Marjan Wouthuyzen-Bakker

Persistent fat malabsorption in cystic fibrosis; lessons from patients and mice

Fat malabsorption in pancreatic insufficient cystic fibrosis (CF) patients is classically treated with pancreatic enzyme replacement therapy (PERT). Despite PERT, intestinal fat absorption remains insufficient in most CF patients. Several factors have been suggested to contribute to the persistent fat malabsorption in CF (CFPFM). We reviewed the current insights concerning the proposed causes of CFPFM and the corresponding intervention studies. Most data are obtained from studies in CF patients and CF mice. Based on the reviewed literature, we conclude that alterations in intestinal pH and intestinal mucosal abnormalities are most likely to contribute to CFPFM. The presently available data indicate that acid suppressive drugs and broad spectrum antibiotics could be helpful in individual CF patients for optimizing fat absorption and/or nutritional status.

Yellow fever in a traveller returning from Suriname to the Netherlands, March 2017

A Dutch traveller returning from Suriname in early March 2017, presented with fever and severe acute liver injury. Yellow fever was diagnosed by (q)RT-PCR and sequencing. During hospital stay, the patient’s condition deteriorated and she developed hepatic encephalopathy requiring transfer to the intensive care. Although yellow fever has not been reported in the last four decades in Suriname, vaccination is recommended by the World Health Organization for visitors to this country.

Persistent Fat Malabsorption in Cystic Fibrosis

Despite pancreas enzyme replacement therapy, intestinal fat absorption remains insufficient in most cystic fibrosis (CF) patients. We reviewed the potential causes of CF-related persistent intestinal fat malabsorption. Data are obtained from studies in patients and in CF experimental animal models. Based on the physiology of intestinal fat absorption, we discuss the pathology in CF conditions. The chapter covers CF-related alterations of intestinal pH and bicarbonate secretion, bile salt metabolism, and enterohepatic circulation and intestinal mucosal abnormalities.

Effect of antibiotic treatment on fat absorption in mice with cystic fibrosis

Introduction:Improving fat absorption remains a challenge in cystic fibrosis (CF). Antibiotics (AB) treatment has been shown to improve body weight in CF mice. The mechanism may include improvement in fat absorption. We aimed to determine the effect of AB on fat absorption in two CF mouse models.Results:AB did not improve total fat absorption. Interestingly, AB accelerated the absorption of isotope-labeled fats, in both Δ/Δ and WT mice. The changes observed were not related to the solubilization capacity of bile or to changes in the bacteria in the small intestine. AB reduced the fecal excretion of cholate by ~50% (P < 0.05) in both CF mouse models, indicating improved intestinal bile salt absorption.Discussion:In conclusion, AB treatment does not improve total fat absorption in CF mice but does decrease fecal loss of bile salts and accelerate long-chain fatty acid (LCFA) absorption.Methods:For 3 weeks, we administered oral AB (ciprofloxacin/metronidazole) or control treatment to homozygous ΔF508 (Δ/Δ), cystic fibrosis transmembrane conductance regulator (CFTR) knockout (−/−), and wild-type (WT) mice and quantified fat absorption using a 72-h fat balance test. In Δ/Δ mice, we assessed fat absorption kinetics by administering tri-1-13C-palmitin and 1-13C-stearate intragastrically and determining the appearance of stable isotope-labeled fats in plasma. We quantified biliary and fecal bile salts (gas chromatography) and small intestinal bacteria (quantitative-PCR).

Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice

Cystic fibrosis liver disease (CFLD) is treated with ursodeoxycholate (UDCA). Our aim was to evaluate, in cystic fibrosis transmembrane regulator knockout (Cftr(-/-)) mice and wild-type controls, whether the supposed therapeutic action of UDCA is mediated via choleretic activity or effects on bile salt metabolism. Cftr(-/-) mice and controls, under general anesthesia, were intravenously infused with tauroursodeoxycholate (TUDCA) in increasing dosage or were fed either standard or UDCA-enriched chow (0.5% wt/wt) for 3 wk. Bile flow and bile composition were characterized. In chow-fed mice, we analyzed bile salt synthesis and pool size of cholate (CA). In both Cftr(-/-) and controls intravenous TUDCA stimulated bile flow by ∼250% and dietary UDCA by ∼500%, compared with untreated animals (P < 0.05). In non-UDCA-treated Cftr(-/-) mice, the proportion of CA in bile was higher compared with that in controls (61 ± 4 vs. 46 ± 4%; P < 0.05), accompanied by an increased CA synthesis [16 ± 1 vs. 10 ± 2 μmol·h(-1)·100 g body wt (BW)(-1); P < 0.05] and CA pool size (28 ± 3 vs. 19 ± 1 μmol/100 g BW; P < 0.05). In both Cftr(-/-) and controls, UDCA treatment drastically reduced the proportion of CA in bile below 5% and diminished CA synthesis (2.3 ± 0.3 vs. 2.2 ± 0.4 μmol·day(-1)·100 g BW(-1); nonsignificant) and CA pool size (3.6 ± 0.6 vs. 1.5 ± 0.3 μmol/100 g BW; P < 0.05). Acute TUDCA infusion and chronic UDCA treatment both stimulate bile flow in cystic fibrosis conditions independently from Cftr function. Chronic UDCA treatment reduces the hydrophobicity of the bile salt pool in Cftr(-/-) mice. These results support a potential beneficial effect of UDCA on bile flow and bile salt metabolism in cystic fibrosis conditions.

Synovial calprotectin: a potential biomarker to exclude a prosthetic joint infection

Aims Recently, several synovial biomarkers have been introduced into the algorithm for the diagnosis of a prosthetic joint infection (PJI). Alpha defensin is a promising biomarker, with a high sensitivity and specificity, but it is expensive. Calprotectin is a protein that is present in the cytoplasm of neutrophils, is released upon neutrophil activation and exhibits antimicrobial activity. Our aim, in this study, was to determine the diagnostic potential of synovial calprotectin in the diagnosis of a PJI. Patients and Methods In this pilot study, we prospectively collected synovial fluid from the hip, knee, shoulder and elbow of 19 patients with a proven PJI and from a control group of 42 patients who underwent revision surgery without a PJI. PJI was diagnosed according to the current diagnostic criteria of the Musculoskeletal Infection Society. Synovial fluid was centrifuged and the supernatant was used to measure the level of calprotectin after applying a lateral flow immunoassay. Results The median synovial calprotectin level was 991 mg/L (interquartile range (IQR) 154 to 1787) in those with a PJI and 11 mg/L (IQR 3 to 29) in the control group (p < 0.0001). Using a cutoff value of 50 mg/L, this level showed an excellent diagnostic accuracy, with an area under the curve of 0.94. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) was 89%, 90%, 81% and 95% respectively. The NPV was 97% in the nine patients with a chronic PJI. Conclusion Synovial calprotectin may be a valuable biomarker in the diagnosis of a PJI, especially in the exclusion of an infection. With a lateral flow immunoassay, a relatively rapid quantitative diagnosis can be made. The measurement is cheap and is easy to use.

Predicting Failure in Early Acute Prosthetic Joint Infection Treated With Debridement, Antibiotics, and Implant Retention: External Validation of the KLIC Score

BACKGROUND Debridement, antibiotics, and implant retention (DAIR) is a widely used treatment modality for early acute prosthetic joint infection (PJI). A preoperative risk score was previously designed for predicting DAIR failure, consisting of chronic renal failure (K), liver cirrhosis (L), index surgery (I), cemented prosthesis (C), and C-reactive protein >115 mg/L (KLIC). The aim of this study was to validate the KLIC score in an external cohort. METHODS We retrospectively evaluated patients with early acute PJI treated with DAIR between 2006 and 2016 in 3 Dutch hospitals. Early acute PJI was defined as <21 days of symptoms and DAIR performed within 90 days after index surgery. Failure was defined as the need for (1) second DAIR, (2) implant removal, (3) suppressive antimicrobial treatment, or (4) infection-related death within 60 days after debridement. RESULTS A total of 386 patients were included. Failure occurred in 148 patients (38.3%). Patients with KLIC scores of ≤2, 2.5-3.5, 4-5, 5.5-6.5, and ≥7 had failure rates of 27.9%, 37.1%, 49.3%, 54.5%, and 85.7%, respectively (P < .001). The receiver-operating characteristic curve showed an area under the curve of 0.64 (95% confidence interval 0.59-0.69). A KLIC score higher than 6 points showed a specificity of 97.9%. CONCLUSION The KLIC score is a relatively good preoperative risk score for DAIR failure in patients with early acute PJI and appears to be most useful in clinical practice for patients with low or high KLIC scores.

The effect of preoperative antimicrobial prophylaxis on intraoperative culture results in patients with a suspected or confirmed prosthetic joint infection. A systematic review.

ABSTRACT Obtaining reliable cultures during revision arthroplasty is important to adequately diagnose and treat a prosthetic joint infection (PJI). The influence of antimicrobial prophylaxis on culture results remains unclear. Since withholding prophylaxis increases the risk for surgical site infections, clarification on this topic is critical. A systematic review was performed with the following research question: in patients who undergo revision surgery of a prosthetic joint, does preoperative antimicrobial prophylaxis affect the culture yield of intraoperative samples in comparison with nonpreoperative antimicrobial prophylaxis? Seven articles were included in the final analysis. In most studies, standard diagnostic culture techniques were used. In patients with a PJI, pooled analysis showed a culture yield of 88% (145/165) in the prophylaxis group versus 95% (344/362) in the nonprophylaxis group (P = 0.004). Subanalysis of patients with chronic PJIs showed positive cultures in 88% (78/89) versus 91% (52/57), respectively (P = 0.59). In patients with a suspected chronic infection, a maximum difference of 4% in culture yield between the prophylaxis and nonprophylaxis groups was observed. With the use of standard culture techniques, antimicrobial prophylaxis seems to affect cultures in a minority of patients. Along with the known risk of surgical site infections due to inadequate timing of antimicrobial prophylaxis, we discourage the postponement of prophylaxis until tissue samples are obtained in revision surgery. Future studies are necessary to conclude whether the small percentage of false-negative cultures after prophylaxis can be further reduced with the use of more-sensitive culture techniques, like sonication.

Managing persistent wound leakage after total knee and hip arthroplasty : Results of a nationwide survey among Dutch orthopaedic surgeons

Background: Persistent wound leakage after joint arthroplasty is a scantily investigated topic, despite the claimed relation with a higher risk of periprosthetic joint infection. This results in a lack of evidence-based clinical guidelines for the diagnosis and treatment of persistent wound leakage after joint arthroplasty. Without such guideline, clinical practice in orthopaedic hospitals varies widely. In preparation of a nationwide multicenter randomized controlled trial on the optimal treatment of persistent wound leakage, we evaluated current Dutch orthopaedic care for persistent wound leakage after joint arthroplasty. Methods: We conducted a questionnaire-based online survey among all 700 members of the Netherlands Orthopaedic Association, consisting of 23 questions on the definition, classification, diagnosis and treatment of persistent wound leakage after joint arthroplasty. Results: The questionnaire was completed by 127 respondents, representing 68% of the Dutch hospitals that perform orthopaedic surgery. The results showed wide variation in the classification, definition, diagnosis and treatment of persistent wound leakage among Dutch orthopaedic surgeons. 56.7% of the respondents used a protocol for diagnosis and treatment of persistent wound leakage, but only 26.8% utilized the protocol in every patient. Most respondents (59.1%) reported a maximum period of persistent wound leakage before starting non-surgical treatment of 3 to 7 days after index surgery and 44.1% of respondents reported a maximum period of wound leakage of 10 days before converting to surgical treatment. Conclusions: The wide variety in clinical practice underscores the importance of developing an evidence-based clinical guideline for the diagnosis and treatment of persistent wound leakage after joint arthroplasty. To this end, a nationwide multicenter randomized controlled trial will be conducted in the Netherlands, which may provide evidence on this important and poorly understood topic.

LEAK study: design of a nationwide randomised controlled trial to find the best way to treat wound leakage after primary hip and knee arthroplasty

Introduction Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are highly successful treatment modalities for advanced osteoarthritis. However, prolonged wound leakage after arthroplasty is linked to prosthetic joint infection (PJI), which is a potentially devastating complication. On the one hand, wound leakage is reported as a risk factor for PJI with a leaking wound acting as a porte d’entrée for micro-organisms. On the other hand, prolonged wound leakage can be a symptom of PJI. Literature addressing prolonged wound leakage is scarce, contradictory and of poor methodological quality. Hence, treatment of prolonged wound leakage varies considerably with both non-surgical and surgical treatment modalities. There is a definite need for evidence concerning the best way to treat prolonged wound leakage after joint arthroplasty. Methods and analysis A prospective nationwide randomised controlled trial will be conducted in 35 hospitals in the Netherlands. The goal is to include 388 patients with persistent wound leakage 9–10 days after THA or TKA. These patients will be randomly allocated to non-surgical treatment (pressure bandages, (bed) rest and wound care) or surgical treatment (debridement, antibiotics and implant retention (DAIR)). DAIR will also be performed on all non-surgically treated patients with persistent wound leakage at day 16–17 after index surgery, regardless of amount of wound leakage, other clinical parameters or C reactive protein. Clinical data are entered into a web-based database. Patients are asked to fill in questionnaires about disease-specific outcomes, quality of life and cost effectiveness at 3, 6 and 12 months after surgery. Primary outcome is the number of revision surgeries due to infection within a year of arthroplasty. Ethics and dissemination The Review Board of each participating hospital has approved the local feasibility. The results will be published in peer-reviewed scientific journals. Trial registration number NTR5960;Pre-results.