Table Viii

Anopheles Vectors of Human Malaria Parasites in 12 Epidemiologic Zones: Subgenera, Species, and Geographic Distributions are Given

Malaria epidemiologic Zone

Anopheles vectors

North American

Subgenus Anopheles: freeborni, punctipennis, quadrimaculatus Subgenus Nyssorhynchus: albimanus

Central American

Subgenus Anopheles: azteeus, pseudopunctipennis, punctimacula,

Subgenus Nyssorhynchus: albimanus, albitarsis, allopha, aquasalis, argyritarsis, darlingi

South American

Subgenus Anopheles: pseudopunctipennis, punctimacula

Subgenus Nyssorhynchus: albimanus, albitarsis, aquasalis, argyritarsis, braziliensis, darlingi, nuneztovari Subgenus Kerteszia: bellator, cruzii

North Eurasian

Subgenus Anopheles: atroparvus, messeae, sacharovi, sinensis Subgenus Cellia: pattoni


Subgenus Anopheles: atroparvus, claviger, labranchiae, messeae, sacharovi Subgenus Cellia: hispaniola, pattoni


Subgenus Cellia: hispaniola, multicolor, pharoensis, sergentii


Subgenus Cellia: arabiensis, christyi, funestus, gambiae, melas, merus, moucheti, nili, pharoensis,


Subgenus Anopheles: sacharovi

Subgenus Cellia: annularis, culicifacies, fluviatilis, pulcherrimus, stephensi, superpictus, tesselatus

Indo-Chinese hills

Subgenus Anopheles: nigerrimus

Subgenus Cellia: annularis, culicifacies, dirus, fluviatilis, maculatus, minimus


Subgenus Anopheles: campestris, donaldi, letifer, nigerrimus, whartoni Subgenus Cellia: aconitus, balabacensis, dirus, flavirostris, leucosphyrus, ludlowae, maculatus, minimus, philippinensis, subpictus, sundaicus


Subgenus Anopheles: anthropophagus, sinensis Subgenus Cellia: pattoni


Subgenus Anopheles: bancrofti

Subgenus Cellia: annulipes, farauti, karwari, koliensis, punctulatus, subpictus

Modified from Macdonald, 1957, and others.

Modified from Macdonald, 1957, and others.

liver, symptoms do not appear until days to weeks later (up to a month in P. malariae), when erythrocytic mero-gony begins in the blood. In P. vivax and P. ovale, if the sporozoites develop into hypnozoites in the liver cells, relapses are possible long after inoculation and initial onset of symptoms, with an intervening period of no apparent symptoms of infection. For P. falciparum and P. malariae, there are no persistent exoerythrocytic stages of the parasites, and relapses do not occur. However, infection with P. malariae may recrudesce years after initial infection owing to persistent erythrocytic infections. Therefore, in human malaria there is a clear distinction between relapse and recrudescence of infection. The course of infection of malaria in humans varies with many factors, including history of past exposure; presence of antibodies; age, health, and nutritional status; and genetic resistance factors such as the sickle-cell anemia trait, Duffy-negative blood type, certain hemoglobin types such as hemoglobin S and fetal hemoglobin, and deficiency of the erythrocytic enzyme glucose-6-phospate dehydrogenase.

Mosquito Vectors and Epidemiology

Many different species of Anopheles mosquitoes are competent vectors of malaria organisms (Table VIII). However, most Anopheles species are not, because of variation in host-selection patterns, longevity, abundance, and vector competence. In North America, An. quadrimacula-tus, which forms a complex with four more localized but nearly identical species (Reinert etal., 1997), is the principal vector of malaria in the eastern two-thirds of the continent. It develops along the edges of permanent pools, lakes, and swamps that provide relatively clean, still, sunlit water, with lush emergent vegetation, marginal brush, or floating debris to provide partial shade and protection from wave action. In western North America, An. free-borni is the main vector, an inhabitant of clear water in open, shallow, sunlit pools, ponds, ditches, and seepage areas that are partially shaded by vegetation. An. hermsi also is a vector in California.

Other important vectors include An. albimanus in Central America, An. darlingi in South America,

FIGURE 12.31 Anophelesgambiae female feeding on blood. This is che major vector of malaria in Africa. (Photo by W, A. Foster.)

An.gambiae (Fig. 12.31) and An. funestus in Africa, An. culicifacies in Asia, and An. dirus in Southeast Asia. An. gambiae is considered the most important of all, because of its involvement in such large numbers of malaria cases and deaths, mainly in Africa. This species lives in close association with humans, on which it primarily feeds, and can complete a gonotrophic cycle in only 2 days. During the rainy seasons, larvae develop in a wide variety of sunlit surface pools, many of which are associated with human activity. These include borrow pits, roadside ditches, wheel ruts, and the hoof prints of domestic animals. Larval development normally takes only about 1 week.

Malaria has been viewed in the context of stable or unstable transmission, reflecting in part attributes of Anopheles species that affect their vectorial capacity. These include density, longevity, tendency to feed on humans, and duration of the extrinsic incubation period of the parasite in the vector. Stable malaria is most often associated with P. falciparum infection in highly endemic settings. It is characterized by low fluctuations in parasite incidence in human and vector populations, high prevalence, and high seroprevalence for antibodies. Epidemics are unlikely under these conditions, even though transmission continues at high rates. In such settings, vectors tend to be highly anthropophagic, exhibit greater longevity, and have relatively low, stable densities but still exhibit considerable seasonal variation. Unstable malaria tends to be associated with P. vivax infections in endemic settings of high fluctuation in disease incidence. Vectors tend to be zoophagic, have seasonally profound variation in population densities, have low or nondetectable field infection rates, and may have shorter longevity than do those in stable malaria settings. Epidemics can occur in conditions of unstable malaria if environmental changes favor increased vector—human contact, e.g., during civil strife, following water projects such as dams or irrigation schemes, or when a new vector is introduced into an area.

Historical Perspective

After the development of the germ theory of disease by Louis Pasteur, the French-Algerian physician Charles Louis Alphonse Laveran examined and described malarial organisms in the red blood cells of his patients in 1870. This finding, along with the work of Patrick Manson on filarial nematodes and mosquitoes in China, inspired Ronald Ross, then a physician in British colonial India, to examine the hypothesis of mosquito transmission of malaria parasites in the 1890s. His persistent and careful experimentation and observation with both human and bird malarias, using Anopheles and Culex mosquitoes, respectively, provided conclusive proof that mosquitoes transmit Plasmodium species by bite. In concurrent research, Giovanni Batista Grassi and colleagues demonstrated transmission of P. falciparum by An. maculipennis— complex mosquitoes in the environs of Rome, Italy. Ross was awarded the Nobel Prize for Medicine in 1902.

Malaria was formerly endemic in many temperate areas of the United States, particularly in the South and Southeast. Malaria became epidemic after the Civil War, as malaria-infected soldiers returned to their homes and brought the infection with them to their local communities. Malaria was an important rural disease in the eastern and southern states, California, and other areas of the United States through the 1930s but gradually disappeared by the 1940s. This was due to a combination of antimosquito measures, improved medical care, a higher standard of living, and transformation of marshes and swamps to agricultural land, largely through organized ditching efforts. Changes in lifestyle because of technological advances such as window screens and the invention of the radio, television, and air conditioning also contributed to the decline in malaria. Boyd (1941) reviewed the history of malaria in the United States and, to a brief degree, elsewhere in the New World.

Roughly 1000 cases of malaria are introduced into the United States each year. In addition, cases involving local or indigenous transmission occur sporadically, including recent outbreaks in California (1988, 1989, 1990), Florida (1990, 1996), Michigan (1995), New Jersey (1993), New York (1993), and Texas (1995). These incidents were due to introductions of infected humans into areas with competent Anopheles vectors. However, airport malaria has occurred near major international airports (e.g., London—Heathrow and Paris-DeGaulle) where infected mosquitoes have been imported on aircraft from endemic regions.

FIGURE 12.33 Geographic distribution of human lymphatic filariasis caused by Brujjia malayi and B. timori. (Reconstructed from Strickland, 1991, and other sources.)

(principally Brazil, Surinam, and French Guyana), the Dominican Republic, and Haiti; southern and eastern India, southeastern Asia, eastern China, and southern Japan; the Malay archipelago, Indonesia, the Philippines, Irian Jaya, and Papua New Guinea; and many island groups of the south Pacific Ocean, including Melanesia, Micronesia, and Polynesia. Within the United States, fi-lariasis was locally endemic in Charleston, SC, but the disease disappeared there in the late 1930s. It disappeared at about the same time from northern Australia. It no longer occurs in regions of the Mediterranean basin and on the Arabian Peninsula. Recently, however, incidence of lymphatic filariasis has increased in the Nile River Delta of Egypt.

Within the area of current distribution, there are an estimated 905 million people at risk of contracting lymphatic filariasis, and there are some 128 million active infections. Of these, about 115 million are caused by W. bancrofti, the causative agent of Bancroftian filariasis, which is widespread in both the Old World and New World tropics (Fig. 12.32). Another 13 million cases are caused by B. malayi, the causative agent of Brugian filariasis or Malayan filariasis, which is restricted to southeastern Asia (Fig. 12.33). About 43 million people have chronic symptoms of elephantiasis, hydrocele, or lymphedema (see below). Another Brugian filariasis, Timorian filariasis, is caused by infection with B. timori and occurs in localized foci among southern islands of Indonesia.

Infection with filarial nematodes in humans begins when infective third-stage larvae enter the skin at the site of the mosquito bite, molt twice, and migrate to the lymphatic vessels and lymph nodes, particularly of the lower abdomen. There, the nematodes develop to the adult stage. Female worms (80-100 mm long at maturity for W. bancrofti and about half of that length for B. malayi) release active, immature worms called microfilariae into the peripheral circulatory system. A female may release 50,000 or more microfilariae each day. Microfilariae of W. bancrofti are 250-300 /xm long and about 7—9 /zm wide; those of B. malayi are somewhat shorter and thinner. Presence of microfilariae in the blood is called microfilaremia and first appears about 6 months to 1 year after adult worms become established in the lymphatic system. An infected human may be microfilaremic for more than 10 years. The density of microfilariae in peripheral blood is highly variable, but it can range from 1 to over 500 microfilariae per 20 mm3.

The appearance of microfilariae in the peripheral blood has a 24-hr cycle; i.e., they exhibit diel periodicity. If microfilariae completely disappear from the peripheral circulation at some time during the day, they are said to be periodic. If the microfilariae fluctuate in density during a 24-hr period but are detectable at all times, they are said to be subperiodic. In most areas, the microfilariae appear only at night and are transmitted by mosquitoes that have night-biting habits. These are the noctur-nally periodic forms of W. bancrofti and B. malayi. Both W. bancrofti and B. malayi also have nocturnally subperiodic and diurnally subperiodic forms, although nocturnally subperiodic bancroftian and diurnally subperiodic Brugian forms have very restricted distributions. In all the subperiodic forms, the microfilariae appear in the peripheral blood of the human host mainly in the evening and night (nocturnally subperiodic) or mainly during the daytime (diurnally subperiodic). These nematodes are associated with two or more species of mosquito vectors, which differ in their typical biting times and whose combined diel patterns of man-biting density are matched by the periodicity of microfilariae. Both nocturnally periodic W. bancrofti and nocturnally periodic B. malayi are now considered to be strictly human pathogens. However, B. malayi in its subperiodic form is a zoonosis, with both leaf monkeys and humans as reservoirs, and with domestic cats and other carnivores also implicated as hosts. B. timori is nocturnally periodic and has no animal reservoir.

Development of W. bancrofti and B. malayi in mosquitoes is similar. Microfilariae ingested with the mosquito blood meal usually shed their outer, sheath-like membrane as they penetrate through the midgut epithelium. Some microfilariae retain the sheath during penetration. The microfilariae move to the indirect flight muscles of the thorax, penetrate individual cells, and transform to a short sausage stage, the L\ or first-stage larva. They molt to more slender Li, or second-stage, larvae and then again to the elongate, filariform L3, or third-stage, infective larvae (about 1.5 mm long). These larvae leave the thoracic flight muscles, traverse the hemocoel of the mosquito, enter the lumen of the mouthparts, and eventually arrive at the apex of the proboscis. When the mosquito blood-feeds, the L3 larvae exit through the cuticle of the labium, crawl onto the skin, and enter through the hole made by the mosquito during feeding. Therefore, technically the transmission method may be said to be contaminative, rather than inoculative. Heavy infections of larval nematodes can be fatal to the mosquito.

Many species of mosquitoes are refractory to filarial development, owing to genetic factors and to their ability to mount adequate immune responses, whereas other species are susceptible to parasite infection and support the development described above. The relationships between W. bancrofti and certain mosquito species exhibit evidence of local adaptation. For example, in West Africa, Cx. quinquefasciatus is not a competent vector of

Filarial Life Cycle

W. bancrofti, whereas Anopheles gambiae is competent there. By contrast, in India, Cx. quinquefasciatus is a competent vector and most Anopheles species are not. Thus, there is geographic variation in susceptibility of mosquitoes to filarial nematodes.

Clinical Disease

Generally, a case of human infection does not occur after the bite of a single, infective mosquito. Rather, it results after accumulation of hundreds to thousands of such infective bites, under conditions in which there is a high probability of parasite maturation and mating. Humans may show disease symptoms without having microfilaremia, or they may have microfilaremia without showing signs of disease. Lymphatic filariasis has both acute and chronic manifestations in the human host. The disease may cause chronic debilitation in untreated cases. Acute lymphatic filariasis is characterized by episodes of fever, swelling, pain, and inflammation in the affected lymph nodes and lymph vessels, a condition called ade-nolymphangitis. The episodes may last for several days and incapacitate the affected individual because of the local and systemic effects. Over time, deep abscesses may develop at the sites of inflammation. Dermal ulcers may form through the skin over these sites, and secondary bacterial infection may ensue.

In the chronic phase, which often occurs years after onset of acute symptoms, the pathology may involve accumulation of lymphatic fluid (lymphedema) in the limbs, breasts, vulva, and scrotum, resulting in swelling and enlargement. In the scrotum, this condition is termed hydrocele. The grotesque distentions and thickening, folding, and nodulation of the skin, notably the lower limbs, is a condition called elephantiasis. Bacterial and fungal infections at affected sites exacerbate these conditions. Appearance of lymph fluid in urine may occur as a consequence of the disruption of the abdominal lymphatic vessels and leakage of lymph fluid into the urinary tract, causing urine to appear whitish, a condition called chyluria. In contrast with W. bancrofti, infection with B. malayi is not associated with scrotal distension, but rather involves only the limbs. Hypersensitivity to parasite-associated antigens also may be part of the syndrome of lymphatic filariasis. It is mediated through elevated immunoglobulin antibodies IgE and IgG4 and is characterized by increased production of eosinophils, coughing, and shortness of breath. This type of filarial disease is called tropical eosinophilia.

Lymphatic filariasis has important social implications in communities where it is endemic. Acutely affected individuals are often feverish and in pain, and they may have difficulty working and thus suffer economic loss. Hard work may bring on attacks of filarial fever, which require rest for recovery. In a study conducted in Ghana, West Africa, the episodes of acute adenolymphangitis lasted about 5 days, with 3 days of incapacitation, and occurred during those months of the year when peak agricultural work was required and when mosquito transmission of infective stage larvae was highest (Gyapong et al., 1996). It is likely that chronically infected individuals are immunologically sensitized to their worm infections, and exposure to new L3 larvae results in hypersensitive reactions such as adenitis. Chronically affected individuals with symptoms of scrotal hydrocele and elephantiasis may have difficulty in their social and personal lives and may suffer incontinence and impotence. Although hydrocele can be treated through fluid aspiration from the scrotum, the gross distention of elephantiasis is more difficult to remedy even with surgery.

Mosquito Vectors and Epidemiology

The filarial nematodes that cause lymphatic filariasis have evolved associations with mosquitoes in the genera Culex, Mansonia, Aedes, Ochlerotatus, and Anopheles (Table IX). This probably has occurred through a process of adaptive radiation from the original Anopheles vectors in Southeast Asia. A very likely scenario for W. bancrofti is that it arose as a human pathogen in forested regions of Indonesia and perhaps other parts of Southeast Asia, where the An. umbrosus group of mosquitoes serves as vectors of W. kalimantani. This filarioid nematode is a parasite of leaf monkeys (also called brow-ridged langurs), Presbytis cristata. Similarly, B. malayi infection in humans probably evolved from subperiodic B. malayi infections in leaf monkeys (Presbytis spp.), with An. hyr-canus as the vector. Human infection and new disease foci probably arose in forests and along forest ecotones with these same Anophelesvtctors. Through time, as people developed agricultural systems and migrated to other regions, both W. bancrofti and B. malayi adapted to these new settings and the competent mosquito vectors there. In some parts of Southeast Asia, members of the Ochlerotatus niveus group are important vectors of the subperiodic form of W. bancrofti, including Oc. niveus in Thailand; this system may have been the origin of the sub-periodic strains that radiated to the Pacific regions.

Transmission of W. bancrofti occurs in both urban and rural areas. The primary mosquito vector in urban areas is Cx. quinquefasciatus. It is the most important vector of nocturnally periodic W. bancrofti in the Americas and parts of Africa and Asia, particularly India. It feeds opportunistically at night on both mammals and birds. This mosquito occurs abundantly in areas with poor sanitation, open sewers, untreated waste water, and pit latrines, which provide the high organic content and low oxygen characteristic of the larval habitat. For this reason,

Mosquito Vectors of Filarioid Nematodes of Humans: Geographic Distribution and Associations with Periodicity of Microfilaremia


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