1253CHAPTER 106 Pediatric Rheumatologic Disease around 70% 23 SLE should always be considered in a patient presenting with pulmonary hemorrhage Presenting symptoms and signs typically include dyspnea[.]
CHAPTER 106 Pediatric Rheumatologic Disease around 70%.23 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.24 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.25 1253 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.30 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.31 It is a verrucous endocarditis, in which fibrinoid nodules form on the cardiac valves, most frequently on the mitral valve.29 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.32,33 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.34 Arrhythmias Interstitial Lung Disease 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 Pulmonary Hypertension 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.35 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.36 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 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.26 Patients with severe ILD are treated with aggressive immunosuppression and supportive therapy In some cases, they may require extracorporeal membrane oxygenation 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.27 Treatments include vasodilator therapy in conjunction with immunosuppressive agents Cardiovascular Manifestations Pericarditis and Pericardial Tamponade 21,28 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.29 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.29,30 Symptoms include fatigue, exercise intolerance, tachycardia, and Acute Coronary Syndrome 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.37 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 1254 S E C T I O N X I Pediatric Critical Care: Immunity and Infection 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.38 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 to 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.39,40 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.41 In addition, the presence of aPLs is highly associated with neurologic symptoms, especially stroke, seizure, headache, and movement disorders.42 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 Antibodymediated 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, lifethreatening 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.43,44 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.43 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.45,46 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.47 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.48 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 1254.e1 • eFig 106.4 Magnetic resonance image of the lungs of a 16-year-old girl with systemic lupus erythematosus This image was obtained after the patient was stabilized Multiple areas of increased signal are scattered throughout both cerebral hemispheres, consistent with ischemic infarctions resulting from lupus cerebritis Other views demonstrated similar infarcts in the brainstem and cerebellar hemisphere Magnetic resonance angiography obtained at the same time revealed normal vasculature, suggesting pathologic involvement of brain tissue but sparing of vessels The patient responded well to pulse intravenous methylprednisolone and cyclophosphamide, with no residual neurologic deficit CHAPTER 106 Pediatric Rheumatologic Disease 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.49 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 hour for to consecutive days Subsequently, prednisone is given IV or by mouth starting at to mg/kg per day divided twice a day in tapering doses over the next several months Steroidsparing 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.50,51 Plasmapheresis may be required as adjunctive therapy in refractory cases.24 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 1255 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.52 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.53 Although definitive evidence of efficacy is lacking, postmenarchal female patients undergoing longer cyclophosphamide-based regimens may benefit from concomitant ovarian suppression.54 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.55 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 months of age, maternal anti-SSA and antiSSB antibodies in the fetal circulation can result in rashes, transaminitis, cytopenias (typically, thrombocytopenia), and heart block.56 The level of maternal antibodies in an infant’s circulation will gradually decline over the first 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.56 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 1256 S E C T I O N X I Pediatric Critical Care: Immunity and Infection 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.57 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.58 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 smallvessel occlusion affecting three or more organ systems, leading to multiorgan failure.59 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-b2 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.60 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.58,59 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.61 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.61 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.62 ... 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... 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... Magnetic resonance image of the lungs of a 16-year-old girl with systemic lupus erythematosus This image was obtained after the patient was stabilized Multiple areas of increased signal are