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
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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
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
A cavity is a walled hollow structure within the lungs. Diagnosis is aided by noting:
wall thickness
wall outline
changes in the surrounding lung
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
• 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 BCC 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.
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
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 4-6%
• 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
Side Effects
• Rifampicin:
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Hepatitis
Small rise in AST acceptable
Stop if bilirubin rises
Orange discolouration of urine & tears
Inactivation of the Pill
• Isoniazid
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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 xhanges 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.
• 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
First Line Drug
Cross-resistance
INH
Ethionamide
RIF
All Rifamycins
PZA and EMB
None
• XDR-TB Linezolid becomes mainstay treatment.
Surgery is a limited option if disease localised.
HIV TB
• World wide TB is the most common cause of death in
people with HIV
• About 1/3 of HIV infected people worldwide are co-infected
with TB (co-infection rates differ: sub-Saharan Africa 75%,
Australia –very low)
• Patients with HIV are at a greater risk of:
– Reactivating latent infection (7-10% annually vs. 5-10% lifetime
risk in non-HIV people)
– 10-20% likely to acquire TB from open contact (vs. 5-10%)
– Developing progressive primary disease (30-40% vs. 5-10%)
– Developing disseminated, miliary or extrapulmonary disease
(>60% vs. <25% in non-HIV people)
– Developing second episode of TB from exogenous infection
Clinical presentation
Characteristic
Advanced HIV infection **
Early HIV infection
Pulmonary : extra
pulmonary disease
50:50
80:20
Clinical presentation
Often resembles primary
TB
Often resembles postprimary TB
Intrathoracic
lymphadenopathy
Common
Rare
Lower lobe involvement
Common
Rare
Cavitation
Rare
Common
Tuberculin anergy
Common
Rare
Sputum smear positivity
Less common
Common
Adverse drug reactions
Common
Rare
Relapse after treatment
Common
Rare
Chest radiograph
** CD4 T lymphocyte count < 200/mm3
Dx of TB in HIV
• All patients with active TB should be tested for HIV.
• Diagnosis difficult due to (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
• In patients with late stage HIV and low CD4 count diagnosis is
usually made by mycobacterial culture of blood, bone marrow
or tissue.
Rx of TB in HIV co-infection
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•
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Rx consists of four drugs (isoniazid, rifampicin, pyrazinamide + ethambutol) for the
first two months. Once sensitivities are confirmed pyrazinamide and ethambutol
are withdrawn, the other two are continued for 4 months.
In some cirumstances Rx maybe extended beyond 6 months (extrapulmonary TB).
Rifampicin has pharmacokinetic interactions with protease inhibitors (PI) and nonnuclease reverse transcriptase inhibitor (NNRTIs) – via cytochrome p450.
There are also overlapping toxicities between HAART and anti – TB drugs: in
particular hepatotoxicity, peripheral neuropathy and GI side effects.
Therapeutic principles in HIV TB:
– Anti TB treatment takes precedence over HAART for HIV
– In patients already on HAART, the same has to continue with modifications
both in HAART and anti- TB treatment.
– In patients not on HAART, the need and timing of initiation are based on the
short term risk of disease progression and death, CD4 count and type of TB,
on an individual basis.
Treatment should be supervised (DOTS). MDR occurs in about 6% of cases of TB in
HIV positive individuals.
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).