Interstitial lung disease with rheumatological diseases
Interstitial Lung Disease With
(1) pulmonary involvement may be associated with high morbidity and mortality in
this population, and
(2) pulmonary disease may be the predominant initial clinical presentation in a
subset of these patients.
Many different types of pulmonary manifestations may occur with each
rheumatologic condition; however, certain patterns of lung involvement
are recognized with increased frequency in each condition. The most
devastating pulmonary manifestation pulmonary fibrosis – may result in
progressive restrictive lung disease and eventual death from respiratory
In the setting of known or suspected rheumatologic disorders, diagnosis
and management of DLD are challenging, and require close collaboration
among rheumatologists, pulmonologists, and other specialists.
Table 1. ILD in Rheumatological disease in children
JIA SLE JDM SSc MCTD Sarcoidosis WG MPA
+ + + +++ ++ + - -
Dell SD, Schneider R. Pulmonary involvement in the systemic inflammatory
diseases of childhood. In Wilmott RW, Boat TF, Bush A, et al., editors.
Kendig and Chernick’s disorders of the respiratory tract in children.
Philadelphia: Elsevier Saunders; 2012.
DIAGNOSTIC APPROACH IN CHILDHOOD
The choice of diagnostic tests depends on presenting signs and symptoms,
age of presentation, severity and progression of the disease,
immunocompetence and family history, and the known or suspected underlying
HRCT is a preferred imaging technique for evaluation of pediatric DLD.
Chest radiographs (CXRs) are commonly performed in children with
respiratory symptoms and suspected DLD; however, though often useful,
they are neither sensitive nor specific and seldom provide specific chILD
controlled ventilation high-resolution computed tomography (CVHRCT)
performed with sedation and mask ventilation or in anesthetized,
intubated child is the preferred technique.
Pulmonary function tests
In systemic inflammatory diseases of childhood with lung involvement, PFTs
with evaluation of lung volumes and diffusing capacity for carbon monoxide
(DLCO) are important in screening for lung disease, determining its severity,
and monitoring for disease progression.
Table 2. Patterns of pulmonary function and gas exchange impairment
in lung disease associated with systemic inflammatory conditions
Pattern of ventilatory
Diffusing capacity for
Chest wall restriction
(muscle weakness or
chest wall deformity
Restrictive defect with low peak
flow in more severe disease
Preserved until severe
loss of volume
With severe disease,
hypoventilation results in
hypercapnia and hypoxia
with normal a–A gradient
Pulmonary fibrosis Restrictive defect Reduced With severe disease, hypoxia
Bronchiectasis Obstructive defect Preserved until severe
end stage disease
With end-stage disease, hypoxia
Diffuse alveolar hemorrhage Variable – often restrictive Increased if hemorrhage
During active bleeding, hypoxia,
often profound with a wide
Pulmonary vascular disease Normal pulmonary function tests Reduced Hypoxia at rest even with
Mixed disease: pulmonary
fibrosis and muscle
Restrictive defect, often severe Less reduced than expected
for degree of restrictive
Hypoxia at rest or with exercise
Dell SD, Schneider R. Pulmonary involvement in the systemic inflammatory diseases of childhood. In Wilmott RW, Boat TF, Bush A, et al., editors. Kendig and Chernick’s disorders of the
respiratory tract in children. Philadelphia: Elsevier Saunders; 2012.
Bronchoscopy with bronchoalveolar lavage
Bronchoscopy with bronchoalveolar lavage (BAL) is a commonly used
invasive technique in patients with ILD, it is helpful for distinguishing chILD
and autoimmune lung disease from infection.
Airway abnormalities suggestive of necrotizing granulomatosis vasculitis
(NGV) or sarcoidosis may be identified.
BAL cytology is important for distinction of chILD from other causes of DLD,
such as aspiration (lipid-laden macrophages), pulmonary hemorrhage
syndromes (hemosiderin-laden macrophages), pulmonary alveolar proteinosis
(PAP) [periodic acid-Schiff (PAS)-positive material in alveolar macrophages],
pulmonary histiocytosis (CD-1a cells), lysosomal storage disorders, and
sarcoidosis. Cytology count differentials may help to narrow the differential
diagnosis of lung disease.
Vece TJ, Fan LL. Diagnosis and management
of diffuse lung disease in children [review].
Paediatr Respir Rev 2011; 12:238–242.
Genetic testing has rendered lung biopsy unnecessary in some infants with
Lung biopsy is still indicated in infants with rapidly progressive or severe
disease when establishing a diagnosis is needed to guide the treatment
options including lung transplant.
In Rheumatologic disorders lung biopsy is reserved for a subset of patients
when a diagnostic dilemma remains despite other diagnostic testing,
particularly if histopathology may change the management.
Nogee LM. Genetic basis of children’s interstitial lung disease. Pediatr
Allergy Immunol Pulmonol 2010; 23:15–24.
Serum and alveolar biomarkers of lung
disease in connective tissue disorders Krebs von den lungen-6 antigen (KL-6)
has been identified as a serum marker of ILD. KL-6 occurs on the surface of
alveolar cells; however, its serum levels increase when type II pneumocytes
proliferate or capillary integrity is disturbed. Increased serum levels of KL-6
have been found in patients with active interstitial pneumonitis associated with
Doishita S, Inokuma S, Asashima H, et al. Serum KL-6 level as an
indicator of active or inactive interstitial pneumonitis associated with
connective tissue diseases. Intern Med 2011; 50:2889–2892.
Juvenile idiopathic arthritis
JIA is the most common chronic rheumatic disease in childhood
with a prevalence of 16 to 150 per 100,000.
Lung involvement, with the exception of transient pleuritis which
associated most times with pericarditis is sufficiently rare in JIA to
warrant investigation. Other rare associations with JIA include
bronchiolitis obliterans organizing pneumonia (BOOP),
pulmonary hemosiderosis and lymphocytic interstitial pneumonitis
Sohn DI, Laborde HA, Bellotti M, Seijo L. Juvenile rheumatoid
arthritis and bronchiolitis obliterans organized pneumonia.
Clin Rheumatol 2007; 6:247–250.
Macrophage-activating syndrome, which occurs in 10% of systemic JIA
patients, is often associated with respiratory failure requiring ventilator support.
The most severe pulmonary manifestations have been seen with the systemic
and polyarticular subtypes.
lipoid pneumonia in children with systemic JIA, not secondary to aspiration, is
a rare complication associated with severe, refractory disease.
Schultz R, Mattila J, Gappa M, Verronen P. Development of progressive
pulmonary interstitial and intra-alveolar cholesterol granulomas (PICG)
associated with therapy-resistant chronic systemic juvenile arthritis (CJA).
Pediatr Pulmonol 2001; 32:397–402.
A 12-year-old child with systemic JIA diagnosed
in infancy . HRCT scan showed bilateral diffuse
interstitial changes, including thickening of the
interlobular septa and areas of fibrosis and
Prognosis is generally good in JIA with mortality well below 1%
Hashkes PJ, Wright BM, Lauer MS, et al. Mortality outcomes in pediatric
rheumatology in the US. Arthritis Rheum 2010; 62:599–608.
TNF Inhibitors –infliximab
IL-1 AND 6 inhibitors.
Corticosteroids and cyclosporine for refractory diseases with pulmo. HTN .
Pulmonary involvement in pediatric SLE has been reported to occur in 18% to
40% of patients within the first year of diagnosis and in 18% to 81% of patients
at any time during the disease course.
Systemic lupus erythematosus
Pleuritis with or without pleural effusion occurs in 9–32% of children at initial
disease presentation and is generally quickly reversible with steroid therapy.
Silverman E, Eddy A. Systemic lupus erythematosus. In Cassidy JT, Petty RE,
Laxer R, Lindsley C, editors. Textbook of pediatric rheumatology. 6th ed.
Philadelphia: Elsevier; 2011. pp. 318.
.Rood MJ, ten Cate R, van Suijlekom-Smit LW, et al. Childhood-onset systemic
lupus erythematosus: clinical presentation and prognosis in 31 patients. Scand J
Rheumatol 1999; 28:222–226
Acute pneumonitis, diffuse alveolar hemorrhage, pulmonary embolism, and
pulmonary hypertension are also rare pulmonary manifestations in SLE.
Swigris JJ, Fischer A, Gilles J, et al. Pulmonary and thrombotic manifestations
of systemic lupus erythematosus. Chest 2008; 133:271–280.
Chronic ILD due to SLE is extremely rare but can occur .in a necropsy series of
90 lupus patients, none had acute or chronic pneumonitis. If chronic
pneumonitis does occur, Sjogren's syndrome, infection, or drug toxicity should
Quadrelli SA, Alvarez C, Arce SC, et al. Pulmonary involvement of
systemic lupus erythematosus: analysis of 90 necropsies. Lupus 2009;
Beresford MW, Cleary AG, Sills JA, et al. Cardio-pulmonary involvement in
juvenile systemic lupus erythematosus. Lupus 2005; 14:152–158.
Shrinking lung syndrome (SLS) is also rare but may result in restrictive
lung disease mimicking ILD . In SLS, a chest CT shows normal lung
parenchyma, whereas ultrasound or electrophysiological studies may
show diaphragmatic dysfunction. SLS usually responds to corticosteroid
therapy and is associated with a good prognosis
Opportunistic infections are a leading cause of death in children with lupus,
so exclusion of infection is necessary before attributing respiratory symptoms
to inflammatory disease activity
Ferguson PJ, Weinberger M. Shrinking lung syndrome in a 14-year-old boy
with systemic lupus erythematosus. Pediatr Pulmonol 2006; 41:194–197.
Oud KTM, Bresser P, Berge RJMt, Jonkers RE. The shrinking lung syndrome
in systemic lupus erythematosus: improvement with corticosteroid therapy.
Lupus 2005; 14:959–963.
Wang LC, Yang YH, Lu MY, Chiang BL. Retrospective analysis of mortality
and morbidity of pediatric systemic lupus erythematosus in the past two
decades. J Microbiol Immunol Infect 2003; 36:203–208.
An example of shrinking lung
syndrome in a patient affected by
Rigorous investigation and treatment of infections.
Exclude other causes.
Corticosteroids corner stone in pulmonary manifestation.
Immunosuppressive agents used as corticosteroids sparing therapy.
Symptomatic lung involvement is rare in children with JDM which is distinct
from adult onset dermatomyositis in which symptomatic lung involvement
occurs in more than half of the patients .
Fathi M, Lundberg IE, Tornling G. Pulmonary complications of
polymyositis and dermatomyositis. Semin Respir Crit Care Med 2007;
Rare autoimmune inflammatory myositis.
There are, however, case reports of acute-onset, steroid-refractory, and
rapidly progressive fatal ILD in children, usually also associated with an air
Prahalad S, Bohnsack JF, Maloney CG, Leslie KO. Fatal acute fibrinous
and organizing pneumonia in a child with juvenile dermatomyositis. J
Pediatrics 2005; 146:289–292.
56. Yamanishi Y, Maeda H, Konishi F, et al. Dermatomyositis associated
with rapidly progressive fatal interstitial pneumonitis and
pneumomediastinum. Scand J Rheumatol 1999; 28:58–61.
ILD in adults may proceed, appear concomitantly with, or develop
after the onset of skin and muscle manifestations .In contrast,
symptomatic pulmonary involvement is infrequent in children.
In studies of adult patients with myositis, the presence of anti-Jo-1
antibodies and antisynthetase antibodies is associated with ILD and
also may be associated with severe disease in children.
Love LA, Leff RL, Fraser DD, et al. A new approach to the classification
of idiopathic inflammatory myopathy: myositis-specific autoantibodies
define useful homogeneous patient groups. Medicine (Baltimore) 1991;
The most common presenting symptoms of ILD are cough and dyspnea,
however, ILD is reported to occur without symptoms. PFTs show a
restrictive ventilatory defect, with decreased lung volumes, reduced
diffusing capacity for carbon monoxide, and a normal or elevated
Pneumomediastinum ,aspiration pneumonia and hypoventilation are
recognized complication in adults.
A 2-year-old child who presented with fever, hypoxia,
persistent chest infiltrates. HRCT showed bilateral
patchy airspace consolidation with air bronchograms. A
lung biopsy confirmed the diagnosis of bronchiolitis
obliterans organizing pneumonia (BOOP). Six months
later the child developed myalgias and heliotrope rash
and was diagnosed with JDM.
High dose corticosteroids
Immunosuppressive therapy methotrexate depending on
Severe or life threatening disease like ILD IV cyclophosphamide
intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review
of efficacy and safety.Riley P, Maillard SM, Wedderburn LR, Woo P, Murray KJ,
Pilkington CA Rheumatology (Oxford). 2004 Apr; 43(4):491-6.
Systemic scleroderma is the prototypic CTD associated with the
development of ILD.
Pulmonary involvement is the leading cause of mortality in SSc.
Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical,
and serologic features and survival in 1,012 Italian patients. Medicine
(Baltimore) 2002; 81:139–153.
Manifestations are ILD and pulmonary arterial hypertension (PAH). ILD
occurs in about 50% of children with SSc, whereas PAH is relatively rare
(5–8%) in children compared with adults
Pulmonary involvement is often asymptomatic. Although dyspnea is the most
frequent symptom in children with lung involvement, it only occurs in 10% to
26% of children with SSc at presentation or during the disease course.
Chest imaging classically shows bibasilar fibrosis with or without traction
bronchiectasis and honeycombing
Schurawitzki H, Stiglbauer R, Graninger W, et al. Interstitial lung disease in
progressive systemic sclerosis: high-resolution CT versus radiography. Radiology
Antitopoisomerase I (anti-Scl-70) antibodies and anti- U3RNP
antibodies are associated with pulmonary fibrosis and poor prognosis.
Arthritis Res Ther. 2003; 5(2): 80–93.
Published online 2003 Feb 12.
Early ILD in teen with scleroderma. HRCT
shows typical changes of peripheral
interlobular septal thickening with fibrosis and
No controlled trials in juvenile SSC
Cyclophosphamide some degree of efficacy.
Lung transplant selected cases in adult.
Autologous stem cell transplant under evaluation.
is a rare diagnosis in children that can have life-threatening pulmonary
involvement. It is characterized by the presence of high titer anti-U1
ribonucleoprotein RNP) antibodies in combination with clinical features of
SLE, SSc, and/or dermatomyositis and was first described as a distinct
clinical phenotype in 1972.
Pulmonary disease is a major source of morbidity and mortality in adults with
MCTD, occurring in about 75% of adult patients.Case series of MCTD in
children suggest a similar frequency of pulmonary involvement , although
pulmonary hypertension seems to be less common and lung disease is
Mier RJ, Shishov M, Higgins GC, et al. Pediatric-onset mixed connective
tissue disease. Rheum Dis Clin N Am 2005; 31:483–496; vii.
No controlled trials available
Variable presentation so therapy should be individualized.
Better outcome in children.
Vasculitis syndromes are generally classified according to their clinical
manifestations, the size and type of blood vessels involved, and the
pathologic features found within the vessel walls.
Pulmonary involvement occurs with most of vasculitis syndromes, with
clinically significant involvement with positive ANC antibodies.
Small vessels necrosis with pulmonary and renal involvement.
Classic" granulomatosis with polyangiitis is a form of systemic vasculitis
(polyangiitis) with necrotizing granulomatous inflammation of the upper
and lower respiratory tracts, systemic necrotizing vasculitis, and
necrotizing glomerulonephritis .
GPA [ Wegener’s granulomatosis]
Pulmonary involvement in GPA can be asymptomatic, insidious in onset,
or severe and fulminant. Pulmonary disease may cause any of the
Pulmonary infiltrates (71%)
Chest discomfort (8%)
Dyspnea (7%) 
Diffuse alveolar hemorrhage due to alveolar capillaritis (5%-45%)
Atelectasis, with dullness on percussion, decreased breath sounds, and
crackles on auscultation Manganelli P, Fietta P, Carotti M, Pesci A, Salaffi F. Respiratory system
involvement in systemic vasculitis. Clin Exp Rheumatol. March-April 2006.
Fauci AS, Haynes BS, Katz P, Wolff SM. Wegener's granulomatosis:
prospective clinical and therapeutic experience with 85 patients for 21
years. Ann Intern Med. January 1983. 98(1):76-85.
Clinical and supportive serology [anti- PR3 ANCA –positive] and
Standard glucocorticoids and cyclophosphamide CPA.
Rituximab for refractory disease.
Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the
management of primary small and medium vessel vasculitis. Ann Rheum Dis.
March 2009. 68:310-317.
Microscopic polyangiitis (MPA) is a necrotizing vasculitis without
granulomatous inflammation that predominantly affects small vessels
(ie, capillaries, venules, or arterioles) and can present with pulmonary
capillaritis or in the context of interstitial lung disease .
CLINICAL FEATURES OF MICROSCOPIC POLYANGIITIS
Clinical Manifestations Frequency (%)
Rapidly progressive glomerulonephritis 100
Pulmonary (hemorrhage, hemoptysis) 10–30
Constitutional symptoms (fever, chills, weight
Cutaneous (purpura, urticaria, subcutaneous
Nervous system (mononeuritis muliplex) 15–50
GI (pain, GI bleeding, infarction, perforation) 30–45
Ocular (conjunctivitis, uveitis) 0–30
Upper airway 0–15
Am Thorac Soc. 2006 Mar; 3(1): 48 57.
Is so rare in children there are, however, case reports of LIP and PAH
occurring in children with Sjo¨gren’s syndrome.
Houghton KM, Cabral DA, Petty RE, Tucker LB. Primary
Sjogren’s syndrome in dizygotic adolescent twins: one case
with lymphocytic interstitial pneumonia. J Rheumatol 2005;
Theander E, Henriksson G, Ljungberg O, et al. Lymphoma and
other malignancies in primary Sjogren’s syndrome: a cohort
study on cancer incidence and lymphoma predictors. Ann
Rheum Dis 2006; 65:796– 803.
Pulmonary involvement occurs in up to 75% of adult patients with
Sjogren's. Small airways obstructive disease is caused by lymphocytic
inflammation around the bronchioles and bronchi. Most lung diseases are
mild and no progressive. LIP and lymphoma are less common but serious
Lymphocytic interstitial pneumonitis or LIP is uncommon,
being seen mainly in patients with autoimmune disease,
particularly Sjogren's syndrome
Chronic inflammatory disease in which granulomatous lesion can develop in
many organs . The current concept is that a still unknown stimulus activates
quiescent T cells and macrophages leading to recruitment and activation of
mononuclear cells. Granuloma formation.
Pulmonary fibrosis and blindness are two potential long-term morbidities
that call for careful consideration for treatment and follow-up of the
Pulmonary involvement occurs in more than 90% and pediatric cases,
commonly affecting the intrathoracic lymph nodes and the pulmonary
Symptoms include cough, dyspnea and wheeze.
Exam may be normal or showing crackles.
elevated serum angiotensin-converting- enzyme may provide additional
evidence of sarcoidosis.
Bronchoalveolar lavage (BAL) cell profiles are not specific for
sarcoidosis, but they may help to narrow the differential diagnosis. BAL
shows a lymphocytosis
in > 85%; neutrophils are normal or low except in late disease;
CD4:CD8 ratio is increased (opposite to findings in ILD associated with
connective tissue diseases) in 50% to 60%. BAL cell profile is not
helpful in monitoring disease progression or response to therapy.
FIGURE 57-11. Bronchoscopy picture of sarcoid
airway: right upper lobe RUL airway involvement
with hypervascularity and waxy nodules
Corticosteroids depending on adults study
Worsening pulmonary symptoms and radiological changes.
Cardiac, neurological, ocular and renal symptoms.
Sever debilitating symptoms.