Acute abdominal pain: a challenging diagnosis.

We hereby describe a case of an acutely ill 41-year-old male without any medical history who presented with an acute abdomen in the emergency department. An abdominal CT showed a dissection of the coeliac trunk and infarction of the spleen. Because of a presumed diagnosis of vasculitis he was started on high dose IV steroids. However, after additional testing the diagnosis of segmental arteriolar Mediolysis (SAM) was made. In this case report we describe the presentation, diagnosis, treatment and follow-up of this patient and provide the readers with background about common differential diagnosis and criteria for diagnosing SAM.

Care for adult non-ICU Covid-19 patients: early experiences from a Belgian tertiary care centre.

The current Covid-19 outbreak poses many challenges on hospital organisation and patient care. Our hospital lies at the epicentre of the Belgian epidemic. On April 1st, a total of 235 Covid-19 patients had been admitted to our hospital. This demanded an unprecedented adaptation of our hospital organisation, and we have met many clinical issues in the care for Covid-19 patients. In this article, we share our experience in the handling of some of the practical and organisational issues in the care for Covid-19 patients.

Mycobacterial skin and soft tissue infections: TB or not TB?

Non-tuberculous mycobacteria are a known cause of skin and soft tissue infections. However, only too often it takes inordinately long to arrive at the appropriate diagnosis and start treatment. Actively searching for predilection factors, exposure risks and specific clinical clues may speed up the diagnostic process. Deep tissue biopsy cultures are indispensable to determine the species and strain of mycobacterium, with important consequences for treatment. Less well known as a causative agent of prolonged tenosynovitis is Mycobacterium tuberculosis. We present a case series and performed a literature search concerning mycobacterial tenosynovitis.

Hepatic schistosomiasis with massive splenomegaly: a case report and literature review.

Schistosomiasis is a parasitic disease caused by Schistosoma species. Intestinal and hepatic schistosomiases are the most common forms of chronic disease. We describe a case of a 26-year old patient from Eritrea who was referred to our hospital with abdominal pain and diarrhea. The diagnosis of hepatosplenic schistosomiasis was made by liver biopsy and the patient was treated with praziquantel. Hepatic schistosomiasis is characterised by deposition of schistosomal eggs in the liver which results in a host cell immune response and leads to granuloma formation and neoangiogenesis. This is hallmarked by different grades of periportal fibrosis with portal hypertension leading to splenomegaly. Normal liver architecture is preserved and periportal fibrosis can be reversible if treated adequately and timely. With a recent native schistosomiasis cluster report from France and the expected influx to Europe of persons from regions endemic for schistosomiasis, increased awareness of this disease in healthcare practitioners is needed. We review the epidemiology, pathogenesis, clinical presentation and treatment of schistosomiasis.

Prevalence of drug-drug interactions in the era of HIV integrase inhibitors: a retrospective clinical study.

BACKGROUND: Antiretroviral agents pose a high risk for drug-drug interactions (DDIs), mainly but not limited to being a substrate, inducer or inhibitor of P450 cytochrome enzymes. In part metabolised by other pathways, integrase inhibitors might show a more favourable profile. The aim of this study was to investigate the prevalence of DDIs in daily clinical practice for patients starting different antiretroviral treatment (ART) regimens. METHODS: All patients starting ART in our centre from January 2009 to April 2016 were included. All prescribed co-medications since the start of ART were recorded retrospectively from the medical files and screened for DDIs using the Liverpool HIV drug interaction database. Only DDIs between antiretroviral and non-antiretroviral drugs were considered. RESULTS: We included 145 patients, of which 42% were on an integrase inhibitor-based regimen, mainly dolutegravir and elvitegravir. Of the patients, 78% (n = 113) took co-medication. Potential DDIs were seen in 63% of the patients with co-medication; contraindicated prescriptions were detected in 1%. Protease inhibitor-based ART was a risk factor for DDI (odds ratio (OR) 2.57; 95% confidence interval (CI) 1.06-6.19), in contrast to non-nucleoside reverse transcriptase inhibitor-based ART (OR 0.77; 95% CI 0.32-1.84). Concerning integrase inhibitors, a significantly lower risk was seen with dolutegravir-based treatment (OR 0.35; 95% CI 0.15-0.82), though not for elvitegravir-based ART (OR 2.51; 95% CI 0.66-9.58). CONCLUSIONS: ART regimens pose a dissimilar risk for drug-drug interactions in clinical practice. Regarding the use of integrase inhibitors, a significantly lower risk was seen with dolutegravir-based treatment.

Managing a cluster outbreak of psittacosis in Belgium linked to a pet shop visit in The Netherlands.

In July 2013, a Belgian couple were admitted to hospital because of pneumonia. Medical history revealed contact with birds. Eleven days earlier, they had purchased a lovebird in a pet shop in The Netherlands. The bird became ill, with respiratory symptoms. The couple's daughter who accompanied them to the pet shop, reported similar symptoms, but was travelling abroad. On the suspicion of psittacosis, pharyngeal swabs from the couple were taken and sent to the Belgian reference laboratory for psittacosis. Culture and nested polymerase chain reaction (PCR) tests were positive for the presence of Chlamydia psittaci, and ompA genotyping indicated genotype A in both patients. The patients were treated with doxycycline and the daughter started quinolone therapy; all three recovered promptly. Psittacosis is a notifiable disease in Belgium and therefore local healthcare authorities were informed. They contacted their Dutch colleagues, who visited the pet shop. Seven pooled faecal samples were taken and analysed using PCR by the Dutch national reference laboratory for notifiable animal diseases for the presence of Chlamydia psittaci. Four (57%) samples tested positive, genotyping revealed genotype A. Enquiring about exposure to pet birds is essential when patients present with pneumonia. Reporting to health authorities, even across borders, is warranted to prevent further spread.

The diagnostic tangle of pyoderma gangrenosum: a case report and review of the literature.

This report describes a 55-year-old patient with the rare inflammatory dermatosis pyoderma gangrenosum. It is an often misdiagnosed condition of unclear origin and pathogenesis. There is an association with underlying systemic disorders such as inflammatory bowel disease, haematological disorders, rheumatological disease or solid malignancies, although this last association is still under investigation. The diagnosis can be challenging and treatment depends upon the severity of the lesions. The long-term prognosis is unpredictable.

Recent insights into the pathogenesis of type AA amyloidosis.

The amyloidoses are a group of life-threatening diseases in which fibrils made of misfolded proteins are deposited in organs and tissues. The fibrils are stable, insoluble aggregates of precursor proteins that have adopted an antiparallel beta-sheet structure. In type AA, or reactive, amyloidosis, the precursor protein of the fibrils is serum amyloid A (SAA). SAA is a 104-amino-acid protein that is produced in the liver in response to proinflammatory cytokines. Although the protein that is produced by the liver contains 104 amino acids, only the N-terminal 66-76 amino acids are found in amyloid fibrils. Furthermore, SAA has been shown to have an alpha-helical structure primarily. Thus, for SAA to be incorporated into an amyloid fibril, two processes have to occur: C-terminal cleavage and conversion into a beta-sheet. Only a minority of patients with elevated SAA levels develop amyloidosis. Factors that contribute to the risk of amyloidosis include the duration and degree of SAA elevation, polymorphisms in SAA, and the type of autoinflammatory syndrome. In the Hyper-IgD syndrome, amyloidosis is less prevalent than in the other autoinflammatory diseases. In vitro work has shown that the isoprenoid pathway influences amyloidogenesis by farnesylated proteins. Although many proteins contain domains that have a potential for self-aggregation, amyloidosis is only a very rare event. Heat shock proteins (HSPs) are chaperones that assist other proteins to attain, maintain, and regain a functional conformation. In this review, recent insights into the pathogenesis of amyloidosis are discussed, in addition to a new hypothesis for a role of HSPs in the pathogenesis of type AA.

Cathepsin D activity protects against development of type AA amyloid fibrils.

BACKGROUND: The extracellular, fibrillar deposits of reactive (secondary) amyloidosis are composed of amyloid A (AA) protein, a proteolytically derived fragment of the acute phase protein serum amyloid A (SAA). While complete degradation of SAA precludes amyloid formation, limited cleavage which generates AA protein is considered part of the pathogenic mechanism. MATERIALS AND METHODS: In this study, we investigated SAA degradation by lysosomal enzymes cathepsins B, D, and K, and assessed the impact of cathepsin activity on AA amyloid formation in a cell culture model using peripheral blood mononuclear cells from healthy volunteers. RESULTS: Lysates of human mononuclear cells were capable of degrading SAA. Degradation was significantly reduced by inhibition of cathepsin D with pepstatin A. Inhibition of cathepsin B or cathepsin K, however, had no effect. The SAA fragment pattern generated by mononuclear cell lysates was similar to that produced by incubating SAA with purified human cathepsin D. Consistent with in vitro findings, amyloid formation in human monocyte cultures was increased by 43% when cathepsin D was inhibited, but remained unaffected by inhibition of cathepsin B or cathepsin K. CONCLUSION: These data provide evidence that cathepsin D but not cathepsin B or cathepsin K is physiologically important in SAA degradation and hence in preventing SAA from accumulating and serving as precursor of AA amyloid fibrils.

Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.

OBJECTIVE: Genetic polymorphisms in serum amyloid A (SAA) have been shown to substantially influence the risk of developing type AA amyloidosis. Recently, a role for MMP-1 has been suggested in the pathogenesis of AA amyloidosis. Therefore, we investigated if the SAA1 isotypes are differentially degraded by MMP-1. METHODS: Degradation of different SAA isotypes by MMP-1 was assessed by immunoblotting. MALDI-TOF mass spectrometry was used to identify degradation fragments. RESULTS: We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57. CONCLUSION: These results may explain the higher risk of amyloidosis in patients with a SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype. In addition, the impaired degradation of SAA1.5 by MMP-1 could also explain the higher serum SAA concentrations in persons with a SAA1.5 genotype.

Lovastatin inhibits formation of AA amyloid.

Amyloid A (AA) amyloidosis is a severe complication of many chronic inflammatory disorders, including the hereditary periodic fever syndromes. However, in one of these periodic fever syndromes, the hyper IgD and periodic fever syndrome, amyloidosis is rare despite vigorous, recurring inflammation. This hereditary syndrome is caused by mutations in the gene coding for mevalonate kinase, an enzyme of the isoprenoid pathway. In this study, we used a cell culture system with human monocytes to show that inhibition of the isoprenoid pathway inhibits amyloidogenesis. Inhibition of the isoprenoid pathway by lovastatin resulted in a dose-dependent reduction of amyloid formed [53% at 10 microM (P=0.01)] compared with mononuclear cells that are exposed only to serum AA. The inhibitory effects of lovastatin are reversible by addition of farnesol but not geranylgeraniol. Farnesyl transferase inhibition also inhibited amyloidogenesis. These results implicate that the isoprenoid metabolism could be a potential target for prevention and treatment of AA amyloidosis.

Beneficial response to anakinra and thalidomide in Schnitzler's syndrome.

BACKGROUND: Schnitzler's syndrome is an inflammatory disorder characterised by chronic urticarial rash and monoclonal gammopathy, accompanied by periodic fever, arthralgia or arthritis, and bone pain. The cause and treatment are still unknown. OBJECTIVE: To assess treatment with thalidomide and an interleukin 1 receptor antagonist, anakinra, in Schnitzler's syndrome. CASE REPORTS: Three patients with Schnitzler's syndrome are described, one with IgM gammopathy, two with IgG type. In one patient, thalidomide induced complete remission, but was stopped because of polyneuropathy. Anakinra 100 mg daily in all three patients led to disappearance of fever and skin lesions within 24 hours. After a follow up of 6-18 months, all patients are free of symptoms. CONCLUSION: Anakinra proved to be effective in three patients with Schnitzler's syndrome. This treatment is preferable to thalidomide, which induced a complete remission in one of our patients, as it has fewer side effects.

Hereditary periodic fever and reactive amyloidosis.

Hereditary periodic fever syndromes (HPF) are a group of diseases characterised by recurrences of fever and inflammation separated by symptom-free intervals. Familial Mediterranean fever (FMF) is the most frequent entity within this group of disorders which further consists of hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS). In recent years the causative genes have been identified. Reactive amyloidosis is a severe complication of HPFs. This is caused by deposition of fibrils that consist of the proteolytically cleaved acutephase protein serum amyloid A (SAA). Several factors have been identified that modulate the risk for developing amyloidosis, including SAA concentrations, polymorphisms in the SAA gene and ethnic origin. Furthermore, the risk of developing amyloidosis varies widely between the different HPFs. Colchicine is the cornerstone in the management of FMF, as it reduces the severity and frequency of attacks and is also effective in preventing amyloidosis. In the other HPFs, the introduction of anticytokine-based therapies is a promising new option in treating these inflammatory conditions and they potentially can prevent amyloidosis.

Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model.

BACKGROUND: Hyper-IgD and periodic fever syndrome (HIDS) is an hereditary autoinflammatory syndrome, characterised by recurrent inflammatory attacks. Treatment of HIDS is difficult, although simvastatin is beneficial and etanercept might be effective. Studying the treatment of a rare periodic syndrome is complicated by the varying frequency and severity of symptoms and low prevalence. Our aim was to develop a system of clinical observations to evaluate effectiveness of treatment-on-demand. METHODS: Seven fever episodes in three HIDS patients were monitored, with and without administration of etanercept or anakinra. We developed a clinical score, which includes 12 symptoms. In one patient, inflammatory attacks were provoked by vaccination. RESULTS AND CONCLUSIONS: At the onset of an attack, all patients reported a clinical score between 20 and 25. The score was used to quantify severity and define the end of an attack. Reproducible monitoring of inflammatory episodes was difficult, even in this pilot study. The effect of early administration of etanercept was variable. In one patient, a fever episode could be readily provoked within 12 to 24 hours by vaccination. In this patient, the IL-1ra analogue anakinra was more successful in aborting the inflammatory attack than etanercept. We propose that this vaccination model will allow evaluation of treatment-on-demand in a controlled setting.

Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome.

BACKGROUND: Hyper-IgD and periodic fever syndrome (HIDS) is an autosomal recessively inherited disorder characterized by recurrent episodes of fever and inflammation. Unlike other chronic inflammatory conditions, amyloidosis is very rare in HIDS. For deposition of amyloid of the AA type, high concentrations of SAA are a prerequisite, together with certain SAA1 gene polymorphisms. The SAA1.1 genotype predisposes for amyloidosis, while SAA1.5 genotype exerts a protective effect. AIM OF THE STUDY: To determine if SAA concentrations and SAA1 gene polymorphisms could explain the virtual absence of amyloidosis in HIDS patients. METHODS: We measured SAA and CRP concentrations in serum of 20 HIDS patients during an attack and during the asymptomatic phase. Genotype of SAA1 gene was determined in 60 HIDS patients. RESULTS: SAA serum concentrations during attacks were very high (median 205 mg/l; range 75-520 mg/l, normal <3.1 mg/l). During attack-free periods 45% of patients still had elevated SAA concentrations. The distribution of the genotype of SAA1 gene in HIDS was similar to healthy controls (SAA1.1 0.41 vs. 0.50 p=0.32). CONCLUSION: Patients with HIDS have high SAA during attacks and show sub-clinical inflammation when asymptomatic. The low incidence of amyloidosis cannot be explained by a predominance of non amyloidogenic SAA related genotypes.

Hypogammaglobulinaemia: cumulative experience in 49 patients in a tertiary care institution.

In this paper, clinical data of 49 adult patients with agammaglobulinaemia (syn. hypogammaglobulinaemia), 15 cases of X-linked agammaglobulinaemia (XLA) and 34 of common variable immunodeficiency (CVID) are reviewed. Although immunoglobulin substitution largely abolished life-threatening respiratory tract infections, considerable infectious and non-infectious morbidity was still encountered in these patients. Almost all patients suffered from chronic or recurrent upper and lower airway infections, mainly caused by Haemophilus influenzae and pneumococci. The lower respiratory tract infections led to cumulative damage to the respiratory tract, especially in XLA patients. Also the incidence of infections outside the respiratory tract (giardiasis, Campylobacter jejuni infections) was more common in XLA patients than in CVID patients. Nodular lymphoid hyperplasia was only found in CVID. A variety of other non-infectious complications were seen especially in CVID. Neoplastic complications occurred in nine patients (two cases of thymoma, two colorectal cancer, one gastric carcinoma, two haematological malignancies, two cases of skin cancer). Six patients died (five XLA patients and one CVID patient, from infectious and non-infectious causes).