The coexistence of fever and rash suggests a relatively wide spectrum of pathologic entities for diagnostic consideration. This spectrum includes local or systemic infection with a wide range of microbial pathogens; toxin-mediated disorders, including those associated with bacterial superantigen production; inflammatory conditions, including vasculitides and rheumatologic diseases; and hypersensitivity disorders. While most conditions causing fever and rash are benign and self-limited, a thorough clinical evaluation is crucial to identify those caused by life-threatening diseases or those requiring specific treatment. The essential elements for accurate diagnosis include a detailed history and a thorough physical examination including a careful systematic observation of the patient for evidence of toxicity. Because this approach lacks perfect sensitivity, the laboratory may play an important role in the diagnostic process.
Fever and Rash
History
Information about the features of the rash includes when it occurred in relation to the fever, its evolution or progression, its anatomic distribution, and whether it is pruritic or painful ( Table 40.1 ). Degree of illness should be evaluated, especially in the infant and toddler, by assessing oral intake, activity level, and urine output. A description of the fever pattern can be useful (see Chapter 39 ) and immunization status will help prioritize the differential diagnosis. Essential information from the epidemiologic and social history should include season of the year; geographic location of the patient’s residence; exposure to known ill contacts; recent travel or exposure to individuals from different geographic areas; exposure to pets, wildlife, or insects; recent immunizations; a detailed list of medications; previous blood transfusion; and for the adolescent patient, intravenous drug use and sexual activity.
| Demographic Data |
| Age |
| Sex |
| Ethnicity |
| Season |
| Geographic area |
| Exposures |
| Ill contacts (home, daycare, school, workplace) |
| Sexual contacts |
| Travel outside area of residence |
| Pets, wildlife, insects (especially ticks) |
| Medications and drugs |
| Transfusions |
| Immunizations |
| Occupational |
| Features of Rash |
| Temporal associations (onset relative to fever) |
| Progression and evolution |
| Location and distribution |
| Pain or pruritus |
| Timing and pattern of desquamation |
| Associated Symptoms |
| Focal (suggesting organ-specific illness) |
| Systemic (suggesting generalized or multisystem illness) |
| Prior Health Status |
| Medical and surgical history |
| Growth and development |
| Recurrent infectious illnesses |
| Family History |
The medical and family history should be used to assess the overall health of the patient over time, as well as that of family members, to determine the possibility of underlying primary or acquired immunodeficiency or diseases associated with autoimmunity or chronic inflammation. A history of increased susceptibility to infection, as manifested by chronic or recurrent infectious illnesses after infancy, such as pneumonia, sinusitis, bronchitis, otitis media, diarrhea, and bacteremia, is an important indicator of underlying immunodeficiency disease (see Chapter 41 ). In addition, the occurrence of an unusually severe infection or an infection with a pathogen of low virulence (e.g., Pneumocystis jiroveci ) should raise a suspicion of an immunodeficiency state. A history of hemolytic anemia, leukopenia, thrombocytopenia, or arthritis suggests an autoimmune disorder or malignancy, which may also be associated with impairment in immune function (see Chapter 33 ).
In a thorough systems review, the clinician should assess the probability of a subacute or chronic underlying infectious, inflammatory, or malignant disease by inquiring about anorexia, nausea, vomiting, weight loss or failure to thrive, night sweats, fatigue, cough, and exercise intolerance. The clinician should seek symptoms suggesting multisystem disease, such as myalgias, arthralgias, headache, precordial pain or pain with inspiration, abdominal pain, jaundice, skin photosensitivity, peripheral edema, alopecia, Raynaud phenomenon, and hematuria. In patients with symptoms that indicate the presence of multisystem disease, a thorough survey of the functional status of the central, peripheral, and autonomic nervous systems is clinically relevant. Specific inquiries into visual disturbances, photophobia, disordered mentation, neck stiffness, paresthesia, weakness, or seizure activity are essential and may reveal potentially life-threatening infection within the central nervous system or a systemic vasculitis involving the nervous system, such as systemic lupus erythematosus (SLE) or polyarteritis nodosa.
Examination
The physical examination is used to refine the probability of underlying serious illness, to identify rashes typical of a specific diagnosis, to look for noncutaneous disease manifestations, and to identify if further testing or treatment is indicated ( Table 40.2 ; also see Chapters 39 and 48 ).
| Degree of Toxicity |
| Vital Signs |
| Fever pattern |
| Tachycardia or bradycardia |
| Tachypnea |
| Hypotension or hypertension |
| Characteristics of Rash |
| Macular |
| Papular |
| Maculopapular |
| Petechiae or purpura |
| Diffuse erythroderma |
| Accentuation in flexural creases |
| Desquamation with stroking (Nikolsky sign) or spontaneous |
| Localized erythroderma |
| Expansile |
| Painful |
| Urticaria |
| Vesicles, pustules, bullae |
| Nodules |
| Ulcers |
| Distribution and Localization of Rash |
| Generalized or localized |
| Symmetric or asymmetric |
| Centripetal or centrifugal |
| Associated Enanthem |
| Buccal mucosa |
| Palate |
| Pharynx and tonsils |
| Genitals |
| Associated Findings (Isolated or in Clusters) |
| Ocular |
| Cardiac |
| Pulmonary |
| Gastrointestinal |
| Musculoskeletal |
| Neurologic |
| Lymphadenopathy |
| Hepatosplenomegaly |
| Arthritis |
A critical 1st step is an assessment of the patient’s vital signs and degree of toxicity. Lethargy, irritability, altered mental status, decreased activity, poor perfusion, pallor, or cyanosis indicate serious illness; resuscitation and treatment directed at the most likely diagnoses should be initiated without delay. The importance of the height of fever in predicting the risk of serious illness is unclear. Underlying chronic illness and degree of toxicity are more useful for risk assessment than fever height. The presence of tachycardia and tachypnea in any patient with fever and rash suggests the possibility of sepsis. Tachycardia may also be seen in endocarditis or in myocarditis secondary to certain viruses, Kawasaki disease (KD), or acute rheumatic fever. Evidence of alteration in mental status suggests either sepsis associated with decreased organ perfusion or primary meningoencephalitis. The presence of hypotension usually indicates septic shock, but other disorders such as toxic shock syndrome (TSS), dengue hemorrhagic shock syndrome, hemorrhagic fever with renal syndrome caused by Hantavirus, and the hemorrhagic shock and encephalopathy syndrome must also be considered in this context. Hypertension may be noted in association with vasculitic disorders involving small- to medium-sized arteries, such as polyarteritis and SLE.
The clinical characteristics of the rash are often helpful in establishing an etiologic diagnosis. A morphologic nomenclature of cutaneous manifestations helps the clinician with differential diagnosis, documentation, and communication (see Chapter 48 ). An exanthem is defined as a skin eruption occurring as a sign of a generalized disease. An enanthem is an eruption on the mucous membranes that occurs in the context of generalized disease. Exanthems and enanthems may be macular, maculopapular, vesicular, urticarial, petechial, or diffusely erythematous. Rashes are usually classified according to their most typical lesion morphology. However, morphology may vary as rashes evolve; the rash of Rocky Mountain spotted fever is classically described as petechial, but it may initially be maculopapular. Because a wide variety of infectious agents, including viruses, bacteria, and the rickettsiae, as well as drugs and inflammatory conditions can cause exanthems and enanthems, few of these eruptions are pathognomonic ( Tables 40.3, 40.4, and 40.5 ).
| Lesion | Pathogen or Associated Factor |
|---|---|
| Maculopapular or Macular Rash | Viruses |
| Measles (confluent), rubella (discrete), roseola (human herpesvirus 6), * fifth disease (parvovirus), * EBV, * enteroviruses, * hepatitis B virus (papular acrodermatitis or Gianotti–Crosti syndrome), HIV, dengue virus, adenovirus | |
| Bacteria | |
| Rheumatic fever (group A streptococcus), scarlet fever, erysipelas, Arcanobacterium haemolyticum , secondary syphilis, leptospirosis, Pseudomonas , meningococcal infection (early), Salmonella (typhoid rose spots), Lyme disease, Mycoplasma pneumoniae , * Listeria monocytogenes , Brucella melitensis | |
| Rickettsiae | |
| Early Rocky Mountain spotted fever, typhus (scrub, endemic), ehrlichiosis (monocytic) | |
| Other | |
| Kawasaki disease, * Coccidioides immitis , drug reactions, SJIA, hereditary fever syndromes, HLH | |
| Diffuse Erythroderma | Bacteria |
| Scarlet fever (group A streptococcus), * other streptococci, toxic shock syndrome ( Staphylococcus aureus and group A streptococcus), * staphylococcal scarlet fever, ehrlichiosis (Ehrlichia chaffeensis) | |
| Fungi | |
| Candida albicans | |
| Urticarial Rash | Viruses |
| EBV, hepatitis B, HIV, enteroviruses | |
| Bacteria | |
| M. pneumoniae , group A streptococci, Shigella , meningococcus, Yersinia | |
| Other | |
| Various parasites, insect bites, food-drug allergens (usually afebrile) | |
| Vesicular, Bullous, Pustular | Viruses |
| Herpes simplex, * varicella-zoster, * coxsackieviruses, * echoviruses, vaccinia, variola | |
| Bacteria | |
| Staphylococcal scalded skin syndrome, staphylococcal bullous impetigo, group A streptococcal crusted impetigo, gonococcemia * | |
| Other | |
| Toxic epidermal necrolysis, Stevens–Johnson syndrome, * rickettsialpox | |
| Petechial-Purpuric | Viruses |
| Atypical measles, congenital rubella, cytomegalovirus, enterovirus, HIV, hemorrhagic fever viruses, hemorrhagic varicella, EBV, hepatitis B, adenovirus, yellow fever | |
| Bacteria | |
| Sepsis (meningococcal, * gonococcal, pneumococcal, * S. aureus , * ), endocarditis, rat-bite fever ( Spirillum minus or Streptobacillus moniliformis ), Pseudomonas aeruginosa , group A streptococcus rickettsiae, Capnocytophaga canimorsus | |
| Rickettsiae | |
| Rocky Mountain spotted fever, * epidemic typhus, ehrlichiosis | |
| Other | |
| Vasculitis, thrombocytopenia, Henoch–Schönlein purpura, * malaria | |
| Erythema Nodosum | Viruses |
| EBV, hepatitis B, C, HSV, HIV | |
| Bacteria | |
| Group A streptococcus, tuberculosis, Yersinia , cat-scratch disease, brucellosis, Q fever, M. pneumoniae , tularemia, syphilis | |
| Fungi | |
| Coccidioidomycosis, histoplasmosis, blastomycosis, sporotrichosis, cryptococcosis | |
| Other | |
| Sarcoidosis, inflammatory bowel disease, estrogen-containing oral contraceptives, systemic lupus erythematosus, Behçet disease, lymphoma | |
| Distinctive Rashes | |
| Ecthyma gangrenosum | P. aeruginosa , Vibrio vulnificus |
| Erythema migrans | Lyme disease |
| Necrotic eschar | Aspergillosis, mucormycosis |
| Erysipelas | Group A streptococcus |
| Koplik spots | Measles |
| Erythema Marginatum | Acute rheumatic fever (group A streptococcus) |
| Erythema Multiforme | Herpes simplex virus or M. pneumoniae |
| Rose spots | Salmonella |
| Disease | Cause | Age | Season | Transmission | Incubation (Days) | Prodrome | Features and Rash Structure | Enanthem | Complications | Prevention/Treatment | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Scarlet fever | Group A streptococcus | School age | Fall, winter, spring | Direct contact, droplets | 1–4 | Sore throat, headache, abdominal pain, cervical lymphadenopathy, fever, 0–2 days, acute onset | Diffuse erythema with “sandpaper” feel: accentuation of erythema in flexural creases (Pastia lines); circumoral pallor, lasts 2–7 days; may exfoliate | Palatal petechiae, strawberry tongue | Peritonsillar abscess, rheumatic fever, glomerulonephritis | Prevent rheumatic fever with penicillin within 10 days of onset of pharyngitis, treat with penicillin | Similar syndrome may be noted with Arcanobacterium haemolyticum in adolescents; group A streptococci may also produce toxic shock or true bacteremic shock syndromes in addition to cellulitis, lymphangitis, and erysipelas; S. aureus may produce a scarlatiniform rash |
| Staphylococcal scalded skin syndrome (SSSS) | Staphylococcus aureus producing exfoliative toxin | Neonates and infants | Any | Colonization, contact | Unknown | None | Sudden onset, tender erythroderma progressing to diffuse flaccid bullae; significant perioral, perinasal peeling; eventual diffuse exfoliation (positive Nikolsky sign), possibly conjunctivitis, purulent rhinorrhea | Unusual | Shock | Treat with intravenous antibacterial active against S. aureus | — |
| Toxic shock syndrome (TSS) | S. aureus producing toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxins (SEs) Group A streptococcus producing Streptococcus pyogenes exotoxins (SPEs) | Adolescent girls if menstrual; others variable | Any | Colonization, contact | Variable, often 1–5 | Myalgias, fevers, and gastrointestinal symptoms May be secondary to wound infection, trivial mucosal or respiratory infection, or necrotizing fasciitis or myositis | Diffuse sunburn-like erythroderma; hypotension, diarrhea, emesis, mental status changes; late desquamation | Conjunctivitis | Shock, multisystem organ dysfunction/failure | Treat with intravenous antibacterial active against S. aureus ; penicillin if group A streptococcus suspected; clindamycin; possible intravenous immune globulin; prevent menstrual-associated TSS by frequent changes of tampon | — |
| Meningococcemia | Neisseria meningitidis | Any (<5 yr and adolescents) | Winter, spring, follows influenza epidemics | Close, prolonged contact | 5–15 | Fever, malaise, myalgia, 1–10 days | Erythematous, nonconfluent, discrete papules (early); petechiae, purpura present on trunk, extremities, palms, soles | Petechiae | Shock, meningitis, pericarditis, arthritis, endophthalmitis, gangrene, disseminated intravascular coagulation | Contacts: rifampin; general: vaccine; treat with ceftriaxone, cefotaxime, penicillin (if sensitive) | Neisseria gonorrhoeae , pneumococcus, Haemophilus influenza type b, group A streptococcus may produce similar clinical manifestations |
| Rocky Mountain spotted fever (RMSF) | Rickettsia rickettsii | Any (>5 yr), male > female | Summer | Carrier ticks | 3–12 | Fever, myalgia, headache, malaise, ill appearance, 2–4 days | Early maculopapular, then petechial or, rarely, purpuric; present on extremities, then trunk, palms, and soles | Petechiae variable | Shock, myocarditis, encephalitis, pneumonia | Remove ticks as soon as possible; use tick repellants; treat with doxycycline | Ehrlichia chaffeensis and other rickettsiae may produce similar illnesses with or without a rash |
| Rickettsialpox | R. akari | Any | Any | Mouse mite | 7–14 | Fever, chills, headache, malaise, 4–7 days | At primary bite site, eschar; secondary papulovesicles in same stage throughout illness; fewer vesicles than in chickenpox (5–30); present on trunk and proximal extremities | Unknown | Usually none | Treat with doxycycline | Often confused with chickenpox; may be more common than expected, especially in crowded urban settings with poor housing |
| Disease | Cause | Age | Season | Transmission | Incubation (Days) | Prodrome | Features and Rash Structure | Enanthem | Complications | Prevention/Treatment | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Measles (rubeola) | Measles virus | Infants, adolescents | Winter, spring | Respiratory droplet | 10–12 | High fever, cough, coryza, conjunctivitis, 2–4 days | Maculopapular (confluent), begins on face, spreads to trunk; lasts 3–6 days Brown color develops; fine desquamation; toxic, uncomfortable appearance, photophobia; rash may be absent in human immunodeficiency virus infection | Koplik spots on buccal mucosa before rash | Febrile seizures, otitis, pneumonia, encephalitis, laryngotracheitis, thrombocytopenia; delayed subacute sclerosing panencephalitis | General: measles vaccine at 12–15 mo and again at 4–6 yr Exposure: measles vaccine if within 72 hr; immune globulin if within 6 days of exposure (must then wait 5–6 mo to vaccinate) The World Health Organization recommends treatment with vitamin A in all patients with measles | Reportable to public health department; epidemics reported, contagious 3 days before symptoms and to 4 days after rash Increasing incidence as vaccination rates are decreasing |
| Rubella (German measles) | Rubella virus | Infants, young adults | Winter, spring | Respiratory droplet | 14–21 | Malaise, fever <101°F, posterior auricular, cervical, occipital adenopathy, 0–4 days | Discrete, nonconfluent, rose-colored macules and papules, begins on face and spreads downward; lasts 1–3 days | Variable erythematous macules on soft palate | Arthritis, thrombocytopenia, encephalopathy; fetal embryopathy | General: rubella vaccine at 12–15 mo and again at 4–6 yr; exposure: possibly immune serum globulin | Reportable to public health department; epidemics reported, contagious 2 days before symptoms and 5–7 days after rash |
| Roseola (exanthem subitum) | Human herpesvirus type 6 (HHV-6), Human herpesvirus type 7 (HHV-7) | Infants (6 mo–2 yr) for HHV-6, can be older children for HHV-7 | Any | Unknown; saliva of asymptomatic carrier? | 9–10 (HHV-6); unknown (HHV-7) | Irritability, high fever 3–7 days, cervical, occipital adenopathy; | Discrete macules on trunk, neck; sudden-onset rash with defervescence; lasts 0.5–2 days; some patients have no rash | Variable erythematous macules on soft palate | Single or recurrent febrile seizures; encephalopathy; dissemination (e.g., liver, CNS, lung) in immunosuppressed patients | None | No epidemics |
| Fifth disease (erythema infectiosum) | Parvovirus B19 | Prepubertal children, schoolteachers | Winter, spring | Respiratory droplets; blood transfusion, placenta | 5–15 | Headache, malaise, myalgia; often afebrile | Local erythema of cheeks (slapped cheek appearance); lacy pink red erythema of trunk and extremities, ± pruritus; rash may lag prodrome by 3–7 days; lasts 2–4 days, may recur 2–3 wk later | None | Arthritis, aplastic crisis in patients with chronic hemolytic anemia (e.g., sickle cell), fetal anemic hydrops, vasculitis, Wegner granulomatosis | Isolation of patients with aplastic crisis but not normal host with fifth disease | Epidemics reported; once rash is present, the normal host is not contagious; patients with aplastic crisis often have no rash |
| Chickenpox (varicella) | Varicella-zoster virus | 1–14 yr | Late fall, winter, early spring | Respiratory droplet | 12–21 | Fever | Pruritic papules, vesicles in various stages, 2–4 crops and then crusts; distributed on trunk and then face, extremities; lasts 7–10 days; recurs years later in dermatomal distribution (zoster, shingles) | Oral mucosa, tongue | Staphylococcal or streptococcal skin infection, arthritis, cerebellar ataxia, encephalitis, thrombocytopenia, Reye syndrome (with aspirin), myocarditis, nephritis, hepatitis, pneumonia; dissemination in immunocompromised | VZIG for exposed immunosuppressed patients, susceptible pregnant women, preterm neonates, and infants at birth whose mother developed varicella 5 days before and 2 days after birth; active immunization with live attenuated vaccine at 12 mo | Acyclovir therapy for immunosuppressed and possibly normal patients (controversial); contagious 1–2 days after rash (usually no longer contagious when all lesions are crusted and no new lesions appear) |
| Enteroviruses | Coxsackievirus, echovirus, and others | Infants, young children | Summer, fall | Fecal-oral | 4–6 | Variable: irritable, fever, sore throat, myalgias, headache | Hand–foot–mouth: vesicles in those locations; others: nonspecific, usually fine nonconfluent, macular or maculopapular rash, rarely petechial, urticarial, or vesicular; lasts 3–7 days | Yes | Aseptic meningitis, hepatitis, myocarditis, paralysis: usually in younger patients | None | Rash may appear with fever or after defervescence; rash may be present in <50% of enteroviral illnesses; epidemics possible, contagious up to 2 wk |
| Mononucleosis | Epstein–Barr virus | Children, adolescents | Any | Close contact, saliva, blood transfusion | 28–49 | Fever, adenopathy, eyelid edema, sore throat, hepatosplenomegaly, malaise; atypical lymphocytosis | Maculopapular or morbilliform on trunk, extremities; may be confluent; often elicited by simultaneous administration of ampicillin or allopurinol; rash in 15% and in 50% with drug-induced form, lasts 2–7 days | Variable | Anemia, thrombocytopenia, aplastic anemia, hepatitis; rarely hemophagocytic lymphohistiocytosis, lymphoproliferative syndrome | None | Cytomegalovirus and toxoplasmosis also produce mononucleosis-like illness; monospot or heterophile tests negative |
| Gianotti–Crosti syndrome (papular acrodermatitis of childhood) | Hepatitis B virus, Epstein–Barr virus, coxsackieviruses, others | 1–6 yr | Any | Variable; fecal, sexual, blood products for hepatitis B | Unknown; 50–180 days for hepatitis B | Usually none except for specific viral disease; arthritis-arthralgia for hepatitis B | Papules, papulovesicles, discrete or confluent; face, arms, extremities, often spares trunk; lasts 4–10 days | Variable | As per specific disease | Hepatitis B: HBIG plus vaccine | — |
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