, given the significance of steroid toxicity, steroid sparing
agents such as azathioprine, mycophenolate, cyclophosphamide, and
rituximab should be considered {[}94, 101-103{]}. Antifibrotic treatment
should be considered if there is evidence of fibrosis or progression.

Pulmonary hypertension in pediatric SLE can occur secondary to ILD or
without associated ILD, with other potential causes including pulmonary
vasculitis, pulmonary thromboembolism (especially with coexisting
antiphospholipid antibodies), and cardiac dysfunction {[}104{]}.
Pulmonary hypertension in SLE can occur at any point during disease
course and may be present in asymptomatic patients or patients with
fatigue, weakness, shortness of breath, exercise intolerance,
presyncope, syncope, hemoptysis, or respiratory failure. Early
identification is important {[}105, 106{]} as the presence of pulmonary
hypertension in SLE negatively affects survival overall {[}107{]}.

Shrinking lung syndrome (SLS) is a rare complication of pediatric SLE
where patients experience dyspnea and pleuritic chest pain, with PFT
evidence of restrictive lung disease and reduced maximal respiratory
pressures and sometimes radiographic signs of reduced lung volumes and
atelectasis. These patients generally do not have evidence of ILD
{[}108, 109{]}. The pathophysiology of SLS is unclear, but may be
related to myositis, myopathy, phrenic nerve dysfunction, and/or
parenchymal reorganization impairing lung compliance {[}109{]}.
Treatment includes immunosuppressive medications and, in our experience,
exercise/pulmonary rehabilitation may be beneficial due to improvements
in diaphragmatic mobility and lung compliance.

Pediatric SLE patients may be asymptomatic from a respiratory standpoint
but have PFT and chest CT abnormalities predating pulmonary symptoms.
Abnormalities in spirometry, plethysmography and diffusion have been
described, with restrictive defect potentially secondary to parenchymal
involvement or respiratory muscle dysfunction and DLCO reduction
secondary to parenchymal disease or pulmonary hypertension. Disease
duration is a risk factor for development of PFT abnormalities and DLCO
may improve with treatment {[}110, 111{]}.

\textbf{Mixed Connective Tissue Disease}

MCTD is characterized by having features of multiple connective tissue
disorders, but primarily SLE, polymyositis/dermatomyositis, and
scleroderma. Symptoms can evolve over time and do not present in a
specific order {[}112{]}. Criteria for diagnosis include 1) Raynaud's
phenomenon 2) detectable anti-RNP antibodies 3) one additional sign or
symptom of SLE, polymyositis/dermatomyositis or SSc {[}113, 114{]}.

MCTD can be accompanied by any of the pulmonary manifestations of SLE,
JDM, or SSc, most often, pleural effusions, pulmonary hypertension, and
ILD. The prevalence of overall pulmonary involvement in children is
unknown, but most adults with MCTD have pulmonary involvement
{[}115-119{]}, which increases the risk for mortality.

The disease course of ILD in pediatric MCTD is not well defined. In a
prior cross-sectional study of 52 pediatric MCTD patients followed for a
mean of 16 years, ILD was diagnosed in 27\%. On PFTs, patients with ILD
had lower FVC and TLC than controls. Notably, in this study, while FVC
declined overtime, CT findings of ILD did not worsen {[}33{]}. A second
long-term follow up study of pediatric MCTD (n = 34) hints at a
potentially progressive nature of ILD in MCTD ---~at initial
presentation, 22\% of patients had restrictive lung disease, 21\% had
reduced DLCO and 14\% had pulmonary fibrosis on chest CT, increased to
64\% with restrictive lung disease, 58\% with reductions in DLCO and
100\% with fibrosis at long term follow up. 6\% of patients in this
series had pulmonary hypertension {[}120{]}. In addition to fibrosis,
chest CT findings previously reported in MCTD include reticulations,
ground glass opacities, interlobular septal thickening, airspace
consolidations, and/or traction bronchiectasis {[}32{]}.

Treatment pediatric MCTD patients is directed at specific complications
that emerge and overlap with treatment paradigms used in SLE,
polymyositis/dermatomyositis and SSc.

\textbf{Sjögren's Syndrome}

Sjögren's syndrome is an autoimmune disorder involving destruction of
exocrine glands which is characterized by sicca (dryness) syndrome,
recurrent parotitis, and other extra-glandular symptoms. Sjögren's is
poorly defined in children with unknown incidence and variable
presentation, with no established diagnostic criteria {[}121{]}.
Pulmonary manifestations in children and adults include restrictive lung
disease from myositis, ILD, airway disease. ILD in children appears to
be exceedingly rare, limited to four case reports in female children
{[}122-125{]} and one case report of a male child {[}121{]}. Given the
limited data on ILD in childhood onset Sjögren's Syndrome, we urge
careful screening for pulmonary involvement through close review of
respiratory symptoms and monitoring of PFTs.

\textbf{Sarcoidosis}

Sarcoidosis is a multi-systemic non-necrotizing granulomatous disease
which can present with hilar lymphadenopathy, pulmonary infiltration and
ocular and cutaneous lesions {[}126{]}. Patients can present with
involvement of one system or multi-systemic disease. The diagnosis is
made when there is pathologic evidence of noncaseating granulomas in
affected tissue and other causes of granulomatous disease have been
excluded. CVID and IEIs should be evaluated for in a pediatric patient
presenting with sarcoidosis. Elevated ACE levels may support the
diagnosis, but this is not necessary for diagnosis. While the incidence
of sarcoidosis is unknown in the pediatric population, it is considered
to be rare -- a Danish case series of children \textgreater{} 15 years
reported an incidence of 0.22 to 0.27 per 100,000 children per year
{[}127{]}. Radiographic findings described in pediatric sarcoidosis
include bilateral hilar lymphadenopathy with and without pulmonary
infiltrates, and nodules with ground glass opacities, and pleural and
interlobular septal thickening {[}128-130{]}. Reported PFT alterations
include hypoxemia, reduced vital capacity, decreased DLCO, and decreased
dynamic lung compliance {[}128, 129{]}.

Decisions around treatment of pulmonary sarcoidosis in adults are
challenging, with no consensus around who should receive treatment,
given that disease can stabilize or resolve without therapy. These
decisions are more complicated still in the pediatric population, with
no studies around which patients to treat and optimal length of
treatment {[}129{]}. Corticosteroids, either daily oral steroids (0.5 to
2 mg/kg/day) or monthly IV pulse steroids are reported as the most-used
treatment {[}128, 129{]}. We recommend treatment of sarcoidosis in
pediatric patients with moderate to severe reduction in pulmonary
function, progressive decline in lung function, significant or worsening
radiographic disease, persistent or worsening symptoms, exercise
desaturation, and/or multisystemic involvement.

\textbf{ANCA Associated Vasculitis}

AAV are small- to medium- vessel vasculitis syndromes primarily
affecting the blood vessels of the airways and the kidneys. They are
generally divided into granulomatosis with polyangiitis (GPA),
microscopic polyangiitis (MPA), and eosinophilic granulomatosis with
polyangiitis (EGPA) {[}131{]}. The incidence of pediatric AAV is not
well established, with reported incidence ranging from 0.5 to 2 per
million. The most common age of onset is in early teenage years,
although some children present in infancy. Lung involvement, considered
to be a hallmark of MPA and GPA, is associated with increased morbidity
and mortality --- in one cohort of 28 patients, half of children
required ICU admission and one third of these admissions were for
respiratory failure, with five patient requiring mechanical ventilation
{[}131-133{]}.

Of the AAVs, GPA is most common in children and classification criteria
can include some of the following features: granulomatous inflammation
on histopathology, renal disease, ANCA positivity and, from a pulmonary
perspective any of the , upper airway involvement (chronic purulent or
bloody nasal discharge, recurrent epistaxis/crusts/granulomata, nasal
septum perforation or saddle nose deformity), laryngo-tracheo-bronchial
involvement (subglottic, tracheal, or bronchial stenosis) and/or
pulmonary involvement (chest x-ray or CT with nodules, cavities or fixed
infiltrates) {[}134{]}.

In pediatric GPA, pulmonary involvement can range from asymptomatic with
radiographic abnormalities (a prior report noted 41\% of radiographic
abnormalities found in patients with pediatric GPA were observed in
asymptomatic patients {[}135{]}) to presentation with fulminant DAH
{[}133{]}. In the ARChiVe cohort, including 183 patients with pediatric
GPA, 74\% had pulmonary involvement, with 54\% reporting chronic cough
and 42\% with massive hemoptysis or alveolar hemorrhage {[}136, 137{]}.
PFTs may show abnormal DLCO (related to parenchymal disease or
hemorrhage), restrictive lung disease, and/or obstructive disease
(related to airway stenosis). CT findings may include nodular lung
lesions (secondary to necrotizing, granulomatous inflammation, which may
demonstrate cavitation and/or a ``halo sign'' related to adjacent
hemorrhage), fixed pulmonary infiltrates, and more rarely (\textless{}
10\% of cases), fibrosis, septal thickening and pneumothorax {[}133,
136{]}. Bronchoalveolar lavage (BAL) with serial aliquots can be useful
in evaluation for pulmonary hemorrhage.

Data on pulmonary manifestations in pediatric MPA is more limited, with
conflicting data. In a case series of 38 patients with AAV (in which MPA
was the predominant AAV), MPA patients had higher prevalence of more
severe pulmonary manifestations than GPA patients, with a subgroup of
five patients experiencing recurrent pulmonary hemorrhage. MPA patients
with early onset disease had worse pulmonary outcomes {[}138{]}. By
contrast, in a retrospective review of 12 children with MPA, the
majority of children (66\%) had no respiratory symptoms at diagnosis
with normal chest radiographs. Pulmonary manifestations at diagnosis
were observed in four children, all with DAH. Among children without
respiratory involvement at diagnosis, only one child developed DAH after
12 months {[}139{]}.

Consensus guidelines and consensus treatment plans for treatment of
pediatric AAV have been established by the SHARE initiative and
Childhood Arthritis and Rheumatology Research Alliance (CARRA) ANCA
vasculitis workgroup {[}140, 141{]}. For severe disease with multi-organ
involvement, induction consists of cyclophosphamide and steroids (pulse
or high dose oral) for 3 - 6 months. Other therapeutic options for
treatment of pediatric AAVs can potentially be extrapolated from adult
RCTs. The RAVE {[}142{]}and RITUXVAS {[}142{]} trials demonstrated
non-inferiority of rituximab for induction therapy, which could be
attractive for pediatric patients due the undesirable side effect
profile (include effects on fertility) of cyclophosphamide. Without
extensive pediatric data however, cyclophosphamide is generally
considered first line therapy. In adults, a trial comparing
mycophenolate mofetil to cyclophosphamide for induction, while
non-inferior to inducing remission, had high rates of relapse {[}143{]}.
Other therapeutics evaluated in the adult population, but with limited
to no data in the pediatric population, include plasmapheresis for
patients with severe disease and avacopan {[}144{]}, an oral C5a
receptor inhibitor thought to slow neutrophil trafficking. For patients
with less severe or localized disease, oral steroids plus methotrexate
or mycophenolate mofetil can be considered for induction.
Trimethoprim-sulfamethoxazole has also been used for GPA limited to the
upper airways {[}145{]}. For maintenance therapy, the three most used
agents are methotrexate {[}146{]}, azathioprine {[}147{]}, and rituximab
{[}148{]}.

Systemic Juvenile Idiopathic Arthritis

Systemic juvenile idiopathic arthritis (sJIA) is an International League
of Associations for Rheumatology (ILAR) subclass of JIA, characterized
by disease driven more by autoinflammation than by autoimmunity.
Diagnostic features include several weeks of fever, classically in a
quotidian or double quotidian pattern, evanescent rash, and arthritis,
which is not always present at disease onset. Males and females are
affected equally with a peak onset between ages 1 to 5 years of age
{[}149{]}. One of the most life-threatening complications unique to sJIA
(vs. other classes of JIA) is macrophage activation syndrome (MAS),
which is driven by IFN-\(\gamma\) and can be seen in 10\% of
patients fulminantly and 30- 40\% of patients subclincially
{[}150-152{]}.

In recent years, significant attention has also been directed to the
pulmonary complications of sJIA, which include pleuritis, pleural
effusions, ILD and pulmonary arterial hypertension {[}153{]}. ILD in
sJIA is referred to as sJIA-LD. Risk factors for sJIA-LD include younger
age of onset (\textless{}2 years old), trisomy 21, history of MAS, and
prior adverse reaction to biologic drugs (including injection site
reactions and delayed type hypersensitivity-like reactions to anti-IL-1
and IL-6 biologics) {[}154-156{]}. In a multi-center cohort, median time
to LD diagnosis after sJIA onset was 1.6 years. Respiratory symptoms
were often absent or subtle. Symptoms in sJIA-LD patients included:
hypoxemia (43\%), pulmonary hypertension (30\%), clubbing (61\%),
digital erythema (50\%), pruritic non-evanescent rashes (56\%) and
eosinophilia (37\%). Mortality was increased in sJIA-LD with a 5-year
survival of 42\%, significantly lower than patients without sJIA-LD
{[}156{]}. This mortality rate has likely improved since these 2019
studies, as patients are being diagnosed earlier with less severe LD and
opportunity for earlier treatment {[}157, 158{]}.

Curiously, most cases of sJIA-LD have been reported after biologics
became first line therapy for sJIA. It is unclear if this is secondary
to increased incidence of sJIA-LD or increased awareness. More recently,
it has been shown that sJIA patients treated with IL-1 or IL-6
inhibitors may develop eosinophilia with an atypical rash, in
association with HLA-DRB1*15 leading to the hypothesis that a drug
reaction was driving the development of MAS and sJIA-LD {[}154{]}. This
hypothesis potentially affects management, as it raises concern about
continued use of biologic agents in treatment of sJIA. However, our
group and others have noted that eosinophilia in sJIA can occur prior to
any treatment with anti-IL-1 and IL-6 therapy {[}159, 160{]}, rendering
it possible that eosinophilia is a reflection of the type of
inflammation characteristic of sJIA, which may be further skewed towards
a Th2 phenotype in the setting of IL-1 and IL-6 blockade {[}161{]}.

Diagnosing sJIA-LD can be challenging -- imaging changes may precede
development of clinical symptoms, and patients at highest risk are often
too young to perform PFTs. There are no consensus guidelines for
screening for sJIA-LD. Our center developed a screening algorithm
recommending patients with sJIA be referred for pulmonary screening if
they have `red flag' features including: diagnosis at age \textless{}2
years, presence of the HLA DRB1*15 risk allele, high disease activity
(history of MAS, sJIA-related ICU admission, persistently elevated
IL-18), anaphylaxis, eosinophilia or atypical rash, respiratory symptoms
or an abnormal pulmonary exam {[}162{]}. Initial evaluation should
include chest x-ray and PFTs, including a 6-minute walk test or exercise
saturation testing in ambulatory children. If a patient's pulmonary
screening is abnormal, or if patients have uncontrolled disease, we
recommended high-resolution chest CT for more sensitive screening of
ILD. Overnight oximetry or polysomnography can be considered to evaluate
for low pulmonary reserve or nocturnal hypoxemia, which may also suggest
the presence of sJIA-LD. Bronchoalveolar lavage to evaluate for
infection is frequently employed when there is concern for sJIA-LD. BAL
fluid from patients with sJIA-LD have been found to have high levels
IL-18 and CXCL9 compared to patients with congenital alveolar
proteinosis {[}155{]}.

CT scan abnormalities in sJIA-LD can include pleural,
interlobular-septal, and bronchial wall/perivascular thickening,
peripheral and periobronchovascular consolidations, ground glass and
tree-in-bud opacities, crazy paving, and lymph node changes (adenopathy,
hyper-enhancing). Fibrosis is uncommon and pleural effusions are rare
{[}155, 156{]}. Pathologic findings include pulmonary alveolar
proteinosis, type II pneumocyte hyperplasia, macrophage accumulation,
endogenous lipoid pneumonia, lymphoplasmocytic inflammation, pulmonary
vascular abnormalities, and rarely, fibrosis {[}155, 156{]}.

In a single center study of 18 patients with sJIA-LD, all continued
biologic treatment after detection of lung disease with a median of 1
year of follow up and range of 0.5 to 13 years. In that cohort, 50\% of
patients had stable LD, 22.2\% worsened, and 27.8\% improved. There was
no differentiating characteristics of those who improved and those who
did not. Importantly, all patients with improved sJIA-LD had control of
their underlying sJIA {[}155{]}.

There are no management guidelines or randomized controlled trials of
therapies in sJIA-LD. As poor sJIA disease control is a risk factor for
the development of sJIA-LD, achieving overall disease control is a
priority. sJIA is thought to be driven by elevated IL-1, IL-6 and IL-18,
and thus first line treatment of sJIA is based on IL-1 and IL-6 blockade
with biologics. Regarding additional therapies, there are case reports
of successful treatment of sJIA-LD with JAK inhibition {[}163-165{]},
and in our experience, adding mycophenolate mofetil, calcineurin
inhibitors or JAK inhibitors to obtain control of sJIA if this is
refractory to or develops while on biologic monotherapy {[}166{]}. Case
reports exist for successful treatment of sJIA-LD with emapalumab
{[}167{]}, an anti-IFN\selectlanguage{greek}γ \selectlanguage{english}monoclonal antibody used to tackle the related
inflammation in MAS, etoposide (also used for MAS) {[}168{]}, bispecific
IL-1/IL-18 blockade {[}169{]} and allogeneic hematopoietic stem cell
transplant (HSCT) {[}170{]}.

\textbf{Supportive Care of the Patient Suspected to have Immune Mediated
chILD}

While disease-specific therapeutic regimens have been discussed
throughout, the importance of generalized supportive care measures for
all diagnoses, cannot be overstated. With underlying inflammation and
increased metabolic demands, patients can experience faltering growth
requiring consultation with nutrition and dietary support. Exercise,
physical therapy, and pulmonary rehabilitation can improve functional
capacity in these patients. Social work and nursing support is critical
to assist with care coordination ---navigating transportation,
education, insurance, durable medical equipment, and the psychosocial
and financial implications of these conditions, which can present a
significant burden to families {[}171{]}.

Counseling patients on avoidance of infectious exposures, smoking,
vaping, and environmental pollutants is essential. Having a low
threshold for evaluating for and treating infections is recommended.
Patients should be encouraged to receive all appropriate vaccinations,
keeping in mind that for patients with IEI or on immunosuppressive
medications, live vaccines are often contraindicated. Depending on the
underlying disorder or immunosuppressive treatment, prophylactic
antimicrobials and intravenous or subcutaneous immunoglobulin treatment
may be considered. In the setting of significant ILD and increased
susceptibility, we recommend a goal IgG trough target of 800-1000 mg/dL.
Higher dose (1-2g/kg) immunoglobulin can also serve an immune-modulatory
purpose in patients with immune dysregulation and autoimmune disease.

In patients with advanced lung disease including ILD, consideration of
lung transplantation may be necessary, particularly if the patient is at
risk of death from pulmonary complications in the next 1-2 years, has
poor quality of life despite optimal medical therapy, and has a
reasonable chance of surviving transplantation. With ILD associated with
connective tissue and immune mediated disorders, the risk for immune
mediated lung disease recurrence in the transplanted lung is an
important consideration, with a paucity of data to guide these decisions
for most of these disorders. In some IEIs, allogeneic SCT may be
curative, but this is more successful if the genetic defect is limited
to the hematopoietic compartment and carries the risk for transplant
related morbidity and mortality {[}22{]}. In advanced ILD cases,
consultation with pediatric palliative and advanced care and ethics
teams may be helpful for the medical team and families.

\textbf{Conclusions}

Recognition, diagnosis, and treatment of chILD associated with
connective tissue disease and immune-mediated disorders requires
thoughtful care from a multi-disciplinary team of providers, with the
pulmonologist playing a key role. These patients have highly complex
systemic disorders, and ILD can have many faces -- sometimes presenting
subtly and progressing insidiously, while other times presenting with
rapid and life-threatening consequences. The diagnostic odyssey and
management challenges associated with immune associated chILD can be a
significant medical, psychologic, and socio-economic burden to patients
and their families. Important next steps in the care of these patients
include improving therapy adherence, conducting randomized trials and
developing pediatric consensus guidelines to generate more
evidence-based and standardized treatment protocols, and developing
novel therapeutics with reduced risk for toxicity and infectious risks.
Despite significant challenges in the care of these complex patients,
advances in molecular and genetic testing have aided in achieving
earlier and less invasive diagnoses, and emerging therapies represent
promising future innovations.

\textbf{Acknowledgements} : The authors would like to thank the Boston
Children's Hospital Children's Interstitial Lung Disease Program and
multi-disciplinary Multiple Immune Dysregulation and Autoimmune Syndrome
(MIDAS) program for their commitment to caring for and advancing the
care of patients with interstitial lung disease and other systemic
complications of IEIs and autoimmunity. HW is funded by a NIAID grant
T32-AI-007512-36 with related work supported by the Rheumatology
Research Foundation Abstract Awards.

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