Toxic shock syndrome differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Toxic shock syndrome (TSS) may have a similar presentation to some diseases which present as a rash, fever and hypotension. Some features are unique to toxic shock syndrome and can be used to differentiate it from other diseases.

Differentiating Toxic Shock Syndrome from other Diseases

Toxic shock syndrome requires all 3 manifestations of fever, hypotension and diffuse scarlatiniform rash (innumerable small red papules that are diffusely distributed plus erythema, which blanches and desquamates one or two weeks after onset of illness). It presents with various signs of infection, hemodynamic dysfunction and organ failure.

Clinical presentation of fever, hypotension and rash must be differentiated from other diseases like:

• Meningococcemia
• Steven Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)

Clinical presentation of fever and rash must be differentiated from other diseases like:

• Gram-negative sepsis
• Scarlet fever
• Viral exanthem
• Rickettsial disease
• Kawasaki disease
• Staphylococcal scalded skin syndrome
• Exfoliative erythroderma syndrome
• Erythema multiforme major
• Drug eruption

Common Differential Diagnoses in Patients with Fever and Rash

Disease	Epidemiology	Predisposing factors	Clinical features					Lab abnormalities
			SignsSigns				Symptoms
Toxic shock syndrome	Occurs in both adults and children (9:1 female predominance)	Occurs in association with vaginitis during menstruation following tampon use (S. aureus); As a complication of soft tissue infections (S. pyogenes or GAS) In females undergoing medical abortion (C. sordellii).	Fever	Hypotension	Diffuse Rash	Other signs
			✔	✔	✔	Nonpitting systemic edema Tachycardia Mucous membrane hyperemia (vaginal, oral, conjunctival)	Diarrhea Vomiting Rash: Diffuse scarlantiform rash (red sunburn-like rash. It is flat and turns white if pressed) Thick skin desquamation appears on the hands and feet at around 1-2 weeks of disease progression, and might be followed by hair desquamation or shedding of fingernails and toenails after 2-3 months	Hyponatremia Uremia Hepatic dysfunction (total bilirubin, serum asparate aminotransferase or serum alanine aminotransferase levels >2 times upper normal limit) Leukocytosis with a polymorphonuclear shift to the left Platelets < 100,000 per mm3(thrombocytopenia) Pyuria of renal origin.
Meningococcemia	Occurs in young adults living in close proximity (college dorms, military recruits)	Close contact with a carrier Intimate kissing and cigarette smoking are associated with increased risk of meningococcal carriage	✔	✔	✔	Positive Kernig's sign Positive Brudzinski's sign Photophobia Cardiac depression	Vomiting Nausea Headache Cool extremities Seizures Rash: petechiae and purpura (star-shaped rash, which can develop into purple bruising. Meningococcal rash can usually be confirmed by a glass test in which the rash does not fade away under pressure.	Positive blood cultures (Neisseria meningitidis) CSF findings typical of bacterial meningitis:[24] Cells >300/uL Predominantly granulocytes Total protein 100-500mg/dl Glucose ratio (CSF/plasma) <0.3 Lactate >2.1 mmol/L CSF gram stain and culture may be positive
Steven Johnson syndrome (SJS)		Triggered by certain medications, most commonly: Anticonvulsants Non-steroidal anti-inflammatory drugs Antibiotics Mycoplasma pneumoniae Herpes simplex virus  HLA-B*1502 gene leads to increased susceptibility	✔	✔	✔	Positive Nikolsky sign (exerting mechanical pressure on several erythematous zones resluts in peeling of skin) Skin macules which rapidly coalescence.	Ocular involvement: eyelid edema, erythema, crusts, and ocular discharge, to conjunctival membrane or pseduomembrane formation or corneal erosion Rash: Purpuric macules and targetoid lesions; full-thickness epidermal necrosis,  presenting as blisters and areas of denuded skin; and mucous membrane involvement	Serum levels of the following are typically elevated in patients with Stevens-Johnson syndrome: Tumor necrosis factor (TNF)-alpha Soluble interleukin 2-receptor Interleukin 6 C-reactive protein Histological work up of skin sections reveal wide spread necrotic epidermis involving all layers
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome		HHV-6 Carbamazepine Minocycline Allopurinol Abacavir Nevirapine Clindamycin	✔	✔	✔		Multi-organ dysfunction: Pneumonitis Hepatitis Renal failure Encephalitis Cardiac failure Hemophagocytosis Lymphadenopathy Rash: Urticarial, maculopapular eruption and, in some instances, vesicles, bullae, pustules, purpura, target lesions, facial edema, cheilitis, and erythroderma	Eosinophilia Leukocytosis Uremia Increased ALT and AST
Redman syndrome
Kawasaki disease	Occurs in children, usually age 1-4 years	Interaction of genetic and environmental factors Infection in combination with genetic predisposition to an autoimmune mechanism (autoimmune vasculitis)	✔	✔	✔	Non-suppurative, painless bilateral conjunctival inflammation (conjunctivitis) Strawberry tongue (marked redness with prominent gustative papillae), Deep transverse grooves across the nails may develop (Beau’s lines), lymphadenopathy present(acute, non-purulent, cervical), Coronary artery aneurysms.	High and persistent fever that is not very responsive to normal treatment with acetaminophen or NSAIDs,  diffuse macular-papular erythematous rash	Liver function tests may show evidence of hepatic inflammation and low serum albumin levels, low hemoglobulin and age-adjusted hemoglobulin concentrations, thrombocytosis, anemia. Echocardiographic abnormalities, such as valvulitis (mitral or tricuspid regurgitation) and coronary artery lesions, are significantly more common in Kawasaki disease. Pyuria of uretheral origin.
Scarlet fever	Distributed equally among both genders. Most commonly affects children between five and fifteen years of age.	Occurs after streptococcal pharyngitis/tonsillitis				Pastia's sign (puncta and skin crease accentuation of the erythema), strawberry tongue, cervical lymphadenopathy may be present. Scarlet fever appears similar to Kawasaki's disease in some aspects, but lacks the eye signs or the swollen, red fingers and toes	Characteristic sandpaper-like rash which appears days after the illness begins (although the rash can appear before illness or up to 7 days later), rash may first appear on the neck, underarm, and groin	Leukocytosis with left shift and possibly eosinophilia a few weeks after convalescence. Anti-deoxyribonuclease B, antistreptolysin-O titers (antibodies to streptococcal extracellular products), antihyaluronidase, and antifibrinolysin may be positive.

Less common Differential Diagnoses in Patients with Fever and Rash

Disease	Features
Impetigo	It commonly presents with pimple-like lesions surrounded by erythematous skin. Lesions are pustules, filled with pus, which then break down over 4-6 days and form a thick crust. It's often associated with insect bites, cuts, and other forms of trauma to the skin.
Insect bites	The insect injects formic acid, which can cause an immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.
Kawasaki disease	Commonly presents with high and persistent fever, red mucous membranes in mouth, "strawberry tongue", swollen lymph nodes and skin rash in early disease, with peeling off of the skin of the hands, feet and genital area.
Measles	Commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.
Monkeypox	The presentation is similar to smallpox, although it is often a milder form, with fever, headache, myalgia, back pain, swollen lymph nodes, a general feeling of discomfort, and exhaustion. Within 1 to 3 days (sometimes longer) after the appearance of fever, the patient develops a papular rash, often first on the face. The lesions usually develop through several stages before crusting and falling off.
Rubella	Commonly presents with a facial rash which then spreads to the trunk and limbs, fading after 3 days, low grade fever, swollen glands, joint pains, headache and conjunctivitis. The rash disappears after a few days with no staining or peeling of the skin. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft palate.
Atypical measles	The symptoms commonly begin about 7-14 days after infection and present as fever, cough, coryza and conjunctivitis. Observation of Koplik's spots is also a characteristic finding in measles.
Coxsackievirus	The most commonly caused disease is the Coxsackie A disease, presenting as hand, foot and mouth disease. It may be asymptomatic or cause mild symptoms, or it may produce fever and painful blisters in the mouth (herpangina), on the palms and fingers of the hand, or on the soles of the feet. There can also be blisters in the throat or above the tonsils. Adults can also be affected. The rash, which can appear several days after high temperature and painful sore throat, can be itchy and painful, especially on the hands/fingers and bottom of feet.
Acne	It is typical of teenagers, usually appears on the face and upper neck, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts"
Syphilis	It commonly presents with gneralized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic It is classically described as: Non-pruritic bilateral symmetrical mucocutaneous rash Non-tender regional lymphadenopathy Condylomata lata and Patchy alopecia.
Molluscum contagiosum	The lesions are commonly flesh-colored, dome-shaped, and pearly in appearance. They are often 1-5 millimeters in diameter, with a dimpled center. Generally not painful, but they may itch or become irritated. Picking or scratching the lesions may lead to further infection or scarring. In about 10% of the cases, eczema develops around the lesions. They may occasionally be complicated by secondary bacterial infections.
Mononucleosis	Common symptoms include low-grade fever without chills, sore throat, white patches on tonsils and back of the throat, muscle weakness and sometime extreme fatigue, tender lymphadenopathy, petechial hemorrhage and skin rash.
Toxic erythema	It is a common rash in infants, with clustered and vesicular appearance.
Rat-bite fever	It commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.
Parvovirus B19	The rash of fifth disease is typically described as "slapped cheeks," with erythema across the cheeks and sparing the nasolabial folds, forehead, and mouth.
Cytomegalovirus	The common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.
Scarlet fever	It commonly includes fever, punctate red macules on the hard and soft palate and uvula (Forchheimer's spots), bright red tongue with a "strawberry" appearance, sore throat and headache and lymphadenopathy. Scarlet fever has a characteristic sandpaper-like rash which appears days after the illness begins (although the rash can appear before illness or up to 7 days later), rash may first appear on the neck, underarm, and groin.
Rocky Mountain spotted fever	The symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.
Stevens-Johnson syndrome	The symptoms may include fever, sore throat and fatigue. Commonly presents ulcers and other lesions in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children. A rash of round lesions about an inch across, may arise on the face, trunk, arms and legs, and soles of the feet, but usually not on the scalp.
Varicella-zoster virus	It commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.
Chickenpox	It commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.
Meningococcemia	It commonly presents with petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting. The petechiae and purpura found in this disease are different from the skin findings in S. aureus TSS. The rash in meningococcemia is star-shaped, which can develop into purple bruising. Meningococcal rash can usually be confirmed by a glass test in which the rash does not fade away under pressure. It is often associated with signs of meningitis (photophobia, neck stifness, nausea, vomiting, headache, positive kernig and brudzinski's signs).
Rickettsial pox	The first symptom is commonly a bump formed by a mite-bite, eventually resulting in a black, crusty scab. Many of the symptoms are flu-like including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.
Meningitis	It commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.

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