Post COVID-19 pulmonary fibrosis; a meta-analysis study
Annals of medicine and surgery (2012). 2022;77:103590
Introduction; Pulmonary fibrosis is a frequently reported COVID-19 sequela in which the exact prevalence and risk factors are yet to be established. This meta-analysis aims to investigate the prevalence of post-COVID-19 pulmonary fibrosis (PCPF) and the potential risk factors. Methods; CINAHL, PubMed/MEDLINE, Cochrane Library, Web of Science, and EMBASE databases were searched to identify English language studies published up to December 3, 2021. Results; The systematic search initially revealed a total of 618 articles - of which only 13 studies reporting 2018 patients were included in this study. Among the patients, 1047 (51.9%) were male and 971 (48.1%) were female. The mean age was 54.5 years (15-94). The prevalence of PCPF was 44.9%. The mean age was 59 years in fibrotic patients and 48.5 years in non-fibrotic patients. Chronic obstructive pulmonary disease was the only comorbidity associated with PCPF. Fibrotic patients more commonly suffered from persistent symptoms of dyspnea, cough, chest pain, fatigue, and myalgia (p-value < 0.05). Factors related to COVID-19 severity that were associated with PCPF development included computed tomography score of ≥18, ICU admission, invasive/non-invasive mechanical ventilation, longer hospitalization period, and steroid, antibiotic and immunoglobulin treatments (p-value < 0.05). Parenchymal bands (284/341), ground-glass opacities (552/753), interlobular septal thickening (220/381), and consolidation (197/319) were the most common lung abnormalities found in fibrotic patients. Conclusion, About 44.9% of COVID-19 survivors appear to have developed pulmonary fibrosis. Factors related to COVID-19 severity were significantly associated with PCPF development.
Subcutaneous immunoglobulin use in immunoglobulin-naive patients with primary immunodeficiency: a systematic review
Aim: Identify and describe published literature on the use of subcutaneous immunoglobulin (SCIG) as initial immunoglobulin (IG)-replacement therapy for patients with primary immunodeficiency diseases (PID). Methods: We systematically identified and summarized literature in MEDLINE, Embase, BioSciences Information Service and Cochrane Library assessing efficacy/effectiveness, safety/tolerability, health-related quality-of-life (HRQoL) and dosing regimens of SCIG for IG-naive patients with PID. Results: Sixteen studies were included. In IG-naive patients, SCIG managed/reduced infections and demonstrated similar pharmacokinetic parameters to IG-experienced patients; adverse events were mostly minor injection-site pain or discomfort. Three studies reported improvements in HRQoL. Quality of studies was difficult to assess due to limited reporting. Conclusion: Although studies were lacking, available data suggest IG-naive and IG-experienced patients initiating SCIG likely have similar outcomes.
Assessing deterioration using impairment and functional outcome measures in chronic inflammatory demyelinating polyneuropathy: a post-hoc analysis of the IOC trial
Journal of the peripheral nervous system : JPNS. 2022
BACKGROUND AND AIMS It is unclear whether frequently used cut-off values for outcome measures defining minimal clinically important differences (MCIDs) can accurately identify meaningful deterioration in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS We used data from the IOC trial, in which sixty clinically stable CIDP patients were randomized to IVIg withdrawal or continuation. We calculated change scores of the Inflammatory Rasch-Built Overall Disability Scale (I-RODS), grip strength, and MRC sum score (MRC-SS) and classified visits based on a treatment anchor (i.e. decision to restart/increase treatment after reaching a predefined early endpoint of deterioration). The variability of scores in patients without deterioration was calculated using the limits of agreement. We defined optimized MCIDs for deterioration and specific combinations of MCIDs from different outcome measures, and subsequently calculated the accuracies of the (combined) MCIDs. RESULTS Substantial variability was found in scores of the I-RODS, grip strength and MRC-SS in patients without deterioration over time, and most MCIDs were within the limits of the variability observed in patients without deterioration. Some MCID cut-offs were insensitive but highly specific for detecting deterioration, e.g. the MCID-SE of -1.96 of the I-RODS and -2 point on the MRC-SS. Others were sensitive, but less specific, e.g. -4 centiles of the I-RODS. Some combined MCIDs resulted in high specificities and moderate sensitivities. INTERPRETATION Our results suggest that clinically important deterioration cannot be distinguished from variability over time with currently used MCIDs on the individual level. Combinations of MCIDs might improve the accuracy of determining deterioration, but this needs validation.
Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial
Lancet (London, England). 2022;399(10324):530-40
BACKGROUND Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77-1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66-1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14-4·29); for patients who were antibody negative, the OR was 0·51 (0·29-0·90; p(interaction)=0·001). INTERPRETATION When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING US National Institutes of Health.
Hospitalised patients with COVID-19 enrolled in the ITAC trial in 11 countries (n= 593).
Hyperimmune intravenous immunoglobulin (hIVIG), (n= 301).
Placebo (n= 292).
The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extra-pulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7. Infusion reactions were more common in the hIVIG group (18.6%) than placebo (9.5%). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%).
Clinical effect of reduning combined with gamma globulin treatment on symptom improvement serum levels of IL-6, 25-(OH)D and LDH in children with severe mycoplasma pneumonia
Pakistan journal of medical sciences. 2022;38(4Part-II):826-832
OBJECTIVES To investigate the effects of Reduning combined with gamma globulin on symptom improvement and serum levels of interleukin-6 (IL-6), 25-hydroxyvitamin D[25-(OH)D] and lactate dehydrogenase (LDH) in children with severe mycoplasma pneumonia (MP). METHODS A total of 123 children with severe MP admitted to the Changzhou Cancer Hospital affiliated to Soochow University from May 2018 to April 2020 were selected as subjects and randomly divided into three groups: control Group-A, control Group-B and the observation group, with 41 cases in each group. Control Group-A was given with Reduning, control Group-B was treated with gamma globulin, while the observation group was treated with Reduning injection combined with gamma globulin. The clinical efficacy, symptom improvement, incidence of adverse reactions, serum levels of IL-6, 25-(OH)D, LDH, Toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88) signaling pathway and T lymphocyte subsets before and after treatment were statistically compared between the three groups. RESULTS The total effective rate of treatment in the observation group was higher than that in control Group-A and control Group-B (p<0.05); The time for body temperature, lung rales, and cough to return to normal in the observation group was shorter than that in control Group-A and control Group-B (p<0.05). After treatment, the observation group had lower serum levels of IL-6, LDH, and higher levels of 25-(OH)D compared with control Group-A and control Group-B (p<0.05). Moreover, the observation group had lower serum expressions of TLR4 and MyD88 (p<0.05), higher serum levels of CD4(+), CD4(+)/CD8(+), and lower CD8(+) compared with control Group-A and control Group-B (p<0.05). No significant difference can be seen in the comparison of the incidence of adverse reactions between the three groups (p>0.05). CONCLUSIONS Reduning combined with gamma globulin in the treatment of severe MP is worthy of clinical promotion and application. With such a treatment regimen, the immune function of children with severe MP can be significantly enhanced, the inflammatory response can be suppressed, and symptom improvement can be promoted, further improving the treatment outcome.
Pharmacologic interventions for Kawasaki disease in children: A network meta-analysis of 56 randomized controlled trials
BACKGROUND Although the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of the current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial and refractory stages of KD. METHODS An NMA of randomised controlled trials (RCTs) was conducted using the frequentist model applied after electronic searches in PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, and Web of Science. The main outcomes were reduced fever duration/diminished severity of fever subsided. The initial stage of KD was defined as the first stage to treat patients with KD; the refractory stage of KD represents KD patients who failed to respond to standard KD treatment. The cut-off points for intravenous immunoglobulin (IVIG) were low (100-400 mg), medium (1 g), and high (at least 2 g). FINDINGS A total of fifty-six RCTs with 6486 participants were included. NMA demonstrated that the medium-dosage IVIG + aspirin + infliximab [mean difference=-1.76 days (95% confidence intervals (95% CIs): -3.65 to 0.13 days) compared to high-dosage IVIG + aspirin] exhibited the shortest fever duration; likewise, the medium-dosage IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95% CIs: 0.18-1.37 compared to high-dosage IVIG + aspirin] exhibited the smallest incidence of coronary artery lesion (CAL) in the initial-stage KD. In the refractory-stage KD, the high-dosage IVIG + pulse steroid therapy (OR=0.04, 95% CIs: 0.00-0.43 compared to the high-dosage IVIG only) had the best rate of decline of fever; likewise, the high-dosage IVIG + ciclosporin [OR=0.05 (95% CIs: 0.00-1.21) compared to the high-dosage IVIG only] exhibited the smallest incidence of CAL. Infliximab significantly improved resolution compared to the high-dosage IVIG only group (OR=0.20, 95%CIs: 0.07-0.62) in refractory-stage KD. INTERPRETATION The NMA demonstrated that the combination therapy with the standard therapy of IVIG and aspirin might have an additional effect on shortening the duration of fever and lowering the CAL incidence rate in patients with acute KD. Moreover, the combination therapy with high-dose IVIG and pulse steroid therapy or cyclosporine therapy might have an additional effect on improving the rate of decline of fever and lowering the incidence rate of CAL in children with refractory KD. Because some of the findings of this NMA should be considered hypothesis-generating rather than confirmatory, further evidence from de novo randomised trials is needed to support our results. FUNDING None.
Characteristics and conflicting recommendations of clinical practice guidelines for COVID-19 management in children: A scoping review
Travel medicine and infectious disease. 2022;48:102354
BACKGROUND Clinical practice guidelines (CPGs) are statements that should be rigorously developed to guide clinicians' decision-making. However, given the scarce evidence for certain vulnerable groups like children, CPGs' recommendations formulation could be challenging. METHODS We conducted a scoping review of CPGs for COVID-19 management in children. Documents were included if they claimed to be a "clinical practice guideline", published between January and October 2021, and described the process followed to issue their recommendations. We assessed the quality using the "Appraisal of Guidelines for Research and Evaluation II" (AGREE-II) and described how the recommendations were reached. RESULTS We found five CPGs that fulfilled our inclusion criteria. The median score on the overall AGREE-II evaluation was 61% (range: 49%-72%), and the score on the third domain referred to the rigor of methodological development was 52% (range: 25%-88%). Recommendations for remdesivir, tocilizumab, and intravenous immunoglobulin were heterogeneous across CPGs (in favor, against, no recommendation), as well as the methodologies used to present the evidence, perform the benefits/harms balance, and issue the recommendation. CONCLUSIONS Heterogeneous recommendations and justifications across CPGs were found in the three assessed topics. Future CPGs should describe in detail their evidence-to-decision process to issue reliable and transparent recommendations.
Efficacy and safety of intravenous immunoglobulin for treating refractory livedoid vasculopathy: a systematic review
Therapeutic advances in chronic disease. 2022;13:20406223221097331
INTRODUCTION Intravenous immunoglobulin (IVIG) was reported to be the third most used monotherapy in livedoid vasculopathy (LV). There is currently a lack of randomized controlled clinical trials and no standardized therapeutic regimen for IVIG therapy in LV. METHODS We performed a systematic review of the efficacy and safety of IVIG in treating patients with LV using PubMed, Cochrane, and Embase databases. RESULTS Eighty LV patients from 17 articles were included, receiving IVIG therapy at a dose of 1-2.1 g/kg body weight every 4 weeks. The effective rate of IVIG therapy in LV patients was 95% (76/80) in published studies, showing a good clinical response for resolution of pain, skin ulcerations, and neurological symptoms, and reducing the dependence on glucocorticoids and immunosuppressive agents. IVIG therapy was well tolerated, and no severe adverse events were observed. CONCLUSION Overall, to a certain degree, IVIG is probably a safe and effective treatment alternative for refractory LV patients, which still need to be confirmed by large-scale randomized controlled clinical trials.
Phase 2 Study of Avatrombopag in Japanese Patients with Chronic Liver Disease and Thrombocytopenia
Hepatology research : the official journal of the Japan Society of Hepatology. 2022
AIM: Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. METHODS Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50×10(9) /L and ≥20×10(9) /L increase from baseline. RESULTS Thirty-nine patients were randomized and completed the study (placebo, n=11; avatrombopag 20 mg, n=7; 40 mg, n=11; 60 mg, n=10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; P=0.004) and 60 mg (40%; P=0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. CONCLUSIONS Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. ClinicalTrials.gov identifier: NCT02227693. This article is protected by copyright. All rights reserved.
Characteristics, treatment, and outcomes of Myasthenia Gravis in COVID-19 patients: A systematic review
Clinical neurology and neurosurgery. 2022;213:107140
OBJECTIVE Recent studies suggest that the clinical course and outcomes of patients with coronavirus disease 2019 (COVID-19) and myasthenia gravis (MG) are highly variable. We performed a systematic review of the relevant literature with a key aim to assess the outcomes of invasive ventilation, mortality, and hospital length of stay (HLoS) for patients presenting with MG and COVID-19. METHODS We searched the PubMed, Scopus, Web of Science, and MedRxiv databases for original articles that reported patients with MG and COVID-19. We included all clinical studies that reported MG in patients with confirmed COVID-19 cases via RT-PCR tests. We collected data on patient background characteristics, symptoms, time between MG and COVID-19 diagnosis, MG and COVID-19 treatments, HLoS, and mortality at last available follow-up. We reported summary statistics as counts and percentages or mean±SD. When necessary, inverse variance weighting was used to aggregate patient-level data and summary statistics. RESULTS Nineteen studies with 152 patients (mean age 54.4 ± 12.7 years; 79/152 [52.0%] female) were included. Hypertension (62/141, 44.0%) and diabetes (30/141, 21.3%) were the most common comorbidities. The mean time between the diagnosis of MG and COVID-19 was7.0 ± 6.3 years. Diagnosis of COVID-19 was confirmed in all patients via RT-PCR tests. Fever (40/59, 67.8%) and ptosis (9/55, 16.4%) were the most frequent COVID-19 and MG symptoms, respectively. Azithromycin and ceftriaxone were the most common COVID-19 treatments, while prednisone and intravenous immunoglobulin were the most common MG treatments. Invasive ventilation treatment was required for 25/59 (42.4%) of patients. The mean HLoS was 18.2 ± 9.9 days. The mortality rate was 18/152 (11.8%). CONCLUSION This report provides an overview of the characteristics, treatment, and outcomes of MG in COVID-19 patients. Although COVID-19 may exaggerate the neurological symptoms and worsens the outcome in MG patients, we did not find enough evidence to support this notion. Further studies with larger numbers of patients with MG and COVID-19 are needed to better assess the clinical outcomes in these patients.