Asparaginase Induced Liver Enzyme Elevation Is More Prevalent in Hispanics Children with ALL and in Patients with SOD2 rs4880 CC Genotype

Background: Asparaginase is an integral component of treatment for pediatric patients with acute lymphoblastic leukemia (ALL). Hepatotoxicity secondary to asparaginase-based treatment is one of the most common treatment-related toxicities in ALL therapy. Hispanic children are at higher risk of ALL and ALL treatment related toxicities compared with other ethnicities. The rs4880 variant in the SOD2 gene, a critical mitochondrial enzyme that protects cells against oxidative stress, was previously found to be associated with increased incidence of hepatotoxicity following asparaginase treatment in an adult ALL cohort of largely European ancestry. Whether this association is also present in pediatric patients with ALL and in Hispanics remains unknown. Importantly, the risk genotype (CC) of rs4880 is more frequent among Hispanics. Here we aim to investigate the prevalence of hepatotoxicity and risk genotype among pediatric patients with ALL particularly of Hispanics ancestry. Method: Blood samples, demographic and clinical data were obtained from 143 pediatric patients treated for ALL between 29 January 2015 and 24 January 2020 at Children's Hospital Los Angeles. We genotyped DNA samples isolated from the patient's blood for the rs4880 variant of SOD2 using TaqMan Allelic Discrimination Assay. Liver enzyme data, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels for each subject following multiple visits before and post asparaginase-based treatment were obtained. Hepatotoxicity is defined as grade 3/4 of both AST and ALT, grade 4 of either AST or ALT, or grade 3/4 of bilirubin. We performed Cox Proportional Hazards models to evaluate the predictive factors of hepatotoxicity overtime. Results: Among the 143 patients, 13 (9.09%) patients had grade > 3 elevated bilirubin levels, and 3 (2.1%) and 55 (38.46%) patients had grade > 4 and > 3 elevated AST levels respectively, and 19 (13.29%) and 109 (76.22%) had grade > 4 and > 3 elevated ALT levels respectively. Hepatotoxicity was observed in 60 (41.96%) of patients. After dichotomizing patients based on ethnicity (Hispanic and non-Hispanic), we found that BMI was significantly higher in Hispanics than non-Hispanic patients (mean BMI: 21.57 vs 18.64, p=0.002). While mean baseline levels of liver enzymes were not significantly different between Hispanic and non-Hispanic patients (bilirubin:0.69 vs 0.64, ALT: 156.06 vs 124.75, and AST: 99.98 vs 82.38), post-treatment levels were significantly higher in hispanics (ALT: 138.105 vs. 101.45, p=0.0005; AST: 84.131 vs. 64.045, p=0.0023). After chemotherapy, grade 3 or 4 elevated bilirubin was found in 11 (12.36%) of 89 Hispanic patients and only in 2 (3.7%) of 54 non-Hispanic patients. Also, there was a statistically significant difference in the frequency of elevated ALT level grade > 4 and grade > 3 between Hispanic and non-Hispanic patients (grade > 4: 17 (19.10%) vs 2 (3.70), p= 0.01; grade > 3: 74 (83.15%) vs 35 (64.8%), p=0.01). Consequently, Hepatotoxicity was more frequent among Hispanic patients than non-Hispanic, 47.19% vs 33.33%; p=0.10, respectively. We also compared hepatotoxicity parameters according to the patient's rs4880 genotypes. Among patients with the SOD2 rs4880 CC genotype 3 (6.32%) had grade > 4 and 23 (50%) had grade > 3 elevated AST compared with 0 (0%) and 21 (30%) among the CT and 0 (0%) and 11 (40.74%) among the TT genotype patients (CC vs. CT and TT; AST grade > 4: p=0.13; grade > 3 : p=0.05). In addition, elevated bilirubin grade > 3 was found more frequently in patients with the SOD2 rs4880 CC genotype (15.22%) compared with those with the CT (5.71%) and TT (7.41%) genotypes. Furthermore, post-treatment bilirubin, ALT and AST median levels were significantly higher in patients with the CC genotype than in patients with CT or TT genotypes (bilirubin: 0.8275 vs. 0.6, p=0.0007; ALT: 142.555 vs. 106.038, p=0.0089; AST: 85.399 vs. 67.888, p= 0.0302). In a multivariate Cox analysis, that included ethnicity, age, gender, BMI and genotype, we identified Ethnicity (Hispanic) as the only significant predictor of hepatotoxicity (hazard ratio [HR] = 1.862, 95% confidence interval [95% CI] 1.-3.465, p=0.0499). Conclusion: Overall, these findings suggested that hepatotoxicity is highly prevalent among Hispanic pediatric patients with ALL, especially those with CC genotype of rs4880. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria.

The pathophysiology of sepsis — 2021 update: Part 2, organ dysfunction and assessment

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose This is the second article in a 2-part series discussing the pathophysiology of sepsis. Part 1 of the series reviewed the immunologic response and overlapping pathways of inflammation and coagulation that contribute to the widespread organ dysfunction. In this article (part 2), major organ systems and their dysfunction in sepsis are reviewed, with discussion of scoring systems used to identify patterns and abnormal vital signs and laboratory values associated with sepsis. Summary Sepsis is a dysregulated host response to infection that produces significant morbidity, and patients with shock due to sepsis have circulatory and cellular and metabolic abnormalities that lead to a higher mortality. Cardiovascular dysfunction produces vasodilation, reduced cardiac output and hypotension/shock requiring fluids, vasopressors, and advanced hemodynamic monitoring. Respiratory dysfunction may require mechanical ventilation and attention to volume status. Renal dysfunction is a frequent manifestation of sepsis. Hematologic dysfunction produces low platelets and either elevation or reduction of leucocytes, so consideration of the neutrophil:lymphocyte ratio may be useful. Procoagulant and antifibrinolytic activity leads to coagulation that is stimulated by inflammation. Hepatic dysfunction manifest as elevated bilirubin is often a late finding in sepsis and may cause reductions in production of essential proteins. Neurologic dysfunction may result from local endothelial injury and systemic inflammation through activity of the vagus nerve. Conclusion Timely recognition and team response with efficient use of therapies can improve patient outcome, and pharmacists with a complete understanding of the pathophysiologic mechanisms and treatments are valuable members of that team.

Mildly Elevated Bilirubin Levels are Associated with Increased Magnetic Resonance Imaging Signal Intensity in the Basal Ganglia of Preterm Neonates

Objective This study aimed to test whether mildly elevated bilirubin levels in preterm infants are associated with increased signal intensity (SI) on magnetic resonance imaging (MRI) of the basal ganglia (BG). Study Design MRI was performed at term equivalent age in 55 postpreterm infants using a neonatal MRI 1-T scanner. SI of the BG was correlated with mild hyperbilirubinemia. Results BG MRI SI was significantly increased in infants with mild hyperbilirubinemia on T1-weighted image (T1; p = 0.0393) and T2-weighted image (T2; p = 0.0309). We found no effect of gestational age or sepsis on BG MRI intensity; however, there was a significant effect of acidosis on T1 (p = 0.0223) but not on T2 (p = 0.2316). Infants with combined hyperbilirubinemia and acidosis had the most significant increase in SI on both T1 and T2 respectively (p = 0.0072 and 0.0195, respectively). Conclusion We found a positive association between increased BG MRI SI and mildly elevated bilirubin levels. The effect was greatly strengthened when hyperbilirubinemia was associated with acidosis. Key Points

Leptospirosis in COVID-19 Positive Pregnancy: A Rare Case Report Mimicking Hellp Syndrome

Leptospirosis in pregnancy is often underdiagnosed and not commonly reported due to its unusual appearance and rarity. It looks like HELLP syndrome, obstetric cholestasis, viral hepatitis & pregnancy-related acute fatty liver. Miscarriages in the first trimester, stillbirths, and neonatal leptospirosis are serious complications that necessitate a high degree of concern, heightened sensitivity, and prompt diagnosis and treatment. We have one such incidence of leptospirosis in a COVID-19 positive pregnant female. A 21-year-old Primigravida with a predisposition of serious anaemia & thrombocytopenia, presented with fever, haematemesis, malena and sore throat at 38 weeks and 2 days gestation, during the COVID-19 pandemic. She had pallor, oedema, and haematuria on catheterization, rest all investigations were within normal limits. Proteinuria, haemolysis, low platelets, and elevated bilirubin were discovered during the investigation. Due to the lack of hypertension and elevated transaminases, the working diagnosis was atypical haemolysis, low platelets (HELLP) syndrome. The patient was tested for COVID-19 RT-PCR, came out to be positive and the fever spikes continued, leading to further investigations for Dengue, Malaria, Scrub Typhus, and Leptospirosis due to the ongoing Covid-19 pandemic. After the EIA (Enzyme Immunoassay) IgM antibody (confirmatory for Leptospirosis) tested positive for Leptospirosis, the decision to start Doxycycline was made. Meanwhile, the patient's CTG (Cardio tocograph) revealed signs of foetal distress, and a decision for an emergency LSCS was taken (Lower Segment Caesarean Section). The histology of the placenta after the section revealed normal findings. Doxycycline was initiated with a neonatal feeding regimen that was acceptable. On day two of life, the newborn had no indications of inherited leptospirosis and was removed from Neonatal Intensive Care. Within one week, the patient's symptoms had disappeared, and her biochemistry had went back to normal within 2 weeks.

Gene therapy for spinal muscular atrophy: the Qatari experience

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma®) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and July 2020. Children <2 years with 5q SMA with a bi-allelic mutation in the SMN1 gene were eligible for gene therapy. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin), platelet count, coagulation profile, troponin-I levels, and motor scores (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]), were regularly monitored following gene therapy. All patients experienced elevated AST or ALT, two experienced high prothrombin time, and one experienced elevated bilirubin; all of these patients were asymptomatic. Furthermore, one event of vomiting after infusion was reported in one patient. Significant improvements in CHOP INTEND scores were observed following therapy. This study describes the short-term outcomes and safety of onasemnogene abeparvovec, which is well tolerated and shows promise for early efficacy.

A 12-year study evaluating the outcomes and predictors of mortality in critically ill cancer patients admitted with septic shock

Background Though sepsis is common in patients with cancer, there are limited studies that evaluated sepsis and septic shock in this patient population. The objective of this study was to evaluate the outcomes and to identify predictors of mortality in cancer patients admitted to the intensive care unit (ICU) with septic shock. Methods This was a retrospective study conducted at a medical-surgical oncologic ICU of a comprehensive cancer center. Adult cancer patients admitted with septic shock between January 1, 2008 and December 31, 2019 were enrolled. Septic shock was defined as an ICU admission diagnosis of sepsis that required initiating vasopressors within 24 h of admission. Patient baseline characteristics, ICU length of stay and ICU and hospital mortality were recorded. Univariate analysis and logistic regression were performed to identify predictors associated with ICU and hospital mortality. Results During the study period, 1408 patients met the inclusion criteria. The mean age was 56.8 ± 16.1 (SD) years and mean Acute Physiology and Chronic Health Evaluation (APACHE) II was 23.0 ± 7.91 (SD). Among the enrolled patients, 67.8% had solid tumors while the remaining had hematological malignancies. Neutropenia and thrombocytopenia were reported in 19.3 and 39.5% of the patients, respectively, and mechanical ventilation was required for 42% of the patients. Positive cultures were reported in 836 (59.4%) patients, most commonly blood (33%) and respiratory (26.6%). Upon admission, about half the patients had acute kidney injury, while elevated total bilirubin and lactic acid levels were reported in 13.8 and 65.2% of the patients, respectively. The median ICU length of stay was 4 days (IQR 3–8), and ICU and hospital mortality were reported in 688 (48.9%) and 914 (64.9%) patients, respectively. Mechanical ventilation, APACHE II, thrombocytopenia, positive cultures, elevated bilirubin and lactic acid levels were significantly associated with both ICU and hospital mortality. Conclusions In a relatively large cohort of patients with solid and hematological malignancies admitted to the ICU with septic shock, hospital mortality was reported in about two-third of the patients. Mechanical ventilation, APACHE II, thrombocytopenia, positive cultures, elevated bilirubin and lactic acid levels were significant predictors of mortality.

Neonatal Physiological Jaundice and Repertoire of Movements on the Second or Third Days of Life

Physiological jaundice appears after the first day of life and has a mild form in most cases. High bilirubin levels can lead to jaundice of the basal ganglia and cause severe movement disorders in the form of extrapyramidal forms of cerebral palsy. The aim of the study was to assess the effect of bilirubin levels on the motor activity of infants and the relationship between bilirubin levels and selected sociometric and biometric characteristics. The study included a group of 77 newborns of both sexes. Medical records were analyzed to determine their socio- and biometric characteristics. Bilirubin levels were evaluated using transcutaneous bilirubin (TcB) measurement with a Minolta JM-103 jaundice meter according to Kramer’s method consisting in bilirubin measurements in different parts of the body. The head measurement was considered the most important for infants on the second or third day of life, and it was considered a reference for other variables. Analysis of neonatal activity was performed using video recording with a Sony camera with Full HD 1080p resolution (1920x1080, 60 fps). Each infant was assessed independently by three experts qualified in Prechtel's General Movements Assessment diagnosis. No statistically significant differences in quantitative movement characteristics were observed between infants with normal and elevated bilirubin levels. The relationships were found between sociometric and biometric characteristics and bilirubin levels measured on the head. The analyses indicated that in the course of physiological jaundice, the bilirubin levels had no effect on their qualitative and quantitative movement parameters in the group of infants studied.

Alkaloidal fraction of Diospyros mespiliformis protect against Trypanosoma evansi-mediated haematological and hepatic impairment in infected rats

The present study investigated the antitrypanosomal activities of crude and an alkaloidal fraction of Diospyros mespiliformis in Trypanosoma evansi - infected rats. A total of twenty-one (21) rats were divided into seven (7) groups of three (3) rats each. Groups 1-6 were infected with the T. evansi parasite and were treated with 100 and 200 mg/kg BW crude extract, 200 and 400 mg/kg BW of the alkaloid fraction of D. mespiliformis, 3.5mg/kg of berenil (standard control) and 0.2 mL/kg BW of normal saline (negative control) respectively. Group 7 serves as the normal control (non-infected and non-treated) rats. Results revealed that the crude extract at 400 mg/kg BW and alkaloid fraction at all doses tested (100 and 200 mg/kg BW) significantly (P<0.05) increased the RBC, PCV, MCH, MCHC, WBC, and reduced the elevated bilirubin when compared with the untreated control. The extract also significantly increased the reduced total proteins. In conclusion, an alkaloid from Diospyros mespiliformis ameliorative effect on T. evansi-induced biochemical and hematological alterations in rats, thus could be considered a novel agent for the development of a new drug against trypanosomiasis

HYPERBILIRUBINEMIA AS AN INDICATOR IN PERFORATED APPENDICITIS

Introduction: Acute appendicitis is one of the most common causes of urgent admission to the hospital.In appendicitis, elevated intra-luminal pressure and ischemic necrosis of mucosa causes tissue gangrene or perforation. This leads to cytotoxin facilitated progressive bacterial invasion or translocation into the hepatic parenchyma through portal system. This phenomenon interferes with the bilirubin excretion into the bile canaliculi. The rate of misdiagnosis of appendicitis and the rate of appendicular perforation has remained constant, inspite of increased use of ultrasonography, computed tomography scanning and laparoscopy. Among commonly used inammation markers of Acute appendicitis, bilirubin concentration is not well studied and thus is rarely applied. Every investigation that can contribute towards a diagnosis of appendicitis is valuable to the emergency general surgeon Aim: 1. To study the relationship between hyperbilirubinemia and acute appendicitis; and to evaluate its credibility as a diagnostic marker for acute appendicitis. 2. To evaluate whether elevated bilirubin levels have a predictive potential for the diagnosis of Appendicular perforation. Material and methods: The study was conducted in the Department of General Surgery, Navodaya Medical College & Research centre, Raichur during the period of January 2020 to December 2020.Patients admitted with clinical diagnosis of acute appendicitis or appendicular perforation under the Department of Surgery, Navodaya Medical College & Research centre, Raichur during the study period. A total of 100 patients with clinical diagnosis of acute appendicitis or appendicular perforation were studied. Results: .Normal bilirubin values were seen in 26% patients while, 74% had raised bilirubin levels (Hyperbilirubinemia). Of 81 patients with acute appendicitis, 71.6% had raised bilirubin levels, while 28.4% had normal levels. 19 patients were diagnosed as Appendicular perforation, 16 patients (84.21%) had raised bilirubin levels, while the remaining 03 patients (15.79%) had normal levels.Amongst the patients diagnosed with Acute appendicitis without perforation (n=81), 58 patients (71.6%) were found to have elevated bilirubin (>1.0 mg/dL) while only 23 patients (28.4%) had normal bilirubin levels (≤1.0 mg/dL). In patients diagnosed with Appendicular perforation (n=19), 16 patients (84.21%) had bilirubin elevated (>1.0 mg/dL), while only 3 patients (15.79%) had normal levels (>1.0 mg/dL). Thus, Hyperbilirubinemia was found in most of the patients diagnosed with acute appendicitis (71.6%) or Appendicular perforation (84.21%). Conclusion: The present study suggests- Serum bilirubin levels appears to be a promising new laboratory marker for diagnosing acute appendicitis, however diagnosis of appendicitis remains essentially still - clinical. Its level come out to be a credible aid in diagnosis of acute appendicitis and would be helpful investigation in decision making. Patients with clinical signs and symptoms of appendicitis and with hyperbilirubinemia higher than the normal range should be identied as having a higher probability of Appendicular perforation suggesting, serum bilirubin levels have a predictive potential for the diagnosis of Appendicular perforation.