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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A few clinical studies have assessed adverse reactions following treatment with DEC and albendazole,9,16 but the burden of adverse reactions in large community-based interventions using DEC and albendazole has not been adequately documented. Little is known about the costs of adverse reaction management. In addition, current guidelines recommend 80% annual treatment coverage for at least 4–6 years. Painful adverse reactions or rumors of severe adverse reactions may deter community members from participating in subsequent mass drug administrations (MDAs).3,4 With an estimated 120 million persons infected with W. bancrofti worldwide,1,3,17 the practicalities of adverse reaction surveillance and treatment are relevant to the success of the Global Program for Elimination of Lymphatic Filariasis. This is especially true for the management of adverse reactions serious enough to require medical attention, in light of the extreme poverty and limited access to health care common in developing country settings where lymphatic filariasis is most highly endemic. In this report we document the frequency, severity, and costs of adverse reactions in a cohort of 71,187 people treated during a four-day MDA in the W. bancrofti-endemic plains of Leogane Haiti.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mass drug administration with DEC and albendazole took place in the plains during a four day period from October 21 to 24, 2000. The drugs were offered at more than 100 distribution posts in the plains that were staffed by CHWs and community volunteers. DEC was offered to all persons more than two years old, including non-pregnant women. Women who had not had a menstrual period during the previous 30 days were excluded from DEC treatment because of possible pregnancy. The dosage of DEC for children was based on age using a weight-for-age curve generated in a local community. Adults received 400 mg of DEC. A 400-mg dose of albendazole was offered to all persons more than two years of age, with the exception of women of childbearing potential, defined by a patient report of having a menstrual cycle. Although there is no contraindication for albendazole use in non-pregnant women of childbearing age, the Ministère de la Santé Publique et de la Population (Ministry of Health) elected to exclude women of this group from treatment on the chance that they may have been pregnant. Persons too old, ill, or frail to walk to a distribution point were excluded from treatment. Data on age, sex, and treatment regimen were collected for each person treated.
Adverse reactions. We developed a three-tiered surveillance and treatment system to detect and treat persons reporting adverse reactions after receiving antifilarial medication. At the time of treatment, people were advised to seek out their CHW in the event of adverse reactions. The CHWs were trained in the use of a simple algorithm, which classified potential adverse reactions according to severity and gave instructions for treatment of minor problems. Adverse reactions were classified as minor (no interference with daily activity), moderate (interference with daily activity), or severe (hospitalized). The CHWs treated minor reactions and referred persons reporting moderate or possible severe reactions to a nurse at one of 10 reference centers located throughout the plains. Nurses treated moderate problems and stabilized and referred to the hospital persons reporting possible severe reactions. Physicians examined and treated patients referred to the hospital, and determined if the reported problem was treatment-related.
Types of adverse reactions were defined in three categories. Systemic adverse reactions were those typically associated with microfilarial death. Systemic reactions included headache, fever, and body aches. Localized adverse reactions were those typically associated with adult worm death. This problem manifests most commonly in men because of inflammatory scrotal nodules that contain dead and degenerating adult worms.10 Much less frequently, nodules are reported elsewhere in the body; however, we restricted the analysis of local adverse reactions to men who reported scrotal reactions. Adverse reactions characterized as other were those that fit neither the systemic nor local definitions. Examples included gastrointestinal upset (stomach pain, vomiting, diarrhea), dizziness, and itching, among other signs and symptoms.
Medication was offered at no cost to persons reporting adverse reactions. The CHWs provided acetaminophen for headache, body ache or scrotal pain, oral rehydration salts for vomiting/diarrhea, and antacids for gastrointestinal upset. Nurses had the same medications, in addition to ibuprofen for moderate or severe scrotal pain, promethazine for itching, and epinepherine and intravenous fluids for shock. Treatment of adverse reactions was available for 11 days, beginning on the first day of the MDA. Information was collected on costs for bulk medicines and for personnel directly involved in adverse reactions surveillance and treatment. Data were collected by CHWs and nurses and entered into Excel® (Microsoft Office 97; Microsoft, Redmond, WA) and Epi-Info software (version 6.04; Centers for Disease Control and prevention, Stone Mountain, GA). Univariate and stratified statistical analyses were performed with Epi-Info software.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Adverse reactions.
Overall, 17,421 (24%) of those treated during the MDA reported one or more adverse reactions (Table 1
). Of these, 15,916 (91%) had minor adverse reactions, which did not interfere with daily activities. The most commonly reported minor adverse reactions were systemic: 9,766 (61%) persons reported some combination of headache, fever, or body aches and 2,170 (14%) reported localized problems associated with adult worm death.
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). Moderate adverse reactions were reported primarily by adults, 1,035 (69%) of whom were between 15 and 44 years old (Table 2). Among children less than 15 years old, boys were less likely to report moderate adverse reactions than girls (relative risk [RR] = 0.8, 95% confidence interval [CI] = 0.6–1.0). In contrast, adult men 15–44 and 
45 years old were more likely to report moderate adverse reactions than women of the same ages (combined RR = 1.9, 95% CI = 1.7–2.1).
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). Of 215 (26%) reporting other moderate adverse reactions, 83 reported itching, 70 reported gastrointestinal problems, 6 reported dizziness, and 56 reported miscellaneous other problems. A total of 801 (53%) persons reported multiple adverse reactions; these were combinations of systemic, localized scrotal, and other problems.
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45 years old accounted for 78 (13%). Overall, men were more likely than women to report a moderate adverse reaction (RR = 1.7, 95% CI = 1.5–1.9). Men did not differ from women in reporting systemic adverse reactions (RR = 1.07, 95% CI = 0.8–1.5). Compared with women, men were less likely to report adverse reactions in the other category (RR = 0.7, 95% CI = 0.5–0.9) and less likely to report a combination of systemic and other problems (RR = 0.6, 95% CI = 0.5–0.7). Men were more likely than women to report multiple types of adverse reactions (RR = 1.3, 95% CI = 1.1–1.4).
Mass distribution of DEC and albendazole occurred during a four-day period in October 2000, beginning on Saturday and ending on Tuesday. Of patients reporting moderate adverse reactions, 1,136 (76%), reported their problems during the four days of mass drug distribution (Figure 1). By the third day after the end of mass drug distribution, 98% (1,465 of 1,502) of all moderate adverse reactions had been reported. After taking antifilarial medication, the median onset time for those reporting only moderate systemic reactions was less than 24 hours (Figure 2). The median onset time for men reporting only localized scrotal moderate reactions was 24–48 hours. The median onset time for those reporting only other moderate reactions was less than 24 hours. Overall, 85% of those reporting moderate adverse reactions of any kind did so within 48 hours of taking treatment for lymphatic filariasis.
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Personnel and costs. Persons seeking care for adverse reactions were not charged for treatment. More than 100 CHWs or their appointed assistants provided adverse reaction advice and care for minor problems and referred persons with moderate problems to one of 10 reference centers. The CHWs and their assistants did not receive payment for these services. Reference centers were staffed during an 11-day period by a rotating group of 25 off-duty nurses and 33 nurse auxiliaries from the local hospital. A physician was available 24 hours per day to care for persons referred to the local hospital. An additional physician was on-duty during peak reporting periods (9:00 AM TO 3:00 PM). Physicians, nurses, and nurse auxiliaries were paid a daily wage. Overall, more than 160 temporary support personnel were trained and deployed to provide adverse reaction treatment services.
The total cost of all MDA and adverse reaction treatment activities was $79,842 (Table 4). Of this amount, $50,587 (63%) was used for MDA activities, and $15,436 (37%) was used for surveillance and treatment of adverse reactions. The largest expenditure in any category was for personnel, accounting for $46,526 (58%) of the overall costs, $31,090 (61%) of mass treatment costs, and $29,255 (53%) of adverse reaction treatment costs. Medications for adverse reactions accounted for $12,704 (43%) of all adverse reaction costs. Together, mass drug administration and management of adverse reactions cost $1.12 per person. The cost per person treated with antifilarial drugs was $0.71. The cost of treatment of adverse reactions was $1.60 per person treated.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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When administered with DEC, albendazole provides enhanced antifilarial and antihelminthic effectiveness and does not appear to significantly increase the frequency or severity of adverse reactions reported.15,20–22 The pattern of outcomes reported here is consistent with those reported in other studies.19 The clear majority of adverse events reported were minor and self-limiting, while severe adverse reactions were uncommon, occurring in approximately one in 25,000 persons treated. All three persons judged to have treatment-related severe adverse reactions recovered fully, and none required extended hospitalization.
Although moderate adverse reactions accounted for only 9% of reports, they represented the greatest burden to the health system and to the community in terms of personnel, cost of medicines, and interference with the daily activities of treated persons. Men outnumbered women two-to-one in reporting moderate adverse reactions. Because men also outnumbered women two-to-one in taking albendazole (38,655: 16,482), it may appear that albendazole use was associated with an increased occurrence of moderate adverse reactions. However, localized scrotal reactions in men accounted for the largest single category of moderate adverse reactions (604 of 1,502, 40%). Although localized adverse reactions due to dying adult filarial occur in other anatomic locations, they are much less commonly reported than those in the scrotum. Diethylcarbamazine has macrofilaricidal effects, which cause localized scrotal reactions in treated men.8,23 Although albendazole in higher doses for prolonged periods has also been associated with macrofilaricidal activity and localized scrotal reactions,15 single, low-dose regimens of albendazole do not appear to increase the frequency of adverse reactions when combined with other antifilarial drugs. When single-dose regimens (400 mg) of albendazole have been combined with ivermectin, which lacks macrofilaricidal activity, no significant increases in adverse reactions were measured when compared with ivermectin alone.24,25 In one study of treatment of Brugia malayi infection, the addition of albendazole to a DEC regimen resulted in no additional adverse reactions when compared with treatment with DEC alone.26
Although almost all treated men (>99%) received albendazole, while roughly half of treated women (52%) received albendazole, men did not differ from women in reporting moderate systemic adverse reactions. Men were less likely than women to report moderate adverse reactions in the other category, and less likely to report a combination of systemic and other problems. These data suggest that the addition of albendazole to a DEC treatment regimen does not correlate with an increased frequency of adverse reactions. Community messages about treatment and possible adverse reactions might target adult men regarding localized scrotal reactions.
The decision on the part of the Haitian Ministry of Health to exclude all women of child-bearing potential from treatment with albendazole was based on concerns regarding the safety of benzimidazole therapy in early pregnancy and the ability of women to accurately determine whether they were pregnant during the first trimester. Because of this decision, women of childbearing potential were excluded from the antihelminthic benefits of albendazole and the enhanced antifilarial efficacy of combination therapy with DEC. Most of the 26 countries engaged in filariasis elimination have elected to offer albendazole to nonpregnant women. In specific circumstances, benzimidazole treatment has been offered to pregnant women. The known benefits of benzimidazole therapy in improving hemoglobin and iron status for treated pregnant women in hookworm-endemic areas led the government of Sri Lanka to recommend treatment with mebendazole for all women after the first trimester, a position that has been supported by WHO.27–30 Potential risks and known benefits of mass treatment using albendazole should be considered carefully.31
The median time to onset of moderate systemic adverse reactions was 24 hours or less, which was consistent with previous reports and typically reflecting the rapid microfilaricidal effects of DEC.8,10 In contrast, the median time to onset of localized scrotal reactions was longer, 24–48 hours, presumably reflecting adult filarial death and the subsequent inflammatory response within the lymphatic vessel. Overall, 85% of those reporting moderate adverse reactions did so within 48 hours of receiving antifilarial drugs. Three-quarters (76%) of all moderate adverse reactions were reported during the four days of mass drug administration and 98% of all moderate adverse reactions were reported within three days after treatment stopped. These data suggest that deployment of health staff and resources should be concentrated early in the course of community treatment efforts, particularly during the days of the MDA, and during the subsequent three days.
The degree to which adverse events are detected or reported varies widely depending on the prevalence of infection and surveillance methods.19 Previous studies have correlated higher levels of microfilaremia with increased severity of adverse events following treatment.9,10,12,25 Active monitoring of documented microfilaremic individuals has resulted in detection of adverse reaction rates as high as 79%.19 Use of passive surveillance to detect adverse reactions following mass treatment with albendazole and DEC in a population with 32.8% prevalence of microfilaremia yielded a reported adverse reaction rate of less than two percent and no reported severe events (Hossain M, unpublished data).
The community treatment program in Leogane is intended to be a model for subsequent programs for the entire country. At the outset of this project, when microfilaremia levels and subsequent post-treatment adverse reactions were expected to be highest, it was felt that a proactive approach to address potential adverse reactions was in the best interest of the community, and of the long-term goals of the program. As a result of this decision to invest in a surveillance system for adverse drug reactions, treatment of reported adverse reactions was costly and labor-intensive. The cost per person treated for reported adverse reactions was more than twice the cost per person treated for lymphatic filariasis, and it required the training and deployment of more than 160 health personnel during an 11-day period. Most filariasis elimination programs cannot sustain such an expenditure of resources, and, in our view, such an expenditure is not necessary.
It may be argued that our active surveillance system, which offered free treatment of self-reported problems, may have encouraged over-reporting or spurious reporting of unrelated problems. While this may be true of minor problems, which were addressed at the community level by CHWs, persons reporting moderate problems were interviewed by nurses, and persons reporting potentially severe problems were examined by a physician. These interviews and examinations helped to limit spurious reports and added credence to the few reports of severe events, which received the highest level of clinical scrutiny. Because of social mobilization activities, pre-treatment education, and the participation of well-known CHWs within this small geographic area, community awareness of filariasis and the potential for adverse reactions following treatment was high. It is possible that over-reporting of minor problems occurred, but we consider it unlikely that a severe problem went unreported.
Microfilaremia levels and subsequent post-treatment adverse reactions might be expected to be lower in MDAs following the first year of treatment. Consequently, the costs and personnel needed to implement an adverse reaction treatment program should be less in subsequent years. Implementation of a more limited adverse reaction management system would be appropriate for MDAs in subsequent years. Such a system could be based on passive surveillance or a shorter period of active surveillance. Persons with minor adverse reactions might be offered advice or counseling, but not provided medication free of charge. Active surveillance and treatment of moderate and severe adverse reactions might continue in targeted, high-risk areas.
The clear majority of adverse events reported were minor and self-limiting, while documented severe adverse reactions were uncommon, occurring in approximately one in 25,000 persons treated. Addressing the needs of persons reporting moderate adverse reactions, those serious enough to interfere with daily activity, accounted for the greatest health system burden in terms of medical personnel and cost. The results documented here suggest that the need for management of adverse reactions is highest during the MDAs and the subsequent three days. Although the adverse reaction surveillance system reported here was labor-intensive and relatively costly to implement, it allowed us to document the frequency, severity, types, onset intervals, and costs of managing adverse reactions. These results highlight a central issue: regardless of the type of surveillance and treatment system chosen, filariasis elimination programs everywhere face the challenge of adverse reaction management.
Received October 3, 2002. Accepted for publication February 3, 2003.
Acknowledgments: We thank the physicians and nursing staff of Hôpital Sainte Croix in Leogane for their efforts in conducting adverse reaction management and surveillance. We also thank Dr. Thomas Streit (Notre Dame University, Notre Dame, IN), Dr. Marcel Parnell, Dr. Marie Denise Milord, Joyanna Wendt, and the community health workers of Leogane for their hard work in support of the filariasis elimination program.
Financial support: Major funding for the filariasis program at Hôpital Sainte Croix was provided by the Emerging Infections Program at the Centers for Disease Control and Prevention. Additional infrastructure support was provided by a grant from the Bill & Melinda Gates Foundation to Notre Dame University.
Authors’ addresses: Steven I. McLaughlin, National Immunization Program, Global Immunization Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop E-05, Atlanta, GA 30333, Telephone: 404-639-8252/1970, Fax: 404-639-8573, E-mail: swm4{at}cdc.gov. Jeanne Radday, David G. Addiss, Michael J. Beach, and Patrick J. Lammie, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341. Marie Carmel Michel and Jack Lafontant, Hopital Sainte Croix, Leogane, Haiti. John Lammie, Department of Family and Preventative Medicine, University of South Carolina School of Medicine, 6 Richland Medical Park, Columbia, SC 29203. Richard Rheingans, Department of International Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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