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Cited by 834Parasitic Diseases Research and TreatmentResearch on Leishmaniasis StudiesHelminth infection and control

Human and animal dirofilariasis: The emergence of a zoonotic mosaic

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Simón, Fernando, Siles-Lucas, Mar, Morchón, Rodrigo, González-Miguel, Javier, Mellado, Isabel, Carretón, Elena, Montoya-Alonso, Jose Alberto·2012·Clinical Microbiology Reviews
DOI 10.1128/cmr.00012-12PMC PMC3416488
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Abstract

SUMMARY: Dirofilariasis represents a zoonotic mosaic, which includes two main filarial species ( Dirofilaria immitis and D. repens ) that have adapted to canine, feline, and human hosts with distinct biological and clinical implications. At the same time, both D. immitis and D. repens are themselves hosts to symbiotic bacteria of the genus Wolbachia , the study of which has resulted in a profound shift in the understanding of filarial biology, the mechanisms of the pathologies that they produce in their hosts, and issues related to dirofilariasis treatment. Moreover, because dirofilariasis is a vector-borne transmitted disease, their distribution and infection rates have undergone significant modifications influenced by global climate change. Despite advances in our knowledge of D. immitis and D. repens and the pathologies that they inflict on different hosts, there are still many unknown aspects of dirofilariasis. This review is focused on human and animal dirofilariasis, including the basic morphology, biology, protein composition, and metabolism of Dirofilaria species; the climate and human behavioral factors that influence distribution dynamics; the disease pathology; the host-parasite relationship; the mechanisms involved in parasite survival; the immune response and pathogenesis; and the clinical management of human and animal infections.

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Written from the paper’s full text.

TL;DR

Dirofilariasis is a zoonotic mosaic caused mainly by *Dirofilaria immitis* and *D. repens*, with dogs as major reservoirs, cats and humans as less suitable hosts, and *Wolbachia* symbionts shaping pathology and treatment. The review synthesizes global epidemiology, clinical disease, diagnosis, treatment, and host-parasite immunology, emphasizing emergence/expansion and major knowledge gaps.

Key findings

  • Approximately 1,782 human dirofilariasis cases have been reported: 372 pulmonary and 1,410 subcutaneous/ocular; *D. immitis* pulmonary cases predominate in the Americas, while *D. repens* subcutaneous/ocular cases predominate in the Old World.
  • Canine *D. immitis* occurs worldwide in tropical and temperate regions, with prevalence examples including 1 to 12% in the United States, up to 48.8% on the Gulf Coast, 2.3 to 45% in Brazil, and 5 to 74% in Argentina; *D. repens* is exclusive to the Old World.
  • Feline *D. immitis* infections tend to occur in the same areas as canine infections but at 5 to 20% of canine prevalence rates; cats often have low parasite burdens, transient or absent microfilaremia, and can develop heartworm-associated respiratory disease.
  • *Wolbachia* are maternally transmitted filarial symbionts involved in molting and embryogenesis; *Wolbachia* surface protein (WSP) drives Th1 proinflammatory responses, and doxycycline is recommended by the American Heartworm Society for beneficial effects in heartworm management.

Methods

  • Narrative review of human and animal dirofilariasis covering morphology, biology, protein composition, metabolism, climate and human behavioral factors, pathology, host-parasite relationships, immune response, and clinical management.
  • Evidence synthesized from published literature, retrospective case reviews, seroepidemiological surveys, experimental and clinical studies, and global prevalence reports; no new primary data are presented.
  • Main analysis is qualitative synthesis, with tables and figures summarizing proteins, human case data, vector species, and host-specific aspects of dirofilariasis.

Limitations

  • The paper states that knowledge of the genome, proteome, biochemistry, metabolism, molting, pathogenesis, and survival mechanisms of *D. immitis* and *D. repens* remains limited, with human dirofilariasis having the greatest dearth of knowledge.
  • The paper notes substantial underreporting and misdiagnosis, especially for pulmonary human cases, and states that retrospective reviews portray only “the tip of the iceberg”; epidemiological data are also limited in many regions, notably Africa.
  • Evident from the text: as a narrative review without a described systematic search or quality appraisal, conclusions rely on heterogeneous studies and reported cases, so prevalence and case estimates may be biased by surveillance and reporting differences.

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Integrity signals

Registry

Crossref · 10.1128/cmr.00012-12

Cites

404 of 404 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingnone given

    In the Americas, D. immitis pulmonary dirofilariasis predominates.

    “In the Americas, D. immitis pulmonary dirofilariasis predominates.”
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  • Findingcitation

    In Japan, most human dirofilariasis cases (152) have been attributed to D. immitis.

    “On the contrary, in Japan, most human cases (152) have been attributed to D. immitis (226,275,368).”
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  • Findingcitation

    In the Old World, subcutaneous/ocular dirofilariasis cases involving D. repens (n=1,370) largely predominate over pulmonary dirofilariasis cases, even in areas where D. immitis is highly endemic.

    “In the Old World, where D. immitis and D. repens cocirculate in populations of animal reservoirs, subcutaneous/ocular dirofilariasis cases involving D. repens (n ϭ 1,370) largely predominate over pulmonary dirofilariasis cases (35), even in areas where D. immitis is highly endemic (391).”
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  • Findingcitation

    By reviewing data for the whole territory of Russia between 1915 and 2008, researchers reported 570 subcutaneous/ocular dirofilariasis cases.

    “By reviewing data for the whole territory of Russia between 1915 and 2008, we have found that researchers reported 570 subcutaneous/ocular dirofilariasis cases (103).”
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  • Findingcitation

    Subcutaneous/ocular infections caused by Dirofilaria species other than D. repens are quite rare in the Old World.

    “Subcutaneous/ocular infections caused by Dirofilaria species other than D. repens are quite rare in the Old World (45,315).”
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    Findingreasoning

    The worldwide distribution of human dirofilariasis does not coincide exactly with that of canine dirofilariasis, mainly due to the lack of data.

    “The worldwide distribution of human dirofilariasis, as it is currently known (Fig. 6), does not coincide exactly with that of canine dirofilariasis, mainly due to the lack of data.”
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    Findingcitation

    Approximately 1,782 human dirofilariasis cases have been reported, 372 pulmonary and 1,410 subcutaneous/ocular.

    “Approximately 1,782 human dirofilariasis cases have been reported, 372 of which were pulmonary and 1,410 of which were subcutaneous/ocular cases.”
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    Findingcitation

    In the United States, 116 human pulmonary dirofilariasis cases have been reported, originating primarily in the southeast regions where canine prevalence rates are highest.

    “In the United States, 116 cases have been reported, originating primarily in the southeast regions, where canine prevalence rates are highest (47,226,285,299,300,400,411,423,448).”
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    Findingcitation

    Epidemiological studies of vectors from around the world indicate that the prevalence of Dirofilaria is lower in mosquitoes than in vertebrate hosts.

    “Epidemiological studies of vectors from around the world indicate that the prevalence of Dirofilaria is lower in mosquitoes than in vertebrate hosts: 1.06 to 1.77% in Aedes polynesiensis in American Polynesia (85), 1.04% in Aedes vexans in Turkey (51), 6.2% in Aedes taeniorhynchus in the Yucatan Peninsula (Mexico) (253), 10% in Culex theileri in Iran (23), 2.3% in Ae. albopictus, 1.38% in Anophe”
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    Findingcitation

    In South America, around 50 human dirofilariasis cases have been found, mainly in southwestern Brazil and sporadically in Costa Rica, Argentina, Venezuela, and Colombia.

    “In South America, around 50 cases have been found, mainly in southwestern Brazil (273,358,442) and sporadically in Costa Rica, Argentina, Venezuela, and Colombia (39,65,370,442).”
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    Findingnone given

    Numerous human cases have been reported for the European Union (586 subcutaneous/ocular and 33 pulmonary), Russia (622 subcutaneous/ocular and 3 pulmonary), and Sri Lanka (more than 132 subcutaneous/ocular).

    “Numerous human cases have also been reported for the European Union (586 subcutaneous/ocular and 33 pulmonary cases), Russia (622 subcutaneous/ocular and 3 pulmonary cases), and Sri Lanka (more than 132 subcutaneous/ocular cases).”
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    Findingcitation

    In the United States, seroprevalences for anti-D. immitis IgG and IgE in children of Hawaii were 13.8% and 16.3%, respectively; in Maryland, 27% (IgG) and 5% (IgE); and in Illinois, 5.2%.

    “In the United States, some epidemiological studies have registered seroprevalences of 13.8% and 16.3% for anti-D.immitis IgG and IgE, respectively, in children of Hawaii (112); 27% (IgG) and 5% (IgE) in inhabitants of Maryland (230); and 5.2% in Illinois (378).”
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    Heartworm disease in dogs usually has a chronic progression.

    “The disease usually has a chronic progression.”
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    Adult D. immitis worms live over 7 years in dogs.

    “Adult worms live over 7 yr”
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    Findingreasoning

    Endothelial cells also increase the expression levels of adhesion/transmigration molecules (ICAM, PECAM, VCAM) and cellular proliferation molecules (E-cadherin and VEGF).

    “Endothelial cells also increase the expression levels of adhesion/transmigration molecules (intercellular adhesion molecule [ICAM], platelet endothelial cell adhesion molecule [PECAM], and migration vascular cell adhesion molecule [VCAM]) and cellular proliferation molecules (E-cadherin and vascular endothelial grow factor [VEGF]).”
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    Findingnone given

    Some of these stimuli are also triggered by D. immitis somatic antigen (DiSA).

    “Some of these stimuli are also triggered by D. immitis somatic antigen (DiSA).”
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    Findingcitation

    Prevalences of D. immitis among canine populations differ significantly by climate zone: 25.47% in the stepparic zone, 30.4% in the mild climate zone, 13.57% in the dry desert climate zone, and 10% in the temperate cold climate zone.

    “the prevalences of D. immitis among the canine populations of each zone are significantly different: 25.47% and 30.4% in the stepparic and mild climate zones, respectively; 13.57% in the dry desert climate zone; and 10% in the temperate cold climate zone (282).”
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    The main route for energy generation in D. immitis is anaerobic glycolysis with lactate as a main end product.

    “The main route for energy generation is anaerobic glycolysis with lactate as a main end product.”
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    Findingnone given

    In heartworm disease in dogs, damages initially affect the arteries, spreading later to the lung parenchyma and the right heart chambers.

    “Initially, the damages affect the arteries, spreading later to the lung parenchyma and the right heart chambers.”
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    Findingreasoning

    In D. immitis infections, expression levels of IL-4 and IL-10 are increased, and antibodies related to the Th2-type response arise: IgG1 in dogs or IgE in humans.

    “The expression levels of IL-4 and IL-10 are increased, and antibodies related to the Th2-type response arise: IgG1 (dogs) or IgE (humans).”
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    Premisecitation

    In microfilariae, aerobic metabolism of carbohydrates predominates, and oxygen is required for motility although apparently not for survival.

    “In contrast, the aerobic metabolism of carbohydrates predominates in microfilariae (188), and oxygen is required for motility although apparently not for survival (207).”
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    Both D. immitis and D. repens are hosts to symbiotic bacteria of the genus Wolbachia.

    “At the same time, both D. immitis and D. repens are themselves hosts to symbiotic bacteria of the genus Wolbachia”
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    Premisecitation

    Adult D. immitis worms are homolactic fermenters because lactate is the main or only product of monosaccharide lysis, indicating that their metabolism is mainly anaerobic.

    “Adult D. immitis worms are regarded as homolactic fermenters because lactate is the main (or only) product of monosaccharide lysis produced by the worms (Fig. 4), indicating that their metabolism is mainly anaerobic (207).”
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    Premisecitation

    D. immitis and D. repens are responsible for human pulmonary and subcutaneous/ocular dirofilariasis, respectively, throughout the world.

    “In addition, D. immitis and D. repens are responsible for human pulmonary and subcutaneous/ocular dirofilariasis, respectively, throughout the world (324,391).”
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    Interpretationcitation

    Symbiotic bacteria are essential for larval development in vertebrate hosts and for the long-term survival of adult worms.

    “These findings suggest that symbiotic bacteria are essential for larval development in vertebrate hosts and for the long-term survival of adult worms (263).”
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    D. repens worms cause subcutaneous nodules and can reach the ocular region in human patients.

    “D. repens worms cause subcutaneous nodules and can reach the ocular region in human patients (321).”
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    Premisecitation

    Mosquitoes' susceptibility and resistance to infection are genetically determined and controlled by a gender-linked recessive allele, with separate genes coding for susceptibility and resistance to D. immitis and D. repens.

    “Mosquitoes' susceptibility and resistance to infection are genetically determined and controlled by a gender-linked recessive allele, with separate genes coding for susceptibility and resistance to D. immitis and D. repens (74).”
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    Both D. immitis and D. repens demonstrate poor vertebrate host specificity, infecting numerous mammalian species.

    “Both D. immitis and D. repens demonstrate poor vertebrate host specificity given that they can infect numerous mammalian species (34).”
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    Nematode molting is regulated by ecdysteroid hormones, which play a similar role in insects.

    “Nematode molting is regulated by ecdysteroid hormones, which play a similar role in insects (31).”
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    Humans and cats are less suitable hosts for D. immitis and D. repens, in which parasite development is dramatically modified compared with dogs.

    “Humans and cats are less suitable hosts (261), in which parasite development is dramatically modified compared with the patterns in dogs.”
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    Premisecitation

    Immature D. immitis worms can reach a branch of the human pulmonary artery, triggering an inflammatory response that destroys the worms, occasionally resulting in pulmonary nodules.

    “Immature D. immitis worms can reach a branch of the human pulmonary artery, triggering an inflammatory response that destroys the worms, occasionally resulting in pulmonary nodules (391).”
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    Adult D. immitis can live over 7 years, and microfilariae live as long as 2 years.

    “Adults can live over 7 years, and microfilariae live as long as 2 years (435).”
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    Premisecitation

    Adult D. repens worms generally reside in the subcutaneous tissues of definitive hosts, although they can also be found in the abdominal cavity and within connective muscular fasciae.

    “Adult D. repens worms generally take residence in the subcutaneous tissues of definitive hosts, although they can also be found in the abdominal cavity and within connective muscular fasciae (148), where they achieve sexual maturity at 6 to 9 m.p.i.(252).”
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    In cats, adult D. immitis maturation extends up to 8 m.p.i.; the worms are shorter than in dogs, have a shorter life expectancy of approximately 2 years maximum, and generally do not produce microfilariae.

    “In cats, the maturation of adult D. immitis worms extends up to 8 m.p.i.; these worms are shorter than those found in dogs, with a shorter life expectancy (approximately 2 years maximum), and they generally do not produce microfilariae.”
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    Premisecitation

    D. repens worms are smaller than D. immitis worms: females are 100 to 170 mm in length and 4.6 to 6.3 mm in diameter, and males are 50 to 70 mm in length and 3.7 to 4.5 mm in diameter.

    “D. repens worms are smaller than D. immitis worms: females are 100 to 170 mm in length and 4.6 to 6.3 mm in diameter, and males are 50 to 70 mm in length and 3.7 to 4.5 mm in diameter (252).”
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    Wolbachia bacteria are involved in molting and embryogenesis of filariae, whereas filariae contribute amino acids for bacterial growth.

    “Those studies suggested that Wolbachia bacteria are involved in molting and embryogenesis of filariae (28), whereas filariae contribute amino acids for bacterial growth (140).”
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    In the area surrounding Rostov-on-Don in southern Russia, in 2011, 20.25% of dogs were infected with Dirofilaria spp., 44.7% of which were infected with D. repens, 30.3% with D. immitis, and 25% were coinfected with both species.

    “In 1997, a prevalence of 30% was reported for D. repens (14), whereas in 2011, 20.25% of dogs were infected with Dirofilaria spp., 44.7% of which were infected with D. repens, 30.3% of which were infected with D. immitis, and 25% of which were coinfected with both species (197).”
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    In South America, Labarthe and Guerrero found increasing prevalence rates in Colombia (from 4.8% to 8.4%) and Argentina (from 3.5% to 5.1%) and declining rates in Brazil (from 7.9% to 2%) based on comparisons of the earliest and most recently published reports.

    “In South America, Labarthe and Guerrero (220) found increasing prevalence rates in Colombia (from 4.8% to 8.4%) and Argentina (from 3.5% to 5.1%) and declining rates in Brazil (from 7.9% to 2%) based on comparisons of the earliest and most recently published reports from those countries.”
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    Premisecitation

    Highly variable D. immitis prevalence rates in wild carnivores have been reported, ranging from 16% in Illinois and 43% in Florida to 71 to 100% in coyotes, red wolves, and their hybrids in Texas, where D. immitis is considered an important cause of morbidity and mortality.

    “Highly variable prevalence rates have been reported, ranging from 16% in Illinois (308) and 43% in Florida (139) to 71 to 100% in coyotes, red wolves, and their hybrids in Texas, where D. immitis is considered an important cause of morbidity and mortality for these species (101).”
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    Interpretationcitation

    In two other California foci, the Northern California Coastal Range and south of San Francisco Bay, prevalence increased 4-fold over the same period and reached levels similar to the Sierra Nevada region, suggesting spread of the parasite from the Sierra Nevada toward the Pacific coast.

    “However, in two other foci, the Northern California Coastal Range and south of the San Francisco Bay, the prevalence increased 4-fold throughout the same period and reached levels similar to those reported for the Sierra Nevada region, suggesting a spread of the parasite from this region toward the Pacific coast (366).”
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    In the United States, feline dirofilariasis has been reported in 29 states, with prevalence rates from 3% to 19%, highest in areas with highest canine endemicity, and in both feral and domestic cats.

    “In the United States, feline dirofilariasis has been reported in 29 states, with prevalence rates from 3% to 19%, with the highest rates in the areas with the highest levels of endemicity in dogs, and has been found in both feral and domestic cats.”
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    In Italy, D. immitis prevalence exceeds 50% in the broad area of endemicity of the Po river valley and is more moderate in central areas; D. repens is present throughout the country, with a prevalence rate of 30% in the Po river valley.

    “In Italy, the prevalence of D. immitis exceeds 50% in the broad area of endemicity of the Po river valley, and more moderate rates are observed in the central areas (147); in contrast, D. repens is present throughout the country (420), with a prevalence rate of 30% in the Po river valley (418).”
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    Premisecitation

    Foxes infected with both D. immitis and D. repens in Italy and foxes and jackals infected with D. immitis in Bulgaria have been found.

    “Foxes infected with both D. immitis and D. repens in Italy (247, 254) and foxes and jackals infected with D. immitis in Bulgaria (reviewed in reference 261) have been found.”
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    Premisecitation

    Studies performed in the United States from 2002 to 2005 demonstrated that incidences of cardiopulmonary dirofilariasis increased in 30 states, decreased in 17 states, and remained steady in 3 states, with a total increase of over 5,000 infected animals.

    “Studies performed in the United States from 2002 to 2005 demonstrated that the incidences of cardiopulmonary dirofilariasis had increased in 30 states, decreased in 17 states, and remained steady in 3 states, with a total increase of over 5,000 infected animals during this period (170).”
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    In Spain, one infection of a wolf and sporadic infections of foxes have been reported for different areas.

    “In Spain, one infection of a wolf and sporadic infections of foxes have been reported for different areas of the country (154,250,383).”
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    D. immitis affects canine populations in most countries of the Americas except Chile, where it has not been found despite epidemiological surveys, and French Guiana and Uruguay, where studies have not been conducted.

    “D. immitis affects canine populations in most countries of the Americas except Chile, where it has not been found despite epidemiological surveys, and French Guiana and Uruguay, where studies have not been conducted (170, 220, 278, 442, 445) (Fig. 5).”
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    The prevalence rates of D. immitis and D. repens in Greece are 10% and 30%, respectively.

    “The prevalence rates of D. immitis and D. repens in Greece are 10% and 30%, respectively (333)”
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    In Central and South America, dirofilariasis prevalence rates range from 20% to 42% in cities on the Gulf Coast of Mexico, 20.4% to 63.2% in the Caribbean, 2.3% to 45% in Brazil, and 5% to 74% in Argentina.

    “In Central and South America, dirofilariasis prevalence rates range from 20% to 42% in cities on the Gulf Coast of Mexico, from 20.4% to 63.2% in the Caribbean (the Bahamas, Curaçao, Cuba, the Dominican Republic, and Puerto Rico), from 2.3% to 45% in Brazil, and from 5% to 74% in Argentina (6,211,218,220,251,442).”
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    • cites [211]

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    • cites [218]

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    • cites [220]

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    • cites [251]

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    • cites [442]

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  • May combine two claims.

    Premisecitation

    In a study on different ecosystems, the highest prevalence of D. immitis in foxes was in agricultural areas (32%), lower in semiarid regions (1.7%), and none in mountain foxes.

    “In a study conducted on different ecosystems, the highest prevalence rate was found for agricultural areas (32%), whereas semiarid regions showed much lower rates (1.7%), and no infections were found in mountain foxes (161).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161]

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  • May combine two claims.

    Interpretationreasoning

    The changes in distribution and prevalence of dirofilariasis could be partially attributed to growing scientific interest and to climate change, which has increased the range of specific Dirofilaria vectors in some regions.

    “These changes could be partially attributed to the growing interest of the scientific community in dirofilariasis, especially with respect to human infections, and to climate change, which has increased the range of specific vectors of Dirofilaria spp. in some regions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Climate change has increased the range of specific vectors of Dirofilaria spp. in some regions.

  • May combine two claims.

    Premisenone given

    The epidemiological profile of canine dirofilariasis in Europe is characterized by the presence of D. immitis and D. repens, coexistence of both species in some countries, and their expansion within traditionally endemic countries and toward northern and central Europe, most noticeably D. repens.

    “As described above, the epidemiological profile of canine dirofilariasis in Europe is characterized by the presence of D. immitis and D. repens, the coexistence of both species in some countries, and their expansion within countries where they are traditionally endemic and toward northern and central Europe (most noticeably D. repens) (Fig. 5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Dirofilariasis is spread throughout the United States, with a 1 to 12% prevalence rate.

    “Dirofilariasis is spread throughout the United States, with a 1 to 12% prevalence rate (226).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [226]

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  • May combine two claims.

    Premisecitation

    After Hurricane Katrina, among dogs and cats relocated to other regions of the United States and Canada, 48.8% of dogs and 3.9% of cats were positive for heartworm, contributing to geographical dissemination.

    “Among the relocated animals, 48.8% of dogs and 3.9% of cats were positive for heartworm, thus contributing to the geographical dissemination of dirofilariasis (229).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229]

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  • May combine two claims.

    Premisecitation

    Vector activity for D. repens has been demonstrated for Anopheles maculipennis, Aedes aegypti, Mansonia uniformis, Mansonia annulifera, Armigeres obturbans, and Aedes albopictus.

    “Specific identification by the localization of enzymatic activity in recovered larvae or PCRbased filarial DNA amplification (130) has demonstrated vector activity for D. repens by Anopheles maculipennis (142), Aedes aegypti (94), Mansonia uniformis (41), Mansonia annulifera and Armigeres obturbans (171), and Aedes albopictus (77).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [142]

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    • cites [94]

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    • cites [41]

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  • May combine two claims.

    Premisecitation

    Global warming affects host-parasite systems by influencing amplification and emergence of parasite populations, inducing changes in development and survival rates of both parasites and vectors, and altering seasonal transmission dynamics.

    “Global warming affects host-parasite systems by influencing the amplification and emergence of parasite populations, inducing changes in the development and survival rates of both parasites and vectors, and altering seasonal transmission dynamics (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] source

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  • May combine two claims.

    Premisecitation

    The prevalence of D. immitis remains at 40% in Podenco Canario hounds, which are kept in poor conditions and exposed to mosquitoes without chemoprophylaxis.

    “However, the prevalence remains at 40% in Podenco Canario hounds (a native breed of hunting and guard dog), which are kept in poor conditions and exposed to mosquitoes without chemoprophylaxis (279, 282).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [279]

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    • cites [282] source

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  • May combine two claims.

    Interpretationreasoning

    The combination of these changes with climate change is driving mosquitoes into large areas of temperate regions and contributing to changes in the global distribution of dirofilariasis.

    “The combination of those changes with climate change is driving mosquitoes into large areas of temperate regions and contributing to changes in the global distribution of dirofilariasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mosquito colonization, development, and activity are regulated by climate, primarily temperature and humidity, and temperature also influences Dirofilaria sp. L3 development inside mosquitoes.

    “Mosquito colonization, development, and activity are regulated by climate, primarily temperature and humidity, and temperature also influences Dirofilaria sp.L3 development inside mosquitoes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74]

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  • May combine two claims.

    Premisecitation

    In Grand Canary Island, the prevalence of D. immitis increased from 28% to 58.9% between 1988 and 1998, followed by a decrease to 19.2% in 2011, coinciding with widespread use of chemoprophylaxis.

    “In Grand Canary Island, the prevalence of D. immitis increased from 28% to 58.9% between 1988 and 1998 (279, 360), followed by a decrease to 19.2% in 2011 (281), coinciding with the widespread use of chemoprophylaxis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [279]

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    • cites [360]

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    • cites [281] source

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  • May combine two claims.

    Interpretationreasoning

    Dirofilariasis transmission is influenced by two factors: human behavior with respect to pets and climatic factors that allow competent vector populations and Dirofilaria larval development in vectors.

    “Therefore, dirofilariasis transmission is influenced by two factors that affect each of the two components of the worms' life cycle: (i) human behavior with respect to pets and (ii) climatic factors that allow for the presence of competent vector populations and Dirofilaria sp.larval development in these vectors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Transmission of Dirofilaria spp. in a given region depends on the presence of a minimum number of dogs infected with adult worms producing microfilariae and on the presence of one or more mosquito species capable of transmitting the parasite.

  • May combine two claims.

    Premisecitation

    Ae. albopictus was introduced into the Americas and Europe by the commercial tire trade and is spreading rapidly in newly colonized areas and becoming established in regions where dirofilariasis is endemic.

    “One example is the Asian tiger mosquito, Ae. albopictus, which was introduced into the Americas and Europe by the commercial tire trade through tires harboring mosquito larvae and which is spreading rapidly in newly colonized areas (3,165,352) and becoming established in regions on both continents where dirofilariasis is endemic.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3]

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    • cites [165]

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    • cites [352]

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  • May combine two claims.

    Interpretationcitation

    Retrospective reviews of reported cases offer only a partial view of human dirofilariasis, and regions of endemicity with zooanthropophilic vectors probably have higher frequencies of human infections than reported.

    “Retrospective reviews of reported cases offer only a partial view of human dirofilariasis; i.e., they portray only “the tip of the iceberg” (391), and regions of endemicity showing vectors with zooanthropophilic habits probably have higher frequencies of human infections than reported in the literature.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [391]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It is estimated that a total increase of 1.1°C to 6.4°C in temperature worldwide will be effected by the end of this century.

    “It is estimated that a total increase of 1.1°C to 6.4°C in temperature all over the world will be effected by the end of this century (186).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is currently a scientific consensus that climate change is due to human activities.

    “There is currently a scientific consensus regarding the phenomenon of climate change due to human activities (427).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [427]

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  • May combine two claims.

    Interpretationcitation

    With respect to dirofilariasis, climate change is lengthening annual periods of mosquito activity, shortening larval development periods, and increasing transmission in many geographical regions.

    “With respect to dirofilariasis, climate change is lengthening annual periods of mosquito activity, shortening larval development periods, and increasing transmission in many geographical regions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] source

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  • May combine two claims.

    Premisecitation

    There are no experimental data regarding pathogenic mechanisms of subcutaneous dirofilariasis in dogs, although lesions have been attributed to mechanical and immunopathological processes.

    “There are no experimental data regarding pathogenic mechanisms, although these alterations and lesions have been attributed to both mechanical and immunopathological processes (164).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164]

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  • May combine two claims.

    Premisecitation

    The longest-known residence of a single pulmonary nodule is 13 years, during which it underwent calcification; a 2-year follow-up of a single nodule did not reveal radiological modifications.

    “To date, the longest-known residence of a single nodule is 13 years (42), during which the nodule underwent calcification, whereas a 2-year follow-up of a single nodule did not reveal any modifications to its radiological features (301).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42]

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    • cites [301]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Times to nodule formation of 2, 3, and 8 months have been reported.

    “In previous reports, times to nodule formation of 2, 3, and 8 months have been reported (191,206,304).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [191]

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    • cites [206]

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    • cites [304]

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  • May combine two claims.

    Premisecitation

    C. pipiens is considered a potential primary vector for dirofilariasis wherever it resides because it is highly abundant in various regions of endemicity in Europe and Asia, remains active throughout summer, and has been found infected by Dirofilaria spp.

    “For example, C. pipiens, which has been found to be infected by Dirofilaria spp., is highly abundant in various regions of endemicity in Europe and Asia, and its populations remain active throughout the summer; consequently, C. pipiens is considered a potential primary vector for dirofilariasis wherever it resides (10,30,286), although other species in the same areas can contribute to transmission”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10]

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    • cites [30] source

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    • cites [286] source

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  • May combine two claims.

    Premisecitation

    Complete L3 development requires 130 HDUs within the mosquito life span, estimated to be 30 days, and development will be completed independent of temperature fluctuations below the 14°C threshold during this period.

    “Complete L3 development requires 130 HDUs within the mosquito life span, which is estimated to be 30 days, and development will be completed independent of temperature fluctuations below the 14°C threshold during this period (245).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [245]

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  • May combine two claims.

    Interpretationreasoning

    The spread of disease across previously infection-free regions permits parasite introduction into naïve canine populations, which are less resistant than those residing in regions of endemicity.

    “Otherwise, the spread of the disease across previously infectionfree regions permits parasite introduction into naïve canine populations, which are less resistant than those residing in regions of endemicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although single nodules appear most frequently, multiple lesions have been described, with a maximum of five in the same individual.

    “Although single nodules appear most frequently, multiple lesions have also been described, with a maximum of five occurring in the same individual (206).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clinical manifestations of subcutaneous dirofilariasis in dogs have been classified into two syndromes: multifocal nodular dermatitis (generally localized to the face) and prurigo papularis dermatitis.

    “Clinical manifestations have been classified into two clinical syndromes (377): multifocal nodular dermatitis, which is generally localized to the face, and prurigo papularis dermatitis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [377]

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  • May combine two claims.

    Premisecitation

    Extradermic symptoms of subcutaneous dirofilariasis in dogs include conjunctivitis (46%), anorexia (35%), vomiting (26%), fever (25%), lethargy (20%), and lymphadenomegaly (10%).

    “Extradermic symptoms include conjunctivitis (46%), anorexia (35%), vomiting (26%), fever (25%), lethargy (20%), and lymphadenomegaly (10%) (417, 418).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    • cites [418]

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  • May combine two claims.

    Premisecitation

    Ae. albopictus has been shown to be a natural vector for both D. immitis and D. repens in Italy and for D. immitis in Taiwan and the United States.

    “Ae. albopictus has been shown to be a natural vector for both D. immitis and D. repens in Italy and for D. immitis in Taiwan and the United States (79,221,235).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [79]

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    • cites [221]

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    • cites [235]

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  • May combine two claims.

    Premisecitation

    Subcutaneous dirofilariasis in dogs is commonly associated with adult D. repens worms in subcutaneous tissues and/or subcutaneous nodules, though they can also occupy other sites including the ocular conjunctiva.

    “Subcutaneous dirofilariasis in dogs is commonly associated with the presence of adult D. repens worms in subcutaneous tissues (see Fig. S2 in the supplemental material) and/or subcutaneous nodules (Fig. 12) (164), although they can occupy other sites, including the ocular conjunctiva (178).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [164]

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    • cites [178]

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  • May combine two claims.

    Premisecitation

    Intravitreous infection in dogs is unusual and may be caused by D. repens or, rarely, D. immitis.

    “Cases involving intravitreous infection in dogs are unusual and may be caused by D. repens (172, 178) or, rarely, by D. immitis (102).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [172]

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    • cites [178]

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    • cites [102]

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  • May combine two claims.

    Premisecitation

    In the United Kingdom, temperatures during two summer seasons between 1995 and 2000 were warm enough to allow complete development of Dirofilaria larvae in southern regions, and in five of those summers, such conditions allowed L3 transmission in areas surrounding London.

    “For example, Medlock et al. (270) demonstrated that in the United Kingdom, the temperatures during two summer seasons between 1995 and 2000 were warm enough to allow the complete development of Dirofilaria larvae in the southern regions, and in five of those summers, such conditions allowed L3 transmission in the areas surrounding London.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [270]

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  • May combine two claims.

    Premisecitation

    Dirofilariasis in Argentina has a seasonal transmission pattern like that in Europe, with a potential transmission window of nearly 6 months for Buenos Aires.

    “Studies by Vezzani et al. (441,442) demonstrated that dirofilariasis in Argentina has a seasonal transmission pattern like that in Europe and established a potential transmission window of nearly 6 months for Buenos Aires.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [441]

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    • cites [442]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ae. albopictus could adapt to conditions in southern England with potential activity in 4 to 5 months per year, thereby increasing the risk of dirofilariasis transmission.

    “Previously, Medlock et al. (269) studied the likelihood of the introduction of Ae. albopictus into England and concluded that this species could adapt to conditions in the south of the island with potential activity in 4 to 5 months per year, thereby increasing the risk of dirofilariasis transmission.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269]

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  • May combine two claims.

    Interpretationreasoning

    Epidemiological studies over the past decade demonstrate both the emergence and reemergence of dirofilariasis in humans and in animal reservoirs.

    “These predictions seem to have been confirmed by epidemiological studies over the past decade that demonstrate both the emergence and the reemergence of dirofilariasis in humans and in animal reservoirs, as mentioned above.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Antigen detection usually produces false-negative results and underestimates number of feline infections.

    “Consequently, antigen detection usually produces false-negative results and underestimates the number of feline infections (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

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  • May combine two claims.

    Interpretationcitation

    The frequently asymptomatic character of D. repens in dogs and lack of clinical diagnosis could contribute to its silent spread through canine reservoirs, increasing risk of human infection in the same areas.

    “The frequently asymptomatic character of D. repens in dogs and, thus, the lack of its clinical diagnosis could contribute to its silent spread through canine reservoirs, increasing the risk of infection in humans residing in the same areas (148).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] source

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  • May combine two claims.

    Interpretationreasoning

    The medical community's knowledge of and vigilance for these parasites can decisively influence detection of human cases, and numbers are likely underestimated in many endemic areas.

    “This shows that the medical community's knowledge of and vigilance for these parasites can decisively influence the successful detection of human cases, the numbers of which are likely to be underestimated in many areas of endemicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pulmonary dirofilariasis lesions often disappear with time, suggesting transient lesions.

    “These lesions often disappear with time, suggesting that pulmonary dirofilariasis can present with transient lesions (98).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98]

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Cases attributed to D. immitis in European patients may not be well characterized and instead represent D. repens infections, rendering D. repens almost exclusively responsible for human infections in Europe.

    “Furthermore, it has been pointed out that cases attributed to D. immitis in European patients may not be well characterized and instead represent D. repens infections (330), thereby rendering D. repens almost exclusively responsible for human infections in Europe.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [330]

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  • May combine two claims.

    Interpretationreasoning

    These data demonstrate that full development and fertilization of D. repens worms in human hosts are feasible, contradicting the belief that Dirofilaria worms cannot fully develop in humans.

    “These data demonstrate that the full development and fertilization of D. repens worms in human hosts are feasible, contradicting the commonly accepted belief that Dirofilaria worms cannot fully develop in human patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    When present, pleural effusion in pulmonary dirofilariasis is of low magnitude.

    “When present, pleural effusion is of a low magnitude (301).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [301]

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  • May combine two claims.

    Premisecitation

    Species can be defined by histochemical staining of anatomical regions with phosphatase activity and by PCR amplification of microfilaria DNA.

    “Species can also be defined by the histochemical staining of anatomical regions with phosphatase activity (84,338) and by the amplification of microfilaria DNA by PCR (130, 131).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [84]

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    • cites [338]

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    • cites [130]

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  • May combine two claims.

    Premisecitation

    Pulmonary dirofilariasis is detected at highest frequencies in male adults with a mean age of 53 years, though patients range from 10 to 79 years.

    “Pulmonary dirofilariasis is detected at the highest frequencies in male adults with a mean age of 53 years, although infected patients range in age from 10 to 79 years (301).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [301]

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    If specific antibodies can block parasitic enzyme activity, these data could account for limited survival of infective D. immitis larvae in human patients and lack of worm maturation.

    “If these specific antibodies can block the activity of parasitic enzymes, these data could account for the limited capacity for survival of infective D. immitis larvae over the infection time in human patients, due to worm metabolism blockage, and, consequently, could account for a lack of worm maturation in this host (158).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158]

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  • May combine two claims.

    Interpretationreasoning

    It is likely that subcutaneous/ocular localization facilitates fast detection of D. repens infection, so many worms may still be intact upon diagnosis.

    “It is likely that, as mentioned above, a subcutaneous/ocular localization facilitates a fast detection of the infection, being frequently referred to by the patients themselves, and as a result, many worms may still be intact upon diagnosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microfilariae in blood are usually detected in concentrated blood specimens by microscopy using the Knott test or other concentration tests.

    “Microfilariae in the blood are usually detected in concentrated blood specimens by microscopy using the Knott test or other tests to concentrate microfilariae (435).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [435]

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  • May combine two claims.

    Interpretationreasoning

    D. immitis pulmonary nodules are internal and mostly asymptomatic, so when diagnosed they are more likely due to old infections, with worms unidentifiable due to destruction and decomposition.

    “In contrast, D. immitis pulmonary nodules are internal, and most are asymptomatic; thus, when they are diagnosed, they are more likely to be due to old infections, with the worms which caused the infection being unidentifiable due to the destruction and decomposition of parasite tissues.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Worms in the ocular conjunctiva can cause inflammation and hyperemic conjunctival tumefaction.

    “Worms in the ocular conjunctiva can also cause inflammation in addition to hyperemic conjunctival tumefaction (364).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [364]

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  • May combine two claims.

    Premisecitation

    Human dirofilariasis is considered an emerging disease in some areas because of a dramatic increase in reported human cases (mostly subcutaneous/ocular) in the last 10 years.

    “Currently, human dirofilariasis is considered an emerging disease in some areas (214) because of the dramatic increase in the number of reported human cases (mostly subcutaneous/ocular cases) in the last 10 years.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214]

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  • May combine two claims.

    Premisecitation

    Concomitant risk factors for treatment include severity of pulmonary disease and restrictions on physical activity.

    “Other concomitant risk factors are the severity of pulmonary disease and the restrictions on physical activity that the dog can realistically endure (122,438).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [122]

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    • cites [438]

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  • May combine two claims.

    Premisecitation

    Radiographic profiles look normal in some infected cats, and alterations may be transient, resulting in erroneous diagnosis.

    “It is also worth noting that radiographic profiles look normal in some cases despite the infection, and alterations in radiographic profiles may be transient (384), resulting in an erroneous diagnosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [384]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Researchers are debating whether possible loss of efficacy of macrocyclic lactones is due to development of resistance or improper use of drug during treatment.

    “Currently, researchers are debating whether the possible loss of efficacy of macrocyclic lactones is due to the development of resistance (57) or the improper use of the drug during treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prophylactic treatment of choice in terms of safety and efficacy consists of macrocyclic lactones such as ivermectin, milbemycinoxime, moxidectin, or selamectin.

    “The prophylactic treatment of choice in terms of safety and efficacy consists of the administration of macrocyclic lactones such as ivermectin, milbemycinoxime, moxidectin, or selamectin (205,260,268).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [205]

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    • cites [260]

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    • cites [268]

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  • May combine two claims.

    Premisecitation

    Risk of pulmonary thromboembolism can be reduced by restricting physical activity for 30-40 days after adulticide treatment and administering heparin and glucocorticoids when necessary.

    “The risk of this condition can be reduced by restricting physical activity for 30 to 40 days following adulticide treatment and by administering heparin and glucocorticoids when necessary (433).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [433]

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  • May combine two claims.

    Premisecitation

    In ELISAs, Di22 exhibits 100% sensitivity and 90% specificity, with positive and negative predictive values of 75% and 100%, respectively.

    “In ELISAs, this protein exhibits 100% sensitivity and 90% specificity, with positive and negative predictive values of 75% and 100%, respectively (336).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336]

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  • May combine two claims.

    Premisecitation

    Chest X ray allows confirmation of pleural effusions but cannot assess parasite load.

    “This technique also allows the confirmation of the presence of pleural effusions (351), although it cannot be used to assess the parasite load (436).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [351]

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    • cites [436]

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  • May combine two claims.

    Premisecitation

    The three-dose alternate protocol of melarsomine kills 98% of worms; first single dose eliminates 90% of male and 10% of female parasites, leading to 50% reduction in overall parasite load, lessening embolic complications.

    “The three-dose alternate protocol (a single dose followed by two injections, which are administered at least 30 days after the initial injection and 24 h apart) kills 98% of worms; besides, the first single dose of melarsomine eliminates 90% of male parasites and 10% of females, leading to a safe 50% reduction in the overall parasite load and thereby lessening the chance for embolic complications”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dogs with one or more conditions (symptoms, abnormal chest X ray, high circulating antigens, visualization of parasites by echocardiography, concomitant ailments, impossibility of limiting physical activity) must be included in high-risk group for thromboembolic complications.

    “Dogs with one or more of the following conditions must be included in the high-risk group for thromboembolic complications: symptoms related to the disease (coughing, exercise intolerance, and ascites), abnormal chest X ray, high levels of circulating antigens, visualization of parasites by echocardiography, concomitant ailments, or the impossibility of limiting physical activity (435).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [435]

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  • May combine two claims.

    Premisecitation

    Tests for circulating antigens become positive 1 month earlier in ferrets than in dogs, probably due to higher concentrations in small blood volume.

    “Tests for the detection of circulating antigens become positive 1 month earlier than tests for detection in dogs, probably due to their higher concentrations in the small blood volume of this host (198,406).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [198]

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    • cites [406]

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  • May combine two claims.

    Premisecitation

    Preliminary results indicate feasibility of troponin I and myoglobin as markers of cardiac damage and D-dimer as confirmatory tool for pulmonary thromboembolism in dogs.

    “The preliminary results obtained indicate the feasibility of the use of troponin I and myoglobin as markers of cardiac damage and of D-dimer as a confirmatory tool for the diagnosis of pulmonary thromboembolism in dogs (80).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Testing for microfilaremia and circulating antigens is necessary in dogs undergoing chemoprophylaxis for first time, in dogs over 1 year old without prior medical history, and at beginning and end of each season in animals receiving routinely scheduled chemoprophylaxis.

    “Testing for microfilaremia and circulating antigens is necessary in dogs undergoing chemoprophylaxis for the first time, in dogs over 1 year old without prior medical history, and at the beginning and end of each season in animals receiving routinely scheduled chemoprophylaxis (146).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146]

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  • May combine two claims.

    Premisecitation

    Ivermectin has partial adulticide effect at 6-12 mg/kg monthly for 16 months, with efficiency reaching 100% if extended to 30 months.

    “Ivermectin has a partial adulticide effect if administered at a dose of 6 to 12 mg/kg of body weight monthly for 16 months, and the efficiency can reach 100% if treatment is extended to 30 months (259).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259]

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  • May combine two claims.

    Premisecitation

    When nodules are detected, malignancy is usually suspected, making human dirofilariasis an essential component of differential detection of subcutaneous and pulmonary nodules.

    “However, in both cases, when nodules are detected, a malignancy is usually suspected, which makes human dirofilariasis an essential component of the differential detection of subcutaneous and pulmonary nodules (391).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [391]

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  • May combine two claims.

    Premisecitation

    Pulmonary nodules are deep and asymptomatic in a high percentage of cases, and only a fraction are accidentally identified during chest X-ray performed for unrelated reasons.

    “In contrast, pulmonary nodules are located deep within the body and are asymptomatic in a high percentage of cases, and only a fraction of lung nodules are accidentally identified during chest X-ray procedures (Fig. 13), which are generally performed for reasons unrelated to dirofilariasis (98).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98]

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  • May combine two claims.

    Premisecitation

    Chest X ray provides evidence of pulmonary artery enlargement, lung parenchymal changes, and right heart cardiomegaly in advanced stages of canine dirofilariasis.

    “A chest X ray provides evidence of pulmonary artery enlargement (Fig. 10A), lung parenchymal changes, and right heart cardiomegaly in advanced stages of canine dirofilariasis (435,443).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [435]

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    • cites [443]

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  • May combine two claims.

    Premisecitation

    In BALB/c mice infected with L. sigmodontis, treatment with rifampin alone or with doxycycline for 14 days eliminates Wolbachia from worms, inhibits development and embryogenesis, and few worms survive after treatment.

    “In BALB/c mice infected with Litomosoides sigmodontis and treated with rifampin alone or with doxycycline for 14 days, the elimination of Wolbachia from worms and the inhibition of development and embryogenesis were shown, and few worms survived after treatment (446).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [446]

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  • May combine two claims.

    Premisecitation

    Tetracycline treatment followed by acaciasides has microfilaricide and adulticide activity.

    “Microfilaricide and adulticide activity (163) and the total elimination of microfilariae for at least 4 months were found when tetracycline treatment was followed by the administration of acaciasides (Acacia auriculiformis-derived saponins) (104).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163]

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  • Classified as probably not a substantial claim.

    Premisecitation

    The most important point in the management of human dirofilariasis is its differentiation from other causes of nodules susceptible to being removed by surgery.

    “the most important point in the management of human dirofilariasis is its differentiation from other causes of nodules susceptible to being removed by surgery (391).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [391]

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  • May combine two claims.

    Premisecitation

    Monthly oral doses of ivermectin or milbemycinoxime, topical selamectin, or moxidectin with imidacloprid are highly effective and safe for routine prophylaxis in cats.

    “Monthly oral doses of ivermectin or milbemycinoxime, topical selamectin, or moxidectin with the addition of imidacloprid are highly effective and safe for routine use (261).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [261]

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  • May combine two claims.

    Premisecitation

    Removal of subcutaneous nodules or worms from the ocular conjunctiva is a simple procedure, but surgical intervention is much more complex for pulmonary, ocular, retro-ocular, or other internal locations.

    “The removal of subcutaneous nodules or worms from the ocular conjunctiva is a simple procedure, but surgical intervention is much more complex for pulmonary, ocular, retro-ocular, or other internal locations (138,208,317).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [138]

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    • cites [208]

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    • cites [317]

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  • May combine two claims.

    Premisecitation

    Tetracycline dramatically depletes Wolbachia population in filariae when applied for 2 weeks prior to L4-to-L5 molting of B. pahangi in the Mongolian gerbil model, although regrowth of bacterial populations was observed after 160 days.

    “dramatically depleting the Wolbachia population in filariae when applied for 2 weeks prior to the L4-to-L5 molting of B. pahangi in the Mongolian gerbil (Meriones unguiculatus) model, although a regrowth of bacterial populations was observed after 160 days (82).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82]

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  • May combine two claims.

    Premisecitation

    The host is often able to control worm burden and maintain it within limits compatible with its survival, destroying most larvae acquired from reinfections.

    “it is generally accepted that the host is often able to control the worm burden and maintain it within limits compatible with its own survival, destroying most of the larvae acquired from reinfections (389).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [389]

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  • May combine two claims.

    Premisecitation

    In chronic D. immitis infections, progressive suppression of cellular immunity is observed, with antibody responses preserved.

    “In chronic infections, a progressive suppression of cellular immunity is observed, with antibody responses being preserved (167,449).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167]

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    • cites [449]

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  • May combine two claims.

    Premisecitation

    Antibodies of different isotypes (IgM, IgG, IgE) against every developmental stage of D. immitis are found, with highest levels in microfilaremic infections.

    “Different antibody isotypes (IgM, IgG, and IgE) against every developmental stage of the parasite are found, with the highest levels of antibodies being found in microfilaremic infections (109, 145, 166-168, 272, 415).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [109]

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    • cites [145]

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    • cites [166]

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    • cites [167]

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    • cites [168]

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  • May combine two claims.

    Premisecitation

    Chirgwin et al. found no changes in molting in the same model following tetracycline treatment, although parasite load decreased after treatment.

    “Chirgwin et al. (90) did not find any changes in molting in the same model following tetracycline treatment, although the parasite load decreased after treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90]

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  • May combine two claims.

    Premisereasoning

    In human dirofilariasis, surgery is usually used when treated, mostly due to suspicion of malignant origin of the nodule or presence of worms in ocular locations.

    “When treated, surgery is usually used, in most cases due to the suspicion of a malignant origin of the nodule or the presence of worms in ocular locations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aspirin and other NSAIDs have not produced demonstrable benefits in cats with dirofilariasis and can exacerbate lung parenchymal disease.

    “Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have not produced demonstrable benefits and can actually exacerbate lung parenchymal disease (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15]

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  • May combine two claims.

    Premisecitation

    In BALB/c mice immunized with DiSA, the Th2 response is directed mainly against D. immitis antigens, whereas the Th1 response is stimulated by Wolbachia.

    “The Th2 response was directed mainly against D. immitis antigens, whereas the Th1 response was stimulated by Wolbachia (256).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256]

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  • May combine two claims.

    Premisecitation

    IgG antibodies specific for WSP have been detected in blood and urine of dogs with various clinical presentations of dirofilariasis, in naturally and experimentally infected cats, and in humans with pulmonary and subcutaneous dirofilariasis.

    “IgG antibodies specific for the dominant Wolbachia surface protein (WSP) have been detected in the blood and urine of dogs with various clinical presentations of dirofilariasis (216, 288), in naturally and experimentally infected cats (38,289), and in humans diagnosed with pulmonary and subcutaneous dirofilariasis (162,396).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [216]

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    • cites [288]

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    • cites [38]

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  • May combine two claims.

    Premisecitation

    Macrophages play a role in activation and regulation of innate response and link innate and adaptive responses.

    “Macrophages play a role in the activation and regulation of this innate response and link the innate and adaptive responses (421).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [421]

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  • May combine two claims.

    Premisecitation

    Most patients with pulmonary dirofilariasis demonstrate an exclusively IgG1-based (Th1) proinflammatory response to WSP, whereas individuals exposed to D. immitis without pulmonary nodules exhibit a predominantly IgE-based (Th2) response specifically stimulated by parasite galectin and aldolase but not by Wolbachia.

    “Most patients diagnosed with pulmonary dirofilariasis demonstrate an exclusively IgG1-based (Th1) proinflammatory response to WSP (390, 396), whereas individuals exposed to D. immitis without pulmonary nodules exhibit a predominantly IgEbased (Th2) response (129, 344) that is specifically stimulated by both a galectin and an aldolase from the parasite but not by Wolbachia (344).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [390] source

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    • cites [396]

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    • cites [129]

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  • May combine two claims.

    Premisecitation

    Macrophages and neutrophils are present in canine D. immitis infections and in human dirofilariasis, and both are the most abundant cell types in pulmonary and subcutaneous nodules.

    “Macrophages and neutrophils are present in canine D. immitis infections (216) and in cases of human dirofilariasis, and both cell types have been described to be the most abundant cell types in pulmonary and subcutaneous nodules (328, 388).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [216]

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    • cites [328]

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    • cites [388]

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  • May combine two claims.

    Premisecitation

    Immunization of BALB/c mice with recombinant WSP induces expression of iNOS and IFN-γ mRNA and production of NO and IgG2a (Th1), related to macrophage-mediated proinflammatory responses.

    “the immunization of BALB/c mice with recombinant WSP induced the expression of iNOS and gamma interferon (IFN-␥) mRNA and the production of NO and IgG2a (Th1), which are related to macrophage-mediated proinflammatory responses (55,287).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] source

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    • cites [287]

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  • May combine two claims.

    Premisecitation

    Human patients with pulmonary dirofilariasis exhibit IgG or IgM responses against somatic and E/S antigens of adult D. immitis, whereas IgE antibodies predominate in asymptomatic individuals.

    “Human patients diagnosed with pulmonary dirofilariasis exhibit IgG or IgM responses against somatic and E/S antigens of adult D. immitis worms (395), whereas IgE antibodies predominate in asymptomatic individuals (129, 374).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [395]

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    • cites [129]

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    • cites [374]

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  • May combine two claims.

    Premisecitation

    Individuals with D. repens subcutaneous dirofilariasis exhibit a strong anti-WSP IgG response and positive immunohistochemical staining for WSP in granuloma inflammatory cells.

    “individuals with D. repens subcutaneous dirofilariasis exhibited a strong anti-WSP IgG response and positive immunohistochemical staining for WSP in granuloma inflammatory cells (162).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162]

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  • May combine two claims.

    Premisecitation

    High levels of anti-WSP IgG are consistently detected in patients with pulmonary dirofilariasis but not in asymptomatic seropositive individuals or in patients with D. repens-associated subcutaneous dirofilariasis.

    “high levels of anti-WSP IgG have consistently been detected in patients with pulmonary dirofilariasis but not in asymptomatic seropositive individuals (396) or in patients with D. repens-associated subcutaneous dirofilariasis (162).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [396]

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    • cites [162]

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  • May combine two claims.

    Premisecitation

    In cats treated with ivermectin at 30 days post-infection, anti-D. immitis IgG levels decrease after larval elimination, while anti-Wolbachia IgG levels continue to increase.

    “In cats treated with ivermectin at 30 d.p.i., anti-D.immitis IgG levels decreased after the elimination of larvae (from 45 d.p.i.onward), whereas anti-Wolbachia IgG levels continued to increase, consistent with the depletion of larvae and the release of Wolbachia into the host's body (346).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [346]

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  • May combine two claims.

    Premisecitation

    In cats experimentally infected with D. immitis L3 larvae, a moderate and short-term IgG response against L3 antigens develops at 0 to 2 months post-infection, while IgG against adult worm antigens is detected from 2 to 6 months post-infection.

    “In cats experimentally infected with L3 larvae, a moderate and short-term IgG response against L3 antigens develops at 0 to 2 m.p.i.(347), whereas IgG production in response to adult worm antigens is detected from 2 m.p.i. until 6 m.p.i.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [347]

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  • May combine two claims.

    Premisecitation

    Microfilariae present surface-linked proteases that lyse epicuticle-binding IgG antibodies, suggesting they can avoid host humoral responses.

    “They present surface-linked proteases that lyse epicuticle-binding IgG antibodies, which suggests that microfilariae can avoid host humoral responses (415).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [415]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Eicosanoids are lipid mediators derived from arachidonic acid that regulate inflammatory processes and modulate interactions between blood cells and endothelial cells.

    “Eicosanoids are lipid mediators derived from arachidonic acid that intervene in the regulation of inflammatory processes and modulate interactions between blood cells and endothelial cells (241).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241]

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  • May combine two claims.

    Premisecitation

    Cats experimentally infected with D. immitis show highest serum PGE2 levels at 60 days post-infection, followed by a dramatic decrease, associating high PGE2 with parasite survival during critical migration phase.

    “cats experimentally infected with D. immitis showed the highest serum PGE2 levels at 60 d.p.i., followed by a dramatic decrease, associating high PGE2 levels with parasite survival during the critical migration phase of the parasite (295).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [295]

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  • May combine two claims.

    Premisereasoning

    Responses to vasoconstrictive agents (methacholine, substance P, A-23187) are suppressed in pulmonary arteries of dogs with dirofilariasis compared with healthy controls, indicating endothelial cell changes contribute to vessel relaxation.

    “Responses to vasoconstrictive agents such as methacholine, substance P, and A-23187 were suppressed in the pulmonary arteries of dogs with dirofilariasis compared with healthy controls, indicating that behavioral changes in endothelial cells, but not smooth muscle cells, contribute to vessel relaxation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    WSP induces chemotaxis of neutrophils and can inhibit their apoptosis in vitro, which could contribute to extension of inflammatory state.

    “some studies indicated that WSP induces the chemotaxis of neutrophils (37) and can inhibit their apoptosis in vitro, which could contribute to the extension of the inflammatory state (36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37]

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    • cites [36]

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  • May combine two claims.

    Premisecitation

    Endothelial cell cultures stimulated with DiE/S show increased PGE2 levels and decreased monocyte transmigration compared with unstimulated cultures.

    “Endothelial cell cultures stimulated with DiE/S showed a significant increase in prostaglandin E2 (PGE2) levels and a significant decrease in monocyte transmigration compared with unstimulated cultures (290).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [290]

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  • May combine two claims.

    Premisecitation

    Changes in arterial wall in vivo are short-lived and completely dependent on high concentrations of molecules released by female parasites.

    “Changes observed for the arterial wall in vivo are short-lived and are completely dependent upon the presence of high concentrations of molecules released by female parasites (425).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [425]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intravascular TxB2 levels increase considerably during septic shock.

    “a considerable increase in intravascular TxB2 levels during septic shock has been demonstrated (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

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  • May combine two claims.

    Interpretationreasoning

    DiE/S can modify vascular environment and limit damage from inflammation in perivascular spaces.

    “suggesting that DiE/S can modify the vascular environment and limit the damage from inflammation in the perivascular spaces.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [290]

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  • May combine two claims.

    Premisecitation

    PGE2 stimulates anti-inflammatory activity, induces vasodilation, and decreases vascular permeability.

    “PGE2 stimulates anti-inflammatory activity (43), induces vasodilation, and decreases vascular permeability (50)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43]

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    • cites [50]

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  • May combine two claims.

    Premisecitation

    Filarial excretions alter physiological functions of endothelial cells but not arterial smooth muscle cells, thereby altering capacity of vascular wall to contract and relax.

    “Such mechanisms are thought to be due to excretions by filariae that alter the physiological functions of endothelial cells but not of arterial smooth muscle cells, thereby altering the capacity of the vascular wall to contract and relax.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    D. immitis and D. repens produce numerous proteins related to survival, including heat shock proteins and antioxidant/detoxification/glycolytic enzymes, linked to stress responses and interference with reactive oxygen species.

    “both D. immitis and D. repens produce numerous proteins that may be related to survival, such as heat shock proteins and enzymes with antioxidant or detoxification and glycolytic functions, all of which have been linked to stress responses and the ability of parasites to interfere with reactive oxygen species released by macrophages and neutrophils (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157]

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  • May combine two claims.

    Premisecitation

    PGE2 is detected during different developmental stages of filariae in humans and in monocytes from hyporeactive individuals with onchocerciasis, related to containment of inflammation.

    “PGE2 has also been detected during different developmental stages of filariae in humans and in monocytes from hyporeactive individuals with onchocerciasis (62,63,242), with its detection being related in all of those cases to the containment of inflammation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62]

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    • cites [63]

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    • cites [242]

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  • May combine two claims.

    Premisecitation

    In cats, intravascular pulmonary macrophages are downregulated with live worms and upregulated with dead worms, linking Wolbachia antigen release to proinflammatory macrophages.

    “the downregulation of intravascular pulmonary macrophages in cats with live worms, in contrast to the upregulation of macrophages in those with dead worms, link the release of Wolbachia antigens to the presence of proinflammatory macrophages (118).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] source

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  • May combine two claims.

    Interpretationreasoning

    Wolbachia itself is only partially responsible for inflammatory responses triggered by filariasis, and parasite molecules may also participate.

    “suggest that Wolbachia itself is only partially responsible for the inflammatory responses triggered by filariasis and that parasite molecules may also participate in this process.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [394]

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  • May combine two claims.

    Premisecitation

    Histamine causes vasoconstriction in healthy dogs but induces vasodilation in arteries of dirofilariasis-infected dogs, switching to vasoconstriction when endothelial cells are eliminated.

    “histamine, which causes vasoconstriction in healthy dogs, induced vasodilation in the arteries of dirofilariasis-infected dogs, which switched to vasoconstriction when arterial endothelial cells were eliminated (194).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194]

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  • May combine two claims.

    Premisecitation

    Adult D. immitis worms can capture platelets and adsorb albumin, IgG, and complement C3 on their external surface in dogs, masking worms and preventing recognition of cuticular antigens.

    “The external surface of D. immitis adults can capture platelets and adsorb albumin, IgG, and complement fraction 3 (C3) in dogs (48,190), thereby masking the worms and preventing the recognition of cuticular antigens.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48]

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    • cites [190]

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  • May combine two claims.

    Interpretationnone given

    Dirofilaria sp. antigens play important roles in parasite survival and in pathogenic processes.

    “the available data suggest that they play important roles not only in parasite survival but also in pathogenic processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Preadult/adult worms have surface nonimmunogenic glycolipids and many isoforms of heat shock proteins (HSPs) and detoxificant enzymes that eliminate toxic products synthesized by macrophages and neutrophils.

    “They have surface nonimmunogenic glycolipids and many isoforms of heat shock proteins (HSPs) and detoxificant enzymes that eliminate toxic products synthesized by macrophages and neutrophils.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Knowledge of the genome, proteome, biochemistry, metabolism, molting, pathogenesis, and survival mechanisms of D. immitis and D. repens is limited to date.

    “Knowledge of the genome, proteome, biochemistry, metabolism, molting, pathogenesis, and survival mechanisms of D. immitis and D. repens is limited to date.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Rapid and significant changes in distribution and prevalence of canine dirofilariasis reservoirs are being reported worldwide, changing epidemiological parameters for human and feline dirofilariasis.

    “Rapid and significant changes in the distribution and prevalence of canine reservoirs are being reported around the world, and these changes in turn change the epidemiological parameters for human and feline dirofilariasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Wolbachia also stimulates the production of the Th1-type antibody response and the expression of proinflammatory mediators by vascular endothelial cells.

    “Wolbachia also stimulates the production of the Th1-type antibody response and the expression of proinflammatory mediators by vascular endothelial cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Human dirofilariasis is likely the branch with the greatest dearth of knowledge.

    “Human dirofilariasis is likely the branch with the greatest dearth of knowledge.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    E/S antigens bind plasminogen and activate plasmin to eliminate thromboembolisms in the presence of tissue plasminogen activator (t-PA), whose expression is also stimulated by E/S antigens in vascular endothelial cells.

    “Additionally, E/S antigens bind plasminogen and activate plasmin to eliminate thromboembolisms in the presence of the tissue plasminogen activator (t-PA), whose expression is also stimulated by E/S antigens in vascular endothelial cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    New tools that allow acquisition of objective parameters to evaluate and describe damage in infected animals are being developed.

    “New tools that allow the acquisition of objective parameters to evaluate and describe the damage in infected animals are being developed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Live adult worms release metabolic products (E/S antigens) that stimulate anti-inflammatory prostaglandin E2 (PGE2) eicosanoid and decrease monocyte transmigration.

    “Live adult worms release metabolic products (E/S antigens) that stimulate anti-inflammatory prostaglandin E2 (PGE2) eicosanoid and decrease monocyte transmigration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Microfilariae have surface proteases that digest host antibodies.

    “Microfilariae have surface proteases that digest host antibodies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Wolbachia surface protein (WSP) stimulates the expression of IFN-γ interacting with monocytes (probably through Toll-like receptors) and inhibits their apoptosis.

    “The Wolbachia surface protein (WSP) stimulates the expression of IFN-␥ interacting with monocytes (probably through Toll-like receptors [TLR]) and inhibits their apoptosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Global warming influences the stages of the parasite life cycle that take place in vectors.

    “Global warming influences the stages of the parasite life cycle that take place in vectors.”
    Quote in the paperNot a substantial claim
159 of 159

  • The paper relies on this without support.

    Dirofilariasis transmission and distribution are susceptible to global climate change.

    “Additionally, the involvement of vectors in the parasite life cycle makes dirofilariasis transmission and distribution susceptible to global climate change, and rates have undergone rapid and significant changes in defined geographic regions in recent years.”

  • The paper relies on this without support.

    Climate change has increased the range of specific vectors of Dirofilaria spp. in some regions.

    “These changes could be partially attributed to the growing interest of the scientific community in dirofilariasis, especially with respect to human infections, and to climate change, which has increased the range of specific vectors of Dirofilaria spp. in some regions.”

  • The paper relies on this without support.

    Domesticated and wild dogs function as reservoirs for D. immitis and D. repens.

    “Among mammalian hosts, they are best adapted to domesticated and wild dogs, which function as reservoirs.”

  • The paper relies on this without support.

    Environmental temperature is the key factor that determines the length of the L3 developmental period in mosquitoes.

    “The environmental temperature is the key factor that determines the length of the L3 developmental period in mosquitoes.”

  • The paper relies on this without support.

    The life cycle of Dirofilaria species comprises a definitive vertebrate host and a vector.

    “The life cycle of Dirofilaria species comprises a definitive vertebrate host and a vector (Fig. 1).”

  • The paper relies on this without support.

    Wherever canine dirofilariasis exists, there is a risk of human infection.

    “Wherever canine dirofilariasis exists, there is a risk of human infection.”

  • The paper relies on this without support.

    Transmission of Dirofilaria spp. in a given region depends on the presence of a minimum number of dogs infected with adult worms producing microfilariae and on the presence of one or more mosquito species capable of transmitting the parasite.

    “The transmission of Dirofilaria spp. in a given region depends on the presence of a minimum number of dogs infected with adult worms producing microfilariae and on the presence of one or more mosquito species capable of transmitting the parasite.”

  • The paper relies on this without support.

    Cats with dirofilariasis can heal spontaneously.

    “because cats can heal spontaneously”

  • The paper relies on this without support.

    Most infected cats experience low parasite loads.

    “Because most infected cats experience low parasite loads”

  • The paper relies on this without support.

    Anaphylactic reactions follow the death of the worms in cats.

    “anaphylactic reactions that follow the death of the worms”

  • The paper relies on this without support.

    The small volume of the right heart chambers and pulmonary arterial circuit favors severe cardiopulmonary decompensation during death of adult worms in cats.

    “the small volume of the right heart chambers and pulmonary arterial circuit favors the unexpected appearance of severe cardiopulmonary decompensation during the death of the adult worms”

  • The paper relies on this without support.

    Cats that live exclusively indoors are at risk for D. immitis infection.

    “Even cats that live exclusively indoors, according to their owners, are at risk for D. immitis infection.”

  • The paper relies on this without support.

    Administration of preventive drugs to cats does not prevent antibody seropositivity.

    “The administration of these drugs to cats does not prevent antibody seropositivity.”

  • The paper relies on this without support.

    Many antigens have great molecular complexity and a large number of isoforms.

    “The great molecular complexity and large number of isoforms of many antigens”

  • The paper relies on this without support.

    Some proteins lack immunogenicity in natural infections.

    “the lack of immunogenicity of some proteins in natural infections”
15 of 15

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Heartworm disease is an endemic disease that is continuously expanding in the European continent from the southern countries to the centre and north.

    “Heartworm disease is an endemic disease that is continuously expanding in the European continent from the southern countries, traditionally endemic, to the centre and north of the continent”

    From Expansion of canine heartworm in Spain (2022) · cites this paper as [2]

  • From 2011, heartworm disease was considered an endemic reality in eastern and central Europe, having spread from southern countries in a short period.

    “From 2011, heartworm disease was considered an endemic reality in eastern and central Europe, where it had spread from southern countries in a short period of time [1,9].”

    From What has happened to heartworm disease in Europe in the last 10 years? (2022) · cites this paper as [1]

  • More optimal conditions created by temperature increases allow the spread of mosquitoes to other areas where previously climatic conditions prevented their presence.

    “This has led to the creation of more optimal conditions that allow the spread of mosquitoes to other areas where previously the climatic conditions prevented their presence [1,55,78,166,167].”

    From What has happened to heartworm disease in Europe in the last 10 years? (2022) · cites this paper as [1]

  • Movement of microfilaremic reservoirs from endemic areas or travel of pets from heartworm-free regions to endemic areas is a factor that could directly influence changes in distribution and expansion of D. immitis.

    “Several epidemiological reviews carried out in this regard [1,2,4,9,168] discussed some of these factors, such as the movement of microfilaremic reservoirs from endemic areas or travel of pets from heartworm-free regions to endemic areas.”

    From What has happened to heartworm disease in Europe in the last 10 years? (2022) · cites this paper as [1]

  • Dirofilaria repens infections are often asymptomatic in dogs, which might lead to a longer time period where a dog is infective.

    “Additionally, D. repens infections are often asymptomatic in dogs which might lead to a longer time period where a dog is infective, and a mosquito can ingest and transmit the parasite to further hosts [6, 73].”

    From Vectors, host range, and spatial distribution of Dirofilaria immitis and D. repens in Europe: a systematic review (2025) · cites this paper as [6]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Anti-WSP IgG findings for subcutaneous D. repens conflict

    Major

    One passage says patients with D. repens subcutaneous dirofilariasis had a strong anti-WSP IgG response; another says high anti-WSP IgG levels were not detected in those patients. Both cite reference 162.

  • Two mosquito species have conflicting genera

    Minor

    The text identifies crucians and punctipennis as Anopheles species, while Table 3 lists both as Aedes species.

  • Russia's pulmonary case count differs between the text and Table 2

    Minor

    The text reports three additional pulmonary cases in Russia, but Table 2 lists two pulmonary cases in total for Russia.

  • Microfilarial nutrient uptake conflicts with Figure 4 caption

    Minor

    The text says microfilariae lack a digestive tract and acquire nutrients exclusively through the cuticle. Figure 4's caption instead describes uptake through both the digestive tract and the cuticle in microfilariae.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 82

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  3. Artamonova A Nagorny S Strelnikova G Levchenko L . 1997. Human and canine dirofilariosis in Rostov Region, p 326–327. In Proceedings of the 7th USSR Congress of the Society of Epidemiologists, Microbiologists, Parasitologists. USSR Congress of the Society of Epidemiologists, Microbiologists, Parasitologists, Moscow, Russia.
  4. Atkins CE De Francesco T Miller M Meurs K Keene BW . 1996. Prevalence of heartworm infection in cats with cardiorespiratory abnormalities, abstr 50. Abstr. 14th ACVIM Forum, San Antonio, TX.
  5. Auer H . 2003. Cases of human dirofilariosis in Austria. In Auer H Hörweg C Prosl H Sattmann H (ed), Helminthological colloquium. Naturhistorisches Museum Wien, Vienna Austria.
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Authors
Simón, F., Siles-Lucas, M., Morchón, R., González-Miguel, J., Mellado, I., Carretón, E., & Montoya-Alonso, J. A.
Affiliations
  • Universidad de Salamanca (ES)
  • Laboratory of Parasitology, IRNASA (CSIC), Salamanca, Spain
  • Laboratory of Parasitology, Faculty of Pharmacy and IBSAL, University of Salamanca, Salamanca, Spain
  • Universidad de Las Palmas de Gran Canaria (ES)
  • Internal Medicine, Faculty of Veterinary Medicine, University of Las Palmas de Gran Canaria, Las Palmas, Spain
ORCID
Venue
Clinical Microbiology Reviews
Publisher
American Society for Microbiology
Published
2012-07
Volume
25
Issue
3
Pages
507-544
ISSN
  • 0893-8512 (ISSN-L)
  • 1098-6618
DOI
10.1128/cmr.00012-12
PMC
PMC3416488
OpenAlex
W1980882764
Cited by
834
References
404
Citations by year
2026: 50 · 2025: 66 · 2024: 85 · 2023: 75 · 2022: 78 · 2021: 78 · 2020: 84 · 2019: 48 · 2018: 45 · 2017: 61 · 2016: 53 · 2015: 47 · 2014: 37 · 2013: 24 · 2012: 3
FWCI
24.51
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Clinical Microbiology Reviews (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
  • Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
Funders
Junta de Castilla y León (SA090/A09)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
  • Health Sciences › Veterinary › Small Animals › Helminth infection and control
Keywords
dirofilariasis, Dirofilaria immitis, Dirofilaria repens, zoonotic filariasis, Wolbachia, host-parasite interactions, vector-borne transmission, human dirofilariasis, clinical management of infections
MeSH terms
Animals, Cats, Dirofilaria immitis, Dirofilariasis, Dogs, Energy Metabolism, Geography, Host-Parasite Interactions, Humans, Insect Vectors, Life Cycle Stages, Population Dynamics, Zoonoses, Helminth Proteins, Wolbachia, Communicable Diseases, Emerging, Dirofilaria repens

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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