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Last 50 Pulmonary Postings

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

September 2014 Pulmonary Case of the Month: A Case for Biblical
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
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
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
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
March 2012 Pulmonary Case of the Month: There’s Air in There
Treatment of Coccidioidomycosis-associated Eosinophilic
   Pneumonia with Corticosteroids
Sympathetic Empyema Arising from Streptococcus anginosus
   Splenic Abscess


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.



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. 


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.


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.


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. 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


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. 


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.


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. 


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). 


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).


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.  


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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  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]
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  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: 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.


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.


  • 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 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: 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



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.


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.


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.


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).


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.


  1. Roy A. Why do hospitals charge $4,423 for $250 ct scans? Blame Arizona Republicans. Forbes. Available at: Accessed 5/13/13.
  2. Accessed 5/13/13.
  5. Meier B, McGinty JC, Creswell J. Hospital billing varies wildly, government data shows. NY Times. 5/8/13. Available at: (accessed 5/13/13).
  6. Federal Register. 2013;78(66):20523-44. Available  at: (accessed 5/27/13).
  7. (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. 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.


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: PDF

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