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Epidemiology and clinical impact of infection in patients awaiting heart transplantation

Open AccessPublished:March 14, 2013DOI:https://doi.org/10.1016/j.ijid.2013.01.021

      Summary

      Objectives

      The aim of this study was to determine the epidemiology and clinical impact of infections in patients awaiting heart transplantation.

      Methods

      We evaluated all patients considered for a heart transplant in our center over a period of 18 months over a period of 18 months from 2007 to 2009. The patients were followed up for 8 months or until death, transplant, or loss to follow-up.

      Results

      Ninety patients were included in the study. During follow-up, 25 infections were recorded in 22 heart transplant candidates (24.4%). Respiratory infections were the most frequent infection (12 bronchitis; 48.0%), followed by skin and soft tissue infections (four infections; 16.0%), intra-abdominal infections (four infectious diarrhea; 16.0%), bacteremia (three infections; 12.0%), and urinary tract infections (two infections; 2.0%). Age, comorbidity, sex, and diabetes were not found to be risk factors for infection. Twenty-four patients (26.7%) were transplanted during follow-up. Infection before transplantation was not associated with an increased risk of mortality or a higher rate of infection in the immediate post-transplant period.

      Conclusions

      Infections are common in heart transplant candidates, affecting almost 25% of them. Respiratory tract infections are the most frequent type of infection. However, they are not associated with increased mortality in the immediate post-transplant period.

      Keywords

      1. Introduction

      There are few reports on the incidence and types of infection in patients with terminal heart failure, although the role of infection in hospital admissions is well known in these patients.
      • Tsuyuki R.T.
      • McKelvie R.S.
      • Arnold J.M.
      • Avezum A.
      • Barreto A.C.
      • Carvalho A.
      • et al.
      Acute precipitants of congestive heart failure exacerbations.
      It is recognized that post-transplant infectious morbidity in heart transplant recipients is moderate,
      • Montoya J.G.
      • Giraldo L.F.
      • Efron B.
      • Stinson E.B.
      • Gamberg P.
      • Hunt S.
      • et al.
      Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center.
      • Miller L.W.
      • Naftel D.C.
      • Bourge R.C.
      • Kirklin J.K.
      • Brozena S.C.
      • Jarcho J.
      • et al.
      Infection after heart transplantation: a multiinstitutional study. Cardiac Transplant Research Database Group.
      • Rodriguez C.
      • Muñoz P.
      • Rodriguez-Creixems M.
      • Yanez J.F.
      • Palomo J.
      • Bouza E.
      Bloodstream infections among heart transplant recipients.
      • van de Beek D.
      • Kremers W.K.
      • Del Pozo J.L.
      • Daly R.C.
      • Edwards B.S.
      • McGregor C.G.
      • Patel R.
      Effect of infectious diseases on outcome after heart transplant.
      and there are many known risk factors for infection in the early post-transplant period.
      • Rodriguez C.
      • Muñoz P.
      • Rodriguez-Creixems M.
      • Yanez J.F.
      • Palomo J.
      • Bouza E.
      Bloodstream infections among heart transplant recipients.
      • Smart F.W.
      • Naftel D.C.
      • Costanzo M.R.
      • Levine T.B.
      • Pelletier G.B.
      • Yanci C.W.
      • et al.
      Risk factors for early, cumulative, and fatal infections after heart transplantation: a multiinstitutional study.
      Nevertheless, there are no communications describing the epidemiology of infection in patients awaiting heart transplantation, and the impact of pre-transplant infection on the early post-transplant period is not known.
      The main aim of this study was to describe the frequency, epidemiology, and risk factors for infection in patients awaiting heart transplantation. Another objective was to determine the influence of infection on waiting-list mortality and early mortality and morbidity after transplantation.

      2. Materials and methods

      2.1 Study population and follow-up

      Our institution is a tertiary care hospital that has had a heart transplantation program since 1986. It is the reference center for heart transplantation for a population of approximately two million, and 542 heart transplants had been performed up until 2011.
      Over a period of 18 months from 2007 to 2009, we prospectively included all adult patients (over the age of 14 years) who were considered for inclusion on the heart transplantation waiting list in our center. The patients were followed up for 8 months from the time they were evaluated, with clinical assessments performed at least monthly. All episodes of bacterial and fungal infection requiring either hospitalization or outpatient treatment were recorded, as well as the etiology of the infection when an etiological diagnosis was made.
      Initial follow-up ended at transplantation, death, or loss to follow-up of the patient. Follow-up did not end if the patient was excluded from the waiting list. Patients who were transplanted were followed up for 1 month after transplantation.

      2.2 Routine antibiotic prophylaxis after transplantation

      Routine antibiotic prophylaxis after heart transplantation in our center is performed with cloxacillin and cefotaxime and is maintained for 5 days. Trimethoprim–sulfamethoxazole is initiated as soon as possible and maintained for the first 3–6 months.

      2.3 Classification of episodes of infection

      The infections were defined according to internationally accepted criteria recommended by organizations such as the American Society of Transplantation,
      • Humar A.
      • Michaels M.
      American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.
      the Infectious Diseases Society of America (IDSA),
      • McGeer A.
      • Campbell B.
      • Emori T.G.
      • Emori T.G.
      • Hierholzer W.J.
      • Jackson M.M.
      • et al.
      Definitions of Infection for Surveillance in long-term care facilities.
      • Mermel L.A.
      • Allon M.
      • Bouza E.
      • Craven D.E.
      • Flynn P.
      • O‘Grady N.P.
      • et al.
      Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America.
      • Guerrant R.L.
      • Van Gilder T.
      • Steiner T.S.
      • Thielman N.M.
      • Slutsker L.
      • Tauxe R.V.
      • et al.
      Practice guidelines for the management of infectious diarrhea.
      and the European Association for the Study of the Liver.
      European Association for the Study of the Liver
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      Infections were classified into the categories listed below.

      2.3.1 Respiratory tract infection

      Proven and probable cases of pneumonia and acute bronchitis were included in this category. A diagnosis of pneumonia was made in the presence of one or more of the following symptoms: cough, hemoptysis, fever, dyspnea, or pleuritic chest pain, in addition to compatible findings on a radiograph or a thoracic computerized tomography. The final diagnosis was established based on fulfillment of the above criteria as well as the presence of a positive culture in a valid respiratory sample. Cases where no organisms were isolated in respiratory samples were considered probable pneumonia. In the presence of clinical criteria for lower respiratory tract infection without radiological evidence of consolidation, a diagnosis of bronchitis was made.
      • McGeer A.
      • Campbell B.
      • Emori T.G.
      • Emori T.G.
      • Hierholzer W.J.
      • Jackson M.M.
      • et al.
      Definitions of Infection for Surveillance in long-term care facilities.

      2.3.2 Urinary tract infection

      Confirmed bacterial urinary tract infection (UTI) included cases of cystitis and pyelonephritis with positive urine culture. Cystitis was defined by the presence of a urine bacteria count of more than 10 000 colony-forming units (cfu)/ml and pyuria (≥3 leukocytes per high-power field or positive leukocyte esterase), with clinical manifestations such as dysuria, high frequency and/or urinary urgency in the absence of pyelonephritis criteria.
      • Humar A.
      • Michaels M.
      American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.
      Pyelonephritis was defined by the presence of a positive urine culture (>10 000 cfu/ml) and pyuria in association with tenderness at the costovertebral angle with fever and/or positive blood culture.
      • Humar A.
      • Michaels M.
      American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.
      Cases of asymptomatic bacteriuria, defined as the presence of a urine bacteria count of >10 000 cfu/ml without clinical manifestations of UTI, were not included.
      • Humar A.
      • Michaels M.
      American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.

      2.3.3 Bacteremia and catheter-related bacteremia

      The diagnosis of bacteremia was made in the case of isolation of a microorganism other than a skin contaminant (diphtheroids, Bacillus spp, or coagulase-negative staphylococci) in one culture and the presence of signs of infection (chills, fever, hypotension), or the isolation of the above contaminants in two consecutive cultures, with signs of infection.
      • Garner J.S.
      • Jarvis W.R.
      • Emori T.G.
      • et al.
      CDC definitions of nosocomial infections.
      When there was a focus other than catheter-related bacteremia, the episode of infection was classified as organ infection. Bacteremia was considered to be catheter-related if it met the criteria established by the IDSA.
      • Mermel L.A.
      • Allon M.
      • Bouza E.
      • Craven D.E.
      • Flynn P.
      • O‘Grady N.P.
      • et al.
      Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America.

      2.3.4 Intra-abdominal infection

      This category included episodes of infectious diarrhea caused by bacteria, spontaneous bacterial peritonitis, and cholangitis. ‘Infectious diarrhea’ was defined as diarrhea due to a bacterial etiology, accompanied by symptoms of nausea, vomiting, or abdominal cramps.
      • Guerrant R.L.
      • Van Gilder T.
      • Steiner T.S.
      • Thielman N.M.
      • Slutsker L.
      • Tauxe R.V.
      • et al.
      Practice guidelines for the management of infectious diarrhea.
      Cholangitis was defined as cases of fever, right upper quadrant abdominal pain and cholestatic enzyme abnormalities, and/or direct hyperbilirubinemia.
      • Humar A.
      • Michaels M.
      American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.
      Spontaneous bacterial peritonitis was defined as the presence of ascites and a polymorphonuclear cell count of more than 0.25 × 109/l in ascitic fluid.
      European Association for the Study of the Liver
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.

      2.3.5 Skin and soft tissue infections

      All skin and soft tissue infections (including surgical site infections) were included in this category regardless of their location and extension. Non-necrotizing infections (impetigo, erysipelas, cellulitis, or pyomyositis) and necrotizing infections (necrotizing cellulitis or fascitis and myonecrosis) were included. Infections secondary to bites, pressure ulcers, and diabetic foot ulcers were also included.
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Everett E.D.
      • Dellinger P.
      • Goldstein E.J.
      • et al.
      Practice guidelines for the diagnosis and management of skin and soft-tissue infections.
      Surgical site infections (SSI) were included in this category. SSI was defined as infection of the skin, independently of the depth of the infection, that occurred within 30 days after the operation if no implant was left in place, or within 1 year if the implant was left in place and the infection appeared to be related to the operation.
      • Horan T.C.
      • Gaynes R.P.
      • Martone W.J.
      • Jarvis W.R.
      • Emori T.G.
      CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections.

      2.4 Mortality

      All occurrences of death during follow-up were defined as ‘crude mortality’. Deaths that could be directly attributed to an infectious episode were defined as ‘death due to infection’.

      2.5 Statistical analysis

      The Chi-square test or Fisher's exact test was used to compare the qualitative variables, while the Student's t-test and Mann–Whitney U-test were used to compare the quantitative variables. To determine risk factors for infection and mortality based on follow-up time, we used the Cox regression analysis. Statistical significance was considered when the p-value was <0.05.

      3. Results

      Ninety patients were included during the study period. The baseline characteristics of patients included in the study are shown in Table 1. At the end of follow-up, 24 candidates were transplanted (26.6% of those evaluated), five (5.5%) patients died before transplantation, 14 (15.5%) patients remained on the waiting list, and 47 (52.2%) patients had been excluded from the active waiting list. No death could be directly attributed to an infectious episode.
      Table 1Baseline characteristics of patients included in the study (N = 90)
      Age, years, mean ± standard deviation51.2 ± 11.8
      Sex, number of males (% males)67 (74.4%)
      Charlson comorbidity index, mean ± standard deviation2.93 ± 1.7
      History of tobacco use, number of patients who use tobacco/total patients (%)44 (48.9%)
      Diabetes mellitus, number of diabetic patients/total patients (%)24 (26.6%)
      Alcohol consumption, number of patients with heavy alcohol consumption/total patients (%)10 (11.1%)
      Treatment with corticoids or other immunosuppressants at first evaluation5 (5.6%)
      Positive Toxoplasma IgG45 (50.0%)
      Positive Epstein–Barr virus IgG78 (86.7%)
      Positive cytomegalovirus IgG75 (83.3%)
      Follow-up time,
      Does not include post-transplant follow-up time (24.6±11.0 days).
      days, mean ± standard deviation
      186.1 ± 89.8
      Underlying cardiopathy
       Dilated48 (53.3%)
       Ischemic24 (26.7%)
       Congenital10 (11.1%)
       Hypertrophic4 (4.4%)
       Retransplant1 (1.1%)
       Other3 (3.3%)
      a Does not include post-transplant follow-up time (24.6 ± 11.0 days).

      3.1 Waiting-list follow-up

      During follow-up, 25 infections were recorded in 22 heart transplant candidates (24.4%). Respiratory infections were the most frequent infection (12 bronchitis; 48.0%), followed by skin and soft tissues infections (four infections; 16.0%), intra-abdominal infections (four infectious diarrhea; 16.0%), bacteremia (three infections; 12.0%), and UTI (two infections; 2.0%).
      The etiology of infection could be confirmed in seven cases (28.0%): Escherichia coli (two UTI and one bacteremia), Staphylococcus aureus (one bacteremia and one soft tissue infection), Staphylococcus epidermidis (one bacteremia), and Candida albicans (one cutaneous infection).
      The association of different variables with the risk of infection in patients on the waiting list is shown in Table 2. None of the variables studied behaved as a statistically significant risk factor for infection in the patients in this study.
      Table 2Risk factors for infection in patients awaiting heart transplantation
      RR95% CIp-Value
      Sex, male1.560.32–7.590.57
      Diabetes mellitus1.960.75–5.060.16
      Age0.980.93–1.030.57
      Charlson comorbidity index1.310.99–1.730.053
      Analysis by multivariate Cox regression. RR, relative risk; CI, confidence interval.
      Patients with an infection during follow-up did not have a higher mortality while on the waiting list than those without infections (mortality in the infection group 13.9% vs. 2.9% for patients without infection; p = 0.11).

      3.2 Immediate post-transplant follow-up

      Baseline characteristics of patients who were transplanted and other aspects concerning the immediate post-transplant period are summarized in Table 3. After transplant, patients were followed up for a mean 24.6 ± 11.0 days. The proportion of transplant recipients who developed an infection in the first month after transplantation was not higher among those who had developed an infection while on the waiting list (12.5% vs. 23.7% in those without previous infection; relative risk (RR) 0.50, 95% confidence interval (CI) 0.06–4.00; p = 0.52). Female sex behaved as a risk factor for early infection after transplantation (RR 6.99, 95% CI 1.34–36.4; p = 0.02). No other factors (age, transplantation in urgency code, diabetes, or Charlson comorbidity index) were associated with a higher frequency of early infections after transplantation.
      Table 3Characteristics of patients who were transplanted during follow-up
      Results are mean ± standard deviation, or n (%).
      All transplanted patients

      (n = 24)
      Early infection after transplant

      (n = 7)
      No early infection

      (n = 17)
      p-Value
      Age, years50.8 ± 13.851.8 ± 13.950.4 ± 14.2NS
      Sex, female8 (33.3%)5 (71.4%)3 (17.6%)0.021
      Diabetes mellitus before transplant4 (16.7%)1 (16.7%)3 (18.8%)NS
      Charlson comorbidity index2.5 ± 1.42.3 ± 1.62.6 ± 1.4NS
      Need for immunosuppressants before transplant2 (8.4%)02 (13.3%)NS
      Underlying myocardiopathy
       Dilated12 (50%)4 (57.1%)9 (52.9%)
       Ischemic5 (20.8%)2 (28.6%)3 (17.6%)
       Hypertrophic4 (16.7%)1 (14.3%)2 (11.8%)
       Congenital1 (4.2%)01 (5.9%)
       Infiltrative1 (4.2%)01 (5.9%)
       Retransplant1 (4.2%)01 (5.9%)NS
      Transplant in urgency code5 (20.8%)2 (28.6%)3 (17.6%)NS
      Need for dialysis after transplant4 (16.7%)1 (16.7%)3 (18.8%)NS
      Organ ischemic time, min199 ± 47190 ± 71203 ± 39NS
      Immunosuppression after transplantNS
       Cyclosporine24 (100%)7 (100%)17 (100%)
       Steroids24 (100%)7 (100%)17 (100%)
       Mycophenolate mofetil22 (91.6%)6 (85.7%)16 (94.1%)
       Everolimus3 (12.5%)1 (14.2%)2 (11.7%)
       Steroids bolus4 (16.7%)2 (28.5%)2 (11.7%)
       Basiliximab1 (4.2%)01 (5.8%)
      Differences were calculated by Mann–Whitney U-test or Fisher's test. NS, not significant.
      a Results are mean ± standard deviation, or n (%).
      Five out of 24 patients (20.8%) died during follow-up after transplantation. Early mortality after transplantation was higher in heart transplant recipients who had developed an infection during the pre-transplant period (50.0% vs. 18.2%), although this difference was not statistically significant (RR 3.83, 95% CI 0.42–34.8; p = 0.23). No deaths after transplantation were attributed directly to infection. The need for dialysis after transplantation (RR 7.68, 95% CI 1.2–46.6; p = 0.027) and a higher Charlson comorbidity index (RR 1.71, 95% CI 1.0–2.93; p = 0.05) were associated with higher mortality rates after transplantation. Recipient age showed a tendency towards a higher mortality (RR 1.1, 95% CI 0.98–1.23; p = 0.09).

      4. Discussion

      Our results show that infection is a common complication in patients awaiting heart transplantation. This had not yet been fully established in heart transplant candidates. Our data indicate that patients with advanced heart disease awaiting transplantation are at high risk of infection, although they are generally mild infections that do not involve increased attributable mortality. In our study, respiratory infections were the most frequent type of infection. Respiratory infection is a common complication in patients with heart failure, and the cause of 60% of all hospital admissions.
      • Tsuyuki R.T.
      • McKelvie R.S.
      • Arnold J.M.
      • Avezum A.
      • Barreto A.C.
      • Carvalho A.
      • et al.
      Acute precipitants of congestive heart failure exacerbations.
      It is therefore not surprising that respiratory infection is the most common infectious complication in patients with advanced heart disease awaiting a heart transplant.
      An adequate control of infection in transplant patients must begin not at the time of transplantation but from the moment the patient is placed on the waiting list. Transplant candidates often have chronic terminal deficiencies that justify a procedure such as transplantation. They frequently have comorbidities and have extensive contact with the healthcare system. The overall clinical profile of these patients explains in itself the risk of infectious complications. This explains why it is difficult to find specific risk factors for infection in these patients, and makes it difficult to predict who will suffer from an infection.
      In our study we found no evidence to suggest that patients with an infection awaiting heart transplantation are at higher risk of having another infectious complication in the first month after heart transplantation. The infections found in the immediate post-transplant period were those expected after surgery (surgical site infection) and during intensive care of the patient (respiratory tract infections, catheter-related bacteremia). These infections are related to surgery and the intensive care management post-transplantation (mechanical ventilation, central venous catheters), so previous infections may have no impact on the incidence of early infections after transplantation. The only risk factor for early infection that we found in our analysis was female sex. Although it is widely known that women are at a higher risk for some types of infections, e.g. UTI
      • Foxman B.
      The epidemiology of urinary tract infection.
      and wound infection after coronary surgery,
      • Nakano J.
      • Okabayashi H.
      • Hanyu M.
      • Soga Y.
      • Nomoto T.
      • Arai Y.
      • et al.
      Risk factors for wound infection after off-pump coronary artery bypass grafting: should bilateral internal thoracic arteries be harvested in patients with diabetes?.
      we have not found female sex described as a risk factor for infection after heart transplantation in previous publications.
      We were not able to demonstrate a worse survival expectancy after heart transplantation in those patients who had suffered from an infection before the transplant. Many factors are known to influence the post-transplant prognosis in patients undergoing heart transplantation, such as those recently included in the IMPACT index
      • Weiss E.S.
      • Allen J.G.
      • Kilic A.
      • Russell S.D.
      • Baumgartner W.A.
      • Conte J.V.
      • Shah A.S.
      Development of a quantitative donor risk index to predict short-term mortality in orthotopic heart transplantation.
      (Index for Mortality Prediction After Cardiac Transplantation) – age, race, gender, underlying heart disease, or need for dialysis – organ ischemic time,
      • Weiss E.S.
      • Allen J.G.
      • Kilic A.
      • Russell S.D.
      • Baumgartner W.A.
      • Conte J.V.
      • Shah A.S.
      Development of a quantitative donor risk index to predict short-term mortality in orthotopic heart transplantation.
      donor age,
      • Weiss E.S.
      • Allen J.G.
      • Kilic A.
      • Russell S.D.
      • Baumgartner W.A.
      • Conte J.V.
      • Shah A.S.
      Development of a quantitative donor risk index to predict short-term mortality in orthotopic heart transplantation.
      transplant urgency,
      • Almenar L.
      • Segovia J.
      • Crespo-Leiro M.G.
      • et al.
      Spanish Heart Transplantation Registry. 21st Official Report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984–2009).
      and the recipient's weight prior to transplantation.
      • Grady K.L.
      • White-Williams C.
      • Naftel D.
      • Costanzo M.R.
      • Pitts D.
      • Rayburn B.
      • et al.
      Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality: a multi-institutional study of preoperative weight–height indices. Cardiac Transplant Research Database (CTRD) Group.
      In our study, the need for dialysis after transplantation, a higher Charlson comorbidity index, and age (the latter did not reach statistical significance) behaved as risk factors for early mortality. The existence of such a large number of factors makes it difficult to determine the true impact of pre-transplant infection as an independent prognostic factor, suggesting that infection is probably less important than the factors mentioned above.
      We found no other series describing the impact of infection before heart transplant on the post-transplant period. In a recent study, Sun et al.
      • Sun H.Y.
      • Cacciarelli T.V.
      • Singh N.
      Impact of pretransplant infections on clinical outcomes of liver transplant recipients.
      also found no differences when comparing mortality at 90 and 180 days after liver transplantation in patients with and without a history of bacterial infection in the year prior to transplantation. In another recent study, Kim et al.
      • Kim B.S.
      • Lee S.G.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • et al.
      Influence of pretransplantation bacterial and fungal culture positivity on outcome after living donor liver transplantation.
      described colonization or infection prior to liver transplantation as a predictor of death in the first 3 months after transplantation. However, in this study no deaths were attributable to infection in the group of patients presenting infection prior to transplantation.
      There are several limitations to our findings, the main one being the number of patients included in the study. It is likely that a larger sample size would have permitted us to obtain significant differences in terms of the prognostic significance of infection in heart transplant candidates.
      In conclusion, the frequency of infection in patients awaiting heart transplant may require collaboration between infectious disease and transplant specialists from the moment the candidate is placed on the transplant waiting list. Infections are common in heart transplant candidates, affecting almost 25% of them. The most frequent type of infection is respiratory tract infection, followed by skin and soft tissue infection and infectious diarrhea. However, infection before heart transplantation is not a risk factor for infection in the early post-transplant period, as these infections are directly related to surgery and intensive care management. Moreover, patients with an infection on the waiting list for heart transplantation do not have a worse prognosis after transplantation.
      Funding: Supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, co-financed by the European Development Regional Fund “A way to achieve Europe” (ERDF), and the Spanish Network for Research in Infectious Diseases (REIPI RD06/0008).
      Ethical approval: This work was approved and meets the ethical requirements of the Declaration of Helsinki.
      Conflict of interest: All authors declare that they have no conflict of interest.

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