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6,801 | (see Fig. 201.5). RP is typically independent of an underlying rheumatic disease (Raynaud disease) but can result from rheumatic diseases such as scleroderma, systemic lupus erythematosus (SLE), and mixed con nective tissue disease (Fig. 201.7). The color changes are brought about by (1) initial arterial vasoconstriction, resulting in hypoperfusion and pallor (blanching), (2) venous stasis (cyanosis), and (3) reflex vasodila tion caused by the factors released from the ischemic phase (erythema). The color change is classically reproduced by immersing the hands in iced water and reversed by warming. During the blanching phase, there is inadequate tissue perfusion in the affected area, associated with pain and paresthesias and resulting in ischemic damage only when associated with a rheumatic disease. The blanching usually affects the distal fingers but may also involve thumbs, toes, ears, and tip of the nose. The affected area is usually well demarcated and uniformly white. Digital ulcers asso ciated with RP are indicative of underlying rheumatic disease. Raynaud disease often begins in adolescence and is character ized by symmetric occurrence, the absence of digital ulcers, tissue necrosis and gangrene, and the lack of manifestations of an under lying rheumatic disease. Children have normal nail fold capillaries (absence of periungual telangiectasias). RP should be distinguished from acrocyanosis and chilblains. Acrocyanosis is a vasospastic dis order resulting in cool, painless, bluish discoloration in the hands and feet despite normal tissue perfusion. It may be exacerbated by stimulant medications used to treat attention deficit disorder. Chil blains is a condition with episodic color changes and the develop ment of nodules related to severe cold exposure and spasm induced vessel and tissue damage; it has been associated with SLE and is also referred to as lupus pernio, but the majority of children with chil blains do not have lupus. DIAGNOSIS The diagnosis of JLS is based on the distribution and depth of charac teristic lesions. Biopsy is helpful to confirm the diagnosis. The diagno sis of JSSc requires proximal sclerosisinduration of the skin and the presence of 2 of 20 minor criteria (see Table 201.3). DIFFERENTIAL DIAGNOSIS The most important condition to differentiate from JLS is JSSc. Contrac tures and synovitis from juvenile arthritis can be differentiated from those caused by LS by the absence of skin changes. Other conditions to consider include chemically induced scleroderma like disease, diabetic cheiro arthropathy, pseudoscleroderma, and scleredema. Pseudoscleroderma comprises a group of unrelated diseases characterized by patchy or diffuse cutaneous fibrosis without the other manifestations of scleroderma. These include phenylketonuria, syndromes of premature aging, and localized idiopathic fibrosis. Scleredema is a transient, self limited disease of both children and adults that has sudden onset after a febrile illness (especially streptococcal infections) and is characterized by patchy sclerodermatous lesions on the neck and shoulders and extending to the face, trunk, and arms. Laboratory Findings No laboratory studies are diagnostic of either localized or systemic scleroderma. Although the results of complete blood counts, serum chemistry analyses, and urinalysis are normal, children may have elevated erythrocyte sedimentation rate, |
6,802 | eosinophilia, or hypergam maglobulinemia, all of which normalize with treatment. Elevations of muscle enzymes, particularly aldolase, can be seen with muscle Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 201 u Scleroderma and Raynaud Phenomenon 1511 involvement. Patients with JSSc may have anemia, leukocytosis, and eosinophilia and autoantibodies (ANA, antiScl 70). Imaging studies delineate the affected area and can be used to follow disease progres sion. MRI is useful in en coup de sabre and Parry Romberg syndrome (facial hemiatrophy) for determination of CNS or orbital involvement. Infrared thermography uses the temperature variation between areas of active and inactive cutaneous disease to help differentiate active dis ease from damage. The role of ultrasound to examine lesion activity is evolving. HRCT, PFTs, echocardiography, and manometry are useful tools for diagnosing and monitoring visceral involvement in JSSc. TREATMENT Treatment for scleroderma varies according to the subtype and sever ity. Superficial morphea may benefit from topical corticosteroids or ultraviolet therapy. For lesions involving deeper structures, sys temic therapy is recommended. A combination of methotrexate and corticosteroids is effective in treating JLS by preventing lesion exten sion and resulting in significant skin softening and improved range of motion of affected joints. The Childhood Arthritis and Rheuma tology Research Alliance (CARRA) consensus treatment plans for JLS include (1) weekly subcutaneous (SC) methotrexate at 1 mgkg (maximum dose 25 mg); (2) weekly SC methotrexate (1 mgkg; max 25 mg) plus either 3 months of high dose intravenous (IV) cortico steroids (30 mgkg; max 1,000 mg) for 3 consecutive days a month or weekly corticosteroids at the same dose for 3 months; or (3) high dose daily oral corticosteroids (2 mgkgday, max 60 mg) with a slow taper over 48 weeks (Fig. 201.8). Mycophenolate mofetil (MMF) and abatacept have shown promise as second line agents for recalcitrant Ask the following screening questions: Are your fingers unusually sensitive to cold? Do they turn white, blue, or both? Do your fingers change color when they are exposed to cold temperatures? The diagnosis of Raynaud phenomenon is confirmed by a positive response to all three questions The diagnosis of Raynaud phenomenon is excluded if responses to second and third questions are negative Thoracic outlet syndrome Atherosclerosis Thromboangiitis obliterans Embolic disease Abnormal findings indicate presence of obstructive vascular disease: Scleroderma Systemic lupus erythematosus Mixed connectivetissue disease Dermatomyositis Polymyositis Sjgren syndrome Vasculitis Antiphospholipid syndrome Undifferentiated CTD Patients with positive results have rheumatic disease: Hypothyroidism Cancer Cold agglutinin syndrome POEMS syndrome Cryoglobulinemia Cryofibrinogenemia Hyperviscosity syndrome Patients with positive results have other systemic diseases: Test for cryoglobulins and cryofibrinogen Thyroidfunction test Serum protein electrophoresis Patients with negative results should have the following studies: Exclude potential causative or aggravating factors: Occupational and environmental factors Drugs Neuropathy Carpal tunnel syndrome Chemotherapeutic agents, interferon, estrogen, nicotine, narcotics, sympathomimetic agents, ergotamines, blockers (nonselective), clonidine Polyvinyl chloride, frostbite, handarm vibration, and hypothenar |
6,803 | hammer syndrome Normal medical history and physical examination (no digital lesions or gangrene, normal nailfold capillaries): Patients do not need to undergo specialized studies and can be considered to have primary Raynaud phenomenon History of single digit asymmetric attacks, absent peripheral pulses, asymmetry of blood pressure, or evidence of critical ischemia: Patients should undergo arterial Doppler ultrasonography, MRIMRA, or angiography Complete blood cell count General blood chemical analyses Urinalysis Test for antinuclear antibodies Test for rheumatoid factor Test for diseasespecific autoantibodies C3 and C4 complement levels Symptoms or signs suggestive of systemic disease (myalgias, arthralgias, fever, weakness, weight loss, rash, arthritis, sicca syndrome, or symptoms of heart or lung disease) with or without abnormal nailfold capillaries: Patients should undergo the following studies: Fig. 201.7 Diagnostic algorithm for Raynaud phenomenon. CTD, Connective tissue disease; MRA, magnetic resonance angiography; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. (From Firestein GS, Budd RC, Gabriel SE, et al., eds. Kelley Firesteins Textbook of Rheumatology, 10th ed. Philadelphia: Elsevier; 2017: Fig 84 3.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Clinical diagnosis of localized scleroderma Moderate to high risk for severe disease? Active disease? New extracutaneous disease? Cosmetic or functional issues? Not better by 3 mo or worse by 6 mo? Cutaneous activity Disease extension or existent lesion(s) with active signs Erythema Violaceous color Skin thickening White or yellow waxy appearance Tactile warmth Biopsy showing active disease Extracutaneous activity Progressive deep tissue involvement (by exam or imaging) New onset or persistent inflammatory arthritis New onset seizures, severe headaches, or CNS vasculitis Uveitis or visual disturbance Progressive joint contractures Progressive growth defects ANDOR Yes, active Yes, moderate or high risk Yes Yes Systemic therapy Topical therapy Continue regimen for min 12 mo from time of disease quiescence Add or adjust therapy Adjunctive therapy Topical therapy, physicaloccupational therapy, mental health support No improvementworsening Improving Subtype All except circumscribed superficial morphea Rapidly progressive or extensive disease Presence of extracutaneous involvement Craniofacial involvement OR WITH OR WITHOUT Methotrexate CARRA dosing: 1 mgkgwk SC, max 25 mg PReS dosing: 15 mgm2wk PO or SC, max 25 mg Mycophenolate mofetil PO 1.25 m2 600 mgm2 twice a day 4050 kg or 1.251.5 m2 750 mg twice a day 50 kg or 1.5 m2 1,000 mg twice a day Corticosteroids IV or PO CARRA dosing Methylprednisolone 30 mgkgdose IV (max 1 gm) 3 consecutive daily dosesmonth 3 mo (9 doses) or, 1 doseweek 12 wk (12 doses) Prednisone 2 mgkgd PO, max 60 mg Gradual taper over 48 wk PReS dosing Prednisone 12 mgKgd PO for 23 mo Methylprednisolone 30 mgKgdose IV for 3 mo Subtype Circumscribed superficial morphea (excludes craniofacial involvement) No extracutaneous involvement Physicaloccupational therapy Mental health support Consider corrective or cosmetic surgery Longterm monitoring Relapse occurs in 1445 of patients Mean time to relapse: 12 y but may occur several years |
6,804 | later Topical corticosteroids Vitamin D derivatives Tacrolimus Imiquimod Phototherapy Not active No No Reassess and observe No, low risk Fig. 201.8 LS treatment recommendations. This algorithm outlines factors to consider when deciding upon treatment and CARRA and PReS recommended treatments. Careful and long term monitoring for both cutaneous and extracutaneous activity is important. The algorithm is based upon the authors experiences and not intended to serve as prescriptive instructions. CARRA, Childhood Arthritis and Rheumatology Research Al liance; IV, intravenous; max, maximum; min, minimum; PO, by mouth; PReS, Pediatric Rheumatology European Society; SC, subcutaneous. (From Vasquez Canizares N, Li SC. Juvenile localized scleroderma updates and differences from adult onset disease. Rheum Dis Clin N Am. 2021;47:737 755, Fig. 5, p. 749.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 201 u Scleroderma and Raynaud Phenomenon 1513 Table 201.5 Organ Specific Treatment of Systemic Sclerosis MANIFESTATION FIRST LINE SECOND LINE VERY SEVERE Raynaud phenomenon Calcium channel blockers PDE 5 inhibitors Fluoxetine Angiotensin II receptor antagonists Topical nitrates Prostacyclins (iloprost) Sympathectomy Botulism toxin Fat grafting Digital ulcers PDE 5 inhibitors Endothelin receptor antagonists Prostacyclins (iloprost) Pulmonary hypertension PDE 5 inhibitors Endothelin receptor antagonists Prostacyclins (epoprostenol) Riociguat Interstitial lung disease Cyclophosphamide Mycophenolate mofetil Corticosteroids Rituximab Hematopoietic stem cell transplantation Skin Methotrexate Mycophenolate mofetil Corticosteroids (low dose) Abatacept Immune globulin Cyclophosphamide Rituximab Renal crisis ACE inhibitors Musculoskeletal NSAIDs Hydroxychloroquine Methotrexate Corticosteroids (low dose) Rituximab Abatacept Tocilizumab Calcium channel blockers (nifedipine, amlodipine). PDE 5 inhibitors (sildenafil, tadalafil). Angiotensin receptor antagonists (losartan). Topical nitrates (glyceryl trinitrate). Prostacyclins (iloprost, epoprostenol). Endothelin receptor antagonist (bosentan, ambrisentan, macitentan). ACE inhibitors (captopril, enalapril). ACE, Angiotensin converting enzyme; NSAIDs, nonsteroidal antiinflammatory drugs; PDE 5, phosphodiesterase 5. From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Table 27.8, p. 395. disease. Physical and occupational therapy are important adjuncts to pharmacologic treatment. Eosinophilic fasciitis often responds well to corticosteroids and methotrexate. Close follow up is necessary in JLS given high rates of relapseup to 40. Treatments for JSSc target specific disease manifestations (Tables 201.5 and 201.6). RP is treated with cold avoidance, and pharmaco logic interventions are reserved for severe disease. Calcium channel blockers (nifedipine 30 60 mg sustained release form daily; amlo dipine 2.5 10 mg daily) are the most common pharmacologic inter ventions. Additional potential therapies for RP include losartan, prazosin, bosentan, and sildenafil. Angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril) are recommended for hyper tension associated with renal disease. Methotrexate or MMF may be beneficial for skin manifestations. Cyclophosphamide and MMF are used to treat pulmonary alveolitis and prevent fibrosis. Corti costeroids should be used cautiously in SSc because of an associa tion with renal crisis. Adults with SSc have been successfully treated with high dose cyclophosphamide, antithymocyte globulin, and autologous stem cell transplantation. Systemic sclerosisassociated interstitial lung disease has been managed with nintedanib, |
6,805 | a tyro sine kinase inhibitor, which has antiinflammatory and antifibrotic effects. Nintedanib combination therapy with MMF is also effective as an initiation therapy or when escalation of therapy is needed. The treatment of RP begins with avoiding cold stimuli, using hand and foot warmers, and avoiding carrying bags by their handles (impairs circulation). Nifedipine (10 20 mg three times dailyadult dose) reduces, but does not eliminate, the number and severity of episodes. Side effects include headache, flushing, and hypotension. Topical nitrates may result in digital vasodilation and may reduce the severity of an episode. PROGNOSIS JLS is ultimately generally self limited, with the initial inflammatory stage followed by a period of stabilization and then softening, for an average disease duration of 3 5 years, although there are reports of active disease lasting up to 20 years. Prolonged disease activity is associated primarily with linear and deep disease subtypes. JLS, especially linear and deep subtypes, can result in significant mor bidity, disfigurement, and disability as a result of joint contractures, muscle atrophy, limb shortening, facial asymmetry, and hyperpig mentation and hypopigmentation. Death from an en coup de sabre lesion with progressive neurologic decline has been reported. JSSc has a more variable prognosis. Although many children have a slow, insidious course, others demonstrate a rapidly progressive form with early organ failure and death. Skin manifestations report edly soften years after disease onset. Overall, the prognosis of JSSc is better than that of the adult form, with 5 , 10 , and 15 year sur vival rates, respectively, in children of 89, 8087, and 7487. The most common cause of death is heart failure caused by myocar dial and pulmonary fibrosis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1514 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Table 201.6 Treatment of Gastrointestinal Manifestations of Juvenile SSc ORGAN MANIFESTATION TREATMENT Oral Buccal, lingual fibrosis Tooth decay Mandibular resorption Gingival recession Dysphagia Dental hygiene Fluoride treatments every 3 months Dental sealant Soft foods, small portions, adequate fluids Gingival mucosa grafting Dietary restriction (low sugar, soft foods) Esophageal Dysmotility Reflux Constriction Metoclopramide, erythromycin Weight loss; small, frequent meals; avoid eating 3 hr before bed; raise head of bed 6 inches Avoid tight clothes, heavy lifting, bending Proton pump inhibitors, H2 blockers Dilatation Stomach GAVE (watermelon stomach) Fructose intolerance Metoclopramide Erythromycin Octreotide Small intestines Bacterial overgrowth Bezoars Malabsorption leading to malnutrition Pseudoobstruction FODMAP diet Vitamin supplementation Low residue, elemental diet Metoclopramide Antibiotics Octreotide Colon Fibrosis of lymphatics Ischemia Erythromycin Metamucil High fiber diet Anorectal Internal anal sphincter atrophy Biofeedback Pelvic floor exercises Sacral nerve stimulation Side effects of erythromycin can be avoided by using low doses (rather than antibiotic level doses). FODMAP, Fermentable oligosaccharides, disaccharides, monosaccharides, and polyol; GAVE, gastric antrum vascular ectasia; SSc, systemic sclerosis. From Petty |
6,806 | RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Table 27.9, p. 398. Behet disease (BD) is classified as a primary multisystem variable ves sel vasculitis because of the involvement of any size and type (arterial, venous) of blood vessel. BD is probably underdiagnosed in children as a result of the heterogeneity in clinical features, the large spectrum of differential diseases, and lack of specific tests. Originally described with recurrent oral ulcerations, uveitis, and skin abnormalities, the BD spectrum is much broader. EPIDEMIOLOGY BD has a high prevalence in countries along the Silk Road, extend ing from Japan to the Eastern Mediterranean. It is increasingly recognized among people of European ancestry as well. BD has a prevalence of 5 7 per 100,000 adults. The increased disease rec ognition might have had a role in the rising prevalence of BD as well as the migrations of the 20th century. Prevalence in children is probably not more than 10 of the adult counterparts in Eastern Chapter 202 Behet Disease Seza Ozen Mediterranean countries; boys and girls are equally affected. A fam ily history of BD is present in approximately 20 of the cases. Onset in children is usually 8 12 years of age. Newborns of affected moth ers have demonstrated symptoms of BD. ETIOLOGY AND PATHOGENESIS The etiology of BD is unknown. It is a polygenic disorder with auto inflammatory features. The autoinflammatory nature of BD is sug gested by its episodic nature, the prominent innate immune system activation, the absence of identifiable autoantibodies, and the co association with the MEFV gene. However, there is evidence support ing the role of the adaptive immune system as well. BD has also been considered to be an MHC I opathy because of the strong association with HLA B51. Genetic contribution to BD is evident through this well known association with HLA B5101, the familial cases, the sib ling and twin recurrence rate, the specific frequency of the disease among people along the Silk Road, evidence for genetic anticipation, and genome wide analysis. Genome wide analysis studies among Turkish and Japanese BD patients confirm the marked association with HLA B5101. Other significant associations include interleukin (IL) 10 and IL 23RIL 12R2 genes. Other possible susceptibility loci demonstrate associations with STAT4 (a transcription factor in a signaling pathway related to cytokines such as IL 12, type I inter ferons, and IL 23) and ERAP1 (an endoplasmic reticulumexpressed Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 202 u Behet Disease 1515 aminopeptidase that functions in the processing of peptides onto major histocompatibility complex class I). An infectious agent may be responsible for inducing the aberrant innate immune system attacks in the genetically predisposed host. A number of infectious agents have been implicated and include strep tococci and herpes simplex virus type 1. |
6,807 | A microbiome study in BD proposed a distinct salivary signature. BD has some genetic and immune similarities to periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome and recurrent aphthous stomatitis, suggesting a spectrum of these disorders. CLINICAL MANIFESTATIONS AND DIAGNOSIS The course of BD is characterized by exacerbations and remissions. There is marked heterogeneity in disease manifestations. The mean age of the first symptom is between 8 and 12 years. The most frequent initial symptom is a painful oral ulcer (Fig. 202.1). The oral ulcers are often recurrent, may be single or multiple, range from 2 to 10 mm, and may be in any location in the oral cavity. They are often very painful. The oral ulcers last 3 10 days and heal without scarring. In contrast, the genital ulcers heal with scars. Genital scars are noted in 6085 of the patient, usually occur after puberty, and are seen on the labia, scrotum, penis, or anal area. Another key feature of BD that has significant morbidity is the bilateral eye involvement seen in 3060 of pediatric patients. The main symptoms of anterior uveitis are blurred vision, redness, periorbital or global pain, and photophobia. Although it is often in the form of panuveitis, anterior uveitis may be seen in females. Uveitis in general is more common in males. Vitritis and retinal vasculitis are the most prominent features of posterior involvement. Complications of uveitis include blindness (unusual with treat ment), glaucoma, and cataracts. Retinal vasculitis, retinal detach ment, and retrobulbar neuritis (optic neuritis) are less common eye manifestations of BD. The skin lesions are the third most common symptom of BD. They range from erythema nodosum (seen in approximately 50 of patients) to papulopustular acneiform lesions (85), folliculitis, purpura, and ulcers. Pathergy (seen in 50) is another skin feature associated with BD and is a pustular reaction occurring 24 48 hours after a sterile needle puncture or saline injection; it is not pathog nomonic of BD. The vasculitis of BD involves both arteries and veins, thrombosis and aneurysm formation, occlusions, or stenosis in arteries of any size. In children, deep venous thrombosis of the lower limbs is the most frequent vasculitic feature. If the hepatic vein is thrombosed, Budd Chiari syndrome may occur. Pulmonary artery aneurysms are the most severe feature of pediatric BD, associated with the highest mortality. Coronary artery aneurysms may confuse BD with Kawasaki or multisystem inflammatory syndrome in children (MIS C) disease. Microvascular involvement may be noted in the nail bed capillaries. Central nervous system (CNS) manifestations (approximately 10) in children include meningoencephalitis (headache, menin gismus, cerebrospinal fluid pleocytosis), encephalomyelitis, pseu dotumor cerebri, dural sinus thrombosis, and organic psychiatric disorders (psychosis, depression, dementia). Dural sinus thrombo sis is the most common CNS manifestation in children. Gastrointestinal (GI) involvement (seen in 1030) manifests with abdominal pain, diarrhea, and intestinal ulcerations, most often in the ileocecal region. Gastrointestinal BD may be difficult to distinguish from inflammatory bowel disease. Oligoarticular arthritisarthralgia is present in 50 of patients and can be |
6,808 | recur rent, but is nondeforming. Other rare manifestations include orchi tis, renal vasculitis, glomerulonephritis, or amyloidosis and cardiac involvement. The International Study Group for Behet Disease (ISG) criteria used to be the most widely used and require the presence of oral ulcers (at least 3 times per year) along with two other major fea tures, including genital ulcers, a positive pathergy test, uveitis, and the characteristic skin lesions. If only one of the criteria is present along with oral ulcerations, the term incomplete or partial Behet disease is applied. The revised International Criteria for Behet Dis ease (ICBD) have been reported to have a much better performance than the 1990 ISG criteria. Additional classification criteria for children have been suggested by the use of an international prospective observational cohort. According to these criteria, BD is diagnosed when three of the following criteria are present: recurrent oral aphthosis, genital ulcers, skin involvement (necrotic folliculitis, acneiform lesions, erythema nodosum), ocu lar involvement, neurologic involvement, and vascular involvement (venous thrombosis, arterial thrombosis, arterial aneurysm). These criteria performed better than the ISG criteria in the pediatric cohort (Table 202.1). There are no specific laboratory tests. Acute phase reactants are often mildly elevated. The diagnosis relies on the constellation of symp toms and excluding other causes. Hughes Stovin syndrome is characterized by thrombophlebitis and multiple bronchial or pulmonary artery aneurysms. This vasculitic Fig. 202.1 A deep aphthous ulcer in a patient with Behet disease. Table 202.1 Consensus Classification of Pediatric Behet Disease ITEM DESCRIPTION Recurrent oral aphthosis At least three attacksyear Genital ulceration or aphthosis Typically with scar Skin involvement Necrotic folliculitis, acneiform lesions, erythema nodosum Ocular involvement Anterior uveitis, posterior uveitis, retinal vasculitis Neurologic signs With the exception of isolated headaches Vascular signs Venous thrombosis, arterial thrombosis, arterial aneurysm From Kon Paut I, Shahram F, Darce Bello M, et al, for PEDBD group. Consensus classification criteria for paediatric Behets disease from a prospective observational cohort: PEDBD. Ann Rheum Dis. 2016;75:958964. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1516 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Sjgren syndrome is a chronic, inflammatory autoimmune disease characterized by progressive lymphocytic and plasma cell infiltration of the exocrine glands, especially salivary and lacrimal (parotid being prototypical), with potential for systemic manifestations. It is rare in children and has classic symptoms of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). EPIDEMIOLOGY Sjgren syndrome typically manifests at 35 45 years of age, with 90 of cases among females, but it is underrecognized in children because symptoms often start in childhood. The mean age at diag nosis in children is 9 10 years; 75 are female. The disease can occur as an isolated disorder, referred to as primary Sjgren syn drome (sicca complex), or as a secondary Sjgren syndrome in association with other rheumatic disorders, such as systemic |
6,809 | lupus erythematosus (SLE), scleroderma, or mixed connective tissue Chapter 203 Sjgren Syndrome C. Egla Rabinovich disease, which usually precedes the associated autoimmune disease by years. ETIOLOGY AND PATHOGENESIS The etiology of Sjgren syndrome is complex and includes genetic predisposition and possibly an infectious trigger. Lymphocytes and plasma cells infiltrate salivary glands, forming distinct periductal and periacinar foci that become confluent and may replace epithelial struc ture. Several genes regulating apoptosis influence the chronicity of lymphocytic infiltration. CLINICAL MANIFESTATIONS International classification criteria have been developed for the diagnosis of Sjgren syndrome in adult patients, but these criteria apply poorly to children. Although diagnostic criteria in children have been proposed, they have not been validated (Table 203.1). Recurrent parotid gland enlargement and parotitis are the most common manifestations in children (70), whereas sicca syn drome (dry mouth, painful mucosa, halitosis, widespread den tal caries) predominates in adults. Children tend to have a higher prevalence of systemic symptoms, including fevers and adenopa thy, compared to adults. In a cross sectional study of children with Sjgren syndrome, manifestations included recurrent parotitis (72), sicca symptoms (38), polyarthritis (18), vulvovaginitis (12), hepatitis (10), Raynaud phenomenon (10), fever (8), renal tubular acidosis (9), lymphadenopathy (8), and central nervous system (CNS) involvement (5). Table 203.1 Proposed Pediatric Criteria for Diagnosis of Sjgren Syndrome (SS) JUVENILE SS CLINICAL SYMPTOMS 1. Recurrent parotitis or parotid enlargement 2. Recurrent conjunctivitis (nonallergic and noninfectious) 3. Recurrent vaginitis 4. Systemic: fever of unknown origin, arthralgias, hypokalemic paralysis, or abdominal pain OBJECTIVE 5. Ocular dryness (ocular staining or a Schirmer test) 6. Abnormal sialography 7. Elevated serum amylase 8. Leukopenia or elevated ESR 9. Hyperimmunoglobulinemia (polyclonal) 10. Renal tubular acidosis SEROLOGY 11. At least one of anti SSA, anti SSB, high titer ANA (speckled pattern), RF HISTOPATHOLOGY 12. Lymphocytic infiltration of salivary glands or other organs DIAGNOSIS OR CLASSIFICATION REQUIREMENTS 13. Diagnosis requires at least 4 of 12 items Modified from Yokogawa N, Lieberman SM, Sherry DD, Vivino FB. Features of childhood Sjgrens syndrome in comparison to adult Sjgrens syndrome: considerations in establishing child specific diagnostic criteria. Clin Exper Rheumatol. 2016;34:343351, Table 1. process is regarded as a clinical variant of BD (partial or incomplete) but without ulcerations. TREATMENT AND PROGNOSIS Azathioprine is highly recommended to treat inflammatory eye disease. Antitumor necrosis factor (TNF) treatment and inter feron (IFN) should be considered for refractory eye disease. For oral and genital ulcers, topical treatment and colchicine are recom mended (sucralfate, corticosteroids). Apremilast, an oral phospho diesterase 4 inhibitor, is effective in treating the oral ulcers of BD. In patients without major organ involvement, colchicine significantly improves oral and genital ulcers, skin features, and disease activ ity. There is no evidence based treatment for GI disease, but 5 ASA derivatives, corticosteroids, azathioprine, and anti TNF agents have been recommended. For CNS disease and venous thrombosis, cor ticosteroids, azathioprine, and anti TNF agents are recommended. Patients treated with anti TNF drugs have had persistent responses in 90, 89, 100, and 91 of patients with resistant mucocuta neous, |
6,810 | ocular, GI, and CNS involvement, respectively. There is no consensus about the benefit of anticoagulation in the management of vein thrombosis in BD. In patients with pulmonary arterial or cardiac involvement, cyclo phosphamide is typically used initially. Mortality in children with BD is low except for the pulmonary aneu rysms. However, BD is a chronic disease associated with significant morbidity. Early diagnosis and effective treatment improve the out come of BD. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 203 u Sjgren Syndrome 1517 Fig. 203.1 T2 weighted MRI of a child with Sjgren syndrome showing parotitis (arrows). Subjective symptoms of xerostomia complaints are relatively rare in juvenile cases, perhaps indicating that Sjgren syndrome is a slowly progressive disease; however, increased dental caries is seen clinically in children. Serologic markers (antinuclear antibod ies ANAs, antibodies to Ro SSA and La SSB) and articular manifestations are significantly more common in adults. Reported frequencies of ANAs and SSA and SSB antibodies in children are 78, 75, and 65, respectively, with rheumatoid factor present in 67. Additional clinical manifestations from a variety of organ involvement patterns include a decreased sense of smell; hoarse ness; chronic otitis media; leukocytoclastic vasculitis (purpura); and internal organ exocrine disease involving the lungs (diffuse interstitial lymphocytosis), pancreas, hepatobiliary system, gastro intestinal tract, kidneys (renal tubular acidosis), musculoskeletal (arthritis and arthralgia), hematologic (cytopenias), peripheral ner vous system (sensory and autonomic neuropathy), and CNS (optic neuritis, transverse myelitis, meningoencephalitis). Nonexocrine disease manifestations of Sjgren syndrome may be related to inflammatory vascular disease (skin, muscle and joints, serosal surfaces, CNS, peripheral nervous system), noninflammatory vascular disease (Raynaud phenomenon), mediator induced disease (hematologic cytopenias, fatigue, fever), and autoimmune endocri nopathy (thyroiditis). DIAGNOSIS Clinical presentation of recurrent parotitis andor recurrent parotid gland swelling in a child or adolescent is characteristic and should raise the suspicion for Sjgren syndrome. The diagnosis is based on clinical features supported by biopsy of salivary or parotid glands demonstrating foci of lymphocytic infiltration, the current gold standard for diagnosis. Children are more likely to have normal minor salivary gland but abnormal parotid gland biopsies. Support ing laboratory abnormalities include cryoglobulinemia, elevated erythrocyte sedimentation rate, hypergammaglobulinemia, positive rheumatoid factor, and presence of SSA and SSB antibodies. The Schirmer test detects abnormal tear production (5 mm of wetting of a filter paper strip in 5 minutes). Special dyes (e.g., fluorescein, Lissamine green) detects damaged ocular epithelial conjunctival and corneal cells. Imaging studies, including MRI, technetium (99mTc) scintigraphy, parotid ultrasound, and sialography, are use ful in the diagnostic evaluation for Sjgren syndrome (Fig. 203.1). DIFFERENTIAL DIAGNOSIS The differential diagnosis of Sjgren syndrome in children includes juvenile recurrent parotitis, characterized by intermittent unilateral parotid swelling typically lasting only a few days; it is frequently asso ciated with fever and may undergo remission with puberty. Unlike in Sjgren syndrome, |
6,811 | there is a male predominance, juvenile recur rent parotitis is seen in the younger children (3 6 years), and there is a lack of focal lymphocytic infiltrates on biopsy. Other conditions in the differential diagnosis include eating disorders, infectious parotitis (mumps, streptococcal and staphylococcal infections, Epstein Barr virus, cytomegalovirus, HIV, parainfluenza, influenza enterovirus), and local trauma to the buccal mucosa. Rarely, polycystic parotid disease, tumors, and sarcoidosis may present with recurrent parotid swelling. In these conditions, sicca complex, rash, arthralgia, and ANAs are usu ally absent. TREATMENT Symptomatic treatment of Sjgren syndrome includes the use of artifi cial tears, massage of the parotids, oral lozenges, and fluids to limit the damaging effects of decreased secretions. Corticosteroids, nonsteroidal antiinflammatory drugs, and hydroxychloroquine are among the more commonly used agents for treatment, with reports of methotrexate and etanercept used for treatment of arthritis. Stronger immunosuppres sive agents, such as cyclosporine and cyclophosphamide, are reserved for severe manifestations (e.g., lung involvement) and life threatening complications. COMPLICATIONS AND PROGNOSIS The symptoms of Sjgren syndrome develop and progress slowly. Diminished salivary flow typically remains constant for years. Because monoclonal B lymphocyte disease originates chiefly from lymphocytic foci within salivary glands or from parenchymal internal organs, there is increased risk for mucosa associated lymphoid tissue lymphoma. Maternal Sjgren syndrome can be an antecedent to neonatal lupus syndrome (see Chapter 199.1). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1530 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Type I interferonopathies refer to a group of inherited autoinflam matory disorders that are characterized by dysregulation of the type I interferon (IFN) pathway (Table 205.1). Type I interferonopathies were recognized when a report described the phenotypic overlap between Aicardi Goutires syndrome (AGS) encephalopathy, congenital viral infections, and monogenic systemic lupus erythematosus (SLE). The clinical similarities of these diseases stimulated the theory of a shared pathologic mechanism. Pathogenic variants involved in type I IFN sig naling were identified to be causative for AGS and monogenic forms of SLE. Several other novel monogenic disorders with aberrant IFN signaling have been identified. Type I IFNs are ubiquitously expressed inflammatory polypep tides that are induced by microbial and viral nucleic acids. During viral replication, accumulation of viral nucleic acids is sensed by several different cellular mechanisms, which leads to downstream IFN production (Fig. 205.1). Type I IFNs are released from the cell and bind to IFN receptors (IFNRs) through autocrine and paracrine action. The IFNR then activates signal translation through Janus kinasesignal transducers and activators of transcription (JAK STAT) pathways, which promotes the expression of IFN simulated genes (ISGs), which stops cell replication and protein translation of the infected cell. There are several molecular mechanisms that lead to altered regulation of IFN signaling: (1) loss of function variants of genes that encode enzymes responsible |
6,812 | for DNA or DNA RNA hybrid molecule degradation; (2) variants that lead to constitutive activation or reduction of the activation threshold of intracytosolic nucleic acid sensors; (3) gain of function variants of positive IFN signaling regulators; (4) loss of function variants of negative IFN signaling regulators; and (5) proteasomal dysfunction leading to the unfolded protein response and downstream IFN pathway activation. Examples of these altered molecular mechanisms and the associated Chapter 205 Interferonopathies Sara E. Sabbagh and James W. Verbsky Table 205.1 Mutated Gene, Protein Function, Pattern of Inheritance, and Main Symptoms of Known Type 1 Interferonopathies DISEASE GENE PROTEIN FUNCTION INHERITANCE SYMPTOMS Aicardi Goutires syndrome (AGS) type 1 TREX 1 3 5 DNA exonuclease AR and AD Classical AGS AGS2 RNASEH2B Components of RNase H2 complex. Removes ribonucleotides from RNA DNA hybrids AR Classical AGS AGS3 RNASEH2C Classical AGS AGS4 RNASEH2A Classical AGS with dysmorphic features AGS5 SAMHD1 Restricts the availability of cytosolic deoxynucleotides AR Mild AGS, mouth ulcer, deforming arthropathy, cerebral vasculopathy with early onset stroke AGS6 ADAR Deaminates adenosine to inosine in endogenous dsRNA, preventing recognition by MDA5 receptor AR and AD Classical AGS, bilateral striatal necrosis AGS7 IFIH1 Cytosolic receptor for dsRNA AD Classic or mild AGS, asymptomatic Retinal vasculopathy with cerebral leukodystrophy (RVCL) TREX 1 3 5 DNA exonuclease AD Adult onset loss of vision, stroke, motor impairment, cognitive decline, Raynaud, and liver involvement Spondyloenchondrodysplasia (SPENCD) ACP5 Lysosomal phosphatase activity AR Spondyloenchondrodysplasia, immune disregulation, and in some cases combined immunodeficiency STING associated vasculopathy with onset in infancy (SAVI) TMEM173 Transduction of cytoplasmic DNA induced signal AD Systemic inflammation, cutaneous vasculopathy, pulmonary inflammation Proteasome associated autoinflammatory syndrome (PRAAS) PSMB8 Part of the proteasome complex AR Autoinflammation, lipodystrophy, dermatosis, hyperimmunoglobulinemia, joint contractures, short stature ISG15 deficiency ISG15 Stabilizes USP18, a negative regulator of type 1 interferon AR Brain calcifications, seizures, mycobacterial susceptibility Singleton Merten syndrome (SMS) IFIH1 Cytosolic receptor for dsRNA AD Dental dysplasia, aortic calcifications, skeletal abnormalities, glaucoma, psoriasis Atypical SMS DDX58 Cytosolic receptor for dsRNA AD Aortic calcifications, skeletal abnormalities, glaucoma, psoriasis Trichohepatoenteric syndrome (THES) SKIV2L RNA helicase AR Severe intractable diarrhea, hair abnormalities (trichorrhexis nodosa), facial dysmorphism, immunodeficiency in most cases From Volpi S, Picco P, Caorsi R, Candotti F, Gattorno M. Type I interferonopathies in pediatric rheumatology. Pediatr Rheumatol Online J. 2016;14(1):35. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 205 u Interferonopathies 1531 genetic variants are depicted in Figure 205.1. Each genetic variant that leads to dysregulation of IFN signaling is causative of a unique clinical syndrome or subtype of a clinical syndrome that has been classified as a type I interferonopathy. Despite some disease hetero geneity, interferonopathies have a characteristic clinical phenotype, which may include recurrent fevers, early onset of skin vasculopa thy with chilblains, livedo reticularis, panniculitis, lipodystrophy, interstitial lung disease with fibrosis, and encephalopathic CNS involvement (Fig. 205.2 and Table 205.2). AUTOINFLAMMATORY |
6,813 | INTERFERONOPATHIES Aicardi Goutires Syndrome AGS is a clinically heterogeneous disease with a spectrum of associ ated phenotypes. AGS is characterized by an early onset progressive encephalopathy with basal ganglia calcifications, leukoencepha lopathy, and cerebral atrophy with elevated type I IFN cerebro spinal fluid (CSF) levels and CSF pleocytosis. Cutaneous features, seen in about 30 of patients, include chilblains, or cold induced acral dermatosis of the digits and auricles secondary to peripheral inflammatory vasculopathy. Other common manifestations include thrombocytopenia, hepatosplenomegaly, transaminitis, psoriasis, interstitial lung disease, and intermittent fever. Most frequently, AGS has an infantile onset in which patients develop abrupt irri tability, sterile pyrexias, and developmental regression within the first few months of life. Neurologic symptoms may include limb hypertonia with truncal hypotonia, dystonia, excessive startle, abnormal eye movements, epileptic seizures, and slowing of head growth. RNASEH2B variants are commonly seen in this context; however, variants of any associated AGS related genes may present with this clinical scenario. AGS may also present prenatally with a striking similarity to transplacentally acquired infections (pseudo TORCH), with onset of disease in utero. At birth, patients may have irritability, feeding difficulties, jitteriness, microcephaly, abnormal movements, epileptic seizures, thrombocytopenia, anemia, and liver dysfunction. This presentation is most frequently associated with TREX1 pathogenic variants and leads to profound develop mental sequelae and increased risk of death in infancy. In both clinical presentations, neuroimaging shows a highly characteristic pattern of diffuse abnormal white matter, intracranial calcifica tions, swelling of temporal or frontal lobes, and cerebral atrophy, similar to radiologic findings seen in congenital infections. Patients may also develop autoimmunity, including type 1 diabetes mellitus, hypothyroidism, hypergammaglobulinemia, and hemolytic anemia. Rarely, AGS can have a later onset with abrupt profound neurologic regression after an extended period of normal development. There are seven recognized genetic variants and correspond ing disease subtypes of AGS (AGS 1 7), all of which are respon sible for RNADNA degradation or detection, resulting in type I dsDNA dsRNA DNARNA hybrids TREX 1 RNASEH2 SAMHD1 STING RIG1 ADAR IFIH1 NTPs IRF3 IRF7TBK1 MAVS Nucleus IFN ERGIC USP18 ISG15 S TA T 1 S TA T 2 S TA T 1 S TA T 1 S TA T 3 S TA T 3 IRF9 P P P P P P ISRE 1 1 1 2 3 4 2 Proteasome ?5 IFNAR2 IFNAR1 IF NAR2 IF NAR1 JA K1 TYK2 Fig. 205.1 Schematic representation of various pathways affected in genetic interferonopathies. Purple rectangles indicate variant proteins in type I interferonopathies. Numbered yellow circles indicate the common mechanistic defect. 1. Loss of function pathogenic variants of genes that encode enzymes responsible for DNA or DNA RNA hybrid molecule degradation. 2. Pathogenic variants that lead to constitutive activation or reduction of activation threshold of intracytosolic nucleic acid sensors. 3. Gain of function pathogenic variants of positive IFN signaling regulators; 4. Loss of function pathogenic variants of negative IFN signaling regulators; and 5. Proteasomal dysfunctional leading to the unfolded protein re sponse and downstream IFN pathway activation. STING: stimulator of interferon |
6,814 | genes; SAMHD1: SAM domain and HD domain deoxynucleoside triphosphate triphosphohydrolase 1; NTPs: nucleoside triphosphates; TREX1: DNA 3 repair exonuclease 1; ISG15: interferon stimulated gene 15; MAVS: mitochondrial antiviral signaling protein; RIG I: retinoic acid inducible gene I; TBK1: TANK binding kinase 1; USP18: ubiquitin specific pepti dase 18; RNASEH2, ribonuclease H domain 2; IFIH1: IFN induced helicase C domain containing protein 1; ADAR: RNA adenosine deaminase; IRF3: interferon regulatory factor 3; IRF7: interferon regulatory factor 7; IRF9: interferon regulatory factor 9; ERGIC: endothelial reticulumGolgi interme diate compartment; IFNAR: interferon receptor; ISGF3: the transcriptional activator induced by interferon ; ISRE: interferon sensitive response element; JAK1: Janus kinase 1; TYK2: tyrosine kinase 2; STAT: signal transducer and activator of transcription. P indicates phosphorylation. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1532 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) IFN production and upregulation of ISGs. These include variants of 3 5 DNA exonuclease TREX1 (AGS1); ribonucleases including RNASEH2B (AGS2), RNASEH2C (AGS3), and RNASEH2A (AGS4); SAM and HD domain containing deoxynucleoside triphosphate tri phosphohydrolase 1 SAMHD1 (AGS5); adenosine deaminase acting on RNA 1 ADAR1 (AGS6); and IFN induced helicase C domain containing protein IFIH1 (AGS7). The majority of AGS subtypes are autosomal recessive; however, heterozygous gain of function variants can also occur in AGS1 and AGS6, and variants causing AGS7 are autosomal dominant. There are several manifestations that are strongly associated with distinct AGS subtypes. Bilateral striatal necrosis with severe dysto nia is associated with variants in ADAR1 (AGS6), and spastic para paresis has been associated with variants in ADAR1 (AGS6), IFIH1 (AGS7), and RNASEH2B (AGS2). Variants involving SAMHD1 (AGS5) have the most variable phenotype with cutaneous involve ment, glaucoma, progressive contractures, stroke, and cerebral aneurysms. Beyond the phenotype diversity between different AGS variants, there are descriptions of marked intrafamilial variation in siblings harboring identical homozygous variants, which raises questions regarding how environmental factors influence disease expression and penetrance. Spondyloenchondrodysplasia Spondyloenchondrodysplasia (SPENCD) is a rare autosomal reces sive disorder best characterized as a skeletal dysplasia with sclerosis, enchondromas, short stature, platyspondyly, and irregularity of verte bral end plates. Patients may also develop intracranial calcifications, spasticity, and a spectrum of autoimmunity that bears resemblance to SLE, including hemolytic anemia, thrombocytopenia, glomerulone phritis, malar rash, myositis, antiphospholipid syndrome, and auto antibody positivity. Patients have also developed hypothyroidism, Raynaud phenomenon, Sjgren syndrome, and vitiligo. SPENCD is caused by variants of the ACP5 gene on chromosome 19p13, which encodes tartrate resistant acid phosphatase (TRAP). Loss of TRAP expression impairs inactivation of osteopontin (Opn), a protein involved in bone metabolism and Th1 differentiation, via signaling through TLR9 in plasmacytoid dendritic cells (pDCs). Increased lev els of Opn thus leads to increased IFN production. STING Associated Vasculopathy with Onset in Infancy STING associated vasculopathy with onset in infancy (SAVI) is a rare disorder that presents with systemic |
6,815 | inflammation, fevers, and elevated inflammatory markers in the first months of life. Fig. 205.2 Characteristic clinical phenotypes of interferonopathies. Chilblain lesions typical of mono genic type I interferonopathies, seen most frequently on the toes, fingers (A), ears (B), and nose. The lesions are generally worse in the cold months. C, Representative brain CT scan of intracranial cal cifications seen in a patient with Aicardi Goutires syndrome due to TREX1 homozygous pathogenic variants. D, Chest CT scan of a SAVI patient (performed at the age of 12.5 years) showing evidence of interstitial lung disease (interlobular septal thickening, intralobular lines, cystic lesions, and some ground glass lesions) and fibrosis (honey combing). (Modified from Melki I, Fremond ML. Type I interferonopa thies: from a novel concept to tar geted therapeutics. Curr Rheum Reports. 2020;22:32, Fig. 1.) A B C D D o w n l o a d e d f o r m o h a m e d a h m e d ( d r . m m s 2 0 2 0 g m a i l . c o m ) a t U n i v e r s i t y o f S o u t h e r n C a l i f o r n i a f r o m C l i n i c a l K e y . c o m b y E l s e v i e r o n A p r i l 2 1 , 2 0 2 4 . F o r p e r s o n a l u s e o n l y . N o o t h e r u s e s w i t h o u t p e r m i s s i o n . C o p y r i g h t 2 0 2 4 . E l s e v i e r I n c . A l l r i g h t s r e s e r v e d . Chapter 205 u Interferonopathies 1533 Table 205.2 Suggestive Features of Type I Interferonopathies Familial history Several affected individuals, even if phenotypic spectrum might be variable within the same family Age of onset Young age at onset, in favor of monogenic disease Later onset also reported Neurologic phenotypes Clinical signs: Spasticity, spastic paraparesis Acute or subacute dystonia Encephalopathy with seizures and progressive microcephaly Cortical blindness Variable developmental delay Ataxia Psychosis Vascular neurologic disease (Moyamoya)strokes Rare demyelinating or multifocal neuropathies Lumbar puncture: Meningitis (inconstant) Elevated pterinsneopterins in the CSF Elevated IFN activity or protein in the CSF Morphologic imaging features: CT scans: ICC, basal ganglia calcifications or progressive cerebral atrophy Cerebral MRI: leukoencephalopathy, white matter rarefaction, delayed myelination, bilateral striatal necrosis, deep white matter cysts, or intracranial aneurysms Cutaneous features ChilblainsFCL; necrotizing vasculitis of fingers, toes, helix, cheeks, and nose, telangiectasia, cutaneous ulcerations Livedo reticularis Panniculitis, violaceous periorbital rash Lentigines Psoriasis |
6,816 | Nail dystrophy, sparse hair Failure to thriveshort stature Secondary to osseous dysplasia (ACP5) Secondary to the inflammatory status (TMEM173) Systemic inflammation and immune features Recurrent fevers Autoimmune featuresSLEautoantibodies (not necessarily specific) Inconstant immune deficiency Elevated IFN I pathway in whole bloodserumplasma Hematologic AI anemia, dyserythropoiesis Thrombocytopenia or thrombocytosis Malignancies (chronic lymphocytic leukemia, cutaneous T cell lymphoma, SAMHD1) Lung features Interstitial lung disease (isolated or not) Lung fibrosis Intraalveolar hemorrhage Macrophagic alveolitis Vascular features Calcification of the aorta or blood vessels Musculoskeletal features Joint pain, arthritis Contractures and joint retractions Jaccoud arthropathy, tendon rupture Muscle weakness and painmyositis Calcinosis X rays: acro osteolysis, wide medullar cavities phalange, deforming arthropathiesjoint subluxation with conserved interarticular space, calcinosis Ophthalmologic features Glaucoma Papillary edemaa Kidney features Lupus nephritis Gastrointestinal features VEO IBD (very severe protein losing enteropathy) Dental anomalies Retained primary teethb Early loss of permanent teeth aReported in one SAVI patient treated with JAK12 inhibitor. bData not published. Ab, Autoantibodies; AI, autoimmune; CSF, cerebrospinal fluid; CT, computerized tomography; FCL, familial chilblain lupus; ICC, intracranial calcifications; IFN, interferon; IFN I, type I interferon; MRI, magnetic resonance imaging; SLE, systemic lupus erythematosus; VEO IBD, very early onset inflammatory bowel disease. From Melki I, Fremond ML. Type I interferonopathies: From a novel concept to targeted therapeutics. Curr Rheum Reports. 2020;22:3, Table 2. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1534 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Cutaneous involvement is characterized by vasculopathic rashes in acral areas (Fig. 205.3). These lesions present as violaceous plaques or nodules on the face, ears, or nose or as distal ulceration and may become necrotic. Lesional skin biopsy reveals leukocyto clastic vasculitis, microthrombotic angiopathy, neutrophilia, and occasional immune complex deposition. As STING is expressed in alveolar macrophages, type 2 pneumocytes, and bronchial epi thelium, patients with SAVI also develop pulmonary complica tions. Paratracheal adenopathy, interstitial lung disease, and lung fibrosis have been described to a variable extent. Patients may also develop myositis, arthritis, arthralgia, oral ulcers, aphthosis, and nasal septum perforation. Low titer autoantibodies (e.g., antinu clear antibody, anticardiolipin antibodies, and antibodies against 2 glycoprotein I) may be seen. Notably, the presence of antineu trophil cytoplasmic antibodies (cANCA) may lead to misdiagnosis of childhood granulomatosis with polyangiitis. SAVI is caused by a dominant gain of function variant in TMEM173, which encodes the stimulator of interferon genes (STING). Working as both a direct cytosolic DNA sensor and as an adaptor protein in type I IFN signaling, STING mediates the production of IFN . Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Proteasome Associated Autoinflammatory Syndromes Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflamma tory disease caused by abnormal functioning of the proteasome immunoproteasome. CANDLE presents in early infancy with fevers, systemic inflammation, and cutaneous involvement including neutrophilic dermatosis, annular erythema, violaceous |
6,817 | eyelid swell ing, and erythema nodosumlike panniculitis. Histology reveals a characteristic mononuclear interstitial infiltrate, which includes immature neutrophils in the dermis. Lipodystrophy, usually of the face, trunk, and upper limbs, begins in early childhood. Arthralgias, without radiographic evidence of arthritis, are common in children, and severe joint contractures may develop into adulthood. Acute attacks of inflammatory myositis, aseptic meningitis, sterile epidid ymitis, conjunctivitis, nodular episcleritis, parotitis, pneumonitis, nephritis, carditis, and otitis have been reported. Autoimmunity can occur, including Coombs positive hemolytic anemia and hypothy roidism. Most commonly, CANDLE is due to loss of function vari ants in the PSMB8 gene, which encodes the proteasome 5i subunit. More recently, variants in other genes encoding other proteasome immunoproteasome subunits or the regulatory protein POMP have been discovered in patients with CANDLE syndrome. The defective proteasome function may lead to an accumulation of damaged pro teins, resulting in cellular stress and type 1 IFN upregulation. ISG15 DeficiencyUSP18 Deficiency Ubiquitin like protein IFN stimulated gene 15 (ISG15) deficiency has only been reported in a few individuals and leads to a pheno type similar to AGS, with intracranial calcifications and seizures. ISG15 is an IFN induced protein that that plays a central role in the host antiviral response, although, in humans, ISG15 deficiency does not cause an increased susceptibility to viral infection. Rather, the absence of intracellular ISG15 prevents the accumulation of ubiquitin specific peptidase 18 (USP18), a potent negative regula tor of IFN signaling, which results in an unchecked IFN Fig. 205.3 Clinical manifestations of stimulator of interferon genes (STING)associated vasculopa thy with onset in infancy (SAVI). A, Typical facial distribution of telan giectatic lesions on the nose and cheeks with atrophy and scarring of the skin with loss of deep tissue of the nose. B, Violaceous, scaling, atrophic plaques on both hands and progressive autoamputations of several fingers. C, Hilar lymphad enopathy and bilateral interstitial infiltrates on high resolution com puted tomography (CT) image. D, Ulcerated lesions on the pinna of the ear with scales and crusts. (Courtesy Dr. Raphaela Goldbach Mansky. From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Fig. 39.11, p. 541.) A C B D Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 205 u Interferonopathies 1535 response. Notably, loss of function recessive variants of USP18 have been reported in five patients, all of whom had neonatal demise soon after birth owing to the dysregulation of type 1 IFN responses. Singleton Merten Syndrome Singleton Merten syndrome (SMS) is an autosomal dominant disor der characterized by early onset severe aortic and valvular calcifica tion, dental anomalies, acro osteolysis, osteoporosis, and glaucoma. There is a broad spectrum of disease with variable expressivity, and patients have been reported to have an SLE or AGS phenotype. SMS is caused by gain of function variants in IFIH1 |
6,818 | and DDX58, which encode retinoic acidinducible gene I (RIG I)like receptor family members melanoma differentiation associated gene 5 (MDA5) and RIG I, respectively. MDA5 and RIG I are cytosolic pattern recogni tion receptors that detect viral RNA and promote type I and III IFN expression. The phenotype variability of SMS suggests that other genetic andor environmental factors may influence the clinical presentation. X Linked Reticulate Pigmentary Disorder X linked reticulate pigmentary disorder (XLPDR) is an X linked dominant disorder that manifests in the first few months of life in affected males with recurrent pneumonia, bronchiectasis, diar rhea, and failure to thrive. Diffuse skin hyperpigmentation occurs in early childhood, and distinct facial features develop. Female car riers typically exhibit only pigmentary changes along the lines of Blaschko. Hypohidrosis, corneal scarring, enterocolitis, and ure thral strictures can develop. The defect in XLPDR is in an intron of the POLA1 gene, which encodes the catalytic subunit of DNA polymerase a. Although this defect does not affect DNA replica tion, it does appear to increase IFN production and IFN induced genes as well as NF Binduced genes in response to dsDNA, cyto solic dsRNA, and TNF . DNAse II Deficiency Deoxyribonucleases (DNAses) degrade double stranded DNA molecules and exist in several forms. DNAse II degrades DNA contained in lysosomes, and recently deficiency of DNAse II was shown to cause a form of monogenic SLE. This autosomal reces sive disease presents with severe anemia, thrombocytopenia, and hepatosplenomegaly at birth that may resolve over time. In child hood patients may then develop membranoproliferative glomeru lonephritis, arthropathy, lipodystrophy, chilblain like vasculitis, and hypogammaglobulinemia. Laboratory testing shows high titer ANA and dsDNA antibodies and high levels of serum IFNs and IFN stimulated gene expression. In addition to DNAse II, there are two extracellular DNAses (DNAse1 and DNAse1L3) that do cause a monogenic form of SLE. Although these are likely to exhibit high IFN signatures, no data are available on these two diseases, and thus they are not classically considered interferonopathies. AUTOIMMUNE INTERFERONOPATHIES Systemic Lupus Erythematosus There were descriptions of increased levels of IFN in the serum of patients with SLE. Further rationale for IFN contributing to SLE pathogenesis was supported by observational studies of patients who developed a lupuslike disease with autoantibody formation after treatment with IFN . Several groups showed that the major ity of patients with SLE have an increased expression of type I IFN regulated genes and that active SLE could be distinguished by an IFN induced gene expression pattern. Many clinical features of SLE are associated with increased production of IFN, and a high IFN signature has been correlated with cytopenia, autoantibody forma tion, and cutaneous disease activity. There are a large number of possible inducers of IFN production in SLE. Neutrophil extracel lular TRAP formation, transposable elements, and immune com plexes have all been associated with IFN production in SLE patients. From a genetic standpoint, over 100 risk loci have been associated with SLE, many of which encode proteins with functions linked to |
6,819 | type I IFN production or response. There are also several rare forms of monogenic SLE that are due to pathogenic variants involv ing type I IFN signaling. Monogenic forms of SLE, including loss of function variants in DNAse II, DNASE1L3, and DNASE1, are classically grouped under the umbrella of interferonopathies and are characterized by typical SLE clinical manifestations with auto antibody formation and immune complex deposition (see Chapter 199). Success of targeting the IFN pathway has been documented in SLE, and multicenter phase 3 randomized placebo controlled trials are currently underway in extrarenal disease. Juvenile Dermatomyositis Dermatomyositis has become recognized as a disease partly driven by aberrant IFN signaling. An elevated IFN signature was first discovered in muscle tissue and later identified in peripheral blood cells of patients with adult and juvenile onset dermatomyositis (DM, JDM). Subse quently, multiple studies have shown an association between type I IFN in the circulation and disease activity in myositis. Targeting the IFN pathway has shown success in treatment of DM and JDM, and there are several ongoing clinical trials evaluating small molecule Janus kinase (JAK) inhibitors for the treatment of dermatomyositis. Therapeutics Targeting the Interferon Pathway Treatments for interferonopathies has been historically empiric. Numerous immunosuppressive medications, including corticoste roids and a variety of biologics, have been tried in case reports with variable results. However, because interferonopathies have a com mon pathway involving IFN signaling, the use of small molecule JAK inhibitors (JAKinibs) has gained interest as a targeted therapy for these disorders. Signaling through the IFN pathway involves JAKs that phosphorylate signal transducers and activators of tran scription (STAT) proteins that then dimerize and enter the nucleus to drive transcription of IFN stimulated genes. JAKinibs block acti vation of JAK proteins and have been used to treat various auto immune diseases. There is Food and Drug Administration (FDA) approval of several JAKinibs, including tofacitinib, baricitinib, and upadacitinib, for the treatment of rheumatoid arthritis; tofacitinib is also approved for the treatment of psoriatic arthritis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis. Clinical trials are underway to test the utility of JAKinibs in interferonopathies. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1536 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Amyloidosis is the result of extracellular deposition of insoluble, fibrous amyloid proteins in various body tissues. It may be caused by a hereditary abnormality in an amyloidogenic protein or occur as a result of chronic inflammation associated with some infectious and rheumatologic diseases. ETIOLOGY Amyloidosis is a result of protein misfolding. These misfolded proteins aggregate and form insoluble fibrils that can affect the normal function of several vital organs. In the amyloidosis nomenclature, a distinction is made between amyloidosis that develops from pathogenic gene vari ants in the amyloid fibril proteins (hereditary amyloidoses) and amy loidosis |
6,820 | associated with genetic mutation in nonamyloid proteins. The hereditary amyloidoses include diseases caused by pathogenic variants in the genes for transthyretin and apolipoprotein A and usually do not present in childhood. However, children may be affected by amyloid A (AA) amyloidosis, which develops in patients with chronic inflam matory states. It is estimated that approximately 45 of all amyloid cases worldwide are AA amyloidosis. In the past, chronic infectious diseases such as tuberculosis, malaria, leprosy, and chronic osteomyeli tis accounted for most cases of AA amyloidosis. Since the development of effective treatments for these infections, other causes of AA have become more common. Individuals with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis, as well as hereditary autoinflammatory dis eases, have an increased risk for the development of AA amyloidosis. AA amyloidosis has also been associated with sarcoidosis, cystic fibro sis, Crohn disease, malignancies (mesothelioma and Hodgkin disease), intravenous drug use disorders, and HIV infection. Approximately 6 of AA amyloidosis cases have no identified disease association. EPIDEMIOLOGY Only AA amyloidosis affects children in appreciable numbers. The factors that determine the risk for amyloidosis as a complication of inflammation are not clear. Many individuals with long standing inflammatory disease do not demonstrate tissue amyloid deposi tion, but some children with relatively recent onset of disease may develop amyloid. In developed countries, before therapy with disease modifying antirheumatic drugs (DMARDs) and biologic agents was available, rheumatoid arthritis was the most common inflammatory disease associated with AA amyloidosis. Patients who had a long his tory of severe and poorly controlled disease with extraarticular mani festations were at the greatest risk of developing amyloidosis, and the median time from first symptoms of their rheumatic condition to the diagnosis of amyloidosis was 212 months. The use of DMARDs and biologic therapy has resulted in a sustained decline in the number of new cases of RA associated amyloidosis. JIA may be associated with AA amyloidosis, with the highest preva lence occurring in patients with systemic JIA, followed by those with polyarticular disease. AA amyloidosis has been observed in JIA patients as soon as 1 year after diagnosis. Before the availability of DMARDs and biologics, the prevalence of AA amyloidosis in JIA patients ranged from 1 to 10. Higher prevalence was seen in Northern European patients, especially Polish patients, who had a prevalence of 10.6; a lower prevalence was observed in North American patients. The rea sons for this discrepancy are not completely understood, although it is speculated that selection bias, genetic background, and tendency toward earlier, more aggressive therapy in North Americans may have played a role. As with RA, the occurrence of new amyloid cases in patients with JIA has significantly decreased in the past 20 years because of the increased efficacy of treatment with DMARDs and biologics. The hereditary autoinflammatory diseases define a group of ill nesses characterized by attacks of seemingly unprovoked recurrent inflammation without significant levels of either autoantibodies or antigen specific T cells, |
6,821 | which are typically found in patients with auto immune diseases. These attacks often appear to be initiated by stress, immunizations, or trauma. Common findings of autoinflammatory diseases include fevers, cutaneous rashes, arthritis, serositis, and ocu lar involvement. The inflammatory attacks are accompanied by intense elevations in inflammatory markers (erythrocyte sedimentation rate and C reactive protein) and high levels of serum amyloid A (SAA). Amyloidosis AA is associated with some, but not all, hereditary auto inflammatory diseases. Familial Mediterranean fever (FMF) is the most common of the Mendelian autoinflammatory diseases and is seen most frequently in the Armenian, Arab, Turkish, and Sephardic Jewish populations. FMF is an autosomal recessive disease that results from pathogenic variants in the MEFV gene, which encodes the pyrin protein. MEFV pathogenic variants affecting the M680 and M694 amino acid residues are associ ated with early onset of symptoms, severe disease, and an increased risk of AA amyloidosis. Patients residing in Armenia, Turkey, and Arab countries have an increased risk of developing AA amyloidosis com pared with patients with the same MEFV mutations living in North America. While one might assume that FMF patients who have fre quent, severe attacks would be at the highest risk for the development of AA amyloidosis, this is not always the case. Some patients with a history of frequent attacks never develop amyloidosis, whereas others develop amyloidosis at an early age. Tumor necrosis factor receptorassociated periodic syndrome (TRAPS) is associated with pathogenic variants in the TNFRSF1A gene, which encodes the 55 kDa tumor necrosis factor (TNF) recep tor protein (TNFR1). It is estimated that 1425 of untreated patients with TRAPS will develop AA amyloidosis. The risk of amyloidosis appears to be greater among patients with cysteine pathogenic variants or the T50M pathogenic variant. These cysteine residues normally cre ate disulfide bonds within the protein, and disruption of these bonds by amino acid substitutions is thought to interfere with protein folding. Pathogenic variants in the NLRP3 (NLR family pyrin domain con taining 3) gene encoding the NLRP3 or cryopyrin protein cause three clinically distinct diseases or cryopyrinopathies: familial cold autoin flammatory syndrome (FCAS, or NLRP3 AID mild), Muckle Wells syndrome (MWS, or NLRP3 AID moderate), and neonatal onset multisystem inflammatory disease (NOMID, or NLRP3 AID severe), also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome. Pathogenic variants in NLRP3 are inherited in an autosomal dominant fashion or as de novo variants in patients with the most severe disease. A few patients have been found to carry somatic variants in NLRP3. FCAS is the least severe of the cryopyrinopathies and is rarely asso ciated with AA amyloidosis. MWS presents with fevers, myalgias, arthralgias, urticarial like rash, and progressive sensorineural hearing loss. AA amyloidosis is quite common in MWS, affecting up to one third of the patients. NOMIDCINCA is the most severe cryopyrinop athy. NOMID patients have not developed AA amyloidosis as often as MWS patients, but this may be attributable to the fact that before the availability of effective treatments, 20 |
6,822 | of NOMID patients died before reaching adulthood. Mevalonate kinase deficiency (MKD) mild (formally known as Hyper IgD syndrome, or HIDS) is an autoinflammatory disease that presents in early childhood with high fevers, abdominal pain, lymph adenopathy, and occasional rash. MVK mild is an autosomal reces sive disease that involves loss of function variants in the MVK gene that encodes the mevalonate kinase enzyme. Patients with MVK mild retain a low level of enzyme activity, whereas patients with MVK severe (mevalonic aciduria) have severe MVK variants that completely abolish enzyme activity, causing recurrent fevers, dysmorphic features, and developmental delays. Inflammatory markers are high during Chapter 206 Amyloidosis Deborah L. Stone and Karyl S. Barron Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 206 u Amyloidosis 1537 MVK mild attacks and may remain elevated between attacks. AA amy loidosis is rare in patients with MVK mild but has been reported, most often associated with the V377II268T genotype. Although seen less frequently than in the hereditary periodic fever syndromes, AA amyloidosis occurs in an estimated 1 of U.S. patients and up to 3 of Northern European patients with Crohn disease. Con versely, AA amyloidosis in patients with ulcerative colitis is extremely rare, with an estimated prevalence of 0.07. Patients with Crohn dis ease and AA usually have a long standing history of aggressive, poorly controlled disease, although there are reports of amyloidosis in patients with well controlled inflammatory markers. Thirty six proteins have been identified as being amyloidogenic in humans, but most of these rarely cause disease during childhood. Transthyretin related hereditary amyloidosis is an autosomal domi nant disorder with variable penetrance and onset in the second to third decades of life. Manifestations include familial amyloidotic polyneu ropathy, familial amyloid cardiomyopathy, nephropathy, and ocular disease. PATHOGENESIS The deposition of AA amyloid fibrils is a result of a prolonged inflam matory state that leads to misfolding of the AA amyloid protein and deposition into tissues. The precursor protein of the fibrils in AA amy loidosis is an apolipoprotein called serum amyloid A. SAA is expressed by three different genes on chromosome 11p15.1. SAA1 and SAA2 are two isoforms that are acute phase reactants synthesized by the liver. SAA is produced in response to proinflammatory cytokines, such as interleukin (IL) 1, IL 6, and TNF , and can increase more than 1,000 fold during inflammation. It has been speculated that SAA has a role as a chemoattractant and in lipid metabolism. Supporting this theory is the finding that amyloid deposition occurs initially in organs that are major sites of lipid and cholesterol metabolism, such as the kidney, liver, and spleen. Approxi mately 80 of secreted SAA1 and SAA2 is bound to lipoproteins. Usu ally SAA secreted by the liver is completely degraded by macrophages. The secreted SAA protein is 104 amino acids in length and is primarily secreted |
6,823 | in an helix structure. For reasons not completely under stood, patients with AA amyloidosis have incomplete degradation and accumulation of intermediate SAA products. In these patients, SAA is transferred to the lysosome where the c terminal portion of the 104amino acid SAA protein is cleaved, allowing the remaining 66 76 amino acid proteins to fold into a pleated sheet configuration. These cleaved fragments polymerize, form fibrils that are deposited in the extracellular space, and bind proteoglycans and other proteins such as serum amyloid P. These fibrils are resistant to proteolysis and deposit in organ tissues. CLINICAL MANIFESTATIONS Although organ involvement may vary, AA amyloidosis most fre quently affects the kidneys; 90 of patients have some degree of renal involvement. Unexplained proteinuria may be the presenting feature in some patients. Nephrotic syndrome and renal failure may develop if the underlying inflammatory condition is not well controlled. Patients with higher SAA levels have a significantly higher risk of death than those with lower SAA levels. Gastrointestinal (GI) involve ment is seen in approximately 20 of patients and usually manifests as chronic diarrhea, GI bleeding, abdominal pain, and malabsorption. When biopsied, the testes are frequently discovered to be involved (87). Relatively uncommon findings associated with AA amyloidosis include anemia, amyloid goiter, hepatomegaly, splenomegaly, adrenal involvement, and pulmonary involvement. The heart, tongue, and skin are rarely involved. DIAGNOSIS The diagnosis of amyloidosis is established by a biopsy demonstrating amyloid fibril proteins in affected tissues. The tissues tested may include kidney, rectum, abdominal fat pad, and gingiva. Amyloid deposits are composed of seemingly homogeneous eosinophilic material that stains with Congo red dye and demonstrates the pathognomonic apple green birefringence in polarized light. Tissue staining and genetic testing are useful for diagnosing transthyretin amyloidosis. LABORATORY FINDINGS In the United States, specific laboratory testing is not commercially available for AA amyloid, but SAA levels are available in some other countries and can be monitored to guide response to treatment. TREATMENT There is no established therapy for AA amyloidosis, and thus the pri mary approach is aggressive management of the underlying inflamma tory or infectious disease. As newer therapies are developed to treat the underlying conditions, emerging evidence shows that the incidence of AA amyloidosis is decreasing. Colchicine is effective not only in con trolling the attacks of FMF but also in preventing the development of amyloidosis associated with FMF. AA amyloidosis associated with other autoinflammatory diseases and chronic rheumatic diseases does not respond to colchicine. Biologic agents against proinflammatory cytokines used to treat RA, JIA, spondyloarthropathies, and the heredi tary autoinflammatory diseases appear to decrease the risk of develop ing AA amyloidosis and may even reverse the deposition of amyloid. The class of medications referred to as the TNF inhibitors have been paramount in the management of RA and other autoimmune diseases, and there are reports documenting the effectiveness of anti TNF agents in blunting the progression of amyloidosis. Adverse effects of anti TNF medications include reactivation of tuberculosis and hepatitis B, and thus screening should be |
6,824 | performed before instituting therapy. Cau tion should be used in prescribing anti TNF agents to patients with a history of heart failure or demyelinating disease, because their use may cause exacerbations of underlying cardiac and neurologic diseases. The IL 1 pathway is the target of three biologic medications used in autoimmune and autoinflammatory diseases. The available IL 1 antag onists are anakinra (IL 1 receptor antagonist), rilonacept (soluble IL 1 receptor decoy), and canakinumab (long acting fully humanized IgG1 antiIL 1 monoclonal antibody). A trial of canakinumab in patients with colchicine resistant FMF, MKD, and TRAPS showed that it was effective in controlling and preventing flares. The vari ous IL 1 inhibitors have been successful at slowing the progression of AA amyloidosis, and in some cases treatment results in regression of amyloid proteinuria. Tocilizumab, an antiIL 6 receptor antibody, has been shown to attenuate experimental AA amyloid and to reverse AA amyloidosis complicating JIA and RA. A trial using eprodisate disodium in AA amyloid patients failed to meet its primary end point of reducing pro gression to end stage renal disease and was halted in 2016. Transthyretin amyloidosis has been treated with liver transplanta tion, which removes the source of mutated transthyretin molecules, and several medications that inhibit the synthesis of the mutated pro tein, stabilize tetramers of the protein, or disrupt fibrils. PROGNOSIS End stage renal failure is the underlying cause of death in 4060 of patients with amyloidosis. According to a large scale study of 374 patients with AA amyloidosis, the factors associated with a poor prog nosis include older age, a lower albumin serum level, end stage renal disease at baseline, and prolonged serum elevation of SAA. An elevated SAA value was the most powerful risk factor for end stage renal disease and death from AA amyloidosis. PREVENTION The primary means of preventing AA amyloidosis is treatment of the underlying inflammatory or infectious disease, resulting in decreases in the level of SAA protein and the risk of amyloid deposition. Although the period of latency between the onset of inflammation from the underlying disease and the initial clinical signs of AA amyloidosis may vary and is often prolonged, progression of the amyloid depositions can be rapid. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1538 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Macrophage activation syndrome (MAS) is a potentially fatal compli cation of rheumatic diseases thought to be caused by excessive activa tion and expansion of macrophages and T cells. These events lead to an overwhelming inflammatory reaction, involving fever, hepatospleno megaly, lymphadenopathy, cytopenias, liver dysfunction, and coagu lopathy resembling disseminated intravascular coagulation (DIC). Extreme hyperferritinemia is a characteristic laboratory feature that separates MAS from primary disease flare. Inflammatory infiltrates composed predominantly of T lymphocytes and hemophagocytic macrophages are |
6,825 | commonly seen in the bone marrow; they are also found in the liver, spleen, or lymph nodes. These hemophagocytic macrophages can infiltrate most organs in the body. Both the systemic and local inflammation can cause severe organ dam age, which can be life threatening and progress to multiple organ fail ure. The abundance of tissue macrophages exhibiting hemophagocytic activity in inflammatory lesions in MAS suggests that MAS is related to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH). EPIDEMIOLOGY Although MAS can occur in many rheumatic diseases, it is seen most frequently in systemic juvenile idiopathic arthritis (SJIA) and in its adult equivalent, adult onset Still disease (AOSD). The reasons for this association remain unclear; elevated interleukin (IL) 18 may be a caus ative factor. Approximately 717 of patients with SJIA develop severe disease, whereas more mild subclinical MAS may be seen in as many as 30 of patients with SJIA. Systemic lupus erythematosus (SLE) and Kawasaki disease are other rheumatologic conditions in which MAS occurs somewhat more frequently than in other rheumatic diseases. In SLE, MAS occurs in approximately 19 of patients. MAS most often occurs subsequent to the onset of rheumatologic disease; MAS has also been known to occur at the initial presentation of a rheumatic illness. Approximately 23 of episodes of MAS have occurred at the onset of SJIA. MAS typically occurs in the setting of active primary rheumatic disease. However, it can occur despite good control of underlying rheumatic disease. Many cases occur in the set ting of infections andor modifications in drug therapy. Both of these triggers are possibly related to subsequent active rheumatic disease. PATHOPHYSIOLOGY AND OTHER HYPERINFLAMMATORY SYNDROMES The exact mechanisms behind MAS remain unclear; however, much has been extrapolated from the pathogenesis of primary HLH (pHLH). Consistent with parallels to pHLH, in MAS there is an abundance of interferon gamma (IFN )producing CD8 T cells in inflammatory lesions. Further suggesting a role for T cellmediated inflammation, cyclosporine A, a therapeutic agent that acts predominantly on T cells, is very effective in the treatment of the majority of MAS patients. CXCL9, a biomarker of IFN activity, is also elevated in patients dur ing an MAS episode. Cytotoxic function appears to be impaired in cer tain subsets of SJIA patients, perhaps specifically in those at risk for MAS, although this finding has been inconsistent. Some studies have demonstrated an enrichment of heterozygous pathogenic variants in known pHLH genes in MAS populations, suggesting that hypomorphic lesions in cytolytic pathways may result in disease. Translational studies in SJIA patients suggest that elevated serum IL 18 is a risk factor for the development of SJIAMAS. A common link to the IFN centric models is that IL 18 is perhaps most noted for its ability to stimulate IFN production by T cells and natural killer cells. In the case of MAS caused by activating pathogenic variants in the NLRC4 gene, IL 18 has been shown to be highly elevated, and case reports of IL 18 |
6,826 | blockade leading to resolution of both disease and IFN activity suggest a causal link. Cytokine Storm A cytokine storm is the common pathophysiologic state in many hyperinflammatory diseases. There is increasing interest in the relative roles of cytokines in MAS pathophysiology, and the similarities and differences to HLH, multisystem inflammatory syndrome in children (MIS C) related to SARS CoV 2 virus, and sepsis. HLH MAS belongs to a group of hemophagocytic disorders, which includes HLH. The current classification of histiocytic disorders distinguishes primary, or familial, HLH and secondary, or reactive, HLH (see Chapter 556.2). Clinically, they may be difficult to distinguish from each other. pHLH is a constellation of rare autosomal recessive immune disorders linked to genetic defects in various genes all affecting the cytolytic path way. The clinical symptoms of pHLH usually become evident within the first months of life. Secondary HLH tends to occur in older children or adults. It may be associated with an identifiable infectious episode, most often Epstein Barr virus (EBV) or cytomegalovirus (CMV) infection. However, when EBV associated HLH occurs as part of a genetic syn drome, such as the X linked proliferative disorders, it is more properly considered pHLH. The group of secondary hemophagocytic disorders also includes malignancy associated HLH. Some consider MAS to be a form of secondary HLH, whereas others make a distinction and prefer the moniker Rheuma HLH to separate MAS from other secondary HLH conditions. The distinction between primary and secondary HLH is becoming less distinct because of other genetic causes, some of which are associated with less severe and more distinct clinical presentations. Some of these may present later in life because heterozygous or com pound heterozygous pathogenic variants in cytolytic pathway genes that confer a partial dominant negative effect on the cytolytic function. The exact relationship between HLH and MAS is an area of extensive investigation, and some rheumatologists believe that MAS should be categorized as secondary HLH occurring in a setting of a rheumatic disease (or MAS HLH). Although there are multiple attempts to try to standardize the nomenclature for these various syndromes, at this point, best practice would be to use the term primary HLH for cases with known molecular diagnoses or a clear genetic component. For secondary cases, there is not yet a prescribed specific terminology, but inclusion of known secondary causes can add clarity to the specific syndromes being described (e.g., SJIA MAS, EBV HLH). Multisystem Inflammatory Syndrome in Children (MIS C) Children may develop a postinfectious hyperinflammatory syndrome after SARS CoV 2 virus exposure that bears some resemblance to MAS. Approximately 4 8 weeks after infection, children developed multiorgan dysfunction, frequently involving persistent fever, abdomi nal pain, and rash, and sometimes accompanied by abnormal cardiac function or hypotension. Laboratory evaluation is significant for eleva tion of markers of inflammation and sometimes hyperferritinemia, coagulopathy, and liver dysfunction. Similar to MAS, this phenom enon occurred after infectious trigger, and cytokine storm has been invoked in multiple studies, especially involving IL 18, IL 10, IL |
6,827 | 6, and the IFN induced CXCL9. CLINICAL AND LABORATORY MANIFESTATIONS The clinical findings in overt MAS are dramatic and often evolve rap idly. High persistent fever, hepatosplenomegaly, generalized lymphade nopathy, liver dysfunction, and changes in mental status are common. Coagulopathy resembling DIC can be associated with hemorrhagic Chapter 207 Macrophage Activation Syndrome Rebecca Trachtman and Edward M. Behrens Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 207 u Macrophage Activation Syndrome 1539 skin rashes ranging from mild petechiae to extensive ecchymotic lesions. These can progress to epistaxis and hematemesis secondary to upper gastrointestinal bleeding. Mental status changes, seizures, and coma are the most common manifestations of CNS disease. Cerebro spinal fluid examination in these patients usually reveals pleocytosis with mildly elevated protein. Deterioration in renal function has been noted in several series and may be associated with particularly high mortality. Pulmonary infiltrates can occur, and hemophagocytic mac rophages can be found in bronchoalveolar lavage fluid. These clinical symptoms are associated with notable laboratory features. A precipitous fall in at least two of three blood cell lines (leukocytes, erythrocytes, or platelets) is one of the early findings, caused in part by increased destruction of cells by phagocytosis and consumption at inflammatory sites. Decreasing erythrocyte sedimentation rate (ESR) despite persistently high CRP is another characteristic laboratory feature. This parallels hypofibrinogen emia, likely secondary to fibrinogen consumption and liver dys function. Prolonged prothrombin and partial thromboplastin times, fibrin degradation products, and moderate deficiency of vitamin Kdependent clotting factors are usually present as well. Liver involvement is common in MAS, and most patients develop marked hepatomegaly, and sometimes mild jaundice. Liver func tion tests frequently reveal high serum transaminase activity and mildly elevated levels of serum bilirubin. Serum ammonia levels are typically normal or only mildly elevated. Additional laboratory findings in MAS include hypertriglyceridemia, hypoalbuminemia, and elevated lactate dehydrogenase (LDH). Perhaps the most striking laboratory change in MAS is the eleva tion of serum ferritin. Although diagnosticclassification criteria set levels of 500 ngmL and 684 ngmL as cutoffs for HLH and SJIA MAS respectively, levels are often greater than 10,000 ngmL. The reasons for this elevated ferritin are not clear and are likely multifactorial. Although extremely high ferritin is often a good serologic marker of HLH and MAS, high levels are not pathognomonic and can be seen in a wide vari ety of conditions. Thus ferritin needs to be interpreted in the context of the other features of the disease to support a diagnosis. Further, serum ferritin is usually 6080 glycosylated, whereas intracellular ferritin is not glycosylated. In hemophagocytic syndromes, the percentage of gly cosylated ferritin in the serum is low, typically below 20; assessment of glycosylated ferritin may also be a useful tool for MAS diagnosis. It has been recognized that as many as one third of patients with active SJIA may have mild subclinical MAS. |
6,828 | These patients typically have moderate hyperferritinemia, highly increased CRP, moder ately decreased hemoglobin, and relatively low platelet counts. These patients may also have mild hepatosplenomegaly and mildly elevated liver enzymes. Serum fibrinogen tends to remain in the normal range despite highly increased CRP. DIAGNOSIS Recognition of MAS is crucial, but early diagnosis is often difficult. There is no single clinical or laboratory feature that is specific for MAS, including hemophagocytosis, and many clinical features of MAS over lap with those seen in the underlying rheumatic diseases. The MAS clinical presentation also overlaps with sepsis like syndromes associ ated with infection. This is further complicated by the fact that MAS may also be triggered by a flare of the underlying rheumatic disease or infection. In a patient with active underlying rheumatologic disease, persistent fevers and decrease in ESR and platelet count in combina tion with increasing serum ferritin and persistently high CRP should raise suspicion for impending MAS. Increasing liver enzymes, aspar tate aminotransferase in particular, is another characteristic laboratory change. The diagnosis of MAS might be confirmed by bone marrow biopsy, with the presence of increased hemophagocytosis. However, demonstration of hemophagocytosis may be limited by sampling error, particularly at the early stages of the syndrome. In such cases, additional staining of the bone marrow with anti CD163 antibodies may be helpful. Features consistent with MAS include massive expan sion of highly activated histiocytes. The diagnosis of MAS is supported by elevated levels of soluble IL2R and soluble CD163 in serum. Evidence is mounting that IFN is the pivotal cytokine in MAS; however, peripheral measurement of IFN can be difficult because of retention in tissues. Therefore the IFN induced chemokine CXCL9 may be a more reliable serum biomarker of MAS. Although substantial elevation in the serum levels of soluble IL2R receptors and CXCL9 in an SJIA patient is highly suggestive of MAS, these assessments remain nonspecific, and elevation can be associated with some malignancies and viral infections, such as viral hepatitis. Striking clinical similarities between MAS and HLH have led some to advocate for the use of the HLH 2004 diagnostic guidelines devel oped by the HLH Study Group of the International Histiocyte Society (see Chapter 556.2). However, the application of the HLH diagnos tic criteria to SJIA patients with suspected MAS is problematic, both because there is significant overlap with common features of active rheumatic disease and because SJIA patients may reach some of the criteria only later in the clinical course. NK function testing as a means to assess cytotoxic activity is problematic, as defects in this pathway are only variably associated with SJIA and MAS. Criteria for the diagnosis of MAS complicating SJIA are noted in Table 207.1. In cross validation analyses, the criteria revealed a sen sitivity of 0.72 0.76 and a specificity 0.97 0.99. It should be noted that these criteria were developed for classification for studies and trials and were not optimized for clinical diagnostic purposes. One limitation of the MAS classification criteria is that |
6,829 | background treat ment with biologics might modify the clinical presentation of MAS. Although IL 1 and IL 6 inhibitors effectively control the disease in the majority of SJIA patients, they do not provide full protection against MAS and may impede diagnosis. Furthermore, the MAS classifica tion criteria are less likely to classify tocilizumab treated patients as having MAS compared with historical controls or canakinumab treated patients. DIFFERENTIAL DIAGNOSIS It is most important to distinguish MAS from a flare of an underlying rheumatologic disease and from intercurrent infection. Further, one must consider other clinical entities associated with hyperferritinemia, hepatic dysfunction, coagulopathy, cytopenias, or encephalopathy, specifically DIC, thrombotic thrombocytopenic purpura (TTP), and malignancy associated HLH. Some other important differential diag noses include sepsis and drug reactions; a thorough infectious workup is necessary for the majority of MAS patients. Hyperferritinemia is not specific for hemophagocytic syndromes and may be observed in vari ous liver and kidney diseases, hematologic malignancies, or conditions requiring chronic blood transfusions. TREATMENT MAS is still associated with high mortality rates; therefore prompt recognition and initiation of immediate therapeutic intervention are critical. To achieve rapid reversal of coagulation abnormalities and cytopenias, most clinicians start with intravenous methylprednisolone pulse therapy (30 mgkg for three consecutive days) followed by 2 to 3 mgkgday in four divided doses. Table 207.1 The Classification Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis A febrile patient with known or suspected systemic juvenile idiopathic arthritis is classified as having macrophage activation syndrome if the following criteria are met: Ferritin 684 ngmL and any two of the following: Platelet count 181 109L Aspartate aminotransferase 48 UL Triglycerides 156 mgdL Fibrinogen 360 mgdL Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1540 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) If response to glucocorticoids is not satisfactory, cyclosporine A (2 7 mgkgday) is usually added to the treatment regimen based on several reports describing the rapid resolution of MAS features in response to this medication. Cyclosporine is preferentially used orally, and careful monitoring for toxicity is required, especially if it is administered intra venously. In many patients, administration of cyclosporine A not only provides rapid control of symptoms but also avoids excessive use of steroids. Case reports support the use of tacrolimus as an alternative to cyclosporine A, as it is often effective and has a desirable safety profile. There is also reported efficacy with the use of anakinra for MAS. Because MAS episodes may be triggered by disease flare, biologics that neutralize IL 1 could extinguish the underlying inflammation driving the cytokine storm. There are several case reports and two case series of anakinra treat ment for MAS with promising results, particularly when used in higher doses. However, in established SJIA, continuous treatment with standard doses of antiIL 1 and antiIL 6 biologic therapies does |
6,830 | not absolutely protect against MAS even if the underlying disease responds well to the treatment. In the phase 3 clinical trial of canakinumab, IL 1 blockade did not confer full protection from MAS even in patients with fully controlled SJIA. These results suggest that IL 1 inhibition effectively treats MAS in many patients, but does not completely prevent the occurrence of MAS, particularly in the setting of viral infection in treated subjects. Intravenous immune globulin treatment has been successful in virus associated reactive HLH. Rituximaba treatment that depletes B lymphocytes, the main type of cells harboring EBV virushas been successfully used in EBV induced lymphoproliferative disease and could be considered in EBV driven MAS. If MAS remains active despite the use of corticosteroids, anakinra, and cyclosporine A, the HLH 2004 treatment protocol developed by the HLH Study Group of the International Histiocyte Society may be considered. In addition to steroids and cyclosporine A, this protocol includes etoposide (or VP16), a podophyllotoxin derivative that inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. However, this pro tocol is limited by the toxicity of etoposide and its likelihood of causing kidney and liver damage. In addition, severe bone marrow suppression, overwhelming infection, and death have been reported. The use of lower doses of etoposide (50 100 mgm2 range rather than 150 mgm2, as sug gested by the HLH 2004 protocol) has been advocated by some groups. It has also been suggested that antithymocyte globulin (ATG) might be a safer alternative to etoposide, particularly in patients with renal and hepatic impairment. ATG depletes both CD4 and CD8 T cells through complement dependent cell lysis. Mild depletion of mono cytes is noted in some patients as well. Although this treatment was tol erated well in reported cases, infusion reactions are frequently reported with the use of ATG, and adequate laboratory and supportive medical resources must be readily available if this treatment is used. Occasional reports describe successful use of cyclophosphamide to control MAS, mainly in patients with SLE. The monoclonal antibody tocilizumab is very effective in treating SJIA. However, in a phase 3 clinical trial of tocilizumab in SJIA, several patients developed MAS. Similar to canakinumab, at the time of MAS presentation, underlying SJIA in most of these patients was well con trolled. Furthermore, tocilizumab can cause normalization of some of the laboratory parameters of MAS, without actually altering the course of MAS activity itself, providing false reassurance of disease control. In a patient with an inflammasomopathy caused by gain of function pathogenic variants in NLRC4, administration of the recombinant IL 18BP resulted in rapid and sustained improvement, including the resolution of all MAS like features. It remains unclear whether a simi lar therapeutic intervention might be effective in MAS as well. Based on their essential roles in transmitting cytokine induced signals, par ticularly from IFN , the JAKSTAT pathways have become a target for pharmacologic manipulation in inflammatory diseases. Ruxolitinib, a potent inhibitor of JAK1 and JAK2, has been shown |
6,831 | to ameliorate the disease influencing patterns of JAKSTAT dependent gene expression in animal models of pHLH, but it remains to be determined whether this treatment will be routinely effective in patients with MAS. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Kawasaki disease (KD), formerly known as mucocutaneous lymph node syndrome and infantile polyarteritis nodosa, is an acute febrile illness of childhood seen worldwide, with the highest incidence occurring in Asian children. KD is a systemic inflammatory disorder manifesting as a vasculitis with a predilection for the coronary arteries. Approximately 2025 of untreated children develop coronary artery abnormalities (CAAs), including aneurysms, whereas 5 of children treated with intravenous immunoglobulin (IVIG) develop CAA. Nonetheless, KD is the leading cause of acquired heart disease in children in most devel oped countries, including the United States and Japan. ETIOLOGY The cause of KD remains unknown. Certain epidemiologic and clini cal features support an infectious origin, including the young age group affected; epidemics with wavelike geographic spread of illness; the self limited nature of the acute febrile illness; and the clinical features of fever, rash, enanthem, conjunctival injection, and cervical lymphadenopathy. Further evidence of an infectious trigger includes the infrequent occurrence of the illness in infants 3 months old, pos sibly the result of protective maternal antibodies, and the rarity of cases in adults, possibly the result of prior exposures with subsequent immunity. Furthermore, the number of hospitalizations per year for KD significantly decreased during the COVID 19 pandemic, both in Japan and the United States, possibly due to low circulating causative viruses. However, there are also features that are not consistent with an infectious origin; it is unusual to have multiple cases present at the same time within a family or daycare center. Furthermore, no single infectious etiologic agent has been successfully identified, despite an exhaustive search. Other environmental triggers such as airborne tox ins and climate shifts have also been speculated to play a role. Genetic factors clearly influence the pathogenesis of KD, as evi denced by the higher risk of KD in Asian children regardless of country of residence and in siblings and children of individuals with a history of KD. The concordance rate among identical twins is approximately 13. Linkage studies and genome wide association studies (GWAS) have identified significant potential associations between polymorphisms in the ITPKC gene, a T cell regulator, with increased susceptibility to KD and more severe disease. Other candidate genes for KD identified by GWAS include CASP3, BLK, and FCGR2A. Lastly, multiple alleles in different human leukocyte antigen (HLA) regions have been reported to influence risk for KD. EPIDEMIOLOGY For the majority of patients, KD is a disease of early childhood, and nearly all epidemiologic studies show a higher susceptibility to KD in males. Large database studies suggest that the hospitalization rate for KD in the United States has been mostly stable over time, although the proportion of hospitalizations complicated by KD shock syndrome has increased over time. In 2017, the Kids Inpatient Database esti mated 19.3 |
6,832 | hospitalizations100,000 children 4 years of age. Children of AsianPacific Islander descent had the highest rates of KD among all racial groups. In other countries, such as the United Kingdom, South Korea, and Japan, the rate of KD seems to be increasing. In Japan, nationwide sur veys have been administered every 2 years to monitor trends in KD incidence. In 2018 the highest recorded rate thus far of 359 per 100,000 children ages 0 4 years was described, with the highest rate in young children ages 9 11 months. Fortunately, the proportion of Japanese Chapter 208 Kawasaki Disease Mindy S. Lo, Mary Beth F. Son, and Jane W. Newburger Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 208 u Kawasaki Disease 1541 Media Intima Adventitia Elastica interna Necrotizing arteritis Aneurysm formation Possible progression to a normal luminal dimension Further progression and ? possible interaction with atherosclerosis risk factors Calcification Organization of thrombus and recanalization Occlusive thrombus formation Destruction of intima, elastica interna, media and, variably, adventitia 1. Subacutechronic vasculitis 2. Luminal myofibroblastic proliferation 3. Laminar nonocclusive thrombosis Myocardial infarction Complex stenosis Ischemic heart disease Mild, transient dilation (resolves within 46 wk) No coronary artery changes Fig. 208.1 Natural history of coronary artery abnormalities. (Modified from Kato H. Cardiovascular complications in Kawasaki disease: coronary artery lumen and long term consequences. Prog Pediatr Cardiol. 2004;19:137145.) patients with coronary aneurysms and myocardial infarction has decreased over time, at 2.6 for the former in the most recent survey. Several risk stratification models have been constructed to deter mine which patients with KD are at highest risk for CAA. Predictors of poor outcome across several studies include young age; being male; persistent prolonged fever; poor response to IVIG; and laboratory abnormalities, including neutrophilia, thrombocytopenia, transami nitis, hyponatremia, hypoalbuminemia, elevated levels of N terminal brain natriuretic protein, and elevated C reactive protein (CRP) levels. Asian, Pacific Islander, and Hispanic ethnicity are also risk factors for CAA. Three risk scores for IVIG resistance, which refers to incom plete response to the first treatment, have been constructed by Japa nese researchers; of these, the Kobayashi score is the most widely used and has high sensitivity and specificity. Unfortunately, when applied to non Japanese populations, these scores do not appear to be as accurate in identifying children at risk for IVIG resistance and CAA. Body sur face area (BSA)adjusted coronary artery dimensions on initial echo cardiography are good predictors of CAA development. In a North American cohort, coronary artery z scores 2.0 are predictive of CAA development; similar findings have been reported in Japanese cohorts as well. Accordingly, coronary artery z scores at initial presentation are useful imaging biomarkers that can be used to guide adjunctive therapy for high risk patients. PATHOLOGY KD is a vasculitis that predominantly affects medium size arteries. The coronary arteries are most often involved, although other arter ies |
6,833 | (e.g., axillary, subclavian, femoral, popliteal, brachial) can also develop dilation. A three phase process to the arteriopathy of KD has been described. The first phase is a neutrophilic necrotizing arteritis occurring in the first 2 weeks of illness that begins in the endothelium and moves through the coronary wall. Saccular aneurysms may form from this arteritis. The second phase is a subacutechronic vasculitis driven by lymphocytes, plasma cells, and eosinophils, which may last weeks to years and results in fusiform aneurysms. The vessels affected by the subacutechronic vasculitis then develop smooth muscle cell myofibroblasts, which may cause diminution of internal lumen dimen sion and progressive stenosis in the third phase. Thrombi may form in the lumen and obstruct blood flow (Fig. 208.1). CLINICAL MANIFESTATIONS Fever is characteristically high (38.3C 101F), persistent, and unre sponsive to antipyretics. The duration of fever without treatment is generally 1 2 weeks but may be as short as 5 days or may persist for 3 4 weeks. In addition to fever, the five principal clinical criteria of KD are (1) bilateral nonexudative conjunctival injection with limbal spar ing; (2) erythema of the oral and pharyngeal mucosa with strawberry tongue and red, cracked lips; (3) edema (induration) and erythema of the hands and feet; (4) rash of various forms (maculopapular, urticarial, erythema multiformelike, scarlatiniform, and rarely, micropustular or psoriatic like); and (5) nonsuppurative cervical lymphadenopathy, usually unilateral, with node size 1.5 cm (Table 208.1 and Figs. 208.2 208.5). Superficial perineal desquamation is common in the acute phase. Periungual desquamation of the fingers and toes begins 2 3 weeks after the onset of illness and may progress to involve the entire hand and foot (Fig. 208.6). Additional symptoms other than the principal clinical criteria are common in the 10 days before diagnosis of KD, which may be explained in part by the finding that up to a third of patients with KD have confirmed, concurrent infections. Gastrointestinal (GI) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1542 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) 0 20 Percentage of Cases 10010 30 5040 70 8060 90 Fever Strawberry tongue Conjunctivitis Desquamation Polymorphous skin rashes Induration Pyuria BCG LAP Diarrhea CAD Arthritis Fig. 208.2 Clinical symptoms and signs of Kawasaki disease. Sum mary of clinical features from 110 cases of Kawasaki disease seen in Ka ohsiung, Taiwan. LAP, Lymphadenopathy in head and neck area; BCG, reactivation of bacille Calmette Gurin inoculation site; CAD, coronary artery dilation, defined by an internal diameter 3 mm. (From Wang CL, Wu YT, Liu CA, et al. Kawasaki disease: infection, immunity and genetics. Pediatr Infect Dis J. 2005;24:9981004.) Fig. 208.3 Kawasaki disease. Strawberry tongue in patient with mu cocutaneous lymph node syndrome. (Courtesy Tomisaku Kawasaki, MD. From Hurwitz S. Clinical Pediatric Dermatology, 2nd ed. Philadelphia: Saunders; 1993.) Table 208.1 Clinical and Laboratory |
6,834 | Features of Kawasaki Disease EPIDEMIOLOGIC CASE DEFINITION (CLASSIC CLINICAL CRITERIA) Fever persisting at least 5 days Presence of at least four principal features: Changes in extremities Acute: erythema of palms, soles; edema of hands, feet Subacute: periungual peeling of fingers, toes in wk 2 and 3 Polymorphous exanthem Bilateral bulbar conjunctival injection without exudate Erythema and cracking of lips, strawberry tongue, andor erythema of oral and pharyngeal mucosa Cervical lymphadenopathy (1.5 cm diameter), usually unilateral Exclusion of other diseases with similar findings These features do not have to occur concurrently. OTHER CLINICAL AND LABORATORY FINDINGS Cardiovascular System Myocarditis, pericarditis, valvular regurgitation, cardiogenic shock Coronary artery abnormalities Aneurysms of medium sized noncoronary arteries Peripheral gangrene Aortic root enlargement Respiratory System Peribronchial and interstitial infiltrates on chest radiograph Pulmonary nodules Musculoskeletal System Arthritis, arthralgias (pleocytosis of synovial fluid) Gastrointestinal Tract Diarrhea, vomiting, abdominal pain Hepatitis, jaundice Hydrops of gallbladder Pancreatitis Parotitis Central Nervous System Extreme irritability Aseptic meningitis (pleocytosis of cerebrospinal fluid) Facial nerve palsy Sensorineural hearing loss Genitourinary System Urethritismeatitis, hydrocele Other Findings Desquamating rash in groin Retropharyngeal phlegmon Anterior uveitis by slit lamp examination Erythema, induration at bacille Calmette Gurin inoculation site LABORATORY FINDINGS IN ACUTE KAWASAKI DISEASE Leukocytosis with neutrophilia and immature forms Elevated erythrocyte sedimentation rate Elevated C reactive protein Elevated nitrogen terminal pro B type natriuretic peptide (NT proBNP) Anemia Abnormal plasma lipids Hypoalbuminemia Hyponatremia Thrombocytosis after wk 1 Sterile pyuria Elevated serum transaminase Elevated serum glutamyl transpeptidase Pleocytosis of cerebrospinal fluid Leukocytosis in synovial fluid Patients with fever at least 5 days and fewer than four principal criteria can be diagnosed with Kawasaki disease when coronary artery abnormalities are detected by two dimensional echocardiography or angiography. In the presence of four or more principal criteria, particularly when redness and swelling of the hands and feet are present, Kawasaki disease diagnosis can be made on day 4 of illness. Experienced clinicians who have treated many patients with Kawasaki disease may establish a diagnosis before day 4 in rare cases. See the differential diagnosis (Table 208.3). Rarely infants present with thrombocytopenia and disseminated intravascular coagulation. From McCrindle BW, Rowley A, Newburger JW, et al. Diagnosis, treatment, and long term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927e999. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 208 u Kawasaki Disease 1543 symptoms (vomiting, diarrhea, or abdominal pain) occur in 60 of patients, and at least one respiratory symptom (rhinorrhea or cough) occurs in 35. Other clinical findings can include significant irritabil ity that is especially prominent in infants and likely caused by aseptic meningitis, mild hepatitis, hydrops of the gallbladder, urethritis and meatitis with sterile pyuria, uveitis, and arthritis. Arthritis may occur early in the illness or may develop in the second or third week. Small or large joints may be affected, and |
6,835 | the arthralgias may persist for several weeks. Patients previously vaccinated with bacillus Calmette Guerin (BCG) may show reactivation at the inoculation site. Clinical features that are not consistent with KD include exudativepurulent conjunc tivitis; exudative pharyngitis; generalized lymphadenopathy; discrete oral lesions (e.g., ulceration); splenomegaly; and bullous, petechial, or vesicular rashes. Cardiac involvement is the most important manifestation of KD. Myocarditis may occur in patients with acute KD and may manifest as tachycardia disproportionate to fever, along with diminished left ventricular systolic function. Occasionally, patients with KD present in cardiogenic shock (KD shock syndrome), with hypotension and greatly diminished left ventricular function. In addition, KD shock syndrome may manifest with thrombocytopenia, a high band count, and a high CRP. Case series of KD shock syndrome indicate that these patients may be at higher risk for coronary artery dilation. Pericarditis with a small pericardial effusion can also occur during the acute ill ness. Mitral regurgitation of at least mild severity is evident on echo cardiography in 1025 of patients at presentation but diminishes over time, except among rare patients with coronary aneurysms and ischemic heart disease. Up to 25 of untreated patients develop CAA by Japanese Ministry of Health criteria in the second to third week of illness; initially these are usually asymptomatic and detected by echo cardiography. Almost all the morbidity and mortality in KD occur in patients with large or giant coronary artery aneurysms, defined by the 2017 American Heart Association (AHA) scientific statement on the diagnosis and treatment of KD as having a z score 10 or an abso lute dimension of 8 mm. Specifically, large or giant aneurysms are associated with the greatest risk of later thrombosis or stenosis, angina, and myocardial infarction (Figs. 208.7 and 208.8A). Rupture of a giant aneurysm is a rare complication that generally occurs in the first month after illness onset and may present as hemopericardium with tampon ade. Axillary, popliteal, iliac, or other systemic medium sized muscular arteries may also become aneurysmal, but always in the setting of giant coronary aneurysms (see Fig. 208.8B); these usually regress. Occasionally KD presents initially with only fever and lymphade nopathy (node first KD). This presentation may be confused with bac terial or viral cervical lymphadenitis and may delay the diagnosis and treatment. Persistence of high fever, lack of response to antibiotics, and subsequent development of other signs of KD suggest the diagnosis. Children with node first KD tend to be older (4 vs 2 years) and have more days of fever and higher CRP levels. In addition to cervical ade nopathy, many node first patients had retropharyngeal and peritonsil lar inflammation on CT scans (Fig. 208.9). Patients with node first KD have a higher incidence of coronary aneurysms. Patients with infec tious adenitis usually respond to antibiotics; they may have abscesses noted on imaging studies (ultrasonography or CT). KD can be divided into three clinical phases. The acute febrile phase is characterized by fever and the other acute signs of illness and usually lasts 1 |
6,836 | 2 weeks. The subacute phase is associated with desquamation, thrombocytosis, development of CAA, and the highest risk of sudden death in patients who develop aneurysms; it generally lasts 3 weeks. The convalescent phase begins when all clinical signs of illness have disappeared and continues until the erythrocyte sedimentation rate (ESR) returns to normal, typically 6 8 weeks after the onset of illness. LABORATORY AND RADIOLOGY FINDINGS There is no diagnostic test for KD, but patients usually have character istic laboratory findings. The leukocyte count is often elevated, with a predominance of neutrophils and immature forms. Normocytic, nor mochromic anemia is common. The platelet count is generally normal in the first week of illness and rapidly increases by the second to third week of illness, sometimes exceeding 1 millionmm3. An elevated ESR or CRP value is universally present in the acute phase of illness. The ESR may remain elevated for weeks, in part from the effect of IVIG. Sterile pyuria, mild elevations of the hepatic transaminases, hyperbili rubinemia, and cerebrospinal fluid pleocytosis may also be present. KD is unlikely if the ESR, CRP, and platelet counts are normal after 7 days of fever. Fig. 208.4 Kawasaki disease. Congestion of bulbar conjunctiva in a patient with mucocutaneous lymph node syndrome. (Courtesy Tomi saku Kawasaki, MD. From Hurwitz S. Clinical Pediatric Dermatology, 2nd ed. Philadelphia: Saunders; 1993.) Fig. 208.5 Kawasaki disease. Indurative edema of the hands in a pa tient with mucocutaneous lymph node syndrome. (Courtesy Tomisaku Kawasaki, MD. From Hurwitz S. Clinical Pediatric Dermatology, 2nd ed. Philadelphia: Saunders; 1993.) Fig. 208.6 Kawasaki disease. Desquamation of the fingers in a pa tient with mucocutaneous lymph node syndrome. (Courtesy Tomisaku Kawasaki, MD. From Hurwitz S. Clinical Pediatric Dermatology, 2nd ed. Philadelphia: Saunders; 1993.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1544 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Two dimensional echocardiography is the most useful test to monitor for development of CAA. Although frank aneurysms are rarely detected in the first week of illness, coronary arteries are commonly dilated. Coro nary artery dimensions, adjusted for BSA (z scores), may increase over the first 6 weeks of illness, and higher z scores at the time of diagnosis are the strongest risk factor for the presence of coronary aneurysms 2 8 weeks after illness onset. Children with non KD febrile illnesses also have mildly increased z scores compared with nonfebrile controls, but to a lesser degree than patients with KD. Aneurysms have been defined with the use of absolute dimensions by the Japanese Ministry of Health and are classified as small (4 mm internal diameter ID), medium (4 to 8 mm ID), or giant (8 mm ID). Some experts believe that a z score based system for classification of aneurysm size may be more discrimi nating, because it adjusts the coronary dimension for |
6,837 | BSA. The AHA z score classification system is noted in Table 208.2. Echocardiography should be performed at diagnosis and again after 1 2 weeks of illness. If the results are normal, a repeat study should be performed 6 8 weeks after onset of illness. If results of either of the initial studies are abnormal or the patient has recurrent fever or symp toms, more frequent echocardiography or other studies may be neces sary. In patients in whom CAA has not developed in the first 4 6 weeks of illness, the patient may be discharged from cardiology care, although follow up through 12 months may be considered. Children and fami lies should be counseled regarding healthy diet and the importance of exercise at regular primary care visits. For patients with CAA, the type of testing and the frequency of cardiology follow up visits are tailored to the patients coronary artery status (see Table 208.2). DIAGNOSIS The diagnosis of KD is based on the presence of characteristic clinical signs. For classic KD, the diagnostic criteria require the presence of fever for at least 5 days and at least four of five of the other princi pal characteristics of the illness (see Table 208.1). The diagnosis of KD should be made within 10 days, and ideally within 7 days, of fever onset to improve coronary artery outcomes. In incomplete KD, patients have persistent fever but fewer than four of the five characteristic clini cal signs. In patients with incomplete KD, laboratory and echocardio graphic data can assist in the diagnosis (Fig. 208.10). Incomplete cases occur most frequently in infants, who also have the highest likelihood of development of CAA. Ambiguous cases should be referred to a cen ter with experience in the diagnosis of KD. Establishing the diagnosis with prompt initiation of treatment is essential to prevent potentially devastating coronary artery disease. For this reason, it is recommended that any infant age 6 months with fever for 7 days and signs of systemic inflammation without explanation undergo echocardiography to assess the coronary arteries. DIFFERENTIAL DIAGNOSIS Adenovirus, measles, and scarlet fever lead the list of common child hood infections that mimic KD (Table 208.3). Children with adenovi rus typically have exudative pharyngitis and exudative conjunctivitis, allowing differentiation from KD. A common clinical problem is the differentiation of scarlet fever from KD in a child who is a group A streptococcal carrier. Patients with scarlet fever typically have a rapid clinical response to appropriate antibiotic therapy. Such treatment for 24 48 hours with clinical reassessment generally clarifies the diagnosis. Furthermore, ocular findings are quite rare in group A streptococcal pharyngitis and may assist in the diagnosis of KD. Features of measles that distinguish it from KD include exudative conjunctivitis, Koplik spots, rash that begins on the face and hairline and behind the ears, and leukopenia. Cervical lymphadenitis can be the initial diagnosis in children who are ultimately recognized to have KD. Less com mon infections such as Rocky Mountain spotted fever and leptospirosis are occasionally |
6,838 | confused with KD. Rocky Mountain spotted fever is a poten tially lethal bacterial infection, and appropriate antibiotics should not be withheld if the diagnosis is under consideration. Its distinguishing features include pronounced myalgias and headache at onset, centripetal rash, and petechiae on the palms and soles. Leptospirosis can also be an illness of considerable severity. Risk factors include exposure to water contaminated LAD RCA Fig. 208.7 Coronary angiograms in 6 yr old boy with Kawasaki dis ease. Left, Giant aneurysm of the left anterior descending coronary ar tery (LAD) with obstruction. Right, Giant aneurysm of the right coronary artery (RCA) with an area of severe narrowing. (From Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long term management of Kawasaki disease. Pediatrics. 2004;114:17081733.) A B Fig. 208.8 MRI of coronary and peripheral artery aneurysms in Kawa saki disease. A, Image of left ventricular outflow tract showing a giant right coronary artery (RCA) aneurysm with nonocclusive thrombus (yellow arrow) and a giant left main coronary artery (LMCA) aneurysm. Ao, Aorta; AoV, aortic valve; LV, left ventricle; RV, right ventricle. B, Aneurysms in the axillary and subclavian arteries and the iliac and femoral arteries (ar rows). (From McCrindle BW, Rowley A, Newburger JW, et al. Diagnosis, treatment, and long term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 2017;13517:e927e999, Fig. 2G and H, p. e935.) A B Fig. 208.9 Contrast enhanced CT in 3 yr old boy with Kawasaki dis ease. A, Right sided cervical lymphadenopathy (arrows), peritonsillar hypodense area (curved arrow), and swelling of right palatine tonsil (arrowhead). B, Right sided cervical lymphadenopathy with perinodal infiltration (arrows) and intranodal focal low attenuation (arrowheads). (From Kato H, Kanematsu M, Kato Z, et al. Computed tomographic findings of Kawasaki disease with cervical lymphadenopathy. J Comput Assist Tomogr. 2012;361:138142, Fig. 1, p. 139.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 208 u Kawasaki Disease 1545 with urine from infected animals. The classic description of leptospirosis is of a biphasic illness with a few asymptomatic days between an initial period of fever and headache and a late phase with renal and hepatic fail ure. In contrast, patients with KD have consecutive days of fever at diagno sis and rarely have renal or hepatic failure. Drug hypersensitivity reactions, including Stevens Johnson syn drome, share some characteristics with KD. Drug reaction features such as the presence of oral ulcerations and a normal or minimally elevated ESR are not seen in KD. Systemic juvenile idiopathic arthritis (sJIA) is also characterized by fever and rash, but physical findings include dif fuse lymphadenopathy and hepatosplenomegaly. Arthritis may or may not be present in the initial illness. Fevers typically show a quotidian or double quotidian pattern, in contrast to the unremitting fevers seen in KD. Laboratory findings may include coagulopathy, elevated fibrin |
6,839 | deg radation product values, and hyperferritinemia. Interestingly, there are reports of children with sJIA who have echocardiographic evidence of CAA. Coronary aneurysms have also been reported in Behet disease, primary cytomegalovirus infection, granulomatosis with polyangiitis, lupus, infantile polyarteritis nodosa, hyperIgE syndrome, hyperIgD syndrome (mevalonic aciduria), and meningococcemia. Children with KD may present with Kawasaki disease shock syndrome, with a clinical picture similar to that of toxic shock syn drome or of the multisystem inflammatory syndrome in children associated with COVID 19 (MIS C; see Chapter 311). Features of toxic shock syndrome that are not usually seen in KD include renal insufficiency, coagulopathy, pancytopenia, and myositis. With COVID 19 disease, some children developed a KD like ill nesses presenting in cardiogenic shock. multisystem inflammatory syndrome in children (MISC), also known as pediatric inflamma tory multisystem syndrome temporally associated with SARS CoV 2 (PIMS TS), occurs 2 6 weeks after infection with SARS CoV 2. The initial infection may be asymptomatic. Children with MIS C may show conjunctival injection, oropharyngeal changes, and rashes similar to that seen in KD. CAAs have also been described in MIS C, but the risk of CAA in MIS C does not strictly correlate with criteria for incomplete or complete KD. Furthermore, patients are often older and have a greater degree of myocardial dysfunction as compared with KD; distinguishing laboratory features include greater hyperferritinemia, more pronounced cytopenias, and ele vated d dimer in MIS C (Table 208.4). Table 208.2 Classification of Coronary Artery Dilation or Aneurysms (after AHA Guidance with Modification) CLASSIFICATION OF RISK LEVEL DESCRIPTION OF CORONARY ARTERIES FOLLOW UP INTERVAL IMAGING REQUIRED TO ASSESS FOR INDUCIBLE ISCHEMIA (STRESS ECHO OR STRESS MRI) PSP REGIONAL SPECIALIST KAWASAKI DISEASE CLINIC 1 No involvement at any time point (z score2) 2 wk 6 wk 6 mo 12 mo Discharge if normal at 12 mo None No Noannual cardiac and general health review with GP recommended 2 Dilation only (2 z score 2.5): resolves within 1 year 2 wk 6 wk 6 mo 12 mo Discharge if normal at 12 mo None No Noannual cardiac and general health review with GP recommended 3 Small aneurysm (2.5 z score 5): (a) current or persistent (b) decreased to normal or z score 2.5 2 wk 6 wk 6 mo 12 mo Annual review Coronary angiography (preferably CT) at 12 mo as baseline Consider stress imaging for inducible myocardial ischemia every 2 years Imaging (echo) for coronary surveillance annually Yes Yes 4 Medium aneurysm (5 z score 10): (a) persistent aneurysm (b) decreased to normal or z score 2.5 2 wk 6 wk 6 mo 12 mo Annual review Coronary angiography (preferably CT) at 12 mo as baseline Consider stress imaging for inducible myocardial ischemia annually Imaging (echo, CT, or MRI) for coronary thrombus surveillance annually Yes Yes 5 Giant aneurysm (z score 10 or 8 mm): (a) persistent giant aneurysm (b) persistent aneurysm (but regressed to medium or small aneurysms) (c) regressed to normal dimensions 2 wk 6 wk 3 mo |
6,840 | 6 mo 9 mo 12 mo Then every 6 mo Coronary angiography (preferably CT) at 6 12 mo as baseline Consider stress imaging for inducible myocardial ischemia annually Imaging (echo, CT, or MRI) for coronary thrombus surveillance every 6 mo Yes Yes GP review should include clinical examination, blood pressure measurement, general health discussion, and advice on avoidance of cardiovascular risk factors and lifestyle choices, including maintaining a healthy weight, reducing the risk of diabetes, avoiding smoking, and taking regular exercise. This provides the opportunity to discuss any parent or patient questions and concerns. CT should not be used repeatedly if possible. Use MRI or ultrasound where possible to reduce radiation exposure. ADP, Adenosine diphosphate; AHA, American Heart Association; FBC, full blood count; GP, general practitioner; PSP, person specific protocol. From McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and longterm management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association published correction appears in Circulation. 2019 Jul 30;140(5):e181e184. Circulation. 2017;135(17):e927e999.). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1546 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) TREATMENT Patients with acute KD should be treated with 2 gkg of IVIG as a single infusion, usually administered over 10 12 hours within 10 days of dis ease onset, and ideally as soon as possible after diagnosis (Table 208.5). Evaluation of suspected incomplete Kawasaki disease1 Assess laboratory tests Serial clinical and laboratory reevaluation if fevers persist Echocardiogram if typical peeling6 develops Treat5 NO YES 1) Anemia for age 2) Platelet count of 450,000 after the 7th day of fever 3) Albumin 3.0 gdL 4) Elevated ALT level 5) WBC count of 15,000mm3 6) Urine 10 WBChpf CRP3.0 mgdL and ESR40 mmhr CRP3.0 mgdL andor ESR40 mmhr 3 or more laboratory findings: Positive echocardiogram4 OR Children with fever 5 days and 2 or 3 compatible clinical criteria2 OR infants with fever for 7 days without other explanation3 Fig. 208.10 Algorithm for the evaluation of suspected incomplete Kawasaki disease (KD). 1In the absence of a gold standard for diagnosis of KD, this algorithm cannot be evidence based, but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought any time assistance is needed. 2Clinical findings of KD are listed in Table 208.1. Characteristics suggesting that another diagnosis should be considered include exudative conjunctivitis, exudative pharyngitis, ulcerative intraoral lesions, bullous or vesicular rash, generalized adenopathy, and splenomegaly. 3Infants 6 months of age are most likely to develop prolonged fever without other clinical criteria for KD; these infants are at particularly high risk of developing coronary artery abnormalities. 4Echocardiography is considered positive for purposes of this algorithm if any of three conditions are met: z score of left anterior descending coronary artery or right coronary artery 2.5; coronary artery aneurysm is |
6,841 | observed; or three or more other suggestive features exist, including decreased left ventricular function, mitral regurgitation, pericardial effusion, or z scores in the left anterior descending coronary artery or right coronary artery of 2 2.5. 5If the echocardiogram is positive, treatment should be given within 10 days of fever onset or after the 10th day of fever in the presence of clinical and laboratory signs (C reactive protein CRP, erythrocyte sedimentation rate ESR) of ongoing inflammation. 6Typical peeling begins under the nail beds of fingers and toes. ALT, Alanine transaminase; WBC, white blood cell. (From McCrindle BW, Rowley A, Newburger JW, et al. Diagnosis, treatment, and long term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927e999, Fig. 2, p. e937.) Table 208.4 Comparing and Contrasting Multisystem Inflammatory Syndrome in Children (MIS C) with Kawasaki Disease MIS C KAWASAKI DISEASE Mean age 8 12 years Mean age 5 years Fever 24 hr Fever 5 days GI symptoms common (severe abdominal pain) (5090) GI complaints not common (20) Myocarditismyocardial dysfunction (left ventricular dysfunction) Myocardial function normal mildly reduced Coronary artery dilation or aneurysms (2550) Coronary artery abnormalities such as aneurysms common if untreated Hypotension Normal BP Renal involvement more common Renal involvement rare Proinflammatory state common Proinflammatory state common Lymphopenia common Lymphopenia not common Thrombocytopenia Thrombocytosis Elevated ferritin Ferritin usually normal Except in Kawasaki shock syndrome (5). GI, Gastrointestinal. Modified from Naka F, Melnick L, Gorelik M, et al. A dermatologic perspective on multisystem inflammatory syndrome in children. Clin Dermatol. 2021;39(1):163168, Table 5. Table 208.3 Differential Diagnosis of Kawasaki Disease VIRAL INFECTIONS Adenovirus Enterovirus Measles Epstein Barr virus Cytomegalovirus BACTERIAL INFECTIONS Scarlet fever Rocky Mountain spotted fever Leptospirosis Bacterial cervical lymphadenitis retropharyngeal phlegmon Meningococcemia Urinary tract infection RHEUMATOLOGIC DISEASE Systemic onset juvenile idiopathic arthritis Behet disease Rheumatic fever Polyarteritis nodosa Takayasu arteritis OTHER Multisystem inflammatory syndrome in children (MIS C) associated with COVID 19 Toxic shock syndromes Serum sickness Staphylococcal scalded skin syndrome Macrophage activation syndrome (may also complicate Kawasaki disease) Hemophagocytic lymphohistiocytosis Drug hypersensitivity reactions Stevens Johnson syndrome Aseptic meningitis Autoinflammatory diseases Detection of a virus does not exclude Kawasaki disease in the presence of the principal clinical features (see Table 208.1). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 208 u Kawasaki Disease 1547 In addition, moderate dose (30 50 mgkgday divided every 6 hours) aspirin should be administered until the patient is afebrile, then low ered to antiplatelet doses (3 5 mgkgday). Other NSAIDs should not be given during therapy with aspirin because they may block aspirins antiplatelet effect. The mechanism of action of IVIG in KD is likely multifaceted, but treatment results in defervescence and resolution of clinical signs of illness in approximately 85 of patients. Using Japa nese Ministry of Health criteria, the prevalence of coronary disease is 2025 in children |
6,842 | treated with aspirin alone and falls to 5 in those treated with IVIG and aspirin within the first 10 days of illness. In chil dren diagnosed after the 10th day of fever, IVIG should still be offered to patients with persistent fever, abnormal dimensions of the coronary arteries, or signs of systemic inflammation. Low dose aspirin is contin ued for its antithrombotic effect until 6 8 weeks after illness onset and is then discontinued in patients who have had normal echocardiogra phy findings throughout the course of their illness. Patients with CAA continue with aspirin therapy longer and may require anticoagulation, depending on the degree of coronary dilation (see later). Glucocorticoids have been used as primary therapy with the first dose of IVIG in hopes of improving coronary outcomes. A North American trial using a single pulse dose of intravenous methylprednisolone (30 mg kg) with IVIG as primary therapy did not improve coronary outcomes. However, a trial in Japan using the Kobayashi score to identify high risk children demonstrated improved coronary outcomes with a regimen of methylprednisoloneprednisolone (2 mgkgday, divided every 12 hours) plus IVIG as primary therapy. Furthermore, a systematic review and meta analysis of 16 comparative studies demonstrated that early treat ment with glucocorticoids improved coronary artery outcomes in chil dren with KD. These data suggest that primary glucocorticoid therapy in addition to standard of care (IVIG plus aspirin) may be helpful in chil dren at high risk for CAA. Fewer data are available to support the use of TNF alpha inhibitors for prevention of coronary artery aneurysms. IVIG resistant KD (nonresponders) occurs in approximately 15 of patients and is defined by persistent or recrudescent fever 36 hours after completion of the initial IVIG infusion. Patients with IVIG resis tance are at increased risk for CAA. Therapeutic options for the child with IVIG resistance include a second dose of IVIG (2 gkg), a taper ing course of glucocorticoids, infliximab, or possibly anakinra (Table 208.6). For the most severely affected patients with enlarging coronary aneurysms, additional therapies such as cyclosporine or cyclophospha mide may be administered, with consultation from specialists in pedi atric rheumatology and cardiology. COMPLICATIONS Acute KD is complicated in 12 of patients by macrophage activa tion syndrome (MAS; see Chapter 207), a syndrome of life threatening hyperinflammation on the spectrum of hemophagocytic lymphohis tiocytosis. MAS may mimic MIS C. These patients may present with hyperferritinemia, coagulopathy, thrombocytopenia, and shock, war ranting more aggressive immunosuppressive therapy. In all phases of KD, patients with giant coronary aneurysms may experience myocardial infarction, angina, and sudden death due to thrombosis. For this reason, aspirin is continued indefinitely in chil dren with coronary aneurysms (Table 208.7). When aneurysms are moderate sized, dual antiplatelet therapy (e.g., aspirin and clopidogrel) is sometimes administered. For those with large or giant aneurysms, anti coagulation with warfarin or low molecular weight heparin is added to aspirin. For acute thrombosis that occasionally occurs in an aneurysmal or stenotic coronary artery, thrombolytic therapy may be lifesaving. In very |
6,843 | rare circumstances of severe, giant aneurysms, rupture can occur. Long term follow up of patients with CAAs is tailored to the past (i.e., worst ever) and current coronary status, with a schedule of testing recom mended in the 2017 AHA scientific statement on KD (see Table 208.2). Testing may include echocardiography, assessment for inducible ischemia, advanced imaging (CT, MRI, or invasive angiography), physical activ ity counseling, and cardiovascular risk factor assessment and manage ment. Patients with coronary artery stenosis and inducible ischemia may be managed with coronary artery bypass grafting (CABG) or catheter Table 208.6 Treatment Options for IVIG Resistant Patients with Kawasaki Disease AGENT DESCRIPTION DOSE MOST FREQUENTLY ADMINISTERED IVIG: second infusion Pooled polyclonal IG 2 gkg IV IVIG methylprednisolone prednisolone IVIG glucocorticoid IVIG: 2 gkg IV methylprednisolone 2 mgkgd IV divided every 12 hr until afebrile, then oral prednisolone 2 mgkgd divided twice daily Infliximab Monoclonal antibody against TNF Single infusion: 5 10 mgkg IV ALTERNATIVE TREATMENTS Anakinra Recombinant IL 1 receptor antagonist 2 8 mgkgday given by subcutaneous injection or IV infusion Cyclosporine Inhibitor of calcineurin NFAT pathway IV: 3 mgkgd divided every 12 hr PO: 4 8 mgkgd divided every 12 hr Adjust dose to achieve trough 50 150 ngmL; 2 hr peak level 300 600 ngmL Cyclophosphamide Alkylating agent blocks DNA replication 10 15 mgkg IV, 1 or 2 doses Plasma exchange Replaces plasma with albumin 15 cycles IVIG resistance is defined as persistent or recrudescent fever at least 36 hr and 7 days after completion of first IVIG infusion. The top three treatments have been most frequently used, although no comparative effectiveness trial has been performed. Pulsed high dose corticosteroid treatment is not recommended. The alternative treatments have been used in a limited number of patients with KD. CRP, C reactive protein; IG, immunoglobulin; IL, interleukin; IV, intravenous(ly); IVIG, intravenous immune globulin; NFAT, nuclear factor of activated T cells; PO, oral; TNF, tumor necrosis factor. Table 208.5 Treatment of Kawasaki Disease ACUTE STAGE Standard risk: Intravenous immune globulin 2 gkg over 10 12 hr and Aspirin 30 50 mgkgday divided every 6 hr orally until patient is afebrile for at least 48 hr High risk for coronary artery abnormalities: Intravenous immune globulin and aspirin as above, plus methylprednisolone 2 mgkgd IV divided q12hr until afebrile, then prednisolone orally until CRP normalized, then taper over 23 wk CONVALESCENT STAGE Aspirin 3 5 mgkg once daily orally until 6 after illness onset if normal coronary findings throughout course High risk for coronary artery abnormalities is defined as age 6 months or baseline left anterior descending (LAD) or right circumflex artery (RCA) zscore greater than or equal to 2.5. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1548 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) interventions, including percutaneous transluminal coronary rotational ablation, directional coronary atherectomy, |
6,844 | and stent implantation. Patients undergoing long term aspirin therapy should receive annual influenza vaccination to reduce the risk of Reye syndrome. A different antiplatelet agent can be substituted for aspirin during the 6 weeks after varicella vaccination. IVIG may interfere with the immune response to live virus vaccines as a result of a specific antiviral antibody, so the measles mumps rubella and varicella vaccinations should generally be deferred until 11 months after IVIG administration. Nonlive vaccina tions do not need to be delayed. PROGNOSIS The vast majority of patients with KD return to normal health; timely treatment reduces the risk of coronary aneurysms to 5. Acute KD recurs in 13 of cases. Published fatality rates are very low, generally 1. The prognosis for patients with CAA depends on the severity of coronary disease; therefore recommendations for follow up and management are stratified according to coro nary artery status. A 6 week echocardiogram may be unnecessary in patients with normal coronary artery measurements at baseline and at 2 weeks of illness, as these children very rarely develop new abnormalities over time. Overall, 50 of CAAs remodel to normal lumen diameter by 1 2 years after the illness, with smaller aneu rysms being more likely to regress. Intravascular ultrasonography has demonstrated that regressed aneurysms are associated with marked myointimal thickening and abnormal vascular function. Giant aneurysms are less likely to regress to normal lumen diameter and are more likely to lead to thrombosis or stenosis. Bypass graft ing may be required if there is inducible ischemia; it is best accom plished with the use of arterial grafts, which grow with the child and are more likely than venous grafts to remain patent over the long term. Heart transplantation has been required in rare cases where revascularization is not feasible because of distal coronary stenoses, distal aneurysms, or severe ischemic cardiomyopathy. A study from Japan reported outcomes in adult patients with a history of KD and giant aneurysms. These patients required multiple cardiac and sur gical procedures, but the 30 years survival rate approached 90. The long term outcomes of children who have had KD and never had coronary artery abnormalities, based upon reliable echocardio grams performed early in the course of disease, appear to be similar to those in the normative population. Although studies of endothelial dysfunction in children with a history of KD and normal coronary dimensions have produced conflicting results, reassuring data suggest that the standardized mortality ratio among adults in Japan who had KD in childhood without aneurysms is indistinguishable from that of the general population. All children with a history of KD should be counseled regarding a heart healthy diet, adequate amounts of exer cise, tobacco avoidance, and intermittent lipid monitoring. Among children with coronary aneurysms, the AHA recommends treatment thresholds for risk factors for atherosclerotic heart disease that are lower than those for the normal population. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 208.7 Anticoagulation for Coronary Artery Abnormalities in Kawasaki Disease LONG TERM THERAPY Small |
6,845 | aneurysms: Aspirin 35 mgkgd Medium aneurysms: Aspirin clopidogrel 1 mgkgd (max 75 mgd) Giant aneurysms: Aspirin anticoagulation with warfarin, low molecular weight heparin, or direct oral anticoagulants (e.g. apixaban) ACUTE CORONARY THROMBOSIS Prompt fibrinolytic therapy with tissue plasminogen activator or other thrombolytic agent under the supervision of a pediatric cardiologist Sarcoidosis is a rare multisystem granulomatous disease of unknown etiology. There appears to be two distinct, age dependent patterns of disease among children with sarcoidosis. The clinical features in older children are similar to those in adults (pediatric onset adult sarcoid osis), with frequent systemic features (fever, weight loss, malaise), pul monary involvement, and lymphadenopathy. In contrast, early onset sarcoidosis manifesting in children 4 years of age is characterized by the triad of rash, uveitis, and polyarthritis. ETIOLOGY The etiology of sarcoidosis remains obscure but likely results from exposure of a genetically susceptible individual to one or more uniden tified antigens. This exposure initiates an exaggerated immunologic response that ultimately leads to the formation of granulomas. The human major histocompatibility complex is located on chromosome 6, and specific human leukocyte antigen (HLA) class I and class II alleles are associated with disease phenotype. Genetic polymorphisms involving various cytokines and chemokines may also have a role in development of sarcoidosis. Familial clustering supports the contri bution of genetic factors to sarcoidosis susceptibility. Environmental and occupational exposures are also associated with disease risk. There are positive associations between sarcoidosis and agricultural employ ment, occupational exposure to insecticides, and moldy environments typically associated with microbial bioaerosols. Blau syndrome is an autosomal dominant, familial form of sarcoid osis and is typified by the early onset of granulomatous inflammation involving the skin, eyes, and joints. Pathogenic genetic variants in the CARD15NOD2 gene have been found in affected family members and appear to be associated with development of sarcoidosis. Similar genetic variants have been found in individuals with a sporadic early onset sarcoidosis (EOS) (rash, uveitis, arthritis), suggesting that this nonfamilial form and Blau syndrome are genetically and phenotypi cally identical (see Chapter 204). EPIDEMIOLOGY A nationwide patient registry of childhood sarcoidosis in Denmark estimated the annual incidence to be 0.22 0.27 per 100,000 children. The incidence increases with age, and peak onset occurs at 20 39 years. The most common age of reported childhood cases is 13 15 years. In comparison, an international registry and Spanish cohort of Blau syn drome and EOS reported the mean age of disease onset as 30 months and 36 months, respectively. There is no clear gender predilection in any form of childhood sarcoidosis. The majority of U.S. childhood sar coidosis cases are reported in the southeastern and southcentral states. PATHOLOGY AND PATHOGENESIS Noncaseating, epithelioid granulomatous lesions are a cardinal feature of sarcoidosis. Activated macrophages, epithelioid cells, and multi nucleated giant cells, as well as CD4 T lymphocytes, accumulate and become tightly packed in the center of the granuloma. The causative agent that initiates this inflammatory process is unknown. The periph ery of the granuloma contains a loose collection of |
6,846 | monocytes, CD4 and CD8 T lymphocytes, and fibroblasts. The interaction between the macrophages and CD4 T lymphocytes is important in the formation and maintenance of the granuloma. The activated macrophages secrete high levels of tumor necrosis factor (TNF) and other proinflamma tory mediators. The CD4 T lymphocytes differentiate into type 1 helper T cells and release interleukin (IL) 2 and interferon (IFN) , promot ing proliferation of lymphocytes. Granulomas may heal or resolve with complete preservation of the parenchyma. In approximately 20 of the Chapter 209 Sarcoidosis Laura Cannon and Eveline Y. Wu Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 209 u Sarcoidosis 1549 lesions, the fibroblasts in the periphery proliferate and produce fibrotic scar tissue, leading to significant and irreversible organ dysfunction. The sarcoid macrophage is able to produce and secrete 1,25 (OH)2 vitamin D, or calcitriol, an active form of vitamin D typi cally produced in the kidneys. The hormones natural functions are to increase intestinal absorption of calcium and bone resorption and decrease renal excretion of calcium and phosphate. An excess of cal citriol may result in hypercalcemia and hypercalciuria in patients with sarcoidosis. CLINICAL MANIFESTATIONS Sarcoidosis is a multisystem disease, and granulomatous lesions may occur in any organ of the body. The clinical manifestations depend on the extent and degree of granulomatous inflammation and are extremely variable. Children may present with nonspecific symptoms, such as fever, weight loss, and general malaise. In adults and older chil dren, pulmonary involvement is most frequent, with infiltration of the thoracic lymph nodes and lung parenchyma. Isolated bilateral hilar adenopathy on chest radiograph is the most common finding (Fig. 209.1), but parenchymal infiltrates and miliary nodules may also be seen (Figs. 209.2, 209.3, and 209.4). Patients with lung involvement are usually found to have restrictive changes on pulmonary function test ing. Symptoms of pulmonary disease are seldom severe and generally consist of a dry, persistent cough. Extrathoracic lymphadenopathy and infiltration of the liver, spleen, and bone marrow also occur often (Table 209.1). Infiltration of the liver and spleen typically leads to isolated hepatomegaly and splenomegaly, respectively, but actual organ dysfunction is rare. Cutaneous disease, such as plaques, nodules, erythema nodosum in acute disease, or lupus pernio in chronic sarcoidosis, appears in one quarter of cases and is usu ally present at onset. Red brown to purple maculopapular lesions 1 cm on the face, neck, upper back, and extremities are the most com mon skin finding (Fig. 209.5). Papulonodular granulomatous lesions have been reported to develop in cosmetic (eyebrows) and decorative tattoos (tattoo sarcoidosis). Ocular involvement is frequent and has variable manifestations, including anterior or posterior uveitis, conjunc tival granulomas, eyelid inflammation, and orbital or lacrimal gland infiltration. The arthritis in sarcoidosis can be confused with juvenile idiopathic arthritis (JIA). Central nervous system (CNS) involvement is rare in early childhood but may manifest |
6,847 | as seizures, cranial nerve involvement, intracranial mass lesions, and hypothalamic dysfunction (Fig. 209.6). Kidney disease occurs infrequently in children but typically Fig. 209.1 Sarcoidosis. Chest radiograph demonstrating stage I dis ease with enlarged mediastinal and hilar lymph nodes. (From Iannuzzi M. Sarcoidosis. In Goldman L, Schafer AI, eds. Goldmans Cecil Medi cine, 24th ed. Philadelphia: Saunders; 2012: Fig. 95 1, p. 582.) Fig. 209.2 Sarcoidosis. Chest radiograph of 10 year old girl showing widely disseminated peribronchial infiltrates, multiple small nodular densities, hyperaeration of the lungs, and hilar lymphadenopathy. A B Fig. 209.3 Typical features of lung sarcoidosis on CT. A, Usual peri lymphatic distribution of micronodules with fissural spreading. B, Typi cal nodules with irregular margins and satellite micronodules known as the galaxy sign. (From Valerye D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:11551167, Fig. 2, p. 1158.) manifests as renal insufficiency, proteinuria, transient pyuria, or micro scopic hematuria caused by early monocellular infiltration or granuloma formation in kidney tissue. Only a small fraction of children have hyper calcemia or hypercalciuria. Sarcoid granulomas can also infiltrate the heart and lead to cardiac arrhythmias and, rarely, sudden death. Other Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1550 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) rare sites of disease involvement include blood vessels of any size, the gastrointestinal tract, parotid gland, muscles, bones, and testes. In contrast to the variable clinical presentation of sarcoidosis in older children, Blau syndrome and EOS (NOD2 associated sarcoid osis) classically manifest as the triad of uveitis, arthritis, and rash (see Chapter 204). Infantile onset panniculitis with uveitis and sys temic granulomatosis is an uncommon manifestation of sarcoidosis. LABORATORY FINDINGS There is no single standard laboratory test diagnostic of sarcoidosis. Anemia, leukopenia, and eosinophilia may be seen. Other nonspecific findings include hypergammaglobulinemia and elevations in acute phase reactants, including ESR and CRP. Hypercalcemia andor hyper calciuria occur in only a small proportion of children with sarcoidosis. Angiotensin converting enzyme (ACE) is produced by the epithelioid cells of the granuloma, and its serum value may be elevated, but this finding lacks diagnostic sensitivity and specificity. ACE levels are esti mated to be elevated in 50 of children with sarcoidosis. In addition, ACE values may be difficult to interpret because reference values for serum ACE are age dependent. Fluorodeoxyglucosepositron emis sion tomography (FDG PET) (with either CT or MRI) can help iden tify nonpulmonary (lymph nodes, bone, cardiac, liver, spleen) sites for a diagnostic evaluation or biopsy (Fig. 209.7). DIAGNOSIS Definitive diagnosis ultimately requires demonstration of the charac teristic noncaseating granulomatous lesions in a biopsy specimen (usu ally taken from the most readily available affected organ) and exclusion of other known causes of granulomatous inflammation. Skin and trans bronchial lung biopsies have higher yield, greater specificity, and fewer associated adverse events than biopsy of |
6,848 | mediastinal lymph nodes or liver. Additional diagnostic testing includes chest radiography, pulmo nary function testing with measurement of diffusion capacity, hepatic enzyme measurements, and renal function assessment. Ophthalmo logic slit lamp examination is essential because ocular inflammation is frequently present and may be asymptomatic in sarcoidosis, and vision loss is a sequela of untreated disease. Bronchoalveolar lavage may be used to assess for disease activity, and the fluid typically reveals an excess of lymphocytes with an increased CD4CD8 ratio of 2 13:1. In addition to flexible bronchoscopy with transbronchial biopsy, endosonographic guided intrathoracic node aspiration has been valuable in obtaining tissue to assess for noncaseat ing granulomas. Fig. 209.4 Confluent parenchymal lung nodules and mediastinal and bilateral hilar lymphadenopathy with increased FDG uptake in a female with biopsy proven sarcoidosis. PETCT shows confluent parenchymal lung nodules (yellow arrow) and mediastinal and bilateral hilar lymphad enopathy (blue arrow). These abnormalities show increased FDG up take on fused PETCT. (Modified from Prabhakar HB, Rabinowitz CB, Gibbons FK, et al. Imaging features of sarcoidosis on MDCT, FDG PET, and PETCT. AJR Am J Roentgenol. 2008;190:S1S6, Fig. 6, p. S4.) Table 209.1 Sarcoidosis: Extrapulmonary Localizations SYMPTOMS Skin Papules, nodules, plaques, scar sarcoidosis, lupus pernio, subcutaneous sarcoidosis, granuloma annulare, lip granulomas, vitiligo, erythema nodosum, Lofgren syndrome Peripheral lymphadenopathy Mostly cervical or supraclavicular; inguinal, axillary, epitrochlear, or submandibular lymph node sites also possible; painless and mobile Eye Anterior, intermediate, or posterior uveitis; retinal vascular change; conjunctival nodules; lacrimal gland enlargement Liver Often symptom free; abnormal liver function tests in 2030 of patients; hepatomegaly; rarely hepatic insufficiency, chronic intrahepatic cholestasis, or portal hypertension Spleen Splenomegaly; rarely, pain or pancytopenia; very rarely, splenic rupture Heart Atrioventricular or bundle branch block; ventricular tachycardia or fibrillation; congestive heart failure; pericarditis; impairment of sympathetic nerve activity; sudden death Nervous system Facial nerve palsy, optic neuritis, leptomeningitis, diabetes insipidus, hypopituitarism, seizures, cognitive dysfunction, deficits, hydrocephalus, psychiatric manifestations, spinal cord disease, polyneuropathy, small fiber neuropathy Kidney Rare symptoms; increased creatinine sometimes associated with hypercalcemia; nephrocalcinosis; kidney stones Parotitis Symmetric parotid swelling; Heerfordt syndrome when associated with uveitis, fever, and facial palsy Nose Nasal stuffiness, nasal bleeding, crusting, anosmia Larynx Hoarseness, breathlessness, stridor, dysphagia Bones Often asymptomatic; hands and feet classically most involved, also large bones and axial skeleton Skeletal muscles Proximal muscle weakness, amyotrophy, myalgia, intramuscular nodules Genitourinary tract All organs can be involved, including breast, uterus, epididymis, and testicle Gastrointestinal tract Most often symptom free, but the esophagus, stomach, small intestine, and colon can be involved Lofgren syndrome: acute arthritis, erythema nodosum, and hilar adenopathy. Adapted from Valerye D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155 1167, Table 1. Fig. 209.5 Sarcoidosis nodules on the face. (From Shah BR, Laude TA. Atlas of Pediatric Clinical Diagnosis. Philadelphia: Saunders; 2000.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 209 u Sarcoidosis 1551 DIFFERENTIAL DIAGNOSIS |
6,849 | Because of its protean manifestations, the differential diagnosis of sarcoid osis is extremely broad and depends largely on the initial clinical manifesta tions. Granulomatous infections, including tuberculosis, cryptococcosis, pulmonary mycoses (histoplasmosis, blastomycosis, coccidioidomycosis), brucellosis, tularemia, and toxoplasmosis, must be excluded. Other causes of granulomatous inflammation are granulomatosis with polyangiitis (for merly Wegener granulomatosis), hypersensitivity pneumonia, chronic berylliosis, and other occupational exposures to metals. Localized granu lomatous lesions of the head and neck may be due to orofacial granu lomatosis (Melkersson Rosenthal syndrome). Other granulomatous lesions involving the head, neck, and orofacial regions are noted in Table 209.2. Immunodeficiencies that may manifest with granulomatous lesions include common variable immunodeficiency, selective IgA deficiency, chronic granulomatous disease, ataxia telangiectasia, and severe combined immunodeficiency. Granulomas of the lung, skin, or lymph nodes have been reported in patients treated with anti TNF agents. Lymphoma should be ruled out in cases of hilar or other lymphadenopathy. Sarcoid arthritis may mimic JIA. Evaluation for endocrine disorders is needed in the setting of hypercalcemia or hypercalciuria. TREATMENT Treatment should be based on disease severity and the number and type of organs involved. Corticosteroids are the mainstay of treatment for most acute and chronic disease manifestations. The optimal dose and duration of corticosteroid therapy in children have not been estab lished. Induction treatment typically begins with oral prednisone or prednisolone (1 2 mgkgday up to 40 mg daily) for 8 12 weeks until manifestations improve. Corticosteroid dosage is then gradually decreased over 6 12 months to the minimal effective maintenance dose (e.g., 5 10 mgday) that controls symptoms, or discontinued if symptoms resolve. Methotrexate or leflunomide may be effective as a corticosteroid sparing agent. On the basis of the role of TNF in the formation of granulomas, there is rationale for the use of TNF antag onists. Results of small clinical trials showed modest effects with inf liximab and adalimumab treatment of selected disease manifestations (CNS, lupus pernio, pulmonary, ocular), whereas etanercept does not appear to be particularly effective. Other therapeutics used for sarcoid osis manifestations include topical corticosteroids (eye), inhaled cor ticosteroids (lung), azathioprine (CNS), cyclophosphamide (cardiac, CNS), hydroxychloroquine (skin), mycophenolate mofetil (CNS, skin), thalidomide or its analogs (skin), and nonsteroidal antiinflammatory drugs (joints). PROGNOSIS The prognosis of childhood sarcoidosis is not well defined. The dis ease may be self limited with complete recovery or may persist with a progressive or relapsing course. Outcome is worse in the setting of Fig. 209.6 Neurologic involvement in sarcoidosis. Typical involve ment of hypothalamus, pituitary gland, and optic chiasm seen on a sag ittal gadolinium enhanced T1 weighted sequence MRI (small arrow). Abnormal nodular enhancement of the fourth ventricle is seen (large arrow). (Modified from Valerye D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:11551167, Fig. 3D, p. 1160.) Fig. 209.7 Palpable submental lymph node with FDG uptake. Axial fused contrast enhanced PETCT image shows enlarged left submental lymph node (arrow) with increased FDG uptake. Lesion was biopsied and was consistent with sarcoidosis. (From Prabhakar HB, Rabinowitz CB, Gibbons FK, |
6,850 | et al. Imaging features of sarcoidosis on MDCT, FDG PET, and PETCT. AJR Am J Roentgenol. 2008;190:S1S6, Fig. 5, p. S3.) Table 209.2 Granulomatous Disorders with Head and Neck Manifestations AUTOIMMUNE GPA (Wegener granulomatosis) Churg Strauss syndrome Behet disease INFECTIOUS Tuberculosis Cat scratch fever Syphilis Leprosy Fungal (blastomycosis, histoplasmosis) Actinomycosis IDIOPATHICINFLAMMATION Sarcoidosis Orofacial granulomatosis (Melkersson Rosenthal syndrome) HEREDITARY CGD OTHER DISEASES WITH SECONDARY GRANULOMATOUS MANIFESTATIONS Relapsing polychondritis LCH SLE Rheumatoid arthritis Chemical exposure (e.g., cocaine, talc, beryllium) CGD, chronic granulomatous disease; GPA, Granulomatosis with polyangiitis; LCH, Langerhans cell histiocytosis; SLE, systemic lupus erythematosus. Modified from Nwawka OK, Nadgir R, Fujita A, Sakai O. Granulomatous disease in the head and neck: Developing a differential diagnosis. RadioGraphics. 2014;34(5):1240 1256, Table 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1552 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) multiorgan or CNS involvement. Most children requiring treatment experience considerable improvement with corticosteroids, although a significant number have morbid sequelae, mainly involving the lungs and eyes. Children with early onset sarcoidosis have a poorer progno sis and generally experience a more chronic, progressive disease course. The greatest morbidity is associated with ocular involvement, includ ing cataract formation, development of synechiae, and loss of visual acuity or blindness. Long term systemic treatment may be required for the eye disease. Progressive polyarthritis may result in joint destruc tion. The overall mortality rate in older children with sarcoidosis is low. Serial pulmonary function tests and chest radiographs are useful in following the course of lung involvement. Monitoring for other organ involvement should also include electrocardiogram with consideration of an echocardiogram, urinalysis, renal function tests, and measure ments of hepatic enzymes and serum calcium. Other potential indi cators of disease activity include inflammatory markers and serum ACE, although changes in ACE level do not always correlate with other indicators of disease status. Given the frequency of asymptomatic eye disease and the ocular morbidity associated with pediatric sarcoidosis, all patients should have an ophthalmologic examination at presenta tion with monitoring at regular intervals, perhaps every 3 6 months, as recommended in children with JIA. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. INTRODUCTION Childhood vasculitis encompasses a broad spectrum of diseases that share inflammation of the blood vessels as the central pathophysiology. The pathogenesis of the vasculitides is generally idiopathic. Some forms of vasculitis are associated with infectious agents and medications, whereas others may occur in the setting of preexisting autoimmune or autoinflammatory diseases. The pattern of vessel injury provides insight into the form of vasculitis and serves as a framework to delineate the different vasculitic syndromes. The distribution of vascular injury includes small vessels (capillaries, arterioles, and postcapillary venules), medium vessels (renal arteries, mesenteric vasculature, and coronary arteries), and large vessels (the aorta and its proximal branches) (Fig. 210.1). Additionally, some forms of small vessel vasculitis are char |
6,851 | acterized by the presence of antineutrophil cytoplasmic antibodies (ANCAs), whereas others are associated with immune complex depo sition in affected tissues. A combination of clinical features, histologic appearance of involved vessels, and laboratory data is used to classify vasculitis (Tables 210.1 210.4). A nomenclature system from the 2012 International Chapel Hill Consensus Conference (see Table 210.1) has proposed using the pathologic diagnosis rather than eponyms for vas culitis nomenclature. For example, Henoch Schnlein purpura would be referred to as IgA vasculitis. Additionally, the classification crite ria endorsed by the European League Against Rheumatism (EULAR), Pediatric Rheumatology International Trial Organization (PRINTO), and Pediatric Rheumatology European Society (PRES) have been vali dated in childhood vasculitis (see Table 210.2). Chapter 210 Vasculitis Syndromes Vidya Sivaraman, Edward C. Fels, and Stacy P. Ardoin Immune Complex Small Vessel Vasculitis Cryoglobulinemic Vasculitis IgA Vasculitis (HenochSchnlein) Hypocomplementemic Urticarial Vasculitis (AntiC1q Vasculitis) ANCAAssociated Small Vessel Vasculitis Microscopic Polyangiitis Granulomatosis with Polyangiitis (Wegeners) Eosinophilic Granulomatosis with Polyangiitis (ChurgStrauss) Medium Vessel Vasculitis Polyarteritis Nodosa Kawasaki Disease Large Vessel Vasculitis Takayasu Arteritis Giant Cell Arteritis AntiGBM Disease Fig. 210.1 Distribution of vessel involvement in large, medium, and small vessel vasculitis. There is substantial overlap with respect to arte rial involvement, and all three major categories of vasculitis can affect any size artery. Large vessel vasculitis affects large arteries more often than other vasculitides. Medium vessel vasculitis predominantly affects medium arteries. Small vessel vasculitis predominantly affects small vessels, but medium arteries and veins may be affected, although im mune complex small vessel vasculitis rarely affects arteries. Not shown is variable vessel vasculitis, which can affect any type of vessel, from aorta to veins. The diagram depicts (from left to right) aorta, large ar tery, medium artery, small arteryarteriole, capillary, venule, and vein. ANCA, Antineutrophil cytoplasmic antibody; GBM, glomerular base ment membrane. (From Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:111, Fig. 2, p. 4.) Childhood vasculitis varies from a relatively benign and self limited disease such as Henoch Schnlein purpura (IgA vasculitis) to cata strophic disease with end organ damage, as seen in granulomatosis with polyangiitis (formerly Wegener granulomatosis). Vasculitis generally manifests as a heterogeneous multisystem disease. Although some fea tures, such as purpura, are easily identifiable, others, such as hypertension secondary to renal artery stenosis or glomerulonephritis, can be subtler. Ultimately, the key to recognizing vasculitis relies heavily on pattern rec ognition. Demonstration of vessel injury and inflammation on biopsy or vascular imaging is required to confirm a diagnosis of vasculitis. Clues to the diagnosis of a vasculitis disorder are noted in Table 210.3, and a broad diagnostic approach is noted in Table 210.5. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 210.1 Henoch Schnlein Purpura (IgA Vasculitis) Vidya Sivaraman, Edward C. Fels, and Stacy P. Ardoin Henoch Schnlein purpura (HSP) is the most common vasculitis of childhood and is characterized by leukocytoclastic vasculitis and immunoglobulin A deposition in the small vessels in the skin, joints, gastrointestinal tract, and |
6,852 | kidney. HSP is also referred to as IgA vas culitis, based on the presence of vasculitis with predominance of IgA deposits affecting small vessels. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1553 Table 210.1 2012 Chapel Hill Consensus Conference on Nomenclature of Systemic Vasculitis LARGE VESSEL VASCULITIS (LVV) Giant cell (temporal) arteritis (GCA) Granulomatous arteritis of the aorta and its major branches with a predilection for the extracranial branches of the carotid artery Often involves the temporal artery Usually occurs in patients older than 50 yr of age and often associated with polymyalgia rheumatica Takayasu arteritis (TAK) Granulomatous inflammation of the aorta and its major branches Usually occurs in patients much younger than 50 yr of age MEDIUM VESSEL VASCULITIS (MVV) Polyarteritis nodosa (PAN) Necrotizing inflammation of medium sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules and not associated with ANCAs Kawasaki disease (KD) Arteritis involving large, medium sized, and small arteries associated with mucocutaneous lymph node syndrome Coronary arteries are often involved Aorta and veins may be affected Usually occurs in children SMALL VESSEL VASCULITIS (SVV) ANCA associated vasculitis (AAV) Granulomatosis with polyangiitis (Wegener) (GPA) Granulomatous inflammation involving the respiratory tract associated with necrotizing vasculitis affecting small to medium sized vessels Necrotizing glomerulonephritis is common Eosinophilic granulomatosis with polyangiitis (Churg Strauss) (EGPA) Eosinophilic and granulomatous inflammation involving the respiratory tract accompanied by necrotizing vasculitis affecting small to medium sized vessels associated with asthma and eosinophilia Microscopic polyangiitis (MPA) Necrotizing vasculitis with few or no immune deposits, affecting small vessels Necrotizing arteritis involving small and medium sized arteries may be present Necrotizing glomerulonephritis is common Pulmonary capillaritis often occurs Immune Complex Small Vessel Vasculitis IgA vasculitis (Henoch Schnlein) (IgAV) Vasculitis characterized by immunoglobin Adominant immune deposits affecting small vessels Typically involves skin, gut, and glomeruli. Arthralgias and arthritis are common Cryoglobulinemic vasculitis (CPV) Vasculitis with cryoglobulin immune deposits affecting small vessels associated with cryoglobulinemia Skin and glomeruli are often involved Antiglomerular basement membrane (anti GBM) disease Vasculitis affecting pulmonary and renal capillaries with deposition of antiglomerular basement membrane antibodies Hypocomplementemic urticarial vasculitis Associated with anti Clq antibodies Affects kidney, joints, lungs, and eyes VARIABLE VESSEL VASCULITIS (VVV) Behet disease (BD) Cogan syndrome (CS) Affects arteries and veins with thrombosis, arteritis, and arterial aneurysms Oral andor genital aphthous ulcers and can involve skin, eyes, joints, and central nervous system Affects small, medium, or large arteries; aortitis, aortic, and mitral valvulitis SINGLE ORGAN VASCULITIS (SOV) Cutaneous leukocytoclastic angiitis Vasculitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis Cutaneous arteritis Cutaneous vasculitis not associated with systemic vasculitis Primary central nervous system vasculitis CNS vasculitis not associated with systemic vasculitis Isolated aortitis Aortitis not associated with systemic vasculitis Others VASCULITIS ASSOCIATED WITH SYSTEMIC DISEASE Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis Others VASCULITIS ASSOCIATED WITH PROBABLE ETIOLOGY |
6,853 | Hepatitis Cassociated cryoglobulinemia vasculitis Hepatitis Bassociated vasculitis Syphilis associated vasculitis Drug associated immune complex vasculitis Drug associated ANCA associated vasculitis Cancer associated vasculitis Others Large vessels: aorta and its larger branches directed toward major anatomic regions; medium vessels: renal, hepatic, coronary, and mesenteric arteries; small vessels: venules, capillaries, arterioles, and intraparenchymal distal arteries and arterioles. Essential components are in normal type; italicized type represents usual, but not essential, components. Adapted from Jennette JC, Falk RJ, Bacon P, et al. Arthritis Rheum. 2013;65(1):111. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1554 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) EPIDEMIOLOGY HSP occurs worldwide and affects all ethnic groups. The incidence is estimated at 14 20 per 100,000 children per year and affects males more than females, with a 1.2 1.8:1 malefemale ratio. Approximately 90 of HSP cases occur in children, usually between ages 3 and 10 years. HSP is distinctly less common in adults, who often have severe and chronic complications. HSP is more common in the winter and spring and is unusual in summer months. Many cases of HSP follow a documented upper respiratory infection. PATHOLOGY Skin biopsies demonstrate leukocytoclastic vasculitis of the der mal capillaries and postcapillary venules. The inflammatory infiltrate includes neutrophils and monocytes. Renal histopathology typically shows endocapillary proliferative glomerulonephritis, ranging from a focal segmental process to extensive crescentic involvement. In all tis sues, immunofluorescence identifies IgA deposition in walls of small vessels (Fig. 210.2), accompanied to a lesser extent by deposition of C3, fibrin, and IgM. PATHOGENESIS The exact pathogenesis of HSP remains unknown. Given the seasonal ity of HSP and the frequency of preceding upper respiratory infections, infectious triggers such as group A hemolytic streptococcus, Staphy lococcus aureus, Mycoplasma, and adenovirus have been suspected. The common finding of deposition of IgA, specifically IgA1, suggests that HSP is a disease mediated by IgA and IgA immune complexes. HSP occasionally clusters in families, suggesting a genetic component. HLA B34 and HLA DRB101 alleles have been linked to HSP nephri tis. Patients with familial Mediterranean fever, hereditary periodic fever syndromes, and complement deficiencies are at increased risk for developing HSP, suggesting that genetically determined immune dys regulation may contribute. CLINICAL MANIFESTATIONS The hallmark of HSP is its rash: palpable purpura starting as pink mac ules or wheals and developing into petechiae, raised purpura, or larger ecchymoses. Occasionally, bullae and ulcerations develop. The skin lesions are usually symmetric and occur in gravity dependent areas (lower extremities), the extensor aspect of the upper extremities, or on pressure points (buttocks) (Figs. 210.2 and 210.3). The skin lesions often evolve in groups, typically lasting 3 10 days, and may recur up to 4 months after initial presentation. Subcutaneous edema localized to the dorsa of the hands and feet, periorbital area, lips, scrotum, or scalp is also common. Musculoskeletal involvement, including |
6,854 | arthritis and arthralgias, is common, occurring in up to 75 of children with HSP. The arthritis tends to be self limited and oligoarticular, with a predilection for large joints such as the knees and ankles, and does not lead to deformities. Periarticular swelling and tenderness without erythema or effusions are common. The arthritis usually resolves within 2 weeks but can recur. Gastrointestinal (GI) manifestations occur in up to 80 of children with HSP and include abdominal pain, vomiting, diarrhea, paralytic ileus, and melena. Intussusception, mesenteric ischemia, and intestinal perforation are rare but serious complications. Endoscopic evaluation is usually not needed but may identify vasculitis of the intestinal tract. Renal involvement occurs in up to 30 of children with HSP, mani festing as microscopic hematuria, proteinuria, hypertension, frank nephritis, nephrotic syndrome, and acute or chronic renal failure. However, progression to end stage renal disease (ESRD) is uncommon in children (12) (see Chapter 560.3). Renal manifestations can be delayed for several months after the initial illness, so close follow up with serial urinalyses and blood pressure monitoring is necessary. Neurologic manifestations of HSP, caused by hypertension (poste rior reversible encephalopathy syndrome) or central nervous system (CNS) vasculitis, may also occur, including intracerebral hemor rhage, seizures, headaches, depressed level of consciousness, cranial or peripheral neuropathies, and behavior changes. Other, less common potential manifestations of HSP are inflammatory eye disease, carditis, pulmonary hemorrhage, orchitis, and testicular torsion. DIAGNOSIS The diagnosis of HSP is clinical and often straightforward when the typical rash is present. However, in at least 25 of cases, the rash appears after other manifestations, making early diagnosis challenging. Table 210.2 EULARPRES Classification of Childhood Vasculitis I. PREDOMINANTLY LARGE SIZED VESSEL VASCULITIS Takayasu arteritis II. PREDOMINANTLY MEDIUM SIZED VESSEL VASCULITIS Childhood polyarteritis nodosa Cutaneous polyarteritis Kawasaki disease III. PREDOMINANTLY SMALL SIZED VESSEL VASCULITIS A. Granulomatous Wegener granulomatosis Churg Strauss syndrome B. Nongranulomatous Microscopic polyangiitis Henoch Schnlein purpura Isolated cutaneous leukocytoclastic vasculitis Hypocomplementemic urticarial vasculitis IV. OTHER VASCULITIDES Behet disease Vasculitis secondary to infection (including hepatitis Bassociated polyarteritis nodosa), malignancies, and drugs (including hypersensitivity vasculitis) Vasculitis associated with connective tissue diseases Isolated vasculitis of the central nervous system Cogan syndrome Unclassified This classification predated the removal of eponyms and histopathologic subclassification by the CHCC 2012. From Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, et al. EULARPReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936941. Table 210.3 Features that Suggest a Vasculitic Syndrome CLINICAL FEATURES Fever, weight loss, fatigue of unknown origin Skin lesions (palpable purpura, fixed urticaria, livedo reticularis, nodules, ulcers) Neurologic lesions (headache, mononeuritis multiplex, focal central nervous system lesions) Arthralgia or arthritis, myalgia, or myositis, serositis Hypertension, hematuria, renal failure Pulmonary infiltrates or hemorrhage Myocardial ischemia, arrhythmias LABORATORY FEATURES Increased erythrocyte sedimentation rate or C reactive protein level Leukocytosis, anemia, thrombocytosis Eosinophilia Antineutrophil cytoplasmic antibodies Elevated factor VIIIrelated antigen (von Willebrand factor) Cryoglobulinemia Circulating immune complexes Hematuria From Petty RE, Laxer RM, Lindsley CB, Wedderburn LR. Textbook of Pediatric Rheumatology, 7th ed. |
6,855 | Philadelphia: Saunders; 2016. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1555 Table 210.6 summarizes the EULARPRES classification criteria for HSP. Most patients are afebrile. The differential diagnosis for HSP depends on specific organ involvement, but usually includes other small vessel leukocytoclastic vasculitides (Table 210.7), infections, acute poststreptococcal glomer ulonephritis, hemolytic uremic syndrome, coagulopathies, and other acute intraabdominal processes. Additional disorders in the differen tial include papular purpuric glove and sock syndrome, systemic lupus erythematosus (SLE), other vasculitides (urticarial, hypersensitivity), and thrombocytopenia. Infantile acute hemorrhagic edema (AHE), an isolated cutaneous leukocytoclastic vasculitis that affects infants 2 years of age, resembles HSP clinically. AHE manifests as fever; tender edema of the face, scro tum, hands, and feet; and ecchymosis (usually larger than the purpura of HSP) on the face and extremities (Fig. 210.4). The trunk is spared, but petechiae may be seen in mucous membranes. The patient usu ally appears well except for the rash. The platelet count is normal or elevated, and the urinalysis results are normal. The younger age, nature of the lesions, absence of other organ involvement, and a biopsy may help distinguish infantile AHE from HSP. LABORATORY FINDINGS No laboratory finding is diagnostic of HSP. Common but nonspecific findings include leukocytosis, thrombocytosis, mild anemia, and eleva tions of erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). The platelet count is normal in HSP. Occult blood is frequently found in stool specimens. Serum albumin levels may be low because of renal or intestinal protein loss. Autoantibody testing such as anti nuclear antibody (ANA) is not useful diagnostically except to exclude other diseases. Serum IgA values are often elevated but are not rou tinely measured. Assessment of renal involvement with blood pressure, urinalysis, and serum creatinine is necessary. Ultrasound is often used in the setting of GI complaints to look for bowel wall edema or the rare occurrence of an associated intussuscep tion. Barium enema can also be used to both diagnose and treat intus susception. Although often unnecessary in typical HSP, biopsies of skin and kidney can provide important diagnostic information, particularly in atypical or severe cases, and characteristically show leukocytoclastic vasculitis with IgA deposition in affected tissues. TREATMENT Treatment for mild and self limited HSP is supportive, with an emphasis on ensuring adequate hydration, nutrition, and analgesia. Corticosteroids are most often used to treat significant GI involve ment or other life threatening manifestations. Glucocorticoids such as oral prednisone (1 2 mgkgday), or in severe cases, intravenous (IV) methylprednisolone for 1 2 weeks, followed by taper, reduce abdominal and joint pain but do not alter the overall prognosis. Cor ticosteroids are not routinely recommended for prevention of compli cations such as nephritis. Rapid tapering of corticosteroids may lead to a flare of HSP symptoms. Although few data are available to dem onstrate efficacy, intravenous immunoglobulin (IVIG) |
6,856 | and plasma exchange are sometimes used for severe disease. In some patients, chronic HSP renal disease is managed with a variety of immunosup pressants, including azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil. ESRD develops in 5 of children with HSP nephritis. COMPLICATIONS Acutely, serious GI involvement, including intussusception and intes tinal perforation, imparts significant morbidity and mortality. Renal disease is the major long term complication, occurring in 12 of children with HSP. Renal disease can develop up to 6 months after diagnosis but rarely does so if the initial urinalysis findings are normal. Therefore, it is recommended that children with HSP undergo serial monitoring of blood pressure and urinalysis for at least 6 months after diagnosis to monitor for development of nephritis. PROGNOSIS Overall, the prognosis for childhood HSP is excellent, and most children experience an acute, self limited course lasting on average 4 weeks. However, 1560 of children with HSP experience one or more recurrences, typically within 4 6 months of diagnosis. With each relapse, symptoms are usually milder than at presentation. Children Table 210.4 Clinicopathologic Characteristics of Vasculitides in Childhood SYNDROME FREQUENCY VESSELS AFFECTED CHARACTERISTIC PATHOLOGY POLYARTERITIS Polyarteritis nodosa Rare Medium size and small muscular arteries and sometimes arterioles Focal segmental (often near bifurcations); fibrinoid necrosis; gastrointestinal, renal microaneurysms; lesions at various stages of evolution Kawasaki disease Common Coronary and other muscular arteries Thrombosis, fibrosis, aneurysms, especially of coronary vessels LEUKOCYTOCLASTIC VASCULITIS Henoch Schnlein purpura (IgA vasculitis) Common Arterioles and venules, often small arteries and veins Leukocytoclasis; mixed cells, eosinophils, IgA deposits in affected vessels Hypersensitivity angiitis Rare Arterioles and venules Leukocytoclastic or lymphocytic, varying eosinophils, occasionally granulomatous; widespread lesions at same stage of evolution GRANULOMATOUS VASCULITIS Granulomatosis with polyangiitis (Wegener granulomatosis) Rare Small arteries and veins, occasionally larger vessels Upper and lower respiratory tract, necrotizing granulomata glomerulo nephritis Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome) Rare Small arteries and veins, often arterioles and venules Necrotizing extravascular granulomata; lung involvement; eosinophilia GIANT CELL ARTERITIS Takayasu arteries Uncommon Large arteries Granulomatous inflammation, giant cells; aneurysms, dissection Temporal arteritis Rare Medium size and large arteries Granulomatous inflammation, giant cell arteries Adapted from Cassidy JT, Petty RE. Textbook of Pediatric Rheumatology, 6th ed. Philadelphia: Saunders; 2011. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1556 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) with a more severe initial course are at higher risk for relapse. The long term prognosis usually depends on the severity and duration of GI or renal involvement. Chronic renal disease develops in 12 of children with HSP, and 5 of those with HSP nephritis go on to have ESRD. The risk of HSP recurrence and graft loss after renal transplantation is estimated at 7.5 after 10 years. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 210.5 Recommendations on the Diagnosis of Rare Pediatric Systemic Vasculitides RECOMMENDATION 1. |
6,857 | In any pediatric patient with ongoing or a history of unexplained systemic inflammation, the diagnosis of systemic vasculitis should be considered and referral to a pediatric rheumatologist should be made, particularly in the presence of unexplained organ involvement. 2. Clinical features combined with laboratory evidence of inflammation that suggest a vasculitic syndrome warranting referral to a pediatric rheumatologist are included in the following nonexhaustive list: Pyrexia of unknown origin Vasculitic skin rash PNS or CNS involvement Unexplained arthritis, myalgia, serositis Unexplained pulmonary, gastrointestinal, cardiovascular, or renal disease 3. When vasculitis is suspected, the diagnosis is often difficult and differential diagnoses are broad. The general workup for diagnosis of a specific vasculitic syndrome should include tissue histology, imaging, and determination of ANCA. 4. In every patient in whom a specific vasculitic syndrome is suspected, basic screening investigations, along with blood pressure measurement, should include: Hematology and acute phase reactants: Full blood count, ESR, CRP, clotting, prothrombotic screen (if patchy ischemia of digits or skin) Peripheral blood smear Basic biochemistry: Renal function, liver function, CPK, LDH Urine dipstick test of urine with UA:UC ratio or UP:UC ratio Infection: Routine pediatric infection screen Antistreptolysin O antibody titer (ASOT) andor antiDNase b VZV antibody status Immunologic tests: ANA, ENA antibodies, ANCA, antiphospholipid antibodies Immunoglobulins IgGIgAIgMIgE Complement (C3, C4) RF (if nephritis or interstitial lung disease) GBM antibody Radiologicother: CXR Doppler abdominal ultrasound scan ECG; echocardiography Digital clinical photography of lesions 5. When considering a specific vasculitic syndrome, depending on presenting symptoms, tests with specific indications should be considered: The following may be useful if blood pressure abnormalities: Four limb blood pressure measurements 24 hr ambulatory blood pressure monitor The following may be useful if evidencesuspicion of specific organ involvement: CT (e.g., thorax, abdomen, brain) MRI MRIMRA of aorta and major branches RECOMMENDATION Selective contrast visceral arteriography Tissue biopsy (e.g., skin, nasal or sinus, kidney, sural nerve, lung, liver, gut, temporal artery, brain) Nail fold capillaroscopy Possible bonejoint involvement: radiograph of suspected sites Eye symptoms: ophthalmology screen Pulmonary symptoms: VQ scan Renal involvement: Tc 99m DMSA scan Peripheral vascular symptoms: ultrasound scan Doppler of peripheral arteries Neuropathy: nerve conduction studies Cerebral involvement: MRIMRA of brain and cerebral contrast angiography Organ specific autoantibodies (e.g., ASCAs, brainneuronal specific autoantibodies) Cryoglobulins or cryoprecipitants (technical expertise required), particularly if skin involved predominantly at peripheral sites The following may be useful when the differential diagnosis includes malignancy: Lymph node excision biopsy Bone marrow analysis PET CT The following may be useful when the differential diagnosis includes infection: Tuberculosis screen PCR for viral infection (e.g., CMV, EBV, enterovirus, adenovirus, VZV, HBV, HCV) Serology for HIV, rickettsiae, Borrelia burgdorferi, Mycoplasma Viral serology for hepatitis B and C, parvovirus B19 Cryoglobulins or cryoprecipitants (technical expertise required) The following may be useful when the differential diagnosis includes autoinflammatory syndromes: DNA analysis for MEFV (familial Mediterranean fever), TNFRSF1A (TNF receptorassociated periodic fever syndrome TRAPS), MVK (mevalonate kinase deficiency; previously referred to as hyper IgD syndrome HIDS), NLRP3 (cryopyrin associated periodic syndrome CAPS), NOD2 (CrohnBlau juvenile |
6,858 | sarcoid mutations), ADA2 (deficiency of ADA2), genetic screening for SAVI (TMEM173) and CANDLE (PSMB8, 4, 9, and other proteasome genes if available). 6. In the clinical assessment of suspected systemic vasculitis, a structured multiorgan assessment should take place. 7. For suspected systemic vasculitis, the Pediatric Vasculitis Activity Score (PVAS) may facilitate structured multiorgan assessment. The PVAS can be found here: http:ard.bmj.comcontent72101628.short 8. At diagnosis and in ongoing follow up of systemic vasculitis, a PVAS score should be performed to assess disease activity. 9. At diagnosis and in ongoing follow up of systemic vasculitis, a multiorgan assessment of damage should be undertaken. 10. There is no currently validated tool to assess pediatric vasculitis damage. This is an ongoing unmet need. The PVDI, while unvalidated, can be assessed here: https:ard.bmj.comcontent73 Suppl2696.4 PNS, Peripheral nervous system; PVAS, pediatric vasculitis activity score; PVDI, pediatric vasculitis damage index; CNS, central nervous system; CPK, creatine phosphokinase; LDH, lactate dehydrogenase; UA:UC, urine albumin to urinary creatinine ratio; UP:UC, urine protein to urinary creatinine ratio; VZV, varicellazoster virus; CXR, chest x ray; ECG, electrocardiogram; MRA, magnetic resonance angiography; VQ, ventilationperfusion; DMSA, dimercaptosuccinic acid; ASCA, antiSaccharomyces cerevisiae antibodies; SAVI, STING associated vasculitis of infancy; CANDLE, chronic atypical neutrophilic dermatosis lipodystrophy and elevated temperature. Modified from de Graeff N, Groot N, Brogan P, et al. European consensus based recommendations for the diagnosis and treatment of rare paediatric vasculitides the SHARE initiative. Rheumatology. 2019;58(4):656671, Table 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1557 210.2 Takayasu Arteritis Vidya Sivaraman, Edward C. Fels, and Stacy P. Ardoin Takayasu arteritis (TA), also known as pulseless disease, is a chronic large vessel vasculitis of unknown etiology that predominantly involves the aorta and its major branches. EPIDEMIOLOGY Although TA occurs worldwide and can affect all ethnic groups, the disease is most common in those of Asian descent. Age of onset is typically between 10 and 40 years. Most children are diagnosed as adolescents, on average at age 13 years. Up to 20 of individuals with TA are diagnosed before 19 years. Younger children may be affected, but diagnosis in infancy is rare. TA preferentially affects females, with a reported 2 4:1 femalemale ratio in children and adolescents and a 9:1 ratio among adults. Occlusive complications are more common in the United States, Western Europe, and Japan, whereas aneurysms pre dominate in Southeast Asia and Africa. PATHOLOGY TA is characterized by inflammation of the vessel wall, starting in the vasa vasorum. Involved vessels are infiltrated by T cells, natural killer cells, plasma cells, and macrophages. Giant cells and granulomatous inflammation develop in the media. Persistent inflammation dam ages the elastic lamina and muscular media, leading to blood vessel A B Fig. 210.2 Henoch Schnlein purpura. A, Typical palpable purpura in lower extremities. B, Skin biopsy of lesion shows direct immunofluores cence of IgA (arrows) |
6,859 | within the walls of dermal capillaries. Fig. 210.3 Henoch Schnlein purpura. (From Korting GW. Haut krankheiten bei Kindern und Jungendlichen, 3rd ed. Stuttgart: FK Schattaur Verlag; 1982.) Table 210.6 Classification Criteria for Henoch Schnlein Purpura EUROPEAN LEAGUE AGAINST RHEUMATISMPEDIATRIC RHEUMATOLOGY EUROPEAN SOCIETY CRITERIA Palpable purpura (in absence of coagulopathy or thrombocytopenia) and one or more of the following criteria must be present: Abdominal pain (acute, diffuse, colicky pain) Arthritis or arthralgia Biopsy of affected tissue demonstrating predominant IgA deposition Renal involvement (proteinuria 0.3 g24 hr), hematuria, or red cell casts Classification criteria are developed for use in research and are not validated for clinical diagnosis. Developed for use in pediatric populations only. Adapted from Ozen S, Pistorio A, Iusan SM, et al. EULARPRINTOPRES criteria for Henoch Schnlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II. Final classification criteria. Ann Rheum Dis. 2010;69:798806. Table 210.7 Conditions Associated with Leukocytoclastic Vasculitis Immunoglobulin (Ig) A vasculitis (Henoch Schnlein) Hypersensitivity vasculitis Hypocomplementemic urticarial vasculitis Mixed cryoglobulinemia Cutaneous polyarteritis Antineutrophil cytoplasmic antibody (ANCA)associated small vessel vasculitis Goodpasture syndrome Rheumatic disorders: systemic lupus erythematosus (SLE), juvenile dermatomyositis, mixed connective tissue disease (MCTD), scleroderma, juvenile idiopathic arthritis (JIA) Mucha Habermann disease Relapsing polychondritis Khlmeier Degos syndrome Antiphospholipid antibody syndrome Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome Malignancy associated disease Sweet syndrome Cronkhite Canada syndrome Stevens Johnson syndrome Erythema elevatum diutinum COVID 19MIS C Leukocytoclastic vasculitis may occur in cutaneous lesions in some patients with ANCA associated vasculitis and collagen vascular diseases. Modified from Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Box 33.1, p. 457. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1558 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) dilation and the formation of aneurysms. Progressive scarring and inti mal proliferation can result in stenotic or occluded vessels. The sub clavian, renal, and carotid arteries are the most commonly involved aortic branches; pulmonary, coronary, and vertebral arteries may also be affected. PATHOGENESIS The etiology of TA remains unknown. The presence of abundant T cells with a restricted repertoire of T cell receptors in TA vascular lesions points to the importance of cellular immunity and suggests the exis tence of a specific but unknown aortic tissue antigen. Expression of interleukin (IL) 1, IL 6, and tumor necrosis factor (TNF) is reported to be higher in patients with active TA than in patients with inactive TA and in healthy controls. In some patient populations, IL 1 genetic poly morphisms are linked to TA. Some individuals with TA have elevated serum values of antiendothelial antibodies. The increased prevalence of TA in certain ethnic populations and its occasional occurrence in monozygotic twins and families suggest a genetic predisposition to the disease. CLINICAL MANIFESTATIONS The diagnosis of |
6,860 | TA is challenging because early disease manifesta tions are often nonspecific. As a result, diagnosis can be delayed for several months, and the time to diagnosis is usually longer in chil dren than in adults. Fever, malaise, weight loss, headache, hyperten sion, myalgias, arthralgias, dizziness, and abdominal pain are common early complaints in the prepulseless phase of the disease. Among chil dren, hypertension and headache are particularly common presenting manifestations and should prompt consideration of TA when present without alternative explanation. Some individuals with TA report no systemic symptoms and instead present with vascular complications. It is only after substantial vascular injury that evidence of hypoperfu sion becomes clinically evident. Later manifestations of disease include diminished pulse, asymmetric blood pressure, claudication, Raynaud phenomenon, renal failure, and symptoms of pulmonary or cardiac ischemia. Inflammation can extend to the aortic valve, resulting in valvular insufficiency. Other findings may include pericardial effusion, pericarditis, pleuritis, splenomegaly, and arthritis. Supradiaphragmatic (aortic arch) disease often manifests with CNS (stroke, transient ischemic attack) and cardiac (heart failure, palpita tions) symptoms. Infradiaphragmatic (midaortic syndrome) disease may produce hypertension, abdominal bruits, and pain. Most patients have involvement in both areas. DIAGNOSIS Specific pediatric criteria for TA have been proposed (Table 210.8). The 2022 ACR EULAR classification criteria for Takayasu arteritis propose a criterionbased scoring system in adults (Table 210.9). Radiographic demonstration of large vessel vasculitis is necessary. A thorough physi cal examination is required to detect an aortic murmur, diminished or asymmetric pulses, and vascular bruits. Four extremity blood pres sures should be measured; 10 mm Hg asymmetry in systolic pressure is indicative of disease. DIFFERENTIAL DIAGNOSIS In the early phase of TA, when nonspecific symptoms predominate, the differential diagnosis includes a wide array of systemic infections, auto immune conditions, and malignancies. Although giant cell arteritis, also known as temporal arteritis, is a common large vessel vasculitis in older adults, this entity is rare in childhood. Noninflammatory conditions that can cause large vessel compromise include fibromus cular dysplasia, Marfan syndrome, and Ehlers Danlos syndrome. LABORATORY FINDINGS The laboratory findings in TA are nonspecific, and there is no specific diagnostic laboratory test. ESR and CRP values are typically elevated, and other nonspecific markers of chronic inflammation may include leuko cytosis, thrombocytosis, anemia of chronic inflammation, and hyper gammaglobulinemia. Autoantibodies, including ANA and ANCA, are not useful in diagnosing TA except to help exclude other autoimmune diseases. Radiographic assessment is essential to establish large vessel arterial involvement. Conventional arteriography of the aorta and major branches, including carotid, subclavian, pulmonary, renal, and mesenteric branches, can identify luminal defects, including dilation, aneurysms, and steno ses, even in smaller vessels such as the mesenteric arteries. Figure 210.5 shows a conventional arteriogram in a child with TA. Although not yet thoroughly validated in TA, magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) also provide important information about vessel wall thickness and enhancement, although they may not image smaller vessels as well as conventional angiography. Posi tron emission tomography (PET) may detect vessel wall inflammation |
6,861 | but has not been studied extensively. Ultrasound with duplex color flow Doppler imaging may identify vessel wall thickening and assesses arte rial flow. Echocardiography is recommended to assess for aortic valvular Fig. 210.4 Infantile acute hemorrhagic edema. Typical lesions on the arm of an infant. (From Eichenfield LF, Frieden IJ, Esterly NB. Textbook of Neonatal Dermatology. Philadelphia: Saunders; 2001.) Table 210.8 Proposed Classification Criteria for Pediatric Onset Takayasu Arteritis Angiographic abnormalities (conventional, CT, or magnetic resonance angiography) of the aorta or its main branches and at least one of the following criteria: Decreased peripheral artery pulse(s) andor claudication of extremities Blood pressure difference between arms or legs of 10 mm Hg Bruits over the aorta andor its major branches Hypertension (defined by childhood normative data) Elevated acute phase reactant (erythrocyte sedimentation rate or C reactive protein) Adapted from Ozen S, Pistorio A, Iusan SM, et al. EULARPRINTOPRES criteria for Henoch Schnlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II. Final classification criteria. Ann Rheum Dis. 2010;69:798806. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1559 involvement. Serial vascular imaging is usually necessary to assess response to treatment and to detect progressive vascular damage. TREATMENT Glucocorticoids are the mainstay of therapy, typically starting with high doses (1 2 mgkgday of prednisone or methylprednisolone IV) followed by gradual dosage tapering. When TA progresses or recurs, steroid sparing therapy is often required, usually involving methotrexate or aza thioprine. Cyclophosphamide is reserved for severe or refractory disease. Results of small case series also suggest that mycophenolate mofetil or antiTNF therapy may be beneficial in select patients. AntiIL 6 ther apy with tocilizumab has shown promising results in a small case series of children with TA. Antihypertensive medications are often necessary to control blood pressure caused by renovascular disease. COMPLICATIONS Progressive vascular damage can result in arterial stenoses, aneurysms, and occlusions, which produce ischemic symptoms and can be organ or life threatening. Potential ischemic complications include stroke, renal impairment or failure, myocardial infarction, mesenteric isch emia, and limb threatening arterial disease. When these complications occur or are imminent, intervention with surgical vascular grafting or catheter based angioplasty and stent placement may be necessary to restore adequate blood flow. A high rate of recurrent stenosis has been reported after angioplasty and stent placement. Aortic valve replace ment may be required if significant aortic insufficiency develops. PROGNOSIS Although up to 20 of individuals with TA have a monophasic course and achieve sustained remission, most suffer relapses. Survival for indi viduals with TA has improved considerably over the decades, although higher mortality rates are reported in children and adolescents. The overall estimated survival for individuals with TA is 93 at 5 years and 87 at 10 years. However, morbidity from vascular complications remains high, particularly when there is evidence of |
6,862 | ongoing active inflammation as detected by elevated CRP or ESR. Given the chronic endothelial insult and inflammation, children and adolescents with TA are probably at high risk for accelerated atherosclerosis. Early detection and treatment are critical to optimizing outcomes in TA. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 210.5 Child with Takayasu arteritis. Conventional angiogram shows massive bilateral carotid dilation, stenosis, and poststenotic dilation. Table 210.9 2022 American College of Rheumatology EULAR Classification Criteria for Takayasu Arteritis Considerations when applying these criteria: These classification criteria should be applied to classify the patient as having Takayasu arteritis when a diagnosis of mediumvessel or largevessel vasculitis has been made. Alternate diagnoses mimicking vasculitis should be excluded before applying the criteria. ABSOLUTE REQUIREMENTS Age 60 yr at time of diagnosis Evidence of vasculitis on imaging1 ADDITIONAL CLINICAL CRITERIA Female sex 1 Angina or ischemic cardiac pain 2 Arm or leg claudication 2 Vascular bruit2 2 Reduced pulse in upper extemity3 2 Carotid artery abnormality4 2 Systolic blood pressure difference in arms 20 mm Hg 1 ADDITIONAL IMAGING CRITERIA Number of affected arterial territories (select one)5 One arterial territory 1 Two arterial territories 2 Three arterial territories 3 Symmetric involvement of paired arteries6 1 Abdominal aorta involvement with renal or mesenteric involvement7 3 TOTAL: Sum the scores for 10 items, if present. A score of 5 points is needed for the classification of Takayasu arteritis. 1Evidence of vasculitis in the aorta or branch arteries must be confirmed by vascular imaging (e.g., computed tomographiccatheterbasedmagnetic resonance angiography, ultrasonography, positron emission tomography). 2Bruit detected by auscultation of a large artery, including the aorta, carotid, subclavian, axillary, brachial, renal, or iliofemoral arteries. 3Reduction or absence of pulse by physical examination of the axillary, brachial, or radial arteries. 4Reduction or absence of pulse of the carotid artery or tenderness of the carotid artery. 5Number of arterial territories with luminal damage (e.g., stenosis, occlusion, or aneurysm) detected by angiography or ultrasonography from the following nine territories: thoracic aorta, abdominal aorta, mesenteric, left or right carotid, left or right subclavian, left or right renal arteries. 6Bilateral luminal damage (stenosis, occlusion, or aneurysm) detected by angiography or ultrasonography in any of the following paired vascular territories: carotid, subclavian, or renal arteries. 7Luminal damage (stenosis, occlusion, aneurysm) detected by angiography or ultrasonography involving the abdominal aorta and either the renal or mesenteric arteries. From Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology EULAR classification criteria for Takayasu arteritis. Ann Rheum Dis. 2022;81(12): 16541660. Fig. 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1560 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) 210.3 Polyarteritis Nodosa and Cutaneous Polyarteritis Nodosa Vidya Sivaraman, Edward C. Fels, and Stacy P. Ardoin Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis affect ing small and medium size arteries. Aneurysms and stenoses |
6,863 | form at irregular intervals throughout affected arteries. Cutaneous PAN is lim ited to the skin. EPIDEMIOLOGY PAN is rare in childhood. Males and females are equally affected, and the mean age at presentation is 9 years. The cause is unknown, but the development of PAN after infections, including group A streptococcus and chronic hepatitis B, suggests that PAN may represent a postinfec tious autoimmune response. Infections with other organisms, including Epstein Barr virus, Mycobacterium tuberculosis, cytomegalovirus, parvovi rus B19, and hepatitis C virus, have also been associated with PAN. There is a possible association between PAN and familial Mediterranean fever. PATHOLOGY Biopsies show necrotizing vasculitis with granulocytes and monocytes infiltrating the walls of small and medium size arteries. Involvement is usually segmental and tends to occur at vessel bifurcations. Granulomatous inflammation is not present, and deposition of complement and immune complexes is rarely observed. Different stages of inflammation are found, ranging from mild inflammatory changes to panmural fibrinoid necrosis associated with aneurysm formation, thrombosis, and vascular occlusion. PATHOGENESIS Immune complexes are believed to be pathogenic, but the mechanism is poorly understood. It is not known why PAN has a predilection for small and medium size blood vessels. The inflamed vessel wall becomes thickened and narrowed, impeding blood flow and contributing to end organ damage characteristic of this disease. Although there is no clear genetic association with PAN, PAN like vasculitis is a component of three recently described monogenic autoinflammatory conditions. Deficiency in adenosine deaminase 2 (DADA2), caused by muta tions in the CECR1 gene, causes a familial form of vasculitis with an autosomal recessive inheritance (see Chapter 204). CLINICAL MANIFESTATIONS The clinical presentation of PAN is variable but generally reflects the distribution of inflamed vessels. Constitutional symptoms are present in most children at disease onset. Weight loss and severe abdominal pain suggest mesenteric arterial inflammation and ischemia. Reno vascular arteritis can cause hypertension, hematuria, or proteinuria, although glomerulonephritis is not typical. Cutaneous manifestations include purpura, livedo reticularis, ulcerations, digital ischemia, and painful nodules (Fig. 210.6). Arteritis affecting the nervous system can result in cerebrovascular accidents, transient ischemic attacks, psycho sis, and ischemic motor or sensory peripheral neuropathy (mononeu ritis multiplex). Myocarditis or coronary arteritis can lead to heart failure and myocardial ischemia; pericarditis and arrhythmias have also been reported. Arthralgias, arthritis, or myalgias are frequently present. Less common symptoms include testicular pain that mimics testicular torsion, bone pain, and vision loss as a result of retinal arteri tis. The pulmonary vasculature is usually spared in PAN. DIAGNOSIS The diagnosis of PAN requires demonstration of vessel involvement on biopsy or angiography (Table 210.10). Biopsy of cutaneous lesions shows small or medium vessel vasculitis. Kidney biopsy in patients with renal manifestations may show necrotizing arteritis. Electromyography in children with peripheral neuropathy identifies affected nerves, and sural nerve biopsy may reveal vasculitis. Conventional arteriography is the gold standard diagnostic imaging study for PAN and reveals areas of aneurysmal dilation and segmental stenosis, the classic beads on a string appearance (Fig. 210.7). MRA and |
6,864 | CTA, less invasive imaging alternatives, are gaining acceptance but may not be as effective in iden tifying small vessel disease or in younger children. DIFFERENTIAL DIAGNOSIS Early skin lesions may resemble those of HSP, although the finding of nodular lesions and the presence of systemic features help distinguish PAN. Because pulmonary vascular involvement is very rare in PAN, pulmonary lesions suggest ANCA associated vasculitis or Goodpasture disease. Other rheumatic diseases, including SLE, have characteristic target organ involvement and associated autoantibodies distinguishing them from PAN. Prolonged fever and weight loss should also prompt consideration of inflammatory bowel disease or malignancy. Deficiency of DADA2 is a mimic of PAN and should be suspected in the presence of vasculitic rash (Fig. 210.8), hypogammaglobulinemia, cytopenias, and strokes. In addition, SAVI (STING associated vascu lopathy with onset in infancy) presents in infancy with ulcerating skin lesions that form eschars, cytopenias, interstitial lung disease, and fail ure to thrive (see Chapter 204). LABORATORY FINDINGS Nonspecific laboratory findings include elevations of ESR and CRP, anemia, leukocytosis, and hypergammaglobulinemia. Abnormal urine sediment, proteinuria, and hematuria indicate renal disease. Labora tory findings may be normal in cutaneous PAN or similar to those of systemic PAN. Elevated hepatic enzyme values may suggest hepatitis B or C infection. Serologic tests for hepatitis (hepatitis B surface antigen and hepatitis C antibody) should be performed in all patients. Fig. 210.6 Purpuric and necrotic lesions on the legs of a child with polyarteritis nodosa. (From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Fig. 34.1, p. 468.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1561 TREATMENT Oral prednisone (1 2 mgkgday) or IV pulse methylprednisolone (30 mgkgday) are the mainstay of therapy. Oral or IV cyclophospha mide is often used as adjunctive therapy, and plasma exchange may be warranted for life threatening disease. If hepatitis B is identified, appropriate antiviral therapy should be initiated (see Chapter 406). Most cases of cutaneous PAN can be treated with less intense therapy such as corticosteroids alone, nonsteroidal antiinflammatory drugs (NSAIDs), and methotrexate. Azathioprine, mycophenolate mofetil, IVIG, thalidomide, cyclosporine, and anti TNF agents such as inflix imab have all been reported as successful in the treatment of refractory cutaneous or systemic PAN. If an infectious trigger for PAN is identi fied, antibiotic prophylaxis can be considered. COMPLICATIONS Cutaneous nodules may ulcerate and become infected. Hypertension and chronic renal disease may develop from renovascular involvement in PAN. Cardiac involvement may lead to decreased cardiac func tion or coronary artery disease. Mesenteric vasculitis can predispose to bowel infarction, rupture, and malabsorption. Stroke and rupture of hepatic arterial aneurysm are uncommon complications of this disorder. PROGNOSIS The course of PAN varies from mild disease with few complications to a severe, multiorgan disease with high morbidity and mortality. Poor prog |
6,865 | nostic factors in PAN include elevated serum creatinine, proteinuria, severe GI involvement, cardiomyopathy, and CNS involvement. Early and aggressive immunosuppressive therapy increases the likelihood of clinical remission. Compared with disease in adults, childhood PAN is associated with less mortality. Cutaneous PAN is unlikely to transition to systemic disease. Early recognition and treatment of the disease are important to minimizing potential long term vascular complications. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 210.4 Antineutrophilic Cytoplasmic AntibodyAssociated Vasculitis Vidya Sivaraman, Edward C. Fels, and Stacy P. Ardoin The ANCA associated vasculitides are characterized by small vessel involvement, circulating ANCAs, and a paucity of immune complex deposition in affected tissues, thus the term pauci immune vascu litis. ANCA associated vasculitis is categorized into three distinct forms: granulomatosis with polyangiitis (GPA) (Table 210.11), Fig. 201.8 Retiform purpura in a child with deficiency of adenosine deaminase type 2. (From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021, Fig. 34.3, p. 469.) Table 210.10 Proposed Classification Criteria for Pediatric Onset Polyarteritis Nodosa CRITERION FINDINGS Histopathology Necrotizing vasculitis in medium or small arteries Angiographic abnormalities Angiography showing aneurysm, stenosis, or occlusion of medium or small artery not from noninflammatory cause Cutaneous findings Livedo reticularis, tender subcutaneous nodules, superficial skin ulcers, deep skin ulcers, digital necrosis, nail bed infarctions, or splinter hemorrhages Muscle involvement Myalgia or muscle tenderness Hypertension Systolic or diastolic blood pressure 95th percentile for height Peripheral neuropathy Sensory peripheral neuropathy, motor mononeuritis multiplex Renal involvement Proteinuria (300 mg24 hr equivalent), hematuria or red blood cell casts, impaired renal function (glomerular filtration rate 50 normal) The presence of five criteria provides 89.6 sensitivity and 99.6 specificity for the diagnosis of childhood onset polyarteritis nodosa. Adapted from Ozen S, Pistorio A, Iusan SM, et al: EULARPRINTOPRES criteria for Henoch Schnlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II. Final classification criteria. Ann Rheum Dis. 2010;69:798806. Fig. 210.7 Child with polyarteritis nodosa. Abdominal aortogram shows bilateral renal artery aneurysms (arrows), superior mesenteric artery aneurysm (asterisk), and left common iliac artery occlusion (ar rowhead). (Courtesy Dr. M. Hogan.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1562 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) formerly Wegener granulomatosis; microscopic polyangiitis (MPA) (Table 210.12); and eosinophilic granulomatosis with polyangiitis (Table 210.13), formerly Churg Strauss syndrome (CSS). The 2022 ACR EULAR classification criteria for adults with GPA, MPA and EGPA employ a criterionbased scoring system for classification of these vasculitides. EPIDEMIOLOGY GPA is a necrotizing, granulomatous, small and medium vessel vascu litis that occurs at all ages and targets the upper and lower respiratory tracts and the kidneys. Most cases of GPA occur in adults; the disease also occurs in children with a mean age at diagnosis of 14 years. There is a |
6,866 | female predominance of 3 4:1, and pediatric GPA is most prevalent in the White population. MPA is a small vessel necrotizing vasculitis with clinical features similar to those of GPA, but without granulomas and upper air way involvement. CSS is a small vessel necrotizing granulomatous (allergic granulomatosis) vasculitis associated with a history of refractory asthma and peripheral eosinophilia. MPA and CSS are rare in children, and there does not appear to be a gender predilec tion in either disease. PATHOLOGY Necrotizing vasculitis is the cardinal histologic feature in both GPA and MPA. Kidney biopsies typically demonstrate crescentic glomerulonephritis with little or no immune complex deposition (pauci immune), in contrast to biopsies from patients with SLE. Although granulomatous inflammation is common in GPA and CSS, it is typically not present in MPA. Biopsies showing peri vascular eosinophilic infiltrates distinguish CSS from both MPA and GPA. Table 210.12 Presenting Manifestations (Reported as Percentages) in Children with Granulomatosis with Polyangiitis and Microscopic Polyangiitis from the ARChiVe Cohort (n 231) CLINICAL FEATURE GPA (n 183) MPA (n 48) CONSTITUTIONALGENERAL 88 85 Malaise, fatigue 83 77 Fever 53 52 Weight loss 44 31 RENAL 83 75 Proteinuria 72 69 Hematuria 72 60 Biopsy proven glomerulonephritis 94 (101 of 108) 94 (30 of 32) Elevated serum creatinine 54 58 PULMONARY 74 44 Hemoptysisalveolar hemorrhage 42 15 Nodules 54 0 Fixed pulmonary infiltrates 36 0 Oxygen dependency 22 13 Pleurisy 14 8 Requiring ventilation 12 4 EAR, NOSE, THROAT 70 4 Nasal involvement 53 0 Sinusitis 39 0 Otitismastoiditis 17 0 Subglottic involvement 10 0 Hearing loss 10 0 Oral ulcers 15 4 MUSCULOSKELETAL 65 52 Arthralgiaarthritis 61 42 Myalgia, muscle weakness, or myositis 14 19 CUTANEOUS 47 52 Palpable purpurapetechia 27 31 EYES 43 31 Nonspecific red eye 10 2 Conjunctivitis 11 6 Scleritisepiscleritis 8 4 GASTROINTESTINAL 36 58 Nonspecific abdominal pain 22 38 Chronic nausea 12 33 NERVOUS SYSTEM 20 21 Severe headache 11 13 Dizziness 7 4 CARDIOVASCULAR 5 6 Arthralgias and arthritis at disease onset were not reported separately. GPA, Granulomatosis with polyangiitis; MPA, microscopic polyangiitis. From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Table 36.2, p. 487. Table 210.11 2022 American College of Rheumatology EULAR Classification Criteria for Granulomatosis with Polyangiitis Considerations when applying these criteria: These classification criteria should be applied to classify a patient as having granulomatosis with polyangiitis when a diagnosis of smallvessel or mediumvessel vasculitis has been made. Alternate diagnoses mimicking vasculitis should be excluded before applying the criteria. CLINICAL CRITERIA Nasal involvement: bloody discharge, ulcers, crusting, congestion, blockage, or septal defect perforation 3 Cartilaginous involvement (inflammation of ear or nose cartilage, hoarse voice or stridor, endobronchial involvement, or saddle nose deformity 2 Conductive or sensorineural hearing loss 1 LABORATORY, IMAGING, AND BIOPSY CRITERIA Positive test for cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) or antiproteinase 3 (antiPR3) antibodies 5 Pulmonary nodules, mass, or cavitation on chest imaging 2 Granuloma, extravascular granulomatous inflammation, or giant cells on biopsy 2 |
6,867 | Inflammation, consolidation, or effusion of the nasal paranasal sinuses, or mastoiditis on imaging 1 Pauciimmune glomerulonephritis on biopsy 1 Positive test for perinuclear antineutrophil cytoplasmic antibodies (pANCA) or antimyeloperoxidase (antiMPO) antibodies 1 Blood eosinophil count 1 109liter 4 TOTAL: Sum the scores for 10 items, if present. A score of 5 points is needed for the classification of granulomatosis with polyangiitis. From Robson JC, Grayson PC, Ponte C, et al. 2022 American College of RheumatologyEuropean Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis. 2022;81(3):315320. Fig. 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1563 PATHOGENESIS The etiology of ANCA associated vasculitis remains unknown, although neutrophils, monocytes, and endothelial cells are involved in disease pathogenesis. Neutrophils and monocytes are activated by ANCAs, specifically by the ANCA associated anti gens proteinase 3 (PR3) and myeloperoxidase (MPO), and release proinflammatory cytokines such as TNF and IL 8. Localization of these inflammatory cells to the endothelium results in vascular damage characteristic of the ANCA vasculitides. Why the respira tory tract and kidneys are preferential targets in GPA and MPA is unknown. CLINICAL MANIFESTATIONS The early disease course is characterized by nonspecific constitu tional symptoms, including fever, malaise, weight loss, myalgias, and arthralgias. In GPA, upper airway involvement can manifest as sinusitis, nasal ulceration, epistaxis, otitis media, and hearing loss. Lower respiratory tract symptoms in GPA include cough, wheez ing, dyspnea, and hemoptysis. Pulmonary hemorrhage can cause rapid respiratory failure. Compared with adults, childhood GPA is more frequently complicated by subglottic stenosis (Fig. 210.9). Inflammation induced damage to the nasal cartilage can produce a saddle nose deformity (see Fig. 210.9). Ophthalmic involvement includes conjunctivitis, scleritis, uveitis, optic neuritis, and inva sive orbital pseudotumor (causing proptosis). Perineural vasculi tis or direct compression on nerves by granulomatous lesions can cause cranial and peripheral neuropathies. Hematuria, proteinuria, and hypertension in GPA signal renal disease. Cutaneous lesions include palpable purpura and ulcers. Venous thromboembolism is a rare but potentially fatal complication of GPA. The frequencies of organ system involvement throughout the disease course in GPA are as follows: respiratory tract, 74; kidneys, 83; joints, 65; eyes, 43; skin, 47; sinuses, 70; and nervous system, 20. Table 210.11 lists the classification criteria for pediatric onset GPA. The clinical presentation of MPA closely resembles that of GPA, although sinus disease is less common; systemic features of fever, mal aise, weight loss, myalgias, and arthralgias may be dominant. MPA pre dominantly affects the kidney and lungs; other organ systems include skin, CNS, muscle, heart, and eyes (see Table 210.12). CSS frequently causes inflammation of the upper and lower respira tory tracts, but cartilage destruction is rare. CSS may initially demon strate chronic or recurrent rhinitissinusitis, nasal polyposis, nonfixed pulmonary lesions, and difficult to treat asthma. Eosinophilia (10 of leukocytes) with pulmonary infiltrates may precede |
6,868 | a vasculitic phase. Other organ involvement includes skin, cardiac, peripheral neu ropathy, GI tract, and muscle. Renal involvement in CSS is uncommon. DIAGNOSIS GPA should be considered in children who have recalcitrant sinusitis, pulmonary infiltrates, and evidence of nephritis. Chest radiography often fails to detect pulmonary lesions, and chest CT may show nod ules, ground glass opacities, mediastinal lymphadenopathy, and cavi tary lesions (Fig. 210.10). The diagnosis is confirmed by the presence of c ANCA with anti PR3 specificity (PR3 ANCAs) and the finding of nec rotizing granulomatous vasculitis on pulmonary, sinus, or renal biopsy. The ANCA test result is positive in approximately 90 of children with GPA, and the presence of anti PR3 increases the specificity of the test. In MPA, ANCAs are also frequently present (70 of patients) but are usually p ANCA with reactivity to MPO (MPO ANCAs). MPA can be distinguished from PAN by the presence of ANCAs and the tendency for small vessel involvement. The ANCA test result is positive in 5070 of cases of CSS, and MPO ANCAs are more common than PR3 ANCAs. In addition, the presence of chronic asthma and periph eral eosinophilia suggests the diagnosis of CSS. DIFFERENTIAL DIAGNOSIS ANCAs are absent in other granulomatous diseases, such as sarcoid osis and tuberculosis. Goodpasture syndrome is characterized by antibodies to glomerular basement membrane. Medications such as propylthiouracil, hydralazine, and minocycline are associated with drug induced ANCA (usually perinuclear ANCA) vasculitis. SLE and HSP can manifest as pulmonary hemorrhage and nephritis. LABORATORY FINDINGS Nonspecific laboratory abnormalities include elevated ESR and CRP values, leukocytosis, and thrombocytosis, which are present in most patients with an ANCA associated vasculitis but are nonspecific. Anemia may be caused by chronic inflammation or pulmonary hem orrhage. ANCA antibodies show two distinct immunofluorescence patterns: perinuclear (p ANCA) and cytoplasmic (c ANCA). In addition, ANCAs can be defined by their specificity for PR3 or MPO antigen. GPA is strongly associated with c ANCAsanti PR3 antibodies, whereas 75 of patients with MPA have a positive p ANCA. There is no clear correla tion between ANCA titers and disease activity or relapse. TREATMENT When the lower respiratory tract or kidneys are significantly involved, initial induction therapy usually consists of prednisone (oral 2 mg kgday oral or IV methylprednisolone 30 mgkgday 3 days) in con junction with daily oral or monthly IV cyclophosphamide. Rituximab, a monoclonal antibody to CD20 on activated B cells, is an option for induction therapy in ANCA positive vasculitides, although it has been studied primarily in adults. Plasmapheresis in conjunction with meth ylprednisolone has a role in the therapy of patients with severe disease manifestations such as pulmonary hemorrhage or ESRD, with the poten tial for reducing dialysis dependency. Patients are transitioned to a less toxic maintenance medication (usually methotrexate, azathioprine, or Table 210.13 American College of Rheumatology Criteria for Classification of Eosinophilic Granulomatosis with Polyangiitis Syndrome CRITERION DESCRIPTION Asthma History of wheezing or diffuse high pitched rales on expiration Eosinophilia Eosinophils 10 of differential white blood cell count History |
6,869 | of allergy History of seasonal allergy (e.g., allergic rhinitis) or documented allergies, including food, contactants, and others (except for drug allergies) Mononeuropathy or polyneuropathy Mononeuropathy, multiple mono neuropathies or polyneuropathy (i.e., glovestocking distribution) attributable to a systemic vasculitis Pulmonary infiltrates Migratory or transitory pulmonary infiltrates on radiographs attributable to a systemic vasculitis Paranasal sinus abnormality History of acute or chronic paranasal sinus pain or tenderness or radiographic opacification of the paranasal sinuses Extravascular eosinophils Biopsy including artery, arteriole, or venule, showing accumulation of eosinophils in extravascular areas For classification purposes, a patient is said to have EGPA if at least four of these criteria are present. The presence of any four or more criteria has a sensitivity of 85 and a specificity of 99.7. From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021, Fig. 36.7, p. 495. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1564 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) mycophenolate mofetil) within 3 6 months once remission is achieved. The Childhood Arthritis and Rheumatology Research Alliance has pub lished treatment guidelines for the induction and maintenance therapy of children with severe ANCA associated vasculitides consisting of induc tion therapy with cyclophosphamide or rituximab and maintenance therapy with rituximab, methotrexate, or azathioprine. Trimethoprim sulfamethoxazole (one 160 mg800 mg tablet 3 daysweek) is often pre scribed both for prophylaxis against Pneumocystis jirovecii infection and to reduce upper respiratory bacterial colonization with S. aureus, which may trigger disease activity. If disease is limited to the upper respiratory tract, corticosteroids (1 2 mgkgday) and methotrexate (0.5 1.0 mgkg week) may be first line treatment. Avacopan, a C5a receptor inhibitor, has been shown to be effective in reducing the need for corticosteroids in addition to standard therapy in adults with ANCA associated vasculitis but has not been studied in children. Mepolizumab, an antiIL 5 monoclonal antibody, may have a role in the treatment of eosinophilic granulomatosis with polyangiitis (CSS). COMPLICATIONS Upper respiratory tract lesions can invade the orbit and threaten the optic nerve, and lesions in the ear can cause permanent hearing loss. Respiratory complications include potentially life threatening pulmo nary hemorrhage and upper airway obstruction caused by subglottic stenosis. Chronic lung disease secondary to granulomatous inflamma tion, cavitary lesions, and scarring can predispose to infectious compli cations. Chronic glomerulonephritis may progress to ESRD in a subset of patients with advanced or undertreated disease. PROGNOSIS The course is variable, but disease relapse occurs in up to 60 of patients. Mortality has been reduced with the introduction of cyclo phosphamide and other immunosuppressive agents. Compared with adults, children are more likely to develop multiorgan involvement, renal involvement, and subglottic stenosis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. A CB Fig. 210.9 Adolescent with granulomatosis with polyangiitis. A and B, Anterior |
6,870 | and lateral views of saddle nose deformity. C, Segment of subglot tic posterior tracheal irregularity (between arrows) on lateral neck radiograph. A B Fig. 210.10 Radiographs of lower respiratory tract disease in granulomatosis with polyangiitis (GPA). A, Chest radiograph of 14 yr old girl with GPA and pulmonary hemorrhage. Extensive bilateral, fluffy infiltrates are visualized. B, Chest CT scan in 17 yr old boy with GPA. Air space consoli dation, septal thickening, and a single cavitary lesion are present. (A from Cassidy JT, Petty RE. Granulomatous vasculitis, giant cell arteritis and sarcoidosis. In Textbook of Pediatric Rheumatology, 3rd ed. Philadelphia: Saunders; 1995; B from Kuhn JP, Slovis TL, Haller JO. Caffeys Pediatric Diagnostic Imaging, 10th ed. Philadelphia: Mosby; 2004.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 210 u Vasculitis Syndromes 1565 210.5 Other Vasculitis Syndromes: Hypersensitivity, CNS, and COVID 19 Related Vidya Sivaraman, Edward C. Fels, and Stacy P. Ardoin Other vasculitic conditions can occur in childhood; the most common is Kawasaki disease (see Chapter 208). Behet disease is a rare form of vasculitis seen in children of Turkish and Mediterranean descent, char acterized by the triad of recurrent aphthous stomatitis, genital ulcers, and uveitis (see Chapter 202). Hypersensitivity vasculitis is a cutaneous vasculitis triggered by medication or toxin exposure. The rash consists of palpable pur pura or other nonspecific rash. Skin biopsies reveal characteristic changes of leukocytoclastic vasculitis (small vessels with neutro philic perivascular or extravascular neutrophilic infiltration) (Table 210.14). Hypocomplementemic urticarial vasculitis involves small vessels and manifests as recurrent urticaria that resolves over several days but leaves residual hyperpigmentation. This condition is associated with low levels of complement component C1q and systemic findings that include fever, GI symptoms, arthritis, and glomerulonephritis. Some patients with urticarial vasculitis have normal complement levels. Cryoglobulinemic vasculitis can com plicate mixed essential cryoglobulinemia and is a small vessel vas culitis affecting skin, joints, kidneys, and lungs. Primary angiitis of the central nervous system represents vas culitis confined to the CNS and requires exclusion of other systemic vasculitides. Large vessel disease (angiography positive) may be progressive or nonprogressive and may manifest with focal deficits similar to an occlusive stroke, with hemiparesis, focal gross or fine motor deficits, language disorders, or cranial nerve deficits. Diffuse cognitive, memory, and concentration deficits and behavioral dis orders are seen in 3040 of patients. Small vessel disease (angi ography negative, biopsy positive) more often results in language problems and diffuse deficits, such as cognitive, memory, behavior, and concentration problems, as well as focal seizures. In both types of cerebral angiitis, patients may have an elevated ESR or CRP and abnormal CSF findings (increased protein, pleocytosis), although these are not consistent findings in all patients. Diagnosis remains a challenge, and brain biopsy is often indicated to confirm the diag nosis and exclude vasculitis mimics such as infections that could worsen with immunosuppressive |
6,871 | therapy (Table 210.15). Table 210.15 Differential Diagnosis of Small Vessel Primary Central Nervous System (CNS) Vasculitis in Children CNS VASCULITIS COMPLICATING OTHER DISEASES Infections Bacterial: Mycobacterium tuberculosis, Mycoplasma pneumoniae, Streptococcus pneumoniae Viral: Epstein Barr virus, cytomegalovirus, enterovirus, varicella zoster virus, hepatitis C virus, parvovirus B19, West Nile virus Fungal: Candida albicans, Actinomyces, Aspergillus Spirochetal: Borrelia burgdorferi, Treponema pallidum Rheumatic and Inflammatory Diseases Systemic vasculitis such as granulomatosis with polyangiitis, microscopic polyangiitis, Henoch Schnlein purpura, Kawasaki disease, polyarteritis nodosa, Behet disease Systemic lupus erythematosus, juvenile dermatomyositis, morphea Inflammatory bowel disease Autoinflammatory syndromes Hemophagocytic lymphohistiocytosis Neurosarcoidosis Adenosine deaminase 2 deficiency Other Drug induced vasculitis Malignancy associated vasculitis NONVASCULITIS INFLAMMATORY BRAIN DISEASES Demyelinating Diseases Multiple sclerosis, acute demyelinating encephalomyelitis (ADEM), optic neuritis, transverse myelitis Antibody Mediated Inflammatory Brain Disease AntiNMDA receptor encephalitis, neuromyelitis optica (NMO), antibody associated limbic encephalitis (antibodies against LGI, AMP, AMP binding protein), Hashimoto encephalopathy, celiac disease, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) T CellAssociated Inflammatory Brain Disease Rasmussen encephalitis Other Febrile infection related epilepsy syndrome (FIRES) NONINFLAMMATORY VASCULOPATHIES Hemoglobinopathies (sickle cell disease), thromboembolic disease Radiation vasculopathy, graft versus host disease Metabolic and genetic diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), Moyamoya disease, Fabry disease Malignancy (lymphoma) Modified from Gowdie P, Twilt M, Benseler SM. Primary and secondary central nervous system vasculitis. J Child Neurol. 2012;27:14481459. Table 210.14 Criteria for Diagnosis of Hypersensitivity Vasculitis CRITERION DEFINITION Age at onset 16 yr Development of symptoms after 16 yr of age Medication at disease onset Medication that may have been a precipitating factor was taken at the onset of symptoms Palpable purpura Slightly elevated purpuric rash over one or more areas; does not blanch with pressure and is not related to thrombocytopenia Maculopapular rash Flat and raised lesions of various sizes over one or more areas of the skin Biopsy, including arteriole and venule Histologic changes showing granulocytes in a perivascular or extravascular location For purposes of classification, a patient is said to have hypersensitivity vasculitis if at least three of these criteria are present. The presence of three or more criteria has a diagnostic sensitivity of 71.0 and specificity of 83.9. The age criterion is not applicable for children. Adapted from Calabrese LH, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum. 1990;33:11081113, Table 2, p. 1110; and Petty RE, Laxer RM, Lindsley CB, Wedderburn LR. Textbook of Pediatric Rheumatology, 7th ed. Philadelphia: Saunders; 2016: Table 38.2, p. 511. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1566 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Nonprogressive angiography positive CNS vasculitis, also known as transient CNS angiopathy, represents a more benign |
6,872 | vari ant and can be seen after varicella infection. Cogan syndrome is rare in children; its potential clinical manifestations include con stitutional symptoms; inflammatory eye disease such as uveitis, episcleritis, or interstitial keratitis; vestibuloauditory dysfunction (vertigo, hearing loss, tinnitus); arthritis; and large vessel vasculitis or aortitis. Cerebral autosomal dominant arteriopathy with sub cortical infarcts and leukoencephalopathy (CADASIL) is caused by pathogenic variants in the NOTCH3 gene and manifests with stroke, mood changes, cognitive decline, and migraines; it is a vas culitis mimic and demonstrates osmophilic granules in cerebral arteries. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is another mimic of angiitis caused by pathogenic variants in the HTRA1 gene. It mani fests with early onset hair loss, spasticity, stroke, memory loss, and personality changes. Identification of these vasculitis syndromes requires a compre hensive history and physical examination. Table 210.16 outlines other diagnostic considerations. Although tailored to disease sever ity, treatment generally includes prednisone (up to 2 mgkgday). Potent immunosuppressive medications, such as cyclophospha mide, are often indicated, particularly in primary angiitis of the CNS to prevent rapid neurologic decline. For hypersensitivity vas culitis, withdrawal of the triggering medication or toxin is indicated if possible. COVID 19, including multisystem inflammatory syndrome in children (MIS C), has been associated with a variety of cutaneous lesions that resemble vasculitis, vasculopathy, and vasoocclusive etiologies (see Chapter 311) (Table 210.17, Fig. 210.11). Lesions include pernio (chilblain: COVID toes)like lesions suggestive of a vasculitis. Other cutaneous manifestations include urticarial vascu litis and livedo reticularislike or livedo racemosaboth resemble a pauci inflammatory occlusive vasculitis. Sweet syndrome and erythema multiformelike lesions have also been described. Most cutaneous lesions associated with known COVID 19 or MIS C do not require a biopsy, but some of those that were biopsied have demonstrated a leukocytoclastic vasculitis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. A B C D Fig. 210.11 Pernio like lesions in children. A, A child with purpuric papules on the first, second, fourth, and fifth right digits and second proxi mal left digit. B, Digits on the same child appearing with increased erythema. C, Right toes of a child appearing with pink and dusky papules and plaques, also involving the childs left digits (D). (From Neale H, Hawryluk EB. COVID 19 pediatric dermatology. Dermatol Clin. 2021;39:505519, Fig. 3, p. 511.) Table 210.16 Diagnostic Considerations for Other Vasculitis Syndromes VASCULITIS SYNDROME APPROACH TO DIAGNOSIS Hypersensitivity vasculitis Skin biopsy demonstrating leukocytoclastic vasculitis Hypocomplementemic urticarial vasculitis Biopsy of affected tissue demonstrating small vessel vasculitis Low levels of circulating C1q Cryoglobulinemic vasculitis Biopsy of affected tissue demonstrating small vessel vasculitis Measurement of serum cryoglobulins Exclusion of hepatitides B and C infections Primary angiitis of CNS Conventional, CT, or MRA evidence of CNS vasculitis Consideration of dura or brain biopsy Nonprogressive angiography positive CNS vasculitis Conventional, CT, or MRA evidence of CNS vasculitis Cogan syndrome Ophthalmology and audiology evaluations Conventional, CT, or MRA evidence of CNS or aortic vasculitis Table 210.17 Acral and Nonacral Potential Cutaneous Manifestations of Pediatric COVID 19 |
6,873 | ACRAL NONACRAL Pernio like lesions EM like lesions Plantar papules Retiform purpura Ecchymotic like lesions Livedo reticularis Urticaria Erythematous patches EM like lesions Vesiclespapulovesicles Herpetiform oral eruption Roseola like rash Maculopapular rash Macular eruption Lingual papillitis Eccrine hidradenitis Erythema nodosum Petechiae Purpura Modified from Neale H, Hawryluk EB. COVID 19 pediatric dermatology. Dermatol Clin. 2021;39:505519, Table 4, p. 513. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 211 u Musculoskeletal Pain Syndromes 1567 Musculoskeletal pain is a frequent reason for children to visit a health care provider and is the most common problem referred to pediatric rheumatology clinics. Prevalence estimates of persistent musculoskel etal pain in community samples range from 10 to 40. Although inflammatory diseases such as juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are associated with musculoskel etal pain, noninflammatory conditions such as trauma, hypermobil ity, overuse, and idiopathic pain syndromes are much more common causes of musculoskeletal pain in children. CLINICAL MANIFESTATIONS Acute and subacute musculoskeletal pain in children is most com monly the result of trauma, overuse, hypermobility, or some combi nation of these. The history and physical findings of trauma are most often readily apparent, and the pain associated with overuse or hyper mobility is most often described as related to activities and improving with rest. The physical examination of children with pain related to overuse, hypermobility, and other mechanical causes of pain does not reveal signs of inflammation such as warmth, swelling, or limited range of motion and most often reveals hypermobility with perhaps mild ten derness over tendons and their insertion points. Chronic idiopathic musculoskeletal pain syndromes are defined by pain of at least 3 months duration in the absence of objective abnor malities on physical examination or laboratory screening (see Chapter 212). The prevalence of chronic idiopathic musculoskeletal pain syn dromes increases with age and is higher in females. These syndromes often persist despite treatment with nonsteroidal antiinflammatory drugs (NSAIDs) and other analgesics. Chronic pain may occur any where and is most often diffuse and poorly localized, but may some times involve only a single extremity or part of an extremity. Pain may start in one location before potentially developing in other areas over time. Psychologic and emotional distress, including anxiety, depres sion, stress, or a combination of these, is quite common in those with chronic idiopathic musculoskeletal pain syndromes. Frequent cry ing, school and social stress, poor concentration, and excessive worry are often described. Sleep disturbance in children with chronic pain syndromes may include difficulty falling asleep, multiple night awak enings, disrupted sleep wake cycles with increased daytime sleeping, nonrestorative sleep, and fatigue. Children who are high achievers, excellent students, mature, and responsible, with high expectations of themselves have a predisposition to the development of pain syndromes in general, including chronic musculoskeletal pain. As a result, headaches and abdominal pain or other |
6,874 | gastrointestinal symptoms are also frequently present in those with chronic idiopathic musculoskeletal pain syndromes. The constellation of chronic pain, psychologic distress, and sleep dis turbance often leads to a high degree of functional impairment. Poor school attendance is common, and children may struggle to complete other daily activities relating to self care and participation in household chores. Decreased physical fitness can also occur, along with changes in gait and posture, as children avoid the use of the area affected by pain. Peer relationships may also be disrupted by decreased opportunities for social interaction because of pain. Loneliness and social isolation characterized by few friends and lack of participation in extracurricu lar activities are common. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of a musculoskeletal pain syndrome is based primar ily on history and physical examination. Children with pain require a thorough clinical history, including a complete social history and review of systems, and a careful, comprehensive physical examination. The specific characteristics of the pain should be defined, evidence of potential systemic disease should be sought, and any additional associ ated symptoms and signs should be elicited. The need for laboratory testing and imaging studies should be indi vidualized, depending on the information elicited in the history and discovered with the physical examination. Possible indicators of an inflammatory cause for musculoskeletal pain include objective joint warmth, swelling, limited range of joint motion on physical examina tion, localized bone tenderness, and muscle weakness; potential indica tors of a systemic disease include poor linear growth, weight loss, and constitutional symptoms. The lack of these symptoms and objective abnormalities on physical examination is more suggestive of a non inflammatory cause for pain (Table 211.1). The complete blood count (CBC) and erythrocyte sedimentation rate (ESR) are often abnormal in children whose pain is secondary to a bone or joint infection, rheu matic disease, or a malignancy. Bone tumors, fractures, and other focal pathology resulting from infection, malignancy, or trauma can often be identified through imaging studies, including plain radiographs or MRI. The presence of chronic, persistent pain, accompanied by psycho logic distress, sleep disturbance, andor functional impairment, in the absence of objective laboratory or physical examination abnormali ties, suggests the diagnosis of an idiopathic musculoskeletal pain syndrome. Table 211.2 outlines common causes of pediatric muscu loskeletal pain according to anatomic location, including growing pains (see Chapter 211.1), diffuse amplified pain syndromes and chronic widespread pain (see Chapter 211.3), complex regional pain syndrome (see Chapter 211.4), localized pain syndromes, low back pain, and chronic overuse related pain (e.g., Osgood Schlatter dis ease). A differential diagnosis of more serious conditions is noted in Table 211.3. TREATMENT The primary goal of treatment for acute and subacute musculoskele tal pain related to trauma, hypermobility, overuse, or other mechan ical factors is to minimize the discomfort as much as possible and to promote normal activities. Rest, topical analgesics, mechanical joint support to be worn with activities, ice, oral analgesics, and physical therapy may all be used. Education of children and families |
6,875 | regard ing pain related to these mechanical factors is critical in helping them to understand what to expect. Although it is common for the discomfort related to hypermobility and overuse to be recurrent, the prognosis for these mechanical pains is excellent, and most children learn to manage their discomfort with few, if any, restrictions on activities. The primary goal of treatment of chronic idiopathic musculoskel etal pain syndromes is to improve function and relieve pain; these outcomes may not occur simultaneously or quickly. Pain may persist even as children resume normal function (e.g., increased school atten dance and participation in extracurricular activities). For all children and adolescents with pediatric musculoskeletal pain syndromes whose school attendance has been affected by their symptoms, regular school attendance is a primary initial goal. The dual nature of treatment, tar geting both function and pain, needs to be clearly explained. Children and families need to be supported in disengaging from the sole pursuit of pain relief and embracing the equally imperative goal of improved functioning. Recommended treatment modalities include physical andor occupa tional therapy, pharmacologic interventions, and cognitive behavioral andor other psychotherapeutic interventions. The overarching goal of physical therapy is to improve childrens physical function and should emphasize participation in aggressive but graduated aerobic exercise. Pharmacologic interventions should be used judiciously. Low dose Chapter 211 Musculoskeletal Pain Syndromes James J. Nocton Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1568 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) tricyclic antidepressants (amitriptyline 0.1 mgkg at bedtime; can increase to 0.5 to 2 mgkg as tolerated) may improve sleep; selective serotonin reuptake inhibitors (sertraline 25 100 mg daily) may help to alleviate symptoms of depression and anxiety if present. Cognitive behavioral therapy (CBT) andor other psychotherapeutic interven tions are designed to teach children and adolescents coping skills for controlling the behavioral, cognitive, and physiologic responses to pain. Specific components often include cognitive restructuring, relax ation, distraction, and problem solving skills. Parent education and involvement in the psychologic intervention are important to ensure maintenance of progress. More intensive family based approaches are warranted if barriers to treatment success are identified at the family level. These could include parenting strategies or family dynamics that serve to maintain childrens pain complaints, such as overly solicitous responses to the childs pain and maladaptive models for coping with pain. COMPLICATIONS AND PROGNOSIS Musculoskeletal pain related to hypermobility andor overuse may be recurrent and related to specific activities, but is typically mild, does not usually significantly limit activities, and is most often managed symptomatically. Conversely, chronic idiopathic musculoskeletal pain syndromes have a much greater potential to negatively affect develop ment and future role functioning. Worsening pain and the symptoms of depression and anxiety associated with chronic pain can lead to substantial school absences, peer isolation, and developmental delays later in adolescence and |
6,876 | early adulthood. Specifically, adolescents with chronic idiopathic musculoskeletal pain syndromes may fail to achieve the level of autonomy and independence necessary for age appropriate activities, such as attending college, living away from home, and main taining a job. Fortunately, not all children and adolescents with these syndromes experience this degree of impairment. Factors that contrib ute to the persistence of pain are increasingly understood and include female gender, pubertal stage at pain onset, older age of pain onset, increased psychologic distress associated with the pain, and greater functional impairment. The likelihood of positive health outcomes is increased with multidisciplinary treatment addressing the pain, the functional disabilities, and the psychologic comorbidities associated with pain. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 211.2 Common Musculoskeletal Pain Syndromes in Children by Anatomic Region ANATOMIC REGION PAIN SYNDROMES Shoulder Impingement syndrome Elbow Little League elbow Avulsion fractures Osteochondritis dissecans Tennis elbow Panner disease Arm Localized hypermobility syndrome Complex regional pain syndrome Pelvis and hip Avulsion injuries Legg Calv Perthes syndrome Slipped capital femoral epiphysis Congenital hip dysplasia Knee Osteochondritis dissecans Osgood Schlatter disease Sinding Larsen syndrome Patellofemoral syndrome Malalignment syndromes Leg Growing pains Complex regional pain syndrome Localized hypermobility syndrome Shin splints Stress fractures Compartment syndromes Foot Plantar fasciitis Tarsal coalition Stress fractures Achilles tendonitis Juvenile bunion Spine Musculoskeletal strain Spondylolisthesis Spondylolysis Scoliosis Scheuermann disease (kyphosis) Low back pain Generalized Hypermobility syndrome Diffuse amplified pain syndrome Chronic widespread pain Adapted from Anthony KK, Schanberg LE. Assessment and management of pain syndromes and arthritis pain in children and adolescents. Rheum Dis Clin North Am. 2007;33:625660, Box 1. Table 211.1 Potential Indicators of Inflammatory vs Noninflammatory Causes of Musculoskeletal Pain CLINICAL FINDING NONINFLAMMATORY INFLAMMATORY Effects of rest vs activity on pain Relieved by rest and worsened by activity Present at rest and may be relieved by activity Time of day pain andor stiffness occurs End of the day and nights Morning Objective joint swelling No Yes Joint characteristics Hypermobilenormal Stiffness, limited range of motion Bone tenderness No Possible Muscle strength Normal Possible weakness Gait Normal Limp Growth Normal growth pattern or weight gain Poor growth andor weight loss Constitutional symptoms Fatigue without other constitutional symptoms Possible Laboratory findings Normal CBC, ESR, CRP Abnormal CBC, raised ESR and CRP Imaging findings Normal Effusion, osteopenia, radiolucent metaphyseal lines, joint space loss, bone destruction Cancer pain is often severe and worst at night. CBC, Complete blood count; CRP, C reactive protein level; ESR, erythrocyte sedimentation rate. Data from Malleson PN, Beauchamp RD. Diagnosing musculoskeletal pain in children. CMAJ 2001;165:183188. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 211 u Musculoskeletal Pain Syndromes 1569 211.1 Growing Pains (Benign Limb Pain of Childhood) James J. Nocton The cause of benign limb pain of childhood, historically referred to as growing pains, is unknown. Low pain threshold, overuse, and behavioral causes have been postulated, and |
6,877 | it is possible that there are multiple causes for these pains. This pain affects 1020 of children, with peak incidence between age 4 and 12 years. Benign limb pains of childhood are intermittent and usually bilateral, poorly localized, and predominantly affecting the anterior thigh, shin, and calf. Occasionally, bilateral upper extremity pain may be associated with leg pain. Chil dren typically describe cramping or aching that occurs most often in the late afternoon or evening. Pain may wake the child from sleep, may be severe, and may last a few minutes to hours, but typically resolves quickly with massage or analgesics; pain is nearly always resolved by the following morning (Table 211.4). Pain may often follow a day with increased or excessive physical activity. Physical examination is nor mal, and gait is not impaired. Treatment should focus on reassurance, education, and healthy sleep hygiene while preparing parents and children for the possibility that the pain may occur intermittently for years, with eventual reso lution. Massage, acetaminophen, or NSAIDs during the episode are nearly always effective. Restless legs syndrome (RLS), seen more frequently among ado lescents and adults, is a sensorimotor disturbance that may be con fused with growing pains (see Chapter 31). Often familial, RLS is a difficult to control urge to move the leg that is exacerbated during rest and at night and is relieved by movement (see Table 211.4). There is significant overlap in the diagnostic features of growing pains and RLS. Moreover, these conditions can be comorbid, and there is a high incidence of RLS in the parents of children with growing pains. RLS appears to be best distinguished from growing pains by the urge to move the legs, associated uncomfortable leg sensations that may not be described as painful; worsening with periods of rest; and relief through movement. Iron supplementation may benefit pediatric patients with RLS. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 211.2 Small Fiber Polyneuropathy James J. Nocton Some patients with juvenile onset widespread pain syndromes have evidence of a small fiber polyneuropathy causing dysfunctional or degeneration of small diameter unmyelinated C fibers and thinly myelinated A delta fibers that mediate nociception and the autonomic nervous system. In addition to pain, these children may have dizziness, postural orthostatic tachycardia syndrome (POTS), constipation and or gastrointestinal dysmotility, and other symptoms suggestive of dys autonomia (Fig. 211.1). The diagnosis of small fiber polyneuropathy requires distal leg immunolabeled skin biopsy to identify epidermal nociceptive fibers and autonomic function testing to examine cardiovagal, adrenergic, and sudomotor small fiber function. Genetic testing for pathogenic variants in genes coding for sodium channels may reveal SCN9A, SCN10A, or SCN11A variants. Some small studies have reported the presence of autoantibodies to trisulfated disaccharide and fibroblast growth factor receptor 3, suggestive of immune mediated pathogen esis. Other potential etiologies for small fiber neuropathy are noted in Table 211.5; most cases are idiopathic. In addition, other genetic pain ful neuropathies should be considered (Table 211.6). Optimal treatment of patients with small fiber polyneuropathy is |
6,878 | unknown. Corticosteroids and intravenous immune globulin have been effective in very small numbers of patients. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 211.3 Diffuse Amplified Pain Syndromes James J. Nocton Diffuse amplified pain syndrome is more common in children than localized amplified pain. In addition to widespread pain, children fre quently have associated chronic fatigue, sleep disturbance, headaches, chronic abdominal pain and gastrointestinal symptoms, stress, anxi ety, andor symptoms of depression (see also Chapter 212). The terms diffuse amplified pain syndrome, chronic widespread pain syndrome, chronic myofascial pain syndrome, and juvenile primary fibromyalgia syndrome are often used to describe the same constellation of symp toms. Some of these children have findings that fulfill the criteria that have been developed for adult patients with fibromyalgia by either the American College of Rheumatology (Table 211.7) or the Analge sic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks American Pain Society (Table 211.8 and Table 211.3 Differential Diagnosis of Idiopathic Musculoskeletal Pain Syndrome CHANNELOPATHIES Erythromelalgia: primary (associated with the SCN9A gene) or secondary Paroxysmal extreme pain disorder (SCN9A gene) Small fiber neuropathy (SCN9A, SCN1OA genes) Familial episodic pain syndrome (SCN11A, TRPA1 genes) CONNECTIVE TISSUE DISORDERS Ehlers Danlos syndrome Marfan syndrome IMMUNEAUTOIMMUNE Systemic lupus erythematosus Sarcoidosis Juvenile idiopathic arthritis Sjgren syndrome Familial Mediterranean fever and other autoinflammatory recurrent fever syndromes Hereditary angioedema Chronic nonbacterial osteomyelitis Mononeuritis multiplex associated with vasculitis METABOLICNUTRITION Fabry disease Gaucher disease Porphyria Mitochondrial neuropathies Vitamin deficiency (thiamine, B12, C, D) X linked adrenoleukodystrophy OTHER Guillain Barr syndrome Multiple sclerosis Toxic: lead, arsenic, chemotherapy HIV Familial amyloid neuropathy Complex regional pain syndrome types 1 and 2 Sickle cell anemia Thalamic stroke Primary, metastatic, or recurrent malignancy (acute lymphocytic leukemia, neuroblastoma) Neurofibromatosis Radiculopathy Nerve entrapment syndromes 1. Peroneal 2. Suprascapular 3. Anterior, posterior hip 4. Anterior cutaneous nerve (abdominal) From Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023: Table 33.2, p. 547. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1570 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Fig. 211.2). Separate criteria for the diagnosis of juvenile primary fibro myalgia syndrome in children have been proposed, but these have not been validated (Table 211.9). The evaluation of fibromyalgia tender points has not been useful or diagnostic. Although the precise cause of diffuse amplified pain is unknown, there is an emerging understanding that the development and main tenance of chronic pain are related both to biologic and psychologic factors. Diffuse amplified pain likely has multifactorial causes and is hypothesized to be an abnormality of central pain processing associated with disordered sleep physiology, enhanced pain perception, disor dered mood, and dysregulation of hypothalamic pituitary adrenal and other neuroendocrine axes, resulting in lower pain thresholds and increased pain sensitivity. Children and adolescents with diffuse amplified pain often find themselves in |
6,879 | a vicious cycle of pain, where symptoms build on one another and contribute to the onset and main tenance of new symptoms. Diffuse amplified pain has a chronic course that can detrimen tally affect child health and development. Adolescents who do not Table 211.4 Inclusion and Exclusion Criteria for Growing Pains Including Features of Restless Legs Syndromes (RLS) INCLUSIONS EXCLUSIONS RLS FEATURES Nature of pain Intermittent; some pain free days and nights, deep aching, cramping Persistent; increasing intensity, pain during the day Urge to move legs often accompanied by unpleasant sensations in legs, but may not be painful Unilateral or bilateral Bilateral Unilateral Location of pain Anterior thigh, calf, posterior kneein muscles not the joints Articular, back, or groin pain Urge to move and discomfort throughout leg Onset of pain Late afternoon or evening Pain still present next morning Worse later in day or night but also present at periods of rest or inactivity throughout the day Physical findings Normal Swelling, erythema, tenderness; local trauma or infection; reduced joint range of motion; limping, fever, weight loss, mass Laboratory findings Normal Objective evidence of abnormalities; increased erythrocyte sedimentation rate or C reactive protein; abnormal complete blood count, radiography, bone scan, or MRI Adapted from Evans AM, Scutter SD. Prevalence of growing pains in young children. J Pediatr. 2004;145:255258; and Walters AS, Gabelia D, Frauscher B. Restless legs syndrome (Willis Ekbom disease) and growing pains: are they the same thing? A side by side comparison of the diagnostic criteria for both and recommendations for future research. Sleep Med. 2013;14:12471252. Small fiber neuropathy Autonomic symptomsPain Small fiber sodium channel dysfunction Cramps Muscle pain Cognitive dysfunction Sleep disturbances Fatigue Irritable bowel syndrome Wide spread pain Burning Tingling Stabbing Numbness Gl symptoms Heart rate dysregulation Temperature sensitivities Small fiber mediated widespread pain Small fiber mediated painful neuropathy Muscle cramps Fibromyalgia Small fiber mediated autonomic dysfunction Erythromelalgia and paroxysmal extreme pain syndrome Fig. 211.1 Small fiber neuropathy symptom clusters and neuropathy classifications. (From Levine TD. Small fiber neuropathy: disease classification beyond pain and burning. J Central Nervous Sys Dis. 2018;10:16, Fig. 1, p. 3). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 211 u Musculoskeletal Pain Syndromes 1571 receive treatment or who are inadequately treated may withdraw from school and the social milieu, complicating their transition to adulthood. Treatment of diffuse amplified pain is ideally multidis ciplinary. The major goals are to restore function and alleviate pain and to improve comorbid mood and sleep disorders. Treatment strat egies include parentchild education, pharmacologic interventions, exercise based interventions, and psychologic interventions. Gradu ated aerobic exercise is the recommended exercise based interven tion, whereas psychologic interventions should include training in pain coping skills, stress management skills, emotional support, and sleep hygiene. CBT is particularly effective in reducing symptoms of depression in children and adolescents with chronic pain and helps to reduce functional |
6,880 | disability. Drug therapies, although largely unsuccessful in isolation, may include tricyclic antidepressants (amitriptyline 0.1 mgkg at bedtime; can increase to 0.5 to 2 mgkg as tolerated), selective serotonin reup take inhibitors (sertraline 25 100 mg daily), and anticonvulsants. Pre gabalin and duloxetine hydrochloride are approved by the U.S. Food and Drug Administration (FDA) for treatment of fibromyalgia in adults (18 years of age); however, data regarding the efficacy of these medications in children are limited. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 211.4 Complex Regional Pain Syndrome James J. Nocton Complex regional pain syndrome (CRPS) is characterized by chronic, persistent limb pain, often burning in character. CRPS type 1, also termed reflex sympathetic dystrophy, has no evidence of nerve injury, whereas the less common CRPS type 2 is associated with a known mechanism of nerve injury. The pain of CRPS is typically extreme and disproportionate to the inciting event. Associated features include allo dynia (a heightened pain response to normally non noxious stimuli), hyperalgesia (exaggerated pain reactivity to noxious stimuli), swell ing of the affected extremity, and indicators of autonomic dysfunction (cyanosis, mottling, hyperhidrosis). There are no diagnostic criteria specifically for pediatric CRPS; in adults, several sets of criteria have been developed (Table 211.10); the clinical utility of these criteria is controversial. The diagnosis of CRPS is clinical and can be made when continuous pain is present that is dis proportionate to any potential inciting event with associated allodynia, or hyperalgesia, evidence of edema, skin blood flow abnormalities, or excessive sweating activity, and exclusion of other disorders. Other fea tures that may be present include atrophy of hair or nails, loss of joint mobility, weakness, tremor, and dystonia. Although many pediatric patients with CRPS present with a history of minor trauma or repeated stress injury (e.g., caused by competitive sports), a significant proportion are unable to identify a precipitating event. Usual age of onset is between 8 and 16 years, and females out number males with the disease by as much as 6:1. Childhood CRPS differs from the adult form in that lower extremities, rather than upper extremities, are most often affected. The incidence of CRPS in children is unknown, largely because it is often undiagnosed or diag nosed late. Left untreated, CRPS can have severe consequences for children, including bone demineralization, muscle wasting, and joint contractures. The treatment of CRPS, like that of more diffuse pain syndromes, is ideally multidisciplinary. Aggressive physical therapy (PT) should be initiated as soon as the diagnosis is made, and CBT added as needed. PT is recommended three to four times a week, and children may need analgesic premedication at the onset, particularly before PT sessions. PT is initially limited to desensitization and then moves to weight bear ing, range of motion, and other functional activities. CBT used as an adjunctive therapy targets psychosocial obstacles to fully participating in PT and provides pain coping skills training. The goal of both phar macologic and adjunctive treatments for CRPS is to provide sufficient pain relief to |
6,881 | allow the child to participate in aggressive physical reha bilitation. Multiple studies have shown that noninvasive treatments, particularly PT and CBT, are at least as efficacious as nerve blocks in helping children with CRPS achieve resolution of their symptoms. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 211.5 Erythromelalgia James J. Nocton Children with erythromelalgia experience episodes of intense burning pain, erythema, edema, and heat, most often in the hands and feet (Fig. 211.3) and less frequently in other locations. Symptoms are most often triggered by exposure to heat or exercise and typically last for hours to days. Erythromelalgia is more common in females during adolescence, and the diagnosis is often delayed for many years. Although many cases are sporadic, an autosomal dominant hereditary form results most often from gain of function pathogenic variants of the SCN9A gene, which encodes the alpha subunit of the sodium channel NaV1.7 found in nociceptive neurons that transmit pain signals. Age of onset for the Table 211.5 Causes of Small Fiber Neuropathy PRIMARY SECONDARY IDIOPATHIC Idiopathic small fiber neuropathy Burning mouth syndrome METABOLIC Impaired glucose tolerance Diabetes mellitus Rapid glycemic control Vitamin B12 deficiency Dyslipidemia Hypothyroidism Chronic kidney disease HEREDITARYGENETIC Familial amyloid polyneuropathy Fabry disease Tangier disease Sodium channelopathies (see text) INFECTIONS HIV Hepatitis C Influenza TOXINS AND DRUGS Antiretrovirals Antibioticsmetronidazole, nitrofurantoin, linezolid Chemotherapybortezomib Flecainide Statin Alcohol Vitamin B6 toxicity IMMUNE MEDIATED Celiac disease Sarcoidosis Sjgren syndrome Rheumatoid arthritis Systemic lupus erythematosus Vasculitis Inflammatory bowel disease Paraneoplastic Monoclonal gammopathy amyloid Note that a number of these conditions may present as a small fiber neuropathy and then evolve to include large fibers. Modified from Themistocleous AC, Ramirez JD, Serra J, Bennett DLH. The clinical approach to small fibre neuropathy and painful channelopathy. Pract Neurol. 2014;14:368379, Table 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1572 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) familial form ranges from 1 to 16 years. Secondary erythromelalgia is associated with many disorders, including myeloproliferative dis eases, peripheral neuropathies, frostbite, and rheumatic diseases. The differential diagnosis includes Fabry disease, Raynaud phenomenon or disease, reflex sympathetic dystrophy, and peripheral neuropathies. In contrast to Raynaud phenomenon, the pain in erythromelalgia is relieved by cooling the affected area. Treatment includes avoidance of heat exposure and other precipitating situations and the use of cool ing techniques that do not cause tissue damage during attacks. There is no proven reliably efficacious treatment, and NSAIDs, narcotics, anesthetic agents (lidocaine patch), anticonvulsants (oxcarbazepine, carbamazepine, gabapentin), antidepressants, sodium nitroprusside, magnesium, mexiletine, and misoprostol, as well as biofeedback, medi cal and surgical nerve blocks, and hypnosis have had variable efficacy. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 211.6 Clinical Features of Human Disorders Caused by Pathogenic Gene Variants in Ion Channel Genes that Lead to Altered Pain Perception and Are Inherited in a Mendelian Manner GENE (PROTEIN) |
6,882 | TYPE AND EFFECT OF GENE VARIANT MAIN PHENOTYPE ADDITIONAL FEATURES Inherited erythromelalgia SCN9A (Nav1.7) Heterozygous, activating Onset by age 20 yr; episodic pain triggered by warmth; feet affected more frequently than hands Erythema of feet Paroxysmal extreme pain disorder SCN9A (Nav1.7) Heterozygous, activating Onset at birth; episodic pain; sacral region is affected most frequently; face is affected more often than the limbs; physical triggers include defecation Erythema of the sacrum; tonic attacks Small fiber neuropathy SCN9A (Nav1.7) Heterozygous, activating Onset at any age but more common in early adulthood; persistent burning pain; feet affected more frequently than hands Could be autonomic features Small fiber neuropathy SCN10A (Nav1.8) Heterozygous, activating Persistent burning pain Could be autonomic features Familial episodic pain syndrome type I TRPA1 (TRPA1) Heterozygous, activating Onset at birth or in infancy; episodic chest or arm pain; triggers are hunger and cold Familial episodic pain syndrome type III SCN11A (Nav1.9) Heterozygous, activating Onset in first decade; episodic hand and foot pain; triggers are intercurrent illness or exercise Nav, Sodium ion channel. Modified from Bennett DLH, Woods CG. Painful and painless channelopathies. Lancet Neurol. 2014;13:587599, Table 1. Table 211.7 American College of Rheumatology Fibromyalgia Diagnostic Criteria (2016 Revision) The following three conditions must be met: 1. Widespread Pain Index (WPI) 7 and Symptom Severity Scale (SSS) score 5 or WPI 4 6 and SSS score 9. 2. Generalized pain, defined as pain in at least four of five regions, must be present. Jaw, chest, and abdominal pain are not included in generalized pain definition. 3. Symptoms have been generally present for at least 3 mo. ASCERTAINMENT OF WPI The WPI is the number of areas in which a patient has had pain over the last week. The score will be between 0 and 19: Left Upper Region: left jaw, left shoulder girdle, left upper arm, left lower arm; Right Upper Region: right jaw, right shoulder girdle, right upper arm, right lower arm; Left Lower Region: left hip (buttock, trochanter), left upper leg, left lower leg; Right Lower Region: right hip (buttock, trochanter), right upper leg, right lower leg; Axial Region: chest, abdomen, upper back, lower back, and neck. ASCERTAINMENT OF SSS SCORE The SSS score is the sum of the severity of three symptoms (fatigue, waking unrefreshed, and cognitive symptoms) over the past week (each given a score from 0 to 3) plus the sum of the number of the following symptoms the patient has been bothered by that occurred during the previous 6 mo: headaches, pain or cramps in the lower abdomen, and depression (each given a score from 0 to 1). The final score will be between 0 and 12. For fatigue, waking unrefreshed, and cognitive symptoms, the level of severity over the past week is rated using the following scale: 0 No problem 1 Slight or mild problems, generally mild or intermittent 2 Moderate, considerable problems, often present andor at a moderate level 3 Severe: pervasive, continuous, life disturbing problems For headaches, pain or cramps in the lower |
6,883 | abdomen, and depression, the severity for each is scored as 0 or 1. Adapted from Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2016 Revisions to the 20102011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46(3):319329. Table 211.8 Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks American Pain Society Pain Taxonomy (AAPT) Fibromyalgia Diagnostic Criteria Core diagnostic criteria: 1. Musculoskeletal pain defined as 6 or more pain sites from a total of 19 possible sites (see Fig. 211.2) 2. Moderate to severe sleep problems OR fatigue 3. Musculoskeletal pain plus fatigue or sleep problems must have been present for at least 3 mo NOTE: The presence of another pain disorder or related symptoms does not rule out a diagnosis of fibromyalgia. However, a clinical assessment is recommended to evaluate for any condition that could fully account for the patients symptoms or contribute to the severity of the symptoms. Adapted from Arnold LM, Bennett RM, Crofford LJ, et al. AAPT Diagnostic Criteria for Fibromyalgia. J Pain. 2019;20:611628. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 211 u Musculoskeletal Pain Syndromes 1573 Fig. 211.2 Widespread pain index. (Modified from Fraix M. Fibro myalgia. In Tallia AF, Scherger JE, Dickey NW (eds). Swansons Family Medicine Review, 9th ed. Philadelphia: Elsevier, 2022. Fig 47.1.) Widespread Pain Index (1 point per circle; score range: 019 points) Please indicate if you have had pain or tenderness during the past 7 days in the areas shown below. Fill in the circles on the diagram for each area in which you have had pain or tenderness. Right jaw Left jaw Neck Chest or breast Abdomen Upper back Lower back Right shoulder Left shoulder Right upper arm Right lower arm Left lower arm Right upper leg Left upper leg Right hip or buttocks Left hip or buttocks Right lower leg Left lower leg Left upp r arm Left shoulder Table 211.9 Suggested Diagnostic Criteria for Juvenile Primary Fibromyalgia Syndrome (JPFS) MAJOR CRITERIA 1. Generalized musculoskeletal aching at three or more sites for 3 mo 2. Absence of an underlying conditioncause 3. Normal laboratory tests 4. Five or more typical tender points MINOR CRITERIA 1. Chronic anxiety or tension 2. Fatigue 3. Poor sleep 4. Chronic headaches 5. Irritable bowel syndrome 6. Subjective soft tissue swelling 7. Numbness 8. Pain modulated by physical activities 9. Pain modulated by changes in weather 10. Pain modulated by anxietystress Thirty one potential tender points were listed for these criteria when proposed in 1985. JPFS is diagnosed when all major criteria are met, plus three of the minor criteria or when there are four tender points and five minor criteria. Adapted from Coles M, Weissmann R, Uziel Y. Juvenile primary fibromyalgia syndrome: Epidemiology, etiology, pathogenesis, clinical manifestations and diagnosis. Pediatr Rheumatol Online J. 2021;19(1):22. Table 211.10 Budapest Clinical Diagnostic Criteria for Complex Regional Pain Syndrome |
6,884 | All of the following criteria must be met: 1. Continuing pain, which is disproportionate to any inciting event 2. Must report at least one symptom in each of the following four categories: Sensory: Hyperesthesia andor allodynia Vasomotor: Temperature asymmetry, skin color changes, andor skin color asymmetry Sudomotoredema: Edema, sweating changes, andor sweating asymmetry Motortrophic: Decreased range of motion, motor dysfunction (tremor, weakness, dystonia) andor trophic changes (hair, nail, skin) 3. Must display at least one sign at time of evaluation in two or more of the following four categories: Sensory: Evidence of hyperesthesia (to pin prick) andor allodynia (to light touch, temperature sensation, deep somatic pressure, andor joint movement) Vasomotor: Evidence of temperature asymmetry (1C), skin color changes, andor skin color asymmetry Sudomotoredema: Edema, sweating changes, andor sweating asymmetry Motortrophic: Decreased range of motion, motor dysfunction (tremor, weakness, dystonia) andor trophic changes (hair, nail, skin) 4. There is no other diagnosis that better explains the signs and symptoms. Adapted from Harden RN, Bruel S, Stanton Hicks, et al. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8:326331. Fig. 211.3 Characteristic redness and edema of the foot associated with erythromelalgia. (From Pfund Z, Stankovics J, Decsi T, Illes Z. Child hood steroid responsive acute erythromelalgia with axonal neuropathy of large myelinated fibers: a dysimmune neuropathy? Neuromuscul Disord. 2009;19:4952, Fig. 1A, p. 50.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1574 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) In chronic overlapping pain conditions (COPCs), several pain ful symptoms affecting different body systems coexist without clear underlying pathophysiology. Other terms for COPCs include medi cally unexplained symptoms, functional somatic syndromes (FSS), and central sensitivity syndromes. These disorders are probably highly prevalent; for example, two COPCs, irritable bowel syndrome (IBS) and migraine, each affect 1020 of the population. Pediatric COPC studies usually focus on populations with one painful condition (headaches) and their psychiatric comorbidities, rather than somatic comorbidities. The overlap of these disorders with psychiatric condi tions has led both the public and the medical specialists to dichoto mize these disorders artificially into physical, by implication, real disorders and psychologic, by implication, not real disorders. This classification ignores the unity of brain and body and hinders progress in understanding these disorders. COPC connotes a nonassumptive neutral position, appropriately attributing no assumed pathophysi ology to the disorder, in contrast to other terms, such as medically unexplained syndrome, subtly suggesting a psychologic process, more strongly implied in the term functional. PREVALENCE The prevalence of COPCs is unknown depending on which symp tom is being assessed and how much overlap exists across disorders. A large study from 28 countries (about 400,000 participants) found a prevalence of headache of 54, stomachache 50, and backache 37, occurring at least once a month for at least 6 months. Females had a higher prevalence of |
6,885 | having all three complaints when compared with males; the prevalence increased with age. These three pain syndromes, headache, stomachache, and backache, frequently coexist. IBS and chronic abdominal pain affect 620 of children and adolescents. Idiopathic musculoskeletal pain affects about 16 of schoolchildren age 5 16 years and is often associated with sleep dis turbances, headache, abdominal pain, daytime tiredness, and feeling sad. Migraines present 6 months occur in about 8 of the popula tion (children and adolescents 20 years). Fibromyalgia is present in 1.26. The prevalence of chronic disabling fatigue increases during adolescence from about 1.9 at age 13 to 3 at 18 years. As with most COPCs, fibromyalgia has many comorbid disorders, such as sleep dis turbance, fatigue, headache, sore throat, joint pain, and abdominal pain. The American College of Rheumatology definition of fibromyal gia incorporates some of these comorbid conditions. SYMPTOMDISORDER OVERLAP Diagnostic criteria of many of these disorders overlap with one another, making differentiation between two disorders more of a semantic issue rather than a clinical differentiation. Chronic fatigue syndrome (CFS), clinically the most concerning symptom, shares many of the diagnostic criteria with fibromyalgia. Patients with a single pain condition, such as fibromyalgia, CFS, IBS, multiple chemical sensitivity (MCS), head aches, or temporomandibular joint disorder (TMJD), will typically have another disorder. This overlap of symptoms may reflect a shared pathophysiology, possibly a central nervous system (CNS) dysfunc tion, as was implied in the prior term central sensitization syndrome. A CNS pathophysiology would also explain the invisibility of these disorders to usual screening tools that most often target an end organ. COPCs also harbor many symptoms that are not strictly pain, although they may be equally or more disabling. Adolescents seen in a tertiary referral center with a functional gastrointestinal disorder (FGID) also manifest dizziness, chronic nausea, chronic fatigue, and sleep disturbance, as well as migraines. Up to 50 of adolescents com plain of weekly fatigue, and 15, daily fatigue. COPCs are studied in their disciplinespecific silos rather than collectively as a group. Migraine headaches are frequently associated with anxiety and depression. Anxiety also predicts the persistence of migraine head aches. Sleep disturbance and migraine also interact closely. Poor sleep can trigger a migraine or a migraine cluster; migraine headache itself disturbs sleep. Juvenile fibromyalgia is associated with sleep disturbances such as prolonged sleep latency, frequent awakening, less total sleep time, and periodic limb movements. Adult patients with IBS also have sleep disturbances, correlating with anxiety, depression, and stress. The comorbidities of hypermobility Ehlers Danlos (hEDS) and postural orthostatic tachycardia syndrome (POTS) with COPC have been significant. Patients with hEDS may complain of widespread and sometimes debilitating pain with or after activity, severe fatigue, hand writing difficulties, cracking of joints, joint swelling, joint dislocation, subluxation, or back pain. The chronic pain reduces exercise tolerance, with poorer quality of life and an ever worsening cycle because exer cise is a key piece of management. Patients with FGID may also have hEDS, fibromyalgia, chronic pain, and higher somatizations scores than |
6,886 | those with organic gastrointestinal (GI) disorders. The diagnosis of pediatric POTS requires an increase in heart rate 40 beatsmin in the first 10 minutes of upright tilt test associated with orthostatic symptoms. POTS is also associated with multiple comorbidities, including sleep disruption, chronic pain, Raynaud like symptoms, GI abnormalities, and less frequently, headaches, syncope, and urinary complaints. Patients with both POTS and hEDS usually have more migraines and syncope than those with POTS alone. The prevalence of comorbid disorders in children with COPC is identical whether they have POTS or hEDS. PSYCHIATRIC COMORBIDITIES Many of these disorders have significant psychiatric comorbidities. Juvenile fibromyalgia is associated with anxiety disorders and major mood disorders. Children with medically unexplained symptoms generally have more anxiety and depression than children with other chronic disorders. Other associations include disruptive behaviors, symptom internalization, fearfulness, greater dependency, hyperactiv ity, and concern about sickness. PREDISPOSING FACTORS Female gender and older age (adolescence) increase the risk of COPCs. Certain conditions (e.g., headache) are more common in males or have similar prevalence across genders during childhood, but the prevalence in females increases after puberty. Trauma or posttraumatic stress dis order increases psychologic comorbidities in juvenile fibromyalgia. Some studies suggest that anxiety predisposes to chronic pain. A population based study following children from 18 months to 14 years of age suggested that maternal psychologic distress in early childhood and depressive and pain complaints in preadolescence increase the risk of recurrent abdominal pain at age 14. Postinfectious IBS is an identifi able risk factor for new onset anxiety, depression, and sleep disruption in adults. Children with recurrent abdominal pain often have parents with abdominal pain. It is unclear if this association is caused by a com mon environmentalgenetic factor or a learned behavior of the child imitating the parent. NATURAL HISTORY The natural history of COPC is not well known. Chronic disabling fatigue in the general adolescent population persists 2 3 years in about 25 of patients, but only 8 of youth affected at age 13 still had the complaints at ages 16 and 18. A meta analysis suggests that the prog nosis of CFS in children is usually good, with a small minority having persistent disabling symptoms. The patients belief in an underlying Chapter 212 Chronic Overlapping Pain Conditions Thomas C. Chelimsky and Gisela G. Chelimsky Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 212 u Chronic Overlapping Pain Conditions 1575 physical disorder and the presence of psychiatric comorbidities predict a poorer outcome. In a study of children with FGID, the outcome depended on specific variables. Those who perceived their abdominal pain as more threaten ing, with high levels of pain catastrophization and little capacity to cope with pain because of reduced activity levels, had a poorer outcome. This high pain dysfunctional profile subgroup was predominantly female (70) with a mean age of 12.2 years. |
6,887 | Two thirds of this subgroup still complained of FGID at follow up vs about one third of those in the other groups. These groups included a high pain adaptive profile group with similar pain levels but better adaptive skills and less catastrophization, predominantly slightly younger (11.8 years) females, and a low pain adaptive profile group, slightly younger (11.1 years), with equal males and females but less abdominal pain, better coping mechanisms, and less impairment of daily activities. In the high pain dysfunctional profile group, 41 had both FGID and nonabdominal chronic pain at follow up vs 11 in the high pain adaptive and 17 in the low pain adaptive group. Another study following children ages 4 16.6 years with IBS dem onstrated resolution of symptoms in 58, usually without medication. The differences between these studies may result from the age of the groups, with better outcome in the younger patients, as well as the number of comorbidities and psychologic profile. Similarly, in juvenile fibromyal gia, symptoms are still present 26 years later in about 60 of affected children. The psychiatric comorbidities, mainly depression, and control ling family environments are associated with a poor prognosis. PROPOSED PATHOPHYSIOLOGY There may be dysfunction in the hypothalamic hypophyseal adrenal axis, circadian patterns, autonomic responses, some aspects of CNS processing, the inflammatory immune response, and the musculoskel etal system. Vagal tone measured by heart rate variability is decreased in some children with FGID symptoms and in children with COPCs. Alterations in the autonomic nervous system may affect the immune system and circadian patterns. The stress response may increase mus cle tone, which in turn leads to body aches and tension headaches. In fibromyalgia the cortisol response is altered, with lower cortisol levels on awakening and throughout the day. Orthostatic intolerance from autonomic abnormalities may also contribute to poor concentration from brain hypoperfusion and blood pooling in the lower extremities. The pathophysiology has been better studied in myalgic encephalomyeli tis (ME)CFS. MECFS has been associated with joint hypermobility, ortho static intolerance, decreased range of motion, and reduced activity. These patients demonstrate excessive glial activation resulting in neuroexcitation, neuroinflammation, and possibly neurodegeneration. These features may contribute to the cognitive issues and fatigue present in this disorder. Neuroinflammation and other changes in processing may lead to abnormal descending inhibitory pain pathways, resulting in distal pain and central sensitization. The malfunction of descending antinocicep tive pathways allows pain to spread in the body, associated with increased activity of the nociceptive facilitator pathways. These facilitator pathways are further activated by psychologic factors, such as catastrophization, depression, lack of acceptance, and hypervigilance. Other signals such as pressure, sound, heat, and cold are also aberrantly processed, with activation of areas of the brain that are typically activated only by acute pain stimuli, such as the insula, prefrontal cortex, and anterior cingulate cortex, as well as some regions usually not involved in pain processing. The neuromechanisms involved in dysregulated brain gut interactions in patients with FGID include changes in functional connectivity between brain |
6,888 | regions associated with nociceptive processing and the somato sensory cortexes. Enhanced sensory processing of the gut homeostasis (homeostatic afferent) and attentive responses to salience stimuli (salience network) as well as changes in certain brain regions are noted in patients with FGID (Fig. 212.1). These alterations affect the perception of pain and may affect the endocrine and autonomic nervous systems. What was once called FGIDs is currently considered disorders of gut brain interactions. Proposed mechanisms are noted in Figure 212.2. Research investigat ing the role of the microbiome in regulating microglia, astrocytes, and immune cells may lead to central sensitization and chronic pain. TREATMENT In general, chronic pain should never be treated with opioids; cognitive behavioral therapy (CBT) and a gradually progressive exercise program Fig. 212.1 Brain areas demonstrating more (red) or less (blue) activation in ir ritable bowel syndrome compared with healthy control in a meta analysis of rectal distention. (From Tillisch K, Mayer EA, La bus JS. Quantitative meta analysis identi fies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology. 2011;140:91100, Fig. 3.). 4 0 3 38 20323843 14 10 0 8 50453628 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1576 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) constitute the cornerstones of treatment. The complex comorbid nature of COPCs typically requires a multidisciplinary approach. Because neither CBT nor exercise will have any effect in the absence of full patient engagement and understanding, the team must include the family and the patient, a pain psychologist with experience in CBT, a physical therapist, and the primary care physician. Depending on comorbid conditions, rheumatology, neurology, or gastroenterol ogy may have important roles for symptom management and a pos sible alternative diagnosis. Depending on the initial symptomatology, the differential diagnosis should include inflammatory bowel disease, celiac disease, juvenile idiopathic arthritis, systemic lupus erythema tosus, dermatomyositis, autoinflammatory disorders, Fabry disease, porphyrias, hereditary sensory autonomic neuropathies, and Ehlers Danlos syndrome. Red flags suggesting a medicalorganic etiology for abdominal pain (Table 212.1), headache (Tables 212.2 and 212.3), and musculoskeletal pain (Table 212.4) must be assessed. When a thorough evaluation for a structural cause of symptoms is unrevealing, an important next step is patient and family education. This should include the common presentation, the expectation that mark ers for these types of disorders would typically be absent, and the pres ence of solid management tools with high probability of improvement. Families and patients need to receive encouragement to stop seeking a magic diagnosis and cure and to begin the path to full recovery. With out this step, critical patient engagement in the treatment will not occur. In our practice, we sometimes call functional disorders a problem of software, in contrast to structural issues that would involve hardware. We explain that successful management must change the software, not just mask symptoms. Approaches |
6,889 | that accomplish such a goal include CBT and a rehabilitative program that may require physical therapy, a vigorous exercise program with interval training, meditation, and or yoga. Patients are often deconditioned and may need to start with a very low level of physical activity. In addition, their exercise tolerance may be significantly hampered by an orthostatic intolerance syndrome (e.g., POTS). For these reasons, we frequently recommend starting with a water aerobics program, which provides several benefits: (1) very low gravitational force, so the patient can be set up for success, working only on conditioning and not simultaneously fighting an orthostatic chal lenge; (2) builds both limb and core strength; and (3) gentle on joints for those with arthralgias or a hypermobility syndrome. When water is unavailable, we recommend starting with a recumbent exercise program such as a recumbent stationary bike. In both circumstances, we then slowly introduce upright aerobic activities on land over 2 3 months. Strength exercises are also useful. A Cochrane review in adults with painful disorders showed exercise to have minimal side effects and to improve functionality, reduce pain, and improve quality of life. Patients with fibromyalgia who undergo a 3 month multidisciplinary program with twice weekly physical therapy and CBT benefited in function and physical activity level, and most importantly continued to exercise regu larly at 1 year follow up. Pharmacologic interventions have less impact than nonmedical treatments. When children are missing school or are homebound, it is important to work closely with the school to encourage reentry. This may require modifying the school schedule initially, starting with fewer hours at school, and providing extra time for homework on days that the chil dren are not feeling well. Although medications such as tricyclic antidepressants are often added to the treatment, the improvement with these medications for chronic pain is minimal, and the side effects need to be considered. Nonetheless, amitriptyline and anticonvulsants like gabapentin are often used because they help in treating headaches and abdominal pain and improve sleep quality, a critical element to manage any chronic pain condition. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 212.1 Chronic Fatigue Syndrome Mark R. Magnusson Chronic fatigue syndrome (CFS), also known as myalgic encepha lomyelitis (ME), is a complex, diverse, and debilitating illness char acterized by chronic or intermittent fatigue accompanied by select symptoms and occurring in children, adolescents, and adults. The combination of fatigue and other symptoms interferes significantly with daily activities and has no identified medical explanation (Fig. 212.3). The fatigue does not require exertion by the patient, nor does rest relieve it. Some consider postexertion malaise, or worsening of KEY EFFECTORS A FUNCTIONS Serotonin (5HT) Norepinephrine Dopamine Emotional arousal network Salience network Central executive network Sensorimotor network ANS HPA axis Immune cells Enteric Nervous System (ENS) Intestinal microbiota B C D E F Catecholamines Acetylcholine Corticotropinreleasing hormone (CRH) Glucocorticoids Cytokines (IL1, IL6, IL1B, TNF) Activated mast cells Monocytes T lymphocytes Acetylcholine Dopamine Serotonin (5HT) and Serotonergic receptors Short chain fatty acids Secondary bile acids Luminal |
6,890 | 5HT release Affective responses to pain and aversive stimuli Stimulus appraisal Attentional processes Perception of visceral stimuli Fight or flight arousal response (sympathetic) Rest and digest (parasympathetic) Acute and chronic stress responses Altered intestinal permeability Modulation of ENS and ANS signaling Bowel sensory and motor function Regulation of mucosal secretion and blood flow Local endocrine and immune responses Altered intestinal permeability Influence bowel secretion and contractility Low grade intestinal inflammation Modify visceral sensation and autonomic tone Fig. 212.2 Key effectors and functions of the brain gut microbiota axis. ANS, autonomic nervous system; HPA, hypothalamic pituitary axis. (From Tait C, Sayuk GS. The brain gut microbial axis: A framework for understanding functional GI illness and their therapeutic interventions. Eur J Int Med. 2021;84:19, Fig. 2.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 212 u Chronic Overlapping Pain Conditions 1577 the fatigue with additional symptoms after mental or physical exertion and lasting 24 hours, to be characteristic of CFS. A definitive causal agent or process has not been identified, although the differential diag nosis includes infectious, inflammatory, metabolic, genetic, and auto immune diseases. Our understanding of this condition is largely from studies of adults and adolescents, with limited descriptions of chronic fatiguing illnesses in younger children. Table 212.1 Red Flags and Clues to an Organic Cause of Abdominal Pain Age 4 yr old Localized pain in nonperiumbilical site Referred pain Sudden onset of excruciating pain Crescendo nature of pain Sudden worsening of pain Fever (high fever 39.4C suggests pneumonia, pyelonephritis, dysentery, cholangitis, more than perforation or abscess) Jaundice Distention Dysphagia Dysuria Emesis (especially bilious) Anorexia Weight loss, failure to thrive Positive family history (metabolic disorders, peptic ulcer disease) Change in urine or stool color (blood, acholic) or frequency Vaginal discharge Menstrual abnormalities (amenorrhea) Sexual activity Delayed sexual development (chronic pain) Anemia Elevated erythrocyte sedimentation rate Elevated stool calprotectin Specific physical findings (hepatomegaly, splenomegaly, absent bowel sounds, adnexal tenderness, palpable mass, involuntary guarding, focal or diffuse tenderness, positive rectal examination results, perianal disease, joint swelling, rashes) Consider the five Fs: fat, feces, flatus (aerophagia, obstruction), fluid (ascites, hydronephrosis, cysts), fetus (pregnancy or fetal like abnormal growth e.g., tumors). Family history is also positive for chronic pain syndromes (constipation, irritable bowel, dysmenorrhea, and lactase or sucrase deficiency). Modified from Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023: Table 13.8, p. 229. Table 212.2 History Related Red Flags for Secondary Headaches Quality: Thunderclap rapid onset headache or the worst headache of my life Recent worsening in severity or frequency Change in quality New onset symptoms consistent with cluster headache Location: Unilateral without alteration of sides Chronic or recurrent occipital headache Timing: Awakens from sleep Occurs in morning or causes morning vomiting Acute or chronic progressive pattern Positional or activity related variations: Worsened in the recumbent position |
6,891 | or when bending over Headache experienced or worsened with cough or the Valsalva maneuver Associated neurologic history: Neurologic dysfunction other than typical aura Altered sensorium during headache Sensory deficits or changes in vision, gait, or coordination Other focal neurologic deficits Seizures or syncope Decreased visual acuity Mental status changes (e.g., confusion or disorientation) Regression in fine or gross motor developmental skills Decline in cognition or school performance Change in mood, behavior, or personality Associated general history: Vomiting without nausea and morningfasting nausea or vomiting Polyuria or polydipsia Preschool or younger age History of head trauma Neck pain: Medical comorbidities History of ventriculoperitoneal shunt Certain medications Signs of systemic or localized headneck infection Negative family history of primary headache disorders From Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023: Table 34.5, p. 553. Table 212.3 Physical Examination Red Flags for Secondary Headaches Abnormal vital signs: Hypertension Growth failure Increased head circumference or bulging fontanel Fever Meningeal signs with or without fever Evidence of cranial trauma Cranial bruit Frontal bony tenderness Macrocephaly Abnormal ophthalmologic findings: Papilledema Abnormal ocular movements Squinting Pathologic pupillary response Visual field defects Abnormal neurologic findings: Impaired mental status Cranial nerve palsy Ataxia Abnormal gait Abnormal coordination Abnormal reflexes Asymmetric motor or sensory examination Hemiparesis Developmental regression Precocious, delayed, or arrested puberty Skin findings: Caf au lait or ash leaf macules Petechiae or purpura Facial hemangioma Malar rash From Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023: Table 34.6, p. 553. Table 212.4 MusculoskeletalJoint Pain Warning Signals Requiring Further Workup Arthritis: Erythema, warmth, swelling, pain on palpation Painstiffness in the morning Abnormal radiographic findings Pain at rest, relieved by activity Pain at night: Worsened by massage, analgesics ineffective Refusal to walk Extremity atrophy Bony tenderness Poor growth Weight loss Fever Rash Abnormal blood results: Including complete blood count (CBC), C reactive protein (CRP), erythrocyte sedimentation rate Modified from Friedrichsdorf SJ, Giordano J, Dakoji KD, et al. Chronic pain in children and adolescents: Diagnosis and treatment of primary pain disorders in head, abdomen, muscles and joints. Children. 2016;3:42, Table 3. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1578 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) The illness was formally defined in 1988 as chronic fatigue syn drome because persistent unexplained fatigue was considered the principal and invariable physical symptom. A variety of other names have been used to describe the illness, including chronic mononucleosis, chronic Epstein Barr virus (EBV) infection, postin fection syndrome, and immune dysfunction syndrome. Several case definitions have been developed and are in use in both clinical care and research (Table 212.5). The Institute of Medicine (IOM) 2015 recommendations apply to all ages and include a special focus on pediatrics. The IOM |
6,892 | sug gested new diagnostic criteria and a new name, systemic exertion intolerance disease (SEID), to emphasize the postexertion malaise criterion and better understand the illness (Table 212.6). EPIDEMIOLOGY Based on worldwide studies, 0.22.3 of adolescents or children have CFS. Most epidemiology studies use the 1994 definition. CFS is more prevalent in adolescents than in younger children. The vari ation in CFS prevalence estimates may result from variations in case definition, study methodology and application, study population composition (specialty vs general practice or general population), and data collection (parent, self reporting vs clinician evaluation). Gender distribution in children differs from that in adults, with a more equal distribution in children 15 years old, while remaining two fold to three fold higher in females 15 18 years old. Few stud ies have reported the incidence of CFS among children 10 years old. In adolescents in the Netherlands, the pediatrician diagnosed incidence of CFSME was 0.01, and in the United Kingdom, 0.5. PATHOGENESIS Although the etiology and pathophysiology of CFS are unknown, some patients and clinicians correlate the onset with a recent epi sode of a viral illness such as infectious mononucleosis (1012) (EBV; see Chapter 301). A pathophysiologic relationship of CFS to infection is suggested because the symptoms and biologic markers elicited by the nonspecific innate host responses to infections in general are present in CFS. CFS like illness after infectious mono nucleosis is not predicted by viremia or altered host response to EBV infection, but is associated with the severity of the primary infection. A wide variety of other candidate viral infections have been associated with postinfectious fatigue syndromes, particu larly in adolescents and adults. SARS CoV 2COVID 19 infection has also been implicated, as patients with a history of COVID 19 infection have presented with symptoms similar to patients with MECFS, labeled long COVID, post acute sequalae of SARS CoV 2 infection (PASC), or postCOVID 19 conditions (Table 212.7) (see 100 80 60 40 S F 3 6 sc or es 20 0 Physical functioning Bodily pain General health Vitality Subscale Outliers Mean Median Mean scores of 213 healthy controls Mental health Role physical Role emotional Social functioning Fig. 212.3 Functional status of 471 patients enrolled in the CDC Multisite Clinical Assessment of MECFSUnited States, September 2015. Measured by box plots of scores in the eight subscales of Short Form Health Survey (SF 36) scores (25th and 75th percentile at bottom and top of box). SF 36 scores range from 0 to 100, with higher scores indicating better functioning. https:www.cdc.govcfsprogramsclinical assessmentindex.html. MECFS (myalgic encephalomyelitischronic fatigue syndrome) patients show significant impairment, particularly in vitality and physical functioning subscale scores, but with preservation of mental health and emotional role functioning. (From Unger ER, Lin JMS, Brimmer DJ, et al. CDC Grand Rounds: Chronic fatigue syndromeadvancing research and clinical education. MMWR. 2016;655051:14341438.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. |
6,893 | All rights reserved. Chapter 212 u Chronic Overlapping Pain Conditions 1579 Chapter 449.1). Similar features have been described in postinten sive care syndrome. Similarities between CFS symptoms and those experienced by patients with autoimmune and other inflammatory disorders sug gests primary perturbation of immune function in the pathogenesis of CFS. Hypogammaglobulinemia and hypergammaglobulinemia, immunoglobulin subclass deficiencies, elevated levels of circulating immune complexes, altered helpersuppressor lymphocyte ratios, natural killer cell dysfunction, elevated cytokines, and monocyte dysfunction have been inconsistently reported in adult patients with CFS. These findings have not been consistent among studies. CFS patients as a group differ from healthy controls, but most labo ratory values of the immune parameters are not outside the normal range. Autonomic nervous system (ANS) changes are suggested by the orthostatic intolerance (OI) experienced by some patients with CFS. OI syndromes with circulatory dysfunction include neutrally mediated hypotension and POTS and have been observed in some patients with CFS and could contribute to the syndrome. The patho physiology of these manifestations among adolescents with CFS is unclear, but in postinfectious states could be associated with unre plenished fluid and electrolyte losses associated with acute infection or immune mediated injury (autoantibodies directed against ANS). Because the widespread musculoskeletal pain in CFS is similar to fibro myalgia, and because some consider these to be overlapping syndromes, fibromyalgia and CFS may share similarities in pathogenesis. Other hypotheses under investigation for the biologic basis of CFS involve altera tions in energy metabolism (e.g., mitochondrion, particularly as related to exercise intolerance and postexertion malaise), alterations in sleep, the stress response, and the hypothalamic pituitary axis. Understanding CFS has proved so challenging because it likely represents more than one underlying pathophysiology. Current studies and guidelines are attempt ing to stratify or subgroup patients to address this possibility. Table 212.6 Criteria for Diagnosis of Myalgic EncephalomyelitisChronic Fatigue Syndrome (MECFS) Patient has each of the following three symptoms at least half the time to at least a moderately severe degree: A substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social, or personal activities that persists for 6 mo and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest. Postexertional malaise Unrefreshing sleep Plus at least one of the two following manifestations (chronic, severe): Cognitive impairment Orthostatic intolerance Frequency and severity of symptoms should be assessed. The diagnosis of MECFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity. From Institute of Medicine. Beyond Myalgic EncephalomyelitisChronic Fatigue Syndrome. Washington, DC: National Academies Press; 2015. Table 212.5 Overview of Current Case Definitions for Systemic Exertion Intolerance Disease (SEID) and Past Definitions of Chronic Fatigue Syndrome or Myalgic Encephalomyelitis SYMPTOM SEID CFS ME Fatigue and impairment of daily function 6 mo 6 mo 6 mo Sudden onset Yes Yes Muscle weakness Yes Muscle pain |
6,894 | Yes Postexertional symptoms Yes Yes Yes Sleep disturbance Yes Yes Memory or cognitive disturbances Yes Yes Autonomic symptoms Yes Sore throat Yes Lymph node involvement Yes Cardiovascular symptoms Yes Headaches Yes Arthralgias Yes Yes CFS, Chronic fatigue syndrome; ME, myalgic encephalomyelitis. Data from Institute of Medicine. Beyond Myalgic EncephalomyelitisChronic Fatigue Syndrome Redefining an Illness. Washington, DC: National Academies Press; 2015; Jason L, Evans M, Porter N, et al. The development of a revised Canadian myalgic encephalomyelitis chronic fatigue syndrome case definition. Am J Biochem Biotechnol. 2010;6:120135; Reeves WC, Wagner D, Nisenbaum R, et al. Chronic fatigue syndromea clinically empirical approach to its definition and study. BMC Med. 2005;3:19. Table 212.7 WHO Definition of Long (Post)COVID 19 Condition PostCOVID 19 condition occurs in individuals with a history of probable or confirmed SARS CoV 2 infection, usually 3 mo from the onset of COVID 19, with symptoms that last for at least 2 mo and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction and generally have an impact on everyday functioning. Symptoms might be new onset after initial recovery from an acute COVID 19 episode or persist from the initial illness. Symptoms might also fluctuate or relapse over time; a separate definition might be applicable for children. Modified from Munblit D, OHara ME, Akrami A, et al. Long COVID: Aiming for a consensus. Lancet Respir Med. 2022;10(7):632634. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1580 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) CLINICAL MANIFESTATIONS The dominant symptom expressed by adolescents and adults is a substantial reduction or impairment in the ability to engage in pre illness levels of activity, accompanied by fatigue (see Fig. 212.2). In younger children, who often do not spontaneously report symp toms, exertion induces behavioral changes, manifested by a lack of their usual energy and reduced participation in activities. In adoles cents, fatigue and postexertion malaise may lead to decreased par ticipation in school, family activities, and social exchange. Cognitive impairment includes reported difficulties in concen trating, which are common and indicated by reduced participa tion in school, difficulty keeping up with homework, and a drop in grades. Sleep may be impaired, and nonrestorative sleep is com mon. Other sleep complaints include difficulty falling asleep and staying asleep, whereas diagnosed sleep disorders, including rest less legs syndrome, parasomnias, and sleep apnea, are less com mon. Myalgia and arthralgia may accompany fatigue and altered sleep. Sore throat and cervical lymph node tenderness can occur but may be part of an inciting illness. Adolescents also have increased reports of headache, abdominal pain, nausea, and sensitivity to light and sound with amplified pain. Patients diagnosed with CFS in primary care practices are more likely to report abrupt onset of their symptoms, often as part of an initial virus like |
6,895 | illness, whereas gradual onset is more common in those identified in population based studies. School absenteeism is a major social issue. In one study, two thirds of adolescents missed 2 weeks over a 6 week observation period, and one third required home tutoring. Unlike school phobia, inactivity due to CFS persists on the weekends and during holidays the same as it does during the school week. Although fatigue and accompanying symptoms are subjective, the magnitude of impairment of each component can be measured by questionnaires addressing pain and function or, in the case of sus pected orthostatic instability, by recording routine supine and stand ing heart rate and blood pressure measurements. Fatigue cannot be dismissed as a minor ailment. It generally manifests as lassitude, profound tiredness, intolerance of exertion with easy fatigability, and general malaise. Abnormal physical examination findings are conspicuously absent, providing both reassurance and consternation for the patient, family, and physician. The presence of alarm symptoms such as weight loss, chest pain with exertion, paresthesia, dry mouth and eyes, fevers, diar rhea, cough, night sweats, and rash is uncommon and warrants consid eration of a diagnosis other than CFS. DIAGNOSIS There are no pathognomonic signs or diagnostic tests for CFS. The diagnosis is clinically defined based on inclusion and exclusion cri teria (Fig. 212.4). The diagnostic criteria are applicable to adults and adolescents 11 years old because of the current requirement for a self generated history. Whereas duration of symptoms is 3 6 months depending on age, symptom management should not wait until this criterion is met. CFS is difficult to diagnose in children, who may have difficulty describing their symptoms and articulating their concerns. Sole reliance on parental history can be fraught with confusion because parents may also struggle to interpret their childrens symptoms and feelings in providing accurate historical information. A combina tion of child and parent reporting is most effective. It is important to document the childs activity levels and worsening of symptoms after physical or mental endeavors. Changes in participation in hobbies and family or other social activities can help identify the impact of CFS on function. The diagnosis of CFS can be established only after other medi cal and psychiatric causes of fatigue and other symptoms, many of which are treatable, have been excluded. These include medical con ditions presenting with chronic symptoms, such as hypothyroidism, adrenal insufficiency, respiratory and food allergies, sleep apnea, narcolepsy, substance abuse, posttraumatic stress disorder, adverse drug reactions, and obesity. A previously diagnosed medical con dition with incomplete or uncertain resolution that may explain fatigue needs be considered. Certain illnesses (e.g., fibromyalgia), amplified pain syndrome, postCOVID 19 condition, postintensive care syndrome, and depression share similar symptoms with CFS but are not exclusion ary diagnoses. These should be considered in the differential diag nosis in select cases. There is concern that CFS might be mistaken for readily identifiable psychiatric disorders such as anxiety and mood disorders, but evidence supports differences in their clinical presentation from CFS. CFS should not |
6,896 | be diagnosed in persons with a prior diagnosis of major depressive disorder with psychotic or melancholic features, bipolar affective disorders, schizophrenia Patient presents with profound fatigue Substantial decrease in function Symptom management Consider another diagnosis Persists 6 months Yes No No No Symptom management Reassess for 6 months Consider another diagnosis Patient diagnosed with MECFS Post exertional malaise and unrefreshing sleep Cognitive impairment andor orthostatic intolerance Consider another diagnosis Yes Yes Yes No Consider another diagnosis Fig. 212.4 Diagnostic algorithm for myalgic encephalomyelitischron ic fatigue syndrome (MECFS). ANS, autonomic nervous system; HPA, hypothalamic pituitary axis. (From Institute of Medicine. Beyond Myal gic EncephalomyelitisChronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Press; 2015.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 213 u Miscellaneous Conditions Associated with Arthritis 1581 of any subtype, delusional disorders of any subtype, dementia of any subtype, eating disorder of any type, or alcohol or other substance abuse within 2 years before the onset of the chronic fatigue or any time thereafter. Although evaluation of each patient should be individualized, initial laboratory evaluation should be limited to screening labo ratory testing sufficient to provide reassurance of the lack of sig nificant medical illness. Further evaluation should be directed primarily toward excluding treatable illnesses that may be suggested by the history, symptoms, signs, or physical exam findings present in specific patients. MANAGEMENT Management of CFS is based on relief of the core and most disrup tive symptoms in the individual patient. The diagnostic criterion of 6 months duration of illness should not delay evaluation and symp tom management, because these may be initiated as soon as the child or adolescent presents with a CFS like picture. Problems with sleep can be addressed by encouraging patients to adopt good sleep habits using standard sleep hygiene techniques. It may be beneficial to refer the patient to a sleep medicine specialist for the identifica tion and treatment of sleep disorders and disturbances. Once pain is found not to be related to other specific disease or illness, nonphar macologic treatment is indicated. One of the nonpharmacologic approaches to pain management, CBT, may also assist the patient in managing and coping with CFS. Through explanation and changes in perception of the illness, CBT may help patients and their families develop coping skills and pro vide emotional support. Improved methods of coping may allow some improved function while living with the illness. Comorbid psychiatric conditions such as anxiety require appropriate evaluation and inter vention. Guided graded exercise therapy may be beneficial and added to CBT. Although the overall goal is to help patients with CFS tolerate activity, children and adolescents with CFS should limit physical or mental efforts that result in aggravated symptoms. Return to school should be initiated gradually and systematically with the goal to return to full time attendance. Home tutoring, cyber school, |
6,897 | and partial attendance can be interim steps. Parents and clinicians can work with teachers and school administrators to define appropriate expectations for attendance and performance for children with CFS. Because of the crucial importance of learning socialization skills, even brief attendance in school or participation in school activities should be encouraged, remembering that too rapid remobilization usually exacerbates symptoms and should be avoided. Continued empathy and support by the treating physician are cru cial in maintaining a physician parent patient relationship that is con ducive to managing this illness. Careful attention must be directed to family dynamics to identify and resolve family problems or psycho pathology that may be contributing to childrens perception of their symptoms. PROGNOSIS The natural history of CFS is highly variable, and patients and fami lies understand that the symptoms will wax and wane. Children and adolescents with CFS appear to have a more optimistic outcome than adults, typically with an undulating course of gradual improvement over several years. Overall, a good functional outcome has been reported in up to 80 of patients. Poor prognostic factors include gradual onset, increased school absenteeism, lower socioeconomic status, chronic maternal health problems, and untreated comorbid individual and family psychiatric disorders. Favorable prognostic factors include patient control of the rehabilitation program, with continuing support from health professionals and family members, and improvement in orthostatic intolerance. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. RELAPSING POLYCHONDRITIS Relapsing polychondritis (RP) is a rare condition characterized by episodic chondritis causing cartilage destruction and deformation of the ears (spar ing the earlobes), nose, larynx, and tracheobronchial tree. Antibodies to matrillin 1 and collagen (types II, IX, and XI) are present in approximately 60 of patients with RP, suggesting an autoimmune pathogenesis. Patients may experience arthritis, uveitis, and hearing loss resulting from inflam mation near the auditory and vestibular nerves. Children may initially relate episodes of intense erythema over the outer ears. Other dermatologic manifestations may include erythema nodosum, maculopapular rash, and purpura. Cardiac involvement, including conduction defects and coronary vasculitis, has been reported. Severe, progressive, and potentially fatal dis ease resulting from destruction of the tracheobronchial tree and airway obstruction is unusual in childhood. Diagnostic criteria established for adults are useful guidelines for evaluating children with suggestive symp toms (Table 213.1). The clinical course of RP is variable; flares of disease are often associated with elevations of acute phase reactants and may remit spontaneously. Although seen more often in the adult population, RP may coexist with other rheumatic disease (e.g., systemic lupus erythe matosus, Sjgren syndrome, Henoch Schnlein purpura) in up to 30 of patients. The differential diagnosis includes ANCA associated vasculitis (granulomatosis with polyangiitis) (see Chapter 210.4) and Cogan syn drome, which is characterized by auditory nerve inflammation and kera titis but not chondritis. MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome has many similarities to Behet disease (see Chapter 202). A genetic syndrome named vacuoles, E1 enzyme, X linked, autoin flammatory, somatic (VEXAS) syndrome is caused by somatic pathogenic variants affecting the |
6,898 | UBA1 gene. Adolescent and adult patients (most are male) with this syndrome may have fevers, myalgia, arthralgia, auricular chondritis, and erythema nodosum. Approximately 50 of patients with VEXAS meet criteria for relapsing polychondritis. Between 5 and 10 of patients originally thought to have RP have pathogenic variants in UBA1. Affected patients have a high CRP and ESR in addition to lower platelet counts when compared with patients with only RP. Many children respond to nonsteroidal antiinflammatory drugs, but some require corticosteroids or other immunosuppressive agents Chapter 213 Miscellaneous Conditions Associated with Arthritis Angela Byun Robinson and C. Egla Rabinovich Table 213.1 Suggested Criteria for Relapsing Polychondritis MAJOR Typical inflammatory episodes of ear cartilage Typical inflammatory episodes of nose cartilage Typical inflammatory episodes of laryngotracheal cartilage MINOR Eye inflammation (conjunctivitis, keratitis, episcleritis, uveitis) Hearing loss Vestibular dysfunction Seronegative inflammatory arthritis The diagnosis is established by the presence of two major or one major and two minor criteria. Histologic examination of affected cartilage is required when the presentation is atypical. Data from Michet CJ Jr, McKenna CH, Luthra HS, et al. Relapsing polychondritis: Survival and predictive role of early disease manifestations. Ann Intern Med. 1986;104:7478. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1582 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) (azathioprine, methotrexate, hydroxychloroquine, colchicine, cyclo phosphamide, cyclosporine, and antitumor necrosis factor TNF agents), as reported in small series and case reports. MUCHA HABERMANN DISEASEPITYRIASIS LICHENOIDES ET VARIOLIFORMIS ACUTA Pityriasis lichenoides et varioliformis acuta (PLEVA) is a benign, self limited cutaneous vasculitis characterized by episodes of macules, papules, and papulovesicular lesions that can develop central ulceration, necrosis, and crusting (Fig. 213.1). Different stages of development are usually seen at once. PLEVA fulminans or febrile ulceronecrotic Mucha Habermann disease (FUMHD) is the severe, life threatening form of PLEVA. Large, coalescing, ulceronecrotic lesions are seen, accompanied by high fever and elevated ESR. Systemic manifestations can include interstitial pneumonitis, abdominal pain, malabsorption, arthritis, and neurologic manifestations. PLEVA has a male predominance and occurs more frequently in childhood. The diagnosis is confirmed by biopsy of skin lesions, which reveals perivas cular and intramural lymphocytic inflammation affecting capillaries and venules in the upper dermis that may lead to keratinocyte necrosis. Pho totherapy has been used in some cases of PLEVA. When disease is severe, corticosteroids have been used with questionable effect, and methotrexate has been reported to induce rapid remission in resistant cases. Cyclospo rine and anti TNF agents have also been efficacious in case reports. SWEET SYNDROME Sweet syndrome, or acute febrile neutrophilic dermatosis, is a rare entity in children. It is characterized by fever, elevated neutrophil count, and raised, tender erythematous plaques and nodules over the face, extremities, and trunk. Skin biopsy reveals neutrophilic perivas cular infiltration in the upper dermis. Female predominance is seen in the adult population, whereas gender distribution is |
6,899 | equal in children. Established criteria are useful for diagnosis (Table 213.2). Children can also have arthritis, multifocal nonbacterial osteomyelitis, myositis, and other extracutaneous manifestations. Sweet syndrome may be idiopathic or secondary to malignancy (particularly acute myelogenous leukemia), drugs (granulocyte colony stimulating factor, tretinoin, azathioprine, or trimethoprim sulfamethoxazole), or rheumatic diseases (Behet disease, antiphospholipid antibody syndrome, systemic lupus erythematosus). It has also been reported in association with COVID 19, VEXAS, CAN DLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), Majeed syndrome, and deficiency of interleukin1 receptor antagonist (DIRA) and pyrin associated autoinflammation with neutrophilic dermatosis (PAAND) syndromes (see Chapter 204). The condition usually responds to treatment with corticosteroids, treat ment of underlying disease, or removal of the associated medication. HYPERTROPHIC OSTEOARTHROPATHY Children with chronic disease, especially pulmonary or cardiac disease, can demonstrate clubbing of the terminal phalanges and have associated periosteal reaction and arthritis. These findings characterize the classic presentation of hypertrophic osteoarthropathy (HOA). HOA can be pri mary (idiopathic) or secondary. Although rare, secondary HOA is more common in children and is seen in those with chronic pulmonary disease (cystic fibrosis), congenital heart disease, gastrointestinal disease (mal absorption syndromes, biliary atresia, inflammatory bowel disease), and malignancy (nasopharyngeal sarcoma, osteosarcoma, Hodgkin disease). It may precede a diagnosis of cardiopulmonary disease or malignancy. The pathogenesis of secondary HOA is unknown; symptoms often improve if the underlying condition is treated successfully. HOA related pain can be disabling; in adults, management with bisphosphonates has been reported. Evaluation of children presenting with HOA should include a chest radio graph to evaluate for pulmonary disease or intrathoracic mass. Autosomal recessive pathogenic variants in prostaglandin pathway genes have been described in primary HOA, also described as pachydermoperiostosis. PLANT THORN SYNOVITIS A diagnosis of plant thorn synovitis should be considered in children with monoarticular arthritis nonresponsive to antiinflammatory therapy. Acute or chronic arthritis can occur after a plant thorn or other foreign object penetrates a joint. Unlike septic arthritis, children with plant thorn synovi tis are usually afebrile. The most common organism seen with plant thorn synovitis is Pantoea agglomerans, although cultures are often negative. The initial injury may be unknown or forgotten, making the diagnosis difficult. Ultrasound or MRI can be useful in identifying the foreign body. Removal of the foreign body using arthroscopy, followed by an antibiotic course, is the accepted therapy. PIGMENTED VILLONODULAR SYNOVITIS Proliferation of synovial tissue is seen in pigmented villonodular synovitis (PVNS). This proliferation is localized or diffuse and can affect the joint, tendon sheath, or bursa. Macrophages and multinucleated giant cells with brownish hemosiderin are present histologically. It is unclear if the etiology of PVNS is inflammatory or neoplastic in nature. Although findings are not pathognomonic, MRI with contrast is a useful diagnostic tool by which PVNS can be seen as a mass or bone erosion. Brown or bloody synovial fluid is seen with arthrocentesis, but the diagnosis is made by tissue biopsy. Surgical removal of the affected tissue is the therapeutic modality, and with diffuse disease, a total |
6,900 | synovectomy is recommended. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 213.1 Pityriasis lichenoides et varioliformis acuta (PLEVA). Symmet ric, oval and round, reddish brown macular, papular, necrotic, and crusted lesions on the chest of 9 yr old boy. (From Paller AS, Mancini AJ, eds. Hur witz Clinical Pediatric Dermatology, 5th ed. Philadelphia: Elsevier; 2016: Fig. 4 33, p. 87.) Table 213.2 Diagnostic Criteria for Classic Sweet Syndrome MAJOR CRITERIA Abrupt onset of painful erythematous plaques or nodules Histopathologic evidence of dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis MINOR CRITERIA Pyrexia 38C Association with underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy or preceded by an upper respiratory or gastrointestinal infection or vaccination Excellent response to systemic corticosteroids or potassium iodide Abnormal laboratory values at presentation (three of four): Erythrocyte sedimentation rate 20 mmhr Positive C reactive protein test result 8,000 leukocytesmm3 70 neutrophilsmm3 The diagnosis is established by the presence of two major criteria plus two of the four minor criteria. Adapted from Walker DC, Cohen PR. Trimethoprim sulfamethoxazole associated acute febrile neutrophilic dermatosis: Case report and review of drug induced Sweets syndrome. J Am Acad Dermatol. 1996;34:918923. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. PART XVInfectious Diseases Section 1 General Considerations 1583 INTRODUCTION Public health as a field aims to promote healthy lifestyles and com munities and to protect the public at large from health threats from known and emerging diseases, chronic noncommunicable diseases, and environmental risks and vulnerabilities. In this context, public health authorities have a core role in prevention, preparedness, and response to epidemic and pandemic infectious diseases. The field of public health has a long and storied history in investigating and ending outbreaks of infectious diseases, extending back to one of the founders of modern epidemiology, John Snow, and the Broad Street pump chol era outbreak. Modern epidemiology and public health practices have an integral role in the management of outbreaks, epidemics, and pan demics, using both traditional methodologies that look like the shoe leather epidemiology of John Snows time, meshed with modern best practices that leverage genomic sequencing, data analytics, and medi cal innovations in therapeutics and vaccination. DEFINITIONS Infectious disease outbreak response hinges on an understanding of current and ongoing incidence and prevalence of the disease in the affected community. The transmission dynamics of a disease will look different in a population that is entirely susceptible (e.g., a novel or emerging disease) than in a population in which some members are recoveredimmune (e.g., a disease has been present for some time). Sporadic diseases occur infrequently and irregularly in a population. Endemic diseases are continually circulating, often at low levels, maintain ing a constant presence among members of the community. Epidemic dis ease occurs when there is a substantial increase above the baseline amount of a disease. This may occur as an increase in a |
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