Pulmonary infections in cancer patients

Lymphangitis carcinomatosa refers to pulmonary interstitial involvement by cancer and is a dreaded clinical finding in oncology because it is a late manifestation indicative of metastatic malignancy, from either a lung or a nonlung primary cancer, and is associated with poor prognosis. Its presentation is nonspecific, often with subacute dyspnoea and a nonproductive cough in a person with a known history of malignancy, but in some cases is the first manifestation of cancer. CT imaging can be suggestive, typically demonstrating thickening of the peribronchovascular interstitium, interlobular septa and fissures. However, a biopsy may be required to confirm the pathological diagnosis as these changes can also be due to concurrent disease such as heart failure, ILD, infection, radiation pneumonitis and drug reactions. Diagnosis allows symptomatic treatment, with personalised treatment directed towards the primary cancer most likely to provide a meaningful benefit. Future research should focus on prospective clinical trials to identify new interventions to improve both diagnosis and treatment of lymphangitis carcinomatosa.Copyright © ERS 2021.

Cytomegalovirus reactivation with high viral load in a patient of coronavirus disease 2019 acute respiratory distress syndrome: a case report.

INTRODUCTION: Cytomegalovirus establishes life-long latency after primary infection in childhood. Cytomegalovirus reactivation has been well reported in immune-compromised patients; however, in the last few years it has been observed that cytomegalovirus reactivation also occurs in critically ill patients without exogenous immunosuppression, which increases length of intensive care unit stay and mortality rate. CASE REPORT: A 63-year-old Indian male, without any known comorbidity, developed severe coronavirus disease 2019 and was admitted to the intensive care unit. He received remdesivir, tocilizumab, steroids, anticoagulants, and empiric antibiotics over the next 3 weeks. However, his clinical condition did not improve much, and during the 9th week of illness his condition started deteriorating and routine bacterial cultures, fungal cultures, and cytomegalovirus real-time polymerase chain reaction on blood were negative. His clinical condition worsened rapidly, which led to the need for invasive mechanical ventilation. Tracheal aspirate bacterial and fungal culture showed no growth, but cytomegalovirus real-time polymerase chain reaction showed 21,86,000 copies/mL in tracheal aspirates. After 4 weeks of ganciclovir treatment, the patient improved clinically and was discharged. Currently he is doing well and able to do his routine activity without the need of oxygen. CONCLUSION: Timely management with ganciclovir is associated with favorable outcome in cytomegalovirus infection. Thus, it can be suggested that treatment should be initiated with ganciclovir if a patient with coronavirus disease 2019 has high cytomegalovirus load in tracheal aspirates, along with unexplained and prolonged clinical and/or radiological features.

Revealing Potential Binding Affinity of FDA Approved Therapeutics Targeting Main Protease (3CLpro) in Impairing Novel Coronavirus (SARS-CoV-2) Replication that Causes COVID-19

Background: Spread of COVID-19 attains a crucial transition in reveling its pandemic across the boundaries. In combating the infection caused by SARS-CoV-2, there is a spectrum of ideal strategies that have been adopted globally, of which repurposing of approved drugs considerably having high clinical relevance. 3-chymotrypsin-like protease (3CL pro) is considered to be the potential target for the researchers as it is highly essential for cleavage of polyprotein to get 16 nonstructural proteins (called nsp1-nsp16). These proteins are highly essential for viral replication and hence become a primary target for enzyme inhibitors. 3CL pro, having a structural projectile helical chain with biologically active site involved in processing viral polyproteins that are evolved from RNA genome translation. Objective(s): The major objective of the present investigation is to evaluate the enzyme inhibition potential of FDA approved therapeutic leads in targeting 3CLpro that medicates the viral replication. Method(s): Docking calculations were carried out for an array of FDA approved molecules which leads to a notable few molecules such as Emtricitabine, Oseltamivir, Ganciclovir, Chloroquine, Baricitinib, Favipiravir, Lopinavir, Ritonavir, Remdesivir, Ribavirin, Tenofovir, Umifenovir, Carbapenam, Ertap-enem and Imipenam which have both specificity and selectivity in terms of binding efficiency against 3CL proenzyme. Result(s): A combinatorial evaluation employing in-silico screening shows a major lead for remdesivir which possesses a substantial affinity to 3CL pro binding on core amino acid residues, such as Leu 27, His 41, Gly 143, Cys 145, His 164, Met 165, Glu 166, Pro 168 and His 172 which share the biological significance in mediating enzymatic action. Results of docking simulation by Autodock over a host of FDA approved molecules show high degree of selectivity and specificity in the increasing order of binding capacity;Remdesivir> Ertapenem> Imipenam> Tenofovir> Umifenovir> Chloroquine> Lopinavir> Ritonavir> Emtricitabine> Ganciclovir> Baricitinib> Ribavirin>Oseltamivir>Favipiravir> Carbapenam. Conclusion(s): Till date, there is no known cure attained for treating COVID-19 infection. In conclusion, lead molecules from already approved sources provoke promising potential which grabs the attention of the clinicians in availing potential therapeutic candidate as a drug of choice in the clinical management of COVID-19 time-dependently.Copyright © 2020 Bentham Science Publishers.

Infeccao Aguda Por Citomegalovirus Associada a Glomerulonefrite Rapidamente Progressiva No Paciente Em Terapia De Manutencao Para Leucemia Pro Mielocitica Aguda Com Fusao Pml Rara

Objetivo: O presente estudo tem por objetivo relatar caso de infeccao aguda por citomegalovirus associada a glomerulonefrite rapidamente progressiva no paciente em terapia de manutencao para leucemia pro mielocitica aguda. Relato de caso: Paciente masculino de 25 anos, sem comorbidades, em seguimento no servico de hematologia da UNIFESP por quadro de Leucemia Pro Mielocitica Aguda (diagnostico em julho/2021), em protocolo de manutencao desde janeiro/2022 com 6-mercaptopurina, metotrexato e ATRA, em remissao morfologica e molecular, evolui com quadro de febre diaria ha 10 dias associada a odinofagia e tosse, com linfopenia, sem alteracoes ao exame fisico e rastreio infeccioso ambulatorial negativo. Solicitadas pesquisas de Citomegalovirus, Parvovirus, Epstein-Barr e SARS-Cov-2, suspensos os farmacos do protocolo de manutencao e indicada internacao hospitalar. Sem melhora do quadro relatado acima, paciente evoluiu com pancitopenia associada a um aumento de DHL e ferritina, sem figuras de hemofagocitose no aspirado de medular, alem de sindrome nefrotica e lesao renal rapidamente progressiva KDIGO III com indicacao de dialise. Visto tambem que nao haviam esquizocitos em sangue periferico, alteracoes no coagulograma ou outras disfuncoes organicas. Constatadas sorologias IgM e IgG positiva para CMV alem de carga viral serica elevada para CMV, confirmando a infeccao aguda por CMV associada a glomerulonefrite rapidamente progressiva. A biopsia renal demonstrou podocitos com alteracoes degenerativas, ausencia de depositos glomerulares e infiltrado linfocitario intersticial. Apos tratamento adequado com ganciclovir paciente evoluiu com melhora da febre e retorno da funcao renal de base. Discussao: Em individuos imunocompetentes a infeccao assintomatica pelo citomegalovirus e comum, e quando ocorrem sintomas ha um quadro clinico semelhante a mononucleose infecciosa, que pode cursar com sintomas de vias aereas superiores associados a linfadenopatia, esplenomegalia e linfopenia. No contexto clinico dos pacientes imunossuprimidos e mais comum que ocorra uma reativacao viral que pode levar a lesao organica aguda com acometimento de orgao unico ou lesao multissitemica. E descrito em literatura que a infeccao por citomegalovirus associada a lesao renal aguda exclusiva esta mais associada ao contexto do paciente imunossuprimido pos transplante renal em uso de drogas com maior potencial imunossupressor, diferentemente do caso relatado. Conclusao: A partir das manifestacoes clinicas e do rastreio infeccioso direcionado as infeccoes oportunistas que acometem o paciente imunossuprimido foi possivel associar o quadro de glomerulonefrite rapidamente progressiva a infeccao aguda por CMV, quadro pouco conhecido na pratica clinica, visto a predilecao para doenca invasiva em sistema nervoso central, retina, trato gastrointestinal e trato respiratorio. Alem disso, notou-se que nesse caso o tratamento com Ganciclovir foi efetivo neste tipo de apresentacao clinica, visto o retorno da funcao renal de base apos o tratamento adequado. Copyright © 2022

A RARE CASE OF PNEUMONIA BY CONCURRENT PNEUMOCYSTIS JIROVECI AND CYTOMEGALOVIRUS INFECTIONS

SESSION TITLE: Unusual Pneumonias SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Cytomegalovirus (CMV) is an important infectious organism in the morbidity and mortality of immunocompromised patients. CMV is a known cause of pneumoina in transplant patients, such as lung transplant recepients. Pneumocytis Jiroveci Pneumonia (PCP) is also a known risk factor for potentially life-threatening infections in immunocompromised patients. In this , we are presenting a rare case of an immunocompromised patient who had penumonia caused by a concurrent CMV and PCP infections. CASE PRESENTATION: A 53 year-old female patient with history of Rheumatoid Arthritis treated with immunomodulating medications admitted for Shortness of breath, fatigue and tiredness but no fever. COVID-19 and influenza infections (PCR) tests were both negative. At presentation, her WBC was 9900. CT with contrast of her chest showed no embolism, but multi-focal widespread groundglass opacities. Blood culture was negative, MRSA screen was negativetoo, but Fungitell test was positive (with a value of more than 500) and serum LDH test was elevated to 382. CMV quantitaive PCR was elevated to 10,000 copies. A bronchoscopy was done and CMV PCR Bronchoalveolar lavage (BAL) is detected at 650 copies/ ml. A BAL EBV PCR tests was negative. Pneumocystis Jiroveci pneumonia was detected on BAL Direct fluorescent antibody test (DFA). CMV retinitis has been ruled out by an ophthalmology exam. Patient was diagnosed with concurrent CMV and PCP pneumonia infection and her respiratory status worsened mandating a brief ICU stay. Treatment was started with Bactrim, Valganciclovir and Ganciclovir with progressive improvement. In a follow up appointment at the infectious diease clinic two months later, the patient condition improved but was still in need for supplemental oxygen through nasal canula. DISCUSSION: A concurrent CMV and PCP microorganisms lung infection is rare, but patient with underlying immunocompromise constitue a major risk factor for that. CONCLUSIONS: Patients with underlying immuncompromise conditions are at risk of many infections with grave morbidity and mortality risks. Though it is a rare to have a concurrent CMV and PCP lung infection, a patient treated with immunomodulating medications including methotrexate, prednisone and rituximab was a culprit for severe infection. Reference #1: Peghin, M., Hirsch, H. H., Len, Ó., Codina, G., Berastegui, C., Sáez, B., Solé, J., Cabral, E., Solé, A., Zurbano, F., López-Medrano, F., Román, A., & Gavaldá, J. (2016). Epidemiology and immediate indirect effects of respiratory viruses in lung transplant recipients: A 5-year prospective study. American Journal of Transplantation, 17(5), 1304–1312. https://doi.org/10.1111/ajt.14042 DISCLOSURES: No relevant relationships by MohD Ibrahim

HERPES SIMPLEX VIRUS PNEUMONITIS IN A CRITICALLY ILL PATIENT WITH SARS-COV-2

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Herpes simplex type 1 (HSV-1) related respiratory tract infections have been described in critically ill or immunocompromised patients. We present a case of HSV-1 pneumonia in a mechanically ventilated and immunocompromised patient in the setting of SARS CoV-2 infection. CASE PRESENTATION: A 54-year-old female on Rituximab for Rheumatoid arthritis presented with shortness of breath and cough. She was afebrile, tachypneic and hypoxic. She was discharged 1 week prior after a 3 weeklong treatment for COVID-19 pneumonia. CT Angiogram showed extensive bilateral patchy consolidations with ground-glass infiltrates and subsegmental pulmonary emboli. Patient was initiated on heparin and broad-spectrum IV antibiotics with steroids for presumed ARDS with superimposed bacterial pneumonia. Her respiratory failure worsened requiring invasive mechanical ventilation. Failing oxygenation despite aggressive therapy prompted further workup that showed a normal echo and negative blood cultures. Sputum was negative for Pneumocystis pneumonia and Tuberculosis. Cytology from tracheal aspirate showed bronchial cells with inclusions and multinucleations consistent with HSV-associated cytopathic changes. A positive serum HSV-1 IgG and serum quantitative PCR of HSV-1 DNA solidified the diagnosis. Ganciclovir therapy was initiated to cover for HSV and Cytomegalovirus (CMV), however, a serum CMV PCR was negative. Within a day, her clinical course took a downward spiral. CT chest was repeated which showed worsening airspace disease. Despite ganciclovir therapy, the severity of lung disease led to eventual failure of oxygenation and patient demise. DISCUSSION: Prolonged mechanical ventilation due to ARDS is a risk factor for HSV bronchopneumonia in patients with COVID-19 and has shown an increased mortality 1,2. Diagnosis can be achieved by viral culture or observing cytopathic effects of HSV on cells in tracheobronchial aspirates, bronchoalveolar lavage, or biopsy3. In critically ill patients early treatment has been shown to prolong the ICU time to death and improved oxygenation4. It is important to test for co-infections as about 65% of HSV pneumonia cases are associated with pathogens like CMV and Pneumocystis5. CONCLUSIONS: Worsening respiratory disease in mechanically ventilated COVID-19 patients despite antibiotic therapy for suspected superimposed bacterial infection warrants a workup for secondary viral infections like HSV. Increased mortality is seen if not promptly treated. Reference #1: 1. Meyer A, Buetti N, Houhou-Fidouh N, et al. HSV-1 reactivation is associated with an increased risk of mortality and pneumonia in critically ill COVID-19 patients. Critical Care. 2021/12/06 2021;25(1):417. doi:10.1186/s13054-021-03843-8 Reference #2: Le Balc'h P, Pinceaux K, Pronier C, Seguin P, Tadié J-M, Reizine F. Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients. Critical Care. 2020/08/28 2020;24(1):530. doi:10.1186/s13054-020-03252-3 Reference #3: Shah JN, Chemaly RF. Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies. Pulmonary Involvement in Patients with Hematological Malignancies. 2010:301-311. doi:10.1007/978-3-642-15742-4_24 DISCLOSURES: No relevant relationships by Andrew Cox No relevant relationships by Syeda Hassan No relevant relationships by Maria Khan No relevant relationships by Malik Muhammad Uzair Khan No relevant relationships by Rameesha Mehreen No relevant relationships by Rahat Ahmed Memon No relevant relationships by Ifrah Naeem No relevant relationships by Laura Walters

ASSESSING GENOMIC SAFETY OF ANTIVIRAL NUCLEOSIDE ANALOGS IN HEMATOPOIETIC STEM CELLS

Background: Nucleoside analog (NAs) drugs are used for the treatment of a variety of diseases, such as cancers and viral infections. After phosphorylation of viral and host kinases, NA drugs compete with the corresponding naturally occurring nucleotide during DNA replication of the infected cell. After incorporation, they can lead to mutations, or chain termination. However, because of their mechanism of action, NA are also potentially mutagenic to the genome of physiologically normal cells. Indeed, we have shown that treatment with the antiviral NA ganciclovir (GCV) after stem cell transplantation induces an increased mutation burden in the hematopoietic stem and progenitor cells (HSPCs) of pediatric leukemia patients. Using mutational signature analysis, we provided evidence that GCV-induced mutagenesis contributes to development of relapses and second malignancies in pediatric patients by inducing driver mutations. Over 30 NA drugs have been approved for clinical use and millions of people receive antiviral treatment worldwide to treat viral infections, including COVID-19. However, the mutagenicity in normal cells and potential carcinogenicity is unclear. Aims: Here, we aimed to systematically assess the mutational consequences of antiviral NAs in human HSPCs and identify underlying mechanisms. Methods: By combining in vitro treatment of umbilical cord blood-derived HSPCs with whole-genome sequencing (WGS) analyses, we provide a compendium of mutational consequences of antiviral NAs in a relevant human tissue (i.e., toxicity to the hematopoietic system is often dose-limiting). We treated HSPCs with IC40-60 concentration of the assessed compound followed by clonal expansions to obtain sufficient DNA for WGS. Using established bioinformatic pipelines, we catalogued the somatic mutations and mutational signatures in these cells. Results: At time of writing, 5 out of 7 tested antiviral NAs induce an enhanced mutation burden in exposed HSPCs. For some of this antiviral NAs we were able to identify unique unreported mutational signatures. Of note, the thymidine analog brivudine showed the highest increase in single base substitutions, which were characterized by a T>C signature, depleted for flanking cytosines. Furthermore, like GCV, we also observed a signature characterized by C>ApA substitution after treatment with the penciclovir, a molecule nearly identical to GCV. Currently we are working on machine learning approach to identify relevant mutation characteristics and modes of action as well as to screen cancer genome databases for mutational signature occurrence. Summary/Conclusion: Many compounds of the NA class currently prescribed for the treatment of viral infections are mutagenic to healthy cells. This calls for more thorough screening of these drugs, incorporation of information on mutagenicity to healthy cells in drug safety guidelines and patient surveillance over time.

A Case Report of Novel Coronavirus-2019 (COVID-19) Disease and Cytomegalovirus (CMV) Co-Infection: A Lethal Combination

Aim and background: The novel coronavirus-2019 (COVID-19) pandemic is raging all across the world. As we are delving more into the management of COVID-19, many new challenges are emerging, which may pose additional threats. One of these is the emergence or re-activation of concomitant viral infections owing to lymphopenia, use of immunosuppressants, underlying comorbidities, and immune dysregulation. Although we have come across the threat of fungal infections and resistant bacterial infections, experience regarding reactivation or co-infection with other viral infections is still limited. We hereby describe a case of COVID-19 disease with cytomegalovirus (CMV) co-infection. Case summary: COVID-19 with Cytomegalovirus (CMV) Co-infection. A 55-year-old male, COVID unvaccinated, chronic smoker, overweight, and hypertensive patient was admitted to our ICU with a 1-week history of fever, cough, and breathlessness. SARSCoV- 2 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive. At admission, he had hypoxaemia (SpO2 86% on room air), respiratory rate (RR) 35-40/minute, and ground-glass opacities in chest X-ray involving 50% of bilateral lung parenchyma suggestive of severe COVID-19 pneumonia. He was managed with lung-protective invasive mechanical ventilation, restrictive fluid strategy, 16-18 hour/day proning sessions (4-5), intravenous (IV) remdesivir, IV dexamethasone 6 mg 12 hourly, and enoxaparin thromboprophylaxis. After 2 weeks of ICU stay, weaning was attempted but the weaning attempts failed due to underlying neuromuscular weakness. On examination, bilateral (B/L) cranial nerve palsies, areflexia, and motor power 0/5 in bilateral upper and lower limbs were noticed. A possibility of Guillain-Barre Syndrome (GBS) was kept and IV immunoglobulin therapy was empirically administered for 5 days with some improvement in power up to 1/5 in upper limbs. On day 35 of hospitalization, he developed pancytopenia along with features of deranged liver function and gut dysfunction (in the form of paralytic ileus and abdominal distension). In evaluation, polymerase chain reaction (PCR) for CMV turned out to be positive in blood with a very high viral load.Bone marrow aspiration and biopsy showed hemopoiesis with viral inclusion bodies and haemophagocytosis (HLH). Histological evidence of CMV inclusion bodies was present in the bone marrow besides viremia (detected by PCR for CMV), which confirmed the diagnosis of CMV co-infection. IV ganciclovir was initiated along with steroids in view of HLH. There was a decrease in CMV viral load after initiation of IV gancyclovir with subtle clinical recovery. However, the patient continued to deteriorate and succumbed to his illness in the 8th week of the ICU stay.

A Case Report of Coronavirus (COVID-19) Disease and Herpesviridae Viral Co-Infections: A Lethal Combination? ABS0138)

Introduction: COVID-19 pandemic has affected the whole world. Besides COVID, other viral infections may emerge during the course of the disease owing to lymphopenia, use of immunosuppressants, underlying comorbidities, and immune dysregulation, which may pose additional threats.1 We hereby describe two cases of COVID- 19 with viral co-infections belonging to the Herpesviridae family with undulating clinical course. Case 1: Cytomegalovirus (CMV) Co-infection: A 55-year-old male, COVID unvaccinated, chronic smoker, overweight and hypertensive was admitted to our ICU with a 1-week history of fever, cough, and breathlessness. SARSCoV- 2 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive. At admission, he had hypoxaemia (SpO2 86%on room air), respiratory rate 35-40/minute, and ground-glass opacities in chest X-ray involving 50% of bilateral lung parenchyma suggestive of severe COVID-19 pneumonia. He was managed with lung-protective invasive mechanical ventilation, restrictive fluid strategy, 16-18 hour/day proning sessions (4-5), intravenous (IV) remdesivir, IV dexamethasone 6 mg 12 hourly, and enoxaparin thromboprophylaxis. After 2 weeks of ICU stay, weaning was attempted but the weaning attempts failed due to underlying neuromuscular weakness. On examination, bilateral (B/L) cranial nerve palsies, areflexia, and motor power 0/5 in bilateral upper and lower limbs were noticed. possibility of Guillain-Barre syndrome (GBS) was kept and IV immunoglobulin therapy was empirically administered for 5 days with some improvement in power up to 1/5 in upper limbs. On day 35 of hospitalization, he developed pancytopenia along with features of deranged liver function and gut dysfunction. In evaluation, PCR for CMV turned out to be positive in blood. Bone marrow aspiration and biopsy showed hemopoiesis with viral inclusion bodies and hemophagocytosis (HLH) [Figs 1 and 2]. A diagnosis of secondary HLH related to CMV was contemplated and IV ganciclovir was initiated along with steroids. Histological evidence of CMV co-infection was present and moreover, the quantitative viral load of CMV showed a decreasing trend after initiating IV gancyclovir. However, the patient continued to deteriorate and succumbed to his illness in the 8th week of the ICU stay. Case 2: Herpes Simplex Virus (HSV) Co-infection: Twenty-three years postpartum female with no comorbidities and uneventful obstetric history was referred to our hospital two weeks after a full-term normal vaginal delivery. She developed generalized status epilepticus on the 10th day of delivery, which was managed with anti-epileptic drugs (AEDs). During the hospital stay, RTPCR for COVID-19 turned out to be positive but she remained asymptomatic and seizures were well-controlled on AEDs. On admission to our hospital, she was fully conscious and alert with no neurological deficits. Notable findings were pancytopenia with megaloblastic features, B/L pedal edema, and hepatosplenomegaly. NCCT brain revealed mild subarachnoid hemorrhage (SAH) along the bilateral parietooccipital region for which conservative management was planned. 2D echocardiography was normal. Ultrasonography of the abdomen showed gross splenomegaly and mild hepatomegaly with mesenteric lymphadenopathy. NCCT thorax and abdomen were unremarkable apart from hepatosplenomegaly. In pancytopenia workup, IgM anti-HSV-1 antibodies turned out to be positive in blood. In addition, tropical workup was suggestive of Leptospirosis (IgM antibodies positive). Serological evidence was suggestive of acute HSV-1 infection (based on antibody titers). Bone marrow workup had features of trilineage hematopoiesis with micronormoblastic maturation consistent with iron deficiency anemia without any evidence of hemophagocytosis. IV acyclovir, IV doxycycline, and iron replacement were added, after which she improved clinically and was discharged in stable condition. Tables 1 and 2 show a detailed description of these cases. Discussion: Herpesviridae family is the most important group of viruses responsible for persistent vi al infections in humans, of which CMV contributes to 60-90% of infections in adults, especially in developing countries.2 In healthy individuals, these viruses are kept dormant by the body's immune mechanisms but in an immunocompromised population, reactivation from the latent state can occur. SARS-CoV-2 infection predisposes patients to concomitant viral co-infections, owing to T-cell lymphopenia, decreased NK cell number, and use of immunosuppressive medications.3,4 The first case of CMV co-infection was first reported by D'Ardes and co-workers in 2020.5 Since then, many studies have been emerging in this area. In an observational study from France, 38 COVID-19 patients on >7 days of MV were studied for HSV and CMV pulmonary co-infections (by quantitative real-time PCR in tracheal samples) out of which 47% of patients had one of these infections (24% HSV, 5% CMV, 18% both).6 Another study looking for HSV-1 in patients on invasive MV found HSV-1 reactivation between days 11 and 40, which correlated with immunological markers of decreased innate immunity.7 A case series looking for CMV infection (by PCR in plasma or BAL) in COVID-19, also found CMV reactivation between day 7 and 45 of illness. Most of these patients were above 60 years of age and immunosuppressed (HIV, diabetes mellitus, medications).8 Although immunocompromised individuals are more vulnerable, healthy immunocompetent adults who are critically ill or on prolonged MV may also be susceptible to these infections.9-12 This may be explained by a state of immunoparalysis inherent to prolonged critical illness. In case 1, an ICU stay of around 9 weeks complicated with recurrent nosocomial infections, multiple blood product transfusions, and steroid usage could have the likely triggers. Whether viral co-infections are merely bystanders or truly pathogenic is difficult to comment but timely management is essential to avoid end-organ damage (EOD) which may occur directly (by enhanced viral load secondary to compromised host immunity) or indirectly (by inflammatory changes consequent to prolonged cell-mediated immunity required to maintain viral dormancy).2-4,13 It also seems imperative to study if a viral co-infection has a proclivity to develop more severe hematological anomalies (besides the inherent risk of HLH with COVID) as was seen in case 1, in which the patient had a downward spiral of illness with multiorgan dysfunction.14-15 Limitations: Dynamics of PCR trends and virology studies of samples from trachea, gut, and urine could not be analysed in our patients. Conclusion: Viral co-infections can occur in COVID-19 disease as these patients are often immunocompromised and critically ill. A high index of suspicion and prompt management is needed to improve the outcome of patients. Patients with organ dysfunctions especially hematologic abnormalities with bone marrow involvement should be worked up in detail to look for concomitant viral co-infections. In the future, large-scale research is needed to better elucidate the relationship between SARS-CoV-2 and other viral co-infections.

Challenges Faced by an ECMO Patient

Aim and objective: To elaborate the challenges faced by an ECMO patient and the issues to be overcome and how to address them and combat with the help of a multidisciplinary team. This is a case of a 34-year-old male patient without any comorbidities who tested positive for COVID on 08/07/21 who was on home quarantine for 8 days and reported to hospital on 16/07 in view of breathlessness, was started on oxygen, bipap and tried on remdesivir, steroids, and tocilizumab and baricitinib. The patient was not maintaining saturations and was intubated on 26/07 and as there was refractory hypoxaemia was initiated on ECMO on the next day. The patient was started on ceftazidime and levoflox along with voriconazole as serum galactomannan was positive and ET cultures showed Stenotrophomonas maltophilia. The patient was tracheostomized on 01/08 and was keeping well till 12/08 when there were episodes of desaturation and tachypnoea and blood culture showed Candida auris and BAL culture showed Chryseobacterium and MDR Klebsiella with NDM, OXA-48 AND VIM+. The patient developed septic shock and required dual vasopressors. BAL galactomannan had titres of 4.5 and the patient was initiated on a mixture of ceftazidime, avibactum, voriconazole, and anidulafungin. The patient started having hemoglobinuria subsequently and acute kidney injury secondary to this and required 3 sessions of dialysis and the whole ECMO circuit was changed. Improvement in the parameters followed with normalization of blood pressure and urine output too. When there was a sigh of relief as things were getting normal patient started having heavy bouts of tracheal bleeding and bronchoscopy was done again with endobronchial biopsy showing CMV endobronchitis with focal ulceration and was started on ganciclovir. There were maleana episodes too which normalized after initiation of antivirals and CMV enterocolitis was suspected to be the cause. Now the patient is on trial off mode with decannulation being planned.

Pregnancy Outcomes with Coronavirus Infection (COVID-19)

Introduction: The clinical therapy of COVID-19 infection during pregnancy is still insufficient and limited. The current literature on COVID-19 infection during pregnancy and childbirth is summarized in this article, with a focus on maternal and neonatal outcomes. Material and methods: From June 1 to September 7, 2020, a systematic search of pertinent medical subject heading (MeSH) terms, covered by the electronic databases Web of Science and Scopus, PubMed, Google Scholar, and SID key phrases including coronavirus or COVID-19 and pregnancy was undertaken. The search and selection criteria were restricted to English and Farsi literature. COVID-19 in pregnancy articles of all types were considered in the study. The references of relevant studies were also searched. After deleting duplicate and ineligible items, a total of 21 articles were collected. Result: We found 21 studies with a total of 6,569 pregnant women who had COVID-19 infection: only one publication provided disease severity: 368 (95.6%) mild cases, 14 (3.6%) severe cases, and three (0.8%) serious cases. A total of 6,569 women gave birth more often by caesarean than by vaginal delivery. With multiple organ dysfunction syndromes (MODS), some women developed symptoms that necessitated ICU admission. The most commonly administered treatments for pregnant women with COVID-19 were hydroxychloroquine, Beclomethasone, Calamine, diclofenac sodium, Methylprednisolone, Azithromycin, Ganciclovir, Chinese herbal medicine, and Oseltamivir. The most commonly reported symptoms were fever and cough, followed by rhinorrhea, chest tightness, dyspnea, nasal congestion, and myalgias. Maternal outcomes included premature rupture of membranes, maternal death (21), gestational diabetes, preeclampsia, placental abruption, fetal distress, anemia, preterm birth (< 37 weeks), and fetal growth restriction, miscarriage, hypertension, and influenza. Neonatal intensive care unit (NICU) admission, prematurity, birth weight 2,500 g, preterm delivery (37 weeks), fetal discomfort, neonatal asphyxia, stillbirth (5), and neonatal death (9) were among the outcomes for babies. All of the infants had good Apgar scores. Conclusion: Prenatal and neonatal outcomes appear to be favorable in the majority of cases. Pregnant women and babies should be considered particularly vulnerable populations in terms of COVID-19 preventive and management strategies.

Hypoxic Respiratory Failure Due to Pneumocystis Jiroveci and Cytomegalovirus Co-Infection in a Severely Immunocompromised Patient

Introduction:Immunocompromised individuals, such as those with HIV and low CD4 counts, are at increased risk for opportunistic infections. Although uncommon, these patients can be infected with multiple organisms, making diagnosis and management challenging for clinicians. Mortality remains high, as the data on initiating and adjusting antimicrobials when there is concern for co-infection is lacking. We present a case of Pneumocystis jiroveci (PCP) and cytomegalovirus (CMV) coinfection resulting in severe hypoxic respiratory failure and death. Case Report:A 38-year-old male with no past medical history presented with fever, dyspnea, and nonproductive cough. Vital signs were notable for a fever of 102.3°F, respiratory rate of 24, and oxygen saturation of 77% on room air. Physical examination revealed an ill-appearing male with bilateral rhonchi who became dyspneic with minimal conversation. Laboratory studies were significant for an elevated c-reactive protein, erythrocyte sedimentation rate, ferritin and lactate dehydrogenase. CT chest demonstrated bilateral ground glass opacities with multifocal consolidations. The patient was admitted for hypoxic respiratory failure secondary to suspected COVID pneumonia, despite negative testing. By hospital day 4, the patient had shown little improvement. Further work-up revealed that he was HIV positive with a CD4 count of 5, so he was empirically started on oral trimethoprim-sulfamethoxazole (TMPSMX) for presumed PCP pneumonia. On hospital day 9, the patient underwent endotracheal intubation for worsening hypoxia and subsequent bronchoscopy for further evaluation. PCP PCR confirmed the diagnosis, and the patient was transitioned to intravenous TMP-SMX. Still with minimal improvement, micafungin was added as potential salvage therapy. After 12 days of TMPSMX, treatment was changed to clindamycin/primaquine. CMV PCR from the bronchoalveolar lavage fluid came back positive at this time, so ganciclovir was added to the regimen. Despite multiple antimicrobials, the patient continued to decline. He was deemed not to be a candidate for ECMO given his profoundly immunocompromised status and ultimately died. Discussion:This case highlights the difficulties clinicians have in managing severely immunocompromised patients who worsen despite appropriate care. Little data exists providing guidelines on when to change to second and/or third-line agents in treating PCP pneumonia. Additionally, further studies need to be completed to delineate in whom empiric antimicrobials should be initiated early when co-infection is a possibility. ECMO may serve a purpose in this patient population given that lung rest is necessary to allow healing, but only a few cases of its use exist at this time.

CYTOMEGALOVIRUS PROCTITIS DEVELOPING AFTER CORONAVIRUS DISEASE 2019 (COVID-19) VACCINE: CAUSALITY OR CASUALTY?

AIM: The COVID-19 epidemic is still raging over the globe, and vaccination is supposed to help us overcome it. Although the vaccinations' efficacy is undeniable, their safety is still a concern. This is the first case of CMV proctitis following vaccination since the invention of the COVID-19 vaccine, suggesting that the COVID-19 vaccine may not only cause immune hyperactivity but also cause immune deficiency. We report this case to provoke new thinking about the safety of COVID-19 vaccines. METHODS: We described a case of a 58-year-old Chinese woman, without obvious cause of immunosuppression, who developed persistent constipation three days after the second COVID-19 vaccination. Electronic colonoscopy revealed new circumferential growth at the anorectal junction, with uneven surface and ulceration, which mimicked rectal carcinoma. Rectal biopsy revealed severe active chronic proctitis with CMV infection. The clinical course was favorable with ganciclovir therapy. In this case, we used laboratory biochemical examination, colonoscopy, immunohistochemistry, and other methods to detect, and finally confirmed the existence of CMV proctitis. RESULTS: Ganciclovir was used to treat the patient, and a good effect was observed. Cytomegalovirus (CMV) infection of the gastrointestinal tract occurs mainly in immunosuppressed patients. While in our case, there was no evidence of immunodeficiency, except for earlier vaccination against COVID-19. Therefore, it is plausible to doubt that COVID-19 vaccination caused the occurrence of CMV proctitis in the patient. CONCLUSIONS: It is speculated that the vaccine can cause immune dysfunction, and thus may not only lead to the occurrence of immune hyperactivity disorders but also immune deficient diseases. The clinical course of CMV proctitis was favorable with ganciclovir therapy.

REATIVAÇÃO DE CITOMEGALOVÍRUS EM PACIENTES COM DIAGNÓSTICO DE MIELOMA MÚLTIPLO OU AMILOIDOSE EM TRATAMENTO COM BORTEZOMIBE NO SERVIÇO DE HEMATOLOGIA E HEMOTERAPIA DO HOSPITAL DAS CLÍNICAS DA USP RIBEIRÃO PRETO/SP NO ANO DE 2020: UMA SÉRIE DE CASOS

Introdução: O Bortezomibe (Velcade®) é um inibidor do proteassoma, especificamente do proteassoma 26S, cuja ligação irreversível leva à ativação de cascatas de sinalização que culminam com a parada do ciclo celular e apoptose. Ele foi aprovado e incluído como quimioterapia de primeira linha nas Diretrizes Diagnósticas e Terapêuticas do Mieloma Múltiplo (Portaria n.° 2017) publicadas em agosto de 2015 mas apenas em setembro de 2020 foram publicadas três Portarias do Ministério da Saúde que incorporaram este medicamento para o tratamento de pacientes com Mieloma Múltiplo no SUS (para pacientes não tratados, inelegíveis ao transplante de células-tronco;para pacientes não tratados, elegíveis ao transplante e para pacientes previamente tratados). Esta incorporação permitiu o uso mais amplo desta medicação e trouxe à tona complicações possivelmente relacionadas ao seu uso como a reativação de citomegalovírus e suas diversas formas de apresentação clínica como pneumonites, infecções gastrointestinais, hepatites, encefalites, retinites, entre outras. Série de casos: No ano de 2020, foram identificados 5 casos de infecção por citomegalovírus em pacientes em tratamento de Mieloma Múltiplo e Amiloidose em uso de esquemas quimioterápicos contendo Bortezomibe no serviço de Hematologia e Hemoterapia do Hospital das Clínicas de Ribeirão Preto/SP. Três casos foram identificados na investigação etiológica de diarréia subaguda, um foi identificado na estratificação de colite neutropênica com características enteroinvasivas e o último na investigação de pneumonite aguda com sinais de infecção viral em tomografia de tórax (neste caso, foi excluída infecção por Covid-19 após dois testes PCR-RT negativos). Em todos os casos, após identificação da infecção por CMV (por sorologia - Elisa e confirmação de carga viral por PCR-RT), foi instituída terapêutica específica com antiviral, tanto Ganciclovir endovenoso quanto Valganciclovir via oral. Apesar da alta morbimortalidade associada a esta infecção em pacientes imunossuprimidos, apenas um dos cinco pacientes faleceu de complicações associadas. Discussão: A soroprevalência elevada de infecção por citomegalovírus no Brasil está relacionada a fatores socioeconômicos e condições precárias de saneamento básico e aumenta a morbimortalidade em pacientes imunossuprimidos. O uso mais frequente do Bortezomibe como primeira linha em pacientes com Mieloma Múltiplo e Amiloidose no nosso serviço e no Brasil traz à tona este agente como diagnóstico diferencial nas suspeitas clínicas infecciosas de diversos órgãos e sistemas.

Cytomegalovirus pneumonia in patients with severe covid-19 disease

Background: 70-90 % of the adult population carries latent cytomegalovirus (CMV), which may be reactivated by inflammation and immune suppression. CMV reactivation has been seen in up to one-third of critically ill patients, and is associated with worse clinical outcomes. Here, the authors present two challenging cases, wherein the management of severe COVID-19 disease was complicated by CMV pneumonia. Case Reports: Our patients presented with severe COVID-19 pneumonia with acute respiratory distress syndrome and were admitted in the intensive care unit (ICU). The patients received immunosuppressive therapy, either tocilizumab or methylprednisolone pulse therapy. Both the patients had a prolonged hospital stay, and showed an initial improvement followed by clinical deterioration, with recurrence of fever, worsening respiratory failure, and development of consolidations on CT thorax. A thorough work up for opportunistic infections revealed CMV infection. Both patients were treated with intravenous Ganciclovir and showed marked improvement. Discussion: The use of steroids and other immunomodulatory therapies in the treatment of severe COVID-19 disease, along with immune suppression caused by severe COVID-19 itself, predisposes patients to reactivation of CMV. Furthermore, CMV reactivation is associated with a longer ICU length of stay, prolonged mechanical ventilation, increased risk of secondary infections, and mortality. Conclusion: These cases highlight the importance of considering CMV disease as a differential diagnosis in critically ill patients with COVID-19 with unexplained worsening, especially in the setting of immunomodulatory therapies, as early treatment may prevent adverse clinical outcomes and mortality.

The Role of Nanotechnology in Antiviral Regime: An Overview

Nanomedicine or nanotechnology exhibits outstanding features to challenge severe health issues including pathogenic viral infections, the most culpable invaders in the present situation. The perpetual mutational pattern in viruses topped with raising resistance to drug epitomizes the current situation as a trigger to explore nanotech platforms in antiviral therapies. Referring to novel physicochemical features of nanomaterials associated with effective drug delivery, it is viewed as an ideal strategy for treatment of viral infections. The coronavirus induced pathogenesis, including MERS, SARS and SARS-CoV-2 infections, has triggered alarming and highly dangerous precedents against existence of humans. Applications of nanotechnology can serve a new direction for disinfection or treatment of viruses. Presently, various types of nanomaterials, such as nanogels, nanospheres, nanocapsules, liposomes, nanoparticles and many others, that have been investigated in vivo and in vitro for successful drug delivery, vaccination, diagnostic assay and device development with anticipation to be translated in advanced clinical practices, need a collective relook. This paper intents to contribute insightful critique of current studies on the efficacy of nanoplatforms as drug transporter, diagnostic tool and vaccine candidate against pathogenic viruses counting the highly pathogenic and incurable "coronaviruses".

COVID-19 associated EBV reactivation and effects of ganciclovir treatment.

BACKGROUND: Systemic reactivation of Epstein-Barr virus (EBV) may occur in novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the clinical consequences of EBV reactivation remain uncertain. METHODS: In this retrospective study, we screened 1314 patients with confirmed COVID-19 who died or were discharged between January 1, 2020 and March 12, 2020, in Wuhan Infectious Disease Hospital, Wuhan, China. Patients who had complete data for EBV serology and cytomegalovirus (CMV) serology were eligible. Serum levels of viral capsid antigen (VCA)-immunoglobulin G (IgG), Epstein-Barr nuclear antigen-IgG, VCA-IgM, early antigen (EA)-IgG, CMV-IgG, and CMV-IgM were compared between survivors and nonsurvivors. Dynamic changes of laboratory tests and outcomes were compared in patients with and without ganciclovir treatment. We used 1:1 matching based on age, gender, and illness severity to balance baseline characteristics. RESULTS: EBV reactivation was present in 55 of 217 patients. EBV reactivation was associated with age (57.91 [13.19] vs. 50.28 [12.66] years, p < .001), female gender (31 [56%] vs. 60 [37%], p = .02). Patients with EBV reactivation have statistically nonsignificant higher mortality rate (12 [22%] vs. 18 [11%], p = .08). EA-IgG levels were significantly higher in nonsurvivors than in survivors (median difference: -0.00005, 95% confidence interval, CI [-3.10, 0.00], p = .05). As compared to patients with COVID-19 who did not receive ganciclovir therapy, ganciclovir-treated patients had improved survival rate (0.98, 95% CI [0.95, 1.00] vs. 0.88, 95% CI [0.81, 0.95], p = .01). Hemoglobin (p < .001) and prealbumin (p = .02) levels were significantly higher in ganciclovir-treated patients. CONCLUSION: A high proportion of COVID-19 patients had EBV reactivation that may be associated with an increased risk of death. Whether treatment with ganciclovir may decrease the mortality of COVID-19 patients complicated with EBV reactivation warrants to be addressed in a placebo-controlled randomized trial in the future.

POS-760 PULMONARY ANGIOINVASIVE ASPERGILLOSIS IN A KIDNEY RECIPIENT: AN ATYPICAL CLINICAL PRESENTATION

Introduction: Angioinvasive aspergillosis is a rare opportunistic infection. its occurrence increases the mortality and morbidity of organ transplant recipients. Methods: It is about a 27-year-old patient with a history of end-stage renal failure due to an apparent mineralocorticoid deficiency, hemodialysis for 10 months until he received a kidney transplant from a related living donor sharing 4 HLA identities. He received induction therapy with globulin antithymocyte and methylprednisolone followed by maintenance therapy with Mycophenolate Mofetil, prednisolone, tacrolimus. Since the recipient was not immune to cytomegalovirus (CMV), he received ganciclovir prophylaxis immediately after transplant. Post-transplant evolution was marked by the immediate resumption of diuresis, creatinine figures stagnating between 200 and 250 µmol/l. The remainder of her usual treatment consists of a proton pump inhibitor, β-blocker, cotrimoxazole. Our patient presented 2 months post transplant with febrile neutropenia. Clinically, apart from a fever of 38 °, the examination was without abnormalities. Biologically, pancytopenia, inflammatory syndrome (high CRP and procalcitonin), hypokalaemia, hypophosphatemia and hypomagnesemia, hyperferritinemia and hypertriglyceridemia were noted. A post-infectious macrophagic activation syndrome was suspected, confirmed by a sternal puncture. An etiological investigation has been launched;viral serologies (HBV, HCV, HIV, EBV, CMV, COVID 19, HSV) were negative, a cardiac ultrasound ruled out infective endocarditis, a thoracoabdominal CT scan showed multifocal sub-segmental parenchymal condensations of the right lung surrounded by a halo, an appearance suggesting angio-invasive pulmonary aspergillosis and intracortical graft hematomas. Sputum bacteriological examination did not show pneumocystis but isolated two types of candida crucei and tropicalis. A weakly positive aspergillus antigenemia (index : 0.53) was noticed. Our patient received triple antibiotic therapy (vancomycin / imipenem / levofloxacin) and an antifungal (voriconazole) after adaptation according to the antibiogram for a total duration of 15 days with daily dosage of tacrolimus. In addition, he received venoglobulins for 5 days at a dose of (0.4 mg / kg / day). The clinical and biological course was favorable with apyrexia and improvement in the blood count from the third day of treatment. Aspergillus antigenemia and a follow-up chest CT scan were scheduled after the end of treatment. Results: Initially, In view of the intensity of the induction treatment received, leuconeutropenia and in order of frequency, the 2 most evoked causes were CMV et covid19 but the CT aspect straightened the diagnosis, which was supported by aspergillary antigenemia. The emerging interest of this case report is the clinical and computed tomography discordance and the unusual rapidly favorable outcome to an aspect of angioinvasive pulmonary aspergillosis which usually show respiratory signs such as cough, hemoptysis or even respiratory distress. Conclusions: Invasive mycoses, associated with significant morbidity and mortality, are a frequent difficulty in solid organ transplantation. The clinical pictures differ and we could be faced with an atypical presentation which affects the therapeutic management. No conflict of interest