Of history, half-truths, and rheumatic fever.

Once upon a time, not too long ago, rheumatic heart disease (RHD) was the leading cause of death in children in some parts of the world.[1] Mysteriously, and mercifully, the illness became not only less common, but milder; even before the advent of antibiotics.[23] Previously, it had taken a while, a few centuries, to sort out the connection between sore throat and acute rheumatic fever (ARF).[4] However, the progress has been relatively rapid since then. ARF has served as a prototype for medical understanding and action. Generations of medical students have learnt the paradigm of dealing with uncertainty by wading their way through the Jones criteria, and have learnt the principles of primary and secondary prevention through the management of ARF. Those who saw rheumatic fever (RF) and RHD in a full flurry in the west are relieved with the current state of affairs, while physicians in other parts of the world languidly linger for the pattern to be replicated. Socioeconomic changes, rampant use of Penicillin, divinely ordained change in the rheumatic virulence of the Streptococcus, proper primary and secondary prophylaxis, any or all of the above have caused the turnaround in the west,[1256] and such is perhaps happening elsewhere. Meanwhile, the treatment strategies for ARF have been standardized.[7] But, ARF and RHD continue unabated in many areas of the world, with devastating impact. Global research priorities for RHD control have been articulated.[8] But the progress in the research around ARF and RHD control is slow. One important reason for this state of affairs, amongst others, is that the RHD story is considered a solved case. Its control is perceived only as a matter of good management. But certain aspects of the neat ARF/RHD story and its control strategies, as we understand today, need to be re-evaluated. It is the natural tendency of human mind to engage itself in a mystery. If we can still perceive the mystery in the workings of this disease, we can possibly accelerate research and improve the control of the disease.

Theoretically at least, if a disease changes its character faster than the understanding regarding the disease; there remains a possibility of misunderstanding about the disease. Whether such a thing really happened with ARF is a moot point. Some of the aspects of ARF, however, do cause anxiety from incomplete understanding, even as we repeat these statements from textbooks to textbooks. There are issues regarding our understanding about the primary prophylaxis, secondary prophylaxis, treatment of acute attack, damage from recurrent carditis, pathogenesis of ARF and other aspects of the RHD story, even as our algorithms to manage and control RHD show no hints of self doubt. Attempts to address these have been made at various times, but for the most, we have accepted the contradictions in the stride.

For example, the fact that streptococcal sore throat rates have not changed in the US,[9] but ARF has virtually disappeared, suggests that either the treatment is very effective, or the sore throat does not cause ARF now. However, the fact that as many as half of the sore throats preceding ARF may be asymptomatic[10] and yet ARF has vanished, strengthens the latter argument. That Streptococci behave differentially in different parts of the globe, or at different times, have been suggested,[911] but nonetheless appear mysterious. Asymptomatic or mildly symptomatic patients, who may not seek medical attention, have been one of the major hurdles in accepting primary prophylaxis as the preferred strategy to control RHD. We must employ all the strategies available to control RHD, but whether primary prophylaxis is a cost-effective strategy, has been both forwarded[12] and rejected.[13]

The secondary prophylaxis of ARF is a triumph of modern medicine. That antibiotics can prevent infection and thus prevent recurrence of ARF cannot be contested. However, the utility of secondary prophylaxis in altering the outcomes in different patient groups need to be studied using modern methods. The published literature in this regard, though voluminous,[1415] is far from conclusive in outcomes. The idiom that recurrent attacks of ARF is the primary problem responsible for the burden of RHD seems likely, but is not proven. It is well known that patients with severe carditis in the initial episode suffer from more recurrences, and those who escape carditis are less likely to develop carditis subsequently.[1617] The carditis is usually mild, even if it develops in them. Only a proportion of people with mild carditis in the initial episode may develop significant damage with recurrences.[17] The feeling that most of the ravages of RHD is a result of recurrent attacks undermine the importance of the initial episode and other host factors. It has eclipsed the attention that should have been given to treatment of the initial carditis. Some of the data regarding secondary prophylaxis has compared their outcomes with that of the report of Bland and Jones in the pre-prophylaxis era. In the latter report, 48% of the patients who were initially free from heart disease developed it on a 20-year follow up.[16] Subsequent studies have shown comparatively fewer patients have heart disease on follow up with secondary prophylaxis, but many of the studies lacked controls.[1518] The conclusions that the absence of mitral stenosis or aortic stenosis, on follow up in these patients, is due to effective secondary prophylaxis[1819] may be erroneous, as discussed below.

There are intriguing observations regarding the host factors that have not received enough attention. Patients with mitral regurgitation (MR) and severe carditis at presentation do not often develop mitral stenosis (MS) on follow up. In all the follow up studies, less than 10% of such patients develop MS.[141819] Patients with chorea and no obvious carditis go on to develop MS on follow up. There were a large number of such patients in the Bland and Jones study, and they developed only mitral stenosis on follow up. Whether there is a fundamental difference in patient response pattern leading to dominant MR or MS has not been well dissected.[20] A number of MS patients present with fully developed MS, and a lesser percentage of these report a past episode of ARF compared to patients with MR. Prophylaxis in patients with fully developed MS is presumed to retard the progression of MS, or avoid aortic valve damage, but its effectiveness actually remains unknown. Further, it is well known that Aschoff nodules are found in patients with MS undergoing valve surgery years later, suggesting a chronic ongoing activity in the absence of clinical ARF, (and presumably with continued secondary prophylaxis in some of them).[21] Whether prophylaxis, as is practiced, influences the progress of MS has not been adequately demonstrated. Alternative methods of retarding the progression of MS may be possible, like drugs retarding fibrosis or antiplatelet agents.

Similarly, the waxing question of Juvenile MS — severe MS at an early age in young patients of RHD in some parts of the world[22] — has never been correctly deciphered. Such severe MS at an early age was not seen in the west even during the worst phase of RHD. It has been attributed to recurrent episodes of ARF in these patients without any direct evidence. In fact, only 12% of the patients with severe Juvenile MS had recurrent episodes in one study.[23] Other patient-related factors need to be studied, for example, dietary deficiency or other infections, etc., Notwithstanding the inconsistency and lack of understanding cited above, it is true that MS has also disappeared in parts of the world where RHD has disappeared.

The sudden surge of echocardiographically detected RHD, 10 to 30 times more than that was clinically obvious,[242526] calls for reconsideration of the secondary prophylaxis question. A careful follow up of these patients might open new vistas in the understanding of ARF; but for now, the secondary prophylaxis is not indicated in them in the absence of clinical disease. An alternative frame of belief in secondary prophylaxis in such a situation may result in 2-3% of asymptomatic school children receiving painful injections.

Finally, some recurrences of ARF (though little) do occur in patients, while they are on rigorous secondary prophylaxis, and these have generally been brushed aside as noncompliance, but might mean more. The impact of irregular penicillin prophylaxis is not clear.[27] In a controlled study of Penicillin for sore throat in normal children, early treatment was associated with more recurrences compared to treatment 48 hours later, underlining the importance of natural immunity.[28] Streptococcal infections and the propensity to develop ARF following these, both decrease with age: Therefore, the recommendations for life-long prophylaxis are extrapolations from books to books. Also, the impact of continuous prophylaxis on the host immune function, if any, is not known.

The treatment of the carditis of ARF is in a time warp since the 1950s, and has not evolved. As initial carditis is the all important determinant of prognosis, if only we could treat the episode of carditis and reduce its severity! Stronger and newer immunosuppression might just do that. But, we are preoccupied with aspirin Vs steroid question, which, as a meta-analysis noted,[29] might never be resolved. Use of steroids in the treatment of ARF varies with the age of the physician and his/her experience of having seen sicker patients in the past! There is much progress in the treatment of other immunological disorders with pharmacotherapy in the last 50 years, but our rigid framework of thinking of ARF has not generated any alternative ideas in this arena.

The pathogenesis of ARF continues to evade.[3031] Although molecular mimicry and genetic susceptibility[32] have remained the focus of intensive research, the actual culprit molecule/s, or the modus operandi of the Streptococcus have not been tracked. Talks of myosin and autoantibodies that held center stage for long have been replaced with focus on Vimentin, cell-mediated immunity, and superantigen. Genetic factors, although helpful in the understanding of the disease, are unlikely to be of direct utility in view of the global occurrence of ARF in the less well-developed regions. The discovery of the importance of Streptococcus C and G and streptococcal pyoderma in ARF has shown chinks in the armor of our ARF paradigm.[33] The now-and-then talked about viruses in ARF have not made much impact,[34] but the possibility of copathogenicity has not been excluded. Perhaps the studies from a controversial arena like those of Streptococcus in psoriasis,[35] or in PANDAS,[36] or other areas might provide some of the missing links serendipitously. Given the uncertainty of the pathogenesis of ARF, the hurdles of autoimmunity, and the diversity of Streptococci, the promise of a vaccine for ARF is elusive and contentious, as only a small minority of patients develop the disease following streptococcal sore throat. A different approach to streptococcal vaccine development that is relevant to all streptococcal diseases globally might be more acceptable.[373839]

In summary, we must not posit ARF-RHD and its control as a solved case. We must not cease exploring.