Week 1 TropMed 2020 – dr.

Alvin

1. Pasien seperti apakah yang at risk kena viral pneumonia

Everyone has some risk of catching viral pneumonia, since it’s airborne and contagious.
You may have a higher risk of developing pneumonia if you:
 work or live in a hospital or nursing care setting
 are 65 years of age or older
 are 2 years or younger
 are pregnant
Having a weakened or suppressed immune system due to HIV/AIDS, chemotherapy, or
immunosuppressant medications also increases your risk for pneumonia and its
complications.
Other factors include:
 having a chronic illness such as an autoimmune disease, heart disease, asthma, or
a respiratory infection
 cancer or any other condition that’s being treated with chemotherapy
 recent viral infection
 smoking tobacco, which damages your body’s defenses against pneumonia

2. All about Pneumonia?

Pneumonia is a respiratory infection characterized by inflammation of the alveolar

space and/or the interstitial tissue of the lungs. In industrialized nations, it is the leading
infectious cause of death.
Pneumonia is commonly transmitted via aspiration of airborne pathogens (primarily
bacteria) but may also result from the aspiration of stomach contents. The spectrum of
causal pathogens is mainly determined by patient age, immune status, and where the
infection was acquired (community-acquired or hospital-acquired).
Pneumonia is also classified based on clinical features as either typical and atypical; each
type has its own spectrum of commonly associated pathogens.
Typical pneumonia presents with sudden onset of malaise, fever, and a
productive cough. On auscultation, crackles and bronchial breath sounds are
audible. Atypical pneumonia, on the other hand, presents with gradual onset of
unproductive cough, dyspnea, and extrapulmonary manifestations. Auscultation is
typically unremarkable. In reality, some patients may present with elements of both types.
Diagnostics include blood tests for inflammatory parameters and pathogen detection in
blood, urine, or sputum samples. Chest x-ray in cases of typical pneumonia shows
extensive opacity restricted to one lobe, while atypical pneumonia presents with diffuse,
often subtle infiltrates. A newly developed pulmonary infiltrate on chest x-ray in
combination with the clinical features confirms the diagnosis. Management consists of
supportive measures, such as oxygen administration or physiotherapy,
and antibiotic treatment. Antibiotics are initially administered empirically and later adapted
based on the results of bacterial culture.
Definition
 Primary pneumonia: no apparent preexisting conditions that may predispose to
pneumonia
 Secondary pneumonia
 Bronchial asthma, COPD, heart failure, cystic fibrosis
 Viral upper respiratory tract infections with bacterial superinfection
 Anatomical abnormalities such as tubercular caverns, bronchial tumors, or
stenosis (post-obstructive pneumonia)
 Aspiration (aspiration pneumonia)
 Community-acquired pneumonia (CAP): pneumonia that is acquired outside of a
health care establishment
 Hospital-acquired pneumonia (HAP): nosocomial pneumonia, with onset > 48
hours after admission
 Typical pneumonia
 Pneumonia featuring classic symptoms (see “Clinical features” below); typical
findings on auscultation and percussion
 Manifests as lobar pneumonia or bronchopneumonia
 Atypical pneumonia
 Pneumonia with less distinct classical symptoms and often unremarkable
findings on auscultation and percussion
 Manifests as interstitial pneumonia

Etiology
Pathogens
Type of pneumonia Common pathogens
Community- Typical  Streptococcus pneumoniae (most
acquired pneumonia pneumonia common)
Most common also in nursing home patients
 Haemophilus influenzae

Atypical  Mycoplasma pneumoniae (most common

pneumonia in the ambulatory setting)
 Chlamydophila pneumoniae
 Legionella pneumophila → legionellosis
 Coxiella burnetii

Hospital-acquired pneumonia  Gram-negative pathogens

Pseudomonas aeruginosa
Enterobacteriaceae
 Staphylococci (Staphylococcus aureus)
 Streptococcus pneumoniae
Special groups
Pneumonia  Encapsulated bacteria
in immunocompromised patients  Pneumocystis jirovecii → Pneumocystis
jirovecii pneumonia

Pneumonia in newborn infants
Recurrent pneumonia
 Aspergillus fumigatus → aspergillosis
 Candida species → candidiasis
 Cytomegalovirus
 Escherichia coli
 Group B streptococcus (Streptococcus
agalactiae)
 Streptococcus pneumoniae
 Haemophilus influenzae
 Unusual organisms (e.g., Nocardia, Coxiella
burnetii, Aspergillus, Pseudomonas aeruginosa)

Routes of infection
 Most common: microaspiration (droplet infection) of airborne pathogens or
oropharyngeal secretions
 Aspiration of gastric acid (Mendelson's syndrome) , or of food or liquids
 Hematogenous dissemination in rare cases

Risk factors
 Old age and immobility of any cause
 Chronic diseases
 Preexistingcardiopulmonary conditions (e.g., bronchial asthma, COPD, heart
failure)
 Acquired or congenital abnormalities of
the airways (e.g., bronchiectasis, space-occupying lesions, cystic fibrosis)
 Immunosuppression (e.g., HIV infection, diabetes mellitus, cytostatic
therapy, alcoholism, immunosuppressive therapy)
 Smoking

Pathophysiology
 Pulmonary protective mechanisms (cough reflex, mucociliary clearance , alveolar
macrophages ) fail → microbial infiltration of the pulmonary parenchyma cannot be
prevented
 Pathogen infiltrates pulmonary parenchyma → interstitial and
alveolar inflammation → impaired alveolar ventilation → Ventilation/perfusion (V/Q)
mismatch with intrapulmonary shunting (right to left) → hypoxia due to
increased alveolar-arterial oxygen gradient (This effect is worsened if the
affected lung is in the dependent position since perfusion is better to the
dependent lung than the non-dependent lung)
 Pattern of involvement
 Lobar pneumonia: classic (typical) pneumonia of an entire lobe,
primarily caused by pneumococci
 Classic disease progression in stages
 Congestion (day 1): serous exudate in blood-rich lungs,
numerous bacteria evident
  Red hepatization (days 2–3): exudate rich in fibrin and
inflammatory cells with many bacteria still
visible; lungs take on a liver-like texture. Lung loses
some spongy quality
 Gray hepatization (days 4–7): erythrocytes are
degraded but inflammatory cells persist; most bacteria
have been destroyed by this stage. Lung is now firm
 Resolution (day 8 to week 4): fibrinolysis by enzymatic
means and removal of
the purulent exudate via productive cough
 Bronchopneumonia: mostly descending infection that affects
the bronchioles and adjacent alveoli; usually involves the lower lobes
or right middle lobe; manifests as typical pneumonia
 Primarily caused by pneumococci and/or other streptococci
 Necrotizing bronchopneumonia (and pneumatocele) are
caused by Staphylococcus aureus and are often preceded by
an influenza infection.
 Interstitial pneumonia: interstitial inflammation, particularly caused
by mycoplasma and viral infections; manifests as atypical pneumonia
 Miliary pneumonia: multiple small infiltrations caused by
hematogenous dissemination (e.g., of tuberculosis)

Clinical features
Typical pneumonia
Typical pneumonia presents with a sudden onset of symptoms caused by lobar infiltration.
 Severe malaise
 High fever and chills
 Productive cough with purulent sputum (yellow-greenish)
 Crackles, bronchial, and decreased breath sounds on
auscultation
 Enhanced bronchophony, egophony, and tactile fremitus
 Dullness on percussion
 Tachypnea and dyspnea (nasal flaring, thoracic retractions)
 Pleuritic chest pain when breathing, often accompanying pleural effusion
 Pain projecting to the abdomen and epigastric region (particularly in children)
Suspect bacterial pneumonia in immunocompromised patients with
acute high fever and pleural effusion!

Atypical pneumonia
Atypical pneumonia typically takes an indolent course (slow onset) with an emphasis on
extrapulmonary symptoms. Common pathogens include mycoplasma,
legionella, chlamydiae, and viruses such as RSV, influenza, CMV, and adenovirus.
 Low-grade fever
 Non-productive, dry cough
 Dyspnea
 Common extrapulmonary features include fatigue, headaches, sore
throat, myalgias, malaise
  Auscultation often unremarkable
A clear distinction between typical and atypical pneumonia is not always possible based
solely on the symptoms. As both forms may be caused by any pathogen, the distinction
has little bearing on therapeutic decisions!

Subtypes and variants

Aspiration pneumonia
 Definition: Aspiration is the inhalation of foreign material into the respiratory
tract. It often occurs after instrumentation of the
upper airways or esophagus (e.g., upper GI endoscopy), or secondary to vomiting
and regurgitation of gastric content.
 Mendelson syndrome
 Aspiration of gastric acid initially causing tracheobronchitis with
rapid progression to chemical pneumonitis
 May cause ARDS in extreme cases
 Risk factors
 Altered consciousness: alcohol, sedation, general anesthesia
 Apoplexy and neurodegenerative conditions
 Gastroesophageal reflux disease, esophageal motility disorders
 Pathogens: mixed infections with anaerobic organisms are
common (e.g., Klebsiella)
 Clinical findings
 Immediate symptoms: bronchospasms , crackles on
auscultation, hypoxemia with cyanosis
 Late symptoms: fever, shortness of breath, cough with foul-
smelling sputum
 Diagnosis
 Arterial blood gas analysis (↓ PaO2, pH < 7.35, PaCO2 > 45 mm Hg)
 Radiologic imaging: The lung region in which the infiltrates are seen
in depends on the patient's position on aspiration. :
 Supine position: superior segment of the right lower lobe (most
common site of aspiration)
 Standing/sitting: posterior basal segment of the right lower lobe
 Right lateral decubitus position: posterior segment of the right
upper lobe or right middle lobe
 Management
 Immediate (re)intubation with administration of 100% O2
 Endotracheal suction with microbiological analysis of bronchial
secretions
 Antibiotic treatment that covers anaerobes (e.g., ampicillin-
sulbactam, carbapenems, or clindamycin)
 Regular monitoring: arterial blood gas, radiologic imaging
 Prevention: optimize therapy and/or prophylaxis of underlying causes to reduce
the risk of aspiration

Pathogen-specific pneumonia
 Mycoplasma pneumonia:
  Epidemiology
 One of the most common causes of atypical pneumonia
 More common in young individuals
 Outbreaks may occur in schools, colleges, prisons, and military
facilities
 Clinical features
 See atypical pneumonia
 Generalized papular rash, erythema multiforme
 Diagnostics
 Subclinical hemolytic anemia: associated with elevated cold
agglutinin titers (IgM)
 Interstitial pneumonia, often with reticulonodular pattern
on CXR
 Treatment: macrolides, doxycycline, and fluoroquinolones
 Legionnaires’ disease
 Pneumocystis pneumonia
 Tuberculosis
 Primary influenza pneumonia
 Various viral infections (e.g., respiratory-syncytial-
virus, hantavirus, adenovirus, CMV)
 SARS
 Ornithosis
 Pseudomonas aeruginosa: causes ventilator associated pneumonia

Lung abscess
 Definition: a localized collection of pus and necrotic tissue
within lung parenchyma caused by microbial infection
 Risk factors
 Predisposition to aspiration due to: reduced level of
consciousness , dysphagia
 Bronchial obstruction: lung cancer, foreign body aspiration, bronchial
stenosis
 Immunocompromised state
 Pathogens
 Most commonly: mixed infections caused by anaerobic bacteria that
colonize the oral
cavity (e.g., Peptostreptococcus, Prevotella, Bacteroides, Fusobacteri
um spp.)
 Less commonly: monomicrobial lung abscess caused by S.
aureus, Klebsiella pneumoniae, Streptococcus
pyogenes, Streptococcus anginosus
 Clinical findings: indolent presentation with symptoms that evolve over weeks to
months
 Fever
 Cough with production of foul-smelling sputum
 Anorexia, weight loss
 Night sweats
  Hemoptysis
 Diagnosis

Gram stain, culture, and sensitivity of expectorated sputum

Radiologic imaging (x-ray or CT): irregular rounded cavity with an air-
fluid level in lung region on aspiration that is dependent on body
position
 Management
 Antibiotic treatment that covers anaerobes (e.g., ampicillin-
sulbactam, carbapenems, or clindamycin )
 If medical therapy fails, percutaneous catheter drainage or surgical
resection may be considered.
Diagnostics
Laboratory tests
 Blood
 ↑ CRP, ↑ ESR, leukocytosis, ↑ procalcitonin (PCT)
 ABG to rule out respiratory failure ( ↓ PaO2, pH < 7.35, PaCO2 > 45
mm Hg)
 Pathogen detection
 Blood cultures are always recommended.
 Urine
 Legionella antigen detection (if legionellosis is suspected)
 Urine pneumococcal antigen test (if Streptococcus
pneumoniae is suspected)
 PCR and antibody tests to detect Chlamydia pneumoniae

Imaging
 Chest x-ray
 Lobar pneumonia: extensive opacity restricted to one pulmonary
lobe; positive air bronchogram ; unilateral pleural effusion may be
visible
 Bronchopneumonia: poorly defined patchy infiltrates scattered
throughout the lungs, air bronchogram is unusual
 Atypical or interstitial pneumonia: diffuse reticular opacity, absent (or
minimal) consolidation
A newly developed pulmonary infiltrate on chest x-ray in a patient with the classic
symptoms of pneumonia confirms the diagnosis!
 Thorax CT
 Indications: inconclusive chest x-ray, recurrent pneumonia
 Advantages: more reliable evaluation of circumscribed opacities,
pleural emphysema, or sites of colliquation
Typical pneumonia usually appears as a lobar pneumonia on x-ray, while atypical
pneumonia tends to appear as interstitial pneumonia. However, the underlying pathogen
cannot be conclusively identified based on the imaging results!

Further diagnostics
The following tests are not part of the initial diagnostic workup; they are predominantly
used for further investigation if the results of previous tests are negative or inconclusive.
  Sputum : testing for multiresistant pathogens ; severe, rapid
progressive nosocomial pneumonia
 Pleurocentesis
 pH metry value (normally 7.60–7.64)
 Leukocyte count > 1000 WBCs/mm3 and protein levels (> 1-2 g/dL)
 Inoculation of blood cultures with the puncture fluid and subsequent
analysis
 Bronchoscopy: indicated to visualize and biopsy a central mass discovered
on CT imaging, or if CT results are inconclusive

Treatment

Criteria for hospitalization

 Based on CURB-65 score
 Confusion (disorientation, impaired consciousness)
 Urea > 7 mmol/L (20 mg/dL)
 Respiratory rate ≥ 30/min
 Blood pressure: systolic BP ≤ 90 mm Hg or diastolic BP ≤ 60 mm Hg
 Age ≥ 65 years
  Interpretation
 Each finding is appointed 1 point; max. 5 points possible
 CURB-65 score ≤ 1: The patient may be treated as an
outpatient.
 CURB-65 score ≥ 2: Hospitalization is indicated.
 CURB-65 score ≥ 3: ICU-care should be considered.
Any patient being treated in a primary care setting should be reexamined after 48–72
hours to evaluate the efficacy of the prescribed antibiotic!

General measures
 Sufficient rest (not absolute bedrest) and physical therapy
 High liquid intake (prevents dehydration, reduces bronchial secretion viscosity)
 Pulse oximetry monitoring
 Oxygen via nasal tube in cases of hypoxia
 Antipyretics, analgesics (e.g., acetaminophen, ibuprofen)
 Expectorants and mucolytics
 Antitussives (e.g., codeine)

Medical treatment of pneumonia

As laboratory results with definite pathogen identification may take time to obtain,
initial empiric antibiotic treatment with broad coverage is recommended.
Community-acquired pneumonia
Treatment parameters Regimen
Outp Patients without risk factors  Macrolide (e.g., azithromycin, clarithromycin
atient , erythromycin )
treat  OR doxycycline
ment
 Patients with risk factors  A 3rd or 4th generation respiratory
 Recent antibiotic treatme fluoroquinolone (e.g., levofloxacin, moxifloxa
nt cin, gemifloxacin )
 Preexisting neurological  OR an antipneumococcal beta-
conditions or diseases of lactam (e.g., amoxicillin ± clavulanate, ceftria
internal organs (e.g., xone, cefpodoxime, cefuroxime)
chronic heart, lung, liver, + macrolide (OR doxycycline)
or renal disease, diabetes
mellitus,
malignancy, asplenia, im
munosuppression, alcoho
lism)
 Living in nursing homes

 Non-ICU treatment
Inpati  Respiratory fluoroquinolone
ent  OR an antipneumococcal beta-
treat lactam (e.g., cefotaxime, ceftriaxone, ampicil
ment lin/sulbactam) + macrolide (OR doxycycline)
Community-acquired pneumonia

 ICU treatment for  An antipneumococcal beta-

 Acute respiratory failure lactam (ceftriaxone, cefotaxime,
 Septic shock or ampicillin/sulbactam)
 Decompensation of + azithromycin
comorbidities (e.g., OR + a respiratory fluoroquinolone
cardial decompensation,  If penicillin allergy: respiratory
exacerbation fluoroquinolone plus aztreonam
of COPD, acute renal
failure)

 If Pseudomonas
Speci  Antipneumococcal,
al aeruginosa is suspected antipseudomonal beta-
case lactam (piperacillin/tazobactam, cefepime, m
s eropenem, or imipenem)
+ respiratory fluoroquinolone ±
an aminoglycoside
OR + azithromycin + aminoglycoside

 If MRSA is suspected  Add vancomycin or linezolid

Antibiotic treatment may be terminated 2–3 days after the fever subsides. In cases
of community-acquired pneumonia that can be treated in the outpatient setting, seven
days of antibiotic treatment are usually sufficient!

Hospital-acquired pneumonia
Hospital-acquired pneumonia
Treatment parameters
Low/moder Patients
ate risk without risk
of mortality factors
for multiresist
ant pathogens
Regimen
 An antipneumococcal, antipseudomonal beta-
lactam (e.g., piperacillin-
tazobactam, cefepime, meropenem, or imipenem)
 OR a
respiratory fluoroquinolone (e.g., levofloxacin, mo
xifloxacin)

Patients with  An antipneumococcal, antipseudomonal beta-

risk factors lactam (piperacillin/tazobactam, cefepime, merope
for multiresist nem, or imipenem)
ant  OR a
pathogens* respiratory fluoroquinolone (e.g., levofloxacin, mo
xifloxacin)
 OR aztreonam
 PLUS vancomycin or linezolid

High risk of mortality or  Two of the following (avoid 2 beta-lactams)

history of recent - An antipneumococcal, antipseudomonal beta-
Hospital-acquired pneumonia
Treatment parameters Regimen
IV antibiotic use (< 90 days) lactam (piperacillin/tazobactam, cefepime, merope
nem, or imipenem)
- A
respiratory fluoroquinolone (e.g., levofloxacin, mo
xifloxacin)
-
An aminoglycoside (e.g., amikacin, gentamicin, tobr
amycin)
- Aztreonam
 PLUS vancomycin or linezolid
* Risk factors include: recent IV antibiotic treatment; hospitalization
(on ICU); colonization with multiresistant pathogens; structural lung disease

3. Bacterial Pneumonia vs. Viral Pneumonia

A. Bacterial Pneumonia

The word "pneumonia" originates from the ancient Greek word "pneumon" which means
"lung," so the word "pneumonia" becomes "lung disease." Medically it is an inflammation
of one or both lung's parenchyma that is more often but not always caused by infections.
The many causes of pneumonia include bacteria, viruses, fungi, and parasites. This
article is about bacterial causes of pneumonia as it is the major cause of mortality and
morbidity by pneumonia. According to the new classification of pneumonia, there are
four categories: community-acquired (CAP), hospital-acquired (HAP), healthcare-
associated (HCAP) and ventilator-associated pneumonia (VAP). [1][2][3]
Types of Bacterial Pneumonia
 CAP: The acute infection of lung tissue in a patient who has acquired it from the
community.
 HAP: The acute infection of lung tissue that develops 48 hours or longer after the
hospitalization of a non-intubated patient.
 VAP: A type of nosocomial infection of lung tissue that usually develops 48 hours
or longer after intubation for mechanical ventilation.
 HCAP: The acute infection of lung tissue acquired from healthcare facilities such as
nursing homes, dialysis centres, and outpatient clinics or a patient with
hospitalization within the past 3 months (previously included in HAP but becomes a
separate category after some cases presenting as outpatients
with pneumonia have been found to be infected with multidrug-resistant (MDR)
pathogens previously associated with HAP).
Some articles include both HAP and VAP under the category of HCAP, so defining HCAP
is problematic and controversial.
Etiology
Etiology of community-acquired pneumonia is an extensive list of agents that include
bacteria, viruses, fungi, and parasites, but this article is about bacterial pneumonia and
its causes. Bacteria have classically been categorized into two divisions on the basis of
etiology, "typical" and "atypical" organisms. Typical organisms can be cultured on
standard media or seen on Gram stain, but "atypical" organisms do not have such
properties. [4]
1. Typical pneumonia refers to pneumonia caused by Streptococcus pneumoniae,
Haemophilus influenzae, S. aureus, Group A streptococci, Moraxella catarrhalis,
anaerobes, and aerobic gram-negative bacteria.
2. Atypical pneumonia is mostly caused by Legionella spp, Mycoplasma
pneumoniae, Chlamydia pneumoniae, and C. psittaci.
The most common causes of community-acquired pneumonia (CAP) is S. pneumoniae
followed by Klebsiella pneumoniae, Haemophilus influenzae, and Pseudomonas
aeruginosa. The most common causes of HCAP and HAP are MRSA (methicillin-resistant
Staphylococcus aureus) and Pseudomonas aeruginosa respectively. The causative
agents of VAP include both multi-drug resistant (MDR) agents (e.g., S. pneumoniae, other
Strep spp, H. influenzae and MSSA) and non-MDR (e.g., P. aeruginosa, methicillin-
resistant Staphylococcus aureus, Acinetobacter spp. and antibiotic-resistant
Enterobacteriaceae) bacterial pathogens.

Epidemiology
The incidence of CAP in the United States is more than 5 million per year; 80% of these
new cases are treated as outpatients with the mortality rate of less than 1%, and 20% are
treated as inpatients with the mortality rate of 12% to 40%. The incidence of CAP varies
among different genders; for example, it is more common in males and African Americans
than females and other Americans. The incidence rates are higher at extremes of age
distribution range; the adult rate is usually 5.15 to 7.06 cases per 1000 persons per
year, but in the population of age less than 4 years and greater than 60 years, the rate is
more than 12 cases per 1000 persons. In 2005, influenza and pneumonia combined was
the eighth most common cause of death in the United States and the seventh Most
common cause of death in Canada. The mortality rate also is variable among different
regions at 7.3% for the United States and Canada, 9.1% for Europe, and 13.3% for Latin
America.

Pathophysiology
The lower respiratory tract is not sterile, it always is exposed to environmental pathogens.
Invasion and propagation of the above-mentioned bacteria into lung parenchyma at
alveolar level causes bacterial pneumonia, and the body's inflammatory response
against it causes the clinical syndrome of pneumonia. To prevent this proliferation of
microorganisms there are a number of host defenses working together in lungs such as
mechanical (e.g., hair in nostrils and mucus on nasopharynx and oropharynx) and
chemical (e.g., proteins produced by alveolar epithelial cells like surfactant protein A and
D, which have the intrinsic property of opsonizing bacteria). Another component of the
pulmonary defense system is made up of immune cells such as alveolar macrophages,
which work to engulf and kill proliferating bacteria, but once bacteria overcome the
capacity of host defenses, they start proliferation. In this setting, the alveolar macrophages
kickoff the inflammatory response to strengthen the lower respiratory tract defenses. This
inflammatory response is the main culprit of clinical manifestation
of bacterial pneumonia. Cytokines are released in response to the inflammatory reaction
and cause the constitutional symptoms, for example, IL-1 (interleukin-1) and TNF (tumor
necrosis factor) causes fever. Chemokine-like IL-8 (interleukin-8) and colony-stimulating
factors like G-CSF (granulocyte colony-stimulating factor) promote chemotaxis and
neutrophils maturation respectively, resulting in leukocytosis on serological lab and
purulent secretions. These cytokines are responsible for the leakage of the alveolar-
capillary membrane at the site of inflammation, causing a decrease in compliance and
shortness of breath. Sometimes even erythrocytes cross this barrier and result in
hemoptysis.

Histopathology
Pathologically, lobar pneumonia is the acute exudative inflammation of a lung lobe. It has
the following four advanced stages if left untreated:
 Congestion: In this stage, pulmonary parenchyma is not fully consolidated, and
microscopically, the alveoli have serous exudates, pathogens, few neutrophils, and
macrophages.
 Red hepatization: Here the lobe is now consolidated, firm, and liver-like.
Microscopically, there is an addition of fibrin along with serous exudate, pathogens,
neutrophils, and macrophages. The capillaries are congested, and the alveolar
walls are thickened.
 Gray hepatization: The lobe is still liver-like in consistency but gray in color due to
suppurative and exudative filled alveoli.
 Resolution: After a week, it starts resolving as lymphatic drainage or a productive
cough clear the exudate.

History and Physical

The history findings of bacterial pneumonia may vary from indolent to fulminant. Clinical
manifestation includes both constitutional findings and findings due to damage to the lung
and related tissue. The following are major history findings:
 Fever with tachycardia and/or chills and sweats.
 The cough may be either nonproductive or productive with mucoid, purulent or
blood-tinged sputum.
 Pleuritic chest pain, if the pleura is involved.
 Shortness of breath with normal daily routine work.
 Other symptoms include fatigue, headache, myalgia, and arthralgia.
Physical findings also vary from patient to patient and mainly depend on the severity of
lung consolidation and existence or nonexistence of pleural effusion. The following
are major clinical findings:
 Increased respiratory rate.
 Percussion sounds vary from flat to dull.
 Tactile fremitus.
 Crackles, rales, and bronchial breath sounds are heard on auscultation.
Confusion manifests earlier in older patients. A critically ill patient may present with sepsis
or multi-organ failure.
Evaluation
The approach to evaluate and diagnose pneumonia depends on different modalities but
primarily it is like a tripod stand which has 3 legs which are summed up as:
 Clinical Evaluation: It includes taking a careful patient history and performing a
thorough physical examination to judge the clinical signs and symptoms mentioned
above.
 Laboratory Evaluation: This includes lab values such as complete blood count
with differentials, inflammatory biomarkers like ESR and C-reactive protein, blood
cultures, sputum analysis or Gram staining and/or urine antigen testing or
polymerase chain reaction for nucleic acid detection of certain bacteria.
 An arterial blood gas may reveal hypoxia and respiratory acidosis
 Pulse oximetry of less than 92% indicates severe hypoxia and elevated CRP
predicts a serious infection.
 Blood cultures should be obtained before administering antibiotics. Unfortunately,
they are only positive in 40% of cases
 Sputum evaluation if good quality may reveal more than 25 WBC per low power
field and less than 10 squamous epithelial cells
 Radiological Evaluation: It includes chest x-ray as an initial imaging test and the
finding of pulmonary infiltrates on plain film is considered as a gold standard for
diagnosis when the lab and clinical features are supportive.[10][2]
 The chest x-ray may reveal a consolidation or parapneumonic effusion.
 Chest CT is done for complex cases where the cause is not known.
 Bronchoalveolar lavage is done in patients who are intubated and can provide
samples for culture.

Treatment / Management
In all patients with bacterial pneumonia, empirical therapy should be started as soon as
possible. The first step in treatment is a risk assessment to know whether the patient
should be treated in an outpatient or inpatient setting. Cardiopulmonary conditions, age,
and severity of symptoms affect risk for bacterial pneumonia, especially CAP.[11][12][13]
An expanded CURB-65 or CURB-65 pneumonia severity score can be used for risk
quantification. It includes C = Confusion, U = Uremia (BUN greater than 20 mg/dL), R =
Respiratory rate (greater than 30 per min), B = B.P (BP less than 90/60 mmHg) and age
greater than 65 years. One point is scored for each previously mentioned risk factor. If the
total of the score is 2 or more than 2, it indicates hospital admission. If the total is 4 or
more than 4, it indicates ICU admission. Recommended therapy for different settings
are as follows:
 Outpatient Setting: For patients having comorbid conditions ( e.g., diabetes,
malignancy, etc.) the regimen is "fluoroquinolone" or "beta-lactams + macrolide."
For patients with no comorbid conditions, we can use "macrolide" or "doxycycline"
empirically. Testing is usually not performed as the empiric regimen is almost
always successful.
 Inpatient Setting (non-ICU): Recommended therapy is fluoroquinolone or
macrolide + beta-lactam.
 Inpatient setting (ICU): Recommended therapy is beta-lactam + macrolide or
beta-lactam + fluoroquinolone.
  MRSA: Vancomycin or linezolid can be added.
After getting a culture-positive lab result, therapies should be directed to the culture-
specific pathogen.
The patient also can benefit from smoking cessation counseling and influenza and
pneumococcal vaccination.
All patients treated at home should be scheduled for a follow-up visit within 2 days to
assess any complication of pneumonia.
The role of corticosteroids remains controversial and may be used in patients who remain
hypotensive with presumed adrenal insufficiency.
Other measures:
 Hydration
 Chest physical therapy
 Monitoring with pulse oximetry
 Upright positioning
 Respiratory therapy with bronchodilators
 Mechanical support if patients are in respiratory distress
 Nutrition
 Early mobilization

Differential Diagnosis
Differential Diagnosis in Children
 Asthma or reactive airway disease
 Bronchiolitis
 Croup
 Respiratory distress syndrome
Differential Diagnosis in Adults
 Acute and chronic bronchitis
 Aspiration of a foreign body
 Asthma
 Atelectasis
 Bronchiectasis
 Bronchiolitis
 Chronic obstructive pulmonary disease
 Fungal
 Lung abscess
 Pneumocystis jiroveci pneumonia
 Respiratory failure
 Viral

Prognosis
Prognosis of pneumonia depends on many factors including age, comorbidities, and
hospital setting (inpatient or outpatient). Patients older than 60 years or younger than 4
years of age have a relatively poorer prognosis than young adults. Antibiotic resistance,
very concerning due to the enhancement of antibiotic regimens, and infectious diseases,
especially those like bacterial pneumonia, can be easily cured.

Complications
The most common complications of bacterial pneumonia are respiratory failure, sepsis,
multiorgan failure, coagulopathy, and exacerbation of preexisting comorbidities. Three
distinct complications are metastatic infections, lung abscess, and complicated pleural
effusion.

Deterrence and Patient Education

To prevent bacterial pneumonia, recommendations include:
1. Vaccination against pneumococcus
2. Annual vaccine against H influenza

Pearls and Other Issues

 Most patients respond with improvement within 48-72 hours.
 The chest x-ray findings lag behind clinical features and may take 6-12 weeks to
clear
 If patients fail to improve within 72 hours, another cause should be suspected,
antibiotic resistance or development of complication like empyema

Enhancing Healthcare Team Outcomes

The management of pneumonia requires an interprofessional team. The reason is that
most patients are managed as outpatients but if not properly treated, the morbidity and
mortality are high.
Besides the administration of antibiotics, these patients often require chest physical
therapy, a dietary consult, physical therapy to help regain muscle mass and a dental
consult. The key is to educate the patient on the discontinuation of smoking and
abstaining from alcohol.
Patients need to be referred to a dietitian to ensure that they are eating healthy.
Further, the clinicians should encourage patients to get appropriate influenza and
pneumococcal vaccines. The pharmacist should not only teach about antibiotic
compliance but ensure that the patient is prescribed the right antibiotics aimed at the
target organism. An infectious disease specialty-trained pharmacist is particularly helpful
in assisting the team with difficult antibiotic treatment choices. Nursing can counsel on the
appropriate dosing and administration of medications and answer patient questions, as
well as charting treatment progress, and reporting any issues to the clinician managing the
case.
Finally, it is important to educate the patient to follow up with clinicians if they want a
complete resolution of the infectious process.[13][14] (Level V) Only with open
communication between the interprofessional team can the morbidity of pneumonia be
lowered.

Outcomes
In healthy people, the outcome after bacterial pneumonia is excellent. However, in
people with advanced age, lung disease, immunosuppression, infection with aggressive
gram-negative organisms (Klebsiella) and other comorbidities, the outcomes are usually
poor. When pneumonia is left untreated, it carries mortality in excess of
25%. Pneumonia can also lead to extensive lung damage and lead to residual
impairment in lung function. Other reported complications of pneumonia that occur in 1-
5% of patients include lung abscess, empyema, and bronchiectasis.[15][16] (Level V)
B. Viral Pneumonia

Viral pneumonia is defined as a disease entity wherein there is the viral causation of
oxygen and carbon dioxide gas exchange abnormalities at the level of the alveoli,
secondary to viral-mediated and/or immune response-mediated inflammation. The
traditional role of viral pneumonia was as a disease found predominantly in the
very young, the elderly, and those exposed to influenza. In the past, the diagnosis of viral
pneumonia was predicated on it being somewhat a diagnosis of exclusion. History,
physical exam, chest radiography, and available lab work (until recently) lacked sensitivity
and specificity. Once bacterial pneumonia has been excluded, then viral pneumonia
diagnosis was entertained.[1][2][3]
Traditionally, the treatment of viral pneumonia revolved around supportive care:
 Supplemental oxygen when indicated
 Airway augmentation as appropriate
 Monitoring of and replacement of any fluid deficits
 Symptomatic control of temperature and cough
 Rest to reduce oxygen demand
 Treatment of any comorbidities and/or concomitant bacterial pneumonia
The concepts of diagnosis, prevalence, clinical role, and treatment of viral pneumonia are
in flux for several reasons.
1. There is a growing population at increased risk of viral pneumonia:
 The increases in life span and early infant survivability have created an additional
population at greater risk of viral pneumonia.
 The increased number of those receiving immune-impairing therapy (radiation
and/or chemotherapy) for cancer.
 The increased use of disease-modifying hematological/immunological agents in
chronic illness, resulting in secondary impaired immunity.
 The advent of HIV
 The increase in the number of patients with inborn immune impairment serving
bacterial infection secondary to antibiotic therapy.
 The increased incidence of organ transplantation and immunosuppressive therapy.
2. The availability of sensitive, specific, real-time-result-available testing for viral entities:
 Polymerase chain reaction (PCR) technology is replacing viral cultures and serial
viral antigen titers. Both viral culture results and serial antigen testing were
problematic because test results were not available until weeks after the acute
illness, and viral culturing for pneumonia could involve invasive sampling
techniques to acquire.
 The availability of PCR testing has resulted in increased testing in general.
 The mechanism of PCR itself is more sensitive and specific because many viruses
are notoriously difficult to grow in culture and are very sample dependent.
3. The positive feedback loop that results from improved viral pneumonia testing
modalities:
 The test availability results in an increased number of diagnoses.
 The increased number of diagnosis raises the clinical index of suspicion for the
entity.
 The increased clinical index of suspicion raises the number of tests ordered.
4. The availability of safe, tolerable, and somewhat specific antiviral therapies:
  Prior viral pneumonia treatment was essentially supportive measures only.
 Initial efforts at antiviral therapy were not well tolerated.
 The availability of some specific and effective treatments now spur earlier testing
and a greater appreciation of the role of viral infection in pneumonia.
 Disease-modifying therapy for HIV is now available.
5. The increasing role of viral pathogens in pneumonia and the increased realization of the
role of bacterial and viral co-infection necessitate a higher clinical index of suspicion and
early identification of viral pulmonary pathogens. Counterbalance seeing this new clinical
burden is the availability of the following:
 Enhanced laboratory detection via ELISA and PCR testing modalities
 Enhanced radiographic detection for a high thin section CAT scan
 An increasing number of safe and efficacious antiviral drugs
 Increased recognition of the role of prevention in viral infectious disease.

Etiology
As pneumonia can be considered somewhat a final common pathway of infection,
especially for those who are immune-compromised, a great number of viruses can cause
pneumonia. In general, these viruses can be divided into those containing DNA or RNA as
their nucleic acid. As this is a bit of an artificial division, a more meaningful approach to
etiology is to define by clinical syndromes produced and demographics affected.[4][5][6]

Etiologies of Viral Influenza

Respiratory syncytial virus (RSV)
 RNA virus
 RSV is the most common cause of viral pneumonia in small children and infants.
Rhinovirus
 RNA
 Rhinovirus is the most common cause of upper respiratory tract infection across all
age groups, although it is not as commonly represented as a cause of viral
pneumonia.
Influenza A, B and C viruses
 RNA
 Influenza A is the greatest cause of mortality and morbidity among the viral types
of pneumonia.
 There are multiple subtypes of Influenza A. Two particularly concerning subtypes
to be aware of are the avian flu (H5N1)and swine flu (H1N1).
Human metapneumovirus
 RNA
 Human Metapneumovirus is a novel viral pathogen that is increasingly recognized
as a cause of viral pneumonia and is implicated as the cause of the SARS
outbreak.
Parainfluenza viruses type 1, 2, 3, and 4
 RNA
 Parainfluenza virus has multiple serotypes and is most commonly associated with
pneumonia-like illness in young children seasonally. Spring and fall predominate.
Human bocavirusCoronavirus
 RNA
  Coronal viruses are already viruses that cause pneumonia, typically in immune
incompetent people.
 However, one subtype of coronavirus is the virus causing Middle Eastern
respiratory syndrome, and another has been implicated in severe acute respiratory
syndrome.
Adenovirus
 DNA
 Adenovirus most commonly causes pneumonia in people with solid organ
transplantation or hematological transplantation
Enteroviruses
 RNA
 Enteroviruses, although common causes of polio, gastrointestinal, and upper
respiratory tract syndromes, are less common causes of viral pneumonia.
Varicella-zoster virus
 DNA
 Varicella-zoster virus is associated with both chickenpox and shingles and may
cause severe types of pneumonia, particularly in non-immune pregnant women,
non-gravid-adults with chickenpox. It is a fairly common cause of pneumonia in
people with HIV post-shingles outbreak
Hantavirus
 RNA
 Hantavirus is a zoonotic viral pathogen that emerged in the American Southwest
and is associated with rodent feces exposure.
 Hantavirus pneumonia is associated with frequent rapid respiratory failure and
cardiovascular collapse.
ParechovirusesEpstein-Barr virus (EBV)
 DNA
 Epstein-Barr virus, although commonly implicated in mono-like syndromes, can be
rarely associated with viral pneumonia. The majority of which occur in people with
hematological dyscrasias.
Human herpesvirus 6 and 7
 DNA
Herpes simplex virus
 DNA
 HSV I and II are both associated with viral pneumonia in immune-compromised
patients, including those with HIV, solid organ transplantation, and hematopoietic
transplantation.
Minimi virusCytomegalovirus (CMV)
 DNA
 CMV is a significant cause of pneumonia in HIV-infected patients with a CD4 count
less than 100 cells per millimeter squared.
 CMV is also frequently implicated in pneumonia in recipients of solid organ
transplant and hematopoietic transplant.
Measles
 RNA
  A childhood exanthemata’s illness that, although less common in the industrialized
world secondary to vaccination, remains a major contributor to worldwide childhood
mortality secondary to viral pneumonia as a sequela.
Middle East Respiratory Syndrome (Coronavirus)
 RNA
 A subset of the coronavirus associated with severe pneumonia. This was first
observed in the Middle East and had an initial mortality rate of 30%.
Severe Acute Respiratory Syndrome (Metapneumovirus)
 RNA
 A subset of Coronavirus causing life-threatening pneumonia

Epidemiology
A number of epidemiological cues can aid in the diagnosis of viral pneumonia,
including the following:
Age - Viral pneumonia is most common in the very young and in the elderly. There is a
steep decline in the incidence of viral pneumonia from adolescence through the fifth or
sixth decade of life. Then an upsurge as age-related immunosuppression and age-
related pathologies result in immunosuppression increase.[7][8][9]
Pregnancy - Viral pneumonia continues to be quite concerning in pregnancy. Of particular
concern is influenza-related pneumonia secondary to the ubiquitous nature of influenza
from late fall to late spring; the last two major flu epidemics, 1918 and 1957, produced
respective mortality rates of 50% and 10%. This increased mortality is a major factor in the
CDC recommendation that all otherwise healthy women receive an inactivated influenza
virus vaccine during the second and third trimesters of pregnancy. An additional, though
less common, cause of viral pneumonia in pregnant women is varicella. Limited data
reflects a very substantial mortality rate, and current recommendations are for treatment
with varicella-zoster immune globulin within 96 hours of exposure to varicella in a non-
immune gravid female.
Immune competence - Decreased immune competence can be a result of the following:
 Chemotherapy (and/or) radiation therapy for neoplasm
 Treatment of chronic inflammatory illness with immunosuppressive therapy
 Organ transplantation requiring immunosuppressive medications
 Acquired immune incompetence secondary to HIV
 Inherited diseases of diminished immune competency
The aforementioned may result in increased susceptibility to viral pneumonia.
Comorbid circumstances - A number of comorbid circumstances can predispose
patients to viral pneumonia including:
1. Trauma
2. Severe burns
3. Uncontrolled diabetes
4. Malnutrition
5. Poverty
6. Environmental exposure
7. Group living

Pathophysiology
On a macroscopic level, viral pneumonia can occur through one of three mechanisms:
  Direct inoculation of viral particle into the lung (e.g., RSV or influenza)
 Spread in a contiguous fashion from viral infections near the upper respiratory tract
(e.g., measles)
 Hematogenous spread from a distant viral infection (e.g., CMV)
On a microscopic level, the general pattern of viral pneumonia pathogenesis is as follows.
Note that individual viral species causing pneumonia will have some variation from this
scheme.
 The target cell is the pneumocyte with resultant alveolar damage.
 The submucosa of the alveoli is targeted, causing inflammation and secondary
edema, microhemorrhage, and cellular immune reaction.
 The cellular reaction consists of mononuclear lymphocytes and progresses to
PMNs recruitment.
 Fibrin is released.
 Both CD4 and CD8 cells are involved, beginning a cascade of immune product
secretion that can end in increased vascular permeability and resultant edema.
 This process may lead to intra-alveolar organization and an obliterans clinical
picture.
 The far end of the spectrum of the process includes interstitial pneumonia,
pulmonary edema, and cardiogenic shock.

History and Physical

There are no pathognomonic history cues for the diagnosis of viral pneumonia as opposed
to bacterial pneumonia. However, cues are suggestive in the differential diagnosis of viral
pneumonia:
 Gradual onset as opposed to the sudden onset of symptoms.
 Lower temperature
 Lack of purulent sputum
 History of immunosuppression
 Prodromal viral upper respiratory tract illness
 History of HIV
 History of solid organ transplantation or hematopoietic transplantation
 History of neoplasm
 Concomitant flu symptoms
 Concomitant gastrointestinal symptoms
There are no pathognomonic physical examination findings for the diagnosis of viral
pneumonia as opposed to bacterial pneumonia. However, physical findings are suggestive
in the differential diagnosis of viral pneumonia:
 Tachycardia or tachypnea out of proportion to the temperature
 Temperature elevation disproportionately low to the level of debility
 Concomitant upper respiratory tract infection
 Rash
 The paucity of physical findings on pulmonary exam disproportionate to the level of
debility
 Bilateral positive lung findings
Evaluation
As noted above, both history and physical examination may provide few diagnostic cues
as to the etiology of pneumonia (bacterial versus virus). With the existence of specific
effective treatment modalities, diagnoses of and identification of viruses causing
pneumonia is of increased importance. Fortunately, the diagnostic acuity of laboratory
examination in combination with radiography and history and physical examination has
progressed.[10][11][12] Laboratory Examination CBC with differential - There are no
absolute diagnostic findings as viral pneumonia may result in elevated, normal, or
decreased WBC counts. However, viral etiology is less commonly associated with
elevated WBC and "left shifts" of the differential than bacterial types of
pneumonia. Chemistry panel - Useful for gauging the degree of dehydration, relative
renal dysfunction, and dosing of renal excreted medications C-reactive protein - As a
reactive phase reactant, the CRP level may be elevated with viral pneumonia, although
this is not a specific or sensitive finding. ELISA - rapid antigen tests - ELISA tests allow
real-time data for a number of viral pneumonia pathogens. Commonly available ELISA
tests include the following:
 Herpes simplex virus (HSV)
 Respiratory syncytial virus (RSV)
 Influenza A and B
 Cytomegalovirus (CMV)
A caveat is that many viruses may be detected via ELISA in the presence of other known
bacterial pathogens, and in some cases, the detection of a viral pathogen does not always
indicate active disease. Gene amplification - First and second-generation PCR testing
exists and may allow viral pneumonia etiology diagnosis within clinically relevant
timing. Clinically available tests using PCR methodology include the following:
1. CMV
2. RSV
3. HPV
4. Coronal viruses
Cytological evaluation - No single cytological evaluation of patient tissue cells is entirely
diagnostic for viral pneumonia. However, the generalization can be made that DNA
viruses typically produce intra-nuclear inclusions, and RNA viruses typically produce
cytoplasmic inclusions. Viral culture - Although viral cultures are the gold standard for
the final diagnosis of viral pneumonia, there are limitations such as the following:
 Viral cultures are routinely not available for 10 to 15 days, which limits them for
acute clinical care decisions.
 The cultures are very dependent on obtaining a valid specimen.
 The success of delivering a viable specimen to the lab varies as many of the
viruses have very specific transport requirements.
 The fastidious nature of some viral pathogens limits the validity of a negative
culture result.
Viral antigens serology - The great majority of the viral entities involved in viral
pneumonia have serological markers that can be obtained in the tract. Diagnostic
problems include positive serology obtained for people with chronic viral infections that are
not a factor in the presence of pneumonia and the limited use in acute treatment and
decision making of viral pneumonia. Chest x-ray - As there is a tremendous overlap in
findings on chest x-ray with both bacterial pneumonia and viral pneumonia, no one
finding or set of findings is pathognomonic.
Features that are suggestive of bacterial pneumonia include the following:
 Alveolar infiltrates
 Lobar consolidation
 Nodular densities
 Pleural effusion
Features that are more suggestive of viral pneumonia include the following:
 Interstitial infiltrates
 Patchy distribution of interstitial infiltrates
 Bilateral infiltrates
 Pneumonia-like syndrome with an unremarkable chest x-ray
Chest CT scan - The advent of thin-section CT scan has revolutionized the radiographic
diagnosis of viral pneumonia. It has been observed, particularly in cases of viral
pneumonia-like clinical presentation and normal chest radiography, thin-section CT scan
will be positive for parenchymal defects and aid in diagnosis.

Treatment / Management
The cornerstone of treatment of viral pneumonia consists of the following: Supportive
Care
 The first priority of supportive care is to maintain oxygenation as needed. This may
entail nasal cannula, noninvasive airway, or mechanical ventilation.
 The second priority of supportive care is to maintain hydration either via supervised
oral intake or intravenous fluids.
 The third priority of supportive care is to maintain rest and decrease oxygen
demand.
 A final priority of supportive care is to meet the increased calorie needs of the
patient, secondary to the increased respiratory effort.
Management of Comorbid Illnesses Appropriate treatment of Coexisting Bacterial
Types of Pneumonia
Most current evidence indicates the frequent existence of concomitant bacterial types of
pneumonia. The prototypical example is the observation that the majority of mortality
during the 1917-1918 influenza pandemic was secondary to bacterial pneumonia,
superimposed on the initial influenza pneumonia.[13][14][15]
Specific antiviral therapy for a number of viral pneumonia exists as does preventative or
prophylactic therapies for those at high risk would have been exposed:
Influenza virus
 Treatment: Oseltamivir or peramivir or zanamivir
 Prophylaxis: Influenza vaccine and/or chemoprophylaxis with zanamivir or
oseltamivir
Respiratory syncytial virus (RSV)
 Treatment: Ribavirin
 Prophylaxis: RSV immunoglobulin and/or palivizumab
Parainfluenza virus
 Treatment: Ribavirin
 Prophylaxis: Not available
Herpes simplex virus (HSV)
  Treatment: Acyclovir
 Prophylaxis: Not available
Adenovirus
 Treatment: Ribavirin
 Prophylaxis: Not available
Measles virus
 Treatment: Ribavirin
 Prophylaxis: intravenous immunoglobulin
Cytomegalovirus (CMV)
 Treatment: Ganciclovir or foscarnet
 Prophylaxis: intravenous immunoglobulin
Varicella-zoster virus (VZ)
 Treatment: Acyclovir
 Prophylaxis: Varicella-zoster immunoglobulin (VZIG)

Differential Diagnosis
The differential diagnosis for viral pneumonia is broad and includes the following:
 Bacterial pneumonia
 Bacterial or viral bronchitis
 Fungal pneumonia
 Lipoid pneumonia
 Sarcoidosis
 Amyloidosis
 Pulmonary edema
 Congestive heart failure
 Pulmonary embolism
 Pulmonary hypertension
 Pulmonary fibrosis
 Hyperreactive airway disease

Prognosis
Multiple variables determine the prognosis of each case of viral pneumonia, such as the
following:
 The relative for virulence of the species of infecting virus-for example, hantavirus,
SARS, or MERS carries a much worse prognosis than RSV or influenza virus.
 The immune competence of the patient such that immune impaired patients with
HIV carry a much worse prognosis than a gravid female or a previously well,
immuno-competent baby.
 The underlying pathologies of the patient, such as the presence of COPD,
congestive heart failure, diabetes, cancer, and/or hematological dyscrasias,
greatly increases the anticipated morbidity and mortality.
 The presence or absence of concomitant bacterial infection
 The relative point during the infective process at which diagnosis was made and
definitive treatment started (if available).

Complications
Complications of viral pneumonia include the following:
 1. Concomitant bacterial infection, resulting in an abscess, empyema, and or pleural
effusion
2. Sepsis with secondary multiple organ failure
3. Acute respiratory failure
4. Cardiovascular collapse
5. Acute respiratory distress syndrome

Consultations
 Consultation with infectious disease specialists can be useful in both ascertaining
the etiology of viral pneumonia and its relative clinical role if bacterial co-infection is
suspected.
 Consultation with a pulmonary/critical care physician is advisable if the patient is
hypoxic or requires advanced airway or placement in a critical care setting.

Deterrence and Patient Education

Patient education and preventative medicine play a key role in the clinical management of
viral pneumonia:
1. Education to promote universal vaccination against measles and varicella
2. Education to promote appropriate influenza vaccination and post-exposure
prophylaxis
3. Education of prenatal patient's about influenza and varicella immunity
4. HIV prevention and CD4 count surveillance with appropriate prophylaxis
5. Education and surveillance of the chronically immunosuppressed, including
those receiving chemotherapy, radiation therapy, immunosuppressive drugs

Pearls and Other Issues

 The role of viruses in primary pneumonia is increasing, and viral respiratory
pathogens are increasingly recognized as a cofactor in bacterial pneumonia
secondary to the increasing prevalence of immunosuppression-cancer treatment,
organ transplant, and HIV.
 Prevention, especially in the form of immunization against influenza and measles,
can significantly decrease the incidence of viral pneumonia.
 Increasingly, specific and sensitive real-time diagnostic laboratory tools are
available in the form of ELISA and PCR modalities for the specific diagnosis of viral
pneumonia and assignment of specific treatment when existent.
 Although there are no pathognomonic history or physical findings for viral
pneumonia as opposed to bacterial pneumonia, there are a number of clinical cues
that are quite suggestive.
 Although specific antiviral agents do exist, the cornerstone of treatment for viral
pneumonia remains supportive care.

Enhancing Healthcare Team Outcomes

An interprofessional team of healthcare workers manages viral pneumonia. While
physicians may treat the infection, the role of the nurse and pharmacist are vital for
prevention. The patient should be urged to get the annual influenza vaccine, as this can
lower the morbidity and mortality. Pharmacists review prescriptions for dose and
interactions and educate patients about side effects and the importance of compliance. All
patients should be urged to quit smoking and abstain from alcohol. Further, patients
should be educated about hand and personal hygiene to prevent transmission of the virus
to others. Patients who are immunocompromised should be educated about the
symptoms of pneumonia and when to seek medical care. Finally, patients should be urged
to lead a healthy lifestyle, eat healthily, and exercise regularly. Close communication
between the interprofessional team is essential if one wants to improve
outcomes. [16][9] (Level 5)

Outcomes
The outcomes in most healthy people with viral pneumonia are excellent. However, in
individuals who are immunocompromised or at extremes of age, the prognosis is guarded.
Several adenovirus serotypes are known to cause severe pneumonia leading to
bronchiectasis and irreversible atelectasis. It is estimated that anywhere from 10%-40% of
children may suffer some irreversible lung damage after adenovirus pneumonia. Viral
pneumonia in a patient with an underlying disease can add morbidity and lead to marked
hypoxia. Overall, most patients recover with supportive measures and have no residual
sequelae. [17][18](Level 5)

C. Pediatric Pneumonia

Globally, pneumonia is a leading cause of morbidity and mortality in children younger

than the age of 5 years.[1] Although the majority of deaths attributed to pneumonia in
children are mostly in the developing world, the burden of disease is substantial, and there
are significant healthcare-associated costs related to pneumonia in the developed
world.[2]

Etiology
The etiology of pneumonia in the pediatric population can be classified by age-specific
versus pathogen-specific organisms.[3] Neonates are at risk for bacterial pathogens
present in the birth canal, and this includes organisms such as group B
streptococci, Klebsiella, Escherichia coli, and Listeria
monocytogenes.[4][5][6] Streptococcus pneumoniae, Streptococcus
pyogenes, and Staphylococcus aureus can be identified in late-onset
neonatal pneumonia.[4] Viruses are the main cause of pneumonia in older infants and
toddlers between 30 days and 2 years old.[7] In children 2 to 5 years old, respiratory
viruses are also the most common.[8][9] The rise of cases related to S. pneumoniae and
H. influenzae type B is observed in this age
group.[10][11] Mycoplasma pneumonia frequently occurs in children in the range from 5
to 13 years old[12][13]; however, S. pneumoniae is still the most commonly identified
organism.[8] Adolescents usually have the same infectious risks as adults. It is important
to consider tuberculosis (TB) in immigrants from high prevalence areas, and children with
known exposures. Children with chronic diseases are also at risk for specific pathogens.
In cystic fibrosis, pneumonia secondary to S. aureus and Pseudomonas aeruginosa is
ubiquitous.[14] Patients with sickle cell disease are at risk of infection from encapsulated
organisms.[15] Children who are immunocompromised should be evaluated
for Pneumocystis jirovecii, cytomegalovirus, and fungal species if no other organism is
identified.[16] Unvaccinated children are at risk for vaccine-preventable pathogens.
Epidemiology
There are an estimated 120 million cases of pneumonia annually worldwide, resulting in
as many as 1.3 million deaths.[3] Younger children under the age of 2 in the developing
world, account for nearly 80% of pediatric deaths secondary to pneumonia.[17] Prognosis
of pneumonia is better in the developed world, with fewer lives claimed, but the burden of
disease is extreme, with roughly 2.5 million cases yearly. Approximately a third to half of
these cases lead to hospitalizations.[18]
The introduction of the pneumococcal vaccine has significantly lowered the risk
of pneumonia in the United States.

Pathophysiology
Pneumonia is an invasion of the lower respiratory tract, below the larynx by pathogens
either by inhalation, aspiration, respiratory epithelium invasion, or hematogenous
spread.[19] There are barriers to infection that include anatomical structures (nasal hairs,
turbinates, epiglottis, cilia), and humoral and cellular immunity.[19] Once these barriers
are breached, infection, either by fomite/droplet spread (mostly viruses) or
nasopharyngeal colonization (mostly bacterial), results in inflammation and injury or death
of surrounding epithelium and alveoli. This is ultimately accompanied by a migration of
inflammatory cells to the site of infection, causing an exudative process, which in
turn impairs oxygenation.[20] In the majority of cases, the microbe is not identified, and
the most common cause is of viral etiology.
There are four stages of lobar pneumonia. The first stage occurs within 24 hours and is
characterized by alveolar edema and vascular congestion. Both bacteria and neutrophils
are present.
Red hepatization is the second stage, and it has the consistency of the liver. The stage is
characterized by neutrophils, red blood cells, and desquamated epithelial cells. Fibrin
deposits in the alveoli are common.
The third of gray hepatization stage occurs 2-3 days later, and the lung appears dark
brown. There is an accumulation of hemosiderin and hemolysis of red cells.
The fourth stage is the resolution stage, where the cellula infiltrates is resorbed, and the
pulmonary architecture is restored. If the healing is not ideal, then it may lead to
parapneumonic effusions and pleural adhesions.
In bronchopneumonia, there is often patch consolidation of one or more lobes. The
neutrophilic infiltrate is chiefly around the center of the bronchi.

History and Physical

In many cases, complaints associated with pneumonia are nonspecific, including cough,
fever, tachypnea, and difficulty breathing.[21] Young children may present with abdominal
pain. Important history to obtain includes the duration of symptoms, exposures, travel, sick
contacts, baseline health of the child, chronic diseases, recurrent symptoms, choking,
immunization history, maternal health, or birth complications in neonates.[22]
Physical exam should include observation for signs of respiratory distress, including
tachypnea, nasal flaring, lower chest in-drawing, or hypoxia on room air.[21] Note that
infants may present with reported inability to tolerate feeds, with grunting or apnea.
Auscultation for rales or rhonchi in all lung fields with the appropriately sized stethoscope
can also aid in diagnosis. In the developed world, other adjuncts like laboratory testing
and imaging can be a helpful part of the physical exam. No isolated physical exam finding
can accurately diagnose pneumonia.[23] However, the combination of symptoms,
including fever, tachypnea, focal crackles, and decreased breath sounds together, raises
the sensitivity for finding pneumonia on x-ray.[23] Pneumonia is a clinical diagnosis that
should take into consideration the history of present illness, physical exam findings,
adjunct testing, and imaging modalities.

Evaluation
Laboratory evaluation in children suspected of having pneumonia should ideally start with
non-invasive, rapid bedside testing including nasopharyngeal swab assays for influenza,
respiratory syncytial virus, and human metapneumovirus when available and appropriate.
This can help minimize unnecessary imaging and antibiotic treatment in children with
influenza or bronchiolitis. Children who present with severe disease and appear toxic
should have complete blood count (CBC), electrolytes, renal/hepatic function testing, and
blood cultures performed.[24] These tests are generally not required in children who
present with mild disease. Inflammatory markers do not help distinguish between viral
and bacterial pneumonia in the pediatric population.[24][25] However, these tests may
be obtained to trend disease progression and serve as prognostic indicators. Children who
have been in areas endemic to TB, or have exposure history, and present with signs and
symptoms suspicious for pneumonia should have sputum samples or gastric aspirates
collected for culture.
Sputum gram stain and culture are not productive as the samples are often contaminated
by oral flora. Blood cultures can be done but are often negative. Today, serology is being
used to determine the presence of mycoplasma, legionella, and chlamydia species. PCR
is becoming available in most hospitals, but still, the results take 24-48 hours.
There are no clear guidelines for the routine use of chest x-ray in the pediatric
population.[24] Although the chest x-ray can be helpful in diagnosis and confirmation
of pneumonia,[26] it carries with it risks, including radiation exposure, healthcare-
associated costs, and false-negative results, increasing the use of unwarranted antibiotics.
Imaging should be restricted to children who appear toxic, those with the recurrent or
prolonged course of illness despite treatment, infants age 0 to 3 months with a fever,
suspected foreign body aspiration, or congenital lung malformation. Imaging can also be
considered in children younger than 5 years old, who present with fever, leukocytosis, and
no identifiable source of infection.[26] Imaging may also be useful in those with acute
worsening of upper respiratory infections or to rule out underlying mass in children who
have "round pneumonia."[27][28]

Treatment / Management
Treatment should be targeted to a specific pathogen that is suspected based on
information obtained from history and physical exam. Supportive and symptomatic
management is key and includes supplemental oxygen for hypoxia, antipyretics for fever,
and fluids for dehydration. This is especially important for non-infectious pneumonitis and
viral pneumonia for which antibiotics are not indicated.[21][29] Cough suppressants are
not recommended.
If bacterial pneumonia is suspected, treat empirically with antibiotics, keeping in mind
significant history and bacterial pathogens that are common to specific age groups.
Neonates should receive ampicillin plus an aminoglycoside or third-generation
cephalosporin[21][30], however, not ceftriaxone, as it can displace bound bilirubin and
lead to kernicterus.
Atypical pneumonia is common in infants 1 to 3 months old, and this group should have
additional antibiotic coverage with erythromycin or clarithromycin.[21][30]
For infants and children over 3 months old, S. pneumoniae is the most common, for which
the drug of choice is high-dose oral amoxicillin[21][30] or another beta-lactam antibiotic.
In children older than 5 years old, atypical agents have a more important role,
and macrolide antibiotics are usually first-line therapy.[21]
Special attention should be given to children with chronic illnesses, as these might alter
choices for antibiotics[21]. Children with sickle cell anemia will need cefotaxime,
macrolide, vancomycin if severely ill. Children with cystic fibrosis will require piperacillin or
ceftazidime plus tobramycin. Treat fulminant viral pneumonia as indicated, depending on
the virus identified. For Varicella, use acyclovir and for the respiratory syncytial virus
(RSV), use ribavirin for high-risk patients. Patients with HIV should be treated with
sulfamethoxazole/trimethoprim and prednisone, and for Cytomegalovirus, ganciclovir and
gamma globulin are the preferred agents. If methicillin-resistant Staphylococcus
aureus (MRSA) is suspected, clindamycin or vancomycin may be given.
It is important to have a high index of suspicion for complications, especially in patients
returning for repeat evaluation. For patients sent home with symptomatic or supportive
management for suspected viral pneumonia, consider a secondary bacterial infection or
other diagnoses upon re-evaluation.[31] Children with uncomplicated bacterial infections
who fail to respond to treatment within 72 hours should be assessed for complications,
including pneumothorax, empyema, or pleural effusion.[32] Other systemic complications
of pneumonia include sepsis, dehydration, arthritis, meningitis, and hemolytic uremic
syndrome.
Neonates and infants younger than 90 days old should be hospitalized for treatment, in
addition to children who are immunocompromised or have other underlying chronic
diseases like sickle cell anemia or cystic fibrosis.[21] Children with social factors that
preclude access to care, have failed outpatient therapy, or present with presumed
tuberculosis, should also be hospitalized.[33]
Admission is often required for patients with respiratory distress and low oxygenation. In
most cases, the presence of a parapneumonic effusion requires admission. Children with
severe respiratory distress may require chest therapy, CPAP, or even mechanical
ventilation. A large pleural effusion requires drainage for diagnostic and therapeutic
purposes.
It is essential to ensure that clear discharge instructions and return precautions are given
to parents or caregivers of children being discharged home in addition to close
pediatrician follow-up.

Prognosis
For most children, the prognosis is good. Viral pneumonia tends to resolve without
treatment. Long term sequelae are rare. However, both staphylococcal and
varicella pneumonia have guarded outcomes in children.
Children with tuberculosis are at high risk for disease progression if the condition is not
treated Immunocompromized children have the worst prognosis. Each year, roughly 3
million children die from pneumonia and the majority of these children also have other
comorbidities like congenital heart disease, immunosuppression or chronic lung disease of
prematurity.

Complications
 Empyema
 Pleural effusion
 Lung abscess
 Necrotizing pneumonia
 Sepsis

Enhancing Healthcare Team Outcomes

Pediatric pneumonia is often undertreated or missed, leading to high morbidity and
mortality. The condition is best managed by an interprofessional team to improve
outcomes. The majority of patients are managed by the pediatrician, nurse practitioner, or
primary care provider. Patient and caregiver education is vital. Parents need to be told to
avoid smoking, and the importance of handwashing cannot be overstated. In addition, all
clinicians looking after children should emphasize vaccination against pneumococcus and
influenza.
Healthcare professionals, including physicians, nurses, physician assistants, nurse
practitioners, pharmacists, ideally work together in close environments for optimum patient
care. When caring for children with pneumonia, pharmacists can be of significant help
with geographic resistance patterns for better treatment outcomes with selected antibiotic
choices.
Caregivers should be educated about signs of respiratory difficulty and when to seek
medical assistance. Only through a team approach can pneumonia in children be treated
promptly with minimal morbidity.

4. Global Pandemic Control WHO

In nature, influenza viruses circulate continuously among animals, especially birds.

Even though such viruses might theoretically develop into pandemic viruses, in Phase
1 no viruses circulating among animals have been reported to cause infections in
humans.
In Phase 2 an animal influenza virus circulating among domesticated or wild animals is
known to have caused infection in humans, and is therefore considered a potential
pandemic threat.
In Phase 3, an animal or human-animal influenza reassortant virus has caused
sporadic cases or small clusters of disease in people, but has not resulted in human-to-
human transmission sufficient to sustain community-level outbreaks. Limited human-to-
human transmission may occur under some circumstances, for example, when there is
close contact between an infected person and an unprotected caregiver. However,
limited transmission under such restricted circumstances does not indicate that the
virus has gained the level of transmissibility among humans necessary to cause a
pandemic.
Phase 4 is characterized by verified human-to-human transmission of an animal or
human-animal influenza reassortant virus able to cause “community-level outbreaks.”
The ability to cause sustained disease outbreaks in a community marks a significant
upwards shift in the risk for a pandemic. Any country that suspects or has verified such
an event should urgently consult with WHO so that the situation can be jointly assessed
and a decision made by the affected country if implementation of a rapid pandemic
containment operation is warranted. Phase 4 indicates a significant increase in risk of a
pandemic but does not necessarily mean that a pandemic is a forgone conclusion.
Phase 5 is characterized by human-to-human spread of the virus into at least two
countries in one WHO region. While most countries will not be affected at this stage,
the declaration of Phase 5 is a strong signal that a pandemic is imminent and that the
time to finalize the organization, communication, and implementation of the planned
mitigation measures is short.
Phase 6, the pandemic phase, is characterized by community level outbreaks in at
least one other country in a different WHO region in addition to the criteria defined
in Phase 5. Designation of this phase will indicate that a global pandemic is under way.
During the post-peak period, pandemic disease levels in most countries with adequate
surveillance will have dropped below peak observed levels. The post-peak period
signifies that pandemic activity appears to be decreasing; however, it is uncertain if
additional waves will occur and countries will need to be prepared for a second wave.
Previous pandemics have been characterized by waves of activity spread over months.
Once the level of disease activity drops, a critical communications task will be to
balance this information with the possibility of another wave. Pandemic waves can be
separated by months and an immediate “at-ease” signal may be premature.
In the post-pandemic period, influenza disease activity will have returned to levels
normally seen for seasonal influenza. It is expected that the pandemic virus will behave
as a seasonal influenza A virus. At this stage, it is important to maintain surveillance
and update pandemic preparedness and response plans accordingly. An intensive
phase of recovery and evaluation may be required.
 5. Describe several types of viral pneumonia. Virus-virus apa saja yang dapat
menyebabkan Pneumonia atau Respiratory Tract Infection? (e.g. RSV, CMV,
Varicella (Chickenpox), Corona Virus, Avian Flu, Spanish Flu, Flu Babi)

ILLNESSES ASSOCIATED WITH RESPIRATORY VIRUSES

Frequency of Respiratory Syndromes
Virus Most Frequent Occasional Infrequent
Rhinoviruses Common cold Exacerbation of Pneumonia in children
chronic bronchitis
and asthma
Coronavirusesa,b Common cold Exacerbation of Pneumonia and
chronic bronchitis bronchiolitis
and asthma
Human respiratory Pneumonia and Common cold in Pneumonia in elderly and
syncytial virus bronchiolitis in young adults immunosuppressed pts
children
Parainfluenza Croup and lower Pharyngitis and Tracheobronchitis in
viruses respiratory tract common cold adults; lower respiratory
 Frequency of Respiratory Syndromes
Virus Most Frequent Occasional Infrequent
disease in young tract disease in
children immunosuppressed pts
Adenoviruses Common cold and Outbreaks of acute Pneumonia in children;
pharyngitis in children respiratory disease in lower respiratory tract
military recruitsc and disseminated
disease in
immunosuppressed pts
Influenza A viruses Influenzad Pneumonia and Pneumonia in healthy
excess mortality in individuals
high-risk pts
Influenza B viruses Influenza d Rhinitis or pharyngitis Pneumonia
alone
Enteroviruses Acute undifferentiated Rhinitis or pharyngitis Pneumonia
febrile illnessese alone
Herpes simplex Gingivostomatitis in Tracheitis and Disseminated infection in
viruses children; pneumonia in immunocompromised pts
pharyngotonsillitis in immunocompromised
adults pts
Human Upper and lower Upper respiratory Pneumonia in elderly and
metapneumoviruses respiratory tract tract illness in adults immunosuppressed pts
disease in children
aSevere acute respiratory syndrome–associated coronavirus (SARS-CoV) caused

epidemics of pneumonia from November 2002 to July 2003 (see text).

bMiddle East respiratory syndrome coronavirus (MERS-CoV) has caused severe

respiratory illnesses from 2012 to the time of this writing (2015); see text.
cSerotypes 4 and 7 most commonly; also serotypes 14 and 21.
dFever, cough, myalgia, malaise.
eMay or may not have a respiratory component.

Comparison of Viruses That Infect the Human Respiratory Tract

Lifelong
Number of Vaccine Viral
Virus Disease Immunity to
Serotypes Available Latency
Disease
RNA viruses
Influenza A virus Influenza Many No + −
Metapneumovirus Croup, Several No − −
bronchiolitis
Parainfluenza virus Croup Many No − −
Respiratory Bronchiolitis, Two No − −
syncytial virus pneumonia
Rubella virus Rubella One Yes + −
Measles virus Measles One Yes + −
Mumps virus Parotitis, One Yes + −
meningitis
 Lifelong
Number of Vaccine Viral
Virus Disease Immunity to
Serotypes Available Latency
Disease
Rhinovirus Common cold Many No − −
Coronavirus Common cold Many No − −
Coxsackievirus Herpangina, Many No − −
pleurodynia
DNA viruses
Herpes simplex Gingivostomatitis One No − +
virus type 1
Epstein-Barr virus Infectious One Yes − +
mononucleosis
Varicella-zoster Chickenpox, One Yesa + +
virus shingles
Adenovirus Pharyngitis, Many No − +
pneumonia

Viral transmission
The mechanism of viral transmission varies with the type of virus. Routes include large-
droplet spread over short distances (< 1 m), hand contact with contaminated skin and
fomites and subsequent inoculation onto the nasal mucosa or conjunctiva (eg, rhinovirus,
RSV), and small-particle aerosol spread (eg, influenza, adenovirus). Some viruses are
extremely fastidious, whereas others have the capability of surviving on environmental
surfaces for as long as 7 hours, on gloves for 2 hours, and on hands for 30 minutes.
Transmission routes for selected viral pneumonias are as follows:
 Environmental factors (adenovirus, enterovirus, rhinovirus)
 Direct contact with contaminated objects (VZV)
 Transplantation of contaminated organs (cytomegalovirus [CMV]) or blood products
(CMV)
  Lower-respiratory aspiration of virus asymptomatically shed in the saliva (CMV,
herpes simplex virus [HSV])
 Reactivation of a latent infection (HSV, CMV)
 Hematogenous spread (CMV)
 Spread by healthcare personnel (SARS, measles, adenovirus, parainfluenza virus,
RSV).
Hantavirus transmission is thought to occur primarily through inhalation of infected excreta
from diseased rodents. The virus is also present in rodent saliva, so transmission can also
occur from bites.
A number of viruses, including adenoviruses, influenza virus, measles virus, PIV, RSV,
rhinoviruses, and VZV, are easily transmitted during hospital stays and cause nosocomial
pneumonia. Adenoviruses, influenza viruses, PIV, and RSV account for 70% of
nosocomial pneumonias due to viruses.

Etiology
Both DNA and RNA viruses are involved in the etiology of viral pneumonia. Some are
well-known lung pathogens that produce common clinical and radiologic manifestations.
Others are rarely involved as lung pathogens.
Etiologic viruses include various families, as follows:
 Adenoviridae ( adenoviruses)
 Coronaviridae (coronaviruses) - SARS, MERS, 2019 novel coronavirus (2019-
nCoV) [14]
 Bunyaviridae (arboviruses) - Hantavirus
 Orthomyxoviridae (orthomyxoviruses) - Influenza virus
 Papovaviridae (polyomavirus) - JC virus, BK virus
 Paramyxoviridae (paramyxoviruses) - Parainfluenza virus (PIV), respiratory syncytial
virus (RSV), human metapneumovirus (hMPV), measles virus
 Picornaviridae (picornaviruses) - Enteroviruses, coxsackievirus, echovirus,
enterovirus 71, rhinovirus
 Reoviridae ( rotavirus)
 Retroviridae (retroviruses) - Human immunodeficiency virus (HIV), human
lymphotropic virus type 1 (HTLV-1)
Most of the members of Herpesviridae family are documented lung pathogens in hosts
with compromised cell immunity and include the following:
o Herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2), also called
human herpesvirus 1 (HHV-1) and human herpesvirus 2 (HHV-2), respectively
o Herpesvirus 6, herpesvirus 7, and herpesvirus 8
o Varicella-zoster virus (VZV)
o Cytomegalovirus (CMV)
o Epstein-Barr virus (EBV)
Influenza virus, respiratory syncytial virus, adenovirus, parainfluenza virus, coronavirus,
rhinovirus, and human metapneumovirus may cause community-acquired viral
pneumonia.
Influenza virus
The influenza viruses are enveloped, single-stranded, RNA viruses of the family
Orthomyxoviridae and are the most common viral cause of pneumonia. Three serotypes
of influenza virus exist: A, B, and C.
Influenza type A can alter surface antigens and infect livestock. This characteristic may
account for its ability to create a reservoir for infection and cause epidemics in humans.
The virus is spread by means of small-particle aerosol and targets the columnar epithelial
cells along the entire respiratory tract.
Influenza type B causes illness that usually is seen in relatively closed populations such
as boarding schools. Influenza type C is less common and occurs as sporadic cases.
Influenza type A is usually the most virulent pathogen. The influenza virus has two
envelope glycoproteins, hemagglutinin (H) and neuraminidase (N), which are important for
a number of reasons. The hemagglutinin initiates infectivity by binding to cellular sialic
acid residues, whereas the N protein cleaves newly synthesized virus from sialic acid on
cell surfaces, thus allowing spread of the virus to other cells.

The influenza virus maintains its infectivity by undergoing antigenic drift (small number of
amino acid substitutions) and shift (large number of amino acid substitutions) due to
changes in the protein structure of the surface protein, hemagglutinin. Epidemics occur
when a viral drift occurs, and pandemics are seen with viral shift (two influenza A viruses
exchange H or N genes during infection of the same hosts) because most people have no
prior immunity to the virus.
Two influenza types have emerged of particular importance: H5N1 avian influenza strain
and the novel H1N1 swine influenza strain.
Respiratory syncytial virus
Respiratory syncytial virus (RSV) is the most frequent cause of lower respiratory tract
infection among infants and children and the second most common viral cause of
pneumonia in adults. It is a medium-sized virus of the Paramyxoviridae family that
consists of only 1 serotype. Structurally, RSV has 10 unique viral polypeptides, 4 of which
are associated with virus envelope, and 2 of these (F and G) are important for infectivity
and pathogenicity. Classic RSV infection causes syncytia formation in cell culture, giving
the virus its name.
RSV is highly contagious, spreading via droplet and fomite exposure. Most children are
infected before age 5 years—the infection rate during an epidemic approaches 100% in
certain settings such as daycare centers—but the resulting immunity is incomplete.
Reinfection in older children and young adults is common but mild. However, the
likelihood of more severe disease and pneumonia increases with advancing age.

Respiratory Syncytial Virus (RSV). This virus is distributed worldwide and is found
wherever it has been sought. It is the leading cause of bronchiolitis and the most
commonly detected virus in children under 2 years of age hospitalized for lower
respiratory infection. It is estimated that half of all children are infected during the first year
of life, and that by 3 years of age all have experienced at least one infection. Immu- nity
following primary infection does not prevent secondary or subsequent infections, caused
by both antigenic differences and failure of RSV to induce (persistent) neutralizing
antibod- ies. In temperate regions, large seasonal epidemics occur annu- ally over cold
winter months, but this seasonality is more variable in the tropics (see below). Two
subtypes (A and B) have been described and may co-circulate, with one usually predomi-
nating in any given year. No obvious differences in disease severity or pathogenesis have
been documented between these two subtypes.
RSV causes a substantial but variable LRTI disease burden in tropical countries. In a
population-based study of infants in Kenya, it was found that RSV was common;
approximately 36% of infections led to LTRI, 23% were severe and 3% of infected children
were hospitalized. RSV was also the most commonly detected respiratory pathogen in
hospitalized children in Vietnam. More recently, it has become clear that RSV causes
significant morbidity in the elderly as well as in infants.

Adenoviruses
Adenoviruses are enveloped DNA viruses that cause a wide spectrum of clinical illnesses
depending on the serotype of the infecting agent. These include asymptomatic illness,
conjunctivitis, febrile upper respiratory disease, pneumonia, gastrointestinal illness,
hemorrhagic cystitis, rash, and neurologic disease. Pneumonia is less common in adults
outside of military recruit camps and similar facilities, but fulminant disease has been
described in infants and in the immunocompromised population and can occur in
apparently healthy hosts. [15]
Although 52 serotypes exist, classified into 7 subgroups or species (A-G), pulmonary
disease is predominantly caused by serotypes 1, 2, 3, 4, 5, 7, 14, and 21. Type 7 viruses
can cause bronchiolitis and pneumonia in infants. Types 4 and 7 viruses are responsible
for outbreaks of respiratory disease in military recruits.
Adenovirus serotype 14 (subgroup B) is a more virulent strain that has been reported to
cause severe respiratory illness and pneumonia. Emergence of this strain was reported in
2005 among civilian and military populations, with outbreaks occurring subsequently at
military training centers throughout the United States.
In 2007, adenovirus serotype 14 caused a large, sustained outbreak of febrile respiratory
illness among military trainees in Texas and, more recently, in a residential care facility in
Washington State. [16, 17, 18] In a community outbreak in Oregon, the median age was 52
years, and 76% required hospitalization, 47% required critical care, 24% required
vasopressors, and 18% died. The majority of these patients were otherwise
immunocompetent adults. [19]
Spread of adenovirus is by respiratory secretions, infectious aerosols, feces, and fomites.
Neonates may acquire infection from exposure to cervical secretions at birth.
Contaminated environmental surfaces can harbor virus capable of causing infection for
weeks. The virus is resistant to lipid disinfectants but is inactivated by heat, formaldehyde,
and bleach.
Adenoviruses are extremely contagious. Studies of new military recruits have shown
seroconversion rates of 34-97% over a 6-week period. [16] The majority of children have
serologic evidence of prior adenovirus infection by the age of 10.
Parainfluenza virus
Parainfluenza virus (PIV) is a common virus that infects most persons during childhood.
PIV is second in importance to only RSV in causing lower respiratory tract disease in
children and pneumonia and bronchiolitis in infants younger than six months.
Transmission is through direct person-to-person contact or large-droplet spread.
PIV is characterized by nucleocapsids, which develop in the cytoplasm of infected cells,
with hemagglutinin present in the virion envelope.
There are four subtypes of PIV, based on antigenic characteristics. PIV type 3 is endemic
year-round, while types 1 and 2 peak during the fall season. Immunity is short term, and
recurrent upper or lower respiratory tract infections occur throughout life. The infections
vary from a mild illness to life-threatening croup, bronchiolitis, or pneumonia. Infection in
immunocompromised hosts can result in life-threatening pneumonia with lung injury and
respiratory failure. In one study, 44% of hematopoietic stem cell transplant (HSCT)
patients with PIV progressed to develop pneumonia, of which 37% died. [20]
Rhinovirus
Some authors report that rhinovirus accounts for up to 30% of cases of all virus-related
pneumonia. Clinical studies show that rhinovirus is the second most frequently recognized
agent associated with pneumonia and bronchiolitis in infants and young children.
Rhinovirus infection is linked to asthma hospitalizations in both adults and children.
A study of 211 French children with rhinovirus infection revealed bronchiolitis or bronchitis
in 25.6% and pneumonia in 6.2%, after cases of dual bacterial or viral infections were
eliminated.
A study from the Netherlands demonstrated that rhinoviruses cause 32% of all lower
respiratory tract infections with an identified pathogen in the elderly (> 60 y) symptomatic
population. Rhinoviruses were identified more frequently than coronaviruses (17%) or
influenza viruses (7%).

1. Picornaviridae, non-enveloped, ssRNA

2. 3 genetic species: HRV-A, HRV-B, HRV-C
3. grow preferentially at 33-34 C (temp. of the human nasal passages)
4. Epid: infants and young children (throughout year, seasonal peaks in early fall and
spring)
5. Transmission: respiratory droplets (hand-to-hand  conjunctival or nasal mucosa)
6. Incubation period: 1-2 days
7. SS: common cold (rinorrhea, sneezing, nasal congestion, sore throat (malaise,
headache, fever)
8. Dx: clinical or PCR
9. Tx: SL or antihistamine or NSAIDs (if necessary)
Rhinoviruses. Virology and clinical textbooks and virtually all web-based information
sources describe the 99 serotypes of human rhinovirus (HRVs) as the most frequent
cause of the common cold, in both the developed and the developing world. Although the
common cold is considered a trivial illness, it is an important disease worldwide in terms of
morbidity and economic impact.
In addition to causing the common cold, there is now con- vincing evidence that HRVs
play a significant role in causing lower respiratory symptoms. HRVs can replicate in the
lower airways and do appear to play a critical role in causing exacerba- tions of asthma
and other chronic lung diseases. They can also drive the infant immune system towards
the asthmatic pheno- type, and cause episodes of bronchiolitis and pneumonia that
require hospitalization.
Until a few years ago, only two groups of HRVs (A and B) were recognized, but
sequencing of HRVs led to the discovery of a third species (HRV-C) in 2006, with distinct
structural, biological and possibly also clinical features.
Other Picornaviridae. The over 100 serotypes of enterovirus (coxsackie A and B viruses,
echoviruses and enteroviruses 68–71) are mainly transmitted by the oral–faecal route but
can be transmitted by respiratory droplets. Enteroviruses are a major cause of aseptic
meningitis in children and adults, but are also associated with common cold, herpangina in
children and large epidemics of acute haemorrhagic conjunctivitis and hand, foot and
mouth disease. Similarly, parechoviruses are another common cause of aseptic
meningitis, but are also implicated as frequent causes of (mild) respiratory illness.

Human metapneumovirus
Human metapneumovirus (hMPV) is a relatively newly discovered respiratory pathogen,
initially described in the Netherlands in 2001. [21] hMPV is in the Paramyxoviridae family
(like RSV and PIV) and is a pleomorphic-shaped virus surrounded by surface protein
projections. This virus is a ubiquitous organism, and most surveys indicate that by age five
years, almost all children have been exposed to it. However, reinfection occurs throughout
life, including in adults. This virus is spread via droplet and fomite exposure.
As a human pathogen, hMPV may have been underestimated. In children and infants,
hMPV was reported to be a notable cause of lower respiratory tract infections such as
bronchiolitis (59%), croup (18%), asthma (14%), and pneumonia (8%).
As with other viruses, the severity of infection increases with older age and with comorbid
(cardiopulmonary disease) or immunosuppressive conditions. The most common
diagnoses associated with adult hospitalizations with hMPV infection are chronic
obstructive pulmonary disease (COPD) exacerbations, bronchitis, and pneumonia. [22] In
immunocompromised hosts (eg, hematologic malignancies), severe pneumonitis requiring
intensive care or resulting in death has been reported. [23, 24]
Coronavirus
Coronaviruses are from the family Coronaviridae and are single-stranded RNA viruses,
the surface of which is covered by crownlike projections, giving the virus its name. This
virus is spread via droplet and fomite exposure. Long known to cause upper respiratory
infections, coronaviruses were not felt to significantly cause pneumonia until relatively
recently. However, the severe acute respiratory syndrome (SARS) pandemic in 2003
brought the ability of this virus to cause life-threatening pneumonia to worldwide attention
(see Zoonotic Viral Pneumonia, below).
Seven human coronaviruses (HCoVs) have now been identified: HCoV-229E, HCoV-
OC43, HCoV-NL63, HCoV-HKU1, SARS-COV (which causes severe acute respiratory
syndrome), MERS-COV (Middle East respiratory syndrome), and 2019-nCoV. All but
2019-nCoV appear to be established human pathogens with worldwide distribution,
causing upper and lower respiratory tract infections, especially in children. Typically,
HCoV infection follows a seasonal pattern similar to that of influenza, although Hong Kong
researchers found that HCoV-NL63 infections mainly occurred in early summer and
autumn. [25]
A novel coronavirus (2019-nCoV) was first reported in late 2019 and early 2020 in
China. [14]

10. ssRNA, crown-like appearance

11. 4 genera: Alphacoronavirus, Betacoronavirus (Severe acure Respiratory syndrome
coronavirus/ SARS-CoV and Middle East Respiratory syndrome/ MERS-CoV)
12. Transmissions: aerosol, fecal-oral
Coronaviruses. Human coronavirus (HCoV) strains 229E and OC43 have been long
recognized as the second main cause of the common cold (10–25%). More recently, two
other viruses associated with similar presentation were detected in humans: NL63 and
HKU1. These four viruses are ubiquitous and regularly detected in respiratory specimens
of a small proportion (1–10%) of children hospitalized with acute respiratory disease in
many parts of the world. Infection with these human coronaviruses may present as an
upper respiratory tract infection, asthma exacerbation, acute bronchiolitis, pneumonia,
febrile seizures and also as croup (especially NL63). Reinfection is common due to rapidly
decreasing antibody levels.

In 2002–2003, a novel severe form of pneumonia of unknown aetiology emerged in

Guangdong, China and was named severe acute respiratory syndrome (SARS). The
rapidly identified culprit, SARS coronavirus, is thought to have jumped to humans in live
animal markets in Guang- dong. The precursor virus is present in wild Rhinolophus
bats.Civet cats and other small mammals sold as delicacies in wet markets provided a
reservoir and amplifier for the virus and the opportunity for adaptation to humans. SARS
was characterized by fever and myalgia rapidly pro- gressing to a respiratory syndrome of
cough, dyspnoea followed by acute respiratory distress syndrome. Mortality was signifi-
cantly lower in children.
SARS is primarily spread by the respiratory route, but oral– faecal transmission has also
been implicated. Why the SARS epidemic did not continue to spread is subject to much
specula- tion. Explanations may include the fact that SARS is most infec- tious in a later
stage of infection, allowing for timely containment, and an extraordinary worldwide public
health effort to control spread.
With the new interest in coronaviruses, more and more closely related coronaviruses from
distantly related animals have been discovered, many of which were the result of recent
interspecies jumping. Coronaviruses are implicated as a likely candidate for future
outbreaks of zoonotic diseases, and - indeed - a novel coronavirus (EMC) is currently
associated with sporadic transmission to humans in the middle-east.
Varicella-zoster virus
Varicella-zoster virus (VZV) is a highly contagious herpes virus that is spread by the
respiratory route or direct contact with skin lesions. Primary infection manifests as
chickenpox. The reactivation results in zoster (shingles).
Pneumonia is a significant and life-threatening complication in otherwise healthy adults
(including pregnant women) and immunocompromised hosts. This pneumonia is rare in
otherwise healthy children but does occur in immunocompromised children.
Complications include secondary bacterial infections, encephalitis, hepatitis, and, with
concomitant aspirin use, Reye syndrome. VZV pneumonia also tends be more severe in
individuals who smoke.
Measles virus
Measles virus is a member of the Paramyxoviridae family and the genus Morbillivirus. It is
a single-stranded RNA virus contained within a nucleocapsid and surrounded by an
envelope. Measles is a respiratory tract virus that causes a febrile illness with rash in
children. Mild pneumonia often occurs but is usually of no consequence in healthy adults.
Measles may result in severe lower respiratory tract infection and high morbidity in hosts
who are immunocompromised and malnourished. This virus is highly contagious and is
transmitted from person to person by droplets. The incubation period is 10-14 days and
peaks in late winter and early spring.
Cytomegalovirus
Cytomegalovirus (CMV) is a herpesvirus that is a common cause of infections, usually
asymptomatic, in the general population. In hosts who are immunocompetent, acute CMV
infection causes a mononucleosis-like syndrome. Transmission is primarily through body
fluid contact. The virus has been found in the cervix and in human milk, semen, and blood
products. The prevalence of antibodies to CMV in adults ranges from 40-100%, with
higher rates in lower socioeconomic areas.
Reactivation of latent infection is almost universal in transplant recipients and individuals
infected with the human immunodeficiency virus. CMV pneumonia may occur and is often
fatal in immunocompromised individuals, primarily hematopoietic stem cell transplant
(HSCT) and solid organ transplant (SOT) recipients. The severity of pneumonia is related
to the intensity of immunosuppression. Additionally, CMV infection is itself
immunosuppressive, causing further immunocompromise in these patients.
In cancer patients receiving allogeneic bone marrow transplants, CMV pneumonia has a
prevalence of 15% and a mortality rate of 85%, making it the most common cause of
death in this population. Acute graft-versus-host disease is the major risk factor for CMV
pneumonia in these patients.
Interestingly, although CMV is a well-recognized pathogen in patients with AIDS
(manifesting as retinitis, colitis, encephalitis, polyradiculitis, and/or cholangiopathy),
clinically relevant pneumonia is very uncommon in this group, even if CMV is cultured
from alveolar fluid and/or seen on lung histology.
Cytomegalovirus (CMV) is a ubiquitous virus of the Herpesviridae family, transmitted
mostly by contact with infectious body fluids (saliva, urine, genital) or by transplacental
route, and it is frequently acquired early in life [[1], [2], [3], [4]]. According to
seroprevalence studies, its prevalence ranges between 50% and 85%, with
epidemiological differences between different age groups and socioeconomic
backgrounds [4,5]. In Portugal, CMV infection is highly prevalent in the population (77%)
[6]. Primary CMV infections are usually asymptomatic, or self-limiting diseases,
manifested by a mononucleosis-like syndrome or hepatitis. In immunocompromised
patients, it is often associated with severe manifestations, causing substantial morbidity
and mortality [1,4]. Although there are a few reports describing severe clinical
manifestations of the CMV infection in immunocompetent patients, the pulmonary
involvement appears to be rare (8%) [1]. CMV pneumonia usually presents with
respiratory failure and with diffuse interstitial infiltrates on chest x-ray. The diagnosis is
done using serologic testing, molecular biology and histological findings on lung biopsy.
Regarding treatment, there are no formal recommendations for the management of severe
disease in immunocompetent patients, including in CMV pneumonia [2,7].

Herpes simplex virus

Herpes simplex virus (HSV) is a rare cause of lower respiratory tract infections and is
seen primarily in severely immunocompromised patients, primarily HSCT and SOT
recipients, patients who are undergoing chemotherapy or are neutropenic, or those who
have congenital immunodeficiency. [26] HSV pneumonia develops either secondary to
upper airway infection (because of direct extension of the virus from the upper to the lower
respiratory tract) or following viremia secondary to dissemination of HSV from genital or
oral lesions.
Herpes simplex virus is spread by contact with active lesions or viral shed by
asymptomatic excreters. While not a classic respiratory virus, herpes simplex virus can
cause pneumonia in compromised hosts, with a mortality rate of 80%. Pneumonia may
develop from primary infection or reactivation.
Zoonotic viral pneumonias
Zoonotic viral pneumonias include those caused by the hantavirus, avian influenza,
severe acute respiratory syndrome (SARS), and H1N1 (swine) influenza.
Hantavirus
Hantavirus is a genus of enveloped RNA viruses in the family Bunyaviridae. The majority
are transmitted by arthropod vectors. Hantaviruses, however, are harbored by rodents,
with each viral species having one major rodent host species. Rodents, which are
chronically infected, excrete hantaviruses from urine, saliva, and feces. Infection occurs
after aerosols of infectious excreta are inhaled.
The hantavirus pulmonary syndrome (HPS) is seen in the Americas and is an acute
pneumonitis caused by the North American hantavirus, most notably the Sin Nombre
Virus. [27, 28] Two other agents, isolated in other parts of North America, can also cause
HPS.
Hantaviruses originally were recognized in the four-corners region of the southwestern
United States (New Mexico, Arizona, Utah, and Colorado) in May 1993. The deer mouse
(Peromyscus maniculatus) was identified to be the reservoir.
Cases of HPS have continued to be reported in the United States. As of July 2010, 545
cases of HPS had been reported in the United States from 32 states. [29]
Avian influenza
In Hong Kong in 1997, an influenza virus (H5N1 virus) previously known to infect only
birds was found to infect humans. Manifestations included pneumonia, which in some
cases led to fatal acute respiratory distress syndrome (ARDS) or multisystem organ
failure.
Prior to the human outbreak, the H5N1 virus caused widespread deaths in chickens on
three farms in Hong Kong. Epidemiologic investigations of this outbreak demonstrated that
individuals in close contact with the index case or with exposure to poultry were at risk of
being infected.
Concern is growing that avian influenza, which is a subtype of influenza A, may result in a
worldwide pandemic in the near future. The avian influenza virus A/H5N1 has several
ominous characteristics, including increased virulence and human-to-human transmission
in several cases, rather than bird-to-human transmission, as is usually necessary. The
disease causes high mortality as a result of pneumonia and respiratory failure.
The 1997 outbreak in Hong Kong was thought to be controlled by depopulating 1.5 million
chickens in local farms and markets. However, human infections occurred in 2001 through
2003 in other parts of Asia, and the virus has been found in poultry and birds in Europe.
The rising incidence and widespread reporting of disease from H5N1 influenza viruses
can probably be attributed to the increasing spread of the virus from existing reservoirs in
domestic waterfowl and live bird markets, leading to greater environmental contamination.
As of January 2014, 650 cases of H5N1 human infections have been reported from 16
countries since 2003, with 386 deaths (59% mortality). [30]
Severe acute respiratory syndrome
Severe acute respiratory syndrome (SARS) was due to a novel coronavirus (CoV) that
crossed the species barrier through close contact between humans and infected animals.
Viral isolation and genomic sequencing have revealed that the SARS virus originated in
the masked palm civet cat (Paguma larvata), raccoon dog (Nyctereutes procyonoides),
and possibly the Chinese ferret-badger (Melogale moschata), with subsequent
interspecies jumping, during which a partial loss of genome probably led to more efficient
human-to-human transmission.
Horseshoe bats (Rhinolophus sinicus) have also been found to harbor SARS-like
coronaviruses (more distantly related to SARS-CoV than that of the palm civets), raising
the possibility of bats being a reservoir for future SARS infections.
SARS was a particularly challenging disease because its long incubation period allowed
seemingly healthy travelers who were infected with the virus to spread it. The SARS
coronavirus (SARS-CoV) quickly spread from China to the rest of the world over a period
of 1 year, affecting more than 8000 patients in 29 countries and resulting in 774 deaths.
Global transmission of SARS was halted in June 2003 after the World Health Organization
instituted traditional public health measures, including finding and isolating case-patients,
quarantining contacts, and using enhanced infection control. [31] No cases of SARS have
been reported since 2004.
H1N1 (swine) influenza
Initially reported as an outbreak in Mexico and subsequently the United States, infection
from a novel swine-origin influenza A (H1N1) virus rapidly spread to become a worldwide
pandemic in 2009. The World Health Organization declared an end to the pandemic in
August 2010.
Virus-associated hemophagocytic syndrome may play an important role in development of
multiorgan failure and ensuing death in H1N1 infection. [32]
For more information on H1N1 influenza, see H1N1 Influenza (Swine Flu). Rare causes of
viral pneumonia include Epstein-Barr virus and rotavirus.
Epstein-Barr virus
Epstein-Barr virus (EBV) is transmitted through infected saliva. Pneumonia as a
complication of mononucleosis is very uncommon. The virus can cause pneumonia in the
absence of mononucleosis.
Lung involvement secondary to EBV infections is more often reported in
immunocompromised people than in others. In 25% of pediatric patients with HIV
infection, EBV can cause lesions related to lymphocytic interstitial pneumonia or
pulmonary lymphoid hyperplasia. [33]
Rotavirus
Although upper respiratory tract infection secondary to rotavirus is common, rotavirus
pneumonia is rare. Just a few cases have been reported.

6. Recognize the emergency condition for referring Avian Influenza Patient

AAFP Avian Influenza

7. Describe the characteristic of the H5N1 virus, transmission (human-human,

poultry-human = WHO) and pathophysiology of H5N1 infection. All about
H5N1, Angka Kematian!
a. Mortality/Morbidity

As of August 27, 2015, 844 cases of H5N1 had been reported worldwide, with 449
deaths. [11] Most cases have been in eastern Asia; some cases have been reported in
Eastern Europe and North Africa.
The extraordinarily high mortality rate of avian influenza (>60% for H5N1; approximately
30% for H7N9) is worrying and reasonably accurate. Race appears to be a factor only to
the extent that geographic differences in the rate of HPAI among birds and the degree of
bird-to-human contact are significant.
Sex
In Egypt, 90% of fatalities due to avian influenza have involved women, a pattern that has
not been readily apparent elsewhere. [13] Most cases of H7N9 have been reported in men.
Age
Avian influenza has the highest case-fatality rate among persons aged 10-39 years.
Unlike seasonal influenza, which disproportionately affects very young and very old
individuals, young adults make up a large proportion of the avian influenza cases.
Fifty percent of reported cases have been in people younger than 20 years. Forty percent
of cases involve persons aged 20-40 years.
In Egypt, avian influenza has been associated with a relatively low mortality rate, which
seems to be associated with a high rate of infection in young children (< 10 y); as of May
2009, the mortality rate in this subpopulation has been zero. The significance and
reproducibility of these findings remains to be seen.

b. Pendahuluan
a. Influenza burung/ Avian influenza (virus influenza tipe A)
b. Influenza virus is an orthomyxovirus—an enveloped, segmented, negative-
sense RNA virus. Influenza virus has 3 strains—A, B, and C.
c. Avian influenza is caused by influenza A virus, which has 8 RNA segments.
Avian influenza is a potential and unpredictable threat to humans because of
the segmented nature of the genome.
d. 2 surface protein marker yang penting: hemaglutinin (H) dan neuraminidase
(N)
 e. Ada 18 suptipe HA dan 11 subtipe NA yang ditemukan pada hewan dan
manusia
f. Human influenza khususnya H1, H2, H3, N1, dan N2
c. Sifat-sifat virus influenza
g. Avian influenza has low-pathogenic (LPAI) and highly pathogenic (HPAI)
strains
h. Bertahan hidup di air sampai 4 hari pada suhu 22 C
i. Lebih dari 30 hari pada suhu 0 C
j. Mati pada pemanasan 60 C selama 30’
k. Atau 56 C selama 3 jam dan 80 C dalam 1’
l. Akan mati dengan deterjen, disinfektan (formalin, iodin, alkohol 70%)
m. Keistimewaan: antigenic shift (cepat) dan antigenic swift (lambat)
i. Shift A, drift B, stable C
d. Transmisi
n. Indonesia negara ke 5 avian flu menular ke manusia (Hongkong, Thailand,
Vietnam, Kamboja, Indonesia)
o. Penularan dari unggas ke manusia
Avian influenza A viruses may be transmitted from animals to humans in two main ways:
o Directly from birds or from avian influenza A virus-contaminated environments to
people.
o Through an intermediate host, such as a pig.
Influenza A viruses have eight separate gene segments. The segmented genome
allows influenza A viruses from different species to mix and create a new virus if influenza
A viruses from two different species infect the same person or animal. For example, if a
pig were infected with a human influenza A virus and an avian influenza A virus at the
same time, the new replicating viruses could mix existing genetic information
(reassortment) and produce a new influenza A virus that had most of the genes from the
human virus, but a hemagglutinin gene and/or neuraminidase gene and other genes from
the avian virus. The resulting new virus might then be able to infect humans and spread
easily from person to person, but it would have surface proteins (hemagglutinin and/or
neuraminidase) different than those currently found in influenza viruses that infect
humans.
This type of major change in the influenza A viruses is known as “antigenic shift.”
Antigenic shift results when a new influenza A virus subtype to which most people have
little or no immune protection infects humans. If this new influenza A virus causes illness
in people and is transmitted easily from person to person in a sustained manner, an
influenza pandemic can occur.
It is possible that the process of genetic reassortment could occur in a person who
is co-infected with an avian influenza A virus and a human influenza A virus. The genetic
information in these viruses could reassort to create a new influenza A virus with a
hemagglutinin gene from the avian virus and other genes from the human virus. Influenza
A viruses with a hemagglutinin against which humans have little or no immunity that have
reassorted with a human influenza virus are more likely to result in sustained human-to-
human transmission and pose a major public health threat of pandemic influenza.
Therefore, careful evaluation of influenza A viruses recovered from humans who are
infected with avian influenza A viruses is very important to identify reassortment if it
occurs.
 e. Patogenesis
p. Droplet infection  mukosa saluran napas atau langsung ke alveoli
(tergantung ukuran droplet)  asam sialat dalam mukosaprotein mengikat
virus  berikatan dengan alpha 2,6 sialiloligosakarida (melalui 2,6 linkage)
 replikasi virus tidak efisien  perlekatan virus dengan sel epitel saluran
napas dapat dicegah
q. Virus yang mengandung protein neuraminidase dapat memecah ikatan
tersebut  melekat pada epitel  replikasi  dalam 4-6 jam dapat
menyebar ke sel-sel sekitarnya  inkubasi 18 jam – 4 hari (esp. sel-sel
kolumnar bersilia)  sel membengkak, inti mengkerut  piknosis +
disintergrasi, cilia hilang  badan inklusi
13. The pathophysiology of avian influenza differs from that of normal influenza. Avian
influenza is still primarily a respiratory infection but involves more of the lower
airways than human influenza typically does. This is likely due to differences in the
hemagglutinin protein and the types of sialic acid residues to which the protein
binds. Avian viruses tend to prefer sialic acid alpha(2-3) galactose, which, in
humans, is found in the terminal bronchi and alveoli. Conversely, human viruses
prefer sialic acid alpha(2-6) galactose, which is found on epithelial cells in the upper
respiratory tract. One group has reported that ex vivo cultures of human tonsillar,
 adenoidal, and nasopharyngeal tissues can support replication of H5N1 avian
influenza. [8]
14. Although this result in a more severe respiratory infection, it probably explains why
few, if any, definite human-to-human transmissions of avian influenza have been
reported; infection of the upper airways is probably required for efficient spread via
coughing and sneezing. Many are concerned that subtle mutation of the
hemagglutinin protein through antigenic drift will result in a virus capable of binding
to upper and lower respiratory epithelium. The 1918 pandemic strain was so lethal
partially because the receptor utilization of the hemagglutinin differed from that of
other strains, and H5N1 has that potential to acquire that same biology through
mutation.
15. Differences in the PA, NP, M1, NS1, and PB2 genes tend to correlate with human
strains of influenza, including human infections with avian influenza. [9] The
functional role of these genetic markers has yet to be determined but likely involves
replication enhancement and immune suppression.
16. Unlike with human influenza, most deaths associated with avian influenza have
been due to primary viral pneumonia, with no evidence of secondary bacterial
infection.

f. Manifestasi klinis (masa inkubasi pendek +/- 3 hari)

a. Ringan sampai berat
b. Influenza like ilness (ILI)  batuk, pilek, demam (cukup tinggi >38C)
c. Cephalgia, sore throat, myalgia, malaise
d. Diare (watery, nonbloody)
e. Conjunctival suffusion/ Conjunctivitis
f. Vomiting
g. Chest/Abdominal Pain
h. ARDS
i. Leukopenia, limfopenia, trombositopenia
j. Tachypnea and Crackles
k. Wheeze
l. CXR: infiltrat bilateral; difus, multilokal, atau menyebar (patchy) – pneumonia
g. Risk Factors
 Travel to (within the last 2 wk) or location in a country with known avian
influenza cases in animals or humans
 Unusual comorbidities such as encephalopathy or diarrhea
 History of exposure to birds, especially living in close proximity to birds,
contact with sick or dying birds, or consumption of incompletely cooked
bird meat
 History of exposure to individuals with known avian influenza, especially
family, or to sick people in a country with known human cases of avian
influenza
h. Pemeriksaan penunjang/ Diagnosis
m. Kultur dan identifikasi virus H5N1
n. PCR untuk H5
o. Uji serologi: Immunofluorescence test (antibodi), uji netralisasi, uji penapisan
(Rapid, HI, ELISA)
WHO Avian Influenza
Avian Influenza
Cause
Highly pathogenic avian influenza A (H5N1) virus or other non-human influenza
subtypes (e.g. H7, H9)

Transmission
Human infections with highly pathogenic avian influenza A(H5N1) virus occur through
bird-to-human, possibly environment-to-human and, very rarely, limited, non-sustained
human-to-human transmission. Direct contact with infected poultry, or with surfaces
and objects contaminated by their droppings, is the main route of transmission to
humans. Exposure risk is considered highest when there is contact with infected avian
faecal material in the environment, especially during slaughter, de-feathering,
butchering and preparation of poultry for cooking. There is no evidence that properly
cooked poultry or poultry products can be a source of infection.

Nature of the disease

Patients usually present initially with symptoms of fever and influenza-like illness
(malaise, myalgia, cough, sore throat). Diarrhoea and other gastrointestinal symptoms
may occur. The disease progresses within days and many patients develop clinically
apparent pneumonia with radiographic infiltrates of varying patterns. Sputum production
is variable and sometimes bloody. Multi-organ failure, sepsis-like syndromes and,
uncommonly, encephalopathy occur. The fatality rate among hospitalized patients with
confirmed H5N1 infection has been high (about 60%), most commonly as a result of
respiratory failure caused by progressive pneumonia and acute respiratory distress
syndrome. Fatal outcome had also been reported for H7N7 infection in human.
However, other avian influenza subtypes (e.g. H9N2) appear to cause mild diseases.
Geographical distribution
Extensive outbreaks in poultry have occurred in parts of Africa, Asia, Europe and the
Middle East since 1997, but only sporadic human infections have occurred to date.
Continued exposure of humans to avian H5N1 viruses increases the likelihood that the
virus will acquire the necessary characteristics for efficient and sustained human-to-
human transmission through either gradual genetic mutation or reassortment with a
human influenza A virus. Between November 2003 and July 2008, nearly 400 human
cases of laboratory-confirmed H5N1 infection were reported to WHO from 15 countries
in Africa, south-east and central Asia, Europe and the Middle East.

Risk for travellers

H5N1 avian influenza is primarily a disease of birds. The virus does not easily cross the
species barrier to infect humans. To date, no traveller is known to have been infected.

Prophylaxis
Neuraminidase inhibitors (oseltamivir, zanamivir) are inhibitory for the virus and have
proven efficacy in vitro and in animal studies for prophylaxis and treatment of H5N1
infection. Studies in hospitalized H5N1 patients, although limited, suggest that early
treatment with oseltamivir improves survival. Late intervention with oseltamivir is also
justified. Neuraminidase inhibitors are recommended for post-exposure prophylaxis in
certain exposed individuals. At present WHO does not recommend pre-exposure
prophylaxis for travellers but advice may change depending on new findings.
Inactivated H5N1 vaccines for human use have been developed and licensed in
several countries but are not yet generally available; however, this situation is expected
to change. Some countries are stockpiling these vaccines as a part of pandemic
preparedness. Although the vaccines are immunogenic, their effectiveness in
preventing the H5N1 infection or reducing disease severity is unknown.

Precautions
In affected countries, travellers should avoid contact with high-risk environments such
as live animal markets and poultry farms, any free-ranging or caged poultry, or surfaces
that might be contaminated by poultry droppings. Travellers in affected countries should
avoid contact with dead migratory birds or wild birds showing signs of disease, and
should avoid consumption of undercooked eggs, poultry or poultry products. Hand
hygiene with frequent washing or use of alcohol rubs is recommended. If exposure to
individuals with suspected H5N1 illness or severe, unexplained respiratory illness
occurs, travellers should urgently consult health professionals. Travellers should
contact their local health providers or national health authorities for supplementary
information.

8. Distinguish 3 types of Avian Influenza case; sign and symptoms of Avian

Influenza and bacterial pneumonia.
- Pasien dalam observasi: seseorang dengan demam >38C disertai satu atau
lebih gejala berikut: batuk, sakit tenggorokan, pilek, sesak napas di mana belum
jelas ada atau tidaknya kontak dengan unggas sakit/ mati mendadak yang
belum diketahui penyebabnya dan produk mentahnya
- Kasus suspek: panas 38C disertai satu atau lebih gejala (batuk, sakit
tenggorokan pilek, sesak, pneumonia) dan diikuti keadaan:
p. Pernah kontak dengan unggas sakit/ mati mendadak yang belum diketahui
penyebabnya dan produk mentahnya dalam 7 hari terakhir sebelum timbul
gejala di atas
q. Pernah tinggal di daerah yang terdapat kematian unggas yang tidak biasa
dalam 14 hari terakhir sebelum gejala di atas
r. Pernah kontak dengan penderita AI konfirmasi dalam 7 hari sebelum timbul
gejala di ats
s. Pernah kontak dengan spesimen AI H5N1 dalam 7 hari terakhir sebelum
timbul gejala di atas (kerja di lab)
t. Leukopenia (<3000)
u. Titer antibodi terhadap H5 dengan pemeriksaan HI test atau ELISA
v. ATAU
w. Kematian akibat ARDS dengan 1 atau lebih keadaan berikut:
i. Leukopenia atau limfopenia dengan atau tanpa trombositopenia
ii. CXR menggambarkan pneumonia atipikal atau infiltrat di kedua sisi
paru yang makin meluas pada serial
- Kasus probabel: kriteria suspek ditambah 1 atau lebih kriteria berikut
 x. Kenaikan titer antibodi min 4 kali terhadap H5 dengan pemeriksaan HI atau
ELISA
y. Hasil lab terbatas untuk influenza H5 menggunakan neutralisasi tes
z. Dalam waktu singkat terjadi pneumonia berat/ gagal napas/ meninggal dan
terbukti tidak ada penyebab lain
- Kasus konfirmasi: kasus suspek atau probabel dengan 1 atau lebih kriteria
berikut:
aa. Kultur positif influenza A/H5N1
bb. PCR positif inf A/H5N1
cc. IFA test ditemukan antigen positif dengan menggunakan antibodi
monoklonal influenza A/H5N1
dd. Kenaikan titer antibodi spesifik influenza H5N1 sebanyak 4 kali dalam paired
serum dengan uji netralisasi

Case definitions
A. Person under investigation
A person whom public health authorities have decided to investigate for possible H5N1
infection.

B. Suspected H5N1 case

A person presenting with unexplained acute lower respiratory illness with fever (>38 ºC)
and cough, shortness of breath or difficulty breathing.
AND
One or more of the following exposures in the 7 days prior to symptom onset:
a. Close contact (within 1 metre) with a person (e.g. caring for, speaking with, or touching)
who is a suspected, probable, or confirmed H5N1 case;

b. Exposure (e.g. handling, slaughtering, defeathering, butchering, preparation for

consumption) to poultry or wild birds or their remains or to environments contaminated by
their faeces in an area where H5N1 infections in animals or humans have been suspected
or confirmed in the last month;
c. Consumption of raw or undercooked poultry products in an area where H5N1 infections
in animals or humans have been suspected or confirmed in the last month;
d. Close contact with a confirmed H5N1 infected animal other than poultry or wild birds
(e.g. cat or pig);
e. Handling samples (animal or human) suspected of containing H5N1 virus in a
laboratory or other setting.

C. Probable H5N1 case (notify WHO)

Probable definition 1:
A person meeting the criteria for a suspected case
AND
One of the following additional criteria:
a. infiltrates or evidence of an acute pneumonia on chest radiograph plus evidence of
respiratory failure (hypoxemia, severe tachypnea)
OR
b. positive laboratory confirmation of an influenza A infection but insufficient laboratory
evidence for H5N1 infection.

Probable definition 2:
A person dying of an unexplained acute respiratory illness who is considered to be
epidemiologically linked by time, place, and exposure to a probable or confirmed H5N1
case.

D. Confirmed H5N1 case (notify WHO)

A person meeting the criteria for a suspected or probable case
AND
One of the following positive results conducted in a national, regional or international
influenza laboratory whose H5N1 test results are accepted by WHO as confirmatory:
a. Isolation of an H5N1 virus;
b. Positive H5 PCR results from tests using two different PCR targets, e.g. primers
specific for influenza A and H5 HA;
c. A fourfold or greater rise in neutralization antibody titer for H5N1 based on testing of an
acute serum specimen (collected 7 days or less after symptom onset) and a convalescent
serum specimen. The convalescent neutralizing antibody titer must also be 1:80 or higher;
d. A microneutralization antibody titer for H5N1 of 1:80 or greater in a single serum
specimen collected at day 14 or later after symptom onset and a positive result using a
different serological assay, for example, a horse red blood cell haemagglutination
inhibition titer of 1:160 or greater or an H5-specific western blot positive result.

Bacterial Pneumonia vs. Avian Influenza

Bacterial Pneumonia:
M. pneumoniae infections usually have long incubation periods (the time between
breathing in the bacteria and developing symptoms). The incubation period is usually
between 1 to 4 weeks.1
The history findings of bacterial pneumonia may vary from indolent to fulminant. Clinical
manifestation includes both constitutional findings and findings due to damage to the lung
and related tissue. The following are major history findings:
 Fever with tachycardia and/or chills and sweats.
 The cough may be either nonproductive or productive with mucoid, purulent or
blood-tinged sputum.
 Pleuritic chest pain, if the pleura is involved.
 Shortness of breath with normal daily routine work.
 Other symptoms include fatigue, headache, myalgia, and arthralgia.
Physical findings also vary from patient to patient and mainly depend on the severity of
lung consolidation and existence or nonexistence of pleural effusion. The following
are major clinical findings:
 Increased respiratory rate.
 Percussion sounds vary from flat to dull.
 Tactile fremitus.
 Crackles, rales, and bronchial breath sounds are heard on auscultation.
Confusion manifests earlier in older patients. A critically ill patient may present with sepsis
or multi-organ failure.

Evaluation
 Laboratory Evaluation: This includes lab values such as complete blood count
with differentials, inflammatory biomarkers like ESR and C-reactive protein, blood
cultures, sputum analysis or Gram staining and/or urine antigen testing or
polymerase chain reaction for nucleic acid detection of certain bacteria.
 An arterial blood gas may reveal hypoxia and respiratory acidosis
 Pulse oximetry of less than 92% indicates severe hypoxia and elevated CRP
predicts a serious infection.
 Blood cultures should be obtained before administering antibiotics. Unfortunately,
they are only positive in 40% of cases
 Sputum evaluation if good quality may reveal more than 25 WBC per low power
field and less than 10 squamous epithelial cells
 Radiological Evaluation: It includes chest x-ray as an initial imaging test and the
finding of pulmonary infiltrates on plain film is considered as a gold standard for
diagnosis when the lab and clinical features are supportive.[10][2]
 The chest x-ray may reveal a consolidation or parapneumonic effusion.
 Chest CT is done for complex cases where the cause is not known.
 Bronchoalveolar lavage is done in patients who are intubated and can provide
samples for culture.

Avian Influenza:
(masa inkubasi pendek +/- 3 hari)
a. Ringan sampai berat
b. Influenza like ilness (ILI)  batuk, pilek, demam (cukup tinggi >38C)
c. Cephalgia, sore throat, myalgia, malaise
d. Diare (watery, nonbloody)
e. Conjunctival suffusion/ Conjunctivitis
f. Vomiting
g. Chest/Abdominal Pain
h. ARDS
i. Leukopenia, limfopenia, trombositopenia
j. Tachypnea and Crackles
k. Wheeze
l. CXR: infiltrat bilateral; difus, multilokal, atau menyebar (patchy) – pneumonia
Laboratory Studies
If avian influenza is suspected, the laboratory should be called ahead of time and
forewarned before specimens for identification of viral infection (eg, nasal washes) are
obtained. Pneumatic tubing is not recommended for transport; hand transport using a
leak-proof specimen bag is preferred. The specimen should be clearly labeled as
"suspected AI," and the person who transports the specimen should use appropriate
protective equipment.
Many laboratories are not equipped to deal with the isolation needed to safely contain
avian influenza (category 3+ containment, higher than that used for HIV). If a sample is
sent, the laboratory may need to be shut down for decontamination. Samples from
patients with suspected avian influenza should be sent to a dedicated central reference
laboratory such as at the Center for Disease Control and Prevention (CDC). The CDC
laboratory can perform antiviral sensitivity testing, as well as subtyping of the virus.
Laboratory tests and findings include the following:
 Nasal wash specimens for detection of virus and viral subtyping are crucial.
 Leukopenia may be present.
 Relative lymphopenia may be present.
 Thrombocytopenia is common.
 Elevated levels of liver enzymes (SGOT/SGPT) are common.
 Disseminated intravascular coagulation (DIC) is rare.
Other tests, including blood cultures, lumbar punctures for CSF analysis (including
polymerase chain reaction [PCR]), and sputum cultures, should be performed based on
clinical suspicion for alternative or complicating diagnoses.

9. Describe the types of clinical specimens and state of the serological and
molecular methods to diagnose H5N1 infections.

Specimen collection and handling directly impacts the validity of the laboratory result.
Samples collected or handled inappropriately can lead to incorrect diagnostic results, even
when testing procedures are followed correctly.
Specimens for H5N1 diagnosis should be collected according to WHO guidance available
in the documents Collecting, preserving and shipping specimens for the diagnosis of avian
influenza A(H5N1) virus infection: Guide for field operations and WHO guidelines for the
storage and transport of human and animal specimens for laboratory diagnosis of
suspected avian influenza A infection. Specimen collection should be done preferably
before initiation of antiviral treatment.
"Golden Rule:" Clinical specimens from humans and from animals should NEVER
be processed in the same laboratory. However they could be processed in the same
institution if separation of working rooms for animal and human specimens is clear
and strict. This is to eliminate risk of cross contamination of human and animal
samples.

a) What specimens to collect from suspect cases

1. Preferred samples
• Upper respiratory tract (take both types of specimen to allow detection of A(H5N1) and
other influenza viruses):
1. Posterior-pharyngeal (throat) swabs are currently the highest yield upper respiratory
tract specimen for detecting A(H5N1) (unlike human influenza). Naso-pharyngeal
swabs may be collected if necessary (see below).
2. Nasal swabs with nasal secretions (from the anterior turbinate area) or
nasopharyngeal aspirates or swabs are appropriate specimens for detecting human
influenza A and B and therefore useful if the influenza is not due to A(H5N1).
• Lower respiratory tract:
3. If the patient is intubated, take a tracheal aspirate or collect a sample during
bronchoalveolar lavage.
• Blood:
 4. Serum (acute and convalescent if possible).

2. Secondary specimens (these are not essential but can be useful if materials
are available)
• Plasma in EDTA (for detection of viral RNA)
• Rectal swab —especially if the patient has diarrhoea
• Spinal fluid if meningitis is suspected and a spinal tap is to be performed for
diagnostic/therapeutic purposes.

b) When to collect the specimens from suspect cases

The figure below (Fig 1) is a summary of the data available at the time of the publication
(October 2006) and will be changed as necessary as more data become available. It must
be emphasized that the bars indicate approximate periods of time after onset of symptoms
when taking specimens is likely to yield results and not periods when sampling will always
be effective.

 A throat swab should be taken (if possible) within three days of onset of symptoms.
Note that the virus is generally detectable in throat swabs from most patients from the
point of onset of symptoms (or even just before) until towards the end of the second
week, and infrequently beginning of the third week, after onset of symptoms. Cases
whose initial specimens are negative for A/H5 but who continue to show symptoms
suggestive of this type of infection and/or who have a history of exposure that would
also support the diagnosis should therefore be sampled at least once again as soon as
possible.
 Virus may be detectable in tracheal aspirates from onset of lower respiratory
complaints (dyspnoea, difficulty breathing, marked cough) or pneumonia until the
second or third week of illness.
 An acute phase serum sample should be taken seven days or less after symptom
onset (this will usually be done when the patient presents and begins treatment) and a
 convalescent sample after 3 to 4 weeks. Note that the limited data available on
antibody kinetics indicate development of positivity (initially ELISA and not necessarily
neutralizing antibody) from day 10 onwards.
 Single serum samples. To be collected at day 14 or later after symptom onset since
the likelihood of detecting neutralizing antibodies increases over time, certainly during
the first 3 to 4 weeks after onset of symptoms.
 Blood serum or plasma for the detection of viral RNA should be taken during the first 7
to 9 days after the development of symptoms because the patient is most likely to be
RNAaemic (have detectable RNA in the bloodstream) at that time (Fig 1).
 Initial specimens (respiratory and blood) should ideally be collected from suspected
patients before antiviral therapy is begun but treatment must not be delayed in order to
take specimens. (Note that standard treatment may render throat swabs negative for
virus after three or more days of treatment but probably has no effect on the
development of neutralizing antibody).
 Specimens should be collected from deceased patients as soon as possible after
death.

5. Available laboratory techniques for detection of influenza A viruses in humans

The following assays may be used to detect (and initially identify) both seasonal and novel
influenza A viruses in specimens from humans. The assays vary in the expertise and
infrastructure required rapidity, cost, and sensitivity/specificity.
 Conventional reverse transcriptase polymerase chain reaction (RT-PCR) and
real- time reverse transcriptase PCR assay. PCR detects viral RNA present in
either clinical specimens or virus cultures, and can be targeted at genes that are
relatively conserved across all influenza A viruses (e.g. matrix gene) or to the
haemagglutinin or neuraminidase genes which are subtype specific. Including the
time taken for viral RNA extraction and for amplicon detection, the turn-around time
of conventional RT-PCR assays is 6–8 hours. Real time RT-PCR methods can
shorten this time interval to around 3–4 hours while providing increased sensitivity
and possibility of quantitation of the viral target gene. 

 Other molecular detection systems. These systems, mostly still under
development, tend to be rapid. They include assays based on nucleic acid
amplification and use various endpoint detection methods. 

• Virus culture. Results are available in 2–10 days using either shell-vial or standard
cell- culture methods. Positive influenza cultures may or may not exhibit cytopathic
effects, thus a second step to specifically identify influenza viruses by
immunofluorescence, haemagglutination – inhibition (HI) or RT-PCR is needed. An
advantage of culture is that viruses are available for further characterization. Virus
culture in appropriate cell lines can also detect other clinically important respiratory
viruses. 
 Most avian viruses grow readily in embryonated eggs and this is the
option of choice for amplification of virus from avian hosts. However, highly
pathogenic avian H5N1 viruses that infect humans are still quite virulent in eggs,
killing them quickly. This makes standard egg culture amplification approaches
more difficult. For this reason and 
 because of the biosafety concern, isolation of
highly pathogenic H5N1 viruses is usually performed only in specially qualified and
equipped laboratories.
• Rapid antigen detection. Viral antigen detection may be carried out by
 immunofluorescence or enzyme immunoassay (EIA) methods. The EIA based
methods are simple and convenient to use. However, such tests are, at present,
directed at conserved viral antigens (e.g. virus nucleoprotein, matrix protein) and
detect all subtypes of influenza A viruses, whether of human or avian origin.
Therefore these tests will not differentiate human virus subtypes H3N2 or H1N1
from avian influenza H5N1. Additionally, current viral antigen detection rapid tests,
while being sensitive for the detection of human seasonal influenza viruses, appear
to have low sensitivity for the diagnosis of avian influenza H5N1 (i.e. a negative
result does not exclude H5N1 disease). Thus overall, presently commercially
available antigen detection tests have limited utility for diagnosis of A(H5N1)
disease in humans.
Examples of protocols for some available assays to detect influenza A(H5N1) viruses are
described in Annex A. The laboratory protocols outlined in this document have proven to
be valid for known H5N1 viruses when the listed reagents and platforms (and/or primers)
are used together as presented, and in accordance with good laboratory practices.
Presented protocols may require updates as new strains of H5N1 evolve.

6. Serological identification of antibodies against avian influenza A(H5N1) viruses

Serological tests available for the measurement of influenza A-specific antibody include
the haemagglutination inhibition test (HI), enzyme immunoassay (EIA), and virus
neutralization tests (VN).
The microneutralization (MN) assay is the currently recommended test for the
measurement of antibodies to highly pathogenic avian influenza A. However, it is
impractical for routine diagnostic testing of clinical cases due to the constraints listed
below. It is therefore most useful for research studies (e.g. for determination of extent of
exposure in case contacts or at risk populations).
Optimally, paired sera, collected first during the acute phase of illness and then 14 days or
later after the onset of illness, should be tested simultaneously. Retrospectively, infection
with H5N1 is confirmed when one the following criteria are met:
1. Fourfold or greater rise in antibody titre against A(H5N1) in paired sera (acute and
convalescent) with the convalescent serum having a titre of 1:80 or higher. 

2. Antibody titre of 1:80 or more in a single serum collected at day 14 or later after
onset of symptoms and a positive result using different serological assay (e.g. titre
of 1:160 or greater in HI using horse red blood cell or an H5 –specific western blot).
Constraints of serological techniques: 

 Antibodies take up to several weeks to develop and become detectable in serum. 

 In general, standard panels of reagents for H5N1 and other novel strains are not
widely available and results among the laboratories performing these tests vary
widely.
 MN assay is technically difficult to perform. 

 VN and MN assays require the use of live virus, thus can only be used in
laboratories 
 with Biosafety Level 3 containment facilities. 

 Difficulties in determining endpoint in HI with horse red blood cells because of their
small size. Adjustment of buffer concentration might overcome the problem. 

 Non-specific cross reactivity in all serological assays may occur due to the previous
infections with human influenza viruses or other factors. Appropriate serum
adsorption before testing is recommended. 
 

 10. Describe the management of the disease
Prinsip penatalaksanaan avian influenza: istirahat, peningkatan daya tahan tubuh,
pengobatan antiviral, pengobatan antibiotik, perawatana respirasi, antiinflamasi,
imunomodulators

ARV sebaiknya diberikan pada awal infeksi yakni pada 48 jam pertama. Pilihan obat:
a. M2 inhibitor:
Amantadine (symadine)
Rimantidin (flu-madine)
Dosis 2x/ hari 100 mg atau 5 mg/kgBB selama 3-5 hari
b. (WHO) Neuraminidase inhibitor:
Zanamivir (relenza)
Oseltamivir (tami-flu)
Dosis 2x 75 mg selama 1 minggu

Depkes RI dalam pedomannya:

1. Pada kasus suspek flu burung diberikan Oseltamivir 2x 75 mg 5 hari, simptomatik
dan antibiotik jika ada indikasi
2. Pada kasus probable flu burung diberikan Oseltamivir 2x 75 mg 5 hari, antibiotik
spektrum luas yang mencakup kuman tipik dan atipikal, dan steroid jika perlu
seperti pada kasus pneumonia berat, ARDS. Respiratory care di ICU sesuai
indikasi
Kriteria rawat:
3. Suspek flu burung dengan gejala klinis berat: 1) sesak napas dengan RR>30x per
menit, 2) HR>100x per menit 3) gangguan kesadaran, kondisi umum lemah
4. Suspek dengan leukopeni
5. Suspek dengan gambaran radiologi pneumoni
6. Kasus probabel dan confirmed

Summary of clinical management advice

 Oseltamivir remains the primary recommended antiviral treatment. Observational
data on treatment with oseltamivir in the early stages of the disease suggest its
usefulness in reducing A(H5N1) virus infection-associated mortality. Furthermore,
evidence that the A(H5N1) virus continues to replicate for a prolonged period
indicates that treatment with oseltamivir is also warranted when the patient
presents to clinical care at a later stage of illness. 

 Modified regimens of oseltamivir treatment, including two-fold higher dosage,
longer duration and possibly combination therapy with amantadine or rimantadine
(in countries where A(H5N1) viruses are likely to be susceptible to adamantanes)
may be considered on a case by case basis, especially in patients with pneumonia
or progressive disease. Ideally this should be done in the context of prospective
data collection. 

 Corticosteroids should not be used routinely, but may be considered for septic
shock with suspected adrenal insufficiency requiring vasopressors . Prolonged or
high dose corticosteroids can result in serious adverse events in A(H5N1) virus-
infected patients, including opportunistic infection. 
 i.e. 150 mg twice daily for
 adults. Agent that causes vasoconstriction and maintains or increases blood
pressure e.g. norepinephrine, epinephrine or dopamine 

 Antibiotic chemoprophylaxis should not be used. However, when pneumonia is
present, antibiotic treatment is appropriate initially for community-acquired
pneumonia according to published evidence-based guidelines. When available, the
results of microbiologic studies should be used to guide antibiotic usage for
suspected bacterial co-infection in patients with A(H5N1) virus infection. 

 Monitoring of oxygen saturation should be performed whenever possible at
presentation and routinely during subsequent care (e.g. pulse oximetry, arterial
blood gases), and supplemental oxygen should be provided to correct hypoxemia.


 Therapy for A(H5N1) virus-associated ARDS should be based upon published
evidence- based guidelines for sepsis-associated ARDS, specifically including lung
protective mechanical ventilation strategies. 


Table. Summary of treatment modalities for clinical management of human

(H5N1) virus infection
Recommended Strategies
modalities
Antivirals Oseltamivir is the primary treatment of choice. Consider
modified regimens
Antibiotics Empiric treatment for community acquired pneumonia
(CAP) per published guidelines pending microbiologic
results (e.g. 2-3 dayas)
Oxygen therapy Monitor oxygen saturation and maintain SaO2 over 90%
with nasal cannule or face mask
IPPV (Invasive positive Early intervention recommended for ARDS. Use lung
pressure ventilation) protective, low tidal volume, low pressure ventilation to
prevent barotrauma and conservative fluid management
Low dose systemic Appropriate for refractory septic shock complicating
corticosteroids ARDS (e.g. hydrocortisone IV 200 mg per day in divided
doses; 50 mg every 6 hrs in adults)
NSAIDs, antipyretics Paracetamol given orally or by suppository will generally
be sufficient in most cases as an antipyretic treatment.
Infection control Whenever risk of infectious aerosols, use particulate
respirator, eye protection, gowns, gloves, and an airborne
precaution room or negative pressure room

Modalities NOT Strategies

Recommended
Adamantane When neuraminidase inhibitors are available,
monotherapy monotherapy with amantadine or rimantadine is not
recommended. Combination therapy is consideration in
areas where A(H5N1) virus is likely susceptible
Antibiotic Not recommended
chemoprophylaxis
NPPV (non-invasive Generally not recommended
 positive pressure
ventilation)
Systemic Moderate to high doses of unproven benefit and
corticosteroids potentially harmful; not recommended
Salicylates Avoid administration of salicylates (such as aspirin and
aspirin containing products) in childen and young adults
(<18 yo) because of the risk of Reye Syndrome

11. Describe the urgency of the disease to be well-managed

Influenza pandemics are epidemics that affect a large proportion of the world due to a
novel virus. Pandemics are unpredictable, but recurring events that can have health,
economic and social consequences worldwide. An influenza pandemic occurs when a
novel influenza virus emerges with the ability to cause sustained human-to-human
transmission, and the human population has little to no immunity against the virus. With
the growth of global travel, a pandemic can spread rapidly globally with little time to
prepare a public health response.
Ongoing circulation of some avian influenza viruses in poultry, such as A(H5) and A(H7)
viruses, are of public health concern as these viruses cause severe disease in humans
and the viruses have the potential to mutate to increase transmissibility among humans.
To date, although human-to-human transmission of these viruses is thought to have
occurred in some instances when there had been close or prolonged contact with a
patient, there has been no sustained human-to-human transmission identified.
Whether currently-circulating avian, swine and other zoonotic influenza viruses will result
in a future pandemic is unknown. However, the diversity of zoonotic influenza viruses that
have caused human infections is alarming and necessitates strengthened surveillance in
both animal and human populations, thorough investigation of every zoonotic infection and
pandemic preparedness planning.

12. Identify the complication of Avian Influenza

 A review of avian influenza cases in 4 countries found that the clinical course
progressed to ARDS and respiratory failure in 70-100% of patients. [31] The mean time
to the development of ARDS was 6 days. Lymphopenia at presentation is a significant
predictor of the progression to ARDS and death. [32]
 Severe cases of avian influenza may progress to multiorgan failure. In a study of 12
hospitalized patients with confirmed H5N1 influenza, 75% had respiratory failure, 42%
had cardiac failure, and 33% had renal failure. [31]

13. Describe the prevention of Avian Influenza

Sebagai profilaksis, bagi yang berisiko tinggi, antara lain:
 Pekerja peternakan/ pemrosesan unggas
 Pekerja laboratorium yang memproses sampel pasien/ unggas terjangkit
 Pengunjung peternakan/ pemrosesan unggas (1 minggu terakhir)
 Pernah kontak dengan unggas (ayam, itik, burung) sakit/ mati mendadak yang
belum diketahui penyebabnya dan atau babi serta produk mentahnya dalam 7 hari
terakhir
Apart from antiviral treatment, the public health management includes personal
protective measures like:
 Regular hand washing with proper drying of the hands
 Good respiratory hygiene – covering mouth and nose when coughing or sneezing,
using tissues and disposing of them correctly
 Early self-isolation of those feeling unwell, feverish and having other symptoms of
influenza
 Avoiding close contact with sick people
 Avoiding touching one’s eyes, nose or mouth
Health care workers preforming aerosol generating procedures should use airborne
precautions. Standard contact and droplet precautions and appropriate personal
protective equipment (PPE) should be made available and used during epidemics.
Travelers to countries and people living in countries with known outbreaks of avian
influenza should, if possible, avoid poultry farms, contact with animals in live poultry
markets, entering areas where poultry may be slaughtered, and contact with any surfaces
that appear to be contaminated with faeces from poultry or other animals. Good food
safety and food hygiene practices e.g. hands washing with soap and water should be
followed. Travelers returning from affected regions should report to local health services if
respiratory symptoms suspecting zoonotic influenza virus infection.
Pre-exposure or post-exposure prophylaxis with antivirals is possible but depends on
several factors e.g. individual factors, type of exposure, and risk associated with the
exposure.

14. Hendra and Nipah Viruses

Hendra Virus. Hendra virus (HeV) infection is a rare emerging zoonosis (disease that can
be transmitted to humans from animals) that causes severe and often fatal disease in both
infected horses and humans. The natural host of the virus has been identified as being
fruit bats of the Pteropodidae Family, Pteropus genus.
HeV was identified during the first recorded outbreak of the disease in the Brisbane
suburb of Hendra, Australia, in 1994. The outbreak involved 21 stabled racehorses and
two human cases. As of July 2016, 53 disease incidents involving over 70 horses have
been reported. These incidents were all confined to the north-eastern coast of Australia. A
total of seven humans have contracted Hendra virus from infected horses, particularly
through close contact during care or necropsy of ill or dead horses
Symptoms of HeV infection in humans range from mild influenza-like illness to fatal
respiratory or neurological disease.There is no specific treatment for human cases of
Hendra virus. Intensive supportive care is provided, and the use of monoclonal antibodies
is being investigated. A registered Hendra animal vaccine exists and vaccination is
recognised as an effective way to reduce the risk of horses becoming infected and to
reduce the likelihood of human exposure.

Nipah Virus. Human Nipah virus infection was first recog- nized in a large outbreak of 276
reported cases in peninsular Malaysia and Singapore from September 1998 through May
1999. Most patients had contact with sick pigs. Patients pre- sented primarily with
encephalitis; 39% died. Large fruit bats of the genus Pteropus are the natural reservoir of
Nipah virus.
In the 10 years following, no further human cases were noted in Malaysia, but annual
human outbreaks have been reported in Bangladesh from May to December. The clinical
presentation is dominated by respiratory symptoms and the case fatality has been over
70%. The most frequently implicated route of infection is inges- tion of fresh date palm
sap. Date palm sap is harvested from December through March, particularly in west
central Bangla- desh. A tap is cut into the tree trunk and sap flows slowly over- night into
an open clay pot. Infrared camera studies have confirmed that Pteropus giganteus bats
frequently visit the trees, lick the sap during collection, thus transmitting infection. Humans
can also become infected through direct contact with bat secretions, contact with domestic
animals that become infected by eating partially eaten bat-saliva-laden fruit or infected
date palm sap, or by human-to-human transmission through infected saliva.

15. All about HIV/AIDS (Global perspective and general clinical manifestation of
HIV infection)!
Infection with the human immunodeficiency virus (HIV) leads to a complex disease pattern
which ultimately results in chronic immunodeficiency. HIV can be transmitted sexually,
parenterally, or vertically (e.g., peripartum from mother to child). Infection is most common
in the young adult population between 20 and 30 years of age. The virus
infects macrophages and other CD4+ cells, leading to the destruction of CD4 T cells and
thereby impairing one of the key mechanisms of cellular immune defense. There are three
major stages: acute infection, clinical latency, and acquired immunodeficiency
syndrome (AIDS). For clinical staging, detailed classifications have been established by
the Centers for Disease Control and Prevention (CDC) and the World Health
Organization (WHO). During the stage of acute infection, the virus reproduces rapidly in
the body, which can lead to acute, nonspecific (e.g., flu-like) symptoms (also known
as acute retroviral syndrome, ARS) within 2–4 weeks. However, approximately half of all
infected individuals remain asymptomatic. Once the stage of acute infection subsides, the
clinical latency stage begins. Again, many individuals remain asymptomatic during this
period, while others develop non-AIDS-defining conditions (e.g., oral hairy leukoplakia).
The last stage, AIDS, is characterized by AIDS-defining conditions (e.g., Kaposi's
sarcoma) and/or a CD4 count < 200 cells/μL. HIV infection can reliably be detected via
antigen/antibody-based tests. In patients with confirmed infection, the most important
parameters for monitoring the disease are CD4 count and viral load. HIV
treatment involves a combination of antiretroviral drugs (combination antiretroviral
therapy, cART). In addition, HIV-related complications (e.g., HIV
wasting syndrome, opportunistic infections) will require management. There have been
significant advances in treatment so that the average life expectancy of HIV
patients receiving current antiretroviral drugs is approaching that of the general
population.

Epidemiology
 Incidence (in the US)
 HIV infection: peak incidence between ages 20 and 30 (∼
35/100,000)
 AIDS: peak incidence approx. age 45 (∼ 14/100,000)
 Ethnicity: Incidence is significantly higher in the Black population than
in other population groups.
 Prevalence
  US: ∼ 1.2 million
 Global: ∼ 37 million

Etiology
Pathogen (human immunodeficiency virus)
 Lymphotropic lentivirus (from the family of retroviridae)
 Consists of the two species HIV-1 and HIV-2
 HIV-1: most common species worldwide
 HIV-2: restricted almost completely to West Africa
Routes of transmission
 Sexual: responsible for ∼ 80% of infections worldwide
 Risk per sexual act
 Risk for men who have sex with men (MSM): 0.5% for
receptive partner
 Risk for male-to-female sex
 0.1% for female partner
 0.05% for male partner
 Modifying factors
 Viral load: studies have shown that transmission is unlikely if
viral load is < 400 copies/ml
 Circumcision: reduced risk of infection for circumcised men
 Coinfection: genital inflammation (e.g., as a result of
coinfection with other pathogens such as HPV or genital
herpes) increases local virus concentration and therefore risk
of transmission
 Genital mucosal damage: increases risk of transmission
 Parenteral transmission
 Needle sharing: 0.67% per exposure through needle-sharing contact
 Needlestick injuries: 0.36% per injury
 Infectious blood on mucous membranes: 0.1% per exposure
 Blood transfusions: 0.00005% risk per transfusion (1 in 2 million)
 Vertical transmission: from mother to child
 During childbirth (∼ 5–15%)
 Through breastfeeding after birth (∼ 5–20%)
Risk of transmission can be lowered significantly if HIV infection is treated consistently
and viral load is below the limit of detection!

Pathophysiology
Structure of HIV
 Physical structure: icosahedral with a spiked envelope
 Genome : 9 genes encoding a total of 15 proteins (e.g., reverse
transcriptase , integrase , and envelope proteins )
 pol gene codes for a polyprotein that consists of protease, reverse
transcriptase, and integrase
  gag gene codes for gag protein, which consists of matrix
protein, nucleocapsids, and capsid proteins
 env gene codes for surface glycoproteins, gp41 and gp120
Natural history of HIV infection
 Initial infection and HIV replication cycle
1. HIV enters the body (e.g., via mucosal lesions or via infection of
mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on target
cells with its gp120 glycoprotein (binding)
 Cells that have CD4 receptors: T lymphocytes (e.g., T helper
cells), macrophages, monocytes, dendritic cells (CNS).
2. Viral envelope fuses with host cell, capsid enters the cell.
 For fusion, CD4 receptor and a coreceptor
(CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must
be present.
 Patients without CCR5 receptors appear to be resistant to HIV,
those patients either have
a homozygous CCR5 mutation (substantial resistance) or
a heterozygous CCR5 mutation (slower course).
3. Virion's RNA is transcribed into DNA and then integrated into the host's DNA
4. Viral DNA is replicated and virions are assembled
5. Virion repurposes a portion of the cell's membrane as envelope and leaves the cell
(budding) → cell death
 Progression to chronic immunodeficency
 HIV infects CD4+ lymphocytes, then reproduces and spreads to
other CD4+ lymphocytes near the original site of infection → infection
of CD4+ lymphocytes concentrated in specialized lymphoid tissue (e.g., lymph
nodes or gut-associated lymphatic tissue (GALT) ) → explosive growth and
dissemination → acute HIV syndrome with high viral load
 Window period: The time between infection and detectability of
HIV antibodies.
 After the acute stage, viral load decreases and remains at roughly that level for
approximately 8–10 years (clinical latency stage )
 → loss of CD4+ lymphocytes (especially T cells) impairs immune function and
thereby facilitates opportunistic infections and development of malignancies
(AIDS) → these secondary diseases are usually the cause of death in patients with
HIV
Viral load predicts the rate of disease progression! CD4 count correlates with immune
function!
Acute HIV syndrome does not develop in all patients! The hallmark of HIV is chronic
persistent infection!

The role of immune response

 Because HIV infects cells of the immune system itself, activation of
cellular immunity is a factor that paradoxically helps the virus spread and ensures
chronic persistence of the infection.
 HIV evades immune control via:
 Genetic mutation and recombination
 Downregulation of MHC class I surface molecules in infected cells
Clinical features
General considerations
 In early HIV infection, patients are often asymptomatic.
 Incubation period: usually 2–4 weeks
 Infectiousness: two peaks (1st peak: within the first months after infection; 2nd peak:
during AIDS-stage)
Acute HIV infection
 Also referred to as acute retroviral syndrome (ARS) or described as
a mononucleosis-like syndrome.
  Fever
 Fatigue
 Myalgia and arthralgia
 Headache
 Generalized nontender lymphadenopathy
 Generalized rash
 Gastrointestinal symptoms (nausea, diarrhea, weight loss)
 Oropharyngeal symptoms (sore throat, ulcerations, painful swallowing)
Clinical latency and AIDS
 Clinical latency
 Patients may still be asymptomatic
 Non-AIDS-defining conditions
 Chronic subfebrile temperatures
 Persistent generalized lymphadenopathy
 Localized opportunistic infections (e.g., oral candidiasis ,
vaginal infections )
 Oral hairy leukoplakia (lesions located mainly on
the lateral borders of the tongue)
 Chronic diarrhea (> 1 month)
 Skin manifestations (e.g. molluscum contagiosum, warts,
exacerbations of psoriasis, shingles)
 AIDS: see learning card on HIV-associated conditions
Test patients with a history of injecting drugs who present with otherwise unexplained
weight loss, depression, and/or dementia for HIV!
Candidiasis in the esophagus, unlike oral candidiasis, is an AIDS-defining condition!

Stages
CDC classification system for HIV
CDC categories of HIV are based on CD4 count in combination with current or
previously diagnosed HIV-related conditions. These stages indicate disease
progression and prognosis. Any patient belonging in categories A3, B3 or C1-C3 is
considered to have AIDS.

CD4 cell count Clinical category A Clinical category B Clinical category C

category Asymptomatic, Acute Symptomatic AIDS-defining
HIV conditions, conditions
or PGL not A or C
(1) ≥ 500 cells/μL A1 B1 C1
(2) 200–499 A2 B2 C2
cells/μL
(3) < 200 cells/μL A3 B3 C3
PGL= Persistent generalized lymphadenopathy
WHO (World Health Organization) classification
WHO classifies individuals with confirmed HIV infection according to clinical features and
diagnostic findings:
 Primary HIV infection: acute retroviral syndrome or asymptomatic
 Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic
 Clinical stage 2: e.g., unexplained moderate weight loss (< 10%), recurrent
fungal/viral/bacterial infections
 Clinical stage 3: e.g., unexplained severe weight loss (> 10%),
unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥
36.7°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial
infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/μL)
and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
 Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma)

Diagnostics
HIV testing
Indications
 Test all patients with clinical features of acute or chronic HIV infection
 All individuals with possible past exposure, especially high-risk individuals : regular
testing (e.g., annually)
 One-time testing is recommended early in every pregnancy
 HIV-testing requires patient consent (opt-out)
Initial diagnostic approach
Both screening tests and confirmatory tests detect anti-HIV antibodies in the blood
 Screening tests
 Combination antigen/antibody tests : detect both HIV antigen (p24)
and anti-HIV antibodies → a negative result essentially rules out HIV
infection (almost 100% sensitivity)
 Antibody-only tests (HIV serology)
 ELISA (enzyme-linked immunosorbent assay): standard
method for detecting antibodies within approx. 1–3 hours;
requires laboratory
 Rapid tests: can deliver results in ∼ 20 minutes and do not
require a laboratory, which makes them suitable as an
alternative to the more complex tests in some outpatient
settings.
 Confirmatory tests
 HIV-1/HIV-2 antibody differentiation immunoassay : can detect
both HIV-1 and HIV-2 in ∼ 20 minutes and distinguish between the
two types
 Western blot: tests may be negative up to 2 months after infection;
results are usually available after several days and HIV subtype O is
not reliably detected.
 Detection of viral RNA
 Can detect HIV infection earlier than antibody/antigen-based tests
but FDA-approved tests are limited to HIV-1
  Indications:
 Neonatal HIV infection
 Patients with indeterminate results
 Patients presenting before seroconversion
 Screening of blood donors
 Post-treatment monitoring
 Viral RNA load: indicator of ART response
 Decrease in viral loads indicates effective treatment
 Prognostic marker in long-term treatment
 CD4+ count: correlates with overall immune function
 CD4+ counts increase in response to successful ART therapy
 Critical measurement for initiating opportunistic
infection prophylaxis
 CD4+:CD8+ ratio: Used in the immunological evaluation of long-
term follow-up cases
 Expected increase in ratio with successful ART therapy
 Correlates with immune dysfunction and viral reservoir size
Additional laboratory studies
 CBC: possibly lymphocytopenia

Treatment
Antiretroviral HIV therapy
 General approach: all persons infected with HIV (regardless of CD4 count)
should begin combined antiretroviral therapy (cART) as soon as possible.
Antiretroviral drugs
 Nucleoside reverse transcriptase inhibitors (NRTI):
e.g., zidovudine, lamivudine, emtricitabine, abacavir, stavudine, didanosine
 Mechanism of action: NRTIs act as nucleoside analogs → prevent the
formation of 3' to 5' phosphodiester linkages → inhibit
reverse transcription of RNA to DNA
 NRTIs require intracellular phosphorylation for activation, and
their efficacy is thus reliant on kinase availability and activity,
which is variable depending on cell functionality and activation
state.
 Side effects
 Bone marrow suppression → neutropenia, anemia
 Mitochondrial toxicity → myopathy, neuropathy, hepatic
steatosis, and lactic acidosis
 Abacavir-related hypersensitivity syndrome
 Didanosine/stavudine: pancreatitis
 HIV-associated lipodystrophy: abnormal distribution of
fat (clinical presentation varies greatly)
 Loss of subcutaneous fatty tissue (lipoatrophy) of
face and extremities
 Metabolic changes: impaired glucose
tolerance, hyperlipoproteinemia (elevated triglycerides,
elevated total cholesterol, lowered HDL)
  Probable accumulation of fat in liver, muscles,
abdomen, breasts and neck (buffalo hump)
 Resistance: caused by mutations in the gene that codes for reverse
transcriptase (pol gene)
 Non-nucleoside reverse-transcriptase inhibitors (NNRTI):
e.g., nevirapine, efavirenz
 Mechanism of action: non-competitive inhibitors of viral reverse
transcriptase
 NNRTIs do not require intracellular phosphorylation for
activation but are direct inhibitors.
 Side effects:
 Hepatotoxicity (nevirapine)
 CNS toxicity (efavirenz)
 Hypersensitivity reactions (including Stevens-
Johnson syndrome)
 Nucleotide analogs (also called nucleotide reverse-
transcriptase inhibitors; NtRTI): e.g., tenofovir
 Protease inhibitors (PI): e.g., indinavir, ritonavir, nelfinavir, lopinavir
 Mechanism of action: inhibition of viral protease → inability to cleave
viral polypeptides → generation of viral proteins impaired → only
immature (non-infectious) virions are produced
 Side effects:
 GI intolerance (nausea, diarrhea), lipodystrophy and fat
accumulation , nephrolithiasis and crystal-induced nephropathy
 Hyperglycemia: inhibition of insulin-dependent glucose
transporters (GLUT 4) → peripheral insulin
resistance → impaired glucose tolerance
 Integrase inhibitors (INI): e.g., raltegravir, dolutegravir
 Mechanism of action: inhibition of the viral integrase .
 Fusion inhibitor: enfuvirtide
 Mechanism of action: competitively binds to the viral protein gp41 and
thereby prevents fusion with the cell
 CCR5-antagonist: maraviroc
 Mechanism of action: blocks the CCR5 coreceptor that is essential to
cell infection for some HIV genotypes (R5 viruses)
 Not generally recommended because of comparatively high costs and
limited clinical data
Regimens
 Recommended regimens
 3 NRTI (e.g., zidovudine, lamivudine, abacavir) OR
 2 NRTI (e.g., lamivudine + abacavir) AND
 1 NNRTI (e.g., efavirenz) OR
 1 PI (e.g., lopinavir) OR
 1 INI (e.g., raltegravir)
Hepatotoxic drugs (e.g. nevirapine) are contraindicated if there is coinfection
with HBV or HCV!
Most NRTIs end in “-ine”, protease inhibitors in “-avir”, and integrase inhibitors end in “-
gravir!”

Prognosis
 Morbidity and mortality among patient subsets
 Untreated HIV infection has a mortality rate of > 90% (average time
from infection to death approx. 8–10 years)
 Progression varies among individuals: some patients may die within a
few years while others remain asymptomatic for decades
 Untreated individuals with advanced HIV infection usually die
within a few years (median survival is 12–18 months)
 Some untreated individuals show only slow progression
and can remain asymptomatic for more than 20 years.
 In rare cases, untreated individuals have no detectable
viremia and continue to have high CD4 counts for long
periods
 The average life expectancy of HIV-infected patients who receive
adequate antiretroviral treatment is ∼ 8 years lower than noninfected
individuals of the same age.
 Individual prognosis depends on various factors, including:
 Adequate antiretroviral treatment
 Viral set point and CD4 count
 Exposure to opportunistic pathogens ,
 Individual genetic properties
 HIV species and subtype
 Preexisting conditions

Prevention
HIV post-exposure prophylaxis
 Indications
 Injury with HIV-contaminated instruments or needles
 Contamination of open wounds or mucous membranes with HIV-
contaminated fluids
 Unprotected sexual activity with a known or potentially HIV-
infected person
 Timing: Initiate as soon as possible (ideally within one to two hours after
exposure)
 Drugs: A three-drug regimen is recommended (similar
to cART treatment). Typically, this includes
a nucleoside/nucleotide combination NRTI plus an integrase inhibitor:
 Tenofovir-emtricitabine + dolutegravir
 Tenofovir-emtricitabine + raltegravir
 Measures after needle stick injury or other contamination
 Let the wound bleed.
 Rinse/flush with water and soap and/or antiseptic agent.
 Immediately seek medical attention.
 If occupational exposure: report incident immediately.
Vaccinations in HIV-infected individuals
 Efficacy of immunization is reduced in HIV-infected individuals (due to impaired
immune function)
 The immunization schedule should be observed with the exception that: live-
attenuated influenza, varicella zoster, and MMR vaccines should not be given
if CD4 count < 200 cells/μl (CD4 percentage < 15% in patients ≤ 5 years) or
if AIDS-defining conditions are present. The inactivated polio vaccine should be
used instead of the live-attenuated polio vaccine.
 Immunizations that are not part of the standard immunization schedule:
 Inactivated vaccines are generally safe
 Live vaccines should generally not be given to
severely immunocompromised patients

Special patient groups

HIV in pregnancy
 Transmission
 Highest risk during birth (perinatal vertical transmission)
 Prenatal transmission is possible
 Risk depends on maternal viral load
 Reducing risk of transmission
 Combined antiretroviral therapy (cART) is recommended
throughout pregnancy
 However, most antiretroviral drugs are not approved for use
during pregnancy.
 Delivery method
 Viral load > 1,000 copies/mL (or unknown) near time of
delivery: increased risk of HIV transmission
 Cesarean delivery should be scheduled at 38
weeks (even if the mother
received cART during pregnancy)
 HIV post-exposure
prophylaxis with zidovudine, lamivudine and nevirapine
OR zidovudine and nevirapine
 Viral load ≤ 1,000 copies/mL and mother has
received cART during pregnancy: low risk of HIV transmission
 Vaginal delivery may be considered as an alternative
to cesarean section
 HIV post-exposure prophylaxis with zidovudine for
the newborn
 Breastfeeding should generally be avoided , because risk of
transmission is 5–20% .
 Diagnosis in infants: if < 18 months, diagnosis is confirmed via PCR, not ELISA
Suspect HIV in infants with failure to thrive, diffuse lymphadenopathy, diarrhea,
and thrush, especially if the mother is a high-risk parent!
 16. All about Leprosy!

Leprosy (Hansen disease) is a chronic infectious disease caused by prolonged exposure

to Mycobacterium leprae, an acid-fast, slow-growing, fastidious bacillus. Leprosy primarily
occurs in tropical and/or developing countries and is rarely observed in the US. There are
various forms whose descriptions differ among two different classification systems, but the
three cardinal clinical manifestations of leprosy are hypopigmented skin lesions, nerve
thickening, and peripheral nerve palsies. Long-standing cases of leprosy classically
develop deformities as a result of contractures following motor nerve palsies and/or
repeated injury due to sensory loss. Other chronic complications include uveitis, orchitis,
and nasal septal perforation. Patients with leprosy may also present with acute lepra
reactions that are characterized by painful skin lesions and neuritis. The diagnosis is
usually confirmed with the help of a biopsy. Lepromin tests aid in the classification of
various forms of leprosy. Treatment consists of prolonged MDT (multi-drug therapy)
with dapsone and rifampin. Clofazimine is added to the therapeutic regimen in patients
with multibacillary leprosy.

Epidemiology
 US statistics
 Incidence: 100–200 new cases annually
 Prevalence: ∼ 4,000 cases in total
 Sex: ♂ > ♀
 Peak incidence: 10–20 years
 Endemic to tropical regions: India, Brazil, Indonesia, Nepal, Myanmar, Nigeria
 By mid-2000, Indonesia had achieved elimination as targeted by WHO. In 2003, the
distribution of leprosy by place and time was as follows: Patients enrolled in
Indonesia at the end of December 2003 were 18,312 patients consisting of 2,814
PB and 15,498 MB with Prevalence Rate 0.86 per 10,000 population in 10
provinces, namely: East Java, West Java, Central Java, South Sulawesi, Papua,
NAD, DKI Jakarta, North Sulawesi, North Maluku and East Nusa Tenggara.7
Bakker et al (2002) found 96 leprosy patients (85 new and 11 old patients) from the
4140 were screened for leprosy 4774 inhabitants living in South Sulawesi
(Indonesia). 8

Etiology
 Pathogen: Mycobacterium leprae is an obligate, intracellular, acid-fast bacilli that
cannot be cultured.
 Route of transmission
 Respiratory droplet transmission
 Close contact with fomites, infected soil, and/or infected individuals
 Transmission usually requires prolonged exposure, and some
individuals seem more predisposed than others
 Infectious type: multibacillary leprosy (see “Pathophysiology” below)
 Reservoirs: infected humans, nine-banded armadillos
Pathophysiology

Leprosy is a slowly progressive, chronic infection with a spectrum of clinical

manifestations depending on the degree of cell immunity.

Clinical features
 Incubation period: 3–5 years
 The clinical manifestations vary depending on the type of leprosy (LL, TT, or
intermediate forms collectively known as Borderline leprosy, which is explained in
further detail in extra information)

The three cardinal clinical manifestations of leprosy are hypopigmented skin lesions,
nerve thickening, and peripheral nerve palsies!
All peripheral nerves can become affected in leprosy, but the most commonly affected are
the ulnar and the peroneal nerves.
Diagnostics

Diffuse hypergammaglobulinemia associated with lepromatous leprosy can cause false

positive VDRL, RF, and/or ANA tests and thus result in diagnostic confusion!

Treatment
 Definitive therapy: Multidrug therapy [1]
Lepromatous leprosy (LL) Tuberculoid leprosy (TT)
Treatment duration 12 months 6 months
Dapsone ✓ ✓
Rifampin ✓ ✓
Clofazimine ✓ x
 Supportive therapy
 Treatment of lepra reactions (see “Complications” below)
  Rehabilitation
 Physiotherapy to prevent contractures
 Surgery to correct deformities (e.g., tendon transfer surgery
for ulnar nerve palsy)
 Wound care

Complications
 Secondary deformities
 Bone destruction → shortened digits, autoamputation
 Neuropathic ulcers on the dorsum of the foot
 Charcot joints
 Nose: saddle nose deformity, anosmia, septal perforation
 Eye
 Lagophthalmos and corneal insensitivity → corneal ulcers
 Invasion of the anterior chamber → chronic uveitis → blindness
 Orchitis → testicular atrophy → hypergonadotropic hypogonadism
 Reactive amyloidosis
 Lepra reactions (see extra information for more details)
Patients may attribute lepra reactions to side effects of medications and stop them.
Therefore, they should be warned about possible lepra reactions and told to seek
treatment as soon as they occur. Treatment of leprosy should not be stopped when lepra
reactions occur.
The presence of tender nerves in a patient with leprosy indicates a lepra reaction!

17. Reye Syndrome? Hubungan dengan Aspirin?

Reye syndrome (Reye- Johnson Syndrome)
This is a special type of nonicteric hepatic encephalopathy occurring in children and
adolescents and characterized by acute brain swelling in association with fatty infiltration
of the viscera, particularly the liver. Mainly, these outbreaks were observed in association
with influenza B virus and varicella infections, but a variety of other viral infections were
implicated (influenza A, echovirus, reovirus, rubella, rubeola, herpes simplex, Epstein-Barr
virus). Later it became apparent that the toxic or adjuvant effects of aspirin given during
these infections played an important role in producing the disease. Today, only
occasional instances of Reye syndrome are observed now that the association
with aspirin administration has become widely known and its use in children with
viral infections has been interdicted.
Most patients are children, boys and girls being equally affected, but rare instances are
known in infants (Huttenlocher and Trauner) and young adults. In most cases, the
encephalopathy is preceded for several days to a week by fever, symptoms of upper
respiratory infection, and protracted vomiting. These are followed by the rapid evolution of
stupor and coma, associated in many cases with focal and generalized seizures, signs of
sympathetic overactivity (tachypnea, tachycardia, mydriasis), decorticate and decerebrate
rigidity, and loss of pupillary, corneal, and vestibuloocular reflexes. One or two such cases
were included in the series of acute "toxic encephalopathy" reported. In infants, respiratory
distress, tachypnea, and apnea are the most prominent features.
The liver may be greatly enlarged, often extending to the pelvis and providing an important
diagnostic clue as to the cause of the cerebral changes. Initially there is a metabolic
acidosis, followed by a respiratory alkalosis (rising arterial pH and falling PCO2). The CSF
is usually under increased pressure and is acellular; glucose values may be low, reflecting
the hypoglycemia. The serum ALT, coagulation times, and blood ammonia are increased,
sometimes to an extreme degree. The EEG is characterized by diffuse arrhythmic delta
activity, progressing to electrocerebral silence in patients who fail to survive. CT and MRI
show the cerebral swelling but are difficult to interpret in these young individuals, who lack
any adult brain atrophy.
The major pathologic findings are cerebral edema, often with cerebellar herniation, and
infiltration of hepatocytes with fine droplets of fat (mainly triglycerides); the renal tubules,
myocardium, skeletal muscles, pancreas, and spleen are infiltrated to a lesser extent.
There are no inflammatory lesions in the brain, liver, or other organs. There is not full
agreement as to the pathogenesis of this disorder and the mechanism of aspirin toxicity
but mitochondrial dysfunction has been implicated.

Reye Syndrome
The cause of Reye syndrome is unknown, but many cases seem to follow infection
with influenza A or B or varicella. Using salicylates (generally aspirin) during such illness
increases the risk by as much as 35-fold. This finding has led to a marked decrease in
salicylate use in the US since the mid-1980s (except when specifically indicated, such as
in Kawasaki disease) and a corresponding decrease in the incidence of Reye syndrome
from several hundred annual cases to about 2. The syndrome occurs almost exclusively
in children < 18 years. In the US, most cases occur in late fall and winter.

The disease affects mitochondrial function, causing disturbance in fatty acid and
carnitine metabolism. Pathophysiology and clinical manifestations are similar to a
number of inherited metabolic disorders of fatty acid transport and mitochondrial
oxidation

Symptoms and Signs

The disease varies greatly in severity but is characteristically biphasic. Initial viral
symptoms (URI or sometimes chickenpox) are followed in 5 to 7 days by pernicious
nausea and vomiting and a sudden change in mental status. The changes in mental
status may vary from a mild amnesia, weakness, vision and hearing changes, and
lethargy to intermittent episodes of disorientation and agitation, which can progress
rapidly to deepening stages of coma manifested by
 Progressive unresponsiveness
 Decorticate and decerebrate posturing
 Seizures
 Flaccidity
 Fixed dilated pupils
 Respiratory arrest
Focal neurologic findings usually are not present. Hepatomegaly occurs in about 40% of
cases, but jaundice is absent.

Complications of Reye syndrome

Complications include
 Electrolyte and fluid disturbances
  Increased intracranial pressure
 Diabetes insipidus
 Syndrome of inappropriate ADH secretion
 Hypotension
 Arrhythmias
 Bleeding diatheses (especially gastrointestinal)
 Pancreatitis
 Respiratory insufficiency
 Hyperammonemia
 Aspiration pneumonia
 Poor temperature regulation
 Uncal herniation and death
Diagnosis
 Clinical findings in association with laboratory testing
 Liver biopsy
Reye syndrome should be suspected in any child exhibiting the acute onset of an
encephalopathy (without known heavy metal or toxin exposure) and pernicious vomiting
associated with hepatic dysfunction. Liver biopsy provides the definitive diagnosis,
showing microvesicular, fatty changes, and is especially useful in sporadic cases and in
children < 2 years. The diagnosis may also be made when the typical clinical findings
and history are associated with the following laboratory findings: increased liver
transaminases (AST, ALT > 3 times normal), normal bilirubin, increased blood ammonia
level, and prolonged PT.
Head CT or MRI is done as for any child with encephalopathy. If head CT or MRI is
normal, a lumbar puncture can be done. CSF examination usually shows increased
pressure, < 8 to 10 WBCs/mcL, and normal protein levels; the CSF glutamine level may
be elevated. Hypoglycemia and hypoglycorrhachia (a very low concentration of CSF
glucose) occur in 15% of cases, especially in children < 4 years; they should be
screened for metabolic disease. The condition is staged from I to V according to
severity.
Signs of metabolic derangement include elevated serum amino acid levels, acid-base
disturbances (usually with hyperventilation, mixed respiratory alkalosis–metabolic
acidosis), osmolar changes, hypernatremia, hypokalemia, and hypophosphatemia.

Differential diagnosis
The differential diagnosis of coma and liver dysfunction includes
 Sepsis or hyperthermia (especially in infants)
 Potentially treatable inborn abnormalities of urea synthesis (eg, ornithine
transcarbamylase deficiency) or fatty acid oxidation (eg, systemic carnitine
deficiency, medium chain acyl-CoA dehydrogenase deficiency)
 Phosphorus or carbon tetrachloride intoxication
 Acute encephalopathy caused by salicylism, other drugs (eg, valproate), or
poisons; viral encephalitis or meningoencephalitis
 Acute hepatitis
Illnesses such as idiopathic steatosis of pregnancy and tetracycline liver toxicity may
show similar light microscopic findings.
Prognosis
Outcome is related to the duration of cerebral dysfunction, severity and rate of
progression of coma, severity of increased intracranial pressure, and degree of blood
ammonia elevation. Progression from stage I to higher stages is likely when the initial
blood ammonia level is > 100 mcg/dL (> 60 mcmol/L) and the PT is ≥ 3 seconds longer
than that of the control. In fatal cases, the mean time from hospitalization to death is 4
days. Fatality rates average 21% but range from < 2% among patients in stage I
to > 80% among patients in stage IV or V.
Prognosis for survivors usually is good, and recurrences are rare. However, the
incidence of neurologic sequelae (eg, intellectual disability, seizure disorders, cranial
nerve palsies, motor dysfunction) is as high as 30% among survivors who developed
seizures or decerebrate posturing during illness.

Treatment
 Support measures
Treatment of Reye syndrome is supportive, with particular attention paid to control of
increased intracranial pressure and blood glucose because glycogen depletion is
common.
Treatment of elevated increased intracranial pressure includes intubation,
hyperventilation, fluid restriction of 1500 mL/m 2/day, elevating the head of the bed,
osmotic diuretics, direct increased intracranial pressure monitoring, and decompressing
craniotomy. Infusion of 10 or 15% dextrose is common to maintain euglycemia.
Coagulopathy may require fresh frozen plasma or vitamin K. Other treatments (eg,
exchange transfusion, hemodialysis, barbiturate-induced deep coma) have not been
proved effective but are sometimes used.

18. All about Sepsis!

o Definition
a. Possibly harmful systemic response: Two or more of the following:
– Fever (oral temperature >38°C [100.4°F]) or hypothermia (oral temperature <36°C
[96.8°F])
– Tachypnea (>24 breaths/min)
– Tachycardia (>90 beats/min)
– Leukocytosis (>12,000/μL), leukopenia (<4000/μL), or >10% bands; may have a
noninfectious etiology
b. Sepsis (or severe sepsis): Harmful systemic response (including some degree of organ
hypofunction) with a proven or suspected microbial etiology
c. Septic shock: Sepsis with hypotension (arterial bp <90 mmHg or 40 mmHg below pt’s
normal bp for at least 1 h despite fluid resuscitation) or need for vasopressors to
maintain systolic bp ≥90 mmHg or mean arterial bp ≥70 mmHg
o Etiology
d. Blood cultures are positive in 20–40% of sepsis cases and in 40–70% of septic shock
cases.
e. For infected pts in ICUs, respiratory infections have been most common (64%).
Microbiologic results have revealed that 62% of isolates are gram-negative bacteria
(most commonly Pseudomonas spp. and Escherichia coli), 47% are gram-positive
bacteria (most commonly Staphylococcus aureus), and 19% are fungi (most
commonly Candida spp.), with some cultures being polymicrobial.
o Epidemiology
f. The incidence of severe sepsis and septic shock in the United States continues to
increase, with >750,000 cases each year contributing to >200,000 deaths.
g. Invasive bacterial infections are a prominent cause of death around the world,
especially among young children.
h. Sepsis-related incidence and mortality rates increase with age and preexisting
comorbidity, with two-thirds of cases occurring in pts with significant underlying disease.
i. The increasing incidence of sepsis has been attributable to the aging of the population,
longer survival of pts with chronic diseases, a relatively high frequency of sepsis among
AIDS pts, and medical treatments that circumvent host defenses (e.g.,
immunosuppressive agents, indwelling catheters, and mechanical devices).
o Pathophysiology
Local and Systemic Host Responses
o Hosts have numerous receptors that recognize highly conserved microbial molecules
(e.g., lipopolysaccharide, lipoproteins, double-stranded RNA), triggering the release of
cytokines and other host molecules that increase blood flow and neutrophil migration to
the infected site, enhance local vascular permeability, and elicit pain.
j. Many local and systemic control mechanisms diminish cellular responses to microbial
molecules, including intravascular thrombosis (which prevents spread of infection and
inflammation) and an increase in anti-inflammatory cytokines (e.g., IL-4 and IL-10).
Organ Dysfunction and Shock
 Widespread vascular endothelial injury is believed to be the major mechanism for
multiorgan dysfunction.
 Septic shock is characterized by compromised oxygen delivery to tissues followed by a
vasodilatory phase (a decrease in peripheral vascular resistance despite increased
levels of vasopressor catecholamines).
o Clinical features
 Hyperventilation that produces respiratory alkalosis
 Encephalopathy (disorientation, confusion)
 Acrocyanosis and ischemic necrosis of peripheral tissues (e.g., digits) due to
hypotension and DIC
 Skin: hemorrhagic lesions, bullae, cellulitis, pustules. Skin lesions may suggest specific
pathogens; e.g., petechiae and purpura suggest Neisseria meningitidis, and ecthyma
gangrenosum suggests Pseudomonas aeruginosa.
 GI: nausea, vomiting, diarrhea, ileus, cholestatic jaundice
Major Complications
 Cardiopulmonary manifestations
– Ventilation-perfusion mismatch, increased alveolar capillary permeability, increased
pulmonary water content, and decreased pulmonary compliance impede oxygen
exchange and lead to ARDS (progressive diffuse pulmonary infiltrates and arterial
hypoxemia) in ~50% of pts.
– Hypotension: Normal or increased cardiac output and decreased systemic vascular
resistance distinguish septic shock from cardiogenic and hypovolemic shock.
– The ejection fraction is decreased, but ventricular dilation allows maintenance of a
normal stroke volume.
 Adrenal insufficiency: may be difficult to diagnose in critically ill pts
 Renal manifestations: oliguria or polyuria, azotemia, proteinuria, and renal failure due to
acute tubular necrosis
 Neurologic manifestations: delirium in the acute phase, polyneuropathy with distal
motor weakness in prolonged sepsis. Survivors may have long-term cognitive
impairment.
 Immunosuppression: Pts may have reactivation of HSV, CMV, or VZV.
Laboratory Findings
1. CBC: leukocytosis with a left shift, thrombocytopenia
2. Coagulation: prolonged thrombin time, decreased fibrinogen, presence of d-dimers
suggestive of DIC. With DIC, platelet counts usually fall below 50,000/μL.
3. Chemistries: metabolic acidosis, elevated anion gap, elevated lactate levels
4. LFTs: transaminitis, hyperbilirubinemia, azotemia, hypoalbuminemia

o Diagnosis
Definitive diagnosis requires isolation of the microorganism from blood or a local site of
infection. Culture of infected cutaneous lesions may help establish the diagnosis.
o Treatment
Pts in whom sepsis is suspected must be managed expeditiously, if possible within 1 h of
presentation.
5. Antibiotic treatment: See Table 12-1.
6. Removal or drainage of a focal source of infection
a. Remove indwelling intravascular catheters; replace Foley and other drainage catheters;
drain local sources of infection.
b. Rule out sinusitis in pts with nasal intubation.
c. Image the chest, abdomen, and/or pelvis to evaluate for abscess.
7. Hemodynamic, respiratory, and metabolic support
o Initiate treatment with 1–2 L of normal saline administered over 1–2 h, keeping the CVP
at 8–12 cmH2O, urine output at >0.5 mL/kg per hour, and mean arterial bp at >65
mmHg. Add vasopressor therapy if needed.
o If hypotension does not respond to fluid replacement therapy, hydrocortisone (50 mg IV
q6h) should be given. If clinical improvement results within 24–48 h, most experts would
continue hydrocortisone treatment for 5–7 days.
o Maintain oxygenation with ventilator support as indicated. Recent studies favor the use
of low tidal volumes—typically 6 mL/kg of ideal body weight—provided the plateau
pressure is ≤30 cmH2O.
o Erythrocyte transfusion is recommended when the blood Hb level decreases to ≤7 g/dL,
with a target level of 9 g/dL.
 General support: Nutritional supplementation should be given to pts with prolonged
sepsis (i.e., that lasting >2–3 days), with available evidence suggesting an enteral
delivery route. Prophylactic heparin should be administered to prevent deep-venous
thrombosis if no active bleeding or coagulopathy is present. Insulin should be used only
if it is needed to maintain the blood glucose concentration below ~180 mg/dL.
TABLE 12-1INITIAL ANTIMICROBIAL THERAPY FOR SEVERE SEPSIS WITH NO
OBVIOUS SOURCE IN ADULTS WITH NORMAL RENAL FUNCTION
Clinical
Antimicrobial Regimens (Intravenous Therapy)
Condition
Immunocompetent The many acceptable regimens include (1) piperacillin-tazobactam (3.375 g
adult q4–6h); (2) imipenem-cilastatin (0.5 g q6h), ertapenem (1 g q24h), or
meropenem (1 g q8h); or (3) cefepime (2 g q12h). If the pt is allergic to β-
lactam agents, use ciprofloxacin (400 mg q12h) or levofloxacin (500–750
mg q12h) plus clindamycin (600 mg q8h). Vancomycin (15 mg/kg q12h)
should be added to each of the above regimens.
Neutropenia Regimens include (1) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h)
(<500 or cefepime (2 g q8h) or (2) piperacillin-tazobactam (3.375 g q4h) plus
neutrophils/μL) tobramycin (5–7 mg/kg q24h). Vancomycin (15 mg/kg q12h) should be
added if the pt has an indwelling vascular catheter, has received quinolone
prophylaxis, or has received intensive chemotherapy that produces
mucosal damage; if staphylococci are suspected; if the institution has a
high incidence of MRSA infections; or if there is a high prevalence of MRSA
isolates in the community. Empirical antifungal therapy with an
echinocandin (for caspofungin: a 70-mg loading dose, then 50 mg daily),
voriconazole (6 mg/kg q12h for 2 doses, then 3 mg/kg q12h), or a lipid
formulation of amphotericin B should be added if the pt is hypotensive, has
been receiving broad-spectrum antibacterial drugs, or remains febrile 5
days after initiation of empirical antibacterial therapy.
Splenectomy Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local
prevalence of cephalosporin-resistant pneumococci is high, add
vancomycin. If the pt is allergic to β-lactam drugs, vancomycin (15 mg/kg
q12h) plus either moxifloxacin (400 mg q24h) or levofloxacin (750 mg q24h)
should be used.
IV drug user Vancomycin (15 mg/kg q12h) is essential.
AIDS Cefepime alone (2 g q8h) or piperacillin-tazobactam (3.375 g q4h) plus
tobramycin (5–7 mg/kg q24h) should be used. If the pt is allergic to β-
lactam drugs, ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h)
plus vancomycin (15 mg/kg q12h) plus tobramycin should be used.

o Prognosis
In all, 20–35% of pts with severe sepsis and 40–60% of pts with septic shock die within 30
days, and further deaths occur within 6 months. Prognostic stratification systems (e.g.,
APACHE II) can estimate the risk of dying of severe sepsis.
o Prevention: Nosocomial infections cause most episodes of severe sepsis and septic
shock in the United States. Measures to reduce those infections could reduce the
incidence of sepsis.
FRIDAY LO

1. Recommendation Protocol Diagnosis WHO for H5N1, SwineFlu, CoronaVirus

paper WHO

Corona Virus
Coronavirus Disease 2019 (COVID-19) Testing
This document provides testing guidelines for the Coronavirus Disease 2019 (COVID-19,
formerly known as 2019-nCoV) associated with an outbreak of respiratory illness that
originated in Wuhan, Hubei Province, China in late 2019. The causative agent for COVID-
19 disease is SARS-CoV-2 virus. For the purpose of clear communication, PHO uses the
term COVID-19 to refer to both the virus and the disease.
Who to test:
PHO Laboratory will accept samples for COVID-19 testing from individuals meeting
criteria for a person under investigation (PUI) or probable case for COVID-19 as
outlined by the Ministry of Health.
Clinical presentations that do not fit case definition, but are considered at risk of COVID-
19 by the assessing clinician will also be accepted for testing. PHO is not currently
recommending routine testing of asymptomatic persons for COVID-19. If the clinician
would like to further discuss the role for testing the PHO Microbiologists on-call are
available and can be contacted through the PHO Laboratory's Customer Service Centre
at 416-235-6556 / 1-877-604-4567 or the After-Hours Emergency Duty Officer at 416-605-
3113.
Mandatory data accompanying testing requests:
In order to expedite testing, as of February 10, 2020 PHO Laboratory pre-approval for
COVID-19 testing is no longer required, provided that the following mandatory
information is included on PHO Laboratory requisition:
1. Whether the individual meets criteria for a person under investigation (yes/ no)
2. Travel history (country and dates)
3. Contact of case or probable case (yes/no); if no, other sick contacts (yes/no; if yes,
describe)
4. Symptom onset date
5. Patient symptoms (fever, cough, runny nose, pneumonia)
6. Patient setting (ICU, hospitalized, ER or outpatient)
This mandatory information can be included in the specific PHO COVID-19 Test
Requisition.
Specimen collection recommendations:
A minimum of two specimens, from two different sites:
 Upper respiratory tract: submit both a nasopharyngeal swab (NPS) AND viral throat
swab collected in universal transport medium.
 Lower respiratory tract specimens: submit when possible.
 Sputum: collect if patient has a productive cough. Do not induce.
Serology for COVID-19 is not available.
STAT testing requirements:
PHO's Laboratory is committed to prioritizing testing to assist health-care providers in
making swift patient care decisions in an urgent or emergency circumstance (“STAT”).
  STAT samples must be shipped separately from routine specimens to the shipping
and receiving dock at 661 University, Toronto Ontario. For delivery instructions
please see Directions to 661 University Shipping Dock for Clinical Samples
 STAT samples must be placed in a clearly marked package indicating ‘STAT’ and
handled in accordance with the Canadian Biosafety Standards and shipped in
accordance with the Transportation of Dangerous Goods Regulations.
 Failure to ship separately will delay testing, primarily due to delays in
transportation, and will be processed as a routine sample.
Specimen Requirements

Test Required Specimen Type Minimum Collection

Requested Requisition(s) Volume Kit

COVID-19 Coronavirus Upper Nasopharyngeal Virus

Disease 2019 respiratory tract: swab in 1 ml Respiratory
(COVID-19) Nasopharyngeal universal Kit order #
Test swab transport media 390082
Requisition (NPS) AND (UTM)

COVID-19 Coronavirus Viral throat Swab in 1 ml Virus

Disease 2019 swab (see universal Culture Kit
(COVID-19) Submission and transport media order
Test Collection Notes (UTM) #390081
Requisition below)

COVID-19 Coronavirus Lower 1.0 ml Tuberculosis

Disease 2019 respiratory tract Kit order#:
(COVID-19) (when possible): 390042
Test sputum, BAL,
Requisition bronch wash,
plueral fluid,
lung tissue (see
Submission and
Collection Notes
below)

Submission and Collection Notes

1. Respiratory Tract Specimens:
Collection of multiple specimens from both the upper and lower respiratory tract, where
possible, is recommended.
I) Upper respiratory tract: submit both a nasopharyngeal swab (NPS) AND viral
throat swab collected in universal transport media.
II) Lower respiratory tract specimens: submit when possible.
III) Sputum: collect if patient has a productive cough. Do not induce.
2. Complete all fields of the COVID-19 Test Requisition form.
Test requested – specify COVID-19
 Specimen type
 Whether the individual meets criteria for a person under investigation (yes/ no)
 Travel history (country and dates)
 Contact of case or probable case (yes/no); if no, other sick contacts (yes/no; if yes,
describe)
 Symptom onset date
 Patient symptoms (fever, cough, runny nose, pneumonia)
 Patient setting (ICU, hospitalized, ER or outpatient)
Preparation Prior to Transport
Place specimen in biohazard bag and seal. Specimens should be stored at 2-8°C
following collection and shipped to PHO Laboratory on ice packs. If transport of specimen
to testing laboratory will be delayed more than 72 hours, specimens should be frozen at -
80°C and shipped on dry ice.
Package and ship primary clinical specimens to the local PHO Laboratory in accordance
with the Transportation of Dangerous Goods Regulations.
Test Frequency and Turnaround Time (TAT)
Testing for COVID-19 is performed at PHO Laboratory Toronto as required. NOTE:
Turnaround time will vary according to geographical location and proximity to PHO
Laboratory Toronto.
All specimens with presumptive positive or inconclusive results for COVID-19 at the PHO
Laboratory are sent to the National Microbiology Laboratory (NML) in Winnipeg, MB for
confirmatory testing.
The current test for COVID-19 at PHO Laboratory takes less than 24 hours to complete.
Reporting
Final results of COVID-19 and the viral multiplex testing from PHO Laboratory are
reported to the ordering health care provider as indicated on the requisition.
As a disease of public health significance, all positive results will be reported to the local
public health unit. As an interim measure we will also be reporting all negative results to
the local public health unit.
Test Methods
Testing for COVID-19 is done by real-time RT-PCR using protocols validated by PHO
Laboratory and the NML. Targets include the RdRp (RNA-dependent RNA polymerase)
gene and E (envelope) gene.
Specimens with any real-time PCR target(s) detected or indeterminate will be tested by
PCR and Sanger sequencing for the RdRp gene. The RdRp gene PCR and sequencing
assay in use at PHO Laboratory is a common coronavirus target designed to provide
broad detection of Betacoronavirus clade C viruses, including COVID-19.
Presumptive positive of COVID-19 at PHO Laboratory consists of:
 Detection of at least two genomic targets by real-time PCR
OR
 Detection of a single target by real-time PCR AND detection by sequencing
PHO Laboratory testing is considered INCONCLUSIVE if:
 A single target is detected by real-time PCR
OR
 One or both targets is/are indeterminate by real-time PCR
AND
  COVID-19 is not detected by sequencing
Presumptive positive and inconclusive specimens from PHO will be sequenced at PHO
and sent to NML for further confirmation.
For further details about the real time PCRs used at PHO for COVID-19 testing:
The following publication contains information on the COVID-19 real-time
PCR: Diagnostic detection of COVID-19 by real-time RT-PCR
For further details of the methods used at PHO for sequencing of presumptive laboratory
confirmed specimens:
The following publication contains additional technical information on the RdRp gene
PCR and sequencing protocol (which was developed as a component of MERS-CoV
PCR): Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC)
infections and Detection of a novel human coronavirus by real-timereverse-
transcription polymerase chain reaction.
Serology for COVID-19 is not currently available.

Algorithm
PHO Testing Algorithm for COVID-19 (as of February 07, 2020)
A. Testing for COVID-19
 Testing for COVID-19 is done by real-time RT-PCR using protocols validated by
PHO Laboratory and the NML. Targets include the RdRp (RNA-dependent RNA
polymerase) gene and E (envelope) gene.
 Specimens with any real-time PCR target(s) detected or indeterminate will be
tested by PCR and Sanger sequencing for the RdRp gene. RdRp sequencing
based PCR is a common coronavirus target designed to provide broad detection of
Betacoronavirus clade C viruses, including COVID-19.
 All specimens that are either positive or indeterminate by real-time RT PCR at PHO
Laboratory are sent to the National Microbiology Laboratory in Winnipeg, MB for
confirmatory testing.
B. Testing for other respiratory viruses:
 At least one respiratory specimen will be tested for influenza by molecular methods
(PCR), and evaluated for possible avian influenza if influenza A is positive and is
not identified as a seasonal subtype.
 Specimens will also be tested for other respiratory viruses by a multiplex respiratory
virus PCR (MRVP), which detects 11 respiratory virus targets. These include
influenza A, influenza A H3 subtype, influenza A H1 (pdm09) subtype, influenza B,
respiratory syncytial virus, parainfluenza, adenovirus, enterovirus, seasonal human
coronaviruses*, rhinovirus and human metapneumovirus.
*Cross-reaction with COVID-19 does not occur based on in-house laboratory
data and available sequence data.
Additional tests to be considered:
Testing for bacterial causes of community-acquired pneumonia:
Patients with pneumonia/parenchymal lung involvement should also be tested for bacterial
causes of community acquired pneumonia (CAP). Recommended testing available at
PHO Laboratory includes:
i. Mycoplasma pneumoniae/Chlamydophila pneumoniae duplex PCR:
 Should be ordered on the same NP or throat swab submitted for COVID-19 testing.
ii. Legionella testing:
  Legionella PCR: can be ordered on the same lower respiratory tract specimens
submitted forCOVID-19 testing (e.g. sputum, BAL, bronchial wash, aspirates, lung
tissue).
 Legionella urinary antigen testing (minimum urine volume 2 ml).
NB. If a person under investigation is worsening or not improving, testing should
be repeated, even if previous tests were positive for another pathogen.

2. Pathophysiology of Sepsis
paper
3. Complication of H5N1, terutama Reyes Syndrome
Reye syndrome is a rare and potentially fatal pediatric illness defined as acute
noninflammatory encephalopathy with fatty liver failure. Australian pathologist R.D.K.
Reye first described this syndrome in 1963. National surveillance of Reye syndrome
began in the United States in the early 1970s and led to strict warnings regarding aspirin
use in children. Reye syndrome typically presents in children as vomiting and confusion
with rapid progression to coma and death. This syndrome often begins in the days
following recovery from a viral illness during which aspirin was administered. Inborn errors
of metabolism (especially fatty acid metabolism), medication reactions and toxins may
also predispose or cause the development of Reye syndrome. This diagnosis is based on
clinical signs as well as laboratory testing. However, there is no test specific to Reye
syndrome.[1][2]

Etiology
Reye syndrome is most commonly precipitated by viral pathogens such as influenza A
and B as well as varicella. Center for Disease Control and Prevention (CDC) surveillance
data between 1980 and 1997 found that cases of Reye syndrome were preceded
by influenza infection 73%, varicella infection 21%, and gastroenteritis infections 14% of
the time. Serum salicylate concentrations were detectable in 82% of cases. Less
commonly associated viral associations are seen with coxsackie, parainfluenza, Epstein-
Barr (EBV), cytomegalovirus (CMV), adenovirus and hepatitis. Bacterial pathogens such
as Chlamydia, Bordetella pertussis, Mycoplasma, and Shigella have also been associated
with the development of Reye syndrome. Epidemiologic studies found a link between use
of salicylate and development of Reye syndrome. While less than 0.1% of children who
took aspirin developed Reye syndrome, more than 80% of children diagnosed with Reye
syndrome had taken aspirin in the preceding 3 weeks. This data led to recommendations
against the use of aspirin in children in 1980. The number of reported cases of Reye
syndrome fell dramatically following the widespread warnings against the use of aspirin in
children.[3][4]

Epidemiology
Reye syndrome is a rare diagnosis with fewer than 2 cases reported annually since 1994.
However, the true incidence may not be known for reporting cases to the CDC is no
longer mandated. The peak age of onset is 5 to 14 years of age; however, cases have
been reported in children less than one year of age. Gender has not been reported as a
risk factor. There is seasonal variation with the majority of cases being reported from
December through April.
National surveillance of Reye syndrome began in 1973. The CDC reported 555 cases
between 1979 and 1980. Between December 1980 through November 1997, the CDC
reported 1207 cases of Reye syndrome in the United States. The incidence fell from an
average of 100 cases per year in 1985 and 1986 to an average of 36 cases per year
between 1987 and 1993. Incidence has fallen off sharply since 1991 with 0.2 to 1.1 case
per million reported in the United States between 1991 and 1994.
Widespread warnings again the use of aspirin in children were issued in the United
States in 1980. A sharp decline in the number of reported cases of Reye
syndrome followed this issuance. Similar patterns of incidence were observed in the
United Kingdom. In 1986, the United Kingdon warned against the use of aspirin in children
under the age of 12. Following that warning, the incidence fell from 0.63 cases per
100,000 in 1983-1984 to 0.11 cases per 100,000 in 1990 through 1991. Similar declines
were also observed in France.
It should be noted that aspirin remains a mainstay of treatment for children diagnosed with
Kawasaki disease. In children who require long-term salicylate therapy, clinicians and
caregivers should remain vigilant in monitoring for signs and symptoms of Reye
syndrome.[5][6]

Pathophysiology
The exact pathophysiology of Reye syndrome is not precisely known; however, it appears
to involve mitochondrial injury in the setting of a viral illness. Aspirin may cause or
perpetuate damage to cellular mitochondria resulting in inhibition of fatty-acid
metabolism. The neurologic features of Reye syndrome likely result from hepatic
mitochondrial dysfunction causing elevated ammonia levels. Hyperammonemia may
induce astrocyte edema resulting in diffuse cerebral edema and subsequent elevated
intracranial pressure. Pathology studies have revealed astrocyte edema, loss of neurons,
fatty degeneration of kidneys, and a swollen and a reduced number of mitochondria.[7]

History and Physical

A high level of suspicion based on the history of presenting illness, clinical signs and
symptoms and laboratory findings are required to make this rare diagnosis. Signs and
symptoms of Reye syndrome typically develop between 12 hours and 3 weeks after
recovery from a viral illness such as upper respiratory tract infection or gastroenteritis. The
most common onset of vomiting occurs between 3 and 6 days after a viral illness. The
CDC has described clinical progression as 5 distinct stages:
Stage 1
 Persistent, copious vomiting
 Lethargy, nightmares, increased somnolence
 Confusion
Stage 2
 Stupor, disorientation, combativeness, delirium
 Hyperreflexia, positive Babinski sign, lack of appropriate response to noxious
stimuli, dilated and sluggish pupils
 Hyperventilation, tachycardia
Stage 3
 Obtunded, comatose, decorticate rigidity
Stage 4
 Pupil dilation with minimal response to light or fixed and dilated pupils, deconjugate
gaze with caloric stimuli
 Deep coma with decerebrate rigidity
Stage 5
 Seizures
 Flaccid paralysis, absent deep tendon reflexes, no pupillary response
 Respiratory arrest
 Death
Evaluation
The CDC has defined Reye syndrome using the following criteria:
"Acute noninflammatory encephalopathy that is documented clinically by a) an alteration in
consciousness and, if available b) a record of cerebrospinal fluid (CSF) containing less
than or equal to 8 leukocytes/cu.mm or a histologic specimen demonstrating cerebral
edema without perivascular or meningeal inflammation.
Hepatopathy documented by either a) a liver biopsy or an autopsy considered to be
diagnostic of Reye syndrome or b) a threefold or greater increased in the levels fo the
serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase
(SGPT) or serum ammonia.
No more reasonable explanation for the cerebral and hepatic abnormalities."
Lab abnormalities associated with Reye syndrome include elevated liver function tests
(ALT, AST, bilirubin), hyperammonemia, abnormal coagulation studies, elevated amylase,
and lipase, decreased serum bicarbonate and lab values consistent with dehydration. The
most common lab finding is an early rise in ammonia occurring within 1 to 2 days of
mental status changes. If lumbar puncture is performed to obtain CSF, the leukocyte
count must be below 8 to meet diagnostic criteria. Opening pressure may be elevated
in later clinical stages of disease but may remain normal early on. [8][9][10]

Treatment / Management
Reye syndrome is a rapidly progressing disease that may require invasive procedures
early on to maintain hemodynamically stability and adequate respiratory function. These
may include placement of central venous access, airway intubation, and placement of a
Foley catheter to monitor urine output. Additional specialized procedures such as liver
biopsy and intracranial pressure monitoring may also be indicated.[11][2][12]
Treatment of Reye syndrome is mainly supportive and requires close monitoring of
multiple clinical parameters best accomplished in an intensive care unit setting.
Aggressive treatment may be required to correct the following serum abnormalities:
 Hypoglycemia may be treated with dextrose-containing fluids (D50, D10, D5, etc)
with a serum glucose goal of 100-120mg/dl.
 Acidosis may be treated with sodium bicarbonate (attention not to over correct or
correct too rapidly) and ventilation management.
 Hyperammonemia may be treated with phenylacetate-sodium benzoate (Immunol)
or sodium polystyrene sulfate (Kayexalate) but may require hemodialysis if level
greater than 500mcg/dl.
 Coaguloathy may be treated (especially before invasive procedures or with
clinically significant bleeding) using cryoprecipitate, fresh frozen plasma (FFP), or
Vitamin K.
Measures to target treatment of increased ICP may include:
 Elevating the head of the bed to 30 degrees
 Control of fever to prevent increased cerebral metabolism and rigors
 ICP monitoring
 Lasix administration
 Careful fluid regulation to prevent overhydration
 Sedation and analgesia
 Mannitol or hypertonic saline
  Seizure treatment and subsequent prophylaxis

Differential Diagnosis
 Drug toxicity
 Hypoglycemia
 Encephalitis
 Meningitis
 Lead and other heavy metal toxicities
 Intracranial bleeding
 Mushroom toxicity

Complications
 Seizures
 Cerebral herniation
 Aspiration pneumonia
 Cardiac arrhythmias
 Cardiovascular collapse
 Pancreatitis
 Gastrointestinal bleeding
 Respiratory failure
 Renal failure
 Sepsis
 Death

Consultations
 Pediatrician
 Neurologist
 Hepatologist

Pearls and Other Issues

Signs and symptoms of Reye syndrome should prompt strong suspicion and investigation
for undiagnosed inborn errors of metabolism (IEM). Features such as lack of viral
prodrome, family history of IEM, a family history of unexplained encephalopathy, pre-
existing neurologic symptoms, and patient age less than one year make the diagnosis of
Reye syndrome less likely.

Enhancing Healthcare Team Outcomes

Given the high mortality of Reye syndrome despite treatment, the focus today is on
prevention. Besides physicians, the nurse and the pharmacist are in a prime position to
educate the parents about risk factors for the disorder. The family should be told to avoid
the use of salicylates in children. Further, the parents should be educated about the
symptoms and signs of Reyes syndrome and when to seek immediate help. Finally, the
CDC recommends that all children over the age of 6 months should receive the
influenza vaccine. The pharmacist should always speak to the family about the safe use of
medications in children and alternative options for the management of fever and
pain.[13][14][15]
Outcomes
Over the past 4 decades, the mortality rate of Reye syndrome has dropped from 60% to
about 20%, chiefly due to early recognition and aggressive management. By preventing
increased intracranial pressure and edema, death can be avoided in many children. For
those who survive, full recovery has been noted in about two-thirds of patients. However,
those children with elevated levels of ammonia usually have residual neurological
deficits.[16][17] (Level III)

Reye's syndrome is a rare but serious condition that results in microvesicular hepatic
steatosis (fatty changes of the liver) and acute encephalopathy (altered mental status)
primarily in children and teenagers recovering from a viral illness (such as influenza or
varicella zoster virus).(1-4) While it is most common in children, it can occur at any
age.(1,2) Approximately 3-5 days after the onset of the viral illness, the signs and
symptoms of Reye's syndrome present in the following order: persistent vomiting, unusual
sleepiness, lethargy, disorientation and confusion, delirium, seizures and loss of
consciousness. Laboratory abnormalities common to Reye's syndrome include a decrease
in serum glucose and pH and increases in alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and ammonia (NH3).(1-3) Recovery is dependent on the rapidity
of syndrome progression, degree of swelling of the brain, injury to the brain and timing of
diagnosis.(1,2)

Given that viral illnesses in children and adolescents are common, why then
is this syndrome so rarely seen in clinical practice?
 It appears to be more common in patients with an inherited metabolic disorder
such as enzyme defects of b-oxidation (required for fatty acid metabolism) or the
urea cycle.(2,5)
 Furthermore, it has been associated with the use of salicylates.(3-6)
 Due to the rarity of this condition and atypical clinical presentation, it is easily
misdiagnosed and therefore is a diagnosis of exclusion.
How does use of aspirin or salicylate increase the risk for developing Reye's
syndrome?
 In order to understand this effect, the syndrome needs to be broken down into its
individual components in the context of aspirin use and then pull it all back
together. These components include the process by which aspirin contributes to
fat accumulation in the liver and hepatocellular damage that causes the
microvesicular hepatic steatosis and the process that result in acute
encephalopathy.
 It is important to remember that this syndrome occurs 3-5 days after the onset of
the viral illness and follows a specific and predictable progression.
  Thus, the effect on the central nervous system (encephalopathy) is a direct result
of the effects on the liver (or hepatocytes).
 Lastly, the exact mechanism by which aspirin contributes to the development of
this syndrome has been a matter of debate for a number of years, but recent
advances in understanding the pathophysiology of the syndrome have offered
insight into the role of aspirin.
What effect does aspirin or salicylate have on fat accumulation and
hepatocellular damage?
 Aspirin is rapidly metabolized to salicylate by plasma cholinesterases.(7) The
high concentrations of salicylate is carried to the liver via the hepatic portal vein
where it undergoes hepatic uptake and first pass metabolism to form a number
of metabolites. The metabolites of interest in Reye's syndrome include those
that are formed by the hepatocyte mitochondria, which include hydroxy
hippurate (HHA) and gentisate.(8,9) The hepatic uptake of salicylate is
important as the concentration in hepatocytes likely exceeds that found in the
serum or other tissues and salicylate is known to have a prolonged biologic half-
life during Reye's syndrome.(10,11) The higher salicylate concentrations within
the hepatocyte, its slower rate of removal, and the presence of a viral infection
creates an environment that alters the metabolism of fatty acids as well as the
ability of the hepatocyte to protect itself from damage and/or death.(10,11)
 As it relates to hepatic fat accumulation, salicylate and its metabolites (in
particular HHA and gentisate) have been shown to competitively inhibit the
enzyme long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) which is
involved in the b-oxidation of fatty acids.(8,12) The inhibition of fatty acid
metabolism is important given the fact that hepatocytes utilize fatty acids via
oxidative phosphorylation through the tricarboxylic acid cycle (TCA) in the
mitochondria to make energy.(8,13) Without the ATP generated through the
utilization of fatty acids, the hepatocytes (liver cells) can fail to maintain their
own intracellular environments/activities as well as the metabolism and
elimination of other metabolic by-products (such as conversion of ammonia to
blood urea nitrogen or BUN).(14) This is especially true during a viral infection
where the metabolic demands are higher. The ATP deficient or compromised
hepatocytes are then at increased risk for initiating intracellular cascades of
injury and possible apoptosis (programmed cell death).(14) These intracellular
cascades are in part initiated by an increased concentration of cytosolic
(cytoplasmic) calcium, which is known to further contribute to mitochondrial
 swelling, injury, and/or dysfunction.(14) Damage to the mitochondria further
impairs its ability to metabolize fatty acids since mitochondrial damage can
result in the loss of mitochondrial membrane potential via the formation of a
mitochondrial permeability transition (MPT) pore and/or through the
mitochondrial release of cytochrome c and other pro-apoptotic proteins that
initiate apoptosis (programmed cell death) of the hepatocyte.(14)
 Unfortunately, both of these effects on the mitochondria can be worsened or
accelerated in the presence of a viral infection and salicylate.(1-6) In regard to
salicylates, their contribution to mitochondrial damage (beyond the inhibition of
fatty acid metabolism) is related to their ability to increase the onset for a
change in the MPT to be compromised.(10) This not only accelerates the
hepatocellular damage by decreasing the liver's ability to handle the
accumulating fatty acids and metabolism of other metabolic by-products as
mentioned above (i.e., in particular, ammonia, NH3), but also disrupts normal
oxidative metabolism, thereby resulting in the accumulation pyruvate that is
shunted to form lactate.(10,15) While the redirection of pyruvate to lactate
allows glycolysis to continue, the accumulation of lactate can decrease the pH,
thereby increasing the risk for metabolic acidosis.(15) Therefore, the overall
effects on the hepatocytes is an accumulation of fat which causes the hepatic
steatosis, cell injury or initiation of apoptosis, and an inability to maintain other
metabolic functions.
How do these effects in the liver translate into the development of acute
encephalopathy?
 The liver is the primary organ involved in the metabolism and elimination of
many end products of metabolism.
 In addition to using free fatty acids for the generation of ATP, the normally
functioning liver also converts ammonia to a less toxic, more water soluble
metabolite called blood urea nitrogen (BUN).(15) The accumulation of
ammonia can result in its entry into the central nervous system (CNS) resulting
in nausea/vomiting and altered mental status that is seen with the presentation
of this condition.
 The persistent vomiting classically seen with Reye's syndrome can result in
electrolyte abnormalities and dehydration, especially in young children.
 This is complicated further by the liver's inability to help regulate blood glucose
levels and metabolize by-products of metabolism such as lactate. In fact,
patients may experience acid base imbalances and/or experience hypoglycemia,
 which if low enough can also contribute to altered mental status, seizures, and
coma.(1,2)
 As such, if Reye's syndrome is left untreated, the outcome can range from minor
brain damage to seizures and even death.(1,2)
 Therefore, based on the clinical presentation, the histological changes seen in the
liver and brain as well as the changes in labs, it would appear that the
underlying problem is an inhibition of oxidative phosphorylation and b-
oxidation (fatty acid metabolism). Furthermore, if left untreated this syndrome
can progress to irreversible brain damage and/or death.

4. Management WHO for H5N1 for human and avian

paper

5. Transmission of avian into human (antigenic shift)?

6. Prevention for H5N1
Prevention
Bird flu vaccine
The Food and Drug Administration has approved one vaccine to prevent infection with one
strain of H5N1 bird flu virus. This vaccine isn't available to the public, but the U.S.
government is stockpiling it and will distribute it in the event of an outbreak.
This vaccine could be used early in such an outbreak to provide limited protection until
another vaccine — designed to protect against the specific form of the virus causing the
outbreak — is developed and produced. Researchers continue to work on other types of
bird flu vaccines.
Recommendations for travelers
If you're traveling to Southeast Asia or to any region with bird flu outbreaks, consider these
public health recommendations:
 Avoid domesticated birds. If possible, avoid rural areas, small farms and open-air
markets.
 Wash your hands. This is one of the simplest and best ways to prevent infections of
all kinds. Use an alcohol-based hand sanitizer containing at least 60 percent alcohol
when you travel.
 Ask about a flu shot. Before traveling, ask your doctor about a flu shot. It won't
protect you specifically from bird flu, but it may help reduce the risk of simultaneous
infection with bird and human flu viruses.
Poultry and egg products
Because heat destroys avian viruses, cooked poultry isn't a health threat. Even so, it's
best to take precautions when handling and preparing poultry, which may be
contaminated with salmonella or other harmful bacteria.
 Avoid cross-contamination. Use hot, soapy water to wash cutting boards, utensils
and all surfaces that have come into contact with raw poultry.
 Cook thoroughly. Cook chicken until the juices run clear, and it reaches a minimum
internal temperature of 165 F (74 C).
 Steer clear of raw eggs. Because eggshells are often contaminated with bird
droppings, avoid foods containing raw or undercooked eggs.