Urgent considerations

See Differentials for more details

Anaphylactic reaction

Anaphylactic reaction is typically a rapid onset of an urticarial eruption within minutes to hours of exposure, most often relating to a drug, food allergy, or insect bite or sting.

  • A maculopapular-appearing eruption may occur initially before the development of clinically typical urticaria.

  • Skin changes are often the first feature of allergic reactions and are present in >80% of patients with anaphylaxis.[81][82]​​ Most patients who present with an acute onset maculopapular eruption in response to an allergen, do not progress to anaphylaxis.[1][2]​ Skin changes without life-threatening airway/breathing/circulation problems are not considered anaphylaxis.​

  • Life-threatening manifestations most often involve the respiratory tract (edema, bronchospasm) and/or the circulatory system (vasodilatory shock).[83]

  • Patients may have wheezing, tachypnea, chest hyperinflation, use of accessory muscles, or inspiratory stridor. Hypotension and tachycardia are often present. The patient may be flushed or pale.

  • Neurologic symptoms include agitation, confusion, dizziness, visual disturbances, tremor, syncope, and seizures. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain are common.

  • Epinephrine is the cornerstone of treatment for anaphylaxis.[83][84]

Important historical considerations include:

  • Prior episodes

  • Intake of new medications (often antibiotics, particularly penicillins; more common with parenteral administration rather than oral ingestion)

  • Foods (often nuts or shellfish).

Emergency intervention for anaphylaxis:[1][2]

  • Call for help

  • Remove trigger if possible (e.g., stop any infusion)

  • Lie patient flat

  • Give intramuscular epinephrine

  • Establish airway

  • Give high flow oxygen

  • Apply monitoring: pulse oximetry, ECG, blood pressure

  • Repeat intramuscular epinephrine after 5 minutes

  • Give intravenous fluid bolus.

Severe cutaneous drug eruptions

Toxic epidermal necrolysis and Stevens-Johnson syndrome are severe generalized eruptions that are most often drug-induced.[19] These eruptions typically start 4 to 28 days after drug exposure.[21] The presence of fixed, sometimes painful skin lesions, dusky lesions with early erosion, and mucous membrane involvement (ocular, oral, and genital) are some defining characteristics of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). Nikolksky sign, where the epidermal layer easily sloughs off when lateral pressure is applied, can occur. The chance of secondary infection is high.

Stevens-Johnson syndrome is milder than toxic epidermal necrolysis, though the mortality rate of Stevens-Johnson syndrome is about 5% to 30%. Common offending medications include:[23][24]​​​​

  • Anticonvulsants

  • Sulfonamides

  • Nonsteroidal anti-inflammatory drugs

  • Allopurinol.

Hospital admission is recommended for people with Stevens-Johnson syndrome or toxic epidermal necrolysis. Patients with toxic epidermal necrolysis should be managed in a burns unit or intensive care unit with:

  • Airway protection

  • Fluid and electrolyte resuscitation

  • Intravenous antibiotics for infection

  • Withdrawal of the culprit drug and all nonessential medications

  • Pain management

  • Nutritional support (e.g., parenteral nutrition)

  • Thermoregulation

  • Wound care and surgical debridement (removal) of dead tissue

  • Possibly intravenous immunoglobulins, cyclosporine, or corticosteroids.[19]

The presentation of drug reaction with eosinophilia and systemic symptoms (DRESS) resembles the morbilliform drug eruption, but the patient is more ill, often with fever, abdominal pain, and facial swelling.[21] Organs are infiltrated with eosinophils or lymphocytes. About 80% of patients have hepatic involvement. Respiratory, cardiac, and renal inflammation can also occur. Immediate withdrawal of the culprit medication is essential. Supportive care includes skin moisturization.[21] Mortality may be 5% to 10%, and there may be no predictive factors for serious outcomes.[21][23][24]​​​​

Sepsis

Sepsis is a spectrum of disease, where there is a systemic and dysregulated host response to an infection.[85] Maculopapular rash may be a feature in patients with sepsis. Associated conditions include staphylococcal scalded skin syndrome, toxic shock syndrome, and meningococcemia.

Presentation ranges from subtle, nonspecific symptoms (e.g., feeling unwell with a normal temperature) to severe symptoms with evidence of multi-organ dysfunction and septic shock. Patients may have signs of tachycardia, tachypnea, hypotension, fever or hypothermia, poor capillary refill, mottled or ashen skin, cyanosis, newly altered mental state, or reduced urine output.[86] Sepsis and septic shock are medical emergencies.

Risk factors for sepsis include: age under 1 year, age over 75 years, frailty, impaired immunity (due to illness or drugs), recent surgery or other invasive procedures, any breach of skin integrity (e.g., cuts, burns), intravenous drug misuse, indwelling lines or catheters, and pregnancy or recent pregnancy.[86]

Early recognition of sepsis is essential because early treatment improves outcomes.[86][87][Evidence C][Evidence C]​​​​​​ However, detection can be challenging because the clinical presentation of sepsis can be subtle and nonspecific. A low threshold for suspecting sepsis is therefore important. The key to early recognition is the systematic identification of any patient who has signs or symptoms suggestive of infection and is at risk of deterioration due to organ dysfunction. Several risk stratification approaches have been proposed. All rely on a structured clinical assessment and recording of the patient’s vital signs.[86][88][89]​​​[90][91]​​​​​ It is important to check local guidance for information on which approach your institution recommends. The timeline of ensuing investigations and treatment should be guided by this early assessment.[90]​ 

Treatment guidelines have been produced by the Surviving Sepsis Campaign and remain the most widely accepted standards.[87][92] Recommended treatment of patients with suspected sepsis is:

  • Measure lactate level, and remeasure lactate if initial lactate is elevated (>18 mg/dL [>2 mmol/L]).

  • Obtain blood cultures before administering antibiotics.

  • Administer broad-spectrum antibiotics early (with methicillin-resistant Staphylococcus aureus [MRSA] coverage if there is a high risk of MRSA) for adults with possible septic shock or a high likelihood for sepsis.

  • For adults with sepsis or septic shock at high risk of fungal infection, empiric antifungal therapy should be administered.

  • Begin rapid administration of crystalloid fluids for hypotension or lactate level >36 mg/dL (>4 mmol/L). Consult local protocols.

  • Administer vasopressors peripherally if hypotensive after fluid resuscitation to maintain mean arterial pressure ≥65 mmHg, rather than delaying initiation until central venous access is secured. Norepinephrine (noradrenaline) is the vasopressor of choice.

  • For adults with sepsis-induced hypoxemic respiratory failure, high-flow nasal oxygen should be given.

Ideally these interventions should all begin in the first hour after sepsis recognition.[92]

For adults with possible sepsis without shock, if concern for infection persists, antibiotics should be given within 3 hours from the time when sepsis was first recognized.[87] For adults with a low likelihood of infection and without shock, antibiotics can be deferred while continuing to closely monitor the patient.[87]

For more information on sepsis, see Sepsis in adults and Sepsis in children.

Bacterial toxin-mediated erythemas

Toxin-mediated erythemas include staphylococcal scalded skin syndrome, toxic shock syndrome, and scarlet fever.[Figure caption and citation for the preceding image starts]: Morbilliform rash (resembling measles) resulting from toxic shock syndromeCourtesy of the CDC Public Health Image Library [Citation ends].com.bmj.content.model.assessment.Caption@1094fb51

Staphylococcal scalded skin syndrome and toxic shock syndrome

  • Staphylococcal scalded skin syndrome is more likely in children ages 5 years or younger, while toxic shock syndrome is more common in postsurgical patients and occasionally is associated with menstruation.

  • Both are characterized by high fever, hypotension, and a desquamating macular rash. Erythema and edema of palms and soles, flexural accentuation of the rash, petechial hemorrhages, mucous membrane hyperemia, and strawberry tongue may also occur.[25]

  • The diagnosis is primarily clinical, as blood and fluid cultures are generally negative, though the clinical setting allows differentiation.

  • Management includes parenteral antibiotics and intensive supportive therapy.

Scarlet fever

  • Approximately 90% of scarlet fever cases occur in children under 10 years old.[61]

  • It is usually a mild illness, but is highly infectious.

  • Presents with a generalized, erythematous rash, which feels like sandpaper and is often preceded by a sore throat (pharyngitis, tonsillitis).

  • Pharyngeal erythema with exudates, palatal petechiae, and a red, swollen (strawberry) tongue are suggestive features.

  • Clinicians are advised to maintain a high index of suspicion, as early recognition and prompt initiation of specific and supportive therapy for patients with invasive group A streptococcal infection can be life-saving.

  • Prompt treatment of scarlet fever with antibiotics is recommended to reduce risk of possible complications, including invasive group A streptococcus, and to limit onward transmission.

  • In countries such as the UK, where rapid antigen detection tests (RADTs) for scarlet fever are not readily available, test confirmation of group A streptococcus infection is not required before starting antibiotics in patients with a clinical diagnosis of scarlet fever.[62]​ In countries where RADTs for scarlet fever are available, a positive test result may be required before starting antibiotics (patients with clear viral symptoms don't need testing for group A streptococcal bacteria).[63]

  • If there is uncertainty about the diagnosis, obtain a throat swab prior to commencing antibiotics.[63][64][65]​​​​​​​​[66] Treatment of scarlet fever with antibiotics based on clinical diagnosis alone should follow in-country clinical guidelines.

  • According to the UK Health Security Agency, notifications of scarlet fever and invasive group A streptococcus (iGAS) disease in England were higher than expected from September 2022 to February 2023, with the peak observed in December 2022.[64][67]​​​​​​​ The notifications have significantly reduced since then and are now in line with the expected number for the time of year.[64]​ Other countries experiencing an increased incidence of scarlet fever and iGAS disease during this period include France, Ireland, the Netherlands, and Sweden. The increase was particularly marked during the second half of 2022.[68]

Meningococcemia

A maculopapular eruption may be an early presenting sign of meningococcemia and is distinct from the more classic petechial or coalesced purpuric eruption that is frequently found later in the disease process. The maculopapular eruption is transient, lasting for a few hours to no more than 48 hours, and resembles a wide variety of viral exanthems. Given the severity of this disease process it is important to consider early meningococcemia in the possible differentials when evaluating a patient with maculopapular eruption.

History factors to assess include:

  • Living conditions (more common in close living conditions such as college dormitories, prisons)

  • Immune status (prior immunization; people with immunization >10 years ago, young children, and older people may have inadequate immunity).

Fever and nuchal rigidity are generally present.

This infectious disorder is treated as an emergency with empiric antibiotic therapy and supportive therapy. The choice of antibiotic is guided by local susceptibility patterns, among other clinical factors.

Rickettsial infection (Rocky Mountain spotted fever)

Fever and generalized rash in the summer or fall is seen 1 week after outdoor activities in which a tick bite might occur.

  • Malaise, myalgia, and headache are common.

  • There is a generalized petechial rash involving the palms and soles. The rash characteristically starts on the wrists and ankles and spreads to the trunk.[70]

  • Approximately half of patients do not recall tick exposure.[70]

  • Serology can confirm the diagnosis.

  • Mortality is >20% in untreated cases.[93]

Patients are treated empirically with doxycycline (preferred).[Figure caption and citation for the preceding image starts]: Characteristic spotted rash of Rocky Mountain spotted feverCourtesy of the CDC Public Health Image Library [Citation ends].com.bmj.content.model.assessment.Caption@2b152053

Kawasaki disease

Kawasaki disease (mucocutaneous lymph node syndrome) is an acute multisystem febrile disease that primarily affects children ages <5 years.[77] The cause is unknown, though an infectious etiology is surmised.

The peak incidence is winter to late spring.

Diagnostic criteria include fever for 5 days plus at least four of the following five signs:[77][78]

  • Conjunctival injection

  • Cervical lymphadenopathy, usually unilateral

  • Oropharyngeal changes (including hyperemia, oral fissures, cracked lips, and strawberry tongue)

  • Peripheral extremity changes (including desquamation of hands and feet, erythema, edema)

  • Polymorphous rash.

The rash is typically generalized and maculopapular, without petechiae; perineal erythema is particularly pronounced. The rash resembles a viral exanthem, though recognition is critical due to the possibly life-threatening complications of untreated Kawasaki disease:

  • Cardiac involvement (the most serious complication), including aneurysms in the coronary arteries (the most common cause of death), myocarditis, and congestive heart failure

  • Multi-organ involvement (common) affecting the central nervous system, eyes, kidney, and gastrointestinal system (including hydrops of the gallbladder).

Vasculitis of small and medium-sized vessels contributes to the pathology.

Diagnosis is made clinically, as no specific diagnostic test is available.[77]​ Treatment generally includes intravenous immune globulin and aspirin.[77]

Ebola virus

  • Maculopapular rash developed early in approximately 25% to 52% of patients in previous outbreaks,[45] However, it only developed in 1% to 5% of patients in the 2014 outbreak.[46][47][48]

  • Frequently described as nonpruritic, erythematous, and maculopapular.

  • The eruption may begin focally, then become diffuse, generalized, and confluent.

  • Rash may become purpuric or petechial later on in the infection in patients with coagulopathy.[49]

  • May be difficult to discern the rash in dark-skinned individuals.

  • The mainstay of treatment is early recognition of infection coupled with effective isolation and best available supportive care in a hospital setting.

  • Therapeutic antiviral monoclonal antibodies are available. The World Health Organization strongly recommends either atoltivimab/maftivimab/odesivimab (also known as REGN-EB3) or ansuvimab (also known as mAb114) for patients with confirmed Zaire ebolavirus infection, and neonates ages ≤7 days with unconfirmed infection who are born to mothers with confirmed Zaire ebolavirus infection.[94]

Dengue hemorrhagic fever

Mosquito-borne viral infection caused by any one of four closely related dengue viruses. Dengue has traditionally been classified as dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS).[95]

Dengue infection has three distinct phases:[95]

  • Febrile

  • Critical

  • Convalescent.

The febrile phase is characterized by a sudden high-grade fever and dehydration that can last from 2 to 7 days.[95]

The critical phase is characterized by plasma leakage, bleeding, shock, and organ impairment and lasts for approximately 24 to 48 hours. It usually starts around the time of defervescence (although this does not always occur), around days 3 to 7 of the infection. The following warning signs indicate that a patient with dengue infection is about to enter the critical phase of infection:[95]

  • Abdominal pain or tenderness

  • Persistent vomiting

  • Clinical fluid accumulation (e.g., ascites, pleural effusion)

  • Mucosal bleeding

  • Lethargy/restlessness

  • Liver enlargement >2 cm

  • Laboratory: increase in hematocrit with rapid decrease in platelet count.

Patients with DHF/DSS go through all three stages; however, patients with DF bypass the critical phase.[95]

Patients with established warning signs, or in the critical phase of infection, with severe plasma leakage (with or without shock), severe hemorrhage, or severe organ impairment (e.g., hepatic or renal impairment, cardiomyopathy, encephalopathy, or encephalitis) require emergency medical intervention. Access to intensive care facilities and blood transfusion should be available. Rapid administration of intravenous crystalloids and colloids is recommended, according to algorithms produced by the World Health Organization.[95][96][97]

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