We're celebrating
40 years!
Last updated:
August 20, 2021
Years published: 2007, 2012, 2015, 2018, 2021
NORD gratefully acknowledges Robert J. Lentz, MD and James Loyd, MD, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, for assistance in the preparation of this report.
Fibrosing mediastinitis (FM) is a rare disease characterized by dense invasive fibrotic infiltration of the mediastinum (middle portion of the chest, situated between the lungs) and/or hilar regions (areas between the upper and lower lobes of each lung) of the chest causing narrowing or occlusion of important chest structures, including pulmonary arteries, pulmonary veins, the superior vena cava, airways/bronchi, or the esophagus. Because of the vital nature of these structures, this slowly progressive disease is associated with significant morbidity and can be fatal if it affects both lungs.
There are two recognized subtypes of FM: 1) post-Histoplasma fibrosing mediastinitis (PHFM) and 2) idiopathic FM. The former is thought to represent an aberrantly prolonged and robust immune reaction to a remote infection with the soil-based fungus Histoplasma capsulatum, perhaps related to ongoing reaction to residual fungal antigens found within lymph nodes regions of the central chest. The latter is even rarer and is associated with IgG4-related disease, ANCA vasculitis, and rare histiocytic disorders.
Both subtypes of FM are rare. Symptoms typically do not develop until the disease has progressed to the point of causing severe compromise of blood flow within an affected vessel or air flow within an affected central airway. The build-up of scar tissue usually occurs very slowly (1 mm/year), though more rapid growth has been observed occasionally. Symptoms may appear suddenly, even though the process has progressed slowly for years, once a critical limitation of blood/air flow occurs. The growth of mediastinal scar tissue itself causes no symptoms.
Histoplasmosis is caused by the most common endemic parasitic fungus in the United States, Histoplasma capsulatum. It resides in soil and thrives when specific conditions with respect to acidity, temperature, nitrogen content, and humidity are present, resulting in large geographic areas of endemicity, most notably along the Mississippi and Ohio River valleys. It also occasionally causes disease in Central and South America. Histoplasma species are also found in Europe, Asia, Africa, and Australia, though histoplasmosis is less prevalent in these regions. It also flourishes in soil fertilized by bird droppings and is found in bat guano; chicken houses and caves or bridge underpasses contaminated with guano are notorious sources of H. capsulatum infection. In urban settings, most exposure is probably related to soil disruption leading to fungal spores becoming airborne. The inhaled fungus typically causes a limited, asymptomatic infection. A minority will experience nonspecific upper respiratory or flu-like symptoms, with progressive pneumonia requiring antifungal treatment being uncommon. Disseminated / systemic infection is rare and most often observed in those who are severely immunocompromised. In endemic areas in the United States, nearly all persons are exposed/infected in childhood.
It is not known why some individuals develop an excessively exuberant immune response to the organism, leading to the excessive scarring and obstruction of vessels or airways that characterizes FM. Fungal yeast forms have been observed to persist within mediastinal lymph nodes; these specimens almost never grow in culture, indicating they most likely represent long-dead fungus, but the continued presence of fungal antigens within or around these fungal forms may stimulate an ongoing immune response in some individuals. Calcification of formerly infected lymph nodes is typical but may require years to develop. Calcifications are also frequently observed within the abnormal mediastinal tissue of PHFM.
Typically, people with PHFM were originally exposed/infected with H. capsulatum as children but the symptoms begin in most patients in the third or fourth decade of life. No evidence suggests an association with specific ancestry or gender. Patients may present with shortness of breath (dyspnea), fatigue or loss of stamina, cough with blood (hemoptysis) or without, chronic chest (pleuritic) pain, recurrent pulmonary infections or pneumonias, difficulty swallowing (dysphagia), or swelling of the arms and face. These symptoms most commonly occur because there is an occlusion or critical narrowing of one of the main vessels in the chest, such as the superior vena cava (the vein which returns blood from the head, neck, and arms the heart), pulmonary arteries, and/or pulmonary veins. Superior vena cava (SVC) syndrome, characterized by face and arm swelling due to obstruction of the vena cava, is a common symptom. Some patients do not develop this syndrome despite having obstruction of the SVC because collateral alternative veins (sometimes visible on the anterior chest) enlarge sufficiently to bypass the SVC as it becomes slowly obstructed and successfully return blood to the heart. Cough and shortness of breath are the most common symptoms when obstruction of a central airway occurs. Pulmonary venous obstruction usually presents with shortness of breath, coughing blood, or sometimes collection of fluid in the space between the lung and the chest wall (pleural effusion). Symptoms can be present for years before diagnosis.
Patients with idiopathic FM may present symptoms of fever, chills, sweats, shortness of breath, cough, or chest pain. They may also have fibrosis or inflammation elsewhere in the body which may cause symptoms at those other sites.
In the majority of patients, FM is triggered by the body’s abnormal excessive immune reaction to prior exposure to Histoplasma capsulatum, a fungus found in soil in endemic areas, most notably along the Mississippi and Ohio River valleys in the United States. The fungus resides in the soil, becomes airborne when the soil is disturbed, and is subsequently inhaled. Histoplasma is also associated with bird and bat droppings, the former of which do not appear to become infected by the fungus but may carry the fungus on their feathers, while the GI tracts of the latter may become colonized with the fungus.
Idiopathic FM is not related to histoplasmosis. It has been reported in the setting of autoimmune disease, Behcet disease, ANCA-associated vasculitides including granulomatosis with polyangitis, IgG4-related disease, rheumatic fever, prior radiation therapy, severe viral infections of coxsackie B, or trauma. It can occur in association with other idiopathic fibroinflammatory disorders at sites outside the chest, including retroperitoneal fibrosis, sclerosing cholangitis, Riedel thyroiditis, pseudotumor of the orbit, and others (many of which are now recognized as other manifestations of systemic IgG4-related disease).
Of the entire population who are exposed to Histoplasma, only a tiny fraction (far fewer than 1%) develop the excessive response to the fungal infection that is the basis of PHFM. Of the many millions of people with repeated exposures to Histoplasma while living in endemic areas, the vast majority never develop symptomatic histoplasmosis, and far fewer go on to develop PHFM. It is estimated that there are only a few hundred cases of PHFM in the United States. At Vanderbilt University Medical Center, a referral center for this condition in an endemic area, approximately 10 new cases have been evaluated annually over the last few decades. PHFM is seen only in individuals who lived in an endemic region sometime during their life. Idiopathic FM is believed to be even rarer, with an estimated several dozen cases known in the United States.
Diagnosing either form of FM is best accomplished by chest CT, a scan that shows the abnormal tissue in the mediastinum. The characteristic appearance of a mediastinal abnormality on chest CT scan in a person who has lived in a region with endemic histoplasmosis can definitively diagnose PHFM in many cases, especially when assessed by a pulmonologist or radiologist with expertise in this disease.
A chest CT scan enhanced with intravenous contrast is often necessary to highlight any vascular narrowing which may be present. Non-enhanced chest CT scans are also useful for definitively identifying calcifications within the abnormal mediastinal tissue, which are characteristic of PHFM. A perfusion nuclear medicine scan might also be performed to quantify the degree of reduction in blood flow to parts of the lung by vascular narrowing. Magnetic resonance angiography (MRA) of the heart or cardiac MRI (cMRI) can be helpful in special circumstances, especially to better evaluate the pulmonary veins where they enter the left atrium, which are commonly affected by FM.
The chest CT scan might also demonstrate one or more nodules within lung tissue, which may also have internal calcifications. These lung nodules often represent the initial focus of inhaled Histoplasma infection within the lungs. Calcifications within the spleen (an immune organ which also helps respond to Histoplasma infection) or, less commonly, the liver, are often also seen. There may be signs of infarction of the lung in patients with complete obstruction of blood flow into or out of a region of the lung, including thickening of septal membranes within the lung or scattered opacities.
In situations where definitive diagnosis is not possible based on the CT scan alone, which most commonly occurs when characteristic internal calcifications within the mediastinal abnormality are absent, Histoplasma serologies are often helpful. This test detects antibodies responding to Histoplasma, and is positive in most but not all cases of PHFM. Ideally, an assay which detects Histoplasma antibodies by both complement fixation and immunodiffusion should be used. Histoplasma antigen testing, which detects proteins shed by living Histoplasma organisms, is invariably negative in FM. Lack of calcifications within a lesion otherwise meeting radiographic criteria for FM often also prompts serological evaluation for conditions known to be associated with idiopathic FM, including IgG4-related disease and granulomatosis with polyangiitis.
Occasionally, biopsy of abnormal mediastinal tissue is required to exclude malignancy such as a lymphoma, especially if the CT scan shows that the abnormal tissue lacks internal calcifications characteristic of a post-Histoplasma syndrome. This can be accomplished via bronchoscopy using linear endobronchial ultrasound guidance to obtain transbronchial needle aspiration samples of the lesion, via CT-guided transthoracic needle biopsy, or surgical biopsy via thoracotomy or mediastinoscopy. Of note, bronchoscopic biopsy should be approached with caution if the lesion is most likely a mediastinal granuloma based on radiographic appearance, as transbronchial sampling of these lesions via the non-sterile airways can contaminate them with bacteria and lead to an infection requiring surgical intervention. Given this, and the fact that the primary alternative diagnosis in many such cases is lymphoma, which tends to require a large surgical biopsy specimen for definitive characterization, surgical biopsy is often preferred to distinguish between mediastinal granuloma and lymphoma. Intra-operative recognition of an encapsulated mediastinal granuloma also permits marsupialization of the lesion via resection of the free wall of the MG capsule during the same procedure, which is the therapeutic operation of choice for this condition.
Diagnosis may be delayed for years because symptoms are not specific or characteristic findings are not recognized on scans. Erroneous initial diagnoses include asthma, pneumonia, chronic obstructive lung disease, pulmonary embolism with lung infarction, and, in cases involving compromise of the pulmonary veins, mitral stenosis with congestive heart failure. The current widespread use of CT of the chest has greatly improved detection and diagnosis of FM.
Treatment
There is no standard therapy for either form of FM. The natural history of idiopathic FM is not known, but there are reports of individual patients who improve after treatment with drugs directed at the underlying etiology. There are also some cases of spontaneous improvement in idiopathic FM, which has not been seen in PHFM. Reports of individual patients with idiopathic FM due to various underlying diseases describe use of the following drugs: prednisone, tamoxifen, non-steroid anti-inflammatory medication such as indomethacin, and immunosuppressants such as azathioprine or cyclosporin. Data is not available about the effectiveness of these treatments, and most reports are individual cases, so it is not possible to be sure whether a favorable response was actually caused by the treatment.
There are no known effective medical therapies for PHFM. Antifungal therapies and corticosteroids have not demonstrated benefit. A single small study involving three patients with FM exhibiting metabolic overactivity within the abnormal fibrotic tissue (as evidenced by intense uptake of fluorodeoxyglucose on positron emission tomography scan) demonstrated decrease in the metabolic activity and some decrease in the size of the mediastinal abnormalities after treatment with rituximab. This work has not been duplicated in a larger study or studied in a clinical trial, so it remains unclear if rituximab represents an effective treatment.
Medical treatments can help address some of the symptoms and complications caused by fibrosing mediastinitis. When fluid retention occurs related to vascular obstructions, patients are treated with diuretic therapy. Antibiotics can be used to treat complications such as pneumonia. Regular exercise is beneficial for heart and muscle function, and is encouraged for all patients as tolerated.
Given the lack of effective medical therapies for PHFM, a mechanical approach has been used to address narrowings caused by FM. When vessels carrying blood to or from the lungs are blocked, pulmonary arterial and/or pulmonary venous catheterization with stenting of the affected vessel(s) to prop them open can be done to restore more normal blood flow. Stenting can also be used to address narrowing of the superior vena cava if it is causing symptoms of SVC syndrome (including arm or neck swelling, headaches). These vascular stenting procedures are typically performed by interventional radiologists or interventional cardiologists. When airways are narrowed by scar tissue, airway stents can be placed via bronchoscopy to hold these airways open. This is generally used as a last resort, as these stents may also promote airway inflammation by foreign body reaction / friction with airway mucosa, which sometimes leads to worsened inflammatory airway narrowing.
If the scar tissue of FM is localized, surgical resection has been used rarely, but is high risk and appropriate for very few patients. This is not a preferred method of treatment and should only be used in the most extreme cases due to a high level of morbidity and mortality associated with surgery in this condition. Surgical intervention should only be considered at specialized centers with extensive experience in managing FM.
Finally, patients with FM can cough up blood (hemoptysis). This may happen via several mechanisms, including an increase in blood pressure in the pulmonary circulation due to pulmonary venous obstruction or narrowing (“pseudo-mitral stenosis”), or the creation of more fragile arterial collateral vessels to bypass obstructed pulmonary arteries which can rupture in the airways. The latter, which generally results in a larger degree of bleeding and is occasionally life-threatening, can be addressed via angiography to identify the aberrant vessel(s) which can then be selectively embolized. The former is generally self-limited but recurrent episodes can be a significant nuisance and lead to repeated hospitalizations. Inhaled tranexamic acid can be used to shorten these episodes.
Prognosis
The prognosis of FM depends on the subtype (post-Histoplasma vs. idiopathic) and the extent of involvement of mediastinal structures. Idiopathic FM has not been well studied related to its extreme rarity, but existing data suggests it is rarely life threatening. PHFM affects one lung in approximately 80% of affected individuals and both lungs in the remaining 20%. Progressive unilateral disease often leads to the loss of function of that lung, sometimes referred to as “autoamputation.” With a remaining healthy lung, life expectancy tends to be normal. Chest pain from vascular narrowing, intermittent coughing up of blood, fluid collecting outside of the affected lung (pleural effusion) and intermittent pneumonias may continue to affect some with unilateral disease.
The early mortality rate when fibrosing mediastinitis affects both lungs is substantial. Recognition of bilateral disease should lead to careful consideration of vascular stenting when vascular narrowing(s) are present. This is associated with symptomatic improvement in most patients and may improve survival in those with both lungs affected. Vascular stenting may also be considered in unilateral disease associated with refractory chest discomfort or pleural effusion.
Prior work has suggested accumulation of B lymphocytes in FM tissue, leading to the hypothesis that pharmacologic B lymphocyte depletion could impact the natural history of the disease. A three-patient pilot study, mentioned above, described some response in positron emission tomography scans after treatment with rituximab, a monoclonal antibody treatment that decreases B lymphocytes. To date, however, a clinical trial to further investigate this treatment has not been developed.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Consultation
Robert J. Lentz, MD, Assistant Professor of Medicine and Thoracic Surgery, Division of Allergy, Pulmonary & Critical Care at Vanderbilt University Medical Center in Nashville, Tennessee, has volunteered to provide consultation for patients with fibrosing mediastinitis or mediastinal granuloma. One of the goals is to understand the stimulus that drives post histoplasmosis fibrosing mediastinitis and mediastinal granuloma.
For more information, contact:
Robert J. Lentz, MD
Assistant Professor of Medicine and Thoracic Surgery
Division of Allergy, Pulmonary & Critical Care
Vanderbilt University Medical Center
T-1218 Medical Center North
1161 21st Ave. S.
Nashville, TN 37232-2650
Email: robert.j.lentz@vumc.org
and/or
Justin C. Hewlett, MD
Assistant Professor of Medicine
Division of Allergy, Pulmonary & Critical Care
Vanderbilt University Medical Center
T-1218 Medical Center North
1161 21st Ave. S.
Nashville, TN 37232-2650
Email: justin.c.hewlett@vumc.org
TEXTBOOKS
Lentz RJ, Loyd J. Chapter 116: Mediastinitis and Fibrosing Mediastinitis. Murray & Nadel’s Textbook of Respiratory Medicine, 7e. Elsevier; 2021. P. 1605-1617.
Carol A. Kauffman CA. Clinical Mycology. In: Histoplasmosis. New York, NY: Oxford University Press, Inc.; 2003:285-298.
JOURNAL ARTICLES
Azar MM, Loyd JL, Relich RF, Wheat LJ, Hage CA. Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes. Semin Respir Crit Care Med 2020;41(1):13–30.
Weingarten AJ, Loyd JE, Doyle TP. Letter to Editor [Stenting is effective for FM]. Int J Cardiol Heart Vasc 2016;13:1–2.
Int J Cardiol Heart Vasc. 2016 Aug 25;13:1-2. doi: 10.1016/j.ijcha.2016.07.010. eCollection 2016 Dec. PMID: 28616551
Hage CA, Azar MM, Bahr N, Loyd J, Wheat LJ. Histoplasmosis: Up-to-Date Evidence-Based Approach to Diagnosis and Management. Semin Respir Crit Care Med. 2015 Oct;36(5):729-45. doi: 10.1055/s-0035-1562899. Epub 2015 Sep 23. Review.PMID:26398539. FM is on pg 740.
Ponamgi SP, DeSimone CV, Lenz CJ, Coylewright M, Asirvatham SJ, Holmes DR, Packer DL. Catheter-based intervention for pulmonary vein stenosis due to fibrosing mediastinitis: The Mayo Clinic experience. Int J Cardiol Heart Vasc. 2015 Sep 1;8:103-107. doi: 10.1016/j.ijcha.2015.06.005. Epub 2015 Jun 18.v
Westerly BD, Johnson GB, Maldonado F, Utz JP, Specks U, Peikert T. Targeting B lymphocytes in progressive fibrosing mediastinitis. Am J Respir Crit Care Med. 2014 Nov 1;190(9):1069-71.
Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539-51.
Albers EL, Pugh ME, Hill KD, Wang L, Loyd JE, Doyle TP. Percutaneous vascular stent implantation as treatment for central vascular obstruction due to fibrosing mediastinitis. Circulation. 2011;123(13):1391-9.
Peikert T, Colby TV, Midthun DE, Pairolero PC, Edell ES, Schroeder DR, Specks U. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and adaptive immune response. Medicine (Baltimore). 2011; 90(6):412-23.
Merkel PA, McCarty D, Sharma A, Stone JR. Case records of the Massachusetts General Hospital. Case 31-2008. A 39-year-old man with chest pain, arthralgias, and a mediastinal mass. N Engl J Med. 2008;359(15):1603-14.
Worrell JA, Donnelly EF, Martin JB, Bastarache JA, Loyd JE. Computed tomography and the idiopathic form of proliferative fibrosing mediastinitis. J Thorac Imaging. 2007 Aug;22(3):235-40. PMID: 17721332
Luby JP, Southern PM, Haley CE, Vahie KL, Munford RS, Haley RW. Clinical Infectious Diseases. 2005;41:170-176.
Rossi SE, McAdams HP, Rosado-de-Christenson ML, Franks TJ, Galvin JR. Fibrosing Mediastinitis. Radiographics. 2001;21:737-757.
Davis AM, Pierson RN, Loyd JE. Mediastinal Fibrosis. Seminars in Respiratory Infections. 2001;16:119-130.
Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal Fibrosis Complicating Histoplasmosis. Medicine. 1988;67:295-309.
Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in Normal Hosts. Medicine. 1981;60:231-266.
INTERNET
Loyd J, Enix L, McIntosh C. Idiopathic Fibrosis Mediastinitis. Questions and Answers. https://www.fibrosing-mediastinitis.com/fmfaq.html Accessed August 18, 2021.
Weinberger SE, Hewlett JC. Mediastinal granuloma and fibrosing mediastinitis. UpToDate. updated Feb 18, 2021. https://www.uptodate.com/contents/mediastinal-granuloma-and-fibrosing-mediastinitis Accessed August 18, 2021.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/