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Competing Interests: Competing interests: None declared.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler's syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research. [ABSTRACT FROM AUTHOR]

Introduction: The 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. Methods: We 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. Results: 530 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). Conclusions: Clinical 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. [ABSTRACT FROM AUTHOR]

• Triple positivity for NS1, IgM and IgG is associated with severe dengue infection. • Triple positivity is predictive of thrombocytopenia and complications of dengue. • Triple positivity is a novel, globally applicable biomarker for severe dengue. 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. We sought to evaluate whether positivity for NS-1, IgM and IgG individually or together is predictive of severe complications of DI. 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. 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 < 0.01). 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. 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. [ABSTRACT FROM AUTHOR]

Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15–20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of "monoclonal gammopathy of clinical significance" entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future. [ABSTRACT FROM AUTHOR]