8/9/2018

Darmawan B Setyanto, MD
ARI Born: 11 April 1961

Acute Respiratory Infection Education:

◼ Medical Doctor, Faculty of Medicine, University of Indonesia, 1986
◼ Pediatrician, Faculty of Medicine, University of Indonesia, 1997
◼ Respirology Consultant, 2005

Current position :
Darmawan B Setyanto ◼ Head of Respirology Division, Dept of Child Health, Faculty of
Medicine, University of Indonesia
Dept of Child Health Organization:
FMUI Jakarta ◼ Chairman of Respirology Coordination Working Unit, Indonesian
Pediatric Society 2008-2014
◼ IPS: Member of C Board, IPS Bulletin
◼ IMA, APSR, ERS, EAACI member

Terminology ARI epidemiology

Acute respiratory infection (ARI) ◼ Pediatric ARI’s are one of the MOST COMMON
◼ Acute -- <2 weeks reasons for physician visits: in industrialised countries
◼ any infection of the upper &/ lower respiratory up to 50% (much more in developing countries)
system ◼ Pediatric ARI’s are associated with substantial
◼ Acute upper respiratory infection (AURI) -- MORBIDITY and MORTALITY (esp in developing
morbidity countries)
◼ Acute lower respiratory infections (ALRI) -- include ◼ 80-90% of ARI’s affect the UPPER (AURI): rhinitis,
severe infections, such as pneumonia – mortality
rhinosinusitis, pharyngitis, laryngitis, otitis media,
◼ Indonesian: IRA – ISPA
◼ 10-20% of RTIs affect the LOWER (ALRI) tracheitis,
◼ Common cold (rhinitis, rhinopharyngitis) ----------
pneumonia bronchiolitis/bronchitis, bronchopneumonia, pneumonia
◼ Role of physicians: treatment & prevention of ARI

Bellanti JA, Drugs 1997, 54 (Suppl 1):1-4

Sign of infection
Infection: Invasion & multiplication of microorganisms
such as bacteria, viruses, and parasites that are not
normally present within the body.

Infection: Invasion by & multiplication of pathogenic fever fussy

microorganisms in a bodily part or tissue, which may
produce subsequent tissue injury and progress to overt
disease through a variety of cellular or toxic
mechanisms.
The Free Dictionary by Farlex

appetite restlessness

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Respiratory symptomatology Dyspnea

Nasal flaring
cough sneeze rhinorrhea

stridor ronchi
tachypnea rales
dyspnea wheezing
Chest indrawing, retraction

Other symptomatology Outline

symptom
◼ Diminish breath sound ◼ Medical problem pathway
◼ Dull on percussion ◼ United airway concept
pathophys
◼ Common cold
◼ Rhinosinusitis
vomite ◼ Pharyngitis pathology

◼ Rhinobronchitis
adaptive
◼ Pneumonia response
◼ ARI treatment

Insult
diarrhea

Outline Medical problem pathway

symptom
◼ Medical problem pathway
◼ United airway concept
pathophys Medicine/Medical.
◼ Common cold a. an injury or trauma
◼ Rhinosinusitis b. an agent that inflicts to affect offensively or
◼ Pharyngitis pathology this damagingly
◼ Rhinobronchitis
adaptive  ANY FACTOR AFFECTING THE PHYSIOLOGIC
◼ Pneumonia response CONDITION (growth, development, process, or
◼ ARI treatment function of the cell, tissue, organ, system, or
individu – DBS
Insult
insults

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2
Integumentary
Medical problem pathway system (skin)

Respiratory Neuro-musculo-
The ability to survive
defense mechns skeletal system
by eliminate, terminate,
defend, avoid, or adjust
to any kind of insults Urinary Adaptive Endocrine
(fight or flight) def mechn responses system

adaptive Gastro-intestinal Autonomic

defense mechns nerve system
responses

insults
Immune
system
1

Medical problem pathway What is ‘INFLAMMATION’?

Diagnosis & Treatment

symptom
symptomatology organism
body system
pathophys organ
pathophysiology tissue
cellular
pathology biochemical
pathology
Ongoing pathology
pathogenesis adaptive adaptive
response symptomatology
responses

insults Insult

The insults symptom Outline

symptom
◼ Medical problem pathway
◼ Microbe Infection
pathophys ◼ United airway concept
◼ Allergen  Allergy pathophys
◼ Common cold
◼ Mechanical trauma
◼ Rhinosinusitis
◼ Injury: thermal, electrical, pathology
◼ Pharyngitis pathology
chemical, irradiation
adaptive ◼ Rhinobronchitis
◼ Autoimmune adaptive
response
◼ Cancer ◼ Pneumonia response
◼ Metabolic ◼ ARI treatment
◼ ...
Insult
Insult

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Historical separation of respiratory tract Airway concepts

Sneeze
(rhinitis)
Upper resp tract Otolaryngologist

Lower resp tract Pulmonologist

The Old-one The New-one
Wheeze Separate United
(asthma)
Different entity One entity

External
Unity, similarity, integration insults
symptom Pollutant Iritant
◼ Anatomy & physiology
◼ Common insults Food Virus
◼ United defense mechanism pathophys
Allergen Bacteria
◼ Naso-bronchial interaction
Respiratory
◼ United inflammatory response
◼ Common pathology
pathology inflammation
◼ Similar pathophysiology & symptomatology Allergy Immuno-
adaptive
◼ Epidemiology of comorbidity response deficiency
◼ United airway disease Anatomical
◼ Integrated management defect Functional
defect Internal
Insult insults

Respiratory inflammation syndrome

Respiratory anatomy, function
Rhinitis/CC Rhinitis Airway: Conducting
(infection) (allergic) Allergic
Nose - bronchioli zone
Otitis conj’tvtis?
media
Nasal polyp
OSAS
COPD
Laryngitis Rhino- Asthma,
Tracheitis Bronchi-
sinusitis bronchitis olitis Parenchyme: Respiratory
Alveoli & capillary zone
UAD, Rhino-sino-bronchitis

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Outline Spectrum of ARI

symptom
◼
◼
Medical problem pathway
United airway concept
AURI ALRI
pathophys
◼ Common cold Common
◼ Rhinosinusitis Bronchitis
cold
◼ Pharyngitis pathology
◼ Rhinobronchitis
Rhino-
Bronchiolitis
adaptive sinusitis
◼ Pneumonia response
◼ ARI treatment Tonsilo-
Pneumonia
pharyngitis
Insult Croup = laryngo-tracheo-bronchitis

Selesma  Etiologies of common cold

Relative frequency Virus
Most common Rhinovirus
Common Coronavirus
Influenza virus*
Parainfluenza virus*
Respiratory syncytial virus
Flu virus Occasional Adenovirus
Rhinovirus Enterovirus

Flu! *Causing other common symptoms of colds

The common cold, Nelson textbook of pediatrics 19th ed, 2011
The common cold, Ped Resp Med, 2nd ed, 2008,

Common cold Contents

Diagnosis & Treatment

◼ Medical problem common pattern

symptomatology
◼ United airway concept
◼ Common cold
pathophysiology
◼ Rhinosinusitis
◼ Pharyngitis
pathology
◼ Rhinobronchitis
pathogenesis adaptive ◼ Pneumonia
response ◼ ARI treatment

insults

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Rhino-sinusitis International guideline

Allergic rhinitis Rhinosinusitis

CT: Cold  sinusitis = rhino-sinusitis MRI: Cold  sinusitis = rhino-sinusitis

◼ young adults, 48-96 hours after the onset of a

common cold
◼ abnormal findings (consistent with mucosal
inflammation) in the paranasal sinuses were
reported in >80% of patients.
◼ imaging studies cannot distinguish inflammation
caused by viruses or bacteria.

N Engl J Med 1994;330:25-30

Pediatrics. 2003 May;111(5 Pt 1):e586-9.

Pathogenesis of acute RS
Rhinorrhea, nasal blocked, sneeze, fever, symptom
cough, throat clearing, itching, snuffles

Obstruction, stagnant mucus, pathophys

mucosal irritation

Mucosal edema, hypersecretion, pathology

respiratory inflammation
adaptive
MC clearance, cough, response
inflammatory cells, mediators

Allergen, virus, fungi, bacteria

anatomical defect Insult

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Uncomplicated viral CC / ARS Classification of RS

◼ Acute viral RS = common cold
Duration of symptoms <10 days

◼ Acute non-viral RS = acute bacterial RS

o Persistent symptoms after 10 days OR
o Severe symptoms at the beginning OR
o Worsening symptoms after 5 days
duration of symptoms <12 weeks

◼ Chronic RS: duration of symptoms >12 weeks

Pediatrics 2013;132:e262–e280

Outline
Acute bacterial Rhinosinusitis symptom
◼ Medical problem pathway
A common cold that: ◼ United airway concept
pathophys
◼ Persistent symptoms, beyond 10 days ◼ Common cold
◼ Severe symptoms than usual (high fever, ◼ Rhinosinusitis
copious purulent discharge, peri-orbital edema ◼ Pharyngitis pathology
and pain) ◼ Rhinobronchitis
adaptive
◼ Worsening symptoms, after several days of ◼ Pneumonia response
improvement (double sickening) ◼ ARI treatment
IDSA Guideline for ABRS d CID 2012
N Engl J Med 2012;367:1128-34.
Insult

Pharyngitis (sore throat) Pharyngitis epidemiology

◼ Children experience >5 ARIs / year and an average
of one streptococcal infection every 4 yrs
◼ Mostly caused by respiratory viruses
◼ The most common viruses: rhinovirus & adenovirus
◼ The most significant bacterial agent causing
pharyngitis in both adults and children is GAS
infection (Streptococcus pyogenes)
◼ 15-30% of pharyngitis cases among school-aged
children in the cooler months are due to GAS.
◼ 10% of adult cases of pharyngitis are due to GAS.

emedicine.medscape.com/article/764304-overview

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Epidemiology & clin features Streptococcal pharyngitis

Viral pharyngitis Streptococ pharyngitis
◼ Conjunctivitis ◼ Sudden onset
◼ Coryza ◼ Age 5–15 years
◼ Cough ◼ Fever
◼ Diarrhea ◼ Headache
◼ Hoarseness ◼ Nausea, vomiting, abd pain palatal ptechiae
patchy exudates
◼ Ulcerative stomatitis ◼ Tonsillopharyngeal
◼ Viral exanthema inflammation
◼ Patchy exudates
◼ Palatal petechiae
IDSA 2012 guidelines
◼ Anterior cervical adenitis

IDSA 2012 GAS phraryngitis diagnosis

◼ Testing for GAS pharyngitis usually is not
recommended for children or adults with acute
pharyngitis with clinical and epidemiological
features that strongly suggest a viral etiology (eg,
cough, rhinorrhea, hoarseness, and oral ulcers;
strong, high).
◼ Swabbing the throat and testing for GAS
pharyngitis by rapid antigen detection test (RADT)
and/or culture should be performed because the
clinical features alone do not reliably discriminate
between GAS and viral pharyngitis
◼ Anti-streptococcal antibody titers are not
recommended in the routine diagnosis

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Outline Rhino-bronchitis
symptom
◼ Medical problem pathway
◼ United airway concept
pathophys
◼ Common cold
◼ Rhinosinusitis
◼ Pharyngitis pathology
◼ Rhinobronchitis
adaptive
◼ Pneumonia response
◼ ARI treatment

Insult

Acute (rhino)bronchitis History, symptomatology

◼ a clinical syndrome produced by inflammation of
◼ begins as a respiratory infection that manifests as
the trachea, bronchi, and bronchioles.
the common cold.
◼ in children, acute bronchitis usually occurs in
◼ symptoms often include coryza, malaise, chills,
association with viral resp infection / common cold
slight fever, sore throat, back & muscle pain.
◼ acute bronchitis is rarely a primary bacterial
◼ cough is usually accompanied by a nasal discharge
infection in otherwise healthy children.
◼ self-limited, with complete healing and full return ◼ purulent nasal discharge is common with viral
respiratory infection & does not imply bacterial
to function typically seen within 10-14 days
infection
following symptom onset
◼ ‘rattling sound’ in the chest due to excessive
mucous production
emedicine.medscape.com/article/1001332-overview emedicine.medscape.com/article/1001332-overview

Diagnosis Outline
symptom
Clinical !!! ◼ Medical problem pathway
◼ natural history: preceded by common cold, ◼ United airway concept
rhinopharyngitis pathophys
◼ Common cold
◼ acute, not recurrent – if recurrent: asthma !!!
◼ Rhinosinusitis
◼ cough initially is dry & may be harsh or raspy
sounding, then loosens & becomes productive ◼ Pharyngitis pathology
◼ lower resp sign: crackles, ronchi, wheezing of large ◼ Rhinobronchitis
airway adaptive
◼ Pneumonia response
Chest films generally appear normal in patients with
uncomplicated bronchitis – not needed ◼ ARI treatment

Insult

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Spectrum of ARI Pneumonia

AURI ALRI Inflammation of the lung parenchyme

parenchyme: alveoli & interstitial tisue

Common
Bronchitis
cold
pneumonitis, alveolitis
Rhino-
Bronchiolitis
sinusitis Infection, aspiration, radiation, ...
Tonsilo-
Pneumonia
pharyngitis

Croup = laryngo-tracheo-bronchitis

Pneumonia, etiology CAP pathogen accoding to age

symptom
▪ Virus Neonates 1-2 months 3-12 months 1-5 years >5 years

▪ Bacteria Streptococcus
group B
Chlamydia
trachomatis
Viruses Viruses S pneumoniae
pathophys ▪ Fungi Enteric gram Ureaplasma Streptococcus S pneumoniae M pneumoniae
▪ Atypical pathogen negative urealyticum pneumoniae
Viruses H influenzae Mycoplasma C pneumoniae
pathology pneumoniae
➢Influenced by age Bordetella Staphylococcu Chlamydia
pertussis s aureus pneumoniae
adaptive Moraxella
response catharrhalis

Disorders of resp tract in children, Kendig’s, 2012

Insult

Pneumonia
1 Acute upper
resp infection
Diagnosis & Treatment

Dyspnea … etc

pathophysiology

pathology
2 Bacteremia
pathogenesis adaptive
responses 3 Adjacent org

insults Pathogenesis

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Pneumonia, symptomatology Gas diffusion

symptom
◼ Preceeded by AURI: fever, rhinorrhea, & cough 1
◼ Fever: viral < bacterial - generally Membrane permeability
pathophys ◼ Tachypnea – most consistent
◼ Dyspnea -  Work of Breathing (WoB) -
2
accessory resp muscle: nasal flaring, retraction
pathology Pressure gradient
of suprasternal, intercostal, arcus costal
(epigastrium)  chest indrawing
adaptive
response
◼ Grunting - infants 3
◼ Head nodding – younger children V/Q match
◼ Chest pain – older children
◼ Cyanosis
Insult

Acute lower respiratory infection

Oxygen saturation
symptom Detection of hypoxemia
Pneumonia  volume  V ◼ Blood gas analysis
pathophys  V/Q mismatch  diffusion ◼ Pulse oxymetry
 hypoxemia  hypoxia
 adaptive response  WoB
pathology
 tachypnea  dyspnea
adaptive
response

Insult pathophysiology 63

Pneumonia, pathology Pneumonia, pathology imaging

symptom symptom
Insulst  adaptive response (esp. immune
response)  inflammation, pathology
pathophys ◼ Red Hepatization stage pathophys
alveoli consist of : leucocyte,
fibrine,erythrocyte, bacteria
pathology pathology
◼ Grey Hepatization stage
adaptive fibrine deposition, phagocytosis adaptive
response ◼ Resolution stage response
neutrophil degeneration, loose of fibrine,
bacterial phagocytosis
Insult Insult

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Pneumonia, adaptive response Pneumonia, DIAGNOSIS

symptom symptom
Combination of all aspects
◼ Clinical course
pathophys pathophys ◼ Symptomatology
◼ Pathophysiology: hypoxemia – BGA, pulse
oxymetry
pathology pathology
◼ Pathology – imaging
◼ Leucocytosis
◼ Adaptive response – blood, inflammation
adaptive ◼ Neutrophyl domination adaptive marker
response ◼ CRP – C-reactive protein – inflammation response
◼ Insults – definitive, but dificult, specimen
◼ Procalcitonin – bacterial availability. Blood culture – not a representative
specimen
Insult Insult

Classification Outline
symptom
◼ Source of infection ◼ Medical problem pathway
o Community acquired pneumonia (CAP) ◼ United airway concept
pathophys
o Hospital acquired pneumonia (HAP) ◼ Common cold
o Ventilator associated pneumonia (VAP) ◼ Rhinosinusitis
◼ Pharyngitis pathology
◼ Diagnosis
o Clinical -- mostly ◼ Rhinobronchitis
adaptive
o Radiological -- supporting ◼ Pneumonia response
o Etiology – difficult, specimen ◼ ARI treatment
◼ Severity -- WHO
Insult

ARI treatment-1 ARI treatment-2

SYMPTOMATIC measures are key ANTIBIOTICS are only rarely indicates1
◼ adequate fluid intake ◼ streptococcal tonsillo-pharyngitis
◼ antipyretics ◼ acute otitis media (especially <6 mos)
◼ oxygen as needed ◼ acute bacterial rhino-sinusitis
◼ minimal handling ◼ suspected/proven bacterial ALRI (pneumonia,
◼ no physiotherapy – even for LRTI (pneumonia) tracheitis)

Jesenak M et al. In Bronchitis 2011 (ed MartAn-Loecher I; InTech):119-148.

WHO. The management of ARI in children. Practical guidelines for outpatient care. 1995 Hersh AL et al. Pediatrics 2013;132(6):1146-54

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Common cold Common prescribed drugs

Diagnosis & Treatment

◼ Antibiotics
symptomatology
◼ Antipyretic
◼ Antitussive
pathophysiology
◼ Antihistamine
◼ Decongestans
pathology
◼ Mucolytic
pathogenesis adaptive ◼ Expectorants
response ◼ Sympathomimetics
◼ …
insults

Use of combination drugs

◼ Many commercial C&C remedies contain several
ingredients: cough suppresants, mucolytics, oral
decongestants, antihistamines, and expectorants
◼ Most of that drugs have no rational basis, e.g.
o ineffective
o combination of opposing effects
o large number of ingredients
o individually subtherapeutic doses
o similar therapeutic properties
2001 ◼ Combination drugs such as these should be avoided
WHO 2001

Recommendations Rhinosinusitis
Diagnosis & Treatment

symptomatology

pathophysiology

pathology
pathogenesis adaptive
response

WHO 2001
insults

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Medical treatment of ARS Medical treatment of ARS

Most episodes of ARS are self-limited
◼ Intranasal steroid (INS)
and will resolve spontaneously
o Mometasone furoate
◼ Antibiotics, the most frequently used o Fluticasone furoate
therapeutic agents
◼ Evidence for INS as additional treatment
◼ Intranasal steroid ◼ Evidence, high dose of INS (twice than AR dose)
◼ Nasal irrigation might be effective as monotherapy for ARS
◼ Antihistamine
◼ Decongestant, oral or intrnasal
Intranasal steroids might have a beneficial
◼ Erdosteine ancillary role in the treatment of ARS
Rhinology, EPOS 2012
Rhinology, EPOS 2012

Daily clinical practice AB treatment of acute rhinosinusitis

Upper resp symptoms
Signs of infection: Antibiotics,
+ source, fever, myalgia, … - ◼ Amoxicillin (+clavulanate) 40-80 mg/kgBW/day
◼ Cephalosporin
Common Allergic rhinitis ◼ Macrolide: clarithromycin, azitrhomycin
cold (non-infection)
• severe onset ie, >39C Antibiotic therapy seems to accelerate resolution,
• >5 days, worsening but whether an acceleration of improvement is
Rhino-sinusitis worth the increased risk of antimicrobial resistance
• >10 days, persistence
acute, viral remains to be determined.

Rhinology; EPOS 2012

Rhino-sinusitis
IDSA 2012 gln Acute rhinosinusitis acute, bacterial Rhinology, EPOS 2012
Pediatrics 2013;132:e262–e280

IDSA 2012 GAS pharyngitis treatment

◼ Patients with acute GAS pharyngitis should be
treated with an appropriate antibiotic at an
appropriate dose for a duration (usually 10 days).
Penicillin or amoxicillin is the recommended drug
of choice (strong, high)

◼ in penicillin-allergic individuals should include a 1st

gen cephalosporin for 10 days, clindamycin or
clarithromycin for 10 days, or azithromycin for 5
days (strong, moderate).
IDSA 2012 guidelines

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Rhinobronchitis treatment
◼ Medical therapy generally targets symptoms and
includes use of analgesics and antipyretics.
◼ Antitussives & expectorants are often prescribed
but have not been demonstrated to be useful
◼ In healthy individuals, antibiotics has no benefit in
relieving symptoms or improving the natural history
◼ Placebo-controlled studies using doxycycline,
erythromycin, and trimethoprim-sulfamethoxazole
have failed to show significant benefit in patients
with acute bronchitis.
◼ Preliminary studies suggest a possible role for
Pelargonium sidoides roots, in the treatment of
pediatric patients (1-18 yrs) with acute bronchitis
emedicine.medscape.com/article/1001332-overview
IDSA 2012 guidelines

Pneumonia Pneumonia, treatment

Diagnosis & Treatment

symptomatology Severe Pneumonia

◼ Hospitalization
◼ Antibiotic administration
pathophysiology
o Pennicilline, Chloramphenicol
o Amoxycillin + Clavulanic Acid
pathology
o Cephalosporine
pathogenesis adaptive ◼ Intra Venous Fluid Drip
response ◼ Oxygen
◼ Detection & management of complications

insults

Overview Upper resp & infection symptoms

Rhinosinusitis
ABRS
Common cold
Pharyngitis
GAS
Thank you
Rhinitis
Otitis Nasopharyngitis
media
Rhinopharyngitis
Rhinobronchitis
Laryngitis, Selesma
Croup

Bronchiolitis
Need AB Pneumonia
Lower resp symptomatology

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Presented at:
◼ Pre-internship seminar
◼ Imeri building
◼ Jakarta
◼ Friday, 10 Aug 2018

Antibiotic consideration
◼ Bacterial pneumonia should be considered in
children when tere is persistent or repetitive
fever >38.5o C with dyspnea & tachypnea

◼ All children with a clear clinical diagnosis of

pneumonia should receive antibiotics as
bacterial and viral pneumonia cannot reliably
be distinguished from each other

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Summary
◼ ARI has a very wide spectrum of clinical diagnosis
◼ Mostly due to viral pathogen
◼ Common cold (rhinitis, rhinopharyngitis) is the
most common ARI diagnosis
◼ Acute rhinosinusitis usually part of common cold
◼ Pharyngitis usually viral origin, strept pharyngitis
diagnosis need a careful clinical investigation
◼ Acute rhinobronchitis also usually part of CC
◼ In daily practice, ARI usually do not need AB
◼ If we need AB, amoxycillin or macrolide (i.e
clarythromycin) are the drug of choice

Two parallel situation Primary care setting

◼ Limited
o Knowledge
o Human resources
hospital puskesmas o Facilities
o Fund
◼ Should be

clinical
o Simple
o Affordable
complete program
diagnostic
o Mass oriented
tools limited
resources

Strategy, advocation Pneumonia, DIAGNOSIS

symptom Highest standard Practical approach
Clinical setting of all aspects Field setting
Combination
◼ Clinical course
pathophys ◼ Symptomatology
◼ Pathophysiology: hypoxemia – BGA, pulse
oxymetry
pathology
◼ Pathology – imaging
◼ Adaptive response – blood, inflammation
adaptive marker
response
◼ Insults – definitive, but dificult, specimen
availability. Blood culture – not a representative
specimen
Insult

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Simple clinical manifestation WHO pneumonia classification

Entry: cough
◼ Fast breathing
Age respiratory rate Signs Classification
< 2 mo 60
• No fast breathing Other respiratory illness
2 - 12 mo 50
1 - 5 yr 40 • Fast breathing Non-severe pneumonia
•Fast breathing Severe pneumonia
•Chest indrawing
◼ Chest indrawing
• Severe resp distress Very severe pneumonia
• Central cyanosis
• Not able to drink

WHO, Hosp care for children, 2007

Treatment Risk factors

◼ Prompt treatment of pneumonia with a full Low birth weight
course of appropriate antibiotics is lifesaving.
Not breastfed Malnutrition
◼ UNICEF & WHO have published guidelines for
diagnosing and treating pneumonia in Incomplete Vit A deficiency
community settings in the developing world immunization

◼ This approach is proven, affordable and relatively PNEUMONIA

Young age Cold weather
straightforward to implement
◼ Cotrimoxazole & amoxicillin are effective drugs High prevalence
‘Kumis pa joko’ pathogen carrier
against bacterial pathogens and are often used to
treat children with pneumonia in developing Exposure to indoor & outdoor pollution
countries.
ETS, biomass fuel, vehicle & industry pollution

Unicef - WHO, Pneumonia the forgotten killer, 2006

Underlying med cond’n: Neuro,Respi,Cardio,GH,Al-Im,

2014

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