Author: Tanner Marshall, MS
Editor: Rishi Desai, MD, MPH, Tanner Marshall, MS “Rheumatism” is used to describe inflammation in the joints, muscles, and the fibrous tissue, so rheumatic fever is a type of inflammatory disease that can damage the heart tissue, and lead to rheumatic heart disease.
Rheumatic fever develops after streptococcal pharyngitis, inflammation of the throat due to Streptococcus pyogenes where pyogenes literally means “makes pus”. The bacteria is sometimes referred to as “Group A beta hemolytic” streptococcus, and the infection itself is most often just called Strep throat. This particular group of streptococcus has an antigen that lumps it into a group called “group A”, and it also produces an enzyme called streptolysin, that completely lyses nearby red blood cells, or causes them rupture—rupturing red blood cells is called hemolysis, right? And when those red blood cells rupture and are destroyed, it’s called beta-hemolysis—as opposed to alpha-hemolysis, where cells aren’t actually destroyed, they’re just damaged or bruised.
Some of these strep bacteria have a protein on their cell wall called “M protein”, and this particular protein is highly antigenic, meaning that the immune system sees it and recognizes it as a foreign molecule, and mounts an immune response, which rightfully so, produces antibodies against these proteins. Those antibodies, though, are thought to cross-react with proteins on some of our body’s own cells, like cells in the myocardium (or heart muscle) and heart valves, but also cells in the joints, the skin and the brain.
This phenomenon, where antibodies accidentally target proteins on our own cells because they look like the proteins on foreign cells, is called molecular mimicry, and is an example of what’s called a type 2 hypersensitivity reaction. Once bound to cardiac tissue, the antibodies activate nearby immune cells, which causes a cytokine-mediated inflammatory response and tissue destruction.
Obviously though, not everyone that gets strep throat gets rheumatic fever, and it’s actually only a small minority that get it, estimated around 3%, and it’s more likely in children or people in areas of poverty and crowding.
A lot of patients that do get rheumatic fever from strep, sometimes called acute rheumatic fever, will have a variety of of clinical findings. The most common of which is migratory polyarthritis of the joints—where multiple large joints become inflamed, swollen and painful, one after another, although this damage isn’t permanent.
Secondly, some patients have pancarditis, or inflammation of all three layers of the heart tissue. The first, endocarditis, is inflammation of the inner lining which includes the valves. The mitral valve is most commonly affected, although the aortic valve might also be affected. The next is myocarditis, inflammation of the myocardium, or heart muscle.
Inflamed areas in the myocardial tissue are called Aschoff bodies, which are areas of fibrinoid necrosis, with immune cells like T cells and these characteristic Anitschkow cells, enlarged macrophages which have characteristic caterpillar-looking nuclei.
It turns out that myocarditis is the most common cause of death in acute rheumatic fever because this inflammation and necrosis makes the heart wall unable to contract with full force, which results in heart failure. Finally there’s pericarditis, or inflammation of the outer covering of the heart called the pericardium, which can cause pain as well as a friction rub from the inflamed visceral pericardium rubbing against the inflamed parietal pericardium- which can be heard with a stethoscope.
In addition to joint and heart problems, the hypersensitivity reaction in rheumatic fever can affect other tissues as well. Patients can develop subcutaneous nodules, these firm lumps under the skin made up of collagen. They might also have erythema marginatum, this reddish rash that shows up as rings on the arms or trunk. Also, they could have Sydenham’s chorea, which is a set of rapid movements of the face and the arms, from an autoimmune reaction against the basal ganglia of the brain, and this one typically won’t appear until late in the disease, at least 3 months after infection.
These five signs constitute the major diagnostic criteria for rheumatic fever, which are known as the Jones criteria. The Jones criteria also include having a blood test that shows evidence of previous streptococcal infection, since these symptoms usually don’t show up for 2-3 weeks after streptococcal infection.
Finally, there are also some minor criteria that help make the diagnosis—things like fever, joint pain, having more white blood cells in the blood than usual, elevated acute-phase reactants which are proteins that increase in the blood in response to inflammation. During inflammation, fibrinogen causes red blood cells to stick together, these clumped up red blood cells fall to the bottom of a test tube faster, called the erythrocyte sedimentation rate or ESR, so someone might have an increased ESR. Finally, due to heart-related symptoms, they might have changes in their electrocardiogram, or ECG.
Acute rheumatic fever usually resolves with rest, anti-inflammatory treatment, and maybe antibiotics like penicillin to wipe out any strep that’s hanging out in the throat.
It’s worth mentioning that some patients might only have a subset of symptoms, in which case they might be classified differently. For example, poststreptococcal reactive arthritis includes patients with joint symptoms and Pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections, or PANDAS, includes patients with neuropsychiatric symptoms.
If repeatedly exposed to group A beta-hemolytic streptococcus, though, the body continues to launch immune attacks against the various tissues, but most notably the heart tissue—which can lead to chronic rheumatic heart disease.
With chronic rheumatic heart disease, the valves, typically the mitral valve but sometimes the aortic valve, develop scar tissue from repeated inflammation. The leaflets of the valves become thicker and can actually fuse together, called commissural fusion, Also the chordae tendinae which are attached to the valves can become thickened as well.
These changes can cause complications with the valves, most commonly stenosis, or narrowing of the opening, sometimes called “fish-mouth” stenosis or “buttonhole” stenosis, but it can also cause regurgitation—which is allowing blood to flow backward. These roughened areas are also at higher risk of microbial attachment and invasion, called infective endocarditis.
Since recurrent attacks of acute rheumatic fever leads to chronic rheumatic heart disease, a major goal is to prevent these attacks of acute rheumatic fever, so essentially reducing recurrent streptococcal infections.
So depending on the severity of symptoms and damage to tissue, patients might receive prophylactic antibiotic treatment for long periods of time, from 10 years to life. Amazingly, resistance to group A Strep to penicillin hasn’t been a problem after more than 50 years of extensive exposure.
Sources
edithttps://circ.ahajournals.org/content/early/2015/04/23/CIR.0000000000000205.full.pdf+html
http://emedicine.medscape.com/article/333103-overview#a6