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Paper PBL 15 – Extreme
Lethargy
Group 4 MMC
Kate, James, Lee, Quaderi, Jeeves,
Satwik, Helen, Shravya, Jo, Nikhil
Case History
• Mr Josh Felix
• 25 years old, roadie for a “grunge band”
• Grew up in Wagga Wagga, moved to Glen
Waverly 5 years ago
Presenting Complaint:
• 6 week history of increasing lethargy,
productive cough, weight loss  he assumed
it was exacerbation of asthma
• Assuming it was asthma, he attended 24 hour
medical clinic for repeat prescription of
asthma medications  given salmeterol,
fluticasone inhalers, prednisolone 5mg and
amoxycillin 500mg for his cough.
• Returned 5 days later due to worsening
symptoms. New doctor on duty takes
thorough history and examination to find…
Josh’s History
• Productive cough – sputum thick, light brown, coughing
one “table spoon” each morning
• No haemoptysis
• Mild dsypnoea on exertion
• No chest pain
• Fever; chills & muscle aches followed by profuse sweating
• Asthma since age 5; 3-4 attacks each year; uses inhalers
intermittently
• No other medications
• Smokes 25 cigarettes per day, done so for 7 years
• Non-IVDU; Alcohol: 4 drinks per day + 2-3 binges per
month
Further Relevant History
• FHx – Josh’s mother was treated for “spitting blood”
18 years ago. Brother has severe asthma.
• Contact Hx – members of band have a “cold”
• Sexual Hx – many different female partners, often
unprotected. Sex with a man on once.
• Travel Hx – Never travelled overseas. Recently spent
2 months in Darwin.
• Animal contact – none of relevance
• Immunisations – can’t be recalled
• Dietary Hx – erratic diet, mainly junk food, no fresh
fruit or vegetables
Physical Examination
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•
•
•
Gaunt, white male; not acutely ill.
Pulse 98/min
BP 130/74 mmHg
RR 16/min
Oral temp 37.6°C
Weight 58kg
Hyperexpanded chest, soft rhonchi bilaterally, no
other focal resp signs
• CVS normal, no hepatomegaly
• Additional notes of tattoos, multiple piercings,
cigarette pack in t-shirt sleeve and no BCG scar
Initial Investigation Results
• FBE: Hb 109g/L, WBC 14.5x10^9/L, platelets 140x10^9/L
• HIV serology: negative
• LFT’s:
–
–
–
–
–
bilirubin 19 (N<17)
ALP 110 (N<120)
ALT 240 (N<56)
GGT 150 (N<75)
Albumin 26 g/L (N35-45)
• CXR: hyperexpanded lung fields, right apex opacity with 2x2cm
cavity, no cardiomegaly, hilar regions normal
• Sputum Gram stain: WBC +++, mixed Pos and Neg organisms
• Sputum Culture: normal oral flora
• Special Cultures:
– Burkholderia pseudomallei: pending
– AFB stain: positive ++ (first specimen)
– AFB culture: in progress
Summary of Findings
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Country of birth: Australia
Productive cough – sputum thick, light brown,
coughing one “table spoon” each morning
Mild dsypnoea on exertion
Fever; chills & muscle aches followed by profuse
sweating
Symptoms progressively worse over 6 weeks with
weight loss
FHx – Josh’s mother was treated for “spitting
blood” 18 years ago.
Sexual Hx – many different female partners, often
unprotected. Sex with a man on once.
Travel Hx – nil overseas, 2 months in Darwin.
Immunisations – can’t be recalled, no HBG scar
7 pack years smoking, high alcohol intake, poor
nutrition
Gaunt, white male; not acutely ill, weight 58kg
Hyperexpanded chest, soft rhonchi bilaterally, no
other focal resp signs
LFT’s: intrahepatic pattern with GGT
CXR: hyperexpanded lung fields, right apex opacity
with 2x2cm cavity, no cardiomegaly, hilar regions
normal
Sputum AFB stain: positive ++
Differential Diagnosis
•Tuberculosis
•Pneumonia/Atypical Pneumonia
•Asthma exacerbation
•COPD
•Bronchiectasis
•Lung carcinoma
•HIV
•Lung abscess
Risk Factors for disease
• Lowered immunity
– HIV, diabetes, ESRD, certain neoplasms (lung,
lymphoma)
– Corticosteroids, transplant drugs
– Age
• Silicosis
• Ethnicity
– Prolonged residence in TB endemic country
– Sub-saharan Africa, SE Asia, Subcontinent
Risk Factors for exposure
• Known contact with someone with TB
• Prolonged Travel to high-risk areas
• Health-Care work
Epidemiology – World Wide
•
•
•
•
No. 1 infectious disease problem
> 2 billion people are infected with TB bacilli
9.4 million new cases (2008)
1.8 million people died (2008)
– 500,000 had HIV
Epidemiology – World Wide
• South-east Asia
– Highest incidence and deaths
– Approx 3.2 million new cases (2008)
• Sub-Saharan Africa
– Highest incidence and mortality rate
– Approx 2.8 million new cases (2008)
Global TB incidence
•2 billion infected
•9.4 million cases 2008
•1.3 million deaths
• 95% cases occur in developing world
WHO 2009
Global TB incidence rates
Global incidence rate 139/100000/yr
WHO 2009
Epidemiology - Australia
Epidemiology - Australia
Investigations
I(x) Active TB
Routine;
FBE
•↑ WCC (Infection)
•↓ Hb (Anaemic of chronic disease)
U&E’s
•(baseline)
LFT’s
•(baseline)
ESR/CRP
•(inflammation/infection)
I(x) Active PTB
Diagnostic
Chest X-Ray
• Abnormal CXR often found with no symptoms but reverse extremely rare
• PTB is unlikely in absence of radiographic abnormalities
• Exception is miliary TB or non-respiratory TB
Findings
• Patchy or nodular shadows in the upper zones
• Loss of volume and fibrosis (with or without cavitation)
• Calcification may be present
Similar CXR findings
• Histoplasmosis, fungal infections (cryptococcosis, coccidiomycosis, blastomycosis,
aspergillosis), bronchial carcinoma, cavitating pulmonary Infarcts
EVERY EFFORT MUST BE MADE TO OBTAIN MICROBIOLOGICAL EVIDENCE
Cavity
Miliary TB
HIV+
I(x) Active TB
Culture Clinical Samples
• sputum, pleura & pleural fluid, urine,
pus, ascites, bone marrow, CSF
• Induce if non-productive
(bronchoscopy & lavage)
• Prolonged culture – 12wks
AFB – acid fast bacilli
• Ziehl-Neelsen stain
• Acid fast bacilli are stained bright red
and stand out against a blue
background
• Resistant to de-colouring when
washed with acid
I(x) Active TB
Other
• Imaging for non-respiratory TB (CT, XR etc)
• PCR – rapid identification of sensitivity/resistance (rifampicin)
• Biopsies – pleura, lymph nodes, solid lesions etc
I(x) Latent TB
• When infected with M Tuberculosis, but do not have active
tuberculosis disease.
• Patients are not infectious.
• TB infections in Australia are predominantly due to reactivation of
latent infection in people who were previously infected in their
countries of birth or during their childhood when TB was more
common in Australia.
• Simply put, the immune system ‘walls off’ the TB bacilli (in a
granulomatous lesion), which can lie dormant for years. It is kept in
this state by the cell-mediated immune system.
• Main Risk: around 10% of these people will develop active TB
during some point in their lives – the greatest risk being within the
first 2 years of being infected.
• Usually when their immune system is weakened.
Investigations – Mantoux Test
(Tuberculin Skin test= TST)
• Readily available test for identifying latent M. tuberculosis infection.
• Works via a hypersensitivity reaction by the cell-mediated immune
system to purified proteins from M. Tuberculosis (called Tuberculin).
• Tuberculin is injected intradermally in the forearm and the
resulting area of induration (not erythema) is measured 48-72
hours later.
• Positive result is based on the size of the induration, considering
the risk-status and prevalence of TB in certain patients.
• Previous vaccination with BCG affects the way results are
interpreted – may give false positives.
• Mantoux test should be done to identify people with an increased
risk of TB, who would benefit from treating the latent infection.
– People with HIV, recent contacts of a person known to have clinically
active TB, health care workers at increased risk, etc.
Tuberculin= Purified Protein
derivative (PPD)- intredermally
48-72 h
Transverse diameter of
induration in mm
Criteria for TST positivity
Induration
Result
Group
> 5 mm
Positive
HIV-infected
Immunosuppressed (TNFa, Tx,
Close contacts of infectious TB
Old TB on CXR
> 10 mm
Positive
Medical risk factors (CRF, CA etc.)
Foreign born endemic TB area
HCW
Nursing home, prisoners
> 15 mm
Positive
All other persons
BCG vaccinated
Investigations – QuantiFERON-TB Assay
• A recently produced blood test that is able to
measure quantitatively the production of cytokine
Interferon-γ by lymphocytes sensitised to
mycobacterial proteins using an ELISA technique.
• Advantages:
– Involves only 1 visit for a blood sample.
– No injection technique/subjective interpretation problems
– Does not boost responses measured by subsequent tests,
which can happen with tuberculin skin tests
– Is not affected by prior BCG vaccination.
Pathophysiology of TB
The Pathogens
• TB is mainly caused by Mycobacterium
tuberculosis.
• It can occasionally be caused by M. bovis or
M. africanum.
• M. tuberculosis divides every 15-20 hours.
• It is has a thick cell wall rich in lipids which
prevents it taking up most stains and helps it
resist digestion in macrophages.
• It is an aerobe & an acid fast bacillus.
Infection & Dormancy
• M. tuberculosis is spread in aerosols released by
coughing/sneezing. It needs to be inhaled for infection to
occur.
• Once inhaled, the bacteria reach the alveoli and are
phagocytosed by the alveolar macrophages. Their lipid
coating and ability to inhibit phagosome-lysosome fusion
enables them to avoid digestion.
• This primary infection site is called a Ghon focus and is
usually in the lower part of the upper lobe or the upper
part of the lower lobe.
• The bacteria soon reach the lymph nodes at the hilum of
the lung. The ghon focus and the infected node constitute a
Ghon complex. These are visible on X ray.
Infection & Dormancy ctd.
• The cell mediated immune reaction causes the
formation of granulomas.
• These are composed of numerous leukocytes
surrounding a core of infected macrophages.
• Most of the bacteria are destroyed but some enter a
dormant state and survive by slowing down their
metabolism.
• Cells in the centre of the granulomas undergo necrosis.
The resulting dead matter looks pale and cheesy and is
called caseous necrosis.
• Some granulomas undergo calcification and can be
seen on X-rays after the disease ceases to be active.
Reactivation
• The primary infection may not be self limiting if
the host is very young/old or
immunocompromised.
• When the immune system is compromised in
someone with latent TB (eg- HIV, diabetes,
steroids) the M. tuberculosis can reactivate and
cause secondary TB.
• Unlike the primary infection this is not self
limiting.
• The bacteria can spread to many parts of the
body and cause serious illness- eg: GIT, brain, liver
Clinical Manifestations
Clinical Manifestations of TB
• Pulmonary disease
– Primary disease
• Occurs soon after the initial infection in areas of high TB transmission, often in
children.
• Generally spreads to the upper zones of the lung
• The lesion which is formed after infection is usually peripheral and is often
accompanied by hilar or paratracheal lymphadenopathy.
• The initial lesion heals spontaneously in the majority of cases and may later be seen
as a small calcified nodule (Ghon lesion)
• However in children and immunocompromised people, the lesion can increase in
size and result in either a pleural effusion due to infiltration of bacteria into the
pleural space, or the primary site may rapidly enlarge causing central necrosis and
cavitation.
• Enlarged lymph nodes may compress bronchi, creating obstruction and hence
segmental or lobar collapse.
• This presents generally with fever, malaise, cough, weight loss and haemoptysis.
• There may also be a small pleural effusion or erythema nodosum due to
hypersensitivity reaction to the infective proves.
Clinical Manifestations of TB
• Pulmonary disease
– Post-primary
• Also known as reactivation TB, this results from endogenous
reactivation of latent TB.
• This also favours the upper zones.
• Typically there is a gradual onset of symptoms over weeks to
months.
• Presents with lethargy, malaise, anorexia and loss of weight with a
fever and couch.
• Sputum may be mucoid, purulent or blood-stained. A pleural
effusion or pneumonia may be the presenting feature.
• On examination, finger clubbing may be present in advanced
disease. Often there are no physical signs in the chest though
occasionally persistent crackles can be heard.
• Signs of pleural effusion, pneumonia and fibrosis may be seen.
Clinical Manifestations of TB
• Extrapulmonary disease
– Miliary or Disseminated Tuberculosis
• Due to haematogenous spread of bacteria and can be due to either
primary infection or reactivation.
• Nonspecific signs such as fever, night sweats, anorexia, weakness and
weight loss are the presenting symptoms.
• Eventually liver and spleen enlarge and tubercle lesions will appear
– Tuberculous meningitis
• Seen most often in children or immunocompromised adults.
• Results from haematogenous spread of pulmonary disease.
• May present with headache and slight mental changes, weeks of lowgrade fever, anorexia, malaise, anorexia and irritability.
• May evolve acutely with severe headache, confusion, lethargy, altered
sensation and neck rigidity.
• Diagnosed via LP and if unrecognised it can be fatal.
Clinical Manifestations of TB
• Extrapulmonary disease
– Cardiac
• Pericarditis and pericardial effusions
• This can lead to constrictive pericarditis due to fibrosis and calcification an can
be fatal.
– Eyes
• Choroiditis
– Genitourinary
• Pyuria and haematuria, flank pain, frequency, dysuria, nocturia
– GIT
• Peritoneal TB causing abdominal pain and GI upset (AFB in ascites).
– Skeletal
• Vertebral collapse, septic arthritis and osteomyelitis
– Skin
• Jelly-like nodular rash (lupus vulgaris) and possible erythema nodosum due to
hypersensitivity reaction to infection
TB CNS disease
Tuberculoma
TB meningitis
Treatment
Treatment
• Bed rest doesn’t affect outcome
• Hospitalisation:
– Ill, smear positive, highly infectious patients
– Esp in multi-drug resistant TB
• Continuous self-admin of drugs for 6 months vital for
successful Rx
– Lack of compliance  5% pts unresponsive to Rx
– Resistance to anti-TB drugs increasing
• Isoniazid resistance 10%
• Multidrug resistance 1%
• Before treatment:
– Test FBC, liver, and renal function
• Need to alter dosages in pts with liver/renal failure
– Test colour vision & acuity
• Ethambutanol can cause (reversible) ocular toxicity
Treatment
• 6 months
– Rifampicin 600-900 mg, daily
– Isoniazid 300 mg daily
– Pyrazinamide 2.5g, 3/week
• First 2 months
– Ethambutanol 30 mg/kg 3/week
• First 2 months
• Longer regimen:
– For bone TB (9 months), tuberculosis meningitis (1yr)
• NEVER use monotherapy
– Except when using Isoniazid for latent TB Rx
• DOTS: Directly Observed Therapy (short-course)
– WHO incentive, to improve detection and compliance
– DOT plan: treating physician/TB nurse
– Bi-weekly, thrice-weekly treatment instead of daily
Treatment of Tuberculosis
Standard Short Course
2 months daily
(H) Isoniazid
(R) Rifampicin
(Z) Pyrazinamide
(E) Ethambutol
‘Initial phase’
4 months
(H) Isoniazid
(R) Rifampicin
Daily, or 3-5x/wk
‘Continuation phase’
Bilateral pneumonia- improvement with treatment
At diagnosis
+ 2 months treatment
Side Effects
• Rifampicin:
–
–
–
–
–
Hepatitis
Small rise in AST acceptable
Stop if bilirubin rises
Orange discolouration of urine & tears
Inactivation of the Pill
• Isoniazid
–
–
–
–
Hepatitis
Neuropathy
Pyridoxine deficit
Agranulocytosis
• Ethambutanol
– Optic neuritis (colour vision fist to deteriorate)
– Pyrazinamide: Hepatitis
– Athralgia (CI: gout, prophyria)
Resistance
• Seen in non-compliant pts
• MDR (multi-drug resistance)
– High mortality (esp in HIV pts)
• Use at least 3 drugs to which organism is sensitive
• Follow-up
– Patients should be seen regularly for duration of
chemotherapy
– Once more after 3 months to check for relapse
• Chemoprophylaxis:
– Pts with x-ray changes compatible with TB, but about to
undergo immunosuppresive long-term Rx (ie dialysis)
– Isoniazid 300-450 mg/day
Drug Resistance
Mono-resistant TB – resistant to only one drug
Poly-resistant TB – resistant to more than one drug but
not the combination of isoniazid and rifampicin.
Multidrug-resistant TB (MDR-TB)
• TB caused by bacteria resistant to at least isoniazid
and rifampicin.
Extensively drug-resistant TB (XDR-TB)
• TB caused by bacteria resistant to isoniazid and
rifampicin (i.e. MDR-TB) plus any fluoroquinolone
and any second-line anti-TB injectable drugs
(amikacin, kanamycin or capreomycin)
There is an estimated 150 000 deaths per year from MDR-TB alone.
Proportion MDRTB in new cases 1994-2009
• Result from either primary infection with resistant
bacteria or may develop secondarily in the course of
treatment due to inadequate treatment regimens or
poor compliance.
• Risk factors include –
1. Previous treatment for TB especially if prolonged
2. Contact with a patient known to have drug resistant TB or
live in an area with high drug-resistant TB prevalence
3. Immunocompromised (HIV in particular)
4. Poor compliance
5. Culture +ve after 2 months treatment
• Can take up to 2 years to treat with drugs less
potent, more toxic and more expensive. Higher
mortality rate.
• Treatment is based on sensitivity testing with at least
3 drugs and an initial bactericidal injectable agent.
• Fluoroquinolone should be used where possible.
Resistance
Alternative
INH, RIF
LEVO, PZA, EMB, AMK
INH, RIF, EMB
LEVO, PZA, AMK, CS +/- PAS/ETH
INH, RIF, PZA
LEVO, EMB, AMK, CS +/- PAS/ETH
INH, RIF, PZA, EMB
LEVO, AMK, CS, PAS/ETH, +/- one
more drug
XDR-TB Linezolid becomes mainstay treatment. Surgery
is a limited option if disease localised.
Prevention
• Bacille Calmette Guerin (BCG) Vaccine
• Live attenuated strain of Mycobacterium bovis; 1921
• Efficacy
• Clinical trials UK: protective effect of 60 to 80%;
• Trials elsewhere have shown variable results; efficacy 
the closer one gets to the equator
– Meta-analysis Colditz et al. (1994) = 50 per cent effective
• Most important protective benefits are in minimising the risk of death,
meningitis and miliary disease in neonates and young children
• WHO recommend  given to all children in countries highly endemic for TB
Australian Recommendations:
1. Aboriginal neonates in areas of high incidence (e.g. NT, Far North Queensland, N WA & SA)
2. Individuals travelling to or living in areas with  prevalence of TB
3. Neonates born to parents with leprosy or a Fx of leprosy;
4. HCWs who may be at high risk of exposure to drug resistant cases
• Very safe
– Anaphylactoid reactions (rare); Most common is
development of a localised abscess at the site of injection,
especially if the vaccination is given too deeply
– Immuno-compromised  risk for disseminated BCG
infection
• C/I: Positive TST of greater than 5-mm diameter in duration;
Immunocompromised (HIV, corticosteroids, chemo,
malignancies ); Pregnant (?); PHx TB; Febrile; Pt suffers
from a generalised skin disease such as eczema and psoariasis
Method
• Tuberculin skin test (Manoux) is done first (except infants
below 6 months where Hx of TB excluded)
• C/I if reactive -  risk of severe local inflammation and
scarring
• Single intradermal injection at the insertion of the deltoid –
other sites: risk of keloid formation
Infection Control
• Isolation = Negative Pressure Rooms – prevent crosscontaminations from room to room
– Generates negative pressure to allow air to flow into the
isolation room but not escape from the room
• Educate patient about transmission  cover mouth
when coughing etc
Prophylaxis
(Isoniazid Preventive Treatment=IPT)
• Screen close contacts with tuberculin test +CXR
– Tuberculin +ve, CXR –ve: nothing further
– Pt with HIV, no BCG - isoniazid prophylaxis ↓risk by
40%
– Child with +ve tuberculin test  treatment
– Tuberculin –ve in children/young adults  repeat in 6
wks; administer BCG if still –ve / treatment if +ve
– Children <1y with family member with TB  isoniazid
6/12 + BCG with strain resistant to isoniazid
– Overall IPT 70-90% effective
HIV TB
• Worldwide TB is the most important opportunistic infection in
HIV patients – its the commonest killer.
• Around 20 million people worldwide are co infected with HIV
and TB.
• Dual infection of HIV and TB is very low in Australia (sub
Saharan Africa > 70%). < 5% of AIDS patients in Australia
develop active TB.
• 1-7% of the HIV infected people with latent TB, will go on to
develop active TB each year – a risk that is 4-25x higher than
in non-HIV patients.
• TB affects the course of HIV infection: in vitro cytokines
released because of MTB enhances HIV replication.
• HIV patients newly infected with MTB are more likely to
develop symptomatic primary infection.
Estimated HIV prevalence in TB cases
• Clinical manifestation depends
on:
– CD4 status (level of
immunosuppresion)
– Whether the TB is from recently
acquired TB or from a reactivation of
latent TB.
• HIV patients with preserved CD4
counts usually present with
pulmonary TB.
• Atypical manifestations, extra
pulmonary or disseminated TB
are more common in:
– HIV patients with primary TB
– Those with reactivated TB
– Impaired immunity ( * CD4 count <
200 per microlitre)
Characteristic
Late HIV
infection *
Early HIV
infection
Pulmonary : extra
pulmonary disease
50:50
80:20
Clinical presentation
Often
resembles
primary TB
Often
resembles
post-primary
TB
Intrathoracic
lymphadenopathy
Common
Rare
Lower lobe
involvement
Common
Rare
Cavitation
Rare
Common
Tuberculin response
Rare
Common
Sputum smear
positivity
Less common
Common
Adverse drug
reactions
Common
Rare
Relapse after
treatment
Common
Rare
Chest radiograph
• Tuberculin skin test or Quantiferon should be part of the
routine tests of every newly diagnosed HIV infection – test for
latent TB.
• Also all newly diagnosed patients with TB should be asked for
HIV risk factors, and tested for HIV.
• A Mantoux rxn of > 5mm or positive Quantiferon indicates TB
infection in people with HIV.
• Diagnosis can be tricky particularly in advanced HIV:
– Frequently negative sputum smear findings
– Atypical radiographic findings
– Higher prevalence of extra-pulmonary TB at inaccessible
sites
– Resemblance to other opportunistic pulmonary infections
• Rx of TB in HIV patients is complicated – only managed by expert
doctors.
• Rifampicin has pharmacokinetic interactions with protease
inhibitors (PI) – via hepatic cytochrome p450.
• overlapping toxicities between HAART and anti-TB drugs
– hepatotoxicity, peripheral neuropathy and GI side effects.
• In HIV patients with TB, Rifampicin containing Rx recommended
• When to start HAART
– Low CD4- 2 weeks after commencing TB therapy
– Higher CD4- delay till 2 months or end of TB therapy
• With those on HAART:
– Rifabutin is used instead of rifampicin if Protease inhibitor used.
– Or rifampicin could be used with efavirenz
– Isonazid, ethambutol and pyrazinamide are used in standard doses.
• Paradoxical treatment rxn – patients who begin HAART and anti-TB
drugs at same times can develop fever, lymph gland enlargement or
pulmonary infiltration week later – due to heightened immune
response to MTB secondary to HAART therapy.
Tuberculosis Quiz
What do all of these people have in common...
...they’ve all had tuberculosis
John Keats – english
poet. 2009 movie Bright
Star with Abbie Cornish.
Singer Cat Stevens (Yusam
Islaf) was close to death
with TB in 1969.
Nicole Kidman’s character
Satine, died from TB in
Moulin Rouge
Singer Tom Jones, of“It’s
not unsual” fame. Had
TB at each 12 (obviously
recovered).