Factors influencing the time between onset of illness and specimen collection in the diagnosis of non-pregnancy associated listeriosis in England and Wales

Listeriosis is an infection caused by the bacterium Listeria monocytogenes. It is a rather uncommon disease but often very severe and with a high case fatality rate [1]. A sub-set of the population including pregnant women and their unborn or new-born babies, the elderly and people who are immunocompromised either as a result of an underlying medical condition or medication are predisposed to listeriosis.

Suspecting a patient has listeriosis can be challenging as infected patients can present with a range of clinical symptoms from non-specific gastroenteritis or influenza-like to those of severe invasive systemic illness. Thus symptoms may include nausea, vomiting, abdominal cramps and diarrhoea, fever, myalgia, general malaise, arthralgia, confusion, neck stiffness and headache. Listeriosis in a healthy adult may present as self-limiting febrile diarrhoea [1]. Where there is central nervous system (CNS) invasion, there is no sign or symptom that securely differentiates listeriosis from other causes of CNS infection [2].

The pathway from the initial exposure of a case to the notification of a laboratory confirmation (the ‘exposure to notification’ pathway) is made up of a number of events some of which include the onset of symptoms of listeriosis and the collection of specimen for laboratory testing. There is currently no information available in the literature on the observed time between onset of listeriosis and collection of a specimen, however measuring the duration between each event from exposure to notification can help focus interventions to the appropriate area to ensure timely surveillance and epidemiological investigations. In this study, we review enhanced surveillance data collected over ten years to measure the time difference between onset of listeriosis and the collection of a specimen from a non-pregnancy associated case in England and Wales. We also investigate the factors that may influence this time difference in order to inform clinical policy, guidelines and interventions.

Laboratory confirmed cases of non-pregnancy associated listeriosis in England and Wales are reported voluntarily to the Public Health England Centre for Infectious Disease Surveillance and Control (PHE, CIDSC). Two standardised questionnaires, clinical and food history, are completed for each reported case. The clinical questionnaire [3], which is completed by the reporting laboratory, collects specific clinical information including: date of onset, date of specimen collection, presenting symptoms, principal illness, underlying medical conditions (any other ongoing illness, either acute or chronic, reported by the microbiologist including cancer, diabetes, Acquired Immune Deficiency Syndrome (AIDS), cardiovascular disease, liver or kidney disease amongst others), current medications (as some may result in the patent being immunocompromised) and patient survival. The food history questionnaire [4], which is completed by the patient or a proxy, collects basic demographic information including age, ethnicity, gender and postcode of residence. It also collects the patient reported date of onset. Information from both sources are merged, de-duplicated and stored in a database.

In the United Kingdom, deprivation scores can be derived from the postcode of the area of residence. Postcodes were used to map geographical areas with an average population size of 1,500 people for which a deprivation score is then calculated using the Index of Multiple Deprivation (IMD) 2007. The IMD 2007 is a composite measure based on 38 indicators grouped in seven domains: income; employment; health deprivation and disability; education, skills and training; barriers to housing and services; crime; living environment [5]. The calculated deprivation score is then assigned to a corresponding postcode and this is ranked and then divided into quintiles with 1 being the least deprived and 5 the most deprived.

Date of onset of symptom, for the purpose of this study, is defined as the first day the patient developed symptoms of listeriosis. This is collected using both the clinical and food history questionnaires and checked to ensure consistency. Where there is a difference in the recorded dates, the date reported on the food history questionnaire is used as this is reported by the patient or a close relative. The date of specimen is defined as the reported date when the first clinical specimen was collected from a suspected case of listeriosis.

The time between onset of symptoms and collection of specimen was calculated as the difference in days between the date of symptom onset and the date of specimen collection. Where either or both dates were unknown, or when the date of specimen was before the date of symptom onset, cases were excluded from this study.

Following exposure to L. monocytogenes, there are certain necessary events that determine the time period between exposure and implementation of epidemiological interventions. This time period, for the purpose of this study has been called the ‘exposure to intervention’ pathway. The events in the pathway after exposure are: onset of illness, contact with medical care, collection of specimen, isolation of L. monocytogenes and notification of a laboratory confirmation. Although treatment can be initiated at any point in the pathway, public health interventions can only commence after notification. The latter can be further delayed when additional molecular typing has to be carried out. A delay between any of the events on the pathway could result in delays in the notification of confirmed cases of listeriosis which can have implications on the effectiveness of public health interventions [7] such as the identification of potential sources of contamination, and the prevention of further cases.

Estimating the incubation period of gastrointestinal pathogens, which is the time between consumption of a contaminated food item (exposure) and onset of illness, can be difficult [8], and even more challenging for listeriosis due to its non-specific clinical symptoms. The incubation period of listeriosis can be less than 24 h and as long as 90 days [9]. Cases involving the CNS have incubations periods ranging from 1 – 14 days and cases of septicaemia have incubation periods between one and twelve days [8]. Symptoms of gastroenteritis can develop from 24 h following infection [10, 11].

The presence of an underlying condition can either decrease or increase the time period between onset of illness and specimen collection, as persons with underlying conditions may have frequent access to health care and the possibility of early specimen collection, or conversely, the presence of an underlying condition in some may make diagnosing listeriosis difficult due to its non-specific symptoms. In the study population described here, the time period for cases with underlying conditions was shorter. In England and Wales, about 85 % of non-pregnancy associated cases report underlying conditions and certain conditions result in higher risk of listeriosis compared to others [12]. Frequently reported conditions were malignancies, diseases of the circulatory and digestive system. Cases with these conditions are likely to be hospital in-patients or have frequent contact with health services thereby increasing the probability of an early specimen collection. However, not all cases with underlying conditions will have a short time period between onset of illness and collection of specimen. Some case reports show patients with a time period of three or four days [13, 14]. The presence of an underlying condition may mask the symptoms of listeriosis as the latter can be non-specific. As the diagnosis of listeriosis primarily relies on blood cultures, it can be extremely difficult to suspect when the patient presents with undifferentiated illness.

Similar to other populations [15, 16], L. monocytogenes serogroups 4 and 1/2a were the most frequently reported serogroups in our study population, however the time difference between onset of illness and collection of specimen was shorter for cases infected with L. monocytogenes serogroup 1/2b. The reason for this time difference is unknown as the distribution of presenting illness is similar across the different serogroups. In this study, the low numbers of cases with serogroup 1/2b means this could be a spurious effect. The virulence difference between L. monocytogenes serogroups, where serogroup 1/2a is considered less virulent [17], could result in cases having milder symptoms and therefore presenting to a General Practitioner (GP) later accounting for the longer time difference between onset of symptoms and collection of specimen. It should be noted that the pathogenic potential of L. monocytogenes and what makes one strain more virulent than another is poorly understood.

Ethnic and gender differences [18] as well as socio-economic differences contribute to health inequalities particularly in accessing secondary and tertiary health care however; these differences may not be related to the health seeking behaviours of patients. According to a UK study [19]; all patients had at least an equal probability of seeking immediate healthcare following perception of need. This may explain the similarity in the time periods between onset of symptoms and collection of specimen for the cases irrespective of gender, ethnicity and socio-economic status. Furthermore, the severity of listeriosis may remove the choice to seek help causing all cases to seek medical care equally as soon as possible. This shows that a patient’s demographic characteristics otherwise do not influence the time period between onset of symptoms and specimen collection.

The date of onset requested on the standardised questionnaires is the first day the patient developed symptoms of listeriosis. However, there may be variations in the interpretation of the question depending on the interviewer. Also, for cases with an underlying condition, it may be difficult to accurately identify when symptoms of listeriosis started. These misinterpretations may have impacted our estimates of the onset of symptoms and thereby resulting in either an overestimation or an underestimation of the time period between onset of illness and collection of specimen particularly in cases that reported over 60 days between onset of illness and collection of specimen.

Pregnancy associated cases were excluded from this study because the non-systematic method of reporting cases could introduce a bias. Both mother and baby (infant under 28 days of age) are regarded as one pregnancy associated case, and details of either mother or baby is recorded in the database. The selection of which case is recorded depends on which laboratory result is received first. If the results of more babies are reported first, the age distribution will be skewed to the 0–9 years, and if the results of more mothers are reported first, the gender distribution will be skewed towards females.

AIDS, acquired immune deficiency syndrome; CNS, central nervous system; GP, general practitioner; IMD, index of multiple deprivation; LRT, likelihood ratio test; PCR, polymerase chain reaction; PHE, CIDSC, Public Health England Centre for Infectious Disease Surveillance and Control