|
 There
is increasing recognition that microbial infections are important contributors
to a wide range of chronic conditions. Peptic ulcer disease may be due
to the bacterium Helicobacter pylori rather than to emotional stress
and diet. For years the conventional wisdom had been that no microbe could
survive the acidic conditions of the stomach. Until recently the blood-brain
barrier was considered impenetrable to plasma proteins, such as antibody
and complement. Now it is purported that several neuropsychiatric disorders
of childhood are rooted in a microbe-triggered autoimmune response. Clearly,
a contributing role for microbial infections in chronic diseases of the
CNS needs to be reassessed.
Inflammation,
sometimes accompanied by a specific immune response, is often a critical
component of chronic diseases associated with infection. A role for microorganisms
in autoimmunity has been suggested for decades, although for many diseases,
such as multiple sclerosis and type I diabetes, the unequivocal identification
of the etiological agent(s) has been met with difficulty. Perhaps the
best-recognized link between autoimmunity and infection lies with acute
rheumatic fever (ARF) and the bacterium Streptococcus pyogenes,
also known as group A b-hemolytic streptococci
(GABHS). Diagnosis of ARF can be tricky, and it generally includes one
or more of the following major manifestations: (1) carditis, typically
involving the mitral valve; (2) a polymigratory arthritis, which resolves
without permanent damage to the joints; and (3) Sydenham chorea, a disorder
of gross motor function.
Essential
to the diagnosis of ARF is evidence of a recent GABHS infection. Documentation
can take the form of a positive throat culture or an elevated antibody
titer to GABHS antigens. However, exceptions are made for some cases of
“pure chorea.” Unlike carditis or polymigratory arthritis, there
is the possibility of a delay of several months between the primary GABHS
infection and the onset of Sydenham chorea symptoms. By this time, the
organism is long gone from the host and anti-streptococcal antibody titers,
as well as plasma markers for acute inflammation (e.g., C-reactive protein),
have declined to normal levels. Inasmuch as chorea often appears during
the acute stage rheumatic fever and is a clearly defined syndrome, its
association with GABHS infection remains unchallenged.
Epidemiological
studies were crucial in establishing the relationship between GABHS and
rheumatic fever. At the close of the 19th century in the United States
and Europe, diseases caused by GABHS, which notably include scarlet fever,
had a public health impact that rivaled tuberculosis. Prior to the widespread
use of antibiotics in the late 1940s, streptococcal infections were difficult
to control. Outbreaks of ARF within the military, around the time of World
War II, provided a rich source of information on the epidemiology of this
disease and its association with primary GABHS infection.
ARF
can follow an untreated GABHS infection of the upper respiratory tract
(URT). In most instances, a host immune response that is directed specifically
toward the invading organism will be mounted, resulting in clearance of
the primary infection within 2 weeks. In some cases, an asymptomatic carrier
state will develop, whereby the bacterium is believed to be in a quiescent
state, perhaps residing within the epithelial cells lining the oropharynx
and hidden from immune attack. There is a delay of 3 to 6 weeks following
the primary bacterial infection and symptoms of ARF.
Not
all individuals experiencing an untreated GABHS infection will develop
ARF. It is estimated that only 3% of the human population has a genetic
predisposition for developing rheumatic fever. Moreover, not all strains
of GABHS will trigger an acute rheumatic attack, even in a highly susceptible
host. This became strikingly apparent in the 1940s at Irvington House,
a group home for children with rheumatic heart disease. It is here that
an M-type 4 strain caused acute pharyngitis in many residents, yet failed
to induce a single episode of recurrent ARF.
It
is widely accepted that only a GABHS infection of the throat can induce
ARF. In addition to pharyngitis, GABHS can cause impetigo, a purulent
infection involving the epidermal layer of the skin. Perhaps the unique
association between ARF and URT infection, but not skin infection, arises
from differences in the drainage of streptococcal antigens into the ducts
of the lymphatic system. There is also speculation that the apparent failure
of skin infection to induce ARF is due to the fact that GABHS strains
which cause impetigo are often distinct from the strains giving rise to
pharyngitis. Numerous epidemiological studies on ARF outbreaks in the
United States and Europe have led to the classification of several M-types
of GABHS as highly “rheumatogenic.”
The
relative incidence of GABHS infection of the URT and skin varies in accordance
with both season and geographic location. In many temperate climates,
pharyngitis is common during the winter, whereas impetigo has a lower
overall prevalence and peaks during the summer months. In contrast, in
many tropical regions impetigo is highly endemic (Fig.
1). The highest reported rate of rheumatic fever is found among the
Aboriginal people of tropical Australia. Curiously, acute pharyngitis
is uncommon in Australian Aborigines, and the so-called “rheumatogenic”
M-types are rarely recovered. Whether or not a throat infection by a rheumatogenic
strain is a strict requirement for ARF remains a hotly contested issue.
A
true GABHS infection, as opposed to carriage, can be defined in serological
terms as a rise in antibody titer to GABHS antigens, such as streptolysin
O or deoxyribonuclease B. However, true infection of the URT need not
necessarily lead to overt clinical symptoms. It is important to note that
a clinically inapparent GABHS infection can trigger ARF. Beginning in
the mid-1980s, the Salt Lake City (Utah) region experienced a marked increase
in the incidence of ARF. Yet in about half of the cases, the patient had
no recollection of a sore throat in the weeks preceding the acute attack.
Were it not for outbreaks of ARF occurring in institutional settings,
such as military bases, at a time prior to the availability of effective
antibiotics, such as penicillin, the link between GABHS infection and
ARF would probably remain elusive, or at least less certain than it is
today.
There
is a connection between GABHS and neuropsychiatric disorders, such as
Tourette syndrome (TS), obsessive-compulsive disorder (OCD), and possibly
attention-deficit/hyperactivity disorder (ADHD). Patients with these neuropsychiatric
disorders have elevated levels of expression of a B-lymphocyte cell surface
marker, known as D8/17, which is also elevated in rheumatic fever patients
and their first-degree relatives. The specificity of D8/17 for rheumatic
fever is very high when compared with several other autoimmune diseases,
such as rheumatoid arthritis. Whether the D8/17 marker has a direct role
in ARF is not yet known. Sydenham chorea is one of the major manifestations
of rheumatic fever, and many patients with Sydenham chorea also exhibit
obsessions and compulsions. Furthermore, considerable comorbidity is observed
among patients with TS, OCD, ADHD, and Sydenham chorea. The basal ganglia
is a primary target organ of Sydenham chorea, a feature it shares with
TS, OCD, and ADHD.
A
practical approach for evaluating the association between GABHS infection
and neuropsychiatric disorders is to model new studies based on our current
knowledge of ARF. However, the epidemiological studies that uncovered
the link between GABHS and ARF may not be wholly applicable to TS, OCD,
and ADHD. Most cases of TS, OCD, and ADHD are sporadic and appear in community
settings. Outbreaks of acute TS, OCD, or ADHD have not been documented.
Even qualifying an episode of TS, OCD, or ADHD symptoms as an acute exacerbation
can be fraught with difficulties. GABHS infections are frequent within
the same group afflicted with TS, OCD, and ADHD. At its peak incidence,
between the ages of 5 and 7 years, it is estimated that half of all children
experience an average of one GABHS infection per year. If the time delay
between GABHS infection and acute episodes of TS, OCD, or ADHD were of
the magnitude observed for pure chorea, then a temporal relationship between
GABHS infection and the neuropsychiatric disorders would be difficult
to establish. The “background” level of GABHS infections may
be too high.
Any
attempt to establish a temporal relationship between GABHS infection and
an acute exacerbation of neuropsychiatric symptoms would be further complicated
if only a subset of patients were susceptible to the effects of GABHS
infection. Yet this is exactly what has been proposed.
Patients
with PANDAS—an acronym for pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infections—are thought to
represent only about 10% of all neuropsychiatric patients. If only some
of the acute episodes experienced by a PANDAS patient were rooted in a
GABHS infection, it may be impractical to design an epidemiological study
that could capture the effect—a very large sample size of human subjects
would be required. However, longitudinal studies of PANDAS patients are
required to help clarify the etiology and to determine whether exacerbations
of symptoms are secondary to repeated GABHS infections.
The
molecular mechanisms underlying the development of ARF remain ill-defined.
Antibodies which react with both streptococcal antigens and human host
tissues, such as the brain and heart, have been identified. For some antibodies,
a pathological role is well-supported by studies using experimental animal
models for carditis. Because there is a strong familial pattern of rheumatic
fever, as there is for TS, OCD, and ADHD, is should be possible to identify
the genetic determinants of susceptibility for each of these diseases
and determine whether they overlap. Significant associations between rheumatic
fever and HLA markers have been observed for several human populations
that share the same ethnic background; however, the HLA markers are unique
to each ethnic group. Aside from the D8/17 antigen present on the surface
of B-lymphocytes, there are no stable biomarkers known for rheumatic fever.
Defining
the relationship between TS, OCD, ADHD, and GABHS infection is a challenging
problem. But the rewards of success could be enormous. ARF is a readily
preventable disease that can be managed through antibiotic prophylaxis.
Identifying those individuals who stand to benefit from antibiotic therapy
remains a central goal. Perhaps the answer will lie not in the classical
epidemiological approach that proved so successful in decades past, but
rather in the precise identification of molecular markers that allow for
stratification of patients into biologically relevant subgroups.
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