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Anaphylaxis

Chapter 364 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Anaphylaxis is a potentially life-threatening systemic allergic reaction involving one or more organ systems that typically occurs within seconds to minutes of exposure to the trigger.
  2. Approximately 80–90% of anaphylactic episodes are uniphasic, while 10–20% are biphasic, with symptoms returning about an hour or longer after resolution of initial symptoms.
  3. Intramuscular epinephrine (0.3–0.5 mL of 1:1000) is the first-line treatment, with repeated doses at 5- to 20-min intervals as needed for a severe reaction.
  4. Serum tryptase peaks 60–90 min after the onset of anaphylaxis and can be measured as long as 5 h after onset; a level 20% above the patient's baseline plus 2 ng/mL is diagnostic for an acute event involving a clinically significant degree of mast cell activation.
  5. Non-IgE-mediated mast cell activation can occur via MRGPRX2 receptor activation (e.g., by neuromuscular blocking drugs, quinolones) or complement activation (e.g., by paclitaxel, heparin contaminants), clinically indistinguishable from classical IgE-mediated hypersensitivity.
  6. Alpha-gal syndrome causes delayed-onset anaphylaxis (3–6 h) after consuming mammalian meat in patients with anti-alpha-gal IgE, a condition not yet well understood.
  7. Preexisting asthma and underlying cardiovascular disease predispose patients to more rapid decompensation and increased mortality associated with anaphylaxis.
  8. Scombroid poisoning mimics anaphylaxis but is distinguished by negative skin tests and lack of elevated tryptase, caused by ingestion of pharmacologically significant histamine from contaminated fish.
  9. Beta blockers may attenuate the response to epinephrine; therefore, an alternative antihypertensive may be considered in patients at high risk of needing emergency epinephrine.
  10. Hereditary alpha-tryptasemia (HAT) is a mostly benign condition featuring elevated baseline serum tryptase in ~6% of Western populations, which may be a risk factor for severe anaphylaxis.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Figure / Illustration

1. DEFINITION & OVERVIEW

Anaphylaxis is a potentially life-threatening systemic allergic reaction involving one or more organ systems that typically occurs within seconds to minutes of exposure to the anaphylactic trigger, most often a drug, food, or Hymenoptera sting.

1.1 Historical Context

  • The term anaphylaxis was first described in 1902 by Charles Richet and Paul Portier.
  • They attempted to immunize dogs against sea anemone toxin in the same way Pasteur was able to vaccinate individuals against the smallpox virus.
  • To their surprise, repeated administration of small, sublethal doses of sea anemone toxin reliably induced acute-onset death when readministered 2–3 weeks after initial 'vaccination' to the toxin.
  • The phenomenon was termed ana (anti)-phylaxis ('protection or guarding') because vaccination with anemone toxin resulted in the opposite intended immune effect.
  • Charles Richet was awarded the Nobel Prize in Physiology or Medicine in 1913 for this work which led to further insights into hypersensitivity and mast cell biology.

1.2 Clinical Course

  • While 80–90% of anaphylactic episodes are uniphasic, about 10–20% of cases are biphasic.
  • In biphasic cases, anaphylactic symptoms return about an hour or longer after resolution of initial symptoms.
  • Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs, leading potentially to cardiovascular collapse or respiratory failure, respectively.
  • There may be upper or lower airway obstruction or both.
  • Laryngeal edema may be experienced as a 'lump' in the throat, hoarseness, or stridor.
  • Bronchial obstruction is associated with a feeling of tightness in the chest and/or audible wheezing.
  • Patients with underlying asthma are predisposed to severe involvement of the lower airways and increased mortality associated with anaphylaxis.
  • In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination.
  • Angioedema resulting in death by mechanical obstruction occurs in the epiglottis and larynx.
  • This process can also be evident in the hypopharynx and trachea.

2. EPIDEMIOLOGY

Risk factors and predisposing conditions for anaphylaxis.

2.1 Predisposing Factors

  • Preexisting asthma and underlying cardiovascular disease could lead to more rapid decompensation from anaphylaxis.
  • Atopy is not generally thought to be a risk factor for anaphylaxis from drug reactions or Hymenoptera stings.
  • Atopy is associated with radiocontrast sensitivity, exercise-induced anaphylaxis, idiopathic anaphylaxis, and allergy to foods or latex.
  • Severe Hymenoptera-induced anaphylaxis (generally with prominent hypotension) is the most common initial presentation for patients with underlying systemic mastocytosis.
  • It is important to check a baseline tryptase (a reflection of mast cell burden) in patients who present with sting-induced anaphylaxis to screen for this condition.
  • Hymenoptera allergy is also more likely in patients whose occupations (i.e., beekeepers, trash haulers, and landscape workers) place them in regular proximity to stinging insects.
  • In the case of allergy to carboplatin, the incidence of hypersensitivity is 27% in patients who have had ≥7 lifetime infusions and as high as 46% in patients who have had ≥15 lifetime infusions.
  • Patients with cystic fibrosis have a relatively high incidence of allergic reactions to IV antibiotics, particularly beta-lactams, that they receive periodically for intermittent 'clean-outs' to maintain airway clearance.

3. ETIOLOGY & PATHOPHYSIOLOGY

Mechanisms of anaphylaxis involving mast cells, basophils, and eosinophils.

3.1 Mast Cell Mediators

  • Many of the important early mediators of anaphylaxis are derived from mast cells, basophils, and eosinophils.
  • Mast cells contain preformed granules comprised of histamine, proteases (tryptase, chymase), proteoglycans (heparin, chondroitin sulfate), and tumor necrosis factor-α.
  • Basophils, like mast cells, contain and release histamine.
  • Mast cells, basophils, and eosinophils are also sources of arachidonic acid–derived products, which include cysteinyl leukotrienes, prostaglandins, and platelet-activating factor (PAF).
  • Histamine release results in flushing, urticaria, pruritus, and, in high concentrations, hypotension and tachycardia.
  • Cysteinyl leukotrienes and prostaglandin D cause bronchoconstriction and increased microvascular permeability.
  • Prostaglandin D causes cutaneous flushing and attracts eosinophils and basophils to the site of mast cell activation.
  • Serum PAF levels correlate with anaphylaxis severity and are inversely proportional to the constitutive level of PAF acetylhydrolase, which is necessary for PAF inactivation.
  • Tryptase and chymase can activate complement and coagulation pathways.
  • Activation of these pathways results in production of the anaphylatoxins, C3a and C5a, and activation of the kallikrein-kinin system, which regulates blood pressure and vascular permeability.
  • The actions of these anaphylactic mediators are likely additive or synergistic at the target tissues.

3.2 Non-IgE Mechanisms

  • Allergic reactions caused by the effector cells and mediators described previously can be triggered by a variety of mechanisms that may not require the presence of sensitizing IgE.
  • Non-IgE-mediated mast cell activation secondary to certain drugs is clinically indistinguishable from classical IgE-mediated hypersensitivity reactions but can occur with first known exposure since there is no prior need for mast cell sensitization by IgE.
  • MRGPRX2, a G protein–coupled receptor that is highly expressed in skin mast cells, has been shown in mouse models and in vitro studies using human cells to induce mast cell activation and mediator release secondary to neuromuscular blocking drugs (NMBDs), quinolones, and icatibant.
  • These findings are clinically significant since NMBDs are needed for procedures done under general anesthesia while quinolones are a commonly used antibiotic family.
  • Icatibant, a bradykinin-2 receptor antagonist administered by subcutaneous injection for the treatment of acute attacks of hereditary angioedema, is known to frequently result in local injection site reactions.
  • Another example of non-IgE-mediated anaphylaxis is demonstrated with paclitaxel, a chemotherapy agent most commonly used in combination with carboplatin to treat ovarian cancer.
  • It is derived from yew tree bark and needles that require polyethoxylated castor oil (Cremophor) to be solubilized into aqueous solution.
  • Cremophor has been shown in vitro to activate the complement cascade, resulting in complement-dependent histamine release from mast cells and basophils.
  • A version of paclitaxel that is solubilized by being bound to albumin nanoparticles, Abraxane, has a far lower rate of hypersensitivity, especially for patients who have had infusion reactions to Cremophor-solubilized paclitaxel.
  • Reactions such as flushing, hives, angioedema, and/or anaphylaxis to radiocontrast, opiates, vancomycin, and nonsteroidal anti-inflammatory drugs (NSAIDs) are other examples of non-IgE-mediated hypersensitivity.
  • An example of non-IgE-mediated food anaphylaxis is scombroid poisoning, caused by the ingestion of a pharmacologically significant dose of histamine from contaminated fish.
  • This is most commonly associated with fish that are rich in histidine, such as mahi-mahi, mackerel, and tuna.
  • If improperly stored, surface contaminant bacteria expressing histidine decarboxylase convert histidine into histamine, which is not broken down by baking or broiling.
  • Scombroid poisoning leads to symptoms including flushing, oropharyngeal pruritis/angioedema, nausea/vomiting, and lightheadedness.
  • Symptoms are often self-limited but still treatable with antihistamines and, if needed, epinephrine.
  • Because the source of histamine is exogenous, tryptase levels are not elevated.
  • A final example of non-IgE-mediated anaphylaxis occurred in clustered cases of anaphylaxis to IV unfractionated heparin in Europe and North America in 2008.
  • Cases were attributable to specific lots of heparin found to be enriched in a contaminant, oversulfated chondroitin sulfate (OSCS).
  • OSCS is able to activate the contact activation system, leading to the generation of bradykinin and the anaphylatoxins C3a and C5a, which led to the anaphylactic symptoms.
  • Heparin is now routinely screened for this contaminant to prevent further outbreaks.

3.3 Alpha-Gal Syndrome

  • A subset of individuals with anti-alpha-gal IgE can develop episodes of delayed-onset anaphylaxis about 3–6 h after consuming mammalian meat (beef, lamb, or pork) in a condition now known as alpha-gal syndrome (AGS).
  • The mechanisms behind AGS are not yet well understood.
  • Cetuximab is derived from a mouse cell line expressing a transferase that tags the Fab′ portion of the cetuximab heavy chain with alpha-gal.
  • Outbreaks of anaphylaxis to the epidermal growth factor receptor (EGFR) antibody, cetuximab, have been reported in association with elevated titers of serum IgE to alpha-1,3-galactose (alpha-gal), an oligosaccharide found in nonprimate mammals.
  • Interestingly, patients with a history of multiple bites from Amblyomma americanum ticks commonly found in the Carolinas, Arkansas, and Tennessee are more likely to have anti-alpha-gal IgE as compared to patients living outside those states.

4. CLINICAL FEATURES

Symptoms and signs of anaphylaxis.

4.1 Cutaneous Manifestations

  • Cutaneous manifestations are among the most common presentations of anaphylaxis (>90% of cases).
  • Symptoms include urticarial eruptions, flushing with diffuse erythema, and/or a feeling of generalized warmth.
  • Urticarial eruptions are intensely pruritic and may be localized or disseminated.
  • They may coalesce to form large urticarial plaques but seldom persist beyond 48 h.

4.2 Respiratory Manifestations

  • There may be upper or lower airway obstruction or both.
  • Laryngeal edema may be experienced as a 'lump' in the throat, hoarseness, or stridor.
  • Bronchial obstruction is associated with a feeling of tightness in the chest and/or audible wheezing.
  • Patients with underlying asthma are predisposed to severe involvement of the lower airways and increased mortality associated with anaphylaxis.
  • In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination.
  • The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosinophilic infiltration, and the acute emphysema is attributed to intractable bronchospasm that subsides with death.

4.3 Cardiovascular Manifestations

  • Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs, leading potentially to cardiovascular collapse or respiratory failure, respectively.
  • Patients dying of vascular collapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumed loss of intravascular fluid volume.
  • The associated electrocardiographic abnormalities in some patients, with or without infarction, may reflect a primary cardiac event mediated by mast cells (which are prominent near the coronary vessels) or may be secondary to a critical reduction in intravascular volume.

4.4 Gastrointestinal Manifestations

  • Gastrointestinal manifestations represent another severe presentation of anaphylaxis.
  • Symptoms include nausea, vomiting, crampy abdominal pain, and/or fecal incontinence.
  • Angioedema of the bowel wall may also cause sufficient intravascular volume depletion to precipitate cardiovascular collapse.

4.5 Histopathology

  • On microscopic examination, there is wide separation of the collagen fibers and the glandular elements.
  • Vascular congestion and eosinophilic infiltration may also be present.

5. DIFFERENTIAL DIAGNOSIS

Conditions that must be distinguished from IgE-mediated anaphylaxis.

5.1 Differential Diagnoses Table

  • Table 364-1 lists other possibilities to consider on the differential for IgE-mediated anaphylaxis.
  • Every attempt to identify the specific cause or causes should be made to minimize the risk of recurrent anaphylaxis.
  • If a particular drug or food is suspected, skin or serum-specific IgE testing can be useful to confirm clinical suspicions.
  • If a specific trigger cannot be identified by history or testing, a workup of underlying baseline atopic diatheses may be useful to identify risk factors that could play potential contributory roles alone or in concert.

Table 1 — Table 364-1 Differential Diagnoses for IgE-Mediated Anaphylaxis

CONDITION DISTINGUISHED BY
Mastocytosis Elevated baseline tryptase, spindle-shaped mast cells (MCs) on bone marrow
Pheochromocytoma Elevated urine metanephrines
Carcinoid syndrome Elevated urine 5-hydroxyindoleacetic acid
Hereditary angioedema Decreased C4 during attacks
Acquired angioedema Decreased C1q
Systemic capillary leak syndrome Severe hypotension on presentation with lack of response to first-line hypersensitivity medications (epinephrine, antihistamines)
Scombroid poisoning Tryptase not elevated; negative skin test and oral challenge to fish
Drugs (opiates, neuromuscular blocking agents, vancomycin) Direct MC degranulation triggered through MRGPRX2 receptor or other as-yet-undetermined mechanism
Radiocontrast As yet-undetermined mechanism

5.2 Specific Conditions

  • Mastocytosis: Elevated baseline tryptase, spindle-shaped mast cells (MCs) on bone marrow.
  • Pheochromocytoma: Elevated urine metanephrines.
  • Carcinoid syndrome: Elevated urine 5-hydroxyindoleacetic acid.
  • Hereditary angioedema: Decreased C4 during attacks.
  • Acquired angioedema: Decreased C1q.
  • Systemic capillary leak syndrome: Severe hypotension on presentation with lack of response to first-line hypersensitivity medications (epinephrine, antihistamines).
  • Scombroid poisoning: Tryptase not elevated; negative skin test and oral challenge to fish.
  • Drugs (opiates, neuromuscular blocking agents, vancomycin): Direct MC degranulation triggered through MRGPRX2 receptor or other as-yet-undetermined mechanism.
  • Radiocontrast: As yet-undetermined mechanism.

6. INVESTIGATIONS & DIAGNOSIS

Diagnostic approach to anaphylaxis.

6.1 Diagnostic Criteria

  • The diagnosis of an anaphylactic reaction depends primarily on a history revealing the onset of symptoms and signs within seconds to minutes after the putative trigger is encountered.
  • An exception is delayed anaphylaxis to mammalian meats in patients with AGS.
  • Every attempt to identify the specific cause or causes should be made to minimize the risk of recurrent anaphylaxis.
  • If a particular drug or food is suspected, skin or serum-specific IgE testing can be useful to confirm clinical suspicions.
  • If a specific trigger cannot be identified by history or testing, a workup of underlying baseline atopic diatheses may be useful to identify risk factors that could play potential contributory roles alone or in concert.
  • In the acute setting, laboratory biomarkers of mast cell degranulation may be useful to document the severity of an anaphylactic episode.

6.2 Biomarkers

  • The most obvious serum biomarker to assay, histamine, has an extremely short serum half-life with a measurable time-window that expires <1 h from the onset of anaphylaxis.
  • A more practical and reliable biomarker is serum tryptase, which is released from mast cells, peaks 60–90 min after the onset of anaphylaxis, and can be measured as long as 5 h after the onset of anaphylaxis.
  • It may be useful to follow up an elevated tryptase measurement in the acute setting with another measurement when the patient is clinically stable to establish a baseline reference since there is considerable variability of baseline serum tryptase (BST) within the general population.
  • For example, ~6% of Western populations have hereditary alpha-tryptasemia (HAT), a mostly benign condition featuring elevated BST due to expression of an extra allele of TPSAB1, the gene that encodes alpha-tryptase.
  • Some studies suggest that HAT may be a risk factor for severe anaphylaxis and is also overrepresented in patients with indolent mastocytosis.
  • Another cause for temporarily elevated BST is high environmental allergen exposure, something that can occur, for example, in regions with distinct pollen seasons.
  • A working group on mast cell disorders in 2010 came up with a formula to better interpret tryptase levels since (1) the range of 'normal' BST is wide within the general population and (2) an acutely elevated tryptase for a given patient may still fall within normal parameters if their BST is low.
  • The '20% + 2' rule stipulates that a tryptase level drawn in the setting of possible anaphylaxis that is 20% above the patient's baseline plus 2 ng/mL is diagnostic for an acute event involving a clinically significant degree of mast cell activation.

7. MANAGEMENT & TREATMENT

Treatment of anaphylaxis.

7.1 First-Line Therapy

  • Early recognition of an anaphylactic reaction and appropriate intervention are critically important because severe, even fatal, complications can occur within minutes after symptoms first appear.
  • The treatment of first choice is intramuscular administration of 0.3–0.5 mL of 1:1000 (1 mg/mL) epinephrine.
  • Repeated doses at 5- to 20-min intervals as needed for a severe reaction.
  • The failure to use epinephrine within the first 20 min of symptoms is a risk factor for poor clinical outcomes in various studies of anaphylaxis.
  • Epinephrine provides both α- and β-adrenergic effects, resulting in vasoconstriction, bronchial smooth-muscle relaxation, and attenuation of enhanced venular permeability.

7.2 Supportive Care

  • IV fluids and vasopressor agents may be administered in the acute medical setting if intractable hypotension occurs.
  • Oxygen alone via a nasal catheter or with nebulized albuterol may be helpful; however, either endotracheal intubation or a tracheostomy is mandatory for oxygen delivery if progressive hypoxia develops.

7.3 Adjunctive Therapies

  • Ancillary agents such as antihistamines, glucocorticoids, and bronchodilators are also useful therapeutics to treat urticaria/angioedema and bronchospasm once the patient is hemodynamically stable.

7.4 Beta-Blocker Considerations

  • Beta blockers may attenuate this response; therefore, an alternative antihypertensive may be considered in patients at high risk of needing emergency epinephrine.

8. PROGNOSIS & COMPLICATIONS

Outcomes and complications of anaphylaxis.

8.1 Clinical Course

  • While 80–90% of anaphylactic episodes are uniphasic, about 10–20% of cases are biphasic, in which anaphylactic symptoms return about an hour or longer after resolution of initial symptoms.
  • Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs, leading potentially to cardiovascular collapse or respiratory failure, respectively.

8.2 Mortality Risk

  • Patients with underlying asthma are predisposed to severe involvement of the lower airways and increased mortality associated with anaphylaxis.
  • In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination.
  • Patients dying of vascular collapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumed loss of intravascular fluid volume.

9. SPECIAL CONSIDERATIONS

Specific populations and triggers.

9.1 Alpha-Gal Syndrome

  • A subset of individuals with anti-alpha-gal IgE can develop episodes of delayed-onset anaphylaxis about 3–6 h after consuming mammalian meat (beef, lamb, or pork) in a condition now known as alpha-gal syndrome (AGS).
  • The mechanisms behind AGS are not yet well understood.
  • In the case of allergy to carboplatin, the incidence of hypersensitivity is 27% in patients who have had ≥7 lifetime infusions and as high as 46% in patients who have had ≥15 lifetime infusions.
  • Patients with cystic fibrosis have a relatively high incidence of allergic reactions to IV antibiotics, particularly beta-lactams, that they receive periodically for intermittent 'clean-outs' to maintain airway clearance.
  • Reactions such as flushing, hives, angioedema, and/or anaphylaxis to radiocontrast, opiates, vancomycin, and nonsteroidal anti-inflammatory drugs (NSAIDs) are other examples of non-IgE-mediated hypersensitivity.
  • An example of non-IgE-mediated food anaphylaxis is scombroid poisoning, caused by the ingestion of a pharmacologically significant dose of histamine from contaminated fish.
  • This is most commonly associated with fish that are rich in histidine, such as mahi-mahi, mackerel, and tuna.
  • If improperly stored, surface contaminant bacteria expressing histidine decarboxylase convert histidine into histamine, which is not broken down by baking or broiling.
  • Scombroid poisoning leads to symptoms including flushing, oropharyngeal pruritis/angioedema, nausea/vomiting, and lightheadedness.
  • Symptoms are often self-limited but still treatable with antihistamines and, if needed, epinephrine.
  • Because the source of histamine is exogenous, tryptase levels are not elevated.
  • A final example of non-IgE-mediated anaphylaxis occurred in clustered cases of anaphylaxis to IV unfractionated heparin in Europe and North America in 2008.
  • Cases were attributable to specific lots of heparin found to be enriched in a contaminant, oversulfated chondroitin sulfate (OSCS).
  • OSCS is able to activate the contact activation system, leading to the generation of bradykinin and the anaphylatoxins C3a and C5a, which led to the anaphylactic symptoms.
  • Heparin is now routinely screened for this contaminant to prevent further outbreaks.

9.3 Occupational Considerations

  • Hymenoptera allergy is also more likely in patients whose occupations (i.e., beekeepers, trash haulers, and landscape workers) place them in regular proximity to stinging insects.

10. KEY PEARLS & CLINICAL TRAPS

Board-exam favorites and must-not-miss diagnoses.

10.1 Diagnostic Pearls

  • The '20% + 2' rule stipulates that a tryptase level drawn in the setting of possible anaphylaxis that is 20% above the patient's baseline plus 2 ng/mL is diagnostic for an acute event involving a clinically significant degree of mast cell activation.
  • For example, ~6% of Western populations have hereditary alpha-tryptasemia (HAT), a mostly benign condition featuring elevated BST due to expression of an extra allele of TPSAB1, the gene that encodes alpha-tryptase.
  • Some studies suggest that HAT may be a risk factor for severe anaphylaxis and is also overrepresented in patients with indolent mastocytosis.
  • Another cause for temporarily elevated BST is high environmental allergen exposure, something that can occur, for example, in regions with distinct pollen seasons.

10.2 Therapeutic Pearls

  • The failure to use epinephrine within the first 20 min of symptoms is a risk factor for poor clinical outcomes in various studies of anaphylaxis.
  • Beta blockers may attenuate this response; therefore, an alternative antihypertensive may be considered in patients at high risk of needing emergency epinephrine.
  • Oxygen alone via a nasal catheter or with nebulized albuterol may be helpful; however, either endotracheal intubation or a tracheostomy is mandatory for oxygen delivery if progressive hypoxia develops.

10.3 Differential Diagnosis Pearls

  • Scombroid poisoning: Tryptase not elevated; negative skin test and oral challenge to fish.
  • Mastocytosis: Elevated baseline tryptase, spindle-shaped mast cells (MCs) on bone marrow.
  • Hereditary angioedema: Decreased C4 during attacks.
  • Acquired angioedema: Decreased C1q.
  • Systemic capillary leak syndrome: Severe hypotension on presentation with lack of response to first-line hypersensitivity medications (epinephrine, antihistamines).

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Pathophysiology of anaphylaxis illustrating mast cell degranulation, release of mediators...

Caption: Figure 364-1. Pathophysiology of anaphylaxis illustrating mast cell degranulation, release of mediators (histamine, leukotrienes, PAF), complement activation, and clinical manifestations including cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.