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Pulmonary

Last 50 Pulmonary Postings

(Click on title to be directed to posting, most recent listed first, CME offerings in Bold)

November 2014 Pulmonary Case of the Month: BAL Eosinophilia
How Does Genetics Influence Valley Fever? Research Underway Now To
   Answer This Question
October 2014 Pulmonary Case of the Month: A Big Clot
September 2014 Pulmonary Case of the Month: A Case for Biblical
   Scholars
Role of Endobronchial Ultrasound in the Diagnosis and Management of
   Bronchogenic Cysts: Two Case Descriptions and Literature Review
Azathioprine Associated Acute Respiratory Distress Syndrome: Case Report
   and Literature Review
August 2014 Pulmonary Case of the Month: A Physician's Job is 
   Never Done
July 2014 Pulmonary Case of the Month: Where Did It Come From?
June 2014 Pulmonary Case of the Month: "Petrified"
May 2014 Pulmonary Case of the Month: Stress Relief
Giant Cell Myocarditis: A Case Report and Review of the Literature
April 2014 Pulmonary Case of the Month: DIP-What?
Wireless Capsule Endo Bronchoscopy
Elevated Tumor Markers In Coccidioidomycosis of the Female Genital Tract
March 2014 Pulmonary Case of the Month: The Cure May Be Worse
   Than the Disease
February 2014 Pulmonary Case of the Month: Faster Is Not Always
   Better
January 2014 Pulmonary Case of the Month: Too Much, Too Late
32 Year Old Man with “Community-Acquired” Pneumonia
December 2013 Pulmonary Case of the Month: Natural
   Progression
November 2013 Pulmonary Case of the Month: Dalmatian Lungs
October 2013 Pulmonary Case of the Month: A Hidden Connection
Bronchoscopic Cryoextraction: A Novel Approach for the Removal
   of Massive Endobronchial Blood Clots Causing Acute Airway
   Obstruction
September 2013 Pulmonary Case of the Month: Chewing the Cud
IgG4-Related Systemic Disease of the Pancreas with Involvement 
   of the Lung: A Case Report and Literature Review
August 2013 Pulmonary Case of the Month: Aids for Diagnosis
Variation in Southwestern Hospital Charges for Pulmonary
   and Critical Care DRGs
July 2013 Pulmonary Case of the Month: Swan Song
June 2013 Pulmonary Case of the Month: Diagnosis
   Makes a Difference
May 2013 Pulmonary Case of the Month: the Cure Can be
   Worse than the Disease
April 2013 Pulmonary Case of the Month: 
   A Suffocating Relationship
Doxycycline Decreases Production of Interleukin-8
   in A549 Human Lung Epithelial Cells
March 2013 Pulmonary Case of the Month:
   Don’t Rein Me In
February 2013 Pulmonary Case of the Month: 
   One Thing Leads to Another
January 2013 Pulmonary Case of the Month:
   Maybe We Should Call GI
December 2012 Pulmonary Case of the Month: Applying Genetics
November 2012 Pulmonary Case of the Month:
   The Wolves Are at the Door
October 2012 Pulmonary Case of the Month: 
   Hemoptysis from an Uncommon Cause
Acetylcholine Stimulation of Human Neutrophil Chemotactic 
Activity Is Directly Inhibited by Tiotropium Involving Gq Protein
   and ERK-1/2 Regulation
September 2012 Pulmonary Case of the Month:
   The War on Drugs
Tiotropium Bromide Inhibits Human Monocyte Chemotaxis 
August 2012 Pulmonary Case of the Month:
   All Eosinophilia Is Not Asthma
COPD Exacerbations: An Evidence-Based Review
July 2012 Pulmonary Case of the Month: Pulmonary Infiltrates -
   Getting to the Heart of the Problem
Cough and Pleural Disease in a Burmese Immigrant – A Masquerader
Meta-Analysis of Self-Management Education for Patients with 
   Chronic Obstructive Pulmonary Disease
June 2012 Pulmonary Case of the Month:
   What’s a Millet Seed Look Like?
May 2012 Pulmonary Case of the Month:
   Things Are Not Always as They Seem
April 2012 Pulmonary Case of the Month:
   Could Have Fooled Me!
Pulmonary Nodules with Cutaneous Manifestations: 
   A Case Report and Discussion

 

For complete pulmonary listings click here.

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

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Friday
Nov012013

November 2013 Pulmonary Case of the Month: Dalmatian Lungs

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

 

Pulmonary Case of the Month CME Information

Members of the Arizona, New Mexico and Colorado Thoracic Societies and the Mayo Clinic are able to receive 0.25 AMA PRA Category 1 Credits™ for each case they complete. Completion of an evaluation form is required to receive credit and a link is provided on the last panel of the activity.

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Lewis J. Wesselius, MD. The author(s)/contributor(s) state that they do not have any financial arrangements that could constitute a conflict of interest. Detailed Information

Learning Objectives:
As a result of this activity I will be better able to:

  1. Correctly interpret and identify clinical practices supported by the highest quality available evidence.
  2. Will be better able to establsh the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
  3. Will improve the translation of the most current clinical information into the delivery of high quality care for patients.
  4. Will integrate new treatment options in discussing available treatment alternatives for patients with pulmonary, critical care and sleep related disorders.

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

CME Sponsor: University of Arizona College of Medicine at the Arizona Health Sciences Center Credit Designation and Accreditation Statements.

Current Approval Period: January 7, 2013 - January 6, 2015

Original Release Date: November 1, 2013

Most Recent Review by Author: November 1, 2013

Most Recent Review by CME Sponsor: November 1, 2013

Financial Support Received: None

 

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

Tuesday
Oct012013

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

 

Pulmonary Case of the Month CME Information

Members of the Arizona, New Mexico, Colorado and California Thoracic Societies and the Mayo Clinic are able to receive 0.25 AMA PRA Category 1 Credits™ for each case they complete. Completion of an evaluation form is required to receive credit and a link is provided on the last panel of the activity.

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Kelly Cawcutt, MD. The author(s)/contributor(s) state that they do not have any financial arrangements that could constitute a conflict of interest. Detailed Information

Learning Objectives:
As a result of this activity I will be better able to:

  1. Correctly interpret and identify clinical practices supported by the highest quality available evidence.
  2. Will be better able to establsh the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
  3. Will improve the translation of the most current clinical information into the delivery of high quality care for patients.
  4. Will integrate new treatment options in discussing available treatment alternatives for patients with pulmonary, critical care and sleep related disorders.

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

CME Sponsor: University of Arizona College of Medicine at the Arizona Health Sciences Center Credit Designation and Accreditation Statements.

Current Approval Period: January 7, 2013 - January 6, 2015

Original Release Date: October 1, 2013

Most Recent Review by Author: October 1, 2013

Most Recent Review by CME Sponsor: October 1, 2013

Financial Support Received: None

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

Saturday
Sep142013

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 

 

Sunday
Sep012013

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

Friday
Aug302013

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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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

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