Subsegmental pulmonary embolism and anticoagulant therapy: the impact of clinical context.

BACKGROUND: Anticoagulation for subsegmental pulmonary embolism (SSPE) is controversial. AIM: To assess the impact of clinical context on anticoagulation and outcomes of SSPE. METHODS: We electronically searched computed tomography pulmonary angiogram reports to identify SSPE. We extracted demographic, risk factor, investigations and outcome data from the electronic medical record. We stratified patients according to anticoagulation and no anticoagulation. RESULTS: From 1 January 2017 to 31 December 2019, we identified 166 patients with SSPE in 5827 pulmonary angiogram reports. Of these, 123 (74%) received anticoagulation. Compared with non-anticoagulated patients, such patients had a different clinical context: higher rates of previous venous thromboembolism (11% vs 0%; P = 0.019), more recent surgery (26% vs 9%; P = 0.015), more elevated serum D-dimer (22% vs 5%; P = 0.004), more lung parenchymal abnormalities (76% vs 61%; P = 0.037) and were almost twice as likely to require inpatient care (76% vs 42%; P < 0.001). Such patients also had twice the all-cause mortality at 1 year (32% vs 16%). CONCLUSIONS: SSPE is diagnosed in almost 3% of pulmonary angiograms and is associated with high mortality, regardless of anticoagulation, due to coexistent disease processes rather than SSPE. Anticoagulation appears dominant but markedly affected by the clinical context of risk factors, alternative indications and illness severity. Thus, the controversy is partly artificial because anticoagulation after SSPE is clinically contextual with SSPE as only one of several factors.

Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR).

INTRODUCTION: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. METHODS AND ANALYSIS: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).

Defective Severe Acute Respiratory Syndrome Coronavirus 2 Immune Responses in an Immunocompromised Individual With Prolonged Viral Replication.

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune responses in a patient with lymphoma and recent programmed death 1 (PD-1) inhibitor therapy with late onset of severe coronavirus disease 2019 disease and prolonged SARS-CoV-2 replication, in comparison to age-matched and immunocompromised controls. High levels of HLA-DR+/CD38+ activation, interleukin 6, and interleukin 18 in the absence of B cells and PD-1 expression was observed. SARS-CoV-2-specific antibody responses were absent and SARS-CoV-2-specific T cells were minimally detected. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses.

Successful use of azithromycin for Escherichia coli-associated renal allograft malakoplakia: a report of two cases.

Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.

The Role of Immunological and Clinical Biomarkers to Predict Clinical COVID-19 Severity and Response to Therapy-A Prospective Longitudinal Study.

Background: The association of pro-inflammatory markers such as interleukin-6 (IL-6) and other biomarkers with severe coronavirus disease 2019 (COVID-19) is of increasing interest, however their kinetics, response to current COVID-related treatments, association with disease severity and comparison with other disease states associated with potential cytokine storm (CS) such as Staphylococcus aureus bacteraemia (SAB) are ill-defined. Methods: A cohort of 55 hospitalized SARS-CoV-2 positive patients was prospectively recruited - blood sampling was performed at baseline, post-treatment and hospital discharge. Serum IL-6, C-reactive protein (CRP) and other laboratory investigations were compared between treatment groups and across timepoints. Acute serum IL-6 and CRP levels were then compared to those with suspected COVID-19 (SCOVID) and age and sex matched patients with SAB and patients hospitalized for any non-infectious condition (NIC). Results: IL-6 was elevated at admission in the SARS-CoV-2 cohort but at lower levels compared to matched SAB patients. Median (IQR) IL-6 at admission was 73.89 pg/mL (30.9, 126.39) in SARS-CoV-2 compared to 92.76 pg/mL (21.75, 246.55) in SAB (p=0.017); 12.50 pg/mL (3.06, 35.77) in patients with NIC; and 95.51 pg/mL (52.17, 756.67) in SCOVID. Median IL-6 and CRP levels decreased between admission and discharge timepoints. This reduction was amplified in patients treated with remdesivir and/or dexamethasone. CRP and bedside vital signs were the strongest predictors of COVID-19 severity. Conclusions: Knowledge of the kinetics of IL-6 did not offer enhanced predictive value for disease severity in COVID-19 over common investigations such as CRP and vital signs.

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3+cTFH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.

Development and Validation of a Penicillin Allergy Clinical Decision Rule.

Importance: Penicillin allergy is a significant public health issue for patients, antimicrobial stewardship programs, and health services. Validated clinical decision rules are urgently needed to identify low-risk penicillin allergies that potentially do not require penicillin skin testing by a specialist. Objective: To develop and validate a penicillin allergy clinical decision rule that enables point-of-care risk assessment of patient-reported penicillin allergies. Design, Setting, and Participants: In this diagnostic study, a multicenter prospective antibiotic allergy-tested cohort of 622 patients from 2 tertiary care sites in Melbourne, Australia (Austin Health and Peter MacCallum Cancer Centre) was used for derivation and internal validation of a penicillin allergy decision rule. Backward stepwise logistic regression was used to derive the model, including clinical variables predictive of a positive penicillin allergy test result. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in retrospective penicillin allergy-tested cohorts consisting of 945 patients from Sydney and Perth, Australia, and Nashville, Tennessee. Patients who reported a penicillin allergy underwent penicillin allergy testing using skin prick, intradermal, or patch testing and/or oral challenge (direct or after skin testing). Data were collected from June 26, 2008, to June 3, 2019, and analyzed from January 9 to 12, 2019. Main Outcomes and Measures: The primary outcome for the model was any positive result of penicillin allergy testing performed during outpatient or inpatient assessment. Results: From an internal derivation and validation cohort of 622 patients (367 female [59.0%]; median age, 60 [interquartile range{IQR}, 48-71] years) and an external validation cohort of 945 patients (662 female [70.1%]; median age, 55 [IQR, 38-68] years), the 4 features associated with a positive penicillin allergy test result on multivariable analysis were summarized in the mnemonic PEN-FAST: penicillin allergy, five or fewer years ago, anaphylaxis/angioedema, severe cutaneous adverse reaction (SCAR), and treatment required for allergy episode. The major criteria included an allergy event occurring 5 or fewer years ago (2 points) and anaphylaxis/angioedema or SCAR (2 points); the minor criterion (1 point), treatment required for an allergy episode. Internal validation showed minimal mean optimism of 0.003 with internally validated area under the curve of 0.805. A cutoff of less than 3 points for PEN-FAST was chosen to classify a low risk of penicillin allergy, for which only 17 of 460 patients (3.7%) had positive results of allergy testing, with a negative predictive value of 96.3% (95% CI, 94.1%-97.8%). External validation resulted in similar findings. Conclusions and Relevance: In this study, PEN-FAST was found to be a simple rule that accurately identified low-risk penicillin allergies that do not require formal allergy testing. The results suggest that a PEN-FAST score of less than 3, associated with a high negative predictive value, could be used by clinicians and antimicrobial stewardship programs to identify low-risk penicillin allergies at the point of care.

Bartonella Quintana prosthetic aortitis successfully treated with doxycycline.

Bartonella quintana is a rare cause of culture-negative endovascular infection, characterised by intracellular persistence. We describe a case of ascending aortic prosthetic graft infection due to B. quintana, in a patient with past unrecognised necrotising aortitis, which was successfully treated with doxycycline monotherapy.

High prevalence of antibiotic allergies in cladribine-treated patients with hairy cell leukemia - lessons for immunopathogenesis and prescribing.

The relationship between hematological malignancy and chemotherapy on the prevalence of antibiotic allergy label (AAL) is ill-defined. We performed a multicenter retrospective case-control study comparing AAL rates among cladribine-treated hairy cell leukemia (C-HCL) cases, non-HCL cladribine-treated controls (control-1), and fludarabine-treated controls (control-2). The prevalence of AALs in C-HCL patients was 60%, compared with control-1 (14%, p < .01) and control-2 patients (25%, p < .01). The predominant phenotype was maculopapular exanthem (92%). The drugs implicated in AAL causality in C-HCL patients included beta-lactams (81%), trimethoprim-sulfamethoxazole (58%), and allopurinol (69%). C-HCL patients demonstrate high rates of AAL, potentially due to immune dysregulation, impacting beta-lactam utilization.

The Safety and Efficacy of an Oral Penicillin Challenge Program in Cancer Patients: A Multicenter Pilot Study.

Antibiotic allergies are reported by up to 1 in 4 cancer patients, almost 50% of which are considered low risk and precede the cancer diagnosis. We demonstrate the successful and safe implementation of a pilot oral penicillin challenge program for cancer patients with low-risk penicillin allergies, increasing the use of penicillin and narrow-spectrum beta-lactams post-testing.

Echocardiography has low utility in cancer patients with Staphylococcus aureus bacteraemia: findings from a retrospective study.

AIM: To describe the incidence of infective endocarditis (IE) detected on echocardiography in cancer patients with confirmed Staphylococcus aureus bacteraemia (SAB). METHODS: We retrospectively identified 95 cases of SAB in cancer patients from January 2007-March 2016. Echocardiography was ordered at the discretion of the treating team, and positive findings defined according to the Modified Duke Criteria. Complicated bacteraemia was defined by prolonged bacteraemia, presence of intracardiac device/prosthetic valve, or signs of metastatic infection. RESULTS: Major predisposing risk factors for IE (intracardiac device, prosthetic valve, valvular disease, diabetes mellitus, renal dialysis) were present in 27% of cases. Fifty-one of 95 (54%) had a central venous catheter and 17 (18%) patients had complicated bacteraemia. Echocardiography was performed in 75/95 (79%) episodes, with transthoracic echocardiography (TTE) alone in 56, transoesophageal echocardiography (TOE) alone in 4 and both in 15. Echocardiography was diagnostic for IE in 2 patients (1 TTE, 1 TOE), including one result that led to the diagnosis of IE in a clinically unsuspected case. Four further cases of IE were diagnosed on clinical findings, resulting in an overall rate of IE of 6% (6/95). Five of these cases occurred in patients with complicated bacteraemia or ≥ 1 risk factor for IE. No patient was readmitted due to IE. CONCLUSION: IE is infrequent in cancer patients with uncomplicated SAB and no risk factors for IE. Performing echocardiography routinely in all cancer patients with SAB rarely alters diagnosis or affects antibiotic management and therefore should be reserved for patients with specific risk factors.

Locally extensive angio-invasive Scedosporium prolificans infection following resection for squamous cell lung carcinoma.

We report a case of Scedosporium prolificans infection in a patient following surgery for squamous cell lung carcinoma. Combination therapy with voriconazole and terbinafine was commenced for intrathoracic infection and mycotic vasculitis. In spite of antifungal treatment, he developed culture-positive sternal and rib osteomyelitis four months later. Scedosporiosis is not commonly reported in patients with solid organ malignancies, and this case highlights its aggressive nature and propensity for direct local invasion.

Refractory Bartonella quintana bacillary angiomatosis following chemotherapy for chronic lymphocytic leukaemia.

Bacillary angiomatosis is a well-recognized infection with cutaneous and systemic manifestations caused by Bartonella henselae or Bartonella quintana and occurs in immunocompromised patients. We report a case of B. quintana bacillary angiomatosis following fludarabine-based chemotherapy for chronic lymphocytic leukaemia that was refractory to standard treatment and was complicated by lymphadenopathy and osteomyelitis.

Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infection.

Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain the last available therapy for some patients with multi-resistant S. aureus infections. Using comparative and functional genomics we investigated the molecular determinants of resistance and SCV formation in sequential S. aureus isolates from a patient who had a persistent and recurrent S. aureus infection, after failed therapy with multiple antimicrobials, including linezolid. Two point mutations in key staphylococcal genes dramatically affected clinical behaviour of the bacterium, altering virulence and antimicrobial resistance. Most strikingly, a single nucleotide substitution in relA (SACOL1689) reduced RelA hydrolase activity and caused accumulation of the intracellular signalling molecule guanosine 3', 5'-bis(diphosphate) (ppGpp) and permanent activation of the stringent response, which has not previously been reported in S. aureus. Using the clinical isolate and a defined mutant with an identical relA mutation, we demonstrate for the first time the impact of an active stringent response in S. aureus, which was associated with reduced growth, and attenuated virulence in the Galleria mellonella model. In addition, a mutation in rlmN (SACOL1230), encoding a ribosomal methyltransferase that methylates 23S rRNA at position A2503, caused a reduction in linezolid susceptibility. These results reinforce the exquisite adaptability of S. aureus and show how subtle molecular changes cause major alterations in bacterial behaviour, as well as highlighting potential weaknesses of current antibiotic treatment regimens.

Neurocysticercosis causing sudden death.

Neurocysticercosis causes significant morbidity due to neurologic manifestations including seizures. Sudden unexpected death in epilepsy (SUDEP) is responsible for mortality associated with seizure disorders. This case highlights death from neurocysticercosis and possible SUDEP in a nonendemic country.