Transcript Long-Term Prognosis of Rheumatic Fever Patients Receiving

Department of Clinical Epidemiology
University of Santo Tomas
Faculty of Medicine and Surgery
Case 1: Acute Rheumatic Fever
Cueto, Mary Anne to Diaz, Cristina
Group 1 – 3B
Clinical Decision on a DIAGNOSTIC
TEST
Case Scenario
E.C., a 28 year old housewife was admitted
because of dyspnea. Three days ago, she had dental
extraction then the next day she began coughing
productive of yellowish sputum. She also had chest
pain radiating to the back lasting for 30 mins and
occurring even at rest. She is febrile (38 C) with joint
pain and myalgia. The Past Medical History - frequent
streptococcal throat infection in childhood; at age 16
years diagnosed to have valvular heart disease and
given monthly Benzathine Penicillin.
Salient Features
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28 year old housewife
Dyspnea
History of dental extraction 3 days ago
Productive cough
Yellowish sputum
Unstable angina
Febrile
Joint pain
Myalgia
Past medical history of frequent streptococcal throat
infection as a child
• Valvular heart disease
Acute Rheumatic Fever and Rheumatic Heart Disease on the Navajo Reservation, 1962-77. JOHN COULEHAN, MD, SHELLIE GRANT, MD, KEITH REISINGER, MD, PAUL KILLIAN,
MD, KENNETH D. ROGERS, MD, CHARLES KALTENBACH, DrPH
Public Health Reports, January-February 1980, Vol. 95, No. 1
Modified Jones Criteria
• Presence of two major or one major and two minor, plus
evidence of antecedent group A streptococcus infection.
Major criteria
Minor criteria
Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Arthralgia
Fever
Raised erythrocyte sedimentation
rate or Creactive
protein concentrations
Prolonged PR interval on
electrocardiogram
Plus evidence of recent streptococcal infection
Differential Diagnosis
Presentation
Polyarthritis and fever
Carditis
Septic arthritis
CT and other autoimmune disorder
Viral arthropathy
Reactive arthropathy
Lyme disease
Sickle cell anemia
Infective carditis
Leukemia or lymphoma
Gout and pseudogout
Innocent murmur
Mitral valve prolapse
Congenital heart disease
Infective endocarditis
Hypertrophic cardiomyopathy
Myocarditis
pericarditis
Clinical Question
How useful is echocardiography in
the evaluation of a 28 year old
female presenting with signs and
symptoms of acute rheumatic fever?
Spectrum of Disease: Rheumatic Fever
65%
25%
75%
• Population: Population: 452 patients with acute
rheumatic fever diagnosed by Jones criteria, 230 males
and 222 females, age range from 1 yr 11mos to 51
years old
• Intervention: Echocardiographic diagnostic procedure
• outcome: incremental role of echocardiography
Search terms: Echocardiography, acute rheumatic
fever, adult
Journal Title:
The Role of Echocardiography in Diagnosing
Carditis in the Setting of Acute Rheumatic Fever
Ishwarappa B. Vijayalakshmi, Jayapal Mithravinda, Arale N. Prabhu
DevaSpectrum of Disease
Critical Appraisal
RELEVANCE
Is the object of the study relevant to your clinical question?
Yes. The aim of the study is to assess the utility of
echocardiography in the diagnosis of acute rheumatic fever
or its recurrence. We want to know whether we could use
echocardiography to diagnose carditis which is a major
criterion for the diagnosis of acute rheumatic fever,
according to Jones criteria. Carditis is the also the most
important prognostic factor in Acute rheumatic fever.
Validity guides:
Was there an independent and blind comparison with a
reference standard? What was the reference standard. Were
they assessed independently?
Yes. The reference standard for the diagnosis of Acute
rheumatic fever is through the Jones criteria which was
performed in all the subjects. A single cardiologist reevaluated
the subjects who was unaware of the diagnosis. Doppler
echocardiography was performed by a well trained and
experienced echocardiographer, who was unaware of the
diagnosis.
Did the patient sample include an appropriate spectrum of
patients with whom the test will be used?
Yes. The patient sample include 492 patients with age
range of 1 year old 11 months to 52 years old. 230 males and
222 were females. All were diagnosed with Acute rheumatic
fever using the Jones criteria.
Was the reference standard done regardless of the result of
the diagnostic test being evaluated?
Yes. Clinical assessment was done whatever the outcome
of the echocardiography was done.
Was the method of performing the test described in
sufficient detail to permit replication?
Yes. Table 1 under the materials and methods described
the findings that were assessed using echocardiography.
Overall is the study valid?
Yes.
WHAT ARE THE RESULTS?
What were the likelihood ratios for the different possible
test results?
• Study population:452
• Polyarthritis n=239
• Clinically diagnosed (+): 164
• Clinically diagnosed (-): 75
• Echocardiography (+): 141
• Echocardiography (-): 98
• Polyarthralgia n=213
• Clinically diagnosed (+): 38
• Clinically diagnosed (-): 88
• Echocardiography (+): 125
• Echocardiography (-): 175
CAN THE RESULTS HELP ME IN
CARING FOR MY PATIENTS?
Will the reproducibility of the test result and its
interpretation be satisfactory in my setting?
Yes. Echocardiography can be easily performed in
our setting.
Are the results applicable to my patient?
Yes. The population of the study has similar characteristics with
our patient.
Will the results change my management?
Post test probability if echocardiography is (+): 89%
Post test probability if echocardiography is (-): 21%
Since the post test probability for both a positive and negative result did
not fall within the testing zone, no further diagnostic tools are needed
and we can proceed to the treatment
Spectrum of disease: Rheumatic Fever
25%
Post-test probability if
echocardiography is (-):
21%
Post-test probability
Lower/upper testing threshold
Pretest probability
65%
75%
Post-test probability if
echocardiography is (+):
81%
RESOLUTION OF THE CASE SCENARIO
Electrocardiography is an accurate diagnostic tool for the
diagnosis of carditis in patients with acute rheumatic fever.
Treatment
• Clinical Question: Can penicillin resolve the symptoms
in patients with Streptococcal infection?
• Search Terms: streptococcal infection, treatment
• Population: 15-60 y/o males and females with sore
throat
• Intervention: Penicillin V
• Comparison: Placebo
• Outcome: Resolution of symptoms in the first week,
eradication of bacteria after two weeks, and
recurrences of sore throat after two, four, and six
months.
Penicillin for acute sore throat: randomised double blind
trial of seven days versus three days treatment or placebo
in adults
Sjoerd Zwart, Alfred P E Sachs, Gijs J H M Ruijs, Jan W Gubbels, Arno W Hoes, Ruut A de Melker
BMJ 2000;320:150–4
• Validity Guides
– Was the assignment of patients to treatment randomized? Was
randomization concealed?
• Yes. Patients were randomly assigned to one of three treatment
groups: penicillin V for seven days, penicillin V for three days
followed by placebo for four days, or placebo for seven days. The
dosage was two 250 mg capsules three times daily. Paracetamol
tablets were supplied to all patients to be used on demand.
(Participants and Methods, Treatment Groups, p. 151)
– Was the follow up sufficiently long and complete?
• Yes. Fourteen days after inclusion the patients were reexamined by
their general practitioner. After two, four, and six months the
patients were interviewed by telephone on recurrent sore throat
and other complaints of the respiratory tract. (Participants and
Methods, Clinical Follow-up, p. 151)
– Was the data analyzed on an intentionto-treat basis?
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Yes. All analyses were carried out
with spss version 7.0, using an
intention to treat approach.
(Participants and Methods, Data
Analysis, p. 151)
– Was there adequate blinding of
subjects and researchers?
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Randomised double blind placebo
controlled trial. (Abstract, Design, p.
150)
Were there similar baseline
characteristics in each group?
Yes. Refer to table 1.
– Groups treated equally other than
intervention?
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Yes.
Clinical Importance
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What is the magnitude of treatment effect?
Endpoint: Sore throat (duration)
There is a -32% relative risk reduction in the end point sore throat using the 7-day
penicillin V treatment. The relative risk (EER/CER) for penicillin is 132%. And we
need to harm 4 (NNT= -4) patients to prevent shortening of sore throat duration.
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Endpoint: bacterial eradication
There is a -929% relative risk reduction of bacterial eradication using the 7-day
penicillin V treatment. The relative risk (EER/CER) for penicillin is 1028.6%. And we
need to harm 2 (NNT= -2) patients to prevent bacterial eradication.
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Endpoint: Sore throat (recurrence)
There is a -75% relative risk reduction in the recurrence of sore throat using the 7day penicillin V treatment. The relative risk (EER/CER) for penicillin is 175%. And
we need to harm 17 (NNT= -17) patients to prevent recurrence of sore throat.
• Relevance
– Is the objective of the article comparing therapeutic interventions similar to
your clinical dilemma?
• Yes, one of the initial steps in the management of acute rheumatic fever is
to eradicate the infecting agent (Group A Beta Hemolytic Streptococci).
• External Validity
– Are The Results of the Study Applicable to the Patient?
• Yes. The patient is included within the age range of the study subjects.
Both male and female subjects were used in the study. The patient also
has history of recurrent streptococcal throat infections since childhood.
– Were All Clinically Important Outcomes Considered?
• Yes, resolution of symptoms, bacteriological response and recurrences and
adverse effects. (Results, p. 152)
–
Is treatment feasible?
• Yes. Penicillin V is readily available and the re
the treatment is easily monitored.
– Patient preferences
Resolution
• The bottom line of this
clinical study is that a 7day course of penicillin
is effective in resolving
the symptoms in
patients with
Streptococcal infection
of the throat.
CRITICAL APPRAISAL OF ARTICLE
ON HARM
Clinical
question
• Among patients with acute rheumatic fever,
will discontinuation of penicillin have adverse
effects?
Population:
• patients with rheumatic fever taking penicillin
Intervention:
Outcome:
• discontinuance of penicillin
• Harm, complications
Discontinuing Rheumatic Fever Prophylaxis in Selected Adolescents and Young Adults:
A Prospective Study
Ximena Berrios, MD; Emilo del Campo, MD; Beatriz Guzman, RN; and Alan L. Bisno, MD
Search terms: penicillin, rheumatic fever, safety, discontinuance
Is the objective of the article similar to your
dilemma?
R
e
l
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v
• Yes. The objective of the study is to assess the safety of discontinuing
prophylaxis with antimicrobial agents in patients judged to be at relatively low
risk for recurrence of acute rheumatic fever.
•(page 1,Abstract,2nd paragraph)
Were there clearly identified comparison
groups?
Validity
• Yes. The investigator only included patients ranging in age at study entry
from 15 to 44 years (mean, 24.5 years). Patients were entered in the
Control and Prevention Program because of an attack of acute rheumatic
fever (observed and documented by the Program physicians) that fulfilled
the modified Jones criteria or because they were referred from ambulatory
clinics with rheumatic valvular heart disease. The latter was confirmed by
Program cardiologists who did clinical examinations as well as reviewed
electrocardiograms and chest roentgenograms.
•
(page 3, Methods: Patients, 2nd paragraph)
a
n
c
e
Validity
Were there clearly identified comparison groups?
• The patients were categorized as those those with aortic valvular involvement,
mitral stenosis, or polyvalvular disease who receive prophylaxis for life In patients
and those who discontinued prophylaxis. Patients who did not have carditis
during their previous attack(s), prophylaxis was discontinued after 5 years or at
age 18, whichever was longer. In those with only mild mitral regurgitation or
healed carditis, prophylaxis was stopped after 10 years or at age 25. The same
regimen was used for patients whose sole cardiac sequela was mild mitral
regurgitation.
• (page 3, Methods: Criteria for cessation of prophlaxis,3rd paragraph)
Were the exposures and outcomes measured in
the same way in the groups compared?
•)
• Yes. The exposures and outcomes were measured in the same way in
the groups compared. The outcomes of all groups were determined
through endoscopic examination of bleeding ulcers in all groups.
• (page 30, Materials and Methods, 4th paragraph)
Was follow-up sufficiently long and
complete?
• Yes the follow up was sufficiently long to detect the outcome.
• Follow up was done every 3 months.
• The study began in July 1982 and terminated in September
1988.
•(page 4, Results: Follow up, 1st paragraph)
Was follow-up sufficiently long and
complete?
• During this period, 59 postprophylactic patients (approximately
80% of whom entered the study during the first 6 months) were
followed prospectively for a total of 1032 scheduled visits and
3346 patient-months (mean months of follow-up per patient,
56.7 months; median, 67.5 months; range, 10 to 75 months).
• Twelve patients entered in the off-prophylaxis protocol did not
complete the study.
• They therefore have a 80 % follow up.
• (page 4, Results:Follow-up,1 paragraph)
s
t
• (page 5, Results: Follow-up, 3rd paragraph)
Is the temporal relationship between the exposure and
outcome correct and dose response gradient present?
• The discontinuation of prophylaxis was done before any
outcome was observed.
• There were two recurrences of rheumatic fever during
the 3346 patient-months (278.8 patient-years) of
follow-up between 1982 and 1986, yielding a
recurrence rate of 0.72 (CI, 0.2 to 2.6) per 100 patientyears of prospective surveillance
•
(page 5, Results: last paragraph)
t
Overall, is the study valid?
• Since almost all the answers for the
validity guides are valid, the study
can be considered valid.
Results
What is the magnitude of the association between
exposure and outcome? Was the estimate of the risk
precise?
• Among 59 patients, 48 had completed their period of prophylaxis
• There were two recurrences of rheumatic fever during the 3346
patient-months (278.8 patient-years) of follow-up
• Recurrence rate: 0.72 (CI, 0.2 to 2.6) per 100 patient-years of
prospective surveillance.
• Ninety-five percent confidence intervals were determined using
the Poisson probability function generator (SAS version 6.03, SAS
Institute Inc., 1988).
(page 5, Results & page 4, Statistical Analysis)
Clinical Applicability
Are the study patients similar to my own?
•
Yes.
•28 year-old female
•cardiovascular problem
•ARF
•40 females (+ 19 males)
•mean age : 15-44 years old
•ARF
(page 1, Abstract: Patients & page 3, Methods: Patients)
Is our patient so different from those in the study that its
results cannot apply?
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No, our patient is the same with the patients included in the study. Therefore, this study
can be applied to our patient.
What is our patient’s risk of benefit and harm from
the exposure?
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prone to develop recurrent attacks if they have immunologically significant group A
streptococcal throat infections
antibacterial prophylaxis with penicillin has an over-all benefit
possibility of recurrence despite completion of therapy affected by exposure to the
pathogens, reliability in reporting promptly to the physician any episodes of pharyngitis, and
the incidence of rheumatic fever in the community.
risk for development of or exacerbation of rheumatic heart disease and carditis
What alternative treatments are available?
There was no mention in the article of alternative medications.
Based on the appraisal, the patient will be advised that
prophylactic treatment of Penicillin for her acute rheumatic
fever may be discontinued after 5 years given that there was
no carditis during the attack. Otherwise, it will have to take 10
years. Individuals who have reached their early twenties, had
their most recent attack more than 5 years ago, and are free
of rheumatic heart disease can be taken off prophylaxis with
relative safety.
PROGNOSIS
CLINICAL QUESTON:
What is the long term prognosis of rheumatic fever patients
receiving regular benzathine penicillin?
Population: Rheumatic fever patients
Intervention: Prophylaxis with benzathine penicillin
Outcome: Valvular heart disease, Recurrence of rheumatic
fever Bacterial endocarditis, Death
Methods: Cohort
SEARCH TERMS:
Rheumatic fever , prophylaxis, long term prognosis
Long-Term Prognosis of Rheumatic
Fever Patients Receiving Regular
Intramuscular Benzathine Penicillin.
Tompkins D, Boxerbaum B, Liebman J.,
Circulation Journal of the American Heart Association
45;543-551, 1972
Critical Appraisal
Relevance
Is the objective of the
article on prognosis
similar to your clinical
dilemma?
Yes, because the objective of the study is to determine the
long term prognosis of rheumatic fever which include
recurrence of rheumatic fever and persistence of cardiac
abnormalities in patients receiving monthly prophylaxis.
(Page 543)
Was there a representative
sample of patients without
the outcome at the start of
observation?
Yes, 115 patients who met the modified Jones criteria for
rheumatic fever and maintained with regular prophylaxis
after their initial attack were included in the study.
(Page 544, selection of patients)
Was follow-up sufficiently
long and complete?
Yes, they followed up the patients every 28 days for ten
years.
(Page 543, Methods)
Critical Appraisal
Relevance
Were the criteria for
determining the prognostic
factor and outcome explicit
and credible?
Yes. Participants were evaluated by physical examination,
electrocardiogram (ECG) and chest X-rays. Recurrent
rheumatic fever was assessed using the modified Jones
criteria.
Was there adjustment for
other prognostic factors?
No. Sex distribution was not specified in the study.
OVERALL, is the study valid?
Yes. Having met the validity guidelines, the study can be
considered valid.
How large is the likelihood of outcome to occur
in those with the prognostic factor in a specified
period of time? Was it statistically significant?
Can the results help me in caring for
my patients?
Are the study patients
similar to my own?
Only patients who met the modified Jones criteria for
acute rheumatic fever, who maintained regular
prophylaxis with benzathine penicillin every 28 days, and
had been followed for 5 years or longer after their initial
episode of ARF were included in the follow-up study.
The average age of the patients at the time of the acute
attack was 8.6 years. Fifty patients were 10 years of age or
older and six were 15 years or more at the time of their
ARF. (Results, p. 544)
The patient in the given case scenario, age 28, has had a
valvular heart disease and has been on monthly
benzathine penicillin since she was 16 years old.
Can I use the results to
guide on the intervention
or reassure my patient?
Yes. Of the 79 patients with acute Mitral Regurgitation
(MR), 70% lost this murmur anywhere from a few days to
8.5 years after it was first noted.
Resolution of the problem in the
scenario
Based on the Thompson et al. study, our group advices
that the patient in the case scenario continue with her
intake of benzathine penicillin monthly even if she had
an incident on rheumatic fever while taking it because
further valvular damage, bacterial endocarditis, higher
risk for recurrence of rheumatic fever and even death
would occur without it.