Tomato Flu/Fever-An analysis of the Hand Foot and Mouth Disease outbreak reported in India

The term "Tomato Flu” or "Tomato Fever” is the colloquial term in India used to describe multiple diseases that present with a fever and rash, with characteristic red, "tomato” shaped blister that appears on different parts of the body, which begin small and increase in size as disease progresses. Some controversy exists on this ‘new viral "flu” that emerged in May 2022 over a period of 2 weeks in areas in the south of India. Currently, local healthcare workers have been encouraged to address the disease as a variant of Hand Foot and Mouth Disease to avoid unnecessary panic on the emergence of a "new outbreak”. With the circulation of other viruses, inadequate testing and poor-quality surveillance in a low resource setting, where healthcare systems are already burdened with ongoing monkeypox outbreak and COVID-19 pandemic, the use of colloquial terms may cause unnecessary panic in the current hypervigilant climate. Confirmation from Government is required to confirm whether this outbreak is due to a mixed infection or a variant of the highly infectious Hand Foot and Mouth Disease virus. © 2022, The authors.

Understanding SARS-CoV-2 Delta and Omicron variant transmission and vaccine impact in schools and child-care settings in Australia: a population-based study.

Background: Over 214 million students globally have been affected by school closures during the COVID-19 pandemic. To address knowledge gaps on transmission of SARS-CoV-2 delta (B.1.617.2) and omicron (B.1.1.529) variants in educational settings we examined virus transmission in schools and early childhood education and care settings (ECECs) in New South Wales (NSW), Australia in relation to mitigation measures, including COVID-19 vaccination. Methods: Secondary transmission from children and adults with laboratory-confirmed SARS-CoV-2 infection who attended a school (n = 3170) or ECECs (n = 5800) while infectious was investigated over two periods: 1) June 16 to September 18, 2021 (delta outbreak), and; 2) October 18 to December 18, 2021 (delta and omicron; schools only). Close contacts of cases underwent 14 days quarantine and SARS-CoV-2 nucleic acid testing. Secondary attack rates (SARs) were calculated and compared with state-wide notification data, school attendance, and vaccination status. Findings: 1187 schools and 300 ECECs had students (n = 1349) or staff (n = 440) attend while infectious. Of 24,277 contacts investigated, most (91.8%; 22,297/24,277) were tested and 912 secondary cases identified. The secondary attack rate (SAR) was 5.9% in 139 ECECs and 3.5% in 312 schools. The risk of becoming a secondary case was higher in unvaccinated school staff (OR 4.7; 95% CI: 1.7-13.3), particularly ECEC staff (OR 9.0; 95% CI: 3.6-22.7) and unvaccinated school students than in vaccinated school staff. SARs were similar for delta (4.9%) and omicron BA.1 (4.1%) in the unvaccinated and higher compared with vaccinated contacts (0.9% and 3.4%, respectively). Increasing school attendance rates raised case incursions and secondary case numbers, but not community-wide infection rates. Interpretation: Vaccination reduced SARS-CoV-2 transmission rates in schools, although less so for omicron than delta variants. Despite higher community-based transmission rates, in-school transmission remained low and stable with high attendance, suggesting that community restrictions, rather than school closures, best mitigated COVID-19 impacts. Funding: NSW Government Department of Health.

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

Objectives: Immune checkpoint blockade (ICB) has demonstrated efficacy in a small fraction of patients with platinum-resistant ovarian cancer (PROC), some with durable responses. The receptor tyrosine kinase AXL and its sole ligand, GAS6, are possible mediators of T cell exclusion and an attractive target due to the expected synergy between AXL inhibition and immune targeting agents. The recommended phase II dose (RP2D), safety, and efficacy of the combination of AXL inhibition via AVB-S6-500 with durvalumab (MEDI4736) were evaluated in patients with PROC. Methods: In this open-label Phase Ib open-label study, patients with PROC received AVB-S6-500 and durvalumab therapy in escalating dosing regimens guided by a Bayesian optimal interval (BOIN) design: durvalumab (1500 mg Q4W) and AVB-S6-500 (10mg/kg Q2W, 15mg/kg Q2W, 20mg/kg Q2W) with durvalumab infused prior to AVB-S6-500. The response was evaluated using modified RECIST v1.1. Pharmacokinetic/pharmacodynamic (PK/PD) studies were collected, and PD-L1 status and tumor/tumor microenvironment AXL and GAS6 staining pre and on-treatment were assessed. Results: Eleven patients with epithelial ovarian cancer (six clear cells [55%], four high-grade serous [36%], one endometrioid histology [1%]) received treatment per protocol. The median number of prior lines of therapy was 3 (range: 1-5);73% (8/11) of patients had received prior bevacizumab. There were no DLTs noted over the 6-week period and no grade ≥3 adverse events attributed to study drugs. Five patients experienced an immune-related AE, most commonly liver enzyme elevations (36%). Infusion reaction with AVB-S6- 500 was noted in the first two subjects, prompting the institution of a premedication regimen, after which only one of the nine additional patients experienced an infusion reaction. Dose delays greater than one week occurred in six (55%) patients;three patients experienced delays for cancer-related complications (small bowel obstruction, pneumonia, severe fatigue), while three patients experienced delays for non-medical causes (COVID/travel, weather). Patients received therapy for a median of two cycles (range: 1-6), and there were no responses noted across all dosing levels. One patient had stable disease, with a duration of response of three months. Only two patients had strong (2+) AXLstaining on pretreatment biopsy, both with high-grade serous histology. The majority of serum AXL levels were within previously demonstrated ranges (range: 5.6-112ng/mL), though two patients had comparatively high levels (102, 112ng/mL). PK/PD analysis revealed expected AVB-S6-500 levels at initial postdose (C1D1), but low levels at trough (C2D1 predose) when compared to prior AVB-S6-500 data [1]. Conclusions: The combination of AVB-S6-500 and durvalumab was tolerable in this PROC patient population at all dosing levels tested. Exploratory studies to correlate lack of response to AXL-GAS6 pathway alterations, tumor microenvironment, and clinical characteristics, such as prior treatment, dosing delays, burden of disease, and ascites, are ongoing.

COVID-19 VACCINE RESPONSE IN PATIENTS ON CANCER THERAPY - EVIDENCE FROM AUSTRALIAN DATA

Background: Cancer patients have increased risk of serious illness or death from COVID-19. Vaccination protects against severe disease, but cancer patients were excluded from COVID-19 vaccine registration trials. Different cancer therapies may have varying impact on immune response. We assessed seroconversion post COVID-19 vaccination among cancer patients in a setting of high vaccine uptake with minimal community transmission. Methods: Solid tumour patients and healthy controls from Canberra who received COVID-19 vaccination between 3/2021 - 1/2022 were included. Patients received active cancer therapy within two weeks of COVID-19 vaccination. Blood was collected at baseline, pre 2nd vaccine dose, then one, three and six months post 2nd dose. SARS-CoV-2 anti-spike receptor binding domain and anti-nucleocapsid immunoglobulin G(IgG) levels were measured by enzyme-linked immunosorbent assay and calibrated with the National Institutes of Health serology standard. Primary endpoint was seroconversion three months post 2nd vaccine dose, or within two weeks prior to 3rd vaccine dose in patients. Results: There were 96 solid tumour patients (76 evaluable for the primary endpoint) and 19 healthy controls. Median age 62 years with 70 (61%) being female. COVID-19 vaccines included AZD1222 (65%) and BNT162b2 (35%). Majority (69%) of patients had metastatic cancer. Baseline lymphopenia (<1.2x10-9/L) was seen in 41% of patients. Median Charlson comorbidity index score was 7 (2 - 12). Among primary endpoint evaluable patients, 47 (62%) patients received chemotherapy, alone or in combination with other cancer therapy;8 (11%) received immunotherapy alone;21 (28%) had targeted therapy. Seroconversion at three months post vaccination occurred in 86% of cancer patients and 100% of controls (p=0.11). Mean anti-spike antibody titre was 88 binding antibody units (BAU)/ml in cancer patients and 179 BAU/ml in controls, p=0.10. No subjects had positive antinucleocapsid IgG confirming absence of past COVID-19 infection. Seroconversion occurred in patients who received chemotherapy alone or in combination (83%), immunotherapy (75%) and targeted therapy (95%;p=0.2). Mean anti-spike IgG levels were 77, 63 and 137 BAU/mL with chemotherapy, immunotherapy and targeted therapy respectively. Age, metastatic disease and lymphocyte count were not associated with antispike antibody level. Among cancer patients, 40% and 95% were seropositive after 1 and 2 vaccine doses respectively. A decline in anti-spike antibody titre was seen from three months post the 2nd vaccine dose. Cancer patients had an increase in anti-spike post 3rd vaccine dose, while levels declined in controls (pre booster), at 6 months post the 2nd vaccine dose. Conclusions: Cancer patients achieved comparable seroconversion rates three months post vaccination compared with healthy controls. Although the anti-spike antibody titre was numerically lower among cancer patients than controls, the difference was not statistically significant. Recent cancer therapy did not appear to significantly affect vaccine response, however, the anti-spike antibody level was numerically lower among recipients of chemotherapy compared with targeted therapy. Patients on immunotherapy had the lowest antibody level, although the small sample size limits definitive conclusion in this subgroup. Reassuringly, a rise in anti-spike antibody occurred after the 3rd primary dose in cancer patients, surpassing the level among controls prior to receipt of booster vaccination.

Longitudinal evaluation of laboratory-based serological assays for SARS-CoV-2 antibody detection.

Serological assays for SARS-CoV-2 infection are now widely available for use in diagnostic laboratories. Limited data are available on the performance characteristics in different settings, and at time periods remote from the initial infection. Validation of the Abbott (Architect SARS-CoV-2 IgG), DiaSorin (Liaison SARS-CoV-2 S1/S2 IgG) and Roche (Cobas Elecsys Anti-SARS-CoV-2) assays was undertaken utilising 217 serum samples from 131 participants up to 7 months following COVID-19 infection. The Abbott and DiaSorin assays were implemented into routine laboratory workflow, with outcomes reported for 2764 clinical specimens. Sensitivity and specificity were concordant with the range reported by the manufacturers for all assays. Sensitivity across the convalescent period was highest for the Roche at 95.2-100% (95% CI 81.0-100%), then the DiaSorin at 88.1-100% (95% CI 76.0-100%), followed by the Abbott 68.2-100% (95% CI 53.4-100%). Sensitivity of the Abbott assay fell from approximately 5 months; on this assay paired serum samples for 45 participants showed a significant drop in the signal-to-cut-off ratio and 10 sero-reversion events. When used in clinical practice, all samples testing positive by both DiaSorin and Abbott assays were confirmed as true positive results. In this low prevalence setting, despite high laboratory specificity, the positive predictive value of a single positive assay was low. Comprehensive validation of serological assays is necessary to determine the optimal assay for each diagnostic setting. In this low prevalence setting we found implementation of two assays with different antibody targets maximised sensitivity and specificity, with confirmatory testing necessary for any sample which was positive in only one assay.

Point of care and intensive care lung ultrasound: A reference guide for practitioners during COVID-19.

Objectives: Current events with the recent COVID-19 outbreak are necessitating steep learning curves for the NHS workforce. Ultrasound, although not used in the diagnosis of COVID-19 may be utilised by practitioners at the point of care (POC) or on the intensive care units (ITUs) where rapid assessment of the lung condition may be required. The aim of this article was to review current literature surrounding the use of lung ultrasound in relation to COVID-19 and provide Sonographers with a quick and digestible reference guide for lung pathologies. Key findings: Ultrasound is being used in Italy and China to help review lung condition during the COVID-19 outbreak however not strictly as a diagnostic tool as Computed Tomography (CT) of the chest and chest radiographs are currently gold standard. Ultrasound is highly sensitive in the detection of multiple lung pathologies which can be demonstrated in conjunction with COVID-19 however to date there are no specific, nor pathognomonic findings which relate to COVID-19 on ultrasound. Conclusion: Lung ultrasound is highly sensitive and can quickly and accurately review lung condition creating potential to assess for changes or resolution over time, especially in the ITU and POC setting. However it should not be used as a diagnostic tool for COVID-19 due to low specificity in relation to the virus. Implications for practice: The adoption of lung ultrasound to monitor lung condition during the COVID-19 outbreak may reduce the need for serial exposure to ionising radiation on the wards and in turn reduce the number of radiographers required to attend infected wards and bays, protecting both patients and the workforce.