Invasive Meningococcal Disease (IMD)

Clinical symptoms and Burden of Diseases

DATE PRESENTATION TITLE 1

Clinical symptoms of IMD
Causative Agent: Neisseria meningitidis

Gram-negative bacteria, produce endotoxin, 100

to 1,000 times greater than normal and more
lethal •Neisseria meningitidis

Meningococci are diplococcal bacteria surrounded

by a polysaccharide capsule1
▪ The polysaccharide structure determines the
pathogen’s serogroup (SG)1
▪ Six (A, B, C, Y, X, and W*) of 12 known SGs account for •Polysaccharide capsule1,4
the majority of epidemics worldwide3

•*W-135 has been replaced with W per new nomenclature.5

•1 Pollard. In: Harrison's Principles of Internal Medicine. 18th ed. 2012;chapter 143; 2Harrison. Clin Infect Dis. 2010;50(Suppl 2)
3 WHO.http://www.who.int/mediacentre/factsheets/fs141/en/; 4Image adapted from Criss. Nat Rev Microbiology. 2012;10(3)
5 Harrison et al. Emerg Infect Dis. 2013;19(4)
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Pathogenesis

The complex physiology of meningococcal

sepsis is largely explained by four basic
processes affecting the microvasculature:
(1) Increased vascular permeability
(2) Pathological vasoconstriction and
vasodilatation
(3) Loss of thromboresistance and
intravascular coagulation
(4) Profound myocardial dysfunction.
These events are responsible for the
development of shock and multiorgan
failure.

Pathan N, Faust SN, Levin M. Arch Dis Child 2003

CNS involvement

• Rapid development of raised intracranial as a consequence

Direct invasion of of the inflammatory process within the brain
• Direct bacterial toxicity, indirect inflammatory processes
the meninges such as cytokine release, neutrophil activation, with
resultant vasculitis, and cellular oedema

Under perfusion • Diminished consciousness and are at risk of cerebral

infarction if perfusion is not improved.
organ in septic • The neurological dysfunction in shock results from reduced
perfusion and microvascular obstruction, which may lead to
shock cerebral infarction.

Pathan N, Faust SN, Levin M. Arch Dis Child 2003

Invasive Meningococcal Diseases (IMD)
Portal of entry : Purpura Broncho- peritonitis
Respiratory fulminans pneumonia
Urogenital
Colonization/infection

Meningitis
Septicemia
Pleurisy
Early Presentations

Clinical forms
(<19h) Necrotizing
Whining, grouchy, fasciitis
hypotonic infant, refusing
to suckle
Fever Septic
Leg pain arthritis pericarditis
Abdominal syndromes
abnormal skin color

<50% of patients are sent

to the hospital
Plotskin’s Vaccine 7th Edit, Chap 38
IMD is difficult to diagnose early and progresses rapidly
Average incubation period: 3–4 days (range 2–10 days)1

IMD progresses rapidly from non-specific symptoms and leads to severe,

life-threatening consequences within 15–24 hours1–3

4–12 hours 12–15 hours 15–24 hours

Non-specific (flu-like)
symptoms, such as fever, Hemorrhagic rash, Confusion or delirium,
irritability, gastrointestinal neck pain, seizure,
symptoms meningismus, unconsciousness;
photophobia3 possible death3
and sore throat3

Hospital admission at median time of 19 hours3

IMD, invasive meningococcal disease
1. WHO. Meningococcal Meningitis Fact Sheet February 2018. http://www.who.int/news-room/fact-sheets/detail/meningococcal-meningitis [Nov 2018]; 2. NICE
Clinical Guidelines. Bacterial Meningitis and Meningococcal Septicaemia in Children.
https://www.ncbi.nlm.nih.gov/books/NBK83078/pdf/Bookshelf_NBK83078.pdf [Jan 2019]; 3. Thompson MJ. Lancet 2006; 367: 397–403
7
Suspected IMD (Jakarta)

6 yrs old, fever the day at admission,

3 hours later the child unconscious, seizures (-)
E3M4V3, hypovolemic shock, meningeal sign(-),
Ptechie, purpura and echimosis (+)
Leucopenia and thrombocytopenia
BGA: metabolic acidosis
Patients treated as septicemia, got AB and
inotrophic agent
Patient died < 24 hours without bacteriological
confirmed from blood and LCS

Septic shock and hemorrhagic rash : remember about IMD

Courtesy of dr Ivan R.Wijaya

Common Clinical Presentations of IMD

Meningitis Meningococcemia
50% of cases 10% to 20% of cases

• Fever and headache • Fever and headache

0-6h • Nausea, vomiting
• Nausea, vomiting

• Stiff neck • Petechial or purpuric rash

• Photophobia 12-15h • DIC

• Altered mental status • Shock

16-22h • Multi-organ failure
• Seizures

Reference: 1. Rosenstein NE, et al. N Engl J Med. 2001;344(18):1378-1388.

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Serious Outcomes of Meningococcal Disease
Meningitis Meningococcemia
< 10% have permanent sequelae6 10% to 20% have permanent sequelae6
• Spastic quadriplegia5 • Limb loss from gangrene1-3
• Hearing loss1-5 • Skin scars from necrosis2,3
• Cortical venous thrombophlebitis4 • Renal failure2
• Cerebral edema4 • Septic arthritis1,2,4
• Cranial nerve palsies4 • Pneumonia1
• Intellectual Disability4 • Epiglottitis1
• Hemiparesis4 • Pericarditis1,4

Fatality rate: 9% - 12%4 Fatality rate: up to 40%4

1. Rosenstein N, et al. N Engl J Med. 2001;344(18):1378-1388. 2. Erickson L, De Wals P. Clin Infect Dis. 1998;26(5):1159-1164. 3. Erickson L, et al.
Clin Infect Dis. 2001;33(5):737-739. 4. Munford RS. Meningococcal infections. In: Braunwald E, et al, eds. Harrison’s Principles of Internal Medicine.
15th ed. New York, NY: McGraw-Hill Professional; 2001:927-931. 5. Fellick JM, et al. Arch Dis Child. 2001;85(1):6-11. 6. Granoff DM, et al. In:
Vaccines. 6th ed. 2012.
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Even when treated, IMD can lead to death or severe sequelae

High fatality
• Overall CFR is 8 to 15%, even after
appropriate treatment1
• The CFR of meningococcemia is up
to 40%2
Severe physical sequelae in
survivors
• Sequelae occur in 10 to 20% of
survivors1
CFR, case fatality rate; IMD, invasive meningococcal disease
1. WHO. Meningococcal Meningitis Fact Sheet February 2018. http://www.who.int/news-room/fact-sheets/detail/meningococcal-meningitis [Nov 2018];
2. CDC. Pink Book. Chapter 14 Meningococcal Disease. https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf [Jan 2019]; 12
3. Martinón-Torres F. J Adolesc Health 2016; 59: S12–20
 IMD Risk: Host Factors
HIV-infected people: 26.5-fold risk
Simmons R, et al. BMC Med 2015;13:297

MSM (aged 18–64 years): several times more likely

Kratz MM, et al. Emerg Infect Dis 2015;21:1379–86

Patients with complement deficiency: 1,000-fold risk

Rosain J, et al. J Infect Dis 2017:215:1131–8

Eculizumab use: up to 10,000-fold higher

Benamu E, et al. Curr Opin Infect Dis 2016;29:319–29

Most cases (>90%) of IMD occur in previously healthy

persons without identified risk factors1
1. Kaplan SL et al. Pediatrics 2006;118:e979–84
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•At-Risk Populations

•Impaired immune system1,2/ •Exposure through close contact with

•lack of antibodies1 •infected person or the live bacteria

•Infants, children1,2Travelers to endemic areas3Caregivers3

•Crowding1,3,4
•Immunocompromised2
•(students, military, Hajj, •Personnel working with
•oil refineries) •N. meningitidis2,3

Pollard. In: Harrison's Principles of Internal Medicine. 18th ed. 2012;chapter 143; 2Bilukha. Pediatr Infect Dis J. 2007;26(5); 3MacNeil. In: Manual for the Surveillance of
•1
Vaccine-Preventable Diseases. 5th ed. 2012; 4Liphaus. Enferm Infecc Microbiol Clin. 2013;31(2)
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Epidemiology and Burden of
Diseases of IMD
 Global Burden of Meningitis 2016

2016 counts Deaths Cases

• The largest decline mortality at least 50% Indonesia 4313 (2041 - 5731) 78,018 (66,547 - 90,966)
between 1990-2016, since introduction of US 1425 16,869
Hib (1995) and PCV (2008) vaccine. Brazil 2382 12,819

GBD 2016 Meningitis Collaborators. Lancet Neurol 2018; 17: 1061–82

Deaths Global Burden of Meningitis 2016
(per 100,000)

Year Age
GBD 2016 Meningitis Collaborators. Lancet Neurol 2018; 17: 1061–82
Previous data in Indonesia

• Between 1995-1996 in Jakarta and Tangerang:

• N.meningitidis is the cause of meningitis in 16.7% (1/6)
bacteriologically confirmed cases in children aged < 5 years.
• Population based study 1998-2002 (818 hamlets encompassing
744.000 individuals) :
• N.meningitidis detected in 3/17 (17.6 %) culture-positive meningitis
case in children aged < 2 years

Pusponegoro HD. Ped Infect Diss J.1998;17:S176-78.

Gessner BD. Lancet 2005;365:43-52
VYSE A et al. Epidemiol. Infect. (2011), 139, 967–985..
Previous data in Indonesia

• During 2000 (WHO:disease reported outbreak)

• 14 cases of meningococcal meningitis with 6 deaths (43%), with
laboratory confirmation of N.meningtidis serogroup B in 1 case.
• Meningococcal meningitis attack rate in Indonesia Hajj pilgrims,
1987 to 2006.
• 1989-1995 and 2004-2005 : there were no reported cases of
meningococcal meningitis
• Highest attack rate in 2001: 9.33 during the W135 serotype outbreak in
the Hajj.

Worlld Health Organization.2000. Meningococcal disease in Singapore,Indonesia, Iran and Marocco.Disease reported
outbreak.
Masdalina Pane, Sholah imari. 27 th ECCMID. Vienna 2017.
 Sporadic case

Data from 14 teaching hospital + 2 hospital :

Medan (North sumatera) :3-4 suspected case , Lampung : 1 suspected case, Jakarta : 2 suspected case, Malang :
2 cultured (+) case and Timika : 2 gram-negative (+) case

Under-recognized or under-reported case ??

 Problems of Meningococcal Epidemiology In Indonesia

• Lack of robust surveillance system

• IMD surveillance is not available in Indonesia
• High prior antibiotic use
• Due to over the counter availability of antibiotics
• Indonesia : parents refused lumbal puncture, antibiotics has to be given before
LP
• Doctors are reluctant to do LP
• Access to healthcare
• Insufficient laboratory capability
• Culture available in referral hospital, but CO2 incubator not available
• PCR in some referral laboratory (University of Indonesia, MOH Lab. Eijkman Lab)
• Not routinely detect serotype of N.meningitidis, lack of lab capacity

Borrow R et al. Vaccine 34 (2016) 5855–5862

The Global meningococcal Initiative 2020
Burden of Diseases

• Moslem pilgrimage once in a year

• Increasing number of Pilgrim of hajj
• The largest number in South-East Asia
• Stay for 2-4 weeks

Data from Ministry of Religious Affairs 2014

Burden of Diseases

• Pilgrim of umrah year round

• Increasing number of Pilgrim of umrah
• Number three after Mesir and Pakistan
• Stay for 9-10 days
• Increasing number of infants and children,
especially during holiday season

Data from Ministry of Religious Affairs 2017

Burden of Diseases

• Indonesia migraint workers

Burden of Diseases

Pilgrims of hajj according to age

Data from Ministry of Religious Affairs 2017

27 • Intervenant • Titre de la Vetter V et al. Expert Rev Vaccines 2016
présentation • jj/mm/aaaa 15(5):641-658
Carriage and disease
35

30
Global carriage rate 10% 10
25

Incidence
% carriers

20

15
5
10

0 0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Age (y)
Parent du Chatelet et al., J Infect 74, 564 (Jun, 2017).
Delbos et al., Eur J Clin Microbiol Infect Dis 32, 1451 (Nov, 2013).
Caugant et al., J Clin Microbiol 32, 323 (Feb, 1994).
Christensen, et al., Lancet Infect Dis 10, 853 (Dec, 2010).
• Overall carriage ranged from 0.0% to 27.4% in Hajj pilgrims.
• Serogroup B was most prevalent in Hajj pilgrims.
• Among Hajj pilgrims, a high endemicity in the country of origin increased the risk of
carriage,
• Preventive vaccination policies for high-risk groups should be based on current
disease data in individual countries, supplemented by carriage data.

Peterson ME, Mile R. Int J of Infect Diss..2018: 109-17.,

 Incidence of IMD in Different Populations

Travelers aged ≥ 2 years to Saudi Arabia who are pilgrims, seasonal workers, or workers
in contact with pilgrims are required to show proof of vaccination with a polysaccharide
or conjugate ACWY vaccine administered at least 10 days and not more than 3 years
(polysaccharide vaccine) or 5 years (conjugate vaccine) before arrival

Wilder-Smith, A Expert Rev Vaccines 2009 Oct;8(10):1343-50

https://www.iamat.org/country/saudi-arabia/risk/meningococcal-meningitis .
https://www.who.int/emergencies/diseases/meningitis/serogroup-distribution-2018.pdf

31
 Indonesia ?
Surveillance and case finding ?
Research about carriage among migrant workers, pilgrims ?
Research about serotype ?
Impact of vaccination ?
 Conclusion

• Sporadic, rare case : under-recognized and lack of surveillance

• High mortality and morbidity
• Burden of disease In Indonesia :
• Migrant workers
• Umra and hajj pilgrimage : more younger age of the pilgrimage
• Students
• High carriage rate
• Can be prevented by vaccination : should be coverage all ages