M
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August2017

Volume 3-The Informed Prescriber

N8

HECK

o

Screening does not reduce cervical cancer deaths
The best and only protective measure is to have adequate nutritionand sleep

Pneumococcal and Hib vaccines for children
Harms may outweigh benefits: not recommended

CONTENTS （August 2017, Vol. 3, No. 8）
Editorial:
Is the intervention really necessary?
The importance of the epidemiologic evidence
Review
Screening does not reduce cervical cancer deaths
The best and only protective measure is to haveadequate nutrition and sleep
Pneumococcal and Hib vaccines for children
Harms may outweigh benefits: not recommended

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M
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-The Informed Prescriber

Editorial

HECK

Is the intervention really necessary?
The importance of the epidemiologic evidence
Translated from the editorial in Med Check-TIP (in Japanese) Jul 2017 ; 17 (72)In order to stress the need of an intervention

hypercholesterolemia (FH) are prone to( treatment or prevention) for a particular illness,myocardial infarction are not because theirsuch phrases are typically used: “The illness ischolesterol (or LDL-cholesterol) level is extremely

increasing” “you should lower levels of this andhigh, but because they are prone to inflammation

that, which is the cause of the illness" or “theand coagulation, and/or have sensitive vascularintervention is essential to prevent death fromendothelium.

the illness".

The phrase “the intervention is essential
to prevent death from the illness" is used to

Denosumab, a new product discussed in thestrengthen the importance of vaccines. We

Japanese issue ( No72, July 2017 ), is one of thecarefully examined the vital statistics andproducts used for reducing a fracture. It wascompared mortality rates from bacterial

developed not because osteoporosis is increasing.

meningitis and bacterial pneumonia, which

If you search epidemiologic evidence carefully,

are the target diseases of Hib vaccine andyou will find a birth cohort study which clearlypneumococcal conjugate vaccines, before andshows that osteoporosis has not been increasing,after introduction of these vaccines. We foundbut rather decreasing. The reason why thethat the number of deaths (or mortality rate) after

manufacturers and their researchers stressinoculation of both vaccines was higher than thatthe need of new products for prevention of

reduced by the vaccines.

osteoporosis, ignoring the fact that the diseasehas been decreasing, is only because they need topromote sales of these products.

A drug always comes together with harm, but
its benefit must outweigh the harm so that theuse is justified. Such a drug may be used with

The typical example for the phrase “youshould lower levels of this and that,caution so that harm would be minimized.

which

How should we deal with interventions thatis the cause of the illness" is “cholesterol, amay save life but may also cause death? The use

cause of atherosclerosis (or arterial sclerosisof such interventions is justified only after strictly

which is preferred in Japan ), should be lowered."weighing the number of deaths (rate) reduced andHowever, cholesterol is actually not the cause

the number of deaths (rate) possibly induced byof atherosclerosis or arterial sclerosis. On thethe interventions.

contrarily, people with relatively high cholesterollevel (or LDL - cholesterol level), who are considered

We are committed to continue evaluating

to be ill or have high risk according to the current

interventions including vaccines based on thismajor guidelines, rather live longer.

principle.

A large number of epidemiologic studies
have proven this as often discussed in thisbulletin. The reasons why people with familial

MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 13

Review
Screening does not reduce cervical cancer deaths
The best and only protective measure is to have adequate nutrition and sleep
Translation from Japanese edition of Med Check-TIP 2017: May(No 71):54-57
Abstract:● It is often argued that screening would prevent cervical cancer even if HPV vaccination is discontinued.
However, this article reviewed thoroughly an English study which is believed to provide evidence for
effectiveness of screening, and found that it has no basis.
● In addition, the only available randomized controlled trials (RCTs) comparing those with screening and control
without screening were conducted in India where mortality from cervical cancer is 4-12 folds higher thanthat in Japan. Screening by cytological examination did not show any statistically significant efficacy even by
the Indian RCT. As for other screening methods, some studies showed significant results while others did not.
Even if the Indian RCTs showed significant results, extrapolation according to the mortality in Japan turns theresults into “not significant”, due to extremely low mortality rate from cervical cancer in Japan. Suppose thatscreening is effective, at least 240 million to 1.5 billion yen would be required in order to reduce one deathfrom cervical cancer.
● Mortality from cervical cancer in Japan has been markedly decreasing, accompanying increase in fat intake.
Excessive dieting among adolescent girls does not only lead to cervical cancer, but is also extremely risky for
their general health. Enough fat and protein intake and adequate sleep without using hypnotics are essential for
prevention of any kind of diseases.
Keywords:
cervical cancer, screening, randomized controlled trials, cytological examination, mortality, HPV detection,
visual inspection with acetic acid (VIA), India,Japan, UK

has been actively recommended as a national project since

Introduction
Harm of HPV vaccination outweighs its benefits. It is often
argued that even if it is discontinued, cervical cancer can be1987. The uptake of screening was 42% in 1988, and greatly
increased up to 85% in 1994.

prevented by screening, and thus HPV vaccine is
not necessary [1,2]. Can screening really prevent

Figure 1: Age standardised mortality from cervical cancer, England, 1950-97

cervical cancer, and reduce mortality from thedisease as well as total mortality?
English Study: basis for effectiveness?
No randomized controlled study ( RCT, faircomparative study ) has been conducted indeveloped countries, including Japan, North
America and Europe, to prove that the screening
reduces mortality from cervical cancer and total
mortality. Therefore, this article examined one
study [3] (Ref. 1 is also based on ref.3), which isconsidered the most important evidence for
efficacy of screening in developed countries.
In England, screening for cervical cancer

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The straight lines show decreasing trends to highlight the difference between the 2 periods(The straight lines are original to Ref. 3).

Figure 2. See the difference in the mortality

Figure 2-a:Age specific mortality from cervical cancer, England,1950-97

between before and after 1987 for each(original figure)age group. In the age group 45-54, thedecreasing trend became milder after 1987.
No change was observed in the age group55-64. In the age 75 and older, the decrease
became milder. No change was found in
the age group 25-34. In the age group35-44, the mortality slightly increased after
the screening project started, and started
decreasing slowly after a few years. Afterall, the mortality decreased only in the agegroup 65-74 while in other groups, almost
no change or even slight increase wasobserved. The mortality among the agegroup 65-74, which had been plateaued,
Figure 1 shows the change in mortality from cervical cancer

started decreasing around 1987. It seems that this timing

in England. The mortality seems to have decreased since thehappened to coincide with the time when the screening

screening project was launched. By only looking at this figure,project was launched.

active promotion of screening seems to have contributed
successfully to the reduction of deaths from cervical cancer. It

Therefore, this English study does not serve as evidence forthe effectiveness of the screening.

is understandable why this study is considered a basis for theefficacy. However, is this really true?
Now, let us take a look at the mortality by age groups in

By closely looking at the change by age groups (see Fig. 2-b
and the commentary below for more details), it is clear that theCommentary：
Figure 2-b : Age specific mortality from cervical cancer, England, 1950-97(for comments in detail)even increased between 1960-1977 (Period B) and
1955-1967 (Period A), respectively. In people aged
75 and older, the decreasing trend became very
mild and almost plateaued, starting around 1980
(Period D).
This figures shows that people who were born
between around 1905 and 1920 maintained highmortality from cervical cancer.
This suggests that people who had beenmalnourished in their adolescent during the FirstWorld War probably were persistently infectedwith HPV virus, and maintained high mortality
from cervical cancer. Therefore, this data do notprovide any evidence for the efficacy of screening inIn the age group 65-74, mortality plateaued between 1970

reducing mortality.

and 1987 (Period C). In 1987, the mortality for this group

Only if early cryosurgery, electrocautery or conization

became higher than that in people aged 75 and older. Afterare proven to reduce mortality, screening can bethat, it rapidly decreased, and approached the line X, which

considered effective. However, screening was not effective,

is an extension of the decreasing trend before 1970. In

and thus early detection and intervention were practicallythe age group 55-64 and 45-54, mortality plateaued or

not beneficial, either.

MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 15

Table:Summary of the cluster randomized controlled studies on the efficacy of cervical screening (from ref 4 ～ 6)

Review
Reviewmortality had been basically decreasing in all groups before

examination, HPV detection and visual inspection with acetic

the active screening. This decreasing trend once plateauedacid ( VIA ). These trials were conducted actively in India,

for about 15 years, and then started decreasing again. The

involving women aged 30-64 [4-6].

time at which the decreasing trend turned to plateau coincide

These trials are not double blinded RCTs, but cluster-with the time when people who had been adolescents during

RCTs. In one cluster, all participants were screened while in

the First World War ( 1914-1918) reached that age group.

another cluster, all were assigned to be given usual care as

It can be inferred that poor nutrition during the war led tothe controlled group. In the screened cluster, the participants

persistent infection with HPV.

were likely to be instructed and observed more intensively
than those in the usual care control group. Therefore, thisIndian Study: Inadequate Evidence

method tends to produce bias for favorable results for

There are 3 long-term clinical trials that compared womeninterventions. In fact, in one of the studies, not only total

who were observed without screening and those who

mortality and mortality from cervical cancer, but all kinds

were screened with any one of the 3 methods: cytologicalof mortality decreased in the intervention (screened) group

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[6]. In another

Table: Summary of the cluster randomized controlled studies on the efficacy of cervical screening (from ref 4-6)

study,In Japan, cytological examination is the common methodage-for screening. Only 1 of the Indian trials examined thisadjusted mortality

method [5], and no significant reduction in mortality was

rate ratio was

observed. (The implication of this result will be explained below.)

not significant,

There is also only 1 trial that studied HPV detection as abut without age

screening method [5]. In this RCT, the screening significantly

adjustment,

reduced mortality.

mortality from

Another method, in which acetic acid was applied to cervix

other causes

to detect abnormality (VIA), was conducted in all 3 clinicaldecreased [6].

trials. In the trials whose main objective was to demonstrate

Therefore, there

the efficacy of this method [4,6], mortality decreased

were probably

significantly. However, in another trial whose main objective

problems in

was to test the efficacy of HPV testing, screening using VIA

the method of

did not significantly reduce mortality [5].

observationand how the

The results of the 3 trials are summarized in Table. For
more details about the evidence, please refer to Table.

participants weredealt with.

Screening in Japan

Mortality rate

Extrapolation of the results of Indian studies to screening(/100,000 person-

in Japan shows that by screening 40,000 – 150,000 persons

years)

fromwould reduce 1 cervical cancer death. However, even if thecervical cancer

same number of people are followed up for the same period

without screeningof time, no significant reduction would be demonstrated

was 16 in urban(Table).

areas [4] andScreening by cytological examination requires about 6,000

approximately

yen per person just as a cost of testing. In order to reduce one

50 to 25 in rural

death from cervical cancer, 240 million – 900 million yen (orareas [5,6].

2.7 to 10 million dollars) would be needed.

In

Japan,

Moreover, this calculation rests on the premise thatmortality rate

screening and surgical treatment on precursor lesions of(/100,000 person-

cervical cancer are not harmful. Harms of surgeries andyears)

unnecessary anticancer agents are unknown as they were notfromcervical cancer

reported in any of the 3 studies.

among women

After all, the efficacy of the screening is unclear even inaged 30-64 and 20-69 (target age group of the screening) wasa country where uptake of screening was as high as 85% as

4.5 and 4.02 in 2015, respectively (calculated based on the vital

shown in the English study.

statistics [7]). This means that mortality from cervical cancer

Even if screening is proven to be effective in some countries

in India at the time of the studies was 3-12 folds higher thanwhere incidence of cervical cancer is very high, in countries

that in Japan in 2015.

like Japan and England, where mortality from cervical cancer

In the Indian trials, when cervical intraepithelial neoplasia( CIN2 and CIN3 ), a precursor lesion of cervical cancer,

has become low, no marked effectiveness of screening isobserved.

was found by screening, treatments such as cryosurgery

Screening takes money and time. In addition, if one isand electrocautery were given. Consequently, when the

diagnosed with a preneoplastic lesion, she will continue

statistically significant results were yielded, the studies

to worry about it even if the lesion is removed by a simple

suggested that screening approximately 5,000 people [6],surgery, electrocautery or cryosurgery. Even if screening

8,000 people [5], or 20,000 people [4,5] reduced 1 cervicalmight have minor benefits, various harms should becancer death.

considered and carefully weighed against them.

MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 17

Review
Review
Figure 3: Age specific cervical cancer mortality in Japan

1. Mortality from cervical cancer has decreased dramatically since 1958.
2. Why is HPV vaccine necessary?
3. Is it true that HPV vaccine is free from harm?

Figure 4: Lipid/fat intake and cervical cancer mortality in Japan
bubble economy had collapsed andthe economy had declined due tobankruptcy of major corporations, fat
intake decreased. Inversely, during thisperiod, morality from cervical cancer in
any age groups below age 60 plateauedor slightly increased ( see Figure 3 formore details). This inverse relationshipis statistically significant in people aged
20-59 when analyzed by 5 year age
group (p<0.001). It is also significant
in people aged 15-19 and 60-74 whenanalyzed by 5 year age group (p<0.05).
Similarly, inverse relationship was
confirmed between mortality fromcervical cancer and protein intake in many age groups.
Inverse relation between fat intake and mortality

However, relationship with fat intake tends to be stronger.

The TIP (Apr. 2013) [8] discusses relation between mortality
from cervical cancer and nutritional intake in Japan in detail.

Having adequate sleep without hypnotics is important for

In Japan, people who were adolescents during the Sino-

good health.

Japanese War and the Russo-Japanese War seem to have the

Sleep and screening are seemingly unrelated. However, ithighest mortality from cervical cancer at whatever age theyis more effective to have adequate sleep and nutrition than toreach.

spend billions of yen for screening to reduce 1 cervical cancer

Except for this age group, mortality from cervicaldeath. Here is the brief explanation.

cancer rapidly decreased as fat intake increased after the

According to a report that studied the relationship between

Second World War. However, in 1990’s after so-called thethe hours of sleep and life expectancy [9], most people usually

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Figure 5: Inverse association between lipid/fat intake and cervical cancer mortality in various age groups (ref 8)

had about 8 hours of sleep. When they were allowed to sleep

In Practiceas much as they wanted, their hours of sleep increased by

HPV vaccine should not be used. Moreover, no evidence

about 3 hours as compared with their usual hours of sleep.

suggests that screening reduces mortality from cervical

After reaching the peak, the hours of sleep gradually started

cancer. We rather recommend to take proper nutrition,

decreasing and stayed at about 8.5 hours. Suppose this isincluding enough fat and protein, and have adequate sleep

how to identify optimal hours of sleep, it is 8.5-8.9 hours(more than 8 hours) without using hypnotics.

for people aged 18-32 and 7.4 hours for people aged 60-76[10,11]. Measurements were made of hormone levels before
and after the participants had secured the optimal hours of
sleep. In the latter, levels of stress hormones was lower andinsulin level was likely to be higher. Glucose level was alsosignificantly lower [10].
According to this result, the optimal hours of sleep is longer
than what we usually think, and securing the optimal hoursof sleep might help reduce stress and contribute to better
health. Risk ratio for death is high in people who usually sleepfor 5-6 hours [9]. This is probably because a lack of sleep can
be a great stressor.
Another study suggests that people who experience
insomnia once or twice (or even 10 times) a month tend to live
longer than those who never do. It also reports that using
hypnotics for insomnia increases mortality risk by about 25%,
and this is as risky as having one major illness [9].
For healthy living, it can be concluded that securing
appropriate hours of sleep to reduce stress and taking
nutritionally balanced diet are the best way [12].

MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 19

References
1) Med Watcher Japan. Refutation_of_GACVS_statement (Dec 17 2015)_
on_the safety_of_HPV_ vaccines by WHO
http://www.yakugai.gr.jp/topics/file/refutation_of_gacvs_statement_on_
safety_of_hpv_vaccines_20151217_japanese.pdf
2) 1. Gøtzsche PC, Jefferson T, Auken M, Brinth L. Complaint to the

N Engl J Med. 2009 Apr 2;360(14):1385-94. doi: 10.1056/
NEJMoa0808516.
http://www.nejm.org/doi/pdf/10.1056/NEJMoa0808516
6) Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R,
Shanthakumari S, Fayette JM, Cherian J.Effect of visual screening on
cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-

European ombudsman over maladministration at the European

randomised trial.

Medicines Agency (EMA) in relation to the safety of the HPV vaccines.

Lancet. 2007 Aug 4;370(9585):398-406.

http://nordic.cochrane.org/sites/nordic.cochrane.org/files/public/
uploads/ResearchHighlights/Complaint-to-ombudsman-over-EMA.pdf[accessed 27.01.17]
3) Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidenceof and mortality from cancer of cervix in England: evaluation based on
routinely collected statistics. BMJ. 1999 Apr 3;318(7188):904-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27810/
4) Shastri SS, Mittra I, Mishra GA, Gupta S, Dikshit R, Singh S, Badwe RA.
Effect of VIA screening by primary health workers: randomized controlled
study in Mumbai, India.
J Natl Cancer Inst. 2014 Mar;106(3):dju009. doi: 10.1093/jnci/dju0
https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/dju009
5) HPV screening for cervical cancer in rural India.
Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh
AM, Hingmire S, Malvi SG, Thorat R, Kothari A, Chinoy R, Kelkar R, Kane S,
Desai S, Keskar VR, Rajeshwarkar R, Panse N, Dinshaw KA.

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https://www.ncbi.nlm.nih.gov/pubmed/17679017
7) Japanese Vital Statistics
http://www.e-stat.go.jp/SG1/estat/OtherList.do?bid=000001041646&cycode=7
8) Hama R et al、Epidemiology of cervical cancer and HPV vaccine. The
Informed Prescriber 2013:28(2):27-31.(in Japanese) http://www.npojip.
org/contents/link/tip-free/2013/2013_04.pdf9) Kripke DF, Garfinkel L, Wingard DL et al. Mortality associated with sleep
duration and insomnia. Arch Gen Psychiatry. 2002 Feb;59(2):131-6.
https://www.ncbi.nlm.nih.gov/pubmed/11825133
10) Klerman EB, Dijk DJ. Age-related reduction in the maximal capacity forsleep--implications for insomnia. Curr Biol. 2008 Aug 5;18(15):1118-23.
file:///C:/Users/Roku/Downloads/srep35812.pdf11) Kitamura S, Katayose Y, Nakazaki K et al. Estimating individual optimal
sleep duration and potential sleep debt. Sci Rep. 2016 Oct 24;6:35812.
http://www.nature.com/articles/srep35812
12) Hama R、 How to stop your medicines、San-go-kan、2017

Review
Review

Pneumococcal and Hib vaccines for children
Harms may outweigh benefits: not recommended
Translation from Japanese edition of Med Check-TIP 2017: Jul(No 72):83-86

Abstract:● Total 58 persons died shortly after inoculation of Hib vaccines and/or pneumococcal conjugate vaccine (PCvaccine) between 2010 and 2016 (average 9.3 deaths per year over about 6 years since 2011), and 48 of them diedof sudden unexpected death (SUD). This figure (48 sudden deaths/58) suggests that sudden death occurs 27 times
more frequently in the vaccinated persons, compared with the non-vaccinated (in 2009) of the same age group.
● The number of deaths due to bacterial meningitis had been already decreasing before the routine vaccination
started in 2010. The actual number of deaths per year since 2010 was 4.5 while the number estimated basedon the previous decreasing trend was 7.0. The actual number of death was smaller by average 2.5/year thanthat estimated by the decreasing trend.
● However, the number of deaths shortly after the vaccines was 9.3 persons/year. In other words, harm ofvaccination might outweigh its benefits. Therefore, PC and Hib vaccines are not recommended for children.
● S. pneumoniae and Hib are normal bacterial flora. Development of serious infections caused by these bacteria
are associated with inappropriate nutrition and environment, air pollution, and smokers in the household. It isnecessary to explain to guardians that they can improve these factors and have a choice not to have theirchildren vaccinated.

Keywords:
pneumococcal conjugated vaccine, Hib vaccine, bacterial meningitis, bacterial pneumonia, mortality, sudden death, SUD

Introduction
Pneumococcus (streptococcus pneumoniae) and H.influenzae
type B (Hib) are normal bacterial flora that may transiently

Hama, an expert in pharmacovigilance insisted that although
there were only limited data, it was too early to resume thevaccination at that time [2].

live in nose and throat of many people. However, they might

In order to have our subscribers to think together aboutoccasionally cause bacterial meningitis, bacterial pneumonia

efficacy and safety of PC vaccine and Hib vaccine forand sepsis, and Hib might occasionally cause acutechildren, the Med Check-TIP No. 70 [3] introduced some

epiglottitis, which may lead to death or sequelae.

data necessary for the review. However, since much had been

In order to prevent them, Hib vaccine ( ActHIB ) andalready discussed in TIP [1] and Kusuri-no-check [2], the Med

pneumococcal conjugate ( PC ) vaccine ( Prevenar, currently

Check-TIP No. 70 did not present all the information. Because

Prevenar 13) were developed. In March 2011, sudden deaths

the information is important, in this article, some information

occurred in succession after administration of these vaccines,

is extracted and explained together with additional

and the vaccination was temporarily withheld. However,information.

it was resumed in April, within less than a month [1,2]. At
that time, this was a controversial issue among editorial

Pneumococcus and Hib are normal bacteria

members and advisors of the Kusuri-no-Check (predecessor

Pneumococcus ( streptococcus pneumoniae ) and Hib areof the present Med Check-TIP). Clinical pediatricians argued

carried by most infants for a while after birth. They carry andthat the vaccinations had been effective in reducing severe

eliminate various types of pneumococcus and Hib, and repeat

bacterial infections, and thus meaningful. Tanida, an expert

this cycle. After the first 6 months of life, they are carried byin infectious diseases said that resuming the vaccinations

20%-50% of infants [4-6] and are eliminated after some time

was appropriate, but all the cases needed to be examined.

[4]. However, because there are many types of pneumococcus
MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 21

and Hib, even if one type is eliminated, another type isare recorded separately. Pneumonia deaths caused bycarried and is later eliminated, and this process is repeated.

pneumococcus and Hib account for 4.5% and 1.5% of all

According to the reference 1, within the survey period of 6

pneumonia deaths, respectively (total 6%).

months, at least 20 different types of bacteria were newly

A recent study reported that after routine PC and Hib

brought in, and 15 types of Haemophilus influenzae (this isvaccines were launched, among bacterial meningitis patients,

bacteria and not influenza virus) disappeared in one group (athe numbers of patients whose causative organism was Hib

kindergarten for 4-6 year-old children).

and pneumococcus fell by 88% and 80%, respectively, as

The research also studied whether the children had had

compared with the previous numbers [9]. Based on such arhinitis, sinusitis and otitis media, and found almost noreport, the vaccination is commonly believed to be effective.

difference between the carriers and non-carriers [5]. Most
children seem to get infected and develop mild rhinitis andChange in deaths due to sepsis, bacterial meningitis, andsinusitis as they stay with other children, and this is part ofbacterial pneumonia

their growth. Whether they develop chronic inflammation

The number of deaths from sepsis, bacterial meningitis andor not may greatly depend on their nutritional condition,

bacterial pneumonia has been decreasing recently. Although aenvironment, air pollution, and presence of smokers in the

population of children aged 0-4 itself has been shrinking, thehousehold such as their parents.

number of deaths is decreasing even when it is recalculated
per population.

Causative organisms for bacterial meningitis and deathIn the Med-Check-TIP No. 70 (p.31) and No. 71 (p.72), only

The three diseases, namely bacterial meningitis, bacterial

the change in the number of deaths was shown. In this article,

pneumonia, and sepsis, are called invasive bacterial infections

mortality rate (deaths/100,000 person-years) is shown (Figure:(IBI ). In any of these, hospitalization and treatment withNote that in the figure, the vertical axis is logarithmic scale).

antibiotics are required. Sepsis and bacterial meningitis areespecially serious infections that easily lead to death.

The figure shows that mortality from sepsis, bacterial
meningitis, and bacterial pneumonia has been decreasing

Types of causative organisms for bacterial meningitis are

steadily year by year. Sepsis and meningitis are often caused

well documented. The most common causative organism is

by Hib. Therefore, if the decreasing trend after 2009,

Haemophilus influenza ( H. influenza ). It is associated with

beginning of the routine vaccination, is more marked thanapproximately 50% of cases in any studies, and in most cases,that in and before 2008, Hib vaccination is presumed to havetype B (Hib) is involved [7-9].

contributed to the decrease. Similarly, if marked change in

For mortality from bacterial pneumonia ( 1996-2015 ),mortality due to bacterial pneumonia is found between before

statics for pneumococcus and Hib as causative organisms

and after 2009, pneumococcus vaccine presumably had agreat impact on the change.

Figure: Mortality trends of three invasive bacterial infections (1996-2015)

Hib vaccine ( ActHIB ) and Pneumococcus
conjugate vaccine ( Prevenar ) were brought
to market in 2009 and 2010, respectively.
Assuming that previous decreasing trend insepsis and bacterial meningitis continued after
2008, average mortality between 2012 and2015 was calculated and compared with theactual number of deaths during the same period.
The average mortality from bacterial
pneumonia was estimated based on thedecreasing trend between 1996 and 2009. The
summary is shown in the Table 1.
When discussed in the Med-Check-TIP No. 71,

The Figure is constructed by the author using vital statistics [10]. Note that the vertical axis is

the average number of deaths per year between

logarithmic scale. Three invasive bacterial infections include sepsis, bacterial meningitis and2012 and 2015 from bacterial meningitis wasbacterial pneumonia.

8.7, estimated by decreasing trends of the

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Table 1: Comparison of average mortality rate and annual number of deaths between

The odds ratio of SUD/non-SUD

2012-2015 (estimated by the decreasing trends and observed data)in causes of death among a general
populat ion ( o dds=272/(1790-272 ))and SUD/non-SUD in causes of death
after inoculation of the 2 vaccines( o dds=48/ ( 58-48 )) is 26.8 ( 95%CI:
13.4-53.6, p<0.0001 ). This suggests

extremely strong association between* P values were calculated by Mann-Whitney U test

the vaccinations and sudden unexpected
number of deaths per year, while the actual number was 4.5

death (SUD).

in the same period. This means that the vaccine presumably

Total 4 deaths were reported after vaccinations other thancontributed to reduce the number of deaths by average 4.2

Hib and PC vaccines. They include 2 deaths after HPV vaccine

per year. However, as a result of recalculation, consideringand another 2 deaths after other vaccinations. One SUD was

the population of children, the estimated number of deaths

reported each in HPV vaccine and other vaccines ( total 2

per year from bacterial meningitis is 7.0 between 2012 anddeaths from SUD).

2015. Therefore, the decrease is only by average 2.5 deaths

In 58 infants who died after Hib and/or PC vaccines,

per year. There was no significant difference in mortality fromthe duration between the inoculation and death was 1

sepsis and bacterial pneumonia (Table 1).

day (approximately within 24 hours) in 25 infants, 2 days in

Total 4 children and 2 children died from pneumonia due to7 infants, 3 days in 8 infants, 4-7 days in 9 infants, 8-14

streptococcus pneumoniae over 14 years between 1996 anddays in 4 infants, and 15 days or longer in 5 infants. The

2009, and over 6 years between 2010 and 2015 respectively.

longest duration was 41 days ( 1 infant ). More than half

Launching of PC vaccine did not have any impact.

of SUDs concentrate on day 1 and 2, and more than twothirds occurred by day 3. This also shows strong association

Strong association between sudden death and vaccination

between sudden unexpected death and the vaccination.

According to the Japanese vital statistics [10], the number

Suppose a half of infants of the same age group haveof deaths among infants aged 2 months to 4 years old wasreceived PC and/or Hib vaccines ( immunization rate 50%),

1,790 in 2015. Of these, when deaths from sudden infant

attributable risk to sudden death associated with these

death syndrome (SIDS) and deaths from unknown cause are

vaccines is approximately 93%. Therefore, 45 of 48 suddenclassified as sudden unexpected death (SUD), the total number

deaths are presumed to be caused by the vaccination.

of deaths from SUD is 272 ( this is the figure for a general
population).

Total 62 deaths after inoculation of various types ofvaccines were reported to the Adverse Reaction Working

On the other hand, benefits of the vaccines include
prevention of permanent injury due to bacterial meningitis.
However, incidence of permanent injury due to the vaccines
is unknown.

Group of the Immunization Vaccine Subcommittee, theMany sudden deaths occurred after the vaccination,

Ministry of Health, Labour and Welfare Science Council

including SIDS, SUD and/or death after status epilepticus. In

between 2011 and May, 2017 [11]. Among them, 60 deaths

such cases as SIDS and/or SUD, respiration was suppressed

were reported after vaccination for infants (two deaths wereduring sleep because even under hypoxic conditions,the cases after receiving HPV vaccine). Of the 60 deaths, 58

respiratory drive was not activated. When cardiac arrest

deaths occurred after Hib vaccine and/or PC vaccine (within

continues for over 4 minutes, it causes some kind of brain

approximately 6 years until Oct. 31, 2016). Among them, 48

damage. Otherwise, the condition may seem to be resolved,

deaths were due to SUD (Note 1).

but delayed hypoxic encephalopathy might occur after 2-3
days, which leads to developmental regression. This might

Note 1：Proportions of deaths from SUD were not so different by thetype of vaccines:. Recipients of 2 vaccines (Hib vaccine and PC vaccine)
only= 84%(16/19), 2 vaccines + other vaccines= 82 ％ (22/25), Hib +others= 83%(5/6), Hib only= 75%(3/4), PC + others= 100%(2/2)、PC
only= none、Vaccines other than 2 vaccines= 50% (1/2).

be falsely diagnosed simply as developmental disorder, andmight not be recognized as the harm of the vaccination.
Apart from sudden death, the vaccination is highly likely
to be associated with seizure and anaphylaxis, and these canlead to death. Even if the 2 vaccines might reduce the number

MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 23

of deaths from bacterial meningitis by average 2.5 persons/vaccines such as inactivated polio, hepatitis B vaccine, andyear, it is noteworthy that they might cause additional 9.3

BCG (Table 2).

deaths/year.

We estimated the mortality rate from each vaccine adjusted
by the influence of multiple simultaneous vaccinations.

Types of vaccinations and mortality
Hib and PC vaccines were associated with the most cases

According to the adjusted methods, the mortality rate fromHib vaccine remained the highest (Table 2).

of deaths after vaccination. This section examines whether

The Ministry of Health, Labour and Welfare considers thatmortality from Hib vaccine and PC vaccine is higher than thatwhen the number of deaths exceeds 0.5 deaths/100,000

from other vaccines.（See Note 2 and foot note of the Table 2 fordoses, safety of the vaccine is questionable [11].

the method of these estimations）

equivalent to more than 1 death/100,000 recipients when

Note 2：If a vaccine is routinely given for 3 times, the average numberof doses given was presumed to be 2.5. Based on this, the number ofvaccine recipients was estimated, and mortality per 100,000 recipientswas calculated (See Table 2 for details).

This isone child receives average 2 doses.
However, as shown in the Figure, Table 1 and Table 2,
the standard safety cut off ( 0.5 deaths/100,000 doses or 1
death/100,000 recipients) set by the ministry is fundamentally

As a result of our examination, mortality rate

wrong. Mortality rate (/100,000 person-years) from bacterial(deaths/100,000 vaccine recipients) after Hib vaccine is 0.52,

meningitis before the start of Hib vaccination ( 2009) was

and is the highest. Mortality rate from PC vaccine is 0.45, andalready 0.2-0.3 and that from bacterial pneumonia before

that after rota virus vaccines (both) is 0.39 and quadrivalent

2009 was already as low as 0.08-0.15. These mortality

vaccine (DPT + inactivated polio) is 0.23, followed by otherrates are far lower than the mortality rate (deaths/100,000

Table 2 ： Estimated number of inoculation, persons vaccinated, number of death, mortality rate after vaccines and mortality
rate due to invasive bacterial infections with and without vaccination program*a：Methods for estimating the number of recipients (Method a): For the vaccines which are routinely administered 3 times, the average number of doses
per person was assumed to be 2.5 times, which was used to estimate the number of recipients. For those which are routinely administered twice, such as
Rotarix and influenza vaccine, the number was calculated as 2.5 X 2/3. For BCG, which is routinely administered once, the number of doses was used as
the number of recipients.
*b：Methods for estimating the number of recipients (Method b)：For the average number of initial doses of Hib vaccine, which is routinely given 3 times,
1.84 was used because the number is based on the estimate of the manufacturer and was used by the Ministry of Labour, Health and Welfare.
*c：Adjustment by multiple simultaneous vaccination: If a single kind of vaccine was given, one death was counted for one person. If 2 kinds or 3 kinds ofvaccines were given simultaneously, it is considered that 1/2 death or 1/3 death occurred after each vaccination, respectively. The number of deaths was
divided by the number of types of vaccines given simultaneously, and the total number of death was calculated for each vaccine.
*d：Estimated mortality rate (/100,000 person-years) without vaccination: mortality rate (/100,000 person-years) over 4 years between 2012-2015 wasestimated based on the decreasing trend since 1996.
*e：Estimated mortality rate (/100,000 person-years) from bacterial meningitis (0.14) : Suppose that Hib vaccination was not introduced, the mortality
rate was estimated based on the methods as described in *d. Mortality rate (/100,000 person-years) after the introduction of Hib vaccination (0.09) islower than that estimated without vaccination (0.14). However, the mortality rates after vaccination (0.22, 0.17) are much greater than the reduction (0.05).
It is also higher than the estimated mortality rate without vaccination (0.14). This clearly shows that the harm outweighs benefits.
*f：Estimated mortality rate (/100,000 person-years) from bacterial pneumonia (0.09): Suppose that pneumococcal vaccination was not introduced, themortality was estimated based on the methods as described in *d. No difference was observed in mortality rate (/100,000 person-years) before and after
introduction of the vaccine (0.09 for both before and after the introduction). Mortality rate (/100,000 persons inoculated) after inoculation of the vaccine(0.17 or 0.12) is much higher that the difference (0.0). It is also higher than the estimated mortality without introduction of the vaccine. This clearlyshows that the harm outweighs benefits.

Page 24 ・ MED CHECK - TIP August 2017/ Vol.3 No.8

recipients) after inoculation of these vaccines (0.52 and 0.45)(Note 3) .

In practice
In clinical setting, the vaccination for infants is practiced
as if there is no other choice. However, while it slightly

Note 3: Mortality rate from bacterial meningitis or bacterial
pneumonia is expressed by the number of deaths per 100,000 personyears, while mortality rate after inoculation of a vaccine is expressedby the number of deaths per 100,000 recipients of vaccine: the units
used are different in these mortality rates. However, the longest
duration between inoculation and death was 41 days, which was far
shorter than one year. Hence, mortality rate after inoculation of thesevaccines expressed by “the number of deaths/100,000 recipient-years”
may be far higher than the mortality rate (/100,000 person-years)
from bacterial meningitis or bacterial pneumonia.

reduces deaths from infections, it causes more deaths. Thissituation should be considered, and these vaccines are notrecommended for children. It is important to explain thefollowing 3 points to guardians.

① Pneumococcus and

Hib are both normal bacterial flora. ② These bacteria aretransiently carried by children and are later eliminated.
③ Development of serious infection is associated withinappropriate nutrition and environment, air pollution, andIn randomized controlled studies
In randomized controlled studies (RCT), efficacy of neither
vaccination is adequately confirmed. Below is an article

smokers in the household, and thus these factors should be
improved. It is also necessary to explain them that they havea choice not to have their children vaccinated.

published in TIP [1]. (see the abstracted article below, reference
numbers are different）。

The Abstract of TIP（Results of RCTs）
There are two randomized controlled trials (RCTs) for Hib vaccine in developed countries 12,13). One trial, which was
conducted in Finland, showed marked effect of the vaccine 12). However, in another trial involving Alaska natives 13), it wasproven ineffective because little increase in antibody titers was observed.
In RCTs and a meta-analysis of case controlled studies 14) in developing countries, relative reduction in (radiologicallyconfirmed) pneumonia was 18% with Hib vaccination, and was not significant (combined risk ratio :0.82, 95%CI: 0.67-1.02). It

was significant in clinical pneumonia and clinical severe pneumonia. However, protective effect was only 4% (95%CI: 3-6%)
and 6% (95%CI: 1-9%), respectively, suggesting minimum clinical significance.
A systematic review on pneumococcal vaccine 15) showed a marked result; protective efficacy (relative risk reduction) ininvasive pneumonia due to bacteria of vaccine serotypes was 80% (95%CI: 58-90%, p<0.0001). This is based mainly on datafrom developing countries. However, protective effect on clinical pneumonia, severe clinical pneumonia, and radiologicallyconfirmed pneumonia was 6% 15) to 7% 14), 7% 14), and 26% 14) to 27% 15), respectively. The most influential study was
conducted in Gambia, Africa, in which mortality in the controlled group was extremely high: 5.6% (491/8719). In a trial
conducted in the Philippines 17), the vaccine did not show any effect on pneumococcal invasive pneumonia including thoseof vaccine serotypes and non-vaccine serotypes. Trials in developed countries 12, 18, 19) did not show any consistent result.
As for RCTs on pneumococcal vaccine in developed countries, the vaccine was proven effective in one trial in the U.S. 20).
However, in Finland, it was shown to be effective in preventing only otitis media, but not pneumonia 18, 19).
On the other hand, in a RCT for Hib vaccine, increased aseptic meningitis and SIDS were reported, but no data were
included 12). RCTs for pneumococcal vaccine, 2 deaths due to volvulus of the bowel were reported 18, 19), but they wereregarded as “not related” to the intervention.

MED CHECK - TIP August 2017 / Vol.3 No.8 ・ Page 25

Referencesin the protection of infants and young children against invasive Haemophilus

1) Hama R、Honzawa T. A review on the Hib vaccine, pneumococcal

influenzae type b disease. N Engl J Med. 1990 Nov 15;323(20):1381-7.

conjugate vaccine and death、The Informed Prescriber 2011: 26(4): 54-60(In Japanese)

13) Ward J, et al. Limited efficacy of a Haemophilus influenzae type b conjugate
vaccine in Alaska Native infants. The Alaska H. influenzae Vaccine Study Group.

2) Feature “Hib and Pneumococcal Conjugate vaccine” Kusuri-no-Check 2011：(43):30-53、58-68. (In Japanese)

N Engl J Med. 1990 Nov 15;323(20):1393-401.
14) Theodoratou E, et al. The effect of Haemophilus influenzae type b and3) Editorial team of MedCheck TIP、Pneumococcal Conjugate vaccine and Hib
vaccine MedCheck TIP 2017: 17(70):31. (In Japanese)

pneumococcal conjugate vaccines on childhood pneumonia incidence,
severe morbidity and mortality.Int J Epidemiol. 2010 Apr;39 Suppl 1:i172-85.

4) Takahashi J et al. Dynamics of Haemophilus Influenzae in pharyngeal flora15) Lucero MG, et al. Pneumococcal conjugate vaccines for preventingof a certain population-. Is the Haemophilus Influenzae a normal flora?

vaccine-type invasive pneumococcal disease and X-ray defined pneumonia

J Infect Dis 1992: 66: 956-963. (In Japanese)in children less than two years of age. Cochrane Database of Systematic5) Hashida K et al, A study on the H. Influenzae and Streptcoccus pneumoniae
in the nasopharynx of children in a nursery. Jpn Ear & Nose. 2006: 109: 821-829.

Reviews 2009, Issue 4. Art. No.: CD004977.
16) Cutts FT, et al. Efficacy of nine-valent pneumococcal conjugate vaccine
against pneumonia and invasive pneumococcal disease in The Gambia:(In Japanese)
6) Asahi E et al. Carrier rate of Haemophilus influenzae type b and bacterial flora ofnasopharynx of suckling infants.J Infect Dis 1997: 71: 236-240. (In Japanese)
7) Kamiya S and Nakano T. The nation-wide surveilance on the invasive bacterial

randomised, double-blind, placebo-controlled trial. Lancet 2005;365(9465):
1139-46.
17) Lucero MG, et al. Efficacy of an 11-valent pneumococcal conjugate vaccine
against radiologically confirmed pneumonia among children less

infection in children、IASR 2010: 31; 94-6. (In Japanese)8) Committee on Public Health of Japan Pediatric Association (Nakayama Y, et al).
The results of a questionnaire survey on systemic infection due to H. Influenzae inthan 2 years of age in the Philippines: a randomized, double-blind, placebocontrolled trial. Pediatr Infect Dis J. 2009 Jun;28(6):455-62.
18) Eskola J, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis

2008. J Jpn Pediatric Association 2009: 38: 195-9.
9) Shinjoh M, et al. Recent trends in pediatric bacterial meningitis in Japan--acountry where Haemophilus influenzae type b and Streptococcus pneumoniae

media. New Engl J Med 2001; 344(6):403–9.
19) Kilpi T, et al. Protective efficacy of a second pneumococcal conjugate

conjugated vaccines have just been introduced. J Infect Chemother. 2014vaccine against pneumococcal acute otitis media in infants and children:

Aug;20(8):477-83

randomized, controlled trial of a 7-valent pneumococcal polysaccharide-10) Vital Statistics of Japan (death), in e-Stat (Statistics by the Japanese Government)
http://www.e-stat.go.jp/SG1/estat/OtherList.do?bid=000001041646&cycode=7
11) Adverse Reaction Working Group of the Immunization Vaccine Subcommittee,

meningococcal outer membrane protein complex conjugate vaccine in 1666
children. Clin Inf Dis 2003; 37(9):1155–64.
20) Black S, et al. Efficacy, safety and immunogenicity of heptavalent

the Ministry of Health, Labour and Welfare Science Council 2011- 2017

pneumococcal conjugate vaccine in children. Pediatric Infectious Disease

http://www.mhlw.go.jp/stf/shingi/shingi-kousei.html?tid=284075

Journal 2000;19(3):187–95.

12) Eskola J, et al. A randomized, prospective field trial of a conjugate vaccine

M
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The Informed Prescriber
2017

Vol.3

No.8

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
Fumiko.(Pharmacist) ; TAKANO, Yoshihiko(MD[ pediatrician ]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

Page 26 ・ MED CHECK - TIP August 2017/ Vol.3 No.8

Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist);
MUKAI, Junji (Pharmacist); SEGAWA,Yusuke; SUMIDA, Sachie(MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro(Pharmacist); UMEDA, Tadahito (MD[psychiatrist])
Editorial Officers: PRAXTONE, Mutsumi; SAKAGUCHI, Keiko
Production Team: MATSUMOTO, Koji ;UMEKI, Yukiko; SAKAGUCHI,
Keiko
Information Technology (IT):KURODA, Akira (Systems Engineer)
Copyright NPOJIP
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