PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1702-1705 (doi:10.1542/peds.2005-2450)
Azithromycin Does Not Cure Pityriasis Rosea
Wayne State University School of Medicine, the Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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OBJECTIVES. Pityriasis rosea (PR) is a common skin disorder in children. Its cause is unknown. A recent publication reported a 73% cure rate in patients with PR after treatment with erythromycin. To duplicate this result using a drug with fewer adverse effects and greater biological half-life, we set out to study the effect of azithromycin on PR. Azithromycin is an azalide antibiotic with a spectrum of antimicrobial activity very similar to that of erythromycin.
DESIGN. We randomly assigned 49 children with PR to receive either azithromycin (12 mg/kg per day, up to a maximum of 500 mg/day) for 5 days or a similar-appearing placebo. Study physicians were blinded to patients' treatment type. Two pediatricians had to agree on the diagnosis of PR before patients could be enrolled. Subjects were seen at follow-up visits 1, 2, and 4 weeks after starting treatment.
OUTCOME MEASURES. We measured the appearance of new lesions and resolution of lesions.
RESULTS. Rates of cure and of partial resolution were similar in the azithromycin and placebo groups.
CONCLUSION. Azithromycin does not cure PR.
Key Words: pityriasis rosea • children • azithromycin
Abbreviations: PR—pityriasis rosea
Pityriasis rosea (PR) is an acute, inflammatory skin disease that commonly affects children and adolescents. Lesions may persist for 4 to 10 weeks and may be pruritic. The first skin lesion to appear is called a "herald patch" and often appears on the trunk as a 2- to 5-cm oval, scaly plaque. Within a week or two, smaller scaly oval plaques appear, often in a "Christmas tree" distribution on the trunk.1 In dark-skinned patients, postinflammatory hyperpigmentation or hypopigmentation may be seen after the lesions resolve. Some epidemiologic features (seasonal variation and clustering in communities) suggest that PR may be an infectious disease. At present, no etiologic agent has been identified.
In 2000, Sharma et al2 published a study that showed great success in inducing resolution of PR in a group of patients (most of whom were <21 years of age) by treating with oral erythromycin for 2 weeks. They produced complete resolution of lesions in 73% of their patients in a double-blind, placebo-controlled study, whereas there was no clearing within 2 weeks in any patient in the placebo group. In a commentary a few months later, the editor of a dermatology journal described the findings of Sharma et al2 as "remarkable and unexpected." He stated that "another study confirming these results would be very useful...."3 Others have expressed the same opinion.4 We undertook the following study to see whether these results could be replicated using azithromycin, an antibiotic with a longer biological half-life and fewer gastrointestinal adverse effects than erythromycin.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Patients between 2 and 18 years of age with a diagnosis of PR were recruited from the General Pediatric Clinic, Adolescent Clinic, and Emergency Department of Children's Hospital of Michigan. Patients in the study had the diagnosis of PR made by both authors in
80% of cases and by 1 study author and another experienced pediatrician in the remainder. Diagnosis was based on characteristic PR features.1, 5 Our patients had "textbook" cases of PR. No eruption seemed to be drug-related, either by clinical appearance or by history. The study authors have 45 combined years of experience practicing pediatrics. If the 2 clinicians did not agree on the diagnosis of PR, the patient was not eligible for study enrollment. Exclusion criteria were receipt of an antibiotic within 2 weeks of the diagnosis of PR, a history of intolerance of azithromycin or erythromycin, or the presence of lesions for >3 weeks at the time of diagnosis. Patient data were collected at the time of the diagnosis on standardized forms. These data included age, gender, race, duration of lesions, presence and location of the herald patch, number of lesions, presence of pruritus, preceding upper respiratory infection, treatments used before the diagnosis, and history of PR exposure. Digital photographs were taken of all of the lesions when the patients were enrolled and at all of the follow-up visits.
This was a double-blind, placebo-controlled prospective study. Patients were randomly assigned to receive azithromycin (n = 25) or placebo (n = 24). Only the study pharmacist was aware of study patients' treatment type. Treatment patients received azithromycin, 12 mg/kg per day for 5 days. The maximum daily dose was 500 mg/day of azithromycin; this was given to all of the patients weighing >40 kg. Placebo patients received an appropriate volume, or number of tablets, of an identical-appearing and similar-tasting placebo.
Patients were seen for follow-up at 1, 2, and 4 weeks after enrolling in the study. Standardized data collection at each follow-up visit included: change in lesion numbers and size, presence of pruritus, medication adverse effects, use of other treatments, and the presence of pigmentary changes. As in the diagnostic visit, the patient was evaluated by the 2 authors in most cases and by 2 physicians in all of the cases. Digital photographs were again taken. Patients were monetarily compensated for attending follow-up visits. This study was approved by the Wayne State University Human Investigation Committee. Informed consent was obtained from the parent accompanying the child.
PR was considered completely resolved if areas involved previously were neither scaly nor raised, and no new lesions had appeared. Erythema was not evident in our patient population (100% black) at any time and was not used as a criterion for disease activity. Partial resolution meant a decrease in lesion number, scaliness, or thickness but with active (ie, raised and scaly) lesions still present. No response (treatment failure) indicated no change in the patients' skin appearance. At each follow-up visit, both examining physicians had to agree on the lesion resolution status of the patient. In cases of disagreement about resolution category, patients were placed into the least-improved category of the 2 categories under consideration (eg, partial resolution over complete resolution or no response over partial response).
Statistical Analysis
We determined that to demonstrate a 30% cure rate with the active medication (versus no cure with placebo), each treatment arm needed 22 subjects. We had an adequate number of subjects to demonstrate such a treatment effect.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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There were 25 patients in the treatment (azithromycin) group and 24 in the placebo group. Mean age was
8 years in both groups. There were more boys (42% vs 24%) in the azithromycin group. Lesions had been present an average of 1.5 weeks before diagnosis in both groups. There were 2 patients in each group who had lesions present for 3 weeks at the time of diagnosis (Table 1).
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Treatment with azithromycin had no influence on the clinical course of PR in our patients. Fifteen patients in the azithromycin group (60%) had complete resolution of their lesions within 2 weeks of starting treatment. Ten (42%) patients in the placebo group had complete resolution of their lesions within 2 weeks of starting treatment (P = .275). Each treatment arm produced 7 patients with partial resolution. There were 3 failures at the 4-week follow-up visit in the azithromycin group and 7 in the placebo group. None of the outcomes reached statistical significance (Table 2). When we combined both complete and partial responders into a single group and compared that group to the nonresponders, there was, again, no difference of statistical significance for azithromycin treatment versus placebo (Fisher's exact test, P = .171).
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The proportion of patients with residual hyperpigmentation was 44% in the azithromycin group and 38% in the placebo group. Hypopigmentation was seen in 12% of patients in the treatment group and 25% of patients getting placebo. Two patients in the placebo group and 1 in the treatment group reported an upper respiratory infection before the onset of lesions. Two patients in the treatment group complained of stomach ache, and 2 complained of diarrhea while receiving azithromycin. There were no similar complaints in the placebo group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We did not reproduce the results of Sharma et al.2 They treated a group of (presumably Indian) patients with erythromycin and had a 73% cure rate in 2 weeks. None of the placebo patients responded in the 2-week period. Their patients were alternately assigned ("pseuorandomization"; ref 6) to the 2 treatment arms. We treated a randomly assigned group of black children with azithromycin and found that the resolution rates for active drug and placebo resembled each other.
We do not think our nondermatologist status had an influence on the validity of our diagnoses or judgment about degree of response. Two physicians needed to agree on each diagnosis and each response evaluation. We reviewed our photographs at the end of the study (before we "broke the code" of treatment assignment) to look for missed areas of disagreement. We found none.
Azithromycin is a member of the azalide subclass of macrolide antibiotics, of which erythromycin is the best-known agent. The range of microbes susceptible to azithromycin is very similar to that of erythromycin, although azithromycin is less active against streptococcus species and enterococci.7 Azithromycin has a long elimination half-life,7 and because of its high and persistent tissue levels, a 5-day course of azithromycin is roughly equivalent to a 10-day course of erythromycin.8
Why might an antibiotic treat PR? There is presumptive evidence that PR may be an infectious disease. In addition, erythromycin is thought to have immunomodulating and antiinflammatory effects. The evidence for an infectious etiology has been concisely summarized by Chuh et al6: (1) there is a distinct clinical course of events in PR (ie, herald patch followed by a secondary eruption followed by complete remission); this is similar to what is seen in many viral infections associated with rashes; (2) most patients do not have a second attack, a finding also seen in many viral diseases; (3) several patients in the same environment or household may develop PR; there is a report of 4 cases of PR occurring within 1 month on a whaling ship in the far north; (4) there are reported associations of PR with respiratory infections and underprivileged economic status; and (5) contact plays a role; a survey showed that 4 times as many dermatologists as otolaryngologists have had PR.
Several organisms have been considered as potential etiologic agents of PR. Among viruses ruled out are cytomegalovirus,9 Epstein-Barr virus,9 parvovirus B19,9 picornaviruses,6 and influenza and parainfluenza viruses.6 Controversy exists about the role of human herpesvirus 7.6, 10 A critical review of the literature found insufficient evidence to conclude that human herpesvirus 7 causes PR.4, 6 No reliable evidence was produced by studies seeking to incriminate chlamydia, legionella, or mycoplasma infections.4, 6 Erythromycin, azithromycin, and clarithromycin have antiinflammatory effects.11 It has been speculated that these effects "might contribute toward the action of erythromycin if any, in PR."4
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Our study showed that a 5-day treatment with azithromycin did not modify the clinical course of PR.
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ACKNOWLEDGMENTS |
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This work was supported by a grant from Pfizer Inc.
We thank Xiaoming Li, PhD, for help with statistical analysis.
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FOOTNOTES |
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Accepted Oct 20, 2005.
Address correspondence to Howard Fischer, MD, Wayne State University School of Medicine, the Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201. E-mail: hfischer{at}dmc.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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- Hurwitz S. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 2nd ed. Philadelphia, PA: WB Saunders Company; 1993:122–123
- Sharma PK, Yadav TP, Gautam RK, Taneja N, Satyanarayana L. Erythromycin in pityriasis rosea: a double-blind, placebo-controlled clinical trial. J Am Acad Dermatol. 2000;42 :241 –244[CrossRef][Web of Science][Medline]
- Bigby M. A remarkable result of a double-masked; placebo-controlled trial of erythromycin in the treatment of pityriasis rosea.
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- Hardman JC, Limbird LE, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw Hill; 2001:1251
- Kucers A, Crowe SM, Grayson ML, Hoy JF, eds. The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. 5th ed. Oxford, United Kingdom: Butterworth-Heinemann; 1977:655
- Chuh AAT. The association of pityriasis rosea with cytomegalovirus, Epstein-Barr virus and parvovirus B19 infections: a prospective case control study by polymerase chain reaction and serology. Eur J Dermatol. 2003;13 :25 –28[Web of Science][Medline]
- Watanabe T, Kawamura T, Jacob SE, et al. Pityriasis rosea is associated with both human herpesvirus-7 and human herpesvirus-6. J Invest Dermatol. 2002;119 :793 –797[CrossRef][Web of Science][Medline]
- Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of macrolide antibiotics.
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[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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