Close to a billion people worldwide remain threatened by lymphatic filariasis, a neglected tropical disease commonly referred to as elephantiasis. This parasitic infection, which is caused by a nematode spread by mosquitoes, impairs the lymphatic system and can lead to the abnormal enlargement of body parts, causing pain, severe disability, and social stigma. The painful and profoundly disfiguring visible manifestations of the disease, such as lymphoedema, elephantiasis, and scrotal swelling occur later in life and can lead to permanent disability. Sadly, these patients are not only physically disabled, but suffer mental, social, and financial losses contributing to stigma and poverty.
While programs such as the Global Program to Eliminate Lymphatic Filariasis seeks to eradicate this disease through mass drug administration to more than 500 million people each year, invariable some patients will experience adverse events following treatment. Now, a team of investigators at Washington University School of Medicine set out to better understand the pathogenesis of adverse effects for treating this debilitating disease. Findings from the new study were published recently in PLOS Neglected Tropical Diseases through an article titled “Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis.”
“This is the first global study of changes in gene expression associated with adverse events (AE) after treatment of lymphatic filariasis,” the authors noted.
Lymphatic filariasis (LF) is caused by infection with parasites classified as nematodes (roundworms) of the family Filariodidea. There are three types of these thread-like filarial worms:
- Wuchereria bancrofti, which is responsible for 90% of cases
- Brugia malayi, which causes most of the remainder of cases
- Brugia timori, causes a minor number of LF cases
Adult worms reside within the lymphatic vessels and interrupt the normal function of the lymphatic system. Incredibly, the worms can live for approximately 6–8 years and, during their lifetime, produce millions of microfilariae (immature larvae) that circulate in the blood.
Mosquitoes are infected with microfilariae by ingesting blood when biting an infected host. Microfilariae mature into infective larvae within the mosquito. When infected mosquitoes bite people, mature parasite larvae are deposited on the skin from where they can enter the body. The larvae then migrate to the lymphatic vessels where they develop into adult worms, thus continuing a cycle of transmission.
Mass drug administration to prevent LF and reduce transmissions generally rely on annual treatment with combinations of two or three drugs. Although treatment is safe, transient mild to moderate systemic adverse events—such as joint pain, fever, rash, or cough—are common in individuals with circulating microfilariae in the blood. Since these AEs are quite uncommon in uninfected individuals, they are believed to be triggered by host responses to dying filarial worms rather than the drugs themselves.
“Some individuals develop AEs after treatment, and this can reduce the willingness of persons in endemic areas to accept treatment,” the authors wrote. “The purpose of this study was to improve understanding of the cause of AEs following treatment. We hypothesized that parasite antigens released into the blood following treatment trigger inflammatory responses that lead to AEs.”
In the current study, the research team studied blood samples from 95 individuals being treated for LF. Nine of these participants experienced moderate AEs, 24 had mild AEs, and 62 had no AEs. Levels of filarial antigens and immune proteins, as well as DNA transcription signatures, were studied.
“We collected blood from LF-infected individuals before and after treatment and clinically assessed them for AEs. We measured parasite antigens, cytokines, and other components of the immune system in blood samples and compared post-treatment changes in persons with and without AEs,” the authors penned. “We also assessed changes in transcription profiles in peripheral blood leukocytes that were associated with post-treatment AEs. Post-treatment changes in transcription profiles and in immune proteins and parasite components in plasma suggest that systemic AEs are triggered by the death of the parasites following treatment with the release of parasite antigens and Wolbachia bacteria into the circulation.”
The Washington University team found that levels of filarial antigens increased after treatment in individuals with AEs, and this suggests that AEs are triggered by host responses to dying parasites. AEs were associated with elevations in serum levels of certain immune molecules called cytokines. Moreover, when the team compared patterns of gene expression in white blood cells between people with moderate AEs and those without AEs, they found 744 genes upregulated in people with AEs, including many genes involved in immune signaling.
“Improved understanding of the pathogenesis of adverse events may lead to improved management, increased MDA compliance, and accelerated LF elimination,” the researchers concluded.