Fever and Rash

OVERVIEW: What every practitioner needs to know

Are you sure your patient has fever and rash? What should you expect to find?

Generalized rashes are among the most frequent conditions seen by primary care physicians and the most common reason for new patient visits to dermatologists. Accurate diagnosis is important, because treatment varies depending on the etiology and because some rashes are life-threatening if not treated promptly.

It is most convenient to categorize patients with fever and rash according to the type of rash and its distribution. They can be grouped according to eruption characteristics. Table I provides information on types of skin lesions.

The distribution or direction of spread of an eruption and the number and type of lesions can help to narrow the diagnosis of fever and rash, but by itself it rarely suggests a single diagnosis. The presence of other lesions, most notable target lesions, may suggest a single diagnosis. In the latter group, infections are frequently the cause of the underlying disease. Table II provides the most common infectious and non-infectious causes of rashes.

Characteristics of the skin lesions:

The distribution of spread of an eruption is highly informative. Most drug and viral infection-associated eruptions begin on the face and trunk and spread outward.

The number of lesions may help to distinguish within and between infections. In patients with Salmonella, those who have paratyphoid fever usually have more skin lesions than those with typhoid fever. In contrast, brucellosis may be associated with only one or a few clinically subtle skin lesions.

It must be emphasized that non-infectious diseases with skin rash can also present with fever and should be considered in the differential diagnosis. Drug adverse reactions occur in approximately 5% of patients. The rate of cutaneous reactions is highest for antibiotics (1-8%). A drug reaction must be considered in those patients with a generalized maculopapular rash, especially if associated with palmoplantar involvement.

It is critical to determine the types of lesions that make up the eruption. Morphologic types of primary skin lesions include macules, papules, nodules, vesicles, bullae, pustules, and plaques. Table I summarizes the descriptions of the lesions. Table II describes the rash pattern and the most frequent associated diseases.

Table I.

Type of Lesion	Description
Macules	Macules (<1 cm) / Patch (>1 cm) – Flat, non-palpable lesions in the plane of the skin
Papules	Small, solid, palpable lesions elevated above the plane of the skin (<5mm)
Plaques	Lesions >5mm with a more rounded configuration
Vesicles (<5mm)Bullae (>5mm)	Circumscribed, elevated lesions containing fluid.
Pustules	Small, palpable lesions filled with purulent exudates.
Non palpable purpuraPalpable purpura	Flat lesion due to bleeding into the skin. If < 3mm the purpuric lesion is called petechiae. If > 3mm are named ecchymosis.Raised lesion secondary to an inflammation of the vessel wall with subsequent hemorrhage.
UlcerEschar	Defect in skin extending at least into the upper layer of the dermis.Necrotic lesion covered with a black crust.

Table II.

Rash Characteristics	Infectious Disorders Associated	Non-infectious causes Associated
Central distributed maculopapular eruptions	MeaslesErythema infectiosumExanthema subitum (roseola)Primary HIV infectionInfectious mononucleosisTyphusRickettsial spotted feverEhrlichiosisTyphoid feverErythema marginatumLeptospirosisLyme diseaseRelapsing feverRat bite	Exanthematous drug-induced eruption(see Figure 1)Systemic lupus erythematousStill’s disease
Peripheral eruptions	Bacterial endocarditisErythema multiformeHand-foot and mouth disease(see Figure 2 and Figure 3)Rocky Mountain Spotted feverSecondary syphilis
Confluent desquamative erythemas	Scarlet feverStreptococcal toxic shock syndromeStaphylococcal toxic shock syndromeStaphylococcal scalded-skin syndromeKawasaki disease	Exfoliative erythroderma syndromeToxic epidermal necrolysis(see Figure 4)
Urticarial eruptions		Urticarial vasculitis
Vesiculobullous eruptions	Varicella (chicken- pox)Disseminated herpes-virus infection(see Figure 5)Vibrio vulnificus infectionEcthyma gangrenosumRickettsial pox
Nodular eruptions	Disseminated infectionErythema nodosum(see Figure 6)Bacillary angiomatosis	Sweet syndromeKaposi sarcoma
Purpuric eruptions (see Figure 7)	Acute meningococcemiaPurpura fulminansChronic meningococcemiaDisseminated gonococcal infectionViral hemorrhagic feverEnteroviral petechial rash	Thrombotic thrombocytopenic purpuraCutaneous small-vessel vasculititis
Eruptions with ulcers and/or eschars	TularemiaAnthrax

Physicians often have difficulty diagnosing generalized rash, because many different conditions produce similar rashes and a single condition can result in different rashes with varied appearances. Although it is important to begin the evaluation with an inclusive differential diagnosis, a focused history and looking for clinical features are key points. One important feature is the timing of the onset in relation to fever, and other symptoms associated with the rash (e.g., pruritus, erythema, redness, pain).

History must include:

Drug ingestion within the past 30 days

History of drug or food allergies

Travel history

Exposure to insects, arthropods, and wild animals

Occupational exposures

Sun exposure

Immunizations in the recent past

Exposure to sexually transmitted disease, including risk factors for infection with human immunodeficiency virus (HIV)

Exposure to febrile ill persons within the recent past

Pets and habits

Season of the year (dramatically affects the epidemiology of febrile rashes of infectious origin)

Cardiac abnormalities

Evaluate the following, if the patient is potentially immune suppressed:

Chemotherapy related immune suppression

Steroid use

Hematologic malignancy

Solid organ or bone marrow transplantation

Asplenia

Physical examination should focus on:

Vital signs

General appearance

Toxic appearance

Lymphadenopathy (check location)

Presence and morphology of genital, mucosal, or conjunctival lesions

Hepatosplenomegaly

Arthritis

Nuchal rigidity, meningismus, or neurologic affection

How did the patient develop fever and rash? What was the primary source from which the infection spread?

The skin may be affected by systemic infections in three ways:

1. Direct involvement by the infectious agent

2. Specific reaction to an infection, and

3. Non-specific reaction to an infection

Epidemiology varies according to each category. A comprehensive history and physical examination is cornerstone in establishing the diagnosis. Infectious diseases are the most common causes related with fever and rash, but it is also important to consider rheumatic and neoplastic diseases, drugs, allergens, and sometimes idiopathic causes. A variation by geographic region has also been observed (i.e., patients with fever, myalgia, and headache during spring or summer from southern Atlantic states of the United States should be strongly considered to have Rocky spotted fever). Table III provides information related to history and physical examination oriented to some categories is provided.

Table III.

Rash and Fever Category	Clues
History suggesting an infectious disorder	Personal/family history of infectionsSimilar illness exposureRecent travel (Asia, Africa, Latin America)Chills or night sweatsHeadache, pharyngitis, conjunctivitis, myalgiasInsect/rodent exposureZoonotic exposure
History suggesting a rheumatic disorder	Personal/family history of rheumatic disordersArthralgias/arthritisSerositisCardiac, pulmonary, renal, hematologic, and vasculitic disease
History suggesting a drug related disorder and allergies	History of allergies (patient and family)Medications/herbal teas and other complementary and alternative medicinesSymmetric distribution
History suggesting a neoplastic disorder (there are few causes, most likely: lymphoma, Kaposi sarcoma and paraneoplastic syndromes)	Personal/family history of malignancyWeight loss (decreased appetite)FatigueNight sweatsLymphadenopathy

Which individuals are of greater risk of developing fever and rash?

There are multiple causes of fever and rash. The risk for developing a specific disease varies according to age; race; exposure to drugs, allergens; and chemicals; geographic location; and season, particularly important for infectious diseases.
Fever and rash caused by infectious agents are frequent. The distribution of the eruption (central versus peripheral) and the type of lesions, along with the clinical syndrome and history taking, are cornerstone in establishing the diagnosis. Table IV provides information according to distribution and type of rash: Central distributed maculopapular eruptions, peripheral eruptions, confluent desquamative erythemas, vesiculo-bullous eruptions, nodular eruptions, purpuric eruptions and eruptions with and/or without eschar are reviewed. For detailed information on epidemiology and clinical presentation, please refer to the chapter related to the specific disease and/or infective agent.

Table IV.n

Type of Rash and Associated Diseases Caused by Infectious Agents

In addition to causes previously described, fever and rash in selected populations needs to be mentioned, as more patients with immune suppression are being seen and international travel is more common. In immunocompromised patients, the clinical picture might be more aggressive, and it is not uncommon to find a non-characteristic presentation.

A detailed epidemiologic history is of utmost importance for returning travelers. The most common infectious diseases with fever and rash are transmitted by vector: Typhus, rickettsial spotted fever, Rocky Mountain spotted fever, Lyme disease, ehrlichiosis, and tularemia.

Immunocompromised patients are most susceptible to herpes-virus dissemination, ecthyma gangrenosum, Streptococcal, and Staphylococcal toxic shock syndrome.

Beware: there are other diseases that can mimic fever and rash:

There are non-infectious diseases that can also show with fever and rash. A differential diagnosis with infectious causes should be addressed. Table V the most frequent non-infectious causes of fever and rash according to type and distribution of rash.

Table V.

Disease	Description	Clinical Syndrome
CENTRAL DISTRIBUTON. MACULOPAPULAR ERUPTIONS
Exanthematous drug-induced eruption*	Intensely pruritic, bright red macules and papules, symmetric on trunk and extremities; may become confluent.	Occurs 2-3 d after exposure in those previously sensitized; otherwise after 2-3 weeks (but can occur anytime). Can be accompanied by fever and eosinophilia.
Systemic lupus erythematous	Macular erythema. Erythema in sun exposed areas (i.e,. V shape), periungual telangiectasias, malar rash, vasculitis, oral erosions.	Young to middle-aged women. Flares precipitated by sun exposure. Arthritis, renal, hematologic, vasculitis and pulmonary-associated disorders.
Still disease	Evanescent and transient 2-5 mm erythematous maculopapular rash (salmon-pink) appearing with fever once a day on trunk and extremities (proximal more common).	Young adults (more common in females). High spiking fever, splenomegaly, polyarthritis, sedimentation rate >100 mm/h.
CONFLUENT DESQUAMATIVE LESIONS
Exfoliative erythroderma syndrome	Diffuse erythema interspersed with lesions of underlying conditions.	Usually occurs in men adults older than 50 yrs. Fever, chills, lymphadenopathy.
Toxic epidermal necrolysis-Steven-Johnson syndrome	Diffuse erythema or target-like lesions progressing to bullae, with sloughing and necrosis of entire epidermis; Nikolsky´s sign. Involvement of palms and soles and mucosal surfaces.	Most common in patients with HIV or graft versus host disease. Dehydration, sepsis. 25% mortality. Look for previous medications (sulfonamides, carbamazepine).
URTICARIAL ERUPTIONS
Urticarial vasculitis	Erythematous, circumscribed areas of edema. Can be indurated, pruritic, burning, sometimes purpuric.	Malaise lymphadenopathy, myalgias, arthralgias.
NODULAR ERUPTIONS
Sweet syndrome (acute febrile neutrophilic dermatosis)	Tender red or blue erythematous papules that evolve into painful plaques; usually on face, neck, upper extremities, back of hands and back.	More common in women. 30-60 yr. 20% associated with malignancy. Headache, arthralgias, leukocytosis.
PURPURIC ERUPTIONS
Purpura fulminans	Large ecchymoses with sharply irregular shapes evolving into hemorrhagic bullae and then into black necrotic lesions.	Individuals with sepsis, malignancy, massive trauma, asplenic patients. Hypotension.
Thrombotic thrombocytopenic purpura	Petechiae	Children and young adults; more common in women. Hemolytic-uremic syndrome seen in children after gastroenteritis caused by Escherichia coli O157:H7. Fever, hemolytic anemia, thrombocytopenia, neurologic and renal dysfunction.
Cutaneous small-vessel vasculitis	Palpable purpuric lesions appearing in crops on legs. May become vesicular or ulcerative, usually resolve over 3-4 weeks.	Connective tissue disease, cryoglobulinemia, malignancy, Henoch-Schönlein purpura. Fever, malaise, arthralgias, myalgias, systemic vasculitis, renal, joint and gastrointestinal involvement.

*Common in patients taking allopurinol, beta-lactam antibiotics, sulfonamides, anticonvulsants, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, hypoglycemic, and thiazide diuretics, but can occur with almost any drug.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Most patients with fever and rash do not need any laboratory tests, as most of them are self-limited with a relatively benign course (i.e., childhood viral exanthemas). However, in some diseases confirmation is required. In these circumstances serologic tests, cultures and/or skin biopsy are most useful. In some conditions, basic non-specific laboratory tests should be ordered (i.e., in thrombotic thrombocytopenic purpura, a urine test should be ordered to rule out renal involvement). In life-threatening situations, such as meningococcemia, in addition to non-specific laboratory tests, cultures and skin biopsy are done. Further testing is dictated by the patients’ condition and the appearance of complications.
The relative frequency of the causes of rash and fever in each category is the basis for a diagnostic approach. Table VI illustrates information on laboratory tests for selected infectious causes. Table VII provides information on laboratory tests for other non-infectious causes of fever and rash.

Table VI.n

Laboratory tests for infectious causes of fever and rash (Common and uncommon causes)

Table VII.

Condition	Tests	Evidence Rate
Lupus	Antinuclear antibody testing. Skin biopsy with direct IFA is diagnostic and often done. Other specific immunological tests.	C
Toxic epidermal necrolysis-Stevens-Johnson syndrome	Skin biopsy is diagnostic and routinely done.	C
Sweet syndrome	Skin biopsy is diagnostic and routinely done.	C
Mycosis fungoides (i.e., cutaneous T-cell lymphoma)	Skin biopsy is diagnostic and routinely done.	C

What imaging studies will be helpful in making or excluding the diagnosis of fever and rash?

Imaging tests are not cornerstone in the diagnostic work-up of an uneventful episode of fever and rash.

Imaging studies are usually ordered in life-threatening conditions, patients with serious underlying diseases (i.e., immunosuppression), and individuals in whom a complication is suspected.

A patient centered evaluation should dictate the sequence and type of study. (See Table VIII)

Average prices of these imaging studies in US dollars can be:

Head CT scan: $200-$2000

Brain MRI: $800-$5000

CT scan (1 region): $600-$2500

Ultrasound: $99-$1000

Transesophageal echocardiography: $3700.00

Table VIII.

Imaging Studies	Clinical Setting	Condition
Head CT and/or Brain MRI	Fever and rash + abnormal neurological examination (aseptic meningitis, meningitis)	Meningococcemia, rickettsial infection. Severe forms of varicella and herpes. Complicated measles
CT Scan (region depends on extent of affection)	Systemic toxicity + rapidly progressing soft tissue necrosis (presence of free air in soft tissues)	Necrotizing fasciitis
Liver and Spleen Ultrasound	Severe hepatosplenomegaly	Infectious mononucleosis (protracted course). Any disease with serious hepatic and/or splenic involvement
Transesophageal Echocardiography	Heart murmur + continuous bacteremia and/or peripheral manifestations of endocarditis	Subacute bacterial endocarditis

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has fever and rash, what therapies should you initiate immediately?

The disorders responsible for fever and rash are numerous, and their manifestations protean; therefore, multiple specialists are frequently involved on the diagnostic approach.

Family Physicians, Dermatologists, Emergency services, Pediatricians, Internal Medicine, and Infectious Diseases Physicians are frequently consulted. Depending on the clinical condition and severity of the disease, Rheumatologists, Intensive Care doctors and Oncologists may also be involved during the diagnostic work-up and treatment. In some life-threatening disorders, such as necrotizing fasciitis, surgeons must be consulted.

Empiric therapy

The utility of empiric therapy is limited to a few causes, because many agents causing fever and rash are of viral etiology.
When patients have a life-threatening condition, empiric therapy is of high priority and should be started even before a diagnostic culture or biopsy can be taken. A focused history and clinical features are most useful; reducing the possibilities to a very limited differential diagnostic list helps in the selection of empiric treatment. Necrotizing fasciitis, meningococcemia and Rocky spotted mountain fever are conditions in which empirical treatment should be started early during patients admission and not be delayed waiting for laboratory results. In some conditions (e.g., necrotizing fasciitis), emergency surgical debridement is also performed.
There are other bacterial infections in which antimicrobial treatment should be initiated as soon as the initial diagnostic work-up has been completed (i.e., leptospirosis, scarlet fever, staphylococcal infections, endocarditis, Lyme disease). For initial drug treatment, please refer to published guidelines and recommendations.

What complications could arise as a consequence of fever and rash?

What should you tell the family about the patient's prognosis?

Prognosis of fever and rash is determined by the cause and by the nature of the underlying disease(s). Childhood viral exanthems are usually self-limited and uneventful.
Patients’ life-threatening conditions, such as meningococcemia, toxic shock syndrome, toxic epidermal necrolysis, and ebola disease have high mortality. Immunocompromised patients have the poorest prognosis.
The underlying cause determines its potential for recurrence. Some diseases have protracted courses and may cause serious complications (e.g., Kawasaki disease, lupus).
Consider if the patient is well enough to provide medical and non-medical information at admission or requires immediate cardio-respiratory support.
If the infectious agent is transmitted by droplet or airborne spread (either viral or bacterial disease), the patient must be isolated. Start appropriate universal precautions. Health care workers should exercise caution and use standard precautions. Gloves should always be worn during examination of the skin, and avoid intimate contact with secretions. In the event of a potential exposure to a pathogen, start post-exposure prophylaxis and determine if work restrictions are needed.
Consider an exotic disease acquired as a result of travel or the intentional release of a potentially bioterrorism agent.

How can fever and rash be prevented?

Prevention of diseases causing fever and rash is difficult. Cough etiquette, contact precautions, and hand hygiene are easy and cost-effective measures in reducing the spread of infectious agents causing fever and rash. Avoiding unnecessary drug prescriptions prevents drug-related adverse events.

For measles, mumps, rubella (MMR) prevention can be achieved by vaccination (two doses in childhood). In adolescents and adults, if none confirmatory immunization documentation exists, they need to receive two doses of MMR, at least 4-week apart. MMR is contraindicated in pregnancy, HIV with CD4 lymphocyte < 200 cells/mm³, or immune compromised patients.

Prevention of varicella and meningococcemia can also be achieved by vaccination. Both vaccines have been accepted in most national immunization programs. There are variations across the globe depending on the epidemiology of the disease (e.g., meningococcal disease), health budget, and authority decisions (e.g., varicella vaccine is not on the immunization program of France or the United Kingdom).

For meningococcal disease, chemoprophylaxis can also be useful. Among household contacts, the incidence of transmission of meningococcus is approximately 5%; therefore, it is recommended that household contacts of bacteriologically confirmed cases receive rifampin (adults: 600 mg bid for a total of 4 doses; children older than 1 month: 10 mg/kg; children younger than 1 month: 5 mg/kg). These contacts should be advised to watch for fever, rash, sore throat, or any symptoms of meningitis. Intimate, non-household contacts who have had mucosal exposure to the patient’s oral secretions should also receive prophylaxis.

Health-care workers are not at an increased risk for the disease and do not require prophylaxis unless they have had direct mucosal contact with patient secretions (i.e., mouth-to-mouth resuscitation, endotracheal intubation, or nasotracheal suctioning). Ciprofloxacin (500 mg by mouth; adults only) or ceftriaxone (250 mg IM for adults or 125 mg IM for children) are single dose alternatives.

With the increasing vector borne diseases (e.g., Zika, chinkungunya, dengue, yellow fever) efforts to prevent mosquito bites are cornerstone. Some of the recommended measures in persons living or traveling to endemic areas are:

– Long-sleeved shirts and pants.
– If possible, keep indoors at sunset.
– Cover water storage containers so that mosquitos cannot get inside to lay eggs.
– Discard or empty regularly any items that hold water like tires, buckets, pools, birdbaths, flowerpot saucers, or trash containers.
– Sleep under a mosquito bed net if you are overseas or outside and are not able to protect yourself from mosquito bites.
– Use Environmental Protection Agency (EPA)-registered insect repellents with one of the following active ingredients: DEET (≥20%), picardin, IR3535, oil of lemon eucalyptus, or para-menthane-diol.

For men who live in or have traveled to an area with Zika, and have a pregnant partner they either have to use condoms correctly from start to finish, every time they have vaginal, anal, and oral sex, or do not have sex during pregnancy.

Women who had Zika virus disease should wait at least 8 weeks after exposure to attempt conception and men with Zika virus disease should wait at least 6 months after symptom onset to attempt conception. Women and men with possible exposure to Zika virus but without clinical illness consistent with Zika virus disease should wait at least 8 weeks after exposure to attempt conception.

Maculopapular rash. Exanthematous drug-induced eruption. Courtesy of Teresa Vega.

Hand-foot and mouth disease in a patient with cancer. Courtesy of Teresa Vega.

Toxic epidermal necrolysis with mucosal involvement. Courtesy of Teresa Vega.

Immunesupressed patient with a vesiculobullous eruption caused by herpes zoster. Courtesy of Teresa Vega.

Erythema nodosum in a young patient with lymphoma. Courtesy of Teresa Vega.

Purpuric eruption, unknown cause. Courtesy of Teresa Vega.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Meurer, WJ, Lavoie, FW.. “Central nervous system infections”. Rosen’s emergency medicine: concepts and clinical practice. 2010.

Gilbert, DN, Chambers, HF, Eliopoulos, GM, Saag, MS. The Sanford Guide to Antimicrobial Therapy. 2015.

“CDC 24/7: Saving Lives. Protecting People. Zika Virus”.

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This article originally appeared on Infectious Disease Advisor