Do we overtreat patients with presumed neutropenic sepsis?

PURPOSE: Many aspects of the management of neutropenic sepsis remain controversial. These include the choice of empiric antibiotic, the duration of antibiotic therapy and the possibility that very low-risk cases may be managed safely with oral rather than intravenous therapy. STUDY DESIGN: Retrospective cohort study conducted in a district general hospital serving a population of 148 000 in south west Scotland. RESULTS: Fifty one patients with cancer, whose neutrophil count was less than 1.0×109/L within 21 days of their last chemotherapy, were admitted as a medical emergency in 2019. All received antibiotic because of presumed neutropenic sepsis. A total of 4 patients had positive blood cultures (group 1), 12 patients had a clinical focus of infection but no clear pathogen (group 2), while 35 patients had neither (group 3). Group 3 patients were more likely to have a solid tumour, less likely to be febrile, had shorter time to neutrophil recovery and higher Multinational Association of Supportive Care in Cancer scores, though not all of these comparisons achieved statistical significance. Median intravenous plus oral antibiotic duration in group 3 patients was 9 days with median hospital stay of 7 days, raising the possibility of overtreatment. Retrospectively, 23 (66%) group 3 patients had MASSC Risk Index greater than 21 suggesting they were at low risk of complications. CONCLUSIONS: It seems likely that many low-risk neutropenic cancer patients with solid tumours could be managed as effectively and as safely with shorter courses of antibiotic, with oral rather than intravenous antibiotic, as outpatients rather than inpatients and with an overall positive impact on antimicrobial stewardship.

A 'train the trainers' approach to infection prevention and control training in pandemic conditions.

Background: The first wave of the SARS-CoV-2 global pandemic in early 2020 required a rapid roll-out of infection prevention and control (IPC) training for healthcare workers (HCW), including use of appropriate personal protective equipment (PPE). Education about respiratory droplet and aerosol transmission was of paramount importance to ensure safe working practices and improve confidence. Methods: A joint working group of Infectious Diseases and IPC staff developed a 'train the trainers' programme, to be rapidly deployed over a three-week period. This model utilised a snowballing approach, training selected staff with the intention that they would train their teams, facilitating swift cascading of information. Targeted invitations prompted staff from diverse departments of the hospital to attend. Pre- and post-session questionnaires evaluated staff confidence with regard to appropriate PPE use. Results: The programme trained 130 HCW over a three week period, was well received and led to increased confidence with PPE use amongst staff. Real-time evaluation ensured content could be adapted to the specific needs of HCW involved. We highlight perceived gaps in training despite existing and enhanced training structures. Conclusion: Provision of face-to-face training in transmission-based precautions, including PPE use, is required to maintain confidence in safe and appropriate IPC amongst hospital staff. We highlight the importance of including non-clinical staff in PPE educational programmes, recognising that these roles are vital for patient care and are frequently patient-facing. We recommend adopting the train the trainers model to facilitate rapid dissemination of education, with interactive multidisciplinary training in future outbreaks to improve HCW confidence and effective IPC.

Hereditary haemochromatosis, haemophagocytic lymphohistiocytosis and COVID-19.

BACKGROUND: Syndromes of iron overload have been shown to increase the risk of severe clinical disease in viral infections. Immune dysfunction is similarly described in hereditary haemochromatosis (HH). We present here the case of a 51-year-old man who developed severe coronavirus disease 2019 (COVID-19) complicated by suspected haemophagocytic lymphohistiocytosis (HLH). He was found to have HH post-mortem and we propose a link between his iron overload and the development of severe COVID-19. CASE REPORT: The initial clinical presentation consisted of cough, shortness of breath and fever. Pancytopenia, markedly elevated ferritin and d-dimer were present. Computed tomography (CT) showed bilateral ground glass changes consistent with COVID-19, widespread lymphadenopathy and splenomegaly. A subsequent combined nose and throat swab was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). HLH was suspected based upon the H-score and Anakinra, an IL-1 receptor antagonist, was commenced. Liver function acutely worsened and magnetic resonance cholangiopancreatography (MRCP) revealed hepatic haemosiderosis. Intense splenic and cervical lymph node uptake were seen on a positron emission tomography (PET) scan and high doses of intravenous steroids were administered due to concerns over haematological malignancy. RESULTS: Day fourteen of admission heralded the start of progressive clinical deterioration with rapid increase in oxygen demands. Continuous positive airway pressure (CPAP) was trialled without success and the patient unfortunately died seventeen days into admission. Results returned after his death showed homozygous C282Y mutation of the HFE gene consistent with a diagnosis of HH. Post-mortem examination revealed widespread haemosiderin deposition in the liver along with lung pathology in keeping with severe COVID-19 and widespread splenic infarctions. CONCLUSION: An association between HH and COVID-19 is not currently described in the literature. What does exist, however, is an evidence base for the detrimental impacts iron overload has on viral infections in general and the negative effects of HH on the immune system. We therefore postulate that the underlying metabolic and immune disturbances seen in HH should be considered a potential risk factor for the development of severe COVID-19. This case also adds to the evidence that hyperinflammation appears to be a unique and interesting characteristic of this novel viral disease.

Hyperinflammation with COVID-19: The key to patient deterioration?

BACKGROUND: The potential risk of cytokine storm in patients with coronavirus disease 2019 (COVID-19) has been described [1]; we write to share our experience treating a 17-year-old male with haemophagocytic lymphohistiocytosis (HLH) secondary to COVID-19 infection. CASE REPORT: This patient presented with cough, sore throat, anorexia and pyrexia. On examination, he had gross cervical lymphadenopathy and palpable splenomegaly. Nose and throat swab for SARS-CoV-2 was positive and blood tests revealed pancytopaenia with very high ferritin, triglyceride and d-dimer levels. The patient's H-Score [2] was calculated at 220, suggesting probability of HLH of 93-96%. Considering Russell and colleagues' [3] comments about potential harm of corticosteroid use in patients with COVID-19 infection, the patient was commenced on treatment with the selective IL-1 receptor antagonist drug, Anakinra, and a two-day course of intravenous immunoglobulin. RESULTS: The patient responded rapidly to treatment, becoming apyrexial after 24 h. His lymph nodes and spleen began to normalise after the first 48 h, at which time point the ferritin also started to decrease. He was discharged after 11 days feeling fit and well. CONCLUSION: This case certainly illustrates the importance of hyperinflammation syndromes in COVID-19. It also raises the question - is the severe pneumonitis seen in patients with COVID-19 an immunological phenomenon? We know that the viral load of patients with COVID-19 seems to peak in the early stages of illness [4,5]; however, patients deteriorate later in the disease course, at around days 10-14. This patient, who had risk factors for deterioration (male, pancytopaenic), did not develop an oxygen requirement and clinically and biochemically improved rapidly on Anakinra with no adverse events. We might suggest Anakinra to the scientific community as a treatment option in COVID-19 infection.

Genomic and transcriptomic characterization of Pseudomonas aeruginosa small colony variants derived from a chronic infection model.

Phenotypic change is a hallmark of bacterial adaptation during chronic infection. In the case of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis, well-characterized phenotypic variants include mucoid and small colony variants (SCVs). It has previously been shown that SCVs can be reproducibly isolated from the murine lung following the establishment of chronic infection with mucoid P. aeruginosa strain NH57388A. Using a combination of single-molecule real-time (PacBio) and Illumina sequencing we identify a large genomic inversion in the SCV through recombination between homologous regions of two rRNA operons and an associated truncation of one of the 16S rRNA genes and suggest this may be the genetic switch for conversion to the SCV phenotype. This phenotypic conversion is associated with large-scale transcriptional changes distributed throughout the genome. This global rewiring of the cellular transcriptomic output results in changes to normally differentially regulated genes that modulate resistance to oxidative stress, central metabolism and virulence. These changes are of clinical relevance because the appearance of SCVs during chronic infection is associated with declining lung function.

Nephrotic syndrome presenting as deep vein thrombosis or pulmonary embolism.

A patient presenting with a swollen left leg and pleuritic chest pain was shown to have deep vein thrombosis (DVT) by Doppler studies. He was anticoagulated but required two further admissions with swelling of both legs before a diagnosis of nephrotic syndrome was considered and confirmed. Renal biopsy showed that this was caused by membranous nephropathy. Two audits were subsequently conducted. The first was of diagnostic discharge codes for nephrotic syndrome and venous thromboembolism in south west Scotland (population 147,000) from 1997 to 2006. A diagnosis of nephrotic syndrome was confirmed in 32 patients, four (12.5%) of whom (including the index case) had presented with DVT (two) or pulmonary embolus (PE) (two). A second audit of 98 consecutive patients with Doppler-positive lower limb DVT presenting to A&E in Dumfries from July 2005 to July 2006 showed that the urine had been tested for protein in one case only. Although nephrotic syndrome remains an uncommon cause of DVT or PE, it is complicated by venous thromboembolism sufficiently frequently for the diagnosis to be considered in all patients with DVT or PE, for whom the take-home message should simply be-Don't forget to dip the urine or ignore a low serum albumin.

Surviving Ebola: A historical cohort study of Ebola mortality and survival in Sierra Leone 2014-2015.

BACKGROUND: While a number of predictors for Ebola mortality have been identified, less is known about post-viral symptoms. The identification of acute-illness predictors for post-viral symptoms could allow the selection of patients for more active follow up in the future, and those in whom early interventions may be beneficial in the long term. Studying predictors of both mortality and post-viral symptoms within a single cohort of patients could also further our understanding of the pathophysiology of survivor sequelae. METHODS/PRINCIPAL FINDINGS: We performed a historical cohort study using data collected as part of routine clinical care from an Ebola Treatment Centre (ETC) in Kerry Town, Sierra Leone, in order to identify predictors of mortality and of post-viral symptoms. Variables included as potential predictors were sex, age, date of admission, first recorded viral load at the ETC and symptoms (recorded upon presentation at the ETC). Multivariable logistic regression was used to identify predictors. Of 263 Ebola-confirmed patients admitted between November 2014 and March 2015, 151 (57%) survived to ETC discharge. Viral load was the strongest predictor of mortality (adjusted OR comparing high with low viral load: 84.97, 95% CI 30.87-345.94). We did not find evidence that a high viral load predicted post-viral symptoms (ocular: 1.17, 95% CI 0.35-3.97; musculoskeletal: 1.07, 95% CI 0.28-4.08). Ocular post-viral symptoms were more common in females (2.31, 95% CI 0.98-5.43) and in those who had experienced hiccups during the acute phase (4.73, 95% CI 0.90-24.73). CONCLUSIONS/SIGNIFICANCE: These findings may add epidemiological support to the hypothesis that post-viral symptoms have an immune-mediated aspect and may not only be a consequence of high viral load and disease severity.