Herodotus and the multidisciplinary clinic

presentation,leading to exposure of mature lymphocytes to self-antigens or epitopes (the antigenic determinants within an antigen) that were not available for presentation to the lymphocytes during their development. In the second situation, autoantibodies may be produced after exposure to a foreign organism that mimics the region of the antigen (epitope) recognised by B cells. If the foreign antigen can also stimulate helper T cells, then these helper T lymphocytes specific for the foreign antigen can provide help for B cells specific for a self-epitope, resulting in the production of autoantibodies. This latter mechanism may explain the production of human autoantibodies to the neutrophil antimicrobial peptide, defensin, as a result of infection with 0 volvulus.’ This parasite, which is transmitted by a black fly, infects millions of people in Africa and Central and South America, causing skin and ocular lesions ("river blindness"). All patients with one form of this disease, sowda, characterised by severe dermatitis with granulomas, vasculitis, and eosinophilia, have antibodies to defensin, compared with 16-52% of individuals with exposure or with other forms of the disease.’ Whether these antibodies are directly responsible for the disease manifestations is unclear, but antibodies to other neutrophil proteins may contribute to the pathogenesis of the closely related group of ANCA (anti-neutrophil cytoplasmic antibodies) diseases,8 by blocking the function of the antimicrobial peptides and thereby promoting an accumulation of inflammatory cells. In sowda, defensin is closely associated with the surface of the parasite; this observation suggests that macromolecular complexes may have formed between defensin and parasite antigens. If so, helper T cells specific for parasite antigen may provide help for B cells specific for defensin. Much seems to depend on the stability of such complexes since T and B cell epitopes must be taken up by the same B cell in order for it to receive specific T-cell help and so produce antibody. 0 volvulus had already delivered some insights into disease mechanisms in autoimmunity. Mimicry by an antigen of the worm of an antigen from retinal pigment epithelium may, via a similar mechanism, lead to immunological cross-reactivity and a pathogenic response in the eye contributing to the blindness associated with this infection.9 In this case, the inciting antigen is a parasite-encoded antigen, which is unlikely for the sowda

example. 17ULIr-IlLN

mu SVWUi;t mavc a

llt::IgllLt::l1t::U IllllllUlluIuglLal

responsiveness to parasiteantigens andcorrespondingly

responsiveness parasite antigens and correspondingly have very few microfilarial parasites in their skin. By contrast, endemic controls (immune individuals) have good cell-mediated immune responses but no detectable parasites, and individuals with the generalised form of onchocerciasis have many parasites but immunological hyporesponsiveness. While the pathology of the sowda form of the disease is associated with immunological hyperresponsiveness, the factors dictating this outcome are unknown. In various systems, high antigen dose is associated with low cell-mediated immunity and low antigen dose with a heightened cell-mediated immunity. For example, high-dose but not low-dose lymphocytic choriomeningitis virus infection of mice can exhaust or tolerise the specific T-cell response," and we have made similar observations with malaria in a rodent model two

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(unpublished). In all these diseases, the T-cell response is associated with abnormalities and a high antigen dose could have the potential to stimulate T cells excessively to the detriment of the host. However, T-cell cytokines" and nitric oxidel2 are capable of self-regulating the T-cell response, and the anergy or immunological hyporesponsiveness associated with excessive antigen may reflect self-regulation as a result of these or other factors. Such self-regulation also occurs in onchocerciasis, but in individuals with sowda, the heightened immune response can almost, but not quite, eliminate the infection. Gallin and colleagues’ may have identified an important factor contributing to this immunological lesion. Perhaps the development of anti-defensin antibodies as a result of tolerance-breaking parasite-defensin complexes impedes the effector arm of the immune response enough to allow the maintenance of low numbers of parasites, a consequent heightened immune response, and ensuing disease.

Michael F Good Queensland Institute of Medical Research, Brisbane, Australia

2

Gallin MY, Jacobi AB, Buttner DW, Schonberger O, Marti T, Erttmann KD. Human autoantibody to defensin: disease association with hyperreactive onchocerciasis (sowda). J Exp Med 1995; 182: 41-47. Oldstone MBA. Molecular mimicry and autoimmune disease. Cell

3

Pruksakon S, Currie B, Brandt E,

1

1987; 50: 819-20. et

al. Identification of T-cell

autoepitopes that cross-react with the carboxylterminal segment of the M protein of group A streptococci. Int Immunol 1994; 6: 1235-44. 4 Bronze MS, Beachey EH, Dale JB. Protective and heart-crossreactive epitopes located within the NH2 terminus of type 19 streptococcal M protein. J Exp Med 1988; 167: 1849-59. 5 Nossal GJV. Cellular mechanisms of immunologic tolerance. 6

7

Annu Rev Immunol 1983; 1: 33-62. Pombo D, Maloy WL, Berzofsky JA, Good MF. Neonatal exposure to immunogenic peptides: differential susceptibility to tolerance induction of helper T cells and B cells reactive to malaria circumsporozoite peptide epitopes. J Immunol 1988; 140: 3594-98. Lanzavecchia A. How can cryptic epitopes trigger autoimmunity?

J Exp Med 1995; 181: 1945-48. Gross WL, Schmitt WH, Csernok E. ANCA and associated diseases: and pathogenetic aspects. Clin Exp Immunol 1993; 91: 1-12. 9 Braun G, McKechnie NM, Connor V, et al. Immunological crossreactivity between a cloned antigen of Onchocerca volvulus and a component of the retinal pigment epithelium. J Exp Med 1991; 174; 169-77. 10 Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993; 362: 758-61. 11 Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994; 12: 635-73. 12 Taylor-Robinson AW, Liew FY, Severn A, et al. Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur J Immunol 1994; 24: 980-84. 8

immunodiagnostic

Herodotus and the

multidisciplinary clinic

scientific analysis, decisiveness, and compassion are the supposed hallmarks of the modem physician. Yet the image may be at odds with the facts when it comes to providing care for patients with complex medical problems. We know a lot, to be sure, much of it derived from clinical trials. But information learnt from groups, whatever the statistical certainty, is not always readily translated to the individual. For example, the randomised trial experience of 120 000 women with breast cancer does not make for particularly straightforward recommendations for the 50-year-old patient with four positive nodes and lupus nephritis, or Clear-minded

for the 42-year-old woman with a chest-wall recurrence. Statistics do not respect the individual. Second, there are many ways to treat, the benefits being perceived differently by each specialty. Where the evidence is clear, there may be agreement. However, in the large grey area there is dissension among the professionals and irreconcilable cognitive dissonance for the patient. In truth, compassion is often lacking in the traditional model of medical care. How could it be otherwise when the patient is progressively fragmented while coursing from one specialist to another? Working separately, specialists do not understand the subtleties of their clinical interface. Consultation is a potential passing of care, not a collaboration. In the children’s game where the ball is passed round the circle until the music stops, the person with the ball is the loser; the loser in the consultation process is the patient. Considerations such as these lead to the concept of the multidisciplinary clinic, wherein "what would you do, doctor?" becomes "what would we do, professionals?". We define the multidisciplinary clinic as one where all the requisite specialists (medical, nursing, psychosocial,. and spiritual) are assembled and available to review individual patients to formulate a comprehensive plan. For specific illnesses where management is complex and the mix of professional skills required shifts over time, this approach makes good sense. The less predictable the pattern of care, the more benefit to the patient from such a clinic. Patients would know that their care is provided by a team led by a strong unbiased leader, and that at any given appointment, irrespective of the team member reviewing their case, management is coordinated-one stop shopping. This concept can be unsettling, especially for professionals reared in the tradition of the doctor as solo case-manager. Is time going to be wasted? Do we all have to stand around and lay hands on each patient? Perhaps at the beginning, until the team comes together. Over time, individuals will manage patients on behalf of the group. They will become increasingly cognisant of and comfortable with the specialty and disciplinary interface are numerous but areas where therapeutic options experience less specific. These interface areas offer fertile ground for clinical research because the multidisciplinary setting exposes them better. For example, research into neo-adjuvant chemotherapy for breast cancer has been hampered because patients generally undergo surgery before they meet the rest of the professionals who will subsequently provide their care. Since breast cancer is now recognised as a systemic disease from the outset, it seems curious that entry to the system continues to be through the portal of local treatment. How might one bring about the change in clinical practice? The first step is also the last. It is a question of attitude-the notion of team management and mutual rather than the soloist. respect sequential clinics as a forum for Multidisciplinary teaching set the stage for the next generation. The odds are that the aggregation of resources, convenience, and patient support will also change attitudes of the current

generation. In practical terms, a cohort of professionals to be identified, and must come together to define the

has

logistics

of the clinic and

to

establish basic

treatment

guidelines.

naturally team workers and catalysts. Particularly at the but as a hallmark of the ongoing beginning, throughout process, grey-area cases must be seen jointly and results reviewed. Such a clinic requires a flexible physical Nurses,

coordinators,

can

be the

accommodate both the technical requirements (ie, biopsy, examination, mammography in the case of breast cancer), and the facilities for professional interaction (wide hallways, conference I rooms, or consultation alcoves).‘ Any institution prepared to adopt the multidisciplinary approach must understand that the process is information driven and will probably be inefficient at the beginning. The necessary investment in data handling infrastructure and learning time for the professionals may be considerable. Once learned, the end result is efficiency (fewer patient visits over the trajectory of an illness), patient satisfaction, and a culture of comprehensive management, inquiry, and progress. Among all the changes in medicine, perhaps the most important ultimately will be those affecting the role of the physician. For the patient there has always been comfort in the relationship with a single doctor. Yet today, for complex problems, the knowledge base and treatment mix are too broad and labile for one person to encompass. The multidisciplinary clinic provides a model wherein if structure

one can.

that

can

person cannot encompass all, one integrated team Our response since Herodotus [c 484-425 BC]

described the situation in Egypt has been to "practise among [us] a plan of separation; each physician treats a single disorder, and no more: thus the country swarms with medical practitioners".-’ Yet the patient remains, to this day, unique and undivided.

Harvey Schipper, Jan Dick University of Manitoba, Winnipeg, Canada 1 2

Durant JR. How to organize a multidisciplinary clinic for the management of breast cancer. Surg Clin N Am 1990; 70: 977-83. Herodotus, the history, the second book (Euterpe) para 84. In: Hutchins RM, Adler MJ, eds. Great books of the western world. Chicago: Encyclopaedia Britannica, 1952; 6: 65.

Does atrial fibrillation confer hypercoagulable state?

a

Both clinical’ and echocardiographic criteria2 are independent predictors of a high risk of stroke and thromboembolism in atrial fibrillation (AF). In terms of Virchow’s triad, clinical and echocardiographic criteria may help to identify the first two postulates for thrombogenesis-abnormalities of blood flow and vessels, as in valvular heart disease and cardiac impairment-but might AF itself alter the third component-blood constituents? If AF affected clotting factors and haemostatic

variables,

hypercoagulable

or

the

outcome

prothrombotic

could

be

a

state.

There was renewed interest in the haemostatic abnormalities in AF at the August meeting of European Society of Cardiology in Amsterdam, where Heppel et aP reported that patients with AF who had left atrial echocontrast on spontaneous transoesophageal had concentrations of various echocardiography higher markers of haemostasis. Spontaneous echocontrast formation seems to reflect blood stasis within the atria of patients with AF/,5 and its presence has been associated with thromboembolism.6

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