Michael P. Broderick

Transmission Dynamics and Prospective Environmental Sampling of Adenovirus in a Military Recruit Setting

Abstract BackgroundHigh levels of morbidity caused by adenovirus among US military recruits have returned since the loss of adenovirus vaccines in 1999. The transmission dynamics of adenovirus have never been well understood, which complicates prevention efforts MethodsEnrollment and end-of-study samples were obtained and active surveillance for febrile respiratory illnesses (FRIs) was performed for 341 recruits and support personnel. Environmental samples were collected simultaneously. Classic and advanced diagnostic techniques were used ResultsSeventy-nine percent (213/271) of new recruits were seronegative for either adenovirus serotype 4 (Ad-4) or adenovirus serotype 7 (Ad-7). FRI caused by Ad-4 was observed in 25% (67/271) of enrolled recruits, with 100% of them occurring in individuals with enrollment titers <1:4. The percentage of recruits seropositive for Ad-4 increased from 34% at enrollment to 97% by the end of the study. Adenovirus was most commonly detected in the environment on pillows, lockers, and rifles ConclusionsPotential sources of adenovirus transmission among US military recruits included the presence of adenovirus on surfaces in living quarters and extended pharyngeal viral shedding over the course of several days. The introduction of new recruits, who were still shedding adenovirus, into new training groups was documented. Serological screening could identify susceptible recruits for the optimal use of available vaccines. New high-throughput technologies show promise in providing valuable data for clinical and research applications

Rapid Detection and Molecular Serotyping of Adenovirus by Use of PCR Followed by Electrospray Ionization Mass Spectrometry

ABSTRACT We have developed a PCR/electrospray ionization mass spectrometry (PCR/ESI-MS) assay for the rapid detection, identification, and serotyping of human adenoviruses. The assay employs a high-performance mass spectrometer to “weigh” the amplicons obtained from PCR using primers designed to amplify known human adenoviruses. Masses are converted to base compositions and, by comparison against a database of the genetic sequences, the serotype present in a sample is determined. The performance of the assay was demonstrated with quantified viral standards and environmental and human clinical samples collected from a military training facility. Over 500 samples per day can be analyzed with sensitivities greater than 100 genomes per reaction. This approach can be applied to many other families of infectious agents for rapid and sensitive analysis.

Broad Spectrum Respiratory Pathogen Analysis of Throat Swabs from Military Recruits Reveals Interference Between Rhinoviruses and Adenoviruses

Military recruits experience a high incidence of febrile respiratory illness (FRI), leading to significant morbidity and lost training time. Adenoviruses, group A Streptococcus pyogenes, and influenza virus are implicated in over half of the FRI cases reported at recruit training center clinics, while the etiology of the remaining cases is unclear. In this study, we explore the carriage rates and disease associations of adenovirus, enterovirus, rhinovirus, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis in military recruits using high-density resequencing microarrays. The results showed that rhinoviruses, adenoviruses, S. pneumoniae, H. influenzae, and N. meningitidis were widely distributed in recruits. Of these five agents, only adenovirus showed significant correlation with illness. Among the samples tested, only pathogens associated with FRI, such as adenovirus 4 and enterovirus 68, revealed strong temporal and spatial clustering of specific strains, indicating that they are transmitted primarily within sites. The results showed a strong negative association between adenoviral FRI and the presence of rhinoviruses in recruits, suggesting some form of viral interference.

Serum Penicillin G Levels Are Lower Than Expected in Adults within Two Weeks of Administration of 1.2 Million Units

When introduced in the 1950s, benzathine penicillin G (BPG) was shown to be effective in eradicating group A beta-hemolytic streptococcus (GAS) for at least 3 weeks after administration. Several studies since the 1990s suggest that at 3–4 weeks serum penicillin G levels are less than adequate (below MIC90 of 0.016 µg/ml). We studied these levels for 4 weeks after the recommended dose of BPG in military recruits, for whom it is used as prophylaxis against GAS. The 329 subjects (mean age 20 years) each received 1.2 million units BPG IM and gave sera 1 day post injection and twice more at staggered time points over 4 weeks. Serum penicillin G levels were measured by liquid chromatography/tandem mass spectometry. The half-life of serum penicillin G was 4.1 days. By day 11, mean levels were <0.02 µg/ml, and by day 15<0.01 µg/ml. Levels in more than 50% of the subjects were below 0.02 µg/ml on day 9, and <.01 µg/ml on day 16. There was no demonstrable effect of subject body-surface area nor of the four different lots of BPG used. These data indicate that in healthy young adults serum penicillin G levels become less than protective <2½ weeks after injection of 1.2 million units of BPG. The findings require serious consideration in future medical and public health recommendations for treatment and prophylaxis of GAS upper respiratory tract infections.

Exploration of the Effectiveness of Social Distancing on Respiratory Pathogen Transmission Implicates Environmental Contributions

Abstract Background. In both military and civilian settings, transmission of respiratory pathogens may be due to person-to-person and environmental contributions. This possibility was explored in a military training setting, where rates of febrile respiratory illness (FRI) often reach epidemic levels. Methods. Population size and FRI rates were monitored over 10 months in the units of 50–90 individuals. Some units were open to the influx of potentially infectious convalescents (hereafter referred to as “open units,” and some were closed to such an influx (hereafter referred to as “closed units”). Virologic testing and polymerase chain reaction analysis were used to detect adenovirus on surface structures. Results. The odds ratio (OR) associated with FRI in closed units, compared with open units, was 1.13 (95% confidence interval [CI], 0.99–1.28). The OR in units with a population greater than the median size, compared with units with a population lower than the median size was 1.38 (95% CI, 1.23–1.55). Between 5% and 9% of surface samples obtained from selected units harbored viable adenovirus. Conclusions. FRI rates were not reduced in units that were closed to potentially contagious individuals. These findings imply that the primary source of the pathogen is likely environmental rather than human, and they underscore what is known about other virus types. Diligence in identifying the relative roles of different transmission routes is suggested for civilian settings similar to those described in the current study.

Factors Associated with Loss of Penicillin G Concentrations in Serum After Intramuscular Benzathine Penicillin G Injection: A Meta-analysis

Background: An interval of 3–4 weeks between intramuscular injections of 1.2 million units of benzathine penicillin G as prophylaxis against group A streptococcal infection is recommended by health organizations for patients with pediatric rheumatic fever and heart disease. Methods: We reviewed the literature for evidence of the persistence of serum penicillin G during the first 4 weeks after the recommended dose of benzathine penicillin G. Results: The weighted-mean concentration was <0.02 µg/mL by 3 weeks after the initial dose. Weighted means were lower in studies done after 1990 than before (P < 0.01), in studies dealing with secondary versus primary prophylaxis (P < 0.01) and in studies in children versus those in adults (P < 0.02). Conclusions: Recommendations for benzathine penicillin G prophylaxis may need reevaluation.

Meningococcal disease in US military personnel before and after adoption of conjugate vaccine.

Abstract : During 2006-2013 only 1 military meningococcal case for which serogroup data are available (n = 28) was not serogroup C (n = 8), B (n = 8), or Y (n = 11). During that period, incidence in the US active-duty military of 0.271 cases per 100,000 person-years was not significantly different (p 0.05) from that of 0.252 in the 2006-2012 age-matched (ages 17-64) US general population. During 2010-2013, military incidence was 0.173 cases per 100,000 person-years compared with 0.218 in the age-matched 2010-2012 US population. There was only 1 military case in 2011 and only 1 in 2012. The incidence of non-serogroup-B cases during the MPSV-4 era is estimated to have been 0.327 cases per 100,000 person-years. On the other hand, the incidence of non-serogroup-B cases during the MCV-4 era (counting only MCV-4- covered cases) 0.081. The difference between the MPSV-4 era and MCV-4 era incidence is significant (p 0.05).

Persistence of serogroup C antibody responses following quadrivalent meningococcal conjugate vaccination in United States military personnel.

Serogroup C meningococcal (MenC) disease accounts for one-third of all meningococcal cases and causes meningococcal outbreaks in the U.S. Quadrivalent meningococcal vaccine conjugated to diphtheria toxoid (MenACYWD) was recommended in 2005 for adolescents and high risk groups such as military recruits. We evaluated anti-MenC antibody persistence in U.S. military personnel vaccinated with either MenACYWD or meningococcal polysaccharide vaccine (MPSV4). Twelve hundred subjects vaccinated with MenACYWD from 2006 to 2008 or MPSV4 from 2002 to 2004 were randomly selected from the Defense Medical Surveillance System. Baseline serologic responses to MenC were assessed in all subjects; 100 subjects per vaccine group were tested during one of the following six post-vaccination time-points: 5–7, 11–13, 17–19, 23–25, 29–31, or 35–37 months. Anti-MenC geometric mean titers (GMT) were measured by rabbit complement serum bactericidal assay (rSBA) and geometric mean concentrations (GMC) by enzyme-linked immunosorbent assay (ELISA). Continuous variables were compared using the Wilcoxon rank sum test and the proportion of subjects with an rSBA titer ≥8 by chi-square. Pre-vaccination rSBA GMT was <8 for the MenACWYD group. rSBA GMT increased to 703 at 5–7 months post-vaccination and decreased by 94% to 43 at 3 years post-vaccination. GMT was significantly lower in the MenACWYD group at 5–7 months post-vaccination compared to the MPSV4 group. The percentage of MenACWYD recipients achieving an rSBA titer of ≥8 decreased from 87% at 5–7 months to 54% at 3 years. There were no significant differences between vaccine groups in the proportion of subjects with a titer of ≥8 at any time-point. GMC for the MenACWYD group was 0.14 µg/mL at baseline, 1.07 µg/mL at 5–7 months, and 0.66 µg/mL at 3 years, and significantly lower than the MPSV4 group at all time-points. Anti-MenC responses wane following vaccination with MenACYWD; a booster dose is needed to maintain protective levels of circulating antibody.

Immune Responses in U.S. Military Personnel Who Received Meningococcal Conjugate Vaccine (MenACWY) Concomitantly with Other Vaccines Were Higher than in Personnel Who Received MenACWY Alone.

ABSTRACT Immunological responses to vaccination can differ depending on whether the vaccine is given alone or with other vaccines. This study was a retrospective evaluation of the immunogenicity of a tetravalent meningococcal conjugate vaccine for serogroups A, C, W, and Y (MenACWY) administered alone (n = 41) or concomitantly with other vaccines (n = 279) to U.S. military personnel (mean age, 21.6 years) entering the military between 2006 and 2008. Concomitant vaccines included tetanus/diphtheria (Td), inactivated polio vaccine (IPV), hepatitis vaccines, and various influenza vaccines, among others; two vaccine groups excluded Tdap and IPV. Immune responses were evaluated in baseline and postvaccination sera for Neisseria meningitidis serogroups C and Y 1 to 12 months (mean, 4.96 months) following vaccination. Functional antibodies were measured by using a serum bactericidal antibody assay with rabbit complement (rSBA) and by measurement of serogroup-specific immunoglobulin G (IgG) antibodies. The percentage of vaccinees reaching threshold levels (IgG concentration in serum, ≥2 μg/ml; rSBA titer, ≥8) corresponding to an immunologic response was higher postvaccination than at baseline (P < 0.001). Administration of MenACWY along with other vaccines was associated with higher geometric means of IgG concentrations and rSBA titers than those measured 4.60 months after a single dose of MenACWY. In addition, higher percentages of vaccinees reached the immunological threshold (range of odds ratios [ORs], 1.5 to 21.7) and more of them seroconverted (OR range, 1.8 to 4.8) when MenACWY was administered with any other vaccine than when administered alone. Additional prospective randomized clinical trials are needed to confirm the observed differences among groups in the immune response to MenACWY when given concomitantly with other vaccines to U.S. military personnel.

A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

ABSTRACT Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.