What is granulomatous inflammation? Complete Guide

Granulomatous inflammation is a type of inflammatory reaction, usually in response to foreign material. This inflammation causes many granulomas, which are collections of immune cells and other tissue that form around the offending materials.

The cause of granulomatous inflammation can be infectious or non-infectious. The most common infectious causes include tuberculosis and fungal infections such as histoplasmosis and coccidioidomycosis. Granulomatous inflammation can also result from hypersensitivity to drugs such as antibiotics (penicillins, cephalosporins, sulfonamides) and organic solvents. There are several non-infectious causes including sarcoidosis and beryllium disease.


Granulomatous inflammation
Granulomatous inflammation


Who gets granulomatous inflammation?

Granulomatous inflammation can occur in both children and adults, but sarcoidosis is most common in women between the ages of 20 and 40 years while tuberculosis typically occurs in teenagers and young adults. Most cases of hypersensitivity to drugs arise in patients with a history of drug use or who are taking medications regularly on a long-term basis (such as those with severe asthma). Workers who inhale organic solvent vapors, such as painters and dry cleaners, are also at risk for developing this type of inflammation.


Causes

Infectious causes: Tuberculosis, Histoplasmosis, Cryptococcosis, Paracoccidioidomycosis, Blastomycosis

Non-infectious causes: Sarcoidosis (a chronic granulomatous disorder that affects multiple organs), Beryllium disease (similar to sarcoidosis with cough and shortness of breath)


Symptoms

Symptoms depend on the specific condition causing inflammation. Tuberculosis typically manifests with chronic weight loss, night sweats, fever, and chest pain. Symptoms tend to be more severe in patients whose immune systems are compromised by other infections. Histoplasmosis is most common among patients who work with bird or bat droppings; it may cause pneumonia or other respiratory problems.

Symptoms of sarcoidosis tend to appear over a period of weeks to years; there may be fever, fatigue, night sweats, and weight loss, as well as lung and lymph node problems. Beryllium disease is similar but typically affects the lungs rather than the lymph nodes. 

Cryptococcosis (caused by cryptococcus neoformans) presents with a variety of symptoms depending on which organ systems are most affected. Allergic reactions to drugs often cause an itchy rash or hives, shortness of breath, and swelling due to angioedema. Histoplasmosis, paracoccidioidomycosis, cryptococcosis, and blastomycosis can also cause pulmonary problems.


Diagnosis

The diagnosis of granulomatous inflammation is based on results of physical examination, imaging studies (X-ray, CT scan), pathological findings, and possibly microbiological evidence (PCR test for tuberculosis). The most common histopathologic finding is non-necrotizing granulomas. Other tests used to confirm the diagnosis include immunohistochemical staining for mycobacteria or fungi, antigen testing (such as cryptococcal antigen), and direct fluorescent antibody testing.



Treatment

Treatment depends on the cause of the inflammatory reaction, but usually includes anti-inflammatory medications such as prednisone and/or antimycotic drugs like itraconazole or fluconazole. Surgery may also be used to remove the source of irritation and drain abscesses.

Pulmonary problems associated with sarcoidosis can typically be treated using corticosteroids such as prednisone, which reduce swelling and inflammation in various parts of the body. Other medications include amcinonide, hydroxychloroquine sulfate, sodium thiosulfate, and anti-malarial medications such as chloroquine phosphate and hydroxychloroquine sulfate. Immunosuppressive drugs like methotrexate may also be effective for managing symptoms in some cases. Treating tuberculosis involves a lengthy course of multiple antibiotics in most cases, but is particularly difficult for patients who have an impaired immune system such as those with HIV.


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What does granulomatous mean?

The definition of granulomatous means: a tissue reaction characterized by the formation of granulomas. Granulomas are small lumps or bumps that develop in response to an immune system reaction caused by foreign substances such as infections and some drugs. They're also seen with certain diseases such as tuberculosis and sarcoidosis.

 They're made up of immune cells, such as macrophages and other lymphocytes.


Granuloma
Granuloma


What types of granulomas exist?

The most typical granulomas are the tuberculous granuloma and the sarcoid granuloma. In a healthy person, these don't cause any symptoms. However, when a person becomes infected with a disease agent that causes a certain type of reaction, these may become activated to produce symptoms. This is referred to as an "exuberant reaction." The main example is tuberculosis infections. With this, there can be many small nodules distributed throughout the organ involved (most often the lungs). These do not usually cause symptoms until they get larger or until enough accumulate to compress or invade nearby tissues.

 The main types of disease agents that cause granulomatous reactions are bacteria, fungi, parasites, and foreign substances. These include:


  • Helminthic infections (roundworms), especially visceral larva migrans 



  • Leprosy 


  • Cat scratch disease 


  • Typhoid fever 


  • Tuberculosis 


  • Rat-bite fever 


  • Granuloma inguinale (donovanosis) 


  • Melioidosis (Burkholderia pseudomallei infection) 


  • Syphilis and Lyme disease (Borrelia spirochetes) also cause a similar reaction.


This list is by no means complete; there are many other infections that can result in granulomatous reactions. Also, not all parasites cause them; some actually resolve without treatment.


How do these granulomas form?

This is a very complex process and is still incompletely understood at this time. These cells have a branch of the immune system called the "innate" armor system that reacts very quickly to harmful stimuli such as microbes or foreign substances by producing different substances, including cytokines and chemokines, which attract further immune cells to start fighting off the infection. It also produces free radicals and nitric oxide from activated macrophages that help kill the infectious agent. When the disease-causing mechanism is resolved, these cells become apoptotic (commit cellular suicide) and disappear. However, sometimes this process can get out of hand and produce a granuloma that won't go away. This is referred to as an "exuberant granulomatous reaction".


 This usually occurs when the infectious agent isn't completely destroyed or eliminated from the body, it comes back again at a later time (relapse), or there are multiple infections going on at the same time. There may also be some genetic factors involved where people have defects in their innate immune system leading to more of a chronic inflammatory response instead of an acute one. In any case, whatever causes this overactivation of the immune system will result in the production of more cytokines and other substances that proliferate and maturate these cells. In this case, because it is a chronic disease process, the granulomas will be larger and more likely to cause symptoms.


 It's also been suggested that exuberant granulomatous reactions can play a role in other diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, and some cancers. However, this may not always occur with these diseases, thus further research needs to be done on this possible connection before this idea becomes accepted by the medical community.


 There may also be some environmental factors that influence whether or not a certain infectious agent or foreign substance will actually result in the production of granulomas because this reaction cannot happen without the proper stimuli from the innate immune system. As with many other things, the body's immune system is "tuned" to react one way or another depending on how it has evolved to deal with specific problems. Therefore, geographic location may affect the process of granulomatous reactions.


 This seems to be true because African Americans living in the United States are more likely to develop certain infections than Caucasians without having an obvious explanation for this discrepancy. There also seems to be a higher risk of developing exuberant granulomas for people who live in Washington State than people living in Alabama. For instance, tuberculosis infection rates are about 20 times higher in African Americans than Caucasian Americans.


 The first step towards understanding all of these factors should include determining if there really is any connection between granulomas and other conditions such as COPD, rheumatoid arthritis, or cancer so more research is needed. However, if this becomes accepted then tuberculosis should be added to the list of diseases that can cause granulomatous reactions along with "Mycobacterium leprae", "Histoplasma capsulatum", and also parasites like "Strongyloides stercoralis" which can all result in chronic inflammatory responses. Also, making sure patients get proper treatment for these infections will reduce the risk of exuberant granulomatous reactions occurring.


What are the outcomes of granulomatous inflammation?

Pathogenesis of granuloma is thought to be largely dependent on the host responses. The most important effector cells are macrophages, neutrophils, and eosinophils with lymphocytes playing a secondary role. The formation of granuloma is associated with fibrosis which impairs tissue functions structure can lead to loss of organ function.

Bacteria, fungi, parasites, and viruses cause granulomatous inflammation. The granuloma may or may not be associated with tissue destruction or other clinical features of the infecting organism e.g., tuberculosis, histoplasmosis, etc.

The pathogenetic mechanisms are still unclear. The following effects have been described:


Macrophages that phagocytose pathogens release enzymes like reactive oxygen species (ROS), proteases, lipases, collagenase, and elastase to kill the pathogen but also damage host cells by lipid peroxidation, protein oxidation, and by degrading connective tissue elements like collagen and elastin. 


The damage of the surrounding tissue by ROS and proteases is not directly proportional to the pathogen load in granulomas. Eosinophils also contribute to this damaging process. Moreover, they release their cytotoxic granule components in order to kill bacteria or fungi even in non-threatened tissues which may lead to significant tissue damage. 

Eosinophilic involvement in chronic inflammation has been found in various gastrointestinal disorders including eosinophilic esophagitis (damage of esophagus) and colonic eosinophilia (inflammation of the colon). Furthermore, eosinophils are thought to perpetuate inflammatory responses by feeding on extracellular proteins like collagen, thus inhibiting the reparative fibrosis of granulomas.

Neutrophils normally kill bacteria by phagocytosis and release bactericidal substances like lysozymes, lactoferrin, and neutrophil elastase. In the case of Mycobacterium tuberculosis-infected macrophages, neutrophils may also induce tissue damage in a process known as NETosis (neutrophil extracellular traps). Activated neutrophils damage surrounding cells by releasing granule contents upon degranulation or by recognized innate immune receptors on their surface such as formyl peptides receptors (FPR) and CXCR4 which trigger the formation of NETs around pathogens including mycobacteria. 

The role of NETs in granulomatous inflammation has been well-documented in histoplasmosis. In tuberculosis, the role of neutrophils is controversial. In the early stages of infection, they appear to support bacterial killing whereas in chronic disease their cytotoxic potential might be harmful to host cells by inducing granuloma necrosis and tissue damage.


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