Elevated Lactate Dehydrogenase Research Articles

Acute Kidney Injury Following CAR-T Cell Therapy: A Nephrologist Perspective

Abstract Chimeric antigen receptor T-cell (CAR-T cell) therapy, an emerging personalized immunotherapy for various hematologic malignancies, autoimmune diseases, and other conditions, involves the modification of patients’ T cells to express a chimeric antigen receptor which recognizes tumor or autoimmune cell antigens. Thereby CAR-T cells destroy cancerous and other target cells selectively. Despite remarkable clinical improvements in patients, multiple adverse effects have been associated with CAR-T cell therapy. Among the most recognized adverse effects are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and tumor lysis syndrome. Even though less recognized, the incidence of acute kidney injury (AKI) ranges from 5% to 33%. The wide range of reported AKI incidence rates might depend on patient population characteristics and comorbidities and specific CAR-T cell therapy features. Even though the exact pathophysiology remains unknown, several key mechanisms including cytokine release syndrome, tumor lysis syndrome, and other factors such as direct renal toxicity of CAR-T cell therapy, conditioning regimens or other medications (e.g. antibiotics), and infectious complications (e.g. sepsis) have been proposed. Risk factors for CAR-T-related AKI include lower baseline glomerular filtration rate, higher rates of allopurinol or rasburicase use, intravenous contrast material exposure, elevated baseline lactate dehydrogenase, and grade 3 or higher cytokine release syndrome. Future prospective studies with larger patient populations are needed to gain more insight regarding the pathophysiology of CAR-T-related AKI, and, more importantly, to be able to prevent as well as to develop novel and more efficient treatment modalities. In this narrative review, we discuss the underlying pathophysiology, risk factors, potential interventions, and future directions related to AKI following CAR-T cell therapy.

Serum lactate dehydrogenase as a prognostic marker for treatment response in IDH wild-type glioblastoma patients undergoing stupp protocol.

Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ). This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination. In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker. Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma.

Abstract B027: Combining total cell-free DNA (cfDNA) and circulating tumor (ctDNA) to enhance the clinical sensitivity of ddPCR assays to detect minimal residual disease (MRD) in stage IIIB/C/IV melanoma patients on adjuvant immunotherapy in CheckMate 238

Abstract Background: In patients (pts) with resected, stage III/IV melanoma receiving adjuvant immunotherapy, pre-treatment (pre-Tx) and on-treatment (on-Tx) ctDNA measurements are associated with relapse free survival; however, clinical adoption has been hindered by suboptimal assay sensitivity. Methods: We used analytically validated, mutation-specific ddPCR assays to measure ctDNA and cfDNA in pre- and on-Tx plasma samples from pts with resected stage IIIB/C/IV melanoma enrolled in CheckMate 238 (NCT02388906) receiving either adjuvant Nivolumab (NIVO) or Ipilimumab (IPI). Assay choice was personalized based on detection of one of the 7 melanoma hot-spot mutations in pt tumors: BRAF V600E/K, NRAS Q61R/L/K, or TERT promotor C228T or C250T. We evaluated associations between ctDNA detection, or high cfDNA based on cutpoint analysis (&amp;gt;6,000 copies/ml of plasma) and recurrence-free survival (RFS), pre-Tx tumor biomarkers including tumor cell PD-L1 expression, IFNg gene signature, CD8 infiltration, and tumor mutational burden. Survival analysis was performed using univariable and multivariable Kaplan-Meier and Cox regression models. Results: Assay mutations were identified in 87% of resected tumors. In the pre-Tx samples, ctDNA alone was detected in 94/753 (12%) pts. The detection rate increased to 20% when assay positivity was defined as either detectable ctDNA or high cfDNA. The sensitivity of ctDNA detection to predict recurrence ≤6 months(m) from pre-Tx samples increased from 25% (ctDNA alone) to 33% when high cfDNA was added to detectable ctDNA; specificity decreased to 84% from 91% (ctDNA alone). The patient subgroup defined by the combined metric of ctDNA+ or high cfDNA in pre- Tx samples was significantly enriched with higher stage of disease, elevated LDH, tumor cell PD-L1 expression &amp;lt; 5%, and tumor IFNg-RNA signature &amp;lt; median. Pts with detectable pre-Tx ctDNA or high cfDNA was associated with shorter RFS in both NIVO (median RFS 20.5 m [95%CI, 2.88, 59.15]) and IPI (median RFS 7.75 m [95%CI, 2.76, 24.08]) arms compared to those with undetectable ctDNA and low cfDNA (NIVO (median RFS 47.95 m [95%CI, 11.09, 59.89]) and IPI (median RFS 24.15 m [95%CI, 5.78, 58.38])). In a multivariable model that included sex, age, treatment, and IFNg gene signature, ctDNA+ or cfDNA high was an independent predictor of shorter RFS [HR 1.624 (95%CI, 1.275, 2.068), p&amp;lt;0.001]. When combining pre-Tx and on-Tx measurements at week 3 (w3) and w7, the assay performance generally increased compared to pre-Tx alone. For example, pre-Tx assay positivity had a 38% positive predictive value (PPV) and 81% negative predictive value (NPV) to predict recurrence at &amp;lt;6 m. In pts who were undetectable at pre-Tx but became positive at w3 and remained positive at w7, PPV increased to 62% and NPV increased to 90%. Conclusions: Incorporating quantitative measurements of cfDNA with ctDNA detection in the evaluation of pre-Tx and on- Tx plasma samples improves the clinical performance of mutation-specific ddPCR assays to detect MRD in patients with resected stage III and stage IV melanoma. Citation Format: Mahrukh M Syeda, Jennifer M Wiggins, Josephine Alegun, Saim Ali, Soutrik Mandal, Tracy (Hao) Tang, Keyur Desai, Sonia Dolfi, Daniel J Tenney, Paolo A Ascierto, James Larkin, Michele Del Vecchio, Jeffrey S Weber, David Polsky. Combining total cell-free DNA (cfDNA) and circulating tumor (ctDNA) to enhance the clinical sensitivity of ddPCR assays to detect minimal residual disease (MRD) in stage IIIB/C/IV melanoma patients on adjuvant immunotherapy in CheckMate 238 [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B027.

Vibrio alginolyticus Reprograms CIK Cell Metabolism via T3SS Effector VopS to Promote Host Cell Ferroptosis

Vibrio alginolyticus is a Gram-negative pathogen of both marine animals and humans, resulting in significant losses for the aquaculture industry. Emerging evidence indicates that V. alginolyticus manipulates cell death for its pathogenicity, but the underlying molecular mechanisms remain unclear. Here, a gene designated vopS in V. alginolyticus HY9901 was identified, which was predicted to encode the T3SS effector protein. To determine whether VopS contributes to the pathogenesis of V. alginolyticus, the ΔvopS mutant strain was constructed and phenotypically characterized. The deletion of VopS not only reduced the ability to secrete extracellular proteases and virulence but also affected the expression of the T3SS genes. Furthermore, VopS was cytotoxic and induced apoptosis, as confirmed by elevated LDH and the activation of caspase-3. Metabolomic analysis revealed considerable metabolomic disruptions upon V. alginolyticus infection. The VopS effector induced host cell ferroptosis by promoting the synthesis of adrenic acid, depleting cellular glutathione, and subsequently increasing the accumulation of ferrous (Fe2+). Taken together, our findings provide that the VopS effector is an essential virulence factor of V. alginolyticus, which can lead to ferroptosis.

H2 protects H9c2 cells from hypoxia/reoxygenation injury by inhibiting the Wnt/CX3CR1 signaling pathway.

Myocardial ischemia-reperfusion injury is a severe cardiovascular disease, and its treatment and prevention are crucial for improving patient prognosis and reducing the economic burden. This study aimed to explore the impact of hydrogen (H2) on hypoxia/reoxygenation (H/R) injury in H9c2 cells (derived from rat embryonic heart tissue) induced by hydrogen peroxide (H2O2) and to elucidate its underlying mechanism. An H/R injury model was established in H9c2 cells via exposure to 15 μM H2O2 for 3 hours, followed by incubation in a 5% CO2 atmosphere at 37°C for 24 hours. Then, the cells were treated with H2 (50%) for 6, 12 or 24 hours. The results demonstrated that H9c2 cells exposed to H2O2 and subjected to H/R injury presented a marked decrease in the cell survival rate, accompanied by severe morphological alterations, such as curling and wrinkling, and elevated lactate dehydrogenase levels. Notably, H2 mitigated H/R injury induced by H2O2 in a time-dependent manner, improving the morphological damage observed in H9c2 cells and decreasing lactate dehydrogenase levels. Compared with the model group, treatment with H2 increased the activities of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase, while concurrently reducing the level of malondialdehyde, an indicator of cellular damage. Furthermore, H2 treatment downregulated the expression of inflammatory cytokines and inflammatory-related factors, specifically interleukin-6, high-mobility group box 1, tumor necrosis factor-alpha, and Toll-like receptor 4, in H9c2 cells post-H/R injury. Furthermore, H2 treatment resulted in a marked decrease in the expression levels of proteins associated with the Wnt/C-X3-C-motif receptor 1 signaling pathway, such as β-catenin, glycogen synthase kinase-3 beta, adenomatous polyposis coli, and Wnt and C-X3-C-motif receptor 1. This observation suggests a potential mechanism for its protective effects against H/R injury. Therefore, H2 exerts a protective effect against H/R injury in H9c2 cells induced by H2O2, potentially by inhibiting the activated Wnt/C-X3-C-motif receptor 1 signaling pathway. This inhibition, in turn, prevents the generation of oxidative stress, inflammatory cytokines, and inflammation-associated factors.

Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma.

Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

Association between Lactate dehydrogenase and 28-day all-cause mortality in patients with non-traumatic Intracerebral hemorrhage: A retrospective analysis of the MIMIC-IV database.

Lactate dehydrogenase (LDH), a nonspecific inflammatory biomarker, has been used in the assessment of acute myocardial infarction, acute hepatitis, acute lung injury, and other severe diseases. However, no studies have evaluated the prognostic value of LDH in patients with non-traumatic intracerebral hemorrhage (ICH). This cohort study aims to assess the association between LDH levels and 28-day all-cause mortality in patients with non-traumatic ICH. Data for this retrospective cohort analysis were obtained from the MIMIC-IV (v2.2) database, and the study included patients with non-traumatic ICH as defined by the International Classification of Diseases, 9th and 10th editions. Patients were categorized into four distinct groups based on their LDH levels. The primary outcome of interest was the 28-day mortality rate. To analyze these associations and assess the consistency of interactions, subgroup analyses, Cox regression analysis, Kaplan-Meier (KM) curves, and nonlinear analysis were conducted. A total of 406 patients with non-traumatic ICH were enrolled in the study and were divided into quartiles based on LDH levels. The KM curve indicated that the 28-day all-cause mortality rate of patients in the Q4 group (LDH > 287.25) was significantly higher than in the Q1 (LDH < 194.7) (P < 0.001) and Q2 (194.7 < LDH < 233.0) (P < 0.001) groups, though not significantly different from Q3 (P = 0.140). Multivariate Cox proportional hazards analysis revealed that patients in the highest LDH quartile had a significantly increased risk of mortality compared to those in the lowest quartile across three models: unadjusted [HR, 3.401; 95% CI, 1.719-6.731; P < 0.001], partially adjusted [HR, 2.422; 95% CI, 1.211-4.846; P = 0.012], and fully adjusted [HR, 3.054; 95% CI, 1.522-6.126; P = 0.002]. Restricted cubic spline (RCS) models revealed an L-shaped association between LDH levels and the 28-day all-cause mortality rate, indicating a non-linear relationship (P < 0.001). No significant interactions were observed between LDH levels and other factors in the subgroup analyses (all P for interaction > 0.05). Our findings indicate a significant association between 28-day all-cause mortality and LDH levels in patients with non-traumatic intracerebral hemorrhage. Specifically, patients with elevated LDH levels within the first 24 hours of ICU admission are at a higher risk of mortality.

Lactate Dehydrogenase Levels after aortic valve replacement: What do they tell us?

Lactate dehydrogenase (LDH) is a standard postoperative marker for hemolysis in the presence of paravalvular leakage (PVL) after aortic valve replacement (AVR). LDH is elevated in certain valves by a fluttering phenomenon. Previous studies suggested a correlation between microparticles (MP) and LDH elevation after AVR. We analyze the postoperative relevance of LDH after AVR with transapical transcatheter aortic valves (TA-TAV) or rapid deployment valves (RDV). We retrospectively analyzed the data from patients who received an AVR with RDV and TA-TAV groups between 2015-2018. We compared PVL and LDH levels before and after surgery, transvalvular gradients, heart block that required pacemaker implantation, and 30-day mortality. 138 consecutive patients were selected: 79 patients in the RDV group (37 Sorin Perceval valve, 42 Edwards Intuity valves) and 59 in the TA-TAV group (Edwards Sapien valve). TA-TAV-group were older (median 10 years) and with higher incidence of PVL (Odds ratio 11, 95% CI from 2.5 - 73.2, p-value 0.04)). TA-TAV-Group showed lower levels of LDH despite higher rates of PVL while the Perceval valve trended towards higher LDH values. Additionally, the RDV group showed an increased arrhythmia profile (p=0.0041) although the results show lower incidence in pacemaker implantation (95 % CI 0.05 - 1.65, p=0.635). 30-day mortality was similar between groups. Our data do not support the association between hemolysis and PVL despite elevated LDH in suture-free valves. LDH could be a marker of extreme heart muscle output or fluttering phenomena and not a marker of hemolysis after sutureless AVR.

Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma.

The activity of anti-CD19 chimerci antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B-cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T-cell therapy in patients with RT (N=30) compared to patients with aggressive B-cell lymphoma (N=283) and patients with transformed indolent non-Hodgkin lymphoma (iNHL) (N=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 inhibitors. Toxicities of CAR T-cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow-up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated lactate dehydrogenase, and more prior lines of therapy. CAR T-cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

P20 Persistent anti-PR3 ANCA positivity in patient with extrapulmonary tuberculosis

Abstract Introduction Granulomatosis with polyangiitis (GPA) and tuberculosis (TB) are both granulomatous disease which can have similar clinical manifestations and organ involvement. This report discusses a case of such overlapping clinical presentation and anti-neutrophil cytoplasmic antibodies (ANCA) positivity, leading to diagnostic uncertainty. Case description A 40-year-old female who lived in sub-Saharan Africa until two years ago presented with a two month history of general malaise, significant weight loss, severe anorexia, diarrhoea, vomiting and nausea. She had no night sweats, blood in stool, abdominal pain, respiratory or cardiac symptoms, sino-nasal symptoms, rashes or neurological features. On examination, she appeared severely malnourished. Blood tests revealed microcytic anaemia (Hb 83 g/l, MCV 69fl), thrombocytosis, hypoalbuminemia (15 g/l), CRP 26 mg/l, elevated procalcitonin (1.46 ug/l), elevated LDH 263U/l. She had a positive double-stranded DNA and anti-cardiolipin IgM. ANCA was moderately positive with an anti-PR3 titre of 78 U/ml. Computerised tomography (CT) chest to pelvis revealed widespread necrotic lymphadenopathy, bilateral pulmonary emboli with infarcts, pancolitis and non-specific gall bladder thickening. Endoscopy revealed inflamed featureless colon with no microscopic granulomata. Acid-fast bacilli were isolated on endobronchial ultrasound guided biopsy of the necrotic nodes leading to confirmation of the diagnosis of extrapulmonary disseminated tuberculosis. Clinical improvement and improvement in CRP and anti-PR3 titre (48 U/ml) were seen following two weeks of anti-tuberculous treatment and a weaning course of steroids for colitis. Discussion Often GPA and tuberculosis can have similar presentations including lung and gastrointestinal involvement along with lymphadenopathy. This case demonstrates how ANCA and PR3 positivity can also be a common feature in these two conditions. Correct diagnosis is crucial in preventing harm to the patient as a diagnosis of GPA would require prompt and aggressive immunosuppression which may result in disseminated mycobacterial infection in the case of misdiagnosis; similarly, anti-mycobacterial therapy is unlikely control systemic GPA. In our patient, although the enteritis, general malaise and weight loss can be features of vasculitis and tuberculosis, careful history suggested no convincing other features of GPA, including the absence of ear, nose, throat, skin, neurological or renal involvement. The social history yielded migration from sub-Saharan Africa where tuberculosis is much more prevalent. A useful distinguishing biochemical test was the elevated procalcitonin which points towards a bacterial infection rather than an autoimmune process. Ultimate conclusive evidence of mycobacterial infection requires either positive acid-fast bacilli on staining or culture; lymph node biopsy allowed us to promptly and correctly diagnose this patient in the absence of sputum or pulmonary tuberculosis. Initiation of anti-tuberculous treatment rapidly settled this patient’s symptoms with a falling CRP. This case report highlights the fact that tuberculosis can mimic ANCA-associated vasculitis with positive anti-PR3 antibodies. In such cases, careful history taking, appropriate imaging and positive acid fast bacilli on staining or culture from sputum or tissue are important for prompt diagnosis and treatment. Both disseminated tuberculosis and systemic GPA can be rapidly progressive and severe if untreated. Although literature described the co-existence of both conditions, this is very rare. Correct diagnosis is key in initiation of the widely different treatment strategies, with the treatment for GPA potentially causing harm in disseminated tuberculosis. Key learning points • ANCA positivity in tuberculosis has been documented in the literature and positive anti-PR3 cannot be used solely to diagnose GPA. Therefore, a thorough history, examination, imaging and tissue examination, including tuberculosis culture and acid-fast staining, are recommended.

OA31 Vitamin C deficiency presenting as juvenile idiopathic arthritis in an autistic child: a case study

Abstract Introduction Considered rare in the UK, we present a case of scurvy presenting as juvenile idiopathic arthritis (JIA). Scurvy is caused by vitamin C deficiency; the incidence is reported as 0.48 cases per 100,000 children under 16 years of age (2015–2017) in the UK. Scurvy is associated with gingival hypertrophy, petechiae, and musculoskeletal pain. The musculoskeletal manifestations and systemic features can present as JIA. This case highlights the importance of considering nutritional deficiencies in the differential diagnosis of paediatric patients presenting with symptoms similar to JIA to avoid misdiagnosis and ensure appropriate management. Case description A seven-year-old child with autism presented to the A/E with a week’s history of limping. Hip X-rays and blood tests were normal, so he was discharged. A week later, he returned with worsening symptoms, including swelling of the right knee. Blood tests and ultrasounds of bilateral hips and knees were normal, and he was once again discharged. On Day 14 of the illness, he was readmitted with increased right knee swelling and fever. Blood tests showed elevated inflammatory markers (ESR 26 mm/hr, CRP 33 mg/L). He was commenced on IV ceftriaxone for suspected osteomyelitis, but continued to experience low-grade fevers and developed swelling in the opposite knee, right ankle and mid-foot. On Day 22 of his illness, he was transferred to the Evelina and was found to have polyarthritis, reduced mobility, gingival hypertrophy and fever. Bloods revealed dropping counts, Hb 74 g/L, WBC 1.9 x 10^9/L and neutrophils 0.5 x 10^9/L, along with rising ferritin (96 -&amp;gt; 301 µg/L), dropping ESR (63 -&amp;gt; 17 mm/hr), and elevated LDH (428 U/L). Immunophenotyping and blood films were negative, leading to a provisional diagnosis of juvenile idiopathic arthritis (JIA) with evolving macrophage activation syndrome (MAS). He was started on anakinra and IV methylprednisolone. A full-body MRI revealed extensive metaphyseal signal abnormalities and mild soft-tissue oedema without active synovitis or joint effusion. The differentials included CRMO, lymphoproliferative disease, and scurvy. By this time, the lab Vitamin C level returned as extremely low at &amp;lt; 2.8 (ref 26-84 µmol/L). Following vitamin C supplementation and dietary support, his full blood count, ferritin, ESR and CRP normalised. He was gradually weaned off anakinra and steroids. His joint swelling, fever, and pain resolved, and he began to remobilise. The patient was discharged under the care of community paediatrics, a dietitian, and the physiotherapy team. Discussion Scurvy results from a severe deficiency of vitamin C in the diet. It is less common than other nutritional deficiencies, often leading to delayed diagnosis, particularly in developed countries. Children with unusual eating habits, global developmental delay or social communication disorders are at higher risk of developing this condition. This was an intriguing case of polyarthritis associated with scurvy. Vitamin C is essential for the synthesis of collagen, carnitine and certain neurotransmitters. It plays a critical role in immune function and the absorption of iron from the gut. Prolonged dietary insufficiency of vitamin C can lead to impaired collagen synthesis. In approximately 80% of instances, scurvy presents with musculoskeletal symptoms such as joint pain, muscle pain, haemarthrosis, and muscle haematomas. Gingival hypertrophy in a child with significant autism was the trigger to investigate vitamin C levels in our patient with polyarthritis. The eventual diagnosis of scurvy was confirmed by low vitamin C levels combined with the MRI findings. This case underscores the importance of considering nutritional deficiencies in patients with complex presentations and highlights the need for a thorough dietary history. Key learning points • Importance of dietary history: The primary learning point from this case is the critical importance of obtaining a comprehensive dietary history in paediatric patients, particularly those with atypical eating habits or developmental delay/social communication disorders. • Importance of a thorough clinical examination: The gingival hypertrophy in the case was the giveaway to check vitamin C levels. • Differential diagnosis of musculoskeletal symptoms: This case highlights the necessity of including nutritional deficiencies, such as scurvy, in the differential diagnosis of musculoskeletal symptoms like joint pain and swelling. • Role of a multidisciplinary approach: The successful management of this case underscores the importance of a multidisciplinary approach. Involving specialists from rheumatology, orthopaedics, nutrition, and general paediatrics was essential in reaching the correct diagnosis and providing comprehensive care. This collaborative effort ensured that all aspects of the patient’s condition were addressed. • Early intervention and treatment: Early intervention with vitamin C supplementation led to a rapid resolution of symptoms and normalisation of inflammatory markers. This case demonstrates the effectiveness of timely treatment in preventing long-term complications and improving patient outcomes. It also highlights the importance of considering vitamin supplementation in patients at risk of dietary deficiencies. The WHO recommends all children under 5 are supplemented with multivitamins.

Role Of Expanded Curb-65 Score In Predicting The Severity Of Community Acquired Pneumonia

Introduction: Assessment of severity and site of care decisions for community-acquired pneumonia patients (CAP) are very important for patients’ safety and optimal use of resources. Late admission to the intensive care unit (ICU) leads to increase the rate of mortality in CAP. We aimed to evaluate the effectiveness of the new expanded CURB-65 score in comparison with CURB-65 in predicting CAP patient outcomes. Materials and Methods: This was a cross sectional study which includes 90 patients presented with CAP in Government hospital for chest and communicable disease, AMC, Visakhapatnam Results: The study included 90 patients hospitalized with CAP of which mean (SD) age distribution is 51.49±16.63 years, with 64.4% being men and 83.3% of CAP patients had associated comorbidities. All patients (100%) had elevated serum LDH (&gt; 230U/L), 87.8% had hypoalbuminemia, 8.9% had thrombocytopenia, and 4.44% had elevated BUN values within 24 hours of admission. Regarding outcomes, the ICU admission rate was 36.7%, the 30-day mortality rate was 14.4%, and 35.6% required mechanical ventilation. There was a significant association between tachypnea (respiratory rate &gt;30/min), confusion, and thrombocytopenia (Platelet Count &lt; 100×103/mm3) with 30-day mortality, according to univariate analysis. The current study found that as 30-day mortality for Expanded CURB score of (0-2), (3-4) and (5-8) is 0,4%and 9% respectively, requirement of mechanical ventilation and ICU admission rate were 2%,22%, 8% and2%,23%,8% respectively. Length of hospital stay increase as the score increase with median length of hospital stay being 7 days. Conclusion: Compared to CURB-65 and other assessment tools, the Expanded-CURB-65 score, which extends independent risk factors to 8 variables in assessing CAP severity, significantly improves identifying high-risk patients and thereby helps in early institution of appropriate therapy

Triple immunostaining demonstrates the possible existence of segregated-nucleus-containing atypical monocytes in human primary myelofibrosis bone marrow: a case report

BackgroundSegregated-nucleus-containing atypical monocytes have recently been identified in mice. Segregated-nucleus-containing atypical monocytes are thought to originate from the bone marrow and induce fibrosis in the drug-injured lung. The Lyc6c− murine monocyte subset is the counterpart to human CD14−CD16++ non-classical monocytes; however, the human counterpart to murine segregated-nucleus-containing atypical monocytes has not yet been identified. Primary myelofibrosis is a well-known disease of progressive marrow fibrosis, and atypical megakaryocytes are thought to be closely related to fibrosis in primary myelofibrosis bone marrow. However, recently, monocytes have been reported to play an important role in marrow fibrosis in primary myelofibrosis. We speculated that, if there is a human counterpart to murine segregated-nucleus-containing atypical monocytes, it would present the same markers as murine segregated-nucleus-containing atypical monocytes, such as CD14−CD16+ macrophage-1 antigen (CD11b/CD18 complex)+, MSR1+, and CEACAM1+, and it might exist in the bone marrow of patients with primary myelofibrosis.Case presentationA 74-year-old Japanese male visited our hospital for clinical follow-up after total prostatectomy for prostatic cancer. Anemia, thrombocytosis, and elevated lactate dehydrogenase were suddenly observed in a periodic examination. CALR mutation type 2 (p.K385fs*47) was observed. The histological features of the patient’s bone marrow were consistent with fibrotic primary myelofibrosis. We immunohistochemically studied the bone marrow in an attempt to identify a human counterpart to murine segregated-nucleus-containing atypical monocytes. We detected a few CD16+MSR1+CEACAM1+ cells, but not CD14+MSR1+CEACAM1+ cells, by triple immunostaining. The patient is in a good condition and does not require treatment for primary myelofibrosis.ConclusionThere is a possibility that human segregated-nucleus-containing atypical monocytes exist in the bone marrow of primary myelofibrosis patients and might be related to marrow fibrosis.

Clinical Characteristics and Treatment Courses of Trauma-Induced Thrombotic Microangiopathy: A Retrospective Study.

Introduction: Thrombotic microangiopathy (TMA), defined by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, is not widely recognized as being trauma-related. This study aimed to describe the clinical features and outcomes of trauma-induced TMA (t-TMA) to assist in early diagnosis and management. Methods: A retrospective review was conducted on 30 trauma patients diagnosed with t-TMA between 2014 and 2019. Demographic, clinical, and laboratory data, as well as treatment methods, were analyzed. Results: Thrombocytopenia (<50,000/µL) occurred, on average, 2.9 days post-trauma, with diagnosis following 3.6 days later. Patients had a mean age of 67.6 years, and 63.3% were male. Clinical presentations included acute kidney injury (AKI) requiring renal replacement therapy (86.7%), altered mental status (53.3%), non-infectious fever (50%), and digital necrosis (43.3%). Eighteen patients were treated with therapeutic plasma exchange (TPE) alone, nine with TPE and methylprednisolone, and three with methylprednisolone alone. Remission was achieved in 96.7% of all cases. The mean TPE duration was 6.1 days, prolonged by prior platelet transfusions. The mortality rate was 26.7% (8/30), with sepsis being the most common cause of death (five patients), particularly for those treated with TPE and methylprednisolone. Conclusions: Trauma-induced TMA should be suspected in trauma patients presenting with unexplained thrombocytopenia, AKI, and elevated LDH. Early diagnosis and prompt treatment are crucial, while unnecessary platelet transfusions should be avoided. Careful infection management is critical to improving patient outcomes, particularly if patients are treated with TPE and methylprednisolone.

Pediatric B-cell Non-Hodgkin Lymphoma: The Impact of Therapy Response and Relapse on Outcome. A Single-center Analysis.

Pediatric patients with primary refractory or relapsed B-cell non-Hodgkin lymphoma (B-NHL) have highly unfavorable prognosis. In this study, we retrospectively analyzed outcomes in pediatric B-NHL patients treated in a single center in Poland from 1995 to 2022, with emphasis on therapy results in patients with progression or relapse. The primary objectives were a 5-year probability of overall survival (pOS) and a 5-year probability of event-free survival (pEFS). The secondary objectives involved the assessment of prognostic factors. A total of 76 children were eligible for the analysis. The 5-year pOS was 76.7%, and the 5-year pEFS was 72.9%. At diagnosis, elevated lactate dehydrogenase activity, the presence of B symptoms, bone marrow, skeletal or mediastinal involvement, and stage IV disease were associated with inferior outcomes. Nine children experienced progression and four relapse. The 5-year pOS for patients with progression was 38.1%. Two patients treated with hematopoietic stem cell transplantation (HSCT) as part of salvage therapy survived. However, only one out of seven patients who were treated without HSCT survived. The 5-year pOS was 0.0% in patients with relapsed disease. The most significant factor related to outcomes in pediatric B-NHL is therapy response, with a high mortality rate in children with refractory disease and relapse. There is no consensus on the salvage therapy approach; however, HSCT appears to be the optimal choice.

Increased serum level of IL-6 predicts poor prognosis in anti-MDA5-positive dermatomyositis with rapidly progressive interstitial lung disease

BackgroudAnti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-positvie DM) is a subtype of dermatomyositis with a poor prognosis, characterized by rapidly progressive interstitial lung disease (RP-ILD). The study aims to investigate the significance of serum cytokines profiles and peripheral lymphocytes in predicting prognoses of anti-MDA5-positvie DM with RP-ILD. Furthermore, it seeks to analyze longitudinal data of lymphocytes during hospitalization to identify distinct trajectories and cluster patients accordingly.MethodsA total of 168 patients with anti-MDA5-positive DM were enrolled in this retrospective study from two cohorts. Univariate and multivariate Cox regression analyses were conducted to determine the predictors of 6-month all-cause mortality and RP-ILD. Group-based trajectory modeling (GBTM) was employed to model the trajectories of longitudinal peripheral lymphocytes.ResultsIn the multivariate Cox regression analysis, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 109 /L, lymphocytes from 0.5 to 1.0 × 109 /L, older age, and elevated LDH were identified as independent predictors of 6-month all-cause mortality. Furthermore, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 109 /L, and lymphocytes from 0.5 to 1.0 × 109 /L were found to be independent predictors of RP-ILD. Additionally, three trajectory groups of lymphocytes within the first week after admission were established based on GBTM. These groups included: Group 1, with low-level of lymphocytes that declined; Group 2, with medium-level of lymphocytes that slightly rose; and Group 3, with high-level of lymphocytes that rose. Notably, group 1 showed the highest mortality (90.7%) and all experiencing RP-ILD. Increased expression of IL-6 in lung tissues was observed in two cases with RP-ILD compared to two cases without RP-ILD. We also found the increased infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, in lung tissues from patients with RP-ILD.ConclusionsOur study demonstrated that increased level of serum IL-6 (≥ 13.41pg/mL) and severe lymphopenia were promising predictors of 6-month all-cause mortality and the occurrence of RP-ILD in anti-MDA5-positive DM patients. Furthermore, tracking distinct trajectories of lymphocytes during hospitalization can be utilized to cluster patients.

Investigating the Relationship Between Demographic and Laboratory Factors with the Incidence of PTE in COVID-19

Background: In 2019, after the first case was discovered in Wuhan, China, the COVID-19 virus began to spread rapidly across the world, leading the WHO to declare the disease a public health emergency. Objectives: Thromboembolism refers to the formation of a clot in a vein, which then travels through the vascular system, potentially blocking blood flow in another location. Methods: This retrospective cohort study aimed to investigate the risk factors for pulmonary embolism in COVID-19 patients hospitalized at Firoozabadi Hospital from May to the end of December 2020. After extracting the required information, the data was entered into SPSS version 26 software for analysis. Results: In total, data from 283 COVID-19 patients admitted to Firouzabadi Hospital in Tehran in 2020 were collected. The average age of the patients was 58.8 ± 15.9 years. Among the 283 patients, 162 (57.6%) were male, 79 patients (27.9%) had pulmonary embolism, 102 patients (36%) were smokers, and 107 patients (37.8%) had a history of hypertension. A significant relationship was observed between the occurrence of pulmonary embolism and elevated levels of, white blood cells (WBC) (P = 0.0001), lactate dehydrogenase (LDH) (P = 0.0001), D-dimer (P = 0.0001), polymorphonuclear neutrophils (PMN) (P = 0.020), lymphocytes (P = 0.013), alkaline phosphatase (Alk.P) (P = 0.025), alanine aminotransferase (ALT) (P = 0.019), and aspartate aminotransferase (AST) (P = 0.017). Conclusions: Based on the results of this study, the incidence of pulmonary embolism in hospitalized COVID-19 patients who underwent CT angiography due to clinical suspicion of thrombosis was 27.9%. Additionally, factors such as smoking, a previous history of pulmonary thromboembolism, high WBC, elevated liver function tests (LFT), and elevated LDH levels were identified as risk factors for the occurrence of pulmonary embolism in these patients.

COMPREENDENDO A INTERSEÇÃO ENTRE HIV/AIDS E PNEUMONIA: UMA ANÁLISE ABRANGENTE DA LITERATURA

INTRODUCTION: The relationship between HIV/AIDS and pneumonia is complex and multifaceted. Individuals infected with HIV have a significantly higher risk of developing pneumonia, caused by both bacterial and viral agents, due to immune suppression from the virus. OBJECTIVE: To identify in the literature the relationship between HIV/AIDS and pneumonia in the context of nursing care. MATERIALS AND METHODS: This is an integrative literature review conducted in the MEDLINE, LILACS, and BDENF databases, using the descriptors: “HIV seropositivity,” “Pneumonia,” and “nursing care.” The descriptors were combined using the boolean operator AND, covering the period from 2018 to 2024. RESULTS: The study found that HIV-positive patients tend to experience a subacute progression of Pneumocystis jirovecii pneumonia (PCP), while immunocompromised patients without HIV face rapid progression, with a higher risk of respiratory failure and mortality. CT scans showed ground-glass opacities and elevated lactate dehydrogenase levels. Non-HIV patients had longer treatment delays and higher hospitalization and mortality rates. Lymphopenia, steroid use, and pneumothorax were associated with 60-day mortality. The incidence of bacterial pneumonia in people living with HIV decreased, linked to improved CD4 counts. Children with HIV showed higher mortality from coronavirus-related pneumonia. CONCLUSIONS: Future research should expand epidemiological surveillance, explore new therapies, and investigate co-infections in at-risk groups, particularly children. Additionally, strengthening public health policies and promoting prevention education are essential to improve clinical outcomes in vulnerable populations.

Risk factors for in-hospital mortality in older patients with acute respiratory distress syndrome due to COVID-19: a retrospective cohort study

BackgroundAdvancing age is associated with an increase in mortality among patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). This study aimed to determine risk factors for in-hospital mortality in patients over 60 years old with COVID-19-related ARDS (C-ARDS).MethodsThis was an observational, analytical, retrospective study conducted on a cohort that included all patients aged 60 years or older diagnosed with COVID-ARDSwho were admitted to a high-complexity hospital in Bogotá, Colombia, between March 2020 and July 2021.ResultsA total of 1563 patients were included in the analysis, with a median age of 73 years (interquartile range [IQR]: 67–80) and 811 deaths (51.8%). Independent risk factors for in-hospital mortality were identified as follows: patients aged 71–80 [OR 1.87 (95% CI 1.33–2.64)], age > 80 [OR 8.74 (95% CI 5.34–14.31)], lactate dehydrogenase (LDH) [OR 1.009 (95% CI 1.003–1.0015)], severe C-ARDS [OR 2.16 (95% CI 1.50–3.11)], use of invasive mechanical ventilation (IMV) [OR 12.94 (95% CI 9.52–17.60)], and use of steroids [OR 1.49 (95% CI 1.09–2.03)]. In patients over 80 years of age (n = 388), the primary risk factor associated with in-hospital mortality was the use of IMV (n = 76) [OR 6.26 (95% CI 2.67–14.69)], resulting in an in-hospital mortality rate of 89.4% (n = 68) when this therapy was implemented.ConclusionsThe primary risk factors for in-hospital mortality in patients older than 60 years were age, the use of IMV, the severity of C-ARDS, use of steroids and elevated LDH values. Among patients older than 80 years, the main risk factor for in-hospital mortality was the use of IMV. In cases of C-ARDS in older patients, the decision to initiate IMV should always be individualized; therefore, the use of alternative oxygen delivery systems as the first-line approach can be considered.

Different antinuclear antibody subgroups of anti-melanoma differentiation-associated gene 5-positive dermatomyositis had variability in clinical presentation: a multicentre retrospective cohort study

IntroductionThis study aimed to investigate the association between ANA and clinical characteristics as well as prognosis in a cohort of patients with anti-MDA5+ DM.Material and methodsWe conducted a systematic retrospective study of medical records from Nanjing Medical University myositis associated interstitial lung disease (ILD) contort.ResultsA total of 246 patients with anti-MDA5+ DM were enrolled in this study, with 28.5% males and 71.5% females. The median age was 53.0 years, the median disease duration was 2 months, and the median follow-up period was 12.0 months. ANA positivity rate at baseline was 52.4% in anti-MDA5+ DM patients. The ANA-positive group showed significantly higher positivity rates of anti-Ro52 antibodies (72.9% vs 54.7%, p=0.003) and anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies (9.3% vs 2.6%, p=0.033) compared to the ANA-negative group, but lower ALT levels [39.0 (21.5, 79.3) vs 51.3 (36.5, 95.8), p=0.006].In a subgroup analysis of the ANA-positive group, MDA5+++ patients had a higher incidence of RPILD compared to the MDA5+ group (P=0.028). In the ANA negative subgroup analysis, MDA5+++ patients had a higher mortality rate and worse prognosis compared to the MDA5+ group (P=0.026). Multivariate COX regression analysis showed that elevated LDH levels and the presence of rapidly progressive interstitial lung disease (RPILD) were associated with poor prognosis in ANA-negative anti-MDA5+ DM patients [hazard ratios of 1.002 (95% CI 1.001, 1.003, P = 0.020) and 13.694 (95% CI 15.032, 37.267, P &lt; 0.001), respectively].ConclusionsANA is frequently found in patients with anti-MDA5+ DM. High titres of anti-MDA5 antibodies are associated with mortality and RPILD.