SEARCH

SEARCH BY CITATION

Keywords:

  • Critically ill;
  • heparin-binding protein (HBP);
  • infection;
  • influenza A(H1N1);
  • respiratory dysfunction

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

Heparin-binding protein (HBP) is an inducer of vascular endothelial leakage in severe infections. Fluid accumulation into alveoli is a general finding in acute respiratory distress syndrome (ARDS). Severe acute respiratory failure with ARDS is a complication of influenza A(H1N1) infection. Accordingly, we studied the HBP levels in critically ill patients with infection of influenza A(H1N1).Critically ill patients in four intensive care units (ICUs) with polymerase chain reaction (PCR) confirmed infection of influenza A(H1N1) were prospectively evaluated. We collected clinical data and blood samples at ICU admission and on day 2. Twenty-nine patients participated in the study. Compared with normal plasma levels, the HBP concentrations were highly elevated at baseline and at day 2: 98 ng/mL (62–183 ng/mL) and 93 ng/mL (62–271 ng/mL) (p 0.876), respectively. HBP concentrations were correlated with the lowest ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PF ratio) during the ICU stay (rho = −0.321, p <0.05). In patients with and without invasive mechanical ventilation, the baseline HBP levels were 152 ng/mL (72–237 ng/mL) and 83 ng/mL (58–108 ng/mL) (p 0.088), respectively. The respective values at day 2 were 223 ng/mL (89–415 ng/mL) and 81 ng/mL (55–97 ng/mL) (p <0.05). The patients with septic shock/severe sepsis (compared with those without) did not have statistically significant differences in HBP concentrations at baseline or day 2. HBP concentrations are markedly elevated in all critically ill patients with influenza A(H1N1) infection. The increase in HBP concentrations seems to be associated with more pronounced respiratory dysfunction.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

Heparin-binding protein (HBP) is an immunomodulatory protein secreted by activated neutrophils [1]. The action of HBP on capillary endothelium is responsible for the leakage of fluid into the extracellular space and is responsible for the neutrophil-evoked permeability changes [2]. HBP is a promising new biomarker for the evolution of septic shock and increased levels have been shown 12 h prior to development of septic shock [3]. However, HBP does not seem to discriminate between patients according to the aetiology of shock (i.e. between non-septic shock and septic shock) [4]. Increased concentrations of HBP have been described in both groups regardless of aetiology of shock compared with patients with local infection only [4].

Influenza A(H1N1)-infected patients most often have a mild clinical course of the disease. Of hospitalized influenza A(H1N1) patients, 6–31% require treatment in intensive care units [5-7]. In ICUs the influenza A(H1N1) patients often present with pneumonia, severe hypoxaemic acute respiratory failure and acute respiratory distress syndrome (ARDS) [6, 8]. Increased alveolar permeability is a major component of the pathogenesis of the development of ARDS. This increased alveolar permeability may be due to injury to alveolar epithelial cells or the capillary endothelium. Either way the leakage of fluid into the interstitium and alveolar space leads to impaired respiratory function. The accumulation of fluid will, in turn, enhance the migration of inflammatory cells into the alveolar space and further enhance the inflammatory reaction [9].

In previous studies, no increase in plasma HBP levels has been detected in patients with local bacterial infections, including pneumonias [4]. Our aim is to study the concentrations in patients with severe viral infection and influenza A(H1N1), and its possible associations with respiratory function.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

This is a prospective substudy of the previously published H1N1 study [10]. In the main study, all patients with ICU admission and high suspicion of pandemic influenza A(H1N1) infection were screened. High suspicion of influenza A(H1N1) infection was defined as oseltamivir treatment and/or real-time reverse transcription polymerase chain reaction (PCR) sample being taken. Only patients with a positive PCR test result for influenza A (H1N1) were included in the main study population. All patients in the main study were eligible for the substudy, which was performed in four ICUs. The study period was during the Finnish H1N1 outbreak from 11 October 2009 to 31 December 2009.

The ethics committee of Helsinki University Central Hospital approved the study. The informed consent was waived for data collection from patient charts in the main study. For the substudy, with collection of blood samples, a signed informed consent was obtained from the patient or next-of-kin.

Data collection

The Finnish Intensive Care Consortium quality database Intensium Ltd (Kuopio, Finland) provided routine benchmarking data and study-specific internet-based case report forms and data warehouse services.

The collected clinical data are described in detail in the main study [10]. With routine benchmarking data we acquired age, gender, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score components, and hospital and ICU admission/discharge times, as well as ICU and hospital mortality. The clinical study data consisted of: patient demographics, details of mechanical ventilation, information on severe sepsis or septic shock, the number of quadrants in chest X-rays with infiltration, presence of acute respiratory distress syndrome (ARDS) [11] and adjunctive therapy for acute respiratory failure and other organ failures.

The plasma samples were collected immediately after ICU admission (baseline) and on the second day of ICU treatment. The samples were centrifuged in local laboratories and stored at −20°C. The samples were transferred and stored at −70°C until analysis. The plasma HBP was determined by enzyme-linked immunosorbent assay as described earlier [1]. The detection limit of the method was 0.25 ng/mL and CV variance was <5%.

Statistical analysis

The data are presented as medians and interquartile range (IQR) or absolute numbers (range), as appropriate. The normality of distribution of continuous parameters was tested with the Kolmogorov-Smirnov one-sample test. In the case of non-normal distribution, the parameters were transformed to natural logarithm before analysis. The differences between study populations were analysed by the Mann–Whitney U-test or Wilcoxon signed rank test, as appropriate. The differences in HBP concentrations between groups were calculated by one-way analysis of variance. In SPSS the missing data are deleted list-wise. The intraclass (ICC) correlation coefficient was used to examine the correlation between HBP levels, the lowest PF ratio, the highest SOFA score, white blood cell (WBC) count and C-reactive protein (CRP). We assessed HBP concentrations above 15 ng/mL as significantly elevated, a cut-off value that has been shown to be the best predictive cut-off value for severe sepsis [3]. p <0.05 is considered statistically significant. We used PASW Statistics 19.0 (SPSS Inc., Chicago, IL, USA) for statistical analysis.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

The main study population consisted of 132 patients with high suspicion of influenza A(H1N1) infection and a positive PCR test. Of these patients, 29 were included in the substudy (28 patients with baseline samples and 25 patients with day 2 samples). The patient characteristics are presented in Table 1.

Table 1. Study patients in main study and HBP substudy. Data are presented as median [interquartile range] or number (percentage)
 All patients in main study (= 132)p value
HBP substudy (= 29)Patients not in substudy (= 103)
  1. SAPS, simplified acute physiology score; SOFA, sequential organ failure assessment; CRP, C-reactive protein; PF, ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen; ARDS, acute respiratory distress syndrome.

  2. a

    Body mass index not calculated for children under 14 years of age, = 9.

Age, years47 [39–56]49 [29–56]0.891
Gender, male20 (69%)65 (63%)0.562
Body mass index >35 kg/m2a11 (38%)22 (21%)0.105
Smoker13 (45%)33 (32%)0.125
Chronic obstructive pulmonary disease1 (3.4%)8 (7.8%)0.411
SAPS II points24 [20–32]29 [21–37]0.093
SOFA score3 [2–7]5 [2–8]0.174
At admission
CRP (mg/L)73 [33–163]101 [39–175]0.533
White blood cell count (x109)6.4 [4.8–10.1]7.3 [4.9–9.8]0.683
Septic shock/severe sepsis7 (24%)29 (28%)0.067
Number of infiltrated quadrants on X-ray4 [2–4]2 [1–4]0.053
PF ratio, mmHg135 [101–261]140 [104–240]0.841
During intensive care unit stay
Ventilatory support
No/non-invasive ventilation16 (55%)49 (48%)
Invasive mechanical ventilation13 (45%)54 (52%)0.196
Length of mechanical ventilation, days2 [0–10]0.9 [0–8]0.510
The lowest PF ratio, mmHg100 [76–134]111 [75–184]0.366
ARDS19 (66%)39 (37.9%)0.013
Steroid treatment17 (59%)55 (53.4%)0.619
Bacterial culture positive (blood)1 (3.4%)8 (7.8%)0.470
Bacterial culture positive (any)8 (28%)30 (29.1%)0.900
Renal replacement therapy1 (3.4%)10 (9.7%)0.283
Maximum SOFA score7 [3–9]6 [4–11]0.664
Intensive care unit length of stay, days4.6 [2.2–9.9]3.9 [1.9–12.1]0.910
Hospital length of stay, days12 [7–16]15 [7–28]0.108
Intensive care unit mortality1 (3.4%)4 (3.9%)0.914
Hospital mortality1 (3.4%)9 (8.7%)0.343

The overall plasma HBP concentrations were similar at both sampling times: 98 ng/mL (62–183 ng/mL) at baseline samples compared with 93 ng/mL (62–271 ng/mL) (p 0.876) at day 2. The HBP concentrations were above 15 ng/mL [3] in all patients, both at baseline and at day 2. The lowest concentration of HBP was 32 ng/mL in a non-septic patient. No patient had severe leucopenia; the WBC count in the lowest tertile was 2.7–4.7 x 109/L. The HBP/WBC ratio at baseline was 15 (9.0–25.9), the smallest value being 6.2. HBP concentrations were correlated with the WBC count at baseline (rho = 0.444, p <0.01) (Fig. 1) and the lowest PF ratio during the ICU stay (rho = −0.321, p <0.05). No correlation could be shown between the HBP concentrations with the highest SOFA score during the ICU stay (rho = 0.255, p 0.08) or HBP concentration and C-reactive protein (CRP) (rho = 0.266, p 0.179) (Fig. 1).

image

Figure 1. Heparin binding protein (HBP) concentrations (ng/mL) at admission correlated with WBC (white blood cell) count (x109) at admission (rho = 0.444, p <0.01) but not with CRP (C-reactive protein, g/L) at admission (rho = 0.266, p 0.179).

Download figure to PowerPoint

When comparing patients with and without invasive mechanical ventilation during ICU stay, a difference in HBP concentrations was observed on day 2. Baseline concentrations were 152 ng/mL (72–237 ng/mL) vs. 83 ng/mL (58–108 ng/mL) (p 0.088) at day 2 and 223 ng/mL (89–415 ng/mL) vs. 81 ng/mL (55–97 ng/mL) at day 2 (p <0.01), respectively (Fig. 2, Table 2). In patients with the lowest PF ratio <100 mmHg, HBP concentrations were significantly higher compared with those with the lowest PF ratio ≥100 mmHg at day 2 (p <0.05), and also significantly higher in patients who received corticosteroid treatment during the ICU stay compared with those who did not receive corticosteroid treatment (p <0.05) (Fig. 3, Table 2). No significant difference was found between patients with the lowest PF ratio <100 mmHg and those with lowest PF ratio ≥100 mmHg or between those treated with corticosteroid and those not treated with corticosteroid at baseline (Fig. 3, Table 2). The patients with septic shock or severe sepsis during their ICU stay had high concentrations of HBP at baseline and day 2, but the difference was not statistically significant when compared with those without septic shock or severe sepsis (Fig. 3, Table 2). The patients with ARDS and those without did not have significant differences in their HBP concentrations at baseline or day 2 (Table 2).

Table 2. Plasma concentrations of HBP (heparin binding protein) in patient subgroups. Data are presented as median [interquartile range]
 All patients with blood sampling (= 29)
HBP concentration baselineHBP concentration day 2
  1. ICU, intensive care unit; PF, ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen; ARDS, acute respiratory distress syndrome.

  2. a

    p <0.01, comparisons of HBP concentrations at day 2 between the subgroups.

  3. b

    p <0.05, comparisons of HBP concentrations at day 2 between the subgroups.

Invasive mechanical ventilation during ICU stay

152 ng/mL

[72–237 ng/mL]

223 ng/mL

[89–415 ng/mL]a

No invasive mechanical ventilation during ICU stay

83 ng/mL

[58–108 ng/mL]

81 ng/mL

[55–97 ng/mL]

The lowest PF ratio < 100 mmHg during ICU stay

108 ng/mL

[59–226 ng/mL]

188 ng/mL

[86–389 ng/mL] b

The lowest PF ratio ≥ 100 mmHg during ICU stay

87 ng/mL

[64–118 ng/mL]

81 ng/mL

[55–112 ng/mL]

ARDS during ICU stay

106 ng/mL

[67–232 ng/mL]

124 ng/mL

[71–364 ng/mL]

No ARDS during ICU stay

72 ng/mL

[48–119 ng/mL]

81 ng/mL

[57–97 ng/mL]

Admission CRP < 100

83 ng/mL

[51–127 ng/mL]

84 ng/mL

[54–108 ng/mL]

Admission CRP ≥ 100

130 ng/mL

[72–296 ng/mL]

128 ng/mL

[84–326 ng/mL]

Corticosteroid treatment during ICU stay

128 ng/mL

[70–219 ng/mL]

124 ng/mL

[84–409 ng/mL]b

No corticosteroid treatment during ICU stay

75 ng/mL

[58–108 ng/mL]

74 ng/mL

[54–113 ng/mL]

Septic shock or severe sepsis during ICU stay

183 ng/mL

[108–247 ng/mL]

223 ng/mL

[54–332 ng/mL]

No septic shock or severe sepsis during ICU stay

83 ng/mL

[58–118 ng/mL]

90 ng/mL

[64–134 ng/mL]

image

Figure 2. Upper panel: HBP concentrations (ng/mL) in patients with and without invasive mechanical ventilation at baseline (p 0.088) and day 2 (p <0.01). Lower panel: HBP concentrations in tertiles of patients divided according to admission PF ratio at baseline and day 2 (p ns).

Download figure to PowerPoint

image

Figure 3. Heparin binding protein concentrations (ng/mL) at baseline and day 2 in patients with and without corticosteroid therapy (p not significant at baseline; p <0.05 at day 2) and with and without severe sepsis or septic shock during their ICU stay (p not significant at baseline and day 2).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

In this prospective observational study we found that plasma HBP concentrations were markedly elevated in critically ill patients with PCR-confirmed influenza A(H1N1) infection compared with normal plasma levels at baseline. Furthermore, we demonstrated a significant difference in concentrations at day 2 between patients with invasive mechanical ventilation and those without, patients with the lowest PF ratio <100 mmHg and those above 100 mmHg, and patients receiving corticosteroid treatment and those without corticosteroids. This implies higher HBP concentrations in patients with more severe pulmonary damage. In patients with septic shock or severe sepsis the difference was not statistically significant. The observed high HBP concentrations were correlated with WBC count at baseline and the lowest PF ratio, but not with the highest SOFA score or CRP levels.

In previous studies, a cut-off value of 15 ng/mL has been shown to have the best predictive value for the development of septic shock [3, 12]. In healthy controls, the median (range) HBP levels have been 6.3 (5.0–9.7) ng/mL and in febrile patients with local infections (urinary tract infection, pneumonia and gastroenteritis) the median (range) concentrations have been 7.1 (4.4–10.2) ng/mL, 7.0 (5.4–10.3) ng/mL and 5.8 (3.7–8.8) ng/mL, respectively [4].In our study population, all patients had HBP concentrations well above the proposed cut-off value for septic shock both at baseline and at day 2. Influenza A(H1N1) infection in our study population presented as lower respiratory tract infection. HBP has been identified as a possible biomarker for septic shock, and to our knowledge, no studies in patients with upper respiratory tract infection have been conducted. In the study by Chew et al. the concentrations of HBP were similar in both healthy controls and febrile patients with pneumonia without systemic inflammatory response syndrome (SIRS) [4].

In earlier studies, the HBP/WBC ratio has been calculated for the correction of possibly low HBP levels due to low neutrophil count [3, 12]. With the use of the HBP/WBC ratio in addition to the HBP concentration cut-off value of 15 ng/mL, additional shock patients have been found [12]. In our H1N1-positive patients the HBP/WBC ratio was above 6 in all of our patients although there were still some patients with low WBC count; the lowest tertile of patients had their WBC count between 2.7 and 4.7 × 109/L.

Influenza A(H1N1) patients rapidly develop severe progressive respiratory failure, which is often associated with failure of other organs [13]. In the early phases of ARDS, there is protein-rich fluid accumulation and disruption of both the alveolar epithelium and the pulmonary capillary endothelium. This inflammatory process is mediated by activated neutrophils and macrophages [9]. Heparin-binding protein may contribute to the neutrophil-associated vascular leakage in acute inflammation [2]. High concentrations of HBP in our patients imply that H1N1 infection results in significant release of HBP in humans. Moreover, association of HBP levels with the severity of respiratory dysfunction suggests a role of the neutrophil-derived protein in the development of lung tissue damage and respiratory failure in influenza A(H1N1) infections. Recently, in a mouse model of H1N1 infection, it was shown that mice depleted of macrophages had severe pulmonary pathology: excessive neutrophil infiltration, alveolar damage and increased viral load. These changes later progressed to ARDS-like pathology, diffuse alveolar damage, pulmonary oedema, haemorrhage and hypoxemia. In contrast, neutrophil-depleted mice had only mild pathological changes in their lungs, pointing to a critical role of neutrophils in H1N1 infections [14]. The authors provided evidence for the formation of neutrophil extracellular traps (NETs), which might contribute to the pulmonary damage.

The role of neutrophils in pulmonary infections with influenza A has not been clearly defined. In severe infections, pulmonary damage is driven by both neutrophils and macrophages [9]. In animal studies, a decreased number of circulating leucocytes with an increased proportion of polymorphonuclear cells has been associated with increased intensity of pulmonary damage [15]. On the other hand, mice depleted of neutrophils have presented with exacerbated pulmonary inflammation, oedema and respiratory dysfunction [16]. In a comparison of macrophage-depleted mice with neutrophil-depleted mice, pulmonary damage was more pronounced in macrophage-depleted mice when infected with influenza A(H1N1) [14]. In human patients who died of influenza A(H1N1) infection, intensive pulmonary infiltration of neutrophils was documented in patients presenting with necrotizing bronchiolitis, but only mild or moderate infiltration in patients without necrotizing bronchiolitis [17].

Previously, increased HBP levels have been associated with the progression of septic shock and severe sepsis in hospitalized patients [3, 12]. In a recently published study, HBP levels were elevated not only in patients with septic shock but also in patients with circulatory shock due to other reasons when compared with healthy control patients or with patients with local infection only [4]. In this study we found no statistically significant differences in HBP concentrations between patients with septic shock/severe sepsis and other influenza A(H1N1) patients. Septic shock/severe sepsis was, however, present in only three of the 29 patients at ICU admission and four additional patients were later diagnosed as having septic shock/severe sepsis during their ICU stay. The concentrations of HBP in septic patients were markedly elevated in both samples. Additionally, even the lowest concentration of HBP in the non-septic patients was 32 ng/mL at baseline (i.e. higher than the previously reported cut-off value for septic shock).

Our study has some limitations. First, the main study was designed to describe the intensive care treatment and outcome in Finnish ICUs during the outbreak of an influenza A(H1N1) pandemic. Due to the observational nature of the main study a waiver of consent was approved. As an informed consent was mandatory for blood sampling in the substudy, there was substantial loss of potential study subjects and the substudy was performed in four ICUs only. However, no significant differences in demographic data between the patient populations were present and thus we consider our results as representative. The small sample size affects the interpretation of the observed HBP concentrations in patient subgroups. Quite large differences in the concentrations of HBP in patient subgroups (Table 2) (e.g. septic shock/severe sepsis vs. non-septic patients) were not statistically significant. We anticipate that type II error may be present (i.e. we could not detect a difference in HBP concentrations in patient subgroups even though it is there). Finally, recurrent samples during the ICU stay may have provided more information regarding the association of HBP and respiratory dysfunction. However, to the best of our knowledge this study is the first to provide important new information regarding HBP levels in H1N1-infected critically ill patients.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

Heparin-binding protein concentrations were markedly elevated in all critically ill patients with influenza A(H1N1) infection even in the presence of a low white cell count. The increase in HBP concentrations seems to be associated with more pronounced respiratory dysfunction.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

We thank research coordinator Sari Sutinen and laboratory technician Monica Heidenholm for skilful assistance with the HBP samples and for the retrieval of original data.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

This study was supported by the Clinical Research funding (EVO T102010070) from Helsinki University Hospital and the National Institute of Health and Welfare. KMK has received a grant for Clinical Research Career from the Academy of Finland. HH's work was supported by the Swedish Research Council (project 7480). LL's work was supported by the Swedish Research Council (project 4342).

The Finnish H1N1 Study Group

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

Participating hospitals and study investigators: Satakunta Central Hospital, Dr Vesa Lund; East Savo Central Hospital, Dr Markku Suvela; Central Finland Central Hospital, Dr Raili Laru-Sompa; South Savo Central Hospital, Dr Heikki Laine; North Karelia Central Hospital, Dr Matti Reinikainen; Seinäjoki Central Hospital, Dr Kari Saarinen; South Karelia Central Hospital, Dr Seppo Hovilehto; Päijät-Häme Central Hospital, Dr Pekka Loisa; Vaasa Central Hospital, Dr Raku Hautamäki; Kanta-Häme Central Hospital, Dr Ari Alaspää; Lappi Central Hospital, Dr Outi Kiviniemi; Keski-Pohjanmaa Central Hospital, Dr Tadeusz Kaminski; Kymenlaakso Central Hospital, Dr Seija Alila, Dr Jussi Pentti; Helsinki University Hospital, Jorvi, Peijas and Meilahti Hospitals, Dr Rita Linko, Dr Tero Varpula, Dr Anne Kuitunen, Dr Tuomas Oksanen, Dr Timo Suonsyrjä; Turku University Hospital, Dr Juha Perttilä; Tampere University Hospital, Dr Sari Karlsson, Dr Jyrki Tenhunen; Länsi-Pohja′s Central Hospital, Dr Jorma Heikkinen; Kuopio University Hospital, Dr Esko Ruokonen, Ilkka Parviainen; Oulu University Hospital, Dr Tero Ala-Kokko, Dr Jouko Laurila; Turku University Hospital, Paediatric ICU, Dr Janne Kataja; Helsinki University Hospital, ICU of Hospital for Children and Adolescents, Dr Paula Rautiainen.

Transparency Declarations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References

Hansa Medical AB has filed a patent application on the use of HBP as a diagnostic tool in sepsis. HH is listed as inventor.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Funding
  10. The Finnish H1N1 Study Group
  11. Transparency Declarations
  12. References
  • 1
    Tapper H, Karlsson A, Morgelin M, Flodgaard H, Herwald H. Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles. Blood 2002; 99: 17851793.
  • 2
    Gautam N, Olofsson AM, Herwald H et al. Heparin-binding protein (HBP/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability. Nat Med 2001; 7: 11231127.
  • 3
    Linder A, Christensson B, Herwald H, Bjorck L, Akesson P. Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis 2009; 49: 10441050.
  • 4
    Chew MS, Linder A, Santen S, Ersson A, Herwald H, Thorlacius H. Increased plasma levels of heparin-binding protein in patients with shock: a prospective, cohort study. Inflamm Res 2012; 61: 375379.
  • 5
    Dominguez-Cherit G, Lapinsky SE, Macias AE et al. Critically Ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009; 302: 18801887.
  • 6
    Kumar A, Zarychanski R, Pinto R et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA 2009; 302: 18721879.
  • 7
    Jain S, Kamimoto L, Bramley AM et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009; 361: 19351944.
  • 8
    Estenssoro E, Rios FG, Apezteguia C et al. Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med 2010; 182: 4148.
  • 9
    Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342: 13341349.
  • 10
    Linko R, Pettila V, Ruokonen E et al. Corticosteroid therapy in intensive care unit patients with PCR-confirmed influenza A(H1N1) infection in Finland. Acta Anaesthesiol Scand 2011; 55: 971979.
  • 11
    Bernard GR, Artigas A, Brigham KL et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: 818824.
  • 12
    Linder A, Akesson P, Inghammar M, Treutiger CJ, Linner A, Sunden-Cullberg J. Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock. Crit Care 2012; 16: R90.
  • 13
    Patel M, Dennis A, Flutter C, Khan Z. Pandemic (H1N1) 2009 influenza. Br J Anaesth 2010; 104: 128142.
  • 14
    Narasaraju T, Yang E, Samy RP et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol 2011; 179: 199210.
  • 15
    Xu T, Qiao J, Zhao L et al. Acute respiratory distress syndrome induced by avian influenza A (H5N1) virus in mice. Am J Respir Crit Care Med 2006; 174: 10111017.
  • 16
    Tate MD, Deng YM, Jones JE, Anderson GP, Brooks AG, Reading PC. Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol 2009; 183: 74417450.
  • 17
    Mauad T, Hajjar LA, Callegari GD et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med 2010; 181: 7279.