Mansonella infections

INTRODUCTION — Three species of Mansonella cause human infections: M. streptocerca, M. perstans, and M. ozzardi. Each species has a limited geographic distribution and typically causes mild symptoms if any at all. A potential fourth species, Mansonella spp "DEUX", that is morphologically similar to M. perstans has been detected by molecular genotyping in blood samples of individuals in Gabon; the clinical relevance of this finding remains uncertain [1].

The epidemiology, clinical features, diagnosis, and treatment of Mansonella infections will be reviewed here (table 1A-B). Other filarial infections, including loiasis, onchocerciasis, and lymphatic filariasis, are discussed separately. (See "Onchocerciasis" and "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis" and "Lymphatic filariasis: Treatment and prevention" and "Loiasis (Loa loa infection)".)

MANSONELLA PERSTANS

Epidemiology — M. perstans is endemic in a large portion of sub-Saharan Africa, from Senegal to Uganda and south to Zimbabwe, and in Central and South America, from Panama to Argentina (figure 1 and figure 2) [2]. Since the majority of infected individuals are asymptomatic and diagnosis is typically based on morphologic examination of blood microfilariae, the epidemiology of M. perstans has not been clearly defined. Nevertheless, it has been estimated that 114 million people may be infected and as many as 581 million people in 33 countries are at risk for M. perstans infection in Africa alone [2]. Molecular analyses suggest that reports of atypical blood microfilariae in residents of the Amazon regions of Brazil and Peru, which were originally thought to be M. perstans, are actually M. ozzardi [3,4]; however, a study has confirmed the presence of both parasites in this region, as well as coinfection with the two parasites in two individuals tested [5]. (See 'Mansonella ozzardi' below.)

In endemic regions, the probability of infection increases with age, with prevalences reaching 100 percent in highly endemic areas. Infection of travelers is uncommon but it does occur [6,7]. Data from Gabon suggest a higher prevalence of M. perstans microfilaremia in people living with human immunodeficiency virus (HIV) infection [8]. Nonhuman primates are occasionally infected with M. perstans but do not appear to be a major reservoir of infection.

M. perstans is transmitted by biting midges (Culicoides). The life cycle is similar to that of other filariae (figure 3). Infective larvae introduced during the bite of an infected midge mature over months into adult worms. The adult worms live in the pleural, pericardial, and peritoneal cavities as well as the mesenteric, perirenal, and retroperitoneal tissues, where they produce unsheathed microfilariae that are found in the bloodstream at all times. Microfilariae are responsible for transmission of infection because they are taken up during the blood meal of the insect vector. The life cycle is completed following maturation of microfilariae into infective third-stage larvae within the midge. The lifespan of the adult worms is unknown, although microfilaria-positive cases have been reported up to 10 years after the infected individual has left the endemic area [9].

Clinical manifestations — Most individuals with M. perstans infection are asymptomatic [7,10,11], although nonspecific symptoms including pruritus, urticaria, arthralgia, abdominal pain, and fatigue reported in patients with M. perstans microfilaremia are often attributed to concomitant infections. When more characteristic symptoms do occur, they are predominantly related to migration of the adult worms and include transient subcutaneous swellings similar to the Calabar swellings of Loa loa infection, serositis (ie, pericarditis and pleuritis), and ocular symptoms (granulomatous nodules in the conjunctiva, retinal lesions, and periorbital inflammation surrounding dead adult worms). Neuropsychiatric manifestations, meningoencephalitis, and hepatitis have also been described.

Nonspecific but characteristic laboratory abnormalities include eosinophilia and elevated serum immunoglobulin (Ig)E levels.

Diagnosis — M. perstans infection should be suspected in an individual with an appropriate epidemiologic exposure, consistent clinical findings, and/or unexplained eosinophilia. The definitive diagnosis is established by identifying the adult worm in tissues or microfilariae in the blood. Serology may also be useful.

Visualizing organisms — The diagnosis of M. perstans infection can be definitively established by detecting microfilariae in a blood smear (picture 1) or, rarely, by the identification of adult worms in tissue specimens. Microscopy sensitivity is increased using concentration techniques, such as Knott's concentration or Nuclepore membrane filtration. However, due to the small size of M. perstans microfilariae, membranes with a 3 mcm pore size are optimal.

Adult worms range in length from 3.5 to 4.5 cm for males and 5 to 8 cm for females. Both are no more than 120 mcm wide. Microfilariae of M. perstans are unsheathed and measure 190 to 200 mcm long in stained blood smears. A round terminal nucleus is found at the tip of the tail, which is blunted (picture 1).

M. perstans has been shown to have a weak diurnal periodicity with peak counts at 8:00 AM [12]. This coincides with the feeding pattern of the vector, thereby potentiating transmission of infection. Their presence in the bloodstream at all times during the day can cause them to be mistaken for microfilariae of L. loa or Wuchereria bancrofti, filarial parasites that overlap in geographic distribution with M. perstans.

Serology and other tests — Serologic tests based on crude filarial antigens are positive in M. perstans infection but do not distinguish between active or past infection and show cross-reactivity between the different filarial species and with other nematode infections. Consequently, their utility is limited, although a negative result can exclude the possibility of infection.

A real-time polymerase chain reaction assay has been developed at the Laboratory of Parasitic Diseases, National Institutes of Health, that can detect and quantitate M. perstans microfilaremia [13]. Assistance with serologic and other diagnostic tests is available from the United States Centers for Disease Control and Prevention ([email protected]) and the Laboratory of Parasitic Diseases, National Institutes of Health (301-496-5398).

Differential diagnosis — M. perstans infection is typically diagnosed in an asymptomatic patient as an incidental finding on a blood smear or during evaluation for other filarial infections. As such, the differential diagnosis is broad and includes all causes of unexplained eosinophilia. (See "Approach to the patient with unexplained eosinophilia".)

The differential diagnosis for symptomatic presentation depends on the specific clinical manifestations. (See "Acute pericarditis: Clinical presentation and diagnosis" and "Pleural fluid analysis in adults with a pleural effusion".)

Angioedema and eye findings can be similar to those seen in loiasis. (See "Loiasis (Loa loa infection)".)

Treatment — M. perstans is relatively resistant to standard antifilarial agents, including diethylcarbamazine (DEC), ivermectin, albendazole, and mebendazole [2,14]. In one study that compared the efficacy of multiple regimens, the best efficacy was observed with a combination of diethylcarbamazine and mebendazole administered for 21 days (37 percent microfilarial clearance at 1 month) [14].

The intracellular endosymbiont Wolbachia has been demonstrated in M. perstans from Mali, Cameroon, and Ghana but appears to be absent in parasites from Uganda and Gabon. Doxycycline (200 mg daily for six weeks), which has activity against Wolbachia, has been shown to be 100 percent effective in clearing M. perstans microfilariae from the blood of infected individuals in Mali for up to 36 months [15] and in Ghana for at least 24 months [16].

The utility of doxycycline in the treatment of M. perstans from other geographic regions has not been explored; cases of imported M. perstans infection treated successfully with doxycycline have been reported [17,18].

Prevention — There have been no studies of chemoprophylaxis against M. perstans infection. Personal protection measures to limit contact with biting midges may have some utility in individual travelers. Repeated mass drug administration using ivermectin has led to a modest decrease in prevalence in some endemic areas [19].

MANSONELLA OZZARDI

Epidemiology — M. ozzardi is endemic in Central America, South America (Argentina, Bolivia, Brazil, Colombia, Guyana, Suriname, and Venezuela), and the Caribbean islands (Antigua, Dominican Republic, Guadeloupe, Haiti, Martinique, Nevis, Puerto Rico, St. Kitts, St. Lucia, St. Vincent, and Trinidad). The overall prevalence of M. ozzardi infection is unknown; up to 70 percent of the residents in endemic foci may have parasites detectable in the blood. A study of blood donors in an endemic area of Brazil found evidence of infection by polymerase chain reaction (PCR) in 23.8 percent of donors [20]. Infection of travelers is uncommon but does occur [6]. Nonhuman primates can be infected experimentally, but humans are the only major reservoir of infection.

M. ozzardi is transmitted by biting midges (Culicoides) and blackflies (Simulium amazonicum). The life cycle is identical to that of M. perstans (figure 4), except that adult worms are found in the lymphatics as well as the thoracic and peritoneal cavities, and microfilariae are found both in the blood and the skin [21]. The lifespan of the adult worms is unknown.

Clinical manifestations — Most individuals with M. ozzardi infection are asymptomatic, although urticaria, pruritic skin eruptions, edema, lymphadenopathy, arthralgias, fever, headache, vertigo, and pulmonary symptoms have been reported [22,23]. An association between M. ozzardi microfilaremia and nummular keratitis has also been reported in the Amazonas region of Brazil [24]. Eosinophilia is common.

Diagnosis — M. ozzardi infection should be suspected in an individual with an appropriate epidemiologic exposure, consistent clinical findings, and/or unexplained eosinophilia. The definitive diagnosis is established by identifying the microfilariae in the blood or skin. Serology may also be useful.

Visualizing organisms — The diagnosis of M. ozzardi infection can be definitively established by detecting microfilariae in a blood smear (picture 2) or skin snips (1 mm skin biopsies obtained using a corneoscleral punch or needle and scalpel that are incubated for 30 minutes to 24 hours in saline and examined under low magnification for the presence of motile microfilariae). Adult worms are rarely identified in tissue specimens. Concentration techniques, such as Knott's concentration or Nuclepore membrane filtration, can be useful in increasing the sensitivity of detection of blood microfilariae.

Adult female worms range in length 6.5 to 8.1 cm and up to 250 mcm wide. No intact male worms have been obtained to date. Microfilariae of M. ozzardi are unsheathed and measure 170 to 240 microns long in stained blood smears. They have a cephalic space that is 2 to 6 microns long with two to three overlapping nuclei and caudal space that is 3 to 8 mcm long with oval terminal nuclei (picture 2).

Serology and other tests — Serologic tests based on crude filarial antigens are positive in M. ozzardi infection but do not distinguish between active or past infection and show cross-reactivity between the different filarial species and with other nematode infections. Consequently, their utility is limited, although a negative result can exclude the possibility of infection.

PCR assays have been developed but are not routinely available outside of research laboratories. Assistance with serologic and other diagnostic tests is available from the United States Centers for Disease Control and Prevention ([email protected]) and the Laboratory of Parasitic Diseases, National Institutes of Health (301-496-5398).

Differential diagnosis — The rash of M. ozzardi infection closely resembles that of onchocerciasis, which, until recently, was coendemic in many areas in Central and South America. With the success of the Onchocerciasis Control Program, however, the only remaining areas endemic for onchocerciasis are in the remote border area between Venezuela and Brazil. (See "Onchocerciasis".)

Most patients present with asymptomatic eosinophilia or nonspecific symptoms, including urticaria and pruritus, which have a broad differential diagnosis. (See "Approach to the patient with unexplained eosinophilia" and "New-onset urticaria".)

Treatment — The treatment of choice for M. ozzardi infection is ivermectin (150 mcg/kg orally). In a randomized trial including more than 40 patients with microfilaremia in Brazil treated with ivermectin or placebo, microfilarial counts on day 3 became undetectable among patients treated with ivermectin in 95 percent of cases; in the placebo group, the average microfilaremia fell from 88 to 25 mf/mL by day 3 [25].

Other antifilarial therapies, including diethylcarbamazine and albendazole [26], appear to be ineffective. Although M. ozzardi does harbor the intracellular endosymbiont Wolbachia [27], there are no published studies of doxycycline or other antibacterial therapies to date.

Prevention — There have been no studies of chemoprophylaxis against M. ozzardi infection. Personal protection measures to limit contact with biting midges and blackflies may have some utility in individual travelers.

MANSONELLA STREPTOCERCA

Epidemiology — M. streptocerca is endemic in the tropical rain forests of western and central Africa, including northern Angola, Cameroon, Central African Republic, Democratic Republic of Congo, Equatorial Guinea, Nigeria, People's Republic of Congo, and western Uganda. The prevalence of M. streptocerca infection is unknown; up to 90 percent of the residents in endemic foci may be infected. Infection of travelers is uncommon but does occur [6]. Nonhuman primates are occasionally infected but do not appear to be a major reservoir of infection.

The life cycle is identical to that of M. perstans (figure 3) except that adult worms reside in the dermis of the upper trunk and shoulder girdle and that microfilariae are found in the skin. The lifespan of the adult worms is unknown. M. streptocerca is transmitted by biting midges (Culicoides).

Clinical manifestations — Most individuals with M. streptocerca infection are asymptomatic. The most common complaint is pruritus, especially over the shoulder girdle and thorax [28]. Dermal thickening, nonanesthetic hypopigmented macules, and bilateral axillary or inguinal lymphadenopathy have been described. Unlike O. volvulus, the adult worms do not form subcutaneous nodules. Eosinophilia is common.

Diagnosis — M. streptocerca infection should be suspected in an individual with an appropriate epidemiologic exposure, pruritus, a macular hypopigmented rash or lymphadenopathy, and/or unexplained eosinophilia. The definitive diagnosis is established by identifying the microfilariae in the skin. Serology may also be useful.

Visualizing organisms — The diagnosis of M. streptocerca infection can be definitively established by detecting microfilariae in skin snips. Reports of adult worms identified in tissue biopsies are extremely few.

Adult worms are approximately 1.7 cm by 50 mcm for males and 2.7 cm by 85 mcm for females. Microfilariae of M. streptocerca are unsheathed, 180 to 240 mcm long, and have a characteristic sharp curve in the posterior end that is reminiscent of a shepherd's crook (picture 3). This unusual feature allows an experienced technician to distinguish M. streptocerca from O. volvulus microfilariae without special staining.

Serology and other tests — Serologic tests based on crude filarial antigens are positive in M. streptocerca infection but do not distinguish between active or past infection and show cross-reactivity between the different filarial species and with other nematode infections. Consequently, their utility is limited, although a negative result can exclude the possibility of infection.

Polymerase chain reaction assays have been developed but are not routinely available outside of research laboratories [29]. Assistance with serologic and other diagnostic tests is available from the United States Centers for Disease Control and Prevention ([email protected]) and the Laboratory of Parasitic Diseases, National Institutes of Health (301-496-5398).

Differential diagnosis — The pruritic rash of M. streptocerca resembles that of onchocerciasis, which is coendemic in many parts of Africa. Nonpruritic hypopigmented lesions seen in onchocerciasis (leopard skin) are smaller than the hypopigmented macules in M. streptocerca infection. Other diseases that must be distinguished include leprosy and tinea. As with the other Mansonella infections, most patients are asymptomatic and are detected incidentally because of eosinophilia. (See "Onchocerciasis" and "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Dermatophyte (tinea) infections" and "Approach to the patient with unexplained eosinophilia".)

Treatment — Diethylcarbamazine (DEC; 6 mg/kg/day for 12 days) is effective for the treatment of M. streptocerca infection and kills both microfilariae and the adult worms, although treatment can be accompanied by exacerbation of clinical symptoms including pruritus, papular eruptions, arthralgias, fever, myalgias, headache, nausea, and vomiting. Furthermore, DEC should not be administered to patients for whom concomitant onchocerciasis cannot be excluded, due to the provocation of serious side effects, including exacerbation of ocular disease. Ivermectin (150 mcg/kg as a single dose) is useful in reducing microfilarial loads [30], although the clinical effects of ivermectin in streptocerciasis are unknown. Neither the presence of Wolbachia nor the utility of doxycycline in the treatment of M. streptocerca have been explored to date.

Prevention — There have been no studies of chemoprophylaxis against M. streptocerca infection. Personal protection measures to limit contact with biting midges may have some utility in individual travelers.

SUMMARY

●There are three species of Mansonella that cause human infections: M. streptocerca, M. perstans, and M. ozzardi. A potential fourth species, Mansonella spp "DEUX" has been described in Gabon. Mansonella infections are frequently asymptomatic but may complicate diagnosis and treatment of other human filarial infections that overlap in geographic distribution and clinical manifestations. (See 'Introduction' above.)

●The epidemiology, clinical manifestations, diagnosis, and treatment vary between Mansonella species and are outlined in the table (table 1A-B). (See 'Mansonella perstans' above and 'Mansonella ozzardi' above and 'Mansonella streptocerca' above.)