key: cord-0933611-413rch02 authors: Chow, Ngai; Hogg-Johnson, Sheilah; Mior, Silvano; Cancelliere, Carol; Injeyan, Stephen; Teodorczyk-Injeyan, Julita; Cassidy, J. David; Taylor-Vaisey, Anne; Côté, Pierre title: Assessment of Studies Evaluating Spinal Manipulative Therapy and Infectious Disease and Immune System Outcomes: A Systematic Review date: 2021-04-13 journal: JAMA Netw Open DOI: 10.1001/jamanetworkopen.2021.5493 sha: 3d1f11eab31ca141d3cb090791b7ae580f5927a7 doc_id: 933611 cord_uid: 413rch02 IMPORTANCE: Claims that spinal manipulative therapy (SMT) can improve immune function have increased substantially during the COVID-19 pandemic and may have contributed to the rapid spread of both accurate and inaccurate information (referred to as an infodemic by the World Health Organization). OBJECTIVE: To identify, appraise, and synthesize the scientific literature on the efficacy and effectiveness of SMT in preventing the development of infectious disease or improving disease-specific outcomes in patients with infectious disease and to examine the association between SMT and selected immunological, endocrine, and other physiological biomarkers. EVIDENCE REVIEW: A literature search of MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, the Index to Chiropractic Literature, the Cochrane Central Register of Controlled Trials, and Embase was conducted from inception to April 15, 2020. Randomized clinical trials and cohort studies were included. Eligible studies were critically appraised, and evidence with high and acceptable quality was synthesized using the Synthesis Without Meta-Analysis guideline. FINDINGS: A total of 2593 records were retrieved; after exclusions, 50 full-text articles were screened, and 16 articles reporting the findings of 13 studies comprising 795 participants were critically appraised. The literature search found no clinical studies that investigated the efficacy or effectiveness of SMT in preventing the development of infectious disease or improving disease-specific outcomes among patients with infectious disease. Eight articles reporting the results of 6 high- and acceptable-quality RCTs comprising 529 participants investigated the effect of SMT on biomarkers. Spinal manipulative therapy was not associated with changes in lymphocyte levels or physiological markers among patients with low back pain or participants who were asymptomatic compared with sham manipulation, a lecture series, and venipuncture control groups. Spinal manipulative therapy was associated with short-term changes in selected immunological biomarkers among asymptomatic participants compared with sham manipulation, a lecture series, and venipuncture control groups. CONCLUSIONS AND RELEVANCE: In this systematic review of 13 studies, no clinical evidence was found to support or refute claims that SMT was efficacious or effective in changing immune system outcomes. Although there were limited preliminary data from basic scientific studies suggesting that SMT may be associated with short-term changes in immunological and endocrine biomarkers, the clinical relevance of these findings is unknown. Given the lack of evidence that SMT is associated with the prevention of infectious diseases or improvements in immune function, further studies should be completed before claims of efficacy or effectiveness are made. Information extracted from each study included study characteristics, (e.g. author, year and country of publication, study design, sample size, length of follow up), participant characteristics (e.g., age, and body region treated), intervention characteristics (e.g., description of interventions and comparison groups), and outcome data (e.g., incidence of infection or infectious disease, disease-specific outcomes, changes in the levels of immunological, endocrine and other physiological biomarkers). We categorized RCTs into the different phases of clinical trials as described by Campbell et al. 21 The purpose of a phase 0 (exploratory) study is to gather preliminary data on whether the intervention behaves as expected in humans based on preclinical studies, and involves limited human exposure (10-15 healthy volunteers) to the intervention, with no therapeutic or diagnostic goals. 21 A phase 1 (safety) study aims to determine safety of the intervention and typically involves 20-80 healthy volunteers. 21 A phase 2 (biologic activity) study aims to establish proof of concept that the intervention has biologic activity, usually involving 100-300 patients with specific diseases. 21 A phase 3 (efficacy) study aims to confirm the efficacy and effectiveness of the intervention, monitor side effects, and frequently involves 300-3000 patients with specific diseases. 21 A phase 4 (post-marketing/confirmatory) study aims to provide surveillance and additional information on the intervention's risks, benefits and best use after the intervention is approved for human use, and involves several thousand patients treated with the intervention. 21 We reported or computed (when data were available), the incidence and 95% confidence intervals (CI) of infection or infectious disease, and mean difference and 95% CI in change in the level of biomarkers. We reported or calculated the pre-post difference in means or mean differences between groups based on data derived from regression models. Incidence was measured by calculating the number of new cases of infection or infectious disease in a group divided by the total number of participants in the same group. Confidence intervals were calculated using incidence of infection or infectious disease in each group, total number of participants in each group, and α = 0.05. We synthesized the evidence from high and acceptable quality studies according to the Synthesis without Meta-Analysis (SWiM) Guideline, 22 study objective, and type of biomarker. We restricted our synthesis to studies with high or acceptable quality because low/unacceptable quality studies are more likely to yield biased estimates of effect sizes. 23 (manipulat* adj3 (chiropract* or naprapath* or osteopath* or orthopedic* or orthopaedic*)).ab,ti. (manipulat* adj3 (spinal or spine or low* back or joint* or lumbar or neck or therap* or thoracic or cervical or intervention* or MSK or manage* or musculoskeletal or treat* or vertebr*)).ab,ti. (instrument* adj3 (manual or mobili?at* or manipulat*)).ab,ti. 1514 14 (manipulat* adj3 (physiotherap* or physical therap*)).ab,ti. 349 (mobili?at* adj3 (chiropract* or naprapath* or osteopath* or orthopedic* or orthopaedic*)).ab,ti. (mobili?at* adj3 (spinal or spine or low* back or joint* or lumbar or neck or thoracic or cervical or MSK or musculoskeletal or vertebr* or therap* or treat* or intervention* or manage*)).ab,ti. (manual adj3 (therap* or treat* or intervention* or manag*)).ab,ti. 7786 18 ((therap* or treat* or intervention* or manag*) adj3 (manual or manipulat* or mobili?at* or MSK or musculoskeletal)).ab,ti. MH Case-Control Studies 0 S16 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 24,932 S15 (therap* or treat* or intervention* or manag*) N3 (manual or manipulat* or mobili?at* or MSK or musculoskeletal) 17,015 S14 (manipulat* or mobili?at*) N4 instrument* 260 S13 mobili?at* N3 (spinal or spine or low* back or joint* or lumbar or neck or thoracic or cervical or MSK or musculoskeletal or vertebr*) Lymphocyte profiles in patients with chronic low back pain enrolled in a clinical trial Enhanced phagocytic cell respiratory burst induced by spinal manipulation: potential role of substance P Spinal manipulative therapy reduces inflammatory cytokines but not substance P production in normal subjects Enhancement of in vitro interleukin-2 production in normal subjects following a single spinal manipulative treatment Interleukin 2-regulated in vitro antibody production following a single spinal manipulative treatment in normal subjects Effects of traditional Thai massage versus joint mobilization on substance P and pain perception in patients with non-specific low back pain Short-term effects of manipulation to the upper thoracic spine of asymptomatic subjects on plasma concentrations of epinephrine and norepinephrine-a randomized and controlled observational study Neuroendocrine response following a thoracic spinal manipulation in healthy men A scoping review of rapid review methods Rapid Reviews to Strengthen Health Policy and Systems: A Practice Guide. Geneva: World Health Organization Rapid evidence assessment: increasing the transparency of an emerging methodology Advancing knowledge of rapid reviews: An analysis of results, conclusions and recommendations from published review articles examining rapid reviews The clinical utility of routine spinal radiographs by chiropractors: a rapid review of the literature The safety of spinal manipulative therapy in children under 10 years: a rapid review The Prisma Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement Spinal manipulative therapy for acute low-back pain Maitland's Vertebral Manipulation Evidence-based management of low back pain Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework Designing and conducting proof-of-concept chronic pain analgesic clinical trials Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline Assessing the impact of attrition in randomized controlled trials Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials The impact of trial baseline imbalances should be considered in systematic reviews: A methodological case study Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: Meta-epidemiological study Red: no effect of SMT; green: effect of SMT; yellow: results depend on processing of cells.b Derived from regression models in Table 1 , using a pre value of 3.0. Note that intercepts in the model are not significantly different, but the slope for SMT is significantly higher (p<.005) than the slope for either sham or soft tissue. c Derived from regression models in Table 2 Abbreviations: C/S cervical spine, HRV heart rate variability, HVLA high velocity low amplitude, LBP low back pain, min minutes, NO nitric oxide, O2Hb oxyhemoglobin, RCT randomized controlled trial, SD standard deviation, SMT spinal manipulative therapy, T/C ratio testosterone/cortisol ratio, T/S thoracic spine, TTM traditional Thai massage, Tx treatment, USA United States of America, w/o without, w/ with, wks weeks, yo years old a Red: no effect of SMT; green: effect of SMT; yellow: results depend on processing of cells. b SI conversion factors: To convert substance P from pg/mL to pmol/ L, multiply values by 0.742.To convert norepinephrine from pg/mL to pmol/L, multiple values by 5.911. To convert epinephrine from pg/mL to pmol/L, multiple values by 5.459. To convert cortisol from μg/dL to nmol/L, multiple values by 27.588. To convert testosterone from ng/dL to nmol/L, multiple values by 0.0347. c We report difference in mean change scores and 95% CI using the reported mean change scores and standard errors from Table 2 and 3. Note that in two instances in Table 2 , the reported mean change scores cannot be reproduced taking differences in means. There is clearly an error in reporting, but we are unable to identify which values are in error. d The reported results cannot be used because they are statistically incorrect. The reported p value was 0.005. There was likely a typo in the reporting of results; therefore, we imputed the 95% CI.