Asymptomatic Seroconversion Research Articles

Modelling person-to-person transmission in an Enterovirus A71 orally infected hamster model of hand-foot-and-mouth disease and encephalomyelitis

Enterovirus A71 (EV-A71) causes hand-foot-and-mouth disease (HFMD), which may be complicated by fatal encephalomyelitis. Although fecal–oral or oral–oral routes are important in person-to-person transmission, how viral shedding and exposure may predispose individuals to infection remains unknown. We investigated person-to-person transmission by using a model of HFMD and encephalomyelitis based on EV-A71 oral infection of 2-week-old hamsters. Animals (index animals) infected with 104 50% cell culture infective doses of virus uniformly developed severe disease four days post-infection (dpi), whereas littermate contacts developed severe disease after six to seven days of exposure to index animals. Virus was detected in oral washes and feces at 3–4 dpi in index animals and at three to eight days after exposure to index animals in littermate contact animals. In a second experiment, non-littermate contact animals exposed for 8 or 12 h to index animals developed the disease six and four days post-exposure, respectively. Tissues from killed index and contact animals, studied by light microscopy, immunohistochemistry and in situ hybridization, exhibited mild inflammatory lesions and/or viral antigens/RNA in the squamous epithelia of the oral cavity, tongue, paws, skin, esophagus, gastric epithelium, salivary glands, lacrimal glands, central nervous system neurons, muscles (skeletal, cardiac and smooth muscles) and liver. Orally shed viruses were probably derived from infected oral mucosa and salivary glands, whereas fecal viruses may have derived from these sites as well as from esophageal and gastric epithelia. Asymptomatic seroconversion in exposed mother hamsters was demonstrated. Our hamster model should be useful in studying person-to-person EV-A71 transmission and how drugs and vaccines may interrupt transmission.Emerging Microbes & Infections (2017) 6, e62; doi:10.1038/emi.2017.49; published online 12 July 2017

Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial

Lyme borreliosis develops in 1-5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings. In this randomised, double-blind, placebo-controlled, multicentre trial done in 28 study sites in Germany and Austria, adults were equally assigned to receive topical 10% azithromycin or placebo twice daily for 3 consecutive days, within 72 h of a tick bite being confirmed. Randomisation numbers, which were stratified by study site, were accessed in study centres via an interactive voice-response system, by pharmacists not involved in the study. The primary outcome was the number of treatment failures, defined as erythema migrans, seroconversion, or both, in participants who were seronegative at baseline, had no further tick bites during the study, and had serology results available at 8 weeks (intention-to-treat [ITT] population). This study is registered with EudraCT, number 2011-000117-39. Between July 7, 2011, and Dec 3, 2012, 1371 participants were randomly assigned to treatment, of whom 995 were included in the ITT population. The trial was stopped early because an improvement in the primary endpoint in the group receiving azithromycin was not reached. At 8 weeks, 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure (odds ratio 0·97, 95% CI 0·42-2·26, p=0·47). Topical azithromycin was well tolerated. Similar numbers of patients had adverse events in the two groups (175 [26%] of 505 vs 177 [26%] of 490, p=0·87), and most adverse events were mild. Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks. Ixodes AG.

Cutaneous Melioidosis Cluster Caused by Contaminated Wound Irrigation Fluid.

Melioidosis, caused by infection with the bacterium Burkholderia pseudomallei, is a disease with manifestations ranging from rapidly fatal septicemia, pneumonia, or meningoencephalitis to localized abscess formation, cellulitis, and asymptomatic seroconversion. This disease occurs most commonly in Southeast Asia and northern Australia after exposure to contaminated soil or surface water (1). The US National Notifiable Diseases Surveillance Systems case definition describes cutaneous melioidosis as “an acute or chronic localized infection which may or may not include symptoms of fever and muscle aches. Such infection often results in ulcer, nodule, or skin abscess” (2). Sporadic cases outside melioidosis-endemic regions usually occur in persons who have a history of travel in the tropics, which can be as long as several decades previously because of the ability of B. pseudomallei to persist undetected after the initial inoculation event (3). In these cases, B. pseudomallei infection might not be considered in the differential diagnosis. Detection of sporadic cases of melioidosis by clinical pathology laboratories requires microbiology laboratories to have robust bacterial identification procedures. Even with advanced equipment, a lack of awareness of the characteristic features of B. pseudomallei can result in misidentification of cultured organisms (4). Only a few point-source outbreaks of melioidosis have been reported (5). Two of these occurred in Western Australia; 1 was attributed to movement of livestock from the tropical north to the temperate southwest (6), and the other was caused by contamination of a potable water supply (7). Neither cluster was healthcare-associated. Only a few cases of healthcare-associated melioidosis have been reported. Some of the earliest accounts of melioidosis identified opiate injection as a potential source of infection (8). In animal healthcare, injected medication was thought responsible for a series of animal infections in northern Australia (9). The first report of hospital-acquired melioidosis originated in Hawaii, USA, and described pulmonary infection after bronchoscopy with a scope contaminated with B. pseudomallei (10). This report indicated that the contaminated bronchoscope had previously been used on a returned traveler with melioidosis. A second report described 2 patients with B. pseudomallei urinary tract infection on different wards of a hospital on whose grounds B. pseudomallei was isolated (11). Nosocomial contamination associated with faulty hospital hygiene and ineffective disinfectant solution was reported from a hospital in Thailand treating patients with melioidosis (12). More recently, cases of neonatal melioidosis from a hospital in Thailand were thought to be healthcare-associated, although the full details of transmission could not be determined (13). Melioidosis became a notifiable infection in Western Australia in January 2000 (14). Physicians, pathology service providers, and the state public health laboratory are required to report a diagnosis of melioidosis to the State Disease Control Directorate. Melioidosis notification is largely laboratory-generated in Western Australia because confirmation of infection according to the Australian Laboratory Case Definition relies on culture of B. pseudomallei from clinical specimens. Pathology service providers therefore routinely refer presumptive B. pseudomallei isolates to the state public health laboratory for confirmation, genotyping, and archiving in a reference culture collection (Western Australian Burkholderia Collection). Here we report the laboratory investigation of a cluster of cutaneous melioidosis in the temperate southwest of Australia, the identification of its source, and means of control.

Low risk of seroconversion or clinical disease in humans after a bite by an Anaplasma phagocytophilum-infected tick

The risk of contracting human granulocytic anaplasmosis (HGA) after a tick bite is mainly unknown. In this study we investigated the clinical and serological response in 30 humans bitten by ticks positive for Anaplasma phagocytophilum (Group A), 30 humans bitten by Borrelia burgdorferi sensu lato (s.l.)-positive ticks (Group B), and 30 humans bitten by ticks negative for both A. phagocytophilum and B. burgdorferi s.l. (Group C). Ticks, blood samples and questionnaires were collected from tick-bitten humans at 34 primary healthcare centres in Sweden and in the Åland Islands, Finland, at the time of the tick bite and after three months. A total of 2553 ticks detached from humans in 2007–2009 were analyzed by polymerase chain reaction, and 31 (1.2%) were positive for A. phagocytophilum, 556 (21.8%) were positive for B. burgdorferi s.l., and eight (0.3%) were co-infected by A. phagocytophilum and B. burgdorferi s.l. The overall prevalence of Anaplasma IgG antibodies in the included participants (n=90) was 17%, and there was no significant difference between the groups A-C. Only one of the participants (in Group C) showed a four-fold increase of IgG antibodies against A. phagocytophilum at the three-month follow-up, but reported no symptoms. The frequency of reported symptoms did not differ between groups A-C, and was unrelated to the findings of A. phagocytophilum and B. burgdorferi s.l. in the detached ticks. We conclude that the risk for HGA or asymptomatic seroconversion after a tick bite in Sweden or in the Åland Islands is low, even if the tick is infected by A. phagocytophilum.

Disease progression of HIV-1 infection in symptomatic and asymptomatic seroconverters in Osaka, Japan: a retrospective observational study.

BackgroundEstimates of the interval from HIV-1 infection to disease progression may be affected by selection bias, and data concerning asymptomatic early seroconverters are limited. We examined the interval until disease progression in HIV-1 seroconverters in whom the timing of infection could be estimated within 1 year before diagnosis.MethodsSubjects included newly diagnosed patients at Osaka National Hospital between 2003 and 2010 who had either (1) symptomatic acute HIV-1 infection with a negative or intermediate reaction on Western blotting and a positive reaction on an HIV RNA test (symptomatic acute group) or (2) a positive reaction on Western blotting at diagnosis and a <1-year interval from the last negative HIV test until the first positive test. The latter was divided into symptomatic recent or asymptomatic recent groups based on the presence or absence, respectively, of any transient fever between the last negative and first positive tests. Disease progression was defined as a fall in the CD4 count to <350 cells/microL on 2 consecutive tests, the start of anti-HIV therapy, or the onset of AIDS-indicator diseases. Information was retrospectively collected from medical records.ResultsSubjects included 210 patients: 91 in the symptomatic acute group, 72 in the symptomatic recent group, and 47 in the asymptomatic recent group. In the symptomatic acute (0.8 years) and symptomatic recent (2.2 years) groups, the Kaplan-Meier estimate of median interval until disease progression was significantly shorter than that in the asymptomatic recent group (2.9 years). Multivariate analysis by Cox’s proportional hazards test showed that the symptomatic acute group (vs. asymptomatic recent group: hazard ratio: 1.93; 95% confidence interval: 1.14–3.36; p = 0.0140) and a baseline CD4 count of <400 cells/microL (hazard ratio: 3.88; 95% confidence interval: 2.57–5.96; p < 0.0001) were independent prognostic factors associated with early disease progression.ConclusionsSymptomatic seroconversion was associated with early disease progression. Furthermore, the estimated median interval until the CD4 count was <350 cells/microL was only 2.9 years even in patients with asymptomatic seroconversion. These results suggest the importance of early diagnosis in early seroconverters.

Melioidosis: evolving concepts in epidemiology, pathogenesis, and treatment.

Infection with Burkholderia pseudomallei can result in asymptomatic seroconversion, a single skin lesion that may or may not heal spontaneously, a pneumonia which can be subacute or chronic and mimic tuberculosis or rapidly progressive resulting in fatal overwhelming sepsis. Latency with subsequent activation of disease is well recognized, but very uncommon. Melioidosis also has a myriad of other clinical presentations and diagnosis is often delayed because of this and because of difficulties with laboratory diagnosis and lack of recognition outside melioidosis-endemic regions. The perception of B. pseudomallei as a top tier biothreat agent has driven large funding for research, yet resources for diagnosis and therapy of melioidosis in many endemic locations remain extremely limited, with mortality as high as 50% in comparison to around 10% in regions where state-of-the-art intensive care therapy for sepsis is available. Fatal melioidosis is extremely unlikely from natural infection in a healthy person, provided the diagnosis is made early, ceftazidime or meropenem is commenced and intensive care therapy is available. While biothreat research is directed toward potential aerosol exposure to B. pseudomallei, the overall proportion of melioidosis cases resulting from inhalation rather than from percutaneous inoculation remains entirely uncertain, although the epidemiology supports a shift to inhalation during severe weather events such as cyclones and typhoons. What makes B. pseudomallei such a dangerous organism for patients with diabetes and other selective risk factors remains unclear, but microbial genome-wide association studies linking clinical aspects of melioidosis cases to nonubiquitous or polymorphic B. pseudomallei genes or genomic islands are beginning to uncover specific virulence signatures. Finally, what also remains uncertain is the global phylogeography of B. pseudomallei and whether melioidosis is spreading beyond historical locations or is just being unmasked in Africa and the Americas by better recognition and increased surveillance.

A Prospective Study of Melioidosis After Environmental Exposure of Healthy Participants to Burkholderia pseudomallei During a Muddy Endurance Challenge

In a prospective study of 123 healthy adults competing in a mud-exposing endurance challenge in the melioidosis-endemic tropical north of the Northern Territory of Australia, there were no asymptomatic seroconversions to Burkholderia pseudomallei using indirect hemagglutination assay. However, one competitor developed melioidosis attributable to infection acquired during the event.

Asymptomatic and chronic carriage of Leptospira interrogans serovar Pomona in California sea lions (Zalophus californianus)

Since 1970, periodic outbreaks of leptospirosis, caused by pathogenic spirochetes in the genus Leptospira, have caused morbidity and mortality of California sea lions (Zalophus californianus) along the Pacific coast of North America. Yearly seasonal epizootics of varying magnitude occur between the months of July and December, with major epizootics occurring every 3-5 years. Genetic and serological data suggest that Leptospira interrogans serovar Pomona is the infecting serovar and is enzootic in the California sea lion population, although the mechanism of persistence is unknown. We report asymptomatic carriage of Leptospira in 39% (33/85) of wild, free-ranging sea lions sampled during the epizootic season, and asymptomatic seroconversion with chronic asymptomatic carriage in a rehabilitated sea lion. This is the first report of asymptomatic carriage in wild, free-ranging California sea lions and the first example of seroconversion and asymptomatic chronic carriage in a sea lion. Detection of asymptomatic chronic carriage of Leptospira in California sea lions, a species known to suffer significant disease and mortality from the same Leptospira strain, goes against widely-held notions regarding leptospirosis in accidental versus maintenance host species. Further, chronic carriage could provide a mechanism for persistent circulation of Leptospira in the California sea lion population, particularly if these animals shed infectious leptospires for months to years.

Epidemiology and Control of Human Granulocytic Anaplasmosis: A Systematic Review

Granulocytic anaplasmosis caused by Anaplasma phagocytophilum is an emerging tick-borne zoonosis worldwide. The obligate intracellular pathogen is transmitted by Ixodes ticks and infects neutrophils in humans and animals, resulting in clinical symptoms ranging from asymptomatic seroconversion to mild, severe, or fatal disease. Since the initial description of human granulocytic anaplasmosis (HGA) in the United States in 1990, HGA has been increasingly recognized in America, Europe, and Asia. This review describes the epidemiology, diagnosis, and treatment of HGA and provides background information on the potential vectors and reservoirs of A. phagocytophilum.

Late Cytomegalovirus Transmission and Impact of T-Depletion in Clinical Islet Transplantation

The epidemiology of cytomegalovirus infection (CMV) in islet transplantation (IT) is not well defined. This study defines incidence, transmission and clinical sequelae of CMV reactivation or disease in 121 patients receiving 266 islet infusions at a single institution. The donor (D)/recipient (R) serostatus was D+/R- 31.2%, D+/R+ 26.3%, D-/R+ 13.2% and D-/R- 29.3%. CMV prophylaxis with oral ganciclovir/valganciclovir was given in 68%. CMV infection occurred in 14/121 patients (11.6%); six had asymptomatic seroconversion and eight others had positive viremia (six asymptomatic and two with CMV febrile symptoms). Median peak viral loads were 1755 copies/mL (range 625-9 100 000). Risk factors for viremia included lymphocyte depletion (thymoglobulin or alemtuzumab, p < 0.001). Viremia was more common in D+/R+ versus D+/R- (p = 0.12), occurring mostly late after transplant (median 306 days). Presumed transmission from IT occurred in 8/83 of D+/R- procedures (9.6%). Of the two cases of CMV disease, one resulted from islet transmission from a CMV positive donor (D+/R-); the other was due to de novo exogenous infection (D-/R-). Therefore, CMV transmission presents rarely after IT and with low incidence compared to solid organ transplantation, but occurs late posttransplant. The use of lymphocyte depleting therapies is a primary risk factor.

Incidence of Symptomatic and Asymptomatic Leishmania donovani Infections in High-Endemic Foci in India and Nepal: A Prospective Study

Incidence of Leishmania donovani infection and Visceral Leishmaniasis (VL) was assessed in a prospective study in Indian and Nepalese high-endemic villages. DAT-seroconversion was used as marker of incident infection in 3 yearly surveys. The study population was followed up to month 30 to identify incident clinical cases. In a cohort of 9034 DAT-negative individuals with neither active signs nor history of VL at baseline, 42 VL cases and 375 asymptomatic seroconversions were recorded in the first year, giving an infection∶disease ratio of 8.9 to 1. In the 18 months' follow-up, 7 extra cases of VL were observed in the seroconverters group (N = 375), against 14 VL cases among the individuals who had not seroconverted in the first year (N = 8570) (RR = 11.5(4.5<RR<28.3)). Incident asymptomatic L. donovani infection in VL high-endemic foci in India and Nepal is nine times more frequent than incident VL disease. About 1 in 50 of these new but latent infections led to VL within the next 18 months.

West Nile Virus Aseptic Meningitis and Stuttering in Woman

To the Editor: West Nile virus (WNV), a mosquito-borne flavivirus, is closely related to St. Louis encephalitis virus and Japanese encephalitis virus (JEV). Most cases of WNV have been mild, but neuroinvasive disease has been observed, especially among older persons and immunocompromised persons (1,2). The most common neurologic manifestations of WNV are aseptic meningitis, meningoencephalitis, and encephalitis with or without acute flaccid paralysis (3). Other less common neurologic manifestations include Guillain-Barre syndrome, chorioretinitis, stroke-like symptoms, and unilateral brachial plexopathy (4,5). We report a case of WNV aseptic meningitis in a 39-year-old immunocompetent woman who had severe headache with new-onset stuttering. Her medical history included lumbar disc herniation and migraines, for which she was taking sumatriptan. Her symptoms started ≈2 weeks before hospitalization and included a severe generalized headache initially thought to be a migraine, but sumatriptan resulted in no improvement. A few days later, she had fever and was intermittently stuttering. She denied recent travel or animal exposure but admitted to having received multiple mosquito bites during the preceding weeks. At admission, she had a temperature of 101.3°F, pulse rate of 92 beats/min, blood pressure of 130/80 mm Hg, and respiratory rate of 16 breaths/min. She appeared mildly ill but was alert and oriented with no nuchal rigidity, photophobia, rash, or limb weakness. Results of a physical examination were unremarkable, and results of a neurologic examination were notable only for stuttering. Laboratory test results included a leukocyte count of 12,300 cells/mm3 (63% neutrophils, 29% lymphocytes, 7% monocytes, 1% basophils) and a platelet count of 204,000 cells/mm3. Other laboratory values were unremarkable, and levels of serum transaminases and creatinine phosphokinase were within reference ranges. Cerebrospinal fluid (CSF) was clear and contained 37 leukocytes/mm3 (2% neutrophils, 78% lymphocytes, 20% monocytes), 2 erythrocytes/mm3, a glucose level of 68 mg/dL, a protein level of 36 mg/dL, and a lactic acid level of 2.1 meq/L. No abnormalities were found on a cranial computed tomography scan. The patient began treatment with acyclovir, 10 mg/kg intravenously, every 8 hours for 3 days. On hospital day 2, she underwent magnetic resonance imaging of the brain; results were within reference limits. On hospital day 3, her headache began to improve and she became afebrile, but she still stuttered occasionally. Results of CSF tests for enterovirus, herpes simplex viruses 1 and 2, and varicella zoster virus and PCR for human herpesvirus 6 were negative, and acyclovir was discontinued. On hospital day 5, she was discharged. Three days later, serum and CSF ELISA results for WNV were positive. A WNV ELISA was performed at ViroMed Laboratories (Minnetonka, MN, USA) by using a Focus Test Kit (Focus Diagnostics, Cypress, CA, USA), and the result was positive. The patient subsequently reported that her stuttering had ceased. A high degree of clinical suspicion for WNV infection should be considered in patients with a recent history of mosquito bites and an acute febrile illness associated with neurologic signs and symptoms (5). Typical CSF findings of infection with WNV include lymphocytic pleocytosis, elevated protein level, reference glucose and lactic acid levels, and no erythrocytes (6). The clinical presentation of WNV infection varied widely from asymptomatic seroconversion to fatal encephalitis. It is possible, but unlikely, that the stuttering in the patient was an indication of a migraine aura. Initially, the patient reported that the headache might have been a migraine, but later reported that its associated symptoms, e.g., photophobia, were not as severe and did not last as long as her usual migraines. Further argument against migraine aura is the lack of response to her migraine medication and the fact that the stuttering continued after the headache resolved. Because WNV resembles JEV, it is interesting to note that a case of stuttering in a young adult infected with JEV has been reported (7). However, the mechanism of stuttering associated with WNV is unknown. One possible explanation is myoclonic contractions of the tongue, i.e., vocal myoclonus.

Role of the HLA System in the Association Between Multiple Sclerosis and Infectious Mononucleosis

To determine whether multiple sclerosis (MS) and infectious mononucleosis (IM) share common HLA associations. A prospective cohort study was conducted from October 1, 1999, through September 30, 2003. University of Edinburgh Richard Verney Health Centre, Edinburgh, Scotland. Participants included 179 individuals who underwent asymptomatic Epstein-Barr virus seroconversion and 175 patients who developed IM. Genotyping for 5 classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1). Diagnosis of IM and allele frequency. Allelic analysis showed that HLA-DRB1*01:01 was significantly associated with the development of IM (odds ratio, 3.2; P < .001). Patients with IM and HLA-DRB1*01:01 had a lower Epstein-Barr virus viral load compared with those without the allele (median, 783 vs 7366 copies/10(6) peripheral blood mononuclear cells; P = .03). HLA-DRB1*01:01 is protective against developing MS; thus, a common genetic basis between IM and MS is not supported.

Travellers and viral haemorrhagic fevers: what are the risks?

Viral haemorrhagic fevers (VHF) are caused by zoonotic viral infections transmitted to humans directly or by ticks or mosquitoes. The overall risk to travellers is conservatively estimated at <1 in 1 million travel episodes to African countries where infection is present, and febrile patients returning from these countries are at least 1000 times more likely to have malaria than Lassa fever or another VHF. No cases have been reported in fellow travellers exposed to a travelling case and only one asymptomatic seroconversion (to Lassa) has been reported in over 2000 contacts following care of VHF cases in modern Western hospital settings. However, healthcare-associated transmission of infection has been a major problem in some endemic settings. The potential for healthcare-associated infection and the threats posed by unrecognised or new agents necessitate a high index of suspicion and a standardised risk assessment approach to febrile travellers. Travel-related hantavirus infections are increasingly being reported from Europe and the Americas. This article summarises the epidemiology and reports of travel-related VHF cases in the past 40 years, together with strategies for their recognition, management and prevention.

Endemic Fungal Infections in Solid Organ Transplant Recipients

Endemic Fungal Infections in Solid Organ Transplant Recipients

Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis

Anaplasma phagocytophilum, Ehrlichia chaffeensis and Ehrlichia ewingii are emerging tick-borne pathogens and are the causative agents of human granulocytic anaplasmosis, human monocytic ehrlichiosis and E. ewingii ehrlichiosis, respectively. Collectively, these are referred to as human ehrlichioses. These obligate intracellular bacterial pathogens of the family Anaplasmataceae are transmitted by Ixodes spp. or Amblyomma americanum ticks and infect peripherally circulating leukocytes to cause infections that range in clinical spectra from asymptomatic seroconversion to mild, severe or, in rare instances, fatal disease. This review describes: the ecology of each pathogen; the epidemiology, clinical signs and symptoms of the human diseases that each causes; the choice methods for diagnosing and treating human ehrlichioses; recommendations for patient management; and is concluded with suggestions for potential future research.

Immunizations and infectious diseases in pediatric liver transplantation

Liver transplantation (LTx) is an established and effective treatment for children with end-stage and metabolic liver disease. Improved surgical techniques and immunosuppressive regimens have led to enhanced short-term and long-term survival rates, which now approach or exceed 90%. Consequently, more children are being referred for LTx, and an increasing numbers of pediatric centers routinely perform this procedure. Infectious complications are an important cause of morbidity and mortality in children undergoing LTx. However, improvements in immune suppression management along with the availability of new antimicrobial agents and diagnostic tools have resulted in improved treatment and preventative regimens, thus reducing the impact of infectious complications on these children. This review provides an overview of the infectious complications and prevention strategies for children undergoing LTx.

Q Fever in Migrant Workers, Scotland

To the Editor: Q fever is a zoonosis caused by infection with Coxiella burnetii and is most commonly associated with occupational exposure to animal-slaughtering facilities. C. burnetii is an obligate intracellular bacterium and causes highly variable disease, ranging from asymptomatic infection to fatal chronic infective endocarditis. In June 2006, the United Kingdom experienced its largest outbreak of Q fever with 138 cases associated with a slaughterhouse near Stirling in Scotland. The slaughterhouse had been processing post-parturition ewes in the lairage (place for keeping livestock temporarily) at the end of May. These animals were thought to be among the most likely to shed the organism (1). Further investigation showed that a ewe had aborted in the lairage toward the end of May. Although the sheep lairage was the most likely source of the infection, no microbiologic evidence confirmed this, as C. burnetii was not isolated from environmental samples. The outbreak was neither remarkable for its putative mode of transmission nor for the industry involved, but both the number and nationalities of migrant workers infected was noteworthy. Since 2004, 12 member states have joined the European Union and this has led to an influx of immigrants to the United Kingdom. The increase in migrant numbers has partly been a result of the government’s managed migration policy, expanding migration to fill vacancies in skilled and low-wage occupations. Employers have difficulty recruiting UK workers because of the jobs’ physical demands, long hours that limit social activities, and low pay. They therefore recruit international workers with a good work ethic and reliability; central and Eastern European workers are compared favorably with UK nationals (2). Migrants from Eastern and central Europe are now more likely to be found in low-wage occupations in agriculture, construction, hospitality, and au pair employment. Of the 138 cases of Q fever, 48 were immigrants from the following countries: Slovakia (41), Poland (3), Czech Republic (2), and Lithuania (2). Unsurprisingly, epidemiologic case interviews were beset with linguistic and logistic problems. The diagnosis of Q fever relies predominantly on its serologic legacy since asymptomatic seroconversion occurs in up to 60% of patients (3). Analysis of our cohort found that non-UK patients were significantly less likely than their UK counterparts to have symptoms (fever, muscle pain, joint pain, headache, and cough) and to subsequently have Q fever confirmed (Table, p<0.001). Twenty-two patients (15 UK, 7 non-UK) did not complete epidemiologic questionnaires and were therefore not included in this analysis. Table χ2 analysis of Q fever symptoms and GP registration by nationality* Furthermore, analysis of cases registered with general practitioners (GPs) identified a significant difference (Table, p<0.001) between UK and non-UK patients with the latter group less likely to be registered with a GP. Although most UK residents were registered with a general practice, only 11 of 43 non-UK cases were registered. Information on GP registration was not known for 17 patients, and these were not included in the analysis. Although the investigating health board took stringent steps to ensure follow-up of all patients, we believe that some asymptomatic non-UK patients may have permanently returned to their native countries with undiagnosed illness, and subsequently, cannot be traced. This unfortunate scenario has potentially catastrophic implications for these patients because proper follow-up clinical management of Q fever is necessary to prevent possible endocarditis (4), unnecessary surgery, and premature death. Persons with known occupational hazards have benefited from an effective Q fever vaccine; abattoir workers and farmers are routinely vaccinated in Australia (5). Given the aforementioned linguistic and coordination issues with follow-up of migrant workers and the potential gravity of inappropriate clinical follow-up, it may be prudent to consider Q fever vaccination for all employees who work within UK meat-processing industries. Public health practitioners should be aware of the continuously evolving multinational makeup of the local population and this should stimulate constant review of local translation services because census data seriously underrecognize the ethnic minority migrant worker population. Furthermore, many migrant workers are unsure of their rights to access primary and hospital care and the structure of healthcare is unfamiliar to many. GPs should consider zoonotic infections, such as Q fever, when patients with acute febrile illness report occupational livestock exposure, especially because migrant workers have become an important source of labor (sometimes preferred over domestic workers) in the agricultural workforce in the United Kingdom (2).

Polymorphisms in Toll-like receptors-2 and -4 are not associated with disease manifestations in acute Q fever

Coxiella burnetii is a macrophage-tropic, Gram-negative organism, which causes acute Q fever infection in humans. This zoonotic infection causes illness ranging from asymptomatic seroconversion to severe and protracted disease featuring hepatitis and pneumonia. Interactions between C. burnetii lipopolysaccharide (LPS) and host Toll-like receptors (TLR)-2 and -4 have been implicated in pathogen recognition, phagocytosis and signaling responses. Nonconservative single nucleotide polymorphisms in the coding regions of TLR-2 (Arg677Trp and Arg753Gln) and TLR-4 (Asp299Gly) have been found to correlate with mycobacterial infections and Gram-negative sepsis respectively. Associations between the TLR-2 and -4 polymorphisms, illness characteristics and immune response parameters were examined in subjects with acute Q fever (n=85) and comparison subjects with viral infections (n=162). No correlation was demonstrated between these polymorphisms and susceptibility to Q fever, illness severity or illness course.

Efficacy and Safety of Inhaled Zanamivir in the Prevention of Influenza in Community-Dwelling, High-Risk Adult and Adolescent Subjects: A 28-day, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Background: Influenza can cause significant morbidity and mortality in subjects at high risk for complications, including the elderly (age ≥65 years) and those with chronic respiratory, cardiovascular, or metabolic conditions. Effective prophylaxis can significantly reduce the disease burden in this population. Previous studies conducted primarily in non-high-risk subjects have reported the efficacy of inhaled zanamivir in preventing influenza. Objective: This study investigated the efficacy and safety of zanamivir in preventing influenza in community-dwelling adult and adolescent subjects at high risk for complications of influenza. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in community-dwelling subjects aged ≥12 years who were at high risk for developing complications of influenza, were able to use the Diskhaler device (Glaxo Group Limited, Research Triangle Park, North Carolina), and were able to take the first dose of study medication within 5 days of laboratory-confirmed local influenza activity. Eligible subjects were randomized to receive inhaled zanamivir 10 mg or placebo once daily for 28 days. The primary end point was the proportion of randomized subjects who developed symptomatic influenza during prophylaxis, as confirmed by culture and/or serology. All adverse events (AEs) occurring after the first dose of study medication were recorded. Results: The study enrolled 3363 subjects, of whom 58% were female and 93% were white; the mean age of participants was 60.4 years (range, 12-94 years), and 4% were adolescents. Significantly fewer zanamivirtreated subjects developed symptomatic, laboratory- confirmed influenza during prophylaxis compared with placebo recipients (4/1678 vs 23/1685, respectively), representing a relative risk (RR) of 0.17 (95% CI, 0.07-0.44; P < 0.001) and a protective efficacy of 83%. The incidence of complications was reduced in zanamivir-treated subjects compared with placebo recipients (1/1678 and 8/1685), representing an RR of 0.12 (95% CI, 0.02-0.73; P = 0.042) and a protective efficacy of 88%. The numbers of zanamivir recipients (151/1678 [9%]) and placebo recipients (169/1685 [ 10 % ] ) who developed symptomatic influenza-like illness regardless of laboratory confirmation did not differ significantly (RR = 0.86; 95% CI, 0.70-1.06), indicating that zanamivir was not effective in preventing influenza-like illness that was not caused by influenza infection. Similarly, there was no significant difference in the numbers of zanamivir and placebo recipients who developed laboratory-confirmed infection regardless of symptoms (39/1678 [2%] and 52/1685 [3%], respectively; RR = 0.76; 95% CI, 0.50-1.15). Of these, 64 subjects (35 and 29) were asymptomatic; seroconversion occurred in all but 1 subject, indicating that zanamivir prophylaxis did not prevent asymptomatic seroconversion. During prophylaxis, 51% of subjects in both treatment groups reported at least 1 AE. There were no major differences in the frequency or nature of AEs between groups. The most commonly reported AEs (≥3% of subjects in each treatment group) were consistent with upper respiratory viral infection (headache: 17% zanamivir, 18% placebo; cough: 14% and 15%, respectively; throat and tonsil discomfort/pain: 13% and 14%). There were no differences between groups in the overall incidence of viral respiratory infections (5% in both groups) or ear, nose, and throat infections (2% in both groups). None of the analyzed isolates from confirmed cases of influenza exhibited reduced susceptibility to zanamivir or genotypic evidence of resistance. Conclusions: Zanamivir, administered once daily for 28 days, was efficacious in preventing infection with the predominant circulating strains in the 2000- 2001 influenza season in the Northern Hemisphere (influenza A/New Calendonia/20/99-1ike and influenza B/ Sichuan/379/99-1ike) in these high-risk community- dwelling subjects aged ≥12 years. Zanamivir was well tolerated, with a safety profile comparable to that of placebo. No emergence of resistant virus was detected. ( Clin Ther. 2007;29:1579-1590) Copyright © 2007 Excerpta Medica, Inc.