Dr Jérôme Salomon, Assistant Director‐General for Communicable and Noncommunicable Diseases at the World Health Organization (WHO), said the guideline is an important step towards addressing the burden of Strongyloides stercoralis disease, and he urged everyone to take note of its recommendations and how it works.
Dr Jérôme Salomon, Assistant Director‐General for Communicable and Noncommunicable Diseases at the World Health Organization (WHO), said the guidelines are an important step towards addressing the burden of Strongyloides stercoralis, and he urged everyone to take note of the recommendations and how they work.
Strongyloidiasis in humans is a chronic parasitic disease caused by infection with Strongyloides stercoralis, a soil‐transmitted or (less commonly) gastrointestinal helminth, estimated to infect 300‐600 million people worldwide. It is a neglected tropical disease (NTD) that is endemic globally, primarily in countries in Southeast Asia, Africa, and the Western Pacific and in South and Central America. Strongyloidiasis has a wide range of nonspecific clinical manifestations, with common symptoms including diarrhea, abdominal pain, and urticaria (known as the triad) and a rare complication called hyperinfection with disseminated disease (hyperinfection with disseminated disease) that can be fatal.
The dreaded complication of strongyloidiasis is disseminated infection that can occur in immunocompromised individuals such as those infected with human T‐cell lymphotropic virus type 1 (TCLVT‐1) and other malignancies, and in patients receiving immunosuppressive drugs such as steroids and anticancer drugs, with an estimated mortality rate of 60%. The standard treatment for chronic S. stercoralis infection is oral ivermectin.
In recent years, Ministries of Health in countries where strongyloidiasis is endemic have sought WHO guidance on how to address the disease as a public health problem, but no specific guidance has been provided by WHO. It has been noted that in some cases, community‐based drug programmes such as mass drug administration (MDA) with ivermectin (IVM) are being implemented to control lymphatic filariasis and African filariasis.
Figure 1. Strongyloides stercoralis larvae stained with 400X lugol’s solution.
A) Ấu trùng Rhabditform có thể nìn thấy phần xung quanh sinh dục (khung vuông) và ống miệng ngắn (mũi tên).
B) Ấu trùng Filariform thấy thực quản nối với ruột ở giữa ấu trùng (tỷ số1:1).
These programs have demonstrated reductions in S. stercoralis infection rates , suggesting that preventive chemotherapy may be a potential public health strategy in areas where strongyloidiasis is endemic. Furthermore, secondary patents for IVM have now expired, leading to WHO pre‐qualification of IVM in 2020 and 2021 at a preferential price for public health use.
In 2021, WHO published the Roadmap for Global Strategy Guidance and Targets for Neglected Tropical Diseases (NTDs) 2021‐2030. This Global Strategy highlights the need for formal guidance on whether to recommend chemoprophylaxis against strongyloidiasis and provides an opportunity to integrate strongyloidiasis control programmes into existing public health programmes for other NTDs.
These programs may target only school‐age children (targeted prevention) or the entire community (MDA) in endemic areas. Therefore, a Guideline Development Group (GDG) was convened to address the need for strongyloidiasis control and develop the Guidelines.
Objectives of the WHO Guidelines
The objectives of this WHO Guide are aligned with the three Sustainable Development Goals “ensure healthy lives for all at all ages”. The World Health Assembly resolution on expanding access to prevention, diagnosis, treatment and care for NTDs as a contribution towards achieving universal health coverage by 2030.
Its objective is to provide evidence‐based recommendations on whether chemoprophylaxis with IVM is appropriate as a public health intervention to reduce the burden of disease caused by strongyloidiasis. Its objective is to provide evidence‐based recommendations on whether chemoprophylaxis with IVM is appropriate as a public health intervention to reduce the burden of disease caused by strongyloidiasis.
- The target population of the implementation program is both adults and school‐age children (e.g. MDA) in endemic areas with a prevalence of strongyloidiasis above the defined threshold
- The program is implemented specifically in schools (targeted preventive treatment) in settings where the prevalence exceeds the defined endemic threshold for strongyloidiasis
- Not to be administered as a prophylactic treatment in place of standard clinical management of the individual case.
Recommendations This public health guideline is not intended to replace any standard of care for the clinical management of strongyloidiasis, and no public health approach can replace the need for prompt diagnosis and treatment of strongyloidiasis through accessible health care.
Theoretical basis for developing WHO Guidelines
The WHO Global Neglected Tropical Diseases Programme convened a meeting in June 2023, with technical experts on strongyloidiasis, to review the available evidence on the global burden of disease of strongyloidiasis and the safety and efficacy at the community level of IVM chemoprevention, to develop WHO Guidelines.
The GDG followed the procedures outlined in the WHO Guideline Development Manual, second edition 2014. The panel used a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to synthesise and evaluate the key evidence and systematic reviews presented to the committee. A mathematical modelling study analysed the cost‐effectiveness of addressing the impact of strongyloidiasis on communities using IVM as preventive treatment at the community level, comparing targeted prophylaxis (only for school‐age children often using existing treatment infrastructure in schools) and MDA (community‐wide drug administration) in different endemicity areas.
Figure 3a. Large numbers of filariform larvae of S. stercoralis found in bronchial lavage fluid specimen (black arrow, hexamine‐silver stained, magnification × 200)
Figure 3b. Image of filariform larvae of S. stercoralis in a case with hyperinfection syndrome
The Committee followed the GRADE process from evidence generation to decision to make recommendations, including consideration of the following criteria: (i) Certainty of the evidence, (ii) Balance of benefits and disadvantages, (iii) Values and preferences, (iv) Use of resources, equity, acceptability and feasibility. The overall scope of the Guideline and prioritization of outcomes were undertaken by the GDG. Evidence‐based recommendations were developed and finalized at a GDG meeting in Geneva, Switzerland (2023). Further remote meetings were held during the preparation of this guideline and its revision. External experts served as technical peer reviewers for the preliminary version of the guideline.
Scientific evidence for WHO Guidelines
The GDG analyzed the major systematic reviews (mainly observational data) and a recent randomized trial to develop guideline recommendations. The evidence was then used to develop a cost‐effectiveness model for strongyloidiasis prevention and other literature. After synthesizing the data, the GDG summarized the main evidence:
- Kể từ cuối năm 1980, thuốc IVM đã được Hướng dẫn để điều trị nhiễm S. stercoralis, trong thực hành lâm sàng đã được điều trị rộng rãi. Nhiều nghiên cứu thực nghiệm trên những bệnh nhân nhiễm giun lươn mãn tính đã chỉ ra với một liều IVM duy nhất có tỷ lệ chữa khỏi > . 90%. Sau đó, các thử nghiệm ngẫu nhiên đã so sánh ivermectin (IVM) với albendazole (ALB) và thiabendazole (TBZ), là hai thuốc điều trị thay thế tiềm năng.Một nghiên cứu đánh giá tổng quan, hệ thống và phân tích tổng hợp đã cung cấp bằng chứng thuyết phục về tính ưu việt của IVM so với ALB. Đối với việc so sánh IVM và TBZ, một loại benzimidazole khác, bằng chứng tích lũy bị hạn chế và do đó không có kết luận. Các cân nhắc khác, chẳng hạn như tính an toàn, ủng hộ IVM trong điều trị nhiễm trùng S. stercoralis hơn nhóm benzimidazole;
- Một nghiên cứu đánh giá tổng quan hệ thống và phân tích tổng hợp dữ liệu quan sát chất lượng thấp về MDA (chỉ định thuốc toàn cộng đồng) với IVM (được thực hiện để kiểm soát các bệnh khác) đã phát hiện ra sự giảm đáng kể về tỷ lệ nhiễm trùng S. stercoralis (được đo bằng xét nghiệm phân hoặc huyết thanh học) sau khidùng IVMtại các vùng có lưu hành S. stercoralis.
- Bằng chứng sử dụng IVM rộng rãi từ các điều trị các bệnh khác như bệnh giun chỉ bạch huyết, bệnh giun chỉ châu Phi Loa Loa, bệnh ghẻ chứng minh tính an toàn của thuốc IVM. Ngoài ra, một nghiên cứu đánh giá có hệ thống và phân tích tổng hợp sáu thử nghiệm lâm sàng ngẫu nhiên bao gồm những bệnh nhân bị nhiễm stercoralis đã chứng minh tính an toàn của IVM, ngay cả khi dùng IVM liều cao (> . 400 µg/kg), ít nhất gấp đôi liều chuẩn là 200 µg/kg được đề xuất cho liệu pháp hóa trị dự phòng cho bệnh giun lươn;
- Một nghiên cứu mô hình toán học, sử dụng MDA (trên toàn cộng đồng) với thuốc IVM là một phương pháp tiếp cận hiệu quả về mặt chi phí để kiểm soát bệnh giun lươn (giảm tỷ lệ mắc bệnh do lây nhiễm và tỷ lệ tử vong do biến chứng nhiễm trùng lan tỏa). Trong các cộng đồng có tỷ lệ nhiễm stercoralis thực tế trên 4‐10% ở trẻ em trong độ tuổi đi học (tỷ lệ mắc bệnh được quan sát thấy là 2‐5% khi dùng xét nghiệm chẩn đoán không hoàn hảo với độ nhạy 50% nhưng độ đặc hiệu hoàn hảo). Nhóm trẻ em trong độ tuổi đi học có tỷ lệ mắc giun lươn thấp, nhưng có tỷ lệ ác tính và tử vong cao. Ở nhóm tuổi lớn hơn, tỷ lệ mắc bệnh giun lươn và nguy cơ suy giảm miễn dịch dự kiến sẽ cao hơn dựa trên các nghiên cứu dịch tễ học. Do đó, việc đưa quần thể người lớn vào MDA vào mô hình đã cải thiện hiệu quả về mặt chi phí so với việc chỉ điều trị dự phòng cho trẻ em trong độ tuổi đi học.
Recommendation
The GDG issued a single recommendation for prophylactic treatment with ivermectin to reduce the public health burden of strongyloidiasis. This recommendation considered several factors, including the certainty of the evidence and the potential benefits and harms of the intervention, the values and acceptance of the target population, and ethical issues, acceptability, and feasibility of using chemoprevention. In endemic areas with a prevalence of strongyloidiasis ≥ 5%, WHO recommends annual mass drug administration (MDA) of a single dose of ivermectin for all age groups 5 years and older to reduce strongyloidiasis.
Comments regarding the interpretation of the recommendations in the Guide
Community goals
The MDA population includes the entire community (currently the age group 5 years and older). Based on modelling evidence, epidemiological data and expert assessment, a greater public health impact is expected when treating the entire community through MDA implementation, compared to treating only school‐age children. The reason is that older populations are at higher risk of cumulative infection and are more likely to develop disseminated strongyloidiasis (due to immunosuppression), and therefore benefit from the use of MDA.
The indication for IVM use in children weighing more than 15 kg has been established, while the safety of IVM use in children weighing less than 15 kg (corresponding to an age cut‐off of 5 years) has not been established and is therefore not recommended. However, further research on the safety of IVM in children weighing less than 15 kg, along with the development of pediatric IVM formulations, is ongoing. The GDG anticipates that this age and/or weight restriction may be removed in the future if sufficient data on the safety of IVM in the younger population 5 years;
Women who are pregnant or breastfeeding during the first week postpartum should be excluded from MDA with IVM due to the current lack of safety data and regulatory approval for IVM in these groups. These exclusion criteria will be re‐evaluated until new data are available to assess the safety of IVM and alternative formulations of IVM.
In areas with any evidence of endemic Loa loa infection, the use of MDA with IVM cannot be recommended due to the risk of adverse events in patients with high levels of Loa loa infection. In such settings, safety precautions as outlined in the WHO guidelines for human filariasis and/or lymphatic filariasis are required. In most cases, the MDA strategy with IVM is not recommended in these areas.
Tại các vùng đang áp dụng MDA với thuốc IVM cho các chỉ định điều trị hay dự phòng bệnh khác (bệnh giun chỉ bạch huyết, giun chỉ Onchocerca spp.), sử dụng chương trình MDA đang sử dụng thuốc IVM là đủ, với điều kiện là phạm vi bao phủ toàn bộ cộng đồng là đủ.
Continued Part 2
Authors: Ths.BS. Nguyen Duc Hong & Dr.BS. Huynh Hong Quang
(IMPE Quy Nhơn)
