February 2014 Pulmonary Case of the Month: Faster Is Not Always Better

Lewis Wesselius MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 56 year old woman with a history of rheumatoid arthritis (RA) for 26 years was seen as an outpatient. She has a recent history of increased cough, sputum and dyspnea.

PMH, FH, SH

She was originally from India but had lived in Singapore from 2011 to June 2013 before moving to Phoenix. In 2009, she was diagnosed with Mycobacterium avium-intracellulare (MAI) on bronchoscopy and started on azithromycin, ethambutol, and rifabutin. She was unable to tolerate rifabutin but was continued on ethambutol and azithromycin. She had been on etanercept for her RA which was held after the diagnosis of MAI. She had negative sputum cultures for MAI in September 2012 and her ethambutol and azithromycin were stopped. In May 2013 she had increased symptoms and bronchoscopy demonstrated Pseudomonas and nontuberculous mycobacterium (NTM). She was treated with cefipime/ciprofloxacin for 6 weeks prior to moving to Phoenix.

She does not smoke or drink. Her FH is noncontributory.

Medications

• Celecoxib 200 mg bid
• Gabapentin 600 bid
• Methotrexate 15 mg weekly
• Prednisone 5 mg daily
• Tramadol 50 mg every 4 hours prn

Physical Examination

Afebrile. SpO2 96% on room air.

Chest: scattered crackles in both lungs, no wheezes.

There were joint deformities typical of chronic RA, but otherwise the remainder of the physical exam was unremarkable.

Radiology

She brings a CT scan from 2009 (Figure 1). 

Figure 1. Panels A-D: Representative static axial lung images from a thoracic CT scan performed in 2009. Lower panel: movie of selected lung images from the thoracic CT scan performed in 2009.

What should be done next? (Click on correct answer to move to next panel)

1. Repeat the CT scan
2. Restart ethambutol and azithromycin
3. Sputum culture
4. 1 + 3
5. All of the above

Reference as: Wesselius LJ. February 2014 pulmonary case of the month: faster is not always better. Southwest J Pulm Crit Care. 2014:8(2):74-8. doi: http://dx.doi.org/10.13175/swjpcc168-13 PDF

January 2014 Pulmonary Case of the Month: Too Much, Too Late

Chidinma Chima-Okereke MD  

Department of Pulmonary Medicine

Cedars Sinai Medical Center

Los Angeles, CA

Chief Complaint: Difficulty breathing

History of Present Illness

A 49-year-old gentleman with history of hepatitis C cirrhosis complicated by ascites presented to the emergency room of Olive View Medical Center in San Fernando Valley, California complaining of worsening shortness of breath. The patient reports that he occasionally has shortness of breath, usually about 2-3 times a year. However for the past 2 months, he has had worsening dyspnea on exertion and cannot walk further than 5 minutes. He also reports orthopnea and paroxysmal nocturnal dyspnea. He has been having a dry cough for the past 3-4 weeks.

He has a history of chronic ascites that has required multiple taps. He has been taking his prescribed diuretics however instead of taking these medications daily he takes them about every other day due to financial constraints.

However, his abdominal distention and his lower extremity swelling are stable. He reports some nausea with decreased appetite. He also has a new symptom of left-sided chest pain that radiates down his left arm and shoulder that lasts about 20 minutes and has no associated symptoms. .

He denies any fevers or chills or weight change. He has no sick contacts.

Past Medical and Surgical History

• Hepatitis C cirrhosis
• Chronic lower extremity edema
• Ascites, status post multiple large volume paracentesis
• History of chronic abdominal pain treated with morphine
• Status post chest tube when he was a 17-year-old due to a gunshot wound

Social History

• History of incarceration, released about 8 months ago
• 6-pack of beer a day – quit 12 years ago.
• Former smoker, quit 10 years ago, 7 pack-years
• IV heroin use 15 years ago
• No cocaine, amphetamines or any inhaled substances
• No recent travel, occupational, pet or bird exposures
• Lives with his fiancé in Lancaster, California

Family History

• Father died of an MI at age 56.
• Mother - SLE, DM, Stroke
• Sister - Colon cancer
• Brother - Hepatitis C cirrhosis

Medications

• Controlled-release morphine sulfate 15 mg p.o. every morning and 30 mg p.o. every evening.
• Furosemide 40 mg p.o. daily.
• Spironolactone 50 mg p.o. daily.
• Lactulose 15 mL p.o. b.i.d. p.r.n.

Review of Systems

Positive for pleuritic chest pain, night sweats, chills, dry cough - unproductive of sputum, lightening and darkening of urine, lower extremity edema, palpitations, decreased appetite, dry mouth, joint stiffness in the morning.    

Physical Examination

• Vital signs: T 97.4 BP 115/67, HR 89, RR 20, SpO2 93%/RA
• Lung exam was significant for bilateral crackles midway up the back.
• Abdominal exam was non-tender and not suggestive of ascites
• Lower extremities: 1+ bilateral pitting edema up to the knees.
• Multiple skin tattoos and erythema in his lower extremities  
• Muscle strength was 3/5 in the lower extremities, 4/5 in upper extremities bilaterally.
• Otherwise the physical exam was unremarkable.

Laboratory

• Basic Metabolic Panel was within normal limits.
• Complete blood count (CBC): White count 6.3 X 10³/mm³ with 8.3% eosinophils, hemoglobin 12.3 g/dL, platelets 130,000/µL.
• Liver function tests (LFTs): AST 78 IU/L, ALT 42 IU/L, alkaline phosphatase 115, total bilirubin 1.3 mg/dL, INR 1.3, albumin 2.7 g/dL.
• Brain naturetic peptide (BNP) 38 ng/L, troponin is 0.008 ng/ml.

Radiography

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

Figure 1. Admission AP (Panel A) and lateral (Panel B) chest x-ray.

The chest x-ray was interpreted as poor inspiration with elevation of the right diaphragm. The heart is at least upper limits of normal in size. Pulmonary vessels are congested. The azygos vein is mildly dilated. No significant pleural effusion is detected in these two views.

A CT angiogram was obtained to rule out pulmonary embolism (Figure 2).

Figure 2. Panels A-D: Representative static axial images from the thoracic CT scan lung windows. Lower panel: movie of representative axial thoracic CT scan lung windows.

Hospital Course

He was admitted to the medicine wards, diuresed with furosemide 40 mg IV, spironolactone 100 mg by mouth and fluid restricted.

At this point which of the following are diagnostic tests that should be ordered? (click on correct answer to move to next panel)

1. Coccidiomycosis serology
2. HIV
3. Quantiferon TB and sputum AFB
4. Rheumatologic work up including anti-neutrophil cytoplasmic antibody (ANCA), ANA and subtypes, RA and anticentromere antibodies
5. All of the above

Reference as: Chima-Okereke C. January 2014 pulmonary case of the month: too much, too late. Southwest J Pulm Crit Care. 2013;8(1):4-17. doi: http://dx.doi.org/10.13175/swjpcc162-13 PDF

32 Year Old Man with “Community-Acquired” Pneumonia

Jill K. Gersh, M.D., MPH¹, Michelle K. Haas MD^2,3,4

¹Department of Medicine, University of Colorado Denver, Aurora, CO; ²Denver Health Medical Center, Denver, CO; ³Denver Metro Tuberculosis Clinic, Denver, CO; ⁴Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, CO

Corresponding author: Jill Gersh, M.D., MPH Phone: 303-602-5052 Fax: 303-602-5055. Email: JILL.GERSH@UCDENVER.EDU

All authors declare they have no conflicts of interest to disclose.

Abstract

Background: Community-acquired pneumonia is a common reason for hospital admission; however underlying pathogens vary depending on host immunity and circulating pathogens in the community.

Case Summary: A 32 year old man from Malawi presented with community-acquired pneumonia. After failing outpatient management, he was admitted and found to have underlying HIV disease. His diagnostic work up was initially inconclusive for M. tuberculosis (TB) and thus his diagnostic evaluation and treatment focused on other etiologies. He was ultimately diagnosed with TB after an invasive procedure and had a rapid clinical response after initiating TB treatment.

Conclusion: Both failure to recognize that TB can present with a syndrome similar to bacterial pneumonia and over-reliance on diagnostic testing delayed the diagnosis of TB. Delays in diagnosis contributed to substantial morbidity and risked nosocomial transmission.  Despite declining incidence in the US, providers should remain cognizant of diagnostic limitations for TB disease and have a low threshold for empiric treatment.

Introduction

Community-acquired pneumonia (CAP) is a common reason for presentation to care. The epidemiology of CAP can vary depending on the patient’s community of origin and underlying co-morbidities (1). We present a case of a 32 year old man who presented with CAP in whom his diagnosis was delayed due to failure to fully consider these factors.  

Case

A 32 year old man from Malawi[1] presented to the emergency department (ED) with cough and dyspnea that failed to respond to a 5 day course of azithromycin. Chest radiography (CXR) was performed (Figure 1), demonstrating right middle lobe consolidation with ipsilateral hilar lymphadenopathy (LAD).

Figure 1. PA view of the chest demonstrating right middle lobe consolidation and ipsilateral hilar lymphadenopathy at the time of his first ED presentation and approximately 10 days into his illness.

He was diagnosed with CAP and discharged with a 7 day course of amoxicillin-clavulanate. His symptoms progressed with fevers, and weight loss.  He presented for the second time to the ED and repeat CXR showed worsening right-sided hilar LAD and right middle lobe consolidation (Figure 2).

Figure 2. PA view of the chest demonstrating worsening of right middle lobe consolidation and right sided hilar lymphadenopathy at the time of admission to the hospital and approximately 17 days into his illness.

A rapid HIV test was positive and his CD4 count was 60 cells/µL. He was admitted and started on ceftriaxone, azithromycin and trimethoprim-sulfamethoxazole daily. He was placed on respiratory isolation and three sputum samples for acid-fast bacilli (AFB) smear and culture were collected, all of which were AFB smear negative. He then underwent bronchoscopy and his bronchoalveolar lavage smear was negative for AFB. His tuberculin skin test (TST) was negative as was an interferon gamma release assay (IGRA). He was then removed from respiratory isolation.

He continued to worsen with daily fevers as high as 43ºC while antimicrobial coverage was broadened to vancomycin and cefepime. He eventually underwent mediastinoscopy and lymph node (LN) biopsy. The following day LN tissue was positive for AFB and probe identified Mycobacterium tuberculosis (TB). Twenty-nine days after his initial presentation and 15 days into his hospitalization he was started on anti-tuberculosis therapy with isoniazid, rifampin, pyrazinamide and ethambutol. His cough improved within 2 days, his fevers were gone by day 4 and he was discharged. All sputum cultures grew TB. Antiretroviral therapy was initiated five weeks into his TB treatment. He had an excellent clinical and radiographic response (Figure 3) and completed 9 months of TB treatment.

Figure 3. PA view of the chest after 9 months of treatment for M. tuberculosis. Noted here is resolution of right sided hilar lymphadenopathy and resolution of his right middle lobe consolidation with some residual scarring noted. Sputum culture converted at 2 months.

Diagnosis: Pulmonary tuberculosis.

Discussion

TB is the leading cause of death among HIV-infected individuals globally and the leading cause of morbidity in HIV-infected individuals (2). TB can present as an acute pneumonia with rapid progression of disease including sepsis and respiratory failure. Cough may not be a prominent feature and may be of less than two weeks duration. Additional signs and symptoms include fevers, night sweats, weight loss, hepatosplenomegaly, and lymphadenopathy. Individuals with CD4 counts < 100 cells/µL are more likely to present with disseminated disease and less likely to have cavitary disease. HIV-infected patients are also more likely to present with AFB smear negative disease even when severely ill (3). Chest radiograph findings vary from normal appearing films to hilar lymphadenopathy, diffuse infiltrates, and lobar consolidation.

TST and IGRAs are often negative and serve as poor screening tools for active disease. Up to 25% of individuals may have a negative TST or IGRA while having active disease, particularly HIV-infected individuals with advanced immunodeficiency (4). A negative result should never lower the clinical suspicion for active TB.

Delays in TB treatment are a major contributor to excess mortality in HIV-infected patients (2). The importance of early empiric treatment in HIV-infected individuals cannot be overstated. The World Health Organization (WHO) published guidelines in 2007 for the management of HIV-infected individuals suspected of having TB (5). While WHO guidelines are developed for low resource settings, these guidelines have relevance in the U.S. when managing patients with HIV who have lived or traveled to areas with a high burden of TB. 

The failure to recognize that his clinical syndrome of CAP included TB as the underlying pathogen led to delayed treatment, prolonged hospitalization and risked nosocomial transmission. One unintended consequence of the success of our TB control programs may be the growing lack of clinical experience with TB among our providers. More broadly, how much of what we do as U.S. healthcare providers is because we can, and instead of what we should? Imagine if he couldn't get a mediastinoscopy and biopsy. Is it possible that his treatment course would have been improved by a lack of these resources?  We would do well to learn from our colleagues practicing in resource limited settings where prescribing empiric TB treatment and assessing for a clinical response is standard of care. In this patient’s case, less really would have been more.

References

1. Nyamande K, Lalloo UG, John M. TB presenting as community-acquired pneumonia in a setting of high TB incidence and high HIV prevalence. Int J Tuberc Lung Dis. 2007;11(12):1308-13. [PubMed] 
2. Wong EB, Omar T, Setlhako GJ, et al. Causes of death on antiretroviral therapy: a post-mortem study from South Africa. PloS one. 2012;7(10):e47542. [CrossRef] [PubMed]
3. Elliott AM, Halwiindi B, Hayes RJ, Luo N, Tembo G, Machiels L, Bem C, Steenbergen G, Pobee JO, Nunn PP, et al. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. J Trop Med Hyg. 1993;96(1):1-11. [PubMed] 
4. Cattamanchi A, Ssewenyana I, Davis JL, Huang L, Worodria W, den Boon S, Yoo S, Andama A, Hopewell PC, Cao H. Role of interferon-gamma release assays in the diagnosis of pulmonary tuberculosis in patients with advanced HIV infection. BMC Infect Dis. 2010;10:75. [CrossRef] [PubMed]
5. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents: recommendations for HIV-prevelent and resource constrained settings. Geneva: World Health Organization;2007.

Acknowledgements

The authors wish to thank Carolyn Welch, MD for her thoughtful review of this case report.

Reference as: Gersh JK, Haas MK. 32 year old man with "community-acquired' pneumonia. Southwest J Pulm Crit Care. 2013;7(6):355-9. doi: http://dx.doi.org/10.13175/swjpcc173-13 PDF

December 2013 Pulmonary Case of the Month: Natural Progression

Robert W. Viggiano, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 68 year old woman was seen for increased back pain in April 2012. In 2000 she had a right lower lobe lung resection for low grade adenocarcinoma, bronchoalveolar type, nonmucinous. Her mass was 2.6 cm in maximal dimension extending to but not invading the pleura. There were clear surgical margins but involvement of one bronchial node. Multiple mediastinal nodes were negative. She had back pain for many years and yearly CTs were negative for metastatic disease.

PMH, SH, FH

Other than the above there was no significant past medical history, social history or family history.

Medications

• Non-steroidal anti-inflammatory drugs for pain
• Nitrofurantoin for chronic urinary tract infections

Physical Examination

There was tenderness to palpation over the mid-thoracic spine and evidence of a previous thoracotomy.

Laboratory

Her complete blood count (CBC), urinanalysis, liver function tests, and calcium were all within normal limits.

Radiology

An x-ray of the chest is interpreted as unchanged from previous x-rays. 

At this point which of the following radiologic testing is not indicated?

1. Bone scan
2. CT scan of the chest
3. Magnetic resonance imaging
4. Serial chest x-rays
5. Thoracic PET scan

Reference as: Viggiano RW. December 2013 pulmonary case of the month: natural progression. Southwest J Pulm Crit Care. 2013;7(6): . doi: http://dx.doi.org/10.13175/swjpcc155-13 PDF

December 2013 Pulmonary Case of the Month: Natural Progression

Robert W. Viggiano, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 68 year old woman was seen for increased back pain in April 2012. In 2000 she had a right lower lobe lung resection for low grade adenocarcinoma, bronchoalveolar type, nonmucinous. Her mass was 2.6 cm in maximal dimension extending to but not invading the pleura. There were clear surgical margins but involvement of one bronchial node. Multiple mediastinal nodes were negative. She had back pain for many years and yearly CTs were negative for metastatic disease.

PMH, SH, FH

Other than the above there was no significant past medical history, social history or family history.

Medications

• Non-steroidal anti-inflammatory drugs for pain 
• Nitrofurantoin for chronic urinary tract infections

Physical Examination

There was tenderness to palpation over the mid-thoracic spine and evidence of a previous thoracotomy.

Laboratory

Her complete blood count (CBC), urinanalysis, liver function tests, and calcium were all within normal limits.

Radiology

An x-ray of the chest is interpreted as unchanged from previous x-rays. 

At this point which of the following radiologic testing is not indicated? (click on correct answer to move to next panel)

1. Bone scan
2. CT scan of the chest
3. Magnetic resonance imaging
4. Serial chest x-rays
5. Thoracic PET scan

Reference as: Viggiano RW. December 2013 pulmonary case of the month: natural progression. Southwest J Pulm Crit Care. 2013;7(6):318-27. doi: http://dx.doi.org/10.13175/swjpcc155-13 PDF

November 2013 Pulmonary Case of the Month: Dalmatian Lungs

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 36 year old woman was referred to the pulmonary clinic at Mayo Clinic Arizona. In early May 2013 she developed headache and blurred vision. She was referred to a neuroopthalmologist who diagnosed a 6th cranial nerve palsy. She had a brain MRI and lumbar puncture (LP). Both were reported as normal. She was treated with corticosteroids and improved.

She was tapered off prednisone in late May and developed discomfort in her left ear with hearing loss and tinnitus.  Some left facial asymmetry was noted.

She was treated with intra-tympanic steroid injections as well as oral steroids with some improvement. Her last dose of corticosteroids was 3 weeks prior to being seen.

At the beginning of August she developed speech and swallowing difficulties and was neurologically diagnosed with palsies in 4th, 6th, 8th, 9th, 10th and 11th cranial nerves. Other symptoms included photophobia and a non-productive cough. Two additional LPs were reported to be normal.

PMH, SH, FH

She had cervical cancer with a cone biopsy 2006 and right arthroscopic shoulder surgery. She is a nonsmoker who is a field engineer for a medical device company. She travels throughout the US extensively. There is no significant family history.

Medications

• Zolpidem 
• Vitamin B and D
• Herbal remedy immunotox

Physical Examination

On neurologic exam she had blurred vision with left gaze and facial asymmetry.

Otherwise, the physical exam was unremarkable.

Laboratory

Her complete blood count (CBC) and erythrocyte sedimentation rate (ESR) were within normal limits.

At this point which of the following are diagnostic tests that should be ordered?

1. Anti-neutrophil cytoplasmic antibody (ANCA)
2. Coccidiomycosis serology
3. Lyme disease serology
4. Serum angiotensin converting enzyme (ACE)
5. All of the above

Reference as: Wesselius LJ. November 2013 pulmonary case of the month: dalmatian lungs. Southwest J Pulm Crit Care. 2013;7(5):271-8. doi: http://dx.doi.org/10.13175/swjpcc130-13 PDF

October 2013 Pulmonary Case of the Month: A Hidden Connection

Kelly Cawcutt, MD

Pritish Tosh, MD 

Jennifer Elmer, RN, CNS

Scott Copeman, RRT

Christina Rivera, Pharm D, RPh

Division of Critical Care

Mayo Clinic

Rochester, Minnesota

History of Present Illness

A 58 year old woman, former smoker, presented to the pulmonary outpatient clinic at Mayo Clinic Rochester with dyspnea on exertion. In clinic, she was found to be tachycardic and febrile, and therefore, she was directly admitted to a medicine ward for possible sepsis.

She had progressive dyspnea on exertion, accompanied by symptoms of dry cough, muscle weakness, dry mouth, easy bruising and constipation without weight loss for approximately 9 months. During this time, she was also diagnosed with an idiopathic pulmonary embolus with initiation of warfarin.

PMH, SH, FH

During an extensive work-up for these symptoms she was found to have a Ca2+ channel antibody, with concern raised for possible paraneoplastic etiology, as positron emission tomography (PET) imaging also revealed abnormal uptake in lungs along with multiple lymph nodes, pancreatic tail, decreased cerebral metabolism suggestive of a diffuse encephalopathy and bilateral pulmonary infiltrates with cavitation in the lingula. She was also noted to have anemia and thrombocytopenia. Of note, she was up-to-date on all recommended cancer screenings.

Physical Examination

The patient was febrile (39°C), tachypneic (30 breaths/min) and tachycardic (110 beats/min) but blood pressure was normal (110/68 mm Hg). Otherwise physical examination was unremarkable.

Laboratory

CBC: Hemoglobin 9.4 g/dL, white blood cell count 6,200 cells/mcL, platelet count 45,000/mcl

Lactate 1.8 mmol/L

INR: 2.1

Radiography

Admission chest x-ray is shown in figure 1 and the PET scan obtained prior to admission in figure 2.

Figure 1. Admission chest x-ray.

Figure 2. Representative coronal images of the PET scan obtained prior to admission showing abnormal uptake in lungs along with multiple lymph nodes, pancreatic tail, decreased cerebral metabolism suggestive of a diffuse encephalopathy and bilateral pulmonary infiltrates with cavitation in the lingula. 

Which of the following should be done on admission?

1. Blood culture, sputum culture and urine culture
2. Broad spectrum antibiotic coverage
3. Intravenous fluids
4. Urine culture
5. All of the above

Reference as: Cawcutt K, Tosh P, Elmer J, Copeman S, Rivera C. October 2013 pulmonary case of the month: a hidden connection. Southwest J Pulm Crit Care. 2013;7(4): . doi: http://dx.doi.org/10.13175/swjpcc108-13 PDF

Bronchoscopic Cryoextraction: A Novel Approach for the Removal of Massive Endobronchial Blood Clots Causing Acute Airway Obstruction

Bhaskar Bhardwaj MBBS (bhaskar_bhardwaj@hotmail.com)¹

Himanshu Bhardwaj MD (himanshu-bhardwaj@ouhsc.edu)²

Houssein A. Youness MD (houssain-youniss@ouhsc.edu)²

Ahmed Awab MD (ahmad-awab@ouhsc.edu)²

¹Indira Gandhi Medical College, Department of Pulmonary Medicine and Tuberculosis,  Shimla, Himachal Pradesh, India

²Pulmonary Medicine & Critical Care, University of Oklahoma Health Sciences Center, Oklahoma City. USA

Abstract

Acute airway obstruction due to large blood clots is known to cause life threatening hypoxemic respiratory failure which can be challenging to diagnose and manage. Different bronchoscopic modalities like rigid bronchoscopy, forceps, snares and catheters can be used to extract these obstructing blood clots but each of these different methods have their own limitations.  We describe a patient with iatrogenic endobronchial bleed with acute airway obstruction due to massive blood clot successfully managed using ‘cryoextraction’. This technique has been described as the treatment of choice for this clinical situation and this case highlights the fact that this technique can save patients from more aggressive invasive procedures. 

Introduction

Bronchoscopic cryoextraction using a cryoprobe is an infrequently used   therapeutic modality for the removal of tracheobronchial tree foreign bodies, especially those containing sufficient water or freezable liquid (1). This technique uses a liquid cryogen or coolant (usually nitrous oxide, nitrogen, or carbon dioxide) which is delivered under pressure to a specially designed cryoprobe that can be passed through the working channel of the flexible bronchoscope (2).  We present a case of acute life-threatening airway obstruction caused by large iatrogenic blood clots which was successfully managed using cryoextraction.

Case Report

A 54 years old male with history of renal transplant and chronic immune suppressive therapy was admitted to the intensive care unit with productive cough, fevers and dyspnea of 3 days duration. His initial vital signs showed blood pressure at 140/100 mm Hg, pulse 110, respiratory rate at 36, temperature 102 degree Fahrenheit and initial oxygen saturation of 70 % on supplemental nasal cannula oxygen at 4 liters/min.   Physical examination revealed diffuse bronchial breath sounds in the right lower lung fields and chest radiograph showed consolidation in the right lower lobe. (Figure 1).

Figure 1. Pre BAL chest radiograph showing right lower lobe consolidation consistent with pneumonia.

Arterial blood gas analysis was consistent with partial pressure of oxygen (PaO2) at 40 mm Hg. Patient remained hypoxic despite supplemental oxygen and eventually required endotracheal intubation with mechanical ventilation due to hypoxic respiratory failure. Patient was also started on empiric antibiotic therapy with ceftriaxone and azithromycin for severe community acquired pneumonia requiring intensive care unit care. Unfortunately, patient’s clinical condition deteriorated in next 48 hours despite continuous antibiotics. His oxygen requirements kept on escalating on mechanical ventilation besides continuous ongoing fever.

At this point, we decided to perform a bronchoscopy with a plan for bronchoalveolar lavage (BAL) given the high risk for atypical lung infections secondary to chronic immunosuppression in this patient. Airway examination during BAL showed extremely friable endobronchial mucosa with thick purulent secretions in the right lower lobe bronchi. Unfortunately, a massive endobronchial bleeding caused by an iatrogenic bronchial mucosal tear complicated the procedure. The most likely cause for this bleeding complication was bronchoscope induced mucosal trauma accentuated by vulnerability of the mucosal capillaries due to ongoing immunosuppression and pneumonia in this patient. BAL was terminated but patient became extremely hypoxic despite increasing fraction of inspired oxygen from initial 50% to 100%. Acute rise in peak airway pressures to 56 cm H2O were also noted. An urgent repeat chest radiograph showed worsening of right lower lobe consolidation with new atelectasis suggestive of an acute airway obstruction (Figure 2).

Figure 2.  Post BAL chest radiograph showing acutely worse right lower lobe infiltrates, consistent with atelectasis and acute airway obstruction due to massive blood clot.

Repeat flexible bronchoscopic exam showed a massive blood clot extending from right main stem bronchus to lower bronchi obstructing the bronchial lumen almost completely. Removal of blood clot was felt to be necessary to improve the hypoxia. Initial attempts to suction the endobronchial clots through flexible bronchoscope and forceps extraction were unsuccessful due to extremely friable nature of the fresh blood clot. We decided to use cryoextraction to remove the endobronchial clot emergently.

A flexible cryoprobe (ERBE cryotherapy system – 1.9 mm size cryoprobe) was extended through the working channel of the bronchoscope into the bronchi, was applied to the clot & frozen for 10 seconds. Frozen clot got firmly attached to the probe and it was successfully pulled out in one large piece (Figure 3).

Figure 3. Massive blood clot extracted from airways, attached to the cryoprobe.

This resulted in immediate improvement in patient’s oxygenation. Patient remained on mechanical ventilation and a repeat bronchoscopic airway examination next day did not show any further bleeding. A non-bleeding mucosal tear in the right main bronchus was identified as the possible source of initial bleed. Patient eventually improved with continued treatment; he was successfully extubated after one week of mechanical ventilatory support.  He was discharged home after total 2 weeks of hospitalization.   

Discussion

Acute airway obstruction due to endobronchial blood clots is an unusual, but not a rare event which can develop in variety of clinical settings like various pulmonary infections, bronchial carcinoma, intrathoracic trauma etc. Some of the common interventions reported to cause acute airway bleeding and subsequent bronchial obstruction due to blood clots include: Iatrogenic mucosal damage from suction catheter manipulation, bronchoalveolar lavage, transbronchial biopsy and tracheostomy placement (Table1) (3).

Clinical consequences of the acute bronchial obstruction can range from minimal impact on respiratory function to life threatening ventilator failure. Pertinent physical examination findings in these patients include decreased or absent breath sounds with occasional inspiratory or expiratory wheezing heard over the affected lobe or lung. Among mechanically ventilated patients, acute rise in peak inspiratory pressure (above 60 cm H2O) with decreased tidal volume are some other notable findings. One unusual presentation of massive endobronchial bleeding in mechanically ventilated patients occurs when the clot adheres to the distal end of the endobronchial tube resulting in ball-valve type obstruction. In this situation, the clot acts as one-way valve allowing only the inspiratory flow into the lower respiratory tract but blocking the expiratory flow. This mechanism can result in unilateral or bilateral lung hyperexpansion, thus increasing the risk of tension pneumothorax. Urgent endobronchial tube exchange in this situation can be lifesaving (3). The extent of hypoxemia due to endobronchial blood clot obstruction depends on the site, degree of obstruction and underlying condition of the lungs (3). Typical imaging findings include lobar or segmental atelectasis or air column cut-off of the trachea and main stem bronchi. The diagnosis is confirmed by direct visualization of the clot through flexible bronchoscope. Initial efforts targeted at the removal of the blood clot involve suctioning and grasping forceps extraction of the clot through a flexible bronchoscope. However, these methods often prove unsuccessful due to the friable structure of the blood clots. Moreover, suctioning through the flexible bronchoscope could pose a risk of re-bleeding. Other management options include rigid bronchoscopy, Fogarty catheter dislodgment of the clot and sometimes the use of topical thrombolytic agents with partial dissolution of clot aiding in suction removal of the clot in piecemeal fashion. Rigid bronchoscopy with clot extraction was used to be the treatment to choice for the management of acute obstructing endobronchial blood clots but it requires general anesthesia and may not be as readily available as needed for these acutely sick patients (4,5).

Cryoextraction using flexible cryoprobe is an underreported novel approach which can be successfully used in removal of large blood clots from the airways. One of the first descriptions of the use of cryoextraction in the removal of endobronchial blood clots was given by Mehta et al in one of their review about various interventions used in tracheobronchial foreign body extraction (6). This method allows freezing of the water component of the blood clots, leading to their removal in en-bloc. Additionally, freezing also has a hemostatic effect through vasoconstriction and rapid slowing of the circulation. Cryoextraction can also be used to extract mucus plugs and other foreign bodies containing some amount of freezable liquid. Under circumstances in which a foreign body does not have any or enough water content, one may consider spraying saline over the object and immediately freezing the foreign body; thus allowing successful cryoextraction. Freezing also leads to shrinking of the foreign objects, thereby easily separating them from inflamed mucosa and facilitating their removal. An additional advantage of this technique is the shorter learning curve needed to utilize the cryoprobe compared to the prolonged training required to master rigid bronchoscopy (7). One concern expressed about the cryoextraction of the massive endobronchial clots is that a large ‘frozen clot’ might be difficult to extract through the smaller sized endotracheal tubes and, if dislodged in that process, could lead to obstruction of the ET tube. 

Conclusion

Our case report illustrates the successful use of cryoextraction as a safe and cost effective tool which can be used in the quick removal of large airway clots causing symptomatic airway obstruction. This modality should be considered as the first line treatment in this clinical situation.¹ Cryoextraction method can also spare patients from more invasive procedures like rigid bronchoscopy often used in these scenarios.⁶ In the absence of well-designed studies, this method must be objectively compared with other methods and more cases are needed to be analyzed in future studies.    

References

1. Weerdt S, Noppen M, Remels L, et al. Successful removal of a massive endobronchial clot by means of cryotherapy. J Bronchol. 2005; 12:23-24. [CrossRef]
2. Rafanan AL, Mehta AC. Adult airway foreign body removal. What's new? Clin Chest Med 2001; 22:319. [CrossRef]
3. Arney KL, Judson MA, Sahn SA. Airway obstruction arising from blood clot: three reports and a review of the literature. Chest. 1999; 115(1):293-300. [CrossRef] [PubMed]
4. Schummer W, Schummer C. Hemorrhagic Tracheobronchial obstruction. J Bronchol. 2001; 8(3):236. [CrossRef]
5. Homasson JP, Vergnon JM .Cryotherapy to extract obstructing blood clots. J Bronchol 2002;9:158-9. [CrossRef]
6. Mehta AC, Rafanan A. Extraction of airway foreign body in adults. J Bronchol. 2001; 8:123–131. [CrossRef]
7. Rubio E, Gupta P, Ie S, Boyd M. Cryoextraction: a novel approach to remove aspirated chewing gum. Ann Thoracic Med. 2013; 8(1):58-59. [CrossRef] [PubMed]

Conflict of Interest disclosures: No financial or nonfinancial conflicts of interests exist for any of the involved authors.

Reference as: Bhardwaj B, Bhardwaj H, Youness HA, Awab A. Bronchoscopic cryoextraction: a novel approach for the removal of massive endobronchial blood clots causing acute airway obstruction. Southwest J Pulm Crit Care. 2013;7(3):184-9. doi: http://dx.doi.org/10.13175/swjpcc112-13 PDF 

September 2013 Pulmonary Case of the Month: Chewing the Cud

Suresh Uppalapu, MD   

Manoj Mathew, MD 

Banner Good Samaritan Medical Center

Phoenix, AZ

History of Present Illness

A 30 year old Hispanic man presented to the emergency department (ED) after being involved in a motor vehicle accident. He was a restrained passenger and his car was hit from behind by another vehicle. His initial presenting complaints were chest and back pain. 

PMH, SH, FH

The patient was originally born in Sonora, Mexico but moved to the Phoenix area in 1998. However, he traveled to Mexico frequently.  He has no allergies and no significant past medical or surgical history.

His social habits include occasional alcohol consumption and a remote minimal smoking history. He denied illicit drug abuse. He was married and has 5 healthy children. He was working as a fork lift operator in a warehouse and was not taking any medications. A tuberculosis skin test and a human immunodeficiency virus (HIV) were negative 3 years ago when he applied for US Citizenship.

His parents are alive with hypertension and type 2 diabetes mellitus.

Physical Examination

His physical exam had normal vital signs and a Glasgow coma scale of 15. Physical exam showed clear lungs, normal heart sounds, and a benign abdominal exam. His neurological exam was normal.

Laboratory

His complete blood count (CBC) showed a white blood cell (WBC) count of 15.4 x 10⁶ cells/mcL, hemoglobin of 11.8 g/dL, a hematocrit of 36 % and a normal platelet count. His basic metabolic profile and liver function chemistries were normal.

Radiography

His chest x-ray is shown in Figure 1.

Figure 1. Admission PA (Panel A) and lateral (Panel B) chest x-ray.

Which of the following best describes the chest x-ray?

1. A density in the right chest consistent with a fractured right mainstem bronchus
2. An air-fluid level in the right chest consistent with a lung abcess
3. Consolidation in the lateral right lung
4. All of the above
5. None of the above

Reference as: Uppalapu S, Mathew M. September 2013 pulmonary case of the month: chewing the cud. Southwest J Pulm Crit Care. 2013;7(3):135-41. http://dx.doi.org/10.13175/swjpcc103-13 PDF

IgG4-Related Systemic Disease of the Pancreas with Involvement of the Lung: A Case Report and Literature Review

Jessica R. Hurley, DO¹

Kevin O. Leslie, MD²

¹Banner Good Samaritan Medical Center, Phoenix, AZ

²Mayo Clinic, Scottsdale, AZ

Abstract

IgG-related systemic disease (ISD) remains exceedingly rare and unfamiliar, particularly extrapancreatic disease. We report a patient with separate presentations of IgG4 pulmonary disease and recurring IgG4 related biliary sclerosis and pancreatitis.  Because of the intricate and perplexing pathogenesis, overlapping organ systems and wide variation in disease presentation, ISD in its entirety remains undefined.  Accurate identification of ISD is critical to avoid permanent organ damage especially since treatment is nearly always successful with corticosteroids.  As recognition and awareness of this disease grows, development of standard diagnostic criteria and treatment plans are needed. 

Introduction

There has been increasing interest in IgG4-related systemic disease (ISD) as it becomes more recognized and the disease spectrum escalates.  Initially thought to be limited to the pancreas and biliary system, ISD has recently been identified in virtually every organ system including several, varying pulmonary presentations (1).  We present a case that demonstrates separate presentations of both pulmonary and pancreatobiliary disease.

Case Report

A 60 year old gentleman was evaluated for progressive dyspnea and radiographic defects that persisted for three months despite appropriate treatment for community acquired pneumonia.  His past medical history was most notable for recurrent pancreatitis attributed to a common bile duct stricture requiring multiple stents.  Pancreatic cancer had been ruled out with an endoscopically obtained brush specimen. 

Physical exam findings were notable for bibasilar faint crackles.  Pertinent work up findings included pulmonary function testing showing a mild restrictive lung disease and a six minute walk test that revealed oxygen desaturation to 88%.  Computed tomography (CT) demonstrated bilateral, patchy consolidation with air bronchograms and focal areas, of dense, nodular-like tissue (Figure 1).  

 

Figure 1. High resolution CT scan reveals patchy, bilateral ground-glass opacities, consolidation and nodules in both upper and lower lobes. 

A surgical lung biopsy revealed dense, non-necrotizing granulomatous and fibrohistiocytic interstitial lung disease with vascular and pleural involvement (Figure 2).  

Figure 2. H&E stain showing a plasma cell rich lymphohistiocytic infiltrate (*lymphocytes stained purple) in the bronchovascular sheath (both bronchiole and pulmonary arteries demonstrated here).

Histopathology diffusely stained positive for IgG4 plasma cells (Figure 3).

Figure 3. IgG4 immunohistochemical stain showing increased numbers of IgG4 positive plasma cells in the infiltrates (> 10 IgG4+  plasma cells per high power (40X) field).

The patient had a markedly elevated IgG4 of 2,830 mg/dL.

He was started on steroid therapy and one month into treatment his repeat chest imaging and serum IgG levels returned to normal and his respiratory symptoms resolved (Figure 4).  

Figure 4. Repeat CT images six weeks after starting treatment revealed nearly complete resolution of the disease.  

Subsequently the patient developed two separate episodes of recurrent pancreatitis, both responding to steroid treatment.  His pancreatitis was re-diagnosed as IgG4-related biliary sclerosis and pancreatitis based on disease presentation, imaging and the rapid response to steroids.  The patient has remained disease free and off steroid therapy.

Discussion

ISD was first described in the pancreas as an autoimmune pancreatitis (AIP). AIP has only recently gained recognition as an IgG4-related disease in the past decade despite the first description dating back to the 1950’s.  Polish physicians Borszewski and Pancewicz-Olszewska (2) noted obstructive jaundice developing from chronic, fibrosing pancreatitis.  In 1961 Sarles et al (3) described chronic scarring and inflammation in the pancreas as a potential autoimmune problem.  It was another decade before researchers realized that elevated immunoglobulins were associated with AIP (4).  In 2001, the IgG4 level was found to specifically correlate with histopathological changes in pancreatic tissue in AIP, aiding in the exclusion of other pancreatic dysfunctions (5).  ISD was therefore  thought to be restricted to the pancreas but by 2003, ISD had been identified in extrapancreatic tissue and since has been found in virtually every tissue type throughout the body, including the lung, first reported in 2004 (6, 7). 

ISD is a relatively new and unfamiliar disorder that occurs when excessive amounts IgG4- positive plasma cells infiltrate organ tissue (8).  This abundance of lymphoplasmacytes induces significant inflammation and fibrosis in the surrounding tissues and can occur in almost every organ system in the body including pancreas, gallbladder and biliary tree, salivary and lacrimal glands, liver, kidney, retroperitoneum, aorta, lymph nodes and lung (7,9,10). 

ISD goes by many identities including “IgG4-related systemic sclerosing disease”, “IgG4-related sclerosing disease”, “IgG4-related disease”, “hyper-IgG4-disease”, and “IgG4-related systemic disease” (7, 8, 10, 11). We use IgG4-related systemic sclerosing disease (ISD) throughout this manuscript.

Symptoms and Presentation

It is unclear if ISD can exclusively occur in one organ without any pancreatic involvement, if it results from an overlap with other autoimmune systemic diseases, or if it is part of one entire systemic disease.  Many case reports and studies that discuss pure extrapancreatic disease fail to rule out additional organ involvement (6, 12-15).  There are several possible explanations for this.  There are no concrete diagnostic criteria for ISD so rarely have asymptomatic organs been evaluated.  Many patients who have been diagnosed with a form of ISD have had additional organ involvement discovered incidentally (12, 16, 17).  This is especially true for many of the retrospective reviews sparked by the recent discovery and exploration of ISD (8, 12, 18).  Because the disease can be asymptomatic and only found unintentionally on imaging or lab work (e.g. CT abdominal scan showing diffusely enlarged pancreas after routine labs showed transaminitis) or due to a secondary disease developing (such as diabetes mellitus type II) from ISD affecting the organ (such as chronic pancreatitis in AIP) (1, 11, 19).  Also, many publications lack adequate length of follow up for the potential development of AIP and also fail to mention if the patients’ ISD was preceded by AIP.  The timing of AIP development can vary and may precede extrapancreatic disease by years or develop months to years after the initial diagnosis (8, 19).  Future case studies in light of advanced research may show otherwise, but for now extrapancreatic ISD seems to nearly always, if not always, occur in the setting of AIP.

It is important to note that nearly all of our knowledge regarding ISD stems from patients diagnosed with AIP as not only is this where ISD was first recognized, it is also the most frequently involved organ.  Of the two AIP subclasses, type I has been established as the pancreatic manifestation of ISD (20).  Both types share some overlap but vary in presentation epidemiologically, symptomatically, on imaging, on pathology, and treatment.  Type I is found mostly in older patients with ages averaging over 60 years old although it has been reported ages 14 to 85 years (1) and appears to favor males with a 4 to 10:1 ratio compared to Type II with an average age of 52 years old and a female:male ratio of 8:10 (8, 10, 19, 20).  Type I clinically presents with classical painless obstructive jaundice whereas type II is more likely to have chronic recurring abdominal pain (20).  Type I AIP patients are also less likely to have allergic disorders or elevated IgE and eosinophilia (21).  Histopathologically, Type I classically has elevated serum IgG4 levels and affected tissue infiltrated with IgG4+ plasma cells and lymphoplasmacytic sclerosing pancreatitis with hypercellular inflamed interlobular stroma compared to type II which has a neutrophilic infiltration surrounding the pancreatic duct with ulceration and abcess formation (20, 22).  On imaging, the pancreatic tail cut-off sign was only seen in type II patients whereas type I features irregular pancreatic duct narrowing and diffuse or focal pancreatic enlargement with development of a capsule-like rim and loss of normal pancreatic architecture.  Also, like all other organ systems affected by ISD, both types of AIP respond quickly to steroids but type I is more likely to recur (20, 22). 

These features seen in type I AIP generally seem to transfer to all organ systems affected by ISD.  Unfortunately epidemiologic data about ISD as a whole remains limited.  This is due to under-recognizing the disease, in part because of its novelty, but also because up to half of all ISD patients may be asymptomatic (8, 9, 12, 19).  Many patients are diagnosed incidentally through lab and imaging findings (6, 10, 12).  A Mayo Clinic study divided patients with imaging evidence of AIP into three groups based on likelihood of being diagnosed with AIP. They found that even in the group most likely to have a diagnosis, 20% had normal IgG4 levels and/or no additional organ involvement in addition to 30% requiring a biopsy or steroid trial to diagnose AIP (23).  Organs affected by ISD generally have signs and symptoms related to the involved organ.  For example, diabetes mellitus is seen in up to two-thirds of patients diagnosed with type I AIP (1, 24).  Lacrimal and salivary gland enlargement is seen in ISD of the head and neck (23).  Patients with ISD of the lung may complain of a dry cough, shortness of breath and allergic symptoms such as sinusitis or rhinitis (9, 12).  Systemic or infectious signs are rarely exhibited.

AIP in itself is quite rare, accounting for 11% of chronic pancreatitis and only 2% of this is type I (22).  The amount of patients with pancreatic ISD is quite impressive, ranging from 50-80% (9).  A majority (around 80%) are most likely to have biliary tree involvement compared to as few as 5% with affected lung (1).  Initially all affected organs were reported in association with pancreatic involvement, however there are now increasing reports of what appear to be sole manifestations of ISD (26).  Since AIP is not always caused by ISD and additional organ involvement was only recently associated with this IgG4 disorder, the extrapancreatic disease is now becoming increasingly researched. 

What is IgG4 and Its role in ISD?

Immunoglobulins differ based on their heavy chain sequences and antigen receptor sites.  Some types of antibodies expose their heavy chains to an antigen-binding site to allow a specific antigen to bond and form an immune complex.  However, this is not the case with IgG4.  Immunoglobulin (Ig) G is divided into four subsets, 1-4, IgG4 being the smallest and normally making up about 3-6% of serum totals (5).  IgG is made of two heavy chain-light chain pairs connected by a disulfide bond which varies among the subclasses.  In IgG4 the disulfide bonds between the heavy chains are unstable, thus they easily form bonds with other IgG4 Fc receptors (the area Ig binds to an antigen and generates a specific immune response) which prevents the exposure of the antigen-binding site, hence preventing an antigen from bonding.  This means it does not activate the complement cascade.  Although IgG4 does not bind complement, it does bind to CD64, i.e. FcgRI.  CD64 is expressed on monocytes and macrophages and plays a role in opsonization and phagocytosis.  Interestingly, IgG4 is capable of forming bispecific antigens due to a mechanism known as the Fab arm exchange (27).  This occurs when a heavy-light chain is swapped with another molecule.  This bispecific antigen could then interact with other immune complexes to prevent them from functioning properly and thus possibly decrease inflammation.

The induction and production of IgG4 is complicated and poorly understood.  B cells create specific antibody isotypes depending on the cytokines in the B cell environment.   Functionally, cytokines can be divided into two categories: inflammatory and anti-inflammatory.  T lymphocytes vary based on the specific type of antigen receptor on their surface, the major co-receptor including either CD4 or CD8.  CD4+ T cells, also called helper T cells, are the largest cytokine producers.  There are two types of helper cells: Th1 which produces the cytokine interferon gamma (IFN γ) and acts as a proinflammatory, and Th2 creates interleukins (IL) 4, 5, and 13 that promote IgE and trigger eosinophils in allergic responses, as well as IL-10 which acts as an anti-inflammatory (28).  The two types of cytokines are thought to keep each other balanced and that a disorder occurs if one form is in excess of the other.  One study in 2005 evaluated the effect IL-10 had on Th1 and Th2 immune systems and demonstrated that IgG4 production correlated with IL-10 regardless if induced through a Th1 or Th2 immune process but not by solely using cytokines IL-4, IL-13, or IFN γ (29).

It has been determined that this cytokine, IL-10, is particularly important in IgG4 production.  Jeannin et al. (30) examined the overlap in class-switching between IgE and IgG4 by inducing an allergic response in five patients and evaluating the response IL-10 had on IL-4-stimulated lymphocytes.  They found that although IL-4 induced class switching to IgG4, this was pathway was increased and likely regulated by IL-10 (30).  In addition to the cytokine IL-10 upregulating IgG4 secretion, there must also be an interaction between T and B cells for maximal production (29).  These details were further exemplified recently when van de Veen et al. (31) discovered that B cells specific for a particular allergen, bee venom in this case, were found to express surface receptors CD73-CD25+CD71+.  These B cells, once enriched, secreted high levels of IL-10 which suppressed antigen-specific CD4+ Th2 cell proliferation and increased expression of IgG4 (31).

This recent research indicates IgG4 is a marker of inflammation, not the cause of ISD.  Zen et al examined pancreas and biliary tissue affected by an autoimmune process (now called ISD), primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) regarding cytokine production and regulatory T (Treg) cell involvement.  They found that the tissue affected by ISD had significantly higher ratios of specific Th2-producing cytokines including IL-4, IL-5, and IL-13 compared to Th1 cytokine IFN γ (32).  Further, ISD tissue had an increase in CD4+CD25+Foxp3+ Treg cells which induce IL-10 to halt the immune reaction that generates inflammation.  They concluded ISD is characterized by Th2-induced inflammation and counteracted with Treg cells.

Despite these recent findings, it remains unclear if the inflammation in ISD is due to a self-antigen (i.e. an autoimmune process) or an unknown allergen.  In general, ISD has no specific autoantibody that has been associated with an autoimmune reaction and the reactions that have been identified are likely markers of tissue injury.  However, AIP has been linked to certain autoantigens including carbonic anhydrase, lactoferrin, pancreatic secretory trypsin inhibitor and trysinogens (38).  The dramatic, rapid response to steroids with few relapses in the disease also favors a hypersensitive/allergic reaction.  While other subclasses of IgG participate in both type II (antibody-dependent) and type III (immune complex disease) forms of hypersensitivity, as mentioned previously IgG4 does not form immune complexes, thus it seems it would be dominated by a type I hypersensitivity (33).  However, this type of hypersensitivity is specifically dominated by IgE-triggered mast cells with less involvement of Th2.  Therefore ISD appears to be more consistent with type IV hypersensitivity, the delayed form.  ISD is homogenous with subtype IVb that involves Th2-directed cytokines IL-5, IL-4, IL-13.  Type I hypersensitivity is not a response to a self-antigen, like it is in type II and III hypersensitivity, but rather is an immune reaction dominated by Th2 cells.  This is the same type of cell repetitively identified in ISD and classically involved in the allergic disorders such as allergic rhinitis and chronic asthma (12, 34, 35). 

Also arguing against autoimmunity is the predisposition for elderly men, contrasting most autoimmune disease diagnosed in young females.   Extrapancreatic ISD appears to favor males.  The exception is ISD of the head and neck, in which the female-male ratio is even.  Interestingly because this form of ISD overlaps with other sclerosing diseases such as Mikulicz’s disease and Sjogren ’s syndrome (SS), it is thought many of these patients may have been misdiagnosed and have ISD.  Men with SS are extremely rare however in one review half of those with this disease actually had ISD upon re-examination (10, 25). 

One well-documented exception to the allergen-induced cause of ISD is seen in some cases of ISD that have had immune complex deposits identified in the basement membranes of pancreatic acini and renal tubules, which is a form of type III hypersensitivity (35).  This finding would support autoimmunity and implies the disease occurs from tissue injury related to self antigens that induce a cytokine response.  The cytokines induced by Th2 cells and naïve regulatory T cells contribute to the stimulation in IgG4 production and lead to the sclerosing response, however it remains unknown what this process is in response to (9, 19, 32).  Clearly a specific antigen would need to be identified before the disease is definitively classified.

IgG4’s pathologic role in ISD remains unclear, as does the use of serum IgG4 levels in diagnosis of ISD.  Several studies have documented that the level of IgG4 varies significantly in healthy individuals, ranging from 1 - 1.4 µg/ml, but is elevated in about 5% and may even be as high as 2 mg/ml (37).  The sensitivity and specificity of using serum IgG4 levels to differentiate AIP from other pancreatic disease, such as malignancy, varies depending on the study and diagnostic criteria used, ranging from 67-97% and 89-100% respectively (38).  Although clearly elevated in a majority of patients with AIP (noted up to 80%), serum IgG4 can still be elevated in as many as 10% of pancreatic cancer patients, as recently reported by Sah and Chari (38).  These statistics carry over to extrapancreatic ISD as well.  In a review by Zen (10) of 114 cases diagnosed with ISD involving any organ, only 86% of patients had elevated IgG4 levels, with 2.6% of patients having an underlying malignancy of the affected organ. 

Pathology

There are four known pulmonary histology patterns in ISD (7, 10, 12, 18).  The solid nodular pattern presents as sclerosing inflammation in the hilar large bronchus walls and distinctly involves bronchial glands as well. The lymphoplasmacytic infiltration occurs in the alveoli around and away from the nodular lesions.  The bronchovascular pattern involves inflammatory infiltration of the pulmonary connective tissue (bronchovascular bundles, alveolar interstitium, interlobular septa, and pleura).  The alveolar interstitial pattern involves sclerosing inflammation of only the interstitium, similar to a nonspecific interstitial pneumonia pattern. 

The histologic presentations specific to pulmonary ISD have both an overlap and slight variation compared to both its pancreatic and extrapancreatic relatives.  Like all involved organs with ISD, pulmonary lesions have a diffuse lymphoplasmacytic infiltration.  Another characteristic feature seen in all forms of ISD is obliterative phlebitis, the destruction of veins from sclerosing inflammation (18, 19).  However, obliterative arteritis is unique to pulmonary ISD, which is rarely, if ever, seen in pancreatic or other extrapancreatic ISD (10, 18, 20). 

Diagnosis

Accurate diagnosis of ISD is essential.  Once malignancy is ruled out, a primary concern in any organ presenting with a mass, proper treatment must ensue to prevent permanent organ damage from disease-induced sclerosis.  Diabetes mellitus may occur with AIP, obstructed pancreaticobiliary tree can cause portal hypertension and cirrhosis, affected retroperitoneum can become permanently scarred, and ISD of the kidney may result in renal failure and life-long dialysis (1, 14, 18, 24).  Although there have been reports of spontaneous remission in untreated AIP, these patients were noted to have evidence of a much lower disease burden on lab and imaging (39). 

The inflammatory sclerosis induced by IgG4+ lymphocytic and plasma cell infiltration is the primary characteristic feature in diagnosing ISD.  Because the disease presents with histopathological differences depending on the organ system affected, there is no single feature used to confirm the diagnosis.  This has also made it difficult to develop unified diagnostic criteria.  Several groups and countries have acquired their own diagnostic criteria which mostly overlap and primarily have only slight variations in defining the histology. Diagnostic criteria are constantly being revised as new research emerges.  A majority of diagnostic criteria require an absolute number of IgG4+ cells per HPF, a ratio of IgG4+ cells per IgG+ cells, and an elevated serum IgG4 (18).  Recently the Japan College of Rheumatology proposed an organ-based algorithm to diagnose the likelihood of ISD and takes into consideration the disease presentation of the involved organ(s), histopathology and serum IgG4 levels (40).  Additional diagnostic considerations not incorporated or required in Japan’s criteria may include imaging and a rapid response to steroid treatment (9).  Regardless of the disparity over precisely defining the histological required minimum number of IgG4+ cells, it is clear that the higher the number, the more sensitive and specific the diagnosis (18). 

Pulmonary ISD was initially identified as an interstitial pneumonia and later as a pseudotumor (6, 39).  Currently it has presented in multiple radiographic patterns including solid parenchymal nodules (mass-like), bronchovascular pattern (often mistaken for sarcoidosis), round-shaped ground-glass opacification (similar to bronchioalveolar carcinoma), alveolar interstitial pattern (presenting with bronchiectasis or honeycombing), areas of diffuse ground-glass opacification (mimicking nonspecific interstitial pneumonia), and air-space consolidation (comparable to organizing pneumonia) (1, 41).  Additionally, ISD has been found in the mediastinum, pleura, interstitium of all lung zones and main airways.  Patients may present with a single feature or have several pulmonary variations (9, 13, 42).

Treatment

Once studies showed AIP treated with corticosteroids went into remission quicker than untreated disease and were able to reverse affected organ symptoms like diabetes, they became standard therapy for all forms of ISD (9, 43).  Steroid dosing for ISD is undefined like most steroid treatment in pulmonary (or any other inflammatory disease for that matter) and ranges from 0.6mg/kg to 10 mg/day (26, 43).  The length of treatment also varies with the Mayo Clinic tapering off all therapy at 11 weeks and Japanese centers, who report  lower relapse rates, treating as long as 6 months followed by a slow-dose maintenance steroid for up to 3 years (44).  Most patients have reversal of the abnormality seen on imaging and many will have a decrease or even normalization of serum IgG4 within 2 weeks of initiating therapy.  Reports of relapse have been seen in up to 25% of patients and ISD can also occur in a completely separate organ system than the first, as seen in our patient.  A failure response is difficult to define because serum IgG4 often remains elevated despite resolution of symptoms and imaging abnormalities and again, patients may be asymptomatic or have disease recur in new primary organ systems (43).  Patients who continue to have evidence of persistent disease after steroids are tapered off have had success with additional immunosuppressants.  The Mayo Clinic has accomplished remission with the use of azathioprine or mycophenolate mofetil in patients with AIP in addition to case reports using rituximab, which deplete IgG4 B lymphocytes, and the anti-plasmacyte medication, bortezomib (45).  

Using IgG4 levels to monitor ISD response to steroids has been shown to be helpful in several studies (5, 6, 8, 12, 13, 18, 41, 46, 47), especially since patients may have little to no symptoms of the organ affected by ISD.  Elevated serum levels have been proven helpful in correlating disease burden, meaning a higher level indicates increased single or multisystem organ involvement (48).    Unfortunately many patients in these studies, despite treatment, continued to have elevated levels (13, 38, 43).  Empiric steroid trials have been found to decrease false positive elevated IgG4 levels so using a decline in serum IgG4 after initiating steroid treatment is also not a consistently reliable tool to track disease progress (38).  Also the serum IgG4 level may not even be elevated and appear normal if the initial patient presentation is during the earlier phase of the disease before IgG4 proliferates (37, 38).  Trending IgG4 levels for evidence of disease relapse has also been suggested however studies involving patients treated with steroids for AIP found that relapse still occurs in 10% of patients whose IgG4 level did return to normal compared to 30% of patients who remained elevated (44).  Unfortunately the amount of disease relapse in ISD is underestimated as most case studies do not have long term follow up and IgG4 is frequently not reported nor is it rechecked unless the patient presents with recurring or new symptoms.  Also, these results were limited to pancreatic ISD so more research is required to determine if these statistics are similar regardless of affected organ.  

Summary

ISD remains exceedingly rare and unfamiliar, particularly extrapancreatic disease. This is one of only a handful of reported patients with separate presentations of IgG4 pulmonary disease and recurring IgG4 related biliary sclerosis and pancreatitis.  Because of the intricate and perplexing pathogenesis, overlapping organ systems and wide variation in disease presentation, ISD in its entirety remains undefined.  Accurate identification of ISD is critical to avoid permanent organ damage especially since treatment is nearly always successful with corticosteroids.  As recognition and awareness of this disease grows, development of standard diagnostic criteria and treatment plans are needed. 

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26. Umeda M, Fujikawa K, Origuchi T, Tsukada T, Kondo A, Tomari S, Inoue Y, Soda H, Nakamura H, Matsui S, Kawakami A. A case of IgG4-related pulmonary disease with rapid improvement. Mod Rheumatol. 2012;22(6):919-23. [PubMed]
27. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, den Bleker TH, Wiegman L, Vink T, Aarden LA, De Baets MH, van de Winkel JG, Aalberse RC, Parren PW. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 200714;317(5844):1554-7. [CrossRef] [PubMed]
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31. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Akdis DG, Rückert B, Akdis CA, Akdis M. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013;131(4):1204-12. [CrossRef] [PubMed]
32. Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, Nakanuma Y. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45(6):1538-46. [CrossRef] [PubMed]
33. Gell PGH, Coombs RRA, eds. Clinical Aspects of Immunology. 1st ed. Oxford, England: Blackwell; 1963.
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35. Ito S, Ko SB, Morioka M, Imaizumi K, Kondo M, Mizuno N, Hasegawa Y. Three cases of bronchial asthma preceding IgG4-related autoimmune pancreatitis. Allergol Int. 2012;61(1):171-4. [CrossRef] [PubMed]
36. Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR, Colvin RB, Lauwers GY. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol. 2006;30(12):1537-45. Erratum in: Am J Surg Pathol. 2007;31(2):328. [CrossRef] [PubMed]
37. Nirula A, Glaser SM, Kalled SL, Taylor FR. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol. 2011;23(1):119-24. [CrossRef] [PubMed]
38. Sah RP, Chari ST. Serological issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol. 2011; 23(1):108-13. [CrossRef] [PubMed]
39. Wakabayashi T, Kawaura Y, Satomura Y, Watanabe H, Motoo Y, Sawabu N. Long-term prognosis of duct-narrowing chronic pancreatitis: strategy for steroid treatment. Pancreas. 2005;30(1):31-9. [PubMed]
40. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Nakamura S, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21-30. [CrossRef] [PubMed]
41. Inoue D, Zen Y, Abo H, Gabata T, Demachi H, Kobayashi T, Yoshikawa J, Miyayama S, Yasui M, Nakanuma Y, Matsui O.Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260-70. [CrossRef] [PubMed]
42. Kobayashi H, Shimokawaji T, Kanoh S, Motoyoshi K, Aida S. IgG4-positive pulmonary disease. J Thorac Imaging. 2007;22(4):360-2. [CrossRef] [PubMed]
43. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23(1):67-71. . [CrossRef] [PubMed]
44. Kamisawa T, Okamoto A, Wakabayashi T, Watanabe H, Sawabu N. Appropriate steroid therapy for autoimmune pancreatitis based on long-term outcome. Scand J Gastroenterol. 2008;43(5):609-13. [CrossRef] [PubMed]
45. Khan ML, Colby TV, Viggiano RW, Fonseca R. Treatment with bortezomib of a patient having hyper IgG4 disease. Clin Lymphoma Myeloma Leuk. 2010;10(3):217-9. [CrossRef] [PubMed]
46. Hirano K, Kawabe T, Komatsu Y, Matsubara S, Togawa O, Arizumi T, Yamamoto N, Nakai Y, Sasahira N, Tsujino T, Toda N, Isayama H, Tada M, Omata M. High-rate pulmonary involvement in autoimmune pancreatitis. Intern Med J. 2006;36(1):58-61. [CrossRef] [PubMed]
47. Zen Y, Kitagawa S, Minato H, Kurumaya H, Katayanagi K, Masuda S, Niwa H, Fujimura M, Nakanuma Y. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol. 2005;36(7):710-7. [CrossRef] [PubMed]
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Reference as: Hurley JR, Leslie KO. IgG4-related systemic disease of the pancreas with involvement of the lung: a case report and literature review. Southwest J Pulm Crit Care. 2013;7(2):117-30. doi: http://dx.doi.org/10.13175/swjpcc039-13 PDF

August 2013 Pulmonary Case of the Month: Aids for Diagnosis

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

An 80 year old man was referred for evaluation of cough, weakness and weight loss over 2-3 months.  He had a chest radiograph 6 weeks ago showing a right lower lobe infiltrate. He was treated with levofloxacin and prednisone without improvement.

PMH, SH, FH

He had a history of hypertension, type 2 diabetes mellitus, hyperlipidemia, and hypothyroidism.

He was born in China, had lived in Philippines, Hong Kong and Phoenix, the later for the last 23 years. He was lifetime nonsmoker and rarely used ethanol.  He had no pets, unusual exposures, and no known tuberculosis exposure (last skin test was negative 10 years ago).

His father died at age 79 from coronary artery disease. His mother had “intestinal cancer”. He has a sister with diabetes mellitus.

Medications

• Atorvastatin 10 mg/day                                          
• Doxazosin 2 mg/day
• Levothyroxin 50 mcg/day
• Metformin 500 mg bid
• Metoprolol XL 25 mg/day
• Zantac 50 mg bid
• Recent Levaquin/Prednisone

Physical Examination

Blood pressure 130/62, Pulse 72, afebrile, SpO2 97%, body mass index 19.5

Chest:  lungs were clear to auscultation and percussion.

There were no significant findings on physical examination.

Laboratory

Laboratory evaluation revealed a slight anemia with hemoglobin of 12.6 g/dL but a normal white count of 7.9 x 10⁶ cells/mcL with 0.06% eosinophils. Erythrocyte sedimentation rate was 53 mm/hr. Albumin was slightly low at 2.9 gm/dL.

Chest Radiography

His chest x-ray is shown in figure 1.

Figure 1. Patient’s posterior-anterior chest radiograph (Panel A) and lateral (Panel B).

Which of the following best describes the chest x-ray?

1. Multifocal nodular consolidation
2. Left lower lobe collapse
3. Right hilar fullness
4. 1 and 3
5. All of the above

Reference as: Wesselius LJ. August 2013 pulmonary case of the month: aids for diagnosis. Southwest J Pulm Crit Care. 2013;7(2):59-65. doi: http://dx.doi.org/10.13175/swjpcc093-13 PDF

Variation in Southwestern Hospital Charges for Pulmonary and Critical Care DRGs

Richard A. Robbins, M.D.

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ

Abstract

Recently, the Centers for Medicare and Medicaid Services (CMS) released nationwide data on hospital charges and CMS payments for the top 100 disease-related groups (DRG). Data obtained from the CMS website was examined for 23 common pulmonary and critical care DRG charges and payments to hospitals in the Southwest United States (Arizona, New Mexico and Colorado). Similar to nationwide trends, charges vastly exceeded payments and varied widely. Normalizing the data to the state average for each DRG, the percent over/under the state average revealed a negative correlation between charges and payments. Urban hospitals billed more but did not receive significantly higher payments. Hospitals that were primary hospitals for residencies did not bill significantly more but did receive higher payments. These data demonstrate that charges and payments for respiratory and critical care DRGs in the Southwest mirror nationwide trends in large overcharges.

Introduction

It has commonly been accepted that hospital charges greatly exceed payments (1). Insurance companies, CMS and other groups negotiate a discounted price from the “charge master” price (1). However, in the absence of a negotiated discount, the “charge master” price applies which may result in the poor and most vulnerable paying the highest prices. In addition, it may result in overbilling for insurance companies who in some instances pay more than patients who pay cash for certain procedures (1).

Some attempt has been made to introduce transparency. For example, a bill was introduced into the Arizona legislature to require posting of hospital and physician prices (1). However, this bill died in committee. The Arizona Department of Health Services requires hospitals to report their charges which are posted on the Arizona Department of Health Services website (2). However, this information does not appear to have been disseminated widely and would appear to be seldom used by consumers when making health care decisions. Similarly, this data does not appear to be well known by healthcare providers. Recently CMS released data on hospital charges. This database was searched for common pulmonary and critical care DRG charges and payments for hospitals in the Southwest.

Methods

CMS data

Data was obtained from the CMS website (3). Hospital-specific charges for the more than 3,000 U.S. hospitals that receive Medicare Inpatient Prospective Payment System (IPPS) payments for the top 100 most frequently billed discharges were examined. Also examined was the amount paid by Medicare based on a rate per discharge using the Medicare Severity Diagnosis Related Group (MS-DRG) for Fiscal Year (FY) 2011. These DRGs represent almost 7 million discharges or about 60 percent of total Medicare IPPS discharges.

Hospitals determine what they will charge for items and services provided to patients and these charges are the amount the hospital bills for an item or service. The Total Payment amount includes the MS-DRG amount, bill total per diem, beneficiary primary payer claim payment amount, beneficiary Part A coinsurance amount, beneficiary deductible amount, beneficiary blood deducible amount and DRG outlier amount.

For these DRGs, average charges and average Medicare payments are calculated at the individual hospital level. The payments are adjusted based on the wage index applicable to the area where the hospital is located, the percentage of low-income patients, if the hospital is an approved teaching hospital and for outlier cases (4).

For the purposes of comparison, urban hospitals were defined as within an urban center (Phoenix, Tucson, Denver, or Albuquerque) or within 50 miles of the city center.

Statistical Analysis

Data was reported as mean + standard error of mean (SEM). The percentage over/under for charges and payments was calculated by taking the state average for each DRG and calculating the percentage above or below for each hospital. Comparison between groups was done using the Student’s t-test. The relationship between continuous variables was obtained using the Pearson correlation coefficient. Significance was defined as p<0.05. All p values reported are nominal, with no correction for multiple comparisons.

Results

Southwest Hospital Charges by State

Covered charges are shown in Table1. Arizona and Colorado charges averaged 24% and 23% above the National average respectively while New Mexico closely approximated the National average.

Table 1. Average Southwest hospital charges for 23 common pulmonary and critical care DRGs. [Editor's Note: It may be necessary to enlarge your browser window to view this and the other tables.]

Southwest Hospital Payments by State

Payments were much lower than charges (Table 2). Payments averaged 25%, 24% and 31% of charges in Arizona, Colorado and New Mexico for the pulmonary and critical care DRGs. These closely approximated the National average of 28% for all charges.  In contrast to billings, payments averaged below the National average in the Southwest. For the pulmonary and critical care DRGs the payments were below the National average for Arizona (-3.76%), Colorado   (-7.46%), and New Mexico (-0.98%).

Table 2. Average Southwest hospital payments for 23 common pulmonary and critical care DRGs.

Individual Hospital Charges

CMS listed hospital charges from 56 hospitals in Arizona, 40 hospitals in Colorado and 31 in New Mexico. The number of DRGs from each hospital was highly variable ranging from a low of 1 to a high of 23. Hospital charges varied widely with large differences between the high and low charges (Table 3).

Table 3. Average differences between high and low charges for each pulmonary and critical care DRG. The percent is the difference between the high and low compared to the state average.

Charges by individual hospitals as a percentage of the average for each state are listed in Appendix 1.

Urban hospital billings were higher than rural hospital billings (3.0 + 3.0% vs. -14.5 + 4.4% of the state average, p= 0.001).

Hospitals charges for the 9 hospitals that are primary hospitals for residencies in the Southwest (6 in Arizona, 2 in Colorado and 1 in New Mexico) averaged 4.0% over the average for their respective state (p=0.21 compared to the other hospitals). In contrast, these hospitals received payments that were 28.9% over their state average (p= 0.015 compared to the other hospitals).

Individual Hospital Payments

CMS listed hospital payments from 56 hospitals in Arizona, 40 hospitals in Colorado and 31 in New Mexico. Like the hospital charges, the number of DRGs from each hospital was highly variable ranging from a low of 1 to a high of 23. Hospital payments varied but less between high and low payments than charges (Table 4).

Table 4. Average differences between high and low payments for each pulmonary and critical care DRG. The percent is the difference between the high and low compared to the state average.

Payments to individual hospitals as a percentage of the average for each state are listed in Appendix 2.

For the Southwestern states there was an inverse relationship between percent of the state average of charges and percent payments (r = -0.2243, p = 0.0112). In other words, the higher the percent charges compared to the state average, the lower the percent payments compared to the state average.

Urban hospital payments did not significantly differ from rural hospital payments (0.8 + 2.7% vs. 7.8 + 3.3% of the state average, p= 0.103).

Hospitals payments to the 9 hospitals that are primary hospitals for residencies in the Southwest averaged 28.9% over their state average (p= 0.015 compared to the other hospitals).

Discussion

The data in this manuscript demonstrates that hospital charges to CMS in the Southwest US for common pulmonary and critical care DRGs greatly exceed CMS payments. These charges reflect national trends for other DRGs (1-5). The data also suggest that there is wide variability in charges between hospitals, again reflecting national trends. Payments also vary, but the degree of variability is much less. Interestingly, higher charges to CMS were associated with lower CMS reimbursement.

The data showing the range of hospital bills does not explain why one hospital charges significantly more for the same DRG than another hospital. Some hospitals have said that higher bills they sent to CMS reflected the fact that they were either teaching hospitals or they had treated sicker patients (5). CMS does make higher payments to certain hospitals based on the wage index applicable to the area where the hospital is located, the percentage of low-income patients, if the hospital is an approved teaching hospital and for outlier cases. However, the inverse relationship we found between the charges and payments in the Southwest US for pulmonary and critical care DRGs suggest that the higher billings are not based on the CMS adjustments.

Teaching would not appear to explain the differences in hospital billing. There are 9 hospitals that are known primary hospitals for residencies in the Southwest (6 in Arizona, 2 in Colorado and 1 in New Mexico). These hospitals had billings that averaged only 4.0% over the average for their respective state. In contrast, these hospitals received payments that were 28.9% over their state averages.

Similarly, high labor costs likely do not explain the differences in billing. The urban centers where wages tend to be higher did bill higher but their payments did not differ. This would seem to indicate that higher billings are not based on higher labor costs. There was considerable variability in billing. For example, the medical centers with the highest billing in each state were in Bullhead City, Arizona (Western Arizona Regional Medical Center); Littleton, Colorado, a suburb of Denver (Centura Health-Littleton Adventist Hospital) and Roswell, New Mexico (Eastern New Mexico Medical Center).

There are several limitations to our study. Hospital billings and payments are based on CMS data. In several instances the average data is based on only one or two DRGs. Billing and payments vary considerably from state to state and it is unclear if this data from the Southwest reflects national trends.

The hospital industry is quick to point out that the charges are irrelevant because private insurers, Medicare or even the uninsured do not pay these amounts (5). Medicare sets standard rates for treatments and insurers negotiate with hospitals. However, experts add that the charges reflect decades of maneuvering by hospitals to gain an edge over insurers and provide themselves with tax advantages. A hospital could use the higher prices when calculating the amount of charity care it was providing. Charity care is important to hospitals which need to demonstrate provision of a high level of “community benefit” in order to maintain its status as a nonprofit hospital. However, the IRS has recently issued new rules that require a hospital to charge uninsured patients a rate that is not more than the “amounts generally billed” to patients with insurance coverage (6).

A small number of hospitals have adopted a strategy to increase their profits by “going out of network” (5). The hospitals sever ties and hence contractual agreements that limit reimbursement rates, with large private insurers. An out-of-network hospital can bill a patient’s insurer at essentially whatever rate it cares to set which likely reflect the “charge master” price. While the insurers can negotiate with the hospital, they generally end up paying more than they would have under a contractual agreement. Data regarding the network affiliations of the hospitals in the Southwest is unavailable.

Transparency in healthcare pricing is needed but few hospitals or physicians have adopted this as a standard policy. One that does post prices is the physician-owned Surgery Center of Oklahoma (7). Their prices appear to be about 50 to 75 percent lower than most major hospitals. Whether this business model will grow as an approach to attract patients is unclear.

Physicians need to act as patient advocates including advocating for affordable healthcare. Transparency is one part in achieving this goal. The release by CMS of hospital charges and payments is a step towards transparency. Release of similar data by healthcare providers and insurers will enhance the transparency and will likely lead to more affordable healthcare for the majority of patients.

References

1. Roy A. Why do hospitals charge $4,423 for $250 ct scans? Blame Arizona Republicans. Forbes. Available at: http://www.forbes.com/sites/aroy/2012/05/27/why-do-hospitals-charge-4423-for-250-ct-scans-blame-arizona-republicans/ Accessed 5/13/13.
2. http://www.azdhs.gov/plan/crr/cr/hospitals.htm Accessed 5/13/13.
3. http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/index.html
4. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/index.html?redirect=/acuteinpatientpps/
5. Meier B, McGinty JC, Creswell J. Hospital billing varies wildly, government data shows. NY Times. 5/8/13. Available at: http://www.nytimes.com/2013/05/08/business/hospital-billing-varies-wildly-us-data-shows.html (accessed 5/13/13).
6. Federal Register. 2013;78(66):20523-44. Available  at: http://www.gpo.gov/fdsys/pkg/FR-2013-04-05/pdf/2013-07959.pdf (accessed 5/27/13).
7. http://www.surgerycenterok.com/index.php (accessed 5/27/13).

Reference as: Robbins RA. Variation in southwestern hospital charges for pulmonary and critical care DRGs. Southwestern J Pulm Crit Care. 2013;7 (1):31-7. doi. http://dx.doi.org/10.13175/swjpcc074-13 PDF

July 2013 Pulmonary Case of the Month: Swan Song

Bridgett Ronan, MD

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 53 year old man presented to the emergency department with a 2 week history of progressive dyspnea. He thought it was anxiety due to quitting drinking just before the onset of his symptoms. He also had fatigue and malaise.

PMH, SH, FH

He had no significant past medical history or family history. He did not smoke but drank 2-6 beers/day until 2 weeks prior to presentation.

Physical Examination

BP 110/60 mm Hg, P 110 beats/min, R 32 breaths/min, T 37.6° C, SpO2 81%

He is pale and appears mildly dyspneic otherwise his physical exam is unremarkable.

Chest Radiography

His chest x-ray is shown in figure 1.

Figure 1. Initial PA (Panel A) and lateral (Panel B) chest x-ray. 

Which of the following laboratory tests is/are not indicated?

1. Arterial blood gases
2. Complete blood count
3. Spiral thoracic CT angiography
4. Urinanalysis
5. All of the above

Reference as: Ronan B, Wesselius LJ. July 2013 pulmonary case of the month: swan song. Southwest J Pulm Crit Care. 2013;7(1):1-9.  doi: http://dx.doi.org/10.13175/swjpcc081-13. PDF

June 2013 Pulmonary Case of the Month: Diagnosis Makes a Difference

Lewis J. Wesselius, MD¹

Henry D. Tazelaar, MD²

Departments of Pulmonary Medicine¹ and Laboratory Medicine and Pathology²

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 64 year old man from Southern Arizona was referred for a second opinion on a diagnosis of chronic eosinophilic pneumonia that was poorly responsive to corticosteroid therapy. The patient first became ill February 2012 with cough and congestion.  His wife was ill at the same time. Both were treated with antibiotics. His wife improved but he never fully recovered with ongoing symptoms of cough and some dyspnea.

He was admitted to another hospital in August 2012 due to worsening shortness of breath and pulmonary infiltrates on chest x-ray. During this admission he underwent bronchoscopy with bronchoalveolar lavage (BAL) that demonstrated 78% eosinophils. A video-assisted thorascopic (VATs) lung biopsy was done and the patient was diagnosed with chronic eosinophilic pneumonia. He was begun on therapy with high dose prednisone (80 mg/day) but had only slight improvement in symptoms.

He was followed by a pulmonologist and continued on prednisone who questioned the possible development of pulmonary fibrosis. Earlier this year he was started on mycophenolate mofetil and the dose was increased to 1000 mg bid while the prednisone was tapered to 5 mg every other day. He was also being treated with fluticasone/salmeterol 250/50 twice a day. The patient continues to have dyspnea with limited activity. His last pulmonary function testing was done in December 2012. At that time his forced vital capacity (FVC) was 51% of predicted and his diffusing capacity for carbon monoxide (DLco) was 40% of predicted.

PMH, SH, FH

He had a history of obstructive sleep apnea (OSA) and had undergone an uvulopharyngoplasty (UPPP). There was also a history of gastroesophageal reflux disease (GERD) and he had a prior Nissen fundoplication. He had a history of osteoarthritis and had undergone a right shoulder replacement.

He had a remote smoking history, a history of modest alcohol use, but no history of using recreational drugs.  He worked as an airline pilot.

His present medications included mycophenolate mofetil 1000 mg twice a day, prednisone 5 mg every other day, voriconazole 200 mg daily (started after BAL showed a few colonies of Aspergillus), and fluticasone/salmeterol 250/50 twice a day.

Physical Examination

Blood pressure 134/88 mm Hg.  Resting oxygen saturation 96%.

Chest:  bibasilar crackles but no wheezes.

Cardiovascular: the heart had a regular rhythm but no murmur.

Extremities: no clubbing or edema.

The remainder of the physical examination was unremarkable.

Chest Radiography

His chest x-ray is shown in figure 1.

Figure 1. Initial chest x-ray.

Which of the following diseases has/have been associated with increased eosinophils in bronchoalveolar lavage fluid?

1. Interstitial lung diseases
2. Acquired immunodeficiency syndrome (AIDS)-associated pneumonia
3. Idiopathic eosinophilic pneumonia
4. Drug-induced lung disease
5. All of the above

Reference as: Wesselius WJ, Tazelaar HD. June 2013 pulmonary case of the month: diagnosis makes a difference. Southwest J Pulm Crit Care. 2013;6(6):247-54. PDF 

May 2013 Pulmonary Case of the Month: the Cure Can be Worse than the Disease

Lewis J. Wesselius, MD¹

Thomas V. Colby, MD²

Departments of Pulmonary Medicine¹ and Laboratory Medicine and Pathology²

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 65 year old man from Colorado presented for evaluation of “lung masses.” He had a prior diagnosis of dermatomyositis made in 2010 and had been with intravenous immunoglobulin (IVIG), prednisone and methotrexate. He had been previously seen in January, 2011 with a 5 mm left lower lobe nodule on thoracic CT which was unchanged compared to August, 2010. A thoracic CT scan done in July, 2011 in Colorado was interpreted as stable.

Over the prior month had been having chest discomfort.  He had a history of pulmonary embolism (PE) and felt the pain was similar in quality to his prior PE. This prompted a chest x-ray and he was told of “lung masses”. He had also experienced 20 pound weight loss.

His current medications included methotrexate 25 mg weekly, prednisone 3 mg every other day and warfarin 7 mg daily.

PMH, SH, FH

In addition to dermatomyositis, he has a history of a left lower extremity deep venous thrombosis with PE. At that time protein S deficiency, activated protein C resistance and factor V Leiden mutation were diagnosed and an inferior vena cava filter were placed. He also has a history of paroxysmal atrial fibrillation and the prior lung nodule noted above.

He was a prior smoker, quitting in 1991, but briefly resuming in 2010.  The patient had social alcohol use but no drug use. 

The patient’s father died at age 75 from prostate cancer; his mother died at age 89 with heart disease; and he had a sister living with throat cancer.

Physical Examination

Vital signs: Afebrile; Blood pressure 114/65 mm/Hg; Pulse 80 regular; Oxygen  Saturation  97% on room air at rest

HEENT: limited ability to open mouth

Chest:  few late exp wheezes

CV: Regular rhythm, no murmur

Skin: diffuse erythema, particularly on face. 

Neuro: muscle strength normal 

Radiography

His thoracic CT is shown in Figure 1.

Figure 1. Movies of the thoracic CT scan showing lung windows (Panel A, upper panel) and mediastinal windows (Panel B, lower panel).

Which of the following are pulmonary manifestations of dermatomyositis?

1. Lung cancer
2. Aspiration pneumonia
3. Interstitial lung disease
4. Metastatic cancer particularly from the cervix, pancreas, breasts, ovaries, gastrointestinal tract and lymph nodes
5. All of the above

Reference as: Wesselius LJ, Colby TV. May 2013 pulmonary case of the month: the cure can be worse than the disease. Southwest J Pulm Crit Care. 2013;6(5):199-208. PDF

April 2013 Pulmonary Case of the Month: A Suffocating Relationship

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 70 year old woman from Oregon was referred by urology for evaluation of an abnormal thoracic CT scan. She was asymptomatic.

PMH, SH, FH

She has a prior history of retroperitoneal fibrosis with ureteral obstructions requiring stents and a transient ischemic attack in 2009. During 2012 she developed hypertension and a thoracic CT was done. She has never smoked and is a widowed housewife. There is no family history of lung disease, although her husband died from lung cancer. Her present medications include: amlodipine 10 mg/day, oxybutynin (Ditropan XL) 10 mg/day, and prednisone 5 mg daily.

Physical Examination

Her physical examination was unremarkable.

Radiography

Her chest CT scan is shown in Figure 1.

Figure 1. Thoracic CT movies from mediastinal windows (upper panel) and lung windows (lower panel).

Which of the following is true regarding the CT scan?

1. There is a right upper lobe mass
2. There are bilateral pleural effusions
3. There is lung fibrosis predominately involving the lower lobes
4. There are diffuse ground glass opacities
5. There are multiple pleural plaques

Reference as: Wesselius LJ. April 2013 pulmonary case of the month: a suffocating relationship. Southwest J Pulm Crit Care. 2013:6(4):154-60. PDF

Doxycycline Decreases Production of Interleukin-8 in A549 Human Lung Epithelial Cells*

Jeffrey C. Hoyt¹

Janelle G. Ballering¹

John M. Hayden¹

Richard A. Robbins^1,2

¹Research Service, Carl T. Hayden VA Medical Center Phoenix, AZ,

²Phoenix Pulmonary and Critical Care Research and Education Foundation, Gilbert, AZ

Abstract

Doxycycline is an antibiotic that possess anti-inflammatory properties.  These anti-inflammatory properties make doxycycline an attractive candidate for possible treatments for a variety of common chronic obstructive airway diseases. Interleukin-8 (IL-8) is a major inflammatory chemokine and a powerful chemo-attractant for both neutrophils and monocytes.  We hypothesized that doxycycline might exert its anti-inflammatory effects, at least in part, by modulating IL-8 production.  To test this hypothesis, A549 human lung epithelial cells were stimulated with cytomix (IL-1beta, TNF-alpha and gamma-IFN) in the presence or absence of varying concentrations of doxycycline.  Doxycycline decreased IL-8 protein production in a concentration- and time-dependent manner.  In the presence of 30 microg/ml doxycycline IL-8 protein production was decreased by 63% through out a 30 hr time course.  In chemotaxis assays monocyte and neutrophil migration was decreased by 55% and 57% respectively.  Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments suggest that doxycycline does not decrease expression of IL-8 mRNA and that use of the RNA polymerase II inhibitor DRB indicates that doxycycline does not effect stability of this mRNA.  In the presence of doxycycline p38-alpha mitogen-activated protein kinase (MAPK) expression is decreased by 36% in cytomix-stimulated cells. These data demonstrate that doxycycline can modulate IL-8 release and suggest that it has potential as an anti-inflammatory in those disorders where IL-8 is an important inflammatory mediator.

Introduction

Chemokines are small, excreted, induced proteins that are involved the initiation and regulation of the inflammatory and immunological responses to the presence of foreign antigens in the body.  Interleukin-8 (IL-8) or CXCL8 belongs to the CXC subfamily and is a major pro-inflammatory chemokine produced during chronic inflammatory lung diseases (1-3).  IL-8 performs a variety of functions including activation of degranulation and the respiratory burst in and chemo-attraction of neutrophils (4-6), chemo-attraction and activation of monocytes (7), chemotaxis of T-cells (8), chemotaxis and adhesion of basophils (9,10), activation of 5-lipoxygenase with release of leukotriene B₄ (11) and adherence of neutrophils (12) and monocytes (13) to various cell layers.

The common obstructive airway diseases such as bronchitis, asthma, cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease (COPD) and diffuse panbronchiolitis are all invariably associated with chronic airway inflammation (14-16).  These disorders are often progressive even with current therapies, including steroid therapy, suggesting that new, more effective therapies are needed.

The tetracyclines and erythromycin are well known, potent antibacterial agents.  In addition both compounds also possess a separate anti-inflammatory mode of action and have been known to reduce inflammation associated with several inflammatory diseases since the 1970’s (17,18).  These compounds include erythromycin A, and many of its derivatives such as azithromycin and clarithromycin, as well as tetracycline and several related compounds such as doxycycline.  These compounds have exhibited anti-inflammatory activity in a variety of inflammatory disorders (18).

We hypothesized that doxycycline possesses potent anti-inflammatory properties, and that treatment with doxycycline leads to a reduction in IL-8 levels in A549 human lung epithelial cells. Such a reduction would lead to an attenuation of many pro-inflammatory responses and possibly limiting tissue damage at the site of inflammation.  Our results show that doxycycline decreases the production of IL-8 in cytomix (a combination of IL-1 beta, TNF-alpha and gamma-IFN) stimulated cells resulting in decreased monocyte and neutrophil chemotaxis.  These results suggest that doxycycline may be beneficial in the control of the inflammatory response in a variety of chronic airway disorders.

Materials and Methods

Culture of A549 Cells. The human lung epithelial cell line, A549, was purchased from the American Type Culture Collection (Manassas, VA) (19). A549 cells were grown in 25 cm² tissue culture flasks (Corning Costar, Cambridge, MA) in Ham's F‑12 containing 10% fetal calf serum, L‑glutamine (2 mM) and penicillin‑streptomycin (100 U/ml‑100 mg/ml) until confluent.  After washing with serum-free media doxycycline hydrochloride, dissolved in distilled water, was added to confluent A549 cultures for 3 hr and the cells were cultured 18 hr in serum-free Ham's F-12 with or without cytomix.  Cytomix (CM) is a combination of recombinant human tumor necrosis factor-alpha (TNF-alpha), human interleukin‑1 beta (IL-1 beta), and human interferon-gamma (IFN-gamma) each at a 5 ng/ml concentration (all cytokines from R&D Systems, Minneapolis, MN) that have been previously used to stimulate the expression of IL-8 (20,21).  Concentrations of doxycycline ranged from 3 to 30 microg/ml and are based on reports of clinically relevant serum and tissue levels (22).  All control cultures contained the appropriate amount of carrier solvent alone.

Cell Viability Assays.  Cell viability was determined by assay for release of lactic acid dehydrogenase into cell culture supernatant fluid using a commercially available assay kit (Sigma, St. Louis, MO) according to the manufacturer’s directions.

Determination of IL-8 Protein Levels.  IL-8 protein levels were determined using a commercially available ELISA kit (R&D Systems, Minneapolis, MN) according to the manufacturer’s directions.  Doxycycline concentrations, cytomix stimulation and culture supernatant collection times were performed as indicated in the figure legends.

Neutrophil and Monocyte Chemotaxis. To perform the neutrophil chemotaxis assay, polymorphonuclear leukocytes were purified from heparinized normal human blood by the method of Böyum (23). The resulting cell pellet routinely consists of > 96% neutrophils and > 98% viable cells as determined by trypan blue and erythrosin exclusion. The cells were suspended in Hanks' balanced salt solution (HBSS) containing 2% bovine serum albumin (BSA, Sigma) at pH 7.4 to give a final concentration of 3.0 x 10⁶ cells/ml. This suspension was used for the neutrophil chemotaxis assay.

Mononuclear cells for the chemotaxis assay were obtained by Ficoll-Hypaque density centrifugation to separate red blood cells and neutrophils from mononuclear cells. This preparation routinely consisted of 30% large monocytes and 70% small lymphocytes determined by morphology and alpha-naphthyl acetate esterase staining with >98% viability as assessed by trypan blue and erythrosin exclusion. The cells were resuspended in HBSS containing 2% bovine serum albumin at pH 7.4 to give a final cell concentration of 5 x 10⁶ cells/ml.

The chemotaxis assay was performed in a 48-well micro-chemotaxis chamber (NeuroProbe Inc., Cabin John, MD). Briefly, 25 μl of the harvested cell culture supernatant fluids were placed into the lower wells and a 10-µm thick polyvinylpyrrolidone-free polycarbonate filter  (Nucleopore, Pleasanton, CA), with a pore size of 3 μm  for neutrophil chemotaxis or 5 µm for monocyte chemotaxis, was placed over the bottom wells. The silicon gasket and upper pieces of the chamber were applied and 50 μl of the appropriate cell suspension added to the upper wells above the filter. The chambers were incubated in humidified air in 5% CO₂ at 37°C for 30 min for neutrophil chemotaxis or 90 min for monocyte chemotaxis. After incubation, the chamber was disassembled and non-migrated cells were wiped away from the filter. The filter was then immersed in methanol for 5 min, stained with Diff-Quik (American Scientific Product, McGraw Park, IL), and mounted on a glass slide. Cells that completely migrated through the filter were counted by using light microscopy in ten random high power fields (HPF) per well.

RNA Isolation and RT-PCR.  IL-8 mRNA was analyzed by reverse transcription‑polymerase chain reaction (RT‑PCR). Total cellular RNA was extracted from adherent cells using a modification of the methods of Chomczynski and Sacchi (24).  The RNA was reverse transcribed using a commercially available RT-PCR kit (Promega, Madison, WI) and commercially available IL-8 primers (R&D Systems, Minneapolis, MN) added at 0.2 μM final concentration. Using a Perkin Elmer model 480-thermal cycler, reverse transcription was performed on 250 ng of total cellular RNA at 48^oC for 45 min.  PCR for IL-8 was performed in the same sample tubes at 94°C for 2 minutes followed by 22 cycles consisting of 94°C for 45 sec, 55°C for 45 sec, 72°C for 2 min, followed by 72°C for an additional 7 min.  Beta-actin was used as a “housekeeping gene" and RT-PCR was performed in a similar manner as for IL-8 except for an annealing temperature of 55°C. The beta-actin primer sequences that were used are:  sense primer 5’-TGACCCAGATCATGTTTGAG-3’ and antisense primer 5’-TCATGAGGTAGTCAGTCAGG-3’.  The DNA fragments were separated by agarose gel electrophoresis on a 2% gel in TAE buffer and then identified, analyzed and quantified by densitometry.  Increasing PCR cycles gave increasing amounts of DNA through a fairly broad range with linearity obtained from about cycles 22-28 beginning with 250 ng of DNA (r=0.99 for IL-8 and beta-actin).

Stability of IL-8 mRNA.  A549 cells were treated with cytomix or cytomix plus doxycycline for 18 hr as described above and then treated with the RNA polymerase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidizaole (DRB) (Calbiochem, La Jolla, CA), 10 μg/ml, to inhibit transcription.  RNA was isolated from cultures at various times and RT-PCR, using conditions described previously, was used to determine the amount of IL-8 mRNA present at indicated times.

Protein Determination.  Protein concentrations were determined spectrophotometrically using the Bradford assay (25).

Western Blotting. Cell extracts were prepared for Western blotting using previously described methods (26).  Cell lysates were clarified by centrifugation prior to electrophoresis.  SDS-PAGE was performed using a 4% T acrylamide stacking gel and a 10% T separating gel.  Twelve micrograms of protein were loaded per lane.  After electrophoresis was complete the separated proteins were transferred to a PVDF membrane for further analysis. Transfer was performed using a Tris-HCl (25 mM), glycine (192 mM) and methanol (20% v/v) buffer system.  The transfer was performed at 4^oC for 16 hr at 30V and then for 30 min at 60V.  Antibody for p38-alpha MAPK (Santa Cruz Biotechnology, Santa Cruz, CA) was used to immunochemically detect p38-alpha MAPK protein on the transfer membranes using goat anti-rabbit IgG alkaline phosphatase as the secondary antibody-enzyme conjugate and NBT/BCIP alkaline phosphatase substrate tablets (Sigma, St. Louis, MO) in 0.1 M Tris-HCl pH 9.1 as the substrate system.   Five microg of antibody were used at each step during the development procedures.  The transfer membranes were blocked with BLOTTO (20 mM Tris base, 180 mM NaCl, 4% nonfat dry milk, 0.02% NaN₃) to minimize nonspecific binding.

Statistical analysis. In cases where multiple experiments were made, differences between groups were tested for significance using one-way analysis of variance (ANOVA) with Fisher’s protected least significant difference (Fisher’s PLSD).  In cases where single measurement was made, the differences between groups were tested for significance using Student’s paired t-test.  In all cases, a p value of <0.05 was considered significant. The data are expressed as mean + SD.

Results

A549 cell culture supernatants from all treatments were assayed for lactic acid dehydrogenase release as a measure of cell viability.  There were no significant differences in the lactic acid dehydrogenase activity in the culture supernatants from all treatment types (data not shown).

Cytomix stimulation of A549 cells results in an increase in IL-8 production from 1100 pg/ml in unstimulated control samples to > 230,000 pg/ml (Fig. 1). 

Figure 1.  Effect of doxycycline concentration on production of IL-8.  Cytomix (CM) with or without 3-30 microg/ml doxycycline (Dox). A549 cells were treated, samples collected and IL-8 ELISA assays were performed as described in Materials and Methods section.  Results are from at least three experiments with each condition repeated in triplicate.  * p< 0.01.

Doxycycline alone at all concentrations tested did not significantly increase IL-8 production over control samples.  Increase in doxycycline concentration in cytomix-stimulated cells results in a concentration-dependent decrease in IL-8 production.  At the highest doxycycline concentration used (30 microg/ml) IL-8 production was decreased 60% over cytomix treatment alone (p < 0.01) (Fig. 1). 

In a time course study 30 microg/ml doxycycline treatment of cytomix-stimulated cells suppressed IL-8 production starting at 2 hr and continuing to the end of the study at 30 hr (p < 0.01 at all times).  Suppression ranged from 70% at 2 hr to 80% at 30 hr (p < 0.01) (Fig. 2).

Figure 2.  Time course for IL-8 production in the presence of cytomix (CM) and 30 microg/ml doxycycline (Dox).  A549 cells were treated and IL-8 ELISA assays were performed as described in Materials and Methods section. Results are from at least three experiments with each condition repeated in triplicate.  Hatched columns are CM alone.  Black columns are CM + Dox.  *In all cases p < 0.01.

Doxycycline treatment decreased neutrophil chemotaxis by 57% in cytomix-stimulated cells relative to cytomix alone (p < 0.01) (Fig 3A).  In companion monocyte chemotaxis experiments doxycycline decreased chemotaxis by 55% relative to cytomix alone (p < 0.01) (Fig. 3B).

Figure 3.  Effect of doxycycline on: (A) neutrophil chemotaxis and (B) monocyte chemotaxis.  Results show the number of cells that migrate into the chemotaxis membrane in each microscope field of view examined. At least five high power microscope fields were counted for each treatment. * In all cases p < 0.01.

Expression of IL-8 mRNA was not affected by the presence of 30 microg/ml doxycycline.  At this doxycycline concentration, cytomix-induced IL-8 mRNA expression is not altered relative to samples treated with cytomix alone (Fig. 4).  Doxycycline alone did not increase IL-8 mRNA expression over untreated control samples (Fig. 4).

Figure 4.  Effect of doxycycline on IL-8 and beta-actin mRNA production.  Total cellular RNA was isolated and RT-PCR was performed as described.  IL-8 RTPCR Panel A:  Lane 1 base pair markers.  Lane 2: 30 μg/ml doxycycline alone.  Lane 3: 4 hr cytomix (CM).  Lane 4: 4 hr CM + 30 μg/ml doxycycline.  Lane 5:  12 hr CM.  Lane 6: 12 hr CM + 30 μg/ml doxycycline. Lane 7:  18 hr CM.  Lane 8: 18 hr CM + 30 μg/ml doxycycline.  Lane 9: 30 hr CM.  Lane 10: 30 hr CM + 30 μg/ml doxycycline.  Lane 11: base pair markers.  Lane 12: IL-8 positive control.  Beta-actin RTPCR panel B: Lane 1: base pair markers.  Lane 2: 30 μg/ml doxycycline alone.  Lane 3: 4 hr cytomix (CM).  Lane 4: 4 hr CM + 30 μg/ml doxycycline.  Lane 5: 12 hr CM.  Lane 6: 12 hr CM + 30 μg/ml doxycycline. Lane 7:  18 hr CM.  Lane 8: 18 hr CM + 30 μg/ml doxycycline.  Lane 9: 30 hr CM.  Lane 10: 30 hr CM + 30 μg/ml doxycycline.  Results are from duplicate experiments with each condition assayed in triplicate.

Stability of IL-8 mRNA in cytomix-stimulated cells does not appear to be affected by doxycycline (Fig. 5).  IL-8 mRNA appears to decrease at the same rate, as indicated by the nearly identical slopes of the decay lines, in the presence or absence of doxycycline over an 8 hr time course.

Figure 5.  .  IL-8 mRNA stability.  Total cellular RNA was isolated in the presence of 10 microg/ml DRB at the indicated times and RT-PCR performed as described.  Solid line:  cytomix alone (r =0.967).  Dashed line:  CM + 30 microg/ml doxycycline (r = 0.645).  Results are from triplicate experiments.          

The effect of doxycycline p38-alpha MAPK was examined (Fig. 6).  Treatment of cytomix-stimulated cells with 30 microg/ml doxycycline decreased p38-alpha protein production by 36% over cytomix-stimulation alone.

Figure 6.  Effect of doxycycline on p38 alpha MAPK.  Cells were lysed and electrophoresis and blotting were performed as described.  Lane: (1) Molecular weight markers (kDa), (2) Control,  (3) Doxycycline (30 microg/ml) alone, (4) CM  alone,  (5) CM  plus doxycycline (30 microg/ml).  20 microg of protein loaded per lane.

Discussion

IL-8 is a major component of the many protein-based chemoattractant molecules that occur in chronic, inflammatory airway diseases (27).  As a chemoattractant it recruits both monocytes and neutrophils to inflamed areas of the body.  We have shown that doxycycline-treatment of cytomix-stimulated A549 human lung epithelial cells results in a concentration-dependent decrease in IL-8 production (Fig. 1) as well as in a time-dependent decrease in IL-8 production (Fig. 2).  The observed decrease in IL-8 production affects neutrophil (Fig. 3A) and monocyte (Fig. 3B) chemotaxis.  Chemotaxis of both neutrophils and monocytes are decreased after doxycycline treatment of stimulated cells indicating a possible reduction in the inflammatory response.  Expression (Fig. 4) and stability (Fig 5) of IL-8 mRNA appear to be unaffected in cytomix-stimulated cells after doxycycline treatment.  The p38 MAPK protein production is also decreased in the presence of doxycycline (Fig. 6).

The lack of effect of doxycycline of IL-8 mRNA expression and stability suggests that the observed decrease in IL-8 protein production may be due to post-translational events and not directly related to regulation of gene activity through involvement of activator protein-1 (AP-1), nuclear factor-kappa beta or other transcriptional regulatory systems.  These events could possibly be a variety of post-translational modifications, such as glycosylation of specific amino acid residues in the IL-8 protein, incorrect or lack of removal of the N-terminal hydrophobic signal peptide, or by increased proteolytic degradation of IL-8 by the proteasome, matrix metalloproteases or other proteolytic activity.  Another intriguing possibility is the report by Li et al. (28) that decreased p38 MAPK activity has no effect of IL-8 gene transcription but that active p38 MAPK plays a critical role in IL-8 protein production in a post-transcriptional manner.  This observation appears to describe the decreased IL-8 and p38 MAPK protein levels and the apparent lack of effect on IL-8 mRNA that we have described.

IL-8 is an important piece of the inflammatory response to invasion of the body by various foreign objects.  However, if the inflammatory response is allowed to progress unchecked substantial cell and tissue damage occurs. 

IL-8 production occurs in a wide variety of inflammatory lung diseases that are characterized by an influx of neutrophils (1).  Asthma is often thought of as a disease that is dependent on T-lymphocytes and eosinophils (1,29).  However there is mounting evidence that neutrophils and IL-8, a powerful chemoattractant for neutrophils, are elevated in severe asthma cases (29).  Diffuse panbronchiolitis (DPB) is a progressive, chronic, inflammatory airway disease that is largely restricted to Japan (30).  Neutrophils, T-lymphocytes and the chemoattractant molecules IL-8 and MCP-1 are thought to play significant roles in the progression of DPB (30).  Cystic fibrosis is characterized by a massive influx of neutrophils into the airways (31).  In addition neutrophil chemoattractants such as IL-8 are found in very high concentration (31).  In COPD IL-8 is a prominent attractant for neutrophils (32-Barnes) and IL-8 levels in induced sputum correlate with disease severity (32).  A common result for these chronic, inflammatory lung diseases is severe, often life threatening, tissue destruction. 

Continuous treatment with some antibiotics, particularly macrolides, reduces exacerbations. A randomized controlled trial with erythromycin reduced exacerbations by 35% compared to placebo (33). In a more recent study, treatment with azithromycin for one year lowered exacerbations by 27% (34). Although the mechanism(s) accounting for the reduction in exacerbations is unknown, current concepts suggest the reduction is likely secondary to the macrolides’ anti-inflammatory properties. However, concern has been raised about a very small, but significant, increase in QT prolongation and cardiovascular deaths with azithromycin (35). In addition, the recent trial with azithromycin raised the concern of hearing loss which occurred in 25% of patients treated with azithromycin compared to 20% of control (34).

Tetracycline and derivatives such as minocycline and doxycycline have been extensively used to treat a wide variety of chronic, inflammatory diseases (36) including acne, rosacea, rheumatoid arthritis and periodontitis.  Nieman and Zerler (37) propose that tetracycline and some of its derivatives may be beneficial in limiting lung damage during adult respiratory syndrome (ARDS).  Although macrolide antibiotics such as erythromycin A have been shown to be effective treatments for cystic fibrosis (38) and diffuse panbronchiolitis (39) development of resistant pathogenic bacteria during the required prolonged therapy is a major concern.  Doxycycline is not the antibiotic of choice for many respiratory bacterial infections so development of resistance to this drug is of less importance than it is for the macrolides.

Systemic inflammation has been correlated with poorer outcomes in COPD (40). Doxycycline has anti-inflammatory properties in addition to suppressing release of IL-8 including reduction of or inducible nitric oxide production and MCP-1 release from lung epithelial cells (41,42). It seems likely that doxycycline might reduce other inflammatory cytokines as well. These results suggest that doxycycline may provide a unique, effective, low cost therapy for management of a wide range of chronic, inflammatory diseases.

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*Funded by the Flight Attendants Medical Research Institute (FAMRI)

 Reference as: Hoyt JC, Ballering JG, Hayden JM, Robbins RA. Doxycycline decreases production of interleukin-8 in a549 human lung epithelial cells. Southwest J Pulm Crit Care. 2013;6(3):130-42. PDF

March 2013 Pulmonary Case of the Month: Don’t Rein Me In

Robert W. Viggiano, MD

Michael B. Gotway, MD

Departments of Pulmonary Medicine and Radiology

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 70 year old man was referred for a pleural effusion. The patient had pitting edema of the lower extremities noted in March, 2013. At that time a myocardial perfusion study and an echocardiogram were interpreted as being normal with an ejection fraction of 55%. His primary care physician stopped the amlodipine he was taking for hypertension and his edema resolved. However, the amlodipine was restarted a few weeks later for blood pressure control.

PMH, SH, FH

He has a past medical history of hypertension and asthma. He was diagnosed with prostrate cancer in mid 2012. At that time a CT scan of his abdomen/pelvis and a MRI of his pelvis were negative for metastatic disease. He underwent robot assisted radical prostatectomy and bilateral pelvic lymph node dissection in August 2012. His final diagnosis was Gleason 4+5 disease present throughout the prostate with focal extraprostatic extension and lymphovascular and perineural invasion and invasion of right seminal vesicle. He was staged T 3B.

Present medications

• Amlodipine 5 mg at bedtime
• Omelsartan (Benicar®) 40 mg/day
• Salmeterol/fluticasone (Advair®) 100/50 1 puff twice a day
• Clonazepam 0.5 mg twice a day
• Lycopene 10 mg daily

He has a 10 year smoking history but no alcohol or drug use.

Family history is unremarkable.

Physical Examination

Vital signs: Normal

Lungs: Decreased breath sounds in both lung bases

Heart: Elevated JVP; Normal S1 and S2

Abdomen: Negative

Extremities: 2-3+ pitting edema

Laboratory

• CBC: normal
• Electrolytes: normal
• Serum creatinine: 1.0 mg/dL
• Total protein: 6.8 g/dL
• Albumin: 4.3 g/dL
• NT-pro brain naturetic peptide (BNP): 255 pg/ml

Radiography

Chest x-ray is shown in figure 1.

Figure 1. PA (panel A) and lateral (panel B) chest radiography.

Which of the following is false?

1. The patient’s chest x-ray shows bilateral pleural effusions right larger than left
2. A NT-pro BNP 255 pg/ml makes heart failure an unlikely diagnosis
3. His pleural effusion is most likely due to metastatic prostate cancer
4. A normal heart size on chest x-ray excludes heart failure
5. A normal echocardiogram excludes heart failure

Reference as: Viggiano RW, Gotway MB. March 2013 pulmonary case of the month: don't rein me in. Soutwest J Pulm Crit Care. 2013;6(3):93-102. PDF

February 2013 Pulmonary Case of the Month: One Thing Leads to Another

Elijah Poulos, MD

Erica Peterson, MD

Robert A. Raschke, MD

Good Samaritan Regional Medical Center

Phoenix, AZ

History of Present Illness

A 63 year-old man from Minnesota with a history of sarcoidosis managed with low-dose prednisone (average 6 mg/day with periodic bursts) for the past 15 years was transferred to our hospital for a higher level of care.  Eight weeks prior to admission he was in Costa Rica for a 3 week vacation where he engulfed himself in local traditions, swam in marine and fresh water, slept in rural areas, ate unprocessed foods, wore no insect repellent and had no prophylactic vaccines or medications. He returned to northern Minnesota and visited his cabin where he noted numerous dog tics.

Four weeks prior to admission he developed intermittent fevers to 102°, rigors and drenching night sweats. Workup initiated in Minnesota was unrevealing. Specifically he had negative malaria smears, blood cultures, leptospirosis and hepatitis panels. Transaminases were elevated in the 100s. An empiric 1 week trial of doxycycline resulted in no improvement.

One week prior to admission he came to Arizona for a golfing trip. He noted ongoing fevers, chills, and sweats as before but now had a left conjunctival hemorrhage, lethargy, ataxia, dysarthria, jaundice and dyspnea. He was taken to the emergency room of another hospital where he was noted to have a fever of 104°, transaminitis, pancytopenia, and hypoglycemia. He was transferred to our care.

Physical Exam

Upon arrival, the patient was a well-nourished male who appeared fatigued, diaphoretic, and in mild respiratory distress. Vitals signs upon admission revealed a temperature 39.4° C, heart rate 118, blood pressure 111/70, respiratory rate 22, and oxygen saturation 93% on 2 liters via nasal cannula. Bibasilar crackles and diffuse wheezes were present on lung auscultation. A left conjunctival hemorrhage, mild jaundice, and upper extremity petechiae, purpura and bruising were present. Abdominal exam revealed hepatosplenomegaly.

Laboratory

CBC: WBC 1.4 X 10³ cells/mcL (47 segs, 29 bands, 5 NRBC, 4 metas, 5 myelos), Hgb 10.2 g/dL, and platelets 14 X 10³ cells/mcL. A peripheral smear was unremarkable except for pancytopenia.

Metabolic studies: BUN 41 mg/dL, creatinine 1.5 mg/dL, glucose 50 mg/dL, AST 362 U/L, ALT 227U/L, LDH 1100 U/L, total bilirubin 3.6 mg/dL, alkaline phosphatase 331 U/L..

Coagulation tests: Prothrombin time 18.2 secs, activated partial thromboplastin time (aPTT) 55 secs, fibrinogen 115 mg/dL, D-dimer 12.8 ng/ml D dimer units.

Lumbar puncture: 2 WBC, glucose 59 mg/dL, protein 56 mg/dL. Cultures were negative.

Miscellaneous: erythrocyte sedimentation rate (ESR) 13 mm/hr: C-reactive protein (CRP) 121 mg/L; ferritin >40,000 ng/ml; triglycerides 272 mg/dL.

ABG’s normal on 2L/min.

Radiography

Admission portable chest x-ray is shown in Figure 1.

Figure 1. Admission portable chest x-ray.

Which of the following is true?

1. A thoracic/abdominal CT scan is indicated
2. High-dose corticosteroids are indicated to suppress a  sarcoidosis flair
3. Open lung biopsy is indicated
4. Artesunic acid should be begun for malaria
5. Chloroquine should be begun for malaria

Reference as: Poulos E, Peterson E, Raschke RA. February 2013 pulmonary case of the month: one thing leads to another. Southwest J Pulm Crit Care. 2013;6(2):55-62. PDF

January 2013 Pulmonary Case of the Month: Maybe We Should Call GI

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 55 year old man from Arizona was undergoing a renal transplant evaluation because of polycystic kidney disease. He was referred for an abnormal chest x-ray. He was a nonsmoker and there were no respiratory symptoms.

PMH, FH and SH

He has a long history of polycystic kidney disease, hypertension, gout, and a history of a kidney stone. He is a life-long nonsmoker. There is no significant family history including polycystic kidney disease. He works as a border patrol agent and is originally from Honduras. His present medications include:

• Allopurinol
• Amlodipine
• Atenolol
• Hydralazine
• Sodium bicarbonate

Physical Examination

His blood pressure is elevated at 142/84, but otherwise his physical examination is unremarkable.

Chest X-ray

His chest X-ray is below (Figure 1).

Figure 1. PA (Panel A) and lateral (Panel B) chest x-ray.

The chest x-ray was interpreted as showing bilateral lower lobe nodules.

Which of the following is appropriate?

1. Obtain old chest x-rays for comparison
2. Spiral CT for pulmonary embolism
3. Coccidioidomycosis serology
4. A + C
5. All of the above

Reference as: Wesselius LJ. January 2013 pulmonary case of the month: maybe we should call GI. Southwest J Pulm Crit Care 2013;6(1):46-51. PDF