Mucocutaneous Symptom Complexes

Generally, in differentiating between bacterial and viral causes of febrile illnesses in children, the more mucous membranes involved in the patient’s illness (e.g., conjunctiva, throat, respiratory, gastrointestinal tract), the more likely the cause is viral. When multiple mucous membranes are involved and an exanthem (i.e., mucocutaneous complex) is present, a self-limited viral cause is likely, but other important diagnoses must be considered. These commonly include inflammatory or immunologically mediated conditions, such as Kawasaki disease (KD), Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), drug hypersensitivity, and bacterial toxin-mediated diseases, including staphylococcal and streptococcal toxic shock, streptococcal scarlatiniform disorders, staphylococcal exfoliative toxin syndromes or staphylococcal scalded-skin syndrome, and multisystem inflammatory syndrome in children (MIS-C) associated with the 2019 severe acute respiratory syndrome novel coronavirus (SARS-CoV-2). A best, if not the definitive, diagnosis can be deduced through careful assessment of (1) the dominant features of the illness; (2) prodromal events and exposures; (3) specific characteristics of the exanthem and abnormality at each affected mucous membrane; and (4) the cadence of the developing constellation. Laboratory features are of secondary importance, heightening or diminishing the fitness of the clinical assessment.

Table 13.1 shows useful differentiating features of commonly considered causes of mucocutaneous symptom complexes. Features distinguishing streptococcal toxic shock due to streptococcal pyrogenic exotoxin (SPE) A or B from staphylococcal toxic shock associated with toxic shock syndrome toxin-1 (TSST-1) are shown in Table 13.2 and are described in the discussion where pertinent. SJS and TEN are considered ends of the same disease spectrum, whereas erythema multiforme (EM) is a separate entity distinct from SJS and TEN. EM is characterized by target lesions, whereas the skin lesions of SJS and TEN are widespread and consist of blistering on erythematous or purpuric macules. Table 13.3 shows differentiating features of EM, SJS, and TEN. ^,

Less common conditions share certain clinical features of the mucocutaneous syndromes shown in Table 13.1 but usually can be distinguished on the basis of circumstances of occurrence, such as recurrences and periodicity of febrile episodes in periodic fever with aphthous stomatitis, pharyngitis, and adenitis (the PFAPA syndrome) and chronicity and additional findings in Behçet disease. Similarly, the presence of fever, elevated markers of inflammation and multisystem organ involvement, usually without an exanthem, in the setting of community activity of the 2019 coronavirus infectious disease (COVID-19) might be a clue for MIS-C. Although the ulcerative gingivitis and pseudomembrane of mucositis associated with neutropenia and anticancer chemotherapy can be indistinguishable from the confluent denuding ulcers of SJS, the clinical setting of the former, as well as the absence of conjunctivitis and rash, distinguishes mucositis from SJS. Most commonly, SJS is associated with receipt of antibiotics or anticonvulsant drugs or with Mycoplasma infection. ^, Medications strongly associated with SJS and TEN include sulfonamides, phenobarbital, lamotrigine, and carbamazepine. Reports of cases and case series, however, implicate myriad medications, including acetaminophen and ibuprofen. Paraneoplastic dermatoses represent the spectrum of cutaneous changes associated with malignancies including pyoderma gangrenosum, Sweet syndrome, and paraneoplastic pemphigus. Other cutaneous manifestations of internal malignancies include metastases to the skin and dermatoses induced by environmental carcinogens.

Rocky Mountain spotted fever (RMSF), an infective vasculitis caused by Rickettsia rickettsii, shares many features of other mucocutaneous syndromes (i.e., high fever, progressive serious illness, conjunctival hyperemia and suffusion, peripheral edema despite hypovolemia, and hyponatremia), but the presence of unremitting headache, peripheral petechial rash, season (illness onset during summer), and exposure to ticks usually sets RMSF apart. Ehrlichiosis and anaplasmosis occur in a similar setting; exanthem is less common, and leukopenia may be a clue. Empiric treatment for RMSF or ehrlichiosis with doxycycline regardless of age sometimes is required because the diagnoses cannot be reasonably or quickly excluded. Leptospirosis is indistinguishable from RMSF, except possibly for a biphasic illness and disproportionate kidney or liver involvement in leptospirosis. Drug hypersensitivity reactions can manifest a variety of mucocutaneous abnormalities, including immediate immunoglobulin E (IgE)-mediated rashes and delayed reactions, SJS, TEN, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). DRESS is characterized by diverse cutaneous eruptions (often evolving into indurated edematous erythroderma), with or without mucosal involvement, and systemic involvement that can include hematologic, hepatic, renal, pulmonary, cardiac, neurologic, gastrointestinal, or endocrine abnormalities. The exanthem of AGEP is generalized with multiple sterile, nonfollicular pustules accentuated in the skinfolds, and it typically spares mucous membranes.

For the previously healthy child or adolescent who comes to medical attention in shock, the following must be considered: septic shock from unrecognized ruptured appendix, urosepsis, invasive meningococcal or pneumococcal infection (especially if petechiae, purpura, or purpura fulminans is present), septic or toxic shock from disseminated staphylococcal, and group A streptococcal infection and MIS-C. Streptococcus pneumoniae and group B streptococcus also can cause toxic shock-like manifestations, which probably are related to cytokine stimulation.