ige against bed bug (cimex lectularius) allergens is common among adults bitten by bed bugs
TRANSCRIPT
J ALLERGY CLIN IMMUNOL
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(beta-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for se-
vere allergic reactions to soy. J Allergy Clin Immunol 2009;123:452-8.
2. Mittag D, Vieths S, Vogel L, Becker WM, Rihs HP, Helbling A, et al. Soybean al-
lergy in patients allergic to birch pollen: clinical investigation and molecular char-
acterization of allergens. J Allergy Clin Immunol 2004;113:148-54.
3. Kosma P, Sjolander S, Landgren E, Borres MP, Hedlin G. Severe reactions after the
intake of soy drink in birch pollen-allergic children sensitized to Gly m 4. Acta Pae-
diatr 2011;100:305-6.
4. van Zuuren EJ, Terreehorst I, Tupker RA,Hiemstra PS, Akkerdaas JH. Anaphylaxis af-
ter consuming soy products in patients with birch pollinosis. Allergy 2010;65:1348-9.
5. Ito K, Sjolander S, Sato S, Moverare R, Tanaka A, Soderstrom L, et al. IgE to Gly m
5 and Gly m 6 is associated with severe allergic reactions to soybean in Japanese
children. J Allergy Clin Immunol 2011;128:673-5.
6. Food and Agriculture Organization of United Nations: FAOSTAT. Available from:
http://faostat.fao.org/site/345/default.aspx. Accessed July 4, 2011.
7. Ebisawa M. [Management of food allergy (Food allergy management 2005 by Na-
tional Food Allergy Research Group)]. Arerugi 2006;55:107-14.
8. Yagami A, Inaba Y, Kuno Y, Suzuki K, Tanaka A, Sjolander S, et al. Two cases of
pollen-food allergy syndrome to soy milk diagnosed by skin prick test, specific se-
rum immunoglobulin E and microarray analysis. J Dermatol 2009;36:50-5.
9. Skypala IJ, Calderon MA, Leeds AR, Emery P, Till SJ, Durham SR. Development
and validation of a structured questionnaire for the diagnosis of oral allergy syn-
drome in subjects with seasonal allergic rhinitis during the UK birch pollen season.
Clin Exp Allergy 2011;41:1001-11.
Available online January 29, 2012.doi:10.1016/j.jaci.2012.01.031
IgE against bed bug (Cimex lectularius) aller-gens is common among adults bitten by bedbugs
To the Editor:Discuss this article on the JACI Journal Club blog: www.jaci-
online.blogspot.com.
Cimex lectularius, the bed bug, is found worldwide and likelyhas been sharing human dwellings dating back to prehistorictimes. With increased use of pesticides after WorldWar II, the re-ports of bed bugs in developed countries decreased significantly.1
Recently, C lectularius has made a resurgence, including in NewYork City (NYC)where housing violations for bed bugs rose from82 to 4084 between 2005 and 2009.2 The potential health impli-cations of this increase in domestic exposure are not known; how-ever, there is some evidence that exposed individuals can make atype 1 allergic response toC lectularius bites (see Table E1 in thisarticle’s Online Repository at www.jacionline.org).3 In the 1990s,researchers in Egypt reported skin test positivity to crude C lectu-larius extract among asthmatic patients.4 Another case reportidentified C lectularius nitrophorin protein (cNP), a nitric ox-ide–carrying protein found in the injected saliva, that elicited anIgE antibody response in 1 patient.5-7 The uniqueness of the
<0.1
1
10
100
23 27 8 26 5 3 20 25 30 4 22 29 7 6
Subject
)Lm/
UI(EgI
FIG 1. Concentrations of IgE antibodies against C lectuprotein, Dermataphagoides farinae, and German cockro
the past year. Absence of a bar indicates that the subje
predicted cNP sequence8 suggests that IgE to cNP would indicatea hypersensitivity response that is specific to C lectularius. Asidefrom the single case described above,5 the development of IgE an-tibodies to cNP among individuals bitten by bed bugs has not beenreported. Our goal was to develop assays for measuring IgE anti-bodies against both the C lectularius extract and the cNP proteinin order to determine the prevalence of sensitization to bed bugallergens among adults with reported bed bug bites.Thirty NYC residents who reported being bitten by bed bugs
were recruited through Web advertisement (www.craigslist.org),fliers, and physician referral. Entry criteria for the study includedreport of having been bitten by a bed bug resulting in an itchyraised bump within the past year. Qualifying consenting partici-pants donated serum and were queried about bed bug exposureand respiratory and allergic symptoms (wheezing, coughing,pruritic rash, itchy eyes, or runny nose) at the time of being bitten.Columbia University’s Institution Review Board approved thisstudy.The C lectularius extract was prepared from 160 mg of dried C
lectularius (generously donated by Louis Sorkin,Museum ofNat-ural History and George Keeney, Ohio State University) by freez-ing it in liquid nitrogen and then grinding it to a powder by usingmortar and pestle. The powder was incubated for 2 hours in 600mL of PBS with Tween 20 at 308C. After 10 minutes of centrifu-gation, the supernatant was dialyzed against PBS to removeTween 20. Recombinant cNP (prepared from Escherichia colias described previously)7 was dialyzed in PBS and diluted to1.7 mg/mL. Both recombinant cNP and the C lectularius extractswere biotinylated (separately) by using EZ-Link Sulfo-NHS-LC-Biotin (Pierce, Rockford, Ill) in a 10 mM solution of the Sulfo-NHS-LC-Biotin reagent. The biotinylated cNP and C lectulariusextracts were bound separately to streptavidin ImmunoCAPs asdescribed previously (Phadia, Portage, Mich).9 Serum from thesubjects was then incubated separately with C lectularius andcNP ImmunoCAPs for 30 minutes at 378C. IgE concentrationswere measured by using standard ImmunoCAP methods.9 Opti-mum C lectularius and cNP coating dilutions were determinedto be 67 and 264 mg/mL, respectively, on the basis of maximalIgE binding experiments with serum samples identified as posi-tive in our initial screening. IgE levels against cockroach anddust mite, 2 major allergens in NYC, and the total IgE levelwere also measured to assess seroatopy. Inhibition of IgE bindingto C lectualrius experiments were conducted with dust mite andcockroach allergen extracts (see the Methods section in this arti-cle’s Online Repository at www.jacionline.org).
Seventeen (57%) subjects had detectable IgE levels (>_0.1IU/mL) against the C lectularius extract (Fig 1). Of these 17, 9
18 24 21 1 2 9 10 11 12 13 14 15 16 17 19 28
ID Number
C lectularius
cNPDust miteCockroach
larius extract, C lectularius nitrophorin recombinant
ach among the 30 adults reporting bed bug bites in
ct had undetectable IgE levels (ie, <0.1 IU/mL).
FIG 2. Western blot of human (subject 23) IgE binding to cNP and C lectu-larius extract. cNP is a 32-kDa protein. A similar sized band can be seen in
the extract. The slight difference in size likely is due to posttranslational
modifications of the cNP.
TABLE I. Percent inhibition* of IgE binding with dust mite and
cockroach extracts
A. Inhibition with dust mite extract
Subject
Cosensitized to
dust mite
Inhibition of IgE againstyDust mite C lectularius
25 Yes 97% >77%�27 Yes 95% 88%
8 No — 14%
23 No — 4%
B. Inhibition with cockroach extract
Subject
Cosensitized to
dust mite
Inhibition of IgE againstyCockroach C lectularius
3 Yes 89% 79%
27 Yes 93% 58%
8 No — 14%
23 No — 4%
*Percent inhibition was calculated by subtracting the IgE level measured after
preincubation with allergen extract from the IgE level measured after incubation with
PBS and dividing by the latter.
�IgE against dust mite, C lectularius, or cockroach measured after inhibition.
�After incubation with dust mite extract, IgE level to C lectularius was below the
limit of detection (<0.1 IU/mL); however, the uninhibited sample was also low
(0.43 IU/mL).
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864 LETTERS TO THE EDITOR
subjects had detectable IgE level against cNP, while 8 did not. Allsubjects with IgE against cNP had measureable levels of IgEagainst theC lectularius extract. The presence of cNP in theC lec-tularius extract was confirmed by Western blot (Fig 2; see theMethods section in this article’s Online Repository at www.jacionline.org). While there was a correlation between IgE to Clectularius and cNP (R5 0.64, P5 .061) among those with mea-surable IgE levels to both, there was a wide range in the anti-cNPIgE/anti-C lectularius IgE ratios (0.05-3.2). The mean totalIgE level was higher among subjects with than among subjectswithout IgE against the C lectularius extract (117 vs 28.8IU/mL; P 5 .002) and cNP (125 vs 47.6 IU/mL; P 5 .057). Theprevalence of IgE against cockroach was more common amongsubjects with than among subjects without IgE against the C lec-tularius extract (65% vs 35%; P 5 .024). Among the 8 subjectswith measurable IgE levels against the C lectularius extract butnot cNP, most had IgE against dust mite (6 of 8 subjects) or cock-roach (7 of 8 subjects). Among the subjects with IgE to dust miteand cockroach, dust mite and cockroach allergen partially (and in1 case, completely) inhibited the IgE response to C lectularius,while inhibition was minimal among the subjects without IgEto cockroach or dust mite (Table I). Reports of symptoms ofwheeze, rhinitis, or cough on the day of or the day after the bitewere similar among thosewithout (>_0.1 IU/mL) than among thosewith IgE to either the C lectularius extract (54% vs 41%; P5 .49)or cNP (52% vs 33%; P 5 .34).In summary, we have developed assays for measuring IgE
antibodies to both the C lectularius extract and a unique proteinfrom C lectularius (cNP). IgE antibodies to C lectularius andcNP were common among adults who reported being bitten andhaving a visible response to bed bugs. That many (30%) individ-uals had IgE to cNP, which has limited homology to proteins fromother species, suggests a response specific to bed bug exposure.That there was variability in the correlation between concentra-tions of IgE to cNP and the C lectularius extract (including indi-viduals with measurable IgE levels to the C lectularius extract,but not cNP) suggests that sensitized individuals were exposedto other allergens found in the C lectularius extract in additionto cNP. Many subjects who had IgE to the C lectularius extractalso had IgE to dust mites and/or cockroaches and among theseindividuals, partial inhibition of binding to C lectularius was ob-served with dust mite and cockroach extracts. This indicates thepresence of cross-reactivity with allergens from cockroachesand/or dust mites. While we were unable to demonstrate an asso-ciation between allergic symptoms and IgE to either the C
lectularius extract or cNP, this may be a function of our study’srelatively small sample size and the limitations of retrospectivereporting of symptoms. Given the large increase in human expo-sure to bed bugs in NYC and elsewhere and the demonstrated IgEresponse to allergens from C lectularius, it is clear that futurestudies need to examine the clinical relevance of IgE responsesto bed bug allergens on allergic symptoms.
Jason B. Price, MDa
Adnan Divjanb
William R. Montfort, PhDc
Kirstie H. Stansfield, MA, PhDb
Greg A. Freyer, PhDb
Matthew S. Perzanowski, PhDb
From athe Department of Pediatrics, College of Physicians and Surgeons, and bthe De-
partment of Environmental Health Sciences, Mailman School of Public Health, Co-
lumbia University, New York, NY, and cthe Department of Chemistry and
Biochemistry, University of Arizona, Tucson, Ariz. E-mail: [email protected].
This study was supported by grant numbers NIH NIEHS P30 ES09089 and NIH R01
HL062969.
Disclosure of potential conflict of interest: M. Perzanowski received research support
from the National Institutes of Health. The rest of the authors declare that they
have no relevant conflicts of interest.
REFERENCES
1. Boase C. Bedbugs back from the brink. Pestic Outlook 2001;12:159-62.
2. Recommendations for the management of bed bugs in New York City: New York
City Bed Bug Advisory Board Report to the Mayor and City Council. New
York, NY; 2010. Available at: http://council.nyc.gov/downloads/pdf/bed_bugs_
report_2010.pdf. Accessed January 4, 2012.
3. Parsons DJ. Bedbug bite anaphylaxis misinterpreted as coronary occlusion. Ohio
Med 1955;51:669.
4. Abou Gamra EM, el Shayed FA, Morsy TA, Hussein HM, Shehata ES. The relation
between Cimex lectularius antigen and bronchial asthma in Egypt. J Egypt Soc Para-
sitol 1991;21:735-46.
5. Leverkus M, Jochim RC, Schad S, Brocker EB, Andersen JF, Valenzuela JG, et al.
Bullous allergic hypersensitivity to bed bug bites mediated by IgE against salivary
nitrophorin. J Invest Dermatol 2006;126:91-6.
6. Walker FA. Nitric oxide interaction with insect nitrophorins and thoughts on the
electron configuration of the {FeNO}6 complex. J Inorg Biochem 2005;99:216-36.
TABLE I. Characteristics of the wave 3 LSAC participants residing
in Australia’s Eastern states and territory
Characteristic
Birth cohort
(4- to 5-year-olds)
Kindergarten
cohort
(8- to 9-year-olds)
Value SD Value SD
No. 3312 4331
Age at interview (y), mean 4.8 0.24 8.8 0.24
Sex (% male) 51.7 51.1
Birth weight (g), mean 3426 570 3405 589
Low birth weight
(% <2500 g)
5.0 6.3
Mother smoked in
pregnancy (%)
14.7 17.0
Season of birth (%)
Summer 23.0 25.9
Fall 24.0 24.2
Winter 26.3 23.8
Spring 26.8 26.2
Weight at interview (kg),
mean
19.5 3.0 31.5 6.8
Advantage/disadvantage
index, mean
1017 76 1011 75
Dog ownership (%) 42.1 50.8
Cat ownership (%) 21.9 21.6
Remoteness of domicile (%)
Highly accessible 54.6 53.4
Accessible 26.1 25.8
Moderately accessible 16.8 17.0
Remote 1.3 2.3
Very remote 1.2 1.5
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7. Weichsel A, Maes EM, Andersen JF, Valenzuela JG, Shokhireva T, Walker FA, et al.
Heme-assisted S-nitrosation of a proximal thiolate in a nitric oxide transport protein.
Proc Natl Acad Sci U S A 2005;102:594-9.
8. Valenzuela JG, Ribeiro JM. Purification and cloning of the salivary nitrophorin from
the hemipteran Cimex lectularius. J Exp Biol 1998;201:2659-64.
9. Erwin EA, Custis NJ, Satinover SM, Perzanowski MS, Woodfolk JA, Crane J,
et al. Quantitative measurement of IgE antibodies to purified allergens using strep-
tavidin linked to a high-capacity solid phase. J Allergy Clin Immunol 2005;115:
1029-35.
Available online February 6, 2012.doi:10.1016/j.jaci.2012.01.034
Prevalence of eczema and food allergy isassociated with latitude in Australia
To the Editor:Recent reports from both Australia1 and the United States2 sug-
gest that vitamin D might play a role in the recent increase in al-lergic disease, in particular food allergy. Using indirect markersof food allergy status, such as prescription of hypoallergenic for-mula,3 EpiPen (Dey Pharma, Basking Ridge, NJ) prescription,and emergency department admission4 for probable food-induced anaphylaxis, they surmised that the further a person re-sides from the equator, the more likely he or she is to have foodallergy. They further suggested that this could be possibly relatedto UVexposure,3 with those cities with the lowest ambient UV ra-diation likely to have the highest proportion of population with vi-tamin D insufficiency.Australia is particularly strongly placed to examine these
associations. It has among the highest prevalences of challenge-proved food allergy,5 eczema,6 and asthma.6 It also has one of thelongest north-south borders in the world, measuring approxi-mately 4500 km from the North of Queensland to the South ofTasmania. It also has a nationally representative epidemiologicstudy, the Longitudinal Study of Australian Children (LSAC),containing information on 2 cohorts of children on state of domi-cile; parental report of food allergy, eczema, and asthma; and po-tential confounders. For this report, we draw on cross-sectionaldata from the third wave of LSAC in 2008, when the 2 cohortsof children were aged 4 to 5 and 8 to 9 years, to examine whetherthe prevalence of food allergy, eczema, and asthma varies by lat-itude in Australia.LSAC used a 2-stage cluster sampling design in which the
primary sampling unit was Australian postcode (stratified by stateof residence and by urban versus rural), from which children (thesecondary sampling units) were then randomly selected by usingthe Health Insurance Commission Medicare database, in whichgreater than 90% of infants and 98% of all 4-year-old Australianchildren are enrolled.7 The LSAC’s 2 cohorts were recruited in2004 at 0 to 1 (birth cohort) and 4 to 5 (kindergarten cohort) yearsof age, respectively, and then followed up biennially. Demo-graphic information on the cohort is reported in Table I. The studyprotocol was approved by the Australian Institute of Family Stud-ies Ethics Committee.We defined theNorth region as the state of Queensland (latitude
approximately 108 to 298S), the Central region as the state of NewSouth Wales and Australian Capital Territory (latitude approxi-mately 298 to 358S), and the South region as the states of Victoriaand Tasmania (latitude approximately 358 to 438S).In wave 3 (2008) parents in both cohorts were asked the
following question: ‘‘Does [study child] have any of theseongoing conditions? (‘Ongoing conditions’ exist for some
period of time (weeks, months or years) or re-occur regularly.They do not have to be diagnosed by a doctor)?,’’ for which‘‘food or digestive allergies or intolerance?’’ was 1 item probed.For parents responding yes, the type of food eliciting the allergicreaction was sought, specifically peanut, hen’s eggs, cow’s milk,soy, sesame, wheat and other. Similarly, parents responded yesor no to the question ‘‘Does child have any of these ongoingproblems?,’’ to which one item probed was ‘‘Eczema?,’’ and‘‘Has a doctor ever told you that [child] has asthma?’’ Any atopywas defined as eczema or asthma or parent-reported food allergyto any food.Logistic regression was used to examine the association
between each indicator of atopic status (all binary outcomes)and categorical exposure region (North, Central, or South),reporting the relative odds of atopy across the regions. Bothcrude and multivariable models were fitted, with the latteradjusting for the potential confounders noted in the footnote ofTable II.8 All analyses were weighted for the multistage samplingdesign. First-order Taylor linearization was used to obtain esti-mates of SEs, taking account the correlation of responses withinpostal codes. Data were analyzed with Stata 12 software (Stata-Corp, College Station, Tex).We found that a latitude gradient existed for both food allergy
(peanut and egg allergy) and eczema, but not for asthma, in bothage groups assessed (Table II). In the 4- to 5-year-old cohort, thesouthernmost children (ie, those residing furthest from the equa-tor) were more likely to have each of food allergy and eczema. Inthe 8- to 9-year-old cohort, the odds of having a peanut allergy
METHODS
Inhibition experimentsFrom subjects with IgE to C lectularius, 2 subjects with IgE to dust mite, 2
subjects with IgE to cockroach, and 2 subjects without IgE to dust mite or
cockroach were selected for inhibition experiments. Skin test extracts forDer-
mataphagoides farina (dust mite) and Blatella germanica (cockroach) (Greer,
Lenoir, NC) were buffer exchanged with PBS in order to remove glycerin by
using the Amicon Ultra-0.5 centrifugal filter unit with a molecular cutoff of 10
kDa (Millipore, Billerica, Mass). Serum (25 mL) was incubated at 378C with
either cockroach or dust mite extract or PBS (25 mL) for 2 hours. Samples
were then assayed for IgE against the C lectuarius extract, cockroach, or
dust mite as described for the undiluted samples. Percent inhibition was cal-
culated by subtracting the IgE level measured after incubation with allergen
extract from the IgE level measured after incubation with PBS and dividing
by the latter concentration.
Western blotApproximately 25mg of cNP and 240mg of theC lecularius extract in sam-
ple buffer (6% glycerol [vol/vol]; 30 mM Tris, pH 6.8; 1.2 mM EDTA; 1.2%
SDS [wt/vol]; and 8.64mMb-mercaptoethanol) were loaded in different wells
of a 12 1 2 well precast Tris-HCl gel (4%-15%) (Criterion; Bio-Rad, Hercu-
les, Calif). Gels were run at 50 mA for 1.5 hours and then protein was trans-
ferred onto a nitrocellulose membrane (500 mA for 1 hour). The membrane
was blocked for 1 hour with Odyssey Blocking Buffer (Licor, Lincoln, Neb)
before being incubated overnight at 48Cwith subject 23’s serum (1:10). Mem-
branes were then incubated with a goat antihuman IgE epsilon DyLight 800
(1:1000, Antibodies Online, Atlanta, Ga) before being visualized by using
the Odyssey imaging system (Licor).
REFERENCES
E1. Kinnear J. Epidemic of bullous erythema on legs due to bed-bugs. Lancet 1948;2:55.
E2. Parsons DJ. Bedbug bite anaphylaxis misinterpreted as coronary occlusion. Ohio
Med 1955;51:669.
E3. Sansom JE, Reynolds NJ, Peachey RD. Delayed reaction to bed bug bites. Arch
Dermatol 1992;128:272-3.
E4. Tharakaram S. Bullous eruption due to Cimex lecticularis. Clin Exp Dermatol
1999;24:241-2.
E5. Fletcher CL, Ardern-Jones MR, Hay RJ. Widespread bullous eruption due to mul-
tiple bed bug bites. Clin Exp Dermatol 2002;27:74-5.
E6. Liebold K, Schliemann-Willers S, Wollina U. Disseminated bullous eruption with
systemic reaction caused by Cimex lectularius. J Eur Acad Dermatol Venereol
2003;17:461-3.
E7. Ter Poorten MC, Prose NS. The return of the common bedbug. Pediatr Dermatol
2005;22:183-7.
E8. Leverkus M, Jochim RC, Schad S, Brocker EB, Andersen JF, Valenzuela JG,
et al. Bullous allergic hypersensitivity to bed bug bites mediated by IgE against
salivary nitrophorin. J Invest Dermatol 2006;126:91-6.
E9. Scarupa MD, Economides A. Bedbug bites masquerading as urticaria. J Allergy
Clin Immunol 2006;117:1508-9.
E10. Masetti M, Bruschi F. Bedbug infestations recorded in Central Italy. Parasitol Int
2007;56:81-3.
E11. Goddard J, de Shazo R. Rapid rise in bed bug populations: the need to include
them in the differential diagnosis of mysterious skin rashes. South Med J 2008;
101:854-5.
E12. Stucki A, Ludwig R. Images in clinical medicine: bedbug bites. New Engl J Med
2008;359:1047.
E13. Mumcuoglu KY. A case of imported bedbug (Cimex lectularius) infestation in Is-
rael. Isr Med Assoc J 2008;10:388-9.
E14. Levy Bencheton A, Berenger JM, Del Giudice P, Delaunay P, Pages F, Morand JJ.
Resurgence of bedbugs in southern France: a local problem or the tip of the ice-
berg? J Eur Acad Dermatol Venereol 2011;25:599-602.
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865.e1 LETTERS TO THE EDITOR
TABLE E1. Previous reports of clinical reactions to bed bugs
Author (year)
No. of
patients Primary clinical presentation Secondary reaction
Kinnear (1948)E1 6 Erythematous bullae on calves None reported
Parsons (1955)E2 1 Itchy lesions and mild neck swelling within 2 h after
bites
Upper extremity, neck, and perioral edema, severe
dyspnea within 3.5 h of bites; diagnosed as
anaphylaxis
Sansom et al (1992)E3 2 Patient 1 developed diffuse intensely pruritic, papular
lesions 60 h after bites; patient 2 developed
nonpruritic, erythematous, papular lesions
Patient 1 developed florid, hemorrhagic, bullous rash
with edema 6 d after bites
Tharakaram (1999)E4 1 Pruritic, erythematous rash that evolved into a
vesiculobullous eruption over 3 wk
None reported
Fletcher et al (2002)E5 1 Extremely pruritic widespread bullous eruption;
urticarial papules and plaques
None reported
Liebold et al (2003)E6 1 Papular pruritic rash Second exposure 4 wk later developed diffuse pruritic,
erythematous large tense bullae with mild pyrexia
Ter Poorten et al (2005)E7 1 Diffuse intensely pruritic erythematous macules and
papules; few discrete urticarial papules
None reported
Leverkus et al (2006)E8 1 Multiple pruritic, erythematous papules, nodules, and
blisters; several nodules with underlying erythema
and moderate peripheral whealing
None reported
Scarupa and
Economides (2006)E917 Papular urticaria–like dermatitis None reported
Masetti and
Bruschi (2007)E102 Patient 1 developed pruritic erythematous macules and
papules; patient 2 developed severe diffuse pruritic
bullous eruptions
None reported
Goddard and
deShazo (2008)E111 Pruritic, erythematous ‘‘bumps’’ 1 d after bite Two days after initial bites developed erythematous
papules; 12 d after initial bites rash improved but
developed worsening pruritis
Stucki and Ludwig (2008)E12 1 Multiple pruritic erythematous papules 1 d after bites None reported
Mumcuoglu (2008)E13 1 Pruritic erythematous ‘‘spots’’ None reported
Levy Bencheton
et al (2011)E142 Patient 1 developed diffuse pruritic erythematous
maculopapular lesions with purpuric centers; patient
2 developed pruritic rash of several months
None reported
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