Functional Outcomes and Morbidity in Pediatric Sepsis Survivors: A Tanzanian Experience

Pediatric sepsis remains a significant cause of childhood morbidity and mortality, disproportionately affecting resource-limited settings. As more patients survive, it is paramount that we improve our understanding of post-sepsis morbidity and its impact on functional outcomes. The functional status scale (FSS) is a pediatric validated outcome measure quantifying functional impairment, previously demonstrating decreased function following critical illnesses, including sepsis, in resource-rich settings. However, functional outcomes utilizing the FSS in pediatric sepsis survivors have never been studied in resource-limited settings or in non-critically ill septic children. In a Tanzanian cohort of pediatric sepsis patients, we aimed to evaluate morbidity associated with an acute septic episode using the FSS modified for resource-limited settings. This was a prospective cohort study at an urban referral hospital in Tanzania, including children with sepsis aged 28 days to 14 years old over a 12-month period. The FSS was adapted to the site's available resources. Functional status scale scores were obtained by interviewing guardians both at the time of presentation to determine the child's baseline and at 28-day follow-up. The primary outcome was “decline in functional status,” as defined by a change in FSS score of at least 3. In this cohort, 4.3% of the 1,359 surviving children completing 28-day follow-up had a “decline in functional status.” Conversely, 13.8% of guardians reported that their child was not yet back to their pre-illness state. Three-quarters of children reported as not fully recovered were not identified via the FSS as having a decline in functional status. In our cohort of pediatric sepsis patients, we identified a low rate of decline in functional status when using the FSS adapted for resource-limited settings. A higher proportion of children were subjectively identified as not being recovered to baseline. This suggests that the FSS has limitations in this population, despite being adapted for resource-limited settings. Next steps include developing and validating a further revised FSS to better capture patients identified as not recovered but missed by the current FSS.

Long-Term Abnormalities of Lipid Profile After a Single Episode of Sepsis

Background: Acute disturbances of the lipid profile are commonplace during acute sepsis episode. However, their long-term persistence has not to be investigated despite pivotal role of dyslipidemia in several comorbidities excessively noted in sepsis survivors (stroke, cardiomyopathy).Methods: A total of 9,861 individuals hospitalized for a singular episode of sepsis between 2009 and 2019 were identified from electronic medical records. Lab measurements of total cholesterol (Tchol), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), very low-density lipoprotein (VLDL), triglycerides (TG), lipoprotein(a) [Lp (a)], apolipoprotein B (ApoB), and C-reactive protein (CRP). The data were examined as baseline values before sepsis, during hospitalization, and <3 months, 3–6 months, 6–12 months, 1–2 years, and more than 2 years from initial sepsis.Results: Significant reductions in HDL-c (HDLbaseline = 44.06 vs. HDLsepsis = 28.2; U = −37.79, p < 0.0001, Cohen's d = 0.22) and LDL-c serum levels were observed during and up to three months post sepsis, with females much less affected. In contrast, male subjects had derangement in HDL present for up to two years after a singular septic episode. Total cholesterol levels were slightly yet significantly elevated for up to two years after sepsis. TG were elevated up to one year [TGbaseline = 128.26 vs. TGsepsis = 170.27, t(8255) = −21.33, p < 0.0001, Cohen's d = 0.49] and normalized. Lp(a) was elevated up to two years after initial episode [Lp(a)baseline = 24.6 ± 16.06; Lp(a)sepsis−2year = 8.25 ± 5.17; Lp(a)morethan2years = 61.4 ± 40.1; ANOVA F(2, 24) = 7.39; p = 0.0032]. Response to statin therapy was blunted in sepsis survivors for several years after sepsis resolution. Significant drop-out in prescription of statins and niacin after sepsis was observed. Serum high sensitivity C-reactive protein was elevated for up to five years after sepsis resolution (H [6;1685] = 502.2; p < 0.0001).Discussion: Lipid abnormalities persisted long after the initial septic insult suggesting potential role in accelerating atherosclerosis and other abnormalities. In addition, sepsis seems to blunt statin effectiveness. Additionally, a significant and unexplained drop in statin use was seen in post-septic period.Conclusions: Our study suggests that persistent derangements of lipid profile components for up to two years after sepsis may be associated with altered risk of atherosclerosis-related events among sepsis survivors.

Glycoproteoform Profiles of Individual Patients’ Plasma Alpha-1-Antichymotrypsin are Unique and Extensively Remodeled Following a Septic Episode

Sepsis and septic shock remain the leading causes of death in intensive care units (ICUs), yet the pathogenesis originating from the inflammatory response during sepsis remains ambiguous. Acute-phase proteins are typically highly glycosylated, and the nature of the glycans have been linked to the incidence and severity of such inflammatory responses. To further build upon these findings we here monitored, the longitudinal changes in the plasma proteome and, in molecular detail, glycoproteoform profiles of alpha-1-antichymotrypsin (AACT) extracted from plasma of ten individual septic patients. For each patient we included four different time-points, including post-operative (before sepsis) and following discharge from the ICU. We isolated AACT from plasma depleted for albumin, IgG and serotransferrin and used high-resolution native mass spectrometry to qualitatively and quantitatively monitor the multifaceted glycan microheterogeneity of desialylated AACT, which allowed us to monitor how changes in the glycoproteoform profiles reflected the patient’s physiological state. Although we observed a general trend in the remodeling of the AACT glycoproteoform profiles, e.g. increased fucosylation and branching/LacNAc elongation, each patient exhibited unique features and responses, providing a resilient proof-of-concept for the importance of personalized longitudinal glycoproteoform profiling. Importantly, we observed that the AACT glycoproteoform changes induced by sepsis did not readily subside after discharge from ICU.

The JAK2-STAT pathway epigenetically regulates tolerized genes during the first encounter with bacterial antigens

ABSTRACTMicrobial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hyporesponsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition of in vitro tolerance. We identified a set of TET2-mediated demethylation events that are specific to toll-like receptor (TLR) 2 and TLR4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes on the first encounter with LPS. This is evidence of a crucial role for this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we assess the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.

Survival prediction of patients with sepsis from age, sex, and septic episode number alone

Sepsis is a life-threatening condition caused by an exaggerated reaction of the body to an infection, that leads to organ failure or even death. Since sepsis can kill a patient even in just one hour, survival prediction is an urgent priority among the medical community: even if laboratory tests and hospital analyses can provide insightful information about the patient, in fact, they might not come in time to allow medical doctors to recognize an immediate death risk and treat it properly. In this context, machine learning can be useful to predict survival of patients within minutes, especially when applied to few medical features easily retrievable. In this study, we show that it is possible to achieve this goal by applying computational intelligence algorithms to three features of patients with sepsis, recorded at hospital admission: sex, age, and septic episode number. We applied several data mining methods to a cohort of 110,204 admissions of patients, and obtained high prediction scores both on this complete dataset (top precision-recall area under the curve PR AUC = 0.966) and on its subset related to the recent Sepsis-3 definition (top PR AUC = 0.860). Additionally, we tested our models on an external validation cohort of 137 patients, and achieved good results in this case too (top PR AUC = 0.863), confirming the generalizability of our approach. Our results can have a huge impact on clinical settings, allowing physicians to forecast the survival of patients by sex, age, and septic episode number alone.

Sepsis Associated Delirium

Sepsis is a potentially life-threatening condition caused by a systemic dysregulated host response to infection. The brain is particularly susceptible to the effects of sepsis with clinical manifestations ranging from mild confusion to a deep comatose state. Sepsis-associated delirium (SAD) is a cerebral manifestation commonly occurring in patients with sepsis and is thought to occur due to a combination of neuroinflammation and disturbances in cerebral perfusion, the blood brain barrier (BBB) and neurotransmission. The neurological impairment associated with SAD can persist for months or even longer, after the initial septic episode has subsided which may impair the rehabilitation potential of sepsis survivors. Early identification and treatment of the underlying sepsis is key in the management of SAD as once present it can be difficult to control. Through the regular use of validated screening tools for delirium, cases of SAD can be identified early; this allows potentially aggravating factors to be addressed promptly. The usefulness of biomarkers, neuroimaging and electroencephalopathy (EEG) in the diagnosis of SAD remains controversial. The Society of Critical Care Medicine (SCCM) guidelines advise against the use of medications to treat delirium unless distressing symptoms are present or it is hindering the patient’s ability to wean from organ support.

P011 An experimental treatment for enteroviral sepsis

BackgroundA male infant was admitted to the neonatal unit with respiratory distress, following delivery by emergency caesarean section at 36/40 for maternal illness (viraemia). The patient’s condition deteriorated with disseminated intravascular coagulation (DIC), abnormal liver function, ascites and pleural effusions. Enteroviral sepsis was diagnosed following positive enterovirus PCR on lumbar puncture and stool sample.Summary of problemThere are no commercially available treatments for enterovirus in the UK. Following an extensive literature search, the neonatology consultant became aware of an experimental treatment with potential action against enterovirus.1 2 Pocapavir is an investigational drug candidate developed for poliovirus indications, but also has antiviral activity against nonpolio enteroviruses. The consultant was keen to exhaust every option, so reached out to the company in the US. The company (Virodefense) offered to provide the drug on a compassionate use/open label trial basis, asking that regular pharmacokinetics tests be carried out as part of the agreement to supply.Pharmacy contributionFollowing the initial contact with Virodefense, there were several challenges for the specialist pharmacist and pharmacy procurement team. Working with IDIS and Virodefense, arrangements were made for shipment of the medication to the pharmacy department. This was complicated by the urgency of the situation and the time differences involved. Pocapavir is in phase 2 clinical trial which required the MHRA to be notified to approve the importing of the drug into the country. The MHRA were quick to give a positive decision which allowed the product to be delivered direct to the hospital while IDIS handled the importing documentation. The advised dose was 25mg/kg daily, the drug came as 500 mg capsules containing 200mg of pocapavir (with 300 mg excipients).The patient (2.7 kg) required 67.5 mg daily. The pharmacy manufacturing unit packed down 170 mg capsule contents (68 mg active ingredient) into individual pots for the neonatal unit to administer. Doses were mixed with EBM and given daily for 14 days.OutcomeThe patient recovered from the acute sepsis episode. The patient was also treated with immunoglobulin and standard supportive care so it is impossible to know how much can be attributed to the pocapavir. Pharmacokinetic samples were taken as agreed. After recovering from the initial acute sepsis the patient developed hypoglycaemia between feeds. These were investigated and metabolic causes were excluded. The working diagnosis was a response to the large hit to the liver during the septic episode, although an adverse effect of pocapavir cannot be excluded. Hypoglycaemic episodes continued and the patient was still fed 3 hourly on discharge. The patient is growing and developing well, tolerating longer fasts of 6 hours without hypoglycaemia and reducing risk in the provision of parenteral nutrition for effects that could occur due to opioid toxicity. The patient has been discharged from neonatal follow up.Lessons to be learnedWhere there’s a will there’s a way! There were many barriers to overcome including regulatory, logistical and practical complications but thanks to a concerted effort from a wide variety of teams, co-ordinated by pharmacy, the patient received this treatment. Although the contribution of this experimental drug is unclear the positive outcome for a very unwell infant should be celebrated.ReferencesModlin JF. Treatment of Neonatal Enterovirus Infections. J Pediatric Infect Dis Soc 2016;5:63–64Torres-Torres S, Myers AL, Klatte M, et al. First Use of Investigational Antiviral Drug Pocapavir (V-073) for Treating Neonatal Enteroviral Sepsis. Pediatr Infect Dis J 2015;34:52–54.

Four-extremity amputation following disseminated intravascular coagulation and purpura fulminans

Purpura fulminans (PF) is a rare but serious complication of septic shock in adults. The complex disease course makes it challenging to manage the condition. Here, we present the case of a healthy young woman who presented with sepsis and new-onset erythematous lesions 4 days after the vaginal delivery of a healthy baby. The infectious source could not be identified, and the patient was started on antibiotics and resuscitated. However, her condition worsened, and she developed disseminated intravascular coagulation and PF. The septic episode slowly decreased in severity, but she sustained extensive ischaemic injuries to her extremities, for which she underwent four-limb amputation.

A dog’s dinner: an interesting case presenting as gastroenteritis

We report a case of a 60-year-old Caucasian man with a history of alcohol excess who presented to the emergency department with a 72-hour history of abdominal pain, profuse diarrhoea and vomiting. He was admitted to the intensive care unit (ICU) 12 hours later in extremis with severe sepsis and multiorgan failure. Collateral history from the patient on admission to ICU identified that he had been bitten by a dog 3 days prior to his symptom onset. Provisional microscopy and Gram staining from peripheral blood cultures taken on admission revealed the presence of long, thin Gram-negative bacilli in the anaerobic bottle only. This was later identified asCapnocytophaga canimorsus. The patient survived the septic episode and was discharged to level 2 care 9 days later under the care of the renal physicians for ongoing renal dialysis.

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy

ABSTRACT Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae . Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.)