Short summary

Haematological malignancy (HM) patients are highly susceptible to infections (e.g. bacteraemia), which exacerbate the prognosis. C-reactive protein (CRP), neutrophils, and serum albumin (SA) are routinely retrieved from HM patients. CRP and neutrophils are markers of infection whereas hypoalbuminaemia can be a marker of several chronic or acute conditions. A decline in SA over longer or shorter periods reflects chronic and acute conditions, respectively. As longitudinal studies of SA levels in HM patients have not been conducted we do not know whether hypoalbuminaemia reflects the severity of HM per se or an accompanying infection. The overall aim is thus to analyse levels of neutrophils, CRP, and SA longitudinally to gain knowledge on the degree of involvement of infections in HM's severity and prognosis.

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Rationale

A main feature of haematological malignancies (HMs) is the patients' higher susceptibility to infectious complications, due to HM's direct impact on the immune system or to standard treatments such as chemotherapy, corticosteroids, monoclonal antibodies, or stem cell transplantations. Seven autopsy studies of HM patients found that about 60% of the deaths were infection-related.

Because HM patients are followed closely in the clinic, routine measurements of neutrophils, C-reactive protein (CRP) and serum albumin (SA) levels are performed. The highly common occurrence of febrile neutropenia (FN) in HM patients asserts a major influence on the muted inflammatory response resulting in more subtle clinical symptoms pertaining to infections. Although more than 95%of FN episodes are believed to be caused by an infection only 20-30% will have a clear clinical site (e.g. pneumonia or cellulitis) and only 25-30% can be microbiologically verified.

Reviews have evaluated inflammatory biomarkers, e.g. CRP, as early markers of infectious episodes in cancer or FN patients, with considerable overlaps between these two entities. Inflammatory biomarker levels are also positively correlated to the severity of different forms of non-infectious fever (e.g. tumour fever) in these patient groups, but unequivocal cut-off values that discriminate between infectious and non-infectious elevations have not been determined.

Hypoalbuminemia has traditionally been related to chronic conditions such as liver failure, malnutrition, or protein losing enteropathy. However, reviews and studies in critically ill patients have indicated that its role as an inflammation biomarker may be more important than as a nutritional marker. Only three studies included longitudinal data, which can further refine knowledge on how quick changes occur, reflecting acute vs. chronic conditions. For CRP, changes over time are probably more valid as a mortality predictor than a single measurement, but little is known about whether this also applies to other outcomes than mortality or to SA. To our knowledge, no study has assessed the SA level as a marker of infectious episodes in HM or FN patients.   

For HM patients, there is thus a need to know whether levels and changes of neutrophils, CRP, and SA can predict the severity of infectious episodes and refine the prediction of mortality.  

Aims:

1. To describe levels and changes of neutrophils, CRP and SA in adult HM patients in relation to clinically well-defined infectious episodes and HM severity
2. To assess whether levels and changes of neutrophils, CRP and SA can predict infectious epi-sodes in adult HM patients 
3. To assess the prognostic utility of levels and changes of neutrophils, CRP, and SA

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Description of the cohort

Adult haematological malignancy patients, Department of Haematology, Odense University Hospital (OUH), 2000-2017. 

Data and biological material

This is a registry study.

Core data have been retrieved from the the Danish National Acute Leukemia Registry, the Danish National Lymphoma Registry, the Danish National Chronic Lymphocytic Leukemia Registry, and the Danish National Multiple Myeloma Registry, all of which are part of the Danish Common Hematological Database.

The core data will be linked to the following registries:

• The Danish Observational Registry of Infectious Syndromes (DORIS) and the Sydbak Registry to obtain all bacteraemia episodes.
• Laboratory information systems of the Department of Clinical Biochemistry and Pharmacology, OUH, to obtain biochemical data.
• The Danish National Hospital Registry to obtain information of diagnosed comorbidity.
• The Danish Civil Registration System to obtain data on vital status.

Collaborating researchers and departments

Center for Clinical Epidemiology, Odense University Hospital and the Research Unit of Clinical Epidemiology, Institute of Clinical Research, University of Southern Denmark

• Clinical Epidemiologist and Associate Professor Kim Oren Gradel, senior DVM, PhD

• Clinical epidemiologist Pernille M. Ljungdalh, MScPH

Polyvalent Intensive Care Unit, Hospital de São Francisco Xavier, CHLO, Estrada do Forte do Alto do Duque, 1449-005 Lisbon, and NOVA Medical School, CEDOC, New University of Lisbon, Campo dos Mártires da Pátria, 1169-056 Lisbon, Portugal

• Consultant Pedro Povoa, MD, PhD

Department of Hematology, Odense University Hospital

• Consultant Henrik Frederiksen, MD, PhD
• Melissa Kreutzfeldt, MD
• Consultant Paul Gram-Hansen, MD

Department of Clinical Microbiology, Odense University Hospital

• Consultant Thøger Gorm Jensen, MD, PhD
• Consultant and Professor Hans Jørn Kolmos, MD, DMSci

Department of Infectious Diseases, Odense University Hospital

• Consultant, professor Court Pedersen, MD, DMSci

• Stig L. Nielsen, PhD, MD

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

• Pernille Just Vinholt, PhD, MD

Department of Emergency Medicine, Odense University Hospital

• Consultant and Professor Annmarie Touborg Lassen, MD, DMSci

Publications associated with the project

Gradel, K.O., Póvoa, P., Garvik, O.S. et al. Longitudinal trajectory patterns of plasma albumin and C-reactive protein levels around diagnosis, relapse, bacteraemia, and death of acute myeloid leukaemia patients. BMC Cancer 20, 249 (2020). https://doi.org/10.1186/s12885-020-06754-z

Kim Oren Gradel , Henriette Engberg , Fernando G. Zampieri , Pedro Póvoa , Simone F. Simonsen , Pernille Just Vinholt , Olav Sivertsen Garvik , Pernille S. Ljungdalh & Henrik Frederiksen (2020) Contributing factors to the plasma albumin level at diagnosis of hematological malignancy, Hospital Practice, 48:4, 223-229, DOI: 10.1080/21548331.2020.1770511

Wästerlid, T., Oren Gradel, K., Eloranta, S., Glimelius, I., El-Galaly, T.C., Frederiksen, H. and Smedby, K.E. (2021), Clinical characteristics and outcomes among 2347 patients aged ≥85 years with major lymphoma subtypes: a Nordic Lymphoma Group study. Br J Haematol, 192: 551-559. https://doi.org/10.1111/bjh.17250