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Fever and rash in the immunocompetent patient

Fever and rash in the immunocompetent patient
Literature review current through: Jan 2024.
This topic last updated: Nov 29, 2023.

INTRODUCTION — Fever with an accompanying rash is a common symptom constellation in patients presenting to clinicians' offices and emergency departments. Skin manifestations may provide the only early clue to an underlying infection, may be the hallmark of contagious disease, and/or may be an early sign of a life-threatening infection or serious noninfectious disorder. The differential diagnosis of fever and rash is extremely broad, but this symptom complex provides an opportunity for the diligent clinician to establish a probable etiology through a careful history and physical examination.

A systematic approach is crucial for establishing a timely diagnosis, determining early therapy when appropriate, and considering isolation of the patient if necessary. Epidemiologic clues are important to pursue, such as [1-6]:

Age of the patient

Season of the year

Travel history

Geographic location

Exposures, including to insects (especially ticks and mosquitoes), animals (both wild and domestic), and ill contacts

Medications

Immunizations and history of childhood illnesses

Immune status of the host

Features of the rash are also important to consider, including:

Characteristics of the lesions

Distribution and progression of the rash

Timing of the onset in relation to fever

Change in morphology, such as papules to vesicles or petechiae

Symptoms associated with the rash (eg, pain, pruritus, numbness)

Despite the strong association between the syndrome of fever and rash and infectious diseases, a variety of noninfectious processes can also cause similar presentations, including deep venous thrombosis, superficial thrombophlebitis, erythromelalgia, relapsing polychondritis, foreign body reactions, drug reactions, gouty arthritis, cutaneous lupus erythematosus, cutaneous vasculitis, and erythema nodosum [7,8].

The approach to the immunocompetent patient with fever and rash and selected presentations that constitute emergencies will be reviewed here. Fever and rash in immunocompromised patients are discussed separately. Skin lesions in the returning traveler are also discussed separately. (See "Fever and rash in immunocompromised patients without HIV infection" and "Fever and rash in patients with HIV" and "Skin lesions in the returning traveler".)

EPIDEMIOLOGY AND ETIOLOGY — Epidemiologic features are extremely helpful in the approach to a patient with a fever and rash [1-4].

Diseases that present in childhood — The age of the patient often assists in narrowing the differential diagnosis. Exanthems associated with a variety of viral illnesses are classically seen in the pediatric age group [9]. The constellation of symptoms and a characteristic rash often allow for a clinically based diagnosis, as illustrated by the following disorders.

Measles (rubeola) – Measles is associated with a blanching erythematous "brick-red" maculopapular rash beginning in the head and neck area and spreading centrifugally to the trunk and extremities (picture 1A-D); patients also typically have fever, cough, coryza, conjunctivitis, and Koplik's spots (picture 2). (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention".)

Chickenpox (varicella) – Chickenpox is characterized by classic vesicular lesions on an erythematous base that appear in crops and are present in different stages from papules through vesicles to crusting (picture 3A-D). (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

Rubella – Rubella has a rash that resembles measles; however, the patient does not appear to be sick (picture 4). Prominent postauricular, posterior cervical, and/or suboccipital adenopathy may also assists in the diagnosis. Forchheimer spots, or punctate soft palate macules, can represent a helpful clue.

Erythema infectiosum (fifth disease) – Erythema infectiosum is due to human parvovirus B19. Children, unlike adults, often develop a characteristic rash with a "slapped cheeks" appearance followed by an erythematous maculopapular rash that spreads from arms to trunk and rash in a reticular pattern (picture 5A-B). (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

Roseola infantum (exanthem subitum; sixth disease) – Roseola infantum, an illness of infants most commonly caused by human herpesvirus 6, is characterized by high fever for three to four days, followed by seizures and a generalized maculopapular rash that starts on the neck and trunk and spreads to the face and extremities. (picture 6). (See "Roseola infantum (exanthem subitum)" and "Human herpesvirus 7 infection", section on 'Primary infection'.)

Other infections accompanied by rash also occur primarily in children:

Scarlet fever – Scarlet fever is an exotoxin (erythrogenic toxin)-mediated diffuse erythematous rash occurring most commonly in the setting of pharyngitis from group A Streptococcus (GAS) infection. Scarlet fever is manifested by a coarse, sandpaper-like, erythematous, blanching rash, which ultimately desquamates (picture 7A-B). This is accompanied by circumoral pallor and a strawberry tongue. (See "Complications of streptococcal tonsillopharyngitis".)

Acute rheumatic fever – Acute rheumatic fever (ARF) is another potential sequela of group A streptococcal pharyngeal infection. The classic dermatologic manifestations of ARF are erythema marginatum (transient macular lesions with central clearing found on the extensor surfaces of the proximal extremities and trunk) and subcutaneous nodules often located over bony prominences (picture 8). (See "Complications of streptococcal tonsillopharyngitis" and "Acute rheumatic fever: Clinical manifestations and diagnosis".)

Kawasaki syndrome – Kawasaki syndrome, a disease of unknown etiology, is usually seen in children less than four years of age. In addition to fever lasting >5 days, some of the criteria for this syndrome are bilateral conjunctival injection; erythematous fissured lips; injected oropharynx or "strawberry tongue" (picture 9); edema and erythema of the hands or feet and/or subsequent periungual desquamation (picture 10A-B); rash (picture 11A-B); and cervical lymphadenopathy [10]. (See "Kawasaki disease: Clinical features and diagnosis".)

Enteroviruses – Nonpolio enteroviruses (coxsackievirus, echovirus) can cause a variety of rashes and should always be included in the differential diagnosis of a young child with fever and rash of undetermined etiology. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

Mononucleosis – An evaluation for Epstein-Barr virus (EBV)–associated infectious mononucleosis should be undertaken in older children and adolescents who present with fever, malaise, sweats, anorexia, nausea, chills, sore throat, posterior cervical lymphadenopathy, splenomegaly, and a maculopapular rash, especially after the administration of ampicillin (picture 12). The rash is usually over the trunk but can involve the extremities, including the hands and feet. Other causes of infectious mononucleosis are discussed below. (See 'Selected diseases that present in adulthood' below and "Infectious mononucleosis".)

Arcanobacterium haemolyticum – Adolescents and young adults with pharyngitis, fever, lymphadenopathy, and/or maculopapular/scarlatiniform rash whose work-up is negative for group A Streptococcus and viral-associated mononucleosis may be infected with A. haemolyticum, a gram-positive rod that appears to be more susceptible to erythromycin than to penicillin [11]. This infection is seen primarily in adolescents and young adults, and the rash, which can be pruritic, is typically seen first over the extensor surfaces before spreading centrally (picture 13) [11]. The rash usually spares the face.

Mycoplasma pneumoniae – M. pneumoniae infection may be accompanied by skin findings, which include a mild erythematous maculopapular or vesicular rash, erythema multiforme, or the Stevens-Johnson syndrome. (See "Mycoplasma pneumoniae infection in children", section on 'Mucocutaneous disease'.)

Selected diseases that present in adulthood — Exanthems associated with a variety of viral illnesses can be seen in adults. Several to consider include:

Measles (rubeola) – Measles (rubeola) is associated with a blanching erythematous "brick-red" maculopapular rash beginning in the head and neck area and spreading centrifugally to the trunk and extremities (picture 1D-E); patients also complain of fever, cough, coryza, and conjunctivitis. Despite the availability of an effective measles vaccine, measles outbreaks continue to occur [12,13]. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Measles: Epidemiology and transmission".)

Mononucleosis – Infectious mononucleosis syndromes can be caused by several different pathogens (eg, EBV, cytomegalovirus, HIV, human herpesvirus 6, Toxoplasma gondii). Young adults who present with fever, malaise, sweats, anorexia, nausea, chills, sore throat, posterior cervical lymphadenopathy, splenomegaly, and a maculopapular rash, especially after the administration of ampicillin, should undergo an evaluation for Epstein-Barr virus–associated infectious mononucleosis (picture 12). The rash is usually over the trunk but can involve the extremities, including the hands and feet. About half of all college freshmen have EBV-associated antibodies, and up to 20 percent of those who do not are expected to seroconvert annually during these years. Importantly, these cases are usually asymptomatic [14]. (See "Infectious mononucleosis".)

Cytomegalovirus should be considered in the heterophile antibody-negative patient with infectious mononucleosis, although lymphadenopathy and pharyngitis may not be as prominent. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'CMV mononucleosis'.)

The acute retroviral syndrome that may occur approximately two to four weeks after primary HIV infection is a mononucleosis-like illness characterized by fever, sore throat, malaise, headache, lymphadenopathy, mucocutaneous ulceration, and rash. The rash, seen in more than 50 percent of patients, is usually transient, maculopapular, nonpruritic, and truncal or facial in location. (See "Acute and early HIV infection: Pathogenesis and epidemiology".)

Adolescents and young adults with pharyngitis, fever, lymphadenopathy, and/or a maculopapular/scarlatiniform rash whose evaluation is negative for group A Streptococcus and viral causes of mononucleosis may be infected with Arcanobacterium haemolyticum, a gram-positive rod that appears to be more susceptible to erythromycin than to penicillin [11]. This infection is seen primarily in adolescents and young adults, and the rash, which can be pruritic, is typically seen first over the extensor surfaces before spreading centrally (picture 13) [11]. The rash usually spares the face.

Erythema infectiosum – Approximately 20 percent of cases of erythema infectiosum occur in adults [15]. Constitutional symptoms in primary infection are more pronounced in adults and typically include lymphadenopathy, arthritis, and fever. The rash, when present, is often described as first macular and then lacy and reticulated, spreading initially from the limbs to the trunk and buttocks (picture 5B). (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

Herpes zoster (shingles) – Individuals who did not have chickenpox during childhood may develop it later in life. Those who did have chickenpox may develop herpes zoster, which is caused by reactivation of latent varicella zoster virus. Incidence and severity increases with age and with increasing immunosuppression. In immunocompetent individuals, herpes zoster is typically manifested as vesicular lesions distributed along a dermatome and ending at the midline (picture 14). (See "Clinical features of varicella-zoster virus infection: Chickenpox" and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

Mycoplasma pneumoniaeM. pneumoniae infection may be accompanied by skin findings, which range from a mild erythematous maculopapular or vesicular rash to the Stevens-Johnson syndrome. (See "Mycoplasma pneumoniae infection in adults", section on 'Mucocutaneous disease'.)

Coronavirus disease 2019 (COVID-19) – In both children and adults with COVID-19, potential skin findings include exanthematous morbilliform rashes, pernio (chilblain)-like acral lesions (picture 15), retiform purpuric/petechial lesions, livedo reticularis-like lesions, necrotic vascular lesions, urticaria, papulo-vesicular varicella-like eruptions, and acral popular erythematous eruptions [16-18]. A diffuse polymorphic erythematous rash, nonexudative conjunctivitis, oral mucositis, and/or indurated edematous feet and hands have been described in children and adults who present with multisystem inflammatory syndrome [19,20]. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous manifestations of COVID-19'.)

Season — A number of infections characterized by fever and rash have a distinct seasonal pattern. As examples, nonpolio enteroviral infections occur in the summer and fall months; Kawasaki syndrome, meningococcal infection, and parvoviral infections present most commonly in the winter or early spring months; measles and rubella are more frequent in the spring; tickborne diseases such as Lyme disease, ehrlichiosis/anaplasmosis, and Rocky Mountain spotted fever (RMSF) primarily occur in the spring and summer; tularemia and plague are usually seen in the summer.

Vibrio vulnificus infections occur between the months of April and October, when warmer ocean waters facilitate propagation of this organism. Septicemia due to this organism typically occurs after consumption of raw seafood (usually oysters). V. vulnificus– and Vibrio parahaemolyticus–associated wound infections can occur after injury to skin in contaminated ocean water (eg, after natural disasters) [21,22]. (See "Vibrio vulnificus infection".)

Geography — Travel to or residence in specific areas of the continental United States or other parts of the world can provide important clues for the diagnosis of fever and rash [23-25]. Examples associated with principal locations (but not necessarily the only locations) in the United States include:

Rocky Mountain spotted fever – South-central and Atlantic states (see "Clinical manifestations and diagnosis of Rocky Mountain spotted fever")

Human monocytic ehrlichiosis and anaplasmosis – Midwestern, south-central, and southeastern states (see "Human ehrlichiosis and anaplasmosis")

Lyme disease – The northeast, midwest, and Pacific northwest (see "Epidemiology of Lyme disease" and "Clinical manifestations of Lyme disease in adults" and "Lyme disease: Clinical manifestations in children")

The tick vectors for tularemia – Western, southeastern, and south-central states (see "Tularemia: Microbiology, epidemiology, and pathogenesis" and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention")

Plague – Western states (see "Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection)" and "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)")

Relapsing fever due to Borrelia hermsii – Mountainous areas of the western United States (see "Microbiology, pathogenesis, and epidemiology of relapsing fever" and "Clinical features, diagnosis, and management of relapsing fever")

Endemic fungal infections – Endemic fungal infections including Blastomyces dermatitidis (southeastern states), Coccidioides immitis (southwestern states), and Histoplasma capsulatum (Mississippi and Ohio River valleys) (see "Clinical manifestations and diagnosis of blastomycosis" and "Primary pulmonary coccidioidal infection" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Pathogenesis and clinical manifestations of disseminated histoplasmosis")

Skin lesions in the returning traveler are discussed in greater detail separately. (See "Skin lesions in the returning traveler".)

Incubation period — Knowledge of the incubation period for infectious agents is particularly helpful to the physician trying to determine the significance of a rash in a patient exposed to another individual with a similar exanthem. A range of incubation periods exists for selected infectious agents that may be associated with fever and rash (table 1).

Exposure history — The category of exposures is a broad one in the differential diagnosis of fever and rash. Exposures to food, water, plant materials, animals, and infected human secretions can lead to rashes and can be associated with both occupational and nonoccupational contacts. As an example, the herpetic whitlow, seen in dental workers exposed to herpes simplex virus–infected mucous membranes and secretions, is a classic occupation-associated infection (picture 16). Animal handlers, pet owners, and laboratory workers are more vulnerable to such infections, including [26-28]:

Toxoplasmosis and cat scratch disease from cats and kittens (picture 17) (see "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease")

Psittacosis from poultry, finches, or parrots (see "Psittacosis")

Cryptococcosis from pigeon, dog, or cat feces (see "Cryptococcus neoformans infection outside the central nervous system")

Plague from goats, rabbits, dogs, squirrels, or coyotes (see "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)")

Rat bite fever or leptospirosis from rats (see "Rat bite fever" and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis")

Tularemia in sheep handlers, wild game cooks, pelt dealers, and veterinarians, which can result in ulceroglandular, oculoglandular, glandular, oropharyngeal, typhoidal, or pneumonic syndromes (picture 18) [29] (see "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention")

Pasteurella-associated wound infections secondary to cat and dog bites [30] (see "Pasteurella infections")

Other environmental occupational exposures include:

Papular or nodular lymphocutaneous lesions that develop on the extremities after trauma associated with an aquarium or swimming pool or after handling seafood are consistent with Mycobacterium marinum infections ("fish tank granuloma") (picture 19)[31,32].

Percutaneous injuries inflicted while handling the fish tilapia have been reported to cause Streptococcus iniae cellulitis of the hand [33].

Erysipelothrix rhusiopathiae, a gram-positive rod whose major host is swine, can produce a localized violaceous, cellulitic process involving primarily the hands or fingers in fish and meat handlers (picture 20). (See "Erysipelothrix infection".)

A gram-negative rod known as Edwardsiella tarda can cause fresh water–associated wound infections. Skin and soft tissue infections caused by this organism include abscesses, bullae, myonecrosis, necrotizing fasciitis, and cellulitis [34].

Pseudomonas aeruginosa folliculitis can occur following exposure to hot tubs or whirlpools (picture 21) [35].

Whirlpool footbaths have been associated with Mycobacterium fortuitum–associated furuncles in individuals who had pedicures [36].

Swimming in contaminated lake water has been associated with the development of hemolytic-uremic syndrome with thrombocytopenia-associated petechial skin lesions [37].

Herpes gladiatorum skin infections caused by herpes simplex virus type 1 have been described in athletes who engage in contact sports like rugby and wrestling (picture 22) [38,39], and outbreaks of group A streptococcal and staphylococcal skin infections can occur in American and European football players after competition [40-42].

In one report, a cutaneous larva migrans infection secondary to Ancylostoma braziliense was observed in a beach volleyball player [43].

Individuals who work with plants and soil (ie, florists, gardeners, farmers) are at risk for developing sporotrichosis, an infection of the extremities caused by the dimorphic fungus Sporothrix schenckii (picture 23). (See "Clinical features and diagnosis of sporotrichosis".)

Arthropod exposures — A variety of conditions accompanied by fever and rash result from arthropod exposures. As examples, black flies are associated with onchocerciasis; deer flies with loiasis; fleas with plague and endemic typhus; mosquitoes with malaria-associated parasites, dengue virus, chikungunya virus, West Nile virus, and Zika virus; assassin or reduviid bugs with Chagas disease; and sand flies with leishmaniasis. (See "Onchocerciasis" and "Loiasis (Loa loa infection)" and "Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection)" and "Murine typhus" and "Malaria: Epidemiology, prevention, and control" and "Dengue virus infection: Epidemiology" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis" and "Zika virus infection: An overview" and "Cutaneous leishmaniasis: Epidemiology and control" and "Chagas disease: Epidemiology, screening, and prevention".)

A report from the United States described 15 patients with West Nile virus fever who presented with a generalized maculopapular rash. A tingling and burning sensation was reported by four patients (27 percent) and pruritus by five patients (33 percent) [44]. (See "Clinical manifestations and diagnosis of West Nile virus infection".)

Tickborne diseases seen in the United States include:

The spirochete Borrelia burgdorferi is the etiologic agent of Lyme disease, an ixodid tick-associated infection seen in the United States. The classic skin lesion in this infection is erythema migrans (EM), a red expanding plaque-like lesion with central clearing that develops at the site of the tick bite (picture 24). (See "Clinical manifestations of Lyme disease in adults".)

Ehrlichiosis/anaplasmosis can present as human monocytic ehrlichiosis (HME) caused by Ehrlichia chaffeensis or human granulocytic anaplasmosis (HGA) due to Anaplasma phagocytophilum [45]. Rash may or may not accompany this infection, which has also been termed "spotless Rocky Mountain spotted fever" [46]. A rash is much more likely to be seen in cases of HME than HGA [47]. (See "Human ehrlichiosis and anaplasmosis".)

Rickettsia rickettsii, the etiologic agent of RMSF, can be transmitted by the dog or wood tick and is primarily seen in the south-central and south Atlantic United States (see below). (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

Southern tick-associated rash illness (STARI), presumably caused by a spirochete carried by lone star ticks (Amblyomma americanum), is characterized by a flu-like illness and an erythema migrans–like rash (picture 25). STARI should be considered in areas where A. americanum ticks are present but where Lyme disease is absent or uncommon [48]. (See "Southern tick-associated rash illness (STARI)".)

Medication history — Although drugs can cause a plethora of skin lesions, the relationship between drug fever and rash may not be as strong as many physicians believe. In one systematic analysis of 148 episodes of drug fever, fewer than 20 percent were associated with rash, and fewer than 50 percent of the rashes were urticarial in nature [49]. Hypersensitivity or allergic-type skin reactions (rash, itching, or hives) were evaluated in over 20,000 hospitalized patients in the Boston Collaborative Drug surveillance program, and, though associated fever was not evaluated, only about 2 percent of patients receiving drugs developed cutaneous reactions [50]. Antibiotics such as penicillins, cephalosporins, and trimethoprim-sulfamethoxazole were associated with high rates of allergic skin reactions. (See "Drug eruptions".)

Skin lesions accompanied by fever (often relatively high fever) are a feature of severe drug reactions, particularly drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. These rare reactions typically develop one to three weeks after the initiation of the culprit agent. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Immunization history — Inadequately immunized individuals are susceptible to the traditional childhood viral infections and serve as an often overlooked reservoir of disease. Recommended immunizations for children in the United States include hepatitis A and B; diphtheria, tetanus and pertussis; Haemophilus influenzae type b; rotavirus; poliovirus; measles-mumps-rubella; varicella; influenza; human papillomavirus; pneumococcus; and meningococcus.

Follow-up of older children with their primary care physicians provides an opportune time for confirming appropriate immunizations. (See "Standard immunizations for children and adolescents: Overview".)

Similarly, zoster vaccination is recommended for adults 50 years of age and older to decrease the incidence of zoster and postherpetic neuralgia. (See "Vaccination for the prevention of shingles (herpes zoster)".)

Sexual history — A thorough sexual history is essential in evaluating the patient with a rash of unknown etiology. Genital or rectal ulcerations may be caused by a variety of infectious agents, including syphilis (picture 26), herpes simplex (picture 27), lymphogranuloma venereum (picture 28), chancroid (picture 29), and donovanosis (picture 30 and table 2). These infections may not be associated with fever.

Syphilis can have a variety of cutaneous manifestations. The primary stage is characterized by the chancre, a painless, often solitary, indurated genital ulceration with elevated, well-defined borders. The skin lesions of secondary syphilis include a generalized papular or maculopapular rash (rarely pustular) that also affects the palms and soles (picture 31A-B). Other lesions seen during this stage include condylomata lata: flat, moist condylomata-like lesions that are gray, infectious, and located around the genitals, mouth, anus, and other moist areas (picture 32). Approximately 15 to 30 percent of infected patients will manifest mucous membrane ulcerations that are sharply demarcated and covered with a gray exudate (ie, mucous patches) (picture 33). Patchy alopecia resulting in a "moth-eaten" appearance of the scalp can also be seen during this stage (picture 34). Following treatment of syphilis with appropriate antibiotics, patients may experience a worsening of preexisting skin lesions accompanied by fever (so-called Jarisch-Herxheimer reaction) in response to rapid release of endotoxin-like proteins from dying spirochetes. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV".)

Classic skin lesions of late, or tertiary, syphilis include the gumma, generally a solitary granulomatous subcutaneous skin or mucous membrane lesion that is initially nodular before ulcerating (picture 35). Enlargement of these lesions can result in local tissue destruction. Also seen in tertiary syphilis are noduloulcerative lesions arranged in characteristic ring-like patterns known as lues maligna (picture 36). Resolution of these lesions results in hyperpigmented scars.

Disseminated gonococcal infection causes a rash in as many as 90 percent of patients. The rash consists of fewer than 20 to 30 papular, nodular, and/or petechial lesions that develop a vesiculopustular component and then, finally, a necrotic, hemorrhagic appearance (picture 37) [51]. The rash contains lesions that, like those of primary varicella infection, are in different stages of evolution and favor distal anatomic sites. (See "Disseminated gonococcal infection" and "Cutaneous manifestations of gonorrhea".)

The acute retroviral syndrome that occurs approximately two to six weeks after primary HIV infection is characterized by fever, sore throat, malaise, headache, lymphadenopathy, mucocutaneous ulceration, and rash. The rash, seen in more than 50 percent of patients, is usually transient, maculopapular, nonpruritic, and truncal or facial in location [52]. This presentation can often be confused for infectious mononucleosis [53]. (See "Acute and early HIV infection: Pathogenesis and epidemiology".)

Immunocompetence of the host — The possible etiologies of fever and rash are quite different if the host is immunosuppressed. Thus, determining the underlying immunologic status of the host is essential in assessing any patient with fever and rash [54]. (See "Fever and rash in immunocompromised patients without HIV infection" and "Fever and rash in patients with HIV".)

SELECTED FEVER AND RASH EMERGENCIES — Several infections associated with fever and rash constitute emergencies that must be recognized promptly by the evaluating clinician. Such infections include meningococcal infection, bacterial endocarditis, Rocky Mountain spotted fever (RMSF), necrotizing fasciitis (including Fournier gangrene), toxic shock syndrome, and miliary tuberculosis.

Meningococcal infection — The gram-negative diplococcus N. meningitidis can cause life-threatening infection in children and young adults; outbreaks of infection can occur, especially among groups with confined living conditions, such as military bases, daycare centers, and dormitories. The infection can also develop in individuals with congenital deficiency of a terminal complement component, an acquired complement deficiency (ie, nephrotic syndrome, systemic lupus erythematosus), or splenectomy. (See "Epidemiology of Neisseria meningitidis infection".)

Meningococcal infection can result in a number of different clinical presentations, but meningococcemia and/or meningitis are the most common. In addition to fever, myalgia, somnolence, headache, and nausea, rash occurs in most patients with meningococcemia. Early lesions may be macular, but rapidly increasing numbers of petechial or purpuric lesions can develop on the distal extremities and trunk, usually sparing the palms and soles (in contrast to RMSF) (picture 38A-B). An urticarial rash can also be seen [55]. Lesions on mucosal surfaces are also common. (See "Clinical manifestations of meningococcal infection".)

In one review of 151 patients with meningococcal infection, 75 percent had petechial/maculopapular lesions, 11 percent purpuric/ecchymotic lesions, and 14 percent no skin lesions [56]. Mortality was considerably higher in those with purpuric/ecchymotic lesions.

Meningococcemia may be rapidly fatal, with mortality rates of approximately 10 to 25 percent. Prompt recognition, supportive therapy to maintain adequate blood pressure and oxygenation, and pathogen-directed therapy with parenteral antibiotics (usually high doses of penicillin or a third-generation cephalosporin) are essential. Purpura fulminans, a particularly severe complication of meningococcemia, refers to the fulminant hemorrhagic skin necrosis that can be seen in association with disseminated intravascular coagulation (DIC) and shock. (See "Treatment and prevention of meningococcal infection".)

Bacterial endocarditis — Skin lesions may offer a clue to the underlying diagnosis of infective endocarditis (IE). Associated peripheral cutaneous or mucocutaneous lesions include petechiae, splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

Petechiae are not specific for infective endocarditis but are its most common skin manifestation. They may be present on the skin, usually on the extremities, or on mucous membranes such as the palate or conjunctivae, the latter usually as hemorrhages best seen with eversion of either upper or lower eyelids (picture 39). Splinter hemorrhages, also nonspecific for endocarditis, are nonblanching, linear reddish-brown lesions found under the nail bed (picture 40).

Janeway lesions, Osler's nodes, and Roth spots are more specific for IE but are also less common; Roth spots are particularly rare. Janeway lesions are macular, nonblanching, nonpainful, and erythematous lesions on the palms and soles (picture 41). By contrast, Osler's nodes are painful, violaceous nodules found in the pulp of fingers and toes and are seen more often in subacute than acute cases of IE (picture 42). Roth spots are exudative, edematous hemorrhagic lesions of the retina. Of note, conjunctival hemorrhage, Janeway lesions, Osler's nodes, and Roth spots are included as minor criteria in the Duke criteria for the diagnosis of infective endocarditis [57].

It is important to recognize the skin manifestations of endocarditis in order to obtain blood cultures and initiate appropriate therapy. A prospective cohort study reported that S. aureus is the most common cause of infective endocarditis in many locations worldwide [58]. Similar data have been reported from a retrospective observational cohort study in the United States using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample [59]. Despite improvements in therapy and the availability of surgical intervention, there is still an appreciable mortality rate of 25 to 40 percent for patients with S. aureus IE who are not injection drug users [60] (see "Clinical manifestations of Staphylococcus aureus infection in adults"). Significantly, the incidence of infective endocarditis has remained unchanged in the last 20 years [61].

Rocky Mountain spotted fever — RMSF is a tickborne disease caused by Rickettsia rickettsii. After an incubation period of as little as two days, fever, headache, malaise, conjunctival suffusion, and myalgia usually develop. In most patients, a rash appears within the following week, initially on the wrists and ankles and later on the palms and soles, before spreading centripetally to include the arms, legs, face, and trunk.

The differential diagnosis includes meningococcemia, infective endocarditis, measles, secondary syphilis, and other rickettsial diseases. The rash is at first erythematous and maculopapular. Progression to a petechial rash is often noted and, in severe cases of RMSF, purpura and hemorrhagic necrosis can occur (picture 43A-C). Associated thrombocytopenia can make the diagnosis of RMSF difficult to distinguish from meningococcemia. However, several clinical clues favor the diagnosis of RMSF, including a history of tick bite or visits to areas where RMSF-associated ticks are present, occurrence of the rash a median of three to four days following the onset of fever, relative leukopenia, and elevated aminotransferases. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

Necrotizing fasciitis — Necrotizing fasciitis is a rare, life-threatening, rapidly spreading infection that involves subcutaneous tissue and superficial fascia and typically spares muscle tissue. Conditions commonly associated with the development of necrotizing fasciitis include diabetes mellitus, peripheral vascular disease, injection drug use, obesity, and immunosuppression. The precipitating event is typically infection or trauma to the skin including abrasion, laceration, needle puncture, bite wound, ulcer, or surgical wound; hematogenous spread may also be responsible. These infections are often categorized as type I or type II [62]. Type I necrotizing fasciitis refers to a polymicrobial infection consisting of aerobic and anaerobic bacteria including facultative streptococci, enterococci, aerobic gram-negative bacilli including Escherichia coli, Proteus, Klebsiella, and/or Pseudomonas (less commonly) and anaerobes including Clostridium, Peptostreptococcus, and Bacteroides. Fournier gangrene refers to a type I necrotizing fasciitis of the male (or female) perineum, usually due to disruption of the urethral or gastrointestinal mucosa, often in patients with diabetes mellitus [63]. Type II necrotizing fasciitis is usually monomicrobial and is usually due to Streptococcus pyogenes or other beta-hemolytic streptococci, methicillin-resistant S. aureus, V. vulnificus, Aeromonas hydrophila, or Clostridium species.

Initially, patients present with a cellulitis that can progress rapidly with associated fever, warmth, swelling, edema, and pain out of proportion to the findings on the physical examination. Crepitus and a firm "woody" induration are classically described upon palpation of affected tissues. As the infection evolves, systemic toxicity can become prominent, cutaneous manifestations may include bullae and ecchymoses with necrosis, and cutaneous anesthesia may develop. Toxic shock syndrome develops in about 50 percent of patients with group A streptococcal necrotizing fasciitis. (See "Necrotizing soft tissue infections" and 'Toxic shock syndrome' below.)

Toxic shock syndrome — Initially used in the late 1970s to describe a disease syndrome in children infected with S. aureus, toxic shock syndrome (TSS) became a well-known entity in the early 1980s when its association with young menstruating women and tampon use was described [64-66]. Nonmenstrual toxic shock syndrome has been associated with surgical wounds, burns, skin ulcerations, catheters, and nasal packings. (See "Staphylococcal toxic shock syndrome".)

Criteria for the diagnosis of TSS include a temperature above 38.9ºC, hypotension, a desquamating rash, involvement of at least three organ systems, and exclusion of clinical mimics such as RMSF, leptospirosis, and measles [67]. Multiple toxins have been described in association with this syndrome, particularly TSS toxin (TSST-1) in menstrual-associated TSS [68].

The rash seen in TSS is diffuse and erythematous and can resemble a sunburn (picture 44A-B). The conjunctivae are also often involved (picture 45). Fever, diarrhea, muscle aches, and nausea/emesis are commonly present. Desquamation, usually of the palms and soles or at the sites of the original rash, is classically described one to three weeks later.

Group A streptococci (GAS) can also produce a toxic shock–like syndrome, most often in association with a skin or soft tissue infection. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

Streptococcal pyrogenic exotoxins that cause cytokine production, analogous to staphylococcal TSST-1, appear to be responsible for initiating this syndrome. Several general differences are noted between TSS caused by GAS and by S. aureus. In GAS TSS, mortality is higher (30 versus 3 percent with S. aureus), bacteremia and tissue necrosis are more common, and generalized erythema is less common [67]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention".)

Miliary tuberculosis — Miliary tuberculosis (TB) may not always be considered in the differential diagnosis of patients who have a nonspecific presentation of fever, rash, night sweats, anorexia, weight loss, weakness, and respiratory complaints. In one series, almost 20 percent of cases with miliary tuberculosis in the United States were diagnosed postmortem [69]. Miliary TB resulting from widely disseminated hematogenous infection can affect any organ including the lung, lymph nodes, joints, bones, liver, central nervous system, pericardium, adrenal glands, genitourinary tract, eye, and skin. Usually seen in immunocompromised patients, the most common cutaneous manifestation (TB cutis miliaris disseminata) consists of small, erythematous to violaceous, macular, papular, purpuric, or vesicular lesions that can break down and become umbilicated with crust formation. These lesions subsequently heal with resultant hypopigmented depressed scars [70,71]. Biopsy of these lesions reveals microabscesses with numerous acid-fast bacilli and possible granulomas. The tuberculin skin test is typically negative as a result of anergy. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Cutaneous manifestations of tuberculosis".)

DIAGNOSTIC APPROACH — The diagnostic approach to the patient with fever and rash should focus on the appearance of the rash in addition to the detailed epidemiologic history listed above.

Characteristics of the rash — A history of the rash should include the following questions [5]:

Was a prodrome present?

Where and when did the rash start?

How has the rash progressed anatomically?

What symptoms are associated with the rash?

Has the rash changed in appearance?

Has any treatment been instituted for the rash?

In examining a rash, it is essential to characterize the lesions, both individually and collectively, according to morphology and arrangement (eg, annular, linear, serpiginous, dermatomal), distribution (eg, isolated versus generalized, bilateral versus unilateral, symmetric, occurring on exposed areas), and evolution (centrifugal versus centripetal) [5,72]. In addition, a differential diagnosis for fever and rash can be based upon the appearance of the rash and its accompanying signs (table 3A-C and table 4A-B). The following definitions are useful in interpreting the tables and characterizing lesions and rashes [73]:

Macule – Nonpalpable, circumscribed lesion that is flat and ≤1 cm in diameter

Papule – Palpable lesion that is solid, elevated, and ≤5 mm in diameter

Maculopapular – Confluent, erythematous rash made up of both macular and papular lesions

Purpura – Papular or macular nonblanching lesions that are due to extravasation of red blood cells; 1 to 2 mm lesions are called petechiae

Nodule – Deep-seated, roundish lesion ≥5 mm in diameter that can involve the epidermal, dermal, and/or subcutaneous tissue

Plaque – A palpable elevated lesion ≥5 mm in diameter

Vesicle – A distinct, elevated skin lesion that contains fluid and is <5 mm in diameter

Bulla – A vesicle ≥5 mm in diameter

Pustule – A vesicle that contains pus

Ulcer – Loss of the epidermis and upper layer of the dermis, resulting in a depressed skin lesion

Eschar – Hard, black-colored adherent necrotic skin, often overlying an area of ulceration

While these categories are useful and descriptive, many rashes have overlapping features, and a number of infectious agents can present with several different rash morphologies. Different infectious agents can also produce similar types of rashes.

Several skin conditions can be identified based upon appearance but can be caused by a variety of infectious and noninfectious etiologies.

Erythema multiforme – Symmetrically distributed "target" lesions reflecting epidermal and dermal involvement that typically involve the palms, soles, and in some cases the mucous membranes (picture 46 and table 5) (see "Erythema multiforme: Pathogenesis, clinical features, and diagnosis")

Erythema nodosum – Painful, red nodular lesions usually found symmetrically on the lower extremities and representing inflammation in the panniculus (picture 47) (see "Erythema nodosum")

Toxic epidermal necrolysis – A severe skin and mucosal disorder that manifests initially as tender widespread erythema with subsequent loss of the epidermis, usually due to drugs such as sulfonamides, allopurinol, nonsteroidal antiinflammatory drugs, and anticonvulsants (picture 48 and table 6)

Urticaria – A skin condition associated with the presence of transient wheals (ie, papules or plaques) due to dermal edema, with no evidence of epidermal involvement or abnormality (table 7 and picture 49A-B) (see "New-onset urticaria")

Enanthems are mucous membrane lesions often associated with exanthems in systemic infectious diseases. Examples include oral or genital mucous patches (secondary syphilis), oral gummatous lesions (tertiary syphilis), oral ulcers (disseminated histoplasmosis, gonococcus, or tuberculosis), palatal petechial lesions (rubella and Epstein-Barr virus mononucleosis), oral vesicular lesions (Coxsackie-associated hand, foot, and mouth syndrome, varicella, and primary herpes simplex virus), and strawberry tongue (scarlet fever, Kawasaki syndrome, toxic shock syndrome). Koplik's spots, the tiny punctate elevated white buccal mucosa lesions located adjacent to the lower molars, are pathognomonic of measles and can precede the rash by 24 to 48 hours (picture 2).

Physical examination — A thorough physical examination should focus on the following [5]:

Vital signs

General appearance to assess the severity of illness

Strict attention to lymph nodes, mucous membranes, conjunctivae, and genitalia

Meningeal signs and complete neurologic evaluation

Liver and spleen size

Joint examination

Skin examination (table 3A-C and table 4A-B)

Laboratory testing — Appropriate laboratory testing includes [5]:

Nonspecific tests such as complete blood count and urinalysis

Blood cultures (including specific media and isolation methods for bacterial, mycobacterial, and fungal organisms) should be inoculated prior to beginning antimicrobial therapy

Serologic tests, when appropriate (eg, for Coccidioides immitis, hepatitis B, Toxoplasma gondii, Borrelia burgdorferi, Treponema pallidum, dengue virus, and HIV)

Antigen tests, when appropriate (eg, serum cryptococcal antigen)

Fluid from vesicular, pustular, petechial, ulcerative, and bullous lesions can be examined. Vesicular lesions should be unroofed so that the base of the lesion can be swabbed; herpes simplex virus and varicella-zoster virus can be diagnosed with direct fluorescent antibody or polymerase chain reaction (PCR) assays. Viral culture can also be performed. Aspirated fluid from pustules and bullous lesions should be Gram stained and cultured in an expeditious fashion by the microbiology laboratory. In suspected cases of syphilis, exudative material from the ulcer base can be evaluated with darkfield microscopy or direct fluorescent antibody testing, if available. (See "Syphilis: Screening and diagnostic testing".)

Skin biopsy can be particularly useful in establishing a diagnosis for nodular lesions but can also be obtained for petechial-purpuric, maculopapular, and ulcerative rashes. Aseptically obtained biopsy material should be sent to the microbiology and pathology laboratories for appropriate culture and histopathologic evaluation. In suspected cases of Rocky Mountain spotted fever, direct immunofluorescent demonstration of rickettsial organisms is diagnostic. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: Scarlet fever (The Basics)" and "Patient education: When to worry about a fever in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical significance – The syndrome of fever and rash has an extremely broad differential diagnosis, ranging from mild infection to severe life-threatening infection or serious noninfectious disorder. (See 'Introduction' above.)

Fever and rash emergencies – Several infections associated with fever and rash constitute emergencies that must be recognized promptly by the evaluating clinician. Such infections include meningococcal infection, bacterial endocarditis, Rocky Mountain spotted fever, necrotizing fasciitis (including Fournier gangrene), and toxic shock syndrome. (See 'Selected fever and rash emergencies' above.)

Approach to diagnosis – A systematic approach is crucial for establishing a timely diagnosis, determining early therapy when appropriate, and considering isolation of the patient if necessary. (See 'Diagnostic approach' above.)

Obtaining a history – A thorough patient history should be performed.

Epidemiologic clues – Specific attention to the epidemiologic setting, including the season, geographic location, and recent travel can narrow the differential. (See 'Season' above and 'Geography' above.)

Patient history – The history should include medications, immunizations and history of childhood illnesses, immune status, sexual history, and exposures to insects (eg, ticks and mosquitoes), animals (both wild and domestic), and sick contacts. The age of the patient may also help to narrow the differential. (See 'Medication history' above and 'Immunization history' above and 'Immunocompetence of the host' above and 'Sexual history' above and 'Exposure history' above and 'Arthropod exposures' above and 'Diseases that present in childhood' above and 'Selected diseases that present in adulthood' above.)

Clinical features of the rash – Important questions include the timing of onset, distribution and progression of the rash, any changes in morphology, associated symptoms (eg, pain, pruritus, numbness), and any prior therapy. (See 'Characteristics of the rash' above.)

Examining the rash – It is essential to characterize the lesions, both individually and collectively, according to morphology and arrangement (annular, linear, serpiginous, dermatomal, etc), distribution (isolated versus generalized, bilateral versus unilateral, symmetric, occurring on exposed areas, etc), and evolution (centrifugal versus centripetal). In addition, a differential diagnosis for fever and rash can be based upon the appearance of the rash and its accompanying signs (table 3A-C and table 4A-B). (See 'Characteristics of the rash' above.)

Laboratory evaluation – Tests include the following:

Nonspecific tests such as complete blood count and urinalysis

Blood cultures (obtained prior antibiotic therapy, if possible)

Serologic tests, when appropriate (eg, for Coccidioides immitis, hepatitis B, Toxoplasma gondii, Borrelia burgdorferi, Treponema pallidum, dengue virus, HIV)

Antigen tests, when appropriate (eg, serum cryptococcal antigen) (see 'Laboratory testing' above)

Fluid from vesicular, pustular, petechial, ulcerative, and bullous lesions. Vesicular lesions should be unroofed so that the base of the lesion can be swabbed; herpes simplex virus and varicella-zoster virus can be diagnosed with direct fluorescent antibody or polymerase chain reaction (PCR) assays performed on vesicular fluid. Viral culture can also be performed. Aspirated fluid from pustules and bullous lesions should be Gram stained and cultured by the microbiology laboratory. (See 'Laboratory testing' above.)

Role of biopsy – Skin biopsy can be particularly useful in establishing a diagnosis for nodular lesions but can also be obtained for petechial-purpuric, maculopapular, and ulcerative rashes. Biopsy material should be sent to the microbiology and pathology laboratories for appropriate culture and histopathologic evaluation. (See 'Laboratory testing' above.)

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Topic 2744 Version 38.0

References

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