Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 ...receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.
Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high‐dose glucocorticoids and etoposide used in ...adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine‐modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult‐onset secondary HLH.
Case series
We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T‐cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings.
Results
All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib.
Conclusions
This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID‐19.
Severe combined immunodeficiency is caused by genetic defects that profoundly impair development of the immune system. The condition is fatal early in life if affected infants do not receive therapy ...to restore immune function in the form of hematopoietic stem cell transplantation, enzyme replacement therapy or gene therapy. Infants with severe combined immunodeficiency commonly appear healthy at birth; consequently, the condition often presents only when the child has already had many infections and secondary organ damage. Early diagnosis is essential, as patients who receive a transplant before 3.5 months of age have the best outcomes. This review informs physicians who may treat newborns in their practice (e.g., family physicians, obstetricians, pediatricians) on how to approach patients and counsel families who are faced with an abnormal screen for severe combined immunodeficiency. We describe the epidemiology, diagnosis and screening of this disorder and provide a brief summary of available treatments.
The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified ...and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) were historically thought to be distinct entities, often managed in isolation. In fact, these conditions are closely ...related. A collaborative approach, which incorporates expertise from subspecialties that previously treated HLH/MAS independently, is needed. We leveraged quality improvement (QI) techniques in the form of an Evidence-Based Guideline (EBG) to build consensus across disciplines on the diagnosis and treatment of HLH/MAS.
A multidisciplinary work group was convened that met monthly to develop the HLH/MAS EBG. Literature review and expert opinion were used to develop a management strategy for HLH/MAS. The EBG was implemented, and quality metrics were selected to monitor outcomes.
An HLH/MAS clinical team was formed with representatives from subspecialties involved in the care of patients with HLH/MAS. Broad entry criteria for the HLH/MAS EBG were established and included fever and ferritin ≥500 ng/mL. The rheumatology team was identified as the "gate-keeper," charged with overseeing the diagnostic evaluation recommended in the EBG. First-line medications were recommended based on the acuity of illness and risk of concurrent infection. Quality metrics to be tracked prospectively based on time to initiation of treatment and clinical response were selected.
HLH/MAS are increasingly considered to be a spectrum of related conditions, and joint management across subspecialties could improve patient outcomes. Our experience in creating a multidisciplinary approach to HLH/MAS management can serve as a model for care at other institutions.
Transcription factors (TFs) are critical components involved in regulating immune system development, maintenance, and function. Monogenic defects in certain TFs can therefore give rise to inborn ...errors of immunity (IEIs) with profound clinical implications ranging from infections, malignancy, and in some cases severe allergic inflammation. This review examines TF defects underlying IEIs with severe atopy as a defining clinical phenotype, including STAT3 loss-of-function, STAT6 gain-of-function, FOXP3 deficiency, and T-bet deficiency. These disorders offer valuable insights into the pathophysiology of allergic inflammation, expanding our understanding of both rare monogenic and common polygenic allergic diseases. Advances in genetic testing will likely uncover new IEIs associated with atopy, enriching our understanding of molecular pathways involved in allergic inflammation. Identification of monogenic disorders profoundly influences patient prognosis, treatment planning, and genetic counseling. Hence, the consideration of IEIs is essential for patients with severe, early-onset atopy. This review highlights the need for continued investigation into TF defects to enhance our understanding and management of allergic diseases.
Severe allergic disease is common, and few monogenic causes of atopy have been described. A new study that convincingly links severe atopic dermatitis to heterozygous CARD11 mutations with ...dominant-interfering activity serves as a timely reminder that clinicians should consider the possibility of an underlying monogenic immune disorder when caring for patients suffering from severe allergic disease.
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