Onchocerciasis and Other Parasitic Diseases

Clinical Appearance

Onchocerciasis, or river blindness, is a disease that affects 17.7 million people worldwide, with more than 123 million people living in its endemic regions. It is estimated that some 270,000 persons are blinded and a half million are severely visually handicapped because of this disease. In developing countries, blindness occurs at 10 times the rate reported in the developed world. ^, Ocular onchocerciasis has been declared by the World Health Organization (WHO) as one of the five major preventable causes of blindness (the others are cataract, trachoma, glaucoma, and xerophthalmia). The disease is caused by a tissue-dwelling parasite, the nematode Onchocerca volvulus. It is spread by the blackflies of the Simulium species and is found in a broad belt across western and central Africa, in Central America, and in small pockets in northern South America and the Arabian peninsula. Zoonotic infections have been reported in many countries, including Hungary. The blackfly needs rapid running water to propagate, and therefore the endemic areas are usually the most fertile, which makes this disease of extraordinary importance for the affected Third World countries.

The infected blackfly bites humans, thereby introducing the infection. Polymerase chain reaction (PCR)–mediated amplification methods and immunoblotting of the silk proteins permit identification of sibling species of biting adult females. Adult worms will ultimately develop and form the nodules found throughout the body, often subcutaneously. These adults will produce microfilariae that are released in extraordinary numbers. The diagnosis of the disease and the determination of the infestation rate are made by counting the number of microfilariae found in skin snips ( Fig. 18.1 ) The microfilariae are the major cause of most of the ocular disease. Table 18.1 lists other ocular manifestations involved in parasitic infections of the eye.

A major complication of Onchocerca infestation is corneal disease. Microfilarial infestation in the cornea is related to visual loss over time, and the presence of a large number of microfilariae in the anterior segment is related to irreversible visual loss. In the cornea, there is punctate keratitis; the presence of “snowflake” opacities in the cornea is associated with a fairly mild infestation. With more intense infestation and over time, sclerosing keratitis and loss of vision are seen ( Figs. 18.2 and 18.3 ).

Iridocyclitis can be seen in conjunction with other aspects of onchocerciasis, although the intensity of reaction can vary considerably. In addition to atrophy of the iris, more serious complications, such as glaucoma and cataract, can occur. Glaucoma has been recognized as a possibly important cause of irreversible visual loss in these patients. In addition, even without the presence of the inflammatory response, microfilariae can be seen in the anterior chamber. However, the patient needs to be placed in a darkened room with the head held down between the knees for a few minutes. With the use of a slit lamp, the observer will note the presence of the swirling microfilariae in the anterior chamber.

Alterations of the posterior pole have been seen as well, and the degree of visual impairment caused by these changes has probably been underestimated in the past. Large areas of chorioretinitis and optic nerve disease leading to atrophy can be seen ( Fig. 18.4 ). Newland et al. examined 800 patients in a hyperendemic region of the rainforest in Liberia, West Africa. They found chorioretinal changes in 75% of those examined, which strongly suggested that visual impairment in those living in this region was largely caused by chorioretinal disease and not by anterior segment changes. In a report describing recent Ethiopian immigrants to Israel, Enk et al. examined 1200 patients and found that 83 had cutaneous signs of onchocerciasis, with 48% having positive skin snip results for the presence of microfilaria. Of the 65 patients who underwent ocular examination, four eyes had evidence of active anterior segment inflammation, and 11 had retinal or choroidal changes.

Relatively few eyes with this condition have been studied histologically. It is thought that the microfilariae may enter through the long and short ciliary vessels. ^, Another possibility is the passage of microfilariae through cerebrospinal fluid (CSF) into the optic nerve sheath or direct invasion through the sclera by the parasite’s release of digestive enzymes.

It should be noted that the ocular disease in most patients is thought to be a result of slow, chronic, and relatively insidious changes. However, acute episodes of glaucoma, uveitis, and optic nerve disease may be important components of the disease in some patients. Egbert et al. examined patients in Ghana and found that 10.6% of those with glaucoma had concomitant onchocerciasis compared with 2.6% of those needing cataract extraction.

Laboratory studies have been attempted to better deduce the mechanism of systemic infestation, and, to a lesser degree, work has concentrated on ocular disease. The only known natural animal host besides the human is the gorilla, although the disease has been induced in the chimpanzee and the cynomolgus monkey, in which Onchocerca lienalis was used. Using a rabbit model, Duke and Garner placed O. volvulus into the vitreous or subretinally and observed chorioretinal alterations. The injection of O. lienalis subconjunctivally in guinea pigs produced a lesion resembling that seen in human onchocercal punctate keratitis. In a monkey model for this disease, disease was induced with the injection of 10,000 live O. volvulus microfilariae into the vitreous and this produced posterior segment lesions similar to those seen in the human disease.

Immune Characteristics

Laboratory studies have suggested that the parasite induces a complex immune response, perhaps partly autoimmune. Immunoglobulin E (IgE) production is a prominent feature of Onchocerca infestation, and circulating immune complexes that presumably contain parasite antigen can be detected. Cell-mediated responsivity is reduced, a phenomenon also noted in other helminth infections. Indeed, it appears that in addition to a predominantly B-cell (i.e., antibody) response, the immune system tries to minimize bystander tissue damage after the death of microfilariae by producing blocking antibodies and downregulating cytokines. Chan et al. examined the ocular fluid and serum from patients with onchocerciasis for the presence of antiretinal autoantibodies and found that these patients had antibodies directed toward the inner retina (nerve fiber, ganglion cell, and Müller cell) that could not be absorbed with the use of either S-antigen (S-Ag) or the interphotoreceptor-binding protein. These observations suggested that autoimmune mechanisms may play a role in the retinal degeneration and optic nerve disease seen so frequently in these patients. Van der Lelij et al. found high titers of anti- Onchocerca antibodies in the aqueous of patients with onchocerciasis and ocular disease and believed that retinal autoimmunity was an improbable factor in the pathogenesis of onchocercal chorioretinopathy.

However, immunologic cross-reactivity between an antigen of O. volvulus and that found in the retinal pigment epithelium (RPE) has been identified. Antisera from patients with onchocerciasis identified a 22-kDa antigen from Onchocerca, whereas a 44-kDa antigen from cultured human RPE was immunoprecipitated with the same antiserum. Klager et al. used Western blotting to show that antibody reactions to this antigen were seen in all patients with onchocerciasis and posterior pole disease but were not seen in controls. These interesting results suggest that molecular mimicry plays a role in the development of at least certain aspects of the ocular complications noted in this disorder. It also strengthens the notion that, as with ocular toxoplasmosis, inflammatory systems can no longer be restricted to only one mechanism and that in some ways, contradictory routes may be stimulated. Autoantibody responses are not restricted to the eye. Such cross-reactivity has been reported against five major autoantigens, anticalreticulin activity, and the 65-kDa arthritis-associated mycobacterial heat shock protein.

The corneal lesions of onchocerciasis have been studied using animal models. There is infiltration of granulocytes and eosinophils into the clear structures. Kaifi et al. found that vascular adhesion molecules are important in this process. These authors demonstrated a regulatory role for platelet endothelial cell adhesion molecule 1 and intercell adhesion molecule in that they recruit neutrophils and eosinophils to the cornea, as does P-selectin. Because there are antibodies that are directed against these molecules, it raises the possibility of their use in immune therapy for the cornea. Other studies by the same group ^, demonstrated the importance of CD4+ T cells in the development of corneal opacification, but not in the early stages of the disease. Saint Andre et al. proposed that the predominant inflammatory response seen in the cornea of Onchocerca -infected animals is, in fact, directed against the endosymbiont of Onchocerca and Wolbachia. Indeed, it may be the essential player in the pathogenesis of river blindness. This endosymbiont is so essential to the nematode that embryogenesis of Onchocerca is completely dependent on the presence of Wolbachia. The O. volvulus–Wolbachia combination initiates activation of many immune indicators ( Table 18.2 ). Indeed, this may open a new avenue for therapy (see below).

With studies of the specialized mechanisms of the parasite, an interesting concept has emerged. Lipid-binding proteins in the nematode, with no known counterpart in mammalian systems, exist. One of these, Ov-FAR-1, has a high affinity for retinal and fatty acids and is present in all life stages of the parasite. Retinol is believed to be important for the growth and differentiation of the organism and for its embryogenesis and glycoprotein synthesis. The concentration of retinol is eight times higher in the Onchocerca nodule than in the surrounding tissue. It is possible that Ov-FAR-1 causes a relatively local or systemic depletion of vitamin A in patients with onchocerciasis and may also be a trigger for the production of collagen, which is found in large quantities in Onchocerca nodules. These could explain why ivermectin therapy may not be effective for the retinal disease in this disorder because microfilaria already present in the retina would continue to produce this lipid-binding protein (see later discussion on ivermectin).

The regulation of interleukin (IL)-5 production in onchocerciasis has been evaluated. It has been suggested that in some helminthic infections, the production of IL-5 may be associated with an immune or a resistant state. It appears that in patients who are “immune” to the effects of Onchocerca, both IL-2 and IL-5 are produced in significantly higher levels than in those with acute infection. IL-2 production is required to induce IL-5. Toll-like receptor 2 (TLR2) appears to regulate chemokine production and neutrophil recruitment to the cornea in experimentally induced Onchocerca/Wolbachia keratitis. Interferon (IFN)-γ responses from TLR2 knockout mice are also deficient.