Overview
Generalized rashes with fever are among the most frequent conditions seen by primary care physicians, and are a common reason for patient visits to the emergency department and dermatologists. The majority of cases do not represent an immediate danger, but some patients may have a life-threatening diagnosis, and a prompt and accurate approach is warranted.
Diagnosing fever and rash is frequently challenging, because there is a wide variety of clinical presentations and etiologies. Although infections are the most common causes, the differential diagnosis remains wide; accurate history and physical examination are necessary to rule out other causes, such as drug reactions (which occurs in approximately 5% of patients), immunologic and rheumatic diseases, allergens, neoplasia, and sometimes idiopathic causes.
An increasing number of emerging infectious diseases can present with fever and rash, and with climate change, migration, and a higher number of individuals traveling to tropical and exotic destinations, physicians will probably see more patients with this syndrome.
Approach to the Patient with Fever and Rash
The epidemiology and presentation of the patient with fever and rash vary according to each category. A comprehensive history and physical examination are the cornerstones in establishing the diagnosis.
History
Key elements from the history include the distribution and progression of the skin lesions and associated symptoms, recent exposures, vaccination status, travel history, pets and habits, occupational exposures, season of the year, drug ingestion within the past 30 days, sun exposure, and history of drug or food allergies.
When asking for recent exposures, it is important to gather precise information on:
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Contact with wild animals.
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Exposure to vector-borne and zoonotic infections, including exposure to specific vectors such as ticks, louses, fleas, and mites. Possible exposure to these infections should be sought by direct questioning, but also through determining indirect exposure, as is not infrequent that individuals do not remember seeing the ticks or mites attached, but a history of activities (e.g., walking in wilderness or rural areas) may reveal valuable information.
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Detailed history for sexually transmitted diseases, including HIV.
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Exposure to febrile ill persons within the recent past.
Initial Assessment and Physical Examination
When seeing patients with fever and rash, is of utmost importance to initially evaluate if:
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The patient shows signs of severe sepsis or organ failure requiring urgent medical care, cardiopulmonary resuscitation, and antibiotic therapy.
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The patient has exposure to pathogens causing serious illness with a risk of nosocomial transmission, requiring immediate isolation with barrier precautions.
A physical examination of the skin, eyes, oropharyngeal mucosa, lymph nodes, abdomen (with special attention to hepatosplenomegaly), and genitalia should be conducted, with particular attention to conjunctivitis, jaundice, erythema, petechiae, exudates, and ulceration. Cerebral impairment and meningism should also be evaluated.
Skin Evaluation
Full exposure of skin is necessary, including the abdomen, back, chest, axilla, palms, soles, and mucous membranes. Palpation of skin lesions with a gloved hand must be conducted to determine if the lesions are flat or raised and the presence of blanching. It should also be assessed if epidermal sloughing with lateral pressure is present.
Based on visual and tactile characteristics of the eruption, skin lesions can be grouped into macules, papules, nodules, plaques, vesicles and bullae, pustules, purpura, ulcers, or eschars. In Table 7.1 , a morphologic description of the skin lesions is provided to help the reader differentiate between the lesions. It is important to mention that exanthem, defined as a widespread, nonspecific rash characterized by a generalized eruption of little erythematous macules and papules, is frequently used as a synonym for rash.
| Type of Lesion | Description |
|---|---|
| Macules | Flat, nonpalpable lesions above the skin surface (see Figs. 7.6, 7.12, and 7.13 ). |
| Papules | Small, superficial, and solid palpable lesions elevated above the skin surface (<5 mm) (see Figs. 7.4, 7.5, and 7.9 ). |
| Nodule | Deep-seated, indurated, roundish lesion ≥5 mm in diameter that can involve the epidermal, dermal, and/or subcutaneous tissue (see Figs. 7.14 and 7.15 ). |
| Plaques | Palpable lesions with elevation above the skin surface >5 mm (see Fig. 7.5 ). |
| Vesicles (<5 mm) Bullae (>5 mm) | Circumscribed, elevated lesions containing fluid (see Fig. 7.3, 7.10, and 7.11 ). |
| Pustules | Small, palpable lesions filled with purulent exudates. |
| Nonpalpable purpura Palpable purpura | Flat lesion due to bleeding into the skin. If <3 mm, the purpuric lesion is called petechiae. If >3 mm, are called ecchymosis (see Fig. 7.6 ). Raised lesion secondary to an inflammation of the vessel wall with subsequent hemorrhage. |
| Ulcer Eschar | Defect in skin extending at least into the upper layer of the dermis. The superficial lesions are called erosions . Necrotic lesion covered with a black crust. |
On examination, the distribution and direction of spread (centrally distributed and peripheral eruptions), along with the type of lesions, help narrow the diagnosis. For an organized and systematic approach, we have grouped the rashes into six different categories: (1) central distributed maculopapular eruptions; (2) confluent desquamative erythema; (3) vesicobullous eruptions; (4) nodular eruptions; (5) petechial/purpuric eruptions; and (6) eruptions with ulcers and/or eschars. For easier reading, the most frequent causes of fever and rash are found in each corresponding vignette. Information on epidemiology, clinical presentation, diagnostic tests, and treatment is provided. A list of common causes of fever and rash according to the type of skin lesions is presented in Table 7.2 . The most important infections and syndromes are described according to the type of rash. For better presentation and comprehension, we designed an acronym, including: I: Important characteristics/epidemiology; C: Clinical-related data; R: Rash characteristics; A: Ancillary diagnostic studies; T: Treatment; and O: Other recommendations
| Maculopapular Rash | ||||
|---|---|---|---|---|
| Febrile/Toxic and Central Distribution | Febrile/Toxic and Peripheral Distribution | Afebrile/Nontoxic, Central or Peripheral | ||
| Measles Rubella Roseola subitum Infectious mononucleosis Primary HIV infection Ehrlichial diseases Typhoid fever Leptospirosis Murine (endemic) typhus Lyme disease Relapsing fever Arbovirosis (dengue, Chikungunya, Zika) Ebola | Erythema infectiosum Secondary syphilis Stevens–Johnson syndrome | Drug reactions Pityriasis Scabies Eczema Psoriasis Erythema multiforme | ||
| Erythematous Rash | ||||
|---|---|---|---|---|
| Febrile and Positive Nikolsky Sign | Febrile and Negative Nikolsky Sign | Afebrile with Nikolsky Sign | Afebrile Without Nikolsky Sign | |
| Staphylococcal scalded skin syndrome Toxic epidermal necrolysis | Toxic shock syndrome Streptococcal toxic shock syndrome Kawasaki disease Scarlet fever | Drug-induced Associated with Mycoplasma pneumoniae , herpes virus infection | Anaphylaxis Scombroid Alcohol flush Medications | |
| Purpuric/Petechial Rash | ||||
|---|---|---|---|---|
| Febrile and Palpable | Febrile and Nonpalpable | Afebrile and Palpable Lesions | Afebrile and Nonpalpable Lesions | |
| Acute meningococcemia Rocky mountain spotted fever Disseminated gonococcal infection Bacterial endocarditis Henoch–Schönlein purpura | Disseminated intravascular coagulation and purpura fulminans Viral hemorrhagic fever Enteroviral rash | Autoimmune vasculitis (lupus erythematosus, rheumatoid arthritis, systemic vasculitides) Chronic hepatitis B or C Medications | Idiopathic thrombocytopenia purpura | |
| Vesiculobullous | ||||
|---|---|---|---|---|
| Febrile with Diffuse Distribution | Febrile and Localized Distribution | No Fever and Diffuse Distribution | No Fever and Localized Distribution | |
| Varicella Smallpox Disseminated intravascular coagulation | Necrotizing fasciitis Hand–foot–mouth disease | Bullous pemphigoid Pemphigus vulgaris | Herpes zoster (shingles) | |
| Nodular, Ulcers, and Eschar Forming | ||||
|---|---|---|---|---|
| Nodular Eruptions | Eruptions with Ulcers and/or Eschars | |||
| Disseminated infections Erythema nodosum Bacillary angiomatosis Sweet syndrome (see Fig. 7.12 ) | Tularemia Anthrax Ecthyma gangrenosum Rickettsial pox | |||
Maculopapular Rash
These are the most common types of rashes, with the broadest differential diagnosis. These rashes are characterized by a combination of two types of lesions: macules, defined as a nonpalpable, circumscribed lesion that is flat, with any size; and papules that are palpable solid lesions, elevated, and the size is ≤0.5 cm in diameter. It is also known as morbilliform exanthem .
These lesions are usually seen in viral illnesses, including the classic childhood viral diseases such as rubella, measles, roseola subitum, and erythema infectiosum, but can also be seen in bacterial infections, drug eruptions, and immune complex–mediated syndromes. The presence of fever and systemic illness or toxic appearance suggests a potentially deadly condition. An important consideration is the location of the lesions: central (chest, abdomen, or back) or peripheral (extremities).
1. Febrile/toxic and central: Includes many benign viral exanthems and some dangerous causes.
Measles
I: Most common in children. Highly contagious: 90% of susceptible individuals will present the disease after exposure. Case-fatality rate: 4% to 10%.
C: Incubation: 6 to 21 days. Prodromes: 2 to 4 days, fever, malaise, anorexia, cough, coryza, conjunctivitis, Koplik spots (white, gray, or blue elevated lesions with an erythematous base, usually on the buccal mucosa opposite the molar teeth). Exanthem: 2 to 4 days. Recovery and immunity: Cough persists 1 to 2 weeks after rash. Complications: diarrhea, respiratory tract, deafness, encephalitis.
R: Discrete blanching, erythematous, “brick-red” lesions; confluent rash spreads from face, neck, trunk, and lastly, the extremities.
A: Thrombocytopenia, leukopenia, lymphopenia. Complicated measles, head computed tomography (CT) and/or brain magnetic resonance imaging (MRI). Diagnosis by serologic antibody testing.
T: Supportive: antipyretics, fluids, and treatment for superinfections. Vitamin A could reduce morbidity and mortality.
O: Patients should be isolated and placed on airborne precautions. Vaccination interrupts transmission and affords protection to unvaccinated individuals.
With the increasing cases of measles across the United States and some countries in Europe and South America, additional epidemiologic information and current immunization recommendations are provided.
Measles was eliminated from the United States and many countries in the Americas in the early 2000s thanks to national vaccination policies. Despite the overall control, small numbers of cases continued to occur annually related to exposure to cases imported from areas of the world where measles is still endemic.
Within 2018 and 2019, localized measles outbreaks have occurred by travel-related introduction of the virus by infected persons, with subsequent spread through groups of undervaccinated subpopulations in the United States and Europe. By mid-June 2019, more than 1000 individual cases of measles have been confirmed in the United States, and countries such as Venezuela and Ukraine experienced important outbreaks in 2019.
Measles can be prevented with a measles-containing vaccine, which is usually administered as the combination measles–mumps–rubella (MMR) vaccine. One dose of MMR vaccine is approximately 93% effective at preventing measles; two doses are 97% effective, and children who received one dose of the live-attenuated measles vaccine between 12 and 15 months of age and a second dose between 4 and 6 years of age are considered fully immunized. People born before 1957 and those who had measles are also considered protected against the measles virus.
Risk Groups for Acquiring Measles
People not vaccinated because of religious or personal beliefs, pregnant women, and immunosuppressed individuals.
People born after 1957 who were not vaccinated or only received one dose of an inactivated measles vaccine and do not have evidence of immunity.
Students in postsecondary educational institutions, international travelers, and households or close contacts of immunocompromised persons with no evidence of immunity.
Vaccination Recommendations
MMR vaccination is the most effective way to prevent spread of the virus, and in the midst of an outbreak with increased public awareness, health care workers need to be updated on the policies and recommendations of measles vaccination. Table 7.3 summarizes the most current recommendations, but we encourage the reader to keep updated on the topic, as the current measles outbreak in the United States and other parts of the world is rapidly changing.
| Patient Category | First Dose | Second Dose |
|---|---|---|
| Children between 12 months and older If traveling a | Age 12–15 months Get the first dose immediately | Age 4–6 years Get a second dose 28 days after the first dose |
| Teenagers and adults with no evidence of immunity If traveling a | As soon as possible | Four weeks apart from the first dose Get a second dose 28 days after the first dose a |
| Students in postsecondary educational institutions, international travelers, and household or close personal contacts of immunocompromised persons with no evidence of immunity to measles, mumps, and rubella | As soon as possible | Only consider a second dose at least 4 weeks apart from the first dose if previously did not receive any MMR or measles/rubella vaccine |
| Health care workers born in 1957 or later with no evidence of immunity to measles, mumps, or rubella | As soon as possible | Four weeks apart from the first dose |
a We encourage the reader to review the Global Travel Notice from the CDC for patients traveling internationally, as several popular travel destinations are experiencing measles outbreaks.
Can we still vaccinate individuals after contact with measles? People exposed to measles who are not able to show evidence of immunity against the disease should be offered postexposure prophylaxis (PEP) and/or be excluded from the setting (hospital, school, nursery) for 3 weeks from the exposure. To potentially provide protection to these susceptible persons, the current recommendations are:
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Administer the vaccine within 72 hours of initial measles exposure.
OR
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Immunoglobulin (IG) within 6 days of exposure. Do not administer the MMR vaccine and IG simultaneously, as this practice invalidates the vaccine.
According to the Centers for Disease Control and Prevention (CDC), if many cases of measles are occurring in infants younger than 12 months of age, vaccination of infants >6 months may be used as an outbreak control measure.
Individuals at high risk of severe illness and complications from measles, such as infants younger than 12 months of age, pregnant women without evidence of measles immunity, and severely immunocompromised individuals, should receive IG.
Individuals receiving the vaccine within the first 72 hours of measles exposure, and after an individualized analysis, may return to child care, school, or work. Health care workers cannot return to work immediately, and they should wait a 3-week period to go back to health care–related activities. If the IG was given, people cannot return to health care settings, and if possible, persons working in child care, school, or other settings should not return to work before a 3-week period. An individualized analysis is suggested.
Contraindications to MMR Vaccination
When being consulted on MMR vaccination, it is of utmost importance to undertake a detailed past medical history and a review of childhood and adult vaccinations. MMR is a live-virus-attenuated vaccinate and should never be prescribed to pregnant women, those with HIV infection with CD4 <200 cells/mL, or any condition that causes immunosuppression (e.g., cancer patients on chemotherapy or primary immunodeficiencies).
MMR is currently not recommended for children younger than 6 months of age, regardless of the risk of exposure.
If you see or suspect a case of measles, the individual must be isolated and placed on respiratory precautions. Their contacts should be followed for at least 21 days, and notification to local public health authorities should be made immediately.
Rubella
I: Usually a childhood disease. Virus may be shed for 1 to 2 weeks before rash, and patients are contagious.
C: Incubation period: 2 weeks. Usually no serious systemic symptoms. Prominent postauricular, posterior cervical, and/or suboccipital adenopathy. Forchheimer spots (red spots on the soft palate).
R: Spreads caudally, usually disappears in 3 days.
A: Serologic assays.
T: Supportive care.
O: The goal of vaccination is to prevent congenital rubella infection. In pregnancy, rubella can lead to fetal death, premature delivery, and congenital abnormalities.
Roseola Subitum
I: Also known as exanthema subitum or sixth disease . Young children, peak prevalence 7 to 13 months. Most cases have known exposure. It is mainly caused by human herpes virus 6 (HHV-6). Also by HHV-7, enterovirus, parainfluenza-1, and adenovirus.
C: Classically starts with 3 to 5 days of high fever >40° C. When the fever abates, the rash begins. Patients can present with seizures. In adults, arthralgias are common.
R: Blanching macular or maculopapular rash; begins in trunk, neck, and extremities and can spare the face. Resolves within 2 days.
A: Neutropenia and mild lymphocytosis.
T: Symptomatic treatment.
O: Supportive, standard hygienic measures, such as handwashing, may prevent its spread.
Infectious Mononucleosis
I: Acute illness due to Epstein–Barr virus (EBV) infection. Most frequently occurs in adolescents and young adults.
C: Malaise, sweats, anorexia, nausea, chills, pharyngitis, palatal petechiae, splenomegaly, and lymphadenopathy (tends to involve posterior cervical nodes).
R: A diffuse maculopapular eruption, urticarial or petechial (more common after the administration of amoxicillin or ampicillin).
A: Lymphocytosis, atypical lymphocytes, and elevated aminotransferases. Heterophile antibody and EBV-specific antibodies. If these studies are negative, consider an alternative cause for mononucleosis-like illness, such as cytomegalovirus, toxoplasmosis, and primary HIV infection.
T: Supportive therapy.
O: For people who regularly exercise, training can be gradually restarted 3 to 4 weeks after the onset of symptoms.
Primary HIV Infection
I: Occurs approximately 2 to 4 weeks after HIV infection.
C: Acute antiretroviral syndrome: sore throat, lymphadenopathy, arthralgias, myalgias, fatigue, headache, and gastrointestinal symptoms. Painful mucocutaneous ulceration is one of the most distinctive manifestations.
R: Nonspecific macules and papules, well circumscribed, oval or round pink to deeply red colored. The rash persists for 5 to 8 days, nonpruritic, trunk or facial in localization.
A: Antigen/antibody immunoassay plus quantitative plasma HIV-1 RNA levels (viral load); it is usually >100,000 copies/mL. Transient CD4 lymphopenia. HIV serology (delay at least 1 month after acute illness).
T: Prompt initiation of antiretroviral therapy reduces the likelihood of HIV transmission to others and can reduce the size of the latent HIV reservoir.
O: High level of suspicion. Patients should be referred promptly to an infectious diseases specialist to review treatment options. Counseling to adopt behaviors that guard against HIV transmission.
Erlichial Diseases
I: Human monocytic ehrlichiosis (HME), caused by Ehrlichia chaffeensis , and human granulocytic anaplasmosis (HGA), caused by Anaplasma phagocytophilum . Most cases occur in spring and summer in the United States. Vector ticks. Mortality rates are between 2% and 5% in HM, and 7% to 10% in HGA.
C: Acute illness. Incubation period of 1 to 2 weeks. Nonspecific symptoms (headache, myalgias, nausea, chills, diarrhea, malaise, altered mental status).
R: HME presents with a central maculopapular eruption sparing the extremities, palms, and soles (30% of patients). HGA: rash is rare.
A: Leukopenia, thrombocytopenia, elevated counts of aminotransferases, hyponatremia. Diagnosis is made by paired acute and convalescent serology.
T: Initiate treatment based upon a presumptive diagnosis. Treatment for adults and children (including pregnant women), is doxycycline 100 mg twice daily for 5 to 10 days. Alternatives: Rifampin has been used successfully in children.
O: Preventive measures include the use of tick repellents or permethrin and removal of ticks after exposure.
Leptospirosis
I: Zoonosis caused by pathogenic spirochetes (Leptospira) , distributed worldwide. The organisms infect mammals, especially rodents, cattle, swine, dogs, horses, sheep, and goats. Exposure to contaminated water or soil with animal urine.
C: Variable clinical course; most cases are mild to moderate (fever, rigors, myalgias, headache, conjunctival suffusion). Severe and complicated: renal failure, uveitis, hemorrhage, acute respiratory distress syndrome with pulmonary hemorrhage, myocarditis, and rhabdomyolysis.
R: Maculopapular eruption; conjunctivitis, sclera hemorrhage in some cases.
A: Serologic testing is the most common. Molecular diagnosis is a good option. The microscopic agglutination test is a reference standard assay.
T: Antimicrobial use shortens the duration of illness and reduces shedding of the organism in the urine. Mild: doxycycline 100 mg bid PO or ampicillin 500 to 750 mg q6h PO or amoxicillin 500 mg q6h PO. Severe: parenteral penicillin 1.5 MU intravenously (IV) q6h, doxycycline 100 mg IV twice daily, or ceftriaxone 2 g IV q 24 h or ampicillin 0.5 to 1 g IV q6h. The duration of treatment in severe disease is usually seven days.
O: The majority of infections are self-limiting. Prevention includes avoiding potential sources of infection, prophylaxis (doxycycline) for individuals at high risk of exposure, and animal vaccination.
Murine (Endemic) Typhus
I: Disease caused by Rickettsia typhi . Primarily transmitted by the rat flea (also by cats, opossums, and others). Humans are infected by inoculation of infective flea feces within bite wounds.
C: Mild illness. Incubation period between 8 and 16 days. Onset is abrupt, with nonspecific signs (headache, myalgias, fever). In severe cases, hepatic, renal, cardiac, neurologic, and pulmonary dysfunction can occur.
R: Maculopapular eruption is most commonly observed in the trunk, sparing the face, palms, and soles.
A: Thrombocytopenia (50% of patients). Serologic and indirect fluorescent antibody tests. A fourfold rise in immunoglobulin G (IgG) titer from acute illness to convalescence confirms the diagnosis.
T: It should be initiated even if laboratory confirmation is not available to avoid severe or potentially fatal infection. Doxycycline 100 mg twice daily for 7 to 10 days is the treatment of choice. Chloramphenicol 12.5 mg/kg q6h PO or IV (maximum 4 g daily) is the alternative treatment in pregnancy.
O: Prevention is directed to control the flea vectors and potential flea hosts. Advanced age and deficiency of glucose-6-phosphate dehydrogenase (G6PD) are associated with severe or fatal disease.
Lyme Disease
I: Tick-borne illness caused by a spirochete, Borrelia burgdorferi.
C: Three phases: (1) Early localized (erythema migrans) with nonspecific findings, headache, myalgias, chills, photophobia. (2) Early disseminated (acute neurologic or cardiac involvement usually weeks to months after the bite). (3) Late disease, months to years after the onset of infection (arthritis as the main manifestation).
R: Large papule, with central clearing at the site of the tick bite (“bull’s eye”), often found in the axilla, inguinal region, popliteal fossa, or at the belt line. It may burn or itch and is hot to the touch. Sometimes concentric rings, or indurated, or vesicular center, or multiple secondary lesions are observed.
A: Serologic testing should be performed in patients with a recent history or traveling to an endemic area and the presence of risk factors and symptoms consistent with Lyme disease. Recommendation is a whole cell–based enzyme-linked immunosorbent assay (ELISA) followed by a Western blot testing.
T: Early localized: Doxycycline 100 mg bid, amoxicillin 500 mg three times a day (tid) for 10 to 14 days. Early disseminated: same treatment or ceftriaxone 2 g bid for 14 to 28 days. Late disease: Ceftriaxone for at least 28 days. Extended courses of antibiotics are not recommended (lack of evidence for benefit and the potential of adverse effects).
O: Personal protection to avoid tick bites and tick checks after exposure in endemic areas.
Relapsing Fever
I: Caused by spirochetes of the Borrelia genus. Arthropod-borne infection that occurs in two forms: tick-borne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF). Mortality is 4% to 10% in TBRF and 10% to 70% in LBRF.
C: Recurrent fever above 39° C (fever is present for 3 days, alternating with afebrile periods lasting about 7 days), nonspecific symptoms (headache, myalgias, arthralgias, shaking chills, abdominal complaints), and hepatosplenomegaly.
R: Central rash at the end of febrile episode; sometimes petechial.
A: Thin and thick smears of blood should be performed during the febrile period. Polymerase chain reaction (PCR) test can be performed if the organism is not identified on smear.
T: Severe: Ceftriaxone 2 g IV once per day or doxycycline 100 mg bid for 10 to 14 days. Jarisch–Herxheimer reactions are common, and the patient should be observed for about 3 hours after starting antibiotics.
O: Decrease louse and tick exposures. PEP with doxycycline should be administered after tick exposure in an endemic area.
Arbovirosis (Dengue, Chikungunya, Zika)
I: Travel to endemic areas. Arthropod-borne infection transmitted by mosquitoes. Humans are infected after being bitten by an infected female Aedes mosquito ( aegypti and albopictus ). Mosquito usually bites during the daytime and breeds in standing water.
C: Incubation period: 3 to 7 days. Dengue is characterized by retro-orbital, muscle, and joint pain. Chikungunya is characterized by long-standing polyarthralgias, arthritis, and tenosynovitis. Arthralgias are bilateral and symmetric, involving distal and proximal joints. Severe forms: meningoencephalitis, cardiopulmonary decompensation, acute renal failure, and death. Zika virus is mild and self-limited, often with pruritus, dysesthesias, conjunctivitis (nonpurulent), and arthralgia (notably in small joints of the hands and feet).
R: Maculopapular pruritic rash; intense itching may be observed toward the end of the febrile period. Rash may be present on the face, trunk, extremities, palms, and soles ( Figs. 7.1, 7.2, and 7.3 ). The rash of dengue may become petechial or hemorrhagic.
