Cytokine release syndrome: a primer for generalists

Covering the Cover

Objective To construct the active monitoring system for adverse drug reactions based on the trigger technology and explore its application value. Methods Based on the DTHealth system and electronic medical records system, using the Brower/Server architecture, DHCMedBase2.0.doc, Ext 3.1-API Documentation technology to design the trigger of the data definition language. The monitoring group selected the adverse drug reactions which can be used to reflect with the laboratory information, 12 triggers were chosen after communicating with the clinical medical staff, the related procedures were embedded in the hospital information system, accordingly, the active monitoring system of adverse drug reaction based on the trigger technology were constructed. By the three pharmacists the full-time work, the monitoring work within 23 wards of the hospital about 800 patients were finished through the triggers of adverse drug reactions monitor, and the suspected adverse drug reactions were filtered, evaluated and reported. Results The active monitoring system of adverse drug reactions based on the trigger technology started operation in January 1st, 2014, and run until the June 30th, 2014, 561 positive patients were monitored by the triggers, and 71 adverse drug reactions which involved 28 kinds of drugs were identified, the total positive rate was 12.7%. The laboratory index of 21 patients were found to have a marked abnormality but not beyond the normal range, among them the 12 patients had to change the treatment to avoid the possible adverse drug reactions. Conclusion The application of the trigger technology successfully constructed the active monitoring system of adverse drug reactions, which can improve efficiency of the active monitoring for adverse drug reactions, at the same time, realize the early warning function. Key words: Drug-related side effects and adverse reactions; Drug monitoring; Automatic data processing

To evaluate the pattern of immunosuppressive drug adverse reactions in adult kidney transplant recipients in Iran. Adult kidney transplant outpatients under immunosuppressive therapy were recruited into the study. All adverse drug reactions to immunosuppressants and their relevant clinical and paraclinical characteristics were recorded. Causality assessment was performed by the Naranjo algorithm. The seriousness of adverse drug reactions was determined by the World Health Organization definition. The Schumock and Thornton questionnaire was used to assess the preventability of adverse drug reactions. Statistical analyses were performed. A total of 1100 adverse drug reactions were detected from 120 kidney transplant recipients. Increased appetite (9.09%) was the adverse reaction reported most frequently. Causality assessment revealed that 1019 adverse drug reactions (92.64%) were possible. Forty adverse drug reactions (3.64%) were identified as serious. Six hundred seventy-one adverse drug reactions (61%) were preventable. Posttransplant duration was significantly correlated with the number of adverse drug reactions (R=0.19; P = .035). All renal allograft recipients experienced at least 1 immunosuppressant-related adverse reaction. Prolongation of immunosuppressive treatment resulted in an increase in adverse drug reactions.

Systemic Inflammatory Response Syndrome After Cardiac Surgery: Time for a Change

High frequency of adverse drug reactions (ADRs) challenges multiple sclerosis (MS) treatment. This study aims to assess the nature and frequency of ADRs induced by MS medications in an observational cross-sectional study. ADRs of all outpatients who had seen a neurologist and had received at least one disease-modifying therapy (DMT) for MS during the last three months were investigated. A total of 484 ADRs were detected in these patients. The preventability rate was 5.9%, and 0.61% of reactions were serious. The high frequency of adverse drug reactions in this study shows a strong need for strategy planning to increase patients' adherence to treatment. Adverse drug reactions (ADRs) are common in MS patients using disease modifying therapies.Such ADRs are more common in women than men.Various brand names of biosimilar disease-modifying therapy (DMT)s may have a different ADR profile. Multiple sclerosis (MS) is a condition that can be managed by using disease modifying medications. Such medication could trigger an adverse reaction in the patients., affecting their commitment to the treatment. By identifying these adverse reactions and educating the MS patients about these reactions and how the adverse effects can be managed, healthcare providers can improve the treatment process. This study recorded the adverse drug reactions in 250 MS patients who were receiving the medication for at least three months. Most of the patients (76.4%) experienced some kind of adverse reaction. A bigger proportion of women experienced adverse reactions than men. About 84% of these reactions occurred within the first 3 hours of receiving the medication. Depending on the medication's brand name, the rate of adverse drug reactions were different in some cases. The results of this study point out the fact that experiencing adverse drug reactions is common in MS patients and these experiences could be different for each medication with a different brand name. Therefore, it is important for the healthcare providers to inform the patients about such reactions and the patients should seek all the information they need to manage these adverse effects by consulting their physician.

In 2018, the European Medicines Agency issued some risk minimisation measures related to unresolved adverse drug reactions (ADRs) reported for fluoroquinolones, including sensory ADRs. Spontaneous reporting databases frequently report unresolved outcomes for gustatory, olfactory and auditory (GOA) ADRs. However, such a high volume of unresolved GOA ADRs could reflect an under-investigated clinical issue or an intrinsic difficulty in the outcome assessment. The objectives of the study were: (1) to investigate whether unresolved outcomes are reported more frequently for GOA ADRs than for other ADRs to systemic antibiotics and (2) to identify possible signals of unresolved GOA ADRs for systemic antibiotics. We used the EudraVigilance database to extract the number of ADRs to systemic antibiotics of the Anatomical Therapeutic Chemical class J01 up to February 2019. We classified ADRs in "non-GOA ADRs" and "GOA ADRs". Adverse drug reactions were categorised in three groups according to the outcome: defined, persistent/permanent (unresolved) and undetermined ADRs. We performed disproportionality analyses with the case/non-case methodology, by calculating the crude reporting odds ratio (ROR) and 95% confidence interval (CI). Cases were all persistent/permanent ADRs, and non-cases were defined and undetermined ADRs. For the first objective, index groups were gustatory or olfactory or auditory ADRs, while reference group included all non-GOA ADRs. For the second objective, we performed a disproportionality analysis by using the sub-set of GOA ADRs. Index and reference groups varied with subgroups of drugs and drug class, so that each drug and drug class was compared with the others. We conducted two sensitivity analyses for each analysis by varying the case definition. We extracted 748,798 ADRs, including 10,770 GOA ADRs. The first analysis showed that GOA ADRs were reported more frequently as unresolved events compared with all other ADRs (ROR: 2.68 95% CI 2.51-2.85; ROR: 5.20 95% CI 4.66-5.81; and ROR: 2.64 (95% CI 2.51-2.79, respectively). Gustatory ADRs were reported more frequently as unresolved for doxycycline (ROR: 1.69, 95% CI 1.18-2.41, p = 0.0038), azithromycin (ROR: 2.07, 95% CI 1.58-2.72, p < 0.0001) and levofloxacin (ROR: 1.59, 95% CI 1.22-2.07, p < 0.001) compared with GOA ADRs of all other antibiotics. Olfactory ADRs were reported more frequently as unresolved for doxycycline (ROR: 2.4, 95% CI 1.26-4.58, p = 0.0078) and levofloxacin (ROR: 1.92, 95% CI 1.28-2.86, p = 0.0014). Auditory ADRs were reported more frequently as unresolved for doxycycline (ROR: 1.52, 95% CI 1.09-2.12, p = 0.013) and clarithromycin (ROR: 1.31, 95% CI 1.09-1.59, p = 0.0049). We tested and used an appropriate expected frequency standard, which allows us to identify possible signals of unresolved GOA ADRs to antibiotic drugs in the EudraVigilance database. This approach could be used to generate signals of persistent or even irreversible events for other drugs or adverse reactions. However, these signals must be confirmed with a thorough clinical assessment.

An agenda for research on adverse drug reactions

BackgroundThe prediction of the real-world cost of adverse drug reactions (ADRs) has historically relied on the data from randomized controlled trials (RCT). However, trial conditions do not always reflect the real-world applications of pharmaceutical products; hence, they may not accurately portray the actual risks of ADRs associated with them. The objective of this study is two-fold: (a) demonstrate whether and how post-market and RCT ADR data could lead to different conclusions for a set of drugs of interest, and (b) evaluate the potential economic impact of the post-market ADRs associated with those drugs.MethodsWe selected two TNF-α inhibitor biologics, infliximab and adalimumab, and used the Canada Vigilance Adverse Reaction (CVAR) online database as a source of post-market ADR data. Adverse reaction data from RCTs were obtained from ClinicalTrials.gov. Direct healthcare costs associated with adverse reactions were obtained from Canadian Institute for Health Information (CIHI) or Interactive Health Data Application, Alberta. We calculated post-market ADR rates and compared them with those found in the randomized controlled trials of these two drugs. Using the post-market data, we estimated the costs associated with serious ADRs from three perspectives: patient, health system, and societal.ResultsFor both drugs, the post-market and RCT data exhibited significantly different adverse reaction rates for several different clinical outcomes. As a general trend, more serious adverse reactions, such as death, appeared to have a higher rate in post-market applications compared to the clinical trials. The estimated average annual economic burden of the severe adverse reaction outcomes ranged from $10 million to $20 million for infliximab and $6 million to $19 million for adalimumab.ConclusionsThe frequency and severity of post-market adverse reactions associated with pharmaceutical products may significantly differ from those detected in the clinical trials. Despite possible methodological differences, this is due to the fact that post-market data reflect the externalities of the real-world that are absent in RCTs. The economic burden of adverse reactions can be substantial, and the cost calculated using post-market data is better reflective of the cost of ADRs in the real-world.

Background: Animal models have demonstrated the deleterious contribution that immunocytes from the spleen exert on secondary brain injury after stroke. While previous work has demonstrated that there is splenic contraction (SC) in patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH), no clinical studies have connected the systemic inflammatory response syndrome (SIRS) with SC. We aim to associate SIRS and its individual components with SC in acute stroke Methods: This is a retrospective analysis of a previous prospective observational study where daily spleen sizes were evaluated in 178 acute stroke patients in a tertiary care center from 2010-2013. Spleen contraction was defined compared to previously established normograms of healthy volunteers from the same study. SIRS was defined as the presence of 2 or more of the following: body temperature &lt;36 or &gt;38C, heart rate &gt;90 beats, respiratory rate &gt;20, and serum white blood cell count &gt;12,000 or &lt;4000 mm3 in the absence of infection. SC was evaluated in patients at 24 and 72 hrs after AIS with SIRS as a primary outcome. Results: 91 patients had verified AIS without concurrent infection at admission and 70 of these patients remained inpatient at 72 hrs. SIRS was not associated with admission SC at 24hr and 72 hrs. Patients with SIRS at 24 and 72 hrs were more likely to have higher admission NIHSS. SIRS was associated with higher discharge mRS (OR 4.24, 95% CI 1.64-10.9, p=0.0028) and PEG placement (OR 3.70, 95% CI 0.95-15.11, p=0.05). 16 patients (22.9%) developed SIRS by 72hrs, only 5 of whom had SC initially. 28 patients (47%) had SIRS on admission that persisted, 12 of whom had SC. SC was not associated with SIRS at 72 hrs (OR 1.05, 95% CI 0.35-2.79, p = 0.92). 14 patients (15%) developed infections while hospitalized, of which 85% had SIRS on admission. Conclusion: Based on our initial evaluation, SC detected within 24 hrs of stroke onset is not associated with SIRS suggesting that the relationship between the two may be more complicated in humans. Consistent with prior studies, however, SIRS is associated with worse outcome. Further studies and additional time points are necessary to further clarify the role of the spleen in the development of SIRS in stroke patients.

Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. Single-center, prospective, observational cohort study. ICU at an university-affiliated hospital. Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. None. We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin.

Background and Purpose: Systemic Inflammatory Response Syndrome (SIRS) has been shown to predict outcomes after intracerebral hemorrhage (ICH) in a single-center cohort. We hypothesized that SIRS would predict outcomes in a multicenter multi-ethnic cohort of ICH patients. Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multi-center observational study of ICH among whites, blacks, and Hispanics. SIRS on admission was defined according to standard criteria as 2 or more of the following: (1) body temperature 38°C, (2) heart rate &gt; 90 beats per minute, (3) respiratory rate &gt; 20/minute, or (4) white blood cell count 12,000/mm3. Patients were excluded if they died within 72 hours of admission, or if missing vital signs or laboratory tests did not allow for assessment of SIRS on admission. Associations of SIRS with baseline characteristics, infection, and poor outcomes (modified Rankin Scale 3-6) at discharge and 3 months were assessed using t-tests, chi-square, and logistic regression. Results: Of 2411 patients included, 340 (14%) met SIRS criteria at admission. Patients with SIRS were younger (58.0 vs. 62.3 years; p&lt;.0001) and more likely to have intraventricular hemorrhage (IVH) (52.9% vs. 36.5%; p&lt;.0001), higher baseline ICH volume (25.2 vs. 17.4; p&lt;.0001), and lower baseline Glasgow Coma Score (GCS; 10.7 vs. 13.1; p&lt;.0001). SIRS was not associated with subsequent infection (OR 1.40, 95%CI 0.84-2.34). In unadjusted analyses, SIRS was associated with poor outcome at discharge (OR 2.0, 95%CI 1.5-2.7) and 3-months (OR 1.8, 95%CI 1.4-2.3). In patients with milder ICH (ICH score 0-2), SIRS was associated with poor mRS at discharge and 3 months, but SIRS was not related to outcomes for patients with baseline ICH score 3-5. After adjusting for age, IVH, ICH volume, GCS, ICH location, and pre-onset mRS, SIRS was no longer associated with poor outcomes. Conclusions: SIRS at admission is an indicator of stroke severity and thus a predictor of poor functional outcome, but not infection, after ICH. Further study is needed to better understand systemic inflammation after ICH.

After major surgery many patients develop signs and symptoms of generalized inflammation, which is defined as Systemic Inflammatory Response Syndrome (SIRS). To examine the systemic inflammatory response syndrome in the intensive care unit (ICU) after cardiac and thoracic surgery a retrospective study was performed on 1674 selected patients admitted in the Cardiothoracic ICU of the University Hospital of Vienna. SIRS was defined according to the American College of Chest Physicians / Society of Critical Care Medicine (ACCP / SCCM) Consensus Conference. The term's SIRS, sepsis, septic shock and MODS (multi organ dysfunction syndrome) are used to describe the different extents of inflammation and infections. In the first phase the moment of the first occurrence of SIRS, and of severe SIRS was determined. An SIRS episode was defined as a time interval from the beginning of SIRS until the receding of the symptoms for more than 24 hours. Based on this information, an artificial neural network (ANN) was constructed to predict severe SIRS. SIRS was present in 1544 patients (92.2%), SIRS with additional signs of organ dysfunction evolving in 76.1% of the cases; the progression took less than 24 hours in 87.9% of the cases. The presence of signs of the SIRS on the first operative day is hardly suitable for the risk prediction. A significant correlation between the number of SIRS episodes and the outcome for each individual patient was found. The number of SIRS episodes could be an accurate parameter for estimating the outcome and the treatment outlay.

The objective of the present study was to quantify the reported cardiovascular adverse reactions and adverse reactions to cardiovascular drugs to help to design and implement monitoring and prevention strategies. The pharmacovigilance unit (PU) is a peripheral effector of National Pharmacovigilance Center and receives adverse drug reactions notifications from 10 teaching hospitals. Data on adverse reactions beginning in 2004 and notified to the PU were extracted from the database. Cardiovascular adverse drug reactions and adverse reactions to cardiovascular drugs were identified using Medical Dictionary for Regulatory Activities (MedDRA), and the Anatomical Therapeutic Chemical (ATC) Classification System respectively. The reports of adverse reactions were classified according to their seriousness. From 2004 to 2010, 2516 notifications were received (2383 adverse reactions, 106 lack of efficacy, 26 quality failures). These notifications included 151 cardiovascular adverse reactions and 594 adverse reactions caused by cardiovascular drugs. In the first group, of the 151 cardiovascular adverse reactions through MedDRA SOC classification caused by all ATC group classes, 118 (78.2%) were caused by non cardiovascular drugs. Among them antimicrobials (27,2%) and neurologic drugs (21,2%) were the most frequent. 22 (14.6%) adverse reactions were serious. Long QT syndrome, peripheral edema, hypotension, tachycardia, and bradycardia, were the most frequent. In the second group, of the 594 reports identifying adverse reactions involving all MedDRA SOCs but caused only by cardiovascular drugs, 559 reports (94.1%) were non cardiovascular adverse reactions. Enalapril and furosemide accounted for 65.2% there were 33 (5.6%) serious adverse reactions. The most frequent adverse reactions were hyponatremia, impaired renal function, hypokalemia, metabolic alkalosis, asymptomatic elevation of liver enzymes, hyperkalemia, hyperglycemia, edema, and cough. Non-cardiovascular adverse reactions were the most frequent manifestation of adverse drug reactions caused by cardiovascular drugs and cardiovascular adverse reactions were most often caused by non cardiovascular drugs. This report highlights the importance of systematic evaluation of adverse drug reactions.

Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm. This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses. 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS. SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Systemic inflammatory response syndrome (SIRS) is a severe inflammatory response that can lead to organ dysfunction and death. Modulating the gut microbiome is a promising therapeutic approach for managing SIRS. This study assesses the therapeutic potential of the Xuanfei Baidu (XFBD) formula in treating SIRS. The results showed that XFBD administration effectively reduced mortality rates and inflammation in SIRS mice. Using 16S rRNA sequencing and fecal microbiota transplantation (FMT), we substantiated that the therapeutic effects of XFBD are partly attributed to gut microbiota modulation. We conducted in vitro experiments to accurately assess the gut microbiome remodeling effects of 51 compounds isolated from XFBD. These compounds exhibited varying abilities to induce a microbial structure that closely resembles that of the healthy control group. By quantifying their impact on microbial structure and clustering their regulatory patterns, we devised multiple gut microbiome remodeling compound (GMRC) cocktails. GMRC cocktail C, comprising aucubin, gentiopicroside, syringic acid, gallic acid, p-hydroxybenzaldehyde, para-hydroxybenzoic acid, and isoimperatorin, demonstrated superior efficacy in treating SIRS compared to a single compound or to other cocktails. Finally, in vitro experiments showcased that GMRC cocktail C effectively rebalanced bacteria composition in SIRS patients. This study underscores XFBD's therapeutic potential in SIRS and highlights the importance of innovative treatment approaches for this disease by targeting the gut microbiota.IMPORTANCEDeveloping effective treatment strategies for systemic inflammatory response syndrome (SIRS) is crucial due to its severe and often life-threatening nature. While traditional treatments like dexamethasone have shown efficacy, they also come with significant side effects and limitations. This study makes significant strides by demonstrating that the Xuanfei Baidu (XFBD) formula can substantially reduce mortality rates and inflammation in SIRS mice through effective modulation of the gut microbiota. By quantitatively assessing the impact of 51 compounds derived from XFBD on the gut microbiome, we developed a potent gut microbiome remodeling compound cocktail. This cocktail outperformed individual compounds and other mixtures in efficacy against SIRS. These findings highlight the potential of XFBD as a therapeutic solution for SIRS and underscore the critical role of innovative strategies targeting the gut microbiota in addressing this severe inflammatory condition.