Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted 12 March 2020-30 December 2021 to the pediatric intensive care unit (PICU) or high-acuity unit for acute COVID-19 were included. RESULTS: Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs 4.6%, P = .005) and hospitalization was longer (P = .01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, P = .40). In patients with ICCs, bacterial coinfection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

Critically ill children with SARS-COV-2 Omicron infection at a national children medical center, Guangdong, China.

BACKGROUND: SARS-CoV-2 infection is described as asymptomatic, mild, or moderate disease in most children. SARS-CoV-2 infection related death in children and adolescents is rare according to the current reports. COVID-19 cases increased significantly in China during the omicron surge, clinical data regarding pediatric critical patients infected with the omicron variant is limited. In this study, we aim to provide an overview of the clinical characteristics and outcomes of critically ill children admitted to a national children's medical center in Guangdong Province, China, during the outbreak of the omicron variant infection. METHODS: We conducted a retrospective study from November 25, 2022, to February 8, 2023, which included 63 critically ill children, under the age of 18, diagnosed with SARS-CoV-2 infection. The patients were referred from medical institutions of Guangdong province. The medical records of these patients were analyzed and summarized. RESULTS: The median age of patients was 2 years (Interquartile Range, IQR: 1.0-8.0), sex-ratio (male/female) was 1.52. 12 (19%) patients (age ≥ 3 years) were vaccinated. The median length of hospital stay was 14 days (IQR: 6.5-23) in 63 cases, and duration of fever was 5 days (IQR: 3-8.5), pediatric intensive care unit (PICU) stay was 8 days (IQR 4.0-14.0) in 57 cases. 30 (48%) cases had clear contact history with family members who were infected with SARS-CoV-2. Three children who tested positive for SARS-CoV-2 infection did not show any abnormalities on chest imaging examination. Out of the total patients, 33 (52%) had a bacterial co-infection, with Staphylococcus aureus being the most commonly detected bacterial pathogen. Our cohort exhibited respiratory and nervous system involvement as the primary features. Furthermore, fifty (79%) patients required mechanical ventilation, with a median duration of 7 days (IQR 3.75-13.0). Among these patients, 35 (56%) developed respiratory failure, 16 (25%) patients experienced a deteriorating progression of symptoms and ultimately succumbed to the illness, septic shock was the most common condition among these patients (15 cases), followed by multiple organ failure in 12 cases, and encephalopathy identified in 7 cases. CONCLUSION: We present a case series of critically ill children infected with the SARS-CoV-2 omicron variant. While there is evidence suggesting that Omicron may cause less severe symptoms, it is important to continue striving for measures that can minimize the pathogenic impact of SARS-CoV-2 infection in children.

Microbial and Immune Regulation of the Gut-Lung Axis during Viral-Bacterial Coinfection.

Viral-bacterial coinfections of the respiratory tract have long been associated with worsened disease outcomes. Clinical and basic research studies demonstrate that these infections are driven via complex interactions between the infecting pathogens, microbiome, and host immune response, although how these interactions contribute to disease progression is still not fully understood. Research over the last decade shows that the gut has a significant role in mediating respiratory outcomes, in a phenomenon known as the "gut-lung axis." Emerging literature demonstrates that acute respiratory viruses can modulate the gut-lung axis, suggesting that dysregulation of gut-lung cross talk may be a contributing factor during respiratory coinfection. This review will summarize the current literature regarding modulation of the gut-lung axis during acute respiratory infection, with a focus on the role of the microbiome, secondary infections, and the host immune response.

The clinical predictors of and vaccine protection against severe influenza infection in children.

Influenza infection in children causes a tremendous global burden. In this study, we aimed to investigate the clinical predictors of severe influenza among children. We retrospectively included hospitalized children who had laboratory-confirmed influenza infection and were admitted to a medical center in Taiwan between 2010 and 2018. Severe influenza infection was defined as needing intensive care. We compared demographics, comorbidities, vaccine status and outcomes between patients with severe and nonsevere infection. There were 1030 children hospitalized for influenza infection: 162 patients needed intensive care and 868 patients did not. Multivariable analysis revealed that an age below 2 years (adjusted odds ratio [aOR] 3.31, 95% confidence interval [CI] 2.22-4.95), underlying cardiovascular disease (aOR 1.84, 95% CI 1.04-3.25), neuropsychological (aOR 4.09, 95% CI 2.59-6.45) or respiratory disease (aOR 3.87, 95% CI 1.42-10.60), patchy infiltrates (aOR 2.52, 95% CI 1.29-4.93), pleural effusion (aOR 6.56, 95% CI 1.66-25.91), and invasive bacterial coinfection (aOR 21.89, 95% CI 2.19-218.77) were significant clinical predictors of severe disease, whereas severe infection was less likely in individuals who had received influenza and pneumococcal conjugate vaccines (PCVs) (aOR 0.51, 95% CI 0.28-0.91; aOR 0.35, 95% CI 0.23-0.51, respectively). The most significant risk factors associated with severe influenza infection were an age under 2 years, comorbidities (cardiovascular, neuropsychological, and respiratory diseases), patchy infiltrates or effusion shown on chest X-rays, and bacterial coinfections. The incidence rate of severe disease was significantly lower in those who had received influenza vaccines and PCVs.

Bacterial co-infection and antibiotic stewardship in patients with COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Understanding the proportion of patients with COVID-19 who have respiratory bacterial co-infections and the responsible pathogens is important for managing COVID-19 effectively while ensuring responsible antibiotic use. OBJECTIVE: To estimate the frequency of bacterial co-infection in COVID-19 hospitalized patients and of antibiotic prescribing during the early pandemic period and to appraise the use of antibiotic stewardship criteria. METHODS: Systematic review and meta-analysis was performed using major databases up to May 5, 2021. We included studies that reported proportion/prevalence of bacterial co-infection in hospitalized COVID-19 patients and use of antibiotics. Where available, data on duration and type of antibiotics, adverse events, and any information about antibiotic stewardship policies were also collected. RESULTS: We retrieved 6,798 studies and included 85 studies with data from more than 30,000 patients. The overall prevalence of bacterial co-infection was 11% (95% CI 8% to 16%; 70 studies). When only confirmed bacterial co-infections were included the prevalence was 4% (95% CI 3% to 6%; 20 studies). Overall antibiotic use was 60% (95% CI 52% to 68%; 52 studies). Empirical antibiotic use rate was 62% (95% CI 55% to 69%; 11 studies). Few studies described criteria for stopping antibiotics. CONCLUSION: There is currently insufficient evidence to support widespread empirical use of antibiotics in most hospitalised patients with COVID-19, as the overall proportion of bacterial co-infection is low. Furthermore, as the use of antibiotics during the study period appears to have been largely empirical, clinical guidelines to promote and support more targeted administration of antibiotics in patients admitted to hospital with COVID-19 are required.

Candidate Role for Toll-like Receptor 3 L412F Polymorphism and Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular antiviral responses and is associated with accelerated disease progression in idiopathic pulmonary fibrosis (IPF). The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objectives: To characterize the association between TLR3 L412F and AE-related death in IPF. To determine the effect of TLR3 L412F on the lung microbiome and on antibacterial TLR responses of primary lung fibroblasts from patients with IPF. Methods: TLR-mediated antibacterial and antiviral responses were quantitated in L412F wild-type and 412F-heterozygous primary lung fibroblasts from patients with IPF using ELISA, Western blot analysis, and quantitative PCR. Hierarchical heatmap analysis was employed to establish bacterial and viral clustering in nasopharyngeal lavage samples from patients with AE-IPF. 16S ribosomal RNA quantitative PCR and pyrosequencing were used to determine the effect of TLR3 L412F on the IPF lung microbiome. Measurements and Main Results: A significant increase in AE-related death in patients with 412F-variant IPF was reported. We established that 412F-heterozygous IPF lung fibroblasts have reduced antibacterial TLR responses to LPS (TLR4), Pam3CYSK4 (TLR1/2), flagellin (TLR5), and FSL-1 (TLR6/1) and have reduced responses to live Pseudomonas aeruginosa infection. Using 16S ribosomal RNA sequencing, we demonstrated that 412F-heterozygous patients with IPF have a dysregulated lung microbiome with increased frequencies of Streptococcus and Staphylococcus spp. Conclusions: This study reveals that TLR3 L412F dysregulates the IPF lung microbiome and reduces the responses of IPF lung fibroblasts to bacterial TLR agonists and live bacterial infection. These findings identify a candidate role for TLR3 L412F in viral- and bacterial-mediated AE death.

From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children.

Neutrophilia and the production of neutrophil extracellular traps (NETs) are two of many measures of increased inflammation in severe COVID-19 that also accompany its autoimmune complications, including coagulopathies, myocarditis and multisystem inflammatory syndrome in children (MIS-C). This paper integrates currently disparate measures of innate hyperactivation in severe COVID-19 and its autoimmune complications, and relates these to SARS-CoV-2 activation of innate immunity. Aggregated data include activation of Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) receptors, NOD leucine-rich repeat and pyrin-domain-containing receptors (NLRPs), retinoic acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA-5). SARS-CoV-2 mainly activates the virus-associated innate receptors TLR3, TLR7, TLR8, NLRP3, RIG-1 and MDA-5. Severe COVID-19, however, is characterized by additional activation of TLR1, TLR2, TLR4, TLR5, TLR6, NOD1 and NOD2, which are primarily responsive to bacterial antigens. The innate activation patterns in autoimmune coagulopathies, myocarditis and Kawasaki disease, or MIS-C, mimic those of severe COVID-19 rather than SARS-CoV-2 alone suggesting that autoimmunity follows combined SARS-CoV-2-bacterial infections. Viral and bacterial receptors are known to synergize to produce the increased inflammation required to support autoimmune disease pathology. Additional studies demonstrate that anti-bacterial antibodies are also required to account for known autoantigen targets in COVID-19 autoimmune complications.

Bacterial complications in patients with coronavirus infection, new diagnostic and therapeutic possibilities.

We present the case of a young patient who developed pneumonia during the COVID-19 outbreak. The course of the disease with involvement of interstitial lung tissue atypical for bacterial infections, the picture of infection markers could indicate SARS-CoV-2. The patient was tested by PCR method on admission with negative results. Due to the atypical follow-up of the disease, suggesting a severe course of SARS, PCR testing of the material collected by BAL was performed BIOFIRE® FILMARRAY® Pneumonia plus Panel (bioMérieux). Legionella pneumophilla and coronavirus genetic materials were found. We conclude that in the described case there was a bacterial co-infection, paved by virus infection. The similar radiological picture of the two cases of pneumonia, as well as the similar infectious response in the blood, specific for atypical infections, may pose a problem in the differential diagnosis. The study was able to confirm the bacterial etiology of pneumonia and introduce targeted treatment. The patient was discharged from the hospital. We believe that in any case of pneumonia of non-bacterial etiology, extending the diagnosis with a PCR pulmonary panel allows early and effective treatment of patients. In the treatment of patients with pulmonary interstitial lesions in the course of virus infections, one should always keep in mind the possibility of atypical co-infections.

Evaluation of bacterial agents isolated from endotracheal aspirate cultures of Covid-19 general intensive care patients and their antibiotic resistance profiles compared to pre-pandemic conditions.

BACKGROUND: Early reports have shown that critically ill patients infected with SARS-CoV-2 have a high prevalence of nosocomial pneumonia, particularly ventilator-associated pneumonia (VAP). METHOD: In the present study, we determined the bacterial agents isolated from endotracheal aspirate (ETA) cultures of Covid-19 general intensive care patients and evaluated the antibiotic resistance profiles of common bacterial agents compared to the pre-pandemic period. RESULTS: While a total of 119 significant growths with polymicrobial growths were detected in the ETA cultures of 73 (7.5%) of 971 patients hospitalized in the intensive care unit before the pandemic, 87 significant growths were detected in the ETA cultures of 67 (11.1%) of 602 patients hospitalized in the Covid-19 intensive care unit (ICU) after the pandemic. While 61 (83.6%) of patients in the ICU died before the pandemic, 63 (94.0%) of patients in the Covid-19 ICU died after the pandemic. In terms of age, gender, and mortality, there was no significant difference between the two ICUs (p > 0.05). Before the pandemic, the mean length of stay in the ICU was 33.59 ± 32.89 days, and after the pandemic, it was 13.49 ± 8.03 days. This was a statistically significant difference (p < 0.05). Acinetobacter baumannii (28.5%), Klebsiella pneumoniae (22.6%), Pseudomonas aeruginosa (15.9%), Staphylococcus aureus (6.7%), Escherichia coli (7.5%), Candida spp. (5.0%) were the most prevalent causal microorganisms discovered in pre-pandemic ICU ETA samples, whereas A. baumannii (54.0%), K. pneumoniae (10.3%), P. aeruginosa (6.8%), E. faecium (8%), and Candida spp.(13.7%) were the most common causative microorganisms detected in Covid-19 ICU ETA samples. Except for tigecycline, antibiotic resistance rates in A. baumannii strains increased following the pandemic. Only tobramycin showed a significant difference in the increase of resistance among these antibiotics (p = 0.037). The rate of tigecycline resistance, on the other hand, was 17.6% before the pandemic and 2.2% afterward (p < 0.05). After the pandemic, increased resistance of K. pneumoniae strains to colistin, meropenem, ertapenem, amoxicillin-clavulanic acid, piperacillin-tazobactam, ciprofloxacin, tigecycline, and cefepime antibiotics was observed. However, these increases were not statistically significant. Except for imipenem, antibiotic resistance rates in P. aeruginosa strains increased following the pandemic. The increase in resistance of ceftazidime and levofloxacin was statistically significant (p < 0.05). CONCLUSION: As a result, the Covid-19 pandemic requires intensive care follow-ups at an earlier age and with a more mortal course. Although the length of stay in the intensive care unit has been shortened, it is observed that this situation is observed due to early mortality. In P. aeruginosa strains, a significant difference was detected in the resistance increase of the ceftazidime and levofloxacin (p < 0.05) and with the exception of tigecycline, antibiotic resistance rates in A. baumannii strains increased following the pandemic. Only tobramycin showed a significant difference in the increase of resistance among these antibiotics (p = 0.037). Secondary infections in patients create more difficult treatment processes due to both Covid-19 and increasing antibiotic resistance today.

Predictive model for bacterial co-infection in patients hospitalized for COVID-19: a multicenter observational cohort study.

OBJECTIVE: The aim of our study was to build a predictive model able to stratify the risk of bacterial co-infection at hospitalization in patients with COVID-19. METHODS: Multicenter observational study of adult patients hospitalized from February to December 2020 with confirmed COVID-19 diagnosis. Endpoint was microbiologically documented bacterial co-infection diagnosed within 72 h from hospitalization. The cohort was randomly split into derivation and validation cohort. To investigate risk factors for co-infection univariable and multivariable logistic regression analyses were performed. Predictive risk score was obtained assigning a point value corresponding to ß-coefficients to the variables in the multivariable model. ROC analysis in the validation cohort was used to estimate prediction accuracy. RESULTS: Overall, 1733 patients were analyzed: 61.4% males, median age 69 years (IQR 57-80), median Charlson 3 (IQR 2-6). Co-infection was diagnosed in 110 (6.3%) patients. Empirical antibiotics were started in 64.2 and 59.5% of patients with and without co-infection (p = 0.35). At multivariable analysis in the derivation cohort: WBC ≥ 7.7/mm3, PCT ≥ 0.2 ng/mL, and Charlson index ≥ 5 were risk factors for bacterial co-infection. A point was assigned to each variable obtaining a predictive score ranging from 0 to 5. In the validation cohort, ROC analysis showed AUC of 0.83 (95%CI 0.75-0.90). The optimal cut-point was ≥2 with sensitivity 70.0%, specificity 75.9%, positive predictive value 16.0% and negative predictive value 97.5%. According to individual risk score, patients were classified at low (point 0), intermediate (point 1), and high risk (point ≥ 2). CURB-65 ≥ 2 was further proposed to identify patients at intermediate risk who would benefit from early antibiotic coverage. CONCLUSIONS: Our score may be useful in stratifying bacterial co-infection risk in COVID-19 hospitalized patients, optimizing diagnostic testing and antibiotic use.

Diagnostic concordance between BioFire® FilmArray® Pneumonia Panel and culture in patients with COVID-19 pneumonia admitted to intensive care units: the experience of the third wave in eight hospitals in Colombia.

BACKGROUND: The detection of coinfections is important to initiate appropriate antimicrobial therapy. Molecular diagnostic testing identifies pathogens at a greater rate than conventional microbiology. We assessed both bacterial coinfections identified via culture or the BioFire® FilmArray® Pneumonia Panel (FA-PNEU) in patients infected with SARS-CoV-2 in the ICU and the concordance between these techniques. METHODS: This was a prospective study of patients with SARS-CoV-2 who were hospitalized for no more than 48 h and on mechanical ventilation for no longer than 24 h in 8 ICUs in Medellín, Colombia. We studied mini-bronchoalveolar lavage or endotracheal aspirate samples processed via conventional culture and the FA-PNEU. Coinfection was defined as the identification of a respiratory pathogen using the FA-PNEU or cultures. Serum samples of leukocytes, C-reactive protein, and procalcitonin were taken on the first day of intubation. We analyzed the empirical antibiotics and the changes in antibiotic management according to the results of the FA-PNEUM and cultures. RESULTS: Of 110 patients whose samples underwent both methods, FA-PNEU- and culture-positive samples comprised 24.54% versus 17.27%, respectively. Eighteen samples were positive in both techniques, 82 were negative, 1 was culture-positive with a negative FA-PNEU result, and 9 were FA-PNEU-positive with negative culture. The two bacteria most frequently detected by the FA-PNEU were Staphylococcus aureus (37.5%) and Streptococcus agalactiae (20%), and those detected by culture were Staphylococcus aureus (34.78%) and Klebsiella pneumoniae (26.08%). The overall concordance was 90.1%, and when stratified by microorganism, it was between 92.7 and 100%. The positive predictive value (PPV) was between 50 and 100% and were lower for Enterobacter cloacae and Staphylococcus aureus. The negative predictive value (NPV) was high (between 99.1 and 100%); MecA/C/MREJ had a specificity of 94.55% and an NPV of 100%. The inflammatory response tests showed no significant differences between patients whose samples were positive and negative for both techniques. Sixty-one patients (55.45%) received at least one dose of empirical antibiotics. CONCLUSIONS: The overall concordance was 90.1%, and it was between 92.7% and 100% when stratified by microorganisms. The positive predictive value was between 50 and 100%, with a very high NPV.

Bacterial and parasite co-infection in Mexican golden trout (Oncorhynchus chrysogaster) by Aeromonas bestiarum, Aeromonas sobria, Plesiomonas shigelloides and Ichthyobodo necator.

BACKGROUND: Bacterial infections are responsible of high economic losses in aquaculture. Mexican golden trout (Oncorhynchus chrysogaster) is a threatened native trout species that has been introduced in aquaculture both for species conservation and breeding for production and for which no studies of bacterial infections have been reported. CASE PRESENTATION: Fish from juvenile stages of Mexican golden trout showed an infectious outbreak in a farm in co-culture with rainbow trout (Oncorhynchus mykiss), showing external puntiform red lesions around the mouth and caudal pedunculus resembling furuncles by Aeromonas spp. and causing an accumulated mortality of 91%. Isolation and molecular identification of bacteria from lesions and internal organs showed the presence of Aeromonas bestiarum, Aeromonas sobria, Plesiomonas shigelloides and Ichthyobodo necator isolated from a single individual. All bacterial isolates were resistant to amoxicillin-clavulanic acid and cefazoline. P. shigelloides was resistant to third generation ß-lactamics. CONCLUSIONS: This is the first report of coinfection by Aeromonas bestiarum, Aeromonas sobria, Plesiomonas shigelloides and Ichthyobodo necator in an individual of Mexican golden trout in co-culture with rainbow trout. Resistance to ß-lactams suggests the acquisition of genetic determinants from water contamination by human- or livestock-associated activities.

Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Invasive Pneumococcal Disease and Risk of Pneumococcal Coinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Prospective National Cohort Study, England.

BACKGROUND: Streptococcus pneumoniae coinfection with influenza results in synergistic lethality, but there are limited data on pneumococcal coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Public Health England conducts invasive pneumococcal disease (IPD) and SARS-CoV-2 surveillance in England. IPD trends during 2000/2001-2019/2020 epidemiological years were analyzed and cases during February-June 2020 linked with laboratory-confirmed SARS-CoV-2 infections. Multivariable logistic regression was used to assess risk factors for death. RESULTS: IPD incidence in 2019/2020 (7.6/100 000; n = 3964) was 30% (IRR, .70; 95% CI, .18-2.67) lower compared with 2018/2019 (10.9/100 000; n = 5666), with large reductions observed across all age groups during March-June 2020. There were 160 886 SARS-CoV-2 and 1137 IPD cases during February-June 2020, including 40 IPD/coronavirus disease 2019 (COVID-19) co-infections (.025% [95% CI, .018-.034] of SARS-CoV-2 infections; 3.5% [2.5-4.8] of IPD cases), 21 with COVID-19 diagnosed 3-27 days after IPD, and 27 who developed COVID-19 ≥28 days after IPD. Case-fatality rates (CFRs) were 62.5 (25/40), 47.6% (10/21), and 33.3% (9/27), respectively (P < .001). In addition to an independent association with increasing age and serotype group, CFR was 7.8-fold (95% CI, 3.8-15.8) higher in those with IPD/COVID-19 coinfection and 3.9-fold (95% CI, 1.4-10.7) higher in patients who developed COVID-19 3-27 days after IPD compared with patients with IPD only. CONCLUSIONS: Large declines in IPD were observed following COVID-19 lockdown. IPD/COVID-19 coinfections were rare but associated with high CFR, mainly in older adults. The rarity, age and serotype distribution of IPD/COVID-19 coinfections do not support wider extension of pneumococcal vaccination.

Antibiotic Use and Bacterial Infection among Inpatients in the First Wave of COVID-19: a Retrospective Cohort Study of 64,691 Patients.

Hospitalized patients with SARS-CoV-2 infection (COVID-19) often receive antibiotics for suspected bacterial coinfection. We estimated the incidence of bacterial coinfection and secondary infection in COVID-19 using clinical diagnoses to determine how frequently antibiotics are administered when bacterial infection is absent. We performed a retrospective cohort study of inpatients with COVID-19 present on admission to hospitals in the Premier Healthcare Database between April and June 2020. Bacterial infections were defined using ICD-10-CM diagnosis codes and associated "present on admission" coding. Coinfections were defined by bacterial infection present on admission, while secondary infections were defined by bacterial infection that developed after admission. Coinfection and secondary infection were not mutually exclusive. A total of 18.5% of 64,961 COVID-19 patients (n = 12,040) presented with bacterial infection at admission, 3.8% (n = 2,506) developed secondary infection after admission, and 0.9% (n = 574) had both; 76.3% (n = 49,551) received an antibiotic while hospitalized, including 71% of patients who had no diagnosis of bacterial infection. Secondary bacterial infection occurred in 5.7% of patients receiving steroids in the first 2 days of hospitalization, 9.9% receiving tocilizumab in the first 2 days of hospitalization, and 10.3% of patients receiving both. After adjusting for patient and hospital characteristics, bacterial coinfection (adjusted relative risk [aRR], 1.15; 95% confidence interval [CI], 1.11 to 1.20) and secondary infection (aRR 1.93; 95% CI, 1.82 to 2.04) were both independently associated with increased mortality. Although 1 in 5 inpatients with COVID-19 presents with bacterial infection, secondary infections in the hospital are uncommon. Most inpatients with COVID-19 receive antibiotic therapy, including 71% of those not diagnosed with bacterial infection.

Year-Round, Routine Testing of Multiple Body Site Specimens for Human Parechovirus in Young Febrile Infants.

OBJECTIVES: To test our hypothesis that routine year-round testing of specimens from multiple body sites and genotyping of detected virus would describe seasonal changes, increase diagnostic yield, and provide a better definition of clinical manifestations of human parechovirus (PeV-A) infections in young febrile infants. STUDY DESIGN: PeV-A reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was incorporated in routine evaluation of infants aged ≤60 days hospitalized at Nationwide Children's Hospital for fever and/or suspected sepsis-like syndrome beginning in July 2013. We reviewed electronic medical records of infants who tested positive for PeV-A between July 2013 and September 2016. Genotyping was performed with specific type 3 RT-PCR and sequencing. RESULTS: Of 1475 infants evaluated, 130 (9%) tested positive for PeV-A in 1 or more sites: 100 (77%) in blood, 84 (65%) in a nonsterile site, and 53 (41%) in cerebrospinal fluid (CSF). Five infants (4%) were CSF-only positive, 31 (24%) were blood-only positive, and 20 (15%) were nonsterile site-only positive. PeV-A3 was the most common type (85%) and the only type detected in CSF. Although the majority (79%) of infections were diagnosed between July and December, PeV-A was detected year-round. The median age at detection was 29 days. Fever (96%), fussiness (75%), and lymphopenia (56%) were common. Among infants with PeV-A-positive CSF, 77% had no CSF pleocytosis. The median duration of hospitalization was 41 hours. Four infants had bacterial coinfections diagnosed within 24 hours of admission; 40 infants had viral coinfections. CONCLUSIONS: Although most frequent in summer and fall, PeV-A infections were encountered in every calendar month within the 3-year period of study. More than one-half of patients had PeV-A detected at more than 1 body site. Coinfections were common. PeV-A3 was the most common type identified and the only type detected in the CSF.

Differentiating influenza from COVID-19 in patients presenting with suspected sepsis.

There is a need for a quick assessment of severely ill patients presenting to the hospital. The objectives of this study were to identify clinical, laboratory and imaging parameters that could differentiate between influenza and COVID-19 and to assess the frequency and impact of early bacterial co-infection. A prospective observational cohort study was performed between February 2019 and April 2020. A retrospective cohort was studied early in the COVID-19 pandemic. Patients suspected of sepsis with PCR-confirmed influenza or SARS-CoV-2 were included. A multivariable logistic regression model was built to differentiate COVID-19 from influenza. In total, 103 patients tested positive for influenza and 110 patients for SARS-CoV-2, respectively. Hypertension (OR 6.550), both unilateral (OR 4.764) and bilateral (OR 7.916), chest X-ray abnormalities, lower temperature (OR 0.535), lower absolute leukocyte count (OR 0.857), lower AST levels (OR 0.946), higher LDH (OR 1.008), higher ALT (OR 1.044) and higher ferritin (OR 1.001) were predictive of COVID-19. Early bacterial co-infection was more frequent in patients with influenza (10.7% vs. 2.7%). Empiric antibiotic usage was high (76.7% vs. 84.5%). Several factors determined at presentation to the hospital can differentiate between influenza and COVID-19. In the future, this could help in triage, diagnosis and early management. Clinicaltrial.gov Identifier: NCT03841162.

Bacterial coinfection in critically ill COVID-19 patients with severe pneumonia.

Severe 2019 novel coronavirus infectious disease (COVID-19) with pneumonia is associated with high rates of admission to the intensive care unit (ICU). Bacterial coinfection has been reported to be rare. We aimed at describing the rate of bacterial coinfection in critically ill adult patients with severe COVID-19 pneumonia. All the patients with laboratory-confirmed severe COVID-19 pneumonia admitted to the ICU of Tenon University-teaching hospital, from February 22 to May 7th, 2020 were included. Respiratory tract specimens were obtained within the first 48 h of ICU admission. During the study period, 101 patients were referred to the ICU for COVID-19 with severe pneumonia. Most patients (n = 83; 82.2%) were intubated and mechanically ventilated on ICU admission. Overall, 20 (19.8%) respiratory tract specimens obtained within the first 48 h. Staphylococcus aureus was the main pathogen identified, accounting for almost half of the early-onset bacterial etiologies. We found a high prevalence of early-onset bacterial coinfection during severe COVID-19 pneumonia, with a high proportion of S. aureus. Our data support the current WHO guidelines for the management of severe COVID-19 patients, in whom antibiotic therapy directed to respiratory pathogens is recommended.

Informing antimicrobial management in the context of COVID-19: understanding the longitudinal dynamics of C-reactive protein and procalcitonin.

BACKGROUND: To characterise the longitudinal dynamics of C-reactive protein (CRP) and Procalcitonin (PCT) in a cohort of hospitalised patients with COVID-19 and support antimicrobial decision-making. METHODS: Longitudinal CRP and PCT concentrations and trajectories of 237 hospitalised patients with COVID-19 were modelled. The dataset comprised of 2,021 data points for CRP and 284 points for PCT. Pairwise comparisons were performed between: (i) those with or without significant bacterial growth from cultures, and (ii) those who survived or died in hospital. RESULTS: CRP concentrations were higher over time in COVID-19 patients with positive microbiology (day 9: 236 vs 123 mg/L, p < 0.0001) and in those who died (day 8: 226 vs 152 mg/L, p < 0.0001) but only after day 7 of COVID-related symptom onset. Failure for CRP to reduce in the first week of hospital admission was associated with significantly higher odds of death. PCT concentrations were higher in patients with COVID-19 and positive microbiology or in those who died, although these differences were not statistically significant. CONCLUSIONS: Both the absolute CRP concentration and the trajectory during the first week of hospital admission are important factors predicting microbiology culture positivity and outcome in patients hospitalised with COVID-19. Further work is needed to describe the role of PCT for co-infection. Understanding relationships of these biomarkers can support development of risk models and inform optimal antimicrobial strategies.

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions.

Severe COVID-19 is characterized by a "cytokine storm", the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.

Bacterial coinfections and secondary infections in COVID-19 patients from a tertiary care hospital of northern India: Time to adhere to culture-based practices.

OBJECTIVE: Bacterial co-pathogens are common in various viral respiratory tract infections, leading to increased disease severity and mortality. Still, they are understudied during large outbreaks and pandemics. This study was conducted to highlight the overall burden of these infections in COVID-19 patients admitted to our tertiary care hospital, along with their antibiotic susceptibility patterns. MATERIAL AND METHODS: During the six-month study period, clinical samples (blood samples, respiratory samples, and sterile body fluids, including cerebrospinal fluid [CSF]) of COVID-19 patients with suspected bacterial coinfections (at presentation) or secondary infections (after 48 hours of hospitalization) were received and processed for the same. RESULTS: Clinical samples of 814 COVID-19 patients were received for bacterial culture and susceptibility. Out of the total patient sample, 75% had already received empirical antibiotics before the samples were sent for analysis. Overall, 17.9% of cultures were positive for bacterial infections. Out of the total patients with bacterial infection, 74% (108/146) of patients had secondary bacterial infections (after 48 hours of hospitalization) and 26% (38/146) had bacterial coinfections (at the time of admission). Out of the 143 total isolates obtained, the majority (86%) were gram-negative organisms, of which Acinetobacter species was the commonest organism (35.6%), followed by Klebsiella pneumoniae (18.1%). The majority (50.7%) of the pathogenic organisms reported were multidrug resistant. CONCLUSION: The overall rate of secondary bacterial infections (SBIs) in our study was lower (7.9%) than reported by other studies. A rational approach would be to adhere to the practice of initiating culture-based guidance for antibiotics and to restrict unnecessary empirical antimicrobial therapy.