Where in the World Did You Get That Rash?

Abstract

The challenge to diagnose cutaneous eruptions and lesions in patients who have spent time in foreign countries is increasingly common. With the advent of increased global travel, foreign adoptions, immigration, and refugee seekers, rashes that were once relegated to the realm of the exotic and likely to show up in a tropical diseases clinic may now present to a general pediatrician. Furthermore, the pediatric traveler is at increased risk for dermatoses. (1) It behooves the practitioner to be aware of these skin findings, to be able to recognize them and distinguish them from other skin conditions.After completing this article, readers should be able to:Along with the current COVID-19 (coronavirus 2019) outbreak, this review article draws attention to the fact that international travel can introduce unexpected diseases throughout the world.Joseph A. Zenel, MDEditor-in-ChiefIn patients with a travel history, there are different frameworks for organizing an approach to rashes. One approach is to consider the infectious agents present commonly in the countries of exposure. However, this approach will miss many more mundane infections, noninfectious causes of skin disease, and perhaps disease unrelated to travel but occurring coincidentally with travel.Perhaps the most practical approach to skin lesions in those with a travel history is to consider the morphology of the presenting skin findings and to consider the infectious (both tropical and cosmopolitan) as well as noninfectious (both travel-related and non–travel-related) causes of similar skin features. Considering rashes by morphologic pattern allows for a practical starting point for diagnosis. Herein, 7 morphologic patterns are examined in detail with approaches to diagnoses within each group (Table 1).The focus will be on 1) the approach to patients with skin lesions and a history of time spent in other locations, 2) review of the common eruptions seen in such patients and how to distinguish these eruptions from those unrelated to travel, and 3) some key eruptions that should not be missed in the approach to these patients.Much of the data available on diseases in patients who have been to foreign destinations has been collected internationally by the GeoSentinel Surveillance Network. Cutaneous diseases are the third most common group behind respiratory signs and symptoms, diarrhea, and fever in travel-related diseases. (1)(2)(3) Studies of the pediatric traveler are limited, although they compose part of the larger studies on diseases in returning travelers. Lederman et al (1) found that returning travelers with a dermatologic diagnosis had greater odds of being younger than 18 years. As such, data from broader populations are discussed herein.We, therefore, determined a profile of common dermatologic problems in travelers, both tropical and cosmopolitan, from GeoSentinel data (Table 2).There are potential pitfalls when assessing skin disease in the returning traveler. When a patient with a travel history presents with skin lesions or a rash, it is tempting to assume that an exotic infection was picked up during travel. This narrowed approach will often neglect many other possible—although perhaps more mundane—infections that can be acquired during travel. Travel may also be unrelated to an infection incubating before travel but presenting coincidentally with travel. A much broader approach to the patient’s history will ensure attention to other diagnostic considerations. A second pitfall may be to ignore remote infectious exposures for which a latency period causes the skin disease to develop months or years after the exposure. One needs to take into consideration travel-related skin disease in such cases to appropriately acquire the patient’s history.Figure 1 presents a diagnostic framework with which to consider cutaneous disease in the returning traveler.Fever is rarely associated with skin findings. (1) However, fever and morbilliform rash in the returning traveler should alert the physician to consider arboviruses such as dengue and typhoid. Emerging entities to also consider are chikungunya and Zika viruses, and vaccine-preventable cosmopolitan illnesses such as measles.Dengue fever (DF) is one of the most frequent causes of febrile illness among pediatric travelers returning from southeast Asia, Latin America, and the Caribbean. (3) It is transmitted to humans by the mosquito Aedes aegypti. There are 4 serotypes, and immunity after infection is distinct to the serotype. (8)The incubation period of DF ranges from 3 to 14 days, with clinical features including retro-orbital pain, myalgia, arthralgia, and adenopathy. (8) Cutaneous manifestations are found in 50% to 82% of DF-positive cases but may vary in presentation among different age groups. (9) Transient flushing erythema of the face, neck, and chest occurs within the first 24 to 48 hours of fever. (8) Three to 5 days later, a generalized maculopapular rash appears resembling “white islands in a sea of red” as small islets of skin are spared. (8) This confluent rash starts on the extremities and moves centrally, tends to spare the face, and is not usually associated with pruritus. (9) Hemorrhagic manifestations such as petechiae/purpura and a positive tourniquet test result may also be present (Fig 2). (10)Diagnosis is with viral isolation, viral polymerase chain reaction (PCR) positivity, or paired serology (acute and convalescent-phase serum), and management is supportive with fluid therapy. Mosquito avoidance strategies can aid in prevention. (8)Chikungunya is another Aedes mosquito-borne disease, most commonly reported in travelers returning from the Caribbean, particularly Haiti and south central Asia. (11)With an incubation period ranging from 1 to 12 days, the infection presents with acute-onset fever, headache, arthralgia, lymphadenopathy, and a rash that is reported in 30% to 60% of children. (1) This skin eruption initially presents as a flushing erythema of the face, neck, and trunk, which then progresses into a generalized, nonpruritic, morbilliform rash with islands of spared skin 3 to 5 days later (Fig 3). (8)(10) Of note, the cutaneous manifestations of chikungunya vary across different age groups. The initial flushing of the skin has been followed by vesiculobullous lesions in some infants. (12) Chikungunya fever is oftentimes hard to distinguish clinically from the initial stages of DF. (3) With that said, arthralgia is more severe in patients with chikungunya fever, whereas myalgia is the more prominent feature in DF. (13)Laboratory diagnosis is through reverse transcriptase PCR (RT-PCR) and serologic testing; treatment is supportive, and mosquito avoidance is recommended. (12)Zika virus infection is a major global health concern due to recent outbreaks in South and Central America, along with the Caribbean. (14)It is transmitted to humans mainly through A aegypti mosquitoes. Zika virus has an incubation period of 3 to 12 days, and its clinical manifestations include arthralgia, nonpurulent conjunctivitis, and headache. Skin findings are present in 90% of patients. (10)(14) Fever is mild if present. Along with hyperemic conjunctivitis, pruritic micropapular exanthema has been reported as a unique mucocutaneous finding in Zika virus infection. Skin eruption starts on the trunk and descends to the lower body. Petechiae are also found on the palate. (10)Infection can be confirmed with RT-PCR, and treatment is supportive. (10)(14)Typhoid fever is caused by the bacterium Salmonella typhi, which is shed in the stool during the illness and in asymptomatic carriers. It is transmitted through the fecal-oral route. Typhoid fever was found to be the most common cause of fever in children returning from Asia. (15)The incubation period for S typhi can range from 3 to 60 days. (16) Clinical features are prolonged high fever, abdominal pain, and classic cutaneous “rose spots.” These are discrete pink and blanchable macules 2 to 4 mm in diameter appearing on the trunk and abdomen during the second week of the illness (Fig 4). These nonpruritic rose spots last 2 to 5 days and disappear without scarring. (17)(18)Blood culture is the main diagnostic method. (16) Third-generation cephalosporins or azithromycin are first-line treatments. (19) Hand hygiene is one preventive strategy, and a vaccination is available, although its benefit may wane over time, necessitating a booster. (20)Measles remains a major disease in developing countries and is increasingly reported in industrialized countries due to a decline in vaccination rates. (21) It is found mainly in Asia, as well as in Africa and Europe. Children who are not sufficiently vaccinated are at increased risk for contracting this viral illness. (21)Measles virus is mainly transmitted by respiratory droplets and has an incubation period of 7 to 21 days. A classic tetrad of prodromal features includes cough, coryza, conjunctivitis, and Koplik spots. (21) Koplik spots are gray-white papules on an erythematous base and usually appear on the buccal mucosa (Fig 5). (22) A nonpruritic rash develops 2 to 4 days after the onset of symptoms. Erythematous macules and papules first appear on the face and descend toward the extremities, lasting 4 to 7 days (Fig 6). (21) The exanthem is around sebaceous glands and hair follicles and can be mildly hemorrhagic. Patients are infectious from 4 days before to 4 days after rash onset. (22)Laboratory diagnosis is made through serologic testing and RT-PCR of the throat swab and urine. (23) In addition to treating measles symptomatically and treating the complications, there are some therapies that may be helpful. Vaccine administered within 72 hours of contact may limit disease development. The same is true of postexposure intramuscular immune serum globulin provided within 6 days of contact. This can be used for high-risk patients. Adjunct vitamin A treatment reduces blindness and death rates. (24)Of note, the previously mentioned infections could present with a feverless exanthema, and the differential diagnosis of a patient with a morbilliform rash is essentially the same whether or not fever is present.Drug eruption can be a non–travel-related cause of a maculopapular rash. It can be difficult to recognize exanthematous drug eruptions at times because many patients who have nonspecific infectious symptoms are given antibiotic drugs. Timing, reaction patterns, and other clinical findings can help differentiate drug eruptions from infectious causes. This is an important determination not only to make the correct diagnosis but also to prevent a patient from inappropriately being labeled as having a drug allergy if in fact the rash is due to the infectious process. At times, an interaction between an infection and antibiotic drug treatment can produce an exanthema. Amoxicillin taken by a patient infected by Epstein-Barr virus is such an example (Fig 7). (25)It is pertinent to remember, however, that drug eruptions can closely mimic various dermatoses and must be included in the differential diagnosis in any patient presenting with skin findings when medications have concomitantly been used.Kawasaki disease (KD) is a vasculitis of childhood—as yet of unknown etiology. The diagnostic criteria include a fever lasting for at least 5 days and 4 of the following clinical findings: a polymorphous rash, conjunctivitis, cervical lymphadenopathy, oropharyngeal mucositis, erythema, and edema in the extremities. (26)(27)A morbilliform eruption is the most common form of the exanthem, distributed over the trunk and extremities, including the perineal region, where early desquamation occurs (Fig 8). (26) Attention to the diagnostic criteria of KD should help distinguish it from a travel-related rash. KD is self-limited, but prompt administration of intravenous immunoglobulin helps reduce the risk of cardiac complications. (28)Consistent throughout studies, 2 papular eruptions—cutaneous larva migrans and arthropod bites—were the most commonly reported travel-acquired dermatologic illnesses in children in addition to animal bites, although the latter would present as a wound and not as a papular eruption. (15)Other conditions to consider in the differential diagnosis of papular eruptions include swimmer’s itch and seabather’s eruption.Cutaneous larva migrans (CLM) is a skin infestation caused by larvae of the dog or cat hookworm, Ancylostoma braziliense. It is among the top dermatoses in the pediatric traveler returning typically from the Caribbean. It is also common in travelers of sub-Saharan Africa, south central Asia, and Central or South America. (5) Incidence of CLM is associated with direct skin exposure with contaminated soil on the beach or in a sandbox. (1)CLM has a short incubation period of approximately 8 days. (4) The eruption initially presents with a local erythematous papule. The larvae remain in the epidermis and migrate, creating a linear, serpiginous rash that progresses at approximately 2 to 5 mm per day and is highly pruritic (Fig 9). The infestation is commonly seen on the distal legs, dorsa of the feet, buttocks, and hands. Less common morphologies include vesicular and follicular variants. Purulent discharge may be seen, associated with secondary bacterial infections. (29)Diagnosis of CLM is clinical, and although the eruption is self-resolving, it can be treated with albendazole in children. (4) Pretravel counseling includes educating parents on strategies to prevent direct contact of skin with wet soil, such as protective footwear and use of towels. (30)Arthropod-related eruptions can occur from mosquito, fly, flea, tick, mite, and lice bites acquired during travel to a broad range of regions.Insect bites or stings can induce hypersensitivity reactions, or papular urticaria, and often occur in a single family member. (31) Lesions may present as small groups or linear papules, either discrete or widespread on exposed parts of the body. The urticarial papules may have a visible punctum that can crust with scratching. Arthropod bites are classically very pruritic. Secondary bacterial infection is common, and patients may present with signs of impetigo, cellulitis, and abscesses. (1)(31)Lesions usually self-resolve, but antihistamines or topical corticosteroids can help with pruritus. Frequently they leave behind hypopigmented or hyperpigmented skin that ultimately resolves in most patients without treatment. Arthropod bites are important in travel medicine not only as agents of a pruritic rash but also as vectors for many travel-related diseases. Thus, prevention strategies, such as insect repellants and protective clothing, are critical. (31)Lyme disease is a tick-borne infection caused by Borrelia burgdorferi. The bacteria-infected tick is prevalent in many areas of North America, Germany, and Italy. Therefore, history of exposure may not always include far away or exotic destinations. Regional excursions, camping, hiking, time spent in wooded areas, and similar activities should form part of a travel history. (3)The incubation period can vary from 3 to 32 days after the tick bite. (32) The classic cutaneous manifestation of Lyme disease is erythema chronicum migrans and occurs early in the disease course. This localized lesion begins as a small erythematous papule at the site of the bite and enlarges in diameter, forming a uniformly homogenous annular lesion. While classically presenting as a target lesion with rings alternating with clearing, only a small number of lesions have central clearing (Fig 10). (32) In younger children, the lesions are more likely to occur on the head or neck, and in older children they occur more frequently on the arms and legs. (33) Disseminated disease can present with multiple lesions that appear over weeks. (33) Associated symptoms include low-grade fever, headache, myalgia, arthralgia, and fatigue. (32)Diagnosis in the early stage should be clinical because serum antibodies against B burgdorferi may not be detectable for 3 to 8 weeks after infection. A 2-tiered approach with screening and confirmatory serologic testing is used in late disease. (34) Early oral antibiotic drug therapy is highly effective, and prevention strategies include using tick repellants and avoiding tick-infested areas. (32)Cercarial dermatitis (CD), or “swimmer’s itch,” is an inflammatory response to larval forms of avian schistosomes invading the skin. (35) It is common in temperate and tropical regions and can be seen after exposure to mostly freshwater but also brackish and marine habitats where aquatic snails release cecariae. (36) Freshwater CD is frequently reported in Asia, Africa, North America, and continental Europe. (35)Despite the word dermatitis, this eruption typically presents as papules rather than as a dermatitis rash (Fig 11). The eruption is a type I hypersensitivity reaction where on reexposure, highly pruritic and erythematous papules develop within 24 hours. Lesions may start as macules and are widely distributed in areas exposed to contaminated water. A systemic allergic reaction or Katayama fever can occur and is marked by pyrexia, diaphoresis, headache, eosinophilia, and urticaria. (36)Although diagnosis of CD is clinical, evidence of ova in the urine or feces and serologic findings can provide confirmation. The condition self-resolves within 3 weeks, but antihistamines and topical corticosteroids may be used to treat symptoms. Avoiding shallow and stagnant water in hot weather is advised. (37)Seabather’s eruption is a hypersensitivity reaction to the sting of the larvae of certain sea anemones found in marine waters. The stinging cells retained in fabric discharge toxin with mechanical pressure or change in osmotic pressure, such as post-swim rinse with fresh water. (38) This condition is commonly seen in Mexico, the Caribbean, Bermuda, and Florida. (39)Within hours of exposure, a sensation of tingling occurs, which develops into a pruritic papular eruption. (38)(40) Compared with CD, papules are smaller in diameter. (39) The rash is distributed under swimwear, particularly in areas compressed against the skin, such as the abdomen, buttocks, breasts, and areas under bathing suit straps. The lesions can last 3 to 7 days. (38)Diagnosis is mainly clinical. Treatment of the rash is symptomatic, and topical cortisones can help. Prompt removal of the bathing suit and patting skin dry may prevent reaction. (38)Urticaria is a common eruption and may or may not be related to travel. Most cases are idiopathic or a reaction to a viral illness. Urticaria can also be seen as a reaction to a parasitic infection and, thus, should be considered in returning travelers. (4)Urticaria presents as dermal wheals with a flare and can vary in size from tiny to giant (Fig 12). They can present as round papules/plaques or as annular and serpiginous lesions. They do not have scale or crust, and each lesion disappears within 24 to 48 hours, leaving behind no skin marking. (41)If there are no other systemic features, such as fever or respiratory or gastrointestinal issues, to suggest infection, one should consider occult infections such as parasites. Therefore, testing a stool sample for ova and parasites might be indicated. (4) Specific lesions that last longer than 48 hours or leave behind skin changes or dyspigmentation should be considered urticarial rather than urticaria and may warrant further investigation, including skin biopsy. Although urticaria is self-limiting, antihistamines can aid in management. (41)Erythema multiforme is considered a hypersensitivity reaction precipitated by infections or medications. The most common infectious cause is herpes simplex virus (HSV) infection, (42) and mycoplasma is known to cause a bullous erythema multiforme–like eruption. (43)The characteristic clinical presentation is of erythematous papules that form fixed target lesions that have 3 zones of color change: outer red and pale rings surround a dusky center (Fig 13). (44) Lesions present in a symmetrical distribution, and there is a predilection for the palms and soles. Other symptoms include burning and mild pruritus. (41)Diagnosis of this self-limiting lesion is clinical. Treatment includes topical corticosteroids, or systemic corticosteroids if lesions are widely distributed. (41) Herpes simplex, if present, can be treated with antiviral medications. If the target lesions are atypical or vesicular, in conjunction with mucosal erosions and crusts, consideration should be given to mycoplasma with appropriate diagnostic tests and antibiotic drug therapy.Polymorphous light eruption is a reactive eruption occurring in sun-exposed areas. Although typically isolated, a small number of patients can have associated autoimmunity. (45) This papular eruption occurs usually at first exposure to sunlight in the spring or early summer or when there is travel to a sunny location. Although polymorphous light eruption is a self-limiting photodermatosis, topical corticosteroids and antihistamines can be used to reduce the inflammation, and application of sunscreen may help prevent its recurrence. (46)Verrucae, or cutaneous warts, are caused by the human papillomavirus. The infection is spread through direct contact with skin or objects and is especially common in school-age children. (47) Lesions are few and localized, mostly on the hands, head, and neck. (48) They are also extremely common on the plantar surface. Characteristic papules are dome shaped and skin colored, with discrete margins. Hyperkeratosis gives these lesions a hard and rough texture. (49) Although warts often self-resolve within 2 years, topical therapies or localized physical interventions can be used in treatment. (48)Endemic syphilis (bejel) is a rare, chronic, and nonvenereal bacterial disease caused by treponemal infection in dry climates. It can be transmitted through infectious household utensils and direct or indirect contact. Early lesions present as localized oral papules. (50) Papules, macules, mucous patches, and angular stomatitis are commonly present in moist body areas. (51) In the late stage of the disease, destruction of the nasal septum and palate can occur. (52) Clinical diagnosis is confirmed by serology, and antibiotics against Treponema pallidum are used in treatment. (51)Papulonecrotic tuberculid is a rare hypersensitivity reaction to Mycobacterium tuberculosis.Firm and dusky red papular eruptions are asymptomatic and symmetrical in distribution on the extensor surface of joints, acral areas of limbs, and ears. (53)(54) Lesions eventually undergo necrosis and heal with atrophic scarring. History in these patients is positive for tuberculosis contacts, Mantoux test, and previous or current tuberculosis. Histopathologic analysis aids in diagnosis, and the reaction responds to antituberculous therapy. (53)Scabies is a hypersensitivity reaction to the mite Sarcoptes scabiei burrowing into the epidermis. (55) The infestation is mainly transmitted through skin-skin contact, which explains its high prevalence in developing countries and orphanages. The highest incidence rates are seen in tropical regions of east Asia, southeast Asia, Oceania, and Latin America. (56)Onset of symptoms after primary infestation is 4 to 6 weeks. (55) Pruritic nocturnal and familial eruptions are often found on history. (57) However, because the pruritus and rash are manifestations of the host response to the scabetic infestation, the absence of those features is not sufficient to exclude the diagnosis in close contacts. Hence, asymptomatic close contacts should be treated as well. Although serpiginous or linear burrows are pathognomonic for scabies, papulonodules, papulopustules, dermatitis, and vesicles can also occur (Fig 14). (57) Lesions are more commonly seen on the palms and soles in younger children, and they are more widespread and excoriated in older children. (57)On microscopic examination of skin scrapings, identification of mites, eggs, or fecal pellets is diagnostic. (58) Permethrin is the treatment of choice for scabies. (55)Bacterial skin infections are a major cosmopolitan cause of dermatoses. Pyoderma is commonly seen in most of the series reported in the literature. (4)(6) Infections include impetigo, ecthyma, or erysipelas. Insect bites or stings are frequently found to be the inciting event leading to an infection, along with other cutaneous trauma acting as portals of infection. (4)(6) In particular, children younger than 18 years are more likely to develop superinfected insect bites. (1)Impetigo is a superficial bacterial skin infection, of which nonbullous impetigo is the predominant type. Impetigo is primarily caused by Streptococcus pyogenes or Staphylococcus aureus. Lesions are distributed on the face and extremities. Initial vesicles and pustules rupture and turn into a characteristic honey-colored crusted plaque. (59)Culture and sensitivity testing are recommended to aid in the diagnosis and treatment of resistant strains. (59) Pretravel advice should include options for self-treatment of early lesions, such as topical and oral antibiotic agents. (1)Cutaneous myiasis is caused by the larvae of African tumbu fly Cordylobia anthropophaga, found in tropical Africa, and human botfly Dermatobia hominis, found in South and Central America. (60) It is frequently reported in travelers returning from Belize, Bolivia, and Costa Rica. (1)Clinical symptoms are related to the larval life cycle and range from mild pruritus to severe pain, agitation, and insomnia. Furuncles with central punctum are surrounded by erythematous and edematous skin, which is tender to touch. (61) Serous discharge and sensation of movement under the skin are also described. (60)Cutaneous myiasis is self-limited as larvae mature and emerge in 8 to 20 days. However, the larvae are usually extracted to prevent secondary infections. Before removal, occlusive substances such as petroleum can be applied to the lesions to block larval air exchange and induce asphyxiation. Use of repellents and mosquito nets is recommended to avoid bites. (60)Tungiasis is caused by the epidermal burrowing of the female sand flea, Tunga penetrans. It can be seen in those with travel to Central and South America, sub-Saharan Africa, India, and Pakistan. (62) Poor hygiene and contact with domestic animals in endemic countries have been responsible for its transmission.As the infestation at the site of penetration grows, an erythematous nodule with a black central punctum and a surrounding white halo is observed. (63)(64) There may be egg or serosanguineous fluid discharge. (62) Lesions are found on the hands, buttocks, genitals, and, most commonly, feet. These distributions are associated with the behavior of children walking barefoot and sitting unclothed in sand. (64) Superinfections are common and may present with pustules, ulcerations, and suppuration. (63)Lesions self-resolve, but the sand flea can be removed with a sterile needle. Broad spectrum antibiotic drugs are used for bacterial superinfection, and tetanus prophylaxis is recommended. (62)(63) Use of insect repellants, adequate clothing, and footwear is recommended while traveling in endemic areas. (62)(63)(64)Picker’s papules are common lesions presenting as 1 or several crusted papules. These occur in patients who tend to pick at their skin, either as a reaction to stress or as habit. Often there is an originating lesion that starts the process and the patient then continuously picks off the crust each time it forms, creating an excoriated infiltrated papule.Leishmaniasis is caused by the Leishmania protozoan parasite, transmitted by sandflies. Rodents and canines are the reservoir for the parasite, with humans as the accidental host. The 2 major types of leishmaniasis include Old World and New World cutaneous leishmaniasis (CL) and visceral leishmaniasis. Old World CL is acquired in sub-Saharan and northern Africa, the Mediterranean basin, the Middle East, southern Asia, and China. New World CL is commonly seen in travelers of South and Central America. (65)(66)With an incubation period ranging from weeks to months, CL initially manifests as papules on exposed sites, evolving into nodules, and finally painless crusted ulcers with raised borders (Fig 15). Lesions are usually 0.5 to 8 cm in diameter. (67) Secondary infections and painful ulceration may occur once the crust is sloughed off (Fig 16). (68) These lesions can last for months to years, and although they may self-resolve, it is often with scarring. (69) Infection with New World CL may lead to mucosal lesions of the nose and mouth, appearing long after the cutaneous lesions have healed. (69) A common site for this complication is the cartilaginous septum, and it may be accompanied by erythema, secretions, pain, and epistaxis. (68)(69) Of note, leishmaniasis recidivans refers to recurrent lesions at the original site. Post-kala-azar dermal leishmaniasis are skin lesions that develop years after the primary visceral infection is treated. (67)Diagnosis of CL is confirmed with skin biopsy, dermal scraping, or fine needle aspirate. PCR provides a rapid and more sensitive and specific tool in diagnosis. (70) Old World CL is typically self-limiting, and treatment for New World CL is recommended to prevent dermal and mucosal spread. Standard therapy includes antimonial agents and pentamidine. (65) CL can be prevented through appropriate use of insect repellants and insecticides while traveling in endemic areas.Leprosy is a stigmatizing, deforming disease caused by Mycobacterium leprae. This bacterium tends to live in the skin, the superficial nerves, and tissues with lower temperature. Transmission of leprosy is through close or intimate contact via nasal and oral droplets, and its contractibility may depend on genetic susceptibility. (71) The incidence is higher in patients born and rais