Differential diagnosis of anaphylaxis in adults and children

INTRODUCTION — Anaphylaxis is an acute, potentially life-threatening multisystem syndrome caused by the sudden release of mast cell mediators into the systemic circulation. It most often results from immunoglobulin (Ig)E-mediated reactions to foods, drugs, and insect stings, but any agent capable of producing a sudden, systemic degranulation of mast cells can produce it. The diagnosis can be challenging, and clinical criteria may be helpful in recognizing anaphylaxis (table 1) [1]. Anaphylaxis recognition may be straightforward in patients with a clear history of exposure to a known or likely allergen in the time immediately preceding onset of characteristic symptoms in several body systems (table 2). However, the signs and symptoms of anaphylaxis overlap with those of many other disorders, and the diagnosis can be quite difficult to make with certainty in some situations [1-3]. (See "Anaphylaxis: Acute diagnosis".)

Disorders that may present with similar symptoms and signs to anaphylaxis in children and adults will be reviewed here. The differential diagnosis of anaphylaxis in infants (ie, children under two years of age) and in pregnant persons during labor and delivery is reviewed separately. The rapid recognition and acute treatment of anaphylaxis are also presented separately. (See "Anaphylaxis in infants" and "Anaphylaxis during pregnancy and delivery" and "Anaphylaxis: Emergency treatment".)

COMMON DISORDERS — Common disorders that mimic anaphylaxis include acute generalized urticaria, acute angioedema, acute asthma exacerbations, syncope (faint), and panic attacks or acute anxiety (table 3).

Acute generalized urticaria and/or angioedema — Sudden onset of generalized urticaria and angioedema may be symptoms of anaphylaxis or may occur as an isolated problem. Urticaria, with or without angioedema, is limited to the skin and subcutaneous tissues, while anaphylaxis involves other organ systems.

Urticaria can be associated with allergen exposure as well as infections or physical stimuli, such as heat and cold. (See "New-onset urticaria", section on 'Etiologies'.)

The various allergic and nonallergic disorders associated with angioedema are reviewed separately. (See "An overview of angioedema: Pathogenesis and causes".)

Patients with bradykinin-mediated hereditary or acquired angioedema (C1 inhibitor deficiency) or angiotensin-converting enzyme (ACE) inhibitor-induced angioedema have intermittent episodes of swelling not associated with itching or erythema. Episodes of angioedema develop in the deep cutaneous or mucosal tissues of the face, extremities, or genitalia as well as the tongue and larynx, potentially leading to life-threatening asphyxia. Angioedema may also affect the bowel wall, leading to recurrent abdominal pain that varies in severity from mild discomfort to severe intractable pain accompanied by vomiting, diarrhea, and hypovolemic shock. In C1-deficiency angioedema, complement (C4) levels are reduced during acute attacks, and C4 is usually low even between episodes. C1-esterase inhibitor is deficient or functionally absent in most patients with this condition [4,5]. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

Asthma exacerbation — Sudden onset of wheeze, cough, and shortness of breath may occur during anaphylaxis or these symptoms may occur during an acute asthma episode. The diagnosis of anaphylaxis should be considered in any patient presenting with acute wheezing, coughing, or shortness of breath associated with symptoms such as itching, flushing, urticaria, angioedema, hoarseness, throat tightness, abdominal pain, vomiting, diarrhea, dizziness, collapse, or hypotension. The diagnosis of anaphylaxis should also be considered in patients who present with respiratory symptoms within minutes to a few hours after exposure to a likely or known allergic trigger; for example, a food, medication, or insect sting [1,3].

Vasovagal syncope — Syncope (faint) may be a symptom of anaphylaxis or may occur as an isolated problem. Typically, vasovagal syncope is associated with pallor, diaphoresis, weakness, nausea, and bradycardia. It is relieved by recumbency.

Anaphylaxis, in contrast, is usually characterized by sudden onset of flushing rather than pallor and other symptoms and signs that are not typically seen with vasovagal syncope, including sudden onset of itching, urticaria, angioedema, hoarseness, throat tightness, stridor, wheeze, cough, shortness of breath, abdominal pain, or diarrhea. In anaphylaxis, tachycardia is more common than bradycardia [1,3].

Patients with recurrent syncope require further evaluation. (See "Causes of syncope in children and adolescents" and "Approach to the adult patient with syncope in the emergency department" and "Syncope in adults: Epidemiology, pathogenesis, and etiologies".)

Panic attack/acute anxiety — In a panic attack or acute anxiety, symptoms can include a sense of impending doom, breathlessness, flushing, sweating, trembling, palpitations, globus sensation (feeling of a lump in the throat), gastrointestinal symptoms, lightheadedness, chest pain, and numbness or tingling of the extremities [1,3]. (See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis" and "Globus sensation".)

Some of these symptoms and signs may occur in anaphylaxis; however, other symptoms characteristic of an anaphylaxis episode but not a panic or acute anxiety attack include itching, urticaria, angioedema, hoarseness, stridor, wheezing, coughing, hypotension, and/or collapse [1,6].

OTHER RESPIRATORY EVENTS — Other causes of sudden onset of respiratory distress include vocal cord dysfunction, choking/foreign body aspiration, epiglottitis, pulmonary embolism, pneumothorax, and hyperventilation. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Clinical presentation and diagnosis of pneumothorax" and "Epiglottitis (supraglottitis): Clinical features and diagnosis".)

Vocal cord dysfunction — Vocal cord dysfunction involves the involuntary, paradoxical adduction of the vocal cords during inspiration. Symptoms and signs include dyspnea, cough, inspiratory stridor, or expiratory wheezing. This disorder is most common in young women, although it has been reported in adults and children of both sexes [7]. In a symptomatic patient, direct observation of the adducted vocal cords by laryngoscopy is diagnostic. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)".)

CARDIAC EVENTS — Anaphylaxis can also rarely present as sudden collapse without skin symptoms or signs, hence the possibility for diagnostic confusion. The differential diagnosis for sudden collapse or syncope is broad and includes cardiac etiologies, including myocardial ischemia, cardiac arrhythmias and structural cardiac disease (including aortic stenosis and hypertrophic cardiomyopathy). Elevated tryptase levels can be found in some patients with a myocardial infarction as well as in anaphylaxis [1,6,8-11]. Thus, in patients presenting with acute collapse, the clinical history and results of other diagnostic studies, especially the electrocardiogram, are important for determination of the underlying etiology. Other etiologies of syncope are discussed elsewhere in this topic, including vasovagal syncope, causes of shock, and neurologic events.

SHOCK — Shock is characterized by a significant systemic reduction in tissue perfusion, resulting in decreased tissue oxygen delivery. Shock can be described as hypovolemic (eg, gastrointestinal bleeding, ruptured ectopic pregnancy, ruptured aortic aneurysm, systemic capillary leak syndrome), cardiogenic, distributive (eg, sepsis, spinal cord injury), and obstructive (eg, pulmonary embolism, tension pneumothorax, cardiac tamponade). The approach to a patient presenting with apparent shock is reviewed separately [1,3]. (See "Definition, classification, etiology, and pathophysiology of shock in adults" and "Initial evaluation of shock in children".)

Capillary leak syndrome — Idiopathic systemic capillary leak syndrome is an extremely rare but often fatal disease characterized by recurrent episodes of angioedema, gastrointestinal symptoms, and shock with hemoconcentration, usually associated with a monoclonal gammopathy. The diagnosis is suggested by an elevated hematocrit during an episode of hypotension. Treatment involves aggressive fluid resuscitation and supportive care [12]. (See "Idiopathic systemic capillary leak syndrome".)

FLUSHING — Flushing is defined as a sensation of warmth accompanied by a visible reddening of the skin. Typically, it is prominent in the classic blush area that includes the face, neck, upper portion of the chest, and upper limbs. In anaphylaxis, sudden onset of flushing is a common symptom.

Recurrent flushing may be a prominent symptom during perimenopause and may occur after the administration of certain medications, after the ingestion of alcohol (ethanol), and in association with several uncommon tumors or autonomic epilepsy [13].

Perimenopause — The perimenopausal state is commonly associated with brief episodes of flushing that last less than five minutes and can occur several times daily. Perimenopausal flushing is not associated with urticaria, angioedema, itching, or significant hypotension [3,13]. (See "Menopausal hot flashes".)

Medications — Medications associated with flushing are discussed in more detail separately. (See "Approach to flushing in adults".)

Alcohol — Some people are susceptible to flushing after ingestion of alcoholic beverages because of genetic variations in the enzyme aldehyde dehydrogenase 2. In addition, ethanol can also amplify food-induced anaphylaxis by increasing the rate of intestinal absorption of food allergens [13-17]. Ethanol-induced flushing can be potentiated by certain medications. These include chlorpropamide, chloramphenicol, cephalosporins, disulfiram, griseofulvin, ketoconazole, metronidazole, phentolamine, niacin, and topical tacrolimus [13].

Vancomycin — Vancomycin flushing syndrome (VFS) is a common adverse reaction to vancomycin. VFS is characterized by flushing, erythema, and pruritus, usually of the upper body. Chest or back pains and hypotension may also occur. It is a rate-related infusion reaction caused by direct activation of mast cells by the drug. Other agents that activate mast cells, such as opioids, muscle relaxants, and radiocontrast media, can predispose patients to developing VFS with vancomycin infusion (table 4). (See "Vancomycin hypersensitivity", section on 'Vancomycin infusion reaction'.)

Tumors — Carcinoid tumors, gastrointestinal tumors, medullary carcinoma of the thyroid, renal cell carcinoma, and pancreatic carcinoma can present with flushing. Some of these tumors will be described below:

●Carcinoid tumors – Carcinoid syndrome refers to a constellation of symptoms mediated by serotonin, substance P, and other vasoactive substances released by some carcinoid tumors (eg, those in the small bowel, appendix, and colon). Episodic flushing occurs in most patients, typically affecting the face, neck, and upper chest. The areas become red to violaceous or purple, and there may be a mild burning sensation in the discolored skin. Flushing episodes begin suddenly and last 20 to 30 seconds, although they may become more prolonged over time. Diarrhea is also a common symptom. Wheezing can occur [13,18]. If carcinoid syndrome is suspected, 24-hour urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (HIAA) should be measured at a time when the patient is avoiding foods that may contain high levels of serotonin and tryptophan. (See "Clinical features of carcinoid syndrome" and "Diagnosis of carcinoid syndrome and tumor localization", section on 'Biochemical testing for carcinoid syndrome'.)

●Other gastrointestinal tumors – Gastrointestinal tumors producing vasoactive intestinal polypeptide (VIP) or substance P are extremely rare. Most patients have watery diarrhea, hypokalemia, and hypochlorhydria, and a minority (20 percent) experience associated flushing episodes. Measurement of serum VIP or substance P is helpful in diagnosis [13]. (See "VIPoma: Clinical manifestations, diagnosis, and management".)

●Medullary carcinoma of the thyroid – This carcinoma typically presents as a solitary thyroid nodule in a middle-aged adult. Facial flushing and diarrhea can occur in advanced disease [13]. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)

POSTPRANDIAL SYNDROMES

Scombroidosis — Scombroid syndrome, also called histamine fish poisoning, occurs within 15 to 90 minutes of eating spoiled finned fish, such as tuna, mackerel, saury, mahi mahi, sardines, anchovies, herring, and others. It is characterized by acute onset of flushing, headache, nausea, vomiting, diarrhea, abdominal pain, dysphagia, palpitations, dizziness, and hypotension after fish ingestion. Urticaria and itching are uncommon [19].

Symptoms are due to elevated levels of histamine in the fish. The histamine production occurs under conditions of inadequate refrigeration or preservation, when bacterial decomposition in the fish muscle leads to decarboxylation of the amino acid L-histidine to histamine. Cooking the fish does not reduce its histamine content. Clustering of cases (ie, several people developing similar symptoms after eating the same fish served at a meal) is consistent with the diagnosis of scombroidosis [1,3]. Scombroid poisoning can be distinguished from fish allergy by skin tests and/or measurement of serum-specific immunoglobulin (Ig)E levels to the fish implicated by the history. In fish allergy, these tests are positive, whereas, in scombroidosis, they are not [19]. If a sample of the suspect fish is still available, it can be used for skin testing and would be expected to yield positive results in both the patient and control subjects [20]. (See "Scombroid (histamine) poisoning".)

Pollen-food allergy syndrome — This syndrome, also known as oral allergy syndrome, typically occurs in patients with allergic rhinoconjunctivitis and pollen allergy. It is induced by ingestion of uncooked fruits and vegetables or occasionally nuts containing food proteins, such as profilins, or lipid transfer proteins that cross-react with pollen proteins. Common cross-reactivities include apple, carrot, kiwi, celery, or pear, among others, with birch pollen; melon or banana with ragweed pollen; and potato, tomato, watermelon, or kiwi with grass pollen. Typical symptoms include itching, tingling, and angioedema of the lips, tongue, palate, throat, and ears after eating raw, but not cooked, fruits and vegetables [21]. A small percentage of patients with pollen-food allergy syndrome can experience true anaphylaxis, but most have symptoms limited to the oral mucosa. (See "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Clinical manifestations'.)

Food poisoning — Food poisoning refers to an acute illness caused by microorganisms or microbial toxins in food. Food poisoning may present with vomiting, crampy abdominal pain, and diarrhea within a few hours of ingesting a meal. Symptoms and signs of food poisoning are usually limited to the gastrointestinal tract. (See "Causes of acute infectious diarrhea and other foodborne illnesses in resource-abundant settings".)

In contrast, the gastrointestinal symptoms of anaphylaxis are typically accompanied by symptoms in at least one other body organ system; for example, itching, flushing, urticaria, angioedema, hoarseness, throat tightness, stridor, wheeze, cough, shortness of breath, dizziness, collapse, or hypotension.

Caustic ingestion (young children) — Accidental ingestion of caustic liquids by young children may be mistaken for anaphylaxis due to symptoms of nausea, vomiting, difficulty swallowing, and swelling of the lips, tongue, or pharynx [22]. Caretakers may not have witnessed the ingestion or may not report it for fear of reprisal. Clinical clues to the diagnosis of caustic ingestion include the lack of a history of food allergy or other allergic disease and failure to respond to treatment for anaphylaxis. Visualization of the affected areas with endoscopy or microlaryngoscopy can identify ulceration and mucosal damage to the upper airway and esophagus. (See "Caustic esophageal injury in children".)

NEUROLOGIC EVENTS — Seizures and strokes (including intraparenchymal and subarachnoid hemorrhage as well as vertebrobasilar ischemia) can cause sudden collapse but would typically not be accompanied by other symptoms suggestive of anaphylaxis (eg, itching, flushing, urticaria, angioedema, hoarseness, throat tightness, stridor, wheeze, cough, or shortness of breath).

HEMATOLOGIC DISORDERS

Certain forms of leukemia — There may be an overproduction of histamine-containing cells in basophilic leukemia and in patients with acute promyelocytic leukemia receiving treatment with tretinoin [23]. (See "Initial treatment of acute promyelocytic leukemia in adults" and "Acute myeloid leukemia in adults: Overview" and "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Acute myeloid leukemia: Classification", section on 'Acute basophilic leukemia'.)

Mast cell disorders — Primary disorders of mast cells are rare and include mastocytosis (both cutaneous and systemic) and monoclonal mast cell activation syndrome. Patients can experience true anaphylaxis, but they can also present with episodes of flushing in association with signs and symptoms affecting the gastrointestinal tract and upper and lower respiratory tracts, the cardiovascular system, and the musculoskeletal system. Serum tryptase can be constitutively elevated. (See "Mast cell disorders: An overview".)

NONORGANIC DISEASE

Munchausen stridor — Some individuals with Munchausen syndrome (in which the patient consciously and voluntarily produces physical symptoms of illness for secondary gain) have a similar presentation to those with vocal cord dysfunction; however, they are usually able to adduct their vocal cords voluntarily, and they can be distracted by requests to perform maneuvers such as coughing. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Clinical presentation'.)

Munchausen anaphylaxis — Munchausen anaphylaxis is induced when the patient consciously self-triggers anaphylaxis; for example, by knowingly ingesting a food or medication to which the patient is sensitized [24,25]. (See "Factitious disorder imposed on self (Munchausen syndrome)".)

Undifferentiated somatoform anaphylaxis — Patients with this disorder present with symptoms, such as throat closure, shortness of breath, and syncope; however, there are no objective signs of anaphylaxis (for example, no evidence of upper or lower airway obstruction or hypotension) [3].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anaphylaxis".)

SUMMARY

●The diagnosis of anaphylaxis is based on recognition of sudden onset of characteristic symptoms and signs within minutes to a few hours after exposure to potential triggering agents or events (table 1). The presentation can vary from patient to patient and in the same patient from one episode to another.

●Anaphylaxis can potentially present with different permutations and combinations of more than 40 symptoms and signs, typically involving two or more body organ systems: skin, respiratory tract, gastrointestinal tract, cardiovascular system, and the central nervous system (CNS) (table 2).

●Common disorders that mimic anaphylaxis include acute generalized urticaria, acute angioedema, acute asthma, vasovagal syncope (faint), and panic attacks or acute anxiety (table 3). (See 'Common disorders' above.)

●Other entities that need to be considered in the differential diagnosis of anaphylaxis include other causes of acute respiratory distress (such as vocal cord dysfunction), cardiac events, other forms of shock, and neurologic events (table 3). (See 'Other respiratory events' above and 'Cardiac events' above and 'Shock' above and 'Neurologic events' above.)

●The differential of anaphylaxis can sometimes be narrowed when flushing was the primary presentation or when the event occurred after eating. (See 'Flushing' above and 'Hematologic disorders' above and 'Postprandial syndromes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F Estelle R Simons, MD, FRCPC, who contributed to earlier versions of this topic review.