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.

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.

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.

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.

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.

The evolution of cellular deficiency in GATA2 mutation.

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.

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.

IL-10 combined with procalcitonin improves early prediction of complications of febrile neutropenia in hematological patients.

Early diagnosis of complicated course in febrile neutropenia is cumbersome due to the non-specificity of clinical and laboratory signs of severe infection. This prospective study included 100 adult hematological patients with febrile neutropenia after intensive chemotherapy at the onset of fever (d0) and for 3 days (d1-d3) thereafter. The study aim was to find early predictors for complicated course of febrile neutropenia, defined as bacteremia or septic shock. Interleukin 6 (IL-6), interleukin 10 (IL-10), procalcitonin (PCT) and C-reactive protein (CRP) all predicted complicated course of febrile neutropenia on d0, but only PCT was predictive throughout the study period. For IL-10 on d0-1 with cut-off 37 ng/L, sensitivity was 0.71, specificity 0.82, positive predictive value 0.52 and negative predictive value 0.92. For PCT on d0-1 with cut-off 0.13 µg/L, the respective measures were 0.95, 0.53, 0.36, and 0.98. For the combination of IL-10 and PCT on d0-1 with the same cut-offs, specificity improved to 0.85 and positive predictive value to 0.56. In conclusion, the present study confirms the high negative predictive value of PCT and provides new evidence for IL-10 as an early predictor for complicated course of febrile neutropenia in hematological patients. Combining IL-10 with PCT improves the early prediction for complicated course of febrile neutropenia.

[Mycoplasma pneumoniae and Stevens-Johnson syndrome]. / Nuoren miehen Mycoplasma pneumoniae-infektio ja limakalvoille rajoittunut Stevens-Johnsonin oireyhtymä.

Mycoplasma pneumoniae causes up to 10-40 % of community-acquired pneumonias. The incidence of M. pneumoniae pneumonia is greatest among children and young adults. The symptoms of M. pneumoniae upper and lower respiratory infections are usually mild and often self-limited. The most frequent extrapulmonary complications present in CNS, heart and skin. The skin affiliations are usually transient erythematous maculopapular or vesicular rashes but may sometimes evolve into Stevens-Johnson syndrome. M. pneumoniae is one of the most common microbe behind the infectious causes of SJS. We present a patient who developed incomplete Stevens-Johnson syndrome concomitant of Mycoplasma pneumoniae pneumonia.

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.

High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients.

We evaluated pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy. Pentraxin 3 and C-reactive protein were measured at fever onset and then daily to day 3. Bacteremia was observed in 19 patients and septic shock in 5 patients (three deaths). In comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein. High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels. To conclude, pentraxin 3 is an early predictor of complications in hematologic patients with neutropenic fever. High level of pentraxin 3 predicts septic shock and bacteremia already at the onset of febrile neutropenia. (ClinicalTrials.gov Identifier: NCT00781040.).

Serum cortisol and inflammatory response in neutropenic fever.

There are no data on serum cortisol of hematological patients at the onset of neutropenic fever and its possible association with the severity of infection. The purpose of this study was to evaluate the association of serum cortisol with the level of C-reactive protein (CRP) and procalcitonin (PCT), widely used markers of infection and inflammation, and with the development of severe sepsis in this patient group. All clinical data were collected prospectively at the hematology ward of Kuopio University Hospital. Altogether, 69 hematological patients with 93 periods of neutropenic fever were included. Nineteen patients received therapy for acute myeloid leukemia, and 50 patients were autologous stem cell transplantation recipients. Each period of neutropenic fever was classified as severe sepsis or not. Serum cortisol, CRP, and PCT were determined at the onset of fever on day 0 and then at 8-9 a.m. on days 1-4. Level of serum cortisol correlated positively with maximal CRP level during days 0 to 4 in neutropenic fever periods without severe sepsis, but no correlation was observed in fever periods with severe sepsis. To conclude, the level of cortisol correlated with the severity of infection measured as maximal CRP or elevated PCT in fever periods without severe sepsis, but in fever periods with severe sepsis, the cortisol response was attenuated.

Pentraxin 3 predicts complicated course of febrile neutropenia in haematological patients, but the decision level depends on the underlying malignancy.

OBJECTIVES: This study aimed at assessing the cut-off levels for pentraxin 3 (PTX3) in predicting complications of neutropenic fever (bacteraemia, septic shock) in haematological patients. METHODS: A prospective study during 2006-2009 was performed at haematology ward in Kuopio University Hospital. A patient was eligible for the study if having neutropenic fever after intensive therapy for acute myeloid leukaemia (AML) (n = 32) or non-Hodgkin lymphoma (NHL) (n = 35). Blood cultures were taken, and maximal PTX3 and C-reactive protein (CRP) were evaluated during d0 to d3 from the beginning of fever onset. RESULTS: The level of PTX3 was associated with both the underlying malignancy and the presence of complications, with highest level in NHL patients with complicated course of febrile neutropenia and lowest in AML patients with non-complicated course. The cut-off level of PTX3 to predict complications was ten-fold in patients with NHL (115 µg/L) in comparison with patients with AML (11.5 µg/L). In combined analysis based on separate cut-offs, PTX3 predicted complications of febrile neutropenia with sensitivity of 0.86, specificity of 0.83, positive predictive value of 0.57 and negative predictive value of 0.96. CONCLUSIONS: PTX3 was superior to CRP in predicting complicated course of febrile neutropenia, but only when the effect of the underlying malignancy had been taken into account.

Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia.

OBJECTIVE: To compare semi-quantitative procalcitonin with C-reactive protein in predicting bacteraemia in haematological patients with neutropenic fever. METHODS: A total of 77 patients treated with intensive chemotherapy for haematological malignancy at Kuopio University Hospital were candidates for study entry. Eleven of these patients did not fulfil the criteria for neutropenic fever, and 66 patients were finally included. Nineteen patients had acute myeloid leukaemia and 47 had received high-dose chemotherapy supported by autologous stem cell transplant. Ninety neutropenic fever episodes in these 66 patients fulfilled the study entry criteria, with microbiological cultures, procalcitonin and C-reactive protein measurements available. Serum procalcitonin and C-reactive protein were analyzed at the onset of each neutropenic fever episode on day 0, and then daily from days 1 to 4. RESULTS: Bacteraemia was observed in 21 episodes (23%) and the criteria for severe sepsis were fulfilled in 13 episodes (14%). Half of the bacteraemic episodes were caused by Gram-negative bacteria. The kinetics of procalcitonin and C-reactive protein were similar, with increasing levels for 2 to 4 days after the onset of fever. The procalcitonin level on days 1, 2, 3 and 4 was associated with bacteraemia and Gram-negative bacteraemia, but not with the development of severe sepsis. On day 1, a procalcitonin level above 0.5 ng/ml had a sensitivity of 57% and 70% and specificity of 81% and 77% to predict bacteraemia and Gram-negative bacteraemia, respectively. CONCLUSIONS: An elevated level of procalcitonin within 24 h after the onset of neutropenic fever predicts bacteraemia and Gram-negative bacteraemia in haematological patients.

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.