Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies.

BACKGROUND: The factors contributing to the accelerated convergent evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not fully understood. Unraveling the contribution of viral replication in immunocompromised patients is important for the early detection of novel mutations and developing approaches to limit COVID-19. METHODS: We deep sequenced SARS-CoV-2 RNA from 192 patients (64% hospitalized, 39% immunosuppressed) and compared the viral genetic diversity within the patient groups of different immunity and hospitalization status. Serial sampling of 14 patients was evaluated for viral evolution in response to antiviral treatments. RESULTS: We identified hospitalized and immunosuppressed patients with significantly higher levels of viral genetic diversity and variability. Further evaluation of serial samples revealed accumulated mutations associated with escape from neutralizing antibodies in a subset of the immunosuppressed patients treated with antiviral therapies. Interestingly, the accumulated viral mutations that arose in this early Omicron wave, which were not common in the patient viral lineages, represent convergent mutations that are prevalent in the later Omicron sublineages, including the XBB, BA.2.86.1 and its descendent JN sublineages. CONCLUSIONS: Our results illustrate the importance of identifying convergent mutations generated during antiviral therapy in immunosuppressed patients, as they may contribute to the future evolutionary landscape of SARS-CoV-2. Our study also provides evidence of a correlation between SARS-CoV-2 convergent mutations and specific antiviral treatments. Evaluating high-confidence genomes from distinct waves in the pandemic with detailed patient metadata allows for discerning of convergent mutations that contribute to the ongoing evolution of SARS-CoV-2.

Systemic Bacillus Calmette-Guerin Infection One Year After Intravesical Immunotherapy Mimicking Sarcoidosis.

A patient presented with pancytopenia and hypercalcemia after intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) for bladder cancer. Bone marrow biopsy performed six months later revealed noncaseating granulomas with negative stains for AFB. He was diagnosed with sarcoidosis and treated with prednisone. Hypercalcemia resolved, but mild pancytopenia persisted. One year later, he developed sepsis. Blood cultures six weeks later grew Mycobacterium tuberculosis complex, ultimately identified as Mycobacterium bovis. Despite triple antibiotic therapy, the patient progressively declined and expired.

Sequencing during Times of Change: Evaluating SARS-CoV-2 Clinical Samples during the Transition from the Delta to Omicron Wave.

The pandemic of SARS-CoV-2 is characterized by the emergence of new variants of concern (VOCs) that supplant previous waves of infection. Here, we describe our investigation of the lineages and host-specific mutations identified in a particularly vulnerable population of predominantly older and immunosuppressed SARS-CoV-2-infected patients seen at our medical center in Chicago during the transition from the Delta to Omicron wave. We compare two primer schemes, ArticV4.1 and VarSkip2, used for short read amplicon sequencing, and describe our strategy for bioinformatics analysis that facilitates identifying lineage-associated mutations and host-specific mutations that arise during infection. This study illustrates the ongoing evolution of SARS-CoV-2 VOCs in our community and documents novel constellations of mutations that arise in individual patients. The ongoing evaluation of the evolution of SARS-CoV-2 during this pandemic is important for informing our public health strategies.

Antibody Response to SARS-CoV-2 Infection and Vaccination in COVID-19-naïve and Experienced Individuals.

Understanding the magnitude of responses to vaccination during the ongoing SARS-CoV-2 pandemic is essential for ultimate mitigation of the disease. Here, we describe a cohort of 102 subjects (70 COVID-19-naïve, 32 COVID-19-experienced) who received two doses of one of the mRNA vaccines (BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)). We document that a single exposure to antigen via infection or vaccination induces a variable antibody response which is affected by age, gender, race, and co-morbidities. In response to a second antigen dose, both COVID-19-naïve and experienced subjects exhibited elevated levels of anti-spike and SARS-CoV-2 neutralizing activity; however, COVID-19-experienced individuals achieved higher antibody levels and neutralization activity as a group. The COVID-19-experienced subjects exhibited no significant increase in antibody or neutralization titer in response to the second vaccine dose (i.e., third antigen exposure). Finally, we found that COVID-19-naïve individuals who received the Moderna vaccine exhibited a more robust boost response to the second vaccine dose (p = 0.004) as compared to the response to Pfizer-BioNTech. Ongoing studies with this cohort will continue to contribute to our understanding of the range and durability of responses to SARS-CoV-2 mRNA vaccines.

Escherichia coli associated hematogenous sternoclavicular joint osteomyelitis: A rare condition with a rare causative pathogen.

Escherichia coli is the most common microorganism that causes urinary tract infections (UTIs), including acute prostatitis. However, E. coli osteomyelitis, especially ones that involve the sternoclavicular joint, are rare hematogenous complications. We present a case of an immunocompetent man who presented with symptoms of UTI and right shoulder pain. Urine cultures and blood cultures grew E. coli. There was radiographic evidence of prostatic abscess and a right sternoclavicular joint osteomyelitis. This case is unique given the rare occurrence of non-traumatic clavicular bacterial osteomyelitis and the type of bacteria involved. In conclusion, it is important for clinicians to be aware of E. coli sternoclavicular osteomyelitis in adults with preceding bacterial prostatitis.

Breakthrough Infections with Multiple Lineages of SARS-CoV-2 Variants Reveals Continued Risk of Severe Disease in Immunosuppressed Patients.

The pandemic of COVID-19 caused by SARS-CoV-2 infection continues to spread around the world. Vaccines that elicit protective immunity have reduced infection and mortality, however new viral variants are arising that may evade vaccine-induced immunity or cause disease in individuals who are unable to develop robust vaccine-induced responses. Investigating the role of viral variants in causing severe disease, evading vaccine-elicited immunity, and infecting vulnerable individuals is important for developing strategies to control the pandemic. Here, we report fourteen breakthrough infections of SARS-CoV-2 in vaccinated individuals with symptoms ranging from asymptomatic/mild (6/14) to severe disease (8/14). High viral loads with a median Ct value of 19.6 were detected in the nasopharyngeal specimens from subjects regardless of disease severity. Sequence analysis revealed four distinct virus lineages, including alpha and gamma variants of concern. Immunosuppressed individuals were more likely to be hospitalized after infection (p = 0.047), however no specific variant was associated with severe disease. Our results highlight the high viral load that can occur in asymptomatic breakthrough infections and the vulnerability of immunosuppressed individuals to post-vaccination infections by diverse variants of SARS-CoV-2.

Nocardia spp.: A Rare Cause of Pneumonia Globally.

Members of the Nocardia genus are ubiquitous in the environment. These aerobic, gram-positive organisms can lead to life-threatening infection, typically in immunocompromised hosts such as solid organ transplant recipients or those receiving immunosuppressive medications for other reasons. This current review discusses the microbiology of nocardiosis, risk factors for infection, clinical manifestations, methods for diagnosis, and treatment. Nocardiosis primarily affects the lung but may also cause skin and soft tissue infection, cerebral abscess, bloodstream infection, or infection involving other organs. Although rare as a cause of community-acquired pneumonia, Nocardia can have severe morbidity and mortality, particularly in patients with comorbidities or compromised immunity. Early diagnosis and timely initiation of therapy are critical to optimizing patient outcomes. Species identification is important in determining treatment, as is in vitro susceptibility testing. Sulfonamide therapy is usually indicated, although a variety of other antimicrobials may be useful, depending on the species and susceptibility testing. Prolonged therapy is usually indicated, for 6 to 12 months, and in some cases surgical debridement may be required to resolve infection.

The Struggling Infectious Diseases Fellow: Remediation Challenges and Opportunities.

Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases Society of America Training Program Directors' Committee focused the 2018 National Fellowship Program Directors' Meeting at IDWeek on "Remediation of the Struggling Fellow." Small group discussions addressed 7 core topics, including feedback and evaluations, performance management and remediation, knowledge deficits, fellow well-being, efficiency and time management, teaching skills, and career development. This manuscript synthesizes those discussions around a competency-based framework to provide program directors and other educators with a roadmap for addressing common contemporary remediation challenges.

In Vitro Pharmacodynamic Analyses Help Guide the Treatment of Multidrug-Resistant Enterococcus faecium and Carbapenem-Resistant Enterobacter cloacae Bacteremia in a Liver Transplant Patient.

BACKGROUND: Infections due to multidrug-resistant pathogens are particularly deadly and difficult to treat in immunocompromised patients, where few data exist to guide optimal antimicrobial therapy. In the absence of adequate clinical data, in vitro pharmacokinetic (PK)/pharmacodynamic (PD) analyses can help to design treatment regimens that are bactericidal and may be clinically effective. METHODS: We report a case in which in vitro pharmacodynamic analyses were utilized to guide the treatment of complex, recurrent bacteremias due to vancomycin-, daptomycin-, and linezolid-resistant Enterococcus faecium and carbapenem-resistant Enterobacter cloacae complex in a liver transplant patient. RESULTS: Whole-genome sequencing revealed unique underlying resistance mechanisms and explained the rapid evolution of phenotypic resistance and complicated intrahost genomic dynamics observed in vivo. Performing this comprehensive genotypic and phenotypic testing and time-kill analyses, along with knowledge of institution and patient-specific factors, allowed us to use precision medicine to design a treatment regimen that maximized PK/PD. CONCLUSIONS: This work provides a motivating example of clinicians and scientists uniting to optimize care in the era of escalating antimicrobial resistance.

Mucormycosis.

Mucormycosis is an infection caused by a group of filamentous molds within the order Mucorales. Infections may result from ingestion of contaminated food, inhalation of spores into the nares or lungs, or inoculation into disrupted skin or wounds. In developed countries, mucormycosis occurs primarily in severely immunocompromised hosts (e.g., those with hematological malignancies, organ transplantation, neutropenia, autoimmune disorders, or other impairments in immunity). Only 6 to 10% of cases occur in subjects with no underlying disease. In contrast, in developing countries, most cases of mucormycosis occur in persons with poorly controlled diabetes mellitus or in immunocompetent subjects following trauma. Mucormycosis exhibits a marked propensity to invade blood vessels, leading to thrombosis, necrosis, and infarction of tissue. Mortality associated with invasive mucormycosis is high (> 30-50%), with 90% mortality associated with disseminated disease. Mortality rates are much lower, though still significant (10-30%), among patients with localized cutaneous disease.The diagnosis of mucormycosis relies upon histopathology and culture. Blood tests are of limited diagnostic value. Even with disseminated disease, blood cultures are usually negative. Mucorales have a distinct histological appearance, with irregular, nonseptate hyphae that branch at right angles. Cultures and/or polymerase chain reaction (PCR) are important to identify the genera.Based on anatomic localization, mucormycosis can be classified as one of six forms: (1) rhino-orbital-cerebral mucormycosis (ROCM), (2) pulmonary, (3) cutaneous, (4) gastrointestinal (GI), (5) disseminated, and (6) mucormycosis of uncommon sites. Among diabetics, ROCM is the most common clinical presentation, whereas lung involvement is uncommon. In contrast, among organ transplant recipients or patients with hematological malignancies (HemeM), pulmonary and disseminated diseases are most common. Mucormycosis can progress rapidly, and delay in initiation of treatment by even a few days markedly worsens outcomes.Due to the rarity of mucormycosis, randomized controlled therapeutic trials have not been performed. Lipid formulations of amphotericin B (LFAB) are the mainstay of therapy, but the newer triazoles, posaconazole (POSA) and isavuconazole (ISAV) (the active component of the prodrug isavuconazonium sulfate), may be effective in patients refractory to or intolerant of LFAB. Early surgical debridement or excision plays an important adjunctive role. Additional studies are required to assess the optimal duration of therapy as well as the specific roles of LFAB and the triazoles in the treatment of mucormycosis.

Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially, so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer-causing strains. Organ transplant recipients should be screened for HPV-associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.

Humoral response to natural influenza infection in solid organ transplant recipients.

The humoral immune response of transplant recipients to influenza vaccination has been studied in detail. In contrast, the hemagglutinin inhibiting (HI) antibody response evoked by natural influenza infection and its impact on viral kinetics is unknown. In this prospective, multicenter, cohort study of natural influenza infection in transplant recipients, we measured HI antibody titers at presentation and 4 weeks later. Serial nasopharyngeal viral loads were determined using a quantitative influenza A polymerase chain reaction (PCR). We analyzed 196 transplant recipients with influenza infection. In the cohort of organ transplant patients with influenza A (n = 116), seropositivity rates for strain-specific antibodies were 44.0% (95% confidence interval [CI] 31.5-53.2%) at diagnosis and 64.7% (95% CI 55.4-72.9%) 4 weeks postinfection. Seroconversion was observed in 32.8% (95% CI 24.7-41.9%) of the cases. Lung transplant recipients were more likely to seroconvert (P = .002) and vaccine recipients were less likely to seroconvert (P = .024). A subset of patients (n = 30) who were unresponsive to prior vaccination were also unresponsive to natural infection. There was no correlation between viral kinetics and antibody response. This study provides novel data on the seroresponse to influenza infection in transplant patients and its relationship to a number of parameters including a prior vaccination status, virologic measures, and clinical variables.

Cytokine Profiles and Severity of Influenza Infection in Transplant Recipients.

Influenza is responsible for significant morbidity after transplantation. We evaluated T-helper 1/T-helper 2 (Th2) cytokines and interleukin (IL) 10 levels during influenza infection in the posttransplant setting. Serum samples from 277 transplant recipients were analyzed at influenza diagnosis and 28 days later for interferon gamma (IFN-γ), IL-4, IL-13, and IL-10. IL-13 levels were associated with protection against pneumonia and intensive care unit (ICU) admission, whereas the IFN-γ/IL-13 ratio and IL-10 levels were associated with an increased risk of pneumonia and ICU admission. This association was independent of viral load. A skewing of immune responses toward Th2 in transplant patients appears to confer protection from severe influenza infection, independent of viral load.

A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients.

Background: Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease. Methods: Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed. Results: We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively). Conclusions: Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

Psychosocial outcomes in a cohort of perinatally HIV-infected adolescents in Western Jamaica.

BACKGROUND: Psychosocial factors interact with adolescent development and affect the ability of HIV-infected adolescents to cope with and adhere to treatment. AIM: To evaluate psychosocial outcomes in perinatally HIV-infected adolescents (PHIVAs) in Western Jamaica after psychosocial intervention. METHODS: The Bright Futures Paediatric Symptom Checklist (BF-PSC) was used for psychological screening of PHIVAs in Western Jamaica. Referred patients were evaluated using the Youth version of the Columbia Impairment Scale (CIS). Demographic, laboratory and clinical data obtained between July 2014 and June 2016 were evaluated retrospectively and outcomes were reviewed before and after psychosocial intervention. RESULTS: Sixty PHIVAs were enrolled and 36 (60%) had a positive BF-PSC score that necessitated referral. The BF-PSC correctly identified 89% of patients with impaired psychosocial assessment by CIS scores. Referred patients were less likely to adhere to treatment, to be virologically suppressed or to have a CD4+ count of >500 cells/µl, and were more likely to be in the late teenage group or to be of orphan status. After intervention, the prevalence of viral suppression increased and median viral load decreased. A difference in mean CD4+ cell count was detected before but not after intervention in teenage and orphan groups. CONCLUSIONS: The BF-PSC identified at-risk PHIVAs with impaired psychosocial functioning. Increased vulnerability was noted in orphans and older teenagers. Psychosocial interventions (including family therapy) reduced psychosocial impairment and improved virological suppression. Mental health intervention should be instituted to facilitate improved clinical outcomes, autonomy of care and transition to adult care.

Acute pancreatitis: A 7 year retrospective cohort study of the epidemiology, aetiology and outcome from a tertiary hospital in Jamaica.

BACKGROUND: Acute pancreatitis (AP) is a significant cause of acute abdominal pain, morbidity and hospitalisation. There was previously a dearth of studies exploring the incidence, risk factors and outcome of AP in the Caribbean region. MATERIALS AND METHODS: All patients with a diagnosis of AP admitted to the University Hospital of the West Indies (UHWI) between 2006 and 2012 were reviewed. The epidemiological profile, risk factors, clinical presentation and outcomes of patients with AP were retrospectively studied. RESULTS: There were 70 females and 21 males with a median age of 44 years (range 2-86). The median age of males was significantly higher than that of females (p = 0.041). The incidence of AP was 74 per 100,000 admissions per year. Vomiting and abdominal tenderness were noted in the majority of patients. The most common aetiology was biliary disease (71.4%), idiopathic (12%), post-ERCP (6.6%) and alcohol (5.5%). Alcoholic pancreatitis was only seen in males whereas idiopathic and post-ERCP pancreatitis only occurred in females. The mean duration of hospitalisation was 9.51 ± 8.28 days. Disease severity was mild in 61.1%, moderately severe in 26.7%, and severe in 12.2% of patients. Factors associated with more severe disease included overweight/obesity, idiopathic aetiology and post-ERCP status. The case fatality rate was 2%. CONCLUSION: The incidence of AP was 74/100,000 hospital admissions annually. There was an unusual female preponderance, with biliary pancreatitis being the most common type occurring at an equal frequency among males and females. Only 12.2% of the total cases seen were severe. The case fatality rate was 2%. Local health policy should target timely interventions for biliary pancreatitis and should also address the local factors affecting disease severity.

Update in the treatment of non-influenza respiratory virus infection in solid organ transplant recipients.

INTRODUCTION: Despite the improved outcomes in solid organ transplantation with regard to prevention of rejection and increased patient and graft survival, infection remains a common cause of morbidity and mortality. Respiratory viruses are a frequent and potentially serious cause of infection after solid organ transplantation. Furthermore, clinical manifestations of respiratory virus infection (RVI) may be more severe and unusual in solid organ transplant recipients (SOTRs) compared with the non-immunocompromised population. Areas covered: This article reviews the non-influenza RVIs that are commonly encountered in SOTRs. Epidemiologic and clinical characteristics are highlighted and available treatment options are discussed. Expert opinion: New diagnostic tools, particularly rapid molecular assays, have expanded the ability to identify specific RVI pathogens in SOTRs. This is not only useful from a treatment standpoint but also to guide infection control practices. More data are needed on RVIs in the solid organ transplant population, particularly regarding their effect on rejection and graft dysfunction. There is also a need for new antiviral agents active against these infections as well as markers that can identify which patients would most benefit from treatment.

Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes.

Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and human herpesvirus-6, -7, and -8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies.

Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis.

OBJECTIVES: Limited options for treating MDR organisms have led clinicians to turn to older antimicrobial agents that may display activity against such infections. One such agent is fosfomycin, an oral drug with activity against a variety of Gram-positive and -negative bacteria, but only approved for use in the USA for urinary tract infection (UTI) due to Escherichia coli and Enterococcus faecalis. The purpose of this study was to assess the efficacy of fosfomycin treatment of MDR UTI and identify predictors of outcome. PATIENTS AND METHODS: A retrospective review was performed of patients treated for MDR UTI at a large quaternary medical centre between 1 January 2010 and 30 September 2014. Sixty patients received 69 courses of fosfomycin in the inpatient or outpatient setting for UTIs due to Enterobacteriaceae, Pseudomonas aeruginosa or VRE. RESULTS: In the 58 patients for whom follow-up data were available, the treatment success rate (no persistent or recurrent infection) was 55%. Chronic kidney disease was associated with persistent infection (OR = 3.56, 95% CI = 1.02-12.40, P = 0.04). No other factors, including comorbidities, infecting organism, fosfomycin MIC or number of doses of fosfomycin received, were associated with recurrent infection or treatment failure. CONCLUSIONS: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure.

Bacterial and viral co-infections complicating severe influenza: Incidence and impact among 507 U.S. patients, 2013-14.

BACKGROUND: Influenza acts synergistically with bacterial co-pathogens. Few studies have described co-infection in a large cohort with severe influenza infection. OBJECTIVES: To describe the spectrum and clinical impact of co-infections. STUDY DESIGN: Retrospective cohort study of patients with severe influenza infection from September 2013 through April 2014 in intensive care units at 33 U.S. hospitals comparing characteristics of cases with and without co-infection in bivariable and multivariable analysis. RESULTS: Of 507 adult and pediatric patients, 114 (22.5%) developed bacterial co-infection and 23 (4.5%) developed viral co-infection. Staphylococcus aureus was the most common cause of co-infection, isolated in 47 (9.3%) patients. Characteristics independently associated with the development of bacterial co-infection of adult patients in a logistic regression model included the absence of cardiovascular disease (OR 0.41 [0.23-0.73], p=0.003), leukocytosis (>11K/µl, OR 3.7 [2.2-6.2], p<0.001; reference: normal WBC 3.5-11K/µl) at ICU admission and a higher ICU admission SOFA score (for each increase by 1 in SOFA score, OR 1.1 [1.0-1.2], p=0.001). Bacterial co-infections (OR 2.2 [1.4-3.6], p=0.001) and viral co-infections (OR 3.1 [1.3-7.4], p=0.010) were both associated with death in bivariable analysis. Patients with a bacterial co-infection had a longer hospital stay, a longer ICU stay and were likely to have had a greater delay in the initiation of antiviral administration than patients without co-infection (p<0.05) in bivariable analysis. CONCLUSIONS: Bacterial co-infections were common, resulted in delay of antiviral therapy and were associated with increased resource allocation and higher mortality.