Pressure injuries in ventilated COVID-19 patients

Prolonged high-flow nasal oxygenation (HFNO), or non-invasive ventilation (NIV), or endotracheal intubation with prone ventilation in COVID-19 patients may result in pressure sores or ulcers at points on sustained pressure at patient-equipment interphase. Expert nursing care and following the relevant guidelines can prevent the development of such injuries. Copyright © 2022 Faculty of Anaesthesia, Pain and Intensive Care, AFMS. All rights reserved.

SARS-CoV-2 and HIV: Impact on Pulmonary Epithelial Cells.

The SARS-CoV-2 pandemic provides a natural opportunity for the collision of coronavirus disease-2019 (COVID-19) with chronic infections, which place numerous individuals at high risk of severe COVID-19. Infection with Human Immunodeficiency Virus (HIV), a global epidemic, remains a major public health concern. Whether prior HIV+ status exacerbates COVID-19 warrants investigation. Herein, we characterized the impact of SARS-CoV-2 in human bronchial epithelial cells (HBECs) previously exposed to HIV. We optimized the air-liquid interface (ALI) cell culture technique to allow for challenges with HIV at the basolateral cell surface and SARS-CoV-2 spike protein on the apical surface, followed by genetic analyses for cellular stress/toxicity and innate/adaptive immune responses. Our results suggest that the IL-10 pathway was consistently activated in HBECs treated with spike, HIV, or a combination. Recombinant spike protein elicited COVID-19 cytokine storms while HIV activated different signaling pathways. HIV-treated HBECs could no longer activate NF-kB, pro-inflammatory TRAF-6 ubiquitination nor RIP1 signaling. Combinations of HIV and SARS-CoV-2 spike increased gene expression for activation of endoplasmic reticulum-phagosome pathway and downregulated non-canonical NF-kB pathways that are key in functional regulatory T cells and RNA Polymerase II transcription. Our in vitro studies suggest that prior HIV infection may not exacerbate COVID-19. Further in vivo studies are warranted to advance this field.

Enhancing Immunization Clinical Decision Support to Support Personalized Guidance and Shared Decision Making Recommendations

Background: Immunization clinical decision support (CDS) systems provide much needed guidance for clinicians in interpreting immunization guidelines and determining when vaccinations are due. In most circumstances, patients should be vaccinated according to the standard Advisory Committee on Immunization Practices (ACIP) schedule. However, for some patients the standard recommendations encoded into the CDS fail to address individual health. For example, underspecfication in ICD-10 codes for immunocompromised status led to confusion about whether a patient should or should not be given vaccines. Additionally, the system we currently used only allowed for limited 'on' and 'off' designations, resulting in some families choosing to self-select as “no to all vaccines” even there were some vaccines they were interested in their child receiving such as school required vaccines. As some new vaccines have included a shared decision making recommendation, including the meningitis B vaccine and the COVID vaccines, we recognized the need for a more finite level of control in our immunization CDS. Methods: We overhauled our immunization CDS backend to provide increased flexibility in rule interpretation and recommendation presentation. First, we switched from a binary interpretation of rules (due or not due) to a three-level interpretation (due and default selected, due but not default selected, or not due). Diagnoses that previously had shut off notices that a vaccine were due were re-interpreted to note that the vaccine would be due, but that a specific diagnosis in the chart indicated it should not be defaulted as selected. We developed a provider portal accessible by the clinician in real time to update rule recommendations at the patient level allowing a clinician to control for a patient what immunizations would be recommended at the antigen level. To facilitate ease of use for the clinician, we included pre-populated selections for reasons a parent may elect to defer on default immunizations. Additionally, we provided links to content on supporting shared decision making for immunizations. Results: The updated immunization CDS successfully allowed clinicians to modify recommended vaccinations at the patient and antigen level. Multiple scenarios were tested including personal history of varicella, which can be driven by problem list entries, and history of hepatitis A infection with natural immunity, for which diagnosis data is insufficient for altering the recommendations. In all cases clinicians were able to unselect default recommendation for immunizations. Conclusion: Immunization CDS, which previously only allowed for default selection of immunizations was successfully modified to support personal preferences, finite recommendations related to previously inaccessible information within the EHR, and to allow for future implementation of shared decision making recommendation level immunizations. The interphase developed allowed for clinician updating of immunization recommendations in realtime at the patient level and antigen level. After the rules engine has determined which vaccines are potentially due, presentation of products occurs through this order screen. Products with a shared decision making recommendation status as per ACIP are not defaulted. Where possible, patient data from the EHR is used to support recommendation evaluated (e.g. for varicella). Where notpossible due to underspecification of ICD-10 codes, clinician entered information is used to enhance the specificity of alerts. Narrative text describing all modifications to recommendations, including the source of the modification, is displayed. This is the user interface used by clinicians to modify recommendations at the patient level. With a single click clinicians can add or remove personalizations to the routinely recommended immunizations. By default all antigens are recommended. When a clinician unselected a check box products containing that antigen are still listed as due, but no longer defaulted. Any combination products containing that an igen are not recommended so that the system can have other portions of the combination product still be default ordered.

Successful retreatment of CLL with venetoclax following clonal evolution during 37 months of tirabrutinib and idelalisib

The BCL2-specific inhibitor, venetoclax, has demonstrated remarkable clinical activity in the treatment of chronic lymphocytic leukemia (CLL), either alone or in combination with CD20 antibodies. Nevertheless, patients who fail to attain a complete remission relapse, and require further therapy. Data on retreatment with venetoclax at disease progression are currently limited. Here, we report patterns of clonal evolution in an R/R CLL patient that has demonstrated successful retreatment. A 57 year-old lady with chemotherapy- refractory (FCR, RCHOP, high dose methyl prednisolone) TP53 mutant CLL was treated for 21 months with single-agent venetoclax in 2014 (NCT01889186). She attained an MRD positive CR with the resolution of massive lymphadenopathy and with only low-level (0.01%) disease in the bone marrow. However, she subsequently progressed rapidly with a lymphocyte doubling time of only 4 weeks and was treated with tirabrutinib and idelalisib in combination (NCT02968563) from December 2015 for 37 months before progressing December 2019. She was retreated with venetoclax and rituximab but died of COVID-19-induced respiratory failure in March 2020. To study the clonal evolution underlying these events, in vitro drug sensitivity assays and whole exome sequencing (WES) were used to study peripheral blood mononuclear (PBMC) and bone marrow samples. WES of sample 1 showed multiple mutations in CLL driver genes: SF3B1 R625C, KMT2C R4434Q, and TP53 R110L at VAFs of 37, 17, 35%, respectively. Mutations in other genes associated with CLL included FANCA L217F (47%) and SPEN P3402S (46%). At disease progression (sample 2), following venetoclax, there was the loss of detectable (WES at 100× coverage) TP53 R110L (with loss of 17p deletion on interphase FISH and analysis of copy number) but maintenance of SF3B1 R625C (44%), KMT2C R4434Q 30%), FANCA L217F (47%), and SPEN P3402S (55%). These data, therefore, suggest the TP53 mutant subclone was largely lost during therapy. No other mutations were identified as possible resistance mediators. There were no detectable BCL2 mutations. In vitro drug sensitivity testing to venetoclax showed an EC50 of 228nM (CLL EC50 usually 3-5 nM). The patient was then treated with the BTK inhibitor tirabrutinib in combination with idelalisib, with an excellent clinical response. After 10 months (sample 3, during the lymphocytosis induced by BTKi/PI3Kdi) SF3B1, KMT2C, FANCA, and SPEN mutations were detected at VAFs of 26, 30, 54, and 56%, respectively. At this point the TP53 R110L mutation was detected again at a VAF of 4%, indicating that stopping venetoclax allowed the clone to re-emerge. At this time, there were no detectable BTK or PLCG2 mutations. The patient then responded for a further 37 months before disease progression. At progression (sample 4), SF3B1, KMT2C, FANCA, and SPEN mutations were still detected in the peripheral blood at VAFs of 43, 31, 48, and 50%, respectively. The VAF of the TP53 R110L mutation had increased to 33%. Additionally, a BTK mutation (T474I) was identified with a VAF of 16%. Identical results were obtained using a bone marrow sample. Now, however, in vitro analysis demonstrated a high degree of sensitivity to venetoclax (EC50 0.72 nM). The patient was, therefore, retreated with venetoclax and rituximab. At the point of re-treatment, VAFs were maintained, with the emergence of a new subclonal NOTCH1 G1001D mutation at a VAF of 3%. The patient, unfortunately, died 4 months after commencing therapy due to COVID-19 associated pneumonitis. A full disease reassessment was not made but the patient's blood count had normalized, with rapid clearance of CLL cells from the peripheral blood, recovery of normal hematological indices, resolution of splenomegaly, and partial resolution of lymphadenopathy on CT scan. These data, therefore, suggest that re-treatment with venetoclax in CLL can be successful. Regaining sensitivity to venetoclax may largely depend on shifting clonal dynamics. The molecular basis of venetoclax resistance in this case is currently being investigated. A so in this particular case, it appears that the TP53 mutant subclone was more sensitive to BCL2 inhibition than TP53 wild-type subclone(s), and was largely eliminated by initial venetoclax treatment, contrasting with recently published data suggesting resistance of TP53 mutant hematological malignancies to BCL2 inhibition due to increased thresholds for BAX/BAK activation (Thijssen et al., 2021).

A new translocation partner for CBFB in acute myeloid leukemia, t(10;16)(p13;q22)

Cytogenetic abnormalities involving chromosome 16 are found in 5– 8% of acute myeloid leukemia (AML). These are typically a pericentric inversion inv(16)(p13.1q22) or a translocation, t(16;16)(p13.1;q22), involving the MYH11 and CBFB genes localized to chromosome 16p13.1 and 16q22, respectively. In addition, less common rearrangements include deletion of the long arm of chromosome 16, del(16) (q22), and cryptic insertions involving the MYH11 and the CBFB genes with otherwise normal karyotypes. In this report, we present the first AML case with a new translocation involving the CBFB gene. The more common CBFB - MYH11 fusion product resulting from the inversion and/or translocation of chromosome(s) 16 leads to an AML with monocytic and granulocytic differentiation and abnormal eosinophil component with large, purple to violet color eosinophilic granules. This entity typically corresponds to the adult AML-M4Eo in French-American- British (FAB) Classification and now called AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH1 in the new 2017 WHO Classification. Patients may present with myeloid sarcoma at initial diagnosis or at relapse. We present a case of an 80-year-old male with a history of prostate cancer post radiotherapy who was referred for COVID-19 testing. A complete blood count with differential revealed neutropenia and a macrocytic anemia. A bone marrow biopsy and a bone marrow aspirate confirmed a diagnosis of AML with 33% blasts including myeloblasts and promonocytes. Interphase fluorescence in situ hybridization (FISH) analysis with a break-apart probe for CBFB showed an abnormal hybridization pattern consistent with rearrangement of CBFB in 66% of nuclei. Chromosome analysis revealed an abnormal karyotype with two related clones: 47,XY, t(10;16)(p13;q22),+22[4]/48,idem,+8[16]. Sequential GTG-FISH confirmed that the 3’ region of CBFB was translocated to 10p13 in the t(10;16) and the 5’ region remained on 16q. Based on the karyotype, the patient’s bone barrow exhibits clonal evolution having acquired additional chromosome abnormalities (trisomy 22 and trisomy 8). Molecular studies by next generation sequencing showed NRAS p.Gln61Lys mutation with a VAF of 11.21%. No genomic alterations were detected in KIT, KRAS or FLT3 genes. AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is associated with a high rate of complete remission and favorable overall survival when treated with intensive consolidation therapy. However, their prognostic advantage may be affected by additional cytogenetic abnormalities and/or other gene mutations. Specifically, trisomy 22, is a frequent abnormality additional to inv(16) detected as a secondary finding which has been associated with an improved outcome when compared to the prognosis associated with inv(16) alone. Furthermore, KIT (in 30–40%), FLT3 (in 14%), NRAS (in 45%) and KRAS (in 13%) mutations are common in this AML type. The prognostic implications of KIT mutation (especially involving exon 8) do not appear to be significantly poor prognostic compared to other AML types. On the other hand FLT3-TKD mutations and trisomy 8 are associated with a worse outcome. The patient is currently receiving Vidaza 75 mg/m2, days 1–7 of a 28 days cycle with Venetoclax mg daily of a 28-day cycle and his clinical prognosis is currently unclear. Further analysis by DNA sequencing may help to characterize the molecular nature of the fusion gene product resulting from the novel t(10;16)(p13;q22). To the best of our knowledge, this is the first reported case of an AML patient with translocation t(10;16)(p13;q22) involving the CBFB gene. Given the rarity and lack of additional information regarding the effects of this abnormality, the prognosis and survival cannot be predicted.

Pathophysiological and molecular considerations of viral and bacterial infections during maternal-fetal and -neonatal interactions of SARS-CoV-2, Zika, and Mycoplasma infectious diseases.

During pregnancy, a series of physiological changes are determined at the molecular, cellular and macroscopic level that make the mother and fetus more susceptible to certain viral and bacterial infections, especially the infections in this and the companion review. Particular situations increase susceptibility to infection in neonates. The enhanced susceptibility to certain infections increases the risk of developing particular diseases that can progress to become morbidly severe. For example, during the current pandemic caused by the SARS-CoV-2 virus, epidemiological studies have established that pregnant women with COVID-19 disease are more likely to be hospitalized. However, the risk for intensive care unit admission and mechanical ventilation is not increased compared with nonpregnant women. Although much remains unknown with this particular infection, the elevated risk of progression during pregnancy towards more severe manifestations of COVID-19 disease is not associated with an increased risk of death. In addition, the epidemiological data available in neonates suggest that their risk of acquiring COVID-19 is low compared with infants (<12 months of age). However, they might be at higher risk for progression to severe COVID-19 disease compared with older children. The data on clinical presentation and disease severity among neonates are limited and based on case reports and small case series. It is well documented the importance of the Zika virus infection as the main cause of several congenital anomalies and birth defects such as microcephaly, and also adverse pregnancy outcomes. Mycoplasma infections also increase adverse pregnancy outcomes. This review will focus on the molecular, pathophysiological and biophysical characteristics of the mother/placental-fetal/neonatal interactions and the possible mechanisms of these pathogens (SARS-CoV-2, ZIKV, and Mycoplasmas) for promoting disease at this level.