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Covid-19 and the Trojan horse that eroded the World Health Organization

August 2020

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United Nations University (UNU)

OPINION: Covid-19 and the Trojan horse that eroded the World Health Organization MT Bulletin of the Netherlands Society for Tropical Medicine and International Health. No. 2 August 2020. Volume 58. ISSN 0166-9303. p17-18. https://www.nvtg.org/uploads/MTb-PDF/2020_MT_Covid-19.pdf

Symptoms of patients with suspected Covid-19.

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COVID-19

NO 02 / august 2020 - v O l u m e 58

BULLETIN of the NETHERLANDS SOCIETY for TROPICAL MEDICINE and INTERNATIONAL HEALTH

2 MT BULLETIN OF NVTG 2020 AUGUST 02

EDITORIAL

COVID-19:

CONTRADICTIONS,

CONFUSION, AND

COMPLEXITY

It is mid-July 2020. Some

countries are experiencing

the peak of the Covid-19

pandemic, while others have

loosened their lockdown

measures, anticipating a

continued slowdown of

the epidemic. Meanwhile

scientists around the

world are working on the

development of an effective

vaccine.

CONTRADICTIONS

In Japan, the management of a sea

aquarium invites visitors to video chat

with their 300 sea eels and wave at them

as they showed signs of stress because

of the absence of the public in the

past months. Hundreds of thousands

of mainly female garment workers

in Bangladesh ignore the nationwide

lockdown in order to earn back some of

the income loss they experienced over

the past months. More than 49 million

women are lacking contraceptives, a

situation which according to the WHO

is likely to result in a baby boom. Donald

Trump asks scientists to research the

effect of injecting disinfects into a per-

son in order to ﬁght the virus. While the

Italian government still provided food

rations for the needy, shrewd business-

men developed protective plastic shields

for the sunbeds – in anticipation of the

tourists that would come as soon as

lockdown restrictions in Italy were to

be released. State prisons in California

are releasing 3,500 inmates to protect

them from potential exposure to the

virus as a result of the conditions in

the prisons. Research from Stanford

University shows that, in a country were

some 1.6 million people die each year

of respiratory diseases, the improved

air quality has saved the lives of more

than 1,400 children under age 5, and

51,700 adults above 70 years of age.

Meanwhile the virus has spread to 188

countries, with more than 13,876,441

CONTENT

EDITORIAL - 2

REVIEW

Management of Covid-19 - 4

A novel virus, a recurring

threat: looking at past

pandemic threats to understand

how SARS-CoV-2 has evaded

global control efforts - 7

In the shadow of the

coronavirus: a global rise

of infectious diseases due

to Covid-19 containment

measures - 13

PERSONAL REFLECTIONS FROM

THE FIELD - 9

Covid-19 in context - 9

How Ebola prepared us to ﬁght

Covid-19 in the DRC - 9

Corona free country? - 10

The heritage of a highly lethal virus

outbreak - 11

Suddenly working in the intensive care

unit - 12

INTERVIEW

Moria, 20,000 refugees waiting

for a disaster to happen - 15

OPINION

Covid-19 and the Trojan horse

that eroded the World Health

Organization - 17

Pooling of knowledge,

know-how and intellectual

property to counteract vaccine

nationalism - 22

RESEARCH

Outbreak of Covid-19 like

illness in a remote village in

Papua, Indonesia - 19

BOOK REVIEW

Epidemics and pandemics - 21

A constant state of emergency:

Paul de Kruif, microbe hunter

and health activist - 23

With pleasure we

announce our renewed

media pages:

YOU

are invited to visit these

pages for additional

articles, blogs, and other

posts on topical issues in

global health and tropical

medicine. Also, on these

pages you can access

previous editions of MTb

and International Health

Alerts.

linkedin.com/company/mtbulletin

facebook.com/BulletinoftheNVTG

AUGUST 02 2020 MT BULLETIN OF NVTG 3

EDITORIAL

conﬁrmed cases of Covid-19 (7.3 million

in the Americas), including 593,087

deaths reported to the WHO.[1, 2]

CONFUSION

In the absence of a vaccine we have wit-

nessed a wave of containment measures,

roughly ranging from total lockdown

to the so-called intelligent lockdown

(relying on the idea of group or herd

immunity and a sense of responsibility

on the part of the population) intro-

duced in the Netherlands. The Dutch

were accused of lacking solidarity with

neighbouring countries’ approaches - an

interesting observation, given the overall

lack of solidarity and coordination at

European (and global) levels.[3] With

this approach, the Dutch government

wanted to ‘cushion the social, economic

and psychological costs of social isola-

tion and make the eventual return to

normality more manageable’.[4] And

while social distancing in high-income

countries may have saved lives, the

question is at what cost? Low-income

countries are anticipating counterpro-

ductive effects, including a potential

rise in other (infectious) diseases and

rising morbidity and mortality ﬁgures

caused by other diseases, as well as a

devastating effect on fragile economies

and informal sector workers. Adding to

the confusion are the many variations in

tracking and reporting approaches and

misleading or missing data. Reﬂecting

on the past months challenges us to

decide on a “new” normal. Can we

push a “reset” button, thereby building

on some of the (positive) lessons – for

example working from home and reduc-

ing our ecological footprint by (r)evolu-

tionizing international conferences.[5]

COMPLEXITY

Currently it still feels like a global Catch-

22. Without a concrete prospect of a vac-

cine or treatment, the virus will hold the

world in its grip for months and possibly

years to come. While some countries

seem to have succeeded in containing

Covid-19 (China, Taiwan, Vietnam),

others are experiencing a peak in infec-

tions (countries in Latin America and

South Asia). Meanwhile, in some part

of the USA the situation is spinning

out of control, and African countries

are experiencing an early state of the

epidemic. Europe seems to be some-

where in between.[6] It feels like we are at

a crossroads, and much will depend on

the choices that we the public, our gov-

ernments, and world leaders are mak-

ing - choices that will have an impact

on societies at large, impacting on all

aspects of life. The Covid-19 crisis is

testing our capa city to deal with the soci-

etal consequences of pandemics and to

balance economic interests without los-

ing sight of the (health) risks involved.

With this edition of MTb, we intend to

challenge these three Cs in a construc-

tive manner with articles shedding

light on the clinical management of

the disease, Covid-19 against a his-

torical perspective of epidemics, ﬁeld

experiences in LMICs, the effect of

the pandemic on the refugee crisis

in Greece, the role of the WHO, and

efforts to counteract vaccine national-

isms. We look forward to your reﬂec-

tions and invite you to react using

one of our (social) media channels.

Esther Jurgens, Ed Zijlstra

REFERENCES

1. World Health O rganization [ Internet]. Gene va:

World Health Organiz ation. WHO coronavir us

diseas e (COVID-19): dashb oard; [updated 202 0

Jul 21]. Avai lable from: htt ps://covid19.who.i nt

2. Contrad ictions collate d in the magazi ne 360 (2020

Jul 9-Au g 20;183), based on ex periences from

corresp ondents of the Swiss m agazine Reportagen.

3. Deen B, K ruijver, K. Coron avirus: EU’s ex istential

crisi s: why the lack of solid arity thre atens not

only the Un ion’s health a nd economy, but also

it’s secu rity [Inter net]. The Hague : Clingendael

Instit ute; 2020 Apr. 5 p. Avail able from: https://

www.clin gendael.org/sites/default/ﬁles/2020- 04/

Alert_Corona_ Existential_C risis_April _2020.pdf

4. Holliga n A. Coronavir us: why Dutch loc kdown

may be a hig h-risk strate gy. BBC News [Intern et].

2020 Apr 5. Av ailable from: ht tps://www.

bbc.com/news/world-eu rope-5213581 4

5. Bousema T, Yaka r D, et al. Opinie: w etenschapper s, het

is niet va n deze tijd de wereld ov er te vliegen voor iede r

congres . De Volkskrant [Int ernet]. 2020 Jul 1 . Available

from: http s://www.volkskrant. nl/columns-opinie/

opinie-wetenschappers-het-is-niet-van- deze-tijd-de-

wereld-over-te -vliegen-voor-ieder-con gres~b4ed69ab/?

referer=https%3A%2F%2Fwww.radboudumc.nl%2F

6. The new nor mal: Covid-19 i s here to stay: the wor ld

is workin g out how to live with it . The Economist

[Inter net]. 2020 Jul 4. Ava ilable from: htt ps://www.

economist.com/inter national/2020/07/04/covid-19-is-

here-to-st ay-the-world-is-work ing-out-how-to- live-with-it

4 MT BULLETIN OF NVTG 2020 AUGUST 02

REVIEW

Management of Covid-19

The Covid-19 (corona virus di sease,

detected in 2019) pandemic is

keeping a ﬁrm grip on the world

and affects the health of those

ill with Covid-19 as well as those

with other illnesses; it overbur-

dens health services and causes

delays in diagnosis and treatment

of other conditions. While there is

universal fear of infection, this is

especially evident among service

providers and people accessing

health facilities. Population-based

screening programmes to detect

breast, cervix and colon cancer have

been suspended; the waiting lists

for elective surgical procedures are

becoming longer. In addition to the

impact on health, severe damage to

the economy is caused by lockdown

measures affecting small and big

businesses. Especially in low- and

middle-income countries, lock-

down and social distancing affect

the informal sector and thereby

people’s livelihoods, resulting in

food shortages and malnutri-

tion. Control efforts for various

tropical diseases and vaccination

programmes have been suspended.

The overall morbidity and mortality

caused by the pandemic is therefore

not restricted to Covid-19. There is

no speciﬁc treatment for Covid-19

infection, and the pandemic has

sparked a ﬂurry of research projects

that focus on inhibiting the replica-

tion of the virus, on its effects on

the human respiratory system and

other organs, and on the immune

response triggered by Covid-19.

In this paper, current insight into

the management of Covid-19 infec-

tion as well as the main features of

ongoing drug studies are discussed.

Lastly, issues in publication inclu-

ding peer review are discussed.

CLINICAL SYNDROME

Covid-19 infection is caused by the

SARS-CoV-2 virus; the name refers to

the severe acute respiratory syndrome

caused by a similar corona virus,

SARS-CoV-1. The virus enters the body

through person-to-person airborne

transmission. There is no proven animal

reservoir; in the Netherlands, the infec-

tion was detected in mink farms but was

thought to originate from humans. The

virus is spread in crowded conditions

and mass gatherings: the celebration of

carnival (province of North Brabant, the

Netherlands), winter ski holidays (North

Italy, Austria) and (international) foot-

ball matches like the Champions League

match between Atalanta Bergamo vs

Valencia on February 19 with 40,000

Italian and Spanish supporters (with

subsequent outbreaks in Italy and

Spain) are thought to have contribu-

ted to major outbreaks in Europe.

The clinical picture is dominated by

respiratory symptoms, with fever,

shortness of breath, and cough. Fatigue

is common and other non-respiratory

symptoms include confusion and diar-

rhoea. Most infections are only mildly

symptomatic and self-cure within

days or weeks. Other patients require

hospitalization and develop pneumonia

with so-called ground glass opacities

on a CT scan; oxygen administra-

tion is needed and other supportive

care, including admission to intensive

care units with intubation and artiﬁ-

cial ventilation, often because of the

adult respiratory disease syndrome

(ARDS). Severe pneumonia and death

occur in 4-5% of admitted patients in

a setting with optimal care (Lancet,

Covid-19 clinical research coalition, 25

April 2020). While in hospital, sud-

den deterioration may occur caused

by thromboembolism in the major

lung vessels and the brain, with poor

outcome. Viral sepsis has been sug-

gested among explanations causing

damage to blood vessels; other organs

may be affected as the virus spreads to

other parts of the body. An overreaction

of the immune system may occur with

cytokine release storm (CSR) which

may also contribute to organ damage.

All this may contribute to development

of acute renal failure, viral myocardi-

tis, multi-organ failure and death.

RISK FACTORS AND DIAGNOSIS

Risk factors for a severe course of the

disease are co-morbidities such as

chronic heart disease, diabetes mellitus,

underlying respiratory conditions such

as COPD and asthma, malignancy and

obesity. In addition, the risk for severe

disease increases with advanced age

>60 years. In contrast, young children

are usually asymptomatic. The diag-

nosis is made by demonstrating the

virus via PCR in a nasal and/or throat

swab. Serological tests for IgM and IgG

antibodies are currently continually

being improved in terms of sensitivity

and speciﬁcity; these tests only indi-

cate past exposure and are not suitable

yet for conﬁrmation of the diagnosis

in someone who is sympto matic.

Currently, in populations in Europe

not more than 5% of people tested have

antibodies showing previous infec-

tion (asymptomatic or symptomatic);

it is not clear whether these antibodies

are fully protective and for how long.

INTERVENTIONS

Currently there is no treatment with

proven efﬁcacy. A multitude of observa-

tional and randomised controlled trials

(RCTs) are ongoing, that initially mainly

focused on drugs that had been studied

for SARS, MERS (Middle East respira-

tory syndrome) or Ebola disease, but

that unfortunately were not develop ed

further when these outbreaks lost their

epidemiological importance. Some

drugs are still experimental and have

not been used or studied in humans,

and therefore existing drugs (for what-

ever indication) that can be re-purposed

for Covid-19, are clearly preferred. While

most studies focus on mitigation of

Covid-19 disease, other efforts focus

on prophylaxis. The early drugs that

are considered for potential beneﬁt in

Covid-19 are included in the Solidarity

trial of the World Health Organization

(WHO) in patients hospitalized for

conﬁrmed Covid-19. It has four arms:

• HIV protease inhibitors:

lopinavir/ritonavir

• antimalarials: hydroxychlo-

roquine and chloroquine

AUGUST 02 2020 MT BULLETIN OF NVTG 5

REVIEW

• antiviral (RNA polymerase

inhibitor): remdesivir

• immunomodulatory agent: lopi-

navir/ritonavir with interferon 1a

Other early major studies include the

RECOVERY trial (randomised evalua-

tion of Covid-19 therapy) in the United

Kingdom in hospitalised patients,

primarily studying the effect of hydroxy-

chloroquine, lopinavir/ritonavir, azithro-

mycin, dexamethasone vs no additional

treatment. Patients are further random-

ized to receive tocilizumab (an interleu-

kin-6 blocker) and convalescent plasma.

ANTIMALARIAL DRUGS

Recently published preliminary data

on antimalarials are not encourag-

ing. Hydroxy-chloroquine and chloro-

quine were among the ﬁrst candidate

drugs suggested. The effect of these

anti malarials is thought to be a pH-

mediated at the level of virus entry in

the cell as well as disruption of viral

replication.[1] A combination therapy

with azithromycin was suggested to

have a beneﬁcial effect.[2] This publica-

tion was recently criticised and could not

stand up to scrutiny. There is increasing

evidence that these drugs are of no clini-

cal beneﬁt and severe cardiotoxicity has

been reported, which seems aggravated

by co-administration of azithromy-

cin.[3] Prophylactic use of hydroxy-

chloroquine after high-risk or moderate

risk post exposure to Covid-19 did not

prevent illness in a recent study.[4]

ANTIVIRAL DRUGS

Remdesivir is an antiviral drug (RNA

polymerase inhibitor) that inhibits

SARS-CoV-2 (that causes Covid-19),

as well as SARS-CoV-1 (that causes

SARS) and MERS-CoV (that causes

MERS) in animal models. In a recently

published RCT, there was no clinical

beneﬁt although early treatment might

shorten time to clinical improvement.[5]

There is no evidence yet that remdesivir

is beneﬁcial in severe Covid-19 infec-

tion in a patient on the intensive care.

The drug was recently registered by the

European Medicines Agency (EMA).

Lopinavir/ritonavir, an antiretroviral

drug used in HIV/AIDS has so far

failed to show a clinical beneﬁt in early

reports. In hospitalized adults with

severe Covid-19 infection, no clini-

cal beneﬁt was found.[6] Combination

treatment with interferon and ribavirin

showed better alleviation of clinical

symptoms as well as shortening of dura-

tion to negative nasal swab and hospital

stay in mild to moderate Covid-19.[7]

RCTs on other antiviral drugs against

SARS-CoV-2, including favipiravir are

ongoing as there are mixed reports

about their in vitro and in vivo efﬁc ac y.[8]

IMMUNE MODULATION

This is also a subject of study; the

evidence on the use of corticosteroids

is controversial. While the immuno-

suppressive effect may be beneﬁcial,

there is concern of prolonged viral

shedding and secondary infections.[ 9,10 ]

The timing of such intervention in the

course of the disease may be crucial.

The excessive immune response in

the cytokine release is characterized

by high levels of cytokines such as

interleukin (IL)-6. Tocilizumab is an

IL-6 blocker that is used for example

in rheumatoid arthritis; a small study

in 22 patients recently published

showed remarkable clinical improve-

ment in Covid-19, and RCTs are eagerly

being awaited.[11 ] Similarly, the effect

of inhibition of IL-1 is being studied.

Other immune therapies include

the use of immunoglobulins and

re-convalescent plasma of patients

who have recovered from Covid-19.

PHOTO: MOHS EN NABIL / SHUT TERSTOC K.COM

6 MT BULLETIN OF NVTG 2020 AUGUST 02

REVIEW

ALTERNATIVE DRUGS

Ivermectin and nitazoxanide have

shown anti-SARS-CoV-2 activity

in vitro and are licensed for other

conditions, and thus they can be

studied directly in Covid-19.

Latest reports: in a webinar on 30 June

2020, the RECOVERY trial showed

unpublished data indicating that in

admitted patients who are on oxygen or

ventilation, mortality was reduced by 1/5

and 1/3, respectively, after administra-

tion of low dose (6 mg) dexamethasone

for 10 days. In similar patients, hydroxy-

chloroquine or lopinavir/ritonavir did

not show an effect on mortality. It

should be noted that the latter two drugs

were studied for their antiviral effect,

whereas dexamethasone in general

inﬂuences inﬂammatory damage to

the lungs and is already used in severe

ARDS caused by other conditions.

CONTROVERSY

The SARS-CoV-2 virus uses receptors

to bind to a respiratory cell before being

able to enter the cell and replicate. The

angiotensin-converting enzyme (ACE)

2 receptor is among these. Patients with

high blood pressure have higher levels

of these receptors and treatment for

hypertension with an ACE inhibitor or

angiotensin receptor blocker (ARB) such

as losartan may increase expression of

the receptor. It has therefore been specu-

lated that these patients are at increased

risk of severe Covid-19. However, there

is also the possibility that losartan treat-

ment may be beneﬁcial by blocking the

binding of the virus. Currently, there

is no conclusive evidence and patients

on losartan treatment are advised

not to discontinue their treatment.

PUBLICATION STRESS

Every week a plethora of reports are

published in scientiﬁc journals includ-

ing the authoritative The Lancet and

the New England Journal of Medicine

(NEJM). While publication, often after

expedited peer-review, of any useful

result in Covid-19 is clearly impor-

tant, mistakes have been made. Both

The Lancet and NEJM have retracted

papers that were criticized for meth-

odological ﬂaws or poor quality of

data after publication.[ 12-16 ] The above

mentioned work on hydroxychloro-

quine by the French virologist Didier

Raoult, who is held in high esteem in

France, particularly in his hometown

Marseille, was criticised as many of

his publications appeared in journals

in which he or his co-workers were

among the members of the editorial

board. (The Economist, June 13th, 2020;

NRC Handelsblad, June 13th, 2020).

CONCLUSION

Covid-19 causes severe and fatal disease,

be it in a minority of cases. Currently

there is no drug treatment that has been

proved effective and safe, in prophylaxis

or in mitigation of clinical disease.

Management is therefore largely sup-

portive with intervention by administra-

tion of potentially effective drugs based

on clinical experience and evolving

evidence in the scientiﬁc literature.

Note of the author: ever y week new

studies are published that change

insight on the management of Covid-

19; this paper summarized informa-

tion available up to 30 June 2020.

Ed Zijlstra

Internist, Specialist in Infectious Disease

and Tropical Medicine, Rotterdam Centre

for Tropical Medicine, the Netherlands

e.e.zijlstra@roctm.com

REFERENCES

1. Stur rock BR, Chevas sut TJ. Chloroqu ine and COVID-

19: a potent ial game chan ger? Clin Med (Lon d).

2020 Apr 17 ;20(3):278- 81. Online ah ead of print

2. Gautret P, Lag ier JC, Parola P, et al. Cl inical

and microbiologica l effect of a combination of

hydroxy chloroquine a nd azithromyci n in 80

COVID- 19 patients with at l east a six-day fol low up:

A pilot obse rvational st udy. Travel Med Infect ious

Dis. 202 0 Mar-Apr;34:101663 . Epub 2020 Apr 11

3. Juurlink DN. Safet y considerations wit h chloroquine,

hydroxy chloroquine a nd azithromyci n in the

manag ement of SARS-C oV-2 infec tion. CMAJ.

2020 Apr 27 ;192(17):E450-E 3. Epub 2020 Apr 8

4. Boulwa re DR, Pullen MF, Ban gdiwala AS, et a l.

A randomi zed trial of hyd roxychloroqu ine as

postex posure prophyla xis for Covid-19 . N Engl J Med.

2020 Jun 3;N EJMoa2016638. On line ahead of print

5. Wang Y, Zhang D, D u G, et al. Remdesiv ir in adults

with se vere COVID-19: a ra ndomised, double -blind,

placebo-control led, multicentre trial. La ncet. 2020

May 16;395(1023 6):1569-78. Epub 2 020 Apr 29

6. Cao B, Zha ng D, Wang C. A tria l of lopinavir-

ritonav ir in Covid-19: re ply. N Engl J Med. 2020

May 21;382 (21):e68. Epub 2020 May 5

7. Hun g IF, Lung KC, Tso E Y, et al. Triple co mbination

of inter feron beta-1b, lopin avir-ritonavi r, and

ribav irin in the tre atment of patients ad mitted

to hospita l with COVID- 19: an open-label ,

randomi sed, phase 2 tri al. Lancet. 2 020 May

30;395(10238 ):1695-704. Epub 2 020 May 10

8. Coomes EA , Haghbayan H. Fav ipiravir, an

antiv iral for COVID-19 ? J Antimicrob Ch emother.

2020 Jul 1; 75(7):2013-4 . Epub 2020 May 18

9. So C, Ro S, Mur akami M, et al . High-dose,

short-term cor ticosteroids for ARDS caused by

COVID- 19: a case series. Re spirol Case Rep.

2020 Jun 4;8 (6):e00596. Epub 2020 Ju n 10

10. Fadel R, Mor rison AR, Vahi a A, et al. Early

short course cort icosteroids in hospitalized

patient s with COVID-19 . Clin Infect D is. 2020

May 19;cia a601. Online ah ead of print

11. Xu X, Han M, Li T, et al. Ef fective trea tment of severe

COVID- 19 patients with to cilizuma b. Proc Natl Acad Sci

U S A. 2020 Ma y 19;117(20):10970 -5. Epub 2020 Apr 29

12. Mehr a MR, Desai SS, Kuy S, e t al. Cardiovas cular

diseas e, drug therap y, and morta lity in Covid -19. N Engl

J Med. 2020 Ju n 18;382(25):e102. Epu b 2020 May 1

13. Mehr a MR, Desai SS, Kuy S, et a l. Retract ion:

cardiov ascular di sease, drug t herapy, and mortal ity in

Covid- 19. N Engl J Me d. 2020 Jun 25;382(2 6):2582.

DOI: 10.1056/N EJMoa2007621 . Epub 2020 Jun 4

14. Rubin EJ . Expression of conce rn: Mehra MR et al .

Cardiov ascular di sease, drug t herapy, and mortal ity

in Covid -19. N Engl J Med. 202 0 Jun 18;382(25):2464 .

DOI: 10.1056/N EJMoa2007621 . Epub 2020 Jun 2

15. Solomon M D, McNult y EJ, Rana JS, et al.

The Cov id-19 pandemic and t he incidence of

acute myo cardial infa rction. N Engl J Me d.

2020 May 19. O nline ahead of pr int

16. Mehra M R, Desai SS, Rusc hitzka F, et al. RE TRACTED:

hydroxych loroquine or chloroquine with or

without a m acrolide for treat ment of COVID-19: a

multin ational regis try analysi s. Lancet. 2020 M ay

22;S014 0-6736(20)31 180-6. Onl ine ahead of print

AUGUST 02 2020 MT BULLETIN OF NVTG 7

REVIEW

A novel virus, a recurring threat: looking at past

pandemic threats to understand how SARS-CoV-2

has evaded global control efforts

Shortly after the New Year, the

reporting of emerging clusters

of pneumonia from an unknown

pathogen in Wuhan, China, began

to draw the attention of infectious

disease experts and public health

ofﬁcials globally. In spite of Chinese

control efforts, including what up

until that point was the largest

population lockdown in human

history, it did not take long for the

localized viral infection to disperse

itself ubiquitously throughout

much of the world. As of the end of

June, SARS-CoV-2, the once novel

coronavirus, has claimed nearly half

a million lives and affected roughly

213 countries and territories.

SARS-CoV-2 is categorized as an

emerging infectious disease, deﬁned

by the World Health Organiza-

tion (WHO) as any disease that has

‘appeared in a population for the

ﬁrst time, or that may have existed

previously but is rapidly increasing

in incidence or geographic range.’[1 ]

Emerging infectious diseases are

primarily zoonotic, meaning they

are transmitted to humans from

animal hosts, and have been the

culprits of most pandemic threats

in the past decades, like SARS-CoV

(SARS), Ebola, Swine inﬂuenza and

Zika. With emerging infectious

diseases now making an appearance

on the global stage every few years,

it is vital to look at the speciﬁc

characteristics of SARS-CoV-2 and

the coronavirus disease (Covid-19)

that have allowed the virus to

evade global control efforts and

pose such a grave threat to society.

Comparing SARS-CoV-2 to disease

agents that have caused former

pandemics and global health crises

helps to contextualize the threat of

the current viral outbreak, and also

illuminates how response efforts

have been shaped in the wake of

international disease threats.

TRANSMISSIBILIT Y

It was late in the year when health care

practitioners in Southern China ﬁrst

encountered cases of a mysterious

viral illness that manifested as severe

pneumonia leading to acute respira-

tory distress. With variant strains of

avian ﬂu starting to become a seasonal

norm, Chinese public health ofﬁcials

did not at ﬁrst sound any global alarm

bells. After spreading to Beijing and

then Hong Kong, it boarded planes

bound for other continents and began

to make its way across land. Almost

simultaneously, three separate labs in

Hong Kong, Germany, and the United

States of America, ﬁnally identiﬁed the

pathogen causing this fatal pneumo-

nia as a novel coronavirus. The Global

Outbreak Alert and Response Network

was activated, and the WHO provided a

rapid and measured response helping to

advise every affected nation. By July, the

virus was controlled. But this was 2003,

and the novel coronavirus was SARS.

The international community learned

numerous lessons from SARS, namely

about the importance of having strong

disease surveillance and centralized

health systems. The outbreak led to

many countries boosting their infec-

tious disease control capacities, which

included the creation of the Center

for Infectious Disease Control here

in the Netherlands, the resources

of which have been integral to help-

ing the control efforts for combat-

ting the current outbreak nationally.

Global detection systems, however,

had evidently not prepared enough

for handling the very different trans-

mission dynamics of the SARS coro-

navirus successor, SARS-CoV-2.

The basic reproductive number, or R0,

refers to the average number of cases

generated by an infectious person, and

is considered an important indicator

of transmissibility. Although the R0

of SARS-CoV-2 is estimated to be only

slightly higher than that of SARS (3-5.3

and 2-5, respectively), SARS-CoV-2,

possesses numerous qualities that

make it not only more transmissible,

but more able to evade the surveillance

measures that had been able to stop

SARS.[2] The period of infectious ness

in SARS-CoV-2, for example, not only

begins before the onset of symptoms,

but in many cases peaks days before

most people even know they are sick.

[3] This makes mitigating the spread of

the virus much more challenging than

SARS, which during its 2003 out break

was transmitted primarily when patients

were severely ill and clearly symptom-

atic. Furthermore, there were only a

few known documented asymptomatic

SARS cases, which differs vastly from

SARS-CoV-2, where asymptomatic cases

are suspected to climb into the millions

globally. Epidemiologist are still seeking

to understand the capacity for asymp-

tomatic cases to spread the virus, but

like all unknown elements, it presents

further challenges in creating control

strategies and ﬁnding methods to estab-

lish normalcy in a world with Covid-19.

Additionally, other elements such as

longer relative incubation periods for

SARS-CoV-2 (most likely 3-10 days, but

potentially as long as 14) may have facili-

tated its spread during the initial out-

break, allowing people to carry the virus

far from disease epicenters under the

assumption that they had not contracted

the virus since they were not yet sick.[2 ]

PATHOGENICITY

Ten years after the last cases of SARS

were treated, a much more virulent

threat began lurking in the jungle of

Southern Guinea. By the summer of

2014, the Ebola virus disease (EVD),

never before seen in Western Africa

or able to reach an urban area, had

inﬁltrated the capital cities of Guinea,

Sierra Leone and Liberia. For two chaos

driven years, the worst Ebola outbreak in

8 MT BULLETIN OF NVTG 2020 AUGUST 02

REVIEW

history rocked Western Africa, sending

ripples of fear that the epidemic would

spread globally.[4] EVD is infamous for

its devastating hemorrhagic symptoms

and high pathogenicity, with case fatal-

ity rates (CFRs) from previous outbreaks

being as high as 90%. The CFR for the

2014-2016 West Africa Ebola outbreak

was 40%, making early estimates of

SARS-CoV-2 appear relatively low at

2.3%.[2] With SARS-CoV-2, however,

the virus’s capacity to transmit so

efﬁciently, ability to evade control, and

prevalence worldwide in addition to its

pathogenicity is what makes it so lethal.

To understand the true pathogenic-

ity of SARS-CoV-2, one can compare

its CFR to another virus that trans-

mits globally, the seasonal inﬂuenza.

Seasonal inﬂuenza, with a CFR of under

0.1%, is over twenty times less likely

to cause death than SARS-CoV-2,[5]

which would seemingly discredit the

minority of people who have claimed

that Covid-19 is just ‘another ﬂu’.

The Ebola outbreak being primarily

contained to three countries in West

Africa does not mean that it was not

a global threat. Partly due to very late

intervention from the WHO – for which

they have been vehemently criticized

– the virus became unmanageable in

West Africa and made appearances

in seven other countries.[4] Following

the outbreak, the global health com-

munity demanded that the WHO

improve responsiveness to emerg-

ing infectious diseases.[6] In 2019,

perhaps with the understanding that

the next emerging infectious disease

outbreak was merely a matter of time,

the WHO did make major adjustments

to help them focus on preparedness

and improve emergency response - a

component that would become useful

just months after its implementation.[7]

EPIDEMIOLOGY

As Ebola terrorized West Africa, a mos-

quito-borne pathogen called Zika virus

was making its way through much of

Brazil and spreading throughout South

and Central America. While Zika virus-

associated birth defects rose at incred-

ible rates, the disease strangely began to

recede within a couple of years of its ini-

tial emergence. Epidemiologists suspect

that Zika virus had hit its herd immu-

nity threshold (HIT).[8] Herd immunity

occurs when a certain percentage of

the population becomes immune to

a disease, either through contracting

the illness or from getting vaccinated.

The herd immunity required to reduce

transmission to below epidemic levels

varies for every disease, but is in theory

easier to achieve in diseases like Zika

that are limited to speciﬁc geographic

boundaries or demographic factors,

in this case to areas in which the Zika

transmitting mosquito was endemic.

SARS-CoV-2, conversely, is ubiquitous

and not limited by any geographic area,

gender, race, or for the most part, age,

although it has shown signiﬁcantly

higher associations of severe disease

and mortality with older age groups.

The herd immunity needed for reduced

transmission of SARS-CoV-2 to below

epidemic levels is estimated to be

somewhere between 50% and 75% of

the population.[9] These estimates take

many characteristics of the pathogen

into account. There are very few, if

any, health care systems in the world

capable of handling the volume of

Covid-19 patients if a country were to

attempt to reach herd immunity as a

control measure. Even if that weren’t the

case, some would suggest that allow-

ing for 75% of the population to get

infected with a disease that has such

a high case fatality rate (CFR) would

result in an unconscionable amount

of deaths. Perhaps most signiﬁcantly,

herd immunity is dependent on the

population becoming immune. As we

still have no conclusive evidence that

Covid-19 infection grants lifelong or

even long-term immunity, reaching herd

immunity and ultimately controlling

SARS-CoV-2 will most likely be contin-

gent on the development of a vaccine.

CONCLUSION

The characteristics that make SARS-

CoV-2 so transmissible, pathogenic,

and widespread have presented extreme

challenges to disease control special-

ists, as well as to a considerable percent

of the global population in some form

or another. During the 1918 Spanish

inﬂuenza pandemic that killed between

20 and 40 million people, governing

bodies issued public health warnings

centered around three components: try

to stay inside, socially distance yourself

from others whenever possible, and if

you must leave your house wear a mask.

If it is disheartening to see how little

has changed in our individual capac-

ity to control the spread of a pandemic

virus, perhaps there is solace in the

understanding that remarkable advances

have been made in surveillance,

diagnostics, and vaccine production,

largely informed by previous epidem-

ics of emerging infectious diseases.

Learning from the disease speciﬁc

elements that made SARS-CoV-2 so

uncontainable will help shape cur-

rent control efforts and inform future

outbreaks. Every large-scale epidemic

should come with numerous lessons not

only for containment, but for prepared-

ness, as the arrival of a new pandemic

threat is merely just a matter of time.

Jake Mathewson, MSc

Infectious Disease Consultant, the

Netherlands

jake.mathewson@gmail.com

REFERENCES

1. LeDuc , JW, Barr y, MA. SA RS, the ﬁrst pan demic of

the 21st C entury [Inte rnet]. Emerg Infe ct Dis. 2004

Nov;10(11),e26 . DOI: 10.3201/eid1011.04 0797_02

2. Chen J. Path ogenicity and t ransmissibi lity of

2019-nC oV: a quick over view and compar ison with

other eme rging viru ses. Microbes In fect. 2020

Mar;22(2): 69-71. DOI:10.1016/j.mic inf.2020.01.004

3. He X, Lau EH Y, Wu P, et al. Temporal dy namics

in vira l shedding and t ransmissibi lity of COVID-

19. Nat Med. 2 020 May;25(5):672 -675. Epub 202 0

Apr 15. DOI: 10 .1038/s41591-020 -0869-5

4. Centers for D isease Control and P revention [Inte rnet].

2014-2 016 Ebola outbreak i n West Afr ica; [reviewed

2019 Mar 8]. Ava ilable from: htt ps://www.cd c.gov/

vhf/ebola/his tory/2014-2016 -outbreak /index.ht ml

5. Russell T W, Hellewell J, Jar vis CI, et al. Es timating

the infe ction and case fa tality ratio fo r coronavirus

diseas e (COVID-19) usin g age-adjusted d ata from the

outbreak on t he Diamond Pri ncess cruise sh ip, February

2020. Eur o Surveill. 20 20 Mar;25(12):20 00256.

DOI:10.2807/1560- 7917.ES.2020. 25.12.20 00256

6. World Health O rganization [I nternet]. Q&A : inﬂuenza

and COVID -19: similar ities and diff erences; 2020

Mar 17. Avai lable from: http s://www.who.int/

emergencies/diseases/novel- coronaviru s-2019/

question-and -answers-hub/q-a- detail/q-a- similar ities-

and-differences-covid-19-and-inﬂuenza?

7. World Hea lth Organizat ion Regional Of ﬁce for

South-E ast Asia. Five- year regional st rategic plan to

strengt hen public health preparedness and res ponse

[Inter net]. India: World Hea lth Organizat ion, 2019-

2023; 2019. 35 . Available from: ht tps://apps.who.int/

iris/bitstrea m/handle/10665/326856/9789290227236-

eng.pdf?sequence= 1&isAllowed=y

8. Netto EM , Moreira Soto A, Pedro so C, et al. High Z ika

viru s seroprevalence i n Salvador, North eastern Brazi l

limit s the potential fo r further outb reaks. mBio. 2017

Nov 14;8(6)e01390 -17. DOI: 10.1128/mBio.01390-17

9. Britton T, Ba ll F, Trapman P. A mathe matical

model rev eals the inﬂue nce of population

heteroge neity on herd immun ity to SARS- CoV-2.

Science. 2 020 Jun 23;eabc6810. DO I: 10.1126/

science.abc6810. Onl ine ahead of print

AUGUST 02 2020 MT BULLETIN OF NVTG 9

PERSONAL REFLECTIONS FROM THE FIELD

Covid-19 in context

The end of my work in a

hospital in rural Congo-

Brazzaville coincided with

the worldwide Covid-19

outbreak. It was painful

to leave, knowing that the

pandemic would also hit

Congo-Brazzaville in the

very near future. Luckily,

my fellow doctors and

I had recently prepared

for a possible spread of

Ebola virus disease, and

we had stockpiled a

big container with

personal protective

equipment

just before

global demands

skyrocketed. When

I left, the hospital

staff was worried

that I would contract

Covid-19 in Europe, as

the number of new cases

was rising quickly. It felt

like the world upside

down, and leaving amidst

all this was difﬁcult as it

gave me a sense of letting

them down. Many of

my fellow global health

doctors had to adapt to

the pandemic. Everybody

was eager to connect

professionally, share

resources, ask questions

and discuss evidence, but

there are personal stories

as well. Here, we share

four experiences of global

health doctors around the

world during the Covid-19

outbreak in the spring of

2020.

Remco van Egmond, MD

Global Health and Tropical Medicine,

previous afﬁliation: Clinique Médicale

CIB, Pokola, Congo-Brazzaville

vanegmond.remco@gmail.com

How Ebola prepared us to

ﬁght Covid-19 in the DRC

It was in October 2019 that I received

my ﬁrst patient infected with Ebola.

There is a ﬁrst time for everything,

but some things can better be avoided.

Within a few days, I found myself alone

in our house: my wife and our three

children were temporarily elsewhere, as

violence against Ebola response teams

put the whole village in turmoil. Our

55-bed mission hospital in the Northeast

of the DRC became almost empty with

no outpatients anymore. Now, eight

months later, we have no more

Ebola in our area and I gladly

use the experience that I

acquired and apply it to

the Covid-19 outbreak that

is threatening us now.

In reality, every epidemic

has its own characteristics,

and I have learned to see differ-

ences and similarities. The mortality

of Covid-19 in the DRC (2.2%) is much

lower than for Ebola virus disease (EVD)

during the epidemic in the area served

by our hospital (66%).[1] Contact tracing

and isolation of suspect cases, however,

seems much easier for EVD than for

Covid-19, since EVD hardly occurs with-

out any symptoms. Vaccines are crucial

in ﬁghting against an outbreak, and

the EVD vaccine possibly saved my life.

Some epidemics gain more attention

than others. For instance, few people

know that the DRC had almost 370,000

measles cases and 6,779 deaths by mea-

sles in just the year 2019.[1] However,

when I asked the Ebola surveillance

team that was visiting our hospital

on a daily basis in their 4x4s whether

they had seen the measles-epidemic-

Landcruisers, they grinned sheepishly.

There are also many similarities. In

an outbreak it is crucial to inform all

relevant parties and get them on board.

If you forget to respect a village chief in

the Congolese culture you will struggle

to get anything done. Community

resistance had massively hindered a

thorough uptake of EVD cases, contact

tracing and clinical management in

our area.[2] So, when we saw the ﬁrst

few cases of Covid-19 in our region, we

compiled small information sheets in

French and Congolese Swahili about

symptoms, prevention and the most

important dos and don’ts. When bring-

ing this to chiefs, government ofﬁcials,

church leaders and anyone interested,

I found myself directly amidst good

conversations, clarifying many things

about Covid-19. Outbreaks often

negatively impact continuity of care for

other conditions, such as malaria and

obstetric complications in affected areas,

because of closure of health facilities,

lack of staff or fear among patients to

contract the disease in the facilities.

[3] That is what we saw with the Ebola

cases in our hospital, and that is what I

also feared when Covid-19 would hit us.

But luckily, with all Covid-19 measures

in place now (borders, schools and

churches closed, and meetings >20

people forbidden), hospital visits did not

decline and villagers accepted the com-

bined Ebola/Covid-19 triage at the gate

knowing that it would help ever yone.

I have yet to see the ﬁrst Covid-19 case

in our hospital. We feel at least a bit

prepared with a triage and a small

isolation unit, but we know that there

are many things we cannot control.

The Ebola epidemic brought us teams

of experts in 4x 4s and NGOs with

water, sanitation and hygiene (WASH)-

projects. Covid-19 brought us a pro-

vincial response protocol and many

restrictions, but the government’s main

focus has been on the highly urbanized

area of Kinshasa, the country’s capital

thousands of kilometres away, where

cases augment rapidly. Our provincial

health authorities designated hospitals

without even an oxygen concentrator

PERSONAL REFLECTIONS FROM THE FIELD

as Covid-19 treatment centres. Not a

single hospital in our area can provide

advanced respiratory support. We feel

blessed with two oxygen concentrators

we are certainly highly underequipped

compared to high- or middle-income

settings. Unfortunately, most WHO

and NGO experts have left the region.

Our area continues to be plagued

by insecurity, and outbreaks add

to these difﬁculties. I am learning

resilience from my colleagues, some

of whom have ﬂed war zones or have

been kidnapped or lost relatives and

have learned to rebuild their lives

after the loss of all their possessions.

Our hope and our prayer is that this

Covid-19 epidemic will make us

stronger, as the Ebola epidemic did.

Mark F.P. Godeschalk, MD

Global Health and Tropical Medicine

(AIGT), Lolwa Referral Hospital, Democratic

Republic of the Congo.

godeschalk@hotmail.com

mgodeschalk@gzb.nl

www.gzb.nl/ZorginCongo

REFERENCES

1. World Health O rganization . We ekly bullet in on

outbreak s and other emergen cies [Internet ]. Brazzavill e:

WHO Regi onal Ofﬁce for Af rica; 2020 May 31 (2 2): 19

p. Availab le from: https://apps.who.int /iris/bitstre am/

handle/10665/3322 46/OEW22-253105202 0.pdf

2. Nguyen VK . An epidemic of su spicion: Ebola a nd

violence i n the DRC [Interne t]. N Engl J Med. 2019

Apr;380:1 298–9. DOI: 10.1056/NEJMp19 02682

3. McQuil kin PA, Udhayash ankar K, Niesc ierenko M, et

al. Heal th-care acces s during the Eb ola virus epid emic

in Libe ria. Am J Trop Med Hyg. 201 7 Sep;97(3):931– 6

EBOLA

IS MORE

OF AN OPEN

WOUND

THAN A SCAR

Corona free country?

‘My little son has a fever and we will be

travelling tomorrow, what shall we do?’

January, 2020, a colleague was return-

ing from abroad to Papua, Indonesia.

Something was going on in China, and

airport authorities in Thailand started

doing prior temperature checks on trav-

ellers as part of boarding procedures.

Wasn’t this just a kind of ﬂu, not

too severe? ‘Don’t worry, just

give him some paracetamol

so that you can pass that

temperature check. They are

just a little nervous there.’

A month later this “mild ﬂu”

apparently was something more

serious. More and more deaths were

reported and suddenly two brand new

hospitals were built in China. Indonesia

has quite strong ties with China, includ-

ing daily ﬂights to Wuhan, so I expected

to hear very soon about cases of this

new illness. All countries in Southeast

Asia reported rapidly rising numbers,

but not Indonesia. Instead, the govern-

ment invested millions of dollars to

advertise Indonesia as a corona-free

country: ‘Come for holidays to Bali!’

Late February, one of my patients was

evacuated from Papua to Jakarta for

surgery. He was admitted to one of the

best hospitals in Indonesia, which was

apparently ﬁlled with dengue patients.

He got a mattress on the ﬂoor. The

strange thing was that these patients

were coughing persistently; some looked

really sick and disappeared secretly

during the night. He got his surgery and

ﬁnally a normal bed on a surgical ward.

After a few days, he developed fever and

started having a sore throat and a dry

cough. What to do? I advised him to ask

for a Covid test. His doctor was startled:

‘We don’t have that illness in Indonesia,

and you didn’t come from abroad.

Furthermore, your blood tests and X-ray

were totally ﬁne on admission. No need

to test. Your wound might be infected,

so I will start antibiotics.’ The only

thing I could do was to strongly advise

self-quarantine after he got back in our

little Papuan town. The wounds looked

perfectly clean and healing, but the fever

persisted for a week. Early March, the

ﬁrst Covid-19 cases were reported. But

that was in Jakarta, not on our island,

far away to the east of Java. Strangely

enough, our expat medical team got

Read more on the appeal, and the

support from European doctors and

citizens on the initiative website: ht t p s://

www.sosmoria.eu/?lang=en

REFERENCES

1. Chapma n A. A doctor’s stor y: inside the ‘l iving hell’

of Moria ref ugee camp. The G uardian. 2020 Feb

9 [accessed 2 020 Jun 7]. Available f rom: https://

ww w.theg uar dian .com/ world/2 020/feb/0 9/

moria-refu gee-camp -doctors -story-lesbo s-greece

2. Nuttin g T. Headache s in Moria: a reﬂec tion

on mental h ealthcare in t he refugee camp

popula tion of Lesbos. BJPs ych Int. 2019

Nov;16(4):96- 8. DOI:10.1192/bji.2019. 2

3. Sherall y J. The corona pandem ic: How to

prevent a me dical disaste r? Lecture pre sented

at; 2020 Apr 2 0; Utrecht Univer sity

4. Iacobucci G . Covid-19: docto rs warn of

humanitarian catastrophe at Europe’s largest

refuge e camp. BMJ, 2020 Mar 1 7;368:m1097.

5. Greek Repo rter [Interne t]. MSF Says Greece’s Moria

Migra nt Camp is a Coronavi rus “Time Bomb”; 202 0 Apr

3 [accessed 2 020 Jun 7]. Available f rom: https://greece.

greekrepor ter.com/2020/04/03/msf-says-greeces-

moria-mig rant-camp -is-a-coronav irus-t ime-bomb/

6. Worldometer [I nternet]. Greece ; [updated 2020 Jul 15;

accessed 2 020 Jun 7]. Available f rom: https://www.

worldometers.in fo/coronavirus/country/greece/

7. #50 0kinderen [Inte rnet]; [accesse d 2020 Jul 7]. Availabl e

from: https://www.500ki nderen.nl/petitie-g riekenland

THE MAIN GOAL SHOULD NOT BE TO PIMP MORIA

WITH ICU BEDS AND OTHER FANCY MEASURES.

THE GOAL SHOULD BE FOR MORIA TO DISAPPEAR.

THERE SHOULDN’T BE A CAMP IN THE FIRST PLACE

AUGUST 02 2020 MT BULLETIN OF NVTG 17

OPINION

Covid-19 and the Trojan horse that eroded the

World Health Organization

The Covid-19 pandemic has created

havoc around the world since the

early days of 2020. My attendance

at a civil society meeting in Geneva

coincided with the World Health

Organization (WHO) declaring the

Covid-19 epidemic a public health

emergency of international concern

(PHEIC).[1,2] Mike Ryan, director of

WHO Health Emergencies Pro-

gramme was worried, yet still opti-

mistic, estimating that the epidemic

could be contained at the regional

level in Asia. I shared the same

sentiment and travelled on after the

meeting to Indonesia without real

concerns. I returned to the Neth-

erlands just before the epidemic

escalated and international borders

were closed.

June 2020, we are six months into

the pandemic and over 9 million

conﬁrmed cases of Covid-19 have

now been reported to the WHO,

including more than 470,000

deaths. [3] Questions have been

raised about the role and capacity

of the WHO and other international

actors in assisting countries to

prepare for and respond to a viral

pandemic of this magnitude. Ac-

cording to Dr Tedros, WHO’s director

general, the main reason for declar-

ing this PHEIC was ‘not because of

what is happening in China, but be-

cause of what is happening in other

countries. Our greatest concern is

the potential for the virus to spread

to countries with weaker health

systems, and which are ill-prepared

to deal with it.’[1 ]

The WHO was prepared, in the

sense that it was well aware of the

emergence of another “Disease-

X” – a yet unknown pathogen

causing a human disease which

eventually would lead to a seri-

ous epidemic.[4] The world had

witnessed such epidemics before,

like the SARS epidemic in 2003,

which remained largely contained

to China, the Ebola-epidemic

which impacted mainly countries

in West Africa (2014-2015), as well

as other emerging zoonoses such

as avian ﬂu, Zika, and Lassa fever.

These epidemics all raised global

concern (some more than others),

and inspired global health actors

and national government leaders to

underscore the need to strengthen

global health security. Sadly, few

countries really acted upon their

initial commitments and failed to

invest in an essential public health

function that others have labelled a

global public good.[5]

INTERNATIONAL HEALTH REGULATIONS

Following the 2003 SARS epidemic, the

World Health Assembly (WHA) adopted

a revised version of the international

health regulations (IHR), which since

their adoption in 1969 had served as the

main framework governing the interna-

tional response and a country’s capacity

to deal with public health emergencies,

including major infectious disease out-

breaks.[6,7] Under the IHR, and upon dec-

laration of a PHEIC, the WHO has the

power to provide countries with tempo-

rary, non-mandatory recommendations

on how to deal with the emergency at

hand. Countries are not legally obliged

to adopt such recommendations, such

as in this case testing for Covid-19 virus,

tracking possible cases, and identifying

risk-groups. However, the IHR obliges

countries not to implement policies that

would prevent international trade and

mobility. For example, WHO member

states cannot suddenly make medical

examinations, vaccinations or prophy-

laxis compulsory for travellers in case

they are potentially infectious. This did

not prevent Austria and other European

states from requesting foreign travellers

to their countries to provide a certiﬁcate

of a negative Covid-19 test result. These

actions clearly constituted a breach of

the IHR,[8] but they could not be fol-

lowed by any sanctions. Other multilat-

eral organisations perform better in this

sense. The World Trade Organization

(WTO), for example, uses international

dispute settlement mechanisms and

a sanction regime when international

trade rules are violated. It has become

clear that WHO’s IHR provides only

limited resources, mandate, and legiti-

macy to direct sovereign countries in

addressing their approaches to disease

outbreaks and other public health

risks. Interestingly though, a hundred

years before WHO’s establishment,

countries already tried to regulate

international public health responses.

[9] In the words of leading global health

lawyers: ‘The IHR is no “magic bullet”

for global health problems. Previous

transformations in international law’s

relationship with public health have over

time atrophied into insigniﬁcance.’[7]

POLITICAL TENSIONS BETWEEN THE

UNITED STATES OF AMERICA AND CHINA

The recent critique by the Trump

administration that WHO has an

‘alarming lack of independence from

the People’s Republic of China’ in

addressing the Covid-19 pandemic is

unfounded.[10] Donald Trump’s deci-

sion to sever ties with the WHO and

his threat to halt funding must be seen

as part of a larger geopolitical conﬂict

between the USA and China. A kind of

Cold War 2.0 meant to divert atten-

tion from the disastrous response and

poor performance of the USA’s health

system itself.[11] China has made errors

in dealing with Covid-19, especially

in terms of transparency at the begin-

ning of the epidemic. Human rights

violations have been an issue in the

stringent lockdown and surveillance by

the Chinese state.[12] Nevertheless, the

rapid public health response by China,

and Southeast Asia more generally,

has so far proven effective in contain-

ing the virus. This has been noted by

other low- and middle-income coun-

tries (LMICs) and by the WHO. In the

report by a WHO evaluation mission

to China in February, Dr Tedros hailed

the country’s swift response and

approach.[13 ] For diplomatic and global

18 MT BULLETIN OF NVTG 2020 AUGUST 02

OPINION

health objectives, it is important that

the WHO keeps working closely with

the world’s most populous country (1.4

billion inhabitants). At the same time,

there are informal complaints regarding

controlled and restricted access to China

for the WHO ofﬁcials. Meanwhile,

China has committed to stepping up

multilateral collaboration, pledging US$

2 billion to the United Nations (UN) for

its Covid-19 response, and it has agreed

to a full evaluation of the international

response once the pandemic is over.[14]

In any case, this is a watershed moment

in global health, not only for the WHO.

In the coming years we are likely to see

the USA retreating from international

health cooperation in LMICs while

China may considerably step up its bilat-

eral health collaboration with African,

Asian and Latin American countries.[15 ]

THE EROSION OF THE WHO

Ironically, the USA, along with some

afﬂuent European countries are respon-

sible for WHO’s limited capacity to deal

with transnational health emergen-

cies. The roots of this problem lie in

the governance structure, in which the

WHA, composed of all 190+ member

states, decides collectively on WHO’s

programme of work. In the 1980s, high-

income countries, in response to the

growing inﬂuence of LMICs, decided

to review their ﬁnancial contributions

to the UN and the WHO in particular,

changing to voluntary payments. In the

current set-up, eighty percent of WHO’s

budget is comprised of voluntary con-

tributions by member states, philan-

thropic organisations (such as the Bill &

Melinda Gates Foundation), and private

donors. This has led to a situation in

which donors no longer provide core

funding, but rather support particular

programmes, i.e. those that ﬁt their own

(domestic) interests. Examples include

the USA’s ﬁnancial support for polio

eradication, and the Netherlands’ target-

ing of funds to sexual and reproductive

health and rights programmes of the

WHO. The result has been severe under-

funding of certain other programmes,

such as emergency preparedness, health

systems strengthening (including health

workforce strengthening) in LMICs and

programmes aimed at achieving univer-

sal health coverage. Meanwhile, we have

witnessed a surge of global health initia-

tives for disease-speciﬁc approaches,

such as the Global Fund to Fight AIDS,

Tuberculosis and Malaria (GFATM),

Gavi, the Vaccine Alliance, the Global

Health Security Agenda (GHSA), and

others. They generally deliver short term

results, over which the donor countries

have more direct control. In the process,

the WHO has become hamstrung by

its donors, limited in its autonomy,

and become relatively neglected in a

neoliberal era in which policy objec-

tives such as “value for money” and

“enlightened self-interest” received

priority over the provision of global

public goods, such as the international

capacity to respond to pandemics.

This trend is also described as “Trojan

multilateralism” and has seriously

eroded the UN over the last decade.[16]

SOLIDARIT Y AND SHARED

RESPONSIBILITIES

The World Health Report 2007 on

health security stated that ‘57 countries,

most of them in Sub-Saharan Africa and

Southeast Asia, are struggling to provide

even basic health security to their popu-

lations.’[17 ] In response to the 2014-2015

Ebola epidemic, there has been much

talk about the need to develop strong

and resilient health systems. No less

than four international commissions

have provided recommendations on how

to improve the international response

to health emergencies.[18] All of these

commissions recommended strength-

ening WHO’s mandate, autonomy and

ﬁnancial basis, as well as reforming the

IHR with a view to strengthen its capac-

ity to address global public health risks.

The Covid-19 pandemic may provide the

“shock momentum” that was needed to

stabilize and improve – in a democratic

way – the only internationally man-

dated health organisation in the world.

In his media brieﬁng in late June

2020, Dr Tedros made a plea for global

solidarity and urged countries to work

together to ensure that supplies (e.g.

dexamethasone, oxygen, personal

protective equipment) and vaccine

development are prioritized for coun-

tries with large numbers of critically

ill Covid-19 patients. ‘The world is

learning the hard way that health is

not a luxury item; it’s the cornerstone

of security, stability and prosperity.’[19]

Germany has announced it will make

an unprecedented € 500 million pledge

to the WHO. This must be seen as a

plug for the large funding gap left by

the withdrawal of the USA.[20] It can

also be seen as a geopolitical signal to

the world. Germany prefers in these

uncertain times to invest in health

security (WHO) rather than military

security (NATO). So far, the Dutch

government has committed US$ 6.5

million to the WHO for the Covid-19

response.[21] At the same time, it is

providing its national airline, KLM, with

a € 3.6 billion (!) guarantee to secure

its position in international trade and

mobility. Will the Netherlands eventu-

ally realize that this interconnectedness

relies on the peace, wellbeing and health

of societies in other parts of the world?

Isn’t it time to put aside such a frugal

attitude and instead invest seriously in

global public health? That would be the

real call, in the current era of pandemic

threats, climate emergency, economic

instability and growing disparities.

Remco van de Pas, MD

Global Health Policy, Institute of Tropical

Medical, Antwerp, Belgium, and Clingendael

Institute, The Hague, the Netherlands

rvandepas@itg.be

REFERENCES

1. World Health O rganization [ Internet]. Gene va: World

Health O rganization. W HO Director-G eneral’s

stateme nt on IHR Emergency Com mittee on novel

coronavi rus (2019-nCoV); 2 020 Jan 30. Available

from : https://w ww.who.in t/dg/spee ches/deta il/

who-director-general-s-statement-on-ihr-emergency-

committee -on-novel-coronaviru s-(2019-ncov)

2. G2H2 Genev a Global Health Hub [I nternet]. Gene va:

Geneva Gl obal Health Hub. Civ il society me etings

ahead of t he 146th Session of t he WHO Executiv e

Board, 31 Ja nuary and 1 Febr uary 2020; 2019 D ec 30.

Available from : http://g2h2.org/po sts/january2020/

3. World Health O rganization [I nternet]. Gene va:

World Health Organiz ation. WHO coronavir us

diseas e (COVID-19) dashb oard; updated 202 0 Jul

15. Avail able from: https ://covid19.who.int/

4. World Health O rganization [I nternet]. Gene va:

World Health O rganization . Prioritizi ng diseases

for researc h and development i n emergency

context s; 2020. Available f rom: https://www.who.

int/activit ies/priorit izing-d iseases-for-re search-

and-development-in-emergency-contexts

5. Smith RD, Ma cKellar L. G lobal public goods a nd

the glob al health agend a: problems, prior ities

and potent ial. Global Hea lth. 2007 Sep 22 ;3:9

6. World Health O rganization. I nternationa l Health

Regul ations (2005): th ird edition [Inte rnet].

Geneva : Wo rld Health Organ ization; 2016.

84 p. Avail able from: https://ww w.w ho.int/

ihr/publicati ons/9789241580496/en/

7. Fid ler DP, G ostin LO. The ne w Internationa l

AUGUST 02 2020 MT BULLETIN OF NVTG 19

OPINION

Health R egulations: a n historic develo pment

for inter national law and p ublic health. J L aw

Med Ethi cs. Spring 2006 ;34(1):85-94, 4 .

8. Schengen Visa Info [Internet]. Schengenvisainfo.com;

2012-2 020. Number of EU count ries asking t ravellers

for COVID -19 negative test res ults is on the rise ; 2020

Jun 1. Avai lable from: http s://www.sch engenvisain fo.

com/news/number-of-eu- countries -asking-t ravellers-

for-covid-19-negative-test-results-is-on-the-rise/

9. Fidler DP. The glo balization of pub lic health: the

ﬁrst 100 y ears of internat ional health d iplomacy.

Bull World Hea lth Organ. 200 1;79:842-9

10. Lett er by The White Hou se to Dr. Tedros

Adhananom Ghebre yesus, Director-Genera l of

the World Heal th Organizat ion on May 18, 2020.

Available from: https://www.whitehouse.gov/

wp-content/uploads/2020/05/Tedros-Letter.pdf

11. Huang Y. Tru mp’s decision t o pull U.S. out of WHO

will b oost China’s inﬂu ence. Washington Po st

[Inter net]. 2020 Jun 23. Ava ilable from: htt ps:// www.

washing tonpost.com/politic s/2020/06/23/trumps-

decision-pul l-us-out-who-will-boo st-chinas-inﬂuence/

12. Zha ngrun X, Ba rmé GR. Viral a larm: when

fur y overcomes fear. Chi naFile [Interne t].

2020 Feb 10. Ava ilable from: htt ps:// www.

chinaﬁ le.com/reporti ng-opinion/v iewpoint/

viral-a larm-when-fury-overcomes-fe ar

13. World Healt h Organizat ion. Report of the W HO:

China j oint mission on coronav irus diseas e 2019

(COVID -19): 16-24 Febru ary 2020. Genev a:

World Health O rganization ; 2020. 40 p.

14. Lau S. X i Jinping defends C hina: WHO coronav irus

response f or ﬁrst time on world s tage. South

China M orning Post [Int ernet]. 2020 May 18 .

Available from: https://ww w.scmp.com/news/

china/diplomac y/article/3084916/coronavirus -xi-

jinping-defends -china-and-who-respon se-world

15. Husai n L, Bloom G. Underst anding Chi na’s growing

involveme nt in global healt h and managin g processes

of chan ge. Global Health . 2020 May 1;16(1):39

16. Van de Pas R, v an Schaik LG. D emocratizi ng

the World Heal th Organizat ion. Public

Health. 201 4 Feb;128(2):195-201

17. World H ealth Organi zation. The world he alth

report 2 007: a safer fut ure: global publ ic

health s ecurity in t he 21st centur y. Geneva :

World Health O rganization ; 2007. 96 p.

18. Gost in LO, Tomori O, Wibulpolpr asert S, et al. Toward a

common secure fut ure: four global commissions in the

wake of Eb ola. PLoS Med. 2016 M ay 19;13(5):e1002042

19. Van de Pas R, v an Schaik LG. D emocratizin g

the World Heal th Organizat ion. Public

Health. 201 4 Feb;128(2):195-201

20. World Health O rganization. T he world health

report 2 007: a safer fut ure: global publ ic

health s ecurity in t he 21st centur y. Geneva :

World Health O rganization ; 2007. 96 p.

21. Gost in LO, Tomori O, Wibulpolpr asert S, et al. Toward a

common secure fut ure: four global commissions in the

wake of Eb ola. PLoS Med. 2016 M ay 19;13(5):e1002042

22. World Health O rganization [I nternet]. Genev a: World

Health O rganization. W HO Director-G eneral’s

openin g remarks at the med ia brieﬁng on

Covid- 19: 22 June 202 0; 2020 Jun 22. Avai lable

from : https://w ww.who.in t/dg/spee ches/deta il/

who-director-general-s-opening-remarks-at-the -

media-brie ﬁng-on- covid-19- --22-june -2020

23. Health Pol icy Watch [Interne t]. Germany ma kes

€ 500 mil lion pledge to WHO: p lug for ‘major

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Available from: ht tps://healthpol icy-watch.news/

germany-makes -e-500-m illion-pledge-to -who-a-

plug-for-major-funding-gap-left-by-united-states/

24. World Healt h Organizatio n [Internet]. Ge neva: World

Health O rganization. D onors and part ners: 2020 Jun

19. Available from: https://www.who.int/emergencies/

diseases/novel-coron avirus -2019/donors-and-part ners

Outbreak of Covid-19 like illness in a remote village

in Papua, Indonesia

The Covid-19 pandemic is hitting

low- and middle-income coun-

tries, where health care resources

are already stretched. This article

describes the spread of a Covid-

19-like illness in M20 (a pseud-

onym), an isolated village without

medical facilities in Indonesia. M20

is situated at an altitude of 6,700

feet in the central mountain range

of Indonesia’s easternmost prov-

ince, Papua. It is typically served on

request by a small six to eight-seat

aircraft, or reached by trekking on

foot from other villages. The vil-

lage consists of seven hamlets of

two to six huts, separated by ﬁve

to ten-minute walks. Villagers are

closely related to inhabitants of

other villages in the area, and visit

each other often. In the villages

of the Papuan highland, men and/

or families sleep together in one

hut, and children sleep with their

mothers or families (sometimes up

to 30 people in one hut). The clos-

est neighbouring village to M20 is

about 1.5 hour by foot, with people

visiting multiple times a week. The

actual population varies with these

interactions and ranges from 150 to

200 people. M20’s gender distribu-

tion is estimated at 60% women,

and 40% men, due to a combina-

tion of a higher life expectancy of

women (66.8 years compared to

63.0 years for men) and men spend-

ing most of their time in towns.[1]

Approximately half of the popula-

tion is under twelve years of age.

There are four to six matriarchs, and

others are teenagers, young adults

and adults in their thirties to ﬁfties.

Most men smoke, and most people

live in huts with central ﬁre pits,

which are used throughout the day

for cooking and during the evening

and night for heating.[2] The closest

government health centre is about

three hours by foot, but trained

health workers are typically absent,

as is common in this region.[3] In

M20, lay health workers hold daily

clinics where they perform primary

health care and dispense medica-

tion.

METHODS

This account of an outbreak in a remote

village in Papua is compiled from

patient care records kept by lay health-

care workers in M20 during and after

an outbreak, as well as medical doc-

tors responding to online requests for

help. We use a pseudonym to conceal

the name of the village and protect its

population; patient data were analysed

anonymously. Symptoms of villagers

seeking medical help were recorded

by lay health workers, so initial mild

symptoms were not systematically

recorded. In most cases with infectious

diseases the exact onset of infection is

not clear. A major caveat is that poly-

merase chain reaction (PCR) testing

RESEARCH

20 MT BULLETIN OF NVTG 2020 AUGUST 02

RESEARCH

for Covid-19 was not possible due to the

lack of tests and test facilities. Our team

repeatedly contacted the government

health services, but PCR testing, or

testing using reliable antibody tests, was

not possible until the time of submis-

sion of this report (as of end of June).

To collect information on Covid-19

symptoms of all villagers present during

the outbreak, the lay medical workers

also asked individuals who did not seek

medical help about Covid-19 symptoms.

EPIDEMIOLOGIC TIMELINE

On 22 March 2020, the ﬁrst case of

conﬁrmed Covid-19 was reported in

Indonesia. However, suspected cases

with links to Wuhan China were

reported earlier in Jakarta in February

2020. On 20 February 2020, the ﬁrst

suspected Covid-19 patient reported in

M20 for care with symptoms of fever,

sore throat, cough and stomach com-

plaints although at that time Indonesia

had no ofﬁcial Covid-19 cases. Two

weeks after the index case in M20, the

number of cases rose steeply with 26

patients on one day (Figure 1). Covid-19

had become the top of the differential

diagnosis list, as symptoms were in line

with the WHO deﬁnition of Covid-19,

and the index case had been in con-

tact, prior to symptom onset, with a

person who had travelled to Jakarta

where probable Covid-19 cases were

reported.[4] On 3 June 2020, Papua

had 862 cases of Covid-19, while all

of Indonesia counted 28,233 cases.[5]

Clinic records showed symptoms as

summarized in Table 1. Table 2 presents

the characteristics of the 101 suspected

Covid-19 patients in M20. The illness

started with several days of sore throat,

followed by stomach complaints, and

fever within 24 hours of stomach

complaints. Fever and fatigue were

constant, lasting 3-5 days. In severe

cases (Table 2), fevers above 40°C often

accompanied shortness of breath and

chest pain, starting after day ﬁve of ill-

ness. Two villagers died after 48 hours

of extreme shortness of breath. Both

were male, over 40 years of age, and

had underlying chronic illness (most

likely chronic kidney disease). The lay

healthcare workers treated patients with

the limited resources available to them;

those with moderate symptoms mainly

received paracetamol, up to four times

a day. Severely ill patients were given

empiric amoxicillin treatment (49% of

101 patients) to prevent and/or treat a

possible secondary bacterial pneumonia.

Those with fevers over 40°C received

a different antibiotic: amoxicillin/

clavulanic acid (2% of the patients) or

azithromycin (3% of the patients). The

actual effect of antibiotics on recovery

is not evident. Based upon advice early

on in the worldwide epidemic to use

chloroquine as a possible treatment

SEVERE SYMPTOMS APPROXIMATE PERCENTAGE OF PATIENTS REPORTING

Fever (either mild 37-38.5°C or high <38.5) 80%

Shortness of breath 70%

MILD SYMPTOMS

Sore or dry throat 90-95% adults. 60-70% children

Coughing (usually at night) 80%

Fatigue 90%

Lethargy (most of the children) 80-90% children

Headache (late in the illness) 60%

Muscle and joint pain 10-20%

Diarrhoea 20-30%

Vomiting 10%

Table 2. Symptoms of patients with suspected Covid-19.

MILD TO MODERATE SYMPTOMS SEVERE SYMPTOMS

AGE MALE FEMALE MALE FEMALE

0-5 7 6.9% 5 5.0% 2 2.0% 2 2.0%

6-10 7 6.9% 15 14.9% 1 1.0% 1 1.0%

11-15 2 2.0% 2 2.0% 0 1 1.0%

16-20 8 7.9% 1 1.0% 0 0

21-25 2 2.0% 2 2.0% 1 1.0% 0

26-30 4 4.0% 3 3.0% 1 1.0% 3 3.0%

31-35 3 3.0% 6 5.9% 1 1.0% 0

36-40 3 3.0% 5 5.0% 1 1.0% 0

41-45 1 1.0% 3 3.0% 0 0

46-50 2 2.0% 1 1.0% 3 3.0% 1 1.0%

50+ 0 0 0 1 1.0%

(median = 17)

Total 39 38.6% 43 42.6% 10 10.1% 9 8.9%

Table 1. Suspected Covid-19 patients treated in M20.

31 mar

29 mar

27 mar

25 mar

23 mar

21 mar

19 mar

17 mar

15 mar

13 mar

11 mr

20 feb

22 feb

24 feb

26 feb

28 feb

1 mar

3 mar

5 mar

7 mar

9 mar

Physicians are involved

through online consultation.

Physical distancing measures

implemented.

Male | Mild

Female | Mild

Male | Severe

Female | Severe

Figure 1: Number of patients with symptoms observed over time.

AUGUST 02 2020 MT BULLETIN OF NVTG 21

RESEARCH

for Covid-19, severely ill and high-risk

patients (aged above 40), were given 150

mg chloroquine twice a day for seven

days (14% of the patients).[6] Except for

the two patients who died, all patients

recovered. The effect of chloroquine and

antibiotics on recovery is unknown.

As Figure 1 shows, the entire epidemic

curve involved 101 patients (about

half of the population of the village)

over a period of four weeks. Informal

questioning in the community revealed

that only about ten villagers denied

having had any symptoms yielding a

presumptive infection rate of 90-95% of

all residents. Of the twelve patients over

age 40, ﬁve were severely sick (41%),

and two died (17%). Approximately 50%

had mild or no symptoms (Table 2). The

median patient age is low (17 years),

which might explain the unexpectedly

low mortality of 1% given minimal

health facilities and no mitigating

measures.[7] The high proportion of

females in the population may explain

that more women (51.5% of the patients)

were affected than men. Physical

distancing measures were imple-

mented, but their effect was unclear.

CONCLUSION

This outbreak pattern of suspected

SARS-CoV-2 in a village in the high-

lands of Papua (Indonesia) presents a

unique report of the course of infec-

tion in an entire village population.

The dense social structure of the

village resulted in the rapid infection

of 90-95% of the population within

four weeks. Physical distancing and

isolation measures were used, but

probably not implemented optimally

and too late. An effect on the ill-

ness course could not be observed.

The M20 population is young, which

partially may explain the impact of the

suspected Covid-19 outbreak and the

relatively low case fatality rate (CFR)

and overall death rate (1%), given

the scarcity of direct health facilities

and the difﬁculty of complying with

mitigating measures like physical

distancing. Treatment was provided

in the form of chloroquine phosphate

and azithromycin for severely ill

and high-risk patients. However, no

unequivocal conclusions regarding

their efﬁcacy can be drawn, something

which requires further studies.[8]

Wijnanda van Burg-Verhage, MD

Global Health and Tropical Medicine,

Stichting Lentera Papua, Wamena, Papua,

Indonesia

wijnandaverhage@gmail.com

Elco van Burg (corresponding author)

School of Business and Economics, Vrije

Universiteit Amsterdam, the Netherlands

j.c.v.burg@vu.nl

REFERENCES

1. Badan P usat Statisti k Provinsi Papua

[Inter net]. Jayapura: St atistics Indone sia;

2020. Inf ormasi terbar u; [cited 2020 Apr 23] .

Availabl e from: https://papua. bps.go.id

2. Anderso n B. Dying for noth ing [Interne t].

Inside Indo nesia. 2014 Feb 11;1 15:1–16

3. Vriend WH . Smoky ﬁres: The me rits of

development co- operation for inculturation of

health improvements [dissertation]. Amsterdam:

Vrije Unive rsiteit Amsterd am; 2003.

4. World Health Organizat ion. Coronavirus

diseas e 2019 (COVID-19). Gene va: World Health

Organi zation; 2020. 9 p. Re port No.: 49

5. World Health Organizat ion Indonesia. Coronavirus

diseas e 2019 (COVID-19). Gene va: World Health

Organi zation; 2020. 20 p. R eport No.: 10

6. Wang M, Cao R, Z hang L, et al . Remdesivir

and chloroquine ef fectively inhibit the recently

emerged nov el coronaviru s (2019-nCoV) in

vitro. C ell Res. 2020 Mar ;30(3):269- 71

7. Gua n W, Ni Z , Hu Y, et al. Cl inical cha racteristi cs

of coronavi rus disease 2 019 in China. N Eng l

J Med. 2020 A pr 30;382(18):1708 -20

8. Wong YK, Yang J, He Y. Ca ution and clari ty

require d in the use of chlor oquine for COVID -

19. Lanc et Rheumatol. 2 020 May;2(5):e255

Epidemics and pandemics

By Roel Coutinho

Singel Uitgeverijen

ISBN 978 90 253 1257 2/ NUR 680

Fifth edition 2020, 159 pages, in Dutch

Roel Coutinho, medical

doctor and microbiologist,

emeritus professor of Life

Sciences at the Utrecht

University Medical Center (UMC)

and former director of the Centre for

Infectious Disease Control (CIb) in the

Netherlands, takes us on a journey of

discovery to many corners of the globe

where epidemics occurred, some of

which developed into pandemics. He

writes extensively about the spread of

HIV from 1980 onwards, the Ebola

outbreak in 2014,

the cholera epidemic

in Haiti after the

2010 earthquake,

and the 2009 swine

ﬂu pandemic. It

is an account of

recent epidemics

and pandemics that

have gripped the

world and cost many

lives. The author

shows how these,

as well as age-old

infectious diseases

such as plague, cholera, and inﬂuenza,

developed and spread, how profession-

als and affected populations coped with

them, and to what extent

they had been anticipated

by epidemiologists, micro-

biologists and virologists.

Other potential public

health threats include bio-

logical warfare and declin-

ing vaccination coverage.

The earliest known case

of HIV-1 infection was

in 1959 in Kinshasa,

Democratic Republic of

the Congo. However, HIV

exploded in the beginning

of the 1980s worldwide, especially in

Southern Africa where it caused 20% to

25% seropositivity among the general

BOOK REVIEW

22 MT BULLETIN OF NVTG 2020 AUGUST 02

BOOK REVIEW

population with many people succumb-

ing to AIDS and a steep decline in life

expectancy as a result. Forty years later,

it has become a chronic condition, and

there is still no vaccine available. The

2009 Mexican ﬂu and 1918 Spanish

ﬂu epidemics, especially the latter,

took a huge death toll; probably one

hundred million people died, more

than in both world wars combined.

Another interesting chapter to read is

about the cholera epidemic in Haiti,

which started in 2010, brought into the

country from Asia by Nepalese soldiers

who were based on the island because

of a devastating earthquake earlier that

year. Yersinia pestis and plague are

usually considered a problem of the

past but plague was not uncommon

during the Vietnam War due to acts

of violence, and these days the disease

is still endemic in Madagascar and in

California, United States of America.

Ebola ravaged Western Africa from

2014; Guinea, Sierra Leone and

Liberia suffered great losses. Many

health personnel died. Following this

outbreak, a vaccine was developed

with a very high protection rate and

formally approved and licensed by the

World Health Organization (WHO) in

November 2019. Agents that can be

used as biological weaponry, such as

anthrax, yersinia pestis, cowpox, and

salmonella typhimurium, as well as

diseases transmitted by mosquitoes,

such as chikunkunya and malaria,

are described with suggestions on

how to deal with them in the future.

The anti-vax movement gets criti-

cal comments from the author; there

are some 250,000 people in the

Netherlands - mostly living in the

so-called bible belt - who reject vac-

cination on religious grounds.

The book concludes with a reﬂexion

on the recent Covid-19 pandemic. It

shows that new infections as well as

their spread are difﬁcult to contain,

resulting in enormous economic

losses as well as social implica-

tions in our globalised world.

In his vote of thanks at the end of

the book, the author emphasises

that he himself has gained more

insights in epidemics and pandem-

ics while writing the book, and read-

ers may experience the same.

Jan Auke Dijkstra

Specialist General Medicine, France

janauked@gmail.com

Pooling of knowledge, know-how and intellectual

property to counteract vaccine nationalism

Over the past two months,

numerous news articles on

potential Covid-19 treat-

ments and vaccines have

been published. Even though the vast

majority of these new medical technolo-

gies are still in a development stage,

governments are already looking for

ways to secure them. This may induce

“vaccine nationalism” – countries

wanting to skip the queue to be ﬁrst to

access vaccines once they have proven

effective and become available. The cur-

rent system of pharmaceutical develop-

ment incentivises innovation through

patents, leading to monopoly positions

for pharmaceutical companies, who

then unilaterally decide on the market

price for their products. The combina-

tion of vaccine nationalism and market

monopolies is dangerous for Covid-19

treatments and vaccines because it will

hamper equitable access. At Wemos,

a Dutch NGO working on various

global health topics, we believe that a

global crisis requires a global response.

Current and future efforts must make

sure that they result in maximising both

availability and affordability. Creating

a pooling mechanism of knowledge,

patents and know-how is the best

answer to growing vaccine nationalism

and monopolies for life-saving medical

technologies. The concept of collect-

ing expiring pharmaceutical patents

and licensing them non-exclusively to

manufacturers of generic products is

not new. The Geneva-based Medicines

Patent Pool (MPP) has been doing

exactly this for almost ten years.[1]

With this concept, the organisation is a

crucial actor in increasing competition

and improving access to medicines

against HIV, hepatitis, and tuberculosis.

Non-exclusive licensing will be key for

future Covid-19 treatments and vac-

cines, as it seems very unlikely that a

single pharmaceutical company will

be able to produce enough vaccines

or medicines to satisfy the worldwide

demand. Since the desired outcome of

such a pool is global access to future

pharmaceutical products against Covid-

19, Wemos believes the best organisa-

tion to manage such an initiative is the

World Health Organization (WHO).

The government of Costa Rica was the

ﬁrst to suggest a global database. In an

open letter to the WHO, it suggested

creating a voluntary pooling mechanism

– in line with the MPP – for Covid-

19 related knowledge, know-how and

intellectual property.[2] The initiative

prompted NGOs in various WHO mem-

ber states to call upon their governments

OPINION

AUGUST 02 2020 MT BULLETIN OF NVTG 23

OPINION

to support this Costa Rican initative. In

the Netherlands, Wemos won the sup-

port of many Dutch NGOs and public

health experts.[3] Together with follow-

up lobbying activities, this resulted in

support from the Dutch government

for a Covid-19 technology access pool,

or C-TAP in short.[4] The Dutch health

minister was one of the only country

representatives at the World Health

Assembly (WHA) to mention C-TAP in

his statement to the rest of the WHA.

The permanent representative of the

Netherlands to the United Nations in

Geneva, Switzerland also made a strong

statement during the ofﬁcial launch

of C-TAP on the 29th of May. Despite

the compelling presentations, it is not

yet clear how the Dutch government

will translate these words into action.

At Wemos, we believe that despite the

voluntary character of C-TAP, govern-

ments are in a good position to negoti-

ate with pharmaceutical companies to

contribute to the pool, for instance by

attaching conditions to public funding.

Such a condition could be that patents

of Covid-19 pharmaceutical products

that are developed with Dutch public

funding are automatically shared with

the C-TAP. In order to counter vaccine

nationalism and promote global access

to new pharmaceutical products, coun-

tries around the world should embrace

C-TAP. It is likely to be the best way to

maximise production and affordabil-

ity. Now that C-TAP has been formally

established, it is essential that countries

do their best to make it work. The role

of national governments in supporting

C-TAP to become a successful global

access mechanism for Covid-19 vaccines

and treatments is crucial, starting with

convincing pharmaceutical companies

to contribute to the pool. Considering

the large amount of public funding that

is currently being spent on research

and development, governments have

a powerful tool to promote access,

namely by attaching conditions to these

investments. This is vital: it is in the

best interest of the public and would

be a strong signal of global solidarity.

Tom Buis, MSc

Global Health Advocate, Wemos,

Amsterdam, the Netherlands

tom.buis@wemos.nl

REFERENCES

1. Medici nes Patent Pool [Inter net]. About us;

[accessed 2 020 Jun 6]. Available f rom: https://

medicinespatent pool.org/who-we-are/about-us/

2. Knowled ge Ecology Intern ational [Inter net]. Open let ter

to the WHO a nd its member state s on the proposal by

Costa R ica to create a globa l pool for rights i n the data,

knowled ge and technolog ies useful in t he prevention,

detection a nd treatment of the coronav irus/COVID-

19 pandem ic; 2020 Mar 27 [access ed 2020 Jun 30].

Available from: htt ps://w ww.keionline.org/32599

3. Wemos Health Un limited [Inte rnet]. The Net herlands

suppor ts a global ‘Covid -19 pool’; 2020 Apr 8 [accesse d

2020 Jun 30] . Availab le from: https://ww w.wemos.nl/

en/the-netherlands-supports-a-global-covid-19-pool/

4. World Health O rganization [I nternet]. Solid arity

call to a ction; maki ng the response to C OVID-

19 a public com mon good; [accessed 2 020

Jun 30]. Avai lable from: htt ps:// www.who.int/

emergencies/diseases/novel- coronaviru s-2019/

global-resea rch-on-novel- coronaviru s-2019-ncov/

covid-19-tec hnology-access -pool/solidarit y-call -to-action

A constant state of emergency

Paul de Kruif, microbe hunter and health activist

By Jan Peter Verhave

Van Raalte Press

ISBN-10: 1950572064;

ISBN-13: 978-1950572069

2020, 678 pages

How apt, this title for the

biography of Paul de

Kruif – microbiologist,

journalist, and health

activist. Apt, considering the current

Covid-19 pandemic sweeping across

the world. Also, De Kruif seemed to

be in a constant state of emergency

himself, considering the rapid speed at

which he produced articles and books

on medicine and science, his politi-

cal swinging from progressive during

the Great Depression, to eventually

more conservative, leaving behind his

(in those times) more radical views on

socialized medicine and compulsory

health insurance. Also, in his ﬁnal years

he converted back to religion, after

being a lifelong atheist although born

into a conservative Calvinist family in

Zeeland, Michigan (USA).

There is no statue for

this remarkable person,

though one could con-

sider Jan-Peter Verhave’s

biography as such. T he

bulky book reads as a

tribute to this man who

seemed to be overlooked

by (medical) historians and

policy makers, although

some may remember Paul

de Kruif (1890-1971) as

the author of the Microbe

Hunters (1926), the book

that became an international bestseller,

translated into eighteen languages and

is still in reprint. Enthusiasts described

Microbe Hunters as a most exciting

book ‘dealing with villains and heroes,

blood and thunder’, and as a ‘war upon

pathogenic organisms

coming out of the labora-

tory’. These descriptions

make you want to pick

up a copy of this book,

especially now that the

Covid-19 pandemic has

many scientists work-

ing against the clock to

unravel the pathogenic

effects of SARS-CoV-2.

As in the early decades of

the twentieth century, it

is a very challenging and

arduous task to develop

a safe and effective vac-

cine. De Kruif brought the pioneers

of microbiology and biomedicine,

BOOK REVIEW

24 MT BULLETIN OF NVTG 2020 AUGUST 02

and their discoveries of cures for

various infectious diseases to life by

telling the fascinating story of the

microbes and scientists involved in

language everyone could understand.

With this book, the promising microbi-

ologist deﬁnitely changed his career path

by trading the laboratory for his type-

writer. No more experiments, as when

in the context of a study on the agents

of inﬂuenza and the common cold he

volunteered to shut himself up naked

in an icebox for an hour day after day.

Gradually he became a household name

and, as a star reporter for The Reader’s

Digest and other magazines, he was able

to reach large audiences with his popu-

lar writings on medical discoveries, new

drugs, causes and cures of diseases, vita-

mins and hormones, and health insur-

ance. He did so much to the appreciation

of the general public, but to a lesser

extent of the medical professionals, who

rejected him as someone writing about

medical matters ‘while not even being

a medical doctor’, expressing their fear

that public health systems would take

away their patients (and their fees).

Verhave’s book is a treat, as it took me

on a journey learning about his lifelong

mission to popularize medicine and

educate people, and getting to know the

person behind this public health advo-

cate for policies that take into account

the social determinants of health. To

do so, he had to leave the “ivory tower”

of science, using his typewriter as ‘a

weapon against medical abuses and a

ﬁst to bounce the table’. And it bounced.

He rallied the public against tuberculo-

sis in Detroit, unsilenced “the big S” of

syphilis (a condition that had become

highly prevalent during the economic

crisis in the 1920s with one out of ten

Americans infected), and steering polio

eradication. His quest resulted in more

than 200 articles on the common health

problems of his time: the dangers of raw

milk, maternal deaths, childbed fever,

diabetes, parrot fever, health insurance,

and the deplorable health situation in

Midwestern states and city slums.

Ingeniously, Jan Peter Verhave inter-

weaves Paul de Kruif’s work as a catalyst

for change with a quite detailed account

of his personal life, his ﬂamboyant life

style, and his friendship with famous

writers, including the poet Ezra Pound,

Ernest Hemingway, John Steinbeck,

and Sinclair Lewis, with whom he wrote

Arrowsmith – a novel about a young med-

ical doctor who gradually diverges from

caring for patients to focusing on public

health and controlling disease out-

breaks. As a “champion for the poor” he

was on speaking terms with President

Franklin D. Roosevelt, and a close friend

of Vice-President Henry Wallace and

Surgeon General Thomas Parran.

In many ways, he was ahead of his time,

as De Kruif fully understood the public

beneﬁt of disseminating his work using

mass media like theatre, ﬁlm, radio,

and even the new medium of the 1930s,

comic books. The staging of one of his

plays Yel low Jack in the Netherlands in

1934 impressed the audience, though

considered a dicey experiment of bring-

ing science to the stage. The play was

based on a chapter in Microbe Hunters on

the tragic death of yellow fever research-

ers dying in Cuba from experimental

exposure to infective mosquitos.

Six hundred words are not enough to

cover the wealth of information Verhave

presents us in the more than 600

pages of a biography of ‘a hard-drinking

womanizer with a blasphemous tongue’,

as Verhave describes De Kruif in his

foreword. For Verhave, retired biologist

and parasitologist (and author of The

Moses of Malaria (2011), a biography

of the parasitologist Schwellengrebel),

it was clear that the man who fought

against poverty and horrible diseases

deserved more attention. He deﬁnitely

succeeded in placing De Kruif in the

spotlight by taking us along ‘a medi-

cal history, a history of taking risks in

moving doctors, scientists and lay

people toward each other and toward a

commonly shared healthcare system’.

A story to note and to learn from.

Esther Jurgens

Editor MTb, Policy Advisor NVTG and

Consultant Global Health

estherjurgens@xs4all.nl

BOOK REVIEW

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Please submit your contributions and

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Netherlands Society for Tropical

Medicine and International Health

president

J.A.E. (Joop) Raams

secretary

J.J. (Jaco) Verweij

secretariat

J.M. (Janneke) Pala-Van Eechoud

P.O. Box 43 8130 AA Wijhe | The

Netherlands | +31(0)6 156 154 73 |

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COLOPHON

MT Bulletin of the Netherlands Society

for Tropical Medicine and International

Health

ISSN 0166-9303

CHIEF EDITOR

Leon Bijlmakers

EDITORIAL BOARD

Maud Ariaans, Jan Auke Dijkstra,

Remco van Egmond, Esther Jurgens,

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The potential public health consequences of COVID-19 on malaria in Africa

Article

Full-text available

Sep 2020
NAT MED

The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising1. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-22,3. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed4. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs)5, with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000–119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics. Transmission dynamics models of COVID-19 and malaria reveal how different scenarios of COVID-19 spread and varying levels of interruption to antimalarial programs could result in increased deaths in sub-Saharan Africa.

Routine childhood immunisation during the COVID-19 pandemic in Africa: a benefit–risk analysis of health benefits versus excess risk of SARS-CoV-2 infection

Article

Full-text available

Jul 2020

Background National immunisation programmes globally are at risk of suspension due to the severe health system constraints and physical distancing measures in place to mitigate the ongoing COVID-19 pandemic. We aimed to compare the health benefits of sustaining routine childhood immunisation in Africa with the risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through visiting routine vaccination service delivery points. Methods We considered a high-impact scenario and a low-impact scenario to approximate the child deaths that could be caused by immunisation coverage reductions during COVID-19 outbreaks. In the high-impact scenario, we used previously reported country-specific child mortality impact estimates of childhood immunisation for diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, Streptococcus pneumoniae, rotavirus, measles, meningitis A, rubella, and yellow fever to approximate the future deaths averted before 5 years of age by routine childhood vaccination during a 6-month COVID-19 risk period without catch-up campaigns. In the low-impact scenario, we approximated the health benefits of sustaining routine childhood immunisation on only the child deaths averted from measles outbreaks during the COVID-19 risk period. We assumed that contact-reducing interventions flattened the outbreak curve during the COVID-19 risk period, that 60% of the population will have been infected by the end of that period, that children can be infected by either vaccinators or during transport, and that upon child infection the whole household will be infected. Country-specific household age structure estimates and age-dependent infection-fatality rates were applied to calculate the number of deaths attributable to the vaccination clinic visits. We present benefit–risk ratios for routine childhood immunisation, with 95% uncertainty intervals (UIs) from a probabilistic sensitivity analysis. Findings In the high-impact scenario, for every one excess COVID-19 death attributable to SARS-CoV-2 infections acquired during routine vaccination clinic visits, 84 (95% UI 14–267) deaths in children could be prevented by sustaining routine childhood immunisation in Africa. The benefit–risk ratio for the vaccinated children is 85 000 (4900–546 000), for their siblings (<20 years) is 75 000 (4400–483 000), for their parents or adult carers (aged 20–60 years) is 769 (148–2700), and for older adults (>60 years) is 96 (14–307). In the low-impact scenario that approximates the health benefits to only the child deaths averted from measles outbreaks, the benefit–risk ratio to the households of vaccinated children is 3 (0–10); if the risk to only the vaccinated children is considered, the benefit–risk ratio is 3000 (182–21 000). Interpretation The deaths prevented by sustaining routine childhood immunisation in Africa outweigh the excess risk of COVID-19 deaths associated with vaccination clinic visits, especially for the vaccinated children. Routine childhood immunisation should be sustained in Africa as much as possible, while considering other factors such as logistical constraints, staff shortages, and reallocation of resources during the COVID-19 pandemic. Funding Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation.

High‐dose, short‐term corticosteroids for ARDS caused by COVID‐19: a case series

Article

Full-text available

Jun 2020

We report a case series of seven mechanically ventilated patients with acute respiratory distress syndrome (ARDS) caused by coronavirus disease (COVID‐19) who received early treatment with high‐dose, short‐term systemic corticosteroids to prevent cytokine overproduction. Of the seven patients, four were male and median age was 69 years. They were intubated within seven days after admission when their respiratory status rapidly worsened. At that time, we administered 1000 or 500 mg/day for three days of methylprednisolone intravenously, followed by 1 mg/kg and tapered off. The median duration for the total administration of corticosteroids was 13 days. This high‐dose, short‐term corticosteroid therapy enabled extubation of the patients within seven days. Many questions on the clinical management of COVID‐19 remain unanswered, and data on corticosteroid therapy as a choice of treatment are mixed. We present the clinical course of our cases, review the previous evidence, and discuss management. Many questions on the clinical management of coronavirus disease (COVID‐19) remain unanswered, and data on corticosteroid therapy as a choice of treatment are mixed. We present the clinical course of seven patients, review the previous evidence, and discuss management.

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Article

Full-text available

Jun 2020

Background Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days. Results We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported. Conclusions After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.)

Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study

Article

Full-text available

May 2020

Background While the COVID-19 pandemic will increase mortality due to the virus, it is also likely to increase mortality indirectly. In this study, we estimate the additional maternal and under-5 child deaths resulting from the potential disruption of health systems and decreased access to food. Methods We modelled three scenarios in which the coverage of essential maternal and child health interventions is reduced by 9·8–51·9% and the prevalence of wasting is increased by 10–50%. Although our scenarios are hypothetical, we sought to reflect real-world possibilities, given emerging reports of the supply-side and demand-side effects of the pandemic. We used the Lives Saved Tool to estimate the additional maternal and under-5 child deaths under each scenario, in 118 low-income and middle-income countries. We estimated additional deaths for a single month and extrapolated for 3 months, 6 months, and 12 months. Findings Our least severe scenario (coverage reductions of 9·8–18·5% and wasting increase of 10%) over 6 months would result in 253 500 additional child deaths and 12 200 additional maternal deaths. Our most severe scenario (coverage reductions of 39·3–51·9% and wasting increase of 50%) over 6 months would result in 1 157 000 additional child deaths and 56 700 additional maternal deaths. These additional deaths would represent an increase of 9·8–44·7% in under-5 child deaths per month, and an 8·3–38·6% increase in maternal deaths per month, across the 118 countries. Across our three scenarios, the reduced coverage of four childbirth interventions (parenteral administration of uterotonics, antibiotics, and anticonvulsants, and clean birth environments) would account for approximately 60% of additional maternal deaths. The increase in wasting prevalence would account for 18–23% of additional child deaths and reduced coverage of antibiotics for pneumonia and neonatal sepsis and of oral rehydration solution for diarrhoea would together account for around 41% of additional child deaths. Interpretation Our estimates are based on tentative assumptions and represent a wide range of outcomes. Nonetheless, they show that, if routine health care is disrupted and access to food is decreased (as a result of unavoidable shocks, health system collapse, or intentional choices made in responding to the pandemic), the increase in child and maternal deaths will be devastating. We hope these numbers add context as policy makers establish guidelines and allocate resources in the days and months to come. Funding Bill & Melinda Gates Foundation, Global Affairs Canada.

Understanding China’s growing involvement in global health and managing processes of change

Article

Full-text available

May 2020

Background: Recent years have seen a rapid change in China's global engagement and a recognition that solving global challenges will need to take the changing role of China into account. The paper discusses China's growing involvement in global health. Health is an area where there is broad agreement over global priorities and, potentially, a fertile space to build new forms of collaboration that point the way towards the adaptation of global governance to a rapidly changing context. Results: Drawing on previous analyses of China's management of change in its domestic health reforms and interviews with a range of stakeholders in China, the UK and Switzerland, the paper argues that China's engagement in global health is developing and diversifying rapidly in response to the central government's desire to see a greater role for China in global health. This diversification is part of a pattern of change management familiar from China's domestic reform experience. Explorations underway by a range of Chinese agencies form part of a process of rapid experimentation and experiential learning that are informing China's search for (a) new global role(s). Conclusions: China is undergoing rapid institutional innovation and developing capacity for greater global engagement, including in health; however, substantial, recent leadership commitments make clear Chinese agencies' need for continued exploration, innovation and rapid learning. How China engages globally is of significance to the world, not just China. The challenge for China, other global actors and multilateral organisations is to incorporate new approaches into existing global governance arrangements, including for the management of global health. This will require a willingness on all sides to learn from each other and invest the effort needed to build governance arrangements appropriate for the coming decades. This is not only important as a means of protecting global public health, but also as a demonstration of how governance arrangements can be adapted to the needs of a pluralistic global order in a context of rapid change.

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Article

May 2020

Background Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19. Methods We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation). Findings 96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation. Interpretation We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19. Funding William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women's Hospital.

The Covid-19 Pandemic and the Incidence of Acute Myocardial Infarction

Article

May 2020

Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Article

May 2020

Background Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19. Methods This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688. Findings Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4·37 [95% CI 1·86–10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study. Interpretation Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted. Funding The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

Article

May 2020

Background Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context. Methods Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020. Results Of the 8910 patients with Covid-19 for whom discharge status was available at the time of the analysis, a total of 515 died in the hospital (5.8%) and 8395 survived to discharge. The factors we found to be independently associated with an increased risk of in-hospital death were an age greater than 65 years (mortality of 10.0%, vs. 4.9% among those ≤65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41), coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51), heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40), and current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 2.47). No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74). Conclusions Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.)

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