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SEVERE CUTANEOUS REACTIONS TO SULFADOXINE-PYRIMETHAMINE AND TRIMETHOPRIM-SULFAMETHOXAZOLE IN BLANTYRE DISTRICT, MALAWI

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  • 1 Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; Blantyre District Health Office, Blantyre, Malawi; Institute for Hygiene and Public Health, University of Bonn, Bonn, Germany; Blantyre Integrated Malaria Initiative, Blantyre, Malawi; Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

We estimated the frequency of clinically diagnosed Stevens-Johnson syndrome and toxic epidermal necrolysis associated with sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (CTX) in Blantyre District, Malawi. Cases were detected by passive surveillance at 22 health centers from March 2001 through September 2002. Denominators were estimated from the Malawi national census for Blantyre District and the frequency of SP and CTX use reported in five household surveys. Crude rates of adverse reactions were estimated to be 1.2 per 100,000 exposures for SP and 1.5 per 100,000 exposures for CTX. Rates were higher in adults (1.7 cases per 100,000 SP exposures and 2.6 cases per 100,000 CTX exposures) and in persons positive for human immunodeficiency virus (4.9 cases per 100,000 SP exposures and 8.4 cases per 100,000 CTX exposures). Infrequent treatment doses with SP are associated with a low risk of an adverse cutaneous reaction, and SP can be recommended for treatment of malaria in areas where P. falciparum is susceptible.

Sulfadoxine-pyrimethamine (SP), alone or in combination with other drugs, has replaced chloroquine as first-line therapy for uncomplicated Plasmodium falciparum malaria in many African countries because of increasing chloroquine resistance.1 Trimethroprim-sulfamethoxazole (cotrimoxazole or CTX) is used for the treatment of urinary tract or lower respiratory infections and is increasingly being advocated for prophylaxis against opportunistic infections in persons infected with human immunodeficiency virus (HIV).2,3 Sulfonamide drugs, including SP and CTX, cause a variety of adverse reactions including the skin conditions erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).47 Although there is substantial variability in the use of the terms EM, SJS, and TEN among medical practitioners, distinct clinical patterns permit a more reliable classification of these mucocutaneous disorders. The classification we used in this study was proposed in 1993 and subsequently validated in a large case control study supports EM as a condition that differs in both clinical presentation and etiology from SJS and TEN.811 Erythema multiforme is the least serious of these conditions. In addition to mucosal blistering or ulcers, typical target or raised atypical target lesions acrally distributed are seen. The extent of blisters or epidermal detachment is usually low and almost always less than 10%. Erythema multiforme is most associated with infection, with drugs an infrequent cause.12,13

SJS, TEN, and SJS/TEN overlap represent a severity spectrum of a single condition that is usually drug induced. SJS is characterized by typical or atypical targets on the trunk and face that are often confluent. Although > 10% of the body surface is affected, skin detachment usually occurs on less than 10% of the body surface. Extensive, often confluent, lesions are observed in TEN cases. The outer layer of the epidermis readily separates from the basal layer with lateral pressure and bullae/skin detachment occurs over more than 30% of the body surface. Cases with 10–30% skin detachment have often been described as SJS/TEN overlap. Mucosal erosions have been reported in more than 90% of cases with SJS or TEN. Typically, cases with SJS/TEN are febrile. Lesions of the respiratory and gastrointestinal tracts may occur.811 Case fatality rates as high as 30% have been observed in TEN patients in North American health facilities.9,10 Resistance to the adoption and implementation of SP for malaria treatment because of concerns about adverse reactions has been reported among both policy-makers14 and the general public.15

Estimates of the frequency of adverse cutaneous reactions in travelers using SP for malaria chemoprophylaxis have ranged from 0.01 to 20.4 adverse events per 100,000 exposures.1618 It has been estimated that persons taking regular, repeated doses of SP for prophylaxis have a 40-fold higher risk compared with those using it for single-dose treatment.16 However, the frequency of adverse events from treatment may have been underestimated and there is concern that, in disease-endemic areas, repeated treatment doses might lead to sensitization and an increased occurrence of side effects, even in persons receiving only a single treatment dose each time.

Another concern is the effect of HIV infection. It has been shown for several different drugs, including CTX, that HIV-infected persons experience higher rates of adverse reactions relative to HIV-negative persons.1921 With a high prevalence in many parts of sub-Saharan Africa, HIV may contribute to higher rates of the adverse reactions to numerous drugs, including SP.

In 1993, Malawi became the first country in sub-Saharan Africa to implement SP nationally as first-line treatment for uncomplicated Plasmodium falciparum malaria. Since its implementation, there have been anecdotal reports of severe cutaneous reactions but the frequency of these adverse events has never been estimated. We therefore set up a surveillance system in Blantyre District, Malawi to estimate the incidence of SJS and TEN to SP and CTX.

MATERIALS AND METHODS

Study population.

Blantyre District in southern Malawi has an area of 2,000 km2. Most of the district is located on a plateau at an elevation of 1,000 meters with low points of 300 meters along the Shire River. Based upon the 1998 population and housing census, there were 782,226 persons residing in the district, with 61% in urban/peri-urban Blantyre city. Children less than 15 years of age comprise 40.3% of the population and in a recent survey 9.6% of the women were pregnant.22 Malaria transmission varies seasonally, with a peak coinciding with the rains from November to March. Transmission is highest in rural areas but also occurs within Blantyre city.

Surveillance system.

Surveillance was established in all 17 government health clinics, a mobile clinic, and the four major hospitals within Blantyre District. At each facility, a clinical officer or medical assistant was identified as the contact person and trained to recognize symptoms and signs of SJS/TEN. Cases that would be considered EM were excluded because they were considered unlikely to present at a health center and have been shown to be a distinct syndrome with different underlying risk factors.12,13 A suspected case was defined as having at least two of the following symptoms: 1) a widespread, disseminated rash, 2) blisters or skin detachment > 3 cm in diameter, or 3) lesions on at least one mucous membrane. Reported history of SP or CTX use was not part of the suspected case definition. Suspected cases were reported to the District Health Office (DHO) and followed-up by a surveillance officer who confirmed that suspected cases met the screening definition and interviewed confirmed cases to assess case demographics, details of the adverse reaction, and exposure history. All cases were also offered counseling and testing for HIV according to Malawi national guidelines. The HIV testing was done using two rapid diagnostic tests (Determine HIV 1/2™; Abbott Laboratories, Abbott Park, IL and Hema-Strip HIV 1/2; Saliva Diagnostics Systems, Brooklyn, NY). A third test (UniGold Recombigen® HIV 1/2; Trinity Biotech Plc., Bray, Ireland) was used in the case of discordant results. For quality assurance, a blood sample was collected on filter paper and tested by an enzyme-linked immunosorbent assay (Vironostika® HIV Uni-Form II Ag/Ab; bioMerieux Inc., Durham, NC or Enzygnost® Anti-HIV 1/2 Plus, Dade Behring, Deerfield, IL). Surveillance was done from March 2001 through September 2002.

Cases that met the screening definition were further classified as unlikely, possible, or probable SJS/TEN based upon a modification of the classification schemes of Roujeau and Stern10 and Stern and others.11 Possible cases of SJS/TEN were defined as persons with skin detachment or blisters on at least two body areas (arms, legs, chest/abdomen, back, or head) plus at least one of the following: lesions in at least two mucous membranes, skin detachment or blisters on the back, chest/abdomen, and head, or Nikolsky’s sign (detachment of skin with slight lateral pressure). Probable cases were defined as persons with skin detachment or blisters on at least two body areas, lesions in at least two mucous membranes, and one of the following: skin detachment or blisters on the back, chest/abdomen and head, or Nikolsky’s sign. Persons without skin detachment or blisters were considered unlikely to have SJS/TEN. Written case reports of persons that initially did not fall into one of these three categories were submitted for review by the study dermatologist.

Household surveys.

To assess the frequency of exposure to SP and CTX in Blantyre District, five household surveys were conducted at 3–4-month intervals during the surveillance period. Surveys were conducted in 36 census enumeration areas that were randomly selected with probability of selection proportional to size. The same enumeration areas were visited during each survey. At each survey, 25 households were systematically sampled in each enumeration area and the head of household or spouse was interviewed to determine use of SP and CTX in all family members within the house during the two weeks before the survey. No effort was made to include or exclude the same households in subsequent surveys.

Estimation of rates.

Numerators included all cases that met the initial case definition and had a history of exposure to SP or CTX. A case was considered exposed if he or she reported use of SP or CTX in the 30 days before the appearance of the initial symptoms of their reaction. For cases with a history of exposure to both SP and CTX, the drug taken nearest to the onset of the adverse reaction was assumed to be the primary cause. Denominators were estimated from the 1998 Malawi national census and SP and CTX use reported in the household surveys. The average number of drug exposures in Blantyre District for every two-week period from March 2001 through October 2002 was estimated by multiplying the population size by the frequency of reported drug use in the household surveys. The total number of drug exposures during the surveillance was estimated by multiplying the estimated number of exposures in a two-week period by the number of two-week periods (i.e., 40) covered by the surveillance.

Estimates stratified by age and by HIV status were also calculated. Denominators for persons < 15 years of age or ≥ 15 years of age were obtained directly from the Malawi national census and the household surveys. For rates stratified by HIV status, denominators were estimated using the UNAIDS countrywide prevalence (15%) from 2002 for persons 15–49 years of age.23 The total number of people in this age group was calculated from the Malawi national census and the proportion in this age group in the household surveys. Use of SP and CTX was assumed to be the same in HIV-positive and HIV negative persons. Rates were also calculated for persons reporting exposure to both SP and CTX and for pregnant and non-pregnant women reporting exposure to SP. Denominators were estimated by assuming that 9.6% of women were pregnant at a single point in time as reported for Blantyre District22 and that the frequency of SP exposure in pregnant and non-pregnant women was the same.

Written informed consent was obtained from all cases as well as from all persons interviewed in the household surveys. Ethical approval for this study was obtained from the Malawi National Health Sciences Research Committee and the Institutional Review Board of the U.S. Centers for Disease Control and Prevention.

RESULTS

A total of 96 persons were reported to the DHO. Five were lost to follow-up (three were not found, one died, and one resided outside of Blantyre District). Fifty cases were excluded by the surveillance officer because they either did not truly meet the case definition (47 persons) or did not consent to be interviewed (3 persons). The remaining 41 cases were interviewed by the surveillance officer and offered HIV testing and counseling; 31 consented to HIV testing. Upon further review, 16 cases were classified as possible SJS/TEN, 21 cases were classified as probable, and 4 cases were considered unlikely. However, to provide a conservative estimate, all cases that met the screening case definition, including those subsequently classified as unlikely, were included in the estimation of rates of adverse reactions. Demographic characteristics of the 41 cases are shown in Table 1.

Exposure to SP was reported in 21 cases and exposure to CTX was reported in 17 cases. Seven cases reported use of both SP and CTX; SP was considered the primary exposure in 4 cases and CTX was considered the primary exposure in the remaining 3 cases. In 30 cases with a history of SP or CTX use, concurrent use of other drugs was also reported. Drugs used concurrently with SP or CTX included aspirin, paracetamol, ibuprofen, quinine, doxycycline, amoxicillin, penicillin, chlorphenirame, tofranil, and indomethacin. Neither SP nor CTX was used by three of the cases; use of indomethacin, doxycycline, and gentamicin/doxycycline were reported by these persons.

A total of 4,378 persons were interviewed in the five household surveys. Including their family members, frequency of exposure to SP and CTX was obtained for 19,719 people for estimating denominators. Rates of adverse reactions in Blantyre District were estimated to be 1.2 adverse events per 100,000 SP exposures and 1.5 adverse events per 100,000 CTX exposures (Table 2). There were 0.3 adverse events per 100,000 SP exposures in children less than 15 years of age and there were 1.7 adverse events per 100,000 SP exposures in adults ≥ 15 years of age. For CTX, the rate of adverse events was 0.4 per 100,000 exposures in children and 2.6 per 100,000 exposures in adults. There were 0.7 adverse events per 100,000 SP exposures in HIV-negative adults and there were 4.9 adverse events per 100,000 SP exposures in HIV-positive adults. For CTX, the rate of adverse events was 0.7 per 100,000 exposures in HIV-negative persons and 8.4 per 100,000 exposures in HIV-positive persons.

Rates of adverse reactions in persons using SP and CTX concurrently were estimated based upon the seven cases that reported exposure to both drugs; the rate was 3.4 cases per 100,000 exposures among all persons in Blantyre District. Among HIV-positive persons, the rate was 20.4 cases per 100,000 exposures. Pregnancy status was known for four of the seven women reporting exposure to SP. One reported being pregnant at the time of SP exposure. Rates of adverse reactions to SP in pregnant and non-pregnant women were estimated to be 1.7 and 0.5 adverse events per 100,000 SP exposures, respectively. Two persons identified with severe cutaneous reactions died. Both had taken SP. The risk of death due to an adverse reaction to SP was estimated to be 0.11 deaths per 100,000 SP exposures.

DISCUSSION

The rates of severe cutaneous reactions to SP ranged from 0.3 cases in children to 4.9 cases per 100,000 exposures in adults, and the rates of adverse reactions to CTX ranged from 0.4 to 8.4 cases per 100,000 exposures. The rates of adverse cutaneous reactions to SP and CTX were highest in HIV-positive adults, and the rates in HIV-negative adults were similar to those in children. There was evidence of a possible interaction between SP and CTX because the rate of cutaneous reactions in persons with a history of exposure to both drugs was more than twice the rate in persons exposed to either SP or CTX alone. The rate of adverse reactions to SP was low in both pregnant and non-pregnant women.

Our estimated crude rate of cutaneous reactions to SP in Blantyre District was low relative to previously reported rates.16,17 The low rate observed in this study may be due to several factors. First, case definitions may have been different because cases of EM were not captured by our surveillance system. Second, underreporting is a possibility in Blantyre District where access to health facilities is difficult compared with studies done among travelers in the United States and Europe. Third, some individuals may have a genetic predisposition to adverse cutaneous reactions to sulfonamide drugs,2426 and it has been suggested that Africans are less predisposed to adverse reactions to sulfonamides.27 Last, repeated doses of SP or sulfadoxine alone have been associated with higher rates of adverse reactions, and the single use of SP for treatment may partially account for the lower rates observed in Blantyre District.16,28

Rates of cutaneous reactions in persons using SP for malaria prophylaxis have been estimated to be as high as 20 per 100,000 exposures and 20.4 per 100,000 exposures in the United States18 and in Britain,17 respectively. Similarly, rates in Swedish travelers were estimated at 10 per 100,000 users.29 In contrast, rates of adverse reactions to SP were estimated to be 2.4 per 100,000 exposures in Malaysia where less than half of the persons exposed to SP were using it for prophylaxis.30 In a survey of 27 countries, rates of adverse reactions to SP were estimated to be 40 times higher in developed countries where SP was used in multiple doses for prophylaxis than in developing countries where SP was used mainly as a single dose for treatment.16 In Sweden, the incidence of serious adverse reactions to sulfonamide drugs was higher among persons on prophylaxis and continuous therapy compared with that among short-term users of the drugs.31 Furthermore, there is evidence that repeated exposures are associated with more severe cases. In Morocco, there were no deaths due to severe cutaneous reactions to a single dose of sulfadoxine (2.5 g) among 36,673 patients, but there were 11 deaths among 72,500 persons taking multiple doses.28 In the United States and Britain, travelers who experienced cutaneous reactions after taking SP for malaria prophylaxis were more likely to have died if they had taken a higher dose or if they continued prophylaxis after the onset of symptoms.17,18 Similarly, in the study in Sweden, drugs with longer elimination half-lives had higher case fatality rates.31 Our study also indicates that the risk of a severe adverse reaction to sulfonamide drugs and the risk of a fatal outcome among those who do have an adverse reaction is low for those taking single-treatment doses.

Higher rates of cutaneous reactions to SP and CTX were observed in HIV-positive persons when compared with HIV-negative persons. The HIV prevalence among cases who consented to testing (48.4%) was more than three times the 2002 UNAIDS countrywide estimate for Malawi (15%).23 However, the rates in HIV-positive persons may be biased because we assumed exposure rates to be the same in HIV-positive and HIV-negative persons. CTX is recommended for prophylaxis against opportunistic infections in HIV-infected persons. Although only 3% of HIV-infected persons in Malawi were reported using CTX prophylaxis in 2003,32 it is likely that HIV-positive persons seek treatment of malaria and other infections more often than HIV-negative persons. More dramatic differences in rates of cutaneous reactions to various drugs, including CTX, among HIV-positive and HIV-negative persons have been reported elsewhere.20,21 These apparent discrepancies may be partly related to the stage of progression to acquired immunodeficiency syndrome.19

SP is recommended for intermittent preventive treatment (IPT) for the prevention of malaria during pregnancy. Malawi national policy (2002) is to give at least two treatment doses of SP during the second and third trimesters (between 28 and 34 weeks). We estimated similar rates of cutaneous reactions to SP among pregnant and non-pregnant women. These estimates were based on a small number of women reporting SP exposure; small changes in these numbers could drastically alter our estimated rates of adverse reactions. Furthermore, our estimates assumed that the frequency of SP exposure was the same in both pregnant and non-pregnant women. This likely resulted in an underestimate of the frequency of SP exposure in pregnant women in Blantyre District, where a 2002 survey found that 96% of women received at least 1 dose of SP for IPT during pregnancy and 69% received at least 2 doses (Campbell CH, unpublished data). Thus, the rate of cutaneous reactions to SP in pregnant women is likely lower than that shown in Table 2 and similar to the rate in non-pregnant women.

Although we demonstrated a low rate of adverse reactions to SP and CTX, it is important to note the limitations of this study. First, cases were identified by generalist clinicians rather than trained dermatologists and confirmatory skin biopsy specimens were not available. Although the clinical presentations of SJS/TEN are often striking, we cannot rule out misclassification of cases. Second, we may have missed persons who failed to seek health care or attended private clinics that did not participate in the surveillance. Third, denominators were estimated from the 1998 Malawi national population census and reported rates of SP and CTX use in five household surveys. This required several assumptions that may not be true. In particular, these assumptions likely underestimated exposure rates in pregnant women and HIV-positive persons and may have lead to overestimation of the rates of adverse cutaneous reactions in these groups. Last, we assumed all cases with a history of SP or CTX use to have been caused by SP or CTX, even when other drugs reported to be associated with SJS/TEN (paracetamol,5,6 penicillin,7 amoxicillin,57 doxycycline,6 indomethacin5) were used concomitantly.

Since most drugs have some side effects, it is important to weigh the benefits of the drug against the risk of adverse events. The cutaneous reactions caused by sulfonamides can be severe and potentially fatal. However, malaria exacts a heavy burden on the populations it afflicts. In sub-Saharan Africa, the mortality rate due to P. falciparum in children less than five years of age has been estimated between 100 and 1,000 per 100,000 per year.33 Effective antimalarial treatment may reduce the probability of dying from malaria by up to 50-fold.34 In Malawi, the introduction of SP as first-line treatment for uncomplicated malaria in 1993 coincided with a decrease in all-cause child mortality.22 Although many factors likely contributed to the decrease, it is noteworthy that child mortality remained steady or increased in Tanzania and Kenya where chloroquine remained the first-line treatment of malaria until recently.35,36 Thus, in areas where malaria parasites are sensitive to SP, the benefit of this drug in reducing severe disease and death due to malaria outweighs the risk of an adverse cutaneous reaction.

Table 1

Demographic characteristics of 41 confirmed cases of severe cutaneous reactions reported to Blantyre District Health Office, Malawi*

No.%
* HIV = human immunodeficiency virus; SP = sulfadoxine-pyrimethamine; CTX = trimethoprim-sulfamethoxazole.
† 10 cases consented to interviews but refused consent for HIV testing.
‡ Four cases with a history of exposure to both SP and CTX were considered to have SP as their primary exposure while three were considered to have CTX as their primary exposure.
Age (years)
    Mean37.4
    Range0.3–77
Number of children < 15 years of age49.8
Number of males2765.9
Fatal cases24.9
HIV prevalence†15/3148.4
    Among persons 15–49 years of age13/2356.5
Cases with SP as primary exposure2151.2
    Mean time between SP exposure and onset of symptoms (days)3.0
Cases with CTX as preimary exposure1741.5
    Mean time between CTX exposure and onset of symptoms (days)1.6
Cases with no history of exposure to SP or CTX37.3
Cases with a history of exposure to both SP and CTX‡717.1
Table 2

Estimated rates of severe cutaneous reactions to sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (CTX) in Blantyre District, Malawi*

ExposureNo. of casesPopulation size†Percent exposed‡Total no. of exposures§Rate per 100,000 exposures
* HIV = human immunodeficiency virus.
† Population size was taken directly from the 1998 Malawi national census estimates except for HIV+/− population size and the number of pregnant women. For estimates of HIV+/− population size, the population 15–49 years of age was estimated from the Malawi national census and the proportion in that age group in the household surveys. The number of HIV+/− persons was estimated by using the countrywide estimate of 15% HIV prevalence in persons aged 15–49 years of age. The number of pregnant women was estimated by assuming 9.6% of women 15–49 years of age were pregnant.
‡ Proportion using SP or CTX in a two-week period as reported in household surveys. Rates of use were assumed to be the same for HIV+ and HIV− persons. Rates of SP use were assumed to be the same for pregnant and non-pregnant women.
§ Estimated total number of exposures from March 2001 through September 2002 was calculated by multiplying the population size by the proportion reporting exposure to SP or CTX in a two-week period and by the total number of two-week periods covered by the surveillance (40).
Sulfadoxine-pyrimethamine (SP)
    Crude estimate21782,2265.781,808,5071.2
    Children < 15 years of age2315,3295.51694,9850.3
    Adults ≥ 15 years of age19466,8915.991,118,6711.7
    HIV−6335,3056.01806,0740.7
    HIV+759,1726.01142,2484.9
    Pregnant130,5807.4390,8831.7
    Not pregnant3173,2857.43515,0040.5
Trimethroprim-sulfamethoxazole (CTX)
    Crude estimate17782,2263.621,132,6631.5
    Children < 15 years of age2315,3294.25536,0590.4
    Adults ≥ 15 years of age15466,8913.12582,6802.6
    HIV−3335,3053.01403,7080.7
    HIV+659,1723.0171,2438.4

*

Address correspondence to John E. Gimnig, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway, Chamblee, GA 30341. E-mail: hzg1@cdc.gov

Authors’ addresses: John E. Gimnig, John R. MacArthur, Robert D. Newman, and Richard W. Steketee, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway, Chamblee, GA 30341, E-mail: hzg1@cdc.gov. Maurice M’bang’ombe and Chris Mkandala, Blantyre District Health Office, Chipatala Avenue, Blantyre, Malawi. Michael H. Kramer, Institute for Hygiene and Public Health, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany. Nyson Chizani and Carl H. Campbell, Blantyre Integrated Malaria Initiative, Private Bag 240, Chipatala Avenue, Blantyre, Malawi. Robert S. Stern, Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.

Acknowledgments: We thank the Blantyre District Health Management Team for their support in designing and implementing the surveillance system. We also thank the laboratory staff at the Queen Elizabeth Central Hospital for conducting quality assurance for HIV testing.

Financial support: This project was supported by the United States Agency for International Development (USAID) under the Community Health Partnerships Project and the African Integrated Malaria Initiative in partnership with the Blantyre District Health Office and the Malawi Ministry of Health and Population, Lilongwe, Malawi.

Disclaimer: The opinions or assertions contained in this manuscript are the private ones of the authors and are not to be construed as official or reflecting the views of the U.S. Public Health Service or Department of Health and Human Services. Use of trade names is for identification only and does not imply endorsement by U.S. Public Health Service or Department of Health and Human Services.

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