Fever and Rash

Maculopapular Eruptions

Macules are flat, nonpalpable circumscribed lesions, while papules are <1 cm, circumscribed palpable lesions. Maculopapular lesions may coalesce into a more confluent morbilliform (measles-like) eruption. A rash with multiple small papules that feels like sandpaper is described as scarlatiniform . Maculopapular rashes are usually seen in viral illnesses, drug eruptions, and immune complex–mediated disorders. The classic childhood exanthems such as measles, rubella, erythema infectiosum (fifth disease, caused by parvovirus B19), and roseola (exanthem subitum, caused by human herpesvirus types 6 and 7) produce a maculopapular rash and are usually clinically recognizable ( Figs. 53.1 and 53.2 ; see Table 53.6 ). Other organisms that commonly cause a maculopapular rash include enteroviruses, Epstein-Barr virus (EBV), cytomegalovirus, adenovirus, acute HIV, and hepatitis B virus. Erythema migrans, the distinctive rash of Lyme disease (caused by the tick-borne spirochete Borrelia burgdorferi ), begins as a papule at the site of a recent tick bite and slowly expands over days to weeks to form an erythematous, annular lesion, sometimes with partial central clearing ( Fig. 53.3 ). The rash of southern tick-associated rash illness (STARI) appears similarly. Erythema marginatum, a rare but major manifestation of acute rheumatic fever, is also distinctive ( Fig. 53.4 ).

Morbilliform drug eruptions are often indistinguishable from viral exanthems and typically present 7–14 days after exposure to a drug ( Fig. 53.5 ). As with most viral exanthems, the rash starts on the trunk and spreads to the extremities. Examples of causative agents include aminopenicillins, cephalosporins, antiepileptics, and sulfonamides. Morbilliform drug eruptions usually resolve spontaneously after discontinuation of the culprit drug, but sometimes they are the first sign of the potentially life-threatening syndrome drug rash with eosinophilia and systemic symptoms ( DRESS , also known as drug-induced hypersensitivity syndrome, formerly anticonvulsant hypersensitivity syndrome).

Inflammatory diseases can also present with fever and maculopapular rash. Systemic juvenile idiopathic arthritis (SJIA, Still disease) classically presents with an evanescent, salmon-colored macular rash on the trunk and proximal extremities that coincide with fever spikes (see Chapter 44 ). Many of the hereditary periodic fever syndromes manifest with macular, maculopapular, or urticarial rashes associated with fever (see Chapter 54 ).

Petechiae and Purpura

Extravasation of red blood cells from the vasculature into the skin produces petechiae and purpura. These lesions do not blanch with applied pressure. Petechiae are pinpoint lesions (<3 mm). Purpura are larger lesions and can be either palpable or nonpalpable. While the majority of patients with fever and petechiae have a benign illness, their presence, especially in a child younger than 24 months, is of particular concern. Between 2% and 20% of affected patients have an underlying bacterial infection, and depending on the clinical setting, 0.5–10% have sepsis caused by Neisseria meningitidis . Other potentially serious infections signaled by a petechial rash and fever include bacterial endocarditis and Rocky Mountain spotted fever. Group A streptococcal (GAS) pharyngitis is the most common bacterial cause of fever and petechiae, with up to 20% of patients with fever and petechiae being diagnosed with GAS pharyngitis in some studies. Common viral causes include enterovirus and adenovirus. Febrile children may develop petechiae after coughing or vomiting; petechiae in this setting are almost always located in the superior vena cava distribution above the nipple line. Further, petechiae confined solely to the area above the nipple line is rarely associated with invasive bacterial disease. Noninfectious causes of fever and petechiae include drug eruptions and acute leukemia. Not all children with fever and petechiae have thrombocytopenia.

Diffuse purpuric lesions may be noted in a wide variety of disorders. These include infectious diseases associated with organisms with a predilection for vascular endothelium, such as N. meningitidis ( Fig. 53.6 ) and rickettsiae ( Fig. 53.7 ), uncommon bacterial diseases such as rat-bite fever ( Fig. 53.8 ) and Vibrio vulnificus or Brazilian purpuric fever caused by Haemophilus aegyptius , and a number of viral hemorrhagic fever diseases. Purpura is also associated with disseminated intravascular coagulation (DIC) and profound thrombocytopenia, such as in idiopathic thrombocytopenic purpura (see Chapter 51 ). Purpura followed by subsequent necrosis of skin is referred to as purpura fulminans , a severe, life-threatening condition that has been reported after relatively benign infections such as varicella or with more serious disorders (meningococcemia) ( Fig. 53.9 ). Purpura can also occur in the noninfectious vasculitides, such as Henoch-Schönlein purpura (HSP) and granulomatosis with polyangiitis. Discrete, raised purpuric lesions (palpable purpura) distributed predominantly over the buttocks and lower extremities are typical for this disorder. While bacteremia must be considered for all febrile patients presenting with diffuse or discrete purpuric lesions (see Figs. 53.6, 53.7, 53.8, and 53.9 ), patients with HSP are generally well-appearing but may have significant discomfort from arthritis or abdominal pain.

Vesiculobullous Eruptions

Vesicular rashes (sharply demarcated, raised lesions containing clear fluid), bullae (vesicles exceeding 1 cm in diameter), or pustules (raised lesions containing cloudy fluid composed of serum and inflammatory cells) may be suggestive of focal or disseminated infection with various pathogens or signal a serious drug reaction. Localized vesicles may suggest infection with herpes simplex virus (HSV) type 1 or 2 (especially if the vesicles are grouped on an erythematous base), varicella-zoster virus (especially if grouped vesicles are distributed in a dermatomal pattern) ( Fig. 53.10 ), or infection with nonviral pathogens, such as Rickettsia akari (the cause of rickettsialpox , a mouse mite–borne rickettsiosis found worldwide but common in New York City). Localized pustules and bullae are usually suggestive of pyodermas caused by Staphylococcus aureus , but pustular lesions distributed on the palms and soles in the context of fever may represent infective emboli with microabscess formation (Janeway lesions), which are often caused by S. aureus endocarditis.

Vesicles distributed in a more generalized pattern , especially with a concentration of lesions over the head and trunk in various stages of evolution, are suggestive of primary varicella-zoster virus infection ( chickenpox ). A more generalized pattern with a concentration over the extremities is suggestive of enteroviral infection, especially with coxsackievirus A16 ( hand-foot-and-mouth disease ), or A6 in even more severe presentations. Orthopoxviruses such as monkeypox, like smallpox, cause a systemic febrile rash illness with lesions that progress from papules to vesicles to pustules concentrated on the face and extremities. Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous hypersensitivity reaction characterized by numerous sterile pustules beginning on the face and spreading to the trunk and limbs. It typically presents within 24 hours after exposure to an offending drug, usually a β-lactam or macrolide antibiotic. The clinician evaluating the sexually active patient presenting with asymmetric generalized pustules or vesicopustular lesions should also consider disseminated infection with Neisseria gonorrhoeae . Diffuse vesiculobullae may be noted in Stevens-Johnson syndrome (SJS) or in toxic epidermal necrolysis (TEN), life-threatening mucocutaneous hypersensitivity diseases usually related to drugs.

Nodules

Nodules (discrete, raised, firm, well-demarcated lesions without fixation to the overlying skin) may be associated with a number of underlying infectious or inflammatory disorders, such as polyarteritis nodosa and Sweet syndrome (acute febrile neutrophilic dermatosis). Red, pink, or plum-colored nodules distributed in a seemingly random manner over the skin surface may represent leukemic infiltrates. The subcutaneous nodules of acute rheumatic fever are usually located over bony extensor surfaces near tendons and are found in <5% of patients with acute rheumatic fever. They may also be found in patients with polyarticular JIA and dermatomyositis.

Erythema nodosum (erythematous and painful nodules usually distributed over the extremities) may be associated with viral infections including hepatitis B and C; bacterial infectious agents including group A β-hemolytic streptococcus (most common), chlamydia, Brucella species, and Yersinia species; mycobacterial infections; fungal infections, particularly Coccidioides immitis and less often Histoplasma capsulatum , Blastomyces dermatitidis, or Cryptococcus neoformans ; or drug reactions, especially in response to oral contraceptives and sulfonamides. Other noninfectious causes include SLE, sarcoidosis, and inflammatory bowel disease.

Ulcers

Ulcers are depressed lesions in which the epidermis and some or all of the dermis has been destroyed. In immunocompromised hosts, infection with HSV may manifest with shallow erosive or ulcerative lesions. In immunocompetent hosts, cutaneous ulcerations may be noted in noninfectious disorders associated with vasculitis, such as SLE, polyarteritis nodosa, and HSP.

Pyoderma gangrenosum and ecthyma gangrenosum are painful cutaneous ulcerative lesions with an erythematous, raised edge. The lesions usually begin as a papule and break down rapidly with central necrosis. It may be seen in immunocompromised patients, typically in the setting of neutropenia, often with systemic infections with bacterial pathogens (typically gram-negative), such as Pseudomonas aeruginosa or Stenotrophomonas maltophilia (ecthyma). In immunocompetent patients, the lesion may manifest in the context of inflammatory bowel disease (pyoderma gangrenosum), PAPA (pyogenic arthritis, pyoderma gangrenosum, acne), or rheumatoid arthritis. Digital ulcerations may be noted in patients with small-vessel vasculitis, such as SLE. Oral ulcerations may be noted in those with herpes simplex or coxsackievirus (hand-foot-and-mouth disease) or as a manifestation of Behçet disease, SLE, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis), cyclic neutropenia, or inflammatory bowel disease.

Erythema

Diffuse erythema ( erythroderma ) is associated with toxin-mediated disorders characterized by superantigen production. Bacterial superantigens cause nonspecific T-cell stimulation resulting in several acute rash-fever disorders, such as staphylococcal scalded skin syndrome (SSSS; Fig. 53.11 ), streptococcal scarlet fever, staphylococcal or streptococcal TSS, and possibly KD.

Localized erythema in the context of acute fever is strongly suggestive of cellulitis, erysipelas, or abscess. The presence of warmth, tenderness, and associated lymphangitis is highly indicative. Organisms causing cellulitis or abscess formation are usually inoculated directly into the skin as a result of trauma. However, bacteremic localization is well described among young children with preseptal or facial cellulitis associated with Haemophilus influenzae type b (pre– H. influenzae type b vaccine) or Streptococcus pneumoniae .

Patients with SLE or dermatomyositis may present with an isolated erythematous malar rash (butterfly rash), which is exacerbated by exposure to sunlight. The acute onset of intense “slapped-cheek” erythema of the face suggests erythema infectiosum, a recognizable exanthem caused by parvovirus B19, and should be differentiated easily from the malar rash of SLE, which usually manifests other characteristics, such as chronicity as well as hyperkeratosis and follicular plugging. In addition, patients with erythema infectiosum tend to have a maculopapular, lacelike rash over the arms, which may spread to the buttocks and thighs ( Fig. 53.12 ; see Table 53.6 ).

Patients with dermatomyositis may have localized lilac-colored lesions over the eyelids (heliotrope rash), which may be associated with periorbital edema. Such patients characteristically, but not invariably, have an erythematous, scaly eruption on the face, neck, knees, elbows, and phalanges. When the rash is localized over the knuckles, it resembles dripped wax and has been referred to as Gottron papules. Patients with autoinflammatory disorders (periodic fever syndromes) may present with localized erythema or fasciitis (see Chapter 54 ).