1. Paper PBL 15 – Extreme Lethargy Group 4 MMC Kate, James, Lee, Quaderi, Jeeves, Satwik, Helen, Shravya, Jo, Nikhil

2. 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

3. 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…

4. 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

5. 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

6. Physical Examination 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

7. 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

8. Differential Diagnosis 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 ++ Summary of Findings Tuberculosis Pneumonia/Atypical Pneumonia Asthma exacerbation COPD Bronchiectasis Lung carcinoma HIV Lung abscess

9. Investigations

10. I(x) Active TB Routine; FBE ↑ WCC (Infection) ↓ Hb (Anaemic of chronic disease) U&E’s (baseline) LFT’s (baseline) ESR/CRP (inflammation/infection)

11. 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

12. A cavity is a walled hollow structure within the lungs. Diagnosis is aided by noting: wall thickness wall outline changes in the surrounding lung

13. 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

14. 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

15. 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.

17. 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.

19. 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.

20. Pathophysiology of TB

21. 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.

22. 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.

24. 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.

26. 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

27. Clinical Manifestations

28. 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.

29. 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.

30. 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 low- grade 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.

31. 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

32. Treatment

33. 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

34. 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

35. 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)

36. 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

37. 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.

38. 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.

39. Treatment is based on sensitivity testing with at least 3 drugs and an initial bactericidal injectable agent. Fluoroquinolone should be used where possible. XDR-TB Linezolid becomes mainstay treatment. Surgery is a limited option if disease localised. ResistanceAlternative INH, RIFLEVO, PZA, EMB, AMK INH, RIF, EMBLEVO, PZA, AMK, CS +/- PAS/ETH INH, RIF, PZALEVO, EMB, AMK, CS +/- PAS/ETH INH, RIF, PZA, EMBLEVO, AMK, CS, PAS/ETH, +/- one more drug First Line DrugCross-resistance INHEthionamide RIFAll Rifamycins PZA and EMBNone

40. HIV TB

41. 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

42. Clinical presentation CharacteristicAdvanced HIV infection **Early HIV infection Pulmonary : extra pulmonary disease 50:5080:20 Clinical presentationOften resembles primary TB Often resembles post- primary TB Chest radiograph Intrathoracic lymphadenopathy CommonRare Lower lobe involvementCommonRare CavitationRareCommon Tuberculin anergyCommonRare Sputum smear positivityLess commonCommon Adverse drug reactionsCommonRare Relapse after treatmentCommonRare ** CD4 T lymphocyte count < 200/mm3

43. 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.

44. Rx of TB in HIV co-infection 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 non- nuclease 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.

45. Tuberculosis Quiz

46. What do all of these people have in common... John Keats – english poet. 2009 movie Bright Star with Abbie Cornish. Singer Tom Jones, of“It’s not unsual” fame. Had TB at each 12 (obviously recovered). Singer Cat Stevens (Yusam Islaf) was close to death with TB in 1969. Nicole Kidman’s character Satine, died from TB in Moulin Rouge...they’ve all had tuberculosis