Cold sensitivity and associated factors: a nested case–control study performed in Northern Sweden

Cold sensitivity and associated factors: a nested case–control study performed in Northern Sweden Purpose To identify factors associated with the reporting of cold sensitivity, by comparing cases to controls with regard to anthropometry, previous illnesses and injuries, as well as external exposures such as hand–arm vibration (HAV) and ambi- ent cold. Methods Through a questionnaire responded to by the general population, ages 18–70, living in Northern Sweden (N = 12,627), cold sensitivity cases (N = 502) and matched controls (N = 1004) were identified, and asked to respond to a second questionnaire focusing on different aspects of cold sensitivity as well as individual and external exposure factors suggested to be related to the condition. Conditional logistic regression analyses were performed to determine statistical significance. Results In total, 997 out of 1506 study subjects answered the second questionnaire, yielding a response rate of 81.7%. In the multiple conditional logistic regression model, identified associated factors among cold sensitive cases were: frostbite affecting the hands (OR 10.3, 95% CI 5.5–19.3); rheumatic disease (OR 3.1, 95% CI 1.7–5.7); upper extremity nerve injury (OR 2.0, 95% CI 1.3–3.0); migraines (OR 2.4, 95% CI 1.3–4.3); and vascular disease (OR 1.9, 95% CI 1.2–2.9). A body mass index ≥ 25 was inversely related to reporting of cold sensitivity (0.4, 95% CI 0.3–0.6). Conclusions Cold sensitivity was associated with both individual and external exposure factors. Being overweight was associ- ated with a lower occurrence of cold sensitivity; and among the acquired conditions, both cold injuries, rheumatic diseases, nerve injuries, migraines and vascular diseases were associated with the reporting of cold sensitivity. Keywords Cold exposure · Sweden · Hand · Frostbite · Cold sensitivity Introduction et  al. 1997). The pathophysiological mechanisms are not fully elucidated, but seem to involve a multifactorial etiol- Cold sensitivity is an elusive condition that has previously ogy, including neural (Irwin et al. 1997), vascular (Hope been defined as an exaggerated or abnormal reaction to cold et al. 2014), as well as humoral (Koman et al. 1998) aspects. exposure, causing discomfort or the avoidance of cold (Kay Cold sensitivity has previously been studied as a sequela to 1985). It can be accompanied by pain, numbness, stiffness, upper extremity injuries, such as digital and hand amputa- weakness, swelling and skin color changes in the affected tion (Lithell et al. 1997; Tark et al. 1989), hand fracture body part, most often the hands (Irwin et al. 1997). However, (Nijhuis et al. 2010), peripheral nerve and brachial plexus there is no universally accepted symptom-based definition of injury (Novak et al. 2012; Ruijs et al. 2007), upper extrem- cold sensitivity, although attempts have been made (Lithell ity arterial injury (Klocker et al. 2012), flexor tendon repair (Riaz et al. 1999), corrective surgery for Dupuytren’s dis- ease (McKirdy 2007), carpal tunnel syndrome (Thomsen * Albin Stjernbrandt et al. 2009), freezing cold injury (Carlsson et al. 2014), and albin.stjernbrandt@umu.se hand–arm vibration (HAV) syndrome (Carlsson et al. 2010c; Department of Public Health and Clinical Medicine, Necking et al. 2002). Injuries aside, cold sensitivity has also Occupational and Environmental Medicine, Umeå been described in relation to diabetes mellitus (Thomsen University, 901 87 Umeå, Sweden et al. 2009), and rheumatic diseases (Merkel et al. 2002). Occupational and Environmental Medicine, University In several publications, cold sensitivity was found to be the Hospital of Umeå, 901 85 Umeå, Sweden Vol.:(0123456789) 1 3 786 International Archives of Occupational and Environmental Health (2018) 91:785–797 worst and longest-lasting problem following a hand injury register. The rationale and methodology for the CHINS1 (Carlsson et al. 2010a; Lithell et al. 1997), and was shown study have previously been described in detail (Stjernbrandt to reduce quality of life (Carlsson et al. 2010c; Koman et al. et al. 2017). 1998). To our knowledge, cold sensitivity has not previously From the collected baseline data, cases with cold sensi- been investigated in population-based studies. tivity were identified through the use of two questionnaire In occupational health standards, ambient temperatures at items: or below 10 °C have been defined as cold exposure (Inter - national Organization for Standardization 2008). The expe- 1. “I am oversensitive to cold” to which the study partici- rience of being cold can also be defined from a subjective pant could answer on a fixed numerical scale ranging standpoint, regardless of ambient temperature (Makinen and from 1 (“do not agree”) to 10 (“agree completely”). An Hassi 2002). Cold exposure may occur during both work answer of 4 or more was considered a positive response. and leisure-time, and is often associated with aggravating 2. “I experience pain/discomfort when fingers/hands are environmental conditions such as wind, rain or snow (Keim exposed to cold” to which the study participant could et al. 2002). In addition, indoor cold store work, contact with answer on a four-grade scale, in the form of “none”, cold objects, and cold water immersion can contribute to the “insignificant”, “somewhat” or “a lot”. Answering “a effects of cold (Baldus et al. 2012). These effects are also lot” was considered a positive response. modified by individual factors such as sex, age, nutritional status, pre-existing diseases, medication, thermal clothing A positive response on both questions fulfilled our case insulation, and activity level (Raatikka et al. 2007). Swedish definition for cold sensitivity. All cases were invited to par - national statistics from 2015 report that 23% of working men ticipate in a second data collection, here titled CHINS2, and 14% of working women in Sweden are occupationally which was a questionnaire-based nested case–control study. exposed to an ambient cold climate for at least one quarter Controls were randomly selected with a ratio of 2:1 among of their working hours (Swedish Work Environment Author- study subjects from CHINS1 according to the following ity 2016). During leisure-time, 30% of men, and 25% of inclusion criteria: women, living in Northern Sweden, report a high cold expo- sure (Stjernbrandt et al. 2017). 1. No reported cold sensitivity according to the definition The aim of the present study was to identify factors asso- described above. ciated with the reporting of cold sensitivity, by comparing 2. No reported Raynaud’s phenomenon. cases to controls with regard to anthropometry, previous ill- 3. Matching the case with regard to geographical area, sex, nesses and injuries, as well as external exposures such as and age (± 2 years). HAV and ambient cold. The CHINS2 study was initiated on the 10th of Octo- ber 2015, and ended on the 10th of March 2016. Cases and Methods controls received the same questionnaire. Details regard- ing the data collection are presented in Fig. 1. The study Participants and data collection protocol was approved by the Regional Ethical Review Board situated at Umeå University (DNR 2015-24-31M and In the spring of 2015, a research project called Cold and 2014-286-31M). Health in Northern Sweden (CHINS) was launched, with the purpose of investigating cold-related health effects in Study design Northern Sweden. The project was conducted in the four northernmost counties in Sweden: Norrbotten; Västerbotten; The study questionnaire was designed by a team of physi- Västernorrland; and Jämtland. The study region holds a pop- cians, occupational and environmental hygienists, engineers, ulation of approximately 880,000 people (Statistics Sweden and ergonomists; and collected data on demographic and 2016), and is located between the 62°N and 69°N latitude, anthropometric variables such as place of livelihood, sex, with a mixed subarctic and temperate climate. age, height, and weight. Geographical location was deter- The first data collection, here titled CHINS1, was initi- mined by postal code and stratified into 44 municipalities ated on the 5th of February and ended on the 5th of May, that were then grouped together to form three broad cat- 2015. It consisted of a large questionnaire-based study per- egories—coastal, inland, and alpine. The occupations of formed on a sample of men and women between ages 18 the study participants were collected in free text, and then and 70 years living in the study area. The study sample was coded in accordance with the International Standard Clas- randomly selected from the national Swedish population sification of Occupations (International Labour Organization 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 787 Fig. 1 Data collection for the CHINS1 and CHINS2 studies. The shown in parentheses. CHINS1 the first, population-based, data col- number of study subjects in each step of the data collection process lection. CHINS2 the second, case-based, data collection. CS cold sen- is illustrated, and the response rates for each of the questionnaires are sitivity, RP Raynaud’s phenomenon 2012). The use of tobacco, either cigarettes or snuff, was on picture) when exposed to moisture or cold?” and was also included. supported by a standardized color chart that has previously To quantify the severity of cold sensitivity, we added a been shown to increase the diagnostic specificity (Negro 100 mm visual analogue scale (VAS), where the study par- et al. 2008). Other questions asked if the study participants ticipants were asked to mark the extent of problems with had been diagnosed by a physician for any of the follow- their hands they experience when exposed to cold climate. ing: hypertension; angina pectoris; myocardial infarction; We also included the Swedish version of the Cold Intoler- stroke; diabetes mellitus; joint disease; or migraines. Ques- ance Symptom Severity (CISS) score (Carlsson et al. 2008) tions were also posed about the presence of rheumatic dis- in our questionnaire. This inventory scores subjective prob- ease, upper extremity nerve injury, polyneuropathy, carpal lems with ambient cold exposure on a scale ranging from tunnel syndrome, and peripheral vascular disease, and the 4 to 100, where a value exceeding 50 has been suggested study participants were asked to specify the condition in to indicate abnormal cold sensitivity, based on a cohort of detail (in free text). randomly selected Swedish healthy volunteers (Carlsson The use of therapeutic drugs was collected in free text, et al. 2010b). and coded by one of the study physicians (AS) into two Frostbite affecting the hands was categorized as first broad categories based on whether the substance has a docu- degree (white spots), second degree (blisters), or third mented negative effect on either peripheral nerves (Asbury degree (blood-filled blisters). The occurrence of Raynaud’s 2006; Chan and Wilder-Smith 2016) or circulation (Bakst phenomenon was investigated through a single item ques- et al. 2008; Block and Sequeira 2001). Drugs classified as tion; “Does one or more of your fingers turn white (as shown having a negative effect on peripheral nerves were statins 1 3 788 International Archives of Occupational and Environmental Health (2018) 91:785–797 (pravastatin, simvastatin, atorvastatin, rosuvastatin), cer- forward stepwise procedure where, in each step, the associ- tain antibiotics (metronidazole, nitrofurantoin, linezolide, ated factor with the lowest P value when entered into the isoniazide), certain immunosuppressive drugs (etanercept, model was added (Table 4). P values were obtained using the infliximab, adalimumab, certolizumab pegol, golimumab, Wald test. Only associated factors with a P value less than leflunomid), certain antineoplastic agents (cisplatin, taxol, 0.05 when entered were subsequently added to the model. vincristine, oxaliplatin, bortezomib), amiodarone, dapsone, Sex-specific subgroup analyses were also conducted for both phenytoin, and hydralazine. Drugs considered to have a neg- the univariate and multiple models. All statistical analyses ative effect on peripheral circulation were beta-adrenergic were performed using IBM SPSS Statistics for Windows antagonists (metoprolol, bisoprolol, atenolol, propranolol, (version 23.0, IBM Corporation, Armonk, NY, USA). pindolol, carvedilol), interferons (alpha and beta), systemic hormone replacement or contraceptive treatment, certain antineoplastic agents (cisplatin, bleomycin, vinblastine, tegafur), certain sympathomimetic drugs (methylampheta- Results mine, dexamphetamine), lithium, clonidine, and ergotamine. Ambient cold exposure was investigated with several Participants (Fig. 1; Table 1) questions, partly rephrased from the Potential Work Expo- sure Scale (McCabe et al. 1991). For example, study par- The case definition for cold sensitivity was fulfilled by 502 ticipants were asked if their work required them to manually participants (4.0%) in the CHINS1 dataset, and they were all handle objects with a temperature near or below freezing. invited to participate in the nested case–control study. Also They were also asked to grade their occupational and lei- from the CHINS1 dataset, 10,845 eligible controls were iden- sure-time cold exposure on a fixed numerical rating scale tified, of which 1004 randomly selected matched controls (NRS) ranging from 1 to 10, respectively. The two scales were invited to participate. Of the 502 cases, 397 (79.1%) were subsequently added together to form a cumulative returned the CHINS2 questionnaire, and of the 1004 controls, measurement of cold exposure ranging from 2 to 20. For 833 (83.0%) responded. In total, 1230 out of 1506 question- HAV, the study participants were asked to specify if they had naires were returned, giving an overall response rate of 81.7%. recurrent occupational exposure to impact tools (chipping However, 23 responding cases lacked at least one matching hammers, rotary hammers, rock drills, impact drills, nailers, responding control, and were subsequently excluded from impact wrenches), rapidly rotating tools (dentist drills, den- analyses. A further 210 controls lacking responding cases tal technician instruments, foot files), forestry and gardening were also excluded. The final study population consisted of equipment (chainsaws, brush cutters, lawn mowers, hedge 997 individuals, of which 374 were cases and 623 matching trimmers), vibrating tools (screwdrivers, drilling machines, controls. All cases had at least one matching control. The data circular saws, belt sanders), heavily vibrating tools (recip- collection is described in detail in Fig. 1. rocating saws, jigsaws, oscillating sanders, soil compac- tors, concrete vibrators), or vehicles with vibrating controls (graders, tractors, trucks, snowmobiles, all-terrain vehicles). Study population characteristics (Table 1) Statistical analysis The final study population had a predominance of women (63.6% of cases and 63.2% of controls). Cases were com- Descriptive characteristics for cases and controls were pre- parable to controls with regard to age (mean 50.5 and sented as means and standard deviation (SD) for continuous 51.8 years, respectively), as well as geographical and occu- variables, and as numbers and percentages for categorical pational distribution pattern (Table  1). Body mass index variables. Numerical rating scales for occupational and (BMI) was also comparable for cases and controls (mean leisure-time, as well as for cumulative cold exposure, were 25.4 and 26.3 kg/m ). According to the Swedish version of dichotomized into high or low exposure based on the 50th CISS, 146 (46.6%) cases and 31 (6.6%) controls exceeded percentile. The cumulative cold exposure scale was also cat- the cut-o ff value for abnormal cold sensitivity. Cases graded egorized into quartiles. their cold sensitivity higher on VAS (mean 77.8, SD 19.2) Associations between cold sensitivity and each of the than controls (mean 28.9, SD 27.4). Lifetime-occurrence candidate factors were assessed separately using univariate of frostbite affecting the hands was reported by 114 cases conditional logistic regression, and presented as odds ratios (30.5%), and 34 controls (5.5%) of controls (N = 34), of of reporting cold sensitivity (Tables 2, 3). P values less than which most were first degree injuries (95.5% and 97.0%, 0.05 were considered statistically significant. Thereafter, respectively). Raynaud’s phenomenon was reported by multiple conditional logistic regression was used to iden- 61.5% (N = 228) of cases, and null among controls (exclu- tify the most important associated factors using a manual sion criteria). 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 789 Table 1 Descriptive characteristics for cases and controls as numbers and percentages, presented in total and separated by sex All subjects Men Women Cases Controls Cases Controls Cases Controls N (%) N (%) N (%) N (%) N (%) N (%) Responders 374 (37.5) 623 (62.5) 136 (37.3) 229 (62.7) 238 (37.7) 394 (62.3) Age category (years)  18–30 38 (10.2) 58 (9.3) 9 (6.6) 13 (5.7) 29 (12.2) 45 (11.4)  30–40 45 (12.0) 62 (10.0) 9 (6.6) 12 (5.2) 36 (15.1) 50 (12.7)  40–50 85 (22.7) 137 (22.0) 21 (15.4) 32 (14.0) 64 (26.9) 105 (26.6)  50–60 105 (28.1) 173 (27.8) 44 (32.4) 70 (30.6) 61 (25.6) 103 (26.1)  60–70 101 (27.0) 193 (31.0) 53 (39.0) 102 (44.5) 48 (20.2) 91 (23.1) BMI category  Underweight (BMI < 18.5) 5 (1.4) 5 (0.8) 0 (0) 0 (0) 5 (2.1) 5 (1.3)  Normal weight (18.5 ≤ BMI < 25) 206 (56.0) 261 (43.0) 63 (47.0) 73 (32.6) 143 (61.1) 188 (49.1)  Overweight (25 ≤ BMI < 30) 102 (27.7) 230 (37.9) 48 (35.8) 110 (49.1) 54 (23.1) 120 (31.3)  Obese (BMI ≥ 30) 55 (14.9) 111 (18.3) 23 (17.2) 41 (18.3) 32 (13.7) 70 (18.3) Tobacco use  Daily cigarette smoking 33 (8.9) 49 (7.9) 9 (6.7) 19 (8.3) 24 (10.1) 30 (7.7)  Daily snuff use 57 (15.4) 66 (10.7) 37 (27.4) 46 (20.3) 20 (8.5) 20 (5.2)  Any daily tobacco use 89 (23.8) 107 (17.2) 45 (33.1) 61 (26.6) 44 (18.5) 46 (11.7) Area of livelihood  Alpine 87 (23.3) 146 (23.4) 33 (24.3) 60 (26.2) 54 (22.7) 86 (21.8)  Inland 110 (29.4) 176 (28.3) 46 (33.8) 72 (31.4) 64 (26.9) 104 (26.4)  Coastal 177 (47.3) 301 (48.3) 57 (41.9) 97 (42.4) 120 (50.4) 204 (51.8) Occupation  Armed forces occupations 2 (0.6) 3 (0.5) 1 (0.8) 2 (0.9) 1 (0.4) 1 (0.3)  Managers 9 (2.5) 22 (3.6) 6 (4.5) 7 (3.1) 3 (1.3) 15 (3.9)  Professionals 73 (20.2) 115 (19.0) 17 (12.9) 24 (10.7) 56 (24.5) 91 (23.9)  Technicians and associate professionals 28 (7.8) 70 (11.6) 14 (10.6) 34 (15.2) 14 (6.1) 36 (9.4)  Clerical support workers 40 (11.1) 47 (7.8) 10 (7.6) 12 (5.4) 30 (13.1) 35 (9.2)  Service and sales workers 57 (15.8) 107 (17.7) 11 (8.3) 30 (13.4) 46 (20.1) 77 (20.2)  Skilled agricultural, forestry, and fishery workers 6 (1.7) 9 (1.5) 2 (1.5) 3 (1.3) 4 (1.7) 6 (1.6)  Crafts and related trades workers 17 (4.7) 26 (4.3) 14 (10.6) 19 (8.5) 3 (1.3) 7 (1.8)  Plant and machine operators and assemblers 27 (7.5) 27 (4.5) 22 (16.7) 22 (9.8) 5 (2.2) 5 (1.3)  Elementary occupations 6 (1.7) 13 (2.1) 3 (2.3) 5 (2.2) 3 (1.3) 8 (2.1)  Self-employed 8 (2.2) 13 (2.1) 2 (1.5) 8 (3.6) 6 (2.6) 9 (2.4)  Students 11 (3.0) 16 (2.6) 1 (0.8) 0 (0) 10 (4.4) 16 (4.2)  Unemployed 4 (1.1) 9 (1.5) 2 (1.5) 4 (1.8) 2 (0.9) 5 (1.3)  Parental leave 3 (0.8) 4 (0.7) 0 (0) 0 (0) 3 (1.3) 4 (1.0)  Sick leave 12 (3.3) 12 (2.0) 1 (0.8) 3 (1.3) 11 (4.8) 9 (2.4)  Retired 58 (16.1) 112 (18.5) 26 (19.7) 51 (22.8) 32 (14.0) 61 (16.0) BMI body mass index daily use of tobacco was associated with cold sensitivity (OR Univariate conditional logistic regression analyses 1.5, 95% CI 1.1–2.0), but this was not statistically significant (Tables 2, 3) among men when analyzed separately. The use of therapeu- tic drugs with documented harmful effects on peripheral Regarding individual factors, being overweight nerves or circulation did not show any association with (25 ≤ BMI < 30) was associated with a lower reported fre- cold sensitivity. The cold sensitivity cases reported a higher quency of cold sensitivity (OR 0.5, 95% CI 0.4–0.7) com- frequency of vascular disease (OR 1.8, 95% CI 1.3–2.6), pared to being normal weight (18.5 ≤ BMI < 25 kg/m ). Any 1 3 790 International Archives of Occupational and Environmental Health (2018) 91:785–797 1 3 Table 2 Univariate conditional logistic regression of factors suggested to be associated with cold sensitivity, including BMI, tobacco use, therapeutic drug use, diseases, and injuries Factor Exposure level All subjects Men Women Cases Controls OR (95% CI) Cases Controls OR (95% CI) Cases Controls OR (95% CI) N (%) N (%) N (%) N (%) N (%) N (%) BMI category BMI < 18.5 5 (1.4) 5 (0.8) 1.6 (0.4–6.7) 0 (0.0) 0 (0.0) – 5 (2.1) 5 (1.3) 1.6 (0.4–6.7) 18.5 ≤ BMI < 25 206 (56.0) 261 (43.0) Reference 63 (47.0) 73 (32.6) Reference 143 (61.1) 188 (49.1) Reference 25 ≤ BMI < 30 102 (27.7) 230 (37.9) 0.5 (0.4–0.7)* 48 (35.8) 110 (49.1) 0.5 (0.3–0.8)* 54 (23.1) 120 (31.3) 0.6 (0.4–0.8)* BMI ≥ 30 55 (14.9) 111 (18.3) 0.6 (0.4–9)* 23 (17.2) 41 (18.3) 0.6 (0.3–1.1) 32 (13.7) 70 (18.3) 0.6 (0.4–0.96)* Any daily tobacco use Yes 89 (23.8) 107 (17.2) 1.5 (1.1–2.0)* 45 (33.1) 61 (26.6) 1.3 (0.9–2.1) 44 (18.5) 46 (11.7) 1.6 (1.04–2.6)* No 285 (76.2) 516 (82.8) Reference 91 (66.9) 168 (73.4) Reference 194 (81.5) 348 (88.3) Reference Therapeutic drug use  Affecting peripheral nerves Yes 33 (11.1) 54 (12.3) 1.0 (0.6–1.7) 19 (18.3) 31 (20.3) 0.7 (0.4–1.6) 14 (7.3) 23 (8.1) 1.3 (0.6-3.0) No 263 (88.9) 384 (87.7) Reference 85 (81.7) 122 (79.7) Reference 178 (92.7) 262 (91.9) Reference  Affecting peripheral circulation Yes 55 (19.1) 81 (18.9) 1.3 (0.8–2.1) 22 (22.0) 24 (16.4) 1.7 (0.7–3.7) 33 (17.6) 57 (20.1) 1.1 (0.6-2.0) No 233 (80.9) 348 (81.1) Reference 78 (78.0) 122 (83.6) Reference 155 (82.4) 226 (79.9) Reference Diseases and injuries  Vascular disease Yes 109 (29.1) 151 (25.5) 1.8 (1.3–2.6)* 50 (41.0) 70 (32.4) 2.2 (1.2–3.9)* 59 (26.6) 81 (21.6) 1.6 (1.04–2.5)* No 235 (68.3) 440 (74.5) Reference 72 (59.0) 146 (67.6) Reference 163 (73.4) 294 (78.4) Reference  Diabetes mellitus Yes 13 (3.5) 28 (4.6) 0.9 (0.5–1.8) 6 (4.4) 12 (5.4) 0.9 (0.3–2.4) 7 (3.0) 16 (4.1) 0.9 (0.4–2.3) No 356 (96.5) 581 (95.4) Reference 129 (95.6) 211 (94.6) Reference 227 (97.0) 370 (95.9) Reference  Migraines Yes 59 (16.1) 50 (8.2) 2.2 (1.4–3.3)* 12 (9.0) 10 (4.4) 2.0 (0.9–4.7) 47 (20.2) 40 (10.5) 2.2 (1.4–3.6)* No 307 (83.9) 558 (91.8) Reference 121 (91.0) 216 (95.6) Reference 186 (79.8) 342 (89.5) Reference  Rheumatic disease Yes 66 (18.1) 45 (7.4) 3.2 (2.1-5.0)* 15 (11.4) 16 (7.1) 2.0 (0.9–4.3) 51 (21.9) 29 (7.6) 3.9 (2.3–6.8)* No 299 (81.9) 562 (92.6) Reference 117 (88.6) 208 (92.9) Reference 182 (78.1) 354 (92.4) Reference  Carpal tunnel syndrome Yes 39 (10.9) 50 (8.2) 1.5 (0.9–2.3) 13 (10.0) 19 (8.5) 1.3 (0.6-3.0) 26 (11.4) 31 (8.1) 1.6 (0.9–2.7) No 320 (89.1) 559 (91.8) Reference 117 (90.0) 205 (91.5) Reference 203 (88.6) 354 (91.9) Reference  Polyneuropathy Yes 13 (3.6) 4 (0.7) 7.4 (2.1–26.4)* 7 (5.3) 2 (0.9) 10.2 (1.2–85.4)* 6 (2.6) 2 (0.5) 6.0 (1.2–29.7)* No 350 (96.4) 602 (99.3) Reference 125 (94.7) 222 (99.1) Reference 225 (97.4) 380 (99.5) Reference Upper extremity nerve injury Yes 119 (32.6) 112 (18.3) 2.3 (1.7–3.1)* 50 (37.6) 47 (20.6) 2.3 (1.4–3.7)* 69 (29.7) 65 (16.9) 2.3 (1.5–3.5)* No 246 (67.4) 500 (81.7) Reference 83 (62.4) 181 (79.4) Reference 163 (70.3) 319 (83.1) Reference Frostbite hands Yes 114 (30.6) 34 (5.5) 10.2 (6.0–17.2)* 53 (39.0) 13 (5.7) 18.9 (6.8–52.6)* 61 (25.8) 21 (5.4) 7.2 (3.9–13.6)*  No 258 (69.4) 583 (94.5) Reference 83 (61.0) 215 (94.3) Reference 175 (74.2) 368 (94.6) Reference  Data presented in total and separated by sex BMI body mass index *Bold values indicate odds ratios with significant 95% confidence intervals Statins, antibiotics, immunosuppressive drugs, antineoplastic agents, amiodarone, dapsone, phenytoin and/or hydralazine Beta-adrenergic antagonists, interferons, systemic hormone replacement or contraceptive treatment, antineoplastic agents, sympathomimetics drugs, lithium, clonidine, and/or ergotamine Hypertension, angina pectoris, myocardial infarction, stroke, and/or peripheral vascular disease Systemic sclerosis, CREST syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, reactive arthritis, unspecified arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, Sjogren’s syndrome, Ehlers–Danlos syndrome, fibromyalgia, gout, polymyositis, dermatomyositis, Dercum’s disease, and/or mixed connective tissue disease International Archives of Occupational and Environmental Health (2018) 91:785–797 791 1 3 Table 3 Univariate conditional logistic regression of external exposure factors suggested to be associated with cold sensitivity, including different cold and hand–arm vibration exposure meas- ures Factor Exposure level All subjects Men Women Cases Controls OR (95% CI) Cases Controls OR (95% CI) Cases Controls OR (95% CI) N (%) N (%) N (%) N (%) N (%) N (%) Cold exposure measures  Occupational cold exposure (NRS 1–10) High (NRS > 1) 182 (50.4) 242 (40.8) 1.4 (1.1–1.9)* 88 (67.7) 132 (60.8) 1.3 (0.8–2.1) 94 (40.7) 110 (29.3) 1.5 (1.1–2.2)* Low (NRS 1) 179 (49.6) 351 (59.2) Reference 42 (32.3) 85 (39.2) Reference 137 (59.3) 266 (70.7) Reference  Leisure-time cold exposure (NRS 1–10) High (NRS > 5) 194 (52.9) 301 (49.3) 1.1 (0.8–1.4) 69 (51.1) 118 (52.0) 1.0 (0.6–1.4) 125 (53.9) 183 (47.8) 1.2 (0.9–1.7) Low (NRS ≤ 5) 173 (47.1) 309 (50.7) Reference 66 (48.9) 109 (48.0) Reference 107 (46.1) 200 (52.2) Reference  Cumulative cold exposure (NRS 2–20) High (NRS > 8) 198 (55.3) 253 (43.0) 1.6 (1.2–2.1)* 81 (62.3) 122 (56.5) 1.2 (0.7–1.9) 117 (51.3) 131 (35.2) 1.8 (1.3–2.6)* Low (NRS ≤ 8) 160 (44.7) 335 (57.0) Reference 49 (37.7) 94 (43.5) Reference 111 (48.7) 241 (64.8) Reference  Cumulative cold exposure (NRS 2–20) 1st quartile 69 (19.3) 141 (24.0) Reference 22 (16.9) 34 (15.7) Reference 47 (20.6) 107 (28.8) Reference 2nd quartile 91 (25.4) 194 (33.0) 1.0 (0.7–1.5) 27 (20.8) 60 (27.8) 0.8 (0.4–1.6) 64 (28.1) 134 (36.0) 1.1 (0.7–1.8) 3rd quartile 110 (30.7) 147 (25.0) 1.5 (1.04–2.3)* 36 (27.7) 62 (28.7) 0.97 (0.5–1.9) 74 (32.5) 85 (22.8) 1.9 (1.2–3.1) 4th quartile 88 (24.6) 106 (18.0) 1.6 (1.1–2.5)* 45 (34.6) 60 (27.8) 1.1 (0.6–2.2) 43 (18.9) 46 (12.4) 1.9 (1.1–3.4)*  Handling cold objects during work Yes 123 (33.5) 108 (17.6) 2.6 (1.9–3.6)* 77 (57.0) 73 (32.0) 2.8 (1.8–4.5)* 46 (19.8) 35 (9.1) 2.4 (1.5–3.9)* No 244 (66.5) 506 (82.4) Reference 58 (43.0) 155 (68.0) Reference 186 (80.2) 351 (90.9) Reference  Extreme cold, wind or cooling moist during work Yes 133 (36.3) 146 (23.8) 2.3 (1.7–3.3)* 85 (63.9) 103 (45.2) 2.4 (1.5–3.9)* 48 (20.6) 43 (11.1) 2.2 (1.4–3.6)* No 233 (63.7) 468 (76.2) Reference 48 (36.1) 125 (54.8) Reference 185 (79.4) 343 (88.9) Reference Occupational HAV exposure measures  Impact tools Yes 56 (15.2) 47 (7.7) 2.4 (1.5–3.9)* 50 (37.3) 40 (17.5) 2.8 (1.7–4.6)* 6 (2.6) 7 (1.8) 1.3 (0.4-4.0) No 312 (84.8) 567 (92.3) Reference 84 (62.7) 188 (82.5) Reference 228 (97.4) 379 (98.2) Reference  Rapidly rotating tools Yes 14 (3.7) 11 (1.8) 1.9 (0.9–4.2) 10 (7.6) 7 (3.1) 2.3 (0.9-6.0) 4 (1.7) 4 (1.0) 1.3 (0.3–5.3) No 352 (96.2) 602 (98.2) Reference 122 (92.4) 220 (96.9) Reference 230 (98.3) 382 (99.0) Reference  Forestry/gardening tools Yes 53 (14.5) 75 (12.3) 1.4 (0.9–2.2) 47 (35.3) 68 (29.8) 1.4 (0.9–2.4) 6 (2.6) 7 (1.8) 1.3 (0.4-4.0) No 313 (85.5) 537 (87.7) Reference 86 (64.7) 160 (70.2) Reference 227 (97.4) 377 (98.2) Reference  Vibrating tools Yes 62 (16.8) 65 (10.6) 1.9 (1.2–2.9)* 54 (40.6) 58 (25.6) 2.0 (1.2–3.2)* 8 (3.4) 7 (1.8) 1.5 (0.5–4.2) No 306 (83.2) 548 (89.4) Reference 79 (59.4) 169 (74.4) Reference 227 (96.6) 379 (98.2) Reference  Heavily vibrating tools Yes 54 (14.7) 52 (8.5) 2.4 (1.5–3.9)* 51 (38.3) 49 (21.7) 2.5 (1.5–4.1)* 3 (1.3) 3 (0.8) 1.6 (0.3–8.1) No 313 (85.3) 560 (91.5) Reference 82 (61.7) 177 (78.3) Reference 177 (78.3) 383 (99.2) Reference  Vehicles with vibrating controls Yes 50 (13.6) 66 (10.8) 1.5 (0.95–2.3) 42 (31.6) 58 (25.4) 1.5 (0.9–2.4) 8 (3.4) 8 (2.1) 1.6 (0.6–4.2) No 317 (86.4) 547 (89.2) Reference 91 (68.4) 170 (74.6) Reference 226 (96.6) 377 (97.9) Reference  Any HAV exposure Yes 111 (30.3) 131 (21.4) 2.1 (1.4–3.0)* 89 (66.4) 107 (46.9) 2.6 (1.6–4.3)* 22 (9.5) 24 (6.2) 1.4 (0.8–2.6) No 255 (69.7) 482 (78.6) Reference 45 (33.6) 121 (53.1) Reference 210 (90.5) 361 (93.8) Reference 792 International Archives of Occupational and Environmental Health (2018) 91:785–797 polyneuropathy (OR 7.4, 95% CI 2.1–26.4), upper extremity nerve injury (OR 2.3, 95% CI 1.7–3.1), and frostbite affect- ing the hands (OR 10.2, 95% CI 6.0–17.2). This relationship was also seen when analyzing men and women separately. Cases also reported a higher prevalence of migraines (OR 2.2, 95% CI 1.4–3.3), and rheumatic disease (OR 3.2, 95% 2.1–5.0), but this was not statistically significant among men when sex-specific subgroup analyses were performed. For ambient factors, handling cold objects at work was associated with cold sensitivity (OR 2.6, 95% CI 1.9–3.6), as well as exposure to extreme cold, wind, or cooling moisture during work (OR 2.3, 95% CI 1.7–3.3). These ambient fac- tors were also associated among both men and women, ana- lyzed separately. A high occupational cold exposure (above the 50th percentile, translating to NRS > 1 on a scale ranging from 1 to 10) was associated with reporting cold sensitivity (OR 1.4, 95% CI 1.1–1.9), as was a high cumulative cold exposure (above the 50th percentile, translating to NRS > 8 on a scale ranging from 2 to 20) with an OR of 1.6 (95% CI 1.2–2.1). However, these findings were not statistically sig- nificant for men. When the cumulative cold exposure meas- ure was divided into quartiles, a dose–response trend was discernible but not statistically significant in every subgroup. The use of impact tools (OR 2.4, 95% CI 1.5–3.9), vibrating tools (OR 1.9, 95% CI 1.2–2.9), and heavily vibrating tools (OR 2.4, 95% CI 1.5–3.9) all showed associations with cold sensitivity, but only among men. Multiple conditional logistic regression analyses (Table 4) In the multiple model for all cases, cold sensitivity was associated with frostbite affecting the hands (OR 10.3, 95% CI 5.5–19.3), rheumatic disease (OR 3.1, 95% CI 1.7–5.7), upper extremity nerve injury (OR 2.0, 95% CI 1.3–3.0), migraines (OR 2.4, 95% CI 1.3–4.3), and vascular disease (OR 1.9, 95% CI 1.2–2.9). Subjects with BMI ≥ 25 kg/m were less likely to report cold sensitivity than those of nor- mal weight (OR 0.4, 95% CI 0.3–0.6). Among men, cold sensitivity was associated with frost- bite affecting the hands (OR 17.9, 95% CI 6.1–52.1), any HAV exposure (OR 2.2, 95% CI 1.2–4.2), and upper extremity nerve injury (OR 2.4, 95% CI 1.2–4.6). Men with BMI ≥ 25 kg/m were also less likely to report cold sensitiv- ity than normal-weight subjects (OR 0.4, 95% CI 0.2–0.8). Women reporting cold sensitivity showed associations with frostbite affecting the hands (OR 7.6, 95% CI 3.5–16.6), rheumatic disease (OR 4.2, 95% CI 1.9–9.0), migraines (OR 2.3, 95% CI 1.2–4.5), and a high cumulative cold exposure (above the 50th percentile, translating to NRS > 8 on a scale ranging from 2 to 20) (OR 1.6, 95% CI 1.04–2.4). In 1 3 Table 3 (continued) Data presented in total and separated by sex NRS numerical rating scale, HAV hand–arm vibration *Bold values indicate odds ratios with significant 95% confidence intervals Self-estimated occupational cold exposure, reported on a ten-point numerical rating scales (NRS), where a value above the 50th percentile (NRS > 1) was denoted high, while a value below (NRS 1) was denoted low Self-estimated leisure-time cold exposure, reported on a ten-point numerical rating scales (NRS), where a value above the 50th percentile (NRS > 5) was denoted high, while a value below (NRS ≤ 5) was denoted low Self-estimated occupational and leisure-time cold exposure, reported on two separate ten-point numerical rating scales (NRS), were added together to form a cumulative measurement of cold exposure ranging from 2 to 20, and a value above the 50th percentile (NRS > 8) was denoted high, while a value below (NRS ≤ 8) was denoted low First quartile corresponds to NRS 2–5, second quartile NRS 6–8, third quartile NRS 9–11, and forth quartile NRS 12–20 Any occupational use of impact tools, rapidly rotating tools, forestry and gardening tools, vibrating tools, heavily vibrating tools, and/or vehicles with vibrating controls International Archives of Occupational and Environmental Health (2018) 91:785–797 793 Table 4 Manual forward Factor Exposure level Cases Controls OR (95% CI) stepwise multiple conditional N % N % logistic regression of factors associated with cold sensitivity All subjects in the univariate analyses  Frostbite hands Yes 97 30 32 6 10.3 (5.5–19.3)* No 225 70 527 94 Reference –  Rheumatic disease Yes 58 18 36 6 3.1 (1.7–5.7)* No 264 82 523 94 Reference –  BMI category (kg/m ) BMI < 18.5 5 2 5 1 1.1 (0.1–9.9) 18.5 ≤ BMI < 25 185 57 243 43 Reference – BMI ≥ 25 132 41 311 56 0.4 (0.3–0.6)*  Upper extremity nerve injury Yes 98 30 99 18 2.0 (1.3-3.0)* No 224 70 460 82 Reference –  Migraines Yes 51 16 42 8 2.4 (1.3–4.3)* No 271 84 517 92 Reference –  Vascular disease Yes 101 31 142 25 1.9 (1.2–2.9)* No 221 69 417 75 Reference – Men  Frostbite hands Yes 51 39 13 6 17.9 (6.1–52.1)* No 79 61 209 94 Reference –  Any HAV exposure Yes 87 67 103 46 2.2 (1.2–4.2)* No 43 33 119 54 Reference –  BMI category (kg/m ) BMI < 18.5 0 0 0 0 – – 18.5 ≤ BMI < 25 62 48 73 33 Reference – BMI ≥ 25 68 52 149 67 0.4 (0.2–0.8)*  Upper extremity nerve injury Yes 49 38 46 21 2.4 (1.2–4.6)* No 81 62 176 79 Reference – Women  Frostbite hands Yes 53 25 19 6 7.6 (3.5–16.6)* No 159 75 326 94 Reference –  Rheumatic disease Yes 45 21 23 7 4.2 (1.9-9.0)* No 167 79 322 93 Reference –  BMI category (kg/m ) BMI < 18.5 5 2 5 1 1.5 (0.2–13.4) 18.5 ≤ BMI < 25 130 61 168 49 Reference – BMI ≥ 25 77 36 172 50 0.5 (0.3–0.8)*  Upper extremity nerve injury Yes 57 27 55 16 1.5 (0.9–2.7) No 155 73 290 84 Reference –  Migraines Yes 42 20 34 16 2.3 (1.2–4.5)* No 170 80 311 84 Reference –  Cumulative cold exposure High (NRS > 8) 106 50 119 34 1.6 (1.04–2.4)* Low (NRS ≤ 8) 106 50 226 66 Reference – Data presented in total and separated by sex BMI body mass index, HAV hand–arm vibration *Bold values indicate odds ratios with significant 95% confidence intervals Systemic sclerosis, CREST syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, reactive arthri- tis, unspecified arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, Sjogren’s syndrome, Ehlers–Danlos syndrome, fibromyalgia, gout, polymyositis, dermatomyositis, Dercum’s disease, and/or mixed connective tissue disease Hypertension, angina pectoris, myocardial infarction, stroke, and/or peripheral vascular disease Any occupational use of impact tools, rapidly rating tools, forestry and gardening tools, vibrating tools, heavily vibrating tools, and/or vehicles with vibrating controls Self-estimated occupational and leisure-time cold exposure, reported on two separate ten-point numerical rating scales (NRS), were added together to form a cumulative measurement of cold exposure ranging from 2 to 20, and a value above the 50th percentile (NRS > 8) was denoted high, while a value below (NRS ≤ 8) was denoted low 1 3 794 International Archives of Occupational and Environmental Health (2018) 91:785–797 conformity with the other results, a BMI ≥ 25 showed an below 0 °C, and non-freezing cold injuries (such as chil- inverse relationship (OR 0.5, 95% CI 0.3–0.8) to reporting blains) which occur at temperatures above 0 °C and often cold sensitivity. in conjunction with moisture and local pressure (Imray and Oakley 2005). In this study, ambient cold exposure for women, and previous frostbite occurrence in both men and Discussion women were generally more pronounced among cases than controls, which adds to the increasing body of data sup- Key results porting cold exposure as being a cause of cold sensitivity. However, in an earlier study we demonstrated that high- The present study shows that cold sensitivity, on a popula- cumulative ambient cold exposure in the general population tion level, is associated with several individual and external is positively related to symptoms of cold sensitivity, even in exposure factors and that the associations are somewhat the absence of overt cold injury (Stjernbrandt et al. 2017). A dependent on sex. In the multiple conditional logistic regres- recently published study on heavily cold-exposed Swedish sion model, previous occurrence of frostbite affecting the military conscripts showed a significant increase in symp- hands had the strongest association with reporting increased toms of cold sensitivity after winter training, present also in cold sensitivity for both men and women. Being overweight subjects where no cold injury had been reported (Carlsson seemed to be a protection against reporting cold sensitivity et al. 2016). Earlier reports from the Falklands War revealed for both sexes. For men, HAV exposure and upper extremity marked cold sensitivity in British servicemen with mild or nerve injury were positively associated with cold sensitivity, even subclinical cases of cold injury (Thomas and Oakley while women showed associations with rheumatic disease, 2001). Hence, at the present time there is not enough data to migraines, and cumulative cold exposure. Vascular disease establish a safe lower limit for ambient cold exposure, and was statistically associated with cold sensitivity only when the traditional classification of cold injuries into freezing and men and women were analyzed together. non-freezing does not seem to aid in the recognition of cold sensitivity development. Interpretation and comparison In our univariate analyses, HAV exposure of any kind showed an association with cold sensitivity among men, but The case definition in this study was fulfilled predominantly not in women. This sex difference is suspected to be due by non-smoking middle-aged women. Some previous stud- to a small sample of exposed women, causing issues with ies have reported associations between cold sensitivity and statistical power. When looking at subgroups of vibrating age (Schlenker et al. 1980), gender (Ruijs et al. 2007), and equipment, the tools commonly recognized to have the most tobacco use (Irwin et al. 1997), while others have not found harmful effects (impact tools and heavily vibrating tools) such relations (Collins et al. 1996; Craigen et al. 1999; Nan- were the ones that showed significant associations with carrow et al. 1996). Our nested case–control study design cold sensitivity. Thus, our findings support previous studies with matching did not allow analyses on age and gender to reporting a relationship between HAV exposure and cold be made, but univariate analyses supported the notion that sensitivity (Carlsson et al. 2010c; Necking et al. 2002). tobacco use can aggravate cold sensitivity, possibly through There were several diseases and injuries that were more a vasoconstrictive mechanism mediated by nicotine. The use prevalent among the cold sensitivity cases than the con- of drugs with negative effects on peripheral nerve function trols in the present study. Upper extremity nerve injuries and circulation did not differ significantly between cases were particularly common, and this is in line with previous and controls. Thus, the adverse effects of medication are research (Engkvist et al. 1985; Nylander et al. 1987). Some probably not the primary explanation for cold sensitivity. authors have argued that nerve injury should be considered An alternative view may be that the results are skewed by the main determinant of cold sensitivity (Ruijs et al. 2007), discontinuation of such drugs in cold sensitivity cases, e.g., while others have argued that in traumatic hand injury, both beta-adrenergic antagonists being exchanged for other anti- vascular, neural, humoral, and bony components can been hypertensive drugs in patients who report cold hands. A high associated with cold sensitivity (Carlsson and Dahlin 2014). BMI was inversely associated with cold sensitivity, which The presence of vascular disease showed a relationship with suggests that it acts as a protective factor, possibly through cold sensitivity in our study, which would support the theory a passive insulating mechanism. of a vascular mechanism. This finding was seen in all univar - Frostbite was very common in our case population, and iate analyses, but only when men and women were grouped increased cold sensitivity is a recognized sequela in individ- together in the multiple analyses. Furthermore, female cases uals with previous cold injury (Thomas and Oakley 2001). had a significantly higher frequency of rheumatic disease Local cold injuries are traditionally categorized into freezing than controls. Among patients with rheumatic disease, cold injuries (such as frostbite), occurring at temperatures both cold sensitivity (Merkel et al. 2002) and Raynaud’s 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 795 phenomenon (Garner et  al. 2015) have previously been Raynaud’s phenomenon, which makes the diagnosis diffi- reported as a common complaint. In the present study, there cult to establish. Our cases reported a high occurrence of was also a very high prevalence of Raynaud’s phenomenon Raynaud’s phenomenon, but this was excluded for among among cases. Thus, cold sensitivity and Raynaud’s phenom- controls, which could possibly have introduced a systematic enon seem to be heavily overlapping conditions that may bias into our results. However, since the expected frequency share some pathophysiological mechanisms, which war- of Raynaud’s phenomenon among healthy controls is low, rants further research. One novel finding in our study was we believe this possible effect to be rather weak. The cold the association between migraines and cold sensitivity (OR exposure estimates in our study are defined from a subjec- 2.4, 95% CI 1.3–4.3 in the multiple analyses for all subjects). tive standpoint. These conditions limit the generalizability Some studies have reported a dysfunctional vasoregulatory of the results and increase the uncertainty in risk estimates. response to cold exposure in cold sensitive subjects, with There are several possible reporting biases; firstly, there is a increased vasoconstriction (Hope et al. 2014) or abnormal possibility that symptomatic subjects might be more prone baroreceptor response (Marchant et al. 1994). One may thus to respond to questionnaires of this kind, and this might lead hypothesize that cold sensitivity is not primarily related to to an overestimation of both exposure and symptoms; sec- atherosclerotic vascular disease, but rather to a dysfunctional ondly, there is a risk that a selection effect diminishes the vasoregulatory system, in which neural function also may cold exposure estimates in cold sensitive cases, since one play an important role. would expect that such individuals leave cold-exposed occu- Abnormal cold sensitivity according to CISS (score > 50) pations, and are deterred from leisure-time cold exposure was seen in 46.6% of cases and 6.6% of controls in the pre- as well, as was the case in previous studies (Carlsson and sent study, all selected from the general population. This Dahlin 2014). The number of retired respondents was high, supports our case selection criteria being relevant. In another which might weaken any possible associations with occu- Swedish study using the same inventory and cut-off value, pational factors. The study region comprises a large area abnormal cold sensitivity was seen in 75.0% of patients with with a mean monthly temperature during the study period HAV injury, 51.0% of patients with previous amputation that spanned from about − 9 to 5 °C during the initial data injury, 37.1% of patients with nerve injury, and 4.9% of collection, meaning that there is reason to suspect a variance healthy controls (Carlsson et al. 2010c), closely resembling in ambient cold exposure that has not been adjusted for in our results. A simpler but less validated approach to grading the analyses. Thus, the results in our study can be used to the condition would be the use of the VAS, which is easy generate hypotheses regarding the mechanisms behind cold to report and gives an intuitive result. In the present study, sensitivity, but must be cautiously interpreted with regard to VAS showed a clear distinction between cases and controls, limitations in the study design. supporting its usefulness. The experience of cold sensitivity is influenced by psy - Strengths chological factors (Carlsson et al. 2010a), and recent labora- tory studies have shown a more pronounced pain response However, to our knowledge this was the first population- to a cold pressor test among individuals with high anxiety based study on cold sensitivity, and it included almost a sensitivity (Dodo and Hashimoto 2017). Additionally, per- thousand participants. The anthropometric data, tobacco use, ception thresholds to cold and pain are often assessed by and disease spectrum in our cohort roughly corresponded psychophysical methods, where the responses are modulated with other recent Swedish investigations (Eriksson et al. by psychological factors (Carlsson et al. 2016). The present 2011), which indicates that our study has included a rep- study did not include psychological variables, and this topic resentative sample of the population. Our previously pub- remains an important issue for further research. lished non-responder analysis revealed no major differences between responders and non-responders regarding geograph- Limits ical region, which was the expected main determinant of cold exposure variables (Stjernbrandt et al. 2017). Thus the There are several limitations to our study. The nested possible bias introduced by a low response rate in the first case–control study design does not allow causal relations questionnaire (CHINS1) is not believed to have affected the to be established. The response rate to the initial ques- exposure data in the present study to any larger extent. The tionnaire (CHINS1) was low (35.9%), and as only 4.0% cold sensitivity questionnaire (CHINS2) was sent out during of that group subsequently fulfilled our case definition for the coldest period of the year, which should lessen the risk the second questionnaire (CHINS2), the cases are highly of recall bias regarding ambient cold exposure. The study selected. There is no universally established definition of population was randomly selected from the entire northern cold sensitivity, and the condition seems to overlap with region of Sweden, and contains a heterogeneous group of 1 3 796 International Archives of Occupational and Environmental Health (2018) 91:785–797 Bakst R, Merola JF, Franks AG Jr, Sanchez M (2008) Raynaud’s phe- participants from many different backgrounds. Instead of nomenon: pathogenesis and management. J Am Acad Dermatol only investigating subjects experiencing cold sensitivity as 59:633–653. https ://doi.org/10.1016/j.jaad.2008.06.004 a sequela to a certain injury or disease, this study takes a Baldus S, Kluth K, Strasser H (2012) Order-picking in deep cold–phys- general population’s perspective on cold sensitivity. iological responses of younger and older females. Part 2: body core temperature and skin surface temperature. Work 41(Suppl 1):3010–3017. https ://doi.org/10.3233/WOR-2012-0557-3010 Block JA, Sequeira W (2001) Raynaud’s phenomenon. Lancet Conclusion 357:2042–2048. https://doi.or g/10.1016/S0140-6736(00)05118 -7 Carlsson IK, Dahlin LB (2014) Self-reported cold sensitivity in patients with traumatic hand injuries or hand-arm vibration syndrome - an Cold sensitivity was associated with both individual and eight year follow up. BMC Musculoskelet Disord 15:83. https :// external exposure factors. Being overweight was associated doi.org/10.1186/1471-2474-15-83 with a lower occurrence of cold sensitivity; and among the Carlsson I, Cederlund R, Hoglund P, Lundborg G, Rosen B (2008) acquired conditions, both cold injuries, rheumatic diseases, Hand injuries and cold sensitivity: reliability and validity of cold sensitivity questionnaires. Disabil Rehabil 30:1920–1928. https:// nerve injuries, migraines, and vascular diseases were asso- doi.org/10.1080/09638 28070 16797 05 ciated with the reporting of cold sensitivity. More research Carlsson IK, Edberg AK, Wann-Hansson C (2010a) Hand-injured is needed to confirm a causal relation and determine the patients’ experiences of cold sensitivity and the consequences pathophysiological mechanisms involved. Among external and adaptation for daily life: a qualitative study. J Hand Ther 23:53–61. https ://doi.org/10.1016/j.jht.2009.07.008 exposures, cold climate and HAV exposure were associated Carlsson IK, Nilsson JA, Dahlin LB (2010b) Cut-off value for self- with cold sensitivity, and both are suitable targets for pri- reported abnormal cold sensitivity and predictors for abnormality mary preventive measures. and severity in hand injuries. J Hand Surg Eur 35:409–416. https ://doi.org/10.1177/17531 93409 35418 4 Acknowledgements We gratefully acknowledge the valuable statistical Carlsson IK, Rosen B, Dahlin LB (2010c) Self-reported cold sensitivity contributions of Dr. Johan Nilsson Sommar at the Department of Public in normal subjects and in patients with traumatic hand injuries or Health and Clinical Medicine at Umeå University. hand-arm vibration syndrome. BMC Musculoskelet Disord 11:89. https ://doi.org/10.1186/1471-2474-11-89 Carlsson D, Burstrom L, Lillieskold VH, Nilsson T, Nordh E, Wahl- Funding Financial support was provided through a regional agree- strom J (2014) Neurosensory sequelae assessed by thermal and ment between Umeå University and Västerbotten County Council, vibrotactile perception thresholds after local cold injury. Int J Cir- in addition to a research grant from Västerbotten County Council cumpolar Health. https ://doi.org/10.3402/ijch.v73.23540 (VLL-646641). Carlsson D, Pettersson H, Burstrom L, Nilsson T, Wahlstrom J (2016) Neurosensory and vascular function after 14 months of military Compliance with ethical standards training comprising cold winter conditions. Scand J Work Environ Health 42:61–70. https ://doi.org/10.5271/sjweh .3530 Ethical standards All procedures performed in studies involving Chan AC, Wilder-Smith EP (2016) Small fiber neuropathy: getting human participants were in accordance with the ethical standards of bigger! Muscle Nerve 53:671–682. https ://doi.or g/10.1002/ the institutional and/or national research committee, and with the 1964 mus.25082 Helsinki Declaration and its later amendments or comparable ethical Collins ED, Novak CB, Mackinnon SE, Weisenborn SA (1996) Long- standards. The study protocol was approved by the Regional Ethical term follow-up evaluation of cold sensitivity following nerve Review Board situated at Umeå University (DNR 2015-24-31M and injury. J Hand Surg Am 21:1078–1085 2014-286-31M). Craigen M, Kleinert JM, Crain GM, McCabe SJ (1999) Patient and injury characteristics in the development of cold sensitivity of the Informed consent Informed consent was obtained from all individual hand: a prospective cohort study. J Hand Surg Am 24:8–15. https participants included in the study. ://doi.org/10.1053/jhsu.1999.jhsu2 4a000 8 Dodo N, Hashimoto R (2017) The effect of anxiety sensitivity on psychological and biological variables during the cold pressor Conflict of interest The authors declare that they have no conflicts of test. Auton Neurosci 205:72–76. https ://doi.org/10.1016/j.autne interest. u.2017.05.006 Engkvist O, Wahren LK, Wallin G, Torebjrk E, Nystrom B (1985) Open Access This article is distributed under the terms of the Crea- Effects of regional intravenous guanethidine block in post- tive Commons Attribution 4.0 International License (http://creat iveco traumatic cold intolerance in hand amputees. J Hand Surg Br mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- 10:145–150 tion, and reproduction in any medium, provided you give appropriate Eriksson M, Holmgren L, Janlert U, Jansson JH, Lundblad D, Steg- credit to the original author(s) and the source, provide a link to the mayr B et al (2011) Large improvements in major cardiovascular Creative Commons license, and indicate if changes were made. risk factors in the population of Northern Sweden: the MONICA study 1986–2009. J Intern Med 269:219–231. https ://doi.org/10. 1111/j.1365-2796.2010.02312 .x Garner R, Kumari R, Lanyon P, Doherty M, Zhang W (2015) Preva- References lence, risk factors and associations of primary Raynaud’s phe- nomenon: systematic review and meta-analysis of observational Asbury A (2006) Approach to the patient with peripheral neuropa- studies. BMJ Open 5:e006389. https ://doi.or g/10.1136/bmjop thy. In: Hauser S (ed) Harrison’s neurology in clinical medicine. en-2014-00638 9 MgGraw-Hill, San Francisco, pp 491–508 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 797 Hope K, Eglin C, Golden F, Tipton M (2014) Sublingual glyceryl Arch Occup Environ Health 81:633–638. https://doi.or g/10.1007/ trinitrate and the peripheral thermal responses in normal and s0042 0-007-0248-2 cold-sensitive individuals. Microvasc Res 91:84–89. https ://doi. Nijhuis TH, Smits ES, Jaquet JB, Van Oosterom FJ, Selles RW, Hovius org/10.1016/j.mvr.2013.11.002 SE (2010) Prevalence and severity of cold intolerance in patients Imray CH, Oakley EH (2005) Cold still kills: cold-related illnesses in after hand fracture. J Hand Surg Eur 35:306–311. https ://doi. military practice freezing and non-freezing cold injury. J R Army org/10.1177/17531 93409 34305 0 Med Corps 151:218–222 Novak CB, Anastakis DJ, Beaton DE, Mackinnon SE, Katz J (2012) International Labour Organization (2012) International Standard Clas- Cold intolerance after brachial plexus nerve injury. Hand (N Y) sification of Occupations (ISCO-08), Geneva, Switzerland. ISBN 7:66–71. https ://doi.org/10.1007/s1155 2-011-9370-4 978-92-2-125953-4 Nylander G, Nylander E, Lassvik C (1987) Cold sensitivity after International Organization for Standardization (2008) ISO replantation in relation to arterial circulation and vasoregulation. 15743:2008—Ergonomics of the thermal environment—Cold J Hand Surg Br 12:78–81 workplaces—Risk assessment and management, Brussels Raatikka VP, Rytkonen M, Nayha S, Hassi J (2007) Prevalence of Irwin MS, Gilbert SE, Terenghi G, Smith RW, Green CJ (1997) Cold cold-related complaints, symptoms and injuries in the general intolerance following peripheral nerve injury. Natural history population: the FINRISK 2002 cold substudy. Int J Biometeorol and factors predicting severity of symptoms. J Hand Surg Br 51:441–448. https ://doi.org/10.1007/s0048 4-006-0076-1 22:308–316 Riaz M, Hill C, Khan K, Small JO (1999) Long term outcome of Kay S (1985) Venous occlusion plethysmography in patients with cold early active mobilization following flexor tendon repair in related symptoms after digital salvage procedures. J Hand Surg zone 2. J Hand Surg Br 24:157–160. h t t p s : / / d o i . o r g /1 0 .1 0 5 4 / Br 10:151–154 jhsb.1998.0175 Keim SM, Guisto JA, Sullivan JB Jr (2002) Environmental thermal Ruijs AC, Jaquet JB, van Riel WG, Daanen HA, Hovius SE (2007) stress. Ann Agric Environ Med 9:1–15 Cold intolerance following median and ulnar nerve injuries: prog- Klocker J, Peter T, Pellegrini L, Mattesich M, Loescher W, Sieb M nosis and predictors. J Hand Surg Eur Vol 32:434–439. https://doi. et al (2012) Incidence and predisposing factors of cold intoler- org/10.1016/j.jhsb.2007.02.012 ance after arterial repair in upper extremity injuries. J Vasc Surg Schlenker JD, Kleinert HE, Tsai TM (1980) Methods and results of 56:410–414. https ://doi.org/10.1016/j.jvs.2012.01.060 replantation following traumatic amputation of the thumb in sixty- Koman LA, Slone SA, Smith BP, Ruch DS, Poehling GG (1998) Sig- four patients. J Hand Surg Am 5:63–70 nificance of cold intolerance in upper extremity disorders. J South Statistics Sweden (2016) Swedish National Population Statistics. Orthop Assoc 7:192–197 Stockholm: Statistics Sweden. http://www.scb.se. Accessed 26 Lithell M, Backman C, Nystrom A (1997) Pattern recognition in post- April 2016 traumatic cold intolerance. J Hand Surg Br 22:783–787 Stjernbrandt A, Bjor B, Andersson M, Burstrom L, Liljelind I, Nils- Makinen TM, Hassi J (2002) Usability of isothermal standards for son T et al (2017) Neurovascular hand symptoms in relation to cold risk assessment in the workplace. Int J Circumpolar Health cold exposure in Northern Sweden: a population-based study. Int 61:142–153 Arch Occup Env Health 90:587–595. https ://doi.or g/10.1007/ Marchant B, Donaldson G, Mridha K, Scarborough M, Timmis AD s0042 0-017-1221-3 (1994) Mechanisms of cold intolerance in patients with angina. J Swedish Work Environment Authority (2016) The Work Environment Am Coll Cardiol 23:630–636 2015, Report no. 2016:2, Stockholm: Swedish Work Environment McCabe SJ, Mizgala C, Glickman L (1991) The measurement of cold Authority sensitivity of the hand. J Hand Surg Am 16:1037–1040 Tark KC, Kim YW, Lee YH, Lew JD (1989) Replantation and revas- McKirdy S (2007) A retrospective review of cold intolerance follow- cularization of hands: clinical analysis and functional results of ing corrective surgery for Dupuytren’s disease. Br J Hand Ther 261 cases. J Hand Surg Am 14:17–27 12:55–59 Thomas J, Oakley EH (2001) Nonfreezing cold injury. In: Pandolf K, Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P et al Burr R (eds) Textbook of military Medicine, Medical aspects of (2002) Measuring disease activity and functional status in patients harsh environments, vol 1. US Army, Washington, pp 467–490 with scleroderma and Raynaud’s phenomenon. Arthritis Rheum Thomsen NO, Cederlund R, Rosen I, Bjork J, Dahlin LB (2009) Clini- 46:2410–2420. https ://doi.org/10.1002/art.10486 cal outcomes of surgical release among diabetic patients with Nancarrow JD, Rai SA, Sterne GD, Thomas AK (1996) The natural carpal tunnel syndrome: prospective follow-up with matched con- history of cold intolerance of the hand. Injury 27:607–611 trols. J Hand Surg Am 34:1177–1187. https ://doi.org/10.1016/j. Necking LE, Lundborg G, Friden J (2002) Hand muscle weakness in jhsa.2009.04.006 long-term vibration exposure. J Hand Surg Br 27:520–525 Negro C, Rui F, D’Agostin F, Bovenzi M (2008) Use of color charts for the diagnosis of finger whiteness in vibration-exposed workers. Int 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Archives of Occupational and Environmental Health Springer Journals

Cold sensitivity and associated factors: a nested case–control study performed in Northern Sweden

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Copyright © 2018 by The Author(s)
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Environment; Environmental Health; Rehabilitation; Occupational Medicine/Industrial Medicine
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Abstract

Purpose To identify factors associated with the reporting of cold sensitivity, by comparing cases to controls with regard to anthropometry, previous illnesses and injuries, as well as external exposures such as hand–arm vibration (HAV) and ambi- ent cold. Methods Through a questionnaire responded to by the general population, ages 18–70, living in Northern Sweden (N = 12,627), cold sensitivity cases (N = 502) and matched controls (N = 1004) were identified, and asked to respond to a second questionnaire focusing on different aspects of cold sensitivity as well as individual and external exposure factors suggested to be related to the condition. Conditional logistic regression analyses were performed to determine statistical significance. Results In total, 997 out of 1506 study subjects answered the second questionnaire, yielding a response rate of 81.7%. In the multiple conditional logistic regression model, identified associated factors among cold sensitive cases were: frostbite affecting the hands (OR 10.3, 95% CI 5.5–19.3); rheumatic disease (OR 3.1, 95% CI 1.7–5.7); upper extremity nerve injury (OR 2.0, 95% CI 1.3–3.0); migraines (OR 2.4, 95% CI 1.3–4.3); and vascular disease (OR 1.9, 95% CI 1.2–2.9). A body mass index ≥ 25 was inversely related to reporting of cold sensitivity (0.4, 95% CI 0.3–0.6). Conclusions Cold sensitivity was associated with both individual and external exposure factors. Being overweight was associ- ated with a lower occurrence of cold sensitivity; and among the acquired conditions, both cold injuries, rheumatic diseases, nerve injuries, migraines and vascular diseases were associated with the reporting of cold sensitivity. Keywords Cold exposure · Sweden · Hand · Frostbite · Cold sensitivity Introduction et  al. 1997). The pathophysiological mechanisms are not fully elucidated, but seem to involve a multifactorial etiol- Cold sensitivity is an elusive condition that has previously ogy, including neural (Irwin et al. 1997), vascular (Hope been defined as an exaggerated or abnormal reaction to cold et al. 2014), as well as humoral (Koman et al. 1998) aspects. exposure, causing discomfort or the avoidance of cold (Kay Cold sensitivity has previously been studied as a sequela to 1985). It can be accompanied by pain, numbness, stiffness, upper extremity injuries, such as digital and hand amputa- weakness, swelling and skin color changes in the affected tion (Lithell et al. 1997; Tark et al. 1989), hand fracture body part, most often the hands (Irwin et al. 1997). However, (Nijhuis et al. 2010), peripheral nerve and brachial plexus there is no universally accepted symptom-based definition of injury (Novak et al. 2012; Ruijs et al. 2007), upper extrem- cold sensitivity, although attempts have been made (Lithell ity arterial injury (Klocker et al. 2012), flexor tendon repair (Riaz et al. 1999), corrective surgery for Dupuytren’s dis- ease (McKirdy 2007), carpal tunnel syndrome (Thomsen * Albin Stjernbrandt et al. 2009), freezing cold injury (Carlsson et al. 2014), and albin.stjernbrandt@umu.se hand–arm vibration (HAV) syndrome (Carlsson et al. 2010c; Department of Public Health and Clinical Medicine, Necking et al. 2002). Injuries aside, cold sensitivity has also Occupational and Environmental Medicine, Umeå been described in relation to diabetes mellitus (Thomsen University, 901 87 Umeå, Sweden et al. 2009), and rheumatic diseases (Merkel et al. 2002). Occupational and Environmental Medicine, University In several publications, cold sensitivity was found to be the Hospital of Umeå, 901 85 Umeå, Sweden Vol.:(0123456789) 1 3 786 International Archives of Occupational and Environmental Health (2018) 91:785–797 worst and longest-lasting problem following a hand injury register. The rationale and methodology for the CHINS1 (Carlsson et al. 2010a; Lithell et al. 1997), and was shown study have previously been described in detail (Stjernbrandt to reduce quality of life (Carlsson et al. 2010c; Koman et al. et al. 2017). 1998). To our knowledge, cold sensitivity has not previously From the collected baseline data, cases with cold sensi- been investigated in population-based studies. tivity were identified through the use of two questionnaire In occupational health standards, ambient temperatures at items: or below 10 °C have been defined as cold exposure (Inter - national Organization for Standardization 2008). The expe- 1. “I am oversensitive to cold” to which the study partici- rience of being cold can also be defined from a subjective pant could answer on a fixed numerical scale ranging standpoint, regardless of ambient temperature (Makinen and from 1 (“do not agree”) to 10 (“agree completely”). An Hassi 2002). Cold exposure may occur during both work answer of 4 or more was considered a positive response. and leisure-time, and is often associated with aggravating 2. “I experience pain/discomfort when fingers/hands are environmental conditions such as wind, rain or snow (Keim exposed to cold” to which the study participant could et al. 2002). In addition, indoor cold store work, contact with answer on a four-grade scale, in the form of “none”, cold objects, and cold water immersion can contribute to the “insignificant”, “somewhat” or “a lot”. Answering “a effects of cold (Baldus et al. 2012). These effects are also lot” was considered a positive response. modified by individual factors such as sex, age, nutritional status, pre-existing diseases, medication, thermal clothing A positive response on both questions fulfilled our case insulation, and activity level (Raatikka et al. 2007). Swedish definition for cold sensitivity. All cases were invited to par - national statistics from 2015 report that 23% of working men ticipate in a second data collection, here titled CHINS2, and 14% of working women in Sweden are occupationally which was a questionnaire-based nested case–control study. exposed to an ambient cold climate for at least one quarter Controls were randomly selected with a ratio of 2:1 among of their working hours (Swedish Work Environment Author- study subjects from CHINS1 according to the following ity 2016). During leisure-time, 30% of men, and 25% of inclusion criteria: women, living in Northern Sweden, report a high cold expo- sure (Stjernbrandt et al. 2017). 1. No reported cold sensitivity according to the definition The aim of the present study was to identify factors asso- described above. ciated with the reporting of cold sensitivity, by comparing 2. No reported Raynaud’s phenomenon. cases to controls with regard to anthropometry, previous ill- 3. Matching the case with regard to geographical area, sex, nesses and injuries, as well as external exposures such as and age (± 2 years). HAV and ambient cold. The CHINS2 study was initiated on the 10th of Octo- ber 2015, and ended on the 10th of March 2016. Cases and Methods controls received the same questionnaire. Details regard- ing the data collection are presented in Fig. 1. The study Participants and data collection protocol was approved by the Regional Ethical Review Board situated at Umeå University (DNR 2015-24-31M and In the spring of 2015, a research project called Cold and 2014-286-31M). Health in Northern Sweden (CHINS) was launched, with the purpose of investigating cold-related health effects in Study design Northern Sweden. The project was conducted in the four northernmost counties in Sweden: Norrbotten; Västerbotten; The study questionnaire was designed by a team of physi- Västernorrland; and Jämtland. The study region holds a pop- cians, occupational and environmental hygienists, engineers, ulation of approximately 880,000 people (Statistics Sweden and ergonomists; and collected data on demographic and 2016), and is located between the 62°N and 69°N latitude, anthropometric variables such as place of livelihood, sex, with a mixed subarctic and temperate climate. age, height, and weight. Geographical location was deter- The first data collection, here titled CHINS1, was initi- mined by postal code and stratified into 44 municipalities ated on the 5th of February and ended on the 5th of May, that were then grouped together to form three broad cat- 2015. It consisted of a large questionnaire-based study per- egories—coastal, inland, and alpine. The occupations of formed on a sample of men and women between ages 18 the study participants were collected in free text, and then and 70 years living in the study area. The study sample was coded in accordance with the International Standard Clas- randomly selected from the national Swedish population sification of Occupations (International Labour Organization 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 787 Fig. 1 Data collection for the CHINS1 and CHINS2 studies. The shown in parentheses. CHINS1 the first, population-based, data col- number of study subjects in each step of the data collection process lection. CHINS2 the second, case-based, data collection. CS cold sen- is illustrated, and the response rates for each of the questionnaires are sitivity, RP Raynaud’s phenomenon 2012). The use of tobacco, either cigarettes or snuff, was on picture) when exposed to moisture or cold?” and was also included. supported by a standardized color chart that has previously To quantify the severity of cold sensitivity, we added a been shown to increase the diagnostic specificity (Negro 100 mm visual analogue scale (VAS), where the study par- et al. 2008). Other questions asked if the study participants ticipants were asked to mark the extent of problems with had been diagnosed by a physician for any of the follow- their hands they experience when exposed to cold climate. ing: hypertension; angina pectoris; myocardial infarction; We also included the Swedish version of the Cold Intoler- stroke; diabetes mellitus; joint disease; or migraines. Ques- ance Symptom Severity (CISS) score (Carlsson et al. 2008) tions were also posed about the presence of rheumatic dis- in our questionnaire. This inventory scores subjective prob- ease, upper extremity nerve injury, polyneuropathy, carpal lems with ambient cold exposure on a scale ranging from tunnel syndrome, and peripheral vascular disease, and the 4 to 100, where a value exceeding 50 has been suggested study participants were asked to specify the condition in to indicate abnormal cold sensitivity, based on a cohort of detail (in free text). randomly selected Swedish healthy volunteers (Carlsson The use of therapeutic drugs was collected in free text, et al. 2010b). and coded by one of the study physicians (AS) into two Frostbite affecting the hands was categorized as first broad categories based on whether the substance has a docu- degree (white spots), second degree (blisters), or third mented negative effect on either peripheral nerves (Asbury degree (blood-filled blisters). The occurrence of Raynaud’s 2006; Chan and Wilder-Smith 2016) or circulation (Bakst phenomenon was investigated through a single item ques- et al. 2008; Block and Sequeira 2001). Drugs classified as tion; “Does one or more of your fingers turn white (as shown having a negative effect on peripheral nerves were statins 1 3 788 International Archives of Occupational and Environmental Health (2018) 91:785–797 (pravastatin, simvastatin, atorvastatin, rosuvastatin), cer- forward stepwise procedure where, in each step, the associ- tain antibiotics (metronidazole, nitrofurantoin, linezolide, ated factor with the lowest P value when entered into the isoniazide), certain immunosuppressive drugs (etanercept, model was added (Table 4). P values were obtained using the infliximab, adalimumab, certolizumab pegol, golimumab, Wald test. Only associated factors with a P value less than leflunomid), certain antineoplastic agents (cisplatin, taxol, 0.05 when entered were subsequently added to the model. vincristine, oxaliplatin, bortezomib), amiodarone, dapsone, Sex-specific subgroup analyses were also conducted for both phenytoin, and hydralazine. Drugs considered to have a neg- the univariate and multiple models. All statistical analyses ative effect on peripheral circulation were beta-adrenergic were performed using IBM SPSS Statistics for Windows antagonists (metoprolol, bisoprolol, atenolol, propranolol, (version 23.0, IBM Corporation, Armonk, NY, USA). pindolol, carvedilol), interferons (alpha and beta), systemic hormone replacement or contraceptive treatment, certain antineoplastic agents (cisplatin, bleomycin, vinblastine, tegafur), certain sympathomimetic drugs (methylampheta- Results mine, dexamphetamine), lithium, clonidine, and ergotamine. Ambient cold exposure was investigated with several Participants (Fig. 1; Table 1) questions, partly rephrased from the Potential Work Expo- sure Scale (McCabe et al. 1991). For example, study par- The case definition for cold sensitivity was fulfilled by 502 ticipants were asked if their work required them to manually participants (4.0%) in the CHINS1 dataset, and they were all handle objects with a temperature near or below freezing. invited to participate in the nested case–control study. Also They were also asked to grade their occupational and lei- from the CHINS1 dataset, 10,845 eligible controls were iden- sure-time cold exposure on a fixed numerical rating scale tified, of which 1004 randomly selected matched controls (NRS) ranging from 1 to 10, respectively. The two scales were invited to participate. Of the 502 cases, 397 (79.1%) were subsequently added together to form a cumulative returned the CHINS2 questionnaire, and of the 1004 controls, measurement of cold exposure ranging from 2 to 20. For 833 (83.0%) responded. In total, 1230 out of 1506 question- HAV, the study participants were asked to specify if they had naires were returned, giving an overall response rate of 81.7%. recurrent occupational exposure to impact tools (chipping However, 23 responding cases lacked at least one matching hammers, rotary hammers, rock drills, impact drills, nailers, responding control, and were subsequently excluded from impact wrenches), rapidly rotating tools (dentist drills, den- analyses. A further 210 controls lacking responding cases tal technician instruments, foot files), forestry and gardening were also excluded. The final study population consisted of equipment (chainsaws, brush cutters, lawn mowers, hedge 997 individuals, of which 374 were cases and 623 matching trimmers), vibrating tools (screwdrivers, drilling machines, controls. All cases had at least one matching control. The data circular saws, belt sanders), heavily vibrating tools (recip- collection is described in detail in Fig. 1. rocating saws, jigsaws, oscillating sanders, soil compac- tors, concrete vibrators), or vehicles with vibrating controls (graders, tractors, trucks, snowmobiles, all-terrain vehicles). Study population characteristics (Table 1) Statistical analysis The final study population had a predominance of women (63.6% of cases and 63.2% of controls). Cases were com- Descriptive characteristics for cases and controls were pre- parable to controls with regard to age (mean 50.5 and sented as means and standard deviation (SD) for continuous 51.8 years, respectively), as well as geographical and occu- variables, and as numbers and percentages for categorical pational distribution pattern (Table  1). Body mass index variables. Numerical rating scales for occupational and (BMI) was also comparable for cases and controls (mean leisure-time, as well as for cumulative cold exposure, were 25.4 and 26.3 kg/m ). According to the Swedish version of dichotomized into high or low exposure based on the 50th CISS, 146 (46.6%) cases and 31 (6.6%) controls exceeded percentile. The cumulative cold exposure scale was also cat- the cut-o ff value for abnormal cold sensitivity. Cases graded egorized into quartiles. their cold sensitivity higher on VAS (mean 77.8, SD 19.2) Associations between cold sensitivity and each of the than controls (mean 28.9, SD 27.4). Lifetime-occurrence candidate factors were assessed separately using univariate of frostbite affecting the hands was reported by 114 cases conditional logistic regression, and presented as odds ratios (30.5%), and 34 controls (5.5%) of controls (N = 34), of of reporting cold sensitivity (Tables 2, 3). P values less than which most were first degree injuries (95.5% and 97.0%, 0.05 were considered statistically significant. Thereafter, respectively). Raynaud’s phenomenon was reported by multiple conditional logistic regression was used to iden- 61.5% (N = 228) of cases, and null among controls (exclu- tify the most important associated factors using a manual sion criteria). 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 789 Table 1 Descriptive characteristics for cases and controls as numbers and percentages, presented in total and separated by sex All subjects Men Women Cases Controls Cases Controls Cases Controls N (%) N (%) N (%) N (%) N (%) N (%) Responders 374 (37.5) 623 (62.5) 136 (37.3) 229 (62.7) 238 (37.7) 394 (62.3) Age category (years)  18–30 38 (10.2) 58 (9.3) 9 (6.6) 13 (5.7) 29 (12.2) 45 (11.4)  30–40 45 (12.0) 62 (10.0) 9 (6.6) 12 (5.2) 36 (15.1) 50 (12.7)  40–50 85 (22.7) 137 (22.0) 21 (15.4) 32 (14.0) 64 (26.9) 105 (26.6)  50–60 105 (28.1) 173 (27.8) 44 (32.4) 70 (30.6) 61 (25.6) 103 (26.1)  60–70 101 (27.0) 193 (31.0) 53 (39.0) 102 (44.5) 48 (20.2) 91 (23.1) BMI category  Underweight (BMI < 18.5) 5 (1.4) 5 (0.8) 0 (0) 0 (0) 5 (2.1) 5 (1.3)  Normal weight (18.5 ≤ BMI < 25) 206 (56.0) 261 (43.0) 63 (47.0) 73 (32.6) 143 (61.1) 188 (49.1)  Overweight (25 ≤ BMI < 30) 102 (27.7) 230 (37.9) 48 (35.8) 110 (49.1) 54 (23.1) 120 (31.3)  Obese (BMI ≥ 30) 55 (14.9) 111 (18.3) 23 (17.2) 41 (18.3) 32 (13.7) 70 (18.3) Tobacco use  Daily cigarette smoking 33 (8.9) 49 (7.9) 9 (6.7) 19 (8.3) 24 (10.1) 30 (7.7)  Daily snuff use 57 (15.4) 66 (10.7) 37 (27.4) 46 (20.3) 20 (8.5) 20 (5.2)  Any daily tobacco use 89 (23.8) 107 (17.2) 45 (33.1) 61 (26.6) 44 (18.5) 46 (11.7) Area of livelihood  Alpine 87 (23.3) 146 (23.4) 33 (24.3) 60 (26.2) 54 (22.7) 86 (21.8)  Inland 110 (29.4) 176 (28.3) 46 (33.8) 72 (31.4) 64 (26.9) 104 (26.4)  Coastal 177 (47.3) 301 (48.3) 57 (41.9) 97 (42.4) 120 (50.4) 204 (51.8) Occupation  Armed forces occupations 2 (0.6) 3 (0.5) 1 (0.8) 2 (0.9) 1 (0.4) 1 (0.3)  Managers 9 (2.5) 22 (3.6) 6 (4.5) 7 (3.1) 3 (1.3) 15 (3.9)  Professionals 73 (20.2) 115 (19.0) 17 (12.9) 24 (10.7) 56 (24.5) 91 (23.9)  Technicians and associate professionals 28 (7.8) 70 (11.6) 14 (10.6) 34 (15.2) 14 (6.1) 36 (9.4)  Clerical support workers 40 (11.1) 47 (7.8) 10 (7.6) 12 (5.4) 30 (13.1) 35 (9.2)  Service and sales workers 57 (15.8) 107 (17.7) 11 (8.3) 30 (13.4) 46 (20.1) 77 (20.2)  Skilled agricultural, forestry, and fishery workers 6 (1.7) 9 (1.5) 2 (1.5) 3 (1.3) 4 (1.7) 6 (1.6)  Crafts and related trades workers 17 (4.7) 26 (4.3) 14 (10.6) 19 (8.5) 3 (1.3) 7 (1.8)  Plant and machine operators and assemblers 27 (7.5) 27 (4.5) 22 (16.7) 22 (9.8) 5 (2.2) 5 (1.3)  Elementary occupations 6 (1.7) 13 (2.1) 3 (2.3) 5 (2.2) 3 (1.3) 8 (2.1)  Self-employed 8 (2.2) 13 (2.1) 2 (1.5) 8 (3.6) 6 (2.6) 9 (2.4)  Students 11 (3.0) 16 (2.6) 1 (0.8) 0 (0) 10 (4.4) 16 (4.2)  Unemployed 4 (1.1) 9 (1.5) 2 (1.5) 4 (1.8) 2 (0.9) 5 (1.3)  Parental leave 3 (0.8) 4 (0.7) 0 (0) 0 (0) 3 (1.3) 4 (1.0)  Sick leave 12 (3.3) 12 (2.0) 1 (0.8) 3 (1.3) 11 (4.8) 9 (2.4)  Retired 58 (16.1) 112 (18.5) 26 (19.7) 51 (22.8) 32 (14.0) 61 (16.0) BMI body mass index daily use of tobacco was associated with cold sensitivity (OR Univariate conditional logistic regression analyses 1.5, 95% CI 1.1–2.0), but this was not statistically significant (Tables 2, 3) among men when analyzed separately. The use of therapeu- tic drugs with documented harmful effects on peripheral Regarding individual factors, being overweight nerves or circulation did not show any association with (25 ≤ BMI < 30) was associated with a lower reported fre- cold sensitivity. The cold sensitivity cases reported a higher quency of cold sensitivity (OR 0.5, 95% CI 0.4–0.7) com- frequency of vascular disease (OR 1.8, 95% CI 1.3–2.6), pared to being normal weight (18.5 ≤ BMI < 25 kg/m ). Any 1 3 790 International Archives of Occupational and Environmental Health (2018) 91:785–797 1 3 Table 2 Univariate conditional logistic regression of factors suggested to be associated with cold sensitivity, including BMI, tobacco use, therapeutic drug use, diseases, and injuries Factor Exposure level All subjects Men Women Cases Controls OR (95% CI) Cases Controls OR (95% CI) Cases Controls OR (95% CI) N (%) N (%) N (%) N (%) N (%) N (%) BMI category BMI < 18.5 5 (1.4) 5 (0.8) 1.6 (0.4–6.7) 0 (0.0) 0 (0.0) – 5 (2.1) 5 (1.3) 1.6 (0.4–6.7) 18.5 ≤ BMI < 25 206 (56.0) 261 (43.0) Reference 63 (47.0) 73 (32.6) Reference 143 (61.1) 188 (49.1) Reference 25 ≤ BMI < 30 102 (27.7) 230 (37.9) 0.5 (0.4–0.7)* 48 (35.8) 110 (49.1) 0.5 (0.3–0.8)* 54 (23.1) 120 (31.3) 0.6 (0.4–0.8)* BMI ≥ 30 55 (14.9) 111 (18.3) 0.6 (0.4–9)* 23 (17.2) 41 (18.3) 0.6 (0.3–1.1) 32 (13.7) 70 (18.3) 0.6 (0.4–0.96)* Any daily tobacco use Yes 89 (23.8) 107 (17.2) 1.5 (1.1–2.0)* 45 (33.1) 61 (26.6) 1.3 (0.9–2.1) 44 (18.5) 46 (11.7) 1.6 (1.04–2.6)* No 285 (76.2) 516 (82.8) Reference 91 (66.9) 168 (73.4) Reference 194 (81.5) 348 (88.3) Reference Therapeutic drug use  Affecting peripheral nerves Yes 33 (11.1) 54 (12.3) 1.0 (0.6–1.7) 19 (18.3) 31 (20.3) 0.7 (0.4–1.6) 14 (7.3) 23 (8.1) 1.3 (0.6-3.0) No 263 (88.9) 384 (87.7) Reference 85 (81.7) 122 (79.7) Reference 178 (92.7) 262 (91.9) Reference  Affecting peripheral circulation Yes 55 (19.1) 81 (18.9) 1.3 (0.8–2.1) 22 (22.0) 24 (16.4) 1.7 (0.7–3.7) 33 (17.6) 57 (20.1) 1.1 (0.6-2.0) No 233 (80.9) 348 (81.1) Reference 78 (78.0) 122 (83.6) Reference 155 (82.4) 226 (79.9) Reference Diseases and injuries  Vascular disease Yes 109 (29.1) 151 (25.5) 1.8 (1.3–2.6)* 50 (41.0) 70 (32.4) 2.2 (1.2–3.9)* 59 (26.6) 81 (21.6) 1.6 (1.04–2.5)* No 235 (68.3) 440 (74.5) Reference 72 (59.0) 146 (67.6) Reference 163 (73.4) 294 (78.4) Reference  Diabetes mellitus Yes 13 (3.5) 28 (4.6) 0.9 (0.5–1.8) 6 (4.4) 12 (5.4) 0.9 (0.3–2.4) 7 (3.0) 16 (4.1) 0.9 (0.4–2.3) No 356 (96.5) 581 (95.4) Reference 129 (95.6) 211 (94.6) Reference 227 (97.0) 370 (95.9) Reference  Migraines Yes 59 (16.1) 50 (8.2) 2.2 (1.4–3.3)* 12 (9.0) 10 (4.4) 2.0 (0.9–4.7) 47 (20.2) 40 (10.5) 2.2 (1.4–3.6)* No 307 (83.9) 558 (91.8) Reference 121 (91.0) 216 (95.6) Reference 186 (79.8) 342 (89.5) Reference  Rheumatic disease Yes 66 (18.1) 45 (7.4) 3.2 (2.1-5.0)* 15 (11.4) 16 (7.1) 2.0 (0.9–4.3) 51 (21.9) 29 (7.6) 3.9 (2.3–6.8)* No 299 (81.9) 562 (92.6) Reference 117 (88.6) 208 (92.9) Reference 182 (78.1) 354 (92.4) Reference  Carpal tunnel syndrome Yes 39 (10.9) 50 (8.2) 1.5 (0.9–2.3) 13 (10.0) 19 (8.5) 1.3 (0.6-3.0) 26 (11.4) 31 (8.1) 1.6 (0.9–2.7) No 320 (89.1) 559 (91.8) Reference 117 (90.0) 205 (91.5) Reference 203 (88.6) 354 (91.9) Reference  Polyneuropathy Yes 13 (3.6) 4 (0.7) 7.4 (2.1–26.4)* 7 (5.3) 2 (0.9) 10.2 (1.2–85.4)* 6 (2.6) 2 (0.5) 6.0 (1.2–29.7)* No 350 (96.4) 602 (99.3) Reference 125 (94.7) 222 (99.1) Reference 225 (97.4) 380 (99.5) Reference Upper extremity nerve injury Yes 119 (32.6) 112 (18.3) 2.3 (1.7–3.1)* 50 (37.6) 47 (20.6) 2.3 (1.4–3.7)* 69 (29.7) 65 (16.9) 2.3 (1.5–3.5)* No 246 (67.4) 500 (81.7) Reference 83 (62.4) 181 (79.4) Reference 163 (70.3) 319 (83.1) Reference Frostbite hands Yes 114 (30.6) 34 (5.5) 10.2 (6.0–17.2)* 53 (39.0) 13 (5.7) 18.9 (6.8–52.6)* 61 (25.8) 21 (5.4) 7.2 (3.9–13.6)*  No 258 (69.4) 583 (94.5) Reference 83 (61.0) 215 (94.3) Reference 175 (74.2) 368 (94.6) Reference  Data presented in total and separated by sex BMI body mass index *Bold values indicate odds ratios with significant 95% confidence intervals Statins, antibiotics, immunosuppressive drugs, antineoplastic agents, amiodarone, dapsone, phenytoin and/or hydralazine Beta-adrenergic antagonists, interferons, systemic hormone replacement or contraceptive treatment, antineoplastic agents, sympathomimetics drugs, lithium, clonidine, and/or ergotamine Hypertension, angina pectoris, myocardial infarction, stroke, and/or peripheral vascular disease Systemic sclerosis, CREST syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, reactive arthritis, unspecified arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, Sjogren’s syndrome, Ehlers–Danlos syndrome, fibromyalgia, gout, polymyositis, dermatomyositis, Dercum’s disease, and/or mixed connective tissue disease International Archives of Occupational and Environmental Health (2018) 91:785–797 791 1 3 Table 3 Univariate conditional logistic regression of external exposure factors suggested to be associated with cold sensitivity, including different cold and hand–arm vibration exposure meas- ures Factor Exposure level All subjects Men Women Cases Controls OR (95% CI) Cases Controls OR (95% CI) Cases Controls OR (95% CI) N (%) N (%) N (%) N (%) N (%) N (%) Cold exposure measures  Occupational cold exposure (NRS 1–10) High (NRS > 1) 182 (50.4) 242 (40.8) 1.4 (1.1–1.9)* 88 (67.7) 132 (60.8) 1.3 (0.8–2.1) 94 (40.7) 110 (29.3) 1.5 (1.1–2.2)* Low (NRS 1) 179 (49.6) 351 (59.2) Reference 42 (32.3) 85 (39.2) Reference 137 (59.3) 266 (70.7) Reference  Leisure-time cold exposure (NRS 1–10) High (NRS > 5) 194 (52.9) 301 (49.3) 1.1 (0.8–1.4) 69 (51.1) 118 (52.0) 1.0 (0.6–1.4) 125 (53.9) 183 (47.8) 1.2 (0.9–1.7) Low (NRS ≤ 5) 173 (47.1) 309 (50.7) Reference 66 (48.9) 109 (48.0) Reference 107 (46.1) 200 (52.2) Reference  Cumulative cold exposure (NRS 2–20) High (NRS > 8) 198 (55.3) 253 (43.0) 1.6 (1.2–2.1)* 81 (62.3) 122 (56.5) 1.2 (0.7–1.9) 117 (51.3) 131 (35.2) 1.8 (1.3–2.6)* Low (NRS ≤ 8) 160 (44.7) 335 (57.0) Reference 49 (37.7) 94 (43.5) Reference 111 (48.7) 241 (64.8) Reference  Cumulative cold exposure (NRS 2–20) 1st quartile 69 (19.3) 141 (24.0) Reference 22 (16.9) 34 (15.7) Reference 47 (20.6) 107 (28.8) Reference 2nd quartile 91 (25.4) 194 (33.0) 1.0 (0.7–1.5) 27 (20.8) 60 (27.8) 0.8 (0.4–1.6) 64 (28.1) 134 (36.0) 1.1 (0.7–1.8) 3rd quartile 110 (30.7) 147 (25.0) 1.5 (1.04–2.3)* 36 (27.7) 62 (28.7) 0.97 (0.5–1.9) 74 (32.5) 85 (22.8) 1.9 (1.2–3.1) 4th quartile 88 (24.6) 106 (18.0) 1.6 (1.1–2.5)* 45 (34.6) 60 (27.8) 1.1 (0.6–2.2) 43 (18.9) 46 (12.4) 1.9 (1.1–3.4)*  Handling cold objects during work Yes 123 (33.5) 108 (17.6) 2.6 (1.9–3.6)* 77 (57.0) 73 (32.0) 2.8 (1.8–4.5)* 46 (19.8) 35 (9.1) 2.4 (1.5–3.9)* No 244 (66.5) 506 (82.4) Reference 58 (43.0) 155 (68.0) Reference 186 (80.2) 351 (90.9) Reference  Extreme cold, wind or cooling moist during work Yes 133 (36.3) 146 (23.8) 2.3 (1.7–3.3)* 85 (63.9) 103 (45.2) 2.4 (1.5–3.9)* 48 (20.6) 43 (11.1) 2.2 (1.4–3.6)* No 233 (63.7) 468 (76.2) Reference 48 (36.1) 125 (54.8) Reference 185 (79.4) 343 (88.9) Reference Occupational HAV exposure measures  Impact tools Yes 56 (15.2) 47 (7.7) 2.4 (1.5–3.9)* 50 (37.3) 40 (17.5) 2.8 (1.7–4.6)* 6 (2.6) 7 (1.8) 1.3 (0.4-4.0) No 312 (84.8) 567 (92.3) Reference 84 (62.7) 188 (82.5) Reference 228 (97.4) 379 (98.2) Reference  Rapidly rotating tools Yes 14 (3.7) 11 (1.8) 1.9 (0.9–4.2) 10 (7.6) 7 (3.1) 2.3 (0.9-6.0) 4 (1.7) 4 (1.0) 1.3 (0.3–5.3) No 352 (96.2) 602 (98.2) Reference 122 (92.4) 220 (96.9) Reference 230 (98.3) 382 (99.0) Reference  Forestry/gardening tools Yes 53 (14.5) 75 (12.3) 1.4 (0.9–2.2) 47 (35.3) 68 (29.8) 1.4 (0.9–2.4) 6 (2.6) 7 (1.8) 1.3 (0.4-4.0) No 313 (85.5) 537 (87.7) Reference 86 (64.7) 160 (70.2) Reference 227 (97.4) 377 (98.2) Reference  Vibrating tools Yes 62 (16.8) 65 (10.6) 1.9 (1.2–2.9)* 54 (40.6) 58 (25.6) 2.0 (1.2–3.2)* 8 (3.4) 7 (1.8) 1.5 (0.5–4.2) No 306 (83.2) 548 (89.4) Reference 79 (59.4) 169 (74.4) Reference 227 (96.6) 379 (98.2) Reference  Heavily vibrating tools Yes 54 (14.7) 52 (8.5) 2.4 (1.5–3.9)* 51 (38.3) 49 (21.7) 2.5 (1.5–4.1)* 3 (1.3) 3 (0.8) 1.6 (0.3–8.1) No 313 (85.3) 560 (91.5) Reference 82 (61.7) 177 (78.3) Reference 177 (78.3) 383 (99.2) Reference  Vehicles with vibrating controls Yes 50 (13.6) 66 (10.8) 1.5 (0.95–2.3) 42 (31.6) 58 (25.4) 1.5 (0.9–2.4) 8 (3.4) 8 (2.1) 1.6 (0.6–4.2) No 317 (86.4) 547 (89.2) Reference 91 (68.4) 170 (74.6) Reference 226 (96.6) 377 (97.9) Reference  Any HAV exposure Yes 111 (30.3) 131 (21.4) 2.1 (1.4–3.0)* 89 (66.4) 107 (46.9) 2.6 (1.6–4.3)* 22 (9.5) 24 (6.2) 1.4 (0.8–2.6) No 255 (69.7) 482 (78.6) Reference 45 (33.6) 121 (53.1) Reference 210 (90.5) 361 (93.8) Reference 792 International Archives of Occupational and Environmental Health (2018) 91:785–797 polyneuropathy (OR 7.4, 95% CI 2.1–26.4), upper extremity nerve injury (OR 2.3, 95% CI 1.7–3.1), and frostbite affect- ing the hands (OR 10.2, 95% CI 6.0–17.2). This relationship was also seen when analyzing men and women separately. Cases also reported a higher prevalence of migraines (OR 2.2, 95% CI 1.4–3.3), and rheumatic disease (OR 3.2, 95% 2.1–5.0), but this was not statistically significant among men when sex-specific subgroup analyses were performed. For ambient factors, handling cold objects at work was associated with cold sensitivity (OR 2.6, 95% CI 1.9–3.6), as well as exposure to extreme cold, wind, or cooling moisture during work (OR 2.3, 95% CI 1.7–3.3). These ambient fac- tors were also associated among both men and women, ana- lyzed separately. A high occupational cold exposure (above the 50th percentile, translating to NRS > 1 on a scale ranging from 1 to 10) was associated with reporting cold sensitivity (OR 1.4, 95% CI 1.1–1.9), as was a high cumulative cold exposure (above the 50th percentile, translating to NRS > 8 on a scale ranging from 2 to 20) with an OR of 1.6 (95% CI 1.2–2.1). However, these findings were not statistically sig- nificant for men. When the cumulative cold exposure meas- ure was divided into quartiles, a dose–response trend was discernible but not statistically significant in every subgroup. The use of impact tools (OR 2.4, 95% CI 1.5–3.9), vibrating tools (OR 1.9, 95% CI 1.2–2.9), and heavily vibrating tools (OR 2.4, 95% CI 1.5–3.9) all showed associations with cold sensitivity, but only among men. Multiple conditional logistic regression analyses (Table 4) In the multiple model for all cases, cold sensitivity was associated with frostbite affecting the hands (OR 10.3, 95% CI 5.5–19.3), rheumatic disease (OR 3.1, 95% CI 1.7–5.7), upper extremity nerve injury (OR 2.0, 95% CI 1.3–3.0), migraines (OR 2.4, 95% CI 1.3–4.3), and vascular disease (OR 1.9, 95% CI 1.2–2.9). Subjects with BMI ≥ 25 kg/m were less likely to report cold sensitivity than those of nor- mal weight (OR 0.4, 95% CI 0.3–0.6). Among men, cold sensitivity was associated with frost- bite affecting the hands (OR 17.9, 95% CI 6.1–52.1), any HAV exposure (OR 2.2, 95% CI 1.2–4.2), and upper extremity nerve injury (OR 2.4, 95% CI 1.2–4.6). Men with BMI ≥ 25 kg/m were also less likely to report cold sensitiv- ity than normal-weight subjects (OR 0.4, 95% CI 0.2–0.8). Women reporting cold sensitivity showed associations with frostbite affecting the hands (OR 7.6, 95% CI 3.5–16.6), rheumatic disease (OR 4.2, 95% CI 1.9–9.0), migraines (OR 2.3, 95% CI 1.2–4.5), and a high cumulative cold exposure (above the 50th percentile, translating to NRS > 8 on a scale ranging from 2 to 20) (OR 1.6, 95% CI 1.04–2.4). In 1 3 Table 3 (continued) Data presented in total and separated by sex NRS numerical rating scale, HAV hand–arm vibration *Bold values indicate odds ratios with significant 95% confidence intervals Self-estimated occupational cold exposure, reported on a ten-point numerical rating scales (NRS), where a value above the 50th percentile (NRS > 1) was denoted high, while a value below (NRS 1) was denoted low Self-estimated leisure-time cold exposure, reported on a ten-point numerical rating scales (NRS), where a value above the 50th percentile (NRS > 5) was denoted high, while a value below (NRS ≤ 5) was denoted low Self-estimated occupational and leisure-time cold exposure, reported on two separate ten-point numerical rating scales (NRS), were added together to form a cumulative measurement of cold exposure ranging from 2 to 20, and a value above the 50th percentile (NRS > 8) was denoted high, while a value below (NRS ≤ 8) was denoted low First quartile corresponds to NRS 2–5, second quartile NRS 6–8, third quartile NRS 9–11, and forth quartile NRS 12–20 Any occupational use of impact tools, rapidly rotating tools, forestry and gardening tools, vibrating tools, heavily vibrating tools, and/or vehicles with vibrating controls International Archives of Occupational and Environmental Health (2018) 91:785–797 793 Table 4 Manual forward Factor Exposure level Cases Controls OR (95% CI) stepwise multiple conditional N % N % logistic regression of factors associated with cold sensitivity All subjects in the univariate analyses  Frostbite hands Yes 97 30 32 6 10.3 (5.5–19.3)* No 225 70 527 94 Reference –  Rheumatic disease Yes 58 18 36 6 3.1 (1.7–5.7)* No 264 82 523 94 Reference –  BMI category (kg/m ) BMI < 18.5 5 2 5 1 1.1 (0.1–9.9) 18.5 ≤ BMI < 25 185 57 243 43 Reference – BMI ≥ 25 132 41 311 56 0.4 (0.3–0.6)*  Upper extremity nerve injury Yes 98 30 99 18 2.0 (1.3-3.0)* No 224 70 460 82 Reference –  Migraines Yes 51 16 42 8 2.4 (1.3–4.3)* No 271 84 517 92 Reference –  Vascular disease Yes 101 31 142 25 1.9 (1.2–2.9)* No 221 69 417 75 Reference – Men  Frostbite hands Yes 51 39 13 6 17.9 (6.1–52.1)* No 79 61 209 94 Reference –  Any HAV exposure Yes 87 67 103 46 2.2 (1.2–4.2)* No 43 33 119 54 Reference –  BMI category (kg/m ) BMI < 18.5 0 0 0 0 – – 18.5 ≤ BMI < 25 62 48 73 33 Reference – BMI ≥ 25 68 52 149 67 0.4 (0.2–0.8)*  Upper extremity nerve injury Yes 49 38 46 21 2.4 (1.2–4.6)* No 81 62 176 79 Reference – Women  Frostbite hands Yes 53 25 19 6 7.6 (3.5–16.6)* No 159 75 326 94 Reference –  Rheumatic disease Yes 45 21 23 7 4.2 (1.9-9.0)* No 167 79 322 93 Reference –  BMI category (kg/m ) BMI < 18.5 5 2 5 1 1.5 (0.2–13.4) 18.5 ≤ BMI < 25 130 61 168 49 Reference – BMI ≥ 25 77 36 172 50 0.5 (0.3–0.8)*  Upper extremity nerve injury Yes 57 27 55 16 1.5 (0.9–2.7) No 155 73 290 84 Reference –  Migraines Yes 42 20 34 16 2.3 (1.2–4.5)* No 170 80 311 84 Reference –  Cumulative cold exposure High (NRS > 8) 106 50 119 34 1.6 (1.04–2.4)* Low (NRS ≤ 8) 106 50 226 66 Reference – Data presented in total and separated by sex BMI body mass index, HAV hand–arm vibration *Bold values indicate odds ratios with significant 95% confidence intervals Systemic sclerosis, CREST syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, reactive arthri- tis, unspecified arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, Sjogren’s syndrome, Ehlers–Danlos syndrome, fibromyalgia, gout, polymyositis, dermatomyositis, Dercum’s disease, and/or mixed connective tissue disease Hypertension, angina pectoris, myocardial infarction, stroke, and/or peripheral vascular disease Any occupational use of impact tools, rapidly rating tools, forestry and gardening tools, vibrating tools, heavily vibrating tools, and/or vehicles with vibrating controls Self-estimated occupational and leisure-time cold exposure, reported on two separate ten-point numerical rating scales (NRS), were added together to form a cumulative measurement of cold exposure ranging from 2 to 20, and a value above the 50th percentile (NRS > 8) was denoted high, while a value below (NRS ≤ 8) was denoted low 1 3 794 International Archives of Occupational and Environmental Health (2018) 91:785–797 conformity with the other results, a BMI ≥ 25 showed an below 0 °C, and non-freezing cold injuries (such as chil- inverse relationship (OR 0.5, 95% CI 0.3–0.8) to reporting blains) which occur at temperatures above 0 °C and often cold sensitivity. in conjunction with moisture and local pressure (Imray and Oakley 2005). In this study, ambient cold exposure for women, and previous frostbite occurrence in both men and Discussion women were generally more pronounced among cases than controls, which adds to the increasing body of data sup- Key results porting cold exposure as being a cause of cold sensitivity. However, in an earlier study we demonstrated that high- The present study shows that cold sensitivity, on a popula- cumulative ambient cold exposure in the general population tion level, is associated with several individual and external is positively related to symptoms of cold sensitivity, even in exposure factors and that the associations are somewhat the absence of overt cold injury (Stjernbrandt et al. 2017). A dependent on sex. In the multiple conditional logistic regres- recently published study on heavily cold-exposed Swedish sion model, previous occurrence of frostbite affecting the military conscripts showed a significant increase in symp- hands had the strongest association with reporting increased toms of cold sensitivity after winter training, present also in cold sensitivity for both men and women. Being overweight subjects where no cold injury had been reported (Carlsson seemed to be a protection against reporting cold sensitivity et al. 2016). Earlier reports from the Falklands War revealed for both sexes. For men, HAV exposure and upper extremity marked cold sensitivity in British servicemen with mild or nerve injury were positively associated with cold sensitivity, even subclinical cases of cold injury (Thomas and Oakley while women showed associations with rheumatic disease, 2001). Hence, at the present time there is not enough data to migraines, and cumulative cold exposure. Vascular disease establish a safe lower limit for ambient cold exposure, and was statistically associated with cold sensitivity only when the traditional classification of cold injuries into freezing and men and women were analyzed together. non-freezing does not seem to aid in the recognition of cold sensitivity development. Interpretation and comparison In our univariate analyses, HAV exposure of any kind showed an association with cold sensitivity among men, but The case definition in this study was fulfilled predominantly not in women. This sex difference is suspected to be due by non-smoking middle-aged women. Some previous stud- to a small sample of exposed women, causing issues with ies have reported associations between cold sensitivity and statistical power. When looking at subgroups of vibrating age (Schlenker et al. 1980), gender (Ruijs et al. 2007), and equipment, the tools commonly recognized to have the most tobacco use (Irwin et al. 1997), while others have not found harmful effects (impact tools and heavily vibrating tools) such relations (Collins et al. 1996; Craigen et al. 1999; Nan- were the ones that showed significant associations with carrow et al. 1996). Our nested case–control study design cold sensitivity. Thus, our findings support previous studies with matching did not allow analyses on age and gender to reporting a relationship between HAV exposure and cold be made, but univariate analyses supported the notion that sensitivity (Carlsson et al. 2010c; Necking et al. 2002). tobacco use can aggravate cold sensitivity, possibly through There were several diseases and injuries that were more a vasoconstrictive mechanism mediated by nicotine. The use prevalent among the cold sensitivity cases than the con- of drugs with negative effects on peripheral nerve function trols in the present study. Upper extremity nerve injuries and circulation did not differ significantly between cases were particularly common, and this is in line with previous and controls. Thus, the adverse effects of medication are research (Engkvist et al. 1985; Nylander et al. 1987). Some probably not the primary explanation for cold sensitivity. authors have argued that nerve injury should be considered An alternative view may be that the results are skewed by the main determinant of cold sensitivity (Ruijs et al. 2007), discontinuation of such drugs in cold sensitivity cases, e.g., while others have argued that in traumatic hand injury, both beta-adrenergic antagonists being exchanged for other anti- vascular, neural, humoral, and bony components can been hypertensive drugs in patients who report cold hands. A high associated with cold sensitivity (Carlsson and Dahlin 2014). BMI was inversely associated with cold sensitivity, which The presence of vascular disease showed a relationship with suggests that it acts as a protective factor, possibly through cold sensitivity in our study, which would support the theory a passive insulating mechanism. of a vascular mechanism. This finding was seen in all univar - Frostbite was very common in our case population, and iate analyses, but only when men and women were grouped increased cold sensitivity is a recognized sequela in individ- together in the multiple analyses. Furthermore, female cases uals with previous cold injury (Thomas and Oakley 2001). had a significantly higher frequency of rheumatic disease Local cold injuries are traditionally categorized into freezing than controls. Among patients with rheumatic disease, cold injuries (such as frostbite), occurring at temperatures both cold sensitivity (Merkel et al. 2002) and Raynaud’s 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 795 phenomenon (Garner et  al. 2015) have previously been Raynaud’s phenomenon, which makes the diagnosis diffi- reported as a common complaint. In the present study, there cult to establish. Our cases reported a high occurrence of was also a very high prevalence of Raynaud’s phenomenon Raynaud’s phenomenon, but this was excluded for among among cases. Thus, cold sensitivity and Raynaud’s phenom- controls, which could possibly have introduced a systematic enon seem to be heavily overlapping conditions that may bias into our results. However, since the expected frequency share some pathophysiological mechanisms, which war- of Raynaud’s phenomenon among healthy controls is low, rants further research. One novel finding in our study was we believe this possible effect to be rather weak. The cold the association between migraines and cold sensitivity (OR exposure estimates in our study are defined from a subjec- 2.4, 95% CI 1.3–4.3 in the multiple analyses for all subjects). tive standpoint. These conditions limit the generalizability Some studies have reported a dysfunctional vasoregulatory of the results and increase the uncertainty in risk estimates. response to cold exposure in cold sensitive subjects, with There are several possible reporting biases; firstly, there is a increased vasoconstriction (Hope et al. 2014) or abnormal possibility that symptomatic subjects might be more prone baroreceptor response (Marchant et al. 1994). One may thus to respond to questionnaires of this kind, and this might lead hypothesize that cold sensitivity is not primarily related to to an overestimation of both exposure and symptoms; sec- atherosclerotic vascular disease, but rather to a dysfunctional ondly, there is a risk that a selection effect diminishes the vasoregulatory system, in which neural function also may cold exposure estimates in cold sensitive cases, since one play an important role. would expect that such individuals leave cold-exposed occu- Abnormal cold sensitivity according to CISS (score > 50) pations, and are deterred from leisure-time cold exposure was seen in 46.6% of cases and 6.6% of controls in the pre- as well, as was the case in previous studies (Carlsson and sent study, all selected from the general population. This Dahlin 2014). The number of retired respondents was high, supports our case selection criteria being relevant. In another which might weaken any possible associations with occu- Swedish study using the same inventory and cut-off value, pational factors. The study region comprises a large area abnormal cold sensitivity was seen in 75.0% of patients with with a mean monthly temperature during the study period HAV injury, 51.0% of patients with previous amputation that spanned from about − 9 to 5 °C during the initial data injury, 37.1% of patients with nerve injury, and 4.9% of collection, meaning that there is reason to suspect a variance healthy controls (Carlsson et al. 2010c), closely resembling in ambient cold exposure that has not been adjusted for in our results. A simpler but less validated approach to grading the analyses. Thus, the results in our study can be used to the condition would be the use of the VAS, which is easy generate hypotheses regarding the mechanisms behind cold to report and gives an intuitive result. In the present study, sensitivity, but must be cautiously interpreted with regard to VAS showed a clear distinction between cases and controls, limitations in the study design. supporting its usefulness. The experience of cold sensitivity is influenced by psy - Strengths chological factors (Carlsson et al. 2010a), and recent labora- tory studies have shown a more pronounced pain response However, to our knowledge this was the first population- to a cold pressor test among individuals with high anxiety based study on cold sensitivity, and it included almost a sensitivity (Dodo and Hashimoto 2017). Additionally, per- thousand participants. The anthropometric data, tobacco use, ception thresholds to cold and pain are often assessed by and disease spectrum in our cohort roughly corresponded psychophysical methods, where the responses are modulated with other recent Swedish investigations (Eriksson et al. by psychological factors (Carlsson et al. 2016). The present 2011), which indicates that our study has included a rep- study did not include psychological variables, and this topic resentative sample of the population. Our previously pub- remains an important issue for further research. lished non-responder analysis revealed no major differences between responders and non-responders regarding geograph- Limits ical region, which was the expected main determinant of cold exposure variables (Stjernbrandt et al. 2017). Thus the There are several limitations to our study. The nested possible bias introduced by a low response rate in the first case–control study design does not allow causal relations questionnaire (CHINS1) is not believed to have affected the to be established. The response rate to the initial ques- exposure data in the present study to any larger extent. The tionnaire (CHINS1) was low (35.9%), and as only 4.0% cold sensitivity questionnaire (CHINS2) was sent out during of that group subsequently fulfilled our case definition for the coldest period of the year, which should lessen the risk the second questionnaire (CHINS2), the cases are highly of recall bias regarding ambient cold exposure. The study selected. There is no universally established definition of population was randomly selected from the entire northern cold sensitivity, and the condition seems to overlap with region of Sweden, and contains a heterogeneous group of 1 3 796 International Archives of Occupational and Environmental Health (2018) 91:785–797 Bakst R, Merola JF, Franks AG Jr, Sanchez M (2008) Raynaud’s phe- participants from many different backgrounds. Instead of nomenon: pathogenesis and management. J Am Acad Dermatol only investigating subjects experiencing cold sensitivity as 59:633–653. https ://doi.org/10.1016/j.jaad.2008.06.004 a sequela to a certain injury or disease, this study takes a Baldus S, Kluth K, Strasser H (2012) Order-picking in deep cold–phys- general population’s perspective on cold sensitivity. iological responses of younger and older females. Part 2: body core temperature and skin surface temperature. Work 41(Suppl 1):3010–3017. https ://doi.org/10.3233/WOR-2012-0557-3010 Block JA, Sequeira W (2001) Raynaud’s phenomenon. Lancet Conclusion 357:2042–2048. https://doi.or g/10.1016/S0140-6736(00)05118 -7 Carlsson IK, Dahlin LB (2014) Self-reported cold sensitivity in patients with traumatic hand injuries or hand-arm vibration syndrome - an Cold sensitivity was associated with both individual and eight year follow up. BMC Musculoskelet Disord 15:83. https :// external exposure factors. Being overweight was associated doi.org/10.1186/1471-2474-15-83 with a lower occurrence of cold sensitivity; and among the Carlsson I, Cederlund R, Hoglund P, Lundborg G, Rosen B (2008) acquired conditions, both cold injuries, rheumatic diseases, Hand injuries and cold sensitivity: reliability and validity of cold sensitivity questionnaires. Disabil Rehabil 30:1920–1928. https:// nerve injuries, migraines, and vascular diseases were asso- doi.org/10.1080/09638 28070 16797 05 ciated with the reporting of cold sensitivity. More research Carlsson IK, Edberg AK, Wann-Hansson C (2010a) Hand-injured is needed to confirm a causal relation and determine the patients’ experiences of cold sensitivity and the consequences pathophysiological mechanisms involved. Among external and adaptation for daily life: a qualitative study. J Hand Ther 23:53–61. https ://doi.org/10.1016/j.jht.2009.07.008 exposures, cold climate and HAV exposure were associated Carlsson IK, Nilsson JA, Dahlin LB (2010b) Cut-off value for self- with cold sensitivity, and both are suitable targets for pri- reported abnormal cold sensitivity and predictors for abnormality mary preventive measures. and severity in hand injuries. J Hand Surg Eur 35:409–416. https ://doi.org/10.1177/17531 93409 35418 4 Acknowledgements We gratefully acknowledge the valuable statistical Carlsson IK, Rosen B, Dahlin LB (2010c) Self-reported cold sensitivity contributions of Dr. Johan Nilsson Sommar at the Department of Public in normal subjects and in patients with traumatic hand injuries or Health and Clinical Medicine at Umeå University. hand-arm vibration syndrome. BMC Musculoskelet Disord 11:89. https ://doi.org/10.1186/1471-2474-11-89 Carlsson D, Burstrom L, Lillieskold VH, Nilsson T, Nordh E, Wahl- Funding Financial support was provided through a regional agree- strom J (2014) Neurosensory sequelae assessed by thermal and ment between Umeå University and Västerbotten County Council, vibrotactile perception thresholds after local cold injury. Int J Cir- in addition to a research grant from Västerbotten County Council cumpolar Health. https ://doi.org/10.3402/ijch.v73.23540 (VLL-646641). Carlsson D, Pettersson H, Burstrom L, Nilsson T, Wahlstrom J (2016) Neurosensory and vascular function after 14 months of military Compliance with ethical standards training comprising cold winter conditions. Scand J Work Environ Health 42:61–70. https ://doi.org/10.5271/sjweh .3530 Ethical standards All procedures performed in studies involving Chan AC, Wilder-Smith EP (2016) Small fiber neuropathy: getting human participants were in accordance with the ethical standards of bigger! Muscle Nerve 53:671–682. https ://doi.or g/10.1002/ the institutional and/or national research committee, and with the 1964 mus.25082 Helsinki Declaration and its later amendments or comparable ethical Collins ED, Novak CB, Mackinnon SE, Weisenborn SA (1996) Long- standards. The study protocol was approved by the Regional Ethical term follow-up evaluation of cold sensitivity following nerve Review Board situated at Umeå University (DNR 2015-24-31M and injury. J Hand Surg Am 21:1078–1085 2014-286-31M). Craigen M, Kleinert JM, Crain GM, McCabe SJ (1999) Patient and injury characteristics in the development of cold sensitivity of the Informed consent Informed consent was obtained from all individual hand: a prospective cohort study. J Hand Surg Am 24:8–15. https participants included in the study. ://doi.org/10.1053/jhsu.1999.jhsu2 4a000 8 Dodo N, Hashimoto R (2017) The effect of anxiety sensitivity on psychological and biological variables during the cold pressor Conflict of interest The authors declare that they have no conflicts of test. Auton Neurosci 205:72–76. https ://doi.org/10.1016/j.autne interest. u.2017.05.006 Engkvist O, Wahren LK, Wallin G, Torebjrk E, Nystrom B (1985) Open Access This article is distributed under the terms of the Crea- Effects of regional intravenous guanethidine block in post- tive Commons Attribution 4.0 International License (http://creat iveco traumatic cold intolerance in hand amputees. J Hand Surg Br mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- 10:145–150 tion, and reproduction in any medium, provided you give appropriate Eriksson M, Holmgren L, Janlert U, Jansson JH, Lundblad D, Steg- credit to the original author(s) and the source, provide a link to the mayr B et al (2011) Large improvements in major cardiovascular Creative Commons license, and indicate if changes were made. risk factors in the population of Northern Sweden: the MONICA study 1986–2009. J Intern Med 269:219–231. https ://doi.org/10. 1111/j.1365-2796.2010.02312 .x Garner R, Kumari R, Lanyon P, Doherty M, Zhang W (2015) Preva- References lence, risk factors and associations of primary Raynaud’s phe- nomenon: systematic review and meta-analysis of observational Asbury A (2006) Approach to the patient with peripheral neuropa- studies. BMJ Open 5:e006389. https ://doi.or g/10.1136/bmjop thy. In: Hauser S (ed) Harrison’s neurology in clinical medicine. en-2014-00638 9 MgGraw-Hill, San Francisco, pp 491–508 1 3 International Archives of Occupational and Environmental Health (2018) 91:785–797 797 Hope K, Eglin C, Golden F, Tipton M (2014) Sublingual glyceryl Arch Occup Environ Health 81:633–638. https://doi.or g/10.1007/ trinitrate and the peripheral thermal responses in normal and s0042 0-007-0248-2 cold-sensitive individuals. Microvasc Res 91:84–89. https ://doi. Nijhuis TH, Smits ES, Jaquet JB, Van Oosterom FJ, Selles RW, Hovius org/10.1016/j.mvr.2013.11.002 SE (2010) Prevalence and severity of cold intolerance in patients Imray CH, Oakley EH (2005) Cold still kills: cold-related illnesses in after hand fracture. J Hand Surg Eur 35:306–311. https ://doi. military practice freezing and non-freezing cold injury. J R Army org/10.1177/17531 93409 34305 0 Med Corps 151:218–222 Novak CB, Anastakis DJ, Beaton DE, Mackinnon SE, Katz J (2012) International Labour Organization (2012) International Standard Clas- Cold intolerance after brachial plexus nerve injury. Hand (N Y) sification of Occupations (ISCO-08), Geneva, Switzerland. ISBN 7:66–71. https ://doi.org/10.1007/s1155 2-011-9370-4 978-92-2-125953-4 Nylander G, Nylander E, Lassvik C (1987) Cold sensitivity after International Organization for Standardization (2008) ISO replantation in relation to arterial circulation and vasoregulation. 15743:2008—Ergonomics of the thermal environment—Cold J Hand Surg Br 12:78–81 workplaces—Risk assessment and management, Brussels Raatikka VP, Rytkonen M, Nayha S, Hassi J (2007) Prevalence of Irwin MS, Gilbert SE, Terenghi G, Smith RW, Green CJ (1997) Cold cold-related complaints, symptoms and injuries in the general intolerance following peripheral nerve injury. Natural history population: the FINRISK 2002 cold substudy. Int J Biometeorol and factors predicting severity of symptoms. J Hand Surg Br 51:441–448. https ://doi.org/10.1007/s0048 4-006-0076-1 22:308–316 Riaz M, Hill C, Khan K, Small JO (1999) Long term outcome of Kay S (1985) Venous occlusion plethysmography in patients with cold early active mobilization following flexor tendon repair in related symptoms after digital salvage procedures. J Hand Surg zone 2. J Hand Surg Br 24:157–160. h t t p s : / / d o i . o r g /1 0 .1 0 5 4 / Br 10:151–154 jhsb.1998.0175 Keim SM, Guisto JA, Sullivan JB Jr (2002) Environmental thermal Ruijs AC, Jaquet JB, van Riel WG, Daanen HA, Hovius SE (2007) stress. Ann Agric Environ Med 9:1–15 Cold intolerance following median and ulnar nerve injuries: prog- Klocker J, Peter T, Pellegrini L, Mattesich M, Loescher W, Sieb M nosis and predictors. J Hand Surg Eur Vol 32:434–439. https://doi. et al (2012) Incidence and predisposing factors of cold intoler- org/10.1016/j.jhsb.2007.02.012 ance after arterial repair in upper extremity injuries. J Vasc Surg Schlenker JD, Kleinert HE, Tsai TM (1980) Methods and results of 56:410–414. https ://doi.org/10.1016/j.jvs.2012.01.060 replantation following traumatic amputation of the thumb in sixty- Koman LA, Slone SA, Smith BP, Ruch DS, Poehling GG (1998) Sig- four patients. J Hand Surg Am 5:63–70 nificance of cold intolerance in upper extremity disorders. J South Statistics Sweden (2016) Swedish National Population Statistics. Orthop Assoc 7:192–197 Stockholm: Statistics Sweden. http://www.scb.se. Accessed 26 Lithell M, Backman C, Nystrom A (1997) Pattern recognition in post- April 2016 traumatic cold intolerance. J Hand Surg Br 22:783–787 Stjernbrandt A, Bjor B, Andersson M, Burstrom L, Liljelind I, Nils- Makinen TM, Hassi J (2002) Usability of isothermal standards for son T et al (2017) Neurovascular hand symptoms in relation to cold risk assessment in the workplace. Int J Circumpolar Health cold exposure in Northern Sweden: a population-based study. Int 61:142–153 Arch Occup Env Health 90:587–595. https ://doi.or g/10.1007/ Marchant B, Donaldson G, Mridha K, Scarborough M, Timmis AD s0042 0-017-1221-3 (1994) Mechanisms of cold intolerance in patients with angina. J Swedish Work Environment Authority (2016) The Work Environment Am Coll Cardiol 23:630–636 2015, Report no. 2016:2, Stockholm: Swedish Work Environment McCabe SJ, Mizgala C, Glickman L (1991) The measurement of cold Authority sensitivity of the hand. J Hand Surg Am 16:1037–1040 Tark KC, Kim YW, Lee YH, Lew JD (1989) Replantation and revas- McKirdy S (2007) A retrospective review of cold intolerance follow- cularization of hands: clinical analysis and functional results of ing corrective surgery for Dupuytren’s disease. Br J Hand Ther 261 cases. J Hand Surg Am 14:17–27 12:55–59 Thomas J, Oakley EH (2001) Nonfreezing cold injury. In: Pandolf K, Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P et al Burr R (eds) Textbook of military Medicine, Medical aspects of (2002) Measuring disease activity and functional status in patients harsh environments, vol 1. US Army, Washington, pp 467–490 with scleroderma and Raynaud’s phenomenon. Arthritis Rheum Thomsen NO, Cederlund R, Rosen I, Bjork J, Dahlin LB (2009) Clini- 46:2410–2420. https ://doi.org/10.1002/art.10486 cal outcomes of surgical release among diabetic patients with Nancarrow JD, Rai SA, Sterne GD, Thomas AK (1996) The natural carpal tunnel syndrome: prospective follow-up with matched con- history of cold intolerance of the hand. Injury 27:607–611 trols. J Hand Surg Am 34:1177–1187. https ://doi.org/10.1016/j. Necking LE, Lundborg G, Friden J (2002) Hand muscle weakness in jhsa.2009.04.006 long-term vibration exposure. J Hand Surg Br 27:520–525 Negro C, Rui F, D’Agostin F, Bovenzi M (2008) Use of color charts for the diagnosis of finger whiteness in vibration-exposed workers. Int 1 3

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International Archives of Occupational and Environmental HealthSpringer Journals

Published: May 28, 2018

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