Accelerating Tuberculosis Preventive Treatment among Tanzanians Living with Hiv

Background: People living with HIV (PLHIV) bear 20 times higher risk of acquiring tuberculosis (TB) compared to people without HIV. The World Health Organization recommends TB preventive treatment (TPT) for PLHIV to reduce this risk. However, according to the 2020 Global TB Report, only half of PLHIV were started on TPT globally in 2019, with the lowest coverage observed in low-income countries including Tanzania, where TPT provision is part of the standard of care for eligible PLHIV in Tanzania. We describe programmatic efforts to scale up TPT in 11 regions accounting for half of the 1.5 million PLHIV on ART in Tanzania. Method(s): Starting in 2018, PEPFAR, through the U.S. Centers for Disease Control and Prevention (CDC), supported the Government of Tanzania to accelerate TPT provision by: (1) training and mentoring healthcare workers, (2) integrating isoniazid into supply chain plans at the regional level, and (3) convening quarterly meetings at national and regional levels for program and supply chain monitoring and coordination. Additionally, CDC launched focused regional support interventions, with TPT among its priorities, aiming to facilitate real-time data-driven site monitoring, increased accountability, and on-the-ground coordination with local health authorities and implementing partners. We analyzed routine programmatic data reported in PEPFAR's data reporting system for fiscal years (FY) FY2018 through FY2021. Result(s): The number of PLHIV of all ages who initiated TPT increased from 67,510 in FY2018 to 268,909 in FY2019. Despite coinciding with the COVID-19 pandemic, the initiation numbers in FY2020 were sustained at 264,465 and dropped by about one-third in FY2021 (182,823) compared to the previous year. TPT completion rates among those initiated also showed a positive trend;38% in FY2018, 85% in FY2019, 90% in FY2020, and 91% in FY2021. Conclusion(s): Our findings demonstrate substantial acceleration of TPT initiation and a significant increase in TPT completion rates over the four-year period in 11 regions in Tanzania. The policy of once-in-a-lifetime TPT for PLHIV means fewer people are eligible for TPT over time, which might account for lower numbers of PLHIV initiated on TPT in FY2021. Completion remained high among those who initiated TPT. The strategic shift focusing on capacity building, supply chain strengthening, and site-level monitoring may have contributed to the improvements in TPT initiation and completion.

Successful matched unrelated donor hematopoietic stem cell transplantation for infantile Wolman disease

Introduction: Wolman disease is a rare genetic disorder with an autosomal recessive inheritance. A mutation in the LIPA gene causes lysosomal acid lipase (LAL) deficiency results in lipid storage and adrenal insufficiency. Death in early infancy is due to liver failure. Patients and methods: We describe the clinical course of a three-month-old infant diagnosed with Wolman disease. A rapid mutational analysis confirmed a LIPA gene defect. Results: He underwent matched unrelated donor peripheral blood stem cell hematopoietic stem cell transplantation (HSCT) at 3 months of age, with a treosulfan-based conditioning, which resulted in engraftment with donor-derived hematopoietic cells. He required supportive care for sinusoidal obstruction syndrome and mucositis. He was administered low dose prednisolone for grade I skin graft versus host disease, and a complete donor chimerism was documented on several occasions. At one year post HSCT, his growth and development were optimal, and there was no hepatosplenomegaly. He is maintained on glucocorticoid and mineralocorticoid supplements for primary hypoaldosteronism. Conclusion: The case emphasizes the timely diagnosis and the potential for successful treatment of Wolman disease by HSCT. © 2022 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics

Synthesis, antitubercular evaluation, and molecular docking studies of hybrid pyridinium salts derived from isoniazid.

In the quest to develop potent inhibitors for Mycobacterium tuberculosis, novel isoniazid-based pyridinium salts were designed, synthesized, and tested for their antimycobacterial activities against the H37 Rv strain of Mycobacterium tuberculosis using rifampicin as a standard. The pyridinium salts 4k, 4l, and 7d showed exceptional antimycobacterial activities with MIC90 at 1 µg/mL. The in vitro cytotoxicity and pharmacokinetics profiles of these compounds were established for the identification of a lead molecule using in vivo efficacy proof-of-concept studies and found that the lead compound 4k possesses LC50 value at 25 µg/mL. The in vitro antimycobacterial activity results were further supported by in silico studies with good binding affinities ranging from -9.8 to -11.6 kcal/mol for 4k, 4l, and 7d with the target oxidoreductase DprE1 enzyme. These results demonstrate that pyridinium salts derived from isoniazid can be a potentially promising pharmacophore for the development of novel antitubercular candidates.

Not always COVID - pulmonary BCGosis as an unexpected cause of severe respiratory failure and massive ground glass opacities in the lungs

Introduction: Instillations with balcillus Calmette - Guerin (BCG) are established adjuvant therapy for superficial bladder cancer. Although generally safe and well tolerated, they may cause a range of different, local, and systemic complications. Case description: We present a patient treated with BCG instillations for three years, who was admitted to our hospital due to fever and progressive dyspnea. Blood test revealed elevated CRP and liver function tests. On CT scan massive bilateral ground glass opacities in the middle and lower parts of the lungs, parenchymal infiltrations, bronchial walls thickening, and hilar lymphadenopathy were visible. PCR test for SARS-CoV-2 as well as sputum, blood, and urine cultures were negative. Initial empiric antibiotic therapy was ineffective and respiratory failure progressed with the need of oxygen supplementation of 15l/min. Finally, positive cultures for M. tuberculosis ssp. bovis (BCG) were available from sputum and bronchoalveolar lavage fluid. Antituberculous treatment (rifampin, isoniazid, etambuthol) was implemented together with systemic corticosteroids resulting in the quick improvement of the patient's clinical condition. Due to hepatotoxicity and finally reported resistance of the BCG strain to isoniazid, it was replaced with levofloxacin with a good tolerance. Follow up CT scan showed partial resolution of the infiltrates. The patient was discharged home and continued treatment without further side effects. Conclusion(s): The diagnosis of BCG infection in the lungs must be taken into consideration in every patient treated with BCG instillations and symptoms of unexplained infection.

An unusually fulminant case of encephalomyelitis in an 80 year old

Background: There have been reports of demyelinating syndromes in association with COVID-19 and to a much lesser extent COVID 19 vaccines. The association between demyelination and vaccines, in general, remains controversial. We review a presentation of fulminant demyelination, and discuss antecedent COVID-19 vaccination, the formulation of a broader differential diagnosis and ultimately the pathologic diagnosis. Case presentation: An 80-year-old woman presented with seizure, encephalopathy, quadriparesis and ultimately expired. She received a SARS-CoV-2 vaccine one day prior. Imaging revealed contrast enhancing cerebral lesions, longitudinally extensive transverse myelitis. CSF was markedly inflammatory. Pathologic examination of the CNS lesions revealed demyelination and inflammation beyond white matter, not restricted to a perivenular distribution. Conclusion(s): This case depicts a seemingly fulminant course of a diffuse demyelinating syndrome characterized clinicopathologically as Marburg's variant of multiple sclerosis. There are several unique aspects of this case including the extremely rapid course, the unusual evolution of CSF abnormalities, with hypoglycorrhachia and markedly elevated protein. The proximity to vaccination is a pertinent association to document, though we cannot unequivocally prove causation.Copyright © 2022 The Authors

New antidepressants: monoamines and beyond

The monoamine hypothesis of depression has dominated treatment for decades, but for some with treatment-resistant depression, alternative approaches are needed. This article discusses some of the other mechanisms involved in depression and how novel treatments could address these.Copyright © 2023 Wiley Interface Ltd.

N'-isonicotinoylpicolinohydrazonamide: Synthesis, crystal structure, DFT and ADMET studies, and in silico inhibition properties toward a series of COVID-19 proteins

In this work, synthesis as well as detailed structural and computational analyses of the novel isoniazid derivative, namely N'-isonicotinoylpicolinohydrazonamide (1), are reported. The obtained compound was examined by microanalysis, IR, 1H NMR spectroscopy and single crystal X-ray diffraction. The crystal packing was studied by the Hirshfeld surface analysis. Molecules in the crystal structure of 1 are linked through N–H⋯O and N–H⋯N hydrogen bonds, and π⋯π interactions, yielding a 1D supramolecular chain. According to the Hirshfeld surface analysis, crystal packing of 1 is primarily dictated by H⋯H, H⋯C, H⋯N and H⋯O contacts, of which the latter three contacts are highly favoured. The crystal packing is further characterized by highly favoured C⋯C contacts. Compound 1 was also studied using DFT in gas phase, which revealed its pronounced electrophilic features. The most electron-rich (nucleophilic) sites were revealed for the carbonyl oxygen atom, and 4-pyridyl and imine nitrogen atoms, while the most electron-deficient (electrophilic) sites were found for the NH and NH2 hydrogen atoms. Compound 1 was predicted to belong to a fourth class of toxicity and exhibits negative blood–brain barrier penetration and positive gastrointestinal absorption property. In silico molecular docking was applied to probe 1 as a potential inhibitor of a series of the SARS-CoV-2 proteins and it was found that 1 is potentially active against all the applied proteins with the best activity against Nonstructural protein 3 (Nsp3_range 207–379-MES). It was also established that the best docking scores for 1 were found for the cavities, where initial ligands were located, except for the Papain-like protease (PLpro). The best binding affinity of the latter protein with 1 was revealed for the other cavity with about 0.8 kcal/mol being more efficient. Molecular dynamics simulations were also applied to evaluate the stability of complexes PLproI–1, PLproII–1 and Nsp_range 207–379-MES–1. Complex PLproI–1 was found to be highly unstable, while complexes PLproII–1 and Nsp_range 207–379-MES–1 are stable. © 2023 Elsevier Ltd

Reactivation of Tuberculosis and COVID-19 in Pediatric Patients

Objective Mycobacterium tuberculosis is an immobile aerobic bacillus that causes tuberculosis (TB) disease. We aimed to evaluate the association between coronavirus disease 2019 (COVID-19), COVID-19-related drugs, TB reactivation, and TB incidence during the pandemic. Methods Eight patients who were diagnosed as having TB in Meram Medical Faculty, Necmettin Erbakan University between March 1, 2020, and December 31, 2021, at the beginning of the pandemic, were enrolled in this study. The presence of COVID-19 infection was confirmed using COVID-19 antibody tests and the patients' COVID-19 history. We evaluated the demographic data, laboratory findings, imaging tests, and pathology results of all patients. Results We checked all our patients with TB using COVID-19 antibodies (immunoglobulin [Ig]G + IgM) or polymerase chain reaction. Seven of the eight patients were female (87.5%). The median age was 16 years. Family screening of all patients was negative, and they had bacillus Calmette-Guerin vaccine scars. Two patients had chronic diseases. One was diagnosed as having primary ciliary dyskinesia in our department (patient no. 8) and the second was under follow-up by the rheumatology department with a diagnosis of juvenile idiopathic rheumatoid arthritis. Conclusion There has been an increase in the incidence of TB in children, especially in adolescents, during the pandemic period. This may be due to the pathogenic structure of the COVID-19 virus with an unknown mechanism. In addition, lifestyle changes and changes in health care policies during the pandemic may have caused this. Further research should be performed on this topic.Copyright © 2023 Authors. All rights reserved.

Genetic diversity of Mycobacterium tuberculosis isolates from northwest of Iran during COVID-19 era

Background: Tuberculosis (TB) is considered one of the most infectious diseases in the world. In this study, we intended to examine the epidemiology of tuberculosis by MIRU-VNTR to define the changes that occur in the transmission of tuberculosis in the region during the COVID-19 era. A total of 120 Mycobacterium tuberculosis isolates were collected from sputum samples of patients referred to East Azerbaijan Center TB from December 2020 to August 2021. Demographic information such as age, sex, place of birth, previous TB history, and relevant medical data was collected. The proportion method was performed for drug susceptibility testing, and the PCR-based MIRU-VNTR method was applied to identify molecular epidemiology relationships. Result(s): The isolates were collected from 78 male (65%) and 39 female (32.5%) Iranian patients and 3 (2.5%) Azerbaijani patients. Ninety-three distinct patterns were identified including 15 clustered patterns and 36 unique patterns. The largest cluster was composed of seven isolates. Furthermore, one cluster with 5 members, four clusters with 3 members, and nine clusters with 2 members. In MIRU-VNTR typing, 75 clusters belonged to the Tabriz region and just 3 to the Republic of Azerbaijan. All isolates were sensitive to rifampin, isoniazid, and ethambutol. Conclusion(s): Results of the current study showed COVID-19 pandemic had a direct effect on the transmission and diagnosis of tuberculosis. Less diagnosis and less clustering can indicate public controls and hygiene, and the use of masks had a direct effect on the transmission and diagnosis of tuberculosis. However, misidentification and less focus on other respiratory infections are expected during the pandemic. Studies on the co-infection of COVID-19 and tuberculosis and the role of mask and sanitization against TB are strongly recommended. Copyright © 2023, The Author(s).

The impact of the COVID-19 pandemic in tuberculosis preventive treatment in Brazil: a retrospective cohort study using secondary data.

Background: Disruptions in tuberculosis services have been reported around the world since the emergence of the COVID-19 pandemic. However, the pandemic's effect on tuberculosis preventive treatment (TPT) has been poorly explored. We compared TPT-notified prescriptions and outcomes before and during the pandemic in Brazil. Methods: Retrospective cohort using secondary data from the Brazilian TPT information system in five cities with over 1000 notifications. The number of TPT prescriptions was analysed from 6 months after healthcare workers' training, in 2018, to July 2021. The proportion of TPT outcomes by the date of treatment initiation was analysed up to the end of 2020, as most outcomes of TPT started in 2021 were still unknown in July 2021. Joinpoint regression was used to evaluate trends. Findings: 14,014 TPT prescriptions were included, most from São Paulo (8032) and Rio de Janeiro (3187). Compared to the same epidemiological weeks in 2019, the number of TPT prescribed in 2020 increased in Rio de Janeiro (82%) and São Paulo (14%) and decreased in Recife (65%), Fortaleza (31%) and Manaus (44%). In 2021, however, there was a 93% reduction in TPT prescriptions in all cities. The proportion of completed TPT remained constant (median = 74%). Interpretation: The COVID-19 pandemic in Brazil was associated with a dramatic decrease in TPT prescriptions in 2021. Treatment adherence remained constant, suggesting that health services were able to keep people on treatment but did not perform well in providing opportunities for people to enter care. Efforts are needed to expand access to TPT. Funding: Brazilian Ministry of Science, Technology and Innovation, CNPq.

Genetic diversity of Mycobacterium tuberculosis isolates from northwest of Iran during COVID-19 era

BackgroundTuberculosis (TB) is considered one of the most infectious diseases in the world. In this study, we intended to examine the epidemiology of tuberculosis by MIRU-VNTR to define the changes that occur in the transmission of tuberculosis in the region during the COVID-19 era. A total of 120 Mycobacterium tuberculosis isolates were collected from sputum samples of patients referred to East Azerbaijan Center TB from December 2020 to August 2021. Demographic information such as age, sex, place of birth, previous TB history, and relevant medical data was collected. The proportion method was performed for drug susceptibility testing, and the PCR-based MIRU-VNTR method was applied to identify molecular epidemiology relationships.ResultsThe isolates were collected from 78 male (65%) and 39 female (32.5%) Iranian patients and 3 (2.5%) Azerbaijani patients. Ninety-three distinct patterns were identified including 15 clustered patterns and 36 unique patterns. The largest cluster was composed of seven isolates. Furthermore, one cluster with 5 members, four clusters with 3 members, and nine clusters with 2 members. In MIRU-VNTR typing, 75 clusters belonged to the Tabriz region and just 3 to the Republic of Azerbaijan. All isolates were sensitive to rifampin, isoniazid, and ethambutol.ConclusionsResults of the current study showed COVID-19 pandemic had a direct effect on the transmission and diagnosis of tuberculosis. Less diagnosis and less clustering can indicate public controls and hygiene, and the use of masks had a direct effect on the transmission and diagnosis of tuberculosis. However, misidentification and less focus on other respiratory infections are expected during the pandemic. Studies on the co-infection of COVID-19 and tuberculosis and the role of mask and sanitization against TB are strongly recommended.

TB DURING THE SEROCONVERSION PHASE

SESSION TITLE: TB and TB-Involved Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Patients who are HIV positive have a high risk of co-infection with tuberculosis (TB). Screening tests for HIV identify antibodies that are present during the seroconversion, or window phase. Here we present a case of reactivation TB during the seroconversion phase of HIV with an initially negative QuantiFERON test. CASE PRESENTATION: A previously healthy 24-year-old female presented with a productive cough. She was found to have leukopenia and apical consolidation on chest CT and was treated for community-acquired pneumonia with mild improvement of symptoms. Her QuantiFERON, COVID-19, and HIV antibody screen were negative;however, her reflex HIV antigen was positive. She re-presented a month later with a worsening cough, drenching night sweats, weight loss, vomiting, and dysphonia. Her chest CT noted a right apical cavitary lesion and bilateral upper lobe micronodules with endobronchial spreading. Her QuantiFERON and HIV antibody were now both positive. She was started on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) therapy and on raltegravir and emtricitabine/tenofovir. DISCUSSION: Above we describe a case of reactivation TB during the seroconversion phase of HIV with a negative QuantiFERON. Primary TB presents in the middle lobes without signs of structural damage whereas secondary TB typically involves the apices and presents with cavitation. Secondary TB is typically due to reactivation or reinfection in immunosuppressed patients. Although we believe this case is due to reactivation due to radiographic findings, her initial QuantiFERON was negative. However, studies have shown that QuantiFERON may have uncertain results in latent TB infections in patients with underlying HIV (1). Reliable testing for latent TB in HIV-positive individuals is necessary as HIV increases the risk of developing active TB and TB increases the risk of transitioning from HIV to AIDS (2). CONCLUSIONS: TB is one of the top 10 causes of death worldwide and HIV is a common coinfection. To the best of our knowledge, this is the first published report of reactivation TB during the seroconversion phase of HIV with an initially negative QuantiFERON. Overall, more research must be done to identify the risk of infections during the seroconversion phase and physicians must be able to identify radiographic findings concerning for TB in patients with underlying HIV. Reference #1: Elisa Petruccioli, Teresa Chiacchio, Elisa Petruccioli, et al. Effect of HIV-infection on QuantiFERON-plus accuracy in patients with active tuberculosis and latent infection, Journal of Infection, 2020;80(5): 536-546. https://doi.org/10.1016/j.jinf.2020.02.009. Reference #2: Bruchfeld, Judith et al. "Tuberculosis and HIV Coinfection.” Cold Spring Harbor perspectives in medicine vol. 5,7 a017871. 26 Feb. 2015, doi:10.1101/cshperspect.a017871 Reference #3: Johnson JL, Okwera A, Hom DL, et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS. 2001;15(16):2137-2147. doi:10.1097/00002030-200111090-00009 World Health Organization. Tuberculosis [Internet]. 2021 [cited 2022 Mar. 15];Available from: https://www.who.int/news-room/fact-sheets/detail/tuberculosis DISCLOSURES: No relevant relationships by Loor Alshawa No relevant relationships by Angela Binkowski No relevant relationships by Sara Qutubuddin

MISSED TB DIAGNOSIS DURING THE COVID-19 PANDEMIC: MYTH OR REAL

SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Miliary Tuberculosis (TB) is a rare disorder caused by the hematogenous dissemination of Mycobacterium tuberculosis. Patients infected with Mycobacterium tuberculosis can develop Miliary TB from primary infection or reactivation of a latent infection. Many patients with Miliary TB will present with symptoms of classic tuberculosis and in the pandemic time overlaps with symptoms of Covid-19. Since the Covid-19 pandemic the reported TB diagnosis fell 20% in 2020 and remained 13% lower in 2021 as compared to pre-COVID-19 pandemic. Decrease in cases may be due to pandemic-related mitigation efforts, such as social distancing and wearing masks. CASE PRESENTATION: This patient is a 23-year-old undocumented male who presented to the ED, originally in January of 2021, with complaints of generally not feeling well. He reported feeling feverish and having a poor appetite for the past 2 weeks. At this visit, the patient received testing for COVID-19, Influenza and strep;all of which were negative. He was then discharged home and instructed to follow-up outpatient. In July of 2021, the patient again presented to the ED with complaints of weakness, fevers, cough, and weight loss that have progressively worsened. A chest x-ray and CT chest were performed at this time which were positive for innumerable bilateral upper lobe predominant peri-bronchial vascular nodular airspace opacities and patchy areas of consolidation with central cavitation, highly suspicious for tuberculosis. A QuantiFERON gold test was ordered and the patient underwent bronchoscopy. After 2 weeks of hospitalization, a NAAT test came back positive for Tuberculosis. At this point, the patient was immediately started on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE). The patient received 2 weeks of RIPE treatment and after being hospitalized for 1 month, he was then discharged home on RIPE therapy with strict instructions to follow-up outpatient. DISCUSSION: Similarities in symptoms of TB and COVID-19 may mean that some people who have TB are being evaluated for COVID-19, but not tested for TB. The case was very unusual in that the infection of TB went undiagnosed during his initial emergency department (ED) during the Pandemic surges. It had not been discovered until presenting to the ED 5 months later with worsening symptoms. In presenting this case, we hope to further education on Miliary TB and prevent future missed diagnoses given the extremely infectious nature of the disease. CONCLUSIONS: The 2020 and 2021 declines may be related to factors associated with the COVID-19 pandemic like similarities in symptoms between COVID-19 and TB disease may have led to missed TB diagnoses;widespread disruptions to healthcare during the COVID-19 pandemic may have delayed TB diagnoses;and Efforts to prevent COVID-19, such as wearing masks and staying six feet away from others, may also reduce the spread of TB. Reference #1: Masahiro Narita, Grace Hatt, Katelynne Gardner Toren, Kim Vuong, Monica Pecha, John A Jereb, Neela D Goswami, Delayed Tuberculosis Diagnoses During the Coronavirus Disease 2019 (COVID-19) Pandemic in 2020—King County, Washington, Clinical Infectious Diseases, Volume 73, Issue Supplement_1, 15 July 2021, Pages S74–S76, https://doi.org/10.1093/cid/ciab387 Reference #2: Cleverley J, Piper J, Jones MM. The role of chest radiography in confirming COVID-19 pneumonia. BMJ 2020;370 : m2426. Reference #3: https://www.cdc.gov/media/releases/2022/s0324-tuberculosis-covid-19.html DISCLOSURES: No relevant relationships by Nawal Aamir No relevant relationships by Gabrielle Gerbino

REACTIVATION MILIARY TB IN THE SETTING OF POSTINFECTIOUS COVID-19 LUNGS

SESSION TITLE: Pathologies of the Post-COVID-19 World SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Tuberculosis, caused from infection by M. tuberculosis, affects 2.7 per 100,000 people in the United States. 1 Miliary, or disseminated, TB is a progressive disease characterized by lymphohematogenous dissemination of TB infection that occurs in only 1-2% of TB cases. Little research has gone into pulmonary complications post recovery from COVID-19 infection, especially reactivation of latent TB. Here we present a case of reactivation of latent TB and progression to miliary TB in the setting of post COVID infection. CASE PRESENTATION: A 49-year-old male presented to the ER with fever, shortness of breath, and chest pain. His CXR showed diffuse bilateral, multifocal infiltrates and laboratory testing later came back positive for COVID-19. Two days later, he came back to the ED with acute respiratory failure with 87% oxygen saturation with ambulation. A CT chest done that showed diffuse lung disease consistent with COVID-19 infection, and a right upper lobe lesion likely a granuloma (image 1). He was treated for COVID pneumonia for ten days in the hospital with Decadron, Lasix, and tocilizumab. He required high flow nasal canula during the hospitalization and was discharged when his respiratory status had improved. One year later, he returns with few days of hemoptysis, fever, and chills. He had a progressive cough and 19 pound weight loss overt the last month. Clinically, he appeared mildly diaphoretic without acute distress. He had a room-air oxygen saturation of 95% without labored respiration and did not have increased oxygen demand. CT of the showed diffuse pulmonary parenchymal abnormalities and uniform nodular consolidative changes in the upper lobes bilaterally with areas of cavitation and multiple areas of lung parenchymal changes consistent with miliary TB (image 2). Sputum culture was positive for acid-fast bacilli, and he was started on RIPE therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. He was symptomatically improved within one week of admission and was hospitalized until three negative sputum cultures were drawn. DISCUSSION: This case report gives us novel understanding of the extent of possible complications post recovery from COVID-19 infection. We have already started to see many patients who have recovered from an initial COVID infection, but progressed to secondary lung disease due to this. In our patient particularly, during his initial presentation he was seen to have upper lobe granulomatous disease with concern for latent TB. It is likely that due to the extent of damage done to his lung parenchyma over time it led to reactivation of his latent TB. As we see more patients recovering from COVID infections, we are likely to see more of similar cases of latent infection reactivation. CONCLUSIONS: Patients with latent TB are likely at a high risk of reactivation post recovering from COVID-19 infection, due to immunosuppression and lung parenchymal damage Reference #1: Trends 2019 ;Data & Statistics ;TB ;CDC. Cdc.gov. https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm. Published 2021. Accessed September 25, 2021. Reference #2: Rodriquez-Morales AJ et al. Clinical, laboratory, and imaging features of COVID-19: a systemic review and meta-analysis. Travel Med Infect Dis. 34: 101623 Reference #3: Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA. 1994;271(9):698-702 DISCLOSURES: No relevant relationships by Sharmin Asha No relevant relationships by Heather Bernstein no disclosure on file for zachary brittingham;no disclosure on file for Vedee Ramdass;

Secondary Failure of Tocilizumab in Treating Elderly-Onset Rheumatoid Arthritis With Systemic Symptoms Complicated by Diverticulum Perforation.

The treatment of rheumatoid arthritis (RA) has advanced from the use of steroids to disease-modifying anti-rheumatic drugs (DMARDs) and biologics such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) inhibitors. Historically, steroids have been the mainstream in the clinical treatment of RA; however, the development of DMARDs has changed the RA treatment structure. In addition, biologics can alleviate RA symptoms. This case report describes the secondary failure of tocilizumab in treating RA with fatigue symptoms. Treatment with tocilizumab decreases C-reactive protein (CRP) levels, which may make detecting RA exacerbation difficult; therefore, obtaining the patient's precise history and thorough physical examinations are necessary. This case demonstrates the complexity of treating elderly-onset RA and reports practical methods for effective treatment.

COVID-19 Infection in Heart Transplant Recipients: Results of a Six-Month Prospective Survey-Based Study

Solid-organ transplantation recipients were assumed highly vulnerable to coronavirus disease 2019 (COVID-19). However, the results of previous studies in patients with orthotopic heart transplantation (OHT) under immunosuppressive therapy are contradictory. Therefore, we aimed to assess the prevalence of COVID-19 infection and associated risk factors, along with the six-month outcomes in COVID-19 positive OHT patients. This single-center telephone-based survey was conducted on OHT patients. Using a detailed questionnaire, exposure to COVID-19, related symptoms, and preventive self-care measures were collected. Outcomes of COVID-19-positive patients were reassessed using another survey six months later. 118 OHT patients (male: n=87, 73.7%) were included with a mean age of 45.3±13.1 years. Sixteen patients (13.5%) reported one or more symptoms compatible with COVID-19, of whom 12 (10.2%) tested positive. Our results indicated no statistically significant association between COVID-19 and comorbidities. Poor adherence to self-care measures and contact with positive index cases were both significantly associated with COVID-19 infection (P<0.001). A later six months follow-up showed that two out of 12 (16.6%) COVID-19 positive OHT patients died. There was no statistically significant difference between the prevalence of COVID-19 in our patients compared to Iran’s general population (P=251.0). Non-compliance with personal protective protocols and a history of contact with COVID-19 cases were the most risk factors for COVID-19 infection in OHT patients.

Primary Isoniazid Mono-Resistant Pulmonary Tuberculosis in a COVID-19-Positive Male: World's First Case of Its Kind in the Present Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in numerous rare presentations of common diseases. The diseases that were prevalent for a long time like tuberculosis (TB) have been reported in cases of COVID-19. The reports of drug-sensitive, multidrug-resistant, and pre-extensively drug-resistant TB with COVID-19 are available in the medical literature. The situation in high TB burden countries where TB is a great contributor to morbidity and mortality is grisly. Herein, a case of primary isoniazid mono-resistant pulmonary tuberculosis in a COVID-19-positive Indian male is reported. As far as the literature is concerned, no case similar to our index case is ever reported.

SYSTEMATIC LITERATURE REVIEW on the SCREENING and PROPHYLAXIS of CHRONIC and OPPORTUNISTIC INFECTIONS

Background: Opportunistic and chronic infections can arise in the context of treatment used for Autoimmune Rheumatic Diseases (ARDs). Although it is recognized that screening procedures and prophylactic measures must be followed, clinical practice is largely heterogeneous, with relevant recommendations not currently developed or disparately located across the literature. Objectives: To conduct a systematic literature review (SLR) focusing on the screening and prophylaxis of opportunistic and chronic infections in ARDs. This is preparatory work done by members of the respective EULAR task force (TF). Methods: Following the EULAR standardised operating procedures, we conducted an SLR with the following 5 search domains;1) Infection: infectious agents identifed by a scoping review and expert opinion (TF members), 2) Rheumatic Diseases: all ARDs, 3) Immunosuppression: all immunosuppressives/immunomodulators used in rheumatology, 4) Screening: general and specifc (e.g mantoux test) terms, 5) Prophylaxis: general and specifc (e.g trimethop-rim) terms. Articles were retrieved having the terms from domains 1 AND 2 AND 3, plus terms from domains 4 OR 5. Databases searched: Pubmed, Embase, Cochrane. Exclusion criteria: post-operative infections, pediatric ARDs, not ARDs (e.g septic arthritis), not concerning screening or prophylaxis, Covid-19 studies, articles concerning vaccinations and non-Εnglish literature. Quality of studies included was assessed as follows: Newcastle Ottawa scale for non-randomized controlled trials (RCTs), RoB-Cochrane tool for RCTs, AMSTAR2 for SLRs. Results: 5641 studies were initially retrieved (Figure 1). After title and screening and removal of duplicates, 568 full-text articles were assessed for eligibility. Finally, 293 articles were included in the SLR. Most studies were of medium quality. Reasons for exclusion are shown in Figure 1. Results categorized as per type of microbe, are as follows: For Tuberculosis;evidence suggests that tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic DMARDs (csDMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. Conversion of TST/IGRA occurs in about 10-15% of patients treated with biologic DMARDs (bDMARDs). Various prophylactic schemes have been used for latent TB, including isoniazide for 9 months, rifampicin for 4 months, isoniazide/rifampicin for 3-4 months. For hepatitis B (HBV): there is evidence that risk of reactivation is increased in patients positive for hepatitis B surface antigen. These patients should be referred for HBV treatment. Patients who are positive for anti-HBcore antibodies, are at low risk for reactivation when treated with glucocorticoids, cDMARDs and bDMARDs but should be monitored periodically with liver function tests and HBV-viral load. Patients treated with rituximab display higher risk for HBV reactivation especially when anti-HBs titers are low. Risk for reactivation in hepatitis C RNA positive patients, treated with bDMARDs is low. However, all patients should be referred for antiviral treatment and monitored periodically. For pneumocystis jirovecii: prophylaxis with trimeth-oprim/sulfamethoxazole (alternatively with atovaquone or pentamidine) should be considered in patients treated with prednisolone: 15-30mg/day for more than 4 weeks. Few data exist for screening and prophylaxis from viruses like E B V, CMV and Varicella Zoster Virus. Expert opinion supports the screening of rare bugs like histoplasma and trypanosoma in patients considered to be at high risk (e.g living in endemic areas). Conclusion: The risk of chronic and opportunistic infections should be considered in all patients prior to treatment with immunosuppressives/immunomod-ulators. Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics. Collaboration between different disciplines is important.

Mixing NA variants in an antigen presenting cell-targeted DNA vaccine elicits cross-reactive influenza antibody responses

Vaccination is a successful tool against influenza. However, antigenic drift of the virus requires an annual update of the vaccine. A universal vaccine approach which can elicit immune responses reactive to ideally all seasonal as well as zoonotic influenza strains is urgently needed. To explore this we used a flexible DNA vaccine platform, increasing immunogenicity by targeting dimeric vaccine molecules to antigen-presenting cells (APCs). We hypothesize that when including multiple antigen variants from different influenza strains in one heterodimeric APC-targeted mix DNA vaccine, antibody responses can be focused on conserved epitopes which are shared between the different variants. Neuraminidase (NA) is the second most abundant surface protein on the influenza virus after hemagglutinin and has been established as an independent correlate of protection. We have previously shown that an APC-targeted DNA vaccine with NA induced highly protective antibody responses. NA is divided into 9 different subtypes (N1-N9), and two NA-like antigens in bats (N10 and N11). Here, we created a NA mix vaccine which successfully expressed heterodimeric vaccine molecules with 8 different NA variants (N2-N9) that were targeted to MHC class II on APCs. Upon intramuscular DNA immunization and electroporation in mice, the NA mix vaccine induced cross-reactive antibody responses towards N1, which was not included in the vaccine. The NA mix approach has the potential to fill knowledge gaps about NA immunity and would be a great advancement in universal vaccine design for influenza as well as for other emerging and rapidly changing viruses. WS5.4 ;SARS-CoV- 2- specific T cell responses to COVID-19 BNT162b2 vaccination in chronic lymphocytic leukaemia patients Lisa Blixt1,2;David Wullimann2;Soo Aleman1,2;Jeanette Lundin1,2;Puran Chen2;Yu Gao2;Angelica Cuapio2;Mira Akber2;Joshua Lange2;Olga Rivera-Ballesteros2;Marcus Buggert2;Hans-Gustaf Ljunggren2;Anders Hansson;Lotta1,2;Österborg1,2 1Karolinska University Hospital;Stockholm, Sweden;2Karolinska Institutet, Stockholm, Sweden Immunocompromised patients have an increased risk for severe disease and mortality from viral infection. Importantly, disease and treatment reduce humoral and cellular immune responses to vaccination, which offer the best protection from severe COVID-19 disease during the ongoing pandemic. We recently reported from a prospective clinical trial that BNT162b2 vaccination in different immunodeficient groups had significantly lower SARS-CoV- 2- specific antibody titers compared to healthy controls. The seroconversion rate observed was 63% in chronic lymphocytic leukaemia (CLL) patients, with a negative impact of ibrutinib treatment. Whether T cells in the absence of sufficient levels of SARS-CoV- 2- specific antibody titers can confer immunity after BNT162b2 vaccination remains unclear. We measured reactive SARS-CoV- 2- specific T cell responses in uninfected (naive) and previously infected CLL patients following BNT162b2 vaccination. Out of 52 naive CLL patients, 12 (29%) had a specific IFN-γ T cell response compared to 24/41 (59%) in controls after two doses. In previously infected CLL patients, mainly spike-specific CD8 T cells expanded after the third dose, at which 11/12 (92%) had detectable responses, and all 12 (100%) had spike-specific CD4 T cell responses. Relative to the Wuhan reference strain (wild-type) variant, the median reduction of antigen-specific CD8 and CD4 T cells to the B.1.1.529 (Omicron) variant were 51% and 13%, respectively. Collectively, these data indicate that CLL patients respond with T-cells specific to SARS-CoV- 2 spike protein after BNT162b2 vaccination or infection. The increased T-cell response rate after the third dose and ability to recognize the Omicron variant of concern demonstrates the importance of a booster dose in this patient group.

CLUSTER RCT of A MID-LEVEL MANAGER INTERVENTION to PROMOTE IPT UPTAKE in UGANDA

Background: Despite longstanding guidelines endorsing isoniazid preventive therapy (IPT) for persons with HIV, uptake is low across sub-Saharan Africa. Mid-level health managers oversee IPT programs nationally;interventions aimed at this group have not been tested. Methods: We conducted a cluster randomized trial in Uganda among district-level health managers from 2017-2021. The unit of randomization was groups of 4-7 managers. Our intervention convened managers into mini-collaboratives facilitated by Ugandan TB/HIV experts and provided business leadership/management training, SMS platform access, and data feedback. The primary outcome was IPT initiation rates among adults with HIV in health facilities overseen by participants over 2 years (2019-2021). We compared incidence rates using cluster-level targeted minimum loss-based estimation. We conducted pre-specified analyses that excluded Q3-2019 to understand intervention effects independent of a national "100-day push" of IPT tied to a financial contingency during Q3-2019. Qualitative interviews were analyzed to ascertain mechanisms of intervention action. Results: Managers from 82/82 eligible districts (61% of Uganda's 135 districts) were enrolled and randomized: 43 districts to intervention, 39 to control. After one year, in 5-point-Likert quantitative surveys, intervention-group managers demonstrated greater increases in familiarity with IPT (by +0.47 points (95%CI:0.14-0.80)) and knowledge of IPT efficacy (+0.59 points (95%CI:0.06-1.12)) as compared to control. Intervention-group managers reported improved within-district communication and inter-district collaboration and feeling empowered to better manage frontline providers, in contrast to control, in qualitative interviews. Over two years, the IPT initiation rate was 0.74 vs. 0.65 starts/person-year in intervention vs control: incidence rate ratio (IRR)=1.14 (95%CI:0.88-1.46;p=0.16). Excluding Q3-2019, IPT initiation was higher in intervention vs control: 0.32 vs. 0.25 starts/person-year (IRR=1.27, 95%CI:1.00-1.61, p=0.03;Figure). Conclusion: Though overall IPT initiation rates were not significantly higher with the mid-level manager intervention in this cluster randomized trial, rates were significantly higher compared to control when excluding the massive MoH-led "100-day IPT push" in both arms. The higher rates were sustained during the COVID-19 pandemic, suggesting benefits of targeted leadership and management training for mid-level health managers.