Lviv clinical bulletin 2015, 4(12): 56-64

https://doi.org/10.25040/lkv2015.04.056

Comorbidity: a Modern View on the Problem; Classification (first notice)

O. Abrahamovych, O. Fayura, U. Abrahamovych

Danylo Halytsky Lviv National Medical University

Introduction. Researches of the famous scientists proved, that comorbid diseases often worsen the course of the underlying disease and/or lead to its chronicity, cause disability and premature death of the working population, often make inefficient diagnosis and treatment, increase the costs of the health system to provide medical care. According to the research of WHO experts, people under 40 usually have 2-4 diseases, under 60 – there is a “bouquet” of 5-7 diseases, after 70 – 8-10 or more diseases. So-called “polymorbidity” increases from 10.0 % in patients aged <19 years old to 80.0 % in patients aged >80 years old.

Materials and research methods. The work analyzes the literature sources, which deal with the study of comorbid diseases and sufficiently thoroughly reflect the current views of the scientists on the issue.

Results of the investigation and their discussion. There are many synonyms of the term “comorbidity”, among them, often are used the following: “polymorbity”, “multimorbidity”, “multifactorial diseases”, “polypathy”, “multicausal diagnosis”, “dual diagnosis”, “pluripathology” etc., which complicates the understanding of the problem and minimizes the ability to use scientific achievements in clinical practice. In Ukrainian literature the authors often use the term “bicausal diagnosis” to describe comorbidity when there are two underlying diseases, to describe polymorbidity – “multicausal diagnosis” (three or more pathological conditions in one individual). In English scientific literature the authors often use the terms “comorbid diseases”, “comorbid conditions”. In general, the sources of information, used by the researchers to study the problem of polypathies, were and are medical histories, hospital records of the patients and other medical records of family doctors, of insurance companies, archives of the pensions for the elderly. Comorbidity itself can be interpreted as a random combination of the diseases, different by its’ etiology and pathogenesis such as nosological syntropy, ie natural occurrence of the regular determined diseases combinations in one patient. The main causes of comorbidity are: affected organs anatomical proximity, common pathogenesis, causal connections, combination of the diseases or iatrogenic causes. Among the factors, that influence the occurrence of comorbidity in humans, is a chronic infection, inflammation, involutive and systemic metabolic changes, iatrogenic factors, social status, environment and genetic predisposition, and the main way of the development of comorbid disorders is causal. The appearing of a particular disease leads to functional first, and later – to organic lesions and further – to an increase of nosologies quantity. Despite the large number of studies, proposed definitions and synonyms, standardized terminology and conventional classification of comorbidity, that would greatly help in the study of its problems, until now is missing.

Conclusions. Despite many unsolved patterns of comorbidity and lack of the unified terminology, the search for the new variants of combinations of these diseases continues. After all, they can simply be not yet classified syndromal diseases, or vice versa – to be completely incompatible for the appearance and coexistence in one body. This is the key to solve more and more problems for the diagnosis and treatment of the diseases in the field of the practical medicine.

References

1.Artemchuk AF, Sosin IK, Chernobrovkina TV. Ecological Bases of the Addictive Diseases Comorbidity. Kharkiv: Collegium, 2013. 1152 p. (Ukrainian).

2.Belousov YV. Comorbidity in Case of the Gastro-intestinal System Diseases. Health of the Child. 2012;1:134-136. (Ukrainian).

3.Belousov YV. Pediatric Gastroenterology. Clinical lectures. Kharkiv: Fact, 2007. 376 p. (Ukrainian).

4.Belyalov FI. The problem of Сomorbidity in Internal Diseases. Bulletin of the Modern Clinical Medicine. 2010;3(2 Issue):44–47. (Russian).

5.Belyalov FI. Treatment of the Internal Diseases in Case of Comorbidity. Irkutsk: RIOIGMAPO, 2012. 283 p. (Russian).

6.Vertkyn AL, Hovasova NO, Lytvyn TH. Metabolism Correctors – an Important Addition in the Prophylaxis of Post-operative Non-surgical Complications in Patients of General and Vessels’ Surgery Departments. Consilium Medicum. 2011;2:90-98. (Russian).

7.Vertkyn AL, Zayratyanz OV, Zayratyanz YO, Vovk I. Final Diagnosis. Мoskow: HEOTAR-Media, 2008. 576 p. (p. 503). (Russian).

8.Vertkyn AL, Skotnykov AS. The Role of Chronic Inflammation in the Pathogenesis of Allergic Asthma and Rational Pharmacotherapy in Patients with Polypathy. Therapist: Journal of the Practitioner. 2009;4:61-66. (Russian).

9.Hnateyko OZ, Lukyanenko NS. Ecogenetic Aspects of Human Pathology Caused by Exposure to Harmful Environmental Factors. Health of the Child. 2007;6:15-24. (Ukrainian).

10.Humenyuk AF. The Aspects of the Rational Treatment of Cardiological Patients with Polymorbid Disorders. Ukrainian Medical Journal. 2009;5:25–32. (Ukrainian).

11.Dranhoy MH. Age-related Diseases. Мoskow: Eksmo, 2007. 738 p. (Russian).

12.Zhyuhdzha AI, Staponkane MA, Pyatkivichene RI. Frequency and Features of the Ulcer Disease in the Patients with Bronchial Asthma and Chronic Bronchitis. Act. Questions of Gastroenterology: materials of the 1st Bel. rep. conf. on gastroent. – Minsk, 1973. p. 46–49. (Belarusian).

13.Zayratyanz OV, Kakturskyy LV. Formulation and Comparing of the Clinical and Pathologoanatomical Diagnosis. Мoskow: ООО «Medical inform. agency». 2008. 424 p. (p. 15). (Russian).

14.Klymenko VA, Romanova AS. Why it is no Possible to Control Bronchial Asthma: Comorbid Conditions. Clinical Immunology. Allergology. Infectology. 2012;(Special Issue):8-10. (Ukrainian).

17.Vortkin AL, Rumyantsev MA, Skotnikov AS, Laryushkina ED, Sokolova IV, Feldman MA et al. Comorbidity. Consilium Medicum. Diseases of the Heart and of the Vessels. 2011;2:37-41. (Russian).

18.Krylov AA. On the problem of disease association. Clinical Medicine. 2000;1:56-59. (Russian).

19.Lazebnyk LB. Aging and polymorbidity. The news of the medicine and pharmacy. 2007;1:10-11. p. 205. (Ukrainian).

20.Livshyz FM, Ahmedzanov MY. The problem of the Diagnosis at Present Time. Terapevticheskij arkhiv. 1980;9:91-97. (Russian).

21.Luchihin LA. Comorbidity in ENT-practice. Vestnik otorinolaringologii. 2010;2:79-82. (Russian).

22.Mamayeva SN, Karimova AM. Hepato-renal Syndrome of the 1st and the 2nd Type: Modern State of the Problem. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2008;6:4­11. (Russian).

23.Makhov VM, Sokolova AA. Comorbidity of the Irritable Colon Syndrome and Chronic Enteritis. Clinical Observation. Russian Medical Journal. 2009;2:84-86. (Russian).

24.Nadal’-Hynard K. When One Prevent Another – Comorbidity at Thetopic of the day. New Medicine of the Millennium. 2012;6:22-24. (Ukrainian).

25.The Order of Ministry of Health of Ukraine from 12.05.1992. N 81 (13 Suppl.).

26.Nosach OV. Comorbidity and Radiation: Methodological Aspects. Characteristics of the Health State of the Persons Who were Injured by the Factors of Chornobyl’ Accident. Problems of Radiation Medicine and Radiobiology. 2013;18:240-252. (Ukrainian).

27.Nuller YL. Review of the Psychiatry and Medical Psychology. Мoskow, 1993. p. 29-37. (Russian).

28.Lazebnyk LB, Konyev YV, Drozdov VI, Yefremov LI. Polypharmacy: Geriatric Aspect of the Problem. Consilium Medicum. 2007;9:29-34. (Russian).

29.Prophylaxis of the Non-infectious Diseases and the Struggle with Them: Realization of the Global Strategy. 61st World Health Assembly. 2008. Available from: apps.who.int/gb/ebwha/pdf_files/A61/ A61_8_ru.pdf. (Russian).

30.Puzyrev VP. Genetic Basis of Comorbidity in Humans. Russian Journal of Genetics. 2015;51(4):491-502. (Russian).

31.Puzyrev VP. Genetic View at the Phenomenon of the Associated Pathology of a Human. Medical Genetics. 2008;9:3-9). (Russian).

32.Rykov VA. Textbook of the Pathologist. 2004. 246 p. (Ukrainian).

33.Svyrydyuk VZ. Features of the Epidemiology, Disease Course, Diagnosis and Treatment of the Chronic Pancreatitis, Connected with the Metabolic Syndrome [dissertation]. Кyiv, 2009. (Ukrainian).

34.Smulevich AB. Glossary (depression in general medicine). Comorbidity. [Internet]. Available from: http://vocabulary.ru/dictionary/29/word/komorbidnost. (Russian).

35.Smulevich AB, Dubnitskaya EB, Tkhostov ASh et al. Psychopathology of Depressions (to the construction of the typological model). In: Depression and Comorbid Disorders. Smulevich AB, editor. Moskow: NTSPZ RAMS, 1997. p. 28-53. (Russian).

37.Chernobrovkina TV, Kershengolts BM. Synergistic Medicine: Theoretical and Applied Aspects in Addictology. Yoshkar-Ola: Fractal, 2006. 313 p. (Russian).

38.Shirinskii VS, Shirinskii IV. Comorbid Diseases – an Urgent Problem of Clinical Medicine. Siberian Medical Journal. 2014;29(1):7-11. (Russian).

39.Shirinskii IV, Kozlov VA., Shirinskii VS. Statins’ Use – a New Approach to the Therapy of the Autoimmune Diseases. Bulletin of RAMS. 2009;2:26-32. (Russian).

41.Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia MT, Martini S et al. Noradrenalin vs terlipressin in patients with hepatorenal syndromе: а prospective, randomized, unblended, pilotstudy. J Hepatol. 2007;47(4):499-505. https://doi.org/10.1016/j.jhep.2007.04.010

42.Angold A, Costello EJ, Erkanli A. Comorbidity. J Child Pscyhol Psychiatry. 1999;40(1):57-87. https://doi.org/10.1111/1469-7610.00424

43.Aragona M. About and Beyond Comorbidity: Does the Crisis of the DSM Bring on a Radical Rethinking of Descriptive Psychopathology? Philosophy, Psychiatry, Psychology. 2009;16(1):29-33. https://doi.org/10.1353/ppp.0.0214

44.Australian Institute of Health and Welfare (AIHW): Chronic diseases and associated risk factors in Australia. Canberra: ACT, 2006.

45.Berenguer M, Wright TL. Viral Hepatitis. Feldman: sleisenger & fordtran’s gastrointestinal and liver disease. 7th ed. 2002 (e-book).

46.Kerr EA, Heisler M, Krein SL, Kabeto M, Langa KM, Weir D et al. Beyond comorbidity counts: How do comorbidity type and severity influence diabetes patients’ treatment priorities and self-management? J Gen Intern Medicine. 2007;22(12):1635-1640. https://doi.org/10.1007/s11606-007-0313-2

47.Marti S, Mu-oz X, Rios J, Morell F, Ferrer J. Body weight and comorbidity predict mortality in COPD patients treated with oxygen therapy. Eur Respir J. 2006;27(4):689-696. https://doi.org/10.1183/09031936.06.00076405

48.Bonavita V, De Simone R. Towards a definition of comorbidity in the light of clinical complexity. Neurol Scien. 2008;29(1 Suppl):99-102. https://doi.org/10.1007/s10072-008-0898-1

49.Bouchard ChL. Cons. Surles maladies par ralentissement de la nutrition. Paris, 1890. 412 p.

50.Boyd CM, Fortin M. Future of multimorbidity research: How should understanding of multimorbidity inform health system design? Public Health Rev. 2010;32(2): 451-474. Available from: http://www.publichealthreviews.eu/upload/pdf_files/8/PHR_32_2_Boyd.pdf. https://doi.org/10.1007/BF03391611

51.Boyd JH, Burke JD, Gruenberg E, Holzer CE, Rae DS, George LK et al. Exclusion criteria of DSM-III: a study of co-occurrence of hierarchy-free syndromes. Arch Gen Psychiatry. 1984;41(10):983-989. https://doi.org/10.1001/archpsyc.1984.01790210065008

52.Brett T. For the International Research Community on Multimorbidity. Summary of Notre Dame multimorbidity TDB. 2011. Available from: http://pages.usherbrooke.ca/crmcspl-blog/.

53.Campbell-Scherer D. Multimorbidity: a challenge for evidence-based medicine. Evid Based Med. 2010;15(6):165-166. https://doi.org/10.1136/ebm1154

54.Caplan A. Certain unusual radiological appearances in the chest of coalminers suffering from rheumatoid arthritis. Thorax. 1953;8(1):29-37. https://doi.org/10.1136/thx.8.1.29

55.Caughey GE, Roughead EE. Multimorbidity research challenges: where to go from here? J Comorbidity. 2011;1(1):8-10. https://doi.org/10.15256/joc.2011.1.9

56.Gijsen R, Hoeymans N, Schellevis FG, Ruwaard D, Satariano WA, van den Bos GA. Causes and consequences of comorbidity: a review. J Clin Epidemiol. 2001;54(7):661-674. https://doi.org/10.1016/S0895-4356(00)00363-2

58.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. https://doi.org/10.1016/0021-9681(87)90171-8

59.Charlson ME, Sax FL. The therapeutic efficacy of critical care units from two perspectives: a traditional cohort approach vs a new case-control methodology. J Chronic Dis. 1987;40(1):31-39. https://doi.org/10.1016/0021-9681(87)90094-4

60.Sengler C, Heinzmann A, Jerkic SP, Haider A, Sommerfeld C, Niggemann B et al. Clara cell protein 16 gene polymorphism influences the degree of airway responsiveness in asthmatic children. J Allergy Clin Immunol. 2003;111(3):515-519. https://doi.org/10.1067/mai.2003.180

62.Miguel A, García-Ramón R, Pérez-Contreras J, Gómez-Roldán C, Alvari-o J, Escobedo J et al. Comorbidity and Mortality in Peritoneal Dialysis: A Comparative Study of Type 1 and 2 Diabetes versus Nondiabetic Patients. Nephron. 2002;90(3):290-296. https://doi.org/10.1159/000049065

63.Struijs JN, Baan CA, Schellevis FG, Westert GP, van den Bos GA. Comorbidity in patients with diabetes mellitus: impact on medical health care utilization. BMC Health Serv Res. 2006;6:84. https://doi.org/10.1186/1472-6963-6-84

65.Cookson W. The immunogenetics of asthma and eczema: a new focus on theepithelium. Nat Rev Immunol. 2004;4(12):978-988. https://doi.org/10.1038/nri1500

66.Cuijpers P, van Lammeren P, Duzijn B. Relation between quality of life and chronic illnesses in elderly living in residential homes: a prospective study. Int. Psychogeriatr. 1999;11(4):445-454. https://doi.org/10.1017/S1041610299006067

67.Daveluy C, Pica L, Audet N. Enquete Sociale et de Sante 1998. 2nd ed. Quebec: Institut de la statistique du Quebec. 2001.

69.Reliability and validity of a diabetes quality-of-life measure for the diabetes control and complications trial (DCCT). The DCCT Research Group. Diabetes Care. 1998;11(9):725-732.

70.De Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to measure comorbidity: a critical review of available methods. J Clin Epidemiol. 2003;56(3):221-229. https://doi.org/10.1016/S0895-4356(02)00585-1

71.Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009;7(4):357-363. https://doi.org/10.1370/afm.983

74.Ekstrom MP, Wagner P, Strom KE. Trends in Cause-Specific Mortality in Oxygen-dependent Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2011;183(8):1032-1036. https://doi.org/10.1164/rccm.201010-1704OC

75.Feinstein AR. The pre-therapeutic classification of comorbidity in chronic disease. J Chronic Dis. 1970;23(7):455-468. https://doi.org/10.1016/0021-9681(70)90054-8

76.Fuchs Z, Blumstein T, Novikov I, Walter-Ginzburg A, Lyanders M, Gindin J et al. Morbidity, comorbidity, and their association with disability among community-dwelling oldest in Israel. J Gerontol A Biol Sci Med Sci. 1998;53(6):M447-M455. https://doi.org/10.1093/gerona/53A.6.M447

77.Bellamy R, Beyers N, McAdam KP, Ruwende C, Gie R, Samaai P et al. Genetic susceptibility to tuberculosis in Africans: A genome-wide scan. Proc Natl Acad Sci USA. 2000;97(14):8005-8009. https://doi.org/10.1073/pnas.140201897

79.Zekry D, Loures Valle BH, Lardi C, Graf C, Michel JP, Gold G et al. Geriatrics index of comorbidity was the most accurate predictor of death in geriatric hospital among six comorbidity scores. J Clin Epidemiol. 2010;63(9):1036-1044. https://doi.org/10.1016/j.jclinepi.2009.11.013

80.Gill TM, Feinstein AR. A critical appraisal of the quality-of-life measurements. JAMA. 1994;272(8):619-626. https://doi.org/10.1001/jama.1994.03520080061045

81.Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabási AL. The human disease network. Proc Natl Acad Sci USA. 2007;104(21):8685-8690. https://doi.org/10.1073/pnas.0701361104

82.Goldberg D. The need for a special classification of mentaldisorders for general medical practice: towards ICD11 – Primary Care. Eur Psychiatry. 2011;26:53-56.

83.Greenfield S, Apolone G, McNeil BJ, Cleary PD. The importance of coexistent disease in the occurrence of postoperative complications and one-year recovery in patients undergoing total hip replacement: Comorbidity and outcomes after hip replacement. Med Care. 1993;31(2):141-154. https://doi.org/10.1097/00005650-199302000-00005

84.Grimby A, Svanborg A. Morbidity and health-related quality of life among ambulant elderly citizens. Aging (Milano). 1997;9:356-364.

86.Grumbach K. Chronic Illness, Comorbidit5ies, and the Need for Medical Generalism. Ann Fam Med. 2003;1(1):4-7. https://doi.org/10.1370/afm.47

87.Hurler G. Uber einen Typ multipler Abartungen, vorwiegend am Skelettsystem. Berlin: Zeitschrift fUr Kinderheilkunde, 1919;24:220-234. https://doi.org/10.1007/BF02222956

88.Jakovljević M, Crnčević Ž. Comorbidity as an Epistemological Challenge to Modern Psychiatry. Dial Phil Ment Neuro Sci. 2012;5(1):1-13.

89.Jakovljević M, Ostojić L. Comorbidity and multimorbidity in medicine today: challenges and opportunities for bringing separated branches of medicine closer to each other. Psychiatr Danub. 2013;25(Suppl 1):18-28.

90.Jensen I. Proceedings: Pathology and prognostic factors in temporal lobe epilepsy. Follow-up after temporal lobe resection. Acta Neurochir (Wien). 1975;31(3-4):261-262.

92.Kaplan MH, Feinstein AR. The importance of classifying initial comorbidity in evaluating the outcome of diabetes mellitus. J Chronic Dis. 1974;27(7-8):387-404. https://doi.org/10.1016/0021-9681(74)90017-4

93.Kholodenko BN, Bruggeman FJ, Sauro HM. Mechanistic and modular approaches to modeling and inference of cellular regulatory netwoks. Systems biology.2007;13:143-159

94.Klerman GL. Approaches to the phenomen of comorbidity. In: Maser JD, Cloninger CR, editors. Comorbidity of Mood and Anxiety Disorders, 13-37, American Psychiatric Press, Washington DC. 1990.

95.Kraemer HC. Statistical issues in assessing comorbidity. Stat Med. 1995;14(8):721-723. https://doi.org/10.1002/sim.4780140803

96.Krueger RF, Markon KE. Reinterpreting comorbidity: A model-based approach to understanding and classifying psychopathology. Ann Rev Clin Psychol. 2006;2:111-133. https://doi.org/10.1146/annurev.clinpsy.2.022305.095213

97.Linghu B, Snitkin ES, Hu Z, Xia Y, Delisi C. Genome-wide prioritization of disease genes and identification of disease-disease association from an integrated human functional linkage network. Genome Biol. 2009;10(9):R91. https://doi.org/10.1186/gb-2009-10-9-r91

98.Greenwood CM, Fujiwara TM, Boothroyd LJ, Miller MA, Frappier D, Fanning EA et al. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet. 2000;67(2):405-416. https://doi.org/10.1086/303012

101.Maser JD, Cloninger CR. Comorbidity of anxiety and mood disorders: Introduction and overview. In: Comorbidity of mood and anxiety disorders. Maser JD, Cloninger CR, editors. Washington, DC: American Psychiatric Press. 1990. p. 3-12.

102.Huntley AL, Johnson R, Purdy S, Valderas JM, Salisbury C. Measures of Multimorbidity and Morbidity Burden for Use in Primary Care and Community Settings: A Systematic Review and Guide. Ann Fam Med. 2012;10(2):134-141. https://doi.org/10.1370/afm.1363

103.Mercer SW, Gunn J, Wyke S. Improving the health of people with multimorbidity: the need for prospective cohort studies. J Comorbidity. 2011;1(1):4-7.103

104.Michelson H, Bolund C, Brandberg Y. Multiple chronic health problems are negatively associated with health related quality of life (HRQOL) irrespective of age. Qual Life Res. 2000;9(10):1093-1104. https://doi.org/10.1023/A:1016654621784

107.Ibá-ez K, Boullosa C, Tabarés-Seisdedos R, Baudot A, Valencia A. Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers defected by transcriptomic meta analyses. PLoS Genet. 2014;10(2):e1004173. https://doi.org/10.1371/journal.pgen.1004173

108.Fortin M, Lapointe L, Hudon C, Vanasse A, Ntetu AL, Maltais D. Multimorbidity and quality of life in primary care: a systematic review. Health Qual Life Outcomes. 2004;2:51. https://doi.org/10.1186/1477-7525-2-51

109.Van den Akker M, Buntinx F, Metsemakers JF, Roos S, Knottnerus JA. Multimorbidity in general practice: prevalence, incidence, and determinants of co-occurring chronic and recurrent diseases. J Clin Epidemiol. 1998;51:367-375. https://doi.org/10.1016/S0895-4356(97)00306-5

110.Fortin M, Lapointe L, Hudon C, Vanasse A. Multimorbidity in medical literature: is it commonly researched? Can Fam Physician. 2005;51:244-245.

111.Schäfer I, von Leitner EC, Schön G, Koller D, Hansen H, Kolonko T et al. Multimorbidity patterns in the elderly: A new approach of disease clustering identifies complex interrelations between chronic conditions. PLoS One. 2010;5(12):e15941. https://doi.org/10.1371/journal.pone.0015941

112.Von Hertzen L, Klaukka T, Mattila H, Haahtela T. Mycobacterium tuberculosis infection and the subsequent development of asthma and allergic conditions. J Allergy Clin Immunol. 1999;104(6):1211-1214. https://doi.org/10.1016/S0091-6749(99)70015-1

113.Nikolaev YuA, Mitrofanov IM, Pospelov TI. Comorbidity in modern internal medicine. Byull. Sib. Otd. Russ. Akad. Med. Nauk. 2014;34:44-48.

114.Bruce SG, Riediger ND, Zacharias JM, Young TK. Obesity and obesity-related comorbidities in Canadian first nation population. Prev Chronic Dis. 2011;8(1):A03.

115.Suda K, editor. Pancreas: pathological practice and research. Karger: Basel; Freiburg; Paris; London; New York; Bangalore; Bangkok; Singapore; Tokyo; Sydney, 2007. 329 p. https://doi.org/10.1159/isbn.978-3-318-01436-5

117.Pfaundler M, von Seht L. Weiteres über Syntropie kindlicher Krankheitzustände. Z Kinderheilkd. 1921;30;298-313. https://doi.org/10.1007/BF02222706

118.Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriously: Predictive markers, socioeconomic status and comorbidity. J Rheumatol. 1986;13(5):841-845.

119.Ashwood P, Nguyen DV, Hessl D, Hagerman RJ, Tassone F. Plasma cytokine profiles in Fragile X subjects: is there a role for cytokines in the pathogenesis? Brain Behav Immun. 2010;24(6):898-902. https://doi.org/10.1016/j.bbi.2010.01.008

121.Fortin M, Bravo G, Hudon C, Vanasse A, Lapointe L. Prevalence of multimorbidity among adults seen in family practice. Ann Fam Med. 2005;3(3):223-228. https://doi.org/10.1370/afm.272

122.Carvalho AK, Menezes AM, Camelier A, Rosa FW, Nascimento OA, Perez-Padilla R, Jardim JR. Prevalence of self-reported chronic diseases in individuals over the age of 40 in São Paulo, Brazil: the PLATINO study. Cad Saude Publica. 2012;28(5):905-912. https://doi.org/10.1590/S0102-311X2012000500009

123.Rzhetsky A, Wajngurt D, Park N, Zheng T. Probing genetic overlap among complex human phenotypes. Proc Natl Acad Sci USA. 2007;104(28):11694-11699. https://doi.org/10.1073/pnas.0704820104

124.Puzyrev VP, Makeeva OA, Freidin MB. Syntropy, genetics testing and personalized medicine. Person. Med. 2010;7(4):399-405. https://doi.org/10.2217/pme.10.35

125.Stier DM, Greenfield S, Lubeck DP, Dukes KA, Flanders SC, Henning JM et al. Quantifying comorbidity in a disease-specific cohort: adaptation of the total illness burden index to prostate cancer. Urology. 1999;54(3):424-429. https://doi.org/10.1016/S0090-4295(99)00203-4

127.Robins L. How recognizing comorbidities in psychopathology may lead to an improved research nosology. Clinical Psychology. Science and Practice. 1994;1:93-95. https://doi.org/10.1111/j.1468-2850.1994.tb00010.x

128.Samet S, Unes EV, Hasin D. Diagnosing comorbidity: concepts, criteria and methods. Acta Neuropsychiatr. 2004;16(1):9-18. https://doi.org/10.1111/j.1601-5215.2004.0062.x

129.Sanderson WC, Beck AT, Beck J. Syndrome comorbidity in patients with major depression or dysthymia: Prevalence and temporal relationships. Am J Psychiatry. 1990;147(8):1025-1028. https://doi.org/10.1176/ajp.147.8.1025

130.Sandford A, Weir T, Pare P. The genetics of asthma. Am J Respir Crit Care Med. 1996;153(6 Pt 1):1749-1765. https://doi.org/10.1164/ajrccm.153.6.8665031

131.Schellevis FG, van der Velden J, van de Lisdonk E, van Eijk JT, van Weel C. Comorbidity of chronic diseases in general practice. J Clin Epidemiol. 1993;46(5):469-473. https://doi.org/10.1016/0895-4356(93)90024-U

132.Shirinskii VS, Shirinskii IV. Comorbid diseases-actual challenge in clinic medicine. Sib Med Zh. 2014;29;7-11.

133.Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse association between tuberculin responses and atopic disorder. Science. 1997;275(5296):77-79. https://doi.org/10.1126/science.275.5296.77

134.Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc. 2005;2(1):8-11. https://doi.org/10.1513/pats.200404-032MS

135.Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest. 2005;127(6):1952-1959. https://doi.org/10.1378/chest.127.6.1952

136.Starfield B. Threads and Yarns: Weaving the Tapestry of Comorbidity. Ann Fam Med. 2006;4(2):101-103. https://doi.org/10.1370/afm.524

137.Starfield B, Lemke KW, Bernhardt T, Foldes SS, Forrest CB, Weiner JP. Comorbidity: Implications for the Importance of Primary Care in Case Management. Ann Fam Med. 2003;1(1):8-14. https://doi.org/10.1370/afm.1

138.Stene LC, Joner G. Atopic disorders and risk of childhood-onset type 1 diabetes in individuals. Clin Exp Allergy. 2004;34(2):201-206. https://doi.org/10.1111/j.1365-2222.2004.01864.x

139.Tabares Seisdedos R, Valderas JM. Inverse comorbidity: the power of paradox in the advancement of science. J Comorbidity. 2013;3:1-3. https://doi.org/10.15256/joc.2013.3.19

140.Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J et al. The Cardiovascular Disease continuum validated: clinical avidance of improved patient outcomes. Part I. Pathophysiology and Clinical trial evidence (risk factors throughstable coronary artery disease). Circulation. 2006;114(25):2850-2870. https://doi.org/10.1161/CIRCULATIONAHA.106.655688

142.Van Weel C, Schellevis FG. Comorbidity and guidelines: conflicting interests. Lancet. 2006;367(9510):550-551. https://doi.org/10.1016/S0140-6736(06)68198-1

143.Van Der Akker M, Buntinx F, Knottnerus A. Comorbidity or multimorbidity: what’s in a name? A review of literature. Eur J Gen Pract. 1996;2:65-70. https://doi.org/10.3109/13814789609162146

144.Von Hertzen LC, Haahtela T. Could the risk of asthma and atopy be reduced by a vaccine that induces a strong T-helper type 1 response? Am J Respir Cell Mol Biol. 2000;22(2):139-142. https://doi.org/10.1165/ajrcmb.22.2.3753

145.Wolff JL, Starfield B, Anderson C. Prevalence, expenditures, and Complications of Multiple Chronic Conditions in the Elderly. Arch Intern Med. 2002;162(20):2269-2276. https://doi.org/10.1001/archinte.162.20.2269

146.Zhernakova A, Van Diemen CC, Wiymenda C. Detecting shared pathogenesis from shared genetics of immune-related diseases. Nat Rev Genet. 2009;10(1):43-55. https://doi.org/10.1038/nrg2489