What is the life-cycle of C pneumoniae?
Simplifying slightly, C
pneumoniae has two major phases to its life cycle. The infectious
form is called the Elementary Body (EB). This spore-like form
transmits the organism from person to person and, within a person,
from cell to cell. The EB is metabolically inert; it has an external
membrane which includes potentially unstable proteins. When it
attaches to a susceptible host cell a sudden change takes place;
the proteins which are embedded in its external membrane become
loose and the host cell wall closes behind the entering EB. Entry
may be controlled by subversional proteins injected into the
host cell via tiny syringes and needles (The type III secretory
system. Proteins associated with the TTSS have been found in
the EB proteome.)
The organism settles on some
part of the respiratory lining and then invades. A respiratory
infection (sinusitis, bronchitis, pharyngitis or pneumonia) results.
Host defence cells mop up the organism; some become parasitized.
Chl pneumoniae can travel round the body in the blood
monocytes - mobile host defence cells - when these are called
to deal with a remote infection - perhaps a transient virus infection.
As the monocytes pass through the blood vessel walls, Chl
pneumoniae are shed; these infect the lining cells. Microcolonies
of Chl pneumoniae are set up. This can happen in the brain,
in joints, in the vessels which supply the great arteries themselves,
and in the skin. See [Gieffers
J, et al., Phagocytes transmit Chlamydia pneumoniae from the
lungs to the vasculature. Eur Respir J. 2004 Apr;23(4):506-10.]
MS is a many-staged and complex disorder. How can a simple bacterial colonisation/infection cause such complexity?
MS has four variants: relapsing-remitting, where neurological deficits occur suddenly and resolve over a few weeks. Resolution is at first usually complete; later, it is less so. Although called relapsing-remitting, most patients gradually accrue deficits. The disease may change to the secondary-progressive form; remissions are now unusual and deterioration is the rule. The third variant is the primary-progressive form, where the disease worsens from the beginning. The fourth, or so-called benign form, describes rare cases where resolution is always complete; the deficits themselves may cease to happen. (It is unwise to use this term as MS can become aggressive twenty years after its first mild appearance.)
All these forms and stages
would correspond well with an established Chlamydia pneumoniae
infection in the brain. In the relapsing-remitting form the infection
is silent until a new respiratory infection provokes a new host
response. This tends to become more severe as time goes on. (Parallels
are seen in the increasing severity of pneumonias caused by Chlamydia
pneumoniae in those who suffer repeated infections after
seroconversion: the severity is caused by the increasing strength
of the host response.) In the progressive forms the host response
is continuously firing, often against an extracerebral bacterial
infection; a patient with early SPMS will often mention chronic
sinusitis, chronic middle ear disease or new-onset asthma which
began some time before the MS began to slide into the progressive
phase. Sarah experienced a prolonged respiratory infection followed
by new-onset asthma before her illness became progressive.
MS has a genetic component. It also has a marked geographical distribution. How do you account for this, given that Chl pneumoniae is ubiquitous?
MS has a pronounced geographical
distribution. It is most common in the cooler latitudes, becoming
rarer as the tropics are approached. Migration from temperate
to tropical areas confers protection, provided the move is made
before adolescence. People who migrate to temperate areas are
more likely to develop MS than those who have remained behind.
infectious agents, notably Human Herpesvirus 6, have been put
forward as causative agents in MS. How does this square with
a primary Chl pneumoniae infection?
Can a chlamydial cause for MS be proved in an individual patient by serology?
Not at the moment. This because
Chl pneumoniae is a common organism and infections with
the bacterium are common. Antibody levels tend to rise during
life, even in people who are asymptomatic. Patients with extracerebral
infections of some duration (particularly reactive arthritis)
can show high titres in the microimmunofluorescence test; it
is generally reckoned that a titre of 1:512 or above, in the
presence of appropriate clinical findings, supports a diagnosis
of Chl pneumoniae disease. MS is different; the pathology
is at the blood-brain barrier. One would not expect an elevation
of circulating antibodies unless an extracerebral component to
the infection were also present. This may be the case in progressive
disease; there is a statistical elevation of antibodies in a
group of such patients. This supports the idea of a chlamydial
cause for MS, but makes no prediction in an individual. That
is why treatment must at the moment be empirical.
Antibiotics have been around for more than sixty years: surely they must have been tried before.
Neurologists have speculated
from the late 19th century that MS might have an infective origin.
They were used to dealing with infections, particularly syphilis.
Im sure that penicillin, so effective against syphilis,
would have been tried in MS. There is unexpected evidence that
penicillins have some activity against chlamydiae; however, in
the absence of meningitis but they do not achieve high concentrations
in the CNS. By the time tetracycline was invented, neurology,
and the received beliefs about the cause of MS, had changed.
Neurologists now rarely saw patients with underlying infections
and MS was considered a primary auto-immune disorder. And, too,
there is a battle-weariness in the neurology establishment. So
many hopes about finding a treatable cause for MS have been dashed
over the decades. The mind-set of the neurological establishment
needs to be changed. This will happen.
Why doxycycline and roxithromycin (or azithromycin)?
Both are oral, both are active
against Chlamydia pneumoniae, both are relatively inexpensive.
They are relatively risk-free. They act synergically against
test strains of the organism; giving both together would be the
equivalent of giving a four-fold increase of each drug were it
to be given alone. The drugs work on different steps in the bacterial
protein synthesis pathway. Combination therapy reduces the chance
of the emergence of resistance. Both drugs pass into the brain.
Both reach good levels inside cells. This is very important.
Both are well tolerated. Azithromycin is an alternative to roxithromycin.
They deplete the organisms slowly: this is very important, as
the release of bacterial endotoxins should not be sudden.
Why are later short courses of metronidazole to be taken together with these antimicrobials?
Why this complex antibiotic regime?
The literature is filled with
instances of treatment-failure in serologically-proven chronic
Chl pneumoniae infections of non-CNS systems, whether
macrolides, tetracyclines or rifampicin have been used. When
the drug is stopped, even after months of treatment, serology
rises, and the patient relapses.
What are the expected reactions to the antibiotics?
There seems to be two components
to the reactions experienced on taking the antibiotics.
Isnt giving antibiotics for a long time is a bad thing?
That depends on the illness.
Long-term doxycycline is used fairly routinely for certain kinds
of gum disease and for acne. Doxycycline is also used long-term
in malaria prophylaxis.
Does the fact that antibiotics can roll back MS tell us something about the nature of the illness itself?
I think it does. Components of MS, at some stages and in some variants, may be:
A bacterial toxaemia. This
may account for the mental fog, blunting of insight, greatly
increased reaction times and many other non-specific symptoms
which are hard to explain by demyelination alone, including fatigue;
indeed, there is evidence of abnormal cortical activity. [Leocani L et al.,
Neuroimage. 2001;13(6 Pt 1):1186-92.] A toxaemia would be expected to resolve quickly
with effective antibiotic treatment, as has happened here.
Many scientists now believe that Multiple Sclerosis to be a heterogenous group of diseases rather than a single disease entity. How does this fit with the idea infection with a single bacterial species?
Some scientists do consider MS to be a collection of different disease types. Lassmann et al. proposed a classification of MS based on the appearances of lesions. [Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. [Review]. Trends Mol Med 2001; 7: 11521.]
One could argue that these different lesion types represent an immune response dependent on the patient's genetic inheritance: in fact this is a minor piece of evidence that a single pathogenic species is at the root of the disease.
Differences in host immune responses occur in many chronic intracellular infections. One such is leprosy, which can present in numerous different forms which very lesions very different in gross and microscopic appearance.
In relapsing-remitting MS the major cause of relapse, a new respiratory infection with Chlamydia pneumoniae, will be prevented by the antibiotics. However, for the first six months or so it is possible for a relapse to occur secondary to a virus infection. This may be particularly likely in a household with young children.
Not all new deficits which occur during treatment are relapses, though: see page 10.