ABSTRACT
As widely-used immunotherapy has brought therapeutic benefits to cancer patients, some problems begin to come, such as pseudoprogression which has posed a major challenge for clinicians to manage patients receiving novel drugs. If pseudoprogression is mistaken for the progression of the disease, the immunotherapy is stopped, which may lead patients to lose the treatment opportunity. Liquid biopsies based on circulating tumor DNA (ctDNA) play a key role in the evaluation of therapeutic efficacy and drug-resistance mechanism of tumor immunotherapy. This article reviews the potential application of ctDNA in the identification of pseudoprogressio for patients after tumor immunotherapy.
ABSTRACT
ImportanceCoronavirus disease 2019 (COVID-19) has become pandemic, causing more than 1.5 million infections and over ten-thousands of deaths in a short period of time worldwide. However, little is known about its pathological mechanism, and reports on clinical study on specific treatment are few. ObjectiveThe purpose of this study is to determine the clinical efficacy of intravenous immunoglobulin (IVIG) therapy in COVID-19 patients. Design, setting and participantsThis multicenter retrospective cohort study enrolled 325 adult critical COVID-19 patients, including severe type and critical type, according to the clinical classification defined by National Health Commission of China, in 8 government designated treatment centers in China from Dec 23, 2019 to Mar 31, 2020. Demographic, clinical, treatment, and laboratory data as well as prognosis were extracted from electronic medical records. ExposureIVIG was exposure factor. Main outcomes and measuresPrimary outcomes were the 28-day and 60-day mortality, and secondary outcomes were the total length of in-hospital and the total duration of the disease. Meanwhile, the parameters of inflammation responses and organ functions were measured. The risk factors were determined by COX proportional hazards model. The subgroup analysis was carried out according to clinical classification of COVID-19, IVIG dosage, and timing. ResultsIn the enrolled 325 patients, 222 (68%) were severe type and 103 (32%) were critical type; 42 (13%) died in 28-day within hospitalization, and 54 (17%) died within 60-day; The death in 60-day includes 6 (3%) severe type patients and 48 (47%) critical type patients. 174 cases were used IVIG, and 151 cases were not. Compared with the baseline characteristics between two groups, the results showed that the patients in IVIG group presented higher Acute Physiology and Chronic Health Evaluation (APACHII) score and Sequential Organ Failure Assessment (SOFA) score, higher plasm levels of IL-6 and lactate, and lower lymphocyte count and oxygenation index (all P<0.05). The 28-day and 60-day mortality were not improved with IVIG in overall cohort. The in-hospital stay and the total duration of disease were longer in IVIG group (P<0.001). Risk factors were clinical classifications (hazards ratio 0.126, 95% confidence interval 0.039-0.413, P=0.001), and using IVIG (hazards ratio 0.252, 95% confidence interval 0.107-0.591, P=0.002) with COX proportional hazards model. Subgroup analysis showed that only in patients with critical type, IVIG could significantly reduce the 28-day mortality, decrease the inflammatory response, and improve some organ functions (all P<0.05); and application of IVIG in the early stage (admission[≤]7 days) with a high dose (>15 g/d) exhibited significant reduction of 60-day mortality in the critical type patients. Conclusions and RelevanceEarly administration of IVIG with high dose improves the prognosis of critical type patients with COVID-19. This study provides important information on clinical application of the IVIG in treatment of SARS-CoV-2 infection, including patient selection and administration timing and dosage. Key pointsO_ST_ABSQuestionC_ST_ABSIntravenous immunoglobulin (IVIG) was recommended to treat critical Coronavirus disease 2019 (COVID-19) patients in a few reviews, but the clinical study evidence on its efficacy in COVID-19 patients was lacked. FindingIn this multicenter cohort study that included 325 adult critical patients from 8 treatment centers, the results showed that early administration (admission [≤] 7 days) of IVIG with high dose (> 15 g/d) improves the prognosis of critical type patients with COVID-19. MeaningThis study provides important information on clinical application of IVIG in treatment of SARS-CoV-2 infection, including patient selection, administration timing and dosage.
ABSTRACT
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The pathophysiology core issue is that the body initiates a severe inflammatory reaction in response to the invasion of pathogenic microorganisms at the initial stage of disease. Subsequently, the body begins to fight inflammation in order to balance immunity status and eventually induces the immune paralysis or immunosuppressive state characterized by exhaustion of immune cell. Both in innate immunity and in acquired immunity, some co-suppressor molecules on the surface of immune cells play important roles in immunosuppression, such as, programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin-containing protein-3 (TIM-3), cytotoxic T lymphocyte associated antigen-4 (CTLA-4), natural killer cell receptor 2B4 (CD244), B and T lymphocyte attenuator (BTLA) and NKG2A (CD94), et al. Blocking the interaction between these co-suppressor molecules and their ligands can significantly reverse the immunosuppressive state in septic animal models or patients. In order to provide a reference for the monitoring and treatment of sepsis immune dysfunction, this article mainly summarizes the new findings on the role of those co-suppressor molecules in sepsis immune dysfunction in recent years.
