Human and Animal Dirofilariasis: the Emergence of a Zoonotic Mosaic

In the paper

“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.”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [47]
• Not checked yetcites [226]
• Not checked yetcites [285]

In the paper

“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”

What the sources say

• Not checked yetcites [85]
• Not checked yetcites [51]
• Not checked yetcites [253]

In the paper

“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).”

What the sources say

• Not checked yetcites [273]
• Not checked yetcites [358]
• Not checked yetcites [442]

In the paper

“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).”

In the paper

“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).”

What the sources say

• Not checked yetcites [112]
• Not checked yetcites [230]
• Not checked yetcites [378]

In the paper

“The disease usually has a chronic progression.”

In the paper

“Adult worms live over 7 yr”

In the paper

“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]).”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [282] source

In the paper

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

In the paper

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

In the paper

“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).”

In the paper

“In contrast, the aerobic metabolism of carbohydrates predominates in microfilariae (188), and oxygen is required for motility although apparently not for survival (207).”

What the sources say

• Not checked yetcites [188]
• Not checked yetcites [207]

In the paper

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

What the sources say

• Not checked yetcites [134]

In the paper

“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).”

What the sources say

• Not checked yetcites [207]

In the paper

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

What the sources say

• Not checked yetcites [324]
• Not checked yetcites [391]

In the paper

“These findings suggest that symbiotic bacteria are essential for larval development in vertebrate hosts and for the long-term survival of adult worms (263).”

What the sources say

• Not checked yetcites [263]

In the paper

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

What the sources say

• Not checked yetcites [321]

In the paper

“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).”

What the sources say

• Not checked yetcites [74]

In the paper

“Both D. immitis and D. repens demonstrate poor vertebrate host specificity given that they can infect numerous mammalian species (34).”

What the sources say

• Not checked yetcites [34]

In the paper

“Nematode molting is regulated by ecdysteroid hormones, which play a similar role in insects (31).”

What the sources say

• Not checked yetcites [31]

In the paper

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

What the sources say

• Not checked yetcites [261]

In the paper

“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).”

What the sources say

• Not checked yetcites [391]

In the paper

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

What the sources say

• Not checked yetcites [435]

In the paper

“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).”

What the sources say

• Not checked yetcites [148] source

In the paper

“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.”

What the sources say

• Not checked yetcites [252]
• Not checked yetcites [261]

In the paper

“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).”

What the sources say

• Not checked yetcites [252]

In the paper

“Those studies suggested that Wolbachia bacteria are involved in molting and embryogenesis of filariae (28), whereas filariae contribute amino acids for bacterial growth (140).”

What the sources say

• Not checked yetcites [28]
• Not checked yetcites [140]

In the paper

“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).”

What the sources say

• Not checked yetcites [197] source

In the paper

“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.”

What the sources say

• Not checked yetcites [220]

In the paper

“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).”

What the sources say

• Not checked yetcites [308]
• Not checked yetcites [139]
• Not checked yetcites [101]

In the paper

“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).”

What the sources say

• Not checked yetcites [366]

In the paper

“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.”

What the sources say

• Not checked yetcites [309]

In the paper

“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).”

What the sources say

• Not checked yetcites [147]
• Not checked yetcites [420]
• Not checked yetcites [418]

In the paper

“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.”

What the sources say

• Not checked yetcites [247] source
• Not checked yetcites [254] source
• Not checked yetcites [261]

In the paper

“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).”

What the sources say

• Not checked yetcites [170]

In the paper

“In Spain, one infection of a wolf and sporadic infections of foxes have been reported for different areas of the country (154,250,383).”

What the sources say

• Not checked yetcites [154]
• Not checked yetcites [250]
• Not checked yetcites [383]

In the paper

“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).”

What the sources say

• Not checked yetcites [170]
• Not checked yetcites [220]
• Not checked yetcites [278]
• Not checked yetcites [442]
• Not checked yetcites [445]

In the paper

“The prevalence rates of D. immitis and D. repens in Greece are 10% and 30%, respectively (333)”

What the sources say

• Not checked yetcites [333]

In the paper

“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).”

What the sources say

• Not checked yetcites [6]
• Not checked yetcites [211]
• Not checked yetcites [218]
• Not checked yetcites [220]
• Not checked yetcites [251]
• Not checked yetcites [442]

In the paper

“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).”

What the sources say

• Not checked yetcites [161]

In the paper

“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.”

In the paper

“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).”

In the paper

“Dirofilariasis is spread throughout the United States, with a 1 to 12% prevalence rate (226).”

What the sources say

• Not checked yetcites [226]

In the paper

“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).”

What the sources say

• Not checked yetcites [229]

In the paper

“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).”

What the sources say

• Not checked yetcites [142]
• Not checked yetcites [94]
• Not checked yetcites [41]

In the paper

“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).”

What the sources say

• Not checked yetcites [68] source

In the paper

“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).”

What the sources say

• Not checked yetcites [279]
• Not checked yetcites [282] source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [74]

In the paper

“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.”

What the sources say

• Not checked yetcites [279]
• Not checked yetcites [360]
• Not checked yetcites [281] source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [3]
• Not checked yetcites [165]
• Not checked yetcites [352]

In the paper

“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.”

What the sources say

• Not checked yetcites [391]

In the paper

“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).”

What the sources say

• Not checked yetcites [186]

In the paper

“There is currently a scientific consensus regarding the phenomenon of climate change due to human activities (427).”

What the sources say

• Not checked yetcites [427]

In the paper

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

What the sources say

• Not checked yetcites [68] source

In the paper

“There are no experimental data regarding pathogenic mechanisms, although these alterations and lesions have been attributed to both mechanical and immunopathological processes (164).”

What the sources say

• Not checked yetcites [164]

In the paper

“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).”

What the sources say

• Not checked yetcites [42]
• Not checked yetcites [301]

In the paper

“In previous reports, times to nodule formation of 2, 3, and 8 months have been reported (191,206,304).”

What the sources say

• Not checked yetcites [191]
• Not checked yetcites [206]
• Not checked yetcites [304]

In the paper

“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”

What the sources say

• Not checked yetcites [10]
• Not checked yetcites [30] source
• Not checked yetcites [286] source

In the paper

“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).”

What the sources say

• Not checked yetcites [245]

In the paper

“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.”

In the paper

“Although single nodules appear most frequently, multiple lesions have also been described, with a maximum of five occurring in the same individual (206).”

What the sources say

• Not checked yetcites [206]

In the paper

“Clinical manifestations have been classified into two clinical syndromes (377): multifocal nodular dermatitis, which is generally localized to the face, and prurigo papularis dermatitis.”

What the sources say

• Not checked yetcites [377]

In the paper

“Extradermic symptoms include conjunctivitis (46%), anorexia (35%), vomiting (26%), fever (25%), lethargy (20%), and lymphadenomegaly (10%) (417, 418).”

What the sources say

• Not checked yetcites [417]
• Not checked yetcites [418]

In the paper

“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).”

What the sources say

• Not checked yetcites [79]
• Not checked yetcites [221]
• Not checked yetcites [235]

In the paper

“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).”

What the sources say

• Not checked yetcites [164]
• Not checked yetcites [178]

In the paper

“Cases involving intravitreous infection in dogs are unusual and may be caused by D. repens (172, 178) or, rarely, by D. immitis (102).”

What the sources say

• Not checked yetcites [172]
• Not checked yetcites [178]
• Not checked yetcites [102]

In the paper

“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.”

What the sources say

• Not checked yetcites [270]

In the paper

“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.”

What the sources say

• Not checked yetcites [441]
• Not checked yetcites [442]

In the paper

“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.”

What the sources say

• Not checked yetcites [269]

In the paper

“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.”

In the paper

“Consequently, antigen detection usually produces false-negative results and underestimates the number of feline infections (40).”

What the sources say

• Not checked yetcites [40]

In the paper

“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).”

What the sources say

• Not checked yetcites [148] source

In the paper

“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.”

In the paper

“These lesions often disappear with time, suggesting that pulmonary dirofilariasis can present with transient lesions (98).”

What the sources say

• Not checked yetcites [98]

In the paper

“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.”

What the sources say

• Not checked yetcites [330]

In the paper

“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.”

In the paper

“When present, pleural effusion is of a low magnitude (301).”

What the sources say

• Not checked yetcites [301]

In the paper

“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).”

What the sources say

• Not checked yetcites [84]
• Not checked yetcites [338]
• Not checked yetcites [130]

In the paper

“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).”

What the sources say

• Not checked yetcites [301]

In the paper

“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).”

What the sources say

• Not checked yetcites [158]

In the paper

“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.”

In the paper

“Microfilariae in the blood are usually detected in concentrated blood specimens by microscopy using the Knott test or other tests to concentrate microfilariae (435).”

What the sources say

• Not checked yetcites [435]

In the paper

“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.”

In the paper

“Worms in the ocular conjunctiva can also cause inflammation in addition to hyperemic conjunctival tumefaction (364).”

What the sources say

• Not checked yetcites [364]

In the paper

“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.”

What the sources say

• Not checked yetcites [214]

In the paper

“Other concomitant risk factors are the severity of pulmonary disease and the restrictions on physical activity that the dog can realistically endure (122,438).”

What the sources say

• Not checked yetcites [122]
• Not checked yetcites [438]

In the paper

“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.”

What the sources say

• Not checked yetcites [384]

In the paper

“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.”

What the sources say

• Not checked yetcites [57]

In the paper

“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).”

What the sources say

• Not checked yetcites [205]
• Not checked yetcites [260]
• Not checked yetcites [268]

In the paper

“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).”

What the sources say

• Not checked yetcites [433]

In the paper

“In ELISAs, this protein exhibits 100% sensitivity and 90% specificity, with positive and negative predictive values of 75% and 100%, respectively (336).”

What the sources say

• Not checked yetcites [336]

In the paper

“This technique also allows the confirmation of the presence of pleural effusions (351), although it cannot be used to assess the parasite load (436).”

What the sources say

• Not checked yetcites [351]
• Not checked yetcites [436]

In the paper

“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”

What the sources say

• Not checked yetcites [7]

In the paper

“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).”

What the sources say

• Not checked yetcites [435]

In the paper

“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).”

What the sources say

• Not checked yetcites [198]
• Not checked yetcites [406]

In the paper

“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).”

What the sources say

• Not checked yetcites [80]

In the paper

“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).”

What the sources say

• Not checked yetcites [146]

In the paper

“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).”

What the sources say

• Not checked yetcites [259]

In the paper

“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).”

What the sources say

• Not checked yetcites [391]

In the paper

“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).”

What the sources say

• Not checked yetcites [98]

In the paper

“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).”

What the sources say

• Not checked yetcites [435]
• Not checked yetcites [443]

In the paper

“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).”

What the sources say

• Not checked yetcites [446]

In the paper

“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).”

What the sources say

• Not checked yetcites [163]

In the paper

“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).”

What the sources say

• Not checked yetcites [391]

In the paper

“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).”

What the sources say

• Not checked yetcites [261]

In the paper

“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).”

What the sources say

• Not checked yetcites [138]
• Not checked yetcites [208]
• Not checked yetcites [317]

In the paper

“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).”

What the sources say

• Not checked yetcites [82]

In the paper

“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).”

What the sources say

• Not checked yetcites [389]

In the paper

“In chronic infections, a progressive suppression of cellular immunity is observed, with antibody responses being preserved (167,449).”

What the sources say

• Not checked yetcites [167]
• Not checked yetcites [449]

In the paper

“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).”

What the sources say

• Not checked yetcites [109]
• Not checked yetcites [145]
• Not checked yetcites [166]
• Not checked yetcites [167]
• Not checked yetcites [168]

In the paper

“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.”

What the sources say

• Not checked yetcites [90]

In the paper

“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.”

In the paper

“Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have not produced demonstrable benefits and can actually exacerbate lung parenchymal disease (15).”

What the sources say

• Not checked yetcites [15]

In the paper

“The Th2 response was directed mainly against D. immitis antigens, whereas the Th1 response was stimulated by Wolbachia (256).”

What the sources say

• Not checked yetcites [256]

In the paper

“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).”

What the sources say

• Not checked yetcites [216]
• Not checked yetcites [288]
• Not checked yetcites [38]

In the paper

“Macrophages play a role in the activation and regulation of this innate response and link the innate and adaptive responses (421).”

What the sources say

• Not checked yetcites [421]

In the paper

“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).”

What the sources say

• Not checked yetcites [390] source
• Not checked yetcites [396]
• Not checked yetcites [129]

In the paper

“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).”

What the sources say

• Not checked yetcites [216]
• Not checked yetcites [328]
• Not checked yetcites [388]

In the paper

“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).”

What the sources say

• Not checked yetcites [55] source
• Not checked yetcites [287]

In the paper

“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).”

What the sources say

• Not checked yetcites [395]
• Not checked yetcites [129]
• Not checked yetcites [374]

In the paper

“individuals with D. repens subcutaneous dirofilariasis exhibited a strong anti-WSP IgG response and positive immunohistochemical staining for WSP in granuloma inflammatory cells (162).”

What the sources say

• Not checked yetcites [162]

In the paper

“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).”

What the sources say

• Not checked yetcites [396]
• Not checked yetcites [162]

In the paper

“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).”

What the sources say

• Not checked yetcites [346]

In the paper

“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.”

What the sources say

• Not checked yetcites [347]

In the paper

“They present surface-linked proteases that lyse epicuticle-binding IgG antibodies, which suggests that microfilariae can avoid host humoral responses (415).”

What the sources say

• Not checked yetcites [415]

In the paper

“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).”

What the sources say

• Not checked yetcites [241]

In the paper

“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).”

What the sources say

• Not checked yetcites [295]

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [37]
• Not checked yetcites [36]

In the paper

“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).”

What the sources say

• Not checked yetcites [290]

In the paper

“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).”

What the sources say

• Not checked yetcites [425]

In the paper

“a considerable increase in intravascular TxB2 levels during septic shock has been demonstrated (27).”

What the sources say

• Not checked yetcites [27]

In the paper

“suggesting that DiE/S can modify the vascular environment and limit the damage from inflammation in the perivascular spaces.”

What the sources say

• Not checked yetcites [290]

In the paper

“PGE2 stimulates anti-inflammatory activity (43), induces vasodilation, and decreases vascular permeability (50)”

What the sources say

• Not checked yetcites [43]
• Not checked yetcites [50]

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [157]

In the paper

“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.”

What the sources say

• Not checked yetcites [62]
• Not checked yetcites [63]
• Not checked yetcites [242]

In the paper

“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).”

What the sources say

• Not checked yetcites [118] source

In the paper

“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.”

What the sources say

• Not checked yetcites [394]

In the paper

“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).”

What the sources say

• Not checked yetcites [194]

In the paper

“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.”

What the sources say

• Not checked yetcites [48]
• Not checked yetcites [190]

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”