D9359.PDF

Rev. sci. tech. Off. int. Epiz., 2001,20 (1), 325-337
Epidemiology of selected mycobacteria that infect
humans and other animals
(1)
m
D.A. Ashford , E. Whitney , P. Raghunathan(1)& 0. Cosivi
|2)
(1) Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for
Infectious Diseases, Centers for Disease Control, MS-C09,1600 Clifton Road, Atlanta, Georgia 30333. United
States of America
(2) W o r l d Health Organization, Animal and Food-related Public Health Risks, Department of Communicable
Disease Surveillance and Response, 20 avenue Appia, CH-1211 Geneva 27, Switzerland
Summary
T h i s paper provides a s u m m a r y of salient clinical and epidemiological f e a t u r e s of
selected mycobacterial diseases that are c o m m o n to humans and other animals.
Clinical and diagnostic issues are discussed and related to estimates of the
incidence and p r e v a l e n c e of these diseases among humans. S o u r c e of infection,
route of transmission and control m e a s u r e s a r e also p r e s e n t e d . T h e
m y c o b a c t e r i a discussed in this paper are Mycobacterium
bovis, M.
ulcerans,
M. leprae and M. avium complex, although this is by no means a complete list of
the m y c o b a c t e r i a c o m m o n to humans and other animals. Certain generalities can
be made regarding these s p e c i e s of m y c o b a c t e r i a and their o c c u r r e n c e in
humans and other animals; firstly, current understanding of the epidemiology and
control of many of the resultant diseases is incomplete; secondly, environmental
s o u r c e s other than animal r e s e r v o i r s m a y play a role in transmission (with
M. leprae perhaps being the exception); and thirdly, the incidence and p r e v a l e n c e
of t h e s e diseases in m a n y countries of the w o r l d are unclear, principally b e c a u s e
of the complexity of diagnosis and lack of reporting s y s t e m s .
Keywords
Diagnosis - Epidemiology - Mycobacterium avium - Mycobacterium bovis
Mycobacterium leprae - Mycobacterium ulcerans - Public health - Zoonoses.
Mycobacterium
bovis
Aetiology, human disease and diagnosis
Mycobacterium
bovis is a member of the M. tuberculosis
complex of mycobacteria, a group of mycobacterial species
that includes M. tuberculosis,
M. bovis, M. afrieanum and
M. microti. A smooth colony variant of M. tuberculosis, named
M. canetti, has been proposed as an additional member of this
complex. The above-mentioned species are slowly growing,
non-photochromogenic acid-fast bacilli ( 8 4 ) . Infection of
humans with any one of these four mycobacteria can result in
the disease termed 'tuberculosis', and regardless of the species
responsible, the resulting disease is indistinguishable
clinically, radiologically and pathologically (108). However,
prior to bovine tuberculosis control programmes, and in areas
of the world in which milk is still the primary vector for
M. bovis, this species was and is more commonly associated
with primary tuberculosis outside the lung (extra-pulmonary
disease) ( 6 5 , 9 9 ) . Prior to the control of bovine tuberculosis
-
and the implementation of pasteurisation programmes in
Northern Europe, the majority of cases of M. bovis infection
among humans were extra-pulmonary, with the following
organ systems being affected in decreasing order of frequency:
lymph nodes, skin, skeletal, genito-urinary and central
nervous system (meningitis) ( 5 7 , 6 6 , 1 2 4 ) .
Following exposure, development of disease in humans
depends on the ability of the mycobacterium to establish
infection and grow within host cells. Some evidence suggests
that M. bovis does not establish itself in humans as readily as
M. tuberculosis
( 5 7 ) . Following infection, M. bovis is
phagocytised by macrophages, and is carried to lymph nodes,
parenchyma of the lung and other sites. In macrophages,
bacilli resist being killed by blocking maturation and fusion of
phagosomal compartments, and limiting their differentiation
into active vacuoles (7, 5 8 , 5 9 , 6 0 ) , and natural resistance to
the oxidative burst ( 8 9 , 1 3 7 , 1 3 9 ) . Thus, the bacilli are able to
multiply, destroy phagocytes and escape into intracellular
326
spaces. This, in turn, stimulates the accumulation of other
phagocytes, creating the typical histopathological lesion of
tuberculosis - the granuloma. These granulomas can continue
to expand with new phagocytic cell infiltration, giant cell
formation and fibrosis. Eventually, macroscopic lesions
known as tubercles are formed (139). The resulting disease is
known as tuberculosis. The incubation period can last from
weeks to decades.
Although the diagnosis of tuberculosis can be performed
using radiology and microscopic examination of smears of
sputum (or other secretions or tissues) using acid-fast or other
stains, the identification of the specific aetiological agent (as
M. bovis or another mycobacterium) depends on the ability to
culture the organism and identify any mycobacteria that are
isolated ( 2 5 , 1 0 8 ) . Both culture and identification of these
mycobacterial species are complicated, potentially dangerous,
and require expertise that is common in the developed world,
but extremely rare in the developing world. Since
identification of the infecting species has minimal effect on
management of the tuberculosis patient, there is little
incentive from health care providers to identify the
mycobacterial species associated with tuberculosis. In the
United States of America (USA), the current molecular probe
diagnostic assay, which is routinely used for confirmation of
suspected tuberculosis cases, does not distinguish among the
species of the M. tuberculosis complex.
Incidence, prevalence and groups at risk
As identification of the species of infecting mycobacteria
among tuberculosis cases is not routine in most of the world,
and because no specific serological or skin test exists, the
precise incidence and prevalence of human disease caused by
M. bovis are unknown. However, the burden of M. bovis
infections among humans can be estimated from existing data
of tuberculosis incidence and data regarding the proportion of
tuberculosis due to M. bovis in various parts of the world (52,
85). In Europe and North America, 0 . 5 % to 1.0% of human
tuberculosis cases are estimated to be a result of M. bovis
infection (69, 1 2 1 , 123, 150). This represents a considerable
reduction since the 1960s and the intensification of bovine
tuberculosis control programmes; before this time, the
proportion of cases due to M. bovis was between 5% and 2 0 %
(62). In countries in which bovine tuberculosis is still
common and pasteurisation of milk rare, an estimated 10% to
15% of human cases of tuberculosis are caused by M. bovis
infection. In countries of South America such as Argentina,
where the prevalence of infection in cattle may be higher than
in North America or Northern Europe, but where milk is
routinely pasteurised or boiled before consumption, M. bovis
infection is responsible for 1% to 6% of human tuberculosis
cases ( 4 1 , 8 7 ) . In the 1990s, an estimated nine million cases of
tuberculosis occurred each year world-wide (approximately
10% of which were among individuals infected with human
immunodeficiency virus [HIV]) ( 9 3 ) . From the country and
regional data suggesting that 1% to 1 5 % of those cases may be
Rev. sci. tech. Off. int. Epiz., 20 (1)
caused by M. bovis, an annual incidence world-wide of
between 9 0 , 0 0 0 and 1,350,000 cases of M. bovis-associated
tuberculosis can be estimated. The prevalence of bovine
tuberculosis in the world has been recently reviewed (31).
Sub-populations at risk for M. bovis infection include any
population consuming unpasteurized contaminated milk,
abattoir workers, veterinarians, hunters and HIV-infected or
other potentially immunologically-compromised populations
(36, 37, 6 2 , 6 4 , 8 8 , 119). Given that both HIV and M. bovis
transmission are high in Africa, with 9 0 % of the population of
Africa living in areas where neither pasteurisation nor bovine
tuberculosis programmes occur and up to one in ten adults
being infected with HIV, the association between these two
diseases is of particular concern for much of this continent
(88).
Source of infection, route of transmission and
infectious dose for human disease
Mycobacterium
bovis causes tuberculosis in a broad range of
mammalian hosts including cattle and other ruminants, felids,
canids, lagomorphs, porcids, camelids, cervids and primates
including humans (12, 15, 16, 2 0 , 2 4 , 2 6 , 2 9 , 3 0 , 4 3 , 56,
100, 102, 122, 136). Infection in livestock and wild animals is
discussed in more detail in the papers by Cousins, de Lisle
et al. and Skinner et al. in this issue of the Review (32, 44,
127). Maintenance of M. bovis is believed to be primarily
related to ruminants, although other species of animals have
been demonstrated to maintain infection from generation to
generation ( 2 0 , 1 0 2 ) . Unpasteurised contaminated milk (133)
and other secretions or tissues from any of these species (but
primarily from cattle) can serve as the source of infection for
humans ( 6 2 ) . Although M. bovis may survive in soil, on
fomites and in faeces for days to months, depending on local
environmental conditions and sunlight, this is not considered
an important source of infection for humans (but may be for
cattle) (6, 4 7 , 9 0 ) .
Mycobacterium
bovis can enter human hosts through
ingestion, inhalation or direct contact with mucous
membranes or broken skin. Milk is still regarded as the
principal vehicle for transmission to humans in countries
where bovine tuberculosis is not controlled. Ingestion of
contaminated milk or other dairy products is more often
associated with scrofula, abdominal tuberculosis and other
extra-pulmonary forms of the disease (124). Among cattle,
M. bovis is spread primarily by the respiratory route, and
humans can also be infected by this route (34, 8 8 , 119, 126).
Although considered uncommon, contact of contaminated
animal products with broken skin can lead to cutaneous
tuberculosis, also known as butcher's or prosector's wart (63).
Whatever the route, the infectious dose for humans is
unknown, but estimated to be in the region of tens to
hundreds of organisms by the respiratory route and millions
by the gastrointestinal route (108). Based on animal models
and outbreak investigations, the infectious dose is known to
327
Rev. sci. tech. Off. int. Epiz., 20 (1)
be influenced by species of host (potentially higher for
humans than cattle), other host factors (e.g. immune status),
route of infection (higher for ingestion) and strain of bacteria
(108).
Human-to-human infection has been reported ( 6 7 , 1 4 3 ) , but
is considered unlikely (62). One report of human-to-human
transmission was among HIV-infected individuals in a
hospital setting (67), suggesting that the HIV epidemic might
increase the potential for human-to-human spread of
M. bovis.
Control
As this disease is primarily transmitted from cattle to humans
in milk, control of human infection can be achieved by
pasteurisation and control of bovine tuberculosis. Testing of
cattle with an intradermal tuberculosis test (or by inspection
at slaughter), combined with removal or quarantine of
infected herds and pasteurisation of milk, has proven very
effective in reducing the incidence of M. bovis infection in
humans (26, 102, 108). Elimination is complicated by the
several wildlife reservoirs of M. bovis present in most countries
of the world ( 4 3 , 5 6 , 122). However, practical elimination of
human infection can be achieved with a control programme
targeting only domestic animals. Such control programmes
may appear simple, but require the following elements:
a) political commitment to control the disease
b) public agreement regarding the benefit
c) adequate public funding for a potentially very expensive
disease control programme
d) an extensive public or private veterinary infrastructure
e) organised meat inspection for identification and tracing of
infected herds
ƒ) availability and maintenance of skin test antigen for
identification of infected animals
g) a centralised dairy industry that employs pasteurisation or
public education regarding the risks of unpasteurised dairy
products.
Without these requirements, as seen in much of the
developing world, M. bovis will continue to be a common
public health problem.
Mycobacterium
ulcerans
Aetiology, human disease and diagnosis
Mycobacterium
ulcerans is a slow-growing acid-fast bacillus
that causes a cutaneous infection known as Buruli ulcer, now
considered the third most common mycobacterial infection in
immunocompetent humans (8, 115). In common with
M. haemophilum
and M. marinum, M. ulcerans prefers low
temperatures (32°C), which may restrict spread to the body
surfaces ( 4 5 ) . Unusual among mycobacteria, M. ulcerans
produces one or more polyketide toxins strongly implicated
in disease ( 4 5 , 8 6 ) . The disease is believed to begin with the
entrance of the organism into the dermis or subcutis, where
following a latent period of undetermined length, the bacteria
proliferate and secrete toxin (74, 8 0 ) . The toxin appears to
cause preferential necrosis of adipocytes, without provoking a
local inflammatory response. At this stage, a pre-ulcerative
lesion may become clinically apparent in the form of a
painless, palpable subcutaneous nodule. Alternatively, active
disease can first manifest as a raised papule, a diffuse,
non-pitting oedema or a well-defined, elevated, indurated
plaque
(8). Histopathological
examination
at
the
pre-ulcerative stage reveals abundant acid-fast bacilli in the
centre of a region of fat necrosis. Without treatment, a
pre-ulcerative lesion may progress to an ulcer over the course
of several weeks to - months (107, 1 2 5 ) . Progressive
penetration of the mycobacterial toxin through the
panniculus, in combination with destruction of blood vessels,
causes extensive necrosis within the dermis. Damage to the
epidermis results, leading to an ulcer with deeply undermined
edges, often reaching the fascia, but not affecting the muscle
(74, 8 0 , 1 4 2 ) . In the ulcerative stage, microcolonies of
acid-fast bacilli are observed in the necrotic base of the ulcer
or in the necrotic fat at the ulcer margin, which can extend
quite far underneath the damaged skin. Healing starts with
the formation of granulation tissue at the base of the ulcer, and
may be linked to the initiation of a cell-mediated immune
response (138). Healed ulcers are often marked by a
characteristic depressed stellate scar. Serious sequelae include
contraction deformities, ankylosis and, less frequently,
osteomyelitis and amputation (142). The existence of
disseminated disease arising from recurrent M. ulcerans
infection is controversial (80, 113). The incubation period for
active disease is unknown, but estimates range between one to
four weeks and three to four months (5, 1 2 5 ) .
Currently available diagnostic methods for Buruli ulcer are
time-consuming and labour-intensive. Culture of M. ulcerans
from clinical specimens is expensive, difficult and
insufficiently sensitive (142). Ziehl-Neelsen staining for
acid-fast bacilli is the simplest method to confirm M. ulcerans
infection, but commonly yields false-negative results (142).
Histopathological examination of lesions is considered to be a
time-tested, sensitive and reliable technique, but requires
significant expertise (27, 7 4 ) . Recently, polymerase chain
reaction
(PCR) has
been
used
to
detect
the
M. ulcerans-specific insertion sequence, IS2404, in clinical
specimens ( 6 8 ) . The sensitivity of this repetitive sequence
PCR technique compares favourably with histology ( 6 8 ) .
Other PCR techniques (such as amplified fragment length
polymorphism [AFLP]) and 16S ribosomal ribonucleic acid
(rRNA) sequencing hold great promise for fingerprinting
strains to characterise transmission patterns within particular
regions (8, 6 8 , 1 1 1 , 112). However, the areas in which Buruli
ulcer is highly endemic are developing countries where PCR
technology is restricted to specialised reference laboratories
and therefore is impractical for routine diagnosis. As a result,
328
diagnosis based on clinical criteria prevails in those areas in
which M. ulcerans infection is most common.
Incidence, prevalence and groups at risk
Buruli ulcer occurs in tropical countries, with prominent foci
in West Africa (3, 3 8 , 97, 1 0 1 , 1 0 4 ) , Central Africa (9, 4 2 ,
128) and the Western Pacific ( 2 3 , 72, 1 1 8 ) . Cases have also
been reported from Asia and the Americas (8, 5 1 , 140). The
true incidence and prevalence of the disease world-wide is
unknown, due to inadequate surveillance data at national and
international levels. Moreover, the routine lack of case
confirmation, and the likely under-reporting from passive
surveillance systems, renders an estimation of the global
burden of Buruli ulcer difficult.
Rev. sci. tech. Off. int. Epiz., 20 (1)
Naucoris and Diplonychus that feed on other water-filtering
organisms, and could passively concentrate M. ulcerans,
subsequently transmitting the organism to humans via bites
(114, 134). Koalas, rats and possums have been shown to be
naturally infected in endemic areas of Australia (14, 7 5 , 98),
and armadillos can be infected experimentally (147).
The route of infection is unknown. The organism is
postulated to enter at sites of trauma to the skin ( 9 4 ) . No
confirmatory
evidence
exists
for
human-to-human
transmission ( 1 0 ) , although prolonged skin-to-skin contact
leading to ulcer has been suggested (8). Animal models for
M. ulcerans infection exist, including mice, guinea-pigs and
armadillos, but it is difficult to extrapolate these data to
humans. Inoculation of 1 0 - 1 0 colony-forming units (CFU)
is sufficient to induce swelling in the mouse footpad model
(40), but the infectious dose for humans is not known.
3
Incidence and prevalence have been reported in a few
locations under special circumstances. In Uganda, cases of
Buruli ulcer were observed for the first time in a group of
2 , 5 0 0 refugees from Rwanda that had been moved to a camp
near the Nile River in 1964. This cohort was monitored
intensively until 1 9 7 0 , when the population moved away
from the endemic area (5). The highest annual rate recorded
was 7/100 people in the ten- to fifteen-year-old age group in
1 9 6 6 and 1967 (5).
In endemic villages of the Amansie West District of Ghana,
prevalence has been reported to range from 4 % to 2 4 % (8). In
the course of conducting a case-control study in the Daloa
Region of Côte d'Ivoire, overall prevalence of past or present
Buruli ulcer was estimated to be between 1.3% and 1.6%,
reaching 1 6 % in certain villages ( 8 ) . Populations at risk
appear to be those in tropical climates, exposed to stagnant,
slow-moving water sources. In almost all of the case series
analysed, the sexes are equally represented, but children
between the ages of two and fifteen years are
disproportionately affected. The reasons are unknown, but
some aspect of behaviour among children is presumed to
place them at higher risk. In Africa, the majority of those
afflicted are poor rural farmers who live adjacent to swampy
environments; farming near the Lobo River was found to be a
risk factor in a case-control investigation. However, the
disease does not discriminate by race or socio-economic
status; in Australia, Buruli ulcer appeared in a relatively
wealthy white community near an irrigated golf course (120).
Source of infection, route of transmission and
infectious dose for human disease
Despite the long-standing inability to culture M. ulcerans from
environmental specimens ( 1 1 , 134), the organism is clearly
associated with swampy, riverine environments with
stagnant, slow-moving bodies of water. Another key feature of
outbreak settings is environmental change, for example the
damming of a stream to create an artificial lake on a university
campus in Nigeria ( 1 0 7 ) , flooding in Uganda (73), irrigation
of a golf course with water from a swamp created by damming
in Phillip Island in Australia (120). A suggested mode of
transmission is through predatory insects of the genera
4
Control
Due to a fundamental lack of understanding of the
mechanism of disease transmission, prevention strategies
have not been developed. Vaccination with bacillus
Calmette-Guérin (BCG) has been suggested to have a
moderate, short-lived protective effect against Buruli ulcer (4,
130). Currently, control methods in endemic countries are
limited to early diagnosis and surgical treatment. Surgical
intervention at the pre-ulcerative stage of disease can prevent
the development of the ulcerative disease. However,
well-controlled clinical trials have not been published.
Education of the population at risk may be an important
strategy to reduce the marginal increased morbidity and
mortality that results from delayed treatment.
Mycobacterium
leprae
Aetiology, human disease and diagnosis
Mycobacterium, leprae is a slowly growing, acid-fast bacillus
which causes leprosy. Mycobacterium
leprae grows best
between 27°C and 30°C, thus restricting the disease to cooler
areas of the human body. Attempts to culture M. leprae on
artificial media have proved unsuccessful, but fortunately, the
use of animal models such as the armadillo, nude mouse and
the mouse footpad has allowed therapeutic, pathological and
immunological studies to be undertaken ( 8 2 ) . Much of the
pathogenesis of M. leprae infection remains unknown (2).
Among persons who develop disease, the incubation period
can last between five and twenty years (154). Many patients
may develop single lesions that self heal (intermediate
leprosy). Without treatment and in the absence of
self-healing, the disease progresses to the paucibacillary or
multibacillary stage ( 5 4 ) . The World Health Organization
(WHO) defines paucibacillary leprosy as five or fewer skin
lesions with no acid-fast bacilli on skin smears, and
multibacillary leprosy as six or more lesions with positive
acid-fast bacilli (154).
329
Rev. sci. tech. Off. int. Epiz., 20 (1)
Diagnosis is based on clinical suspicion of anaesthetic or
hypoanaesthetic cutaneous lesions as well as palpation of
peripheral nerves for enlargement and/or tenderness with
sensory and motor evaluation, followed by confirmation via
biopsy of the skin lesion ( 8 2 ) . The Ziehl-Neelsen staining
technique can be employed to examine nasal excretions for
acid-fast bacilli in individuals with lepromatous or borderline
leprosy, whereas the Fite-Faraco stain is recommended for
histopathological preparations ( 2 8 ) . The development of
additional diagnostic assays such as measurement of phenolic
glycolipid-I (PGL-I) antibodies, deoxyribonucleic acid (DNA)
specific probes, and DNA amplification of M. leprae may
allow for a more rapid, specific diagnostic test for leprosy.
These techniques may be used to complement clinical and
histopathological diagnosis in patients when definitive
diagnosis is hampered by a lack of bacilli (17, 8 3 , 151). The
latter techniques are not widely available in the developing
world.
Infection and disease also occurs naturally in wild animals.
Natural M. leprae infections have been documented in the
nine-banded armadillo (Dasypus novemcinctus),
the sooty
mangabey monkey (Cercocebus atys), and in chimpanzees
( 4 6 , 9 5 , 9 6 , 1 2 9 ) . Aerosol transmission and maternal milk are
probable routes of transmission among armadillos (148). No
concrete evidence has been uncovered to suggest that any of
these animals serve as the reservoir of human infection.
Incidence, prevalence and groups at risk
Control
The true incidence of leprosy is unknown ( 5 5 , 1 3 1 ) . The
-WHO uses prevalence as an indicator for world-wide leprosy
by using case detection rates (CDR; i.e. all new cases
registered annually at health care facilities). This figure is
inherently flawed as an indicator of incidence for several
reasons. Many factors prevent infected people from seeking
treatment (e.g. the long incubation period, the stigma of
diagnosis of leprosy and the inaccessibility of health services),
therefore many 'new cases' are not new but represent a hidden
'backlog'. In addition, duplicate registering, relapse cases, and
identification of cases that self-heal may inflate the number of
new cases registered (144).
At the beginning of the year 2 0 0 0 , 7 3 8 , 2 8 4 new cases were
registered ( 1 2 . 3 / 1 0 0 , 0 0 0 ) , 7 5 3 , 2 6 3 cases were in treatment
(1.25/100,000) and 10,759,213 people were cured with
multi-drug therapy (MDT). South-East Asia accounted for
84.2% of new cases, followed by 7.5% in Africa. In 1999, the
following thirty-two countries reported a leprosy prevalence
exceeding 1/100,000: Bangladesh, Benin, Brazil, Burkina
Faso, Cambodia, Chad, Colombia, Congo, Democratic
Republic of the Congo, Côte d'Ivoire, Egypt, Ethiopia,
Guinea, India, Indonesia, Madagascar, Mali, Mexico,
Mozambique, Myanmar, Nepal, Niger, Nigeria, Pakistan,
Philippines, Senegal, Sudan, Thailand, Venezuela, Vietnam,
Yemen and Zambia. Eleven countries accounted for 6 7 2 , 5 9 6
registered cases: India, Brazil, Myanmar, Indonesia, Nepal,
Madagascar, Ethiopia, Mozambique, Democratic Republic of
the Congo, Tanzania and Guinea. During the 1990s, the
registered prevalence decreased dramatically, but currently
shows signs of levelling off ( 1 5 4 ) .
Source of infection, route of transmission and
infectious dose for human disease
The principal reservoir of M. leprae is humans. Mycobacterium
leprae is transmitted through frequent close contact with
untreated, infected persons by droplets from the nose and
mouth, whereas dissemination through skin lesions seems to
be of lesser importance (1). Mycobacterium
leprae is not
thought to be extremely pathogenic, since most infections do
not result in disease. Polymerase chain reaction studies on
nasal carriage suggest that infected individuals have a period
of transient nasal excretion, lending evidence to temporary
carriage or subclinical infection, and further indicating the
poor ability of M. leprae to cause disease ( 3 3 , 7 0 , 141). The
infectious dose of M. leprae for humans is unknown.
Current efforts to control leprosy are dependent upon early
detection of infection, adequate treatment using MDT with
rifampicin, clofazimine and dapsone, and examination of
contacts of the index case. Public education to reduce the
stigma associated with leprosy as well as effective treatment is
essential for the control of the disease. Multi-drug therapy is
recommended for twelve months for multibacillary patients
and six months for paucibacillary patients. Many countries
employing the MDT according to W H O guidelines have been
successful in achieving a significant reduction in the
prevalence and number of new cases detected. The W H O
target prevalence level is 1/10,000. Prevalence is used as a tool
to measure the success of the elimination strategy rather than
incidence, due to the long incubation period before disease
development and the lack of tools to measure infection and
disease status. Thus, new cases will continue to occur despite
implementation of MDT, because of the long incubation
period. Expansion of MDT to poorly served areas in endemic
countries will further the reduction as new cases appear.
Contact examination will remain an important aspect of
control in addition to patient follow-up to maintain
compliance with MDT (154).
Mycobacterium avium complex
Aetiology, human disease and diagnosis
The M. avium complex (MAC) of mycobacteria addressed in
this section includes both M. avium and M.
intracellulare.
These are slowly growing, non-photochromogenic, acid-fast
bacilli that were first isolated from birds in the 19th Century
(149). The first case of human disease due to M. avium was
reported in 1943, in a middle-aged man with underlying lung
disease (53). Following an incubation period suspected to be
weeks to months, infection of humans with these
mycobacteria can lead to three basic forms of disease:
pulmonary disease, lymphadenitis and disseminated disease.
However, any organ system may be affected. Disease due to
330
MAC can occur among healthy or, more commonly, among
immunologically compromised populations. The disease is
characterised, on pathological examination, by granuloma
and tubercle formation. The pulmonary form of MAC
infection has been observed primarily in white males from
forty-five to sixty-five years old, with underlying lung disease
(49, 5 0 , 146). The symptoms of this form of MAC infection
are non-specific, with fever, weight loss, non-productive
cough, dyspnoea, sweats, fatigue and haemoptysis.
Cavitational lesions, diffuse interstitial infiltrates and nodular
lesions have all been described following radiographical
examinations of the chest (22, 116). Mycobacterium
avium
complex is a common cause of granulomatous lymphadenitis
in children of one to five years of age. This form of MAC
infection is characterised by painless unilateral enlargement of
cervical, sub-maxillary, sub-mandibular or pre-auricular
lymph nodes ( 1 3 , 6 1 ) . Disseminated disease rarely occurs in
individuals not affected by acquired immune deficiency
syndrome (AIDS) ( 7 7 ) . Prior to the availability of antiviral
therapy for HIV infection, disseminated MAC infection was
the most frequent bacterial complication of AIDS, constituting
4 5 % or more of AIDS-defining infection in the USA, Japan
and Europe (76). Among AIDS patients, disseminated MAC
infection is characterised by weight loss, fever, anaemia,
sweats, diarrhoea and anorexia (although none of these are
pathognomonic signs) (76, 1 5 6 ) . A CD4 cell count of less
than 100 is an important predisposing risk factor ( 7 9 ) .
Disseminated MAC infection usually involves widespread
involvement of the reticuloendothelial system, with resulting
hepato-splenomegaly and lymphadenopathy (117).
The diagnosis of disease caused by MAC requires isolation of
the organism and compatible clinical and pathological
features. Respiratory tract colonisation can occur and must be
distinguished from disease ( 2 1 , 132). The microscopic
appearance of M. tuberculosis and MAC bacteria are identical,
and culture and identification by biochemical analysis or DNA
probes are required to distinguish these species. Culture from
a normally sterile tissue source, such as blood, is highly
correlated with disseminated MAC ( 7 1 , 1 3 5 ) . Culture and
identification of MAC require expertise that is common in the
developed world, but extremely rare in the developing world.
Incidence, prevalence and groups at risk
The true incidence and prevalence of MAC infection
world-wide are unknown. Prior to improved combination
therapy for HIV infection, between 2 5 % and 5 0 % of AIDS
patients in the USA were infected with MAC ( 7 6 , 105), and
proportions were similar in other parts of the developed
world (39, 7 8 , 1 1 0 ) . Since the introduction of potent
anti-retroviral therapies, these proportions have been
considerably reduced in the developed world. In one study
conducted between 1 9 9 4 and 1 9 9 7 , the period when these
Rev. sci. tech. Off. int. Epiz., 20 (1)
new anti-HIV therapies were being introduced, the rates of
MAC disease decreased from 22 to 4 cases per 100 AIDS
patient person years (109). Available data suggest that, even
before the introduction of improved anti-retroviral therapies,
the incidence of MAC infections among AIDS patients in the
developing world was low (103, 106). As stated, the primary
risk groups are immunocompromised populations in the
developed world, and possibly patients with chronic lung
disease.
Source of infection, route of transmission and
infectious dose for human disease
Mycobacterium
avium complex is ubiquitous in the
environment, and has been isolated from water, soil, food,
dust and domestic and wild animals ( 8 1 , 152, 153, 155).
Mycobacterium avium infection is an important disease of
poultry and swine, and the pathogen is commonly excreted in
the faeces of birds, but not swine (92). However, no particular
source has been identified as being more likely for human
infection, and the mode of transmission and route of infection
are unknown. Hospital water systems appeared to be the
source of infection in one cluster of five AIDS patients affected
by MAC (145). Ingestion has been postulated as the route of
infection for AIDS patients (19, 3 5 ) . Results of skin test
surveys of relatives and housemates of case-patients suggest
that human-to-human transmission of M. avium did not
occur (48). The infectious dose for humans is unknown.
Control
Control strategies for interrupting transmission are not
possible without knowledge of sources of infection and routes
of transmission. In addition, due to the ubiquitous presence of
M. avium, strategies aimed at controlling particular sources
are not likely to be successful. Control strategies among AIDS
patients have been limited to reducing the likelihood of
developing disease through the use of chemoprophylaxis
(18). Chemoprophylaxis with clarithromycin or azithromycin
has been demonstrated to reduce the likelihood of developing
MAC disease among AIDS patients ( 1 8 ) . Furthermore,
improved anti-retroviral therapy also contributes to
controlling the incidence and prevalence of this disease (109).
Morbidity and mortality can also be reduced through early
use of combined therapy with at least clarithromycin and
ethambutol (91).
331
Rev. sci. tech. Off. int. Epiz., 20 (1)
Épidémiologie de quelques maladies dues à des mycobactéries
communes à l'homme et aux animaux
D.A. Ashford, E. Whitney, P. Raghunathan & 0. Cosivi
Résumé
Les auteurs présentent un résumé des principales caractéristiques cliniques et
épidémiologiques de quelques maladies dues à des mycobactéries c o m m u n e s à
l'homme et aux animaux. Ils traitent ce sujet sous l'angle de la clinique et du
diagnostic ainsi que de la relation avec les estimations relatives à l'incidence et à
la p r é v a l e n c e de ces maladies c h e z l'homme. Ils passent également en revue les
s o u r c e s d'infection, les modes de transmission et les mesures de prophylaxie. Les
mycobactéries objet de cet article sont Mycobacterium
bovis, M.
ulcerans,
M. leprae et le complexe M. avium, sachant que cette liste des mycobactéries
c o m m u n e s à l'homme et aux animaux n'est en aucun cas exhaustive. Ces
e s p è c e s de mycobactéries et leur p r é s e n c e c h e z l'homme et les animaux
appellent plusieurs remarques à c a r a c t è r e général ; tout d'abord, la
connaissance de l'épidémiologie et de la prophylaxie de nombre de maladies qui
en résultent est, pour le moment, incomplète ; ensuite, des s o u r c e s d'infection
présentes dans l'environnement, autres que les animaux réservoirs, peuvent
jouer un rôle dans la transmission (à l'exception, peut-être, de M. leprae); et,
enfin, on ne connaît pas e n c o r e avec précision l'incidence et la prévalence de ces
maladies dans nombre de pays, essentiellement en raison de la complexité du
diagnostic et de l'absence de s y s t è m e s de notification.
Mots-clés
Diagnostic - Épidémiologie - Mycobacterium avium - Mycobacterium bovis
Mycobacterium leprae - Mycobacterium ulcerans - Santé publique - Zoonoses.
-
Epidemiología de determinadas micobacteriosis comunes al
hombre y a los animales
D.A. Ashford, E. Whitney, P. Raghunathan & 0. Cosivi
Resumen
Los autores ofrecen un resumen de las principales características clínicas y
epidemiológicas de una serie de micobacteriosis comunes al hombre y a los
animales. Tras examinar diversos aspectos clínicos y de diagnóstico de esas
enfermedades, explican la relación que guardan c o n las estimaciones de s u
incidencia y prevalencia en el hombre. También repasan las fuentes de infección,
vía de transmisión y medidas de control de esas patologías. Las especies aquí
tratadas son Mycobacterium
bovis, M. ulcerans, M. leprae y el complejo de
M. avium, aunque estas son sólo unas pocas de las micobacterias c o m u n e s al
hombre y a los animales. Respecto de estas especies micobacterianas y de su
presencia en el hombre y los animales cabe formular algunas consideraciones
generales: en primer lugar, queda bastante por saber sobre la epidemiología y el
control de muchas de las enfermedades que p r o v o c a n ; en segundo lugar, en la
transmisión pueden intervenir fuentes infecciosas ambientales distintas de los
animales reservorios (con la posible salvedad de M. leprae); y en t e r c e r lugar, no
332
Rev. sci. tech. Off. int. Epiz., 20 (1)
se c o n o c e c o n precisión el nivel de incidencia y prevalencia de esas
enfermedades en m u c h o s países del mundo, debido principalmente a la
complejidad de su diagnóstico y a la falta de sistemas de notificación.
Palabras clave
Diagnóstico - Epidemiología - Mycobacterium avium - Mycobacterium bovis Mycobacterium leprae - Mycobacterium ulcerans - Salud pública - Zoonosis.
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