Med - Tb,para,atbp

TB , PARASITIC , VIRAL & FUNGAL LUNG DISEASES Charles Y. Yu, MD ,MSc DLSU Professor of Medicine Vice-Chancellor, Mission & Linkages

OUTLINE • • • • • • •

Definitions Clinical Symptoms: reliability Radiologic features Mycobacterial lung diseases Viral Lung Diseases Parasitic Lung Diseases Fungal Lung Diseases

ILLUSTRATIVE CASE • A 32 year old male Filipino presents with a history of cough of more than 4 weeks duration, on and off fever lasting 2 weeks, weight loss of 10%. 1 day prior to admission he complains of blood-streaked phlegm which alarms him and he seeks OPD consult. • P.E. is unremarkable

TB SITUATION • One of the 20 high-burdened countries ( WHO TB Watchlist ) • 3rd in the Western Pacific - Case Notification • 6th leading cause of deaths (1997) • 6th leading cause of morbidity • Prevalence of Smear (+) cases - 3.1 /1000 (240,000 cases)

THE URGENT NEED FOR NEW DRUGS

TB SYMPTOMATIC • Constitutional Symptoms – Fever – Weight Loss – Anorexia – Body Malaise

• Respiratory Symptoms – Cough – Hemoptysis – Chest/Back Pains

Natural History of TB (in the absence of HIV infection) 50%

50%

10% 90%

Courtesy of Dr. Anne Ginsberg, Global TB Alliance

The TB Life Cycle

Index Case Exposure N o t I n f e c t e d

In 90-95% of infected patients, M. tb remains dormant in the body

A TB patient infects 10-15 persons / yr

Infection 30% of untreated TB undergoes spont. remission

Healthy Subjects

5-10% lifetime risk

Disease > 90% CURE RATE (w/ DOTS)

Only active TB pts (specially smear (+)) can infect others

Untreated, 70% will die in 5 yrs

Death

Model for the Epidemiology of Tuberculosis A Model for the Epidemiology of Tuberculosis Risk factors

Risk factors

Risk factors

Risk factors Infectious tuberculosis

Exposure

Subclinical infection

Death Non-infectious tuberculosis

Rieder HL. Infection 1995;23:1-4

Reider HL. Infection, 1995

WHAT IS LATENT TB INFECTION? • In latent infection, a person carries the bacteria but does not have signs of active disease…LTBI is important because it can be transmitted to others and or become active infection--- Ringold S, Glass M JAMA 2005 • While the infection is latent, the person has no symptoms or detectable signs of infection except for a positive tuberculin skin test reaction • LTBI is a clinical condition characterized by a positive tuberculin skin test (TST) in the absence of clinical or radiological signs of active tuberculosis disease— Nuermberger et al Center for TB Research Johns Hopkins Seminars in Resp & Crit Care Medicine 2004 • LTBI is a condition in which an individual is infected with M.Tb but does not currently have active disease--ATS/CDC/IDSA AJRCCM 2005

RATIONALE FOR TREATMENT OF LTBI • Treatment of LTBI reduces an individual’s risk and imparts public health benefit by reducing the pool of latently infected individuals who could develop active TB in the future • TB is a suitable disease to target for screening because of long and variable latent infection • Acceptable treatment for LTBI that will reduce the likelihood of disease by 75% Chaulk, CP. JAMA 1998 (279) 943-949

Risk Factors For PTB Given That TB Infection Has Occurred

Testing for TB Disease and Infection

Purpose of Targeted Testing • Find persons with LTBI who would benefit from treatment • Find persons with TB disease who would benefit from treatment • Groups that are not high risk for TB should not be tested routinely

Administering the Tuberculin Skin Te

Inject intradermally 0.1 ml of 2 U PPD tuberculin

Produce wheal 6 mm to 10 mm n diameter

Do not recap, bend, or break eedles, or remove needles from syringes

Follow universal precautions for infection control

Reading the Tuberculin Skin Test •Read reaction 48-72 hours after injection •Measure only induration •Record reaction in millimeters

Limitations of the tuberculin skin test (TST) • Reader variability • False-positive test results due to crossreactivity with environmental mycobacteria and with previous BCG vaccination • False-negative results due to anergy in immuno-suppressed individuals, malnutrition

QuantiFERRON vs TST IFN-gamma Gp 1 No identifiable risk Gp 2 Recent casual contacts Gp 3 Recent close contacts Gp 4 Bacterio/patho TB

4% 10% 44% 81%

TST 51% 60% 71% 78%

Conclusions: the IFN-gamma assay is a better indicator of Risk of M tuberculosis infection than TST in a BCG-vaccinated population Source: Kang, YA,(JAMA 2005) Discrepancy between the Tuberculin Skin test and whole blood interferon (gamma) assay for Diagnosis of LTBI in an intermediate TB-burden country

DEFINITIONS: • TB mimic has been classically defined as diseases that manifest like TB but turn out to be other diseases • TB mimic may also mean the protean picture of TB .i.e. the multiplicity of manifestations from any organ in the body that eventually turned out to be TB

DEFINITIONS • Symptomatic PTB – At least 2 sp+ for AFB with or without x-ray abnormalities – 1 sp+ & with radio abnormalities consistent with (active) PTB (as defined by a clinician*) – All 3 sp- but w/ x-rays consistent with PTB, w no hx of anti-TB treatment and with a previous normal chest x-ray 2003 Comprehensive Unified Policy (CUP) Philippines,ratified March 7,2003 *2003 WHO Guidelines for National Country Programs

Can clinical signs and symptoms discriminate between PTB and non-PTB respiratory disease? CONSENSUS STATEMENT: Of the symptoms commonly associated with PTB, only a chronic cough appears to consistently differentiate between PTB and non-TB respiratory disease.

Level of Evidence: 2 Recommendation Grade: B 2000 Philippine CPG on TB

TB Symptomatic: A Differential Diagnosis Clinical Features

Tuberc ulosis

Parago nimiasis

Aspergillosis

Cough

75%

83%

50-95%

+

+

+++

+

Hemoptysis

25%

70%

50%

-

-

++

+

Fever/chills

50%

37%

+

Fatigue

58%

Dyspnea Wt.loss

Silicosis

Carcinoma

++

++ 42%

75%

Crypto coccal lung

+

+

+

++ +++

Coccidio diodes Immitis

Clinical Symptoms • Correlation between Clinical symptomatology and chest radiographic TB • 6 variables correlated with radio. TB : – – – – – –

•

age>45 (7 pts) male sex (5 pts) hemoptysis (6 pts) dyspnea (5 pts) weight loss>25%(6 pts) severity of cough (distressing 11 pts, non-distressing 8 pts)

Logistic regression analysis – Scores greater than 20 were associated with greater probability of radiographic TB – 88% radio TB provided sputum only 20% AFB+ – 70% of hemoptysis had radio TB (TB? Bronchiectasis?) – Cavitary x-rays seen in 74/142 (52%) of which 33% were described as far advanced

•De La Cruz, Roa et al. (PJIM Vol.29:187-203,1991)

Tattevin Study (1999) • • • • • • • • • •

Total : 211 patients Culture proven TB 22.3% Symptoms Typical symptoms (cough,fever,drenching night sweats >3 weeks, hemoptysis) Compatible symptoms (cough,unxplained fever,nonpurulent sputum production, anorexia, weight loss) X-rays Typical of PTB (presence of nodular, alveolar or interstitial Infiltrates in zones above clavicle or cavitations in upper zones or apical segment of lower lobe) Compatible (enlarged hilar nodes, pneumonic lesion,atelectasis, mass lesion,miliary,pleural exudate Atypical (any other pattern including normal CXR) Univariate analysis –

•

Multivariate analysis –

• •

Predictive factors: Symptoms, CXR, age (40.8 TB vs 47.5 non-TB,absence of HIV, immigrant status, BCG CXR (14 pts), aHIV (6 pts) and typical symptoms (12) independently predicted TB,compatible symptoms (5)

Immigrant status (2), BCG (2) homeless (2) Prediction Model 100% sensitive, 48.4% specificity and 25% PPV Tattevin P.et al Chest 1999:115;248-53 The Validity of Medical History, Classic Symptoms, and Chest Radiographs in Predicting Pulmonary Tuberculosis

Negative Predictors • Cohen (1996) absence of ff: – 2 weeks of cough/sputum – Weight loss – Absence of typical x-rays

• Strong negative predictors for PTB • High TB prevalence setting (44%) Cohen R Chest 1996: 109: 420-423

TB Prediction Score (TPS) among sputum negative TB • • • •

Setting: UCSF affiliated public hospital 1993-1998 Patients: 47 PTB patients, 141 controls Results: TPS < 0 low probability of PTB even in high prevalence areas • TPS >0 high probability (esp.in high prevalence areas) Positive predictors: – Positive tuberculin skin test (-1 pt) OR: 4.8 (2,11,9) – HIV seropositivity + Positive mediastinal lymphadenopathy on xray (+2 pts) OR:7.2 (1.4,36)

• Negative predictors: – atypical x-ray (-1 pt) OR: 0.3 (0.1,0.7) – expectoration with cough (-1 pt) OR : 0.3 (0.1,0.6)

• Range of outcomes (-2 to +3) (LRs 0.2-7.1) Kanaya, AM et al. Chest 2001:120; 349-355 Identifying PTB in Patients with Smear- Results

CLINICAL SUSPICION FOR TB (CSTB MULTI-CENTER STUDY) • • • • •

NIH Funding (2004-2006) UCSD-Center for Pacific Rim Studies 5 sites:Philippines (DLSU,UST),Mexico, USA,UK Total of 3000 patients (1100 fm Philippines) CSTB – – – –

Socio-economic/demo/hx & PE (clinical) AFB smear/culture Chest radiography Serology

Catanzaro, A. Natividad, P.,Dalay,V.

Can a patient with no symptoms have PTB? CONSENSUS STATEMENT: PTB does not have to be symptomatic. Even among culture-prove PTB patients, a small percentage (5-6%) may have no symptoms. Asymptomatic PTB is more commonly observed in older age group.

Level of evidence: 6 Recommendation Grade: D

Asymptomatic PTB • Radio abnormalities consistent with PTB & at least 1 sp+ for AFB OR • Previous x-ray normal, current x-ray shows abnormalities consistent with PTB, 3sp• Previous x-ray shows abnormality consistent with PTB, current x-ray shows progression and 3 spNote: If current x-ray shows abnormality & 3 sm-, no previous x-rays & px do not fulfill the criteria, ff-up sputum and x-ray should be done at least 1 month after 2003 Comprehensive Unified Policy (CUP) Philippines,ratified March 7,2003

RADIOLOGIC FEATURES OF PTB CONSENSUS STATEMENT Most of the available evidence indicates that no radiologic feature correlates well with PTB activity One study ( evidence level 2 ) on hospitalized patients indicates that hilar or mediastinal lymphadenopathy and diffuse reticulonodular infiltration may individually correlated with the presence of active PTB in the presence of a respiratory or constitutional symptoms suggestive of respiratory disease. Level of Evidence : 2 Recommendation Grade B

• MINIMAL “ Slight lesions without demonstrable cavitation confined to a small part of one or noth lungs. The total extent ..shall not exceed the equivalent of the volume of lung tissue which lies above the second chondrosternal junction and the spine of the fourth or the body of the fifth vertebrae on one side” “equivalent of one-fifth of one lung)

PTB Classification (Old) • Minimal 1) The affected area is less than the width of an interspace (or rib). 2) No evidence of cavitation is present. 3) May occur anywhere in the lung, commonly in the peripheral portion of the 1st and 2nd interspaces.

PTB Classification (Old) • Moderately advanced 1) The affected portions of the lung comprise all or the greater portion of a lobe. 2) If a cavity is present measuring up to 4 cm in diameter. 3) If there are multiple cavitations, the combined sum of the diameters totals 4 cm or less.

PTB Classification (Old) • Far Advanced 1) There is multilobar involvement. 2) Cavities are larger than 4cm in diameter or the sum of the diameters of the multiple cavitations is larger than 4cm.

• MODERATE “Slight disseminated lesions which may extend through not more thtan the volume of one lung or the equivalent in both lungs” “ Dense and confleunt lesions which may extend through not more than the equivalent of one third the volume of one lung” “total diameter of cavities less than 4 cm”

• FAR ADVANCED “ Lesions more extensive than moderately advanced”

NTP/WHO PTB CLASSIFICATION TB Diagnostic Category I

II

III IV

TB Patients

TB Treatment Regimens Initial Phase Continuation Phase

New smear-positive patients 2HRZE New smear-negative PTB with extensive parenchymal involvement Severe EPTB/HIV disease Previously treated sputum smear-positive PTB -relapse -treatment after interruption -treatment failure New smear-negative PTB (other than category i) Chronic and MDR-TB (still sputum-positive after supervised re-treatment)

4RH (6HE)

2HRZES/1HRZE 5HRE

2HRZE*

4RH (6HE)

Specially designed standardized or individualized regimens (Refer to DOTS Plus Facilities)

* May omit ethambutol if non-cavitary and smear-negative,non-HIV,known fully susceptible bacilli Sources: DOH MOP 2004 WHO Treatment of TB Guidelines for National Programs, 2003

Microscopy is more objective and reliable than X-ray 100

98%

Inter-observer agreement

90 80

70%

70 60 50 40 30 20 10 0

AFB Microscopy

X-ray

Microscopy is a more specific test than X-ray for TB diagnosis 100 90

98%

Specificity

80 70 60

50%

50 40 30 20 10 0

AFB Microscopy

X-ray

Microscopy is more objective and reliable than X-ray 100

Over-diagnosis

80 60 40 20 0 Diagnosed by X-ray alone

Actual Cases

Highlights …. • Radiographic differentiation between active and inactive disease can only be reliably made on the basis of temporal evolution. - fibrosis and calcification are features found in both healed and active disease; disease status based on their presence is unreliable • Radiologic manifestations of PTB are dependent on several factors including prior exposure to TB, age, and underlying immune status. Leung, A. State-of-the-Art: Pulmonary TB The Essentials. Radiology 1999:210:307-322

Do radiologic features of PTB correlate with disease activity? • 2000 Consensus statement: “Most of the available evidence indicates that no radiologic feature correlates well with disease activity” …One hospital study indicated that hilar/mediastinal lymphadenopathy and diffuse reticulonodular infiltrates may individually correlate with active PTB in the PRESENCE of respiratory constitutional symptom of respiratory disease. Grade B 2000 CPGs: Diagnosis , Treatment & Control of TB PCCP,PSMID Task Force p.22

THE

REVISED TUBERCULOSIS CONTROL PROGRAM

BACKGROUND • 80 million population (2003) • Department of Health sets policies, standards, guidelines TB Unit Centers for Health Development • Health program implementation is the mandate of LGUs( Devolution ) Rural Health Units (RHUs) ; Health Centers Barangay Health Stations (BHSs)

WHAT HAD BEEN DONE? 1910 1930 1954 1978 1987 1992 1994 1996 2002 2003

-

PTS organized TB Commission established TB Law passed Nationwide implementation of NTP SCC in Blister-packs introduced Local Government Code implemented PhilCAT organized D.O.T.S. strategy pilot-tested D.O.T.S. nationwide (98% coverage) GDF & GFATM grant approvals - PPM

Directly-Observed Treatment Shortcourse (D.O.T.S.) • • • • •

Political commitment Quality microscopy service Regular availability of drugs Standardized records & reports Supervised treatment

PROGRAM • • • •

Case-finding Case-Holding Recording & Reporting Monitoring & Supervision

PROGRAM COMPONENTS • CASEFINDING: Objectives: To identify TB symptomatics To identify & diagnose TB cases early Passive Casefinding - TB symptomatics present themselves at the health facility. Active Casefinding - purposive effort to find TB cases among the symptomatics who don’t seek consultation.

MAJOR POLICIES ON CASEFINDING •Direct sputum smear microscopy shall be the primary NTP diagnostic tool. •All TB symptomatics must undergo sputum examination, with or without X-ray results. Only contraindication is massive hemoptysis.

•Three sputum specimens must be submitted 1st spot, early morning, 2nd spot

Passive casefinding shall be implemented in all health centers, health stations. Sputum microscopy work shall be performed only by adequately trained health personnel. Quality control of smear examination must be observed. Validation system must be established.

CASEHOLDING

Objectives:

To render as many Smear (+) cases as noninfectious & cured as early as possible. To treat seriously-ill Smear (-) cases & other potentially infectious cases. Classification of TB Cases - based on location of lesions: Pulmonary Smear (+) Smear (-) Extra-pulmonary

Definition of Pulmonary Case • Smear (+): - at least two AFB (+) smears on initial examination OR - one AFB (+) plus radiographic abN as determined by clinician OR - one AFB (+) plus sputum culture positive for M. tb • Smear (-): - three sputum (-) for AFB AND - radiographic abN for PTB AND - no response to a course of antibiotics and/or symptomatic meds AND - decision by clinician to treat with a full course of anti-TB meds

Case Definition • New: never tx or on anti-TB meds for less than a month • Relapse: prev tx for TB with cure or complete outcome and now bacteriologically positive • Failure: while on tx, AFB (+) at 5 mos or later • RAD: returns to tx with (+) bacteriology following interruption for 2 mos or more • Other: starting tx again after interruption for 2 mos but smear (-) - smear (-) then became smear (+) - chronic case: sputum (+) at end of retreatment regimen

NTP – WHO CATEGORIES TB Patients to be Given Treatment (ATS Class III) Regimen I:

New pulmonary smear (+) cases; severe smear (-)

cases Regimen II: Treatment failure, RAD, relapse, others Regimen III: New smear (-) with

TB Treatment Evolution 1950

1970

1960

1946

1952

Strepto- 1 regimen: • Streptomycin mycin 1st used for TB • PAS • Isoniazid st

1963

1970

Rifampin (R) discovered

BMRC Trials add R

1961

Ethambutol (E) discovered 1954 Pyrazinamide (Z) discovered – but liver toxicity

1980 1974

1998

BMRC Trials add R & Z

Rifapentine approved

Standard Therapy 2 months: R, H, Z, E + 4 months: R, H

Standard Regimen by 1960s based on 1952 drugs

Rx shortened to 6 months Rx shortened to 9 months Rx lasts from 12-24 months

2005

Figure 1: TB Drugs targeting distinct M. tuberculosis subpopulation (adapted from Zhang, 2005)

Current TB Drug Therapy  Active, drug-sensitive TB 6 months of therapy (2HRZE/4HR)

 Resistant TB (MDR- and XDR-TB) Individualized, prolonged therapy, few available drugs, poorly tolerated and difficult to administer

 TB/HIV co-infection Treatment as in active TB, but drug interactions with ARVs make simultaneous therapy impractical in resource-limited settings

 Latent TB 9 months of INH therapy

TREATMENT REGIMENS TB Treatment Regimen

TB Patients To Be Given Treatment

DRUGS AND DURATION Initial Phase

Continuation Phase

I

New smear-positive PTB; new smearnegative PTB with extensive parenchymal involvement; new cases of severe forms of extra-pulmonary TB

2 HRZE

4 HR

II

Previously treated smear-positive PTB; relapse; treatment failure; treatment after interruption

2 HRZES/ HRZE

III

New smear-negative PTB (other than in Category I); new less severe forms of extra-pulmonary TB

2 HRZ

IV

Chronic case (still sputum-positive after supervised re-treatment)

Refer to specialized centers with access to second line drugs

1

5 HRE

4 HR

Table 1. Commonly used TB drugs and their targets (adapted from Zhang, 2005)

Sites of Action of TB Alliance Discovery Projects DNA Gyrase  Fluoroquinolones  GyrB inhibitors

Folic Acid Metabolism  p-Aminosalicylic acid

Cell wall synthesis  Isoniazid (prodrug)  Cycloserine  Ethambutol  Novel InhA inhibitors Energy Metabolism  ICL Inhibitors (Discontinued)  Malate synthase inhibitors  E-transport inhibitors  Riminophenazines  Pyrazinamide (prodrug)  ATP Synthase: Diarylquinolines

RNA Polymerase  Rifamycins

DHFA DNA

PABA

mRNA ADP

H+

ATP

Reactive Species Reduction

Peptide

Ribosome (50S)  Macrolides (discontinued)  Pleuromutilins  Oxazolidinones Ribosome (30S)  Aminoglycosides  Capreomycin/Viomycin

Peptide Deformylase Multiple Targets  PDF inhibitors  Nitroimidazoles  Bifunctional drugs

SCHEDULE OF SPUTUM FOLLOW-UP EXAMINATIONS • CAT I :

2nd, (3rd), 4th, 6th

• CAT II :

3rd,

• CAT III :

2nd

(4th), 5th, 8th

Supervised Treatment • a mechanism of ensuring treatment compliance • TB patient is motivated to take his drugs • Cured

* Treatment Partner * • • • •

watches the patient take his drugs daily reports & traces the patient if he defaults provides health education regularly motivates the patient on sputum ff-ups

• Who will undergo supervised treatment ? Priority are the Smear (+) TB cases • Who could serve as Treatment Partner ? Health Staff, Barangay Health Worker, Community Volunteer, Family Member • Where will D.O.T. take place ? Health facility Treatment Partner’s House Patient’s House • How long is treatment supervised ? Daily drug intake is supervised during the entire course of treatment.

RECORDS and REPORTS NTP Laboratory Request Form Laboratory Register NTP Treatment Card NTP Identification Card TB Case Register NTP Referral Form

Reports • Quarterly Report on Laboratory • Quarterly Report on Casefinding • Quarterly Report on Treatment Outcomes

CASEFINDING • Proportion of Sputum (+) (60%) = Total No. Sputum (+) cases discovered Total No. of Pulmonary TB cases

• Proportion of 3 sputum examination (90%) = No. TB symptomatics with 3 specimens Total no. TB symptomatics examined

Casefinding • (15-20%) Positivity = No. Sputum (+)s discovered_________ Total no. TB Symptomatics examined

• Case Detection Rate (CDR=70%) = No. of New Sputum (+) cases discovered TP x 145/100,000 (Incidence)

COHORT ANALYSIS • A group of patients having the same attributes at a certain period of time to determine treatment outcome. • Treatment Outcomes :

Cure R ate = 8 5 % Completion Rate Tx Failure Rate Defaulter Rate Death Rate Trans-Out Rate

Cure Rate = Total no. New Sputum (+)cases who got CURED Total no. New Sputum (+) cases evaluated General Attributes: New, Pulmonary Sputum (+) case Differentiating Attribute - CURED (Tx Outcome) Cure - New Sputum (+) case, completed tx, Sputum (-) at the end of treatment

RECORDING / REPORTING: Objectives: 1. To know how best to assist clients / patients 2. To know how best to assist TB Program implementors RECORDS PERSON(s) IN-CHARGE On Casefinding / Microscopy: Symptomatic Masterlist Midwife Lab Request Form Midwife, Nurse ( upper ) Medtech ( lower ) Lab. Register Medtech

On Caseholding: Treatment Card ID Card TB Case Register Referral Form

Nurse ; Midwife Nurse ; Tx Partner Nurse Nurse ; Physician

REPORTS • • • •

- ALL are on quarterly basis. Casefinding for New Cases & Relapses Retrospective Cohort Report Drug Inventory Laboratory Report

MAJOR POLICIES ON RECORDING/REPORTING: • Shall rely on all government health facilities, including government hospitals. • Shall include all cases of TB, classified according to internationally accepted case definitions. • Shall include private physicians & private clinics, after agreement with parties concerned has been made. • Shall allow the calculation of the main indicators for evaluation. (Cure Rate, Case Detection Rate)

TB DIAGNOSTIC COMMITTEE

RATIONALE:

About 60% of the TOTAL reported PTB Cases diagnosed by CXR (1996) Dr. Pierre Chaulet’s study ( pilot areas of C.R.U.S.H. TB Project) No. of cases assessed 36.5% Doubtful

=

101 Compatible Doubtful

24.8% Compatible w/PTB

No PTB

38.6% NO PTB (1)

VIRAL INFECTIONS OF THE LUNG AND RESPIRATORY TRACT

RESP VIRAL INFXNS Virus Group

Common Cold

Adenovirus Coronavirus Herpesviruses CMV

Clinical Syndrome Pharyngitis Croup Bronchiolitis

Pneumonia

++

+ -

-

+ -

+ -

-

+

-

-

+

EBV HSV VZV Orthomyxovirus Influenza A,B,C + Paramyxoviruses Measles Parainfluenza 1,2,3+ Resp. Syncytial Picornaviruses Enteroviruses +

++ ++ -

-

-

+ + +

++

+

+

++

++ +

+++ ++

++ +++

+ ++

-

-

-

-

COMMON COLD • Self-limited acute coryzal illness • Leading cause of MD consult in OPD, absence from school & work • 5 most common causes – – – – –

Orthomyxoviruses (influenza A & B) Paramyxoviruses (Parainfluenza, RSV) Adenoviruses Picornaviruses (Rhinovirus) Coronaviruses

• 25-30% remain undiagnosed • Frequency of episodes relates to large number of causative viruses & reinfections with certain types (coronaviruses) • Winter months, rainy season

• TRANSMISSION – – – –

Contact with infected secretions Droplet nuclei in the air Hand to hand transmission possible (rhinoviruses) Large & small particle aerosol

• SYMPTOMS – Start 1-3 days after infection – Nasal discharge/obstruction, sneezing, sore throat and cough – Most cold symtpoms last 1 week up to 2 weeks

TREATMENT • Symptom relief – Antibiotics not effective – Decongestants/vasoconstrictors – Anti-tussives – Analgesics/antipyretics

VIRAL PNEUMONIA • Occurs in children & adults, both immunocompetent and immunocompromised • Causes resp. viruses particularly Influenza and RSV • Immunocompromised hosts – Herpesviruses , measles – Tranplant cases (parainfluenza & RSV)

• Children – RSV, parainfluenza viruses, influenza A & B

• Adults – Influenza A & B,adenoviruses, parainfluenza viruses, RSV

TREATMENT • Mainly supportive • Anti-virals – Amantadine, rimantadine not systematically tested vs influenza virus pneumonia – Interferon alpha broad viral activity but not very effective in releiving resp.viral disease – Acyclovir/ganciclovir ineffective

FUNGAL LUNG DISEASES • • • • • • •

Pulmonary Aspergillosis Mucormycosis Candidiasis Blastomycosis Coccidiomycosis Histoplasmosis Cryptococcosis

Coccidiomycosis, a systemic mycosis, in a 20 year old male initially suspected having Hodgkin's disease. A small upper mediastinal mass was identified on a routine chest X-ray. Coccidioides immitis is endemic in the southwest United States and parts of Mexico, Central and South America. Inhalation of Coccidioides immitis arthroconidia, carried by dust storms, causes pulmonary infection. Photograph courtesy of Jack Saiki, M.D., University of New Mexico Department of Medicine.

Chronic Coccidioides Immitis Infection

Cryptococcal lung

GUIDELINES FOR SELECTION OF THERAPY FOR ENDEMIC MYCOSES Infection

Moderate-severe

Histoplasmosis Ampho B Blastomycosis Ampho B Coccidiomycosis Ampho B

Mild

Maintenance

Itraconazole Itraconazole Itraconazole Itraconazole Fluconazole Fluconazole or itraconazole or

itraconazole IPA Ampho B Itraconazole Mucormycosis Ampho B Ampho B Pulmo Candidiasis Ampho B F luconazole

PULMO PARASITIC PARENCHYMAL & VASCULAR DISEASES Manifestations Loeffler-like syndrome*

INFECTION ASCARIASIS

CAUSATIVE ORGANISM INFECTIVE PATHOGENIC STAGE Ascaris Lumbricoides Embryonated eggs Migrating larva in soil HOOKWORMS Ancylostoma duodenale Larvae in soil Migrating larvae Necator americanus larvae in soil STRONGYLOIDES S. Stercoralis Larvae in soil

Pulmonary Eosinophilia

Lymphatic Filariasis Wuchereria bancrofti

Space-occupying Lesions

Echinococcosis PARAGONOMIASIS Schistosomiasis

Larvae in mosquito

Echinococcus granulosus Eggs in soil P. westermani

Metacercariae

Microfilariae Hydatid cysts Adult worms

Schisostoma mansoni Cercariae in fresh water Eggs S. japonicum S. haematobium

•Persistent,irritating non-productive cough,substernal pain, hemoptysis & dyspnea with eosinphilia,patchy or miliary infiltrates

TREATMENT • Mebendazole 100 mg/day for 3 days – Ascaris & Hookworms

• Thiabendazole 25 mg/kg x 2 days – Strongyloides

• Filariasis – Diethylcarbamazine 5mg/kg divided doses for 2-3 weeks

• Scistosomiasis – Praziquantel 40 mg/kg single dose & 20 mg/kg 3 doses for japonicum

• Paragonomiasis – Praziquantel 75 mg/kg per day for 2 days

Scattered areas of patchy pneumonia with "cotton wool" opacities and ring shadows in adult Korean man with pulmonary paragonimus

A 47-year-old Korean woman with pulmonary paragonimiasis showing cysts within an area of consolidation (A) Chest radiograph shows relatively well-defined patchy opacity in upper lobe of right lung that contains cystic cavities (arrows). (B) CT scan shows air-filled cysts (arrows) within the mass-like consolidation, suggesting that fluid in the cysts has already been evacuated. (Courtesy of Dr. J-G Im, et al and AJR 1992).

RB, 51\M, truck driver from Nueva Ecija (last visit 15 years PTC), now residing in Las Pinas, 5 months cough, productive of whitsh phlegm, anorexia, afternoon fever. Positive for ova on sputum.. Paragonimus

10th HD

17th HD (+) resolution of the fever and the other signs and symptoms

CXR:

Other xrays of early paragonimiasis

• TUBERCULOSIS 1.7 billion people • PARAGONIMIASIS 20 million people (WHO, 1994)

COUNTRIES WITH ENDEMIC AREAS • Cameroon

• China • Korea • Laos

• Nigeria • Peru • Ecuador

• Philippines • Thailand (WHO, 1994)

AFFECTED AREAS IN THE PHILIPPINES: • Davao

• Leyte

• Basilan

• Sorsogon

• Cotobato

• Mindoro

• Samar

• Camarines Sur (Belizario et al, 1998)

EPIDIMIOLOGY: Sorsogon “Kinagang”  crab juice in grounded crab meat  wrap in gabi leaves boiled till dry Leyte “Kinilao”  raw crabs mixed with citrus juice Leyte “Sinugba”  roasted until carapace turns yellow (Cabrera 1984)

• 87.5% of the municipalities of Sorsogon (+) Sundathelphusa p. (Cabrera 1979)

• Infection rate of the snail intermediate host (Brotia asperata) .57-.7% (Yogore, 1958A)

• Infection rate of the 2nd intermediate host Sundathelphusa p. 41- 98.5% (Yogore, 1957) 53% (Cabrera, 1973)

PREVALENCE: • 1973-1975  (.57%) sputum • 1974  (12.5%) sputum + feces • 1975-1978  (.15%) sputum

CLINICAL MANIFESTATIONS: • Constellation of symptoms mimic PTB • 50-70% initially diagnosed and treated for PTB • Onset usually months to years after the the initial infection and can become chronic

CLINICAL MANIFESTATIONS OF PULMONARY PARAGONIMIASIS (modified fom Kagawa, 1997) (%)

Shim 1991

Chang 1958

Singh 1986

Johnson 1983

Im 1992

Belizario 1996

Total

Cough

66

100

62

92

62

76

83

Hemoptysis

61

74

95

64

61

25

70

Chest pain

41

94

62

38

22

65

Dypnea

42

53

5

++

42

Fever and chills

11

67

23

++

37

No Symptoms

8

0

54

8

2

RADIOGRAPHIC MANIFESTATIONS OF PARAGONIMISIS

(%)

Consolidation Pleural Effusion* Cysts or Cavities* Linear streaking* Nodules* Pleural thickening Ring shadows* Calcified lesions* Adenopathy* Normal*

Shim Im 1991 199 59 252

66 32 26 22 18 (-) (-) (-) 5

54 46 41 25 7 23 (-) (-) (-)

Sing Johnso h n 1983 1986 62 68

10 13 3 8 28 3 8 3 13

48 20 12 20 12 8 4 (-) 8

Total

58 51 32 25 20 16 9 2 .5 5

SURROUNDING LUNG

CAVITATION

TUBERCULOSIS

PARAGONIMU S

Evidence Of disorder present • fibrosis • contraction • nodulation • ring shadows often with definite walls of variable thickness • cavities may have craggy or smooth walls • fluid levels may be seen

Unaffected lung remains normal No nodulations “bubble cavities” Smooth edged transluscencie s within an area of consolidation. No Fluid levels

PROGRESSION OF LESIONS

TUBERCULOSIS

PARAGONIMU S

• Visible over long periods (> 6 mo.) • Progression usually slow • Leaves scar and calcifications in lungs

• Where linear streaking has not developed, appearance changeable within relatively short intervals. • Marked changes may occur within 3 months even without specific treatment

Stage

Description

LARVAL (77%)

3-12 months

ADULT (18%)

can last for years

HEALING (4-5%)

Clinical features

Radiographic features

hemoptysis (100%) cough (48) chest pain (42) abdominal pain (30)

Ill-defined consolidation (63%) Pleural effusion (53) Pleural thickening (9) Normal (15)

hemoptysis (100%) cough (55)

ring shadows (17%) nodular densities (13) cavities (11)

hemoptysis and cough stable or disappearing

Linear opacities

ECTOPIC SITES; Clinical Presentation • Central headache, vomiting, dizziness abnormal vision, aphasia speech disturbance, motor and sensory deficits • Genital Infertility Swelling of scrotum • Cutaneous Skin cysts or lesions

Casiguran Sorsogon Cross Sectional Survey 76%  chronic cough 25%  hemoptysis and cough 22%  chest or back pain  dyspnea  easy fatigability  fever  weight loss  anorexia  seizures (Bellizario, 1996)

DIAGNOSTICS: • CXR • Sputum exam for ova • Fecal exam for ova • Pleural Fluid Examination • Blood Tests • Intradermal Test • Serological Test

Parasitological Diagnosis Pulmonary paragonimiasis is confirmed when eggs are detected in the sputum, stool, bronchoscopic washing, biopsy specimen or pleural effusion.

Sputum Examination • Main diagnostic tool • The observation of large number of eosinophils and/or Charcot-Leyden crystals in the sputum should raise the suspicion of Paragonimus infection

Sputum Examination Rusty sputum – pathognomonic

• • Ova – Confirmatory – Most common • Eggs are not always present in the sputum of infected individuals • Sensitivity: 30% - 40% Kagawa 1997

The number of ova in the sputum is proportional to the – Severity of symptoms • Blood streaked sputum – Extent of radiological changes • Diffuse infiltrates • Cavitary lesions

Sputum Examination • The egg excretion rates have been reported to be low ( 28-39%). • Im, Jung-Gi, AmJRad, 1992 • Johnson, AmRevResDse, 1983 • Shim, SemResMed, 1991

• Detection of eggs in the sputum is low during the first 2 months or during the • Multiple sputum examination chronic increase the stage. yield to 54% – 89% Kagawa 1997

• Concentration of the sputum increases the positivity rate to 12% Toscano, WHO, 1994

Sensitivity of Sputum Examination # of test

investigators

n

sensitivity 1X

Shim 1991

67

Kim 1970

3518

Kim 1970

607

39% 37% 2X 48%

Sputum Examination • Simple microscopy of a wet sputum smear – Typical yellowish – brown, operculated ova of the paragonimus eggs

Sputum Examination If eggs are not found by direct sputum examination, all sputum produced during a 24 hour period should be examined following alkaline sodium hypochlorite (antiformin)

Stool Examination • Swallowed by infected patients • Concomitant sputum and fecal examinations improve the overall rate of detection of infection.

Sensitivity of Stool Examination

# of test

investigators

n

sensitivity 1X

Shim 1990

53

Kim 1970

141

11%

15%

Pleural Fluid Examination Assist in diagnosis when eggs are not found and is useful in distinguishing paragonimiasis from tuberculosis.

Pleural Fluid Examination • Characteristically sterile • Contains large number of eosinophils and, rarely, eggs can be found in the sediment Barrett-Connoer, AmRevResDse, 1990

Pleural Fluid Examiantion

• Opaque exudate • Glucose <10mg/dl

79%

• LDH >1,000 IU/L

84%

• Protein >3mg/dl

95%

• RBC >1000/m3

92%

• WBC >1000/ m3

97%

• Low pH • Eosinophilia

Blood Examination • Eosinophilia suggests a parasitic infection • Leukocytosis and eosinophilia are commonly observed in paragonimiasis • No quantitative correlation between eggs in the sputum and eosinophilia has been reported • Eosinophilia is consistently present in the • • • •

acute stage Absolute count decreases in the chronic stage Leukocytosis is highest in patients with Increase serum IgE levels symptoms of <6 months Paragonimus-specific IgE estimated by chromatography using immunoabsorbent column

Intradermal Tests • Screening technique – Crude Merthiolated saline extract of adult Paragonimus westermani (Veronal buffered saline [VBS] antigen) • Highly specific & sensitive • Detected within 2 weeks after infection • Persists from 6-24 months after complete disappearance of eggs from the sputum and stool due to treatment • Persists even up to 5 years after cure and Cross-reaction usually up to sinensis 20 years – Clonorchis • No cross-reactivity with tuberculosis or histoplasmosis • Simple & reliable screening test

Serological Tests • Correlate with active infection • Great value in the diagnosis, interpretation of (+) intradermal reactions in epidemiologic studies, ff-up studies after treatment & in the assessment of cure.

Sensitivity & Specificity of Serological Tests Tests Complement Fixation

Investigators Sensitivity Specificity Tsujii 1984

98%

Immunoblot Semenda 1998

96%

Indirect Tsujii 1984 Hemagglutination Parlyanonda 1990

90% 88%

99%

Sensitivity & Specificity of Serological Tests Tests

Investigators SensitivitySpecificity

Monoclonal Antibody

Zhang 1993

100%

Knolbloch 1984

100%

Maleewong 1990

100%

96- 98%

Parlyanonda 1990

100%

97%

IgG ELISA

Immunoelectrophoresis Tsujii 1984 Immunodiffusion

Tsujii 1984

100% 100%

99 + %

TREATMENT Kagawa 1997

Drugs

Dossage

Duration Cure Rate Side Effects 71-75%Dizziness Praziquantel 25mg/kg TID 1d 2d 85-100% HA, GI 3d 100% Bithionol 30-50mg/kg BID 20 – 30 d 91 - 100% GI, rash Niclofolan

2mg/kg

Mebendazole50mg/kg Triclabendazole 10mg/kg

single dose 95% 20d

60%

single dose 80%

Neurotoxicity Hepatotoxicity Dizziness Hypotension

Follow – up examination with multiple stool & sputum specimens 3 – 4 mo after completion of therapy is done to determine if another course is required.

Prognosis • Fair to good • Except when – Worms become lodged in critical foci – Develops to generalized fulminating condition

WHO Diagnostic Guidelines If tuberculosis is suspected in areas where paragonimus infection is prevalent, paragonimiasis should be excluded by parasitological examination of the sputum before proceeding to further examination.

WHO Diagnostic Guidelines Conversely, particularly in endemic areas where suspicion of paragonimus is high, tuberculosis should always be excluded by 3 direct sputum smears, and if available, culture of a concentrated sputum specimen.

WHO Diagnostic Guidelines Tuberculosis laboratories should have the capacity and their staff the necessary training to undertake examination of Paragonimus in the sputum.

WHO Diagnostic Guidelines

• Paragonimus ova are destroyed by ZielNeelsen stain. • Separate sputum examinations for both paragonimus & TB bacilli are strongly recommended. • If not possible, sputum should first be examined

Methods of Control • Chemotherapy • Disinfection of excreta & sputum or its sanitary disposal • Anti – molluscan campaigns • Public education

INVASIVE PULMONARY ASPERGILLOSIS (IPA) • Most common fungal pulmonary infection in severely immuno-compromised patients • Commonly isolated from soil, plant debris, indoor environment, hospital • Diagnosis is based on clinical, radiological,mycological data • Clinical signs low specificity • Typical radiologic findings: nodules with or without the halo sign or air crescent sign • Sensitivity of microscopy and culture of noninvasive collected samples is low • Galactomann/nucleic acid detection in serumor BAL • Treatment: early initiation of antifungal therapy (Voriconazole, Amphotericin B), Surgery (main indication is prevention of severe hemoptysis when lesion is adjacent to a large vessel)

Chest X-ray showing right upper zone volume loss with consolidation changes and a large cavitating lesion with soft tissue mass, which contained the air crescent sign. Computed tomography of the thorax showing a 6 x 6 x 6 cm non-calcified lesion involving the lateral aspect of the right upper ribs with extra-thoracic extension. The lesion was cavitary with a relatively smooth border and intraluminal roundish lesions that gave rise to the crescent sign in keeping with aspergilloma

Mycetoma

TARGET GROUPS FOR SPECIAL INFLUENZA VACCINATION PROGRAMS • Persons 65 > • Residents of nursing homes or chronic care facilities • Adults & children with chronic pulmonary and cardiovascular disorders including asthma • Adults & children with required regular follow-up or hospitalization during preceding year (DM,renal diseases, immunocompromised states)