In sparsely populated areas, transmission by insects is an effective means of spread

Disease transmission by insects has major implications for the host, the vector and the parasite. To consider the parasite first, it requires the organism to be present in the right place (in the blood) and at the right time (some insects, for example, bite only at night). Blood is an inhospitable environment, and this may require quite subtle evasion mechanisms for parasite survival. In addition, the conditions found in the vector are likely to be very different from those in the human host, and the parasite may have to make a remarkably complex transition in a short time. With the larger protozoal and helminth parasites, this transition often involves clearly visible changes in appearance and is responsible for much of the complicated nomenclature of parasite life cycles. Since some insect vectors have lifespans hardly longer than those of their parasites, there is considerable wastage due to death of the vector before the parasite has matured to the infective stage for humans. A difference of a few days in a mosquito’s lifespan can make an enormous difference to the effectiveness of malaria transmission, and indeed this simple factor is believed to underlie much of the difference between the African pattern of endemic infection and the Indian pattern of sporadic epidemics. However, what may be lost from wastage is more than compensated for by the increased distances over which spread of the parasite can occur.

Vector transmission of disease means that the disease may be controlled by controlling the vector and is, for instance, a major reason why malaria is not endemic in many European countries, where it used to be common.

A potential advantage of this type of transmission for the host is that it is sometimes possible to immunize specifically against the stages infective to humans or those responsible for infecting the vector transmission stages of the parasite. Again, malaria can serve as an example – vaccines against the sporozoites, gametocytes and gametes having been clearly shown to block transmission in animal models. Once transmission is blocked, there is a mathematically calculable possibility that the disease will die out. A vaccine against sporozoites has shown promising activity in protecting African children from falciparum malaria.

Arboviruses are arthropod-borne viruses

A wide range of about 500 different viruses is transmitted by arthropods such as ticks, mosquitoes and sandflies. These arboviruses multiply in the arthropod vector, and for each virus there is a natural cycle involving vertebrates (various birds or mammals) and arthropods. The virus enters the arthropod when the latter takes a blood meal from the infected vertebrate, and passes through the gut wall to reach the salivary gland where replication takes place. Once this has occurred, 1–2    weeks after ingesting the virus, the arthropod becomes infectious, and can transmit the virus to another vertebrate during a blood meal. Certain arboviruses that infect ticks are also transmitted directly from adult tick to egg (transovarial transmission), so that future generations of ticks are infected without the need for a vertebrate host.

Only a small number of arboviruses are important causes of human disease

Arboviruses tend to replicate in vascular endothelium, the central nervous system (CNS), skin and muscle, and are therefore multisystem infections. They are generally named after the clinical disease (e.g. yellow fever) or the place where they were first discovered (e.g. Rift Valley fever, Japanese encephalitis). A few (e.g. Ross River virus in Australia and the Pacific and Chikungunya virus in Africa and Asia) cause arthritis.

The human stage of the virus cycle may be essential (urban yellow fever, dengue), there being no other vertebrate host, or it may be ‘accidental’ from the virus’s point of view, with humans acting as ‘dead end’ hosts who do not form a necessary part of the natural cycle (e.g. equine encephalitides, West Nile virus).

Yellow fever virus is transmitted by mosquitoes and is restricted to Africa, Central and South America and the Caribbean

Yellow fever virus is a flavivirus, and there is only one antigenic type. It was taken to the Americas by the early slave traders, and the first recorded case was in Yucatan in 1640. Yellow fever virus is transmitted by two different cycles:

Yellow fever is not transmitted directly from human to human by day-to-day contact, but transmission from ill patients to healthcare workers has been reported, notably after needlestick injury.

Clinical features of yellow fever may be mild, but in 10% to 20% of cases classic yellow fever with liver damage occurs, which can prove fatal

The virus enters dermal tissues or blood vessels at the site of a mosquito bite and spreads through the body, infecting vascular endothelium and liver. After an incubation period of 3–6    days, there is a sudden onset of fever, headache and muscular aches. Although mild cases occur, prostration and shock are not uncommon, and severe liver damage may result in death. Coagulation defects (largely due to prothrombin deficiency) cause haemorrhage into the gastrointestinal tract (manifest as haematemesis and melena) and elsewhere. Renal damage is also seen, with proteinuria and occasionally tubular necrosis. The case mortality rate is in the range of 5–50%.

The diagnosis is usually clinical; there is no specific treatment, but there is a vaccine

The virus can be isolated from blood during the acute stage, and a post-mortem diagnosis can be made from the severe mid-zonal changes and acidophilic inclusion bodies seen in the liver. Virus-specific IgM antibodies are detectable after a week.

The best prevention is to give the live attenuated 17D yellow fever vaccine to those who may be exposed. Protection lasts at least 10    years, and vaccination is necessary for entry into and travel through endemic areas. The international health regulations permit a state to require a valid certificate of vaccination from a traveller from an endemic area to another country where the right mosquitoes are present but the disease does not occur (e.g. from tropical Africa to India). Vaccines based on recombinant DNA technology have been developed. As with all arthropod-borne infections, control of arthropod vectors (insecticides, attention to breeding sites) and reduced exposure (insect repellents, mosquito nets) are also important.

Dengue virus is transmitted by mosquitoes and occurs in SE Asia, the Pacific area, India, South and Central America

Dengue is one of the most rapidly re-emerging arbovirus diseases, with between 50 and 100 million cases each year. Dengue virus is a flavivirus with four antigenic subtypes. The mosquito A. aegypti is the principal human vector. The virus also circulates in monkeys and can be transmitted by mosquitoes to cause ‘jungle’ dengue in humans, a disease analogous to jungle yellow fever.

Dengue fever may be complicated by dengue haemorrhagic fever/dengue shock syndrome

Dengue virus replicates in monocytes and possibly in vascular endothelium. After an incubation period of 4–8    days, there is malaise, fever, headache, arthralgia, nausea and vomiting, and sometimes a maculopapular or erythematous rash. Recovery may be followed by prolonged fatigue and/or depression.

Dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS) is a particularly severe form of the disease. In the past, mortality rates were high, but with prompt access to expert hospital care, a fatality rate of below 1% can be achieved. The pathogenesis of this syndrome is shown in Figure 27.1. After an earlier attack of dengue, antibodies are formed that are specific for that serotype. On subsequent infection with a different serotype, the antibodies bind to the virus and not only fail to neutralize it (as might be expected for a different subtype), but actually enhance its ability to infect monocytes. The Fc portion of the virus-bound immunoglobulin molecule attaches to Fc receptors on monocytes, and entry into the cell by this route increases the efficiency of infection. Infection of increased numbers of monocytes results in an increased release of cytokines into the circulation (see Ch. 17) and this leads to vascular damage, shock and haemorrhage, especially into the gastrointestinal tract and skin. Similar ‘enhancing’ antibodies are formed in many other virus infections, but it is only in dengue haemorrhagic fever that they are known to play a pathogenic role. A number of other factors can influence the course of dengue infection, including age and dengue virus strain virulence.

Figure 27.1 The pathogenesis of dengue haemorrhagic shock syndrome. There are four serotypes of dengue virus. Types 1 and 2 are illustrated as examples. Antibody to type 1 binds to type 2 without preventing infection with type 2.

There is no antiviral therapy for dengue fever. Treatment is supportive. The World Health Organization has published a revised dengue case classification based on the presence or absence of warning signs in order to improve patient care (see bibliography).

There is no currently licensed dengue vaccine. A suitable vaccine must be tetravalent to avoid the danger that a vaccine could induce the type of antibody associated with DHF/DSS. Candidate live attenuated tetravalent vaccines are undergoing field testing.

The encephalitic arboviruses only occasionally cause encephalitis

Six of the ten encephalitic arboviruses listed in Table 27.1 cause disease in the USA, and although most infections are subclinical or mild, fatal encephalitis can occur. The viruses replicate in the CNS, but a cell-mediated immune response to infection makes a major contribution to the encephalitis. Vaccines against Western equine encephalitis (WEE), Eastern equine encephalitis (EEE) and Venezuelan equine encephalitis (VEE), each of which may cause disease in horses, have been used for laboratory workers. A Japanese encephalitis vaccine is also available and is used in the UK for the occasional at-risk traveller. Laboratory diagnosis is carried out in special centres, occasionally by virus isolation, but more commonly by demonstrating a rise in specific antibody.

Table 27.1 Arboviruses causing encephalitis

Prior to the mid-1990s, West Nile virus, which is transmitted from infected birds by Culex mosquitoes and for which humans are considered to be dead-end hosts, was not considered a major public health problem, but viral changes then resulted in cases with severe neurologic disease. The virus, which had not previously been reported from the Western hemisphere, was recorded in New York in 1999 and since then has spread widely in the USA, Canada, Mexico and the Caribbean. In 2006, the CDC reported a total of more than 1500 human cases in the USA and more than 150 blood donors with the virus. By 2010, it was reported to have caused more than 25 000 cases, 12 000 of whom had severe neurologic disease with more than 1100 deaths. Quite how the virus crossed the Atlantic is unknown though it has been suggested that it was probably imported in a live bird. Infection is diagnosed clinically (fever    >       38.8°C, neurologic symptoms, elevated CSF cell count and protein, possible muscular weakness) and serologically. Vaccines and immunotherapeutic agents are being developed.

Arboviruses are major causes of fever in endemic areas of the world

Arbovirus infections are often subclinical or mild, but occasionally there is a severe haemorrhagic illness. Some of the best known of these infections are listed in Table 27.2. Laboratory diagnosis by isolation of virus, by detection of viral genome or by demonstration of a rise in antibody is possible in special centres.

Table 27.2 Arboviruses causing fevers and haemorrhagic disease

The rickettsiae are small bacteria and infections tend to be persistent or become latent

Howard T. Ricketts identified ‘Rocky Mountain spotted fever’ in 1906 and showed that it was transmitted transovarially in ticks. Rickettsiae probably arose as parasites of blood-sucking or other arthropods in which they were maintained by vertical transmission, transfer to the arthropod’s vertebrate host being initially ‘accidental’ and not necessary for rickettsial survival. The infected arthropod does not appear to be adversely affected. Rickettsia prowazekii is perhaps a more recent parasite of the human body louse, because the louse dies 1–3    weeks after infection. As with most arthropod-borne infections, transmission from person to person does not occur.

Typical clinical symptoms of rickettsial infection are fever, headache and rash

Rickettsiae multiply in vascular endothelium to cause vasculitis in skin, CNS and liver, and hence are multisystem infections (Table 27.3). In spite of immune responses, there is a tendency for rickettsial infections to persist in the body for long periods or become latent.

Table 27.3 The principal rickettsial diseases in humans

Except for Q fever (caused by Coxiella burnetii), the typical clinical features are fever, headache and rash. A history suggesting contact with rickettsial vectors or reservoir animals may suggest a diagnosis (e.g. camping, working, engaging in military activities in endemic areas).

Laboratory diagnosis is based on serologic tests

Complement fixation tests are specific for different rickettsiae. However, microimmunofluorescence methods are the most common serological approach, and demonstration of a fourfold or greater rise in titre is considered to be a positive result. Infected patients also make antibody to the rickettsiae that cross-react with the O antigen polysaccharide of various strains of Proteus vulgaris, as detected by agglutination in the Weil–Felix test. The agglutination pattern with three strains of Proteus can be used to identify the rickettsiae. Although the phenomenon is of interest, the test is not of great value, because of false-positive and false-negative results. Earlier diagnosis can often be made by fluorescent antibody staining of skin biopsy material. PCR diagnostic tests are now available. Isolation of rickettsiae is difficult and dangerous, and laboratory infections have occurred.

All rickettsiae are susceptible to tetracyclines

Prevention is based on reducing exposure to the vector (e.g. ticks). A killed R. prowazekii vaccine is available for the military, and a killed C. burnetii vaccine is available for those at high risk (e.g. military, veterinarians, etc.) with no demonstrated sensitivity to the antigen.

Rocky Mountain spotted fever is transmitted by dog ticks and has a mortality of up to 10%

The rickettsiae causing this disease are carried by the dog tick (Dermacentor variabilis) or by wood ticks (Dermacentor andersoni) and are transmitted vertically from adult tick to egg. Human infection occurs in the warm months of the year as ticks become active. Children are most commonly infected, but their disease is milder.

The rickettsiae multiply in the skin at the site of the tick bite, then spread to blood and infect vascular endothelium in the lung, spleen, brain and skin. After an incubation period of about 1    week, there is onset of fever, severe headache and myalgia, and often respiratory symptoms. A generalized maculopapular rash appears a few days later, often becoming petechial or purpuric (Fig. 27.3). There is splenomegaly, and neurologic involvement is frequent, with later onset of clotting defects (disseminated intravascular coagulation), shock and death. Fatal cases are usually those with a delayed diagnosis. Peak mortality is seen in 40–60-year-olds.

Figure 27.3 Generalized maculopapular rash with petechiae in Rocky Mountain spotted fever.

(Courtesy of T.F. Sellers, Jr.)

Mediterranean spotted fever is transmitted by dog ticks

Mediterranean spotted fever is caused by Rickettsia conorii, carried by the dog tick Rhipicephalus sanguineus. Human infection, which occurs mainly in October, is known in all Mediterranean countries and can occur in urban as well as rural areas. After an incubation period of about 1    week, 50% of cases develop fever, headache and myalgia, and 2–4    days later a rash, especially on the palms and soles. The bite usually goes unnoticed as it is caused by immature ticks and is painless; a local lesion is not usually seen.

Rickettsialpox is a mild infection

About 5    days after the bite of a rodent-associated mite (Allodermanyssus sanguineus) infected with R. akari, a local eschar develops with fever and headache occurring approximately 1    week later. After a few more days, a generalized papulovesicular rash then appears. The disease is, however, mild and usually lasts for about 1    week.

Epidemic typhus is transmitted by the human body louse

Epidemic typhus is transmitted from person to person by Pediculus humanus. The rickettsiae (R. prowazekii) multiply in the gut epithelium of the louse and are excreted in faeces during the act of biting. The rickettsiae enter the skin when the bite is scratched. The disease cannot maintain itself unless enough people are infested with lice. Epidemic typhus is therefore classically associated with poverty and war, when clothes and bodies are washed less frequently. There were 30 million cases in Eastern Europe and the Soviet Union from 1918 to 1922. The disease is seen in Africa, Central and South America, and sporadically (as a sylvatic form) in the USA. As there is no direct person-to-person spread, outbreaks can be terminated by delousing campaigns.

Untreated epidemic typhus has a mortality as high as 60%

Rickettsiae proliferate at the site of the bite and then spread in the blood to infect vascular endothelium in skin, heart, CNS, muscle and kidney. About 1    week after the louse bite (there is no eschar) the infected person develops fever, headache and flu-like symptoms. The generalized maculopapular rash appears 5–9    days later and sometimes there is severe meningoencephalitis with delirium and coma. In untreated cases, mortality can range from 20% in healthy individuals to as high as 60% in elderly or compromised patients, due to peripheral vascular collapse or secondary bacterial pneumonia.

Convalescence may take months. In some individuals, the rickettsiae are not eliminated from the body on clinical recovery and remain in the lymph nodes. As much as 50    years later, the infection can reactivate to cause Brill–Zinsser disease, and the patient once again acts as a source of infection for any lice that may be present.