Clinical Aspects of Tuberculosis Professor Mike Mc. Kendrick Lead Physician Department of Infection and Tropical Medicine Royal Hallamshire Hospital Sheffield Honorary Professor Division of Genomic Medicine University of Sheffield Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical aspects of TB l Pathogenisis l Clinical diagnosis l Treatment and monitoring and control l New issues Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical Aspects of Tuberculosis l Pathogenesis of tuberculosis – Infection versus disease Host factors l Pathogen factors l Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Pathogenesis l Host factors include – Social e. g. l l Poverty alcoholism – Age e. g. l l l Baby Teenage girl Old age – Immunity e. g. l l l HIV Gamma interferon SCID Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
![Pathogenesis l Organism factors e. g. – Virulence factors – [Drug resistance] Dpt. Infection](https://present5.com/presentation/b7cbdbc0f914ea6dbc6f1e1e1ddcfa04/image-5.jpg "Pathogenesis l Organism factors e. g. – Virulence factors – [Drug resistance] Dpt. Infection")
Pathogenesis l Organism factors e. g. – Virulence factors – [Drug resistance] Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Pathogenesis MTB into lungs (or to cervical nodes or abdo. nodes) l Replication of organisms l Primary complex (lung and mediastinal lymph nodes) l l Mycobacteraemia with potential for ‘seeding’ l Consequence of tuberculous infection – Symptomatic illness – disease (minority) – immunological control (majority) with Ghon focus on Xray. Infection is ‘contained’ by granuloma but not eliminated Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Pathogenesis l Tuberculous disease is a consequence of: – Primary infection e. g. in baby – Reactivation l l ‘natural’ Associated with immunosupression – Re infection Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical features l Clinical illness – Pulmonary – Extrapulmonary Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical illness l Chest – – l Pulmonary Pleural Mediastinal nodes pericardium Extra pulmonary – – – skin and soft tissues (including lymph nodes) Bone Abdominal Intra cranial other Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical clues for TB l Clinical symptoms – usually ‘chronic’ rather than acute – – Fever Sweats Weight loss Focal symptoms l Epidemiology – History of TB, HIV – Country of origin, recent travel/work – Contact with TB [England, Wales & NI 2004 l l 7, 176 notifications, 414 children 70% foreign born population groups] Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
TB – guidelines for the clinician l Great mimicker l Low index of suspicion l Pulmonary TB usually easy to consider l Non pulmonary often requires ‘lateral thinking’ Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical TB l Laboratory samples – In the current era every effort must be made to obtain adequate samples likely to lead to a microbiological diagnosis before treatment is started (sometimes difficult with surgical specimens!) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
What can the laboratory do to help the clinician? l Awareness of TB e. g. in the patient with recurrent sputum samples for ‘chronic bronchitis’ l ‘Rapid’ diagnosis of infection and resistance – Culture and sensitivities – the clinician wants answers immediately if possible – PCR – further opportunities for development – Gamma interferon based tests? ? – other Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
What samples? Depends on clinical scenario l Chest – – – l Sputum – if productive Induced sputum Bronchoscopic alveolar lavage (BAL) Pleural biopsy Pleural fluid Other – E. g. Lymph node, aspiration of abscess, mesenteric biopsy, stool, bone marrow etc. – What about EMSU? - should be done selectively where it is likely to be helpful Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Induced sputum l Hypertonic saline nebuliser in negative pressure room with HEPA filter and well trained physiotherapist – Study of 27 confirmed positive patients 13 +ve induced sputum only l 1 +ve bronchoscopy only l 13 +ve induced sputum and bronchoscopy l Mc. Williams T et al Thorax 2002: 57; 1010 -1014 Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Audit of induced sputum in Department of Infection in Sheffield – Criteria for procedure – Past history TB or contact with TB in last year – Respiratory symptoms of one or more of: • Non-productive cough • Fever, Night sweats, weight loss • Haemoptysis 114 procedures, 12 positive for TB – Cohort followed up for 12 months, no cases missed - Bell et al. J Infection 2003: 47; 317 -321 Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical cases l Cases of – pulmonary infection – Non pulmonary infection – Examples of spectrum of disease produced by TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Pulmonary and non pulmonary TB disease – Sheffield 2005 l Equal numbers of patients with pulmonary and non pulmonary tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical presentation 1 l 35 year old African lady with fever and dry cough for 3 weeks. l Mildly unwell l Night sweats l Weight loss 4 pounds l No history of contact with TB l CXR Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Case 1 – miliary tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Pulmonary TB typically affects the upper zones of the lung Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Case 1 l Investigation – FBC normal – ESR 53 – U and E normal – LFT – albumen 31 – CRP 40 – Induced sputum – smear negative Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Case 1 l Progress – Clinical diagnosis of TB 4 drug treatment l Clinical improvement l – TB culture positive at week 3 l fully sensitive (week 5) l Modified anti TB drug regime in light of lab results l Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Case 1 l What about HIV testing? – who to test? – Strong association between HIV and TB – Universal testing or selective testing? l What about testing for vitamin D? – Vitamin D has role in activating macrophages to destroy mycobacteria – Vitamin D deficiency in ethnic populations in UK often low Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Case 1 l Cured after standard 6 months therapy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical presentation 2 l 28 year old African lady with backache for 6 weeks l Diagnosed initially as non specific l Developed fever – no obvious cause l ID opinion sought l Investigation with MRI scan Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical case 2 l Diagnosis – Vertebral osteomyelitis with soft tissue mass impinging on the cord l Investigation l Biopsy and culture l Treatment – 4 anti TB drugs and antibiotic therapy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical case 2 What will happen if diagnosis or treatment for TB spinal osteomyelitis is delayed? Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
What will happen if treatment delayed? – gibbus formation (acute angulation of spine with or without neurological damage) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
The physical appearance – Potts disease of spine - gibbus Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical case 2 l Progress – Increasing back pain and neurological symptoms – mild leg weakness – Repeat MRI – changes similar l Treatment – Continue therapy – consider surgical decompression Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical case 2 l Further progress Weakness of legs l Neurosurgery and internal splinting l l Other considerations - clinical Has she got HIV? l Is her vitamin D level normal? l l Other considerations - epidemiological From where has she got infection? l To whom might she have given it? l Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
l TB may affect any tissue of the body including: – – Skin and soft tissue Lymph nodes Bones and joints Intra abdominal structures including peritoneum l Kidneys l Adrenal glands l Lymph nodes l – Central nervous system Tuberculoma l meningitis Dpt. Infection and Tropical Medicine, l Sheffield Teaching Hospitals
Skin and soft tissue Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
25 male African. Expanding non painful lesion in neck - Cervical lymph node TB progressing to abscess (beware deep extension – collar stud abscess) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
TB node in neck with deep extension Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
35 female African – systemically well - hand foot lesions present for 6 months – MTB grown on biopsy by plastic surgeons (HIV neg) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Bony tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Astute radiologist should enable the appropriate further investigation Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Often associated with delay in diagnosis – any chronic discharging lesion must be considered possibly TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Abdominal Tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Renal tuberculosis (may have few or no symptoms) leading to autonephrectomy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
30 middle eastern asylum seeker - abdo pain, fever, sweats – CT scan - peritoneal TB confirmed on biopsy – may mimic malignancy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Intracranial TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
miliary TB on MRI scan tuberclomas on CT scan Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
meningitis – diagnosis usually made on clinical grounds l Clinical l l l Acute or subacute Prognosis related to severity of disease at onset of treatment Commonly delay between presentation and diagnosis Common in children c 100 cases per year in England CSF – – Cell count 50 -500 (50% lymphs, 50% polys) High protein ++ Low glucose Micro often negative (PCR/culture important) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Treatment of TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
l BTS guidelines – 1999 l NICE Thorax 2000: 55; 210 -218 guidelines – 2006 – Sensitive TB – 4 drugs for 2 months 2 drugs for 4 months – Resistant TB - 6 drugs for 24 months (second line drugs are not so effective) [Eng, Wales & NI 2004, 6. 8% Isoniazid resistant, 1% MDR TB (R to Isoniazid and rifampicin)] Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Problems of TB therapy l Toxicity e. g. liver l Multiple therapy l Prolonged treatment l Drug interactions e. g. anti HIV drugs Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Compliance – Treatment will not work if not taken – DOTS (Directly Observed Therapy) if: Likely poor compliance l MDRTB l Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Outcome l WHO target (1991) – detect 70% infectious cases of TB and cure at least 85% by 2005 l Eng, Wales and NI – Probably detect 70% cases infectious TB – Cure rate uncertain l Among all TB patients with a known outcome the proportion of cases that have completed treatment – 79% in 2003 – 78% in 2002 – 79% in 2001 Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals CDR 23 March 2006
Why failure? l Patient non compliance – Deliberate – Failure to understand e. g. language, culture – Social e. g. alcohol l Patient movement e. g. ‘lost to follow up’ l Lack of medical/nursing support l others Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
public health - avoiding transmission TB is statutorily notifiable disease l Multidisciplinary approach – medical, TB nurses, CCDC etc. l l l Identify and manage possible sources of infection and contacts Considerations l l treat as OP where possible multi occupancy housing, social deprivation negative pressure rooms in hospitals (limited facility) beware transmission in OP setting e. g. waiting area Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
New challenges in TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Challenges in TB l Anti TNF therapy (Eg infliximab, etanercept) – May promote breakdown of granulomas and reactivation of TB – How to screen Clinical history l CXR (? With induced sputum) l Skin testing l ? ? Value of gamma interferon tests l Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Challenges in TB What will be the place of Quantiferon and Elispot type tests in clinical practice? Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Clinical need for new and better anti TB drugs Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
l Objective - to lead to more effective shorter course regimen – Better pharmacokinetics longer half life l better penetration to cavities l – Better activity kill TB in dormant phase l Active against resistant strains l – Safer and easier Lack of interaction with anti HIV therapy l Less toxic l – Low cost Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Will there be new affordable therapy for TB? l Global Alliance for TB Drug Development l TB development drug discovery research unit – Astra Zenica – Glaxo Smith. Kline – Novartis l WHO links with pharma l TB trials consortium (US CDC) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Will there be new affordable therapy for TB? l Moxifloxacin l TMC 207 l OPC-67683 l PA-824 l LL 3858 Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Summary l TB is a challenging disease for the clinician l Must have microbiology before starting treatment – more rapid lab tests? l Need to encourage compliance l Need for multidisciplinary approach to diagnosis and management and control l Need shorter, better, cheap anti TB regimes Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals
Скачать презентацию Clinical Aspects of Tuberculosis Professor Mike Mc Kendrick
b7cbdbc0f914ea6dbc6f1e1e1ddcfa04.ppt