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March 2014

General considerations:
The purpose of this educational material is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians The content of this educational material does not intend to replace the clinical criteria of the physician If there is any correction or suggestion to improve the !uality of this educational material, it should "e done directly to the author "y e#mail If there is any !uestion or dou"t a"out the content of this educational material, it should "e done directly to the author "y e#mail

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology %ospital &acional 'dgardo (e"agliati )artins, *ima#Peru +ucapul,-./hotmail com

Juan Flix Aldave Pita, MD


)edical 0irector *uke 1ociety International, Tru+illo#Peru

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

March 2014 content

AC!"# A$D %&$'("#)M MA$A'#M#$" &F F&&D A%%#)'* +*+"#MA",C )#-,#. 2de 1ilva 0, Geromi ), Panesar 11, )uraro A, 3erfel T, %offmann#1ommergru"er 4, (o"erts G, $ardona 5, 0u"ois A'6, %alken 1, %ost A, Poulsen *4, 5an (ee (, 5lieg#7oerstra 76, Agache I, 1heikh A on "ehalf of the 'AA$I 8ood Allergy and Anaphylaxis Guidelines Group Allergy 9:;.< =>: ;?>@;=AB / C&$"),B!",&$+ &F P0A)MAC&'#$#",C+ A$D ")A$+C),P"&M,C+ "& "0# !$D#)+"A$D,$' &F "0# 0*P#)+#$+,",-,"* D)!' )#AC",&$+ 28ernandeC T0, )ayorga $, GuDant 6*, 7lanca ), $orne+o# GarcEa 6A Allergy 9:;.< =>: ;?:@;?-B/ F!$', "0# $#'%#C"#D A%%#)'#$,C +&!)C#+ 2$rameri (, Gar"ani ), (hyner $, %uitema $ Allergy 9:;.< =>: ;A=@;-?B/ ,'#(BA+#D ,MM!$&"0#)AP* &F CA$C#) C0A%%#$'#+ A$D C0A$C#+ 21inger 6, 6ensen#6arolim ' Allergy 9:;.< =>: ;FA@;.>B/ MA$A'#M#$" &F A$AP0*%A1,+ A +*+"#MA",C )#-,#. 20hami 1, Panesar 11, (o"erts G, )uraro A, 3orm ), 7il o )7, $ardona 5, 0u"ois A'6, 0unnGalvin A, 'igenmann P, 8ernandeC#(ivas ), %alken 1, *ack G, &iggemann 7, (ueff 8, 1antos A8, 5lieg#7oerstra 7, Golkipli GH I 1heikh A on "ehalf of the 'AA$I 8ood Allergy and Anaphylaxis Guidelines Group Allergy 9:;.< =>: ;=-@;A?B / P)#-A%#$C# &F A"&P*, #&+,$&P0,%,A, A$D ,2# #%#-A",&$ ,$ ,2'4()#%A"#D D,+#A+# 20ella Torre ', )attoo %, )aha+an 51, $arruthers ), Pillai 1, 1tone 6% Allergy 9:;.< =>: 9=>@9A9B / +#)!M BA+A% ")*P"A+# MA* B# A '&&D MA)3#) F&) P)#D,C",$' "0# ),+3 &F A$AP0*%A1,+ ,$ C0,%D)#$ .,"0 F&&D A%%#)'* 21ahiner J), KavuC 1T, 7uyuktiryaki 7, $avkaytar L, KilmaC 'A, Tuncer A, 1ackesen $ Allergy 9:;.< =>: 9=?@9=-B / -,"AM,$ D A+ A$ ADJ!$C" "& +!BC!"A$#&!+ A%%#)'#$ ,MM!$&"0#)AP* ,$ A+"0MA",C C0,%D)#$ +#$+,",4#D "& 0&!+# D!+" M,"# 27aris 1, 4iykim A, LCen A, Tulunay A, 4arakoc#Aydiner ', 7arlan I7 Allergy 9:;.< =>: 9.=@9?FB / AC5!,)#D C1 ,$0,B,"&) D#F,C,#$C* +0&!%D .# M&$,"&) F&) A++&C,A"#D A$",B&D* D#F,C,#$C*6 2Tohani A, $hua I, Grigoriadou 1, 7uckland )1, *onghurst %6 Ann Allergy Asthma Immunol 9:;.< ;;9: 9=?#9=AB/ #FF#C" &F MA"#)$A% 78 FA""* AC,D +!PP%#M#$"A",&$ &$ ,$FA$" A%%#)'* 2$iaccio $', Girdhar ) Ann Allergy Asthma Immunol 9:;.< ;;9: ;>;#;>.B / #1#)C,+#(,$D!C#D D*+P$#A M&)# "0A$ -&CA% C&)D D*+F!$C",&$ &) %A)*$'&MA%AC,A 23ein"erger ) Ann Allergy Asthma Immunol 9:;.< ;;9: 9A:#9A;B / 0,+"&)* &F A%%#)',C D,+#A+#+ A$D %!$' CA$C#) ),+3 2'l#Gein ), Parent )#', 1iemiatycki 6, (ousseau )#$ Ann Allergy Asthma Immunol 9:;.< ;;9: 9F:#9F=B / ,$")A-#$&!+ 9 A'&$,+"+ A$D +#-#)# P#D,A"),C A+"0MA #1AC#)BA",&$ ",M# F&) A C%&+#) %&&3 A" "#)B!"A%,$#6 24antor 07, Phipatanakul 3 Ann Allergy Asthma Immunol 9:;.< ;;9: ;-AB/ %&$'("#)M F&%%&.(!P &F ,2#(M#D,A"#D F&&D A%%#)'* D#"#)M,$,$' P#)+,+"#$C# -#)+!+ C%,$,CA% "&%#)A$C# 27urks A3, *and )% Ann Allergy Asthma Immunol 9:;.< ;;9: 9::#9:=B / %*MP0&P#$,A ,$D!C#D B* #"A$#)C#P" 2Pepper A&, Talre+a &, $owan G), Glaum )$, *ockey (8 Ann Allergy Asthma Immunol 9:;.< ;;9: 9=9#9=FB/

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

)AD,&C&$")A+"(,$D!C#D ,&D,D# +,A%AD#$&PA"0* A$D $#!")&P0,%,C D#)MA"&+,+ 28ok 61, (amachandran T, 7erce ), 1mith 37 Ann Allergy Asthma Immunol 9:;.< ;;9: 9=9#9=FB / "(C#%% B,&%&'* ,$ ,MM!$&"0#)AP* 21teinke 63, *awrence )G Ann Allergy Asthma Immunol 9:;.< ;;9: ;>?#;>>B/ AD-A$C#+ ,$ P#D,A"),C A+"0MA ,$ 2018 C&&)D,$A",$' A+"0MA CA)# 21Cefler 16 6 Allergy $lin Immunol 9:;.< ;FF: =?.#=;B/ A$ A%'&),"0M F&) ")#A",$' C0)&$,C !)",CA),A .,"0 &MA%,4!MAB D&+# ,$"#)-A% +0&!%D B# ,$D,-,D!A%,4#D 2Jysal P, 'ller ', )ortC $G, 7indslev#6ensen $ 6 Allergy $lin Immunol 9:;.< ;FF: >;.#>;?B/ A!"&,MM!$,"* D!# "& )A' D#F,C,#$C* A$D #+",MA"#D D,+#A+# ,$C,D#$C# ,$ )A'1:2 M!"A",&$+ 2$hen 4, 3u 3, )athew 0, Ghang K, 7rowne 14, (osen *7, )c)anus )P, Pulsipher )A, Kandell ), 7ohnsack 68, 6orde *7, &otarangelo *0, 3alter 6' 6 Allergy $lin Immunol 9:;.< ;FF: --:#--9B / CA)D; M!"A",&$+ %,$3#D "& +!BC!"A$#&!+ P0A#&0*P0&M*C&+,+ A$D "01< C#%% D#F,C,#$C,#+ 23ang M, 3ang 3, *in G, 3ang M, *i T, Ku 6, *iu 3, Tong G, Mu K, Ghang 6, Guan *, 0ai *, Kang K, %an 3, *i ( 6 Allergy $lin Immunol 9:;.< ;FF: >:?#>:-B / CD4;d(#1P)#++,$' $#!")&P0,%+ D,FF#)#$",A"# A"&P,C F)&M $&$A"&P,C ,$D,-,D!A%+ 21igua 6A, 7uelow 7, $heung 01, 7uell ', %unter 0, 4lancnik ), Grayson )% 6 Allergy $lin Immunol 9:;.< ;FF: >:;#>:.B/ ,MM!$&"0#)AP* .0A" %,#+ B#*&$D 2$asale T7, 1tokes 6( 6 Allergy $lin Immunol 9:;.< ;FF: =;9# =;>B/ %&.(AFF,$,"* A%%#)'#$(+P#C,F,C ,2# ,$ C&)D B%&&D A$D AFF,$,"* MA"!)A",&$ AF"#) B,)"0 24amemura &, 4awamoto &, &akamura (, Teshima (, 8ukao T, 4id % 6 Allergy $lin Immunol 9:;.< ;FF: >:.#>:?B/ M#C0A$,+M+ &F A%%#)'#$(+P#C,F,C ,MM!$&"0#)AP* M!%",P%# +!PP)#++&) FAC"&)+ A" .&)3 ,$ ,MM!$# "&%#)A$C# "& A%%#)'#$+ 2Akdis ), Akdis $A 6 Allergy $lin Immunol 9:;.< ;FF: =9;#=F;B/ P#$,C,%%,$ A%%#)'* A+ A P!B%,C 0#A%"0 M#A+!)# 21olensky ( 6 Allergy $lin Immunol 9:;.< ;FF: A>A#A>-B/ P#$,C,%%,!M MA)$#FF#, ,$F#C",&$ A$D ,MPA,)#D ,F$(= ,MM!$,"* ,$ 0!MA$+ .,"0 A!"&+&MA%(D&M,$A$" 'A,$(&F(P0&+P0&)*%A",&$ +"A"1 M!"A",&$+ 2*ee PP3, )ao %, Kang 3, $han 4#3, %o )%4, *ee T#*, $han 683, 3oo P$K, Tu 3, *au K#* 6 Allergy $lin Immunol 9:;.< ;FF: ->.#->AB/ "01< D,FF#)#$",A",&$ CAPAC,"* D#-#%&P+ .,"0,$ "0# F,)+" 8 M&$"0+ &F %,F# 20i+kstra 44, %oeks 17'A, Prakken 76, de (oock 1 6 Allergy $lin Immunol 9:;.< ;FF: ->;#->.B / "0# #D,"&)+> C0&,C# 2*eung 0K), 1Cefler 16 6 Allergy $lin Immunol 9:;.< ;FF: ==9#==FB / AD-#)+# D)!' )#AC",&$+ D!),$' C#F"),A1&$# ")#A"M#$" CA$ CA!+# +#-#)# 0#M&%*+,+ 2*iu 3, Ku 0 Pediatr Allergy Immunol 9:;.: 9?: ;:;#;:9B/ A%%#)'#$(+P#C,F,C ,MM!$&P)&P0*%A1,+ "&.A)D +#C&$DA)* P)#-#$",&$ &F A%%#)',C )0,$,",+6 2)atricardi P) Pediatr Allergy Immunol 9:;.: 9?: ;?@;-B /

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

D,A'$&+",C #-A%!A",&$ &F 0*P#)+#$+,",-,"* )#AC",&$+ "& B#"A(%AC"AM A$",B,&",C+ ,$ A %A)'# P&P!%A",&$ &F C0,%D)#$ 2Gam"onino )A, $orCo 6*, )uNoC $, (e!uena G, AriCa A, )ayorga $, Jrda A, 7lanca ), Torres )6 Pediatr Allergy Immunol 9:;.: 9?: -:@-AB / #''(.0,"#(+P#C,F,C ,'A A$D ,'A2 A$",B&D,#+ ,$ #''(A%%#)',C C0,%D)#$ ,+ "0#)# A )&%# ,$ "&%#)A$C# ,$D!C",&$6 24onstantinou G&, &owak#3eCgrCyn A, 7encharitiwong (, 7ardina *, 1icherer 1%, 1ampson %A Pediatr Allergy Immunol 9:;.: 9?: =.@A:B / F#"A% A$D #A)%*(%,F# &),',$+ &F A%%#)'* 23arner 6L, 3arner 6A Pediatr Allergy Immunol 9:;.: 9?: A@-B/ F&&D A%%#)'* A .,$D,$' )&AD "& "0# P)#+#$" 21ampson %A Pediatr Allergy Immunol 9:;.: 9?: 9?@9=B/ ,$D!C",&$ &F ")#' C#%%+ AF"#) &)A% ,MM!$&"0#)AP* ,$ 0#$>+ #''(A%%#)',C C0,%D)#$ 28uentes#Aparicio 5, Alonso#*e"rero ', Gapatero *, Infante 1, *orente (, )uNoC#8ernOndeC )A, $orrea# (ocha ( Pediatr Allergy Immunol 9:;.: 9?: ;:F@;:=B/ M!C&+A% MA+" C#%% C&!$"+ ,$ P#D,A"),C #&+,$&P0,%,C 'A+")&,$"#+",$A% D,+#A+# 2)ir 1A5, 1chady 0, Llive AP, &agy#1Cakal 0, 4ellermayer ( Pediatr Allergy Immunol 9:;.: 9?: >.@>?B / P#D,A"),C A%%#)'* )#+#A)C0 A)# .# &$ "0# ),'0" ")AC36 27engt 7+PrkstDn Pediatr Allergy Immunol 9:;.: 9?: .@=B/ P#D,A"),C A+"0MA D& .# $##D M&)# ,$$&-A",&$ F&) ")#A"M#$"6 2(iedler 6 Pediatr Allergy Immunol 9:;.: 9?: ;>@9:B/ P)#-#$",&$ .0A" ,+ "0# M&+" P)&M,+,$' APP)&AC06 2%olt PG Pediatr Allergy Immunol 9:;.: 9?: ;9@;.B/ P),MA)* ,MM!$&D#F,C,#$C,#+ &P",&$+ F&) "0# F!"!)# 27adolato ( Pediatr Allergy Immunol 9:;.: 9?: 9A@9>B/ -,"AM,$ D D#F,C,#$C* ,+ A++&C,A"#D .,"0 D,A'$&+,+ A$D +#-#),"* &F C0,%D0&&D A"&P,C D#)MA",",+ 23ang 11, %on 4*, 4ong AP#s, Pong %&#h, 3ong G3#k, *eung T8 Pediatr Allergy Immunol 9:;.: 9?: F:@F?B/ .0A" ,+ $##D#D F&) A%%#)',C C0,%D)#$6 2%aahtela T Pediatr Allergy Immunol 9:;.: 9?: 9;@9.B

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

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AC!"# A$D %&$'("#)M MA$A'#M#$" &F F&&D A%%#)'* +*+"#MA",C )#-,#. 2de 1ilva 0, Geromi ), Panesar 11, )uraro A, 3erfel T, %offmann#1ommergru"er 4, (o"erts G, $ardona 5, 0u"ois A'6, %alken 1, %ost A, Poulsen *4, 5an (ee (, 5lieg#7oerstra 76, Agache I, 1heikh A on "ehalf of the 'AA$I 8ood Allergy and Anaphylaxis Guidelines Group Allergy 9:;.< =>: ;?>@;=AB 8ood allergy 28AB: 2iB Ig'#mediated: urticaria, angioedema, "ronchospasm, GI symptoms, anaphylaxis< 2iiB non#Ig'#mediated: enterocolitis, proctocolitis, %einer syndrome, celiac disease, contact dermatitis< 2iiiB Ig'# and cell#mediated: atopic dermatitis, eosinophilic GI diseases Ig'#mediated 8A: 2iB Q prevalence worldwide 2=R of children, .R of adultsB< 2iiB impact: mortality risk, S Ho*, costs< 2iiiB T;A: foods have "een reported to cause allergic reactions< 2ivB main allergenic foods 2comprise >:R of casesB: milk, egg, peanut, tree nuts, wheat, soy, seafood< 2vB diagnosis: specific Ig' detection "y skin prick test 21PTB or in vitro testing 2sIg', $(0B, "asophil activation test, food challenge 207P$8$ is the gold standardB< 2viB conventional treatment: allergen avoidance 2does not prevent accidental exposureB, epinephrine autoin+ectors, nutritional counseling, follow up to confirm spontaneous development of tolerance 2especially in egg, milk, wheat and soy allergyB, ingestion of extensively heated egg or milk products in children who tolerate them 2this may accelerate resolution of egg and milk allergy, respectivelyB< 2viiB optimal treatment: restore tolerance 2immunotherapyB Authors performed a systematic review to summariCe evidence a"out the management of 8A U 2iB -. studies were included 29/F had high risk of "iasB< 2iiB meta#analysis was not feasi"le due to heterogeneity< 2iiiB acute management of 8A: anti#%; may "e "eneficial in non#life threatening reactions 2weak evidenceB< 2ivB long#term management of 8A: mast cell sta"iliCers may S 8A symptoms 2weak evidenceB< extensively hydrolyCed and amino acid#"ased formulas can "e "eneficial in infants with cowVs milk allergy 2moderate evidenceB< pro"iotics have not proved helpful< food immunotherapy can modify disease< 2vB more evidence is needed AuthorVs commentary: the "est management strategy for 8A likely depends on the patientVs age, the culprit food, the type and severity of 8A, and the response to previous therapies

C&$"),B!",&$+ &F P0A)MAC&'#$#",C+ A$D ")A$+C),P"&M,C+ "& "0# !$D#)+"A$D,$' &F "0# 0*P#)+#$+,",-,"* D)!' )#AC",&$+ 28ernandeC T0, )ayorga $, GuDant 6*, 7lanca ), $orne+o#GarcEa 6A Allergy 9:;.< =>: ;?:@;?-B Authors review the contri"ution of pharmacogenetics and transcriptomics to the understanding of hypersensitivity drug reactions 2%0(sB Adverse drug reaction 2A0(B: Wany noxious, unintended, and undesired effect of a drug that occurs at doses used for prevention, diagnosis, or treatmentX 23%LB %0(s: 2iB =@;:R of all A0(s< 2iiB impact: significant mor"idity, mortality risk, S Ho*, costs< 2iiiB almost any drug can cause %0(s< 2ivB %0(s can "e immune# or non#immune mediated< 2vB immune#mediated %0(s can "e immediate 2Ig'#mediatedB or delayed 2anti"ody# or cell# mediatedB< 2viB diagnosis: clinical history, allergologic tests 2in vivo and in vitroB, drug challenges< 2viiB therapy: avoidance of the culprit drug2sB, use of alternative drugs, drug desensitiCation, preparation for an unexpected %0(

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

8uturistic approach in allergic diseases 2including %0(sB: use of clinical, la"oratory, imaging, histologic and genetic markers to identify specific genotypes/endotypes/phenotypes U give individualiCed therapy 2optimiCe efficacy and safetyB Goals of pharmacogenetics: 2iB to identify specific alleles that can predict efficacy and safety of a drug 2e g %*A#7Y?A::; Q risk of a"acavir hypersensitivity< HLA-B*58:01 Q risk of allopurinol# induced 161/T'&/0('11< HLA-B*15:02 Q risk of car"amaCepine#induced 161/T'&< HLAB*57:01 Q risk of flucoxacilline#induced liver in+ury< variants of FcRI, STAT6, IL-4, IL-13, IL4RA and T F! may Q risk of penicillin allergyB< 2iiB to define personaliCed therapies "ased on the patientVs genetic profile Transcriptomics: 2iB definition: the !uantitative study of all genes expressed in a given "iological state< 2iiB importance: allows investigation of %0( mechanisms "y analyCing gene expression in different hypersensitivity entities 2e g 161/&'T, 0('11, anaphylaxis, etcB

F!$', "0# $#'%#C"#D A%%#)'#$,C +&!)C#+ 2$rameri (, Gar"ani ), (hyner $, %uitema $ Allergy 9:;.< =>: ;A=@;-?B Allergens: 2iB molecules that can cause and trigger allergic diseases< 2iiB allergenic structures can "e found in every species< 2iiiB estimated allergen repertoire: Z?::: different structures< 2ivB current allergen list 23%L/IJI1 Allergen &omenclature 1u"committee # www allergen orgB: A?F molecules< 2vB most ma+or allergens from mites, animal dander, pollens, insects and foods have "een cloned 8ungi: 2iB Z;::,::: reported species< 2iiB important source of allergenic molecules 2enCymes, toxins, cell wall componentsB< 2iiiB officially#approved fungal allergens include ;:? iso#allergens and variants from 9? fungal species of the Ascomycota and 7asidiomycota phyla< 2ivB many more fungal allergens are descri"ed in the literature 2e g Aspergillus fumigatus can produce [-; different Ig'#"inding proteinsB 2vB fungal extracts are not standardiCed, although doCens of commercial products exist 2reasons: differences in source materials and manufacturing procedures, lack of accepted potency assays, vast num"er of allergenic fungal speciesB< 2viB fungal allergens have "een largely neglected in molecular allergology< 2viiB the ;st recom"inant fungal allergens 2Alt a ;, Asp f ; to .B immo"iliCed in Immuno$APs are now commercially availa"le Allergy to fungi: 2iB exaggerated immune responses to fungal molecules U excessive inflammation< 2iiB mechanisms: Ig'#mediated, IgG#mediated, cell#mediated< 2iiiB Z-: mould genera have "een shown to induce Ig'#mediated allergies 2e g Alternaria, Aspergillus, $ladosporium, $andida, Penicillium, $lavularia, )alasseCiaB< 2ivB cross#reactivity "etween homologous fungal allergens has "een demonstrated 2and even "etween distant species such as $andida "oidiini and A fumigatusB General difficulties to diagnose fungal allergy: 2iB most patients sensitiCed to fungi are not aware of the source of exposure< 2iiB fungal extracts for skin tests are not standardiCed< 2iiiB in vitro tests may not "e enough accurate< 2ivB fungal extracts contain cross#reactive car"ohydrate determinants 2often clinically irrelevantB Treatment of fungal allergy includes allergen avoidance 2often nor feasi"le due to u"i!uitous location of fungiB, antifungal drugs 2e g itraconaColeB, antiinflammatory therapy 2e g oral or inhaled corticosteroidsB and specific immunotherapy

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

0iseases where fungal allergy plays an important role: 2iB allergic "ronchopulmonary mycosis \A7P)], such as allergic "ronchopulmonary aspergillosis \A7PA], 2iiB allergic asthma 2especially severe asthma with fungal sensitiCation \1A81]B< 2iiiB allergic rhinosinusitis 2especially allergic fungal rhinosinusitis \A8(1]B< 2ivB atopic dermatitis< 2vB extrinsic allergic alveolitis 2occupational exposure to thermophilic actinomycetesB A7PA: 2iB hypersensitivity to Aspergillus fumigatus in the lower airways< 2iiB affects up to 9 ?R of adults with severe asthma 2patients with severe asthma should "e screened for A7PAB< 2iiiB predisposing conditions: severe asthma, cystic fi"rosis, hyper#Ig' syndrome, chronic granulomatous disease, family history of A7PA< 2ivB complications: uncontrolled asthma, recurrent pneumonias, "ronchiectasis, lung fi"rosis, S lung function, respiratory failure< 2vB differential diagnosis: A7P), 1A81, cystic fi"rosis, "ronchopulmonary infections 3hen to suspect A7PA^ 2iB severe asthma with expectoration of mucous plugs< 2iiB pulmonary infiltrates 2especially in upper or middle lo"eB< 2iiiB perihilar mucous plugging< 2ivB lo"ar or lung collapse< 2vB central "ronchiectasis 2inner 9/F of lung fieldsB< 2viB "lood eosinophils [-R< 2viiB total Ig' T.;A kJ/* 2while not receiving systemic corticosteroidsB< 2viiiB positive skin tests 21PT, I0(B to A fumigatus< 2ixB Q specific Ig' and IgG 2precipitating anti"odiesB to A fumigatus< 2xB A fumigatus in sputum culture< 2xiB suggestive histology 2allergic mucin, fungal hyphae, "ronchi with mucoid impaction, "ronchocentric granulomatosisB< 2xiiB ma+or improvement with systemic corticosteroids 2S infiltrates, S total Ig'B< 2xiiiB concurrent A8(1 0ifficulties to diagnose A7PA: 2iB no pathognomonic test exists 2skin tests appear highly sensitive, in vitro tests \specific Ig' and IgG to A fumigatus] appear highly specificB< 2iiB pulmonary infiltrates and "ronchiectasis can "e relatively silent 8re!uent diagnostic mistakes in A7PA: 2iB to exclude A7PA when anti"odies to A fumigatus are not detected< 2iiB to exclude A7PA when skin testing to A fumigatus is negative< 2iiiB to exclude A7PA when total Ig' is _.;A kJ/* 2Ig' may S during remission stage or corticosteroid useB< 2ivB to exclude A7PA when "ronchiectasis are not present 2seropositive A7PAB A7P): 2iB syndrome similar to A7PA, "ut caused "y other fungi 2e g $andida, Penicillium, $urvularia speciesB< 2iiB less fre!uent than A7PA 1A81: 2iB this term descri"es patients with severe persistent asthma, fungal sensitiCation and good response to antifungal treatment< 2iiB diagnostic criteria are not defined A8(1: 2iB ? #;:R of cases of chronic rhinosinusitis 2$(1B< 2iiB mainly caused "y Aspergillus sp 2other causal fungi: 7ipolaris, 'xserohilum, $urvularia, AlternariaB< 2iiiB more fre!uent in humid and warm regions< 2ivB pathophysiology: entry of fungal spores in the sinuses U fungal growth U Ig' production to fungal allergens U eosinophil attraction and activation U tissue inflammation and damage< 2vB typical presentation: immunocompetent atopic young adult or adolescent with severe $(1 and nasal polyps< 2viB diagnosis: $(1 with nasal polyps 2fre!uently unilateralB, peripheral eosinophilia, Q total Ig', Q specific Ig' to Aspergillus sp 2skin or in vitro testingB, eosinophilic mucous plugs with fungal hyphae 2`allergic mucinVB< 2viiB complications: inflammation/erosion/compression of contiguous structures 2e g "one, or"its, "rainB, secondary "acterial infections< 2viiiB management: team approach 2allergist, L(*, neurologist, etc B, functional endoscopic sinus surgery 2removal of the fungi and secretionsB, steroids for [F months 2intranasal and systemicB, antifungal drugs, fungal immunotherapy

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

0iagnostic criteria for A8(1 27ent and 4uhn, ;>>.B: 2iB nasal polyposis< 2iiB presence of `allergic mucinV 2eosinophil#rich thick secretions with $harcot#*eyden crystals and fungal elementsB without fungal invasion of the paranasal tissues< 2iiiB $T findings suggestive of $(1< 2ivB fungi detection "y histology or culture< 2vB positive specific Ig' to fungal allergens Atopic dermatitis 2A0B: 2iB common chronic skin disease 2FR of adults, 9:R of childrenB< 2iiB impact: S Ho*, high costs, Q predisposition to skin infections and other allergies 2Z;/F of A0 patients develop asthma, Z9/F develop allergic rhinitisB< 2iiiB multiple pathogenic factors: S skin "arrier, immune dysregulation, sensitiCation to foods, micro"ial molecules or self antigens )alasseCia sympodialis: 2iB skin coloniCing yeast 2coloniCation occurs immediately after "irthB< 2iiB may cause Ig'#mediated sensitiCation in A0 patients 2favoring factors: S skin "arrier, immune dysregulationB, contri"uting to A0 chronicity< 2iiiB cross#reactivity reactions "etween ) sympodialis allergens and human proteins can occur 2e g )ala s ;; and human manganese# dependant superoxide dismutase< )ala s ;F and human thioredoxinB

,'#(BA+#D ,MM!$&"0#)AP* &F CA$C#) C0A%%#$'#+ A$D C0A$C#+ 21inger 6, 6ensen# 6arolim ' Allergy 9:;.< =>: ;FA@;.>B Approaches in cancer immunotherapy 2only i, ii and iii are currently practically relevant in pu"lic healthB: 2iB vaccination against tumorigenic viruses< 2iiB passive immunotherapy with monoclonal anti"odies< 2iiiB activation of antitumor immunity via "lockade of immune checkpoints< 2ivB vaccination with tumor cells or tumor#associated antigens 2TAAsB< 2vB in vitro `pulsingV of antigen#presenting cells< 2viB selection/cloning of &4 cells and cytotoxic T cells targeting TAAs Passive immunotherapy with monoclonal anti"odies 2mA"sB against cancer: 2iB mA"s directed specifically against TAAs< 2iiB all 80A#approved mA"s comprise the IgG class 2IgG;, IgG9, IgGFB, although other classes have "een proposed 2Ig), IgA, Ig'B< 2iiiB effector mechanisms of IgG mA"s: inhi"ition of proliferation signals, activation of &4 cells, phagocytes and complement system 2anti"ody#dependent cell#mediated cytotoxicity \A0$$], anti"ody#dependent cell# mediated phagocytosis \A0$P]B< 2ivB some IgG mA"s have "een coupled with cytotoxic molecules to Q killing of cancer cells< 2vB some IgG mA"s have "een modified 2e g site#directed mutagenesis or altered glycosylationB to Q "inding to activating 8ca receptors and Q cytotoxicity 'xamples of IgG mA"s against cancer: 2iB anti#%'(#9 mA"s to treat metastatic "reast cancer overexpressing %'(#9 2human epidermal growth factor receptor#9B< 2iiB anti#'G8( mA"s to treat metastatic colon cancer overexpressing 'G8( 2epidermal growth factor receptorB< 2iiiB anti# $09: mA"s to treat 7#cell non#%odgkinVs lymphoma< 2ivB anti#$T*A#. mA"s 2ipilimuma"B to treat advanced metastatic melanoma< 2vB anti#P0#; 2programmed death#;B mA"s 2nivoluma", lam"roliCuma"B to treat advanced metastatic melanoma Genetic factors that may affect the efficacy of mA"s regarding A0$$: 2iB polymorphisms in 8ca( genes< 2iiB copy num"er variations in 8ca( genes< 2iiiB epigenetic modifications of 8ca( genes< 2ivB posttranslational glycosylation of constant regions in the heavy chains of mA"s Ig': 2iB important role in defense against some parasitic infections< 2iiB its production is dysregulated in allergic diseases< 2iiiB may have high tumoricidic efficacy< 2ivB effector mechanisms: activation of mast cells, eosinophils and "asophils Arguments that favor the use of Ig' mA"s in cancer immunotherapy: 2iB there is an inverse association "etween atopic diseases and some neoplasms 2e g pancreatic cancer, glioma,

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

childhood leukemiaB< 2iiB Ig' can activate effector cells 2eosinophils, monocytes and "asophilsB with a high inflammatory, cytotoxic and/or phagocytic potential upon "inding to Ig' receptors 28cb(I seem to mediate cytotoxicity, 8cb(II \$9F] seem to mediate phagocytosisB< 2iiiB Ig' can restimulate the immune system via facilitated antigen uptake and presentation< 2ivB affinity of Ig' to 8cb receptors is higher than IgG to 8ca receptors< 2vB humans and dogs have a highly compara"le Ig' "iology U canine cancer models can "e useful to predict the therapeutic potential of Ig' mA"s in human cancer Arguments against the use of Ig' mA"s in cancer immunotherapy: 2iB mast cells can promote angiogenesis and tumor development< 2iiB mast cell and "asophil activation can lead to anaphylactic reactions

MA$A'#M#$" &F A$AP0*%A1,+ A +*+"#MA",C )#-,#. 20hami 1, Panesar 11, (o"erts G, )uraro A, 3orm ), 7il o )7, $ardona 5, 0u"ois A'6, 0unnGalvin A, 'igenmann P, 8ernandeC# (ivas ), %alken 1, *ack G, &iggemann 7, (ueff 8, 1antos A8, 5lieg#7oerstra 7, Golkipli GH I 1heikh A on "ehalf of the 'AA$I 8ood Allergy and Anaphylaxis Guidelines Group Allergy 9:;.< =>: ;=-@;A?B Anaphylaxis: 2iB definition: acute, severe, life#threatening systemic hypersensitivity reaction< 2iiB lifetime prevalence: : :?#9R< 2iiiB incidence: ;/;:,::: patient#yr 2incidence is increasingB< 2ivB :# . yr#old children have higher incidence ratesB< 2vB mechanisms: release of mediators from mast cells and "asophils 2mainly Ig'#mediated reactions< IgG#mediated mechanisms have "een shown in miceB< 2viB most common culprits: foods, drugs, hymenoptera venom, latex< 2viiB factors that influence severity: pathogenic mechanism, allergen properties, allergen dose, route of exposure, degree of sensitiCation, affinity of specific Ig', presence of cofactors< 2viiiB augmentation cofactors: exercise, alcohol, infections, &1AI0s, drugs, menses, stress< 2ixB anaphylaxis can present without cutaneous signs 2urticaria or angioedemaB in T9:R of patients< 2xB &IAI0/8AA& criteria to diagnose anaphylaxis U sensitivityc>= AR, specificityc-9 .R )edian times to cardiovascular and/or respiratory collapse during anaphylaxis: 2iB ?#;: min for I5 drugs, 2iiB ;? min for field insect stings and I) drugs, 2iiiB F: min for food and oral drugs Allergists/immunologists must know: 2iB how to treat acute anaphylaxis 2it may occur after immunotherapy application, skin testing or food/drug challengesB< 2iiB how to evaluate and manage a patient with a suspected history of anaphylaxis 2confirm diagnosis, determine the etiology, give a treatment plan to prevent and treat further episodesB Authors performed a systematic review 2?? studiesB to esta"lish the effectiveness of interventions to manage anaphylaxis U key recommendations: 2iB epinephrine is the drug of first choice to manage anaphylaxis, via intramuscular route into the anterolateral portion of the midthigh 2middle of vastus lateralis muscleB< 2iiB failure or delay in epinephrine administration can Q death risk< 2iiiB anaphylaxis management plans may S severity of su"se!uent reactions< 2ivB venom immunotherapy can S anaphylaxis risk and Q Ho* in patients with severe venom allergy< 2vB prophylactic epinephrine can S severe reactions after anti#snake venom administration< 2viB more research is needed

P)#-A%#$C# &F A"&P*, #&+,$&P0,%,A, A$D ,2# #%#-A",&$ ,$ ,2'4()#%A"#D D,+#A+# 20ella Torre ', )attoo %, )aha+an 51, $arruthers ), Pillai 1, 1tone 6% Allergy 9:;.< =>: 9=>@9A9B

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

IgG.: 2iB ?R of total IgG< 2iiB antiinflammatory properties 2negligi"le "inding to $;!< exchangea"le heavy chains \W8a" arm exchangeX] that prevents cross#linking of antigen< higher affinity toward inhi"itory 8ca(II" than to activatory 8ca(IIa and 8ca(IIIaB IgG. autoanti"odies are pathogenic in some autoimmune disorders 2e g pemphigus vulgaris: IgG. to desmoglein< idiopathic mem"ranous glomerulonephritis: IgG. to P*A#9 receptorB IgG.#related disease 2(0B: 2iB multi#organ fi"roinflammatory disease 2tumefactive lesions rich in T cells and IgG.#positive plasma cellsB< 2iiB unclear pathogenesis 2T%9 cells may have a pathogenic roleB< 2iiiB can affect almost every organ< 2ivB usually affects middle#aged to elderly men< 2vB common clinical manifestations: autoimmune pancreatitis, sialadenitis, or"ital disease 2typically affecting lacrimal glandB, allergic diseases, eosinophilia, Q serum Ig'< 2viB F:R of patients have normal serum IgG. concentrations< 2viiB histology: diffuse lymphoplasmacytic infiltrate rich in IgG.#positive plasma cells, storiform fi"rosis, o"literative phle"itis, Q eosinophils< 2viiiB treatment: corticosteroids, immunosuppressants, rituxima" Authors evaluated the prevalence of atopy, peripheral "lood eosinophilia 2P7'B and Q Ig' in A: patients 29.@-9 yrs oldB with "iopsy#proven IgG.#(0 U 2iB .F patients 2=;RB had Q serum IgG. levels< 2iiB 99 patients 2F;RB were atopic 2similar prevalence of atopy to the J1 general populationB< 2iiiB Z9:R of nonatopic su"+ects had P7' and Q Ig' 2hypothesis: processes inherent to IgG.#(0 itself may contri"ute to P7' and Q Ig'B< 2ivB there was a positive correlation "etween serum IgG. levels and "oth serum Ig' and eosinophil counts

+#)!M BA+A% ")*P"A+# MA* B# A '&&D MA)3#) F&) P)#D,C",$' "0# ),+3 &F A$AP0*%A1,+ ,$ C0,%D)#$ .,"0 F&&D A%%#)'* 21ahiner J), KavuC 1T, 7uyuktiryaki 7, $avkaytar L, KilmaC 'A, Tuncer A, 1ackesen $ Allergy 9:;.< =>: 9=?@9=-B 1erum "asal tryptase 2s7TB: 2iB marker of mast cell activity and "urden< 2iiB marker of anaphylaxis< 2iiiB s7TT;; . ng/m* is a risk factor for hymenoptera venom#induced anaphylaxis 2s7T might "e a marker of an underlying clonal diseaseB Authors evaluated the value of s7T to predict the risk of anaphylaxis in children with food allergy 28AB U 2iB s7T level was significantly associated with the risk of moderate to severe anaphylaxis in children with 8A \L(: ; F]< 2iiB s7T levels T? A and ;. ? ng/m* were associated with ?:R and >:R predicted pro"a"ilities, respectively, of moderate to severe anaphylaxis< 2iiiB children with tree nut or peanut allergy, compared to children with milk or egg allergy, had significantly higher levels of s7T and more severe anaphylaxis episodes

-,"AM,$ D A+ A$ ADJ!$C" "& +!BC!"A$#&!+ A%%#)'#$ ,MM!$&"0#)AP* ,$ A+"0MA",C C0,%D)#$ +#$+,",4#D "& 0&!+# D!+" M,"# 21ahiner J), KavuC 1T, 7uyuktiryaki 7, $avkaytar L, KilmaC 'A, Tuncer A, 1ackesen $ Allergy 9:;.< =>: 9=?@9=-B 5it 0 effects on the immune system: 2iB Q skin "arrier function< 2iiB Q production of antimicro"ial peptides 2d#defensins, cathelicidinB< 2iiiB Q phagocytic activity of macrophages< 2ivB S maturation of dendritic cells< 2vB S differentiation of T%; and T%;A cells< 2viB Q differentiation of Treg cells< 2viiB S function of 7#lymphocytes< 2viiiB S production of Ig'< 2ixB Q I*#;: production "y mast cells %ypovitaminosis 0 has "een associated 2fre!uently "ut not uniformlyB with Q occurrence or severity of allergy 2allergic sensitiCation, recurrent wheeCing, asthma, allergic rhinitis, food allergy, atopic dermatitisB

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

'xposure to aeroallergens 2e g house dust mites \%0)]B in genetically suscepti"le su"+ects U specific T%9 responses to aeroallergens U Ig'#mediated allergic respiratory diseases Allergen immunotherapy: 2iB only treatment that can change the natural history of Ig'#mediated allergies< 2iiB method: administration of the specific allergen progressively to induce tolerance< 2iiiB mechanisms: Q Treg cells, Q specific IgG; and IgG., S specific Ig', S reactivity of mast cells and "asophils< 2ivB routes: su"cutaneous 21$ITB, su"lingual, intralymphatic, epicutaneous Authors studied ?? children with asthma and %0) sensitiCation to evaluate the "eneficial effect of vit 0 as an ad+unct to 1$IT U 2iB ?-R of children had S serum vit 0 levels< 2iiB vit 0 levels correlated negatively with the num"er of asthma attacks< 2iiiB 1$IT and \1$IT e vit 0] gave "etter results than pharmacotherapy alone at the end of ; yr< 2ivB vit 0 might "e "eneficial as an ad+unct to 1$IT in asthmatic children sensitiCed to %0) 2more research is warrantedB

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

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AC5!,)#D C1 ,$0,B,"&) D#F,C,#$C* +0&!%D .# M&$,"&) F&) A++&C,A"#D A$",B&D* D#F,C,#$C*6 2Tohani A, $hua I, Grigoriadou 1, 7uckland )1, *onghurst %6 Ann Allergy Asthma Immunol 9:;.< ;;9: 9=?#9=AB Ac!uired angioedema with $;#I&% deficiency 2A$I0B: 2iB recurrent episodes of "radykinin# mediated angioedema due to $;#I&% consumption< 2iiB pathophysiology: lymphoproliferative disease, autoimmune disease, )GJ1 2monoclonal gammopathy of unknown significanceB U autoanti"ody production U activation of the classical complement pathway U consumption of $;!, $;#inh and $. U Q activity of 8MII and kallikrein U Q production of "radykinin U A$I0< 2iiiB usually presents after .: yrs of age< 2ivB clinical manifestations: recurrent swelling of su"cutaneous tissues 2face, hands, arms, legs, "uttocks, genitalsB, a"dominal organs 2stomach, gut, "ladderB or upper airways 2larynxB, unresponsive to antihistamine or corticosteroids Authors report F patients with A$I0, lymphoproliferative disease and anti"ody deficiency U 2iB Patient ;: 9>#yr#old woman with A*P1 due to FAS gene mutation< acute lympho"lastic leukemia with remission after chemotherapy< hypersplenism that re!uired splenectomy< autoimmune hemolysis< immunodeficiency 2recurrent respiratory infections< S IgG levels< S anti"ody responsesB that re!uired I5IG< A$I0 2swelling of left hand and arm< S $., $;! and $;#I&% levelsB treated with tranexamic acid prophylaxis and $;#I&% during attacks 2iiB Patient 9: ??#yr# old woman with A$I0 2recurrent cutaneous swelling and a"dominal pain< S $., $;! and $;# I&% levelsB re!uiring tranexamic acid< hemolytic anemia that re!uired splenectomy< low#grade 7#lymphoplasmacytic lymphoma< immunodeficiency 29 episodes of 1 pneumoniae sepsis< S IgG and IgA levels< S anti"ody responses to pneumococcal vaccinesB that re!uired I5IG 2iiiB Patient F: .A#yr#old man with A$I0 2recurrent facial and hand swelling< S $., $;! and $;#I&% levelsB treated with tranexamic acid prophylaxis and icati"ant or $;#I&% during attacks< )GJ1< mild immunodeficiency 2S IgG and Ig) levels< S anti"ody response to pneumococcal vaccinesB AuthorVs commentary: A$I0 patients should "e monitored for lymphoproliferative disease and anti"ody deficiency

#FF#C" &F MA"#)$A% 78 FA""* AC,D +!PP%#M#$"A",&$ &$ ,$FA$" A%%#)'* 2$iaccio $', Girdhar ) Ann Allergy Asthma Immunol 9:;.< ;;9: ;>;#;>.B Allergic diseases have dramatically increased 2pro"a"ly due to environmental and lifestyle factors< unlikely due to a genetic causeB U proposals to stop this trend: 2iB S allergen exposure 2e g house dust mitesB< 2iiB Q allergen exposure at early age 2e g foodB< 2iiiB promote ;st contacts with allergens in a more `tolerogenic environmentV 2e g use of pro"iotics, pre"iotics, vit A, vit 0, "reastfeeding, fF fatty acidsB< 2ivB restore tolerance to allergens 2e g immunotherapyB fF polyunsaturated fatty acids 2n#F PJ8AsB: 2iB cognitive and cardiac "enefits< 2iiB Q WantiinflammatoryX gut micro"iome< 2iiiB S Ig' synthesis 2e g g#linolenic acid from green leavesB n#= PJ8As: 2iB found in grains 2e g cornB< 2iiB convert into arachidonic acid 2precursor of PG'9 and *T7.B< 2iiiB most Americans eat 9? times more n#= PJ8As than n#F PJ8As 2e g "eef is no longer considered a n#F PJ8A#rich food "ecause cows are now corn#fed rather than grass#fedB 1upplementation with the n#F PJ8As docosahexaenoic acid 20%AB and eicosapentaenoic acid 2'PAB during pregnancy can S risk of atopic diseases, particularly food allergy and ecCema

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

Important remarks: 2iB if n#F PJ8A supplementation is immunomodulatory, the re!uired doses are likely greater than the doses studied to enhance developmental outcomes and the current commercially availa"le doses< 2iiB n#F PJ8A supplementation is likely to "e cost#effective )ore evidence is re!uired to: 2iB determine the appropriate dosing, timing and duration of n#F PJ8A supplementation< 2iiB reveal its effect on asthma and allergic rhinitis< 2iiiB demonstrate if a diet high in green leafy vegeta"les, fish and grass#fed "eef can S the atopic epidemic &)

#1#)C,+#(,$D!C#D D*+P$#A M&)# "0A$ -&CA% C&)D D*+F!$C",&$ %A)*$'&MA%AC,A 23ein"erger ) Ann Allergy Asthma Immunol 9:;.< ;;9: 9A:#9A;B

Authors discuss a"out the most proper way to approach the patient with exercise#induced dyspnea U differential diagnosis: exercise#induced "ronchospasm, exercise#induced vocal cord dysfunction, exercise#induced laryngomalacia, cardiac disease, primary hyperventilation, restrictive physiology, lactic acidosis U monitored exercise challenge 2cardiac and respiratory function, "lood p% and P$L9, laryngeal motionB can help to esta"lish the correct diagnosis Lptions to treat exercise#induced 5$0: speech therapy, prophylactic ipratropium Lptions to treat exercise#induced laryngomalacia: speech therapy, laser laryngoplasty

0,+"&)* &F A%%#)',C D,+#A+#+ A$D %!$' CA$C#) ),+3 2'l#Gein ), Parent )#', 1iemiatycki 6, (ousseau )#$ Ann Allergy Asthma Immunol 9:;.< ;;9: 9F:#9F=B Antigenic hypothesis: immune#stimulating conditions 2e g allergiesB U Q cell proliferation and stimulation U Q random mutations in dividing cells U Q cancer risk Immune surveillance hypothesis: immune#stimulating conditions 2e g allergiesB U Q immune system activity and surveillance U S cancer risk Authors examined the association "etween self#reported history of allergic diseases and lung cancer occurrence using data from a case#control study U asthma, ecCema and hay fever were inversely associated with lung cancer

,$")A-#$&!+ 9 A'&$,+"+ A$D +#-#)# P#D,A"),C A+"0MA #1AC#)BA",&$ ",M# F&) A C%&+#) %&&3 A" "#)B!"A%,$#6 24antor 07, Phipatanakul 3 Ann Allergy Asthma Immunol 9:;.< ;;9: ;-AB Acute exacer"ations: 2iB main cause of mor"idity and mortality in patients with asthma< 2iiB inhaled d9#agonists are the mainstay of emergency asthma management Intravenous d9#agonists 2ter"utalineB: 2iB can improve severe asthma exacer"ations refractory to inhaled "ronchodilators< 2iiB early initiation may prevent progression to respiratory failure< 2iiiB presumed advantage: a"ility to access smooth muscle receptors on o"structed distal airways not accessi"le to aerosoliCed drugs< 2ivB prospective trials evaluating the "enefit of intravenous ter"utaline in acute asthma are needed

%&$'("#)M F&%%&.(!P &F ,2#(M#D,A"#D F&&D A%%#)'* D#"#)M,$,$' P#)+,+"#$C# -#)+!+ C%,$,CA% "&%#)A$C# 27urks A3, *and )% Ann Allergy Asthma Immunol 9:;.< ;;9: 9::#9:=B

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

Ig'#mediated 8A: 2iB increasing prevalence worldwide 2F#-R of the populationB< 2iiB impact: S Ho*, high costs, mortality risk< 2iiiB T;A: foods have "een reported to cause allergic reactions< 2ivB main allergenic foods 2comprise >:R of casesB: milk, egg, peanut, tree nuts, wheat, soy"eans, seafood< 2vB diagnosis: specific Ig' detection "y skin prick test 21PTB or in vitro testing 2sIg', $(0B, "asophil activation test, oral food challenge 2L8$B< 2viB conventional treatment: allergen avoidance 2does not prevent accidental exposureB, epinephrine autoin+ectors, nutritional counseling, 2viiB optimal treatment: restore tolerance "y exposing patients to gradually increasing doses of allergen 2immunotherapyB 8ollow#up to evaluate spontaneous resolution of Ig'#mediated 8A: 2iB follow#up should "e individualiCed< 2iiB milk, egg, soy and wheat allergy are likely to resolve U reevaluate yearly< 2iiiB peanut, tree nut, fish and shellfish allergy are not likely to resolve U reevaluate every 9#F yrs< 2ivB L8$: "est test to evaluate the resolution or persistence of 8A< 2vB skin and in vitro testing can varia"ly predict L8$ results 8actors that influence the decision to perform an L8$: 2iB natural history of the 8A 2e g fish allergy is not likely to resolve while milk allergy is usually outgrownB< 2iiB nutritional value of the culprit food< 2iiiB specific culprit allergen 2e g ovomucoid allergy is more persistent than oval"umin allergy< casein is more sta"le than whey< Ara h ;, 9, F and > are heat#sta"leB< 2ivB time and severity of previous allergic reactions< 2vB patientVs age, comor"idities, sociocultural factors and interest in consuming the food< 2viB results of allergy testing< 2viiB capa"ility of avoiding the culprit food< 2viiiB tolerance to "aked food 2in cases of egg or milk allergyB Allergy testing to predict 8A resolution: 2iB no single test can "e used alone to predict tolerance< 2iiB in the initial diagnosis of 8A, 1PTs have low sensitivity compared with L8$s< 2iiiB in patients with confirmed 8A, 1PTs and sIg' have high sensitivity and &P5 with regard to L8$ outcomes< 2ivB decision points of allergy testing are food#specific 2e g a milk#specific Ig' level h? kJA/* predicts a >:R chance of tolerating heated milkB

%*MP0&P#$,A ,$D!C#D B* #"A$#)C#P" 2Pepper A&, Talre+a &, $owan G), Glaum )$, *ockey (8 Ann Allergy Asthma Immunol 9:;.< ;;9: 9=9#9=FB T&8#g inhi"itors: 2iB can induce lymphocyte apoptosis< 2iiB can cause leukopenia, neutropenia, throm"ocytopenia and pancytopenia< 2iiiB 7ritish 1ociety for (heumatology recommends $7$ count monitoring in patients taking T&8#g inhi"itors Authors report the case of a =.#yr#old woman with seronegative rheumatoid arthritis and rheumatoid#associated lung disease who developed asymptomatic lymphopenia 2lymphocyte countcF:A/i*< S $0F, $0., $0- and $0;> cell counts< IgGc=== mg/d*< S lymphocyte proliferation assays to antigens and mitogensB after ? doses of etanercept 2?: mg/wkB *ymphocyte count was normal 29,:;?/m*B one wk "efore etanercept initiation *ymphopenia resolved F months after etanercept discontinuation

)AD,&C&$")A+"(,$D!C#D ,&D,D# +,A%AD#$&PA"0* A$D $#!")&P0,%,C D#)MA"&+,+ 28ok 61, (amachandran T, 7erce ), 1mith 37 Ann Allergy Asthma Immunol 9:;.< ;;9: 9=9#9=FB %ypersensitivity reactions to iodinated radiocontrast medium 2i($)B: 2iB hypersensitivity to the i($) carrier molecule rather than iodine itself< 2iiB immediate reactions 2I%(sB can "e Ig'# mediated or non#Ig'#mediated 2mechanisms: altered "lood osmolarity and ion concentration, direct activation of mast cells and "asophils, activation of complement system, activation of

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

"radykinin#induced contact systemB< 2iiB delayed reactions 20%(sB: mostly mild reactions 2e g maculopapular exanthema, delayed urticariaB, serious reactions can occur 2e g 1tevens# 6ohnson syndrome, 1weet syndrome \fe"rile neutrophilic papules, pla!ues and nodules]B )ild I%(s: 2iB ionic i($): ;:R of procedures< 2iiB nonionic i($): ;R of procedures 1evere I%(s: 2iB ionic i($): : 9R of procedures< 2iiB nonionic i($): : :9R of procedures 0rug challenge with i($): intravenous administration at .?#min intervals using ? cc, ;? cc, F: cc and ?: cc 2cumulative dose c ;:: ccB Iodine can cause: 2iB iodide mumps: acute sialadenitis, pathogenic mechanism is not fully defined 2physicochemical reaction to excessive iodide ion^B, renal insufficiency is a risk factor 2iodine is excreted "y the kidneysB, likely recurrent after exposure< 2iiB iododerma: rare painful neutrophilic pustular cutaneous reaction, dermal microa"scesses are a cardinal feature, pathogenic mechanism: inflammatory response to high iodide concentrations^ Authors report the case of a A-#yr#old man 2medical history: hypertension, chronic renal insufficiency, dia"etes mellitus, hypothyroidism, aortic aneurysmB who developed acute sialadenitis 2severe pain and swelling in the su"mental and parotid areaB and a 1weet syndrome#like eruption 2multiple, painful, dark purplish nodules and "listers, fever, Q $(P, skin "iopsy consistent with 1weet syndromeB after administration of i($) 2;:: m* of Jltravist FA:, containing A=> mg/m* of iopromide \FA: mg/m* of iodine]B AuthorVs commentary: iodide mumps was likely caused "y a direct reaction to iodine while 1weet#like syndrome was pro"a"ly mediated "y hypersensitivity to i($)

"(C#%% B,&%&'* ,$ ,MM!$&"0#)AP* 21teinke 63, *awrence )G Ann Allergy Asthma Immunol 9:;.< ;;9: ;>?#;>>B Allergen immunotherapy 2AITB: only therapy that has proved to provide long#term "enefit and modulation of allergic disease )echanisms of AIT 2more esta"lished for su"cutaneous ITB: 2iB Q specific T regulatory cells< 2iiB Q I*#;:@secreting 7 regulatory cells 27(; cells \$09?high, $0A;high, $0AFlowB< 2iiiB deletion, anergy and suppression of effector T cells 2T%9, T%;, T%;AB< 2ivB Q specific IgG. and IgA< 2vB S specific Ig' 2poor correlation with clinical improvementB< 2viB very early desensitiCation of mast cells and "asophils 2within hours< mediated "y upregulation of histamine 9 receptors^B< 2viiB S migration and activation of allergy effector cells 2eosinophils, "asophils, mast cellsB )echanism of action of T regulatory cells: 2iB production of I*#;: and TG8#d< 2iiB expression of suppressive costimulatory molecules 2$T*A#., P0#;B< 2iiiB consumption of I*#9< 2ivB production of adenosine "y $0F> and $0AF< 2vB consumption of aminoacids 7ee venom 1$IT U I*#;:#producing peripheral T regulatory cells appear !uickly 2within A daysB "ut full tolerance may re!uire F#? yrs of treatment 8re!uency of 8el d ;#specific T cells in allergic patients: ;/A,::: @ ;/F:,::: 2similar fre!uencies have "een found in other allergen#specific T cellsB

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

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AD-A$C#+ ,$ P#D,A"),C A+"0MA ,$ 2018 C&&)D,$A",$' A+"0MA CA)# 21Cefler 16 6 Allergy $lin Immunol 9:;.< ;FF: =?.#=;B Authors review important advances in pediatric asthma reported in the 6ournal of Allergy and $linical Immunology in 9:;F Advances in pediatric asthma: @iA maternal microchimerism might protect against the development of asthma< @iiA different T*( signaling mechanisms might "e involved in the pathogenesis of atopic and nonatopic asthma< @iiiA many pregnant women incorrectly stop or reduce their asthma medications< @ivA o"esity during pregnancy was associated with Q risk of asthma and wheeCing in offspring< @vA clinical predictive scores for asthma are useful "ecause currently no single "iomarker can predict asthma development< @viA lipid#activated nuclear receptors can control macrophage/dendritic cell function and allergy development 2therapeutic targetB< @viiA increased airway smooth muscle at preschool age is associated with asthma at school age< @viiiA I*#FF is a relatively steroid#resistant mediator that promotes airway remodeling in patients with severe therapy#resistant asthma 2therapeutic targetB< @ixA mild early viral wheeCe is associated with asthma remission while atopic multiple#trigger wheeCe associates with asthma persistence< @xA 8'&L might "e a "etter marker for asthma phenotypes in preschool children compared to measures of airway hyperresponsiveness and lung function< @xiA acetaminophen use may Q eosinophilic inflammation and asthma risk< @xiiA variants at the ;A!9; locus were associated with childhood asthma and specific wheeCing phenotypes< @xiiiA %(5 infections can Q asthma risk and glucocorticoid resistance< @xivA (15 "ronchiolitis is a risk factor for asthma< @xvA early use of paliviCuma" 2anti#(15 mA"B reduced wheeCing days during the ;st yr of life< @xviA long#term oral corticosteroid use is a risk factor for severe or atypical varicella virus infection 2early use of 5G5 immune glo"ulin or antiviral therapy after exposure is encouragedB< @xviiA air pollution Q asthma risk 2e g chronic diesel exhaust particle can Q 8oxpF methylation and Q risk of childhood wheeCing and asthmaB< @xviiiA "isphenol A 2widely used in food container liningsB can Q asthma risk in children< @xixA farm exposure and `tolerogenic micro"iotaV S asthma risk< @xxA mouse allergen can "e a ma+or risk factor of asthma in ur"an homes< @xxiA maternal smoking, stress and o"esity were independently associated with childhood wheeCe< @xxiiA stress in later childhood may Q risk of adult#onset asthma< @xxiiiA early introduction of wheat, rye, oats, "arley, fish and egg seems to S risk of asthma, allergic rhinitis and atopic sensitiCation< @xxivA longer duration of exclusive "reast#feeding was protective against the development of nonatopic "ut not atopic asthma< @xxvA weight loss and environmental control measures might Q asthma control< @xxviA increased *P1#induced T&8#g production at early life was associated with childhood asthma< @xxviiA the Pediatric Asthma $ontrol and $ommunication Instrument accurately measured asthma control in 'nglish# and 1panish#speaking children< @xxviiiA strategies to improve asthma management: Q medication adherence, Q use of guidelines< @xxixA impulse oscillometry can detect small#airways dysfunction at an early age 2important to start early therapyB< @xxxA a specific "ronchodilator cutoff criterion 2e g [;9R increase in 8'5;B may not "e accurate for asthma diagnosis in children< @xxxiA high#resolution $T and )(I with F%e can detect ventilatory a"normalities more accurately, especially in the peripheral airways and alveolar spaces< @xxxiiA !uantitative imaging of the lungs is an evolving tool to understand airway pathophysiology at early life< @xxxiiiA several "iomarkers hold promise for selecting and monitoring asthma therapy 2e g 8'&L, serum Ig', periostin, urinary leukotrienesB< @xxxivA 8'&L 2indicator of local inflammationB and "lood eosinophilia 2indicator of systemic inflammationB offered independent information in
But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

relation to wheeCe prevalence, asthma diagnosis and asthma events< @xxxvA *T0. levels and methacholine "ronchial provocation can predict response to antileukotriene therapy< @xxxviA protectin 0; is an anti#inflammatory lipid mediator 2S production in patients with severe asthmaB< @xxxviiA chitinase#like protein K4*#.: is related to asthma and airway remodeling 2Q levels in children with severe asthmaB< @xxxviiiA variations in '(4 pathway genes might influence asthma development< @xxxixA patients with mild asthma have an altered micro"ial composition in the respiratory tract 2similar to that o"served in patients with more severe asthmaB< @xlA micro(&As regulate key pathogenic mechanisms in allergic inflammation 2e g activation and polariCation of T cells, eosinophil development, epithelial activationB< @xliA micro(&As are potential "iomarkers and therapeutic targets< @xliiA oral corticosteroids do not appear useful during acute lower respiratory tract illnesses in preschool children with recurrent wheeCe< @xliiiA prenatal and/or early#life use of pro"iotics S risk of atopic sensitiCation "ut might not S risk of asthma/wheeCe< @xlivA in a real#world study, patients 2[;9 yrs of ageB were more adherent to I$1 e *A7A than I$1 e antileukotriene< @xlvA I$1 e *A7A therapy appears more effective than I$1 e antileukotriene therapy< @xlviA "oth 1$IT and 1*IT are "eneficial for asthma patients 2evidence is stronger for 1$ITB< @xlviiA for every . patients with well#controlled asthma who stop regular use of low#dose I$1, ; will have an exacer"ation in the next = months that is attri"uta"le to stopping I$1 U step#down therapy should "e done carefully 2avoid step#down at the cold seasonB< @xlviiiA new drugs for asthma: A)G -?F 2a potent, selective, orally "ioavaila"le, dual antagonist of 0#prostanoid and $(T%9B, le"rikiCuma" 2anti@I*#;F mA"B, dupiluma" 2anti#I*#.(g mA"B, "enraliCuma" 2anti#I*#?( mA"B, "ronchial thermoplasty 8uturistic approach in asthma: use of clinical, la"oratory, imaging, respiratory#function, histologic and genetic data to identify specific asthma phenotypes and endotypes U give individualiCed therapy 2e g leukotriene#induced asthma U give antileukotrienesB

A$ A%'&),"0M F&) ")#A",$' C0)&$,C !)",CA),A .,"0 &MA%,4!MAB D&+# ,$"#)-A% +0&!%D B# ,$D,-,D!A%,4#D 2Jysal P, 'ller ', )ortC $G, 7indslev#6ensen $ 6 Allergy $lin Immunol 9:;.< ;FF: >;.#>;?B $hronic urticaria 2$JB: 2iB definition: recurrent wheals for T= wks 2concomitant angioedema may occurB< 2iiB lifetime prevalence: ;#9:R of the population< 2iiiB impact: significant mor"idity, S Ho* 2similar to angina pectorisB, high costs< 2ivB main classification: spontaneous 2no clear triggers< ?:R of cases are `autoimmuneVB, induci"le 2triggered "y stimuli such as cold, heat, touch, pressure, vi"ration, sunlight, water or exerciseB, spontaneous and induci"le urticaria can co# occur in the same patient< 2vB ;st#line treatment: anti#%; at usual dosing 2?:R of patients may not respondB< 2viB 9nd#line treatment: up to !uadruple dose of anti#%; 2?:R of patients may not respond U antihistamine#refractory $JB< 2viiB other reported therapies: mast cell#sta"iliCing drugs 2e g ketotifenB, antileukotrienes, corticosteroids 2topical and systemicB, "iologic therapy 2e g omaliCuma", anti#T&8#g, I5IGB, epinephrine, desensitiCation, moisturiCers, J5 phototherapy, cyclosporin A, sulfasalaCine, chloro!uine, dapsone, calcineurin inhi"itors, mycophenolate, pseudoallergen#free diet, anticholinergic agents, androgens, selective serotonin reuptake inhi"itors, tranexamic acid, psoralens, plasmapheresis, anticoagulants< 2viiiB prognosis: ?:R of cases may resolve spontaneously within ; yr< A?R of cases within ? yrs LmaliCuma": 2iB recom"inant humaniCed anti#Ig' mA" U "inds to free Ig' U S Ig' "inding to its receptors, S expression of Ig' receptors U S Ig'#mediated inflammation< 2iiB approved for \uncontrolled asthma e serum Ig' levels "etween F: and A:: IJ/m* e sensitiCation to perennial allergens]< 2iiiB dose is calculated in a chart, "ased on "ody weight and pretreatment Ig' levels

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

2"etween F: and A:: IJ/m*B< 2ivB alternative formula when the chart is not suita"le: [: :;= mg/kg per Ig' unit every .#wk period< 2vB suggested maximum dose: A?: mg every . wks< 2viB efficacy has also "een documented in chronic urticaria, mastocytosis, anaphylaxis 2idiopathic, exercise#inducedB, eosinophilic chronic rhinosinusitis, atopic dermatitis Authors report an algorithm for treating antihistamine#refractory $J with omaliCuma" in a dose# individualiCed "asis U 2iB 9A patients 2= children and 9; adultsB were included< 2iiB 9F patients had spontaneous $J, ;; patients had induci"le $J 2e g delayed pressure urticaria, cold urticaria, urticaria factitia, heat contact urticariaB< 2iiB ;? patients achieved excellent disease control with a maintenance dose of omaliCuma" ;?: mg every ? to - wks 2F of them could stop omaliCuma" without any relapseB< 2iiiB - patients achieved excellent disease control with a maintenance dose of omaliCuma" F:: mg every . to - wks< 2ivB . patients did not respond to omaliCuma" F:: mg every week< 2vB no serious adverse events were reported during the study AuthorVs commentary: omaliCuma" 2individualiCed regimenB can "e an effective and safe therapy for patients with antihistamine#refractory $J 2"oth spontaneous and physicalB

A!"&,MM!$,"* D!# "& )A' D#F,C,#$C* A$D #+",MA"#D D,+#A+# ,$C,D#$C# ,$ )A'1:2 M!"A",&$+ 2$hen 4, 3u 3, )athew 0, Ghang K, 7rowne 14, (osen *7, )c)anus )P, Pulsipher )A, Kandell ), 7ohnsack 68, 6orde *7, &otarangelo *0, 3alter 6' 6 Allergy $lin Immunol 9:;.< ;FF: --:#--9B (ecom"inase activating gene 2(AGB ; and 9: proteins that play an essential role in the generation of T# and 7#cell receptors (AG;: 0&A "inding and cleavage< (AG9: essential cofactor for (AG; function (AG mutations have diverse clinical presentations: 2iB T#/7#/&4e severe com"ined immunodeficiency 21$I0B< 2iiB Lmenn syndrome< 2iiiB $0.e T#cell lymphopenia< 2ivB hyper#Ig) syndrome< 2vB immunodeficiency with aj T#cell expansion and granulomas Authors report 9 si"lings with early#onset recurrent infections 2viral, "acterialB and autoimmune features 2anemia, neutropenia, ecCema, nephrotic syndromeB U la"oratory analysis: mild lymphopenia, S naive $0.e T#cell counts, Q IgG/Ig) autoanti"odies 2including anti@I8&#gB U genetic analysis: compound heteroCygous (AG; mutations 2c ;.9:$TT \p Arg.A.$ys]< c 9>.>delA \p *ys>-FAsnfsM>]B U treatment: ;:/;: %*A#matched %1$T 2one children responded very well, the other had several episodes of G5%0 and concern for graft failureB U family testing: healthy mother 2carrier of the c 9>.>delA mutationB had several autoanti"odies AuthorVs commentaries: 2iB (AG;/9 mutations may result in com"ined immunodeficiency with autoimmune cytopenias and/or organ#specific autoimmune disease 2incomplete penetrance is possi"leB< 2iiB autoanti"ody generation may depend on an underdeveloped thymus with S AI(' expression< 2iiiB (AG;/9 mutations may contri"ute to unexplained immune dysregulation in the general population 2e g the c 9>.>delA mutation in (AG;, even in heteroCygous state, can result in autoanti"ody productionB< 2ivB patients with moderate#to#severe infections, lymphopenia and autoimmune features should "e screened for (AG;/9 mutations

CA)D; M!"A",&$+ %,$3#D "& +!BC!"A$#&!+ P0A#&0*P0&M*C&+,+ A$D "01< C#%% D#F,C,#$C,#+ 23ang M, 3ang 3, *in G, 3ang M, *i T, Ku 6, *iu 3, Tong G, Mu K, Ghang 6, Guan *, 0ai *, Kang K, %an 3, *i ( 6 Allergy $lin Immunol 9:;.< ;FF: >:?#>:-B

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

Phaeohyphomycosis: group of superficial, cutaneous, su"cutaneous or systemic infections caused "y T;:: species of dematiaceous fungi< characteristics: dematiaceous yeast#like cells, hyphae, pseudohyphae 2sclerotic "odies, characteristics of chromo"lastomycosis, are a"sentB Phialophora verrucosa: 2iB may cause su"cutaneous Phaeohyphomycosis 2early onset, resistant to many systemic antifungalsB< 2iiB isolated from soil, wood and rotting vegetation worldwide $A(0>: 2iB adaptor protein in antifungal defense 2fungal recognition "y 0ectin#;, 0ectin#9 and )incle on macrophages and 0$s U formation of the $A(0>@7$*;:@)A*T; complex U &8# k7 activation U production of inflammatory cytokines U T%;A#cell differentiationB< 2iiB $A(0> deficiency U S T%;A#cell differentiation U chronic mucocutaneous candidiasis Authors report . $hinese patients with phaeohyphomycosis caused "y P verrucosa 2persistent red pla!ues and nodules on the face< no history of other opportunistic infectionsB U histologic analysis: intense inflammatory infiltrations with dematiaceous hyphae, P verrucosa was isolated U la"oratory analysis: S T%;A#cell counts, S serum levels of T%;A cytokines 2I*#;A, I*#99B, S expression of mature $A(0> protein, S production of inflammatory cytokines 2I*#=, T&8#g, I*# ;g, I*#9Fp;>B from macrophages and immature 0$s after stimulation with P verrucosa spores U genetic analysis: mutations in "AR#$ gene 29 compound heteroCygous mutations in patient ; \c ;>;#;>9insTG$T and c .A9$TT, p *=.fsM?> and p H;?-M]< ; homoCygous frameshift mutation in patients 9, F and . \c -;>#-9:insG, p 09A.fsM=:]B U intriguing feature: patients did not have $andida infections "AR#$ mutations can result in T%;A#cell defects and infections "y opportunistic filamentous fungi such as Phialophora verrucosa

CD4;d(#1P)#++,$' $#!")&P0,%+ D,FF#)#$",A"# A"&P,C F)&M $&$A"&P,C ,$D,-,D!A%+ 21igua 6A, 7uelow 7, $heung 01, 7uell ', %unter 0, 4lancnik ), Grayson )% 6 Allergy $lin Immunol 9:;.< ;FF: >:;#>:.B Authors show that: 2iB atopic su"+ects had a significantly higher fre!uency of $0.>d#expressing neutrophils in the peripheral "lood and nasal lavage compared to nonatopic controls< 2iiB $0.>de neutrophils are recruited to the nasal mucosa in response to an allergen challenge AuthorVs commentary: $0.>de neutrophils may have a pathogenic role in allergic diseases

,MM!$&"0#)AP* .0A" %,#+ B#*&$D 2$asale T7, 1tokes 6( 6 Allergy $lin Immunol 9:;.< ;FF: =;9#=;>B Immune tolerance: nonresponsiveness of the adaptive immune system or active Treg cell response to antigens< mechanisms: Treg generation, anergy/deletion of reactive lymphocytes Immune tolerance is essential to prevent: 2iB self#destruction< 2iiB inflammatory response to "eneficial or harmless exogenous molecules 2e g food, commensal "acteria, allergensB *oss of immune tolerance U allergic or autoimmune disorders 2e g exposure to aeroallergens in genetically suscepti"le su"+ects U specific T%9 responses to aeroallergens U Ig'#mediated allergic respiratory diseasesB Allergen immunotherapy 2AITB: 2iB only therapy that can alter the natural history of Ig'#mediated allergies 2su"lingual IT for .#? yrs generated sustained "enefits for A#;9 yrsB< 2iiB o"+ective: restore tolerance to specific allergens< 2iiiB has "een widely used to treat asthma, allergic rhinitis

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

and venom allergy< 2ivB promising therapy for atopic dermatitis and food allergy< 2vB effective AIT should change a patientVs allergen#specific response from an allergic profile 2T%9B to a nonallergic profile 2Treg, T%;B< 2viB current modalities used in clinical practice: su"cutaneous IT 2approved in J1B, su"lingual IT 2not approved in J1B \it is unclear which modality has "etter outcomes]< 2viiB limitations: side effects 2especially with 1$ITB, long treatment duration 2[F yrsB< insufficient efficacy 2except for venom IT \[>:R efficacy]B, 2viiiB in patients with respiratory allergies, _?R of candidates for AIT actually receive it< 2ixB it is necessary to improve AIT efficacy, convenience and safety %ow to Q efficacy and safety of AIT^ 2iB adding omaliCuma" 2anti#Ig' mA"B< 2iiB adding ad+uvants 2e g aluminum salts to slower allergen release from in+ection siteB< 2iiiB using modified allergens 2e g allergoids \altered allergens using formaldyde or glutaraldehyde to S allergenicity while preserving immunogenicity], recom"inant hypoallergenic allergens, tolerogenic peptides, recom"inant 0&A vaccinesB, 2ivB adding immune response modifiers 2monophosphoryl lipid A \T*(#. agonist], $PG#containing 0&A \T*(#> agonist], T*(- agonists, pro"iotics, "acterial lysatesB< 2vB using other administration routes 2epicutaneous, intralymphatic, intradermal, intranasal, oralB< 2viB personaliCing LIT schemes

%&.(AFF,$,"* A%%#)'#$(+P#C,F,C ,2# ,$ C&)D B%&&D A$D AFF,$,"* MA"!)A",&$ AF"#) B,)"0 24amemura &, 4awamoto &, &akamura (, Teshima (, 8ukao T, 4id % 6 Allergy $lin Immunol 9:;.< ;FF: >:.#>:?B Ig': 2iB important role in defense against some parasitic infections< 2iiB its production is dysregulated in allergic diseases< 2iiiB cord "lood and new"orn "lood often contain allergen# specific Ig' 2allergens cross the placenta U intrauterine allergen sensitiCationB< 2ivB high#affinity Ig' is generated through se!uential class switching 2iUaUbB, in which an intermediary IgG phase is necessary for affinity maturation "y somatic hypermutation< 2vB low#affinity Ig' is generated through direct class switching 2iUbB and is much less mutated Authors show the presence of low#affinity ovomucoid#specific Ig' in cord "lood and detected affinity maturation after "irth 2high#affinity ovomucoid#specific Ig' in peripheral "lood of =# and ;.#month#old infantsB 8urther studies are re!uired to assess: 2iB the prognostic value of low#affinity Ig' in cord "lood< 2iiB the mechanisms of affinity maturation after "irth

M#C0A$,+M+ &F A%%#)'#$(+P#C,F,C ,MM!$&"0#)AP* M!%",P%# +!PP)#++&) FAC"&)+ A" .&)3 ,$ ,MM!$# "&%#)A$C# "& A%%#)'#$+ 2Akdis ), Akdis $A 6 Allergy $lin Immunol 9:;.< ;FF: =9;#=F;B Allergen immunotherapy 2AITB: 2iB only therapy that can alter the natural history of Ig'#mediated allergies< 2iiB o"+ective: restore tolerance to specific allergens )echanisms of AIT 2more esta"lished for su"cutaneous ITB: 2iB Q specific T regulatory cells< 2iiB Q I*#;:@secreting 7 regulatory cells 27(; cells \$09?high, $0A;high, $0AFlowB< 2iiiB deletion, anergy and suppression of effector T cells 2T%9, T%;, T%;AB< 2ivB Q specific IgG. and IgA< 2vB S specific Ig' 2poor correlation with clinical improvementB< 2viB very early desensitiCation of mast cells and "asophils 2within hours< mediated "y upregulation of histamine 9 receptors^B< 2viiB S migration and activation of allergy effector cells 2eosinophils, "asophils, mast cellsB

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

)echanism of action of $0.e Treg cells: 2iB production of I*#;: and TG8#d< 2iiB expression of suppressive costimulatory molecules 2$T*A#., P0#;B< 2iiiB consumption of I*#9< 2ivB production of adenosine "y $0F> and $0AF< 2vB consumption of aminoacids Lther cells with regulatory activity: $0-e Treg cells, dou"le#negative 2$0.#$0-#B Treg cells, 7 regulatory cells, &4 regulatory cells 0ominant T#cell su"sets against environmental allergens: 2iB in healthy su"+ects U allergen# specific I*#;:@secreting Treg cells< 2iiB in allergic su"+ects U I*#.@secreting T%9 cells 8uturistic therapy: use of readily#accessi"le cost#effective "iomarkers 2e g in "lood, saliva, nasal secretion or skinB to define an AIT#responsive endotype of allergic diseases 'xample: levels of $;! and sta"ilin ; were increased in AIT#responders compared to AIT#nonresponders $hallenges to use prophylactic AIT: 2iB early#life intervention is re!uired 2safety concernsB< 2iiB lack of early "iomarkers to predict allergy TG8#d signaling U induction of (J&M; and (J&MF U induction of the F%&'3 promoter U generation of 8LMPF#expressing Treg cells )utations in F%&'3 gene U immune dysregulation, polyendocrinopathy, enteropathy, M#linked 2IP'MB syndrome I*#;: signaling U I*#;:( activation U Tyk#9 activation U activation of the phosphatase 1%P# ; U dephosphorylation 2within minutesB of $09- and I$L1 U inhi"ition of effector T cells I*#;: family: 2iB I*#;>: produced "y 7 cells and monocytes in response to G)#$18< promotes I*#. and I*#;F production 2iiB I*#9:: produced "y keratinocytes and monocytes< involved in skin inflammation 2e g psoriasisB 2iiiB I*#99: produced "y activated T cells and mast cells< induce acute#phase reactants "y hepatocytes 2ivB I*#9.: produced "y monocytes, macrophages and T%9 cells< controls cell survival and proliferation< important role in wound healing, psoriasis and cancer 2vB I*#9=: expressed in certain herpesvirus#transformed T cells

P#$,C,%%,$ A%%#)'* A+ A P!B%,C 0#A%"0 M#A+!)# 21olensky ( 6 Allergy $lin Immunol 9:;.< ;FF: A>A#A>-B 8alse#negative diagnosis of drug allergy can lead to severe reactions after exposure 8alse#positive diagnosis of drug allergy can lead to unnecessary avoidance and use of alternative drugs Penicillin 2P&$B allergy: 2iB self#reported in Z;:R of the population< 2iiB confirmed in Z;R of the population< 2iiiB false#positive diagnosis of P&$ allergy U unnecessary use of alternative anti"iotics 2e g !uinolones, vancomycin, clindamycin, cephalosporinsB that Q cost, "acterial resistance 2e g methicillin#resistant 1 aureus, vancomycin#resistant enterococcusB and $ infection< 2ivB reasons for false#positive diagnosis of P&$ allergy: assumption that every rash during P&$ therapy is caused "y P&$ allergy, wrong interpretation of skin or in vitro allergy tests< 2vB appropriate P&$ skin testing can S the rate of false#positive diagnosis of P&$ allergy

P#$,C,%%,!M MA)$#FF#, ,$F#C",&$ A$D ,MPA,)#D ,F$(= ,MM!$,"* ,$ 0!MA$+ .,"0 A!"&+&MA%(D&M,$A$" 'A,$(&F(P0&+P0&)*%A",&$ STAT1 M!"A",&$+ 2*ee PP3, )ao

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

%, Kang 3, $han 4#3, %o )%4, *ee T#*, $han 683, 3oo P$K, Tu 3, *au K#* 6 Allergy $lin Immunol 9:;.< ;FF: ->.#->AB 1TAT;: important molecule for interferonVs signalling 2iB $omplete A( STAT1 deficiency U severe impairment of I8&#a#mediated and I8&#g/d#mediated immunity U life#threatening intracellular "acterial and viral diseases 2iiB Partial A( STAT1 deficiency U mild impairment of I8&#a#mediated and I8&#g/d#mediated immunity U milder intracellular "acterial and viral diseases< 2iiiB 0ominant negative STAT1 mutations U impairment of I8&#a#mediated immunity U suscepti"ility to myco"acterial diseases< 2ivB A0 gain#of#function 2GL8B STAT1 mutations U S production of T%;A cells U fungal infections, autoimmunity, esophageal carcinoma GL8 STAT1 mutations U Q response to interferons and I*#9A U impaired function of 1TATF U T%;A#cell deficiency U suscepti"ility to certain fungal 2e g $)$B and "acterial infections, autoimmunity 2e g hypothyroidism, autoimmune hepatitis, 1*', type I dia"etes mellitusB, malignancy 2e g esophageal carcinomaB &ew reported phenotypes: IP'M#like syndrome< disseminated coccidioidomycosis, histoplasmosis and fusariosis< S 7#cell function Penicillium marneffei: 2iB pathogenic fungus endemic in 1outheast Asia< 2iiB cause opportunistic infections in AI01 patients 2AI01#defining illnessB and other immunodeficiencies 2e g 1$I0, $5I0, hyper#Ig) syndrome, hyper#Ig' syndrome, anti#I8&#a autoanti"odies, dia"etes mellitus, immunosuppressive therapyB< 2iiiB affected individuals often have disseminated disease with rapid progression to multiorgan failure and death< 2ivB pathogenicity: inhalation of conidia U lung disease U dissemination as intracellular yeast via the reticuloendothelial system Authors report F $hinese patients with $)$ and disseminated infection "y Penicillium marneffei U la"oratory analysis: excessive phosphorylation of 1TAT; after stimulation with I8&#g or I8&#a, S $0Fe/I8&#ae T cells, S $0Fe/I*#;AAe T cells, S I8&#a production after stimulation with $ al"icans or P marneffei U genetic analysis: A0 GL8 mutations in the 0&A "inding or coiled#coil domain of STAT1 gene GL8 STAT1 mutations can result in disseminated infections "y Penicillium marneffei

"01< D,FF#)#$",A",&$ CAPAC,"* D#-#%&P+ .,"0,$ "0# F,)+" 8 M&$"0+ &F %,F# 20i+kstra 44, %oeks 17'A, Prakken 76, de (oock 1 6 Allergy $lin Immunol 9:;.< ;FF: ->;#->.B T%;A cells: 2iB important for defense against extracellular "acteria and fungi< 2iiB fre!uent pathogenic role in autoimmunity The neonatal immune system responds differently to the adult system 2e g cytokine production, receptor expression, cell differentiation capacityB Authors show that neonatal T cells: 2iB develop the capacity to differentiate into T%;A cells "efore the age of F months< 2iiB tend to "ecome Treg cells during at least the ;st yr of life U after "irth, immunity against pathogens rises while the immune system remains to have a regulatory profile 2to tolerate allergens and food antigensB

"0# #D,"&)+> C0&,C# 2*eung 0K), 1Cefler 16 6 Allergy $lin Immunol 9:;.< ;FF: ==9#==FB &asal transcriptomics can identify childhood asthma phenotypes 2T%9#high U higher risk for atopy, asthma and rhinitisB

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

>:R of the "ronchial airway transcriptome is expressed in the nasal airway 2highly correlation "etween "oth airway sitesB Q levels of nasal I*#;F are associated with asthma exacer"ations Tiotropium: 2iB improves symptoms and lung function in patients with uncontrolled asthma< 2iiB reduces cough 2mechanism: inhi"ition of T(P5; \transient receptor potential 5;] effect in sensory nervesB RA(1 mutations can result in late#onset com"ined immunodeficiency with autoimmunity ; in ?A.= su"+ects of 'uropean descent might "e homoCygous or compound heteroCygous for pathogenic RA(1)2 mutations 2most of them not presenting with 1$I0 or Lmenn syndromeB RA(1 mutation carriers can "e predisposed to autoimmunity 2the contri"ution of RA(1)2 mutations to autoimmune diseases might "e much higher than previously estimatedB &4 cells can play a role in the promotion of respiratory allergies 2potential therapeutic targetB Genetics can influence the response to inhaled corticosteroids )utations in adenosine deaminase 2A#AB gene U severe com"ined immunodeficiency 21$I0B< autoimmunity can occur 2defective 7#cell tolerance plays a pathogenic roleB Therapeutic options: "one marrow transplantation, gene therapy, enCyme replacement therapy Gene therapy in patients with A0A#1$I0 restored 7#cell proliferation and anti"ody secretion U S risk of autoimmunity

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

P#D,A"),C A%%#)'* A$D ,MM!$&%&'*


AD-#)+# D)!' )#AC",&$+ D!),$' C#F"),A1&$# ")#A"M#$" CA$ CA!+# +#-#)# 0#M&%*+,+ 2*iu 3, Ku 0 Pediatr Allergy Immunol 9:;.: 9?: ;:;#;:9B AuthorVs report the case of a .#yr#old girl with acute laryngotracheal "ronchitis who developed hemolysis 2fever, weakness, a"dominal discomfort, hypotension, anemia \%"c. - g/d*], Q indirect "iliru"in, hemoglo"inuria, ruptured erythrocytes in the "lood smear, positive direct antiglo"ulin test \0AT], splenomegalyB after receiving intravenous ceftriaxone U diagnosis: drug#induced immune hemolytic anemia 20II%AB U succesful treatment: ceftriaxone cessation, oxygen, intravenous fluids, systemic corticosteroids 2authors declare that they made a mistake using steroids in this caseB, sodium "icar"onate 0II%A: 2iB rare condition< 2iiB can "e life#threatening< 2iiiB pathogenic mechanisms are controversial< 2ivB hemolysis usually appears within 9 wks after drug initiation Proposed mechanisms of 0II%A: 2iB "inding of drug#induced anti"odies to proteins 2or drug# protein complexesB on the mem"rane of red "lood cells 2(7$sB U elimination of (7$s "y macrophages and/or the complement system< 2iiB drug#induced protein adsorption 2IgG, complementB on the mem"rane of (7$s 0rug#dependent anti"odies 200A7sB: 2iB detected in vitro only in the presence of drug< 2iiB 00A7s typically show a positive 0AT and negative elution< 2iiiB cefotetan, ceftriaxone and piperacillin are fre!uent causes of 00A7 production< 2ivB treatment: drug cessation, corticosteroids should not "e used 0rug#independent anti"odies 20IA7sB: 2iB can "e detected in vitro in the a"sence of drug< 2iiB mechanism: drug causes production of (7$ autoanti"odies 2identical effect to warm autoimmune hemolytic anemiaB< 2iiiB 0IA7s show a positive 0AT and positive elution 2detection of specific autoanti"odiesB< 2ivB fludara"ine, methyldopa and d#lactamase inhi"itors are fre!uent causes of 0IA7 production< 2vB treatment: drug cessation, systemic corticosteroids

A%%#)'#$(+P#C,F,C ,MM!$&P)&P0*%A1,+ "&.A)D +#C&$DA)* P)#-#$",&$ &F A%%#)',C )0,$,",+6 2)atricardi P) Pediatr Allergy Immunol 9:;.: 9?: ;?@;-B Allergic rhinitis 2A(B: @iA deBinition Ig'#mediated inflammation of the nasal mucosa< @iiA Crevalence up to .:R of the population< @iiiA iDCact S physical, mental and psychological well#"eing< S Ho*< high costs< Q risk of asthma and other comor"idities/complications< @ivA clinical DaniBestations rhinorrhea, nasal "lockage 2most common and "othersome symptom< associated with impaired sleep< occurs when capacitance vessels dilate in the cavernous tissues of the nasal tur"inatesB, sneeCing, itching, mouth "reathing, snoring, nasal voice, cough, `allergic shinersV 2darkened lower eyelids due to chronic congestionB, minor epistaxis< @vA coDorEidities:coDClications con+unctivitis, sinusitis, hyposmia, 'ustachian tu"e dysfunction, middle ear effusion, otitis, S hearing, lymphoid hypertrophy 2adenoids, tonsilsB, pharyngitis, asthma, dental malocclusion, atopic ecCema, pollen#food syndrome, sleep disordered "reathing 2snoring, microarousals, o"structive sleep apnea/hypopnea, chronic nonrestorative sleepB, daytime sleepiness and S concentration, fatigue, stress, S school/work performance, systemic inflammation< @viA dia2nosis clinical history, anterior rhinoscopy, allergy testing 29?R of A( cases are `localV \entopy], which means that specific Ig' is not detected "y skin or serum testsB< @viiA diBBerential dia2nosis 2may coexist with A(B: nonallergic rhinitis 2infectious, irritant#

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

induced, hormonal, drug#induced, vasomotor, idiopathicB, nasal polyps, septal deviation, choanal atresia, stenosis of the piriform aperture, cleft lip, adenoidal hypertrophy, leakage of $18, malignancy, G'(0, foreign "ody< @viiiA treatDent 2depends on severityB: education a"out the disease, allergen avoidance, antihistamines 2oral, intranasalB, corticosteroids 2intranasal, oralB, antileukotrienes, decongestants 2oral, topicalB, intranasal anticholinergics, saline douches, allergen immunotherapy, omaliCuma" 2if concomitant uncontrolled severe asthmaB< @ixA strate2F to Crevent A) promote early tolerance to respiratory allergens Immune tolerance: 2iB definition: nonresponsiveness of the adaptive immune system or active Treg response to antigens< 2iiB mechanisms: anergy/deletion of effector lymphocytes, generation of Treg cells< 2iiiB importance: to prevent self#destruction and inflammatory responses to "eneficial or harmless exogenous molecules 2e g food, commensal "acteria, allergensB *oss of immune tolerance U allergic or autoimmune disorders 2e g exposure to aeroallergens in genetically suscepti"le su"+ects U specific T%9 responses to allergens U allergic rhinitisB 'arly interventions to induce immunologic tolerance U S T%9 immune responses, induction of allergen#specific Treg cells U S Ig'#mediated allergies 8actors that promote immune tolerance: 2iB Q tolerogenic gut micro"iota 2*acto"acillus sp, 7ifido"acterium spB< 2iiB Q tolerogenic dendritic cells< 2iiiB Q tolerogenic molecules 2retinoic acid, TG8#d, T1*P \in the gut environment], indoleamine#9,F#dioxygenase, I*#;:, I*#F?, IgG., IgA, adenosineB< 2ivB Q regulatory cell responses 2$0.e$09?e Tregs, ThF cells, Tr; cells, $0-e Tregs, regulatory 7 cellsB< 2vB "alanced T%; responses Ideas to induce early tolerance to respiratory allergens: 2iB improve skin "arrier< 2iiB ade!uate "reastfeeding, 2iiiB early exposure to allergens, 2ivB avoid active and passive to"acco smoke< 2vB use of pro"iotics and pre"iotics during pregnancy and infancy, 2viB use of cowVs milk hydrolysates when indicated, 2viiB use of "acterial lysates, 2viiiB vit 0 supplementation, 2ixB supplementation with n#F long chain polyunsaturated fatty acids from fatty fish and fish oil< 2xB primary allergen#specific immunoprophylaxis 2"efore Ig' sensitiCation occursB< 2xiB secondary allergen#specific immunoprophylaxis 2after Ig' sensitiCation occursB 'arly specific immunotherapy: W1IT started within ;9 months after onset of allergic symptomsX 1econdary, allergen#specific immunoprophylaxis: Wadministration of an allergen extract to prevent onset of allergic symptoms in healthy "ut already Ig'#sensitiCed childrenX< o"+ectives: restore tolerance "efore symptoms develop, prevent Wmolecular spreadingX $omponent#resolved prophylaxis: Wthe administration of allergenic molecules 2component# resolvedB to prevent onset of allergic symptoms in healthy "ut already Ig'#sensitiCed childrenX )olecular spreading: Wthe se!uential development of anti"ody 2Ig'B responses to distinct non# cross#reacting molecules from the same antigenic 2allergenicB source, starting with an `initiatorV moleculeX Initiator molecule: Wthe allergenic molecule, within an allergenic source, responsi"le for the induction of the ;st Ig' anti"ody response to that allergenic sourceX `'pitope spreadingV: Wthe evolution of T#cell responses during an autoimmune reaction and spreading from one single T#cell epitope to many T#cell epitopes within an individual moleculeX

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

D,A'$&+",C #-A%!A",&$ &F 0*P#)+#$+,",-,"* )#AC",&$+ "& B#"A(%AC"AM A$",B,&",C+ ,$ A %A)'# P&P!%A",&$ &F C0,%D)#$ 2Gam"onino )A, $orCo 6*, )uNoC $, (e!uena G, AriCa A, )ayorga $, Jrda A, 7lanca ), Torres )6 Pediatr Allergy Immunol 9:;.: 9?: -:@-AB Immediate drug hypersensitivity reactions: 2iB usually occur within ; hr of drug intake< 2iiB usually Ig'#mediated< 2iiiB urticaria and anaphylaxis are the most reported entities &on#immediate drug hypersensitivity reactions: 2iB usually occur 9.@.- hrs after drug intake 2interval can "e as short as ; hrB< 2iiB usually T#cell mediated< 2iiiB most fre!uent reactions: maculopapular exanthema, non#immediate urticaria %ypersensitivity reactions to "eta#lactams 27*sB: 2iB fre!uently reported in children< 2iiB amoxicillin and cephalosporins are the most fre!uent culprits 8alse#negative diagnosis of 7* allergy can lead to severe reactions after exposure 8alse#positive diagnosis of 7* allergy can lead to the unnecessary use of alternative anti"iotics that Q cost and "acterial resistance Authors studied A-F children 2;@;. yrs oldB with suspected hypersensitivity to 7*s U 2iB only =9 patients 2A >9RB were confirmed as "eing allergic< 2iiB > patients had immediate reactions: 9 diagnosed "y in vitro testing, 9 "y skin testing and ? "y drug provocation test 20PTB< 2iiiB ?F patients had non#immediate reactions: 9 diagnosed "y skin testing, ?; "y 0PT< 2ivB most fre!uent culprit drugs: amoxicillin#clavulanate, amoxicillin< 2vB most fre!uent reactions: maculopapular exanthema 2usually confused with viral infectionsB, urticaria, angioedema

#''(.0,"#(+P#C,F,C ,'A A$D ,'A2 A$",B&D,#+ ,$ #''(A%%#)',C C0,%D)#$ ,+ "0#)# A )&%# ,$ "&%#)A$C# ,$D!C",&$6 24onstantinou G&, &owak#3eCgrCyn A, 7encharitiwong (, 7ardina *, 1icherer 1%, 1ampson %A Pediatr Allergy Immunol 9:;.: 9?: =.@A:B 1ecretory IgA: 2iB essential role in mucosal immunity< 2iiB main function: immune exclusion 2aggregating, immo"iliCing and neutraliCing pathogenic micro"es and harmful molecules in mucosal surfacesB< 2iiiB IgA production has "een associated with oral tolerance< 2ivB a defective IgA response can "e a risk factor for allergy development 2e g patients with selective, partial or transient IgA deficiency have Q prevalence of allergies, including food allergyB Authors compared egg#white#2'3B#specific IgA and IgA9 levels "etween '3#allergic and '3# tolerating children U conclusions: 2iB IgA9 anti"odies may have a role in the induction of food tolerance< 2iiB S allergen#specific IgA9 levels may "e associated with food allergy development

F#"A% A$D #A)%*(%,F# &),',$+ &F A%%#)'* 23arner 6L, 3arner 6A Pediatr Allergy Immunol 9:;.: 9?: A@-B The ontogeny of allergic disease in humans is not well characteriCed Prevalence of allergic diseases has glo"ally increased over the last F:@.: yrs 2not explaina"le "y genetic factors alone< environmental and epigenetic factors seem very importantB Pregnancy U T%9 and Treg environment 2I*#., I*#;:, I*#;F, TG8#dB U downregulation of the maternal T%; response against fetopaternal antigens U Q pregnancy success

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

'nvironmental exposures during pregnancy 2e g diet, allergens, pollutants, micro"iomeB and "irth 2e g mode of delivery, early use of anti"ioticsB may influence gene expression 2epigeneticsB and allergy development $urrently there is no way to fully prevent allergy development

F&&D A%%#)'* A .,$D,$' )&AD "& "0# P)#+#$" 21ampson %A Pediatr Allergy Immunol 9:;.: 9?: 9?@9=B 8ood allergy 28AB affects up to .@?R of children in some countries 0elayed introduction of foods to high#risk infants can increase the likelihood of 8A The mean wheal diameter in 1PT and food#specific Ig' levels directly correlate with the likelihood of clinical reactivity to foods $omponent#resolved diagnosis 2e g measurement of Ara h 9 from peanutB can help to predict clinically relevant 8A -:R of young children with milk and egg allergy can tolerate these foods in "aked forms 2extensively heated proteinsB< in these patients, ingestion of "aked products can accelerate the development of tolerance to all forms of milk and egg )anagement of 8A is changing toward active induction of tolerance 2immunotherapyB )uch remains to "e discovered a"out the optimal way to prevent, diagnose and manage 8A

,$D!C",&$ &F ")#' C#%%+ AF"#) &)A% ,MM!$&"0#)AP* ,$ 0#$>+ #''(A%%#)',C C0,%D)#$ 28uentes#Aparicio 5, Alonso#*e"rero ', Gapatero *, Infante 1, *orente (, )uNoC# 8ernOndeC )A, $orrea#(ocha ( Pediatr Allergy Immunol 9:;.: 9?: ;:F@;:=B 'ffector#memory $0.e T cells 2T') cellsB: su"set of T cells with immediate effector function that can rapidly produce inflammatory mediators 2T')#T%9 cells play a key role in food allergyB T regulatory cells: su"set of T cells that play a key role in food tolerance Authors treated ;- henVs egg#allergic children 2.@;. yrs oldB with egg oral immunotherapy 2LITB U 2iB Treg cell num"ers increased after desensitiCation achievement< 2iiB the Treg/T') ratio increased 9 F times after LIT 2similar to the ratio o"served in healthy controlsB< 2iiiB LIT did not modify the num"ers of monocytes, "asophils, neutrophils or eosinophils

M!C&+A% MA+" C#%% C&!$"+ ,$ P#D,A"),C #&+,$&P0,%,C 'A+")&,$"#+",$A% D,+#A+# 2)ir 1A5, 1chady 0, Llive AP, &agy#1Cakal 0, 4ellermayer ( Pediatr Allergy Immunol 9:;.: 9?: >.@>?B Primary eosinophilic gastrointestinal disorders 2'GI0B: eosinophilic esophagitis 2'o'B, eosinophilic gastroenteritis, eosinophilic colitis, eosinophilic proctitis Lther diseases that can cause mucosal eosinophilia: inflammatory "owel disease, irrita"le "owel syndrome, celiac disease )ast cell@eosinophil interaction: 2iB mast cell#derived I*#;F can recruit eosinophils< 2iiB mucosal mast cells can "e increased in adults and children with 'o'

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

Authors studied "iopsies from ;9 children with 'GI0 2excluding 'o'< average agec;: . yrsB and ;. healthy controls 2average agec;9 F yrsB U 2iB there was a significant positive correlation "etween eosinophil and mast cell counts in control samples< 2iiB there was no correlation "etween eosinophil and mast cell counts in 'GI0 patients 2disrupted mast cell@ eosinophil interaction^B< 2iiiB study limitation: the utiliCed staining only detects granulated mast cells 2increased degranulated mast cells in 'GI0 patients might have not "een detectedB

P#D,A"),C A%%#)'* )#+#A)C0 A)# .# &$ "0# ),'0" ")AC36 27engt 7+PrkstDn Pediatr Allergy Immunol 9:;.: 9?: .@=B Allergic diseases affect ZF:R of the population under F: yrs of age )odern lifestyle is associated with increased allergy prevalence 8eatures of modern lifestyle: S "reastfeeding< S exercise< Q exposure to pollutants and cigarette smoke< diet rich in salt, sugar and high#saturated fats Prevention of Ig'#mediated allergies: 2iB primary U to prevent Ig'#sensitiCation against defined allergens< 2iiB secondary U to prevent clinical symptoms in an already Ig'#sensitiCed patient< 2iiiB tertiary U to prevent se!uelae and complications of esta"lished allergic diseases 2e g remodelingB< 2ivB preventive measures should "e safe, effective, convenient and fair Ideas to prevent allergy development: 2iB improve skin "arrier< 2iiB ade!uate "reastfeeding, 2iiiB early vs late exposure to allergens, 2ivB avoid active and passive to"acco smoke< 2vB avoid exposure to pollutants 2e g traffic, indoor paintingB< 2viB use of pro"iotics and pre"iotics during pregnancy and infancy, 2viiB use of cowVs milk hydrolysates when indicated, 2viiiB use of "acterial lysates, 2ixB vit 0 supplementation, 2xB supplementation with n#F long chain polyunsaturated fatty acids< 2xiB primary allergen#specific immunoprophylaxis 2"efore Ig' sensitiCation occursB< 2xiiB secondary allergen#specific immunoprophylaxis 2after Ig' sensitiCation occursB 0espite advances in medicine, currently there is no way to fully prevent allergy development

P#D,A"),C A+"0MA D& .# $##D M&)# ,$$&-A",&$ F&) ")#A"M#$"6 2(iedler 6 Pediatr Allergy Immunol 9:;.: 9?: ;>@9:B Asthma: 2iB complex syndrome with multiple endotypes/phenotypes< 2iiB several pathogenic aspects are poorly understood< 2iiiB `omicsV analysis 2genomics, transcriptomics, proteomics, lipidomics, meta"olomicsB in "ody samples 2sputum, "lood, urine, etcB can help to identify disease "iomarkers< 2ivB current pharmacologic therapy is not disease modifying< 2vB .@?R of asthmatic children have therapy#resistant asthma 2significant costs, mor"idity and mortalityB Potential interventions for pediatric asthma: anti#Ig' mA" 2omaliCuma"B, anti#I*#? mA" 2mepoliCuma", resliCuma"B, anti#I*#?( mA" 2"enraliCuma"B, anti#I*#.(g mA" 2dupiluma"B, I*# .(g antagonist 2pitrakinraB, anti#I*#;F mA" 2le"rikiCuma", tralokinuma"B, anti#T&8#g mA" 2golimuma"B, anti#m(&A therapy 2e g targeting the m(&A of $$(FB, immunomodulatory compounds 2macrolides, cyclosporine, methotrexate, T*( agonistsB, allergen#specific immunotherapy 2after symptoms startB, allergen#specific immunoprophylaxis 2"efore symptoms startB, "acterial lysates 2e g L)#-?B, pro"iotics, pre"iotics, vitamin 0, vaccines 2to prevent respiratory viral infectionsB, we"#"ased telemanagement

P)#-#$",&$ .0A" ,+ "0# M&+" P)&M,+,$' APP)&AC06 2%olt PG Pediatr Allergy Immunol 9:;.: 9?: ;9@;.B

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

'arly life U immature T%; responses U Q risk of tolerance failure and allergy development )icro"ial signals from certain environmental pathogens and `tolerogenicV gut micro"iota U normal post#natal maturation of immune functions U protection against allergic sensitiCation T regulatory responses in the airway mucosa U immune tolerance U S respiratory allergies 'arly viral respiratory infections 2%(5, (15B e allergen sensitiCation U synergism to promote asthma development 1evere viral infection U Q secretion of type ; interferons, which diffuse locally and systemically U Q 8cb(; expression on airway mucosal 0$s, 0$ precursors and monocyte precursors U Q Ig'#facilitated allergen presentation to Th9 memory cells U Q Th9 inflammation at the infection site and at distant tissues 2spread of atopic inflammationB 1trategies to prevent asthma development: 2iB S primary Ig'#sensitiCation to aeroallergens 2e g early allergen exposure via the oral mucosaB< 2iiB S consolidation of allergen#specific Th9 immunity 2e g early allergen ITB< 2iiiB S respiratory viral infections 2e g use of viral#specific vaccines or "acterial#derived immunostimulantsB< 2ivB S interactions "etween atopic and antiviral pathways in children with intermittent wheeCe 2e g use of omaliCuma" in atopic wheeCers prior to asthma diagnosisB< 2vB S progression from intermittent to persistent/chronic atopic asthma

P),MA)* ,MM!$&D#F,C,#$C,#+ &P",&$+ F&) "0# F!"!)# 27adolato ( Pediatr Allergy Immunol 9:;.: 9?: 9A@9>B ;>99 U 1chultC et al reported a case of `Agranulocytic anginaV 2;st case of severe neutropenia, which might "e the ;st recogniCed PI0B ;>?: U GlanCmann et al reported 9 infants with fatal candidiasis and lymphopenia< lack of immunoglo"ulins was detected - yrs later 2;>?-B U severe com"ined immunodeficiency ;>?. U 7ruton reported an -#yr#old "oy with recurrent pneumococcal infections and no detecta"le gamma#glo"ulin U agammaglo"ulinemia^ ;>?A U Good et al reported . "oys with a"scesses and lymphadenitis due to staphylococci or Gram#negative "acteria 2`8atal granulomatousV syndrome U chronic granulomatous diseaseB Primary immunodeficiencies 2PI0sB: 2iB inherited disorders of the immune system< 2iiB prevalence: ;:;:,::: to ;:;::,::: su"+ects< 2iiiB impact: severe complications 2infections, autoimmunity, neoplasmsB, S Ho*, high costs< 2ivB early diagnosis and treatment can "e lifesaving< 2vB genetic diagnosis is usually important for therapy, prognosis and genetic counseling< 2viB when indicated, definite therapy of severe PI0s 2e g %$TB should not "e delayed while waiting for genetic diagnosis 0iagnosis of PI0s can "e difficult "ecause: 2iB T9:: different PI0#causing genes have "een descri"ed< 2iiB clinical and la"oratory presentation of PI0s can "e very varia"le 2e g RA( mutations can present with 1$I0, Lmenn syndrome or hyper#Ig) syndrome< *AS' mutations can present with 3iskott#Aldrich syndrome, M#linked throm"ocytopenia or M#linked neutropeniaB< 2iiiB current PI0 diagnostic approach is often dominated "y phenotypic and functional characteriCation 2time#consumingB< 2ivB genetic diagnosis is classically performed since ;>AA "y 1anger se!uencing 2la"orious, time#consuming, not availa"le for several genesB

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014

The purpose of this summary is exclusively educational, to provide practical updated knowledge for Allergy/Immunology Physicians It does not intend to replace the clinical criteria of the physician

&ext#generation se!uencing 2&G1B: 2iB rapid, accurate, low#cost, high#throughput 0&A se!uencing technology that has identified mutations in novel PI0#causing genes 2e g STAT1 mutations in patients with chronic mucocutaneous candidiasis< 'L# mutations in %ermansky@ Pudlak syndrome type >B< 2iiB simultaneously amplify and se!uence millions of 0&A fragments within few days< 2iiiB can "e used to se!uence the whole#genome or the whole#exome 2sum of all exons and their ad+acent nucleotides< approximately -?R of PI0#causing deleterious mutations occur in these regionsB< 2ivB useful diagnostic tool for complex PI0s, particularly for patients with atypical disease presentation< 2vB differentiation "etween pathogenic mutations and irrelevant genetic variations can "e very challenging< 2viB promising tool for early diagnosis and treatment of PI0 in patients presenting with a ;st episode of severe infection 2PI0 screeningB

-,"AM,$ D D#F,C,#$C* ,+ A++&C,A"#D .,"0 D,A'$&+,+ A$D +#-#),"* &F C0,%D0&&D A"&P,C D#)MA",",+ 23ang 11, %on 4*, 4ong AP#s, Pong %&#h, 3ong G3#k, *eung T8 Pediatr Allergy Immunol 9:;.: 9?: F:@F?B Atopic dermatitis 2A0B: 2iB common chronic skin disease 29#;:R of adults, ;?#F:R of childrenB< 2iiB prevalence has Q glo"ally< 2iiiB proposed risk factors: genetic suscepti"ility 2e g skin "arrier defectsB, $esarean delivery, S "reastfeeding, W3esternX diet, early use of "road#spectrum anti"iotics, S farm exposure, S helminth infections, S tolerogenic gut micro"iota, Q exposure to pollutants, irritants and allergens, S exposure to J5 light, o"esity, S exercise, vit 0 deficiency< 2ivB impact: S Ho*, high costs, Q predisposition to skin infections and other allergies 5it 0: 2iB important nutrient in "one health< 2iiB involved in o"esity, cancer, cardiovascular diseases, immune function and maternal/fetal health 'ffects of vit 0 on immune system: 2iB Q skin "arrier function< 2iiB Q production of antimicro"ial peptides 2d#defensins, cathelicidinB< 2iiiB Q phagocytic activity of macrophages< 2ivB S maturation of dendritic cells< 2vB S T%;, T%;A and T%> responses< 2viB Q differentiation of Treg cells< 2viiB S function of 7#lymphocytes< 2viiiB S production of Ig'< 2ixB Q I*#;: production "y mast cells %ypovitaminosis 0 has "een associated 2fre!uently "ut not uniformlyB with Q occurrence or severity of allergy 2allergic sensitiCation, wheeCing, asthma, allergic rhinitis, food allergy, A0B Authors performed a case@control study to investigate the relationship "etween vit 0 deficiency and A0 in %ong 4ong $hinese children U 2iB vit 0 deficiency and insufficiency was prevalent in the studied population, 2iiB vit 0 deficiency was associated with A0 and high total Ig'< 2iiiB serum vit 0 levels correlated inversely with "oth long# and short#term A0 severity< 2ivB prospective trials are necessary to address the "enefits of vit 0 supplementation on A0 outcomes

.0A" ,+ $##D#D F&) A%%#)',C C0,%D)#$6 2%aahtela T Pediatr Allergy Immunol 9:;.: 9?: 9;@9.B 7iodiversity: varia"ility among living organisms, including diversity within species, "etween species and of ecosystems< it concerns "oth environmental and commensal micro"iota The human "ody carries an ecosystem of micro"es weighing around ; ? kg 2the micro"iomeB )icro"ial signals from certain environmental pathogens and `tolerogenicV micro"iota 2skin, gut, airwaysB U induction and maintenance of tolerance U protection against allergies

But knowledge puffs up while love builds up 1 Corinthians 8:1

Juan Carlos Aldave Becerra, MD


Allergy and $linical Immunology (e"agliati )artins &ational %ospital, *ima#Peru

)odern ur"an life U S diversity and a"normal composition of environmental microorganisms 2macro"iomeB U dys"iosis 2S "iodiversity and altered composition of the human micro"iotaB U immune dysregulation U Q inflammatory diseases 2allergies, autoimmune diseases, o"esity, depression, autism, AlCheimer disease, many forms of cancerB (isk factors for immune dysregulation: 2iB genetic suscepti"ility< 2iiB S micro"iota diversity< 2iiiB S `tolerogenicV micro"iota 2e g *acto"acillus, 7ifido"acteriumB, 2ivB S exposure to maternal `tolerogenicV micro"iota 2e g gammaproteo"acteria living on the skin, the axilla and the vaginaB< 2vB cesarean delivery< 2viB S "reastfeeding< 2viiB W3esternX diet< 2viiiB early use of "road#spectrum anti"iotics< 2ixB S farm exposure< 2xB S certain helminth infections< 2xiB Q exposure to pollutants, irritants and allergens< 2xiiB S exercise< 2xiiiB vit 0 deficiency Tolerance is an active process influenced "y the environment 2e g "a"ies put everything in their mouthB 'verything a child eats, drinks, touches or "reaths modulates the micro"iome U every child should have: 2iB a "alanced diet, 2iiB fre!uent physical activity, 2iiiB a `healthyV environment 8ecal micro"iota transplant has "een successfully used to restore the micro"iota "alance in severe therapy#resistant $lostridium difficile infections ?=,::: species of animals and plants are currently classified as threatened due to human activity, which accelerates the natural rate of species extinction "y ;::@;::: times

PEARLS IN ALLERGY AND IMMUNOLOGY March 2014