Multimorbidity—A manifestation of network disturbances? How to investigate? How to treat?

In the opening paper of this, the most recent Complexity Forum of the Journal of Evaluation in Clinical Practice, Joachim Sturmberg and his colleagues1 argue that multimorbidity is the “… manifestation of interconnected physiological processes within an individual in his or her socio-cultural environment” (italicisation theirs). Sturmberg et al justify their thesis by reminding the reader that networks include genomic, metabolomic, proteomic, neuroendocrine, immune, and mitochondrial bioenergetic elements, as well as “social, environmental, and health care networks.” Stress systems—and other physiological mechanisms—create, they contend, feedback loops that “integrate and regulate internal networks within the individual.”1 The authors differentiate between those stresses that are easily distinguished as “minor,” in contradistinction to those more accurately described as “major.” Both of these, the authors assert, exhibit the potential to disturb internal and social networks, with each retaining the capacity to affect both internal and social networks and to precipitate a physiological instability that can at once range from improved resilience on the one hand to unhealthy adaptation and frank clinical disease on the other. So far, so good. But what other considerations are necessary? Sturmberg and his colleagues1 are clear that multimorbidity has to be understood as a “complex adaptive systems response” to bio-behavioural and socio-environmental networks. The authors argue that the design of integrative care delivery, an approach which is increasingly understood as vital in understanding underlying disease processes, in terms of their manifestation of a state of physiological dysregulation, is essential. This is, for Sturmberg et al, an essential “starting point” for shaping a care delivery approach that “more adequately addresses the underlying disease processes as the manifestation of a state of physiological dysregulation.”1 The authors assert that such a framework can “shape care delivery processes to meet the individual's care needs in the context of his or her underlying illness experience.” In this context, Sturmberg and associates1 are clear that “the future of multimorbidity management might become much more discerning by combining the balancing of physiological dysregulation with targeted personalized biotechnology interventions such as small molecule therapeutics targetting specific cellular components of the stress response, with community-embedded interventions that involve addressing psycho-social-cultural impediments that would aim to strengthen personal/social resilience and enhance social capital.”1 The authors' arguments are stimulating and warrant careful consideration. Accordingly, the Journal invited a range of distinguished colleagues to comment on Sturmberg et al's overall thesis and we publish the resulting analyses, sequentially, within the current Forum. We provide below a brief review of the core arguments of the individual articles in advance of considering the nature of their contribution to the development of person-centered health care approaches to the management of chronic multimorbid illness. In the first of the commentaries, Walker and Peterson2 note the existence of a great tradition of studying health and illness from a systems perspective, understanding that for clinicians, and people with illnesses, a great deal can be learned through the process of mapping the interface of different sectors to understand the nature of conditions. The authors present a sociological approach to the understanding of multimorbidity, in order to gain a fuller insight into the experience of illness of people living with multiple coexisting conditions within the “greater social system of health and illness.” They appeal to Parsons' notion of the “sick role,” so as to present a systems concept through which a proper understanding of the role of physicians can be assimilated, alongside an understanding of illness as a social phenomenon that extends beyond the purely personal. Walker and Peterson2 also utilize the concept of habitas and that of structure and indeed agency, here ensuring that the reader gains a real sense of morbidities as being in their nature social and economic phenomena and being of themselves a broader means of understanding current social systems. The commentators posit that one particular option for patient coping with multiple conditions is to change identity and they proceed to describe their meaning. We agree that the physician and patient encounter in dealing with the multimorbid condition is problematic, because, as they point out, it “forces attention on competence and responsibility in that continuing encounter.” Indeed, much work remains to be done on how the therapeutic encounter can be developed with reference to such mutual responsibility. The value of Walker and Peterson's contribution2 is, perhaps, the way in which the commentators apply the sociological approach to suggest an augmentation of what they view as a clinical microsystems approach taken by Sturmberg et al,1 and we look forward to further debate on how such “sociological supplementation” can enhance the development of more person-centered approaches to multimorbidity management that extend beyond the clinic itself. Following Walker and Peterson's paper,2 we come to the contribution by James Marcum.3 In his paper “Multimorbidity, P4 medicine and holism,” Marcum is concerned to examine Sturmberg et al's concept and understanding of holism as part of the authors' efforts to determine the causative factors for multimorbidity and their aim to respond clinically as a result. For Marcum,3 the authors' concept of multimorbidity, though far from reductive in any real sense, relies on an understanding of holism that sees the network's parts or subsystems as functionally independent of one another, but collectively responsible for the properties of the whole individual. In this sense, the authors' holism is general, in that it asserts that given components of the human individual are working together as an integrated unit to create and preserve homeokinetic stability. If this interpretation of Sturmberg et al's understanding is valid, which we think it is, then Marcum is correct in his description of the authors' holism as technoscientific, rather than humanistic or phenomenological, in its nature. Marcum compares and contrasts these two fundamentally differing understandings of holism, concluding that Sturmberg et al's P4 model remains distinctly biomedical in its conception. Accordingly, and with reference to the clinical case example given, Marcum3 asks “But does privileging the predictive and preventive aspects based on these [pathological] mechanisms provide the best possible care for this patient?” Marcum's view is that Sturmberg et al1 have stopped short of providing a definitive “yes” or “no” to this question and, despite the authors' own reference to person-centered care, Marcum feels, as do we, that Sturmberg et al1 have not convincingly demonstrated how they would integrate both internal and external factors relating to, and deriving from, the multimorbid state to achieve a properly holistic model for trial. The third commentary on Sturmberg et al1 in the current Forum has been contributed by Melis and his coworkers.4 For these colleagues, an understanding of multimorbidity as “the sum of individual diseases” risks ignoring the impact of their co-occurrence in the same individual. Melis and associates note that Sturmberg et al1 criticise the definition of multimorbidity as the co-occurrence of two or more diseases in the same person, but the commentators do not see this as the principal problematic in its use. Indeed, for them, a simple counting of the number of different diseases is not very informative, given its inability to provide sufficient clues regarding cause, prognosis, and consequences or the prediction of effect of clinical intervention. They conclude, then, that to move towards a properly person-centered care, there is a need to move beyond such counting and a need to widen the view of multimorbidity as a complex systems phenomenon even further, so that a more comprehensive understanding of multimorbidity for integrated care development and delivery can be achieved. For Melis and colleagues,4 the occurrence of multimorbidity may be causally related to a lack of health “both at the level of the individual and the level of the health care system and the community.” As they rightly point out, current health systems are simply not designed to cope with the problem of multimorbidity and have historically been designed to focus on single, largely acute diagnoses and not the chronic sequelae of multiple co-occurring conditions. Indeed, an urgent focus on the problem and consequences of multimorbidity “ … will need to be able to exist next to a single disease focus, because the fact that there are many persons with multiple diseases does not mean that there are no longer persons with single diseases.”4 We agree. We move next to the commentary by DeHaven.5 DeHaven concurs with the overall thesis presented by Sturmberg et al1 and is clear that the need to improve our understanding of disease processes to be able to intervene more effectively in their management has never been greater, due, perhaps in no small measure, to what DeHaven5 sees as Society's overreliance on the health care system for preventing and managing chronic disease. As he points out, existing health systems are ill equipped to respond to these requirements, not least because they have traditionally been designed to focus on individual organ system dysfunction and treatment, with the overall aim of resolving existing symptoms, with little historical emphasis on genetics, lifestyle, nutrition, exercise, the environment, and socioeconomic status as interacting determinants of predisposition and disease. The current global epidemic of multimorbid illness comes, to say the very least, as a challenge to conventional systems. DeHaven5 believes that persistent chronic disease prevalence can be addressed through community health science and he proceeds to discuss his rationale of how this approach is an alternative yet complementary approach to the more familiar perspectives of biomedical researchers. For DeHaver,5 the approach he presents has the advantage that it conducts research in the “real-world” setting where comorbidity and multimorbidity have become extremely common and where patients with multiple medical conditions are ineligible for entry into “conventional” clinical research trials. The ongoing focus of medical systems and research methodologies in the West continue, as DeHaver5 says, to be conceptualised with a reductionist philosophy and approach, which sees only the parts and not the whole. Yet all the evidence points to the fact that unless we urgently address the multiple causal factors of the multimorbid state, and develop the clinical methods with which to address them, we can reliably predict that the current problems we are experiencing will exacerbate and continue to spiral upwards in their severity. In the fifth commentary within the current Forum, we come to the contribution by Bircher and Hahn.6 For these commentators, it is certainly broadly justified to examine the problem of multimorbidity in the manner described by Sturmberg et al.1 However, the commentators find one question so far unanswered. Is it needed and possible, they ask, “to develop the whole diagnostic picture from molecular genetics to the person and [his/her] surroundings in each case?” In their paper, Bircher and Hahn6 explore the possibility of analysing patients in a more focussed manner through posing the questions “Is it possible to do the best for the patients, when applying a recently described model of health and disease, the Meikirch model? Can it identify the factors that are predominant in rendering a patient diseased, and can it help the patient to evolve further and to emerge into a better state of health?”6 Bircher and Hahn6 proceed to describe the Meikirch model to explain its applicability to the understanding and management of multimorbidity and to compare it with the network model advanced by Sturmberg et al.1 The Meikirch model consists of 5 components and 10 interactions, some or all of which may need to be explored in the context of the patient with multimorbid illness so that the overall process can generate a single, though inevitably complex, assessment of the condition of the given individual patient. Following this procedure, questions can be asked about what has happened, and what can be done, so that a range of options (by no means all of which will be strictly “medical”) become available for discussion with the patient and from which a selection can be made on the basis of priorities for early action. As Bircher and Hahn6 observe, the nature of the model is that it looks at health and the lack of it in the broadest sense and as part of a strong patient-physician relationship/partnership. As the commentators say, this renders a strictly nosological approach less discerning, though the viability of the model in practice will need to be tested through rigorous empirical and mixed methods research. For sure, the Meikirch model as described, possesses, we feel, the potential to help make greater clinical sense of the vision advanced by Sturmberg et al1 and thus to form the basis of a strongly person-centered model of care, an assertion to which we will return later before concluding. In the sixth commentary, David Aron examines Sturmberg and associates'1 thesis from the viewpoint of a clinical endocrinologist. Aron7 structures his analysis into four areas of comment and observation. Firstly, he is concerned to consider current conceptualizations of multimorbidity, moving subsequently to a review of the importance of networks to underlying human health and disease. From there, he proceeds to evaluate the evidence that supports the importance of network disruption in the underlying causal scheme of things, concluding with a discussion of what is “it” that “gets” diabetes. For Aron,7 the original conceptualizations of multimorbidity, which focussed on a simple enumeration of co-occurring diseases and the identification of their causal relationships, represented nothing more than a “unilevel approach to multimorbidity” that, with time (and following from appropriate attention being given to the effects of the interactions of multiple pathologies and the impact that these exert on the overall health, functioning, and quality of life of the patient, in addition to their effects on clinicians and health care systems themselves), has resulted in the development of a wide variety of measures of multimorbidity. This progress has enabled the addition of a vertical dimension, the value of which has been seen in its illustration that “for a given condition, there … (are) … issues at the cellular, organismal and community levels, to name just a few.”7 Aron proceeds to detail and discuss precisely what these “issues” are and how their insightful investigation has the potential to move the study of multimorbidity forward with speed. In concluding, and to remind readers of the importance of context and the risks of a narrow focus in clinical research and practice, Aron7 details a key extract from Francis Peabody's seminal paper, “The Care of the Patient,” published in the Journal of the American Medical Association in 1927,8, 9 following which Aron7 stresses to the reader that “While we hold onto our magnifying glasses, we should not forget to reach for the ‘minifying’ lens which allows one to see a more whole picture.” We agree wholeheartedly. In the seventh commentary, Rohleder10 commends Sturmberg et al1 for providing a new perspective on how central nervous system processes link a range of physiological networks to assist a more developed understanding of the mechanisms of human adaptation to both internal and external demands. Rohleder10 considers how the clinical case example considered by Sturmberg et al1 vividly illustrates the network of interconnected systems that is the subject of study by the authors. For Rohleder,10 it demonstrates, with excellence, the existence of a “network of networks,” providing insight into the aetiology of multimorbidity and thus a basis for modern clinical practices going forward. As he says, Sturmberg et al's1 assertions do indeed represent, collectively, “a powerful reminder that systems in the body are not acting in isolation but are interconnected and affect each other, directly and through the central nervous system, and that understanding these interactions of interconnected networks can explain currently not well understood issues of modern health care.”10 Rohleder reminds the reader that the extraordinary advances in biomedicine and health technology over the last 100 years or so have transformed the ability of medicine to deal with a range of issues and conditions that could simply not be easily dealt with in the past, and we believe that he is right to warn of the (increasing) dangers of superspecialization and to note, wisely, that superspecialization is likely to generate more problems than it will solve. Interestingly, Rohleder10 discusses how the multimorbidity framework presented by Sturmberg et al1 has additional value in providing a more holistic understanding of stress and its effects on the person, and he proceeds to detail in what way the framework contributes to an advanced understanding in this context, specifically how it augments the established allostatic load theory and provides a solid basis for newer modes of clinical research and biobehavioural understanding. The paper by Henry Heng,11 which closes this current Complexity Forum of the JECP, does not comment on Sturmberg et al's1 article in the manner of the seven such articles we have considered above, but surely represents an important contribution to taking forward the arguments within Sturmberg et al's1 article, which Heng considers shortly before concluding. Heng notes that the current era, which has seen the appearance of “big data-driven omics,” has proven a “double-edged sword” for molecular medicine. For sure, the initial optimism has, as he recognises, led to disappointment and confusion, as a function of inherent biological heterogeneity. Nevertheless, the recognition that diseases occur within the context of complex adaptive systems and the factor of cellular evolution, have been important outcomes of research to date and, as theories and models, combat the overenthusiasm for so-called precision medicine.11 For Heng,11 to reconcile the conflicts between the ambition for genetic precision and the correlative relationship between genotype and phenotype, a return to “basics” is required and he poses, in this context, five questions. What, he asks, is the common genetic and environmental basis of diseases? Can we cure the majority of non-Mendelian diseases on the basis of the precision of genetic information? What is the key limitation of current big data approaches to genomic medicine? What is the best way to integrate cellular evolution principles/management of common and complex diseases? Knowing that diseases (occur within) multilevel complex adaptive systems, should future strategies of medicine continue to focus on gene mutation and pathway-based molecular cures? Heng11 is clear that a new framework is necessary to explicate how genetic information is transferred during cellular evolution and how gene/genome/environmental interactions lead to diseases, and he proceeds to provide for the reader a detailed and important discourse, preceded by and organised under 5 specific foci of contention and discussion: (1) Genetic alteration is not just caused by genetic error, (2) Stress is both good and bad and can be linked to diverse molecular mechanisms, (3) Cellular evolution is hard to predict (especially during a long process or when under high-stress conditions that alter the genome), (4) Real-life complexity devalues the beauty of hopeful molecular simplicity, and (5) The common linkage among common diseases. As Heng11 says, many issues need to be discussed in the context of adaptive systems and, for us, the paper by Sturmberg and associates1 is a signal stimulus for such conversations. Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease. It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has. How can we communicate the wisdom that these two Oslerian quotations vividly illustrate to a modern medicine overwhelmingly fixated with scientific progress in biomedicine and technology at the expense of the context of such progress—the person of the patient? How can we return to modern medicine and health care a preferential fixation with the destination of all biomedical and technological advance—the patient as a person who suffers? We will consider such questions here, within the confines of available space, with direct reference to the paper we publish by Sturmberg et al,1 a paper which has, as its primary focus, the “mechanics” of the origins and trajectory of the multimorbid state, but one which also expresses some high ideals that are urgently in need of translation into current clinical practice. Ziegelstein,12 writing in the Journal of the American Medical Association, reflects on the “almost unimaginable” possibilities for patient care that have the potential to be realized through advances in genomics, proteomics, pharmacogenomics, metabolomics, and epigenomics. He is clear, however, that an important element of discussion has been omitted from the ongoing discourse—that individuals are distinguished not only by their inherent biological variability, but also by their response to different disease manifestations. As Ziegelstein12 emphasises, individual people have individual personalities and varying resiliences/resources, which mediate, in significant measure, how they will respond and adapt to stress and illness and how they will respond to treatments, “so that the same disease can alter one individual's personal and family life completely and not affect that of another person much at all,” not forgetting, he points out, that “diseases do not just affect individuals; they affect their families and friends, and their communities.”12 Ziegelstein's12 assertions “dovetail” well, and not just tangentially, with the thesis of Sturmberg et al,1 in reminding the reader of the complex biological and “suprabiological” nature of the human individual and the inherent heterogeneity of the human “organism,” factors that are inescapable in any serious discussion of how we move scientific investigations of multimorbidity and its humanistic person-centered management, respectively, forward. What strikes us particularly in Ziegelstein's article is his conceptualization of the personome. He argues that the personome merits an entirely equal consideration as the genome, proteome, pharmacogenome, metabolome, and epigenome in their impact on the health, disease, well-being, and flourishing of the human person. Here, Ziegelstein12 is clear that the tools of precision medicine, while they have provided for us a much greater understanding of the cellular and molecular determinants of individual uniqueness, have nevertheless generated a set of specific challenges for physicians in training who find it increasingly difficult to get to know their patients as persons. For sure, junior clinicians (often with their seniors), now spend more time gazing into computer screens, replete with laboratory and imaging data, than looking into the depths of the suffering of the patient sitting in front of them—an incontrovertible prerequisite to considering how such suffering can be most humanly and therefore most comprehensively responded to. As Ziegelstein12 notes, the current medical curriculum entirely fails to militate against such an observation, so that it is easy to witness a failure within it to integrate, with the biological sciences, the psychological, social, cultural, behavioural, and economic factors that influence human health and disease. As a direct consequence, students easily gain the distinct impression that the psychosocial and societal issues encountered in clinical practice are somehow less important to patient care than the basic sciences. This is a matter of no small gravity and has direct implications for the ethics and professionalism of medicine and health care. Indeed, if such “modern understandings” are allowed to embed even further, they may prove extremely difficult, if not impossible, to de-inculcate from the collective clinical consciousness of the generation of clinicians that are to come, with all the implications this would have for patients. Sturmberg and colleagues1 appear primarily concerned to examine the biological basis of multimorbidity, drawing from James Marcum a description of their approach as one which is essentially technoscientific, rather than humanistic or phenomenological in its nature.3 We agree, though highlight what Sturmberg et al1 explicitly acknowledge as the way forward—an urgent need for clinicians “to partner with their patients to identify person-centred care that optimizes highly complex and sometimes conflicting information from multiple knowledge sources.” Indeed, there is no small urgency in creating the understanding within modern technoscientific medicine of the necessity for a shift away from scientistic reductionism towards a properly person-centric model through which the patient who suffers can be most appropriately assisted. Sturmberg et al1 are in agreement with such a contention and are clear that “optimal health outcomes – at the subjective and objective levels – are most likely to be achieved if biomedical and psychosocial interventions go hand in hand.” Indeed, the authors rightly argue that clinicians should seek to develop “person-centred holistic strategies aimed at restoring and maintaining physiological network homeokinesis,” so that a newer understanding of multimorbidity and the framework which can result from it, “can shape care delivery approaches to meet the individual's care needs in the context of his or her underlying illness experience” (italicisation theirs).1 These high ideals were the basis, in 2014, of the creation of the European Society for Person Centered Healthcare (ESPCH) and its official journal the European Journal for Person Centered Healthcare (EJPCH). The ESPCH is an international membership organisation which advocates a shift towards humanistic health care and which is currently engaged in the development of practical clinical models for the person-centered health care of a wide range of specific clinical conditions. The development of such models, which by their nature take full account of comorbidity and multimorbidity, is being accompanied by the production of associated clinical guidelines to assist clinicians and health care policymakers in ensuring that the ideal of person-centered health care becomes an operational reality. Additionally, and apart from its major conferences and symposia, the ESPCH has embarked on the organisation and delivery of specific training programmes and masterclasses, which are specifically designed to upskill clinicians in the use of condition-specific guidance and who, following such training, are then able to return to their institutions as teachers, mentors, and leaders. Through such work, which is usefully informed by important studies of multimorbidity such as those being undertaken by Sturmberg et al,1 the ESPCH has already been able to achieve demonstrable changes within the medical and health care culture, in the thinking of politicians and policymakers and in advising the health care industry in how best to make its own contribution to patient-centricity.13-20 As the ESPCH continues to grow rapidly, so does its expertise and the Society welcome enquiries from all colleagues with an interest in or responsibility for the development of person-centered health care. Further information may be obtained by writing to Professor Andrew Miles, Senior Vice President and Secretary General of the ESPCH, at the email address detailed below. In this overarching Editorial Overview to the latest Complexity Forum of the Journal of Evaluation in Clinical Practice, we provide for the reader a rapid overview of the constituent papers of the forum and an insight into how the ideals articulated by Sturmberg and his commentators are currently being translated into operational clinical practice and health care systems. The dramatic rise in long-term comorbid and multimorbid illness is the defining challenge of our current age. Not only does multimorbidity exert a major impact on human health and flourishing, accounting for approximately 70% of global mortality, but it retains the potential to bankrupt health care systems worldwide. The classic clinical strategy of “diagnose, treat, cure, and discharge” cannot apply to the multimorbid state, and different approaches have become urgently necessary as a result. The development of practical clinical models for the person-centered care of patients suffering from the effects of multimorbidity holds great promise for a far more sensitive and clinically effective approach to the management of multiple coexisting and interacting pathologies, and we commend Sturmberg and his associates for their visionary, energetic, and ongoing contribution to this field. We acknowledge the efforts of Dr Joachim Sturmberg and Dr Carmel Martin in their long-standing service and commitment as Co-chairmen of the Complexity Forum of the Journal of Evaluation in Clinical Practice and as Co-chairmen of the Special Interest Group on Complexity and Health of the European Society for Person Centered Healthcare. The authors declare no conflict of interest.