Introduction
Measles has been eliminated in the major
industrialized countries, and control measures have been taken
in terms of imported infectious diseases. In Japan, although the
measles vaccine was introduced in the 1970s, small outbreaks of
measles have been occurring repeatedly in various regions even
in early 21st century. The number of patients reported by the
sentinel hospitals in 2001 was a little more than 35,000 (21 fatalities),
and it is estimated that at least 200,000 people have contracted
the disease throughout Japan (100 fatalities).
Under these circumstances the measles
vaccination with a two-dose regimen was finally introduced in
2006, and at the same time a campaign for educating the public
about vaccination was carried out. As a result, the measles vaccination
coverage increased (80%-90%) and the annual incidence of the disease
was brought down to about 500 cases. However, from 2006 through
2007, measles cases mainly in the age of 15-30s (adult measles)
increased rapidly in Tokyo and neighboring prefectures, and the
disease spread also to Hokkaido and Osaka prefecture. Over 1,000
patients were reported in May 2007 and many high schools and universities
were closed temporarily.
Measles tends to be treated lightly as
"a childhood disease manifested with fever and rash".
However, people may contract concomitantly pneumonia, encephalitis,
etc. and sometimes result in death. Measles is still a serious
infectious disease, in particular for infants and young children.
Adults contracting measles should also be hospitalized and treated,
and serious cases are not rare.
In this article, the author will highlight the nature of measles
on the basis of virological studies on clinical specimens he has
so far dealt with and the results of experiments on measles virus
infections in monkeys.
1. Factors that caused the frequency of adult measles
It is in the 1970s that vaccination with
the further attenuated live measles vaccine began. At that time
the vaccination rate had progressed to about 70%. Afterward a
new trivalent combined vaccine (MMR) composed of the measles,
mumps and rubella components was introduced in 1989. On the other
hand, however, aseptic meningitis due to the mumps vaccine occurred
frequently in vaccinated patients. As a result, the immunization
with the MMR vaccine was discontinued four years after its introduction.
Consequently, the vaccination rate dropped further.
Unvaccinated subjects and vaccinated subjects
with weakened protective immunity became susceptible to measles
in growing numbers. The decrease in opportunities of exposure
to measles virus following the wider use of the vaccine may be
considered as a factor of the frequency of measles in adults.
2.Pathogenicity of the measles virus (MeV)
MeV manifests in a varied pathogenicity
in addition to fever and rash, such as otitis media, croup, bronchitis,
bronchopneumonia, acute postinfectious encephalitis, measles inclusion
body encephalitis (MIBE), subacute sclerosing panencephalitis
(SSPE), etc. Furthermore, various opportunistic infections, including
giant cell pneumonia in immunodeficiency cases and bacterial pneumonia
in compromised hosts and malnutritional children, are induced
and are the cause of mortality.
3. MeV persistent infection
In blood cells, excepting neutrophils,
T, B lymphocytes and macrophages are the target cells of MeV.
Both lymphatic cell line (COBL-a cells) and epithelial cell line
(Vero cells) were inoculated with cloned viruses of 26 strains
of wild type MeV and observed for 60 days. As a result, all the
MeV strains shifted to persistent infection in the COBL-a cells.
On the other hand, no persistent infection developed at all in
the Vero cells. These results lead us to consider that the growth
of MeV in the lymphatic cell line as a target and the formation
of persistent infection in these cells are probably the basis
of the pathogenicity of MeV.
4. Quantity of excreted virus
We determined the infectivity titer of
MeV contained in swabs of the laryngopharynx, nasal cavity, conjunctiva
and genital mucous, urinary sediment cells, dermal tissue of the
rash region in patients with measles infection, all specimen of
which were collected within two days after the manifestation of
rash. As a result, in each of clinical specimen we detected MeV
of >10 7.5, 10 5.5,
10 3.5, 10 2.0,
10 3.0 TCID 50/ml. We found that
a large quantity of virus was excreted notably from the laryngopharynx
mucous. This will probably serve as an evidence for explaining
the extremely strong transmissibility of measles. Virus isolation
tests from the rash tissues of the skin were all negative.
5. Measles of vaccinee (Modified measles)
The clinical symptoms developed in measles
patients who had been vaccinated (modified measles) were relatively
mild compared to those of non-vaccineees. The quantity of virus
in the swabs of the pharynx of the vaccinated patients was extremely
small (< 103.0 TCID 50). We presumed
that the amount of excreted virus is correlated with the manifestation
of clinical symptoms.
6. Infection experiments in monkeys
Monkeys are highly susceptible to MeV,
and it is possible to reproduce measles in monkeys for the purpose
of animal experiments. When inoculating wild MeV (IC-B, EN strain)
isolated in COBL-a cells subcutaneously, transnasally or intravenously
to monkeys, they showed in all the cases a decrease of lymphocytes
in blood in addition to clinical symptoms such as Koplik spots,
generalized rash, etc. as in humans. The most severe lesions were
observed in the thymus in histopathological tests. Giant cells
and necrotized lesions were noted in all the lymphatic tissues
in addition to the tonsils and the appendix (2, 3). Giant cell
lesions followed by necrosis in the whole area of follicles were
formed notably in the thymus, then the cells inside the follicles
dropped out. Over eight weeks were needed to repair these lesions.
Similar lesions are observed also in the thymus of measles patients
(dead subjects). In the meantime the thymus and the lymphatic
tissues may conceivably fall into a condition of dysfunction.
These findings lead us to think that this is correlated to the
mechanism of onset of various opportunistic infections secondary
to measles. A rapid multiplication of the virus was also detected
in the bone marrow and the spleen. (Figure 1).
In addition, all the lymphocyte tissues
such as the superficial lymph nodes of the submandibular, axillary,
inguinal, the lymphatic nodules under the tracheal mucous, the
lymphatic apparatus under the intestinal mucous in the digestive
organ system, the Peyer's patches, the lymphatic tissues under
the mucous of the intestinal tract are the sites of MeV growth.
A degenerative dropout of the cilia and ulcers was observed all
over the tracheal mucous. Under the mucous, giant cells and inflammatory
lesions showing the growth of MeV were seen in the lymphatic apparatus.
The fact that the dropout sites of these cilia became defenseless
to exposure to the bacterium, suggested that this is the mechanism
of induction of bacterial pneumonia secondary to measles.
7. Future concerns
There exist cases of individuals becoming
adults without exposure to MeV due to the widespread use of the
vaccine and to the excellent sanitary environment. In fact, there
are 1-2% of subjects negative to measles antibodies among pregnant
women and nurses, and they may possibly contract measles. Measles
contracted by pregnant women may be the cause of induction of
abortion and stillbirth. Moreover compared to non-pregnant women,
the rate of pneumonia onset is 2-6 times higher and the mortality
increases 6.4 times. Individuals on long term care due to transplantation,
cancer, diabetes, etc. as well as the elderly are considered to
be basically compromised hosts, and the symptoms of measles may
aggravate even if these subjects have been vaccinated and have
a history of measles. Wild MeV (genetic type H1) has been isolated
from the peripheral blood of a pediatrician living in Tokyo (54
years old) presenting measles-like symptoms. He had developed
pneumonia as a complication and he had to be hospitalized for
treatment (unpublished data).
As long as the current vaccination rate
remains as it is, we think that there is a strong possibility
that these concerns could become a real problem. It would be desirable
to measure the measles antibodies of healthcare providers, compromised
hosts and women who intend to become pregnant and to proactively
immunize the negative individuals.
Conclusion
A high number of measles patients were
also encountered in the US until over a decade ago. Adult measles
and modified measles also occurred at the time the use of the
vaccine was wide spread. In Japan, the problem of adverse reactions
with the MMR vaccine has exerted a negative impact on the control
of measles. Immunization with the measles vaccine is the only
reliable tool to prevent this ailment. Continuous efforts to bring
the vaccination coverage to close to 100% are more important than
anything else. In recent years, the vaccination against measles
has been changed to the two-dose regimen in Japan also. It is,
therefore, expected that the vaccination rate will certainly increase
and that a major advance toward the control of measles will be
achieved.
Literature
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‚QDKobune,F.etal.FLab.Anim.Sci.46,315-320,1996
‚R.Griffin,D.E,etal.Fieldvirology(Thirdediti-on).p1290,1996
