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Fibrosis pulmonar como secuela pulmonar parenquimato= sa provocada por COVID 19: una revisión bibliográfica

Pulmonary fibrosis as a = parenchymal pulmonary sequela caused by COVID 19: a literature review=

= ¹

Johana Isabel Ortiz Atiaja

htt= ps://orcid.org/0000-0002-3446-8213=

Estudiante de la Carrera de Medicina de la Universidad Técnica de Ambato=

jortiz1639@uta.edu.ec

	Artículo de Investigación Científica y Tecnológica Enviado: 18/02/2021 Revisado: 07/03/2022 Aceptado: 28/04/2022 Publicado:05/07/2022 DOI: https://doi.o= rg/10.33262/anatomiadigital.v5i3.2158
&= nbsp;
Cítese:		Ortiz Atiaja, J. I. (2022). Fibrosis pulmonar como secuela pulmonar parenquimatosa provocada por COVID 19: una revisión bibliográfica. Anatomía Digital, 5(3), 6-18. https://doi.o= rg/10.33262/anatomiadigital.v5i3.2158
		ANATOMÍA DIGITAL, es una Revista Electónica, Trimestral, que se publicará en soporte electrónico tiene como misión contribuir a la formación de&nb= sp; profesionales competentes con visión humanística y crítica que sean capac= es de exponer sus resultados investigativos y científicos = en la misma medida que se promueva mediante su intervención cambios positivos en la sociedad. https://anatomiadigital.org La revista es editada por la Editorial Ciencia Digital (Editorial de prestigio registrada en la Cámara Ecuatoriana de Libro con = No de Afiliación 663) www.celibro.org.ec<= span style=3D'font-size:8.0pt;font-family:"Times New Roman",serif;mso-fareast-= font-family: "Times New Roman"'>
		Esta revista está protegida ba= jo una licencia Creative Commons AttributionNonCommercialNoDerivatives 4.0 International. Copia de la licencia: http://creativecommons.org/licenses/by-n= c-nd/4.0/
Palabras claves: COVID 19, fibrosis pulmonar, SARS-COV-2, parénquima, secuela.		Resumen = Intr= oducción: se define como la condición que afecta = el parénquima pulmonar debido a que los tejidos se vuelven gruesos y duros dificultando su elasticidad y el paso del oxígeno hacia los vasos sanguín= eos. Objetivo: realizar una revisión bibliográfica acerca del abordaje diagnóstico y terapéutico sobre la fibrosis pulmonar como secuela del SARS-COV-2. Metodología: en la presente revisión se realizó una búsqueda exhaustiva de información sobre fibrosis pulmonar en bases de da= tos como UpToDate, Springer, Google Académico, PUBMED, Revistas y páginas oficiales de información mundial sobre COVID 19. Conclusión: se identificó las principales pruebas de imagen para detectar la presencia de fibrosis, además de tratamientos para mejorar la calidad de vida de los pacientes posterior al alta hospitalaria. <= /span>
Keywords: Covid= 19, pulmonary fibrosis, SARS-COV-2, parenchyma, sequela &= nbsp;		Abstract= Introduction: It is defined as the condition that affects the lung parenchyma because the tissues become thick and hard, hindering its elasticity and the passage of oxygen to the blood vessels. Objective. - Conduct a bibliographic review about t= he diagnostic and therapeutic approach to pulmonary fibrosis. Materials a= nd methods: In the present review, an exhaustive search was conducted for information on pulmonary fibrosis in databases such as UpToDate, Springer, Google Scholar, PUBMED, Journals and official pages of world information = on Covid 19. Conclusion: The main imaging tests to detect the presenc= e of fibrosis were identified, as well as treatments to improve the quality of life of patients after hospital discharge. &= nbsp;

Introducción<= /i>

El COVID 19 desde su aparición en Wuhan en diciembre del 2019 se ha convertido= en un problema a nivel mundial debido al nuevo coronavirus conocido como SARS-COV-2, que afecta el sistema respiratorio al ocasionar el síndrome de distrés respiratorio agudo el mismo que es responsable de incrementar las t= asas de mortalidad debido a la falta de tratamiento oportuno y específico. Este virus se dispersó a nivel mundial debido a su rápida diseminación y alto grado de contagio, ocupando = un puesto preocupante a nivel hospitalario debido a las manifestaciones clínic= as graves como las secuelas que desarrollan al superar la enfermedad (1).

Desde el punto de vista clínico el pulmón= es el órgano más afectado por este virus ya que genera cambios microscópicos c= omo severo dańo endotelial diseminada, lesión pulmonar aguda y fenómenos fibrót= icos y remodelado del parénquima pulmonar dańos compatibles con fibrosis pulmonar (2).

Según las estadísticas recopiladas de la Organización mundial de la salud con actualización de 2 de diciembre del 20= 21 nos muestra a nivel mundial un total de 260,5 millones de personas contagia= das con COVID 19, de las cuál destaca Latinoamérica con 37.1% de contagiados del total (3), en Ecuador se cuenta actualmente con un pico de 37% y subiendo (= 4), en Tungurahua se muestra con un número aproximado de 15014 personas (5). A medida que la pandemia de COVID-19 golpea al mundo repetidamente, es necesa= rio implementar nuevos conocimientos de acuerdo con la fisiopatología, las secu= elas clínicas, manejo y tratamientos adecuados ya que continúa evolucionando. Po= r lo tanto, en la presente revisión se destaca la importancia de establecer estrategias de seguimiento en pacientes con COVID 19 para evaluar la progre= sión hacia la fibrosis pulmonar.

Objetivo

La presente revisión tiene como objetivo recolectar información relevante que brinde conocimientos a su lector, por lo que se usa diferentes artículos científicos para su elaboración tomando en cuenta los principales factores = de riesgo, fisiopatología, abordaje diagnóstico y terapéutico en pacientes que= han superado el COVID 19 y quedan con secuela de fibrosis pulmonar.<= /span>

Metodología

Se realizó un artículo de revisión bibliográfica con búsqueda exhaustiva de información sobre fibrosis pulmonar mediante bases de datos c= omo UpToDate, Springer, Google Académico, PMC, NCBI, Pubmed, Cochrane, y páginas oficiales de información mundial sobre COVID 19, en donde se utilizó palabras cl= ave como: “Fibrosis pulmonar Postcovid”, “Manejo de la fibrosis pulmonar”, “Nue= vos tratamientos de la fibrosis pulmonar secundaria a COVID 19”, “Fibrosis pulm= onar y COVID 19”. Para el estudio se obtuvo un total aproximado de 1660 artículo= s en la búsqueda, de los cuales se fueron excluyendo a los artículos que no cuen= ten con información necesaria y acorde a lo investigado, se incluyó artículos publicados en los últ= imos 3 ańos con un rango de diciembre del 2019 a diciembre del 2021 en idiomas inglés y espańol de relevancia e importancia clínica, teniendo así un total= de 23 artículos para la presente revisión.

Resultados

La fibrosis pulmonar se define como una condición que afecta el parénquima pulmonar debido al proceso de cicatrización, mediante el cual los tejidos se vuelven gruesos y duros lo que dificulta su elasticidad y el paso del oxíge= no hacia los vasos sanguíneos y por consiguiente se producen problemas en su respiración (6). También se la puede definir como un proceso degenerativo q= ue destruye la arquitectura alveolar ocasionando una proliferación a demanda de fibroblastos, depósito de colágeno y proteínas en el espacio de la matriz extracelular que desencadena en una cicatrización anormal de la herida (7).= Esta afectación ocurre posterior a un evento desencadenante como por ejemplo la presencia de neumonía grave que es derivada de la enfermedad inicial produc= ida por el virus del SARSCOV-2 en la cual deteriora la función pulmonar normal = (8).

Epidemiología

La nueva cepa de coronavirus el SARS-COV-2 desató una pandemia a nivel mundial= , debido a que esta enfermedad afecta gravemente a los pulmones manifestándose como síndromes respiratorios agudos o severos, mediante el cual el agente causan= te produce un dańo alveolar difuso seguido de un remodelado fibrótico que al cicatrizarse suele producir fibrosis pulmonar, una de las secuelas que más incidencia tiene en los pacientes que superan la enfermedad y reciben el al= ta hospitalaria (7). A nivel mundial un 40 % de los pacientes que superan la enfermedad de base desarrollan fibrosis pulmonar lo que ocasiona preocupaci= ón sobre todo en pacientes entre la quinta y sexta década de la vida que es do= nde se presenta con más frecuencia (9). En Latinoamérica se ha reportado que un tercio de la población ha progresado a fibrosis pulmonar (10). En Ecuador s= e encuentra en un porcentaje moderado, pero requiere de más estudios de seguimiento para poder establecer una incidencia acertada (11,12).

Fisiopatología

El SARS- COV-2 es un virus de tipo ARN que proviene de la familia Coronavirida= e, especialmente del subgrupo βeta que es uno de los más frecuentes en las infecciones humanas debido a que se une a sus células usando la enzima convertidora de angiotensina 2 (ACE2) para su entrada como componente viral, esta enzima se encuentra con frecuencia en los tejidos de órganos diana com= o el pulmón, rińón, corazón e intestinos (8). Cuando ocurre la liberación de las metaloproteinasas durante la fase inflamatoria del síndrome inflamatorio ag= udo puede desencadenar dańos a nivel epitelial y endotelial que a su paso discu= rren en una fibrosis descontrolada. Los factores de fenotipo secretor asociado a senescencia (SASP) son responsables de la cicatrización que en este caso se encuentran anómalas caracterizándose por presentar perturbación en las célu= las epiteliales y mesenquimales acarreando a una acumulación de miofibroblastos= lo que se expresa como dańos consecuentes a fibrosis (13).
La fibrosis por lo consiguiente es el resultado de la lesión tisular causada p= or los miofibroblastos lo normal es que al iniciar el proceso de cicatrización se restaure el tejido y se promueva el reemplazo a nuevas células parenquimato= sas, pero en pacientes con SARSCOV-2 grave esto ocurre repetitivamente lo que produce un desequilibrio en el entorno en donde se liberan de forma masiva citocinas proinflamatorias y profibróticas (14).

Mecanismos: La lesión que ocurre en los pulmones desencadena la proliferación y esto produce la activación de las células epiteliales alveolares tipo 2 (AEC2) p= ara cubrir el espacio alveolar que se encuentra expuesto. En el proceso de reparación normal también actúan las células epiteliales alveolares de tipo= 1 (AEC1) que se encuentran en un porcentaje del 90% en la superficie alveolar. Cuando las células epiteliales tipo 1 se lesionan o sufren un dańo a ese ni= vel, las células AEC2 realizan apoptosis para restablecer el epitelio a su normalidad, pero cuando se produce una lesión demasiado extensa las células= no son capaces de recuperar el epitelio por lo que se forma una inadecuada reparación tisular con el consiguiente depósito de colágeno, angiogénesis y sobrepoblación de fibroblastos (15).

Los fibroblastos y miofibroblastos son las principales células que actúan en la fibrosis pulmonar, estas células junto con el factor de crecimiento de fibroblastos (FGF), factor de crecimiento transformante beta (TGF-β) y= el factor de crecimiento de derivado de plaquetas (PDGF) estimulan que los fibroblastos migren hacia el tejido lesionado y adquieran un fenotipo fibró= tico en el que son resistentes a la apoptosis y por consiguiente las células AEC= 1 y AEC2 no puedan cumplir con su función normalmente (15). La activación de los macrófagos se produce en respuesta a una actividad inmune en donde se obtie= nen dos vías que comúnmente se conocen como clásica (M1) y alternativa (M2) (3)= . La vía clásica se encarga de la producción de antimicrobianos, citocinas inflamatorias y productos de oxígeno que se encarguen de la fase aguda de la inflamación, mientras que la vía alterna se produce por el efecto de las interleuquinas 4 y 13, encargadas de la producción de citocinas y los facto= res de crecimiento que son los responsables de la reparación de tejidos y dismi= nución del proceso inflamatorio en la vía M1 para la formación de tejido cicatriza= l (8,15).

Factores de Riesgo

Se han determinado ciertos parámetros que influyen a desarrollar fibrosis pulm= onar entre ellos se tiene los siguientes:

Edad. - La fibrosis pulmonar se presenta con mayor prevalencia en personas de edad avanzada es decir a partir de los 50 ańos y es muy rara su presentación ant= es de dicha edad. La edad se correlaciona al riesgo de padecer fibrosis dentro= de los 6 meses posteriores al alta hospitalaria (8).

Gravedad de la enfermedad. - De acuerdo con= la Organización Mundial de la Salud el SARS-COV-2 la presentación de infeccion= es es predominantemente leves y en un bajo porcentaje graves o muy graves, la predisposición de adquirir fibrosis pulmonar se asocia a presentaciones gra= ves de la enfermedad ligados a comorbilidades como son diabetes, enfermedades cardiovasculares e hipertensión (8).

Duración de hospitalización en UCI y uso de ventilación mecánica. Los pacientes con = una presentación grave de SARS-COV-2 generalmente se asocian a la necesidad de soporte ventilatorio y este requerimiento desencadena lesión pulmonar asoci= ada al uso del ventilador por la liberación de moduladores proinflamatorios que empeoran el dańo, aumentan la tasa de mortalidad y el desarrollo consecuent= e a fibrosis (8).

Tabaquismo. - desencadena un estrés oxidativo crónico y elevación de citocinas, así el paciente haya dejado de fumar recientemente, además este hábito se relaciona con una presentación grave y por consiguiente un ingreso a UCI y la necesid= ad de uso de ventilador (8).

Alcoholismo. - se ha relacionado con esta patología debido a que en procesos crónicos provoca dańo en los pulmones a causa del estrés oxidativo crónico, agotamie= nto del glutatión e inflamación aumentando el riesgo de lesión y posterior desarrollo a fibrosis (8,15).

Diagnóstico

Para establecer e indagar en el diagnostico se requiere de una investigación exhaustiva de los antecedentes médicos, sociales, familiares (historia clínica), examen físico, exámenes complementarios de laboratorio (hemograma completo, panel metabólico completo, estudios de coagulopatía como: TP, TTP= , dímero D, fibrinógeno), serología (anticuerpos antifosfolipídicos y anticardiolipi= na) (16).

Pruebas de imagen como la tomografía computarizada en donde podemos observar atrapamiento de aire, opacidades en vidrio esmerilado, engrosamiento septal, pérdida del volumen segmentario o lobar, reticulaciones y bronquiectasias p= or tracción. Radiografía de tórax en donde se ha descrito hallazgos de opacida= des en vidrio esmerilado en parches en los lóbulos inferiores, engrosamiento del tabique, consolidación, cavitación. El engrosamiento del tabique intralobulillar e interlobulillar superó las opacidades en vidrio esmerilado siendo estos los datos más predominantes donde muestran los cambios en curso del sistema pulmonar (17).

Pruebas de función pulmonar. - teniendo como resultados diminución de la capacidad vital forzada (FVC), capacidad pulmonar total (TLC) y la capacidad de difus= ión de monóxido de carbono (DLCO) (17).

En la actualidad tenemos el Krebs Von den Lungen-6 (KL-6) actúa como marcador reflejando el grado de fibrosis pulmonar secundaria a SARS-CoV-2, este nuevo marcador se expresa a nivel del epitelio alveolar tipo 2 que se encuentra dańado o en reparación y en las células epiteliales bronquiolares, se encue= ntra elevado principalmente en pacientes que cursaron con COVID 19 grave por lo = que su elevación ayuda en a predecir la afectación pulmonar fibrótica (18). En = un estudio realizado se obtuvo que los niveles de KL-6 son elevados en pacient= es con fibrosis pulmonar y aún más cuando son irreversibles por lo que es un g= ran predictor de la progresión y remisión de la enfermedad (19).

Pacientes que tuvieron ingreso a unidad de cuidados intensivos arrojaron un mayor deterioro de la función pulmonar total a comparación con los pacientes trat= ados en medicina interna. En estudios realizados se obtuvo resultados de una bio= psia donde se evidenció edema pulmonar, descamación de neumocitos, formación de membranas hialinas en el transcurso de su etapa inicial, transcurrido más tiempo se observó depósitos de fibrina e infiltración de células inflamator= ias y fibroblastos siendo estos las primeras características para ocasionar una fibrosis pulmonar (20).

Tratamiento

Las secuelas provocadas por este virus tienen relación con un cambio del estilo= de vida de cada víctima reduciendo de manera significativa la calidad de vida. Según estudios realizados en cuanto al tratamiento existen dos fármacos principalmente utilizados como nintedanib y pirfenidona que muestran result= ados alentadores para combatir el deterior de la función pulmonar, los mismos qu= e se encuentran aprobados para el tratamiento de la fibrosis pulmonar (21).=

Nintedanib es un inhibidor de la tirosina quinasa activo contra los receptores del fac= tor de crecimiento intrínseca de 14 tirosina. La pirfenidona posee propiedades antiinflamatorias, antioxidantes, con una amplia actividad antifibróticas e= stos medicamentos pueden ralentizar el deterioro funcional de los pulmones, independiente de su etiología. Se debe administrar por vía oral entre 2 o 3 comprimidos 3 veces al día por un tiempo mínimo de 4 semanas. Se ha demostr= ado que este fármaco ayuda a mitigar la proliferación de los fibroblastos, proteínas y citocinas asociadas a la formación de la fibrosis, en algunas pruebas la pirfenidona ha mostrado resultados satisfactorios (21).

Otra de las opciones es el tratamiento con células madre mesenquimales (CMM) pos= een propiedades inmoduladoras y antiinflamatorias que puede reducir la tormenta= de citocinas y previene el desequilibrio de las células T que se ocasiona por = la infección del COVID 19, esta terapia contiene citocinas, quimiocinas, facto= res de crecimiento, actuando en la regeneración pulmonar una terapia de alta ga= ma para la fibrosis pulmonar mejorando su actividad física (15).

Un nuevo enfoque es la formulación de secretoma liofilizado (leyosecretome) ti= ene una amplia capacidad de propiedades antiinflamatorias, inmunomoduladoras, regenerativas, proangiogenicas mejorando la estructura pulmonar (22).<= /o:p>

Prevención

Las estrategias por implementar tienen como objetivo detener o limitar los fact= ores que propaguen o aceleren el dańo pulmonar, respuesta inflamatoria y fibroproliferación. A medida que el SARS-CoV-2 sigue causando dańo se debe poner énfasis en los factores modificables que pueden aumentar el riesgo de fibrosis pulmonar así tenemos; el dańo producido por el ventilador mecánico= se puede realizar configuraciones como el volumen tidal bajo, así como la pres= ión de respiración, produciendo una ventilación pulmonar protectora, generando = una reducción de la mortalidad en un 30% ante un SDRA (síndrome de distrés respiratorio agudo) (17). Una medida que se debe poner en práctica es la educación al paciente tras el alta hospitalaria, deben evitar estar expuest= os a factores ambientales dańinos para su salud. Además, el abandono del hábito = de fumar es algo principal en esto tipo de pacientes, esto reduce el proceso inflamatorio y remodelación pulmonar. Pruebas de función pulmonar, tomograf= ías computarizadas como seguimiento para observar los cambios que pueden presen= tar en la arquitectura y función pulmonar (22,15). Las estrategias complementar= ias para reducir el riesgo de fibrosis pulmonar se basan en tres ejes principal= es: a) inhibición intensa y prolongada de la replicación viral, b) inhibición prolongada de la respuesta inflamatoria, c) administración de fármacos anti fibróticos. En ensayos clínicos realizados el uso de fármacos como los corticoides a dosis bajas durante la estancia hospitalaria pueden prevenir = la remodelación pulmonar sin embargo siempre se debe evaluar el riesgo-benefic= io en cada paciente (17).

Discusión=

Se revisó una serie de artículos de en distintas bases de datos disponibles en internet en donde se recolectó información de relevancia acerca del tema “fibrosis pulmonar como secuela parenquimatosa provocada por el COVID 19”. La enfermedad del COVID 19 ha si= do conocido como relevante en la historia mundial ya que ha provocado una gran morbimortalidad en pacientes que contrajeron la enfermedad y según la Organización mundial de la salud muestra un gran número de contagios en este lapso desde su aparición hasta la actualidad. Entre las principales secuela= s de esta enfermedad se encuentra la fibrosis pulmonar parenquimatosa debido a q= ue afecta la cicatrización normal del tejido pulmonar disminuyendo su elastici= dad y flexibilidad lo que disminuye el flujo sanguíneo y consiguiente dificulta= ndo la respiración siendo este el principal cuadro clínico de los pacientes (6)= . Revisando la etiología de la enfermedad nos encontramos que personas con necesidad de ventilación mecánica durante la estancia hospitalaria, comorbilidades, hábi= tos tóxicos como el alcohol, el tabaco y la edad son factores que inciden en el progreso a fibrosis pulmonar. Cabe destacar que la edad y el antecedente de= una enfermedad pulmonar es un predilecto de mal pronóstico para SARS-CoV-2 suma= do a esta el envejecimiento biológico y la replicación viral tiene mayor predilección por células senescentes. Todo este proceso patológico va de la mano con la gravedad que presenta el cuadro clínico y el tiempo que transcu= rre de la enfermedad (10, 23). Si bien la recuperación del SARS-CoV-2 es lenta = los estudios de imagen nos ayudan a detectar, monitorear y evaluar la eficacia = del tratamiento a implementarse siendo a tomografía computarizada y la radiogra= fía de tórax los recomendados (20). El tratamiento para la fibrosis pulmonar es= un desafío y debe ir de la mano multidisciplinariamente entre fisioterapia respiratoria, uso de fármacos como nuevos estudios recomiendan el uso de 2 fármacos en especial como el nintedanib y pirfenidona que actúan como antii= nflamatorios e inhiben el deterioro pulmonar, además que se debe implementar una educaci= ón saludable al evitar el consumo de tabaco y alcohol y la implementación de deporte diario, todo esto ayuda a mejorar la calidad de vida del paciente posterior a padecer la enfermedad del COVID 19 (21).<= /p>
Conclusiones

·      =    La nueva enfermedad inducida por COVID= 19 ha presentado un gran desafío para el área de salud ya que desde su aparici= ón repentina y rápida propagación se ha desatado una serie de conflictos en la= calidad de vida del paciente especialmen= te en aquellos que han superado la enfermedad inicial, es importante identificar = las secuelas más representativas como son en este caso las pulmonares parenquimatosas destacando la fibrosis pulmonar, la misma que se debe a un curso de la enfermedad inicial grave que se asocie a la unidad de cuidados intensivos o uso de ventilación mecánica que junto a factores asociados desencadenas con frecuencia la fibrosis.

·      =    Un diagnóstico oportuno de la enfermed= ad es esencial por lo que es importante identificarlo mediante estudios imagenológicos como la radiografía y tomografía de tórax que son de gran ay= uda para detectar esta patología.

·      =    El manejo de la fibrosis pulmonar medi= ante los nuevos tratamientos es indispensable de manera oportuna al inicio de la sintomatología clínica y detección de la enfermedad para su actuación de ma= nera eficaz y así mejorar la calidad de vida de los pacientes postcovid 19.=

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