2022年 · 第02卷第02期

Invasive pulmonary aspergillosis (IPA) is a lethal infectious disease with high mortality in patients with liver failure. Early recognition of the risk factors prompting earlier diagnosis and treatment may improve the outcomes. Voriconazole is recommended as the first-line drug for IPA, but hepatotoxicity limits its use in the context of liver diseases. We report a case of a 63-year-old female who was admitted to the Third Affiliated Hospital of Hebei Medical University due to IPA after glucocorticoid therapy for liver failure. The polymorphism of cytochrome P450 (CYP) isoenzymes showed CYP2C19*1/*2 genotype associated with intermediate metabolism of voriconazole. However, the patient developed side effects such as skin rash, vomiting, hyperbilirubinemia, and alteration of consciousness, even if she received half of the recommended dosage for voriconazole. Therapeutic drug monitoring (TDM) was applied to guide the dosage adjustment of voriconazole in this patient, and consequently, the patient presented a favorable outcome. In conclusion, genotyping screening plus TDM dependent individualized treatment of voriconazole may improve the survival of liver failure patient with IPA.

Background: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease and has spread worldwide. Clinical risk factors associated with the severity in COVID-19 patients have not yet been well delineated. The aim of this study was to explore the risk factors related with the progression of severe COVID-19 and establish a prediction model for severity in COVID-19 patients. Methods: We retrospectively recruited patients with confirmed COVID-19 admitted in Enze Hospital, Taizhou Enze Medical Center (Group) and Nanjing Drum Tower Hospital between January 24 and March 12, 2020. Take the Taizhou cohort as the training set and the Nanjing cohort as the validation set. Severe case was defined based on the World Health Organization Interim Guidance Report criteria for severe pneumonia. The patients were divided into severe and non-severe groups. Epidemiological, laboratory, clinical, and imaging data were recorded with data collection forms from the electronic medical record. The predictive model of severe COVID-19 was constructed, and the efficacy of the predictive model in predicting the risk of severe COVID-19 was analyzed by the receiver operating characteristic curve (ROC). Results: A total of 402 COVID-19 patients were included in the study, including 98 patients in the training set (Nanjing cohort) and 304 patients in the validation set (Nanjing cohort). There were 54 cases (13.43%) in severe group and 348 cases (86.57%) in non-severe group. Logistic regression analysis showed that body mass index (BMI) and lymphocyte count were independent risk factors for severe COVID-19 (all P < 0.05). Logistic regression equation based on risk factors was established as follows: Logit (BL)=-5.552-5.473×L+0.418×BMI. The area under the ROC curve (AUC) of the training set and the validation set were 0.928 and 0.848, respectively (all P < 0.001). The model was simplified to get a new model (BMI and lymphocyte count ratio, BLR) for predicting severe COVID-19 patients, and the AUC in the training set and validation set were 0.926 and 0.828, respectively (all P < 0.001). Conclusions: Higher BMI and lower lymphocyte count are critical factors associated with severity of COVID-19 patients. The simplified BLR model has a good predictive value for the severe COVID-19 patients. Metabolic factors involved in the development of COVID-19 need to be further investigated.

Background: Interferon kappa (IFN-κ) is a type I interferon (IFN-I) that inhibits virus replication by evoking interferon-stimulated genes (ISGs). However, as an evolutionarily ancient interferon, IFN-κ may function differently from the later emerged interferon-α and β. Methods: Conventional molecular biology methods were used to determine the localization of IFN-κ and its structure and function. In addition, we employed RT-PCR, western blot, and RNA-Seq technologies to characterize the ISGs expression profile and antiviral activities exerted by IFN-κ or IFN-α2. Results: Human IFN-κ exists in two forms upon ectopic expression, one located on the cell membrane and the other secreted outside the cells. The membrane-anchored IFN-κ showed the ability to induce ISGs and curtail RNA virus replication, whereas the secreted IFN-κ failed to do so. Structural analyses indicated that 1-27aa at the N-terminus was the signal peptide, and 28-37aa was predicted as the transmembrane region. However, our data demonstrated that both of them were not associated with membrane localization of IFN-κ; the former influenced the expression and secretion of IFN-κ, and the latter had an impact on the induction of ISGs. In addition, prokaryotic purified soluble mature human IFN-κ was also capable of inducing ISGs and inhibiting RNA virus replication. Importantly, human IFN-κ induced a faster ISG response but with a lower intensity and a shorter half-life than the response of IFN-α2. In contrast, IFN-α2 started to function later but was stronger and more durable than IFN-κ. Conclusions: Human IFN-κ-induced ISG response and inhibited respiratory RNA virus replication dependent on cell-to-cell interactions. In addition, compared with IFN-α2, IFN-κ exerted effects more rapidly in the early phase, with less intensity and a shorter half-life. Therefore, IFN-κ may constitute the first line of IFN-I against respiratory virus infections.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic that has resulted in millions of casualties. Although researchers have reported the existence of neutralizing antibodies and viral T cell immunity against SARS-CoV-2, little is known about the presence of antibody-dependent cellular cytotoxicity (ADCC) and its role in combating SARS-CoV-2 infection. Methods: Nineteen acute COVID-19 patients at the First Affiliated Hospital of Guangzhou Medical University from January to February, 2020 and 55 recovery COVID-19 patients at the Second Peoples Hospital of Changde City from February, 2020 to February, 2021 were recruited in this study. Longitudinal plasma samples were collected. A virus-specific ADCC assay was performed to study the COVID-19 plasma samples. The correlations between ADCC and total IgG titer, including anti-RBD, anti-N, and neutralizing antibody titer were analyzed. Results: A high level of ADCC with 0.86% of IFN-γ+CD107a+ NK cells induced by anti RBD antibodies and with 0.54% of IFN-γ+CD107a+ NK cells induced by anti N antibodies was observed. This activity peaked at 3 weeks after disease onset with 1.16% and 0.63% of IFN-γ+CD107a+ NK cells induced by anti RBD and anti N antibodies respectively, declined to 0.32% and 0.32% of IFN-γ+CD107a+ NK cells respectively after more than 2 months, and persisted for 12 months after disease onset. The ADCC did not aggravate the severity of COVID-19 in terms of sequential organ failure assessment, although ADCC decreased with the age of COVID-19 patients. Interestingly, ADCC response is not correlated with neutralizing antibody titer or total IgG titers against S protein RBD and N protein in acute patients. ADCC in recovered patients showed a significant correlation with anti RBD IgG titer (R2=0.33, P < 0.001). Conclusion: Antibodies from COVID-19 patients against the N protein and S protein RBD domains could stimulate high levels of ADCC response. Our results provide evidence that vaccination should not only focus on neutralizing antibodies but also binding antibodies that may facilitate the antiviral function of ADCC, especially in the elderly.

Background: The coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease. There is no recommended antiviral treatment approved for COVID-19 in Sierra Leone, and supportive care and protection of vital organ function are performed for the patients. This study summarized the clinical characteristics, drug treatments, and risk factors for the severity and prognosis of COVID-19 in Sierra Leone to provide evidence for the treatment of COVID-19. Methods: Data of 180 adult COVID-19 patients from the 34th Military Hospital in Freetown Sierra Leone between March 31, 2020 and August 11, 2020 were retrospectively collected. Patients with severe and critically ill are classified in the severe group, while patients that presented asymptomatic, mild, and moderate disease were grouped in the non-severe group. The clinical and laboratory information was retrospectively collected to assess the risk factors and treatment strategies for severe COVID-19. Demographic information, travel history, clinical symptoms and signs, laboratory detection results, chest examination findings, therapeutics, and clinical outcomes were collected from each case file. Multivariate logistic analysis was adopted to identify the risk factors for deaths. Additionally, the clinical efficacy of dexamethasone treatment was investigated. Results: Seventy-six (42.22%) cases were confirmed with severe COVID-19, while 104 patients (57.78%) were divided into the non-severe group. Fever (56.67%, 102/180) and cough (50.00%, 90/180) were the common symptoms of COVID-19. The death rate was 18.89% (34/180), and severe pneumonia (44.12%, 15/34) and septic shock (23.53%, 8/34) represented the leading reasons for deaths. The older age population, a combination of hypertension and diabetes, the presence of pneumonia, and high levels of inflammatory markers were significantly associated with severity of COVID-19 development (P < 0.05 for all). Altered level of consciousness [odds ratio (OR)=56.574, 95% confidence interval (CI) 5.645-566.940, P=0.001], high levels of neutrophils (OR=1.341, 95%CI 1.109-1.621, P=0.002) and C-reactive protein (CRP) (OR=1.014, 95%CI 1.003-1.025, P=0.016) might be indicators for COVID-19 deaths. Dexamethasone treatment could reduce mortality [30.36% (17/56) vs. 50.00% (10/20)] among severe COVID-19 cases, but the results were not statistically significant (P > 0.05). Conclusions: The development and prognosis of COVID-19 may be significantly correlated with consciousness status, and the levels of neutrophils and CRP.

Background: Diabetes is a risk factor for acquisition of cryptococcal meningitis (CM). However, the effects of diabetes on outcomes of CM patient have not been fully studied. Methods: In this retrospective study, 49 diabetic CM patients and 98 non-diabetic CM patients from January 2008 to December 2018 in the First Affiliated Hospital of Zhejiang University were included by propensity score-matched method (1:2). Demographic characteristics, symptoms, and clinical assay parameters between the two groups were compared. Kaplan-Meier analysis and Cox proportional hazards model were used to assess factors associated with 10-week mortality. Results: The mean age of diabetic patients was 58.2 ± 13.8 years; 71.4% (35/49) were more than 50 years old and 46.9% were male. No difference in symptoms was found between diabetic and non-diabetic CM patients. The Charlson comorbidity score was higher in the diabetic group (1.9 vs. 0.7, P < 0.001). CM patients with diabetes had higher white blood cells count (×106/L, 111.0 (18.0- 242.5) vs. 50.0 (10.0-140.0), P=0.034) in cerebrospinal fluid (CSF), lower CSF India ink positivity (40.8% vs. 60.2%, P=0.039), and Cryptococcus culture positivity (42.9% vs. 60.2%, P=0.047). The overall 10-week survival rate was 79.7% in diabetic patients vs. 83.2% in non-diabetic patients (log-rank P=0.794). Conclusion: Diabetic CM patients have higher CSF glucose and Charlson comorbidity score, but lower CSF India ink and culture positivity than non-diabetic CM patients. No difference in 10-week mortality was found between patients with and without diabetes. Other comorbidities may have a greater effect on prognosis.

Hepatitis C virus (HCV) causes chronic infection in over 75% of the HCV-infected individuals, resulting in liver cancer in substantial patients. Since its discovery in 1989, HCV experiences a journey from discovery to cure, largely due to the virology studies and success of direct antiviral agent (DAA) development. We reviewed the HCV research journey, from the discovery of this virus to the development of DAAs for cure. Learning the methodology used in HCV studies and the knowledge of developing DAAs against HCV may inspire the studies of other difficult-to-culture viruses, such as hepatitis E virus and norovirus, as well as the development of DAAs for other single-stranded positive-sense RNA viruses, including the pandemic-causing SARS-CoV-2 virus, which shares the common replication strategy of forming a membrane-bound viral replicase.

Acute-on-chronic hepatitis B liver failure (ACHBLF) is a term used to define the acute deterioration of liver function that occurs in patients with chronic hepatitis B virus infection or hepatitis B virus-related liver cirrhosis. The specific pathogenesis of ACHBLF is still not completely understood. Current research has shown that an intense systemic inflammation is involved in the development of acute-on-chronic liver failure (ACLF). Meanwhile, a subsequent immune paresis over the course of ACLF favors the development of infection and sepsis. Deregulation in both the innate and adaptive immunity is the notable feature of ACLF. The dysregulated immune responses play a crucial role in disease progression and potentially drive organ failure and mortality in ACHBLF. In this review, we highlight the current knowledge of innate and adaptive immune cells in ACHBLF.

Increased microbial translocation and chronic immune activation are two critical problems for people living with HIV (PLWH) in the antiretroviral therapy (ART) era. Compared with numerous studies on bacterial microbiomic communities, there are only a limited number of studies focusing on fungal microbiomic composition and products in PLWH. This study protocol is used to evaluate the changes in bacterial and fungal microbiome populations induced by terbinafine treatment, which is an antifungal agent widely used amongst PLWH. Twenty-two PLWH on a stable ART regimen for more than six months, who require treatment for onychomycosis, will be recruited. The participants will be followed-up for a 12-week treatment period (oral terbinafine 250 mg daily) and another 12-weeks of terbinafine discontinuation. Plasma and fecal samples will be collected before and after terbinafine treatment, and for 12weeks after the discontinuation of terbinafine. Plasma gut injury and microbial translocation biomarker assays, in addition to testing for gut microbiome composition, will be undertaken. With this pilot study, we will perform formal sample size calculations and test study feasibility for a possible full-scale study.