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Is Rheumatic fever more Chronic than acute?

Is Rheumatic fever more Chronic than acute?



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It follows from the complication of S.pyogenes' pharyngitis. I am thinking how the inflammatory response behaves: acute or chronic or something between.

I think chronic disease is better description here than acute, however not sure.

What is the type of inflammatory response in the Rheumatic fever?


the inflammatory response it autoimmune reaction, thus it occurs 4 weeks after the Strep infection.

please, look at the picture from the "Nature" -


Pathophysiology and Clinical Presentation

Rheumatic fever only occurs as a result of an untreated group A beta-hemolytic streptococcus pharyngeal infection.

Rheumatic fever can affect the heart, joints, central nervous system, and skin. Symptoms result from an abnormal immune response to the M proteins on the microorgamisms that cross-react with normal body tissues. Antibodies react with streptococci bacterial wall antigen, laminin, cardiac myosin, and neuronal cells.

The antibodies’ reaction with laminin and cardiac myosin affect the endocardium, specifically the heart valves. The reaction that antibodies have with neuronal cells increase dopamine release causing chorea. The antibodies also affect skin, muscles, and synovial joints. As a result of the antibodies reacting with these antigens, inflammation occurs in connective tissues including

McCance & Huether, 2014. Pathogenesis and Structural Alterations of Acute Rheumatic Heart Disease.

the joints, central nervous system, endocardium, and skin. This inflammation leads to damage to the tissues allowing for an increased risk of recurrence and further complications with the heart valves.

There is also a genetic component to rheumatic fever that includes the HLA-DR 1 antigen and HLA-DR 6 antigen. These antigens contribute to a predetermined immune response that that leads to severe, chronic rheumatic heart disease. While rheumatic heart disease affects all layers of the heart, the endocardium is the most susceptible, especially the heart valves. This can lead to bacterial growth, or vegetation, on the valves and chordae tendineae which impedes blood flow through the heart. This vegetation is comprised of fibrin deposits called Aschoff bodies (McCance & Huether, 2014).


How You Get Rheumatic Fever

Rheumatic fever may develop after strep throat or scarlet fever infections that are not treated properly. Bacteria called group A Streptococcus or group A strep cause strep throat and scarlet fever. It usually takes about 1 to 5 weeks after strep throat or scarlet fever for rheumatic fever to develop. Rheumatic fever is thought to be caused by a response of the body&rsquos defense system &mdash the immune system. The immune system responds to the earlier strep throat or scarlet fever infection and causes a generalized inflammatory response.


Diagnosis and Tests

How is rheumatic fever diagnosed?

If you or your child has a sore throat for more than a couple of days, reach out to your healthcare provider. Treating a group A Streptococcal infection can prevent rheumatic fever.

If your provider suspects rheumatic fever, they will first swab your throat to check for group A streptococcus bacteria. They may use a rapid strep test or order a throat culture.

A rapid strep test can provide results within 10 minutes. A throat culture takes a few days to get results. However, rapid step tests sometimes give false-negative results (saying you don’t have strep when you really do).

Depending on your symptoms, your healthcare provider may also order:

  • Blood tests: Sometimes, providers order a blood test to confirm a strep infection. Blood tests can detect antibodies (your body’s defenses against the bacteria) when the bacteria no longer show up on tests. Other blood tests check for substances (like proteins) that show inflammation in the body.
  • Heart tests: Heart tests, such as an electrocardiogram (EKG) or an echocardiogram (Ultrasound of the heart), help providers check your heart function.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Rheumatic Fever. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Patient Registry

  • The Autoimmune Registry supports research for Rheumatic Fever by collecting information about patients with this and other autoimmune diseases. You can join the registry to share your information with researchers and receive updates about participating in new research studies. Learn more about registries.

MYOCARDITIS

Several lines of investigation indicate that myocarditis is not a feature of rheumatic carditis.

Oran et al. found that the creatine kinase MB, myoglobin, and troponin-I in patients with acute RF with active carditis with or without cardiomegaly or congestive failure remain normal on the 3 rd , 7 th , 14 th and 21 st day indicating an absence of significant myocardial damage.[3] Gupta and associates evaluated troponin-I in 22 patients with acute RF (14 with carditis) and 9 scarlet fever controls. They reported that “there was a minimal but not significant degree of elevation of cardiac troponin-I above normal levels in 18 percent of the patients with acute RF. The presence of low troponin-I levels throughout the course of RF especially in the face of active carditis argues against significant cardiomyocyte injury.”[4] Kamblock and associates estimated cardiac troponin-I (cTnl) levels and studied the left ventricular function in 95 consecutive patients of acute RF. They concluded that there was no cTnI elevations or echocardiographic abnormalities suggesting significant myocardial involvement during RF. Congestive heart failure was always associated to severe valvar regurgitation.[5]

Vasan et al. studied the left ventricular function in patients with acute RF with and without carditis as well as with and without congestive failure. Left ventricular contractility and systolic function was normal despite the presence of congestive failure in the majority of patients with rheumatic carditis.[6] They concluded that rheumatic carditis does not result in congestive failure in the absence of hemodynamically significant valve lesions.

Radhakrishnan and associates used technetium 99m stannous pyrophosphate scan in 12 patients of acute RF.[7] Myocardial staining was uniformly absent in all. They concluded that the technique was insensitive for the diagnosis of myocarditis in acute RF. Narula et al. used indium 111 -labeled antimyosin fab in patients with acute RF to identify the presence of myocardial damage.[8] Except in the presence of pericarditis or congestive failure there was very poor staining indicating the absence of significant myosin damage.

Further, Narula et al. used myocardial biopsy in 89 patients of acute RF and chronic rheumatic heart disease to identify the presence of active myocarditis. They concluded that myocardial biopsy performed during acute RF does not add to the clinically obvious myocarditis due to paucity of myocardial damage.[9]

Edwards and Edwards evaluated the role of myocarditis as compared to valvular disease causing congestive failure in RF. They stated that histologic examination in patients with active rheumatic myocarditis does not permit easy acceptance of this concept, because the lesions of active myocarditis are primarily interstitial without evidence of cellular myocardial necrosis. Aortic regurgitation of rheumatic origin strongly indicates an element of intrinsic valvular rather than myocardial disease.[10] “Histologically the amount of myocardial damage due to myocarditis is so little that it fails to explain why patients of acute RF have died” (JEE: Personal communication).

Kinsley and associates replaced mitral and/or the aortic valve in patients of acute RF, with deterioration despite anti-congestive measures.[11] Following mitral or aortic valve replacement, the left ventricular size and function returned to normal and congestive cardiac failure subsided, with clinically ongoing carditis. They concluded that congestive cardiac failure was the result of an acute volume overload secondary to mitral and/or aortic valve regurgitation and not due to myocarditis per se.

Histopathological findings of carditis, summarized by Virmani et al., indicate inflammatory changes in the sub-epicardial, sub-endocardial, and perivascular interstitial tissue with little myocyte disruption. Aschoff nodules (AN) are strictly perivascular in location. The rest of the myocardium and the interstitial tissue is normal.[12] AN contain lymphocytes, macrophages, β cells, and giant cells. Immunopathology of AN, studied by Gulizia and associates, indicates that it does not have any cells of myocardial origin.[13] Therefore, Aschoff nodule, the hallmark of rheumatic carditis, is not derived from myocardial damage.

Thus, the absence of myocarditis has been demonstrated and documented by (1) the absence of increase in markers of myocardial damage (CK-MB, Troponin-I), (2) echocardiographic left ventricular function studies, (3) radionuclide imaging (technetium pyrophosphate, indium 111 , antimyosin fab), (4) myocardial biopsy studies, (5) surgical management during active carditis, (6) histopathology and immunopathology.

Since RF does not cause myocardial damage, and the fact that congestive failure occurs only in the presence of severe mitral and/or aortic regurgitation, it is possible to conclude that rheumatic valvulitis causing acute and chronic valvular damage determines the morbidity and mortality of RF.

Despite this ubiquitous evidence why did involvement of myocardium get primacy?

This could be explained by the similarity in structure between M-protein and the human tropomyosin. The GAS M-protein was identified and established as the virulence factor of the organism by Lancefield.[14,15] Further cross-reactive antibodies between M-protein and tropomyosin have been demonstrated. Research, therefore, was directed exclusively toward myosin.[16,17] Since it is now clear that myocardium (myosin) is not the target in RF, research needs to be directed elsewhere for the pathogenesis of RF to be identified.


Acute Rheumatic Fever

May be effective for GAS pharyngitis, but more expensive than PCN or erythromycin AND macrolide resistance may be prevalent in the US.

Often prescribed for GAS infection in PCN allergic patients however, macrolide resistance common in Europe, and may approach 20-25% in some US cities.

Treatment by benzathine PCN q 4 wks is the preferred choice for secondary prevention of ARF.

Often chosen over penicillin Vk since it can be dosed less frequently. One study (see Lennon ref) found 1500mg once daily equivalent to PCN V 500mg twice daily. Overall, oral therapy is viewed as inferior to injectable therapy.

  • Hx of prior ARF significantly elevates risk of future bouts of ARF and rheumatic heart disease in both children and adults.
  • Only long-term sequela of ARF is rheumatic heart disease (valvular).
    • Only 6% risk if no carditis at initial ARF, climbs to 40-65% w/ murmurs or CHF at initial disease.
    • Historically detected by auscultation but now echos suggested to be performed in all suspected or proven cases.
    • Echocardiography superior sensitivity but expensive in lower resource settings, especially.
    • Advanced RHD should be evaluated at center with expertise in valvular surgery.

      Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015131(20):1806-18. [PMID:25908771]

    Comment: AHA guidelines that now are more in synch with international guidelines, as prior Jones Criteria guidance from 1992, originally developed in 1944. Significant change includes routine use of echocardiography in suspected ARF cases even when overt clinical findings are not present.

    Comment: Focus on the major complication of ARF worldwide with emphasis on RHD screening as well as prevention.

    Comment: Extensive document in which WHO recommends in regions with rates of ARF, community-based screening and control programs along with prophylactic penicillin to prevent recurrent ARF and RHD.

    Comment: Recent review article that serves along with the Jones criteria as the basis for recommendations in this module.

      Beaudoin A, Edison L, Introcaso CE, et al. Acute rheumatic fever and rheumatic heart disease among children--American Samoa, 2011-2012. MMWR Morb Mortal Wkly Rep. 201564(20):555-8. [PMID:26020139]

    Comment: In US, Oceanic islands with highest rates of ARF. Also includes Hawaii.

    Comment: Authors find that current recommendations based on old studies that were not well structured, hence they conclude there is little evidence of benefit using corticosteroids or intravenous immunoglobulins. Modern studies needed. Risks of treatments judged substantial.

    Comment: Authors review why echocardiography clearly superior to stethescope ausculation however, increased sensitivity is burdened by some specificity issues that could be easily misjudged.

    Comment: Hits on hot topics including: 1) echo screening for RHD (not ready for primetime), 2) re-emphasizing the importance of using long-acting benzathine penicillin injections for secondary prophylaxis, 3) early referral for valve surgery in advanced RHD at specialized center. Tensions arise since the populations most at risk for ARF and RHD are most often in low resource settings.

    Comment: Comprehensive review focuses upon the pathophysiology known that leads GAS to cause ARF and RHD.

    Comment: Observations in patients a region endemic for acute rheumatic fever (North Queensland, Australia) found monarthritis, subclinical carditis (SCC) and low-grade fever in a proportion of patients, such that if included into the Revised Jones Criteria would raise diagnostic rate from 71.4% to 91.8% as SCC occurred in 27 of the 98 patients and long-term consequences were observed in a high proportion of patients with SCC.

    Comment: Non-inferiority trial in children with GABHS pharyngitis in 353 children randomized to amoxicillin 1500mg/d v. PCN VK 500mg bid for 10d. The once daily amoxicillin was not inferior to twice-daily PCN. Treatment failures ranged from 5.8% at 3-6d, 12.7% at 12-16d and 10.7% at 26-36d. Only one case of ARF (not well substantiated) occured in the 7d amoxicillin group.

    Comment: Clinical database examination of 503 children diagnosed with ARF in 2000. Hospitalizations were infrequent, but more common at academic medical centers, and averaged 3d.

    Comment: Investigators believe that observation without treatment is probably ok with GAS pharyngitis as this group had the lowest morbidity. However, they note we don't have any good modern data on ARF prevalence to judge whether this would be a safe practice from a risk assessment.

    Comment: Though rare in US adults, ARF still occurs in some localized and usually rural environs in US children. These investigators report of continued ARF in western PA, believing that macrolide resistant strains may be playing a role.
    Rating: Important

    Comment: Review articles explore why in the developing word efforts at controlling ARF through treatment of GAS pharyngitis/colonization have proven ineffective. Authors suggest group C and G streptococci have been shown to exchange key virulence determinants with GAS and are more commonly isolated from the throats of Aboriginal children. In the tropics, GAS pyoderma and/or non-GAS infections may be the driving forces behind ARF. This requires then a rethinking on how to address control issues.

    Comment: Turkish study that delved into the diagnoses of 20 patients suspected of adult-onset juvenile rheumatoid arthritis. In this group, 3/20 were thought to have ARF, and an interesting 50% of them were found to have had a GAS positive throat culture in the preceding 6 months.

    Comment: Poststreptococcal arthritis is a poorly understood and controversial problem in adults that may or may not fall within the spectrum of ARF. 29pts described over a >15yr. period presenting with arthritis thought related to GAS, but only six had criteria in retrospect for ARF. All adult patients had negative throat cultures. Most of diagnoses were based on ASO titers. Even so, ARF remains a very rare problem in the adult population in patients without prior history of ARF.


    Signs and symptoms of rheumatic fever

    Rheumatic fever can cause:

    • Carditis: inflammation of the heart muscle and heart tissue. Carditis can cause a rapid heart rate, fatigue, shortness of breath and exercise intolerance. This is the most serious of the symptoms and may have long-term effects on health. Carditis occurs in approximately 50 percent of those who have rheumatic fever
    • Arthritis: swelling, redness and pain in the joints, especially knees, ankles, elbows and wrists. This is a common symptom and occurs in approximately 70 percent of people who have rheumatic fever
    • Splotchy rash that doesn’t itch
    • Subcutaneous nodules: tiny, hard lumps under the skin
    • Fever
    • Chorea: involuntary movement of the extremities. This is more common in females (previously called “St. Vita’s dance”)

    Pathophysiology

    Antibodies against the streptococcal M protein allow the host to protect itself from future infection from a similar M-type organism.23 However, these antibodies are the pathophysiologic basis for postinfectious autoimmune sequelae: deposition of immune complexes in poststreptococcal glomerulonephritis, antibody-directed molecular mimicry with abnormal host immune response in acute rheumatic fever, and cross-reactive autoantibodies in the basal ganglia in Sydenham chorea.24 – 26 Genetic susceptibility, humoral immunity, and cellular response also have a role.23 – 30


    Why has rheumatic fever declined in the U.S.?

    Speaking of chronic diseases caused by microbial agents, one of the earliest characterized of these is the group A streptococcus (Streptococcus pyogenes). In addition to causing acute diseases such as strep throat and scarlet fever, a wide range of post-infectious sequelae (complications that appear following resolution of infection) have been attributed to S. pyogenes. It can cause glomerulonephritis, a kidney disease. It's long been known infection with the organism can lead to a condition called Sydenham's chorea, a neurologic disease characterized by jerky movements. Infection with S. pyogenes has also been linked to a number of related syndromes, including Tourette's syndrome and tic disorders. Most notably, S. pyogenes causes rheumatic fever, a disease that affects multiple organ systems. Rheumatic fever can lead to damage of the heart valves, resulting in a condition known as rheumatic heart disease. It is thought that this is due to cross-reaction of antibodies against the bacteria: they also react with heart tissue. The recognition that the bacteria causes these diseases is a reason it is recommended that streptococcal infections be rapidly treated with antibiotics, as this significantly decreases the incidence of RF.

    The epidemiology of S. pyogenes infections in the 20th century has been interesting. At the beginning of the 20th century, scarlet fever was still a scourge, with mortality rates as high as 30% in some outbreaks. This started to decline in the early quarter of the century, and is currently considered a mild consequence of S. pyogenes infection. Rheumatic fever also caused significant morbidity and mortality until the 1950s, when it began to decrease (largely due to an increased use of antibiotics to treat strep throat infections). In the 1970s, the incidence of rheumatic fever in the United States further declined, followed by a resurgence in some areas during the 1980s. At the same time, the incidence of severe invasive disease due to S. pyogenes (including streptococcal toxic shock-like syndrome [STSS] and necrotizing fasciitis, the "flesh-eating disease") also increased. How much of this was due to changes in the pathogen, versus changes in the environment or the host, has been the subject of much study.

    Strains of S. pyogenes appear to have different disease potential, which in turn relate to their genetic make-up. This also seems to correlate with their tissue preference. While strep throat is the most common disease manifestation in the United States, it is also a common cause of a skin disease called impetigo. This disease is more common in troical climates. Bessen et al. have shown that this tissue preference appears to have a basis in differences in the emm gene, which encodes the M protein--a key virulence factor, and the determinant of serotype. Additionally, isolates that cause skin infections are infrequently associated with subsequent development of rheumatic fever, but are more commonly a cause of glomerulonephritis. Instead, RF is generally associated with prior infection in the throat. However, not all throat isolates cause RF only a subset of them typically do. (Are you seeing why studying the epidemiology of these organisms is exhausting?) Those that cause RF typically lack a gene called sof, encoding a protein called the serum opacity factor. RF-causing isolates also typically produce large amounts of capsule, a sticky extracellular polysaccharide.

    I've noted before that the development of disease due to an infectious agent results from a complex interaction of host genetics, microbial genetics, and environmental factors (which can include host nutrition and immune status, among other things). In the case of rheumatic fever, only a subset of types of S. pyogenes bacteria generally cause rheumatic fever. As I mentioned above, the incidence of RF has changed over the years. The initial decrease could be attributed to antibiotics, but what about the decrease seen the in 1970s? Or the increase in some areas in the 1980s? A new study examined their changing epidemiology.

    In the US, the incidence of rheumatic fever has dropped dramatically over the past 4 decades (see figure). Was this due to a change in the population structure of S. pyogenes? Previous studies had suggested it was. To test this, Shulman et al. examined the M type of bacteria collected between 1961-8 in Chicago, and from Chicago and a number of other sites across the country between 2000-4. 2 types that are known to cause rheumatic fever (serotypes 1 and 12) had essentially identical percentages over the years and in various geographic regions. However, other rheumatogenic seroypes--3, 6, 5, and 14--were significantly decreased in the recent sampling compared to those found in the 1960s. Other nonrheumatogenic types, conversely, increased, including serotypes 2, 4, 22, and 28.

    So, this suggests that a decrease in rheumatogenic serotypes of S. pyogenes has played a role in the decreasing incidence of rheumatic fever in the United States over the past 40 years. However, rheumatogenic M types have decreased only approximately 2-5 fold, while RF has decreased approximately 20-fold--so we're still not seeing the whole picture. These missing pieces become critical because a vaccine for S. pyogenes based on the M protein is in the works. Though this is a main antigen, it's been tough to design a vaccine against it due to the fact that antibodies to the protein cross-react with heart tissue--an autoimmune reaction that results in the development of RHD. Though this disease is now rare in the US and other developed countries, it is still a scourge worldwide. Chronic RHD is estimated to exist in 5-30 million children and young adults 90,000 patients die from this disease each year.

    This study also highlights the value of surveillance. Especially when designing a vaccine, we need to know what's out there, how the population has changed, and ideally, what's caused that change. Then when the vaccine is implemented, we need additional surveillance to look for emergent strains that may replace those contained in the vaccine. For example, following the introduction of the vaccine against Haemophilus influenzae type B, rates of meningitis caused by this bacterium have decreased dramatically. However, we're now seeing more non-type B isolates of Haemophilus--so a vaccine for a particular pathogen doesn't always represent the end of the story.

    One final thought: though it appears that a change in circulating serotypes of S. pyogenes has played a role in the decline of rheumatic fever in the United States, we don't know what factors caused some of these serotypes to become more dominant, and others to become increasingly rare. That's a very difficult task to figure out. It could be that the strains that took over simply out-competed the strains that are now unusual it could be due to other bacterial agents that share the same niche it could be due to man-made agents (perhaps some are more resistant to antibiotics, or antimicrobial chemicals, even soaps, etc.), or it could be due to a number of other things. This is one of the things that makes studying this area so difficult. Imagine the challenge "regular" ecologists have when they look at changes in the ecology of an area. Now imagine that everything they're studying is invisible to the naked eye, and some can be investigated only by DNA-based methods. It's a challenging, but fascinating, area.

    Article: Shulman ST et al. 2006. Temporal Changes in Streptococcal M Protein Types and the Near-Disappearance of Acute Rheumatic Fever in the United States. CID. 42:441-447.