Accurate diagnosis of the generalized rash can be difficult because of the nonspecific appearance of many rashes. If the diagnosis is not obvious, the physician must resist the common tendency to prematurely close the diagnostic process and instead generate an inclusive differential diagnosis. Part I of this two-part article discusses the common, uncommon, and rare causes of generalized rashes.¹ Part II describes the clinical features that help distinguish these rashes.

Keys to Diagnosis

HISTORY

When the diagnosis of a generalized rash is not obvious, patients should be asked about recent travel, insect and plant exposure, drug exposure (including over-the-counter drugs, alternative medications, and illicit drugs), contact with persons who are ill, pets, hobbies, occupational exposures, chemical exposure, chronic illness, sexual history, and recent systemic symptoms, especially fever (Table 1). Patients should be asked about pruritus, painful lesions, the initial site of involvement, and any personal or family history of atopy (e.g., asthma, allergic rhinitis, childhood eczema).

The patient's age may help narrow the possible diagnoses. For example, acute maculopapular rashes in children are usually caused by viral infections, whereas in adults they are usually caused by drug reactions.² Some rashes are rare in children (e.g., nummular eczema, lichen planus, dermatitis herpetiformis), whereas others are rare in adults (e.g., roseola, Kawasaki disease, scarlet fever).

Patients should be asked about pruritus, because some conditions routinely cause intense pruritus (e.g., scabies, urticaria, atopic dermatitis), whereas others are usually nonpruritic (e.g., seborrheic dermatitis, secondary syphilis, many viral exanthems; Table 2). Most generalized rashes are not painful, but Sweet syndrome, Kawasaki disease, and Stevens-Johnson syndrome are exceptions.

Systemic symptoms, especially fever, can help narrow the differential diagnosis.^3,4 Rashes accompanied by fever are most commonly associated with infections, but drug eruptions and rheumatologic diseases can also cause fever. Although most maculopapular rashes that are associated with fever are caused by self-limited viral infections, empiric antibiotics and laboratory testing are indicated when the history, geography, demographics, and systemic manifestations suggest a more serious infection (e.g., meningococcemia, Lyme disease, Rocky Mountain spotted fever). Petechial rashes require immediate decisions about empiric antibiotics, but life-threatening infections characterized by petechiae (e.g., meningococcemia, Rocky Mountain spotted fever) can start as nonspecific maculopapular rashes.⁵

PHYSICAL EXAMINATION

Characteristics of the rash itself can help narrow the differential diagnosis. In dermatologic diagnosis, it is often helpful to focus on the clinical appearance of the rash after determining the patient's primary symptom, but before taking a more focused history.⁶ This approach may not be intuitive to primary care physicians, who would normally take a complete history first and then perform a physical examination. The size of individual lesions can vary from pinpoint to total-body redness (i.e., erythroderma; Table 3). The shape of individual lesions and their tendency to cluster can also provide important clues. For example, linear patterns of erythema or vesicles are typical of poison ivy; oval lesions are typical of pityriasis rosea; round lesions are typical of nummular eczema; annular lesions are typical of tinea corporis; and geometric patterns may imply a contact component. The color of the lesions should also be noted. Although most generalized rashes are pink or red, lichen planus is characterized by violaceous lesions, and secondary syphilis by red-brown lesions.

In addition to the rash itself, the physician should evaluate the patient's lymph nodes, neurologic status, body temperature, and general appearance. Patients with fever and toxic appearance require prompt evaluation and possibly empiric treatment before reaching a definitive diagnosis.

Dermatologic Signs. Several dermatologic signs may help narrow the differential diagnosis. For example, the Koebner phenomenon (i.e., development of typical lesions at the site of trauma) is characteristic of psoriasis and lichen planus.⁷ The Nikolsky sign (i.e., easy separation of the epidermis from the dermis with lateral pressure) is associated with staphylococcal scalded skin syndrome and toxic epidermal necrolysis.⁸ The value of the Auspitz sign (i.e., the appearance of bleeding points when scale is removed from psoriatic lesions) in the diagnosis of patients with psoriasis has been questioned because of its low sensitivity and specificity.⁹ Blanching of erythematous lesions with brief downward pressure implies that the erythema is the result of vasodilation rather than dermal hemorrhage. Blanching is characteristic of drug eruptions, viral exanthems, Kawasaki disease, roseola, and scarlet fever, whereas the lesions of meningococcemia and the late petechial stage of Rocky Mountain spotted fever do not blanch. The physician should note the presence and quality of scale (e.g., psoriasis, tinea corporis, pityriasis rosea); whether the lesions are evanescent (e.g., urticaria) or stable (e.g., erythema multiforme); and whether lesions tend to become confluent (e.g., urticaria) or remain discrete (e.g., insect bites). When atopic dermatitis is considered, the physician should search for other signs of atopy, such as palmar hyper-linearity, infraorbital folds (Dennie-Morgan lines), dry skin, and lichenification.^10,11

Rash Location. Many rashes tend to avoid or favor certain regions of the body. Physicians should note whether the rash involves the palms, soles, mucous membranes, face, scalp, or extensor or flexor surfaces of extremities. For example, psoriasis usually does not involve the central face, and many generalized rashes avoid the palms and soles, whereas secondary syphilis, erythema multiforme, and rickettsial infections typically include the palms and soles (Table 4). Keratosis pilaris commonly involves the posterolateral upper arms. Scabies involves the fingers, finger webs, wrists, elbows, knees, groin, buttocks, penis, axillae, belt line, ankles, and feet. Seborrheic dermatitis most often involves the scalp margins, the area behind the ears, external ear canals, base of eyelashes, eyebrows, nasolabial folds, and central chest. Patients should be asked where the rash first appeared, because some rashes have a characteristic progression. For example, pityriasis rosea often starts with a relatively large herald patch on the trunk or proximal extremity several days before the smaller oval lesions appear. Rocky Mountain spotted fever often starts on the wrists and ankles before spreading centrally.⁵

TESTS

Blood tests that may be helpful include a complete blood count to determine the presence of leukocytosis or thrombocytopenia, and serologic studies to identify various infectious causes. Mineral oil mounts and potassium hydroxide scrapings can be helpful when scabies or dermatophytes are considered. Skin biopsy, with or without direct or indirect immunofluorescence, is often helpful, especially to confirm lichen planus, dermatitis herpetiformis, mycosis fungoides, and staphylococcal scalded skin syndrome.¹²

“Don't-Miss” Rashes

“Don't-miss” rashes are those that can have serious consequences for the patient or pregnant contacts of the patient. These rashes include various infectious diseases, such as meningococcemia, Lyme disease, and Rocky Mountain spotted fever. Many of these rashes are associated with fever and manifest as petechiae or purpura.⁴ However, there are notable exceptions, such as Lyme disease, which is not petechial, and drug eruptions, which may not be associated with systemic symptoms. Don't-miss rashes can usually be ruled out on the basis of clinical features and demographics, but sometimes further testing is indicated. Some patients should be treated immediately, before a diagnosis can be established. For example, toxic-appearing children and adults with petechiae should be treated immediately for presumed meningococcemia, before undergoing any further evaluation.¹³ Patients from Oklahoma, Tennessee, Arkansas, or the southern Atlantic states who present in the spring or summer with fever, myalgia, and headache—with or without a rash—should be strongly considered for antibiotic treatment of Rocky Mountain spotted fever while awaiting the results of serology or skin biopsy.^14,15 If the physician cannot distinguish between meningococcemia and Rocky Mountain spotted fever on clinical grounds (a common occurrence), patients should be treated for both before undergoing diagnostic tests.^4,16