Paul B. Keiser

Strongyloides stercoralis in the Immunocompromised Population

SUMMARY Strongyloides stercoralis is an intestinal nematode of humans that infects tens of millions of people worldwide. S. stercoralis is unique among intestinal nematodes in its ability to complete its life cycle within the host through an asexual autoinfective cycle, allowing the infection to persist in the host indefinitely. Under some conditions associated with immunocompromise, this autoinfective cycle can become amplified into a potentially fatal hyperinfection syndrome, characterized by increased numbers of infective filariform larvae in stool and sputum and clinical manifestations of the increased parasite burden and migration, such as gastrointestinal bleeding and respiratory distress. S. stercoralis hyperinfection is often accompanied by sepsis or meningitis with enteric organisms. Glucocorticoid treatment and human T-lymphotropic virus type 1 infection are the two conditions most specifically associated with triggering hyperinfection, but cases have been reported in association with hematologic malignancy, malnutrition, and AIDS. Anthelmintic agents such as ivermectin have been used successfully in treating the hyperinfection syndrome as well as for primary and secondary prevention of hyperinfection in patients whose exposure history and underlying condition put them at increased risk.

Bacterial Endosymbionts of Onchocerca volvulus in the Pathogenesis of Posttreatment Reactions

Treatment of onchocerciasis with diethylcarbamazine (DEC) or ivermectin is associated with a posttreatment reaction characterized by fever, tachycardia, hypotension, lymphadenopathy, and pruritus. To investigate the role of the Wolbachia bacterial endosymbiont of Onchocerca volvulus in these reactions, serum samples collected before and after treatment with either anthelmintic were assessed for evidence of Wolbachia DNA. By use of real-time quantitative polymerase chain reaction, Wolbachia DNA was detected in both groups-with significantly higher levels in those who received DEC (P <.0001). In the ivermectin group, there was a significant correlation between levels of bacterial DNA and serum tumor necrosis factor-alpha (P =.013). Peak DNA levels correlated with reaction scores (P =.048). Significant correlations were also seen between Wolbachia DNA and the antibacterial peptides calprotectin (P =.021) and calgranulin B (P <.0001). These findings support a role for Wolbachia products in mediating the inflammatory responses seen following treatment of onchocerciasis and suggest new targets for modulating these reactions.

Treatment of Patients with Refractory Giardiasis

Giardia lamblia is one of the most common parasitic infections. Although standard treatments are usually curative, some immunocompromised patients, including patients with acquired immunodeficiency syndrome as well as healthy patients, have giardiasis that is refractory to recommended regimens. We report our experience with 6 patients with giardiasis, for whom therapy with a combination of quinacrine and metronidazole resulted in cures for 5 of the 6 patients.

Filaria-Induced Monocyte Dysfunction and Its Reversal following Treatment

ABSTRACT Monocyte dysfunction in filarial infection has been proposed as one mechanism underlying the diminished antigen-specific T-cell response seen in patent lymphatic filariasis. Cytokine/chemokine production and gene expression in monocytes from filaria-infected patients and uninfected healthy donors were assessed unstimulated and in response to stimulation with Staphylococcus aureus Cowan I bacteria plus gamma interferon both before and 8 months following treatment. Monocytes from filaria-infected individuals were studded with intracellular microfilarial antigens. Furthermore, monocytes from these individuals were less capable of producing interleukin-8 (IL-8), Exodus II, MIP-1α, MIP-1β, and IL-1α and preferentially expressed genes involved in apoptosis and adhesion compared with monocytes from uninfected donors. Eight months following treatment with a single dose of ivermectin-albendazole, some of these defects were reversed, with monocyte production of IL-8, IL-1α, MIP-1α, and IL-10 being comparable to that seen in the uninfected controls. In addition, a marked increase in mRNA expression of genes associated with protein metabolism, particularly heat shock proteins, was seen compared with pretreatment expression. These data suggest that the function and gene expression of monocytes in filaria-infected patients are altered but that this dysfunction is partially reversible following antifilarial treatment.

Molecular identification of Wolbachia from the filarial nematode Mansonella perstans

Wolbachiae are bacterial endosymbionts of insects and many filarial nematodes whose products trigger inflammation in filarial infections. The dependence of the parasites on their endosymbionts has also led to the use of antibiotics directed against the Wolbachiae, therapy that has been demonstrated to have a profound salutary effect on filarial infections. The identification of Wolbachiae in Mansonella species has been conclusively shown for Mansonella ozzardi (Mo), but not for Mansonella perstans (Mp). Using primers known to amplify the 16S ribosomal DNA of other filarial Wolbachiae, an identical 1393bp band was found in all samples tested. Sequence analysis of these samples demonstrated a single consensus sequence for Mp Wolbachia 16S rDNA that was most similar to Wolbachia sequences from other filarial nematodes. When aligned with the only other Mansonella Wolbachia sequence (Mo) there were only 8 nucleotide differences in the 1369bp overlapping sequence. Phylogenetic dendrograms, examining the relationship of the Mp Wolbachia to other Wolbachia 16S rDNA, showed that the Wolbachia tracked almost identically to the 5S rRNA of their parasite host. Wolbachia surface protein (WSP) was also demonstrated in protein extracted from Mp-containing whole blood. In advance of a treatment trial of Mp, a method for the quantitation of Mp Wolbachia was developed and used to demonstrate not only a relationship between microfilarial numbers and Wolbachia copy numbers, but also to demonstrate the effect of antibiotic on ridding Mp of Wolbachia.

Human Immunoglobulin G Mediates Protective Immunity and Identifies Protective Antigens against Larval Strongyloides stercoralis in Mice

Protective immunity to larval Strongyloides stercoralis in mice has been shown to be dependent on antibody, complement, and granulocytes. The goals of the present study was to determine the following: (1) whether human serum could passively transfer immunity to mice, (2) the mechanism by which the serum mediated killing, and (3) whether the antigens (Ags) recognized by the protective human antibody could induce protective immunity in mice. Immunoglobulin G (IgG) from a S. stercoralis-seropositive individual passively transferred immunity to mice. The antibody required granulocytes, but not eosinophils, and complement activation to kill the larvae. Antibody-dependent cellular cytotoxicity was not required for larval killing. Immunization of mice with soluble larval Ags isolated by use of the protective immune IgG resulted in protective immunity. In conclusion, immunity could be transferred to mice by IgG from immune humans, and Ags identified by the immune human IgG induced protective immunity in mice, which thereby suggests their possible use in a vaccine against this infection.

DNA Immunization with Na+-K+ATPase (Sseat-6) Induces Protective Immunity to Larval Strongyloides stercoralis in Mice

ABSTRACT Strongyloides stercoralis causes chronic asymptomatic infections which can be maintained in the human host for many decades. Identification and treatment of S. stercoralis-infected individuals is required because immunosuppression can lead to fatal hyperinfection. In this study, human immunoglobulin G (IgG) that had previously been shown to transfer protective immunity to mice was used to identify potential protective antigens. Three antigens or genes from S. stercoralis larvae were identified as tropomyosin (Sstmy-1), Na+-K+ATPase (Sseat-6), and LEC-5 (Sslec-5). The genes were cloned into plasmids for DNA immunization, and mice were immunized intradermally with the three plasmids individually in combination with a plasmid containing murine granulocyte-macrophage colony-stimulating factor. Only Na+-K+ATPase induced a significant reduction in larval survival after DNA immunization. Immunization with a combination of all three plasmids, including Na+-K+ATPase, did not induce protective immunity. Serum from mice immunized with DNA encoding Na+-K+ATPase was transferred to naïve mice and resulted in partial protective immunity. Therefore, DNA immunization with Na+-K+ATPase induces protective immunity in mice, and it is the first identified vaccine candidate against infection with larval S. stercoralis.

Prolonged Perilesional Edema after Treatment of Parenchymal Neurocysticercosis: Methotrexate as a Corticosteroid-Sparing Agent

Treatment of neurocysticercosis with larvicidal agents is commonly complicated by seizures and transient neurologic deficits as a result of the host immune response to dying cysts. We report a case in which treatment with high-dose praziquantel resulted in prolonged perilesional edema requiring use of corticosteroids and corticosteroid-sparing agents for >1 year, suggesting a role for methotrexate in the management of this condition.

Vaccines for Filarial Infections

The development of an effective vaccine against lymphatic filariasis and onchocerciasis would improve efforts to eradicate these infections. Despite the limited availability of parasites and animal models, a number of strategies have emerged to identify targets for protective and transmission-blocking immune responses. This chapter reviews these strategies and discusses some of the vaccine candidates that are currently being evaluated.

A 33-Year-Old Woman from Nigeria with Eosinophilia

A 33-year-old woman who had moved to the United States from Nigeria 3 years before presentation had an eosinophil count of 2600 cells/,uL (32% of the total cell count) noted on a routine complete blood cell count. She had a history of subcutaneous swellings that occurred on her trunk and extremities every few months during the past 10 years. These swellings were relatively painless but were warmto the touch, and they always resolved within 3 or 4 days. The findings of a physical examination done at presentation were unremarkable. Specifically, no subcutaneous swellings or dermatologic findings were