Risk factors for human heartworm infections (dirofilariasis) in the south.
Human pulmonary dirofilariasis (HPD) is caused by the transmission of infective third stage larvae of the canine heartworm, Dirofilaria immitis, during blood-feeding by infected mosquitoes. Since humans are incidental hosts that cannot support the parasite's life cycle, infective larvae die after migrating to the pulmonary vascular bed. An initial inflammatory reaction is typically followed by a single pulmonary granuloma, described radiographically as a "coin lesion" that resembles a neoplastic lesion. As a result, the differential diagnosis
of human heartworm disease which is usually asymptomatic requires a lung biopsy by thoracotomy or video-assisted thoracic surgery (VATS). In rare instances, multiple granulomas have been described, and, in one case, an adult heartworm was discovered in the thorax during open heart surgery. (1,2)
Since HPD cases have been reported mainly from regions with high canine heartworm prevalence, such as the southern United States (US), the objectives of this review were (1) to describe the microbiology of the parasite; (2) to resolve any misconceptions regarding the pathophysiology and outcomes of canine versus human heartworm infec tions; (3) to describe the prevalence and parasite burden of canine dirofilariasis in the South compared to other areas; (4) to describe the prevalence of HPD in the South; (5) to identify the most important species of mosquito vectors of dirofilariasis based on seroprevalence rates of infection and transmission efficiency; (6) to identify the key risk factors for HPD in the South; and (7) to recommend new strategies for the diagnosis, management, control, and prevention of HPD.
Internet search engines, including Google[R], Google Scholar[R], PubMed, Medline, and Ovid, were queried with the key words as Medical Subject Heading (MESH) search terms to examine case reports and series of human pulmonary dirofilariasis (HPD). The key words included dirofilariasis, human, pulmonary; heartworms, human, canine. Since this study was a review of the existing scientific literature, Institutional Review Board (IRB) approval was not required.
Dirofilaria Species Microbiology and Life Cycle
The genus Dirofilaria has many species that share similar life cycles and infect a wide range of mammals including carnivores, rodents, and primates. All species rely on mosquito vectors to transmit infective third stage larvae during blood-feeding. The zoonotic reservoir for D. immitis in the US includes domestic and wild dogs and coyotes, which serve as definitive hosts for adult worm mating in the pulmonary arteries. Gravid females release microfilariae into the circulation which can infect several species of peri-domestic mosquitoes during blood-feeding, including Aedes, Culex, Anopheles, and other species. In incidental human hosts, infective Dirofilaria larvae follow the same migratory pathways as in mammalian definitive hosts, but die before maturing into adults producing localized granulomas in the lung (D. immitis), subcutaneous tissue (D. immitis, D. repens), or eye (ocular dirofilariasis caused by D. tenuis). The life cycle of the US canine heartworm, D. immitis, is depicted in (Figure 1).
Common Misconceptions Regarding the Clinical and Radiographic Manifestations of Canine and Human Pulmonary Dirofilariasis
The medical literature continues to refer to canine and human heartworm disease as cardiac infections, and to human pulmonary lesions as ischemic infarcts. (3) Despite its common name, D. immitis dirofilariasis is not a cardiac infection, but a vascular infection in animals and man, and the pathognomonic "coin lesion" in HPD is an organized granuloma and not a pulmonary infarct. (3)
In animals and man, the infective third stage larvae will migrate from the mosquito bite site to the pulmonary arteries for maturation to adulthood and mating. In infected dogs, echocardiographic and angiographic imaging studies have now demonstrated maturing worms in the femoral, pulmonary, and hepatic arteries, inferior vena cava, and right atrium. (3) Heartworms have never been demonstrated in the right ventricle in living dogs, but are commonly found lodged there at autopsy as postmortem artifacts. (3)
In HPD, larval worms also mature in the pulmonary arteries, not in the heart, and wedge in the distal pulmonary circulation after death. The disintegrating larvae release antigens that incite an initial endarteritis and localized pneumonitis followed by an organizing granuloma rather than causing an ischemic pulmonary infarct like a pulmonary artery embolus. (3) As dead worms lodge in pulmonary vessels, patients may experience low grade fever, mild chest pain, with coughing and, rarely, hemoptysis. There is often a mild peripheral eosinophilia, which resolves over time. The end results of human infections are the classical, spherical "coin lesions" on chest X-rays rather than the unique pyramidal, chest imaging signatures of pulmonary infarcts. (3) Unlike canine heartworm disease with massive worm burdens and congestive heart failure, HPD remains an innocuous process in most cases, with a radiographic signature that needs to be differentiated from a neoplastic process, especially in high-risk smokers and those with excessive environmental and occupational exposures to tobacco smoke.
The Prevalence and Parasite Burden of Canine Dirofilariasis in the Southern US
Theis and others have emphasized that human exposures to infective third stage larvae of D. immitis from infected mosquito bites are more common than currently realized and will track the prevalence of canine heartworm disease in the US. (3) Since there are more prevalent cases of canine heartworm disease in the South where mild winters and warm and humid conditions favor prolonged mosquito breeding, there is a higher incidence of HPD.
The Companion Animal Parasite Council (CAPC) collected the results from 4,796,403 canine heartworm tests ordered by US veterinarians in 2011 and performed by several commercial testing laboratories using similar methodologies to detect circulating D. immitis antigen. (4) Of the domestic dogs tested, 1.187% (n = 56,612) were positive for heartworm antigen, indicating active D. immitis infections. (4) Positive antigen tests for active heartworm infections in domestic dogs were most prominent in the lower Mississippi River Valley and throughout the southeastern US from Texas to Florida (Figure 2). (4)
In a 2004 autopsy study of worm burden in D. immitis-infected dogs in Michigan, Kaiser and Williams reported that of 176 dogs autopsied, 59% had 10 or less adult worms in the heart and pulmonary arteries compared to 52% of autopsied dogs with more than 10 adult worms in the heart and pulmonary arteries in a similar autopsy study in Florida. (5) Their data suggested that worm burdens may be higher with higher circulating microfilaria levels in southern canine heartworm infections compared to northern canine heartworm infections. (5)
In summary, increased parasite burdens in a regional population of more dogs with active heartworm infections in areas with several indigenous species of competent mosquito vectors all act in concert to support the enzootic transmission of canine heartworms in the South. (3-5)
The Descriptive Epidemiology of Human Pulmonary Dirofilariasis in the South
The first two cases of human extrapulmonary dirofilariasis were reported from Florida by Faust and co-investigators in 1952, and the first case of HPD was described by Dashiel in 1961. (6,7) In a 1999 case series review of 37 HPD cases in the US, Shah reported 29 cases (78.4%) from southern and southeastern states. (8) All cases occurred in adults with a mean age of 57.3 years (age range = 33-79 years, male:female ratio of 2:1); and most patients were asymptomatic (62.4%) at time of diagnosis. (8)
The combination of higher prevalence rates of canine heartworm disease in the South, canine infections with higher parasite burdens, and a wide array of mosquito vectors have resulted in the steadily increasing prevalence of HPD in the South with the largest single clusters reported in 1989 by Risher et al in New Orleans (n = 5), and in 1992 by Asimacopoulos et al in Houston (n = 10). (9,10) In these cases, the diagnosis of HPD was established by surgical resection of pulmonary coin lesions. (9,10) By 2004, approximately 82 cases of HPD had been reported in the US with most cases (n = 47, 57%), reported from southern US states, with the largest number of cases reported from Texas (n = 12), Louisiana (n = 5), and Florida (n = 4). (1,8-12)
Key Risk Factors for Human Pulmonary Dirofilariasis in the Southern US
The three most important risk factors for canine and human heartworm infections in the US include: (1) the regional prevalence of active infections in domestic dogs, (2) the regional prevalence of active infections in feral dogs and coyotes, and (3) the regional abundance and length of breeding and blood-feeding seasons for the most efficient mosquito vectors for disease transmission.
The Companion Animal Parasite Council (CAPC) established the national prevalence of active heartworm infection in domestic dogs in 2011 as 1.187% (n = 56,612 of 4,769, 403 dogs tested). (4) At that time, positive antigen tests for active heartworm infections in domestic dogs were most prominent in the lower Mississippi River Valley and throughout the southeastern US from Texas to Florida (Figure 2). (4) The regional prevalence of active heartworm infections in domestic dogs in the South is significantly greater than in other areas of the US and is further supported by the high seroprevalence rate (48.8%) of active heartworm infections in dogs evacuated from Gulf Coast states following Hurricanes Katrina and Rita in August-September 2005. (14)
The regional reservoirs of active D. immitis infections are maintained to a greater extent in wild canids than in domestic dogs with a national seroprevalence rate of less than 2%.4 Feral dogs and coyotes provide even greater reservoirs of active D. immitis infections than domestic dogs because they are not confined to kennels or to households and are not covered by heartworm chemoprophylaxis programs. The regional prevalence of active heartworm infections in wild canids has been reported to be greater in Gulf Coast States than in other US states with no coyote infections reported from Washington state and Arizona. (15-18) In 2003, Foster and co-investigators reported a 40% seroprevalence rate for active heartworm infections in coyotes in Florida. (16)
In 2011, Ledesma and Harrington were among the first investigators to recognize the importance of targeting specific mosquito species for vector control in an era of increasing D. immitis resistance to macrocyclic lactones, such as ivermectin, for heartworm chemoprophylaxis. (13) The investigators analyzed several field surveys for the presence of D. immitis in wild mosquito populations and identified nine major potential vectors with the greatest transmission efficiency as Aedes aegypti, Aedes albopictus, Aedes canadensis, Aedes sierrensis, Aedes trivitattus, Aedes vexans, Anopheles punctipennis, Anopheles quadrimaculatus, and Culex quinquefasciatus. (13)
More recently, McKay and co-investigators used polymerase chain reaction (PCR) to detect Dirofilaria immitis presence in six mosquito pools in Arkansas. (19) Arkansas is a southern state in the lower Mississippi River Valley where the domestic dog seroprevalence rate for D. immitis infection is higher than in other areas. The investigators detected D. immitis in 9 mosquito species including Aedes vexans, Anopheles quadrimaculatus, Anopheles punctipennis, Culex pipiens, Culex erraticus, Culiseta inornata, Psorophora columbiae, Psorophora ferox, and Psorophora howardii. (19) The frequency of D. immitis infections from the six collection sites in northeast Arkansas ranged from 2.1% to 19.4%. (19)
When the investigators collected 114 mosquitoes from inside the kennel of a heartworm- positive dog, 84 (73.7%) of the mosquitoes were positive for D. immitis infection by PCR. (19) In addition to comparing the frequency of D. immitis infection in mosquitoes collected near a heartworm-positive dog with indigenous mosquitoes in regional sampling pools, the investigators identified the two most abundant mosquito species collected as Aedes vexans, (58.7%) and Anopheles quadrimaculatus (23.7%) with 9.6% and 6.9% of these species positive for D. immitis respectively. (19)
In summary, seroprevalence surveys in domestic and wild canids and PCR screening of mosquito pools have confirmed the combination of higher prevalence rates of canine heartworm disease in the South, higher prevalence rates of heartworm disease in wild canids in the South, and an abundance of D. immitis-infected mosquito vectors in the South as key risk factors for HPD in the South. Preventive interventions should be specifically targeted to these risk factors to provide better disease control.
The Prevention and Control of Human Pulmonary Dirofilariasis
Traditionally, canine chemoprophylaxis for heartworms relied on the oral macrocyclic lactones, but recent laboratory studies have now demonstrated increasing macrocyclic lactone resistance by D. immitis. (20,21) The oral macrocyclic lactones, such as ivermectin, moxidectin, and others, provided effective chemoprophylaxis for heartworms in domestic dogs until recently. (20,21) In 2005, the Food and Drug Administration (FDA) issued a lack-of-efficacy warning for heartworm chemoprophylaxis with macrocyclic lactones. (20) Since then, epidemiological and laboratory studies have demonstrated increasing macrocyclic lactone antihelminthic resistance by D. immitis. (21)
Since HPD is usually an innocuous process that must be differentiated from a malignant process by surgical and other invasive diagnostic procedures, initial zoonotic control and prevention strategies should focus on improving canine heartworm chemoprophylaxis, canine heartworm testing, and treatment of infections, especially in areas of high canine heartworm prevalence with high parasite burdens. These targeted areas can be better identified by more frequent epidemiological surveys of the extent and location of epizoonoses in domestic and wild canids, and by more frequent mosquito microfilarial surveys. Improved serologic methods for the diagnosis of dirofilariasis are needed for dogs to interrupt transmission cycles and also for humans to avoid interventional diagnostic procedures for inconsequential "coin lesions". Improved canine chemoprophylaxis may require combinations or sequential dosages of the macrocyclic lactones including ivermectin, moxidectin, selamectin, and milbemycin oxime; or by adding another effective antifilarial medication, such as melarsomine dihydrochloride to the prophylactic regimen. (20,21) Lastly, better community mosquito control will reduce heartworm transmission cycles in domestic dogs in high prevalence areas and also protect humans, along with mosquito avoidance and topical repellants, from several other mosquito-borne infectious diseases.
The Diagnosis and Management of Human Pulmonary Dirofilariasis
Since there are no serologic or molecular methods currently available for the noninvasive, laboratory diagnosis of HPD, human D. immitis infections must continue to be diagnosed by finding "coin lesions" on chest X-rays or other imaging studies and identifying the morphologic features of the adult worm in excisional biopsies of pulmonary granulomas or, less frequently observed, subcutaneous nodular granulomas.
In reviewing the radiographic findings in 37 cases of HPD, Shah described the following characteristics of the "coin lesions" on routine chest films. (8) All lesions were well-circumscribed, noncalcified peripheral nodules with a mean diameter of 1.9 cm. (8) Most lesions (89.8%) were solitary; but among the remaining cases, 6 patients (10.2%) had 2 nodules, one had 3, and one patient had multiple nodules in different lobes in both lungs. (8) The shortest period of time between a negative chest X-ray and a "coin lesion" was 5 months. (8) Calcification was rare and only described in 2 nodules among 37 patients with HPD. (8)
Compared to pulmonary Dirofilaria granulomas, only 10 cases of extrapulmonary dirofilariasis with most occurring in subcutaneous nodules have been reported to date. (1) Figure 3 is a hematoxylin-and eosin-stained biopsy specimen of a subcutaneous granulomatous nodule containing the crosssection of a disintegrating Dirofilaria species worm. Similar histopathological patterns would be found in hematoxylinand eosin-stained biopsy specimens of pulmonary granulomatous nodules containing cross-sections of disintegrating D. immitis worms. Some of the more unusual locations for extrapulmonary D. immitis granulomas in humans have included the bladder and a portocaval shunt. (22,23) In 2013, Pozgain and co-authors were the first to report a live adult D. immitis worm in the substernal thorax during open heart surgery. (2) Figure 4 is an adult Dirofilaria species worm, presumed to be D. tenuis, extracted from the anterior chamber of a patient's eye.
Clinical laboratory tests in patients with HPD are usually normal and do not assist diagnoses. By the time nodular or subcutaneous granulomas are discovered, patients are typically asymptomatic without peripheral eosinophilia. Ciferri reported low grade peripheral eosinophilia with a median value of 5% in a series of patients with HPD in 1982. (24)
Although both enzyme-linked immunoabsorbent assay (ELISA) and indirect hemagglutination have been used as screening tests for zoonotic Dirofilaria infections, neither have proven sensitive or specific enough for human diagnoses, and both exhibit a wide range of antibody cross-reactivities with other nematodes. (25) In the absence of immunologic tests to detect HPD, some of the latest diagnostic methods have included video-assisted thoracic surgery techniques for granuloma excisions, and transthoracic fine needle aspiration biopsies under computed tomographic guidance. (26,27)
The Management of Human Pulmonary Dirofilariasis
Although the diagnosis of human dirofilariasis may be delayed and require thoracic surgery, the management of dirofilariasis includes excision of nodular granulomas in the lungs or subcutaneous tissues and careful extraction of adult worms from extrapulmonary sites, such the eye or bladder. Every attempt should be made to extract adult worms intact to avoid further antigenic stimulation of inflammatory reactions (Figure 4). No further antihelminthic therapy is usually required.
Since there are no serologic or molecular methods currently available for the noninvasive, laboratory diagnosis of HPD, human D. immitis infections must continue to be diagnosed by finding "coin lesions" on incidental chest X-rays or other imaging studies and identifying the morphologic features of the adult worm in excisional biopsies of pulmonary or subcutaneous nodular granulomas. In the absence of immunologic tests to detect HPD, some of the latest diagnostic methods to recommend have included video-assisted thoracic surgery techniques for granuloma excisions, and transthoracic fine needle aspiration biopsies (FNAB) of pulmonary lesions under computed tomographic guidance. (26,27)
Since HPD is usually an inconsequential infection that must be differentiated from malignant lung disease by surgical and other interventional radiographic procedures, initial control and prevention strategies for HPD should focus on improving canine heartworm chemoprophylaxis, frequent canine heartworm testing, and immediate treatment of heartworm infections, especially in areas of high canine heartworm prevalence. Clinicians must remain vigilant for the possibility of HPD when solitary "coin lesions" less than 2.0 cm appear on screening chest X-rays in asymptomatic patients without high pre-existing risk factors for lung cancer. The least invasive methods for tissue diagnoses are recommended. Future investigations should focus on targeting specific mosquito species, such as Aedes vexans and Anopheles quadrimaculatus, for improved vector control of D. immitis transmission and on developing new immunologic and molecular methods for diagnosing HPD and eliminating the need for invasive diagnostics for differential diagnosis of innocuous, parasitic "coin lesions".
James H. Diaz, MD, MPH&TM, Dr.PH, William H. Risher, MD
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(27.) Kelly W, Firouz-Abadi A, Roszkowski A, et al. Pulmonary dirofilariasis diagnosed by computerized scan controlled percutaneous needle aspiration. Aust NZ J Med 1969;15:656-657.
Dr. Diaz is a professor of Public Health and Anesthesiology, Schools of Public Health and Medicine at the LSU Health Sciences Center in New Orleans, LA. Dr. Risher is an associate professor of Surgery and Head, Cardiothoracic Surgery, School of Medicine, LSU Health Sciences Center, New Orleans, LA.
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|Author:||Diaz, James H.; Risher, William H.|
|Publication:||The Journal of the Louisiana State Medical Society|
|Date:||Mar 1, 2015|
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