Long COVID in Children, Adults, and Vulnerable Populations: A Comprehensive Overview for an Integrated Approach.

Long COVID affects both children and adults, including subjects who experienced severe, mild, or even asymptomatic SARS-CoV-2 infection. We have provided a comprehensive overview of the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 symptoms in both children and adults, encompassing vulnerable populations, such as pregnant women and oncological patients. Our objective is to emphasize the critical significance of adopting an integrated approach for the early detection and appropriate management of long COVID. The incidence and severity of long COVID symptoms can have a significant impact on the quality of life of patients and the course of disease in the case of pre-existing pathologies. Particularly, in fragile and vulnerable patients, the presence of PASC is related to significantly worse survival, independent from pre-existing vulnerabilities and treatment. It is important try to achieve an early recognition and management. Various mechanisms are implicated, resulting in a wide range of clinical presentations. Understanding the specific mechanisms and risk factors involved in long COVID is crucial for tailoring effective interventions and support strategies. Management approaches involve comprehensive biopsychosocial assessments and treatment of symptoms and comorbidities, such as autonomic dysfunction, as well as multidisciplinary rehabilitation. The overall course of long COVID is one of gradual improvement, with recovery observed in the majority, though not all, of patients. As the research on long-COVID continues to evolve, ongoing studies are likely to shed more light on the intricate relationship between chronic diseases, such as oncological status, cardiovascular diseases, psychiatric disorders, and the persistent effects of SARS-CoV-2 infection. This information could guide healthcare providers, researchers, and policymakers in developing targeted interventions.

Pericardial Diseases in Pregnancy.

Pericardial effusion is the most common manifestation of pericardial diseases during pregnancy. This effusion is benign, mild, or moderate, well tolerated, with spontaneous resolution after delivery; no specific treatment is required. Acute pericarditis is the second most common condition, usually requiring medical therapy during pregnancy. Cardiac tamponade and constrictive pericarditis are rare in pregnancy. Pre-pregnancy counselling is essential in women of childbearing age with recurrent pericarditis to plan pregnancy in a phase of disease quiescence and to review therapy. High-dose aspirin or nonselective nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can be used up to the 20th week of gestation. Low-dose prednisone (2.5-10 mg/d) can be administered throughout pregnancy. All of these medications, apart from high-dose aspirin, may be used during lactation. Colchicine is compatible with pregnancy and breastfeeding, and it can be continued throughout pregnancy to prevent recurrences. Appropriate follow-up with a multidisciplinary team with experience in the field is recommended throughout pregnancy to ensure good maternal and fetal outcomes.

Acute pericarditis with pleuropulmonary involvement, fever and elevated C-reactive protein: A systemic autoinflammatory disease? A cohort study.

OBJECTIVES: This cohort study describes a systemic phenotype of pericarditis, comparing this phenotype with other forms of pericarditis. PATIENTS AND METHODS: Patients in our center were enrolled in a prospectively maintained registry from 2019 to 2022. 412 patients with idiopathic recurrent pericarditis were analyzed. "Systemic inflammatory" subset was defined as the presence of all the following criteria: fever ≥38C°, CRP ≥2 times normal values, pleural effusion detected with any imaging techniques. The absence of any of the 3 criteria was defined as "isolated" subset. RESULTS: We found that 211 (51.2%) of 412 patients (188 female) presented the systemic subset and the variables significantly associated with this subset in univariate analysis (p<0.001) were: higher mean age: 45.5 (±SD 17.2) vs 39.9 (±SD 16.4) years, higher mean CRP values: 128.8 vs 49.9 mg/L, higher proportion of pericardiocentesis: 19% vs 1.5%, higher mean leukocyte count: 13,143.3 vs 9910.3/mm3, higher mean neutrophils number: 10,402.5 vs 6779.8 /mm3 and lower mean lymphocyte count: 1693.9 vs 2079.3 /mm3. As results the neutrophil-to-lymphocyte ratio was higher in systemic inflammatory phenotype: 6.6 vs 3.4 (p< 0.001). Anti-IL1 therapy was started more frequently in the systemic subgroup (26%) than in the isolated subset (7.5%) (p < 0.001). On multivariate analysis neutrophil count and lymphopenia were statistically associated with the systemic subset (p < 0.001). CONCLUSION: This results demonstrate the relevance of the systemic inflammatory phenotype, characterized by pleural effusions, confirming its analogy with autoinflammatory diseases, thus possibly requiring an eventual escalation of therapy to IL-1 inhibitors.

Relapsing pericarditis: Peripheral blood neutrophilia, lymphopenia and high neutrophil-to-lymphocyte ratio herald acute attacks, high-grade inflammation, multiserosal involvement, and predict multiple recurrences.

AIMS: To identify peripheral blood cellular correlates of active pericarditis and to verify whether peripheral blood neutrophils, lymphocytes and the neutrophil to-lymphocyte ratio (NLR) are associated with disease phenotype or prognosis. METHODS: Observational prospective study on a cohort of 63 patients with idiopathic pericarditis followed for 12 months after each pericarditis recurrence. Two distinct analyses were performed: the "index attack" analysis focused on the first pericarditis episode in each patient, while the "all attacks" analysis included all episodes occurring during the study. RESULTS: Absolute and relative neutrophilia and lymphopenia, together with high NLR, were observed during active pericarditis, as compared with disease remission, at both analyses. Neutrophils showed a positive correlation with plasma C-reactive protein levels, while lymphocyte count showed a negative correlation. Relative neutrophil count was higher, and lymphocyte count lower in patients with pleural effusion; a higher NLR and lower absolute lymphocyte count were observed in those with peritoneal involvement. No correlations were found between peripheral blood neutrophil or lymphocyte counts and size of pericardial effusion, or with the presence of myocardial involvement. Peripheral neutrophilia, lymphopenia and NLR during acute attacks predicted the number of recurrences in the following 12 months. CONCLUSIONS: Peripheral blood neutrophilia and lymphopenia are typical of acute idiopathic pericarditis. Acute attacks of pericarditis are associated with neutrophilia and lymphopenia, as compared with disease remission. During acute attacks, neutrophilia and lymphopenia reflect the extent of serosal inflammation and could help to customize therapeutic management after remission has been achieved.

Interleukin-1 Trap Rilonacept Improved Health-Related Quality of Life and Sleep in Patients With Recurrent Pericarditis: Results From the Phase 3 Clinical Trial RHAPSODY.

Background Recurrent pericarditis is characterized by painful flares and inflammation, which negatively impact health-related quality of life. RHAPSODY (rilonacept inhibition of interleukin-1 alpha and beta for recurrent pericarditis: a pivotal symptomatology and outcomes study) evaluated the efficacy and safety of rilonacept (IL-1α and -ß cytokine trap) in recurrent pericarditis. A secondary analysis of these data evaluated the patient-reported outcome questionnaire score change during the trial. Methods and Results Participants completed 5 patient-reported outcome (PRO) questionnaires assessing pericarditis pain, health-related quality of life, general health status, sleep impact, and overall symptom severity. PRO score changes during the treatment run-in period (12 weeks) and the blinded randomized withdrawal period (up to 24 weeks) were evaluated using descriptive statistics and mixed model repeated measures analyses. Participants with PRO data from the run-in period (n=84) and the randomized withdrawal period (n=61; 30 rilonacept, 31 placebo) were included in analyses. Run-in baseline PRO scores indicated that pericarditis symptoms during pericarditis recurrence impacted health-related quality of life. All PRO scores significantly improved (P<0.001) on rilonacept treatment during the run-in period. For the randomized withdrawal period, PRO scores were maintained for participants receiving rilonacept. For those receiving placebo and who experienced a recurrence, PRO scores deteriorated at the time of recurrence and then improved following rilonacept bailout. At randomized withdrawal Week 24/End of Study, scores of participants who received bailout rilonacept were similar to those of participants who had continued rilonacept. Conclusions These results demonstrate the burden of pericarditis recurrences and the improved physical and emotional health of patients with recurrent pericarditis while on rilonacept treatment. These findings extend prior rilonacept efficacy results, demonstrating improvements in patient-reported health-related quality of life, sleep, pain, and global symptom severity while on treatment. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis.

The field of inflammatory disease of the heart or "cardio-immunology" is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

Autoimmune and Autoinflammatory Pericarditis: Definitions and New Treatments.

PURPOSE OF THE REVIEW: The purpose of the review is to analyze the pathogenetic mechanisms that underlie acute pericarditis, with attention to autoimmune and autoinflammatory pericarditis, and, in addition, to review the available therapeutic armamentarium. RECENT FINDINGS: Several studies have been published on the use of anti-IL-1 drugs in recurrent pericarditis, including anakinra and rilonacept. The latest, the RHAPSODY study, based on the use of rilonacept in recurrent pericarditis, has recently reached phase 3 with promising results in terms of efficacy and safety. Alterations in the function of the inflammasome and the consequent overproduction of IL-1 play a pivotal role in the genesis of autoinflammatory pericarditis. Recent studies added evidence to the importance of anti-IL-1 drugs in the treatment of recurrent pericarditis with raised C-reactive protein. In the era of tailored medicine, anti-IL-1 agents may be very useful in the subset of patients with recurrent pericarditis and a clear inflammatory phenotype.

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease.

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

Relationship between previous treatments and onset of symptoms in patients with Whipple's disease.

The clinical features of Whipple's disease (WD) consist of arthropathy that precedes the involvement of other organs, such as the gastrointestinal tract, nervous system and heart. It has been shown that gastrointestinal manifestations can be precipitated by immunosuppressive therapy used to control the arthropathy. In the present study, we investigated the clinical features of the Italian population of patients affected by WD. The clinical histories of 22 patients with WD were reviewed. Relationship between previous treatments and onset of symptoms was analysed. 20/22 patients suffered from arthropathy that had started before gastrointestinal complaints; gastrointestinal symptoms were present in 18 patients and neurological involvement was found in 5. WD must always be taken into account in male patients with long-standing ill-defined arthropathy, and it should be ruled out before starting immunosuppressive or antibiotic treatment that can make correct diagnosis and management very difficult.

Dental enamel defects in adult coeliac disease: prevalence and correlation with symptoms and age at diagnosis.

BACKGROUND: Coeliac disease is a condition characterized by a wide spectrum of clinical manifestations. Any organ can be affected and, among others, dental enamel defects have been described. Our aims were to study the prevalence of dental enamel defects in adults with coeliac disease and to investigate a correlation between the grade of teeth lesion and clinical parameters present at the time of diagnosis of coeliac disease. METHODS: A dental examination was performed in 54 coeliac disease patients (41 F, mean age 37 ± 13 years, mean age at diagnosis 31 ± 14 years). Symptoms leading to diagnosis were diarrhoea/weight loss (32 pts.), anaemia (19 pts.), familiarity (3 pts.); none of the patients was diagnosed because of enamel defects. At the time of evaluation, they were all on a gluten-free diet. Enamel defects were classified from grade 0 to 4 according to its severity. RESULTS: Enamel defects were observed in 46/54 patients (85.2%): grade 1 defects were seen in 18 patients (33.3%) grade 2 in 16 (29.6%), grade 3 in 8 (14.8%), and grade 4 in 4 (7.4%). We also observed that grades 3 and 4 were more frequent in patients diagnosed with classical rather than non-classical coeliac disease (10/32 vs. 2/20). However, this was not statistically significant. CONCLUSION: This study confirms that enamel defects are common in adult coeliac disease. Observation of enamel defects is an opportunity to diagnose coeliac disease.

Prevalence and natural history of potential celiac disease in adult patients.

OBJECTIVE: Potential celiac disease (PCD) is a form of CD characterized by positive endomysial/tissue transglutaminase antibodies and a preserved duodenal mucosa despite a gluten-containing diet (GCD); it can evolve into flat, active CD. This evolution is, however, not certain. Our aim was to retrospectively study the prevalence and the natural history of adult patients with PCD. METHODS: The clinical notes of all 47 patients with PCD attending our clinic between September 1999 and October 2011 were retrospectively reevaluated. To study their clinical features, patients with active CD, randomly selected and matched for sex and date of birth, served as controls. Symptoms, associated diseases, familiarity, and laboratory data at diagnosis were compared. RESULTS: Prevalence of PCD among all celiac patients directly diagnosed in our center was 42/187, (1/4.4, 18.3%, 95% confidence interval (CI) 13.3-23.4%). Age at diagnosis, laboratory data, prevalence of symptoms, associated diseases, and familiarity for CD did not differ between patients with PCD and those with active CD. Some patients with PCD maintained a normal duodenal mucosa for many years and their symptoms spontaneously improved despite maintaining a GCD. CONCLUSIONS: PCD is not a rare form of CD. Having found no difference at all in age at diagnosis and clinical features between PCD and active CD could suggest that PCD is not a prodrome of CD but is a separate entity that can only subsequently evolve into active CD.

Quality of life in coeliac patients: Italian validation of a coeliac questionnaire.

BACKGROUND: Coeliac disease (CD) is a chronic condition requiring a gluten-free diet, which is a very demanding diet to maintain on a life-long basis. For this reason it is a condition that can have serious repercussions on the quality of life (QOL). Therefore the need to elaborate a questionnaire on QOL specifically for patients with CD (CDQ): its original language is German, and the translation/validation process represents a considerable challenge involving not only a translation into Italian but also an adaptation to the country's specific cultural differences. METHODS: The questionnaire has been translated according to a "German → Italian → Italian → German" algorithm with reconciliation of the differences. Scores for CDQ are computed overall and over four areas of four items each: emotion, gastrointestinal symptoms, gastrointestinal worries, social problems. RESULTS: CDQ was administered to 171 coeliacs (F 132, mean age 38 yrs ± 14). Completeness was optimal. Item internal consistency was satisfied for 100% and 97% of patients for the specific and generic part, respectively. Cronbach's α coefficient was 0.7 for all scales. The general CDQ was higher in patients reporting subjective well-being (discriminant validity). CONCLUSIONS: The Italian translation of CDQ sounds natural, is easy to understand and reduces possible cultural biases to a minimum. A field test gave results comparable to the original validation, supporting the use of CDQ in cross-national surveys.

Whipple's disease.

Whipple's disease is a chronic multisystemic infection, due to Tropheryma whipplei, a bacterium ubiquitously present in the environment. Although it is very rare, its clinical features are non-specific and can affect several different districts. Whipple's disease is therefore a condition that should always be kept in mind by doctors working in several branches of medicine, such as internal medicine, gastroenterology, rheumatology, neurology, and cardiology. The condition is fatal if not promptly recognized and treated, but the best treatment is still not completely defined, especially in relapsing disease, neurological manifestations, and in cases of immunoreconstitution after initiation of antibiotic treatment.

Previous immunosuppressive therapy is a risk factor for immune reconstitution inflammatory syndrome in Whipple's disease.

INTRODUCTION: Whipple's disease is a rare chronic infection caused by Tropheryma whipplei. Although most patients respond to antibiotics, in some of them the start of the treatment is followed by recurrence of inflammation. Since polymerase chain reaction is negative for Tropheryma whipplei, this reinflammation cannot be a relapse of Whipple's disease itself. Very recently, it has been recognised as a complication of Whipple's disease and defined immune reconstitution inflammatory syndrome (IRIS). Our aim is to study the prevalence and the clinical features of IRIS in Italian patients with Whipple's disease. METHODS: Evidence of IRIS was retrospectively revaluated in the clinical notes of 22 patients with Whipple's disease. Patients with no evidence of IRIS served as controls for the clinical findings. RESULTS: Recurrence of arthralgia and/or fever allowed a diagnosis of IRIS in 5/22 patients. One patient died. Previous immunosuppressive therapy was found in all patients with IRIS but only in 7/17 controls (Fisher test, p=0.039). Age at diagnosis and diagnostic delay were higher in patients with IRIS compared to controls. However, statistical significance was not reached. CONCLUSIONS: IRIS is a frequent complication of Whipple's disease and it can be fatal. The risk of IRIS is greatly increased in patients previously treated with immunosuppressive therapy.

A score that verifies adherence to a gluten-free diet: a cross-sectional, multicentre validation in real clinical life.

A dietary interview performed by expert personnel is the best method to check whether patients with coeliac disease follow a strict gluten-free diet (GFD). We previously developed a score based on four fast and simple questions that can be administered even by non-expert personnel. The aim of the present study is to verify the reliability of our questionnaire in a new cohort of patients. The questionnaire has a five-level score. From March 2008 to January 2011, the questionnaire was administered to 141 coeliac patients on a GFD, who were undergoing re-evaluation. The score obtained was compared with persistence of both villous atrophy and endomysial antibodies (EMA). The rate of lower scores was higher among the patients with persistence of either villous atrophy (Fisher's exact, P < 0·001; test for trend, P < 0·001) or positive EMA (Fisher's exact, P = 0·001; test for trend, P = 0·018). Given that the coeliac patients have been well instructed on what a GFD means and on how to follow it, our questionnaire is a reliable and simple method to verify compliance to a GFD.

Influence of HLA-DQ2 and DQ8 on severity in celiac Disease.

BACKGROUND: HLA-DQB1*02 homozygosity was shown to be more common in patients with complicated rather than uncomplicated celiac disease (CD). GOALS: To study HLA-DQA1 and DQB1 profile in adult patients with different forms of CD, including patients with complicated and potential CD, the most affected and the most preserved histologic end of the pathologic celiac spectrum. STUDY: HLA-DQA1 and DQB1 molecular typing was performed in 218 adult CD patients (169 with uncomplicated CD, 27 with complicated CD, and 22 with potential CD) and 224 healthy stem cell donors. HLA-DQA1 and DQB1 gene polymorphism was analyzed using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides techniques. RESULTS: As expected, the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the 4 groups. However, multivariate analysis demonstrated that patients with potential CD have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles and a reduced frequency of DQB1*02 homozygosity compared with patients with uncomplicated and complicated CD. CONCLUSIONS: The increased frequency of DQB1*0302 and the reduced frequency of DQB1*02 homozygosity in potential CD is consistent with the idea that different clinical/pathologic evolutions might be related to different immunogeneses. This could be clinically relevant in the future.

Juan César García y el movimiento latinoamericano de medicina social: notas sobre una trayectoria de vida / Juan César García and the Latin American social medicine movement: notes on a life trajectory

Este artículo analiza la trayectoria de Juan César García, uno de los referentes del movimiento latinoamericano de medicina social. La pregunta que desencadenó este trabajo buscó indagar el momento y las circunstancias en que García incorporó para sí la matriz del marxismo para pensar los problemas de salud. De esta manera, siguiendo los lineamientos metodológicos propuestos por Pierre Bourdieu, utilizamos la noción de "trayectoria de vida" para reconstruir un recorrido vital que se bifurca en varias rutas: de su Necochea natal a la ciudad de La Plata, desde allí hasta Santiago de Chile y, finalmente, sus innumerables viajes desde Washington hacia gran parte de América Latina. Para ello, realizamos entrevistas semiestructuradas con informantes clave: familiares, amigos y colegas de Argentina, Brasil, Ecuador y Cuba. Asimismo, analizamos los títulos de su biblioteca personal, donada a la fundación internacional que lleva su nombre, y documentos de distintos archivos particulares.

This article analyzes the trajectory of Juan César García, one of the referential figures of the Latin American social medicine movement. The question that inspired this work sought to uncover in what moment and in what circumstances García incorporated a Marxist framework into his way of thinking about health problems. Following the methodological guidelines proposed by Pierre Bourdieu, we used the concept of "life trajectories" to reconstruct a life path that divides in various directions: from his birthplace in Necochea to the city of La Plata, from there to Santiago de Chile and, finally, his numerous trips from Washington DC to a large part of Latin America. In order to trace these paths, we carried out semi-structured interviews with key informants: family members, friends, and colleagues from Argentina, Brazil, Ecuador and Cuba. We also analyzed the books included in his personal library, donated after his death to the international foundation that carries his name, and documents from different personal archives.