What is fibrosing mediastinitis?

Fibrosing mediastinitis (FM), also known as mediastinal fibrosis or sclerosing mediastinitis, is a rare and progressive condition. It causes an invasive growth of fibrous tissue within the mediastinum, the space in the chest that holds the heart and other important structures in place. Fibrosing mediastinitis is mainly caused by tuberculosis and histoplasmosis but can also be caused by a reaction to drugs and radiation. 

Other rare causes of FM include exposure to aspergillosis, Wuchereria bancrofti, blastomuces dermatitidis and radiation therapy. FM causes the compression of vital mediastinal structures like the heart, great vessels, trachea and essential nerves. Ultimately, FM can become fatal if it causes cor pulmonale (an enlarged right ventricle in the heart) or respiratory compromise (deterioration in respiratory function with a high likelihood of a quick progress to respiratory failure and death).¹ There have also been cases of postobstructive necrotising pneumonia( an infection of the lung parenchyma ) near where the bronchi⁸ have been obstructed and the development of tracheoesophageal fistula (an abnormal connection between the oesophagus and the trachea).⁷

What causes fibrosing mediastinitis?

A hypersensitivity response to histoplasmosis² can cause fibrosing mediastinitis. This is where the immune response is either inappropriate or over reactive to an antigen which goes on to cause undesirable effects. There are 4 kinds of hypersensitivity reaction:

• Type I - IgE mediated immediate reaction
• Type II- Antibody- mediated cytotoxic reaction
• Type III- Immune complex mediated reaction
• Type IV- Cell mediated, delayed hypersensitivity reaction 

Histoplasmosis causes type IV.

The basics of the immune system

The immune system is the body's line of defense against disease. There are many components that make up this system which serve to prevent and subdue invasion by foreign substances. In adults, immune cells are produced by the bone marrow. One type of immune cell is a white blood cell; there are various kinds:

• Neutrophils are early responders to foreign substances and undertake a process called phagocytosis. During phagocytosis a foreign substance is engulfed by the neutrophil and subsequently destroyed, killing foreign substances.
• Lymphocytes are a part of the adaptive immune system which is a more specialised system that will specifically target the substances that are causing an infection. There are two kinds, T cells and B cells
• Monocytes are also early responders that can undertake phagocytosis. They also have the ability to present the antigen of a foreign substance to the immune system in order to stimulate a response. In the tissue these cells mature into macrophages.
• Basophils and eosinophils are granulocytes that bind to antibodies in a defense against parasites. They are also involved in the allergy response.

The inappropriate immune response in fibrosing mediastinitis 

Histoplasmosis causes a type IV hyperactivity reaction. This causes a delayed hypersensitivity reaction which occurs within 24 hours of contact with the fungus that causes histoplasmosis, Histoplasma capsulatum as well as certain types of drugs. This reaction is caused by T cells that will provoke an inflammatory reaction against antigens on self cells (cells with markers that the body recognises as belonging to the body) as well as antigens on cells belonging to Histoplasma capsulatum.  Monocytes, eosinophils and neutrophils may also be involved. 

Once the body is exposed to these antigens there is a local immune and inflammatory response which will attract leukocytes to the site. The antigens will be engulfed by macrophages and monocytes and then presented to t cells. T cells  are unable to destroy the engulfed antigens and as a result the antigen-presenting cells will become massive multinucleated cells, a cell with more than one nucleus. In order for this to happen a lot of cytokines like interleukin 2 and tumour necrosis factor alpha and beta are released as well as chemokines-a type of cytokine that controls cell migration and positioning.⁴ This causes tissue damage that leads to fibrosing mediastinitis. 

Drug induced hypersensitivity happens when a particular drug particle binds to a T cell receptor regardless of if it has been metabolised by an antigen presenting cell  or presented by major histocompatibility complex molecules( groups of genes that code for proteins found on the surface of cells that help the immune system to recognise foreign substances).⁵

The hypersensitivity that causes granulomas occurs when macrophages that have engulfed antigens can't destroy them and so recruit many macrophages to the site of the antigen. This collection of macrophages that contain intracellular antigens is called a granuloma.³

Involvement of lymph nodes

Dissemination of the fungal antigens, Histoplasma capsulatum, in the pulmonary reticulo endothelial system causes the lymph nodes to enlarge. Lymph nodes are small organs located at the convergence of major blood vessels throughout the body that filter substances in the lymph fluid that comes from the blood.⁹ This helps the immune system to fight infections and diseases. The lymph nodes then grow together into one inflamed mass with a central region where the tissue has died. This eventually leads to a hardening of tissue in the mediastinal structures.

What effect does FM caused by prior tuberculosis infection have?

FM caused by tuberculosis will cause superior vena cava syndrome( a condition that affects the flow of blood from the upper body to the heart), bronchial obstruction( damaged and widened airways), pulmonary artery compression as well as impingement of the transverse sinus and its adjacent vascular structures. 

What three changes occur after the onset of the disease ?

• Initially, there is oedematous fibromyxoid tissue ( swelling and a soft tissue tumour) and lots of eosinophils, mast cells, lymphocytes and plasma cells surround the area in an attempt of the immune system to heal the wound. 
• This progresses to thick bands of haphazardly arranged collagen (the protein that provides structure and support to skin, muscles, bone and connective tissue) being laid down. 
• This progresses to dense irregularly shaped collagen and occasional calcification (hardened clumps of calcium) in the tissue.

What effect does this have on the body?

The most common structure that is affected is the superior vena cava (the vein responsible for returning blood without oxygen from the body into the lungs). Initially the body will compensate for this by producing more veins which allows a patient to be asymptomatic initially. As the disease progresses the patient will experience shortness of breath, venous distention of the neck and upper chest region, swelling in their face and features of cor pulmonale.

Summary 

Fibrosing mediastinitis is a rare condition that causes a build up of fibrotic tissue to develop in the chest. This is caused by an incorrect autoimmune response to an infection like tuberculosis which causes the body to attack itself which leads to tissue damage that leads to fibrotic scar tissue forming.

FAQs

What is the survival rate of fibrosing mediastinitis?

The survival rate is dependent on the cause of fibrosing mediastinitis, the severity of the symptoms it causes and the way that it is treated. Patients that receive steroids have survival rates of 88% up to one year, 73% up to 3 years and 56% up to 5 years.¹⁰ 

How do you know if you have mediastinitis?

The most common symptoms are a history of upper respiratory tract infection, recent dental infection, thoracic surgery, fever, chills, chest pain radiating to the neck or interscapular pain.¹¹ However these symptoms will typically be undetectable until the disease has progressed to a stage where there is a severe compromise of blood flow within an affected vessel or air flow within an affected central airway.¹⁴

How do you treat fibrosing mediastinitis?

There are different options for treatment including steroids, methotrexate ( a drug that can suppress the immune system), rituximab ( an antibody that can reduce levels of abnormal B cells in the body). Since fungal antigens are believed to play a role in the development of the condition, treatment with antifungals can also be used as part of medical treatment.¹² Stents can also be used to get rid of central airway vascular obstruction. Surgery can also be used to improve symptoms by relieving the airway, vascular, and esophageal obstruction. There are cases of hemoptysis (bleeding in the lungs) caused by histoplasmosis related mediastinal fibrosis resulting in superior vena cava syndrome that have been treated by bronchial artery embolisation( a procedure that is used to stop bleeding in the lungs by blocking the bronchial artery) and transcatheter percutaneous stent placement. When fluid retention occurs as a result of vascular obstruction, patients are treated with diuretic therapy. Antibiotics can be used to treat complications like pneumonia.¹³ 

How quickly does mediastinitis progress?

The buildup of scar tissue typically occurs very slowly, about 1mm/ year although growth can happen more rapidly occasionally.¹⁴

What are the different types of fibrosing mediastinitis? 

There are two recognised subtypes of fibrosing mediastinitis: post histoplasma fibrosing mediastinitis and idiopathic fibrosing mediastinitis meaning it is of an unknown cause.¹⁴

What part of the body does histoplasmosis affect?

Histoplasmosis is a fungal infection that affects the lungs but may also on occasion invade other parts of the body.¹⁵