Internal medicine review for national license examination 2

Internal Medicine Reviews for National License Examination II

S a n t i S i l a i r a t a n a , M D

D i v i s i o n o f Pu l m o n a r y M e d i c i n e , D e p a r t m e n t o f M e d i c i n e , Fa c u l t y o f M e d i c i n e Va j i r a H o s p i t a l

N a v a m i n d r a d h i r a j U n i v e r s i t y

Pulmonary Medicine and Critical Care

Asthma

COPD

Pneumonia

Tuberculosis

Sepsis and septic shock

Pleural effusion

Airway Diseases: Asthma and COPD

General Steps of Approach of Airway Diseases

Typical symptoms of

airway disease

Detailed history/examination Diagnostic tests

Typical Clinical Features in Airway Diseases

Mucociliary clearance BronchospasmCoughing

Sneezing

Chronic cough Sputum production

Wheezing Dyspnea/shortness of breath

Chest tightness

Spirometry with Bronchodilator Response Test

Airflow limitation: Reduced FEV1/FVC (Normal 0.75-0.80) Reversibility: FEV1 increases >12% and 200 mL

Asthma versus COPD

Asthma COPD

Age group Typically begins in childhood Patient typically >40 years of age

Smoking No direct relationship Mainly smokers and ex-smokers

Dyspnea Episodic attacks with exposures to allergen, irritant, or exercise

Progressive shortness of breath, usually with exertion

Cough Typically a dry cough at night Productive cough, typically in the morning

Asthma

Asthma

3 Episodic breathlessness, wheezing, chest tightness

Associated with airway hyperresponsiveness2

1 Chronic inflammation of airways

5 Reversible either spontaneously or with treatment

4 Airflow limitation

Asthma Phenotypes

Asthma with obesityAllergic asthma Late-onset asthmaNon-allergic asthma

Exercise-induced asthma Occupational asthma Work-aggravated asthma Aspirin-induced asthma Asthma-COPD

overlap syndrome (ACOS)

Pathogenesis of Allergic Asthma

Airway Abnormalities in Asthma

Normal bronchiole Asthmatic bronchiole

1

2

3

4

Smooth muscle hypertrophy

Vascular proliferation Capillary leakage

Submucosal gland hypertrophy

Mucous hypersecretion

Physiologic Change in Asthma

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Airway Resistance

Airway narrowing ⬇

Increased resistance ⬇

Increased work of breathing ⬇

Dyspnea, muscle fatigue ⬇

Respiratory failure

General Steps of Approach: Asthma

Screening typical symptoms of asthma

Detailed history/examination

for asthma

Diagnostic tests for asthma

Evidence of variable respiratory symptoms

Evidence of variable airflow limitation

Symptoms of Asthma

Increased probability of asthma

More than one symptoms of asthma,especially in adults

Symptoms often worse at night orearly morning

Symptoms vary over time and in intensity

Symptoms are triggered by viral infection,exercise, allergen exposure, changes in weather, laughter, or irritants

Decreased probability of asthma

Isolated cough with no other respiratory symptoms

Chronic production of sputum

Shortness of breath associated dizziness,lightheadedness, paresthesia

Chest pain

Exercise-induced dyspnea with noisy inspiration

Diagnostic Tests for Asthma

Peak Expiratory

Flow

Broncho-provocation

testSpirometry Exercise

challenge testInflammatory

markers

FEV1/FVC Reversibility

Methacholine Histamine

Eucapnic hyperventilation Mannitol

Variability Reversibility

Exhaled nitric oxide (FENO) Allergy test

Serum IgE level Sputum eosinophil

(Mini-Wright) Peak Flow Meter

Peak Flow VariabilityPEF max

PEF min

PEF variability = (PEF max - PEF min)

1/2 x (PEF max + PEF min)

Diagnosis of asthma can be made when average daily diurnal PEF variability

>20%

Minimum Morning Pre-bronchodilator PEFPEF max

PEF min

Min%Max = PEF min

PEF max

Diagnosis of asthma can be made when Min%Max

<80%

Previous Guidelines

Methacholine Challenge Testing

Baseline spirometry Repeat spirometry Repeat spirometryuntil FEV1 fall 20%

or the dose of 16 mg/mL

is reached

Methacholine 0.031-0.625 mg/mL

Methacholine 2x-4x of

initial concentration

Albuterol 2 puff

Repeat spirometry

Diagnostic Algorithm for Asthma: Summary

Clinical Features Shortness of breath, Chest tightness, Recurrent wheezing, and Cough Symptoms get worse during nighttime, early morning, seasonal, allergen exposure, or exercise Presence of allergic disease or a family history of allergy or asthma (not required)

Reversibility Spirometry: FEV1/FVC <75% with FEV1 increase ≥12% AND 200 mL post bronchodilator Peak expiratory flow (PEF): Increase ≥20% or ≥60 L/min post bronchodilator

Variability Test Average diurnal PEF variability: >10% Minimum morning PEF: <80%

Bronchoprovocation Test Methacholine test: PC20 <8 mg/mL Exercise challenge test: FEV1 reduces >10%

and 200 mL

Asthma & Asthma Symptoms: Tip of the Iceberg

Airway inflammation

Bronchialhyperresponsiveness

Bronchospasm Airflow limitation

Asthma symptoms

Risk of asthma exacerbation

Treatment for Asthma (symptom) control

Treatment for Worsening/exacerbation

risk

General Principles of Asthma Management

Assessing disease severity Identify risk(s)

Provide treatment and modify risk(s)

Assessment of symptom and risk control

Step treatmentup or down to

maintain control

Initiation of TreatmentGINA 2014

Presenting symptoms Preferred initial controller

Symptoms or SABA use <2/month No waking due to asthma symptom No risk factor

No controller

Infrequent symptoms Presence of ≥1 risk factors for exacerbation Low dose ICS

Symptoms or SABA use >2/month but <2 /week Waking due to asthma ≥1/month Low dose ICS

Symptoms or SABA use >2/week Low dose ICS LTRA or Theophylline

Symptoms in most days Waking due to asthma >1/week

Medium/high dose ICS Low dose ICS/LABA

Severly symptomatic or acute exacerbationShort course of oral corticosteroids AND

High dose ICS OR Moderate dose ICS/LABA

Global Strategy for Asthma Management and Prevention. Revised 2014

Inhaled Corticosteroid Dosage

ICS Low dose (µg) Medium dose (µg) High dose (µg)

Beclometasone 200-500 500-1000 1000-2000

Budesonide 200-400 400-800 800-1600

Fluticasone propionate 100-250 250-500 500-1000

Ciclesonide 80-160 160-320 320-1280

Mometasone furoate 200-400 400-800 800-1200

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Level of Asthma Control

Characteristics Controlled (All of the following)

Partly Controlled (Any measure present

in any week)Uncontrolled

Daytime symptoms None (twice or less/week) More than twice/week

Three or more features of partly controlled asthma

present in any week

Limitations of activities None Any

Nocturnal symptoms/awakening None Any

Need for reliever/rescue treatment None (twice or less/week) More than twice/week

Lung function (PEF or FEV1) Normal <80% predicted or personal best (if known)

Exacerbations None One or more/year One in any week

Management Options

CPU

Uncontrolled Partly Controlled Controlled

Step up treatment

Maintain treatment and observe

Step down treatment

Step up treatment Maintain treatment and observe

3-6 Months

Stepwise Approach

Step 5

Step 4

Refer for add-on treatment

(e.g. anti-IgE)

Step 3

Medium/high doseICS/LABA

Step 1 Step 2Low dose ICS/LABAPreferred Low dose ICS

Optional Consider low dose ICS

LTRA Theo

Medium/high dose ICS Low dose ICS +LTRA Low dose ICS + Theo

High dose ICS + LTRAHigh dose ICS + Theo

Add low dose OCS

As needed short-acting beta2 agonist (SABA)

As needed short-acting beta2 agonist (SABA) or Low dose ICS/formoterol

ICS = Inhaled corticosteroids LTRA = Leukotriene receptor antagonists LABA = Long-acting beta2 agonists Theo = Theophylline OCS = Oral corticosteroids


Options for Stepping Down Treatment

Current Step Current medication and dose Options for stepping down

5High dose ICS/LABA

plus OCS or other add-on agents

Continue high dose ICS/LABA, reduce OCS dose Use sputum-guided approach to reduce OCS Alternate-day OCS treatment Replace OCS with high dose ICS

4

Moderate to high dose ICS/LABA maintenance treatment

Continue combination ICS/LABA with 50% reduction in ICS component by using available combination

Discontinuing LABA (more likely to lead to deterioration)

Medium dose ICS/formoterol as maintenance and reliever

Reduce maintenance ICS/formoterol to low dose, and continue as needed low dose ICS/formoterol reliever

High dose ICS plus second controller Reduce ICS dose by 50% and continue second controller


Options for Stepping Down Treatment

Current Step Current medication and dose Options for stepping down

3

Low dose ICS/LABA maintenance Reduce ICS/LABA to once daily Discontinuing LABA (more likely to lead to deterioration)

Low dose ICS/formoterol as maintenance and reliever

Reduce maintenance ICS/formoterol to once daily, and continue as needed low dose ICS/formoterol reliever

Moderate or high dose ICS Reduce ICS dose by 50%

2

Low dose ICS Once-daily dosing (budesonide, ciclesonide, mometasone)

Low dose ICS or LTRA Stop controller treatment (when no symptoms for 6-12 months

and no risk factor) Complete cessation of ICS (increased risk of exacerbation in adults)


Patient with Poor Symptom Control

1 3 42

Check inhaler technique Discuss adherence

Confirm the diagnosis of asthma

Remove potentialrisk factors

Consider treatment step up

Assess and manage comorbidities

Management of Asthma Exacerbation

Initial assessment

2nd Assessment

Intubation

Unconscious Air hunger

RR <12/min Unstable hemodynamics

A

Hx of intubationHx of steroid use

Admission in 1 year Rescue medication use

>1 canister/month

B

PR >130/min RR >30/min Wheezing

C

Incomplete sentence Accessory muscle used Abdominal paradox Unable to lie down

D

Ramathibodi action plan

Short acting bronchodilators: 4 puffs of salbutamol (100 µg) via spacer q 15-20 min

Salbutamol 1 NB via nebulizer q 15-20 min

if Any of B or D

Systemic corticosteroid: Dexamethasone 4-5 mg iv

Oral prednisolone 40 mg p.o.

PEF

3rd AssessmentA

C

D

PEF


Discharge

4th Assessment

Iprotropium/fenoterol 4 puff via spacer

1 NB via nebulizer

PEFR >70% PEFR >70% + any of C

PEFR 50-70% + any of C

PEFR 50-70% + any of A, D PEFR <50%

PEFR >70%

PEFR 50-70% + any of C

Admit ward Admit ICU

PEF


Treatment in Acute Care Setting

Recommended Oxygen:

to achieve arterial oxygen saturation of 93-95% low flow oxygen is preferred to high flow (100% O2)

Inhaled short-acting beta2-agonist and Iprotropium bromide: The most cost-effective and efficient delivery: pMDI with a spacer When nebulization is used, initiate with continuous therapy, followed by intermittent on-demand therapy Iprotropium bromide - greater improvement in PEF and FEV1

Systemic corticosteroids: Oral administration = intravenous administration Dose: Prednisolone 50 mg/day or Hydrocortisone 200 mg/day Duration: 5-7 days

IMPORTANT!!

Acute exacerbation of asthma = uncontrolled asthma

Review and modify treatment to prevent another exacerbation BEFORE send them home

Discharge Management

Medications Risk Reduction Uncontrolled asthma

symptoms

Excessive SABA use

Inadequate ICS

Low FEV1 (<60% predicted)

Major psychological or socioeconomic problems

Exposures: smoking, allergens

Comorbidity: obesity, rhinosinusitis

Self-management & Asthma action plan

Review inhaler technique

Review PEF technique

Provide written asthma action plan

Evaluate the patient’s response to the exacerbation

Review the patient’s use of controller treatment

Oral corticosteroids: At least 5-7 days of

Prednisolone 1 mg/kg/day (max. 50 mg/day)

Inhaled corticosteroids: Initiate (if not done)

Step up treatment for 2-4 wks Remind adherence

Reliever medications: Transfer back to as-needed use

beta2-agonist is preferred

Chronic Obstructive Pulmonary Disease (COPD)

นพ.สันติ สิลัยรัตน พบ.อายุรแพทย โรคระบบการหายใจและเวชบำบัดวิกฤตทางการหายใจแผนกอายุรกรรม ศูนยแพทยศาสตรศึกษาชั้นคลินิก โรงพยาบาลอุดรธานี

Holistic approach for COPD: Time to Treat Earlier to Prevent Future Risk

ความรูเรื่องโรคปอดอุดกั้นเรื้อรัง

Definition

3 Characterized by persistent airflow limitation

Associated with noxious particles and gases2

1 Chronic inflammation of airways

4 Exacerbation and comorbidities contribute to the overall severity

5 Preventable and treatable

Causes and Pathogenesis of COPDสาเหตุและกลไกการเกิดโรคปอดอุดกั้นเรื้อรัง

Physiologic and Health Effects of COPD

Expiratory airflow limitation

Air trapping

Hyperinflation

Inactivity

Deconditioning Activity limitation Poor quality of life

Dyspnea

Exacerbations

Diagnosisการวินิจฉัยโรคปอดอุดกั้นเรื้อรัง

Grading of COPD Severity

ระดับความรุนแรงของโรคปอดอุดกั้นเรื้อรัง

ระดับความรุนแรง Mild Moderate Severe Very Severe

FEV1/FVC <70%<70%<70%<70%

FEV1(% of

predicted)>80 50-79 30-49

<30หรือ <50 รวมกับมีภาวะ

การหายใจลมเหลวเรื้อรัง หรือมี cor pulmonale

Combined Assessment for COPD

C D

A B

RiskGOLD classification

of Airflow Limitation

1

2

3

4≥2

1

0

RiskExacerbation

history

mMRC 0-1 CAT <10

mMRC ≥2 CAT >10

B CA D

Less symptoms Low risk

MORE symptoms Low risk

Less symptoms HIGH risk

MORE symptoms HIGH risk

Modified Medical Research Council Questionnaire

สำหรับการประเมินระดับอาการเหนื่อยในผู้ป่วยโรคทางเดินหายใจ

Modified Medical Research Council Questionnaire

สำหรับการประเมินระดับอาการเหนื่อยในผูปวยโรคทางเดินหายใจ

เลือกขอใดขอหนึ่งตอไปนี้ตามอาการที่ทานเห็นวาใกลเคียงกับความรูสึกของทานมากที่สุดเลือกขอใดขอหนึ่งตอไปนี้ตามอาการที่ทานเห็นวาใกลเคียงกับความรูสึกของทานมากที่สุดเลือกขอใดขอหนึ่งตอไปนี้ตามอาการที่ทานเห็นวาใกลเคียงกับความรูสึกของทานมากที่สุด

Grade 0: รูสึกเหนื่อยเฉพาะเวลาที่ออกกำลังกายหนัก ๆ ☐

Grade 1: รูสึกเหนื่อยเวลาเดินขึ้นบันได หรือเดินขึ้นเนิน ☐

Grade 2: รูสึกเหนื่อยเมื่อเดินบนพื้นราบจนเดินไดชากวาคนทั่วไป หรือตองพักเมื่อตองเดินไกล ๆ ☐

Grade 3: รูสึกเหนื่อยจนเดินบนพื้นราบไดไมถึง 100 เมตร หรือเดินไดไมกี่นาที ☐

Grade 4: รูสึกเหนื่อยจนไมกลาออกจากบาน หรือเหนื่อยจากการทำกิจวัตรประจำวัน ☐

COPD Assessment Test

0 1 2 3 4 5 คะแนน

ฉันไม่มีอาการไอเลย ⚪ ⚪ ⚪ ⚪ ⚪ ⚪ ฉันไอตลอดเวลา

ฉันไม่มีเสมหะในปอดเลย ⚪ ⚪ ⚪ ⚪ ⚪ ⚪ ปอดของฉันเต็มไปด้วยเสมหะ

ฉันไม่รู้สึกแน่นหน้าอกเลย ⚪ ⚪ ⚪ ⚪ ⚪ ⚪ ฉันรู้สึกแน่นหน้าอกมาก

ฉันรู้สึกหายใจได้คล่องเมื่อต้องเดินขึ้นเนิน

หรือขึ้นบันไดหนึ่งชั้น⚪ ⚪ ⚪ ⚪ ⚪ ⚪

ฉันเหนื่อยหอบอย่างมากเมื่อต้องเดินขึ้นเนิน

หรือขึ้นบันไดหนึ่งชั้น

ฉันทำกิจกรรมต่าง ๆ ที่บ้านได้โดยไม่จำกัด ⚪ ⚪ ⚪ ⚪ ⚪ ⚪ ฉันทำกิจกรรมต่าง ๆ ที่บ้านได้อย่างจำกัดมาก

ฉันมีความมั่นใจที่จะออกไปนอกบ้านได้

แม้ว่าปอดฉันยังมีปัญหา⚪ ⚪ ⚪ ⚪ ⚪ ⚪

ฉันไม่มั่นใจเลยที่จะออกไปนอกบ้านเพราะ

ปัญหาที่ปอด

ฉันนอนหลับได้สนิท ⚪ ⚪ ⚪ ⚪ ⚪ ⚪ ฉันนอนหลับไม่สนิทเพราะปอดมีปัญหา

ฉันรู้สึกกระฉับกระเฉงอย่างมาก ⚪ ⚪ ⚪ ⚪ ⚪ ⚪ ฉันรู้สึกอ่อนเพลียและเหนื่อยล้า

Exacerbations and Progression of COPDการกำเริบเฉียบพลันกับการดำเนินโรค

FEV1

อายุ

ไมมีการกำเริบเสียชีวิต

เริ่มมีอาการ

เกิดการกำเริบเฉียบพลัน

ยิ่งมีการกำเริบของโรคบอย และมาก ยิ่งทำใหเสียชีวิตเร็วยิ่งขึ้นMORE exacerbations HIGHER mortality

Severity Grading and Number of Exacerbationsจำนวนครั้งเฉลี่ยของการกำเริบเฉียบพลันตอปในผูปวย COPD

0"

5"

10"

15"

20"

25"

zero" 0*1" 1*2" 2*3" 3*4" 4*6" 6*8" >8"

%"pa3ents"

Annualised"rate"of"exacerba3ons"

GOLD%Stage%3,4%(FEV1%<%50%%pred)%

Jones"et"al""Eur"Respir"J"2003;"21:"68–73""

0"

5"

10"

15"

20"

25"

30"

zero" 0*1" 1*2" 2*3" 3*4" 4*6" 6*8" >8"

%"pa3ents"

GOLD%Stage%2%%(FEV1%>%50%%pred)%

>40%%

Combined Assessment for COPDอัตราการเกิดการกำเริบปานกลาง/รุนแรงภายหลังการใช ICS

Calverley et al. NEJM 2007; 356:775-789.

0

0.3

0.5

0.8

1.0

1.3

1.5

Placebo Salmeterol Fluticasone Salmeterol/Fluticasone

0.850.930.97

1.13

25% reduction

* ** ✝�

*p < 0.001 vs placebo; †p = 0.002 vs SALM; �p = 0.024 vs FP*p < 0.001 vs placebo; †p = 0.002 vs SALM; ☨p = 0.024 vs FP Calverley et al. NEJM 2007; 356:775-789.

Combined Assessment for COPD

C D

A B

RiskGOLD classification

of Airflow Limitation

1

2

3

4≥2

1

0

RiskExacerbation

history

mMRC 0-1 CAT <10

mMRC ≥2 CAT >10

Components of COPD Management

Component 2: Symptom & Risk Management

Component 1: Identify &

Control risk factors

Component 3: Rehabilitation & Health promotion

Goals of COPD Management

แผนการรักษาผูปวยโรคปอดอุดกั้นเรื้อรัง

เพื่อคง เพื่อลด

สภาพรางกายในปจจุบันใหดีที่สุด ความเสี่ยงที่จะเกิดขึ้นในอนาคต

อาการ โครงสรางและสมรรถภาพปอด

ความถี่ของการใชยาขยาย

หลอดลมตามอาการ

โรคหรือภาวะรวม

สถานะสุขภาพ

กิจกรรมในแตละวัน

การกำเริบของโรค ความเสื่อมสถานะสุขภาพ

ความเสี่อมของโครงสราง

และสมรรถภาพปอด

โรคหรือภาวะรวม

ที่อาจเกิดขึ้นใหม

ผลขางเคียงของยาที่ใช

การเสียชีวิต

แผนการรักษา COPD

เพื่อคง เพื่อลด

Component 1: Identify and Control Risk Factors

Importance of Smoking Cessation in COPDผลของการหยุดบุหรี่กับการเปลี่ยนแปลงของสมรรถภาพปอด

Fletcher C et al. The Natural History of Chronic Bronchitis and Emphysema. 1976.Scanlon PD et al. Am J Respir Crit Care Med 2000; 161: 381-390.

Age25

ผูที่ยังคงสูบบุหรี่

ผูที่ไมสูบบุหรี่

40 70

เริ่มมีอาการ

55

เสียชีวิตเลิกบุหรี่

FEV1

Fletcher C et al. The Natural History of Chronic Bronchitis and Emphysema. 1976. Scanlon PD et al. Am J Respir Crit Care Med 2000; 161: 381-390.

Immunization for COPD Patientsการใหวัคซีนแกผูปวยโรคปอดอุดกั้นเรื้อรัง

Influenza vaccine Pneumococcal vaccine

ควรพิจารณาใหกับผูปวยทุกรายหากเปนไปไดทั้งนี้ขึ้นกับแนวปฏิบัติบริการในประเทศนั้น ๆ

Component 2: Symptom and Risk Management

Treatment Options for COPD

Patient Group First Choice Second Choice Alternative Choice

A SAMA prn SABA prn

LAMA LABA

SAMA + LABATheophylline

B LAMA LABA LAMA+LABA SAMA +SABA

Theophylline

C ICS + LABA LAMA LAMA + LABA

iPDE4 SAMA + SABA Theophylline

D ICS + LABA LAMA

ICS + LAMA ICS + LAMA + LABA ICS + LABA + iPDE4

LAMA + LABALAMA + iPDE4

Carbocysteine SAMA + SABA Theophylline

SAMA = short-acting muscarinic antagonist (anticholinergic) SABA = short-acting beta-2 agonist

ICS = inhaled corticosteroid iPDE2 = phosphodiesterase inhibito

Non ICS

ICS

สรุปหลักการใชยา สำหรับผูปวยโรคปอดอุดกั้นเรื้อรัง

ประเมินความพรอมในการใชอุปกรณ(แรงสูดยา, ความสัมพันธระหวางการสูดกับการกดยา)

เลือกอุปกรณที่เหมาะสมกับผูปวย

ติดตามผลการรักษา(อาการหอบเหนื่อย, CAT, mMRC, การกำเริบของโรค)

ปรับเพิ่มยาขยายหลอดลมเมื่อยังบรรเทาอาการหอบเหนื่อยไดไมเพียงพอ

ปรับเพิ่มยา ICSเมื่อมีการกำเริบบอย หรือยังมีอาการหอบ

Component 3: Rehabilitation and Health Promotion

Rehabilitation for COPD Patientsการฟนฟูสมรรถภาพปอด

เพิ่มความทนทาน

ตอการออกกำลังกาย

PulmonaryRehabilitation

ลดโอกาส

การเสียชีวิต

เสริมประสิทธิภาพของ

การรักษาดวย ICS/LABAทำใหสุขภาพจิตดีขึ้น

คลายความกังวล

ทำใหคุณภาพชีวิตดาน

ภาวะสุขภาพดีขึ้นทำใหกำลังกลามเนื้อแขนขาดีขึ้น

ลดจำนวนและวันใน

การเขารักษาในโรงพยาบาล

ฟนตัวจากอาการ

กำเริบของโรคไดเร็วขึ้น

Tuberculosis

Tuberculosis

20 * Diagnostics for tuberculosis: global demand and market potential *

1CHAPTER

WHO’s Global TB Monitoring and

Surveillance Project experts esti-

mate the total number of cases to

be 8.8 million (3.9 million sputum

smear-positives) (2).

In 2003, 4.1 million cases (1.9 mil-

lion sputum smear-positive) were

notified to public health officials

around the globe. Seven million of

the estimated 8.8 million cases are

concentrated in 22 high-burden

countries of the developing world

(Figure 2). If recent trends should

continue for the rest of this decade,

the projected global number of

new cases will increase to 10 mil-

lion cases in 2015 (3).

Exposure to TB

Subclinical "latent" infection

"active" TB disease

Sputumsmear

positive

Sputumsmear

negative

Drugsensitive

Drugresistant

Pulmonary

Smearpositive

Smearnegative

Drugsensitive

Drugresistant

Extrapulmonary

Fig

ur

e 1 TUBERCULOSIS CLASSIFICATION SCHEME

Fig

ur

e 2 THE ESTIMATED GLOBAL BURDEN OF TUBERCULOSIS

CUMMULATIVEINCIDENCE (%)

20%

35%

43%

47%

51%

54%

57%60%62%64%67%68%

70%72%73%

74%75%76%77%78%79%

80%

100%

ESTIMATEDINCIDENCE

1,788,0431,334,066

627,047362,819360,767278,392251,685241,537236,885195,207194,627160,688

144,942

137,260

110,319

106,20189,351

86,130

85,015

84,546

79,656

71,830

8,810,040

COUNTRY

IndiaChinaIndonesiaNigeriaBangladeshPakistanEthiopiaSouth AfricaPhilippinesKenyaDR CongoRussianFederationViet NamUR TanzaniaBrazilUgandaThailandMozambiqueZimbabweMyanmarAfghanistanCambodia GlobalEstimated TB Cases

Sou

rce:

refe

ren

ce 2

.More people die from TB than from any other curable infectious disease.

Every day 25,000 people develop active TB and 5,000 die of the disease.

WHO. Global tuberculosis control: surveillance, planning, financing: WHO report 2005. Geneva: WHO, 2005.

Poverty

Congregation

HIV pandemic

Tuberculosis-HIV Coinfection

* Diagnostics for tuberculosis: global demand and market potential * 53

resistant, it is estimated that over

400,000 people fall ill with MDR-TB

each year, and that over 50 million

people are latently infected with

MDR strains of TB (7). The regional

distribution of MDR-TB is illustrat-

ed in Figure 4. Two thirds of MDR-

TB cases occur in just three

countries, China, India and the

Russian Federation.

Another serious threat underlying

the need for improved diagnostics

is the HIV pandemic, which greatly

increases susceptibility to TB infec-

tion and disease, and decreases the

effectiveness of conventional diag-

nostic approaches. Globally, 12% of

new adult cases of TB are HIV co-

infected, but the burden of dual dis-

ease is concentrated in Africa and

in some regions in Asia (see Figure

5), where the collision between HIV

and high prevalence of latent TB

infection (50-90%) has sparked a

dramatic rise (3-10 fold in some

countries) in active TB cases.

In summary, tuberculosis is a glob-

al epidemic concentrated in the

developing world, in close associa-

tion with poverty and, increasingly,

HIV. Testing for tuberculosis

remains common in industrialized

countries, where immigrants make

up a large and growing fraction of

all cases. MDR-TB and HIV are both

substantial threats to TB control,

and have prompted significant

increases in expenditure on TB

diagnosis and treatment in devel-

oped countries since the mid-

1980s, when TB was declared to be

in the elimination phase in the

United States.

Global availabilityof TB laboratoryservices

Little information has been accessi-

ble on the availability of TB diag-

nostic services in developing

countries or the volume of testing.

To this end, we carried out a global

survey of TB laboratory services.

Surveys were distributed to 207

WHO Member States to gather

information on the number of pub-

lic and private laboratory facilities

performing sputum smear

microscopy, mycobacterial culture

and drug susceptibility testing

(DST). Information was also col-

lected on the volume of testing in

the public sector. Each survey of

the 116 survey responses was

screened and respondents were

contacted directly to explain errors

and/or unexpected information.

Raw data on the number of testing

centres for TB microscopy, culture

and DST are shown in Table 1.

Fig

ur

e 5 PREVALENT ADULT TB CASES COINFECTED WITH HIV, 2004

Sou

rce:

refe

ren

ce 3

.

Dye C, Watt CJ, Bleed DM et al. Journal of American Medical Association 2005; 293:2767-75.

The Gap between Estimated and Notified Cases

Estimated TB cases 8.8 Million

Health facility

TB casesDiagnostic

tests

Recorded & reported

4.1 Million cases reported

Detected but not notified private sector

military prisons

⊕⊖

WHO. Global tuberculosis control: surveillance, planning, financing: WHO report 2005. Geneva: WHO, 2005.

Multidrug-resistant and Extensively drug-resistant TB

Multidrug-resistant (MDR) TB Resistance against at least

rifampicin and isoniazid

Extensively drug-resistant (XDR) TB MDR-TB PLUS

Resistance to any fluoroquinolones AND

≥1 injectable second-line agents

O’Grady J, Maeurer M, Mwaba P et al. Current Opinion in Pulmonary Medicine 2011, 17; 134-141.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

(ethionamide, prothionamide, cycloserine, terizidone,para-aminosalicylic acid, clofazimine, amoxicillin-clavula-nate, clarithromycin, linezolid) is not recommended [12].Automated liquid culture systems are currently recom-mended by the WHO as the ‘gold standard’ for second-lineDST [12,13!!,14]. In this review, we describe the pheno-typic and genotypic methods currently available for thediagnosis of drug-resistant forms of M. tuberculosis anddiscuss future prospects for TB diagnostics.

Definitions of drug-resistant tuberculosisMDR-TB is defined as resistance to the two key first-lineanti-TB drugs, INH and RIF. XDR-TB is defined as TBcaused by strains of M. tuberculosis resistant to at leastINH and RIF (i.e. MDR-TB), plus any fluoroquinoloneand at least one of three injectable drugs used in anti-TBtreatment, capreomycin, kanamycin or amikacin [7!!,8!!].

Phenotypic drug susceptibility testingCulture-based or phenotypic DST methods are accurateand inexpensive but are disadvantaged by relying on thegrowth on M. tuberculosis, rendering them time consuming[15]. Phenotypic DST methods are performed on solid orliquid media as direct or indirect tests. Direct methods

are those used directly on patient samples where a setof drug-containing and drug-free media is inoculateddirectly with a patient specimen. Indirect DST involvesinoculation of drug-containing media with a pure culturegrown from the original patient specimen [12]. Commer-cial automated liquid culture DST methods have arelatively short turnaround time (because of sensitiveautomation and M. tuberculosis’s relatively faster growthin liquid compared with solid media) and are highlyaccurate but are expensive and require specialist equip-ment [16!]. The WHO considered evidence for theaccuracy and role of a number of noncommercial cul-ture-based methods that utilize widely available andinexpensive laboratory equipment and supplies andrecommended selected methods as interim measureswhile capacity for automated culture DST and/or geno-typic DST are being developed [1!!,17!!,18]. Microscopicobservation drug susceptibility (MODS) [17!!,19–21] andcolorimetric redox indicator (CRI) [22,23] methods and thenitrate reductase assay (NRA) [15,24!!,25] received WHOapproval [17!!]. Such methods have similar accuracy tocommercial liquid culture systems and could be imple-mented in high-burden, low-income settings with mini-mum cost; however, these tests require extensive operatortraining, standardization and quality assurance beforeimplementation [1!!].

136 Infectious diseases

Figure 2 Estimated percentage of multiple drug resistant tuberculosis among new tuberculosis cases, 2008a

, 0 to <3; , 3 to <6; , 6 to <12; , 12 to <18; , "18; ‘, no data available; , subnational data only. Reproduced withpermission from [2].

AFB stain Myc Culture

Drug susceptibility

Chest radiography CT scan

History Chronic productive cough*

Sputum production* Prolonged low grade fever

Night sweats Weight loss

Physical examination Bronchial breath sound

Crepitation Digital clubbing

Establishing Tuberculosis: Pulmonary TB

Imaging

Additional test(s)

Clinical features suggestive for tuberculosis

Microbiology

Sputum Microscopy for Acid-fast Bacilli

Friedrich Carl Adolf Neelsen (1854-1898)

Franz Ziehl (1857-1926)

Neelsen-Ziehl (Acid fast bacilli) Staining

Acid-fast bacilli appear pink in a contrasting methylene blue background

Light Emitting Diode (LED) Fluorescence Microscopy

Same (or slightly more) sensitivity

Cheaper and longer life duration of bulb (10,000 hr)

Cheaper microscopy

A dark room is not required

WHO recommended to use LED fluorescence microscope as a standard technique

WHO. Fluorescent light-emitting diode (LED) microscopy for diagnosis of tuberculosis: policy statement. Geneva: WHO 2011.

Radiographic Patterns of Tuberculosis

Reticulonodular infiltration

Miliary pattern lymphatic/interstitial spread

Cavitation

Bronchiectatic change

Bronchoalveolar pattern bronchial-alveolar spread

Diagnostic Algorithm: Clinically-suggestive

Patient with clinical features suggestive for pulmonary tuberculosis

Sputum examination for acid-fast bacilli Chest radiograph

AFB - positive CXR - compatible with TB

AFB - negative CXR - compatible with TB

AFB - negative CXR - incompatible with TB

Sputum culture and drug susceptibility testing for mycobacteria Treatment for pulmonary tuberculosis

Look for alternative diagnosis

แนวทางเวชปฏิบัติการรักษาวัณโรคในผู้ใหญ่ พ.ศ. 2556 (ฉบับร่าง). สำนักวัณโรค กรมควบคุมโรค สมาคมอุรเวชช์แห่งประเทศไทย

Diagnostic Algorithm: Radiographically-suggestive

Asymptomatic patient withradiographically suggestive tuberculosis

Sputum examination for acid-fast bacilli Review previous chest radiograph

AFB - positive CXR - compatible with TB

AFB - negative CXR - unavailable

AFB - negative CXR - unchanged

Sputum culture and drug susceptibility testing for mycobacteria Treatment for pulmonary tuberculosis

Re-evaluation and repeat CXR in 3 months

AFB - negative CXR - active TB

AFB - negative CXR - old lesion


Mycobacterial Culture

Minion J, et al. The Lancet Infectious Disease. 2010; 10 (10): 688-698.Richter E, et al. Exper Rev Resp Med. 2009; 3 (5): 497-510.

Conventional TB culture

system

Rapid colorimetric drug susceptibility test

20-30 days

Liquid culture-based technique

Mycobacterial growth indicator tube (MGIT)

7-10 days

Treatment Regimen for Pulmonary Tuberculosis

1 2 3 4 5 6 7 8

Isoniazid Rifampin

Pyrazinamide Ethambutol

Isoniazid Rifampin

Isoniazid Rifampin


Streptomycin

Isoniazid Rifampin


Isoniazid Rifampin

Ethambutol

Months of treatment

“New case”

“Retreatment”

Antituberculosis Drug: Dosage

Isoniazid (4-8 mkd)

Rifampin (8-12 mkd)

Pyrazinamide (20-30 mkd)

Ethambutol (15-20 mkd)

Streptomycin (15 mkd)

Body weight

(kg)

35-40 300 450 1000 600 500

41-50 300 450 1250 800 750

50-70 300 600 1500 1000 750-1000

mkd = mg/kg/day

3 weeks 6 weeks

Sputum AFB

Chest x-ray

Response Monitoring in New Case Pulmonary TB: M+

Start 1 2 3 4 5 6

Sputum AFB

Sputum AFB

Chest x-ray

if positive

Sputum culture for TB

if positive

Chest radiograph

2 months 2 months

IRZE IR

Chest radiograph

if positive “failure”

Sputum AFB

Sputum Culture for TB*

Chest radiograph

“High Risk” of Drug-resistance TB

History of close contact to a patient with MDR-TB

Return after default of >2 months

Relapse pulmonary TB

Treatment failure (smear positive at 5th month)

Special population (immigrants, prisoners, HIV infected persons)

Sputum AFB

Chest radiograph

Response Monitoring in New Case Pulmonary TB: M-

Start 1 2 3 4 5 6

Re-evaluate

Look for other cause

Chest radiograph

2 months 2 months

IRZE IR

4 weeks 5 weeks

Chest radiograph

if not improved/progressive

Antituberculosis Drug Side Effects: Minor

Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin

Nausea/vomiting/pain ☑ ☑ ☑

Joint pain ☑ ☑

Numbness ☑

Sedative ☑

Flu-like symptomps ☑

Anti TB drug can be continued; supportive treatment is usually adequate

Antituberculosis Drug Side Effects: Major


Skin rash ☑ ☑ ☑ ☑ ☑

Confusion ☑ ☑ ☑ ☑

Hepatitis/Jaundice ☑ ☑ ☑

Renal dysfunction ☑ ☑

Thrombocytopenia ☑

Nystagmus/vertigo ☑

Visual disturbance ☑

Antituberculosis Drug Side Effects: Minor


Nausea/vomiting/pain ☑ ☑ ☑

Joint pain ☑ ☑

Numbness ☑

Sedative ☑

Flu-like symptomps ☑

Anti TB drug can be continued; supportive treatment is usually adequate

Response Monitoring in Re-treatment Pulmonary TB

2 1 month

Start 1 2 3 4 5 6

Sputum AFB

Sputum AFB

Chest x-ray


Sputum AFB

Chest radiograph

2 months 2 months

IRZES IRE

Chest radiograph

if positive “failure”

Sputum AFB

Sputum Culture for TB

Chest radiograph

7 8

3 wks2 2

IRZE

1 month

if positive


if positive

Treatment After Interruption

Interruption occurred during intensive phase of treatment

Duration of interruption

Duration of interruption

≥80%

Continue treatment

until complete


yes no

Total treatment received

<80%<14 days ≥14 days

Continue treatment

until complete

Start over

<3 months≥3 months

Treatment for Extrapulmonary Tuberculosis

Treatment duration (months)

Lymph node 6-9

Pleura 6

Pericardium 6

Meninges and tuberculoma ≥12

Bone and joint 9-12

Urinary tract 6

Disseminated depends on the organ(s) involved

Community-acquired Pneumonia

The Disease Triangle

Host Pathogen

Environment

Airway-Lung Defense Mechanisms

Mucociliary clearance Bronchospasm Cellular/

chemical immunity

Coughing Sneezing

Mechanical barriers

Transmission and Pathogenesis

3

2

5

4

Inhalation of aerosols Aspiration of oropharyngeal secretions

Hematogenous spread

Reactivation of latent infection

Mycoplasma pneumoniae Chlamydophila pneumoniae

Legionella pneumophila Chlamydophila psittaci

Streptococcus pneumoniae Haemophilus influenzae Gram-negative bacilli

Anaerobes

Mycobacterium tuberculosis Pneumocystis jiroveci

Staphylococcus aureus Extrapulmonary bacteremias

1Direct contact & Droplets

Rhinovirus Adenovirus

Influenza virus

Community-acquired Pneumonia: Common Pathogens

Bacteria Aerobic gram-positive cocci

Aerobic gram-negative bacilli Anaerobic bacteria

“Atypical” pathogen Mycoplasma pneumoniae Legionella pneumophila

Chlamydophila pneumoniae

Viruses RSV

Adenovirus Influenza virus

Pathogen-related Severity

Outpatients (Mild) Non-ICU inpatients ICU (Severe)

S pneumoniae S pneumoniae S pneumonia

M pneumoniae M pneumoniae Legionella spp.

H influenzae C pneumoniae H influenzae

C pneumoniae H influenzae Gram-negative bacilli

Respiratory viruses Legionella spp. S aureus

Aspiration respiratory viruses P aeruginosa

File T M. Lancet 2003; 362:1991-2001.

Host Defense-modifying Conditions

Diabetes

Gram negative bacilli Melioidosis

Mucormycosis Aspergillus spp.

Candida spp.

Alcoholics Liver disease

Gram negative bacilli Anaerobes

Chronic lung disease

Gram negative bacilli P. aeruginosa Nocardia spp.

Aspergillus spp.

AIDS

Pneumocystis jirovecii Toxoplasma spp.

Rhodococcus spp. Histoplasma spp.

C. neoformans Penicillium marneffii

Diagnosis of Pneumonia

Clinical features of pneumonia

Imaging

History Fever

Cough Dyspnea

Chest pain

Physical examination Decreased lung expansion

Dullness on percussion Vocal resonance

Crepitation Tachypnea Cyanosis

New or Presumed new opacity (infiltrates) on

chest radiograph

Host responses

Tissue injuries

Airspace filling/consolidation Interstitial/reticular opacity

Pathologic-Radiographic Patterns

Inter- and intralobular septal thickening

Alveolar space filling with preserved air in bronchi

“Interstitial “Alveolar

Radiographic Patterns

Alveolar filling pattern Interstitial pattern

C U R B - 65Confusion BUN

>7 mmol/L (20 mg/dL)

Respiratory rate

≥30 bpm

Blood pressure SBP <90 mmHg DBP ≤60 mmHg

Age

CURB-65 Score and MortalityM

orta

lity

(%)

0

20

40

60

80

100

Total CURB-65 Scores0 1 2 3 4 5

1 29 15

40

57Total CURB scores:

0-1 Outpatient setting 2 Inpatient setting ≥3 ICU management

Lim WS, van der Eerden MM, Laing R, et al. Thorax 2003; 58:377–82.

Diagnostic Workups

Microbiology workups

Clinical Status workups

Sputum Gram stain

Culture for bacteria

Blood Hemoculture

BUN, CrCBC Arterial Blood Gas

Principles of Empirical Therapy

Confirmation of infection

Defining location of infection

Common pathogen(s)

Host factors

Environmental factors

Infected or suspected organ(s)

Bacteria Virus

fungus

Alternative diagnosis of

noninfectious disease?

AIDS Cirrhosis Diabetes

CKD Alcoholics

Community Hospital

Recommended Empirical Antibiotics: OPD

Previously healthy; No previous ATB use within 3 months

A Macrolide (Roxithromycin, Clarithromycin, Azithromycin)

Doxycycline

Presence of Comorbidities (chronic heart, lung, renal or liver disease, DM,

alcoholism, malignancy, aplenia, immunosuppressed) Previous ATB use within 3 months

A respiratory fluoroquinolone (Levofloxacin, Gemifloxacin, Moxifloxacin)

A beta-lactam (Amoxicillin-clavulanate, Cefdinir, Cefspan) PLUS a macrolide

Incidence of DRSP >25%

A respiratory fluoroquinolone

Mandell L A, Wunderink R G, Anzueto A, et al. CID 2007; 44:S27–72.

Recommended Empirical Antibiotics: IPD & ICU

ICU treatment

A beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) PLUS azithromycin or a respiratory FQ

Pseudomonas infection suspected

An antipneumococcal, antipseudomonal beta-lactam (piperacillin-tazobactam, cefipime, imipenem, meropenem)

PLUS either Ciprofloxacin or Levofloxacin

The above beta-lactam PLUS antipneumococcal fluoroquinolone PLUS an aminoglycoside

MRSA suspected

Add Vancomycin or linezolid

Non-ICU treatment

A respiratory floroquinolone IV A beta-lactam PLUS a macrolide IV

Mandell L A, Wunderink R G, Anzueto A, et al. CID 2007; 44:S27–72.

Supportive Treatment

Respiratory & Hemodynamic support

Drainage & Airway clearance

Chest physical therapy

Postural drainage

Coughing/huffing

Symptomatic treatment

Mucolytic/expectorants

Antipyrexia

Bronchodilators

Oxygen support: Oxygen cannula

Oxygen mask

Ventilatory support: Noninvasive

Invasive

Hemodynamic support: Noninvasive

Invasive

Treatment Modification in Host Defense Abnormalities

Diabetes



Candida spp.





Aspergillus spp.

AIDS




Ceftazidime Meropenem

Amphotericin B Voriconazole

Amoxicillin-clavulanate Ceftazidime Cotrimoxazole

Cotrimoxazole Levofloxacin

Amphotericin B Itraconazole

Complications of Pneumonia

Acute respiratory failure ARDS

Pleural effusion Empyema

Lung abscess Sepsis Septic shock

Pleural Effusion

Pleural Cavity and Pleural Fluid

History of close contact to a patient with MDR-TB

Return after default of >2 months

Relapse pulmonary TB

Treatment failure (smear positive at 5th month)

Special population (immigrants, prisoners, HIV infected persons)

Pleural Effusion: Pathophysiology

Increased pleural fluid production

Decreased pleural fluid reabsorption

High hydrostaticCongestive heart failure

hepatic hydrothorax

Low oncoticCirrhosis

Hypoalbuminemia Nephrotic syndrome

Permeability/LeakagePneumonia

Inflammatory diseases Chylothorax

Lymphatic obstruction

Malignant Effusion

Pleural ThickeningComplicated parapneumonic

effusion Asbestosis

Trapped lung Rheumatoid pleurisy (late)

Diagnosis of Pleural Effusion: Chest Radiograph

Upright film: blunt costophrenic angle

fluid in fissures

Decubitus film: fluid shift to dependent area

of the lung

Supine film: fluid distributed along posterior plane

“Filter effect”

Diagnosis of Pleural Effusion: Ultrasonography

Effusion without fibrin formation Effusion with fibrin formation

Diagnosis of Pleural Effusion: CT scan

Effusion without loculation Effusion with loculation

Pleural Fluid Analysis

Specific biochemical tests

Additional test(s)

Initial biochemical tests

Protein LDH

Glucose

ADA Cholesterol Triglyceride

pH

Cytology Pathology

Tumor/inflammatory markers

Pleural Fluid Analysis: Transudate VS Exudate

Modified Light’s Criteria

Exudate Transudate

Fluid protein/serum protein ratio

>0.5 <0.5

Pleural fluid LDH

>200 IU/L or >2/3 upper limit

of normal

<200 IU/L or <2/3 upper limit

of normal

Fluid LDH/serum LDH ratio >0.6 <0.6

Additional Criteria

Exudate Transudate

Pleural fluid protein >3 g/dL <3 g/dL

Pleural fluid cholesterol >45 mg/dL <45 mg/dL

Fluid cholesterol/serum cholesterol ratio

>0.3 <0.3

Albumin gradient ≤1.2 g/dL >1.2 g/dL

Pleural Fluid Analysis: Cell Count and Differentials

Neutrophil predominated

exudates

Acute bacterial pneumonia Acute pulmonary embolism

Acute pancreatitis Rheumatoid pleurisy (acute) Tuberculous effusion (acute)

Lymphocyte- predominated

exudates

Tuberculous effusion Chylothorax Lymphoma

Rheumatoid pleurisy (chronic) Sarcoidosis

Uremic pleuritis Post surgery

Eosinophil- predominated

exudates

Pneumothorax Hemothorax

Benign asbestos Pulmonary embolism

Parasitic disease Fungal disease

Lymphoma Churg-Strauss syndrome

Pleural Fluid Analysis: Other Special Tests

Diseases Diagnostic pleural fluid tests

Empyema Present of microbial or positive culture

Malignancy Positive cytology

Lupus pleuritis Positive LE cells

Tuberculous pleural effusion Positive AFB stain, ADA >40 IU/L

Esophageal rupture Salivary amylase, pH <6.0

Chylothorax Triglyceride >110 mg/dL; positive chylomicrons

Cholesterol effusion Cholesterol >300 mg/dL; Cholesterol/triglyceride ratio >1.0, cholesterol chrystals

Pleural Fluid Analysis: Other Special Tests

Diseases Diagnostic pleural fluid tests

Hemothorax Hematocrit of pleural effusion/blood ratio >0.5

Rheumatoid pleurisy Characteristic cytology; pH <7.0, glucose <30 mg/dL, LDH >1,000 IU/L

Peritoneal dialysis Protein <1.0 g/dL, glucose >300 mg/dL

Urinothorax Creatinine of pleural fluid/serum ratio >1.0

Parapneumonic Effusion

Clinico-pathological Stage in Pleural Effusion

Exudative phase Fibropurulent phase Organizing stage

Parenchymal inflammation with neutrophilic migration

Release of IL-6, IL-8, TNF-α

Increased vascular permeability

Fluid moves into pleural space

Secondary bacterial invasioninto pleural space

Depression of intrapleural fibrinolytic activity

Fibrin formation and loculation of intrapleural fluid

Release of platelet-derived growth factors (PDGF) and transforming growth factor (TGF-β)

Proliferation of fibroblasts

Pleural scarring

Pleural Fluid Characteristics

Simple parapneumonic effusion

Complicated parapneumonic effusion Empyema

Appearance Maybe turbid Maybe cloudy Pus

Biochemical Markers

pH >7.30 LDH elevated (F/P >0.6)

Protein elevated (F/P >0.5) Glucose >60 mg/dL

pH <7.20 LDH >1000 IU/L

Glucose <35-40 mg/dLn/a

Cell differentials Neutrophil (usually <10,000/µL)

Neutrophil (usually >10,000/µL n/a

Gram stain negative negative positive

Culture negative maybe positive maybe positive

Bacteriology of Pleural Fluid Cultures

6%15%

16%

17%47%Streptococci Staphylococci

Aerobic Gram negatives

AnaerobesOthers

E. coli Klebsiella spp. P. aeruginosa

Enterobacter spp.

S. pneumoniae S. milleri

S. pyogenes

S. aureus MRSA

Management of Parapneumonic Effusion

Confirmation of pleural effusion: Chest radiograph, ultrasonography or CT

pH <7.20 LDH > 1,000 IU/L

Glucose <35 mg/dL Positive Gram stain

Positive culture

Frank pus

Thoracentesis: for pH, LDH, glucose, Gram stain, culture

Drainage

pH >7.30 LDH <1,000 IU/L

Glucose >60 mg/dL Negative microbiology

Fluid amount >1/2 hemithorax Observe

yes no

Sepsis and Septic Shock

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 369;9 nejm.org august 29, 2013844

antiinflammatory phenotype that promotes tis-sue repair, and regulatory T cells and myeloid-derived suppressor cells further reduce inflam-mation. In addition, neural mechanisms can inhibit inflammation.35 In the so-called neuroin-flammatory reflex, sensory input is relayed through the afferent vagus nerve to the brain stem, from which the efferent vagus nerve acti-vates the splenic nerve in the celiac plexus, re-sulting in norepinephrine release in the spleen and acetylcholine secretion by a subset of CD4+

T cells. The acetylcholine release targets α7 cho-linergic receptors on macrophages, suppressing the release of proinflammatory cytokines.36 In animal models of sepsis,35 disruption of this neural-based system by vagotomy increases sus-ceptibility to endotoxin shock, whereas stimula-tion of the efferent vagus nerve or α7 cholinergic receptors attenuates systemic inflammation.

Patients who survive early sepsis but remain dependent on intensive care have evidence of im-munosuppression, in part reflected by reduced

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Proinflammatory response Excessive inflammation causing collateral damage (tissue injury)

Antiinflammatory response

Pathogen factors

Host factors

EnvironmentGeneticsAgeOther illnessesMedications

Load VirulencePathogen-associated molecular patterns

Immunosuppression with enhanced susceptibility to secondary infections

CytokinesProteasesReactive oxygen species Complement products

Perpetuation of inflammation

Coagulation proteases

Damage-associatedmolecular patterns

Leukocyte activation

Neuroendocrine regulation Impaired functionof immune cells

Inhibition of proinflammatory gene transcription

Complement activation Coagulation activation Necrotic cell death

NLRs

RLRs

TLRs

CLRs

Vagus nerve

Apoptosis of T, B, and dendritic cells

Antiinflammatory cytokinesSoluble cytokine receptorsNegative regulators of TLR signalingEpigenetic regulation

Brain

Celiacganglion

Liver,intestine

Norepinephrine

Acetylcholine

Spleen

Adrenalgland

Inhibition of proinflammatorycytokine production

CatecholaminesCortisol

Hypothalamic–pituitary–

adrenal axis

Expansion of regulatory T and myeloid suppressor cells

Impaired phagocytosis

Endosome

Host cell

Figure 1. The Host Response in Severe Sepsis.

The host response to sepsis is characterized by both proinflammatory responses (top of panel, in red) and antiinflammatory immunosup-pressive responses (bottom of panel, in blue). The direction, extent, and duration of these reactions are determined by both host factors (e.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (e.g., microbial load and virulence). In-flammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern-recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding oligomerization domain–like receptors [NLRs]). The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation at least in part by acting on the same pattern-recognition receptors that are triggered by pathogens.

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critical care medicine

n engl j med 369;9 nejm.org august 29, 2013 845

expression of HLA-DR on myeloid cells.37 These patients frequently have ongoing infectious foci, despite antimicrobial therapy, or reactivation of latent viral infection.38,39 Multiple studies have documented reduced responsiveness of blood leukocytes to pathogens in patients with sep-sis,30 findings that were recently corroborated by postmortem studies revealing strong functional impairments of splenocytes obtained from pa-

tients who had died of sepsis in the ICU.37 Be-sides the spleen, the lungs also showed evidence of immunosuppression; both organs had en-hanced expression of ligands for T-cell inhibi-tory receptors on parenchymal cells.37 Enhanced apoptosis, especially of B cells, CD4+ T cells, and follicular dendritic cells, has been implicat-ed in sepsis-associated immunosuppression and death.40,41 Epigenetic regulation of gene expres-

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Release of mitochondrial

contents

Mitochondrialdysfunction

Increased coagulation Decreased anticoagulation

Monocyte

Neutrophil

NETs with trapped

platelets

Tissuefactor

↓ Antithrombin

Endothelial cell↓Tissue

factor pathway inhibitor ↓ TM ↓ Endothelial

protein C receptor

↓ Protein C

↓ Activatedprotein C

↓ Activated protein Cand ↑ thrombin

↓Fibrinolysis↑ PAI-1

Thrombosis

Tissue hypoperfusionLoss of

barrier function

↓Tissue oxygenation

Organ failure

↑PAR1

S1P3 S1P1

↑ S1P3 and ↓ S1P1

↑ Angiopoietin 2

↓ VE cadherin and↓Tight junctions

Cell shrinkageand cell death

Capillary leak and interstitial

edema

Vasodilatation

↓ Blood pressure

↓ Red-cell deformability

Thrombus

Tissue hypoperfusion Loss of barrier function

Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.

Sepsis is associated with microvascular thrombosis caused by concurrent activation of coagulation (mediated by tissue factor) and im-pairment of anticoagulant mechanisms as a consequence of reduced activity of endogenous anticoagulant pathways (mediated by acti-vated protein C, antithrombin, and tissue factor pathway inhibitor), plus impaired fibrinolysis owing to enhanced release of plasminogen activator inhibitor type 1 (PAI-1). The capacity to generate activated protein C is impaired at least in part by reduced expression of two endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated by neu-trophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypoperfusion, which is aggra-vated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired by the loss of barrier function of the endothelium owing to a loss of function of vascular endothelial (VE) cadherin, alterations in endothelial cell-to-cell tight junctions, high levels of angiopoietin 2, and a disturbed balance between sphingosine-1 phosphate receptor 1 (S1P1) and S1P3 within the vascular wall, which is at least in part due to preferential induction of S1P3 through protease activated receptor 1 (PAR1) as a result of a reduced ratio of activated protein C to thrombin. Oxygen use is impaired at the subcellular level because of damage to mitochondria from oxidative stress.

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Management of Sepsis

Component 2: Resuscitation &

Hemodynamic monitoring

Component 1: Diagnosis &

Severity assessment

Component 3: Sepsis workup &

Sepsis control

Component 4: Respiratory &

Metabolic support

Management of

Sepsis

Component 1: Diagnosis &

Severity assessment

Management of

Sepsis

Infectious VS Noninfectious Causes of Fever

Causes of FeverCauses of Fever

Infectious Noninfectious

Central Nervous System MeningitisEncephalitis

Cerebral infarction/hemorrhageSeizure

Respiratory system PneumoniaEmpyemaSinusitis

Deep vein thrombosisAtelectasisPulmonary embolism

Gastrointestinal/Hepatobiliary system Intra-abdominal abscessCholecystitis/cholangitisPeritonitis

GI hemorrhagePancreatitisIschemic colitis

Genitourinary system CystitisPyelonephritis

Skin, soft tissue, bones and joints CellulitisWound infectionSeptic arthritis

ThrombophlebitisGout/pseudogoutVasculitis

Definition

Infection Bacteremia Septicemia Sepsis

Sepsis induced

hypotension

Severe sepsis Septic shock

Presence of microbial invasion

Presence of microbes or toxin in blood

Infection PLUS SIRS

SIRS PLUS

hypotension, fluid

responsive

SIRS PLUS

≥2 organ dysfunction

severe sepsis PLUS

hypotension, fluid

irresponsive

Assessment of Severity: APACHE II Score

Assessment of Severity: APACHE II Score

Component 2: Resuscitation &

Hemodynamic monitoring

Management of

Sepsis

Early Goal-Directed Therapy (EGDT) for Septic Shock

Central Venous Pressure Measurement: Noninvasive

Phlebostatic axis

Central Venous Pressure Measurement: Invasive

Venesection“Cutdown”

Internal Jugular vein cathether

Subclavian vein catheter

Pulmonary arterycatheter

“Swan-Ganz”

Venesection “cutdown”

Internal jugular vein catheter

Subclavian vein catheter

Pulmonary artery (Swan-Ganz)

catheter

Fluid Resuscitation: Types of Solution

Crystalloid ColloidCrystalloid ColloidCrystalloid Colloid

Importance of Fluid Resuscitation

ภาวะปกติ ภาวะติดเชื้อรุนแรง ภาวะติดเชื้อรุนแรงNormal Severe Infection

Vasodilatation

Decreased vascular tension

Fluid resuscitation

Restoration of vascular tension

Fluid Resuscitation: Fluid Challenge Testing

Time CVP (cmH2O) Fluid challenge

Initial reading <15 200 mL in 15 min

≥15 50-100 mL in 15 min

During fluid challenge increase >5 cmH2O Stop and wait

Following fluid challenge increase >3 cmH2O wait

≤3 cmH2O Repeat

Fluid Resuscitation: Target

Central venous pressure (CVP) 12-15 cmH2OAND

Mean arterial pressure (MAP) ≥65 mmHg

Mean arterial pressure = [Systolic blood pressure (SBP) + 2 x Diastolic blood pressure]

3Mean arterial pressure = [Systolic blood pressure (SBP) + 2 x (Diastolic blood pressure (DBP)]

3

Vasopressor Therapy in Patients with Sepsis

Dopamine5-20 µg/kg/min

Norepinephrine0.1 µg/min

Dopamine +

Norepinephrine

+Epinephrine

Resuscitation of Microcirculation Level: Rationale

O2

CO2

Delivery

Consumption

Oxygen Delivery to Tissues

Inspired oxygen

Lung Heart pump Blood content

Oxygen delivery = 10 x Cardiac output x [(1.39 x Hb x SaO2) + (PaO2 x 0.0031)]

Pump Lung OxygenBloodcontent

Lung Heart pump Blood content

Oxygen delivery = 10 x Cardiac output x [(1.39 x Hb x SaO2) + (PaO2 x 0.0031)]

Pump Blood content

Lung Oxygen

Maximizing Oxygen Delivery to Tissues: Oxygen & Lungs

Oxygen TherapyMechanical Ventilatory

SupportOxygen Therapy

Mechanical Ventilatory

SupportOxygen therapy

Mechanical ventilatory support

Maximizing Oxygen Delivery to Tissues: Cardiac Output

Inotropic drugsincrease myocardial contractility

Dopamine 5-20 µg/kg/minDobutamine 5-15 µg/kg/min

Inotropic drugs increase myocardial contractility

Dopamine 5-20 µg/kg/min Dobutamine 5-15 µg/kg/min

Maximizing Oxygen Delivery to Tissues: Blood Content

Inotropic drugsincrease myocardial contractility

Dopamine 5-20 µg/kg/minDobutamine 5-15 µg/kg/min

Red cell transfusion increase Hb-O2 binding capacity

Keep Hct 30%

Component 3: Sepsis workup &

Sepsis control

Management of

Sepsis

Microbiological Studies in Sepsis Workup

Direct identification Culture system

Gram stain AFB stain Fluid/secretion Blood

Primary Source of Infection

Respiratory system Pneumonia

Lung abscess Empyema thoracis

Deep neck infection

KUB system Acute pyelonephritis

Acute cystitis

GU system Tubo-ovarian abscess

Pelvic infection

Skin & Soft tissue Cellulitis

Necrotizing fasciitis

GI system Acute cholangitis

Acute cholecystitis Peritonitis

CNS system Acute meningitis Acute cerebritis

Acute meningoencephalitis

Septic Workup Procedures and Specimen Collection

Lumbar puncture Thoracentesis Paracentesis ArthrocentesisLumbar puncture Thoracentesis Paracentesis Arthrocentesis

Blood Collection for Hemoculture

Catheter/device Peripheral veinCatheter/device Peripheral vein

Principles of Empirical Therapy

Confirmation of infection

Defining location of infection

Common pathogen(s)

Host factors

Environmental factors

Infected or suspected organ(s)

Bacteria Virus

fungus

Alternative diagnosis of

noninfectious disease?

AIDS Cirrhosis Diabetes

CKD Alcoholics

Community or

Hospital

Recommended Antimicrobial Therapy: Community-acquired

Infected/Suspected Organ

Respiratory Intra-abdominal Skin & soft tissue Urinary tract CNS

Common pathogens

S. pneumoniae H. influenzae

Legionella spp. C. pneumoniae

E. coli B. fragilis

S. pyogenes S. aureus

Polymicrobials

E. coli Klebsiella spp.

Proteus spp. Enterococci

S. pneumoniae N. meningitidis

L. monocytogenes H. influenzae

Recommended therapy

Ceftriaxone or cefotaxime

PLUS azithromycin

Ceftriaxone PLUS

metronidazole

Cloxacillin/Vancomycin

OR Amoxicillin-Clavulanate

Ciprofloxacin or Levofloxacin

OR Amoxycillin-clavulanate

Ceftrixone or cefipime

PLUS Ampicillin

Vancomycin

Recommended Antimicrobial Therapy: Hospital-acquired

Infected/Suspected Organ

Respiratory Intra-abdominal Skin & soft tissue Urinary tract CNS

Common pathogens

K. pneumoniae P. aeruginosa A. baumanii

MRSA

E. coli Klebsiella spp. P. aeruginosa Anaerobes

Candida spp.

S. pyogenes S. aureus

Polymicrobials

E. coli Klebsiella spp.

Proteus spp. Enterococci

S. pneumoniae N. meningitidis

L. monocytogenes H. influenzae

Recommended therapy

Imipenem Meropenem PLUS colistin

PLUS vancomycin

Imipenem Meropenem

PLUS aminoglycosides

Imipenem Meropenem

Cefipime PLUS vancomycin

Imipenem Meropenem



Adapted from: Simon D, Trenholme G. Crit Care Clin. 2000;16:215-230.

Host Defense-modifying Conditions

Diabetes



Candida spp.





Aspergillus spp.

AIDS




Speed is Life!

Antimicrobial Therapy Delay and Mortality

Kumar A, Robers D, Wood K E, et al. Crit Care Med 2006; 34:1589-1596.

0

0.25

0.5

0.75

1

0 0.5 1 2 3 4 5 6 9 12 24 >36

Fraction of patients receiving therapyFraction of surviving patients

Time laps from recognition to the first dose of antimicrobials

Fraction of Patients

Kumar A, Robers D, Wood K E, et al. Crit Care Med 2006; 34:1589-1596.

“We recommend that intravenous antibiotic therapy be started as early as possible and

within the first hour

of recognition of septic shock and severe sepsis without septic shock.”

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

Surgical Control of Infection

Drainage Remove

Component 4: Respiratory &

Metabolic support

Management of

Sepsis

Mechanical ventilatory

support

Sedation Analgesia

Stress ulcer prophylaxis

Transfusion therapy

DVT prophylaxis

Renal replacement

Glucose control

Thank You

Health & Medicine

Internal medicine review for national license examination 2