1778 PART 5 Infectious Diseases

granulomas surrounding the Angiostrongylus eggs. In nonsurgical

cases, the diagnosis rests solely on clinical grounds because larvae and

eggs cannot be detected in the stool. Medical therapy for abdominal

angiostrongyliasis is of uncertain efficacy. Careful observation and

surgical resection for severe symptoms are the mainstays of treatment.

■ FURTHER READING

Bethony J et al: Soil-transmitted helminth infections: Ascariasis, trichuriasis, and hookworm. Lancet 367:1521, 2006.

Fox LM: Ivermectin: Uses and impact 20 years on. Curr Opin Infect

Dis 19:588, 2006.

Hochberg NS, Hamer DH: Anisakidosis: Perils of the deep. Clin

Infect Dis 51:806, 2010.

Horton J: Albendazole: A review of anthelmintic efficacy and safety in

humans. Parasitology 121(Suppl):S113, 2000.

Loukas A et al: Hookworm infection. Nat Rev Dis Primers 2:16088,

2016.

Montressor A et al: The global progress of soil-transmitted helminthiases control in 2020 and World Health Organization targets for

2030. PLoS Negl Trop Dis 14:e0008505, 2020.

Nutman TB: Human infection with Strongyloides stercoralis and other

related Strongyloides species. Parasitology 144:263, 2017.

O’Connell EM et al: Ancylostoma ceylanicum hookworm in Myanmar

refugees, Thailand, 2012-2015. Emerg Infect Dis 24:1472, 2018.

Filarial worms are nematodes that dwell in the subcutaneous tissues and

the lymphatics. Eight filarial species infect humans (Table 233-1); of

these, four—Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus,

and Loa loa—are responsible for most symptomatic filarial infections.

Filarial parasites, which infect an estimated 170 million persons worldwide, are transmitted by specific species of mosquitoes or other arthropods and have a complex life cycle, including infective larval stages

carried by insects and adult worms that reside in either lymphatic or

233 Filarial and Related

Infections

Thomas B. Nutman, Peter F. Weller

TABLE 233-1 Characteristics of the Filariae

ORGANISM PERIODICITY DISTRIBUTION VECTOR LOCATION OF ADULT

MICROFILARIAL

LOCATION SHEATH

Wuchereria bancrofti Nocturnal Cosmopolitan areas worldwide,

including South America, Africa,

southern Asia, Papua New Guinea,

China, Indonesia

Culex, Anopheles

(mosquitoes)

Lymphatic tissue Blood +

Subperiodic Eastern Pacific Aedes (mosquitoes) Lymphatic tissue Blood +

Brugia malayi Nocturnal Southeast Asia, Indonesia, India Mansonia, Anopheles

(mosquitoes)

Lymphatic tissue Blood +

Subperiodic Indonesia, Southeast Asia Coquillettidia, Mansonia

(mosquitoes)

Lymphatic tissue Blood +

Brugia timori Nocturnal Indonesia Anopheles (mosquitoes) Lymphatic tissue Blood +

Loa loa Diurnal West and Central Africa Chrysops (deerflies) Subcutaneous tissue Blood +

Onchocerca volvulus None South and Central America, Africa Simulium (blackflies) Subcutaneous tissue Skin, eye –

Mansonella ozzardi None South and Central America Culicoides (midges) Undetermined site Blood –

None Caribbean Simulium (blackflies) Undetermined site Blood –

Mansonella perstans None South and Central America, Africa Culicoides (midges) Body cavities, mesentery,

perirenal tissue

Blood –

Mansonella

streptocerca

None West and Central Africa Culicoides (midges) Subcutaneous tissue Skin –

subcutaneous tissues of humans. The offspring of adults are microfilariae, which, depending on their species, are 200–250 μm long and 5–7 μm

wide, may or may not be enveloped in a loose sheath, and either circulate in the blood or migrate through the skin (Table 233-1). To complete the life cycle, microfilariae are ingested by the arthropod vector

and develop over 1–2 weeks into new infective larvae. Adult worms live

for many years, whereas microfilariae survive for 3–36 months. The

bacterial endosymbiont Wolbachia has been found intracellularly in all

stages of Brugia, Wuchereria, Mansonella, and Onchocerca species and

has become a target for antifilarial chemotherapy.

Usually, infection is established only with repeated, prolonged exposures to infective larvae. Since the clinical manifestations of filarial diseases develop relatively slowly, these infections should be considered to

induce chronic infections with possible long-term debilitating effects.

In terms of the nature, severity, and timing of clinical manifestations,

patients with filarial infections who are native to endemic areas and

have lifelong exposure may differ significantly from those who are

travelers or who have recently moved to these areas. Characteristically,

filarial disease is more acute and intense in newly exposed individuals

than in natives of endemic areas.

LYMPHATIC FILARIASIS

Lymphatic filariasis is caused by W. bancrofti, B. malayi, or Brugia timori.

The threadlike adult parasites reside in afferent lymphatics or lymph

nodes, where they may remain viable for more than two decades.

■ EPIDEMIOLOGY

W. bancrofti, the most widely distributed filarial parasite of humans,

affects an estimated 110 million people and is found throughout the

tropics and subtropics, including Asia and the Pacific Islands, Africa,

areas of South America, and the Caribbean basin. Humans are the

only definitive host for the parasite. Generally, the subperiodic form

is found only in the Pacific Islands; elsewhere, W. bancrofti is nocturnally periodic. Nocturnally periodic forms of microfilariae are scarce

in peripheral blood by day and increase at night, whereas subperiodic

forms are present in peripheral blood at all times and reach maximal

levels in the afternoon. Natural vectors for W. bancrofti are Culex

mosquitoes in urban settings and Anopheles or Aedes mosquitoes in

rural areas.

Brugian filariasis due to B. malayi occurs primarily in eastern India,

Indonesia, Malaysia, and the Philippines. B. malayi also has two forms

distinguished by the periodicity of microfilaremia. The more common

nocturnal form is transmitted in areas of coastal rice fields, while the

subperiodic form is found in forests. B. malayi naturally infects cats as

1779CHAPTER 233 Filarial and Related Infections

well as humans. The distribution of B. timori is limited to the islands of

southeastern Indonesia.

■ PATHOLOGY

The principal pathologic changes result from inflammatory damage

to the lymphatics, which is typically caused by adult worms and not

by microfilariae. Adult worms live in afferent lymphatics or sinuses of

lymph nodes and cause lymphatic dilation and thickening of the vessel

walls. The infiltration of plasma cells, eosinophils, and macrophages in

and around the infected vessels, along with endothelial and connective

tissue proliferation, leads to tortuosity of the lymphatics and damaged

or incompetent lymph valves. Lymphedema and chronic stasis changes

with hard or brawny edema develop in the overlying skin. These

consequences of filarial infection are due both to the direct effects of

the worms and to the host’s inflammatory response to the parasite.

Inflammatory responses are believed to cause the granulomatous and

proliferative processes that precede total lymphatic obstruction. It is

thought that the lymphatic vessel remains patent as long as the worm

remains viable and that the death of the worm leads to enhanced granulomatous reactions and fibrosis. Lymphatic obstruction results, and

despite collateralization, lymphatic function is compromised.

■ CLINICAL FEATURES

The most common presentations of the lymphatic filariases are

asymptomatic (or subclinical) microfilaremia, hydrocele (Fig. 233-1),

acute adenolymphangitis (ADL), and chronic lymphatic disease. In

areas where W. bancrofti or B. malayi is endemic, the overwhelming

majority of infected individuals have few overt clinical manifestations

of filarial infection despite the presence of circulating microfilariae in

the peripheral blood. Although they may be clinically asymptomatic,

virtually all persons with W. bancrofti or B. malayi microfilaremia

have some degree of subclinical disease that includes microscopic

hematuria and/or proteinuria, dilated (and tortuous) lymphatics (visualized by imaging), and—in men with W. bancrofti infection—scrotal

lymphangiectasia (detectable by ultrasound). Despite these findings,

the majority of individuals appear to remain clinically asymptomatic

for years; in relatively few does the infection progress to either acute

or chronic disease.

ADL is characterized by high fever, lymphatic inflammation

(lymphangitis and lymphadenitis), and transient local edema. The

lymphangitis is retrograde, extending peripherally from the lymph

FIGURE 233-1 Hydrocele associated with Wuchereria bancrofti infection.

FIGURE 233-2 Elephantiasis of the lower extremity associated with Wuchereria

bancrofti infection.

node draining the area where the adult parasites reside. Regional

lymph nodes are often enlarged, and the entire lymphatic channel can

become indurated and inflamed. Concomitant local thrombophlebitis

can occur as well. In brugian filariasis, a single local abscess may form

along the involved lymphatic tract and subsequently rupture to the surface. The lymphadenitis and lymphangitis can involve both the upper

and lower extremities in both bancroftian and brugian filariasis, but

involvement of the genital lymphatics occurs almost exclusively with

W. bancrofti infection. This genital involvement can be manifested by

funiculitis, epididymitis, and scrotal pain and tenderness. In endemic

areas, another type of acute disease—dermatolymphangioadenitis

(DLA)—is recognized as a syndrome that includes high fever, chills,

myalgias, and headache. Edematous inflammatory plaques clearly

demarcated from normal skin are seen. Vesicles, ulcers, and hyperpigmentation also may be noted. There is often a history of trauma, burns,

irradiation, insect bites, punctiform lesions, or chemical injury. Entry

lesions, especially in the interdigital area, are common. DLA is often

diagnosed as cellulitis.

If lymphatic damage progresses, transient lymphedema can develop

into lymphatic obstruction and the permanent changes associated with

elephantiasis (Fig. 233-2). Brawny edema follows early pitting edema,

the subcutaneous tissues thicken, and hyperkeratosis occurs. Fissuring

of the skin develops, as do hyperplastic changes. Superinfection of

these poorly vascularized tissues becomes a problem. In bancroftian

filariasis, in which genital involvement is common, hydroceles may

develop (Fig. 233-1); in advanced stages, this condition may evolve

into scrotal lymphedema and scrotal elephantiasis. Furthermore, if

there is obstruction of the retroperitoneal lymphatics, increased renal

lymphatic pressure leads to rupture of the renal lymphatics and the

development of chyluria, which is usually intermittent and most prominent in the morning.

The clinical manifestations of filarial infections in travelers or

transmigrants who have recently entered an endemic region are distinctive. Given a sufficient number of bites by infected vectors, usually

over a 3- to 6-month period, recently exposed patients can develop

acute lymphatic or scrotal inflammation with or without urticaria

and localized angioedema. Lymphadenitis of epitrochlear, axillary,

femoral, or inguinal lymph nodes is often followed by evolving retrograde lymphangitis. Acute attacks are short-lived and are not usually

1780 PART 5 Infectious Diseases

accompanied by fever. With prolonged exposure to infected mosquitoes, these attacks, if untreated, become more severe and lead to permanent lymphatic inflammation and obstruction.

■ DIAGNOSIS

A definitive diagnosis can be made only by detection of the parasites

and hence can be difficult. Adult worms localized in lymphatic vessels or nodes are largely inaccessible. Microfilariae can be found in

blood, in hydrocele fluid, or (occasionally) in other body fluids. Such

fluids can be examined microscopically, either directly or—for greater

sensitivity—after concentration of the parasites by the passage of fluid

through a polycarbonate cylindrical-pore filter (pore size, 3 μm) or by

the centrifugation of fluid fixed in 2% formalin (Knott’s concentration

technique). The timing of blood collection is critical and should be

based on the periodicity of the microfilariae in the endemic region

involved. Many infected individuals do not have microfilaremia, and

definitive diagnosis in such cases can be difficult. Assays for circulating antigens of W. bancrofti permit the diagnosis of microfilaremic

and cryptic (amicrofilaremic) infection. Two tests are commercially

available: an enzyme-linked immunosorbent assay and a rapid-format

immunochromatographic card test. Both assays have sensitivities of

93–100% and specificities approaching 100%. There are currently no

tests for circulating antigens in brugian filariasis.

Polymerase chain reaction (PCR)–based assays for DNA of W. bancrofti and B. malayi in blood have been developed. A number of studies

indicate that the sensitivity of this diagnostic method is equivalent to or

greater than that of parasitologic methods.

In cases of suspected lymphatic filariasis, examination of the scrotum, the lymph nodes, or (in female patients) the breast by means

of high-frequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within

dilated lymphatics. Worms may be visualized in the lymphatics of

the spermatic cord in up to 80% of men infected with W. bancrofti.

Live adult worms have a distinctive pattern of movement within

the lymphatic vessels (termed the filarial dance sign). Radionuclide

lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities in both subclinical microfilaremic

persons and those with clinical manifestations of lymphatic pathology.

Although of potential utility in the delineation of anatomic changes

associated with infection, lymphoscintigraphy is unlikely to assume

primacy in the diagnostic evaluation of individuals with suspected

infection; it is principally a research tool, although it has been used

more widely for assessment of lymphedema of any cause. Eosinophilia

and elevated serum concentrations of IgE and antifilarial antibody

support the diagnosis of lymphatic filariasis. There is, however, extensive cross-reactivity between filarial antigens and antigens of other

helminths. Of note, W. bancrofti– and B. malayi–specific antigens have

been identified and are now available for use in rapid diagnostic tests

with specificities of >98%. However, seropositivity cannot be equated

with active infection: residents of endemic areas can become sensitized

to filarial antigens through exposure to infective mosquitoes without

having patent filarial infections.

The ADL associated with lymphatic filariasis must be distinguished

from thrombophlebitis, infection, and trauma. Retrograde evolution

is a characteristic feature that helps distinguish filarial lymphangitis

from ascending bacterial lymphangitis. Chronic filarial lymphedema

must also be distinguished from the lymphedema of malignancy, postoperative scarring, trauma, chronic edematous states, and congenital

lymphatic system abnormalities.

TREATMENT

Lymphatic Filariasis

With newer definitions of clinical syndromes in lymphatic filariasis

and new tools to assess clinical status (e.g., ultrasound, lymphoscintigraphy, circulating filarial antigen assays, PCR), approaches to

treatment based on infection status can be considered.

Orally administered diethylcarbamazine (DEC; 6 mg/kg daily for

12 days), which has both macro- and microfilaricidal properties,

remains the drug of choice for the treatment of active lymphatic

filariasis (defined by microfilaremia, antigen positivity, or adult

worms on ultrasound), although albendazole (400 mg twice daily by

mouth for 21 days) also has demonstrated macrofilaricidal efficacy.

A 4- to 6-week course of oral doxycycline (targeting the intracellular

Wolbachia) also has significant macrofilaricidal activity, as does DEC/

albendazole used daily for 7 days. The addition of DEC to a 3-week

course of doxycycline is efficacious in lymphatic filariasis.

Regimens that combine single doses of albendazole (400 mg)

with either DEC (6 mg/kg) or ivermectin (200 μg/kg) all have a

sustained microfilaricidal effect and are the mainstay of programs

for the eradication of lymphatic filariasis in Africa (albendazole/

ivermectin) and elsewhere (albendazole/DEC) (see “Prevention

and Control,” below). Recently, a regimen using single doses of the

three major antifilarial drugs (albendazole/DEC/ivermectin) has

been shown to sustain microfilarial clearance out to at least 2 years.

As has already been mentioned, a growing body of evidence

indicates that, although they may be asymptomatic, virtually all

persons with W. bancrofti or B. malayi microfilaremia have some

degree of subclinical disease (hematuria, proteinuria, abnormalities

on lymphoscintigraphy). Thus, early treatment of asymptomatic

persons who have microfilaremia is recommended to prevent further lymphatic damage. For ADL, supportive treatment (including

the administration of antipyretics and analgesics) is recommended,

as is antibiotic therapy if secondary bacterial infection is likely.

Similarly, because lymphatic disease is associated with the presence

of adult worms, treatment with DEC is recommended for microfilaria-negative carriers of adult worms.

In persons with chronic manifestations of lymphatic filariasis,

treatment regimens that emphasize hygiene, prevention of secondary bacterial infections, and physiotherapy have gained wide acceptance for morbidity control. These regimens are similar to those

recommended for lymphedema of most nonfilarial causes and are

known by a variety of names, including complex decongestive physiotherapy and complex lymphedema therapy. Hydroceles (Fig. 233-1)

can be managed surgically. With chronic manifestations of lymphatic filariasis, drug treatment should be reserved for individuals

who have evidence of active infection; however, a 6-week course

of doxycycline has been shown to provide improvement in filarial

lymphedema irrespective of disease activity.

Side effects of DEC treatment include fever, chills, arthralgias,

headaches, nausea, and vomiting. Both the development and the

severity of these reactions are directly related to the number of

microfilariae circulating in the bloodstream. The adverse reactions

may represent either an acute hypersensitivity reaction to the antigens being released by dead and dying parasites or an inflammatory

reaction induced by the intracellular Wolbachia endosymbionts

freed from their intracellular niche.

Ivermectin has a side effect profile similar to that of DEC when

used in lymphatic filariasis. In patients infected with L. loa who

have high levels of microfilaremia, DEC—like ivermectin (see

“Loiasis,” below)—can elicit severe encephalopathic complications.

When used in single-dose regimens for the treatment of lymphatic

filariasis, albendazole is associated with relatively few side effects.

■ PREVENTION AND CONTROL

To protect themselves against filarial infection, individuals must

avoid contact with infected mosquitoes by using personal protective

measures, including bed nets, particularly those impregnated with

insecticides such as permethrin. Mass drug administration (MDA) is

the current approach to elimination of lymphatic filariasis as a public

health problem. The underlying tenet of this approach is that mass

annual distribution of antifilarial chemotherapy—albendazole with

either DEC (for all areas except those where onchocerciasis is coendemic; see section on onchocerciasis treatment, below) or ivermectin

or with both ivermectin and DEC (triple-drug therapy)—will profoundly suppress microfilaremia. If the suppression is sustained, then

transmission can be interrupted.

1781CHAPTER 233 Filarial and Related Infections

Created by the World Health Organization in 1997, the Global

Programme to Eliminate Lymphatic Filariasis is based on mass

administration of single annual doses of DEC plus albendazole in nonAfrican regions and of albendazole plus ivermectin in Africa. Available

information from late 2020 indicated that >792 million persons in

53 countries had thus far participated. Not only has lymphatic filariasis

been eliminated in some defined areas, but collateral benefits—avoidance

of disability and treatment of intestinal helminths and other conditions (e.g., scabies and louse infestation)—also have been noted. The

strategy of the global program is being refined, and attempts are being

made to integrate this effort with other mass-treatment strategies (e.g.,

deworming programs, malaria control, and trachoma control) in an

integrated control strategy.

TROPICAL PULMONARY EOSINOPHILIA

Tropical pulmonary eosinophilia (TPE) is a distinct syndrome that

develops in some individuals infected with the lymphatic-dwelling

filarial species. The majority of cases have been reported from India,

Pakistan, Sri Lanka, Brazil, Guyana, and Southeast Asia; the decreasing

incidence of TPE in the past decade probably reflects global MDA

efforts.

■ CLINICAL FEATURES

The main features include a history of residence in filaria-endemic

regions, paroxysmal cough and wheezing (usually nocturnal and

probably related to the nocturnal periodicity of microfilariae), weight

loss, low-grade fever, lymphadenopathy, and pronounced blood eosinophilia (>3000 eosinophils/μL). Chest x-rays or CT scans may be

normal but generally show increased bronchovascular markings. Diffuse miliary lesions or mottled opacities may be present in the middle

and lower lung fields. Tests of pulmonary function show restrictive

abnormalities in most cases and obstructive defects in half. Characteristically, total serum IgE levels (4–40 KIU/mL) and antifilarial antibody

levels are markedly elevated.

■ PATHOLOGY

In TPE, microfilariae and parasite antigens are rapidly cleared from

the bloodstream by the lungs. The clinical symptoms result from

allergic and inflammatory reactions elicited by the cleared parasites.

In some patients, trapping of microfilariae in other reticuloendothelial

organs can cause hepatomegaly, splenomegaly, or lymphadenopathy. A

prominent, eosinophil-enriched, intra-alveolar infiltrate is common,

and with it comes the release of cytotoxic proinflammatory eosinophil

granule proteins that may mediate some of the pathology seen in TPE.

In the absence of successful treatment, interstitial fibrosis can lead to

progressive pulmonary damage.

■ DIFFERENTIAL DIAGNOSIS

TPE must be distinguished from asthma, Löffler’s syndrome, allergic bronchopulmonary aspergillosis, allergic granulomatosis with

polyangiitis (eosinophilic granulomatosis with polyangiitis or

Churg-Strauss syndrome), other systemic vasculitides (most notably,

periarteritis nodosa), chronic eosinophilic pneumonia, and the hypereosinophilic syndromes (HESs).

TREATMENT

Tropical Pulmonary Eosinophilia

DEC is used at a daily dosage of 4–6 mg/kg for 14 days. Symptoms

usually resolve within 3–7 days after the initiation of therapy.

Relapse, which occurs in ~12–25% of cases (sometimes after an

interval of several years), requires re-treatment.

ONCHOCERCIASIS

■ EPIDEMIOLOGY

Onchocerciasis (“river blindness”) is caused by the filarial nematode

O. volvulus, which infects an estimated 37 million individuals in 31

countries worldwide. The majority of individuals infected with O. volvulus

live in the equatorial region of Africa extending from the Atlantic coast to

the Red Sea. In the Americas, the only remaining countries with isolated

foci are Venezuela and Brazil. The infection is also found in Yemen.

■ ETIOLOGY

Infection in humans begins with the deposition of infective larvae on

the skin by the bite of an infected blackfly. The larvae develop into

adults, which are typically found in subcutaneous nodules. About

7 months to 3 years after infection, the gravid female releases microfilariae that migrate out of the nodule and throughout the tissues,

concentrating in the dermis. Infection is transmitted to other persons

when a female fly ingests microfilariae from the host’s skin and these

microfilariae then develop into infective larvae. Adult O. volvulus

females and males are ~40–60 cm and ~3–6 cm in length, respectively.

The life span of adults can be as long as 18 years, with an average of ~9

years. Because the blackfly vector breeds along free-flowing rivers and

streams (particularly in rapids) and generally restricts its flight to an

area within several kilometers of these breeding sites, both biting and

disease transmission are most intense in these locations.

■ PATHOLOGY

Onchocerciasis primarily affects the skin, eyes, and lymph nodes. In

contrast to the pathology in lymphatic filariasis, the damage in onchocerciasis is elicited by microfilariae and not by adult parasites. In the

skin, there are mild but chronic inflammatory changes that can result

in loss of elastic fibers, atrophy, and fibrosis. The subcutaneous nodules

(onchocercomata) consist primarily of fibrous tissues surrounding the

adult worm, often with a peripheral ring of inflammatory cells surrounded by an endothelial layer (characterized as lymphatic in origin).

In the eye, neovascularization and corneal scarring lead to corneal

opacities and blindness. Inflammation in the anterior and posterior

chambers frequently results in anterior uveitis, chorioretinitis, and

optic atrophy. Although punctate opacities are due to an inflammatory

reaction surrounding dead or dying microfilariae, the pathogenesis of

most manifestations of onchocerciasis is still unclear.

■ CLINICAL FEATURES

Skin Pruritus and rash are the most common manifestations of

onchocerciasis. The pruritus can be incapacitating; the rash is typically

a papular eruption (Fig. 233-3) that is generalized rather than localized

to a particular region of the body. Long-term infection results in exaggerated and premature wrinkling of the skin, loss of elastic fibers, and

epidermal atrophy that can lead to loose, redundant skin and hypo- or

FIGURE 233-3 Papular eruption as a consequence of onchocerciasis.

1782 PART 5 Infectious Diseases

hyperpigmentation. Localized eczematoid dermatitis can cause hyperkeratosis, scaling, and pigmentary changes. In an immunologically

hyperreactive form of onchodermatitis (commonly termed sowdah or

localized onchodermatitis), the affected skin darkens as a consequence

of the profound inflammation that occurs as microfilariae in the skin

are cleared.

Onchocercomata These subcutaneous nodules, which can be palpable and/or visible, contain the adult worm. They are most common

over the coccyx and sacrum, the trochanter of the femur, the lateral

anterior crest, and other bony prominences. Nodules vary in size and

characteristically are firm and not tender. It has been estimated that, for

every palpable nodule, there are four deeper nonpalpable ones.

Ocular Tissue Visual impairment is the most serious complication

of onchocerciasis and usually affects only those persons with moderate or heavy infections. Lesions may develop in all parts of the eye.

The most common early finding is conjunctivitis with photophobia.

Punctate keratitis—acute inflammatory reactions surrounding dying

microfilariae and manifested as “snowflake” opacities—is common

among younger patients and resolves without apparent complications.

Sclerosing keratitis occurs in 1–5% of infected persons and is the leading cause of onchocercal blindness. Anterior uveitis and iridocyclitis

develop in ~5% of infected persons. Characteristic chorioretinal lesions

develop as a result of atrophy and hyperpigmentation of the retinal

pigment epithelium. Constriction of the visual fields and overt optic

atrophy may occur.

Lymph Nodes Mild to moderate lymphadenopathy is common,

particularly in the inguinal and femoral areas, where the enlarged

nodes may hang down in response to gravity (“hanging groin”), sometimes predisposing to inguinal and femoral hernias.

Other Manifestations Some heavily infected individuals develop

cachexia with loss of adipose tissue and muscle mass. A form of dwarfism, Nakalanga dwarfism, has been attributed to pituitary involvement

in this infection. An association between onchocerciasis and epilepsy

(including an epidemic form termed nodding syndrome) has gained

attention recently. Among adults who become blind, there is a three- to

fourfold increase in mortality rate.

■ DIAGNOSIS

Definitive diagnosis depends on the detection of an adult worm in

an excised nodule or, more commonly, of microfilariae in a skin snip.

Skin snips are obtained with a corneal-scleral punch or by lifting of

the skin with the tip of a needle and excision of a small (1- to 3-mm)

piece with a sterile scalpel blade. Both methods collect a blood-free

skin biopsy sample extending to just below the epidermis. The biopsy

tissue can be incubated in tissue culture medium or in saline on a glass

slide or flat-bottomed microtiter plate. After incubation for 2–4 h

(or occasionally overnight in light infections), microfilariae emergent from the skin can be seen by low-power microscopy or can be

detected by PCR.

Eosinophilia and elevated serum IgE levels are common but, because

these features are seen in many parasitic infections, are not diagnostic

in themselves. Immunoassays to detect antibodies to Onchocercaspecific antigens are being used both in specialized laboratories and at

the point of contact in rapid-diagnostic formats.

TREATMENT

Onchocerciasis

The main goals of therapy are to prevent the development of irreversible lesions and to alleviate symptoms. Chemotherapy is the

mainstay of management. Ivermectin, a semisynthetic macrocyclic

lactone active against microfilariae, is the first-line agent for the

treatment of onchocerciasis. It is given orally in a single dose of

150 μg/kg, either yearly or semiannually. More frequent ivermectin

administration (every 3 months) has been suggested to ameliorate

pruritus and skin disease.

After treatment, most individuals have few or no reactions.

Pruritus, cutaneous edema, and/or maculopapular rash occur in

~1–10% of treated individuals. In areas of Africa coendemic for

O. volvulus and L. loa, however, ivermectin is contraindicated (as

it is for pregnant or breast-feeding women) because of severe posttreatment encephalopathy, especially in patients who are heavily

microfilaremic for L. loa (>30,000 microfilariae/mL). Although

ivermectin treatment results in a marked drop in microfilarial density, its effect can be short-lived (<3 months in some cases). Thus,

it is occasionally necessary to give ivermectin more frequently for

persistent symptoms.

A 6-week course of doxycycline is macrofilaristatic, rendering

female adult worms sterile for long periods.

■ PREVENTION

Vector control has been beneficial in highly endemic areas in which

breeding sites are vulnerable to insecticide spraying, but most areas

endemic for onchocerciasis are not suited to this type of control.

Community-based administration of ivermectin every 6–12 months is

being used to interrupt transmission in endemic areas. This measure,

in conjunction with vector control, has already helped eliminate the

infection in most of Latin America and has reduced the prevalence of

disease in many endemic foci in Africa. No drug has proved useful for

prophylaxis of O. volvulus infection.

LOIASIS

■ ETIOLOGY AND EPIDEMIOLOGY

Loiasis is caused by L. loa (the African eye worm), which is present in

the rainforests of West and Central Africa. Adult parasites (females,

50–70 mm long and 0.5 mm wide; males, 25–35 mm long and 0.25 mm

wide) live in subcutaneous tissues. Microfilariae circulate in the blood

with a diurnal periodicity that peaks between 10:00 a.m. and 2:00 p.m.

■ CLINICAL FEATURES

Manifestations of loiasis in natives of endemic areas may differ from

those in temporary residents or visitors. Among the indigenous population, loiasis is often an asymptomatic infection with microfilaremia.

Infection may be recognized only after subconjunctival migration of

an adult worm (Fig. 233-4) or may be manifested by episodic Calabar

swellings—evanescent localized areas of angioedema and erythema

developing on the extremities and less frequently at other sites. Nephropathy, encephalopathy, and cardiomyopathy can occur but are rare.

In patients who are not residents of endemic areas, allergic symptoms

predominate, episodes of Calabar swelling tend to be more frequent,

FIGURE 233-4 Adult Loa loa worm being surgically removed after its subconjunctival

migration.

1783CHAPTER 233 Filarial and Related Infections

microfilaremia is less common, and eosinophilia and increased levels

of antifilarial antibodies are characteristic.

■ PATHOLOGY

The pathogenesis of the manifestations of loiasis is poorly understood.

Calabar swellings are thought to result from a hypersensitivity reaction

to adult worm antigens.

■ DIAGNOSIS

Definitive diagnosis of loiasis requires the detection of microfilariae

in the peripheral blood or the isolation of the adult worm from the

eye (Fig. 233-4) or from a subcutaneous biopsy specimen collected

from a site of swelling developing after treatment. PCR-based assays

for the detection of L. loa DNA in blood are available in specialized

laboratories and are highly sensitive and specific, as are some newer

recombinant antigen–based serologic techniques. In practice, the

diagnosis must often be based on a characteristic history and clinical

presentation, blood eosinophilia, and elevated levels of antifilarial antibodies, particularly in travelers to an endemic region, who are often

amicrofilaremic.

TREATMENT

Loiasis

DEC (8–10 mg/kg per day administered orally for 21 days)

is effective against both the adult and the microfilarial forms of

L. loa, but multiple courses are frequently necessary before loiasis

resolves completely. In cases of heavy microfilaremia, allergic or

other inflammatory reactions can take place during treatment,

including central nervous system involvement with coma and

encephalitis. Heavy infections can be treated initially with apheresis

to remove the microfilariae and with glucocorticoids (40–60 mg of

prednisone per day) followed by doses of DEC (0.5 mg/kg per day).

If antifilarial treatment has no adverse effects, the prednisone dose

can be tapered rapidly and the dose of DEC gradually increased to

8–10 mg/kg per day.

Albendazole or ivermectin is effective in reducing microfilarial

loads, although neither is approved for this purpose by the U.S.

Food and Drug Administration. Moreover, ivermectin is contraindicated in patients with >30,000 microfilariae/mL because this

drug has been associated with severe adverse events (including

encephalopathy and death) in heavily infected patients with loiasis

in West and Central Africa. DEC (300 mg weekly) is an effective

prophylactic regimen for loiasis.

STREPTOCERCIASIS

Mansonella streptocerca, found mainly in the tropical forest belt of

Africa from Ghana to the Democratic Republic of the Congo, is transmitted by biting midges. The major clinical manifestations involve the

skin and include pruritus, papular rashes, and pigmentation changes.

Many infected individuals have inguinal adenopathy, although most

are asymptomatic. The diagnosis is made by detection of the characteristic microfilariae in skin snips. Ivermectin at a single dose of

150 μg/kg leads to sustained suppression of microfilariae in the skin

and is probably the treatment of choice for streptocerciasis.

MANSONELLA PERSTANS INFECTION

M. perstans, distributed across the center of Africa and in northeastern South America, is transmitted by midges. Adult worms reside

in serous cavities—pericardial, pleural, and peritoneal—as well as in

the mesentery and the perirenal and retroperitoneal tissues. Microfilariae circulate in the blood without periodicity. The clinical and

pathologic features of the infection are poorly defined. Most patients

appear to be asymptomatic, but manifestations may include transient

angioedema and pruritus of the arms, face, or other parts of the

body (analogous to the Calabar swellings of loiasis); fever; headache;

arthralgias; and right-upper-quadrant pain. Occasionally, pericarditis

and hepatitis occur. The diagnosis is based on the demonstration of

microfilariae in blood or serosal effusions. Perstans filariasis is often

associated with peripheral-blood eosinophilia and antifilarial antibody

elevations.

With the identification of a Wolbachia endosymbiont in M. perstans,

doxycycline (200 mg twice a day) for 6 weeks has been established as

the first effective treatment for this infection.

MANSONELLA OZZARDI INFECTION

The distribution of M. ozzardi is restricted to Central and South America

and certain Caribbean islands. Adult worms are rarely recovered

from humans. Microfilariae circulate in the blood without periodicity.

Although this organism has often been considered nonpathogenic,

headache, articular pain, fever, pulmonary symptoms, adenopathy,

hepatomegaly, pruritus, and eosinophilia have been ascribed to M.

ozzardi infection. The diagnosis is made by detection of microfilariae

in peripheral blood. Ivermectin is effective in treating this infection.

ZOONOTIC FILARIAL INFECTIONS

Dirofilariae that affect primarily dogs, cats, and raccoons occasionally

infect humans incidentally, as do Brugia and Onchocerca parasites that

affect small mammals. Because humans are an abnormal host, the parasites never develop fully. Pulmonary dirofilarial infection caused by

the canine heartworm Dirofilaria immitis generally presents in humans

as a solitary pulmonary nodule. Chest pain, hemoptysis, and cough are

uncommon. Infections with Dirofilaria repens (from dogs) or Dirofilaria tenuis (from raccoons) can cause local subcutaneous nodules in

humans. Zoonotic Brugia infection can produce isolated lymph node

enlargement, whereas zoonotic Onchocerca species (particularly O. lupi)

can cause subconjunctival masses. Eosinophilia levels and antifilarial

antibody titers are not commonly elevated. Excisional biopsy is both

diagnostic and curative. These infections usually do not respond to

antifilarial chemotherapy.

DRACUNCULIASIS (GUINEA WORM

INFECTION)

■ ETIOLOGY AND EPIDEMIOLOGY

The incidence of dracunculiasis, caused by Dracunculus medinensis,

has declined dramatically because of global eradication efforts. However, between 2017 and 2020, there were increases in the number of

human cases. At the end of 2020, there were a total of 27 human cases

of Guinea worm disease across six African countries, with 12 cases in

Chad, 11 cases in Ethiopia, and 1 each in South Sudan, Angola, Mali,

and Cameroon.

Humans acquire D. medinensis when they ingest water containing

infective larvae derived from Cyclops, a crustacean that is the intermediate host. Larvae penetrate the stomach or intestinal wall, mate,

and mature. The adult male probably dies; the female worm develops

over a year and migrates to subcutaneous tissues, usually in the lower

extremity. As the thin female worm, ranging in length from 30 cm to

1 m, approaches the skin, a blister forms that, over days, breaks down

and forms an ulcer. When the blister opens, large numbers of motile,

rhabditiform larvae can be released into stagnant water; ingestion by

Cyclops completes the life cycle.

■ CLINICAL FEATURES

Few or no clinical manifestations of dracunculiasis are evident until

just before the blister forms, when there is an onset of fever and generalized allergic symptoms, including periorbital edema, wheezing, and

urticaria. The emergence of the worm is associated with local pain and

swelling. When the blister ruptures (usually as a result of immersion

in water) and the adult worm releases larva-rich fluid, symptoms are

relieved. The shallow ulcer surrounding the emerging adult worm

heals over weeks to months. Such ulcers, however, can become secondarily infected, the result being cellulitis, local inflammation, abscess

formation, or (uncommonly) tetanus. Occasionally, the adult worm

does not emerge but becomes encapsulated and calcified.

1784 PART 5 Infectious Diseases

■ DIAGNOSIS

The diagnosis is based on the findings developing with the emergence

of the adult worm, as described above.

TREATMENT

Dracunculiasis

Gradual extraction of the worm by winding of a few centimeters

on a stick each day remains the common and effective practice.

Worms may be excised surgically. No drug is effective in treating

dracunculiasis.

■ PREVENTION

Prevention, which remains the only real control measure, depends on

the provision of safe drinking water.

■ FURTHER READING

Herrick JA et al: Infection-associated immune perturbations resolve

one year following treatment for Loa loa. Clin Infect Dis 72:789, 2021.

Hopkins DR et al: Progress toward global eradication of dracunculiasis—

January 2019–June 2020. Morb Mortal Wkly Rep 69:1563, 2020.

King CL et al: Single-dose triple-drug therapy for Wuchereria bancrofti—5-year follow-up. N Engl J Med 382:1956, 2020.

Mand S et al: Doxycycline improves filarial lymphedema independent

of active filarial infection: A randomized controlled trial. Clin Infect

Dis 55:621, 2012.

Taylor MJ et al: Lymphatic filariasis and onchocerciasis. Lancet

376:1175, 2010.

Trematodes, or flatworms, are a group of helminths that belong to the

phylum Platyhelminthes. The adult flatworms share some common

characteristics, such as macroscopic size (from one to several centimeters); dorsoventrally flattened, bilaterally symmetric bodies; and

two suckers—oral and ventral. Except for schistosomes, which have

separate sexes, all human parasitic trematodes are hermaphroditic.

Their life cycles involve a mammalian/human definitive host, in which

sexual reproduction by adult worms takes place, and an intermediate

host (snails), in which asexual multiplication occurs. Some species of

trematodes have more than one intermediate host.

Humans are infected either by direct penetration of intact skin

(schistosomiasis) or by ingestion of raw freshwater fish, crustaceans, or

aquatic plants with metacercariae—the infective larval stage.

Significant trematode infections of humans may be divided according

to the location of the adult worms: blood, liver (biliary tree), intestines, or

lungs (Table 234-1). Adult worms do not multiply within the mammalian

host but can live for up to 30 years. Infections are often chronic.

Although it is relatively rare to encounter patients with trematode

infections in the United States, many millions of people are infected

worldwide. Both schistosomiasis and food-borne trematode infections

are poverty-related chronic diseases with high morbidity and a significant public health impact. Various factors may increase the spread

of the infections globally. Increasing temperatures may render new

areas suitable for the intermediate host snails, and an increase in travel

and migration may increase the number of patients with trematode

infections—for example, in the United States.

234 Schistosomiasis and

Other Trematode

Infections

Birgitte Jyding Vennervald

TABLE 234–1 Major Human Trematode Infections

TREMATODE TRANSMISSION ROUTE

GEOGRAPHIC

DISTRIBUTION

Blood Flukes

Intestinal schistosomiasis

Schistosoma mansoni Skin penetration by

cercariae released from

snails (Biomphalaria

spp.)

Africa, Brazil, Venezuela,

Surinam, the Caribbean

(low risk)

Shistosoma japonicum Skin penetration by

cercariae released from

snails (Oncomelania spp.)

China, Indonesia,

Philippines

Schistosoma guineensis

and Schistosoma

intercalatum

Skin penetration by

cercariae released from

snails (Bulinus spp.)

Rain forest areas of

Central Africa

Schistosoma mekongi Skin penetration by

cercariae released from

snails (Neotricula aperta)

Several districts of

Cambodia and Lao

People’s Democratic

Republic (PDR)

Urogenital schistosomiasis

Schistosoma

haematobium

Skin penetration by

cercariae released from

snails (Bulinus spp.)

Africa, Middle East,

Corsica (France)

Liver Flukes

Clonorchis sinensis Ingestion of

metacercariae in

freshwater fish

Asia, including Republic

of Korea, China, Taiwan,

Vietnam

Opisthorchis viverrini Ingestion of

metacercariae in

freshwater fish

Northeast Thailand, Lao

PDR, Cambodia, Vietnam

Opisthorchis felineus Ingestion of

metacercariae in

freshwater fish

Former Soviet Union,

Kazakhstan, Ukraine,

Turkey

Fasciola hepatica Ingestion of

metacercariae on

aquatic plants or in water

Worldwide

Fasciola gigantica Ingestion of

metacercariae on

aquatic plants or in water

Africa, Asia

Intestinal Flukes

Fasciolopsis buski Ingestion of

metacercariae on

aquatic plants

Bangladesh, China,

India, Indonesia, Lao

PDR, Malaysia, Taiwan,

Thailand, Vietnam

Echinostoma spp. Ingestion of freshwater

fish, frogs, mussels,

snails

China, India, Indonesia,

Japan, Malaysia, Russia,

Republic of Korea,

Philippines, Thailand

Heterophyes

heterophyes, several

other species

Ingestion of

metacercariae in

freshwater or brackishwater fish

Egypt, Greece, Islamic

Republic of Iran, Italy,

Japan, Republic of Korea,

Sudan, Tunisia, Turkey

Lung Flukes

Paragonimus westermani Ingestion of

metacercariae in crayfish

or crabs

Tropical and subtropical

areas of eastern and

southern Asia and subSaharan Africa

Paragonimus kellicotti Ingestion of

metacercariae in crayfish

or crabs

North America

APPROACH TO THE PATIENT

Trematode Infection

In the evaluation of a patient in whom trematode infection is

suspected, certain questions are highly relevant and can assist in

establishing a diagnosis: Where have you been? If you have traveled, when did you return? What activities have you been involved