Ebook Prevention of cardiovascular diseases from current evidence to clinical practice: Part 2

Rheumatic Heart Disease: A Neglected Heart
Disease
Marcia de Melo Barbosa, Maria do Carmo Pereira Nunes, and Regina Müller

Acute Rheumatic fever (ARF) and its chronic sequel, rheumatic heart disease
(RHD) result from an autoimmune disease that starts with an infection caused by
Streptococcus pyogenes (Group A streptococci—GAS) and remain the most common cause of preventable childhood heart disease worldwide. It follows a nontreated throat infection in susceptible children and teenagers (3- to 19-years old); and
strongly relates to socioeconomic and environmental determinants, such as overcrowding, poor standard of living, poor access to medical care and inadequate
expertise of health-care teams [1, 2].

Epidemiology
Despite being considered today as “virtually eliminated” [3] after a documented
decrease in the incidence of ARF in developed countries during the past 6 decades,
RHD remains a medical and public health problem, especially in low and middleincome countries and in indigenous populations, where it causes disability and

M. de Melo Barbosa, M.D., Ph.D. (*)
ECO Center, Hospital Socor, Belo Horizonte, Brazil
Interamerican Society of Cardiology
e-mail:
M. do Carmo Pereira Nunes, M.D.
School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
e-mail:
R. Müller, M.D., Ph.D.
Working Group on Rheumatic Fever from the World Heart Federation, Geneva, Switzerland
National Heart Institute of Rio de Janeiro, Rio de Janeiro, Brazil
e-mail:
© Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_15

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premature death in children and young adults in their most productive years [1].
As stated recently, RHD does not get the same attention as cancer as a chronic noncommunicable disease (NCD) “because it is a disease of the bottom billion of the
poorest people in the world—one of the most neglected of the neglected diseases” [2].
In 2005, the World Health Organization (WHO) estimated a prevalence of at least
15.6 million cases of RHD worldwide, with 282,000 new cases (ARF) and 233,000
deaths related to RHD each year. The burden of stroke due to RHD in less developed countries was also considered: 144,000–360,000 new strokes each year [4].
However, these are conservative assumptions, and future incoming-data will show
these figures to be dramatically underestimated [5].
In Brazil, estimates based on WHO epidemiological model and data from the last
Census in 2010, appointed to around 30,000 new cases of ARF each year, of which
around 12,800 can develop RHD [1, 6]. Brazilian official figures have shown a significant reduction in the number of hospitalizations due to ARF and RHD in the last
10 years, however, in 2012, 2713 ARF and 4268 RHD hospital admissions were still
reported [7], since, similar to other countries, Brazil has not yet implemented a
national register system and a RHD control program. Underreporting of cases and
difficulties in access to hospital admission, especially for adolescents and young
adults, are very common.
In a recent linkage study with 53,210 Brazilian in-hospital children and adolescents admitted for heart failure (HF) from 2001 to 2007 the survival analysis for the
ARF/RHD patients showed only 61 %, 55 % and 36 % survival rate at 1, 2 and
7 years, respectively, with a hazard ratio observed for RHD patients’ death of 15.5.
These poor results were strongly related to social conditions measured by human
development index (HDI) of the patients’ residence [8].
Another Brazilian study with 100 RHD low-income patients in Sao Paulo analyzing the entire course of the disease concluded that costs of ARF/RHD amounted to
approximately 1.3 % of the annual family income in this population. Direct and
indirect costs, such as school failure rate of 22 %, 23 % parents’ work absenteeism,

about 5 % lost jobs, and the intangible costs associated with RHD, resulting from
premature disability and death, and loss of intellectual opportunities, with its adverse
effects on the socioeconomic family and society development. The estimated annual
cost of RF for society in Brazil was estimated in 2001 as US$ 51,144,347.00 [9].
More recently, advocacy groups, including the World Heart Federation (WHF),
have put greater efforts into rectifying this neglect disease [2]. In April 2013, the
WHF issued a statement of commitment to the strategic objective of a 25 % reduction in premature deaths from ARF and RHD among individuals aged <25 years by
the year 2025. To achieve the objective of controlling RHD and eliminating ARF,
five strategic targets have been identified: (1) Comprehensive register-based control
programs; (2) Global access to Benzathine penicillin G; (3) Identification and development of public figures as “RHD champions”; (4) Expansion of RHD training
hubs; and (5) Support for vaccine development [10].
A recent editorial about RHD discussed that the challenge regarding RHD does
not relate to knowledge of the disease, but to the implementation of measures to
control the disease globally [5], which depends on the political will of the governments and inclusion of ARF in public health policies. It requires advocacy, awareness, commitment, coordination, and resources [5].


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Pathogenesis
The pathogenesis of ARF/RHD is complex and both environmental and genetic
factors contribute to its etiology, but still remains incompletely understood [11].
Streptococcus, in the appropriate condition, triggers the pathogenic sequence that
starts with pharyngitis, leading, in a small percentage of cases (1 to 5 % of susceptible
children), to ARF which, in about 60 % of the cases, will develop life-threatening
valve lesions characteristic of RHD [2].
Several genes associated with RHD have been described, related to both the
innate and adaptive immune responses. The susceptibility of developing ARF/RHD
is associated with some alleles of HLA (human leukocytes antigens) class II genes

(DRB1, DQB and DQA), as well as with TNF-α gene which are all located on
human chromosome 6. HLA alleles are involved in antigen recognition by T lymphocytes through the T cell receptor (TCR). TNF-α gene encodes the inflammatory
TNF alpha protein, which is involved in the inflammatory process mediating hearttissue lesions in RHD. Several other associations have been established through
single nucleotide polymorphisms (SNPs) for genes code for other proteins also
involved with the immune response (innate and adaptive pathways) [11].
Molecular mimicry between streptococcal antigens and human proteins is central to RHD pathogenesis, and mainly cardiac myosin epitopes and vimentin seem
to be the major target antigens. Autoreactive T cells (CD4+) migrate from the
peripheral blood to the heart and proliferate in the valves in response to stimulation
with specific cytokines. High TNF alpha, interferon gamma, and low IL4 are found
in the rheumatic valve. IL-4+ cells are found in the myocardium; however, these
cells are very scarce in the valve lesions of RHD patients. IL-4 is a Th2-type cytokine and plays a regulatory role in the inflammatory response mediated by Th1
cytokines. These findings indicate that the Th1/Th2 cytokine balance has a role in
healing myocarditis, while the low numbers of IL-4-producing cells in the valves
probably induce progressive and permanent valve damage [11].

Diagnosis
The diagnosis of ARF is essentially clinical and laboratory exams are not pathognomonic of the disease, only contributing to confirm the inflammatory process and the
streptococcal infection. Clinical diagnosis of carditis is usually made by the auscultation of a pathological mitral regurgitation (MR) murmur. Jones criteria [12] created in 1944, are characterized in major and minor, and represent the gold standard
for the diagnosis of the first attack. They are an epidemiological and not clinical tool
for the initial attack and have been revised, modified and updated by the American
Heart Association [13, 14] and by the WHO [1] (Tables 1 and 2).
For the initial attack, the presence of two major manifestations or of one major
and two minor manifestations supported by the evidence of a preceding GAS
infection indicates high probability of ARF. For the diagnosis of recurrences in a


146
Table 1 Modified Jones
criteria for the diagnosis of
rheumatic fever (1992)

M. de Melo Barbosa et al.
Major criteria
Carditis
Arthritis
Chorea
Eritema marginatum
Subcutaneous nodulous

Minor criteria
Fever
Arthralgia
Elevation of inflammatory markers
(ESR, CRP)
Prolonged PR interval in the ECG

Evidence of GAS infection
Adapted from Dajani et al., Jones criteria 1992 Update—AHA
ESR erythrocyte sedimentation rate, CRP C-reactive protein
Table 2 WHO Criteria (2004) for the diagnosis of the first attack, recurrence and RHD (based on
the modified Jones criteria)
Diagnostic category
First episode of ARF

Recurrence of ARF in patients without established
RHD
Recurrence of ARF in patients with established
RHD
Sydenham Chorea
Insidious rheumatic carditis

Chronic valve lesions of the RHD: pure MS or MS
and MR diagnosis and/or aortic valve lesion with
characteristic rheumatic involvement

Criteria
2 major criteria or 1 major and 2 minor +
evidence of previous streptococcus
infection
2 major criteria or 1 major and 2 minor +
evidence of previous streptococcus
infection
2 major criteria + evidence of previous
streptococcus infection
No other major criteria or evidence of
previous streptococcus infection is
required
No additional criteria for the diagnosis
of RHD is necessary

Source: WHO 2004

patient with established RHD, just two minor criteria plus evidence of preceding
GAS infection is sufficient. The presence of chorea, insidious carditis and chronic
valve lesions are exception and do not require any other criteria to be considered as
having rheumatic fever [1].
Subclinical carditis (SCC) is also a major concern, since 16.8–27 % may have it.
In endemic areas, strict adherence to the revised Jones criteria can result in underdiagnosis of ARF [15]. Failure to diagnose these patients can lead to severe adverse
consequences since prophylaxis will not be started [16, 17]. In Australia, diagnosis
rates increased significantly when monoarthritis and SCC were included as major
criteria and low-grade fever (≥37.5°) as a minor criterion [17].

The disease usually presents with an acute febrile onset, with variable combinations of arthritis, carditis, chorea and skin manifestations. Published criteria are
useful for epidemiological purposes, but clinical judgment should prevail, especially in areas of the world where RHD is still common.


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Evidence of previous GAS infection is demonstrated by increased or rising antistreptolisin O titer or other antibodies or a positive throat swab for GAS. Inflammatory
markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
are usually elevated. Though unspecific, they can add in monitoring the inflammatory process and its remission.

Major Clinical Manifestations
Arthritis
The classical presentation is that of migratory and asymmetric polyarthritis involving large joints, especially in the legs, and than migrating to other joints with some
overlapping of joints involvement. It occurs in approximately 75 % of the cases and
should be differentiated from arthralgia (no inflammatory signs). When associated
with carditis, there seems to be an inverse correlation between the severity of the
two findings [1]. It responds rapidly to anti-inflammatories and thus, self-medication
may mask the typical presentation.

Carditis
It is the most serious manifestation of the disease, and the only one that leaves
sequelae. Clinically, it is present in 40–70 % of the cases, however the percentage is
much higher when the diagnosis is made by echocardiography [18, 19]. Although
there is a pancarditis (endocardial, myocardial and pericardial involvement), valve
lesions are the ones responsible for the clinical presentation and prognosis.
Myocarditis can be diagnosed by histology, but it does not cause HF and systolic
function is usually preserved at the initial presentation. Pericardium involvement is
not common, does not happen in isolation and does not lead to constriction, but the

presence of a pericardial effusion may help confirm the diagnosis [20].
The most common valve lesion is MR and its pan-systolic murmur does not
indicate permanent lesion. Aortic regurgitation (AR) is less common and stenotic
lesions do not happen in the early stage of the disease. Tricuspid regurgitation may
occur in acute carditis secondary to pulmonary hypertension.
The severity of carditis can vary from SCC to a fulminant form. In SCC, cardiovascular exam, X Ray and ECG are normal (except for a prolonged PR). Doppler
echocardiogram is essential for its diagnosis, as it can detect pathological mild MR
and/or AR [21]. Mild carditis is present when there is tachycardia disproportional to
the degree of fever, diminished S1 and MR systolic murmur. Chest X Ray and ECG
are normal (except for a prolonged PR), but Doppler echocardiogram shows mild or
moderate regurgitations and a normal-sized left ventricle (LV). In the moderate


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form, cardiovascular exam is abnormal, with signs of incipient HF, abnormal
chest X Ray and ECG, and more severe regurgitations in the echocardiogram, with
enlarged LV. Finally, in the severe form, cardiovascular signs are more important,
the patient presents in HF, with murmurs related to more severe degrees of regurgitation, arrhythmias, pericarditis, and several abnormalities on the ECG, chest X Ray
and Doppler echocardiogram [20].

Chorea
Sydenham’s chorea may occur in association with other manifestations, but it may
also be the sole expression. It is a neurological disorder characterized by rapid and
involuntary movements, which are more common during stress and cease during
sleep. Its incidence varies from 5 to 36 % and it occurs predominantly in female
children and adolescents [20].

Eritema Marginatum
It is a rare skin manifestation (4–15 % of the patients), generally occurring at the
beginning of the disease. It is usually associated with carditis, but not with its severity, being characterized by a non-itchy pink-red lesion, which predominantly affects
the trunk and spares the face. It may disappear within hours and it is difficult to
detect in dark-skin patients [20].

Subcutaneous Nodules
They are firm and painless, varying greatly in size, and representing a rare manifestation (2–5 %) of the disease. The overlying skin is not inflamed and they are usually located over bones surfaces or tendons and best detected by palpation and not
inspection. Their presence is strongly associated with severe carditis [20].

Minor Manifestations
They are unspecific and only when associated with major criteria and evidence of
previous GAS infection help to establish the diagnosis. Fever and tachycardia out of
proportion to the fever are usually present. Fever is usually of low grade when there
is carditis without arthritis, and absent in isolated chorea [20].


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After recovery from the initial episode, 72 % of patients will develop valve heart
diseases [18]. Recurrence of the disease can lead to progression of valve lesions
with all its consequences, as HF, atrial fibrillation, stroke, infective endocarditis and
pregnancy-related complications. With progression of the disease, cardiac surgery
becomes mandatory and, if not performed, premature death from RHD and its complications is frequent, with some countries presenting the unacceptable mean age of
death <25 years [22, 23]. Otherwise, patients under regular secondary prophylaxis
may present recovery on the severity of valve lesions.

ECG

ECG is unspecific, since it can be normal in the presence of carditis. A prolonged PR
interval (minor sign) can be present in the absence of carditis. Sinus tachycardia, ST-T
abnormalities, low QRS and T amplitude in the frontal leads can be present [20].

Echocardiogram
Although echocardiogram has been shown to be much more sensitive in the diagnosis
of rheumatic lesions, screening by echocardiography is not always feasible, especially in low-income countries, where the disease is usually more prevalent. Besides,
physiological regurgitations in normal individual can be interpreted as secondary to
RHD. To avoid this misclassification, regurgitation should be considered abnormal
only in the presence of morphological valve abnormalities [21] (Table 3).
Since secondary prevention can avoid adverse outcomes, early echocardiographicbased diagnosis of valve lesions by active surveillance strategies has been shown in
several countries to be of major importance [24–27].
MR is the most frequent lesion in ARF, being present in up to 94 % of the cases.
Valve thickening and focal nodules in the distal portion of the leaflets are frequent
and disappear in the follow-up [28]. AR is not a frequent lesion in ARF, but in males
it can occasionally be an isolated lesion. Stenosis is a late finding. LV dilation may
be present and both cardiomegaly and valve regurgitation can disappear. Systolic
function is usually preserved and HF, when present, is considered nowadays to
occur due to valve lesion and not to myocardium involvement.
In patients with chronic RHD, recurrence is always associated with carditis,
which can be expressed as pericarditis, new or worsening of a pre-existing valve
regurgitation, increase in cardiac silhouette and HF. Size and function of cardiac
chambers, left valve abnormalities (stenosis and regurgitation), tricuspid lesion
(much less frequent) and associated pulmonary hypertension can all be adequately
detected by echocardiography in RHD.


Features in the AV
Irregular or focal thickening
Coaptation defect

Restricted leaflet motion
Prolapse

Pathological aortic regurgitation
Seen in 2 views
In at least 1 view, jet length ≥1 cm
Velocity ≥3 m/s in early diastole
Pan-diastolic jet in at least 1 envelope

Source: WHF criteria for echocardiographic diagnosis of RHD
AMVL anterior mitral valve leaflet, AR aortic regurgitation, AV aortic valve, MR mitral regurgitation, MS mitral stenosis, MV mitral valve, RHD
rheumatic heart disease
a
All four Doppler echocardiographic criteria must be met

Definite RHD (either A, B, C, or D)
A) Pathological MR and at least 2 morphological features of RHD of the MV
B) MS mean gradient ≥4 mmHg
C) Pathological AR and at least 2 morphological features of RHD of the AV
D) Borderline disease of both the AV and MV
Borderline RHD (either A, B, or C)
A) At least 2 morphological features of RHD of the MV without pathological MR or MS
B) Pathological MR
C) Pathological AR
Criteria for pathological regurgitation
Pathological mitral regurgitation
Seen in 2 views
In at least 1 view, jet length ≥2 cm
Velocity ≥3 m/s for 1 complete envelope
Pan-systolic jet in at least 1 envelope

Morphological features of RHD
Features in the MV
AMVL thickeninga ≥3 mm (age-specific)
Chordal thickening
Restricted leaflet motion
Excessive leaflet tip motion during systole

Table 3 Echocardiographic criteria for individuals aged ≤20 years

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Treatment
General Measures
Treatment aims to suppress the acute inflammatory process, minimizing clinical
repercussions on the heart, joints and central nervous system, in addition to eradicating GAS infection and promoting relief of main symptoms [20, 29].
Absolute bed rest is no longer recommended, except in the presence of carditis,
when bed rest, at least during the symptomatic stage, is recommended. Return to
normal activities should be gradual depending on the improvement of symptoms
and normalization or marked reduction of inflammatory activity tests.
In cases of high temperature, paracetamol is recommended as a first option, and
dipyrone as a second. Anti-inflammatory drugs, including acid acetylsalicylic, are
not indicated before the diagnosis of ARF is confirmed [20].

Anti-inflammatory and Corticosteroids

The first lines of symptomatic therapy are anti-inflammatory agents, ranging from
salicylates to steroids [27, 30, 31]. Salicylates markedly reduce fever and relieve joint
pain and swelling, but they have no effect on the natural course of the disease. Adults
may require large doses of aspirin, 0.6–0.9 g every 4 h, while children are treated with
lower doses. Corticosteroids are not frequently used because they offer no therapeutic
benefits and may mask the presence of other illnesses causing arthritis [20, 29].

Therapeutic Modalities
Acute carditis has generally been treated with steroids even though they have
no effect on the progression of RHD. Nevertheless, in the setting of severe, potentially life-threatening HF, steroid administration is largely employed [20, 29–31].
Treatment of cardiac manifestations follows established guidelines, including management of HF and severe valve regurgitation. Digitalis can be used but with special
attention because of the risk of development of heart block. Cardiac surgery should
be avoided whenever possible during ARF, being indicated only in the presence of
severe valve regurgitation with HF refractory to drug therapy [20, 29, 31].
Treatment for chorea is indicated only in severe forms, when uncoordinated
movements interfere with usual activity of the patients. Drugs used to control chorea symptoms are haloperidol, valproic acid, and carbamazepine. Small series have
studied corticosteroids, along with plasmapheresis and intravenous immunoglobulin,
to assess their influence on the severity and time course of symptoms, but there is
not enough evidence for the indication of these therapies [20, 29].


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Prophylaxis for Rheumatic Fever
Primary Prevention
The initial episode of ARF can usually be prevented by early treatment of streptococcal pharyngitis. Patients with evident bacterial pharyngitis and positive test
results for GAS should be treated as early as possible in the suppurative phase.
Effective prevention of ARF is obtained even when antibiotics are started until

9 days after the onset of the infection [20, 29]. Early treatment of streptococcal
pharyngitis is especially recommended in countries with a high prevalence of ARF
to avoid the development of new cases of the disease, since the transmission rate in
untreated patients is approximately 35 % in close contacts (families, schools, or
other agglomerations). It is noteworthy that 24 h after beginning treatment with
penicillin, patient becomes minimally contagious [20].
Intramuscular Benzathine penicillin G and oral V penicillin are the recommended
for the treatment of streptococcal pharyngitis, except in individuals with history of
penicillin allergy (Table 4). Benzathine penicillin remains the drug of choice
because it is cost-effective, has a narrow spectrum of activity, long-standing proven
efficacy, low incidence of side effects, and good adherence to the regimen imposed.
Furthermore, to date, penicillin-resistant GAS has not been registered.
The oral antibiotics of choice are V penicillin and amoxicillin (Table 4). All
patients should continue to take penicillin regularly for an entire 10-day period,
even though they likely become asymptomatic after the first few days. Oral cephalosporin, indicated for penicillin-allergic patients, have been used in shorter than
10-day courses, with high compliance, bacterial elimination and clinical response
that may be superior to penicillin treatment. However, evidence is insufficient to
recommend this treatment regimen in endemic areas. Azithromycin can be used in
shorter treatment regimen (3–5 days) [20, 29], however, proven resistance to GAS
has been reported. Aggressive antibiotic therapy for primary prevention is essential
in areas where RF is prevalent and may represent the best hope for decreasing the
overall health care burden of RHD [32]. In contrast, in populations where ARF is
rare, antibiotic use results in modest therapeutic benefit, and the risk-benefit ratio
has been called into question.
Certain antimicrobials are not recommended for treatment of GAS upper
respiratory tract infections [29]. Tetracyclines should not be used because of the
high prevalence of resistant strains. Sulfonamides and trimethoprim-sulfamethoxazole do not eradicate GAS in patients with pharyngitis. Older fluoroquinolones (eg, ciprofloxacin) have limited activity against GAS and newer
fluoroquinolones (eg, levofloxacin, moxifloxacin) are active in vitro against GAS
but are expensive and have an unnecessarily broad spectrum of activity, and
therefore, they are not recommended for routine treatment of streptococcal pharyngitis [29].

Varies by drug
300 mg PO
500 mg PO day 1
250 mg PO days 2–5
250 mg PO

Dose
<20 kg: 600,000 U IM
≥20 kg: 1,200,000 U IM
500 mg PO
500 mg PO
100 mg/kg/day PO

Sources: Arq Bras Cardiol.2009;93 (3 supl.4):1–18
Circulation. 2009 24; 119(11):1541–51
*
In case of allergy to penicillin and erythromycin [20, 29]

Clarithromycin

Penicillin V
Amoxicillin
Ampicilin
Penicillin allergic
Narrow-spectrum cephalosporins
Clindamycin*
Azithromycin

Antibiotic
Benzathine penicillin G

Table 4 Primary prevention of rheumatic fever

Twice

daily

Varies by drug
Twice daily
Daily

2 or 3 times daily
Thrice daily
Thrice daily

Frequency
1 time

10

days

10 days
10 days
5 days

10 days
10 days

10 days

Duration
Acutely only

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M. de Melo Barbosa et al.

Secondary Prevention
Prevention of recurrent episodes of GAS pharyngitis is the most effective method to
prevent the development of severe RHD [20, 29]. Recurrences of ARF are most
common in patients who have had carditis during their initial episode. A recurrent
attack can be associated with worsening of the severity of RHD that developed after
a first attack, or less frequently with the new onset of RHD in individuals who did
not develop cardiac manifestations during the first attack.
For these reasons, prevention of recurrent ARF requires continuous antimicrobial
prophylaxis. The preferred method of prophylaxis is with Benzathine penicillin G,
1.2 million units intramuscularly every 3 weeks (Table 5) [20, 30].
Successful oral prophylaxis depends primarily on patient adherence to prescribed
regimens. The recommended oral agent is V penicillin. The dosage for children and
adults is 250 mg twice daily (Table 5). There are no published data about the use of
other penicillins, macrolides, azalides, or cephalosporins for the secondary prevention of rheumatic fever. If the patient is allergic to penicillin, sulfadiazine is recommended. Although sulfonamides are not effective in the eradication of GAS, they
prevent infection. For the patient who is allergic to both penicillin and sulfadiazine,
an oral macrolide (erythromycin or clarithromycin) [20, 29].
Recurrences are uncommon after 5 years following the first episode and in

patients over 25 years of age. Prophylaxis is usually discontinued after these times,
except in groups with a high risk of streptococcal infection, such as parents or teachers of young children, nurses, military recruits, etc.
Secondary prevention of RF depends on whether carditis has occurred (Table 6).
If there is no evidence of carditis, preventive therapy can be stopped at age 21.
If carditis has occurred but there is no residual valve disease, it can be stopped at
10 years after the first episode. If carditis has occurred with residual valve involvement,
it should be continued for 10 years after the last episode or until the age of 40 years,
if the patient is in a situation in which re-exposure would be expected [29]. Lifelong
prophylaxis should be considered in high-risk patients according to the severity of
valve heart disease and exposure to group A streptococcus, in a situation in which

Table 5 Secondary prevention of rheumatic fever
Antibiotic
Benzathine

penicillin G

Penicillin V
Penicillin allergic
Sulfadiazine
Penicillin and sulfadiazine allergic
Erythromycin

Dose
<20 kg: 600,000 U IM
≥20 kg: 1,200,000 U IM
250 mg PO

Frequency
Every 3 weeks

1g

Daily

PO

250 mg

Sources: Arq Bras Cardiol.2009;93 (3 supl.4):1–18
Circulation. 2009 24; 119(11):1541–51

PO

Twice

Twice

daily

daily


Rheumatic Heart Disease: A Neglected Heart Disease

155

Table 6 Duration of secondary rheumatic fever prophylaxis
Category
Rheumatic fever with carditis and

residual heart diseasea
Rheumatic fever with carditis, but
no residual heart disease
Rheumatic fever without carditis

Duration after last attack
10 years or until 40 years of age (whichever is longer),
sometimes lifelong prophylaxis
10 years or until 21 years of age (whichever is longer)
5 years or until 21 years of age (whichever is longer)

Sources: Arq Bras Cardiol.2009;93 (3 supl.4):1–18
Circulation. 2009 24; 119(11):1541–51
a
Patients at high risk for repeated episodes of rheumatic fever, such as those at significant risk of
recurrent exposure to group A streptococcus infection, should be considered for life-long antibiotic
prophylaxis

reexposure would be expected. The decision to discontinue prophylaxis should be
made after discussion with the patient of the potential risks and benefits, considering the epidemiological risk factors.
In summary, RHD remains a major public health problem in many countries
throughout the world, with the unfair profile of affecting children and young adults
of poor and developing countries, with devastating personal and economical burden
for this already sacrificed population. Low- or middle-income countries still do not
have coordinated, national control programs [5]. A remarkable transformation leading to increased advocacy for the establishment of comprehensive approaches to
RF/RHD control, encompassing primary and secondary prevention, treatment of
established RHD, broad education and health promotion strategies, is highly necessary [32]. RF vaccine is still a future possibility [5], but its development will bring
new hope to this difficult scenario [20].

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Chagas Disease: A Neglected Disease
José Antonio Marin-Neto, Anis Rassi Jr., Andréa Silvestre de Sousa,
João Carlos Pinto Dias, and Anis Rassi

Introduction
In 1909, the Brazilian physician Carlos Chagas reported to the scientific community
the discovery of a new pathogenic agent, Trypanosoma cruzi (T. cruzi) and the previously unknown illness it caused [1]. Far from being rare, it was soon noted that the
new disease affected millions of people across nearly the entire Latin American
subcontinent. The recovery of T. cruzi genetic material from South American

J.A. Marin-Neto, M.D., Ph.D. (*)
Cardiology and Pneumology from the University of Sao Paulo, Sao Paulo, Brazil
Interventional Cardiology from the Hospital das Clinicas, Ribeirão Preto Medical School,
Sao Paulo, Brazil
e-mail:
A. Rassi Jr., M.D., Ph.D.
Anis Rassi Hospital, Goiania, Goias, Brazil
e-mail:
A.S. de Sousa, M.D., Ph.D.
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Oswaldo Cruz Foundation, Rio de Janeiro, Brazil

e-mail:
J.C.P. Dias, M.D., Ph.D.
School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
Neglected Diseases Committee of the World Health Organization, Genève, Switzerland
e-mail:
A. Rassi , M.D.
Faculty of Medicine, Federal University of Goias, Goiania, Goias, Brazil
© Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_16

159


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mummies in paleoparasitological studies provided evidence that Chagas disease
had already affected human beings at least 9000 years ago [2].
A few years later, Carlos Chagas and a group of collaborators—Belisário Penna,
Eurico Villela, and Ezequiel Dias, among others—succeeded in characterizing the
main clinical manifestations of the disease in the cardiovascular system [3]. The
chief mode of disease transmission between humans, involving hematophagous
mosquitos of the family Triatominae, was described soon afterwards.
Despite the unassailable success and distinction of the aforementioned research,
Chagas disease endured periods of complete oblivion during the twentieth century,
in the words of pathologist Fritz Köberle, in addition to an early continuous relative
neglect by a segment of the medical and scientific communities. As a result, undeniable gaps remain in the elucidation of the pathogenesis of the cardiovascular
involvement, as well as some uncertainty regarding the clinical management of the

disease.
In the present chapter, aspects that remain unclear relative to the pathogenesis of
Chagas heart disease (CHD) and its overlooked prevention at the primary, secondary and tertiary levels are reviewed.

Etiopathogenesis of CHD
The pathogenetic mechanisms that underlie the development of the chronic stage of
CHD have not yet been fully elucidated.
Fundamentally, CHD is an inflammatory form of dilated cardiomyopathy often
accompanied by low-intensity, although effectively relentless myocardial damage,
resulting in reactive and reparative fibrosis and progressive ventricular dysfunction [4].
Among various other particular pathophysiological characteristics germane to
CHD, several investigators have independently observed destruction of the neurons
of the cardiac intramural ganglia, particularly those of the parasympathetic subtype,
with consequent dysregulation of autonomic circulatory control. The cardiac dysautonomia observed in patients with CHD results in abolition of the overall vagal
inhibition of the sinoatrial node and also deprives such patients of the mechanism of
rapid adjustment of the heart rate to transient variations of the systemic arterial pressure and venous return. Based on those changes in the intrinsic cardiac nervous
system, characterized by the (non-exclusive) predominance of parasympathetic
denervation, the so-called neurogenic theory of CHD postulated that autonomic
imbalance accounted for a true heart disease induced by excessive adrenergic stimulation [5]. However, this theory could not be validated due to the lack of correlation
between the degree of parasympathetic denervation and the extent of myocardial
injury, among other factors [4]. Nevertheless, the hypothesis that cardiac dysautonomia may contribute to the occurrence of malignant arrhythmias and sudden death
as well as to the development of disorders of coronary microcirculation regulation,
remains attractive [4].


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Indeed, various microcirculatory abnormalities were described in experimental

models of T. cruzi infection and in human individuals with CHD, including thrombosis, spasm and endothelial dysfunction associated with amplified platelet activity
[6]. Such disorders might be due to the tissue inflammatory changes induced by
infection with T. cruzi, or to the immune reactions consequent to infection. Together,
these microcirculatory abnormalities might cause ischemic myocardial injury and
superimposed fibrosis [7]. These disorders might play a role in the genesis of symptoms, such as atypical angina, which is common among individuals with CHD, and
might cause the myocardial perfusion defects that are frequently observed. Although
the coronary arteries of CHD patients are normal on angiography, abnormal
responses to vasodilator and vasoconstrictor stimuli at subepicardial levels have also
been reported. The hypothesis that microcirculatory abnormalities participate in the
formation of the characteristic fibrotic and aneurysmal lesions found in most patients
with CHD, particularly in the apical and inferoposterior regions of the left ventricle,
namely, vascular areas of relative separation among the various territories of coronary distribution (watershed) is quite plausible [8]. Chest pain is possibly the most
neglected among the symptoms commonly exhibited by CHD patients, and its clinical treatment only recently became the specific target of a study still in progress [9].
Several convincing clues suggest that autoimmune mechanisms participate in the
pathogenesis of CHD, as cardiac injury was found to occur after immunization with
T. cruzi antigens and the passive transfer of lymphocytes from infected animals,
whereas chronic myocarditis was attenuated once the animals became tolerant to
myocardial antigens [10]. The immune response to parasitic infection, involving
polyclonal activation or molecular mimicry, might itself represent a mechanism of
aggression to the myocardium [11].
Nevertheless, the actual role of autoimmunity in the pathogenesis of the lesions
characteristic of the chronic stage of disease is rather poorly established. Yet, the
hypothesis that the nature and intensity of the host’s immune response to the presence of parasites in the tissues might behave as a true “doubled-edged sword”
remains plausible. When the immune system is depressed by disease (e.g., by coinfection with the human immunodeficiency virus—HIV) or iatrogenically (e.g., in
transplanted patients to avoid rejection), infection with T. cruzi is patently exacerbated. This fact indicates that before being suppressed, the immune system seeks to
prevent infection with the parasite, and thus it is an inherently protective factor. In
accord with that theory, a persistently well-modulated immune response might represent the primary mechanism by which most patients with chronic T. cruzi infection remain with the indeterminate form of Chagas disease for life (i.e., without
clinical manifestations of heart disease or gastrointestinal disorders—“megas”).
The impression resulting from the aforementioned considerations on ambivalent
(beneficial or harmful) immune mechanisms in CHD notwithstanding, a growing

consensus holds that the persistence of the parasite in the tissues is the fundamental
pathogenic factor in the myocardial affliction characteristic of the chronic disease
stage [4, 12–14]. The evidence supporting that consensus derive from multiple
sources, including both experimental research and human studies as discussed


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below, together with the all-important issue regarding the prevention of CHD development in patients with chronic T. cruzi infection.
To summarize, several crucial aspects of the etiopathogenesis of CHD have not
yet been definitively elucidated [15]. Whereas the available pathogenetic hypotheses and theories are reasonable to some extent, they lack firm support in conclusive
studies. Thus, in the course of one century of research, some negligence in the
approach to CHD pathogenesis appears to have been unavoidable. Such relative
negligence appears obvious, for example, in the fact that over one decade, some
studies and investigators insisted repeatedly in asserting certain aspects of the
pathophysiology of CHD instead of seeking to investigate more objectively and
persistently the consequences of those disorders to elucidate the prognostic meaning of the abnormalities that were already exhaustively demonstrated [16].

Prevention of CHD
Vector-borne transmission remains the main route of human infection with T. cruzi
and is usually associated with the vector’s blood meals. Indeed, the hematophagous
insects defecate while sucking the host’s blood, and thus the parasites enter the
bloodstream through the skin disruption caused by the sting, or even through intact
mucous membranes close to the sting site. The insects also played a role, albeit
passive, in recently reported outbreaks of infection via the intake of contaminated
food, that is, during the preparation of food (usually during the grinding of sugarcane, açaí palm, etc.) [17, 18]. As a result of the interventions that led to the eradication of the main vectors in Latin America, the oral route of transmission became the
most common route in several countries, including Brazil. The second most frequent route of transmission of infection with T. cruzi is via blood transfusions, the
prevalence of which is most likely underestimated due to poor reporting within the

medical sector [19]. This is the most pertinent route of transmission of infection in
countries where Chagas disease is not endemic, due to the lack of efficacious serologic control and the increasing number of infected immigrants from Latin America,
particularly in Europe and the United States.
The incidence of vertical mother-to-child transmission of infection through the
transplacental route is estimated to vary from 1 % in Brazil to 7 % in some areas of
Bolivia and Paraguay, depending on factors such as parasite strain, the mother’s
immune status and the diagnostic technique used to detect infection [20]. Transmission
is less often due to transplantation of organs donated by infected individuals or to
laboratory accidents. Most of the cases of transmission via transplanted organs occur
in countries where Chagas disease is not endemic and are due to the lack of efficacious and validated serologic techniques, lack of familiarity with the manifestations
of acute disease and the presence of Latin American donors, many of whom have
dual citizenship, which may make the identification of high-risk donors difficult.
Among the parasitic diseases, only malaria and schistosomiasis are more significant from an epidemiological point of view than Chagas disease [21]. Chagas
disease was historically confined to rural areas with very low levels of social develop-


Chagas Disease: A Neglected Disease
Prevention level
Target population

Strategies

Responsible entities
Intervention
aims

163

Primary prevention

Secondary prevention

Individuals
at risk

Early/asymptomatic
stage of disease

Tertiary prevention

Established
disease

• Vector control
• Prevention of
of transmission
via blood transfusions
• Prevention of
transmission
via organ transplantation
• Care in
laboratory
handling ofT. cruzi

• Screening
• Detection of infected
individuals
• Early intervention
• Antiparasitic
treatment

• Periodic health exams

• Antiparasitic disease
(selected cases)
• Pharmacological and
non-pharmacological
interventions
• Symptomatic treatment
• Management of
complications
• Permanent care

• Public health
• Primary care
• Other

• Primary care
• Public health

• Specialized services
• Hospital units

• Prevent transmission
of Chagas disease

• Avoid progression of
the indeterminate form
to the clinical forms
of disease

• To limit the morbidity

Chagas disease
absent

Indeterminate
form

and mortality of
disease
manifestations
Cardiac and
digestive forms

Disease progression

Fig. 1 Strategies for prevention of Chagas disease [28]

ment in nearly all of the continental Latin American countries. That scenario changed
quite recently, as the epidemiological significance of Chagas disease in those countries was greatly reduced [22]. In global terms, 8–10 million people are currently
estimated to be infected [23, 24] versus 16–18 million in the 1990s [25]. In parallel,
as a function of migration circuits involving infected individuals from endemic countries, Chagas disease became a public health problem in the United States and other
countries, such as Spain, Belgium, France, England, Japan and Australia [26]. Such
epidemiological transitions in non-endemic countries accentuated the concern
regarding the possible transmission of infection via blood transfusions, solid organ
donation and the transplacental route. Additionally, the search for diagnostic and
clinical treatment methods for infected individuals was intensified in those countries,
which also targeted the prevention of transmission to other people [27].
The methods available to reduce the medical and social impact of Chagas disease
are based on three levels of prevention, primary, secondary and tertiary, and are

discussed next [28] (Fig. 1).
Primary prevention seeks to avoid the occurrence of new infections, i.e., to eliminate the risk of infection of exposed individuals and to interrupt the chain of
transmission. Those goals are mainly achieved by means of strategies focusing on
the control of both vector- and non-vector-borne transmission. However, in the case
of the vertical route, it should be borne in mind that there is no procedure available
to reliably impede mother-to-child transmission.
Secondary prevention consists of the screening and detection of individuals
infected with T. cruzi in the early stages of disease. This strategy is essential in acute
cases. In chronic cases, and more particularly those with the indeterminate form of


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Chagas disease, particularly asymptomatic individuals who are often unaware of
being infected, the aim of secondary prevention is to provide etiological treatment.
Eradication or reduction of the parasite load may in principle avoid or delay the
progression of disease into the determinate chronic forms and contributes to interrupting the infection’s epidemiological chain of transmission.
Tertiary prevention consists of the clinical interventions performed to limit the
morbidity and mortality of established disease in a special manner as concerns CHD.

Primary Prevention of Chagas Disease
Since the era of Carlos Chagas and colleagues, the belief has been held that the
control of infection could be more easily attained by means of primary prevention.
Currently, primary prevention is still centered on the control of vectors by chemical
means, in addition to the screening of blood donors using sensitive and specific
serologic methods. Such measures must be continuously supported by strategies
targeting basic health education, effective participation of the community in programs, improvement of housing conditions and constant epidemiological
surveillance. The reward for such strategies is immediate when they are rigorously

implemented, as the number of new vector-borne infections is reduced. The rate of
infection through blood transfusions decreases soon afterwards. In areas where
vector-borne and blood transfusion transmission are controlled, the number of
infected pregnant women is progressively reduced, whereby vertical transmission
exhibits a significant tendency towards reduction. The early detection of infection in
fetuses allows for specific treatment of the affected children [29, 30]. Moreover,
primary prevention strategies targeting care in the laboratory handling of T. cruzi are
quite effective by avoiding work accidents. Similarly effective is the adequate
screening of organ donors through the application of universal serologic techniques
in locations where the seroprevalence is high, or also the use of serologic tests combined with specific epidemiological investigation.
Alternatively, the opportunities to diagnose infection with T. cruzi and to provide
etiological treatment before women become pregnant to prevent vertical transmission are rare. Additionally, the prevention of infection by the oral route is practically
impossible. Therefore, in both instances, the most effective strategy to control
infection consists of early detection and trypanosomicidal treatment.
Preventive immunization by means of a safe and effective vaccine is not yet
available, partially as a function of the theoretical risk of adverse immune reactions
[31]. Another hindrance is represented by the multiple molecular variants of T. cruzi
[32], which confounds the search for an adequate vaccine by a rather indefinite
antigenic target [33].
The implementation of control programs depends on three essential factors:
acknowledgment of the medical significance of the disease; definition of its social
impact; and the availability of resources and minimal strategies aimed at control.
Following the most characteristic period of oblivion to Chagas disease, the modern


Chagas Disease: A Neglected Disease

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era of combat against the disease began between 1945 and 1955, when residual

insecticides were used to combat the vectors and pathologic, serologic and clinical
studies became systematized [34]. Beginning in the 1960s, national programs of
vector control were launched; serologic screening for T. cruzi in blood banks became
mandatory in the 1980s, parallel to the measures established for the control of the
emerging HIV pandemic [19, 34].

Control of Vectors
Vector control is essential under conditions of domiciliary and peridomiciliary
infestation, by means of continuous and regular application of residual insecticides
also followed, in principle, by continuous and sustained epidemiological surveillance. Synthetic pyrethroids derived from chrysanthemic acid (deltamethrin,
lambda-cyhalothrin, cyfluthrin, etc.) are currently the most effective insecticides. In
cases of resistance to those agents, which seldom occurs, organochlorine or carbamate compounds may be alternatively used [34].
The perception that population-based educational campaigns and active
participation of the community in strategies for vector control are an essential part
of epidemiological surveillance is universally accepted. Improvement of housing
conditions is also quite effective; however, except for rare exceptions (such as the
2001 experience in Venezuela), this has never been properly prioritized in national
programs [35].
It should be noted that eradication, namely, complete interruption of Chagas disease transmission, is practically an unattainable epidemiological target. Even in
places where that goal could be partially achieved, such as the extinction of transmission by Triatoma infestans in countries such as Uruguay, Chile and Brazil,
entomological surveillance must be maintained for many years. The proposal that
infection with T. cruzi evolved from a primitive type of zoonosis to a true and highly
spread anthropozoonosis is currently very clear. Moreover, the parasite is currently
disseminated across many sylvatic areas, in which its ecotopes are being increasingly altered by human activity (e.g., indiscriminate deforestation) such as in the
Amazon region, where the incidence of autochthonous cases is increasing [36].
Evidence also exists for the presence of several secondary vectors, namely, triatomine insects potentially susceptible to domiciliation, as well as that of vector
resistance to the most commonly used insecticides.

Control of Transmission via Transfusions
Although less rigorous, this strategy was applied as early as the 1990s, through the

serologic detection and chemoprophylaxis of suspected blood, and intensified in parallel with the establishment of measures against infection with HIV. Ideally, two


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highly accurate serologic tests based on two different techniques (e.g., indirect immunofluorescence and ELISA) should be employed for the screening of blood donors.
However, starting in 2002, the World Health Organization (WHO) recommends
performing only one test (ELISA) to detect blood donors infected with T. cruzi [20].
Likely due to technical inadequacies in the performance of the serologic tests, this
recommendation led to a significant reduction in the sensitivity of detecting infected
blood and organ donors, the consequences of which are only beginning to be understood. For example, acute Chagas infection was detected in one individual without
Chagas disease who received the transplanted liver of an allegedly non-infected donor
in Brazil, which is an endemic country [37]. The challenge is heightened by the fact
that a large fraction of the donors and recipients are transfused with large amounts of
blood components on the occasion of the event leading to death or in the perioperative
period of heart transplantation, respectively. Under such circumstances, high-sensitivity serologic control of hemodiluted sera, with sufficient specificity so as not to reject
viable organs should be mandatory. The need to improve the methods for serologic
detection of T. cruzi infection in endemic and non-endemic areas is reinforced by the
recent description of a series of patients with chest pain and segmental wall-motion
abnormalities of the left ventricle (such as apical aneurysm) highly suggestive of
CHD, but who had negative results by the immunofluorescence serologic test [38].

Prevention of Infection Through Solid Organ Donation
The most common scenario of infection via solid organ donation is the case of a
seropositive donor and a seronegative recipient. However, just as in the case cited
above [37], the transmission of Chagas infection through organ transplantation
(heart, kidneys, bone marrow, liver) was also reported relative to allegedly seronegative donors, even in non-endemic countries.
In the absence of more conclusive and informative evidence, the consensus of

specialists converges towards the following prophylactic guidelines based on the
serologic status of organ donors and recipients before transplantation [39, 40].
When the donor is seronegative and the recipient is seropositive, the latter’s postoperative recovery should be closely monitored for the early detection of possible
infection reactivation, which might occur as a function of the immune modulation
regimen required to prevent graft rejection. If parasitemia intensifies or if clinical
indicators consistent with reactivation appear, etiological treatment should be initiated. Prophylactic treatment of recipients with trypanosomicidal agents before
transplantation is a less favored approach, although it is a reasonable option within
the context of heart transplantation [41]. Notably, not even qualitative polymerase
chain reaction (PCR) techniques for the detection of parasitemia have sufficient
sensitivity to define the presence of reactivation, although their negative predictive
value is adequate to rule it out. Quantitative PCR techniques (real-time PCR) are
currently used only for research purposes. However, it is safe to assume that once
cutoff points are established, this method will be used for the indication of preemptive treatment in cases with high parasitemia levels.


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The same principles apply when both donor and recipient are seropositive; as a
rule, specific treatment is recommended for the donor before transplant surgery
[28]. Relative to heart transplantation, which is not allowed when the donor is seropositive, relative to other organs, prior specific consent is required.
Finally, the situation of a seropositive potential donor and a seronegative recipient (in the case of living donors) is a particular cause of concern because
transplantation is a priority that cannot be bypassed. In such cases, it is recommended to administer antitrypanosomal treatment to the donor for at least 10 days
(60 days ideally) to reduce or eliminate the parasitemia as well as to the recipient
along with treatment for 10 days after surgery to minimize the odds of parasite invasion and multiplication in his/her body. If the recipient becomes seropositive,
standard trypanosomicidal treatment for 60–90 days is recommended [28].

Prevention of Laboratory and Hospital Accidents
Training in and compliance with the universally accepted basic principles for work

in environments in which professionals work with people or materials that are
potentially contaminated with T. cruzi are the core of the prevention of transmission
through this route. Ideally, the professionals should be subjected to serologic testing
upon being hired by institutions in which they may be exposed to unintentional risk.
If contamination is suspected, the following procedures should be adopted: immediate disinfection of the eyes or skin lesions using alcohol; start prophylactic etiological treatment with the usual dose for 10 days; notify the head of the laboratory or
hospital unit in which the incident occurred to avoid repetitions; and perform serological testing 30 days after the event. In cases of seroconversion, standard
etiological treatment for 60–90 days is recommended [28].

Preventive Treatment for Cases of Congenital Transmission
Preventive etiological treatment using the currently available drugs is contraindicated for seropositive pregnant women. Pregnant women without a previous diagnosis of Chagas disease should be subjected to serological testing. Incases of
positive results, the early detection of transmission to and treatment of the infected
newborn infants are the basic measures [29, 40]. Newborn infants from mothers
with known or highly suspected infection by T. cruzi should be carefully examined
for signs of acute Chagas disease. Additionally, parasitemia should be investigated
particularly by direct examination of the umbilical cord and the infant’s blood.
The conventional serologic tests (based on the detection of IgG antibodies) are not
indicated in this stage because the maternal antibodies remain in the infant for
approximately 6 months after birth. In contrast, serological tests that investigate
IgM antibodies might contribute to the diagnosis because the latter are indicative
of active infection.


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In confirmed cases of congenital transmission, etiological treatment should be
started immediately, which is usually well tolerated by infants.
In the absence of clinical or laboratory evidence of infection, the infants should
be subjected to conventional serologic testing (investigating IgG antibodies) at age

6–8 months; only positive cases should be administered etiological treatment. The
infants should be then subjected to clinical and laboratory assessments once per
year. Persistently negative serologic results are indicative of cure of infection, which
usually occurs about one year after the onset of treatment. In contrast, positive
results denote therapeutic failure and the infants should be treated again, preferably
with a different trypanosomicidal drug [28].

Oral Transmission
Being unpredictable, primary prevention of transmission by the oral route is unfeasible; only progressive improvement of the population’s educational and hygienic
levels will allow the control of this mechanism of Chagas disease transmission.
Because the parasitic load is usually high, and because the mucosa of the digestive
tract is highly permeable to T. cruzi, the mortality in the acute stage of infection may
be quite high. Healthcare professionals should develop a high degree of diagnostic
suspicion, as atypical cases with gastrointestinal bleeding and myopericarditis with
large pericardial effusions are often described, to achieve effective parasitological
confirmation and to begin etiological treatment immediately. Similarly, epidemiological surveillance should be established later on, also including the people in
contact with patients infected with T. cruzi per the oral route [40].

Secondary Prevention of Chagas Disease
Independent of the route of transmission, human exposure to T. cruzi exhibits three
main scenarios. The first, that of no infection, is based on the assumption that a
quick and efficient immune response might prevent the settlement of the parasite in
the human body. Infection does occur in the other two scenarios, but it may be clinically unapparent (scenario two) or it may manifest the signs and symptoms of the
acute stage of Chagas disease (Fig. 2).
Following vector-borne exposure to T. cruzi, the usual incubation period of the
acute stage is 1–2 weeks (being variable in other routes of transmission), during
which the parasites in trypomastigote (flagellate) form are detectable in the bloodstream by microscopic methods. The acute stage lasts approximately 12 weeks,
with most patients being asymptomatic or oligosymptomatic; because the actual
cause of infection passes unnoticed, the few (unspecific) symptoms are attributed to
other and trivial diseases, such as the flu.

The acute stage of Chagas disease is diagnosed in a very small number of
patients, who exhibit signs and symptoms compatible with myocarditis or severe