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Ocular filariasis in US residents, returning travelers, and expatriates.

DISCUSSION

Intraocular nematode infections are uncommon and usually caused by filarial worms such as Loa loa and Onchocerca volvulus that are transmitted by flies in the tropics. (1,2) Wuchereria bancrofti, Brugia malayi, and B. timori are transmitted by mosquitoes and typically cause lymphatic rather than ocular filariasis in endemic tropical regions worldwide (W. bancrofti) and confined regions of southeast Asia. Zoonotic Dirofilaria and Onchocerca worms are also transmitted by mosquitoes and have caused intraocular filariasis in temperate regions worldwide including Louisiana.

Several factors now place US residents, returning travelers, and expatriates at the risk of contracting ocular filariasis including increasing seroprevalence rates of zoonotic filariasis, international travel bringing tourists to and expatriates from filariasis-endemic regions, and warming temperatures extending distribution ranges of arthropod vectors. As a result, the objectives of this review were to describe the epidemiology and outcomes of ocular filariasis and to recommend strategies for the diagnosis, management, and prevention of ocular filariasis.

METHODS

Internet search engines, including Google[R], Google Scholar[R], PubMed, Medline, and Ovid, were queried with the key words as medical subject heading search terms to examine case reports and series of ocular filariasis in the US. The key words included nematodes, ocular; filariasis, ocular; onchocerciasis, human and canine; loiasis; dirofilariasis, human, ocular, and dirofilariasis, canine. Since this study was a review of the existing scientific literature, Institutional Review Board approval was not required.

RESULTS

Filarial Species Biology and Life Cycles

Loa loa is transmitted by Chrysops species horse flies and causes loiasis with high microfilarial burdens, angioedematous or Calabar swellings as worms migrate subcutaneously, and adult worms traversing the eyes in 3 to 13 million people in confined areas of sub-Saharan Africa (Figure 1). (1) With a much broader distribution range, Onchocerca volvulus is transmitted by Simulium species black flies and causes onchocerciasis with chronic skin and eye infections in about 37 million people in endemic areas of Mexico, Central and South America, West and Central Africa, and the Arabian Peninsula (Yemen). (2) The dirofilarial nematodes, including the canine heartworm, Dirofilaria immitis, are distributed worldwide, have extensive zoonotic reservoirs, are transmitted by several species of mosquitoes, and can cause periorbital, pulmonary, and subcutaneous dirofilariasis. (3,4)

All filarial species share similar life cycles and rely on arthropod vectors to transmit infective third stage larvae during blood-feeding. Humans are the reservoirs for W. bancrofti, O. volvulus, B. malayi, and L. loa, while the zoonotic reservoirs for O. lupi, D. repens, and other dirofilariae are domestic and wild carnivores. Gravid female worms release microfilariae into the reservoir host's circulation which can infect blood-feeding flies and female mosquitoes that transmit infective, third stage larvae to humans.

The Descriptive Epidemiology and Clinical Manifestations of Ocular Filariasis

Although a range of nematodes from ascarids and hookworms to strongylids can invade the eyes, most reported cases of ocular nematode infections have been caused by the filariae which can infect the eyelids, lacrimal glands, conjunctival sacs, orbit, or ocular globe. In 1989, Beaver reviewed 56 cases of ocular filariasis reported in the US between 1771 and 1989 and determined that only six worms removed from the eyes could be accurately identified morphologically. 95) Since the late 1990s, however, several epidemiological investigations have supported the increasing prevalence of human dirofilariasis caused by D. repens throughout Europe, especially in France and Italy. (3,4) 6-9 In a 1999 series of 71 cases of D. repens-caused subcutaneous and periorbital dirofilariasis in France, Raccurt observed that although most cases had been confined to the south of France prior to 1990, new cases had now been reported from formerly non-endemic regions at higher altitude regions in southwestern France and from the north of France. (7) In 2001, Pampiglione and co-investigators described 60 new cases of D. repens-caused subcutaneous and periorbital dirofilariasis in Italy over the period 1990-1999. (4)

Some of the more unusual causes of human ocular dirofilariasis in the US have been caused by D. striata and D. tenius. In 1990, Orihel and Isbey reported the intact removal of a 28-cm long female worm from the orbit of a 9-year-old boy in North Carolina. (8) The investigators identified the specimen as D. striata, a natural parasites of wild felids, including feral cats and bobcats. (8) In 2008, Holcombe and co-authors reported the case of 68-year-old woman in central Louisiana who presented to her ophthalmologist complaining of irritation and foreign body sensation in her left eye. (9) Slit lamp examination demonstrated a large mobile worm in the medial aspect of the subconjunctiva. (9) The ophthalmologist extracted a 40-mm long intact worm, later identified by the US Centers for Disease Control and Prevention (CDC) as an adult male Dirofilaria tenuis, a natural parasite of raccoons. (9) The patient admitted working in her garden on the edge of woods filled with raccoons and being bitten by mosquitoes frequently. (9)

Since the late 1990s, an increasing number of cases of canine ocular onchocerciasis with zoonotic reservoirs primarily in wild carnivores have also been reported from the US and Europe. (10-13) More recently, Onchocerca lupi, first identified in wolves, caused outbreaks of canine ocular onchocerciasis in domestic dogs in Europe and the US, and was reported to have caused human cases of ocular onchocerciasis in Eastern Europe and Turkey. (10-13)

In an exceptional case of an ocular nematode infection caused by a non-filarial worm, Koehsler and co-investigators reported the case of a 14-year-old girl in rural Austria with regular contact with several domestic animals (dogs, cats, and a pet turtle) and a history of progressive pain, redness, and visual loss in the right eye. (14) Slit lamp examination at an eye clinic in Vienna demonstrated a mobile worm in the anterior chamber of the right eye. (14) The surgical removal of the worm was complicated by the excessive mobility of the worm which escaped into the posterior chamber and lodged in a recess of the ciliary body. (14) Lens removal and complete vitrectomy were required to remove the worm intact. (14) One month later, the right eye was no longer irritated, and three months later an artificial intraocular lens was inserted. (14) The worm was later identified by its morphology and by molecular phylogenetic analysis as the third instar larva of Linguatula serrata, the tongue worm. (14)

Tongue worms can cause nasopharyngeal and upper respiratory tract infections in zoonotic reservoirs in domestic and wild canids and felids with intermediate hosts in cattle, sheep, rodents, and occasionally man. (14) Although ocular linguatulosis is rare in Central Europe, it has been described in the Americas, southern Europe, and Israel. (14) Humans become accidental intermediate hosts by ingesting infective eggs or raw or undercooked viscera (liver, lungs, trachea) of infected ungulate hosts. (14)

In summary, descriptive epidemiological, morphological, and molecular evidence now support increasing cases of ocular nematode infections in domestic dogs and humans, with most cases caused by filarial worms including Dirofilaria repens and other zoonotic Dirofilaria species and Onchocerca lupi and other zoonotic Onchocerca species.

The Diagnosis and Management of Intraocular Nematode Infections

The following two reported cases exemplify the complexities of diagnosis and treatment of intraocular filariasis in the US.

Case 1. In 2012, Eberhard and colleagues reported the fourth case of a filarial nematode removed from the eye of a resident of Oregon and the second case of a zoonotic Onchocerca removed from the anterior chamber in the US. (8) A 56-year-old male who denied travel outside of the US presented to his ophthalmologist with a 10-day history of left eye pain and 2 days of blurred vision in that eye. (8) Examination demonstrated reduced visual acuity in the left eye, intraocular pressure of 49 mmHg in the left eye compared to 14 mmHg in the right eye, and normal fundoscopic examination. (8) Slit lamp examination demonstrated a 1.5 cm long thin, white nematode coiled around itself in the anterior chamber that reacted spasmodically to the intense light of the slit lamp. (8) Oral acetazolamide, 500 mg, was administered in order to lower the intraocular pressure in the left eye; and 4 percent pilocarpine, one drop, was applied topically to the left eye to constrict the pupil and prevent the posterior migration of the worm. (8) Hours later, the patient underwent complete removal of the nematode from the anterior chamber under topical anesthesia using irrigation and aspiration cannulas inserted in microincisions. (8) Postoperatively, the patient was treated with topical steroids and a fluoroquinolone and was weaned off a topical P-blocker and a-agonist for intraocular pressure control in the left eye. (8) The patient recovered completely without residual eye damage in a few weeks. (8) The worm was fixed in formalin by consulting pathologists and later identified by its morphology by parasitologists at the CDC as a larval form of a zoonotic Onchocerca. (8) Since the worm was preserved in formalin, molecular typing by polymerase chain reaction (PCR) and speciation of the filarial worm beyond genus level was precluded. (8)

The most important principles of management in this case included: (1) complete eye examination revealed significantly increased intraocular pressure which was reduced pharmacology preoperatively; (2) slit lamp examination demonstrated that the worm was alive and capable of rapid movement anywhere in the eye; (3) the pupil was constricted with topical pilocarpine preoperatively to prevent posterior migration and confine the worm to the anterior chamber for surgical removal; and (4) fixation of the worm in formalin rather than saline precluded molecular typing for precise speciation of the worm.

The prevention of posterior chamber migration of live nematodes during surgical worm extraction is critical in preventing further damage to eye. In the Austrian case of ocular linguatulosis, the pupil was not constricted pharmacologically prior to worm extraction, and the larval tongue worm escaped to the posterior chamber where its removal from a recess in the ciliary body required lens removal and vitrectomy. (14)

Case 2. In 2008, Ali and colleagues reported a case of loiasis in a 30-year-old university exchange student from Cameroon, where loiasis and onchocerciasis are both endemic. (15) The patient reported a five-hour history of foreign body sensation in his right eye during which time he visualized a thin, clear worm traversing his right eye. (15) He presented to the student health clinic the next day with resolution of foreign body sensation and intense conjunctivitis in the right eye. (15) He had been studying in the US for two years and denied any skin rashes or subcutaneous (Calabar) swellings. (15) Laboratory studies demonstrated 8 percent eosinophilia (normal range: 1-6 percent) and normal liver enzymes and renal function tests. A peripheral blood smear demonstrated the presence of sheathed microfilariae of Loa loa quantified at 4,910 microfilariae/mL of blood. A L. loa polymerase chain reaction (PCR) was also positive and confirmed the diagnosis of loiasis. Several skin snips were taken from the shoulders, hips, and thighs bilaterally and submitted to the US National Institute of Health (NIH) which ruled out concomitant infection with Onchocerca volvulus. Co-infections with both filarial worms could complicate treatment for loiasis in patients with excessive microfilarial levels (> 30,000 microfilaria /mL); contraindicate treatment with ivermectin.; and place patients at risk of significant encephalopathy from host response reactions to dying microfilariae in the cerebral circulation and cerebrospinal fluid with resulting meningoencephalitis, cerebral edema, cerebral infarcts, and coma. (15)

The patient underwent apheresis at the NIH for two days on admission, and then received prednisone, 40 mg/day for three days. Following this, he received oral diethylcarbamazine (DEC) in well-tolerated, incrementally increasing doses from 50 mg to 200 mg three times per day for the next three days. At the time of his discharge, microfilarial quantification was 2,250 microfilariae/mL of blood. A later follow-up blood smear was negative for microfilariae. Negative follow-up blood smears for relapse continued at six-month intervals and remained negative for microfilariae during the daytime.

The most important principles of management in this case included: (1) expatriates and returning travelers from West and Central Africa are at risk of having contracted ocular filariasis from either or both L. loa and O. volvulus with adult worms living in the subcutaneous tissues and gravid females producing microfilariae for over 10-15 years; (2) unlike onchocerciasis, loiasis may be relatively asymptomatic and characterized by transient movements of adult worms in the subconjunctiva; (3) peripheral eosinophilia may be low grade (8 percent in this case), despite high peripheral blood microfilariae levels (4,910 microfilaria/mL of blood in this case); and (4) apheresis is indicated to reduce microfilariae levels below 2,500/mL in order to avoid host response reaction to dying microfilariae in the cerebral circulation. (15) Tapering doses of oral corticosteroids prior to definitive DEC therapy may also decrease the adverse cytokine-induced, inflammatory reactions to dying larval and adult worms; (5) ivermectin treatment for concomitant onchocerciasis may also result in fatal central nervous system complications; and (6) skin snip testing is indicated to rule out concomitant onchocerciasis in patients from regions that are endemic for both parasites. (15)

Confusing cases of amicrofilaremic loiasis have also been reported in travelers from non-endemic regions, such as the US, who are only temporary residents of endemic areas. In these cases, patients experience fewer inoculations of infective third stage L. loa larvae due to their shorter durations of stay in endemic regions compared to natives; manifest a lower parasite burden than natives; and mount a heightened immune response to migrating adult worms that may limit female microfilaria production. (16)

In 2008, Yoshikawa and colleagues reported a case of persistent amicrofilaremic loiasis in a 21-year-old Japanese female musician who had spent a month living with and studying the Baka Pygmy people of southeast Cameroon. (16) The patient remained asymptomatic for 10 months until regional edema developed on her left forearm and disappeared within a week. Based on the patient's travel history to a Loa loa-endemic region, the attending physicians suspected loiasis but could not confirm microfilaremia despite increasing peripheral eosinophilia with repeated peripheral smears and Knott concentration tests on blood drawn at midday. (16) After 16 months of migratory Calabar swellings and the appearance of a single migrating ocular worm, the provocative administration of DEC and the therapeutic administration of ivermectin failed to cause any detectable microfilaremia, but did gradually return the eosinophil count to normal and stopped the Calabar swellings. (16) In this case, nested PCR using primer sets specific for the repeat three sequence of the gene encoding for the L. loa 15 kD protein would have molecularly confirmed a diagnosis loiasis in the absence of circulating microfilaria. (16)

The Control and Prevention of Ocular Nematode Infections

There are no vaccines or chemoprophylactic medications available to prevent intraocular nematode infections. The best preventive measures include personal protection against biting flies and mosquitoes including wearing permethrin-treated long sleeves and pants and hats with mosquito hoods, sleeping under permethrin-impregnated mosquito nets, and applying topical insect repellants, such as N, N-dimethyl-meta-toluamide, to any exposed skin. Better community mosquito control will reduce zoonotic Dirofilaria and Onchocerca transmission cycles in domestic and wild animals in high prevalence areas and also protect humans.

The control and potential elimination of the human reservoirs of several filarial diseases, including onchocerciasis and Bancroftian lymphatic filariasis with the mass administration of the microfilaricidal drug, ivermectin (Mectizan[R]) began in the late 1980s with the Mectizan[R] Program. The Mectizan[R] Program initiated in 1987-1988 is a manufacturer-sponsored free drug distribution program of ivermectin in O. volvulus-endemic regions of Africa and the Americas. The Mectizan[R] Program has now been modified in Loa loa-endemic regions of Africa due to the risks of potentially fatal encephalopathy in persons co-infected with Loa loa and exhibiting excessive microfilaremias.

CONCLUSIONS

In conclusion, the principles of diagnosis of intraocular filariasis include: (1) early suspicion of potential infection in US residents, returning travelers, and expatriates from endemic areas who complain of a constellation of red eye, eye pain, foreign body sensation, reduced visual acuity, and migrating ocular nematodes, even without significant peripheral eosinophilia or microfilaremia; (2) measurement of visual acuity and intraocular pressure; (3) slit lamp examination of the anterior chamber for mobile worms or subconjunctival nodules of coiled microfilariae or adult worms; and (4) posterior chamber and fundoscopic examination. Microfilariae of W. bancrofti, B. malayi, and O. volvulus may traverse the eye, but can usually be treated medically following disease confirmation by morphological identification of peripheral microfilariae or molecular confirmation of microfilariae and adults by PCR and do not require surgical removal. However, mobile adult worms trapped in the subconjunctiva or anterior chamber should be removed by eye surgeons to permit precise identification, to prevent posterior uveitis and iritis, and to stop worm migration into the posterior chamber which could cause further eye damage and may require lens removal and vitrectomy for impacted worm extraction.

In cases of zoonotic ocular dirofilariasis, O. lupi onchocerciasis, and zoonotic ocular onchocerciasis, every attempt should be made to extract adult worms intact to avoid further antigenic stimulation of inflammatory reactions. No further antimicrobial or antihelminthic therapy is usually required in these cases compared to ocular filariasis caused by O. volvulus and L. loa, which will require pharmacological treatment with DEC, ivermectin, or albendazole. Extracted worms should not be fixed in formalin or alcohol, which can damage morphological features of extracted worms and interfere with molecular typing and speciation.

James H. Diaz, MD

REFERENCES

(1.) Klion A, Nutman TM. Loiasis and mansonella infections. In Guerrant R, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. Vol. 2. Philadelphia, PA, Churchill Livingstone,1999:861.

(2.) Basanez MG, Pion SD, Churcher TS et al. River blindness: a success story under threat? PLos Med 2006;3:e371.

(3.) Marty P. Human dirofilariasis due to Dirofilaria repens in France: A review of reported cases. Parassitologia 1997;39:383-386.

(4.) Pampligione S, Rivasi F, Angeli G, et al. Dirofilariasis due to Dirofilaria repens in Italy, an emergent zoonosis: report of 60 new cases. Histopathology 2001;38: 344-354.

(5.) Otranto D, Sakru N, Testini G, et al. Case report: First evidence of human zoonotic infection by Onchocerca lupi (Spirudia, Onchocercidae). Am J Trop Med Hyg. 2011;84:55-58.

(6.) Sreter T, Szell Z, Egyed Z, Varga I. Subjunctival zoonotic onchocerciasis in man: aberrant infection with Onchocerca lupi? Ann Trop Med Parasitol 2002;96:497-502.

(7.) Labelle AI, Maddox CW, Daniels JB, et al. Canine ocular onchocerciasis in the United States is associated with Onchocerca lupi. Vet Parasitol 2013;193:297-301.

(8.) Eberhard ML, Sims AC, Bishop HS, et al. Short report: Ocular zoonotic Onchocerca infection in a resident of Oregon. Am J Trop Med Hyg 2012:87: 1073-1075.

(9.) Beaver PC. Intraocular filariasis: A brief review. Am J Trop Med Hyg 1989;40: 40-45.

(10.) Rossi L, Pollono F, Menguez PG, Gribaudo L. et al. An epidemiological study of canine filarioses in northwest Italy: what has changed in 25 years? Vet Red Commun 1996;20:308-315.

(11.) Raccurt CP. Dirofilariasis, an emerging and underestimated zoonosis in France. Med Trop (Mars) 1999;59:389-400.

(12.) Orihel TC, Isbey EK. Dirofilaria striata infection in a North Carolina child. Am J Trop Med Hyg 1990;42:124-126.

(13.) Holcombe D, Pogue M, Russo KL, Miguez MW. An ocular worm in central Louisiana, 2008. Louisiana Morb Mort Rep 2008;19:1-2.

(14.) Koehsler M, Walochnik J, Georgopoulos M, et al. Linguatula serrata tongue worm in human eyes, Austria. Emerg Infect Dis 2011;17:870-872.

(15.) Ali S, Fisher M, Juckett G. The African eye worm: A case report and review. J Travel Med 2008;15:50-52.

(16.) Yoshikawa M, Ouji Y, Hayashi N, Miriya K, et al. Diagnostic problems in a patient with amicrofilaremic Loa loa. J Travel Med 2008;15:53-57.

Dr. Diaz is Professor and Head, Environmental and Occupational Health Sciences, School of Public Health; Professor of Anesthesiology, School of Medicine, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, Louisiana, USA.
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Author:Diaz, James H.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Report
Date:Jul 1, 2015
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