Background We investigate bronchopulmonary colonization patterns in Spanish people with CF (pwCF), gathering clinical, demographic, and microbiological data to supplement nine years of registry information, comparing 2021 findings with a similar multicenter study conducted in 2013. Methods Sixteen CF units from 14 hospitals across Spain participated, each randomly recruiting around 20 patients. Patients provided sputum samples for culture. The clinical, demographical, microbiological, and treatment data from the previous year were recorded. Results Overall, 326 patients (48.5% females) were recruited: 185 adult and 141 pediatrics, with a median age [q3–q1] of 30 [38–24] and 12 [16–6] years, respectively. p.Phe508del mutation was present in 30.6% and 46.4% of patients with homozygosis or heterozygosis, respectively. Median FEV1 (%) was significantly lower in adults (62%, range 75–43%) compared with pediatrics (90%, range 104–81%) (p<0.001). Pancreatic insufficiency was observed in 77.3%, carbohydrate metabolism alteration in 27.3%, and CF-related diabetes in 19.6% of patients. Lower prevalence of Staphylococcus aureus and Pseudomonas aeruginosa colonization were noted compared to 2013, along with a significantly lower correlation in lung function among pwCF colonized by P. aeruginosa (p<0.001). Half of pwCF (51%) exhibited a single pathogen in culture, two in 30%, and three or more in 2.4%. Co-colonization of P. aeruginosa and S. aureus (36.1%) was the most prevalent combination. High resistance rates were observed in P. aeruginosa and methicillin resistant S. aureus isolates. Conclusions We provide a valuable and representative current insight into the observed evolution in the clinical, demographic, and microbiological aspects in recent years among pwCF in Spain.

Antibiotic resistance (AMR) is an alarming concern worldwide and Helicobacter pylori, one of the most prevalent bacteria, is not an exception. With antibiotics being its primary therapy, increasing resistance leads to a higher rate of treatment failure. Understanding the genomic mechanisms of resistance to clarithromycin, levofloxacin, metronidazole, amoxicillin, tetracycline, and rifampicin through next-generation sequencing-based molecular tools, such as whole genome sequencing (WGS), can be of great value, not only to direct a patient's treatment, but also to establish and optimize treatment guidelines according to the local epidemiology and to avoid the use of inappropriate antibiotics. WGS approaches allow us to gain insight into the genomic determinants involved in AMR. To this end, different pipelines and platforms are continuously being developed. In this study, we take a more detailed view of the use and progression of WGS for in-depth study of H. pylori's AMR.

Imipenem combined with beta-lactamase inhibitor relebactam (IMI/REL) has an extensive bactericidal activity against Gram-negative pathogens producing class A or class C beta-lactamases, not active against class B and class D. The phase 3 clinical trial (RESTORE-IMI-2), double-blind, randomized, evaluated IMI/REL vs. piperacillin-tazobactam (PIP/TAZ) for treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), demonstrated non-inferiority at all-cause mortality at 28 days (15.9% vs 21.3%), favorable clinical response at 7-14 days end of treatment (61% vs 59.8%) and with minor serious adverse effects (26.7% vs 32%). IMI/REL is a therapeutic option in HAP and VAP at approved dosage imipenem 500 mg, cilastatin 500 mg and relebactam 250 mg once every 6h, by an IV infusion over 30 min.

This study was carried out to analyze the evolution of the quality indicators in the Spanish National Hip Fracture Registry, after disseminating a series of recommendations based on available clinical practice guidelines to the participating hospitals. Six of the seven proposed quality indicators showed a significant improvement. The Spanish National Hip Fracture Registry (RNFC) arises from the need to know the process and improve the quality of care. Our goal was to analyze the changes in the RNFC’s quality indicators after an intervention based on disseminating specific recommendations among the participating hospitals, following available clinical practice guidelines. Study comparing before and after performing an intervention in hospitals participating in the RNFC. Data from the hospitals that registered cases in 2017, and that kept registering cases in 2019. Seven quality indicators were chosen, and a standard to be achieved for each indicator was proposed. The intervention consisted in the dissemination of 25 recommendations with practical measures to improve each quality indicator, based on available clinical practice guidelines, by drafting and publishing a scientific paper and sending it via email and printed cards. Fulfilment of each quality indicator was measured after carrying out the intervention. Forty-three hospitals registered 2674 cases between January and May, 2017, and 8037 during 2019. The quality indicators chosen and the degree of compliance were (all with p<0.05): (1) surgery ≤48 h increased from 38.9 to 45.8%; (2) patients mobilised on the first postoperative day increased from 58.9 to 70.3%; (3) patients with anti-osteoporotic medication at discharge increased from 34.5 to 49.8%; (4) patients with calcium supplements at discharge increased from 48.7 to 62.8%; (5) patients with vitamin D supplements at discharge increased from 71.5 to 84.7%; (6) patients developing a grade >2 pressure ulcer during admission decreased from 6.5 to 5.0%; (7) patients able to move on their own at 1 month fell from 58.8 to 56.4%. More than 48% of hospitals improved the proposed indicators. Establishing quality indicators and standards and intervening through the dissemination of specific recommendations to improve these indicators achieved an improvement in hospital performance results on a national level.

Infections produced by Helicobacter pylori (H. pylori), a spiral Gram-negative bacterium, can cause chronic gastritis, peptic ulcer, and gastric cancer. Antibiotic therapy is the most effective treatment for H. pylori infection at present. However, owing to the increasing antibiotic resistance of H. pylori strains, it has become a serious threat to human health. Therefore, the accurate diagnosis of H. pylori infections and its antibiotic resistance markers is of great significance. Conventional microbiological diagnosis of H. pylori is based on culture; however, successful isolation of H. pylori from gastric biopsy specimens is a challenging task affected by several factors and has limitations in terms of the time of response. To improve conventional methods, some molecular techniques, such as PCR, have been recently used in both invasive and non-invasive H. pylori diagnosis, enabling simultaneous detection of H. pylori and point mutations responsible for frequent antibiotic resistance. The advantages and disadvantages of molecular methods, mainly PCR, versus conventional culture for the H. pylori identification and the detection of antibiotic resistance are discussed. As expected, the combination of both diagnostic methods will lead to the most efficient identification of the H. pylori strains and the resistance patterns.

Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori from Europe and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying selection to remove them during admixture. Simulations show that population fitness can be restored after bottlenecks by migration and subsequent admixture of small numbers of bacteria from non-bottlenecked populations. We conclude that recent spread of African DNA has been driven by deleterious mutations accumulated during the original out-of-Africa bottleneck.

Older people living in nursing homes fulfil the criteria to be considered as geriatric patients, but they often do not have met their health care needs. Current deficits appeared as a result of COVID-19 pandemic. The need to improve the coordination between hospitals and nursing homes emerged, and in Madrid it materialized with the implantation of Liaison Geriatrics teams or units at public hospitals. The Sociedad Espanola de Geriatria y Gerontologia has defined the role of the geriatricians in the COVID-19 pandemic and they have given guidelines about prevention, early detection, isolation and sectorization, training, care homes classification, patient referral coordination, and the role of the different care settings, among others. These units and teams also must undertake other care activities that have a shortfall currently, like nursing homes-hospital coordination, geriatricians visits to the homes, telemedicine sessions, geriatric assessment in emergency rooms, and primary care and public health services coordination. This paper describes the concept of Liaison Geriatrics and its implementation at the Autonomous Community of Madrid hospitals as a result of COVID-19 pandemic. Activity data from a unit at a hospital with a huge number of nursing homes in its catchment area are reported. The objective is to understand the need of this activity in order to avoid the current fragmentation of care between hospitals and nursing homes. This activity should be consolidated in the future.

Older people living in nursing homes fulfil the criteria to be considered as geriatric patients, but they often do not have met their health care needs. Current deficits appeared as a result of COVID-19 pandemic. The need to improve the coordination between hospitals and nursing homes emerged, and in Madrid it materialized with the implantation of Liaison Geriatrics teams or units at public hospitals. The Sociedad Española de Geriatría y Gerontología has defined the role of the geriatricians in the COVID-19 pandemic and they have given guidelines about prevention, early detection, isolation and sectorization, training, care homes classification, patient referral coordination, and the role of the different care settings, among others. These units and teams also must undertake other care activities that have a shortfall currently, like nursing homes-hospital coordination, geriatricians visits to the homes, telemedicine sessions, geriatric assessment in emergency rooms, and primary care and public health services coordination. This paper describes the concept of Liaison Geriatrics and its implementation at the Autonomous Community of Madrid hospitals as a result of COVID-19 pandemic. Activity data from a unit at a hospital with a huge number of nursing homes in its catchment area are reported. The objective is to understand the need of this activity in order to avoid the current fragmentation of care between hospitals and nursing homes. This activity should be consolidated in the future.

The aim of this study was to develop a predictive model of gait recovery after hip fracture. Data was obtained from a sample of 25,607 patients included in the Spanish National Hip Fracture Registry from 2017 to 2019. The primary outcome was recovery of the baseline level of ambulatory capacity. A logistic regression model was developed using 40% of the sample and the model was validated in the remaining 60% of the sample. The predictors introduced in the model were: age, prefracture gait independence, cognitive impairment, anesthetic risk, fracture type, operative delay, early postoperative mobilization, weight bearing, presence of pressure ulcers and destination at discharge. Five groups of patients or clusters were identified by their predicted probability of recovery, including the most common features of each. A probability threshold of 0.706 in the training set led to an accuracy of the model of 0.64 in the validation set. We present an acceptably accurate predictive model of gait recovery after hip fracture based on the patients' individual characteristics. This model could aid clinicians to better target programs and interventions in this population.

Las personas mayores residentes en instituciones cumplen criterios de pacientes geriátricos complejos, pero con frecuencia no tienen resueltas sus necesidades sanitarias. La pandemia de COVID-19 ha hecho evidentes los déficits existentes en la atención sanitaria a estas personas. Como respuesta a ello surge la necesidad de mejorar la coordinación entre hospitales y residencias, lo que en Madrid se ha materializado en la implantación de equipos o unidades de Geriatría de Enlace en los hospitales públicos. Respecto a las acciones frente a la pandemia por COVID-19, la Sociedad Española de Geriatría y Gerontología ha definido el papel de los geriatras en esta función y ha dado directrices sobre prevención, detección precoz, aislamiento y sectorización, formación, clasificación de las residencias, coordinación de las derivaciones y papel de los diferentes niveles asistenciales, entre otras. Estas unidades también deben dirigir su actividad hacia otras áreas de atención actualmente deficitarias como la coordinación, las visitas presenciales en los centros, las sesiones de telemedicina, la valoración geriátrica en los servicios de urgencias y la coordinación con atención primaria y salud pública. En este artículo se describe la generación del concepto y la implantación de la Geriatría de Enlace en la Comunidad de Madrid a raíz de la pandemia de COVID-19 y se ilustra con los datos de actividad de una unidad cuyo hospital tiene en su área un elevado número de residencias. El objetivo es ayudar a comprender la necesidad de esta actividad, para evitar la fragmentación de cuidados existente en la actualidad entre hospitales y residencias. Actividad que debería consolidarse y mantenerse en el futuro.

Trabajo presentado al World Microbe Forum, celebrado de forma virtual del 20 al 24 de junio de 2021.

Cada vez es mayor el número de pacientes de edad avanzada que está siendo tratado por especialidades diferentes a la geriatría, las cuales, por las características de sus tratamientos, necesitan conocer el pronóstico que tiene su indicación en los pacientes ancianos frágiles y optimizar la situación de estos pacientes para mejorar dicho pronóstico. Las más frecuentes, actualmente, son oncología y hematología, cardiología, cirugía general y otros servicios quirúrgicos. Se entiende por geriatría transversal la ampliación del área de conocimiento y atención de la geriatría en sentido horizontal, fuera de sus unidades habituales, aplicando los principios de la medicina geriátrica con un enfoque multidisciplinar al terreno de otros servicios que atienden a pacientes muy mayores y frágiles con enfermedades graves, con el objetivo de ofrecer una atención centrada en la persona y mejorar su manejo integral. La valoración geriátrica y la detección de la fragilidad en estos casos aportan información pronóstica y ayudan en la toma de decisiones y en la selección de un tratamiento individualizado. En algunos casos es posible mejorar la evolución de los pacientes y la eficiencia del sistema sanitario. En este artículo se revisan estos conceptos, se describen algunos modelos existentes, se mencionan los instrumentos más empleados para esta función y se resumen algunas actividades de esta nueva área de la asistencia geriátrica. Es previsible que cada vez en más hospitales se solicite a los servicios de geriatría la implementación de este tipo de valoraciones e intervenciones. Existe información básica para su puesta en marcha, pero no la suficiente como para considerar que están respondidas todas las preguntas que se plantean. Será, pues, en los próximos años un nuevo reto para esta especialidad.

Background: The objective of this study is to determine the role of mitochondrial oxidative stress in the dysbiosis associated with a high fat diet in rats. In addition, the impact of gut microbiota (GM) in the cardiometabolic consequences of diet-induced obesity in rats has been evaluated. Methods: Male Wistar rats were fed either a high fat diet (HFD) or a control (CT) one for 6 weeks. At the third week, one-half of the animals of each group were treated with the mitochondrial antioxidant MitoTempo (MT; 0.7 mgKg−1day−1 i.p). Results: Animals fed an HFD showed a lower microbiota evenness and diversity in comparison to CT rats. This dysbiosis is characterized by a decrease in Firmicutes/Bacteroidetes ratio and relevant changes at family and genera compared with the CT group. This was accompanied by a reduction in colonic mucin-secreting goblet cells. These changes were reversed by MT treatment. The abundance of certain genera could also be relevant in the metabolic consequences of obesity, as well as in the occurrence of cardiac fibrosis associated with obesity. Conclusions: These results support an interaction between GM and mitochondrial oxidative stress and its relation with development of cardiac fibrosis, suggesting new approaches in the management of obesity-related cardiometabolic consequences.

Here we present an easy flow cytometry protocol to study the viability of Helicobacter pylori which also enables the detection of even low live bacteria densities. This protocol has potential utility for a fast and accurate assessment of experimental eradication methods against H. pylori.

El papel de las micobacterias no tuberculosas (MNT) en los pacientes con fibrosis quística (FQ) está, en ocasiones, en controversia. El objetivo del trabajo es evaluar la prevalencia y las características clínicas/microbiológicas de pacientes adultos con FQ colonizados con MNT, destacando Mycobacterium abscessus (M. abscessus). Se ha realizado un estudio retrospectivo en 92 pacientes adultos con FQ en el que se diferenció: grupo control, 64 pacientes no colonizados por MNT, y grupo a estudio, 28 pacientes colonizados por MNT. Se han analizado variables como la edad, mutación F508del, función pulmonar, afectación pancreática, tinción de auramina y recolonizaciones entre ambos grupos. La prevalencia de MNT encontrada ha sido 30,4%. La MNT más prevalente fue Mycobacterium avium complex seguida por M. abscessus. Para M. abscessus, en el estudio comparativo con pacientes colonizados por otras MNT, se obtuvieron diferencias estadísticamente significativas en las variables de edad. Hemos encontrado alta prevalencia de MNT en pacientes adultos con FQ y relacionamos la aparición de M. asbcessus con edades inferiores a 30 años y F508del. Con el fin de conocer mejor el papel patógeno de las MNT, especialmente de M. asbcessus, se requieren estudios multicéntricos en población con FQ. The role of non-tuberculous mycobacteria (NTM) among cystic fibrosis (CF) patients, on occasion, remains unknown. The aim of our study is to evaluate the prevalence and clinical/microbiological characteristics of CF adult patients colonized by NTM, highlighting Mycobacterium abscessus (M. abscessus). A retrospective study was conducted with 92 CF adult patients: including a control group of 64 patients, not colonized by NTM, and a study group of 28 patients, colonized by NTM. We have analyzed variables such as age, F508del mutation, lung function, pancreatic involvement, auramine staining and co-colonizations between both groups. The prevalence of NTM found was 30.4%. The most prevalent was Mycobacterium avium complex followed by M. abscessus. For M. abscessus, in the comparative study with patients colonized by other NTM, significant results were obtained for variables age. We have found a high prevalence of NTM among adult patients with CF, and we associated the presence of M. asbcessus with ages less than 30 years and F508del. Due to the pathogenic role of NTM, especially M. asbcessus, multicenter studies are required within the population suffering from CF.

Background Linezolid has good penetration to the meninges and could be an alternative for treatment ofStaphylococcus aureusmeningitis. We assessed the efficacy and safety of linezolid therapy for this infection. Methods Retrospective multicenter cohort study of 26 adults treated with linezolid, derived from a cohort of 350 cases ofS. aureusmeningitis diagnosed at 11 university hospitals in Spain (1981-2015). Results There were 15 males (58%) and mean age was 47.3 years. Meningitis was postoperative in 21 (81%) patients. The infection was nosocomial in 23 (88%) cases, and caused by methicillin-resistantS. aureusin 15 cases and methicillin-susceptibleS. aureusin 11. Linezolid was given as empirical therapy in 10 cases, as directed therapy in 10, and due to failure of vancomycin in 6. Monotherapy was given to 16 (62%) patients. Median duration of linezolid therapy was 17 days (IQR 12-22 days) with a daily dose of 1,200 mg in all cases. The clinical response rate to linezolid was 69% (18/26) and microbiological response was observed in 14 of 15 cases evaluated (93%). Overall 30-day mortality was 23% and was directly associated with infection in most cases. When compared with the patients of the cohort, no significant difference in mortality was observed between patients receiving linezolid or vancomycin for therapy of methicillin-resistantS. aureusmeningitis (9% vs. 20%;p = .16) nor between patients receiving linezolid or cloxacillin for therapy of methicillin-susceptibleS. aureusmeningitis (20% vs 14%;p = .68). Adverse events appeared in 14% (3/22) of patients, but linezolid was discontinued in only one patient. Conclusions Linezolid appears to be effective and safe for therapy ofS. aureusmeningitis. Our findings showed that linezolid may be considered an adequate alternative to other antimicrobials in meningitis caused byS. aureus.

Beta-lactam antibiotics are the most popular antibacterial agents used for treating bacterial infections, due to their great activity, broad spectrum, and safety profile. All of them share the beta-lactam ring and because of the particular chemical structure, they are classified into five groups: Penicillins (natural and semisynthetic), cephalosporins (first-, second-, third-, fourth-, and fifth-generation), monobactams, carbapenems and the association of a beta-lactam with a beta-lactamase inhibitor (Beta-lactam and non-beta-lactam inhibitors). Carbapenems have a carbon atom instead of a sulfur or an oxygen atom in the bicyclic nucleus and a hydroxyethyl side chain in trans configuration at position 6 and are the widest spectrum antibiotics available among the beta-lactams. Beta-lactams are bactericidal agents that kill bacteria by inhibiting the synthesis of the cell wall in both Gram-negative and Gram-positive bacteria, interacting with PBPs, so the transpeptidation reaction is blockaded, leading to the cell lysis and death. As a consequence of the widespread use of this antibiotics, bacterial resistance is a growing problem in both community and hospital settings. Emergence and dissemination of beta-lactam resistance have renewed interest in the development of novel beta-lactam antibiotics or beta-lactamase inhibitors, and some of them are currently available for multi-resistant bacteria treatment.

This study was carried out to describe the profile of prescription of antiosteoporotic treatment at discharge after a hip fracture in the Spanish National Hip Fracture Registry. Prescription rates among hospitals ranged from 0 to 94% of patients discharged. The prescription rate was higher among patients with better cognitive and functional baseline status. National hip fracture registries are useful for assessing current care processes. The goals of this study were as follows: first, to know the rate of antiosteoporotic prescription at discharge among hip fracture patients in hospitals participating in the Spanish National Hip Fracture Registry (RNFC); second, to compare the differences between treated and non-treated patients; third, to analyze patients’ characteristics associated with antiosteoporotic prescription at discharge; and fourth, to evaluate whether there were differences in the profile of patients discharged from hospitals with high and low prescription rates. Patients discharged after a fragility hip fracture in 2017 and participating in the RNFC were included. Demographic variables, cognitive and functional status, prefracture osteoporosis treatment, fracture type, anesthetic risk, hospital volume, and antiosteoporotic prescription at discharge were analyzed. Given that patients were clustered within hospitals, intraclass correlation was calculated and generalized estimating equations were fitted. A total of 6701 patients from 54 hospitals were included. Antiosteoporotic prescription at discharge was prescribed to 36.5% (CI95% 35.8–37.2%), with a wide inter-hospital variability (range 0–94%). The intraclass correlation due of clustering of patients within hospitals was 47.9%. Antiosteoporotic prescription was more likely in patients who were younger, lived at home, previously treated for osteoporosis, had better baseline functional and cognitive status, lower anesthetic risk, and were discharged from high-volume hospitals, all with p < 0.001. The general profile of patients discharged from hospitals with high and low rate of prescription was similar. There is a wide variability between hospitals regarding antiosteoporotic prescription after hip fracture. This is more likely to be initiated in patients with better clinical, functional, and mental status and in those discharged from hospitals with larger volumes of patients. These results offer insights regarding the selection of patients receiving secondary prevention and raises questions on who and how many should be treated.

The new coronavirus SARS-CoV-2 detected in December 2019 in Wuhan, China, caused the epidemic disease known as coronavirus disease 2019 (COVID-19). This pandemic, affecting thousands of people worldwide and spreading rapidly, has become a global threat (Lai C-C et al.Lai C-C et al., Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths, Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2020.02.012.Google Scholar). The pandemic has presented Multiple Sclerosis (MS) neurologists with new uncertainties and a changing reality, forcing us to make decisions quickly with a lack of available evidence. It is currently unclear whether MS patients are exposed to a greater risk of severity upon SARS-CoV-2 infection (Brownlee et al., 2020Brownlee W Bourdette D Broadley S et al.Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.Neurology. 2020; (Apr 2pii: 10.1212/WNL.0000000000009507[Epub ahead of print] Sormani et al. Lancet Neurol 2020 Apr 30. pii: S1474-4422(20)30147-2)https://doi.org/10.1212/WNL.0000000000009507Crossref PubMed Scopus (145) Google Scholar, Maria Pia, 2020Maria Pia Sormani An Italian programme for COVID-19 infection in multiple sclerosis.Lancet Neurol. 2020; (Apr 30[Epub ahead of print])https://doi.org/10.1016/S1474-4422(20)30147-2Abstract Full Text Full Text PDF Scopus (159) Google Scholar), although the use of some disease-modifying drugs may entail an additional infection risk for these patients (Wijnands et al., 2018Wijnands JMA Zhu F Kingwell E et al.Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study.J Neurol Neurosurg Psych. 2018; 89: 1050-1056Crossref PubMed Scopus (67) Google Scholar) and many of these drugs are also contraindicated in cases of active infection. In order to minimize the risk associated with administering immunosuppressive treatments, it has been proposed to postpone as long as possible the use of those with a higher risk of inducing lymphopenia in the short to medium term and to use extended administration for other drugs (Brownlee et al., 2020Brownlee W Bourdette D Broadley S et al.Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.Neurology. 2020; (Apr 2pii: 10.1212/WNL.0000000000009507[Epub ahead of print] Sormani et al. Lancet Neurol 2020 Apr 30. pii: S1474-4422(20)30147-2)https://doi.org/10.1212/WNL.0000000000009507Crossref PubMed Scopus (145) Google Scholar, Costa-Frossard et al., 2020Costa-Frossard L Moreno-Torres I Meca-Lallana V García Domínguez JM EMCAM (Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic.Rev Neurol. 2020 May 1; 70: 329-340https://doi.org/10.33588/rn.7009.2020155Crossref PubMed Google Scholar). In patients treated with these drugs or patients with a possible MS relapse, SARS Cov2 infection should also be carefully ruled out as a cause of clinical deterioration and the use of steroids should be considered only in those patients with relapses leading to increased disability (Brownlee et al., 2020Brownlee W Bourdette D Broadley S et al.Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.Neurology. 2020; (Apr 2pii: 10.1212/WNL.0000000000009507[Epub ahead of print] Sormani et al. Lancet Neurol 2020 Apr 30. pii: S1474-4422(20)30147-2)https://doi.org/10.1212/WNL.0000000000009507Crossref PubMed Scopus (145) Google Scholar, Costa-Frossard et al., 2020Costa-Frossard L Moreno-Torres I Meca-Lallana V García Domínguez JM EMCAM (Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic.Rev Neurol. 2020 May 1; 70: 329-340https://doi.org/10.33588/rn.7009.2020155Crossref PubMed Google Scholar) There are a number of reasons why protocols are needed for safe administration of MS treatments:2-The COVID-19 incubation period is variable, ranging from 0 to 24 days (Huang et al., 2020Huang C Yi Wang Li X et al.Clinical features in patients infected with 2019 novel coronavirus in Wuhan.China. Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (32455) Google Scholar)2-Asymptomatic carriers can spread the virus. Immunosuppressive treatments, by modifying the immune response, could activate asymptomatic infections or those in the incubation period. Although such cases are yet to be described, we must take this theoretical concept into account (Yan Bai et al., 2020Yan Bai MD Lingsheng Yao MD Tao Wei MD et al.Presumed Asymptomatic Carrier Transmission of COVID-19.JAMA. 2020; 323: 1406-1407https://doi.org/10.1001/jama.2020.2565Crossref PubMed Scopus (3055) Google Scholar, Ye et al., 2020 MayYe G Pan Z Pan Y Deng Q Chen L Li J Li Y Wang X Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation.J Infect. 2020 May; 80 (Epub 2020 Mar 20): e14-e17https://doi.org/10.1016/j.jinf.2020.03.001Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar)2-Clinical reactivation of infection, i.e. the reappearance of a new infectious case, has been described (Ye et al., 2020 MayYe G Pan Z Pan Y Deng Q Chen L Li J Li Y Wang X Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation.J Infect. 2020 May; 80 (Epub 2020 Mar 20): e14-e17https://doi.org/10.1016/j.jinf.2020.03.001Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). These patients presented negative PCR following the first clinical picture, with a reactivation window period from negative to positive SARS-CoV-2 and a new clinical picture within 4 to17 days. Corticosteroids were used in most of this reactivated patients. This suggests that recovered patients may still carry the virus, which could be reactivated by certain conditions, such as immunosuppression (Ye et al., 2020 MayYe G Pan Z Pan Y Deng Q Chen L Li J Li Y Wang X Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation.J Infect. 2020 May; 80 (Epub 2020 Mar 20): e14-e17https://doi.org/10.1016/j.jinf.2020.03.001Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). The existence of false negatives could lead to these presumed 'reactivations' being interpreted erroneously. Perhaps these patients are still convalescing from their first clinical symptoms (Xiao et al., 2020Xiao A.T. Tong Y.X. Zhang S. False-negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: Rather than recurrence.Journal of Medical Virology. 2020; https://doi.org/10.1002/jmv.25855Crossref Scopus (379) Google Scholar). In any case, the detection of such cases is important. We have had a similar experience with clinical reactivation of a patient after taking a dose of immunosuppressant. This is one of the things that led us to conduct the current work. Despite all this, we must bear in mind that it is unproven (Maria Pia, 2020Maria Pia Sormani An Italian programme for COVID-19 infection in multiple sclerosis.Lancet Neurol. 2020; (Apr 30[Epub ahead of print])https://doi.org/10.1016/S1474-4422(20)30147-2Abstract Full Text Full Text PDF Scopus (159) Google Scholar) whether patients receiving immunosuppression are at greater risk in this pandemic because of the differential characteristics of COVID-19. It is thought that this disease develops in different phases, with the most severe caused by cytokine release syndrome and hyper-inflammatory state, as well as changes resulting from vascular pathology and thrombosis (Wichmann et al., 2020Wichmann D Sperhake JP Lütgehetmann M et al.Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study.Ann Intern Med. 2020; (May 6Epub ahead of print])https://doi.org/10.7326/M20-2003Crossref PubMed Scopus (1725) Google Scholar). In reference to hyper-inflammation, it has been postulated that the previous use of selective immunosuppressive drugs could even offer a protective mechanism (Costa-Frossard et al., 2020Costa-Frossard L Moreno-Torres I Meca-Lallana V García Domínguez JM EMCAM (Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic.Rev Neurol. 2020 May 1; 70: 329-340https://doi.org/10.33588/rn.7009.2020155Crossref PubMed Google Scholar, Huang et al., 2020Huang C Yi Wang Li X et al.Clinical features in patients infected with 2019 novel coronavirus in Wuhan.China. Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (32455) Google Scholar, Siddiqu and MehraSiddiqu HK, Mehra MR. COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. Journal of Heart and Lung Transplantation. doi:10.1016/j.healun.2020.03.012.Google Scholar). Until the evidence increases, however, and in our experience of patient management, our action protocol must focus on safety. The most commonly used technique for diagnosing SARS-CoV-2 infection is to detect viral RNA using RT-PCR in nasopharyngeal swabs (Yan Bai et al., 2020Yan Bai MD Lingsheng Yao MD Tao Wei MD et al.Presumed Asymptomatic Carrier Transmission of COVID-19.JAMA. 2020; 323: 1406-1407https://doi.org/10.1001/jama.2020.2565Crossref PubMed Scopus (3055) Google Scholar). The positive results of this technique depend on the presence of sufficient quantity of viral genome at the sample extraction site, as well as on the sample collection technique, which can lead to false negatives (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar). Negative results may also be obtained when the virus cannot be detected in the exudate because the patient is at an early stage of the disease (window period), the host's immunity has suppressed it, or if samples are obtained late in the course of infection (Zhao et al., 2020Zhao J Yuan Q Wang H et al.Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019.Clin Infect Dis. 2020; (Mar 28. pii: ciaa344[Epub ahead of print])https://doi.org/10.1093/cid/ciaa344Crossref Scopus (1821) Google Scholar). Blood testing for IgM against the virus, a marker of acute infection, can increase diagnostic sensitivity from 51.9% to 98.6%. It also seems that IgM can remain detectable for longer than viral RNA (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar). IgM testing may, however, give false negatives if the samples are taken at the beginning of infection, since IgM has been observed from the fifth day of infection (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar). IgG, on the other hand, a marker of late immunity, appears around day 14 (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar, Zhao et al., 2020Zhao J Yuan Q Wang H et al.Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019.Clin Infect Dis. 2020; (Mar 28. pii: ciaa344[Epub ahead of print])https://doi.org/10.1093/cid/ciaa344Crossref Scopus (1821) Google Scholar), with levels increasing until around day 21, when a sustained 'plateau' can be reached (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar). ELISA IgM and IgG testing has greater than 95% specificity and the use of this technique together with PCR at the onset and in the following two weeks can further increase diagnostic accuracy (Sethuraman et al., 2020Sethuraman N Jeremiah SS Ryo A Interpreting Diagnostic Tests for SARS-CoV-2.JAMA. 2020; (Published online May 06)https://doi.org/10.1001/jama.2020.8259Crossref PubMed Scopus (1071) Google Scholar). This increased diagnostic sensitivity using both PCR and serology has been confirmed in various recent works (Soelberg Sorensen, 2017Soelberg Sorensen P Safety concerns and risk management of multiple sclerosis therapies.Acta Neurol Scand. 2017; 136 (SepEpub 2016 Nov 27): 168-186https://doi.org/10.1111/ane.12712Crossref PubMed Scopus (64) Google Scholar), reaching sensitivity and specificity levels of up to 100% (Long et al., 2020Long Q.-X. Liu B.-Z. Deng H.-J. Wu G.-C. Deng K. Chen Y.-K. Cai X.-F. Antibody responses to SARS-CoV-2 in patients with COVID-19.Nature Medicine. 2020; https://doi.org/10.1038/s41591-020-0897-1Crossref Scopus (2038) Google Scholar). In general, most antibodies are produced to combat the most abundant viral protein, NC, and these tests are therefore the most sensitive (Sethuraman et al., 2020Sethuraman N Jeremiah SS Ryo A Interpreting Diagnostic Tests for SARS-CoV-2.JAMA. 2020; (Published online May 06)https://doi.org/10.1001/jama.2020.8259Crossref PubMed Scopus (1071) Google Scholar). There are several rapid tests of varying quality available on the market that do not in some cases detect precisely the antigens used (Sethuraman et al., 2020Sethuraman N Jeremiah SS Ryo A Interpreting Diagnostic Tests for SARS-CoV-2.JAMA. 2020; (Published online May 06)https://doi.org/10.1001/jama.2020.8259Crossref PubMed Scopus (1071) Google Scholar). We present the safety protocol for treating MS patients established in our MS Unit and its development over the pandemic period. Our aim is not to establish the sensitivity and specificity of the tests used; these findings could be presented in a subsequent broader. Our aim, instead, is to present the safety protocol used in MS patients. We have used a dynamic protocol adapted to the development of the pandemic. During the early days of the pandemic, the first measure was to postpone doses of certain immunosuppressive treatments due to rapid spread of the virus and saturation of emergency services. The need to avoid MS reactivation in our patients, however, led us to implement several protocols for administering treatments as safely as possible. The protocol applies to administering initial doses and all re-doses of natalizumab, ocrelizumab, rituximab, cladribine and alemtuzumab, as well as initial doses of teriflunomide, dimethyl fumarate, fingolimod, and methyl prednisolone in relapses. Injectables are excluded because of their reduced impact on the immune system (Soelberg Sorensen, 2017Soelberg Sorensen P Safety concerns and risk management of multiple sclerosis therapies.Acta Neurol Scand. 2017; 136 (SepEpub 2016 Nov 27): 168-186https://doi.org/10.1111/ane.12712Crossref PubMed Scopus (64) Google Scholar). We stop the protocol in patients where recovery from COVID-19 has been demonstrated. 1st action. Online/telephone pre-treatment interview (2-7 days before treatment):a)Symptomatic: treatment suspension and subsequent general medicine assessmentb)Asymptomatic: PCR testing and SARS-CoV-2 serology 2nd action. PCR testing and serology: 1-7 days before treatment (Sethuraman et al., 2020Sethuraman N Jeremiah SS Ryo A Interpreting Diagnostic Tests for SARS-CoV-2.JAMA. 2020; (Published online May 06)https://doi.org/10.1001/jama.2020.8259Crossref PubMed Scopus (1071) Google Scholar) Test interpretation and actions taken are detailed in Table 1, Table 2, Table 3. Each table corresponds to different moments during the pandemic and different levels of resource availability. Where necessary, results are confirmed at 7 days. It is possible for PCR to remain positive for more than 7 days (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar), but testing is done at 7 days with the aim of conducting close monitoring and not unduly postponing treatment. It is combined with antibodies to increase case detection rates (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar, Long et al., 2020Long Q.-X. Liu B.-Z. Deng H.-J. Wu G.-C. Deng K. Chen Y.-K. Cai X.-F. Antibody responses to SARS-CoV-2 in patients with COVID-19.Nature Medicine. 2020; https://doi.org/10.1038/s41591-020-0897-1Crossref Scopus (2038) Google Scholar, Xiang et al., 2020Xiang F. Wang X. He X. Peng Z. Yang B. Zhang J. Ma W.-L. Antibody Detection and Dynamic Characteristics in Patients with COVID-19.Clinical Infectious Diseases. 2020; https://doi.org/10.1093/cid/ciaa461Crossref Scopus (440) Google Scholar).Table 1Early days of the pandemic. The protocol includes an epidemiological survey (questionnaire shown in Annex 1). If questionnaire was positive, a PCR was performed on nasopharyngeal swabs.EPIDEMIOLOGY CONTACTPCRINTERPRETATIONACTION-N/ANO SARS-CoV-2 CONTACTADMINISTER TREATMENT++ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER- POSTPONE TREATMENTREPEAT PCR 7 DAYS LATER+-NO SARS-CoV-2 CONTACT VS PAST INFECTION (ASYMPTOMATIC) VS WINDOW PERIOD- POSTPONE TREATMENT- REPEAT PCR 7 DAYS LATERN/A: NOT APPLICABLE Open table in a new tab Table 2Pandemic established. The protocol includes IgG + IgM serology. This technique helps us to increase our diagnostic capacity but does not provide information on patients' degree of immunization. Two negative PCRs are necessary for administering treatment. PCR re-test is performed 7 days later.1st PCRIgG + IgM2nd PCRINTERPRETATIONACTION--N/ANO SARS-CoV-2 CONTACTADMINISTER TREATMENT-+-PAST AND RECOVERED INFECTION VS PAST ASYMPTOMATIC CARRIERADMINISTER TREATMENT-++ACTIVE INFECTION (WINDOW PERIOD) VS RECOVERED INFECTION VS ASYMPTOMATIC CARRIER (FALSE NEGATIVE PCR)- POSTPONE TREATMENT - REPEAT PCR 7 DAYS LATER+++ACTIVE INFECTION (WINDOW PERIOD) VS RECOVERED INFECTION VS ASYMPTOMATIC CARRIER- POSTPONE TREATMENT - REPEAT PCR 7 DAYS LATER++-PAST INFECTION VS ASYMPTOMATIC CARRIER- POSTPONE TREATMENT - REPEAT PCR 7 DAYS LATER+-+ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER NOT IMMUNIZED- POSTPONE TREATMENT - REPEAT BOTH TESTS 7 DAYS LATER+--ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER NOT IMMUNIZED- POSTPONE TREATMENT - REPEAT BOTH TESTS 7 DAYS LATERN/A: NOT APPLICABLE Open table in a new tab Table 3Quarantine de-escalation measures will gradually be implemented with a high percentage of infected and recovered patients.PCRIgGIgMINTERPRETATIONACTION---NO SARS-CoV-2 CONTACTADMINISTER TREATMENT-+-PAST AND RECOVERED INFECTIONADMINISTER TREATMENT--+ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER (FALSE NEGATIVE PCR)- POSTPONE TREATMENT - REPEAT BOTH TESTS 7 DAYS LATER-++ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER (FALSE NEGATIVE PCR)- POSTPONE TREATMENT - REPEAT BOTH TESTS 7 DAYS LATER+++ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER- POSTPONE TREATMENT - REPEAT BOTH TESTS 7 DAYS LATER++-PAST AND RECOVERED INFECTION- POSTPONE TREATMENT - REPEAT PCR 7 DAYS LATER+-+ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER- POSTPONE TREATMENT - REPEAT BOTH TESTS 7 DAYS LATER+--ACTIVE INFECTION (WINDOW PERIOD) VS ASYMPTOMATIC CARRIER (NOT IMMUNIZED VS FALSE NEGATIVE)- POSTPONE TREATMENT REPEAT BOTH TESTS 7 DAYS LATERADMINISTER TREATMENTCONFIRM WITH PCRCONFIRM WITH PCR + SEROLOGY Open table in a new tab N/A: NOT APPLICABLE N/A: NOT APPLICABLE If a patient presents COVID-19, the protocol is applied at least 15 days after the complete disappearance of symptoms. If a patient has suspended MS treatment during COVID-19, treatment can only be restarted when COVID-19 is not active according to the protocol and there is no risk of disease relapse associated with each drug (Brownlee et al., 2020Brownlee W Bourdette D Broadley S et al.Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.Neurology. 2020; (Apr 2pii: 10.1212/WNL.0000000000009507[Epub ahead of print] Sormani et al. Lancet Neurol 2020 Apr 30. pii: S1474-4422(20)30147-2)https://doi.org/10.1212/WNL.0000000000009507Crossref PubMed Scopus (145) Google Scholar, Costa-Frossard et al., 2020Costa-Frossard L Moreno-Torres I Meca-Lallana V García Domínguez JM EMCAM (Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic.Rev Neurol. 2020 May 1; 70: 329-340https://doi.org/10.33588/rn.7009.2020155Crossref PubMed Google Scholar). Finally, it is crucial to individualize treatment in each patient. Treatment decisions (maintaining, suspending or delaying treatment) must be individualized and take into account associated risk factors (age, comorbidities, etc.) (Brownlee et al., 2020Brownlee W Bourdette D Broadley S et al.Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.Neurology. 2020; (Apr 2pii: 10.1212/WNL.0000000000009507[Epub ahead of print] Sormani et al. Lancet Neurol 2020 Apr 30. pii: S1474-4422(20)30147-2)https://doi.org/10.1212/WNL.0000000000009507Crossref PubMed Scopus (145) Google Scholar, Costa-Frossard et al., 2020Costa-Frossard L Moreno-Torres I Meca-Lallana V García Domínguez JM EMCAM (Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic.Rev Neurol. 2020 May 1; 70: 329-340https://doi.org/10.33588/rn.7009.2020155Crossref PubMed Google Scholar). We consider that the ideal scenario would be to perform PCR together with IgG and IgM serology testing in all patients scheduled to receive immunosuppressive treatment. We do not currently have a way of interpreting serology tests with absolute certainty. Nevertheless, in addition to increasing diagnostic sensitivity in negative cases (Guo et al., 2020Guo L Ren L Yang S et al.Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19).Clin Infect Dis. 2020; (Mar 21pii: ciaa310[Epub ahead of print])https://doi.org/10.1093/cid/ciaa310Crossref Scopus (1175) Google Scholar, Long et al., 2020Long Q.-X. Liu B.-Z. Deng H.-J. Wu G.-C. Deng K. Chen Y.-K. Cai X.-F. Antibody responses to SARS-CoV-2 in patients with COVID-19.Nature Medicine. 2020; https://doi.org/10.1038/s41591-020-0897-1Crossref Scopus (2038) Google Scholar, Xiang et al., 2020Xiang F. Wang X. He X. Peng Z. Yang B. Zhang J. Ma W.-L. Antibody Detection and Dynamic Characteristics in Patients with COVID-19.Clinical Infectious Diseases. 2020; https://doi.org/10.1093/cid/ciaa461Crossref Scopus (440) Google Scholar), this could increase the safety with which treatments are initiated by reducing the possibility of reactivating the virus after treatment.

BACKGROUND AND AIM:In December 2019, the first cases of SARS-CoV-2 infection were detected in Wuhan. Within two months, it had begun to spread around the world in what became an unprecedented pandemic. Patients with Multiple Sclerosis (MS) in a state of immunosuppression may be considered at risk for complications in the COVID-19 pandemic, although there is increasing evidence postulating a possible protective role of selective immunosuppression. One group of such immunosuppressants used in MS comprises the anti-CD20 monoclonal antibodies (mAbs) ocrelizumab and rituximab. Anti-CD20 mAbs bind to the surface of B cells, causing their depletion. We describe our experience in seven cases of patients with multiple sclerosis who have been affected by SARS-COV-2 (with a clinical/serological diagnosis or PCR diagnosis) and who were being treated with anti-CD20+ monoclonal antibodies.MATERIAL AND METHODS:We review the development of patients during infection as well as the resolution of their clinical picture. We also analyze the serology status against SARS-CoV-2 after resolution of the infection.RESULTS:Although the severity of the clinical pictures was variable, patients' development was good. Not all patients, however, developed antibodies against SARS-CoV-2.CONCLUSIONS:Patients treated with anti-CD20+ have adequate resolution of COVID-19 despite the fact that the presence of antibodies against SARS-CoV-2 was not detected in all cases. It is possible that the presence of humoral immunity is not always necessary fora good clinical course of SARS-CoV-2 infection.