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Clinical Science

Brief Report: Association Between Pain, Pulmonary Function, and Respiratory Symptoms in People With HIV

Singhvi, Deepti G. MDa; Nouraie, Mehdi MD, PhDa; Kessinger, Cathy RNa; McMahon, Deborah K. MDa; Weinman, Renee MPPMa; Crothers, Kristina MDb; Huang, Laurence MDc; Bon, Jessica MD, MSa,d; Morris, Alison MD, MSa,e; Merlin, Jessica MD, PhD, MBAa

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2021 - Volume 87 - Issue 5 - p 1161-1166
doi: 10.1097/QAI.0000000000002696
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Abstract

INTRODUCTION

In the combination antiretroviral therapy (ART) era, people with HIV (PWH) have a near-normal life expectancy1 yet experience a higher than expected number of comorbidities. Chronic pain is one such comorbidity2–6 and is associated with impaired mobility and physical function in PWH.7,8 Pulmonary function abnormalities and dyspnea are also common in PWH, with respiratory symptoms related to airflow obstruction,9 emphysema,10,11 and impaired diffusing capacity.12,13 Abnormalities in pulmonary function have been associated with increased mortality14,15 and decreased 6-minute walk distance16,17 in PWH. HIV is also recognized as an independent risk factor for chronic obstructive pulmonary disease (COPD),18–22 although the prevalence of COPD in HIV cohorts has varied depending on use of tobacco, illicit drugs, and ART.10,23–27 Finally, individuals with both HIV and COPD experience sleep disturbance,28–31 which can significantly impair quality of life and worsen pain.

Chronic pain, sleep disturbance, and respiratory comorbidities have been linked, yet their relationship is not well understood in HIV.32–35 It is clear that pain and lung disease are closely related, and pain may affect the impaired pulmonary function and dyspnea seen in PWH beyond what HIV itself is known to do. Understanding the relationship between these comorbidities could help identify more effective interventions to improve quality of life in PWH. We investigated associations between pain, respiratory symptoms, and pulmonary function in a US cohort of PWH. Our objective was to relate the presence and severity of pain to measures of lung function, respiratory symptoms, and sleep disturbance.

METHODS

Participants from the Pittsburgh HIV Lung Cohort23,36 enrolled from outpatient clinics at the University of Pittsburgh, University of California San Francisco, and University of Washington were included. Subjects with HIV infection, age ≥18 years, were recruited between 2015 and 2019. The study protocol was approved by the institutional review boards of all participating institutions, and all participants signed written, informed consent. At the study visit, demographics, smoking history, illicit drug use, current ART, and comorbidities were collected by standardized participant interview. Participants underwent pulmonary function testing and completed a pain questionnaire on the same day. Peripheral CD4+ counts and plasma HIV RNA levels (viral load) were confirmed by chart review or direct testing within 6 months from the study visit.

A 2-item Brief Chronic Pain Questionnaire was completed asking about pain duration and severity (none, very mild, mild, moderate, severe, and very severe).37,38 Pain was considered chronic if present for >3 months. Individuals who indicated the presence of at least mild pain for >3 months also described its location and completed the three-question Pain, Enjoyment, General Activity Scale, with each question scored between 0 and 10. Participants completed the Pittsburgh Sleep Quality Index (PSQI), evaluating sleep in 7 different domains over a 1-month period,39 with each domain scored from 0 to 3. Higher numbers indicated worse sleep.

Study participants performed spirometry before and after bronchodilator administration, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC),40 and diffusing capacity for carbon monoxide (DLCO)41 following the American Thoracic Society/European Respiratory Society standards.42 DLCO was corrected for hemoglobin and carboxyhemoglobin.42 Hankinson and Neas equations were used to determine percent predicted values of spirometry and DLCO measurements, respectively.42,43 COPD was defined as a postbronchodilator FEV1/FVC ratio less than 0.70 based on the Global Initiative for Chronic Obstructive Lung Disease.44

The majority of participants (93.7%) also performed a 6-minute walk test (6MWT) with distance measured in meters45 to assess impact of pain on exercise capacity. All participants completed the St. George's Respiratory Questionnaire (SGRQ), a validated 50-item questionnaire that measures the impact of respiratory symptoms on overall health, daily life, and perception of well-being (scored from 0 to 100 with higher scores indicating more limitations).46,47

Statistical Analysis

Descriptive statistics were performed to visualize demographic data. Pain severity responses were translated into scores of 0–5, with higher scores indicating more severe pain. The sum of the 7 scores in the PSQI was reported, with a score ≥5 indicating a “poor” sleeper. Associations between pain severity and lung function (FEV1 %predicted, FVC %predicted, and DLCO %predicted), 6MWT, PSQI, and SGRQ were assessed with bivariate and multiple quantile regression analysis. Results of associations were reported with a coefficient, the difference in medians between groups, with a coefficient of zero indicating no difference. Regression analyses were adjusted for age, sex, race, body mass index (BMI), and smoking status. The confounders were selected based on the established association of these variables with the measured outcomes.39,48–50 Statistical analysis was performed using Stata 16.0 (StataCorp LLC, College Station, TX).

RESULTS

One hundred fifty-nine PWH were enrolled. Most participants (69.2%) were men, aged ≥55 (59.7%) years, and 47.2% were Black (Table 1). More than 60% were overweight or obese/morbidly obese (median BMI 26.6). More than two-thirds (69.2%) had ever smoked, with 47.2% currently smoking. The majority (86.8%) reported current or previous illicit drug use. Self-reported comorbid medical conditions included diabetes mellitus (18.2%), cancer (18.2%), hepatitis C virus (24.5%), and sleep apnea (15.7%). Nearly all (92.5%) were taking ART. In the 143 participants with HIV viral loads, 19.6% had detectable viremia (>40 copies/mL). In the 111 participants with CD4+ counts, median CD4+ count was 646 cells/mm3 and 86.5% had a CD4+ count ≥350 cells/mm3.

TABLE 1. - Participant Demographics, Baseline Characteristics, and Pain Prevalence
No. of Participants, n 159
Age, yrs, median (p25, p75, range) 56 (50, 60, 25–81)
Age groups, n (%)
 25–34 9 (5.7)
 35–44 10 (6.3)
 45–54 45 (28.3)
 ≥55 95 (59.7)
Male, n (%) 110 (69.2)
Female, n (%) 49 (30.8)
Race, n (%)
 White 70 (44.0)
 Black 75 (47.2)
 Other 14 (8.8)
BMI, kg/m2, mean (SD) 27.6 (6.5)
 Underweight (<18.5) 3 (1.9)
 Normal (≥18.5, <25) 59 (37.1)
 Overweight (≥25, <30) 52 (32.7)
 Obese/morbidly obese (≥30) 45 (28.3)
Smoking status, n (%)
 Current smoker 75 (47.2)
 Previous smoker 35 (22.0)
 Never smoker 49 (30.8)
History illicit drug use, n (%) 138 (86.8)
Detectable viral load (>40 copies/mL), n (%), n = 143 28 (19.6)
Latest CD4+ count, cells/mm3, median (p25, p75, range), n = 111 646 (442, 847, 0–1546)
CD4+ ranges, n (%)
 <200 8 (7.2)
 200–349 7 (6.3)
 ≥350 96 (86.5)
Currently receiving ART, n (%) 147 (92.5)
Comorbidities (self-reported), n (%)
 Diabetes 29 (18.2)
 Cancer 29 (18.2)
 COPD 28 (17.6)
 Hepatitis C 39 (24.5)
 Sleep apnea 25 (15.7)
 Pulmonary hypertension 1 (0.6)
 Pulmonary tuberculosis 10 (6.3)
Pulmonary function testing
 FEV1 %predicted, mean (SD), n = 155 90.7 (21.5)
 FVC %predicted, mean (SD), n = 155 93.1 (18.3)
 FEV1/FVC ratio, mean (SD), n = 156 0.76 (0.1)
 FEV1/FVC ratio <0.7, n (%) 38 (24.4)
 DLCO %predicted, mean (SD), n = 153 78.4 (18.4)
 DLCO <0.8, n (%), n = 153 79 (51.6)
6MWT distance, m, median (p25, p75, range), n = 149 448 (373, 492, 183–683)
Expected walk distance, m, median (p25, p75, range), n = 159 570 (515, 633, 335–837)
SGRQ score, median (p25, p75, range), n = 159 8.7 (2.9, 19.9, 0–67.4)
PSQI, median (p25, p75, range), n = 158 7 (4, 9, 1–16)
Pain in past 1 wk, n (%)
 None 53 (33.3)
 Very mild 33 (20.8)
 Mild 30 (18.9)
 Moderate 29 (18.2)
 Severe 12 (7.5)
 Very severe 2 (1.3)
Pain prevalence by age, n (%), n = 106
 25–34 4 (3.8)
 35–44 7 (6.6)
 45–54 32 (30.2)
 ≥55 63 (59.4)
Pain lasting >3 mo (chronic pain), n (%) 64 (40.3)

Mean values for postbronchodilator FEV1 %predicted, FVC %predicted, and FEV1/FVC ratio overall were normal (Table 1). Thirty-eight (24.4%) participants met the definition of COPD, although only half of these individuals reported a known clinical diagnosis of COPD. Overall, the mean DLCO value was mildly reduced (78.4% predicted), with 51.6% of participants demonstrating an abnormal DLCO (DLCO %predicted < 80).

One hundred forty-nine participants completed the 6MWT with a median distance of 448 m (range 183–683 m). Expected walk distances for this cohort based on reference equations for the 6MWT in healthy adults ranged from 335 to 837 m with a median of 570 m.51 Participants walked on average 139 m less than expected (P < 0.001). All participants completed the SGRQ with a median score of 8.7 (interquartile range 2.9–19.9), consistent with mild symptoms.52 The median PSQI score was 7 (interquartile range 4—9), indicating poor sleep in most participants.

Two-thirds of participants reported having any pain in the past 1 week, with 46% reporting at least mild pain (Table 1). The prevalence of pain increased with age. More than one-third (40.3%) of participants reported chronic pain. Of the 52 participants with chronic pain who completed additional questions, 50% reported low back pain and 30.8% reported paresthesias in the hands/feet. Pain, Enjoyment, and General Activity scores showed moderate interference of pain in general activity (median score 4.5) and enjoyment of life (median score 4).

Pain severity was higher with female sex (P = 0.038), non-White race (P = 0.005), and current smoker status (P = 0.003) (Table 2). A higher pain score was correlated with a lower CD4+ count (P = 0.035). No associations were found between pain severity and age, BMI, former smoker status, or detectable viremia. There was no association between pain severity and the presence of self-reported comorbidities: pulmonary hypertension (P = 0.719), diabetes (P > 0.9), cancer (P > 0.9), or history of tuberculosis (P = 0.289). After adjustment for age, sex, race, BMI, and smoking status, higher pain severity was correlated with lower postbronchodilator FEV1 %predicted (coefficient = −2.21, P = 0.008, Table 2). A higher pain score was also associated with lower postbronchodilator FVC %predicted (P = 0.019) and the presence of COPD (P = 0.032) after adjustment for these covariates. Although the relationship between pain severity and DLCO %predicted did not achieve statistical significance (P = 0.062), there was a trend toward significance and the coefficient size was comparable to that for FEV1 %predicted and FVC %predicted. Pain severity was not significantly correlated with adjusted 6MWT distance (P > 0.9). A higher SGRQ score was strongly correlated with greater pain severity in both unadjusted and adjusted models (P < 0.001). A higher PSQI score was significantly associated with greater pain severity in both unadjusted and adjusted (both P < 0.001) models (Table 2). A higher SGRQ score was also associated with reduced postbronchodilator FEV1 %predicted (P = 0.009) and reduced FEV1/FVC ratio (P = 0.002) when adjusted for covariates. The presence of pain did not modify these relationships.

TABLE 2. - Association Between Pain Severity and Demographic/Pulmonary Factors From Quantile Regression Analysis
Unadjusted Adjusted for Age, Sex, Race, BMI, and Smoking Status
Coefficient P Coefficient 95% CI P
Age 0 >0.900
Female 1.000 0.038
BMI 0 >0.900
White race −1.000 0.005
Current smoker 0.330 0.003
Former smoker 0 >0.900
CD4+ count (n = 111) −0.001 0.035
Detectable viral load (n = 143) 1.000 0.080
FEV1 %predicted (n = 155) −1.610 0.035 −2.210 −3.840 to −0.570 0.008
FVC %predicted (n = 155) −2.450 0.005 −2.430 −4.450 to −0.410 0.019
FEV1/FVC (n = 156) 0 >0.900 0 −3.770 to 3.770 >0.900
COPD 1.000 0.018 1.000 0.090 to 1.910 0.032
DLCO %predicted (n = 153) 0 >0.900 −2.130 −4.370 to 0.110 0.062
6MWT distance (n = 149) 0 >0.900 0 −0.010 to 0.010 >0.900
SGRQ score (n = 159) 0.040 0.002 0.050 0.030 to 0.080 <0.001
PSQI (n = 158) 0.180 <0.001 0.150 0.070 to 0.230 <0.001
95% CI, 95% confidence interval; coefficient, difference in median between groups, coefficient of 0 indicates no difference; COPD, chronic obstructive pulmonary disease, defined as FEV1/FVC <0.7.

DISCUSSION

We found that greater pain severity was associated with worse pulmonary function and sleep quality in PWH. Pain severity was significantly associated with reduced postbronchodilator FEV1 %predicted, reduced postbronchodilator FVC %predicted, and the presence of COPD. We also detected a trend toward an association between pain severity and reduced DLCO %predicted. In addition, pain was strongly correlated with a higher prevalence of respiratory symptoms and with poor sleep. Despite the established relationship between pain and functional limitations in HIV,7 we did not identify a significant correlation between pain severity and 6MWT distance.

Our finding of pain in two-thirds of participants is consistent with literature demonstrating high levels of pain in PWH.2–4,6 Female sex, non-White race, current smoking status, and lower CD4+ count were significant predictors of pain in our cohort, although these associations are inconsistent in other populations due to variability in participant demographics and limitations of retrospective cross-sectional analyses.

The novel relationships we identified among measures of pain, pulmonary function, and respiratory symptoms are highly relevant given the frequent co-existence of these comorbidities. Associations between lung function and pain have been investigated in COPD, yet findings are inconsistent.53–58 There is, however, a strong correlation between pain and breathlessness in COPD, in both quantitative and qualitative analyses.53,56,58,59

Impaired lung function, symptoms, and pain may be linked in HIV through common underlying causes. Pain and dyspnea are intimately associated,32 and the presence of pain within the neck, thorax, and abdomen may alter respiratory mechanics due to impaired chest wall excursion, leading to breathlessness, obstruction, and restriction.59 Alternately, parenchymal destruction, decreased elasticity, airway inflammation, and airway narrowing—known to occur in PWH10–13—may lead to airflow obstruction and cough, precipitating increased respiratory muscle work of breathing and pain.60 Pain, pulmonary function impairment, and dyspnea have each also been associated with increased systemic inflammation,61–63 and the increase in proinflammatory cytokines known to occur in HIV64 may contribute to an increase in each of these comorbidities. Finally, the presence of depression is strongly correlated with both pain and dyspnea.65,66 The high frequency of depression in PWH67,68 may also provide a link between the concurrent pain and dyspnea these individuals experience.

In our cohort, most individuals also experienced sleep disturbance. Pain severity was highly correlated with a worse PSQI score, yet we found no significant indirect effect of pulmonary function on sleep (data not shown), suggesting that the relationship between pain and sleep impairment is independent of pulmonary function. In our cohort and other studies,69,70 insomnia in PWH seems to be more severe in those with pain, but pulmonary function as a potential mediator has not been previously investigated.

A better understanding of the relationships between pain, lung function, and sleep has substantial clinical relevance in the care of PWH. Identifying these common comorbidities during primary care visits provides an opportunity to improve quality of life, as treatment of pain may affect an individual's perception of dyspnea and vice versa. These concepts will need to be assessed in prospective studies evaluating pain severity and pulmonary function on a longitudinal basis after implementation of specific therapies addressing pain management and/or dyspnea.

There are several limitations to our research. Most importantly, causation between pain and pulmonary factors cannot be established because of our study's cross-sectional nature. In addition, our selection of participants from outpatient clinic may bias our analysis toward healthier individuals. As such, those sampled may not be representative of the overall HIV-infected population in the United States. Our data collection did not include information on pharmacologic pain management, thus pain could be underreported by individuals successfully treated with chronic pain medications. Finally, we did not have objective measures of psychological factors such as depression and anxiety that could confound the associations between pain and respiratory symptoms.

CONCLUSIONS

Our study investigating pain in a cohort of HIV-infected adults in the United States demonstrates that increased levels of pain in PWH correlate with airflow obstruction, worsening respiratory symptoms, and sleep disturbance. Future studies should assess serial measures of pain severity and pulmonary function over time to clarify the direction of this association and underlying mechanisms.

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Keywords:

HIV; pain; pulmonary function; dyspnea

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