Brief report
Persistent infection with a rotavirus vaccine strain in a child suffering from Severe Combined Immunodeficiency in Argentina
Infección persistente por cepa vacunal de rotavirus en un niño con inmunodeficiencia combinada severa en Argentina
María J. Palaua, Cecilia M. Vescinaa, Lorena Regairazb, Diana Cabanillasb, Juan A. Stupkac, Juan I. Degiuseppec,
Corresponding author
a Sala de Microbiología, Laboratorio Central, Hospital Interzonal de Agudos Especializado en Pediatría “Sor María Ludovica”, Calle 14 n° 1631, La Plata, Argentina
b Servicio de Inmunología, Hospital Interzonal de Agudos Especializado en Pediatría “Sor María Ludovica”, Calle 14 n° 1631, La Plata, Argentina
c Laboratorio de Gastroenteritis Virales, INEI – ANLIS “Dr. Carlos G. Malbrán”, Av Vélez Sársfield 563, Ciudad de Buenos Aires, Argentina
Read
2067
Timeswas read the article
462
Total PDF
1605
Total HTML
Share statistics
array:24 [ "pii" => "S0325754120300985" "issn" => "03257541" "doi" => "10.1016/j.ram.2020.10.002" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "423" "copyright" => "Asociación Argentina de Microbiología" "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Argent Microbiol. 2021;53:216-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S0325754120301000" "issn" => "03257541" "doi" => "10.1016/j.ram.2020.10.003" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "425" "copyright" => "Asociación Argentina de Microbiología" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Argent Microbiol. 2021;53:220-4" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">INFORME BREVE</span>" "titulo" => "Infección neumocócica osteoarticular en niños atendidos en un hospital pediátrico de referencia de Misiones, Argentina. Trece años de vigilancia" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:3 [ 0 => "es" 1 => "es" 2 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "220" "paginaFinal" => "224" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Pneumococcal osteoarticular infections in children admitted to a Pediatric Reference Hospital from Misiones, Argentina. Thirteen years of surveillance" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Mónica E. Martínez, Jessica Benítez, Lorena B. Leguizamón, Oscar H. López, Sandra L. Grenón, Marta E. Mollerach, Martha H. von Specht" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Mónica E." "apellidos" => "Martínez" ] 1 => array:2 [ "nombre" => "Jessica" "apellidos" => "Benítez" ] 2 => array:2 [ "nombre" => "Lorena B." "apellidos" => "Leguizamón" ] 3 => array:2 [ "nombre" => "Oscar H." "apellidos" => "López" ] 4 => array:2 [ "nombre" => "Sandra L." "apellidos" => "Grenón" ] 5 => array:2 [ "nombre" => "Marta E." "apellidos" => "Mollerach" ] 6 => array:2 [ "nombre" => "Martha H." "apellidos" => "von Specht" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0100" class="elsevierStylePara elsevierViewall">Las artritis y osteomielitis neumocóccica son poco frecuentes, pero deben vigilarse.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0105" class="elsevierStylePara elsevierViewall">La etiología neumocóccica debe considerarse en la infección osteoarticular en niños.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0110" class="elsevierStylePara elsevierViewall">El cultivo, el aislamiento y el antibiograma permiten instaurar un tratamiento adecuado.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">•</span><p id="par0115" class="elsevierStylePara elsevierViewall">Es escasa la información del impacto de las vacunas en estos cuadros.</p></li></ul></p></span>" ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0325754120301000?idApp=UINPBA00004N" "url" => "/03257541/0000005300000003/v1_202109250622/S0325754120301000/v1_202109250622/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S032575412030095X" "issn" => "03257541" "doi" => "10.1016/j.ram.2020.09.007" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "420" "copyright" => "Asociación Argentina de Microbiología" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Argent Microbiol. 2021;53:210-5" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "First report of pathogenic <span class="elsevierStyleItalic">Leptospira</span> spp. in <span class="elsevierStyleItalic">Tadarida brasiliensis</span> bats (family Molossidae) and <span class="elsevierStyleItalic">Eptesicus furinalis</span> (family Vespertilionidae) of Argentina. New host species in this country?" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "210" "paginaFinal" => "215" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Primer reporte de <span class="elsevierStyleItalic">Leptospira</span> spp. patógena en murciélagos <span class="elsevierStyleItalic">Tadarida brasiliensis</span> (familia: Molossidae) y <span class="elsevierStyleItalic">Eptesicus furinalis</span> (familia: Vespertilionidae) en Argentina. ¿Nuevas especies hospedadoras en el país?" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Vanina Saraullo, Sylvia Grune Loffler, Florencia Pastorino, Olivia Watanabe, Maria Laura Alonso, Micaela Hamer, Cecilia Moreira, Mara Martinez, Gustavo Martinez, Bibiana Brihuega" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Vanina" "apellidos" => "Saraullo" ] 1 => array:2 [ "nombre" => "Sylvia Grune" "apellidos" => "Loffler" ] 2 => array:2 [ "nombre" => "Florencia" "apellidos" => "Pastorino" ] 3 => array:2 [ "nombre" => "Olivia" "apellidos" => "Watanabe" ] 4 => array:2 [ "nombre" => "Maria Laura" "apellidos" => "Alonso" ] 5 => array:2 [ "nombre" => "Micaela" "apellidos" => "Hamer" ] 6 => array:2 [ "nombre" => "Cecilia" "apellidos" => "Moreira" ] 7 => array:2 [ "nombre" => "Mara" "apellidos" => "Martinez" ] 8 => array:2 [ "nombre" => "Gustavo" "apellidos" => "Martinez" ] 9 => array:2 [ "nombre" => "Bibiana" "apellidos" => "Brihuega" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S032575412030095X?idApp=UINPBA00004N" "url" => "/03257541/0000005300000003/v1_202109250622/S032575412030095X/v1_202109250622/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief report</span>" "titulo" => "Persistent infection with a rotavirus vaccine strain in a child suffering from Severe Combined Immunodeficiency in Argentina" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "216" "paginaFinal" => "219" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "María J. Palau, Cecilia M. Vescina, Lorena Regairaz, Diana Cabanillas, Juan A. Stupka, Juan I. Degiuseppe" "autores" => array:6 [ 0 => array:3 [ "nombre" => "María J." "apellidos" => "Palau" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Cecilia M." "apellidos" => "Vescina" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Lorena" "apellidos" => "Regairaz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Diana" "apellidos" => "Cabanillas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Juan A." "apellidos" => "Stupka" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:4 [ "nombre" => "Juan I." "apellidos" => "Degiuseppe" "email" => array:1 [ 0 => "jdegiuseppe@anlis.gov.ar" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Sala de Microbiología, Laboratorio Central, Hospital Interzonal de Agudos Especializado en Pediatría “Sor María Ludovica”, Calle 14 n° 1631, La Plata, Argentina" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital Interzonal de Agudos Especializado en Pediatría “Sor María Ludovica”, Calle 14 n° 1631, La Plata, Argentina" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Laboratorio de Gastroenteritis Virales, INEI – ANLIS “Dr. Carlos G. Malbrán”, Av Vélez Sársfield 563, Ciudad de Buenos Aires, Argentina" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Infección persistente por cepa vacunal de rotavirus en un niño con inmunodeficiencia combinada severa en Argentina" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Rotavirus represents one of the leading causes of acute diarrhea in children worldwide<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">6</span></a>. Because of the high burden of disease associated with this virus, the World Health Organization (WHO) recommends all countries to introduce rotavirus vaccines into their national childhood immunization programs as a part of a comprehensive strategy to control diarrheal diseases among other interventions as improvements in hygiene and sanitation, and overall improvements in case management<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">18</span></a>. Since 2006, two licensed live oral vaccines are available worldwide: monovalent GSK Rotarix™ (RV1, live attenuated G1P[8] strain) and pentavalent Merck RotaTeq™ (RV5, live oral attenuated, G1-4 and P[8] human components in a bovine genetic backbone) and both have demonstrated to be broadly effective and safe<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">14,17</span></a>. In Argentina, the monovalent vaccine has been included for massive administration since 2015 after an extensive cost-effectiveness analysis and its first impact study has shown evidence of successful results<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">5,16</span></a>.</p><p id="par0010" class="elsevierStylePara elsevierViewall">As in other live attenuated oral vaccines (e.g. polio, OPV), vaccine virus shedding in feces occurs after administration and can last for several weeks depending on the doses received and the infants’ clinical aspects<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a>. Rotavirus vaccines have shown low risk of associated adverse events not only in the general population but also in hospitalized, preterm and HIV-infected or HIV-exposed infants<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a>. Conversely, their administration is contraindicated in children with previous allergic reactions to them or any of their ingredients, severe infections with high temperature, diarrhea or vomiting, a previous intussusception event or birth defects of the gastrointestinal system. Noteworthy, between 2009 and 2010, due to postmarketing reports of severe gastroenteritis with persistent vaccine viral shedding in children suffering from severe combined immunodeficiency, both companies later included this disease as an additional contraindication in their product information<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">3</span></a>.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Severe combined immunodeficiency (SCID) is a group of inborn errors of immunity (IEIs) that affects cellular and humoral immunity and is defined by T-cell lymphopenia (CD3+ T cells less than 300/μl)<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a>. Its global incidence remains unknown but in the United States has been estimated in 1 of 50<span class="elsevierStyleHsp" style=""></span>000 to 100<span class="elsevierStyleHsp" style=""></span>000 live births with fatal prognosis due to severe recurring infections and failure to thrive if no hematopoietic cell transplantation is conducted within the first year of life<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a>. As an early diagnosis is unusual when there is no family history of immunodeficiency, the first contact of SCID patients with life-threatening pathogens is set because of the administration of live attenuated vaccines, such as BCG, OPV and rotavirus<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a>. We describe a case of an infant with SCID who suffered from persistent rotavirus symptomatic diarrhea after receiving the oral vaccine and was found to be infected with a rotavirus vaccine strain.</p><p id="par0020" class="elsevierStylePara elsevierViewall">A pre-term (36 weeks) 5 month-old male infant was admitted to a referential children's hospital due to acute diarrhea, oral intolerance, bronchiolitis, oral thrush and failure to thrive. He presented no complications at birth after an uneventful pregnancy. He had received BCG and the first dose of hepatitis B vaccine at birth, and completed polio, pneumococcal, rotavirus, <span class="elsevierStyleItalic">Haemophilus influenzae</span> type b (Hib), and diphtheria, tetanus and pertussis (DTP) schemes (first doses at 2 months of age and second doses at 4.5 months of age). Blood, urine, cerebral-spine fluid (CSF), stool, and nasopharyngeal and gastric aspirate samples were drawn for biochemical and culture studies.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Considering his faltering growth, persistent thrush and a white cell count of 4100/mm<span class="elsevierStyleSup">3</span> (lymphocytes count 984/mm<span class="elsevierStyleSup">3</span>, 24%), further immunological tests were conducted. Nearly undetected levels of IgG were found (1.38<span class="elsevierStyleHsp" style=""></span>mg/dl; range: 650–1600<span class="elsevierStyleHsp" style=""></span>mg/dl), IgA (0.16<span class="elsevierStyleHsp" style=""></span>mg/dl; range: 40–350<span class="elsevierStyleHsp" style=""></span>mg/dl) and IgM (0.88<span class="elsevierStyleHsp" style=""></span>mg/dl; range: 54–300<span class="elsevierStyleHsp" style=""></span>mg/dl). Furthermore, the analysis of lymphocytic populations showed 98.6% of CD19, 1.0% of CD56 and 0.1% of CD3. There was no pathogen recovery from any of the blood, urine, nasopharyngeal aspirate and CSF samples. However, rotavirus was detected by ELISA in the initial stool sample (day +1) and symptomatic diarrhea did not end up after 7 days as expected. Subsequent samples (from days +10, +24, +35 and +50) were also positive for rotavirus. Thus, blood, CSF and stool samples were sent to the National Reference Laboratory of Rotavirus and Norovirus for further studies. Amplification and sequencing of VP7, VP4 and NSP4 genes from the stool sample revealed a G1P[8] strain with high identity at nucleotide level (>99.5%) with the Rotarix™ vaccine strain. No detection of the rotavirus genome was found in blood or CSF samples. On the other hand, acid-fast bacilli were found in the gastric aspirate which led to the diagnosis of BCGitis with meningeal compromise and antimycobacterial drugs were administered.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Final diagnosis of <span class="elsevierStyleSmallCaps">X</span>-linked severe combined immune deficiency (<span class="elsevierStyleSmallCaps">X</span>-SCID) was assessed by confirmation of the presence of the c.63_66delG (p.Gly22fsX2) mutation in the exon 1 of <span class="elsevierStyleItalic">IL2RG</span> gene (heterozygous mutation carrier mother). Thus, a haploidentical hematopoietic cell transplant could be performed once the rotavirus infection cleared (day +72, at 7.5 months of age). Despite the transplant, the patient died 2 months later without immune reconstitution and with evidence of disseminated BCG infection.</p><p id="par0035" class="elsevierStylePara elsevierViewall">To our very best knowledge, this is the first report of a chronic diarrhea case with a rotavirus vaccine strain in an infant suffering from severe combined immunodeficiency in Argentina. Although rotavirus vaccines have been clearly contraindicated for over a decade in children with this particular IEI, this case highlights the need for improvements in earlier diagnosis to permit clinicians to withhold live attenuated immunization. In most countries, newborns are only screened for metabolic and endocrine disorders to rapidly allow to know what kind of nutrition has to be avoided or to implement an early treatment to reduce potential permanent damages. However, primary immune deficiencies are yet still far from being widely screened considering that administration of live attenuated vaccines, such as BCG, OPV and rotavirus occurs within the first weeks of birth and represents the first contact of life-threating pathogens causing severe infections in patients with IEIs. Since SCID is the most severe IEI, several developed countries have already included its screening, using dried blood spot specimens of the newborns’ heel, by detecting T-cell receptor excision circles (TRECs)<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a>. As TRECs are present when T-cells are being produced, infants with few or no T-cells have low levels or absence of them. Nonetheless, a complete blood count with lymphocytic populations’ analysis by flow-cytometry is further needed for confirmatory purposes<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">7</span></a>.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In general, the assessment of SCID diagnosis is set after a severe infection with chronic diarrhea and failure to thrive has already occurred. This delay limits the possibilities of an early and proper treatment and impacts directly on the child prognosis. Thus, until SCID could be included in the newborn screening core panel it is important to reflect on some alternative and feasible strategies for the early detection of this IEI before immunization with live attenuated vaccines in infants with no family backgrounds of genetical disorders.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Oral rotavirus vaccines have been broadly described to be safe and effective in the general population. However, in some particular settings (low and middle-low income countries) its effectiveness is far from expected<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a>. Therefore, efforts are made to analyze if parenteral immunization with an inactivated rotavirus vaccine will show overcoming results<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">8,13</span></a>. Considering that adaptive immunity plays a central role in this disorder, only SCID has been associated with persistent symptomatic infection in rotavirus-vaccinated children, mostly after the second or third dose administration<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">10,11</span></a>. Thus, the future administration of these inactivated vaccines currently in development will represent a valuable tool not only for those children living in areas with documented lower effectiveness but also for children with immunodeficiencies, since even if the response could be suboptimal or even null for them, at least will not represent a threat in terms of severe infection development.</p><p id="par0050" class="elsevierStylePara elsevierViewall">This case attempts to contribute to the discussion of those pathologies that need to be incorporated into a screening program. All things considered, better newborn screening approaches and alternative strategies replacing immunization with live attenuated vaccines are needed for infants with SCID and other immunity disorders to prevent severe infections and to provide prompt treatment so they can achieve healthier lives.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Funding</span><p id="par0055" class="elsevierStylePara elsevierViewall">This research has not received specific aid from public sector agencies, commercial sector or non-profit entities.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conflict of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:3 [ "identificador" => "xres1577098" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1421236" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1577099" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1421235" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-01-28" "fechaAceptado" => "2020-10-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1421236" "palabras" => array:4 [ 0 => "Rotavirus vaccine" 1 => "Severe combined immunodeficiency" 2 => "Diarrhea" 3 => "Argentina" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1421235" "palabras" => array:4 [ 0 => "Vacuna contra rotavirus" 1 => "Inmunodeficiencia combinada severa" 2 => "Diarrea" 3 => "Argentina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Due to the high burden of disease associated with rotavirus, the massive vaccination in children before six months of age has been encouraged. Currently licensed oral live vaccines have shown low risk of associated adverse events in the general population. Noteworthy, postmarketing reports of severe gastroenteritis with persistent vaccine viral shedding in children with severe combined immunodeficiency (SCID) have led companies to include this inborn error of immunity as an additional contraindication. SCID is not usually screened in newborns from developing countries. Therefore, the administration of live attenuated vaccines represents the first contact of these patients with life-threatening pathogens. We describe a clinical case of an infant with SCID who suffered from persistent rotavirus symptomatic diarrhea after receiving the rotavirus oral vaccine and was found to be infected with the vaccine strain. This case attempts to contribute to the discussion of those diseases that need to be incorporated into a screening program since an early diagnosis permits clinicians to withhold live attenuated immunization.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Debido a la elevada carga de enfermedad asociada con rotavirus, se ha aconsejado incorporar la vacunación masiva en los menores de seis meses. Las vacunas vivas orales que se encuentran actualmente licenciadas han mostrado un bajo riesgo de eventos adversos en la población general. Sin embargo, algunos años después del comienzo de su comercialización, la publicación de reportes de gastroenteritis grave con excreción viral persistente de la cepa vacunal en niños con inmunodeficiencia combinada severa (IDCS) llevaron a las compañías productoras de estas vacunas a sumar esta alteración congénita de la inmunidad a la lista de contraindicaciones. La IDSC generalmente no se tamiza en los recién nacidos de países en desarrollo. Por lo tanto, la administración de vacunas vivas atenuadas representa el primer contacto de estos pacientes con agentes patógenos potencialmente mortales. Describimos el caso de un niño con IDSC que presentó diarrea sintomática persistente por rotavirus luego de recibir la vacuna oral y que estaba infectado con la cepa vacunal. Este caso intenta contribuir a la discusión de aquellas enfermedades que deberían incorporarse a un programa de tamizaje debido a que su diagnóstico temprano permite a los médicos evitar la inmunización con virus vivos atenuados.</p></span>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0095" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The 2017 IUIS phenotypic classification for primary immunodeficiencies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:22 [ 0 => "A. Bousfiha" 1 => "L. Jeddane" 2 => "C. Picard" 3 => "F. Ailal" 4 => "H. Bobby Gaspar" 5 => "W. Al-Herz" 6 => "T. Chatila" 7 => "Y.J. Crow" 8 => "C. Cunningham-Rundles" 9 => "A. Etzioni" 10 => "J.L. Franco" 11 => "S.M. Holland" 12 => "C. Klein" 13 => "T. Morio" 14 => "H.D. Ochs" 15 => "E. Oksenhendler" 16 => "J. Puck" 17 => "M.L.K. Tang" 18 => "S.G. Tangye" 19 => "T.R. Torgerson" 20 => "J.L. Casanova" 21 => "K.E. Sullivan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10875-017-0465-8" "Revista" => array:7 [ "tituloSerie" => "J Clin Immunol" "fecha" => "2018" "volumen" => "38" "paginaInicial" => "129" "paginaFinal" => "143" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29226301" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0008418217313327" "estado" => "S300" "issn" => "00084182" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0100" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Universal newborn screening for severe combined immunodeficiency (SCID)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Burg" 1 => "van der" 2 => "N. Mahlaoui" 3 => "H.B. Gaspar" 4 => "S.Y. Pai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fped.2019.00373" "Revista" => array:5 [ "tituloSerie" => "Front Pediatr" "fecha" => "2019" "volumen" => "7" "paginaInicial" => "373" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31620409" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0105" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Addition of severe combined immunodeficiency as a contraindication for administration of rotavirus vaccine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Centers for Disease Control and Prevention (CDC)" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "MMWR Morb Mortal Wkly Rep" "fecha" => "2010" "volumen" => "59" "paginaInicial" => "687" "paginaFinal" => "688" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20535093" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0110" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.M. Cortese" 1 => "U.D. Parashar" 2 => "Centers for Disease Control and Prevention (CDC)" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "MMWR Recomm Rep" "fecha" => "2009" "volumen" => "58" "paginaInicial" => "1" "paginaFinal" => "25" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0115" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "First assessment of all-cause acute diarrhoea and rotavirus-confirmed cases following massive vaccination in Argentina" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.I. Degiuseppe" 1 => "J.A. Stupka" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1017/S0950268818001954" "Revista" => array:6 [ "tituloSerie" => "Epidemiol Infect" "fecha" => "2018" "volumen" => "146" "paginaInicial" => "1948" "paginaFinal" => "1954" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30001762" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0120" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "GBD Diarrhoeal Diseases Collaborators" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(17)30276-1" "Revista" => array:6 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2017" "volumen" => "17" "paginaInicial" => "909" "paginaFinal" => "948" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28579426" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0125" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Genetics Home Reference. Severe combined immunodeficiency: National Library of Medicine (US) [Internet]" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2013" "editorial" => "The Library" "editorialLocalizacion" => "Bethesda (MD)" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0130" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:12 [ 0 => "M.J. Groome" 1 => "A. Koen" 2 => "A. Fix" 3 => "N. Page" 4 => "L. Jose" 5 => "S.A. Madhi" 6 => "M. McNeal" 7 => "L. Dally" 8 => "I. Cho" 9 => "M. Power" 10 => "J. Flores" 11 => "S. Cryz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(17)30242-6" "Revista" => array:6 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2017" "volumen" => "17" "paginaInicial" => "843" "paginaFinal" => "853" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28483414" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0135" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Co-appearance of OPV and BCG vaccine-derived complications in two infants with severe combined immunodeficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "S. Heiman" 1 => "M. Weil" 2 => "L.M. Shulman" 3 => "A.J. Simon" 4 => "A. Lev" 5 => "R. Somech" 6 => "T. Stauber" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12026-018-9007-6" "Revista" => array:6 [ "tituloSerie" => "Immunol Res" "fecha" => "2018" "volumen" => "66" "paginaInicial" => "437" "paginaFinal" => "443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29804197" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0140" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vaccine-acquired rotavirus in infants with severe combined immunodeficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:11 [ 0 => "N.C. Patel" 1 => "P.M. Hertel" 2 => "M.K. Estes" 3 => "M. de la Morena" 4 => "A.M. Petru" 5 => "L.M. Noroski" 6 => "P.A. Revell" 7 => "I.C. Hanson" 8 => "M.E. Paul" 9 => "H.M. Rosenblatt" 10 => "S.L. Abramson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0904485" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2010" "volumen" => "362" "paginaInicial" => "314" "paginaFinal" => "319" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20107217" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0145" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Life-threatening infections due to live-attenuated vaccines: early manifestations of inborn errors of immunity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L. Pöyhönen" 1 => "J. Bustamante" 2 => "J.L. Casanova" 3 => "E. Jouanguy" 4 => "Q. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Immunol" "fecha" => "2019" "volumen" => "39" "paginaInicial" => "376" "paginaFinal" => "390" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0150" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Population-based newborn screening for severe combined immunodeficiency: steps toward implementation" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "SCID Newborn Screening Working Group" "etal" => false "autores" => array:1 [ 0 => "J.M. Puck" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2007.08.043" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2007" "volumen" => "120" "paginaInicial" => "760" "paginaFinal" => "768" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17931561" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0155" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inactivated rotavirus vaccine by parenteral administration induces mucosal immunity in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "T.K. Resch" 1 => "Y. Wang" 2 => "S.S. Moon" 3 => "J. Joyce" 4 => "S. Li" 5 => "M. Prausnitz" 6 => "B. Jiang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41598-017-18973-9" "Revista" => array:5 [ "tituloSerie" => "Sci Rep" "fecha" => "2018" "volumen" => "8" "paginaInicial" => "561" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29330512" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0160" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Human Rotavirus Vaccine Study Group" "etal" => false "autores" => array:36 [ 0 => "G.M. Ruiz-Palacios" 1 => "I. Pérez-Schael" 2 => "F.R. Velázquez" 3 => "H. Abate" 4 => "T. Breuer" 5 => "S.C. Clemens" 6 => "B. Cheuvart" 7 => "F. Espinoza" 8 => "P. Gillard" 9 => "B.L. Innis" 10 => "Y. Cervantes" 11 => "A.C. Linhares" 12 => "P. López" 13 => "M. Macías-Parra" 14 => "E. Ortega-Barría" 15 => "V. Richardson" 16 => "D.M. Rivera-Medina" 17 => "L. Rivera" 18 => "B. Salinas" 19 => "N. Pavía-Ruz" 20 => "J. Salmerón" 21 => "R. Rüttimann" 22 => "J.C. Tinoco" 23 => "P. Rubio" 24 => "E. Nuñez" 25 => "M.L. Guerrero" 26 => "J.P. Yarzábal" 27 => "S. Damaso" 28 => "N. Tornieporth" 29 => "X. Sáez-Llorens" 30 => "R.F. Vergara" 31 => "T. Vesikari" 32 => "A. Bouckenooghe" 33 => "R. Clemens" 34 => "B. De Vos" 35 => "M. O’Ryan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa052434" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2006" "volumen" => "354" "paginaInicial" => "11" "paginaFinal" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16394298" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0165" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of rotavirus vaccines in low and middle-income countries" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K.N.C. Sindhu" 1 => "S. Babji" 2 => "S.K. Ganesan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/QCO.0000000000000397" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Infect Dis" "fecha" => "2017" "volumen" => "30" "paginaInicial" => "473" "paginaFinal" => "481" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28719399" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0170" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cost-effectiveness analysis of rotavirus vaccination in Argentina" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:9 [ 0 => "A. Urueña" 1 => "T. Pippo" 2 => "M.S. Betelu" 3 => "F. Virgilio" 4 => "L. Hernández" 5 => "N. Giglio" 6 => "Á. Gentile" 7 => "M. Diosque" 8 => "C. Vizzotti" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.vaccine.2014.12.074" "Revista" => array:7 [ "tituloSerie" => "Vaccine" "fecha" => "2015" "volumen" => "33" "numero" => "Suppl. 1" "paginaInicial" => "A126" "paginaFinal" => "A134" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25919152" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0175" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rotavirus Efficacy and Safety Trial (REST) Study Team. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:28 [ 0 => "T. Vesikari" 1 => "D.O. Matson" 2 => "P. Dennehy" 3 => "P. Van Damme" 4 => "M. Santosham" 5 => "Z. Rodriguez" 6 => "M.J. Dallas" 7 => "J.F. Heyse" 8 => "M.G. Goveia" 9 => "S.B. Black" 10 => "H.R. Shinefield" 11 => "C.D. Christie" 12 => "S. Ylitalo" 13 => "R.F. Itzler" 14 => "M.L. Coia" 15 => "M.T. Onorato" 16 => "B.A. Adeyi" 17 => "G.S. Marshall" 18 => "L. Gothefors" 19 => "D. Campens" 20 => "A. Karvonen" 21 => "J.P. Watt" 22 => "K.L. O’Brien" 23 => "M.J. DiNubile" 24 => "H.F. Clark" 25 => "J.W. Boslego" 26 => "P.A. Offit" 27 => "P.M. Heaton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa052664" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2006" "volumen" => "354" "paginaInicial" => "23" "paginaFinal" => "33" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16394299" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1695403318300535" "estado" => "S300" "issn" => "16954033" ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0180" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rotavirus vaccines: an update" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "World Health Organization" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Wkly Epidemiol Rec" "fecha" => "2009" "volumen" => "84" "paginaInicial" => "533" "paginaFinal" => "540" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20034143" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/03257541/0000005300000003/v1_202109250622/S0325754120300985/v1_202109250622/en/main.assets" "Apartado" => array:4 [ "identificador" => "37861" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Microbiología clínica y enfermedades infecciosas" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03257541/0000005300000003/v1_202109250622/S0325754120300985/v1_202109250622/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0325754120300985?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 1 | 8 |
| 2024 October | 61 | 8 | 69 |
| 2024 September | 103 | 8 | 111 |
| 2024 August | 64 | 2 | 66 |
| 2024 July | 49 | 7 | 56 |
| 2024 June | 70 | 7 | 77 |
| 2024 May | 46 | 9 | 55 |
| 2024 April | 48 | 6 | 54 |
| 2024 March | 61 | 11 | 72 |
| 2024 February | 52 | 6 | 58 |
| 2024 January | 84 | 8 | 92 |
| 2023 December | 49 | 7 | 56 |
| 2023 November | 67 | 15 | 82 |
| 2023 October | 63 | 10 | 73 |
| 2023 September | 59 | 7 | 66 |
| 2023 August | 36 | 10 | 46 |
| 2023 July | 32 | 8 | 40 |
| 2023 June | 28 | 6 | 34 |
| 2023 May | 29 | 9 | 38 |
| 2023 April | 22 | 6 | 28 |
| 2023 March | 12 | 2 | 14 |
| 2023 February | 16 | 3 | 19 |
| 2023 January | 18 | 6 | 24 |
| 2022 December | 18 | 12 | 30 |
| 2022 November | 12 | 9 | 21 |
| 2022 October | 24 | 15 | 39 |
| 2022 September | 16 | 16 | 32 |
| 2022 August | 21 | 9 | 30 |
| 2022 July | 26 | 10 | 36 |
| 2022 June | 23 | 9 | 32 |
| 2022 May | 20 | 12 | 32 |
| 2022 April | 25 | 16 | 41 |
| 2022 March | 47 | 14 | 61 |
| 2022 February | 45 | 5 | 50 |
| 2022 January | 37 | 6 | 43 |
| 2021 December | 57 | 9 | 66 |
| 2021 November | 43 | 10 | 53 |
| 2021 October | 30 | 29 | 59 |
| 2021 September | 8 | 15 | 23 |
| 2021 August | 5 | 4 | 9 |
| 2021 July | 6 | 4 | 10 |
| 2021 June | 8 | 10 | 18 |
| 2021 May | 8 | 9 | 17 |
| 2021 April | 24 | 13 | 37 |
| 2021 March | 9 | 49 | 58 |
| 2021 February | 16 | 15 | 31 |
| 2021 January | 1 | 0 | 1 |
Show all
