Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.

Innovative approaches to track lymph node germinal center responses to evaluate development of broadly neutralizing antibodies in human HIV vaccine trials.

Phase 1 clinical studies will soon evaluate novel HIV-1 envelope immunogens targeting distinct 'germline' and memory B cell receptors to ultimately elicit HIV-1 broadly neutralizing antibodies (bNAbs). The National Institute of Allergy and Infectious Diseases (NIAID) recently convened a panel of US-based expert scientists, clinicians, sponsors and ethicists to discuss the role of sampling draining lymph nodes within preventive HIV vaccine trials. The meeting addressed the importance of evaluating germinal center (GC) responses following immunization to predict bNAb potency and breadth, and reviewed key aspects of this procedure within the clinical research setting, including informed consent, adverse event monitoring, study participant acceptability, medical expertise and training. We review highlights from the meeting and discuss the advantages and disadvantages of sampling lymph nodes by excisional biopsies compared to fine needle aspirations (FNA) in the context of prophylactic HIV vaccine trials.

Clinical characteristics and factors associated with severe acute respiratory infection and influenza among children in Jingzhou, China.

BACKGROUND: Influenza is an important cause of respiratory illness in children, but data are limited on hospitalized children with laboratory-confirmed influenza in China. METHODS: We conducted active surveillance for severe acute respiratory infection (SARI; fever and at least one sign or symptom of acute respiratory illness) among hospitalized pediatric patients in Jingzhou, Hubei Province, from April 2010 to April 2012. Data were collected from enrolled SARI patients on demographics, underlying health conditions, clinical course of illness, and outcomes. Nasal swabs were collected and tested for influenza viruses by reverse transcription polymerase chain reaction. We described the clinical and epidemiological characteristics of children with influenza and analyzed the association between potential risk factors and SARI patients with influenza. RESULTS: During the study period, 15 354 children aged <15 years with signs and symptoms of SARI were enrolled at hospital admission. severe acute respiratory infection patients aged 5-15 years with confirmed influenza (H3N2) infection were more likely than children without influenza to have radiographic diagnosis of pneumonia (11/31, 36% vs 15/105, 14%. P<.05). Only 16% (1116/7145) of enrolled patients had received seasonal trivalent influenza vaccination within 12 months of hospital admission. Non-vaccinated influenza cases were more likely than vaccinated influenza cases to have pneumonia (31/133, 23% vs 37/256, 15%, P<.05). severe acute respiratory infection cases aged 5-15 years diagnosed with influenza were also more likely to have a household member who smoked cigarettes compared with SARI cases without a smoking household member (54/208, 26% vs 158/960, 16%, P<.05). CONCLUSIONS: Influenza A (H3N2) virus infection was an important contributor to pneumonia requiring hospitalization. Our results highlight the importance of surveillance in identifying factors for influenza hospitalization, monitoring adherence to influenza prevention and treatment strategies, and evaluating the disease burden among hospitalized pediatric SARI patients. Influenza vaccination promotion should target children.

Hepatitis B testing and access to care among racial and ethnic minorities in selected communities across the United States, 2009-2010.

UNLABELLED: Hepatitis B virus (HBV) infection is widely prevalent among racial and ethnic minorities in the United States; however, few data have been available regarding HBV testing and referral to care for these populations. Using survey data collected in 2009-2010 from the Racial and Ethnic Approaches to Community Health (REACH) across the U.S., we assessed rates and determinants of hepatitis B testing and access to care in 28 minority communities in the U.S. Of 53,896 respondents, 21,129 (39.2%) reported having been tested for hepatitis B. Of the 1,235 who reported testing positive, 411 (33.3%) reported currently receiving specialty care. After controlling for demographic and socioeconomic characteristics, the likelihood of having been tested for hepatitis B and receiving care if infected was higher among males, non-English speaking persons, and those having health insurance compared to their counterparts. Compared to college graduates, respondents without a college education were less likely to get tested for hepatitis B. CONCLUSION: These data indicate that more than half of racial/ethnic minority persons in these communities had not been tested for hepatitis B, and only about one-half of those who tested positive had ever received treatment. More state and federal efforts are needed to screen racial/ethnic minorities, especially foreign-born persons, for HBV and link those with infection to care.

Evolving epidemiology of hepatitis C virus in the United States.

The impact of hepatitis C virus (HCV) infection on health and medical care in the United States is a major problem for infectious disease physicians. Although the incidence of HCV infection has declined markedly in the past 2 decades, chronic infection in 3 million or more residents now accounts for more disease and death in the United States than does human immunodeficiency virus (HIV)/AIDS. Current trends in the epidemiology of HCV infection include an apparent increase in young, often suburban heroin injection drug users who initiate use with oral prescription opioid drugs; infections in nonhospital healthcare (clinic) settings; and sexual transmission among HIV-infected persons. Infectious disease physicians will increasingly have the responsibility of diagnosing and treating HCV patients. An understanding of how these patients were infected is important for determining whom to screen and treat.

Hepatitis B vaccination of susceptible elderly residents of long term care facilities during a hepatitis B outbreak.

Protection of older persons, particularly those with diabetes, against hepatitis B virus (HBV) infection is of growing concern because of increased reports of outbreaks among long-term care facility residents receiving assisted blood glucose monitoring. We evaluated hepatitis B vaccine immunogenicity among residents immunized in response to two such outbreaks in skilled nursing facilities during June 2009-July 2010. One hundred forty-eight (71%) of 209 residents were found to be susceptible to HBV infection. Of 105 patients who began a vaccination series with Twinrix(®) (0-, 1-, 6-month dosing), 86 (82%) completed the series and postvaccination testing. Of these, most were elderly (median age 79.5 years; range 45-101), female (56%), and African-American (51%). Twenty-nine (34%) vaccinated residents had post-vaccination hepatitis B surface antibody levels ≥10 mIU/ml. There were no significant differences in vaccine response by age, gender, race, diabetes status, body mass index, or current smoking status. Our findings indicate that a low proportion of skilled nursing facility residents achieved a seroprotective response after hepatitis B vaccination.

The increasing burden of imported chronic hepatitis B--United States, 1974-2008.

BACKGROUND: Without intervention, up to 25% of individuals chronically infected with hepatitis B virus (HBV) die of late complications, including cirrhosis and liver cancer. The United States, which in 1991 implemented a strategy to eliminate HBV transmission through universal immunization, is a country of low prevalence. Approximately 3,000-5,000 U.S.-acquired cases of chronic hepatitis B have occurred annually since 2001. Many more chronically infected persons migrate to the United States yearly from countries of higher prevalence. Although early identification of chronic HBV infection can reduce the likelihood of transmission and late complications, immigrants are not routinely screened for HBV infection during or after immigration. METHODS: To estimate the number of imported cases of chronic hepatitis B, we multiplied country-specific prevalence estimates by the yearly number of immigrants from each country during 1974-2008. RESULTS: During 1974-2008, 27.9 million immigrants entered the U.S. Sixty-three percent were born in countries of intermediate or high chronic hepatitis B prevalence (range 2%-31%). On average, an estimated 53,800 chronic hepatitis B cases were imported to the U.S. yearly from 2004 through 2008. The Philippines, China, and Vietnam contributed the most imported cases (13.4%, 12.5%, and 11.0%, respectively). Imported cases increased from an estimated low of 105,750 during the period 1974-1977 to a high of 268,800 in 2004-2008. CONCLUSIONS: Imported chronic hepatitis B cases account for approximately 95% of new U.S. cases. Earlier case identification and management of infected immigrants would strengthen the U.S. strategy to eliminate HBV transmission, and could delay disease progression and prevent some deaths among new Americans.

Genomic DNA methylation changes in response to folic acid supplementation in a population-based intervention study among women of reproductive age.

Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 µg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 µg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (-14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.

Iron, folate, and B(12) deficiencies and their associations with anemia among women of childbearing age in a rural area in Northern China.

OBJECTIVE: To assess the prevalence of folate, vitamin B(12), and iron deficiencies and their associations with anemia among women of childbearing age in northern China, an area with a reported high incidence of neural tube defects. METHODS: Plasma folate, vitamin B(12), ferritin, and hemoglobin levels were measured among 1,671 non-pregnant women of childbearing age from Xianghe County, Hebei Province, China in June 2004. RESULTS: Geometric means [95 % confidence interval (CI)] of plasma concentrations were 9.3 (4.0, 21.6) nmol/L for folate, 213.1 (82.4, 550.9) pmol/L for vitamin B(12), 17.4 (1.1, 278.6) microg/L for ferritin, and 129.9 (104.6, 161.4) g/L for hemoglobin (Hb). Approximately 24 % of women had biochemical evidence of folate deficiency (<6.8 nmol/L), 21.4 % were deficient (<148 pmol/L) in vitamin B(12), 30.2 % had iron depletion (<15 microg/L), and anemia (Hb < 120 g/L) was detected among 15.4 % of women. Of the three nutrients, only iron depletion (ferritin < 15 microg/L) was independently associated with anemia (adjusted odds ratio = 6.4, 95 % CI 4.8, 8.6). CONCLUSIONS: Although there were substantial proportions of folate and vitamin B(12) deficiencies among women of childbearing age in northern China, iron deficiency was the most important contributor to anemia.

HIV type 1 incidence estimates by detection of recent infection from a cross-sectional sampling of injection drug users in Bangkok: use of the IgG capture BED enzyme immunoassay.

Development of serologic tests to detect recent HIV-1 infection has generated worldwide interest in applying this approach to estimate incidence. We previously devised an IgG-capture BED-EIA (or BED-CEIA) that detects increasing levels of anti-HIV IgG following seroconversion to identify recent infection and to estimate incidence among persons infected with diverse HIV-1 subtypes worldwide. Injection drug users (IDUs; n = 1969) were screened in 1996 for participation in a prospective cohort study. Serum specimens from 594 IDUs were HIV-1 seropositive (30.2%) and were tested with the BED-CEIA. The proportion of recent infections and estimated incidence by different epidemiological risk factors were compared with incidence data measured from the prospective cohort. Of 594 HIV-1-seropositive specimens, 113 (19%) were identified as recent infections. Overall, the estimated annual incidence among persons screened was 17.3%/year (95% CI, 12.8-24.2%/year) compared with 9.0%/year (95% CI, 6.7-11.9%/year) measured from the prospective cohort during the same time period. Estimated incidence was higher among younger aged and unemployed IDUs as well as among those who injected more frequently, confirming previously reported risk factors from this prospective cohort. As persons screened from a cross-sectional sampling probably have higher risk for HIV than selected uninfected individuals who choose to participate and receive risk reduction counseling in a longitudinal cohort study, use of this or other serologic testing strategies to identify populations with high incidence (such as for HIV vaccine trials) may overestimate incidence measured from prospective cohorts.

Evaluation of a sensitive/less sensitive testing algorithm using the bioMérieux Vironostika-LS assay for detecting recent HIV-1 subtype B' or E infection in Thailand.

The performance of the bioMérieux Vironostika-LS EIA (less sensitive enzyme immunoassay) was assessed to detect recent seroconversion among injecting drug users (IDUs) in Bangkok, Thailand who were infected with either HIV-1 subtypes B' or E (also known as circulating recombinant form CRF01_AE). To evaluate the Vironostika-LS EIA in non-B subtypes, we collected longitudinal specimens (n = 796) from 115 IDUs (subtype B' infection, n = 24; subtype E infection, n = 91). After testing HIV-positive specimens with the Vironostika-LS EIA, standardized optical densities (SODs) were calculated using median values to determine the window period, which is the time from seroconversion on a standard EIA to seroconversion on the Vironostika-LS EIA for a given SOD, for either subtype. For an SOD cutoff of 1.0, Vironostika-LS EIA results showed a mean window period of 239 days (95% confidence interval [95% CI], 208-287 days) for subtype B' and 356 days (95% CI, 318-402 days) for subtype E in Thailand. This outcome demonstrates that the Vironostika-LS EIA has significantly different performance characteristics in detecting recent seroconversion between different HIV-1 subtypes. Accurate identification of recent infection and estimation of incidence for HIV-1 strains other than North American subtype B, using the Vironostika-LS EIA, requires knowledge of specimen subtype and use of appropriate cutoffs and mean window periods.

Quantitative detection of increasing HIV type 1 antibodies after seroconversion: a simple assay for detecting recent HIV infection and estimating incidence.

We have devised a simple enzyme immunoassay (EIA) that detects increasing levels of anti-HIV IgG after seroconversion and can be used for detecting recent HIV-1 infection. Use of a branched peptide that included gp41 immunodominant sequences from HIV-1 subtypes B, E, and D allowed similar detection of HIV-specific antibodies among various subtypes. Because of the competitive nature of the capture EIA, a gradual increase in the proportion of HIV-1-specific IgG in total IgG was observed for 2 years after seroconversion. This was in contrast to results obtained with the conventional EIA using the same antigen in solid phase, which plateaus soon after seroconversion. The assay was used to test 622 longitudinal specimens from 139 incident infections in the United States (subtype B) and in Thailand (subtypes B and E). The assay was also performed with an additional 8 M urea incubation step to assess the contribution of high-avidity antibodies. Normalized optical density (OD-n) was calculated (ODspecimen/ODcalibrator), using a calibrator specimen. An incremental analysis indicated that a cutoff of 1.0 OD-n and a seroconversion period of 160 days offered the best combination of sensitivity and specificity for classifying incident or long-term infections. The urea step increased the seroconversion period to 180 days with similar sensitivity and specificity. Separate analysis of B and E subtype specimens yielded the same optimal OD-n threshold and similar seroconversion periods. The assay was further validated in African specimens (subtypes A, C, and D) where the observed incidence was within 10% of the expected incidence. This assay should be useful for detecting recent HIV-1 infection and for estimating incidence among diverse HIV-1 subtypes worldwide.