Harrison’s principles of internal medicine 21st edition 2022 part 14

PART 14 Poisoning, Drug Overdose, and Envenomation 458 Heavy Metal Poisoning Howard Hu Toxic metals (hereafter referred to simply as “metals”) pose a significant threat to health through low-level as well as high level environmental and occupational exposures One indication of their importance relative to other potential hazards is their ranking by the U.S Agency for Toxic Substances and Disease Registry, which maintains an updated list of all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity The first, second, third, and seventh hazards on the list are heavy metals: arsenic, lead, mercury, and cadmium, respectively (http://www.atsdr.cdc.gov/spl/) Specific information pertaining to each of these four metals, including sources and metabolism, toxic effects produced, diagnosis, and the appropriate treatment for poisoning, is summarized in Table 458-1 TABLE 458-1 Heavy Metals Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion) Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in creating dental amalgams) When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors Some organs (e.g., bone, liver, and kidney) sequester metals in relatively high concentrations for years Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements (Chap 333) but are toxic at high levels of exposure Others, such as lead and mercury, are xenobiotic and theoretically are capable of exerting toxic effects at any level of exposure Indeed, much research is currently focused on the contribution of low-level xenobiotic metal exposure to chronic diseases and to subtle changes in health that may have significant public health consequences Genetic factors, such as polymorphisms that encode for variant enzymes with altered properties in terms of metal binding, transport, and effects, also may modify the impact of metals on health and thereby account, at least in part, for individual susceptibility to metal effects The most important component of treatment for metal toxicity is the termination of exposure Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion The principal chelating agents are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their specific use depends on the metal involved and the clinical circumstances Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion In addition to the information provided in Table 458-1, several other aspects of exposure, toxicity, or management are worthy of discussion with respect to the four most hazardous toxicants (arsenic, cadmium, lead, and mercury) Arsenic, even at moderate levels of exposure, has been clearly linked with increased risks for cancer of the skin, bladder, renal pelvis, ureter, kidney, liver, and lung These risks appear to be modified by smoking, folate and selenium status, genetic traits (such as ability to methylate arsenic), and other factors Recent studies in community-based populations have generated strong evidence that arsenic exposure is also a risk factor for increased risk of hypertension, coronary heart disease and stroke, lung function impairment, acute respiratory tract infections, respiratory symptoms, hinhanhykhoa.com and nonmalignant lung disease mortality The association with cardiovascular disease may hold at levels of exposure in drinking water that are below the World Health Organization (WHO) provisional guideline value of 10 μg/L Evidence has also continued to build indicating that low-level arsenic is a likely cause of neurodevelopmental delays in children and likely contributes to the development of diabetes Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak of “itai-itai” (“ouch-ouch”) disease, so named because of cadmiuminduced bone toxicity that led to painful bone fractures Modest exposures from environmental contamination have been associated in some studies with a lower bone density, a higher incidence of fractures, and a faster decline in height in both men and women, effects that may be related to cadmium’s calciuric and other toxic effects on the kidney Cadmium burdens have also been associated with an increased risk of long-term kidney graft failure, and there is evidence for synergy between the adverse impacts of cadmium and lead on kidney function Environmental exposures have also been linked to lower lung function (even after adjusting for smoking cigarettes, which contain cadmium) as well as increased risk of cardiovascular disease and mortality, stroke, and heart failure Cadmium triggers pulmonary inflammation, and a recent populationbased study of U.S adults found that higher cadmium burdens are associated with higher mortality from influenza or pneumonia The International Agency for Research on Cancer has classified cadmium as a known carcinogen, with evidence indicating it contributes to elevated risks of prostate, lung, breast, and endometrial cancer Overall, this growing body of research indicates that cadmium exposure is contributing significantly to morbidity and mortality rates in the general population Advances in our understanding of lead toxicity have recently benefited by the development of K x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone, which, in turn, reflect cumulative exposure over many years, as opposed to blood lead levels, which mostly reflect recent exposure Higher levels of cumulative lead exposure are now known to be a risk factor for chronic disease, even though blood lead levels have continued to decline in the general population over the past few decades following the removal of lead from gasoline, plumbing, solder in food cans, and other consumer products, with mean levels in the U.S population now hovering in the 1–2 μg/dL range For example, higher bone lead levels measured by KXRF have been linked to increased risk of hypertension and accelerated declines in cognition in both men and women living in urban communities These relationships, in conjunction with other epidemiologic and toxicologic studies, persuaded a federal expert panel to conclude they were causal Prospective studies have also demonstrated that higher bone lead levels, as well as blood lead levels as low as 1–7 μg/dL, are a major risk factor for increased cardiovascular morbidity and mortality rates in both community-based and occupationalexposed populations Lead exposure at community levels has also been associated with increased risks of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis With respect to pregnancy-associated risks, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental performance in offspring by age years Offspring have also been shown to have higher blood pressures at age 7–14 years, an age range at which higher blood pressures are known to predict an elevated risk of developing hypertension In a randomized trial, calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization of lead from maternal bone into blood during pregnancy The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercurycontaminated fish With respect to whether the consumption of fish by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury contamination in fish has led to some confusion and inconsistency in public health recommendations Overall, it would appear that it would be best for pregnant women to either limit fish consumption to those species known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources Accumulated evidence has not supported the contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism With regard to adults, there is conflicting evidence as to whether mercury exposure is associated with increased risk of hypertension and cardiovascular disease There is also some evidence that mercury exposure in the general population is associated with the development of diabetes, perturbations in markers of autoimmunity, and depression At this point, conclusions cannot be drawn and the clinical significance of these findings remains unclear Heavy metals pose risks to health that are especially burdensome in selected parts of the world For example, arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a major environmental problem for millions of residents in parts of Bangladesh and Western India Contamination was formerly considered only a problem with deep wells; however, the geology of this region allows most residents only a few alternatives for potable drinking water Arsenic contamination of drinking water is also a major problem in China, Argentina, Chile, Mexico, and some regions of the United States (Maine, New Hampshire, Massachusetts) The global campaign to phase out leaded gasoline has had continued success, with only a few countries still remaining (Algeria, Iraq, Yemen, Myanmar, North Korea, and Afghanistan) However, significant population exposures to lead remain, particularly in the United States with respect to older housing that contains lead paint or that receives drinking water through lead pipes, and there are indications that exposures are beginning to increase again in many low- and middle-income countries due to industrial pollution, electronic waste, and a variety of contaminated consumer products Populations living in the Arctic have been shown to have particularly high exposures to mercury due to long-range transport patterns that concentrate mercury in the polar regions, as well as the traditional dependence of Arctic peoples on the consumption of fish and other wildlife that bioconcentrate methylmercury A few additional metals deserve brief mention but are not covered in Table 458-1 because of the relative rarity of their being clinically encountered or the uncertainty regarding their potential toxicities Aluminum contributes to the encephalopathy in patients with severe renal disease, who are undergoing dialysis (Chap 410) High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer’s disease, as well as in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s The experimental and epidemiologic evidence for the aluminum–Alzheimer’s disease link remains relatively weak, however, and it cannot be concluded that aluminum is a causal agent or a contributing factor in neurodegenerative disease Hexavalent chromium is corrosive and sensitizing Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers Occupational exposure (e.g., of miners, dry-battery manufacturers, and arc welders) to manganese (Mn) can cause a parkinsonian syndrome within 1–2 years, including gait disorders; postural instability; a masked, expressionless face; tremor; and psychiatric symptoms With the introduction of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive, there is concern for the toxic potential of environmental manganese exposure Some epidemiologic studies have found an association between the prevalence of parkinsonian disorders and estimated manganese exposures emitted by local ferroalloy industries; others have found evidence suggesting that manganese may interfere with early childhood neurodevelopment in ways similar to that of lead Manganese toxicity is clearly associated with dopaminergic dysfunction, and its toxicity is likely influenced by age, gender, ethnicity, genetics, and preexisting medical conditions Nickel exposure induces an allergic response, and inhalation of nickel compounds with low aqueous solubility (e.g., nickel subsulfide and nickel oxide) in occupational settings is associated with an increased risk of lung cancer Overexposure to selenium may cause local irritation of the respiratory system and eyes, gastrointestinal irritation, liver inflammation, loss of hair, depigmentation, and peripheral nerve damage Workers exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances, including tremor, convulsions, hallucinations, and psychotic behavior Thallium, which is a component of some insecticides, metal alloys, and fireworks, is absorbed through the skin as well as by ingestion and inhalation Severe poisoning follows a single ingested dose of >1 g or >8 mg/kg Nausea and vomiting, abdominal pain, and hematemesis precede confusion, psychosis, organic brain syndrome, and coma Thallium is radiopaque Induced emesis or gastric lavage is indicated within 4–6 h of acute ingestion; Prussian blue prevents absorption and is given orally at 250 mg/kg in divided doses Unlike other types of metal poisoning, thallium poisoning may be less severe when activated charcoal is used to interrupt its enterohepatic circulation Other measures include forced diuresis, treatment with potassium chloride (which promotes renal excretion of thallium), and peritoneal dialysis Chelation therapy remains the treatment of choice for most toxic metals in the setting of severe acute clinical poisoning However, the use of chelation for treating chronic diseases remains controversial, in part because of the lack of evidence from rigorous randomized clinical trials One area for which there is moderate evidence is the use of chelation in patients with higher than average levels of accumulated lead burdens as a means of improving kidney function The results from a series of randomized trials conducted in Taiwan suggest that among individuals with mildly elevated lead burdens (defined as between 150 and 600 μg of lead per 72-h urine upon an EDTA mobilization test [1 g EDTA]), weekly calcium disodium EDTA chelation treatments for between and 27 months can improve renal function outcomes, both in individuals with and without type diabetes The Trial to Assess Chelation Therapy (TACT), a multicenter, double-blind, placebo-controlled, prospective randomized trial funded by the National Institutes of Health of 1708 patients aged ≥50 hinhanhykhoa.com elsewhere in temperate and subtropical parts of the world The bites of the female widow spiders are notorious for their potent neurotoxins Widow spiders spin their webs under stones, logs, plants, or rock piles and in dark spaces in barns, garages, and outhouses Bites are most common in the summer and early autumn and occur when a web is disturbed or a spider is trapped or provoked The initial bite is perceived as a sharp pinprick or may go unnoticed Fang-puncture marks are uncommon The venom that is injected does not produce local necrosis, and some persons experience no other symptoms α-Latrotoxin, the most active component of the venom, binds irreversibly to presynaptic nerve terminals and causes release and eventual depletion of acetylcholine, norepinephrine, and other neurotransmitters from those terminals Painful cramps may spread within 60 from the bite site to large muscles of the extremities and trunk Extreme rigidity of the abdominal muscles and excruciating pain may suggest peritonitis, but the abdomen is not tender on palpation and surgery is not warranted The pain begins to subside during the first 12 h but may recur during several days or weeks before resolving spontaneously A wide range of other sequelae may include salivation, diaphoresis, vomiting, hypertension, tachycardia, labored breathing, anxiety, headache, weakness, fasciculations, paresthesia, hyperreflexia, urinary retention, uterine contractions, and premature labor Rhabdomyolysis and renal failure have been reported, and respiratory arrest, cerebral hemorrhage, or cardiac failure may end fatally, especially in very young, elderly, or debilitated persons TREATMENT Widow Spider Bites Treatment consists of RICE and tetanus prophylaxis Hypertension that does not respond to analgesics and antispasmodics (e.g., benzodiazepines or methocarbamol) requires specific antihypertensive medication The efficacy and safety of antivenin (i.e., antivenom) made from equine immunoglobulins are controversial for bites of the black widow and the closely related Australian redback spider because of concerns about potential anaphylaxis or serum sickness Antivenins made from monoclonal antibodies are in development Tarantulas and Other Spiders Tarantulas are large hairy spiders of which 30 species are found in the United States, mainly in the Southwest Several species of tarantulas that have become popular household pets are usually imported from Central or South America Tarantulas bite persons only when threatened and usually cause no more harm than a bee sting, but on occasion, the venom causes deep pain and swelling Several species of tarantulas are covered with urticating hairs that are brushed off in the thousands when a threatened spider rubs its hind legs across its dorsal abdomen These hairs can penetrate human skin and produce pruritic papules that may persist for weeks Failure to wear gloves or to wash the hands after handling the Chilean Rose tarantula, a popular pet spider, has resulted in transfer of hairs to the eye with subsequent devastating ocular inflammation Treatment of bites includes local washing and elevation of the bitten area, tetanus prophylaxis, and analgesic administration Antihistamines and topical or systemic glucocorticoids are given for exposure to urticating hairs Atrax robustus, a funnel-web spider of Australia, and Phoneutria species, the South American banana spiders, are among the most dangerous spiders in the world because of their aggressive behavior and potent neurotoxins Envenomation by A robustus causes a rapidly progressive neuromotor syndrome that can be fatal within h The bite of a banana spider causes severe local pain followed by profound systemic symptoms and respiratory paralysis that can lead to death within 2–6 h Specific antivenins for use after bites by each of these spiders are available Yellow sac spiders (Cheiracanthium species) are common in homes worldwide Their bites, though painful, generally lead to only minor erythema, edema, and pruritus ■ SCORPION STINGS Scorpions are arachnids that feed on arthropods and other small animals They paralyze their prey and defend themselves by injecting venom from a stinger on the tip of the tail Painful but relatively harmless scorpion stings need to be distinguished from the potentially lethal envenomations that are produced by ∼30 of the ∼1000 known species and that cause >5000 deaths worldwide each year Scorpions are nocturnal and remain hidden during the day in crevices or burrows or under wood, loose bark, or rocks They occasionally enter houses and tents and may hide in shoes, clothing, or bedding Scorpions sting humans only when threatened Of the 40 or so scorpion species in the United States, only bark scorpions (Centruroides sculpturatus/C exilicauda) in the Southwest produce venom that is potentially lethal to humans This venom contains neurotoxins that cause sodium channels to remain open Such envenomations usually are associated with little swelling, but prominent pain, paresthesia, and hyperesthesia can be accentuated by tapping on the affected area (the tap test) These symptoms soon spread to other locations; dysfunction of cranial nerves and hyperexcitability of skeletal muscles develop within hours Patients present with restlessness, blurred vision, abnormal eye movements, profuse salivation, lacrimation, rhinorrhea, slurred speech, difficulty in handling secretions, diaphoresis, nausea, and vomiting Muscle twitching, jerking, and shaking may be mistaken for a seizure Complications include tachycardia, arrhythmias, hypertension, hyperthermia, rhabdomyolysis, and acidosis Symptoms progress to maximal severity in ∼5 h and subside within a day or two, although pain and paresthesia can last for weeks Fatal respiratory arrest is most common among young children and the elderly Envenomations by Leiurus quinquestriatus in the Middle East and North Africa, by Mesobuthus tamulus in India, by Androctonus species along the Mediterranean littoral and in North Africa and the Middle East, and by Tityus serrulatus in Brazil cause massive release of endogenous catecholamines with hypertensive crises, arrhythmias, pulmonary edema, and myocardial damage Acute pancreatitis occurs with stings of Tityus trinitatis in Trinidad, and central nervous toxicity complicates stings of Parabuthus and Buthotus scorpions of South Africa In Iran and adjacent countries, Hemiscorpius lepturus causes the most scorpion envenomations Its stings are relatively asymptomatic at first, but its cytotoxic venom causes pain, hemolysis, and tissue necrosis after the first day Systemic complications include hemoglobinuria and subsequent acute kidney injury Stings of most other species cause immediate sharp local pain followed by edema, ecchymosis, and a burning sensation Symptoms typically resolve within a few hours, and skin does not slough Allergic reactions to the venom sometimes develop TREATMENT Scorpion Stings Identification of the offending scorpion helps to determine the course of treatment Stings of nonlethal species require at most ice packs, analgesics, or antihistamines Because most victims experience only local discomfort, they can be managed at home with instructions to return to the emergency department if signs of cranial-nerve or neuromuscular dysfunction develop Aggressive supportive care and judicious use of antivenom can reduce or eliminate deaths from more severe envenomations Keeping the patient calm and applying pressure dressings and cold packs to the sting site are measures that decrease the absorption of venom A continuous IV infusion of midazolam controls the agitation, flailing, and involuntary muscle movements produced by scorpion stings Close monitoring during treatment with this drug and other sedatives or narcotics is necessary for persons with neuromuscular symptoms because of the risk of respiratory arrest Hypertension and pulmonary edema respond to nifedipine, nitroprusside, hydralazine, or prazosin Dangerous bradydysrhythmia can be controlled with atropine Commercially prepared antivenins are available in several countries for some of the most dangerous scorpion species An FDA-approved C sculpturatus IgG F(ab’)2 antivenin in horse serum is available IV administration of antivenin rapidly reverses cranialnerve dysfunction and muscular symptoms ■ HYMENOPTERA STINGS Bees, wasps, hornets, yellow jackets, and ants (all of the insect order Hymenoptera) sting in defense or to subdue their prey Their venoms contain a wide array of amines, peptides, and enzymes that cause local and systemic reactions Although the toxic effect of multiple stings can be fatal to a human, nearly all of the ≥100 deaths due to hymenopteran stings in the United States each year result from type 1, immediate-type allergic reactions Bee and Wasp Stings The stinger of the honeybee (Apis mellifera) is unique in being barbed The stinging apparatus and attached venom sac tear loose from the honeybee’s body, and muscular contractions of the venom sac continue to infuse venom into the skin Other kinds of bees, ants, and wasps have smooth stinging mechanisms and can sting numerous times in succession Generally, a person sustains just one sting from a bee or social wasp unless a nest was disturbed Africanized honeybees (now present in South and Central America and the southern and western United States) respond to minimal intrusions more aggressively The sting of an Africanized bee contains less venom than that of its nonAfricanized relatives, but victims tend to sustain far more stings and thus receive a far greater overall volume of venom Most patients who report having sustained a “bee sting” are more likely to have encountered stinging wasps instead The venoms of different kinds of hymenopterans are biochemically and immunologically distinct Direct toxic effects are mediated by mixtures of low-molecular-weight compounds such as serotonin, histamine, acetylcholine, and several kinins Polypeptide toxins in honeybee venom include mellitin, which damages cell membranes; mast cell–degranulating protein, which causes histamine release; the neurotoxin apamin; and the anti-inflammatory compound adolapin Enzymes in venom include hyaluronidase and phospholipases There appears to be little cross-sensitization between the venoms of honeybees and wasps Uncomplicated hymenopteran stings cause immediate pain, a wheal-and-flare reaction, and local edema, all of which usually subside in a few hours Multiple stings can lead to vomiting, diarrhea, generalized edema, dyspnea, hypotension, and non-anaphylactic circulatory collapse Rhabdomyolysis and intravascular hemolysis may cause renal failure Death from the direct (nonallergic) effects of venom has followed stings of several hundred honeybees Stings to the tongue or mouth may induce life-threatening edema of the upper airways Large local reactions accompanied by erythema, edema, warmth, and tenderness that spread ≥10 cm around the sting site over 1–2 days are not uncommon These reactions may resemble bacterial cellulitis but are caused by hypersensitivity rather than by secondary infection Such reactions tend to recur on subsequent exposure but are seldom accompanied by anaphylaxis and are not prevented by venom immunotherapy An estimated 0.4–4.0% of the U.S population exhibits clinical immediate-type hypersensitivity to hymenopteran stings, and 15% may have asymptomatic sensitization manifested by positive skin tests Persons who experience severe allergic reactions are likely to have similar or more severe reactions after subsequent stings by the same or closely related species Mild anaphylactic reactions to insect stings, as to other causes, consist of nausea, abdominal cramping, generalized urticaria or angioedema, and flushing Serious reactions, including upper airway edema, bronchospasm, hypotension, and shock, may be rapidly fatal Severe reactions usually begin within 10 of the sting and only rarely develop after h TREATMENT Bee and Wasp Stings Honeybee stingers embedded in the skin should be removed as soon as possible to limit the quantity of venom delivered The stinger and venom sac may be scraped off with a blade, a fingernail, or the edge of a credit card or may be removed with forceps The site should be cleansed and disinfected and ice packs applied to slow the spread of venom Elevation of the affected site and administration of oral analgesics, oral antihistamines, and topical calamine lotion help relieve symptoms Anaphylactic reactions to bee or wasp venom can be a lifethreatening emergency that requires prompt life-saving actions If the individual carries a bee-sting kit, then a subcutaneous injection of epinephrine hydrochloride (0.3 mL of a 1:1000 dilution) should be considered, with treatment repeated every 20–30 as necessary A tourniquet may slow the spread of venom The patient should be transferred to a hospital emergency room where treatment for profound shock, if required, can be administered safely Such treatment may entail the use of IV epinephrine and other vasopressors, intubation or provision of supplemental oxygen, fluid resuscitation, use of bronchodilators, and parenteral administration of antihistamines Patients should be observed for 24 h for recurrent anaphylaxis, renal failure, or coagulopathy Persons with a history of allergy to insect stings should carry an anaphylaxis kit with a preloaded syringe containing epinephrine for self-administration These patients should seek medical attention immediately after using the kit Prophylactic immunotherapy may greatly reduce the risk of lifethreatening reactions to bee and wasp stings Repeated injections of purified venom produce a blocking IgG antibody response to venom and reduce the incidence of recurrent anaphylaxis Honeybee, wasp, and yellow jacket venoms are commercially available for desensitization and for skin testing Results of skin tests and venom-specific radioallergosorbent tests (RASTs) aid in the selection of patients for immunotherapy and guide the design of such treatment ■ STINGING ANTS Stinging ants are an important medical problem in the United States Imported fire ants (Solenopsis species) infest southern states from Texas to North Carolina, with colonies now established in California, New Mexico, Arizona, and Virginia Slight disturbances of their mound nests have provoked massive outpourings of ants and as many as 10,000 stings on a single person Elderly and immobile persons are at high risk for attacks when fire ants invade dwellings Fire ants attach to skin with powerful mandibles and rotate their bodies while repeatedly injecting venom with posteriorly situated stingers The alkaloid venom consists of cytotoxic and hemolytic piperidines and several proteins with enzymatic activity The initial wheal-and-flare reaction, burning, and itching resolve in ∼30 min, and a sterile pustule develops within 24 h The pustule ulcerates over the next 48 h and then heals in ≥1 week Large areas of erythema and edema lasting several days are not uncommon and, in extreme cases, may compress nerves and blood vessels Anaphylaxis occurs in