Fever and Rash¶

Chapter 21 | Part 2: Cardinal Manifestations and Presentation of Diseases

KEY CLINICAL POINTS¶

The combination of fever and rash often presents a diagnostic challenge requiring systematic evaluation of lesion morphology, distribution, and clinical context
Critical life-threatening conditions (meningococcemia, Rocky Mountain spotted fever, toxic shock syndromes) require immediate recognition and treatment
Rash classification by morphology (maculopapular, vesiculobullous, purpuric, nodular, urticarial) and distribution (central vs peripheral) guides differential diagnosis
A thorough history including immune status, medications, travel, animal exposures, and immunization status is essential for diagnosis
Morphology may evolve over time - petechial rashes may begin as blanchable macules, and presentations can vary significantly from classic descriptions

1. DEFINITION & OVERVIEW¶

Fever accompanied by rash represents a common clinical presentation that can indicate benign viral illness or life-threatening systemic disease. The distinctive appearance of an eruption in concert with clinical syndrome can facilitate prompt diagnosis and institution of life-saving therapy or critical infection-control interventions. This chapter focuses on rashes that reflect systemic disease, excluding localized skin eruptions (cellulitis, impetigo) that may also be associated with fever.

1.1 Lesion Terminology¶

Macules: Flat lesions defined by an area of changed color (blanchable erythema). Papules: Raised, solid lesions <5 mm in diameter. Plaques: Lesions >5 mm in diameter with a flat, plateau-like surface. Nodules: Lesions >5 mm in diameter with a more rounded configuration. Wheals (urticaria, hives): Papules or plaques that are pale pink and may appear annular; classic (nonvasculitic) wheals are transient, lasting only 24 hours in any defined area. Vesicles: Circumscribed, elevated lesions containing fluid (<5 mm). Bullae: Circumscribed, elevated lesions containing fluid (>5 mm). Pustules: Raised lesions containing purulent exudate. Nonpalpable purpura: Flat lesion due to bleeding into the skin - petechiae (<3 mm) or ecchymoses (>3 mm). Palpable purpura: Raised lesion due to inflammation of vessel wall (vasculitis) with subsequent hemorrhage. Ulcer: Defect in skin extending at least into upper layer of dermis. Eschar (tâche noire): Necrotic lesion covered with a black crust.

1.2 Important Rash Characteristics¶

Configuration: Annular or target lesions. Arrangement: Grouped, linear, dermatomal. Distribution: Central (truncal) vs peripheral (acral). Other features: Site of onset, direction and rate of spread.

2. APPROACH TO THE PATIENT¶

A systematic approach to the patient with fever and rash is essential for accurate diagnosis and timely treatment.

2.1 Essential History Elements¶

Immune status (HIV, immunosuppressive medications, malignancy, transplant)
Medications taken within the previous month
Specific travel history (endemic areas for rickettsial diseases, viral hemorrhagic fevers)
Immunization status (measles, varicella, meningococcal)
Exposure to domestic pets and other animals
History of animal (including arthropod) bites
Recent dietary exposures (raw seafood, unpasteurized products)
Existence of cardiac abnormalities (endocarditis risk)
Presence of prosthetic material
Recent exposure to ill individuals
Sexual exposures
Site of onset of rash and direction/rate of spread

2.2 Physical Examination¶

A thorough physical examination requires close attention to the rash with assessment and precise identification of salient features: - Determine lesion type (macule, papule, vesicle, pustule, purpura) - Assess distribution pattern (central vs peripheral, involvement of palms/soles) - Evaluate configuration (annular, target, reticular) - Look for pathognomonic signs (Koplik's spots, Nikolsky's sign, eschar) - Examine mucosal surfaces (oral, conjunctival, genital) - Assess for lymphadenopathy, hepatosplenomegaly - Note presence of arthritis or other systemic findings

3. CLASSIFICATION OF RASH BY MORPHOLOGY AND DISTRIBUTION¶

Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquamative erythematous, vesiculobullous, urticaria-like, nodular, purpuric, ulcerated, or with eschars. This classification is based on most typical disease presentations, but morphology may vary as rashes evolve.

Classification of Fever and Rash by Eruption Type¶

Eruption Type	Key Diseases	Critical Features
Centrally Distributed Maculopapular	Measles, Rubella, Erythema infectiosum, Roseola, Drug reactions, Rickettsial diseases, Typhoid fever, Dengue, Lyme disease	Truncal predominance, may spread to extremities
Peripheral Eruptions	Rocky Mountain spotted fever, Secondary syphilis, Hand-foot-mouth disease, Endocarditis, Erythema multiforme	Acral involvement, often involves palms/soles

Eruption Type	Key Diseases	Critical Features
Confluent Desquamative	Scarlet fever, Kawasaki disease, Toxic shock syndromes, Staphylococcal scalded-skin syndrome, Stevens-Johnson/TEN	Diffuse erythema followed by desquamation
Vesiculobullous/Pustular	Varicella, Herpes simplex, Smallpox, Mpox, Rickettsialpox, Ecthyma gangrenosum	Fluid-filled lesions, may evolve to pustules
Urticaria-like	Urticarial vasculitis, Serum sickness, Drug reactions	Wheals lasting >24 hours suggests vasculitis
Nodular	Disseminated fungal infections, Erythema nodosum, Sweet syndrome, Bacillary angiomatosis	Raised solid lesions, often tender
Purpuric	Meningococcemia, RMSF, DIC, Vasculitis, Viral hemorrhagic fevers	Non-blanching lesions indicate hemorrhage
Ulcers/Eschars	Tularemia, Anthrax, Scrub typhus, Rickettsial spotted fevers	Necrotic lesions often at inoculation site

4. CENTRALLY DISTRIBUTED MACULOPAPULAR ERUPTIONS¶

Centrally distributed rashes, in which lesions are primarily truncal, are the most common type of eruption. These rashes often spread from the trunk to involve extremities.

Classic Viral Exanthems ('Numbered Diseases')¶

Disease	Etiology	Key Rash Features	Pathognomonic Signs	Complications
First Disease (Measles)	Paramyxovirus	Hairline to body, confluent, spares palms/soles	Koplik's spots	Pneumonia, encephalitis
Third Disease (Rubella)	Togavirus	Hairline down, clears as spreads, pruritic	Forchheimer spots (nonspecific)	Congenital rubella syndrome
Fifth Disease (Erythema infectiosum)	Parvovirus B19	Slapped cheeks, lacy reticular rash	Perioral pallor	Arthritis (adults), fetal hydrops
Sixth Disease (Roseola)	HHV-6 or HHV-7	Post-febrile, trunk, 2-3mm rose-pink	Rash after fever resolves	Febrile seizures

4.1 Viral Exanthems¶

MEASLES (Rubeola, First Disease): Etiology: Paramyxovirus. Rash starts at hairline 2-3 days into illness and moves down the body, typically sparing palms and soles. Begins as discrete erythematous lesions that become confluent as rash spreads. Koplik's spots (1-2 mm white or bluish lesions with erythematous halo on buccal mucosa) are pathognomonic and generally seen during first 2 days of symptoms. Associated with cough, conjunctivitis, coryza, severe prostration. RUBELLA (German Measles, Third Disease): Etiology: Togavirus. Spreads from hairline downward but clears from originally affected areas as it migrates. May be pruritic. Forchheimer spots (palatal petechiae) may develop but are nonspecific. Postauricular and suboccipital adenopathy and arthritis common in adults. Exposure of pregnant women should be avoided due to severe congenital abnormalities. ERYTHEMA INFECTIOSUM (Fifth Disease): Etiology: Human parvovirus B19. Primarily affects children 3-12 years old. Develops after fever has resolved as bright blanchable erythema on cheeks ('slapped cheeks') with perioral pallor. A more diffuse lacy reticular eruption appears the next day on trunk and extremities, may wax and wane over 3 weeks. Adults often have arthritis; fetal hydrops can develop in pregnant women. EXANTHEM SUBITUM (Roseola, Sixth Disease): Etiology: Human herpesvirus 6 or 7. Most common in children <3 years. Rash appears after fever subsides - 2-3 mm rose-pink macules and papules on trunk that coalesce rarely, occasionally on extremities (sparing face), fade within 2 days. Febrile seizures may occur.

4.2 Primary HIV and Infectious Mononucleosis¶

PRIMARY HIV INFECTION: Nonspecific diffuse macules and papules most commonly on upper thorax, face, collar region. Less commonly urticarial or vesicular lesions. Oral or genital ulcers may occur. Associated with pharyngitis, adenopathy, arthralgias. INFECTIOUS MONONUCLEOSIS (Epstein-Barr Virus): Diffuse maculopapular eruption historically in ~5% of cases, increasing to ~90% when antibiotics (particularly ampicillin) given. Recent observed rates ~20% without antibiotics with little increase with antibiotics. Urticaria, petechiae may occur. Periorbital edema (50%), palatal petechiae (25%). Associated with hepatosplenomegaly, pharyngitis, cervical lymphadenopathy, atypical lymphocytosis, heterophile antibody.

4.3 Rickettsial Diseases¶

EPIDEMIC TYPHUS: Etiology: Rickettsia prowazekii. Maculopapular eruption appearing in axillae, spreading to trunk then extremities. Usually spares face, palms, soles. Evolves from blanchable macules to confluent eruption with petechiae. Exposure to body lice. Mortality 10-40% if untreated. Recrudescent form (Brill-Zinsser disease) occurs as relapse after 30-50 years with milder presentation. ENDEMIC (MURINE) TYPHUS: Etiology: Rickettsia typhi. Maculopapular eruption, usually sparing palms and soles. Exposure to rat or cat fleas. Associated with headache, myalgias. SCRUB TYPHUS: Etiology: Orientia tsutsugamushi. Diffuse macular rash starting on trunk. Eschar at site of mite bite. Endemic in South Pacific, Australia, Asia. Mortality up to 30% if untreated.

4.4 Drug Reactions¶

EXANTHEMATOUS DRUG-INDUCED ERUPTION: Usually caused by antibiotics, anticonvulsants, diuretics. Intensely pruritic, bright-red macules and papules, symmetric on trunk and extremities that may become confluent. Occurs 2-3 days after exposure in previously sensitized individuals; otherwise after 2-3 weeks. May persist up to 2 weeks after drug discontinuation. People living with HIV have 50-60% rate of rash with sulfa drugs. DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): Also termed DIHS. Often caused by aromatic anticonvulsants, sulfonamides, minocycline. Maculopapular eruption sometimes progressing to exfoliative erythroderma. Profound facial edema. Pustules may occur. Associated with lymphadenopathy, multiorgan failure (especially hepatic), eosinophilia, atypical lymphocytes, HHV6 viremia. ~10% mortality.

4.5 Other Important Causes¶

TYPHOID FEVER: Etiology: Salmonella typhi. Transient, blanchable erythematous macules and papules 2-4 mm, usually on trunk (rose spots). Ingestion of contaminated food/water. Variable abdominal pain and diarrhea, headache, myalgias, hepatosplenomegaly. DENGUE FEVER: Etiology: Dengue virus (4 serotypes, flaviviruses). Rash in 50% of cases. Initially diffuse flushing, then maculopapular rash beginning on trunk and spreading centrifugally. Pruritus, hyperesthesia may occur. Post-defervescence petechiae may occur. Headache, musculoskeletal pain ('breakbone fever'), leukopenia, occasionally biphasic ('saddleback') fever. LYME DISEASE: Etiology: Borrelia burgdorferi (US), B. afzelii, B. garinii. Papule expanding to erythematous annular lesion with central clearing (erythema migrans, average diameter 15 cm). Sometimes concentric rings or indurated/vesicular center. Multiple secondary erythema migrans lesions in some cases. Untreated lesions usually fade within a month but may persist >1 year. ZIKA VIRUS INFECTION: Etiology: Zika virus (flavivirus). Pruritic macular and papular erythema, may begin on trunk and descend. Conjunctival injection, palatal petechiae may occur. Arthralgia (especially small joints), myalgia, lymphadenopathy, low-grade fever. Illness in pregnancy may cause severe birth defects including microcephaly. Neurologic complications including Guillain-Barré may occur.

5. PERIPHERAL ERUPTIONS¶

These rashes are most prominent peripherally or begin in peripheral (acral) areas before spreading centripetally. Several represent medical emergencies requiring immediate treatment.

Peripheral Eruptions: Key Differentiating Features¶

Disease	Distribution	Lesion Evolution	Key Clinical Clues
Rocky Mountain Spotted Fever	Wrists/ankles fi central, palms/soles late	Macules fi petechiae	Tick exposure, severe headache, mortality if untreated
Secondary Syphilis	Palms/soles prominent, generalized	Copper-colored scaly papules	Primary chancre (10%), never vesicular
Hand-Foot-Mouth Disease	Hands, feet, oral cavity	Papules fi vesicles	Children <10, summer/fall, family clusters
Erythema Multiforme	Knees, elbows, palms, soles fi central	Target lesions, may vesiculate	HSV or Mycoplasma trigger common
Endocarditis	Finger/toe pads, palms, soles	Osler nodes (tender) or Janeway (painless)	New murmur, abnormal valve or IVDU

5.1 Rocky Mountain Spotted Fever¶

Etiology: Rickettsia rickettsii. Early diagnosis and therapy critical due to grave prognosis if untreated. Lesions evolve from macular to petechial, start on wrists and ankles, spread centripetally, and appear on palms and soles later in disease. Tick vector, more common in southeastern and southwest-central US. Associated with headache, myalgias, abdominal pain. Mortality rates up to 40% if untreated. IMPORTANT: The classic petechial rash may initially consist of blanchable erythematous macules distributed peripherally. At times the rash may not be predominantly acral, or no rash may develop at all.

5.2 Secondary Syphilis¶

Etiology: Treponema pallidum. Coincident primary chancre in 10% of cases. Copper-colored, scaly papular eruption, diffuse but prominent on palms and soles. Rash never vesicular in adults. Condyloma latum, mucous patches, and alopecia in some cases. Should be considered in differential diagnosis of pityriasis rosea, especially in sexually active patients. Associated with fever, constitutional symptoms.

5.3 Hand-Foot-and-Mouth Disease¶

Etiology: Most commonly coxsackievirus A16 or enterovirus 71; coxsackievirus A6 causes atypical syndrome. Tender vesicles, erosions in mouth. 0.25-1 cm papules on hands and feet with rim of erythema evolving into tender vesicles. Shedding of nails (onychomadesis) can occur 1-2 months after acute illness. Coxsackievirus A6 lesions may be maculopapular, petechial, purpuric, or erosive; atypical form often extends to perioral area, extremities, trunk, buttocks, genitals, and areas affected by eczema (eczema coxsackium). Summer and fall, primarily children <10 years. Enterovirus 71 can be associated with brainstem encephalitis, flaccid paralysis resembling polio, or aseptic meningitis.

5.4 Erythema Multiforme¶

Etiology: Infection (HSV, Mycoplasma pneumoniae most common), drugs (sulfa, phenytoin, penicillin), idiopathic. Target lesions (central erythema surrounded by area of clearing and another rim of erythema) up to 2 cm. Symmetric on knees, elbows, palms, soles; spreads centripetally. Papular, sometimes vesicular. When extensive and involving mucous membranes, termed EM major. 50% of patients <20 years old. Fever more common in EM major, which can be confused with Stevens-Johnson syndrome but lacks prominent skin sloughing.

5.5 Bacterial Endocarditis¶

Etiology: Streptococcus, Staphylococcus, etc. Subacute course (viridans streptococci): Osler's nodes (tender pink nodules on finger or toe pads), petechiae on skin and mucosa, splinter hemorrhages. Acute course (Staphylococcus aureus): Janeway lesions (painless erythematous or hemorrhagic macules, usually on palms and soles). Risk factors: Abnormal heart valve, IV drug use. Associated with new or changing heart murmur.

5.6 COVID-19 Cutaneous Manifestations¶

Etiology: SARS-CoV-2. Cutaneous findings vary by disease severity: Mild or asymptomatic COVID-19: Pernio (macules, papules, or plaques that are tender, erythematous/violaceous; acral distribution, feet more common than hands). Moderate/severe COVID-19: Vesicles, urticaria, maculopapular erythema; often pruritic; occur on trunk, extremities. Severe COVID-19: Retiform purpura (net-like, purple patches/plaques often with necrosis); lesions often asymptomatic; occur on extremities, buttocks. Complications include thrombosis, especially with retiform purpura. Multisystem inflammatory syndrome in children (MIS-C): Findings similar to Kawasaki disease. Occurs ~2-6 weeks following acute (often asymptomatic) infection in older children/adolescents.

5.7 Chikungunya Fever¶

Etiology: Chikungunya virus. Transmitted by Aedes aegypti and A. albopictus mosquitoes in tropical and subtropical regions. Maculopapular eruption typically occurs on trunk but also on extremities and face. Associated with severe polyarticular, migratory arthralgias, especially involving small joints (hands, wrists, ankles).

6. CONFLUENT DESQUAMATIVE ERYTHEMAS¶

These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions caused by group A Streptococcus or Staphylococcus aureus are toxin-mediated and can be life-threatening.

Comparison of Confluent Desquamative Erythemas¶

Condition	Etiology	Nikolsky Sign	Cleavage Plane	Key Features	Mortality
Scarlet Fever	GAS toxins	Negative	N/A	Sandpaper skin, Pastia's lines, strawberry tongue	Low with treatment

Condition	Etiology	Nikolsky Sign	Cleavage Plane	Key Features	Mortality
Staph Scalded-Skin	S. aureus toxins	Positive	Superficial epidermis	Skin tenderness, perioral crusting	Low in children
SJS	Drugs (80%)	Positive	Full epidermis	<10% BSA, mucosal involvement	~5%
TEN	Drugs (80%)	Positive	Full epidermis	>30% BSA, mucosal involvement	Up to 30%
Staph TSS	S. aureus toxins	Negative	N/A	Colonization only, hypotension	~5%
Strep TSS	GAS toxins	Negative	N/A	Severe GAS infection, hypotension	30%

6.1 Scarlet Fever¶

Etiology: Group A Streptococcus (pyrogenic exotoxins A, B, C). Most common among children 2-10 years old, usually follows group A streptococcal pharyngitis. Diffuse blanchable erythema beginning on face and spreading to trunk and extremities. Circumoral pallor. 'Sandpaper' texture to skin. Accentuation of linear erythema in skin folds (Pastia's lines). Enanthem of white evolving into red 'strawberry' tongue. Desquamation in second week. Associated with fever, pharyngitis, headache.

6.2 Kawasaki Disease¶

Etiology: Idiopathic. Children <8 years old. Rash similar to scarlet fever (scarlatiniform) or erythema multiforme. Fissuring of lips, strawberry tongue, conjunctivitis. Edema of hands and feet with desquamation later in disease. Associated with cervical adenopathy, pharyngitis. CRITICAL: Coronary artery vasculitis is a major complication requiring echocardiographic monitoring.

6.3 Toxic Shock Syndromes¶

STREPTOCOCCAL TOXIC SHOCK SYNDROME: Etiology: Group A Streptococcus (pyrogenic exotoxin A and/or B or certain M types). May occur in setting of severe GAS infections (necrotizing fasciitis, bacteremia, pneumonia). When present, rash often scarlatiniform. Multiorgan failure, hypotension. Mortality rate 30%. STAPHYLOCOCCAL TOXIC SHOCK SYNDROME: Etiology: S. aureus (toxic shock syndrome toxin 1, enterotoxins B and others). Usually only S. aureus colonization—not severe infection—documented. Diffuse erythema involving palms, pronounced erythema of mucosal surfaces, conjunctivitis. Desquamation 7-10 days into illness. Fever >39°C (>102°F), hypotension, multiorgan dysfunction.

6.4 Staphylococcal Scalded-Skin Syndrome¶

Etiology: S. aureus, phage group II. Colonization with toxin-producing S. aureus. Occurs in children <10 years old (termed Ritter's disease in neonates) or adults with renal dysfunction. Generalized erythema is often evident during prodrome of fever and malaise. Profound tenderness of the skin is distinctive. In exfoliative stage, skin can be induced to form bullae with light lateral pressure (Nikolsky's sign). IMPORTANT: Cleavage plane is superficial in epidermis (contrast with TEN where entire epidermis sloughs). Irritability and nasal or conjunctival secretions may be present.

6.5 Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis¶

Etiology: Drugs (80% of cases; often allopurinol, anticonvulsants, antibiotics), infection, idiopathic factors. More common among people living with HIV, systemic lupus erythematosus, certain HLA types, or slow acetylators. Uncommon among children. Erythematous and purpuric macules, sometimes targetoid, or diffuse erythema progressing to bullae with sloughing and necrosis of entire epidermis. Nikolsky's sign positive. Involves mucosal surfaces. Classification by body surface area involvement: - Stevens-Johnson syndrome (SJS): <10% epidermal necrosis - SJS/TEN overlap: 10-30% epidermal necrosis - Toxic epidermal necrolysis (TEN): >30% epidermal necrosis Complications: Dehydration, sepsis from loss of skin integrity. Mortality rates up to 30%.

6.6 Exfoliative Erythroderma Syndrome¶

Underlying conditions: Psoriasis, eczema, drug eruption, mycosis fungoides. Usually occurs in adults over age 50, more common among men. Diffuse erythema (often scaling) interspersed with lesions of underlying condition. Associated with fever, chills (difficulty with thermoregulation), lymphadenopathy. This is a serious reaction associated with systemic toxicity.

7. VESICULOBULLOUS OR PUSTULAR ERUPTIONS¶

These eruptions are characterized by fluid-filled lesions that may be clear (vesicles/bullae) or purulent (pustules). Several represent important infectious diseases requiring isolation precautions.

Differentiating Vesicular Eruptions¶

Feature	Varicella	Smallpox	Mpox (2022)	HSV	Rickettsialpox
Lesion distribution	Trunk predominant	Face/extremities , palms/soles	Variable, <20 lesions	Site of inoculation	Face, trunk, extremities
Lesion stage	Different stages in same area	Same stage in same area	May be different stages	Grouped vesicles	Papule/plaque base
Eschar	No	No	No	No	Yes, at bite site
Key feature	Dewdrops on rose petal	Centrifugal spread	Mucosal lesions at inoculation	Painful, recurrent	Urban, mouse mites
Pruritus	Intense	Present	Often painful	Variable	Variable

7.1 Varicella (Chickenpox)¶

Etiology: Varicella-zoster virus (VZV). Highly contagious, often occurring in winter or spring. Incidence down by 90% in US due to vaccination. Usually affects children; 10% of adults susceptible. Rash characteristics: Macules (2-3 mm) evolving into papules, then vesicles (sometimes umbilicated) on an erythematous base ('dewdrops on a rose petal'). Pustules then form and crust. KEY FEATURE: Lesions appearing in crops - within a given region of body, lesions are in different stages of development at any point in time. May involve scalp, mouth. Intensely pruritic. In immunocompromised hosts: Vesicles may lack characteristic erythematous base or may appear hemorrhagic. Complications: Generally mild in healthy children; more severe with complications in adults and immunocompromised children.

7.2 Variola (Smallpox) and Mpox¶

VARIOLA (SMALLPOX): Etiology: Variola major virus. Nonimmune individuals exposed to smallpox. Red macules on tongue and palate evolving to papules and vesicles. Skin macules evolving to papules, then vesicles, then pustules over 1 week with subsequent crusting. KEY DIFFERENCES FROM VARICELLA: (1) Skin lesions in any given area are at same stage of development (2) Prominent distribution on face and extremities including palms and soles. Prodrome of fever, headache, backache, myalgias; vomiting in 50%. MPOX: Etiology: Monkeypox virus. Endemic to Central and West Africa. Classically similar to smallpox with lymphadenopathy and typically milder course. 2022 OUTBREAK: Most cases in men who have sex with men in nonendemic countries. Macules evolve to papules, vesicles, pustules with crusting over 1-2 weeks. Often umbilicated. KEY DIFFERENCES FROM CLASSIC MPOX: Lesions may be in different stages of development; typically number <20; often painful. Mucosal lesions (anorectal, oropharyngeal, ocular) may occur at sites of inoculation. Associated with fever, lymphadenopathy, headache, proctitis, or pharyngitis. Disease may be severe and progressive in advanced HIV.

7.3 Herpes Simplex Virus Infections¶

PRIMARY HSV INFECTION: Etiology: HSV-1 or HSV-2. Erythema rapidly followed by hallmark painful grouped vesicles that may evolve into pustules that ulcerate, especially on mucosal surfaces. Lesions at site of inoculation: commonly gingivostomatitis for HSV-1 and genital lesions for HSV-2. Primary infection most common among children and young adults (HSV-1) and sexually active young adults (HSV-2). Regional lymphadenopathy. Recurrent disease milder (e.g., herpes labialis typically does not involve oral mucosa); no fever in recurrent infection. DISSEMINATED HERPESVIRUS INFECTION: Occurs in patients with immunosuppression, eczema, or neonates. Generalized nongrouped vesicles that can evolve to pustules and ulcerations. HSV may disseminate in eczematous skin (eczema herpeticum). Visceral organ involvement (liver, lungs) in some cases. Neonatal disease particularly severe; skin lesions diagnostically helpful when present but absent in substantial minority of cases.

7.4 Other Vesiculobullous Conditions¶

RICKETTSIALPOX: Etiology: Rickettsia akari. Seen in urban settings, transmitted by mouse mites. Eschar found at site of mite bite. Generalized rash involving face, trunk, extremities; may involve palms and soles. <100 papules and plaques (2-10 mm) with centers developing vesicles or pustules. Mild disease with headache, myalgias, regional adenopathy. ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS: Etiology: Drugs (mostly anticonvulsants or antimicrobials); also viral. Tiny, sterile, nonfollicular pustules on erythematous, edematous skin. Begins on face and in body folds, then becomes generalized. Appears 2-21 days after start of drug therapy. Acute fever, pruritus, leukocytosis. PSEUDOMONAS 'HOT-TUB' FOLLICULITIS: Etiology: Pseudomonas aeruginosa. Pruritic erythematous follicular, papular, vesicular, or pustular lesions involving axillae, buttocks, abdomen, especially areas occluded by bathing suits. Can manifest as tender isolated nodules on palmar or plantar surfaces ('Pseudomonas hot-foot syndrome'). Occurs in outbreaks after bathing in hot tubs or swimming pools. Generally self-limited. ECTHYMA GANGRENOSUM: Etiology: P. aeruginosa, other gram-negative rods, fungi. Usually affects neutropenic patients. Indurated plaque evolving into hemorrhagic bulla or pustule that sloughs, resulting in eschar formation with erythematous halo. Most common in axillary, groin, perianal regions. Occurs in up to 28% of individuals with Pseudomonas bacteremia. Clinical signs of sepsis. DISSEMINATED VIBRIO VULNIFICUS: Etiology: V. vulnificus. Patients with cirrhosis, diabetes, renal failure. Exposure by ingestion of contaminated saltwater or seafood. Erythematous lesions evolving into hemorrhagic bullae then necrotic ulcers. Hypotension; mortality rate 50%. REACTIVE INFECTIOUS MUCOCUTANEOUS ERUPTION (RIME): Etiology: M. pneumoniae, Chlamydia pneumoniae, human metapneumovirus, parainfluenzavirus 2, rhinovirus, influenza B, SARS-CoV-2. More common in males, usually children (mean age 11-12 years). Severe mucositis of at least two sites (oropharynx, ocular, genital) with nearly universal hemorrhagic crusting of lips. Sparse vesiculobullous or atypical targetoid rash over <10% of body. Lesions typically on extremities. Rash sometimes absent. Cough, respiratory infection symptoms often precede rash by ~1 week. Good prognosis; distinct from SJS/TEN.

8. URTICARIA-LIKE ERUPTIONS¶

Classic urticaria (hives) usually represents a hypersensitivity reaction without associated fever. In the presence of fever, urticaria-like eruptions are most often due to urticarial vasculitis.

8.1 Urticarial Vasculitis¶

Erythematous, edematous 'urticaria-like' plaques that are pruritic or burning. KEY DIFFERENCES FROM CLASSIC URTICARIA: 1. Typical lesion duration >24 hours (up to 5 days) vs <24 hours for classic urticaria 2. Lack of complete lesion blanching with compression due to hemorrhage Etiologies include: - Serum sickness (often induced by drugs: penicillins, sulfas, salicylates, barbiturates) - Acute hepatitis B infection - Enteroviral infection - Parasitic infection - Connective-tissue disease (SLE, Sjögren's syndrome) - Malignancy (especially lymphoma) Fever is variable. Associated with arthralgias/arthritis.

9. NODULAR ERUPTIONS¶

In immunocompromised hosts, nodular lesions often represent disseminated infection. In immunocompetent patients, consider inflammatory conditions.

9.1 Disseminated Fungal and Mycobacterial Infections¶

Occur in immunocompromised hosts (bone marrow transplant recipients, patients undergoing chemotherapy, HIV-infected patients). DISSEMINATED CANDIDIASIS: Often due to Candida tropicalis. Triad of fever, myalgias, and eruptive nodules. Subcutaneous nodules up to 3 cm. DISSEMINATED CRYPTOCOCCOSIS: Lesions may resemble molluscum contagiosum. ASPERGILLOSIS AND MUCORMYCOSIS: Necrosis of nodules should raise suspicion. Necrotic nodules commonly found on extremities, periorbital or nasal regions. MYCOBACTERIA: Subcutaneous nodules with fluctuance and draining common.

9.2 Erythema Nodosum¶

Septal panniculitis. Large, violaceous, nonulcerative, subcutaneous nodules. Exquisitely tender. Usually on lower legs but also on upper extremities. More common among females 15-30 years old. Etiologies: - Infections: Streptococcal, fungal (coccidioidomycosis, histoplasmosis), mycobacterial, Yersinia - Drugs: Sulfas, penicillins, oral contraceptives - Sarcoidosis - Inflammatory bowel disease - Idiopathic Associated with arthralgias in 50%. Features vary with associated condition.

9.3 Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)¶

Tender red or blue edematous nodules giving impression of vesiculation. Usually on face, neck, upper extremities; when on lower extremities may mimic erythema nodosum. More common among women and persons 30-60 years old. 20% of cases associated with malignancy (men and women equally affected in this group). Associated conditions: - Yersinia infection - Upper respiratory infection - Inflammatory bowel disease - Pregnancy - Malignancy (usually hematologic) - Drugs (G-CSF) Associated with headache, arthralgias, leukocytosis.

9.4 Bacillary Angiomatosis¶

Etiology: Bartonella henselae, B. quintana. Immunosuppressed individuals, especially those with advanced HIV infection. Many forms including: - Erythematous, smooth vascular nodules - Friable, exophytic lesions - Erythematous plaques (may be dry, scaly) - Subcutaneous nodules (may be erythematous) Peliosis of liver and spleen in some cases. Lesions sometimes involve multiple organs. Bacteremia may occur.

10. PURPURIC ERUPTIONS¶

Purpuric eruptions indicate bleeding into the skin and may represent life-threatening conditions requiring immediate intervention. Palpable purpura suggests vasculitis.

Differential Diagnosis of Purpuric Eruptions¶

Condition	Palpable?	Distribution	Key Distinguishing Features
Acute meningococcemia	No initially, may evolve	Trunk, extremities, can be anywhere	Rapid progression, hypotension, meningitis
Chronic meningococcemia	Variable	Lower extremities common	Recurrent episodes, complement deficiency
Disseminated gonococcal	Yes	Peripheral, near joints	<40 lesions, hemorrhagic pustules, tenosynovitis

Condition	Palpable?	Distribution	Key Distinguishing Features
RMSF	No initially	Wrists/ankles fi central	Tick exposure, evolves macules fi petechiae
Purpura fulminans	No	Irregular ecchymoses	DIC, sepsis, necrosis
Vasculitis (LCV)	Yes	Dependent areas (legs)	Crops of lesions, may ulcerate
TTP/HUS	No	Petechiae	MAHA, thrombocytopenia, normal coagulation

10.1 Acute Meningococcemia¶

Etiology: Neisseria meningitidis. Most common among children, individuals with asplenia or terminal complement component deficiency (C5-C8). Initially pink maculopapular lesions evolving into petechiae. Petechiae rapidly become numerous, sometimes enlarging and becoming vesicular. Trunk and extremities most commonly involved; may appear on face, hands, feet. May include purpura fulminans reflecting DIC. Associated with hypotension, meningitis (sometimes preceded by upper respiratory infection). CRITICAL: Rocky Mountain spotted fever should be considered in differential diagnosis. Echovirus 9 infection may mimic acute meningococcemia - treat as bacterial sepsis until differentiation possible.

10.2 Purpura Fulminans¶

Etiology: Severe DIC. Large ecchymoses with sharply irregular shapes evolving into hemorrhagic bullae and then black necrotic lesions. Occurs in: - Individuals with sepsis (especially N. meningitidis) - Malignancy - Massive trauma - Asplenic patients at high risk for sepsis Associated with hypotension.

10.3 Chronic Meningococcemia¶

Etiology: N. meningitidis. Individuals with complement deficiencies. Variety of recurrent eruptions: - Pink maculopapular - Nodular (usually on lower extremities) - Petechial (sometimes developing vesicular centers) - Purpuric areas with pale blue-gray centers Fevers sometimes intermittent. Associated with arthritis, myalgias, headache.

10.4 Disseminated Gonococcal Infection¶

Etiology: Neisseria gonorrhoeae. Sexually active individuals (more often females), some with complement deficiency. Distinctive lesions: Papules (1-5 mm) evolving over 1-2 days into hemorrhagic pustules with gray necrotic centers. Hemorrhagic bullae occur rarely. Lesions (usually <40) distributed peripherally near joints (more commonly on upper extremities). Associated with low-grade fever, tenosynovitis, arthritis. NOTE: Lesions of chronic meningococcemia and gonococcemia may be indistinguishable in appearance and distribution.

10.5 Viral Hemorrhagic Fevers¶

Etiology: Arenaviruses, bunyaviruses, filoviruses (including Ebola), flaviviruses (including dengue). Petechial rash. Residence in or travel to endemic areas required for diagnosis. Triad: Fever, shock, hemorrhage from mucosa or gastrointestinal tract. Dengue hemorrhagic fever/dengue shock syndrome represents severe dengue.

10.6 Thrombotic Microangiopathies¶

THROMBOTIC THROMBOCYTOPENIC PURPURA / HEMOLYTIC-UREMIC SYNDROME: Etiologies: - Shiga toxin-producing bacteria (commonly E. coli O157:H7) - especially children - Deficiency in ADAMTS13 (cleaves von Willebrand factor) - Drugs (quinine, chemotherapy, immunosuppression) - HIV infection - Autoimmune diseases - Pregnancy/postpartum Petechiae present. Features: Fever (not always present), microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, neurologic dysfunction. IMPORTANT: Coagulation studies normal (differentiates from DIC).

10.7 Cutaneous Small-Vessel Vasculitis (Leukocytoclastic Vasculitis)¶

Palpable purpuric lesions appearing in crops on legs or other dependent areas. May become vesicular or ulcerative. Etiologies: - Infections (group A streptococcal, hepatitis B or C) - Drugs - Connective tissue disease - Cryoglobulinemia - Malignancy - Henoch-Schönlein purpura (HSP) - more common in children Fever not always present. Malaise, arthralgias, myalgias. Systemic vasculitis in some cases. Renal, joint, and GI involvement common in HSP.

11. ERUPTIONS WITH ULCERS AND/OR ESCHARS¶

The presence of an ulcer or eschar in the setting of a more widespread eruption can provide important diagnostic clues, often indicating the site of inoculation.

Diseases Associated with Eschars¶

Disease	Etiology	Eschar Location	Geographic Distribution	Additional Rash
Scrub typhus	Orientia tsutsugamushi	Mite bite site	South Pacific, Australia, Asia	Diffuse macular, trunk
Boutonneuse fever	Rickettsia conorii	Tick bite site	Mediterranean, India, Africa	Maculopapular, extremities fi trunk
African tick-bite fever	Rickettsia africae	Tick bite site	Africa, Caribbean	Maculopapular
Rickettsialpox	Rickettsia akari	Mouse-mite bite	Urban settings	Vesiculopustular
Tularemia	Francisella tularensis	Inoculation site	North America, Europe	Variable (35% of cases)
Anthrax	Bacillus anthracis	Inoculation site	Endemic areas, bioterrorism	Painless ulcer with vesicles
Rat-bite fever (sodoku)	Spirillum minus	Rat bite site	Asia (rare in US)	Blotchy violaceous

11.1 Tularemia¶

Etiology: Francisella tularensis. Exposure to ticks, biting flies, infected animals. Ulceroglandular form: Erythematous, tender papule evolves into necrotic, tender ulcer with raised borders. In 35% of cases, eruptions may occur: maculopapular, vesiculopapular, acneiform, or urticarial; erythema nodosum; or erythema multiforme. Associated with fever, headache, lymphadenopathy.

11.2 Anthrax (Cutaneous)¶

Etiology: Bacillus anthracis. Exposure to infected animals or animal products, other exposure to anthrax spores. Pruritic papule enlarging and evolving into a 1 x 3 cm PAINLESS ulcer surrounded by vesicles, then developing a central eschar with edema. Residual scar. Associated with lymphadenopathy, headache.

11.3 Other Eschar-Producing Conditions¶

SCRUB TYPHUS: Eschar at site of mite bite; diffuse macular rash starting on trunk. RICKETTSIAL SPOTTED FEVERS: Eschar common at bite site in boutonneuse fever and other Old World spotted fevers. RAT-BITE FEVER (Sodoku - Spirillum minus): Eschar at bite site, then blotchy violaceous or red-brown rash involving trunk and extremities. AFRICAN TRYPANOSOMIASIS: Chancre at site of tsetse fly bite may precede rash by several weeks. RICKETTSIALPOX: Eschar at site of mouse-mite bite with generalized vesicular eruption.

12. DIAGNOSTIC APPROACH ALGORITHM¶

A systematic approach to diagnosis is essential given the broad differential diagnosis of fever and rash.

12.1 Step-by-Step Diagnostic Algorithm¶

STEP 1: IDENTIFY LESION MORPHOLOGY - Macular/papular (flat or raised <5mm, blanchable) - Vesiculobullous (fluid-filled) - Pustular (purulent) - Purpuric (petechiae <3mm, ecchymoses >3mm, palpable vs nonpalpable) - Nodular (raised >5mm, solid) - Urticarial (wheals, transient) - Ulcerated/Eschar STEP 2: ASSESS DISTRIBUTION - Central (truncal) → Consider measles, rubella, drug reactions, typhoid, dengue - Peripheral (acral) → Consider RMSF, secondary syphilis, hand-foot-mouth, endocarditis - Involvement of palms/soles → Consider RMSF, secondary syphilis, SJS/TEN, coxsackievirus STEP 3: EVALUATE CRITICAL HISTORICAL FEATURES - Immune status (immunocompromised → disseminated fungal/mycobacterial, ecthyma gangrenosum) - Recent medications (drug eruption, DRESS, SJS/TEN, AGEP) - Travel history (endemic areas for rickettsial, viral hemorrhagic fevers, typhoid) - Animal/arthropod exposures (tick → RMSF, Lyme; rat → rat-bite fever; mite → rickettsialpox) - Sexual exposures (syphilis, gonococcemia, HIV) STEP 4: IDENTIFY LIFE-THREATENING CONDITIONS REQUIRING IMMEDIATE TREATMENT - Purpura with hypotension → Meningococcemia, RMSF, purpura fulminans - Diffuse erythema with desquamation + hypotension → Toxic shock syndromes - Bullae with epidermal sloughing → SJS/TEN, staphylococcal scalded-skin syndrome - Neutropenic patient with ecthyma → Pseudomonas sepsis STEP 5: OBTAIN APPROPRIATE DIAGNOSTIC STUDIES - Blood cultures (all patients with fever and petechiae) - Skin biopsy (vasculitis, uncertain diagnosis) - Serologic testing (rickettsial, viral) - PCR/molecular testing (herpes viruses, rickettsia) - Tzanck smear (vesicular lesions) - Direct fluorescent antibody (HSV, VZV)

13. KEY POINTS & CLINICAL PEARLS¶

13.1 Life-Threatening Conditions Not to Miss¶

MENINGOCOCCEMIA: Petechiae can begin as blanchable macules - treat empirically if suspected; mortality high if delayed
ROCKY MOUNTAIN SPOTTED FEVER: Up to 40% mortality if untreated; rash may be absent or not predominantly acral; treat empirically with doxycycline if suspected
TOXIC SHOCK SYNDROMES: Look for hypotension + diffuse erythema + mucosal involvement
TEN: Nikolsky sign positive, mucosal involvement, >30% BSA; mortality up to 30%
NECROTIZING FASCIITIS with STREP TSS: Skin findings may be minimal initially; mortality 30%

13.2 Pathognomonic Signs¶

KOPLIK'S SPOTS: 1-2 mm white/bluish lesions with erythematous halo on buccal mucosa → Measles - 'DEWDROPS ON A ROSE PETAL': Vesicles on erythematous base → Varicella - PASTIA'S LINES: Accentuated linear erythema in skin folds → Scarlet fever
TARGET LESIONS: Central erythema, clearing, outer erythema → Erythema multiforme - ESCHAR AT INOCULATION SITE: Rickettsial diseases, tularemia, anthrax

13.3 Common Diagnostic Pitfalls¶

RMSF may not have acral predominance or any rash at all
Meningococcemia may present as urticaria initially
Drug rashes can appear 2+ weeks after drug initiation and persist 2 weeks after discontinuation
Infectious mononucleosis rash rate increases to ~90% with ampicillin but recent data show only ~20% baseline and little increase with antibiotics
Forchheimer spots (palatal petechiae) are nonspecific - occur in rubella, infectious mononucleosis, scarlet fever, and Zika
Echovirus 9 may mimic meningococcemia - treat as bacterial sepsis until differentiated
EM major can be confused with SJS but lacks prominent skin sloughing

13.4 High-Yield Associations¶

Slapped cheeks + lacy reticular rash → Parvovirus B19 (erythema infectiosum) - Rash after fever resolves → Roseola (HHV-6) or erythema infectiosum - Sandpaper texture + strawberry tongue → Scarlet fever - Copper-colored papules on palms/soles → Secondary syphilis - Hemorrhagic pustules near joints (<40) → Disseminated gonococcal infection - Nodules that resemble molluscum in immunocompromised → Cryptococcosis - Exquisitely tender nodules on legs → Erythema nodosum - Pernio (acral erythematous/violaceous lesions on feet) → Mild/asymptomatic COVID-19 - Retiform purpura + thrombosis → Severe COVID-19 - Severe mucositis + sparse skin lesions in child with respiratory infection → RIME/MIRM

13.5 Special Populations¶

IMMUNOCOMPROMISED PATIENTS: - Varicella vesicles may lack erythematous base or appear hemorrhagic - Nodular lesions often represent disseminated fungal/mycobacterial infection - HSV may cause extensive progressive mucocutaneous lesions - Ecthyma gangrenosum in neutropenic patients - People living with HIV: 50-60% develop rash with sulfa drugs; more susceptible to SJS/TEN PREGNANT WOMEN: - Rubella exposure must be avoided - causes severe congenital abnormalities - Parvovirus B19 can cause fetal hydrops - Zika virus may cause severe birth defects including microcephaly CHILDREN: - Kawasaki disease: Must monitor for coronary artery vasculitis - Staphylococcal scalded-skin syndrome: More common in children <10 years - RIME/MIRM: Mean age 11-12 years, respiratory infection precedes rash - HUS: Common following E. coli O157:H7 gastroenteritis