A clinical decision rule for management of streptococcal pharyngitis in low-resource settings

Background: Most of the world's children live in regions where laboratory facilities are not available. In these regions, clinical prediction rules can be useful to guide clinicians' decisions on antibiotic therapy for streptococcal pharyngitis, and to reduce routine presumptive antibiotic therapy for all pharyngitis. Methods: Prospective cohort study to assess diagnostic signs and develop a prediction rule. Bivariate and multivariate analyses were used to develop clinical rules. Participants were 410 children in Cairo, Egypt, aged from 2 to 12 y, presenting with complaint of sore throat and whose parents provided consent. Main outcome measures included presence of signs and symptoms, and positive group A beta hemolytic streptococcal (GABHS) culture. Results: 101 (24.6%) children had positive GABHS culture. Pharyngeal exudate, tender or enlarged anterior cervical lymph nodes, season, absence of rash, or cough or rhinitis were associated with positive culture in bivariate and multivariate analyses. Three variables (enlarged nodes, no rash, no rhinitis), when used in a cumulative score, showed 92% sensitivity and 38% specificity in these children.

Conclusions: The proposed three-variable clinical prediction rule for GABHS may be useful when diagnostic laboratories are not available. In this setting, the rule identified more than 90% of true cases. Compared to universal treatment of all pharyngitis, the rule will reduce antibiotic use in GABHS-negative cases by about 40%.     

Evaluation of the WHO clinical decision rule for streptococcal pharyngitis

Aims: To prospectively assess the WHO clinical decision rule (CDR) for group A beta haemolytic streptococcal (GABHS) pharyngitis in three countries. Methods: A prospective, observational cohort study in urban outpatient clinics in Rio de Janeiro, Cairo, and Zagreb. There were 2225 children aged 2–12 years with cough, rhinorrhoea, red or sore throat; 1810 of these with sore throat were included in the analysis. Results: The proportion of children presenting with sore throat and found to have GABHS pharyngitis ranged from 24.6% (Brazil) to 42.0% (Croatia). WHO CDR sensitivity was low for all sites in both age groups. In children age 5 or older, sensitivity ranged from 3.8% in Egypt to 10.8% in Brazil. In children under 5, sensitivity was low (0.0–4.6%) Specificity was high in both age groups in all countries (93.8–97.4%). Conclusions: In these populations, the current WHO CDR has high specificity, but low sensitivity; it did not detect up to 96.0% of children who have laboratory confirmed GABHS pharyngitis. A CDR with higher sensitivity should be developed for use in regions where rheumatic fever and rheumatic heart disease are still major health problems.     

Evaluation of the WHO clinical decision rule for streptococcal pharyngitis.

AIMS: To prospectively assess the WHO clinical decision rule (CDR) for group A beta haemolytic streptococcal (GABHS) pharyngitis in three countries. METHODS: A prospective, observational cohort study in urban outpatient clinics in Rio de Janeiro, Cairo, and Zagreb. There were 2225 children aged 2-12 years with cough, rhinorrhoea, red or sore throat; 1810 of these with sore throat were included in the analysis. RESULTS: The proportion of children presenting with sore throat and found to have GABHS pharyngitis ranged from 24.6% (Brazil) to 42.0% (Croatia). WHO CDR sensitivity was low for all sites in both age groups. In children age 5 or older, sensitivity ranged from 3.8% in Egypt to 10.8% in Brazil. In children under 5, sensitivity was low (0.0-4.6%) Specificity was high in both age groups in all countries (93.8-97.4%). CONCLUSIONS: In these populations, the current WHO CDR has high specificity, but low sensitivity; it did not detect up to 96.0% of children who have laboratory confirmed GABHS pharyngitis. A CDR with higher sensitivity should be developed for use in regions where rheumatic fever and rheumatic heart disease are still major health problems.     

Variation in clinical presentation of childhood group A streptococcal pharyngitis in four countries

We conducted a cross-sectional study from September 2001 to August 2003 during which children between 2 and 12 years of age presenting with complaint of sore throat were recruited from urban pediatric clinics in Brazil, Croatia, Egypt and Latvia. The objective of the study was to compare clinical signs and symptoms of children presenting to urban pediatric clinics with sore throat in and between countries and to identify common clinical criteria predicting group A beta hemolytic streptococcal (GAS) pharyngitis. Using a single standard protocol in all four sites, clinical data were recorded and throat swabs obtained for standard GAS culture in 2040 children. Signs and symptoms were tested for statistical association with GAS positive/negative pharyngitis, and were compared using chi(2) tests, ANOVA and Odds Ratios. Clinical signs of GAS pharyngitis in children presenting to clinics varied significantly between countries, and there were few signs or symptom that could statistically be associated with GAS pharyngitis in all four countries, though several were useful in two or three countries. Our results indicate that the clinical manifestations of pharyngitis in clinics may vary by region. It is therefore critical that clinical decision rules for management of pharyngitis should have local validation.     

Alternative diagnostic method for streptococcal pharyngitis: Breese scoring system

This study was performed to determine the effectiveness of the Breese scoring system for the diagnosis of streptococcal pharyngitis with respect to different age groups. Two hundred and two children aged three years and younger (Group 1), and 514 children over three years old (Group 2) with complaints of acute pharyngitis were evaluated by Breese scoring and throat-swab cultures. In Group 1, no significant difference was detected in Breese scoring between subjects who had positive and negative culture for group A beta-hemolytic streptococci (GABHS). However, in Group 2 the mean value of the Breese scores was found to be higher in subjects who had positive GABHS. The diagnostic value of Breese scoring was examined for each group. Its sensitivity, and positive and negative predictive values were higher in Group 2 than in Group 1. In conclusion, Breese scoring was determined to be helpful in the diagnosis of streptococcal pharyngitis in children over three years of age.     

Management of sore throats in children: a cost-effectiveness analysis.

OBJECTIVE: To perform a cost-effectiveness analysis of treatment management strategies for children older than 3 years who present with signs or symptoms of pharyngitis. DESIGN: Decision model with 7 strategies, including neither testing for streptococcus nor treating with antibiotics; treating empirically with penicillin V; basing treatment on results of a throat culture (Culture); and basing treatment on results of enzyme immunoassay or optical immunoassay rapid tests, performed alone or in combination with throat cultures. In these 7 strategies, all tests are performed in a local reference laboratory. In a sensitivity analysis, we examined the cost-effectiveness of 4 strategies involving office-based testing. We obtained data on event probabilities and test characteristics from our hospital's clinical laboratory and the literature; costs for the analysis were based on resource use. RESULTS: At a baseline prevalence of 20.8% for streptococcal pharyngitis, the Culture strategy was the least expensive and most effective, with an average cost of $6.85 per patient. The outcome was sensitive to the prevalence of streptococcal pharyngitis, the rheumatic fever attack rate, the cost of the enzyme immunoassay test, and the cost of culturing and reporting culture results. The Culture strategy was also preferred if amoxicillin was substituted for oral penicillin. For office-based testing, Culture was the least costly strategy, but treatment based on results of the optical immunoassay test alone had an incremental cost-effectiveness ratio of $1.6 million per additional life saved. CONCLUSION: In a setting with adherent patients, children with sore throats should generally get throat cultures in lieu of rapid streptococcus antigen tests.     

Latex agglutination for the rapid diagnosis of streptococcal pharyngitis: use by house staff in a pediatric emergency service

A rapid latex agglutination (LA) method was evaluated in 2401 consecutive pediatric patients presenting to an emergency service with suspected group A beta-hemolytic streptococcal pharyngitis. LA tests were performed by the treating physicians, who were not blinded to the clinical condition of the children and who made therapeutic decisions based on the results of the tests. When compared with anaerobic culture, the LA method had a sensitivity of 91%, a specificity of 82%, and a positive predictive value of 43%. There was a marked seasonal variation in the positive predictive value: 62% in winter and 16% in summer. However, even in peak streptococcal pharyngitis season (January to March), basing therapy on a positive LA test leads to the unnecessary treatment of a large number of patients. Therefore, we cannot recommend the routine performance of this test by all practitioners in all clinical settings.     

Clinical predictors of influenza in children

BACKGROUND: It is difficult to diagnose influenza infection on clinical grounds alone. Available rapid diagnostic tests have limited sensitivities. OBJECTIVE: To develop a prediction model that identifies children likely to have influenza infection. DESIGN: Prospective study. SETTING: Emergency department of a children's hospital.Patients All patients with a febrile respiratory illness during the influenza season of winter 2002 were eligible. A prospective sample of 128 children who were suspected of having influenza infection based on predetermined criteria was enrolled. Each patient received a nasal wash for viral culture. MAIN OUTCOME MEASURE: Clinical features that are most predictive of influenza infection in children. RESULTS: The mean +/- SD age of patients was 6.2 +/- 5.2 years; 50% were boys. Viral isolates included the following: influenza A, 45 patients (35%); influenza B, 13 (10%); other viruses, 10 (8%); negative results, 60 (47%). Demographic and clinical findings were not significantly different between the influenza A and influenza B groups. Cough (P =.003), headache (P =.04), and pharyngitis (P =.04) were independently associated with influenza infection. This triad used as a prediction model for influenza infection had a sensitivity of 80% (95% confidence interval [CI], 69%-91%); specificity, 78% (95% CI, 67%-89%); and likelihood ratio for a positive viral culture for influenza, 3.7 (95% CI, 2.3-6.3). The posttest probability of this clinical definition is 77% (95% CI, 63%-91%). CONCLUSION: The triad of cough, headache, and pharyngitis is a predictor of influenza infection in children.     

Streptococcal pharyngitis in the 1980s

Streptococcal pharyngitis remains a common problem in children and adolescents. However, the incidence of acute rheumatic fever is now quite low except in developing countries. Proper management of streptococcal pharyngitis has contributed significantly to the decline in ARF. Penicillin treatment has clearly altered the natural history of streptococcal infection; the acute illness is shortened, risk of spread of infection is reduced, suppurative complications are prevented and ARF is prevented. Some cases of acute glomerulonephritis may be prevented. The decline in rheumatic fever has probably contributed to a greater interest in clinical benefits of therapy. Antigen detection tests appear promising for providing a more rapid bacteriologic diagnosis of streptococcal infection, which in turn permits prompt treatment. While penicillin has been the treatment of choice for four decades, a disturbing trend of increasing numbers of clinical relapses or recurrent infections has been noted in recent years. Alternative antibiotics, such as the oral cephalosporins, may now be superior to oral penicillin in terms of lessening the risk of relapse. This advantage must be weighed against other factors including cost effectiveness. The most pressing dilemma for the clinician is management of the patient with repeated episodes of acute streptococcal pharyngitis. Certain of these problem patients may benefit from a period of penicillin prophylaxis during the seasons when streptococcal infections are most prevalent. There is now agreement that posttreatment throat cultures need not be done in the child who remains asymptomatic following therapy. However, it is incumbent on the clinician to make certain that appropriate therapy is prescribed and that compliance with oral regimens of therapy is satisfactory in the management of the patient with acute streptococcal pharyngitis.     

Evaluation of two ELISA tests for the rapid detection of group a Streptococci

We examined 579 oropharyngeal swab specimens from children presenting with pharyngitis in order to compare two rapid diagnostic ELISA tests for group A streptococcal antigen: the TestPack Strep A (TPSA), and the Direct Strep A EIA (DSAE), with an anaerobically incubated sheep blood agar culture. The sensitivities of the methods were respectively 60.8% (TPSA) and 64.4% (DSAE), the specificities 98.3% (TPSA) and 93.2% (DSAE), the positive predictive values 88.6% (TPSA) and 70.3% (DSAE) and the negative predictive values 92.0% (TPSA) and 91.2% (DSAE). We conclude that the TPSA is easy to interpret and is sufficiently specific to initiate treatment in patients with a positive test. It is not sufficiently sensitive to ensure negative or intermediate results. The performance of the DSAE test is similar but the specificity is slightly lower and more false positive results occur.     

Rapid group A streptococcal antigen detection kit: effect on antimicrobial therapy for acute pharyngitis

Newly introduced rapid diagnostic tests for group A streptococcal pharyngitis should facilitate appropriate antimicrobial use in patients with group A streptococcal pharyngitis. Because of high rates of acute pharyngitis in Tuba City, AZ, at the Navajo Indian reservation, the use of rapid diagnostic test was prospectively evaluated. The sensitivity and specificity of the test was measured and changes in physician prescribing patterns attributable to use of the test were correlated. Of 320 patients with pharyngitis enrolled during the present 3-week study, 86 met the study's definition of a patient with streptococcal pharyngitis and 163 met the study's definition of a patient with nonstreptococcal pharyngitis. The rapid test was 62.8% sensitive and 96.9% specific in identifying patients from whom group A streptococci were isolated. Although treatment of patients with streptococcal pharyngitis at the time of the first visit increased from 36.5% in a retrospective sample to 72.5% during the study, treatment of patients in whom cultures were negative remained the same. Further analyses showed that physicians tended to treat patients with signs characteristic of streptococcal pharyngitis and, as the study progressed, to rely less on negative rapid test results as a reason to withhold antimicrobial agents. It was concluded that rapid tests with good specificity but limited sensitivity may improve treatment of patients with streptococcal pharyngitis by allowing earlier specific therapy. A more sensitive test with a higher negative predictive value would be necessary to prevent treatment of persons with nonstreptococcal pharyngitis.     

Cefaclor in treatment of otitis media and pharyngitis in children

The safety and efficacy of cefaclor were compared with amoxicillin trihydrate in the treatment of 130 cases of otitis media, and with penicillin V potassium in 88 cases of streptococcal pharyngitis in two single-blind controlled studies. Patients with otitis media received approximately 40 mg/kg/day of cefaclor or amoxicillin trihydrate for ten days to three weeks; patients with pharyngitis received 20 mg/kg/day of cefaclor or penicillin V potassium for ten days. Overall, patients who received cefaclor for otitis media had fewer acute failures and better total success, especially in cases caused by Haemophilus influenzae; however, the difference between cefaclor and amoxicillin was not statistically significant. There also was no significant difference between the clinical effectiveness of cefaclor and penicillin in the treatment of streptococcal pharyngitis. Cefaclor was well tolerated with no serious side effects.     

Seasonal benzathine penicillin G prophylaxis for recurrent streptococcal pharyngitis in children

Abstract Background. To assess the efficacy of benzathine penicillin G (BPG) prophylaxis in recurrent streptococcal pharyngitis in children.
Methods: One hundred and sixty children, aged4–11 years, who experienced at least two episodes of group A β-hemolytic streptococcal (GABHS) pharyngitis during a 4-month observation period between September and December 1995 were randomly divided into two groups. During the following 4-month period between January and April 1996. 80 children received BPG prophylaxis every 3 weeks as a single intramuscular injection of 1.2 million units for a body weight greater than 27 kg and a half dose for 27 kg or less. Eighty children were accepted as a control group and were not given BPG prophylaxis.
Results: The children in the BPG group experienced significantly less GABHS pharyngitis than those in the control group during the second 4-month period (16 vs 244 episodes, respectively, P < 0.001). BPG prophylaxis decreased streptococcal pharyngitis by 92% in the children in the study group, while the frequency of GABHS pharyngitis was unchanged in those in the control group during the second 4-month period compared with the first 4-month period.
Conclusions: The data in the present study demonstrated that intramuscular BPG prophylaxis is very effective in preventing GABHS pharyngitis in children. It is recommended that it is used every 3 weeks in at least the fall-winter seasons in children susceptible to frequent GABHS pharyngitis.     

Penicillin V and rifampin for the treatment of group A streptococcal pharyngitis: a randomized trial of 10 days penicillin vs 10 days penicillin with rifampin during the final 4 days of therapy

To improve the bacteriologic and clinical cure rates of streptococcal pharyngitis, 79 children were randomly assigned to receive penicillin V alone for 10 days (39 patients) or penicillin for the same duration and rifampin during the last 4 days of penicillin therapy (40 patients). Eleven patients given penicillin had evidence of bacteriologic failure (including eight with relapse of clinical illness) on repeat cultures done 4 to 7 days after treatment, whereas there were no failures in children given combination therapy (P = 0.0015). All eight symptomatic children improved with penicillin-rifampin therapy and subsequent cultures were negative, whereas three asymptomatic children continued to harbor group A streptococci even after combination therapy. Antibody response by antistreptolysin O or antideoxyribonuclease B assay was seen in 50.6% of patients; the antibody responses in both groups were comparable. These results show that addition of rifampin to the penicillin regimen improves the clinical and bacteriologic cure rates in children with streptococcal pharyngitis.     

Group A streptococcal strains in Kuwait: a nine-year prospective study of prevalence and associations.

During a period of 9 years (December, 1980, through November, 1989), 407 Group A streptococcal strains were isolated from 294 children with acute rheumatic fever and 303 of their family contacts, 234 children with acute post-streptococcal glomerulonephritis and 242 of their family contacts and 219 children with uncomplicated Group A streptococcal pharyngitis. Of the 407 strains 216 (53%) were M and/or serum opacity factor typable, 143 (35%) were only T typable and 48 (12%) were nontypable. Throughout the period of study the M12 and M1 were the most prevalent strains; however, important changes among the prevalent strains were observed. Although the study started in 1980 the serotypes M18, M81, M3, M15 and M58 made their first appearance 7 to 9 years later. These findings show the value of long term studies in detecting the changes in the prevalence of streptococcal strains in the community. M18 was isolated from three children with nephritis but not from children with rheumatic fever; this association has not been reported before. M12 was isolated from 26% of the nephritic children and their families vs. 7% from the rheumatic children and their families (P less than 0.05) vs. 17% from children with uncomplicated streptococcal pharyngitis. M49 was isolated from 7% of the nephritic children and their families vs. none from rheumatic children and their families vs. 1.4% from children with uncomplicated streptococcal pharyngitis. These findings support the concept of nephritogenicity of some streptococcal strains.(ABSTRACT TRUNCATED AT 250 WORDS)     

Measuring the quality of care for group A streptococcal pharyngitis in 5 US health plans

BACKGROUND: There is a high degree of professional consensus that children diagnosed with pharyngitis should only receive antibiotics if they have a positive test for group A streptococcus (GAS). OBJECTIVES: To develop and test the validity of a quality of care performance measure that examines GAS testing rates in children diagnosed with pharyngitis and prescribed an antibiotic. DESIGN: The measure developed examines the annual rate of GAS testing in children aged 2 to 18 years with an episode of pharyngitis who were prescribed antibiotics. The measure was tested for feasibility of implementation and validity in 5 health plans in the United States. Health plan administrative data were used to identify episodes of pharyngitis using International Classification of Diseases, Ninth Revision (ICD-9) codes 462, 463, and 034.0. Pharmacy data (National Drug Codes) were used to determine if antibiotics were prescribed for the pharyngitis episode. Laboratory claims data (Current Procedural Terminology codes) were used to determine whether a GAS test was performed. Rates of GAS testing in children with pharyngitis who received antibiotics were calculated for each health plan. Medical record abstractions were performed on a random sample (n = 465) of cases to assess percent agreement with laboratory claims data for GAS testing. Sensitivity of the administrative data for accurately identifying when GAS tests were performed was also assessed. RESULTS: Of the 120 158 children aged 2 to 18 years who had at least 1 episode of pharyngitis during the measurement year, 51 172 (43%) received antibiotics. Group A streptococcal testing rates for patients who were prescribed antibiotics varied widely among the participating health plans (59%-83% of cases; P<.05). Percent agreement between administrative and medical records data for GAS tests was 86%. The sensitivity of the administrative data for accurately identifying when GAS tests were performed was 85%. CONCLUSIONS: This quality measure is feasible to implement at the health plan level and validly assesses GAS testing rates using administrative data. The participating health plans are not performing GAS tests as indicated by current expert practice guidelines in a substantial proportion of cases. Improvements in adhering to these guidelines are warranted given the current levels of antibiotic overuse and antibiotic resistance nationally.     

Adverse effects of steroid therapy in children with pharyngitis with unsuspected malignancy

ABSTRACT: Pharyngitis is a common clinical complaint for children and accounts for 3.1% of all visits to selected ambulatory care settings. Most children with pharyngitis have benign, self-limited disease with infrequent complications such as peritonsillar abscess, mastoiditis, or lymphadenitis. Recent studies have touted the benefits of steroids in the treatment of children with pharyngitis for pain control. These studies do not address the potential life-threatening complication of steroids in patients with pharyngitis or lymphadenopathy in the setting of undiagnosed acute lymphocytic leukemia (ALL) or lymphoma. We report 4 cases of children treated with steroids for pharyngitis or adenitis that subsequently were diagnosed with ALL or lymphoma. If steroids are to be used in children with pharyngitis or adenitis, the following recommendations should be strongly considered: Careful history and physical examination should be obtained. Presence of hepatosplenomegaly or lymphadenopathy outside the cervical region should raise suspicions regarding an underlying malignancy. Normal results of complete blood cell count in the setting of clear cut pharyngitis with exudates and a lack of significant adenopathy essentially rules out the diagnosis of ALL. Because traditional analgesics are available, which do not affect the curability of ALL or lymphoma, the routine use of steroids in pharyngitis in children should be considered only in rare circumstances.     

Diagnosis and treatment of pharyngitis in children

Acute pharyngitis is one of the most common illnesses for which children visit primary care physicians. Most cases of acute pharyngitis in children are caused by viruses and are benign and self-limited. Group A beta-hemolytic streptococcus is the most important of the bacterial causes of acute pharyngitis. Strategies for diagnosis and treatment of acute pharyngitis are directed at distinguishing children with viral pharyngitis, who would not benefit from antimicrobial therapy, from children with group A beta-hemolytic streptococcal pharyngitis, for whom antimicrobial therapy would be beneficial. Making this distinction is crucial in attempting to minimize the unnecessary use of antimicrobial agents in children.     

Streptococcal pharyngitis in children: to treat or not to treat?

Controversy remains about the need for antibiotic therapy of group A streptococcal (GAS) pharyngitis in high-resource settings. Guidelines on the management of GAS pharyngitis differ considerably, especially in children. We performed a literature search on the diagnosis and treatment of GAS pharyngitis in children and compared different guidelines with current epidemiology and the available evidence on management. Some European guidelines only recommend antibiotic treatment in certain high-risk patients, while many other, including all American, still advise antimicrobial treatment for all children with GAS pharyngitis, given the severity and re-emerging incidence of complications. Empirical antimicrobial treatment in children with sore throat and a high clinical suspicion of GAS pharyngitis will still result in significant overtreatment of nonstreptococcal pharyngitis. This is costly and leads to emerging antibiotic resistance. Early differential diagnosis between viral and GAS pharyngitis, by means of a ‘rapid antigen detection test’ (RADT) and/or a throat culture, is therefore needed if ‘pro treatment’ guidelines are used. Conclusion: Large scale randomized controlled trials are necessary to assess the value of antibiotics for GAS pharyngitis in high-resource countries, in order to achieve uniform and evidence-based guidelines. The severity and the possibly increasing incidence of complications in school-aged children suggests that testing and treating proven GAS pharyngitis can still be beneficial.     

Once-daily therapy for streptococcal pharyngitis with amoxicillin

OBJECTIVE: An orally administered antimicrobial regimen for the treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis given once rather than multiple times each day would be more convenient and might result in improved patient compliance. The purpose of this study was to evaluate the effectiveness of once-daily amoxicillin in the treatment of GABHS pharyngitis. PATIENTS: Children presenting to a private pediatric office with GABHS pharyngitis. DESIGN: Patients were randomly assigned to receive orally either amoxicillin (750 mg once daily) or penicillin V (250 mg three times a day) for 10 days. Compliance was monitored by urine antimicrobial activity. OUTCOMES: Outcomes were measured by impact on the clinical course, eradication of GABHS within 18 to 24 hours, and bacteriologic treatment failure rate as determined by follow-up throat cultures 4 to 6 and 14 to 21 days after completing therapy. GABHS isolates were serotyped to distinguish bacteriologic treatment failures (same serotype as initial throat culture) from new acquisitions (different serotypes). RESULTS: During the 16 months of this study, 152 children between 4 and 18 years of age (mean, 9.9 years) were enrolled; 79 children were randomly assigned to receive once-daily amoxicillin and 73 were assigned to receive penicillin V three times a day. The children in the two treatment groups were comparable with respect to age, duration of illness before initiation of therapy, compliance, and signs and symptoms at presentation. There was no significant difference in the clinical or bacteriologic responses of the patients in the two treatment groups at the 18- to 24-hour follow-up visit. Bacteriologic treatment failures occurred in 4 (5%) of the 79 patients in the amoxicillin group and in 8 (11%) of the 73 patients in the penicillin V group. CONCLUSIONS: These data demonstrate that once-daily amoxicillin therapy is as effective as penicillin V therapy given three times a day for the treatment of GABHS pharyngitis, and if confirmed by additional investigations, once-daily amoxicillin therapy could become an alternative regimen for the treatment of this disease.