Novel biomarkers to identify complicated course of febrile neutropenia in hematological patients receiving intensive chemotherapy.

Febrile neutropenia (FN) is a common consequence of intensive chemotherapy in hematological patients. More than 90% of the patients with acute myeloid leukemia (AML) develop FN, and 5%-10% of them die from subsequent sepsis. FN is very common also in autologous stem cell transplant recipients, but the risk of death is lower than in AML patients. In this review, we discuss biomarkers that have been evaluated for diagnostic and prognostic purposes in hematological patients with FN. In general, novel biomarkers have provided little benefit over traditional inflammatory biomarkers, such as C-reactive protein and procalcitonin. The utility of most biomarkers in hematological patients with FN has been evaluated in only a few small studies. Although some of them appear promising, much more data is needed before they can be implemented in the clinical evaluation of FN patients. Currently, close patient follow-up is key to detect complicated course of FN and the need for further interventions such as intensive care unit admission. Scoring systems such as q-SOFA (Quick Sequential Organ Failure Assessment) or NEWS (National Early Warning Sign) combined with traditional and/or novel biomarkers may provide added value in the clinical evaluation of FN patients.

COVID-19 vaccination among health care workers in Finland: coverage, perceptions and attitudes.

AIMS: In this study, we examined the voluntary COVID-19 vaccine coverage among health care workers (HCWs) working in close patient contact. HCWs' beliefs about COVID-19 infection, their opinions of vaccination and reasons for having or declining the COVID-19 vaccination were also evaluated. METHODS: In October 2021, a cross-sectional observational study was carried out in five hospitals in Central and Eastern Finland. The anonymous and voluntary survey was targeted at 5120 doctors and nurses working in close patient contact. RESULTS: Some 1837 responses were included in the study. Ninety-seven per cent of the respondents had received at least one COVID-19 vaccine and 68% of the respondents agreed that all HCWs working in close patient contact should be vaccinated against COVID-19. Vaccination coverage and support for vaccination were higher among older HCWs and doctors. HCWs' main reasons for having the COVID vaccine were willingness to protect themselves, their family and their patients from COVID-19. Concerns about adverse reactions to the COVID-19 vaccine was the main reason for declining it. CONCLUSIONS: The overall COVID-19 vaccination coverage and support for vaccinations among HCWs working in close patient contact were high without actual mandatory policies being introduced. Prioritising HCWs for COVID-19 vaccinations and widespread vaccine availability, as well as low general vaccine hesitancy and high seasonal influenza vaccination coverage among the study population were check marks in achieving high COVID-19 vaccination coverage rapidly.

Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae.

Nuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.

Disease burden caused by respiratory syncytial virus compared with influenza among adults: a retrospective cohort study from Eastern Finland in 2017-2018.

OBJECTIVES: Respiratory syncytial virus (RSV) is one of the most important causes of lower respiratory tract illnesses. In this study, we examined the number and severity of RSV infections among adult patients. The underlying diseases and background information of patients with RSV were examined and compared with the patients with influenza. DESIGN: Retrospective cohort study. SETTING: Patients receiving tertiary care services in Kuopio University Hospital (KUH) district in Eastern Finland. PARTICIPANTS: 725 patients (152 with RSV infection and 573 with influenza) treated in KUH between November 2017 and May 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospitalisation and mortality. RESULTS: Compared with influenza, RSV caused a more serious disease in terms of hospitalisation (84.2% vs 66.0%, p<0.001), incidence of pneumonia (37.5% vs 23.2%, p<0.001), need for antibiotics (67.1% vs 47.3%, p<0.001) and supplemental oxygen (50.7% vs 31.2%, p<0.001). The all-cause mortality during hospitalisation and 30 days after discharge was higher among the RSV-infected patients (8.6% vs 3.5%, p=0.010). Solid malignancies (23.1% vs 5.0%, p=0.042) and chronic kidney disease (30.8% vs 5.8%, p=0.011) were more common among the RSV-infected non-survivors compared with survivors. RSV was an independent risk factor for hospitalisation (adjusted OR (aOR) 2.035; 95% CI 1.17 to 3.55) and mortality (aOR 2.288; 95% CI 1.09 to 4.81) compared with influenza. CONCLUSIONS: Among all the screened patients, those with RSV infection were older and had more underlying conditions than patients with influenza. They had increased likelihood of hospitalisation and mortality when compared with influenza. Solid malignancies and chronic kidney disease seemed to be independent risk factors for death among RSV-infected patients. During RSV and influenza epidemics, it is important to test patients with respiratory symptoms for RSV and influenza to prevent the spread of the infections among elderly and chronically ill patients.

Serum caspase-cleaved cytokeratin-18 fragment as a prognostic biomarker in hematological patients with febrile neutropenia.

The study aim was to determine the benefit of the measurement of serum caspase-cleaved cytokeratin-18 (CK-18) fragment as a prognostic marker of febrile neutropenia (FN) in hematological patients. The study population consisted of 86 consecutive patients with FN who received intensive chemotherapy for hematological malignancy at the adult hematology ward of Kuopio University Hospital. Twenty-three patients (27%) had acute myeloid leukemia, and 63 patients (73%) were autologous stem cell transplant recipients. Serum caspase-cleaved CK-18 fragment M30, C-reactive protein (CRP) and procalcitonin (PCT) were measured at the onset of FN (d0), on day 1 (d1), and on day 2 (d2). Eight patients (9%) developed severe sepsis, including three patients with septic shock. Eighteen patients (21%) had a blood culture-positive infection. Serum CK-18 fragment peaked on the first day after fever onset in patients with severe sepsis. Higher CK-18 level was associated with severe sepsis, intensive care unit treatment, and fatal outcome, but not with blood culture positivity. In ROC curve analysis, d1 serum CK-18 fragment predicted severe sepsis with an area under the curve (AUC) of 0.767, CRP with an AUC of 0.764, and PCT with an AUC of 0.731. On d2, the best predictive capacity was observed for CRP with an AUC of 0.832. The optimal cutoff of caspase-cleaved CK-18 fragment M30 for predicting severe sepsis was 205 U/L on d1. In hematological patients, serum CK-18 fragment was found to be a potential prognostic marker of severe sepsis at early stages of FN.

Support among healthcare workers for the new mandatory seasonal influenza vaccination policy and its effects on vaccination coverage.

INTRODUCTION: Finland was the first European country to introduce a nation-wide mandatory seasonal influenza vaccination policy for healthcare workers (HCWs) by mandating that administrators of health care institutions only employ vaccinated HCWs. In this study, we examine the effects of the new policy and the view of HCWs on the new policy. METHODS: A cross-sectional observational study was conducted in Kuopio University Hospital among HCWs working in close patient contact. The statistics on vaccination coverage were obtained from the hospital's own databases, where employees were asked to self-report their suitability for work. An anonymous survey was sent to HCWs in 2015-2016 (n = 987) and 2018-2019 (n = 821). RESULTS: Vaccination coverage increased from 59.5 to 99.6%, according to the hospital's own records. Among the survey respondents, the seasonal influenza vaccination coverage of HCWs increased from 68.2 to 95.4%. 83.8% of doctors and 49.4% of nurses supported the new policy. 12.7% of doctors and 41.5% of nurses found the new mandate coercive or that it restricted their self-determination. CONCLUSIONS: Our study confirms the positive effects of mandating the administrators of health care institutions to only employ vaccinated HCWs. The majority (57.9%) of all HCWs supported the new policy, with doctors being more compliant than nurses. Key messages Finland became the first European country to mandate influenza vaccination for HCWs by mandating that administrators of health care institutions only employ vaccinated HCWs. After the new act, the vaccination coverage of HCWs increased close to 100%. Most of the HCWs supported the new act and did not find it coercive.

Febrile neutropenia in patients with acute myeloid leukemia: Outcome in relation to qSOFA score, C-reactive protein, and blood culture findings.

OBJECTIVES: To evaluate quick Sequential Organ Failure Assessment (qSOFA) score during febrile neutropenia (FN) in adult patients receiving intensive chemotherapy for acute myeloid leukemia (AML). METHODS: qSOFA score, as well as the association of qSOFA score with ICU admission, infectious mortality, blood culture findings, and C-reactive protein (CRP) measurements during FN were assessed among 125 adult AML patients with 355 FN periods receiving intensive chemotherapy in a tertiary care hospital from November 2006 to December 2018. RESULTS: The multivariate model for qSOFA score ≥ 2 included CRP ≥ 150 mg/L on d0-2 [OR 2.9 (95% CI 1.1-7.3), P = .026], Gram-negative bacteremia [OR 2.7 (95% CI 1.1-6.9), P = .034], and treatment according to AML-2003 vs more recent protocols [OR 2.7 (95% CI 1.0-7.4), P = .047]. Age or gender did not gain significance in the model. qSOFA score ≥ 2 was associated with ICU treatment and infectious mortality during FN with sensitivity and specificity of 0.700 and 0.979, and 1.000 and 0.971, respectively. CONCLUSION: qSOFA offers a useful tool to evaluate the risk of serious complications in AML patients during FN.

Plasma level of interleukin-18 and complicated course of febrile neutropenia in hematological patients after intensive chemotherapy.

In search of a biomarker for complicated course of febrile neutropenia (FN), plasma IL-18 was measured in 92 hematological patients after intensive chemotherapy at the beginning of FN (days 0-3). Complicated course was defined as blood culture positivity or septic shock. IL-18 varied according to background hematological malignancy and showed an inverse correlation with leukocyte count. IL-18 was not associated with complicated course of FN, defined as blood culture positivity or septic shock, in the whole study group, but an association was observed on d1 and d2 after the onset of FN in the subgroup of autologous stem cell transplant recipients with non-Hodgkin lymphoma.

Review of clinical practice guidelines on the use of procalcitonin in infections.

Background: Procalcitonin is a biomarker that can be used to diagnose bacterial infection and monitor treatment. Clinical practice guidelines are evidence-based recommendations by experts that aim to aid decision-making. In this systematic review, we searched for clinical practice guidelines and evaluated recommendations given regarding use of procalcitonin.Methods: Four biomedical databases (PubMed, Scopus, Cochrane Database and Web of Science) and various national medical sites were searched for clinical practice guidelines. Guidelines that mentioned procalcitonin were included in the review.Results: Seventeen guidelines were included. The earliest were published in 2009 and the latest in 2018. A majority (12/17) recommended use of procalcitonin or stated that it can be useful. One national guideline did not recommend procalcitonin, stating that there is no need for any biomarkers in diagnostics of community-acquired pneumonia in adults. Four guidelines stated no evidence to recommend or not recommend procalcitonin use. Thirteen of the guidelines commented on other concomitant or alternate biomarkers, mainly C-reactive protein. Five guidelines suggested decision limits for procalcitonin. None took a stand on how often procalcitonin should be analysed, and if it should be used as a single or as multiple measurements.Conclusions: One international and 11 national clinical practice guidelines endorse the use of procalcitonin in differential diagnosis of bacterial infections and/or to monitor antibiotic therapy. However, the evidence for or against the use of procalcitonin is weak.

MMP-10 and TIMP-1 as indicators of severe sepsis in adult hematological patients with febrile neutropenia.

Commonly used indicators of sepsis are nonspecific and insufficient for predicting the course of febrile neutropenia (FN) in hematological patients. We analyzed data from 91 adult FN patients who received intensive chemotherapy for acute myeloid leukemia or autologous stem cell transplantation. Compared to patients with non-severe sepsis, patients with severe sepsis had significantly higher serum levels of tissue inhibitor of metalloproteinases-1 on the day of first occurrence of fever (day 0: 172 vs. 112 µg/L, p= .002) and for the two following days (day 1: 219 vs. 128 µg/L, p< .001; day 2: 443 vs. 128 µg/L, p= .001), and significantly higher serum levels of matrix metalloproteinase-10 on day 1 (1975 vs. 876 ng/L, p= .001) and day 2 (2020 vs. 841 ng/L, p< .001). We conclude that the measurement of these biomarkers may be useful in predicting the severity of sepsis in FN patients.

Interleukin-1 receptor antagonist as a biomarker of sepsis in neutropenic haematological patients.

OBJECTIVE: The study aim was to compare the performance of interleukin-1 receptor antagonist (IL-1Ra) to C-reactive protein (CRP) and procalcitonin (PCT) in early prediction of the clinical course of febrile neutropenia. METHODS: The study population consisted of 86 consecutive patients with febrile neutropenia who received intensive chemotherapy for haematological malignancy between November 2009 and November 2012 at the adult haematology ward of Kuopio University Hospital. Twenty-three (27%) patients had acute myeloid leukaemia and 63 (73%) patients were autologous stem cell transplant recipients. IL-1Ra, CRP and procalcitonin were measured at the onset of fever (d0), on day 1 (d1) and on day 2 (d2). RESULTS: Eight patients developed severe sepsis, including three patients with septic shock. Eighteen patients had bacteraemia. After the onset of febrile neutropenia Youden´s indices (with their 95% confidence intervals) to identify severe sepsis were for IL-1Ra on d0 0.57 (0.20-0.71) and on d1 0.65 (0.28-0.78), for CRP on d0 0.41 (0.04-0.61) and on d1 0.47 (0.11-0.67) and for PCT on d0 0.39 (0.05-0.66) and on d1 0.52 (0.18-0.76). CONCLUSIONS: In haematological patients, IL-1Ra has a comparable capacity with CRP and PCT to predict severe sepsis at the early stages of febrile neutropenia.

Novel Biomarker Candidates for Febrile Neutropenia in Hematological Patients Using Nontargeted Metabolomics.

BACKGROUND: Novel potential small molecular biomarkers for sepsis were analyzed with nontargeted metabolite profiling to find biomarkers for febrile neutropenia after intensive chemotherapy for hematological malignancies. METHODS: Altogether, 85 patients were included into this prospective study at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The plasma samples for the nontargeted metabolite profiling analysis by liquid chromatography-mass spectrometry were taken when fever rose over 38° and on the next morning. RESULTS: Altogether, 90 differential molecular features were shown to explain the differences between patients with complicated (bacteremia, severe sepsis, or fatal outcome) and noncomplicated courses of febrile neutropenia. The most differential compounds were an androgen hormone, citrulline, and phosphatidylethanolamine PE(18:0/20:4). The clinical relevance of the findings was evaluated by comparing them with conventional biomarkers like C-reactive protein and procalcitonin. CONCLUSION: These results hold promise to find out novel biomarkers for febrile neutropenia, including citrulline. Furthermore, androgen metabolism merits further studies.

Changes in the microbiological epidemiology of febrile neutropenia in autologous stem cell transplant recipients.

BACKGROUND: The aim of the study was to explore the incidence, microbiological etiology and outcome of febrile neutropenia among adult hematological patients following autologous stem cell transplantation (ASCT). METHODS: The study population consisted of patients who received ASCT between 1 December 2006 and 30 November 2012. The epidemiology was compared to a retrospective series covering eleven previous years at the same institution. Non-Hodgkin lymphoma (NHL) patients, who had been identified as a risk group in the retrospective study, received ciprofloxacin prophylaxis from January 2008. RESULTS: Altogether, 142 out of 178 of the included patients (80%) developed febrile neutropenia. The blood cultures were positive in 24 cases (17%). Of all bacteremia's, 88% were caused by Gram-positive and 12% by Gram-negative bacteria. The number of Gram-negative bacteremia were significantly lower in the prospective study compared to the retrospective study (3/142, 2.1% vs. 23/265, 8.7%, p = .01). Pseudomonas aeruginosa was prevalent in the retrospective series but not discovered in the present series. Enterococcus faecium was found more frequently in the prospective study (6/142, 4.2 vs. 2/265, 0.8%, p = .02). The infectious mortality among patients with febrile neutropenia was 4/142 (2.8%) in the present series and 9/265 (3.4%) in those who received ASCT in 1996-2006. CONCLUSION: Most patients who received ASCT developed febrile neutropenia and a minority had bacteraemia. In comparison to the earlier time period, the incidence of Gram-negative bacteraemias decreased, probably due to ciprofloxacin prophylaxis in NHL patients, but simultaneously the incidence of Enterococcus bacteraemias increased. Infectious mortality during febrile neutropenia was low in both series.

Soluble CD14 as a Diagnostic and Prognostic Biomarker in Hematological Patients with Febrile Neutropenia.

OBJECTIVE: Elevated levels of a cell surface glycoprotein, soluble cluster of differentiation 14 (sCD14), have been observed in patients with sepsis. Only scarce data are available on sCD14 in hematological patients with chemotherapy-induced febrile neutropenia. The study aim was to investigate sCD14 as an early biomarker in febrile neutropenia after intensive chemotherapy to detect a rapidly deteriorating clinical course early enough to avoid serious infectious complications. PATIENTS AND METHODS: This prospective study included 87 adult hematological patients at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The study endpoints were septic shock, severe sepsis, and positive blood culture findings. sCD14 was analyzed from day 0 to day 2, and its prognostic capacity was compared to that of C-reactive protein and procalcitonin. RESULTS: Plasma level of sCD14 predicted the development of septic shock on day 1 (p = 0.001) and day 2 but not the development of severe sepsis or blood culture positivity in hematological patients with chemotherapy-induced febrile neutropenia. CONCLUSIONS: Soluble CD14 did not predict an overall complicated course at the early stages of febrile neutropenia. However, it was helpful in predicting the progression of the clinical course of neutropenic fever to septic shock.

Asymmetric dimethylarginine in the assessment of febrile neutropenia in hematological patients.

Asymmetric dimethylarginine (ADMA) has been recognized as an independent prognostic factor for sepsis mortality in intensive care units. No data are available on kinetics or prognostic value of ADMA in hematological patients. We evaluated the ability of ADMA to act as a predictor for complicated course of febrile neutropenia, defined as bacteremia and/or septic shock in adult hematological patients receiving intensive chemotherapy. This prospective study included 87 adult hematological patients with febrile neutropenia after an intensive chemotherapy for acute myeloid leukemia (AML) or after an autologous stem cell transplantation (ASCT). Plasma ADMA and serum C-reactive protein (CRP) levels were measured from the onset of fever (d0) and for 2 days (d1-d2) thereafter. The levels of ADMA were stable or had only minimal changes during the study period. There was no difference between the levels at any time-point in patients having complicated course compared to those without it. On the other hand, CRP levels were significantly higher on d1 (p = 0.016) in patients with bacteremia and/or septic shock than in those without. ADMA was not able to differentiate hematological patients with a complicated course from those without complications. Elevated ADMA levels are probably associated with organ dysfunction, which is rare in this group of patients, of whom about 95% can be successfully managed at the hematology ward.

Enrichment of rare variants in population isolates: single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland.

Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T>C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P<0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P<0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.

Biomarkers of neutropenic sepsis.

Neutropenic sepsis is a common clinical problem in hematological patients receiving intensive chemotherapy. Complications will develop in a minority of these patients. Biomarkers can be used for the recognition of infection as well as to estimate its severity and risk of complications and also to assess treatment response. Experience gained from other patient groups or sepsis patients treated in intensive care units cannot be directly extrapolated to hematological patients. Numerous biomarkers of infections have been investigated in hematological patients, but no optimal marker has been found. C-reactive protein is still the most commonly used biomarker in hematological patients, but procalcitonin may be a real challenger, although more studies are still needed.

An autochthonous case of cystic echinococcosis in Finland, 2015.

We report a case of pulmonary cystic echinococcosis in a child from eastern Finland with no history of travelling abroad. The cyst was surgically removed and the organism molecularly identified as Echinococcus canadensis genotype G10. This parasite is maintained in eastern Finland in a sylvatic life cycle involving wolves and moose; in the present case, the infection was presumably transmitted by hunting dogs.