Rodney Jones

Recurring outbreaks of an infection apparently targeting immune function, and consequent unprecedented growth in medical admission and costs in the United Kingdom: a review.

Background: The National Health Service (NHS) in the UK has been beset by unprecedented growth in emergency admissions to hospital which are specifically medical in nature, while surgical and trauma admissions are only showing the level of low growth expected from demographic change, or what is called the ageing population. There has never been an adequate explanation for this dichotomy. An Infectious Basis: The proposed infectious basis rests upon the observation that growth in medical admissions occurs in spurts which occur approximately five years apart, albeit three years between spurts have also been observed during the 1990’s. It is these spurts which are driving the long-term growth, rather than the relatively minor growth which occurs in the interval between the spurts. These periods of high growth are characterized by spikes in all-cause mortality, and typically result in a 15% increases in admissions to the medical group of specialties. However much higher growth is seen for particular conditions/diagnoses which appear to have a common Review Article Jones; BJMMR, 6(8): 735-770, 2015; Article no.BJMMR.2015.251 736 immune function basis via infection, inflammation and autoimmunity. These outbreaks can be seen across Europe, and the last three outbreaks commenced around Mar-02, Mar-05 and Mar-10 with subsequent spread over the next two years. The middle of these three outbreaks had the lowest increase in deaths and medical admissions. Implications: There is now an overwhelming body of evidence pointing to a recurring series of infectious-like events. In the UK, the 2012/2013 outbreak led to 45,000 extra deaths while across the 27 EU countries, each outbreak appears to result in somewhere in excess of 467,000 deaths. In Europe, the outbreaks tend to occur earlier in Denmark, Romania, Bulgaria and Slovakia, while they tend to occur later in the UK, Belgium, Greece and Slovenia. Emphasis now needs to switch toward clinical studies which screen the population for changes in the levels of specific IgM and IgG antibodies against a range of potential candidate organisms, and post mortem examination of the tissues of persons who die from a particular range of conditions such as neurological disorders including dementia and Alzheimer’s; respiratory and gastrointestinal tract diseases, and cardio/vascular conditions. Conclusion: This new disease has the potential to be a highly disruptive discovery involving changes in fundamental health care policy, and our understanding of the role of immune function in the exacerbation of a range of common medical conditions.

The case for recurring outbreaks of a new type of infectious disease across all parts of the United Kingdom

The higher than expected increase in medical emergency hospital admissions has been a matter of debate for many years. While regular growth of around 1.0-1.5% per annum may be expected due to demography recent evidence has emerged from England and Scotland that the increase over time appears to occur in concentrated spurts of growth at an interval of 3 to 6 years resulting in an approximate 10% step-like increase in certain medical and mental health related diagnoses. A characteristic time-related pattern in admissions then follows each step-increase. Outbreaks of a previously uncharacterised infectious disease have been proposed to account for this behaviour. Evidence is presented to show that simultaneous outbreak(s) across the remainder of the UK (Wales and Northern Ireland) are occurring with step-like increases in a similar range of diagnoses. The infectious agent is proposed to be a member of the group of persistent viruses and appears to show some form of collective switch to a dormant state around 3½ years after the initial outbreak. This behaviour accounts for the unique pattern of hospital admissions seen over time and is so strong that any underlying demographic trends are overwhelmed. This particular pattern of admissions will have uniquely profound financial effects upon the cost pressures experienced within the health services.

Infectious-like spread of an agent leading to increased medical hospital admission in the North East Essex area of the East of England

This work documents the spread of a new type of infectious-like outbreak leading to a step-increase in emergency medical admissions. It employs a running 12 month sum of emergency medical admissions to detect step-like changes in admissions from small areas, namely Mid Super Output Area (MSOA) geographical areas and from GP practice enrolled patients. A general 25% step-like increase in emergency medical admissions occurred around November of 2008 in North East Essex due to gradual spatial spread of an infectious-like agent. Earliest incidence seems to be around August 2007 at a GP surgery in the Castle ward of Colchester leading to a 21% increase in medical admissions. The next major incidence appears to be around January of 2008 at a GP Surgery in the Shrub End ward of Colchester with a 32% increase in admissions. Sporadic occurrences can be seen in April and May of 2008 in four small areas with 21% to 65% increases in medical admissions. The major outbreak occurred in October, November and December of 2008, hence the apparent November 2008 date seen in the aggregated data for the entire area. Further sporadic spread continues through to October 2009. Several small areas appear to have escaped the outbreak, notably a rural GP practice in the village of Lawford and an area of Colchester dominated by student bed sits. More deprived elderly communities represent the social groups most affected. The outbreak shows strong age dependence which is reminiscent of what is termed ‘original antigenic sin’, i.e. age at first exposure to a strain of an infectious agent determines the quality of the immune response to later exposure to different strains of the same agent. There is evidence to suggest that residents of nursing homes are affected earlier and more strongly than others while those who die in hospital show only a modest increase, i.e. the infection generally leads to sustained poor health rather than death. Analysis of the primary diagnoses for those admitted to hospital strongly suggests that the agent may be the common herpes virus cytomegalovirus and this is consistent with the apparent time cascade in disease which emanates out of each outbreak. Other explanations may be possible. These findings have profound public health implications regarding the infectious origin of disease, to the funding formula used to distribute health care funds both in the UK and elsewhere and to the interpretation of age-standardized admission rates for medical admissions.

A Previously Uncharacterized Infectious-like Event Leading to Spatial Spread of Deaths Across England and Wales: Characteristics of the most Recent Event and a Time Series for Past Events

Aims: In 2003, 2008 and 2012, deaths in the UK showed unexpected and unexplained large increases similar in magnitude to the larger influenza epidemics seen before 2000. However there were no unusual levels of influenza to explain these spikes. This study aims to investigate the spread of a presumed infectious agent across England and Wales during the 2012 event, and to establish a longer time-series for these outbreaks. Study Design: Longitudinal study of deaths. Place and Duration of Study: Deaths for residents of Local Authority (LA) and regional areas in England and Wales from January 2009 to July 2014. Analysis of monthly deaths from January 1951 to December 2012 for the whole of England & Wales, to detect events prior to 2012. Analysis of calendar year deaths between 1963 and 2013. Methodology: Running twelve month totals are used to detect the onset of a step-like increase in deaths which endures for twelve to eighteen months before abating. Results: These events can be traced back to the early 1950’s where they were intertwined with influenza epidemics. Moderately slow infectious-like spread across the UK occurs over a two year Original Research Article Rodney P. Jones; BJMMR, 5(11): 1361-1380, 2015; Article no.BJMMR.2015.154 1362 period. The last event which peaked in 2012 and 2013 led to a minimum estimate of 42,000 excess deaths, although 60,000 deaths are a more likely estimate. An additional event in 2010, which affects around 30% of LAs, appears linked with the swine flu epidemic and leads to underestimation of deaths in these locations for the 2012 event. The magnitude of the increase associated with the 2012 event decreased with increasing LA size, an effect which is due to the modifiable areal unit problem (MAUP). These events are always linked to large increases in emergency medical activity and emergency department attendances. The increase in deaths at local authority level is highly variable ranging from +5% to +30%, and this variability leads to large differentials in the cost pressures experienced by the local health services. In particular, 90% of LAs in London experienced the lowest percentage increase from the 2012 event. As a general rule it was observed that local authorities experiencing a low percentage increase in death for the 2012 outbreak, had experienced a high percentage increase following the 2008 outbreak and vice versa. This implies that the events are linked to the same agent. Conclusion: The existence of a new type of infectious outbreak, with relatively slow spread, has been confirmed and is part of a longer time-series of outbreaks. Large numbers of deaths appear to be associated with each event, although the 2012/2013 event appears to have led to the highest number of deaths in any of these outbreaks since 1950. Urgent action is required since the next outbreak is due around 2016 to 2018.

Unexpected, periodic and permanent increase in medical inpatient care: man-made or new disease?

For many years medical admissions to acute hospitals have been increasing at a rate far higher than expected from demographic change. Factors such as emergency re-admission, GP thresholds, breakdown of the family unit and deficiencies in community and social care have been suggested to explain this widening gap. Solutions to the problem have revolved around demand management strategies. While such strategies do result in a relative reduction in demand they are unable to prevent the underlying long-term behaviour. Analysis of daily admissions in Scotland, England and at individual hospitals over the past 25 years shows that the admissions tend to increase in a step-like manner at an interval of three to six years. This causes a typical 10% step-increase in physician work-load and inpatient medical costs and across England adds over 1,200,000 occupied bed days of additional bed demand into the health service within the space of around three months. There are knock-on effects to demand for ambulance services, accident and emergency attendance and GP referral. The step-increase is characterised by a cluster of diagnoses, increases with age and effects women more than men. Such behaviour has similarities to an infectious outbreak and the evidence for this and alternative hypotheses are discussed.

Can time-related patterns in diagnosis for hospital admission help identify common root causes for disease expression?

For many years medical admissions to acute hospitals have been increasing at a rate far higher than expected from demographic change. Analysis shows that the admissions tend to increase in a step-like manner at an interval of 3-6 years. This study characterises the specific diagnoses associated with the step-changes and uses the resulting pattern in admissions over time to identify further diagnoses with a far lower incidence which may also conform to this pattern. All of the diagnoses located using this method have a common immune function linkage in the expression of the chronic form of the condition. It is proposed that the wider use of data mining techniques may enable association between diagnoses associated with the need for inpatient care arising from unexpected common causes.

Infectious-Like Spread of an Agent Leading to Increased Medical Admissions and Deaths in Wigan (England), During 2011 and 2012

Aims: To demonstrate infectious-like spread of an agent leading to a period of higher death and medical admissions in the Wigan local authority, part of the greater Manchester area of England, during 2011 and 2012. Study Design: Longitudinal study of deaths and hospital admissions. Place and Duration of Study: Deaths (all-cause mortality) for the resident population of Wigan from January 2006 to February 2014. Patients admitted to the Wigan Infirmary, a large acute hospital on the outskirts of Manchester, England, between 2008 and 2013. Methodology: Running twelve month totals for deaths and medical admissions were used to detect step-like increases in these factors. Additional analysis by age, length of stay and for clusters of persons living in over 40 small areas (called mid super output areas) containing approximately 5,000 population within Wigan and surrounds. Results: A step-like increase in total deaths can be seen for all-cause mortality in Wigan commencing around February of 2012. Medical admissions to the hospital also show a step-like increase at this point. Deaths and medical admissions remain high for around 15 months before beginning to abate. Infectious-like spread of medical admissions can be observed within 40 small area population groups in Wigan during the period January 2011 to April 2012. Certain medical conditions appear to be affected earlier than others, and the pattern of increased admissions show evidence of saw-tooth behavior with age, which is indicative of ‘antigenic original sin’ and which has also been demonstrated for deaths in England and Wales during 2012. Conclusion: The spread of a previously unidentified infectious agent is implicated in the Original Research Article British Journal of Medicine & Medical Research, 4(28): 4723-4741, 2014 4724 synchronous increases in death (both inand out-of-hospital) and in medical admissions (some of which result in death). This is not the first occurrence of an outbreak of this agent and urgent research is required to identify both the agent and clarify its mode of action which appears to be via immune modulation. The ubiquitous herpes virus, cytomegalovirus, which is known to have powerful immune modulating properties, may be involved.

Unexpected and disruptive changes in admissions associated with an infectious-like event experienced at a hospital in Berkshire, England around May of 2012.

Aims: To study the effect of a large infectious-like event on admissions to, and bed occupancy in, a very large acute hospital in Reading (western Berkshire) England, observed to commence in the early part of 2012. These changes occurred in parallel with infectious-like spread of an agent leading to increased medical admissions across the whole of Berkshire. Study Design: Longitudinal study of hospital admissions, bed occupancy and deaths. Place and Duration of Study: Admissions and deaths at the Royal Berkshire Hospital NHS Foundation Trust (England) between April 2008 and September 2013. Methodology: A running 12 month total of admissions, deaths and occupied beds was constructed from aggregated hospital admission and discharge data. Trends were analysed by admission type, discharge destination, specialty, International Classification of Diseases (ICD-10) primary diagnosis and Healthcare Resource Group (HRG) v4 chapter. Results: Admissions, deaths and occupied beds all showed a simultaneous step-like increase around March to June of 2012, which led to considerable operational pressure and a marked reduction in elective overnight surgery due to reduced bed availability. The increase in in-hospital Original Research Article Jones; BJMMR, 6(1): 56-76, 2015; Article no.BJMMR.2015.184 57 deaths exhibited a curious time cascade which was specific for various diagnoses. Deaths first increased for those with cancers or intestinal conditions in January 2012, followed by hepatic, diabetic and asthma in February 2012, then a time series of other conditions, through to arthritis and arthrosis conditions in July 2012. All of these occurred at a time when deaths across the whole of the UK showed a large and unexpected increase. Conclusion: A new type of infectious event is strongly implicated which appears to exert its clinical effects via some form of immune impairment. The agent leads to a persistent infection. The immune modifying virus, cytomegalovirus, which (in other studies) is associated with a 20% higher odds ratio for all-cause mortality, has been circumstantially implicated, however, this requires confirmation.

A study of an unexplained and large increase in respiratory deaths in England and Wales: is the pattern of diagnoses consistent with the potential involvement of cytomegalovirus?

Aims: To determine if the ubiquitous herpes virus, cytomegalovirus (CMV), could be involved in a large and unexplained increase in all-cause mortality in England and Wales in 2012, and more specifically if this involvement was via a respiratory etiology. Study Design: Analysis of respiratory system cause of death in England and Wales and of respiratory system emergency hospital admissions in England. Place and Duration of Study: Cause of death statistics with primary respiratory system involvement in England and Wales in 2011 and 2012. Trends in emergency hospital admissions in England where there is a respiratory system primary diagnosis over the period 2000/01 to 2012/13. Methodology: Respiratory diagnoses which show a statistically significant increase as cause of death in 2012 were identified, as were diagnoses showing a statistically significant increase as the primary cause of an emergency hospital admission in 2012/13. These diagnoses were then compared with medical case studies for hospitalization and death due to CMV. Results: Deaths in England and Wales showed a sudden and unexplained increase in early 2012 which continued for 18 months before abating. The increase was equivalent to a large influenza epidemic, although higher levels attributable to influenza were absent. The increase was age and gender specific, and highest among those with neurodegenerative diseases (+15%); however, due to the way in which the primary Original Research Article British Journal of Medicine & Medical Research, 4(33): 5193-5217, 2014 5194 cause of death is coded the role of respiratory diseases as the trigger for decease can be obscured. The next highest increase was for respiratory conditions, the most notable for bronchiectasis (+19%), asthma (female +14%), lung diseases due to external agents (+12%), interstitial pulmonary diseases (female +12%), chronic pulmonary disease (+7%) and a range of other conditions with >4% increases. After adjusting for the way in which deaths in the dementia group are coded the increase due to pneumonia rises to +8% for males and +15% for females. For the whole of the respiratory group augmented with the dementia group the increase in deaths was specific to those aged over 65 (average for 65+ of male +8.3%, female + 8.7%) with a peak at 90-94 (male + 15%, female + 17%). A corresponding large increase in respiratory admissions accompanies the increase in deaths. Given that the increase in admissions and deaths moved across England and Wales in a time-based spread, indicative of an infectious agent, with spurts of rapid local spread compatible with respiratory transmission, the increase in respiratory deaths were examined to see if the nature of any putative infectious agent could be discerned. There was a striking match with the known clinical effects of CMV. Conclusion: In an aged population lifelong exposure to the immune erosive effects of CMV presents the potential for the emergence of diseases reliant on immune impairment for their modus operandi. The lung is a primary reservoir for permanent CMV infection in humans and conditions/diagnoses showing a large increase in both death and hospital admissions in 2012 are all potentially CMV-mediated. In view of the very large increase in death for particular respiratory diagnoses further research is urgently required.

Unexpected and unexplained increase in death due to neurological disorders in 2012 in England and Wales: Is cytomegalovirus implicated?

In early 2012 deaths (all-cause mortality) in England and Wales showed an unexpected and unexplained increase which continued for 18 months before abating. The highest percentage increase in deaths was noted to be for neurological degenerations (mainly dementia, Alzheimers, Parkinsons). This study seeks to understand why increased deaths should focus on these conditions and if an unrecognized infectious outbreak could be implicated. Cause of death statistics for England and Wales were compared for 2012 versus 2011 as was the diagnosis for first outpatient appointment and inpatient admissions for these conditions. Deaths for dementia, Alzheimers and Parkinsons showed a 15% increase with associated age specificity. The increase could not be explained by changes in the coding relating to cause of death. The increase coincided with increased GP referral (as first outpatient attendance) and inpatient admission for a range of neurological conditions. These increases were also observed on previous occasions of a similar event where deaths peaked in 2003 and 2008. A cascade of debility leading to immobility and institutionalization along with specific immune impairments appears to render those suffering from neurological degenerations sensitive to infectious outbreaks and more specifically to the particular agent behind these events. These and other studies point to outbreaks of a previously uncharacterized agent with the outbreak peaking in 2003, 2008 and 2012 (and in other years prior to these dates). Cytomegalovirus is a potential candidate and the necessary research to test this hypothesis is outlined.