Dirofilariasis

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Practice Essentials

Human dirofilariasis typically manifests as either subcutaneous nodules or lung parenchymal disease, in many cases asymptomatically. The zoonotic filariae of Dirofilaria immitis and Dirofilaria (Nochtiella) repens have become increasingly recognized worldwide as inadvertent human pathogens,[1] with the usual hosts of these infective nematodes being domestic and wild carnivores. 

Signs and symptoms

D immitis

Most patients (approximately 60%) with human pulmonary dirofilariasis (HPD), caused by D immitis, are asymptomatic. When they do occur, symptoms can include the following:

D repens

Usually, patients notice a single painful subcutaneous lump in the affected area. The areas most commonly affected include the following:

Ophthalmic involvement may be periorbital,[2, 3] subconjunctival,[4] subtenon,[5] or intraocular.[6]

See Clinical Presentation for more detail.

Diagnosis

Studies used in the diagnosis and evaluation of dirofilariasis include the following:

See Workup for more detail.

Management

Antifilarial medications

In many cases, antifilarial medications are not administered prior to surgical resection of dirofilarial lesions. One group of authors, however, has recommended a single dose of ivermectin followed by 3 doses of diethylcarbamazine (DEC) if the syndrome is strongly suspected prior to surgery.

Surgery

Surgical excision of lesions and affected areas is the treatment of choice for dirofilariasis.[7] Patients with subcutaneous dirofilarial lesions can usually be treated as outpatients or undergo day-case surgical procedures.

See Treatment and Medication for more detail.

Background

Human dirofilariasis typically manifests as either subcutaneous nodules or lung parenchymal disease, in many cases asymptomatically. (See Pathophysiology and Clinical Presentation.)

The zoonotic filariae of Dirofilaria immitis and D (Nochtiella) repens have become increasingly recognized worldwide as inadvertent human pathogens,[1] with the usual hosts of these infective nematodes being domestic and wild carnivores. The pathology of dirofilariasis results from the aberrant localization of immature worms intended for nonhuman hosts. The worms do not reach adulthood in humans, which is why microfilariae are almost always absent (see the image below). (See Pathophysiology, Etiology, and Workup.)



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Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

Dirofilaria, from the Latin dirus (“fearful” or “ominous”) plus filum (“thread”), is a genus of nematodes of the superfamily Filarioidea. The dog heartworm was named Filaria by American parasitologist Joseph Leidy in 1856, and the genus was renamed Dirofilaria by French parasitologists Railliet and Henry in 1911.[8]

Patient education

Teaching patients to avoid mosquito bites in endemic areas may decrease exposure to infection. (See Treatment.)

Pathophysiology

The dirofilarial life cycle, like that of all filarial and helminthic nematodes, consists of 5 developmental or larval stages in a vertebral host, an arthropod (mosquito) intermediate host, and a vector. Adult female worms produce thousands of first-stage larvae (microfilariae), which are ingested by a feeding insect vector. After ingestion, microfilariae eventually transform into third-stage larvae within the mosquito and migrate from the abdomen to the thorax and finally to the salivary glands, allowing transmission of infection to a new host upon a subsequent blood meal.[9]

The usual definitive host of D immitis and D repens is the domestic dog, although cats, wolves, coyotes, foxes, muskrats, and sea lions may act as suitable hosts and reservoirs of the disease. Mosquitoes of the genera Aedes, Anopheles, and Culex all are suitable intermediate hosts and vectors. Some species of fleas, lice, and ticks may also act as vectors. (See the image below.)



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Adult Dirofilaria immitis worm extracted from the heart and pulmonary artery of a dog. Worms usually are 1-3 mm in diameter, and females may grow to a....

In the dog, adult D immitis resides in the right ventricle and pulmonary arteries of the lung. Female worms produce and release thousands of microfilariae larvae into the circulation daily, which are ingested by mosquitoes in a blood meal. Larvae develop into infective larvae over the subsequent 10-16 days, depending on environmental conditions, before being reintroduced back into the dog. These larvae reside and mature in the subcutaneous tissues and along muscle sheaths for the next several months before migrating to the heart, where the nematode matures for 6-7 months. Adult worms are 1-3 mm in diameter, with females being 25-30 cm in length and males generally shorter.

The adults of D repens, in contrast, reside in the subcutaneous tissues of dogs and cats, although the life cycle and release of microfilaria in the peripheral circulation remain the same as for D immitis.

Human hosts

Human hosts are infected in the same way that the natural animal hosts are. Humans are accidental, dead-end hosts of dirofilariae, as the worms do not reach maturity in the heart or skin. Most infective larvae injected into humans are thought to perish; therefore, infected individuals are normally not microfilaremic.

Indeed, only 1 degenerate, immature (fourth-stage) larva or adult worm (fifth-stage larva) is usually isolated from an ectopic position of the body. Moreover, dirofilariae, like other nematodes, rely on sexual reproduction before microfilariae are produced. Only 1 report of circulating microfilaremia in a human exists in the medical literature.[10]

D immitis infection

The true prevalence of human D immitis exposure and disease may be underestimated, because canine infection is widespread throughout the world and most infected people are asymptomatic. A study of D immitis infections in endemic areas of northeastern Italy indicated that the mosquito host Culex pipiens fed on dogs 70% of the time and on humans 26% of the time.[11]

D immitis is most often associated with coin lesions of the lung (human pulmonary dirofilariasis, or HPD), but isolated reports exist of D immitis or D immitis –like worms causing cutaneous or conjunctival disease.

Extrapulmonary D immitis infections described in the literature include a hepatic nodule,[12] eosinophilic meningitis,[13] intraocular infection,[14] adipose tissue of the mesentery,[15] and a testicular lesion.[16]

Acute thromboembolism and endarteritis can result from exposure of vascular endothelium to a high concentration of D immitis antigenic products, caused by the sudden death of a significant number of adult worms; this is true whether or not the worms died naturally or were killed by a filaricide treatment.[17]

To date, only 4 cases of cardiovascular dirofilariasis have been reported worldwide. In the first case, D immitis (male and female) was found in the left ventricle of a Brazilian boy (Magelhaes, 1887).[18] Another case was in Japan, where Takeuchi et al[19] found 2 slender nematodes in the heart and inferior vena cava of a 36-year-old Japanese man who died of liver cirrhosis. Both worms were identified as nongravid adult females of D immitis. The other 2 cases, both involving D immitis, were reported in New Orleans in the United States.[18]

Takayama et al described a rare case of cavity formation in pulmonary dirofilariasis in a Japanese woman infected with D immitis.[20] A subcutaneous or subconjunctival lesion due to D immitis is also rare.

D repens infection

D repens infection is the most frequent and widespread form of dirofilariasis in the world. The most common form is a subcutaneous or submucosal nodule.

Ophthalmic involvement is also described, and the worm can be directly visualized in the bulbar conjunctiva.

Breast nodules due to infection with D repens, which are observed in hyperendemic areas for the parasite, usually Italy and Sri Lanka, may be misdiagnosed as potential malignancies. Imported cases of D repens affecting the breast have been reported in the United States, Canada, Japan, and Australia, while pulmonary and abdominal lesions due to D repens infection have been reported in endemic areas of Italy, France, and Greece.

Lung involvement, which is the most common of the noncutaneous/nonocular manifestations of dirofilariasis, is frequently misdiagnosed as a primary or metastatic lung tumor.[21]

Bacterial endosymbiont

Like many filarial worms, D repens harbors the bacterial endosymbiont Wolbachia, which has been implicated in filarial infections. In a study by Grandi et al, immunohistochemical staining of Wolbachia surface protein (WSP) on 14 skin nodules showed numerous bacteria within the intact worms and occasionally within surrounding inflammatory infiltrates. Serum samples from most of patients studied were positive for total immunoglobulin G (IgG) titers against WSP on enzyme-linked immunosorbent assay (ELISA), indicating a specific immune response to Wolbachia in patients with subcutaneous dirofilariasis.[22, 23]

Heartworm-associated respiratory disease results from the vascular and parenchymal inflammatory response associated with the arrival and death of Dimmitis worms into the distal pulmonary arteries. Some studies suggest the involvement of Wolbachia in the development of the inflammatory reaction and in the polarization of the host immune response against the parasite.[24] This parasite harbors intracellular Wolbachia, an endosymbiont bacteria. Fourteen seropositive cats to Wolbachia and 8 seronegative cats were put into the plethysmograph chamber and different respiratory variables were measured. Significant differences were found for bronchoconstriction index (pause [PAU]), suggesting Wolbachia seems to produce a greater acute inflammatoryresponse at bronchial, vascular, and parenchymal levels, worsening the state of bronchoreactivity associated with the presence of seropositivity to D immitis.

Immune response

Dirofilariasis is characterized by a dual Th1/Th2–type immune response.[25] Analysis of mRNA expression of cytokines and of serum antibody subisotopes in naturally infected dogs has demonstrated that microfilaremic infections associate to a predominant Th2-type response mainly directed against D immitis antigens, while a Th1-type response against the WSP predominates in amicrofilaremic infections.[26]

Among human dirofilariasis cases, exposed individuals who have not developed further pathology demonstrate production of Th2-mediated immunoglobulin E (IgE) antibodies directed against specific proteins from D immitis,[27] while a Th1-type response against WSP is detected in most patients with human pulmonary dirofilariasis (HPD), a pulmonary form of D immitis infection.[28]

Etiology

Dirofilariasis is a helmintic infection caused by parasites of the Dirofilaria genus (genus Dirofilaria, family Onchocercidae, which is included in the class of Nematodes). It is a common zoonotic disease affecting mostly dogs (lord hosts), other canines (wolves, coyotes), foxes, and cats.

The Dirofilaria species that most commonly cause human infection are D immitis (heartworm) and D repens. It is transmitted to humans through arthropods; mosquitoes are the vector for Dirofilaria. Infection with these nematodes, however, is independent of dog ownership, although residence in or travel to an area where canine dirofilariasis is endemic is almost universal among cases of human dirofilariasis.

Because some mosquito species that transmit dirofilariasis feed indiscriminately on numerous animal species and humans, the occurrence of D immitis and D repens infections in a canine population implies a risk of infection for the local feline and human populations.[28]

Human disease caused by Dirofilaria species that infect other animals—including D tenuis (raccoon worm), D ursi (bear), D subdermata (porcupine), D lutrae (North American otter), D striata (wild American felines), and D spectans (Brazilian otter)—is occasionally reported in the medical literature.

D tenuis has been described as a cause of subcutaneous facial nodules and ophthalmic dirofilariasis in Florida, while an adult female D striata was removed from the orbit of a 6-year-old boy living in North Carolina, and D spectans was extracted from a digital artery lesion of a Brazilian man.

Human immunodeficiency predisposing to dirofilariasis

Initial theories suggested that the increased incidence of HPD found in elderly individuals (in contrast to the correspondingly low incidence of the condition in children) was the result of failing immunity. This theory has been disputed, however, as only 14% of adults diagnosed with HPD have a coexistent immune defect.

Dirofilariasis in wildlife

The presence of D immitis infection is becoming increasingly recognized in North American wildlife (ie, coyotes, foxes, wolves, black bears) that share environments with humans. This may become increasingly relevant in the future control of dirofilariasis, because prophylactic antifilarials can be administered to domestic canines to eradicate and control Dirofilaria in urban areas.

Wild canids

In the United States, the prevalence of D immitis in coyotes varies from 7% (Missouri) to 75% (Georgia) to 91% (northern California, United States).[29, 30, 31]

Two to 24 months after the release of captive red wolves, who had initially tested negative for microfilariae, into the Alligator River National Wildlife Refuge, in North Carolina, 14% of them tested positive for D immitis.

Fifty-six percent of dingoes (Australian wild dogs, or Canis familiaris dingo) in a tropical region of Australia’s Northern Territory were found to be infected with adult D immitis worms.

Foxes

In the United States, the prevalence of D immitis in foxes varies from 6% (Missouri) to 21% (South Carolina).[32]

The urban prevalence of D immitis in red foxes in Australia ranges from 6.4% (Melbourne) to 8.8% (Sydney).[33] In the Melbourne study, 2 known species of mosquito vector were also identified, increasing the risk of human infection. In Spain, 11% of red foxes in the Pyrenees region were found to be infected.

Raccoons and bears

In the United States, D tenuis was detected in 20% of wild raccoons trapped in southeast Georgia.[34]

D ursi has been detected in 0.2% of black bears in New Brunswick, Canada.[35]

Epidemiology

Prevalence in animals

D immitis

The prevalence of dirofilariasis in domestic dogs and cats varies by state and geographic region throughout the United States. All states except Nevada have reported D immitis infection in dogs, with the prevalence varying from low levels in some states (0.3%, 0.5%, and 1.2% in Colorado, Washington, and Montana, respectively) to as high as 40% in Florida and South Carolina. Of stray cats in Michigan, 3% were found to have adult D immitis worms at autopsy. In general, the infection is more prevalent in dogs than in cats, in which prophylaxis is not routinely recommended.

A similar variation in prevalence of D immitis in dogs and cats occurs elsewhere in the world, except Japan, where as many as 10% of stray cats are infected.[36] In Europe, the recorded prevalence rate of D immitis in dogs is as follows:

In other parts of the word, the prevalence of D immitis in dogs includes the following:

D repens

The prevalence of D repens in dogs is also substantial in endemic areas of southern Europe. The reported rates are as follows:

The rate of dirofilariasis in dogs in Sri Lanka, another area endemic for D repens, is high, with rates of 30-60%.

Occurrence in the United States

The epidemiology of human dirofilariasis is related to the prevalence of canine dirofilariasis, the presence of suitable mosquito vectors, and human activities that lead to exposure.

D immitis causes most cases human dirofilariasis in the United States, with the prevalence of canine dirofilariasis having increased since the late 20th century. The geographic spread of the human disease has paralleled that of the dog population, although human dirofilariasis tends to be independent of dog ownership.

Most HPD cases have been found in the states adjacent to the Gulf of Mexico and the southern Atlantic states, where the prevalence of canine D immitis infection has been documented to be as high as 40%. The entire range of canine D immitis infection extends much further, however, existing along the Mississippi River Valley and into southern Canada. Canine dirofilariasis has been described in all of the lower 48 states except Nevada.

The first human case of dirofilariasis in the United States was described in a female cadaver in New Orleans in 1941. The first description of HPD causing pulmonary infarction was in 1961. Since then, at least 197 cases of HPD, presumably caused by D immitis, have been reported. Ten cases of D ursi infection, 3 cases of D tenuis subcutaneous infection, and isolated cases of D striata and possible D lutrae infection have also been reported.

International occurrence

The most commonly reported manifestation of human dirofilariasis worldwide is subcutaneous or ocular disease caused by D repens, with 800 case reports in the medical literature. D repens is an Old World parasite and has not been described in the Americas, Japan, or Australia.

At temperatures below 14°C, Dirofilaria stops developing, explaining the predominant occurrence of dirofilarial infections in warmer climatic zones.[41]

Dirofilariasis is endemic around the Mediterranean basin,[42] with Italy being the European country with the highest prevalence of human dirofilariasis (66%), followed by France (22%), Greece (8%), and Spain (4%). The great majority of cases reported in France have occurred below the 46th parallel.[43]

However, although most human cases of dirofilariasis have been diagnosed in areas where canine dirofilariasis has been endemic for many years, Dirofilaria nematodes are currently considered emerging agents of parasitic zoonoses in Europe. Currently, 45% of the total human population of Europe, as well as their domestic and companion animals, are exposed to the risk of vector-borne helminths (VBH) causing diseases. Canine dirofilarioses by D immitis and D repens are key examples of the success of VBH spreading into nonendemic areas.[44]

Climatic changes and an increase in the movement of the parasite’s reservoirs (mostly infected dogs) have caused an increase in the geographic range of Dirofilaria from the traditionally endemic/hyperendemic southern regions, and the risk of human infection has consequently increased as well. In the last several years, forecast models have predicted that current summer temperatures are sufficient to facilitate extrinsic incubation of Dirofilaria in many areas of Europe. Drepens is currently the filarial species most commonly reported as spreading from southern to northern areas.[45, 46, 47]

The global warming anticipated by the Intergovernmental Panel on Climate Change suggests that warm summers suitable for Dirofilaria transmission in Europe will become more common; if this eventuates, filarial infection may spread into previously infection-free areas.[41, 48]

Until 2006, only imported cases of canine and human disease had been described in northern Europe. Szénási et al, however, subsequently described the first autochthonous human case of D repens infection in Hungary, supporting the concept that dirofilariasis is an emerging zoonosis in Hungary and potentially elsewhere in Central Europe.[49] Autochthonous human dirofilariasis also exists in Ukraine, Russia, and Belarus, which have seen a dramatic increase in the number of reported cases.[50, 51] Most cases are reported in the southwestern regions of Russian Federation; however, the disease has spread into northern areas, changing its limit from latitude 45 N to 61 N in 2013.[52] A few cases have also been reported in Croatia and Slovakia.[53, 54] Endemic foci of D repens infection exist in Asia Minor, Central Asia, and Sri Lanka.[55]

Most cases of HPD have been detected in the United States and Japan, but the disease has also been described in many other countries on all inhabited continents, including South America (Brazil), Europe (France, Italy, Spain), Asia (Ukraine, Japan, India), Africa, and Australia.[56]

The incidence of ocular dirofilariasis is on the rise in several parts of India, particularly in Kerala.[3] Human exposure to D immitis larvae has also been reported in isolated communities of Colombian Indian tribes of the Amazon rainforest.

Overall, the volume of reported cases of dirofilariasis and the number of affected countries have been on the increase. In addition to the aforementioned climate changes, several other factors may be responsible for the increase, including greater medical awareness in more countries. Another factor may be increased travel to endemic countries; most described cases of dirofilariasis in central and northern Europe have been attributed to travel to endemic zones of southern Europe or the United States.

According to some suggestions, the true prevalence of human exposure to and disease caused by D immitis is underestimated, because canine infection is widespread throughout the world and most infected people are asymptomatic.

A seroprevalence study in Spain, where 33% of dogs are infected with D immitis,[57] revealed that 22% of humans were seropositive (immunoglobulin G [IgG], 5.8%; IgM, 3.5%; IgE, 12.6%).[58, 59] IgG seroconversion was most prevalent in people older than 60 years, whereas IgM seropositivity was most common in persons younger than 19 years. The level of IgE was also found to decrease with age. The authors concluded that repeated contact with D immitis in this endemic population was common and began at an early age.

Race-related demographics

All studies of HPD from the United States have reported a predominance of infection in people of European descent (as high as 95%). This probably indicates a selection bias, with more white Americans presenting for radiologic screening investigations than African Americans.

Sex-related demographics

The incidence and prevalence of human dirofilariasis shows a sex preference that depends on the infecting species, as follows:

Age-related demographics

D immitis infection

All reviews of HPD report that most affected adults are age 50-60 years. However, this may be explained by selection bias, as adults are more likely to undergo chest radiography for cancer screening or clinical pulmonary disease. HPD has been described in children as young as age 8 years.[42, 60]

D repens infection

This also occurs more commonly in adults, peaking in individuals aged 40-49 years. The exception is in Sri Lanka, where children younger than 9 years are most likely to be infected. The youngest infected individual reported there was aged 4 months. This pediatric predominance is attributed to the custom in Sri Lanka of allowing male toddlers to completely eschew clothing or to wear only upper garments. The theory is supported by the observation that most pediatric cases in Sri Lanka are localized to the scrotum, penis, and perineal regions of the body.[55]

Prognosis

In general, following diagnosis and resection of the affected tissue, the prognosis for patients with dirofilariasis is excellent.

Complications with dirofilariasis are rare. The most common ones are nonspecific respiratory symptoms or a small pulmonary infarct that brings the infection to medical attention. Intraocular, subconjunctival, and retro-orbital[61] infections have also been reported.[62, 63, 64] A single case report describes meningoencephalitis and aphasia complicating infection with D repens.[65] No recorded fatalities due directly to dirofilariasis have been reported in the medical literature.

The primary clinical significance of HPD is the almost invariable radiologic misdiagnosis of a primary or metastatic lung tumor, which usually leads to thoracotomy with open lung biopsy or wedge resection of the lung to obtain the correct diagnosis.

History

The symptoms of dirofilariasis depend on the causative species and the body site involved. Patients with the disease rarely, if ever, remember being bitten by mosquitoes in the months preceding the appearance of symptoms. However, establishing the patient's place of residence and travel history to confirm possible exposure to suitable mosquito vectors is useful.

Coincidentally, some adult patients report a history of heavy tobacco use, which increases the suspicion of a malignant pulmonary process when a coin lesion is observed on chest radiography. (See the image below.)



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Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

D immitis infection

Most patients (approximately 60%) with human pulmonary dirofilariasis (HPD) are asymptomatic. When they do occur, symptoms can include the following:

One patient reported loss of consciousness following chest pain. Another patient experienced acute bilateral knee pain and swelling with fever.

Aberrant mucocutaneous sites may be involved (eg, conjunctiva), the most common symptom of which is eye pain.[66] Patients may also complain of floaters (described as ”shadows“).[67]

Acute thromboembolism and endarteritis can result from exposure of vascular endothelium to a high concentration of D immitis antigenic products, caused by the sudden death of a significant number of adult worms. This is true whether or not the worms died naturally or were killed by a filaricide treatment.[17]

D repens and other dirofilarial infections

Usually, patients notice a single painful subcutaneous lump in the affected area. The areas most commonly affected include the following:

In one pediatric case report of intradural dirofilariasis, the patient presented with a stiff neck and a frontal headache.[42]

Presentation with an acute abdomen, heralding development of peritonitis as a result of D repens intraabdominal infection, has been described.[68]

Physical Examination

The signs of dirofilariasis also depend on the causative species and body site involved.

D immitis infection

Physical examination of patients with HPD is usually noncontributory, whether patients are symptomatic or not. However, the rare subcutaneous or subconjunctival lesion caused by D immitis infection is easily detectable (in contrast to HPD).

D repens and other dirofilarial infections

Superficial infections (subcutaneous or subconjunctival lesions) are easily detected. A single nodule is the usual presentation.

A review of all reported cases of D repens dirofilariasis emphasizes a greater prevalence of infections in upper body sites (76%), compared with lower body sites (24%). This is thought to reflect the biting patterns of the mosquito vector. Upper body sites, in order of involvement, are as follows:

Ophthalmic involvement may be periorbital,[2, 3] subconjunctival,[4] subtenon,[5] or intraocular.[6] One case of ocular dirofilariasis with cellulitis presented as a periorbital mass. Clinical data of D repens human infection in the Russian Federation and Belarus indicate the ocular location was observed at a significantly higher frequency than the other anatomical locations.[52]

A single report described a pseudotumoral intradural location for D repens in a 6-year-old child that was initially misdiagnosed as a Langerhans cell histiocytosis. The physical examination showed a stiff and painful cervical spine, with spasm of the trapezius and sternocleidal-mastoid muscles.[42]

The lower body sites affected by D repens include lower limbs (11%), abdominal wall (5%), and male genitalia (6%).

A minority of D repens infections have been isolated from deep internal body sites, including lung-associated sites with subpleural infarction, as well as the gastrosplenic ligament, omentum, peritoneal cavity, mesocolon, and pancreas. A perirectal nodule has also been found.

In Sri Lanka, D repens has a predilection for the infection of male genitalia (21%) in comparison with other sites, such as the conjunctiva (19%), eye adnexa (16%), upper limbs (11%), face and/or cheek (9%), chest wall and/or breast (7%), neck (6%), lower limbs (4%), abdominal wall (3%), and peritoneal cavity (1%).

Approach Considerations

Studies used in the diagnosis and evaluation of dirofilariasis include the following:

Serology

Experimental complement fixation tests, indirect hemagglutination, and ELISAs using whole-body or somatic antigens (SA) have been employed in the diagnosis of dirofilariasis. Serologic studies using ELISA may yield positive results in 75% of patients with HPD. While these are useful tools in epidemiologic surveys in known endemic areas, they have low specificity in the general population and are not routinely available.

Findings may be false-positive in as many as 30% of patients being tested for dirofilariasis, because of cross-reactions with other nematode antigens (eg, Toxocara canis). This means that the antigens chosen for such tests in humans must be shown not to react with antibodies against T canis, Ascaris lumbricoides, Strongyloides stercoralis, Ancylostoma duodenale, or Necator americanus. All of these nematodes have a migratory pathway that potentially exposes humans to antigens, enabling them to stimulate an antibody response.[69] In regions outside the United States, antibody to taxonomically more distantly related helminths (eg, Taenia solium, Clonorchis sinensis) may have to be shown to be non–cross-reactive with the D immitis antigen.

An improved specificity with ELISA has been demonstrated if a 22-kd protein (Di22) from adult D immitis or recombinant antigens (ie, a 35-kd fusion protein, P22U, phospholipase A2 [PLA2]) are used for antibody capture. P22U and PLA2 are larval excretory/secretory proteins of D immitis. P22U is probably related to Di22 and is not recognized in Western blot tests of sera from patients with other parasitic and nonparasitic pulmonary diseases. PLA2 is not related to Di22 but reacts specifically with sera from patients with subcutaneous dirofilariasis.

Nevertheless, because of the low pretest probability of HPD, a positive ELISA result using Di22 or other antigens must be supported by radiologic characteristics, presentation, patient residence and travel history, and other data so that the clinician can decide whether invasive techniques are needed to reach a definitive diagnosis.

PCR Assay

Recently, a duplex real-time PCR has been assessed for the discrimination between D immitis and D repens and their quantification in blood samples and mosquitoes.[70]

A multiplex PCR based on the amplification of a mitochondrial gene of blood-circulating microfilariae of D immitis and D repens has also been shown to be useful for their molecular detection and differentiation in blood and skin samples.[71]

PCR assay using paraffin samples can be used for diagnosis when identification of the species is not possible with conventional morphology owing to poor conservation of the worm.[72] D immitis and D repens infections have been successfully diagnosed with amplification of genomic DNA extracted from single worms isolated in patients with clinical dirofilariasis.

The biopsy material or worms intended for PCR assay should be not be stored in formalin, because formalin fragments genomic DNA and interferes with Taq polymerase.

Imaging Studies

Chest radiography

The incidental finding of a pulmonary lesion on chest radiography is the usual presentation of HPD. The lesion is usually a well-circumscribed, peripheral coin lesion or nodule. In as many as 90% of cases, there is a solitary nodule. The lesions are usually smaller than 30 mm[73] and are typically subpleural (68%) and on the right side (76%), showing a particular preference for the right lower lobe (46% of all cases). Multiple lesions can be observed in either the same lobe or multiple lobes. (See the image below.)



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Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

Pulmonary lesions can be transitory. The coin lesion is an end-stage result of the parasite's death in the vascular bed of the lungs and the stimulation of a pneumonitis followed by granuloma formation. This pneumonitis phase of HPD often goes unrecognized by the radiologist, because the developing nodule is obscured by the lung inflammation.[69] The shortest time reported between a normal finding on chest radiography and the presence of a coin lesion due to D immitis infection was 5 months. Miyoshi et al noted pleural effusions in 13% of patients with HPD.[73]

The diagnosis in children may underappreciated, as dirofilarial lesions may be may be mistakenly labeled as Ghon foci secondary to pulmonary tuberculosis and, as such, not followed or treated.

CT scanning

Chest or abdominal CT scanning may be performed for further evaluation of pulmonary or abdominal lesions and for assessment of mediastinal lymphadenopathy. It may also be used to guide fine-needle aspiration and biopsy of suspicious lesions

MRI

MRI may be useful in differentiating subcutaneous dirofilarial lesions of the head and eyes from lesions of other etiologies (eg, histiocytosis, neuroblastoma).

Ultrasonography

Ultrasonography of abdominal or cutaneous lesions assists in the etiologic diagnosis of dirofilariasis and may guide fine-needle aspiration biopsy of the lesions.

Pulsed-Field Gel Electrophoresis

Multilocus electrophoresis analysis of DNA from worms recovered from pulmonary or subcutaneous nodules may be useful in identifying specific Dirofilaria species, especially in areas where both D repens and D immitis are present. (Histologic and phenotypic features of recovered worms may be damaged during removal or they may degenerate, preventing accurate identification.)

Biopsy

Surgical biopsy of subcutaneous nodules

D repens usually presents as a subcutaneous nodule in the body sites discussed earlier. The nodule almost always is excised for histopathologic diagnosis and confirmation of infection. The size of the nodules can vary from 0.5-2.5 cm in diameter.

Fine-needle aspiration of peripheral pulmonary lesions

Transthoracic needle aspiration (which can be performed with or without CT guidance) has been employed successfully in the diagnosis of HPD, having been used to identify morphologic features of D immitis and prevent invasive surgery.

Bronchoscopy with cytology and transbronchial biopsy

Bronchoscopy has been attempted in cases of HPD, with little success in positively identifying the cause of the pulmonary lesion.[74]

Results of cytology of bronchoalveolar lavage specimens and brushings should be interpreted with caution because the bronchial mucosa in patients with HPD may be focally metaplastic and mimic invasive squamous cell carcinoma.

A predominance of eosinophils or the presence of eosinophilic pneumonia may be a clue to the diagnosis of HPD.

Open lung biopsy with wedge resection of affected lung segment

Upon removal, most lesions are well-circumscribed, spherical, and gray-yellow in appearance. Wedge-shaped lesions may be observed in 32% of cases.

Fine-needle aspiration of retroperitoneal dirofilarial masses

The successful use of ultrasonographically guided fine-needle aspiration to obtain a biopsy of a pseudotumorous para-aortic mass has been described.[75]

Histologic Findings

Differentiating D repens from D immitis in microscopic sections is based on the diameter of the parasites, the thickness of the cuticle, the number and distribution of the fibers in the muscular layer, and other morphologic details, including the presence or absence of external cuticular ridges (found in D repens but not in D immitis).[76]

Diagnosing dirofilariasis based purely on histopathology has its pitfalls, however, especially when the morphology of the nematode is altered owing to inflammatory response or surgical artifact. (See the images below.)[77]



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Transverse section through an immature adult Dirofilaria immitis removed from the right chest wall of an 18-month-old child in Sydney, Australia. The ....



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Low-power view of a bulbar conjunctival biopsy specimen obtained from a 72-year-old man from Queensland, Australia, showing degenerate pieces of an im....



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Midpower view of bulbar conjunctival biopsy specimen showing degenerate pieces of an immature Dirofilaria immitis worm in cross-section and longitudin....



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High-power view of bulbar conjunctival biopsy specimen showing a cross-section of immature Dirofilaria immitis. The thin, smooth cuticle with internal....

HPD with D immitis infection

On microscopy, lesions have a necrotic center of lung tissue around a centrally thrombosed artery, with fragments of a nonviable, immature worm. This core is surrounded by a granulomatous zone of epithelial cells, plasma cells, lymphocytes, and a fibrous capsule rich in eosinophils (66% of cases). The overlying pleura is usually inflamed and fibrotic (75%). Calcification and caseous necrosis may be present (41%). Charcot-Leyden crystals may be detected in the nodules (27%).

The adjacent lung may show a desquamative, interstitial, pneumonia–like reaction (66%); follicular bronchiolitis (46%); and patchy organizing pneumonia (34%). A focal vasculitis involving the muscular arteries and capillaries is recognized in 51% of cases.

Anatomic features of the worm are better appreciated when histologic sections are stained with Movat pentachrome, Gomori methenamine-silver (GMS), or periodic acid-Schiff (PAS) stains. The ability to identify internal features of the worm (ie, digestive system, genital tract) is common. Nonspecific fluorescent whitener stains have also been used to rapidly identify worms in pulmonary specimens. Worms have been identified on frozen section biopsy specimens in 2 cases.

D repens infection

In most cases, the worm contained in the lesion shows varying grades of degradation. Some areas of the worm show more degeneration than others (ie, myoid fibers, lateral chords). Other features, such as the cuticle (outer covering), walls of the digestive tract, and sexual tubules, offer a certain resistance to attack. The external ridges of the cuticle are the feature that most easily distinguishes D repens from D immitis in such lesions.

The worm is surrounded by a large number of eosinophils and other inflammatory cells of varying degrees. An epithelioid, granulomatous reaction with multinucleate giant cells is observed in as many as 33% of cases and may resemble mycobacterial or fungal infections. Lymphocytes may form large aggregates and follicles with germinal centers that can extend into the connective tissue, mimicking lymphoma.

A fibrotic capsule and calcification may be observed in 6% of cases. The subcutaneous fat shows a septal and lobular inflammation mediated by eosinophils and lymphocytes. The absence of fat necrosis in the presence of inflammation with such cells indicates a diagnosis of dirofilariasis. However, sparganosis, a parasitic zoonosis caused by the larval stage of Spirometra species, may cause a similar lesion. (See the images below.)



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Transverse section through a mature female Dirofilaria repens removed from the superomedial orbital rim of a 67-year-old man. The patient was infected....



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Higher-magnification image of the Dirofilaria repens displayed in the previous image. The nematode was removed from the eye of a 67-year-old man. The ....

Approach Considerations

The use of anthelmintic chemotherapy is not routinely recommended after the removal of nodules. If secondary lesions are suspected or confirmed in deep body sites (ie, chest, abdomen), a course of ivermectin and diethylcarbamazine (DEC) may be advisable to prevent further invasive surgery. A course of chemotherapy may also be warranted after heavy exposure to mosquitoes in an area known to be endemic for dirofilariasis.

A novel approach for the treatment of cardiopulmonary dirofilariosis is targeting the Wolbachia rickettsial endosymbionts. Treatment with tetracyclines has been reported to damage D immitis, even causing death of adult worms.[78]

Long-lasting administration of both doxycycline and ivermectin before or in the place of melarsomine injections can eliminate adult worms and reduce the risk of thromboembolism. Therefore, it has been suggested that a combination of doxycycline for 30 days and ivermectin for 6 months has a potential efficacy, as high as 73%, in the adulticide therapy in dogs infested with D immitis.[79, 80]

Inappropriate treatment

Although this scenario is much less likely than incorrect diagnosis, inappropriate treatment of dirofilariasis is a potential issue, even if the diagnosis is made correctly.

One case has been reported in which a mastectomy was mistakenly performed because of a presumptive diagnosis of carcinoma when in fact the patient had breast dirofilariasis.

To prevent inappropriate treatment, consult an infectious disease specialist in all cases of suspected dirofilariasis.

Reaction to treatment

Care must be taken to ascertain whether a patient with dirofilariasis has ever had any antiparasitic drugs and if the drugs were ever noted to cause problems.

Monitoring

Patients with dirofilariasis who undergo surgical removal of lesions usually receive follow-up care at least once in the postoperative period for the removal of sutures and to monitor wound healing.

Patients with dirofilariasis may be at risk for other parasites. After treatment, patients should be monitored for other symptomology characteristic of parasitic infections.

Deterrence/prevention

Avoidance of mosquito bites during peak biting times of the day in areas known to be endemic for D immitis or D repens is the best method of preventing dirofilariasis.

Antifilarial Medications

Parasite biochemical pathways are sufficiently different from the human host to allow selective interference by chemotherapeutic agents in relatively small doses.

In many cases, antifilarial medications are not administered prior to surgical resection of dirofilarial lesions. One group of authors, however, has recommended a single dose of ivermectin followed by 3 doses of diethylcarbamazine (DEC) if the syndrome is strongly suspected prior to surgery. However, almost all cases are diagnosed only when histopathologic sections of biopsy or excised material are viewed.

Surgical Excision

Surgical excision of lesions and affected areas is the treatment of choice for patients with dirofilariasis.[7] Some authors have recommended a period of observing chest coin lesions for several months if dirofilariasis is suspected and no other features in the history or examination suggesting malignancy or other infection are present.

Patients with human pulmonary dirofilariasis (HPD) who have undergone wedge resection of a lung lesion require routine postoperative care for thoracic surgery (eg, intercostal drainage, monitoring of blood loss, chest wound care).

Patients with subcutaneous dirofilarial lesions can usually be treated as outpatients or undergo day-case surgical procedures.

Transfer

Transfer to an institution performing thoracic surgery may be required in patients with HPD in whom a fine-needle aspiration lung biopsy, wedge resection, or both is thought necessary for diagnosis.

Consultations

The following specialists may be involved in the treatment of dirofilariasis:

Medication Summary

Biochemical pathways in parasites are different from those in their human host; thus, the toxicity of anthelmintics is directed at the parasite, egg, or larvae. The mechanism of action varies within the drug class. Antiparasitic actions may include the following:

Ivermectin (Stromectol)

Clinical Context:  Ivermectin is a macrocyclic lactone derivative of avermectin (22,23-dihydroavermectin). It binds selectively with glutamate-gated chloride ion channels in invertebrate nerve and muscle cells, causing cell death. The drug, which is metabolized in the liver, has a 16-hour half-life.

Ivermectin exerts its antiparasitic action by acting as a potent agonist at GABA receptors and potentiating the inhibitory signals sent to motor neurons, paralyzing the parasite. Because GABA is confined to the central nervous system (CNS) in humans and ivermectin does not cross the blood-brain barrier, the drug has no paralytic action in humans.

Class Summary

Biochemical pathways in parasites are different from those in the human host; thus, the toxicity of anthelmintics is directed at the parasite, egg, or larvae. The mechanism of action varies within the drug class. Ivermectin, for example, acts as a potent agonist at gamma-aminobutyric acid (GABA) receptors and potentiates the inhibitory signals sent to motor neurons, paralyzing the nematode.

Author

Alena Klochko, MD, Infectious Disease Physician, Orlando Health, Florida

Disclosure: Nothing to disclose.

Coauthor(s)

Mark R Wallace, MD, FACP, FIDSA, Infectious Disease Physician, Skagit Valley Hospital, Skagit Regional Health

Disclosure: Nothing to disclose.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Glenn Fennelly, MD, MPH Director, Division of Infectious Diseases, Lewis M Fraad Department of Pediatrics, Jacobi Medical Center; Clinical Associate Professor of Pediatrics, Albert Einstein College of Medicine

Glenn Fennelly, MD, MPH is a member of the following medical societies: Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Charles S Levy, MD Associate Professor, Department of Medicine, Section of Infectious Disease, George Washington University School of Medicine

Charles S Levy, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America, and Medical Society of the District of Columbia

Disclosure: Nothing to disclose.

Michael D Nissen, MBBS, FRACP, FRCPA Associate Professor in Biomolecular, Biomedical Science & Health, Griffith University; Director of Infectious Diseases and Unit Head of Queensland Paediatric Infectious Laboratory, Sir Albert Sakzewski Viral Research Centre, Royal Children's Hospital

Michael D Nissen, MBBS, FRACP, FRCPA is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, Pediatric Infectious Diseases Society, Royal Australasian College of Physicians, and Royal College of Pathologists of Australasia

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Robert W Tolan Jr, MD Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine

Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility

Disclosure: Novartis Honoraria Speaking and teaching

John Charles Walker, MSc, PhD Head, Department of Parasitology, Center for Infectious Diseases and Microbiology, Westmead Hospital; Senior Lecturer, Department of Medicine, University of Sydney, Australia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

Adult Dirofilaria immitis worm extracted from the heart and pulmonary artery of a dog. Worms usually are 1-3 mm in diameter, and females may grow to as long as 30 cm.

Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

Transverse section through an immature adult Dirofilaria immitis removed from the right chest wall of an 18-month-old child in Sydney, Australia. The large lateral chords and multilayered cuticle are typical of Dirofilaria. The smooth cuticle is a feature of D immitis.

Low-power view of a bulbar conjunctival biopsy specimen obtained from a 72-year-old man from Queensland, Australia, showing degenerate pieces of an immature Dirofilaria immitis worm in cross-sections and longitudinal sections with Masson stain.

Midpower view of bulbar conjunctival biopsy specimen showing degenerate pieces of an immature Dirofilaria immitis worm in cross-section and longitudinal section view with Masson stain.

High-power view of bulbar conjunctival biopsy specimen showing a cross-section of immature Dirofilaria immitis. The thin, smooth cuticle with internal, lateral, longitudinal ridges; the thin hypodermis; the large lateral cords; the well-developed coelomyarial muscles; and the ill-defined reproductive organs are diagnostic of an immature D immitis (hematoxylin and eosin stain).

Transverse section through a mature female Dirofilaria repens removed from the superomedial orbital rim of a 67-year-old man. The patient was infected in Corfu, Greece, 6 months prior to diagnosis in Sydney, Australia. Features characteristic of Dirofilaria are the arrangement of the longitudinal muscles and the multilayered cuticle, which is expanded in the region of the large lateral chords.

Higher-magnification image of the Dirofilaria repens displayed in the previous image. The nematode was removed from the eye of a 67-year-old man. The features characteristic of D repens are the longitudinal ridges on the cuticle; the ridges are 6-7 micrometers wide, spaced at 11- to 12-micrometer intervals.

Plain chest radiographic appearance of pulmonary coin lesion secondary to Dirofilaria immitis infection in a man.

Adult Dirofilaria immitis worm extracted from the heart and pulmonary artery of a dog. Worms usually are 1-3 mm in diameter, and females may grow to as long as 30 cm.

Transverse section through an immature adult Dirofilaria immitis removed from the right chest wall of an 18-month-old child in Sydney, Australia. The large lateral chords and multilayered cuticle are typical of Dirofilaria. The smooth cuticle is a feature of D immitis.

Transverse section through a mature female Dirofilaria repens removed from the superomedial orbital rim of a 67-year-old man. The patient was infected in Corfu, Greece, 6 months prior to diagnosis in Sydney, Australia. Features characteristic of Dirofilaria are the arrangement of the longitudinal muscles and the multilayered cuticle, which is expanded in the region of the large lateral chords.

Higher-magnification image of the Dirofilaria repens displayed in the previous image. The nematode was removed from the eye of a 67-year-old man. The features characteristic of D repens are the longitudinal ridges on the cuticle; the ridges are 6-7 micrometers wide, spaced at 11- to 12-micrometer intervals.

Low-power view of a bulbar conjunctival biopsy specimen obtained from a 72-year-old man from Queensland, Australia, showing degenerate pieces of an immature Dirofilaria immitis worm in cross-sections and longitudinal sections with Masson stain.

Midpower view of bulbar conjunctival biopsy specimen showing degenerate pieces of an immature Dirofilaria immitis worm in cross-section and longitudinal section view with Masson stain.

High-power view of bulbar conjunctival biopsy specimen showing a cross-section of immature Dirofilaria immitis. The thin, smooth cuticle with internal, lateral, longitudinal ridges; the thin hypodermis; the large lateral cords; the well-developed coelomyarial muscles; and the ill-defined reproductive organs are diagnostic of an immature D immitis (hematoxylin and eosin stain).