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or sequelae that may be incapacitating or decisive in terms of their survival&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">To approach this reality in an adequate manner&#44; the first issue we must address is the definition of uniform criteria to describe such a polymorphous and heterogeneous clinical presentation beyond the severe infection phase&#46; In this regard&#44; on 18 December 2020&#44; the National Institute for Health and Care Excellence published a guideline defining the stages of COVID-19 disease<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; The guideline defines the acute phase of infection as the start of infection through to 4 weeks of evolution&#46; &#8220;Ongoing symptomatic COVID-19&#8221; is defined as cases in which signs and symptoms of disease are present from 4 to 12 weeks&#44; and &#8220;post-COVID-19 syndrome&#8221; as when the signs and symptoms developed during or after an infection compatible with COVID-19 continue for more than 12 weeks and cannot be explained via an alternative diagnosis&#46; The guideline also uses the term &#8220;long COVID&#8221; to describe signs and symptoms that continue or develop after acute COVID&#8209;19&#44; with both post-COVID-19 syndrome and ongoing symptomatic COVID-19 included under this umbrella term&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Along these lines&#44; in Spain&#44; the Spanish Society for General Medicine &#40;SEMG according to the Spanish acronym&#41; published the data from its survey of patients with &#8220;long COVID&#8221;&#44; a term the society uses to refer the set of symptoms affecting multiple organs of patients who have had COVID-19 &#40;without or without a confirmed diagnosis&#41;&#44; and who continue to experience symptoms after what is considered to be the acute phase of the disease has ended<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; A total of 2&#44;120 patients participated in the survey&#44; of which 1&#44;834 presented symptoms compatible with long COVID&#46; 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It analyses 28 studies&#58; 16 cohort studies&#44; 10 cross-sectional studies&#44; and 2 case series&#46; The analysis included 9&#44;442 adults with COVID-19 from 13 different countries&#46; The longest average follow-up time was 111 days after hospital discharge&#46; A wide range of systemic&#44; cardiopulmonary&#44; gastrointestinal&#44; neurological and psychosocial symptoms are listed&#44; of which the most common were dyspnoea&#44; altered sense of smell and taste&#44; the presence of fatigue&#44; and anxiety&#46; Persistent symptoms were described in both admitted patients and those seen in outpatient services&#46; However&#44; the quality of the evidence of the studies included in this review is low&#44; with an elevated risk of bias and extensive heterogeneity in terms of disease prevalence&#46; In addition&#44; its external validity is very limited&#44; with no control groups and limited studies including children&#46; None were performed in developing countries or a primary care setting<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The meta-analysis conducted by Lopez-Leon et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> includes 15 studies published through 1 January 2021 with a total of 47&#44;910 patients&#46; 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MERS&#41; are of a respiratory&#44; musculoskeletal&#44; and neuropsychiatric nature<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; In patients with COVID-19&#44; admission to ICU due to acute respiratory distress syndrome is associated with long-term functional disability with both pulmonary and extrapulmonary conditions<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46; The data on disease prevalence varies greatly&#58; some studies estimate that 20&#37; of patients present symptoms at 4 weeks and 10&#37; at 12 weeks<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#44; while others detect up to 70&#37; 4 months post-onset of COVID-19<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To date&#44; three theories have been suggested in an attempt to explain the pathogenesis of long COVID manifestations&#58; the presence of the virus in immunologically privileged locations such as the central nervous system&#44; an abnormal immune response&#44; and autoimmune phenomena secondary to infection<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Along these lines&#44; Gaebler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> studied the evolution of humoral and cell immunity for 6&#46;2 months in a cohort of 87 patients after infection with SARS-CoV-2 and observed that the titres of IgM and IgG antibodies against the receptor-binding domain &#40;RBD&#41; of the SARS-CoV-2 spike protein decreased significantly over this time period&#44; with IgA being less affected&#46; By contrast&#44; the number of RBD-specific memory B cells remained unchanged following infection&#46; The memory B cells showed clonal turnover after 6&#46;2 months and the antibodies they express had greater somatic hypermutation&#44; resistance to the RBD mutations&#44; and higher potency&#44; which could indicate continuous evolution of the humoral response&#46; On the other hand&#44; immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months post-onset of infection revealed the persistence of fragments of nucleic acid from the SARS-CoV-2 virus and the presence of immunoreactivity in the small bowel in 7 out of 14 individuals&#44; which could cause the chronic inflammation that is responsible for long-term symptoms&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">A recent study in the pre-publication phase using the high-throughput technique Rapid Extracellular Antigen Profiling to identify autoantibodies against 2&#44;770 extracellular and secreted proteins in a cohort of 194 patients with SARS-CoV-2 infection and a control group of healthy healthcare workers&#44; showed a dramatic increase in autoimmune reactivities in the infected subjects&#44; particularly against immunomodulatory proteins&#44; including cytokines&#44; chemokines&#44; complement components and cell surface proteins<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In a murine model of SARS-CoV-2 infection&#44; it was found that equivalent autoantibodies altered the immune response and impaired virological control by inhibiting immunoreceptor signals and modifying the distribution of peripheral immune cells&#44; thereby exacerbating disease severity&#46; The analysis of autoantibodies targeted against tissue antigens revealed their association with specific clinical characteristics and disease severity<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46; Many of those cell antigens are found in specifically affected tissue and organs in patients with long COVID&#44; though their potential association with this clinical presentation has not yet been studied&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Another challenge we face is how to therapeutically manage patients with persistent symptomatology&#44; which to date has been symptom-based and with few satisfactory results&#46; The National Library of Medicine database has currently recorded 58 clinical trials with different approaches to treating this clinical process&#46; One of them&#44; Esperanza COVID&#44; is conducted in Spain using montelukast&#59; others are aimed at therapies with naltrexone&#47;food supplements with NDA&#43;&#44; or drugs already used in patients with myalgic encephalomyelitis&#47;chronic fatigue syndrome &#40;ME&#47;CFS&#41;&#59; another with deupirfenidone &#40;LYT-100&#41;&#44; with leronlimab&#44; monoclonal antibody against the CCR5 cell receptor&#44; with physical exercise-based therapy or psychological therapy&#44; as well as antivirals such as remdesivir or favipiravir&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">When determining the healthcare system&#8217;s response to the COVID-19 pandemic&#44; we must consider the full cost of the chronic consequences of SARS-CoV-2 infection&#44; and we must design strategies to provide comprehensive care to individuals suffering from these sequelae&#46; In this regard&#44; in December 2020&#44; the prestigious journal Nature Medicine posed a challenge to the scientific community&#58; to address and produce solutions for long COVID syndrome<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; Caring for patients with long COVID may require the participation of multiple specialists&#44; resulting in a logistical nightmare for patients seeking diagnosis and treatment&#46; As such&#44; a more comprehensive approach is needed to take the weight off of patients and to improve their care&#46; Along this line&#44; multidisciplinary units are being established to care for patients with long COVID such as those implemented at Mount Sinai hospital in New York and Penn-Presbyterian hospital in Pennsylvania&#44; or the clinics established in the United Kingdom&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Specialised units or clinics have also been founded in Spain to care for patients with long COVID&#46; These have drafted various consensus documents and interdisciplinary collaboration agreements&#44; such as the &#8220;MARCO-19 project for the care of individuals with long COVID&#8221;&#44; promoted by the SEMG and with the participation of 27 scientific societies<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;18</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The complex nature of post-COVID-19 sequelae surpasses and exceeds the specific competencies of the different medical specialties&#46; Therefore&#44; according to the various consensus documents&#44; these specialised units should include specialists in internal medicine&#44; neurology&#44; mental health&#44; and rehabilitation&#44; as well as support from nursing staff&#44; particularly that involved in case management&#44; and in close contact with primary care professionals and other specialists&#46; These units should also rely on collaboration from basic researchers in the fields of virology&#44; genetics and immunology&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The fundamental aims of these units will be to&#58; define the clinical spectrum&#44; pathogenesis&#44; pathophysiology&#44; and natural history of the disease&#44; rule out patients with suspected long COVID in the presence of other processes unrelated to the infection&#44; evaluate functional affectation&#44; identify groups of patients with specific needs and characteristics in order to schedule specific interventions&#44; and evaluate the safety and efficacy of specific interventions or treatments in controlled clinical trials&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There is a clear need to conduct controlled&#44; prospective cohort studies that include different at-risk populations and settings&#46; Likewise&#44; there is also a clear need to gather data in a standardised manner through national and international platforms in order to take the utmost advantage of all the scientific work that is being done&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Internal Medicine must not remain indifferent to these initiatives&#44; considering the leading role it has played from the very start of the effort to address the pandemic in Spain&#46; This effort can be seen in the COVID-19 patient registry from the Spanish Society for Internal Medicine&#44; one of the largest in the world&#44; which has already gathered data on more than 18&#44;000 patients<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Internal Medicine&#44; with its comprehensive vision and holistic training of its specialists&#44; which has enabled them to adapt and respond to the wide-ranging challenges and crises that have arisen in recent years<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#44; is in a strategic position to take on the challenge of creating and coordinating multidisciplinary units to care for patients with persistent symptoms post-SARS-CoV-2 infection&#46; On the other hand&#44; beyond the symptomatology of long COVID&#44; we cannot forget both the physical as well as psychological or psychiatric sequelae that patients who have overcome severe COVID-19 may present and that are currently still unknown to us&#46; Nor must we forget the repercussions that SARS-CoV-2 infection may have on the evolution of common chronic diseases such as ischaemic heart disease&#44; COPD or diabetes mellitus&#46; In this scenario&#44; the role of Internal Medicine is once again fundamental to the post-COVID-19 era&#46;</p></span>"
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            1 => "S&#237;ndrome COVID-19 prolongado"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Infection with the new SARS-CoV-2 coronavirus has reached pandemic proportions&#44; with a very high death toll worldwide&#46; Despite the scientific community&#39;s strenuous efforts to address this disease in its acute phase&#44; as well as in prevention through the development of vaccines in record time&#44; there remains another important workhorse&#58; understanding and treating the persistence of symptoms beyond the acute phase&#44; the so-called protracted COVID-19 syndrome or persistent COVID&#46; These persistent manifestations affect several organs and systems and may depend on both the pathogenic mechanisms of the virus and the pathophysiological response of the patient&#46; One year after the onset of this pandemic&#44; there is an urgent need to address this situation from a comprehensive approach&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por el nuevo coronavirus SARS-CoV-2 ha alcanzado proporciones de pandemia&#44; con un n&#250;mero de muertes muy elevado en todo el mundo&#46; A pesar del esfuerzo &#237;mprobo desarrollado por la comunidad cient&#237;fica para abordar esta enfermedad en su fase aguda&#44; as&#237; como en la prevenci&#243;n mediante la creaci&#243;n de vacunas en tiempo r&#233;cord&#44; a&#250;n queda otro caballo de batalla importante&#58; comprender y tratar la persistencia de s&#237;ntomas m&#225;s all&#225; de la fase aguda&#44; el llamado &#171;s&#237;ndrome COVID-19 prolongado&#187; o &#171;COVID persistente&#187;&#46; Estas manifestaciones persistentes afectan a varios &#243;rganos y sistemas y podr&#237;an depender tanto de los mecanismos patog&#233;nicos del virus como de la respuesta fisiopatol&#243;gica del paciente&#46; Un a&#241;o despu&#233;s del inicio de esta pandemia es una necesidad urgente abordar esta situaci&#243;n desde un enfoque integral&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mart&#237;n-Garrido I&#44; Medrano-Ortega FJ&#46; M&#225;s all&#225; de la infecci&#243;n aguda por SARS-CoV-2&#58; un nuevo desaf&#237;o para la Medicina Interna&#46; Rev Cl&#237;n Esp&#46; 2022&#59;222&#58;176&#8211;179&#46;</p>"
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Journal Information
Vol. 222. Issue 3.
Pages 176-179 (March 2022)
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Vol. 222. Issue 3.
Pages 176-179 (March 2022)
Review
Beyond acute SARS-CoV-2 infection: A new challenge for Internal Medicine
Más allá de la infección aguda por SARS-CoV-2: un nuevo desafío para la Medicina Interna
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I. Martín-Garridoa,
Corresponding author
isamartinga@gmail.com

Corresponding author.
, F.J. Medrano-Ortegaa,b
a Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain
b Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla y CIBERESP, Sevilla, Spain
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Abstract

Infection with the new SARS-CoV-2 coronavirus has reached pandemic proportions, with a very high death toll worldwide. Despite the scientific community's strenuous efforts to address this disease in its acute phase, as well as in prevention through the development of vaccines in record time, there remains another important workhorse: understanding and treating the persistence of symptoms beyond the acute phase, the so-called protracted COVID-19 syndrome or persistent COVID. These persistent manifestations affect several organs and systems and may depend on both the pathogenic mechanisms of the virus and the pathophysiological response of the patient. One year after the onset of this pandemic, there is an urgent need to address this situation from a comprehensive approach.

Keywords:
Long COVID
Post-COVID syndrome
Post-acute COVID-19
Long COVID haulers
Resumen

La infección por el nuevo coronavirus SARS-CoV-2 ha alcanzado proporciones de pandemia, con un número de muertes muy elevado en todo el mundo. A pesar del esfuerzo ímprobo desarrollado por la comunidad científica para abordar esta enfermedad en su fase aguda, así como en la prevención mediante la creación de vacunas en tiempo récord, aún queda otro caballo de batalla importante: comprender y tratar la persistencia de síntomas más allá de la fase aguda, el llamado «síndrome COVID-19 prolongado» o «COVID persistente». Estas manifestaciones persistentes afectan a varios órganos y sistemas y podrían depender tanto de los mecanismos patogénicos del virus como de la respuesta fisiopatológica del paciente. Un año después del inicio de esta pandemia es una necesidad urgente abordar esta situación desde un enfoque integral.

Palabras clave:
COVID persistente
Síndrome COVID-19 prolongado
Síndrome pos-COVID
Síndrome pos-COVID-19 agudo

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