IgG4 disease

An common dilemma in medicine is distinguishing between worsening autoimmune disease and infection in patients with chronic autoimmune disease when they present with worsening symptoms. Increasing dyspnea may represent a worsening inflammation in lungs, versus a pulmonary infection secondary to immunosuppressant drugs. In a recently discussed case,  we encountered this scenario in a patient with IgG4 disease (pancreatitis and sclerosing cholangitis) and a positive cytomegalovirus PCR in bronchoalveolar fluid lavage.

IgG4 related disease is relatively new entity, first being recognized in 2003. Initially felt to be solely with autoimmune pancreatitis, it has now been identified to cause disease in nearly all organs. Its involvement in disease development is currently unclear, where its role as a primary or secondary factor in pathogenesis is yet to be confirmed. Interestingly IgG4 levels in serum and tissue are helpful but not necessary (negative ~30%) to confirm a diagnosis, where additional pathologic features can be helpful. Clinically, patients tend to present with subacute disease involving one ore more organs. Fever and elevated inflammatory markers are uncommon. Organ sclerofibrosis with tumour like lesions and atopic symptoms (asthma, allergy) are a common manifestations. A list of organs that can be involved are listed from a recent NEJM review:

1. Mikulicz’s syndrome (affecting the salivary and lacrimal glands)

2. Küttner’s tumor (affecting the submandibular glands)

3. Riedel’s thyroiditis

4. Eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory 7.tract)

5. Multifocal fibrosclerosis (orbits, thyroid gland, retroperitoneum, mediastinum etc)

6.Inflammatory pseudotumor (affecting the orbits, lungs, kidneys, and other organs)

7. Mediastinal fibrosis

8. Retroperitoneal fibrosis (Ormond’s disease)

9. Periaortitis and periarteritis

10. Inflammatory aortic aneurysm

11. Tubulointerstitial nephritis with extensive tubulointerstitial deposits

Treatment can be monitoring (in slowly progressing asymtpomatic) or involve immunosuppressants. Prednisone is the mainstay with slow tapers over months +/- sparing agents like azathiaprine, methotrexate or mycophenylate. Rituximab use has also been reported. 

Given the patients medications, infection was considered as the underlying cause, specifically CMV pneumonitis. CMV infection most commonly occurs in the GI tract and lungs, when clinically significant. There are multiple ways to test for infection, including serology, cultures, antigen detection and molecular amplification. There are no consensus guidelines for the diagnosis CMV pneumonitis. PCR testing is quite sensitive, but there are no cut-off levels for diagnosing pneumonitis, where low levels are not interpretable. High levels in the appropriate clincal context chould prompt consideration of gancylovir treatment. CMV is often detected in patients with autoimmune disease without clinical symptoms on BAL (~20% -CHEST 2001). In patients with pneumonitis (dyspnea, hypoxia, infiltrates) immunostaining for CMV in BAL samples has a high sensitivity and specificity and is useful test in confirming disease. This is a challenging scenario and may require further discussion with both ID and respiratory medicine specialists. See below for additional information. 

Diagnosing CMV in BAL

IgG4 Review