Immunologic, Reactive, and Purpuric Disorders

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 ).

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.

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.

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.

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.

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.

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.