July 05,2023

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Clinical Reports

Autochthonous Leprosy in the United States
- Historically, leprosy was thought to be transmitted exclusively through extended, close human-to-human contact, with infection acquired during brief travel considered to be exceedingly rare. In the 1970s, the nine-banded armadillo was identified as a zoonotic reservoir of Mycobacterium leprae, which has been implicated in autochthonous leprosy among persons born and living in the United States. However, autochthonous leprosy without armadillo exposure has also been reported. The long incubation period of leprosy often makes it challenging to pinpoint the exposure source. This is the report of six cases of autochthonous leprosy in U.S.-born men (mean age, 68.3 years) that were diagnosed between 2017 and 2022 in California. No patients had known exposure to an infected person, and one patient reported armadillo exposure more than 50 years earlier. All six patients reported international travel, and most reported domestic travel to the U.S. Gulf Coast. The interval between the initial clinical manifestation to diagnosis ranged from months to years. Five of the six patients were older than 65 years of age, and all had multibacillary infection.
A systematic review to identify novel clinical characteristics of monkeypox virus infection and therapeutic and preventive strategies to combat the virus
- Since May 2022, there has been a global increase in the number of Mpox virus (MPXV) cases in countries that were previously considered non-endemic. In July 2022, the World Health Organization (WHO) declared this outbreak a public health emergency of international concern. The objective of this systematic review is to examine the novel clinical features of Mpox and to assess the available treatment options for managing the disease in patients who are afflicted with it. Researchers conducted a systematic search in several databases, including PubMed, Google Scholar, Cochrane Library, and the grey literature, from May 2022 to February 2023. Researchers identified 21 eligible studies, which included 18,275 Mpox cases, for final qualitative analysis. The majority of cases were reported in men who have sex with men (MSM) and immunocompromised individuals with HIV (36.1%). The median incubation period was 7 days (IQR: 3–21). The novel clinical manifestations include severe skin lesions on the palms, oral and anogenital regions, as well as proctitis, penile edema, tonsillitis, ocular disease, myalgia, lethargy, and sore throat, without any preceding prodromal symptoms or systemic illness. In addition, fully asymptomatic cases were documented, and various complications, including encephalomyelitis and angina, were noted. Clinicians must be familiar with these novel clinical characteristics, as they can aid in testing and tracing such patients, as well as asymptomatic high-risk populations such as heterosexuals and MSM. In addition to supportive care, currently, there are several effective prophylactic and treatment strategies available to combat Mpox, including the vaccines ACAM2000 and MVA-BN7, as well as the immunoglobulin VIGIV and the antivirals tecovirimat, brincidofovir, and cidofovir against severe Mpox infection.
Genome-wide Association Study of Long COVID
- Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. Researchers leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. Researchers identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While researchers identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. These findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

Antiviral Therapeutics and Vaccines

Two-year duration of immunity of inactivated poliovirus vaccine: A follow-up study in Pakistan in 2020
- This was a follow-up study conducted in 2020 assessing changes in levels of type 2 poliovirus-neutralizing antibodies two years post-immunization in children who received inactivated poliovirus vaccine (IPV) in Karachi, Pakistan. Unexpectedly, the findings revealed an increase in seroprevalence of type 2 antibodies from 73.1% to 81.6% one and two years after IPV, respectively. The increase in type 2 immunity could result from the intensive transmission of circulating vaccine-derived poliovirus type 2 (cVDPV2) in Karachi during the second year of IPV administration. This study suggests that the cVDPV2 outbreak detected in Pakistan infected large proportions of children in Karachi.
Evaluation of novel oral polio vaccine type 2 SIA impact in a large outbreak of circulating vaccine-derived poliovirus in Nigeria
- Novel Oral Polio Vaccine Type 2 (nOPV2) has been made available for outbreak response under an Emergency Use Listing authorization based on supportive clinical trial data. Since 2021 over 350 million doses of nOPV2 were used for control of a large outbreak of circulating vaccine-derived poliovirus type 2 (cVDPV2) in Nigeria. Using a Bayesian time-series susceptible-infectious-recovered (TSIR) model, researchers evaluate the field effectiveness of nOPV2 immunization campaigns in Nigeria compared to those using monovalent oral polio vaccine type 2 (mOPV2). Researchers found that both nOPV2 and mOPV2 campaigns were highly effective in reducing transmission of cVDPV2, on average reducing the susceptible population by 42% (95% CI 0.28-0.54) and 38% (95% CI 0.20-0.51) per campaign, respectively, which were indistinguishable from each other in this analysis (relative effect 1.1, 95% CI 0.7-1.9). Impact was found to vary across areas and between immunization campaigns. These results are consistent with the comparable individual immunogenicity of nOPV2 and mOPV2 found in clinical trials, but also suggest that outbreak response campaigns may have small impacts in some areas requiring more campaigns than are suggested in current outbreak response procedures.
Effectiveness of the Coronavirus Disease 2019 Bivalent Vaccine
- The purpose of this study was to evaluate whether a bivalent coronavirus disease 2019 (COVID-19) vaccine protects against COVID-19. The study included employees of Cleveland Clinic in employment when the bivalent COVID-19 vaccine first became available. Cumulative incidence of COVID-19 over the following 26 weeks was examined. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression, with change in dominant circulating lineages over time accounted for by time-dependent coefficients. The analysis was adjusted for the pandemic phase when the last prior COVID-19 episode occurred and the number of prior vaccine doses. Among 51 017 employees, COVID-19 occurred in 4424 (8.7%) during the study. In multivariable analysis, the bivalent-vaccinated state was associated with lower risk of COVID-19 during the BA.4/5-dominant (hazard ratio, 0.71 [95% confidence interval, .63–79]) and the BQ-dominant (0.80 [.69–.94]) phases, but decreased risk was not found during the XBB-dominant phase (0.96 [.82–.1.12]). The estimated vaccine effectiveness was 29% (95% confidence interval, 21%–37%), 20% (6%–31%), and 4% (−12% to 18%), during the BA.4/5-, BQ-, and XBB-dominant phases, respectively. The risk of COVID-19 also increased with time since the most recent prior COVID-19 episode and with the number of vaccine doses previously received. The bivalent COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19 while the BA.4/5 lineages were the dominant circulating strains, afforded less protection when the BQ lineages were dominant, and effectiveness was not demonstrated when the XBB lineages were dominant.
Oral Nirmatrelvir and Ritonavir for Covid-19 in Vaccinated, Non-Hospitalized Adults, Ages 18-50 Year
- The effects of Nirmatrelvir/Ritonavir (NMV-r or Paxlovid) on Covid-19 outcomes in younger vaccinated adults are unclear. Researchers generated two propensity-matched cohorts of 2,547 patients from an 86,119-person cohort assembled from the TriNetX database. Patients in one cohort received NMV-r, and patients in the matched control cohort did not. The composite outcome was detected in 4.9% of the NMV-r cohort and 7.0% of the non-NMV-r cohort (OR 0.683, CI 0.540-0.864; p=0.001), indicating a 30% relative risk reduction. The number needed to treat (NNT) for the primary outcome was 47. Subgroup analyses found significant associations for patients with cancer (NNT=45), cardiovascular disease (NNT=30), and both conditions (NNT=16). No benefit was found for patients with only chronic lower respiratory disorders (asthma/COPD) or without serious comorbidities. 32% of NMV-r prescriptions in the overall database were for 18-50-year-olds. NMV-r use in vaccinated adults aged 18-50, especially with serious comorbidities, was associated with reduced all-cause hospital visits, hospitalization, and mortality in the first 30 days of Covid-19 illness. However, NMR-r in patients without significant comorbidities or with only asthma/COPD had no association of benefit. Therefore, identifying high-risk patients should be a priority and avoid over-prescription should be avoided.
Vaccination Ameliorates Cellular Inflammatory Responses in SARS-CoV-2 Breakthrough Infections
- Data on cellular immune responses in persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following vaccination are limited. The evaluation of these patients with SARS-CoV-2 breakthrough infections may provide insight into how vaccinations limit the escalation of deleterious host inflammatory responses. Researchers conducted a prospective study of peripheral blood cellular immune responses to SARS-CoV-2 infection in 21 vaccinated patients, all with mild disease, and 97 unvaccinated patients stratified based on disease severity. Researchers enrolled 118 persons (aged 50 years [SD 14.5 years], 52 women) with SARS-CoV-2 infection. Compared to unvaccinated patients, vaccinated patients with breakthrough infections had a higher percentage of antigen-presenting monocytes (HLA-DR+), mature monocytes (CD83+), functionally competent T cells (CD127+), and mature neutrophils (CD10+); and lower percentages of activated T cells (CD38+), activated neutrophils (CD64+), and immature B cells (CD127+CD19+). These differences widened with increased disease severity in unvaccinated patients. Longitudinal analysis showed that cellular activation decreased over time but persisted in unvaccinated patients with mild disease at 8-month follow-up. Patients with SARS-CoV-2 breakthrough infections exhibit cellular immune responses that limit the progression of inflammatory responses and suggest mechanisms by which vaccination limits disease severity. These data may have implications for developing more effective vaccines and therapies.

Diagnostics

Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection
- The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours.

Epidemiology

High incidence of autonomic dysfunction and postural orthostatic tachycardia syndrome in patients with long-COVID: Implications for management and healthcare planning
- Autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS) has been reported in individuals with post-acute sequelae of Covid-19 (PASC). However, the degree of dysautonomia in PASC has not been compared to those with POTS and healthy controls. All participants were prospectively enrolled between 5th August 2021 and 31st October 2022. Autonomic testing included beat-to-beat hemodynamic monitoring to assess respiratory sinus arrhythmia, Valsalva ratio and orthostatic changes during a 10-minute active standing test as well as Sudomotor assessment. The Composite Autonomic Symptom Score (COMPASS-31) was used to assess symptoms and the Euroquol 5-Dimension survey (EQ-5D-5L) was used to assess health-related quality of life (HrQoL) measures. A total of 99 participants (n=33 PASC, n=33 POTS and n=33 healthy controls; median age 32 [18], 85.9% females) were included. Compared to healthy controls, the PASC and POTS cohorts demonstrated significantly reduced respiratory sinus arrhythmia (p<0.001), greater heart rate increase during 10-minute active standing test (p<0.001), greater burden of autonomic dysfunction evidenced by higher COMPASS-31 scores across all subdomains (all p<0.001) and poor HrQoL across all EQ-5D-5L domains (all p<0.001), lower median EQ-VAS (p<0.001) and lower utility scores (p<0.001). The majority (79%) of those with PASC met the internationally established criteria for POTS. The prevalence of autonomic symptomology or POTS was high in those with PASC, leading to poor HrQoL and high health disutility. Autonomic testing should be routinely undertaken in those with PASC to aid diagnosis and direct appropriate management to improve health outcomes.