Burden of Pertussis in Adults Aged 50 Years and Older: A Retrospective Database Study in England.

INTRODUCTION: Pertussis, a highly infectious respiratory disease caused by Bordetella pertussis, affects people of all ages. Older adults are particularly susceptible to its severe outcomes and complications. METHODS: In this retrospective cohort study, the incidence rate of pertussis among individuals aged ≥ 50 years was assessed during 2009-2018 using Clinical Practice Research Datalink and Hospital Episode Statistics databases, United Kingdom. Health care resource utilisation (HCRU) and direct medical costs (DMCs) were compared between patients with a pertussis diagnosis and propensity score-matched controls (matched on demographic and clinical variables). RESULTS: Among 5,222,860 individuals, 1638 had a pertussis diagnosis (incidence rate: 5.8 per 100,000 person-years; 95% confidence interval 5.5-6.0). Baseline (- 18 to - 6 months) HCRU and DMC were similar among 1480 pertussis patients and 1480 matched controls. However, there were increases in HCRU in the pertussis vs. matched cohort around the pertussis diagnosis (from months - 6 to - 1 to 5-11). The most notable increases (pertussis vs. controls) were in the rates of general practitioner (GP)/nurse visits (4.7-fold), clinical assessments (4.1-fold), and accident and emergency visits (3.0-fold) during the month before diagnosis and GP/nurse visits during the 2 months after diagnosis (2.5-fold) (all p < 0.001). DMCs were significantly higher in the pertussis cohort (p < 0.001). Total excess DMC in the pertussis cohort during months - 1 to + 11 was £318 per patient. CONCLUSION: A pertussis diagnosis among adults aged ≥ 50 years resulted in significant increases in HCRU and DMC across several months around diagnosis. These results highlight the need for increased awareness of pertussis infection among adults aged ≥ 50 years and suggest that pertussis booster doses among this population should be considered.

Descriptive Overview of Pertussis Epidemiology Among Older Adults in Europe During 2010-2020.

INTRODUCTION: Following the introduction of pertussis vaccination during infancy, the age-related demographics of pertussis epidemiology have changed. METHODS: To better understand the pertussis burden (defined here as number of cases and/or incidence rate [IR]) among older adults (OA; at least 50 years of age) in Europe, we collected data on the reported number of cases and IR in this population in Denmark, England and Scotland, Finland, Germany, the Netherlands, Norway and Sweden from 2010 to 2020. Additionally, we collected contextual epidemiological information on surveillance systems, case definitions, laboratory diagnostics and vaccination approaches. RESULTS: We observed large heterogeneity in the burden among OA between countries: annual IRs ranged from 0.4 (England, 2010) to 54.5 (Norway, 2011) per 100,000 population; 9% (Denmark, 2010) to 45% (England, 2017) of all reported cases occurred in OA. No clear impact of changes in contextual epidemiological information or common trends between countries could be observed, highlighting the need for standardised pertussis surveillance programmes across Europe. The epidemiological trends observed in OA were similar to those observed in 0-4-year-olds. CONCLUSION: This analysis showed that B. pertussis continues to circulate among OA in Europe, suggesting that current vaccination strategies are insufficient to decrease the disease burden in all age groups. This may indicate that improved monitoring of pertussis in OA and booster vaccination throughout adulthood are necessary to control the total pertussis burden.

Whooping cough is an infectious, vaccine-preventable disease that is primarily serious in unvaccinated infants but can also affect adults (at least 50 years old). While vaccination is well established in children, many countries do not routinely vaccinate older adults. Moreover, whooping cough infections in older adults can be difficult to identify for healthcare professionals because of the atypical and mild nature of symptoms. Consequently, the extent of whooping cough occurrence in this population is underestimated. To better understand the extent of disease occurrence, we studied whooping cough infections in Denmark, England and Scotland, Finland, Germany, the Netherlands, Norway and Sweden from 2010 to 2020. Our study was based on the number of laboratory-confirmed cases reported to relevant institutions. We also assessed whether we could identify links between disease occurrence among older adults and contextual epidemiological information, such as disease monitoring systems, methods used for laboratory confirmation, vaccination schedules and vaccination coverage rates. Our study confirmed that whooping cough affects older adults and disease occurrence follows similar trends to those in 0- to 4-year-old children. Because the contextual epidemiological information differed over time and between countries, we could not establish links with disease occurrence in older adults. These data may provide further evidence to authorities that whooping cough among older adults would be better controlled and its burden more accurately estimated with a reinforced comprehensive approach around vaccination and monitoring. Because adults can also infect children who are not yet fully vaccinated, such an approach might help further control the disease in children.

Burden of Pertussis in Individuals with a Diagnosis of Asthma: A Retrospective Database Study in England.

PURPOSE: The impact of pertussis in individuals with asthma is not fully understood. We estimated the incidence, health care resource utilization (HCRU), and direct medical costs (DMC) of pertussis in patients with asthma. PATIENTS AND METHODS: In this retrospective cohort study, the incidence rate of pertussis (identified using diagnostic codes) among individuals aged ≥50 years with an asthma diagnosis was assessed during 2009-2018 using Clinical Practice Research Datalink and Hospital Episode Statistics databases. HCRU and DMC were compared - between patients with diagnoses of asthma and pertussis (asthma+/pertussis+) and propensity score-matched patients with a diagnosis of asthma without pertussis (asthma+/pertussis-) - in the months around the pertussis diagnosis (-6 to +11). RESULTS: Among 687,105 individuals, 346 had a reported pertussis event (incidence rate: 9.6/100,000 person-years of follow-up; 95% confidence interval: 8.6-10.7). HCRU and DMC were assessed among 314 asthma+/pertussis+ patients and 1256 matched asthma+/pertussis- controls. Baseline HCRU was similar in both cohorts, but increases were observed in the asthma+/pertussis+ cohort from -6 to -1 month before to 2-5 months after diagnosis. Rates of accident and emergency visits, general practitioner (GP)/nurse visits, and GP prescriptions were 4.3-, 3.1-, and 1.3-fold, respectively, in the asthma+/pertussis+ vs asthma+/pertussis- cohorts during the month before diagnosis; GP/nurse visit rates were 2.0- and 1.2-fold during 0-2 and 2-5 months after diagnosis, respectively (all p<0.001). DMC was 1.9- and 1.6-fold during the month before and 2 months from diagnosis, respectively, in the asthma+/pertussis+ vs asthma+/pertussis- cohorts (both p<0.001). During months -1 to +11, DMC in the asthma+/pertussis+ cohort was £370 higher than in the asthma+/pertussis- controls. CONCLUSION: A pertussis diagnosis among adults aged ≥50 years with asthma resulted in significant increases in HCRU and DMC across several months around diagnosis, suggesting lengthy diagnosis times and highlighting the need for prevention strategies.

Neurovirulence and latency of drug-resistant clinical herpes simplex viruses in animal models.

Herpes simplex virus (HSV) resistance to acyclovir or foscarnet results from mutations in viral thymidine kinase (TK) and/or DNA polymerase (pol) genes. Replication kinetics and virulence of TK and/or DNA pol clinical mutants were assessed using models of mouse encephalitis and cotton rat genital infection. Replication capacities in Vero cells of a DNA pol altered strain (L850I) and a TK/DNA pol mutant (C467deletion/A912V) were significantly lower than those of unrelated wild-type (WT) strains, while a double DNA pol mutant (S724N/P920S) demonstrated replication kinetics similar to the WT. The replication of a TK-deficient mutant (G439.5addition) was impaired (low m.o.i.) or unaltered (high m.o.i.) compared to that of a WT virus depending on the viral inoculum. Compared to a survival rate of 6% for mice infected intranasally with WT HSV-1 or -2 viruses, G439.5add, C467deletion/A912V and L850I strains were associated with survival rates of 100% (P < 0.05) whereas mice infected with the S724N/P920S mutant had a survival rate of 33% (P = 0.08). Brain viral titers were higher in mice infected with WT HSV-1 or -2 strains and the double DNA pol mutant. All strains except the DNA pol mutant L850I were able to establish latency in the dorsal root ganglia of cotton rats. A good correlation was generally found between replication kinetics of DNA pol mutants and their neurovirulence potential in mice whereas such correlation was not straightforward for TK mutants.

Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes.

Drug-resistant herpes simplex virus type 1 (HSV-1) recombinant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes were evaluated for their susceptibility to various antivirals in the presence of 25 microg/ml of hydroxyurea (HyU). The latter compound decreased the 50% inhibitory concentrations of acyclovir by 1.5-3.8-fold and that of cidofovir by 2.7-14.4-fold. However, HyU did not affect the susceptibilities of the various recombinant mutants to foscarnet. Hydroxyurea, a ribonucleotide reductase inhibitor, can increase the activity of nucleoside/nucleotide analogues against drug-resistant viruses.

Longitudinal evaluation of herpes simplex virus DNA load during episodes of herpes labialis.

BACKGROUND: Few studies have performed sequential evaluation of the herpes simplex virus (HSV) load using quantitative PCR during episodes of herpes labialis. OBJECTIVE: To determine HSV viral load kinetics during recurrences of herpes labialis. STUDY DESIGN: Twenty-two subjects were monitored by daily swabs during recurrences of herpes labialis. A real-time PCR detecting both HSV-1 and HSV-2 was used to quantify the viral load. RESULTS: Median duration of HSV-1 shedding was 60 h and 48 h by PCR and culture, respectively. No HSV-2 DNA was detected in that study. Peak viral DNA load (123.6 copies/cell) occurred at 48 h with no virus detected beyond 96 h of onset of symptoms. CONCLUSIONS: These viral load kinetics data could be used as surrogate markers of antiviral activity in future clinical trials.

Effect of pretreatment with toll-like receptor agonists in a mouse model of herpes simplex virus type 1 encephalitis.

BACKGROUND: We evaluated the effect of pretreatment with Toll-like receptor (TLR) agonists in a mouse model of herpes simplex virus type 1 (HSV-1) encephalitis. METHODS: BALB/c mice received a single intraperitoneal or intranasal injection of polyinosinic:polycytidylic acid (poly I:C), a TLR3 agonist; lipopolysaccharide (LPS), a TLR4 agonist; oligodeoxynucleotide (ODN), a TLR9 agonist; or control vehicle. Twenty-four hours later, animals were infected with 5000 plaque-forming units of HSV-1. RESULTS: Mice that received intraperitoneal pretreatment with vehicle, LPS, and poly I:C had survival rates of 7%, 13%, and 56%, respectively, and mean life expectancies of 156.80+/-9.56, 176.00+/-9.24, and 213.00+/-7.71 h, respectively (p< .05, poly I:C group vs. other groups). Similarly, intranasal pretreatment with vehicle, LPS, ODN, and poly I:C were associated with survival rates of 20%, 47%, 60%, and 94%, respectively, and mean life expectancies of 153.60+/-11.71, 188.80+/-12.97, 204.80+/-11.73, and 234.00+/-5.81 h, respectively (p< .05, ODN and poly I:C groups vs. vehicle group). Pretreatment with intranasal poly I:C induced early expression of several immune genes in the brain and resulted in a significantly lower virus load. CONCLUSION: TLR3 stimulation by poly I:C 24 h before infection reinforces a natural innate immune mechanism of neuroprotection against HSV-1.

Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis.

BACKGROUND: The innate immune response after herpes simplex type 1 (HSV-1) encephalitis could be protective or, paradoxically, implicated in neuronal damage. We investigated the role of the innate immune response in such infection using a C57BL/6 mouse knockout (KO) model for tumor necrosis factor (TNF)-alpha and/or interleukin (IL)-1beta. METHODS: Encephalitis was induced by intranasal infection with a clinical strain of HSV-1 in 1-month-old KO or wild-type (WT) mice. Mice were monitored for survival, brain viral load was quantified by real-time polymerase chain reaction, and the inflammatory response was assessed by in situ hybridization in groups of mice killed on days 3-7. RESULTS: WT mice had a significantly higher mean life expectancy (P=.0001, log-rank test) than other groups. IL-1beta and TNF-alpha KO mice had a similar mean life expectancy, and encephalitis was lethal to all TNF-alpha /IL-1beta-deficient mice. Brain viral loads were lower in WT than in KO mice that had disseminated viral replication in the pons and medulla. Moreover, TNF- alpha and IL-1beta KO mice failed to initiate an adequate immune response, as shown by the virtual absence of expression of proinflammatory molecules in the brain. CONCLUSION: These data clearly demonstrate the importance of TNF-alpha and IL-1beta in protection against HSV-1 encephalitis in this mouse model.

Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice.

BACKGROUND: Glucocorticoids (GCs) have not been established as an evidence-based therapy for herpes simplex virus (HSV) encephalitis. We sought to evaluate the effects of early versus delayed GC administration in a model of HSV-1 encephalitis. METHODS: Mice were inoculated intranasally with a clinical HSV-1 strain and had access to corticosterone (Cort; 0.2 mg/mL) in drinking water or received dexamethasone (DEX; 10 mg/kg) intraperitoneally. Cort was started immediately or 72 h after infection, whereas DEX was administrated 3 days after infection. RESULTS: Expression of the thymidine kinase transcript indicated widespread viral replication in the brain stem and many regions of the mediovestibular system. This neurovirulence provoked neuronal death and transcriptional activation of several immune genes. Notably, Toll-like receptors 2, 3, and 9 transcripts were strongly up-regulated. Mean life expectancy was higher in the group of mice that received delayed Cort (56%) than in the mice that received no Cort (44%) or early Cort treatments (13%) (P<.05, early vs. delayed or no Cort treatments). Delayed DEX treatment suppressed not only the expression of inflammatory genes as expected but also that of viral genes. CONCLUSIONS: Administration of GCs at a critical time during viral infection is associated with neuroprotection and survival in experimental HSV-1 encephalitis.

Thymidine kinase mutations conferring acyclovir resistance in herpes simplex type 1 recombinant viruses.

Contributions of thymidine kinase (TK) mutations to acyclovir (ACV) resistance were evaluated in herpes simplex virus type 1 recombinant viruses generated using a set of overlapping cosmids and plasmids. Alterations in both conserved and nonconserved regions of the TK gene were shown to confer high levels of resistance to ACV.

Evaluation of susceptibility of human herpesvirus 8 to antiviral drugs by quantitative real-time PCR.

A new in vitro system based on real-time PCR was developed for evaluation of human herpesvirus 8 susceptibility to antiviral agents. Cidofovir had the greatest inhibitory activity against HHV-8 (50% inhibitory concentration [IC(50)], 0.43 microM) followed by ganciclovir (2.61 microM), adefovir (18.00 microM), acyclovir (31.00 microM), and foscarnet (34.15 microM). The potential therapeutic efficacy for HHV-8 (i.e., peak serum drug level/IC(50)) is highest for cidofovir (167) and foscarnet (22).

Comparative evaluation of three serological methods for detection of human herpesvirus 8-specific antibodies in Canadian allogeneic stem cell transplant recipients.

Human herpesvirus 8 (HHV-8) has been associated with all types of Kaposi's sarcoma (KS), including posttransplantation KS. However, little is known regarding HHV-8 infections in hematopoietic stem cell transplant (SCT) recipients. In this study, we used a variety of serological assays, including in-house-developed enzyme immunoassays (EIAs) utilizing synthetic peptides corresponding to lytic viral antigens (ORFs 65 and K8.1) and a commercial EIA kit based on a whole virus lysate (Advanced Biotechnologies Inc.), as well as latent- and lytyc-antigen-based immunofluorescence assays (IFAs) to determine the seroprevalence of HHV-8 in 42 allogeneic SCT recipients from Canada. Using the two peptide-based EIA methods as for screening, HHV-8-specific antibodies were detected in five (12%) patients between days 21 and 91, although only one (2%) subject was positive for HHV-8-specific antibodies before transplantation. All positive results from these five patients were confirmed by at least one of the IFAs, with an additional patient showing seropositivity before transplantation. However, the commercial EIA was negative at all time points (days -7, 21, and 91) in those five patients. The episodes of seroconversion or reactivation were not associated with sustained viremia, since HHV-8 DNA was not detected by real-time PCR in the corresponding leukocytes and plasma of the seropositive patients. No clinical or laboratory abnormalities were clearly associated with HHV-8 seropositivity. This study confirms the utility of simple peptide-based EIA methods to assess the presence of HHV-8-specific antibodies in immunocompromised patients and emphasizes the need of conducting prospective studies to determine the source of HHV-8 infection in SCT recipients.