Clinical Hematology International

Volume 2, Issue 4, December 2020, Pages 168 - 172

The Incidence and Timing of Blood Cultures in Multiple Myeloma – Results from a Retrospective, Single Center, Real-World Study

Authors
Agoston Gyula Szabo1, 2, *, ORCID, Katrine Fladeland Iversen1, 2, ORCID, Flemming Schønning Rosenvinge3, ORCID, Sören Möller2, 4, ORCID, Torben Plesner1, 2
1Department of Hematology, Vejle Hospital, Beriderbakken 4, Vejle 7100, Denmark
2University of Southern Denmark, J.B. Winsløws Vej 9 A, Odense C 5000, Denmark
3Department of Clinical Microbiology, Odense University Hospital, J.B. Winsløws Vej 4, Odense C 5000, Denmark
4OPEN – Open Patient data Explorative Network, Odense University Hospital and Department of Clinical Research, Odense C 5000, Denmark
*Corresponding author. Email: agoston.gyula.szabo@rsyd.dk
Corresponding Author
Agoston Gyula Szabo
Received 14 May 2020, Accepted 9 July 2020, Available Online 10 August 2020.
DOI
https://doi.org/10.2991/chi.k.200719.001How to use a DOI?
Keywords
Blood cultures; multiple myeloma; infection; incidence; risk factor
Copyright
© 2020 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V.
Open Access
This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

1. INTRODUCTION

Multiple myeloma (MM) is a cancer of the immune system characterized by complex cellular and humoral immunodeficiency [13]. Patients with MM often have advanced age, increased comorbidity and are exposed to immunosuppressive drugs during therapy [4]. These factors contribute to markedly increased risk of infections, mainly pneumonia and sepsis [57]. These complications are responsible for a substantial part of early deaths in MM [79]. The incidence of bacterial infections peaks in the first six months after diagnosis [10,11]. We have previously reported the results of a retrospective, single-center, real-world study conducted at Vejle Hospital (a primary and secondary referral center receiving approximately 30 newly diagnosed cases of MM per year), in which we reviewed the clinical course of 303 patients with MM who initiated treatment from 2006 to 2016 [12]. The aims of the present study were to describe, in a single-center cohort of patients with MM, the results of blood cultures, to determine their incidence and timing, and to assess their associations with baseline clinical characteristics and treatment-related factors. Moreover, we assessed the use of immunoglobulin replacement therapy (IGRT) in the study population.

We collected blood culture results from the Danish microbiology register (MiBA [13]) of all hospitals where patients were treated. A ‘blood culture day’ (BCD) was defined as a day a patient had at least one blood culture performed. A positive BCD was defined as a day a patient had at least one positive blood culture result. Blood cultures were categorized as “negative”, “positive” or “possible contamination” according to the guidelines for classification of hospital-acquired blood stream infections in the Danish Healthcare-associated Infections Database [14]. Blood cultures classified initially as “possible contamination” were reclassified as blood stream infections if the same microorganism was identified in the patient’s blood cultures more than once in a period of 14 days. We assessed the time to first blood culture and first positive blood culture by the Kaplan–Meier method. We calculated BCDs over time as counts per 1000 patients. The number of BCDs was described with median, range and interquartile range (IQR). We investigated univariate and multivariate association of baseline patient characteristics and treatment-related factors, reported as hazard ratios with 95% confidence intervals, with time to BCDs by Cox regression. We included repeated events in the Cox regression model to take into account multiple blood cultures for the same patient. Blood culture data were available in 302 patients. Two hundred and eighty-two patients had at least one blood culture result and 113 patients had at least one positive blood culture result. We identified 4992 blood culture results: 4243 were negative and 249 were positive. Fifty-nine positive blood culture results were classified as possible contaminations. The most frequently cultured pathogenic microorganisms were Enterobacterales (31%; of these 75% Escherichia coli), Streptococcus pneumoniae (17%) and Coagulase-negative Staphylococci (11%). The full list of cultured microorganisms is shown in Table S1. The median number of blood cultures per patient was six (IQR: 3; 11; range: 0; 43). The incidence of BCDs peaked in the month of diagnosis (>500/1000 patients/month) and was elevated in the first 6 months after diagnosis (Figure 1A). After this period, the incidence of BCDs was constantly below 200/1000 patients/month. Fifty-one percent, 67% and 74% of patients had a BCD 3, 6 and 12 months after diagnosis, respectively (Figure 1B). Besides the time of diagnosis, we found incidence peaks in BCDs in relation to initiation of both the first and later lines of therapy (>600/1000/month) and events of progressive disease (>700/1000/month), as shown in Figure 2.

Figure 1

(A) Adjusted incidence of blood culture positivity from the time of diagnosis. (B) Cumulative incidence of blood culture positivity from the month prior to diagnosis until death or follow up at 60 months.

Figure 2

(A) Adjusted incidence of blood culture days in relation to initiation of any line of therapy. (B) Adjusted incidence of blood culture days in relation to the date of initiation of the first line of therapy. (C) Adjusted incidence of blood culture days in relation to the date of initiation of any subsequent line of therapy. (D) Adjusted incidence of blood culture days in relation to the dates of progressive disease.

Univariate and multivariate analyses of risk factors for blood culture days are shown in Table S2. Among clinical baseline characteristics, low hemoglobin, high ionized calcium, high creatinine, low immunoglobulin (Ig) M, M-protein of IgA isotype, light-chain only disease and poor Eastern Cooperative Oncology Group (ECOG) performance status were independently associated with higher risk of BCDs. Among treatment-related factors, worse than very good partial response to the ongoing line of therapy, increasing number of prior lines of therapy and a recent event of progressive disease were independently associated with higher risk of BCDs. Among the assessed treatment regimens, high-dose melphalan (days 0–30), proteasome inhibitor-steroid doublets, chemotherapy-steroid doublets, daratumumab monotherapy and intensive combination regimens including five or more drugs were independently associated with such higher risk of BCDs. Two hundred and nine (69%) patients were exposed to immunoglobulin replacement therapy with a median time of 3.2 (IQR: 0.9; 22.3) months after diagnosis.

In conclusion, the burden of infections in our cohort of MM patients was high. Blood stream infections were mainly caused by Gram-negative bacteria. Patients were especially susceptible to infections at the time of diagnosis and in situations of insufficient disease control. Certain anti-myeloma regimens, such as proteasome inhibitor-­steroid doublets, chemotherapy-steroid doublets, daratumumab monotherapy and combination regimens including five or more drugs may require increased attention to infectious complications.

CONFLICTS OF INTEREST

AGS: consulting for Janssen; TP: consulting for Janssen, Celgene, Takeda, Abbvie, Genmab; KFI: no conflicts of interest; SM: no conflicts of interest; FSR: no conflicts of interest.

AUTHORS’ CONTRIBUTION

AGS designed the study, created the study database, conducted patient chart review, wrote the manuscript and designed the figures. KFI conducted patient chart review and contributed to writing the manuscript. SM carried out data analysis and statistics and contributed to writing the manuscript. FSR reviewed and categorized the blood culture results and contributed to writing the manuscript. TP supervised the study, contributed to writing the manuscript and designing the figures.

FUNDING

The authors received no financial support for the research, authorship or publication of this article.

ACKNOWLEDGMENTS

We thank the Department of Internal Medicine and the Hematological Clinical Research Unit at Vejle Hospital for providing the financial and logistical background for this study. Data management for this project was carried out by Open Patient Data Exploratory Network, University of Southern Denmark.

SUPPLEMENTARY MATERIALS

Pathogenic microorganism n Percentage (%)
Enterobacterales* 59 31
Streptococcus pneumoniae 33 17
Coagulase-negative Staphylococci 21 11
Staphylococcus aureus 14 7
Anaerobic bacteria 14 7
Enterococci 13 7
Viridans streptococci 7 4
Listeria monocytogenes 6 3
Pseudomonas aeruginosa 6 3
Candida 6 3
Beta-hemolytic streptococci 6 3
Other bacteria 5 3
Total (pathogenic microorganisms) 190
Possible contaminations 59
Total (positive) 249
*

44 (75%) Escherichia coli. A positive BCD was defined as a day a patient had at least one positive blood culture result.

Table S1

Microorganisms cultured on positive blood culture days

Variable Number of observations Univariate analysis p Multivariate analysis p


HR (95% CI) HR (95% CI)
Demographics
Age
  <50 14 Reference Reference
  50–60 36 0.94 (0.77; 1.15) 0.567 0.67 (0.53; 0.85) 0.001
  60–70 106 1.07 (0.90; 1.28) 0.434 0.67 (0.54; 0.83) <0.001
  >70 146 1.01 (0.84; 1.21) 0.939 0.61 (0.49; 0.75) <0.001
Sex
  Male 175 Reference Reference
  Female 127 0.85 (0.79; 0.93) <0.001 0.93 (0.85; 1.03) 0.154
CRAB features
  Hemoglobin <6.2 mmol/L 102 0.85 (0.82; 0.88) <0.001 0.91 (0.86; 0.95) <0.001
  Ionized calcium >1.345 mmol/L 79 1.65 (1.36; 2.01) <0.001 1.38 (1.09; 1.76) 0.008
  Creatinine >177 μmol/L 57 1.00 (1.00; 1.00) <0.001 1.00 (1.00; 1.00) 0.005
  Osteolytic lesion on either skeletal X-ray or WBLDCT not present 97 Reference Reference
  Osteolytic lesion on either skeletal X-ray or WBLDCT present 205 0.85 (0.78; 0.93) <0.001 0.75 (0.68; 0.83) <0.001
Immunoglobulins
  IgA ≥ 0.7 g/L (excluding patients with IgA M-protein isotype) 133 Reference Reference
  IgA < 0.7 g/L (excluding patients with IgA M-protein isotype) 169 1.05 (0.97; 1.14) 0.213 0.91 (0.80; 1.04) 0.180
  IgG ≥ 6.1 g/L (excluding patients with IgG M-protein isotype) 190 Reference Reference
  IgG < 6.1 g/L (excluding patients with IgG M-protein isotype) 112 1.33 (1.23; 1.45) <0.001 0.61 (0.49; 0.75) <0.001
  IgM ≥ 0.4 g/L 50 Reference Reference
  IgM < 0.4 g/L 252 1.90 (1.67; 2.17) <0.001 1.77 (1.48; 2.11) <0.001
M-protein isotype
  IgA 59 1.44 (1.30; 1.60) <0.001 1.52 (1.18; 1.94) 0.001
  IgG 168 Reference Reference
  Light-chain only 54 1.02 (0.91; 1.14) 0.789 1.37 (1.11; 1.69) 0.004
  Non-secretory 6 0.76 (0.55; 1.04) 0.088 1.06 (0.72; 1.56) 0.779
  Other 2 2.71 (1.68; 4.39) <0.001 4.15 (2.34; 7.34) <0.001
Myeloma risk profile
  ISS I 88 Reference Reference
  ISS II 92 1.11 (1.00; 1.23) 0.043 1.01 (0.89; 1.14) 0.848
  ISS III 72 1.55 (1.39; 1.73) <0.001 0.87 (0.75; 1.01) 0.076
  ISS not determined 47 1.16 (1.02; 1.32) 0.024 0.92 (0.79; 1.08) 0.300
  High risk cytogenetics [t(4;14), t(14;16) or del(17p)] by FISH not present 254 Reference Reference
  High risk cytogenetics [t(4;14), t(14;16) or del(17p)] by FISH present 48 1.18 (1.06; 1.32) 0.003 0.99 (0.87; 1.13) 0.875
ECOG Performance status
  0 111 Reference Reference
  1 116 1.41 (1.28; 1.54) <0.001 1.41 (1.27; 1.56) <0.001
  2 45 1.25 (1.09; 1.43) 0.001 1.12 (0.97; 1.30) 0.129
  3 26 1.47 (1.27; 1.69) <0.001 1.40 (1.17; 1.66) <0.001
Best response to ongoing line of therapy §
  sCR/CR/VGPR 1050 Reference Reference
  PR/MR 1136 1.23 (1.13; 1.35) <0.001 1.45 (1.29; 1.63) <0.001
  SD/PD 442 1.42 (1.26; 1.60) <0.001 1.46 (1.24; 1.71) <0.001
Number of prior lines of therapy §
  1 873 Reference Reference
  2 519 0.95 (0.85; 1.07) 0.415 1.15 (1.00; 1.33) 0.051
  3 400 1.10 (0.97; 1.26) 0.131 1.27 (1.07; 1.50) 0.006
  4 314 1.30 (1.13; 1.50) <0.001 1.42 (1.16; 1.74) 0.001
  5 191 0.94 (0.80; 1.12) 0.513 0.91 (0.72; 1.15) 0.429
  6 212 1.60 (1.35; 1.90) <0.001 1.83 (1.43; 2.33) <0.001
  7+ 276 1.05 (0.89; 1.23) 0.566 1.45 (1.14; 1.84) 0.002
Ongoing line of therapy by regimen §
  Melphalan 200 mg/m2 days 0–30 434 1.19 (1.04; 1.37) 0.012 1.28 (1.07; 1.53) 0.006
  IMID ± steroid 487 Reference Reference
  PI ± steroid 280 1.72 (1.46; 2.02) <0.001 1.80 (1.50; 2.15) <0.001
  CH ± steroid 201 2.01 (1.68; 2.40) <0.001 1.79 (1.48; 2.18) <0.001
  IMID + PI ± steroid 224 1.29 (1.08; 1.53) 0.004 1.19 (0.99; 1.44) 0.067
  PI + CH ± steroid 173 1.48 (1.23; 1.78) <0.001 0.94 (0.76; 1.16) 0.547
  IMID + CH ± steroid 301 1.46 (1.24; 1.70) <0.001 1.14 (0.95; 1.36) 0.165
  Daratumumab ± steroid 147 1.15 (0.93; 1.42) 0.192 1.29 (1.02; 1.63) 0.033
  Daratumumab + PI ± steroid 37 0.60 (0.41; 0.89) 0.011 0.90 (0.59; 1.37) 0.624
  Daratumumab + IMID ± steroid 171 1.26 (1.04; 1.53) 0.020 1.21 (0.97; 1.51) 0.094
  Daratumumab + PI + IMID ± steroid 3 0.79 (0.25; 2.45) 0.677 0.85 (0.26; 2.82) 0.791
  Five or more drugs 294 2.18 (1.87; 2.54) <0.001 1.79 (1.50; 2.14) <0.001
  Other 33 2.31 (1.50; 3.55) <0.001 1.02 (0.63; 1.63) 0.949
Time from diagnosis §
  0–91 days after 77 Reference Reference
  92–183 days after 472 0.53 (0.45; 0.63) <0.001 0.52 (0.42; 0.65) <0.001
  183–365 days after 278 0.61 (0.51; 0.72) <0.001 0.44 (0.34; 0.56) <0.001
  365–730 days after 270 0.40 (0.34; 0.47) <0.001 0.26 (0.20; 0.32) <0.001
  More than 730 days after 404 0.26 (0.23; 0.30) <0.001 0.12 (0.10; 0.16) <0.001
Time from initiation of immunoglobulin replacement therapy §
  Before 524 Reference Reference
  0–91 days after 335 2.34 (2.02; 2.71) <0.001 2.06 (1.75; 2.43) <0.001
  92–183 days after 179 1.57 (1.31; 1.88) <0.001 1.26 (1.02; 1.56) 0.033
  184–365 days after 249 2.39 (2.03; 2.82) <0.001 2.05 (1.69; 2.48) <0.001
Time from dates of progressive disease §
  Before 1315 Reference Reference
  0–91 days after 281 1.13 (0.98; 1.30) 0.087 1.17 (1.00; 1.37) 0.051
  92–183 days after 33 0.95 (0.65; 1.40) 0.810 0.91 (0.59; 1.41) 0.682
  184–365 days after 20 0.61 (0.37; 1.01) 0.054 0.71 (0.39; 1.29) 0.260

§, the same patient is taken into account multiple times. CH, chemotherapy (cyclophosphamide/low-dose melphalan/bendamustine/doxorubicine/liposomal doxorubicine/melflufen); CR, complete response; FISH, fluorescence in situ hybridisation; IMID, immunomodulatory agent (thalidomide/lenalidomide/pomalidomide); ISS, international staging system; sCR, stringent complete response; MR, minimal response; PD, progressive disease; PI, proteasome inhibitor (bortezomib/carfilzomib/ixazomib); PR, partial response; SD, stable disease; VGPR, very good partial response; WBLDCT, whole-body low-dose computer tomography.

Table S2

Univariate and multivariate analysis of risk factors for blood culture days

Footnotes

Peer review under responsibility of the International Academy for Clinical Hematology

REFERENCES

[13]MiBa, the Danish Microbiology Database. Available from: https://miba.ssi.dk/service/english.
Journal
Clinical Hematology International
Volume-Issue
2 - 4
Pages
168 - 172
Publication Date
2020/08/10
ISSN (Online)
2590-0048
DOI
https://doi.org/10.2991/chi.k.200719.001How to use a DOI?
Copyright
© 2020 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V.
Open Access
This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

Cite this article

TY  - JOUR
AU  - Agoston Gyula Szabo
AU  - Katrine Fladeland Iversen
AU  - Flemming Schønning Rosenvinge
AU  - Sören Möller
AU  - Torben Plesner
PY  - 2020
DA  - 2020/08/10
TI  - The Incidence and Timing of Blood Cultures in Multiple Myeloma – Results from a Retrospective, Single Center, Real-World Study
JO  - Clinical Hematology International
SP  - 168
EP  - 172
VL  - 2
IS  - 4
SN  - 2590-0048
UR  - https://doi.org/10.2991/chi.k.200719.001
DO  - https://doi.org/10.2991/chi.k.200719.001
ID  - Szabo2020
ER  -