Differential diagnosis of annular erythemas

Differential diagnosis includes other eruptions with ring-like lesions, such as neonatal lupus, erythema multiforme, urticaria, urticarial lesions of pemphigoid, fungal infections, erythema chronicum migrans, and congenital Lyme disease.

Serum antibody determinations (antinuclear, SS-A, and SS-B) are recommended to exclude neonatal lupus. Scraping any scaly lesion for KOH preparation is also advisable.

Cutaneous findings

Of infants with NLE, 50% have skin lesions, and congenital heart block is present in about 10%. Lesions commonly develop at a few weeks of age but may be apparent at birth, which suggests that ultraviolet (UV) radiation is not essential for the development of skin lesions. Ulcerations, bullae, and extensive atrophy may be present, particularly in cases that are present at birth and transient bullous lesions from severe vacuolar damage of the basal cell layer have been reported as unusual manifestations of NLE. These cases might more accurately be called ‘congenital LE’ rather than NLE ( Fig. 20.2 ).

Neonatal lupus with atrophic skin lesions present at birth.

(Courtesy of Linda-Beets-Shay, MD.)

The more common skin manifestations of NLE fall into two main morphologies, papulosquamous and annular. Papulosquamous lesions are more common and are characterized by erythematous, nonindurated scaly plaques ( Fig. 20.3 ), sometimes with an atrophic appearance ( Fig. 20.4 ). In contrast to discoid lupus, scarring and follicular plugging are usually absent. The annular variant consists of well-circumscribed round plaques. Lupus profundus and generalized poikiloderma with erosions and patchy alopecia are rare manifestations.

Neonatal lupus erythematosus.

Annular scaly plaques resembling tinea corporis.

Neonatal lupus erythematosus.

Atrophic plaques and raccoon eyes on the faces of twins

NLE lesions are most common on the face and scalp, predominantly affecting the periorbital and malar areas, often causing the ‘raccoon eyes’ appearance ( Figs 20.4 , 20.5 ), but can occur on virtually any body site. The eruption is frequently precipitated or aggravated by sun exposure, but lesions can develop in sun-protected areas (e.g., the diaper region, palms, and soles). Skin lesions are transient and cease to appear around the age of 6 months, after the disappearance of maternal antibodies. Transient or persistent hypopigmentation and epidermal atrophy may result ( Fig. 20.6 ). Telangiectases, vascular ectasias resembling petechiae, persistent livedo or cutis marmorata, features of cutis marmorata telangiectatica congenita, and widespread erythema mimicking an extensive capillary malformation have been observed but are much less common manifestations. In some cases, these findings can be an initial sign of NLE, occurring without preceding identifiable inflammatory lesions. A rare report of a case of NLE with a serological profile consistent with drug-induced lupus has been described in a newborn whose mother was treated with α-interferon during pregnancy.

Neonatal lupus erythematosus.

‘Raccoon eyes’ and prominent facial erythema in an infant with neonatal lupus.

(Courtesy of Dr Joseph Lam).

Neonatal lupus erythematosus

Atrophy and pigmentary changes in an infant with neonatal lupus erythematosus. This boy also had congenital A-V heart block.

Extracutaneous findings

The most significant manifestation is isolated complete congenital heart block. More than 90% of such cases are due to NLE. Most patients have third-degree block, but progression from a second-degree block has been reported. Heart block can often be detected as early as 20 weeks’ gestation. Cardio­myopathy and other types of arrhythmias are associated with NLE.

Transient liver disease, manifesting as hepatomegaly (with a picture of cholestasis) or elevation of liver enzymes, and thrombocytopenia or other isolated cytopenias, may occur. Petechiae and purpura have been described as presenting signs of NLE. Less common findings include thrombosis associated with anticardiolipin antibodies, hypocalcemia, spastic paraparesis, pneumonitis, and transient myasthenia gravis. Central nervous system (CNS) involvement has been emphasized in some reports, and can be asymptomatic, with only ultrasound and CT scan abnormalities, suggesting a transient phenomenon. However, hydrocephalus has been reported in 8% of children with NLE. NLE is a cause of chondrodysplasia punctata, seen in X-rays as stippling of the epiphyses and the spine. Between 30% and 50% of mothers of infants with NLE have a connective tissue disease, most commonly SLE or Sjögren syndrome. Most, however, are asymptomatic. The risk for developing overt connective tissue disease in these mothers is highly debated, with estimates ranging from 2% to more than 70%.

Etiology and pathogenesis

Placentally transmitted maternal IgG autoantibodies are associated with the pathogenesis of NLE. The most commonly implicated autoantibodies have been anti-Ro/SS-A and anti-La/SS-B, present in 95% and 60–80%, respectively. A small subset of affected infants have neither Ro or La antibodies, but instead have anti-U1RNP. Antibodies against the 52/60-kD Ro and 48-kD La ribonucleoproteins are associated with heart block, whereas antibodies against the 50-kD La ribonucleoprotein are associated with cutaneous disease. Significantly more symptomatic mothers of children with congenital heart block have anti-La antibodies than do disease-matched mothers with unaffected children. Moreover, the mean level of anti-La seems to be higher in mothers of infants with congenital heart block than in mothers of children with cutaneous NLE. It is likely that the amount of maternal antibodies, rather than their presence, is associated with fetal injury.

Why less than 5% of mothers with anti-Ro and anti-La antibodies give birth to affected children is not understood, nor is the fact that mothers of affected infants are often asymptomatic despite having these antibodies. Fraternal twins are often discordant for NLE, and NLE does not occur in every subsequent pregnancy. Genetic factors may be important for the development of NLE in children with maternal lupus antibodies. A link has been suggested between NLE rash and the allele HLA-DRB1*03, as well as a -308A polymorphism in the TNF-α gene. Alternatively, maternal and/or sibling microchimerism may play an additional role, as levels of microchimerism have been reported to correlate with NLE disease activity.

Laboratory tests and histopathology

Serologic studies for autoantibodies in the mother and infant demonstrate anti-Ro, anti-La, and/or anti-U1RNP antibodies. Anti-NDNA, anticardiolipin antibodies, antinuclear antibody, and rheumatoid factor may also be present. Anti-Sm antibody, highly specific for systemic lupus erythematosus, is not found in NLE. The maternal antibody titer is usually higher than the infant titer. In apparently seronegative infants, more sensitive studies such as ELISA, immunoblotting, or line immunoassay, should be used instead of immunodiffusion techniques. Skin biopsy, which is usually not necessary for diagnosis, shows changes characteristic of lupus erythematosus, i.e., epidermal atrophy, vacuolization of the basal layer with a sparse lymphohistiocytic infiltrate at the dermoepidermal junction with a periappendageal distribution. In many instances, histopathological features in children with NLE rash are subtle. Direct immunofluorescence is positive in 50% of cases, demonstrating granular deposits of IgG, C3, and IgM at the dermoepidermal junction.

Differential diagnosis

The differential diagnosis encompasses congenital infections including rubella, cytomegalovirus and syphilis, congenital graft-versus-host disease, annular erythema of infancy, tinea corporis, and seborrheic dermatitis. False-positive VDRL tests for syphilis may occur in NLE. Telangiectasia and photosensitivity may suggest Bloom syndrome or Rothmund–Thomson syndrome. Serologic studies for autoantibodies in both infant and mother help to confirm the diagnosis. Skin biopsy for histologic and direct immunofluorescence studies is seldom necessary.

Course, management, treatment, and prognosis

Neonates with suspected NLE should receive a complete physical examination, electrocardiogram, complete blood count with platelet count, and liver function tests ( Box 20.1 ).

Skin lesions are transient. Treatment of skin disease consists of sun protection and the application of topical steroids. Pulsed dye laser therapy may be considered for residual telangiectasia. Congenital heart block is permanent. Half of newborns with complete congenital heart block require implantation of a pacemaker in the neonatal period. The average mortality rate from complete congenital heart block in the neonatal period is 15%; another 10–20% die of pacemaker complications. Late-onset cardiomyopathy may develop in a few infants.

Mothers with anti-Ro or anti-La antibodies have a risk of delivering an infant with NLE in the range of 1–20%, depending on whether they have asymptomatic or symptomatic SLE. The risk of recurrence of congenital heart block in subsequent pregnancies may be as high as 25%. Such pregnancies should be closely monitored, ideally by obstetricians familiar with managing high-risk pregnancies. Although NLE is usually self-limited, SLE or other rheumatologic/autoimmune diseases may develop later in life in a small subset of patients. The exact risk is unknown.

Cutaneous findings

Cutaneous involvement is widespread but usually involves the trunk and consists of flat targetoid lesions with two zones of erythema or ill-defined confluent flat erythematous to purpuric macules. Underlying erythema and blisters may be seen in both presentations (see Fig. 10.34 ). Mucosal erosions are reported to be present in more than 90% of patients, and a majority have two or more affected membranes with oral and conjunctival mucosa most commonly affected, and less frequently genital, anal, pharyngeal, and upper respiratory tract involvement developing ( Fig. 20.12 ; Box 20.1 ). Numerous reports have described patients with ‘atypical SJS’ who were infected with Mycoplasma pneumoniae and presented with severe mucositis without skin lesions.

Oral mucosal involvement in Stevens–Johnson syndrome

Extracutaneous findings

SJS and TEN patients are febrile with malaise and constitutional symptoms. In cases of extensive involvement, an elevated sedimentation rate, leukocytosis, and mild elevation of transaminases may be seen, as well as eosinophilia in drug-related cases. Electrolyte imbalance and hypoproteinemia may be encountered in SJS.

Etiology and pathogenesis

Both SJS and TEN are considered to be immune-mediated mucocutaneous reactions, usually secondary to medications or infections. Mycoplasma pneumoniae infection is a well-documented cause. In children, the majority of cases are triggered by anticonvulsants, sulfonamides, and oxicam nonsteroidal anti-inflammatory drugs. Cases of TEN in newborns due to E. coli sepsis have been reported; other cases have been related to antibiotics and phenobarbital. The greatest risk of development of SJS occurs during 7–21 days after a medication has been started. Other reported triggers of SJS include immunizations and viral infections, and as an acute manifestation of graft-versus-host disease in infants with severe combined immunodeficiency or after bone-marrow transplantation.

Histopathology

Skin biopsy reveals a superficial perivascular mixed infiltrate with vacuolar interface change and apoptotic keratinocytes progressing to full-thickness epidermal necrosis in TEN.

Differential diagnosis

The main differential diagnosis in cases with severe mucosal involvement is erythema multiforme (EM), which is most often triggered by herpes simplex virus infection (see below). Staphylococcal scalded skin syndrome (SSSS) can also resemble SJS, particularly early SJS, but the lack of intraoral involvement and level of blistering are helpful clues to differentiate the two conditions.

Treatment

SJS and TEN are potentially life-threatening conditions and their clinical course is typically prolonged, even after drug discontinuation. There is no evidence-based standardized treatment other than supportive care ( Box 20.2 ). Therapies such as systemic corticosteroids and intravenous immunoglobulin, alone or in combination, are often used but are controversial. Recurrences have been reported in up to 20% of patients, a high rate that strongly suggests a potential genetic predisposition. Such mechanisms have been shown in Asian patients with the HLA-B*1502 genotype, who have a strong tendency to develop carbamazepine-induced SJS. Mycoplasma pneumoniae -induced SJS has a better prognosis than its drug-induced counterpart. Long-term sequelae due to genital and ocular scarring may impact the long-term prognosis.

Cutaneous findings

The prototypic lesion of EM is a 1–3 cm targetoid lesion with a dusky vesicular, purpuric, or necrotic center surrounded by a raised edematous ring of pallor and an erythematous outer ring. In some cases, only two zones are seen, with a single ring around the central papule (atypical target lesions). The lesions are distributed symmetrically on the extensor surface of the extremities and acral parts of the body ( Fig. 20.13 ). They may extend to the trunk, flexural surfaces, palms, and soles. In children, lesions on the face and ears are common, but are rare on the scalp. Areas of epidermal detachment may occur, but usually affect less than 10% of the body surface area. Mucosal lesions may occur in EM but are usually milder that in SJS.

Target lesions of erythema multiforme in a newborn.

Extracutaneous findings

Mild, nonspecific, prodromal symptoms of cough, rhinitis, and low-grade fever are occasionally present in EM.

Etiology and pathogenesis

EM has been considered a hypersensitivity reaction to multiple precipitating factors such as infectious agents, medications, or even severe contact dermatitis. In children, herpes simplex infections are thought to be responsible for more than 80% of EM, although clinical infection may be minor or inapparent. HSV-associated EM follows the lesions of herpes by 1–3 weeks. It can recur but not necessarily with every episode of HSV infection. HSV-specific DNA has been detected by polymerase chain reaction and in situ hybridization in lesional skin from children with EM, whether ‘idiopathic’ or clearly HSV-related. Cow’s milk intolerance has been described as a cause of erythema multiforme in a neonate. Vaccinations were the only known possible causative agents in a newborn and two infants with erythema multiforme.

Laboratory tests and histopathology

The diagnosis is generally made clinically. Histopathologic examination of early lesions reveals a lymphocytic band-like infiltrate at the dermoepidermal junction, with exocytosis and individual necrotic keratinocytes in close proximity to lymphocytes (‘satellite cell necrosis’). There is vacuolization of the basal layer with focal cleft formation at the dermoepidermal junction. The upper dermis is edematous. Over time, more extensive confluent necrosis of the epidermis supervenes, resulting in subepidermal blister formation.

Differential diagnosis

The most common mimic of EM is urticarial multiforme or serum sickness-like reactions (see below). Others include urticarial vasculitis, acute hemorrhagic edema of infancy, Kawasaki disease, EM-like drug eruptions, and Stevens–Johnson syndrome ( Table 20.3 ).

Course, management, treatment, and prognosis

Erythema multiforme is usually self-limited. Individual lesions heal in 1–2 weeks, with residual hyperpigmentation. Conservative supportive care is the preferred form of treatment. Possible underlying causes should be sought and treated. Corticosteroids are usually unnecessary and may even worsen a concurrent infection. In HSV-associated EM, early intervention or even prophylactic treatment with oral acyclovir may be beneficial.

Cutaneous findings

Urticaria is characterized by transient pruritic wheals that in younger children, may have certain characteristic features. Itching may be absent and may be replaced by pain in this age group. The hives tend to coalesce, forming bizarre polycyclic, serpiginous, or annular shapes (figurative urticaria, Fig. 20.15 ; or annular urticaria, Fig. 20.16 ), and may become hemorrhagic. The term ‘urticaria multiforme’ has been coined to describe this form of annular urticaria, as it is often confused with erythema multiforme, especially in cases where there is an ecchymotic dusky center. Sometimes there may be purpura or ecchymosis in urticaria multiforme and the term ‘hemorrhagic urticaria’ has been coined for this. In these cases, the purpura persists longer than 24 hours but the erythematous edematous plaques change from area to area. These features confer a very dramatic appearance to the eruption.

Polycyclic lesions of urticaria associated with prostaglandin E ₂ infusion.

Annular urticaria of unknown etiology.

Urticaria multiforme may be also confused with serum sickness-like reaction because there is often associated facial, hand, and feet edema (angioedema). However, in serum sickness-like reaction, often triggered by antibiotics, there may be accompanying fever and arthralgias.

Extracutaneous findings

Acute urticaria may be accompanied by signs of anaphylactic shock. Urticaria may have associated angioedema with a deep swelling of the face, extremities and genitalia, as well as abdominal pain, diarrhea, vomiting, respiratory compromise, and joint pain. Chronic urticaria in children may be the first presenting sign or be seen in autoimmune disorders such as thyroid autoimmunity, systemic lupus, or juvenile arthritis.

Etiology and pathogenesis

In conventional urticaria, hives develop as a result of an increased permeability of capillaries and small venules, which leads to leakage of fluid into the extravascular space. Mast cell activation leads to release of mediators, such as histamine, that are responsible for these changes. Many triggers (secretagogues) initiate mast cell degranulation through receptors on mast cell membranes, either via an IgE-dependent mechanism or through complement activation (immunologic secretagogues), or by acting directly without the need for receptors (nonimmunologic secretagogues).

The most common provocative agents of acute urticaria in children are infections, drugs, and foods, which account for 40% of the cases of acute urticaria. In the majority of cases of urticaria in children, there is a history of upper respiratory tract infection, otitis media or viral symptoms preceding the onset and many infectious agents have been reported, including mycoplasma, group A Streptococcus , adenovirus, herpes virus type 6, parvovirus, Helicobacter pylori, and others. However, exhaustive diagnostic evaluations for an infectious etiology are generally not helpful unless directed by other signs or symptoms. Antibiotics (penicillins, macrolides, and oral cephalosporins), anticonvulsants and NSAIDs are the most frequently incriminated drugs. In IgE, mediated food allergy hives usually appear within minutes to 2 hours after ingestion, and respiratory, gastrointestinal and/or cardiovascular signs and symptoms may also be present. In infants, cow’s milk is the most common food for food-induced urticaria and anaphylaxis. Urticaria may be more common and recurrent in atopic patients.

Identifying the cause of chronic urticaria is even more difficult as it is often idiopathic. Occult infections should be considered (such as a low-grade urinary tract infection or otitis), as well as autoimmune disorders. Thyroid autoimmunity, juvenile idiopathic arthritis, systemic lupus erythematosus, type 1 diabetes, and coeliac disease have been associated with chronic urticaria in children, but not in infants.

Diagnosis

The diagnosis of urticaria is usually made clinically. In atypical or chronic cases, skin biopsy may be helpful, particularly if persistent or if prominent systemic symptoms are present. Histopathologic examination demonstrates vascular dilation, edema, and a perivascular inflammatory infiltrate most typically composed of lymphohistiocytic cells, polymorphonuclear cells, and eosinophils. The presence of neutrophils, particularly if predominant, can be an important clue to an autoinflammatory disease, which requires different evaluation and management (see below).

In most cases, laboratory tests are not usually necessary to evaluate acute urticaria, unless signs point to a specific infection. An exhaustive search for an underlying cause not elicited by history alone is unwarranted. In drug-induced urticaria, the eosinophil count may be elevated. In cases with recurring episodes, it may be useful to keep a diary of triggering factors. In many patients, no cause is identified. For chronic urticaria the same principles apply and investigation of thyroid autoimmunity, celiac disease and other autoimmune conditions may be considered if suggested by the patient’s history or signs.

Differential diagnosis

Urticaria in infants is often misdiagnosed as erythema multiforme, acute hemorrhagic edema and other forms of vasculitis, annular erythema of infancy, Kawasaki disease, or serum sickness. In neonates, generalized hive-like eruptions and dermatographism can also be seen in diffuse cutaneous mastocytosis (see Chapter 28 ). Hemorrhagic urticaria and annular urticaria especially may be mistaken for erythema multiforme because the dusky center gives a targetoid configuration ( Table 20.4 ). However in urticaria, there are no epidermal changes, blistering, or necrotic centers. Autoinflammatory conditions should always be considered in the differential diagnosis of neonates with urticaria, especially in febrile infants (see below).

Course, management, treatment, and prognosis

Acute urticaria in infants is usually benign and self-limiting. If medication is required, oral antihistamines are the mainstay of therapy. First generation antihistamines are safe in older infants, however, in newborns who have an increased susceptibility to antimuscarinic side-effects, they may cause central nervous system (CNS) excitation, which in rare cases can lead to seizures. Second generation antihistamines such as cetirizine and levocetirizine have been proved to be safe in infants older than 6 months. Systemic corticosteroids are rarely necessary.

Cutaneous findings

A skin eruption is usually the first manifestation of the disease and is present at birth or develops during the first 6 months of life. It is characterized by generalized, evanescent, urticarial macules and papules that migrate over the course of a single day and wax and wane in intensity ( Fig. 20.17 ). The rash is typically always present but can worsen with increased disease activity flare-ups. The lesions are usually asymptomatic, but can be pruritic, especially after sun exposure. Geographic tongue and oral ulcers have been noted in a single patient.

Chronic infantile neurological cutaneous and articular syndrome (CINCA).

Extracutaneous findings

Symmetric or asymmetric arthropathy is another constant finding and is severe in half of patients. It is often absent in the first few weeks of life, but usually develops during the first year. The knees are most frequently affected, followed by the ankles and feet, elbows, wrists, and hands. Neurologic signs and symptoms such as headache, vomiting, and seizures develop at a variable age, and intellectual impairment, spasticity, and hypotonia have been described. Progressive sensorineural hearing loss and hoarseness are also common. Ocular disease, an inconstant finding, may include papilledema, uveitis, keratitis, conjunctivitis, and chorioretinitis. Affected children may have a characteristic phenotype with growth retardation, and an increased head circumference, with frontal bossing. Icterus may be present in the neonatal period, especially in patients with severe arthropathy.

Etiology and pathogenesis

Mutations in the CIAS1 gene have been identified in 60% of patients with CINCA syndrome. In a subset of patients in whom the mutation was not detected by standard techniques, molecular cloning has revealed somatic CIAS1 mutations. CIAS1 encodes a protein called ‘cryopyrin’, which is involved in the regulation of apoptosis and the inflammatory signaling pathway. It is proposed that familial cold urticaria and CINCA represent extreme groups of the same disease, defined by the magnitude of phenotypic expression. Considerable clinical overlapping exists between these disorders.

Laboratory tests, radiologic findings, and histopathology

Nonspecific findings typical of a chronic inflammatory process include microcytic anemia; leukocytosis with high neutrophil and eosinophil counts; elevated platelet counts; sedimentation rates, and acute-phase reactants; and polyclonal hyperglobulinemia G, A, or M. Rheumatoid factor and antinuclear antibodies are usually absent. Liver enzymes may be mildly elevated. CSF examination shows pleocytosis and high protein levels.

Radiologic studies of the affected joints show irregularly enlarged, bizarre, spiculated epiphyses with a grossly coarsened trabecular appearance. There is periosteal new bone formation, and growth cartilage abnormalities are frequent. With time, there is bowing deformity of long bones and shortening of diaphyseal length. CT scans of the head have demonstrated hydrocephalus and cerebral atrophy.

Histopathologic examination of the skin reveals interstitial and perivascular neutrophilia. Neutrophilic eccrine hidradenitis has been described. Biopsies of lymph nodes, liver, and synovium show nonspecific signs of chronic inflammation.

Differential diagnosis

CINCA must be differentiated from systemic onset juvenile arthritis. The main differences are its neonatal onset, persistent rash, the short duration of bouts of fever, absence of morning stiffness, and central nervous system involvement. The arthro­pathy is more deforming, and the radiographic findings of enlarged and disorganized epiphyses are distinctive. In addition, the response to NSAIDs is poor. Urticaria should also be considered and the predominance of eosinophils in skin biopsy may be a relative clue.

Course, management, treatment, and prognosis

Untreated, the disease follows a chronic course with acute febrile exacerbations and can have a fatal course. Occasionally, it causes death in the first or second decade. Nonsteroidal anti-inflammatory drugs may be effective for pain relief but do not alter the course of the disease. Prednisone has been palliative in doses ranging from 0.5 to 2.0 mg/kg per day. Chlorambucil and penicillamine have been tried, with limited success. Thalidomide has shown beneficial effects in a single patient. Other choices include methotrexate, the recombinant human IL-1 receptor antagonist anakinra, and the anti-TNF-α agent etanercept. Other IL-blocking agents such as rilonacept and canakinumab, are very effective and promising agents.

Cutaneous findings

The lesions of Sweet syndrome typically have an acute, explosive onset and are characterized by indurated, tender, erythematous plaques, or nodules that vary in size from 0.5 to 4 cm ( Fig. 20.19 ). Pustules may also be present, though usually at a later stage. The borders may be raised, mammillated, or even vesicular. Some lesions may show central clearing, forming annular or gyrate plaques ( Fig. 20.20 ). The lesions are usually multiple and distributed over the face and extremities or, more rarely, the trunk. Pathergy is not uncommon. Without treatment, they tend to heal spontaneously within a few months. In some patients, especially children, the lesions heal with areas of secondary cutis laxa, also known as ‘Marshall syndrome’.

Nodular lesions of Sweet syndrome with central crusting.

Progression of lesions of Sweet syndrome in the same patient as in Figure 20.19 . Plaques and nodules have flattened and are clearing centrally.

Extracutaneous findings

A high, spiking fever is characteristic but may be absent in up to 50% of patients. Arthralgias or asymmetric arthritis may be associated, and conjunctivitis or iridocyclitis may be seen in one-third of patients. Renal involvement manifesting as proteinuria or hematuria, as well as lung involvement with infiltrates visible on chest radiographs, has also been described. Central nervous system involvement may occur in rare instances and manifests as headaches, convulsions, or disturbance of consciousness. Cerebrospinal fluid pleocytosis with lymphocyte predominance is usually found in such cases. Neonatal lupus erythematosus has been reported to present with a neutrophilic dermatosis in newborns.

Etiology and pathogenesis

The pathogenesis is unknown. Many of the patients reported have had a preceding respiratory tract infection or elevated anti-streptolysin O titers. Of the cases, 10% have been seen in the setting of a variety of hematologic malignancies, particularly acute myeloid and myelomonocytic leukemias. Sweet syndrome has also been associated with solid tumors, inflammatory bowel disease, connective tissue diseases, and chronic granulomatous disease, or it may occur as an adverse reaction to drugs, particularly granulocyte colony-stimulating factor or after vaccination. Because of these associations and the rapid response to systemic corticosteroids, Sweet syndrome is thought to represent a hypersensitivity reaction to infectious agents or tumoral antigens.

Laboratory tests and histopathology

An elevated erythrocyte sedimentation rate and peripheral leukocytosis are frequent accompanying abnormalities. Eosinophilia, microcytic anemia, mild elevation of liver enzymes, and urinalysis abnormalities may be present occasionally. Antineutrophil cytoplasmic antibodies have been detected in some cases. α ₁ -Antitrypsin deficiency has been documented in one case of Marshall syndrome.

The histopathologic findings are diagnostic. There is a dense perivascular infiltrate composed almost entirely of neutrophils. The dermis appears edematous, and subepidermal blisters may form. Spongiosis, exocytosis, and intraepidermal vesiculation may be seen. There is endothelial swelling and nuclear dust, but true vasculitis is characteristically absent.

Differential diagnosis

The lesions of Sweet syndrome may initially resemble those of EM or acute hemorrhagic edema. Lesions on the lower extremities may resemble those of erythema nodosum, but lesions more characteristic of Sweet syndrome are usually present in other locations.

Course, management, treatment, and prognosis

Sweet syndrome itself is a benign disease but may be a marker of malignancy. If left untreated, it resolves spontaneously over weeks to months. However, recurrences are common. Marshall syndrome may have a poorer prognosis, with the development of elastolysis in the lungs or cardiovascular involvement.

Oral corticosteroids are the treatment of choice and usually elicit a prompt response. Potassium iodide administration has been successful in a few cases, as have colchicine, dapsone, clofazimine, and intravenous immunoglobulin.

There is considerable clinical and histopathologic overlap between Sweet syndrome and pyoderma gangrenosum in infants.

Cutaneous findings

The skin is involved in virtually all patients. The initial signs are often diffuse erythema and painful induration of the hands and feet.

A polymorphous exanthem on the trunk and proximal extremities usually appears within 5 days of onset of fever ( Fig. 20.21 ). The morphology is most often a nonspecific, diffuse maculopapular or morbilliform eruption, but may be urticarial, scarlatiniform, targetoid, or even pustular. Bullous or vesicular eruptions have not been described. The rash involves the perineum in up to two-thirds of cases, with early desquamation, far earlier than that appearing on the fingers and toes ( Fig. 20.22 ).

(A) Morbilliform eruption in an infant with Kawasaki disease. (B) Cracked lips and early desquamation in the anogenital area in a febrile toddler with Kawasaki disease.

(A) Early perineal desquamative eruption of Kawasaki disease. (B) Genital desquamation. (C) Fingertip and hand desquamation in Kawasaki disease.

Changes in the lips and oral mucosa include erythema, swelling and fissuring of the lips, strawberry tongue, and erythema of the oropharynx. Oral ulcerations and pharyngeal exudates are not seen. Intermittent acrocyanosis as well as peripheral gangrene have been observed in infants younger than 6 months of age. Inflammatory changes with necrosis at the site of a previous BCG inoculation have also been described.

Between 1 and 3 weeks after disease onset, the eruption characteristically begins to desquamate beneath the distal nail plates, and peeling may extend to involve the entire palm and sole. Horizontal depressions in the nail plates (Beau’s lines) usually result. A maculopapular eruption may appear in the convalescent phase, that may represent an adverse effect of intravenous γ-globulin (IVIG) therapy, as it appears approximately 10 days after the infusion. It is usually self-limited and does not require specific treatment. Plaque-type, guttate, and pustular psoriasis have been described, either during the acute or the convalescent phase of the disease, which supports a superantigen-mediated etiology.

Extracutaneous findings

Fever lasting for at least 5 days is the cardinal and initial feature of the disease. It usually begins abruptly and reaches temperatures as high as 39–40°C. Irritability is usually prominent. Other extracutaneous features include nonexudative conjunctival injection, involving mainly the bulbar conjunctivae, anterior uveitis, and cervical lymphadenopathy, which is present in approximately 65% of cases. Enlarged nodes are usually firm, nonfluctuant, slightly tender, unilateral, and confined to the anterior cervical triangle. Cardiac disease is the main cause of long-term morbidity and mortality. The pericardium, myocardium, endocardium, and coronary arteries may all be involved. Without treatment, coronary artery aneurysms develop in 20% of cases, and are most commonly detected 10 days to 4 weeks after onset. Risk factors for the development of coronary aneurysms include age younger than 1 year, male gender, fever for more than 2 weeks, recurrent fever, and delayed treatment. Aneurysms may also develop in systemic medium-sized arteries and result in peripheral gangrene.

Polyarticular arthritis and arthralgias may occur in the first weeks of the illness, affecting small as well as large joints. Lethargy and other signs of aseptic meningitis may be present. Abdominal symptoms such as vomiting, diarrhea, and pain are common. Respiratory symptoms due to pulmonary nodules, infiltrates, or pleural effusion may also be observed. Rare findings include testicular swelling, hemophagocytic syndrome, transient unilateral peripheral facial nerve palsy, and transient high-frequency sensorineural hearing loss (20–35 dB).

Etiology and pathogenesis

Epidemiologic and clinical data suggest that Kawasaki disease has features of infectious disease in an immunologically susceptible host and of an immune-mediated vasculitis. Many infectious etiologic agents have been suggested as a trigger but none has been consistently demonstrated. Regardless of the cause, evidence points to a generalized immune activation with production of various proinflammatory cytokines and endothelial cell activation which lead to coronary artery alteration.

Host genetic determinants play a role in both susceptibility and coronary artery outcome in Kawasaki disease. The incidence rate in siblings is 10 times the population incidence. The risk of occurrence in twins is higher than in ordinary siblings. Parents who had Kawasaki disease in childhood are more likely to have affected children, and children with recurrent disease.

Laboratory tests and histopathology

In the acute phase, laboratory studies show leukocytosis (~15 000/mm ³ ) with a left shift, normochromic normocytic anemia, increased sedimentation rate and C-reactive protein, depressed albumin, and elevated IgM and IgE levels. After IVIG treatment, the value of ESR becomes uninterpretable due to increased plasma viscosity. In the subacute stage, in the second and third weeks of illness, there is a marked and almost universal thrombocytosis, which returns to normal in 4–8 weeks. Thrombocytopenia is rarely seen in the acute stage and may be a sign of disseminated intravascular coagulation. Plasma lipids are altered in the acute stage, with depressed plasma cholesterol and HDL. There may be mild elevation of transaminases and polyclonal hypergammaglobulinemia. There may be sterile pyuria with mild proteinuria. Cerebrospinal fluid shows a mononuclear pleocytosis with normal protein and glucose levels. Skin biopsy findings are not specific. There is edema in the papillary dermis, with a mild perivascular mononuclear cell infiltrate. Vasculitis of medium and large arteries is observed.

Diagnosis

Kawasaki disease should be suspected in any patient with fever lasting at least 5 days, nonpurulent conjunctivitis, a polymorphous exanthem, erythema, and swelling of the hands and feet, inflammatory changes of the lips and oral cavity, and acute nonpurulent cervical adenopathy.

While there is no single diagnostic test for Kawasaki disease, widely accepted clinical criteria have been established for diagnosis ( Box 20.4 ). Incomplete KD is more common in young infants than in older children, making accurate diagnosis and timely treatment especially important in these young patients who are at substantial risk of developing coronary abnormalities. In 2004, the American Heart Association recommended incorporating laboratory tests and early echocardiography for diagnosing incomplete KD. Patients with fever for ≥five days (with 2 or 3 principal clinical features for KD) and infants ≤6 months old with fever for ≥7 days without other explanation, should undergo laboratory testing, and if there is evidence of systemic inflammation, an echocardiogram should be obtained even if the patient does not fully meet the clinical criteria for KD ( Box 20.4 ). Although aneurysms rarely form before day 10 of illness, there may be signs of coronary arteritis, decreased contractibility, mitral regurgitation, and pericardial effusion. With all these considerations, a new algorithm has been proposed to help in deciding which patient with incomplete Kawasaki disease should undergo echocardiography or receive IVIG treatment ( Fig. 20.23 ).

Evaluation of suspected incomplete Kawasaki disease.

(Modified from Newburger JW, Takahashi M, Gerber MA, et al. Pediatrics 2004; 114(6):1708–1733.)

Sometimes KD may be ‘atypical,’ presenting at onset with clinical features that are not generally seen, such as acute abdominal pain, renal impairment, meningeal irritation, pneumonia, or retropharyngeal abscess.

Differential diagnosis

Many diseases mimic Kawasaki disease, including viral infections – particularly adenovirus infection; streptococcal infection; juvenile rheumatoid arthritis; erythema multiforme; SSSS; toxic shock syndrome; drug hypersensitivity reactions; Rocky Mountain spotted fever; leptospirosis; mercury hypersensitivity reaction (acrodynia); and bacterial cervical adenitis. Low white blood cell count, lymphocytosis, and low platelet count may be useful in suggesting a viral infection instead of Kawasaki disease. Mucosal changes, conjunctivitis, extremity abnormalities and perineal desquamation, elevated C-reactive protein and platelet counts suggest the diagnosis of Kawasaki disease.

Course, management, treatment, and prognosis

The morbidity and mortality of KD depend primarily on coronary artery lesions. Coronary artery aneurysms or ectasias develop in 15–25% of untreated children and may lead to ischemic heart disease or sudden death. With early treatment, the risk is reduced to around 5–12%. Small aneurysms resolve completely within the first 2 years after disease onset in 30–60% of these patients. However, coronary aneurysms, especially if giant (>8 mm), may persist and be complicated by thrombotic occlusion or the development of stenosis at the outlet of the aneurysm. Stenotic lesions, as well as early coronary atherosclerosis, may develop gradually over several years, so long-term follow-up is warranted.

Echocardiography should be performed as soon as the diagnosis is suspected and should be repeated at 2 weeks and at 6–8 weeks after disease onset. Other noninvasive imaging modalities, such as MRI, MRA, and ultrafast CT, as well as cardiac stress testing, are being evaluated in the management of Kawasaki disease.

Treatment in the acute phase of the disease is directed to reducing inflammation in the coronary artery wall and preventing coronary thrombosis, whereas long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction. Intravenous γ-globulin (IVIG) combined with high-dose aspirin (80–100 mg/kg divided into four) is the treatment of choice in the acute phase of the disease. The duration of high-dose aspirin varies in different centers for up to 48–72 after the child has been afebrile for 14 days of illness. Following this acute phase, low-dose aspirin (3–5 mg/kg) is given as an antiplatelet agent for 6–8 weeks from disease onset.

IVIG has been shown to reduce the incidence of coronary artery aneurisms from 20% to 3–4%. A single dose of 2 mg/kg has been shown to be superior than lower doses for 4 consecutive days. IVIG should be started early, within 10 days of disease onset but not before day 5, because it may be associated with an increased need for IVIG re-treatment. Treatment after day 10 should be considered if there are still signs of ongoing inflammation (elevated ESR or CRP) or persistent fever. Some patients with persistent or recrudescent fever require a second dose.

The usefulness of steroids (prednisolone 2 mg/kg per day) in combination with IVIG in the initial therapy of KD is not well established. Steroids have also been used for IVIG treatment failures, but the benefit of pulse methylprednisolone (30 mg/kg for 1–3 days) over a second course of IVIG has not been demonstrated.

Other treatments for IVIG-nonresponsive KD are controversial.

Cutaneous findings

The disease is characterized by the abrupt onset of fever; tender edema of the face, eyelids, ears, scrotum, and acral extremities; and ecchymotic purpura on the face and extremities. The trunk is usually spared. Individual lesions often have a darker center and expand centrifugally, giving them a cockade or target-like configuration. Lesions range in size from 0.5 to 4.0 cm and may become confluent, forming polycyclic, annular plaques ( Fig. 20.24 ). Necrotic and bullous lesions may be seen, as well as petechiae involving the mucous membranes.

Acute hemorrhagic edema.

Extracutaneous findings

Except for fever, there are usually no associated manifestations in most cases. Gastrointestinal symptoms, including abdominal pain, diarrhea and intussusception have been reported occasionally. In many patients, there is a preceding upper respiratory tract infection. The dramatic cutaneous findings contrast with the general well-being of the patient.

Etiology and pathogenesis

The cause of AHE is unknown. It is thought to represent an immune complex-mediated disease precipitated by a preceding infection, particularly an upper respiratory tract infection, drug intake, or immunization. Staphylococcus and Streptococcus spp. and viruses (adenoviruses, rotavirus) have been implicated most commonly.

Laboratory tests and histopathology

Leukocytosis (both lymphocytic and granulocytic), thrombocytosis, eosinophilia, and an elevated ESR may be present. Urinalysis, tests for occult blood in the stool, immunoglobulin, and complement levels are usually normal or negative. Circulating immunocomplexes may occasionally be found.

Histopathologic examination of skin biopsy specimens demonstrates a small vessel leukocytoclastic vasculitis. Direct immunofluorescence shows deposition of C3 and fibrinogen in the vessel wall. IgM, IgG, IgA, and IgE deposition has also been noted in up to one-third of cases.

Differential diagnosis

The differential diagnosis includes Henoch–Schönlein purpura, child abuse, meningococcemia and other infectious purpuras, erythema multiforme, Kawasaki disease, and Sweet syndrome. Distinction from Henoch–Schönlein purpura may be difficult ( Table 20.5 ). Perivascular deposits of IgA are not useful for differentiation because they may be present in both entities.

Course, management, and prognosis

The prognosis is excellent. The eruption resolves spontaneously without sequelae in 1–3 weeks. Treatment with corticosteroids is not necessary and may lead to complications and worsen the prognosis. Exacerbations may be observed during the clinical evolution, with new crops of lesions and fever, but true recurrences weeks or months after the first episode are rare. There has been a single report of a fatal ileo-ileal intussusception in an infant with cutaneous lesions otherwise typical for AHE, and recurrent AHE was the presenting manifestation of Wiskott–Aldrich disease in another.

Cutaneous findings

Skin lesions are always present, and are the first manifestations in 75% of cases, but in some cases, joint involvement or abdominal pain precedes the rash by up to 2 weeks. Initially, skin lesions may be urticarial or appear as an erythematous macular-papular rash before evolving to palpable purpura. The purpuric papules are typically 2–5 mm in size, symmetrically distributed on the legs and buttocks ( Fig. 20.25 ). In cases with severe vascular damage, there may be large ecchymoses as well as blistering and necrosis. Lesions may appear at sites of trauma (Koebner phenomenon) and on more atypical locations such as the face, trunk, or arms, but they rarely affect mucosa, palms, and soles. In younger children, there may be painful swelling of the scalp, face, periocular region, ears, limbs, and scrotum, mimicking testicular torsion. The lesions heal spontaneously within 1–2 weeks, but exacerbations often occur in the course of the disease.

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