A Causality Assessment Framework for COVID-19 Vaccines and Adverse Events at the COVID-19 Vaccine Safety Research Center

During the coronavirus disease 2019 (COVID-19) pandemic, conclusively evaluating possible associations between COVID-19 vaccines and potential adverse events was of critical importance. The National Academy of Medicine of Korea established the COVID-19 Vaccine Safety Research Center (CoVaSC) with support from the Korea Disease Control and Prevention Agency to investigate the scientific relationship between COVID-19 vaccines and suspected adverse events. Although determining whether the COVID-19 vaccine was responsible for any suspected adverse event necessitated a systematic approach, traditional causal inference theories, such as Hill's criteria, encountered certain limitations and criticisms. To facilitate a systematic and evidence-based evaluation, the United States Institute of Medicine, at the request of the Centers for Disease Control and Prevention, offered a detailed causality assessment framework in 2012, which was updated in the recent report by the National Academies of Sciences, Engineering, and Medicine (NASEM) in 2024.This framework, based on a weight-of-evidence approach, allows the independent evaluation of both epidemiological and mechanistic evidence, culminating in a comprehensive conclusion about causality. Epidemiological evidence derived from population studies is categorized into four levels—high, moderate, limited, or insufficient—while mechanistic evidence, primarily from biological and clinical studies in animals and individuals, is classified as strong, intermediate, weak, or lacking. The committee then synthesizes these two types of evidence to draw a conclusion about the causal relationship, which can be described as “convincingly supports” (“evidence established” in the 2024 NASEM report), “favors acceptance,” “favors rejection,” or “inadequate to accept or reject.” The CoVaSC has established an independent committee to conduct causality assessments using the weightof-evidence framework, specifically for evaluating the causality of adverse events associated with COVID-19 vaccines. The aim of this study is to provide an overview of the weight-ofevidence framework and to detail the considerations involved in its practical application in the CoVaSC.

Psychiatric adverse events associated with the COVID-19 vaccines approved in the Republic of Korea: a systematic review

This systematic review evaluated psychiatric adverse events (AEs) following vaccination against coronavirus disease 2019 (COVID-19). We included studies that reported or investigated psychiatric AEs in individuals who had received an approved COVID-19 vaccine in the Republic of Korea. Systematic electronic searches of Ovid-Medline, Embase, CENTRAL, and KoreaMed databases were conducted on March 22, 2023. Risk of bias was assessed using the Risk of Bias Assessment Tool for Non-randomized Studies 2.0. The study protocol was registered in the International Prospective Register of Systematic Reviews (CRD42023449422). Of the 301 articles initially selected, 7 were included in the final analysis. All studies reported on sleep disturbances, and 2 highlighted anxiety-related AEs. Sleep disorders like insomnia and narcolepsy were the most prevalent AEs, while depression was not reported. Our review suggests that these AEs may have been influenced by biological mechanisms as well as the broader psychosocial context of the COVID-19 pandemic. Although this study had limitations, such as a primary focus on the BNT162b2 vaccine and an observational study design, it offered a systematic, multi-vaccine analysis that fills a critical gap in the existing literature. This review underscores the need for continued surveillance of psychiatric AEs and guides future research to investigate underlying mechanisms, identify risk factors, and inform clinical management.

The COVID-19 Vaccine Safety Research Center: a cornerstone for strengthening safety evidence for COVID-19 vaccination in the Republic of Korea

The COVID-19 Vaccine Safety Research Committee (CoVaSC) was established in November 2021 to address the growing need for independent, in-depth scientific evidence on adverse events (AEs) following coronavirus disease 2019 (COVID-19) vaccination. This initiative was requested by the Korea Disease Control and Prevention Agency and led by the National Academy of Medicine of Korea. In September 2022, the COVID-19 Vaccine Safety Research Center was established, strengthening CoVaSC’s initiatives. The center has conducted various studies on the safety of COVID-19 vaccines. During CoVaSC’s second research year, from September 29, 2022 to July 19, 2023, the center was restructured into 4 departments: Epidemiological Research, Clinical Research, Communication & Education, and International Cooperation & Policy Research. Its main activities include (1) managing CoVaSC and the COVID-19 Vaccine Safety Research Center, (2) surveying domestic and international trends in AE causality investigation, (3) assessing AEs following COVID-19 vaccination, (4) fostering international collaboration and policy research, and (5) organizing regular fora and training sessions for the public and clinicians. Causality assessments have been conducted for 27 diseases, and independent research has been conducted after organizing ad hoc committees comprising both epidemiologists and clinical experts on each AE of interest. The research process included protocol development, data analysis, interpretation of results, and causality assessment. These research outcomes have been shared transparently with the public and healthcare experts through various fora. The COVID-19 Vaccine Safety Research Center plans to continue strengthening and expanding its research activities to provide reliable, high-quality safety information to the public.

A framework for nationwide COVID-19 vaccine safety research in the Republic of Korea: the COVID-19 Vaccine Safety Research Committee

With the introduction of coronavirus disease 2019 (COVID-19) vaccines, the Korea Disease Control and Prevention Agency (KDCA) commissioned the National Academy of Medicine of Korea to gather experts to independently assess post-vaccination adverse events. Accordingly, the COVID-19 Vaccine Safety Research Committee (CoVaSC) was launched in November 2021 to perform safety studies and establish evidence for policy guidance. The CoVaSC established 3 committees for epidemiology, clinical research, and communication. The CoVaSC mainly utilizes pseudonymized data linking KDCA’s COVID-19 vaccination data and the National Health Insurance Service’s claims data. The CoVaSC’s 5-step research process involves defining the target diseases and organizing ad-hoc committees, developing research protocols, performing analyses, assessing causal relationships, and announcing research findings and utilizing them to guide compensation policies. As of 2022, the CoVaSC completed this research process for 15 adverse events. The CoVaSC launched the COVID-19 Vaccine Safety Research Center in September 2022 and has been reorganized into 4 divisions to promote research including international collaborative studies, long-/short-term follow-up studies, and education programs. Through these enhancements, the CoVaSC will continue to swiftly provide scientific evidence for COVID-19 vaccine research and compensation and may serve as a model for preparing for future epidemics of new diseases.

Empirical Treatment and Prevention of COVID-19 / 감염과화학요법

The rapid spread of severe acute respiratory coronavirus syndrome 2 (SARS-CoV-2) in the population and throughout the cells within our body has been developing. Another major cycle of coronavirus disease 2019 (COVID-19), which is expected in the coming fall, could be even more severe than the current one. Therefore, effective countermeasures should be developed based on the already obtained clinical and research information about SARSCoV- 2. The aim of this review was to summarize the data on the empirical treatment of COVID-19 acquired during this SARS-CoV-2 infection cycle; this would aid the establishment of an appropriate healthcare policy to meet the challenges in the future. The infectious disease caused by SARS-CoV-2 is characterized by common cold along with hypersensitivity reaction. Thus, in addition to treating common cold, it is essential to minimize the exposure of cells to the virus and to mitigate the uncontrolled immune response. A proper combination of antiviral agents, immune modulators such as prednisolone, and anticoagulants such as heparin and anti-C5a antagonists could be employed to minimize lung damage and prevent systemic involvements. Finally, strategies to achieve population immunity against SARS-CoV-2 should be developed through understanding of the interaction between the immune system and the virus.

Mixed Infection with Plasmodium falciparum and Plasmodium ovale in a Returned Traveller: the First Case in Korea

Mixed-species malaria infections are often unrecognized or underestimated. We hereby report the first described case of mixed infection with Plasmodium falciparum and Plasmodium ovale malaria in a returned traveller in Korea. In August 2016, a 25-year-old returned traveller from Cameroon and Democratic Republic of Congo presented with fever. He was diagnosed as P. falciparum malaria and successfully treated with artesunate. And 5 weeks after the completion of treatment, he presented with fever and diagnosed as P. ovale infection. P. ovale infection is a rare cause of malaria and often shows delayed presentation due to its dormant liver stage as hypnozoites. At re-presentation, the immunochromatographic test and microscopic examinations of our patient did not reveal P. ovale, which was only detected via polymerase chain reaction (PCR) assay. This case highlights the importance of considering malaria infection even in persons who have previously received malaria treatment. It also shows the usefulness of PCR testing for diagnosing P. ovale infections, which often present with a low level of parasitaemia.

Depression as a Mediator of Chronic Fatigue and Post-Traumatic Stress Symptoms in Middle East Respiratory Syndrome Survivors

OBJECTIVE: The relationship among chronic fatigue, depressive symptoms, and post-traumatic stress symptoms (PTSSs) among Middle East respiratory syndrome (MERS) survivors is poorly understood. METHODS: Of 148 survivors who consented to be registered and underwent assessments at 12 months (T1) and 18 months (T2) after the MERS outbreak, 72 (48.65%) were evaluated for chronic fatigue, depressive symptoms, and PTSSs based on the Impact of Event ScaleRevised (IES-R), the Patient Health Questionnaire-9 (PHQ-9), and the Fatigue Severity Scale (FSS). Data from 52 subjects, who completed both assessments, were analyzed using a regression-based serial multiple mediation model (PROCESS Model 6). RESULTS: Bootstrap analyses indicated no direct effects of T1 FSS on T2 IES-R but significant positive indirect effects of T1 FSS on T2 IESR through T1 PHQ-9 and T2 PHQ-9 (B=2.1601, SE=1.3268, 95% confidence interval=0.4250–6.1307). In other words, both T1 PHQ-9 and T2 PHQ-9 fully mediated the relationship between T1 FSS and T2 IES. CONCLUSION: Chronic fatigue 12 months after MERS had indirect effects on prolonged PTSSs 18 months after MERS via persisting depression in MERS survivors. This finding supports the need to promote interventional programs for emerging infectious disease survivors with chronic fatigue to reduce depression and prevent prolonged PTSSs.

Psychiatric Morbidity of Survivors One Year after the Outbreak of Middle East Respiratory Syndrome in Korea, 2015 / 신경정신의학

OBJECTIVES: Patients with an infectious diseases during an outbreak can experience extreme fear and traumatic events in addition to suffering from their medical illness. This study examined the long-term impact of the outbreak of Middle East Respiratory Syndrome (MERS) in Korea, 2015 on the mental health of the survivors. METHODS: Sixty-three survivors from MERS were recruited from a prospective cohort study at six hospitals one year after the outbreak in 2015. The Korean-Symptom Check List 95 was administered to evaluate their psychiatric problems and analyzed according to the patient's characteristics and exposure to traumatic events during the outbreak. RESULTS: A total of 63.5% of survivors suffered from significant psychiatric problems: post-traumatic symptoms (36.5%), sleep problems (36.5%), anxiety (34.9%), and depression (30.2%). Survivors with a history of a ventilator treatment during the MERS epidemic, a family member who died from MERS, and a past psychiatric history showed higher post traumatic stress disorder, anxiety, depression, and suicidality than people who do not have those histories. CONCLUSION: The study suggests that MERS survivors could have a high chance of adverse psychiatric consequences, even after their recovery from MERS. Exposure to traumatic events during the outbreak and premorbid individual vulnerability would affect the long-term mental health problems.

Psychiatric Findings in Suspected and Confirmed Middle East Respiratory Syndrome Patients Quarantined in Hospital: A Retrospective Chart Analysis

OBJECTIVE: Little is known about the psychiatric complications or risk factors for depression in suspected or confirmed Middle East Respiratory Syndrome (MERS) patients quarantined in hospital. METHODS: A retrospective chart review was performed of all the patients admitted to the acute MERS inpatient unit at the NMC during the 2015 outbreak. RESULTS: 30 (75%) were confirmed to be MERS-CoV positive among 40 admitted cases. Among the 24 MERS survivors, 17 (70.8%) exhibited psychiatric symptoms and 10 (41.7%) received a psychiatric diagnosis and medication during their hospital stay. Suspected MERS patients did not exhibit psychiatric symptoms or receive a psychiatric diagnosis. 27 suspected or confirmed MERS patients (age 41.15±18.64, male 37.0%) completed psychological assessments. A multiple linear regression analysis revealed that the Korean National Health and Nutrition Examination Survey-Short form and the Impact of Event Scale-Revised scores were significantly positively correlated with Patient Health Questionnaire-9 scores. CONCLUSION: Our findings indicate that the acute treatment of MERS-CoV infections in quarantine had a significant impact on the patients’ mental health. Furthermore, assessment of the risk factors for depression may identify vulnerable patients who require psychiatric care and attention during hospital quarantine.

Integrase Strand Transfer Inhibitor Resistance Mutations in Antiretroviral Treatment-naïve Patients in Korea: a Prospective, Observational Study

The present study investigated prevalence of integrase strand transfer inhibitors (INSTI) resistance mutations in HIV-1-infected antiretroviral therapy (ART)-naïve patients in Korea. From 106 plasma samples, amplification and sequencing of integrase genes was performed, and major or minor mutations were calculated by the Stanford HIV drug resistance mutation interpretation algorithm. No major INSTI resistance mutations were found, and 14 minor mutations were detected in 13 (12.3%) patients. The present data support the recommendation that routine testing for INSTI resistance mutations before starting ART is not necessary.

Correlation between Pneumonia Severity and Pulmonary Complications in Middle East Respiratory Syndrome

This nationwide, prospective cohort study evaluated pulmonary function and radiological sequelae according to infection severity in 73 survivors from the 2015 Middle East respiratory syndrome (MERS) outbreak in Korea. Patients with severe pneumonia in MERS-coronavirus infection had more impaired pulmonary function than those with no or mild pneumonia at the 1-year follow-up, which was compatible with the radiological sequelae. Severe pneumonia significantly impairs pulmonary function and makes long radiological sequelae in MERS.

Clinical Presentation and Outcomes of Middle East Respiratory Syndrome in the Republic of Korea / 감염과화학요법

BACKGROUND: From May to July 2015, the Republic of Korea experienced the largest outbreak of Middle East respiratory syndrome (MERS) outside the Arabian Peninsula. A total of 186 patients, including 36 deaths, had been diagnosed with MERS-coronavirus (MERS-CoV) infection as of September 30th, 2015. MATERIALS AND METHODS: We obtained information of patients who were confirmed to have MERS-CoV infection. MERS-CoV infection was diagnosed using real-time reverse-transcriptase polymerase chain reaction assay. RESULTS: The median age of the patients was 55 years (range, 16 to 86). A total of 55.4% of the patients had one or more coexisting medical conditions. The most common symptom was fever (95.2%). At admission, leukopenia (42.6%), thrombocytopenia (46.6%), and elevation of aspartate aminotransferase (42.7%) were observed. Pneumonia was detected in 68.3% of patients at admission and developed in 80.8% during the disease course. Antiviral agents were used for 74.7% of patients. Mechanical ventilation, extracorporeal membrane oxygenation, and convalescent serum were employed for 24.5%, 7.1%, and 3.8% of patients, respectively. Older age, presence of coexisting medical conditions including diabetes or chronic lung disease, presence of dyspnea, hypotension, and leukocytosis at admission, and the use of mechanical ventilation were revealed to be independent predictors of death. CONCLUSION: The clinical features of MERS-CoV infection in the Republic of Korea were similar to those of previous outbreaks in the Middle East. However, the overall mortality rate (20.4%) was lower than that in previous reports. Enhanced surveillance and active management of patients during the outbreak may have resulted in improved outcomes.

A Case Report of a Middle East Respiratory Syndrome Survivor with Kidney Biopsy Results

A 68-year old man diagnosed with Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) presented with multiple pneumonic infiltrations on his chest X-ray, and the patient was placed on a mechanical ventilator because of progressive respiratory failure. Urinary protein excretion steadily increased for a microalbumin to creatinine ratio of 538.4 mg/g Cr and a protein to creatinine ratio of 3,025.8 mg/g Cr. The isotope dilution mass spectrometry traceable serum creatinine level increased to 3.0 mg/dL. We performed a kidney biopsy 8 weeks after the onset of symptoms. Acute tubular necrosis was the main finding, and proteinaceous cast formation and acute tubulointerstitial nephritis were found. There were no electron dense deposits observed with electron microscopy. We could not verify the virus itself by in situ hybridization and confocal microscopy (MERS-CoV co-stained with dipeptidyl peptidase 4). The viremic status, urinary virus excretion, and timely kidney biopsy results should be investigated with thorough precautions to reveal the direct effects of MERS-CoV with respect to renal complications.

A Case of Sequential Lymphoma in an Human Immunodeficiency Virus-Infected Patient / 대한내과학회지

Rarely, two different histological types of lymphoma develop in the same person. Sequential lymphoma is defined as two different types of lymphoma occurring in the same person sequentially. A 47-year-old patient with human immunodeficiency virus (HIV) infection who had been diagnosed with mixed cellularity Hodgkin's lymphoma was treated with adriamycin, bleomycin, vinblastine, and dacarbazine combination chemotherapy. After six cycles of chemotherapy, abdominal computed tomography showed multiple liver masses. A percutaneous needle biopsy of the liver and polymerase chain reaction single-strand conformation polymorphism revealed hepatosplenic T-cell lymphoma. The patient died 3 months after the diagnosis of hepatosplenic T-cell lymphoma. To our knowledge, this is the first case of the sequential development of hepatosplenic T-cell lymphoma after Hodgkin's lymphoma in a Korean HIV-infected patient.

HIV-Infected Patients with Osteoporotic Fractures: A Case Report and Review of the Literature / 대한내과학회지

The average life expectancy of human immunodeficiency virus (HIV)-infected patients has improved dramatically following the advent of highly active anti-retroviral therapy. However, this increased life expectancy has led to a greater incidence of non-acquired immune deficiency syndrome related diseases, including cardiovascular diseases and other malignancies. Increased bone fragility is also a significant concern, with the incidence of osteoporosis and osteoporotic fractures 3- and 2-times more likely, respectively, among HIV-infected patients. Bone mineral density screenings for osteoporosis will therefore become more important as the HIV-infected population ages. Here, we describe six cases of osteoporotic fractures in HIV-infected patients in Korea.

Clinical Features of Seizures in Patients with Human Immunodeficiency Virus Infection

Patients with human immunodeficiency virus (HIV) infection have a higher burden of seizures, but few studies have examined seizures in HIV-infected individuals in Korea. A retrospective study was conducted to determine the epidemiology and clinical characteristics of seizures in patients with HIV infection. Among a total of 1,141 patients, 34 (3%) had seizures or epilepsy; 4 of these individuals had epilepsy before HIV infection, and the others showed new-onset seizures. Most patients exhibited moderate (200 to 500, n = 13) or low (below 200, n = 16) CD4 counts. The most common seizure etiology was progressive multifocal leukoencephalopathy (n = 14), followed by other HIV-associated central nervous system (CNS) complications (n = 6). Imaging studies revealed brain lesions in 21 patients. A total of 9 patients experienced only one seizure during the follow-up period, and 25 patients experienced multiple seizures or status epilepticus (n = 2). Multiple seizures were more common in patients with brain etiologies (P = 0.019) or epileptiform discharges on EEG (P = 0.032). Most seizures were controlled without anticonvulsants (n = 12) or with a single anticonvulsant (n = 12). Among patients with HIV infection, seizures are significantly more prevalent than in the general population. Most seizures, with the exception of status epilepticus, have a benign clinical course and few complications.

Renal Complications and Their Prognosis in Korean Patients with Middle East Respiratory Syndrome-Coronavirus from the Central MERS-CoV Designated Hospital

Some cases of Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) infection presented renal function impairment after the first MERS-CoV patient died of progressive respiratory and renal failure. Thus, MERS-CoV may include kidney tropism. However, reports about the natural courses of MERS-CoV infection in terms of renal complications are scarce. We examined 30 MERS-CoV patients admitted to National Medical Center, Korea. We conducted a retrospective analysis of the serum creatinine (SCr), estimated glomerular filtration rate (eGFR), urine dipstick tests, urinary protein quantitation (ACR or PCR), and other clinical parameters in all patients. Two consecutive results of more than trace (or 1+) of albumin and blood on dipstick test occurred in 18 (60%) (12 [40%]) and 22 (73.3%) (19 [63.3%]) patients, respectively. Fifteen (50.0%) patients showed a random urine ACR or PCR more than 100 mg/g Cr. Eight (26.7%) patients showed acute kidney injury (AKI), and the mean and median durations to the occurrence of AKI from symptom onset were 18 and 16 days, respectively. Old age was associated with a higher occurrence of AKI in the univariate analysis (HR [95% CI]: 1.069 [1.013-1.128], P = 0.016) and remained a significant predictor of the occurrence of AKI after adjustment for comorbidities and the application of a mechanical ventilator. Diabetes, AKI, and the application of a continuous renal replacement therapy (CRRT) were risk factors for mortality in the univariate analysis (HR [95% CI]: diabetes; 10.133 [1.692-60.697], AKI; 12.744 [1.418-114.565], CRRT; 10.254 [1.626-64.666], respectively). Here, we report renal complications and their prognosis in 30 Korean patients with MERS-CoV.

Antiviral Treatment Guidelines for Middle East Respiratory Syndrome / 감염과화학요법

Middle East respiratory syndrome (MERS) is an acute infectious disease of the respiratory system caused by the new betacoronavirus (MERS coronavirus, MERS-CoV), which shows high mortality rates. The typical symptoms of MERS are fever, cough, and shortness of breath, and it is often accompanied by pneumonia. The MERS-CoV was introduced to Republic of Korea in May 2015 by a patient returning from Saudi Arabia. The disease spread mostly through hospital infections, and by the time the epidemic ended in August, the total number of confirmed diagnoses was 186, among which 36 patients died. Reflecting the latest evidence for antiviral drugs in the treatment of MERS-CoV infection and the experiences of treating MERS patients in Republic of Korea, these guidelines focus on antiviral drugs to achieve effective treatment of MERS-CoV infections.

Anti-inflammatory, Antioxidant and Antimicrobial Effects of Artemisinin Extracts from Artemisia annua L

The anti-inflammatory, antioxidant, and antimicrobial properties of artemisinin derived from water, methanol, ethanol, or acetone extracts of Artemisia annua L. were evaluated. All 4 artemisinin-containing extracts had anti-inflammatory effects. Of these, the acetone extract had the greatest inhibitory effect on lipopolysaccharide-induced nitric oxide (NO), prostaglandin E2 (PGE2), and proinflammatory cytokine (IL-1beta , IL-6, and IL-10) production. Antioxidant activity evaluations revealed that the ethanol extract had the highest free radical scavenging activity, (91.0+/-3.2%), similar to alpha-tocopherol (99.9%). The extracts had antimicrobial activity against the periodontopathic microorganisms Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum subsp. animalis, Fusobacterium nucleatum subsp. polymorphum, and Prevotella intermedia. This study shows that Artemisia annua L. extracts contain anti-inflammatory, antioxidant, and antimicrobial substances and should be considered for use in pharmaceutical products for the treatment of dental diseases.

Clinical Characteristics and Use of Psychotropic Agents among HIV-Infected/AIDS Patients Referred for Psychiatric Consultation / 정신신체의학

OBJECTIVES: This study aimed to investigate the psychiatric status of HIV-infected/AIDS inpatients in a general hospital over the past 2.5 years. METHODS: A retrospective chart review was conducted of psychiatric consultations performed between January 1, 2011, and July 30, 2013. The records of 97 HIV-infected/AIDS patients were analyzed. These included a total of 282 psychiatric consultations. RESULTS: Of the 97 patients, 91(93.8%) were male, the mean age was 48 years, and mean number of consultations was 2.8. Depressed mood was reported in 102 consultations(23.8%), insomnia in 60(14.0%), and anxiety in 31(7.2%). Psychiatric disorders diagnosed on initial consultation included depressive disorder(37 patients ; 37.0%), cognitive disorder(11 ; 11.0%), and delirium(9 ; 9.0%). Recommended psychotropic medication included Lorazepam(99 ; 17.2%), Escitalopram(90 ; 15.7%), and Quetiapine(84 ; 14.6%). CONCLUSIONS: The main complaints of HIV-infected/AIDS patients were depressed mood, insomnia, and suicidal ideation(including suicide attempts). In total, 85(93.3%) patients of those consulted were diagnosed as meeting the criteria for a psychiatric condition. However, considering that only 16.9% of patients consulted received follow-up treatment, longitudinal research is needed to examine the influence of psychiatric disorders on the transmission of HIV-infection/AIDS, as well as on prognosis and treatment adherence.