An Embedded Multiscale Modelling to Guide Control and Elimination of Paratuberculosis in Ruminants

In recent years, multiscale modelling approach has begun to receive an overwhelming appreciation as an appropriate technique to characterize the complexity of infectious disease systems. In this study, we develop an embedded multiscale model of paratuberculosis in ruminants at host level that integrates the within-host scale and the between-host. A key feature of embedded multiscale models developed at host level of organization of an infectious disease system is that the within-host scale and the between-host scale influence each other in a reciprocal (i.e., both) way through superinfection, that is, through repeated infection before the host recovers from the initial infectious episode. This key feature is demonstrated in this study through a multiscale model of paratuberculosis in ruminants. The results of this study, through numerical analysis of the multiscale model, show that superinfection influences the dynamics of paratuberculosis only at the start of the infection, while the MAP bacteria replication continuously influences paratuberculosis dynamics throughout the infection until the host recovers from the initial infectious episode. This is largely because the replication of MAP bacteria at the within-host scale sustains the dynamics of paratuberculosis at this scale domain. We further use the embedded multiscale model developed in this study to evaluate the comparative effectiveness of paratuberculosis health interventions that influence the disease dynamics at different scales from efficacy data.

Severe Anemia Is Associated with a Risk of Infection in Patients with Myelodysplastic Syndromes

Introduction: Infections are a well-recognized complication in patients (pts) with myelodysplastic syndromes (MDS) that contribute substantially to the morbidity and mortality particularly in pts suffering from neutropenia. Neutropenia and other immune defects including impaired neutrophil function have been reported to be predisposing factors for severe infections. Furthermore, some of the therapies may worsen neutropenia and lead to an additional risk factor to develop infectious episodes. Since infectious complications are no primary endpoint in clinical trials epidemiological data on infections in large cohorts of MDS pts is sparse. Methods: We performed a retrospective analysis of 3.787 MDS-patients from the Duesseldorf MDS Registry who were diagnosed between 1980 and 2018. Infectious complications were defined as clinical symptoms of infection associated with the need for antibiotic and/or antifungal therapy, and/or the isolation of a pathogen and/or an identifiable site of infection by physical examination. Infectious episodes were categorized as fever of unknown origin, microbiologically or clinically documented infection. Results: Amongst our study cohort, 42% of the pts suffered from at least one infectious complication of any type during the course of their disease. Most infectious diseases were of bacterial origin (34.7%) and in 17% a pathogen was isolated. Pneumonia was the most common site of infection (64%). Pts who experienced at least one infectious episode had a significant poorer overall survival (OS) than pts without such events (21 vs 37 months, p<0.001). Pts with a higher risk disease according to the IPSS-R had fewer infections during the course of the disease than pts with a lower-risk MDS (487 total infections vs 1481, p<0.001). Nevertheless, the presence of any infectious episode lead to an inferior OS in lower-risk (40 vs 29 months, p<0.001) as well as in higher-risk disease (38 vs 24 months, p=0.006). In univariate analyses comparing pts who had no infections versus those who had one or more, pts with older age (>65 years) tended to have a higher incidence of infectious episodes (p<0.001). In addition, patients older than 65 suffering from infections had a shorter OS than patients who did not experience an infectious complication. The difference in OS was highly significant with 16 months for pts suffering from infectious complications compared to 24 months (p<0.001). Likewise, an excruciating higher incidence of infections was noted in MDS pts compared to infections incidence in a non-MDS population in Germany. The risk of a 65-year-old or older MDS pt to suffer from pneumonia was 6.9 times higher compared to a non-MDS pt of the same age. We found a highly significant negative correlation between the depth of cytopenia in all three myeloid lineages and the presence of infections (p<0.001), suggesting that patients with severe cytopenia suffer from infectious episodes more frequently. However, pts with an isolated neutropenia having an absolute neutrophil count below a threshold of 0.8 × 10 9/L and suffering from infectious episodes had no inferior OS than neutropenic pts without any infection (25 vs 32 months, p=0.583). Pts with isolated severe thrombocytopenia with a platelet count <50 × 10 9/L had a similar OS of 26 months for pts with infectious complications. The difference in OS between pts with and without infections was even more pronounced in this group (26 vs 48 months, p=0.002). Still, a low hemoglobin (Hb) level <9g/dl appeared to be the most significant risk factor for pts with infections, resulting in the poorest OAS of only 17 months in pts with isolated anemia suffering from infections. In multivariate analyses, we found that Hb <9g/dl, followed by ANC <0.8 × 10 9/L, were independently associated with the risk to suffer from an infection during the disease. In addition, a Hb <9g/dl was the most important blood count parameter with regard to OS when compared to platelets <50 × 10 9/L, and ANC <0.8 × 10 9/L. Conclusion: The incidence of infections significantly increases in pts with advanced age. MDS-pts in general are more vulnerable for infection-related morbidity and mortality than non-MDS-pts. Low hemoglobin and platelet counts were both found to be associated with a worse prognosis compared to low neutrophil counts. The appearance of at least one infectious episode leads to an inferior Disclosures Nachtkamp: Jazz: Speakers Bureau; bsh medical: Speakers Bureau; Celgene: Other: Travel Support. Kobbe: Celgene: Research Funding. Gattermann: Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria.

Co-Occurrence of Myeloid and Lymphoid Neoplasms: Clinical Characterization and Impact on Outcome. A Single-Center Cohort Study

The co-occurrence of myeloid neoplasms and lymphoproliferative diseases (LPDs) has been epidemiologically described, particularly in myeloproliferative neoplasms (MPNs). However, the clinical features of these patients are poorly known. In this study, we evaluated a single-center cohort of 44 patients with a diagnosis of myeloid and LPD focusing on clinical features, therapy requirement, and outcome. The two diagnoses were concomitant in 32% of patients, while myeloid disease preceded LPD in 52% of cases (after a median of 37 months, 6–318), and LPD preceded myeloid neoplasm in 16% (after a median of 41 months, 5–242). The most prevalent LPD was non-Hodgkin lymphoma (50%), particularly lymphoplasmacytic lymphoma (54.5%), followed by chronic lymphocytic leukemia (27%), plasma cell dyscrasias (18.2%), and rarer associations such as Hodgkin lymphoma and Erdheim–Chester disease. Overall, 80% of BCR-ABL1-negative MPN patients required a myeloid-specific treatment and LPD received therapy in 45.5% of cases. Seven subjects experienced vascular events, 13 a grade >/= 3 infectious episode (9 pneumonias, 3 urinary tract infection, and 1 sepsis), and 9 developed a solid tumor. Finally, nine patients died due to solid tumor (four), leukemic progression (two), infectious complications (two), and brain bleeding (one). Longer survival was observed in younger patients (p = 0.001), with better performance status (p = 0.02) and in the presence of driver mutations (p = 0.003). Contrarily, a worse survival was significantly associated with the occurrence of infections (p < 0.0001). These data suggest that in subjects with co-occurrence of myeloid and lymphoid neoplasms, high medical surveillance for infectious complications is needed, along with patient education, since they may negatively impact outcome.

Alveolar Macrophages: Adaptation to Their Anatomic Niche during and after Inflammation

At the early stages of life development, alveoli are colonized by embryonic macrophages, which become resident alveolar macrophages (ResAM) and self-sustain by local division. Genetic and epigenetic signatures and, to some extent, the functions of ResAM are dictated by the lung microenvironment, which uses cytokines, ligand-receptor interactions, and stroma cells to orchestrate lung homeostasis. In resting conditions, the lung microenvironment induces in ResAM a tolerogenic programming that prevents unnecessary and potentially harmful inflammation responses to the foreign bodies, which continuously challenge the airways. Throughout life, any episode of acute inflammation, pneumonia being likely the most frequent cause, depletes the pool of ResAM, leaving space for the recruitment of inflammatory monocytes that locally develop in monocyte-derived alveolar macrophages (InfAM). During lung infection, the local microenvironment induces a temporary inflammatory signature to the recruited InfAM to handle the tissue injury and eliminate the pathogens. After a few days, the recruited InfAM, which locally self-sustain and develop as new ResAM, gain profibrotic functions required for tissue healing. After the complete resolution of the infectious episode, the functional programming of both embryonic and monocyte-derived ResAM remains altered for months and possibly for the entire life. Adult lungs thus contain a wide diversity of ResAM since every infection brings new waves of InfAM which fill the room left open by the inflammatory process. The memory of these innate cells called trained immunity constitutes an immunologic scar left by inflammation, notably pneumonia. This memory of ResAM has advantages and drawbacks. In some cases, lung-trained immunity offers better defense capacities against autoimmune disorders and the long-term risk of infection. At the opposite, it can perpetuate a harmful process and lead to a pathological state, as is the case among critically ill patients who have immune paralysis and are highly susceptible to hospital-acquired pneumonia and acute respiratory distress syndrome. The progress in understanding the kinetics of response of alveolar macrophages (AM) to lung inflammation is paving the way to new treatments of pneumonia and lung inflammatory process.

Visual outcome of endogenous endophthalmitis in Thailand

To evaluate a 10-year visual outcome of endogenous endophthalmitis (EE) patients. A 10-year retrospective chart review of EE patients. Thirty-eight patients (40 eyes) were diagnosed with EE at the mean age of 42. Among the identifiable pathogens (71.1% culture positive), the causative agents were predominantly gram-negative bacteria (48.1%). The most common specie was Klebsiella pneumoniae (25.9%). About a quarter of the patients required surgical eye removal, and the remaining 45.7% had visual acuity (VA) worse than hand motion at one month after the infectious episode. The most common complication was ocular hypertension (52.5%). Poor initial VA was significantly associated with a worse visual outcome in the early post-treatment period (p 0.12, adjusted OR 10.20, 95% CI 1.65–62.96). Five patients continued to visit the clinic for at least ten years. One patient had gained his vision from hand motion to 6/7.5. Two patients had visual deterioration, one from corneal decompensation, and the other from chronic retinal re-detachment. Two patients developed phthisis bulbi, with either some VA perception of light or no light perception. Poor initial VA is the only prognostic factor of a poor early post-treatment visual outcome of EE.

Case Report: Analysis of Inflammatory Cytokines IL-6, CCL2/MCP1, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP10 in a Cystic Fibrosis Patient Cohort During the First Wave of the COVID-19 Pandemic

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, data registered in the European countries revealed increasing cases of infection in cystic fibrosis (CF) patients. In the course of this pandemic, we enrolled 17 CF patients for a study evaluating inflammatory markers. One of them developed COVID-19, giving us the possibility to analyze inflammatory markers in the acute phase as compared to levels detected before and after the infectious episode and to levels measured in the other CF patients enrolled to the study who did not experience COVID-19 and 23 patients referred to our center for SARS-CoV-2 infection.

POS1155 INFECTIOUS RISK DURING BIOLOGIC THERAPY FOR INFLAMMATORY RHEUMATIC DISEASES: DATA FROM THE TUNISIAN BINAR REGISTRY

Background:The development of biologics for the treatment of systemic rheumatic diseases increased the risk of infections. The management of this complication deserves particular attention since it remains a major cause of morbidity and mortality.Objectives:The aim of our study was to determine infection frequency under biological treatment and consequences on the therapeutic management.Methods:Patients included in the Biological National Registry (BINAR) from 2016 to 2020. Data related to the disease, biological agents, and infections occurring under biologic disease-modifying antirheumatic drugs (bDMARDs) were collected.Results:The study included 298 patients with a mean age of 49.2 years [18-79] 175 patients with rheumatoid arthritis and 123 with spondyloarthritis (Axial Spondyloarthritis=48, Enteropathic Arthritis=41, Psoriatic Arthritis=34). Anti Tumor necrosis factor-alpha (Anti-TNF) agents were the most prescribed bDMARDs in 87.9% (n=263) of patients: Infliximab 20.4% (n=61),Etanercept 23.1%(n=69), Adalimumab 24.6%(n=74) and Certolizumab (n=79). No patients were treated with Golimumab. Tocilizumab and Rituximab were prescribed respectively in 10.4% (n=31) and 5% (n=15) of patients. Infections occured in 9 patients (3.1%) with a total of 13 infectious episodes 12 bacterial and a viral one. The site of infections was: respiratory (38%), urinary (15%), cutaneous (23%), ORL (8%), infective endocarditis (8%), and other (8%). The infectious agent was identified in only 3 patients. The outcomes were favorable in most cases except in one patient where there was a definitive interruption of bDMARDs. The patient was hospitalized for sepsis complicating a cutaneous infection with favorable outcomes under antibiotics within a week. The biological agent with higher risk of infections was Tocilizumab (p = 0.056), unlike Rituximab (p = 0.483) and Anti-TNF (p = 0.082). All patients who had an infectious episode were under corticosteroids.Conclusion:Our results confirm that bDMARDs are predisposing to infections, but data from BINAR showed that most infections were trivial with no serious outcomes. Therefore, infections should be assessed in patients under bDMARDs for an early therapeutic intervention.Disclosure of Interests:None declared.

Whole Exome Sequencing as a Diagnostic Tool of Primary Complement Component Deficiencies: A Multicenter Experience of Three Novel Mutations

Diagnosis of primary complement deficiencies requires a high index of suspicion. Thus, susceptible patients are often underdiagnosed and untreated. Here, we present a multi-center experience with three novel inborn errors of the classical complement system. This is a retrospective multicenter analysis of computerized medical records of children (> 18 years) admitted in the period between 2003 and 2018 at Shaare Zedek Medical Center in Jerusalem and Edmond and Lily Safra Children's Hospital, Tel-Hashomer Medical Center, in Ramat Gan, Israel. Patients were genetically diagnosed by a complimentary immune work-up. We identified 5 patients (3 males) from four different consanguineous families harboring three novel mutations in the complement components C6-C8. Genetic mutations were identified by whole exome sequencing. Clinical manifestations consisted of meningitis with or without meningococcemia. The immune work-up demonstrated nearly absent levels of CH50, compatible with a complement pathway defect. The mean diagnosis delay was 10.56 (0–30) years. Conclusion: Invasive meningococcal infections may be life-threatening and cause severe neurological sequela. Awareness of risk factors for primary complement deficiencies, even at the firs infectious episode, should facilitate prompt immune and genetic investigations, commencing diagnosis and proper treatment.

Acute Coronary Syndrome and Arrhytmia Induced by SARS-CoV-2 Infection in a Patient with Non-Significant LAD Lesion. A Case Report

Background: Coronavirus disease 2019 (COVID-19) has emerged as a pandemic and public health crisis of an unprecedent effect. Clinical studies reported an association between COVID-19 and cardiovascular disease, whereas COVID-19 itself can induce myocardial injury, arrhythmia, acute coronary syndrome, and venous thromboembolism. Case summary: A patient diagnosed via screening coronary computed tomography angiography with non-obstructive coronary artery disease was hospitalized with non-ST elevation myocardial infarction and atrial flutter during a severe respiratory infection episode with SARS-CoV-2. After recovery from the infectious episode, fractional flow reserve-guided elective percutaneous coronary intervention with drug-eluting stent was performed. Conclusions: COVID-19 intercurrence in a cardiovascular patient with nonobstructive coronary artery disease triggered coronary plaque vulnerabilization with subsequent development of an acute coronary syndrome. SARS-CoV-2 proved to be involved via direct viral tissue involvement and concomitant mechanisms derived from systemic illness in the development of a severe supraventricular arrhythmic event.

MBCL-41. LYMPHOHEMATOPOIETIC TOXICITY IDENTIFIED IN PATIENTS WITH MEDULLOBLASTOMA RECEIVING CRANIOSPINAL IRRADIATION

BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor of childhood. MB easily disseminates through the spinal fluid. Surgery followed by radiotherapy, applied to the entire craniospinal axis (CSI), and adjuvant chemotherapy, represent the treatment of choice for patients aged ≥3 years. Since the bone marrow of the skull and vertebral column are the major hematopoietic organs, we investigated the myelosuppressive effect of irradiation treatment in patients with MB retrospectively. METHODS Medical records of newly diagnosed MB patients treated at our hospital from 2007–2019 were analyzed. Children <3 years old were excluded because they did not receive CSI to avoid potential neurotoxicity. RESULTS Medical records of 18 patients (11 males and 7 females, aged 6–26, median 11 years) were reviewed. Eight patients were stratified as high-risk disease and 10 patients with standard risk. All patients received CSI (dosage range 23.4–39.6 Gy based on disease risk) and posterior fossa boost. All patients developed lymphocytopenia (<0.5×109/L) during irradiation, and for 11 of 18 patients, lymphocytopenia (<0.2×109/L) was severe. Although 13 patients recovered from the lymphocytopenia before the initiation of chemotherapy, five patients underwent chemotherapy without recovery. Conversely, only six patients developed neutropenia (<1.0×109/L), and five of the six patients were <10 years old. CONCLUSION Although infectious episode associated with lymphocytopenia was not observed in this study, CSI treatment in children and adolescents may induce immunodeficient condition particularly in the lymphocytic system. Pediatric oncologists should pay attention to the impaired immunity of patients with MB who receive CSI.