Differentials
Common
Allergy to food or drug
History
rapid onset, urticarial eruption within minutes to hours of exposure
Exam
maculopapular-appearing eruption, sometimes before development of urticaria; skin and mucosal changes can be dramatic and uncomfortable; anaphylaxis is recognised by the sudden onset of life-threatening airway and/or breathing and/or circulation problems
1st investigation
- none:
diagnosis is clinical
Other investigations
- skin tests (prick tests, intradermal tests, patch tests):
positive test may confirm diagnosis
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Insect bites or stings
History
rapid onset, urticarial eruption within minutes to hours of exposure to insect bite or sting
Exam
maculopapular-appearing eruption, sometimes before development of urticaria; skin and mucosal changes can be dramatic and uncomfortable; anaphylaxis is recognised by the sudden onset of life-threatening airway and/or breathing and/or circulation problems
1st investigation
- none:
diagnosis is clinical
Other investigations
- skin tests (prick tests, intradermal tests, patch tests):
positive test may confirm diagnosis
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Adverse drug reaction (e.g., to antibiotic, anticonvulsant, or allopurinol)
History
recent use of drug, typically antibiotics such as penicillins, sulfonamides, cephalosporins, past history of medication allergy, eruption occurs within several (typically within 6-10) days of exposure to a new medication, or 3 days of a second exposure (rash due to an existing chronic medication is possible but less common); may accompany new nutritional or herbal supplements in 1 in 1000 or present as influenza-like syndrome after recent immunisations
Exam
maculopapular eruption on the trunk and extremities; ill-appearing patient, usually adult, often febrile; in allergic reactions, cutaneous findings predominate; patients may show mild malaise, specific infectious signs are absent; itch may be mild to severe
1st investigation
- none:
diagnosis is clinical
Chemotherapy
History
recent chemotherapy (e.g., cytarabine, dacarbazine, hydroxyurea, paclitaxel, and procarbazine); likelihood generally noted in prescribing information
Exam
maculopapular rash, characterised by monomorphic erythematous papules
1st investigation
- none:
diagnosis is clinical
Other investigations
- skin tests (prick tests, intradermal tests, patch tests):
positive test may confirm diagnosis
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Enterovirus and echovirus infection
History
fever and malaise with abrupt synchronous generalised rash, more common in autumn and summer (e.g., hand-foot-and-mouth disease, usually coxsackievirus types A16 and A7)
Exam
generalised maculopapular rash; pharyngitis common, sometimes petechiae, oral erosions, and conjunctival haemorrhage; involvement of central nervous system (encephalitis, meningitis) and heart (myocarditis) rare; hand-foot-and-mouth disease may present with vesicular eruption on the palms and soles with a vesicular stomatitis
1st investigation
- none:
clinical diagnosis
Fifth disease (erythema infectiosum)
History
mild prodrome, particularly in children aged 4 to 10 years during the winter and spring, joint pain not uncommon; infection during pregnancy can lead to anaemia, fetal hydrops, and fetal death
Exam
initial slapped cheeks erythema, followed in 1 to 4 days by a lacy rash on the extremities; arthralgia of the hands, wrists, ankles, feet
1st investigation
- none:
clinical diagnosis
Other investigations
- anti-parvovirus B19 IgM antibody:
positive
Roseola infantum (sixth disease)
History
rash during defervescence from high fever, especially in infants; may predispose to seizures, encephalopathy, and aseptic meningitis; mild upper respiratory symptoms sometimes present
Exam
high fever; abrupt appearance of a generalised rose-pink rash on the trunk and proximal extremities during defervescence; bulging fontanelles indicate risk of central nervous system involvement; cervical or occipital lymphadenopathy sometimes present; red papules and erosions of soft palate and uvula (Nagayama spots) characteristic
1st investigation
- none:
clinical diagnosis
Other investigations
- serum for anti-human herpes virus 6 antibodies:
positive
Epstein Barr virus (EBV) infection (infectious mononucleosis)
History
cutaneous eruption with pharyngitis, fever, and lymphadenopathy, adolescents or young adults
Exam
fever, rash at day 4 to 6 of illness, initially on trunk and upper extremities, extends to forearms and face; petechiae commonly present, lymphadenopathy (cervical, submandibular, or generalised), hepatosplenomegaly common
1st investigation
- heterophile antibodies:
positive
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Cytomegalovirus (CMV) infection
History
mononucleosis-like, may last 2 weeks, rarely associated with hepatitis; risk of death in immunocompromised patients (organ transplant recipients and HIV); congenital infection with high fetal risk, teratogenicity
Exam
fever, non-specific maculopapular eruption; petechiae commonly present, lymphadenopathy (cervical, submandibular, or generalised)
1st investigation
- serology for CMV:
positive
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Other investigations
Uncommon
Iodinated contrast media non-immediate adverse reaction
History
onset of maculopapular eruption with a temporal association to injection of iodinated contrast media
Exam
maculopapular eruption, may also develop urticaria
1st investigation
- none:
primarily clinical diagnosis
Other investigations
Toxic epidermal necrolysis/Stevens-Johnson syndrome
History
most often drug-induced (e.g., antibiotics, anticonvulsants, sulfonamides, non-steroidal anti-inflammatories, and allopurinol); prodromal symptoms of malaise, fever, photophobia, and anorexia, followed by mucocutaneous inflammation and pain
Exam
widespread cutaneous involvement, involvement of ≥2 mucosal surfaces (oral, conjunctival, anogenital); skin lesions initially targetoid, often become confluent; dusky red or purple ill-defined macules on trunk, face, or proximal limbs; superficial erosion precedes cutaneous necrosis; positive Nikolsky's sign (epidermal layer sloughs off easily when lateral pressure is applied); lesions are painful, patient appears acutely unwell
1st investigation
- none:
diagnosis is clinical, and tests are not routinely recommended
Other investigations
- skin biopsy:
not required for diagnosis but could be considered depending on the clinical scenario
Drug reaction with eosinophilia and systemic symptoms
History
recent use of sulfonamides, anticonvulsants, including carbamazepine, allopurinol, and minocycline; medication intake may be 2 to 6 weeks prior to symptom development
Exam
a maculopapular drug eruption, acutely unwell patient with fever, abdominal pain, and facial swelling
1st investigation
- none:
diagnosis is clinical, and tests are not routinely recommended
Other investigations
- FBC:
eosinophilia, atypical lymphocytosis
- urinalysis:
proteinuria, abnormal urinary sediment with occasional eosinophils indicating interstitial nephritis
- skin biopsy:
not required for diagnosis but could be considered depending on the clinical scenario
Erythema multiforme
History
possible herpes simplex or Mycoplasma pneumoniae infection; recent new use of certain drugs, including sulfonamides, penicillin, and non-steroidal anti-inflammatory drugs; lesions erupt over 24 to 48 hours
Exam
characterised by target lesions that resemble a bull’s eye; symmetrical distribution, usually of distal extremities, affecting <10% body surface area; minimal mucous membrane involvement; if mucous membrane involvement present, tender erosions, blisters, and crusts can affect any mucous membrane
1st investigation
- none:
diagnosis is clinical, and tests are not routinely recommended
Other investigations
- skin biopsy:
not required for diagnosis but can be useful where there is diagnostic uncertainty
HIV-seroconversion exanthema (also known as acute retroviral syndrome)
History
HIV-infected blood transfusion, intravenous drug use, unprotected sexual intercourse, and percutaneous needle prick injury; acute syndrome 3 to 6 weeks after exposure, fatigue, malaise, headache, sore throat, lymphadenopathy, and myalgia
Exam
fine morbilliform eruption trunk and upper arms, occasionally palms and soles; lasts for 4 to 5 days, resolves spontaneously
1st investigation
- HIV viral RNA or core antigen:
positive
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Other investigations
- HIV serology:
positive
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Mpox
History
a characteristic rash that progresses in sequential stages (from macules, to papules, vesicles, and pustules); anorectal symptoms have been reported (e.g., severe/intense anorectal pain, tenesmus, rectal bleeding, or purulent or bloody stools, pruritus, dyschezia, burning and swelling), and may occur in the absence of a rash; fever may be a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all; other common symptoms may include myalgia, fatigue, asthenia, malaise headache, sore throat, back ache, cough, nausea/vomiting; there may be a history of recent travel to/living in endemic country or country with outbreak, or contact with suspected, probable, or confirmed case
Exam
rash or skin lesion(s) are usually the first sign of infection; physical examination may reveal a rash or lesion(s), and possibly lymphadenopathy; rash generally starts on the face and body and spreads centrifugally to the palms and soles (it may be preceded by a rash affecting the oropharynx and tongue in the 24 hours prior that often passes unnoticed); lesions simultaneously progress through four stages - macular, papular, vesicular, and pustular - with each stage lasting 1 to 2 days, before scabbing over and resolving; lesions are typically 5 to 10 mm in diameter, may be discrete or confluent, and may be few in number or several thousand; vesicles are well-circumscribed and located deep in the dermis; the rash may appear as a single lesion in the genital area without a prodromal phase; perianal/rectal lesions and proctitis may be present; lymphadenopathy typically occurs with onset of fever preceding the rash or, rarely, with rash onset, may be submandibular and cervical, axillary, or inguinal, and occur on both sides of the body or just one side; inguinal lymphadenopathy has been commonly reported
1st investigation
- full blood count:
may show leukocytosis, lymphocytosis, thrombocytopenia
- urea and electrolytes:
may show low urea or other derangements
- liver function tests:
may show elevated transaminases, hypoalbuminaemia
- polymerase chain reaction:
positive for monkeypox or orthopoxvirus virus DNA
More - sexually transmitted infection (STI) tests:
variable (depends on the infection present)
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Sepsis
History
symptoms of localised infection; non-specific symptoms include fever or shivering, dizziness, nausea and vomiting, muscle pain, feeling confused or disoriented; may be history of risk factors (e.g., immunosuppression, pregnancy or postnatal period, frailty, recent surgery or invasive procedures, intravenous drug use, or breach of skin integrity)
Exam
tachycardia, tachypnoea, hypotension, fever (>38℃) or hypothermia (<36℃), prolonged capillary refill, mottled or ashen skin, cyanosis, low oxygen saturation, newly altered mental state, reduced urine output
1st investigation
- blood culture:
may be positive for organism
More - serum lactate:
may be elevated; levels >2 mmol/L (>18 mg/dL) associated with adverse prognosis; even worse prognosis with levels >4 mmol/L (>36 mg/dL) elevated
More - FBC with differential:
WBC count >12×10⁹/L (12,000/microlitre) (leukocytosis); WBC count <4×10⁹/L (4000/microlitre) (leukopenia); or a normal WBC count with >10% immature forms; low platelets
More - C-reactive protein:
elevated
- blood urea and serum electrolytes:
serum electrolytes may be deranged; blood urea may be elevated
- serum creatinine:
may be elevated
More - liver function tests:
may show elevated bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma glutamyl transpeptidase
More - coagulation studies:
may be abnormal
- ABG:
may be hypoxia, hypercapnia, elevated anion gap, metabolic acidosis
Other investigations
- ECG:
may show evidence of ischaemia, atrial fibrillation, or other arrhythmia; may be normal
More - chest x-ray:
may show consolidation; demonstrates position of central venous catheter and tracheal tube
- urine microscopy and culture:
may be positive for nitrites, protein, or blood; elevated leukocyte count; positive culture for organism
- sputum culture:
may be positive for organism
- lumbar puncture:
may be elevated WBC count, presence of organism on microscopy, and positive culture
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Acute hepatitis B virus infection
History
antenatal exposure, multiple sexual partners, men who have sex with men, injection drug use, family history of hepatitis B virus or hepatocellular epithelioma, incarceration, living in/travel to a highly endemic region, and household contact with an infected individual; variable cutaneous findings accompany viraemic phase of acute hepatitis B virus infection
Exam
rash may be maculopapular; other cutaneous findings, including vasculitis, urticaria, lichen planus, cryoglobulinaemia, and porphyria cutanea tarda; hepatic or generalised abdominal tenderness
1st investigation
- acute hepatitis B serology:
positive
More - liver function tests:
elevated aminotransferases
Other investigations
Acute hepatitis C virus infection
History
unsafe medical practices, intravenous or intranasal drug use, and history of blood transfusion or organ transplant; variable cutaneous findings accompany viraemic phase of acute hepatitis C virus infection
Exam
rash may be maculopapular; other cutaneous findings, including vasculitis, urticaria, lichen planus, cryoglobulinaemia, and porphyria cutanea tarda; hepatic or generalised abdominal tenderness
1st investigation
- liver function tests:
elevated aminotransferases
- hepatitis C serology:
positive
Other investigations
- hepatitis C serology:
positive
Rubella (German measles)
History
16- to 18-day incubation period, prodrome of fever, headache, and upper respiratory symptoms; more common in unimmunised or immunodeficient patients
Exam
maculopapular eruption beginning on the face and spreading cephalocaudally, petechial macules on the soft palate (Forscheimer spots), tender cervical lymphadenopathy; joint pain common
1st investigation
- serum rubella-specific antibodies:
IgM: positive in acute serum; IgG: seroconversion or 4-fold rise between acute and convalescent titres
Other investigations
Rubeola (measles)
History
travel to measles-endemic area; exposure to individual with measles; attendance at high-risk mass gathering/event; prodrome of cough, coryza, conjunctivitis, and Koplik's spots; unimmunised or immunodeficient patient; lasts about 5 days
Exam
erythematous macules and papules begin on the forehead, hairline, and behind the ears, then extend cephalocaudally, Koplik's spots (grey-white papules on the buccal mucosa)
1st investigation
- measles-specific serology:
positive
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Other investigations
- polymerase chain reaction (PCR) for measles RNA:
positive
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Meningococcaemia
History
more common in close living conditions such as college dormitories, prisons; no prior immunisation or immunisation >10 years ago, young children, older people
Exam
maculopapular rash may be an early presenting sign and is distinct from the more classic petechial or coalesced purpuric eruption that is frequently found later in the disease process; fever and nuchal rigidity generally present
1st investigation
- blood cultures:
gram-negative diplococci
- lumbar puncture:
gram-negative diplococci may be present
Other investigations
Scarlet fever
History
scarlatiniform rash, fever, sore throat, headache, nausea and vomiting, abdominal pain, skin or soft-tissue infection including impetigo, surgical wound infection, absence of cough or other viral symptoms; scarlatiniform rash may present prior to or independent of symptoms of pharyngitis, especially in children aged <5 years
Exam
scarlatiniform rash: diffuse, finely papular (sandpaper-like), erythematous rash that blanches with pressure, accentuated in flexor creases producing red streaks known as Pastia's lines, flushed 'scarlet' bilateral cheeks with circumoral pallor, in patients with darker skin may appear as though sunburnt; inflamed tongue with a white coating and prominent papillae ('strawberry tongue'); tonsillopharyngeal inflammation, patchy tonsillopharyngeal exudates, palatal petechiae, tender and enlarged anterior cervical lymph nodes; skin desquamation is a late finding (3-4 days after scarlatiniform rash); pyoderma
1st investigation
- clinical diagnosis:
diagnosis is mainly clinical
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Staphylococcal scalded skin syndrome
History
child (typically neonates and children younger than 5 years old) or immunosuppressed/renally insufficient adult; history of recent infection of skin, respiratory tract, mouth, or gastrointestinal tract; history of skin infection in household members; diffuse erythematous rash; prodrome of fever, malaise, and tender skin
Exam
generalised erythema with fever; fragile bullae on the surface of skin, positive Nikolsky's sign (epidermal layer sloughs off easily when lateral pressure is applied)
1st investigation
- culture from blister:
often negative
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Toxic shock syndrome (Staphylococcus exotoxin)
History
young adult, post-surgical with packing, abscess, infected mesh; hypotension, renal failure, pharyngitis, headache, gastrointestinal symptoms; maybe menstrual related
Exam
fever, hypotension, diffuse scarlatiniform rash; the rash starts on the trunk and spreads centripetally with later desquamation, multi-organ involvement (≥3 of: gastrointestinal, muscular, central nervous system, renal, hepatic, mucous membranes, haematological [thrombocytopenia with platelet count <100 x 10⁹/L; 100 x 10³/microlitre])
1st investigation
Other investigations
Rocky Mountain spotted fever or Mediterranean spotted fever
History
summer/autumn incidence, outdoor activity pre-disposing to tick exposure about 1 week before development of influenza-like syndrome, gastrointestinal symptoms, rash develops 2 to 4 days later, seizures uncommon
Exam
fever, rash begins as petechial macules on the wrists, ankles, palms, soles, becomes generalised and maculopapular, sparing the face, intense inflammation or ecchymoses may be present at the site of the tick bite, hepatomegaly not uncommon
1st investigation
- serological assays for rickettsia:
positive (titre 1:128) during second week of illness
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Other investigations
Acute graft-versus-host disease
History
allogeneic haematopoietic stem cell transplant; also after blood product transfusion or solid organ transplant; typically occurs 1 to 3 weeks after transplant, occurring in 25% to 40% of HLA-identical siblings and in more than 50% of those who received transplants from unrelated donors
Exam
maculopapular exanthema, begins on the hands and feet as acral erythema, favours the upper back, ears, cheeks, and neck; severe cases with diffuse erythroderma and desquamation; mucous membranes (particularly conjunctiva) involved, gastrointestinal tract and liver involvement may occur
1st investigation
Other investigations
Kawasaki disease (mucocutaneous lymph node syndrome)
History
children <5 years of age, winter to late spring, fever for 5 days
Exam
fever, cervical lymphadenopathy (usually unilateral), conjunctival injection; oral hyperaemia, cracked lips, and strawberry tongue; erythema and oedema of extremities with a desquamating rash on the palms and soles; maculopapular rash on the trunk, occasionally marked perineal erythema, variable multi-system findings
1st investigation
Other investigations
- echocardiogram:
may show dilated coronary vessels
More - electrocardiogram:
may show prolonged PR interval, non-specific ST- and T-wave changes
Juvenile-onset or adult-onset Still disease
History
periodic, transient fevers associated with rapid rash onset; rash disappears as the fever remits; arthritis and myalgia commonly present
Exam
fever, salmon-pink macular rash, favours the trunk and sites of pressure; joint pain, inflammation commonly affecting knees, ankles (juvenile), and carpals (adults); splenomegaly in children
1st investigation
Other investigations
Syphilis (secondary)
History
non-pruritic rash; typically develops some 4 to 10 weeks after the primary lesion (painless genital ulcer); often associated with fever and systemic symptoms (e.g., malaise, myalgia, arthralgia, sore throat, and weight loss)
Exam
maculopapular eruption on the trunk and extremities, and particularly the palms and soles; variable appearance, most commonly of pink to red-brown appearance, ranging from 2 to 20 mm in diameter
1st investigation
- serum rapid plasma reagin:
positive
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Ebola virus infection
History
history of exposure to infected person or travel in endemic area; initial stages of infection are non-specific; patients may have fever, headache, myalgia, gastrointestinal symptoms, conjunctivitis, and bleeding; maculopapular rash develops early in the course of illness
Exam
rash frequently described as non-pruritic, erythematous, and maculopapular; it may begin focally, then become diffuse, generalised, and confluent; rash may become purpuric or petechial later on in the infection in patients with coagulopathy
1st investigation
- reverse transcriptase-polymerase chain reaction:
positive for Ebola virus RNA
Other investigations
Zika virus infection
History
residence in/travel from a Zika-affected region, or unprotected sexual contact with infected individual; symptomatic patients generally present with a mild, self-limited illness including fever, maculopapular rash, arthralgia/myalgia, and conjunctivitis
Exam
rash is characteristic of infection; may be morbilliform and may be pruritic; 10% patients have lower limb petechial purpura, gingival bleeding, or limb oedema
1st investigation
- reverse transcriptase-polymerase chain reaction:
positive for Zika virus RNA
- serology:
positive for Zika virus antibodies
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Other investigations
Chikungunya virus infection
History
residence in/travel from endemic area; fever and joint aches are common; dermatological manifestations include rash, hyperpigmentation, lesions, and ulcers
Exam
maculopapular rash with global distribution; may be pruritic
1st investigation
- enzyme-linked immunosorbent assay/indirect fluorescent antibody:
positive for chikungunya virus antibodies
- reverse transcriptase-polymerase chain reaction:
positive for chikungunya virus RNA
Other investigations
Dengue fever
History
living in or recent travel to area where virus is endemic (Southeast Asian and Western Pacific regions, Caribbean, Latin America, and some regions in US, Africa, and Middle East); fever (usually abrupt onset); skin flushing of face, neck, and chest before development of maculopapular rash affecting the whole body; myalgia, arthralgia; headache; anorexia; nausea/vomiting
Exam
eruption of diffuse distribution, may be pruritic; high grade fever; difficulty ambulating; retro-orbital pain; dengue haemorrhagic fever: petechiae, epistaxis, signs of bleeding from other sites, hepatosplenomegaly, may develop shock
1st investigation
Other investigations
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