September 2021 Pulmonary Case of the Month: A 45-Year-Old Woman with Multiple Lung Cysts

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 45-year-old woman presented with increasing dyspnea on exertion and a history of recurrent pneumothoraces. In March 2018 she had laparoscopic ovarian cyst removal and noted some subsequent shortness of breath. In August 2018 she developed a right pneumothorax requiring chest tube placement. In September 2018 she had recurrent right pneumothorax and had video-assisted thoracoscopic surgery (VATS) with a right pleurodesis. The operative note from the outside VATS indicates a RUL bleb was removed and a wedge biopsy was done from posterior segment of the RUL. Pathology from the wedge biopsy reported “minimal emphysematous disease without other diagnostic abnormality”. She continued to be short of breath after the operation.

PMH, SH, and FH

• In 1975 she reportedly had pulmonary tuberculosis.  
• In 2018 the pneumothoraces, pleurodesis and the right ovarian cyst resection noted above.  
• She is a never smoker and has no family history of lung disease or pneumothoraces.

Medications

• Advair 115-21
• Hydroxyzine

Review of Systems

• In addition to her dyspnea she also reported a dry mouth.

Physical Examination

• Vital Signs: BP 143/93, afebrile, SpO2 99% at rest, Body Mass Index (BMI) 25.9
• Chest:  breath sounds diminished, no crackles
• CV: regular, no murmur
• Ext:  no clubbing or edema

Radiography

Prior outside CT scans are available from January 2019 (Figure 1) and December 2020.

Figure 1. Representative images from January 2019 high resolution thoracic CT scan in lung windows.

The thoracic CT scan in Figure 1 shows which of the following. (Click on the correct answer to be directed to the second of six pages)

1. Pleural thickening and scarring
2. A subpleural pulmonary nodule in the RUL
3. Multiple lung cysts
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. September 2021 Pulmonary Case of the Month: A 45­-Year-Old Woman with Multiple Lung Cysts. Southwest J Pulm Crit Care. 2021;23(3):64-72. doi: https://doi.org/10.13175/swjpcc036-21 PDF

A Case Series of Electronic or Vaping Induced Lung Injury

Ronald Ferrer Espinosa DO¹

Abdirahman Hussein MD²

Matthew Sehring DO¹

Mohamad Rachid MD¹

Ryan Dunn MD¹

Deepak Taneja MD¹

Department of Pulmonary and Critical Care Medicine¹

Department of Internal Medicine²

University of Illinois College of Medicine at Peoria

Peoria, Illinois 

Abstract

Introduction: Since their introduction, electronic cigarette use has increased and was even proposed as an alternative to traditional tobacco use. Recently, a series of patients with acute respiratory failure due electronic cigarette, or vaping, associated lung injury (EVALI) in 2019 has been described which has largely been attributed to tetrahydrocannabinol (THC) containing vaporizer itself, as well as vitamin E acetate. Several case series have been published regarding the acute presentation, diagnosis and management. In addition to diagnosis and management of EVALI, we sought to describe potential long-term effects of lung parenchyma in these patients.

Methods: A retrospective review was performed on 16 patients with clinically diagnosed EVALI at OSF St Francis Medical Center between August 01 2019 and February 1 2020. Relevant demographic and clinical data were collected in patients diagnosed with EVALI.

Results: Of the 16 patients in the study the median age (IQR) age was 25.25 (20-29) and 94% were male. The predominant presenting symptoms were dyspnea (94%), cough (56%), nausea 63%), vomiting (63%), abdominal pain (50%), diarrhea (50%), and fever (63%). 2 (13%) patients required endotracheal intubation. Common features of computerized tomography (CT) scan were bilateral diffuse ground glass opacity (93%), septal thickening (53%), and subpleural sparing (47%). Bronchoalveolar lavage (BAL) was obtained in 3 patients and all demonstrated neutrophil predominance of 69% (56-90). One BAL was significant for hemosiderin laden macrophages. Post hospital follow up pulmonary function tests were obtained in 3 and 2 of these were significant for obstructive lung disease.

Conclusions: In this case series of patients diagnosed with vaping associated lung injury, obstructive lung disease may be seen on pulmonary function testing and surveillance of these patients should occur regardless of duration.

Keywords: CT scan, EVALI, bronchoalveolar lavage, electronic cigarette, pulmonary function testing, respiratory failure, tetrahydrocannabinol, vaping, vaping associated lung injury, vitamin E,

Introduction

The first cases of vaping associated lung injury (EVALI) were reported in Wisconsin and Illinois in the summer of 2019 which reached its peak in the fall of 2019 (1). This sudden epidemic of respiratory failure in patients who used tetrahydrocannabinol (THC) containing vaporizing devices lead the Food and Drug Administration (FDA), Center for Disease Control (CDC) and local public health departments to initiate investigations and research into the causative mechanisms of this disease. Currently, it is postulated that vitamin E acetate plays a role in the pathogenesis of VALI, as this substance was found in samples of vaping cartridges and in the bronchoalveolar fluid of patients with the disease (2,3). These pathological pathways are still being elucidated. Little is known about the long-term damage to the respiratory system in patients with EVALI. In this study, we sought to describe the diagnostic commonalities in patients with EVALI and describe potential long-term complications.

Methods

The study was a retrospective cohort analysis. Institutional Review Board (IRB) approval (1593746-1) was obtained through the University of Illinois College of Medicine at Peoria IRB. Data was collected for consecutive patients over 18 years of age who were diagnosed with EVALI between the dates of August 1, 2019 and February 1, 2020. The diagnosis of EVALI was consistent with the outbreak case surveillance definition. A confirmed case required the following to satisfy criteria: e-cigarette or dabbing in 90 days before symptom onset, pulmonary infiltrate, absence of infection, and no evidence of alternative plausible causes. A presumptive case definition included the above definition except for possibility of another cause of the patient’s symptoms such as infection. Data were extracted from the electronic medical record. The recorded data included the following: age, gender, co-morbidities, tobacco and electronic cigarette use history, need for endotracheal intubation, symptoms on presentation to the emergency department, computerized tomography findings, pulmonary function test values, bronchoalveolar lavage fluid studies, and discharge treatment plans. Obstructive lung disease is based on the American Thoracic Society/European Respiratory Society criteria that recommends the fifth percentile of the distribution in a population of healthy lifelong nonsmokers as the lower limit of normal. One patient described in this study has been previously described (4). Continuous variables are presented at median and interquartile range (IQR) with 95% CI. Categorical variables are described as number of patients (percentage).

Results

From August 1, 2019 to February 1, 2020, a total of 16 patients with either confirmed or presumptive vaping associated lung injury were reviewed. Table 1 shows the demographic data obtained from these patients.

 

The median age was 25.25 (IQR, 20-29) and the majority of patients were male 94% (n=15). Only 13% (n=2) of patients had previously diagnosed lung conditions, both of which were asthma. Of the reported THC brands, Dank© was the most commonly reported occurring in 25% (n=4) of patients (Table 2).

However, 50% (n=8) of THC products were not clearly stated in the patient’s medical record. Tobacco cigarette and tobacco electronic cigarette use were also documented, occurring in 63% (n=10) and 44% (n=7) of patients, respectively. Of those reporting tobacco use, the median pack years was 1.5 (IQR, 0.5-4.25). 7 patients reported no prior tobacco use. 13% (n=2) of patients required endotracheal intubation
 

Patients' symptoms are summarized in Table 3.

Any respiratory symptom occurred in 94% (n=15) of patients which included dyspnea 94% (n=15), cough 56% (n=9), chest pain 25% (n=4), and hemoptysis 19% (n=3). Abdominal symptoms were common and occurred in 75% (n=12) of patients. The most common gastrointestinal symptom were both nausea and vomiting 63% (n=10). These were followed by abdominal pain and diarrhea 50% (n=8). Fever was the most common constitutional symptom occurring in 63% (n=10) of patients. Less common constitutional symptoms included fatigue and chills both of which occurred in 13% (n=2) of patients. 

Chest computerized tomography (CT) scans were available in 94% (n=15) of patients. The findings are summarized in Table 4.

The most common radiographic feature was bilateral diffuse ground glass opacity (GGO), which occurred in 93% (n=14) of patients. Septal thickening and subpleural sparing were the next most common radiographic findings, occurring in 53% (n=8) and 47% (n=7) patients, respectively. Less common features that were described on chest CT scan were centrilobular nodular consolidations occurring in 27% (n=4) and reverse haloing occurring in 7% (n=1, Figure 1).

Figure 1.  Reverse halo sign in a patient with EVALI.

Three patients diagnosed with EVALI underwent bronchoscopy with bronchoalveolar lavage which are summarized in table 5.

Bronchoscopy was performed when the outbreak case definition was not met or there was a clinical concern for a secondary pathological process. The “typical” bronchoalveolar lavage (BAL) differential was neutrophilic predominant (56%-90%) with elevated macrophage and/or monocyte counts (4-19%, 0-23%). The lymphocyte count was typically low (0-4%) as well as the eosinophil count (0-1%). All the microbiologic data from these lavage samples were negative and included the following tests: aerobic and anaerobic bacterial cultures, fungal cultures, silver stain, acid fast bacilli smear and culture, varicella zoster polymerase chain reaction (PCR), histoplasma antigen and galactomannan. The results of cytology were different in all three BAL samples and were significant fore alveolar macrophages, atypical glandular cells and hemosiderin laden macrophages. At the time of bronchoscopy, only 1 or 3 patients was on or received systemic steroids therapy.

A few complications occurred in our cohort which included pneumothorax, pneumorrhachis, pulmonary embolism and Takutsubo cardiomyopathy. The case of Takusubo cardiomyopathy has been reported in the literature (4). The rate of pneumothorax was 13% (n=2). The pneumorrhachis 6% (n=1) occurred in a patient with pneumothoraces. Pulmonary embolism was only seen in 1 patient.

The discharge treatment course involved mainly systemic corticosteroids which were given in 81% (n=13) of patients. Antibiotics were continued at discharge in a minority of patients 38% (n=6). The majority of patients (94%) recovered and were asymptomatic at a later clinic visit. One patient remained symptomatic with persistent dyspnea.

Full pulmonary function tests were obtained in 3 patients (Table 6).

The timing of the pulmonary function tests occurred 3-4 weeks post hospital discharge. THC vape duration for these patients ranged from 4-12 weeks and tobacco pack years ranged from 0-2. Forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratios were 70%, 71%, and 86%. FEV1% ranged from 70 to 119%. FVC ranged from 81% to 119%. The total lung capacity in these three patients ranged from 85% to 109%. Diffusing capacity of carbon monoxide (DLCO) ranged from 60% to 100%. The flow volume loops of two patients demonstrate coving of the expiratory limb (Figure 2).

Pre-EVALI pulmonary function testing was not available for review in any of the patients.

Discussion

In this case series of patients with vaping associated lung injury of 16 patients in Central Illinois from August 1 2019 through February 1, 2020 the majority were younger men with respiratory and gastrointestinal symptoms. The symptomatology was consistent with previously published data (1,5,6,7). The exact pathophysiologic mechanisms implicated in vaping associated lung injury are currently still under investigation, but vitamin E acetate has recently been implicated possibly through the transition of tocopherols induced transition of phosphatidiylcholines from gel to liquid crystalline, causing surfactant dysfunction (2). The same authors proposed an alternative mechanism whereby ketene, created while heating e-cigarette products, causes direct lung irritation. However, many branded vaping products are not commercially produced and the heterogenous ingredients such as propylene glycol and other flavoring ingredients in these products may reflect its informal creation, which may influence the development of different disease mechanisms, clinical phenotypes and imaging findings (8,9).

A growing body of EVALI cases demonstrate predominant features on computerized tomography which include basilar predominant centrilobular nodular ground glass opacities and ground glass opacities with subpleural sparing. An initial study proposed four imaging patterns which included acute eosinophilic pneumonia, diffuse alveolar damage, organizing pneumonia and lipoid pneumonia and predicted the dominant CT scan findings (10). Later in a small case series of pediatric patients, centrilobular ground glass opacities were present in 92% and ground glass opacities with subpleural sparing were present in 75% of patients (11). The importance of recognizing these patterns is essential, especially in the adolescent and young adult populations where disclosure of medical history may prove to be difficult. Our findings support the cases in literature, with 93% of patients having bilateral diffuse basilar predominant GGO (93%), some associated with subpleural sparing (47%) and to a lesser degree centrilobular nodular consolidation (27%).

The role of bronchoscopy in patients with vaping associated lung injury has waned with as the characterization of clinical and radiographic findings has matured. Importantly, there is no finding on bronchoscopy that is specific for diagnosis of EVALI. Recently, the role of bronchoscopy with bronchoalveolar lavage (BAL) has been suggested to be performed in cases with a high pretest probability of EVALI with atypical features that cannot be attributed to vaping (5).  Lipid laden macrophages (LLM) are a non-specific finding in many different illnesses such as infection, aspiration, drug reactions, lipoid pneumonia, pulmonary alveolar proteinosis and autoimmune disorders, but the absence of LLM, argued by Aberegg, would be an atypical finding in EVALI (5,12). Our BAL fluid differentials are consistent with the published data, with elevations in neutrophils and/or monocytes and macrophages, with scant lymphocytes and eosinophils. In our institution, staining for lipid laden macrophages was not routinely performed. However, in one of our cytologic BAL samples hemosiderin macrophages were identified. The inconsistent cytologic findings on BAL in our series supports the notion of heterogenous underlying pathophysiologic mechanisms involved in EVALI.

The long-term effects of EVALI on lung parenchyma are unknown. Prior studies evaluating the effects of electronic cigarette use prior to the EVALI epidemic have suggested airway hyper responsiveness and an obstructive pattern on spirometry. In mice, it has been previously demonstrated that aerosolized nicotine induced airway hyperreactivity (13). A human study of 30 electronic cigarette users with at least 6 months of use compared with matched controls, demonstrated PFTs consistent with peripheral obstruction (14). A different study comparing vaping asthmatics versus healthy controls demonstrated acute declines in the FEV1/FVC ratio (15). Additionally, a few recent reports of pulmonary function testing have been documented in patients diagnosed with EVALI in late 2019 and early 2020. One study of intubated adults reported one follow-up PFT that was significant for only a low DLCO (16). A case series of pediatric patients describes two patients with 6 week follow up PFT’s that were significant for obstructive lung disease, and one of these patients had a low DLCO (11). Our study contributes 3 full PFT’s in adult patients diagnosed with EVALI performed at either 3 or 4 weeks following hospital discharge. Two of these PFT’s demonstrated obstructive lung disease, of which one had a low DLCO. The duration of vaping in these two abnormal cases were 8 and 12 weeks, and the pack years of tobacco use were 2 and 1.25 years. This small data set suggests that patients who participate in electronic cigarette use, or vaping, may be at higher risk for developing obstructive lung disease regardless of the duration of use. It is also important to take into account that a fixed FEV1/FVC ratio may underestimate young patients with obstructive lung disease (17). Using the lower limit of normal in this younger patient population is likely to be more sensitive in detecting obstructive physiology. It is plausible that vaping may cause an accelerated obstructive lung pattern due to the many potential pathways for lung injury. Full pulmonary function testing in any patient who was diagnosed with EVALI or continues to use electronic cigarettes, or vaping, products should be considered.

This study has several limitations. First, this was a retrospective study of patients at a single center in one geographic location. Second, our sample size was relatively small. Third, our clinical follow up rate was only 50%, of which only 37% completed PFT’s.

Conclusions

In our case series of 16 patients, predominantly male, diagnosed with EVALI there was a high incidence of gastrointestinal symptoms on presentation and follow up pulmonary function tests suggested there may be an increased risk for obstructive lung disease. Avoidance of vaping products, especially “Dank” and other similarly formulated products, is strongly recommended.

References

1. Layden JE, Ghinai I, Pray I, et al. Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Final Report. N Engl J Med. 2020 Mar 5;382(10):903-916. [CrossRef] [PubMed] 
2. Blount BC, Karwowski MP, Shields PG, et al. Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI. N Engl J Med. 2020 Feb 20;382(8):697-705. [CrossRef] [PubMed] 
3. Taylor J, Wiens T, Peterson J, et al. Characteristics of E-cigarette, or Vaping, Products Used by Patients with 18 and 2019. MMWR Morb Mortal Wkly Rep. 2019 Nov 29;68(47):1096-1100. [CrossRef] [PubMed]
4. Rachid M, Yin J, Mier N, et al. Reversed Takutsubo Cardiomyopathy in a young patient with vaping induced acute lung injury. ATS International Conference Abstract Presentation. 2020 May 15-20. Philadelphia, PA. Abstract nr A1839.
5. Aberegg SK, Maddock SD, Blagev DP, Callahan SJ. Diagnosis of EVALI: General Approach and the Role of Bronchoscopy. Chest. 2020 Aug;158(2):820-827. [CrossRef] [PubMed]
6. Blagev DP, Harris D, Dunn AC, Guidry DW, Grissom CK, Lanspa MJ. Clinical presentation, treatment, and short-term outcomes of lung injury associated with e-cigarettes or vaping: a prospective observational cohort study. Lancet. 2019 Dec 7;394(10214):2073-2083. [CrossRef] [PubMed]
7. Kalininskiy A, Bach CT, Nacca NE, et al. E-cigarette, or vaping, product use associated lung injury (EVALI): case series and diagnostic approach. Lancet Respir Med. 2019 Dec;7(12):1017-1026. [CrossRef] [PubMed]
8. Heinzerling A, Armatas C, Karmarkar E, et al. Severe Lung Injury Associated With Use of e-Cigarette, or Vaping, Products-California, 2019. JAMA Intern Med. 2020 Jun 1;180(6):861-869. [CrossRef] [PubMed]
9. Puebla Neira D, Tambra S, Bhasin V, Nawgiri R, Duarte AG. Discordant bilateral bronchoalveolar lavage findings in a patient with acute eosinophilic pneumonia associated with counterfeit tetrahydrocannabinol oil vaping. Respir Med Case Rep. 2020 Feb 3;29:101015. [CrossRef] [PubMed]
10. Henry TS, Kanne JP, Kligerman SJ. Imaging of Vaping-Associated Lung Disease. N Engl J Med. 2019 Oct 10;381(15):1486-1487. [CrossRef] [PubMed]
11. Thakrar PD, Boyd KP, Swanson CP, Wideburg E, Kumbhar SS. E-cigarette, or vaping, product use-associated lung injury in adolescents: a review of imaging features. Pediatr Radiol. 2020 Mar;50(3):338-344. [CrossRef] [PubMed]
12. Larsen BT, Butt YM, Smith ML. More on the Pathology of Vaping-Associated Lung Injury. Reply. N Engl J Med. 2020 Jan 23;382(4):388-390. [CrossRef] [PubMed]
13. Larcombe AN, Janka MA, Mullins BJ, Berry LJ, Bredin A, Franklin PJ. The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. Am J Physiol Lung Cell Mol Physiol. 2017 Jul 1;313(1):L67-L79. [CrossRef] [PubMed]
14. Meo SA, Ansary MA, Barayan FR, Almusallam AS, Almehaid AM, Alarifi NS, Alsohaibani TA, Zia I. Electronic Cigarettes: Impact on Lung Function and Fractional Exhaled Nitric Oxide Among Healthy Adults. Am J Mens Health. 2019 Jan-Feb;13(1):1557988318806073. [CrossRef] [PubMed]
15. Kotoulas SC, Pataka A, Domvri K, et al. Acute effects of e-cigarette vaping on pulmonary function and airway inflammation in healthy individuals and in patients with asthma. Respirology. 2020 Oct;25(10):1037-1045. [CrossRef] [PubMed]
16. Choe J, Chen P, Falk JA, Nguyen L, Ng D, Parimon T, Ghandehari S. A Case Series of Vaping-Associated Lung Injury Requiring Mechanical Ventilation. Crit Care Explor. 2020 Jan 29;2(1):e0079. [CrossRef] [PubMed]
17. Cerveri I, Corsico AG, Accordini S, et al. Underestimation of airflow obstruction among young adults using FEV1/FVC <70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes. Thorax. 2008 Dec;63(12):1040-5. [CrossRef] [PubMed]

Cite as: Espinosa RF, Hussein A, Sehring M, Rachid M, Dunn R, Taneja D. A Case Series of Electronic or Vaping Induced Lung Injury. Southwest J Pulm Crit Care. 2021;23(2):62-9. doi: https://doi.org/10.13175/swjpcc032-21 PDF 

June 2021 Pulmonary Case of the Month: More Than a Frog in the Throat

Michael B. Gotway, MD

Department of Radiology, Mayo Clinic Arizona

Phoenix, Arizona 85054

A 66-year-old woman with a history of GERD and previous renal transplant due to lithium toxicity was seen in the clinic complaining of a shortness of breath and nonproductive cough. She was on immunosuppression due to her renal transplant done about 5 months ago. These include daily trimethoprim (TMP) – sulfamethoxazole (SMX). She also had asthma and was on a long-acting bronchodilator with an inhaled corticosteroid. Because of a previous history of oropharyngeal candidiasis (thrush), she was doing nystatin swish and swallow four times a day.

Which of the following should be included in your differential diagnosis in this clinical setting? (Click on the correct answer to be directed to the second of 5 pages. Multiple guesses are allowed.)

1. Candida esophagitis
2. COVID-19 Infection
3. Cytomegalovirus esophagitis
4. Group A Streptococcus infection
5. All of the above

Cite as: Gotway MB. June 2021 Pulmonary Case of the Month: More Than a Frog in the Throat. Southwest J Pulm Crit Care. 2021;22(6):109-13. doi: https://doi.org/10.13175/swjpcc017-21 PDF 

March 2021 Pulmonary Case of the Month: Transfer for ECMO Evaluation

Nicholas G. Blackstone, MD

April Olson, MD

Angela Gibbs, MD

Bhupinder Natt, MD

Janet Campion, MD

University of Arizona College of Medicine – Tucson

Tucson, AZ USA

History of present illness

A 31-year-old male fire fighter with a history of recurrent “atypical pneumonia”, environmental and drug allergies, nasal polyps, asthma, and Crohns disease (not on immunosuppressants) was transferred from an outside hospital for management of acute hypoxic respiratory failure with peripheral eosinophilia. Prior to admission he reported a 2-week history of worsening dyspnea, productive cough and wheezing, prompting an urgent care visit where he was prescribed amoxicillin-clavulanate for suspected community acquired pneumonia. Despite multiple days on this medication, his symptoms significantly worsened until he was unable to lie flat without coughing or wheezing. He was ultimately admitted to an outside hospital where his labs were notable for a leukocytosis to 22,000 and peripheral eosinophilia with an absolute eosinophil count of 9700 cells/microL. His blood cultures and urine cultures were negative, and a radiograph of the chest demonstrated bilateral nodular infiltrates. With these imaging findings combined with the peripheral eosinophilia there was a concern for Coccidioidomycosis infection and he was subsequentially started on empirical fluconazole in addition to ceftriaxone and azithromycin. Bronchoalveolar lavage (BAL) was performed revealing 80% eosinophils, 14% polymorphic nuclear cells (PMNs), 4% monocytes and 2% lymphocytes, no pathogens were identified. The patient’s clinical status continued to decline despite antimicrobial therapy, and he was intubated for refractory hypoxia. At this point, the patient was transferred to our hospital for further care.

What is the most likely diagnosis in this patient? (Click on the correct answer to be directed to the second of four pages.)

1. Acute asthma exacerbation
2. Bacterial pneumonia
3. Coccidioidomycosis pneumonia
4. Eosinophilic pneumonia
5. Rocky Mountain Spotted Fever

Cite as: Blackstone NG, Olson A, Gibbs A, Natt B, Campion J. March 2021 Pulmonary Case of the Month: Transfer for ECMO Evaluation. Southwest J Pulm Crit Care. 2021;22(3):69-75. doi: https://doi.org/10.13175/swjpcc069-20 PDF

Association between Spirometric Parameters and Depressive Symptoms in New Mexico Uranium Workers

Shiva Sharma MD, MPH¹

Xin W. Shore MS²

Satyajit Mohite MD, MPH³

Orrin Myers PhD²

Denece Kesler MD, MPH¹

Kevin Vlahovich MD, MS¹

Akshay Sood MD, MPH⁴

¹Preventive Medicine Section, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM USA

²Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque, NM USA

³Department of Behavioral Health, Psychiatry & Psychology, Mayo Clinic Health System, Mankato, MN USA

⁴Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM USA

Abstract

Background: Uranium workers are at risk of developing lung disease, characterized by low forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC). Previous studies have found an association between decreased lung function and depressive symptoms in patients with pulmonary pathologies, but this association has not been well examined in occupational cohorts, especially uranium workers.

Methods: This cross-sectional study evaluated the association between spirometric measures and depressive symptoms in a sample of elderly former uranium workers screened by the New Mexico Radiation Exposure Screening & Education Program (NM-RESEP). Race- and ethnicity-specific reference equations were used to determine predicted spirometric indices (predictor variable). At least one depressive symptom [depressed mood and/or anhedonia, as determined by a modified Patient Health Questionnaire-2 (PHQ-2)], was the outcome variables. Chi-square tests and multivariable logistic regression models were used for statistical analyses.

Results: At least one depressive symptom was self-reported by 7.6% of uranium workers. Depressed mood was reported over twice as much as anhedonia (7.2% versus 3.3%). Abnormal FVC was associated with at least one depressive symptom after adjustment for covariates. There was no significant interaction between race/ethnicity and spirometric indices on depressive symptoms.

Conclusions: Although depressive symptoms are uncommonly reported in uranium workers, they are an important comorbidity due to their overall clinical impact. Abnormal FVC was associated with depressive symptoms. Race/ethnicity was not found to be an effect modifier for the association between abnormal FVC and depressive symptoms. To better understand the mechanism underlying this association and determine if a causal relationship exists between spirometric indices and depressive symptoms in occupational populations at risk for developing lung disease, larger longitudinal studies are required. We recommend screening for depressive symptoms for current and former uranium workers as part of routine health surveillance of this occupational cohort. Such screening may help overcome workers’ reluctance to self-report and seek treatment for depression and may avoid negative consequences to health and safety from missed diagnoses.

Introduction

Uranium workers are at risk of pulmonary injury via two primary mechanisms: inhalation of radon daughters causing radiation-induced lung damage (1,2) and dust inhalation (3). Exposed workers are additionally at risk for developing cardiovascular pathology (4). Lung diseases can result in a clinically significant decline in pulmonary function and have been associated with various neuropsychiatric sequelae (5,6). Screening for and treatment of depression in interstitial lung disease (ILD) has been proposed to improve quality of life (6-8). Significant levels of depressive symptoms are described in patients with silicosis (8) and may adversely affect quality of life (9). In a study of patients with ILD, depressive symptoms correlate with dyspnea, forced vital capacity (FVC), sleep quality, and pain (7).

Presence of depressed mood or anhedonia, which is a significant decrease in deriving pleasure from the majority of one’s daily activities, on most days, is requisite for diagnosis of major depressive disorder (10). Individual inquiry of depressed mood has demonstrated 85-90% sensitivity for detection of depression; and addition of another question, specific for anhedonia, raises overall sensitivity to 95% for the two-question inquiry (11).

Our objective was to evaluate the prevalence of depressive symptoms in uranium workers, to examine their association with spirometric values, and examine race/ethnicity interaction with spirometry on depressive symptoms. We studied uranium workers enrolled in the New Mexico Radiation Exposure Screening and Education Program (NM-RESEP). New Mexico workers have been significantly impacted by uranium extraction activities and many are compensated through the Radiation Exposure Compensation Act (RECA) (12). The findings from this study may help elucidate the biopsychosocial impact of uranium-related lung abnormalities in New Mexico workers.

Methods

Study Design:

This is a cross-sectional analysis of baseline evaluation data from former New Mexico uranium workers (i.e., miners, millers, and ore transporters) voluntarily enrolled between 2004 and 2017 in NM-RESEP, a federally-funded health-screening and education program, located at the University of New Mexico (UNM) Health Sciences Center, serving Albuquerque and surrounding communities.

Data Collection:

Data were obtained from a self-reported questionnaire administered by a trained interviewer and confirmed by a physician/nurse practitioner. The questionnaire included demographics, severity of dyspnea via the modified Medical Research Council (mMRC) Dyspnea Scale (13), information on smoking history, cardiovascular status, and screening for depressive symptoms (using the modified Patient Health Questionnaire or PHQ-2) which includes two items on depressed mood and anhedonia (14). Body mass index (BMI) was calculated using measured height and weight. A prebronchodilator spirometry was obtained by trained technicians, utilizing standard guidelines from the American Thoracic Society and the European Respiratory Society (15). Test results were independently reviewed for quality by a pulmonologist. Gender- and race/ethnicity- specific reference equations were used to determine predicted normative values for spirometry (16). Abnormal values were defined by the lower limit of normal obtained from reference standards. Data was entered into a secure web-based Research Electronic Data Capture (REDCap) database.

Predictor and Outcome Variables:

The outcome included a positive response for PHQ-2 item on either depressive symptom, i.e., depressed mood or anhedonia. Predictor variables included spirometric parameters and race/ethnicity, including the absolute and percent-predicted values for FVC), forced expiratory volume in one second (FEV1), and the absolute value of the FEV1/FVC ratio. Lower limits of normal obtained from the reference standards from the Third National Health and Nutrition Examination Survey (NHANES III) were used to define abnormal spirometric values (16).

Statistical Methods:

Frequencies, percentages, means, and standard deviations in a univariate analysis were reported. For the purpose of analyses, the outcome variable was endorsement of either depressive symptom. Chi-Square tests were used to analyze categorical outcome variables and generate p-values to determine significance of the findings. In the multivariable logistic regression analysis, variables that were evaluated for potential confounding included smoking status and pack-years.

Ethical Approval and Funding:

This study was approved by the UNM Institutional Review Board or Human Resources Protections Office (14-058). The study was supported by NM-RESEP, which is funded by the Health Resources Services Administration (HRSA), and UNM Health Science Center CTSC Grant Number: UL1TR001449.

Results

Subject characteristics are shown in Table 1. Of the 570 uranium workers, 97.1% were men, 66.7% were of racial/ethnic minority with the largest group being American Indian (36.6%). Most workers were older (mean age of 68.5 ± 8.1 years) with BMI values in the overweight or obese categories (82.1%). 7.6% of workers reported at least one depressive symptom, with 7.2% and 3.3% reporting depressed mood and anhedonia, respectively. The prevalence of at least one depressive symptom in Hispanic, American Indian, and non-Hispanic White workers were 11.4%, 7.2%, and 4.1%, respectively (p=0.14 for all race/ethnicity group comparison) and post-hoc comparison between Hispanic and non-Hispanic White workers was significant (p=0.001) (not shown in Table 1). 66.9% of workers were either former or current smokers. With regards to previous pulmonary history, 15.3% and 10.0% of workers reported positive history of COPD and asthma, respectively.

Table 1. NM-RESEP Uranium Workers (2004-2017).

Both unadjusted univariate and adjusted multivariable analyses revealed that workers with abnormal FVC were at least 2.9 times more likely to endorse at least one depressive symptom. No associations were found between abnormal FEV1 or abnormal FEV1/FVC ratios and depressive symptoms (Table 2).

Table 2. Unadjusted and Adjusted Associations of the Presence of Depressive Symptoms on Spirometric Indices.

*Covariates in the above multivariable model using logistic regression analysis included: smoking status and smoking pack-years. **Further adjustment for the following covariates: age, gender, and race/ethnicity did not change results in the multivariable model (FVC OR: 2.86, 95% CI: 1.18-6.96, p=0.02).

Although the associations between spirometric indices and depressive symptoms appeared stronger among Hispanic workers than other race/ethnicity subgroups, this was not borne by a formal test of interaction between race/ethnicity and spirometric indices on either depressive symptom. However, interaction testing identified a trend towards significance for Hispanic workers between abnormal FEV1 and self-reporting of depressive symptoms (p=0.07) (Table 3).

Table 3: Interaction between Spirometric Indices and Race/Ethnicity on Depressive Symptoms.

*Logistic regression analysis was used.

Discussion

A minority of uranium workers sampled in this secondary analysis self-reported at least one depressive symptom (7.6%). Depressed mood was reported over twice as much as anhedonia was reported (7.2% vs 3.3%). Abnormal FVC on spirometry was found to be associated with depressive symptoms after adjustment for covariates. There was no significant interaction between race/ethnicity and spirometric indices on depressive symptoms.

Uranium ore extraction in New Mexico occurs in open pit or underground mines. Subsequently, uranium is isolated from ore via milling or heap leaching (17). Most of the workers in this study were subjected to hazardous working conditions marked by lack of provision of personal protective equipment (including respirators) to handle uranium and inhalational dust exposure. Inadequate ventilation in underground mines also led to increased radon and dust exposure and workers were not adequately informed of these occupational exposures by mining companies or federal agencies (i.e. US Atomic Energy Commission, Nuclear Regulatory Commission, US Department of Energy) (12).

Uranium enters the human body primarily via inhalation and ingestion (18). It deposits primarily in the lungs and skeleton (insoluble uranium) and kidneys (soluble uranium) (19) where it causes chemical and radiological damage to these organs (20). In a murine study, uranium was found to enter the central nervous system, crossing the blood-brain barrier and accumulating in the hippocampus, resulting in detrimental neurophysiological effects and changes in REM sleep patterns (21). A case study involving 81 American Indian uranium workers found anxiety and depression to be the most common mental health problems, and respiratory complaints and skin rashes were the most common physical health issues (22). Radon gas, a byproduct of the uranium decay process, attaches to dust particles and when inhaled into the lungs the alpha radiation released by radon daughters damages lung tissue. Like non-uranium industry workers engaged in other types of mining-related activities, uranium workers are at risk for occupational pneumoconiosis, presenting with features similar to silicosis (23), and chronic fibrotic ILD (3). Pneumoconiosis has been associated with increased risk of other pulmonary conditions, including pulmonary emboli (24), lung carcinoma (23), chronic obstructive pulmonary disease (COPD) (26), tuberculosis (27), and clinically significant decline in lung function (28).

Many chronic pulmonary conditions such as asthma, COPD (29), bronchiectasis (30), and lung cancer (31) are associated with depressive symptoms. In a prospective study of patients with bronchiectasis, low FEV1 values were observed among patients with depressive symptoms (30). In a study of French dairy farmers, Guillien (32) found depression was associated with lower FEV1. A 2013 systematic review and meta-analysis revealed that the relationship between COPD and depression is bidirectional (33). Our study did not contain information regarding history of a prior or current diagnosis of depression for enrolled patients, thus our secondary analysis is not a like-for-like comparison to existing literature on this topic. Our study involved individuals with mostly normal lung function, indicating that the association between abnormal FVC and depressive symptoms may be seen relatively early in the disease course.

Psychosocial factors may play a role in the development of workplace-associated disability in workers with respiratory impairment, but evidence-based guidance to address these psychosocial factors is limited (34). The low prevalence of depressive symptoms in our study may reflect the high proportion of men enrolled (97.1%), as overall prevalence of depression in men is approximately half that of women (35). Alternatively, men may under-report due to a lack of awareness and understanding of depression and fear of stigmatization for self-reporting amongst coworkers or wider society. Additionally, use of the standard PHQ-2 and DSM diagnostic criteria in American Indians may not produce reliable results due to potential cultural and linguistic differences (36). The rate of depression in American indigenous populations has found to be 8.9% (which is higher than all other racial/ethnic groups except biracial individuals) and can range from 10-30% (37), however, the prevalence of depressive symptoms in American Indian workers in our study was 7.2%. To the best of our knowledge, no validation studies have been performed for use of any version of the PHQ-2 in New Mexican American Indian populations. The PHQ-2 has been validated in English- and Spanish-speaking Hispanic Americans (38). Perini found ethnic minorities diagnosed with “chronic nonspecific lung disease” exhibited higher absolute prevalence of depressive symptoms than the ethnic majority (29). Our study findings partially agree with Perini’s findings in that Hispanic uranium workers were more likely to endorse depressed mood than non-Hispanic White workers.

Our study was a cross-sectional, secondary analysis of an occupational cohort of mostly elderly, former uranium workers enrolled in NM-RESEP. Longitudinal analysis of this association may further elucidate the direction of the association. Our study could benefit from culture-specific depression diagnostic criteria paired with spirometric measures to specific pulmonary diagnoses. While anhedonia has customarily been associated with loss of pleasure (10), the construct has recently expanded to include interest in activity, effort, and discrimination between anticipation and consummatory forms of pleasure. New approaches for anhedonia assessment are in development (39). Our assessment of anhedonia may have been limited and a more robust screening tool that screens for additional depressive symptoms beyond depressed mood and anhedonia, such as the PHQ-9 or Hospital Anxiety and Depression Scale (HADS) rather than the PHQ-2, could improve result validity. As depression has a complex nature, a more rigorous biopsychosocial assessment would help in determining the role pulmonary pathology plays in depression in this study sample. To the best of our knowledge, this is the first study to examine the association of spirometric indices with depressive symptoms in former uranium workers. The strengths of our study include the robust participation of minority workers due to use of a mobile screening unit, its clinical relevance in light of ongoing uranium-associated activity, and potential future impact on health. Further study on this topic is merited as untreated depression in workers poses potential risks to workplace safety. As industrial use of nuclear material continues in the United States and other countries such as Kazakhstan, Canada, and Australia, this area of study is relevant to occupational health on a global scale. We recommend screening for depressive symptoms in current and former uranium workers as part of routine health surveillance to better address reluctance to self-report and seek treatment for depression, as well as to avoid potential negative consequences to health and safety from a missed diagnosis.

Acknowledgments

Guarantor: Akshay Sood MD, MPH takes responsibility for the content of the manuscript, including the data and analysis.

Author contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed substantially to the data analysis and interpretation and the writing of the manuscript.

Financial/non-financial disclosures: All authors report no conflict of interest.

Abbreviation List

• BMI: body mass index
• COPD: chronic obstructive pulmonary disease
• CTSC: Clinical and Translational Science Center
• DSM: Diagnostic and Statistical Manual of Mental Disorders
• FEV1: forced expiratory volume in one second
• FVC: forced vital capacity
• HADS: Hospital Anxiety and Depression Scale
• ILD: interstitial lung disease
• mMRC: modified Medical Research Council
• NHANES III: The Third National Health and Nutrition Examination Survey
• NM-RESEP: New Mexico Radiation Exposure Screening and Education Program
• PHQ-2/PHQ-9: Patient Health Questionnaire-2/Patient Health Questionnaire-9
• RECA: Radiation Exposure Compensation Act
• REDCap: Research Electronic Data Capture
• UNM: University of New Mexico

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Cite as: Sharma S, Shore XW, Mohite S, Myers O, Kesler D, Vlahovich K, Sood A. Association between Spirometric Parameters and Depressive Symptoms in New Mexico Uranium Workers. Southwest J Pulm Crit Care. 2021;21(2):58-68. doi: https://doi.org/10.13175/swjpcc015-20 PDF