Search

Risk of MI after Acute Infection Among patients who are hospitalized for pneumococcal pneumonia, the incidence of myocardial infarction is 7 to 8%. The true incidence of postinfection myocardial in...

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T-cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating IL-15. CD8+ T cell activation was apparent without signs of exhaustion. While cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19., A multiparameter metric developed by integrating circulating cytokines, multimodal single cell profiling, cell surface protein and immune cell analyses of COVID-19 patients over time, reveals a late wave of diverging inflammatory and host immune responses that predicts recovery versus fatality.

Background: Accurate determination of the microbial etiology of pneumonia has important consequences for appropriate administration of antimicrobials and antimicrobial stewardship. Procalcitonin (PCT) is a biomarker that is finding increasing diagnostic and prognostic utility in lower respiratory infections, however, it remains unclear whether it can be helpful in predicting the bacterial etiology of pneumonia. In this study, we examined the relationship between serial PCT measurements and bacterial etiology in hospitalized patients with community-acquired pneumonia, including those at high risk for infections due to multi-drug resistant organisms (MDRO), to determine whether PCT at admission and its trajectory early in the hospital course of patients provides distinguishing information between different bacterial causes of pneumonia.Methods: We analyzed data collected from a prospective cohort study of 505 patients admitted to a tertiary care center with a clinical syndrome consistent with pneumonia. Bacterial etiology of pneumonia was determined from high quality respiratory samples, blood cultures and other relevant diagnostic tests according to standard protocols in conjunction with clinical review. Daily plasma procalcitonin levels were measured for these patients serially during the first four days of hospitalization. We compared procalcitonin levels associated with different bacterial etiologies of pneumonia over the first four days of admission, using the Mann-Whitney-U test to assess for statistical significance.Results: Out of 505 patients, the diagnosis of pneumonia was adjudicated in 322, and bacterial etiology determined in 64 cases. The predominant pathogens were Staphylococcus aureus (n = 19; 12 Methicillin Resistant (MRSA) and 7 Methicillin Susceptible (MSSA)), Pseudomonas aeruginosa (n = 12), Streptococcus pneumoniae (n = 6), and Haemophilus influenza (n=5). We found higher procalcitonin values for S. pneumoniae relative to other etiologies, a delayed rise for Pseudomonas over time, and consistently low PCT values for infections due to multiple bacteria. In addition, our results also suggest that procalcitonin values on the second day of hospitalization, rather than at admission, may have the most utility in distinguishing between bacterial etiologies.Conclusion: Serial procalcitonin values during the early course of bacterial pneumonia reveal a difference between pneumococcal and other bacterial etiologies, and may have an adjunct role in guiding antibiotic choice and duration.

Type‐I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID‐19). Several lines of evidence suggest that impaired type‐I IFN signaling may predispose to severe COVID‐19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type‐I IFNs influence outcomes in patients with COVID‐19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type‐I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID‐19 at three Italian hospitals. The presence of circulating AAbs to type‐I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type‐I IFN AAbs. Our findings provide further support for the role of type‐I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID‐19 pneumonia in severe acute respiratory syndrome coronavirus 2‐infected individuals., Neutralizing autoantibodies to type‐I interferons predispose people to severe coronavirus disease 19 (COVID‐19). These autoantibodies are associated with admission to the intensive care unit and delayed viral clearance. However, in our study, they were not associated with increased mortality.

The clearance of both tumors and microbes depends on highly coordinated immune responses that are sufficiently potent to kill malignant or microbial cells while avoiding immunopathology from an overly exuberant inflammatory response. A molecular understanding of the immune pathways that regulate these responses paved the way for the development of checkpoint inhibitors (CPIs) as a therapeutic strategy to boost endogenous antitumor immunity. CPIs have demonstrated survival benefits across a wide spectrum of cancers. While infectious complications of CPIs are uncommon, immune-related adverse events occur frequently and often require immunosuppressive therapies that increase the risk of infection.

Humans are continuously exposed to fungi at barrier sites, yet invasive or persistent mucocutaneous infection ensues in a small proportion of individuals. In recent years, there has been a surge of studies uncovering the immune mechanisms responsible for controlling these organisms, which exhibit fungus-, tissue-, and cell-type specificity. Significant insight into the molecular basis for host defense against fungi has been gleaned by studying individuals with inborn errors of fungal immunity. In this chapter, we review some of the Mendelian disorders that predispose to chronic mucocutaneous and/or invasive fungal infections and we discuss the clinically relevant aspects of host genetics, pathogenesis, diagnosis, and management.

Understanding of the microbiology of pneumonia has evolved. The role of pneumococcus has greatly declined. “Atypical” agents cause only a very small proportion of cases. Viruses are prominent. Intensive investigations fail to identify a causative organism in more than 50% of cases., Before 1945, Streptococcus pneumoniae caused more than 90% of cases of pneumonia in adults. After 1950, the proportion of pneumonia caused by pneumococcus began to decline. Pneumococcus has continued to decline; at present, this organism is identified in fewer than fewer10%–15% of cases. This proportion is higher in Europe, a finding likely related to differences in vaccination practices and smoking. Gram-negative bacilli, Staphylococcus aureus, Chlamydia, Mycoplasma, and Legionella are each identified in 2%–5% of patients with pneumonia who require hospitalization. Viruses are found in 25% of patients, up to one-third of these have bacterial coinfection. Recent studies fail to identify a causative organism in more than 50% of cases, which remains the most important challenge to understanding lower respiratory infection. Our findings have important implications for antibiotic stewardship and should be considered as new policies for empiric pneumonia management are developed.

The mammalian immune system has evolved the capacity to detect and destroy tumor cells. Tumors utilize multiple strategies to evade host immune surveillance, including the induction of the checkpoint molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to suppress antitumor immunity. Pharmacologic blockade of these molecules with checkpoint inhibitors (CPIs) restores T cell function and prolongs survival in patients with various malignancies. Emerging evidence suggests that the same checkpoint pathways may play a crucial role during infections. Indeed, CPIs appear promising as immunotherapeutic agents in infectious diseases, although their efficacy varies depending on pathogen-, cell-, and organ-specific factors. More research will be necessary to clarify the effects and safety of CPIs on clinically relevant outcomes of human infection.

Neutrophils employ several mechanisms to restrict fungi, including the action of enzymes such as myeloperoxidase (MPO) or NADPH oxidase, and the release of neutrophil extracellular traps (NETs). Moreover, they cooperate, forming “swarms” to attack fungi that are larger than individual neutrophils. Here, we designed an assay for studying how these mechanisms work together and contribute to neutrophil's ability to contain clusters of live Candida. We find that neutrophil swarming over Candida clusters delays germination through the action of MPO and NADPH oxidase, and restricts fungal growth through NET release within the swarm. In comparison with neutrophils from healthy subjects, those from patients with chronic granulomatous disease produce larger swarms against Candida, but their release of NETs is delayed, resulting in impaired control of fungal growth. We also show that granulocyte colony-stimulating factors (GCSF and GM-CSF) enhance swarming and neutrophil ability to restrict fungal growth, even during treatment with chemical inhibitors that disrupt neutrophil function.

Background. Postobstructive community-acquired pneumonia (PO-CAP) is relatively common in clinical practice. The clinical syndrome is poorly defined, and the role of infection as a cause of the infiltrate is uncertain. We prospectively studied patients with PO-CAP and compared them to a cohort of patients with bacterial community-acquired pneumonia (B-CAP). Methods. We prospectively studied patients hospitalized for CAP; 5.4% had PO-CAP, defined as a pulmonary infiltrate occurring distal to an obstructed bronchus. Sputum and blood cultures, viral polymerase chain reaction, urinary antigen tests, and serum procalcitonin (PCT) were done in nearly all cases. Clinical and laboratory characteristics of patients with PO-CAP were compared to those of patients with B-CAP. Results. In a 2-year period, we identified 30 patients with PO-CAP. Compared to patients with B-CAP, patients with PO-CAP had longer duration of symptoms (median, 14 vs 5 days; P < .001). Weight loss and cavitary lesions were more common (P < .01 for both comparisons) and leukocytosis was less common (P < .01) in patients with PO-CAP. A bacterial pathogen was implicated in only 3 (10%) PO-CAP cases. PCT was

Neutrophils employ several mechanisms to restrict fungi, including the action of enzymes such as myeloperoxidase (MPO) or NADPH oxidase, and the release of neutrophil extracellular traps (NETs). Moreover, they cooperate, forming “swarms” to attack fungi that are larger than individual neutrophils. Here, we designed an assay for studying how these mechanisms work together and contribute to neutrophil's ability to contain clusters of live Candida. We find that neutrophil swarming over Candida clusters delays germination through the action of MPO and NADPH oxidase, and restricts fungal growth through NET release within the swarm. In comparison with neutrophils from healthy subjects, those from patients with chronic granulomatous disease produce larger swarms against Candida, but their release of NETs is delayed, resulting in impaired control of fungal growth. We also show that granulocyte colony-stimulating factors (GCSF and GM-CSF) enhance swarming and neutrophil ability to restrict fungal growth, even during treatment with chemical inhibitors that disrupt neutrophil function., Neutrophils employ several mechanisms to control the growth of fungi, including enzymes, reactive oxygen species, extracellular traps, and formation of “swarms”. Here, Hopke et al. study how the different mechanisms work together, using an in vitro assay with human neutrophils and clusters of live Candida cells.

Background Procalcitonin (PCT) is a prohormone that rises in bacterial pneumonia and has promise in reducing antibiotic use. Despite these attributes, there are inconclusive data on its use for clinical prognostication. We hypothesize that serial PCT measurements can predict mortality, intensive care unit (ICU) admission, and bacteremia. Methods A prospective cohort study of inpatients diagnosed with pneumonia was performed at a large tertiary care center in Boston, Massachusetts. Procalcitonin was measured on days 1 through 4. The primary endpoint was a composite adverse outcome defined as all-cause mortality, ICU admission, and bacteremia. Regression models were calculated with area under the receiver operating characteristic curve (AUC) as a measure of discrimination. Results Of 505 patients, 317 patients had a final diagnosis of community-acquired pneumonia (CAP) or healthcare-associated pneumonia (HCAP). Procalcitonin was significantly higher for CAP and HCAP patients meeting the composite primary endpoint, bacteremia, and ICU admission, but not mortality. Incorporation of serial PCT levels into a statistical model including the Pneumonia Severity Index (PSI) improved the prognostic performance of the PSI with respect to the primary composite endpoint (AUC from 0.61 to 0.66), bacteremia (AUC from 0.67 to 0.85), and need for ICU-level care (AUC from 0.58 to 0.64). For patients in the highest risk class PSI >130, PCT was capable of further risk stratification for prediction of adverse outcomes. Conclusion Serial PCT measurement in patients with pneumonia shows promise for predicting adverse clinical outcomes, including in those at highest mortality risk.

Antiretroviral drugs are associated with a variety of adverse effects on the central and peripheral nervous systems. The frequency and severity of neuropsychiatric adverse events is highly variable, with differences between the antiretroviral classes and amongst the individual drugs in each class. In the developing world, where the nucleoside reverse transcriptase inhibitor (NRTI) stavudine remains a commonly prescribed antiretroviral, peripheral neuropathy is an important complication of treatment. Importantly, this clinical entity is often difficult to distinguish from human immunodeficiency virus (HIV)-induced peripheral neuropathy. Several clinical trials have addressed the efficacy of various agents in the treatment of NRTI-induced neurotoxicity. NRTI-induced neurotoxicity is caused by inhibition of mitochondrial DNA polymerase. This mechanism is also responsible for the mitochondrial myopathy and lactic acidosis that occur with zidovudine. NRTIs, particularly zidovudine and abacavir, may also cause central nervous system (CNS) manifestations, including mania and psychosis. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is perhaps the antiretroviral most commonly associated with CNS toxicity, causing insomnia, irritability and vivid dreams. Recent studies have suggested that the risk of developing these adverse effects is increased in patients with various cytochrome P450 2B6 alleles. Protease inhibitors cause perioral paraesthesias and may indirectly increase the relative risk of stroke by promoting atherogenesis. HIV integrase inhibitors, C-C chemokine receptor type 5 (CCR5) inhibitors and fusion inhibitors rarely cause neuropsychiatric manifestations.

Abnormal movements are frequently encountered in patients with brain injury hospitalized in intensive care units (ICUs), yet characterization of these movements and their underlying pathophysiology is difficult due to the comatose or uncooperative state of the patient. In addition, the available diagnostic approaches are largely derived from outpatients with neurodegenerative or developmental disorders frequently encountered in the outpatient setting, thereby limiting the applicability to inpatients with acute brain injuries. Thus, we reviewed the available literature regarding abnormal movements encountered in acutely ill patients with brain injuries. We classified the brain injury into the following categories: anoxic, vascular, infectious, inflammatory, traumatic, toxic-metabolic, tumor-related and seizures. Then, we identified the abnormal movements seen in each category as well as their epidemiologic, semiologic and clinicopathologic correlates. We propose a practical paradigm that can be applied at the bedside for diagnosing abnormal movements in the ICU. This model seeks to classify observed abnormal movements in light of various patient-specific factors. It begins with classifying the patient’s level of consciousness. Then, it integrates the frequency and type of each movement with the availability of ancillary diagnostic tests and the specific etiology of brain injury.

Prolonged neutropenia is generally thought to be the major factor for invasive pulmonary aspergillosis (IPA). In the present study, we characterize the frequency, severity, and duration of neutropenia that immediately precedes IPA. Prolonged neutropenia was identified in only one third of all IPA cases and occurred exclusively in hematologic patients.

We studied the microbiology reports of urine cultures collected from external (condom catheters) versus indwelling (Foley) catheters. The equal prevalence of Enterobacteriaceae and Enterococci in samples from both catheter types calls into question the practice of switching from indwelling to external catheters to decrease catheter-associated bacteriuria.

Two major troponin I (TnI) genes, fetal TnI (ssTnI) and adult TnI (cTnI), are expressed in the mammalian heart under the control of a developmentally regulated program. In this study, the up-stream domain ( approximately 1,800 bp) of mouse fetal TnI gene has been cloned and characterized. There is a high homology of this region among mouse, rat and human. Analysis of the sequence revealed several putative regulatory domains and binding sites (Sp1 binding sites, GATA binding site, MyoD, CREB, MEF2, AP1, NFkappaB, etc). Transfection assays indicated that conserved GA-rich sequences, CREB and a CCAAT box within the first 300 bp upstream of the transcription start site were critical for the gene expression. Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays revealed binding proteins to CREB site in nuclear extracts from myocardial cells. An inhibitory domain was revealed within the sequence between -1,700 to -1,780. Thyroid hormone (T(3)) caused a significant inhibitory effect on ssTnI expression in myocardial cells whereas this effect was not evident in CHO cells.

Background The safety of corticosteroid use (CSU) during active infection is controversial. In the invasive aspergillosis (IA) literature, CSU is typically defined using the time period prior to IA onset. Clinicians caring for patients with IA are unable to control prior CSU. The more clinically relevant question is whether CSU after IA onset is harmful. Methods Patients hospitalized at our institution from 2004 to 2014 with IA were retrospectively identified. CSU, defined as the average daily prednisone equivalent dose during the 7-day period following IA onset, was calculated for each patient. A CSU cut-off of 7.5mg was used to assign patients to treatment (>7.5mg) or control (7.5mg prior to IA 78.7% (48/61) 70.5% (43/61) .41 Leukemia 52.5% (32/61) 49.2% (30/61) .86 Allogeneic bone marrow transplant 26.2% (16/61) 29.5% (18/61) .84 Graft vs. host disease 3.3% (2/61) 11.5% (7/61) .16 Neutropenia 48.3% (28/58) 42.9% (24/56) .58 Solid organ transplant 11.5% (7/61) 6.6% (4/61) .53 Obstructive lung disease 21.3% (13/61) 24.6% (15/61) .83 Diabetes mellitus 26.2% (16/61) 29.5% (18/61) .84 Pulmonary IA 94.8% (55/58) 94.9% (56/59) .99 Coinfection 23.0% (14/61) 21.3% (13/61) .99 Data presented as median (interquartile range) or % (n with feature/n with data available) Figure. Kaplan–Meier curves comparing 6-week survival Disclosures All authors: No reported disclosures.

Background Procalcitonin (PCT) is a biomarker that is finding increasing diagnostic and prognostic utility in lower respiratory infections. It remains unclear, however, whether it can be helpful in predicting the bacterial etiology of pneumonia, with a view to informing antibiotic choice and duration. This study examines the relationship between serial PCT measurements and microbial etiology in patients hospitalized for pneumonia to determine whether changes in PCT levels provide discriminatory information on microbial etiology. Methods We performed a subgroup analysis of data from a prospective cohort study of 505 patients admitted to a tertiary care center with findings concerning for pneumonia. Microbial etiology of pneumonia was determined from high quality respiratory samples, blood cultures or other relevant diagnostic tests according to standard protocols. Procalcitonin levels were measured serially during the first four days of hospitalization. We compared procalcitonin levels between different bacterial etiologies over the first four days of admission, using the Mann–Whitney-U test to assess for statistical significance. Results Out of 505 patients, the diagnosis of pneumonia was adjudicated in 317, and bacterial etiology determined in 62 cases. The predominant pathogens were Staphylococcus aureus (N = 18), Streptococcus pneumoniae (N = 6), Pseudomonas aeruginosa (N = 11) and Haemophilus influenza (N = 5). Admission levels of PCT were lowest in Pseudomonas infections and highest in pneumococcal infections, though not reaching statistical significance. On hospital days two and three, pneumococcal procalcitonin levels were significantly higher than all other etiologies, but on day four, there was no statistically significant difference in PCT values for different microbial etiologies. Conclusion Serial procalcitonin levels during the early course of bacterial pneumonia reveal a difference between pneumococcal and other bacterial etiologies, and may have an adjunct role in guiding antibiotic choice and duration. Disclosures All authors: No reported disclosures.

A variety of prediction scores have been developed to identify at the time of presentation patients with community-acquired pneumonia at risk for intensive care unit (ICU) admission or death within 30 days. The effectiveness of each scoring score is typically assessed by calculation of the area under the receiver-operator characteristic curve (AUROC). Although this statistical parameter is helpful in determining the discriminatory value of a score, it assumes equal importance of false negatives and false positives in the tradeoff between sensitivity and specificity. Because patient safety takes precedence over cost, the balance between limiting false negatives (unnecessarily strict ICU admission policy) and false positives (unnecessarily liberal ICU admission policy) should favor the reduction of false negatives. Instead of using AUROC as the primary measure to evaluate prediction rules, we propose the use of sensitivity as a more appropriate alternative.

We appreciate the gracious and insightful comments by Chalmers1 on our recent opinion paper.2 To fully consider the points raised by Chalmers, we decided to calculate the positive and negative likelihood ratio (+LR and –LR, respectively) for several scoring systems, using data from our recently published prospective study of community-acquired pneumonia …

To the Editor,In a recent case–control study, Kim et al. compared the predicted 10-y cardiovascular mortality between HIV-infected and uninfected patients [1]. Applying the Framingham risk score (F...