Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease
Identifieur interne : 000975 ( Pmc/Corpus ); précédent : 000974; suivant : 000976Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease
Auteurs : Amali E. Samarasinghe ; Jason W. RoschSource :
- Frontiers in Immunology [ 1664-3224 ] ; 2020.
Abstract
The underlying pathologies of sickle cell disease and asthma share many characteristics in terms of respiratory inflammation. The principal mechanisms of pulmonary inflammation are largely distinct, but activation of common pathways downstream of the initial inflammatory triggers may lead to exacerbation of both disease states. The altered inflammatory landscape of these respiratory pathologies can differentially impact respiratory pathogen susceptibility in patients with sickle cell disease and asthma. How these two distinct diseases behave in a comorbid setting can further exacerbate pulmonary complications associated with both disease states and impact susceptibility to respiratory infection. This review will provide a concise overview of how asthma distinctly affects individuals with sickle cell disease and how pulmonary physiology and inflammation are impacted during comorbidity.
Url:
DOI: 10.3389/fimmu.2019.03058
PubMed: 32038616
PubMed Central: 6992560
Links to Exploration step
PMC:6992560Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease</title><author><name sortKey="Samarasinghe, Amali E" sort="Samarasinghe, Amali E" uniqKey="Samarasinghe A" first="Amali E." last="Samarasinghe">Amali E. Samarasinghe</name><affiliation><nlm:aff id="aff1"><institution>Division of Pulmonology, Allergy-Immunology, and Sleep, Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Department of Microbiology Immunology and Biochemistry, College of Medicine, University of Tennessee Health Science Center</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Children's Foundation Research Institute</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation></author><author><name sortKey="Rosch, Jason W" sort="Rosch, Jason W" uniqKey="Rosch J" first="Jason W." last="Rosch">Jason W. Rosch</name><affiliation><nlm:aff id="aff4"><institution>Department of Infectious Diseases, St. Jude Children's Research Hospital</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32038616</idno><idno type="pmc">6992560</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992560</idno><idno type="RBID">PMC:6992560</idno><idno type="doi">10.3389/fimmu.2019.03058</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000975</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000975</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease</title><author><name sortKey="Samarasinghe, Amali E" sort="Samarasinghe, Amali E" uniqKey="Samarasinghe A" first="Amali E." last="Samarasinghe">Amali E. Samarasinghe</name><affiliation><nlm:aff id="aff1"><institution>Division of Pulmonology, Allergy-Immunology, and Sleep, Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Department of Microbiology Immunology and Biochemistry, College of Medicine, University of Tennessee Health Science Center</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Children's Foundation Research Institute</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation></author><author><name sortKey="Rosch, Jason W" sort="Rosch, Jason W" uniqKey="Rosch J" first="Jason W." last="Rosch">Jason W. Rosch</name><affiliation><nlm:aff id="aff4"><institution>Department of Infectious Diseases, St. Jude Children's Research Hospital</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></nlm:aff></affiliation></author></analytic><series><title level="j">Frontiers in Immunology</title><idno type="eISSN">1664-3224</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The underlying pathologies of sickle cell disease and asthma share many characteristics in terms of respiratory inflammation. The principal mechanisms of pulmonary inflammation are largely distinct, but activation of common pathways downstream of the initial inflammatory triggers may lead to exacerbation of both disease states. The altered inflammatory landscape of these respiratory pathologies can differentially impact respiratory pathogen susceptibility in patients with sickle cell disease and asthma. How these two distinct diseases behave in a comorbid setting can further exacerbate pulmonary complications associated with both disease states and impact susceptibility to respiratory infection. This review will provide a concise overview of how asthma distinctly affects individuals with sickle cell disease and how pulmonary physiology and inflammation are impacted during comorbidity.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Platt, Os" uniqKey="Platt O">OS Platt</name></author><author><name sortKey="Brambilla, Dj" uniqKey="Brambilla D">DJ Brambilla</name></author><author><name sortKey="Rosse, Wf" uniqKey="Rosse W">WF Rosse</name></author><author><name sortKey="Milner, Pf" uniqKey="Milner P">PF Milner</name></author><author><name sortKey="Castro, O" uniqKey="Castro O">O Castro</name></author><author><name sortKey="Steinberg, Mh" uniqKey="Steinberg M">MH Steinberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ojodu, J" uniqKey="Ojodu J">J Ojodu</name></author><author><name sortKey="Hulihan, Mm" uniqKey="Hulihan M">MM Hulihan</name></author><author><name sortKey="Pope, Sn" uniqKey="Pope S">SN Pope</name></author><author><name sortKey="Grant, Am" uniqKey="Grant A">AM Grant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kauf, Tl" uniqKey="Kauf T">TL Kauf</name></author><author><name sortKey="Coates, Td" uniqKey="Coates T">TD Coates</name></author><author><name sortKey="Huazhi, L" uniqKey="Huazhi L">L Huazhi</name></author><author><name sortKey="Mody Patel, N" uniqKey="Mody Patel N">N Mody-Patel</name></author><author><name sortKey="Hartzema, Ag" uniqKey="Hartzema A">AG Hartzema</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Elmariah, H" uniqKey="Elmariah H">H Elmariah</name></author><author><name sortKey="Garrett, Me" uniqKey="Garrett M">ME Garrett</name></author><author><name sortKey="De Castro, Lm" uniqKey="De Castro L">LM De Castro</name></author><author><name sortKey="Jonassaint, Jc" uniqKey="Jonassaint J">JC Jonassaint</name></author><author><name sortKey="Ataga, Ki" uniqKey="Ataga K">KI Ataga</name></author><author><name sortKey="Eckman, Jr" uniqKey="Eckman J">JR Eckman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Telen, Mj" uniqKey="Telen M">MJ Telen</name></author><author><name sortKey="Malik, P" uniqKey="Malik P">P Malik</name></author><author><name sortKey="Vercellotti, Gm" uniqKey="Vercellotti G">GM Vercellotti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rees, Dc" uniqKey="Rees D">DC Rees</name></author><author><name sortKey="Williams, Tn" uniqKey="Williams T">TN Williams</name></author><author><name sortKey="Gladwin, Mt" uniqKey="Gladwin M">MT Gladwin</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Network, Ga" uniqKey="Network G">GA Network</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="An, P" uniqKey="An P">P An</name></author><author><name sortKey="Barron Casella, Ea" uniqKey="Barron Casella E">EA Barron-Casella</name></author><author><name sortKey="Strunk, Rc" uniqKey="Strunk R">RC Strunk</name></author><author><name sortKey="Hamilton, Rg" uniqKey="Hamilton R">RG Hamilton</name></author><author><name sortKey="Casella, Jf" uniqKey="Casella J">JF Casella</name></author><author><name sortKey="Debaun, Mr" uniqKey="Debaun M">MR Debaun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Debaun, Mr" uniqKey="Debaun M">MR Debaun</name></author><author><name sortKey="Strunk, Rc" uniqKey="Strunk R">RC Strunk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Akinbami, Lj" uniqKey="Akinbami L">LJ Akinbami</name></author><author><name sortKey="Moorman, Je" uniqKey="Moorman J">JE Moorman</name></author><author><name sortKey="Liu, X" uniqKey="Liu X">X Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boyd, Jh" uniqKey="Boyd J">JH Boyd</name></author><author><name sortKey="Macklin, Ea" uniqKey="Macklin E">EA Macklin</name></author><author><name sortKey="Strunk, Rc" uniqKey="Strunk R">RC Strunk</name></author><author><name sortKey="Debaun, Mr" uniqKey="Debaun M">MR Debaun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bernaudin, F" uniqKey="Bernaudin F">F Bernaudin</name></author><author><name sortKey="Strunk, Rc" uniqKey="Strunk R">RC Strunk</name></author><author><name sortKey="Kamdem, A" uniqKey="Kamdem A">A Kamdem</name></author><author><name sortKey="Arnaud, C" uniqKey="Arnaud C">C Arnaud</name></author><author><name sortKey="An, P" uniqKey="An P">P An</name></author><author><name sortKey="Torres, M" uniqKey="Torres M">M Torres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Debaun, Mr" uniqKey="Debaun M">MR Debaun</name></author><author><name sortKey="Rodeghier, M" uniqKey="Rodeghier M">M Rodeghier</name></author><author><name sortKey="Cohen, R" uniqKey="Cohen R">R Cohen</name></author><author><name sortKey="Kirkham, Fj" uniqKey="Kirkham F">FJ Kirkham</name></author><author><name sortKey="Rosen, Cl" uniqKey="Rosen C">CL Rosen</name></author><author><name sortKey="Roberts, I" uniqKey="Roberts I">I Roberts</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nandedkar, Sd" uniqKey="Nandedkar S">SD Nandedkar</name></author><author><name sortKey="Feroah, Tr" uniqKey="Feroah T">TR Feroah</name></author><author><name sortKey="Hutchins, W" uniqKey="Hutchins W">W Hutchins</name></author><author><name sortKey="Weihrauch, D" uniqKey="Weihrauch D">D Weihrauch</name></author><author><name sortKey="Konduri, Ks" uniqKey="Konduri K">KS Konduri</name></author><author><name sortKey="Wang, J" uniqKey="Wang J">J Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lunt, A" uniqKey="Lunt A">A Lunt</name></author><author><name sortKey="Desai, Sr" uniqKey="Desai S">SR Desai</name></author><author><name sortKey="Wells, Au" uniqKey="Wells A">AU Wells</name></author><author><name sortKey="Hansell, Dm" uniqKey="Hansell D">DM Hansell</name></author><author><name sortKey="Mushemi, S" uniqKey="Mushemi S">S Mushemi</name></author><author><name sortKey="Melikian, N" uniqKey="Melikian N">N Melikian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Intzes, S" uniqKey="Intzes S">S Intzes</name></author><author><name sortKey="Kalpatthi, Rv" uniqKey="Kalpatthi R">RV Kalpatthi</name></author><author><name sortKey="Short, R" uniqKey="Short R">R Short</name></author><author><name sortKey="Imran, H" uniqKey="Imran H">H Imran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Canalli, Aa" uniqKey="Canalli A">AA Canalli</name></author><author><name sortKey="Costa, Ff" uniqKey="Costa F">FF Costa</name></author><author><name sortKey="Saad, St" uniqKey="Saad S">ST Saad</name></author><author><name sortKey="Conran, N" uniqKey="Conran N">N Conran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belcher, Jd" uniqKey="Belcher J">JD Belcher</name></author><author><name sortKey="Marker, Ph" uniqKey="Marker P">PH Marker</name></author><author><name sortKey="Weber, Jp" uniqKey="Weber J">JP Weber</name></author><author><name sortKey="Hebbel, Rp" uniqKey="Hebbel R">RP Hebbel</name></author><author><name sortKey="Vercellotti, Gm" uniqKey="Vercellotti G">GM Vercellotti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belcher, Jd" uniqKey="Belcher J">JD Belcher</name></author><author><name sortKey="Chen, C" uniqKey="Chen C">C Chen</name></author><author><name sortKey="Nguyen, J" uniqKey="Nguyen J">J Nguyen</name></author><author><name sortKey="Zhang, P" uniqKey="Zhang P">P Zhang</name></author><author><name sortKey="Abdulla, F" uniqKey="Abdulla F">F Abdulla</name></author><author><name sortKey="Nguyen, P" uniqKey="Nguyen P">P Nguyen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Conran, N" uniqKey="Conran N">N Conran</name></author><author><name sortKey="Saad, St" uniqKey="Saad S">ST Saad</name></author><author><name sortKey="Costa, Ff" uniqKey="Costa F">FF Costa</name></author><author><name sortKey="Ikuta, T" uniqKey="Ikuta T">T Ikuta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Croizat, H" uniqKey="Croizat H">H Croizat</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Graido Gonzalez, E" uniqKey="Graido Gonzalez E">E Graido-Gonzalez</name></author><author><name sortKey="Doherty, Jc" uniqKey="Doherty J">JC Doherty</name></author><author><name sortKey="Bergreen, Ew" uniqKey="Bergreen E">EW Bergreen</name></author><author><name sortKey="Organ, G" uniqKey="Organ G">G Organ</name></author><author><name sortKey="Telfer, M" uniqKey="Telfer M">M Telfer</name></author><author><name sortKey="Mcmillen, Ma" uniqKey="Mcmillen M">MA Mcmillen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Malave, I" uniqKey="Malave I">I Malave</name></author><author><name sortKey="Perdomo, Y" uniqKey="Perdomo Y">Y Perdomo</name></author><author><name sortKey="Escalona, E" uniqKey="Escalona E">E Escalona</name></author><author><name sortKey="Rodriguez, E" uniqKey="Rodriguez E">E Rodriguez</name></author><author><name sortKey="Anchustegui, M" uniqKey="Anchustegui M">M Anchustegui</name></author><author><name sortKey="Malave, H" uniqKey="Malave H">H Malave</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, G" uniqKey="Chen G">G Chen</name></author><author><name sortKey="Zhang, D" uniqKey="Zhang D">D Zhang</name></author><author><name sortKey="Fuchs, Ta" uniqKey="Fuchs T">TA Fuchs</name></author><author><name sortKey="Manwani, D" uniqKey="Manwani D">D Manwani</name></author><author><name sortKey="Wagner, Dd" uniqKey="Wagner D">DD Wagner</name></author><author><name sortKey="Frenette, Ps" uniqKey="Frenette P">PS Frenette</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Holtzclaw, Jd" uniqKey="Holtzclaw J">JD Holtzclaw</name></author><author><name sortKey="Jack, D" uniqKey="Jack D">D Jack</name></author><author><name sortKey="Aguayo, Sm" uniqKey="Aguayo S">SM Aguayo</name></author><author><name sortKey="Eckman, Jr" uniqKey="Eckman J">JR Eckman</name></author><author><name sortKey="Roman, J" uniqKey="Roman J">J Roman</name></author><author><name sortKey="Hsu, Ll" uniqKey="Hsu L">LL Hsu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Green, Ce" uniqKey="Green C">CE Green</name></author><author><name sortKey="Turner, Am" uniqKey="Turner A">AM Turner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Asosingh, K" uniqKey="Asosingh K">K Asosingh</name></author><author><name sortKey="Weiss, K" uniqKey="Weiss K">K Weiss</name></author><author><name sortKey="Queisser, K" uniqKey="Queisser K">K Queisser</name></author><author><name sortKey="Wanner, N" uniqKey="Wanner N">N Wanner</name></author><author><name sortKey="Yin, M" uniqKey="Yin M">M Yin</name></author><author><name sortKey="Aronica, M" uniqKey="Aronica M">M Aronica</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Toews, Gb" uniqKey="Toews G">GB Toews</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lebensburger, Jd" uniqKey="Lebensburger J">JD Lebensburger</name></author><author><name sortKey="Howard, T" uniqKey="Howard T">T Howard</name></author><author><name sortKey="Hu, Y" uniqKey="Hu Y">Y Hu</name></author><author><name sortKey="Pestina, Ti" uniqKey="Pestina T">TI Pestina</name></author><author><name sortKey="Gao, G" uniqKey="Gao G">G Gao</name></author><author><name sortKey="Johnson, M" uniqKey="Johnson M">M Johnson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Asquith, Kl" uniqKey="Asquith K">KL Asquith</name></author><author><name sortKey="Ramshaw, Hs" uniqKey="Ramshaw H">HS Ramshaw</name></author><author><name sortKey="Hansbro, Pm" uniqKey="Hansbro P">PM Hansbro</name></author><author><name sortKey="Beagley, Kw" uniqKey="Beagley K">KW Beagley</name></author><author><name sortKey="Lopez, Af" uniqKey="Lopez A">AF Lopez</name></author><author><name sortKey="Foster, Ps" uniqKey="Foster P">PS Foster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tomaki, M" uniqKey="Tomaki M">M Tomaki</name></author><author><name sortKey="Zhao, Ll" uniqKey="Zhao L">LL Zhao</name></author><author><name sortKey="Sjostrand, M" uniqKey="Sjostrand M">M Sjostrand</name></author><author><name sortKey="Linden, A" uniqKey="Linden A">A Linden</name></author><author><name sortKey="Ichinose, M" uniqKey="Ichinose M">M Ichinose</name></author><author><name sortKey="Lotvall, J" uniqKey="Lotvall J">J Lotvall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Profita, M" uniqKey="Profita M">M Profita</name></author><author><name sortKey="Sala, A" uniqKey="Sala A">A Sala</name></author><author><name sortKey="Bonanno, A" uniqKey="Bonanno A">A Bonanno</name></author><author><name sortKey="Riccobono, L" uniqKey="Riccobono L">L Riccobono</name></author><author><name sortKey="Siena, L" uniqKey="Siena L">L Siena</name></author><author><name sortKey="Melis, Mr" uniqKey="Melis M">MR Melis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aun, Mv" uniqKey="Aun M">MV Aun</name></author><author><name sortKey="Bonamichi Santos, R" uniqKey="Bonamichi Santos R">R Bonamichi-Santos</name></author><author><name sortKey="Arantes Costa, Fm" uniqKey="Arantes Costa F">FM Arantes-Costa</name></author><author><name sortKey="Kalil, J" uniqKey="Kalil J">J Kalil</name></author><author><name sortKey="Giavina Bianchi, P" uniqKey="Giavina Bianchi P">P Giavina-Bianchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pritchard, Ka" uniqKey="Pritchard K">KA Pritchard</name></author><author><name sortKey="Feroah, Tr" uniqKey="Feroah T">TR Feroah</name></author><author><name sortKey="Nandedkar, Sd" uniqKey="Nandedkar S">SD Nandedkar</name></author><author><name sortKey="Holzhauer, Sl" uniqKey="Holzhauer S">SL Holzhauer</name></author><author><name sortKey="Hutchins, W" uniqKey="Hutchins W">W Hutchins</name></author><author><name sortKey="Schulte, Ml" uniqKey="Schulte M">ML Schulte</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andemariam, B" uniqKey="Andemariam B">B Andemariam</name></author><author><name sortKey="Adami, Aj" uniqKey="Adami A">AJ Adami</name></author><author><name sortKey="Singh, A" uniqKey="Singh A">A Singh</name></author><author><name sortKey="Mcnamara, Jt" uniqKey="Mcnamara J">JT Mcnamara</name></author><author><name sortKey="Secor, Er" uniqKey="Secor E">ER Secor</name></author><author><name sortKey="Guernsey, La" uniqKey="Guernsey L">LA Guernsey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Field, Jj" uniqKey="Field J">JJ Field</name></author><author><name sortKey="Stocks, J" uniqKey="Stocks J">J Stocks</name></author><author><name sortKey="Kirkham, Fj" uniqKey="Kirkham F">FJ Kirkham</name></author><author><name sortKey="Rosen, Cl" uniqKey="Rosen C">CL Rosen</name></author><author><name sortKey="Dietzen, Dj" uniqKey="Dietzen D">DJ Dietzen</name></author><author><name sortKey="Semon, T" uniqKey="Semon T">T Semon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chapman, Dg" uniqKey="Chapman D">DG Chapman</name></author><author><name sortKey="Irvin, Cg" uniqKey="Irvin C">CG Irvin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kumar, Rk" uniqKey="Kumar R">RK Kumar</name></author><author><name sortKey="Herbert, C" uniqKey="Herbert C">C Herbert</name></author><author><name sortKey="Foster, Ps" uniqKey="Foster P">PS Foster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jiang, C" uniqKey="Jiang C">C Jiang</name></author><author><name sortKey="Gavitt, Td" uniqKey="Gavitt T">TD Gavitt</name></author><author><name sortKey="Szczepanek, Sm" uniqKey="Szczepanek S">SM Szczepanek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Buchman, Al" uniqKey="Buchman A">AL Buchman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sobota, A" uniqKey="Sobota A">A Sobota</name></author><author><name sortKey="Graham, Da" uniqKey="Graham D">DA Graham</name></author><author><name sortKey="Heeney, Mm" uniqKey="Heeney M">MM Heeney</name></author><author><name sortKey="Neufeld, Ej" uniqKey="Neufeld E">EJ Neufeld</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gomez, E" uniqKey="Gomez E">E Gomez</name></author><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leikin, Sl" uniqKey="Leikin S">SL Leikin</name></author><author><name sortKey="Gallagher, D" uniqKey="Gallagher D">D Gallagher</name></author><author><name sortKey="Kinney, Tr" uniqKey="Kinney T">TR Kinney</name></author><author><name sortKey="Sloane, D" uniqKey="Sloane D">D Sloane</name></author><author><name sortKey="Klug, P" uniqKey="Klug P">P Klug</name></author><author><name sortKey="Rida, W" uniqKey="Rida W">W Rida</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, L" uniqKey="Zhang L">L Zhang</name></author><author><name sortKey="Prietsch, So" uniqKey="Prietsch S">SO Prietsch</name></author><author><name sortKey="Mendes, Ap" uniqKey="Mendes A">AP Mendes</name></author><author><name sortKey="Von Groll, A" uniqKey="Von Groll A">A Von Groll</name></author><author><name sortKey="Rocha, Gp" uniqKey="Rocha G">GP Rocha</name></author><author><name sortKey="Carrion, L" uniqKey="Carrion L">L Carrion</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vance Utset, L" uniqKey="Vance Utset L">L Vance Utset</name></author><author><name sortKey="Ivy, Z" uniqKey="Ivy Z">Z Ivy</name></author><author><name sortKey="Willen, Sm" uniqKey="Willen S">SM Willen</name></author><author><name sortKey="Rodeghier, M" uniqKey="Rodeghier M">M Rodeghier</name></author><author><name sortKey="Watt, A" uniqKey="Watt A">A Watt</name></author><author><name sortKey="Schilling, L" uniqKey="Schilling L">L Schilling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Glassberg, J" uniqKey="Glassberg J">J Glassberg</name></author><author><name sortKey="Minnitti, C" uniqKey="Minnitti C">C Minnitti</name></author><author><name sortKey="Cromwell, C" uniqKey="Cromwell C">C Cromwell</name></author><author><name sortKey="Cytryn, L" uniqKey="Cytryn L">L Cytryn</name></author><author><name sortKey="Kraus, T" uniqKey="Kraus T">T Kraus</name></author><author><name sortKey="Skloot, Gs" uniqKey="Skloot G">GS Skloot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carden, Ma" uniqKey="Carden M">MA Carden</name></author><author><name sortKey="Little, J" uniqKey="Little J">J Little</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Langer, Al" uniqKey="Langer A">AL Langer</name></author><author><name sortKey="Leader, A" uniqKey="Leader A">A Leader</name></author><author><name sortKey="Kim Schulze, S" uniqKey="Kim Schulze S">S Kim-Schulze</name></author><author><name sortKey="Ginzburg, Y" uniqKey="Ginzburg Y">Y Ginzburg</name></author><author><name sortKey="Merad, M" uniqKey="Merad M">M Merad</name></author><author><name sortKey="Glassberg, J" uniqKey="Glassberg J">J Glassberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gill, Fm" uniqKey="Gill F">FM Gill</name></author><author><name sortKey="Sleeper, La" uniqKey="Sleeper L">LA Sleeper</name></author><author><name sortKey="Weiner, Sj" uniqKey="Weiner S">SJ Weiner</name></author><author><name sortKey="Brown, Ak" uniqKey="Brown A">AK Brown</name></author><author><name sortKey="Bellevue, R" uniqKey="Bellevue R">R Bellevue</name></author><author><name sortKey="Grover, R" uniqKey="Grover R">R Grover</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Overturf, Gd" uniqKey="Overturf G">GD Overturf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suara, Ro" uniqKey="Suara R">RO Suara</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dean, D" uniqKey="Dean D">D Dean</name></author><author><name sortKey="Neumayr, L" uniqKey="Neumayr L">L Neumayr</name></author><author><name sortKey="Kelly, Dm" uniqKey="Kelly D">DM Kelly</name></author><author><name sortKey="Ballas, Sk" uniqKey="Ballas S">SK Ballas</name></author><author><name sortKey="Kleman, K" uniqKey="Kleman K">K Kleman</name></author><author><name sortKey="Robertson, S" uniqKey="Robertson S">S Robertson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Tuijn, Cf" uniqKey="Van Tuijn C">CF Van Tuijn</name></author><author><name sortKey="Nur, E" uniqKey="Nur E">E Nur</name></author><author><name sortKey="Van Beers, Ej" uniqKey="Van Beers E">EJ Van Beers</name></author><author><name sortKey="Zaaijer, Hl" uniqKey="Zaaijer H">HL Zaaijer</name></author><author><name sortKey="Biemond, Bj" uniqKey="Biemond B">BJ Biemond</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rosch, Jw" uniqKey="Rosch J">JW Rosch</name></author><author><name sortKey="Boyd, Ar" uniqKey="Boyd A">AR Boyd</name></author><author><name sortKey="Hinojosa, E" uniqKey="Hinojosa E">E Hinojosa</name></author><author><name sortKey="Pestina, T" uniqKey="Pestina T">T Pestina</name></author><author><name sortKey="Hu, Y" uniqKey="Hu Y">Y Hu</name></author><author><name sortKey="Persons, Da" uniqKey="Persons D">DA Persons</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carter, R" uniqKey="Carter R">R Carter</name></author><author><name sortKey="Wolf, J" uniqKey="Wolf J">J Wolf</name></author><author><name sortKey="Van Opijnen, T" uniqKey="Van Opijnen T">T Van Opijnen</name></author><author><name sortKey="Muller, M" uniqKey="Muller M">M Muller</name></author><author><name sortKey="Obert, C" uniqKey="Obert C">C Obert</name></author><author><name sortKey="Burnham, C" uniqKey="Burnham C">C Burnham</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karlsson, Ea" uniqKey="Karlsson E">EA Karlsson</name></author><author><name sortKey="Oguin, Th" uniqKey="Oguin T">TH Oguin</name></author><author><name sortKey="Meliopoulos, V" uniqKey="Meliopoulos V">V Meliopoulos</name></author><author><name sortKey="Iverson, A" uniqKey="Iverson A">A Iverson</name></author><author><name sortKey="Broadnax, A" uniqKey="Broadnax A">A Broadnax</name></author><author><name sortKey="Yoon, Sw" uniqKey="Yoon S">SW Yoon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ellison, Am" uniqKey="Ellison A">AM Ellison</name></author><author><name sortKey="Ota, Kv" uniqKey="Ota K">KV Ota</name></author><author><name sortKey="Mcgowan, Kl" uniqKey="Mcgowan K">KL Mcgowan</name></author><author><name sortKey="Smith Whitley, K" uniqKey="Smith Whitley K">K Smith-Whitley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Santoro, Jd" uniqKey="Santoro J">JD Santoro</name></author><author><name sortKey="Myers, L" uniqKey="Myers L">L Myers</name></author><author><name sortKey="Kanter, J" uniqKey="Kanter J">J Kanter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Szczepanek, Sm" uniqKey="Szczepanek S">SM Szczepanek</name></author><author><name sortKey="Roberts, S" uniqKey="Roberts S">S Roberts</name></author><author><name sortKey="Rogers, K" uniqKey="Rogers K">K Rogers</name></author><author><name sortKey="Cotte, C" uniqKey="Cotte C">C Cotte</name></author><author><name sortKey="Adami, Aj" uniqKey="Adami A">AJ Adami</name></author><author><name sortKey="Bracken, Sj" uniqKey="Bracken S">SJ Bracken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Torres, A" uniqKey="Torres A">A Torres</name></author><author><name sortKey="Blasi, F" uniqKey="Blasi F">F Blasi</name></author><author><name sortKey="Dartois, N" uniqKey="Dartois N">N Dartois</name></author><author><name sortKey="Akova, M" uniqKey="Akova M">M Akova</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, M" uniqKey="Han M">M Han</name></author><author><name sortKey="Rajput, C" uniqKey="Rajput C">C Rajput</name></author><author><name sortKey="Ishikawa, T" uniqKey="Ishikawa T">T Ishikawa</name></author><author><name sortKey="Jarman, Cr" uniqKey="Jarman C">CR Jarman</name></author><author><name sortKey="Lee, J" uniqKey="Lee J">J Lee</name></author><author><name sortKey="Hershenson, Mb" uniqKey="Hershenson M">MB Hershenson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Samarasinghe, Ae" uniqKey="Samarasinghe A">AE Samarasinghe</name></author><author><name sortKey="Woolard, Sn" uniqKey="Woolard S">SN Woolard</name></author><author><name sortKey="Boyd, Kl" uniqKey="Boyd K">KL Boyd</name></author><author><name sortKey="Hoselton, Sa" uniqKey="Hoselton S">SA Hoselton</name></author><author><name sortKey="Schuh, Jm" uniqKey="Schuh J">JM Schuh</name></author><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA Mccullers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Furuya, Y" uniqKey="Furuya Y">Y Furuya</name></author><author><name sortKey="Furuya, Ak" uniqKey="Furuya A">AK Furuya</name></author><author><name sortKey="Roberts, S" uniqKey="Roberts S">S Roberts</name></author><author><name sortKey="Sanfilippo, Am" uniqKey="Sanfilippo A">AM Sanfilippo</name></author><author><name sortKey="Salmon, Sl" uniqKey="Salmon S">SL Salmon</name></author><author><name sortKey="Metzger, Dw" uniqKey="Metzger D">DW Metzger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gaston, Mh" uniqKey="Gaston M">MH Gaston</name></author><author><name sortKey="Verter, Ji" uniqKey="Verter J">JI Verter</name></author><author><name sortKey="Woods, G" uniqKey="Woods G">G Woods</name></author><author><name sortKey="Pegelow, C" uniqKey="Pegelow C">C Pegelow</name></author><author><name sortKey="Kelleher, J" uniqKey="Kelleher J">J Kelleher</name></author><author><name sortKey="Presbury, G" uniqKey="Presbury G">G Presbury</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falletta, Jm" uniqKey="Falletta J">JM Falletta</name></author><author><name sortKey="Woods, Gm" uniqKey="Woods G">GM Woods</name></author><author><name sortKey="Verter, Ji" uniqKey="Verter J">JI Verter</name></author><author><name sortKey="Buchanan, Gr" uniqKey="Buchanan G">GR Buchanan</name></author><author><name sortKey="Pegelow, Ch" uniqKey="Pegelow C">CH Pegelow</name></author><author><name sortKey="Iyer, Rv" uniqKey="Iyer R">RV Iyer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adamkiewicz, Tv" uniqKey="Adamkiewicz T">TV Adamkiewicz</name></author><author><name sortKey="Sarnaik, S" uniqKey="Sarnaik S">S Sarnaik</name></author><author><name sortKey="Buchanan, Gr" uniqKey="Buchanan G">GR Buchanan</name></author><author><name sortKey="Iyer, Rv" uniqKey="Iyer R">RV Iyer</name></author><author><name sortKey="Miller, St" uniqKey="Miller S">ST Miller</name></author><author><name sortKey="Pegelow, Ch" uniqKey="Pegelow C">CH Pegelow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccavit, Tl" uniqKey="Mccavit T">TL Mccavit</name></author><author><name sortKey="Gilbert, M" uniqKey="Gilbert M">M Gilbert</name></author><author><name sortKey="Buchanan, Gr" uniqKey="Buchanan G">GR Buchanan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Navalkele, P" uniqKey="Navalkele P">P Navalkele</name></author><author><name sortKey="Ozgonenel, B" uniqKey="Ozgonenel B">B Ozgonenel</name></author><author><name sortKey="Mcgrath, E" uniqKey="Mcgrath E">E Mcgrath</name></author><author><name sortKey="Lephart, P" uniqKey="Lephart P">P Lephart</name></author><author><name sortKey="Sarnaik, S" uniqKey="Sarnaik S">S Sarnaik</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marra, F" uniqKey="Marra F">F Marra</name></author><author><name sortKey="Lynd, L" uniqKey="Lynd L">L Lynd</name></author><author><name sortKey="Coombes, M" uniqKey="Coombes M">M Coombes</name></author><author><name sortKey="Richardson, K" uniqKey="Richardson K">K Richardson</name></author><author><name sortKey="Legal, M" uniqKey="Legal M">M Legal</name></author><author><name sortKey="Fitzgerald, Jm" uniqKey="Fitzgerald J">JM Fitzgerald</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reynolds, La" uniqKey="Reynolds L">LA Reynolds</name></author><author><name sortKey="Finlay, Bb" uniqKey="Finlay B">BB Finlay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ortqvist, Ak" uniqKey="Ortqvist A">AK Ortqvist</name></author><author><name sortKey="Lundholm, C" uniqKey="Lundholm C">C Lundholm</name></author><author><name sortKey="Kieler, H" uniqKey="Kieler H">H Kieler</name></author><author><name sortKey="Ludvigsson, Jf" uniqKey="Ludvigsson J">JF Ludvigsson</name></author><author><name sortKey="Fall, T" uniqKey="Fall T">T Fall</name></author><author><name sortKey="Ye, W" uniqKey="Ye W">W Ye</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stokholm, J" uniqKey="Stokholm J">J Stokholm</name></author><author><name sortKey="Sevelsted, A" uniqKey="Sevelsted A">A Sevelsted</name></author><author><name sortKey="Bonnelykke, K" uniqKey="Bonnelykke K">K Bonnelykke</name></author><author><name sortKey="Bisgaard, H" uniqKey="Bisgaard H">H Bisgaard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pitter, G" uniqKey="Pitter G">G Pitter</name></author><author><name sortKey="Ludvigsson, Jf" uniqKey="Ludvigsson J">JF Ludvigsson</name></author><author><name sortKey="Romor, P" uniqKey="Romor P">P Romor</name></author><author><name sortKey="Zanier, L" uniqKey="Zanier L">L Zanier</name></author><author><name sortKey="Zanotti, R" uniqKey="Zanotti R">R Zanotti</name></author><author><name sortKey="Simonato, L" uniqKey="Simonato L">L Simonato</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hirsch, Ag" uniqKey="Hirsch A">AG Hirsch</name></author><author><name sortKey="Pollak, J" uniqKey="Pollak J">J Pollak</name></author><author><name sortKey="Glass, Ta" uniqKey="Glass T">TA Glass</name></author><author><name sortKey="Poulsen, Mn" uniqKey="Poulsen M">MN Poulsen</name></author><author><name sortKey="Bailey Davis, L" uniqKey="Bailey Davis L">L Bailey-Davis</name></author><author><name sortKey="Mowery, J" uniqKey="Mowery J">J Mowery</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yamamoto Hanada, K" uniqKey="Yamamoto Hanada K">K Yamamoto-Hanada</name></author><author><name sortKey="Yang, L" uniqKey="Yang L">L Yang</name></author><author><name sortKey="Narita, M" uniqKey="Narita M">M Narita</name></author><author><name sortKey="Saito, H" uniqKey="Saito H">H Saito</name></author><author><name sortKey="Ohya, Y" uniqKey="Ohya Y">Y Ohya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adami, Aj" uniqKey="Adami A">AJ Adami</name></author><author><name sortKey="Bracken, Sj" uniqKey="Bracken S">SJ Bracken</name></author><author><name sortKey="Guernsey, La" uniqKey="Guernsey L">LA Guernsey</name></author><author><name sortKey="Rafti, E" uniqKey="Rafti E">E Rafti</name></author><author><name sortKey="Maas, Kr" uniqKey="Maas K">KR Maas</name></author><author><name sortKey="Graf, J" uniqKey="Graf J">J Graf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yoshida, S" uniqKey="Yoshida S">S Yoshida</name></author><author><name sortKey="Ide, K" uniqKey="Ide K">K Ide</name></author><author><name sortKey="Takeuchi, M" uniqKey="Takeuchi M">M Takeuchi</name></author><author><name sortKey="Kawakami, K" uniqKey="Kawakami K">K Kawakami</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Murk, W" uniqKey="Murk W">W Murk</name></author><author><name sortKey="Risnes, Kr" uniqKey="Risnes K">KR Risnes</name></author><author><name sortKey="Bracken, Mb" uniqKey="Bracken M">MB Bracken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Risnes, Kr" uniqKey="Risnes K">KR Risnes</name></author><author><name sortKey="Belanger, K" uniqKey="Belanger K">K Belanger</name></author><author><name sortKey="Murk, W" uniqKey="Murk W">W Murk</name></author><author><name sortKey="Bracken, Mb" uniqKey="Bracken M">MB Bracken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ver Heul, A" uniqKey="Ver Heul A">A Ver Heul</name></author><author><name sortKey="Planer, J" uniqKey="Planer J">J Planer</name></author><author><name sortKey="Kau, Al" uniqKey="Kau A">AL Kau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fukuda, Jt" uniqKey="Fukuda J">JT Fukuda</name></author><author><name sortKey="Sonis, Al" uniqKey="Sonis A">AL Sonis</name></author><author><name sortKey="Platt, Os" uniqKey="Platt O">OS Platt</name></author><author><name sortKey="Kurth, S" uniqKey="Kurth S">S Kurth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zeissig, S" uniqKey="Zeissig S">S Zeissig</name></author><author><name sortKey="Blumberg, Rs" uniqKey="Blumberg R">RS Blumberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schulfer, A" uniqKey="Schulfer A">A Schulfer</name></author><author><name sortKey="Blaser, Mj" uniqKey="Blaser M">MJ Blaser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lim, Sh" uniqKey="Lim S">SH Lim</name></author><author><name sortKey="Morris, A" uniqKey="Morris A">A Morris</name></author><author><name sortKey="Li, K" uniqKey="Li K">K Li</name></author><author><name sortKey="Fitch, Ac" uniqKey="Fitch A">AC Fitch</name></author><author><name sortKey="Fast, L" uniqKey="Fast L">L Fast</name></author><author><name sortKey="Goldberg, L" uniqKey="Goldberg L">L Goldberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Enwonwu, Co" uniqKey="Enwonwu C">CO Enwonwu</name></author><author><name sortKey="Xu, Xx" uniqKey="Xu X">XX Xu</name></author><author><name sortKey="Turner, E" uniqKey="Turner E">E Turner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author><author><name sortKey="Kato, Gj" uniqKey="Kato G">GJ Kato</name></author><author><name sortKey="Poljakovic, M" uniqKey="Poljakovic M">M Poljakovic</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Blackwelder, Wc" uniqKey="Blackwelder W">WC Blackwelder</name></author><author><name sortKey="Sachdev, V" uniqKey="Sachdev V">V Sachdev</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author><author><name sortKey="Kuypers, Fa" uniqKey="Kuypers F">FA Kuypers</name></author><author><name sortKey="Larkin, S" uniqKey="Larkin S">S Larkin</name></author><author><name sortKey="Vichinsky, Ep" uniqKey="Vichinsky E">EP Vichinsky</name></author><author><name sortKey="Styles, La" uniqKey="Styles L">LA Styles</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lopez, Bl" uniqKey="Lopez B">BL Lopez</name></author><author><name sortKey="Kreshak, Aa" uniqKey="Kreshak A">AA Kreshak</name></author><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author><author><name sortKey="Davis Moon, L" uniqKey="Davis Moon L">L Davis-Moon</name></author><author><name sortKey="Ballas, Sk" uniqKey="Ballas S">SK Ballas</name></author><author><name sortKey="Ma, Xl" uniqKey="Ma X">XL Ma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author><author><name sortKey="Kuypers, Fa" uniqKey="Kuypers F">FA Kuypers</name></author><author><name sortKey="Lavrisha, L" uniqKey="Lavrisha L">L Lavrisha</name></author><author><name sortKey="Ansari, M" uniqKey="Ansari M">M Ansari</name></author><author><name sortKey="Sweeters, N" uniqKey="Sweeters N">N Sweeters</name></author><author><name sortKey="Stewart, M" uniqKey="Stewart M">M Stewart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Solomons, C" uniqKey="Solomons C">C Solomons</name></author><author><name sortKey="Hathaway, W" uniqKey="Hathaway W">W Hathaway</name></author><author><name sortKey="Cotton, E" uniqKey="Cotton E">E Cotton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author><author><name sortKey="Kuypers, Fa" uniqKey="Kuypers F">FA Kuypers</name></author><author><name sortKey="Larkin, S" uniqKey="Larkin S">S Larkin</name></author><author><name sortKey="Sweeters, N" uniqKey="Sweeters N">N Sweeters</name></author><author><name sortKey="Simon, J" uniqKey="Simon J">J Simon</name></author><author><name sortKey="Vichinsky, Ep" uniqKey="Vichinsky E">EP Vichinsky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bakshi, N" uniqKey="Bakshi N">N Bakshi</name></author><author><name sortKey="Morris, Cr" uniqKey="Morris C">CR Morris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cox, Se" uniqKey="Cox S">SE Cox</name></author><author><name sortKey="Ellins, Ea" uniqKey="Ellins E">EA Ellins</name></author><author><name sortKey="Marealle, Ai" uniqKey="Marealle A">AI Marealle</name></author><author><name sortKey="Newton, Cr" uniqKey="Newton C">CR Newton</name></author><author><name sortKey="Soka, D" uniqKey="Soka D">D Soka</name></author><author><name sortKey="Sasi, P" uniqKey="Sasi P">P Sasi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saleh, D" uniqKey="Saleh D">D Saleh</name></author><author><name sortKey="Ernst, P" uniqKey="Ernst P">P Ernst</name></author><author><name sortKey="Lim, S" uniqKey="Lim S">S Lim</name></author><author><name sortKey="Barnes, Pj" uniqKey="Barnes P">PJ Barnes</name></author><author><name sortKey="Giaid, A" uniqKey="Giaid A">A Giaid</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcbrien, Cn" uniqKey="Mcbrien C">CN Mcbrien</name></author><author><name sortKey="Menzies Gow, A" uniqKey="Menzies Gow A">A Menzies-Gow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rath, M" uniqKey="Rath M">M Rath</name></author><author><name sortKey="Muller, I" uniqKey="Muller I">I Muller</name></author><author><name sortKey="Kropf, P" uniqKey="Kropf P">P Kropf</name></author><author><name sortKey="Closs, Ei" uniqKey="Closs E">EI Closs</name></author><author><name sortKey="Munder, M" uniqKey="Munder M">M Munder</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Front Immunol</journal-id><journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id><journal-title-group><journal-title>Frontiers in Immunology</journal-title></journal-title-group><issn pub-type="epub">1664-3224</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32038616</article-id><article-id pub-id-type="pmc">6992560</article-id><article-id pub-id-type="doi">10.3389/fimmu.2019.03058</article-id><article-categories><subj-group subj-group-type="heading"><subject>Immunology</subject><subj-group><subject>Mini Review</subject></subj-group></subj-group></article-categories><title-group><article-title>Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Samarasinghe</surname><given-names>Amali E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="author-notes" rid="fn002"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rosch</surname><given-names>Jason W.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="corresp" rid="c001"><sup>*</sup></xref><xref ref-type="author-notes" rid="fn002"><sup>†</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/83095/overview"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Division of Pulmonology, Allergy-Immunology, and Sleep, Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></aff><aff id="aff2"><sup>2</sup><institution>Department of Microbiology Immunology and Biochemistry, College of Medicine, University of Tennessee Health Science Center</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></aff><aff id="aff3"><sup>3</sup><institution>Children's Foundation Research Institute</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></aff><aff id="aff4"><sup>4</sup><institution>Department of Infectious Diseases, St. Jude Children's Research Hospital</institution>,<addr-line>Memphis, TN</addr-line>,<country>United States</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Nadeem Khan, University of North Dakota, United States</p></fn><fn fn-type="edited-by"><p>Reviewed by: Bibhuti Mishra, University of Massachusetts Medical School, United States; Timothy J. Chapman, Rochester Regional Health, United States</p></fn><corresp id="c001">*Correspondence: Jason W. Rosch <email>jason.rosch@stjude.org</email></corresp><fn fn-type="other" id="fn001"><p>This article was submitted to Inflammation, a section of the journal Frontiers in Immunology</p></fn><fn fn-type="other" id="fn002"><p>†These authors have contributed equally to this work</p></fn></author-notes><pub-date pub-type="epub"><day>24</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>3058</elocation-id><history><date date-type="received"><day>29</day><month>10</month><year>2019</year></date><date date-type="accepted"><day>16</day><month>12</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2020 Samarasinghe and Rosch.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Samarasinghe and Rosch</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p>The underlying pathologies of sickle cell disease and asthma share many characteristics in terms of respiratory inflammation. The principal mechanisms of pulmonary inflammation are largely distinct, but activation of common pathways downstream of the initial inflammatory triggers may lead to exacerbation of both disease states. The altered inflammatory landscape of these respiratory pathologies can differentially impact respiratory pathogen susceptibility in patients with sickle cell disease and asthma. How these two distinct diseases behave in a comorbid setting can further exacerbate pulmonary complications associated with both disease states and impact susceptibility to respiratory infection. This review will provide a concise overview of how asthma distinctly affects individuals with sickle cell disease and how pulmonary physiology and inflammation are impacted during comorbidity.</p></abstract><kwd-group><kwd>sickle cell disease (SCD)</kwd><kwd>asthma</kwd><kwd>acute chest syndrome (ACS)</kwd><kwd>respiratory infection</kwd><kwd>pulmonary inflammation</kwd></kwd-group><funding-group><award-group><funding-source id="cn001">American Lebanese Syrian Associated Charities<named-content content-type="fundref-id">10.13039/100012524</named-content></funding-source><award-id rid="cn001">1RO1AI110618</award-id><award-id rid="cn001">1U01AI124302</award-id><award-id rid="cn001">ALSAC</award-id><award-id rid="cn001">R01-AI125481</award-id></award-group></funding-group><counts><fig-count count="2"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="99"></ref-count><page-count count="8"></page-count><word-count count="6715"></word-count></counts></article-meta></front><body><sec sec-type="intro" id="s1"><title>Introduction</title><p>Red blood cells (RBCs) constitute the largest number of mobile cells in the human body (about 3 × 10<sup>12</sup>) that perform the primary function of O<sub>2</sub> (and CO<sub>2</sub>) transportation through hemoglobin (Hb). Alterations that occur in Hb through inherited genes can lead to a change in RBC morphology and function leading to sickle cell disease (SCD), a common inherited disorder leading to anemia, incidences of vaso-occlusive crises, acute chest syndrome (ACS), cumulative organ damage, and a number of additional chronic comorbidities (<xref rid="B1" ref-type="bibr">1</xref>). A large number of individuals carry the sickle cell trait, wherein a single sickle cell gene (“<italic>S</italic>”) is inherited, and are mostly asymptomatic (<xref rid="B2" ref-type="bibr">2</xref>). However, a patient with two sickle genes are named to have the Hb<italic>SS</italic> form of SCD, while a patient who inherits one <italic>S</italic> gene and another abnormal hemoglobin gene (C, beta thalassemia, D, E, or O) will have alternate types of SCD such as HbSC or HbS beta thalassemia. Patients with SCD represent a significant health care burden in terms of cost, and despite a number of therapeutic strategies, life expectancy in this population remains decades premature compared to that of the general population (<xref rid="B3" ref-type="bibr">3</xref>–<xref rid="B5" ref-type="bibr">5</xref>). As the most commonly inherited blood disease, SCD affects >100,000 in the United States and millions more worldwide (<xref rid="B6" ref-type="bibr">6</xref>). With 1:13 babies born with the sickle cell trait and 1:365 patients having SCD, African Americans have the highest incidence of SCD in the U.S. (<xref rid="B7" ref-type="bibr">7</xref>). The high occurrence of pulmonary complications in SCD patients has led to the consideration of possible complications from other respiratory conditions that have similar symptomatologies, like asthma.</p><p>Asthma is a syndrome of the respiratory system that affects 26 million Americans and 300 million globally. Like SCD, the incidence of asthma is predicted to continue to increase as indicated by the 3.6% increase in prevalence since 2006 (<xref rid="B8" ref-type="bibr">8</xref>). Of note is the observation that individuals with SCD have an increased incidence of asthma when compared to the general population. In children, the incidence of asthma diagnosis is as high as 27% in individuals with SCD (<xref rid="B9" ref-type="bibr">9</xref>). Approximately 30–70% of patients with SCD also suffer from asthma (<xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B11" ref-type="bibr">11</xref>) leading to a poorer quality of life. Like SCD, African Americans (especially women) are more likely to have asthma and African American children have a much higher likelihood of dying from asthma compared to other ethnicities (<xref rid="B12" ref-type="bibr">12</xref>). While it is unclear why asthma incidence is disproportionately elevated in African American children with SCD, socioeconomic factors and perhaps even overdiagnosis of asthma in SCD patients may contribute to this bias. ACS, one of the most frequent complications of SCD, is correlated with the incidence of asthma in the SCD population (<xref rid="B13" ref-type="bibr">13</xref>–<xref rid="B15" ref-type="bibr">15</xref>). As such, gaining an understanding of the clinical and immunological consequences of asthma in the context of SCD is of critical importance for improving patient outcomes in this patient group.</p><p>Asthma and SCD share a number of similarities in terms of the immunological factors associated with their respective disease states. Both conditions result in inflammation and airway hyperreactivity, both conditions impact susceptibility to respiratory infections, and both require specific interventions to mitigate the complications associated with them. Despite the recognition that asthma in the context of SCD likely results in a comorbid condition distinct from the general population, there is relatively little mechanistic insight into how these two disease pathologies co-function. In this review we highlight the potential immunological synergies between asthma and SCD garnered from both clinical data and murine modeling studies to showcase how these conditions may exacerbate each other, thereby representing a unique comorbid condition in these high-risk patient populations.</p></sec><sec id="s2"><title>Immunologic Consequences of Asthma in SCD</title><p>The immunologic sequelae associated with SCD and asthma are complex but have some overlap. Given that both asthma and SCD impact inflammation in distinct ways, the interplay into how these two conditions function when present in a comorbid state raises important questions. Elevated IgE levels in children with SCD is much more common than in the general population and is associated with both asthma and increased morbidity in children (<xref rid="B9" ref-type="bibr">9</xref>). Increased serum IgE is a well-accepted biomarker of allergic asthma, and SCD patients have elevated IgE in sera which may occur as a result of non-specific immune activation in these patients, leading to a T<sub>H</sub>2 bias and increased risk for asthma as a consequence. This enhanced serum IgE availability is also reflected in murine models, whereby the increase in total IgE in sensitized SCD mice is significantly greater than what is observed in sensitized wild type animals (<xref rid="B16" ref-type="bibr">16</xref>). Pulmonary function testing is often utilized to distinguish allergic asthma from other IgE mediated inflammatory conditions. Adult patients with SCD have a high incidence, up to 80%, of abnormal pulmonary function when tested (<xref rid="B17" ref-type="bibr">17</xref>). A similar, but less severe pattern is observed in children with SCD, with ~50% of patients having abnormal results (<xref rid="B18" ref-type="bibr">18</xref>). Abnormal results were more prevalant in the asthmatic pediatric SCD patients, underscoring applicability of pulmonary function analysis as part of making an appropriate diagnosis of asthma in SCD patients (<xref rid="B18" ref-type="bibr">18</xref>). The utility of screening for respiratory disorders such as asthma in children and adults using pulmonary function tests has not been fully established and current guidelines suggest routine collection of a thorough respiratory history to identify pulmonary disease in patients with SCD. This is of particular importance in young children because pulmonary function tests can be unreliable in this population. While asthma represents a major and frequent health concern for patients with SCD, the mechanistic factors driving the development and immunological features of asthma in the context of SCD remain poorly elucidated and create barriers to appropriate asthma management in SCD patients.</p><p>Endothelial activation is considered to be a major pathway by which sickled RBCs contribute to vaso-occlusion. Sickled RBC binding to integrins on endothelial cells lead to injury via reactive oxygen species that also function in a feed-forward loop to continue to activate endothelial cells (<xref rid="B19" ref-type="bibr">19</xref>). This activation leads to the infiltration of other cells such as monocytes and neutrophils which contribute to uncontrolled cell adhesion that occurs in blood vessels of SCD patients (<xref rid="B20" ref-type="bibr">20</xref>, <xref rid="B21" ref-type="bibr">21</xref>). Increased levels of pro-inflammatory cytokines such as IL-3, GM-CSF, and PGE2 have also been noted to occur in SCD patients (<xref rid="B22" ref-type="bibr">22</xref>–<xref rid="B24" ref-type="bibr">24</xref>). Steady state levels of TNF-α, IL-α, IL-1β, and IL-6 are all elevated in SCD (<xref rid="B23" ref-type="bibr">23</xref>–<xref rid="B25" ref-type="bibr">25</xref>). Elevated neutrophil counts are characteristic of SCD and can form neutrophil extracellular traps in the pulmonary vasculature, contributing to acute lung injury resulting from inflammatory cytokine signaling (<xref rid="B26" ref-type="bibr">26</xref>). Both the pulmonary and systemic responses to inflammatory stimuli are greatly elevated in the context of SCD with enhanced levels of TNF-α, IL-1β, s-VCAM-1 being observed following endotoxin treatment (<xref rid="B27" ref-type="bibr">27</xref>). This heightened inflammatory landscape contributes to multiple complications of SCD, ranging from pulmonary disfunction and infection susceptibility.</p><p>Airway inflammation is a canonical hallmark of asthma and eosinophils may dominate as the infiltrating leukocyte in severe allergic asthma. Endothelial activation is fundamental to the initiation of inflammation in asthma (<xref rid="B28" ref-type="bibr">28</xref>) wherein endothelial cells upregulate integrins and selectins in response to allergenic stimuli (<xref rid="B29" ref-type="bibr">29</xref>) and cytokines produced <italic>in situ</italic> by resident leukocytes (<xref rid="B30" ref-type="bibr">30</xref>). Markers of endothelial activation including ICAM-1, VCAM-1, P-selection, and E-selectin are also elevated in the context of SCD (<xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B31" ref-type="bibr">31</xref>). Similarly, IL-3 and GM-CSF can promote the allergic milieu (<xref rid="B32" ref-type="bibr">32</xref>) and support activation and survival of eosinophils in the airways (<xref rid="B33" ref-type="bibr">33</xref>). While the exact role of PGE2 in the lungs of asthmatics is still unclear, its elevation correlates with eosinophilia (<xref rid="B34" ref-type="bibr">34</xref>). Common inflammatory pathways between SCD and asthma may therefore lead to an asthma-like phenotype in patients with SCD (<xref ref-type="fig" rid="F1">Figure 1</xref>), or indeed, increase the likelihood of asthma pathogenesis in these patients.</p><fig id="F1" position="float"><label>Figure 1</label><caption><p>Endothelial activation by sickled red blood cells that may exacerbate asthma. Sickled red cells induce endothelial upregulation of integrins, ICAM, and VCAM, that enhance attachment and subsequent infiltration of neutrophils and monocytes into the pulmonary tissue. Increased margination of these leukocytes trigger further interaction with endothelial cells through the production of pro-inflammatory cytokines that together with sickled red blood cells cause endothelial cell production of reactive oxygen and nitrogen species that can trigger blood vessel injury. Recruited cells further activate the bronchial epithelium leading to a positive feedback loop to promote heightened inflammation and airway hyperreactivity.</p></caption><graphic xlink:href="fimmu-10-03058-g0001"></graphic></fig></sec><sec id="s3"><title>Modeling Asthma and SCD in Mice</title><p>While SCD is a hereditary condition, asthma development is dependent on genetic and environmental components. Although rodents do not naturally develop asthma, asthma-like disease can be triggered in them through continuous exposure to natural aeroallergens or ovalbumin (OVA) (<xref rid="B35" ref-type="bibr">35</xref>). The possible overlap between asthma and SCD based on shared symptoms such as airway inflammation, hyperresponsiveness, and architectural damage has created a demand for animal models of asthma and SCD comorbidity, although only a few have been created to date using OVA and house dust mite (HDM) as triggering allergens.</p><p>Existing models of asthma in SCD mice after OVA sensitization and challenge suggest that mice with SCD respond more severely to allergen exposures (<xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B36" ref-type="bibr">36</xref>, <xref rid="B37" ref-type="bibr">37</xref>). OVA exposure leads to the development of peribronchovascular inflammation (with active eosinophils) and inflammatory foci, elevated serum IgE, and bronchial epithelial hyperplasia in BERK SCD mice to equivalent levels as wild-type controls (<xref rid="B16" ref-type="bibr">16</xref>). However, more severe pathologic changes occur in SCD mice when OVA-challenge duration is prolonged causing death in about 30% of the animals (<xref rid="B16" ref-type="bibr">16</xref>), suggesting that the BERK SCD mice may have a lower threshold for asthma exacerbation. Using a bone marrow chimeric mouse model of SCD and shortened exposures to aerosolized OVA, Pritchard et al. demonstrated that OVA-induced allergic inflammation in these SCD mice correlates with a heightened T<sub>H</sub>2 cytokine milieu and pulmonary tissue resistance marked by a decrease in lung tissue elasticity suggestive of greater alveolar occlusion (<xref rid="B36" ref-type="bibr">36</xref>). This trend in airway inflammation and general T<sub>H</sub>2 skewing was recapitulated by Andemariam et al. using the BERK mouse model of SCD and a more standard model of OVA exposure (<xref rid="B37" ref-type="bibr">37</xref>). Of note, naïve BERK SCD have increased levels of T<sub>H</sub>2-type cytokines in the bronchoalveolar lavage fluid and a higher number of T-lymphocytes in the lungs (<xref rid="B37" ref-type="bibr">37</xref>). Airway hyperresponsiveness is a shared hallmark of SCD and asthma (<xref rid="B38" ref-type="bibr">38</xref>, <xref rid="B39" ref-type="bibr">39</xref>), that generally correlates with pulmonary inflammation. Despite heightened airway inflammation in response to OVA, BERK SCD mice had lower airway reactivity compared to wild-type mice even at very high doses of methacholine (<xref rid="B37" ref-type="bibr">37</xref>), suggesting that inflammation and airway hyperresponsiveness may be disjointed in SCD.</p><p>Although OVA is a commonly used trigger to induce allergic asthma-like disease in mice, due to its limitations as a clinically relevant aeroallergen, utilization of more relevant allergens such as HDM, cockroach, fungal, and viral antigens have gained popularity among investigators that model asthma in mice (<xref rid="B40" ref-type="bibr">40</xref>). Most recently, Jiang et al. found no differences between BERK SCD and wild-type mice in the inflammatory index, airway cytokines, or HDM-specific IgE levels after HDM exposure (<xref rid="B41" ref-type="bibr">41</xref>). These findings are exciting as they confirm that variation in outcome occurs based on the antigen, route of exposure, and adjuvants in SCD mice. Mouse models of SCD with asthma that can be used to decipher mechanisms that underlie asthma pathogenesis in patients with SCD is an important gap in technology to address.</p></sec><sec id="s4"><title>Treatment of Asthma in Individuals with Sickle Cell Disease</title><p>Information amassed on the immunologic basis of asthma has resulted in the development of biologics targeted for patients with specific endotypes. However, since the efficacy of these therapeutics are quite low, corticosteroids are used to alleviate the symptoms during asthma attacks despite our knowledge of the long term negative impact of steroids on human health (<xref rid="B42" ref-type="bibr">42</xref>). Although the SCD-asthma comorbid condition is prevalent, relatively little evidence based models exist for its management. Current models for asthma management in SCD are based on NIH guidelines for the general population and include liberal use of inhaled steroids, despite the extensive literature recognizing SCD patients as a uniquely susceptible and vulnerable patient population (<xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B43" ref-type="bibr">43</xref>, <xref rid="B44" ref-type="bibr">44</xref>). Use of inhaled steroids further increases the risk of colonization of <italic>S. pneumoniae</italic> which may increase the likelihood for the development of invasive disease to which the SCD population is particularly susceptible (<xref rid="B45" ref-type="bibr">45</xref>, <xref rid="B46" ref-type="bibr">46</xref>). Inhaled corticosteroids have been proposed to be used to prevent additional episodes of vaso-occlusive crisis in pediatric patients, and recent studies have underscored the feasibility of this approach in young children (<xref rid="B47" ref-type="bibr">47</xref>). Inhaled steroids given to non-asthmatic patients with SCD have demonstrated considerable promise, with significant reductions in pain and sVCAM levels as well as inflammatory macrophage markers, underscoring the potential for targeting inflammation to improve health outcomes in these patients (<xref rid="B48" ref-type="bibr">48</xref>–<xref rid="B50" ref-type="bibr">50</xref>). Whether treatments for specific asthma endotypes can be extended to patients with SCD remains unclear, though given the underlying differences in inflammation tailored therapeutic strategies may be required.</p></sec><sec id="s5"><title>SCD and Asthma: Independent Pathways to Infection Susceptibility</title><p>Asthma and SCD both fundamentally alter susceptibility and immune responses to respiratory infection. Patients with SCD are overwhelmingly susceptible to multiple respiratory pathogens, most importantly the pneumococcus (<xref rid="B51" ref-type="bibr">51</xref>, <xref rid="B52" ref-type="bibr">52</xref>), and infectious diseases increase the development of ACS in these patients (<xref rid="B53" ref-type="bibr">53</xref>–<xref rid="B55" ref-type="bibr">55</xref>). The heightened sensitivity to infection is recapitulated in the murine model of SCD, whereby the SCD mice demonstrate dramatically enhanced susceptibility to both bacterial and viral respiratory infections (<xref rid="B56" ref-type="bibr">56</xref>–<xref rid="B58" ref-type="bibr">58</xref>). This issue can be further confounded by strains outside of vaccine coverage causing invasive disease in these patients, as is the case with <italic>S. pneumoniae</italic> (<xref rid="B59" ref-type="bibr">59</xref>). Immunogenic responses to vaccines in SCD patients may also be suboptimal to confer effective protection as the responses have been reported to wane more rapidly to a number of serotypes included in the current pneumococcal vaccines, an observation that has been recapitulated in murine models of SCD (<xref rid="B60" ref-type="bibr">60</xref>, <xref rid="B61" ref-type="bibr">61</xref>). These underscore the importance of appropriate prophylactic strategies to mitigate infection risk in individuals with SCD.</p><p>Similar but distinct to what is observed in the context of SCD, allergic asthma dramatically also alters susceptibility to multiple respiratory pathogens including both viral and bacterial pathogens (<xref rid="B62" ref-type="bibr">62</xref>). However, unlike in the case of SCD, allergic asthma has been found to confer both sensitivity and resistance to subsequent respiratory infection, wherein outcomes are more likely to be dependent on the type of pathogen. Asthma exacerbations triggered by rhinoviruses and respiratory syncytial virus, for example, can be detrimental to the host (<xref rid="B63" ref-type="bibr">63</xref>), while asthma exacerbations triggered by influenza virus infection is tolerated by the host which also exhibit reduced signs of influenza morbidity and enhanced viral clearance (<xref rid="B64" ref-type="bibr">64</xref>, <xref rid="B65" ref-type="bibr">65</xref>). Immune responses to viruses in hosts with asthma may be dependent on a multitude of factors including gender, age, virus strain and prior exposures, endotype of asthma, and environmental factors including pollution and nutrition. How these alterations in pulmonary inflammation during the asthma-SCD comorbid state differentially impact the risk of infection remains poorly understood, though given the distinct nature of these two disease settings, it may be anticipated that together they impact infection susceptibility in a manner distinct from the general population.</p></sec><sec id="s6"><title>Antibiotic Exposure and Asthma</title><p>Due to the propensity of patients with SCD to develop fulminant lethal sepsis caused by <italic>S. pneumoniae</italic>, during childhood, penicillin prophylaxis is prescribed for all children with SCD until the age of 5 years, which has dramatically improved mortality in this patient population prior to the advent of the pneumococcal conjugate vaccine (<xref rid="B66" ref-type="bibr">66</xref>–<xref rid="B70" ref-type="bibr">70</xref>). There is considerable evidence linking antibiotic exposure to the development of childhood asthma and other allergic disease in the general population, though there are challenges in terms of confounding respiratory infections (<xref rid="B71" ref-type="bibr">71</xref>–<xref rid="B79" ref-type="bibr">79</xref>). Early antibiotic use is associated with allergic asthma in young children even when accounting for bias inherent from antibiotic prescriptions to treat early symptoms of asthma; this is predictable as bacterial colonization of the respiratory and gastrointestinal tract are critical mediators that shape susceptibility to allergic airway inflammation (<xref rid="B80" ref-type="bibr">80</xref>–<xref rid="B82" ref-type="bibr">82</xref>). These effects may be amplified in SCD patients due to the prolonged exposure to antibiotics.</p><p>Administering penicillin to patients with SCD eliminates several bacterial species from the nasal-oral microbiota (<xref rid="B83" ref-type="bibr">83</xref>). Exposure to antibiotics early in life can have long lasting consequences on the developing bacterial microbiome (<xref rid="B84" ref-type="bibr">84</xref>, <xref rid="B85" ref-type="bibr">85</xref>). Bacterial colonization of the respiratory and gastrointestinal tract are critical mediators that can shape susceptibility to allergic airway inflammation (<xref rid="B82" ref-type="bibr">82</xref>). Numerous gaps in knowledge including alterations that may naturally occur in the microbiome of the SCD host (<xref rid="B86" ref-type="bibr">86</xref>), the relative impact of long-term penicillin prophylaxis on the intestinal and respiratory flora of these patients, and whether this long-term prophylaxis also impacts the likelihood of subsequent asthma development preclude our understanding of disease pathogenesis in SCD patients and those that may develop asthma.</p></sec><sec id="s7"><title>Arginine Deficiency: A Common Crossroad in SCD and Asthma Pathophysiology</title><p>Arginine deficiency has long been recognized as an important aspect of SCD pathophysiology (<xref rid="B87" ref-type="bibr">87</xref>, <xref rid="B88" ref-type="bibr">88</xref>). Low arginine bioavailability is associated with a multitude of complications in SCD including pulmonary hypertension and vaso-occlusive pain episodes (<xref rid="B89" ref-type="bibr">89</xref>–<xref rid="B91" ref-type="bibr">91</xref>). The decreased arginine availability in SCD is severe enough to impact the contribution of bacterial arginine biosynthesis and uptake pathways to virulence (<xref rid="B57" ref-type="bibr">57</xref>). Due to the multiple facets of host pathophysiology, arginine supplementation has been proposed as a therapeutic intervention for SCD (<xref rid="B92" ref-type="bibr">92</xref>, <xref rid="B93" ref-type="bibr">93</xref>). Arginine supplementation has been suggested as a means by which to alleviate complications in patients with SCD and improve overall health (<xref rid="B94" ref-type="bibr">94</xref>, <xref rid="B95" ref-type="bibr">95</xref>). Clinical trials further support the potential for arginine supplementation to confer benefit in SCD individuals in terms of endothelial function and to induce nitric oxide production during vaso-occlusive crisis (<xref rid="B93" ref-type="bibr">93</xref>, <xref rid="B96" ref-type="bibr">96</xref>).</p><p>Arginine deficiency is a common feature underlying the pathophysiology of both allergic asthma and SCD (<xref ref-type="fig" rid="F2">Figure 2</xref>). Murine models of allergic asthma have demonstrated that arginine deficiency to nitric oxide synthase (NOS) results in deficiencies in nitric oxide, a bronchodilator, in tandem with increased peroxynitrite, a pro-contractile molecule, both of which contribute to airway hyperresponsiveness in the context of asthma. Polycation secretion by eosinophils, which are dramatically elevated in allergic asthma, can inhibit arginine uptake via the y+ system (<xref rid="B97" ref-type="bibr">97</xref>, <xref rid="B98" ref-type="bibr">98</xref>). In the context of SCD, there are additional mechanisms underlying arginine deficiency that are independent of pathways operative during asthma. The increased hemolysis of RBCs leads to the release of cellular arginase which can scavenge arginine prior to cellular uptake. In the context of asthma and SCD comorbidity, heightened baseline inflammation may lead to increased expression of both iNOS and arginase, thereby further depleting cellular arginine pools (<xref rid="B99" ref-type="bibr">99</xref>). As such, the extracellular arginase released by hemolysis coupled with the increased pulmonary eosinophil infiltrate inhibiting arginine uptake are likely to have an additive effect. Likewise, the increased arginase and iNOS activity resulting from increased levels of inflammatory cytokines inherent in both SCD and allergic asthma, are also potentially synergistic in terms of arginine depletion. Due to the divergence of many of these arginine depleting pathways, it would be expected that such deficiency may be synergistic in comorbid patients with SCD and asthma.</p><fig id="F2" position="float"><label>Figure 2</label><caption><p>Arginine deficiencies in Sickle cell disease and asthma. Sickle cell disease and asthma share complementary and potentially synergistic mechanisms of arginine deficiency. Many of the pathways operative extracellularly are different, while the intracellular pathways are shared.</p></caption><graphic xlink:href="fimmu-10-03058-g0002"></graphic></fig><p>The benefits conferred by arginine supplementation may be most evident in comorbid patients with both SCD and asthma due to the non-overlapping mechanisms of arginine deficiency.</p></sec><sec sec-type="discussion" id="s8"><title>Discussion</title><p>SCD and asthma share similar manifestations in terms of airway hyperreactivity despite being immunologically distinct diseases. Experimental modeling and clinical data suggest that asthma impacts individuals with SCD in a specific manner distinct from the general population. Laying a mechanistic foundation for understanding pulmonary complications of sickle cell disease and how these complications can be rationally targeted in a SCD-specific manner may provide novel opportunities for treatment. Given the unique host pathophysiology that underlies SCD, these individuals may benefit from tailored interventions for the treatment of asthma.</p></sec><sec id="s9"><title>Author Contributions</title><p>JR and AS wrote the manuscript jointly.</p><sec><title>Conflict of Interest</title><p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec></sec></body><back><fn-group><fn fn-type="financial-disclosure"><p><bold>Funding.</bold> AS was partially funded through the NIH, NIAID 1R01-AI125481, and the Plough Foundation. JR was partially funded through ALSAC, NIAID 1U01-AI124302, and 1R01-AI110618.</p></fn></fn-group><ref-list><title>References</title><ref id="B1"><label>1.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Platt</surname><given-names>OS</given-names></name><name><surname>Brambilla</surname><given-names>DJ</given-names></name><name><surname>Rosse</surname><given-names>WF</given-names></name><name><surname>Milner</surname><given-names>PF</given-names></name><name><surname>Castro</surname><given-names>O</given-names></name><name><surname>Steinberg</surname><given-names>MH</given-names></name><etal></etal></person-group>. <article-title>Mortality in sickle cell disease. Life expectancy and risk factors for early death</article-title>. <source>N Engl J Med</source>. (<year>1994</year>) <volume>330</volume>:<fpage>1639</fpage>–<lpage>44</lpage>. <pub-id pub-id-type="doi">10.1056/NEJM199406093302303</pub-id><pub-id pub-id-type="pmid">7993409</pub-id></mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ojodu</surname><given-names>J</given-names></name><name><surname>Hulihan</surname><given-names>MM</given-names></name><name><surname>Pope</surname><given-names>SN</given-names></name><name><surname>Grant</surname><given-names>AM</given-names></name><collab>Centers for Disease Control and Prevention</collab></person-group>. <article-title>Incidence of sickle cell trait–United States, 2010</article-title>. <source>MMWR Morb Mortal Wkly Rep.</source> (<year>2014</year>) <volume>63</volume>:<fpage>1155</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="pmid">25503918</pub-id></mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kauf</surname><given-names>TL</given-names></name><name><surname>Coates</surname><given-names>TD</given-names></name><name><surname>Huazhi</surname><given-names>L</given-names></name><name><surname>Mody-Patel</surname><given-names>N</given-names></name><name><surname>Hartzema</surname><given-names>AG</given-names></name></person-group>. <article-title>The cost of health care for children and adults with sickle cell disease</article-title>. <source>Am J Hematol.</source> (<year>2009</year>) <volume>84</volume>:<fpage>323</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.21408</pub-id><pub-id pub-id-type="pmid">19358302</pub-id></mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Elmariah</surname><given-names>H</given-names></name><name><surname>Garrett</surname><given-names>ME</given-names></name><name><surname>De Castro</surname><given-names>LM</given-names></name><name><surname>Jonassaint</surname><given-names>JC</given-names></name><name><surname>Ataga</surname><given-names>KI</given-names></name><name><surname>Eckman</surname><given-names>JR</given-names></name><etal></etal></person-group>. <article-title>Factors associated with survival in a contemporary adult sickle cell disease cohort</article-title>. <source>Am J Hematol.</source> (<year>2014</year>) <volume>89</volume>:<fpage>530</fpage>–<lpage>5</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.23683</pub-id><pub-id pub-id-type="pmid">24478166</pub-id></mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Telen</surname><given-names>MJ</given-names></name><name><surname>Malik</surname><given-names>P</given-names></name><name><surname>Vercellotti</surname><given-names>GM</given-names></name></person-group>. <article-title>Therapeutic strategies for sickle cell disease: towards a multi-agent approach</article-title>. <source>Nat Rev Drug Discov.</source> (<year>2018</year>) <volume>18</volume>:<fpage>139</fpage>–<lpage>58</lpage>. <pub-id pub-id-type="doi">10.1038/s41573-018-0003-2</pub-id><pub-id pub-id-type="pmid">30514970</pub-id></mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rees</surname><given-names>DC</given-names></name><name><surname>Williams</surname><given-names>TN</given-names></name><name><surname>Gladwin</surname><given-names>MT</given-names></name></person-group><article-title>Sickle-cell disease</article-title>. <source>Lancet.</source> (<year>2010</year>) <volume>376</volume>:<fpage>2018</fpage>–<lpage>31</lpage>. <pub-id pub-id-type="doi">10.1016/S0140-6736(10)61029-X</pub-id><pub-id pub-id-type="pmid">21131035</pub-id></mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation publication-type="webpage"><person-group person-group-type="author"><collab>Centers for Disease Control Sickle Cell Disease (SCD)</collab></person-group> (<year>2019</year>). Available online at: <ext-link ext-link-type="uri" xlink:href="https://www.cdc.gov/ncbddd/sicklecell/index.html">https://www.cdc.gov/ncbddd/sicklecell/index.html</ext-link> (accessed October 22, 2019).</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Network</surname><given-names>GA</given-names></name></person-group><source>The Global Asthma Report 2018</source>. <publisher-loc>Auckland</publisher-loc>: <publisher-name>Global Asthma Network</publisher-name> (<year>2018</year>).</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>An</surname><given-names>P</given-names></name><name><surname>Barron-Casella</surname><given-names>EA</given-names></name><name><surname>Strunk</surname><given-names>RC</given-names></name><name><surname>Hamilton</surname><given-names>RG</given-names></name><name><surname>Casella</surname><given-names>JF</given-names></name><name><surname>Debaun</surname><given-names>MR</given-names></name></person-group>. <article-title>Elevation of IgE in children with sickle cell disease is associated with doctor diagnosis of asthma and increased morbidity</article-title>. <source>J Allergy Clin Immunol.</source> (<year>2011</year>) <volume>127</volume>:<fpage>1440</fpage>–<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1016/j.jaci.2010.12.1114</pub-id><pub-id pub-id-type="pmid">21388662</pub-id></mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>CR</given-names></name></person-group>. <article-title>Asthma management: reinventing the wheel in sickle cell disease</article-title>. <source>Am J Hematol.</source> (<year>2009</year>) <volume>84</volume>:<fpage>234</fpage>–<lpage>41</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.21359</pub-id><pub-id pub-id-type="pmid">19229984</pub-id></mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Debaun</surname><given-names>MR</given-names></name><name><surname>Strunk</surname><given-names>RC</given-names></name></person-group>. <article-title>The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia</article-title>. <source>Lancet.</source> (<year>2016</year>) <volume>387</volume>:<fpage>2545</fpage>–<lpage>53</lpage>. <pub-id pub-id-type="doi">10.1016/S0140-6736(16)00145-8</pub-id><pub-id pub-id-type="pmid">27353685</pub-id></mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Akinbami</surname><given-names>LJ</given-names></name><name><surname>Moorman</surname><given-names>JE</given-names></name><name><surname>Liu</surname><given-names>X</given-names></name></person-group><article-title>Asthma prevalence, health care use, and mortality: United States, 2005–2009</article-title>. <source>Natl Health Stat Report.</source> (<year>2011</year>) <volume>32</volume>:<fpage>1</fpage>–<lpage>14</lpage>.</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boyd</surname><given-names>JH</given-names></name><name><surname>Macklin</surname><given-names>EA</given-names></name><name><surname>Strunk</surname><given-names>RC</given-names></name><name><surname>Debaun</surname><given-names>MR</given-names></name></person-group>. <article-title>Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia</article-title>. <source>Blood.</source> (<year>2006</year>) <volume>108</volume>:<fpage>2923</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1182/blood-2006-01-011072</pub-id><pub-id pub-id-type="pmid">16690969</pub-id></mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bernaudin</surname><given-names>F</given-names></name><name><surname>Strunk</surname><given-names>RC</given-names></name><name><surname>Kamdem</surname><given-names>A</given-names></name><name><surname>Arnaud</surname><given-names>C</given-names></name><name><surname>An</surname><given-names>P</given-names></name><name><surname>Torres</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Asthma is associated with acute chest syndrome, but not with an increased rate of hospitalization for pain among children in France with sickle cell anemia: a retrospective cohort study</article-title>. <source>Haematologica.</source> (<year>2008</year>) <volume>93</volume>:<fpage>1917</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.3324/haematol.13090</pub-id><pub-id pub-id-type="pmid">18815195</pub-id></mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Debaun</surname><given-names>MR</given-names></name><name><surname>Rodeghier</surname><given-names>M</given-names></name><name><surname>Cohen</surname><given-names>R</given-names></name><name><surname>Kirkham</surname><given-names>FJ</given-names></name><name><surname>Rosen</surname><given-names>CL</given-names></name><name><surname>Roberts</surname><given-names>I</given-names></name><etal></etal></person-group>. <article-title>Factors predicting future ACS episodes in children with sickle cell anemia</article-title>. <source>Am J Hematol.</source> (<year>2014</year>) <volume>89</volume>:<fpage>E212</fpage>–<lpage>17</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.23819</pub-id><pub-id pub-id-type="pmid">25088663</pub-id></mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nandedkar</surname><given-names>SD</given-names></name><name><surname>Feroah</surname><given-names>TR</given-names></name><name><surname>Hutchins</surname><given-names>W</given-names></name><name><surname>Weihrauch</surname><given-names>D</given-names></name><name><surname>Konduri</surname><given-names>KS</given-names></name><name><surname>Wang</surname><given-names>J</given-names></name><etal></etal></person-group>. <article-title>Histopathology of experimentally induced asthma in a murine model of sickle cell disease</article-title>. <source>Blood.</source> (<year>2008</year>) <volume>112</volume>:<fpage>2529</fpage>–<lpage>38</lpage>. <pub-id pub-id-type="doi">10.1182/blood-2008-01-132506</pub-id><pub-id pub-id-type="pmid">18579795</pub-id></mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lunt</surname><given-names>A</given-names></name><name><surname>Desai</surname><given-names>SR</given-names></name><name><surname>Wells</surname><given-names>AU</given-names></name><name><surname>Hansell</surname><given-names>DM</given-names></name><name><surname>Mushemi</surname><given-names>S</given-names></name><name><surname>Melikian</surname><given-names>N</given-names></name><etal></etal></person-group>. <article-title>Pulmonary function, CT and echocardiographic abnormalities in sickle cell disease</article-title>. <source>Thorax.</source> (<year>2014</year>) <volume>69</volume>:<fpage>746</fpage>–<lpage>51</lpage>. <pub-id pub-id-type="doi">10.1136/thoraxjnl-2013-204809</pub-id><pub-id pub-id-type="pmid">24682519</pub-id></mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Intzes</surname><given-names>S</given-names></name><name><surname>Kalpatthi</surname><given-names>RV</given-names></name><name><surname>Short</surname><given-names>R</given-names></name><name><surname>Imran</surname><given-names>H</given-names></name></person-group>. <article-title>Pulmonary function abnormalities and asthma are prevalent in children with sickle cell disease and are associated with acute chest syndrome</article-title>. <source>Pediatr Hematol Oncol.</source> (<year>2013</year>) <volume>30</volume>:<fpage>726</fpage>–<lpage>32</lpage>. <pub-id pub-id-type="doi">10.3109/08880018.2012.756961</pub-id><pub-id pub-id-type="pmid">23301782</pub-id></mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Canalli</surname><given-names>AA</given-names></name><name><surname>Costa</surname><given-names>FF</given-names></name><name><surname>Saad</surname><given-names>ST</given-names></name><name><surname>Conran</surname><given-names>N</given-names></name></person-group>. <article-title>Granulocytic adhesive interactions and their role in sickle cell vaso-occlusion</article-title>. <source>Hematology.</source> (<year>2005</year>) <volume>10</volume>:<fpage>419</fpage>–<lpage>25</lpage>. <pub-id pub-id-type="doi">10.1080/10245330500141259</pub-id><pub-id pub-id-type="pmid">16273736</pub-id></mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belcher</surname><given-names>JD</given-names></name><name><surname>Marker</surname><given-names>PH</given-names></name><name><surname>Weber</surname><given-names>JP</given-names></name><name><surname>Hebbel</surname><given-names>RP</given-names></name><name><surname>Vercellotti</surname><given-names>GM</given-names></name></person-group>. <article-title>Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion</article-title>. <source>Blood.</source> (<year>2000</year>) <volume>96</volume>:<fpage>2451</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1182/blood.V96.7.2451</pub-id><pub-id pub-id-type="pmid">11001897</pub-id></mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belcher</surname><given-names>JD</given-names></name><name><surname>Chen</surname><given-names>C</given-names></name><name><surname>Nguyen</surname><given-names>J</given-names></name><name><surname>Zhang</surname><given-names>P</given-names></name><name><surname>Abdulla</surname><given-names>F</given-names></name><name><surname>Nguyen</surname><given-names>P</given-names></name><etal></etal></person-group>. <article-title>Control of oxidative stress and inflammation in sickle cell disease with the Nrf2 activator dimethyl fumarate</article-title>. <source>Antioxid Redox Signal.</source> (<year>2017</year>) <volume>26</volume>:<fpage>748</fpage>–<lpage>62</lpage>. <pub-id pub-id-type="doi">10.1089/ars.2015.6571</pub-id><pub-id pub-id-type="pmid">26914345</pub-id></mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Conran</surname><given-names>N</given-names></name><name><surname>Saad</surname><given-names>ST</given-names></name><name><surname>Costa</surname><given-names>FF</given-names></name><name><surname>Ikuta</surname><given-names>T</given-names></name></person-group>. <article-title>Leukocyte numbers correlate with plasma levels of granulocyte-macrophage colony-stimulating factor in sickle cell disease</article-title>. <source>Ann Hematol.</source> (<year>2007</year>) <volume>86</volume>:<fpage>255</fpage>–<lpage>61</lpage>. <pub-id pub-id-type="doi">10.1007/s00277-006-0246-6</pub-id><pub-id pub-id-type="pmid">17205286</pub-id></mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Croizat</surname><given-names>H</given-names></name></person-group>. <article-title>Circulating cytokines in sickle cell patients during steady state</article-title>. <source>Br J Haematol.</source> (<year>1994</year>) <volume>87</volume>:<fpage>592</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1111/j.1365-2141.1994.tb08318.x</pub-id><pub-id pub-id-type="pmid">7527647</pub-id></mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Graido-Gonzalez</surname><given-names>E</given-names></name><name><surname>Doherty</surname><given-names>JC</given-names></name><name><surname>Bergreen</surname><given-names>EW</given-names></name><name><surname>Organ</surname><given-names>G</given-names></name><name><surname>Telfer</surname><given-names>M</given-names></name><name><surname>Mcmillen</surname><given-names>MA</given-names></name></person-group>. <article-title>Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis</article-title>. <source>Blood.</source> (<year>1998</year>) <volume>92</volume>:<fpage>2551</fpage>–<lpage>5</lpage>. <pub-id pub-id-type="doi">10.1182/blood.V92.7.2551</pub-id><pub-id pub-id-type="pmid">9746797</pub-id></mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Malave</surname><given-names>I</given-names></name><name><surname>Perdomo</surname><given-names>Y</given-names></name><name><surname>Escalona</surname><given-names>E</given-names></name><name><surname>Rodriguez</surname><given-names>E</given-names></name><name><surname>Anchustegui</surname><given-names>M</given-names></name><name><surname>Malave</surname><given-names>H</given-names></name><etal></etal></person-group>. <article-title>Levels of tumor necrosis factor alpha/cachectin (TNF alpha) in sera from patients with sickle cell disease</article-title>. <source>Acta Haematol.</source> (<year>1993</year>) <volume>90</volume>:<fpage>172</fpage>–<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1159/000204452</pub-id><pub-id pub-id-type="pmid">8140855</pub-id></mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>G</given-names></name><name><surname>Zhang</surname><given-names>D</given-names></name><name><surname>Fuchs</surname><given-names>TA</given-names></name><name><surname>Manwani</surname><given-names>D</given-names></name><name><surname>Wagner</surname><given-names>DD</given-names></name><name><surname>Frenette</surname><given-names>PS</given-names></name></person-group>. <article-title>Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease</article-title>. <source>Blood.</source> (<year>2014</year>) <volume>123</volume>:<fpage>3818</fpage>–<lpage>27</lpage>. <pub-id pub-id-type="doi">10.1182/blood-2013-10-529982</pub-id><pub-id pub-id-type="pmid">24620350</pub-id></mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Holtzclaw</surname><given-names>JD</given-names></name><name><surname>Jack</surname><given-names>D</given-names></name><name><surname>Aguayo</surname><given-names>SM</given-names></name><name><surname>Eckman</surname><given-names>JR</given-names></name><name><surname>Roman</surname><given-names>J</given-names></name><name><surname>Hsu</surname><given-names>LL</given-names></name></person-group>. <article-title>Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice</article-title>. <source>Am J Respir Crit Care Med.</source> (<year>2004</year>) <volume>169</volume>:<fpage>687</fpage>–<lpage>95</lpage>. <pub-id pub-id-type="doi">10.1164/rccm.200302-224OC</pub-id><pub-id pub-id-type="pmid">14684557</pub-id></mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Green</surname><given-names>CE</given-names></name><name><surname>Turner</surname><given-names>AM</given-names></name></person-group>. <article-title>The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD)</article-title>. <source>Respir Res.</source> (<year>2017</year>) <volume>18</volume>:<fpage>20</fpage>. <pub-id pub-id-type="doi">10.1186/s12931-017-0505-1</pub-id><pub-id pub-id-type="pmid">28100233</pub-id></mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Asosingh</surname><given-names>K</given-names></name><name><surname>Weiss</surname><given-names>K</given-names></name><name><surname>Queisser</surname><given-names>K</given-names></name><name><surname>Wanner</surname><given-names>N</given-names></name><name><surname>Yin</surname><given-names>M</given-names></name><name><surname>Aronica</surname><given-names>M</given-names></name><etal></etal></person-group>. <article-title>Endothelial cells in the innate response to allergens and initiation of atopic asthma</article-title>. <source>J Clin Invest.</source> (<year>2018</year>) <volume>128</volume>:<fpage>3116</fpage>–<lpage>28</lpage>. <pub-id pub-id-type="doi">10.1172/JCI97720</pub-id><pub-id pub-id-type="pmid">29911993</pub-id></mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Toews</surname><given-names>GB</given-names></name></person-group>. <article-title>Cytokines and the lung</article-title>. <source>Eur Respir J Suppl.</source> (<year>2001</year>) <volume>34</volume>:<fpage>3s</fpage>–<lpage>17s</lpage>. <pub-id pub-id-type="doi">10.1183/09031936.01.00266001</pub-id><pub-id pub-id-type="pmid">12392030</pub-id></mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lebensburger</surname><given-names>JD</given-names></name><name><surname>Howard</surname><given-names>T</given-names></name><name><surname>Hu</surname><given-names>Y</given-names></name><name><surname>Pestina</surname><given-names>TI</given-names></name><name><surname>Gao</surname><given-names>G</given-names></name><name><surname>Johnson</surname><given-names>M</given-names></name><etal></etal></person-group>. <article-title>Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin</article-title>. <source>Blood.</source> (<year>2012</year>) <volume>119</volume>:<fpage>1915</fpage>–<lpage>21</lpage>. <pub-id pub-id-type="doi">10.1182/blood-2011-08-374447</pub-id><pub-id pub-id-type="pmid">22130804</pub-id></mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Asquith</surname><given-names>KL</given-names></name><name><surname>Ramshaw</surname><given-names>HS</given-names></name><name><surname>Hansbro</surname><given-names>PM</given-names></name><name><surname>Beagley</surname><given-names>KW</given-names></name><name><surname>Lopez</surname><given-names>AF</given-names></name><name><surname>Foster</surname><given-names>PS</given-names></name></person-group>. <article-title>The IL-3/IL-5/GM-CSF common receptor plays a pivotal role in the regulation of Th2 immunity and allergic airway inflammation</article-title>. <source>J Immunol.</source> (<year>2008</year>) <volume>180</volume>:<fpage>1199</fpage>–<lpage>206</lpage>. <pub-id pub-id-type="doi">10.4049/jimmunol.180.2.1199</pub-id><pub-id pub-id-type="pmid">18178860</pub-id></mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tomaki</surname><given-names>M</given-names></name><name><surname>Zhao</surname><given-names>LL</given-names></name><name><surname>Sjostrand</surname><given-names>M</given-names></name><name><surname>Linden</surname><given-names>A</given-names></name><name><surname>Ichinose</surname><given-names>M</given-names></name><name><surname>Lotvall</surname><given-names>J</given-names></name></person-group>. <article-title>Comparison of effects of anti-IL-3, IL-5 and GM-CSF treatments on eosinophilopoiesis and airway eosinophilia induced by allergen</article-title>. <source>Pulm Pharmacol Ther.</source> (<year>2002</year>) <volume>15</volume>:<fpage>161</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1006/pupt.2001.0333</pub-id><pub-id pub-id-type="pmid">12090790</pub-id></mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Profita</surname><given-names>M</given-names></name><name><surname>Sala</surname><given-names>A</given-names></name><name><surname>Bonanno</surname><given-names>A</given-names></name><name><surname>Riccobono</surname><given-names>L</given-names></name><name><surname>Siena</surname><given-names>L</given-names></name><name><surname>Melis</surname><given-names>MR</given-names></name><etal></etal></person-group>. <article-title>Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia</article-title>. <source>J Allergy Clin Immunol.</source> (<year>2003</year>) <volume>112</volume>:<fpage>709</fpage>–<lpage>16</lpage>. <pub-id pub-id-type="doi">10.1016/S0091-6749(03)01889-X</pub-id><pub-id pub-id-type="pmid">14564348</pub-id></mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Aun</surname><given-names>MV</given-names></name><name><surname>Bonamichi-Santos</surname><given-names>R</given-names></name><name><surname>Arantes-Costa</surname><given-names>FM</given-names></name><name><surname>Kalil</surname><given-names>J</given-names></name><name><surname>Giavina-Bianchi</surname><given-names>P</given-names></name></person-group>. <article-title>Animal models of asthma: utility and limitations</article-title>. <source>J Asthma Allergy.</source> (<year>2017</year>) <volume>10</volume>:<fpage>293</fpage>–<lpage>301</lpage>. <pub-id pub-id-type="doi">10.2147/JAA.S121092</pub-id><pub-id pub-id-type="pmid">29158683</pub-id></mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pritchard</surname><given-names>KA</given-names><suffix>Jr</suffix></name><name><surname>Feroah</surname><given-names>TR</given-names></name><name><surname>Nandedkar</surname><given-names>SD</given-names></name><name><surname>Holzhauer</surname><given-names>SL</given-names></name><name><surname>Hutchins</surname><given-names>W</given-names></name><name><surname>Schulte</surname><given-names>ML</given-names></name><etal></etal></person-group>. <article-title>Effects of experimental asthma on inflammation and lung mechanics in sickle cell mice</article-title>. <source>Am J Respir Cell Mol Biol.</source> (<year>2012</year>) <volume>46</volume>:<fpage>389</fpage>–<lpage>96</lpage>. <pub-id pub-id-type="doi">10.1165/rcmb.2011-0097OC</pub-id><pub-id pub-id-type="pmid">22033263</pub-id></mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Andemariam</surname><given-names>B</given-names></name><name><surname>Adami</surname><given-names>AJ</given-names></name><name><surname>Singh</surname><given-names>A</given-names></name><name><surname>Mcnamara</surname><given-names>JT</given-names></name><name><surname>Secor</surname><given-names>ER</given-names></name><name><surname>Guernsey</surname><given-names>LA</given-names></name><etal></etal></person-group>. <article-title>The sickle cell mouse lung: proinflammatory and primed for allergic inflammation</article-title>. <source>Transl Res.</source> (<year>2015</year>) <volume>166</volume>:<fpage>254</fpage>–<lpage>68</lpage>. <pub-id pub-id-type="doi">10.1016/j.trsl.2015.03.001</pub-id><pub-id pub-id-type="pmid">25843670</pub-id></mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Field</surname><given-names>JJ</given-names></name><name><surname>Stocks</surname><given-names>J</given-names></name><name><surname>Kirkham</surname><given-names>FJ</given-names></name><name><surname>Rosen</surname><given-names>CL</given-names></name><name><surname>Dietzen</surname><given-names>DJ</given-names></name><name><surname>Semon</surname><given-names>T</given-names></name><etal></etal></person-group>. <article-title>Airway hyperresponsiveness in children with sickle cell anemia</article-title>. <source>Chest.</source> (<year>2011</year>) <volume>139</volume>:<fpage>563</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1378/chest.10-1243</pub-id><pub-id pub-id-type="pmid">20724735</pub-id></mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chapman</surname><given-names>DG</given-names></name><name><surname>Irvin</surname><given-names>CG</given-names></name></person-group>. <article-title>Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come</article-title>. <source>Clin Exp Allergy.</source> (<year>2015</year>) <volume>45</volume>:<fpage>706</fpage>–<lpage>19</lpage>. <pub-id pub-id-type="doi">10.1111/cea.12506</pub-id><pub-id pub-id-type="pmid">25651937</pub-id></mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kumar</surname><given-names>RK</given-names></name><name><surname>Herbert</surname><given-names>C</given-names></name><name><surname>Foster</surname><given-names>PS</given-names></name></person-group>. <article-title>Mouse models of acute exacerbations of allergic asthma</article-title>. <source>Respirology.</source> (<year>2016</year>) <volume>21</volume>:<fpage>842</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1111/resp.12760</pub-id><pub-id pub-id-type="pmid">26922049</pub-id></mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jiang</surname><given-names>C</given-names></name><name><surname>Gavitt</surname><given-names>TD</given-names></name><name><surname>Szczepanek</surname><given-names>SM</given-names></name></person-group><article-title>House dust mite-induced allergic lung inflammation is not exacerbated in sickle cell disease Mice</article-title>. <source>Int Arch Allergy Immunol.</source> (<year>2019</year>) <volume>179</volume>:<fpage>192</fpage>–<lpage>200</lpage>. <pub-id pub-id-type="doi">10.1159/000499043</pub-id><pub-id pub-id-type="pmid">30999298</pub-id></mixed-citation></ref><ref id="B42"><label>42.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Buchman</surname><given-names>AL</given-names></name></person-group>. <article-title>Side effects of corticosteroid therapy</article-title>. <source>J Clin Gastroenterol.</source> (<year>2001</year>) <volume>33</volume>:<fpage>289</fpage>–<lpage>94</lpage>. <pub-id pub-id-type="doi">10.1097/00004836-200110000-00006</pub-id><pub-id pub-id-type="pmid">11588541</pub-id></mixed-citation></ref><ref id="B43"><label>43.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sobota</surname><given-names>A</given-names></name><name><surname>Graham</surname><given-names>DA</given-names></name><name><surname>Heeney</surname><given-names>MM</given-names></name><name><surname>Neufeld</surname><given-names>EJ</given-names></name></person-group>. <article-title>Corticosteroids for acute chest syndrome in children with sickle cell disease: variation in use and association with length of stay and readmission</article-title>. <source>Am J Hematol.</source> (<year>2010</year>) <volume>85</volume>:<fpage>24</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.21565</pub-id><pub-id pub-id-type="pmid">19957348</pub-id></mixed-citation></ref><ref id="B44"><label>44.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gomez</surname><given-names>E</given-names></name><name><surname>Morris</surname><given-names>CR</given-names></name></person-group>. <article-title>Asthma management in sickle cell disease</article-title>. <source>Biomed Res Int.</source> (<year>2013</year>) <volume>2013</volume>:<fpage>604140</fpage>. <pub-id pub-id-type="doi">10.1155/2013/604140</pub-id><pub-id pub-id-type="pmid">24324967</pub-id></mixed-citation></ref><ref id="B45"><label>45.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leikin</surname><given-names>SL</given-names></name><name><surname>Gallagher</surname><given-names>D</given-names></name><name><surname>Kinney</surname><given-names>TR</given-names></name><name><surname>Sloane</surname><given-names>D</given-names></name><name><surname>Klug</surname><given-names>P</given-names></name><name><surname>Rida</surname><given-names>W</given-names></name></person-group>. <article-title>Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease</article-title>. <source>Pediatrics.</source> (<year>1989</year>) <volume>84</volume>:<fpage>500</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="pmid">2671914</pub-id></mixed-citation></ref><ref id="B46"><label>46.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>L</given-names></name><name><surname>Prietsch</surname><given-names>SO</given-names></name><name><surname>Mendes</surname><given-names>AP</given-names></name><name><surname>Von Groll</surname><given-names>A</given-names></name><name><surname>Rocha</surname><given-names>GP</given-names></name><name><surname>Carrion</surname><given-names>L</given-names></name><etal></etal></person-group>. <article-title>Inhaled corticosteroids increase the risk of oropharyngeal colonization by Streptococcus pneumoniae in children with asthma</article-title>. <source>Respirology.</source> (<year>2013</year>) <volume>18</volume>:<fpage>272</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1111/j.1440-1843.2012.02280.x</pub-id><pub-id pub-id-type="pmid">23039314</pub-id></mixed-citation></ref><ref id="B47"><label>47.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vance Utset</surname><given-names>L</given-names></name><name><surname>Ivy</surname><given-names>Z</given-names></name><name><surname>Willen</surname><given-names>SM</given-names></name><name><surname>Rodeghier</surname><given-names>M</given-names></name><name><surname>Watt</surname><given-names>A</given-names></name><name><surname>Schilling</surname><given-names>L</given-names></name><etal></etal></person-group>. <article-title>Inhaled corticosteroid use to prevent severe vaso-occlusive episode recurrence in children between 1 and 4 years of age with sickle cell disease: a multicenter feasibility trial</article-title>. <source>Am J Hematol.</source> (<year>2018</year>) <volume>93</volume>:<fpage>E101</fpage>–<lpage>3</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.25033</pub-id><pub-id pub-id-type="pmid">29322539</pub-id></mixed-citation></ref><ref id="B48"><label>48.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Glassberg</surname><given-names>J</given-names></name><name><surname>Minnitti</surname><given-names>C</given-names></name><name><surname>Cromwell</surname><given-names>C</given-names></name><name><surname>Cytryn</surname><given-names>L</given-names></name><name><surname>Kraus</surname><given-names>T</given-names></name><name><surname>Skloot</surname><given-names>GS</given-names></name><etal></etal></person-group>. <article-title>Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: a triple-blind, randomized trial</article-title>. <source>Am J Hematol.</source> (<year>2017</year>) <volume>92</volume>:<fpage>622</fpage>–<lpage>31</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.24742</pub-id><pub-id pub-id-type="pmid">28370266</pub-id></mixed-citation></ref><ref id="B49"><label>49.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carden</surname><given-names>MA</given-names></name><name><surname>Little</surname><given-names>J</given-names></name></person-group>. <article-title>Emerging disease-modifying therapies for sickle cell disease</article-title>. <source>Haematologica.</source> (<year>2019</year>) <volume>104</volume>:<fpage>1710</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.3324/haematol.2018.207357</pub-id><pub-id pub-id-type="pmid">31413089</pub-id></mixed-citation></ref><ref id="B50"><label>50.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Langer</surname><given-names>AL</given-names></name><name><surname>Leader</surname><given-names>A</given-names></name><name><surname>Kim-Schulze</surname><given-names>S</given-names></name><name><surname>Ginzburg</surname><given-names>Y</given-names></name><name><surname>Merad</surname><given-names>M</given-names></name><name><surname>Glassberg</surname><given-names>J</given-names></name></person-group>. <article-title>Inhaled steroids associated with decreased macrophage markers in nonasthmatic individuals with sickle cell disease in a randomized trial</article-title>. <source>Ann Hematol.</source> (<year>2019</year>) <volume>98</volume>:<fpage>841</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1007/s00277-019-03635-9</pub-id><pub-id pub-id-type="pmid">30783732</pub-id></mixed-citation></ref><ref id="B51"><label>51.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gill</surname><given-names>FM</given-names></name><name><surname>Sleeper</surname><given-names>LA</given-names></name><name><surname>Weiner</surname><given-names>SJ</given-names></name><name><surname>Brown</surname><given-names>AK</given-names></name><name><surname>Bellevue</surname><given-names>R</given-names></name><name><surname>Grover</surname><given-names>R</given-names></name><etal></etal></person-group>. <article-title>Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease</article-title>. <source>Blood.</source> (<year>1995</year>) <volume>86</volume>:<fpage>776</fpage>–<lpage>83</lpage>. <pub-id pub-id-type="doi">10.1182/blood.V86.2.776.bloodjournal862776</pub-id><pub-id pub-id-type="pmid">7606007</pub-id></mixed-citation></ref><ref id="B52"><label>52.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Overturf</surname><given-names>GD</given-names></name></person-group>. <article-title>Infections and immunizations of children with sickle cell disease</article-title>. <source>Adv Pediatr Infect Dis.</source> (<year>1999</year>) <volume>14</volume>:<fpage>191</fpage>–<lpage>218</lpage>. <pub-id pub-id-type="pmid">10079855</pub-id></mixed-citation></ref><ref id="B53"><label>53.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Suara</surname><given-names>RO</given-names></name></person-group>. <article-title>Group A beta-haemolytic streptococcal acute chest event in a child with sickle cell anaemia</article-title>. <source>Ann Trop Paediatr.</source> (<year>2001</year>) <volume>21</volume>:<fpage>175</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1080/02724930120058278</pub-id><pub-id pub-id-type="pmid">11471264</pub-id></mixed-citation></ref><ref id="B54"><label>54.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dean</surname><given-names>D</given-names></name><name><surname>Neumayr</surname><given-names>L</given-names></name><name><surname>Kelly</surname><given-names>DM</given-names></name><name><surname>Ballas</surname><given-names>SK</given-names></name><name><surname>Kleman</surname><given-names>K</given-names></name><name><surname>Robertson</surname><given-names>S</given-names></name><etal></etal></person-group>. <article-title><italic>Chlamydia pneumoniae</italic> and acute chest syndrome in patients with sickle cell disease</article-title>. <source>J Pediatr Hematol Oncol.</source> (<year>2003</year>) <volume>25</volume>:<fpage>46</fpage>–<lpage>55</lpage>. <pub-id pub-id-type="doi">10.1097/00043426-200301000-00010</pub-id><pub-id pub-id-type="pmid">12544773</pub-id></mixed-citation></ref><ref id="B55"><label>55.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van Tuijn</surname><given-names>CF</given-names></name><name><surname>Nur</surname><given-names>E</given-names></name><name><surname>Van Beers</surname><given-names>EJ</given-names></name><name><surname>Zaaijer</surname><given-names>HL</given-names></name><name><surname>Biemond</surname><given-names>BJ</given-names></name></person-group>. <article-title>Acute chest syndrome in sickle cell disease due to the new influenza A (H1N1) virus infection</article-title>. <source>Am J Hematol.</source> (<year>2010</year>) <volume>85</volume>:<fpage>303</fpage>–<lpage>4</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.21638</pub-id><pub-id pub-id-type="pmid">20169545</pub-id></mixed-citation></ref><ref id="B56"><label>56.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rosch</surname><given-names>JW</given-names></name><name><surname>Boyd</surname><given-names>AR</given-names></name><name><surname>Hinojosa</surname><given-names>E</given-names></name><name><surname>Pestina</surname><given-names>T</given-names></name><name><surname>Hu</surname><given-names>Y</given-names></name><name><surname>Persons</surname><given-names>DA</given-names></name><etal></etal></person-group>. <article-title>Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease</article-title>. <source>J Clin Invest.</source> (<year>2010</year>) <volume>120</volume>:<fpage>627</fpage>–<lpage>35</lpage>. <pub-id pub-id-type="doi">10.1172/JCI39843</pub-id><pub-id pub-id-type="pmid">20093777</pub-id></mixed-citation></ref><ref id="B57"><label>57.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carter</surname><given-names>R</given-names></name><name><surname>Wolf</surname><given-names>J</given-names></name><name><surname>Van Opijnen</surname><given-names>T</given-names></name><name><surname>Muller</surname><given-names>M</given-names></name><name><surname>Obert</surname><given-names>C</given-names></name><name><surname>Burnham</surname><given-names>C</given-names></name><etal></etal></person-group>. <article-title>Genomic analyses of pneumococci from children with sickle cell disease expose host-specific bacterial adaptations and deficits in current interventions</article-title>. <source>Cell Host Microbe.</source> (<year>2014</year>) <volume>15</volume>:<fpage>587</fpage>–<lpage>99</lpage>. <pub-id pub-id-type="doi">10.1016/j.chom.2014.04.005</pub-id><pub-id pub-id-type="pmid">24832453</pub-id></mixed-citation></ref><ref id="B58"><label>58.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karlsson</surname><given-names>EA</given-names></name><name><surname>Oguin</surname><given-names>TH</given-names></name><name><surname>Meliopoulos</surname><given-names>V</given-names></name><name><surname>Iverson</surname><given-names>A</given-names></name><name><surname>Broadnax</surname><given-names>A</given-names></name><name><surname>Yoon</surname><given-names>SW</given-names></name><etal></etal></person-group>. <article-title>Vascular permeability drives susceptibility to influenza infection in a murine model of sickle cell disease</article-title>. <source>Sci Rep.</source> (<year>2017</year>) <volume>7</volume>:<fpage>43308</fpage>. <pub-id pub-id-type="doi">10.1038/srep43308</pub-id><pub-id pub-id-type="pmid">28256526</pub-id></mixed-citation></ref><ref id="B59"><label>59.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ellison</surname><given-names>AM</given-names></name><name><surname>Ota</surname><given-names>KV</given-names></name><name><surname>Mcgowan</surname><given-names>KL</given-names></name><name><surname>Smith-Whitley</surname><given-names>K</given-names></name></person-group>. <article-title>Pneumococcal bacteremia in a vaccinated pediatric sickle cell disease population</article-title>. <source>Pediatr Infect Dis J.</source> (<year>2012</year>) <volume>31</volume>:<fpage>534</fpage>–<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1097/INF.0b013e3182480fed</pub-id><pub-id pub-id-type="pmid">22228232</pub-id></mixed-citation></ref><ref id="B60"><label>60.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Santoro</surname><given-names>JD</given-names></name><name><surname>Myers</surname><given-names>L</given-names></name><name><surname>Kanter</surname><given-names>J</given-names></name></person-group>. <article-title>Assessing the immunogenic response of a single center's pneumococcal vaccination protocol in sickle cell disease</article-title>. <source>J Pediatr Hematol Oncol.</source> (<year>2016</year>) <volume>38</volume>:<fpage>e102</fpage>–<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1097/MPH.0000000000000510</pub-id><pub-id pub-id-type="pmid">26886376</pub-id></mixed-citation></ref><ref id="B61"><label>61.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Szczepanek</surname><given-names>SM</given-names></name><name><surname>Roberts</surname><given-names>S</given-names></name><name><surname>Rogers</surname><given-names>K</given-names></name><name><surname>Cotte</surname><given-names>C</given-names></name><name><surname>Adami</surname><given-names>AJ</given-names></name><name><surname>Bracken</surname><given-names>SJ</given-names></name><etal></etal></person-group>. <article-title>Poor long-term efficacy of prevnar-13 in sickle cell disease mice is associated with an inability to sustain pneumococcal-specific antibody titers</article-title>. <source>PLoS ONE.</source> (<year>2016</year>) <volume>11</volume>:<fpage>e0149261</fpage>. <pub-id pub-id-type="doi">10.1371/journal.pone.0149261</pub-id><pub-id pub-id-type="pmid">26910228</pub-id></mixed-citation></ref><ref id="B62"><label>62.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Torres</surname><given-names>A</given-names></name><name><surname>Blasi</surname><given-names>F</given-names></name><name><surname>Dartois</surname><given-names>N</given-names></name><name><surname>Akova</surname><given-names>M</given-names></name></person-group>. <article-title>Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease</article-title>. <source>Thorax.</source> (<year>2015</year>) <volume>70</volume>:<fpage>984</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1136/thoraxjnl-2015-206780</pub-id><pub-id pub-id-type="pmid">26219979</pub-id></mixed-citation></ref><ref id="B63"><label>63.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Han</surname><given-names>M</given-names></name><name><surname>Rajput</surname><given-names>C</given-names></name><name><surname>Ishikawa</surname><given-names>T</given-names></name><name><surname>Jarman</surname><given-names>CR</given-names></name><name><surname>Lee</surname><given-names>J</given-names></name><name><surname>Hershenson</surname><given-names>MB</given-names></name></person-group>. <article-title>Small animal models of respiratory viral infection related to asthma</article-title>. <source>Viruses.</source> (<year>2018</year>) <volume>10</volume>:<fpage>E682</fpage>. <pub-id pub-id-type="doi">10.3390/v10120682</pub-id><pub-id pub-id-type="pmid">30513770</pub-id></mixed-citation></ref><ref id="B64"><label>64.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Samarasinghe</surname><given-names>AE</given-names></name><name><surname>Woolard</surname><given-names>SN</given-names></name><name><surname>Boyd</surname><given-names>KL</given-names></name><name><surname>Hoselton</surname><given-names>SA</given-names></name><name><surname>Schuh</surname><given-names>JM</given-names></name><name><surname>Mccullers</surname><given-names>JA</given-names></name></person-group>. <article-title>The immune profile associated with acute allergic asthma accelerates clearance of influenza virus</article-title>. <source>Immunol Cell Biol.</source> (<year>2014</year>) <volume>92</volume>:<fpage>449</fpage>–<lpage>59</lpage>. <pub-id pub-id-type="doi">10.1038/icb.2013.113</pub-id><pub-id pub-id-type="pmid">24469764</pub-id></mixed-citation></ref><ref id="B65"><label>65.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Furuya</surname><given-names>Y</given-names></name><name><surname>Furuya</surname><given-names>AK</given-names></name><name><surname>Roberts</surname><given-names>S</given-names></name><name><surname>Sanfilippo</surname><given-names>AM</given-names></name><name><surname>Salmon</surname><given-names>SL</given-names></name><name><surname>Metzger</surname><given-names>DW</given-names></name></person-group>. <article-title>Prevention of influenza virus-induced immunopathology by TGF-beta produced during allergic asthma</article-title>. <source>PLoS Pathog.</source> (<year>2015</year>) <volume>11</volume>:<fpage>e1005180</fpage>. <pub-id pub-id-type="doi">10.1371/journal.ppat.1005180</pub-id><pub-id pub-id-type="pmid">26407325</pub-id></mixed-citation></ref><ref id="B66"><label>66.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gaston</surname><given-names>MH</given-names></name><name><surname>Verter</surname><given-names>JI</given-names></name><name><surname>Woods</surname><given-names>G</given-names></name><name><surname>Pegelow</surname><given-names>C</given-names></name><name><surname>Kelleher</surname><given-names>J</given-names></name><name><surname>Presbury</surname><given-names>G</given-names></name><etal></etal></person-group>. <article-title>Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial</article-title>. <source>N Engl J Med.</source> (<year>1986</year>) <volume>314</volume>:<fpage>1593</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1056/NEJM198606193142501</pub-id><pub-id pub-id-type="pmid">3086721</pub-id></mixed-citation></ref><ref id="B67"><label>67.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falletta</surname><given-names>JM</given-names></name><name><surname>Woods</surname><given-names>GM</given-names></name><name><surname>Verter</surname><given-names>JI</given-names></name><name><surname>Buchanan</surname><given-names>GR</given-names></name><name><surname>Pegelow</surname><given-names>CH</given-names></name><name><surname>Iyer</surname><given-names>RV</given-names></name><etal></etal></person-group>. <article-title>Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II</article-title>. <source>J Pediatr.</source> (<year>1995</year>) <volume>127</volume>:<fpage>685</fpage>–<lpage>90</lpage>. <pub-id pub-id-type="doi">10.1016/S0022-3476(95)70154-0</pub-id><pub-id pub-id-type="pmid">7472817</pub-id></mixed-citation></ref><ref id="B68"><label>68.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Adamkiewicz</surname><given-names>TV</given-names></name><name><surname>Sarnaik</surname><given-names>S</given-names></name><name><surname>Buchanan</surname><given-names>GR</given-names></name><name><surname>Iyer</surname><given-names>RV</given-names></name><name><surname>Miller</surname><given-names>ST</given-names></name><name><surname>Pegelow</surname><given-names>CH</given-names></name><etal></etal></person-group>. <article-title>Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination</article-title>. <source>J Pediatr.</source> (<year>2003</year>) <volume>143</volume>:<fpage>438</fpage>–<lpage>44</lpage>. <pub-id pub-id-type="doi">10.1067/S0022-3476(03)00331-7</pub-id><pub-id pub-id-type="pmid">14571216</pub-id></mixed-citation></ref><ref id="B69"><label>69.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mccavit</surname><given-names>TL</given-names></name><name><surname>Gilbert</surname><given-names>M</given-names></name><name><surname>Buchanan</surname><given-names>GR</given-names></name></person-group>. <article-title>Prophylactic penicillin after 5 years of age in patients with sickle cell disease: a survey of sickle cell disease experts</article-title>. <source>Pediatr Blood Cancer.</source> (<year>2013</year>) <volume>60</volume>:<fpage>935</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1002/pbc.24395</pub-id><pub-id pub-id-type="pmid">23193095</pub-id></mixed-citation></ref><ref id="B70"><label>70.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Navalkele</surname><given-names>P</given-names></name><name><surname>Ozgonenel</surname><given-names>B</given-names></name><name><surname>Mcgrath</surname><given-names>E</given-names></name><name><surname>Lephart</surname><given-names>P</given-names></name><name><surname>Sarnaik</surname><given-names>S</given-names></name></person-group>. <article-title>Invasive pneumococcal disease in patients with sickle cell disease</article-title>. <source>J Pediatr Hematol Oncol.</source> (<year>2017</year>) <volume>39</volume>:<fpage>341</fpage>–<lpage>4</lpage>. <pub-id pub-id-type="doi">10.1097/MPH.0000000000000858</pub-id><pub-id pub-id-type="pmid">28538501</pub-id></mixed-citation></ref><ref id="B71"><label>71.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Marra</surname><given-names>F</given-names></name><name><surname>Lynd</surname><given-names>L</given-names></name><name><surname>Coombes</surname><given-names>M</given-names></name><name><surname>Richardson</surname><given-names>K</given-names></name><name><surname>Legal</surname><given-names>M</given-names></name><name><surname>Fitzgerald</surname><given-names>JM</given-names></name><etal></etal></person-group>. <article-title>Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis</article-title>. <source>Chest.</source> (<year>2006</year>) <volume>129</volume>:<fpage>610</fpage>–<lpage>18</lpage>. <pub-id pub-id-type="doi">10.1378/chest.129.3.610</pub-id><pub-id pub-id-type="pmid">16537858</pub-id></mixed-citation></ref><ref id="B72"><label>72.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reynolds</surname><given-names>LA</given-names></name><name><surname>Finlay</surname><given-names>BB</given-names></name></person-group>. <article-title>A case for antibiotic perturbation of the microbiota leading to allergy development</article-title>. <source>Expert Rev Clin Immunol.</source> (<year>2013</year>) <volume>9</volume>:<fpage>1019</fpage>–<lpage>30</lpage>. <pub-id pub-id-type="doi">10.1586/1744666X.2013.851603</pub-id><pub-id pub-id-type="pmid">24168410</pub-id></mixed-citation></ref><ref id="B73"><label>73.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ortqvist</surname><given-names>AK</given-names></name><name><surname>Lundholm</surname><given-names>C</given-names></name><name><surname>Kieler</surname><given-names>H</given-names></name><name><surname>Ludvigsson</surname><given-names>JF</given-names></name><name><surname>Fall</surname><given-names>T</given-names></name><name><surname>Ye</surname><given-names>W</given-names></name><etal></etal></person-group>. <article-title>Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis</article-title>. <source>BMJ.</source> (<year>2014</year>) <volume>349</volume>:<fpage>g6979</fpage>. <pub-id pub-id-type="doi">10.1136/bmj.g6979</pub-id><pub-id pub-id-type="pmid">25432937</pub-id></mixed-citation></ref><ref id="B74"><label>74.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stokholm</surname><given-names>J</given-names></name><name><surname>Sevelsted</surname><given-names>A</given-names></name><name><surname>Bonnelykke</surname><given-names>K</given-names></name><name><surname>Bisgaard</surname><given-names>H</given-names></name></person-group>. <article-title>Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study</article-title>. <source>Lancet Respir Med.</source> (<year>2014</year>) <volume>2</volume>:<fpage>631</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1016/S2213-2600(14)70152-3</pub-id><pub-id pub-id-type="pmid">25066330</pub-id></mixed-citation></ref><ref id="B75"><label>75.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pitter</surname><given-names>G</given-names></name><name><surname>Ludvigsson</surname><given-names>JF</given-names></name><name><surname>Romor</surname><given-names>P</given-names></name><name><surname>Zanier</surname><given-names>L</given-names></name><name><surname>Zanotti</surname><given-names>R</given-names></name><name><surname>Simonato</surname><given-names>L</given-names></name><etal></etal></person-group>. <article-title>Antibiotic exposure in the first year of life and later treated asthma, a population based birth cohort study of 143,000 children</article-title>. <source>Eur J Epidemiol.</source> (<year>2016</year>) <volume>31</volume>:<fpage>85</fpage>–<lpage>94</lpage>. <pub-id pub-id-type="doi">10.1007/s10654-015-0038-1</pub-id><pub-id pub-id-type="pmid">25957084</pub-id></mixed-citation></ref><ref id="B76"><label>76.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hirsch</surname><given-names>AG</given-names></name><name><surname>Pollak</surname><given-names>J</given-names></name><name><surname>Glass</surname><given-names>TA</given-names></name><name><surname>Poulsen</surname><given-names>MN</given-names></name><name><surname>Bailey-Davis</surname><given-names>L</given-names></name><name><surname>Mowery</surname><given-names>J</given-names></name><etal></etal></person-group>. <article-title>Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases</article-title>. <source>Clin Exp Allergy.</source> (<year>2017</year>) <volume>47</volume>:<fpage>236</fpage>–<lpage>44</lpage>. <pub-id pub-id-type="doi">10.1111/cea.12807</pub-id><pub-id pub-id-type="pmid">27562571</pub-id></mixed-citation></ref><ref id="B77"><label>77.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yamamoto-Hanada</surname><given-names>K</given-names></name><name><surname>Yang</surname><given-names>L</given-names></name><name><surname>Narita</surname><given-names>M</given-names></name><name><surname>Saito</surname><given-names>H</given-names></name><name><surname>Ohya</surname><given-names>Y</given-names></name></person-group>. <article-title>Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5</article-title>. <source>Ann Allergy Asthma Immunol.</source> (<year>2017</year>) <volume>119</volume>:<fpage>54</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1016/j.anai.2017.05.013</pub-id><pub-id pub-id-type="pmid">28668240</pub-id></mixed-citation></ref><ref id="B78"><label>78.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Adami</surname><given-names>AJ</given-names></name><name><surname>Bracken</surname><given-names>SJ</given-names></name><name><surname>Guernsey</surname><given-names>LA</given-names></name><name><surname>Rafti</surname><given-names>E</given-names></name><name><surname>Maas</surname><given-names>KR</given-names></name><name><surname>Graf</surname><given-names>J</given-names></name><etal></etal></person-group>. <article-title>Early-life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite-induced asthma</article-title>. <source>Pediatr Res.</source> (<year>2018</year>) <volume>84</volume>:<fpage>426</fpage>–<lpage>34</lpage>. <pub-id pub-id-type="doi">10.1038/s41390-018-0031-y</pub-id><pub-id pub-id-type="pmid">29967529</pub-id></mixed-citation></ref><ref id="B79"><label>79.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yoshida</surname><given-names>S</given-names></name><name><surname>Ide</surname><given-names>K</given-names></name><name><surname>Takeuchi</surname><given-names>M</given-names></name><name><surname>Kawakami</surname><given-names>K</given-names></name></person-group>. <article-title>Prenatal and early-life antibiotic use and risk of childhood asthma: a retrospective cohort study</article-title>. <source>Pediatr Allergy Immunol.</source> (<year>2018</year>) <volume>29</volume>:<fpage>490</fpage>–<lpage>5</lpage>. <pub-id pub-id-type="doi">10.1111/pai.12902</pub-id><pub-id pub-id-type="pmid">29604125</pub-id></mixed-citation></ref><ref id="B80"><label>80.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Murk</surname><given-names>W</given-names></name><name><surname>Risnes</surname><given-names>KR</given-names></name><name><surname>Bracken</surname><given-names>MB</given-names></name></person-group>. <article-title>Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review</article-title>. <source>Pediatrics.</source> (<year>2011</year>) <volume>127</volume>:<fpage>1125</fpage>–<lpage>38</lpage>. <pub-id pub-id-type="doi">10.1542/peds.2010-2092</pub-id><pub-id pub-id-type="pmid">21606151</pub-id></mixed-citation></ref><ref id="B81"><label>81.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Risnes</surname><given-names>KR</given-names></name><name><surname>Belanger</surname><given-names>K</given-names></name><name><surname>Murk</surname><given-names>W</given-names></name><name><surname>Bracken</surname><given-names>MB</given-names></name></person-group>. <article-title>Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in a cohort of 1,401 US children</article-title>. <source>Am J Epidemiol.</source> (<year>2011</year>) <volume>173</volume>:<fpage>310</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1093/aje/kwq400</pub-id><pub-id pub-id-type="pmid">21190986</pub-id></mixed-citation></ref><ref id="B82"><label>82.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ver Heul</surname><given-names>A</given-names></name><name><surname>Planer</surname><given-names>J</given-names></name><name><surname>Kau</surname><given-names>AL</given-names></name></person-group>. <article-title>The human microbiota and asthma</article-title>. <source>Clin Rev Allergy Immunol.</source> (<year>2018</year>) <volume>57</volume>:<fpage>350</fpage>–<lpage>63</lpage>. <pub-id pub-id-type="doi">10.1007/s12016-018-8719-7</pub-id><pub-id pub-id-type="pmid">30426401</pub-id></mixed-citation></ref><ref id="B83"><label>83.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fukuda</surname><given-names>JT</given-names></name><name><surname>Sonis</surname><given-names>AL</given-names></name><name><surname>Platt</surname><given-names>OS</given-names></name><name><surname>Kurth</surname><given-names>S</given-names></name></person-group>. <article-title>Acquisition of mutans streptococci and caries prevalence in pediatric sickle cell anemia patients receiving long-term antibiotic therapy</article-title>. <source>Pediatr Dent.</source> (<year>2005</year>) <volume>27</volume>:<fpage>186</fpage>–<lpage>90</lpage>. <pub-id pub-id-type="pmid">16173221</pub-id></mixed-citation></ref><ref id="B84"><label>84.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zeissig</surname><given-names>S</given-names></name><name><surname>Blumberg</surname><given-names>RS</given-names></name></person-group>. <article-title>Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease</article-title>. <source>Nat Immunol.</source> (<year>2014</year>) <volume>15</volume>:<fpage>307</fpage>–<lpage>10</lpage>. <pub-id pub-id-type="doi">10.1038/ni.2847</pub-id><pub-id pub-id-type="pmid">24646587</pub-id></mixed-citation></ref><ref id="B85"><label>85.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schulfer</surname><given-names>A</given-names></name><name><surname>Blaser</surname><given-names>MJ</given-names></name></person-group>. <article-title>Risks of antibiotic exposures early in life on the developing microbiome</article-title>. <source>PLoS Pathog.</source> (<year>2015</year>) <volume>11</volume>:<fpage>e1004903</fpage>. <pub-id pub-id-type="doi">10.1371/journal.ppat.1004903</pub-id><pub-id pub-id-type="pmid">26135581</pub-id></mixed-citation></ref><ref id="B86"><label>86.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lim</surname><given-names>SH</given-names></name><name><surname>Morris</surname><given-names>A</given-names></name><name><surname>Li</surname><given-names>K</given-names></name><name><surname>Fitch</surname><given-names>AC</given-names></name><name><surname>Fast</surname><given-names>L</given-names></name><name><surname>Goldberg</surname><given-names>L</given-names></name><etal></etal></person-group>. <article-title>Intestinal microbiome analysis revealed dysbiosis in sickle cell disease</article-title>. <source>Am J Hematol.</source> (<year>2018</year>) <volume>93</volume>:<fpage>E91</fpage>–<lpage>3</lpage>. <pub-id pub-id-type="doi">10.1002/ajh.25019</pub-id><pub-id pub-id-type="pmid">29274089</pub-id></mixed-citation></ref><ref id="B87"><label>87.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Enwonwu</surname><given-names>CO</given-names></name><name><surname>Xu</surname><given-names>XX</given-names></name><name><surname>Turner</surname><given-names>E</given-names></name></person-group>. <article-title>Nitrogen metabolism in sickle cell anemia: free amino acids in plasma and urine</article-title>. <source>Am J Med Sci.</source> (<year>1990</year>) <volume>300</volume>:<fpage>366</fpage>–<lpage>71</lpage>. <pub-id pub-id-type="doi">10.1097/00000441-199012000-00005</pub-id><pub-id pub-id-type="pmid">2264574</pub-id></mixed-citation></ref><ref id="B88"><label>88.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>CR</given-names></name><name><surname>Kato</surname><given-names>GJ</given-names></name><name><surname>Poljakovic</surname><given-names>M</given-names></name><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Blackwelder</surname><given-names>WC</given-names></name><name><surname>Sachdev</surname><given-names>V</given-names></name><etal></etal></person-group>. <article-title>Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease</article-title>. <source>JAMA.</source> (<year>2005</year>) <volume>294</volume>:<fpage>81</fpage>–<lpage>90</lpage>. <pub-id pub-id-type="doi">10.1001/jama.294.1.81</pub-id><pub-id pub-id-type="pmid">15998894</pub-id></mixed-citation></ref><ref id="B89"><label>89.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>CR</given-names></name><name><surname>Kuypers</surname><given-names>FA</given-names></name><name><surname>Larkin</surname><given-names>S</given-names></name><name><surname>Vichinsky</surname><given-names>EP</given-names></name><name><surname>Styles</surname><given-names>LA</given-names></name></person-group>. <article-title>Patterns of arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive crisis and acute chest syndrome</article-title>. <source>J Pediatr Hematol Oncol.</source> (<year>2000</year>) <volume>22</volume>:<fpage>515</fpage>–<lpage>20</lpage>. <pub-id pub-id-type="doi">10.1097/00043426-200011000-00009</pub-id><pub-id pub-id-type="pmid">11132219</pub-id></mixed-citation></ref><ref id="B90"><label>90.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lopez</surname><given-names>BL</given-names></name><name><surname>Kreshak</surname><given-names>AA</given-names></name><name><surname>Morris</surname><given-names>CR</given-names></name><name><surname>Davis-Moon</surname><given-names>L</given-names></name><name><surname>Ballas</surname><given-names>SK</given-names></name><name><surname>Ma</surname><given-names>XL</given-names></name></person-group>. <article-title>L-arginine levels are diminished in adult acute vaso-occlusive sickle cell crisis in the emergency department</article-title>. <source>Br J Haematol.</source> (<year>2003</year>) <volume>120</volume>:<fpage>532</fpage>–<lpage>4</lpage>. <pub-id pub-id-type="doi">10.1046/j.1365-2141.2003.04109.x</pub-id><pub-id pub-id-type="pmid">12580975</pub-id></mixed-citation></ref><ref id="B91"><label>91.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>CR</given-names></name><name><surname>Kuypers</surname><given-names>FA</given-names></name><name><surname>Lavrisha</surname><given-names>L</given-names></name><name><surname>Ansari</surname><given-names>M</given-names></name><name><surname>Sweeters</surname><given-names>N</given-names></name><name><surname>Stewart</surname><given-names>M</given-names></name><etal></etal></person-group>. <article-title>A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes</article-title>. <source>Haematologica.</source> (<year>2013</year>) <volume>98</volume>:<fpage>1375</fpage>–<lpage>82</lpage>. <pub-id pub-id-type="doi">10.3324/haematol.2013.086637</pub-id><pub-id pub-id-type="pmid">23645695</pub-id></mixed-citation></ref><ref id="B92"><label>92.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Solomons</surname><given-names>C</given-names></name><name><surname>Hathaway</surname><given-names>W</given-names></name><name><surname>Cotton</surname><given-names>E</given-names></name></person-group>. <article-title>L-arginine, the sickling phenomenon, and cystic fibrosis</article-title>. <source>Pediatrics.</source> (<year>1972</year>) <volume>49</volume>:<fpage>933</fpage>. <pub-id pub-id-type="pmid">5041331</pub-id></mixed-citation></ref><ref id="B93"><label>93.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>CR</given-names></name><name><surname>Kuypers</surname><given-names>FA</given-names></name><name><surname>Larkin</surname><given-names>S</given-names></name><name><surname>Sweeters</surname><given-names>N</given-names></name><name><surname>Simon</surname><given-names>J</given-names></name><name><surname>Vichinsky</surname><given-names>EP</given-names></name><etal></etal></person-group>. <article-title>Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease</article-title>. <source>Br J Haematol.</source> (<year>2000</year>) <volume>111</volume>:<fpage>498</fpage>–<lpage>500</lpage>. <pub-id pub-id-type="doi">10.1046/j.1365-2141.2000.02403.x</pub-id><pub-id pub-id-type="pmid">11122090</pub-id></mixed-citation></ref><ref id="B94"><label>94.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>CR</given-names></name></person-group>. <article-title>Alterations of the arginine metabolome in sickle cell disease: a growing rationale for arginine therapy</article-title>. <source>Hematol Oncol Clin North Am.</source> (<year>2014</year>) <volume>28</volume>:<fpage>301</fpage>–<lpage>21</lpage>. <pub-id pub-id-type="doi">10.1016/j.hoc.2013.11.008</pub-id><pub-id pub-id-type="pmid">24589268</pub-id></mixed-citation></ref><ref id="B95"><label>95.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bakshi</surname><given-names>N</given-names></name><name><surname>Morris</surname><given-names>CR</given-names></name></person-group>. <article-title>The role of the arginine metabolome in pain: implications for sickle cell disease</article-title>. <source>J Pain Res.</source> (<year>2016</year>) <volume>9</volume>:<fpage>167</fpage>–<lpage>75</lpage>. <pub-id pub-id-type="doi">10.2147/JPR.S55571</pub-id><pub-id pub-id-type="pmid">27099528</pub-id></mixed-citation></ref><ref id="B96"><label>96.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cox</surname><given-names>SE</given-names></name><name><surname>Ellins</surname><given-names>EA</given-names></name><name><surname>Marealle</surname><given-names>AI</given-names></name><name><surname>Newton</surname><given-names>CR</given-names></name><name><surname>Soka</surname><given-names>D</given-names></name><name><surname>Sasi</surname><given-names>P</given-names></name><etal></etal></person-group>. <article-title>Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial</article-title>. <source>Lancet Haematol.</source> (<year>2018</year>) <volume>5</volume>:<fpage>e147</fpage>–<lpage>60</lpage>. <pub-id pub-id-type="doi">10.1016/S2352-3026(18)30020-6</pub-id><pub-id pub-id-type="pmid">29548623</pub-id></mixed-citation></ref><ref id="B97"><label>97.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saleh</surname><given-names>D</given-names></name><name><surname>Ernst</surname><given-names>P</given-names></name><name><surname>Lim</surname><given-names>S</given-names></name><name><surname>Barnes</surname><given-names>PJ</given-names></name><name><surname>Giaid</surname><given-names>A</given-names></name></person-group>. <article-title>Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid</article-title>. <source>FASEB J.</source> (<year>1998</year>) <volume>12</volume>:<fpage>929</fpage>–<lpage>37</lpage>. <pub-id pub-id-type="doi">10.1096/fasebj.12.11.929</pub-id><pub-id pub-id-type="pmid">9707165</pub-id></mixed-citation></ref><ref id="B98"><label>98.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mcbrien</surname><given-names>CN</given-names></name><name><surname>Menzies-Gow</surname><given-names>A</given-names></name></person-group>. <article-title>The biology of eosinophils and their role in asthma</article-title>. <source>Front Med.</source> (<year>2017</year>) <volume>4</volume>:<fpage>93</fpage>. <pub-id pub-id-type="doi">10.3389/fmed.2017.00093</pub-id><pub-id pub-id-type="pmid">28713812</pub-id></mixed-citation></ref><ref id="B99"><label>99.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rath</surname><given-names>M</given-names></name><name><surname>Muller</surname><given-names>I</given-names></name><name><surname>Kropf</surname><given-names>P</given-names></name><name><surname>Closs</surname><given-names>EI</given-names></name><name><surname>Munder</surname><given-names>M</given-names></name></person-group>. <article-title>Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages</article-title>. <source>Front Immunol.</source> (<year>2014</year>) <volume>5</volume>:<fpage>532</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2014.00532</pub-id><pub-id pub-id-type="pmid">25386178</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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