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Editorial
Anaphylaxis
New Products
Vaccines for COVID-19: Is it useful in Japan?
Review
Anaphylaxis:Adrenaline & corticosteroids are essential
CONTENTS （April 2021, Vol. 7, No. 20）
Editorial
Anaphylaxis

2

New Products
Vaccines for COVID-19: Is it useful in Japan?

3

Review
Anaphylaxis:Adrenaline & corticosteroids are essential

12

Adverse Reactions
Vaccines for COVID-19:
High incidence of anaphylaxis: 1 in 4400 vaccinated21

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April 2021/ Vol.7 No.20 ・ Page 

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Editorial

HECK

Anaphylaxis
Translated from the Editorial in Med Check(in Japanese) Ｍａｙ 2021 ; 21 (95) ： 2

The review article of this issue is a criticaleffect other than β receptors.

appraisal of the anaphylaxis guidelines.

The use of glucagon in this context is

Pfizer's vaccine against COVID-19 began togaining worldwide recognition, but in reality

be given to healthcare professionals in Japan,

it is groundless. As is clear from our review,

and it was found that it caused anaphylaxis

bisoprolol is a β1-selective β-blocker and does

as frequently as 1 in 4,400 persons (see page

not affect the β2 action of adrenaline, which

21).

is the essential pharmacological base for the

A TV drama "Unsung Cinderella," in which

treatment of anaphylaxis. Therefore, it turns

a hospital pharmacist is the main characterout that glucagon is overrated not only inshowed an anaphylactic shock case caused

this drama but also in the most anaphylaxis

by a wasp in the first episode. The ER

guidelines.

doctor of the hospital where the patient

Another important issue with anaphylaxis

was transported ordered the pharmacist to

guidelines is that the position of cortico-

prepare an intramuscular injection of 0.3 mg

steroids essential for anaphylaxis is lowerof adrenaline.

than that of antihistamines. It is strange that

The doctor also directed the preparation of

the evaluation of corticosteroids is low notcorticosteroids and antihistamines. Despite

only in Japan but also all over the world.

using adrenaline three times, the patient

Anaphylaxis develops suddenly, and mostdeveloped cardiac arrest. It is a condition

doctors who treated it did use corticosteroids,

considered to be refractory anaphylactic

making comparative studies impossible now.

shock. When the doctor was wondering

Therefore, there is no choice but to properly

why adrenaline didn't work, the pharmacist

analyze observational studies, but thefound a medicine bag labeled bisoprolol insituation is critical that an essential treatment

the pocket of the patient's pants and said,

with corticosteroids for anaphylaxis can be"The patient may be using a beta blocker. I

burried with incorrect analysis.

urge glucagon administration." The doctor

If you read the review article "Criticalinjected glucagon intravenously, suspiciously.

appraisal of anaphylaxis guidelines" carefully,

The patient then recovered. The medical

you will be able to treat patients without

supervision of the official blog of this drama

hesitation when you experience anaphylaxis.

explains that glucagon exerts a cardiotonic

Page  ・ MED CHECK

April 2021/ Vol.7 No.20

New Products
Vaccines for COVID-19: Is it useful in Japan?

For both elderly and young people, harm outweighs benefit.
For medical/welfare workers, unknown due to lack of data.
Translated and revised from Med Check (in Japanese) Mar 2021 ; 21 (94):28-33
Med Check Editorial Team

Abstract● RNA vaccines manufactured by Pfizer Biontech (BNT) and Moderna (MOD) are being inoculated around the world
as vaccines provisionally approved for COVID-19 (emergency use authorization).
● From the published information, the suppression rate of COVID-19 with onset (overt infection = symptomatic and
PCR positive cases) is 82 to 90% at about 2 to 3 months after the first dose, and about 95% for 1.5 to 2 months 1 to 2

weeks after the second dose. There was no difference among age groups. They prevented severe COVID-19 by 90%
or higher, but the preventive effect on death is unknown.
● The suppression rate of COVID-19 with onset by AstraZeneca's vaccine (AZD) which is a viral vector vaccine is 60%.
It is inferior to that of the other two vaccines (mRNA vaccine), and autoimmune neurological diseases were observed
at a high rate: 10 to 80 times higher than that in the general population. Incidence of and mortality from deep veinthrombosis especially cerebral venous sinus thrombosis is extremely high.
● The preventive effect on asymptomatic infection of COVID-19 (PCR positive without onset) is unknown with BNT and
MOD, but AZD was totally ineffective.
● Incidence of serious adverse events is not different from that in placebo in both mRNA vaccines, but severe
adverse events, such as fever and pain, are observed 1.7 to 2.5 times more frequently than in placebo in a shortterm after vaccination.
● In Norway, 1 in 1300 elderly people who received the vaccine has died, and causal relation with the vaccine has
been suspected. In the case of Hank Aaron's death (sudden death during sleep 2 weeks after vaccination), the causal
relationship with the vaccine cannot be denied. The long-term harm of vaccines, such as other autoimmune diseases
and nervous system disorders, is totally unknown.
● We calculated how many people should be vaccinated in order to reduce 1 death from COVID-19 in Japan,
assuming that the vaccine has the maximum suppression rate of COVID-19 with onset and the number of death
due to COVID-19 is fairly high in Japan. We found that 1700, 6400, 20,000, 60,000, 200,000, 600,000 and 2 million
people need to be vaccinated to prevent 1 death from COVID-19 in people aged 80 and over and those in their 70s,
60s, 50s, 40s, 30s and 20s, respectively.
● In other words, even if the effect of vaccine is assumed to be maximum and the harm is minimum, in those aged
80 and over, whose incidence of severe COVID-19 and mortality are high, the number of death from the vaccine isestimated to be higher than the number of deaths it can reduce.
● For medical and welfare workers who have a higher chance of infection, the benefits may outweigh the harms, butsince there is no data on mortality among this high-risk group, accurate analysis cannot be made.
Conclusion: Harm may outweigh benefits for both older and younger people
Harm-benefit balance is unknown for medical and welfare workers due to a lack of data.
Keywords:
vaccine, onset suppression rate, asymptomatic infection suppression rate, death of the elderly, sudden death during sleep, anaphylaxis

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April 2021/ Vol.7 No.20 ・ Page New Products
population aged 70-79 has completed the second

Introduction

vaccination at the end of January [12]. In Norway, 1 in

We made preliminary analysis for COVID-19 vaccines

1300 people aged 75 and over who received vaccination(candidates) before authorization in Med-Check in English

has died, and the relationship with the vaccine has been

No. 19 [1] and related materials [2].

suspected [13].

As of February 10th, 2021, RNA vaccines developedby Pfizer and Biontech (BNT162b2, hereinafter "BNT"),The points for evaluating harm and efficacy

and Moderna (mRNA1273, hereinafter "MOD") , andof the vaccines

a viral vector vaccine developed by AstraZeneca

The important points we considered when we(AZD1222, hereinafter "AZD") have received emergency

examined the efficacy and safety of these vaccines wereuse authorization and are now the main vaccines used

whether the reported 95% protection against COVID-19

against COVID-19 [3-5]. Since their approval is justis true or not, safety and the balance between them. We

provisional, they are "vaccine candidates", but to make italso reviewed how many people must be vaccinated tosimple, they are referred to as "vaccines" in this article.

reduce aggravation, especially death, due to COVID-19

Summaries of phase 3 trials (BNT [6], MOD [7]) andin case inoculation is widely implemented in Japan.

trials up to Phase 3 (AZD) [8] have been published for

The analysis was made by age based on the cumulative

each vaccine as well as results of regulatory evaluation

number of deaths as of February 3rd, 2021 [14].
The difference in the mechanism of action between[9-11].
It has been reported that in Israel, 80% of themRNA vaccine and viral vector vaccine are basically as

Table 1: Comparison of 3 major vaccines* a: This means that 200 persons need to be vaccinated to reduce the number of severe COVID-19 disease among population in which 1 of 190 persons develop severe
COVID-19 annually.
* b: Fever with 40℃ or higher (life-threatening or grade 4) in 13 patients and life-threatening vomiting in 1 patient in MOD group and only 3 patients had fever with
40℃ or higher in Placebo group.
* c, d: One of them died from COVID-19, and all others died unrelated to COVID-19.
* e: According to EU product information [11].
* f: There was no protection effect of asymptomatic or symptoms unknown COVID-19. Including these, the protection rate of PCR test positive persons was 46.3% .
* g: 156 / 100,000 person-years is equivalent to 13 to 80 times the incidence of multiple sclerosis in general population (2 to 12 per 100,000 person-years).

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April 2021/ Vol.7 No.20

follows. The former is directly taken up by macrophages
and produces spike proteins of antigenic substances inmacrophages. On the other hand, the latter works in 2
steps. It first infects cells other than macrophages andEfficacy (protection rate) after the first dose is 82% (50produces spike proteins in them which are recognizedin BNT vs 275 in placebo). The primary outcome, efficacy

by antigen producing cells or macrophages and thenrate 7 days after the second dose (excluding patients who

destroyed by cell-mediated immunity. (See [15-23]).

were already infected at the time of vaccination), is 95% (8in BNT vs 162 in placebo). There is no major difference by

Clinical efficacy

age (93.7%-95.6%).

Table 1 summarizes the characteristics (basic

Prevention rate for aggravation is 89% (1 in BNT vs 9

properties, efficacy and harm) of the 3 preparations. We

in placebo). When MOD is included, it is 96%. In otherwill explain about each of them below following the datawords, the vaccine prevented aggravation in 1 in 300

on the table.

persons annually in the high-risk group in which 1 in
200 persons experience aggravation annually. Two

Pfizer/Biontech’s preparation (BNT)

persons and 4 persons died in BNT and placebo groups,

A phase 3 study for BNT [6,9] is a randomized placebo-

respectively, during the study, and no COVID-19 related

controlled trial (RCT), in which a half of the participants

death has been reported. Severity of the symptoms was(age 16 and above) were injected with BNT and the otherjudged by medical experts from Pfizer, who were nothalf with saline as placebo. Approximately 20,000

informed of the treatment assignment ([6] protocol).

participants received one or more injections in each

There are no comparative data on asymptomaticgroup, and they were observed for more than 1 week

infection, and preventive effect for such cases isafter the second shot. At baseline, in each group, 18,000

unknown.

participants had no COVID-19. The observation was

Serious adverse events have been reported at similar

carried out for 46 days, about 2300 person-years in eachfrequency in both groups. However, although details

group.

are unknown, some kind of adverse events (adverse

No difference was found in baseline characteristics

reactions) associated with the vaccine occurred in 21%

between the 2 groups. However, at the time of 2-monthof the participants in BNT and 5

follow-up (mean duration), 37,306 people were included,in placebo (odds ratio=approximately 5, p <0.00001) ,while 43,448 people had received one or more shotsand severe adverse events occurred 1.7 times more

after randomization. This means that 5742 people had

frequently in the vaccine group. The number of people

been withdrawn in the process. The biggest question is

who needed analgesics or antipyretics due to pain or

why they dropped out, but it is unknown because thefever was particularly high after the second dose in BNT

reasons of withdrawal were not reported.

group than in placebo group: 45 % vs 13 % in younger

Confirmed COVID-19 with onset was defined as thepresence of at least one of the following symptoms: fever,new or increased cough, new or increased shortness of% of the participants

subgroup (18 to 55 years) and 38 % vs 10 % in older
subgroup (>55 years). Odds ratio were both about 5.6(p<0.00001).

breath, chills, new or increased muscle pain, new lossof taste or smell, sore throat, diarrhea, or vomiting,Moderna’s preparation (MOD)combined with a respiratory specimen obtained during

A phase 3 study conducted by Moderna [7,10] is athe symptomatic period or within 4 days before or after

randomized placebo-controlled trial (RCT), in which about

it that was positive for SARS-CoV-2 by PCR testing.

a half of the participants aged 18 years and older wereAs shown in the formula below, protection rate (%)

injected with MOD and the other half with saline. Aboutagainst COVID-19 with onset is the ratio of the difference

30,000 people (15,000 people in each group) received

between the incidence in placebo group and vaccine

one or more injections. At the start of the study, 27,000

group to the incidence in the placebo group, and this isparticipants in both groups had no COVID-19 and wereconsidered as the efficacy rate of the vaccine.

followed at least 2 weeks after the second dose (duration
MED CHECK

April 2021/ Vol.7 No.20 ・ Page New Productsof follow up: 3400 person-years in each group).

pharynx. In animal studies, viral load in the nasopharynx

In this study, the participants and observers were

was not different from that of the control group, andmasked, but investigators were not, meaning that the

no protective effect against COVID-19 infection wastrial was not properly double-masked. This means thatobserved. The fact that subclinical infection is not

inoculators knew the assignment, and there might have

prevented in humans is in accordance with the theory,

be subtle difference in how they dealt with participants

and is quite predictable from the results of animalin the two groups.

experiments.

The protection rates was 90% after the first doseOn the other hand, in the observation for 1280 person-and 94% at least 14 days after the second dose, which

years (Note 1), total 2 cases of autoimmune neurological

was almost the same result as that with BNT. There isdiseases were reported: 1 case with transverse myelitis

no comparative data on asymptomatic infections, andand 1 apparent case with multiple sclerosis. This isprotection of overall infection is unknown also on MOD.

156 per 100,000 person-years (95% confidence interval:

Regarding harm, some kind of serious reactions

18.9-563). It is a very high rate: 10-80 times higher thanoccurred in 20% of the participants in MOD group. Inthat of incidence rate of multiple sclerosis in general

addition, related adverse events (adverse reactions) were

population (2 to 12 per 100,000 persons-years).

found 2.5 times more frequently in the vaccine group:
71 (0.5%) with MOD vs. 28 (0.2%) with placebo. It is also

In Norway, 1 in 1300 elderly people diednoteworthy that fever above 40℃ (rated as grade 4 = life-

In Norway, 42,000 elderly people aged 75 and overthreatening) or life-threatening vomiting occurred in 1

were vaccinated with BNT, and 33 died within a few daysin 1000 people in the MOD group. These are criticalafter the vaccination [24]. Norwegian Medicines Agency

because they may cause death in the elderly.

has investigated 13 of the deaths so far and concluded

Note 1:In our article in Med-Check in English No 19 [1], it wasestimated to be about 1600 person-years, but the published data
revealed that it was 1280 person-years [8].

AstraZeneca’s preparation (AZD)

that common adverse reactions of mRNA vaccines, suchas fever, nausea, and diarrhoea, may have contributed
to fatal outcomes in some of the frail patients. The
Norwegian Institute of Public Health said that for thosewith the severest frailty even relatively mild side effects

The reports on AZD [8,11] are mainly Phase 2/3

can have serious consequences and that the benefits ofand Phase 3 trials, but they also include two Phasethe vaccine to those with a very short life expectancy

1/2 trials. In both Phase 2/3 and Phase 3 trials, only

may be marginal or irrelevant. It also recommended thatthe participants were masked, but inoculators anddoctors carefully consider the benefits and disadvantages

observers were not. Even so, follow-up was carried outof giving the vaccine to extremely frail patients (such as

for maximum 1300 person-years, and only 680 person-

those whose frailty is ranked 8 or 9 on the Clinical Frailty

years from 2 weeks after the second inoculation. Efficacy

Scale or equivalent) and terminally ill patients ahead ofrate is 60% which is lower than BNT and MOD. Thisvaccination. [24].

result is consistent with that of the animal experiment

For example, as described above, a clinical trial has
reported that MOD caused life-threatening fever above

with monkeys.
Total 34 and 37 patients with subclinical infection

40 ℃ or life-threatening vomiting in 1/1000 people [7].

(asymptomatic or unknown symptom) were reported in

If this happens in the frail elderly, it can actually lead to

AZD and control groups, respectively, and prevention

death.

rate was 7.8% (no significant difference). However, when
the numbers of people with symptoms (63 vs 150) wereHank Aaron's death may also be related

subtracted from the numbers of participants with PCR

Hank Aaron, an 86-year-old former major league

positive (102 vs 189), and were compared, the prevention

legend and home run king who overtook Babe Ruth,

rate turned out to be 0%.

received the first dose of Moderna's vaccine for

Intramuscular injection of AZD does not induce IgA

COVID-19 with his wife on January 5, 2021, and theantibody that protects against infection in the nose andnews was covered by the media [25]. It was supposed toPage  ・ MED CHECK

April 2021/ Vol.7 No.20

be a message to black Americans that "vaccines are safe".
He wrote in Twitter "I was proud to get the COVID-19
vaccine earlier today at Morehouse School of Medicine.

Apnea due to inflammation not only ininfants but also in adults

I hope you do the same! " [26] . However, on January

Let us explain the mechanism of inflammation-related

22nd, 17 days after the injection, he died during sleep.

loss of respiratory drive. Inflammations occur not

It was reported that no other cause of death had been

only by infections, allergy and vaccines, but also non-identified [25].

infectious non-allergic inflammations occur. The latter

After his death was reported, the relationship with theare the process of repairing injuries caused by severe

vaccine was denied by a flood of comments insisting thatobesity and/or by ischemia-reperfusion injuries (caused

the death followed a natural course [27,28].

by sustained stress and its withdrawal). Interleukin-1β(IL-The relationship between sudden infant death1β) , a type of pro-inflammatory cytokine, enhances

syndrome (SIDS) or unexpected sudden death (SUD)

cycloxygenase which produces prostaglandin E2, anand vaccinat ion is epidemiolog ically confirmed

inflammatory substance, in the cells of the capillaries[29-31] (Note 2). A series of sudden deaths due to Hibof the brain, and releases it into the brain. It acts on theand pneumococcal vaccines led to the suspension of

respiratory center in the medulla oblongata, impairing

vaccination in March, 2011. Although it was resumed

the respiratory drive and suppressing breathing. It

after one month, the relationship between vaccination

is believed that hypoxia induces tissue injuries withand sudden death was highly suspected [30,31].

inflammation which increase of prostaglandin E2

After that, 50 cases diagnosed with SIDS by forensic
autopsy were examined in Japan. Vaccination was

production more, causing a vicious cycle of hypoxia andrespiratory arrest [37,38].

confirmed in 32 cases. Among them, it was reported that

These are the findings from animal studies thatvaccine was given 7 days before death in 7 cases, andcorrespond to human infants [37,38], but similar effects

the association with the vaccine is strongly suspectedhave been observed even after some growth[37, 39].

[32]. Many cases have been reported, in which twins

This mechanism also applies to "sleep apnea

died suddenly on the same day after vaccination

syndrome" in adults. The syndrome is believed to be[33-35], suggesting a very strong relationship between

primarily caused by obesity-induced airway obstruction

vaccination and sudden death.

[40], but this is not the only cause.

Note 2: Meta-analysis result of case-control studies [36] indicatesthat vaccination was effective in halving the incidence of SIDS.
However, these studies ignore "healthy vaccinee effect", meaning

In highly obese people, cytokines, such as TNF-α andinterleukin (IL, especially IL-6 and IL-1β) , are induced,
causing various inflammatory reactions in the bodythat vaccinated people are usually healthy and those with fever or

to cause heart disease and diabetes [41]. Moreover,illness would avoid vaccination [29-31]. It can be considered thatcytokines increase prostaglandin E2, which maythese studies showed the opposite result because of this effect.

cause apnea and hypoxia during sleep. In sleep apnea

Why sudden death occurs after vaccination

syndrome, cytokines, such as TNF- α and interleukin, areincreased [42]. The condition of high cytokine level due

This question was discussed in Med-Check No. 43 [31]to obesity can cause apnea, and hypoxia caused by apnea

and TIP 2011 April Issue [30]. When hypoxemia occurs

can also enhance the condition of high cytokine level,for some reason, the respiratory center of the brain

causing increased prostaglandin E2 and inflammation

normally senses a lack of oxygen and orders to promote[42], resulting in a vicious cycle [37,38].

breathing by respiratory drive function and increase
oxygen concentration. However, it is believed that if

Fever and local swelling can be caused bythis mechanism is impaired by drugs (Tamiflu, sleeping

COVID-19 vaccine

pills, opioids, etc.) , bacterial toxins, and inflammatory

With pneumococcal vaccine, nearly 40% of children

conditions due to infectious diseases, respiratory drive

experience fever, and some percentage to 10% of themdoes not function in hypoxic condition, leading todevelop a temperature of 39℃ and above. One-fifth to one-deterioration and respiratory arrest.

third of them fall asleep after each vaccination [31].
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April 2021/ Vol.7 No.20 ・ Page New Products
Vaccines for COVID-19, BNT and MOD, cause fever inon December 18th, 2020. He developed idiopathic

about 10% to 20%. They also cause local swelling inthrombocytopenic purpura (ITP) after 3 days and died of

response to foreign substances, and substantial amount

cerebral hemorrhage 16 days after vaccination [45].

of inflammatory cytokines are released, leading to

A characteristic of autoimmune diseases after

inflammatory state, including arthritis etc. It has been

vaccination, including nervous system disorders suchreported that mild viral or bacterial infections are also

as multiple sclerosis, is that they may occur long after

found in 70-80% of SIDS cases [31]. As vaccines create

vaccination. Since no long-term observation has beensuch a condition of infection, it is reasonable to thinkconducted so far, the true nature of harm of COVID-19

that they are related.

vaccines is completely unknown.

In the case of Hank Aaron, it can be suspected thatJapan’s Ministry of Health, Labor and Welfare (MHLW)

mild inflammation was caused by the vaccine, anddisclosed that 6 health care workers died within 20

respiratory drive did not function even at hypoxic

days after one million doses of BNT were inoculated. Of

condition, leading to progressed hypoxia and sudden

these, all four women died from hemorrhagic stroke,

death due to respiratory arrest. Regulators and the

2 subarachnoidal hemorrhage and 2 intracerebral

media deny the causal relationship, insisting that hishemorrhage. The age of one woman was 26 years old.

death followed the "natural course". However, nobody

Combined odds ratio of hemorrhagic stroke of women

expected that a man who enthusiastically advocated for

who received vaccination by age, compared with that ofthe vaccine on TV would have respiratory arrest andgeneral population in 2019 was 9.58 (95%CI: 1.50, 61.17,

die from old age 2 weeks after the injection. It is too

p=0.017, I2 = 40.9%) while combined all cause mortality

unrealistic to make it "unrelated".

by age compared with that of general population in2019 was 0.08 (95%CI: 0.03, 0.21, p<0.0001, I2 = 5.2%).

Anaphylaxis occurs 1 in 4000

Reporting odds ratio for mortality from hemorrhagic

In the U.S. and the U.K., it has been reported thatstroke was 209.7 (95%CI: 9.2, 4590, p<0.0001). Women

anaphylaxis occurred in 5 and 20 persons in 1 million

who received vaccination are far healthier than generaldoses, respectively. However, it is based on spontaneous

population in 2019 but died far more frequently from

reports and highly inaccurate.

hemorrhagic stroke.

According to a detailed survey at medical institutionsin the U.S., anaphylaxis occurred in 270 persons (BNT)

What would happen when applied in Japanor 230 persons (MOD) in 1 million doses [43]. In other

In Japan, vaccination will start for medicalwords, anaphylaxis occurred in 1 in about 4000 persons.

professionals by the end of February. In the published

In Japan, information on anaphylaxis cases has beentrials of BNT and MOD, the effect of vaccine candidates

actively collected and disclosed. The review by the Med-was tested on a group of people, 7-8% of which was

Check Team revealed that anaphylaxis occurred in 132

estimated to have symptomatic COVID-19 annually.

persons (73%) per 580,000 doses. This means that

However, in Japan, morbidity of COVID-19, including

anaphylaxis occurs in 230 persons in 1 million doses,

asymptomatic infection, is only 0.3% annually. If only

and approximately 1 in 4400 persons. [44]with symptomatic infection, the number would be far

Anaphylaxis occurs immediately after vaccination andsmaller. As compared to the participants of the trials,

can be treated by prompt and appropriate medication

morbidity is 1/30-40, and mortality is about 1/30 in(adrenaline and corticosteroids) . No death has been

Japan.

reported so far. However, since it can be also fatal withIt should be examined how the vaccines would reduce

delayed or wrong treatment, it requires very careful

severe cases as well. However, unfortunately, thetreatment.

cumulative number of severely ill patients has not been
published, and the cumulative number by age is also

Doctor dies of autoimmune disease

unknown. Only the number of deaths can be analyzed

A 56-year-old obstetrician-gynecologist in Miami,

by age. In June 2020, MHLW issued a notification to

the U.S. received the first Pfizer Biontech vaccine

prefectural governments to report all deaths if SARS-

Page  ・ MED CHECK

April 2021/ Vol.7 No.20

CoV-2 was positive in the PCR test [46]. Strictly speaking,it was very cold this winter compared to last winter,even deaths from other causes are also counted as

the epidemic is much greater than in the previous twodeaths from COVID-19. Therefore, the actual number ofseasons (April and July-August). As of February 14th, death

deaths from COVID-19 should be less than the disclosed

toll is still increasing. Therefore, the number of deaths

data, but for the time being, the data disclosed by thefrom the fall of 2020 to the third term may be more than

MHLW are used in this article.

double the number of deaths from the beginning of theOn the other hand, because of the scale of the trials

third term to date.

and the duration of observation, there was only 1 deathWe calculated how many people need to be vaccinatedfrom COVID-19 each in control groups in MOD and AZD

in order to reduce 1 death from COVID-19, assuming

trials, making it impossible to directly examine the effectthat the number of deaths in one year until the end of

on reducing deaths.

the third term will be double the number of deaths by

Therefore, assuming that the efficacy rate of BNT and

February 3, this year (Table 2). This is to ensure that

MOD (95%) can be applied to the preventive effect on

the effect of the vaccine is not underestimated. We also

death, and that the preventive effect lasts for 1 year, we

assumed that the vaccine reduces the number of death

examined how useful the vaccines would be in Japan. It

by 95%. To avoid misunderstanding, we would like tois a calculation of how many people in Japan need to beemphasize here again that the number of deaths that we

inoculated to reduce 1 death from COVID-19.

used for the calculation is fairly high.

The cumulative number of deaths and the number

The numbers of vaccinees required to reduce 1 deathof confirmed infections by age in Japan as of February

from COVID-19 are 1700, 6400, 20,000, 60,000,

3rd, 2021 [14] was published (Table 2). Partly because

600,000 and 2,000,000 for people aged 80 and over,Table 2: How many people need to be vaccinated to reduce 1 death from COVID-19 in Japan ?

A , B: From outbreak trends of COVID-19 in Japan (preliminary figures) (as of 2001 / 2/3. 18:00) [14]Approximate number in F: For example, it shows that when 1700 people aged 80 and over are vaccinated, 1 death can be reduced. In people aged below
30, about 6 million people need to be vaccinated to reduce 1 death in Japan.
G: In the U.K. and the U.S., where clinical trials for BNT, MOD, and AZD were conducted, 1 in 600 to 700 people die annually from COVID-19. Since thenumber of deaths by age in these countries is not available, our calculation is based on the assumption that it was the same as the distribution of deathsby age in Japan. In people aged 80 and over, inoculating 60 people can reduce 1 death per year in UK or in US. This suggests that except for the very frail
elderly, the vaccine is worth inoculating.
H: The number of deaths from pneumonia and the annual mortality rate (per 100,000) in 2019.
I: The mortality rate for 1 year since the start of COVID-19 epidemic. In those aged below 70, it is as low as 1/6 to 1/11 of the mortality rate for pneumonia
in 2019. For those aged 80 and over, it is even lower: 1/23 of the mortality rate for pneumonia in 2019.
In addition, the number of deaths from pneumonia from February to September 2019 was 60,593, and the number of deaths from pneumonia during thesame period in 2020 was 49,467, a decrease of 11,126 (18% ). As of the end of September, the number of deaths from COVID-19 is 1564, which is only
1/30 of the number of deaths from pneumonia and 1/7 of the decreased number in deaths from pneumonia.

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April 2021/ Vol.7 No.20 ・ Page New Products
and those in their 70s, 60s, 50s, 40s, 30s, and 20s,

and sudden death during sleep if so many doses arerespectively. Since there has been no death in those aged

given just to reduce 1 death.

below 20, the vaccine cannot reduce death in this age

Effect for healthcare professionals

group at all.
The number of deaths shortly after the vaccination in

In medical and welfare workers, who have a higher

people aged 75 and over in Norway is higher than the

chance of infection, the benefit may outweigh thenumber of deaths the vaccine could save in those aged

harm. Since there is no data on the mortality rate of

80 and over.

these high-risk individuals, it is not possible to make an

Including sudden death during sleep, such as theaccurate assessment. However, almost 10 times morecase of Hank Aaron, whose association authorities havefrequent sudden deaths from hemorrhagic stroke weredenied, and autoimmune diseases, such as the case of

already reported in female health care workers who

the obstetrician-gynecologist in the U.S., are taken into

were vaccinated, including one very young woman in

account, the harm can be greater, not only in the elderly,

her twenties, the age group in which no women havebut also in the younger age groups.

died from COVID-19 in Japan. Decision must be madeIn particular, in people aged below 30, 6 million people

according to the situation of each individual. We will

are required to be vaccinated in order to reduce 1 death.

continue to collect information, and publish them as

It is immeasurable how many people will experiencesoon as the data necessary for analysis are available.

anaphylaxis, autoimmune diseases, hemorrhagic strokes

https://www.timesofisrael.com/over-3-million-receive-1st-vaccine-shot-

Referencesbut-covid-outbreak-still-raging/1) MedCheck Editorial team. COVID-19 Vaccine Candidates: Efficacy and Safety:13) Torjesen I. COVID-19: Doctors in Norway told to assess severely frail patients for

Is frequent neurotoxicity related to new technologies? Med Check in English

vaccination.

2020：6（19）：64-70.

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https://www.npojip.org/english/MedCheck/Med% 20Check% 20Tip-19-2020-12-24.pdf
2) MedCheck Editorial team. Web-supplement for https://www.npojip.org/chk_tip.
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14) MHLW. Domestic outbreak trends of new coronavirus infections (preliminary
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1. https://www.npojip.org/chk_tip/No92-f06.pdf
2. https://www.npojip.org/chk_tip/No92-f07.xlsx
3. https://www.npojip.org/chk_tip/No92-f08.xlsx3) CDC. ACIP Evidence to Recommendations for Use of Pfizer-BioNTech COVID-19
Vaccine under an Emergency Use Authorization
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15) BioNTech, How mRNA-based voccine work. https://biontech.de/covid-19-portal/
mrna-vaccines16) CDC, Understanding mRNA COVID-19 Vaccines
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4) Reuters, U.S. authorizes Moderna COVID-19 vaccine, elderly next in line for shotsrhesus macaques from SARS-CoV-2. Nature.

5) AstraZeneca , AstraZeneca’s COVID-19 vaccine authorised for emergency supply

https://doi.org/10.1038/s41586-021-03275-y (2021). PMID:33524990

in the UK(https://www.biorxiv.org/content/10.1101/2020.09.08.280818v1.full.pdf6) Polack FP, Thomas SJ, Kitchin N et al. Safety and Efficacy of the BNT162b2 mRNA
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against SARS-CoV-2 in Nonhuman Primates N Engl J Med 2020;383(16):1544-55.

b)Supplement: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2034577/
suppl_file/nejmoa2034577_appendix.pdfc)Protocol: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2034577/
suppl_file/nejmoa2034577_protocol.pdf
7) Baden LR, El Sahly HM, Essink B et al. Efficacy and Safety of the mRNA-1273
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PMID:32722908
19) Jonathan Corum and Carl Zimmer How the Oxford-AstraZeneca Vaccine Works,
The New York Times. https://www.nytimes.com/interactive/2020/health/oxfordastrazeneca-covid-19-vaccine.html
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coronavirus/2019-ncov/vaccines/different-vaccines/viralvector.html21) van Doremalen N, Lambe T, Spencer A et al ChAdOx1 nCoV-19 vaccine prevents

8) Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1
nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four
randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan
9;397(10269):99-111. Epub 2020 Dec 8. PMID: 33306989
9) Pfizer-BioNTech COVID-19 Vaccine、FDA Briefing Document. Vaccines and Related
Biological Products Advisory Committee Meeting (December 10, 2020) https://www.fda.gov/media/144245/download10) Moderna COVID-19 Vaccine、FDA Briefing Document. Vaccines and Related
Biological Products Advisory Committee Meeting (December 17, 2020) https://www.fda.gov/media/144452/download11) https://www.ema.europa.eu/en/medicines/human/summaries-opinion/covid-19vaccine-astrazeneca

SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020
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22) van Doremalen N, Purushotham J, Schulz J et al. Intranasal ChAdOx1 nCoV-19/
AZD1222 vaccination reduces shedding of SARS-CoV-2 D614G in rhesus
macaques. bioRxiv. 2021 Jan 11:2021.01.09.426058. doi: 10.1101/2021.01.09.4
26058. Preprint.PMID: 33447831
23) Wu S, Zhong G, Zhang J et al A single dose of an adenovirus-vectored vaccine
provides protection against SARS-CoV-2 challenge. Nat Commun. 2020 Aug
14;11(1):4081. PMID: 32796842
24) Torjesen I. COVID-19: Doctors in Norway told to assess severely frail patients for
vaccination https://www.bmj.com/content/bmj/372/bmj.n167.full.pdf
25) US baseball legend and civil rights icon Hank Aaron dies. https://www.aljazeera.

12) Times of Israel. Over 3 million receive 1st vaccine shot, but COVID outbreak still
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2020-9-8)18) Cobet KS, Flynn B, Foulds KE et al. Evaluation of the mRNA-1273 Vaccine

com/news/2021/1/22/baseball-legend-hank-aaron-dies-at-age-86
26) Hank Aaron

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27) Fact Check: Hank Aaron's Death Was Not Related to COVID-19 Vaccine
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28) Hank Aaron's Death Erroneously Linked to COVID-19 Vaccination
https://www.hollywoodreporter.com/news/hank-aarons-death-erroneously-linkedto-covid-19-vaccination
29) von Kries R, Toschke AM, Strassburger K et al. Sudden and unexpected deaths
after the administration of hexavalent vaccines (diphtheria, tetanus, pertussis,
poliomyelitis, hepatitis B, Haemophilius influenzae type b): is there a signal? Eur J
Pediatr. 2005 Feb;164(2):61-9. PMID: 15602672
30) Hama R and Honzawa T. Death after vaccination of Hib vaccine and/or
pneumococcal vaccine. The Informed Prescriber, 201: 26(4): 54-61.
31) Hama R. It is too early to resume vaccination with hib and/or pneumococcal
vaccine. MedCheck 2011：11(43):58-68.
32) Vennemann MM, Höffgen M, Bajanowski T et al Do immunisations reduce
the risk for SIDS? A meta-analysis. Vaccine. 2007 Jun 21;25(26):4875-9.
PMID:17400342
33) Osawa M, Nagao R, Kakimoto Y et al. Sudden Infant Death After
Vaccination: Survey of Forensic Autopsy Files. Am J Forensic Med Pathol. 2019
Sep;40(3):232-237. PMID:31205057
34) Smialek JE. Sudden infant death syndrome (Letter to the edito). Am J Forensic
Med Pathol. 1981;2:280.
35) Roberts SC. Vaccination and cot deaths in perspective. Arch Dis Child.
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36) Koechler SA, Ladham S, Shakir A, et al. Simultaneous sudden infant death
syndrome: a proposed definition and worldwide review of cases. Am J Forensic
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is a key regulator of the respiratory response to infection and hypoxia in neonates.
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9894-9. PMID: 17535900
38) Vege A, Ole Rognum T. Sudden infant death syndrome, infection andinflammatory responses. FEMS Immunol Med Microbiol. 2004 Sep 1;42(1):3-10.
PMID: 15325392
39) Tai TC, Adamson SL. Developmental changes in respiratory, febrile, andcardiovascular responses to PGE(2) in newborn lambs. Am J Physiol Regul Integr
Comp Physiol. 2000 Jun;278(6):R1460-73.PMID: 10848512
40) de Sousa AG, Cercato C, Mancini MC, Halpern A. Obesity and obstructive sleep
apnea-hypopnea syndrome. Obes Rev. 2008 Jul;9(4):340-54. PMID:18363635
41) Yao L, Herlea-Pana O, Heuser-Baker J, Roles of the chemokine system indevelopment of obesity, insulin resistance, and cardiovascular disease. J Immunol
Res. 2014;2014:181450. PMID: 24741577
42) Kheirandish-Gozal L, Gozal D. Obstructive Sleep Apnea and Inflammation: Proofof Concept Based on Two Illustrative Cytokines. Int J Mol Sci. 2019 Jan
22;20(3):459. PMID: 30678164
43) CDC reports more allergic reactions to COVID-19 vaccines, but cases remain few
https://www.statnews.com/2021/01/06/cdc-reports-more-allergic-reactions-tocovid-19-vaccines-but-cases-remain-few/44) Miami Obstetrician Develops Bleeding Disorder, Dies After Getting COVID-19
Vaccinehttps://thevaccinereaction.org/2021/01/miami-obstetrician-develops-bleedingdisorder-dies-after-getting-covid-19-vaccine/45) Ministry of Health, Labor and Welfare Novel Coronavirus Infectious Disease
Countermeasure Promotion Headquarters. On the report of sudden deterioration
or death of patients with COVID-19.
https://www.mhlw.go.jp/content/000641629.pdf

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Review
2021 Annual Theme: Critical Appraisal of Treatment Guideline Series (19)Anaphylaxis: Both adrenaline andcorticosteroids are essential
Translated and revised from Med Check (in Japanese) May 2021 ; 21 (95):52-57
Med Check Editorial Team

Abstract● Anaphylaxis is a life-threatening adverse reaction to medicines, but it can be treated successfully with appropriate
treatment.
● The key sign leading to death is that of airway obstruction due to laryngeal edema. It may appear without skin
symptoms leading to asphyxia.
● If a patient is diagnosed with anaphylaxis, she/he should be promptly injected with adrenaline intramuscularly
and corticosteroids subsequently. Delayed use of adrenaline may threaten patient's life. In particular, its use after
cardiac arrest is almost ineffective.
● Adrenaline works via its β2 action which suppresses mast cell degranulation that is the fundamental cause ofanaphylaxis.
● However, resistance against adrenaline is developed and it becomes less effective within one to a few hours.
Corticosteroids in turn become effective at that time, so corticosteroids should always be used just after adrenaline.
The more severe the anaphylaxis is, the more necessary it is.
● It is appropriate that the guidelines emphasize the importance of adrenaline. However, it is inappropriate toemphasize the pressor and bronchodilator effects of adrenaline rather than the stabilization of mast cells via β2
receptors.
● The evaluation of corticosteroids is too low in the WAO guidelines. No use of corticosteroids is related to theincreased risk of biphasic anaphylaxis by 12-fold.
● If adrenaline and corticosteroids were used appropriately, they work effectively in cases of anaphylaxis exposedwith β blockers. There is no evidence base to use glucagon.
● The percentage of people who have experienced anaphylaxis is increasing rapidly. Anybody has a chance
to experience anaphylaxis and should be familiar with the initial symptoms of anaphylaxis in order to receive
appropriate treatment quickly.
Conclusion: Anaphylaxis should be immediately treated both with adrenaline andcorticosteroids.

Keywords:
laryngeal edema, airway obstruction, mast cells, degranulation, β2 receptors, tolerance, glucagon

using Pfizer-BioNTech vaccine since February 17 2021.

Introduction

The incidence of anaphylaxis caused by this vaccine

Vaccinat ion ag ainst COVID-19 (so-called novel

was 230 per million doses [1] (page 21) by our analysis

coronavirus disease) has been in progress also in Japan

based on the data targeting healthcare professionals

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April 2021/ Vol.7 No.20

issued by the Japanese Ministry of Health, Labor andand Richet after they observed a phenomenon during

Welfare [2]. According to a detailed survey targeting

their studies in 1902, using Actinia toxins instead ofhealthcare professionals in the United States., incidence

Physalia toxins. It was reported as follows: A healthy dogof anaphylaxis induced by Pfizer-BioNTech vaccine wasreceived a low dose of actinium toxin on day 0 and day

270 per million doses [3] which is similar to that in

3, which was tolerated with ‘almost no reaction’. After

Japan.

22 days, he received the same dose when in excellent

The number of people who have history of anaphylaxis

general condition. However, some seconds after thehas been rapidly increasing: the percentage of

injections the dog began to gasp and to wheeze, thechildren/ elementary to high school students who haveanimal was agonized, was not able to stand and lay on

experienced anaphylaxis was 0.14% (about 1 in 700) in

his side, developed bloody vomiting and died within 25

2004, but increased to 0.48% (about 1 in 200) in 2013 [4].

min. [8]. This was a phenomenon in which a toxin worked

Food allergies (2.6% to 4.5%) and allergic rhinitis (9.2 toreversely (ana-) to a defense (phylaxis), so it was named

12.8%) are also increasing, but the degree of increase in"anaphylaxis".

anaphylaxis is far more remarkable. It has been reported

After that, this phenomenon was found to be a typethat 1.6% of people, including adults, have experienced it

I allergy caused by sensitization of dogs that were firstin the United States [5].

inoculated with actinium toxin [9]. Of the four types ofEven if the incidence of anaphylaxis to individual drugs

allergies, type I allergy produces IgE antibodies against

or foods is very rare (i.e. 1 in tens of thousands), there are

the antigen in the body at the first inoculation, which

thousands of drugs and foods, so the total incidence maybinds to the second inoculated antigen, which stimulates

be considerable.

mast cells to cause a reaction. Anaphylaxis is the mostAnaphylaxis is a serious adverse reaction to drugs

serious reaction of type I allergies.

that can occur on a daily basis. It is caused by various
substances including drugs, bee or wasp stings or by

Serious symptoms are due to mast cell

various foods [5-7]. Medical malpractice may occur withdegranulation.

inappropriate treatment. In fatal cases, symptoms may be

Serious symptoms of anaphylaxis are basically caused

serious from the beginning, but delay both in diagnosis

by two mechanisms:

and in adrenaline administration are closely related to(1) Degranulation: Mast cells release granules containing

death (see below).

inflammatory substances that have been stored in

On the other hand, the false guidelines

advance (symptoms appear immediately).

(recommendations for noradrenaline) issued in the(2) New synthesized inflammatory substances are

1970s are no longer seen in recent articles in medical

released (details will be described later).

journals and guidelines, and the use of adrenaline is

Anaphylaxis is most often caused by type I allergic

recommended equivocally. This is appropriate.

reactions, but this is not the only cause (Note 1). It can

However, Anaphylaxis Guidelines by the Japaneseoccur without allergies, but with chemical stimuli, non-Society of Allergology [5] and the Guidelines by theallergic drug hypersensitivity (opioids, vancomycin,

World Allergy Organization ( WAO) [6] have some

contrast media, disinfectants such as chlorhexidine, etc.), andinappropriate statements. It may result in delayedeven physical stimuli such as cold or abrasions caused

diagnosis or incorrect treatment. Therefore, we

by slipping accidents in the mountains [5-7].

thoroughly and critically appraised these guidelines.
We hope that understanding the pathophysiology ofanaphylaxis correctly by this article will lead to prompt
diagnosis and appropriate treatment which will save thelives of patients.

Note 1: Severe attacks in some asthma patients due tohypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs)
such as aspirin are not mediated by mast cells, but are sometimes
included in anaphylaxis. It also occurs, very rarely, in type II
allergies (cytotoxic) and type III allergies (immune complexes)that are not mediated by mast cells [10-12].

What is anaphylaxis?
Anaphylaxis is a name of the disease given by Portier
MED CHECK

April 2021/ Vol.7 No.20 ・ Page 13

Review
Symptoms of anaphylaxis
Regardless of the cause, the symptoms of anaphylaxis

each person.
Symptoms of anaphylaxis need to be given special
attention in the order of A, B, C.

are basically due to the stimulants pre-formed and

A: Airway, B: Breathing, and C: Circulation, which are

stored in the granules and the newly synthesised pro-important in an emergency requiring resuscitation, also

inflammatory substances which are released by theapply to symptoms of anaphylaxis [7] (Table 1).

activated mast cells. These points are particularly
important which will be explained in detail later, because(A) Airway

suppression of activated mast cells to stop degranulation

The most serious and life-threatening symptom is theand new production of pro-inflammatory substances isobstruction of airway due to laryngeal edema. The larynx

directly linked to rapid recovery from anaphylaxis (Note 1:(the part with the vocal cords) is so narrow hence if it ismechanisms other than Aspirin/NSAIDs-induced asthma areswollen, the airways would be obstructed, resulting in

extremely rare exceptions).

serious hypoxia, loss of consciousness, convulsions, andHistamine is the main stimulatory substance preformed and stored in the granules of mast cells. It causes

shock. Shocks that occur by profound hypoxia are themost important cause of death from anaphylaxis.

anaphylaxis, but its half-life is as short as a few minutes

In this condition, a patient stops breathing before[9], so if release of new granules is prevented, its effects

complaining of respiratory symptoms such as dyspnea

will subside quickly.

or wheeze [14,15]. These conditions occur without skinOn the other hand, leukotrienes and prostaglandins

manifestations, so an inexperienced doctor may not

are newly produced pro-inflammatory substances inknow what happened. Blood pressure does not risemast cells. This comes out about 5 to 30 minutes after

even if pressor agents were aggressively administered.

the mast cells are stimulated. Cytokines such as TNF α

Adrenaline should be used promptly (preferably slowly

and interleukin-4 (IL-4) are also produced on an hourly

intravenously) in life threatening cases and tracheal

basis [9].

intubated for oxygenation. Then you need a continuous

Mast cells are distributed throughout the bodyinfusion of adrenaline and corticosteroids. Moderate(submucosa and connective tissue), but the density of mastand mild airway symptoms include stridor (inspiratory

cell by organ varies individually. Those who are prone tolaryngeal sound), changes in voice (wheezing = hoarseness)

atopic dermatitis, prone to pollen conjunctivitis, prone

and stuffy throat.

to pollen rhinitis, and those who are prone to bronchial(B) Breathing

asthma may have lot of mast cells in each organ.

Bronchial anaphylaxis causes coughing and wheezing

Migraine headaches are also related to the activation of(expiratory bronchial sound), dyspnea, tachypnea, hypoxic

brain and/or meningeal mast cells [13]. The symptoms ofdelirium, and cyanosis: those symptoms frequently

anaphylaxis also differ from person to person. This may

observed in bronchial asthma attacks. As mentioned

also be related to the density of mast cells by organ ofin (A) above, sudden respiratory arrest may occur

Table 1:Symptoms of anaphylaxis: ABC in order of seriousness

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April 2021/ Vol.7 No.20

without apparent dyspnea or wheeze. Milder breathing/respiratory symptoms include rhinorrhea, sneezing, sorethroat, etc.
(C) Circulation

Adrenaline and corticosteroids are essential
It is the degranulation from activated mast cells thatcauses the symptoms of anaphylaxis. Even if you try to

When anaphylactic reactions occurs around a bloodraise the blood pressure that was lowered by histamine,

vessels, they may dilate, fluids exudate out of theit will come out from the mast cells one after another.

blood vessel, blood pressure drops, and tachycardia

Therefore, symptoms of anaphylaxis will not subside

occurs. However, severe dyspnea due to anaphylaxis

unless supply of histamine, i.e. degranulation is shut

may often rise blood pressure at early stage. This

off. How can degranulation from activated mast cells be

occurs because endogenous adrenaline is excreted insuppressed?

emergencies. But even in this situation with raised blood

The main player that suppress degranulation andpressure, adrenaline is needed to treat anaphylaxis toactivation of mast cell are adrenaline β 2 action andstabilize activation of mast cells. Hesitation of adrenalin

corticosteroids. Both receptors are present on theadministration may worsen anaphylaxis.

cytoplasmic membrane of mast cells.

(D) Derma / mucous membrane

Adrenaline acts on its β2 receptor and suppresses mast

Urticaria, rashes, itchiness, and redness occur on thecell activation and degranulation in seconds [16-18]. It

skin and mucous membranes of the mouth or eyes.

not only suppresses the release of histamine, but also it

In sudden cases, only subjective symptoms such as

suppresses new production and release of leukotrienes

numbness and flickering of the lips and fingers without

and prostaglandins [16,18].

apparent skin lesion may preceed.

Over the past decades, it was widely assumed that(E) Entero-Intestine (digestive tract)

corticosteroids work solely through regulating gene

When it occurs in the digestive tract, it causes nausea,

expression, which needs several hours to take effect.

abdominal pain, diarrhea, and vomiting. Anaphylaxis

However, it is revealed that corticosteroids have a second

caused by food or oral medication often causes swellingmechanism, termed rapid action that takes place withinof the gastrointestinal mucosa, causing nausea andseconds to minutes after the exposure. This rapid action

abdominal pain, followed by diarrhea, and then urticaria.

may involve plasma membrane and cytoplasmic activities

If the cause is food or oral medication, the first timeof the corticosteroids receptor [19,20].

only abdominal symptoms occur, the second time

Adrenaline is, of course, essential for the treatment of

abdominal symptoms and urticaria may occur. In theanaphylaxis. But not only that, corticosteroids need tothird time, generalised urticaria and shock may occur

be used immediately. In the guidelines [5,6], this idea of

due to anaphylaxis [13].

"cutting off the source" is basically weak.

(F) Others
If it occurs in the brain, headache, dizziness, anxiety,behavioral changes, delirium, and in severe cases,
convulsions and unconsciousness may occur.
C a r d i a c a n a p hylaxis may be manifested w i t harrhythmia or myocardial ischemia.
Anaphylaxis can occur in any organ, including the
bladder and uterus.
Anyway, obstruction of the airways due to laryngeal
edema is life-threatening and is the most important

Noradrenaline has no β2 effect and is ineffective
The α action (peripheral vasoconstriction) and β1 action(enhancement of cardiac contractility) of adrenaline andnoradrenaline are almost the same. If α and β1 actionsof adrenaline are important for treatment of anaphylaxis,
noradrenaline should also work for anaphylaxis in cirtain
extent. But in reality it is completely ineffective. Hencethe β 2 action, which noradrenaline does not have, isessential for the treatment of anaphylaxis (Figure 1).

cause of death from anaphylaxis. Hypoxic shock requires

In this regard as well, the description of the Japaneseoxygen. No matter how much the pressor agent is used,

and WAO anaphylaxis guidelines [5,6] are extremely

it is ineffective. Please be fully aware. In this regard, thevague.

guidelines are inadequate.

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April 2021/ Vol.7 No.20 ・ Page 15

Review
Adrenaline after cardiac arrest is ineffective
The fact that adrenalin injection fails to improveof no benefit in the acute management of anaphylaxis,
and may even be harmful; their routine use is becoming
controversial. " [6].

the circulatory state in the situation where mast cell

However, it takes only 30 minutes, rather than a few

degranulation has almost completed [21-24] also shows

hours, for corticosteroid to bind to mast cell receptors

the importance of "cutting off the source".

and act on nuclear genes to suppress pro-inflammatory

Death from anaphylaxis is due to the seriousness of

substances [19]. Moreover, it also acts on non-genetic

the reaction itself occurring within minutes, in addition

receptors on the cytoplasmic membrane of mast cells todelayed adrenaline injection is crucial [22-24].

suppress degranulation in seconds or minutes [19,20].

For example, if you hesitate to inject adrenaline

M o r e o ve r a n d i m p o r t a n t l y, b e c a u s e w h e n β 2because the patient's blood pressure is normal or

receptor resistance to adrenaline develop within aeven high in the early stages of anaphylaxis, patient's

short period, namely one hour or so (Note 2) , thehypoxemia may progress and blood pressure may drop

effects of corticosteroid become stronger [16,25,26].

suddenly resulting cardiorespiratory arrest.

This mechanism works naturally in the human body.

Adrenaline was used in treatment of 62% of fatal

However, adrenaline and corticosteroid must be used toanaphylaxis but it was used before arrest in only 14%.

work properly against the special external stimulus of[23,24]. Several other studies have been reported

anaphylaxis.

suggesting that delayed adrenaline use led to death [24].

C o r t i c o s t e r o i d s a r e a l s o e s s e n t i a l fo r
anaphylaxis treatment

Note 2: In the event of a crisis, one responds by secreting
adrenaline and dopamine, but continuous excitement and/or
hard fighting causes ischemia in various parts of the body.
Therefore, one reduces the number of receptors stimulated so

Another flaw in the guidelines is that they putthat they do not continue to fight. This is called "down regulation".

little focus on the need of corticosteroid. Japanese

A 50-minute class and a 10-minute break (recently adopted at theguidelines describe "it takes several hours to develop
action and may prevent biphasic anaphylaxis, but its
effect has not been proven" [5]. WAO guidelines argue"Glucocorticosteroids are commonly used in anaphylaxis,
with the objective of preventing protracted symptoms,

university) is a reasonable way to prevent ischemic damage to thebody due to sustained stress.

E v i d e n c e s h o w s CS p r e ve n t s b i p h a s i creactionsin particular in patients with asthmatic symptoms,

Corticosteroid (CS) is underrated by not only in theand also to prevent biphasic reactions (eg, intravenous

Japanese guidelines [5] but also in the World Allergyhydrocortisone, or methylprednisolone). However, there is

Organization (WAO) guidelines [7] as above. However,increasing evidence that glucocorticosteroids may be

we comprehensively analysed a review paper [27] that is
one of the most important references that

Figure 1:Difference of actions and effects between adrenaline andnoradrenaline

WAO guidelines cited and found that thedata on a paper [28] which concluded thatcorticosteroids were meaningless indicatedthat no use of corticosteroid is related toincreased risk with biphasic reaction clearly(Figure2).

Of the 240 extremely severe anaphylaxis
cases in which patients were hospitalized
for more than 8 hours after onset,
corticosteroid was not used only in one case.
Therefore, it is considered that the causeof the aggravation (or biphasic reaction) was
something other than corticosteroid use orPage 16 ・ MED CHECK

April 2021/ Vol.7 No.20

Figure 2:Corticosteroids prevent biphasic reactionof anaphylaxis(Analysis of 292 anaphylaxis cases who were discharged within 8 hours)of adrenaline increased the blood pressure once.
However, 2 cases [14,30] required 3 ampoules (1 mg x 3)
intravenous bolus injection of adrenaline within 10 to 15
minutes. In one case [29], the pressor effect disappeared
after 5 minutes.
The duration of the effect of bolus adrenaline isextremely short, within a few minutes, so continuous
infusion is absolutely necessary in these cases (Note
3 [32-35]) . However, all three cases did not receive

c o n t i n u o u s i n f u s i o n o f a d r e n a l i n . I n t w o cases[14,30], glucagon was used after continuously infusednoradrenaline and dopamine which failed to treat (Note 4[36,37]) and blood pressure decreased again.

unuse (the cases were primarily serious).

In one case [29], the blood pressure increased for 5

On the other hand, of the 292 anaphylaxis patientsto 10 seconds to 80/50 mmHg and heart rate increased

who were discharged within 8 hours after the onset

transiently to 60 /min after intravenous injection of 1

(which is considered to be relatively mild or moderate), 277

mL of adrenaline (1:10,000) and intravenous saline. So

were on corticosteroid among which only 8 (3%) got

it was effective. However, when the patient failed toworse again (biphasic). However, 4 (27%) of the 15 non-respond to adrenalin within 5 minutes, reason of shortuser of corticosteroids got worse again (biphasic). The

duration of effect of adrenalin was mistakenly consideredrisk of biphasic due to nonuse of corticosteroids was 12

the concomitant use of beta-blocker (atenolol), a 1 mg

times higher (Figure2).

intravenous bolus glucagon was given and mean arterial
blood pressure increased from 55 to 75 mmHg. He

No glucagon required

received another 1mg bolus glucagon but blood pressure

There are descriptions that glucagon can be usefuldecreased again after 30 minutes. Then he was given

to treat refractory anaphylaxis in a patient taking acontinuous intravenous infusion of glucagon. He wasbeta-blocker [5-7]. This method is gaining worldwide

also given intravenous methylprednisolon 125 mg every

recognition, but only two case reports [29,30] are the

6 hours and diphenhydramine 50 mg intramuscularly.

basis for the recommendation. In addition, we found 2

In these cases sufficient continuous infusion of

more cases [14,31] including a Japanese literature[14].

adrenaline shall be surely effective. But in these cases

We examined these four cases in detail. First of all, it is

no or insufficient continuous infusion of adrenaline

noted that the β-blockers used were all cardiac-selective,

was used. Treatment failure with adrenalin in thesethat is, β1-selective β-blockers in four cases. Atenolol in

anaphylaxis cases is not surprising.

2 cases [29,30], bisoprolol in 1 case [14] and metoprolol

Another case [31] was a 54-year-old woman who

in 1 case [31]. Since these β1-selective β-blockers do not

had anaphylaxis induced by the anti-interleukin-5

inhibit β2 action of adrenalin. Administered adrenalin

monoclonal antibody mepolizumab for bronchial asthma.

can act on β2 receptors on mast cell and shall be fully

After intramuscular injection of 0.3 mg of adrenaline

effective.

three times and intravenous injection of 125 mg ofSecond, careful examination of the treatment course of

methylprednisolone, blood pressure finally improved toeach case, revealed that the use (dose and infusion speed)

186/118 and heart rate 77/min. However, glucagon wasof adrenaline was inappropriate in all 4 cases.

used because she continued to feel that her throat was

Three cases [14,29,30] had a decrease in blood

closing and other medication review revealed that shepressure immediately after the use of contrast media.

was on metprolol treatment, although she was saturating

In one sudden case [14], cardiac arrest occurred only

96% on room air.

2 minutes after administration of contrast media.

Mepolizumab is an extremely long acting drug

In all three cases, intravenous bolus administration

with a peak blood concentration of 2 to 3 hours after
MED CHECK

April 2021/ Vol.7 No.20 ・ Page 17

Review
intravenous injection, 5 days for subcutaneous injection,

properly used, glucagon is not needed at all.

and a half-life of around 20 days (according to a Japanese

Adrenaline while using antipsychotics

package insert).

Therefore, it is considered that the anaphylactic

Adrenaline was previously contraindicated insymptoms continued, as antigen stimulation persisted

combination with neuroleptics (antipsychotics) such aswith feeling of obstruction of the larynx. Both blood

haloperidol and risperidone, but recently it is no longer

pressure and heart rate were completely recovered (blood

contraindicated in the case of anaphylaxis [40].

pressure 186/118) and no adverse effect of β-blockers

was seen when glucagon was given.

Adrenaline is still contraindicated for overdose of
antipsychotics with circulatory collapsed shock. In fact,

In summary, all four cases in which anaphylaxis

some cases were reported [41,42]. The mechanisms

was intractable due to the use of β-blockers were only

are summarized that large amounts of neuroleptics

intractable due to inappropriate use of adrenaline

antagonize the α action of adrenaline, and the β2 action

and corticosteroids. With proper use of adrenalineof adrenaline causes the blood vessels in the muscles

and corticosteroid (Note 4) , glucagon is absolutely

to dilate and to decrease blood pressure. In this case,unnecessary.

noradrenaline, which has no β2 action should be used toincrease blood pressure.

Note 3: The duration of effect of isoprenaline is about 3 minutes[32], and the duration of effect of adrenaline is shorter thanisoprenaline [33]. In anaphylaxis, intramuscular injection of

Noradrenaline is ineffect ive for treatment ofanaphylaxis developed in a person taking recommended
doses of antipsychotics. Adrenaline is absolutely needed,adrenaline has a peak effect after 5 to 10 minutes and lasts forand it is unlikely to cause a paradoxical decrease in blood

about 40 minutes [5,34]. However, from the results of animalpressure in a patient treated with recommended dose ofexperiments, in super-severe cases of sudden cardiac arrest,

neuroleptics. However, in very rare condition in which

neither intramuscular nor subcutaneous injection are effective,
and the effect of one intravenous injection is temporary andineffective without continuous infusion. [35].
Note 4: In the cases in reference [14], adrenaline was continuously

airway is no longer obstructed, there is no difficulty
breathing, and only recovery of blood pressure is poor,
noradrenaline might be necessary.

infused after three bolus intravenous administration, but it was
0.02 to 0.08 μ g/kg/min, which is extremely low compared withthe recommended dose for severe cases (0.3 to 0.45 μ g / kg /min) [36,37]. In any case, the use of adrenaline was inappropriate.
In this case, corticosteroid were not used for at least 2 hours after
the onset, and it is assumed that the timing of glucagon injection
coincided with the timing of the commencement of effectivenessof delayed use of corticosteroid.

In practice
The principles of treatment for anaphylaxis are shownin Table 2 with some modifications to the UK guidelines[8,43].
Anaphylaxis is a serious adverse reaction caused bydrugs. Inappropriate treatment may not save lives, butproper treatment can prevent death.

Glucagon is merely an adjunct to betablocker overdose
Glucagon acts on a site different from adrenaline toincrease c-AMP, which is the source of energy in thecell, acts like adrenaline, and also acts on mast cells,
vascular smooth muscle, and myocardium [38]. However,even in the case of overdose of beta-blocker, the basic
treatments are adrenaline, isoprenaline, and vasopressin,
and glucagon has only a supplementary meaning [39].
Moreover, non-toxic doses of beta-blockers, especially
β1-selective beta-blockers, do not antagonize the β2 actionof adrenaline, so if adrenaline and corticosteroids are
Page 18 ・ MED CHECK

April 2021/ Vol.7 No.20

Diagnose anaphylaxis appropriately as soon as
possible, inject adrenaline immediately, and remember touse corticosteroids subsequently.

Table 2: Principles of anaphylaxis treatment

Modified from ref. [8]*: However, for patients with a history of aspirin/NSAIDs-induced asthma, oral prednisolone 50 mg or betamethasone injection 4-8 mg should beselected, because these are not a succinate ester and does not contain parabens (methyl paraben or propyl paraben).

References

https://hospital.city.sendai.jp/pdf/p062-065% 2035.pdf
15) Hama R et al., Phytonadione (Vitamin K) and anaphylactic-type shock, The

1) Ministry of Health, Labor and Welfare, Vaccine Adverse Reaction Study Group,
Drug Safety Measures Investigation Committee (jointly held) Material (2021-3-26)
https://www.mhlw.go.jp/stf/newpage_17448.html (in Japanese)
2) MedCheck editorial team, High Incidence of anaphylaxis: 1 in 4400, MedCheck
Rapid report No194 (in Japanese)
https://www.npojip.org/sokuho/210405.html
3) Blumenthal KG, Robinson LB, Camargo CA Jr, et al. Acute Allergic Reactions tomRNA COVID-19 Vaccines. JAMA. 2021 Mar 8. PMID: 33683290
4) Ministry of Education, Culture, Sports, Science and Technology: Survey on healthmanagement in school life. (2013) (in Japanese)
https://www.gakkohoken.jp/books/archives/159
5) Japanese Society of Allergology, Anaphylaxis Guidelines 2014 https://anaphylaxisguideline.jp/pdf/anaphylaxis_guideline.PDF
6) Cardona V, Ansotegui IJ, Ebisawa M et al. World allergy organization anaphylaxis
guidance 2020. World Allergy Organ J. 2020 Oct 30;13(10):100472. PMID:
33204386 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607509/pdf/main.pdf
7) Resuscitation Council (UK). Emergency treatment of anaphylactic reactions.
Guidelines for healthcare providers. Resuscitation Council (UK). London, 2008.
http://www.resus.org.uk/pages/reaction.pdf
8) Ring J, Grosber M, Brockow K, Bergmann KC. Anaphylaxis. Chem Immunol Allergy.
2014;100:54-61.PMID: 24925384
9) Male D. et al Japanese version translated by Kozu S et al Immunology 7th Edition,
Mosby Elsevier 2006. (in Japanese)
10) Justiz Vaillant AA, Vashisht R, Zito PM. Immediate Hypersensitivity Reactions.
2020 Dec 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;
PMID: 30020687
11) Roitt I. et al. Japanese version translated by Tada T et al Immunology (Originally
5th ed)、Nankodo、2000 (in Japanese)
12) Hama R. Cefaclor ：High incidence of serious allegic reactions. The Informed
Prescriber 1988：3(8)：57-63．(in Japanese)13) Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A The
role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev. 2005
Jul;49(1):65-76. PMID: 15960987
14) IzutsuT et al. A case of cardiopulmonary arrest due to anaphylactic shock, acontrast medium that was difficult to treat due to oral administration of
β-blockers, was saved by administration of glucagon, Sendai City Hospital Medical
Journal 2015: 35 : 62-65. (in Japanese)

Informed Prescriber 1986: 1 (2): 9-12. (in Japanese)16) Kay LJ, Peachell PT. Mast cell beta2-adrenoceptors. Chem Immunol Allergy.
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17) Duffy SM, Cruse G, Lawley WJ, Bradding P. Beta2-adrenoceptor regulation of
the K+ channel iKCa1 in human mast cells. FASEB J. 2005 Jun;19(8):1006-8. PMID:
15817638
18) Wang XS, Lau HY. Beta-adrenoceptor-mediated inhibition of mediator releasefrom human peripheral blood-derived mast cells. Clin Exp Pharmacol Physiol.
2006. PMID: 16895550
19) Oppong E, Flink N, Cato AC. Molecular mechanisms of glucocorticoid action inmast cells. Mol Cell Endocrinol. 2013 Nov 5;380(1-2):119-26. PMID: 23707629
20) Zhou J, Liu DF, Liu C et al. Glucocorticoids inhibit degranulation of mast cells inallergic asthma via nongenomic mechanism. Allergy. 2008 Sep;63(9):1177-85.
PMID: 18699934
21) Bautista E, Simons FE, Simons KJ et al. Epinephrine fails to hasten hemodynamic
recovery in fully developed canine anaphylactic shock. Int Arch Allergy Immunol.
2002 Jun;128(2):151-64. PMID: 12065916
22) Kemp SF, Lockey RF, Simons FE (World Allergy Organization ad hoc Committee
on Epinephrine in Anaphylaxis). Epinephrine: the drug of choice for anaphylaxis-a
statement of the world allergy organization. World Allergy Organ J. 2008 Jul;1(7Suppl):S18-26. PMID: 23282530
23) Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal
reactions. Clin Exp Allergy. 2000 Aug;30(8):1144-50. PMID: 10931122
24) McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatmentof anaphylaxis: what is the evidence? BMJ. 2003 Dec 6;327(7427):1332-5. PMID:
14656845
25) Chong LK, Morice AH, Yeo WW, Peachell P. Functional desensitization of betaagonist responses in human lung mast cells. Am J Respir Cell Mol Biol. 1995
Nov;13(5):540-6. PMID: 7576689
26) Peachell P. Regulation of mast cells by beta-agonists. Clin Rev Allergy Immunol.
2006 Oct-Dec;31(2-3):131-42. PMID: 17085789
27) Pourmand A, Robinson C, Syed W et al. Biphasic anaphylaxis: A review of theliterature and implications for emergency management. Am J Emerg Med. 2018
Aug;36(8):1480-1485. PMID: 29759531
28) Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic anaphylactic reactions:occurrence and mortality. Allergy. 2014 Jun;69(6):791-7. PMID: 24725226
29) Zaloga GP, Delacey W, Holmboe E, et al. Glucagon reversal of hypotension in a

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Reviewcase of anaphylactoid shock. Ann Intern Med 1986;105(1):65–6. PMID: 3717811
30) Javeed N, Javeed H, Javeed S, et al. Refractory anaphylactoid shock potentiatedby beta-blockers. Cathet Cardiovasc Diagn 1996;39(4):383–4. PMID: 8958428
31) Rukma P. Glucagon for Refractory Anaphylaxis. Am J Ther. 2019 Nov/Dec;26(6):e755-e756. PMID: 30648988
32) Kosinski EJ, Malindzak GS Jr. Glucagon and isoproterenol in reversing
propranolol toxicity. Arch Intern Med. 1973 Dec;132(6):840-3.PMID: 4757253
33) Brunton LB et al. Goodman & Gilman’s The Pharmacological Basis ofTherapeutics 12th ed McGraw-Hill, 201134) Simons FE, Roberts JR, Gu X, Simons KJ Epinephrine absorption in children witha history of anaphylaxis. .J Allergy Clin Immunol. 1998 Jan;101(1 Pt 1):33-7.
PMID: 9449498
35) Mink SN. Simons FER, Simons KJ et al. Constant infusion of epinephrine, but notbolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs
Clin Exp Allergy 2004; 34:1776–1783 PMID: 15544604
36) Brown SG, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis;
prospective evaluation of treatment with intravenous adrenaline and volume
resuscitation Emerg Med J. 2004 Mar;21(2): 149-54. PMID: 14988337
37) Brown SG. Anaphylaxis: clinical concepts and research priorities. Emerg Med
Australas. 2006 Apr;18(2):155-69. PMID: 16669942
38) Morris CH, Baker J. Glucagon. 2020 Jun 14. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2021 Jan–.PMID: 32644621
39) Graudins A, Lee HM, Druda D Calcium channel antagonist and betablocker overdose: antidotes and adjunct therapies..Br J Clin Pharmacol. 2016
Mar;81(3):453-61. PMID: 26344579
40) Ministry of Health, Labor and Welfare, Pharmaceutical Safety Measures
Investigation Committee, Revision of Precautions for Use of Adrenaline
Preparations (in Japanese)
https://www.mhlw.go.jp/file/05-Shingikai-11121000-IyakushokuhinkyokuSoumuka/0000197888.pdf41) Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response toadrenaline infusions in massive quetiapine overdose. Crit Care Resusc. 2008
Dec;10(4):320-2.PMID: 19049484
42) Watson A. Alpha adrenergic blockers and adrenaline. A mysterious collapse. AustFam Physician. 1998 Aug;27(8):714-5.PMID: 9735490
43) Burton C, Worth A. UK Resuscitation Council guidelines on emergency
treatment of anaphylactic reactions: a primary care perspective. Prim Care Respir J.
2008;17(2):60-1. PMID: 18418500

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April 2021/ Vol.7 No.20

Adverse Reactions
Vaccines for COVID-19

High incidence of anaphylaxis: 1 in 4400
vaccinatedTranslated from Med Check (in Japanese) May 2021 ; 21(95):64-65
Med Check Editorial Team

Abstract● The Ministry of Health, Labor and Welfare (MHLW) said that out of 181 reported anaphylaxis cases after about
580,000 doses, only 47 met the diagnostic criteria and that there was no serious concern.
● However, according to our careful examination, there were 132 anaphylaxis cases which are clinically diagnosedout of 181 (73%). The incidence of anaphylaxis was calculated as 230 per million doses, or about 1 in 4,400.
● Reported incidences of 5 and 20 per million doses in the United States and Europe respectively are, based on the
spontaneous reports. Hence they are extremely inaccurate. In fact, in the United States, a precise survey shows thatthe incidence is as high as 230 to 270 per million times (1 in 4000).
● Considering that healthy people receive the vaccine, it should be said that the incidence is extremely high.

Keywords:
anaphylaxis, Brighton criteria, adrenaline, Epipen, polyethylene glycol, bronchial spasm, laryngeal edema

Introduction

among health workers including doctors, pharmacists[5] and nurses [6] based on the statistics of MHLW in

The Ministry of Health, Labor and Welfare (MHLW)

2018 was 77% (1.7 million among 2.2 million in total) .

announced on March 12, 2021 that it had received 36

Compared with the proportion, 95.6% is significantly

anaphylaxis case reports [1] and on March 26 that ahigh (p<0.00001).

total of 181 anaphylaxis case reports with approximately

The vaccine contains a lipid nano-particle to prevent

580,000 vaccinations by March 21[2]. As a result

degradation of mRNA. It is polyethylene glycol (PEG)of experts' assessments by applying the Brighton

which is also contained in many cosmetics or personal

Collaboration case definition [3], which is widely usedcare products etc. [7], Women who use cosmetics arein the diagnosis of anaphylaxis, 47 out of 181 reported

more easily sensitized and develop allergy to lipid PEG.

cases (26%) met the definition, or 81 per million doses.

It seems that this is one of the most important causes

Therefore, they judged that "no serious concern was

why the proportion of females is high among those withfound" [4]. Here we report the results of our careful

anaphylaxis.

assessment of these reported cases.

Among 181 cases, 125 (69%) had some kind of
hypersensitivity, and of the 125 people, 36 (nearly 30%)

Characteristics of 181 cases reported
Age distribution of 181 cases was as follows: 33%

had a history of asthma. There were 17 (14%) people
who had experienced anaphylaxis in the past.

was in their 40s, around 20% was in their 20s, 30s, and50s, and 3% was in their 60s. Only 8 were males (4.4%)
and 173 (95.6%) were females. The proportion of female

Clinical anaphylaxis cases were 132
According to our assessment by applying the Brighton
MED CHECK

April 2021/ Vol.7 No.20 ・ Page 21

Adverse Reactions
Collaboration case definition to the 181 reported cases,

Expert’s assessment: Brighton classification: Category

81 (45%) met the definition. The Brighton definition

4 (Reported anaphylaxis with insufficient evidence to meet

often excludes some clinically important anaphylaxis

the case definition)cases as shown later in this article including extremely

Expert's comments: It is not a case of anaphylaxis

serious cases, or those in which adrenalin etc. was usedbecause only respiratory symptoms were reported.

at a very early stage and subsequently other symptoms

Comments by MedCheck：Symptoms appeared about

did not appear. We included these cases as anaphylaxis

5 minutes after vaccination. Hence it meets the firstin addition to cases identified by the Brighton casecriteria of diagnosis of anaphylaxis (1) sudden onset.

definition. As a result, 132 cases (73%) were classified as

Moreover, dyspnea with sign of airway stenosis isanaphylaxis.

prominent with rapid progression: (2) signs andIncidence of anaphylaxis is 230 per 1 million dose
(132/580,000) or about 1 in 4400 doses.

s ym p t o m s a t a ve r y e a r l y s t a g e . F o u r d o s e s o f
intramuscular injections of adrenaline indicate theseverity of this case.

Same incidence as the rigorous US survey

Criterion (3) the symptoms in two or more organs was

Ve r y l o w i n c i d e n c e s o f a n a p h y l a x i s , 5 o r 2 0

not met. Therefore in spite of severe anaphylaxis, it wasanaphylaxis per 1 million doses in the United States andclassified as Category 5 (Not a case of anaphylaxis) by thein Europe [1,2] are based on the spontaneous reports andBrighton classification.

are extremely inaccurate.

However, she has a history of anaphylaxis. If a doctor

A rigorous survey of healthcare professionals in the

had waited without treating her with adrenaline until

United States [8] reported anaphylaxis in 270 per million

some urticaria or other skin symptoms appear, she mightdoses with the Pfizer vaccine and 230 per million doses

have been deteriorated with airway obstruction. Hencewith the Moderna vaccine. Both are about 1 in 4000

it was absolutely appropriate that the doctor decided topeople. These results in the United States are very close

administer adrenaline before skin reactions appeared.

to that in Japan, so it is certain that the anaphylaxis isThis is one of the most excellent examples showing avery frequently occurring in the world.

defect in the Brighton case definition.
If applied to the latest WAO guidelines：Because a

Cases excluded from anaphylaxis by theserious and definite anaphylaxis case might be excluded

authorities

by the former criteria and/or Brighton case definition,

Among the cases [2] excluded from anaphylaxis cases

the latest guidelines of the World Allergy Organization

by expert examination, two largely questionable cases(WAO) issued in 2020 [8] revised their diagnostic criteria

are shown (for other problematic cases, refer to the rapid

and added an item as follows:

report No191 [9] and No194 [10]).

Acute onset of hypotension or bronchospasm orCase 42:

laryngeal involvement after exposure to a known

A 26-year-old woman with a history of anaphylaxis

or highly probable allergen for that patient (minutes

induced by crabs and pineapples. Epipen (a portable

to several hours) , even in the absence of typical skinadrenaline injection) is prescribed.

involvement.

The vaccine (Pfizer/Biontec) was injected
intramuscularly, and 5 minutes later, nasal discharge

If this new criterion is applied, the case 42 is definitely

and cough appeared. Dyspnea occurred and worsened

anaphylaxis. Hesitating to inject adrenaline due to theimmediately with remarkable airway obstruction

absence of skin lesions may have led to hypoxic shock

symptoms. Adrenaline was injected intramuscularly,

with cardiopulmonary arrest and death. The revised

four doses in total. In addition, she was treated with

criterion is extremely important.

corticosteroids and antihistamines. She subsequently
recovered but she was hospitalized for follow-up
observation.
Page 22 ・ MED CHECK

Case 13:
A 53-year-old woman with a history of hypertension

April 2021/ Vol.7 No.20

and hyperlipidemia.
About 15 minutes after vaccination, precordial
redness with rash and dyspnea occurred. A sound

References
1) Ministry of Health, Labor and Welfare, Vaccine Adverse Reaction Study Group,
Drug Safety Measures Investigation Committee (jointly held) Material (2021-3-12)https://www.mhlw.go.jp/stf/newpage_17208.html (in Japanese)of upper airway stenosis was heard. Adrenalin was2) Ministry of Health, Labor and Welfare, Vaccine Adverse Reaction Study Group,

injected intramuscularly and symptoms improved. A

https://www.mhlw.go.jp/stf/newpage_17448.html (in Japanese)

Drug Safety Measures Investigation Committee (jointly held) Material (2021-3-26)

histamin H1 antagonist, a H2-blocker and an intravenous

3) Rüggeberg JU, Gold MS, Bayas JM et al. (Brighton Collaboration Anaphylaxis

corticosteroid were administered subsequently. After acollection, analysis, and presentation of immunization safety data. Vaccine.

follow-up for a while and recovery was confirmed, she4) The Japan Times. Japan reports 47 anaphylaxis cases after 580,000 vaccine shots,

Working Group) Anaphylaxis: case definit ion and guidelines for data
2007;25(31):5675-84. PMID: 17448577

was discharged.

but ministry confirms safety

Expert's assessment: Brighton case definition：

reaction-vaccines/

Category 4

hw/ishi/18/dl/toukeihyo.pdf

https://www.japantimes.co.jp/news/2021/03/27/national/science-health/allergic5) MHLW. Statistics on healthcare workers https://www.mhlw.go.jp/toukei/saikin/

Expert's comments: Each symptom is not clear enough6) MHLW. Statistics on healthcare workershttps://www.mhlw.go.jp/toukei/saikin/for diagnosis as anaphylaxis.

7) The Society of Cosmetic Chemist of Japan, Polyethylenglycol

Comments by MedCheck：The sound of upper airway
stenosis is called "stridor" which indicates that thepatient has laryngeal edema, one of the most important
symptoms leading to death without appropriate
treatment, i.e. immediate administration of adrenaline.

hw/eisei/18/dl/gaikyo.pdf
https://www.sccj-ifscc.com/library/glossary_detail/1656 (in Japanese)
8) Blumenthal KG, Robinson LB, Camargo CA et al Acute Allergic Reactions to mRNA
COVID-19 Vaccines. .JAMA. 2021 Mar 8:e213976. PMID: 33683290
9)MedCheck rapid report No191: https://www.npojip.org/sokuho/210317.html (inJapanese)10) MedCheck rapid report No194: https://www.npojip.org/sokuho/210405.html (inJapanese)Hence it is one of the major respiratory symptoms of theBrighton case definition. Precordial redness with rash is
at least one of the minor criteria on the skin. Therefore,
it can be judged as Category 2 (level 2) by the Brighton
case definition. It is not understandable why the experts
excluded this case from anaphylaxis by applying theBrighton case definition.

Conclusion
People who have some problems such as fever orheadache on the day of inoculation will not receive thevaccine. In other words, a healthy person who is in good
physical condition at least on that day can receive thevaccine.
Considering these, the incidence of 1 in 4400 asshown in this article is extremely high. It must be said
that the incidence of anaphylaxis is too high comparedwith the benefit.

MED CHECK

April 2021/ Vol.7 No.20 ・ Page 23

M
C

ED

HECK

2021

Vol.7

No.20

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

Page 24 ・ MED CHECK

April 2021/ Vol.7 No.20

Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist); MUKAI,
Junji (Pharmacist); SUMIDA, Sachie(MD [Dermatologist]); TERAOKA,
Akio (Pharmacist) ; TOI, Chihiro (Pharmacist); UMEDA, Tadahito(MD[psychiatrist])
Editorial Officer: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO, Koji
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