28 Multisystem zoonoses
In these infections, a non-human vertebrate host is the reservoir of infection and humans are involved only incidentally. The human infection follows contact with or ingestion of infective material passed by an infected host, but is not essential for the microbe’s life cycle, or for its maintenance in nature. One striking feature of zoonotic infections, and of the arthropod-borne infections described in Chapter 27, is that few are transmitted effectively from human to human.
Sometimes, however, the zoonotic origin of these infections is less clear. For example, tularaemia can be acquired either by direct contact with the reservoir host or from an arthropod vector, and is included in this chapter. Plague is included because it is transmitted from infected rats via the rat flea, although it is also transmissible directly from human to human.
Other zoonoses are dealt with in their relevant chapters (e.g. toxoplasmosis in Chs 23–25, rabies in Ch. 24, salmonellosis in Ch. 22).
Many zoonoses are caused by enveloped single-stranded RNA viruses with a genome consisting of two RNA segments called arenaviruses. On electron microscopy (Fig. 28.1) these pleomorphic virus particles with a diameter of 50–300 nm can be seen to contain ribosomes that have a sand-like granular appearance, giving rise to the name arena (Latin: arena, sand). Arenaviruses are carried by various species of rodent in which they cause a harmless lifelong infection with continuous excretion of virus in urine and faeces of apparently healthy infected animals. Humans may become infected via direct contact with infected rodents, inhalation of infectious excreta, working in agricultural environments or trekking in areas where the rodents exist, and may develop severe and often lethal disease involving extensive haemorrhaging and multiorgan involvement. A selection of arenaviruses and the diseases they cause are included in Table 28.1. Since 2007, nine new arenaviruses have been identified, some as a result of recombination events within one segment. They are divided into the Old and New World groups, of which the Old World viruses, Lassa fever and lymphocytic choriomeningitis virus (LCMV), are associated with the most common human infections involving this family. The distribution of the host is concordant with the distribution of the virus. LCMV is the only arenavirus with a worldwide distribution, the rest being seen in Africa or the New World. Of the New World Tacaribe serocomplex viruses, serious illness is associated with the Junin and Machupo viruses that cause Argentine and Bolivian haemorrhagic fevers, respectively. LCMV can cause acute central nervous system disease. As with most zoonoses, infection is not transmitted, or is transmitted with low efficiency, from human to human. However, healthcare workers have been infected by direct contact with blood or secretions from patients infected with Lassa fever virus, but this can be prevented by using barrier nursing techniques.
(Courtesy of K. Mannweiler and F. Lehmann-Grübe.)
Prevention of infection by reducing exposure to the virus concerned was dramatically illustrated when rodent trapping terminated outbreaks of Bolivian haemorrhagic fever (Box 28.1). Treatment with the antiviral agent ribavirin has been successful if used early in Lassa fever infection. Post-exposure prophylaxis with oral ribavirin has been used. There are no World Health Organization-approved vaccines against arenaviruses. However, a live attenuated Junin virus vaccine was licensed in 2006 for use only in Argentina.
Box 28.1 Lessons in microbiology
In 1962, there was an outbreak of a severe and often lethal infectious disease in the small town of San Joachim, Bolivia. Patients developed fever, myalgia and an enanthem (internal rash), followed by capillary leakage, haemorrhage, shock and a neurologic illness. This disease was termed ‘Bolivian haemorrhagic fever’ and had a mortality rate of 15%. Extensive investigations failed to incriminate an arthropod vector, but the evidence pointed to a role for mice in the epidemic. Acting on this possibility, hundreds of mouse traps were airlifted to the beleaguered town, and it was soon shown that trapping mice had a dramatic effect on the incidence of the disease. The epidemic was completely halted. Quite separately, a virus was isolated from the tissues of a trapped local bush mouse (Calomys callosus). The virus was shown to cause a harmless lifelong infection in this animal, with continued excretion of virus in urine and faeces. The virus (given the name ‘Machupo’) was an arenavirus, a group that includes lymphocytic choriomeningitis (LCM) virus (infecting mice and hamsters) and Lassa fever virus (infecting an African bush rat). These viruses cause a harmless, persistent infection in the natural rodent host, but an often severe disease in humans exposed to infected animals.
This outbreak of Bolivian haemorrhagic fever provided an important lesson in ecology. Because of the high incidence of malaria in the San Joachim area, extensive DDT spraying had been carried out to control mosquitoes. As a result, geckos (small lizards that eat insects) accumulated DDT in their tissues and the local cats that preyed on geckos began to die with lethal concentrations of DDT in their livers. The shortage of cats, in turn, allowed the bush mice to invade human dwellings. The close vicinity of infected mice to humans and human food led to the epidemic (Fig. 28.2).
Infection arising from human exposure to infected rats, Mastomys natalensis, or their urine results in a febrile disease, which is generally not very severe. Viral entry into host cells is directed by a fusion glycoprotein sited in the viral outer lipid envelope. The cellular receptor for Lassa fever and certain other arenaviruses is α-dystroglycan, a membrane protein found in the mast cells, that anchors the cytoskeleton and the extracellular matrix. There are about 300 000 cases with 5000 deaths/year, and Lassa fever is the commonest febrile illness in hospitals in parts of Sierra Leone. Transfer of virus from hospital patient to healthcare worker via blood or tissue fluids can result in a more severe illness with high mortality. This involves haemorrhage, capillary damage, haemoconcentration and collapse, and was seen when the disease was first recognized in Americans in the village of Lassa in 1969. However, person-to-person transmission via droplet spread is thought to be rare. The usual incubation period is 5–10 days.
Outbreaks have been reported in Central Africa, Liberia, Nigeria and Sierra Leone. An outbreak in Sierra Leone, from January 1996 to April 1997, involved 823 cases with a mortality rate of 19%. The incubation period would allow an infected individual to carry the disease anywhere in the world and, indeed, there have been cases imported into Europe and the USA. Therefore, Lassa fever must be considered in travellers from these endemic areas with fevers of unknown origin.
Lymphocytic choriomeningitis (LCM) has caused sporadic infection in people living in mouse-infested dwellings, and has been reported in children possessing apparently healthy, but infected hamsters. There is generally a non-specific febrile illness, but occasionally an aseptic lymphocytic meningitis occurs, with recovery.
The Hantaan and Seoul viruses are bunyaviruses that causes a harmless persistent infection in various species of mice and rats. They differ from other bunyaviruses as the latter are transmitted by arthropod vectors. After exposure to the urine of infected animals, there is a febrile illness, often with hypotension, haemorrhage and a renal syndrome. Many American soldiers suffered severe infections in Korea, and a milder disease is seen in Eastern Europe and Scandinavia. Related viruses are present in mice and rats in the USA, and outbreaks in the southwestern USA caused 26 deaths with severe pulmonary disease. The latter is called hantavirus cardiopulmonary syndrome and has been reported in the Americas as a result of Sin Nombre virus infection. In Europe, Puumala virus causes a mild form of HFRS known as nephropathia epidemica. Laboratory diagnosis is by molecular and serological methods detecting viral RNA or specific IgM or IgG antibody, respectively.
Marburg and Ebola haemorrhagic fevers occur in central and east Africa and are caused by filoviruses, long filamentous single-stranded RNA viruses. Patients develop fever, haemorrhage, rash and disseminated intravascular coagulation (see Ch. 17). There is no specific treatment and no vaccine for either virus. The reservoir of origin and natural cycle of maintenance for Marburg virus was not known until Marburg virus RNA was detected in cave-dwelling fruit bats after a small outbreak of Marburg haemorrhagic fever was seen in some miners in Uganda in 2007. A fruit bat reservoir was also found for the Zaire Ebola virus, one of five Ebola virus species.
Infection with Marburg virus was first recognized in 1967 in Marburg, Germany, after exposure of laboratory workers to infected African green monkeys from Uganda. However, these monkeys are not the natural hosts. Mortality was about 20% and, as with Ebola virus infection, it was noted that the virus could be detected in semen for months after clinical recovery; one patient transmitted the infection to his wife by this route.
Outbreaks of a similar disease occurred in 1976 in southern Sudan and in the region of the Ebola River in Zaire (now Democratic Republic of the Congo). Overall, there were 602 cases and 397 deaths. Person-to-person transmission took place in local hospitals via contaminated syringes and needles, burial preparations and, rarely, sexual contact. The virus enters through mucous membranes or abraded skin. Infection does not occur through aerosol transmission. In 1989, monkeys infected with a similar virus were inadvertently imported into the USA from the Philippines. A number of the monkeys died but, although at least four people were infected, none developed disease. In 2004–2005, there was a large outbreak in Angola with a high mortality rate.
A large epidemic was seen in Kikwit, Zaire, in 1995, with 315 cases and 244 deaths. Gabon had three epidemics between 1994 and 1997 and the disease appeared in northern Uganda in 2000. A major outbreak in Congo-Brazzaville in 2003 claimed more than 100 lives, also killing many gorillas and chimpanzees.
Ecological niche modelling models have been used to predict where one might expect to find these filovirus infections. Interestingly, Ebola mapped to the broadleaf tropical rainforest and humid areas in equatorial Central Africa and parts of West Africa (although Angola did not fit this model). Marburg, however, mapped to the opposite, drier, more open areas away from the equator. In these models, bats were thought to be the potential reservoir hosts. Subsequently, tropical rain forest fruit bats were identified as the Ebola virus reservoir.
Crimean–Congo haemorrhagic fever (CCHF), a severe haemorrhagic fever, with shock and disseminated intravascular coagulation, was described clinically during a large outbreak in the Crimea, part of the former Soviet Union, in 1944. The CCHF virus of the Bunyaviridae family, Nairovirus genus, was identified in 1967 and has a wide geographic range, including Africa, Asia, Central and Eastern Europe and the Middle East. It is transmitted by the bite of Ixodid ticks (both reservoir and vector), by contact with infected animals or person to person by exposure to infected body fluids including blood. A number of nosocomial outbreaks have been reported around the world. Although mortality rates of up to 80% have been reported, supportive management and the use of ribavirin have been shown to be effective.
The disease Q fever was first recognized in Australia in 1935, but the cause was unknown for several years – hence Q (‘query’) fever. The causative rickettsia, Coxiella burnetii, differs from other rickettsiae (see Ch. 27) in the following ways:
C. burnetii can infect many species of wild and domestic animals. In many countries (e.g. USA) infection of livestock is quite common, but there are few human cases (132 reported in 2008 in the USA). Large seasonal Q fever outbreaks occurred in the Netherlands between 2007–2009. Infected dairy goat farms were the source of infection. More than 3500 human infections were notified over that time period. The southern part of the Netherlands was most affected, with >12% of the population found to have C. burnetii antibodies. People who come into contact with infected animals, especially their placentas (e.g. veterinarians, farmers, abattoir workers) are at risk from aerosolized organisms. Unpasteurized milk, tissue fluids and dust from infected stock can also transmit the disease.
After inhalation, the microbe multiplies in the terminal airways of the lung, and about 3 weeks later the patient develops fever, severe headache, and often respiratory symptoms and an atypical pneumonia. The rickettsia can also spread to the liver, commonly causing hepatitis. Recovery is usually complete in 2 weeks, but the disease can become chronic. The heart is then sometimes involved (endocarditis), with thrombocytopenia and purpura in some patients, and this condition is fatal if untreated.
Polymerase chain reaction (PCR) can be used to determine whether a patient has Q fever; however, the sensitivity of this approach decreases after the first week of illness. C. burnetti cannot be detected in blood cultures and cannot be isolated by culture except in specialized laboratories. Thus, serological diagnosis is important. A fourfold or greater rise in complement fixing antibody titre is significant. There are two antigenic forms of the rickettsial lipopolysaccharide (LPS): phase 1 and phase 2. Increased antibody to phase 2 compared to phase 1 is seen in acute Q fever, while the reverse (higher antibody titres to phase 1 than phase 2) is seen in chronic disease. Definitive serological confirmation of acute Q fever is demonstrated by a fourfold increase in antibody titres measured by indirect immunofluorescence assay (IFA). The Weil–Felix test (see Ch. 27) is not used.
Acute infection is treated with oral tetracyclines; chronic infections may require drug combinations such as rifampin and doxycycline or trimethoprim-sulphamethoxazole. A killed vaccine is available for those at risk. The rickettsiae are destroyed when milk is pasteurized.
Bacillus anthracis is a large Gram-positive rod and is aerobic and non-motile. Most members of the genus Bacillus are harmless saprophytes, present in soil, water, air and vegetation. Bacillus cereus is a cause of food poisoning, but B. anthracis is the principal pathogen and is unique in having an antiphagocytic capsule made of D-glutamic acid. It forms spores, which survive for years in soil.
Anthrax is a disease of herbivores such as sheep, goats, cattle and horses, and bacilli are excreted in faeces, urine and saliva. Humans are relatively resistant, infection occurring following direct contact with infected animals, or by contact with spores present in animal products. The spores can enter the body via the skin and mucous membranes or, less commonly, via the respiratory tract. In resource-rich countries, where animal infection is now uncommon, human infection is rare and has been due to exposure to contaminated imported goods such as hides, skin, wool, goat hair and bristles, bones and bone-meal in fertilizers. Spores have also been used in bioterrorism.
B. anthracis spores germinate in tissues at the site of entry. The bacteria then multiply and produce the anthrax toxin, which consists of a protective antigen, an oedema factor (an adenylate cyclase) and a lethal factor; all are plasmid-coded. Toxic activity requires the protective antigen and at least one of the other two. Host defences are inhibited by the antiphagocytic capsule surrounding the bacillus (see Ch. 14).
The skin is the usual site of entry. As the toxic material accumulates, there is oedema and congestion, and a papule develops within 12–36 h. The papule ulcerates, the centre becoming black and necrotic to form an eschar or ‘malignant pustule’ (although there is no pus) which is painless and is often surrounded by a ring of vesicles (Fig. 28.3). The bacilli spread to the lymphatics and in about 10% of cases reach the blood to cause septicaemia. Continued multiplication and production of the toxin causes generalized toxic effects, oedema and death.