Importance of standard precautions to febrile neutropenia prevention in patients with cancer during COVID 19 outbreak (preprint)

Purpose Intensive cytotoxic chemotherapy increases the risk of infection in patients with cancer by inducing bone marrow suppression and mucosal injury. Febrile neutropenia (FN) is the most important clinical adverse event in patients with cancer who receiving cytotoxic chemotherapy. To prevent FN, prophylactic antibiotics, colony stimulating factors (CSFs) and also standard precautions including hand and respiratory hygiene are generally recommended but the exact effect of non-pharmacologic intervention such as standard precaution has not been clearly proven in the clinical setting. we aimed to compare the incidence of FN between pre-coronavirus disease 19 (COVID 19) era versus post-COVID 19 era.Material and methods We retrospectively enrolled patients with breast cancer who received adjuvant adriamycin and cyclosphosphamide (AC) chemotherapy at Jeju national university hospital.Results In total, 149 patients well enrolled, including 94 who received AC chemotherapy in pre-COVDI 19 era and 55 who received at post-COVID 19 era. Sixteen (10.7%) patients experienced the FN. Fourteen events (14.9%) and two events (3.6%) were occurred in pre-COVID 19 and post-COVDI 19 era, respectively. The post-COVID 19 era was the only risk factor for FN. (p = 0.032)Conclusion We found an association between FN occurrence and COVID 19 outbreak; thus, providing indirect evidence of the importance of non-pharmacological measure to reduce FN risk in patients with cancer. Further research is required to confirm the standard precautions for FN prevention in patients with cancer.

In Vivo Antiviral Efficacy of LCTG-002, a Pooled, Purified Human Milk Secretory IgA product, Against SARS-CoV-2 in a Murine Model of COVID-19 (preprint)

Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosal compartments including the respiratory tract, with the secretory form of IgA (sIgA) being dominant and uniquely stable in these environments. sIgA is naturally found in human milk, which could be considered a global resource for this biologic, justifying the development of human milk sIgA as a dedicated airway therapeutic for respiratory infections such as SARS-CoV-2. In the present study, methods were therefore developed to efficiently extract human milk sIgA from donors who were either immunologically naive to SARS-CoV-2 (pooled as a control IgA) or had recovered from a PCR-confirmed SARS-CoV-2 infection that elicited high-titer anti-SARS-CoV-2 Spike sIgA Abs in their milk (pooled together to make LCTG-002). Mass spectrometry determined that proteins with a relative abundance of 1.0% or greater were all associated with sIgA. None of the proteins exhibited statistically significant differences between batches. Western blot demonstrated all batches consisted predominantly of sIgA. Compared to control IgA, LCTG-002 demonstrated significantly higher binding to Spike, and was also capable of blocking the Spike - ACE2 interaction in vitro with 6.3x greater potency compared to control IgA (58% inhibition at ~240ug/mL). LCTG-002 was then tested in vivo for its capacity to reduce viral burden in the lungs of K18+hACE2 transgenic mice inoculated with SARS-CoV-2. LCTG-002 was demonstrated to significantly reduce SARS-CoV-2 titers in the lungs compared to control IgA when administered at either 250ug/day or 1 mg/day, as measured by TCID50, plaque forming units (PFU), and qRT-PCR, with a maximum reduction of 4.9 logs. This innovative study demonstrates that LCTG-002 is highly pure, efficacious, and well tolerated in vivo, supporting further development of milk-derived, polyclonal sIgA therapeutics against SARS-CoV-2 and other mucosal infections.

Evaluation of oral mucositis, candidiasis, and quality of life in patients with head and neck cancer treated with a hypofractionated or conventional radiotherapy protocol: a longitudinal, prospective, observational study.

BACKGROUND: Due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, recently, Radiotherapy (RT) protocols requiring fewer sessions (hypofractionated) have been used to shorten RT treatment and minimize patient exposure to medical centers, and decrease the risk of SARS-CoV-2 infection. METHODS: This longitudinal, prospective, observational study aimed to compare the quality of life (QoL) and the incidence of oral mucositis and candidiasis in 66 patients with head and neck cancer (HNC) who undergo a hypofractionated RT protocol (GHipo), total of 55 Gy for 4 weeks, or a conventional RT protocol (GConv), total of 66 - 70 Gy for 6 - 7 weeks. PURPOSE: To assess the incidence and severity of oral mucositis, the incidence of candidiasis, and QoL were evaluated using the World Health Organization scale, clinical evaluation, and the QLC-30 and H&N-35 questionnaires, respectively, at the beginning and the end of RT. RESULTS: The incidence of candidiasis did not show differences between the two groups. However, at the end of RT, mucositis had a higher incidence (p < 0.01) and severity (p < 0.05) in GHipo. QoL was not markedly different between the two groups. Although mucositis worsened in patients treated with hypofractionated RT, QoL did not worsen for patients on this regimen. CONCLUSIONS: Our results open perspectives for the potential use of RT protocols for HNC with fewer sessions in conditions that require faster, cheaper, and more practical treatments.

Effects of coronavirus disease 19 on the gastrointestinal tract and the potential impact on gastrointestinal toxicities during cancer treatment.

PURPOSE OF REVIEW: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has resulted in a global pandemic, with people with other conditions at greater risk of severe infection with intensified symptoms across multiple organ systems. Patients with cancer are at greater risk, and it is likely that those receiving treatment will experience greater incidence and severity of gastrointestinal toxicities, such as gastrointestinal mucositis, due to SARS-CoV-2 binding to angiotensin-converting enzyme (ACE)2 in the intestine. RECENT FINDINGS: Recent studies have shown that SARS-CoV-2 patients experience gastrointestinal toxicities, and SARS-CoV-2 has capacity to infect intestinal cells through binding to ACE2 expressed in the intestine. ACE2 has a key role in intestinal homeostasis, and as such there is a concern for the impact of SARS-CoV-2 binding to ACE2 in terms of the implications for cancer treatment-induced gastrointestinal toxicities. SUMMARY: SARS-CoV-2 is a high-risk infection for cancer patients receiving treatment. It is important to understand the mechanisms of intestinal infection with SARS-CoV-2 to determine the effect of SARS-CoV-2 infections on gastrointestinal toxicities, such as mucositis.

Mycoplasma pneumoniae-induced rash and mucositis.

Mycoplasma pneumoniae-induced rash and mucositis (MIRM) is a recently defined clinical entity characterized by pneumonia caused by M. pneumoniae with associated mucositis and frequent cutaneous lesions of a characteristic pattern. Although often similar in presentation, MIRM has distinct clinical and histologic features that are different from erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis. We report a case of MIRM in a nine-year-old boy.

Comparative evaluation of oral lesions: Tale - the Covid 19 Tells (preprint)

Abstract: Introduction & Objectives: The COVID-19 pandemic has been raging across the globe since early January 2020. India has reported over 27 million cases and more than 3, 00,000 deaths. This study was planned to analyze the differences in demographic, clinical features, and oral manifestations of COVID 19 patients hospitalized during the COVID-19 pandemic. Methods: This observational pilot study had a total of 36 participants, 12 each of mild, moderate, and severe RT-PCR positive COVID cases hospitalized during the COVID 19 pandemic. All demographic, clinical features, treatment details, and oral manifestations were noted from the first day of admission to the hospital till treatment completion with a follow-up of a minimum of 7 days. Results: Mean age of the patients was 39.44 years with M: F ratio of 5:4. Most common clinical presentation was fever, shortness of breath, and treatment involved was symptomatic with supplemental oxygen & mechanical ventilation. The most common oral site involved was the tongue & oral lesions observed were herpes labialis, mucositis, burning sensation, dryness of oral cavity, angular cheilitis, aphthous ulcers, geographic tongue, fissuring of the tongue, candidiasis, coated tongue, sublingual varicosity, & scalloped tongue. Interpretation and Conclusion: All demographic, clinical, and oral manifestations were significantly different in mild, moderate, and severe cases of covid hospitalized patients. Though clinical symptoms were improved, oral lesions were worsened. Oral Lesions seen in covid patients were associated with multiple drug therapy for illness along with poor oral hygiene, but further etiology for lesions needs to be evaluated. Sublingual varicosity was observed in our hospitalized covid patients, but a large sample observation is required for confirmation of findings and maybe an early oral feature for covid detection. Prevention is always better than cure, so all patients positive for Covid should have a full mouth examination. Oral health should be a priority during the overall management of COVID patients and dentists should be a part of the Covid management team. Key Words: Oral Lesions, COVID 19, Sublingual varicosity, Candidiasis, Tongue.

A Single Dose of COVID-19 mRNA Vaccine Induces Airway Immunity in COVID-19 Convalescent Patients (preprint)

BackgroundMucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine. MethodsTwenty-three COVID-19 convalescent patients and 20 SARS-CoV-2-naive subjects were vaccinated with respectively one and two doses of the Pfizer-BioNTech COVID-19 RNA vaccine. Nasal Epithelial Lining Fluid (NELF) and plasma were collected before and after vaccination and assessed for Immunoglobulin (Ig)G and IgA to Spike and for their ability to inhibit the binding of Spike to its ACE-2 receptor. Blood was analyzed one week after vaccination for the number of Spike-specific Antibody Secreting Cells (ASCs) with a mucosal tropism. ResultsIn COVID-19 convalescent patients, a single dose of vaccine amplified pre-existing Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after two vaccine doses ConclusionThis study showed that a parenteral booster injection of a COVID-19 RNA vaccine promoted stronger mucosal immune responses in COVID-19 convalescent patients compared to SARS-CoV-2 naive subjects who had received a first vaccine dose.

COVID-19 and abdominal pain: a pediatric case report and a point of view in pediatric emergency medicine.

COVID-19 is to date a global pandemic that can affect all age groups; gastrointestinal symptoms are quite common in patients with COVID-19 and a new clinical entity defined as Multisystem Inflammatory Syndrome in Children (MIS-C) has been described in children and adolescents previously affected by COVID-19. Presenting symptoms of this new disease include high fever and severe abdominal pain that can mimic more common causes of abdominal pain; patients can rapidly deteriorate presenting severe cardiac dysfunction and multiorgan failure. Some fatalities due to this serious illness have been reported. We describe the case of a ten-year-old patient presenting with persistent high fever associated with continuous and worsening abdominal pain. Various hypotheses were performed during his diagnostic workup and an initial appendectomy was performed in the suspect of acute appendicitis. As his clinical picture deteriorated, the child was subsequently diagnosed and successfully treated as a case of MIS-C. The objective of this case report and brief review of abdominal pain in children throughout the age groups is to provide the emergency pediatrician with updated suggestions in diagnosing abdominal pain in children during the COVID-19 pandemic.

Myeloid cell-driven nonregenerative pulmonary scarring is conserved in multiple nonhuman primate species regardless of SARS-CoV-2 infection modality (preprint)

The novel coronavirus SARS-CoV-2 has caused a worldwide pandemic resulting in widespread efforts in development of animal models that recapitulate human disease for evaluation of medical countermeasures, and to dissect COVID-19 immunopathogenesis. We tested whether route of experimental infection substantially changes COVID-19 disease characteristics in two species (Macaca mulatta; rhesus macaques; RM, Chlorocebus atheiops; African green monkeys; AGM) of nonhuman primates. Species-specific cohorts of RM and AGM Rhesus macaques (Macaca mulatta, RMs) and African green monkeys (Chlorocebus aethiops, AGMs) were experimentally infected with homologous SARS-CoV-2 by either direct mucosal instillation or small particle aerosol in route-discrete subcohorts. Both species demonstrated equivalent infection initially by either exposure route although the magnitude and duration of viral loading was greater in AGMs than that of the RM. Clinical onset was nearly immediate (+1dpi) in mucosally-exposed cohorts whereas aerosol-infected animals began to show signs +7dpi. Myeloid cell responses indicative of the development of pulmonary scarring and extended lack of regenerative capacity in the pulmonary compartment was a conserved pathologic response in both species by either exposure modality. This pathological commonality may be useful in future anti-fibrosis therapeutic evaluations and expands our understanding of how SARS-CoV-2 infection leads to ARDS and functional lung damage.

Reactive infectious mucocutaneous eruption in children diagnosed with COVID-19.

We describe the cases of two immunocompetent children who developed mucositis with oral, ocular, and genital involvement during acute COVID-19 illness. The pattern of mucosal involvement with no other cutaneous involvement was consistent with reactive infectious mucocutaneous eruption (RIME). No other intercurrent infections or new medications were identified, suggesting that COVID-19 was causative. Both patients noted improvement with systemic corticosteroid therapy.

Intra-host SARS-CoV-2 evolution in the gut of mucosally-infected Chlorocebus aethiops (African green monkeys) (preprint)

In recent months, several SARS-CoV-2 variants have emerged that enhance transmissibility and escape host humoral immunity. Hence, the tracking of viral evolutionary trajectories is clearly of great importance. Little is known about SARS-CoV-2 evolution in nonhuman primate models used to test vaccines and therapies and to model human disease. Viral RNA was sequenced from rectal swabs from Chlorocebus aethiops (African green monkeys) after experimental respiratory SARS-CoV-2 infection. Two distinct patterns of viral evolution were identified that were shared between all collected samples. First, mutations in the furin cleavage site that were initially present in the virus as a consequence of VeroE6 cell culture adaptation were subsequently lost in virus recovered in rectal swabs, confirming the necessity of this motif for viral infection in vivo. Three amino acid changes were also identified; ORF 1a S2103F, and spike D215G and H655Y, that were detected in rectal swabs from all sampled animals. These findings are demonstrative of intra-host SARS-CoV-2 evolution unique to this nonhuman primate species and may identify a host-adapted variant of SARS-CoV-2 that would be useful in future development of primate disease models.

Protective mucosal immunity against SARS-CoV-2 after heterologous systemic RNA-mucosal adenoviral vector immunization (preprint)

Several effective SARS-CoV-2 vaccines are currently in use, but in the light of waning immunity and the emergence of novel variants, effective boost modalities are needed in order to maintain or even increase immunity. Here we report that intranasal vaccinations with adenovirus 5 and 19a vectored vaccines following a systemic DNA or mRNA priming result in strong systemic and mucosal immunity in mice. In contrast to two intramuscular injections with an mRNA vaccine, the mucosal boost with adenoviral vectors induced high levels of IgA and tissue-resident memory T cells in the respiratory tract. Mucosal neutralization of virus variants of concern was also enhanced by the intranasal boosts. Importantly, priming with mRNA provoked a more comprehensive T cell response consisting of circulating and tissue-resident memory T cells after the boost, while a DNA priming induced mostly mucosal T cells. Concomitantly, the intranasal boost strategies provided protection against symptomatic disease. Therefore, a mucosal booster immunization after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses.

Mucosal Respiratory Syndrome: A Systematic Literature Review.

BACKGROUND: Mycoplasma pneumoniae atypical pneumonia is frequently associated with erythema multiforme. Occasionally, a mycoplasma infection does not trigger any cutaneous but exclusively mucosal lesions. The term mucosal respiratory syndrome is employed to denote the latter condition. Available reviews do not address the possible association of mucosal respiratory syndrome with further atypical bacterial pathogens such as Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Francisella tularensis, or Legionella species. We therefore performed a systematic review of the literature addressing this issue in the National Library of Medicine, Excerpta Medica, and Web of Science databases. SUMMARY: We found 63 patients (≤18 years, n = 36; >18 years, n = 27; 54 males and 9 females) affected by a mucosal respiratory syndrome. Fifty-three cases were temporally associated with a M. pneumoniae and 5 with a C. pneumoniae infection. No cases temporally associated with C. psittaci, C. burnetii, F. tularensis, or Legionella species infection were found. Two cases were temporally associated with Epstein-Barr virus or influenzavirus B, respectively.

Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children.

BACKGROUND: Little is known about mucocutaneous disease in acutely ill children and adolescents with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). OBJECTIVE: To characterize mucocutaneous disease and its relation to clinical course among hospitalized patients with COVID-19 and MIS-C. METHODS: Descriptive cohort study of prospectively and consecutively hospitalized eligible patients between May 11, 2020 and June 5, 2020. RESULTS: In COVID-19 patients, 4 of 12 (33%) had rash and/or mucositis, including erythema, morbilliform pattern, and lip mucositis. In MIS-C patients, 9 of 19 (47%) had rash and/or mucositis, including erythema, morbilliform, retiform purpura, targetoid and urticarial patterns, along with acral edema, lip mucositis, tongue papillitis, and conjunctivitis. COVID-19 patients with rash had less frequent respiratory symptoms, pediatric intensive care unit admission, invasive ventilation, and shorter stay versus COVID-19 patients without rash. MIS-C patients with rash had less frequent pediatric intensive care unit admission, shock, ventilation, as well as lower levels of C-reactive protein, ferritin, D-dimer, and troponin (vs MIS-C without rash). Neutrophil-to-lymphocyte ratio was similar for patients with and without rash in both groups. None of the MIS-C patients met criteria for Kawasaki disease. LIMITATIONS: Small sample sizes. CONCLUSIONS: Mucocutaneous disease is common among children and adolescents with COVID-19 and MIS-C. Laboratory trends observed in patients with rash may prognosticate a less severe course.

A Young Adult with COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C)-like Illness: A Case Report (preprint)

Background: A healthy 25-year-old woman developed COVID-19 disease with clinical characteristics resembling Multisystem Inflammatory Syndrome in Children (MIS-C), a rare form of COVID-19 described primarily in children under 21 years of age.Case Presentation: The patient presented with one week of weakness, dyspnea, and low-grade fevers, followed by mild cough, sore throat, vomiting, diarrhea, and lymph node swelling. She was otherwise healthy, with no prior medical history. Her hospital course was notable for profound acute kidney injury, leukocytosis, hypotension, and cardiac dysfunction requiring ICU admission and vasopressor support. MIS-C-like illness secondary to COVID-19 was suspected due to physical exam findings of conjunctivitis, mucositis, and shock. She improved following IVIG, aspirin, and supportive care, and was discharged on hospital day 5.Conclusion: MIS-C-like illness should be considered in adults presenting with atypical clinical findings and concern for COVID-19. Further research is needed to support the role of IVIG and aspirin in this patient population.

Ankaferd hemostat (ABS) as a potential mucosal topical agent for the management of COVID-19 syndrome based on its PAR-1 inhibitory effect and oestrogen content.

COVID-19 due to the SARS-CoV-2 infection is a multi-systemic immune syndrome affecting mainly the lungs, oropharyngeal region, and other vascular endothelial beds. There are tremendous ongoing efforts for the aim of developing drugs against the COVID-19 syndrome-associated inflammation. However, currently no specific medicine is present for the absolute pharmacological cure of COVID-19 mucositis. The re-purposing/re-positioning of already existing drugs is a very important strategy for the management of ongoing pandemy since the development of a new drug needs decades. Apart from altering angiotensin signaling pathways, novel drug candidates for re-purposing comprise medications shall target COVID-19 pathobiology, including pharmaceutical formulations that antagonize proteinase-activated receptors (PARs), mainly PAR-1. Activation of the PAR-1, mediators and hormones impact on the hemostasis, endothelial activation, alveolar epithelial cells and mucosal inflammatory responses which are the essentials of the COVID-19 pathophysiology. In this context, Ankaferd hemostat (Ankaferd Blood Stopper, ABS) which is an already approved hemostatic agent affecting via vital erythroid aggregation and fibrinogen gamma could be a potential topical remedy for the mucosal management of COVID-19. ABS is a clinically safe and effective topical hemostatic agent of plant origin capable of exerting pleiotropic effects on the endothelial cells, angiogenesis, cell proliferation and vascular dynamics. ABS had been approved as a topically applied hemostatic agent for the management of post-surgical/dental bleedings and healing of infected inflammatory mucosal wounds. The anti-inflammatory and proteinase-activated receptor axis properties of ABS with a considerable amount of oestrogenic hormone presence highlight this unique topical hemostatic drug regarding the clinical re-positioning for COVID-19-associated mucositis. Topical ABS as a biological response modifier may lessen SARS-CoV-2 associated microthrombosis, endothelial dysfunction, oropharyngeal inflammation and mucosal lung damage. Moreover, PAR-1 inhibition ability of ABS might be helpful for reducing the initial virus propagation and mocasal spread of COVID-19.

The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. (preprint)

Many pathogens take advantage of the dependence of the host on the interaction of hundreds of extracellular proteins with the glycosaminoglycans heparan sulphate to regulate homeostasis and use heparan sulphate as a means to adhere and gain access to cells. Moreover, mucosal epithelia such as that of the respiratory tract are protected by a layer of mucin polysaccharides, which are usually sulphated. Consequently, the polydisperse, natural products of heparan sulphate and the allied polysaccharide, heparin have been found to be involved and prevent infection by a range of viruses including S-associated coronavirus strain HSR1. Here we use surface plasmon resonance and circular dichroism to measure the interaction between the SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) and heparin. The data demonstrate an interaction between the recombinant surface receptor binding domain and the polysaccharide. This has implications for the rapid development of a first-line therapeutic by repurposing heparin and for next-generation, tailor-made, GAG-based antivirals.