Human inherited complete STAT2 deficiency underlies inflammatory viral diseases.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

Long-Acting Antiretroviral Drug Therapy in Adolescents: Current Status and Future Prospects.

Approximately 50% of human immunodeficiency virus (HIV)-infected adolescents fail to achieve complete viral suppression, largely due to nonadherence to their antiretroviral drug regimens. Numerous personal, financial, and societal barriers contribute to nonadherence, which may lead to the development of HIV drug resistance. Long-acting antiretroviral drugs hold the promise of improved adherence because they remove the need for swallowing one or more pills daily. Cabotegravir (an integrase strand transfer inhibitor) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor) can now be intramuscularly co-administered to HIV-infected adolescents every 4-8 weeks if they are virologically suppressed and without resistance mutations to cabotegravir or rilpivirine. Adverse effects are few and non-severe. Widespread use of this complete antiretroviral therapy may be limited by drug costs, need for sites and skilled personnel who can administer the injections, and ethical challenges. Other long-acting medications and new antiretroviral therapy delivery systems are under active investigation and show great promise.

mRNA Coronavirus Disease 2019 Vaccine-Associated Myopericarditis in Adolescents: A Survey Study.

In this survey study of institutions across the US, marked variability in evaluation, treatment, and follow-up of adolescents 12 through 18 years of age with mRNA coronavirus disease 2019 (COVID-19) vaccine-associated myopericarditis was noted. Only one adolescent with life-threatening complications was reported, with no deaths at any of the participating institutions.

Diversity of Cardiac and Gastrointestinal Presentations of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Case Series.

COVID-19 is generally a benign or asymptomatic infection in children, but can occasionally be severe or fatal. Delayed presentation of COVID-19 with hyperinflammation and multi-organ involvement was recently recognized, designated the Multisystem Inflammatory Syndrome in Children (MIS-C). Six children with MIS-C with molecular and serologic evidence of SARS-CoV-2 infection were admitted to our hospital between May 5, 2020 and June 25, 2020. All had fever and weakness; 4/6 presented with gastrointestinal symptoms. Two children had features of complete Kawasaki disease, 3 had incomplete Kawasaki disease, while 1 had terminal ileitis with delayed onset of circulatory shock. Treatment consisted of intravenous immunoglobulin and aspirin for Kawasaki-like disease. Remdesivir, corticosteroids, and infliximab were used when indicated. Median hospitalization was 7 days. Immediate treatment resulted in rapid clinical improvement. In children presenting with hyperinflammatory syndromes without cardiac manifestations, testing for SARS-CoV-2 RNA and antibodies, with close cardiac monitoring should be pursued due to the manifold presentations of SARS-CoV-2 infection in children.

Eculizumab-Associated Moraxella lacunata Bacteremia and Systemic Inflammatory Response Syndrome in a Toddler with Atypical Hemolytic Uremic Syndrome.

Moraxella lacunata, a low-virulence Gram-negative coccobacillus, is classically associated with conjunctivitis and upper respiratory tract infections; systemic infections such as sepsis have rarely been reported, especially in children. We describe a 28-month-old girl with atypical hemolytic uremic syndrome and stage II chronic kidney disease on long-term eculizumab therapy who presented with systemic inflammatory response syndrome and was found to have Moraxella lacunata bloodstream infection. Eculizumab, a humanized monoclonal anti-C5 antibody, has been associated with susceptibility to infections with encapsulated bacteria, especially Neisseria meningitidis. This is the first report of an invasive bacterial infection with Moraxella lacunata in a pediatric eculizumab recipient.

Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child.

BACKGROUND: Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens. CASE PRESENTATION: A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. Tracheal aspirate samples for mycobacterial DNA and culture from days 22 and 27 of illness were negative by PCR but grew Mycobacterium tuberculosis after 8 weeks, long after the child's passing. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread. CONCLUSION: The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.

Comparison of clinical outcomes of influenza A and B at the 2017-2018 influenza season: a cohort study.

Influenza has significant morbidity and mortality. Some experts consider infection with influenza B as milder than that with influenza A. The objective of this study is to evaluate the outcomes of hospitalized patients with laboratory-confirmed influenza A or B in 2017-2018 influenza season. All hospitalized patients between October 2017 and April 2018 with laboratory-confirmed influenza A and B were included. The primary composite outcomes were pneumonia/myocarditis/encephalitis, mechanical ventilation, ICU admission, and 30-day mortality. Secondary outcomes were 30-/90-day mortality, length of hospital stay, and readmission rates. The study included 201 influenza A and 325 influenza B. For the primary composite outcome, no significant difference was demonstrated between influenza A and B. Rates of mortality were similar at 30 and 90 days. Influenza A had higher pneumonia rates and mechanical ventilation. On multivariate analysis, higher Charlson's score, hypoalbuminemia, and vasopressor use were associated with 30-day mortality, while infection with either influenza A or B was not. Influenza A was associated with higher pneumonia and mechanical ventilation rates. However, influenza B resulted with similar 30-day mortality rate as influenza A.

Life-Threatening Influenza, Hemophagocytic Lymphohistiocytosis and Probable Vaccine-Strain Varicella in a Novel Case of Homozygous STAT2 Deficiency.

STAT2 is a transcription factor that plays an essential role in antiviral immunity by mediating the activity of type I and III interferons (IFN-I and IFN-III). It also has a recently established function in the negative regulation of IFN-I signaling. Homozygous STAT2 deficiency is an ultra-rare inborn error of immunity which provides unique insight into the pathologic consequence of STAT2 dysfunction. We report here a novel genetic cause of homozygous STAT2 deficiency with several notable clinical features. The proband presented aged 12 months with hemophagocytic lymphohistiocytosis (HLH) closely followed by clinical varicella, both occurring within three weeks of measles, mumps, and rubella (MMR) and varicella vaccinations. There was a history of life-threatening influenza A virus (IAV) disease 2 months previously. Genetic investigation uncovered homozygosity for a novel nonsense variant in STAT2 (c. 1999C>T, p. Arg667Ter) that abrogated STAT2 protein expression. Compatible with STAT2 deficiency, dermal fibroblasts from the child demonstrated a defect of interferon-stimulated gene expression and a failure to mount an antiviral state in response to treatment with IFN-I, a phenotype that was rescued by lentiviral complementation by wild type STAT2. This case significantly expands the phenotypic spectrum of STAT2 deficiency. The occurrence of life-threatening influenza, which has not previously been reported in this condition, adds STAT2 to the list of monogenetic causes of this phenotype and underscores the critical importance of IFN-I and IFN-III to influenza immunity. The development of probable vaccine-strain varicella is also a novel occurrence in STAT2 deficiency, implying a role for IFN-I/III immunity in control of attenuated varicella zoster virus in vivo and reinforcing the susceptibility to pathologic effects of live-attenuated viral vaccines in disorders of IFN-I immunity. Finally, the occurrence of HLH in this case reinforces emerging links to hyperinflammation in patients with STAT2 deficiency and other related defects of IFN-I signaling-highlighting an important avenue for further scientific enquiry.

High blood glucose variability is associated with bacteremia and mortality in patients hospitalized with acute infection.

BACKGROUND: Limited data are available regarding the association between glucose levels variability (GV) and outcomes of patients hospitalized with acute infectious diseases. AIM: To determine the association between GV and bacteremia, length of stay (LOS) and mortality. METHODS: A retrospective study of patients hospitalized in departments of medicine with respiratory tract, urinary tract and skin and soft tissue infections during 2011-17. GV was assessed by the coefficient of variation (CV) of glucose levels during hospitalization and was divided into tertiles (CV ≤ 16%, 17-29%, >29%). LOS, bacteremia rates and all-cause mortality (30 days, 90 days and after 5 years) were evaluated for the patients with and without DM according the three GV categories. RESULTS: The study consisted of 1485 patients, 838 (56%) were diabetic. There was no significant association between GV and LOS. Bacteremia rates were higher in the upper GV tertile compared with the lower one (6% vs. 2%, P = 0.007). Mid and upper tertiles compared with the lower one were significantly associated with increased 30-day mortality (13% vs. 5%, P = 0.005; and 40% vs. 5%, P = 0.002, respectively). A decreased 5 years survival was observed for both diabetic and non-diabetic patients in the mid and upper GV tertiles [adjusted HRs 0.8 (95% CI, 0.6-1.04) and 0.6 (95% CI, 0.5-0.9) in diabetic patients and 0.7 (95% CI, 0.5-0.9) and 0.5 (95% CI, 0.3-0.7) in the non-diabetic ones]. CONCLUSION: In diabetic and non-diabetic patients, hospitalized in non-ICU setting with acute infectious diseases, increased GV is associated with increased risk of bacteremia, short and long-term mortality.

Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single-centre before-after study.

OBJECTIVES: We aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). METHODS: This is a quasi-experimental, retrospective, before-after study. We compared the incidence of bacterial-related complications among 356 patients with multiple myeloma (MM) (n = 202) and lymphoma (n = 154) who underwent AHCT with (n = 177) or without (n = 179) ciprofloxacin prophylaxis between 03/2007 and 10/2012 and between 10/2012 and 07/2016, respectively, at a single centre. RESULTS: Febrile neutropaenia, bacteraemia, and pneumonia were significantly more common among patients who underwent AHCT during the second study period and did not receive antibacterial prophylaxis compared with patients who underwent AHCT during the first study period and received antibacterial prophylaxis (89.9% (161/179) vs. 83.1% (147/177), difference 6.9%, 95% CI 0-14.1%, P = 0.002; 15.1% (27/179) vs. 4.5% (8/177), difference 10.6%, 95% CI 4.4-16.9%, p < 0.0001; 12.3% (22/179) vs. 6.2% (11/177), difference 6.1%, 95% CI 0-12.3%, p = 0.04, respectively). The number-needed-to-treat to prevent one episode of bacteraemia, pneumonia, and febrile neutropaenia was 8.6, 8.5, and 13.7, respectively. Patients with ciprofloxacin prophylaxis had higher rates of ciprofloxacin-resistant bacteraemia (62.5% (5/8) vs. 18.5% (5/27), difference 44%, 95% CI 7-70%, p = 0.01). In multivariate analysis, ciprofloxacin prophylaxis significantly decreased the odds of bacteraemia (OR 0.19, 95% CI 0.07-0.52; p < 0.0001) and pneumonia (OR 0.37, 95% CI 0.16-0.85, p = 0.02). CONCLUSION: According to our single-centre experience, patients with MM and lymphoma undergoing AHCT may benefit from antibacterial prophylaxis with ciprofloxacin.

Severe Mitral Regurgitation in a Child With Henoch-Schönlein Purpura and Pulmonary Hemorrhage.

Introduction: Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood. The classic triad of HSP consists of nonthrombocytopenic purpura, arthritis/arthralgia, and gastrointestinal complaints. Pulmonary hemorrhage and cardiac involvement are rare complications of HSP. Case Report: We report the case of a 10-year-old girl with HSP complicated by both severe mitral regurgitation and pulmonary hemorrhage. Discussion: HSP is typically a self-limited illness with an excellent prognosis in children. Pulmonary hemorrhage is a rare complication that increases morbidity and mortality; it generally indicates the presence of severe vasculitis. Cardiac involvement in HSP is extremely rare and associated with a poor prognosis. Conclusion: Cardiac involvement in HSP may be more common than believed. Because of the increased morbidity and mortality associated with HSP complicated by pulmonary hemorrhage and cardiac involvement, it is important for clinicians to be aware of these potential complications.

International experts' practice in the antibiotic therapy of infective endocarditis is not following the guidelines.

OBJECTIVE: The management of infective endocarditis (IE) may differ from international guidelines, even in reference centres. This is probably because most recommendations are not based on hard evidence, so the consensus obtained for the guidelines does not represent actual practices. For this reason, we aimed to evaluate this question in the particular field of antibiotic therapy. METHODS: Thirteen international centres specialized in the management of IE were selected, according to their reputation, clinical results, original research publications and quotations. They were asked to detail their actual practice in terms of IE antibiotic treatment in various bacteriological and clinical situations. They were also asked to declare their IE-related in-hospital mortality for the year 2015. RESULTS: The global compliance with guidelines concerning antibiotic therapy was 58%, revealing the differences between theoretical 'consensus', local recommendations and actual practice. Some conflicts of interest were also probably expressed. The adherence to guidelines was 100% when the protocol was simple, and decreased with the seriousness of the situation (Staphylococus spp. 54%-62%) or in blood-culture-negative endocarditis (0%-15%) that requires adaptation to clinical and epidemiological data. CONCLUSION: Worldwide experts in IE management, although the majority of them were involved and co-signed the guidelines, do not follow international consensus guidelines on the particular point of the use of antibiotics.

How obesity impacts outcomes of infectious diseases.

Obesity is associated with co-morbidities and increased risk of acquiring infections with worse outcomes. Paradoxically, a few studies indicate that obesity may have a decreased mortality in hospitalized patients with pneumonia. The objective of this study was to determine the impact of body mass index (BMI) on short-term all-cause mortality and clinical outcomes among hospitalized adults with pneumonia, urinary tract infections, skin and soft tissue infections, and bacteremia. The study cohort included 1437 consecutive patients who were admitted with infectious disease including pneumonia (717), urinary tract infection (506), bacteremia (69), and skin and soft tissue infections (145), and hospitalized in internal medical departments, during 2013-2015. BMI was categorized as underweight (≤20 kg/m2), normal (20-25 kg/m2), overweight (25.1-29.9 kg/m2), and obese (≥30 kg/m2). Clinical outcomes of 30- and 90-day all-cause mortality rates, length of hospital stay, and transfer to the intensive care unit (ICU) were compared among groups, sorted according to BMI and different infectious diseases. Obesity was associated with decreased 30-day mortality in patients with pneumonia [odds ratio (OR) = 0.26, 95 % confidence interval (CI) 0.06-1.01; p = 0.052]. On the contrary, increased 30-day mortality was observed in the underweight patients (OR = 2.89, 95 % CI 1.1-7.6; p = 0.03). Similar impacts were not found for urinary tract infections, skin and soft tissue infections, or bloodstream infections. Furthermore, obesity had no effect on 90-day mortality, length of hospital stay, or transfer to the ICU in all kinds of infectious diseases. Obesity is associated with reduced short-term mortality among hospitalized patients with pneumonia. Whether gut microbiota in obese individuals plays a role in this protective effect remains to be investigated by further studies.

The effect of statins on the outcome of Clostridium difficile infection in hospitalized patients.

UNLABELLED: Several studies have shown an association between exposure to statins and favorable clinical outcomes for various types of infections. We aimed to assess the impact of statin use on mortality, disease severity and complications among hospitalized patients with Clostridium difficile infection (CDI). Data were analyzed from a retrospectively collected database of 499 patients diagnosed with CDI during 2009-2014. We compared infection outcomes between 178 statin (36 %) users and 321 (64 %) non-users. On multivariate analysis, we found that statin use did not have a significant impact on 30-day mortality (OR = 1.54; 95 % CI, 0.85-2.79; p = 0.15) or any significant effect on CDI severity and complication. Concomitant statin use has no significant impact on short-term mortality or effect on CDI severity and complications among hospitalized patients with CDI. However, patients in the statin group were older and had higher Charlson score compared with the non-statin group. Whether these factors affected a possible impact of statins on the disease course remains to be investigated. KEY MESSAGES: • Clostridium difficile is the most common cause of infectious nosocomial diarrhea among hospitalized adult patients in the developed countries. • There is an increasing morbidity and mortality of CDI patients due to the emergence of new strains of high virulence. • Recent studies demonstrated that prior statin use has protective and ameliorating effects on morbidity and mortality among CDI patients. • Our study showed that concomitant statin use has no significant impact on short-term mortality, CDI severity and its complications.

Risk factors for long-term mortality of Staphylococcus aureus bacteremia.

Staphylococcus aureus bacteremia (SAB) is a fatal disease. We aimed to describe risk factors for long-term mortality with SAB. We analyzed data from a retrospectively collected database including 1,692 patients with SAB. We considered variables of infection and background conditions for the analysis of long-term survival. The Kaplan-Meier procedure was used for analysis of long-term survival. Variables significantly associated with mortality were analyzed using a Cox regression model. We included 1,692 patients in the analysis. Patients were followed for up to 22 years. Within one year, 62% of patients died and within 5 years 72% died. A total of 82% of patients aged 65 years and older died within 5 years. Independent predictors of long-term mortality were older age (Hazard ratio 1.029, 95% confidence interval 1.022-1.036), female gender (HR 1.302, 95% CI 1.118-1.517), pneumonia or primary/ unknown source of infection (HR 1.441, 95% CI 1.230-1.689), dementia (HR 1.234, 95% CI 1.004-1.516), higher Charlson score (HR 1.155, 95% CI 1.115-1.196), shock at onset (HR 1.776, 95% CI 1.430-2.207) and arrival to hospitalization from an institution (HR 1.319, 95% CI 1.095-1.563). Long-term survival of patients older than 65 years and of women with SAB is severely curtailed.

Neonatal Pasteurella multocida subsp. septica Meningitis Traced to Household Cats: Molecular Linkage Analysis Using Repetitive-Sequence-Based PCR.

Pasteurella multocida is a rare cause of neonatal bacterial meningitis. We describe such a case and verify two household cats as the source of infection using repetitive-element PCR (rep-PCR) molecular fingering.

Multidrug-resistant Acinetobacter baumannii infections in lung transplant patients in the cardiothoracic intensive care unit.

BACKGROUND: Multidrug-resistant (MDR) gram-negative bacteria are a growing threat to solid organ transplantation (SOT) patients in the intensive care unit (ICU). We aimed to examine the mortality rates of gram-negative MDR bacterial infection in SOT patients compared with patient population undergoing other cardiothoracic surgeries and hospitalized under similar ICU conditions. METHODS: A retrospective study from a single medical center, including patients with MDR Acinetobacter baumannii and carbapenem-resistant Klebsiella pneumoniae infection, hospitalized in the cardiothoracic ICU. Data were collected from computerized databases, and data were verified using the hospitalization files. Microbiological data were provided by the microbiology laboratory. RESULTS: During the study period, 205 SOT patients and 5031 other patients were hospitalized in the cardiothoracic ICU. Active infection with gram-negative MDR bacteria was identified in 147 patients, of which 37 underwent SOT (18% of total transplant recipients) and 110 underwent another cardiothoracic surgery (2% of total patients who are not transplant recipients). Mortality rates were high among both groups of patients, with no significant difference between them. CONCLUSIONS: Infection with resistant bacteria is more prevalent among patients following SOT compared with patients following other cardiothoracic surgeries. Mortality is high in all patients regardless of the immunocompromised condition.

The role of FDG-PET/CT imaging in early detection of extra-cardiac complications of infective endocarditis.

The exact incidence of extra-cardiac complications (ECC) in patients with infective endocarditis (IE) is unknown but presumed to be high. These patients, although mostly asymptomatic, may require a more aggressive therapeutic approach. (18)fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is used for the diagnosis of infections, but its role in the early diagnosis of IE complications is still unclear. This study aimed to evaluate the role of FDG-PET/CT in the early diagnosis of ECC in IE and its implications for medical management. We prospectively studied 40 consecutive patients with a confirmed diagnosis of IE (according to the modified Duke criteria) who underwent a whole body FDG-PET/CT study within 14 days from diagnosis. The FDG-PET/CT demonstrated ECC in 17 (42.5%) patients, while 8 (38.1%) of them were asymptomatic. The most frequent embolic sites were musculoskeletal and splenic. Owing to the FDG-PET/CT findings, treatment planning was modified in 14 (35%) patients. This included antibiotic treatment prolongation (27.5%), referral to surgical procedures (15%) and, most substantially, prevention of unnecessary device extraction (17.7%). According to our experiences, FDG-PET/CT imaging was useful in the detection of embolic and metastatic infections in IE. This clinical information had a significant diagnostic and therapeutic impact in managing IE disease.

Predicting Clostridium difficile infection in diabetic patients and the effect of metformin therapy: a retrospective, case-control study.

Data on risk factors for Clostridium difficile infection (CDI) in diabetic patients are scarce. Recently, it has been shown that metformin increases the Bacteroidetes/Firmicutes ratio; therefore, it may yield a protective effect against CDI. We aimed to assess risk factors for CDI in diabetic patients beyond antibiotic treatment, and to determine the impact of metformin therapy on the development of CDI in these patients. In this retrospective, case-control study, all consecutive CDI diabetic patients, from January 2009 to December 2013, were included and compared to consecutive diabetic patients without CDI, hospitalized during the same period and in the same departments. Of 7,670 patients tested for C. difficile toxins, 486 were diabetics. Of them, 150 (30.8 %) were positive for C. difficile toxins and 336 (69.1 %) were negative. On multivariate analysis, metformin treatment was associated with a significant reduction in CDI [odds ratio (OR) = 0.58; 95 % confidence interval (CI), 0.37-0.93; p = 0.023], while heart failure was associated with significantly higher rates of CDI (OR = 1.654; 95 % CI, 1.007-2.716; p = 0.047), together with poor functional status, previous hospitalization, and abdominal surgery. Our findings suggest that, in diabetic patients, in addition to the well-recognized risk factors, heart failure is an additional risk factor for CDI, while metformin treatment seems to have a protective effect against the development of CDI. The exact mechanisms underlying this protective effect remain to be fully understood.