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COVID-19 is caused by SARS-CoV-2. Although pulmonary manifestations have been identified as the major symptoms, several hematological abnormalities have also been identified. This review summarizes the reported hematological abnormalities (changes in platelet, white blood cell, and hemoglobin, and coagulation/fibrinolytic alterations), explores their patho-mechanisms, and discusses its management. Common hematological abnormalities in COVID-19 are lymphopenia, thrombocytopenia, and elevated D-dimer levels. These alterations are significantly more common/prominent in patients with severe COVID-19 disease, and thus may serve as a possible biomarker for those needing hospitalization and intensive care unit care. Close attention needs to be paid to coagulation abnormalities, and steps should be taken to prevent these occurring or to mitigate their harmful effects. The effect of COVID-19 in patients with hematological abnormalities and recognized hematological drug toxicities of therapies for COVID-19 are also outlined.

Star fruit (Averrhoa carambola), a popular fruit in many parts of the world, is considered to have many beneficial nutritional and medicinal effects. However, harmful nephrotoxic and neurotoxic effects have also been described. In this review, we have discussed the reported beneficial effects of star fruit, explored the potential mechanisms for such beneficial effects, and outline factors that may affect the safe level of consumption. The beneficial effects include the following: antioxidant (mediated via L‐ascorbic acid, epicatechin, and gallic acid), hypoglycemic (mediated via high fiber levels and 2‐dodecyl‐6‐methoxycyclohexa‐2,5‐diene‐1,4‐dione), hypotensive (mediated via apigenin), hypocholesterolemic (mediated via micronized fiber), anti‐inflammatory, anti‐infective, antitumor effects, and immune‐boosting effects. The presence of chronic kidney disease, gastroenteropathies, chronic pancreatitis, dehydration, consumption on an empty stomach, and higher concentration of oxalate in fruit/juice consumed predisposes to toxicity. The level of ingestion at which the beneficial effects transition to nephrotoxicity and neurotoxicity is still to be accurately ascertained. Furthermore, the relationship between the amount of star fruit ingested and the severity of toxicity is not certain and warrants further study., The nutritional and medical properties of star fruit include antioxidant, hypoglycemic, hypotensive, hypocholesterolemic, anti‐inflammatory, anti‐infective, and antitumor effects. However, majority of these findings are extrapolated from in vitro or animal studies. On the other hand, star fruit ingestion has also been shown to cause nephrotoxicity and neurotoxicity. Future studies should focus on the level of ingestion and conditions at which the beneficial effects become toxic.

Dengue infections are increasing globally and account for significant morbidity and mortality. Severe dengue results in microvascular changes and coagulopathy that may make surgical intervention risky and the overall surgical management challenging. We outline the potential surgical manifestations and complications following dengue infections and describe the clinical, pathogenetic, diagnostic, and treatment aspects of dengue and surgical patients. The main surgical presentations were acute cholecystitis, acute pancreatitis, acute appendicitis, splenic rupture, bowel perforation, gastrointestinal bleeding, and hematomas. Dengue may also mimic an acute abdomen without any true surgical complications. A majority were treated nonoperatively. Misdiagnosis and unnecessary surgical intervention resulted in poor outcomes. Better knowledge of the potential surgical complications would help in early diagnosis, treatment, and referral to specialized centers and thus improve outcomes. A high degree of suspicion of dengue fever is necessary when patients in a dengue-epidemic area present with acute abdomen or bleeding manifestations. In endemic areas, early dengue antigen testing and abdominal imaging before surgical intervention may help in the diagnoses. Multidisciplinary team involvement with case-by-case decision-making is needed for optimal care.

Dengue is an important global health problem and is endemic in many developing and developed countries. Transmission of dengue may occur in several ways and information on transfusion-transmitted dengue is limited. We conducted a literature search on transfusion-related dengue using the PubMed, Scopus, Embase and Google Scholar databases and have summarized the findings. A number of apparently healthy blood donors have been found to be infected with the dengue virus (DENV) and thus may transmit the virus onto recipients of this blood. It is not possible to identify and exclude such donors at the donor selection stage and thus reliable screening tests should be available in highly endemic areas to ensure a safe blood supply.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, emerged in Wuhan, China in December 2019. It has now spread to all parts of the world and as of 26th July 2020, more than 16 million cases and over 600,000 deaths have been reported. The commonest presentation is respiratory in nature with non-productive cough, fever and shortness of breath. Some COVID-19 patients have had atypical or unusual presentations involving the neurological, metabolic, gastrointestinal, renal, haematological, cutaneous and cardiovascular systems. In this mini-review, we have outlined the main atypical or unusual clinical presentations of COVID-19.

Background The role of steroids in dengue infection (DI) remains uncertain. Methods A retrospective chart review was conducted on patients ≥18 y of age diagnosed with DI based on positivity for dengue non-structural antigen 1 or immunoglobulin M between October 2017 and November 2018. Results Hydrocortisone was administered to 106 of 406 patients. DI with warning signs occurred in nine patients (9.5%) in the steroid cohort and eight patients (2.5%) in the non-steroid group. The incidence of severe DI, bleeding and admission duration were similar between the groups. Conclusions Our study shows no significant benefit of empirical steroids in DI.

Background:It is not well-understood why symptom severity varies between patients with peanut allergy (PA).Objective:To gain insight into the clinical profile of subjects with mild-to-moderate and severe PA, and investigate individual and collective predictive accuracy of clinical background and IgE to peanut extract and components for PA severity.Methods:Data on demographics, patient history and sensitization at extract and component level of 393 patients with probable PA (symptoms ≤ 2 h + IgE sensitization) from 12 EuroPrevall centers were analyzed. Univariable and penalized multivariable regression analyses were used to evaluate risk factors and biomarkers for severity.Results:Female sex, age at onset of PA, symptoms elicited by skin contact with peanut, family atopy, atopic dermatitis, house dust mite and latex allergy were independently associated with severe PA; birch pollen allergy with mild-to-moderate PA. The cross-validated AUC of all clinical background determinants combined (0.74) was significantly larger than the AUC of tests for sensitization to extract (0.63) or peanut components (0.54–0.64). Although larger skin prick test wheal size, and higher IgE to peanut extract, Ara h 1 and Ara h 2/6, were associated with severe PA, and higher IgE to Ara h 8 with mild-to-moderate PA, addition of these measurements of sensitization to the clinical background model did not significantly improve the AUC.Conclusions:Models combining clinical characteristics and IgE sensitization patterns can help establish the risk of severe reactions for peanut allergic patients, but clinical background determinants are most valuable for predicting severity of probable PA in an individual patient.

Coronavirus disease 2019 (COVID-19), a respiratory viral infection, has affected more than 78 million individuals worldwide as of the end of December 2020. Previous studies reported that severe acute respiratory syndrome coronavirus 1 and Middle East respiratory syndrome–related coronavirus infections may affect the gastrointestinal (GI) system. In this review we outline the important GI manifestations of COVID-19 and discuss the possible underlying pathophysiological mechanisms and their diagnosis and management. GI manifestations are reported in 11.4–61.1% of individuals with COVID-19, with variable onset and severity. The majority of COVID-19-associated GI symptoms are mild and self-limiting and include anorexia, diarrhoea, nausea, vomiting and abdominal pain/discomfort. A minority of patients present with an acute abdomen with aetiologies such as acute pancreatitis, acute appendicitis, intestinal obstruction, bowel ischaemia, haemoperitoneum or abdominal compartment syndrome. Severe acute respiratory syndrome coronavirus 2 RNA has been found in biopsies from all parts of the alimentary canal. Involvement of the GI tract may be due to direct viral injury and/or an inflammatory immune response and may lead to malabsorption, an imbalance in intestinal secretions and gut mucosal integrity and activation of the enteric nervous system. Supportive and symptomatic care is the mainstay of therapy. However, a minority may require surgical or endoscopic treatment for acute abdomen and GI bleeding.

ObjectiveWe aimed to describe the clinical characteristics of chronic pancreatitis (CP) and patient quality of life (QOL) in a resource-limited setting.MethodsWe performed a cross-sectional study including patients with clinical and radiological features of CP. We collected clinical data and assessed QOL using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire.ResultsWe included 103 patients (median age 44 years, 84 men). Median age at symptom onset was 36 (4–78) years. Around 70% of patients had diabetes mellitus and 62.1% had consumed alcohol; 36 (35%) were current smokers. The mean overall global QOL score was 68.7. Most patients (91.3%) sought treatment from multiple centers. Nineteen (18.5%) had pancreatic stone disease, 38 (36.9%) had persistent abdominal pain (median severity 7.8/10, 59 (57.3%) had steatorrhea, and 56 (54.4%) had jaundice. Poor QOL was significantly associated with weight loss, loss of appetite, and intractable pain. No correlation with age, sex, or alcohol consumption was noted.ConclusionA considerable proportion of patients with CP had troublesome symptoms. Intractable pain, loss of appetite, and weight loss were significantly associated with poor QOL. Further assessment is needed of patients’ psychosocial well-being and its association with QOL.

Background Ultrasound (US) is an investigation available in many acute care settings. Thrombocytopenia is a well-described complication of dengue infection and has been shown to correlate with disease severity. The purpose of this study was to assess the utility of admission ultrasonography in predicting thrombocytopenia and disease severity in patients infected with dengue virus. Methods Data were collected prospectively on 176 patients (male, n=86; female, n=90) admitted to the Nawaloka Hospital, Sri Lanka with dengue infection between December 2016 and August 2018. All patients had an US scan on admission and disease severity was determined using the World Health Organization 2009 classification. Results There were 106 (60.2%) cases of dengue with/without warning signs and 70 (39.8%) cases of severe dengue. Patients with an abnormal US on admission were more likely to have severe dengue. Gallbladder wall thickening was the most common US abnormality. Abnormal US findings significantly correlated with more pronounced thrombocytopenia from day 2 of admission. Conclusions An abnormal US scan on admission can aid in identification of patients at risk of developing severe dengue and can be used as a novel clinical tool to identify patients at risk of severe thrombocytopenia.

Introduction: Analyzing dengue disease patterns from different parts of the world should help us formulate more evidence based treatment guidelines and appropriately allocate limited healthcare resources. Therefore, we described the disease characteristics of hospitalised pediatric patients with dengue infections from Sri Lanka during the 2017 dengue epidemic. Methods: Clinical and biochemical characteristics of pediatric dengue patients treated at a secondary care hospital in Sri Lanka from 1 June 2017 to 31 August 2017 were analyzed. Our findings were compared with previous pediatric dengue studies in Asia. Results: A total of 305 patients (number of males = 184(60%); mean age = 8.6 years) were analyzed. DF (Dengue Fever)—245 (80.3%), DHF (Dengue Hemorrhagic fever)—I:52 (17%), DHF—II:7 (2.3%), and DHF—III:1 (0.3%). Significant associations were found between DHF and abdominal symptoms/signs and overt bleeding manifestations ( P Conclusion: In Sri Lankan pediatric dengue patients, we found abdominal symptoms and signs, decreased WBC and platelet counts and bleeding manifestations were to be significantly associated with DHF. Liver enzyme derangement did not predict DHF. The time of onset of the critical phase was difficult to predict due to the considerable variations noted.

Objective Current guidelines on rectal cancer (RC) management recommend pre-operative MRI for loco-regional staging and CT for staging of metastases. This allows appropriate selection of patients for chemo-radiotherapy (CRT). However, MRI is not freely available in many low-income countries. We assessed the status of pre-operative imaging for RC in Sri Lanka and evaluated the performance of CT in RC staging. Results A pre-tested interview-administered questionnaire was used to assess the pre-operative use of MRI and CT in RC. CT findings from 37 RC patients were then compared with histopathology findings. Of the 64 surgeons interviewed, 57 (89.1%) did not request an MRI for their RC patients. Reasons cited included limited availability and long waiting times due to competing health needs. A CT was requested by all. In RC, the overall accuracy of CT for T staging was 43.2% and 29.7% of T1–T2 tumours were over-staged as T3. The overall accuracy of CT for regional lymph node staging was 70.3%. In summary, CT alone is not suitable for RC staging in any setting. It leads to over-staging and patients may thus receive unnecessary CRT. Steps must be taken to improve access to pre-operative MRI among Sri Lankan RC patients.

In recent times, star fruit (Averrhoa carambola) nephrotoxicity and neurotoxicity have been increasingly reported, both in individuals with pre-existing renal disease and those with previously normal renal function. We summarise the clinical findings of star fruit toxicity in humans and outline the important pathogenetic insights provided by animal studies. Google Scholar, EMBASE, Scopus and PubMed were searched from 1995 through July 2020 for case reports/series on renal or neurological manifestations of star fruit toxicity in humans and mechanisms of star fruit toxicity in animal studies. Ten case series and 28 case reports in humans (total number of individuals=136) were included and 8 animal studies were analysed. Ninety-four (69.1%) patients had prior renal impairment. Renal histology showed acute oxalate nephropathy with tubulointerstitial nephritis or tubular necrosis. Neurotoxicity manifestations ranged from hiccups to status epilepticus. Oxalate and caramboxin are considered the main substances causing nephrotoxicity and neurotoxicity. Caramboxin inhibits GABA binding and activates the glutamatergic receptors. Haemodialysis improved outcomes in neurotoxicity. Nephrotoxicity and neurotoxicity need to be looked for with star fruit toxicity, both in individuals with abnormal or normal renal function. Once star fruit intoxication is identified, early renal replacement therapy should be considered. Further studies on the mechanisms of star fruit toxicity are needed.

COVID-19, a respiratory viral infection, has affected more than 10 million individuals worldwide. Common symptoms include fever, dry cough, fatigue and shortness of breath. Some patients show neurological manifestations such as headache, dizziness, cerebrovascular disease, peripheral nerve and muscle symptoms and smell and taste impairment. In previous studies, SARS-CoV-1 and MERS-CoV were found to affect the nervous system. Given the high similarity between SARS-CoV-1 and SARS-CoV-2, effects on the nervous system by SARS-CoV-2 are a possibility. We have outlined the common neurological manifestations in COVID-19 (information are up-to-date as of June 2020) and discussed the possible pathogenetic mechanisms and management options.

Introduction: Due to the shortcomings in the 1997-World Health Organisation (WHO) dengue case classification (DCC), a revised classification was proposed in 2009. This study was aimed to assess the clinical usefulness of the two classifications during a large dengue epidemic. Methodology: Clinical data of dengue patients admitted to selected units at National Hospital of Sri Lanka, Panadura Base Hospital and Nawaloka Hospital Colombo between June and August 2017 were collected prospectively. Cases were classified using the 1997 and 2009 WHO DCCs. Results: 1,878 patients [adult = 1,573 (83.8%)] were studied. Based on 1997-WHO-DCC-DF (Dengue Fever): 1,316 (70.1%), DHF (Dengue Haemorrhagic Fever) -1: 468 (24.9%), DHF-2: 86 (4.6%) and DHF-3: 8 (0.4%). Based on 2009-WHO-DCC–Dengue with warning signs (WS): 1647 (87.7%), Dengue without WS: 231 (12.3%) and severe dengue (SD): 41 (2.18%). A total of 1,088 (82.7%) DF and 559 (99.5%) DHF patients developed WS. Of those without WS, 228 (17.3%) were DF patients and 3 (0.5%) were DHF patients. Three (0.23%) DF and 38 (6.76%) DHF patients had SD. All SD patients had WS. The level of agreement between the two systems of classification was poor (Kappa = - 0.035, p < 0.001). Conclusions: The 2009-WHO-DCC was more useful than 1997-WHO-DCC in predicting dengue disease severity as few DF patients also had SD. Furthermore, the presence of WS identified patients with SD. However, the 2009-WHO-DCC may not suit the resource limited countries as WS are non-specific, and lack of diagnostic tests can result in case overload.

BACKGROUND: Walnut allergy is common across the globe, but data on the involvement of individual walnut components are scarce.OBJECTIVES: To identify geographical differences in walnut component sensitization across Europe, explore cosensitization and cross-reactivity, and assess associations of clinical and serological determinants with severity of walnut allergy.METHODS: As part of the EuroPrevall outpatient surveys in 12 European cities, standardized clinical evaluation was conducted in 531 individuals reporting symptoms to walnut, with sensitization to all known walnut components assessed in 202 subjects. Multivariable Lasso regression was applied to investigate predictors for walnut allergy severity.RESULTS: Birch-pollen-related walnut sensitization (Jug r 5) dominated in Northern and Central Europe and lipid transfer protein sensitization (Jug r 3) in Southern Europe. Profilin sensitization (Jug r 7) was prominent throughout Europe. Sensitization to storage proteins (Jug r 1, 2, 4, and 6) was detected in up to 10% of subjects. The walnut components that showed strong correlations with pollen and other foods differed between centers. The combination of determinants best predicting walnut allergy severity were symptoms upon skin contact with walnut, atopic dermatitis (ever), family history of atopic disease, mugwort pollen allergy, sensitization to cat or dog, positive skin prick test result to walnut, and IgE to Jug r 1, 5, 7, or carbohydrate determinants (area under the curve = 0.81; 95% CI, 0.73-0.89).CONCLUSIONS: Walnut-allergic subjects across Europe show clear geographical differences in walnut component sensitization and cosensitization patterns. A predictive model combining results from component-based serology testing with results from extract-based testing and information on clinical background allows for good discrimination between mild to moderate and severe walnut allergy.

Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Background Hyper IgE recurrent infection syndrome (HIES) is a rare immune deficiency, characterized by recurrent staphylococcal skin and lung abscesses, pneumonia and increased IgE levels. The majority of autosomal dominant HIES (AD HIGE) is due to hypomorphic mutations in the signal transducer and the activator of transcription 3 (STAT3) gene. Case presentation Five patients were diagnosed with HIES, based on the clinical criteria and scoring system developed at the National Institutes of Health (NIH), USA. The STAT3 gene was sequenced and previously described mutations were identified in all five patients. We compare the clinical features of our patients with those from Asia, Europe and the US. Conclusion Even though the number of patients is limited, there are some clinical differences in patients from South Asia compared to European and even East Asian patients. However, the mutations detected are located at hot spots seen in western and Asian patients with AD HIGE.

Objectives There has been a global increase in the incidence and prevalence of NAFLD. We assessed the knowledge and awareness of NAFLD among gastroenterology doctors in three state sector hospitals. Results 80 medical officers and 58 post-graduate trainee doctors/consultants responded. 110 (79.7%) considered NAFLD a major health problem whilst 97 (70.3%) thought the prevalence of NAFLD was 10–40%. 52.9% saw 12–24 patients with NAFLD/year. A vast majority knew the risk factors for NAFLD: 127 (92.7%) diabetes mellitus, 135 (97.8%) Obesity, 132 (95.7%) Dyslipidemia and 87 (63%) PCOS. The methods for diagnosis were recognized by: USS 132 (95.7%), MRI 34 (24.6%), transient elastography 23 (16.7%) and liver biopsy 88 (63.8%) while, 53 (38.4%) recognized the non-invasive methods available for diagnosis. The trends in referral were lower than expected: 85 (61.6%) refer to a Gastroenterologist/Physician, 53 (38.4%) to a Gym, 67 (48.6%) to a weight loss clinic and 45 (32.6%) to a dietician. Significantly more postgraduate trainee doctors: recognized the availability of non-invasive investigations for NAFLD (P = 0.01) and read guidelines on NAFLD (P = 0.02) compared to non-trainee doctors. As a whole, a majority (57.2%) had not attended a lecture or read a guideline on NAFLD. The barriers for management included: lack of confidence 70 (50.7%) and time constraints 58 (42%). Electronic supplementary material The online version of this article (10.1186/s13104-018-3673-2) contains supplementary material, which is available to authorized users.

Invasive dermatophyte infection, with extension beyond the dermis, in immunocompetent hosts is exceptionally rare. Dermatophytes are keratinophilic and are usually confined to the stratum corneum, hair and nails. Susceptibility to dermatophyte infections is incompletely understood, but inherited mutations in key signalling pathways of the innate immune system have been identified. We report the first case of an invasive dermatophyte infection associated with abrupt onset of a prurigo-induced pseudoperforation and a loss-of-function mutation in signal transducer and activator of transcription 3 (STAT3).

Background Sri Lanka experienced its largest dengue epidemic in 2017. This study describes the disease pattern of adult dengue patients from two hospitals in Sri Lanka. Methods Demographic, clinical and investigation findings of adult dengue patients admitted to the two hospitals from June to August 2017 were collected and analysed. Results A total of 1167 patients (777 males [66.2%], mean age 32.9 y) were studied. There were 775 (66.4%) patients with dengue fever (DF), 334 (28.6%) with dengue haemorrhagic fever grade I, 54 (4.6%) with DHF grade II and 4 (0.3%) with DHF grade III. DHF was significantly associated with abdominal symptoms/signs and bleeding manifestations (p

Diagnostic and therapeutic reagents are unavailable for anaphylaxis arising from stings by Apis dorsata. Venom profiles and cross-reactivity of A. dorsata and Apis mellifera were compared, to ascertain whether venom of A. mellifera can be used for diagnosis in A. dorsata allergy. Both venom profiles were similar by High Performance Liquid Chromatography and SDS-PAGE. Sera of 29 of 30 (96.7%) patients with anaphylaxis to A. dorsata stings had IgE to the phospholipase-2 (PLA2) doublet (15 and 16 kDa) of A. dorsata venom by immunoblot, compared to 26 of 30 (86.7%) with the PLA2 of A. mellifera and a purified preparation of PLA2. Twelve patients (40%) with severe anaphylaxis had IgE reactivity to a 39 kDa protein band of venom of both species, a third band, identified in immunoblot as hyaluronidase. The cross-reactivity of PLA2 and hyaluronidase of A. dorsata and A. mellifera were further confirmed by immunoblot inhibition results. Twenty five of 30 (83.3%) of our patients had positive venom specific IgE (>0.35 KUA/L) reactivity to Phadia ImmunoCAPs of A. mellifera venom. The observed IgE cross reactivity suggests the possibility of using A. mellifera venom as a diagnostic test for A. dorsata venom allergy.

Dengue viral infections are endemic or epidemic in virtually all tropical countries. Among individuals infected with the dengue virus, severe dengue syndromes (i.e., dengue haemorrhagic fever and dengue shock syndromes) tend to affect only some and this may be due to a combination of host genetic susceptibility and viral factors. In this review article we analyse and discuss the present knowledge of non-human leucocyte antigen host genetic susceptibility to severe dengue syndromes. The relevance of genetic polymorphisms in the pathways of antigen recognition, uptake, processing and presentation, activation of interferon α responses, mast cell and complement activation and T cell activation and dengue disease severity has been reviewed and analysed.

Background The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. Methods Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. Results Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). Conclusions Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient’s refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. Trial registration The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency (CVID) with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T cell function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-negative Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal blocking compounds, distinguished CTLA-4 from LRBA mutations. Short term T cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene sequencing approaches.

Well known for their role in allergic disorders, mast cells (MCs) play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury, with an array of chemical mediators. After being recruited to connective tissues, resident MCs progenitors undergo further differentiation, under the influence of signals from surrounding microenvironment. It is the differential tissue homing and local maturation factors which result in a diverse population of resident MC phenotypes. An abundance of MC reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts). Situated near nerve fibers, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, MCs can modulate the function of local and distant structures (e.g., other immune cell populations, fibroblasts, angiogenesis), and MC dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders (CTDs). This report reviews basic biology of mast cells and mast cell activation as well as recent research efforts, which implicate a role of MC dysregulation beyond atopic disorders and in a cluster of Ehlers-Danlos Syndromes, non-IGE mediated hypersensitivity disorders, and dysautonomia. © 2017 Wiley Periodicals, Inc.

Introduction: In the absence of robust clinical evidence and guidelines the management of GLILD (a rare complication of common variable immunodeficiency disorders, CVID) is primarily based on clinical experience. We run the largest GLILD centre in the UK and have used a treatment protocol for years. Our current first line treatment is high-dose prednisolone (up to 1mg/kg/day). Pulmonary function tests (PFT) are performed to evaluate the course of GLILD and treatment response. We assessed initial PFT responses to steroids, regarding the magnitude of change in spirometry and gas transfer to inform which parameters were affected most. Method: Data on treatment and lung function tests were collected from 9 patients (5 males, 4 females, age 32-71y), all on immunoglobulin replacement, starting steroids for GLILD at the Respiratory Immunology service of the Royal Free Hospital, London. We assessed change in %predicted FEV1, FVC, DLCO and KCO. Comparisons were performed for the initial change with prednisolone therapy. Results: The results are presented in the Table. The median (IQR) time between the pre- and post1-treatment tests was 1 (1-2) months and post2 2(1-4) months. Gas transfer increased in 5/9 patients suggesting that PFT responses to steroids are heterogeneous Conclusion: Prednisolone improves lung function in GLILD but responses are heterogeneous. The greatest initial changes are observed in spirometry than gas transfer. Reference: Hurst JR, et al. BLF/UKPIN Consesus Statement, J Allergy Clin Immunol Pract. 2017 Jul - Aug;5(4):938-945

Despite advances in treating Systemic lupus erythematosus (SLE), a proportion of patients continue to face significant morbidity and mortality. Haemopoietic stem cell transplant (HSCT) has been recognized as an option for such patients. We analysed the evidence on efficacy and safety of HSCT in patients with SLE. A database search was done for articles on HSCT in SLE up to July 2017 in PUBMED, Cochrane library, LILACS and clinical trial registration databases to select prospective or retrospective studies with 8 or more patients. Of the 732 search results from the PUBMED, Cochrane and LILACS database search, following duplicate removal, 15 studies were eligible for detailed assessment. Findings of an additional trial were obtained from the clinical trial registration database. Data were extracted on study design, patient characteristics, nature of intervention, outcomes, complications and study quality. Case reports and small case series were summarised without detailed qualitative analysis. Most of the studies showed remission in the majority of patients. Relapse of the original disease increased with longer follow-up. Common adverse effects included: infections and secondary autoimmune disorders. Short follow up period and lack of randomised controlled trials were the main limitations restricting the generalizability of study results. A meta-analysis was not performed due to heterogeneity of studies. Although HSCT is a viable option in SLE, its exact clinical utility needs to be further evaluated in well-designed studies.

Background Early identification of patients at risk of severe dengue disease (DD) is critical to guide its management. We evaluated whether the atypical lymphocyte count (ALC), generated from the Sysmex automated full blood count analyzer, is predictive of severe thrombocytopenia secondary to Dengue infection. Methods We prospectively collected data on patients admitted with DD between December 2017 and October 2018. ALC data were extracted from the Sysmex XS500i analyzer from day 1 to day 7 of admission. Clinical data were obtained from patients' medical records. Results We enrolled 256 patients with DD. A negative correlation between ALC on admission and platelet count on day 5 to day 7 (Spearmen's correlation; day 5:-0.485, day 6:-0.428 and day 7:-0.344) (p=0.001) was observed. Based on receiver operator characteristic curve analysis, we found that an ALC of >0.5x103/L had 90% sensitivity and 70% specificity for severe thrombocytopenia (platelet count Conclusions We propose that ALC on admission may be a novel negative predictive factor for severe thrombocytopenia on day 5 to day 7 of DD. Further studies are required to validate our findings and evaluate whether ALC is predictive of other complications of DD.

Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.

Background As of November 2020, SARS-CoV-2 has resulted in 55 million infections worldwide and over 1.3 million deaths from COVID-19. Outcomes following SARS-CoV-2 infection in individuals with primary immunodeficiency or symptomatic secondary immunodeficiency remain uncertain. Objectives To document the outcomes of individuals with primary or symptomatic secondary immunodeficiency following COVID-19 in the United Kingdom. Methods At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network (UK PIN) established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. Results 100 patients had been enrolled by 1st July 2020, 60 with primary immunodeficiency (PID), 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency and 33 with symptomatic secondary immunodeficiency (SID). In individuals with PID, 53.3% (n=32/60) were hospitalized, the infection fatality rate (IFR) was 20.0% (n=12/60), the case fatality rate (CFR) was 31.6% (n=12/38) and the inpatient mortality 37.5% (n=12/32). Individuals with SID had worse outcomes than those with PID. 75.8% (n=25/33) were hospitalized, the IFR was 33.3% (n=11/33), the CFR was 39.2% (n=11/28), and inpatient mortality 44.0% (n=11/25). Conclusions In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus., Capsule summary: This large case series of outcomes following COVID-19 demonstrates that, in comparison to the general population, adults with primary and secondary immunodeficiencies are at increased risk of morbidity and mortality following SARS-CoV-2 infection.

Problem Antiphospholipid syndrome is associated with recurrent pregnancy loss, and specific treatment improves pregnancy outcome. Laboratory diagnosis is limited in South Asia. We assessed management outcomes of definite/probable antiphospholipid syndrome treated at a tertiary centre in Sri Lanka. Method Descriptive cross-sectional study of pregnancy outcomes with heparin and aspirin therapy. Outcome measures: miscarriage, intrauterine death and live birth when compared to previous untreated pregnancies. Results Of 646 gestations in 145 women, 146 (22.6%) received specific treatment. In the preceding pregnancies without specific treatment, the rates of miscarriage, late fetal loss, stillbirth and live birth were 60%, 26%, 8% and 7%, respectively. Following specific treatment with low-dose aspirin ± low-molecular weight heparin in 146 pregnancies (145 women), the rates of miscarriage, late fetal loss, stillbirth and live birth were 14%, 10%, 3% and 74%, respectively. Mean birth weight was 2.54 ± 0.62 kg, preterm births complicated 32 (29.6%) with a mean gestational age at delivery 33.7 ± 2.6 weeks, with three neonatal deaths. Maternal complications were: pre-eclampsia 16 (10.9%), gestational diabetes 28 (19.2%), antepartum haemorrhage in 1 patient. Only 73/145 (50.3%) women had laboratory confirmation of antiphospholipid syndrome, while others were treated empirically. Live births in diagnosed vs. empiric treatment – 80.8% vs. 67.1%. Conclusion Pregnant women with clinical antiphospholipid syndrome when treated with low-dose aspirin and heparin, the live birth rate of 7% in the previous pregnancy resulted in live births of 74% in a resource limited South Asian setting.

Background The early identification of patients at risk of severe dengue infection (DI) is critical to guide clinical management. Non-structural antigen 1 (NS-1), immunoglobulin M (IgM) and immunoglobulin G (IgG) are used routinely for the diagnosis of DI. Objectives We sought to evaluate whether positivity for NS-1, IgM and IgG individually or together is predictive of severe complications of DI. Methods & materials A prospective study was conducted among patients with DI admitted to our institution between 2014 and 2019. DI was diagnosed based on a positive NS1 or IgM. IgG was also tested on all the patients. Clinical data was obtained from electronic medical records at NH. Statistical analyses were performed using SPSS version 20. Results We collected data on 3504 patients. Patients who were positive for NS1, IgM and IgG (triple positive: TP) were more likely to develop severe DI (63.8 %) in comparison to those who were only NS1 positive (single positive: SP) (3.0 %) and patients with positive NS1 and IgM (double positive: DP) (7.5 %). [p = 0.001]. Regression analysis confirmed that TP status on admission was predictive of severe complications. (p Receiver operator characteristic curve (ROC) analysis showed (AUC: 84.8; sensitivity = 90.7 and specificity = 83.2) that TP status on admission is predictive of thrombocytopenia on day 5. The predictive power of TP status was superior to that of NS1 and IgG positivity. Conclusions We propose that TP status on admission is a novel predictive factor for severe DI. Further studies are required to explore the biological basis for this finding.

BACKGROUND: Component-resolved diagnosis (CRD) has revealed significant associations between IgE against individual allergens and severity of hazelnut allergy. Less attention has been given to combining them with clinical factors in predicting severity. AIM: To analyze associations between severity and sensitization patterns, patient characteristics and clinical history, and to develop models to improve predictive accuracy. METHODS: Patients reporting hazelnut allergy (n = 423) from 12 European cities were tested for IgE against individual hazelnut allergens. Symptoms (reported and during Double-blind placebo-controlled food challenge [DBPCFC]) were categorized in mild, moderate, and severe. Multiple regression models to predict severity were generated from clinical factors and sensitization patterns (CRD- and extract-based). Odds ratios (ORs) and areas under receiver-operating characteristic (ROC) curves (AUCs) were used to evaluate their predictive value. RESULTS: Cor a 9 and 14 were positively (OR 10.5 and 10.1, respectively), and Cor a 1 negatively (OR 0.14) associated with severe symptoms during DBPCFC, with AUCs of 0.70-073. Combining Cor a 1 and 9 improved this to 0.76. A model using a combination of atopic dermatitis (risk), pollen allergy (protection), IgE against Cor a 14 (risk) and walnut (risk) increased the AUC to 0.91. At 92% sensitivity, the specificity was 76.3%, and the positive and negative predictive values 62.2% and 95.7%, respectively. For reported symptoms, associations and generated models proved to be almost identical but weaker. CONCLUSION: A model combining CRD with clinical background and extract-based serology is superior to CRD alone in assessing the risk of severe reactions to hazelnut, particular in ruling out severe reactions.

Item does not contain fulltext BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

"Çalışmada 57 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır.” Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers. Federal Ministry of Education & Research (BMBF) - IFB/CCI: 01EO1303 - E:med/SysInflame: 012X1306F - DZIF: 8000805-3 German Research Foundation (DFG) - FR 2821/6-1

WOS: 000352238600022, PubMed ID: 25595268, Background: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. Objective: We sought to define the outcomes of HSCT for patients with CVID. Methods: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. Results: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. Conclusion: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01 EO 0803]; Dutch Cancer SocietyKWF Kankerbestrijding [2013-5883]; Medical Research CouncilMedical Research Council UK (MRC) [G0501468], Supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803). C.L. is supported by a clinical fellowship from the Dutch Cancer Society (2013-5883).

Dengue fever is the commonest viral haemorrhagic fever worldwide and is a leading cause of morbidity and mortality in the tropics. Dengue viral infections are frequently associated with varying degrees of liver injury. Liver injury is more severe in dengue haemorrhagic fever or severe dengue. We review the current knowledge on liver involvement following dengue viral infections and explore the links between clinical manifestations, pathogenesis, and their impact on management.

Measurement of an individuals ability to respond to polysaccharide antigens is a crucial test to determine adaptive immunity. Currently the response to Pneumovax® is utilized but with the success of Prevnar®, measurement of the response to Pneumovax may be challenging. The aim of the study was to assess the response to Typhi Vi vaccination in both children and adult control groups and patients with primary immunodeficiency (PID). In the control groups, >95% of the individuals had pre Typhi Vi vaccination concentrations 94% achieving ≥3 fold increase in concentration (FI). The response to Typhi Vi vaccination was significantly lower in both children (p = 0.006) and adult (p = 0.002) PID groups when compared to their control groups. 11% and 55% of the children and adult PID groups respectively did not obtain a response >3FI. There were no significant differences between the responses obtained in the children and adult PID groups. When all individuals with PID were separated into those with either hypogammaglobulinemia (HYPO) or common variable immunodeficiency (CVID), both groups had a significantly lower median FI than the control group (19, 95%CI 5–56 vs 59, 95%CI 7–237; p = 0.01 and 1, 95%CI 1–56 vs 32, 95%CI 5–136; p = 0.005). Further, a >3FI differentiated the antibody responses between both the CVID and HYPO groups and their control groups (AUC: 0.83, 95%CI: 0.65–1.00, p = 0.005 and 0.81, 95% CI: 0.65–0.97, p = 0.01). The data suggests that measurement of the response to Typhi Vi vaccination could represent a complementary assay for the assessment of the response to a polysaccharide vaccine.

Dengue is a significant health problem in many countries. In recent years, complications involving specific organ systems have been increasingly observed and appear to have important effects on overall dengue related morbidity and mortality. Renal involvement in dengue could potentially cause increased mortality and long term effects. We review the different renal manifestations associated with dengue virus infections and explore their potential underlying pathophysiological mechanisms. The serum electrolyte and urinary abnormalities seen in dengue are discussed and Acute Kidney Injury (AKI) due to acute glomerulonephritis, rhabdomyolysis and haemolytic uraemic syndrome following dengue are explored. Renal manifestations of dengue in patients with chronic kidney disease or a transplanted kidney provides new insights into the pathophysiology of the disease.

Background Patients with common variable immunodeficiency (CVID) suffer frequent respiratory tract infections despite immunoglobulin replacement and are prescribed significant quantities of antibiotics. The clinical and microbiological nature of these exacerbations, the symptomatic triggers to take antibiotics, and the response to treatment have not been previously investigated. Objectives To describe the nature, frequency, treatment, and clinical course of respiratory tract exacerbations in patients with CVID and to describe pathogens isolated during respiratory tract exacerbations. Methods We performed a prospective diary card exercise in 69 patients with CVID recruited from a primary immunodeficiency clinic in the United Kingdom, generating 6210 days of symptom data. We collected microbiology (sputum microscopy and culture, atypical bacterial PCR, and mycobacterial culture) and virology (nasopharyngeal swab multiplex PCR) samples from symptomatic patients with CVID. Results There were 170 symptomatic exacerbations and 76 exacerbations treated by antibiotics. The strongest symptomatic predictors for commencing antibiotics were cough, shortness of breath, and purulent sputum. There was a median delay of 5 days from the onset of symptoms to commencing antibiotics. Episodes characterized by purulent sputum responded more quickly to antibiotics, whereas sore throat and upper respiratory tract symptoms responded less quickly. A pathogenic virus was isolated in 56% of respiratory exacerbations and a potentially pathogenic bacteria in 33%. Conclusions Patients with CVID delay and avoid treatment of symptomatic respiratory exacerbations, which could result in structural lung damage. However, viruses are commonly represented and illnesses dominated by upper respiratory tract symptoms respond poorly to antibiotics, suggesting that antibiotic usage could be better targeted.

IntroductionThe early identification of patients at risk of severe dengue infection (DI) is critical to guide clinical management. There is currently no validated laboratory test which can predict severe complications of DI. The Atypical lymphocyte count (ALC) is a research parameter generated at no extra cost when an automated Full Blood Count (FBC) is performed. The purpose of this study was to assess the association of ALC with the severity of DI.MethodsWe prospectively collected data on patients admitted to Nawaloka Hospital Sri Lanka (NH) with DI between December 2016 and November 2017. DI was diagnosed based on a positive Non-structural antigen 1 (NS1) or dengue IgM antibody. ALC (absolute ALC and percentage) data were extracted from the Sysmex XS500i automated full blood count (FBC) analyzer (Sysmex Corporation Kobe, Japan). Clinical data was recorded from medical records and the computerized data base maintained by NH.Results530 patients were enrolled. Patients with clinical manifestations of severe dengue have a significantly higher AL % compared to dengue without warning signs. Patients who presented with respiratory compromise had statistically significantly higher AL% compared to those without. (AL%; 8.65±12.09 vs 2.17±4.25 [p = 0.01]). Similarly, patients who developed hypotension had higher AL% compared to those who did not suffered from shock (AL%; 8.40±1.26 vs 2.18±4.25 [p = 0.001]). The AL% of dengue patients presenting with bleeding, at 4.07%, is also higher than those without bleeding complications, at 2.15%. There was a significant negative association between platelet count and AL% (p = 0.04).ConclusionsClinical manifestations of severe dengue have a significantly higher AL % compared to dengue without warning signs. AL % at presentation may be predictive of severe DI and future larger prospective longitudinal studies should be done to determine if AL % on admission is predictive of the complications of DI.

WOS: 000398771800023, PubMed ID: 27697500, Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. Results: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 +/- 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates., Jeffrey Modell Foundation; National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease [U54 AI 082973, R13AI094943], Supported by a grant from Jeffrey Modell Foundation (to M.d.l.M.). The Primary Immune Deficiency Treatment Consortium (PIDTC) is supported by the National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease grants U54 AI 082973 and R13AI094943.

A proportion of people living with common variable\ud immunodeficiency disorders develop granulomatouslymphocytic\ud interstitial lung disease (GLILD). We aimed to\ud develop a consensus statement on the definition, diagnosis, and\ud management of GLILD. All UK specialist centers were contacted\ud and relevant physicians were invited to take part in a 3-round\ud online Delphi process. Responses were graded as Strongly Agree,\ud Tend to Agree, Neither Agree nor Disagree, Tend to Disagree,\ud and Strongly Disagree, scored D1, D0.5, 0, L0.5, and L1,\ud respectively. Agreement was defined as greater than or equal to\ud 80% consensus. Scores are reported as mean – SD. There was\ud 100% agreement (score, 0.92 – 0.19) for the following\ud definition: “GLILD is a distinct clinico-radio-pathological ILD\ud occurring in patients with [common variable immunodeficiency\ud disorders], associated with a lymphocytic infiltrate and/or\ud granuloma in the lung, and in whom other conditions have been\ud considered and where possible excluded.” There was consensus\ud that the workup of suspected GLILD requires chest computed\ud tomography (CT) (0.98 – 0.01), lung function tests (eg, gas\ud transfer, 0.94 – 0.17), bronchoscopy to exclude infection (0.63 –\ud 0.50), and lung biopsy (0.58 – 0.40). There was no consensus on\ud whether expectant management following optimization of\ud immunoglobulin therapy was acceptable: 67% agreed, 25%\ud disagreed, score 0.38 – 0.59; 90% agreed that when treatment\ud was required, first-line treatment should be with corticosteroids\ud alone (score, 0.55 – 0.51).

Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications. Using a functional read-out, we previously identified a functional subgroup of CVID patients with plasmablasts (PBs) producing IgM only. We have now further characterized such CVID patients by a direct functional comparison with patients having genetically well-characterized CSR defects in CD40L, activation-induced cytidine deaminase (AID) and uracil N-glycosylase activity (UNG). The CSR-like CVID patients showed a failure in B cell activation patterns similar to the classical AID/UNG defects in three out of five CVID patients and distinct more individual defects in the two other CVID cases when tested for cellular activation and PB differentiation. Thus, functional categorization of B cell activation and differentiation pathways extends the expected variation in CVID to CSR-like defects of as yet unknown genetic etiology. Electronic supplementary material The online version of this article (doi:10.1007/s10875-016-0321-2) contains supplementary material, which is available to authorized users.

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.

Item does not contain fulltext BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. OBJECTIVE: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. METHODS: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. RESULTS: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. CONCLUSION: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.