Pulmonary

The Southwest Journal of Pulmonary and Critical Care publishes articles broadly related to pulmonary medicine including thoracic surgery, transplantation, airways disease, pediatric pulmonology, anesthesiolgy, pharmacology, nursing and more. Manuscripts may be either basic or clinical original investigations or review articles. Potential authors of review articles are encouraged to contact the editors before submission, however, unsolicited review articles will be considered.

Rick Robbins, M.D. 12/2/19 Rick Robbins, M.D. 12/2/19

December 2019 Pulmonary Case of the Month: A 56-Year-Old Woman with Pneumonia

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 56-year-old woman complained of 6 weeks of increasing cough and shortness of breath. She had been treated for pneumonia with antibiotics, but when she failed to improve, she was begun on prednisone. She was receiving oxygen at 4 L/min by nasal cannula at the time she was seen.

PMH, SH, and FH

Her past medical history, social history and family were unremarkable other than a previous history of silicone breast implants. She was a nonsmoker.

Physical Examination

Her physical examination showed bibasilar crackles but was otherwise unremarkable.

Radiography

Her chest x-ray is shown in Figure 1.

Figure 1. Patient’s chest x-ray taken 6 weeks after the beginning of her illness.

Which of the following should be done at this time? (Click on the correct answer to be directed to the second of seven pages)

Cite as: Wesselius LJ. December 2019 Pulmonary case of the month: a 56-year-old woman with pneumonia. Southwest J Pulm Crit Care. 2019;19(6):149-55. doi: https://doi.org/10.13175/swjpcc067-19 PDF

Rick Robbins, M.D. 9/23/19 Rick Robbins, M.D. 9/23/19

Severe Respiratory Disease Associated with Vaping: A Case Report

Evan Denis Schmitz MD

La Jolla, CA USA

Abstract

A case of severe respiratory disease associated with vaping cannabinoid oil is reported in a 38-year-old woman. She presented with shortness of breath and nonproductive cough. Chest x-ray and CT scan showed diffuse ground glass opacities and consolidation. Bronchoscopy showed diffuse bronchial erythema and bronchoalveolar lavage contained an increased percentage of eosinophils (59%). She was treated with high dose corticosteroids and rapidly improved.

Case Report

History of Present Illness

A 38-year-old woman complained of worsening shortness of breath and nonproductive cough for four weeks. She used to be able to climb three flights of stairs but now can barely walk ten feet. She had been treated with various forms of antibiotics, inhalers and steroids and was taking 20 mg of prednisone a day on the day of hospitalization. She also received opiates to help control her cough. She denied any hemoptysis, fever, chills, or sputum production. Because of her progressive symptoms she was hospitalized for further evaluation and management.

Past Medical History, Social History and Family History

She has a history of obesity and fibromyalgia. She has a prior history of smoking one to two packs a day for five years quitting approximately 15 years ago. Because of a family crisis she tried vaping cannabidiol (CBD) oil approximately one month prior to admission. She also resumed smoking tobacco one half a pack per day. Her family history was unremarkable.

Medications

She was taking prednisone 20 mg/day and cyclobenzaprine (Flexeril®) for her fibromyalgia. She was also taking codeine cough syrup.

Review of Symptoms

She did have some chest pain associated with her shortness of breath as well as chronic muscle aches and intermittent lower extremity edema. Her review of systems was otherwise unremarkable.

Physical Examination

Vital Signs: BP 137/72 mm Hg, Pulse 84 beats/min, temperature 98.8 °F, respirations 22 breaths/min, height 5’0, weight 231 lbs, SpO2 96%

General: She was morbidly obese and only able to speak in short sentences.

Mouth: Moist. Mallampati 3.

Pulmonary: Faint expiratory crackles. No wheezing.

Cardiovascular: Normal rate, regular rhythm, normal heart sounds and intact distal pulses. Exam reveals no gallop and no friction rub. No murmur heard.

Abdominal: Soft, bowel sounds normal. No distension, mass or tenderness. No rebound or guarding. Centripetal obesity.

Extremities: Normal range of motion. No edema or tenderness.

Lymphatics: No cervical or supraclavicular adenopathy.

Neurological: Alert and oriented to person, place and time.

Skin: Warm and dry. No rash, erythema or pallor. Not diaphoretic. Capillary refill within normal limits. No skin tenting.

Psychiatric: Depressed mood.

Laboratory

Pertinent findings are on her laboratory evaluation include an elevated white blood cell count of 16,850 cells/µL with an increased number of neutrophils. Her electrolytes, liver enzymes, creatinine, blood urea nitrogen and urinalysis were within normal limits.

Radiology

Her admission chest x-ray is shown in Figure 1.

Figure 1. The admission portable chest x-ray showed bilateral patchy pulmonary infiltrates.

To better define the areas of consolidation, a thoracic CT scan was performed (Figure 2).

Figure 2. Representative images in lung windows from contrast enhanced thoracic CT scan showing nonspecific patchy areas of ground glass and alveolar opacities with septal thickening involving both lungs.

Hospital Course

Echocardiography was unremarkable. Bronchoscopy with bronchoalveolar lavage was performed. She had diffuse upper and lower airway erythema and considerable coughing during the procedure. The cell differential revealed an increase in eosinophils (59%) and multiple foamy macrophages. Smears and cultures of the lavage fluid were negative for pathogens. She was treated with high dose corticosteroids (methylprednisolone 1000 mg/day). She rapidly improved over four days with her cough and shortness of breath resolving. A chest x-ray at discharge revealed improvement of the pulmonary infiltrates (Figure 3).

Figure 3. Chest x-ray on the morning of discharge showing near resolution of her pulmonary infiltrates.

Discussion

At the time of this writing (9/21/19) there have been 530 cases of lung injury associated with e-cigarette product use or vaping reported with seven deaths (1). Nearly three fourths (72%) of cases have been male with two thirds (67%) 18 to 34 years old. Most patients have reported a history of using e-cigarette products containing tetrahydrocannabinol (THC). Many patients have reported using THC and nicotine. Some have reported the use of e-cigarette products containing only nicotine.

At present no specific e-cigarette or vaping product (devices, liquids, refill pods, and/or cartridges) or substance has been linked to all cases. It seems likely that there may be different mechanisms of lung injury from different substances. In support of this concept, the present case had high numbers of eosinophils in the bronchoalveolar lavage while other cases have shown an increase in neutrophils (2). Our patient was treated with high dose corticosteroids and did improve while on the corticosteroids. However, the time course does not establish a definite relationship between corticosteroid treatment and her improvement.

At present the CDC recommends refraining from using e-cigarette or vaping products (1). Anyone who uses an e-cigarette or vaping product should not buy these products (e.g., e-cigarette or vaping products with THC or CBD oils) off the street, and should not modify or add any substances to these products that are not intended by the manufacturer.

References

CDC. Outbreak of lung injury associated with e-cigarette use, or vaping. September 19, 2019. Available at: https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html (accessed 9/21/19).
Arizona Thoracic Society. September 2019 Arizona thoracic society notes. Southwest J Pulm Crit Care. 2019;19(3):99-100. [CrossRef]

Cite as: Schmitz ED. Severe respiratory disease associated with vaping: a case report. Southwest J Pulm Crit Care. 2019;19(3):105-9. doi: https://doi.org/10.13175/swjpcc062-19 PDF

Rick Robbins, M.D. 9/1/19 Rick Robbins, M.D. 9/1/19

September 2019 Pulmonary Case of the Month: An HIV Patient with a Fever

William P. Diehl IV, DO

Nicholas Villalobos, MD

Department of Internal Medicine

University of New Mexico

Albuquerque, NM USA

History of Present Illness

A 33-year old transgender male to female presented from human immunodeficiency virus (HIV) clinic for two months of fevers, intermittent shortness of breath, cough with blood streaked sputum, headache, and nausea. The clinic provider was concerned when labs showed up trending HIV viral load (3.3 million copies) and an absolute CD4 count of 57.

Past Medical History, Social History and Family History

The patient had a history of stage-III HIV diagnosed in 2014 on bictegravir, emtricitabine, tenofovir (Biktarvy) and latent tuberculosis (TB) diagnosed 2017 on isoniazid and B6. She is from Nicaragua and arrived in Albuquerque, NM in 2017. Social history is pertinent for sex trafficking and methamphetamine use.

Physical Examination

Upon admission, the patient’s vital signs were notable for a temperature of 39.2 degrees Celsius, blood pressure of 114/71 mmHg, oxygen saturation of 95% on room air with a respiratory rate of 18 breaths per minute. Physical exam was notable for an absence of rash, palpable lymphadenopathy or cachexia.

Which of the following should be done? (Click on the correct answer to be directed to the second of six pages)

Cite as: Diehl WP IV, Villalobos N. September 2019 pulmonary case of the month: an HIV patient with a fever. Southwest J Pulm Crit Care. 2019;19(3):87-94. doi: https://doi.org/10.13175/swjpcc056-19 PDF

Rick Robbins, M.D. 6/18/19 Rick Robbins, M.D. 6/18/19

Adherence to Prescribed Medication and Its Association with Quality of Life Among COPD Patients Treated at a Tertiary Care Hospital in Puducherry – A Cross Sectional Study

S Keerti kumar S

B Maharani, MD

R Venkateswara Babu, MD

M Prakash, MD

Departments of Pharmacology, Respiratory Medicine and Community Medicine

Indira Gandhi Medical College and Research Institute

Puducherry, India

Abstract

Introduction: Medication adherence is a major determinant for the success of therapy among chronic obstructive pulmonary disease (COPD) patients. The research objectives of the present study were to assess the adherence to prescribed medications and its association with quality of life among COPD patients, to determine the major factors that influence the medication adherence and to assess patient’s knowledge on COPD and its relation to medication adherence.

Methods: It was a hospital based cross-sectional study. Patient demographic characteristics, smoking and alcoholic status, severity grading of COPD, concomitant disease, affordability of patients to medication, patient knowledge on COPD (Knowledge Questionnaire), adherence to medication and inhaler, major factors influencing adherence, disease control and quality of life (COPD Assessment Test) were recorded.

Results: Most of the patients were non-smokers and patients exposed to occupational air pollutants was high. Complete adherence to prescribed medication was found among 47% (MAS Score 6) of the participants and 81% of the participants were partially adherent (MAS score, range of 1-6). Highly adherent group was found to have high CAT score which was statistically significant. (P=0.020). Major factors for medication non-adherence were forgetfulness (82.5%) and symptomatic relief of illness (12.5%). There was no statistically significant association between individual knowledge questions and medication adherence except the question “COPD medicines prevent the disease from getting worse” (P=0.021).

Conclusion: There was a statistically significant association between medication adherence and quality of life. Appropriate health education should be implemented for improving patient awareness and medication adherence.

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases (1).In industrialized and developed countries, it is one of the leading causes of morbidity and mortality (2).The World Health Organization predicts that COPD will become the third leading cause of death by 2030 (3). Currently, various drugs like β2 agonist (long and short acting), inhalational anticholinergics, inhalational corticosteroids and methyl xanthines are utilized to prevent, control the symptoms and also to minimize the occurrence of COPD exacerbations (4,5).

The main factor that determines the success of therapy appears to be medication adherence. The medication adherence rates among COPD patients in clinical trials has been found to be 70 to 90% but in clinical practice it was very low accounting for only 10 to 40% (6-11). Non-adherence to therapy may lead to poor health and increased morbidity and health care cost, which in turn alters the quality of life (12). There appear to be few studies in India on medication adherence among COPD patients. This study is novel in assessing the adherence to drug therapy and its relation to quality of life, patients’ knowledge on COPD and its relationship to medication adherence and major factors influencing the medication adherence among COPD patients attending the tertiary care Institute in one of the Union Territory in India.

Methods

Study design and setting: A cross-sectional study was conducted in a tertiary care hospital. The study center was a referral hospital for nearby primary and secondary care hospitals and a separate COPD clinic was run every week for treating COPD patients. The study was conducted for a period of 6 months after obtaining Institutional Ethics Committee clearance.

Study Population: Eligible patients were those referred and diagnosed with COPD by FEV1 and categorized according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging and were receiving medications (with no alterations in treatment regimen during the past 3 months). Since the study was on medication adherence, all the COPD patients attending the outpatient department during the study period were considered. Patients with a history of asthma, allergic rhinitis, hospitalization for COPD exacerbation in last 3 months, heart failure or serious liver disease or renal failure or acute coronary syndrome patients and mental illness patients were excluded.

Data Collection: The patients satisfying the inclusion criteria were interviewed after obtaining their written informed consent. Patient demographic details, smoking and alcoholic status, occupational exposure to air pollutants, age at diagnosis of COPD, duration of COPD, concomitant disease, affordability of patients to medication were recorded. Post-bronchodilator FEV1 was measured with spirometry and grading of COPD was done following Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (13).

Questionnaires used: Patient knowledge on COPD was assessed using COPD Knowledge Questionnaire (COPD-Q) (14).It is a valid, reliable and low-literacy tool to assess COPD related knowledge in patients. Adherence to medication and inhaler was evaluated by using Medication Adherence Scale (MAS)and Medication adherence report scale (MARS) (15,16).Reasons for non-adherence (missing or discontinuing the dose) were also obtained from the patients. Disease control and quality of life was assessed by using COPD assessment Test (CAT) (17). CAT score varies with changes in treatment and exacerbations of disease due to poor adherence. CAT scoring ranges between 0 and 40. Score of

> 30 - very high impact of COPD on patients

>20 - high impact of COPD on patients

10 to 20 - medium impact of COPD on patients

<10 - low impact of COPD on patients

5 - very low impact of COPD on patients

Statistical Analysis: Data entry was done in MS Excel 2010. Data was analyzed using professional statistics package EPI Info 7.0 version for windows. Descriptive data was represented as mean ± SD, median and interquartile range for numeric variables, percentages and proportions for categorical variables. Appropriate tests of significance were used depending on nature & distribution of variables like Chi square test, student’s t test for categorical variables. Values of p<0.05 were considered statistically significant. Spearman’s correlation test was used to find out the relationship between medication adherence and quality of life.

Results

During the six months study period, 157 COPD patients were contacted. Out of the 157 patients, 19 patients refused to participate in the study, 5 patients were not able to answer appropriately and 42 patients had not satisfied the inclusion criteria. A total of 91 patients completed the study and gave complete responses to the questionnaire.

Sociodemographic characteristics of the patients were summarized in Table 1.

Table 1. Sociodemographic characteristics of the study participants.

Most of the patients were non-smokers and patients exposed to occupational air pollutants was high. Based on GOLD staging of severity of COPD, 14% were graded as mild, 63% were graded as moderate, 20% were graded as severe and 3% of patients had very severe form of COPD. Concomitant diseases like diabetes, hypertension and hyperthyroidism was found in 74.7% of the participants. Nearly 50% of the participants belong to very low socioeconomic status as per Modified Prasad Classification and medication cost was affordable only by 24.2%.

Patient responses to COPD – Knowledge Questionnaire (COPD-Q) and its relation to medication adherence were summarized in Table 2.

Table 2. COPD Knowledge Questionnaire responses and its relation to medication adherence among study participants.

*p<0.05 - statistically significant.

There was no statistically significant association between individual knowledge questions and medication adherence except the question “COPD medicines prevent the disease from getting worse” (P=0.021). Average COPD-knowledge score was 6.23 ± 1.57.

Responses to medication adherence scale were summarized in Table 3.

Table 3. Responses to COPD medication adherence.

The adherent sum score ranged between 1-6, 43 (47%) participants who had a sum score of 6 were fully adherent to prescribed medications, 27 (30%) participants had a sum score of 5 and others had a sum score of 1-4 were partially adherent to prescribed medications. The overall medication adherence (range 1-6) among the participants was 81%.

Inhalational medications were used only by 43 (47.3%) patients. Responses to adherence to inhaled medications were summarized in Table 4.

Table 4. Responses to inhalational medication adherence.

MARS sum score was 23.55±3.95. Higher score indicates higher self-reported adherence. MARS sum score ranged between 5-25. Out of 43 patients, 39 (91%) had the sum score in the range of 21-25.

The common reasons for medication non-adherence were forgetfulness (82.5%), symptomatic relief of illness (12.5%), 10% responded that medicines got exhausted and 2.5% reported that it was socially inconvenient to take the medications.

CAT score of the patients and grading were summarized in Tables 5 and 6.

Table 5. COPD Assessment Test (CAT) – Individual item responses.

Table 6. Categorization of study participants based on CAT Score.

There was a statistically significant difference between adherent and partially adherent groups with respect to CAT score of the participants (Student’s t test; p value=0.020).

Highly adherent group was found to have high CAT score. (Table 7).

Table 7. Association between medication adherence score and CAT score.

Student’s t test; p value=0.020.

There was a statistically significant weak positive correlation (r=0.246) between medication adherence sum and CAT score.

Discussion

The patients in the present study had adherence to the medication at 47%. The percentage of adherence was less than the studies conducted in Hungary (58.2%)and Nepal (65%) (18,19). Although complete adherence was less than 50%, majority of the participants were partially adherent to the medications which was at 81% (Table-3). The most common cause for non-adherence was forgetfulness (82.5%). The percentage was very high when compared to other studies in which forgetfulness accounted for about 50% (15,19).

There was a statistically significant association between medication adherence score and the CAT score similar to the study done by Kocakaya et.al. (20). The study had revealed better the adherence, better the quality of life. Though there is weak positive spearman’s correlation which was statistically significant, it may not be clinically significant. This can be overcome by increasing the sample size. Only 43 participants used inhalational medications and there was higher self-reported adherence to inhalational medications. That data is similar to a study done by Tommelein et al. (16).

In the tertiary care Institute where the study was conducted, patients with moderate and severe symptoms alone were advised to purchase inhaler and during inhaler introduction they were properly trained on how to use the inhaler. Further, compliance to the inhalational medications were checked during each follow-up. Since moderate to severe symptomatic patients were comfortable with inhalational medications, there was high degree of adherence to inhalational medications.

The patient’s COPD knowledge score was 6.23 ± 1.57. It was less when compared to the study done by Ray SM., et al. (7.6 ± 2.1) (14). Awareness of the patients on smoking and its association with COPD, reversal of COPD with quitting of smoking was only around 50% but comparable to prior studies (14). The percentage of COPD patients with smoking was only 22%. The results were similar to the study done by Mahmood T et.al., in which the percentage of nonsmokers with COPD was higher when compared to smokers with COPD (21). It was interesting to note that 100% of the participants were not aware about the importance of flu and pneumonia vaccination. It may be because of poor literacy rate and lack of awareness among the participants.

The results of our study are not surprising and consistent with prior studies. However, sociodemographic factors affect compliance. To our knowledge this is the first study to show the association between adherence and quality of life in COPD in a unique Indian population.

Conclusion

The study showed a statistically significant association between medication adherence and quality of life. Further studies evaluating the impact of education on medication adherence and quality of life are needed.

References

Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. Am J Respir Crit Care Med. 2017;195(5):557–82. [CrossRef] [PubMed]
Viegi G, Scognamiglio A, Baldacci S, Pistelli F, Carrozzi L. Epidemiology of chronic obstructive pulmonary disease (COPD). Respiration. 2001;68:4–19. [CrossRef] [PubMed]
World Health Organisation. Chronic obstructive pulmonary disease (COPD) [Internet]. WHO. [cited 2017 Dec 28]. Available from: http://www.who.int/respiratory/copd/en/ (accessed 6/18/19)
Toy EL, Beaulieu NU, McHale JM, et al. Treatment of COPD: Relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105(3):435–41. [CrossRef] [PubMed]
Cazzola M, Dahl R. Inhaled Combination Therapy with Long-Acting β2-Agonists and Corticosteroids in Stable COPD. Chest. 2004;126(1):220–37. [CrossRef] [PubMed]
Rand CS, Nides M, Cowles MK, Wise RA, Connett J. Long-term metered-dose inhaler adherence in a clinical trial. The Lung Health Study Research Group. Am J Respir Crit Care Med. 1995;152:580–8. [CrossRef] [PubMed]
Kesten S, Flanders J, Serby CW, Witek TJ. Compliance with tiotropium, a once daily dry powder inhaled bronchodilator, in one-year COPD trials. Chest. 2000;118:191s– 192s.
Van Grunsven PM, Van Schayck CP, Van Deuveren M, Van Herwaarden CL, Akkermans RP, Van Weel C. Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (COPD): results of the Detection, Intervention and Monitoring Program of COPD and Asthma (DIMCA) Study. J Asthma. 2000;37:225–34. [PubMed]
Krigsman K, Nilsson JL, Ring L. Refill adherence for patients with asthma and COPD: comparison of a pharmacy record database with manually collected repeat prescriptions. Pharmacoepidemiol Drug Saf. 2007;16:441–8. [CrossRef] [PubMed]
Bender BG, Pedan A, Varasteh LT. Adherence and persistence with fluticasone propionate/salmeterol combination therapy. J Allergy Clin Immunol. 2006;118:899-904. [CrossRef] [PubMed]
Breekveldt-Postma NS, Gerrits CMJM, Lammers JWJ, Raaijmakers J a. M, Herings RMC. Persistence with inhaled corticosteroid therapy in daily practice. Respir Med. 2004;98(8):752–9. [PubMed]
Montes de Oca M, Menezes A, Wehrmeister FC, et al. Adherence to inhaled therapies of COPD patients from seven Latin American countries: The LASSYC study. PLoS ONE. 2017;12(11):e0186777. [CrossRef] [PubMed]
Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: 2019 report. Available at: https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-v1.7-FINAL-14Nov2018-WMS.pdf (accessed 6/18/19).
Ray SM, Helmer RS, Stevens AB, Franks AS, Wallace LS. Clinical utility of the chronic obstructive pulmonary disease knowledge questionnaire. Fam Med. 2013;45(3):197–200. [PubMed]
Dolce JJ, Crisp C, Manzella B, Richards JM, Hardin JM, Bailey WC. Medication adherence patterns in chronic obstructive pulmonary disease. Chest. 1991;99(4):837–41. [PubMed]
Tommelein E, Mehuys E, Van Tongelen I, Brusselle G, Boussery K. Accuracy of the Medication Adherence Report Scale (MARS-5) as a quantitative measure of adherence to inhalation medication in patients with COPD. Ann Pharmacother. 2014;48(5):589–95. [CrossRef] [PubMed]
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34:648-654. [CrossRef] [PubMed]
Agh T, Inotai A, Meszaros A. Factors Associated with Medication Adherence in Patients with Chronic Obstructive Pulmonary Disease. Respiration. 2011;82(4):328–34. [CrossRef] [PubMed]
Shrestha R, Pant A, Shakya Shrestha S, Shrestha B, Gurung RB, Karmacharya BM. A Cross-Sectional Study of Medication Adherence Pattern and Factors Affecting the Adherence in Chronic Obstructive Pulmonary Disease. Kathmandu Univ Med J. 2015;13(49):64–70. [PubMed]
Kocakaya D, Yıldızeli ŞO, Arıkan H, et al. The relationship between symptom scores and medication adherence in stable COPD patients. Eur Respir J. 2017;50(61):PA1062.
Mahmood T, Singh RK, Kant S, Shukla AD, Chandra A, Srivastava RK. Prevalence and etiological profile of chronic obstructive pulmonary disease in nonsmokers. Lung India. 2017;34(2):122–6. [CrossRef] [PubMed]

Cite as: kumar S KS, Maharni B, Babu RV, Prakash M. Adherence to prescribed medication and its association with quality of life among COPD patients treated at a tertiary care hospital in Puducherry – a cross sectional study. Southwest J Pulm Crit Care. 2019;18(6):157-66. doi: https://doi.org/10.13175/swjpcc021-19 PDF

Rick Robbins, M.D. 6/1/19 Rick Robbins, M.D. 6/1/19

June 2019 Pulmonary Case of the Month: Try, Try Again

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 53-year-old woman from presented with a 3-year history of shortness of breath. She was diagnosed with pneumonia in 2016, but even after treatment with antibiotics, continued to require supplemental oxygen. A CT-guided biopsy of a lung nodule was performed but there were no diagnostic findings. A surgical lung biopsy at another hospital was done but the report is unavailable. She had been diagnosed with possible scleroderma and treated with mycophenolate for 3 months and then azathioprine.

Past Medical History, Social History and Family History

Aside from her history as in the HPI she has a remarkably negative past medical history. She does not smoke. Family history is noncontributory.

Physical Examination

HEENT: negative
Chest: Fine crackles at both lung bases
Cardiovascular: regular rhythm, no murmur
Skin: skin thickening on fingers and distal forearms, but not elsewhere. No pitting, ulcerations or calcinosis

Radiology

A chest x-ray was performed (Figure 1).

Figure 1. PA chest radiography done on presentation.

Which of the following should be done? (Click on the correct answer to be directed to the second of six pages)

Cite as: Wesselius LJ. June 2019 pulmonary case of the month: Try, try again. Southwest J Pulm Crit Care. 2019;18(6):144-51. doi: https://doi.org/10.13175/swjpcc026-19 PDF

Rick Robbins, M.D. 4/16/19 Rick Robbins, M.D. 4/16/19

Update and Arizona Thoracic Society Position Statement on Stem Cell Therapy for Lung Disease

Summary

Infusions of stem cells are increasingly being offered for a variety of diseases, including chronic lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. However, the potential for harm, the lack of any proven benefit, and the high fees that many of these programs charge make recommending stem cell therapy untenable. At the time of this writing (April 2019) it appears that stem cell therapy can be safely performed, although the long-term side effects remain unknown. However, the little data available show no benefit in meaningful outcomes, such as mortality, morbidity or patient well-being, for stem cell treatment of chronic lung disorders. Patients with severe, incurable diseases may be motivated to seek innovative therapies. We encourage such patients to contact their primary care physician or pulmonologist. Clinical trials in the United States and Canada investigating stem cell therapy for lung diseases can be found on the website of the National Institutes of Health at Clinicaltrials.gov. The Arizona Thoracic Society encourages regulatory agencies to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

Introduction

A central component of the mission of medical societies is to translate new scientific information into patient education. There appears to be increasing direct-to-consumer advertising of untested, unapproved, and potentially ineffective “stem-cell” treatments for a variety of diseases, including lung disorders (1). One may come across information regarding stem cell therapy for chronic obstructive pulmonary disorders and fibrotic lung disease, in the United States and worldwide, on the internet, patient support groups, or other sources. Recently, a direct mailing to the home of one of the members of the Arizona Thoracic Society was received (Figure 1).

Figure 1. Direct mailing for stem cell therapy for several diseases including COPD received by one of the members of the Arizona Thoracic Society.

These programs are often characterized by:

Exorbitant fees
Misrepresentation of risks and benefits
Overreliance on, and advertisement of, patient testimony
Poor patient follow-up
Absence of regulatory oversight and objective clinical evidence for claimed benefits

Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies.

Chronic Obstructive Pulmonary Disease (COPD)

Stem cells can differentiate into several different lung cell types, including the alveolar epithelial cells. Since COPD is a disease associated with destruction of alveoli induced by cigarette smoke, the concept of rebuilding the alveoli through stem cell therapy is attractive. Pre-clinical trials in animal models have suggested regeneration of alveolar-like structures, repair of emphysematous lungs, and reduction of inflammatory responses, with the greatest success being in acute lung injury models.

Currently, regenerative therapies are divided into extrinsic therapeutic strategies and intrinsic cell therapy methods. Extrinsic cell therapy refers to the vascular infusion of (or endotracheal installation) of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), mesenchymal stem cells (MSCs), and human lung stem cells (hLSCs). Intrinsic therapy refers to the delivery of small molecules (retinoid compounds have been the most studied) that can stimulate the endogenous lung stem/progenitor cells to regenerate and replace damaged structures.

A number of recent review articles have summarized the current state of research in the use of stem cells in COPD (2-4). These review articles all contain summaries of trials conducted to date using both extrinsic and intrinsic therapies. There have been several phase I clinical trials, primarily assessing safety, and a handful of small phase II clinical trials that have been negative for meaningful clinical outcomes. Sun et al. (3) point out that the available trials have all been conducted on patients with advanced COPD. The authors suggest that further research is required on how to enhance the engraftment of exogenous mesenchymal stem cells in damaged lungs. Further, considering the anti-inflammatory and immunomodulatory effects of exogenous mesenchymal stem cells, they may be most effective potentially in treating acute lung disease, as opposed to chronic progressive disease with severe structural damage.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease of unknown etiology characterized by a combination of histological changes, including extracellular matrix (ECM) deposition, phenotypic changes of fibroblasts, and alveolar epithelial cells, the formation of fibroblastic foci, and scattered areas of aberrant wound healing interspersed with normal lung parenchyma (5).

There are two approved compounds for the treatment of IPF: pirfenidone and nintedanib. Pirfenidone is an antifibrotic compound with an unclear mechanism of action, targeting several molecules, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin 6 (6). Nintedanib is a tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR) (7). While the use of pirfenidone and nintedanib has been shown to slow the progression of IPF, neither is curative and morbidity and mortality from IPF remains high (8,9).

Because of the inadequacy of therapy in IPF, the use of mesenchymal stem cells (MSCs) has attracted interest as a potential option. Early clinical studies have shown that the MSCs can be safely administered (5,10-12). A phase Ib study of endobronchially administered autologous adipose-derived MSCs showed not only acceptable safety outcomes, but also improvements in quality of life parameters (12). However, there were no significant differences in any of the studied functional parameters (FVC, FVC%pred. and DLCO% pred.) at baseline and 6 and 12 months following 3 endobronchial infusions of MSCs.

Cystic Fibrosis

Cystic fibrosis (CF) is a genetic syndrome usually resulting in a high mortality rate due to progressive lung disease. Several drugs targeting specific mutated cystic fibrosis transmembrane regulator (CFTR) proteins are already in clinical trials. However, new therapies, based on stem cells, are also emerging. Interest has focused on induced pluripotent stem (iPS) cells. It is possible to make iPS cells using cells from people with CF, and then use gene editing to correct CFTR mutations in those cells (13). This suggests the possibility of re-implanting the corrected iPS cells into the lungs of people with CF to generate healthy lung cells. Currently, three trials examining the safety of stem cells in cystic fibrosis are ongoing according to Clinicaltrials.gov.

Adult Respiratory Distress Syndrome (ARDS)

Four clinical trials are listed on Clinicaltrials.gov for ARDS and stem cells; one, which involved 3 patients, has been completed (14). No outcome information is available.

Other Lung Diseases

We are unaware of any human trials at this time with outcomes in other lung diseases.

Regulatory and Legal Actions

The Food and Drug Administration (FDA) and the Attorney General of New York have both expressed concern over stem cell therapy. The concerns follow reports of three patients becoming blind after receiving injections of stem cells into the eye and twelve patients who became seriously ill after receiving injections that purportedly contained stem cells from umbilical cord blood (15,16). The FDA has issued warning letters to stem cell clinics, including one letter claiming violation of Federal law, and another 20 warnings to clinics of that their claims and actions were subject to FDA approval. The NY Attorney has filed a lawsuit against a for-profit stem cell clinic, Park Avenue Stem Cell, claiming it performed unproven procedures on patients with a wide range of medical conditions, from erectile dysfunction to heart disease (17).

The Arizona Thoracic Society encourages further investigation into stem cell transplantation in lung disease. However, we do not at this time encourage non-investigational use of stem cells since the therapy has not been shown to have meaningful patient benefits. We also encourage state and local regulatory agencies in the Southwest to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

References

American Lung Association. Statement on Unproven Stem Cell Interventions for Lung Diseases (July 2016). Available at: https://www.thoracic.org/members/assemblies/assemblies/rcmb/working-groups/stem-cell/resources/statement-on-unproven-stem-cell-interventions-for-lung-diseases.pdf (accessed 4/5/19).
Balkissoon R. Stem Cell Therapy for COPD: Where are we? Chronic Obstr Pulm Dis. 2018;5(2):148-53. [CrossRef] [PubMed]
Sun Z, Li F, Zhou X, Chung KF, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. J Thorac Dis. 2018 Feb;10(2):1084-98. [CrossRef] [PubMed]
Cheng SL, Lin CH, Yao CL. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science. Stem Cells Int. 2017;2017:8916570. [CrossRef] [PubMed]
Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal stem cells for the treatment of idiopathic pulmonary fibrosis. Front Med (Lausanne). 2018 May 15;5:142. [CrossRef] [PubMed]
Kolb M, Bonella F, Wollin L. Therapeutic targets in idiopathic pulmonary fibrosis. Respir Med. 2017;131:49–57. [CrossRef] [PubMed]
Fletcher S, Jones MG, Spinks K, et al. The safety of new drug treatments for idiopathic pulmonary fibrosis. Expert Opin Drug Saf. 2016;15:1483–9. [CrossRef] [PubMed]
King TE, Bradford WZ, Castro-Bernardini S, et al. Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92. [CrossRef] [PubMed]
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82. [CrossRef] [PubMed]
Tzouvelekis A, Ntolios P, Karampitsakos T, et al. Safety and efficacy of pirfenidone in severe idiopathic pulmonary fibrosis: a real-world observational study. Pulm Pharmacol Ther. 2017;46:48-53. [CrossRef] [PubMed]
Tzouvelekis A, Koliakos G, Ntolios P, et al. Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal. J Transl Med. 2011;9:182. [CrossRef] [PubMed]
Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171. [CrossRef] [PubMed]
The Cystic Fibrosis Foundation. Stem cells for cystic fibrosis therapy. Available at: https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Stem-Cells-for-Cystic-Fibrosis-Therapy/ (accessed 4/5/19).
Clinicaltrials.gov. Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START). Available at: https://www.clinicaltrials.gov/ct2/show/results/NCT01775774?term=Stem+cells&cond=ARDS&rank=4 (accessed 4/5/19).
Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med. 2017 Mar 16;376(11):1047-53. [CrossRef] [PubMed]
Grady D. 12 People hospitalized with infections from stem cell shots. NY Times. Dec. 20, 2018. Available at: https://www.nytimes.com/2018/12/20/health/stem-cell-shots-bacteria-fda.html?action=click&module=RelatedCoverage&pgtype=Article&region=Footer (accessed 4/9/19).
Abelson R. N.Y. attorney general sues Manhattan stem cell clinic, citing rogue therapies. NY Times. April 4, 2019. Available at: https://www.nytimes.com/2019/04/04/health/stem-cells-lawsuit-new-york.html (accessed 4/9/19).

Cite as: Arizona Thoracic Society*. Update and Arizona Thoracic Society position statement on stem cell therapy for lung disease. Southwest J Pulm Crit Care. 2019;18(4):82-6. doi: https://doi.org/10.13175/swjpcc020-19 PDF

*The below contributed to the update and position statement on stem cell therapy

Bhargavi Gali, MD
Michael B. Gotway, MD
Kenneth S. Knox, MD
Timothy T. Kuberski, MD
Stuart F. Quan, MD
George Parides, DO
Richard A. Robbins, MD
Gerald F. Schwartzberg, MD
Allen R. Thomas, MD
Lewis J. Wesselius, MD

Rick Robbins, M.D. 3/1/19 Rick Robbins, M.D. 3/1/19

March 2019 Pulmonary Case of the Month: A 59-Year-Old Woman with Fatigue

Lewis J. Wesselius, MD¹

Michael B. Gotway, MD²

¹Department of Pulmonary Medicine and ²Department of Radiology

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 59-year-old woman from Kingman, Arizona had a one-year history of fatigue with some shortness of breath. For this reason, she saw her primary care physician.

Past Medical History, Social History and Family History

She has no significant past medical history. She does not smoke. Family history is noncontributory.

Physical Examination

Physical examination was unremarkable.

Which of the following should be done? (Click on the correct answer to be directed to the second of seven pages)

Cite as: Wesselius LJ, Gotway MB. March 2019 pulmonary case of the month: A 59-year-old woman with fatigue. Southwest J Pulm Crit Care. 2019;18(3):52-7. doi: https://doi.org/10.13175/swjpcc008-19 PDF

Rick Robbins, M.D. 1/24/19 Rick Robbins, M.D. 1/24/19

Co-Infection with Nocardia and Mycobacterium Avium Complex (MAC) in a Patient with Acquired Immunodeficiency Syndrome

Zahira Babwani DO

Kenneth Wojnowski Jr DO

Sunil Kumar MD

Broward Health Medical Center

Fort Lauderdale, FL USA

Abstract

We present a case in which a patient with acquired immunodeficiency syndrome (AIDS) and nocardiosis was found to have co-infection with Mycobacterium avium complex (MAC). Despite the fact that MAC is a known colonizer of the pulmonary system, it is possible to have co-infection and a high degree of suspicion is necessary to ensure prompt treatment of both organisms. We wish to describe how radiologic findings were instrumental in guiding our differential diagnosis.

Case Report

History of Present Illness: A 64-year-old man with history of alcohol and tobacco abuse presented with a chronic, productive cough for 5-6 months. Associated symptoms included shortness of breath and 30-pound weight loss. He denied all other symptoms.

Physical Exam: Pertinent positives revealed temporal wasting, poor dental hygiene, oral thrush and diffuse rhonchi bilaterally. Initial vital signs were within normal limits.

Laboratory and Radiology: Pertinent laboratory findings revealed leukocytosis with a left shift. Viral respiratory polymerase chain reaction (PCR) testing was negative. Human immunodeficiency virus (HIV) testing was positive with a CD4 count of 46 cells/mm³. QuantiFERON gold testing was negative. Sputum cultures, acid-fast bacilli (AFB) and blood cultures were obtained. Bronchoalveolar lavage (BAL) was performed with no evidence of Pneumocystis jirovecii (PJP). Chest X-ray (CXR) and computed tomography (CT) of the chest (Figure 1) revealed a multifocal right lung abscess with complex pleural fluid, empyema, nodular cavitary lesion in the left lower lobe and hilar lymphadenopathy.

Figure 1. Panel A: initial chest X-ray shows a complex infiltrate and effusion in the right lung. There is a cavitary lesion with air-fluid level vs lung abscess on the right. A nodule or consolidation is present in the left lung base. Panel B: A representative image from the initial CT of the chest showing a multifocal right lung abscess and complex pleural fluid.

Hospital Course: After admission, the patient was started on broad spectrum antimicrobials with vancomycin and piperacillin-tazobactam. A thoracentesis was performed due to right sided pleural effusion which yielded 65 cc of thick, purulent, green fluid. Thoracotomy with complete decortication of the right lung was performed with biopsies of the abscesses. Two 32-French chest tubes were placed due to the presence of multiple intraparenchymal lung abscesses, loculations, and empyema. Biopsy and pleural fluid cultures grew gram positive, beaded organisms which were later identified as nocardia, with no evidence of MAC or Mycobacterium tuberculosis (MTB). The patient was started on amikacin, meropenem and trimethoprim-sulfamethoxazole for newly diagnosed pulmonary nocardiosis. MAC prophylaxis was initiated due to his low CD4 count. After initiation of therapy for nocardiosis, three sputum AFB cultures began to stain positive. Since nocardiosis stains weakly positive for AFB, we initially did not suspect non-tuberculous Mycobacteria (NTM). Repeat CT scan of the chest (Figure 2) revealed ground glass opacities, nodular densities and both mediastinal and hilar lymphadenopathy.

Figure 2. Panel A: after initiation of treatment for nocardiosis, improvement of right empyema and cavitary lesion with bilateral patchy airspace disease right greater than left. Panel B: CT of the chest after initiation of treatment for nocardiosis, prominent lymph nodes in the hilar regions and mediastinum. less cavitation than the previous study. There are innumerable ground glass and nodular densities throughout both lungs, right greater than left.

Suspicion for active MAC co-infection was raised, the prophylactic dose of azithromycin was increased to the treatment dose, and ethambutol was initiated. After three weeks of intravenous amikacin, meropenem and trimethoprim-sulfamethoxazole the patient showed considerable improvement in his respiratory symptoms and was transitioned to oral trimethoprim-sulfamethoxazole for outpatient treatment of nocardiosis with continuation of ethambutol and clarithromycin for MAC.

Discussion

The Mycobacterium Avium Complex (MAC) is a Non-tuberculous mycobacterium (NTM) that is commonly found in patients with HIV and a CD4 count of less than 50. The diagnosis of NTM is challenging due to the fact that the organism is a known colonizer of the pulmonary system (1) . Supportive radiologic evidence is needed to distinguish colonization from active infection (2).

Common CT findings of nocardiosis include ground glass opacities, lung nodules, cavitation, pleural effusion and masses (3). The presence of mediastinal and hilar lymphadenopathy is the most common finding in immunosuppressed patients with MAC infection but is not a usual feature of pulmonary nocardiosis (3,4) . Our patient’s repeat CT scan showed mediastinal and hilar lymphadenopathy with improvement of cavitary lesions which suggests improvement of CT findings related to nocardiosis, but persistent findings related to NTM (5). This led us to believe that the patient was appropriately treated for nocardiosis, but with an underlying presence of active MAC infection that presented with atypical radiographic findings. As per the American Thoracic Society (ATS) guidelines for NTM pulmonary infection (6) , this patient’s pulmonary symptoms, radiological evidence on the chest CT, and positive AFB cultures from at least two separate expectorated sputum samples lends credibility to MAC as a true active infection in the setting of nocardiosis and AIDS. The patient was appropriately placed on clarithromycin and ethambutol as an outpatient, and our suspicions were confirmed for MAC with no evidence of MTB by PCR testing 5 weeks after initial AFB smears were collected.

Co-infection with Nocardiosis and MAC may be underestimated since they both often develop in immunocompromised hosts. MAC, along with other NTM species account for 20% of mycobacterium pulmonary infections in HIV infected patients (5). Nocardia accounts for less than 3% of pulmonary infections in HIV infected patients (5). A high degree of clinical suspicion is imperative to promptly treat infection with both organisms.

References

Young J, Balagopal A, Reddy NS, Schlesinger LS. Differentiating colonization from infection can be difficult Nontuberculous mycobacterial infections: Diagnosis and treatment. Patient Care. 2007. Available at: http://www.patientcareonline.com/infection/differentiating-colonization-infection-can-be-difficult-nontuberculous-mycobacterial-infections (accessed 10/3/18).
Trinidad JM, Teira R, Zubero S, Santamaría JM.Coinfection by Nocardia asteroides and Mycobacterium avium- intracellulare in a patient with AIDS. Enferm Infecc Microbiol Clin. 1992 Dec;10(10):630-1. [PubMed]
Kanne JP, Yandow DR, Mohammed TL, Meyer CA. CT findings of pulmonary nocardiosis. AJR Am J Roentgenol. 2011 Aug;197(2):W266-72. [CrossRef] [PubMed]
Erasmus JJ, McAdams HP, Farrell MA, Patz EF Jr. Pulmonary nontuberculous mycobacterial infection: radiologic manifestations. Radiographics. 1999 Nov-Dec;19(6):1487-505. [PubMed]
Benito N, Moreno A, Miro JM, Torres A. Pulmonary infections in HIV-infected patients: an update in the 21st century. Eur Respir J. 2012 Mar;39(3):730-45. [CrossRef] [PubMed]
Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. [CrossRef] [PubMed]

Cite as: Babwani Z, Wojnowski K Jr, Kumar S. Co-Infection with Nocardia and Mycobacterium avium complex (MAC) in a patient with acquired immunodeficiency syndrome. Southwest J Pulm Crit Care. 2019;18(1):22-5. doi: https://doi.org/10.13175/swjpcc123-18 PDF

Rick Robbins, M.D. 1/8/19 Rick Robbins, M.D. 1/8/19

Progressive Massive Fibrosis in Workers Outside the Coal Industry: A Case Series from New Mexico

Landon Casaus, MD¹

Sapna Bhatia, MD¹

Akshay Sood, MD, MPH^{1, 2}

¹Department of Internal Medicine

University of New Mexico School of Medicine

Albuquerque, NM, USA

²Miners’ Colfax Medical Center

Raton, NM USA

Abstract

Introduction

The worldwide prevalence of silicosis peaked by the beginning of the 20^th century during the development of mechanized industry (1). Outbreaks of silicosis are still noted in the developed world, particularly where workers are consistently exposed to silica particles that are small enough to be inhaled (≤10 µm in diameter) and at levels above a “safe” concentration (action level of 25 µm/m³as a time-weighted average over an 8-hour work day, as recommended by the U.S. Occupational Safety and Health Administration or OSHA) (2,3). The four Appalachian coal mining states of Pennsylvania, West Virginia, Virginia, and Kentucky accounted for more than 75 percent of all silicosis-related deaths in the United States (U.S.) in 2007 (4). A recent study however indicates that the age-standardized mortality rate from silicosis in the U.S. in 2014 was amongst the highest in the mining intense regions of the Southwest, particularly in the Four Corners area where the borders of New Mexico, Arizona, Utah, and Colorado meet (5). The number of diagnosed silicosis cases has increased in New Mexico between 2000 and 2011, and residents of New Mexico are twice as likely to die from or with silicosis when compared to the rest of the country for reasons that are unexplained (6).

Four clinical patterns of diffuse lung disease may be seen with silicosis: acute silicosis or silicoproteinosis (the latter resembling pulmonary alveolar proteinosis), simple nodular sclerosis, accelerated silicosis, and progressive massive fibrosis (PMF). PMF represents the coalescence of multiple small pneumoconiotic opacities to form larger opacities or conglomerate masses measuring over 10 millimeters in size on a chest radiograph, with smaller rounded opacities usually seen in simple silicosis. Silicotic opacities are classified on their shape, size, and profusion using the International Labour Organization’s (ILO) International Classification of Radiographs for Pneumoconiosis system (commonly referred to as B reads) (7-9). The 1970-2017 radiographic data from the National Institute for Occupational Safety and Health (NIOSH) surveillance program concluded that the national prevalence of coal workers’ pneumoconiosis in coal miners with 25 years or more of tenure now exceeds 10% (10). This is an increase from the previous estimate of 7% in 2012 (11,12). A resurgence of progressive massive fibrosis in coal miners has also been described, particularly those working in smaller mines (13). The rate of PMF in silica exposed workers outside of the coal mine industry, similar to those illustrated in this paper, is unknown. We herein describe three New Mexico non-coal miners with PMF that were followed at the University of New Mexico Occupational Pulmonary Medicine Clinic. Each of the three cases had already received compensation under the United States Energy Employees Occupational Illness Compensation Program, based upon prior abnormal B reads of chest radiographs. The epidemiology, pathogenesis, and management of PMF is also reviewed.

Case reports

Case 1

An 83-year-old man presented in 2017 with worsening dyspnea over the prior 10 years. He worked at a federal national laboratory in northern New Mexico, from 1962-1992 as a construction worker. His work included digging ditches, removing insulation, demolishing buildings, breaking up concrete with jackhammers, and working around sandblasters in enclosed areas, without any respiratory protection. He had a 5-pack year smoking history, and quit 50 years prior.

A 2017 chest radiograph showed small, upper lobe predominant, nodular opacities. A high-resolution computed tomography (CT) scan in 2009 showed innumerable micronodules in the upper lobes of the lung with a centrilobular distribution. A repeat CT scan obtained in 2017 (Figure 1) showed new-onset coalescence of several upper lobe nodules, as large as 1.5 cm x 2 cm.

Figure 1. Computed tomography scan of the chest showing several silicotic opacities in both lung apices and coalescence to progressive massive fibrosis in right apex.

His pulmonary function tests (PFT) showed mild obstruction with evidence of air trapping. A diagnostic bronchoscopy showed no evidence of infection or neoplasm.

Case 2

A 78-year-old man presented in 2014 with several-years history of progressive New York Heart Association Class III dyspnea. The patient worked as an underground uranium miner from 1960 to 1989 where he was exposed to hauling, “mucking” (a term referring to the loading of fragmented ore), and blasting. He wore a respirator intermittently. He had a five-pack year smoking history, quitting in 1981.

Chest x-ray showed innumerable micronodules, predominately in the upper lobes. A CT scan of the chest with 3 mm cuts in 2012 showed innumerable upper lobe predominant micronodules in a perilymphatic and centrilobular distribution, with coalescence in the upper lobes. Repeat CT scans in 2014 and 2015 demonstrated no disease progression (Figure 2).

Figure 2. Computed tomography scan of the chest demonstrating progressive massive fibrosis in the right upper lung and several silicotic opacities in bilateral upper lungs.

PFTs showed a mild restrictive defect. An infectious etiology was ruled out by negative sputum acid fast bacilli (AFB), and bacterial smears and cultures.

Case 3

A 79-year-old man presented with dyspnea at rest and upon exertion, and chronic bronchitis symptoms, with occasional hemoptysis. The patient worked as an underground uranium miner from 1959-1980 performing drilling, blasting and “mucking”, with significant self-reported exposure to dust and without use of respiratory protection. The patient reported a 15-pack year smoking history, but quit in 1976.

A chest x-ray showed hilar and mediastinal nodal calcifications with small scattered lung nodules. A HRCT scan of the chest in 2016 (Figure 3) showed multiple calcified nodules as well as calcified hilar and mediastinal lymph nodes.

Figure 3. Computed tomography scan of the chest demonstrating progressive massive fibrosis with evidence of traction in both lobes.

Conglomerate masses in the upper lobes measuring up to 3.3 cm were noted and moderate background emphysematous changes were also noted. The PFTs on initial evaluation were within normal limits. He was noted to be hypoxic on room air, necessitating 2 L/min oxygen supplementation. Sputum AFB smears and cultures were negative.

Discussion

PMF is seen in workers employed in industries that cut, grind, or drill silica-containing materials such as concrete, masonry, tile and/or rock (3). Most cases of PMF in the literature have been reported among coal miners, likely a reflection of the fact that coal miners undergo active surveillance due to governmental regulations (12). Although more commonly believed to occur in underground coal miners, PMF can be seen in surface coal miners as well (14). PMF outside the coal industry has been described in limited studies of barium miners, sandblasters, blacksmiths, welders, metal polishers, and quartz surface fabricators (15-17). More recently, PMF has been reported in ‘distressed’ denim jean industry workers (18). In this case series, we report PMF in New Mexico construction and uranium workers.

The latency for PMF is usually 10-30 years. Latency is greatly impacted by the exposure concentration and duration, as well as type of silica exposure. Additionally, it is influenced by underlying diseases, genetics, and smoking. Although PMF typically occurs in a setting of high cumulative dust exposures (14), some studies indicate that the host patterns of deposition and clearance of dust may be more relevant (19).

The pathogenesis of PMF is not completely understood; however, it is known that alveolar macrophages initiate a complex cascade results in inflammation and fibrosis (20). Histopathological findings include nodules, usually located near the respiratory bronchioles, composed of silica particles surrounded by whorled collagen in concentric layers. Larger masses of collagen define the lesion of PMF, which may be associated with avascular necrosis in the center and endarteritis in the periphery (21). The extensive fibrotic reaction in PMF is associated with high serum levels of interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1, which are important as neutrophil attractants and adhesion molecules (22).

The clinical diagnosis of PMF has three requirements: the patient must have a history of inhalational silica exposure significant enough to cause disease; chest imaging must be consistent with PMF; and other illnesses that mimic PMF must be reasonably ruled out (1). The disease presentation of PMF is highly variable. Patients may have debilitating symptoms of dyspnea on exertion and exercise intolerance, obstructive and/or restrictive patterns on PFTs, as well as experience complications such as cor pulmonale, spontaneous pneumothorax, and hypoxic respiratory failure (23). On the other hand, a normal spirogram is described in up to 11% of subjects with PMF, as also noted in Case 3 above (23). The level of pulmonary impairment in patients with PMF generally increases with increasing radiologic size of large opacities (23). Spirometry is repeated upon follow-up visits to assess for functional deterioration (24). Invasive tests such as arterial blood gas or cardiopulmonary exercise test are usually not indicated. Surveillance chest radiographs are classified for small and large opacities using the International Labour Organization’s (ILO) International Classification of Radiographs for Pneumoconiosis system (7-9). CT scan of the chest is more sensitive in diagnosing PMF than chest radiographs, and may be considered if the radiograph fails to show large opacities but demonstrates small opacities of relatively larger diameter or a tendency for opacities to coalesce (25,26). Lung tissue for histology or mineral analysis is rarely needed. The presence of atypical features in a patient with simple silicosis such as fever, hemoptysis, worsening dyspnea, weight loss, disproportionate fatigue, and the presence of a new infiltrate or cavitation of a pre-existing lesion on chest imaging should prompt the clinician to look for PMF, tuberculosis, or lung cancer. Patients with PMF are at elevated risk for concomitant tuberculosis. This risk is directly proportional to the level of profusion of silicotic small opacities (27), and the risk in patients with the highest level of profusion is comparable to that in patients with HIV infection (3). Autopsy studies from Welsh coal workers during the period 1952–1954 demonstrated tubercle bacilli in as many as 35% of cases with PMF (21). A recently published study from Brazil reported coexisting microbiologically confirmed tuberculosis in about half of patients with PMF, raising concerns about tuberculosis infection as a risk factor for the development of PMF ¹⁵. Patients with silicosis are also at high risk for lung cancer (28), with a greater risk for lung cancer described in patients with PMF as compared to patients with simple coal workers pneumoconiosis in one study (29). Positron emission tomography with F-18 fluorodeoxyglucose is of limited utility in differentiating malignancy from PMF lesions (30).

The prevention of PMF remains a focus at the exposed workplace. This includes primary prevention such as worker education; control of airborne dust exposure via engineering and work practice interventions such as improving ventilation, providing a means of exhaust, adding water to the cutting surface, and using enclosed cabs or booths; and use of respiratory protective devices (3). In June 2018, OSHA mandated personal breathing zone air sampling to monitor exposure and medical surveillance of workers with exposure above the permissible exposure limits (31). Medical surveillance constitutes secondary prevention, facilitating early diagnosis and treatment. Surveillance should be done periodically and should include a medical examination and occupational questionnaire, chest radiograph with B read interpretation, tuberculosis screening, and spirometry, with referral of affected workers to a pulmonologist or occupational medicine physician for further evaluation (32).

Once PMF has been diagnosed, it is important to immunize the patient against influenza and pneumococcal infection, assess the need for oxygen supplementation, and encourage pulmonary rehabilitation. Exclusion of active tuberculosis is recommended and screening for latent tuberculosis infection by either skin testing or interferon gamma release assay should be considered (33). Systemic corticosteroids, inhaled aluminum citrate, poly(vinlypyridine-N-oxide) and whole lung lavage are unlikely to benefit patients with PMF and lung transplantation may be considered (4).

Patients with PMF are considered ‘totally disabled’ from coal mine employment under the Black Lung Benefits Act in the United States. Outside the coal industry, they may be eligible for benefits under the Social Security Impairment system or the state workers’ compensation systems.

Conclusion

PMF represents the coalescence of smaller radiographic pneumoconiotic opacities to those over 10 millimeters in size. The rate of PMF in American coal miners has recently increased. Although most cases of PMF are reported among coal miners, this is likely a reflection of the fact that coal miners undergo active surveillance due to governmental regulations ¹². In this case series, we report PMF in workers outside the coal industry. Physicians and policymakers need to be aware of this condition in workers exposed to silica within and outside the coal industry.

Acknowledgments

Guarantor: Landon Casaus, M.D., 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.

Abbreviations List

AFB: Acid fast bacilli
CT: computed tomography
HIV: Human immunodeficiency virus
HRCT: High resolution computed tomography
IL: interleukin
ICAM: Intercellular adhesion molecule
NIOSH: National Institute for Occupational Safety and Health
OSHA: Occupational Safety and Health Administration
PMF: Progressive massive fibrosis
PFT: Pulmonary function test
US: United States

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Cite as: Casaus L, Bhatia S, Sood A. Progressive massive fibrosis in workers outside the coal industry: A case series from New Mexico. Southwest J Pulm Crit Care. 2019;18(1):10-9. doi: https://doi.org/10.13175/swjpcc110-18 PDF

Rick Robbins, M.D. 12/1/18 Rick Robbins, M.D. 12/1/18

December 2018 Pulmonary Case of the Month: A Young Man with Multiple Lung Masses

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 28-year-old man from Tennessee has been feeling ill with malaise and weight loss for the past 3 months. He had been in the in the Palm Springs area a few weeks prior to becoming ill. He works as a musician.

Past Medical History, Social History and Family History

He has a history of Wolf-Parkinson-White syndrome and had a prior ablation procedure at age 16. He does not smoke tobacco but does smoke marijuana occasionally. Family history is noncontributory.

Physical Examination

Physical examination was unremarkable.

Which of the following are indicated at this time? (Click on the correct answer to be directed to the second of eight pages)

Cite as: Wesselius LJ. December 2018 pulmonary case of the month: a young man with multiple lung masses. Southwest J Pulm Crit Care. 2018;17(6):138-45. doi: https://doi.org/10.13175/swjpcc118-18 PDF

Rick Robbins, M.D. 9/21/18 Rick Robbins, M.D. 9/21/18

Antibiotics as Anti-inflammatories in Pulmonary Diseases

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

Abstract

The currently available evidence for the use of chronic antibiotic therapy, principally macrolides and tetracyclines, as anti-inflammatory therapy in pulmonary disorders is reviewed. Historically, treatment of a number of chronic diseases with tetracyclines showed modest benefits but reports of the successful treatment of diffuse panbronchiolitis with erythromycin stimulated research in other lung diseases as well as shifting the focus from tetracyclines to macrolides. Chronic macrolide therapy is now recommended for patients with frequent exacerbations of cystic fibrosis and COPD and considerable evidence exists for potential benefits in asthma. There is also evidence of macrolide efficacy in the prevention of obliterative bronchiolitis after lung transplantation. Small trials have suggested possible benefit of macrolides in IPF. Taken together these suggest a potential for antibiotics, particularly macrolides, in some pulmonary inflammatory disorders.

History

Based on responses to antibiotics the concept arose over 70 years ago that several common diseases might have an infectious origin. In 1949, Thomas McPherson Brown reported favorable results of tetracycline treatment for rheumatoid arthritis patients at the 7th International Congress on Rheumatic Diseases (1). It was hypothesized these effects were due to a mycoplasma infection. However, the beneficial effects of cortisone in the treatment of arthritis were described at the same meeting. The effect of tetracycline paled beside that of steroids, and the salutary effects of antibiotics on rheumatoid arthritis were largely ignored.

Acne rosacea is a common, chronic dermatologic condition, whose cause remains unknown. Tetracyclines were the first systemic drugs used in the treatment of rosacea, and have been the mainstay therapy for more than 50 years (2). More recently, sub-antimicrobial doses of tetracyclines have been shown to be effective in rosacea presumably through an anti-inflammatory effect (3). Dermatitis herpetiformis is a disease now thought to be secondary to gluten sensitivity. However, this disorder has been treated with dapsone for over 60 years despite its non-infectious origin (4).

Tetracyclines have long been used for periodontal disease with clinical benefit presumed to be from their antimicrobial properties. However, as early as 1983, Golub (5) proposed that tetracyclines might have a beneficial effect by modifying inflammation. Now the tetracyclines are thought to exert their beneficial effects by anti-inflammatory effects, anti-collagenase effects, and a reduction in bone loss (6).

In 1959 the late Neil Cherniack published a double-blind study of 67 patients with chronic bronchitis or bronchiectasis treated with tetracycline, penicillin, a combination of oleandomycin and penicillin, or placebo for 3 to 22 months (7). Patients who received tetracycline had significantly fewer lower respiratory illnesses than those treated with placebos or penicillin. The average duration of these illnesses was also shorter in patients treated with tetracycline.

The anti-inflammatory effects of the macrolides were brought to light because of their effects on an uncommon pulmonary disease, diffuse panbronchiolitis (DPB). DPB is a rare disease seen in Japan and characterized by a chronic inflammatory neutrophilic inflammation of the airways, DPB has a 5-year survival rate of just 63% but only 8% when patients’ airways became colonized with Pseudomonas aeruginosa (8). However, in the early 1980s it was discovered that chronic treatment with erythromycin resulted in dramatically improved 5-year survival to 92% (8). This improvement occurred despite a failure to eliminate the bacterial colonization and was associated with a dramatic decrease in the accumulation of airway neutrophils (8,9). Interestingly, the effect on neutrophilic inflammation was found to be a nonspecific effect of the macrolides. Other macrolides (clarithromycin, roxithromycin and azithromycin) produced a similar suppression of the neutrophilic inflammation (10).

Gradually, with a better understanding of the pathogenesis of these common disease and basic studies examining anti-inflammatory effects, the macrolides and tetracyclines were recognized as anti-inflammatories. Inflammation is proposed to play a role in the pathogenesis of a number of pulmonary disorders. The encouraging results of the above suggested that macrolides and tetracyclines might be beneficial in pulmonary inflammatory conditions. Studies have examined a number of disorders including cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, and asthma.

Anti-inflammatory Mechanisms of Action

Macrolides and tetracyclines exert their antibacterial effects by inhibiting bacterial protein synthesis. Although the anti-inflammatory mechanisms of action of the tetracyclines and macrolides are likely multiple, one important mechanism by both is a reduction in production of a multitude of pro-inflammatory cytokines. Most of these cytokines are regulated at the transcriptional level through proteins such as nuclear factor-κβ (NF- κβ), activator protein-1 (AP-1) and/or p38 mitogen-activated protein kinases (p38 MAPK). Although the studies have varied depending on the in vitro systems examined, most have described a shortening of the half-life of pro-inflammatory cytokine mRNA usually through effect on one or more of the transcriptional control proteins (10-13).

Cystic Fibrosis

A major step in the use of antibiotics as anti-inflammatories occurred with the introduction of macrolides as adjunctive therapy in cystic fibrosis in 2003. Like diffuse panbronchiolitis, airways of cystic fibrosis patients show chronic inflammation with neutrophils which are often infected with Pseudomonas aeruginosa. Saiman et al. (14) conducted a multicenter, randomized, double-blind, placebo-controlled trial of azithromycin in cystic fibrosis patients infected with Pseudomonas. They found a reduction in exacerbations and greater weight gain in those treated with azithromycin compared to control. Following several confirming studies, cystic fibrosis patients are now commonly treated with macrolide antibiotics, especially when infected with Pseudomonas (15).

Tetracyclines have been less commonly used probably because of the staining of teeth and bone in younger, growing children. However, a recent small trial of 19 adult cystic fibrosis treated with chronic doxycycline showed an improvement in FEV1 and an increase in time to the next exacerbation compared to 20 placebo-treated controls (16). This might suggest an alternative in older patients or those at high risk for side effects from macrolides.

Non-CF Bronchiectasis

Long-term treatment with antibiotics has been recommended in patients with bronchiectasis and frequent exacerbations (17). This is based on studies showing decreased rates of exacerbations and some improvement in quality of life. It is not clear whether this effect is due to the antibacterial or anti-inflammatory properties of macrolides. In addition to Cherniak’s tetracycline trial which included bronchiectatics (7), an early MRC trial in 1957 showed that long-term twice weekly oxytetracycline over 1 year led to reduced sputum purulence, fewer days confined to bed and fewer days off work (18). Later trials in non-CF bronchiectasis have been done primarily with azithromycin and it is noted that there is an increased risk of macrolide-resistant organisms developing in these patients, as well as other risks associated with macrolide therapy including ototoxicity and QT prolongation (19).

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is one of the most expensive diseases to treat (20). A number of studies examining costs of COPD have shown that exacerbations, especially those resulting in hospitalization, account for the majority of costs (21,22). Although treatment with glucocorticoids, long-acting beta2-agonists, and long-acting muscarinic antagonists reduce the frequency of acute exacerbations, COPD patients receiving all three of these medications still average 1.4 acute exacerbations per year (23). Beginning in the early 2000’s there were a number of studies that reported an improvement in COPD exacerbations with macrolides (24-27). This culminated in a large, NIH-sponsored, randomized, placebo-controlled, multi-center trial demonstrating that azithromycin decreased COPD exacerbations by about 20% (28).

However, despite overwhelming data that macrolides modestly reduce COPD exacerbations and professional society recommendations for macrolide use in COPD patients at high risk for COPD exacerbations, adoption of chronic therapy with macrolides in COPD has been slow (29). The major reason appears to be concerns over side effects (29). Although azithromycin is well tolerated in the majority of patients, the drug can have serious adverse effects as noted in the trials in non-CF bronchiectasis including hearing loss and QT prolongation (29). The latter is especially concerning given that within less than one year of publication of the azithromycin NIH trial in the New England Journal of Medicine, a large trial the same reported a near 3-fold increase in mortality in patients receiving macrolides (30).

Despite early trials demonstrating efficacy in decreasing COPD exacerbations, tetracyclines have received little attention compared to macrolides. In addition to Cherniak’s study (7) there is a confirming report by Norman in 1962 (31). Tetracyclines might represent an alternative to macrolides in patients at high risk for complications from the macrolides.

Asthma

Asthma, like cystic fibrosis and COPD, is an inflammatory airway disease although usually characterized by eosinophilic inflammation. Studies suggesting macrolides might be useful as anti-inflammatories in asthma go back as far as 1970 (32). After the initial study by Itkin and Menzel (32), few studies were performed until the 2000’s. However, a 1993 study from National Jewish suggested troleandomycin might be useful as a steroid-sparing agent in children with asthma and two Japanese studies published in 1999 and 2000 with roxithromycin and clarithromycin both gave positive results in small numbers of patients (33-35).

In studies whose logic is reminiscent of Thomas McPherson Brown’s concept of mycoplasma infection in rheumatoid arthritis, Kraft et al. (36) investigated chronic chlamydia and mycoplasma infection in asthma and the response to macrolide therapy. In 2002 they reported that clarithromycin treatment increased FEV1 in asthmatics but only in those with evidence of C. pneumoniae or M. pneumoniae infection by PCR in upper and lower airway samples. Sutherland and co-workers (37) also showed improvement in airway hyper-responsiveness with clarithromycin therapy but in both PCR-positive and negative groups. The difference likely resides in identifying and chronic chlamydia and mycoplasma infection. A positive PCR does not necessarily equate to chronic infection and the serologic results from different assays are variable complicating these studies (38,39).

A number of studies have been conducted since Kraft’s investigation examining clarithromycin or azithromycin and assessing various clinical responses and inflammatory parameters in asthma (40-47). These studies have been inconsistent with some showing benefits while others did not. A Cochrane review in 2005 by Richeldi et al. (48) and a review article in 2014 by Wong et al. (49) both concluded that insufficient data existed to recommend chronic macrolide therapy in asthma.

The inconsistency in these results might be explained by the small patient numbers and because various phenotypes of asthma were included. Brusselle et al. (47) reported that azithromycin treatment significantly reduced exacerbation rates only in patients with severe neutrophilic asthma compared with placebo. However, neutrophilic asthma has been associated with increased bacterial load confusing whether benefits are due to an anti-inflammatory or an antibiotic effect (50). Furthermore, clarithromycin reduces neutrophil numbers in patients with severe asthma and it has been suggested that those patients with a neutrophilic phenotype might respond better to the anti-inflammatory effects of macrolide therapy (44,51).

A recent well-done recent study from Australia might tip the balance in favor of chronic macrolide therapy in difficult-to-control asthma. Gibson et al. (52) performed a randomized, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in 420 adults with symptomatic asthma despite current use of inhaled corticosteroid and a long-acting bronchodilator. Patients were randomly assigned to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Azithromycin reduced asthma exacerbations by nearly half and significantly improved asthma-related quality of life.

Tetracyclines as anti-inflammatories in asthma have received much less attention than the macrolides. In 2008 Daoud et al. (53) reported that minocycline allowed for a reduction in steroid dose in asthmatics who were steroid-dependent. A study from India demonstrated an improvement in post bronchodilator FEV1, the FVC, and the FEF (25-75) in asthmatics treated with doxycycline (54).

Obliterative Bronchiolitis

Obliterative bronchiolitis (OB) has historically gone by a variety of terms including bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia (BOOP) and, more recently, cryptogenic organizing pneumonia (COP) although some now separate OB as a separate entity (55). Histologically OB is very similar to diffuse panbronchiolitis, and in fact, panbronchiolitis has been grouped with OB (55). The OB histological pattern is now most commonly seen after lung transplantation or hematopoietic stem-cell transplantation (HSCT). However, OB can be seen with autoimmune disease, particularly rheumatoid arthritis; exposure to inhalational toxins such as sulfur dioxide, hydrogen sulfide, nitrogen oxides, and fly ash; and as an unusual complication following infection with adenovirus, measles virus, or mycoplasma (55).

The treatment of OB is usually corticosteroids or other immunosuppressants (55). However, since OB can result in death or decreased respiratory function, studies with adjunctive therapy or prevention of OB have been of interest. Azithromycin has resulted in improved pulmonary function in approximately 50% of lung-transplant recipients with obliterative bronchiolitis (56,57). A retrospective analysis indicated that the administration of azithromycin in patients with obliterative bronchiolitis after lung transplantation is associated with improved survival (58). Studies examining azithromycin after HSCT were done given the beneficial effects after lung transplantation. Surprisingly, the results were completely different. In a randomized clinical trial that included 465 patients, 2-year airflow decline-free survival was significantly worse for the azithromycin group than for the placebo group (59). The trial was terminated early for a significant increased risk in the azithromycin group of hematological relapses. The FDA recently issued a warning against using chronic azithromycin therapy in HSCT.

There is a paucity of data on treatment of OB with macrolides in non-transplant conditions. In 1993, Ichikawa et al. (60) used erythromycin for 3-4 months in six patients with a diagnosis of bronchiolitis obliterans OP confirmed on histological examination. All improved by the completion of therapy. However, a recent trial of azithromycin in eight patients with post-infectious OB did not produce an improvement in pulmonary function parameters (61). No studies were identified using tetracyclines as therapy in OB.

Cryptogenic Organizing Pneumonia

This entity, which was formerly known as bronchiolitis with organizing pneumonia (BOOP) can involve small airways, but also involves alveolar ducts and alveoli and can present as patchy peripheral opacities (62). It is considered an inflammatory disease which is usually very responsive to corticosteroid therapy, but may relapse when steroid therapy is withdrawn (63). There are several reports now that cryptogenic organizing pneumonia responds to treatment with macrolide and suggest that long term suppression with macrolides can avoid side effects associated with long term steroid therapy (63).

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a condition that has also been associated with neutrophils but with inflammation in the alveoli rather than the airways. With the introduction of nintedanib and pirfenidone and the realization that corticosteroids are of no benefit, the management of IPF has dramatically changed over the past decade (64). A recent publication done during the course of the shift in IPF therapy suggests that azithromycin added to conventional reduced the incidence of acute exacerbations (65). However, these retrospective results need to be interpreted with caution, since as noted above “conventional therapy” for IPF has changed profoundly. For example, many of the patients included in this study were subjected to corticosteroid therapy or other immunosuppressive agents, both of which are no longer recommended in IPF treatment (65). A similar study was performed by Kawamura et al. (66) performed from 2005-16. This single-center retrospective study of patients with IPF demonstrated that treatment of 38 consecutive patients with azithromycin (500 mg/day) for 5 days led to increased survival compared to 47 historical controls treated with a fluoroquinolone-based regimen.

A trial with minocycline in IPF was registered at clinicaltrials.gov but results were apparently never published (67). A small trial in 6 IPF patients treated with doxycycline for 24 weeks showed significant improvement in 6-minute walk time, St. George’s Respiratory Questionnaire, FVC, and quality of life compared to 6 controls (68).

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease that lead to progressive cystic destruction of the lungs. A recent study with doxycycline in LAM patients produced no effect upon vital capacity, gas transfer, shuttle walk distance or quality of life (69). The authors concluded that it is unlikely that doxycycline has a useful effect in LAM.

Summary

Macrolides are clinically useful in reducing exacerbations of cystic fibrosis, chronic obstructive pulmonary disease, bronchiolitis obliterans after lung transplantation, and possibly asthma. Tetracyclines might be considered as a substitute in some situations.

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Hahn DL, Plane MB, Mahdi OS, Byrne GI. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006;1: e11. [CrossRef] [PubMed]
Piacentini GL, Peroni DG, Bodini A, et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc 2007; 28: 194–98. [CrossRef] [PubMed]
Strunk RC, Bacharier LB, Phillips BR, et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate to-severe childhood asthma study. J Allergy Clin Immunol 2008;122:1138-44. [CrossRef] [PubMed]
Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008; 177:148-55. [CrossRef] [PubMed]
Hahn DL, Grasmick M, Hetzel S, Yale S, and the AZMATICS (AZithroMycin-Asthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-59. [CrossRef] [PubMed]
Cameron EJ, Chaudhuri R, Mair F, et al. Randomised controlled trial of azithromycin in smokers with asthma. Eur Respir J. 2013;42:1412-5. [CrossRef] [PubMed]
Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-9. [CrossRef] [PubMed]
Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2005;4:CD002997. [CrossRef]
Wong EH, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med. 2014 Aug;2(8):657-70. [CrossRef]
Wood LG, Simpson JL, Hansbro PM, Gibson PG. Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia. Free Radic Res. 2010;44:146-54. [CrossRef] [PubMed]
Brusselle GG, Joos G. Is there a role for macrolides in severe asthma? Curr Opin Pulm Med. 2014 Jan;20(1):95-102. [CrossRef] [PubMed]
Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 12;390(10095):659-68. [CrossRef]
Daoud A, Gloria CJ, Taningco G, et al. Minocycline treatment results in reduced oral steroid requirements in adult asthma. Allergy Asthma Proc. 2008 May-Jun;29(3):286-94. [CrossRef] [PubMed]
Bhattacharyya P, Paul R, Bhattacharjee P, et al. Long-term use of doxycycline can improve chronic asthma and possibly remodeling: the result of a pilot observation. J Asthma Allergy. 2012;5:33-7. [CrossRef] [PubMed]
Barker AF, Bergeron A, Rom WN, Hertz MI. Obliterative bronchiolitis. N Engl J Med. 2014 May 8;370(19):1820-8. [CrossRef] [PubMed]
Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003;168:121-5. [CrossRef] [PubMed]
Federica M, Nadia S, Monica M, et al. Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clin Transplant. 2011;25:E381-9. [CrossRef] [PubMed]
Jain R, Hachem RR, Morrell MR, et al. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2010;29:531-7. [CrossRef] [PubMed]
Bergeron A, Chevret S, Granata A, et al. Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial. JAMA. 2017;318(6):557-66. [CrossRef] [PubMed]
Ichikawa Y, Ninomiya H, Katsuki M, et al. Low-dose/long-term erythromycin for treatment of bronchiolitis obliterans organizing pneumonia (BOOP). Kurume Med J. 1993; 40:65–7. [CrossRef] [PubMed]
Zeynep Seda Uyan ZS, Levent Midyat L, Erkan Çakir E, et al. Azithromycin therapy in children with postinfectious bronchiolitis obliterans. Eur Respir J. 2016;48 (suppl 60):PA1602.
Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312:152-8.
Pathak V, Kuhn JM, Durham C, Funkhouser WK, Henke DC. Macrolide use leads to clinical and radiological improvement in patients with cryptogenic organizing pneumonia. Ann Am Thorac Soc. 2014 Jan;11(1):87-91. [CrossRef] [PubMed]
Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015 Jul 15;192(2):e3-19. [CrossRef] [PubMed]
Kuse N, Abe S, Hayashi H, et al. Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis: a retrospective analysis. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33:242-6. [PubMed]
Kawamura K, Ichikado K, Yasuda Y, Anan K, Suga M. Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. BMC Pulm Med. 2017 Jun 19;17(1):94. [CrossRef] [PubMed]
Minocycline therapy for lung scarring in patients with idiopathic pulmonary fibrosis - a pilot study. Available at: https://clinicaltrials.gov/ct2/show/NCT00203697 (accessed 8/29/18).
Mishra A, Bhattacharya P, Paul S, Paul R, Swarnakar S. An alternative therapy for idiopathic pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India. 2011 Jul;28(3):174-9. [CrossRef] [PubMed]
Chang WY, Cane JL, Kumaran M, et al. A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis. Eur Respir J. 2014;43:1114-23. [CrossRef] [PubMed]

Cite as: Robbins RA. Antibiotics as anti-inflammatories in pulmonary diseases. Southwest J Pulm Crit Care. 2018;17(3):97-107. doi: https://doi.org/10.13175/swjpcc104-18 PDF

Rick Robbins, M.D. 9/1/18 Rick Robbins, M.D. 9/1/18

September 2018 Pulmonary Case of the Month: Lung Cysts

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last page of the activity.

0.50 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.50 hours

Lead Author(s): Lewis J. Wesselius, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives: As a result of completing this activity, participants will be better able to:

Interpret and identify clinical practices supported by the highest quality available evidence.
Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Translate the most current clinical information into the delivery of high quality care for patients.
Integrate new treatment options for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: The University of Arizona College of Medicine-Tucson

Current Approval Period: January 1, 2017-December 31, 2018

Financial Support Received: None

History of Present Illness

A 67-year-old woman was referred for mild shortness of breath for several years, but worse since January 2018. She has dyspnea on exertion after 1 block. An outside chest x-ray, electrocardiogram and echocardiogram are reported as normal. She was begun on prednisone at 40 mg/day and her symptoms improved. However, her symptoms worsened when the dose tapered to 5 mg/day. She gained 35 pounds while on the prednisone and tried a steroid inhaler therapy without benefit. She is still dyspneic after 1 block of exertion.

Past Medical History, Social History, Family History

Her past medical history was only positive for gastroesophageal reflux for which she takes ranitidine and hypertension for which she takes lisinopril.
She was a life-long nonsmoker.
There was no occupational history, hot tub or bird exposures.
Family history is noncontributory.

Physical Examination

Her SpO2 was 94% on room air.
Chest: few crackles noted at right base.
Cardiovascular: regular rate and rhythm without a murmur.
Extremities: no edema or clubbing.

Which of the following should be done at this time? (Click on the correct answer to be directed to the second of eight pages)

Cite as: Wesselius LJ. September 2018 pulmonary case of the month: lung cysts. Southwest J Pulm Crit Care. 2018;17(3):85-92. doi: https://doi.org/10.13175/swjpcc101-18 PDF

Rick Robbins, M.D. 8/25/18 Rick Robbins, M.D. 8/25/18

Infected Chylothorax: A Case Report and Review

Louis Eubank¹, Luke Gabe¹, Monica Kraft¹, and Dean Billheimer²

¹Departments of Medicine and Biostatistics, College of Medicine

²Department of Biostatistics, College of Public Health

University of Arizona Health Sciences Center

Tucson, AZ USA

Abstract

Infected chylothorax is a rare complication of a rare pathology with limited literature entirely consisting of case reports, meeting abstracts, and letters to the editor. The case of a 56-year-old male with a spontaneous infected chylothorax successfully treated and discharged to home without any residual effects is described. A systematic review of the literature revealed 11 prior cases of infected chylothoraces. Their etiologies (when known), initial pleural fluid values, and treatment are described. These cases show that while infected chylothorax has a varied presentation and affects a broad range of patients, conservative management including antibiotics, pleural fluid drainage, and symptomatic relief is a safe and appropriate starting point.

Introduction

Chylothorax, a pleural effusion caused by chyle accumulation from obstruction or disruption of the thoracic duct (please see SWJPCC’s Image of the week: chylothorax for an image of non-infected chyle fluid), is a rare condition that may arise from a diversity of etiologies broadly categorized as traumatic or non-traumatic/spontaneous (1). Traumatic causes commonly include iatrogenic injury and chest trauma, although insults as minor as sneezing, light exercise and emesis have been reported (1-3). Non-traumatic chylothorax has been linked to several immunologic and infectious etiologies (1). Regardless of the underlying mechanism, chyle has classically been considered inherently bacteriostatic (1). We present a case of spontaneous infected chylothorax and the first review of infected chylothoraces reported in the literature.

Case Report

A 56-year-old man with alcoholic cirrhosis and remote right-sided hepatic hydrothorax presented to the emergency department complaining of shortness of breath. Patient reported slowly worsening dyspnea over the last six weeks without any other symptoms that had acutely worsened on morning of presentation

Initial vital signs were temperature 38.0°C, heart rate 115, blood pressure 81/60mmHg, and respiratory rate 30 breaths/min on 4L O₂ by nasal cannula; labs significant for white blood cell count of 3100/mm³ and lactate 5.0 mmol/L (normal <2.0 mmol/L). Physical exam demonstrated a fatigued patient with accessory muscle use on inspiration and absent breath sounds at the left lung base. Computed tomography (CT) study of the chest showed a large free-flowing left-sided pleural effusion (Figure 1A&B) as well as subacute rib fractures (Image 1C).

Figure 1. Thoracic CT on the day of presentation. Panel A: Axial view showing pleural effusion. Panel B: Sagittal view showing pleural effusion. Panel C: Coronal view showing rib fractures (white arrows).

Chart review demonstrated an emergency department visit five months previously for a fall with acute left-sided rib fractures and minimal left-sided pleural effusion.

Thoracentesis removed two liters free-flowing, brown, milky, purulent fluid; analysis significant for 58,880 total nucleated cells (32,800 RBCs), 94% neutrophils, glucose <5, LDH 573 IU/dL (serum 193 IU/dL), triglycerides 191 mg/dL, albumin 1.8 g/dL (serum albumin 2.6 g/dL, laboratory lower limit of normal 3.4 g/dL).

The patient remained hypotensive despite fluid boluses, tachypneic with increasing oxygen requirements, and a repeat lactate was 6.4 mmol/L. Norepinephrine and broad-spectrum antibiotics were started and patient was admitted to the intensive care unit.

Pleural fluid and blood cultures grew Escherichia coli resistant to fluoroquinolones. Chest x-ray showed persistent pleural effusion; a chest tube was placed which drained an additional 1.6 L over the following 24 hrs. The patient subsequently improved: serum lactate normalized within 24 hours, vasopressors were weaned within 36 hours, and supplemental oxygen was discontinued within 72 hours.

Chest tube output decreased to less than 200 ml/day within 48 hours of placement; however, repeat thoracic CT demonstrated a persistent multi-loculated left pleural effusion. Surgical evacuation and pleurodesis were considered given the lack of literature regarding intrapleural lytic therapy in infected chylothorax (a single case report described use of streptokinase in a persistent non-infected chylothorax, 1). However, the patient’s operative risk was considered prohibitively high. He was managed conservatively with a fat-free diet to reduce chyle leak.

Eleven days after initial presentation fluid studies were significant for triglyceride 45mg/dL with negative cultures. Given that a pleural fluid triglyceride level <50mg/dL yields a less than 5% likelihood of being chylous and the clinical stability of the patient, the chylothorax was felt to be resolved (1). The patient was discharged to home twelve days after initial presentation.

The etiology of patient’s infected chylothorax was never fully elucidated. The most likely explanation is the trauma causing rib fractures also caused a traumatic chylothorax that later became infected. The thoracic duct lies alongside the vertebrae until it drains into the left brachiocephalic vein (Figure 2).

Figure 2. Thoracic duct anatomy (black arrows).

A blow to the posterior left thorax sufficient to fracture multiple ribs is more than sufficient to damage the nearby thoracic duct (1-4). Arguing against this is most patients with large traumatic chylothoraces present within 10 days of injury (1,2).

Another explanation is the patient developed bacterial empyema secondary to hepatic hydrothorax (ascites that has passed through diaphragm from the peritoneal cavity) followed by non-traumatic chylothorax. These empyemas can demonstrate an indolent course and Escherichia coli is one of the most common causative pathogens isolated (1). Arguing against this is the patient’s previous hepatic hydrothorax was right-sided.

Finally, the chylothorax may have arisen from one of the many known causative medical pathologies (2). Chylous ascites secondary to cirrhosis that migrates into the pleural space via diaphragmatic leaks defects is a known phenomenon, albeit extremely rare (2).

In follow-up two months after discharge the patient had total resolution of respiratory symptoms and no recurrence of the effusion.

Systematic Review

Methods

A MEDLINE search (PubMed) from January 1975 to January 2018 and a Google Scholar search (all years) was conducted to identify eligible studies using the following terms: “Infected Chylothorax” (all fields) OR “Infection AND Chylothorax” (all fields) OR “Chylothorax AND Empyema” (all fields) OR “Chylous Empyema” (all fields). The inclusion criteria for studies were patients with infected non-traumatic chylothorax. A triglyceride level > 110 mg/dL or the presence of chylomicrons in pleural fluid was used to confirm the diagnosis of chylothorax; pleural fluid culture speciation was used to confirm the infection. The exclusion criteria were a lack of laboratory data and duplicate data. Two reviewers (LE, LG) independently reviewed the titles, abstracts, and, when necessary, the full text regarding the inclusion/exclusion criteria. Data extraction was performed independently by two reviewers (LE, LG) using data extraction forms defined beforehand. Discrepancies were resolved by consensus discussion with a third reviewer (MK).

Results

Eight case reports, two published abstracts, and one letter to the editor met the inclusion criteria; all elevenwere included in the analysis (Figure 3, 13-23).

Figure 3. Flow diagram of the literature review.

The general characteristics, demographics, and etiology of infected chylothorax are summarized in Table 1, the initial pleural fluid values are reported in Table 2.

Table 1. Population data.

Table 2. Initial pleural fluid values.

There were 11 patients total: six males and five females; age range 5 days-78 years, mean age 40.5 years (standard deviation 28.5 years). One patient was pharmacologically immunosuppressed while others had chronic diseases known to reduce immune system function including diabetes, excessive alcohol intake, and obesity (24-26). Four (36%) were iatrogenic. Three patients (27%) were infected with Streptococcus viridans and five (45%) were infected with Streptococcus genus. In those with available data, three of ten patients (30%) required intravenous vasopressors. No patients required ventilator management for their chylothorax (two patients were already intubated, one for acute respiratory distress syndrome, the other for unstable hemodynamics secondary to large subarachnoid hemorrhage). Two patients (18%) were managed surgically – one was specifically noted to have failed conservative management (17). Of the known outcomes, eight of nine (89%) survived to discharge and all eight remained asymptomatic at follow-up. The mean follow-up duration was 13.3 months (range 6-24 months).

Discussion

Given the paucity of published experience regarding infected chylothoraces, we believe a descriptive summary is warranted. First, there is a large variation in patient characteristics, including age range, immune competence, comorbid medical conditions, and infectious organism (eight different bacterial species and one parasite).

Second, many of the reviewed cases had a more benign presentation than might be anticipated in the context of a large, infected intrathoracic fluid collection. Seven of the patients (73%) were hemodynamically stable on presentation and the majority of these patients had very mild chief complaints.

Third, the available data suggest a surprisingly good prognosis considering a previously estimated morality of 10-25% in non-infected chylothoraces, depending on etiology (27). The one patient who did not survive to discharge died due to brain herniation. Those with documented outpatient follow-up were asymptomatic up to 16 months post-discharge.

Fourth, conservative management was frequently efficacious. Eight patients (73%) were medically managed without complication and did not require extensive antibiotic duration, intrapleural lytic therapy, or surgical intervention. The decision to pursue surgical intervention is not well defined given the very limited number of cases requiring surgical management. A brief discussion of non-infected chylothoraces and their management is therefore warranted.

Non-infected chylothorax is universally described as a rare event, although its exact incidence has not been described. Chylous ascites, which sometimes shares pathogenesis with chylothorax and is one of the causes of spontaneous chylothorax, has an occurrence of one in 20,000 hospital admissions (12). Trauma accounts for approximately 50% of chylothoraces, with esophagectomy being the most common iatrogenic cause (28). Thirty percent are due to malignancy; lymphoma accounts for 70-75% of malignant cases (11). While there are no consensus guidelines on how to treat chylothoraces, many authors agree that first line treatment is conservative management with thoracentesis or chest tube drainage, fat free or medium chain triglyceride diet, and consideration of somatostatin or octreotide (1,5,11,27-29). Although somatostatin or octreotide are used at many institutions, data regarding indications & efficacy of these medications are limited and/or inconsistent – some institutions use these medications at the beginning of treatment, others only if/when initial management has failed (5,27).

Additional treatments may depend on the etiology of the chylothorax: it is suggested that earlier surgical intervention in iatrogenic traumatic chylothoraces, especially post-esophagectomy, may be beneficial (30). Conservative management is likely to fail and surgical intervention is recommended in the following situations: 1) daily drainage greater than 1000 mL chyle (adults) or greater than 100mL chyle/kg body weight (children); 2) chyle leak that persists for more than 14 days; 3) unchanged chest tube output for 7-14 days; 4) clinical deterioration (27,28).

Conservative management for infected chylothoraces appears efficacious in our small sample size with the obvious modification of treating the infection. Most antibiotics adequately penetrate the pleural space, although aminoglycosides should be avoided as they appear to be inactivated by the low pH and relative anaerobic conditions (31).

Limitations

The limitation of this systematic review was the inclusion of only case reports, abstracts, and letters to the editor and the small sample size. Unfortunately, given the rarity of infected chylothoraces, studies with sufficient sample size are unlikely to be available.

Conclusion

Infected chylothorax is a rare complication of an already rare pathology. Our case report and literature review show that it can affect any age group, can be caused by several different organisms, and has a variable presentation. Our data suggests that an initial conservative management strategy in infected chylothoraces can be a safe and effective option.

References

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Cite as: Eubank L, Gabe L, Kraft M, Billheimer D. Infected chylothorax: a case report and review. Southwest J Pulm Crit Care. 2018;17(2):76-84. doi: https://doi.org/10.13175/swjpcc097-18 PDF

Rick Robbins, M.D. 8/1/18 Rick Robbins, M.D. 8/1/18

August 2018 Pulmonary Case of the Month

Arooj Kayani, MD

Richard Sue, MD

Banner University Medical Center Phoenix

Phoenix, AZ USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last page of the activity.

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Arooj Kayani, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives: As a result of completing this activity, participants will be better able to:

Interpret and identify clinical practices supported by the highest quality available evidence.
Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Translate the most current clinical information into the delivery of high quality care for patients.
Integrate new treatment options for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2017-December 31, 201

Financial Support Received: None

History of Present Illness

A 59-year-old woman referred because of worsening dyspnea over the past 2 months along with cough and wheezing. She has a history of chronic obstructive pulmonary disease (COPD) and is on continuous oxygen @ 2 L/min.

PMH, SH, and FH

In addition to her COPD she has a history of hypothyroidism, pneumonia, tonsillectomy, hip lipoma resection, hysterectomy, and a herniorrhaphy. She has a 30 pack-year history of smoking. She currently smokes half pack/day. No family history of lung disease or cancer.

Medications

Fluticasone/salmeterol
Tiotropium
Albuterol
Levothyroxine

Physical Examination

Vitals: HR 79/min, BP 100/69 mmHg, RR 16/min, SpO2 92% on 2 L/min.
General: Alert and oriented. Healthy appearing in no distress.
Lungs: Expiratory stridor and expiratory wheezing loudest over left lung. No crackles.
Cardiac: Regular rhythm with no murmurs. No edema.
The remainder of physical examination was unremarkable.

Which of the following should be performed? (Click on the correct answer to proceed to the second of four pages)

Cite as: Kayani A, Sue R. August 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;17(2):47-52. doi: https://doi.org/10.13175/swjpcc093-18 PDF

Rick Robbins, M.D. 7/1/18 Rick Robbins, M.D. 7/1/18

July 2018 Pulmonary Case of the Month

Anjuli M. Brighton, MB, BCh, BAO

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last page of the activity.

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Anjuli M. Brighton, MB. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives: As a result of completing this activity, participants will be better able to:

Interpret and identify clinical practices supported by the highest quality available evidence.
Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
Translate the most current clinical information into the delivery of high quality care for patients.
Integrate new treatment options for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2017-December 31, 2018

Financial Support Received: None

History of Present Illness

An 81-year-old gentleman was admitted for syncope. He had felt unwell for one month. His recent illness started with the “flu”. He had lingering productive cough, low volume hemoptysis and felt very fatigued. After a coughing episode he apparently lost consciousness and was taken to the emergency department.

Past Medical History, Social History and Family History

He has a past medical history of hypertension, glaucoma, diverticulosis and COPD. He was taking only antihypertensives including a diuretic. He has a 30 pack-year history of smoking but quit 10 years ago.

Physical Examination

Normotensive
Tachypneic
SpO2 96% on 2L NC
Afebrile
Diffuse wheezing, diminished at L base
Irregularly irregular heart rate

Which of the following are indicated at this time? (Click on the correct answer to be directed to the second of six pages)

Cite as: Brighton AM. July 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;17(1):1-6. doi: https://doi.org/10.13175/swjpcc073-18 PDF

Rick Robbins, M.D. 6/28/18 Rick Robbins, M.D. 6/28/18

Phrenic Nerve Injury Post Catheter Ablation for Atrial Fibrillation

Payal Sen, MD¹

Uddalak Majumdar, MD²

Ali Imran Saeed, MD¹

¹University of New Mexico

Albuquerque, NM USA

²Cleveland Clinic Foundation

Cleveland, Ohio USA

Abstract

Objective: Phrenic nerve injury (PNI) is a complication of catheter ablation treatment of atrial fibrillation (AF). This condition can mimic that of comorbid conditions like congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD).

Case details: A 77-year-old woman with past medical history of heart failure with preserved ejection fraction and mild COPD, presented with dyspnea for 8 days. One week ago, she had undergone radiofrequency catheter ablation for persistent symptomatic AF. After the ablation, she reported dyspnea during PCP and pulmonary office visits and was given increasing doses of diuretics and inhalers since her symptoms were attributed to acute exacerbation of heart failure in the setting of COPD. However, a chest x-ray showed elevation of the right hemidiaphragm, and she had a positive sniff test. She was thus diagnosed with right sided phrenic nerve palsy and was treated with oxygen therapy.

Discussion: Phrenic nerve injury can be diagnosed via clinical exam, chest x-ray and sniff test. A sniff Test which shows paradoxical elevation of the paralyzed hemidiaphragm with inspiration, compared with the rapid descent of the normal hemidiaphragm.

Conclusion: Phrenic nerve palsy is a complication which occurs in 6.6 percent of cases, post catheter ablation procedure for atrial fibrillation. This condition can mimic pulmonary conditions like acute exacerbation of COPD. Not keeping this complication in mind can lead to biased diagnostic reasoning and missed or delayed diagnosis.

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (1). In the past decade, catheter ablation of AF has evolved from an investigational procedure to a frequent therapeutic one (2). Phrenic nerve injury (PNI) is a complication of ablation that pulmonologists should be familiar with, due to its increasing incidence (3). This condition can mimic that of comorbid conditions like congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). Hence it is important to develop clinical suspicion of phrenic nerve injury, and correlate onset of symptoms to the ablation, to prevent missed or delayed diagnosis, and to avoid falling prey to availability bias.

Case Report

History of Present Illness: A 77-year-old Caucasian woman with past medical history of heart failure with preserved ejection fraction and mild COPD (GOLD Stage 1), presented with dyspnea and right sided chest discomfort for 7 days. One week ago, she had undergone radiofrequency catheter ablation at the University of New Mexico, for persistent symptomatic AF. After the ablation, she reported dyspnea during PCP and pulmonary office visits, which was attributed to acute exacerbation of heart failure in the setting of COPD. She had been given increasing doses of diuretics which did not relieve her symptoms. A short course of azithromycin and prednisone had also been prescribed for possible acute exacerbation of COPD, but her symptoms had remained unchanged. Review of systems were negative for fever, chills, cough, leg swelling and hemoptysis. She led an active lifestyle, did not require oxygen, and had quit smoking 10 years ago. There was no history of cardio- respiratory diseases in the family.

Physical Examination:

Vitals: Temperature: 97.1°F, Pulse – 88/minute, RR 22/minute, BP –

140/70 mm Hg., Spo2 – 90% in Room air (baseline >95 percent).

She appeared to be in mild distress. Baseline dry weight had not increased. She had no clinical signs of heart failure- no peripheral edema, no JVD, no S3, no bibasilar crackles. There were decreased breath sounds in the base of the right lung but no rales or rhonchi. No significant wheezing was heard in any of the lobes of the lungs.

No clubbing or cyanosis was noted. The rest of the exam was unremarkable with a normal abdominal, and skin exam. There was no lymphadenopathy.

Laboratory: White blood cell count 10,000/mm³, hemoglobin 11 g/dL, with normal electrolytes, liver function tests and negative troponins. Arterial blood gases on room air showed a pH 7.38, paO2 of 62 mm Hg, pCO2 41 mm Hg and HCO3^- 25.

EKG: negative for signs of ischemia.

Radiography: Chest radiography showed an elevated right diaphragm (Figure 1).

Figure 1. A: PA chest radiograph and B: 3 weeks earlier for comparison.

Sniff test performed under fluoroscopy showed paradoxical elevation of the right hemidiaphragm with inspiration, compared with rapid descent of the left hemidiaphragm, confirming right hemidiaphragm paralysis (Figure 2).

Figure 2. Static images from sniff test under fluoroscopy: A: pre-sniff. B: post-sniff. When the patient sniffs in, the left hemidiaphragm moves downwards but right hemidiaphragm does not (actually moves upwards very slightly).

After obtaining proper imaging, the patient was finally diagnosed with right-sided diaphragmatic paralysis due to phrenic nerve injury from the catheter ablation procedure done to treat AF. She was discharged with home oxygen and her symptoms have resolved. Follow up clinic visits revealed complete resolution of symptoms.

Discussion

Ectopic discharges from pulmonary veins are an important cause of atrial fibrillation, the most common sustained cardiac arrhythmia (1). Calkins et al. (4) carried out a study in 2009, where they showed statistically significant improvement in symptoms and quality of life in patients receiving ablation therapy versus those patients who received anti arrhythmic drugs (4). Traditionally, isolating the pulmonary vein by point-by-point radiofrequency catheter ablation was the cornerstone of catheter ablation strategies for the treatment of atrial fibrillation (2). However, this procedure had various complications such as thromboembolism, cardiac perforation, injury to adjacent structures and pulmonary vein stenosis (5). Hence, with the hope of finding an effective alternative approach with less complications, cryothermal ablation was started. This particular procedure involves electrically isolating pulmonary veins, by creating circumferential lesions by means of a cryoballoon catheter (6). Nonetheless, in both techniques, the most common complication is hemi‐diaphragmatic paralysis, due to phrenic nerve injury. This especially occurs whilst trying to isolate the right superior pulmonary vein (3). The approximate incidence of this complication is close to 3–11% (7). It is thought that the phrenic nerve gets injured due to the close anatomic relationship of the phrenic nerve to the heart (Figure 3).

Figure 3. Thoracic CT scan showing anatomical relationships (yellow star is the right phrenic nerve).

Both the right and the left phrenic nerves can get damaged - the right phrenic nerve is specifically at risk when ablations are carried out in the superior caval vein and the right superior pulmonary vein, and the left phrenic nerve is liable to damage during lead implantation into the great cardiac and left obtuse marginal veins (8). In our patient, the right phrenic nerve, which runs along the lateral surfaces of the superior vena cava and right atrium, was injured by energy delivered to the adjacent area during ablation.

In 2005 Bunch et al. (9) investigated the specific mechanism of phrenic nerve injury. Their study revealed that the phrenic nerve tended to retain heat after ablation. This phenomenon resulted in higher local temperatures with subsequent energy deliveries, causing early transient injury. Andrade et al. (3) in 2014, were the first to define this phrenic nerve injury histopathologically. According to them, phrenic nerve injury consisted of Wallerian degeneration characterized by loss of large myelinated axons with variable degrees of endoneural edema, vacuolated macrophages, myelin ovoids, and myelin digestion chambers (6).

Phrenic nerve injury can be diagnosed on clinical exam, and via a chest X-ray. Thereafter one can confirm the diagnosis with the sniff test or phrenic nerve stimulation/diaphragm electromyography. An upright chest x-ray will reveal an elevated diaphragm on the affected side. This test is sensitive, but not specific for the diagnosis of unilateral diaphragmatic paralysis (10). Another frequently done test is the sniff test which shows paradoxical elevation of the paralyzed hemidiaphragm with inspiration, compared with the rapid descent of the normal hemidiaphragm (11). The sniff test has more than 90 percent sensitivity (11). In 2014, Linhart et al. (12) performed studies to show that fluoroscopic assessment of diaphragm movement during spontaneous breathing was more sensitive for the diagnosis of phrenic nerve injury as compared to SVC pacing (12). It has also been seen that EMG‐guided approach results in less damage to the phrenic nerve and a significant reduction in hemi‐diaphragmatic paralysis as compared to current methods of abdominal palpation and fluoroscopy (13).

In unilateral diaphragmatic paralysis, patients are usually asymptomatic, have good prognosis and do not always need treatment. This is specifically true in the absence of underlying lung disease (14). Another procedure often done is the surgical plication of the affected hemidiaphragm (15). In bilateral diaphragm paralysis, ventilatory failure often occurs and these patients may require continuous positive airway pressure or mechanical ventilation and tracheostomy (16). According to Kauffman (17) in 2014, functional restoration of the paralyzed diaphragm should also be part of the standard treatment algorithm in managing symptomatic patients.

Conclusion

Phrenic nerve palsy is a complication which occurs in about 6 percent of cases post catheter ablation procedure for atrial fibrillation. This condition can mimic pulmonary conditions like acute exacerbation of COPD. It is important to develop clinical suspicion and correlate onset of symptoms to the ablation. Not keeping this complication in mind can lead to biased diagnostic reasoning and missed or delayed diagnosis.

References

Yamazaki M, Filgueiras-Rama D, Berenfeld O, Kalifa J. Ectopic and reentrant activation patterns in the posterior left atrium during stretch-related atrial fibrillation. Prog Biophys Mol Biol. 2012 Oct-Nov;110(2-3):269-77. [CrossRef] [PubMed]
Pedrote A, Acosta J, Jauregui-Garrido B, Frutos-Lopez M, Arana-Rueda E. Paroxysmal atrial fibrillation ablation: Achieving permanent pulmonary vein isolation by point-by-point radiofrequency lesions. World J Cardiol. 2017 Mar 26;9(3):230-40. [CrossRef] [PubMed]
Andrade JG, Dubuc M, Ferreira J, Guerra PG, Landry E, Coulombe N, et al. Histopathology of cryoballoon ablation-induced phrenic nerve injury. J Cardiovasc Electrophysiol. 2014 Feb;25(2):187-94. [CrossRef] [PubMed]
Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and metaanalyses. Circ Arrhythm Electrophysiol. 2009 Aug;2(4):349-61. [CrossRef] [PubMed]
Sarabanda AV, Bunch TJ, Johnson SB, et al. Efficacy and safety of circumferential pulmonary vein isolation using a novel cryothermal balloon ablation system. J Am Coll Cardiol. 2005 Nov 15;46(10):1902-12. [CrossRef] [PubMed]
Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: a systematic review of published studies. Heart Rhythm. 2011 Sep;8(9):1444-51. [CrossRef] [PubMed]
Omran H, Gutleben KJ, Molatta S, et al. Second generation cryoballoon ablation for persistent atrial fibrillation: an updated meta-analysis. Clin Res Cardiol. 2018 Feb;107(2):182-92. [CrossRef] [PubMed]
Sanchez-Quintana D, Cabrera JA, Climent V, Farre J, Weiglein A, Ho SY. How close are the phrenic nerves to cardiac structures? Implications for cardiac interventionalists. J Cardiovasc Electrophysiol. 2005 Mar;16(3):309-13. [CrossRef] [PubMed]
Bunch TJ, Bruce GK, Mahapatra S, et al. Mechanisms of phrenic nerve injury during radiofrequency ablation at the pulmonary vein orifice. J Cardiovasc Electrophysiol. 2005 Dec;16(12):1318-25. [CrossRef] [PubMed]
Chetta A, Rehman AK, Moxham J, Carr DH, Polkey MI. Chest radiography cannot predict diaphragm function. Respir Med. 2005 Jan;99(1):39-44. [CrossRef] [PubMed]
Alexander C. Diaphragm movements and the diagnosis of diaphragmatic paralysis. Clin Radiol. 1966 Jan;17(1):79-83. [CrossRef] [PubMed]
Linhart M, Nielson A, Andrie RP, et al. Fluoroscopy of spontaneous breathing is more sensitive than phrenic nerve stimulation for detection of right phrenic nerve injury during cryoballoon ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2014 Aug;25(8):859-65. [CrossRef] [PubMed]
Miyazaki S, Ichihara N, Nakamura H, et al. Prospective evaluation of electromyography-guided phrenic nerve monitoring during superior vena cava isolation to anticipate phrenic nerve injury. J Cardiovasc Electrophysiol. 2016 Apr;27(4):390-5. [CrossRef] [PubMed]
Piehler JM, Pairolero PC, Gracey DR, Bernatz PE. Unexplained diaphragmatic paralysis: a harbinger of malignant disease? J Thorac Cardiovasc Surg. 1982 Dec;84(6):861-4. [PubMed]
Kuniyoshi Y, Yamashiro S, Miyagi K, Uezu T, Arakaki K, Koja K. Diaphragmatic plication in adult patients with diaphragm paralysis after cardiac surgery. Ann Thorac Cardiovasc Surg. 2004 Jun;10(3):160-6. [PubMed]
Davis J, Goldman M, Loh L, Casson M. Diaphragm function and alveolar hypoventilation. Q J Med. 1976 Jan;45(177):87-100. [PubMed]
Kaufman MR, Elkwood AI, Colicchio AR, et al. Functional restoration of diaphragmatic paralysis: an evaluation of phrenic nerve reconstruction. Ann Thorac Surg. 2014 Jan;97(1):260-6. [CrossRef]

Cite as: Sen P, Majumdar U, Saeed AI. Phrenic nerve injury post catheter ablation for atrial fibrillation. Southwest J Pulm Crit Care. 2018;16(6):362-7. doi: https://doi.org/10.13175/swjpcc070-18 PDF

Rick Robbins, M.D. 6/26/18 Rick Robbins, M.D. 6/26/18

Evaluating a Scoring System for Predicting Thirty-Day Hospital Readmissions for Chronic Obstructive Pulmonary Disease Exacerbation

Vanessa Yap, MD¹

Diahann Wilcox, APRN, DNP¹

Richard ZuWallack, MD²

Debapriya Datta, MD¹

¹Division of Pulmonary & Critical Care Medicine

University of CT Health Center

Farmington, CT USA

²Division of Pulmonary & Critical Care Medicine

St Francis Hospital & Medical Center

Hartford, CT USA

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) results in 700,000 hospitalizations annually in the United States and 12-25% of patients are readmitted within 30 days of hospital discharge. A simple scoring system to risk-stratify these patients would be useful in allocating scarce resources.

Objective: The objectives of this study were to identify possible predictor variables to develop a clinically-useful instrument that can predict 30-day hospital readmissions in COPD patients.

Methods: Fifty patients hospitalized for a COPD exacerbation at two hospitals over a one-month period were studied prospectively. Demographics, disease severity, symptoms, functional status, psychological, and co-morbidity variables were assessed during the hospitalization. Patients were contacted telephonically thirty days post-discharge to determine readmission. Baseline variables were tested as predictors of 30-day readmissions.

Results: Mean age was 71 ± 11 years; 77% were female, 60% had Medical Research Council dyspnea 3 or 4; mean FEV1 was 41 ± 13% of predicted. Mean length of stay was 4.3 ± 3.2 days. Sixty percent had ≥ 1 clinical exacerbations in the preceding year, 52% had been hospitalized at least once for a respiratory exacerbation; 61% had been hospitalized at least once; 26% were on chronic prednisone. Thirty-day readmission rate was 24%. Three variables were found to be predictive of hospitalization: Clinical exacerbations in the previous year, chronic prednisone use, and functional limitation from dyspnea predictive of hospitalization.

Conclusions: Exacerbations in the previous year, chronic prednisone use, and functional limitation from dyspnea hold promise in a scoring system used to predict 30-day re-hospitalization and could be quickly assessed from a review of hospital record or a brief interview.

Introduction

Chronic obstructive pulmonary disease (COPD) is a common disease and is a leading cause of mortality in the United States (1). Much of the cost of care in COPD involves expenses related to exacerbations of this disease (2). Hospital readmissions within 30 days in COPD are frequent – with approximately 9-20% being readmitted (3-6). Hospitals will soon be financially penalized for 30-day readmissions for COPD. Risk stratification would be useful in directing scarce medical resources toward those patients most likely to be readmitted. The objectives of our study were: 1. To evaluate predictors of 30-day hospital readmission in patients hospitalized for an exacerbation of COPD and 2. To develop a simple, clinically-useful instrument that can predict any-cause 30-day hospital readmissions in COPD patients. To this end, the final tool would have to be brief (taking < 10 minutes to complete), convenient to use and have sufficient predictive power to predict hospital readmission.

Methods

This was a prospective study, performed by means of review of medical records and patient interview. Approval for the study was obtained from the IRBs of both participating institutions. There was no extramural funding for the study.

Fifty patients admitted with acute exacerbation of COPD over a 3-month period were studied. The primary inclusion criterion was a clinical diagnosis of a COPD exacerbation resulting in hospitalization. Patients with primary diagnosis of acute exacerbation of COPD exacerbation but with concomitant diagnosis of heart failure or pneumonia were included in the analysis. Inability to effectively communicate with the investigator, including language barrier or cognitive defect was the exclusion criterion.

The hospitalist physician, after receiving verbal approval from the hospitalized COPD patient of his/her potential willingness to see an investigator for a clinical research study, was then seen by an investigator, and informed consent was obtained. Following this, an interview and review of medical records were performed to obtain demographic and disease variables. Variables (from interview or record review) included: demographics (age, gender), disease severity, all-cause and respiratory-related hospitalizations over the preceding year, outpatient treated respiratory exacerbations over the preceding year, functional status, co-morbidities, psychological status, treatment upon admission. COPD assessment test (CAT) (7), Charlson Comorbidity Index (CCI) (8) and LACE Index (9) were determined for all patients. We also measured the treating physician’s “gut feeling” of the likelihood of a 30-day readmission. The treating physician was blinded as to the specific variables we measured. (All variables tested are detailed in Appendix. Post-bronchodilator forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were obtained from previous spirometry (within 3 years), if available. The patients without a historical spirometric diagnosis of COPD had spirometry before hospital discharge. Consented patients were then contacted at 30-days to determine whether they had readmissions and if so, for what cause.

General statistics are reported as means ± standard deviations (SD). Univariate logistic regression analyses were used to determine which of our tested variables predicted 30-day admission for exacerbation of COPD. Following this, multivariate forward logistic regression, incorporating variables that were predictive in univariate analyses, was utilized to determine which variables were predictive of 30-day hospitalization for COPD exacerbations.

Hospitalizations were analyzed as binary variables (yes-no). Based on the univariate analysis, two scoring systems were developed to predict readmission. The 2 scoring systems, each including three variables, significantly predicted 30-day readmissions.

The first scoring system (scoring system I) was as follows:

MRC dyspnea. This score ranges from 0 (least) to 4 (greatest) dyspnea. Our scoring was dichotomized to 0 (MRC 0, 1, 3, or 3) or 1 (MRC 4: “too short of breath to leave the house or short of breath dressing/undressing.”
Exacerbation history: Those with 1 or more hospitalizations for exacerbations in the preceding year were given a score of 1; those below this threshold had a score of 0.
Chronic prednisone use prior to admission: Chronic prednisone use was defined as prednisone used on all or most days for at least three months prior to admission. Those meeting this criterion were given a score of 1, those without chronic prednisone use had a score of 0.

The second scoring system (scoring system II) was as follows:

MRC dyspnea. This was identical to # 1 in the first scoring system.
Exacerbation history: Those with 2 or more outpatient -treated exacerbations (some of these could result in hospitalization) in the preceding year were given a score of 1; those below this threshold had a score of 0.
Chronic prednisone use prior to admission: This was identical to # 3 in the first scoring system.

Scores for each of the above scoring systems could, therefore, range from 0-3. The relationship between the above scores and 30-day hospital readmissions were evaluated using receiver operating characteristic (ROC) curves, which plot the true-positive rate (sensitivity) versus the false-positive rate (1-specificity).

A receiver operating characteristic (ROC) curve, plotting the true-positive rate (sensitivity) versus the false-positive rate (1-specificity) was used to characterize the relation. The ROC model was used to predict the likelihood of readmission for scoring system I and scoring system II.

Results

Of the 50 studied patients, 77% were female; mean age was 71 ± 11 years. The body mass index (BMI) was 29.65 + 9 kg/m2. Clinical characteristics of subjects are shown in Table 1.

Table 1. Clinical characteristics of studied subjects.

Sixty percent had Medical Research Council (MRC) dyspnea 3 or 4 (moderate to severe). Mean length of stay was 4.3 ± 3.2 days. Thirty-four percent lived alone at home.

In our study, all patients readmitted within thirty days had respiratory exacerbations of COPD as principal diagnoses (i.e., the frequency of respiratory-related and all-cause 30-day readmissions was identical). Thirty-day readmission rate for exacerbation of COPD was 24%. Of the studied parameters, the ones that did not predict rehospitalization in univariate logistic regression analyses are shown in Table 2.

Table 2. Variables that did not predict 30-day readmission.

Variables that significantly predicted or tended to predict readmission included: 1) two or more clinical exacerbations (not necessarily resulting in hospitalization) in the previous year (OR 4.6, p= 0.04); 2) prednisone use (chronic or prior to admission) (OR 4.4, p< 0.04); 3) MRC = 4 (OR 2.7, p = 0.16); 4) one or more respiratory hospitalizations in the preceding year (OR 3.1, p = 0.08).

Using scoring system I, 16 patients had a score of 0; 16 had a score of 1, 14 patients had a score of 2, and 4 had a score of 3. Readmission rates for each of these categories were as follows: 13%, 19%, 29%, and 75%, respectively. Using the ROC model (Figure 1), odds ratios for readmission for- Score 0 versus 3 was 18; (2) odds ratios for readmission for score 1 versus 3 was 16 and (3) odds ratios for readmission for score 2 versus 3 was 6.7.

Figure 1. Receiver operating characteristic (ROC) curve for scoring system I, showing odds ratio for readmission for Score 0 versus 3, Score 1 versus 3 and Score 2 versus 3.

In scoring system II, 19 had a score of 0, 16 had a score of 1, 11 had a score of 2, and 4 had a score of 3. Readmission rates for each of these categories were as follows: 11%, 19%, 36%, and 75%, respectively. Using the ROC model (Figure 2), odds ratios for readmission for- Score 0 versus 3 was 24; (2) Score 1 versus 3 was 15 and (3) Score 2 versus 3 was 4.5.

Figure 2. Receiver operating characteristic (ROC) curve for scoring system II, showing odds ratio for readmission for score 0 versus 3, score 1 versus 3 and score 2 versus 3.

In both scoring systems, the combined score of 3, with all 3 variables present, was associated with a high rate of readmission. The odds ratio was calculated for the clinical scores as it provides a valid effect measure and allows comparison of the clinical scores with regards to outcome, i.e. the readmission for COPD exacerbation, in a small study such as this.

The closer AUC is to 1, the better the predictive performance of the test, with the practical lower limit for the AUC of a predictive test being 0.5. In this study, scoring system I with an AUC of 0.69 (Figure 1) and scoring system II, with an AUC of 0.73 (Figure 2), indicate fair strength as predictors for COPD readmission.

Discussion

The purpose of our study was to create a simple scoring system that might predict 30-day readmissions in patients hospitalized with COPD exacerbations. Data regarding factors which predisposes to hospital readmissions within 30 days of discharge after hospitalization for acute exacerbations of COPD is variable and remains limited (4-6, 10,11). Our study aimed at identifying potential risk factors and evaluating probable predictors of hospital re-admission in COPD patients within a month of discharge.

In our study, three variables held promise in a scoring system used to predict re-hospitalization within 30 days: exacerbations (either clinically-treated or hospitalized), chronic prednisone use, and functional limitation from dyspnea. These three variables could be assessed within a few minutes from a review of the inpatient hospital record or from a brief interview.

Previous studies evaluating readmission risk factors in COPD up to one year have identified several variables. These include: a lower FEV1 (12- 16), reduced physical activity, functional limitation and poor health-related quality of life (2,4,17-19), need for self-care assistance, active/ passive smoking, long term supplemental O2-requirement (12,16-18), and presence of selected co-morbid conditions (20, 21).

More recent studies found low physical activity to be a significant factor (5,18). Minutes of physical activity per day in the first week following discharge was lower in those readmitted (42 + 14 minutes vs. 114 + 19 minutes, p = 0.02) (5). Ngyuen et al. (19) reported an 18% readmission rate in 4000 patients, with independent predictors of increased readmission including reduced activity, anemia, prior hospitalizations, longer lengths of stay, more comorbidities, receipt of a new oxygen prescription at discharge, use of the emergency department or observational stay before the readmission. In another retrospective study, multivariate analysis showed the following risk factors to be associated with early readmission within 30 days of discharge- male gender, history of heart failure, lung cancer, osteoporosis, and depression; no prior prescription of statin within 12 months of the index hospitalization and no prescription of short-acting bronchodilator, oral steroid and antibiotic on discharge; length of stay, <2 or >5 days and lack of follow-up visit after discharge (10). Another study found these variables to have a significant association with 30-day readmissions: age, diastolic blood pressure, COPD severity score, length of stay, pH, paCO2, FEV1< 50%, number of previous days until exacerbation (6). This study also found an increased mortality at 6 months and one year in patients readmitted within 30 days of discharge (6).

In our study, the most influential variable 30-day readmission was the history of two or more exacerbations in the preceding year (OR: 2.47, CI= 1.51-4.05, p< 0.001). This variable was also found in our study to be significantly associated with 30-day readmission, following discharge for a COPD exacerbation hospitalization.

Our study found steroid use (chronic or prior to admission) to be a significant predictor of COPD readmissions. Steroid use has been associated with a significantly increased risk of readmission in a few other studies (12,13,16,22). We hypothesize chronic prednisone use reflects instability and variability in the chronic respiratory disease or a recent exacerbation prior to the index hospitalization- hence its relatively strong relationship to re-hospitalization.

The second significant predictor in our study, exacerbations resulting in hospital admission in the preceding year, has been found to be a risk factor readmission in prior studies (6,12,13,23). Three admissions in the year preceding recruitment was found to increase risk for readmission for COPD exacerbation (12,13,23). Frequent exacerbations in the preceding year likely reflect the severity of disease in these patients. A retrospective study found no association between the number of previous hospital COPD admissions and readmission (24).

Our third significant predictor, the severity of dyspnea has also been reported in some studies to be an independent risk factor for hospital admission for an acute exacerbation of COPD. Kessler et al. (14) reported that COPD patients with a dyspnea of grade 3, 4 or 5 (defined as breathlessness with mild, minimal or limited exertion respectively), had a significant risk of hospitalization at one year but those with dyspnea of grade 2 did not. Patients with “severe dyspnea” have been found to be more likely to be readmitted to hospital in studies (15,18). Our study using the MRC rating for dyspnea and found patients with an MRC rating of 4, which is equal to the most severe grading of dyspnea in this scale. The severity of dyspnea by MRC dyspnea being a predictor for readmission in COPD indicates that the severity of the disease predisposes to exacerbations of COPD and consequent readmissions.

A systematic review of studies on risk factors for readmission for patients with COPD exacerbation found 3 predictive factors similar to our study, namely- previous hospital admission, dyspnea and oral corticosteroids (25). This review also identified other variables including use of LTOT, having low health status or poor health related quality of life and reduced routine physical activity as risk factors for admission and readmission for COPD exacerbation (25).

A scoring system similar to ours, using 3 the significant predictors of COPD readmission (chronic prednisone use, MRC dyspnea rating and prior exacerbations, either clinical or requiring hospitalizations) has not been studied in predicting the 30 day- readmission for COPD exacerbation. This scoring system was a fairly strong predictor of readmission for COPD and may serve as a useful tool in risk-stratifying patients and directing medical resources toward those patients most at risk for readmission. This is especially of relevance at the present time when hospitals will face financial penalties for 30-day readmissions for COPD.

The risk factors identified for COPD readmission in this study are not modifiable. However, if patients more at risk for readmissions can be identified based on these risk factors, more resources can be directed to these group of patients- such as closer outpatient follow-up, VNA services, inpatient and outpatient pulmonary rehabilitation, more gradual steroid taper and institution of anti-inflammatory therapy such as azithromycin.

One limiting factor of this study is the small number of patients. The scoring system generated by the study using the 3 identified predictors, though fairly predictive of readmissions for COPD exacerbations, cannot be used without corroboration. The validity of the scoring system using needs to be established in a larger group of patients. Based on the results of this study, we intend to assess these variables as part of a quality assurance study on a larger number of hospitalized COPD patients. We plan to attempt to refine the scoring system, if possible, with an emphasis on simplicity in assessing data, brevity in data collection and predictive power for 30-day and subsequent hospitalization.

Conclusions

A simple 3-point scoring system, incorporating three variables: 1) chronic prednisone use; 2) MRC dyspnea rating; and 3) prior exacerbations (either clinical or requiring hospitalizations) has a fairly high predictive value for 30 -day readmission due to COPD exacerbation. This can be easily assessed within a few minutes from a review of the inpatient hospital record or from a brief patient interview. It can serve as a useful tool in risk-stratifying patients and directing medical resources toward those patients most at risk for readmission. This scoring system using these three variables holds promise for future validation studies.

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Cite as: Yap V, Wilcox D, ZuWallack R, Datta D. Evaluating a scoring system for predicting thirty-day hospital readmissions for chronic obstructive pulmonary disease exacerbation. Southwest J Pulm Crit Care. 2018;16(6):350-9. doi: https://doi.org/10.13175/swjpcc054-18 PDF

Rick Robbins, M.D. 6/22/18 Rick Robbins, M.D. 6/22/18

Intralobar Bronchopulmonary Sequestration: A Case and Brief Review

Uddalak Majumdar, MD¹

Payal Sen, MD²

Akshay Sood, MD²

¹Cleveland Clinic Foundation, Cleveland, OH USA

²Univeristy of New Mexico, Albuquerque, NM USA

Abstract

Objective: Bronchopulmonary sequestration is a rare congenital abnormality of the lower respiratory tract, seen mostly in children but often in adults. The term implies a mass of lung tissue that has no function and lacks normal communication with the rest of the tracheobronchial tree.

Case: A 40-year-old man presented with acute onset of left flank pain for 4 hours. He was born in Yemen and emigrated to the US in 1998; at that time, he had been tested for tuberculosis which was negative. In this admission, he met systemic inflammatory response (SIRS) criteria and had basilar crackles in the left lower lobe of the lung. CT scan revealed a cavitary lesion with air-fluid level in the left lower lobe airspace. There was systemic arterial blood supply to this region arising off the celiac axis. He was diagnosed with an infected intralobar bronchopulmonary sequestration and underwent video-assisted thoracoscopic wedge resection. On follow up 3 months later, he was doing well.

Discussion: Pulmonary sequestration is a rare congenital anomaly of a mass of lung tissue, which can have cystic changes and is a very important differential diagnosis of cavities in the lung. Confirmation of diagnosis is by visualization of a systemic vessel supplying sequestrated pulmonary, and this is accomplished by contrast-enhanced CT scan, MRI or invasive angiography.

Conclusion: The delay in diagnosis in our patient was due to falling prey to anchoring and availability biases and chasing the diagnosis of tuberculosis in a patient from Yemen with a lower lobe cavitation.

Case

History of Present Illness: A 40-year-old man with a past medical history of atrial fibrillation presented to the hospital with acute onset of left flank pain for 4 hours, fevers and chills. The pain was sharp and stabbing, pleuritic, non-radiating, and was severe with an intensity of 10/10. He denied extraneous activity or trauma earlier in the day, denied substernal pain, cough, night sweats, weight loss or change in urinary habits. He was born in Yemen and emigrated to the US in 1998; at that time, he was tested for tuberculosis (TB) which was negative. He was known to have a cavitary lesion in left lower lobe since 2005, and had undergone extensive evaluation (imaging, sputum and PPD) which showed no form of tuberculosis. He denied taking prophylactic TB treatment. Annual PPD testing had always been negative.

The patient worked on a ship, which travelled in the Great Lakes on the US-Canada border. He was a current smoker with a 20-pack-year smoking history. He lived at home with his wife and children. There was no history of IV drug use, prior imprisonment or homelessness. He denied being in contact with anyone with TB while in Yemen. He was sexually active with his wife and had no other sexual partners. He denied history of sexually transmitted infections.

Physical Examination:

Vital Signs: Temp – 38.3 degrees Fahrenheit, Pulse- 111/minute, RR- 18/min, BP- 151/66 mm Hg. Spo2- 90 % on Room Air.

Basilar crackles and rhonchi in the left lower lobe of the lung. No cervical or inguinal lymphadenopathy. Rest of the physical exam was normal.

Significant Laboratory Findings:

WBC elevated at 15,500/mm³ with 65 percent Neutrophils.

Lactate - 1.1 mmol/dL

Radiography:

Chest x-ray was done while in the emergency department, which revealed left basilar sub-segmental atelectasis (Figure 1).

Fig.1. Chest x-ray showing left basilar sub-segmental atelectasis without focal consolidation, large pleural effusion or pneumothorax.

Initial CT scan of abdomen and pelvis was done to rule out renal/ureteral stone. It showed a left lower lobe airspace consolidation with bronchiectasis and bronchiolectasis and a cavitary lesion with air-fluid level (Figure 2).

Figure 2. Representative images from the CT scan in lung windows showing left lower lobe airspace consolidation concerning for an acute on chronic process.

C-reactive protein and erythrocyte sedimentation rate were normal, CRP and ESR- normal; blood cultures revealed no growth; procalcitonin 0.4 ng/mL (normal <0.15); anti-nuclear antibody – negative; Aspergillus antigen – negative; urine Legionella antigen – negative; Streptococcus pneumoniae antigen – positive.

Sputum Gram stain and acid-fast bacilli culture/stain could not be obtained because the patient did not produce any sputum.

Subsequently CT chest with IV contrast was done which showed findings compatible with a pneumonia within a left lower lobe intrapulmonary sequestration. (Figure 3).

Figure 3. Representative images from the thoracic CT chest with IV contrast. The left lower lobe demonstrates a 69 x 83 mm heterogeneous fluid collection with multiple locules of air. There was systemic arterial blood supply to this region arising off the celiac axis (arrows).

The patient was diagnosed with an infected intralobar bronchopulmonary sequestration. He was treated initially with intravenous fluids and piperacillin-tazobactam. He underwent video-assisted thoracoscopic wedge resection of infected bronchopulmonary sequestration in left lower lobe and ligation of the systemic feeding vessels from the celiac artery. Pathologic examination revealed a fibrotic lung with areas of centrilobular emphysema, bronchiolectasis, mucus pooling and microscopic honeycomb changes. Findings also showed an elastic artery, with features most suggestive of intralobar sequestration. His symptoms completely resolved after his operation.

Discussion

Bronchopulmonary sequestration is a rare congenital abnormality of the lower respiratory tract, seen mostly in children but often in adults, like in our patient (1). In 1946, Pryce coined the term "pulmonary sequestration" to describe a disconnected bronchopulmonary mass or cyst with an anomalous arterial supply (2). The term implies a mass of lung tissue that has no function and lacks normal communication with the rest of the tracheobronchial tree. This mass of non-functional lung tissue receives blood supply from the systemic circulation (3). The exact etiology is unknown and is thought to be an embryologic process error in foregut budding (4), although some have indicated a non-congenital acquired process in intralobar sequestration.

Sequestration may be intra- or extralobar based on its relation with the normal lung lobes. An intralobar sequestration (ILS), like the name suggests, is located within a normal lobe, lacks its own visceral pleura (5) and also has aberrant connections to bronchi, and lung parenchyma, or even the gastrointestinal tract, and often presents with recurrent infections (6,7). Compared to ILS, an extralobar sequestration (ELS) is located outside the normal lung and has its own visceral pleura (8), with the rare occurrence of infectious complications (9). About 75% of BPS is intralobar while 25% is extralobar (10). Bronchopulmonary sequestration is often associated with other congenital abnormalities like congenital diaphragmatic hernia, vertebral anomalies, congenital heart disease, pulmonary hypoplasia, colonic duplication, and congenital pulmonary airway malformation (11).

Clinically, pulmonary sequestration is latent until infection leads to symptoms (12). Symptoms, like that of any pathological lung condition depend on the type, size, and location of the lesion. Sepsis and extracardiac shunting are common complications of untreated sequestration. Hemoptysis can also be a presentation. The mechanism of pneumonia is post-obstructive and usually recurrence of pneumonia leads to diagnosis. Recurrent pneumonia especially in the lower lobes should always include intralobar sequestration in the differential diagnoses. But the pathophysiology of infection and/or hemoptysis when ILS is not connected to airway is a mystery. Sometimes there is a partial or anatomically abnormal connection to the tracheobronchial tree, which can lead to poor mucus clearance, plugging and recurrent infection.

The mainstay of diagnosis is pre-operative imaging and post-operative histopathology of the resected specimen. The pathognomonic imaging characteristic is systemic vascular supply of the affected area of the lung (intra or extra-lobar), which is seen in about 80% of CT scans. Recurrent infection can lead to cystic areas within the mass (clusters of “ring shadows” on X-ray) (13). The surrounding normal lung may have air trapping and show emphysematous changes. Radiologic signs of BPS are a spectrum and represent the chronic and recurrent inflammation of the sequestrated lung: recurrent focal airspace disease, a parenchymal mass, a cavitary consolidation or mass, cystic lesions, localized bronchiectasis or adjacent emphysema. Bronchoscopy has little role in the management of BPS, which needs to be kept in mind by clinicians investigating cystic lung lesions. Identifying the systemic feeding vessel also helps with surgical planning.

Symptomatic patients are treated with surgical excision; surgery is curative and is associated with minimal morbidity (14). Surgery is urgent in patients with significant respiratory distress but may be an elective procedure in adults or older children with less symptoms (15, 16).

For asymptomatic patients of any age, management depends on how ‘high risk’ they are considered for developing complications. High risk patients are those with large lesions occupying >20 percent of the hemithorax, bilateral or multifocal cysts, or those with pneumothorax. In these patients, surgical resection is preferred to observation (17). On the other hand, in asymptomatic patients without these high-risk characteristics, either elective surgical resection or conservative management with observation are reasonable options (18).

Apart from surgery, even embolization of the anomalous arterial supply has been reported to result in a complete resolution of symptoms and imaging changes to a certain in some cases (19). Since identification of vascular supply during surgery may be difficult during surgery, presurgical embolization may reduce risk of vascular complications (19). Embolization also has a more important role in hemoptysis and heart failure from shunting.

Conclusions

Pulmonary sequestration is a rare congenital anomaly of a mass of lung tissue without a normal connection to the tracheobronchial tree and a systemic vascular supply.
Presentation in adults is due to complication of the mass, undiagnosed in childhood.
Sequestrated lung can have cystic changes and is a very important differential diagnosis of the cavitation.
Confirmation of diagnosis is by visualization of a systemic vessel supplying sequestrated pulmonary, and this is usually accomplished by contrast-enhanced CT scan, MRI or invasive angiography.

Teaching points

This is a case of adult presentation of congenital pulmonary malformation and represents a delay in diagnosis, even though the patient’s symptoms started 10 years ago. The delay was due to falling prey to anchoring and availability biases and chasing the diagnosis of TB ten years ago in a patient from Yemen with a lower lobe cavitation.

The feeding vessel from the celiac axis can only be demonstrated via a contrast enhanced CT, and thus, when in doubt, we should always get angiography by contrast-enhanced-CT or MRI or by invasive angiography. Had it been thought of and done 10 years ago, the patient would’ve been diagnosed and treated earlier.

Disclosure Statement

Drs. Majumdar, Sen and Sood have no conflicts of interest or financial ties to disclose.

References

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Cite as: Majumdar U, Sen P, Sood A. Intralobar bronchopulmonary sequestration: A case and brief review. Southwest J Pulm Crit Care. 2018;16(6):343-9. doi: https://doi.org/10.13175/swjpcc075-18 PDF

Rick Robbins, M.D. 6/4/18 Rick Robbins, M.D. 6/4/18

Sharpening Occam’s Razor – A Diagnostic Dilemma

Payal Sen, MD¹

Uddalak Majumdar, MD²

Patrick Rendon, MD¹

Ali Imran Saeed, MD¹

Akshay Sood, MD¹

¹University of New Mexico

Albuquerque, NM US

²Cleveland Clinic Foundation

Cleveland, OH USA

Abstract

Objective: Physicians often search for Occam’s Razor, that is, to have a single diagnosis explain all clinical manifestations in an individual patient. Herein, we describe a case which was significant for a dual clinical diagnosis, thus proving that Occam’s razor may not always hold true.

Case Summary: A 22-year-old Caucasian man presented with 4 days history of fever, and dry cough. Chest x-ray revealed a right middle lobe pneumonia. Mycoplasma IgM antibody titer was significantly elevated (>1:320), using the rapid diagnosis enzyme-immunoassay (EIA) test, and clinical course was complicated by rhabdomyolysis. He was treated with oral azithromycin for 5 days. The patient however returned to the ER in 2 weeks with similar symptoms and repeat chest x-ray revealed a persistent right middle lobe infiltrate. Endobronchial biopsy revealed necrotizing granulomatous inflammation which stained positive for Histoplasma capsulatum. Serum complement fixation antibody test for Histoplasma demonstrated an elevated titer of 1:64. The patient was diagnosed to have an ‘atypical pneumonia due to sub-acute Histoplasma capsulatum and acute Mycoplasma Pneumoniae infections, complicated by rhabdomyolysis.’

Discussion: This case is unusual because the patient had an acute community-acquired atypical pneumonia from Mycoplasma pneumoniae, complicated by rhabdomyolysis, and also had subacute Histoplasma pneumonia. Physicians often search for Occam’s Razor. However, following Hickam’s dictum, we made the unusual diagnosis of concomitant lung infection in an immunocompetent host with Mycoplasma pneumoniae and Histoplasma capsulatum.

Conclusion: This was an immunocompetent patient who ran a complex, protracted, and unusual course of community acquired pneumonia. Often, the pursuit of additional or alternative diagnoses may require repeated and multiple invasive diagnostic sampling. Occam’s razor may not always hold true.

Introduction

Occam's razor proposes that the simplest explanation is usually the correct one. However, in the science of medicine, simple solutions may be elusive. Often there is an incredibly complex constellation of symptoms co-occurring with one another, thereby confounding the scientific community. We described the diagnostic conundrums in managing our patient who ran a complex protracted course of community acquired pneumonia.

Case

A 22-year-old Caucasian male college student with no significant past medical history, initially presented to the University hospital in New Mexico, United States, with 4 days’ history of fever, dry cough, and dyspnea. He had recently returned from a family vacation in Illinois and had spent several weeks fishing on the Mississippi river. Review of systems was negative for chest pain, headache, fever, chills, or night sweats. He denied any sick contacts. He did not smoke and did not use recreational drugs. His grandfather, who had been a heavy cigar smoker, had died of lung cancer.

His vital signs were significant for a body temperature of 100.6° Fahrenheit, respiratory rate of 32 breaths per minute, pulse rate of 94 bpm, blood pressure of 130/82 millimeters of mercury, and pulse oximetry of 90 percent on room air. Physical examination demonstrated that he was in mild respiratory distress. Chest auscultation revealed decreased breath sounds over the right mid to lower lung field. The rest of his physical examination was otherwise unremarkable.

His laboratory tests revealed a normal complete blood count with a hematocrit of 40.5%, white blood cell count of 8,200 cells per microliter, and platelet count of 263,000 per microliter. His electrolyte levels showed a serum sodium of 136 mEq per liter, potassium of 3.4 mEq per liter, chloride of 100 mEq per liter, bicarbonate of 21 mEq per liter, blood urea nitrogen of 15 mg/dL and creatinine of 0.9 mg/dL. His blood glucose was normal at 98 mg/dL. His urine analysis revealed 3+ blood without red blood cells. His liver function tests demonstrated an elevated aspartate aminotransferase at 244 units per liter, elevated alanine aminotransferase at 72 units per liter, with normal total bilirubin, albumin, and alkaline phosphatase levels. His serum creatinine kinase (CK) was highly elevated at 26,000 units per liter (normal reference range 39-308 units per liter). His arterial blood gas at rest on room air at an elevation of 5500 feet above sea level showed acute respiratory alkalosis with a normal alveolar arterial gradient with a pH of 7.57, PaCO2 of 28 mmHg, PaO2 of 77 mmHg, and bicarbonate of 22 mEq per liter. His mycoplasma IgM antibody titer was significantly elevated (> 1:320) using the rapid diagnosis enzyme-immunoassay (EIA) test. Anti-mycoplasma pneumoniae IgA was also elevated. The urinary legionella and pneumococcal antigen levels, sputum culture, blood cultures, and urine toxicology screen were negative. Chest radiograph revealed a right middle and lower lobe pneumonia (Figure 1).

Figure 1. CXR revealed right mid and lower lobe pneumonia.

The patient was diagnosed with sepsis secondary to Mycoplasma pneumoniae infection of the lungs, with the added complication of rhabdomyolysis. He was treated with intravenous followed by oral azithromycin 500 mg daily for 5 days and given intense hydration therapy. Within 48 hours, his low-grade fever subsided, CK decreased to 1000 units per liter, and the patient felt better. He was then discharged on Day 3 of hospitalization.

The patient however returned to the emergency department 2 weeks after discharge with persistent cough, chest discomfort, and loss of wellbeing. Repeat chest radiograph revealed a persistent right lower lobe infiltrate. Computed tomography (CT) scan of the chest revealed a right lower lobe consolidation with surrounding nodular opacities with a possible endobronchial lesion in the right lower lobe (Figure 2).

Figure 2. Panel A: Coronal view of thoracic CT scan showing right lateral basilar segment consolidation. Panel B: Axial view showing consolidation in the right lower lobe with surrounding nodular opacities.

He underwent bronchoscopy which revealed a mass-like endobronchial lesion in the lateral basilar segmental bronchus of the right lower lobe (Figure 3).

Figure 3. Bronchoscopy revealing a mass-like endobronchial lesion in a lateral segmental bronchus of the right lower lobe.

Endobronchial biopsy revealed necrotizing granulomatous inflammation and stained positive for the yeast form of Histoplasma capsulatum. Serum complement fixation antibody test for Histoplasma demonstrated an elevated titer of 1:64. Acid fast bacilli were not seen on smear or culture and cytology and histopathology tests did not reveal malignancy.

The patient was diagnosed with an atypical pneumonia due to sub-acute Histoplasma capsulatum and acute Mycoplasma Pneumoniae infections, complicated by rhabdomyolysis. The mycoplasma infection and rhabdomyolysis had already been treated and resolved. For the subacute pulmonary histoplasmosis, the patient was treated with 10 weeks of oral itraconazole. Post treatment clinic follow-up revealed resolution of symptoms and radiological abnormalities.

Discussion

Mycoplasma pneumoniae is a common causative pathogen for community-acquired pneumonia in both children and adults (1). Apart from respiratory tract symptoms, it is associated with a variety of extra-pulmonary manifestations (2). Recognizing this association can lead to timely diagnosis and treatment of both the mycoplasma infection and its complications. In this case report, we also want to highlight the fact that infection with endemic mycoses can often be mistaken for community acquired pneumonias, and thus having a high index of suspicion for fungal infection is very important, even in immunocompetent patients (3), to prevent a delay in treatment. Physicians often search for Occam’s Razor, i.e., to have a single diagnosis explain all clinical manifestations in an individual patient. This case is significant because of a dual clinical diagnosis, thus proving that Occam’s razor may not always hold true in an individual patient.

Mycoplasma infection can cause several unusual extra-pulmonary manifestations such as hemolytic anemia, immune thrombocytopenic purpura, transverse myelitis, Guillain-Barre syndrome, acute hepatitis and arthritis (4). Another lesser known complication of mycoplasma infection is rhabdomyolysis (5). Rhabdomyolysis is a syndrome caused by injury to the skeletal muscles, thereby resulting in leakage of myoglobin into blood (6). The classic triad of mycoplasma infection consists of myalgias, pigmenturia, and generalized muscle weakness, but this classic triad is seen in less than 10 percent of infected patients (7). Acute renal failure due to acute tubular necrosis as a result of mechanical obstruction by myoglobin is the most common complication, in particular if the serum CK level is >16,000 IU/l, which may be as high as 100,000 IU/l (8). In addition to mycoplasma infection, more common causes of rhabdomyolysis are trauma, immobilization, and recreational drug and alcohol use (9).

Other organisms known to cause rhabdomyolysis are Influenza A and B virus, Coxsackie virus, Epstein-Barr virus, Primary Human Immunodeficiency virus, Legionella species, Staphylococcus aureus, and Streptococcus pyogenes (9). With respect to Mycoplasma pneumoniae infection, a possible mechanism for rhabdomyolysis is the induction of inflammatory cytokines, such as tumor necrosis factor-alfa (TNF-α) and interleukin-1 (IL-1), which may cause proteolysis of skeletal muscles (10).

The rapid and reliable diagnosis of Mycoplasma pneumoniae (Mp) enables the correct and prompt use of antibiotics. Methods for identifying Mp infection include culture, molecular detection of pathogen specific antigen or nucleic acid, and serological analysis (11). Each of these methods has its pros and cons. Culture is the definitive method for diagnosis and is critical for monitoring trends in epidemiology but is slow and requires specialized media and trained personnel (11). Although molecular methods for nucleic acid or antigen detection have emerged as the primary techniques for identification of MP pneumoniae in surveillance programs, adoption of these methods is still lagging behind in USA.

Serologic analysis can prove to be problematic due to poor sensitivity and specificity, and the inability to characterize the specific Mp strain. Having said that, most physicians in the United States continue to rely on serological testing in concordance with the IDSA guidelines (11). It is well known that a single serologic test is of limited value in the early diagnosis of mycoplasma pneumoniae since there are often no IgM antibodies in the early stage of infection, and these IgM antibodies may persist long after the infection (12). However, if these IgM antibodies are present along with anti-Mycoplasma pneumoniae IgA, it is usually indicative of recent primary mycoplasma pneumoniae infection (13). A single high Mp-specific antibody titer (> 1:320) has been regarded as a diagnostic marker of mycoplasma pneumoniae, although it is present in only about 30 percent of the patients (12). Since our hospital relies on serological testing, we tested for the specific Mycoplasma pneumoniae IgM and IgA, both of which were positive. The MP-specific antibody titer was also greater than 1:320, thus signifying it indeed was early MP infection.

Symptoms of Mp infection generally resolve within 3–4 weeks after disease onset but can be shortened with antibiotic therapy; macrolides and doxycycline are the mainstay of this treatment (14). The mainstay for the prevention of pigment-induced acute kidney injury is the correction of volume depletion, prevention of intratubular cast formation, and the treatment of the underlying cause of rhabdomyolysis (4). This is done by aggressive fluid resuscitation resulting in increased renal blood flow and thus increasing the urinary flow with consequential wash out of partially obstructing tubular casts (4). Physicians will be served well to watch out for mycoplasma associated rhabdomyolysis in patients with atypical pneumonia and manifestations like myalgia, elevated aminotransferase levels, and myoglobinuria.

Moving on to the second teaching point, endemic mycoses like coccidioidomycosis, histoplasmosis, and blastomycosis are often overlooked causes for community acquired pneumonia, particularly when immunocompetent patients travel out of the endemic zones (15). Often, testing is not even performed until the patient has failed to improve on antibacterial therapy. Delays in recognition, diagnosis and proper treatment may lead to disastrous outcomes (3). Performance of fungal antigen testing on bronchial washings or lavage fluid may improve the sensitivity for diagnosis over microscopic examination and the speed of diagnosis over culture even though isolation of the fungus by culture remains the gold standard method for definitive diagnosis (16). In this case, our patient was previously treated as mycoplasma pneumonia, thus leading to prolonged symptom course from histoplasmosis.

This case is unusual because the patient had an acute community-acquired atypical pneumonia from Mycoplasma pneumoniae, complicated by rhabdomyolysis, and also had subacute Histoplasma pneumonia. Physicians often search for Occam’s Razor, a principle from philosophy that when presented with competing hypothetical answers to a problem, one should select the one that makes the fewest assumptions. Countering

Occam’s Razor, Dr. John Hickam said “Patients can have as many diseases as they damn well please!” (17). Following Hickam’s dictum, we made the unusual diagnosis of concomitant lung infection in an immunocompetent host with Mycoplasma pneumoniae and Histoplasma capsulatum.

Conclusion

With this case report, the authors wish to highlight two important teaching points. The first being that rhabdomyolysis is a serious but treatable extrapulmonary complication of Mycoplasma pneumoniae infection of the lungs. Having a high index of suspicion can limit treatment delay for rhabdomyolysis caused by mycoplasma infection and will therefore limit consequential morbidity like renal insufficiency. The second point that the authors wish to emphasize is that endemic fungal infection can often be mistaken for bacterial and viral community-acquired pneumonia in an immunocompetent host, particularly when they present with symptoms outside the endemic zone, thus delaying timely management. Hence one should have a high suspicion for fungal infection in immunocompetent hosts with unusual presentations such as history of travel to endemic zone, chronicity of symptoms, lack of response to therapy for community-acquired pneumonia, nodular lung lesions, and endobronchial abnormalities.

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Cite as: Sen P, Majumdar U, Rendon P, Saeed AI, Sood A. Sharpening Occam's razor-a diagnostic dilemma. Southwest J Pulm Crit Care. 2018;16(6):324-31. doi: https://doi.org/10.13175/swjpcc061-18 PDF

Rick Robbins, M.D. 6/1/18 Rick Robbins, M.D. 6/1/18

June 2018 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

The patient is a 53-year-old man who presented in January 2018 for a second opinion on interstitial lung disease first diagnosed in 2011. He lives in Los Angeles and had one year of increasing dyspnea on exertion prior to diagnosis. He had an outside surgical lung biopsy and was treated with prednisone, then started on azathioprine and the prednisone tapered. He was followed regularly and had limited progression over next 7 years. However, recently he had increasing shortness of breath.

Past Medical History, Social History, Family History

He has no significant past medical history. He is a nonsmoker and denies any significant occupational exposures.

Physical Examination

Physical examination was unremarkable without rales or clubbing.

Which of the following should be obtained at this time? (Click on the correct answer to proceed to the second of five pages)

Cite as: Wesselius LJ. June 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(6):296-303. doi: https://doi.org/10.13175/swjpcc063-18 PDF