Time course of dementia following sepsis in German health claims data

Discussion

Next to acute and negative symptoms of sepsis on cognition and behavior, persistent cognitive deficits have been demonstrated, and an increased risk of developing neurodegenerative disorders has been postulated.¹⁴ Using a large sample of claims data obtained from the largest German statutory health insurance, we showed that as expected, delirium most frequently preceded with diagnosis of dementia. Next followed an independent effect of a prior diagnosis of sepsis, then a prior occurrence of an ICU stay and a previous surgery. For all of these clinical events, the incidence of dementia diagnosis was highest in the quarter during which the respective clinical event occurred. Thereafter incidence declined, but continued to persist at a raised level up to 2 years. This may suggest that the described clinical events all represent risk factors for a relatively rapid cognitive decline, even reaching the level of dementia within the first quarter.

A possible confounding factor could have been the higher medical attention that patients having these conditions received during hospitalization, and thus, previously unrecognized dementia cases may have been identified for the first time. Alternatively, clinical events such as perturbation of cerebral homeostasis during sepsis, delirium, procedures during ICU, or surgery may have accelerated clinically silent cases of predementia syndromes, moreover, because age represents the strongest risk factor for the development of dementia and all included patients were aged 65 years or older. This is supported by our finding that the immediate effect of sepsis on dementia diagnosis was largest among those aged 85 years and older. Last, documented delirium does not cover all cases of delirium, which actually occurred. Hence, the effect of delirium, which was coded, was higher than that of sepsis, which is not equivalent to the effect of delirium per se. Further, the observation period of 2 years without a diagnosis of either dementia or sepsis does not exclude the possibility that a case of sepsis occurred prior to 2004. Nor does it exclude a given claimant having had experienced previous ICU stays or surgical procedures.

Precise pathologic mechanisms could not be identified by our data set due to the diversity of microbial pathogens inducing sepsis, the heterogeneity of pathogenetic mechanisms underlying delirium,¹⁵ the divers interventions during an ICU stay, or the different surgical procedures. Despite this, all 4 clinical events were subsequently associated with the increased incidence of dementia either concurrently or thereafter. This is congruous with previous studies showing increased incidence of cognitive decline and dementia after sepsis,^2,16,17 delirium,^18,–,20 hospitalization for critical illness,^4,5,21 and cardiac and noncardiac surgery.^22,23 Possible mechanisms that may contribute to the sepsis-induced neurocognitive deterioration may include compromised microglial clearance function and subsequent accumulation of cerebral beta-amyloid,²⁴ inflammatory changes at the synapse level²⁵ or increased susceptibility to excitotoxic events after exposure to bacterial lipopolysaccharide.²⁶ It is important to note that pathogenetic mechanisms have mostly been identified using rodent models, which in the case of sepsis share only a minor number of molecular signaling mechanisms with men.²⁷ Thus, the underlying pathologic processes need to be further explored in particular in humanized models or the actual human cases itself. Of note, the incidence of dementia diagnoses following the described clinical events progressively lessened during the subsequent quarters, yet remained significantly greater than that of the respective case controls up to 2 years after the event. For delirium, the effect extended even beyond this period.

The comparison of different age clusters (65–74, 75–84, and 85+ years) revealed that dementia incidence after sepsis increased by age and that the oldest cluster was at highest risk of incidental dementia after sepsis, possibly indicating a contributing factor of immune senescence or reduced compensatory mechanisms of the brain to cope with the sepsis-caused challenge.²⁸ Nevertheless, it seems important to note that the risk of developing dementia and, in particular, Alzheimer disease follows a similar age-dependent slope. When considering the decrease of incident dementia after the quarter of the respective clinical event, one may have expected a longer lasting effect of sepsis on the risk of developing dementia. One reason why sepsis may not show a more obvious effect on the incidence of dementia in the subsequent years may be the increased mortality of patients after initially surviving sepsis, which is in line with earlier epidemiologic studies of sepsis-related mortality.^29,30 Here, cases of hospitalization in an ICU showed increased mortality as compared to sepsis cases, which had not required intensive care. One underlying and frequent reason for ICU admission during sepsis is the occurrence of a multiorgan failure, which may reflect the severity of the infection,³¹ the frailty of the respective individual, and, certainly, a higher risk of cerebral involvement.³² The results may indicate a selection effect, with less cognitive-impaired and less frail individuals being healthy enough to survive the rigors of intensive care. Either way it is remarkable that sepsis increases mortality immediately in its aftermath but has no medium- and long-term consequences on survival.

One major methodological problem is to cleanly separate the effects of delirium, sepsis, and underlying acute or chronic diseases.^20,33,34 However, the effect of sepsis on dementia risk in our data was independent of other critical events, age, sex, or comorbidities. In sensitivity analyses excluding patients with a delirium diagnosis, as a strong driver for dementia risk, we yielded consistent results for sepsis. Another problem is that we cannot differentiate between primary degenerative, progressive, and irreversible cognitive decline and potentially reversible dementia of secondary origin. The latter may be caused by physical diseases or injuries.³⁵ For example, distinguishing delirium from dementia can be difficult.³⁶ If such reversible dementia is assigned to one of the dementia diagnoses included in our study and persists over a longer period, our validation procedure may define these cases as valid dementia cases. Using the subsample without patients with delirium diagnosis, surgery or ICU treatment may partly exclude cases with potentially reversible dementia due to these critical events. Again, we yielded consistent results for sepsis.

The primary objectives of administrative health claims data are cost reimbursement and calculation, with implications for secondary data analyses. Not every diagnosis is relevant for the purposes of cost calculation. Thus, a patient's cognitive impairment or mild dementia might not be documented if no further treatment is given. The incidence of dementia will certainly be biased to higher ages, when the symptoms of the disease become more obvious.¹⁰ We thus cannot explore premorbid cognitive data as long as there is no diagnosis. Hence, it is difficult to disentangle whether such patients may in fact have had preexisting cognitive impairments or generally lower cognitive abilities before the major event, potentially even leading to a higher risk of admission to ICU or diagnoses such as sepsis or delirium. Our results may partly reflect such reverse causality.^36,–,38 Preliminary analyses with sepsis diagnosis as the dependent variable revealed that ever experiencing a dementia diagnosis during the observation period is associated with an increased risk of incident sepsis diagnosis (results available on request), indicating such bidirectional relationships. Delirium is known to be undercoded in administrative data using ICD, ninth edition or ICD-10 criteria compared with data using, e.g., Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.^39,40 Delirium diagnoses, particularly in severe cases, are most often made in the inpatient setting where we are not able to define the specific type of physician who made the diagnosis. In general, such a diagnostic code is made either by a neurologist or psychiatrist. Furthermore, we are not able to define the severity of sepsis. Health claims data do not include clinical parameters, and clinical sepsis codes (R65.0! for sepsis and R65.1! for severe sepsis in 2005; R57.2 for septic shock in 2010) were introduced later and may not have been used consistently over time. In our study, we used ICD code A41, which may be associated with an underestimation of sepsis cases, but with a high positive predictive value.^41,42

We are not able to explore the association between sepsis and a specific dementia type. Health claims data do not represent the actual distribution of specific dementia diagnoses. In the AOK data, 45%–50% of the dementia diagnoses were of unspecified dementia, and only 27% of dementia cases were diagnoses of Alzheimer disease dementia. That is in contrast to the prevalence of Alzheimer disease dementia (60%–80%) in epidemiologic studies.⁴³ The significantly different distributions by etiology compared with population-based cohort studies result from the lack of standardized criteria of diagnoses in claims data. The main reason for the different diagnosis pattern is that about 42% of dementia diagnoses are made by general practitioners, who are unable to identify the exact etiology of the disease.⁴⁴ This is primarily attributable to the fact that in contrast to specialist care, general practitioners are not obliged to code the complete 5-digit ICD-10 code. Furthermore, often, computer-based practice information systems only require a documentation of 3 digits and add a “.9” for unspecified types of a disease.⁴⁵ But even specialists such as neurologists and psychiatrists have been shown to classify 31% of their patients with dementia as having unspecified dementia.⁴⁴ However, recent research revealed that single diagnoses of dementia disease, such as Alzheimer disease, become rarer with advancing age and that mixed pathologies prevail.⁴⁶ We therefore used an overall indicator for dementia.

Dementia diagnoses in medical claims data are neither specific nor standardized, and a claims-based definition of dementia and other diagnoses is not the same as prospective clinical assessment. However, the prevalence and incidence based on AOK claims data fit well with other national and international studies.^9,10 Furthermore, using formal medical diagnoses prevents recall bias by the patient. Health claims data do not provide lifestyle and medical information, such as intensity of former or current tobacco use, dietary habits, or body mass index, which could potentially affect the association between sepsis and dementia.

We analyzed a nationwide population-based data set with a large sample size that allowed investigating the relationship between sepsis and dementia. The analysis of health claims data avoids potential biases that often occur in population-based surveys. There is no bias arising from response behavior or self-selection, selection by the health care provider, or the study design. In particular, community dwelling and people living in nursing homes are included, with the latter usually missing in surveys. All of the data were legally made available in anonymous form, thereby eschewing any selection bias due to active volunteerism. In addition, medical diagnoses were documented, preventing recall bias by individual participants, and were validated, avoiding use of false-positive diagnoses.

Our observational study showed that for up to 2 years after sepsis, incidents of dementia doubled and even tripled compared with those without sepsis, after accounting for other clinical events, such as delirium. Hence, incident dementia may be precipitated by or perhaps even induced by sepsis, in addition to or in combination with other clinical events such as delirium, surgery, and/or intensive care stay. To our knowledge, this independent effect has not been shown for sepsis diagnosis until now. Further research using primary data analysis will need to consider factors ameliorating or rescuing patients from cognitive decline and dementia following these events. Focus should rest on medical therapies and interventions, premorbid cognitive ability, including cognitive reserve, psychiatric illness, physical rehabilitation and after care, and potential confluences of causal factors sepsis and delirium and neurodegeneration.