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Approximately 1 child in 250 has a rheumatologic disease.
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A child may present to the intensive care unit (ICU) with a life-threatening manifestation of an undiagnosed rheumatologic disease or with severe complications of a known rheumatologic disorder.
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Suspicion for rheumatologic disease should be high when children present with persistent fevers of unknown origin, multisystem involvement, joint involvement, or unexplained high inflammatory markers.
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Diagnosing rheumatologic diseases is challenging, as few clinical features are pathognomonic and few diagnostic tests are confirmatory. A thorough history and physical examination are essential.
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Infectious and oncologic processes may mimic rheumatologic diseases and must be excluded.
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Macrophage activation syndrome is a severe “cytokine storm” due to immune dysregulation in the setting of rheumatologic diseases, infections, and malignancy. Early recognition and aggressive treatment are essential, as it can lead to severe morbidity and death.
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High-dose corticosteroid therapy is frequently used at diagnosis and for severe disease flares to bring inflammation under control quickly. Corticosteroids are typically not sufficient to maintain long-term disease control and have many associated risks. Thus, additional immunosuppressive therapy is employed to induce and maintain remission.
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Immunosuppressive therapy used to treat rheumatologic diseases can lead to complications, including infections, liver disease, renal disease, and cytopenias. Adrenal insufficiency following chronic corticosteroid use can occur if corticosteroid treatment is stopped abruptly.
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Therapy for rheumatologic disease may be initiated in the ICU, which often includes high-dose corticosteroids; cyclophosphamide, anticytokine, and anticellular biological therapies; intravenous immunoglobulin; and plasmapheresis.
The field of pediatric rheumatology encompasses a diverse set of fascinating but poorly understood disorders. Although the exact pathophysiology of many rheumatologic conditions remains elusive, most are thought to be immune mediated in etiology. Recent advances in immunology have allowed for important breakthroughs in identification of genetic and environmental contributions to these diseases as well as in increasingly effective treatments. In particular, options for pharmacologic therapy of rheumatologic diseases have increased markedly since the early 2000s. Biological medications that modulate the immune system are also being used in an increasing array of conditions outside traditional rheumatologic disorders, which have applications in cancer therapeutics, transplantation, and even in response to certain infections.
It is estimated that approximately 1 child in 250 has a rheumatologic condition. Although most patients are managed in the outpatient setting, children with rheumatologic disorders have the potential to become acutely ill and suffer life-threatening complications. The exact number of children with rheumatologic disease who require intensive care management is unknown, but early diagnosis and rapid treatment can significantly decrease morbidity and mortality. , Patients may present to the intensive care unit (ICU) with severe manifestations of new-onset rheumatologic disease, severe complications of a known disorder, or complications secondary to immunosuppressive therapy. This chapter provides an overview of the most common pediatric rheumatologic diseases followed by a discussion of the conditions and complications most likely to be encountered in the intensive care setting.
Rheumatologic diseases: Overview
Most rheumatologic diseases have historically been classified as autoimmune disorders. Classical autoimmune diseases are characterized by adaptive immune dysfunction leading to loss of normal self-tolerance, inappropriate generation of autoantibodies, and resultant tissue injury. Over the past several decades, research has also begun to demonstrate the importance of innate immune pathways in the generation and propagation of immune-mediated pathophysiology. Increasingly, rheumatologists are conceptualizing an immune-mediated disease spectrum with variable contributions of autoinflammatory and autoimmune responses ( Fig. 106.1 ). While certain rare monogenic diseases provide examples “pure” autoinflammatory or autoimmune processes, most rheumatologic diseases likely involve a complex interplay of aberrant innate and adaptive immune responses. Similarly, a broader understanding of the role of tolerance and inflammation in host responses to infection and malignancy indicates that rheumatologic diseases are but one manifestation of a larger continuum of immune dysregulation. Patients with defects in one immune function often demonstrate difficulty with other aspects of immunity. Thus, patients with immunodeficiency and predisposition to infection often also develop autoimmune phenomenon. Patients with malignancies such as leukemia and lymphoma may generate abnormal autoantibodies and/or inflammatory cytokine profiles. Additionally, patients with underlying immune-mediated diseases have increased predisposition to development of malignancy due to effects of long-standing inflammation.
These considerations have important ramifications for diagnosis, treatment and management of rheumatologic diseases. Rheumatologic diseases in children present in highly variable ways and can be difficult to diagnose and treat. Given that immune-mediated diseases may present with systemwide involvement, these conditions require a thorough history and physical examination for accurate diagnosis. Symptoms that should raise suspicion for an underlying immune-mediated disease include unexplained fevers or constitutional symptoms, multiorgan dysfunction, or persistent inflammation unresponsive to usual first-line therapies. While laboratory tests may be helpful to support a certain disease, almost all rheumatologic diagnoses rely heavily on clinical criteria. By definition, immune-mediated diseases are diagnoses of exclusion; given the overlapping nature of immune roles, exclusion of ongoing infectious insults or underlying malignancy as sources of persistent inflammation is an essential first step in establishing a disease as immune mediated. Thus, laboratory tests are often more prognostic than diagnostic and suspicion for rheumatologic disease cannot be easily confirmed or eliminated by laboratory testing alone.
Arthritis is often considered the hallmark feature of rheumatologic diseases. Almost any rheumatologic disease can potentially present with joint involvement. However, certain rheumatologic diseases may present without overt joint inflammation. In a patient who does have arthritis, it is important to assess for extraarticular manifestations. Fig. 106.2 provides one conceptual framework for categorization of rheumatologic diseases. A full discussion of all of these disorders is beyond the scope of this chapter. An overview of the clinical presentation, diagnosis, and treatment of representative diseases is presented next.
Rheumatologic diseases: Clinical presentation, diagnosis, and treatment
Juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatologic disease, representing a heterogeneous collection of chronic arthritides that are organized into subtypes based on clinical features ( Fig. 106.3 ). Most children with JIA are managed as outpatients, but the disease and its complications occasionally require intensive care.
An important distinction exists between systemic JIA (sJIA) and the other subtypes of JIA with regard to pathophysiology, presentation, clinical course, and treatment. Advances in our understanding of the immunopathogenesis of sJIA indicate that this disorder closely resembles other so-called autoinflammatory diseases in which systemic inflammation is driven by defects in innate immune pathways. While adaptive immune cells are also involved in the pathogenesis, these disorders often lack detectable autoantibodies that are characteristic of more classic autoimmune diseases. sJIA, which accounts for about 10% to 20% of children with JIA, is the JIA subtype that most often presents to the ICU. sJIA is often complicated by severe multisystem disease, including a life-threatening cytokine storm known as macrophage activation syndrome (MAS), discussed later in the chapter.
Systemic juvenile idiopathic arthritis
Key points
sJIA presents with quotidian fevers, evanescent rash, lymphadenopathy, and serositis. Arthritis may not be present at onset. The most serious complication of sJIA is MAS, a form of secondary hemophagocytic lymphohistiocytosis (HLH). sJIA can mimic malignancy and severe sepsis. Severe hyperferritinemia can help diagnose sJIA but is not specific or sensitive as a single diagnostic criterion. Treatment involves targeted therapy with interleukin-1 (IL-1) and IL-6 inhibitors.
Clinical presentation
The classic features of sJIA include daily high fevers, a characteristic evanescent rash, and arthritis. The fevers (≥39°C) typically occur daily in a spiking quotidian pattern with return to normal temperature for at least 2 weeks. The rash is typically a nonpruritic, salmon-colored, macular rash that can be subtle. It usually occurs with fever spikes and is rapidly migratory, often disappearing completely when the temperature normalizes. Arthritis can be present in any number of joints, with some patients having minimal joint involvement and others with extensive polyarticular joint disease. While a complete joint examination is essential, arthritis may not be a prominent feature early in disease and can lag behind other manifestations of inflammation, such as pericardial effusion or serositis. Other clinical features may include diffuse lymphadenopathy and hepatosplenomegaly.
Cardiac involvement in sJIA occurs in up to 10% of patients at onset and typically presents as pericarditis with or without pericardial effusion. Pericarditis is often recurrent but usually benign and rarely causes cardiac tamponade. Pleuritis is the most common pulmonary complication, but parenchymal disease can occur as well. Patients with severe disease are at risk of developing interstitial lung disease, alveolar proteinosis, bronchiolitis obliterans, and pulmonary hypertension. , Interstitial lung disease can rarely occur in non-sJIA, particularly in rheumatoid factor–positive polyarticular JIA or secondary to drug toxicity (methotrexate).
Laboratory studies
Laboratory findings consistent with sJIA include anemia (with hemoglobin levels often between 6–8 g/dL); elevated white blood cell (WBC) counts, sometimes in the leukemoid range; and elevated platelet counts. Cytopenias should prompt consideration of malignancy or MAS.
C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually markedly elevated. However, in the setting of MAS, the ESR may fall owing to declining fibrinogen levels. Consumptive pathophysiology may also result in inappropriately “normal” WBC and platelet counts or frank cytopenias. Hyperferritinemia is commonly seen both at onset and during flares of disease activity and is a marker for increased risk of MAS. , Antinuclear antibodies (ANAs), rheumatoid factor, and anticyclic citrullinated peptide (anti-CCP) antibodies are all typically negative. Unfortunately, there is no one laboratory test that can confirm or refute a diagnosis of sJIA, which is a diagnosis of exclusion by definition. A thorough evaluation for alternative etiologies is essential. Underlying malignancies, including leukemia and lymphoma, may present with fevers, rashes, and diffuse lymphadenopathy. If more than two cell lines are decreased, hematology/oncology consultation for bone marrow biopsy and/or lymph node biopsy is often indicated, especially prior to treatment with corticosteroids. Infectious disease consultation to evaluate for pathogens that present with prolonged fevers, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV), rickettsial diseases, infectious endocarditis, and other more rare entities should also be performed before sJIA can be diagnosed.
Management
Children with active sJIA should be treated aggressively. Patients with life-threatening disease are often managed with high-dose pulse intravenous (IV) methylprednisolone (30 mg/kg per day, maximum dose 1000 mg) administered over 1 hour for 3 consecutive days. Subsequent maintenance prednisone is given IV or by mouth until disease control is achieved and appropriate steroid-sparing medications have been started. Biological response modifiers, such as IL-1 inhibitors (anakinra, canakinumab, and rilonacept) and the IL-6 inhibitor (tocilizumab), should be started shortly after diagnosis for patients with severe disease and often provide good control of both systemic features (fevers, serositis, rash) and arthritis. These agents are used in consultation with a pediatric rheumatologist to induce remission and maintain disease control as corticosteroids are weaned. Anakinra, in particular, is often preferentially used in ICU settings due to efficacy in treating MAS and a short half-life, which allows flexibility with dose adjustments and minimal short-term immunosuppressive effects. Given the immediate and long-term complications of high-dose corticosteroid therapy, anti-lL-1 monotherapy is being increasingly used in many centers for initial treatment of sJIA.
Systemic lupus erythematosus
Key points
Systemic lupus erythematosus (SLE) is a systemic autoimmune condition that can affect almost any organ system. A positive ANA has good sensitivity but poor specificity for SLE; diagnosis relies on clinical criteria. Pulmonary, cardiac, renal, and central nervous system (CNS) manifestations can be severe and life-threatening, requiring critical care and aggressive immunosuppressive medications. Infections are a major cause for morbidity and mortality in SLE patients due to immunocompromise from active disease and/or treatments. CRP levels are often normal in active SLE: an elevated CRP in a patient with SLE should raise suspicion for acute infection.
SLE is a systemic autoimmune disease characterized by loss of immunologic tolerance and development of multiple autoantibodies targeting self-antigens. The hallmark of SLE is tissue injury from immune complex deposition, which results in activation of complement and recruitment of downstream inflammatory cells and chemical mediators. The tendency for immune complexes to deposit in tissues with a large supply of small blood vessels—such as the skin, joints, and kidneys—helps explain the predilection for involvement of these systems in many SLE patients. However, autoantibodies can also cause tissue damage through direct mechanisms; thus, almost any organ system may be affected in this disease. Although the exact pathogenesis is still under study, evidence suggests that immune dysregulation—as well as genetic, environmental, and hormonal factors—all contribute to the development of this disease. Adolescent females are most likely to be affected; however, males and younger children can also develop SLE. Onset of SLE prior to age 10 years is rare and suggests the possibility of an underlying genetic etiology.
There are multiple sets of classification criteria for SLE ( eTable 106.1 ), which were initially developed in adults for research purposes to define a more homogenous group of patients. However, these criteria are often applied clinically to support a diagnosis of SLE in children. These various criteria schemes vary in terms of estimated sensitivity and specificity for pediatric SLE. , Generally, if four criteria are met and other confusable infectious or neoplastic diagnoses have been eliminated, a diagnosis of SLE is highly likely. SLE presentation can be extremely variable—any organ may be affected and the disease can be mild to life threatening. If the diagnosis is suspected, it is important to perform serologic testing for SLE-specific autoantibodies as well as a thorough evaluation of all organ systems to look for potential involvement.
| ACR Criteria b | SLICC Criteria c | |
|---|---|---|
| Skin and mucosa | Malar rash | Acute cutaneous lupus or subacute cutaneous lupus |
| Discoid rash | Chronic cutaneous lupus | |
| Oral or nasopharyngeal ulceration | Palate, tongue, or nasal ulcers | |
| Photosensitivity | Nonscarring alopecia | |
| Joints | Nonerosive arthritis involving two or more peripheral joints | Synovitis involving two or more joints |
| Serositis | Pleuritis, pericarditis | Pleurisy, pleural effusions or pleural rub, typical pericardial pain, pericardial effusion or pericardial rub |
| Renal disorder | Persistent proteinuria >0.5 g/day or cellular casts (red cell, hemoglobin, granular, tubular, or mixed) | Urine protein/creatinine (or 24-h urine protein) representing 500 mg of protein/24 h or red blood cell casts |
| Neurologic disorder | Seizures or psychosis | Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, acute confusional state |
| Hematologic disorder | Hemolytic anemia | Hemolytic anemia |
| Leukopenia (<4000/mm) or lymphopenia (<1000/mm) Thrombocytopenia (<100,000/mm) | |
| Immunologic criteria | An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay | ANA above laboratory reference range |
| Anti-dsDNA, anti-Sm, or positive finding of antiphospholipid antibodies | Anti-dsDNA Anti-Sm Antiphospholipid antibody: lupus anticoagulant, false-positive RPR Medium- or high-titer anticardiolipin (IgA, IgG, or IgM) or anti-β 2 glycoprotein 1 (IgA, IgG, or IgM) Low complement (C3, C4, CH-50) Positive direct Coombs test in the absence of hemolytic anemia |
a All criteria should be in the absence of other identifiable causes, such as offending medications, infection, metabolic derangements, etc.
b ACR criteria: For the purpose of identifying patients in clinical studies, a person is defined as having SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.
c SLICC criteria: A person is defined as having SLE if at least 4 out of 17 criteria are met (at least one clinical criterion and one immunologic criterion) or biopsy-proven lupus nephritis with a positive ANA or positive dsDNA. Criteria are cumulative and do not have to be present concurrently.
Clinical presentation
Mucocutaneous manifestations
Malar rash, discoid rash, photosensitivity, painless oral ulcerations (especially over the hard palate), and nasal ulcerations are classic skin and oropharyngeal findings. However, almost any kind of rash, including bullous lesions, may be seen. Skin biopsy with immunofluorescence staining to demonstrate immune complex deposition (the SLE band test) can be helpful.
Musculoskeletal manifestations
Arthritis is common, occurring in about 65% of patients with SLE. A musculoskeletal examination should be performed to look for joint tenderness, contracture, or effusion. Myositis is less common but can also occur. Avascular necrosis can occur, which may be due to the disease itself or to corticosteroid treatment.
Pulmonary manifestations
Pulmonary involvement is a common finding in many patients. Included here are clinically significant pulmonary manifestations in SLE.
Pleuritis and pleural effusion
Pleuritis is included in the SLE classification criteria and may be severe. Patients typically have pleuritic chest pain, respiratory distress, and orthopnea. Pleural effusions can be large enough to compromise lung function. Most respond to treatment of the underlying inflammatory disease, but occasionally aspiration and drainage of effusions are necessary.
Pulmonary hemorrhage
Although relatively rare, pulmonary hemorrhage is one of the most serious pulmonary complications, with a mortality rate around 70%. SLE should always be considered in a patient presenting with pulmonary hemorrhage. Presenting symptoms and signs typically include dyspnea and hemoptysis or a sudden decline in hemoglobin. Acute pulmonary hemorrhage can be rapidly progressive and catastrophic, leading to acute hypoxemic respiratory failure and hemorrhagic shock. Evaluation for concomitant bacterial, viral, and fungal pathogens is essential, as pulmonary infections may trigger hemorrhage. Chest radiography typically reveals diffuse alveolar airspace-filling defects. However, in milder cases, there may be only focal abnormalities. High-resolution computed tomography (HRCT) is more sensitive than chest radiography and typically reveals ground-glass opacities. Bronchoscopy with bronchoalveolar lavage may reveal gross blood and hemosiderin-laden macrophages.
Pulmonary embolism
Pulmonary embolism may occur secondary to antiphospholipid antibodies (aPLs) or other hypercoagulable states, such as nephrotic syndrome from renal involvement. Smaller and recurrent emboli may contribute to the development of pulmonary hypertension, another severe SLE complication. Patients typically present with pleuritic chest pain, tachypnea, tachycardia, and hypoxia but can sometimes be asymptomatic. Chest CT with angiography is a very helpful diagnostic test. Early intervention with systemic thrombolytic agents improves survival in pediatric patients.
Interstitial lung disease
Pediatric SLE patients routinely undergo pulmonary function tests (PFTs) for monitoring and may develop interstitial lung disease (ILD). Patients may be asymptomatic or present with fever, cough, respiratory distress, or pleuritic chest pain. Chest radiographs may show interstitial changes but are not always sensitive enough to detect ILD. HRCT is a more sensitive study and may reveal characteristic findings, such as basilar ground-glass opacities, honeycombing, subpleural nodules, and bronchiectasis. Patients with severe ILD are treated with aggressive immunosuppression and supportive therapy. In some cases, they may require extracorporeal membrane oxygenation.
Pulmonary hypertension
Pulmonary hypertension may occur in SLE patients secondary to vasculitis, vasospasm, advanced ILD, and/or recurrent thromboembolism, with the latter observed in patients with aPL positivity. Patients may present with dyspnea or signs of right-sided heart failure. Treatments include vasodilator therapy in conjunction with immunosuppressive agents.
Cardiovascular manifestations
Pericarditis and pericardial tamponade
Pericarditis is the most common cardiac manifestation of SLE. , Acute pericarditis with effusion may lead to cardiac tamponade. In severe cases or if there is concern for an underlying infection, pericardiocentesis may be necessary. Chronic pericarditis may cause restrictive cardiac disease. Evaluation for pericarditis includes electrocardiography (ECG) and echocardiography. Symptoms should improve with medical management of the underlying systemic inflammatory disease.
Myocarditis
Although rare, patients with SLE may present with myocarditis, manifested by poor cardiac output and congestive heart failure. , Symptoms include fatigue, exercise intolerance, tachycardia, and respiratory distress, with rales and hepatomegaly on examination. Chest radiography may demonstrate cardiomegaly with pulmonary edema and echocardiography can show diminished ventricular systolic function. Management involves diuresis, inotropic support, and aggressive immunosuppressive therapy.
Valvular disease
Libman-Sacks endocarditis (LSE) involves the development of sterile vegetations on the cardiac valves and is usually associated with the presence of aPLs. It is a verrucous endocarditis, in which fibrinoid nodules form on the cardiac valves, most frequently on the mitral valve. Vegetations and valvular thickening can lead to severe regurgitation and stenosis. Echocardiography is the best diagnostic study; in some cases, a transthoracic study may not be sensitive enough to detect valvular disease and a transesophageal study is necessary. , Many patients respond to medical treatment of the underlying SLE; in severe cases, valve replacement surgery may be indicated. Infective endocarditis (IE) can mimic LSE in an immunosuppressed SLE patient presenting with fever and new-onset murmur. Thus, it is important to differentiate between the two conditions.
Arrhythmias
SLE is associated with an increased risk for conduction abnormalities, including premature atrial beats, supraventricular tachycardia, atrioventricular block, and right bundle branch block. This is best diagnosed by ECG and echocardiography. Patients usually respond to pharmacologic antiarrhythmics. Pacemakers are indicated for complete atrioventricular block, particularly in neonatal lupus, discussed later.
Acute coronary syndrome
There is a well-recognized increased risk for acute myocardial infarction in SLE secondary to premature atherosclerosis, probably related to the combined effect of disease-related dyslipidemia, coronary artery inflammation, and long-term corticosteroid therapy. Patients with SLE are at higher risk for premature cardiovascular disease, such as hyperlipidemia and hypertension, which may relate to chronic inflammation and side effects of long-term steroid use. Vasculitis in the coronary vessels increases the risk of myocardial infarction. In any child with SLE presenting with chest pain or dyspnea, myocardial infarction should be considered. ECG may demonstrate ST-segment elevation; in that circumstance, laboratory testing, including serum troponin, may be helpful. The underlying SLE should be treated; cardiology consultation is beneficial for management and long-term cardiac monitoring.
Renal manifestations
Renal disease is estimated to occur in 50% to 80% of children with SLE and is often more severe than renal disease in adult patients. Renal disease may be present at the time of initial diagnosis or may evolve later. Laboratory evaluation includes determination of serum electrolytes, blood urea nitrogen, creatinine, and albumin; urinalysis; spot urine protein/creatinine ratio (ideally, first morning void); and 24-hour urine protein and creatinine collection. Lupus nephritis can manifest in various ways, with oliguria or anuria, hematuria, hypertension, nephrotic syndrome, and renal failure requiring dialysis. Hypertension can be severe, leading to neurologic manifestations such as posterior reversible encephalopathy syndrome and other end-organ complications, and must be managed with aggressive antihypertensive therapy. Renal biopsy helps to determine the severity, type, and extent of lupus nephritis, which has major implications for treatment. However, in cases complicated by significant thrombocytopenia, hypercoagulability, or severe hypertension, the risks and benefits of renal biopsy must be weighed closely.
The severity of the renal disease often dictates the intensity of the overall treatment approach for a given patient. Response times to treatment vary—it often takes 3 to 6 months of intensive treatment for the kidney disease to become quiescent. Despite aggressive treatment, a subset of patients will have ongoing refractory renal disease activity, leading to decline in renal function. Acute flares over time may also contribute to renal insufficiency and need for dialysis acutely or more chronically. Renal transplantation has been successfully performed in pediatric patients, but there is a risk of disease recurrence. ,
Central nervous system manifestations
Seizures and psychosis are the CNS manifestations included in the SLE classification criteria, but the neuropsychiatric features of SLE are diverse and of variable severity. These features may be the initial presentation of SLE or occur at any point during the disease course, even when other features of the disease are under good control. In addition, the presence of aPLs is highly associated with neurologic symptoms, especially stroke, seizure, headache, and movement disorders. It is important to carefully evaluate behavioral changes in critically ill SLE patients, as changes may be subtle and must be differentiated from medication side effects or ICU psychosis. When SLE patients present with neurologic symptoms, CNS infection (viral, bacterial, and fungal) must also be considered. Testing for aPLs should be repeated whenever new neurologic symptoms present. Additional diagnostic studies—such as brain magnetic resonance imaging (MRI)/magnetic resonance angiography ( eFig. 106.4 ), electroencephalography, and evaluation of spinal fluid should be performed and may be helpful to guide response to therapy. However, there is no gold standard test to confirm or refute CNS involvement in SLE. Aggressive immunosuppression is generally indicated for suspected CNS involvement. Concurrent use of anticonvulsant and/or antipsychotic medications may be necessary. In the setting of thrombotic stroke, anticoagulation is generally indicated.
Hematologic involvement
Anemia and thrombocytopenia are common and are often presenting features of SLE. Lymphopenia is also frequent and in many patients may be an indicator of disease activity. Antibody-mediated cytopenias (such as Coombs-positive hemolytic anemia or microangiopathic hemolytic anemia [MAHA] syndromes) are frequent. However, other factors—such as blood loss, bone marrow suppression, medications, or infection—should also be considered.
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening MAHA spectrum hematologic disorder that can be inherited or acquired. It is strongly associated with SLE, especially in pediatric patients. Diagnosis is based on five clinical features: (1) thrombocytopenia and disseminated platelet aggregation, (2) MAHA, (3) neurologic abnormalities, (4) fever, and (5) renal disease. , The pathophysiology is based on dysfunction of the ADAMTS-13 enzyme, which normally cleaves von Willebrand factor (vWF) multimers. In TTP, there is a lack of vWF cleavage leading to an accumulation of vWF multimers, which bind to platelets leading to clot formation and end-organ damage. In congenital TTP, there is a deficiency of ADAMTS-13, while in acquired TTP an inhibitory autoantibody inactivates ADAMTS-13. In patients with clinical suspicion for TTP, demonstrating reduced levels of ADAMTS-13 activity (<5%) is confirmatory. Treatment for TTP includes plasmapheresis acutely along with immunosuppression. The early use of plasmapheresis significantly decreases the mortality rate, which otherwise is high.
Immune dysfunction
Patients with SLE are immunosuppressed by the disease itself due to abnormal B- and T-cell function and low complement levels that impair opsonization of encapsulated organisms. The immunosuppressive agents used to control the disease additionally impair the ability to fight infection. Infection is thus a common reason for ICU admission and a leading cause of death in patients with SLE. , Children being treated for SLE may not manifest typical signs of infection, such as fever, due to chronic immunosuppression. As SLE patients may have baseline hypertension, a relative decline in blood pressure is concerning for sepsis, even if the child remains normotensive. Similarly, SLE patients often have baseline leukopenia; thus, a relative rise in WBC count may indicate infection even in the absence of true leukocytosis. Given the underlying inflammatory disease, inflammatory markers may also be difficult to interpret. Patients with SLE are also at risk of developing MAS, discussed elsewhere, which is often triggered in the setting of acute infections. Therefore, a high index of suspicion for infection and early initiation of broad-spectrum antimicrobial therapy are warranted in acutely ill SLE patients.
Acute abdominal manifestations: Peritonitis, serositis, pancreatitis, and intestinal perforation
Nonbacterial peritonitis and serositis of the abdominal organs are common manifestations of SLE. Patients may present with severe symptoms, including a surgical abdomen. However, immunosuppressive therapy can also mask clinical signs and symptoms, leading to delayed diagnosis. Patients are also at risk for infectious pathology, such as bacterial peritonitis with abscess formation, and for intestinal perforation. In cases in which infection and perforation have been excluded and symptoms are thought to relate to noninfectious serositis, the underlying disease should be treated aggressively to bring symptoms under control.
Severe acute pancreatitis may complicate SLE. It may be disease related or secondary to medications, such as high-dose corticosteroids and azathioprine. In patients with nonlocalizing abdominal pain, pancreatitis should be considered and appropriate laboratory screening and imaging performed to look for inflammation, stones, and pseudocysts. Inciting drugs should be avoided if possible.
Laboratory studies
Auto-antibody testing
More than 95% of patients with SLE have persistent evidence of ANAs, a positive ANA test. Thus, a negative ANA test has a good negative predictive power for the diagnosis of SLE in particular. However, a positive ANA test is not specific for SLE; ANAs can be induced transiently in the setting of infection and can be detected in many other conditions, including malignancies, other rheumatologic diseases, and in healthy people. Unlike the ANA, anti–double-stranded DNA (dsDNA) antibodies are much more specific for SLE and are elevated in 80% to 90% of children with SLE at some point in the disease course. Anti-Smith (Sm) antibodies are also highly specific for SLE but are seen less commonly, in approximately 20% of pediatric patients. Other autoantibodies—including anti-SSA, anti-SSB, and anti-ribonucleoprotein (RNP), commonly included in an extractable nuclear antigen (ENA) or multiplex array panel, occur in varying frequency in SLE patients. These antibodies may be helpful to monitor for specific patterns of organ involvement and disease complications but are not diagnostic of SLE.
High-titer ANA results (>1:640 dilution) are more concerning than lower-titer values for the presence of an underlying autoimmune disease. However, even high-titer ANAs are not specific for SLE and may be seen in the setting of other rheumatologic disorders, such as systemic sclerosis (scleroderma), mixed connective tissue disease (MCTD), dermatomyositis, or Sjögren syndrome.
Scleroderma and MCTD are discussed further on ExpertConsult.com .
In terms of SLE disease activity monitoring, complement levels (C3 and C4) are typically low in active SLE, reflecting consumption in the setting of immune complex formation. Serial measurements of C3, C4, and anti-dsDNA are often used in monitoring response to therapy but may not reflect all aspects of disease activity. Importantly, assessment of SLE disease activity requires a holistic approach, including clinical parameters, and individual patients may exhibit different patterns in disease activity markers.
Markers of systemic inflammation are elevated in active SLE. ESR can be markedly elevated and is a strong indicator of active disease. Interestingly, CRP levels are often normal or only modestly elevated in active lupus. Patients presenting to the ICU with signs of persistent inflammation and a significant discordance between ESR and CRP should be evaluated for SLE as an underlying diagnosis. Even modest elevations in CRP in known SLE patients should raise suspicion for acute infection.
Management
Patients with SLE often require ICU-level care; they can be severely ill at diagnosis and with disease flares. Treatment is often divided conceptually into initial induction therapy designed to gain control of active disease followed by longer-term maintenance regimens. For hospitalized patients, induction treatment is typically initiated with high-dose pulse IV methylprednisolone (30 mg/kg per day, maximum dose 1000 mg), administered over 1 hour for 3 to 5 consecutive days. Subsequently, prednisone is given IV or by mouth starting at 1 to 2 mg/kg per day divided twice a day in tapering doses over the next several months. Steroid-sparing agents, such as cyclophosphamide and rituximab (an anti-CD20 antibody), are typically necessary in patients with significant life-threatening or major organ (CNS, renal, pulmonary) involvement. Choice of specific agent is dependent on the type of disease manifestation and patient-specific factors. Treatment of pulmonary hemorrhage typically involves a combination of supportive therapies and aggressive immunosuppression. Despite the need for systemic heparinization, extracorporeal membrane oxygenation has been found to be safe and life-saving in children with pulmonary hemorrhage who fail conventional therapy. , Plasmapheresis may be required as adjunctive therapy in refractory cases. TTP should also be treated with corticosteroids and plasmapheresis followed by cyclophosphamide or rituximab. Nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and colchicine may be used acutely for symptom relief in conjunction with traditional steroid-sparing medications to treat pericarditis. Severe renal involvement warrants treatment with high-dose IV steroid therapy, cyclophosphamide, and/or mycophenolate mofetil. Treatment for CNS involvement includes high-dose IV steroid therapy and cyclophosphamide. Plasmapheresis may be necessary in severe cases. Rituximab is also increasingly used but remains an experimental therapy.
Cyclophosphamide dosing is typically based on body surface area and dosing is lower than what is used in oncologic treatment. Side effects of cyclophosphamide include alopecia, nausea, vomiting, cytopenias, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Patients must be adequately hydrated to prevent development of hemorrhagic cystitis. Longer term, there is a risk of subfertility or infertility related to cumulative dose and increasing age. Although definitive evidence of efficacy is lacking, postmenarchal female patients undergoing longer cyclophosphamide-based regimens may benefit from concomitant ovarian suppression.
Rituximab may cause a hypersensitivity reaction as well as hypogammaglobulinemia and cytopenias, increasing risk of infection. A significant potential future side effect is the risk of progressive multifocal encephalopathy. For patients with less severe disease manifestations, mycophenolate mofetil (MMF) or azathioprine are typically used to induce and maintain remission. Renal failure, nephrotic syndrome, and dialysis can all affect drug metabolism and clearance; consultation with pediatric nephrology and pharmacy services may assist with proper dosing.
Neonatal systemic lupus erythematosus
Infants can develop antibody-mediated disease due to transmission of maternal antibodies in utero; mothers may or may not be symptomatic from these autoantibodies. Symptoms can present prenatally or, up to 6 months of age, maternal anti-SSA and anti-SSB antibodies in the fetal circulation can result in rashes, transaminitis, cytopenias (typically, thrombocytopenia), and heart block. The level of maternal antibodies in an infant’s circulation will gradually decline over the first 9 months of life. Thus, most manifestations other than heart block usually resolve without treatment; however, exchange transfusion has been used as acute therapy in severe cases. Unfortunately, heart block often develops prenatally, can be severe, and is usually irreversible. Affected infants may require a pacemaker and ionotropic support.
Raynaud phenomenon
Asymmetric triphasic color changes presenting in prepubertal females or any male in childhood deserves further evaluation for underlying systemic disease. Raynaud phenomenon is a triphasic color change typically in the distal extremities (fingers and toes; rarely, ears, nose). Transient vasoconstriction causes a white or gray (depending on underlying skin pigmentation) numb phase, often followed by a blue tinge due to vascular congestion and then a red, painful reperfusion phase. This should be differentiated from the more symmetric, cyanotic appearance of acrocyanosis. Raynaud phenomenon can occur as a primary idiopathic process in otherwise healthy individuals or can be secondary to an underlying rheumatologic disease, most commonly SLE, MCTD, scleroderma, antiphospholipid syndrome (APS), or a primary vasculitis. Idiopathic or primary Raynaud phenomenon often presents in older adolescent females and is rarely associated with morbidity. However, true Raynaud phenomenon presenting in a prepubertal child or male of any age should raise suspicion for an underlying rheumatologic disease. Raynaud phenomenon due to underlying rheumatologic disease may be difficult to control; vasospasm may be persistent due to the underlying vascular inflammation and irritability. If vasospasm persists, it may compromise distal tissue integrity and require ICU-level intervention, including initiation of vasodilating agents such as iloprost, to prevent digit loss.
Antiphospholipid syndrome
Key points
Children presenting with unexplained stroke or thrombosis should be evaluated for APS as part of a hypercoagulability evaluation. Acute thrombotic microangiopathy affecting multiple organ systems should prompt consideration of catastrophic antiphospholipid syndrome (CAPS).
Clinical presentation
APS is an autoimmune, prothrombotic state characterized by arterial or venous thrombosis, pregnancy morbidity, and specific laboratory features. It may occur as a primary disorder, secondary to other autoimmune diseases (typically SLE), or in the setting of infection or malignancy. Circulating autoantibodies to a variety of cell membrane proteins result in inappropriate platelet and/or endothelial activation and subsequent pathophysiology. The clinical presentation depends on the site and type of vascular involvement and accompanying nonthrombotic manifestations. Venous thrombosis occurs most commonly in pediatric patients and can present in various ways, including superficial thrombophlebitis, deep vein thrombosis, pulmonary thromboembolism, and cerebral venous sinus thrombosis. Arterial occlusion may also occur, though is less common and may also present in a variety of ways, including stroke, renal thrombotic microangiopathy, myocardial infarction, bone infarction, or mesenteric artery thrombosis. Rarely, autoantibodies may target prothrombin itself and lead to a combined bleeding diathesis as well as tendency toward hypercoagulability with factor II replacement. Nonthrombotic clinical features are extremely variable but include cytopenias; neurologic abnormalities (movement disorders, migraine, transverse myelitis); skin findings (livedo reticularis, cutaneous necrosis, skin ulcerations, Raynaud phenomenon); valvular heart disease; and renal involvement (hypertension, hematuria). CAPS refers to the acute onset (<1 week) of small-vessel occlusion affecting three or more organ systems, leading to multiorgan failure.
Laboratory studies
For any child presenting with a vascular thrombosis, a full hypercoagulability workup should be undertaken (see also Chapter 89 ). To diagnose APS, children must have one or more of the characteristic laboratory features: positive anticardiolipin antibodies, anti-β 2 glycoprotein antibodies, or lupus anticoagulant. The activated partial thromboplastin time (aPPT) may be prolonged and does not correct with addition of normal serum (mixing study), indicating the presence of an interfering antibody. As these aPLs can be transiently induced in the setting of infection, a definite diagnosis of APS requires evidence of persistent elevation on two or more occasions 12 weeks apart.
Management
For children with vascular thrombosis due to APS, anticoagulation is typically initiated with unfractionated heparin. Given that lupus anticoagulant can artificially prolong the aPPT, monitoring antifactor Xa levels may be a more reliable measure of therapeutic anticoagulation. For acute, severe thrombotic events, thrombolytic therapy, such as tissue plasminogen activator, has been used successfully in children.
Given the high mortality rate in CAPS, aggressive therapy is essential and should include anticoagulation, high-dose corticosteroids, and occasionally plasma exchange; IV immunoglobulin (IVIG), cyclophosphamide, and rituximab may be of additional benefit. ,
Juvenile dermatomyositis
Key points
Juvenile dermatomyositis (JDM) is a systemic inflammatory vasculopathy that presents with rashes and weakness of proximal muscle groups. Patients presenting with persistently elevated aspartate transaminase (AST) greater than alanine transaminase (ALT) without liver pathology should be evaluated for myositis. Levels of creatine kinase (CK), aldolase, and lactate dehydrogenase (LDH) levels may be helpful, along with MRI. Aspiration due to pharyngeal muscle involvement in JDM patients may be clinically silent. Patients with newly diagnosed or active JDM presenting with acute abdominal pain should be evaluated for intestinal perforation due to possible gastrointestinal (GI) involvement.
Clinical presentation
JDM is a vasculopathy that primarily targets the skin and muscles. It is characterized by weakness and skin findings: rash over the eyelids (heliotrope rash); face (malar rash); neck and upper back (shawl sign); extensor surfaces of the joints in the hands, elbows, and knees (Gottron papules); and periungual telangiectasias. The inflammation primarily affects striated muscle but can also involve smooth muscle. Typically, proximal rather than distal muscle groups are affected, often leading to profound shoulder and hip girdle muscle weakness. The muscles of the palate, pharynx, and upper third of the esophagus can also be involved, resulting in dysphagia, dysphonia, and risk of aspiration. In severe cases, weakness may lead to respiratory failure. However, this may not be apparent, as weakness can mask retractions and typical signs of respiratory distress.
The vascular injury in JDM can also target the gastrointestinal (GI) tract and may cause bleeding, necrosis, and perforation. Cardiac muscle can also become inflamed and, rarely, myocarditis and conduction defects have been reported. ILD occurs secondary to disease activity and/or chronic aspiration and may be difficult to detect early in disease. The kidneys are not typically targeted by vasculitis in JDM, but rhabdomyolysis with secondary renal impairment can rarely occur, especially with initial presentation or acute disease flares. As with many of the rheumatologic diseases, severely ill patients with JDM can develop MAS. A more long-term complication of uncontrolled JDM disease activity is calcinosis, with calcium precipitation in the skin and underlying fascial tissues, particularly around the joints and sites of repeated trauma. In severe cases, this can impair mobility. As opposed to adult patients where dermatomyositis may be the presenting sign of an underlying malignancy, JDM is rarely a paraneoplastic syndrome in younger pediatric patients. However, older adolescent patients who present with JDM require a careful screen for teratoma or other underlying cancer prior to initiation of immunosuppressive treatment regimens.
Laboratory studies
Laboratory studies are useful to support the diagnosis, monitor disease activity, and guide treatment. Serum levels of muscle enzymes—including CK, AST, ALT, aldolase, and LDH—are usually markedly elevated in active disease and normalize over time with treatment. In patients with long-standing disease, however, serum enzyme levels may remain normal despite active muscle inflammation. Imaging may be necessary to assess disease activity. Mild anemia may be present initially, but the WBC and platelet counts are usually normal. Severe anemia, leukopenia, and/or thrombocytopenia should prompt consideration of MAS or investigation of causes other than JDM. ANAs are positive in approximately 70% of patients at diagnosis but are not part of diagnostic criteria for JDM. Although specific myositis-associated antibodies have low sensitivity for this disease, the anti-p155/140 (TIF1) and anti-MJ (NXP2) autoantibodies are highly specific for JDM and are often useful in predicting the clinical course.
Imaging
The muscle edema and inflammation of JDM are best detected by MRI with short tau inversion recovery (STIR) sequence. MRI can also help to identify an appropriate site for biopsy in cases with diagnostic uncertainty. For patients with dysphonia or dysphagia, a video fluoroscopic swallowing study (VFSS) can establish aspiration risk and whether alternative feeding methods are necessary. Clinical swallow examinations may be falsely reassuring in patients with JDM, as weakness of the pharyngeal muscles may impair the normal cough reflex, resulting in silent aspiration events. As with other systemic immune diseases, a thorough organ survey is recommended to establish the extent of any cardiopulmonary or GI involvement.
Management
An aggressive treatment approach is essential and typically includes high-dose IV corticosteroids, methotrexate, and IVIG. Other agents—such as cyclosporine, MMF, cyclophosphamide, and rituximab—may be used in refractory or severe cases. In cases complicated by GI involvement, oral medications may not be absorbed reliably and parenteral administration is preferred.
Systemic vasculitis
Key points
Vasculitis secondary to underlying infection and/or medications (drug-induced hypersensitivity) is much more common than immune-mediated vasculitis. A thorough evaluation for inciting agents is required prior to diagnosis of primary vasculitis. Vascular inflammation can lead to vessel stenosis, occlusion, and/or rupture. Patients are at high risk of thrombosis, insufficiency syndromes, and hemorrhage. Primary vasculitides in pediatrics are often categorized as small-, medium-, or large-vessel syndromes. Clinical manifestations and patterns of organ involvement can be used to help pinpoint the size of affected vessels. Patients presenting with unexplained hypertension, multiorgan dysfunction, and/or persistent signs of systemic inflammation should be evaluated for underlying vasculitis. Serologic studies for evaluation of vasculitis are limited; tissue biopsy and/or vascular imaging is usually required for confirmation of diagnosis.
The vasculitides are a heterogeneous group of disorders that can be classified in various ways, including by size of the affected vessels and by characteristic laboratory features. These disorders previously had high morbidity and mortality rates, but advances in treatment have led to markedly improved prognosis in pediatric patients. Primary systemic vasculitis is a diagnosis of exclusion—predisposing factors such as infection and medication-induced syndromes must be ruled out before a diagnosis is made. The most common forms of primary vasculitis in children are Henoch-Schönlein purpura (HSP) and Kawasaki disease (KD). However, children can develop other more rare disorders, such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), Takayasu arteritis (TA), and primary vasculitis of the CNS.
Small-vessel vasculitis
Immune-complex small-vessel vasculitis
Henoch-schönlein purpura
HSP is an immunoglobulin (Ig) A–mediated small-vessel vasculitis, often triggered by a preceding infection, often β-hemolytic Streptococcus pyogenes . The classic clinical features include palpable purpura predominantly on the lower extremities, arthritis or arthralgias, abdominal pain, and hematuria. Most cases are mild and resolve spontaneously within about 1 month. Up to 30% of patients with HSP develop GI hemorrhage, although severe hemorrhage, irreducible intussusception, and perforation are rare. Rarely, pulmonary hemorrhage and CNS involvement have been reported, although these complications should prompt evaluation for other more rare forms of small-vessel vasculitis described later. , Nephrotic syndrome at disease onset and increased age are associated with worse outcomes. ,
Laboratory tests are nonspecific, usually showing only mildly elevated WBC counts and inflammatory markers. Coagulation studies and platelet counts are normal. The serum IgA level is often elevated but is not sensitive or specific HSP. In unclear or severe cases, a skin or renal biopsy can be performed and should demonstrate leukocytoclastic vasculitis with IgA deposition.
Treatment of HSP
In most cases, HSP is a self-limited condition that can be managed in the outpatient setting. When severe manifestations are present, hospitalization may be necessary. Treatment is primarily supportive, including hydration and nutritional support. Pain control can often be achieved with acetaminophen or NSAIDs. Oral or IV high-dose corticosteroids may be used for abdominal pain with vomiting or concern for suspected intussusception. Current data suggests that while corticosteroids cannot prevent the development of renal disease, they may be an effective treatment option in certain cases for severe disease manifestations. Unfortunately, rebound symptoms upon taper of glucocorticoids are common and prolonged tapers are often required. In children with severe disease, corticosteroids can be combined with cyclophosphamide and plasmapheresis. However, data supporting this type of treatment is lacking. Other reported treatment options include azathioprine, MMF, cyclosporine, IVIG, and plasmapheresis. Given the lack of high-quality, evidence-based trials and consensus guidelines, considerable variability in the treatment of severe HSP may exist between institutions.
Pauci-immune small-vessel vasculitis (antineutrophil cytoplasmic antibody–associated vasculitis)
Granulomatosis with polyangiitis
GPA (formerly known as Wegener granulomatosis) is a granulomatous vasculitis that targets the sinuses and middle ear, lungs, and kidneys. Severe manifestations include subglottic stenosis with dyspnea and stridor, pulmonary hemorrhage, necrotizing cavitary lung lesions, and rapidly progressive necrotizing glomerulonephritis. Additional symptoms can include fever, weight loss, hearing loss, conjunctivitis, purpura or petechiae, arthritis, headache, and dizziness. For a patient presenting with pulmonary-renal syndrome, other diagnoses should be considered in addition to GPA, including MPA, Goodpasture syndrome, and SLE ( eTable 106.2 ).
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