Immunomodulation enhances parasite fitness by reducing inflammation-induced morbidity in the mammalian host, as well as by attenuating parasite-targeting immune responses. Using a whole proteome differential screening method, we identified Schistosoma japonicum Helminth Defense Molecule (SjHDM-1) as a target of antibodies expressed by S. japonicum resistant, but not susceptible, individuals. In a longitudinal cohort study (N=644) conducted in a S. japonicum endemic region of the Philippines, antibody levels to SjHDM-1 did not predict resistance to reinfection but were associated with increased measures of inflammation. Individuals with high levels of anti-SjHDM-1 IgG had higher levels of C-reactive protein compared to individuals with low anti-SjHDM-1. High anti-SjHDM-1 IgG responses were also associated with reduced biomarkers of nutritional status (albumin), as well as decreased anthropometric measures of nutritional status (WAZ and HAZ) and increased measures of hepatomegaly. Our results suggest that anti-SjHDM-1 responses inhibit the immunomodulatory function of SjHDM-1, resulting in increased morbidity.

Together with its β-subunit OSTM1, ClC-7 performs 2Cl-/H+ exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies, including osteopetrosis and lysosomal storage. CLCN7 variants can cause recessive or dominant disease. Different variants entail different sets of symptoms. Loss of ClC-7 causes osteopetrosis and mostly neuronal lysosomal storage. A recently reported de novo CLCN7 mutation (p.Tyr715Cys) causes widespread severe lysosome pathology (hypopigmentation, organomegaly, and delayed myelination and development, \"HOD syndrome\"), but no osteopetrosis. We now describe two additional HOD individuals with the previously described p.Tyr715Cys and a novel p.Lys285Thr mutation, respectively. Both mutations decreased ClC-7 inhibition by PI(3,5)P2 and affected residues lining its binding pocket, and shifted voltage-dependent gating to less positive potentials, an effect partially conferred to WT subunits in WT/mutant heteromers. This shift predicts augmented pH gradient-driven Cl- uptake into vesicles. Overexpressing either mutant induced large lysosome-related vacuoles. This effect depended on Cl-/H+-exchange, as shown using mutants carrying uncoupling mutations. Fibroblasts from the p.Y715C patient also displayed giant vacuoles. This was not observed with p.K285T fibroblasts probably due to residual PI(3,5)P2 sensitivity. The gain of function caused by the shifted voltage-dependence of either mutant likely is the main pathogenic factor. Loss of PI(3,5)P2 inhibition will further increase current amplitudes, but may not be a general feature of HOD. Overactivity of ClC-7 induces pathologically enlarged vacuoles in many tissues, which is distinct from lysosomal storage observed with the loss of ClC-7 function. Osteopetrosis results from a loss of ClC-7, but osteoclasts remain resilient to increased ClC-7 activity.

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman\'s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman\'s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Clinical findings of hepatomegaly and splenomegaly, the abnormal enlargement of the liver and spleen, respectively, should prompt a broad differential diagnosis that includes metabolic, congestive, neoplastic, infectious, toxic, and inflammatory conditions. Among the metabolic diseases, lysosomal storage diseases (LSDs) are a group of rare and ultrarare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins. As a result, abnormal metabolites accumulate in the organelle, leading to dysfunction. Therapeutic advances, including early diagnosis and disease-targeted management, have improved the life expectancy and quality of life of people affected by certain LSDs. To access these new interventions, LSDs must be considered in patients presenting with hepatomegaly and splenomegaly throughout the lifespan. This review article navigates the diagnostic approach for individuals with hepatosplenomegaly particularly focusing on LSDs. We provide hints in the history, physical exam, laboratories, and imaging that may identify LSDs. Additionally, we discuss molecular testing, arguably the preferred confirmatory test (over biopsy), accompanied by enzymatic testing when feasible.

Osteopetrosis encompasses rare inherited metabolic bone disorders with defect in the osteoclast activity. Severe forms of presentation such as malignant infantile osteopetrosis are seen in infants and milder forms in older children. The clinical presentation includes failure to thrive, severe pallor, optic atrophy and hepatosplenomegaly. The disorder is characterised by dense bone on radiography, hence the name marble bone disease. A 10-month-old boy who presented with developmental delay, failure to thrive, nystagmus (which the mother described as wandering eye movements), splenomegaly of 16 cm and hepatomegaly of 8 cm. Investigations demonstrated severe anaemia (5.7 g/dL) and thrombocytopenia (34 x 109/L). Radiological signs which help in the diagnosis include diffuse sclerosis, bone within bone appearance, sandwich vertebrae and Erlenmeyer flask deformity. Plain radiography is an easily available and cost effective tool which can aid in the diagnosis of osteopetrosis.

Adult-onset Still\'s disease (AOSD) is a rare multi-systemic inflammatory disorder characterized by high spiking fevers, nonpruritic, salmon-colored rash, and severe polyarthralgia. Laboratory features typically include elevation in white blood cells, liver enzymes, and ferritin. Central nervous system and cardiac involvements, particularly myocarditis, are rare. Macrophage activation syndrome (MAS) is a well-described complication of AOSD, leading to a high mortality rate. Herein, we describe a case of AOSD complicated by MAS in a 32-year-old male presenting with atypical clinical manifestations, including recurrent seizures, scaly, pruritic, and hyperpigmented rash, and right heart failure due to lymphocytic myocarditis. The patient exhibited a delayed onset of fever, leukocytosis, and transaminitis that initially deterred eligibility for Yamaguchi criteria for AOSD. Bone marrow and lymph node biopsies did not show malignancy, infection, or hemophagocytosis. However, soluble interleukin-2 receptor alpha or soluble CD-25 was elevated. The patient experienced significant improvement on combination therapy of anakinra, methotrexate, and stress-dose steroids. HScore was later indicative of a high probability for MAS. Outpatient management involved prednisone, cyclosporine, and canakinumab for MAS. Seizure and myocarditis are possible presenting features of atypical AOSD. Early recognition of non-criteria AOSD and MAS and prompt initiation of therapy may prevent mortality.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a rare paraneoplastic syndrome that encompass multiple systems. The most common clinical symptoms of POEMS syndrome are progressive sensorimotor polyneuropathy, organ enlargement, endocrine disorders, darkening skin, a monoclonal plasma cell proliferative disorder, and lymph node hyperplasia. The organomegaly consists of hepatosplenomegaly and/or lymphadenopathy; cases of cardiomyopathy are rare. Diagnoses are often delayed because of the atypical nature of the syndrome, exposing patients to possibly severe disability. Therefore, identifying atypical symptoms can improve the prognosis and quality of life among POEMS syndrome patients.
METHODS: Herein, we report the case of a 59-year-old woman with POEMS syndrome that involved dilated cardiomyopathy. The patient presented to the hospital with complaints of shortness of breath and discomfort in the chest. The patient reported previous experiences of limb numbness. During hospitalization, the brain natriuretic peptide levels were 3504.0 pg/mL. Color doppler echocardiography showed an enlarged left side of the heart, along with ventricular wall hypokinesis and compromised functioning of the same side of the heart. Abdominal color ultrasonography revealed that the patient\'s spleen was enlarged. Observations from cardiac magnetic resonance imaging showed that the left side of the heart was enlarged. Slight myocardical fibrosis was also observed. Electromyography was described as a symmetric sensorimotor demyelinating polyneuropathy. Further immunoelectrophoresis of the serum showed the presence of a monoclonal IGA λ M protein. The vascular endothelial growth factor levels were 622.56 pg/mL. Flow cytometric and immunohistochemical staining of the bone marrow detected no monoclonal plasma cells. Finally, the patient was diagnosed with POEMS syndrome associated with dilated cardiomyopathy. The chest-related discomfort and the shortness of breath resolved after the administration of lenalidomide and dexamethasone.
CONCLUSIONS: When patients with cardiomyopathy have systemic manifestations such as numb limbs and darkening skin, the POEMS syndrome is the most possible diagnosis.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment.
RESULTS: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event.
CONCLUSIONS: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

Disseminated histoplasmosis is a progressive granulomatous disease caused by Histoplasma capsulatum, which is an intracellular dimorphic fungus endemic to the Ohio and Mississippi River valleys in the United States. It is usually thought to be due to the failure of the activation of the T-cell-mediated immune response. Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition, in which histiocytes and lymphocytes build up in and damage organs and other blood cells. We present a 37-year-old man with a past medical history of systemic lupus erythematosus (SLE) complicated by lupus nephritis on immunosuppressive therapy who presented to the emergency department with hypotension and was admitted for acute kidney injury. Prior to the presentation, he had persistent fever, myalgias, cough, mild shortness of breath, and back pain. Computed tomography (CT) chest shows \"eggshell\" calcification; microbiology evaluation of peripheral blood smear revealed intracellular organism, morphologically consistent with H. capsulatum; and urine histoplasmosis antigen test confirmed the diagnosis of histoplasmosis. HLH diagnosis was made clinically after \"clinical and testing criteria\" were evaluated. Despite further management, he developed coagulopathy and sepsis, which led to his death. At autopsy, we found organomegaly of the liver, spleen, and kidneys. Microscopically, these enlarged organs show old fibrotic granulomas and granulomatous inflammation with suspected fungal organisms. Gomori\'s methenamine silver special stain confirmed these fungal organisms to be consistent with Histoplasma species (3-5 micron budding yeasts). This case highlights that physicians should be aware of the diagnostic challenge that disseminated histoplasmosis with HLH could pose in a patient with SLE, especially in patients on immunosuppression. Failure to recognize the infection promptly could lead to grievous complications and possibly death.

Renomegaly has been reported in dogs with congenital portosystemic shunts (PSS). However, no study has objectively evaluated the degree of renomegaly in dogs with different types of PSS. The purpose of this retrospective, analytical, cross-sectional study was to determine kidney size (renal length-to-L2 vertebral body ratio; RL/L2 ratio) using CT in dogs with different types of PSS and correlate with clinical information. A medical record search for dogs with a PSS diagnosed using CT between 2016 and 2020 was conducted. Breed, age, sex, body weight, and biochemistry results were recorded. Kidney and L2 vertebral body lengths were measured using multiplanar reformatted CT images, and the RL/L2 ratio was calculated. Dogs were categorized into four groups based on PSS morphology for comparisons: intrahepatic (IH; n = 19), extrahepatic portocaval (EHPC; n = 20), extrahepatic portoazygos (EHPA; n = 7), or extrahepatic portophrenic (EHPP, n = 7). The RL/L2 ratio (mean ± SD) was largest in IH (3.55 ± 0.38) and EHPC (3.55 ± 0.38), followed by EHPP (3.10 ± 0.23), and EHPA (2.78 ± 0.18). RL/L2 ratio was significantly larger in EHPC and IH (vs. EHPA and EHPP [P < .01]). Significant correlations between kidney size and creatinine, alkaline phosphatase, albumin, total protein, and ammonia were present. Renomegaly was observed in 86.8% of dogs with PSS overall, but it was uncommon in dogs with EHPA and less common in dogs with EHPP, as these two groups showed clinical signs later in life, made evident by older age at presentation. The authors suggest that the severity of hepatic dysfunction and the shunted blood volume may influence the development of renomegaly in dogs with PSS.