Fever, a common presenting complaint in the acute care setting, may be associated with rash. The disorders that present with fever and rash range from benign and self-limited to rapidly progressive and life threatening. The entire clinical picture must be considered in a child presenting with fever and rash to facilitate timely diagnosis and treatment.

Skin lesions can be characterized by their morphology, color, distribution, and pattern. Based on this characterization, rash can be considered in six major categories:

1. 
   

   Morbilliform

   
   
2. 
   

   Vesiculobullous

   
   
3. 
   

   Erythema multiforme

   
   
4. 
   

   Scarlatiniform

   
   
5. 
   

   Erythroderma

   
   
6. 
   

   Petechiae and purpura

The character of the rash combined with other signs and symptoms often suggests a specific cause of the illness.

A morbilliform rash appears as a generalized erythematous to pink maculopapular rash that blanches with pressure. Measles and rubella are classic infections (Table 97-1) representing this category. While widespread vaccination makes these diagnoses less likely, recent clusters of cases, particularly in unimmunized communities, should prompt consideration of these infections. Among immunized pediatric patients with morbilliform rash, a specific cause is identified in 37% to 48% of cases.^1,2 Common culprits include parvovirus, human herpesvirus 6, enteroviruses, and group A Streptococcus. Other patients likely have unspecified self-limited viral infections, although drug eruption and Kawasaki disease should be considered in the differential diagnosis. Fever, rhinorrhea, and cough typically occur with these illnesses.

The causes of vesiculobullous rash and fever are better defined. A generalized pattern of vesicles on an erythematous base (“dewdrops on a rose petal”) in various stages of eruption is characteristic of varicella, commonly called chickenpox. A dermatomal distribution suggests herpes zoster, particularly in patients with a history of varicella infection or vaccination. Vesicular lesions distributed on the palms and soles associated with mouth ulcers suggest hand-foot-and-mouth disease secondary to enterovirus infection, most commonly caused by coxsackievirus A16. Herpes simplex virus (HSV) causes localized vesicular lesions such as gingivostomatitis, herpes labialis and other genital infections, herpetic whitlow, and keratoconjunctivitis, typically with periocular skin involvement. A vesicular eruption in the neonatal period, with or without fever, raises the suspicion for neonatal HSV infection. Bullae associated with erythema multiforme and mucosal involvement are characteristic of Stevens-Johnson syndrome (Figure 97-1). Staphylococcal scalded skin syndrome and toxic epidermal necrolysis result in bullae with significant skin peeling.

Target lesions are the hallmark of erythema multiforme, appearing as fixed, symmetrical, round lesions with concentric rings and central duskiness. The distribution is typically acral. Erythema multiforme major and minor are differentiated by the presence or absence of mucosal involvement (Figure 97-2). The diagnosis of erythema multiforme major requires the involvement of two or more mucous membrane surfaces, and the lesions may develop bullae. Some experts believe that erythema multiforme major and Stevens-Johnson syndrome are synonymous. Others differentiate the two along a continuum of disease spectrum, with the presence of bullae and a more truncal distribution defining Stevens-Johnson syndrome. Although a host of infectious diseases can be associated with erythema multiforme, HSV is associated with more than 50% of cases of the minor type, whereas Mycoplasma pneumoniae is the agent most commonly implicated in patients with Stevens-Johnson syndrome.³ A separate entity, called urticaria multiforme, may also be confused with erythema multiforme; this rash syndrome is a hypersensitivity reaction characterized by annular, often pruritic, wheals with edema of the face or extremities, and sometimes fever.⁴ It is often associated with a preceding infection or drug exposure.

Scarlatina, or Scarlet fever, is a diffuse, fine papular rash with a “sandpaper” texture, and it is associated with group A Streptococcus infection (Figure 97-3). A characteristic of this rash is exaggeration in the antecubital, axillary, and inguinal folds known as Pastia lines. Erythroderma is a diffuse erythema of the skin that is similar in appearance to sunburn (Figure 97-4). A distinguishing feature is extensive involvement of the skin that does not follow the pattern of sun exposure seen with sunburn. Scarlatina and erythroderma raise the possibility of bacterial toxin production and toxic shock syndrome.

Petechiae are small red or purple lesions that do not blanch with pressure. Purpura are larger, non-blanching, purple or brown lesions; these may be raised, or palpable. Fever associated with petechiae (e.g. rickettsiae, Neisseria meningitidis) or purpura (e.g. N. meningitidis) may be life-threatening conditions.

The remainder of this chapter focuses on specific infectious diseases, including further discussion of the differential diagnoses of febrile illnesses associated with these dermatologic manifestations.

Meningococcal infections are caused by the gram-negative diplococcus N. meningitidis. The peak incidence of these infections is during the first year of life, after passive maternal antibody protection begins to wane; 40% of cases occur in children younger than 5 years. A smaller peak occurs during adolescence and young adulthood, with military recruits and college freshmen living in crowded dormitories at higher risk. Asplenia, complement deficiencies, immunoglobulin deficiencies, and infection with human immunodeficiency virus (HIV) are risk factors for the development of meningococcal infections.

N. meningitidis is classified into serotypes based on the immunologic response to polysaccharides in the capsule. Further subclassification is based on outer membrane proteins and genetic sequencing of the bacteria. Historically, serotypes B and C accounted for the majority of meningococcal infections in the United States and the rest of the industrialized world. In the United States, however, there has been a recent increase in the number of cases attributable to serotype Y; as a result, serotypes B, C, and Y each account for approximately 30% of the total cases. Less common strains, such as W-135, account for the remainder of cases in the United States. Serotype A is responsible for meningococcal epidemics, particularly in sub-Saharan Africa, the so-called meningitis belt.

Humans are the only reservoir for N. meningitidis, and the bacteria reside in the nasopharynx. In non-endemic areas, 5% to 10% of individuals are asymptomatic carriers. Transmission is person to person through respiratory droplets or direct contact with secretions through activities such as kissing or sharing of drinking glasses. Disease develops when a pathogenic strain of N. meningitidis translocates across the mucosal barrier, with subsequent bacteremia. Exposure to cigarette smoke and concurrent upper respiratory infection are risk factors for this process.

PATHOPHYSIOLOGY

Once the bacteria enter the bloodstream, the release of lipopolysaccharides and other bacterial factors results in the release of cytokines and tumor necrosis factor, activation of the complement system, and subsequent development of the systemic inflammatory response. This response, in conjunction with a bacteria-induced procoagulant state, results in the clinical features seen in meningococcemia. Petechiae and purpura develop as a result of vasculitis and thrombosis in the blood vessels of the skin. Meningococcal meningitis is secondary to bacterial seeding of the meninges subsequent to bacteremia.

CLINICAL PRESENTATION

The classic presentation of meningococcemia is the acute onset of fever in association with petechiae or purpura. Headache, myalgia, nausea, and vomiting may be present. Altered mental status, photophobia, and neck stiffness suggest meningitis. Tachycardia, hypotension, and poor perfusion are evidence of septic shock. Early in the course of disease, the rash can appear as a nonspecific, erythematous, maculopapular rash that blanches (Figure 97-5), followed by rapid progression to petechiae and purpura (Figure 97-6). Rash may be absent in a minority of cases.

Rapid progression to multiorgan failure can occur; complications include shock, acute respiratory distress syndrome, seizures, increased intracranial pressure, electrolyte abnormalities, renal failure, adrenal hemorrhage, anemia, thrombocytopenia, coagulopathy, pancreatitis, myocardial dysfunction, and compartment syndrome. Purpura fulminans (Figure 97-7), with necrosis of the skin and extremities (Figure 97-8), can develop.

Overall case fatality rate is 9% to 12%, with a higher rate in meningococcemia of up to 40%.⁵ The lower mortality rate seen in patients with meningitis is explained by the belief that patients who survive the initial bacteremia long enough to develop meningitis have a less pathogenic strain of meningococcus. Among survivors, permanent sequelae occur in 20% of people, with sensorineural deafness being the most common deficit. Other sequelae include neurologic damage and extremity or skin necrosis requiring amputation or skin grafting.

DIFFERENTIAL DIAGNOSIS

Current incidence rates of meningococcal disease in patients presenting with fever and petechial rash are not well defined. Past studies of patients presenting to the emergency department with fever and petechiae show that the incidence of invasive bacterial infections range from 2% to 8%,^6,7 and the incidence of meningococcal infections may be as high as 7%.⁸ In pediatric patients hospitalized for fever and petechiae, the incidence of meningococcal infections may be as high as 15%.⁹ Invasive infections other than N. meningitidis causing fever and petechiae include Staphylococcal aureus, group A Streptococcus, Streptococcus pneumoniae, Escherichia coli, Rickettsia rickettsii, and Ehrlichia chaffeensis. Haemophilus influenzae type B should also be considered in an unimmunized population. Noninvasive causes of petechiae are listed in Table 97-2.

DIAGNOSTIC EVALUATION

Laboratory abnormalities often include leukocytosis, anemia, acidosis, electrolyte abnormalities, and uremia. Thrombocytopenia, prolonged prothrombin time and partial thromboplastin time, elevated fibrin degradation products, and depressed fibrinogen levels are characteristic of the disseminated intravascular coagulopathy of bacterial sepsis. In patients with meningitis, cerebrospinal fluid analysis may show an elevated white blood cell (WBC) count with high protein and low glucose levels, and gram-negative diplococci may be seen on Gram stain.

A number of studies have evaluated clinical and laboratory features in an attempt to exclude meningococcal infection at presentation.^6-10 Petechiae limited to the distribution of the superior vena cava (superior to the nipple line), particularly if associated with coughing or vomiting, make meningococcal infection unlikely. Worrisome findings include ill appearance, evidence of shock, the presence of purpura, WBC count less than 5000 cells/dL or greater than 15,000 cells/dL, and C-reactive protein level greater than 5 mg/L. One study found a 100% negative predictive value for invasive bacterial infections using the criteria of well appearance, no evidence of shock, and normal values for WBC count and C-reactive protein.⁶