Plasma Levels of Mid-Regional Proadrenomedullin Accurately Identify H1N1pdm09 Influenza Virus Patients with Risk of Intensive Care Admission and Mortality in the Emergency Department

Early identification of severe viral pneumonia in influenza virus A (H1N1pdm09) patients is extremely important for prompt admission to the ICU. The objective is to evaluate the usefulness of MR-proadrenomedullin (MR-proADM) compared to C reactive protein (CRP), procalcitonin (PCT), and ferritin in the prognosis of influenza A pneumonia. This prospective, observational, multicenter study included one hundred thirteen patients with confirmed influenza virus A (H1N1pdm09) admitted to an Emergency Department and ICUs of six hospitals in Spain. Measurements and Main Results: one-hundred thirteen patients with confirmed influenza virus A (H1N1pdm09) were enrolled. Seventy-five subjects (mortality 29.3%) with severe pneumonia caused by influenza A H1N1pdm09 virus (H1N1vIPN) were compared with 38 controls (CG).The median MR-proADM levels at hospital admission were 1.2 nmol/L (IQR (0.8–2.6) vs. 0.5 nmol/L (IQR 0.2–0.9) in the CG (p = 0.01), and PCT levels were 0.43 μg/L (IQR 0.2–1.2) in the H1N1vIPN group and 0.1 μg/L (IQR 0.1–0.2) in the CG (p < 0.01). CRP levels at admission were 15.5 mg/dL(IQR 9.2–24.9) in H1N1vIPN and 8.6 mg/dL(IQR 3–17.3) in the CG (p < 0.01). Ferritin levels at admission were 558.1 ng/mL(IQR 180–1880) in H1N1vIPN and 167.7 ng/mL(IQR 34.8–292.9) in the CG (p < 0.01). A breakpoint for hospital admission of MR-proADM of 1.1 nmol/L showed a sensitivity of 55% and a specificity of 90% (AUC-ROC0.822). Non-survivors showed higher MR-proADM levels: median of 2.5 nmol/L vs. 0.9 nmol/L among survivors (p < 0.01). PCT, CRP, and ferritin levels also showed significant differences in predicting mortality. The MR-proADM AUC-ROC for mortality was 0.853 (p < 0.01). In a Cox proportional hazards model, MR-proADM levels > 1.2 nmol/L at hospital admission were significant predictive factors for ICU and 90-day mortality (HR: 1.3). Conclusions: the initial MR-proADM, ferritin, CRP, and PCT levels effectively determine adverse outcomes and risk of ICU admission and mortality in patients with influenza virus pneumonia. MR-proADM has the highest potency for survival prediction.

A Lower Level of Post-Vaccinal Antibody Titer against Influenza Virus A H1N1 May Protect Patients with Autoimmune Rheumatic Diseases from Respiratory Viral Infections

Background and Objectives: The concentration of antibodies against virus influenza A H1N1 in the titer (≥1:32) positively correlates with resistance to flu in healthy persons. In elderly and immune-compromised patients, an influenza vaccine may be less immunogenic. Hypothesis: A lower post-vaccinal antibody titer (≥1:16) may be sero-protective against respiratory viral infections in patients with autoimmune rheumatic diseases. Materials and Methods: Fifty patients with autoimmune rheumatic diseases (Systemic Lupus Erythematosus—24; Rheumatoid Arthritis—15; and Sjögren’s Syndrome—11), who were at least 65 years old or whose relative disease duration (disease duration/age) was greater than 1/8, were examined. Thirty-four of them were vaccinated with a trivalent inactivated non-adjuvant influenza vaccine. The antibody concentration against influenza virus A H1N1 was measured using the standardized hemagglutination inhibition test and patients who got any respiratory viral infection were registered. To test the hypothesis, a correlative analysis was applied, followed by a binary logistic regression that included potential confounding variables, such as age, disease duration and therapy (personal/health-related conditions). Results: Vaccinated patients were significantly less affected by respiratory viral infections (21% vs. 75%). The lower titer considered (≥1:16) was significantly present more often among vaccinated patients (68% vs. 6%). The correlation between its presence/absence and that of respiratory viral infections was –0.34 (p < 0.05). The binary logistic regression evidenced the relevance of this correlation, confirming the hypothesis. Vaccination was associated with the 87.3% reduction in the likelihood of getting respiratory viral infections, whereas the lower antibody titer (≥1:16) was associated with the 77.6% reduction in the likelihood of getting respiratory viral infections. The vaccine was well tolerated by all patients and after vaccination no exacerbation of the underlying disease was observed. Conclusions: A lower antibody titer (≥1:16) against influenza virus A H1N1 could be protective against respiratory viral infections for certain autoimmune rheumatic diseases patients, which confirms the clinical effectiveness of influenza vaccination.

Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.

A Comparative Analysis of the Spanish Flu 1918 and COVID-19 Pandemics

Two devastating pandemics, the Spanish Flu and COVID-19, emerged globally in 1918 from America and 2019 from China, respectively. Influenza virus A H1N1, which caused Spanish Flu and SARS-CoV2, which caused COVID-19, belong to different virus family and bear different structure, genomic organization and pathogenicity. However, the trajectory of the current outbreak of COVID-19 depicts a similar picture of the Spanish Flu outbreak. Estimates suggest that ~500 million infected cases and ~50 million deaths occurred globally from 1918-1919 due to the H1N1 virus. While SARS-CoV2 accounted for ~2 million cases and 130,885 deaths just within three and a half months, and the number is still increasing. To contain the spread of COVID-19 and to prevent the situation which happened a century back, it becomes essential to examine and correlate these pandemics in terms of their origin, epidemiology and clinical scenario. The strategies tailored to control the Spanish Flu pandemic may help to contain the current pandemic within time.

Etiological and epidemiological characteristics of severe acute respiratory infection caused by multiple viruses and Mycoplasma pneumoniae in adult patients in Jinshan, Shanghai: A pilot hospital-based surveillance study

Background Severe acute respiratory infection (SARI) results in a tremendous disease burden worldwide. Available research on active surveillance among hospitalized adult patients suffering from SARI in China is limited. This pilot study aimed to identify associated etiologies and describe the demographic, epidemiological and clinical profiles of hospitalized SARI patients aged over 16 years in Jinshan, Shanghai. Methods Active surveillance was conducted at 1 sentinel hospital in Jinshan district, Shanghai, from April 2017 to March 2018. Hospitalized SARI patients aged over 16 years old were enrolled, and nasopharyngeal swabs were collected within 24 hours of admission and tested for multiple respiratory viruses (including 18 common viruses) and Mycoplasma pneumoniae with real-time polymerase chain reaction. Demographic, epidemiological and clinical information was obtained from case report forms. Results In total, 397 SARI patients were enrolled; the median age was 68 years, and 194 (48.9%) patients were male. A total of 278 (70.0%) patients had at least one underlying chronic medical condition. The most frequent symptoms were cough (99.2%) and sputum production (88.4%). The median duration of hospitalization was 10 days. A total of 250 infection patients (63.0%) were positive for at least one pathogen, of whom 198 (49.9%) were positive for a single pathogen and 52 (13.1%) were positive for multiple pathogens. The pathogens identified most frequently were M. pneumoniae (23.9%, 95/397), followed by adenovirus (AdV) (11.6%, 46/397), influenza virus A/H3N2 (Flu A/H3N2) (11.1%, 44/397), human rhinovirus (HRhV) (8.1%, 32/397), influenza virus B/Yamagata (Flu B/Yamagata) (6.3%, 25/397), pandemic influenza virus A/H1N1 (Flu A/pH1N1) (4.0%, 16/397), parainfluenza virus (PIV) type 1 (2.0%, 8/397), human coronavirus (HCoV) type NL63 (2.0%, 8/397), HCoV 229E (1.5%, 6/397), HCoV HKU1 (1.5%, 6/397), PIV 3 (1.5%, 6/397), human metapneumovirus (HMPV) (1.5%, 6/397), PIV 4 (1.3%, 5/397), HCoV OC43 (1.0%, 4/397), influenza virus B/Victoria (Flu B/Victoria) (0.5%, 2/397), respiratory syncytial virus (RSV) type B (0.5%, 2/397), and human bocavirus (HBoV) (0.3%, 1/397). The seasonality of pathogen-confirmed SARI patients had a bimodal distribution, with the first peak in the summer and the second peak in the winter. Statistically significant differences were observed with respect to the rates of dyspnea, radiographically diagnosed pneumonia and the presence of at least one comorbidity in patients who were infected with only M. pneumoniae, AdV, HRhV, Flu A/H3N2, Flu A /pH1N1 or Flu B/Yamagata. The differences in the positivity rates of the above 6 pathogens among the different age groups were nonsignificant. Conclusions M. pneumoniae, AdV and Flu A/H3N2 were the main pathogens detected in hospitalized SARI patients aged over 16 years old in Jinshan district, Shanghai. Our findings highlight the importance of sustained multipathogen surveillance among SARI patients in sentinel hospitals, which can provide useful information on SARI etiologies, epidemiology, and clinical characteristics.