Association between Acute and Chronic Inflammatory States: A Case-Control Study

Abstract

Background Fever is the hallmark of efficient acute inflammatory response, which may be disrupted in chronic inflammatory conditions. The “continuum theory” proposes that the return of acute inflammatory states with high fever predicts improvement in chronic diseases during treatment. Our objective was to investigate the observation made, during classical homeopathic treatment, that such an association exists between chronic inflammation and efficient acute inflammation.

Methods In a case-control study, the reports of patients diagnosed with chronic inflammatory conditions with at least 6 months of follow-up under homeopathic treatment were retrospectively sampled from homeopathic medical practices from Greece, India, Romania and Russia. Twenty patients who improved under homeopathic treatment and 20 age-matched controls of those who did not improve were selected. The occurrence of common acute infectious diseases with fever during the follow-up period was investigated.

Results The average age of the cases and controls was 28.4 (SD: 16.64) and 27.9 (SD: 17.19) years respectively. 18/20 cases and 4/20 controls developed common infectious diseases with fever. Cramer's V co-efficient value was found to be 0.551 (p < 0.01), indicating that improvement was more in patients with fever than without. Odds ratio of improving with respect to development of acute infectious diseases was 36.0 (95% CI: 5.8 to 223.5). The binary logistic regression model indicated significant contribution of occurrence of acute infections with fever as a predictor for improvement in chronic inflammatory disease.

Conclusions Classical homeopathic clinical observations indicate an association between chronic inflammatory status in the body and the ability to mount efficient acute inflammation. In this case-control study, the occurrence of common infections with fever during treatment heralded improvement in chronic inflammatory disease. Further powered studies are necessary to substantiate this finding.

Keywords

inflammation - fever - homeopathy

Preprint

Initial ethical clearance for data collection was for a larger retrospective analysis of a clinical database including 11,800 cases, as described in a preprint publication: https://doi.org/10.22541/au.160269741.18547290/v1

The present study utilised data from the above repository for a different study design (case-control study) and its preprint is available online: https://doi.org/10.21203/rs.3.rs-2083679/v1, posted on November 22nd, 2022. The later alteration to the study's data analysis did not require specific additional ethical approval. Changes made to the current manuscript compared with the preprint were as follows:

The title was changed from “Correlation” to “Association” between Acute and Chronic Inflammatory States, a Case-control Study. The abstract is structured and the homeopathic paradigm was added to the hypothesis. Further clarification on inclusion/exclusion criteria, including clarity on the meaning of “chronic inflammatory state”, was added. Ethical clearance statements were clarified to reflect the nature of the original approval. The graphs in the Results section of the 20 cases and controls were removed as they did not add to the understanding of the findings. Statistical analysis was enhanced, along with the calculation of odds ratio, Pearson's chi square was calculated and correlational statistical analysis was performed. A binary logistic regression model was also developed and described in Results. The context of homeopathy was added to conclusions.

Availability of Data and Material

The datasets generated and/or analysed during the current study may be requested by writing to the authors.

Authors' Contributions

S.M., M.M., V.V., V.S., E.S., N.K., D.C., D.T., L.J., and A.J. were the primary physicians who collected and analysed the data. S.M. wrote the manuscript and attended to the referencing. G.V. is the approver and guarantor of the work. All authors read the final version of the manuscript and approved its submission to the journal.

Publikationsverlauf

Eingereicht: 12. April 2023

Angenommen: 05. Oktober 2023

Artikel online veröffentlicht:
09. Februar 2024

• References

• 1 Rather LJ. Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus. Bull N Y Acad Med 1971; 47: 303-322
• 2 Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 2015; 15: 335-349
• 3 Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol 2005; 6: 1191-1197
• 4 Panigrahy D, Gilligan MM, Huang S. et al. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?. Cancer Metastasis Rev 2020; 39: 337-340
• 5 Serhan CN. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J 2017; 31: 1273-1288
• 6 Blatteis CM. Fever: pathological or physiological, injurious or beneficial?. J Therm Biol 2003; 28: 1-13
• 7 Shimazui T, Nakada TA, Walley KR. et al. Significance of body temperature in elderly patients with sepsis. Crit Care 2020; 24: 387
• 8 Martín S, Pérez A, Aldecoa C. Sepsis and immunosenescence in the elderly patient: a review. Front Med (Lausanne) 2017; 4: 20
• 9 Wrotek S, LeGrand EK, Dzialuk A, Alcock J. Let fever do its job: the meaning of fever in the pandemic era. Evol Med Public Health 2020; 9: 26-35
• 10 Bhavani SV, Huang ES, Verhoef PA, Churpek MM. Novel temperature trajectory subphenotypes in COVID-19. Chest 2020; 158: 2436-2439
• 11 Smith BJ, Price DJ, Johnson D. et al. Influenza with and without fever: clinical predictors and impact on outcomes in patients requiring hospitalization. Open Forum Infect Dis 2020; 7: ofaa268
• 12 Liu E, Lewis K, Al-Saffar H. et al. Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation. Am J Physiol Regul Integr Comp Physiol 2012; 302: R1372-R1383
• 13 Wrotek S, Sobocińska J, Kozłowski HM, Pawlikowska M, Jędrzejewski T, Dzialuk A. New insights into the role of glutathione in the mechanism of fever. Int J Mol Sci 2020; 21: 1393
• 14 Wrotek S, Jędrzejewski T, Nowakowska A, Kozak W. Glutathione deficiency attenuates endotoxic fever in rats. Int J Hyperthermia 2015; 31: 793-799
• 15 Perricone C, De Carolis C, Perricone R. Glutathione: a key player in autoimmunity. Autoimmun Rev 2009; 8: 697-701
• 16 Mahesh S, Mallappa M, Habchi O. et al. Appearance of acute inflammatory state indicates improvement in atopic dermatitis cases under classical homeopathic treatment: a case series. Clin Med Insights Case Rep 2021; 14: 1179547621994103
• 17 Mahesh S, Jaggi L, Jaggi A, Tsintzas D, Vithoulkas G. Individualised homeopathic therapy in ANCA-negative rapidly progressive necrotising crescentic glomerulonephritis with severe renal insufficiency—a case report. J Med Life 2019; 12: 49-55
• 18 Chabanov D, Tsintzas D, Vithoulkas G. Levels of health theory with the example of a case of juvenile rheumatoid arthritis. J Evid Based Integr Med 2018; 23: X18777995
• 19 Vithoulkas G, Carlino S. The “continuum” of a unified theory of diseases. Med Sci Monit 2010; 16: SR7-SR15
• 20 Wrotek S, Kamecki K, Kwiatkowski S, Kozak W. Cancer patients report a history of fewer fevers during infections than healthy controls. J Pre Clin Res 2009; 3: 31-35
• 21 Donati D. Viral infections and multiple sclerosis. Drug Discov Today Dis Models 2020; 32: 27-33
• 22 Mastrangelo G, Fadda E, Milan G. Cancer increased after a reduction of infections in the first half of this century in Italy: etiologic and preventive implications. Eur J Epidemiol 1998; 14: 749-754
• 23 Witkin SS, Linhares I, Giraldo P, Jeremias J, Ledger WJ. Individual immunity and susceptibility to female genital tract infection. Am J Obstet Gynecol 2000; 183: 252-256
• 24 Luebke RW, Parks C, Luster MI. Suppression of immune function and susceptibility to infections in humans: association of immune function with clinical disease. J Immunotoxicol 2004; 1: 15-24
• 25 Pana ZD, Farmaki E, Roilides E. Host genetics and opportunistic fungal infections. Clin Microbiol Infect 2014; 20: 1254-1264
• 26 Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19 disproportionately affect older people?. Aging (Albany NY) 2020; 12: 9959-9981
• 27 Bajaj V, Gadi N, Spihlman AP, Wu SC, Choi CH, Moulton VR. Aging, immunity, and COVID-19: how age influences the host immune response to coronavirus infections?. Front Physiol 2021; 11: 571416
• 28 Schmitt BD, Offit PA. Could fever improve COVID-19 outcomes?. Contemp Pediatr 2020; 37: 8-9
• 29 Chiappetta S, Sharma AM, Bottino V, Stier C. COVID-19 and the role of chronic inflammation in patients with obesity. Int J Obes 2020; 44: 1790-1792
• 30 Rajakariar R, Yaqoob MM, Gilroy DW. COX-2 in inflammation and resolution. Mol Interv 2006; 6: 199-207
• 31 Wang X, Ni L, Wan S. et al. Febrile temperature critically controls the differentiation and pathogenicity of T helper 17 cells. Immunity 2020; 52: 328-341.e5
• 32 Fisher DT, Vardam TD, Muhitch JB, Evans SS. Fine-tuning immune surveillance by fever-range thermal stress. Immunol Res 2010; 46: 177-188