Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Immunogenicity and safety of heterologous versus homologous prime-boost schedules with inactivated and adenoviral vectored SARS-CoV-2 vaccines - A prospective multi-center study.

Background: During the peak of Coronavirus disease (COVID-19) pandemic in Thailand when the emergence of delta variant reduced the efficacy of inactivated vaccine, Thailand had abundance of inactivated vaccine but mRNA vaccine was not available and the supply of adenoviral-vectored vaccine was limited. The heterologous vaccination using CoronaVac and ChAdOx1-nCoV-19 vaccines was applied. We aim to compare the immunogenicity of immune response of primary vaccination with homologous ChAdOx1 nCoV-19 and heterologous vaccination with CoronaVac and ChAdOx1 nCoV-19. Methods: A total of 430 adults, scheduled to receive ChAdOx1-nCoV-19 as their second dose of primary COVID-19 vaccination, were enrolled. Participants were classified into two groups based on the first dose vaccine as CoronaVac (heterologous group) or ChAdOx1 nCoV-19 (homologous group). The primary outcome was antibodies to the SARS-CoV-2 spike protein receptor binding domain (anti-RBD) titres at 28 days after the second dose of vaccination. Secondary outcomes were anti-RBD titres at 90 days, surrogate viral neutralizing test (sVNT) at 28 and 90 days, and adverse events. Findings: In 358 participants with correct vaccine interval, the anti-RBD geometric mean titre ratio for the heterologous versus homologous group was 0.55 (95%CI; 0.44-0.067); p < 0.001 at day 28, and 0.80 (95%CI; 0.65-1.00); P = 0.05 at day 90. Median sVNT neutralizing activity was not significantly different in the heterologous versus homologous group at 28 days (93.5 vs 92.7 %); p = 0.13, but significantly higher in the heterologous group at day 90 (82.9 vs 76.4 %); p = 0.01. Interpretation: The homologous vaccination resulted in higher anti-RBD titres at 28 days after vaccination, but titres in the homologous group showed more rapid decline at 90 days. In the sVNT assay, median neutralization was similar at 28 days, but was longer-lasting and higher in the heterologous group at 90 days. Funding: This research received funding from the Royal College of Physicians of Thailand special grant 2021 for research initiative during COVID-19 pandemic.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Clinical Features of Cryptococcal Meningoencephalitis in HIV-Positive and -Negative Patients in a Resource-Limited Setting.

Cryptococcal meningoencephalitis is a systemic fungal infection in immunocompromised and immunocompetent individuals. This study investigated the clinical characteristics and factors associated with mortality in HIV-associated and non-HIV-associated cryptococcal meningoencephalitis in a resource-limited setting. This was a retrospective cohort study of patients with cryptococcal meningoencephalitis between January 2009 and December 2019 at a tertiary teaching hospital in Thailand. Overall, 1019 patients with cryptococcal meningoencephalitis were enrolled, and 923 (90.6%) were HIV-positive. The patients with HIV-associated cryptococcal meningoencephalitis were younger than the HIV-negative patients (37 versus 56 years, p < 0.01). The HIV-negative patients were more likely to have underlying conditions (52.1% versus 7.5%; p < 0.01), had a longer median duration of headaches prior to admission (14 days versus 6 days, p < 0.01), and were more likely to have an altered mental status at presentation (36.5% versus 18.6%, p < 0.01) and pulmonary involvement (15.6% versus 0.8%, p < 0.01). The HIV-positive patients had lower cerebrospinal fluid (CSF) white blood cell counts (4 versus 94 cells/mm3; p < 0.01), lower CSF protein (69 versus 157 mg/dL; p < 0.01), higher CSF glucose (38.8 versus 21 mg/dL; p < 0.01), and more frequent cryptococcemia (44.1% versus 20.5%; p < 0.01). The mortality rate was high but not significantly different between the two groups (30.2% versus 33.2%; p = 0.53). The HIV-positive patients with comorbidities, fever, an altered mental status at presentation, a CSF white blood cell count below 20 cell/mm3, fungemia, and positive CSF India ink were independently associated with 30-day mortality. In comparison, an altered mental status at presentation and fungemia were associated with 30-day mortality in HIV-negative patients. In conclusion, HIV-negative patients with cryptococcal meningoencephalitis had more extensive central nervous system inflammation, although the two groups' mortality rates were similar. Unfavorable prognostic factors included comorbidities, fever, an altered mental status at presentation, a low CSF white blood cell count, fungemia, and positive CSF India ink.

Long-term multiple metabolic abnormalities among healthy and high-risk people following nonsevere COVID-19.

Few studies have identified the metabolic consequences of the post-acute phase of nonsevere COVID-19. This prospective study examined metabolic outcomes and associated factors in nonsevere, RT-PCR-confirmed COVID-19. The participants' metabolic parameters, the prevalence of long-term multiple metabolic abnormalities (≥ 2 components), and factors influencing the prevalence were assessed at 1, 3, and 6 months post-onset. Six hundred individuals (mean age 45.5 ± 14.5 years, 61.7% female, 38% high-risk individuals) with nonsevere COVID-19 attended at least one follow-up visit. The prevalence of worsening metabolic abnormalities was 26.0% for BMI, 43.2% for glucose, 40.5% for LDL-c, 19.1% for liver, and 14.8% for C-reactive protein. Except for lipids, metabolic-component abnormalities were more prevalent in high-risk hosts than in healthy individuals. The prevalence of multiple metabolic abnormalities at the 6-month follow-up was 41.3% and significantly higher in high-risk than healthy hosts (49.2% vs 36.5%; P = 0.007). Factors independently associated with a lower risk of these abnormalities were being female, having dyslipidemia, and receiving at least 3 doses of the COVID-19 vaccine. These findings suggest that multiple metabolic abnormalities are the long-term consequences of COVID-19. For both high-risk and healthy individuals with nonsevere COVID-19, healthcare providers should monitor metabolic profiles, encourage healthy behaviors, and ensure complete vaccination.

Efficacy and safety of Lianhua Qingwen capsules combined with standard of care in the treatment of adult patients with mild to moderate COVID-19 (FLOSAN): protocol for a randomized, double-blind, international multicenter clinical trial.

Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).

Dynamics of Antibody Responses after Asymptomatic and Mild to Moderate SARS-CoV-2 Infections: Real-World Data in a Resource-Limited Country.

The dynamics of humoral immune responses of patients after SARS-CoV-2 infection is unclear. This study prospectively observed changes in anti-receptor binding domain immunoglobulin G (anti-RBD IgG) and neutralizing antibodies against the Wuhan and Delta strains at 1, 3, and 6 months postinfection between October 2021 and May 2022. Demographic data, clinical characteristics, baseline parameters, and blood samples of participants were collected. Of 5059 SARS-CoV-2 infected adult patients, only 600 underwent assessment at least once between 3 and 6 months after symptom onset. Patients were categorized as immunocompetent (n = 566), immunocompromised (n = 14), or reinfected (n = 20). A booster dose of a COVID-19 vaccine was strongly associated with maintained or increased COVID-19 antibody levels. The booster dose was also more strongly associated with antibody responses than the primary vaccination series. Among patients receiving a booster dose of a mRNA vaccine or a heterologous regimen, antibody levels remained steady or even increased for 3 to 6 months after symptom onset compared with inactivated or viral vector vaccines. There was a strong correlation between anti-RBD IgG and neutralizing antibodies against the Delta variant. This study is relevant to resource-limited countries for administering COVID-19 vaccines 3 to 6 months after infection.

Performance of Cytomegalovirus Real-Time Polymerase Chain Reaction Assays of Fecal and Plasma Specimens for Diagnosing Cytomegalovirus Colitis.

INTRODUCTION: Cytomegalovirus (CMV) viral load detected by real-time polymerase chain reaction (PCR) in plasma or stool may facilitate detection of CMV colitis. METHODS: This prospective study enrolled 117 patients with clinically suspected CMV colitis. Patients presenting with gastrointestinal symptoms and having increased risk of CMV infection were eligible. All participants underwent colonoscopy with tissue biopsy. Five patients underwent colonoscopy twice because of clinical recurrence, resulting in a total of 122 colonoscopies. Stool CMV-PCR and plasma CMV-PCR were performed within 7 days before/after colonoscopy. Twenty asymptomatic volunteers also underwent the same protocol. RESULTS: Twenty-seven (23.1%) of 122 colonoscopies yielded positive for CMV colitis. The sensitivity and specificity was 70.4% and 91.6% for stool CMV-PCR and 66.7% and 94.7% for plasma CMV-PCR, respectively. The sensitivity of either positive plasma or positive stool CMV-PCR was 81.5%, which is significantly higher than that of plasma CMV-PCR alone ( P = 0.045). However, positive results from both tests yielded a specificity of 95.8%, which is significantly higher than that of stool CMV-PCR alone ( P = 0.045). There was a good and significant correlation between stool CMV-PCR and plasma CMV-PCR ( r = 0.71, P < 0.01), and both tests significantly correlated with the cytomegalic cell count ( r = 0.62, P < 0.01 for stool and r = 0.64, P < 0.01 for plasma). There were no positive stool or plasma CMV-PCR assays among volunteers. DISCUSSION: The results of this study strongly suggest that the combination of stool CMV-PCR and plasma CMV-PCR can be used to confidently rule in (both positive) or rule out (both negative) a diagnosis of CMV colitis.

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.

BACKGROUND: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING: Cidara Therapeutics and Mundipharma.

Impact of the Disk Diffusion Test on Fluconazole De-Escalation in Patients with Candidemia.

Disk diffusion (DD) is a simple antifungal susceptibility method for Candida. This study examined the impact of fluconazole DD testing on antifungal de-escalation. We enrolled patients with candidemia whose Candida isolates were tested for fluconazole susceptibility using DD between January 2019 and January 2020. The historical controls were patients with candidemia who underwent fluconazole susceptibility testing using the broth microdilution (BMD) method. Clinical data including antifungal therapy were analyzed. In total, 108 patients were enrolled. Most baseline characteristics were comparable between the groups. C. tropicalis was the predominant isolate (54.6%), followed by C. albicans (17.6%). The rates of antifungal de-escalation within 72 h were 25.9 and 9.3% in the DD and BMD groups, respectively (p = 0.023). The median time to de-escalation was 3 days in the DD group, versus 6 days in the BMD group (p = 0.037). The 14-day mortality rate and antifungal cost tended to be lower in the DD group. There were no differences in the length of hospital stay and treatment-related complications between the two groups. The agreement between the DD and BMD results was 90%. DD testing can be substituted for BMD to enhance antifungal de-escalation and antifungal stewardship.

Early antiviral and supervisory dexamethasone treatment improve clinical outcomes of nonsevere COVID-19 patients.

This study aimed to evaluate the efficacy of early antiviral treatment in preventing clinical deterioration in asymptomatic or mildly symptomatic severe acute respiratory syndrome coronavirus 2 infected (COVID-19) patients in home isolation and to share our experiences with the ambulatory management of nonsevere COVID-19 patients. This retrospective study included mild COVID-19 adult patients confirmed by real-time reverse transcription-polymerase chain reaction. They received care via an ambulatory management strategy between July 2021 and November 2021. Demographic data, clinical progression, and outcomes were collected. Both descriptive and inferential statistics were performed to illustrate the cohort's characteristic and outcomes of the study. Univariable and multivariable logistic regression models were employed to investigate the associations between clinical factors and disease progression. A total of 1940 patients in the Siriraj home isolation system met the inclusion criteria. Their mean age was 42.1 ±â€…14.9 years, with 14.2% older than 60 years, 54.3% female, and 7.1% with a body weight ≥ 90 kg. Only 115 patients (5.9%) had deterioration of clinical symptoms. Two-thirds of these could be managed at home by dexamethasone treatment under physician supervision; however, 38 of the 115 patients (2.0% of the study cohort) needed hospitalization. Early favipiravir outpatient treatment (≤ 5 days from onset of symptoms) in nonsevere COVID-19 patients was significantly associated with a lower rate of symptom deterioration than late favipiravir treatment (50 [4.6%] vs 65 [7.5%] patients, respectively; P = .008; odds ratio 1.669; 95% confidence interval, 1.141-2.441). The unfavorable prognostic factors for symptom deterioration were advanced age, body weight ≥ 90 kg, unvaccinated status, higher reverse transcription-polymerase chain reaction cycle threshold, and late favipiravir treatment. The early delivery of essential treatment, including antiviral and supervisory dexamethasone, to ambulatory nonsevere COVID-19 patients yielded favorable outcomes during the COVID-19 pandemic in Thailand.

Early diagnosis by antigen test kit and early treatment by antiviral therapy: An ambulatory management strategy during COVID-19 crisis in Thailand.

This study aimed to assess the clinical characteristics of patients who registered at the Siriraj Favipiravir Clinic and to share our experiences in this comparatively unique clinical setting. This retrospective study included patients who registered at the Siriraj Favipiravir Clinic during August 11, 2021 to September 14, 2021. Included adult patients were those with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) infection confirmed by antigen test kit (ATK) or real-time reverse transcription-polymerase chain reaction, no favipiravir contraindication, no prior COVID-19 treatment, and not receiving care from another medical facility. Demographic data and outcomes were collected and analyzed. Of the 1168 patients (mean age: 44.8 ± 16.4 years, 55.7% female) who registered at the clinic, 117 (10%) did not meet the treatment criteria, and 141 (12%) patients did not pick up their medication. One-third of patients had at least 1 symptom that indicated severe disease. Higher proportion of unvaccinated status (56.7% vs 47.5%, P = .005), higher proportion of persons with risk factors for disease progression (37.7% vs 31.3%, P = .028), and longer duration between the date of clinic registration and the date of positive diagnostic test (3 vs 2 days, P = .004) were significantly more commonly observed in the severe disease group compared to the nonsevere disease group. The duration between symptom onset and the date of clinic registration was significantly longer in the real-time reverse transcription-polymerase chain reaction group than in the ATK group (6 vs 4 days, P < .001). Most patients (90.0%) had completed favipiravir treatment regimen. The improvement and mortality rates were 86.7% and 1.2%, respectively. COVID-19 severity is associated with vaccination status, baseline risk factors, and timing between disease detection and treatment. The use of ATK influences patients to seek treatment significantly earlier in ambulatory setting. Our early diagnosis and antiviral treatment strategy yielded favorable results in an outpatient setting during a COVID-19 outbreak in Thailand.

Unmet needs and practical solutions in the management of invasive mould infections in Asia.

Management of invasive mould infections (IMIs) is challenging in Asia, as awareness among medical practitioners can be low and resources are limited. Timely diagnosis and appropriate treatment of IMIs can mitigate the impact on morbidity and mortality, but diagnostic methods, as well as access to preferred antifungal medications, may vary throughout the region. Knowledge of local epidemiology and accurate diagnosis and identification of causal pathogens would facilitate optimal treatment but data in Asia are lacking. To address these unmet needs in the management of IMIs, this paper is a call for urgent action in the following areas: improving awareness of the threat of IMIs; providing education to frontline clinicians across a broad range of specialties on 'red flags' for suspicion of IMIs; prioritizing cost-effective rapid diagnostic testing; improving access to preferred antifungal medications; and closing the gaps in local epidemiological data on IMIs to inform local treatment guidelines.

SARS-CoV-2 Antibody Response against Mild-to-Moderate Breakthrough COVID-19 in Home Isolation Setting in Thailand.

Background: In December 2021, Omicron replaced Delta as the dominant coronavirus disease 2019 (COVID-19) variant in Thailand. Both variants embody diverse epidemiological trends and immunogenicity. We investigated whether Delta and Omicron patients' biological and clinical characteristics and immunogenicity differed post-COVID-19 infection. Methods: This retrospective cohort study investigated the clinical outcomes and laboratory data of 5181 patients with mild-to-moderate COVID-19 (Delta, 2704; Omicron, 2477) under home isolation. We evaluated anti-receptor-binding domain immunoglobulin G (anti-RBD IgG) and surrogate viral neutralizing (sVNT) activity in 495 individuals post-COVID-19 infection during the Delta pandemic. Results: Approximately 84% of all patients received favipiravir. The median cycle threshold (Ct) values were lower for Omicron patients than Delta patients (19 vs. 21; p < 0.001), regardless of vaccination status. Upper respiratory tract symptoms were more frequent with Omicron patients than Delta patients. There were no significant associations between Ct and Omicron symptoms (95% confidence interval 0.98−1.02). A two-dose vaccine regimen reduced hospital readmission by 10% to 30% and death by under 1%. Anti-RBD IgG and sVNT against Delta were higher among older individuals post-COVID-19 infection. Older individuals expressed anti-RBD IgG and sVNT for a more extended period after two-dose vaccination than other age groups. Conclusions: After a full vaccination course, breakthrough mild-to-moderate Delta and Omicron infections have limited immunogenicity. Prior infections exert reduced protection against later reinfection or infection from novel variants. However, this protection may be sufficient to prevent hospitalization and death, particularly in countries where vaccine supplies are limited.

Safety and Efficacy of Ivermectin for the Prevention and Treatment of COVID-19: A Double-Blinded Randomized Placebo-Controlled Study.

The safety and efficacy of ivermectin for the prevention and treatment of COVID-19 are still controversial topics. From August to November 2021, we conducted a double-blinded, randomized controlled trial at Siriraj Hospital, Thailand. Eligible participants were adults ≥ 18 years with suspected COVID-19 who underwent a SARS-CoV-2 RT-PCR test. After enrollment, the participants were randomized to receive either ivermectin (400−600 µg/kg/d) or placebo once daily for 3 days. Among 983 participants, 536 (54.5%) with a negative RT-PCR result were enrolled in the prevention study, and 447 (45.5%) with a positive RT-PCR result were enrolled in the treatment study. In the prevention study, the incidence of COVID-19 on Day 14 was similar between the ivermectin and the placebo group (4.7% vs. 5.2%; p = 0.844; Δ = −0.4%; 95% CI; −4.3−3.5%). In the treatment study, there was no significant difference between the ivermectin and placebo group for any Day 14 treatment outcome: proportion with oxygen desaturation (2.7% vs. 1.9%; p = 0.75), change in WHO score from baseline (1 [−5, 1] vs. 1 [−5, 1]; p = 0.50), and symptom resolution (76% vs. 82.2%; p = 0.13). The ivermectin group had a significantly higher proportion of transient blurred vision (5.6% vs. 0.6%; p < 0.001). Our study failed to demonstrate the efficacy of a 3-day once daily of ivermectin for the prevention and treatment of COVID-19. The given regimen of ivermectin should not be used for either prevention or treatment of COVID-19 in populations with a high rate of COVID-19 vaccination.

QuantiFERON-Cytomegalovirus Assay for Prediction of Cytomegalovirus Viremia in Kidney Transplant Recipients: Study From High Cytomegalovirus Seroprevalence Country.

Background: Early studies showed the utility of pretransplant QuantiFERON-Cytomegalovirus (QF-CMV) assays for CMV-disease prediction post kidney transplant (KT). However, recent data are conflicting. Methods: This prospective cohort study enrolled adult patients undergoing KT between July 2017 and May 2019. Patients with antithymocyte globulin therapy or negative pretransplant CMV IgG were excluded. QF-CMV assays were performed on transplantation day and one month thereafter, and CMV viral loads were obtained 1, 3, and 6 months posttransplantation. The primary outcome was CMV viremia within 6 months. The QF-CMV assay-posttransplant CMV viremia association was analyzed. Results: Fifty-five patients were enrolled (male, 58.2%; mean (SD) age, 46.5 (10.2) years). Fifty-two (94.5%) received CMV-seropositive donor kidneys. Over 6 months, 29 patients developed CMV viremia (52.7%), with 14 (25.5%) having significant viremia requiring antiviral therapy. The CMV-viremia incidence of patients with nonreactive and reactive baseline QF-CMV assays did not differ significantly (55.3% and 47.1%; p = 0.573). Among patients with reactive pretransplant QF-CMV assays, there was a trend toward a lower incidence of CMV viremia for those who were persistently reactive at 1 month after KTs, although there was no statistically significant difference (50% vs 83%; p = 0.132). Conclusions: Our study could not support the use of single-timepoint pretransplant or 1-month posttransplant QF-CMV assays as a predictor for posttransplant CMV viremia in CMV seropositive KT recipients. Investigation of the association between dynamic QF-CMV-status changes and CMV-viremia incidence are needed.

Characteristics and Outcomes of Patients with Invasive Pulmonary Aspergillosis and Respiratory Tract Aspergillus Colonization from a Tertiary University Hospital in Thailand.

Positive culture for Aspergillus spp. from respiratory specimens needs to be interpreted together with relevant clinical conditions/settings to differentiate invasive infection from colonization. In this study, we aimed to investigate the association between positive culture for Aspergillus spp. from respiratory specimens and the presence of invasive pulmonary aspergillosis. Hospitalized patients with positive culture for Aspergillus spp. from any respiratory sample were retrospectively recruited. Patients were classified into two groups: those with invasive pulmonary aspergillosis and those with non-invasive aspergillosis/colonization. Two hundred and forty-one patients (48.1% male; mean age: 59.8 ± 14.5 years) were included. The most common Aspergillus spp. was A. fumigatus (21.0%). The most common underlying condition was chronic lung disease (23.7%), followed by solid tumor (22.4%). Myeloproliferative disease (aOR: 69.2, 95% CI: 2.4-1991.9), neutropenia ≥ 10 days (aOR: 31.8; 95% CI: 1.10-920.53), and corticosteroid treatment (aOR: 42.8, 95% CI: 6.5-281.3) were independent predictors of the invasive form. Chronic lung disease was independently inversely related to invasive form (OR: 0.04; 95% CI: 0.003-0.49). Serum galactomannan was positive in 69.2% of patients with invasive aspergillosis (OR: 25.9, 95% CI: 5.2-127.8). All inappropriately treated patients with invasive form died. In conclusion, positive culture for Aspergillus spp. from respiratory specimens with coexisting myeloproliferative disease, neutropenia ≥ 10 days, corticosteroid treatment, or positive serum galactomannan is highly suggestive of invasive pulmonary aspergillosis.

Risk Factors, Clinical Characteristics, Management, and Outcomes of Musculoskeletal Fungal Infection at Thailand's Largest National Tertiary Referral Center.

To investigate the risk factors, clinical characteristics, management, and outcomes of musculoskeletal fungal infection in Thai patients, patients aged ≥18 years definitively diagnosed with musculoskeletal fungal infection by culture and/or histopathology at Siriraj Hospital (Bangkok, Thailand) during 2002-2020 were retrospectively enrolled. Twenty-eight patients (median age: 58.5 years [range: 22-81], 57.1% male) with fungal osteomyelitis (n = 22), septic arthritis (n = 1), or fungal osteomyelitis with septic arthritis (n = 5) were included. Immunocompromised status was common (82%). Most patients had de novo infection from hematogenous spreading that usually presented at a single, non-contiguous site. The median symptom duration prior to diagnosis was 2 months. The tibia and knee were the most common site of osteomyelitis (30%) and septic arthritis (72%), respectively. The most common pathogens were Talaromyces marneffei and Cryptococcus neoformans. Organism identification from tissues at the affected sites was required in all cases. Most patients (82%) required combination surgery and systemic antifungal therapy. Among those with complete follow-up (23/28), 61% and 39% had complete and partial responses, respectively. Musculoskeletal fungal infection is an uncommon disease with insidious onset and non-specific manifestations that requires pathogen identification via tissue cultures and histopathologic studies. Combination surgery and systemic antifungal therapy yielded generally favorable outcomes.

The Impact of Sex on the Outcomes of Prosthetic Joint Infection Treatment with Debridement, Antibiotics and Implant Retention: A Systematic Review and Individual Patient Data Meta-analysis.

BACKGROUND: The influence of sex on the failure of débridement antibiotics and implant retention (DAIR) for treating prosthetic joint infection (PJI) is important for decision-making, patient counseling, and equitable health care. However, very few studies in the orthopaedic literature conduct sex-specific analyses. AIM: The primary aim was to determine whether sex influences treatment success after DAIR. METHODS: A systematic review and individual patient data (IPD) meta-analysis was conducted. MEDLINE (Ovid), EMBASE (Ovid), Web of Science, and Google Scholar were searched, and IPD was requested via e-mail. Patients who underwent DAIR after developing PJI within 12 months of a primary total hip or knee arthroplasty were included in the analysis. Treatment failure was defined by the Delphi International Consensus criteria. Adjusted odds ratios for treatment failure were calculated using a mixed-effects logistic regression. RESULTS: The study collected and analyzed IPD of 1,116 patients from 21 cohorts. The odds of treatment failure were 29% lower in women (odds ratio, 0.71; 95% CI 0.54 to 0.017; P = 0.017), after adjusting for duration of symptoms >7 days and Staphylococcus aureus infection (methicillin-susceptible Staphylococcus aureus or any infection with S aureus). None of the 64 studies included in the systematic review conducted a sex-specific analysis. CONCLUSION: For patients who developed a PJI within 1 year postsurgery, females have lower odds of DAIR failure than males. Other factors also have varying effects on outcome for men and women. It is essential to implement sex-specific analysis in orthopaedic research.

Understanding the Potential Impact of Different Drug Properties on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission and Disease Burden: A Modelling Analysis.

BACKGROUND: The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. METHODS: Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. RESULTS: The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. CONCLUSIONS: Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.