Screening for asymptomatic deep vein thrombosis in COVID-19 patients admitted to the medical ward: a cross-sectional study.

PURPOSE: Patients with COVID-19 have an increased risk for venous thrombo-embolism (VTE), especially pulmonary embolism. The exact prevalence of asymptomatic DVT is not known, as is the usefulness of screening for DVT in patients admitted to ward with COVID-19. We have studied the prevalence of asymptomatic DVT. METHODS: We performed a cross-sectional observational multi-center study at four university medical centers in The Netherlands. All adult patients admitted with COVID-19 to a medical ward were eligible for inclusion, including patients who were transferred back from the ICU to the ward. The study protocol consisted of weekly cross-sectional rounds of compression ultrasound. RESULTS: In total, 125 patients were included in the study. A significant proportion of patients (N = 34 (27%)) had developed a VTE during their admission for COVID-19 before the study ultrasound was performed. In most VTE cases (N = 27 (79%)) this concerned pulmonary embolism. A new asymptomatic DVT was found in 5 of 125 patients (4.0%; 95% CI 1.3-9.1%) (Table 2). Nine patients (7.2%; 95% CI 3.3-13.2%) developed a VTE (all PE) diagnosed within 28 days after the screening US was performed. CONCLUSION: We have shown a low prevalence (4%) of newly discovered asymptomatic DVT outside the ICU-setting in COVID-19 patients. Despite this low prevalence, nine patients developed PE (7%) within 28 days after ultrasound. This favors the hypothesis of local thrombus formation in the lungs. Based on our findings and literature, we do not recommend US-screening of asymptomatic patients with COVID-19 admitted to the ward.

Toxinotype A Clostridium perfringens causing septicaemia with intravascular haemolysis: two cases and review of the literature.

BACKGROUND: Septicaemia with intravascular haemolysis is a rare, but often fatal, presentation of Clostridium perfringens infection. C. perfringens is a Gram-positive, anaerobic bacterium that can produce multiple toxins. Toxinotyping is not performed regularly. METHODS: This article describes two human cases of C. perfringens infections. Toxinotyping was performed using polymerase chain reaction (PCR). Additionally, a structured review of the literature was performed which searched specifically for cases of C. perfringens infection with haemolysis. RESULTS: Both cases were identified as toxinotype A strains and both cases were fatal. Also, both cases showed marked haemolysis during their clinical course, which is assumed to have played a significant role in their outcome. In total, 83 references were identified describing human C. perfringens infection with haemolysis. Mortality rates have been stable over the last 10 years at 80%. Toxinotyping has been performed in a total of six cases. Of the four cases analysed by PCR, all were identified as toxinotype A. CONCLUSIONS: Haemolytic C. perfringens infections are rare but are fatal in most cases. Toxinotyping is performed rarely. The authors advocate increased use of toxinotyping to gain insight into pathophysiology and more effective interventions.

Pulmonary infarction in acute pulmonary embolism.

Pulmonary infarction results from occlusion of the distal pulmonary arteries leading to ischemia, hemorrhage and ultimately necrosis of the lung parenchyma. It is most commonly caused by acute pulmonary embolism (PE), with a reported incidence of around 30%. Following an occlusion of the pulmonary artery, the bronchial arteries are recruited as primary source of perfusion of the pulmonary capillaries. The relatively higher blood pressure in the bronchial circulation causes an increase in the capillary blood flow, leading to extravasation of erythrocytes (i.e. alveolar hemorrhage). If this hemorrhage cannot be resorbed, it results in tissue necrosis and infarction. Different definitions of pulmonary infarction are used in literature (clinical, radiological and histological), although the diagnosis is nowadays mostly based on radiological characteristics. Notably, the infarcted area is only replaced by a fibrotic scar over a period of months. Hence and formally, the diagnosis of pulmonary infarction cannot be confirmed upon diagnosis of acute PE. Little is known of the impact and relevance of pulmonary infarction in acute PE, and whether specific management strategies should be applied to prevent and/or treat complications such as pain, pneumonia or post-PE syndrome. In this review we will summarize current knowledge on the pathophysiology, epidemiology, diagnosis and prognosis of pulmonary infarction in the setting of acute PE. We highlight the need for dedicated studies to overcome the current knowledge gaps.

[Clinical history in times of big data; a plea for a standard for the structured recording of the clinical history]. / Anamnese in tijden van big data.

Clinical decision support systems to aid the clinician in making a correct diagnosis will only succeed if data from the clinical history are taken into account. However, currently, very little is known on diagnostic test characteristics of specific symptoms, let alone of a pattern of several symptoms with all their cardinal features. We plead for the nation-wide introduction of a standard for the structured recording of the clinical history. To allow for such structured recording, user interfaces of electronic healthcare records must become far more user-friendly. Furthermore, scribes may be used, or, ideally, a digital scribe, a computer application that records the conversation between healthcare professional and patient and creates an automated summary. So far, to our knowledge, no digital scribe encompassing the entire patient history has been implemented into medical practice. We are currently trying to develop such a digital scribe.

[POCUS is a great asset to general practice]. / POCUS is een grote aanwinst voor de algemene praktijk.

Point of care ultrasonography (POCUS) is a specific form of ultrasonography that aims to quickly rule in or out specific abnormalities with a high impact on diagnostic or therapeutic management as an adjunct to physical examination. As such, it is of great value to every physician who performs physical examinations, especially if there is an acute problem that may involve several organ systems.

Marburg haemorrhagic fever in returning travellers: an overview aimed at clinicians.

Marburg virus haemorrhagic fever (MARV HF) is a dramatic disease that can occur in a traveller returning from an area where the virus is endemic. In this article, we provide an overview of MARV HF as an imported infection with an emphasis on clinical aspects. Although late features such as rash, signs of haemorrhagic diathesis and liver necrosis may point to the diagnosis, the initial clinical picture is non-specific. If in this early phase the patient's epidemiological exposure history is compatible with MARV HF, the patient should be isolated and managed according to viral haemorrhagic fever protocol and RT-PCR should be performed on the patient's blood as soon as possible to rule out MARV HF (or other possible viral haemorrhagic fevers). In severe cases, direct electron microscopy of blood in specialized centres (e.g. Bernhard-Nocht Institute in Hamburg, Germany) may be considered if the result of the RT-PCR is not readily available. Adequate diagnostics and empirical treatment for other acute life-threatening illnesses should not be withheld while test results are awaited, but all management and diagnostics should be weighed against the risks of nosocomial transmission.

Update of treatment algorithms for Clostridium difficile infection.

BACKGROUND: Clostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI. AIM: To review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies. SOURCES: A literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017. CONTENT: We analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2). IMPLICATIONS: Metronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy.

How to: Establish and run a stool bank.

BACKGROUND: Since 2013, several stool banks have been developed following publications reporting on clinical success of 'faecal microbiota transplantation' (FMT) for recurrent Clostridium difficile infections (CDI). However, protocols for donor screening, faecal suspension preparation, and transfer of the faecal suspension differ between countries and institutions. Moreover, no European consensus exists regarding the legislative aspects of the faecal suspension product. Internationally standardized recommendations about the above mentioned aspects have not yet been established. OBJECTIVE: In 2015, the Netherlands Donor Feces Bank (NDFB) was founded with the primary aim of providing a standardized product for the treatment of patients with recurrent CDI in the Netherlands. Standard operation procedures for donor recruitment, donor selection, donor screening, and production, storage, and distribution of frozen faecal suspensions for FMT were formulated. RESULTS AND DISCUSSION: Our experience summarized in this review addresses current donor recruitment and screening, preparation of the faecal suspension, transfer of the faecal microbiota suspension, and the experiences and follow-up of the patients treated with donor faeces from the NDFB.

Humoral immune response as predictor of recurrence in Clostridium difficile infection.

Low serum concentrations of antibodies directed against the toxins TcdA and TcdB have been associated with a higher risk of recurrence of Clostridium difficile infection (CDI) after successful antibiotic treatment. However, there are conflicting reports. Herein, we compared serum levels of antibodies of patients with a single episode of CDI with those of patients who subsequently suffered a recurrence. We used a serum bank from patients who received an experimental whey protein product following successful antibiotic treatment for CDI. We determined levels of IgA and IgG directed against TcdA, TcdB and non-toxin cell surface antigens in serum collected directly and 3 weeks after completing a 10-day course of antibiotic treatment for CDI. We also developed an objective flow cytometry-based assay to determine the proportion of cells exhibiting cytopathic effect after exposure to TcdB. Using this method, we measured the TcdB-neutralizing capacity of sera. We compared the results for patients without a subsequent recurrence with those of patients who suffered a recurrence within 60 days after completing the antibiotic treatment. Advanced age, comorbidity other than immunocompromised state and low serum levels of anti-TcdA and anti-TcdB antibodies were associated with recurrence, whereas serum levels of antibodies directed against cell surface antigens were not. Serum TcdB-neutralizing capacity, which correlated only weakly with serum IgG anti-TcdB, was not significantly associated with recurrence.

Patients with cystic fibrosis have a high carriage rate of non-toxigenic Clostridium difficile.

Thirty-year-old observations report frequent asymptomatic Clostridium difficile carriage among cystic fibrosis (CF) patients. In this case-control study, we found more carriers among CF patients than controls (47% versus 11%), but most strains carried by CF patients were non-toxigenic (77% versus 17%). Among CF patients, carriers were younger, with more severe pulmonary disease than non-carriers. Strains belonged to multiple PCR-ribotypes, suggesting that these CF patients did not acquire strains from each other.

European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection.

In 2009 the first European Society of Clinical Microbiology and Infection (ESCMID) treatment guidance document for Clostridium difficile infection (CDI) was published. The guideline has been applied widely in clinical practice. In this document an update and review on the comparative effectiveness of the currently available treatment modalities of CDI is given, thereby providing evidence-based recommendations on this issue. A computerized literature search was carried out to investigate randomized and non-randomized trials investigating the effect of an intervention on the clinical outcome of CDI. The Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was used to grade the strength of our recommendations and the quality of the evidence. The ESCMID and an international team of experts from 11 European countries supported the process. To improve clinical guidance in the treatment of CDI, recommendations are specified for various patient groups, e.g. initial non-severe disease, severe CDI, first recurrence or risk for recurrent disease, multiple recurrences and treatment of CDI when oral administration is not possible. Treatment options that are reviewed include: antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, and faecal or bacterial intestinal transplantation. Except for very mild CDI that is clearly induced by antibiotic usage antibiotic treatment is advised. The main antibiotics that are recommended are metronidazole, vancomycin and fidaxomicin. Faecal transplantation is strongly recommended for multiple recurrent CDI. In case of perforation of the colon and/or systemic inflammation and deteriorating clinical condition despite antibiotic therapy, total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended.

The changing epidemiology of Clostridium difficile infections.

The epidemiology of Clostridium difficile infection (CDI) has changed dramatically during this millennium. Infection rates have increased markedly in most countries with detailed surveillance data. There have been clear changes in the clinical presentation, response to treatment, and outcome of CDI. These changes have been driven to a major degree by the emergence and epidemic spread of a novel strain, known as PCR ribotype 027 (sometimes referred to as BI/NAP1/027). We review the evidence for the changing epidemiology, clinical virulence and outcome of treatment of CDI, and the similarities and differences between data from various countries and continents. Community-acquired CDI has also emerged, although the evidence for this as a distinct new entity is less clear. There are new data on the etiology of and potential risk factors for CDI; controversial issues include specific antimicrobial agents, gastric acid suppressants, potential animal and food sources of C. difficile, and the effect of the use of alcohol-based hand hygiene agents.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI).

Clostridium difficile infection (CDI) is a potentially fatal illness with an increasing incidence worldwide. Despite extensive ongoing research into CDI treatment, management of CDI still poses important problems, such as a high propensity to relapse and refractoriness to treatment, especially when there is an ileus and oral drugs cannot be administered. This guideline evaluates the available literature, discusses criteria for disease severity and provides recommendations for CDI treatment, indicating level of evidence and strength of recommendation.

Clinical and microbiological characteristics of community-onset Clostridium difficile infection in The Netherlands.

To elucidate the prevalence, characteristics and risk factors of community-onset Clostridium difficile infection (CO-CDI), an uncontrolled prospective study was performed. For 3 months in 2007-2008, three laboratories in The Netherlands tested all unformed stool samples submitted by general practitioners (GPs) for C. difficile by enzyme immunoassay for toxins A and B, irrespective of whether GPs specifically requested this. Patients with positive results were asked to complete a questionnaire. Positive stool samples were cultured for C. difficile, and isolates were characterized. In all, 2443 stool samples from 2423 patients were tested, and 37 patients (1.5%) with positive toxin test results were identified. Mixed infections were not found. Age varied from 1 to 92 years, and 18% were under the age of 20 years. Diarrhoea was typically frequent and watery, sometimes with admixture of blood or fever. Eight of 28 patients (29%) suffered recurrences. Among 31 patients with toxin-positive stool samples for whom information was available, 20 (65%) had not been admitted to a healthcare institution in the year before, 13 (42%) had not used antibiotics during the 6 months before, and eight (26%) had neither risk factor. A separate analysis for patients whose samples were both toxin-positive and culture-positive produced similar results. Cultured C. difficile isolates belonged to 13 different PCR ribotypes, and 24% of the isolates were non-typeable (rare or new) PCR ribotypes. In conclusion, CO-CDI can affect all age groups, and many patients do not have known risk factors. Several PCR ribotypes not encountered in hospital-associated outbreaks were found, suggesting the absence of a direct link between outbreaks and community-onset cases.

[Recurrence of Clostridium difficile-associated diarrhoea prevented by the administration of a whey concentrate from specifically immunised cows; prospective study]. / Recidieven van Clostridium difficile-geassocieerde diarree voorkómen door toediening van een weiconcentraat van specifiek geïmmuniseerde koeien; prospectief onderzoek.

OBJECTIVE: To try to prevent recurrences of Clostridium difficile-associated diarrhoea (CDAD) by treatment with a specific neutralising secretory IgA-enriched whey-protein concentrate (40%) made from the milk of cows immunised with C. difficile and its toxins. DESIGN: Prospective, non-blinded, clinical cohort study. METHOD: In 2005-2006, 100 consecutive patients with CDAD received the whey concentrate for 2 weeks after completion of standard antibiotic therapy. For a period of 60 days after the start of the administration, the safety and preliminary efficacy of the whey concentrate were evaluated by means of a diary, blood determinations, active surveillance for adverse events, and the recurrence of CDAD. RESULTS: The whey concentrate was well tolerated and no safety issues were raised. Eleven out of 109 episodes (10%) were followed by a recurrence. After completion of the whey concentrate therapy, a positive test for faecal toxins or culture of C. difficile was predictive for the recurrence of CDAD (relative risk: 8.2 (95% CI: 1.04-64), and 4.7 (95% CI: 0.5-47), respectively). A positive faeces toxin during administration of the whey concentrate was also associated with an early recurrence of CDAD. CONCLUSION: Compared to historical and contemporary findings in control groups, the whey concentrate appeared to reduce the recurrence of CDAD by about 50%. However, the standard dose of the whey concentrate was probably not sufficient to fully neutralise the C. difficile toxins in faeces in all episodes.

Community-onset Clostridium difficile-associated diarrhoea not associated with antibiotic usage--two case reports with review of the changing epidemiology of Clostridium difficile-associated diarrhoea.

The emergence of hypervirulent strains of Clostridium difficile causing outbreaks in hospitals and nursing homes may result in a greater than before spread of the bacterium in the community. By consequence, the incidence of community-onset cases of Clostridium difficile-associated diarrhoea (CDAD) may increase outside known risk groups that are currently characterised by prior hospitalisation, prior antibiotic usage, older age and significant comorbidity. Here, we describe two case histories of community-onset CDAD. The first concerns a previously healthy young female with community-acquired CDAD without recent hospitalisation or antibiotic usage. The second patient developed diarrhoea in the community after discharge from a hospital where--in retrospect--an outbreak of CDAD occurred. The cases illustrate that CDAD should be included in the differential diagnosis of patients seeking care for community-onset diarrhoea, even in those without characteristic risk factors for CDAD.

The challenges of extrapulmonary presentations of sarcoidosis: A case report and review of diagnostic strategies.

A patient presenting with overweight, amenorrhea, diabetes insipidus, and oral, nasal, and pharyngeal inflammation was admitted to our hospital. Using a non-invasive approach, we were able to narrow the differential diagnosis down to a systemic lymphoproliferative or granulomatous disease, most likely sarcoidosis. This diagnosis was eventually confirmed by a biopsy of an enlarged tonsil. To our knowledge, tonsil biopsies have not been reported to be of help in the diagnostic strategy for systemic sarcoidosis. In this report, we review the possible diagnostic approaches and point out that the pharyngeal tonsils, if enlarged or inflamed, can be targeted to obtain tissue for histological confirmation.

Isolation of gonadal mutations in adult zebrafish from a chemical mutagenesis screen.

A mutagenesis screen was conducted on zebrafish using N:-ethyl N:-nitrosourea as a mutagen and an F2 crossing scheme to obtain homozygous mutants in the F3 generation. Whole abdomens of 3-mo-old F3 zebrafish progeny were fixed and mass-embedded in paraffin blocks. Blocks were cut with a microtome to obtain cross-sections of the entire body cavity that included the ovaries and testes. Slides of the cross-sections were analyzed for alterations in gonadal structure and gametogenesis and were compared with gonads of wild-type fish. A total of 125 mutagenized genomes in 81 families were screened and 11 mutations were observed that produced visible phenotypes in only one sex per family. Male mutations included testes without mature sperm that contained either predominantly spermatocytes or spermatogonia. Female mutations included ovaries containing 1) degenerating oocytes surrounded by hypertrophied follicle walls or stroma, 2) extrafollicular tissue proliferation, 3) proliferating postovulatory follicle walls, and 4) large numbers of degenerating preovulatory and postovulatory oocytes. While past screens on zebrafish have concentrated on early developmental mutations, the results of this study demonstrate for the first time that mutagenesis can be used with zebrafish to study reproduction in adult animals.

Conservation of steroidogenic acute regulatory (StAR) protein structure and expression in vertebrates.

Complementary DNAs for the open reading frames of the chicken, Xenopus and zebrafish StAR homologs were cloned along with a partial cDNA of the zebrafish homolog to MLN64, a StAR-related protein. A comparison of the amino acid sequences of piscine, amphibian, avian and mammalian StARs, indicates strong conservation of the protein across divergent vertebrate groups. On Northern blots probed with species specific StAR cDNAs, expression of StAR transcripts was observed in the ovary and adrenal of chicken, and the ovary, testis, kidney and head of zebrafish. The expression of StAR mRNA in various compartments of the hen ovary was consistent with the results of past studies on steroidogenesis; expression was first observed in follicles selected into the preovulatory hierarchy and was greatest in the largest preovulatory follicle. The expression of StAR mRNA was also consistent with aromatase expression in zebrafish ovaries. The conserved deduced protein sequence and expression pattern of StAR transcripts in chicken and zebrafish tissues, strongly suggest that StAR is also involved in the regulation of steroidogenesis in nonmammalian vertebrates.

Phenol/cresol degradation by the thermophilic Bacillus thermoglucosidasius A7: cloning and sequence analysis of five genes involved in the pathway.

Bacillus thermoglucosidasius A7 degraded phenol at 65 degrees C via the meta cleavage pathway. Five enzymes used in the metabolism of phenol were cloned from B. thermoglucosidasius A7 into pUC18. Nine open reading frames were present on the 8.1kb insert, six of which could be assigned a function in phenol degradation using database homologies and enzyme activities. The phenol hydroxylase is a two-component enzyme encoded by pheA1 and pheA2. The larger component (50kDa) has 49% amino acid identity with the 4-hydroxyphenylacetate hydroxylase of Escherichia coli, while the smaller component (19kDa) is most related (30% amino acid identity) to the styrene monoxygenase component B from Pseudomonas fluorescens. Both components were neccessary for activity. The catechol 2, 3-dioxygenase encoded by pheB has 45% amino acid identity with dmpB of Pseudomonas sp. CF600 and could be assigned to superfamily I, family 2 and a new subfamily of the Eltis and Bolin grouping. The 2-hydroxymuconic acid semialdehyde hydrolase (2HMSH), encoded by pheC, revealed the highest amino acid identity (36%) to the equivalent enzyme from Pseudomonas sp. strain CF600, encoded by dmpD. Based on sequence identity, pheD and pheE were deduced to encode the 2-hydroxypenta-2,4-dienoate hydratase (2HDH), demonstrating 45% amino acid identity to the gene product of cumE from Pseudomonas fluorescens and the acetaldehyde dehydrogenase (acylating) demonstrating 57% amino acid identity to the gene product of bphJ from Pseudomonas LB400.