M
C

April

2020

Volume 6

ED
N 16

HECK

o

Editorial
The Plague (La Peste in French)
Urgent Recommendations
Five Don'ts to Prevent COVID-19 and Death
CONTENTS （April 2020, Vol. 6, No. 16）
Editorial
The Plague (La Peste in French)

2

Urgent Recommendations
Five Don'ts to Prevent Novel Coronavirus Infection (COVID-19)
and Death
1. Don't use ibuprofen or other NSAIDs
2. Don't use corticosteroids especially in the early phase of fever

33
8

Please read below in the next issue (No 17)
3. Don't use Tamiflu and Xofluza
4. Avoid ACE2 enhancers and (hidden) immunosuppressants
5. Don't sit up late at night. Lack of sleep is the strongest stress
impairing your immunity

MED CHECK

April 2020/ Vol.6 No.16 ・ Page 

M
C

ED

HECK

Editorial

The Plague (La Peste in French)
Translated from the Editorial in Med Check(in Japanese) May 2020 ; 21 (51) ahead of print,

The Plague is a masterpiece of Albert Camus (November 7, 1913-January 4, 1960), a novel
written in 1947, shortly after the end of World War II. It predicts the status of the current
world being swept by the pandemic of the novel coronavirus infection (COVID-19).
I read it for the first time when I was in the second grade of junior high school. It's
been a long time, but a strange feeling after reading was completely different from othermasterpieces I read in those days and has remained in my memory.
The second time I read it was during the harsh days after the Tokyo Electric Power
Company's Fukushima Daiichi Nuclear Power Plant Accident following the Great East Japan
Earthquake in March, 2011. I decided to read it again because I thought superposing thefear among people in Oran (port city in Algeria) attacked by the plague on the fear amongpeople in Japan who were afraid of radiation would bring me mental stability. Nine years
have passed since the accident (considering half-life of radioactive materials, this is still such ashort time), and I have begun reading the novel again for the third time.
The following is taken from The Pest (translated from the Japanese edition by MIYAZAKI,
Mineo). "My fellow citizens in Oran do a lot of work, but that is always to become rich."
Isn’t this similar to the current state of Japan, where people are so concerned about
the impact of the new coronavirus on the Tokyo Olympics 2020, calling off of which
would guarantee great financial loss? Camus also writes in the novel “Meantime, due to
speculative intervention, daily necessities become scarce and are sold at unbelievable prices
in the regular market.” This reminds us of the shortage of masks in Japan, which are now
sold online at unreasonable prices. In the end of the story, Dr. Rieux, who fought against
the plague, says that in the life-or-death battle against the plague, humans were able to win
because they had knowledge and memory. The fuss over COVID-19 will soon end, but it will
be our responsibility to accurately record and remember what happened and to pass thatknowledge on to the next generation.
Now that many events have been canceled and recreational facilities are closed, why
don't you read The Plague? (KIMOTO, Yasusuke)

Page  ・ MED CHECK

April 2020/ Vol.6 No.16

Urgent Recommendations
Five Don'ts to Prevent Novel Coronavirus Infection(COVID-19) and Death
Translated from Med-Check News No.184 (March 15 2020) with a little revision on March 25, 2020
Med Check Editorial Team

This article discusses 2 points of the 5 points which you should avoid to prevent novel corona virus infection(COVID-19) and death. The remaining three points will be discussed in the next issue. English version of Med
Check News No. 183 that explained five points you should follow in details and No 185 will appear in the Med
Check in English No 17 that will be published on around March 30.

Don’ts (Summary of 5 points)
1.Do not use antipyretics to lower fever. Human body can endure fever at 40-41℃ . Because viruses are weak
to heat, lowering fever with antipyretics will lead to regrowth of the viruses. In particular, non-steroidal antiinflammatory drugs (NSAIDs) should be avoided, because they also weaken your defense system. Acetaminophen(paracetamol) is basically harmful, as well.

2.Do not use corticosteroids for the same reason. Its use in the early phase of infection leads to higher mortality.
3.Do not use Tamiflu and Xofluza as they suppress immunity.
4. Avoid ACE inhibitor and ARB (angiotensin II receptor blocker) as possible, because they increase ACE2, an enzyme
counteracting angiotensin II which act as a main receptor for SARS-CoV-2 to infect human. Apart from anticancer
drugs, corticosteroids and overt immunosuppressants used for collagen diseases etc, there are many other drugs
that reduce your immunity (hidden immunosuppressants) They include antihypertensive drugs especially ARBs
and calcium antagonists, sleeping pills, anxiolytics, cholesterol lowering agents, antidiabetics (glitazons, DPP-4
inhibitors, GLP-1 agonists) and PPIs etc. They should be avoided unless they are essential.

5. Do not sit up late at night. A lack of sleep can be the strongest stress impairing your immunity.

Keywords:
COVID-19, ibuprofen, NSAIDs, paracetamol, corticosteroid, SARS-CoV, ACE-I, ARB, immunosuppressants, sleeping pills, glitazones
hidden-immunosuppressants

1. Do not lower fever with antipyretics

it takes longer to kill viruses and bacteria, and theymight regrow and might make your body temperature

Summary
A human being as well as other animals can endure
fever of 40-42

measures because you feel that you cannot endure fever,℃ for 24 hours unless s/he has severe

illness. As shown in Med Check News No. 183,higher than the initial temperature.
Especially, non-steroidal anti-inflammatory drugs(NSAIDs) , such as aspirin, ibuprofen, diclofenac and

SARS virus and its surrogate viruses were inactivatedmefenamate do not only lower fever, but also impair

at temperature 40 ℃ and relative humidity > 95% in 6

immunity, leading to aggravation of infection andhours.

increase mortality. They should never be used.

If you lower your high body temperature to near

Acetaminophen (paracetamol) is less harmful thannormal by using antipyretics and/or other physical

NSAIDs, but when it is used in high dose for lowering
MED CHECK

April 2020/ Vol.6 No.16 ・ Page fever to the normal temperature, it can aggravate

their body temperature.

infection. For instance, when it was used in children

At any points of days 1, 2 and 3, and one week, lower

with chickenpox (varicella), the time to recovery wastemperature was associated with higher mortality.

prolonged. Moreover, when it was used to lower fever

Likewise as the temperature increased, mortality wasto the normal temperature in serious infection such as

decreased. After 24 hours, three-fourths (9 /12 ) , two-

sepsis, risk for death was increased by seven-fold inthirds (8/12) and half (18/36) of the animals died athuman.

34 ℃ , 36 ℃ , 38 ℃ , respectively. However at 40 ℃ ,Aspirin is considered to have relatively mild effectonly one-sevenths (2/14) died and at 42℃ there was noamong NSAIDs. However, it is epidemiologically anddeath. After 3.5 days, mortality at each temperature was

medically established that it causes Reye syndrome, in

100%, 75%, 70%, 33% and 8%, respectively. After one

which mainly children experienced encephalitis and liver

week at 42℃ , the mortality increased to 25%. However,damage after infection, which became an international

considering that 34% of uninfected animals died at 42℃

issue in 1970’s (risk is about 20 times higher).

after one week. It can be said that at 42℃ , the animals

Ibuprofen is generally believed to be less harmful

died not from infection but from high temperature.

than diclofenac and mefenamate. However, it aggravates
infection in human and increases mortality when used inThis suggests that having fever of 42℃ for many days

critically ill patients with infection as well as in infected

is risky, but it can be endured for one day. Moreover, atanimals. Mortality risk is 7 times higher for human and

42℃ , infection is not the cause of death.

about 20 times higher in infected animals. Do not use
any antipyretics.

In reality, body temperature does not increase higher
than 41℃ in infection. Rather, it tends to become higher(1)Infected animals did not die at 42℃ , but 3/4

when it recurs after once lowered with antipyretics.

of them died at 34℃
Figure 1 shows the comparison of mortality in lizards
which were infected with bacteria and placed in rooms(2)Strong antipyretics aggravate infection andincrease mortality by 10 to 20 folds.

at 34℃ , 36℃ , 38℃ , 40℃ or 42℃ [1]. Comparison was

A highly fatal disease, in which infection such as

made in this way because reptiles can hardly increaseinfluenza or chickenpox was followed by encephalitis

Figure 1: Should fever of 40℃ and above be lowered?
No: Fever of 42℃ can be endured for 24 hours. If not lowered, infection can be cured faster.

Cited from ref [1]Page  ・ MED CHECK

April 2020/ Vol.6 No.16

Figure 2: NSAIDs such as aspirin or diclofenac increase death from Reye’s syndrome/influenza
encephalitis by 20-folds (meta-analysis of case-control studies in the U.S. and Japan)

but also with other mild
infections like common
cold or varicella. In
Japan, instead of aspirin,
antipyretics with stronger
anti-inflammatory
action had been used.
These non-steroidal
anti-inflammatory
drugs (NSAIDs) included
diclofenac, mefenamic
acid (mefenamate). Many
studies were conductedby a task force of Japan'sJapan: A case-control study of influenza associated encephalopathy comparing use of NSAIDs including

Ministry of Health anddiclofenac and mefenamate. Others: all are case-control studies for Reye’s syndrome conducted in US. .

Welfare (MHW before
2000). Quasi case-control

studies using the case series of acute encephalopathy
and liver damage, was reported in 1960’s. This conditionof unknown cause untill ‘97 showed that the NSAIDs

was named after a doctor who found it and is called Reye

increased the risk of encephalitis by 26-folds (Figure 3).

Syndrome. It was intensively studied around 1980, and it

However, Japanese government did not admit it before

was found that aspirin was the cause and increased thethe study in 1999.

risk of the syndrome by about 20-folds (Figure 2). They
stopped using aspirin in the West and no Reye syndromecase has occurred since then [2].

As a result of banning the use of these antipyretics
in children, proportion of death from encephalopathy

In Japan, aspirin has been rarely used. However,following mild infections including influenza has

syndrome of acute encephalopathy of unknown cause

rapidly decreased (30% to less than 10%, data notwith multi-organ failures after common cold or influenza

shown). Currently, only acetaminophen is used as anin which patients deteriorated much more rapidly

antipyretic in children and in most adults as well inthan Reye’s syndrome, became an issue. It was later

Japan. However, after the introduction of Tamiflu again

investigated as influenza associated encephalopathy

increased death related to influenza.

but the syndrome is not only associated with influenza
Figure 3: Meta-analysis of Japanese studies on encephalopathy and NSAIDs
RS: Reye’s Syndrome, IAE: influenza
associated encephalopathy The study‘02 was only a case-control study.
Others were all quasi case-control
studies using case series of infection
associated encephalopathy or Reye’s syndrome. NSAID use in influenza
increases risk of death from IAE or RS
by about 15 times compared with nouse of NSAIDs as antipyretics. Data by
1997 showed risk increase by 26 times
already (Combined odds ratio of studies’94 and ’97 =26.5(5.8,103)、p<0.0001)

MED CHECK

April 2020/ Vol.6 No.16 ・ Page 

(3)Acetaminophen may also increase mortality

4) . This suggests that even acetaminophen increases

when it is actively used.

mortality by 7-folds when it is used to lower fever

Currently, acetaminophen (paracetamol) is consideredaggressively to the near normal temperature.

to be the safest among antipyretics, compared with many
NSAIDs including aspirin. It is correct. However, it is nottrue that it has no harm in increasing death.

(4)Ibuprofen also aggravates infection
Ibuprofen is considered to be the mildest among
NSAIDs, and is marketed as OTC antipyretics andIn many countries including Japan, according to thecommonly used in Western countries. In Japan, the dailylabel, 40mg/kg/day (maximum 60mg/kg/day) is allowed to

dosage for adults is 600 mg. However, in the U.S., one

use in children with fever. This dose, 40mg/kg/day, wastablet (of even OTC drug) contains 400 mg or 600 mg ofused in children with chickenpox for 4 days. It prolonged

ibuprofen, and is purchased without prescription.

the time to total scabbing by 1.1 days as compared withplacebo (p=0.048) [5].

The safety of ibuprofen is claimed based on the
two large-scale controlled studies [3,4] showing that
there was no difference in safely between ibuprofen

There is a study involving critically ill adult patientsand acetaminophen. However, it is harmful to use

staying at ICU longer than 72h with body temperatureacetaminophen to lower temperature as shown in aboveof >38.5 degree C [6]. They were randomized into

RCTs [5,6]. Therefore, it may be true that ibuprofen also

aggressive or permissive groups. The aggressive

aggravates infection.

group received acetaminophen 650 mg every 6 h forThis is actually shown in some studies. Chickenpox istemperature of >38.5 degrees C and a cooling blanket

sometimes complicated with bacterial infection, leading

was added for temperature of >39.5 degrees C. The

to severe bacterial infection in subcutaneous tissues,

permissive group received no treatment for temperaturesuch as necrotizing fasciitis. We found three case-control

at 40 degrees C or less, but instead had treatment

studies that examined the association between theinitiated at temperature of >40 degrees C, at which timecomplication of varicella and use of NSAIDs antipyretics,

acetaminophen and cooling blankets were used until

including ibuprofen [7-9]. As a result of meta-analyzing

temperature decrease less than 40 degrees C. While inthese studies, it was concluded that ibuprofen use is

the permissive group, only 2.6% of the patients (1/38)

associated with increased severe infection of varicella by

died, 16% of the patients (7/44) died in the aggressive

10-folds (p=0.0009) (Figure 5).

group (odds ratio=7.0, p=0.06 by Fisher’s exact test) (Figure
Figure 4: Adverse effect of antipyretic therapy upon outcome

Figure 5: Ibuprofen* increases sever complication ** of humanof critically ill patients: randomized prospective study

by 10 times (meta-analysis of three case-control studies)

Data from ref [6].
Aggressive: acetaminophen 650mg, 6 hourly if BT>38.5℃ to reduceBT<38.5℃+ cooling blanket when >39.5℃ to reduce BT<38.5℃ .
Permissive: same dose if BT>40 ℃ to reduce BT <40 ℃ . The study was
stopped after the first interim analysis due to the mortality difference(OR=7.0, p=0.06 by Fisher’s exact test).

Page  ・ MED CHECK

April 2020/ Vol.6 No.16* : Souyri’s study [9] include other NSAIDs than ibuprofen.
**: Cased were all severe soft tissue infection after varicella including
necrotizing fasciculitis.
Meta-analysis results of three studies: Zerr 1999 [7], Lesko 2001 [8],Souyri [9]）(5) Mortality risk of NSAIDs is well proven by

showed that NSAIDs antipyretics increased deaths ofmany infected animal studies

infected animals by about 15 folds.

There are numerous kinds of infected animal studies
which equivocally indicate that NSAIDs increased

Figure 6 shows the results of a meta-analysis of themortality of infected animals. Animals used include

risk when ibuprofen is used for infectious diseases in

mice, rats, rabbits, chickens and goats etc. and microbial

various animals. Infected microbial includes influenza

include bacteria, viruses and protozoa etc. NSAIDs

virus, bacteria from cecal ligation and puncture.

include aspirin, mefenamates, ibuprofen, indomethacin

Ibuprofen has been shown to increase the deaths ofand flurbiprofen etc. Acetaminophen is also tested in

infected animals by 22 folds compared to vehicle only

some studies

without NSAIDs.

So far until March l3, 2020, we got data from 25
experiments that compared the mortality rate between

Figure 7 is the meta-analysis results of four influenza

NSAIDs group and the vehicle group. A meta-analysis

infected animal studies showing that NSAIDs increased

Figure 6: Ibuprofen increases mortality of infected animals by 20-folds

Pooled odds ratio (Fixed effects, conditional maximum likelihood)= 22.2 (95% CI=7.3, 84.6), P<0.0001
Infected microbial includes influenza virus, bacteria from cecal ligation and puncture.

Figure 7: NSAIDs increased mortality of influenza-infected animals at least by 10-fold (meta-analysis results)

Pooled odds ratio (Fixed effects, conditional maximum likelihood) = infinity (3.75, infinity), P < 0.0001
Study of Ibuprofen is the same as the study by Mukhopadhyay 1992 in Figure 6.

MED CHECK

April 2020/ Vol.6 No.16 ・ Page risk of mortality from influenza infection at least by
10 folds: Pooled odds ratio is infinity (95%CI: 3.75,
infinity, p<0.0001) by fixed effects, conditional maximum

likelihood method (references are not shown).

2.Do not use corticosteroids especiallyin the early phase of fever
Summary
NSAIDs make infections more severe if used to reduce(6) The risk from NSAIDs use in humans and infever. If corticosteroid is used instead of NSAIDs it also

other animals is similar

worsens infection. Human and animal studies have

In humans, Aspirin or NSAIDs antipyretics increased

equivocally shown that the earlier the corticosteroid isrisk of Reye's syndrome and influenza associatedused, the more severe the infection and the higher theencephalopathy by 20 times, ibuprofen increased severemortality rate become. Let's take a closer look.

varicella infections by 10 times, and even acetaminophen
increased mortality by 7 times when used in order to(1) Severe or increased death when used earlylower fever aggressively as mentioned in the section (3).

in the onset of influenza

In infected animals as shown in the previous section (5),NSAIDs increased mortality by 10 to 20 times.

A study [10] was conducted on the 2009/10 influenza(so called pH1N1 infection) , suspecting a relationshipThus, the level of increased risk of mortality or

between the severity of the influenza and the early use of

exacerbation of human infections and increased mortality

corticosteroids. In China primary care practitioners useof infected animals are indeed in good agreement.

them as antipyretics, potentially exposing hundreds ofTherefore, not only NSAIDs antipyretics, but alsoacetaminophen worsens infection if used aggressively
for lowering to near normal temperature.
It is extremely harmful to use antipyretic agents for
reduction of fever in the novel coronavirus infection.

millions to this risk [10], while it is rarely prescribed bydoctors for influenza in Japan.
The purpose of this study [10] was to determine
whether the use of corticosteroids in the early stage ofinfluenza (onset within 72 hours = 3 days) or late (after 72
hours) had increase severity and/or death from influenza

compared with never use of corticosteroids. As a result,

Never use NSAIDs including ibuprofen
in the novel coronavirus infection(COVID-19).

it was found that using corticosteroids early increases
the severity of the disease, including death, by 6.5 times(Table 1).

The study also indicated that the late use ofDon’ t use acetaminophen/paracetamol
to lower temperature aggressively.

corticosteroids (after 3 days) is associated with 3-folds
increase of severity or death from influenza infection [10].
Ma et al reported that glucocorticoid and pyrazolone
use as antipyretics is associated with life-threatening

Table1: Early use of corticosteroids increased severity or mortality by 6.5 times

Early: Use within 72 hours of onset, Late: Use after 72 hours of onset. This study is quasi-case-control study, hence odds ratio should be
used for risk analysis. Note that levels of adjusted risk ratio or hazard ratio are larger than crude ratio. Hence, crude odds ratio may be under
estimated for the true risk of early corticosteroid use.

Page  ・ MED CHECK

April 2020/ Vol.6 No.16

Table2: Antipyretic use and serious complication from EV71 infection.

Numbers of denominators are different because unknown users were excluded. Numbers of denominators for Both/none were the sumof both and non-users. From the data by Ma et al [11].

human enterovirus 71 (EV71) infection during an

serious unless time related bias is well controlled

outbreak in China [11]. They say “About 50% of the 28[12]. However, these studies [10, 11] examinedcases and 18% of the 40 controls received an injection

corticosteroids used in the early stages of onset whento treat fever during the first 96 hours after onset (Odds

the infection was not severe. Hence they have least time

ratio =7.0, 95% confidence interval: 1.8 –28). Injections

related bias.

containing exclusively glucocorticoids (OR = 4.8, 95%

In addition, animal studies [13] have shown that the

CI: 1.2-21) or pyrazolones (OR = 4.1, 95% CI: 0.91-19, P=

use of corticosteroids one day after inoculation of virus

0.047) were risk factors for severe HEV71 infection.

showed the highest mortality, as described later.

About 25% of cases and 5% of controls received bothAt the early phase of infection especially just after

drugs parenterally while 7% of cases and 30% of

the start of fever, you have to concentrate on fighting

controls received neither (OR = 21, 95% CI: 1.8-305) .

to reduce virus by utilizing your whole defense

Conversely, cases and controls had identical averagesystem including fever and other immune functions.

initial temperature, and did not differ significantly by

At that time, if your body temperature is reduced

age, sex, nutritional measurements, use of other drugs, orby corticosteroids and/or NSAIDs antipyretic, yourtimeliness of medical care received.” Table 2 summarizes

defense system including immune response as well as

the results by Ma et al (Table 2).

inflammatory response are suppressed, the virus will
not be destroyed and may increase and enter deep into

Ma et al discussed “In general, dexamethasone wasyour body and induce more cytokines to fight against

more commonly given early in the course of the illness

increased viruses leading to cytokine storm and multi-

and methyl prednisolone later. We did not detect aorgan failure. Considering the mechanism of action

similar time trend with pyrazolones. We were not able toof corticosteroids, the results in humans and animal

retrieve the actual dose of glucocorticoids or pyrazolones

experiments described later is quite reasonable.

given to these patients but it was common practice toadminister up to 50 mg of dexamethasone and up to(2) Corticosteroid treatment for patients with

550 mg of aminopyrine for fever reduction.” [11]severe influenza increases death

These data strongly indicate that use of corticosteroids

Corticosteroids are often used when a patient

especially combined with NSAIDs antipyretics at thewith influenza become seriously ill and hospitalized

early phase of mild infection leads to deterioration ofespecially admitted to ICU. The systematic review andotherwise mild infection.

meta-analysis of observational studies reporting therisk of death with corticosteroid use for hospitalized

There are relatively many observational studies onwhether corticosteroid use for serious infection is related

patients with influenza [16] indicate the risk was 4.8
times higher (Figure 8).

to the increased mortality. In these cases, it is difficult
to determine whether the corticosteroid was used due

It is difficult to judge whether the mortality rate hasto the severity of the disease or it caused the infection

increased due to the severity of the disease or the use
MED CHECK

April 2020/ Vol.6 No.16 ・ Page Figure 8: Adverse effect of corticosteroid therapy on death in influenza inpatients

Cited from Ref. [16]of corticosteroids. However, combined odds ratio by

use had little meaning and early use of corticosteroids

adjusting timing of corticosteroid use was 2.23. Hence,for mild infection worsens the infection.

it can be said that corticosteroid use increases themortality (Figure 8).

(4)The earlier a corticosteroid is used, thegreater the risk of death becomes: Results of(3)Even with septic shock, high dose
corticosteroids are harmful

Animal studies
Experiments with infected animals have confirmed

Pulse treatment using large doses (1000 mg/day) ofthat corticosteroids use for infection increases mortality.

methylprednisolone for 3 days which is commonly used

Moreover, it has been confirmed that the earlier thefor septic shock is also harmful. The Japanese label

infection, the greater the mortality rate becomes [13].

of methylprednisolone warns “there is a report [15]Enterovirus 71 (EV71) is a causative virus of hand,indicating that high dose of this drug increased mortality

foot, and mouth disease (HFMD) or herpang ina.

in patients with septic shock with high creatinine level (>These infections are usually mild but sporadic cases

2.0 mg/dL)".

of neurologic disease or outbreaks of severe, life
threatening disease including encephalitis, acute

Another Cochrane review [16] reported that in patients

respiratory failure and excess mortality were reported inwith septic shock, corticosteroids equivalent to 200mg/

the Asia-Pacific region including China [10,11,13] where

day of hydrocortisone reduced deaths up to 28 days

353 severe cases of HFMD and 22 fatalities out of overafter hospitalization. However the mortality was not

6000 cases were reported in Fuyang in 2008 [17].

different after 6 month.
In conclusion, even for septic shock, corticosteroids
Page 10 ・ MED CHECK

April 2020/ Vol.6 No.16

In severe cases, corticosteroids are often used torelieve cytokine storms (Note). However, a series ofNote: When infected with the virus, the body produces various

disease severity of mice infected with enterovirus 71

chemicals called cytokines such as interferon and tumor necrosis(EV71) compared with those treated with saline (phosphatefactor, along with high temperature, to fight the virus. When thebuffer saline: PBS) [13]. However, EV71 infected miceamount of virus increases, it becomes necessary to release manywith corticosteroids treatment starting from 1 day post-

cytokines. When the amount of virus increases extremely, theinfection died one after another (Figure 9).

cytokine comes out like a storm and attacks the virus. However,
not only viruses but also body cells are attacked and damaged.
Antipyretics and corticosteroids do not kill the virus, but rather
the virus needs to produce more cytokines for the virus tomultiply, resulting in a cytokine storm.

Mortality of severely infected mice with 6 x 105 PFU/
mouse of EV71 increased even with PBS, but all withcorticosteroid treatment starting one day post-infection
died on the ninth day (Figure10).

infected animal studies were conducted on suspicions

Meta-analysis of the three experiments showed thatthat corticosteroids might worsen the symptoms ofcorticosteroids starting from one day post-infection

infection [13]. Figure 9 ~11 shows some results of theseincreased the risk of death by 70-fold compared tostudies.

PBS (Figure 11) . Pooled odds ratio by the conditional

Corticosteroid (dexamethazone) treatment starting from4 or 8 days post-infection did not affect mortality andmaximum likelihood (Fixed effects) was 70.8 (95%CI:7.6,
3880, < 0.0001, I2 ＝ 0%)

Figure 9: The mortality risk increases with early use of corticosteroids (1)The survival rates of mice were comparedwhen dexamethasone was started 1, 3, 4,
and 8 days post-infection of enterovirus 71(EV71) and control mice treated with saline(phosphate buffer saline: PBS) starting 1 day
post-infection. The greatest risk of death wasobserved when corticosteroids were started 1
day post-infection. .

From ref. [13]Figure10: The mortality risk increases with early use of corticosteroids (2) Infected with high doses of virus

From ref. [13]MED CHECK

April 2020/ Vol.6 No.16 ・ Page 11

Figure 11: Starting corticosteroids on 1 day post-infection increases mortality of mice infected with EV71 by 70 folds

Viral load is expressed as PFU (plaque forming unit): Meta-analysis results of three experiments in Ref. [15]: Pooled odds ratio by conditional
maximum likelihood (Fixed effects) = 70.8 (95% CI: 7.6, 3880), P <0.0001

Details for the following 3 Don'ts will be explained with

Details for the following 5 Do's will also be described

evidence in the next issue of Med Check in English No.17

with evidence in Med Check in English No.17

3.Do not use Tamiflu and Xofluza as they suppress

1. Simple mask-wearing is effective. It reduced illness

immunity.

from SARS to one-third, and is more effective thanfrequent hand-washing (>10/day) that halved it.

4.Avoid ACE inhibitor and ARB (angiotensin II receptor
blocker) as possible, because they increase ACE2, an

2. Mask-wearing is effective because SARS-CoV isenzyme counteracting angiotensin II which act as avulnerable to high temperature with humidity. It helps

main receptor for SARS-CoV-2 to infect human. Apart

your nose and throat keep warm and moisturized.

from anticancer drugs, corticosteroids and overt
immunosuppressants used for collagen diseases etc,

3. When masks are not available, make it with cloths orthere are many other drugs that reduce your immunity

handkerchief. They can be washed and used repeatedly.

(hidden immunosuppressants)
They include antihypertensive drugs especially ARBs

4. Drink hot drinks such as “kuzuyu (drink made fromand calcium antagonists, sleeping pills, anxiolytics,

arrowroot starch). Blowing on and sipping it help warm

cholesterol lowering agents, antidiabetics (glitazons,

the throat and the whole body.

DPP-4 inhibitors, GLP-1 agonists) and PPIs etc. They
should be avoided unless they are essential.

5. Get moderate exercise during the day, and haveenough sleep at night, but without sleeping pills.

5.Do not sit up late at night. A lack of sleep can be thebiggest cause of stress that impairs your immunity.

Page 12 ・ MED CHECK

April 2020/ Vol.6 No.16

References

9) Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M; French Network of1) Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science. 1975

nonsteroidal anti-inflammatory drugs. Clin Exp Dermatol. 2008 May;33(3):249-55.

11;188(4184):166-8. PMID: 1114347
2) Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB.
Reye's syndrome in the United States from 1981 through 1997. N Engl J Med.
1999 May 6;340(18):1377-82. PMID:10228187
3) Lesko SM, Mitchell AA An assessment of the safety of pediatric ibuprofen. A
practitioner-based randomized clinical trial. JAMA. 1995 Mar 22-29;273(12):929-33.
PMID: 7884951
4) Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen amongchildren younger than two years old. Pediatrics. 1999 Oct;104(4):e39. PMID:
10506264
5) Doran TF, De Angelis C, Baumgardner RA, Mellits ED. Acetaminophen: more harmthan good for chickenpox? J Pediatr. 1989 Jun;114(6):1045-8. PMID: 2656959
6) Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D,
Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM. The effect of antipyretic
therapy upon outcomes in critically ill patients: a randomized, prospective study.
Surg Infect (Larchmt). 2005 Winter;6(4):369-75. Erratum in: Surg Infect (Larchmt).
2010 Oct;11(5):495. Li, Pam [corrected to Li, Pamela]; Alhaddad, Ahmed [corrected
to Elhaddad, Ahmed].PMID:16433601
7) Zerr DM, Alexander ER, Duchin JS, Koutsky LA, Rubens CE. A case-control studyof necrotizing fasciitis during primary varicella. Pediatrics. 1999 Apr;103(4 Pt
1):783-90. PMID:10103303
8) Lesko SM, O'Brien KL, Schwartz B, Vezina R, Mitchell AA. Invasive group A
streptococcal infection and nonsteroidal antiinflammatory drug use among children
with primary varicella. Pediatrics. 2001 May;107(5):1108-15. PMID: 11331694

M
C

Pharmacovigilance Centres Severe necrotizing soft-tissue infections andPMID:18261144
10) Han K et al. Early use of glucocorticoids was a risk factor for critical disease anddeath from pH1N1 infection. Clin Infect Dis. 2011;53(4):326-33.PMID: 21810744
11) Ma H, He F, Wan J, Jin D et al. Glucocorticoid and pyrazolone treatment of acute
fever is a risk factor for critical and life-threatening human enterovirus 71 infection
during an outbreak in China, 2008. Pediatr Infect Dis J. 2010 Jun;29(6):524-9.
PMID:20104199
12) Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases inobservational studies. Diabetes Care. 2012 Dec;35(12):2665-73. PMID:23173135
13) Shen FH, Shen TJ, Chang TM, Su IJ, Chen SH. Early dexamethasone treatment
exacerbates enterovirus 71 infection in mice. Virology. 2014 Sep;464-465:218-227.
PMID: 25104614
14) Lansbury L et al. Corticosteroids as adjunctive therapy in the treatment
of influenza Cochrane Database of Systematic Reviews 2019, Issue 2. Art.No.:
CD010406. PMID: 30798570
15) Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled
clinical trial of high-dose methylprednisolone in the treatment of severe sepsis andseptic shock. N Engl J Med. 1987 Sep 10;317(11):653-8. PMID:3306374
16) Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y, Pirracchio
R, Rochwerg B. Corticosteroids for treating sepsis in children and adults.
Cochrane Database of Systematic Reviews 2019, Issue 12. Art. No.: CD002243.
PMID:31808551
17) Qiu J. Enterovirus 71 infection: a new threat to global public health? Lancet
Neurol. 2008 Oct;7(10):868-9. PMID: 18848307

ED

HECK

2020

Vol.6

No.16

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (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

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: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO, Koji
Information Technology (IT): KURODA, Akira (Systems Engineer)
Copyright NPOJIP
www.npojip.org
Registered address:#602, Katsuyama 2-14-8, Tennouji-ku,
Osaka JAPAN 543-0043
E-mail: npojip@mbr.nifty.com

MED CHECK

April 2020/ Vol.6 No.16 ・ Page 13