Is Cytomegalovirus Involved in Recurring Periods of Higher than Expected Death and Medical Admissions, Occurring as Clustered Outbreaks in the Northern and Southern Hemispheres?.

A series of clustered infectious-like events have been recently documented in both the northern hemisphere (Canada, UK [England, Northern Ireland, Scotland and Wales], all countries in the European Union, and the USA) and the southern hemisphere (Australia and New Zealand), in which both deaths and emergency admissions for a range of medical conditions appear to simultaneously rise in a step-like manner, stay high for a period of 12 to 18 months, and then revert back to the expected time trajectory. These unique events are also observed in very small geographical areas within the population area of a single hospital or Primary Care Organisation (PCO), and this precludes explanations based on acute thresholds to admission or to PCO funding, procedures and practice. These events have been overlooked by traditional health surveillance methodologies, simply because it was assumed that neither deaths nor medical admissions could behave in this unique way. Indeed, in the UK it has been widely assumed that the increases in medical admissions arising from these events are solely due to deficiencies in the organization and delivery of health and social care, often labelled as ‘failure to manage demand’. Based on the spectrum of medical conditions which are associated with the increased admissions and deaths, it has been proposed that the ubiquitous herpes virus, cytomegalovirus (CMV), may in some way be associated with these outbreaks. This involvement could be either by (re-)infection with a new strain, or by opportunistic reactivation in the presence of another agent. This review will examine if CMV is indeed capable of causing substantial increases in both deaths and medical admissions, and which conditions in particular would be affected.

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 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.

Small Area Spread of a New Type of infectious Condition across Berkshire in England between June 2011 and March 2013: Effect on Medical Emergency Admissions.

Aims: This study aims to investigate the small area spread of a presumed infectious agent, and to determine which factors determined the point of initiation, speed of the spread and the resulting increase in emergency medical admissions. Study Design: Analysis of a monthly time series of medical admissions using small area population aggregates of around 7,000 population contained within the census spatial unit called a Mid Super Output Area (MSOA). Place and Duration of Study: Emergency medical group admissions for residents of the six unitary authority locations in Berkshire, southern England between January 2008 and March 2013. Methodology: A running twelve month total of admissions was used to determine the point of initiation and the extent of a step-like increase in medical admissions. Results: Analysis shows evidence for spatial spread initiating around June 2011 through to March 2013. At onset, medical admissions increase and stay high for 12 to 18 months before beginning to abate. This spread commenced earlier among mainly Asian small areas (clustered from July 2011 onward) and later (clustered around March 2012) in predominantly affluent white areas. The observed percentage increase in admissions within the unitary authority areas varied from 25% to 51% (median value), however the average increase was highest as the geographic area became smaller, and this is suggested to arise from the aggregation of smaller social networks where the point of initiation of infectious spread occurs over time. The percentage increase in admissions displayed high single-year-of-age specificity suggestive of the immune phenomena called antigenic original sin, and is therefore suggestive of a different strain of an agent with previous outbreaks. The increase in emergency admissions showed a month-of-year pattern which appeared to follow the seasonal pattern of vitamin D levels in the blood. The presence of nursing homes, deprivation and ethnicity also has an effect on the average increase in admissions. Conclusion: It is suggested that all the above point to an outbreak of a previously uncharacterized type of infectious agent. There are profound implications regarding the use of standard five year age bands for the standardization of medical admission rates.

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 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.

An Unexpected Increase in Adult Appendicitis in England (2000/01 to 2012/13): Could Cytomegalovirus (CMV) be Risk Factor?

Aims: To study the trends in admission for diseases of the appendix and to attempt to present a potential basis for the observed (complex) age-dependent trends and etiologies. Study Design: Longitudinal study of admissions relating to the appendix with analysis by age and gender. Place and Duration of Study: Admissions for diseases affecting the appendix for the residents of England over the period 2000/01 to 2012/13. Methodology: Retrospective application of age-standardized admission rates based on 2012/13 as the base year to determine what proportion of the increase in admissions is due to demography or to non-demographic forces. Synthesis of available literature covering diseases of the appendix to propose possible causes for the increase in admissions. Results: Based on admissions in 2012/13 diseases of the appendix cost the NHS in England around £107 million per annum (roughly £2 per head of population per annum). Admission rates peak at age 17 but have been increasing over the past 14 years in adults but not children. The rate of increase escalates with age and is more rapid in females. The trend for females shows far higher volatility than that for males and both show some degree of cyclic behavior. Depending on age, demographic change can only explain between 20% and 40% of the long-term increase. Social and health service factors are unlikely to explain this gap. Conclusion: An immune/infectious basis for increasing admission rates appears most likely. A possible role for the immune modulating herpes virus, cytomegalovirus (CMV), is discussed in the context of a potential linkage between infection with multiple agents (called the infectious burden) and the development of multiple morbidity. Both of which increase with age and are amenable to manipulation by CMV. The suggested mechanism may also provide insight into why the rates for admission of certain medical diagnoses are increasing far faster than due to demographic change.

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 primarycause 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.

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 synchronous increases in death (both in- and 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 Single-year-of-age Changes in the Elderly Mortality Rate in England and Wales During 2012.

Aims: To evaluate single-year-of-age specificity in deaths in England and Wales associated with a large, unexpected and unexplained increase in 2012. To demonstrate that this type of event has occurred previously across the entire UK. To demonstrate that infectious-like spread at a regional level in England may be involved. Study Design: Longitudinal study of annual (calendar year) deaths (all-cause mortality) in the United Kingdom and England and Wales using publically available statistics available from the Office for National Statistics (ONS). Place and Duration of Study: United Kingdom, England & Wales, local authorities within England & Wales covering a variety of time spans designed to illustrate various key points. Methodology: Deaths between 1974 and 2012 in the United Kingdom. Live population and deaths for residents of England and Wales and of English local authorities. Calculation of single-year-of-age death rates in 2011 and 2012 which are the years before and after the large and unexpected increase in deaths. Results: A recurring series of infectious-like events can be demonstrated which prior to 2000 had been largely assumed to be due to influenza epidemics. The event in 2012 shows specificity for the elderly particularly above age 75, which is somewhat expected given increased susceptibility to the environment as we age. The single year of age mortality rate shows saw tooth behavior for deaths in 2011 and even more exaggerated saw tooth behavior is seen in the difference between 2011 and 2012. Similar saw tooth behavior is seen in the difference between single-year-of-age standardized admissions via the emergency department in England between 2008 and 2012. The infectious spread across England behind this phenomenon is illustrated at regional level and probably results in a 40% underestimation of the saw tooth behavior. Conclusion: The saw tooth behavior is known to be associated with what is called ‘original antigenic sin’. Hence the saw tooth behavior appears to indicate that the unexpected high elderly mortality in 2012 was due to an outbreak of an infectious agent which has multiple strains. This behavior confirms the results of other studies investigating simultaneous increase in medical admissions to hospital during the time that the deaths increase. The ubiquitous herpes virus, cytomegalovirus may be involved, although at the moment this virus provides a prototype for the sort of immune modulating agent that may be responsible. The use of five year age bands to age standardize mortality and medical admission rates may be subject to misleading outcomes where the periodicity behind these outbreaks and their cumulative effect on immune mediated responses is out of synchrony with the basic saw tooth behavior seen in both mortality and admission rates. This has major implication to the calculation of hospital standardized mortality rates (HSMR).