Progressive Respiratory Failure Research Articles

P8.152: Clinical Characteristics and Factors Related to Recurrent Cytomegalovirus Infection Post-kidney Transplant in Adult Patients at Cho Ray Hospital

Introduction: Cytomegalovirus (CMV) is one of the main causes of opportunistic infections after kidney transplantation. Manifestations of CMV disease in post renal transplantation patients are quite discreet, non-specific and difficult to diagnose early. Asymptomatic recurrent CMV infection has been reported remarkably to increase mortality rate and rejection incidence, and effect on graft survival. The recently follow-up and treatment procedures’ changes make it urgent to re-evaluate the incidence and the factors related to the risk of CMV recurrence as well as the clinical characteristics of CMV infection in postkidney transplantation patients. This helps to control the recurrence of CMV infection as well as to diagnose CMV disease early and treat it promptly and appropriately to reduce the mortality rate of patients after transplantation. Method: Objective 1: Retrospective cohort study of adult renal transplant recipients between January 1, 2015 and December 31, 2018. Objective 2: A cross - sectional descriptive study on 22 cases of CMV disease in post kidney transplant patients to present a review of the main clinical aspects of cytomegalovirus infection in renal transplants with a focus on clinical approach and its future perspectives. Results: Objective 1: A total of 365 patients who received a renal transplant at Cho Ray hospital in the study time period were reviewed for the presence of CMV infection occurring less than 540 days after transplant. The recurrent CMV infection was observed in 254 cases (69,6%), but only 3 patients (0,8%) developed CMV disease. Independent risk factors of CMV infection were HLA >80 (HR = 2,309, 95% CI 1,021 – 4,071, p = 0,044), daily oral Prednisone doses used <0,5 mg/kg/day (HR = 0,178, 95% CI 0,084 – 0,374, p <0,001), Tacrolimus whole blood trough concentration ≤10 µg/L (HR = 0,445, 95% CI 0,243 – 0,816, p = 0,009), Cyclosporine wole blood trough concentration >150 µg/L (HR = 4,25, 95% CI 1,97 – 9,2, p < 0,001). Objective 2: Male majority (2/3), with average age of 47,5 ± 4,5. Rate of symptomic recurrence CMV infection in the first 6 months, 6 - 12 months, 1 - 5 years, 5 - 10 years after transplant were 45,4%, 9,1%, 27,3% and 18,2% respectively. Common clinical manifestations are fever 59,1%, respiratory, renal and gastrointestinal manifestations 31,8%, 27,3% and 13,6%, respectively. Two cases of CMV retinitis with typical fundus lesions were treated with intraocular Ganciclovir, however, vision was not fully recovered. Lymphopenia <1.000 cells/mm3 was observed in most cases of CMV disease after kidney transplantation. Quantitative PCR of CMV DNA in plasma ranged from 375 – 6.533.850 copies/mL. 6 of 22 cases of PCR CMV DNA in plasma >4.000 copies/mL, of which 5 severe cases developed rapidlly progressive respiratory failure and 2 deaths. Conclusion: Recurrent CMV infection has a high rate in adult patients after kidney transplantation, so it is necessary to take initiactive for screening, monitoring and treating early to reduce mortality and protect the transplanted kidney. The appropriate dose of immunosuppressants plays an important role in the prevention of recurrent CMV infection and the successful treatment of disease due to it. Key words: Cytomegalovirus, Kidney transplantation, Post-transplant infection. * Deparment of Tropical diseases– Cho Ray Hospital ** Nephrology Surgery – Cho Ray Hospital Coresponding author: Tho A. N. Vo, Deparment of Tropical diseases– Cho Ray Hospital. Email: [email protected]. Mobile: 0983888841.

Bilioptysis associated with alcohol hepatitis without evidence of bronchobiliary fistula: A rare case report

The presence of bilirubin in the sputum is uncommon but, when present, is most commonly associated with the presence of bronchobiliary fistula, which could be associated with a number of underlying conditions. However, the finding of bilioptysis without bronchobiliary fistula is uncommon, with one associated mechanism postulated to involve increased capillary membrane permeability. This case report describes a patient presenting with bilioptysis while being medically managed with prednisolone for severe alcoholic hepatitis. The patient developed hospital‐acquired pneumonia during her hospitalization associated with bilioptysis, resulting in progressive respiratory failure requiring ventilatory support. Alcohol‐related pulmonary dysfunction alters pulmonary immune processes, leading to increased susceptibility to pulmonary infection and disrupting the basal alveolar epithelial membrane, thus increasing permeability. This patient's findings were in the absence of a bronchobiliary or bronchopleural fistula, and we hypothesize that increased capillary membrane permeability was contributory to the bilioptysis in this case.

Prognostic value of neutrophils to lymphocytes and platelets ratio for 28-day mortality in patients with acute respiratory distress syndrome: a retrospective study

BackgroundAcute respiratory distress syndrome (ARDS) is a rapidly progressive and fatal respiratory failure disease that often occurs in critically ill patients. Since ARDS is associated with immune dysregulation and coagulation abnormalities, it is necessary to identify an appropriate predictor that can accurately predict ARDS mortality based on its pathophysiology. Therefore, this study aimed to evaluate the clinical value of neutrophils to lymphocytes and platelets ratio (N/LPR) in predicting 28-day mortality in ARDS patients.MethodsFrom July 2018 to October 2021, the medical records of ARDS patients were retrospective reviewed. Neutrophil count, lymphocyte count, and platelet count were collected, and the neutrophil-to-lymphocyte ratio (NLR) and N/LPR were calculated. Multivariate logistic regression analyses were performed to identify independent predictors of 28-day mortality in ARDS. Receiver operating characteristic (ROC) curve with the area under curve (AUC) was used to evaluate optimal cut-off values for 28-day mortality in ARDS. Kaplan–Meier analysis was used to estimate the 28-day survival probabilities stratified by optimal cut-off values of N/LPR and NLR.ResultsA total of 136 ARDS patients were included in this study and were further divided into survivors (n = 69) and non-survivors (n = 67) groups according to their survival status on day 28. There were no significant differences between the two groups in age, sex, history of smoking and drinking, comorbidities, and reasons of admission (P > 0.05). Non-survivors had significantly higher neutrophil counts, NLR and N/LPR and had significantly lower platelet counts than survivors (P < 0.05). Multivariate regression analysis revealed that N/LPR, NLR and platelet counts were independent predictors for 28-day mortality in ARDS (P < 0.05). The ROC analyses showed that N/LPR with optimal cut-off value of 10.57 (sensitivity: 74.6%; specificity: 72.5%) is a more reliable predictor for 28-day mortality in ARDS than NLR and platelet count (AUC: 0.785 vs. 0.679 vs. 0.326). Further subgroup analysis confirmed that ARDS patients with N/LPR < 10.57 had significantly lower 28-day mortality than patients with N/LPR ≥ 10.57 (P < 0.001). Kaplan–Meier analysis also confirmed that ARDS patients with N/LPR < 10.57 had significantly longer survival.ConclusionN/LPR is an independent risk factor associated with 28-day mortality in ARDS patients and shows better performance in predicting mortality rate than NLR.

Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) develops rapidly and has high mortality. ALI/ARDS is mainly manifested as acute or progressive hypoxic respiratory failure. At present, there is no effective clinical intervention for the treatment of ALI/ARDS. Mesenchymal stromal cells (MSCs) show promise for ALI/ARDS treatment due to their biological characteristics, easy cultivation, low immunogenicity, and abundant sources. The therapeutic mechanisms of MSCs in diseases are related to their homing capability, multidirectional differentiation, anti-inflammatory effect, paracrine signaling, macrophage polarization, the polarization of the MSCs themselves, and MSCs-derived exosomes. In this review, we discuss the pathogenesis of ALI/ARDS along with the biological characteristics and mechanisms of MSCs in the treatment of ALI/ARDS.

Characterisation of Progressive Skeletal Muscle Fibrosis in the Mdx Mouse Model of Duchenne Muscular Dystrophy: An In Vivo and In Vitro Study.

Duchenne muscular dystrophy (DMD) is a rare genetic disease leading to progressive muscle wasting, respiratory failure, and cardiomyopathy. Although muscle fibrosis represents a DMD hallmark, the organisation of the extracellular matrix and the molecular changes in its turnover are still not fully understood. To define the architectural changes over time in muscle fibrosis, we used an mdx mouse model of DMD and analysed collagen and glycosaminoglycans/proteoglycans content in skeletal muscle sections at different time points during disease progression and in comparison with age-matched controls. Collagen significantly increased particularly in the diaphragm, quadriceps, and gastrocnemius in adult mdx, with fibrosis significantly correlating with muscle degeneration. We also analysed collagen turnover pathways underlying fibrosis development in cultured primary quadriceps-derived fibroblasts. Collagen secretion and matrix metalloproteinases (MMPs) remained unaffected in both young and adult mdx compared to wt fibroblasts, whereas collagen cross-linking and tissue inhibitors of MMP (TIMP) expression significantly increased. We conclude that, in the DMD model we used, fibrosis mostly affects diaphragm and quadriceps with a higher collagen cross-linking and inhibition of MMPs that contribute differently to progressive collagen accumulation during fibrotic remodelling. This study offers a comprehensive histological and molecular characterisation of DMD-associated muscle fibrosis; it may thus provide new targets for tailored therapeutic interventions.

Fatal systemic disorder caused by biallelic variants in FARSA

BackgroundAminoacyl tRNA transferases play an essential role in protein biosynthesis, and variants of these enzymes result in various human diseases. FARSA, which encodes the α subunit of cytosolic phenylalanyl-tRNA synthetase, was recently reported as a suspected causal gene for multiorgan disorder. This study aimed to validate the pathogenicity of variants in the FARSA gene.ResultsExome sequencing revealed novel compound heterozygous variants in FARSA, P347L and R475Q, from a patient who initially presented neonatal-onset failure to thrive, liver dysfunction, and frequent respiratory infections. His developmental milestones were nearly arrested, and the patient died at 28 months of age as a result of progressive hepatic and respiratory failure. The P347L variant was predicted to disrupt heterodimer interaction and failed to form a functional heterotetramer by structural and biochemical analyses. R475 is located at a highly conserved site and is reported to be involved in phenylalanine activation and transfer to tRNA. The R475Q mutant FARSA were co-purified with FARSB, but the mutant enzyme showed an approximately 36% reduction in activity in our assay relative to the wild-type protein. Additional functional analyses on variants from previous reports (N410K, F256L, R404C, E418D, and F277V) were conducted. The R404C variant from a patient waiting for organ transplantation also failed to form tetramers but the E418D, N410K, F256L, and F277V variants did not affect tetramer formation. In the functional assay, the N410K located at the phenylalanine-binding site exhibited no catalytic activity, whereas other variants (E418D, F256L and F277V) exhibited lower ATPase activity than wild-type FARSA at low phenylalanine concentrations.ConclusionsOur data demonstrated the pathogenicity of biallelic variants in FARSA and suggested the implication of hypomorphic variants in severe phenotypes.

COVID-19 Infection in Pregnancy: A Review.

Coronavirus disease 2019 (COVID-19), which is a highly contagious viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a catastrophic effect on the world's demographics, resulting in more than 3.8 million deaths worldwide and establishing itself as the most serious global health crisis since the 1918 influenza pandemic. Several questions remain unanswered regarding the effects of COVID-19 disease during pregnancy. Although most infections are mild in high-risk populations, the severe disease frequently leads to intubation, intensive care unit admission, and, in some cases, death. Hormonal and physiological changes in the immune and respiratory systems, cardiovascular function, and coagulation may affect the progression of COVID-19 disease in pregnancy. However, the consequences of coronavirus infection on implantation, fetal growth and development, labor, and newborn health have yet to be determined, and, consequently, a coordinated global effort is needed in this respect. Principles of management concerning COVID-19 in pregnancy include early isolation, aggressive infection control procedures, oxygen therapy, avoidance of fluid overload, consideration of empiric antibiotics (secondary to bacterial infection risk), laboratory testing for the virus and co-infection, fetal and uterine contraction monitoring, prevention, and / or treatment of thromboembolism early mechanical ventilation for progressive respiratory failure, individualized delivery planning, and a team-based approach with multispecialty consultations. This review focuses on COVID-19 during pregnancy, its management, and the area where further investigations are needed to reduce the risk to mothers and their newborns.

Pentalogy of Cantrell Associated with Ectopia Cordis: A Case Report

Pentalogy of Cantrell is a congenital anomaly of the median mesodermal constructions with a poor prognosis. It is characterized by defects of the anterior diaphragm, the lower sternum, the abdominal wall, pericardium, and various congenital heart malformations. We present a case of ectopia cordis and Pentalogy of Cantrell in a newborn of a healthy 35-year-old woman with no history of embryotoxic exposure or smoking. The infant was first diagnosed with the anomaly in the second trimester of pregnancy and was delivered at 35 weeks of gestational age via a caesarian section. Shortly after birth, he was transferred to the neonatal intensive care unit (NICU) due to progressive respiratory failure, which ultimately, along with septicemia, led to infant death on the second day. In conclusion, the Pentalogy of Cantrell should be appropriately assessed for effective prenatal counseling and postnatal management with a multidisciplinary team; since infant survival assessment and early diagnosis give the parents the option of terminating the pregnancy.

EJS-3 How do we, as a society, respond to COVID-19?

In most cases of new coronavirus infection (COVID-19), sore throats and mild cold symptoms such as low fever last for about a week, and then gradually become mild. However, in some patients, coughing and high fever begin around one week after the onset of symptoms, and pneumonia occurs. In severe cases, progressive respiratory failure may occur and treatment with mechanical ventilation or extracorporeal membrane oxygenation may be required. In Japan, dexamethasone and baricitinib have been approved as immunomodulators to intervene in the process of cytokine release due to immune system dysregulation, which is the mechanism of severe disease.

Radiation Induced Lung Injury (RILI) and COVID-19 Pneumonia: Are There Similarities by The Radiation Oncologist’s Point of View?

Coronavirus disease 2019 (COVID-19), is a novel infectious disease responsible for a severe acute respiratory syndrome due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, which was firstly reported in January 2020 in Wuhan, Hubei Province, China, and then rapidly spread to other countries beyond China with a pandemic proportion in these last two years. In its severe lung expression, disease onset may result in death due to massive alveolar damage and progressive respiratory failure due to acute lung injury (ALI) which predisposes to fatal acute respiratory distress syndrome (ARDS). Autopsies reports describe a diffuse alveolar damage with vascular congestion, inflammatory cell population entrapped, thrombosis with hyaline membrane formation in the alveolar walls allowing to an irreversible lung destruction. Altogether these findings remind the radiation oncologists many similarities with radiation induced lung injury which is a well-known side effect of radiotherapy for lung cancer. A fascinating hypothesis is that a common inflammatory paradoxical response of lung could be underlying the injury whatever the causes may be, virus, drugs or ionizing radiation. In this paper we will review the similarities between these two illnesses just going through the mechanisms of ALI-ARDS and the role of the most important immune cells and cytokines involved.

PB2036: RISK AND PATTERN OF INFECTIONS IN NEWLY DIAGNOSED PATIENTS OF MULTIPLE MYELOMA VACCINATED UPFRONT AGAINST PNEUMOCOCCUS &amp; INFLUENZA

Background: Infections contribute to an early mortality risk of 15 percent in newly diagnosed multiple myeloma(NDMM) cases. There is a limited literature on the type of infections in fully vaccinated NDMM patients. Aims: To study epidemiology, clinical profile and predictors of infection in NDMM who are immunised against pneumococci and influenza. Methods: NDMM patients were prospectively studied for 6 months for the pattern of infections. All patients were vaccinated with pneumococcal and Influenza vaccine at diagnosis. PJP prophylaxis and fluconazole prophylaxis was given for patients receiving high dose steroids while acyclovir was given to all. Infections were classified as microbiologically defined, clinically defined and fever of unknown focus according to definitions published by the International Immunocompromised Host Society. Severity of infections were graded according to the NCI CTCAE Ver5. Results: Forty-eight NDMM patients with a median age 55 years comprising of 26 males and 22 females were enrolled. Renal involvement was noted in 42% of enrolled patients and two third of them required renal replacement therapy. ISSIII and R–ISS III were 70.8 % and 62.5 % respectively. 85% had poor performance status(ECOG ≥2) at baseline. RVD was the most common regimen (37%)used. 6 patients received daratumumab based regimen. Treatment response of atleast VGPR was seen in 97 % of NDMM patients. A total of 19 episodes of infections were observed during 6 months. All episodes of infections were reported in the first 45 of myeloma diagnosis(Median 6 days; Range 0–45). Ten of these episodes of infection were diagnosed during the initial evaluation for myeloma defining events. Microbiological diagnosis was possible in 63 %. Commonest infectious agent was COVID 19(n=8) followed by Gram negative bacteria (n=5) viz E.coli and Klebsiella pneumoniae. None of the eight patients who developed COVID 19 infection had received COVID vaccine as they antedated the operationalisation of national guidelines for immunisation. Respiratory and the urinary tract were the most common focus of infection. All critically ill COVID patients succumbed to progressive respiratory failure and all patients with mild and moderate COVID illness recovered uneventfully. Early mortality in our cohort of forty eight patients was twenty percent(n=10). Three fourths of infections in our cohort were Grade≥3 severity. A total of seven deaths were attributable to infectious diseases in this cohort of NDMM patients. Imune paresis was seen in eighty four percent of patients at diagnosis. On follow up at 6 months; immune paresis had persisted in only thirty seven percent. Regression analysis of variables with odds of infection is shown in Table 1 Baseline BMI<18.5 kg/m2; albumin<3g/dl and ISS or R–ISS stage ≥ 2 was found to be have statistically significant odds of predicting infection risk in the cohort of patients. The choice of myeloma regimen, presence of high risk cytogenetics and response to therapy did not correlate with increased odds of infection in our cohort. Image:Summary/Conclusion: Conclusion In this prospective study of NDMM patients vaccinated against pneumococci and influenza at baseline; infection attributable early mortality was 14.5 %. Advanced stage of presentation, hypoalbuminemia and baseline BMI < 18.5 kg/m2 correlated with increased odds of infection. COVID vaccination and COVID appropriate behavioural practices may mitigate COVID related outcomes including deaths in myeloma patients.

Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19.

COVID-19 is a highly infectious respiratory disease caused by a new coronavirus known as SARS-CoV-2. COVID-19 is characterized by progressive respiratory failure resulting from diffuse alveolar damage, inflammatory infiltrates, endotheliitis, and pulmonary and systemic coagulopathy forming obstructive microthrombi with multi-organ dysfunction, indicating that endothelial cells (ECs) play a central role in the pathogenesis of COVID-19. The glycocalyx is defined as a complex gel-like layer of glycosylated lipid–protein mixtures, which surrounds all living cells and acts as a buffer between the cell and the extracellular matrix. The endothelial glycocalyx layer (EGL) plays an important role in vascular homeostasis via regulating vascular permeability, cell adhesion, mechanosensing for hemodynamic shear stresses, and antithrombotic and anti-inflammatory functions. Here, we review the new findings that described EGL damage in ARDS, coagulopathy, and the multisystem inflammatory disease associated with COVID-19. Mechanistically, the inflammatory mediators, reactive oxygen species (ROS), matrix metalloproteases (MMPs), the glycocalyx fragments, and the viral proteins may contribute to endothelial glycocalyx damage in COVID-19. In addition, the potential therapeutic strategies targeting the EGL for the treatment of severe COVID-19 are summarized and discussed.

Successful treatment with steroid pulse therapy for a COVID-19 case with progressive respiratory failure during treatment for pleural metastasis of breast cancer

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients are at high risk for developing severe conditions if other comorbidities are present, such as advanced cancer. Although the regulation of immune response is thought to play an important role in the treatment of coronavirus disease 2019 (COVID-19), physicians often have difficulties in selecting the most appropriate treatment. Furthermore, the impact that interrupting breast cancer treatment due to a COVID-19 infection has on patient outcomes is still unknown. Herein we report a case of advanced breast cancer in a patient whose COVID-19 acute respiratory failure was successfully treated with minimal interruption to their anticancer therapy for recurrent breast cancer.Case presentationA 48-year-old woman developed carcinomatous pleurisy after curative surgery for breast cancer. One month after the initiation of targeted therapy with palbociclib and fulvestrant, the pleural effusion decreased, but soon after she developed a COVID-19 infection. Dexamethasone (8 mg/day) was administered due to a prolonged fever, but her respiratory symptoms got worse and pneumonia appeared on a computed tomography (CT) scan 7 days after hospitalization. Thus, steroid pulse therapy (methylprednisolone 1000 mg/day) was administered for 3 days. Her respiratory condition rapidly improved. Two weeks after hospital discharge, complete regression of pneumonia was confirmed on CT scan, and her targeted therapy was resumed at the same dose and strength. More than 6 months later, her metastatic disease remains stable while on the same treatment. Retrospective analysis of the patient's neutralizing antibodies found the neutralizing activity was low in the early stages of infection, but became high after recovery. This suggests the patient acquired an immunity to SARS-CoV-2 through the infection, despite having a mild myelosuppression due to treatment for recurrent breast cancer.ConclusionsSteroid pulse therapy is available worldwide, and may have an important role in cancer patients who develop severe pneumonia from SARS-CoV-2, by enabling them to avoid any long-term disruption to anticancer therapy. Moreover, it might also be useful when antiviral therapies lose their efficacy due to mutations of the virus, such as the Omicron variant. A critical element in cases such as this one is that treatment decisions are made by a team of specialists, including pulmonologists.

Spontaneous pneumothorax as a manifestation of COVID-19: A case report

Spontaneous pneumothorax (SP) is an uncommon complication of COVID-19, mostly in association with pre-existing lung conditions or under positive pressure ventilation. SP has been reported to occur in approximately 1% of the patients with COVID-19. We report here a case of a 47-year-old non-smoker gentleman without any pre-existing lung disease, who was admitted to our facility with fever, cough and shortness of breath and for 3 days with progressive worsening and chest pain over last 24 hours. Chest radiography revealed the diagnosis of right-sided pneumothorax with widespread patchy infiltrates on the left lung field. He was tested positive for COVID-19 and cultures for secondary bacterial infections were negative. A chest drain was secured and he was given antibiotics, steroid, heparin and remdesivir. However, the patient died within next 2 days due to progressive respiratory failure. This report emphasizes awareness of the possibility of SP as a complication of COVID-19; early identification and treatment of this entity may help decrease the associated mortality and morbidity. In conclusion, the possibility of SP should always be considered in the workup of a patient of SARS-CoV-2 infection having acute shortness of breath with or without chest pain. We would like to highlight this significant, though rare, presentation of COVID-19 and urge clinicians to maintain a high index of suspicion.

Spinal muscular atrophy: Surviving respiratory failure, intensive care and pursuing creatively fulfilled life.

Spinal muscular atrophy is a congenital condition associated with mutations in the SMN1 gene. Patients have normal intellectual development, but the natural history is progressive respiratory failure resulting in premature death. Diagnosed with spinal muscular atrophy type 2 in early primary school, the wheelchair-bound girl developed severe pneumonia on one occasion, when she became critically ill and was admitted to the paediatric intensive care unit with multiorgan dysfunction, requiring mechanical ventilation and high inotropic support. Parents and the patient expressed strong desire for full respiratory and intensive care support to be given. Survived the episode, she is wheelchair ambulatory and continues to pursue a creative artistic career. Children with SMA and their families need to be supported by a comprehensive multi-disciplinary team to manage this illness. Pediatricians and healthcare givers must provide up-to-date health advice on COVID-19 prophylaxis and management to special groups of patients with respiratory and neurological risks.

Recent SARS-CoV-2 infection: too early to vaccinate?

Recent SARS-CoV-2 infection: too early to vaccinate?

COVID-19, air quality and space monitoring.

Due to the worldwide spread of the coronavirus disease 2019 (COVID-19), human mobility and economic activity have slowed down considerably since early 2020. A relatively high number of those infected develop serious pneumonia leading to progressive respiratory failure, system disease and often death. Apart from close human-to-human contact, the acceleration and global diffusion of this pandemic has been shown to be associated with changes in atmospheric chemistry and air pollution by microscopic particulate matter (PM). Breathing air with high concentrations of nitrogen dioxide and PM can result in over-expression of the angiotensin converting enzyme-2 (ACE-2) leading to stress of organs, such as heart and kidneys. Satellite monitoring can play a crucial role in spatio-temporal surveillance of the disease by producing data on pollution as proxy for industrial activity, transport and traffic circulation. Real-time monitoring of COVID-19 in air and chemical pollution of the atmospheric boundary layer available from Earth-observing satellites commuting with Health Information Systems (HIS) would be useful for decision makers involved with public health.

192P Randomized, phase II, placebo-controlled trial of nintedanib for the treatment of radiation pneumonitis

Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. RP can cause substantial morbidity and often progresses to permanent fibrosis. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares many pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a standard prednisone taper compared to a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP. In this phase II, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib 150mg twice daily for 12 weeks or placebo, in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations within one year. Secondary endpoints included total number of exacerbations and pulmonary function tests (PFTs). Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbation. The study was closed early due to slow accrual. Thirty-four patients were enrolled, three patients withdrew consent, and one was not treated. Of the evaluable 30 patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to control Arm B (placebo + prednisone taper). Freedom from exacerbation at one year was 72% (CI 54%-96%) in Arm A and 40% (CI 20%-82%) in Arm B (one-sided p=0.037). In Arm A there were 16 G2+ adverse events possibly or probably related to treatment compared to five in the placebo arm. There were two deaths during the study period in arm A due to cardiac failure and progressive respiratory failure, respectively. No baseline patient characteristics were associated with freedom from exacerbations, and there were no statistically significant changes in PFTs between treatment arms. After the initial onset of G2+ RP, treatment with nintedanib plus prednisone taper improved freedom from pulmonary exacerbations at one year compared to placebo plus prednisone taper. These findings show promise for the use of nintedanib in the treatment of radiation pneumonitis.

Rare Immune Dysregulatory Disorder Leading to Lung Transplantation

<h3>Introduction</h3> Interleukin-12 receptor β1 is a common receptor chain of the pro-inflammatory cytokines IL-12 and -23. IL-12/IL-23Rβ1 deficiency is a rare autosomal recessive disorder characterized by predisposition to mycobacteria infections, whereas IL-12/IL-23Rβ1 gain-of-function mutation may cause a systemic disease that manifests as a chronic inflammatory condition and organ fibrosis. We describe the first case of lung transplantation (LTx) in lung-fibrosis due to this immune dysregulatory disorder. <h3>Case Report</h3> We present a 27-year-old patient diagnosed with gain-of-function mutation in IL-12/IL-23Rβ1. The disorder led to multi-organ involvement consisting of interstitial lung disease with secondary pulmonary hypertension, hepatitis, dermatosis and hepatosplenomegaly. Multiple immunosuppressive and modulating agents were tried without improving lung function. The patient showed no susceptibility to infections. With increasing pulmonary hypertension and progressive respiratory failure, he reached indication for LTx. Prior to listing, concerns were raised due to his exceptional pro-inflammatory immunodeficiency and potentially increased risk of rejection. After extended research and with few other treatment options left, LTx was performed in 2017 (ABO-compatible and negative crossmatch) with an uncomplicated perioperative course. He received standard immunosuppression with the goal of high cyclosporine level within standard target range. In his first year post-transplant he was treated 3 times successfully for minimal acute rejection and has since then had no further rejections. In 2018 he developed Candida dubliensis sepsis and osteomyelitis and was treated for 16 months. A pan-JAK-inhibitor was initiated, while mycophenolate was reduced and stopped, to try to inhibit a progressive sterile liver and bone inflammation. The regimen had remarkable effect on the patient`s general condition. Recurring CMV reactivation ensued and in 2020 also systemic Mycobacterium avium intracellulare infection, still requiring treatment. Pulmonary function is stable. <h3>Summary</h3> Our experience suggests that LTx is a valid option for this indication resulting in much improved quality of life. It remains challenging to find the right balance between treating the underlying disease while providing adequate immunosuppression to prevent rejection and avoiding infections.

Combined Lung-Liver Transplantation Can Be Safely Performed in Patients with Hypokalemic Periodic Paralysis

<h3>Introduction</h3> Combined lung-liver transplantation (CLLT) is rare and accounts for <0.01% of multiorgan transplants performed. Due to its infrequency, the criteria for CLLT candidacy have not been clearly elucidated. However, since post-transplant rehabilitation is critical for a successful outcome, any condition that may compromise a patient's postoperative mobility is considered a potential contraindication to transplantation. We report our experience with CLLT in a patient who had hypokalemic periodic paralysis (HPP), a rare genetic disorder that affects muscle ion channels and manifests as hypokalemia with episodes of severe weakness or paralysis. To our knowledge, we present the first reported case of transplantation in a HPP patient. <h3>Case Report</h3> The patient was a 63-year-old male with 7-year history of idiopathic pulmonary fibrosis and cryptogenic cirrhosis. Other comorbidities included HPP since childhood. His HPP exacerbations, which manifested as weakness without respiratory symptoms, were precipitated by various medications and were treated with correction of hypokalemia. He was previously declined for CLLT by 9 other programs due to his age and HPP, but our multidisciplinary team determined that the patient's HPP could be adequately managed and should not preclude him from CLLT. While hospitalized for progressive respiratory failure, donor organs became available. Bilateral lungs and a liver were recovered from a brain-dead donor. Bilateral lung transplantation was performed followed by orthotopic liver transplantation. There were no intraoperative complications. Standard post-transplant care was initiated after surgery. He was transferred out of the ICU on postoperative day (POD) #5, and was discharged to home on POD #22. The patient's postoperative hospitalization was complicated by antibody-mediated rejection (AMR) from <i>de novo</i> donor-specific antibodies. His AMR was adequately managed with methylprednisone, plasmapheresis, and intravenous immunoglobulins. Meticulously maintaining serum potassium levels above 4 mEq/L and avoiding precipitating medications sufficiently prevented any HPP exacerbations. The patient has been home for 8 months and has been doing well. <h3>Summary</h3> The limits on candidacy for CLLT have not been clearly defined, but we demonstrated for the first time that CLLT can be safely performed in patients with HPP.