This chapter highlights important pulmonary manifestations of the systemic inflammatory diseases of childhood. We focus on diseases that are either common in the pediatric rheumatology clinic or those that commonly involve the lungs. This includes juvenile idiopathic arthritis (JIA), connective tissue diseases, vasculitides (especially granulomatosis with polyangiitis [GPA]), and sarcoidosis. This topic is important, as (1) pulmonary involvement may be associated with high morbidity and mortality and (2) pulmonary disease may be the predominant initial clinical presentation in a subset of these patients. Symptom patterns along with specific autoantibody serological tests are most useful for diagnosing the underlying systemic inflammatory disease. Lung disease may involve any compartment of the lung (chest wall, pleura, airways, parenchyma, and vasculature), and certain patterns of lung disease are recognized with greater frequency in specific entities. For example, interstitial lung disease (ILD) is characteristic of systemic sclerosis, while pleuritis and pleural effusions are characteristic of JIA and lupus. Lung toxicity due to potent pharmacotherapies and opportunistic infections must be distinguished from the possibility of the lung being a target organ of the underlying inflammatory disease. Treatment of lung disease is specific to the underlying systemic disease and is often effective at reducing pulmonary morbidity. Prognosis is variable and dependent on the severity of the disease and its response to therapy. Lung disease progression is monitored by following symptoms, pulmonary function, and high-resolution computed tomography imaging. The role of serological biomarkers to detect and monitor progression of ILD is an area of active investigation. As prognosis for the systemic inflammatory diseases improves, increasing emphasis is being placed on early detection and treatment of lung disease.
Keywordsconnective tissue disease, vasculitis, interstitial lung disease, diffuse alveolar hemorrhage, tracheobronchial stenosis, biological therapies
Overview of Chapter
In this chapter, we will highlight pulmonary manifestations of the systemic inflammatory diseases of childhood. We will focus on the diseases that are either common in the pediatric rheumatology clinic or those that commonly involve the lungs. These include juvenile idiopathic arthritis (JIA), the connective tissue diseases (systemic lupus erythematosus [SLE], scleroderma [SSc], juvenile dermatomyositis [JDM], and mixed connective tissue disease [MCTD]), vasculitides (especially granulomatosis with polyangiitis [GPA]), and sarcoidosis. Clinically significant pulmonary involvement due to systemic inflammatory disease is rare in the pediatric setting. However, it is important for the pediatric pulmonologist to be familiar with this topic for two reasons: (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. The systemic inflammatory diseases most frequently encountered by the pediatric pulmonologist include GPA, SLE, SSc, and MCTD. Symptom patterns along with specific autoantibody serological tests are most useful for diagnosing the underlying systemic inflammatory disease ( Table 58.1 ). Pulmonary involvement in these cases can often be a difficult diagnostic dilemma, as lung toxicity due to potent pharmacotherapies and opportunistic infections must be considered alongside the possibility of the lung being a target organ of the underlying inflammatory disease. Lung disease may involve any compartment of the lung (chest wall, pleura, airways, parenchyma, and vasculature), and often more than one pulmonary etiology may be present simultaneously (e.g., pulmonary fibrosis and chest wall restriction). Although there is certainly overlap in the pulmonary manifestations between different diseases, certain patterns are recognized with greater frequency in some entities ( Table 58.2 ). For example, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are characteristic of systemic sclerosis, while pleuritis and pleural effusions are characteristic of JIA and SLE and would be very unusual in the context of JDM. For the purposes of classifying lung disease in this chapter, ILD will be defined as a clinical diagnosis of “pulmonary fibrosis” or a lung biopsy histopathological pattern of nonspecific interstitial pneumonitis (NSIP), usual interstitial pneumonitis (UIP), lymphocytic interstitial pneumonitis (LIP), bronchiolitis obliterans (BO) organizing pneumonia (BOOP, also known as cryptogenic organizing pneumonia), or diffuse alveolar damage (DAD). Treatment of lung disease is specific to the underlying systemic disease and is often effective at reducing pulmonary morbidity. Prognosis is variable and dependent on the severity of the disease and its response to therapy. Disease progression is monitored by following symptoms, particularly dyspnea, the use of routine pulmonary function and exercise testing, and high-resolution computed tomography (HRCT) imaging. The role of serological biomarkers to detect and monitor progression of ILD, particularly SP-D and KL-6, is an area of active investigation. As the prognosis for the systemic inflammatory diseases improves, increasing emphasis is being placed on early detection and treatment of lung disease.
|Autoantibody Serologic Test||Disease Entity||Comments|
|ANA||Nonrheumatic disease||Present in 10% of normal children; may occur with infection, drug, malignancy|
|SLE||Present in virtually 100% of SLE, but not specific|
|Oligoarticular JIA||Present in 60%–80%, marker for uveitis|
|JDM||Present in 50%–75%|
|SSc||Present in 90% systemic sclerosis, 50% of localized scleroderma|
|MCTD||Present in 100%, speckled pattern and very high titer|
|Anti-dsDNA||SLE||Present in 60%–90%; very specific; titer correlates with disease activity|
|Anti-Sm||SLE||Present in 25%–40%; very specific; correlates with renal disease|
|Anti-Ro/anti-La||SLE, Sjögren’s syndrome|
|Anti-RNP||SLE, MCTD, scleroderma||When present in very high titer, suggests MCTD|
|Anticardiolipin||SLE, Antiphospholipid antibody syndrome||May also occur in infection and malignancy; IgG isotype associated with thrombosis|
|Anti-Jo-1||Myositis||Rare in children; marker for ILD in adult dermatomyositis|
|Anti-Scl-70||SSc||Marker for severe lung disease|
|Anticentromere||Limited SSc||Rare in children; marker for late development of pulmonary hypertension|
|ANCA ||Vasculitides |
|May also occur with SLE and inflammatory bowel disease |
Sensitive (>90%) and specific for GPA
Sensitive (~70%) and specific for MPA
|Rheumatoid factor||RF+ polyarticular JIA||Poor sensitivity and specificity for JIA; when present in patients with JIA it is associated with severe disease (usually adolescent females). Also positive in 50% GPA.|
|Frequency at initial presentation a||+||++||+||+++||+||+++||+++||+|
|Frequency during disease course b||+||+++||+||+++||+++||+++||+++||++|
|Chest wall/diaphragm c||+||+||+++||+||+||−||−||−|
|Pleural disease d||++||+++||−||+||++||+||+||−|
|Large airway lesions e||−||−||−||−||−||++||++||−|
|Acute pneumonitis f||+||++||+||−||−||−||−||−|
f A clinical diagnosis with acute onset of fever, tachypnea, hypoxia, and pulmonary infiltrates with or without pleural effusion on chest imaging, in the absence of infection and usually responding quickly to antiinflammatory treatment.
g Includes clinical diagnosis of “pulmonary fibrosis” and histopathological diagnosis of usual interstitial pneumonia (UIP), nonspecific interstitial pneumonitis (NSIP), lymphocytic interstitial pneumonitis (LIP), bronchiolitis obliterans organizing pneumonia (BOOP), and diffuse alveolar damage (DAD).
Juvenile Idiopathic Arthritis
JIA is the most common chronic rheumatic disease in childhood, with a prevalence of 16–150 per 100,000. The term JIA includes a heterogeneous group of diseases that have in common the following characteristics: arthritis, which begins before the age of 16 years, persists for at least 6 weeks, and for which no specific cause can be found. Overall, girls are affected approximately twice as commonly as boys are, but this varies considerably with the different subtypes. The age of onset ranges from less than 1 year to 16 years, with a peak between 1 and 3 years for the most common subtypes. The onset of JIA in the first 6 months of life is rare and should raise suspicion of another diagnosis. In a large multiethnic cohort of JIA patients, children of European descent had an increased risk of JIA, and there were significant differences in the frequency of different subtypes of JIA in different ethnic groups.
Etiology and Pathogenesis
The cause of JIA remains unknown, and the pathogenesis has not been clearly elucidated. Given the heterogeneity of the disease phenotypes, it is not surprising that the different subtypes have different genetic predispositions and associations, different autoantibody profiles, and differences in immune dysregulation. JIA is a complex genetic disease, where there are multiple genetic associations. HLA-A2 is associated with early-onset JIA, especially in the oligoarticular subtype. There are strong HLA associations with oligoarticular JIA (HLA-DRB1*08, 11, and 13 and DPB1*02). HLA DRB1*08 is also associated with rheumatoid factor negative polyarticular JIA), and RF-positive JIA is associated with DRB1*04, DQA1*03, and DQB1*03. There is also a significant association of HLA-B27 with enthesitis-related arthritis (ERA) and juvenile ankylosing spondylitis. A number of polymorphisms have been associated with JIA, including a polymorphism involving the protein tyrosine phosphatase N22 gene (PTPN22). Antinuclear antibodies are frequently found in children with oligoarticular disease and somewhat less frequently seen in polyarticular JIA. The presence of ANA is clearly associated with a higher risk of uveitis, the most common extraarticular manifestation of both oligoarthritis (occurring in 21%) and RF-negative polyarticular arthritis (14%). The systemic subtype is characterized by a lack of autoantibodies and by dysregulation of interleukin-1β production and significant elevations of interleukin-6 (IL-6). Studies using biologic agents that block the actions of IL-6 (tocilizumab) and IL-1β (anakinra, canakinamab, and rilonacept) have proven to be effective in treating patients with active systemic disease. The dysregulation of IL-1β in systemic JIA and the efficacy of IL-1β inhibitors in reversing manifestations of the disease suggest that it is more likely an autoinflammatory disease than an autoimmune disease.
The clinical manifestations of JIA depend on the subtype, which is defined by the presenting features within the first 6 months of disease onset ( Table 58.3 ). The most common subtype in Europe and North America is oligoarticular JIA, which primarily affects large joints. This can remain oligoarticular or extend after the first 6 months to involve additional joints. Both oligoarticular and RF-negative polyarticular JIA most commonly affect young preschool age girls. Asymptomatic anterior uveitis occurs in oligoarticular JIA, RF-negative polyarticular JIA, and psoriatic arthritis. If undetected by routine slit lamp examination, uveitis can result in blindness. Rheumatoid factor-positive polyarticular JIA most commonly first manifests in older girls, is phenotypically similar to adult rheumatoid arthritis, where arthritis affects small and large joints in a symmetrical pattern, and is sometimes associated with rheumatoid nodules. ERA typically develops in boys over the age of 8 years and is characterized by predominantly lower limb arthritis in association with enthesitis, inflammation where ligaments, tendons, or joint capsules attach to bone. This may be the forerunner of ankylosing spondylitis in adult life. The heel and knee are the most commonly involved entheses. ERA may be accompanied by symptomatic anterior uveitis with a painful, red eye in a proportion of patients. Arthritis may occur at disease onset but sometimes only develops after weeks or even months. The diagnosis of psoriatic arthritis in children may depend on arthritis associated with psoriatic nail changes, dactylitis, or a family history of psoriasis, since arthritis frequently precedes the development of psoriatic skin lesions by many years. Systemic arthritis is distinct from the other subtypes, both clinically and biologically, since the systemic manifestations of fever, rash, hepatosplenomegaly, lymphadenopathy, and serositis (particularly pericarditis) are usually prominent at onset, and it is thought to have an autoinflammatory pathobiology.
|Subtype||Subtype Inclusion Criteria (9)||% of All JIA (2)||Sex Ratio (2)|
|Systemic||Arthritis PLUS fever for 2 weeks, daily for at least 3 days PLUS at least one of the following: ||4%–17%||F=M|
|Oligoarticular||4 or fewer affected joints within first 6 months |
Persistent—remain with ≤ four joints
Extended—>four joints after 6 months
|Polyarticular RF negative||≥Five joints in first 6 months||11%–28%||F≫M|
|Polyarticular RF positive||≥Five joints in first 6 months||2%–7%|
|Enthesitis related arthritis||Arthritis PLUS enthesitis OR |
Arthritis OR enthesitis PLUS at least 2 of the following:
|Psoriatic arthritis||Arthritis PLUS Psoriasis OR |
Arthritis PLUS at least 2 of:
|Unclassified||Does not meet criteria for one of above OR |
Meets criteria for >1 of above
Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of JIA, occurring in approximately 10% of children with the systemic subtype. Characteristic clinical features are sustained, high fever, hepatosplenomegaly, lymphadenopathy, and sometimes bleeding, bruising, and encephalopathy. Characteristic laboratory features include a sudden drop in white blood cell count, platelet count, and hemoglobin, with elevated transaminases, LDH, coagulopathy, and very high levels of serum ferritin. Dysregulation of the IL-1β pathway is prominent in both sJIA and MAS. The mortality in a recent large series of patients with systemic JIA and MAS was 8%.
Classification and Diagnosis of Juvenile Idiopathic Arthritis
The International League of Associations for Rheumatology (ILAR) criteria for the classification are widely accepted. The inclusion criteria for the different subtypes are listed in Table 58.3 . There are also a number of exclusions for each category that are beyond the scope of this chapter.
Pulmonary Involvement in Juvenile Idiopathic Arthritis
Pulmonary involvement in JIA is uncommon and significant pulmonary manifestations, except for pleuritis, are sufficiently rare that these warrant thorough evaluation for other conditions such as infections, systemic vasculitis, SLE, and other connective tissue diseases. Pleuritis is a well-reported manifestation of systemic JIA, but it is usually accompanied by pericarditis. One should be particularly careful to exclude the diagnosis of SLE in an older girl who presents with isolated pleuritis and arthritis. There are few reports of pulmonary disease in JIA. One of the earliest studies completed more than 30 years ago found pulmonary disease in 4% of JIA patients. The radiological abnormalities included pneumonitis, interstitial reticular and nodular infiltrates, and pleural effusions. Pathologic correlates of these findings were pulmonary hemosiderosis, lymphoid follicular bronchiolitis, and LIP. Some patients with parenchymal disease developed radiographic evidence of interstitial fibrosis. There are additional reports of pulmonary hemosiderosis in JIA and a report of LIP that actually preceded the diagnosis of RF-positive JIA by 10 years. Recently patients with familial JIA-like symptoms and ILD have been described with COPA (coatomer subunit α) gene mutations, which impair vesicular transport and cause endoplasmic reticulum stress. It is possible that some of the extreme phenotypes of lung disease in association with JIA are also inherited monogenic inflammatory diseases that we will discover as our knowledge increases and with improved genetic testing.
Severe pulmonary manifestations, seen predominantly with systemic JIA, are uncommon but may be associated with a high mortality rate. An international series described 25 patients with systemic JIA and PAH ( n = 16), ILD ( n = 7), and/or alveolar proteinosis (AP; n = 5), with six patients having more than one diagnosis. In comparison to a large cohort of systemic JIA patients in a North American registry, these patients were more likely to be female and to have active systemic disease features, and were more likely to have been treated with biological agents, most commonly IL-1 inhibitors, which were used in two-thirds of patients. There was a striking association of these pulmonary complications with MAS, which was reported in 60% of patients at the time of the pulmonary diagnosis, approximately 6 times the rate at which MAS is reported to occur at any time during the disease course. Symptoms most commonly reported were shortness of breath, exertional dyspnea, cough, and chest pain, but some patients only had digital clubbing. Most concerning is that 17 patients died within a mean period of less than 9 months from the time of the pulmonary disease diagnosis. Since almost all patients developed severe pulmonary complications in the biological era (after the year 2000), biological agents have neither prevented nor effectively treated these complications. Further surveillance studies will help determine whether biological agents may potentially be involved in their pathogenesis.
One systemic JIA patient with PAH in the absence of documented pulmonary parenchymal disease responded well to treatment with cyclosporine and systemic corticosteroids. A 5-year-old girl who developed radiographic features suggestive of progressive pulmonary fibrosis had interstitial and intraalveolar cholesterol granulomas identified on lung biopsy. Although she appeared to stabilize on immunosuppressive treatment with methotrexate and etanercept, she subsequently succumbed with respiratory failure. We have seen an additional systemic JIA patient with a similarly refractory disease course who developed fatal pulmonary lipoid pneumonia ( Fig. 58.1 ). A 21-year-old male, following a long history of severe systemic JIA with persistent systemic symptoms and damaging arthritis, developed endogenous lipoid pneumonia that was ultimately treated with double lung transplantation.
Pulmonary manifestations of MAS include lung infiltrates, pneumonitis, pulmonary hemorrhage, and pulmonary edema, which may result from myocardial dysfunction associated with the hypercytokinemia typical of MAS. One large series reported pulmonary involvement in 50% of patients, and one-third of all patients required ventilatory support.
BOOP has been described in adults with rheumatoid arthritis, but there are few reports of this complication associated with JIA. BO was described in a 12-year-old girl following treatment of her arthritis with intramuscular gold injections. Despite immunosuppressive treatment and subsequent lung transplantation, the BO was progressive and fatal. BO has also been reported in a patient with JIA whose first symptoms were those related to pneumomediastinum.
Studies of pulmonary function in JIA have detected abnormal pulmonary function tests (PFTs) in more than 50% of asymptomatic patients. Restrictive disease patterns have been more commonly identified than obstructive abnormalities. Results of diffusing capacity of the lungs for carbon monoxide (DLCO) measurements have been more variable with reductions in DLCO reported in 3.7%–45%. Reductions of maximum inspiratory and expiratory pressures, suggestive of respiratory muscle weakness, may influence PFTs in these patients, but there may also be a correlation of impaired pulmonary function with disease severity, as measured by the erythrocyte sedimentation rate (ESR) and requirement for treatment with methotrexate. Since methotrexate is the most commonly used second-line drug for the treatment of JIA, it is important to consider whether it has any impact on the development of lung disease. Low-dose weekly methotrexate has been reported to cause an acute pneumonitis associated with fever, cough, and dyspnea. There have also been concerns raised about methotrexate-induced chronic, progressive pulmonary fibrosis. However, several studies suggest that methotrexate does not increase the risk of pulmonary disease in children with arthritis.
Nonsteroidal antiinflammatory drugs (NSAIDs) and intraarticular corticosteroid injections are considered first-line treatments for children with JIA and may be all that is required to treat oligoarticular involvement or mild disease. Children whose arthritis does not respond adequately, especially those with a polyarticular course, are treated with low-dose weekly methotrexate. The advent of biological agents has dramatically improved outcomes for children whose arthritis is refractory to methotrexate. Tumor necrosis factor alpha (TNFα) inhibitors, such as etanercept, adalimumab, or infliximab, are usually used if there is an inadequate response to methotrexate or if there is intolerance to methotrexate. Newer biological options for polyarticular course JIA include abatacept and tocilizumab. There are different treatment algorithms followed for different subtypes: neither methotrexate nor TNFα inhibitors are particularly effective for systemic JIA. Children who have persistent systemic symptoms and arthritis despite NSAIDs usually respond to systemic corticosteroids. IL-1 antagonists such as anakinra, canakinumab, and rilonacept or the IL-6 antagonist, tocilizumab, have proven to be highly efficacious for steroid-dependent systemic JIA. Pediatric rheumatologists are changing the treatment paradigm to treat earlier and more aggressively to try to change the course of the immune response and prevent long-term joint damage in all subtypes of JIA. For example, many treat JIA patients with IL-1 inhibition, even before corticosteroids are used. Acute symptomatic serositis, especially pericarditis, may require intravenous pulsed methylprednisolone. A similar approach is taken for MAS with early use of cyclosporine or IL-1 inhibitors if there is not a rapid response. ERA does not respond as well as other subtypes to methotrexate but may respond to treatment with sulfasalazine. Axial spine involvement may need early institution of TNFα inhibitors.
The mortality in JIA is well below 1%, with a disproportionately higher mortality risk in the systemic subtype, largely because of MAS associated with the disease and infections associated with immunosuppressive therapy. Overall, active arthritis persists on long-term follow-up, even into adult life, in more than 50% of patients. Poor prognostic features of the systemic subtype include persistent systemic symptoms, marked thrombocytosis, and polyarticular arthritis in the first 6 months of disease. For the other subtypes, positive rheumatoid factor, marked and persistent elevation of inflammatory markers, involvement of the hip joint, and early joint space loss and erosions predict poor outcome. Acute pleuritis usually responds well to treatment without sequelae, but the pulmonary manifestations such as PAH, ILD, and AP carry a high mortality.
Systemic Lupus Erythematosus
SLE predominantly affects young women, but in approximately 15%–20% of individuals, the disease presents prior to the age of 18 years. SLE is relatively rare in children, with an estimated incidence of 10–20 per 100,000 that is considerably higher in black, Hispanic, South and South-East Asian, as well as North American First Nations populations. In postpubertal adolescents, females are clearly more commonly affected than males (~6 : 1), but in the younger age groups, the female predominance is much less marked.
SLE is the prototypic autoimmune disease, characterized by presence of autoantibodies in virtually all patients. There is substantial evidence of both innate and adaptive immune dysregulation and of immune activation and autoimmunity, resulting from the interaction of lupus-associated genes with environmental triggers. Environmental triggers include ultraviolet radiation, infections, drugs, and chemicals. The activation of the immune system is amplified by lupus autoantibodies and their associated nucleic acids, together with cytokines and chemokines, resulting in inflammation and tissue damage. Autoantibodies can actually be detected many years before the development of clinically symptomatic SLE.
Common presenting symptoms of SLE in children are rash, joint pain, and constitutional symptoms such as fatigue, fever, and weight loss. The most common presenting features in a large cohort of pediatric lupus patients were arthritis (67%), malar rash (66%), nephritis (55%), and central nervous system disease (27%).
The American College of Rheumatology criteria for the classification of lupus in adults appear to apply well to children with SLE ( Box 58.1 ) and have been reported to achieve a sensitivity of 96% and specificity of 100% for the diagnosis of SLE in a pediatric population. Although the classification criteria require that four or more of the 11 criteria are present, there are no published diagnostic criteria, and the diagnosis of SLE in children can certainly be made when fewer than four criteria are present.
Nasal or oral ulcers
Arthritis involving at least two joints
Proteinuria >0.5 g/day, or
Cellular casts in the urine
Hemolytic anemia, or
Leukopenia (<4000/mm), or
Lymphopenia (<1500/mm), or
Anti-DNA antibody, or
Anti-Sm antibody, or
Positive antinuclear antibody
A person is classified as having SLE if at least 4 of the 11 criteria are present serially or simultaneously.
SLE, Systemic lupus erythematosus.
Pulmonary involvement in pediatric SLE has been reported to occur in 18%–40% of patients within the first year of diagnosis and in 18%–81% of patients at any time during the disease course. It occurs more frequently in Afro-Caribbeans. Studies that report higher rates of pulmonary involvement include abnormal pulmonary function tests or abnormal imaging studies, even in the absence of symptoms. Pulmonary involvement can indeed be very mild, or even asymptomatic, but can also be life-threatening with respiratory failure. Pulmonary lupus has been reported to be more severe when SLE begins within the first 2 years of life. Pleuritis with pleural effusion is the only pulmonary manifestation to be included among the criteria for the classification of SLE and occurs in 9%–32% of patients, and may even be the initial clinical manifestation of SLE. In a large cohort of adult lupus patients, pleuritis was found to occur more frequently in patients with a younger age at disease onset, and longer disease duration, who manifested more cumulative disease-related damage, and in those who had positive anti-Sm and anti-RNP antibodies. Pleural effusions are exudative and may be unilateral or bilateral. These must be differentiated from infectious exudative effusions and from transudative effusions related to renal or cardiac disease. SLE is associated with an increased risk of a wide range of infections, including bacterial, viral, mycobacterial, fungal, and parasitic infections, with the respiratory tract as one of the common sites. In addition, immunosuppressive treatments to control the disease confer an increased risk of opportunistic infections such as pneumocystis, cytomegalovirus, and fungal infections. Inflammatory pulmonary lesions may be difficult or even impossible to differentiate from pulmonary hemorrhage or pulmonary infections. Since infection is the leading cause of death in children with lupus, rigorous exclusion of potential infections is necessary before attributing pulmonary manifestations to disease activity. Cultures of sputum (if obtainable), nasopharyngeal secretions, blood, and pleural fluid should be performed, but bronchoalveolar lavage (BAL) and lung biopsy may be necessary. Children at risk should be carefully evaluated for tuberculosis.
Acute pneumonitis is uncommon in adults with lupus and even less common in pediatric lupus. The presentation includes fever, nonproductive cough, dyspnea, pleuritic chest pain, and tachypnea. Chest radiographic findings are nonspecific, with infiltrates that can mimic infections or hemorrhage and that may be accompanied by pleural effusions ( Fig. 58.2 ). Chronic ILD due to SLE is extremely rare; in a necropsy series of 90 lupus patients, none had acute or chronic pneumonitis. If chronic pneumonitis does occur, Sjögren syndrome (SS), infection, or drug toxicity should be excluded. Chronic ILD can follow acute lupus pneumonitis but can also develop in a more insidious manner with exertional dyspnea, chronic cough, pleuritic chest pain, and basal rales. Patients tend to have multisystem manifestations of SLE. Pulmonary function studies typically follow a slowly progressive course with a restrictive pattern, but may improve or at least stabilize. Histopathology demonstrates alveolar wall thickening, interstitial fibrosis, interstitial lymphocytic infiltrates, and granular deposits of immunoglobulin and complement.
Pulmonary hemorrhage is a rare but potentially life-threatening complication of SLE in children that has been reported to occur at disease onset or during the course of the disease. Significant acute pulmonary hemorrhage is accompanied by severe dyspnea with or without hemoptysis and a sudden drop in hemoglobin, and it may progress rapidly to respiratory failure. Lupus nephritis is present in a high proportion of patients. The mortality resulting from pulmonary hemorrhage in adult series of SLE has been as high as 50%, and one report suggests an even higher mortality in childhood lupus. Chest radiographs show diffuse alveolar opacities indistinguishable from fluid or infection. Lupus patients with acute pulmonary hemorrhage should be carefully investigated for pulmonary infections. In one report, more than 50% of patients had an infection identified within 48 hours of presentation with pulmonary hemorrhage. Infections identified included pseudomonas, cytomegalovirus, and aspergillus. Empiric treatment with antibiotics may improve survival. Thrombotic thrombocytopenic purpura should be ruled out, particularly in the presence of fever, thrombocytopenia, and renal dysfunction, since this may be associated with SLE.
Pulmonary hypertension is rare in children with SLE, but has been reported in 14% of adult patients, followed at a tertiary care center. In a large series of adult patients followed at nontertiary care centers, the prevalence of pulmonary hypertension determined by echocardiography was found to be 4.2%. The presence of a lupus anticoagulant was the only risk factor identified for the development of pulmonary hypertension in this cohort. Raynaud phenomenon occurs more frequently in lupus patients with pulmonary hypertension than in other lupus patients. Potential causes of pulmonary hypertension in SLE include pulmonary vasculitis, pulmonary thromboembolism, ILD, and valvular heart disease. Serum endothelin levels have been found to be higher in patients with pulmonary hypertension than in other lupus patients, and antiendothelial cell antibodies are elevated in patients with active lupus and pulmonary hypertension.
Antiphosphospholipid antibodies are found more frequently in SLE than other connective tissue diseases, with a prevalence of 44% for anticardiolipin antibodies, 40% for anti-β2 glycoprotein I, and 22% for the lupus anticoagulant. Anticardiolipin titers correlate with lupus disease activity. Several studies have confirmed a strong association with antiphospholipid antibodies and vascular thromboses in children with SLE. Lupus anticoagulant appears to confer the highest risk of thrombosis, but there is also a clear association of thrombosis with anticardiolipin and anti-β2GPI, Pulmonary embolism is the most frequent pulmonary manifestations of the antiphospholipid antibody syndrome, and recurrent pulmonary embolism can result in pulmonary hypertension.
Shrinking lung syndrome occurs predominantly in adults with SLE but has also been reported in children. It typically presents with progressive dyspnea, pleuritic chest pain, and tachypnea. Chest radiographs may demonstrate reduced lung volumes, raised hemidiaphragms, and basal atelectasis ( Fig. 58.3 ); PFTs are usually restrictive. Chest computed tomography (CT) scans do not reveal significant pleural or parenchymal lung disease. The cause of this syndrome in SLE remains unclear, but diaphragmatic dysfunction with poor diaphragmatic movement demonstrable on fluoroscopy has been reported in some pediatric cases. Diaphragmatic dysfunction with subsequent shrinking lung syndrome has been linked to symptomatic pleuritis. Although the optimum treatment is not clear, some patients appear to respond to immunosuppressive therapy.
Studies in pediatric SLE patients without clinically or radiographically apparent lung disease have found PFT abnormalities in at least one-third, with a range of 38%–84%. PFT abnormalities most frequently seen are restrictive with or without a diffusion abnormality. Most studies have not shown any correlation between PFT abnormalities and lupus disease activity. It is important to note that isolated abnormal pulmonary function tests in children with lupus do not predict progressive lung disease.
High-resolution CT imaging in a cohort of 60 Norwegian patients with childhood-onset SLE revealed that 8% had abnormal findings, including micronodules and bronchiectasis, but none had ILD. These findings did not correlate with PFT abnormalities, but a more recent study did show some correlations. Although CT imaging is more sensitive than plain chest radiography, routine screening of asymptomatic pediatric lupus patients with CT is not recommended.
Since infection is the major cause of mortality in pediatric SLE, children with pulmonary manifestations require rigorous investigation and treatment of infectious complications. It is also important to exclude other causes of pulmonary pathology in SLE, such as thromboembolism, drug toxicity, and the impact of cardiac or renal disease. Corticosteroids are highly effective in treating lupus pleuritis and pleural effusions, and remain the mainstay of treatment for moderate to severe pulmonary manifestations of SLE in children. The majority of children with SLE are treated with hydroxychloroquine, which is particularly effective for cutaneous disease, arthritis, and mild constitutional symptoms, and in reducing the risk of disease flares. Immunosuppressive drugs such as azathioprine and mycophenolate mofetil are frequently used to prevent organ damage and as corticosteroid-sparing agents. There may also be a role for methotrexate and cyclosporine. For the most severe manifestations such as pulmonary hemorrhage, pulse methylprednisolone (30 mg/kg per dose up to 1000 mg) may be administered daily for 3 days or longer, followed by high-dose daily oral systemic corticosteroids. Although there are no controlled clinical trials for the treatment of pulmonary hemorrhage, intravenous pulse cyclophosphamide (CYC) is frequently used and appears to be associated with improved survival. Although plasmapheresis is not of proven benefit, it has been used in life-threatening pulmonary hemorrhage. Certainly, in patients with TTP and catastrophic antiphospholipid antibody syndrome, plasmapheresis can be a life-saving therapy. Rituximab, a B-cell depleting biologic agent, is assuming an increasing role in the treatment of pediatric SLE, but its role in the treatment of pulmonary manifestations remains to be defined. Vascular thromboses associated with antiphospholipid antibodies require anticoagulation.
Disease severity is greater in children with SLE than in adults, and the majority of children develop organ damage within 5–10 years of diagnosis. Long-term morbidity includes premature atherosclerosis and osteoporosis. Five-year survival rates in pediatric SLE range from 85% to 95%, but this may be improving, with a recent study reporting a 99.6% survival rate. Renal disease and infections were the most common causes of death.
JDM is a rare autoimmune inflammatory myositis in which a capillary vasculopathy causes characteristic cutaneous and muscle manifestations, although other organs can be affected. In children, symptomatic lung involvement is infrequent, which is distinct from adult dermatomyositis (DM), where symptomatic lung involvement occurs in more than half of patients.
JDM is the most common inflammatory myopathy in children, accounting for approximately 85% of cases and has an incidence of 0.2–0.4 per 100,000 children. It is a distinct disease entity from adult DM. Peak incidence occurs from 5 to 10 years of age, and females are 2 to 5 times more likely to develop the disease than males. A case report in monozygotic twins has suggested a genetic predisposition to JDM in some families.
Although the etiology of JDM is unknown, genetics, environmental exposure, and infections are thought to be related to the disease development. No specific causative gene has been found, but certain HLA alleles (HLA-B8, HLA-DQA1*0301, and HLA-DQA1*0501) and polymorphisms in tumor necrosis factor-alpha and interleukin-1 receptor antagonist have been reported as risk factors for the development of JDM and for certain phenotypes. There is increased type I interferon gene expression and upregulation of MHC class I expression on the surface of muscle fibers. JDM is characterized by various degrees of vasculopathy with immune complex deposition and the development of calcinosis in the later stages of disease.
JDM has a relatively homogeneous presentation in children with mainly cutaneous and muscle manifestations. The initial symptoms are usually skin rash (often with heliotrope rash over the eyelids and Gottron’s papules over extensor surfaces of joints), fever, and proximal muscle weakness. Characteristic changes in the nail fold capillary bed are common, and measuring the density of capillaries/mm may be a useful tool for monitoring clinical activity in JDM. Other disease manifestations include skin ulcerations, soft tissue calcification, arthritis, lipodystrophy, and insulin resistance. Serious gastrointestinal and lung involvement occur only occasionally.
According to the traditional criteria of Bohan and Peter, the diagnosis of JDM is based on the following five criteria: proximal muscle weakness, characteristic rash, elevated muscle enzymes, characteristic myopathic findings on electromyography, and typical muscle biopsy findings. Criteria for definite JDM are the pathognomonic rash and three other criteria, while the diagnosis of probable JDM requires the rash and two other criteria. Most children with JDM do have both proximal muscle weakness and rash, and elevated serum muscle enzymes are usually, but not always, present. Newer proposed criteria include the presence of nail fold capillary abnormalities, magnetic resonance imaging that demonstrates the presence of muscle inflammation, calcinosis, and dysphonia. In cases where the diagnosis remains uncertain, the more invasive muscle biopsy may be necessary. JDM must be differentiated from other noninflammatory causes of muscle weakness (muscular dystrophies and metabolic myopathies), transient postviral myositis, and myositis due to other rheumatologic diseases (systemic scleroderma, SLE, MCTD, and systemic JIA). Elevated C-reactive protein and erythrocyte sedimentation rate and the presence of antinuclear antibodies are common but nonspecific findings that have limited diagnostic value. Myositis-specific antibodies, which are commonly associated with adult forms of DM and polymyositis, are uncommon in JDM; hence they are not usually helpful in making the diagnosis. However, the presence of anti-Jo-1 and antisynthetase antibodies are associated with ILD in adults and may also be associated with more severe disease in children that more closely resembles adult DM.
ILD is a common cause of morbidity and mortality for adult onset DM and polymyositis, occurring in up to 65% of cases. In adults, ILD may precede, appear concomitantly with, or develop after the onset of skin and muscle manifestations. In contrast, symptomatic pulmonary involvement is infrequent in children with JDM. In the largest case series of JDM presented to date, only 1 of 105 patients (<1%) at the Hospital for Sick Children in Toronto, Canada, developed symptomatic ILD ( Fig. 58.4 ). Other case series have reported higher rates of ILD detected by pulmonary function testing and HRCT scanning; however, most of these cases were not histologically confirmed. Although symptomatic ILD is rare enough that its description is mainly limited to case reports, it is important to recognize its onset, as it can be rapidly progressive and fatal ( Fig. 58.5 ). A Japanese nationwide collaborative study identified 10 cases of rapidly progressive interstitial lung disease (RP-ILD), seven of whom died. Antimelanoma differentiation-associated gene 5 (MDA5) antibodies, and high serum levels of interleukin 18 (Il-18), Krebs von den Lungen-6 (KL-6), and ferritin were associated with RP-ILD. Pneumomediastinum is a characteristic complication of adult DM with interstitial pneumonitis and has also been reported in JDM ( Fig. 58.6 ). Aspiration pneumonia and hypoventilation are also frequently reported pulmonary complications in adult DM. In adult studies, the strongest predictive factor for ILD in patients with myositis is the presence of anti-Jo-1 antibodies.
The most common presenting symptoms of ILD are cough and dyspnea, although ILD has been reported to occur without symptoms. Pulmonary function tests show a restrictive ventilation defect, with decreased lung volumes, reduced diffusing capacity for carbon monoxide and normal or elevated FEV 1 :FVC ratio. Decreased DLCO is not specific for ILD, as it may also occur with pulmonary hypertension, which can occur in patients with a variety of connective tissue diseases. Chest radiographs may have changes suggestive of ILD, but HRCT of the lungs is considered the standard procedure for initial evaluation of patients with suspected ILD. The most common pattern observed in adult DM is irregular linear opacities with areas of consolidation and ground-glass attenuation, suggesting active inflammation. Honeycombing occurs uncommonly. The differential diagnosis for ILD always includes infection and drug-induced lung disease. BAL can help rule out infection. Although lung biopsies are not routinely performed in adult DM, in children where ILD is uncommon and there are no data on the role of HCRT in predicting histological patterns, a lung biopsy may be required to obtain a diagnosis. Pulmonary fibrosis, acute interstitial pneumonitis, BOOP (see Fig. 58.4 ), and DAD have all been reported as lung histological findings in JDM.
Many observational studies have reported asymptomatic pulmonary function abnormalities in 30%–40% of children with JDM, A small longitudinal case series reported pulmonary function abnormalities in 5 of 12 patients with JDM who had no respiratory symptoms, but these abnormalities were generally of a mild nature and nonprogressive, showing a restrictive defect. More recently, a larger case-control study of 59 JDM patients from Oslo showed a restrictive ventilatory defect in 26% compared with 9% of controls. These mild nonprogressive restrictive pulmonary defects have generally been attributed to respiratory muscle weakness or calcinosis in the chest wall and need to be differentiated from the reduced lung compliance that occurs with ILD. Findings of reduced maximal inspiratory and expiratory pressures, reduced maximal voluntary ventilation, normal DLCO, and increased residual volume without decreased FEV 1 :FVC ratio help distinguish respiratory muscle weakness from ILD.
The mainstay of treatment is high-dose corticosteroids, usually weaned slowly over a 1–2 years period. Intravenous pulse methylprednisolone is frequently used for children with more severe weakness. Immunosuppressive therapy is used to treat JDM, based mainly upon results reported in observational studies and clinical experience. In a single randomized but unblended multicenter trial, 139 children with new-onset JDM were assigned to prednisone alone, prednisone plus methotrexate, or prednisone plus cyclosporine: the two combination arms had better efficacy but more adverse events, particularly infection, compared with prednisone alone. The most commonly used immunosuppressive agent is methotrexate administered weekly. Since reports of the benefits of methotrexate in reducing the duration and cumulative dose of systemic corticosteroids have emerged, in many centers, methotrexate is routinely added to systemic steroids at the initiation of treatment. There are also reports of the efficacy and steroid sparing effects of cyclosporine in JDM, and some clinicians use cyclosporine as initial therapy together with prednisone. Cyclosporine has also been reported to be effective in combination with systemic corticosteroids in the treatment of a small series of children with JDM-associated ILD. Controlled trials of intravenous immunoglobulin in adults, and uncontrolled trials in children, support its use. In patients with severe or life-threatening disease, such as ILD, chronic skin ulceration, or gastrointestinal involvement, intravenous CYC (500–750 mg/m 2 every 4 weeks) is used in combination with high-dose corticosteroid therapy. Rituximab has been shown to be associated with clinical improvement in two small case series of severe JDM and a randomized trial that included 48 children with refractory JDM. Case reports have also suggested improvement in selected refractory JDM patients with infliximab and abatacept.
Mortality rates for JDM declined from more than 30% in the 1960s before routine glucocorticoid therapy was given, to less than 3% in the 2000s with the advent of early combination immunosuppressive therapy. Patients with typical disease who are treated with early immunosuppressive therapy now usually have an excellent prognosis. Long-term morbidity is generally related to disease complications, such as calcinosis and other complications related to drug toxicity, including growth retardation and osteoporosis. Acute onset and rapidly progressive ILD with associated air leak is only very occasionally a cause of mortality in JDM. Small defects in pulmonary function should be followed over time to ensure that slowly progressive ILD, which is well described in adult DM, does not develop.
Systemic scleroderma, also known as systemic sclerosis (SSc), is a connective tissue disease marked by typical skin thickening and hardening (sclerosis) and multiorgan fibrotic changes. It is rare in childhood. One study of Finnish children found an incidence of juvenile SSc of 0.05 per 100,000, while a 2005–2007 survey in the UK and Ireland found an incidence of 0.27 cases per million children. It has been estimated that up to 10% of adults with SSc have the onset of their disease in childhood. In a large series of children from multiple countries, juvenile SSc was almost four times more common in females and began at a mean age of 8 years.
SSc usually has an insidious onset in children with skin changes in the hands and face and/or Raynaud phenomenon. Other common presenting findings are constitutional symptoms (fatigue, weight loss), arthralgia, muscle weakness and pain, subcutaneous calcifications, dysphagia, and dyspnea. The time interval between onset of symptoms and diagnosis is often prolonged (average 1.9 years).
The skin abnormalities are often heralded by a phase of edema, which is then followed by the development of skin tightening and sclerosis, and as this becomes more prominent, contractures develop. When sclerosis affects the face, loss of wrinkling of the skin results in the pathognomonic expressionless facies. The skin can subsequently atrophy and develop telangiectasia. The vasculopathy is reflected in abnormalities easily seen in the nail fold capillaries with dropout, dilatation, tortuosity, and hemorrhages. Digital ulcers (with resulting digital pitting scars) accompanying Raynaud phenomena is very suggestive of SSc. The most common, nondermatologic clinical features of juvenile SSc in the two largest series reported to date were Raynaud phenomenon (72%–84%), followed by musculoskeletal (arthralgias, muscle weakness and pain 64%–79%), gastrointestinal (esophageal dysfunction 65%–69%), and pulmonary (42%–50%) involvement. Cardiovascular (29%–44%), renal (10%–13%), and neurologic disease (3%–16%) occurred less frequently. Calcinosis developed in 18%–27%. The disease tends to be most active during the first 5 years after onset, when skin sclerosis advances rapidly and visceral involvement commonly occurs. After 5 years, constitutional symptoms abate, skin abnormalities often stabilize or even improve, but visceral disease may progress.
Systemic sclerosis can be divided into limited and diffuse forms. Skin involvement is limited to an acral distribution (hands, face, and feet) with limited disease, while diffuse disease has truncal and acral skin involvement and usually early and significant multiorgan disease. More than 90% of children with juvenile SSc have the diffuse form. A higher proportion of children than adults with the disease have features of an overlap connective tissue disease syndrome.
SSc is classified according to the extent of skin and pattern of internal organ involvement. Consensus-based classification criteria for juvenile SSc have been proposed for children whose disease begins before the age of 16 years. These criteria require the presence of the major criterion of proximal sclerodermatous changes and at least two of the minor criteria, which have been expanded to 20 items, including involvement of other organ systems as well as some serological abnormalities (ANA and systemic sclerosis selective autoantibodies). The minor criteria are sclerodactyly, peripheral vascular disease (Raynaud phenomenon, nail fold capillary abnormalities, digital tip ulcers), gastrointestinal (dysphagia, reflux), cardiac (arrhythmia, heart failure), renal (renal crisis, hypertension), neurologic (neuropathy, carpal tunnel syndrome) and musculoskeletal disease (tendon friction rub, arthritis, myositis), respiratory (DLCO of <80% predicted), PAH, and pulmonary fibrosis seen on chest radiography or HRCT and serology (antinuclear antibodies, SSc selective autoantibodies [anticentromere, antitopoisomerase I [Scl-70], antifibrillarin, anti-PM/Scl, antifibrillin, or anti-RNA polymerase I or III]). The 1980 criteria for adult SSc have been widely used for children in the past. These rely on either the presence of the major criterion of sclerodermatous changes proximal to the metacarpophalangeal or metatarsophalangeal joints or the presence of at least two of the following minor criteria: sclerodactyly, digital pitting scars, or bibasilar pulmonary fibrosis.
SSc is characterized by inflammation, excessive fibrosis and vasculopathy affecting the skin, and multiple organs with evidence of immune, endothelial, and fibroblast dysfunction. While the etiology and exact pathogenetic mechanisms remain elusive, endothelial cell injury appears to be an early and important event. Endothelin-1 has emerged as an important mediator of the vascular changes, and serum levels correlate with disease severity markers. There are features of autoimmunity with the following SSc-selective autoantibodies included in the new proposed minor criteria: anticentromere, antitopoisomerase I (Scl-70), antifibrillarin, anti-PM-Scl, antifibrillin, and anti-RNA polymerase I or III. ANA is found in approximately 80%, ENA in 40%, and anti-Scl-70 in approximately one-third of pediatric patients.
ILD ( Figs. 58.7 and 58.8 ), PAH, and cardiomyopathy are dreaded organ manifestations associated with mortality in children; initial workup and monitoring should focus on detecting these manifestations. ILD, while relatively common in adults, is rare in children. Hence, most of what we know about the characteristics and risk factors for ILD, prognosis and treatment comes from adult studies. ILD is best detected on HRCT. Dyspnea and dry cough are late symptoms. Pulmonary function tests (FVC and DLCO) correlate with severity of disease. The typical form of ILD (seen in 77.5% of adult cases) has a histological pattern of NSIP, while a few cases have a UIP pattern. When ILD occurs, it usually is detected at initial presentation or within the first 3 years after onset of symptoms. Not all cases of ILD progress; hence decisions on which cases to treat can be difficult.
SSc is also associated with pleuritis, pleural effusions, bronchiectasis, BOOP, and alveolar hemorrhage. Spontaneous pneumothorax with severe fibrosis and aspiration pneumonia associated with esophageal reflux may also be seen. ILD and progressive decline of pulmonary function have been associated with more severe esophageal dysmotility in adults with SSc.
Pulmonary involvement is often asymptomatic. Although dyspnea is the most frequent symptom in children with lung involvement, it only occurs in 10%–26% of children with SSc at presentation or during the disease course. Dry cough is even less frequent. Abnormal chest radiography is seen at presentation in 12% and in 29% during the disease course. Ground-glass opacities are suggestive of ILD, and a reticular pattern and traction bronchiectasis may be seen. High-resolution CT is a more sensitive method of detecting these findings and may find additional abnormalities in addition to ground glass densities, such as subpleural micronodules, linear opacities, and honeycombing appearance. Patients with normal HRCT scans on initial assessment are likely to have normal HRCT scans after a follow-up period of 5 years. One study in adults with SSc found that ground-glass opacity was the most common finding on HRCT and was only reversible in a small minority of patients who had sequential scans, suggesting that ground-glass opacity may actually indicate fine fibrosis.
Global disease activity is monitored with a multidimensional disease severity score, the Juvenile Systemic Sclerosis Severity Score (J4S), which includes measures of spirometry, DLCO, HRCT, and oxygen dependency. PFTs are important in the initial assessment and ongoing monitoring of patients with SSc. Reduced DLCO may be an early marker of ILD or PAH and also correlates with the severity of these disease manifestations. Children with SSc most often have reduced forced vital capacity with a restrictive PFT pattern (42%–65%). It is important to note that almost half of those with abnormal PFTs do not have lung imaging abnormalities, calling into question the etiology of the decrements in lung function. It is this author’s opinion that some of these unexplained PFT decrements are due to limited chest wall expansion due to sclerodermatous changes of the thorax. Serial PFTs in adults with SSc and severe pulmonary fibrosis demonstrate that most of the lung volume loss occurs in the first 4 years of the disease.
The best way to monitor pediatric SSc patients for the new onset of ILD or progression of ILD is not clear. A study of serial PFTs and HRCT in children with SSc found that PFTs, particularly lung volume studies, correlate with findings on HRCT, suggesting that monitoring with PFTs can identify which patients require follow-up HRCT. The authors acknowledge, however, that PFTs do not completely exclude mild pulmonary involvement, and they therefore entertain the notion of a surveillance low-radiation dose HRCT at some point during follow-up for lung disease. More extensive disease on HRCT correlates with poor prognosis in adult SSc patients.
In adults, anti-Scl-70 antibodies are associated with ILD, while anticentromere antibodies are protective. In children, serum KL-6 has been reported as a potentially useful biomarker of ILD in juvenile SSc and correlates with PFT abnormalities and the severity of ILD. Lung biopsy is generally not required when the clinical features, pulmonary function test results, and imaging findings are typical for ILD. Moreover, pathological findings do not reliably predict disease course and outcome. BAL has not been found to predict disease course reliably or response to treatment.
PAH may occur as an isolated phenomenon or in association with ILD. Right heart catheterization may be the gold standard for identifying PAH, but Doppler echocardiography is effective and noninvasive. Anticentromere antibodies are associated with isolated PAH, and anti-U3 RNP antibodies are associated with PAH in adults with SSc.
Nonpharmacologic therapy measures include skin care, exercise programs, and corrective splints as needed. Pharmacologic therapy tends to be targeted toward controlling disease in specifically involved organs. There have been no controlled treatment trials in juvenile SSc. Treatment approaches for juvenile SSc–related lung disease have therefore drawn heavily on reports of successful treatment in adults. Both daily oral CYC and monthly intravenous CYC have demonstrated some degree of efficacy in ILD associated with SSc, with only modest benefits on respiratory function. There are only uncontrolled studies using mycophenolate mofetil, azathioprine, and rituximab in adults. Lung transplantation has been successful in carefully selected patients who have limited involvement of other major organs. Autologous hematopoietic stem cell transplantation has also been shown to stabilize major organ disease and is currently being evaluated in controlled trials.
Prognosis is generally better in childhood-onset compared with adult-onset SSc, likely due to lower rates of ILD and PAH. Survival rates of juvenile SSc at 5, 10, 15, and 20 years after diagnosis are 89%, 80%–87%, 74%–87%, and 69%–82%, respectively. The mortality risk in adults with SSc is dramatically higher with PAH, and survival is negatively impacted by lung disease, even without PAH. Survival in pulmonary hypertension associated with ILD is significantly worse than isolated PAH. Similarly, in children with a fatal outcome, pulmonary involvement occurs more frequently and earlier in the disease course. Antitopoisomerase I (anti-Scl-70) antibodies and anti-U3RNP antibodies are associated with pulmonary fibrosis and poor prognosis in adults, but not children. However, some children with early organ involvement have a rapidly progressive course. Scleroderma-related heart disease is a frequent cause of death among children with SSc. In adults, some risk factors for mortality and progression of SSc associated ILD have been identified, including older age, lower FVC, lower diffusing capacity for carbon monoxide, and extent of disease on HRCT chest imaging. Similar work has not been done in childhood onset SSc and is more difficult due to the rarity of ILD in children. However, one should cautiously and carefully monitor children with ILD, as some do follow a rapidly progressive course.
Mixed Connective Tissue Disease
MCTD is a very rare diagnosis in children but 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, or DM and was first described as a distinct clinical phenotype in 1972.
Epidemiology and Pathogenesis
MCTD accounts for only 0.1%–0.5% of pediatric rheumatology cases. Median age of childhood onset is approximately 11 years (4–16 years) with girls diagnosed three times more often than boys. More commonly MCTD presents in women in the second to third decade of life, although pediatric onset accounts for 25% of cases.
The etiology of MCTD is unknown. Complex interactions occur between the innate and adaptive immune system, and there is evidence that anti-RNP antibodies are involved in pathogenesis of disease.
Clinical Manifestations and Diagnosis
Children usually have an insidious onset of disease, with Raynaud phenomenon, constitutional symptoms (malaise, fatigue, and low-grade fever) and polyarthritis as initial clinical symptoms in combination with a high titer of speckled ANA pattern. A high titer of anti-RNP antibodies is a strong predictor of the eventual evolution to MCTD. Classic clinical manifestations of other connective tissue diseases (often the skin rash of SLE or JDM, SSc skin, swollen hands, proximal muscle weakness, esophageal dysmotility, pericarditis, leukopenia, and pulmonary dysfunction) develop sequentially over time but not in any predictable manner or time frame. A clear diagnosis of MCTD may not be evident for years, and the initial presenting syndrome may be referred to as “undifferentiated CTD.”
Several sets of diagnostic criteria for MCTD exist; however, Kasukawa’s criteria are used most frequently in children and are the most restrictive. Three criteria must be fulfilled for diagnosis of MCTD: (1) Raynaud phenomenon or swollen fingers or hands, (2) anti-RNP antibody positive, and (3) at least one abnormal sign or symptom from two or more of these categories: SLE, SSc, or DM. Almost any organ can be involved in MCTD; however, there are four clinical features that are distinctive for MCTD: (1) the presence of Raynaud phenomenon and swollen hands or fingers, (2) the absence of severe renal or central nervous system disease (differentiates MCTD from SLE), (3) more severe arthritis with insidious onset of pulmonary hypertension (without pulmonary fibrosis), and (4) autoantibodies with specificity to anti-U1 RNP.
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 generally mild. Pulmonary disease onset is often initially asymptomatic and develops insidiously. Common symptoms include dry cough, dyspnea with exertion, and chest pain. Pulmonary fibrosis, pleural effusions, and PAH are the most common manifestations. Other findings include thromboembolic disease, pulmonary hemorrhage, diaphragmatic dysfunction, and aspiration pneumonitis.
PAH is due to a pulmonary vasculopathy with intimal proliferation and medial hypertrophy of pulmonary arterioles. Unlike SSc, the lung parenchyma is not fibrotic. Although PAH is rare in children with MCTD, it can develop rapidly. One adult case of pulmonary hypertension due to veno-occlusive disease has been reported. PAH should be suspected, with symptoms of exertional dyspnea, increased second heart sound, dilatation of pulmonary arteries on chest imaging, or reduced DLCO on pulmonary function testing.
No controlled trials are available to guide therapy of MCTD, so that treatment is based on case series experience and conventional therapies that are known to be effective for manifestations of disease common to other CTDs (SLE, SSc, PM/DM). Since the clinical course of disease in MCTD is variable, therapy should be individualized to address specific organ involvement and disease severity. Most clinical manifestations of MCTD, with the exception of Raynaud phenomenon, are steroid responsive. Low-dose glucocorticoids, nonsteroidal antiinflammatory drugs, hydroxychloroquine, or combinations of these medications are used for early nonaggressive disease. Vasodilating drugs are used for Raynaud phenomenon, with nifedipine the most common. High dose systemic corticosteroids, methotrexate, or cytotoxics may be added for more severe disease, particularly organ threatening disease.
PAH may require treatment with the same classes of drugs used to treat idiopathic PAH (prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors—see Chapter 72 for management of PAH). PAH can be fatal but is not always progressive and sometimes resolves. Multiple case reports in adults and children also report successful treatment of PAH with immunosuppressive therapy (corticosteroid and CYC), considering the PAH as part of a “disease flare.” Heart and lung transplantation is an option for end-stage PAH.
MCTD is considered incurable and outcomes are variable depending on organ involvement; however, most children have a favorable prognosis. Ten years mortality is reported to be 16%–28% in adults and 7.6% in children. Deaths are most often due to rapid-onset pulmonary hypertension in adults and infection in children.
Sarcoidosis is a chronic multisystem disorder of unknown etiology affecting mostly young adults and rarely children. It is characterized by noncaseating epithelioid cell granulomas, which have a predilection for thoracic lymph nodes and lung tissue. Children with sarcoidosis commonly have disease manifestations similar to adults with sarcoidosis, with bilateral hilar lymph adenopathy (BHL) with or without parenchymal infiltrates. At least half of adult cases will resolve spontaneously within 2 years without any specific therapy. However, progression of lung disease to pulmonary fibrosis and uveitis to blindness are two potential long-term morbidities that call for careful consideration for treatment and follow-up of the sarcoidosis patient.
Early onset sarcoidosis (EOS), with symptom onset at the age of 4 years or younger and a unique phenotype of skin rash, uveitis, arthritis, and absence of lung disease, was previously described to be a rare presentation of sarcoidosis. However, it is now believed that EOS is the sporadic form of Blau syndrome, a familial autoinflammatory disease with autosomal dominant inheritance caused by mutations in the NOD2/CARD15 gene. With increasing recognition of EOS, previously unidentified visceral involvement, including interstitial pneumonitis, has now been reported. EOS tends to present to the pediatric rheumatologist and will not be discussed further in this chapter. However, the pulmonologist should consider genetic causes in the differential diagnosis of sarcoidosis in young children and familial cases.
The incidence of sarcoidosis varies by geographic location, race, and age, but usually develops before the age of 50 years and peaks in incidence between 20 and 39 years. The highest incidence of disease has been reported in northern European countries (5–40 cases per 100,000 people) and among black Americans (35.5 cases per 100,000 compared with 10.9 per 100,000 in white Americans). The incidence in children is less well described but is generally felt to be much lower than in adults. Data from the Danish national patient registry show an overall incidence of 0.29 per 100,000 children-years (15 years of age and younger) compared with the overall Danish incidence of 7.2/100,000 person-years. Incidence in children increases with age and peaks at 1.02 per 100,000 in the 14–15-year-old age group. In the two largest American pediatric case series from Virginia and North Carolina, 75% of children with sarcoidosis were black, and most were over the age of 10 years. Males and females are equally affected. There is some familial clustering of cases, but no inheritance pattern has been established.
Etiology and Pathogenesis
The etiology of sarcoidosis remains largely unknown; however, a variety of environmental, occupational, and genetic risk factors have been associated with the disease. Current models of pathogenesis suggest that an exaggerated TH-1 immune response to unidentified antigen(s) in individuals who are genetically susceptible leads to granuloma formation in many different organs. The mycobacterium tuberculosis catalase-peroxidase protein has been identified as a potential sarcoidosis antigen, and several associations of sarcoidosis with MHC-2 alleles have been described.
Granulomatous lesions are the hallmark of sarcoidosis, and they may occur in any organ of the body. These are typically noncaseating, which distinguishes them from the necrotizing granulomatous lesions of tuberculosis and GPA. The granulomas consist of tightly organized collections of predominantly CD4 + T lymphocytes and mononuclear phagocytes (epithelioid cells, macrophages, and multinucleated giant cells). The epithelioid and giant cells may contain Schaumann or asteroid inclusion bodies. In the lung, most granulomas are located in the perilymphatic areas, including near bronchioles, in the subpleural space and the perilobular spaces ( Fig. 58.9 ). In more mature granulomas, fibroblasts and collagen may encase the ball-like cluster of cells. Special stains for fungi and mycobacteria are negative. The granulomatous lesions usually heal with preservation of lung parenchyma; however, in 20%–25% of patients, fibroblasts proliferate at the periphery of the granuloma and produce fibrotic scar tissue.