Pulmonary Infection: An Atlas of Investigation and Management

An Atlas of Investigation and Management

PULMONARY INFECTION

An Atlas of Investigation and Management

PULMONARY INFECTION Adam T Hill Consultant Physician Royal Infirmary of Edinburgh Scotland William AH Wallace Consultant Pathologist Royal Infirmary of Edinburgh Scotland Xavier Emmanuel Consultant Microbiologist Royal Infirmary of Edinburgh Scotland

CLINICAL PUBLISHING OXFORD Distributed worldwide by CRC Press Boca Raton London New York Washington D.C.

Clinical Publishing An imprint of Atlas Medical Publishing Ltd Oxford Centre for Innovation Mill Street, Oxford OX2 0JX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 Web: http://www.clinicalpublishing.co.uk/ This edition published in the Taylor & Francis e-Library, 2006. “ To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” Distributed by: CRC Press LLC 2000 NW Corporate Blvd Boca Raton, FL 33431, USA E-mail: [email protected] CRC Press UK 23–25 Blades Court Deodar Road London SW15 2NU, UK E-mail: [email protected] © Atlas Medical Publishing Ltd 2005 First published 2005 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A catalogue record for this book is available from the British Library. ISBN 0-203-02493-1 Master e-book ISBN

ISBN - (Adobe eReader Format) ISBN 1 904392 19 9 (Print Edition) The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work.

Contents Acknowledgements

vi

Foreword

vii

Abbreviations

viii

1 Community-Acquired Pneumonia

1

2 Hospital-Acquired Pneumonia

41

3 Pneumonia in the Severely Immunocompromised Patient

49

4 Tuberculosis

73

5 Chronic Obstructive Pulmonary Disease

121

6 Bronchiectasis

130

7 Miscellaneous Respiratory Infections

149

Index

175

Acknowledgements To our wives, Lucy, Amanda and Jacintha, for their continuous support and understanding without which this atlas and many other things would never have been successfully completed.

Foreword Many of us have largely visual memories. This extensively illustrated book will make an immediate impact. For clinicians at any stage of training, that impact is likely to persist. Moreover the illustrations and their explanatory texts provide complementary reality behind the heavier paragraphs of standard textbooks. To more experienced clinicians, the book will be valuable as a reference, especially when they encounter less familiar clinical problems. Conversely, trainees in microbiology, radiology, and pathology will here find a rapid insight into the potential contributions fellow disciplines can make to a diagnosis. The brief texts on clinical and therapeutic aspects are written in clear straightforward English, again summarizing the essentials. The authors and publisher have done an excellent job. I wish the book all the success it deserves, Sir John Crofton Professor Emeritus University of Edinburgh Scotland

Abbreviations AFB

acid-fast bacilli

AIDS

acquired immune deficiency syndrome

CFT

complement fixation test

CMV

cytomegalovirus

COPD

chronic obstructive pulmonary disease

CT

computed tomography

EGG

electrocardiogram

ESAT

early secretory antigenic target

FEV1

forced expiratory volume in 1 second

FiO2

inspired oxygen concentration

G-CSF

granulocyte colony stimulating factor

IFNγ

interferon gamma

i.v.

intravenous

LDH

lactate dehydrogenase

MOTT

mycobacteria other than M. tuberculosis

MRSA

methicillin-resistant Staphylococcus aureus

NIV

noninvasive ventilation

PaO2

partial pressure of arterial oxygen

PAS

periodic acid Schiff

PCP

Pneumocystis carinii pneumonia

PCR

polymerase chain reaction

SaO2

oxygen saturation

TB

tuberculosis

TNF

tumour necrosis factor

VAP

ventilator-associated pneumonia

Chapter 1 Community-Acquired Pneumonia Introduction Internationally, community-acquired pneumonia is a common problem both for community and hospital physicians. It occurs with an annual incidence of about 5–11 per 1,000 adult population and rises with age, to about 34 per 1,000 population for patients aged over 75 years. The annual incidence of patients that require hospital admission varies from approximately 1–4 per 1,000 population. The mortality rates are low (<1%) for patients managed in the community, higher in patients admitted to hospital, around 5– 12%, and highest for patients requiring mechanical ventilation with rates from around 35% to >50%. It is thus a common disease and can have considerable impact on health care resources. This section on community-acquired pneumonia, with illustrative radiology, microbiology, and pathology, discusses the investigation, diagnosis, and management of community-acquired pneumonia in adults. Key areas covered include the common causative organisms, patient presentation including severity assessment, a recommended investigation strategy, and treatment options. Finally, the complications of communityacquired pneumonia are illustrated with particular emphasis on the investigation, diagnosis, and management of lung abscess and pleural infection.

Aetiology In most cases of mild community-acquired pneumonia, a microbiological cause is not determined. When sputum samples are cultured by routine bacteriological methods, the commonest pathogen isolated is Streptococcus pneumoniae. Less commonly, Haemophilus influenzae or Moraxella catarrhalis may be cultured, particularly in patients with previous airways damage. Some important respiratory pathogens cannot be cultured by routine methods, but are usually detected by immunological or molecular methods. These, the so-called ‘atypical’ causes of pneumonia, include Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae, Chlamydia psittaci, Coxiella burnetti, and respiratory viruses such as influenza viruses, adenoviruses, and respiratory syncytial virus. Most organisms associated with mild pneumonia can also cause severe communityacquired pneumonia. Particularly severe pneumonia with septic shock may result when viral infections, such as influenza, lead to secondary lung infections with virulent pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, or Streptococcus pyogenes.

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Presentation • Patients may have had preceding viral upper respiratory tract symptoms. • New onset of lower respiratory tract symptoms occurs (usually cough±sputum production [sometimes haemoptysis], breathlessness, fever, and sometimes pleurisy). • Systemic features are often present (general malaise, anorexia, sweating, fevers, shivers, or aches and pains). • Extrapulmonary symptoms can be present. • New onset confusion can arise in severe cases. • New focal chest signs occur. The clinical signs in practice can be highly variable (the classical teaching in lobar pneumonia is reduced expansion, coarse inspiratory crackles, reduced percussion, bronchial breathing, and increased vocal resonance in the affected lobe). • New chest radiographic consolidation is present. • There is no other explanation for illness. Overall, the likely aetiological agent cannot be accurately predicted from clinical features. Severity score To guide placement and treatment, it is helpful to stratify patients according to illness severity. Patients with severe pneumonia have two or more of the following: • New onset mental confusion. • Blood urea >7 mmol/l. • Respiratory rate ≥30/min. • Systolic blood pressure <90 mmHg or diastolic <60 mmHg. Other adverse prognostic factors include: • Age ≥50 years. • Co-morbid illness, e.g. congestive cardiac failure; ischaemic heart disease; cerebrovascular disease; diabetes; chronic lung disease; carcinoma. • Physical findings including respiratory rate ≥30/min, pulse ≥125/min, low blood pressure (systolic <90 mmHg and/or diastolic <60 mmHg), and temperature <35°C or ≥40°C. • Laboratory findings with blood urea >7 mmol/1, white blood cell count <4×109/l or >20×109/l or an absolute neutrophil count <1×109/l, and hypoxaemia.. The British Thoracic Society guidelines on pneumonia define hypoxaemia as SaO2 <92% or PaO2 <8 kPa (60 mmHg) regardless of inspired oxygen concentration, whereas the American Thoracic Society guidelines on pneumonia define it as PaO2/FiO2 <250. • Bilateral or multi-lobe involvement of the chest radiograph. • Positive blood culture.

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Investigations The following investigations are routine: • Chest radiograph. • Full blood count. • Urea, electrolytes, and liver function tests. • Inflammatory markers such as erythrocyte sedimentation rate and C reactive protein. • Oxygen saturations on air and arterial blood gases if <92% or in patients with severe pneumonia. Common chest radiographic abnormalities are presented in Table 1.1. Overall there are no characteristic features on the chest radiograph that allow the accurate prediction of the likely pathogen. This is normally identified with further microbiological investigations. Table 1.2 presents the common blood test abnormalities. Illustrative cases Figures 1.1–1.12 are examples of radiographic, CT scanning and macro- and microscopic abnormalities seen in pneumonia. The chest radiograph from a 20-year-old male is shown in 1.1. He presented with a right middle lobe pneumonia due to Streptococcus pneumoniae. Due to consolidation, there is loss of the right heart border in keeping with pneumonia affecting the right middle lobe. The consolidation is limited to the right middle lobe in keeping with a lobar pneumonia.

Table 1.1 Common chest radiographic abnormalities Pattern

Aetiologic agent often identified

Lobar pneumonia

Streptococcus pneumoniae, Legionella pneumoniae, Gram-negative organisms

Bronchopneumonia

Staphylococcus aureus, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis

Cavitation

Staphylococcus aureus, anaerobic bacteria, β-haemolytic streptococcus, virulent Streptococcus pneumoniae, Mycobacterium tuberculosis, fungal infections, e.g. histoplasmosis

Interstitial pneumonia

Mycoplasma pneumoniae, Chlamydia pneumoniae, viral infections, e.g. adenovirus

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1.1 Chest radiograph showing right middle lobe consolidation due to lobar pneumonia (arrow). Table 1.2 Common blood test abnormalities Test

Abnormalities identified

Full blood count

1 Raised white cell count >10×109/l 2 White cell count <4×109/l or >20×109/l in severe pneumonia 3 Lymphopenia may be present in Legionella and viral pneumonia 4 Normocytic anaemia commonly seen in severe pneumonia

Urea and electrolytes

1 Pre-renal or acute renal failure can develop (increased blood urea >7 mmol/l is an indicator of severe pneumonia) 2 Low sodium can be found due to the syndrome of inappropriate antidiuretic hormone secretion 3 Low albumin 4 Deranged liver function tests often identified; can be related to the pneumonia itself or the antibiotics prescribed

Inflammatory markers

1 Raised erythrocyte sedimentation rate 2 Raised C-reactive protein

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The CT images in 1.2 reveal the features of pneumonia, with air space consolidation and an air bronchogram present. The air bronchogram is seen because patent bronchi are visible against airless alveoli filled with exudative fluid.

1.2A–C CT scans demonstrate pneumonia, with air space consolidation (arrow) and an air bronchogram (arrowhead). (A, B: lung

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window settings; C: mediastinal window setting.) A 57-year-old female presented with left upper lobe pneumonia. No pathogen was isolated but the pneumonia resolved with a 7-day course of amoxicillin and clarithromycin. The chest radiograph is shown in 1.3. There is extensive consolidation with air bronchograms present within the left upper lobe. The consolidation is limited to the left upper lobe in keeping with a lobar pneumonia. 1.4 shows a macroscopic picture of a lung, demonstrating a wedge-shaped area of yellow consolidation which is bounded by fibrous septa. Areas of cavitation and abscess formation can be seen focally within the consolidated lung. The organism responsible in this case was Staphylococcus aureus.

1.3 Chest radiograph showing left upper lobe pneumonia with extensive consolidation and air bronchograms present within the left upper lobe (arrow).

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1.4 Macroscopic picture of lung tissue with areas of consolidation and abscess formation within the consolidated lung, due to Staphylococcus aureus infection. Microscopy from a case of lobar pneumonia is shown in 1.5. The alveolar spaces are filled with neutrophils and fibrin leading to ‘consolidation’ of the lung. In the event of resolution, this inflammatory process is removed and the lung architecture may be left intact. With some organisms, such as Staphylococcus aureus, there may be extensive necrosis and destruction of alveolar walls with healing by scarring. A 66-year-old male presented with severe bilateral bronchopneumonia. The chest radiograph (1.6) demonstrates that there is also a small right pleural effusion and evidence of an old healed right 8th posterior rib fracture. There is patchy bilateral consolidation affecting multiple lobes, in keeping with a bilateral bronchopneumonia. 1.7 presents a macroscopic picture from a case of bronchopneumonia. Unlike in lobar pneumonia, the majority of the lung parenchyma appears normal but spotty areas of pale consolidation are seen. The reason for the focal nature of the change is that the consolidation is centred on the airways rather than diffusely involving the alveolated lung parenchyma. Histologically focal areas of acute inflammation are present in the lung (1.8A, B) which are centred on the airways, with some spilling of inflammatory debris into adjacent alveolar airspaces.

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1.5 Microscopy of lung tissue from a case of lobar pneumonia. The alveolar spaces are filled with neutrophils and fibrin leading to ‘consolidation’ of the lung.

1.6 Chest radiograph showing bilateral bronchopneumonia (two areas of consolidation are arrowed). (Courtesy of Dr. T.Sethi, Consultant Respiratory Physician, Royal Infirmary, Edinburgh, Scotland.)

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1.7 Macroscopic picture of lung tissue showing focal pale consolidation due to bronchopneumonia (arrows).

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1.8A, B Photomicrographs (A: low power; B: high power) of lung tissue from a patient with bronchopneumonia, showing acute inflammatory cells and debris within a bronchus (arrows). A 37-year-old male presented with a bilateral pneumonia due to Legionella pneumophila (1.9). This pattern of pneumonia is, however, seen with other pathogens and other patterns can be seen in patients with pneumonia due to Legionella pneumophila (see Table 1.1). A 79-year-old presented with cavitating right upper lobe pneumonia due to Klebsietta pneumoniae. Note that on the chest radiographs (1.10A, B) there is lobar enlargement with the bulging fissure sign (the minor fissure is inferiorly displaced due to the increased volume of the right upper lobe). This pattern of pneumonia is commonly seen with Klebsietta pneumoniae, but can be seen with other virulent organisms such as Staphylococcus aureus and Pseudomonas species. A 21-year-old male presented with diffuse interstitial shadowing due to Mycoplasma pneumoniae (there were no risk factors for immunodeficiency). There is diffuse reticulonodular shadowing throughout the lung fields, which is particularly noticeable on the chest radiograph (1.11) in the intercostal spaces. Interstitial pneumonia in the immunocompetent host can be seen in viral pneumonias, such as adenovirus, influenza or varicella, and in pneumonias due to ‘atypical pathogens’, such as Mycoplasma and Chlamydia pneumoniae. Note that other patterns of pneumonia can occur with these pathogens (see Table 1.1). A 35-year-old male presented with varicella pneumonia. There are diffuse ill-defined foci of air space disease (predominantly nodular shadowing is seen in this film) (1.12). This was associated with disseminated skin lesions of chickenpox.

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1.9 Chest radiograph showing bilateral pneumonia (arrows) due to Legionella pneumophila.

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1.10A, B Chest radiographs (A: PA; B: lateral) showing cavitating right upper lobar pneumonia due to Klebsiella pneumoniae. Note that on the chest radiographs there is lobar enlargement with the bulging fissure

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sign (arrows). (Courtesy of Dr. D.Patel, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

1.11 Chest radiograph showing interstitial pneumonia due to Mycoplasma pneumoniae.

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1.12 Chest radiograph showing nodular shadowing due to varicella pneumonia (one area is arrowed). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

1.13 Gram stain of expectorated sputum sample from a patient with pneumococcal lobar pneumonia, showing Gram-positive diplococci.

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Tests available to determine microbiological aetiology Attempts should be made to establish a specific microbial aetiology in all cases of severe pneumonia. The following tests are useful: • Expectorated sputum (when available) and blood cultures should be obtained before antibiotic therapy is started. • Induced sputum or bronchoalveolar lavage should be considered when expectorated sputum is not available or when Legionnaire’s disease is suspected. • Pleural fluid, if aspirated, should be sent for microscopy and culture, including culture for Legionella. • In patients who have already received antibiotics, tests for pneumococcal capsular antigen may be performed on sputum, blood, or urine samples. • Urine can be sent for Legionella antigen testing. • Acute serum sample can be taken for testing for respiratory viruses and atypical pathogens. Figures 1.13–1.25 show cultures and staining of organisms in pneumonia. A Gram stain of expectorated sputum sample from a patient with pneumococcal lobar pneumonia is shown (1.13); Gram-positive cocci in pairs are present (diplococci), presumed to be Streptococcus pneumoniae. The sputum sample in 1.13 was cultured on blood agar (1.14). This shows colonies of Streptococcus pneumoniae after 18 hours’ incubation at 37°C.

1.14 Culture of the sputum sample in 1.13 on blood agar showing colonies of Streptococcus pneumoniae, showing characteristic zone of inhibition by optochin (pale area) on the bottom part

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of the plate (arrow). Commensal viridans streptococci shown on the top part of the plate show no zone of inhibition. A Gram stain of an expectorated sputum sample from a patient with bronchopneumonia is shown (1.15). Pleomorphic Gram-negative bacilli are present, which were found to be Haemophilus influenzae on culture on a ‘chocolate’ (heated blood) agar plate (1.16).

1.15 Gram stain of an expectorated sputum sample from a patient with bronchopneumonia, showing pleomorphic Gram-negative bacilli.

1.16 Culture of sputum from 1.15 on chocolate agar showing characteristic

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translucent soft colonies of Haemophilus influenzae. Figure 1.17 shows a Gram stain of a sputum sample from a patient with acute exacerbation of COPD. Gram-negative diplococci are present, which were shown to be Moraxella catarrhalis on culture on blood agar (1.18).

1.17 Gram stain of a sputum sample from a patient with acute exacerbation of COPD, showing Gram-negative diplococci.

1.18 Culture of sputum from 1.17 on blood agar showing colonies of Moraxella catarrhalis.

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A Gram stain of a bronchoalveolar lavage sample from a patient with severe communityacquired pneumonia complicating influenza A virus infection is shown (1.19). The Grampositive cocci are arranged in long chains. Culture of the sample on blood agar grew Group A streptococci (1.20) and demonstrates haemolysis caused by Streptococcus pyogenes. Figure 1.21 shows a Gram stain of a sputum sample from a patient with severe community-acquired pneumonia during an outbreak of influenza A infection. Many neutrophil polymorphs and Gram-positive cocci occurring in clumps are shown. Culture of the sputum sample for 24 h on blood agar shows colonies of Staphylococcus aureus (1.22). Figure 1.23 shows direct immunofluorescence stain of a centrifuged deposit of bronchoalveolar lavage sample from an elderly patient with severe pneumonia. The stain uses monoclonal antibodies to Legionella pneumophila labelled with fluorescein dye. Legionella pneumophila are seen as apple-green rods. Culture of 1.23 for 72 hours on specific Legionella culture medium shows the characteristic ground-glass appearance of Legionella pneumophila (1.24).

1.19 Gram stain of a bronchoalveolar lavage sample from a patient with severe community-acquired pneumonia complicating influenza A virus infection. Stain shows chains of Gram-positive cocci.

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1.20 Culture of bronchoalveolar lavage sample from 1.19 on blood agar demonstrating haemolysis caused by Streptococcus pyogenes.

1.21 Gram stain of a sputum sample from a patient with severe communityacquired pneumonia during an outbreak of influenza A infection, showing Gram-positive cocci and neutrophil polymorphs.

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1.22 Culture of sputum from 1.21 on blood agar showing colonies of Staphylococcus aureus.

1.23 Direct immunofluorescence stain of a bronchoalveolar lavage sample from a patient with hospital-acquired pneumonia. Rods of Legionella pneumophila stain apple green. Growth of influenza A virus in tissue culture inoculated with an endotracheal aspirate sample from an elderly patient with severe pneumonia is shown in 1.25. The virus is demonstrated using direct immunofluorescence staining with fluorescein-labelled monoclonal antibodies specific for influenza A virus. This technique may also be used directly (without prior tissue culture) on samples of respiratory secretions as a means of rapid diagnosis, but the sensitivity of the test will be lower.

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Complement fixation test (CFT) is commonly used as a screening test for lower respiratory tract infections caused by ‘atypical’ organisms. Specific antibody levels are estimated using serum from clotted blood samples (5–10 ml of blood in sterile plain plastic or glass sample containers). Titres may be low or normal in the early (acute) stages of infection; a fourfold rise in specific titre, when acute (early as possible) and convalescent (10–28 days later) samples are compared, provides good retrospective evidence of specific aetiology. This test is useful for demonstrating infections with: • Influenza viruses A and B. • Mycoplasma pneumoniae. • Chlamydia pneumoniae. • Chlamydia psittacci. • Coxiella burnetti.

1.24 Culture of bronchoalveolar lavage sample from 1.23 showing the characteristic ground-glass appearance of Legionella pneumophila colonies.

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1.25 Direct immunofluorescence staining for influenza A in tissue culture of endotracheal aspirate from a patient with severe pneumonia. Therapy Patients with community-acquired pneumonia and no adverse risk factors have a good prognosis and mortality rates are low. Treatment of such patients is feasible at home, assuming social circumstances permit and patients’ progress can be monitored in the community. It is not always clear-cut whether to treat patients with community-acquired pneumonia at home or in hospital and such cases should be decided by an experienced clinician taking into account the social and community backup. Patients with more than two of the following features should be regarded as having a severe pneumonia and should be managed in hospital: • New mental confusion. • Blood urea >7 mmol/1. • Respiratory rate ≥30/min. • Low blood pressure (systolic <90 mmHg and/or diastolic <60 mmHg). Patients with severe pneumonia who do not respond to medical treatment should ideally be transferred to a high dependency unit or an intensive care unit. In particular, assisted ventilation should be considered for patients with persistent hypoxia with PaO2 <8 kPa (60 mmHg) despite maximal oxygen therapy, progressive hypercapnia, severe acidosis (pH <7.26), shock, or depressed consciousness. Antibiotic therapy For patients managed in the community or for patients admitted to hospital with nonsevere, uncomplicated pneumonia, 7 days of antibiotic therapy is recommended. A

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combination of amoxicillin (500 mg-1 g three times per day) and erythromycin (500 mg four times per day) or clarithromycin (500 mg twice daily) for 7 days should be effective. Patients with severe microbiologically undefined pneumonia should receive 10 days of antibiotic therapy, but this should be extended to 14–21 days where Legionella, staphylococcal or Gram-negative enteric bacilli pneumonia are suspected or confirmed. Often treatment is empirical in the first instance but can be tailored if the microbiological aetiology is identified. Table 1.3 (page 26) presents the recommended regimens from the British and American Thoracic Societies for patients with severe pneumonia. The American Thoracic Society advises antibiotic therapy dependent on place of therapy, the presence of cardiopulmonary disease, and the presence of ‘modifying factors’ such as risk factors for drug resistant Streptococcus pneumoniae, enteric Gram-negative organisms, and Pseudomonas aeruginosa. Indications for intravenous antibiotics Intravenous antibiotic therapy should be used in the following circumstances: • Initial management of severe pneumonia. • Patients with impaired consciousness. • Patients with loss of the swallowing reflex. • Functional or anatomical reasons for malabsorption.

Complications of pneumonia Complications of pneumonia are varied and include the following: • Lung abscess. • Parapneumonic effusions. • Pneumothorax. • Pulmonary embolism. • Metastatic infection. • Extrapulmonary complications, e.g. pericarditis and renal failure with Legionella infection. • Septicaemia. • Adult respiratory distress syndrome. • Multi-organ failure. • Death. Lung abscess A lung abscess is a pus-containing necrotic lesion of the lung parenchyma that often contains an air/fluid level. It most commonly complicates pneumonia in debilitated patients, patients with alcohol excess, and in aspiration pneumonia. The abscess can be metastatic when caused by organisms such as Staphylococcus aureus from endocarditis

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or osteomyelitis. Culture of purulent sputum or pus often yields a mixture of pathogens, including Staphylococcus aureus, anaerobic cocci, anaerobic Gram-negative bacilli such as Bacteroides sp., ‘coliform’ organisms such as Klebsiella pneumoniae, and pathogenic oral streptococci of the ‘Streptococcus milleri group’. A chest radiograph or CT chest scan reveals a thick-walled cavity usually with and an air/fluid level. Figures 1.26–1.29 present chest radiographs, CT scans, and macroscopic picture of lung tissue from patients with lung abscesses.

Table 1.3 Recommended antibiotic regimens for severe community-acquired pneumonia Treatment

Standard

Alternative

Hospital

Co-amoxiclav or cefuroxime Levofloxacin+benzylpenicillin or cefotaxime or ceftriaxone+ erythromycin OR Clarithromycin±rifampicin

British

Inpatients not in an intensive care unit with no cardiopulmonary disease and no modifying risk factors

Azithromycin

β-lactam (cefotaxime or ceftriaxone or ampicillin/sulbactam or high dose ampicillin)+doxycycline OR monotherapy with an antipneumococcal quinolone

American

Inpatients not in an intensive care unit with cardiopulmonary disease and/or modifying risk factors

β-lactam* + macrolide or doxycycline

Monotherapy with an antipneumococcal quinolone

American

Intensive care unit with no risk factors for Pseudomonas aeruginosa

β-lactam (cefotaxime, ceftriaxone) + macrolide (azithromycin)

β-lactam (cefotaxime, ceftriaxone) + fluoroquinolone

American

Intensive care unit with risk factors for Pseudomonas aeruginosa

Antipseudomonal β-lactam (cefepime or imipenem or meropenum or piperacillin/tazobactam) + antipseudomonal quinolone (ciprofloxacin)

Antipseudomonal β-lactam + aminoglycoside + macrolide or nonpseudomonal fluoroquinolone

American

* Only use antipseudomonal drugs if risk factors present for Pseudomonas aeruginosa.

Guideline

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Illustrative cases A 66-year-old male presented with a severe bilateral pneumonia, a right lower lobe lung abscess, and a small right pleural effusion shown on chest radiograph (1.26A). A CT scan of a right lower lobe lung abscess is shown in 1.26B, C. On the mediastinal window setting (1.26B) there is a thick walled cavity with an air/fluid level in keeping with a lung abscess. There is also a small right pleural effusion. On the lung window setting (1.26C) the right lower lobe lung abscess is seen but there is also evidence of bilateral bronchopneumonia.

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1.26A–C A: Chest radiograph of a patient with a right lower lobe lung abscess, bilateral pneumonia, and a

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small right pleural effusion. B, C: CT chest scan of the patient in A, confirming a right lower lobe abscess (arrow), right pleural effusion (arrowhead), and bilateral bronchopneumonia (short arrows). (Courtesy of Dr. T.Sethi, Consultant Respiratory Physician, Royal Infirmary, Edinburgh, Scotland.) Figure 1.27 shows a macroscopic picture of a lung from a patient with an acute staphylococcal pneumonia. A central area of yellow pus forming a central cavity is seen, with surrounding consolidation of the lung. A 33-year-old male presented with a lung abscess in the left lung. The chest radiographs are presented (1.28A: PA; B: lateral). Note the thick-walled cavity with an air/fluid level. The CT scan (1.29) confirms a thick-walled cavity with an air/fluid level, as was demonstrated on the plain chest radiograph. There is also a small pleural effusion.

1.27 Macroscopic picture of lung tissue from a patient with an acute staphylococcal pneumonia, showing a pus-filled cavity with surrounding consolidation.

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1.28A Chest radiograph (PA) with an abscess in the left lower zone (arrow).

1.28B Chest radiograph (lateral) with an abscess in the lingula/left lower lobe (arrow).

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1.29 CT scan of the patient in 1.28, confirming a thick-walled cavity with an air/fluid level consistent with an abscess (arrow). Figure 1.30 shows a chest radiograph from a 21-year-old patient with bilateral pneumonia with cavitation. There is also a small right pleural effusion. The patient was an intravenous drug abuser who developed right-sided endocarditis affecting the tricuspid valve, with multiple pulmonary abscesses due to septic emboli from Staphylococcus aureus. Differential diagnosis of cavitating lung lesions • Cavitating lung carcinoma (usually squamous carcinoma). • Lung abscess. • Infected bulla. • Localized empyema. • Cavitating pneumoconiotic lesions, such as progressive massive fibrosis. • Hiatus hernia. • Tuberculosis. • Fungal infections, such as histoplasmosis, coccidiomycosis, and aspergilloma. • Higher bacterial infections, such as Nocardia and actinomycosis. • Hydatid cysts. • Pulmonary infarct. • Wegener’s granulomatosis. • Sarcoidosis (rare).

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Pathology Figure 1.31 shows a macroscopic picture of lung tissue from a patient with staphylococcal septicaemia complicating osteomyelitis. Multiple abscesses are present with cavitation. The abscesses appear more chronic in nature that that seen in 1.27, having thickened fibrous walls associated with some distortion of the adjacent lung. Treatment of a lung abscess Most patients with a lung abscess respond to antibiotic therapy; where possible, antibiotics should be guided by bacterial culture results. Antibiotic courses are usually given for 4–6 weeks in the first instance, but prolonged courses may be needed. Many antibiotic regimens are available. A recommended regimen is highlighted below: • Cefotaxime or ceftriaxone+metronidazole, or co-amoxiclav+metronidazole. • If Staphylococcus aureus (non-MRSA) is suspected, add in flucloxacillin±rifampicin. • If MRSA, is suspected, add in vancomycin or teicoplanin ±rifampicin. • Daily postural drainage is recommended. • Percutaneous drainage, open surgical drainage, or resection may be required if there has been a poor response to prolonged antibiotic therapy. Parapneumonic effusion Parapneumonic effusion is present in up to 57% of patients with pneumonia. All patients should have pleural fluid aspirated and sent for pH, lactate dehydrogenase (LDH), protein and glucose. A sample of pleural fluid should also be sent for Gram stain and culture. Parapneumonic effusions can be separated into simple and complicated parapneumonic effusions and empyema. Simple parapneumonic effusion: • Pleural fluid is macroscopically clear. • pH >7.2, protein >30 g/l, LDH <1000 IU/l, glucose >2.2 mmol/l. • No organisms on Gram stain or culture. • The pleural effusion should resolve with antibiotic therapy alone. Drainage of the pleural effusion is not required unless the effusion is large, which may be of symptomatic benefit if drained. Complicated parapneumonic effusion: • Pleural fluid is macroscopically clear or can be cloudy or turbid. • pH <7.2, protein >30 g/l, LDH >1000 IU/l, glucose <2.2 mmol/l. • May be positive on Gram stain or culture, but is dependent on whether the patient had received prior antibiotic therapy. • The pleural effusion should be drained with an intercostal chest drain.

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Empyema: • Pleural fluid is macroscopically purulent. • pH <7.2, protein >30g/l, LDH >1000 IU/l, glucose <2.2 mmol/l. • May be positive on Gram stain or culture, but is dependent on whether the patient had received prior antibiotic therapy. • The empyema should be drained with an intercostal chest drain.

1.30 Chest radiograph of a patient with multiple pulmonary abscesses, due to septic emboli (one is arrowed) from Staphylococcus aureus, and a small right-sided pleural effusion. (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

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1.31 Macroscopic picture of lung from a patient with staphylococcal septicaemia, complicating osteomyelitis, showing multiple lung abscesses (four are arrowed). Illustrative cases Figures 1.32–1.38 show chest radiographs, ultrasound and CT scans, and macroscopic pictures of lung tissue from patients with parapneumonic effusions and empyema. A 54year-old male presented and a left-sided pneumonia with a left-sided pleural effusion (1.32A). The ultrasound scan (1.32B) confirms that there is a pleural effusion and minimal loculation. Aspiration confirmed a complicated parapneumonic effusion. This resolved with antibiotic therapy and removal of the pleural fluid with an intercostal chest drain, without the need for adjunctive fibrinolytic therapy via the intercostal chest drain. Figure 1.33 presents a chest radiograph from a 34-year-old male with bilateral pneumonia and a left pleural effusion. This was aspirated and confirmed to be an empyema. A 62-year-old male presented with a right-sided loculated empyema and also encysted fluid in the oblique fissure (1.34). Note the right pleural effusion, the separate D- shaped opacity in the right midzone, and the encysted fluid in the oblique fissure in keeping with a loculated empyema.

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1.32A Chest radiograph from a patient with a left-sided pleural effusion (arrow).

1.32B Ultrasound scan from the patient in A, confirming a complicated parapneumonic effusion (arrow) with minimal loculation.

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1.33 Chest radiograph from a patient with a left pleural effusion (arrow); aspiration confirmed an empyema.

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1.34 Chest radiograph from a patient with a right-sided loculated empyema (arrow, right pleural effusion; short arrow, D-shaped opacity in the right midzone; arrowhead, encysted fluid in the oblique fissure). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

1.35 Chest radiograph from a patient with a left-sided loculated empyema (arrow). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

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1.36A Chest radiograph from a patient with left-sided pneumonia and left pleural effusion (arrow). A chest radiograph from a 73-year-old patient with a permanent pacemaker is shown in 1.35. There is a D-shaped opacity in the left chest that is highly suggestive of an empyema; this was confirmed following pleural aspiration. A 64-year-old female presented with a left-sided pneumonia with a left pleural effusion. The chest radiograph is shown in 1.36A. Ultrasound suggests a loculated pleural effusion (1.36B) which was confirmed to be an empyema following aspiration. Little pleural fluid was drained following insertion of an intercostal chest drain. There was, however, successful drainage following 3 days of intrapleural streptokinase and no surgical intervention was required. Figure 1.36C is a CT chest scan (mediastinal window setting), revealing a loculated right-sided empyema with the split pleural sign (due to the thickened visceral and parietal pleura). There are separate pleural collections in keeping with a loculated empyema.

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1.36B Ultrasound scan from the patient in A, confirming a loculated pleural effusion (arrow), found to be an empyema on aspiration.

1.36C CT scan (mediastinal window setting) showing a loculated rightsided empyema (two areas are arrowed) with a split pleural sign. Macroscopic picture of an empyema is shown in 1.37. The lung is compressed and the pleura thickened and fibrotic. Particularly the subpulmonary area of the pleural space is filled with pale inflammatory debris which has become loculated. This represents the empyema cavity.

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Bacteriology of pleural infection Infective agents isolated from patients who present with primary empyema, i.e. have not undergone prior surgical intervention, are often derived from endogenous mouth and throat flora. These include oral streptococci such as those of the ‘Streptococcus milleri’ group, anaerobes such as anaerobic cocci and Bocteroides group and, less commonly, ‘coliforms’ such as Escherichia coli, Klebsietta pneumoniae, and Enterobacter spp. Pleural effusions are common with Streptococcus pneumoniae pneumonia. The effusions are usually sterile but occasionally Streptococcus pneumoniae is cultured from the pleural fluid. Empyema occurring as a surgical complication, such as following aspiration or drainage of pleural effusion, post-thoracotomy, or oesophageal rupture, may have a more extensive range of aetiological agents, including Staphylococcus aureus (often methicillin resistant), yeasts such as Candida albicans, Pseudomonas aeruginosa, and antibioticresistant ‘coliforms’. Treatment Antibiotic therapy alone is inadequate treatment for empyema (see ‘Adjunctive treatment’, below). Therapy should be guided by bacterial culture results, where possible. Treatment with antibiotics for 3 weeks is recommended in the first instance but prolonged courses may be needed. Many regimens are available for treatment of primary empyema, such as cefotaxime or ceftriaxone+metronidazole. When treating empyema occurring as a surgical complication, antibiotic therapy should be guided by bacterial culture results since resistant organisms are often encountered. Adjunctive treatment Patients should have an intercostal chest drain in addition to antibiotic therapy. The size of the intercostal chest drain used is open to debate. Many physicians and surgeons believe large gauge tubes should be used (≥20G). Smaller bore catheters inserted using the Seldingher technique may be equally efficacious (usually 10–14G) but clinical trials are needed. Currently, larger gauge catheters are used for empyema (≥20G), but if smaller tubes are used they require regular flushing to avoid blockage. In patients failing to respond to antibiotics and percutaneous drainage, an ultrasound and/or CT scan of the chest is recommended to determine the extent of the pleural effusion and whether there are loculations. Intrapleural fibrinolysis should be considered in patients failing to respond with a residual pleural collection, particularly if septations are present (a loculated pleural effusion). Therapy with 3 days of either streptokinase (250,000 IU every 12 hours) or urokinase (100,000 IU every 24 hours) is recommended. If the patient fails to respond with chest tube drainage, antibiotics and/or fibrinolytic drugs after approximately 7 days, the clinician should discuss the option of surgical treatment with a thoracic surgeon. A number of surgical approaches are available, including video-assisted thoracoscopic surgery, open thoracic drainage, or thoracotomy with decortication. Although the surgical preference is thoracotomy and decortication for empyema that has failed to resolve with medical therapy, some patients are not surgically

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fit for this procedure. An alternative is rib resection (1.38A, B) with open drainage, the patient being left with an empyema tube.

1.37 Macroscopic picture of a lung from a patient with empyema. There is pleural thickening and loculated collections are seen below the lung (arrow). Arrowheads indicate lung parenchyma.

1.38A Rib resection in a patient medically unfit for thoracotomy and decortication for empyema that has failed to resolve with medical therapy. (Courtesy of Mr W.Walker, Consultant Thoracic Surgeon, Royal Infirmary, Edinburgh, Scotland.)

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1.38B Thoracoscopic view of an empyema revealing pus and blood and fibrinous adhesions (arrow). (Courtesy of Mr W.Walker, Consultant Thoracic Surgeon, Royal Infirmary, Edinburgh, Scotland.) Conclusion • Community-acquired pneumonia is a common condition presenting to both community and hospital physicians. • A microbiological diagnosis is desirable but is often not established. • There is international consensus on effective treatment.

Further reading British Thoracic Society Standards of Care Committee (2001). BTS Guidelines for the management of community-acquired pneumonia in adults. Thorax 56(Suppl. 4):IV 1–64. Niederman MS, Mandell LA, Anzueto A, et al. (2001). Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. American Journal of Respiratory Critical Care Medicine 163(7):1730–1754.

Chpater 2 Hospital-Acquired Pneumonia Introduction Pneumonia is one of the commonest of the ‘nosocomial infections’, that is, infections which are acquired by patients as a result of their stay in hospital. The incidence rises with age with rates of up to 15 per 1,000 hospitalized patients >65 years of age. It is associated with significant mortality, particularly when it affects patients in intensive care units (10–50% in ventilated patients). Several factors contribute to the increased risk of pneumonia in hospitalized patients: the proximity of other patients harbouring potential respiratory pathogens; immunocompromisation due to existing disease or treatment; impaired airways clearance due to anaesthesia, depressed consciousness, or post-surgical pain; disturbance of the normal commensal flora of the upper respiratory tract due to treatment with broadspectrum antibiotics and intubation to facilitate mechanical ventilation. The pathogenic organisms which invade the lung in hospitalized patients are often derived from the population of organisms which have colonized the patient’s own upper respiratory tract. The intensity of this colonization, the species of organisms involved, and their resistance to antibiotics are adversely influenced by treatment with broadspectrum antibiotics and access for mechanical ventilation. Established hospital strains of antibiotic-resistant organisms may become predominant in this colonization. Poor infection control practice, particularly by clinical staff who come in close contact with the patients, contributes to cross-infection with such hospital strains. Accurate clinical diagnosis of hospital-acquired lung infec-tion is often difficult because a number of disease processes apart from infection show similar clinical and radiological manifestations. Microbiological diagnosis is also often uncer-tain because of the difficulty in distinguishing the organisms which are invasive from those which are merely colonizers.

Aetiology The aetiological agents involved in hospital-acquired pneumonia are related to the origin of the infection. Crossinfection, from other patients or health care workers, involves viruses such as influenza A or B, adenoviruses, respiratory syncytial virus and, more recently, SARS coronavirus. Diagnosis is rapid by immunofluorescence tests or specific molecular probes and polymerase chain reaction (PCR). Bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and resistant Gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter spp., antibiotic-resistant ‘coliforms’) may also be acquired by cross-infection and may cause pneumonia in vulnerable patients, e.g.

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ventilated patients or neutropenic patients. Infections can also arise from the hospital environment. Legionella pneumophila commonly originates from faulty hospital water and ventilation systems, Aspergillus fumigatus from airborne contamination, and resistant Gram-negative organisms from contaminated equipment. Patients on ventilators are particlarly at risk. Infection usually derives from hospitalacquired colonization of the patient’s upper respiratory tract with potential pathogens such as MRSA, resistant Gram-negative bacilli, or yeasts. These are often strains which are selected for resistance because of antibiotic therapy. Less commonly, infection arises from contamination of airways, equipment, or humidifiers with resistant Gram-negative bacilli.

Presentation Patients with hospital-acquired pneumonia may present with the following features: • New onset pyrexia. • Change of sputum or tracheal aspirate characteristics such as increasing volume, increased viscosity, and/or increasing purulence. • Development of leucocytosis on the full blood count. • New lung infiltrate on the chest radiograph unexplained by other causes.

Investigations Isolation of specific aetiological agents and antibiotic sus-ceptibility tests should always be attempted, since infection is often due to resistant organisms. Samples of respiratory secretions for microscopy and culture may include: • Expectorated sputum. • Aspirates of nasopharyngeal secretions (for viruses). • Endotracheal secretions. • Bronchoalveolar lavage. • Pleural fluid. • Transbronchial biopsy. • Open lung biopsy. Antibiotics agents Methicillin-resistant strains of Staphylococcus aureus are always resistant to all penicillin and cephalosporin antibiotics. They are also often resistant to other groups of antibiotics such as quinolones (e.g. ciprofloxacin, ofloxacin) and macrolides (e.g. erythromycin, clarithromycin), and some strains are resistant to aminoglycosides (e.g. gentamicin, tobramycin). They are almost always sensitive to glycopeptide antibiotics such as vancomycin or teicoplanin, although there have been rare reports of partial resistance.

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Antibiotics for oral administration which are effective against many strains of MRSA include rifampicin, fucidin, tetracycline, and cotrimoxazole. Effective new antibiotics such as linezolid have been recently introduced into clinical care. Illustrative cases Figures 2.1–2.4 show Gram-staining and culture of sputum samples from patients with possible hospital-acquired infection. A Gram stain of a sample from a neutropenic patient with severe hospital-acquired pneumonia and sepsis is shown (2.1), demonstrating long, slender, Gram-negative bacilli. Culture yielded nonlactose fermenting colonies of Pseudomonas aeruginosa which are oxidase positive (2.2). Nonmucoid and mucoid strains are identified. Figure 2.3 is a Gram stain of a purulent sputum sample from a patient with suspected hospital-acquired pneumonia due to aspiration. Large numbers of polymorphonuclear neutrophils and Gram-negative bacilli are present, with outlines of the polysaccharide capsule visible. Overnight culture on McConkey agar yielded a heavy growth of lactosefermenting (pink), mucoid colonies of Klebsiella pneumoniae (2.4).

2.1 Gram stain of sputum samples from patients with hospital-acquired pneumonia. The figure shows nonmucoid Gram-negative bacilli (left) and mucoid Gram-negative bacilli (right).

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2.2 Cultures of sputum sample from 2.1 on Pseudomonas selective agar showing nonmucoid (left) and mucoid (right) strains of Pseudomonas aeruginosa.

2.3 Gram stain of a purulent sputum sample from a patient with suspected hospital-acquired pneumonia due to aspiration, showing polymorphonuclear neutrophils and Gramnegative bacilli.

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2.4 Culture of sputum sample from 2.3 on McConkey agar showing lactosefermenting, mucoid colonies of Klebsiella pneumoniae. Therapy Although specific organisms are difficult to implicate with certainty, antibiotic therapy, in combination if necessary, is chosen to cover organisms shown by culture and sensitivity testing to predominate in the respiratory secretions of the patient. Intravenous vancomycin and meropenem or ceftazidime are often used, but antibiotic choice should be guided by local resistance patterns and the microbiological findings in the individual patient. Ventilator-associated pneumonia In patients with ventilator-associated pneumonia (VAP), accurate identification of the causative organism is often difficult since the organisms involved are often those which colonize the upper airways in ventilated patients (resistant Gram-negative organisms and Staphylococcus aureus, including MRSA). Pneumonia in ventilated patients is suspected if there are features such as new infiltrates on the chest radiograph, a drop in arterial PO2, changes in pattern of fever, or increased respiratory secretions. These criteria are not highly specific and may have other explanations, such as myocardial infarction, pulmonary embolism, or acute respiratory distress syndrome. Microbiological investi-gations, including invasive sampling (tracheal aspirates, bronchoalveolar lavage or distal blind brush), are essential in order to ensure that the antibiotics used cover the predominant organisms.

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Figures 2.5, 2.6 present chest radiographs from patients with VAP. Figure 2.5 is a radiograph from a 43-year-old female, showing extensive bilateral consolidation. There is an endotracheal tube in situ. Figure 2.6 is a chest radiograph of a patient with VAP following abdominal aortic aneurysm repair 5 days earlier. There was initially a right upper lobe pneumonia but, despite treatment, the patient deteriorated and developed adult respiratory distress syndrome; note the diffuse interstitial shadowing without cardiomegaly. The patient was unable to be weaned and subsequently died. There are an endotracheal tube, a central venous line, and a pulmonary artery catheter in situ.

2.5 Chest radiograph showing extensive consolidation in right and left lung fields (arrows). (Courtesy of Dr. C.Selby, Consultant Physician, Queen Margaret Hospital, Fife, Scotland.)

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2.6 Chest radiograph showing diffuse interstitial shadowing due to pneumonia and adult respiratory distress syndrome, following abdominal aortic aneurysm repair. Bacteriology and treatment Most frequent infecting organisms are coliforms, Pseudomonas spp., Acinetobacter spp., or Staphylococcus aureus. Antibioticresistant strains (such as MRSA or extended spectrum β-lactamase-producing coliforms) often predominate, because of prior antibiotic usage. Sources of these organisms are the patient’s own endogenous bacteria or crossinfection from other patients or staff. Respiratory equipment such as tubing or nebulizers may be implicated, with a particular risk of Legionella infections. Though specific organisms are difficult to implicate with certainty, antibiotic therapy, in combination if necessary, is chosen to cover organisms shown by culture and sensitivity testing to predominate in the respiratory secretions of the patient. Intravenous vancomycin and meropenum or ceftazidime are often used but antibiotic choice should be guided by local resistance patterns and the microbiological findings in the individual patient.

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Conclusion • Pneumonia is a common and serious consequence of hospital stay. • It is often difficult to diagnose with certainty. • Close clinical and microbiological monitoring is essential for early recognition and effective treatment. • Good infection control practice and judicious use of antibiotics are crucial to reducing the risk of infection with antibiotic-resistant organisms.

Further reading George DL (1996). Nosocomial pneumonia. In: Hospital Epidemiology and Infection Control. CG Mayhall (ed). William and Wilkins, Baltimore. Chapter 12, pp. 175–195. Strausbaugh SJ (2000). Nosocomial respiratory infections. In: Principles and Practice of Infectious Diseases, 5th edn. GL Mandell, JC Bennett, R Dolin (eds). Churchill Livingstone, Philadelphia. Chapter 293, pp. 3020–3028. Torres A, Carlet J (2001). Ventilator-associated pneumonia. European Task Force on ventilatorassociated pneumonia. European Respiratory Journal 17(5):1034–1045. Chastre J, Fagon JY (2002). Ventilator-associated pneumonia. American Journal of Respiratory Critical Care Medicine 165(7):867–903. Ewig S, Bauer T, Torres A (2002). The pulmonary physician in critical care: nosocomial pneumonia. Thorax 57(4):366–371.

Chapter 3 Pneumonia in the Severely Immunocompromised Patient Introduction Lung infection in patients with suppressed or impaired immune function is a common clinical problem. The majority of these patients have relatively impaired function secondary to age, common conditions such as diabetes mellitus, or treatment for chronic disease with corticosteroid therapy. These patients have an increased risk of lung infection but typically this is with common bacterial organisms that may also be seen in the wider population and can be investigated and managed in a similar fashion. Infection with the more uncommon organisms that are usually associated with the immunocompromised patient are relatively rare and confined to those with severely impaired immune function, commonly patients with acquired immune deficiency syndrome (AIDS), those on immunosuppressive therapy, or patients undergoing chemotherapy for malignancy. In this chapter an algorithm is presented for the investigation of severely immunocompromised patients with suspected lung infection and the clinical, radiological, microbiological, and pathological features of infection with cytomegalovirus (CMV), Pneumocystis carinii, Aspergillus spp., and Candida spp. are discussed, with recommendations on possible treatment regimens.

Aetiology Pneumonia in patients with severe neutropenia (e.g. bone marrow transplantation, chemotherapy for malignancies) is often due to bacteria, such as Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, other ‘coliforms’ and fungi such as Aspergillus fumigatus and Candida albicans. Patients with predominantly T-lymphocyte deficiencies, such as in AIDS, or with therapeuticallyinduced immunodeficiency states, such as after solid organ transplantation, are more often associated with infections due to CMV or Pneumocystis carinii. There is considerable overlap between these two groups, and infections due to rarer organisms (see Chapter 7) often occur in immunocompromised patients.

Presentation Immunocompromised patients may present in a wide range of paediatric and adult clinical settings. Classification of immunodeficiency states is as follows:

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• Primary: – Antibody defects/deficiencies. – Cell-mediated defects. – Combined defects. • Acquired/secondary: – Immunosuppressive therapy. – Chemotherapy. – Underlying malignancy. – HIV infection. – Steroid therapy. – Extremes of age. – Diabetes mellitus. While the more severe primary defects invariably present in childhood, some of the less severe forms, such as IgG subclass deficiencies, may not present until adulthood and must be considered in patients with persistent or recurrent chest infections. The commonest causes of secondary immuno-deficiency states are extremes of age, diabetes, steroid therapy, immunosuppressant therapy, and intercurrent illness, particu-larly malignancy. Infection with the more unusual organisms such as P. carinii, CMV, and invasive fungal infections are, however, usually seen in the more severely immunosuppressed patient such as those receiving chemotherapy or immuno-suppressive agents, or with HIV infection.

Investigations Figure 3.1 presents a flow chart of the standard investigations used in the care of the immunocompromised patient. The following specific infections in the immunocompromised patient will be discussed: • CMV. • P. carinii. • Aspergillus spp. (usually A. fumigatus). • Candida spp. (usually C. albicans).

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3.1 Flow chart of standard investigations used in the immunocompromised patient suspected of having pneumonia. CMV pneumonitis CMV pneumonitis presents in up to 40% of recipients of solid organ transplants. Mortality rates are high, at up to 50% even with treatment. Clinical signs are not specific for CMV pneumonitis, with patients usually presenting with unproductive cough, breathlessness, pyrexia, tachypnoea, and hypoxaemia. Investigations Blood tests A full blood count may show neutropenia and reduced platelet count. Liver function tests may be deranged. Inflammatory markers are usually raised, with an elevated erythrocyte sedimentation rate and C-reactive protein. Arterial blood gases often show hypoxaemia with a type 1 respiratory failure. Radiology

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Chest radiographic changes are not specific for CMV pneumonitis, and may be subtle or even absent. Changes are usually bilateral, with diffuse or focal opacification or diffuse interstitial infiltrates. Similarly, changes seen on high resolution CT scans of the chest are not specific but commonly show diffuse, multiple, small nodules, patchy areas of dense consolidation, and ‘ground glass’ attenuation. Illustrative case Figures 3.2A is a chest radiograph from a 74-year-old male with renal failure due to microscopic polyarteritis, on immunosuppressant therapy. He developed a fever and increased breathlessness. The chest radiograph shows widespread interstitial shadowing thought initially to be due to fluid overload but he did not respond to treatment. Note also the Portacath in situ for dialysis. The CT scans (3.2B, C) show a mixture of ground glass changes, areas with consolidation, and mild interlobular septal thickening. There is a predominant peripheral distribution and more marked disease in the mid and lower zones. This was confirmed as CMV pneumonitis.

3.2A Chest radiograph from a patient on immunosuppressant therapy showing widespread interstitial shadowing. One area is highlighted (arrow).

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3.2B, C High resolution CT chest scans (lung window setting) from the patient in A, showing ground glass changes, consolidation, and mild interlobular septal thickening, predominantly in a peripheral distribution. This was confirmed as CMV pneumonitis. Pathology Figure 3.3 is a photomicrograph of a lung showing an acute CMV pneumonia. The lung shows foci of necrotizing inflam-mation with destruction of the alveolar architecture. Severe necrotizing pneumonia in profoundly immunosuppressed patients may arise as a

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result of bacterial, fungal, or viral infec-tion. Identification of the aetiological agent may be possible histologically, but in some cases this will not be obvious and the results of microbiological investigation will be required to make a diagnosis. A higher power photomicrograph of the same specimen (3.4) shows the typical ‘owl’s eye’ nuclear inclusions seen with CMV infection. When the specimen is stained immunohistochemically with a monoclonal antibody to CMV, infected cells stain brown (3.5). This shows intense nuclear and weaker cytoplasmic staining of the cell, reflecting the distribution of the viral antigen.

3.3 Photomicrograph of a lung showing foci of necrotizing inflammation with destruction of the alveolar architecture, due to an acute CMV pneumonia.

3.4 High power micrograph of the specimen in 3.3, showing the typical

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‘owl’s eye’ nuclear inclusions seen with CMV infection (arrow).

3.5 Immunohistochemical staining of the specimen in 3.3 with a monoclonal antibody to CMV, showing intense nuclear and weaker cytoplasmic brown staining of the cell, reflecting the distribution of the viral antigen (arrow). CMV infection is very common, but severe clinical manifestations usually occur only in immunocompromised individuals. Interstitial pneumonitis is the commonest organ specific manifestation in patients with AIDS or after organ or bone marrow transplantation. Other co-existing or competing pathogens are frequently found (e.g. HIV pneumonitis, PCP). Spontaneous sputum is not an appropriate sample for the diagnosis of CMV pneumonia. Definitive diagnosis requires laboratory examination of induced sputum, bronchoalveolar lavage, lung biopsy, or buffy coat from anticoagulated blood samples. Laboratory examination must include tissue culture to achieve maximal sensitivity and specificity, although a number of newer methods allow more rapid diagnosis. These latter methods include immunofluorescence using monoclonal antibodies to detect early antigens in tissue cultures or tissue samples, and nucleic acid probes on respiratory and tissue samples and on peripheral blood buffy coat to detect CMV-specific DNA or RNA sequences. Serology may also be helpful: rising titres indicate recent infection, and raised IgM titres suggest active infection. Treatment The decision to treat can be difficult; isolation of CMV from either induced sputum or bronchoalveolar lavage fluid is not sufficient alone to determine treatment. If, however,

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in addition there is an associated pneumonitis from the chest radiograph or the CT scans of the chest then treatment would be recommended. The optimum investigations would include the combination of bronchoalveolar lavage fluid with transbronchial lung biopsies and PCR from venous blood. By combining these test results with radiology, the decision to treat is facilitated. In active infec-tion patients who would normally be expected to show radiological changes, CMV would be detected by PCR from blood and/or bronchoalveolar lavage and there would be typical histological features of CMV pneumonitis. A recommended treatment is i.v. ganciclovir for 14–21 days ±CMV-specific immune globulin or immunoglobulin. Intravenous foscarnet and cidofovir are alternatives. Most centres focus on the prevention of CMV infection; transplant centres are rigorous on donor selection and the use of CMVnegative or irradiated blood products, and use prophylaxis, often with ganciclovir, at least in the early stages (usually 1–3 months) posttransplantation. Pneumocystis carinii pneumonia P. carinii pneumonia (PCP) can present with nonspecific clinical signs developing over several weeks. They usually present with an unproductive cough, breathlessness, low grade pyrexia, and occasionally with a pneumothorax. High fevers, purulent sputum, and pleurisy are uncommon. Investigations Radiology Chest radiography may be normal (usually <10%). There is usually bilateral, symmetric, finely granular or reticular opacities, although they can be asymmetric. These changes begin in the peri-hilar region and extend distally as disease severity worsens. Pneumatoceles, which can cause a pneumothorax, are seen in up to 20% of cases. Pleural effusions and lymphadenopathy are unusual. High resolution CT scans of the chest show patchy ground glass opacities (but they can have a mosaic pattern), interlobular septal thickening, and pneumatoceles. Illustrative cases Figure 3.6 is a chest radiograph from a 27-year-old female who presented with cough, fever, breathlessness, and type 1 respiratory failure. The chest radiograph reveals interstitial shadowing with perihilar predominance. Note the normal heart size, no Kerley B lines, no upper lobe diversion, and no pleural effusions. This was confirmed as PCP pneumonia and HIV infection was subsequently diagnosed. This distribution is also seen in left ventricular failure; however, in left ventricular failure there are often other signs including cardiomegaly, Kerley B lines, upper lobe diversion±pleural effusions. Figure 3.7A is a chest radiograph from a 30-year-old male who presented with cough, fever, breathlessness, and weight loss. The chest radiograph shows interstitial shadowing with a perihilar predominance. The CT chest scans (3.7B, C) reveals bilateral, scattered,

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ground glass densities and the presence of thin-walled cysts, particularly in the upper lobes. This was confirmed as PCP pneumonia and HIV infection was subsequently diagnosed.

3.6 Chest radiograph showing interstitial shadowing with perihilar predominance, due to PCP pneumonia.

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3.7A Chest radiograph showing interstitial shadowing with a perihilar predominance, due to PCP pneumonia (arrow).

3.7B, C High resolution CT chest scans (lung window setting) from the patient in A, showing bilateral, scattered ground glass densities (arrow) and the presence of thin-walled cysts, particularly in the upper lobes (arrowhead).

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3.8A Chest radiograph from an HIV patient, showing interstitial infiltrate, perihilar predominance, and quite marked bilateral cystic changes, due to recurrent PCP infection. A chest radiograph of a 31-year-old HIV patient with recurrent PCP infection, not on antiretroviral therapy, is shown in 3.8A. Note the interstitial infiltrate, the perihilar predominance, and quite marked bilateral cystic changes. This was confirmed to be recurrent PCP infection. At the start of treatment, the patient developed bilateral spontaneous pneumothoraces, which is a recognized com-plication of PCP (3.8B). The pneumothorax is thought to be due to spontaneous rupture of the thin-walled cysts. Note there is a right intercostal chest drain, a small right apical pneumothorax, and surgical emphysema. On the left side there is a large pneumothorax. Other tests • Elevated serum lactate dehydrogenase is often found. • Lung function tests can reveal a restrictive defect and reduced carbon monoxide gas transfer. • Exercise tests show oxygen desaturation (a reduction of oxygen saturations of 3% or more). A typical example of exercise desaturation in a patient with PCP is shown in 3.9. The resting oxygen saturations were 94% on air. He managed 255 metres and stopped because of breathlessness. The oxygen saturations fell to 85% at the end of exercise. The saturations returned to resting level within 1 minute post-exercise.

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3.8A Chest radiograph from the patient in A developed bilateral spontaneous pneumothoraces. Note the right intercostal chest drain, a small right apical pneumothorax, surgical emphysema and a left untreated pneumothorax.

3.9 Exercise test results from a patient with PCP, showing a reduced oxygen saturation on exercise.

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Microbiology and pathology Standard respiratory investigations are not specific for P. carinii. Specific microbiology investigations must be carried out if PCP is suspected. Spontaneous sputum samples are not appropriate for the diagnosis of PCP. Useful diagnostic samples may be obtained by inducing cough and respiratory secretions with inhalations of nebulized hypertonic saline (3–5%). Bronchoalveolar lavage (of the upper lobes) and transbronchial biopsies may yield positive results in patients who are clinically suspected to have PCP, but in whom induced sputum samples are negative. Samples are examined in the laboratory by specific direct immunofluorescence microscopy or staining by Giemsa stain. Laboratory culture or sensitivity tests are not available. Figure 3.10 presents a photomicrograph of a lung showing filling of the alveolar space by fluffy exudates which in places have a rather foamy appearance. These histological features are typical of infection with P. carinii. The photomicrograph presented in 3.11 shows a lung from a patient with PCP, stained with a silver stain (Grocott). The walls of the pneumocysts within the foamy alveolar exudates stain black. Confirmation of the result can be obtained by staining sections immunohistochemically. Fluorescent microscopy of a centrifuged deposit of induced sputum sample obtained from a patient with newly diagnosed AIDS is shown in 3.12. The sample was stained with a fluorescein-labelled monoclonal antibody to P. carinii. The organisms are stained apple green by this method. Figure 3.13 is a Giemsa stain of a lung biopsy showing clusters of the trophozoite form of P. carinii. Treatment Mortality rates for PCP vary in the literature from 5–43%. Treatment for 21 days is recommended, with i.v. trimethoprim-sulfamethoxazole (cotrimoxazole). Com-monly used alternatives include i.v. pentamidine isethionate, oral atovaquone, oral dapsone+trimethoprim, and oral clindamycin+primaquine. In moderate to severe disease (PaO2 <70 mmHg [9.3 kPa]) adjunctive steroid therapy is recommended with prednisolone 50–80 mg per day for 5 days and gradually reduced over 21 days. The introduction of antiretrovirals in HIV patients has significantly reduced the incidence of PCP infection in these patients. In other immunosuppressed patients at risk of PCP infection, secondary prophylaxis with oral cotrimoxazole or nebulized pentamidine is frequently used to reduce the incidence of PCP infection.

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3.10 Photomicrograph of a lung showing filling of the alveolar space by fluffy, foamy exudates, typical of infection with P. carinii (arrow).

3.11 Photomicrograph of a lung from a patient with PCP, stained with a silver stain (Grocott); the walls of the pneumocysts within the foamy alveolar exudates stain black (arrow).

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3.12 Fluorescent microscopy of a centrifuged deposit of induced sputum sample obtained from a patient with newly diagnosed AIDS, stained with a fluorescein-labelled monoclonal antibody to P. carinii.

3.13 Giemsa stain of a lung biopsy showing a large nodular mass (clusters of the trophozoite form of P. carinii) within the alveolar space. Pneumonia due to Aspergillus spp. Pneumonia due to Aspergillus spp. presents in up to around 50% of immunosuppressed patients. Mortality rates can be high (>50%) so early treatment is recommended. The clinical signs are not specific for fungal pneumonitis. Patients usually present with cough,

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sometimes with haemoptysis, breathlessness, pleurisy, pyrexia, tachypnoea, and hypoxaemia. Investigations Radiology Chest radiographic changes are not specific for fungal pneumonia and can be normal in the early stages. When changes are apparent, rounded densities, pleural-based infiltrates, and cavitation are common; pleural effusions and adenopathy are rare. Similarly, high resolution CT scans of the chest do not identify changes that are specific for fungal pneumonia. Multiple ill-defined 1–2 cm nodules that coalesce into larger masses or areas of consolidation are seen. The halo sign is an early finding: a rim of ground glass opacity surrounding the nodules. The crescent sign is a later finding, of a central necrotic nodule with a surrounding rim of air. Both the halo and crescent signs are nonspecific for fungal pneumonia. Illustrative cases A PA and lateral chest radiograph of a 35-year-old female with aspergillus pneumonia in the left upper lobe and left lower lobe are shown in 3.14A, B. Note the two large rounded masses; biopsy of these masses confirmed invasive Aspergillus spp. infection. Figure 3.15A shows a chest radiograph from a 21-yearold female with leukaemia. There are widespread nodular changes throughout the X-ray. This was confirmed to be Aspergillus pneumonia. A high resolution CT scan of the chest shows invasive Aspergillus infection, with multiple fungal balls and a surrounding halo of ground glass opacity (3.15B–D).

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3.14A, B Chest radiographs (A: PA; B: lateral), showing masses due to invasive Aspergillus spp. infection (arrows). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

3.15A Chest radiograph from a patient with Aspergillus pneumonia, showing widespread nodular changes (one is arrowed). (Courtesy of Dr. J.Murchison, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

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3.15B, C High resolution CT chest scans (lung window setting) showing invasive Aspergillus infection, with multiple fungal balls (one is highlighted, arrow) and a surrounding halo of ground glass opacity (one is shown, arrowhead). (Courtesy of Dr. J.Murchison, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

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3.15D High resolution CT chest scan (lung window setting) showing invasive Aspergillus infection, with multiple fungal balls and a surrounding halo of ground glass opacity. (Courtesy of Dr. J.Murchison, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

3.16 Photomicrograph of a bronchoalveolar lavage sample, showing hyphae of Aspergillus spp. (arrow).

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A photomicrograph of a bronchoalveolar lavage sample from a patient being investigated for lung cancer is shown in 3.16. A few hyphae are seen, the morphology of which is consistent with Aspergillus spp. This organism is widely present in the environment and may been seen incidentally in respiratory samples examined cytologically; its presence does not necessarily imply an infective process. However, 3.17 presents a photomicrograph of a lung showing the presence of extensive necrotizing pneumonia with destruction of the lung architecture. In this case fungal hyphae were identified within the necrotic tissue and invading adjacent viable tissue, particularly blood vessels. Grocott stain of the specimen demonstrates the fungal hyphae typical of Aspergillus spp. present within the lung tissue (3.18). The hyphae can be seen invading a vessel wall. The vessel has thrombosed and the wall is becoming necrotic.

3.17 Photomicrograph of a lung showing extensive necrotizing pneumonia with destruction of the lung architecture (arrow). Fungal hyphae are present within the necrotic tissue and are invading adjacent viable tissue, particularly blood vessels.

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3.18 Grocott stain of the specimen in 3.17, showing invasive hyphae in a thrombosed vessel wall (arrows). The hyphae stain black with Grocott. Investigations Specific microbiological diagnosis of pneumonia due to Aspergillus fumigatus may be suspected, but not proven, by examination of respiratory secretions (spontaneous or induced sputum or bronchoalveolar lavage); the presence of Aspergillus spp. in these samples may represent colonization or contamin-ation rather than true invasive disease of the lung. To diagnose invasive aspergillus disease, there needs to be evidence of fungi invading the pulmonary tissue. This can be inferred from clinical findings and radiology, but the gold standard is confirmation from a lung biopsy. Figures 3.19, 3.20 demon-strate the typical appearance of Aspergillus fumigatus grown in culture on malt agar. The characteristic ‘fruiting bodies’ of A. fumigatus stained with lactophenol-blue from a sellotape-onglass slide preparation are shown in 3.19. Figure 3.20 shows the characteristic large smoky blue colonies of A. fumigatus after 48 hours, incubation on malt agar in air at 37°C.

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3.19 Lactophenol-blue stain of fruiting bodies of Aspergillus fumigatus (arrow) from a sellotape-on-glass slide preparation from culture on malt agar. (Courtesy of Dr. L.Milne, formerly Consultant Mycologist, Edinburgh, Scotland.)

3.20 Characteristic large smoky blue colonies of A. fumigatus after 48 hours culture on malt agar in air. (Courtesy of Dr. L.Milne, formerly Consultant Mycologist, Edinburgh, Scotland.) Treatment

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The recommended treatment of aspergillus pneumonia is 14–21 days of i.v. amphotericin B. Liposomal amphotericin B has fewer side-effects. Alternatives include voriconazole and caspofungin. In cases of prolonged neutropenia, the addition of growth factors such as G-CSF may be a useful adjunct to antifungal treatment. Infections due to yeasts Colonization by yeasts such as Candida albicans, C. tropicalis, and Torulopsis glabrata is very common in immunocompromised patients, and organisms can reach very high numbers. Mucosal infection (thrush) of the mouth, upper respiratory tract, and oesophagus also occurs commonly. True invasive infection of the lung is uncommon and, when it occurs, is often part of severe systemic candidiasis. Respiratory secretions, including bronchoscopic samples, often contain yeasts, and their presence in these samples is not diagnostic of pneumonitis. Histological examination of open lung biopsies provides conclusive proof, but is often performed too late for successful treatment. Clinical management often falls back on early initiation of antifungal therapy when fungal infection is suspected on clinical grounds with appropriate radiology, but the gold standard is confirmation from a lung biopsy. Recommended treatment is i.v. fluconazole for Candida albicans and i.v. amphotericin for other yeasts for 14–21 days. Sensitivity tests are available from specialist my-cology laboratories. Figure 3.21 shows colonies of C. albicans cultured on malt agar after 48 hours’ incubation in air at 37°C.

Conclusion Severely immunocompromised patients are at risk of infection with a range of unusual and potentially life-threatening infections. An accurate diagnosis requires a multidisciplinary approach with integration of microbiological, pathological, and clinical features. Co-existing infection with more than one organism may occur in these patients.

Further reading Travis WD, Colby TV, Koss MN, Rosado-de-Chritenson ML, Muller NL, King TE (2001). Lung infections. In: Non-neoplastic Disorders of the Lower Respiratory Tract. Armed Forces Institute of Pathology, Washington DC, pp. 539–703. Hopkin J (2000). Respiratory infection in the immunosuppressed. In: Oxford Text of Medicine. JGG Ledingham, DA Warrell (eds). Oxford University Press, Oxford, pp. 380–383. De Pauw BE, Donnelly PJ (2000). Infection in the immunocompromised host: general principles. In: Principles and Practice of Infectious Diseases, 5th edn. GL Mandell, JC Bennett, R Dolin (eds). Churchill Livingstone, Philadelphia, London, Toronto, Montreal, Sydney, Tokyo, Edinburgh, pp. 3079–3090.

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Chapter 4 Tuberculosis Introduction Tuberculosis (TB) is a chronic infective granulomatous disease. The World Health Organization (WHO) estimates that one-third of the world’s population is infected with Mycobacterium tuberculosis and TB accounts for over 3 million deaths throughout the world per year. Multi-drug resistant TB (resistance to at least rifampicin and isoniazid) is an international problem with approximate prevalence rates for new cases of TB of around 1% but for patients with prior treatment for TB they are at around 9%. In certain regions, e.g. in Iran, rates >50% have been reported. In order to reduce the spread of disease, there has been a focus on treating active TB and on rigorous contact tracing. In addition, due to poor treatment completion rates, supervision of therapy has been considered important. However, the evidence base suggests that supervised therapy is not a universal requirement but should be focused on groups at high risk of nonadherence to treatment, such as patients that abuse alcohol. This section on TB, with illustrative radiology, microbiology, and pathology, discusses the investigation, diagnosis, and management of TB. Key areas covered include primary TB, post-primary TB with a particular focus on pulmonary, pleural, and mediastinal lymph node TB, multi-drug resistant TB, and mycobacteria other than M. tuberculosis (MOTT). The final section deals with TB long-term sequelae.

Aetiology Tuberculosis is due to Mycobacterium tuberculosis complex, which includes M. tuberculosis, M. bovis, M. africanum, and M. microti. In humans, M. tuberculosis remains the predominant pathogen. There are many risk factors for the development of TB, including: • Contact with an infectious case of tuberculosis (ado-lescents, young adults, and the elderly are particularly at risk). • Nonwhite ethnic groups, in particular black African and Indian subcontinent. • Recent immigration from a country with a high prevalence of TB within the last 5 years. • Malnutrition. • Alcoholism. • Social deprivation. • Immunosuppression, in particular HIV infection and immunosuppression related to drug treatment (e.g. corticosteroids, immunosuppressants, and TNF alpha-blockers such as infliximab).

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• Diseases with impaired cell-mediated immunity such as lymphoma or leukaemia. • Co-morbid illness such as diabetes, chronic renal failure, gastrectomy. • Solid organ transplantation. • Cancer. • Silicosis. • Old TB on the chest radiograph. Primary tuberculosis Primary TB refers to the first exposure, usually in a child or young adult with no specific immunity. The majority (>90%) of patients are asymptomatic. The chest radiograph shows consolidation usually in the mid or lower zones (Ghon focus), although any lobe can be affected. This is usually associated with ipsilateral hilar lymphadenopathy and is termed the primary complex. Prior to the cellmediated immunity there is haematogenous and lymphatic spread. Cell-mediated immunity occurs within a 3 week to 2 month period. Healing occurs within 6 months, occasionally leaving a small calcified or fibrotic scar and sometimes calcified hilar glands. There is an approximately 10% lifetime risk for the development of active TB (5% within the first 2 years and 5% usually later in life). Illustrative cases Figure 4.1A shows a chest radiograph demonstrating a primary complex with left mid zone consolidation (Ghon focus) and associated left hilar lymphadenopathy. Figure 4.1B shows a chest radiograph taken 6 months following resolution of the primary complex. Note the calcified left mid zone Ghon focus and calcified left hilar glands. Figure 4.2 is a macroscopic picture of a pulmonary resec-tion specimen showing a rounded calcified nodule in the lung parenchyma. No evidence of granulomatous inflamma-tion was identified histologically and the appearance is typical of that seen with a healed primary tuberculous infection with subsequent calcification (Ghon focus). These lesions may be seen incidentally on chest radiographs or be identified in pulmonary resection specimens performed for lung cancer. The term ‘tuberculoma’ is sometimes applied to solitary rounded lesions in the lung which may mimic the appearances of lung cancer. These lesions may be composed of fibrous scars representing old, inactive TB or show features suggesting some residual active infection.

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4.1A Chest radiograph showing a primary complex with left mid zone consolidation and associated left hilar lymphadenopathy, due to primary TB (arrows). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

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4.1 B Chest radiograph from the patient in A, 6 months following resolution of the primary complex. Note the calcified left mid zone Ghon focus and calcified left hilar glands (arrows). (Courtesy of Dr. A Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland.)

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4.2 Macroscopic picture of a pulmonary resection specimen showing a rounded calcified nodule in the lung parenchyma, typical of a healed primary tuberculosis infection (Ghon focus) (arrow). Complications of primary TB Complications of primary TB include the following: • Erythema nodosum. • Phlyctenular keratoconjunctivitis. • Progressive pulmonary disease. • Tuberculoma (a small isolated rounded shadow or a shadow associated with a minimal adjacent infiltration), representing either active or inactive disease. In active disease the histology reveals a mass of granulomas with central caseation and scanty TB organisms may be seen. In inactive disease the lesion is predominantly hyalinized. One of the main concerns is that it is mass-like and often thought to be a primary lung cancer. • Atelectasis from bronchial obstruction because of enlarged lymph nodes. • Pleural or pericardial effusion. • Miliary TB. • Meningitis. • Broncholith. Illustrative cases Figures 4.3–4.6 present chest radiographs and pathology from patients with miliary TB. The chest radiographs (4.3, 4.4) show features of miliary tuberculosis with <5 mm diffuse nodules throughout the lung fields. These are particularly noticeable in the intercostal spaces. Figure 4.5 is a macroscopic picture of a lung specimen from a patient with miliary TB. It shows the presence of numerous small pale nodules on the cut surface, measuring a few millimetres in diameter. Figure 4.6 is a photomicrograph of the specimen shown in 4.5. It demonstrates small nodular areas of inflammation in the lung parenchyma with necrotic centres. The necrotic debris is surrounded predominantly by macrophages. Well developed granulomas and giant cells are usually less obvious in miliary TB. Organisms are, however, more frequently seen with Ziehl-Neelsen stains than in the more typical fibrocaseous tuberculous infection, where much of the pathological process identified is the result of a hypersensitivity reaction. The chest radiograph in 4.7 is from a 9-year-old girl and shows active TB in the lingula, presumed to be due to progression from a primary lesion that has not healed. Note the loss of definition of the left heart border in keeping with disease affecting the lingula.

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4.3 Chest radiograph showing diffuse nodules particularly noticeable in the intercostal spaces due to miliary TB (arrow).

4.4 Chest radiograph showing diffuse nodules particularly noticeable in the intercostal spaces due to miliary TB (arrow).

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4.5 Macroscopic pictures of lung tissue showing diffuse pale nodules, due to miliary TB (arrow).

4.6 Photomicrograph of the specimen in 4.5 demonstrating small nodular inflammatory areas with necrotic centres, due to miliary TB.

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4.7 Chest radiograph showing active TB in the lingula (arrow). Post-primary TB Post-primary TB follows direct progression of a primary lesion, endogenous reactivation of quiescent primary or postprimary lesion, or exogenous reinfection. Pulmonary TB remains the commonest form in both HIV-positive and HIVnegative patients. Extrapulmonary TB is less common but more prevalent in HIV-positive patients. In extrapulmonary TB, the lymph nodes, pleura, and bones/joints are the most common sites to be affected. Illustrative cases A macroscopic picture of a pulmonary resection specimen is shown in 4.8, and demonstrates the typical appearance of fibrocaseous TB. The lung contains a relatively well circum-scribed grey mass, showing some cavitation and indrawing of the overlying pleura due to fibrosis within the lung parenchyma. The photomicrograph (4.9) shows caseous granulomatous inflammation. Amorphous eosinophilic necrotic debris is bounded by an inflammatory cell infiltrate composed predominantly of macrophages with admixed Langhan’s-type giant cells. Granulomatous inflammation in the lung may be seen in a wide range of conditions including sarcoidosis, extrinsic allergic alveoltitis, and vasculitis. Granulomatous inflammation with caseous necrosis, however, is usually indicative of an infective aetiology with mycobacteria or fungi, such as histoplasma.

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The photomicrograph presented in 4.10 is of a lung section from a patient with TB, stained with the Ziehl-Neelsen stain for acid- and alcohol-fast bacilli. In the centre of the picture a single red rod-shaped bacillus can be seen, characteristic of a mycobacterium. Presentation of post-primary TB The majority of patients with post-primary TB present after feeling unwell for several weeks to several months. Patients often present with a new cough (sometimes productive with or without haemoptysis), usually associated with symptoms such as fever, night sweats, weight loss, and general malaise. Patients with pleural TB may, in addition, have pleurisy and breathlessness. Patients with mediastinal lymph node TB may present only with fever, weight loss, night sweats, and general malaise.

4.8 Macroscopic picture of a pulmonary resection specimen with a grey mass showing focal cavitation and fibrosis typical of fibrocaseous TB (arrow).

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4.9 Photomicrograph of lung tissue demonstrating caseous granulomatous inflammation, due to active TB (arrow, caseous necrosis; arrowhead, giant cell).

4.10 Ziehl-Neelsen stain of lung tissue from a patient with active TB, showing a rod-shaped mycobacterium (arrow). Investigations Radiology Active TB The chest radiograph is an essential first line investigation in patients suspected of having respiratory TB (pulmonary, pleural, or mediastinal lymph node sites). Patients with active respiratory TB will have an abnormal chest radiograph. Active pulmonary TB typically presents in the upper lobes, and can be unilateral or bilateral. The posterior and apical segments are the commonest sites to be affected. There can be widespread changes involving all lobes in extensive disease. Active TB is suggested if there is consolidation, nodular infiltration, and cavitation. Although these changes should alert the clinician to suspect TB, these appearances are not specific for TB, and other conditions, e.g. pneumonia and sarcoidosis, can present similarly.

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Illustrative cases Figures 4.11–4.13 show chest radiographs from patients with active pulmonary tuberculosis. Note the infiltration, consolidation, and cavitation that should always alert the clinician to suspect active TB. The patient in 4.11 had unilateral disease in the right upper lobe. The patients in 4.12 and 4.13 had bilateral disease; these patients are usually systemically unwell and are often cachectic. The radiographic changes due to active respiratory TB in HIV-positive patients can vary depending on the severity of the HIV disease. Patients with early HIV disease will have a typical presentation similar to non-HIV patients. In advanced HIV disease, patients often have atypical presentations: the changes on the chest radiograph can present in atypical sites such as the lower zones; patients may present with diffuse consolidation, and cavitation is less frequent, and mediastinal lymphadenopathy is more frequent. Figures 4.14–4.16 present chest radiographs from HIV-positive patients with active pulmonary TB.

4.11 Chest radiograph showing right upper lobe consolidation, infiltration, and cavitation confirmed to be of active TB (arrow).

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4.12, 4.13 Chest radiographs showing bilateral consolidation, infiltration, and cavitation, due to active TB (arrows).

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A chest radiograph of a 45-year-old female with extensive bilateral bronchopneumonia due to TB is shown in 4.14. Note the widespread nodular shadowing with cavitation in the left upper lobe. The patient was subsequently proven to be HIV-positive. Figure 4.15 is a chest radiograph from a 40-year-old male with advanced HIV disease (he was not on antiretroviral therapy). There was minor consolidation without cavitation in the right mid zone. This patient was smear- and culturepositive forM. tuberculosis. The chest radiograph shown in 4.16 is from an HIVpositive patient and shows right lower lobe consolidation without cavitation. This was confirmed to be due to M. tuberculosis from bronchoalveolar lavage samples. Miliary, mediastinal and lymph node TB In patients with miliary, pleural, and mediastinal lymph node TB, radiographic changes may be specific to the type of TB. Chest radiographs from patients with miliary tuberculosis reflect the inadequacy of the host defences in containing the tuberculous infection. The chest radiograph is grossly abnormal with diffuse miliary change, defined as <5 mm nodules that appear widespread (see 4.3, 4.4). In pleural TB, there is usually a unilateral pleural effusion and there may or may not be associated parenchymal lung abnormalities. Commonly, patients with mediastinal lymph node TB present with mediastinal lymphadenopathy alone. Figures 4.17–4.20 present chest radiographs from patients with pleural and mediastinal lymph node TB. Illustrative cases Figure 4.17 shows a chest radiograph from a 40-year-old male with left pleural and left upper lobe pulmonary TB (consolidation and cavitation in the left upper lobe). A chest radiograph from an 80-year-old female with left pleural and left upper lobe pulmonary TB is shown (4.18), with consolidation and cavitation in the left upper lobe. Figure 4.19 shows a chest radiograph from an 85-year-old female with right pleural TB alone, without any associated pulmonary changes. Figure 4.20 is a chest radiograph from a patient with mediastinal lymph node TB. In particular there is right paratracheal lymphadenopathy and a prominent right hilum due to lymphadenopathy. The lung fields are otherwise clear.

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4.14 Chest radiograph showing widespread nodular shadowing with cavitation (arrow), due to active TB in an HIV-positive patient. (Courtesy of Dr. Ramage and Dr. Patel, Department of Radiology, Royal Infirmary, Edinburgh, Scotland.)

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4.15 Chest radiograph showing minor consolidation without cavitation in the right mid zone from a patient with advanced HIV (arrow). Active TB was confirmed from TB cultures from induced sputum.

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4.16 Chest radiograph showing right lower lobe consolidation (arrow) without cavitation from an HIVpositive patient. Active TB was confirmed from TB cultures from bronchoalveolar lavage. (Courtesy of Dr. Venkatesan, Consultant Physician, City Hospital, Nottingham, England.)

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4.17 Chest radiograph showing left pleural (arrow) and left upper lobe pulmonary TB (arrowhead), with consolidation and cavitation in the left upper lobe.

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4.18 Chest radiograph showing left pleural (arrow) and left upper lobe pulmonary TB (arrowhead), with consolidation and cavitation in the left upper lobe.

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4.19 Chest radiograph from a patient with right pleural TB without any associated pulmonary changes (arrow).

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4.20 Chest radiograph showing right paratracheal lymphadenopathy and prominent right hilum from a patient with mediastinal lymph node TB (arrows). Inactive TB TB heals with fibrosis, scarring, calcification, and often upper lobe contraction on the chest radiograph. It is common to find areas of bronchiectasis within the affected lobe. In addition, patients can be left with residual cavities, which predispose to the development of an aspergilloma. There can be residual pleural thickening following successful treatment of a tuberculous pleural effusion. Calcification of the glands can be seen in patients with lymph node TB. Illustrative cases Figures 4.21–4.23 show chest radiographs from patients with old healed TB. The patient in 4.21 was a 36-year-old female who successfully completed 1 year’s anti-TB treatment. At the end of treatment there was scarring and fibrosis in both upper lobes with associated traction bronchiectasis. Note that there is elevation of both the right and left hilum in keeping with contraction of the upper lobes. The chest radiograph in 4.22 shows calcified hilar glands, bilateral calcification, scarring, and contracted right upper lobe. Figure 4.23 shows calcified right hilar glands, scarring in the right upper lobe, left upper lobe collapse, and left pleural calcification. It is not always clear cut whether the chest radiograph represents inactive or active disease, e.g. in patients with suspected reactivation on the background of old healed TB. Changes could represent reactivation but similarly could be due to other bacterial pathogens, bleeding from bronchiectasis, or may represent another aetiology, such as a scar carcinoma.

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4.21 Chest radiograph showing scarring and fibrosis in both upper lobes with associated traction bronchiectasis due to old healed TB. Note that there is elevation of both the right and left hilum in keeping with contraction of the upper lobes.

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4.22 Chest radiograph showing calcified hilar glands, bilateral calcification, scarring, and contracted right upper lobe, due to old healed TB

4.23 Chest radiograph showing calcified right hilar glands (arrow), scarring in the right upper lobe, left upper lobe collapse (arrowhead), and left pleural calcification (short arrow). Laboratory investigations In view of the pitfalls in interpreting changes on the chest radiograph, it is important to pursue further investigations. Central to this is obtaining samples for TB smear and culture/histology. In addition, previous chest and follow-up radiographs, blood tests, and a tuberculin skin test can be helpful. When testing for pulmonary TB, if the patient produces sputum, three early morning sputum samples should be sent for TB smear and culture. In nonsputum producers, samples can be obtained using induced sputum with hypertonic saline (3–5% hypertonic saline until an adequate sample is obtained). Alternatively, samples can be obtained from bronchoalveolar lavage with a fibreoptic bronchoscope. In addition, transbronchial lung biopsies can be sent for both TB culture and histological assessment (examining for evidence of granulomas with central caseating necrosis with/without the identification of M. tuberculosis). If these samples cannot be obtained, early morning gastric aspirates or,

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after discussion with the laboratory, stool samples may be sent for smear and culture for acid-fast bacilli (AFB). These latter investigations are not routinely recommended unless sputum or bronchoalveolar lavage samples cannot be obtained or the patient is a child. In HIV-positive patients it is worthwhile sending blood cultures in special mycobacterial culture bottles supplied by the laboratory. When investigating for pleural TB, the combination of pleural aspirate and pleural biopsy gives a greater yield than pleural aspirate alone. The pleural aspirate should be sent for measurement of pH, protein, and glucose (in tuberculous empyema pH is <7.2, the protein is >30 g/l, and the pleural glucose/blood glucose is <0.5). The pleural fluid should be sent for acid-fast smear and culture, and for differential cell count (in a container with anticoagulants to prevent clotting due to high plasma protein content). A predominant lymphocytosis is seen in a tuberculous pleural effusion. The pleural biopsy should be sent in normal saline for smear and mycobacterial culture and in formaldehyde for histological examination for evidence of granulomas with central caseating necrosis with/without the presence of AFB. M. tuberculosis can be frequently cultured from induced sputum in patients with pleural TB even in the absence of pulmonary changes on the chest radiograph. This offers another method for the investigation of pleural TB but does not replace the gold standard investigation of sending both pleural fluid and pleural biopsy for smear, culture, and histological examination.

4.24 Photomicrograph of a pleural biopsy taken from the patient in 4.18, showing fibrotic and thickened pleura with caseating granulomatous inflammation (arrow). Illustrative cases Figure 4.24 is a photomicrograph of a pleural biopsy taken from the patient with the chest radiograph shown in 4.18. The pleura is fibrotic and thickened and shows the presence of

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caseating granulomatous inflammation. Although no acid- and alcohol-fast bacilli were seen with a Ziehl-Neelsen stain, the appearances are typical of mycobacterial infection and confirmation of the organism and sensitivities can be obtained using microbiological investigations. When investigating patients with suspected mediastinal lymph node TB, it is important to exclude other serious pathology, such as lymphoma. It is recommended that patients have a conventional CT scan of the chest. In the absence of pulmonary disease, patients should be referred for a mediastinoscopy and lymph node samples should be sent for TB smear, culture, and for histological examination for evidence of granulomas with central caseating necrosis with/without the identification of M. tuberculosis. Microbiological investigations A defining characteristic of the genus Mycobacterium is acid-fastness, that is, the ability to remain stained after rinsing with acid or alcohol. Both the auramine-phenol and the classical Ziehl-Neelsen techniques are based on this property. Positive results indicate the presence of a mycobacterial organism (AFB) but the tests are not specific for M. tuberculosis. These results are usually available within 24 hours. Figure 4.25 presents a flow chart for the recommended tests on sputum samples for mycobacteria. Figure 4.26A shows a diagram to illustrate the principle of acid-fast stain, and a positive Ziehl-Neelsen stain of sputum from a patient with cavitating pulmonary TB is presented in 4.26B. The stain shows numerous positive AFB which have retained the red carbol fuchsin stain. The host cells are stained blue with counterstain.

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4.25 Flow chart presenting the recommended tests on sputum samples for mycobacteria. Recommended turn around times are indicated on the right.

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4.26A Diagram to illustrate the principle of acid-fast stain. Carbol fuchsin stains both the cells and mycobacteria red. Following washing with acid/alcohol the red stain remains in the mycobacteria (acid and alcohol fast) but is lost from cells and other bacteria. Methylene blue staining allows visualization of background cells. Figure 4.27 presents an auramine-phenol stain showing positive AFB, stained apple green under fluorescent microscopy. The organisms are easier to detect than when using

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ordinary light microscopic methods, and the method is especially useful for screening large numbers of samples. Liquid culture systems allow more rapid growth of M. tuberculosis. This allows early detection of positive cultures, especially when combined with continuous monitoring of growth by automated detection of radioactive CO2, or by nonradioactivity-dependent detection of changes in the medium. Unless great care is taken, liquid culture systems are more prone to contamination than cultures on solid agar. Some clinically important strains of mycobacteria grow better on egg-based solid media such as Lowenstein-Jensen medium. Figure 4.28 shows the growth of M. tuberculosis colonies on a slope of Lowenstein-Jensen medium, after 3 weeks’ incubation in air at 37°C. The medium contains potato starch, glycerol, and egg yolk to provide the nutrients required for the formation of the lipid-rich mycobacterial cell wall.

4.26B Positive Ziehl-Neelsen stain of a sputum sample from a patient with cavitating pulmonary TB, showing numerous AFB stained red.

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4.27 Auramine-phenol stain to demonstrate AFB, stained apple green under fluorescent microscopy.

4.28 Culture of M. tuberculosis on Lowenstein-Jensen medium in air after 3 weeks. Molecular investigations Nucleic acid amplification tests are available as laboratory diagnostic kits which may be more sensitive and specific compared with conventional acid-fast staining methods. These may allow individual species of mycobacterium to be identified directly and rapidly from the sample. Specific probes are available for the common mycobacterial species, including M. tuberculosis, M. avium, M. kansasii, M. gordonae, and M. malmoense. Although the sensitivity of PCR-based tests may be higher than the conventional smear, it is not sufficiently high to exclude TB when a negative nucleic acid amplification result is obtained. Falsepositive tests may occur, as with most PCR-based tests.

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The rapid determination of species, especially the distinction between M. tuberculosis and other species, is useful for initial clinical management, infection control, and in patients with histology in keeping with mycobacterial infection where the clinical or radiological features are not typical. However, these tests are subject to false-positive and false-negative results, and must be supported by conventional AFB staining and culture methods. Analysis of DNA obtained from cultures of clinical isolates of mycobacteria are used for molecular identi-fication of mycobacterial species other than M. tuberculosis. A common method for this purpose is based on the PCR amplification and analysis of the mycobacterial heat-shock protein gene, hsp 65. In addition, molecular fingerprinting or typing of strains of M. tuberculosis facilitates contact tracing and epidemiological studies. Many methods are available for typing, usually based on the analysis of common repetitive sequences in the M. tuberculosis genome. Sensitivity testing The susceptibility of strains of M. tuberculosis to antibiotics is assessed in the laboratory by observing the growth of diluted suspensions of the organism in culture media containing the antibiotic at predetermined concentrations, and comparing the growth with growth of the same suspension in antibiotic-free media. The use of liquid media and automatic growth monitoring allows results to be available as early as 5 days from the time of the organism being first available in culture. The antimycobacterial agents most commonly used in combination therapy are routinely tested first on all clinical strains of mycobacteria. These ‘first line’ drugs may include isoniazid, rifampicin (rifampin), ethambutol, and pyrazinamide, or other agents depending on local usage preferences. A ‘second line’ battery of drugs are tested if resistance is present to first line drugs or if the patient shows drug intolerance. These may include streptomycin, amikacin, ciprofloxacin, moxifloxacin, ethionamide, capreomycin, clofazamine, thiacetazone, and rifabutin. Mycobacterium species which are similar to M. tuberculosis in terms of growth rate (e.g. M. avium, M. intracellulare, M.kansasii, M. malmoense) are tested for drug susceptibility using similar methods to those used for M. tuberculosis. However, the first line battery of antimyco-bacterial drugs differs, as these organisms are usually resistant to isoniazid, but are often sensitive to clarithromycin or azithromycin. Rapidly growing mycobacteria, such as M. chelonae, M. fortuitum, M. marinum, and M. abscessus, are tested using disc sensitivity methods or modified versions of this test such as the ‘E-test’. Results are available within 3–4 days. These organisms are often sensitive to common antibacterial drugs such as cotrimoxazole and tetracyclines, but may rapidly become resistant. Tuberculin skin testing Intradermal skin testing can aid in the diagnosis of TB. Patients with active disease usually have a strongly positive tuberculin skin test (grade 3 or 4 Heaf test or ≥15 mm from a Mantoux test), although the skin test can be negative in patients with fulminant TB. Conventional methods use intradermal injection of purified protein derivative

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performed using either a Heaf or Mantoux test. The tests are carried out on the flexor surface of the left forearm at the junction of the upper third with the lower two thirds. The Heaf test is carried out using a multi-puncture gun (100,000 U/ml), whereas the Mantoux test is carried out using a 1 ml syringe with a 25G or 26G needle. In the UK, the standard dose is 10 U although 5 U is an alternative dose. If active TB is suspected a dose of 1 U should be used first. The Heaf test is normally read after 3–10 days and the Mantoux test is read after 48– 72 hours. The grading of the Heaf test (0–4) is shown in 4.29: Grade 0: puncture scars without induration; Grade 1: ≥3 small raised indurations; Grade 2: coalescence of indurations to form a ring; Grade 3: central infilling forming a disc; Grade 4: >1 cm with or without vesiculation or ulceration. In the Mantoux test, the transverse diameter of the indurated area is measured. The interpretation of the Heaf and Mantoux tests is shown in Table 4.1. However, environmental mycobacteria, high mycobacterial load, concomitant infections, prior BCG vaccination, immunosuppression (in particular HIV infection), and other disease processes, such as sarcoidosis can influence the skin test. It is also prone to errors both in

Table 4.1 Interpretation of the Heaf and Mantoux tests Heaf grade

Mantoux Interpretation Usual explanation

0 or 1

0–5 mm

2

5–14 mm Positive

Previous BCG vaccination or exposure to environmental mycobacteria

3 or 4

≥15 mm

Prior infection with Mycobacterium tuberculosis, active disease, or strong response to prior BCG vaccination

Negative

Strongly positive

No immunity

the placement and reading of results. Because of these inaccuracies, there remains concern about the specificity of the tuberculin skin test. The discovery of the role of T-lymphocytes and interferon gamma (IFNγ) in the immune response has led to the development of in vitro assays for the cell-mediated immune reaction to M, tuberculosis. Recent studies have investigated the use of IFNγ assay from blood using both the purified protein derivative and more specific antigens such as early secretory antigenic target (ESAT-6). ESAT-6 is restricted to M. tuberculosis complex, M. kansasii, M. marinum, M. flavescens, and M. szulgai. It is therefore absent from all strains of M. bovis (including BCG) and the majority of environmental bacteria. Preliminary studies have found that the more specific antigens, such as ESAT-6, have increased specificity compared with the tuberculin skin test, in that they are less influenced by prior BCG vaccination and environmental bacteria. The IFNγ assay looks promising and further multi-centre studies are awaited. It is not, however, currently available for routine clinical testing and, in the meantime, the conventional tuberculin skin test is the recommended investigation.

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Blood tests Blood tests including a full blood count, erythrocyte sedi-mentation rate, urea and electrolytes, and liver function tests serve as useful baseline results. A variety of abnormali-ties can present in patients with active TB, including anaemia of chronic disease, a raised erythrocyte sedimenta-tion rate, hyponatraemia, hypoalbuminaemia, and deranged liver function tests (even prior to anti-TB treatment).

4.29 Interpretation of the Heaf skin test for TB. (Reproduced with permission of Bignell Surgical Instruments Ltd, Arundel, West Sussex.)

Therapy The following treatments have been used in the past in the management of TB:

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• Thoracoplasty. • Plombage. • Artificial pneumothorax. •Phrenic nerve crush. • Lobectomy or pneumonectomy. Illustrative cases Figures 4.30 and 4.31 show chest radiographs of these techniques. Figure 4.30 is a chest radiograph of a left-sided thoracoplasty (note the removal of several left-sided ribs). The patient survived and there is evidence of old healed TB with bilateral calcification evident. These patients can subsequently develop a severe restrictive defect and may require assistance with domiciliary ventilatory support. Figure 4.31 shows a chest radiograph following left-sided plombage. This technique consisted of denuding the ribs overlying the diseased area, selectively collapsing the parenchymal cavities, the major sources of bacillary proliferation, and maintaining the collapse by filling the subcostal extraperiostal space with a ‘plomb’, mainly lucite spheres. Current treament Current managment rarely requires surgery. The clinician must notify public health so that contact tracing procedures can be organized. The standard treatment for TB is over 6 months, using the regimens in Table 4.2. Treatment is extended to 1 year for meningitis, miliary TB, and is considered for patients with extensive disease. Monitoring compliance is essential, usually by pill checks, urine testing for rifampicin staining, and by monitoring the clinical response. In addition, oral corticosteroids are recommended for patients with extensive TB, meningitis, and pericardial effusions and should be considered in patients with genitourinary TB, pleural effusions, and drug hypersensitivity reactions. The usual doses used are 40–80 mg of prednisolone. Due to enzyme induction with rifampicin therapy, this will have the biological equivalent of 20–40 mg prednisolone. Pyridoxine 10 mg every 24 hours is recom-mended if the patient is nutritionally depleted to prevent isoniazid-induced peripheral neuropathy. Surgery is currently a rare treatment for TB, due to the effectiveness of antimycobacterial therapy. Surgery can be considered as an adjunct to medical therapy in patients with localized disease and good cardiopulmonary status who have failed to respond to antimycobacterial therapy. Failure is defined as failing to respond clinically (after at least 2 months), remaining smear- and culture-positive despite treatment, and with deterioration in the chest radiograph. Illustrative cases Figures 4.32A, B show chest radiographs from a patient who failed to respond to antimycobacterial therapy. Despite receiving 6 months of antimycobacterial therapy, this 48year-old female relapsed approximately 2 months after finishing treatment (smearpositive). The chest radiograph at this stage reveals loss of volume in the left lung and a destroyed left lung with multiple cavities (4.32A). The decision at this stage was that the

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patient would receive a combination of further antimycobacterial therapy and be referred for a left pneumonectomy. She received 2 months’ antimycobacterial therapy with rifampicin, isoniazid.

Table 4.2 Regimens for treatment of tuberculosis Fully sensitive Mycobacterium tuberculosis

Initiation treatment (first 2 months)

Maintenance therapy (4–10 months)

Rifampicin Isoniazid Pyrazinamide Ethambutol Pyridoxine

Rifampicin Isoniazid Pyridoxine

4.30 Chest radiograph of a left-sided thoracoplasty (note the removal of several leftsided ribs) (arrow), with evidence of old healed TB with bilateral calcification.

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4.31 Chest radiograph following leftsided plombage (arrow).

4.32A Chest radiograph showing loss of volume in the left lung and a destroyed left lung with multiple

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cavities (arrow), from a patient who failed to respond to 6 months’ antimycobacterial therapy.

4.32B Chest radiograph showing clear lung fields after the patient in A had received further antimycobacterial therapy and a left pneumonectomy (arrow).

4.33 Urine samples showing typical orange staining due to rifampicin therapy (1: no medication; 2: butanol

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added to sample 1; 3: rifampicin medication; 4: butanol added to sample 3). ethambutol, and pyrazinamide and then underwent a successful left pneumonectomy. Post-surgery she received 10 months’ further antimycobacterial therapy. Two years later she remains well and the chest radiograph reveals a left pneumonectomy but otherwise the lung fields are clear (4.32B). Rifampicin normally stains the urine an orange colour. Figure 4.33 shows urine samples from a patient not receiving rifampicin (samples 1, 2) and from a patient receiving rifampicin (samples 3, 4). Note the normal urine colour in a patient not on antimycobacterial therapy (sample 1), the stained urine due to rifampicin (sample 3), and the absence and presence, respectively in samples 2 and 4 of an orange line in the top layer when butanol is added. Multi-drug resistant TB Multi-drug resistant TB is defined as resistance to at least rifampicin and isoniazid, but is usually resistant to multiple drugs. The incidence is variable worldwide, with current estimations at <1% in the UK, to 48% in Asia. The recom-mended treatment is with at least three susceptible drugs (preferably five) and to continue treatment for 18 months after conversion to a negative TB culture. Cure rates with this approach have been reported to be up to 77%. Surgery can be a useful adjunct in patients with localized disease, those with failure of conversion from sputum smear positivity, and in patients with no significant comorbidities who are intolerant of therapy. Studies to date have continued anti-TB treatment for 12–18 months post-surgery. A variety of drugs are available for use in multi-drug resis-tant TB. Some of the commonly used medications include: • Streptomycin. • Amikacin. • Capreomycin. • Kanamycin. • Ethionamide or prothionamide. • Cycloserine. • Moxifloxacin. • Rifabutin. • Thiacetazone. • Clofazimine. • PAS sodium. Other mycobacteria Mycobacteria other than M. tuberculosis (MOTT, also known as ‘atypical’ mycobacteria) are occasionally asso-ciated with pulmonary infections. Chronic fibrocaseating disease

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closely resembling TB may be caused by ‘atypical’ mycobacterial infection in patients who have relatively normal immune function. Mycobacterial species often associated with these infections are M. avium, M. intracellulare, M. kansasii, M. xenopi, and M. malmoense. The last mentioned species is more common in the more northern latitudes, especially in Europe. A wide variety of other species of ‘atypical’ mycobacteria, in addition to the species mentioned above, can cause pulmonary infections in immunocompromised patients. The more common species include: M. chelonae, M. gordonae, M. szulgai, M. simiae, M. fortuitum, and M. abscessus. M. abscessus and M. fortuitum are particularly associated with cystic fibrosis. Presentation Patients present with nonspecific symptoms which can be indistinguishable from those caused by M. tuberculosis, including weight loss, cough with or without sputum production and with or without haemoptysis, night sweats, and general malaise. The chest radiograph presentation is similar to M. tuberculosis. Treatment outcomes are not as good as with M. tuberculosis: overall at 5 years, 17–42% can be cured (17% with M. xenopi and 42% with M. malmoense) with 2 years’ treatment with rifampicin and ethambutol with or without the addition of isoniazid. Illustrative cases Figures 4.34–4.36 present examples of ‘atypical’ mycobacteria. A chest radiograph from a patient with left upper lobe disease due to M. malmoense is shown (4.34). Note the consolidation and cavitation in the left upper lobe. This is indistinguishable from disease due to M. tuberculosis. Figure 4.35 is a photomicrograph of lung tissue obtained from a case of pulmonary infection with M. avium intracellulare. The histological appearance is identical to that seem with M. tuberculosis, with foci of caseating granulomatous inflammation (see 4.9). Ziehl-Neelsen stains may, however, be negative in cases of atypical mycobacterial infection and the organisms may be more effectively stained using a Wade Fite stain. Figure 4.36 is a culture on Lowenstein-Jensen medium showing growth of M. kansasii. Strains of this species are often pigmented. This species is occasionally associated with pulmonary infection that is clinically and radiologically very similar to TB. Strains of M. malmoense and M. avium intracellulare complex can also cause similar clinical disease. Diagnosis Though there is variation between the different species of mycobacteria in their appearance in acid-fast stained microscopy, these differences are not characteristic enough to enable reliable distinction between species. Specific nucleic acid probes are available to identify rapidly M. tuberculosis complex and some of the clinically important atypical mycobacterium species, including M. avium, M. kansasii, M. malmoense, and M. chelonae. These tests can be performed

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directly on AFB film-positive samples, and provide clinically and epidemiologically valuable, information at an early stage. Optimal conditions for culture for some atypical M. chelonae produce visible colonies within a few days. Full species identification of atypical mycobacteria using conventional methods is time consuming, and these are now being replaced by molecular methods. Treatment The recommendation for infection with atypical myco-bacteria is 18–24 months’ treatment with rifampicin and ethambutol and either ciprofloxacin or clarithromycin. At present it is not known whether vaccination with heat-killed M. vaccae confers any additional benefit. Studies are currently being carried out comparing the cure rates of this recommended antibiotic regimen with the traditional regimens using rifampicin and ethambutol with or without isoniazid. Surgery can be reserved as an adjunct in patients with localized disease and in patients with no significant comorbidities and good cardiopulmonary status who have failed to respond or are intolerant to medical therapy.

4.34 Chest radiograph showing left upper lobe disease due to M. malmoense (arrow).

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4.35 Photomicrograph of lung tissue showing foci of caseating granulomatous inflammation (arrow), due to infection with M. avium intracellulare.

4.36 Culture on Lowenstein-Jensen medium showing growth of orange pigmented colonies of M. kansasii. Long-term sequelae TB is a serious disease and has long-term sequelae including: • Broncholith: calcified material eroding into a bronchus. • Aspergilloma. • Bronchiectasis with the propensity for recurrent chest infections. • Tuberculosis reactivation. • Tuberculoma.

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Broncholith A macroscopic picture is shown in 4.37, showing a broncholith. Broncholiths represent foci of old calcified TB either within the lung parenchyma or within hilar nodes and can be the result of either primary or secondary infections. The calcified nodule of tissue may erode through the wall of a bronchus resulting in airway obstruction or be coughed up as a foreign body. Figure 4.37 shows a broncholith eroding through the proximal lobar bronchial wall from an adjacent peri-bronchial hilar lymph node. Aspergilloma An aspergilloma is a fungal ball in a pre-existing cavity, usually with Aspergillus fumigatus. Patients are usually asymptomatic but can present with life-threatening haemoptysis. The natural history is variable: some regress, some remain static, and some progress. Aspergillus precipitins tests are usually positive and Aspergillus can be cultured from sputum samples. No treatment is required unless life-threatening haemop-tysis occurs. Haemoptysis should be treated conservatively with antibiotics in the first instance. If the haemoptysis does not settle then surgical removal of the cavity is recom-mended if the patient is medically fit. Alternative therapies include intracavitory instillation of amphotericin or bronchial artery embolization. Illustrative cases Figures 4.38–4.45 present radiography, macroscopic pictures, and photomicrographs from patients with Aspergillus infection. Figure 4.38 is a chest radiograph showing a right apical aspergilloma. Note the cavity filled with a fungal ball (mobile opacity with a surrounding halo of air demonstrated in a cavity). There is associated pleural thickening. A left apical aspergilloma is shown in 4.39, with evidence of old healed TB with the bilateral calcification. Figure 4.40A and B show chest radiographs of a left apical aspergilloma before (A) and after (B) the fungal ball was expectorated. Figures 4.41 and 4.42 are macroscopic pictures of pul-monary resection specimens demonstrating the presence of an old tuberculous cavities which have become colonized by Aspergillus. The fungus grows as an irregular and friable mass within the cavity which has a relatively thick fibrous wall.

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4.37 Macroscopic picture of a pulmonary resection specimen, showing a broncholith (arrow) eroding through the proximal lobar bronchial wall from an adjacent peri-bronchial hilar lymph node.

4.38 Chest radiograph showing a right apical aspergilloma presenting as a mobile opacity with a surrounding halo

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of air in a cavity and associated pleural thickening (arrow).

4.39 Chest radiograph showing a left apical aspergilloma (arrow) with evidence of old healed TB as bilateral calcification.

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4.40A, B Chest radiographs of a left apical aspergilloma before (A) and after (B) the fungal ball was expectorated (arrows). (Courtesy of

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Dr. J.Simpson, Senior Lecturer, Royal Infirmary, Edinburgh, Scotland.)

4.41, 4.42 Macroscopic pictures of pulmonary resection specimens demonstrating the presence of an old tuberculous cavities which have become colonized by Aspergillus (arrows).

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A photomicrograph of an aspergilloma is shown in 4.43 demonstrating the thick fibrous wall of the cavity and the presence of inflammatory debris admixed with Aspergillus hyphae in the lumen. The inner surface of the cavity may be lined by squamous epithelium but is often ulcerated and lined by highly vascular inflamed granulation tissue which may account for episodes of haemoptysis, although larger haemorrhages are believed to result from erosion by the inflammatory process involving the branches of the bronchial arterial system. Figure 4.44 shows hyphae of A. fumigatus in a bronchoalveolar lavage sample from a patient with aspergilloma. Figure 4.45 presents a gel precipitation test demonstrating the presence of serum antibodies (precipitins) to A. fumigatus. A positive precipitin test supports a diagnosis of aspergilloma. Bronchiectasis A CT chest scan from a patient with post-tuberculous left upper lobe bronchiectasis is shown in 4.46. TB heals with scarring and fibrosis and, not infrequently, is associated with traction bronchiectasis; note the dilated bronchus in comparison to the adjacent vessel. Such patients can present with recurrent chest infections (see Chapter 6).

4.43 Photomicrograph of an aspergilloma demonstrating the thick fibrous wall of the cavity (arrow) and the presence of inflammatory debris admixed with Aspergillus hyphae in the lumen (arrowhead).

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4.44 Fluorescence microscopy of a bronchoalveolar lavage sample, showing hyphae of Aspergillus fumigatus (one is arrowed). (Courtesy of Dr. L.Milne, formerly Consultant Mycologist, Edinburgh, Scotland.) Conclusions • Internationally TB remains the most important lung infection. • Although effective treatment is available, the battle against TB is not being won. • Accurate microbiological assessments with drug sensitivities are essential. • The key for control of TB is the early diagnosis and effective management of cases.

Further reading Blumberg HM, Burman WJ, Chaisson RE, et al. (2003). American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. American Journal of Respiratory Critical Care Medicine 167(4):603–662. Joint Tuberculosis Committee of the British Thoracic Society (1998). Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 53(7):536–548. Friedman LN (ed) (2001). Tuberculosis: Current Concepts and Treatment, 2nd edn. CRC Press, London.

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4.45 Gel precipitation of serum antibodies to Aspergillus fumigatus. 1: Aspergillus antigen in central well; 2: test serum samples; 3: positive tests; 4: negative tests. (Courtesy of Dr. L.Milne, formerly Consultant Mycologist, Edinburgh, Scotland.)

4.46 CT chest of a post-tuberculous left upper bronchiectasis (arrow) (lung window setting).

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Chapter 5 Chronic Obstructive Pulmonary Disease Introduction Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation as a result of small airway disease and parenchymal destruction (emphysema), most commonly related to cigarette smoking. The condition is a major cause of morbidity and mortality; in the UK COPD is the fifth leading cause of death and results in 240,000 hospital admissions annually, at a cost of £486 million (US$778 million). Exacerbations of COPD precipitating admission may be the result of lung infection but the airways of these patients are often chronically colonized with common bacterial pathogens and the significance of the organisms to worsening of respiratory symptoms may be difficult to define. The clinical, radiological, and microbiological aspects of COPD exacer-bations are reviewed in this chapter.

Aetiology Exacerbation of COPD is defined as a deterioration in symptoms from when the patient is clinically stable. Usually patients present with increased breathlessness, wheeze, and chest tightness. In addition, some patients have increased sputum volume and sputum purulence. Both infection (viral and/or bacterial) and air pollution can precipitate an exacerbation. Secondary causes of an exacerbation include pneumonia, pulmonary embolism, pneumothorax, rib fractures, inappropriate medication such as β-blockers or excess sedatives, cardiac arrhythmias, cardiac failure, or other diseases such as gastrointestinal bleeding. The bronchial tree in patients with COPD is often chronically colonized with potential pathogens. These include Streptococcus pneumoniae and Haemophilus influenzae (capsulate and noncapsulate strains). Exacerbations are associated with a marked increase in pathogen numbers, detected by quantitative sputum culture. Moraxella catarrhalis is associated with acute purulent exacerbations. Other organisms which may colonize the airways and contribute to exacerbation include antibiotic-resistant Gram-negative bacilli such as Pseudomonas aeruginosa. Illustrative cases Figure 5.1 presents a chest radiograph from a 68-year-old man with severe COPD (FEV1: 0.8 l, 27% predicted) with hyperinflated lung fields, flattened widely spaced ribs, and flattening of the hemidiaphragms. In this case the patient had a noninfective exacerbation of COPD.

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Figures 5.2, 5.3 are high resolution CT chest scans (lung window setting) from patients with severe COPD (both FEV1<30% predicted). The scan in 5.2 shows focal areas of low attenuation without discernable walls. This is most noticeable in the upper lobes and is consistent with centrilobular emphysema. 5.3 is a scan from a 54-year-old male with α1-antitrypsin deficiency, revealing confluence of low attenuation areas without discernable walls and sparse lung vascular markings. This is most noticeable in the lower lobes and is consistent with pan-acinar emphysema. A macroscopic picture of an inflated lung slice is shown (5.4) demonstrating the presence of centri-acinar emphy-sema. The enlarged airspaces are seen as ‘holes’ within the lung parenchyma. As only the central part of the acinar unit around the respiratory bronchioles is affected in centriacinar emphysema, uninvolved normal lung parenchyma is seen around the emphysematous spaces. This is the classical pattern of emphysema seen in smokers and typically affects the upper lobes.

5.1 Chest radiograph showing hyperinflated lung fields, flattened widely spaced ribs, and flattening of the hemidiaphragms due to a noninfective exacerbation of COPD.

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5.2 High resolution CT chest scan showing focal areas of low attenuation without discernable walls, most noticeable in the upper lobes, and consistent with centrilobular emphysema (one example is arrowed).

5.3 High resolution chest CT scan showing a confluence of low attenuation areas without discernable walls and sparse lung vascular markings, most noticeable in the lower

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lobes, and consistent with panacinar emphysema (one area is arrowed).

5.4 Macroscopic picture of an inflated lung slice showing the presence of centri-acinar emphysema (one example is arrowed). Figure 5.5 is a macroscopic picture of an inflated lung slice demonstrating the presence of pan-acinar emphysema. In pan-acinar emphysema the alveolar walls of the entire acinar unit are lost resulting in larger ‘holes’ in the lung without any surviving surrounding lung parenchyma. Panacinar emphysema may be seen in α1-antitrypsin deficiency; it is more variable in its distribution and is often more pro-nounced in the lower lobes than centrilobular emphysema.

Investigations The following investigations should be performed with moderate and severe exacerbations: • Full history and examination. • Arterial blood gases. • EGG to identify if right heart strain, arrhythmias, or ischaemia are present. • Chest radiography is useful in identifying an alternative diagnosis. • Sputum sample for Gram stain, culture, and sensitivity testing. • Blood cultures if pneumonia is suspected.

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• Full blood count, urea and electrolytes, and inflammatory markers such as erythrocyte sedimentation rate and Creactive protein can be helpful. It is not routine to screen for respiratory viruses or atypical infections. Illustrative cases A Gram stain of a sputum sample from a patient with acute exacerbation of COPD is shown in 5.6, showing Gramnegative diplococci, which on culture were found to be Moraxella catarrhalis. Figure 5.7 is a drawing of the appearance of a Gram-stained sample of sputum from a patient with exacerbation of COPD, showing polymorphonuclear cells and two organisms commonly seen in this con-dition (Haemophilus influenzae and Streptococcus pneumoniae).

Therapy Patients will either be treated in the community, hospital general ward, hospital specialist respiratory ward, high dependency unit, or an intensive care unit. Bronchodilator therapy should be optimized; nebulized bronchodilators are recommended for more severe exacerbations. A combina-tion of β2 agonist and anticholinergics are often used (every 4– 6 hours). Antibiotic therapy should be given if the patient has at least two of the following: increased breathlessness, increased sputum volume, or increased sputum purulence. A recommended choice is amoxicillin 500 mg every 8 hours or clarithromycin 500 mg every 12 hours for 5–7 days, but this will depend on local bacteriological sensitivity data. The newer quinolone antibiotics, however, may improve bacterial clearance and time to next exacerbation. Future studies are needed. Oral corticosteroids are reserved for more severe exacerbations, e.g. prednisolone 30– 40 mg for 7–10 days. Oxygen therapy should be given if the PaO2 is <7.3 kPa air, at a dose of 1–2 l by nasal prongs or 24% or 28% by Venturi mask. Diuretics are recommended if there is evidence of right heart failure, and prophylactic heparin administered for prevention of venous thrombosis. In patients that, despite the above medical therapy, have type 2 respiratory failure, noninvasive ventilation, doxapram 1–4 mg/min or intermittent positive pressure ventilation should be considered. Doxapram is normally reserved for patients who do not wish or cannot tolerate noninvasive ventilation and do not require intermittent positive pressure ventilation.

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5.5 Macroscopic picture of an inflated lung slice showing the presence of pan-acinar emphysema (one area is arrowed).

5.6 Gram stain of a sputum sample from a patient with acute exacerbation of COPD, showing Gram-negative diplococci, which on culture were found to be Moraxella catarrhalis.

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5.7 Drawing of a Gram-stain sample of sputum from a patient with exacerbation of COPD, showing polymorphonuclear cells and two organisms commonly seen in this condition, namely Haemophilus influenzae (Gramnegative rods, arrow) and Streptococcus pneumoniae (Grampositive diplococcus, arrowhead). (From the teaching archives of the Department of Clinical Microbiology, University of Edinburgh.) Noninvasive ventilation Noninvasive ventilation (NIV) should be considered in patients that, despite medical therapy, have acidosis, with pH <7.35, PaCO2 >6 kPa, and PaO2 <7.3 kPa. The patient must be cooperative, haemodynamically stable, and able to protect their own airway. No excessive secretions must be present. Contraindications to noninvasive ventilation include: • Respiratory arrest. • Cardiovascular instability (hypotension, arrhythmias, or myocardial infarction). • Impaired consciousness. • Uncooperative patient. • Pneumothorax. • Severe bullous lung disease. • Copious secretions. • Epistaxis.

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• Burns. • Recent facial or gastro-oesophageal surgery. Intermittent positive pressure ventilation Intermittent positive pressure ventilation should be considered for patients with the following indications: • Failure to respond to medical treatment ± doxapram or NIV (pH <7.26, PaCO2 >8 kPa, and PaO2 <7.3 kPa). • Impaired consciousness. • Tiring with medical therapy±doxapram or NIV. • Reasonable pre-morbid state. • Reversible factors. • Expected to survive intermittent positive pressure ventilation. • No other major co-morbid illness. • Single system failure. Treatment at home is feasible in mild exacerbations. Patients with a more severe exacerbation thought to require hospital admission may be able to have an assisted discharge and be treated at home following assessment in hospital if: • The patient can cope at home. • Respiratory rate <30/min. • No cyanosis or peripheral oedema. • No confusion or altered consciousness. • No significant co-morbid illnesses. • Good social circumstances. • Arterial blood gases on air reveal a PaO2 >7.3 kPa and pH >7.35. • No changes on the chest radiograph. • The hospital has respiratory nurse specialists that can support assisted discharge and follow-up of patients in the community. Patients with assisted discharge are usually provided with oral corticosteroids, antibiotics if required, and a nebulizer on loan for bronchodilator therapy.

Conclusions • COPD is a common condition with a high morbidity and mortality. • Airways of patients with COPD are commonly colonized with a range of bacterial pathogens. • Antibiotic therapy is indicated in the clinical setting of worsening symptoms associated with increased sputum volume and purulence.

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Further reading Calverley P, MacNee W, Pride N, Rennard S (eds) (2003). Chronic Obstructive Pulmonary Disease, 2nd edn. Arnold, London. Global Initiative for Chronic Obstructive Lung Disease. Executive Summary. NIH 1998 and 2003.

Chapter 6 Bronchiectasis Introduction Bronchiectasis is a chronic condition with irreversible dilatation and destruction of bronchi commonly diagnosed by high resolution CT scan of the chest. Before the establishment of this technique the diagnosis was made by bronchogram. This section on bronchiectasis, with illustrative radiology, microbiology, and pathology, discusses the investigation, diagnosis, and management of bronchiectasis. In addition, the investigation, diagnosis, and manage-ment of allergic bronchopulmonary aspergillosis and cystic fibrosis are covered in this section.

Aetiology The initial bronchial damage which leads to bronchiectasis is often caused by childhood infections such as whooping cough or measles. Severe lung infections in adults, such as Staphylococcus aureus pneumonia, aspiration pneumonia, or TB may also result in bronchiectasis. Other conditions associated with bronchiectasis include: • Infective, e.g. post whooping cough, pneumonia, or TB. • Inflammatory, e.g. Wegener’s granulomatosis. • Rheumatoid arthritis. • Inflammatory bowel disease. • Immunodeficiency, e.g. common variable immuno-deficiency and HIV infection. • Mucociliary defects such as cystic fibrosis, Kartagener’s syndrome, primary ciliary dyskinesia, and Young’s syndrome. • Allergic bronchopulmonary aspergillosis. • α1-antitrypsin deficiency. • Bronchial obstruction and bronchopulmonary seques-tration. • Congenital cartilage deficiency and tracheobronchomegaly. • Yellow nail syndrome. • Unilateral hyperlucent lung. Patients with established bronchiectasis are commonly chronically colonized with upper respiratory tract organisms. Pathogens which cause recurrent purulent infections include Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus. Streptococcus pneumoniae, coliforms

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such as Klebsiella pneumoniae, anaerobic cocci and Pseudomonas aeruginosa. In cystic bronchiectasis, mucoid strains of Pseudomonas aeruginosa may establish persistent colonization. The distribution of the bronchiectasis may give an idea of aetiology. Upper lobe bronchiectasis can be seen typically post-TB and in patients with cystic fibrosis, while proximal bronchiectasis is seen with allergic bronchopulmonary aspergillosis. Localized bronchiectasis can be seen distal to a foreign body.

Presentation Patients usually present with recurrent chest infections, but the presentation is variable depending on the severity of the bronchiectasis. Between exacerbations, patients with mild bronchiectasis (tubular bronchiectasis) may have no sputum production or small volumes (<5 ml) of mucoid or light mucopurulent phlegm (6.1). With more advanced bron-chiectasis (varicose and cystic bronchiectasis, cystic bronchiectasis being the most severe), between exacer-bations patients usually expectorate mucopurulent or frankly purulent sputum on a daily basis even when apparently clinically stable (6.2). In patients with advanced cystic bronchiectasis, the sputum volume can be >50 ml/24 h. Patients with more advanced bronchiectasis usually suffer the greatest frequency of chest infections.

6.1 Sputum sample from a patient with mild tubular bronchiectasis predominantly expectorating mucoid sputum (clear/grey) when clinically stable.

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6.2 Sputum sample from a patient with advanced cystic bronchiectasis expectorating purulent sputum (dark yellow or green) even when clinically stable.

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6.3 Bronchogram used historically to diagnose bronchiectasis. There is bronchial dilatation in the left lower lobe in keeping with left lower lobe bronchiectasis (one area is arrowed). Investigations Radiology Before the establishment of CT scanning the gold standard for diagnosing bronchiectasis was a bronchogram. Illustrative cases The bronchogram revealed bronchial dilatation in the left lower lobe in keeping with bronchiectasis (6.3). Figures 6.4, 6.5 are CT chest scans (lung window setting) showing tubular bronchiectasis. In 6.4, the bronchus is larger than the adjacent vessel in both lower lobes, the ‘signet ring’ sign. In

6.4 Chest CT scan from a patient with tubular bronchiectasis, in which the bronchus is larger than the adjacent vessel in both lower lobes, the ‘signet ring’ sign (one example is arrowed).

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6.5 Chest CT scan from a patient with tubular bronchiectasis, in which the bronchus has a thick wall and is larger than the adjacent vessel, in particular affecting the right middle lobe (one example is arrowed). 6.5 the scan reveals tubular bronchiectasis in which the bronchus has a thick wall and is larger than the adjacent vessel, in particular affecting the right middle lobe. The degree of bronchiectasis is variable from mild bronchiectasis (tubular bronchiectasis), in which the bronchus is dilated and thickened compared to the adjacent vessel, to patients having varicose bronchiectasis, in which the bronchus is irregular and nontapering, to patients with advanced cystic bronchiectasis. Often the chest radiograph is normal in patients with tubular bronchiectasis and the condition is only diagnosed from a high resolution CT chest scan. A chest radiograph of a patient with cystic bronchiectasis is shown (6.6). Note in this case the large thin-walled cysts that often contain mucus. Common

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6.6 A chest radiograph from a patient with cystic bronchiectasis, showing large thinwalled cysts that often contain mucus.

6.7 Chest CT scan from a patient with cystic bronchiectasis, showing cystic lesions (one example is arrowed) that are often fluid filled. findings on a chest radiograph with advanced bronchiectasis include tramline shadows, cystic lesions that can be fluid filled, and volume loss with fibrotic scarring. Cystic

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lesions are demonstrated in 6.7 in a CT scan from a patient with cystic bronchiectasis. Macroscopic picture of lung tissue with cystic bronchiectasis is shown in 6.8. The lung contains numerous thin-walled cysts which represent damaged and cystically dilated airways. Figure 6.9 is a photomicrograph from a lung showing bronchiectasis. These is evidence of inflammation in the airway wall associated with fibrous scarring. This pattern of bronchiectasis arises secondary to inflammation and scarring in the lung parenchyma and is typical of that which may be seen as a complication of tuberculous infection.

6.8 Macroscopic picture of lung tissue with cystic bronchiectasis (one example is arrowed).

6.9 Photomicrograph from a lung with bronchiectasis showing dilatation of

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the airway with inflammation in the wall associated with fibrous scarring (arrow). Gram stain of sputum samples from two patients with cystic bronchiectasis infected with Pseudomonas aeruginosa, one mucoid (right panel) and the other nonmucoid (left panel) are shown in 6.10. The organisms of the mucoid strain are found as microcolonies within the extracellular alginate that they secrete. Similar strains are found in patients with cystic fibrosis. Patients with cystic bronchi-ectasis may acquire persistent infections with mucoid strains of Pseudomonas aeruginosa. These strains produce copious amounts of extracellular alginate in vivo. The alginate blocks access to antibiotics and host immune responses, and also hinders mechanical removal of bronchial secretions. Figures 6.11 and 6.12 show culture and an electron micrograph of mucoid Pseudomonas aeruginosa, respectively.

6.10 Gram stain of sputum samples from two patients with cystic bronchiectasis infected with mucoid (right panel) and nonmucoid (left panel) Pseudomonas aeruginosa. (Courtesy of Prof. J.Govan, University of Edinburgh, Scotland.)

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6.11 Culture of mucoid (right panel) and non-mucoid (left panel) Pseudomonas aeruginosa. (Courtesy of Prof. J.Govan, University of Edinburgh, Scotland.)

6.12 Electron micrograph of a mucoid strain of Pseudomonas aeruginosa, showing extracellular alginate (arrows). (Courtesy of Prof. J.Govan, University of Edinburgh, Scotland.) Therapy The conventional treatment is prompt antibiotics for infective exacerbations. The antibiotics used should be guided on the isolate and sensitivity testing. A 10–14 day antibiotic course is recommended for exacerbations. Longterm antibiotics are reserved

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for patients with recurrent exacerbations (usually >6 per year) or in patients chronically colonized with Pseudomonas aeruginosa. In such patients, treatment with nebulized antibiotics is recommended (usually gentamicin, tobramycin, or colomycin). Influenza vaccination is recommended annually and consideration should be given for pneumococcal vac-cination. Chest physiotherapy should be performed twice daily, particularly in patients with cystic bronchiectasis. Treatment with inhaled corticosteroids may reduce the inflammation in bronchiectasis, and treatment with bronchodilators may be helpful if there is airflow obstruction.

Allergic bronchopulmonary aspergillosis Allergic bronchopulmonary aspergillosis is a disorder occurring in patients with asthma and cystic fibrosis. It is thought to be a type 1 and 3 hypersensitivity reaction and commonly Aspergillus fumigatus is implicated, although other Aspergillus species and fungi have been implicated. This causes fleeting infiltrates on the chest radiograph and, pathologically, is characterized by eosinophilic infiltration in the lung with features of eosinophilic pneumonia. In addition, mucus plugging is characteristic. The plug is infiltrated with Aspergillus hyphae but fungi do not invade the bronchial wall or surrounding lung. The bronchi also contain numerous eosinophils, Charcot Leyden crystals, fibrin, and Curschmann’s spirals. The chest radiograph can show segmental, lobar, or pulmonary collapse. This can eventually lead to proximal and central bronchiectasis. Diagnosis Conventional diagnosis of allergic bronchopulmonary aspergillosis is based on the following: • Patients with pre-existing asthma or cystic fibrosis. • Fleeting infiltrates on the chest radiograph or proximal bronchiectasis. • Eosinophilia on the peripheral full blood count. • Raised serum IgE. • Raised IgE to Aspergillus. • Positive skin prick tests to Aspergillus. • Aspergillus precipitin tests may be positive. • Sputum culture may grow Aspergillus spp.

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6.13 Chest radiograph from a patient with chronic asthma who presented with left lower lobe collapse and right middle lobe atelectasis, with thick inspissated secretions on bronchoscopy, associated with Aspergillus fumigatus (arrows). (Courtesy of Dr. K.Skwarski, Associate Specialist, Royal Infirmary, Edinburgh, Scotland.)

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6.14A Chest radiograph from a patient with chronic asthma, allergic bronchopulmonary aspergillosis, and proximal bronchiectasis. Illustrative cases A chest radiograph is shown from a 43-year-old female with chronic asthma who presented with left lower lobe collapse and atelectasis in the right middle lobe (6.13). At bronchoscopy there were thick inspissated secretions in the left lower lobe and middle lobe. The left lower lobe reexpanded following bronchoscopy. Aspergillus fumigatus was isolated from the plugs removed at bronchoscopy. Figure 6.14A is a chest radiograph from a 43-year-old patient with chronic asthma, allergic bronchopulmonary aspergillosis and proximal bronchiectasis. The chest CT scan (6.14B) confirms proximal bronchiectasis only. A photomicrograph is shown of aspergillus hyphae found in sputum submitted for cytology from a patient with bronchiectasis (6.15). The presence of Aspergillus in a sputum sample in this situation is not in itself diagnostic of allergic bronchopulmonary aspergillosis, and its presence must be correlated with other clinical features.

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6.14B Chest CT scan confirms proximal bronchiectasis (one example is arrowed).

6.15 Photomicrograph is shown of Aspergillus hyphae (arrow) found in sputum submitted for cytology from a patient with bronchiectasis. Therapy Oral steroids are often required and dosing should be tailored with chest radiography, monitoring of the symptoms, and monitoring, in particular, of the peripheral eosinophil count, total IgE, and IgE level to Aspergillus.

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There is some evidence that the addition of antifungal agents such as itraconazole may be additive and potentially can help in the reduction of oral steroids. There is no requirement for i.v. treatment with amphotericin. In patients with lobar or pulmonary collapse, bronchoscopy with suction of the plug can re-expand the lung. Patients are then subsequently treated with oral steroids.

Cystic fibrosis Cystic fibrosis is a common condition in Caucasian populations of European origin, affecting 1 in 2,500 live births in the UK. The genetic defect is a homozygous mutation of the CFTR gene on the long arm of chromo-some 7 (the commonest being ∆ f508). The main problems in cystic fibrosis relate to the development of pancreatic insufficiency and bronchiectasis.

Investigations

Tests Patients are diagnosed using the sweat test, which reveals an elevated sweat sodium and chloride (>70 mmol/l; normal <50mmol/l), and by genetic testing using PCR from either capillary blood spots, buccal mouth wash, or venous blood samples. Illustrative cases Figure 6.16 is a chest radiograph from an 18-year-old male with cystic fibrosis and bilateral bronchiectasis with an upper lobe predominance. A chest CT scan shows typical advanced bilateral upper lobe bronchiectasis (6.17A, B). In advanced disease the bronchiectasis becomes widespread. Note the thick-walled cysts that are often fluid filled, loss of volume, and varicose nontapering bronchi.

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6.16 Chest radiograph from a patient with cystic fibrosis and bilateral bronchiectasis.

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6.17A, B Chest CT scans showing typical advanced, bilateral, upper lobe bronchiectasis (two areas are arrowed), with thick-walled, fluidfilled cysts and nontapering bronchi. Microbiology and pathology Initial infections are caused by Staphylococcus aureus and Haemophilus influenzae. As repeated infections with these initial organisms are treated, infection with resistant organisms, particularly Pseudomonas aeruginosa, becomes more frequent, initially with nonmucoid strains but later with alginate-producing mucoid strains, which are resistant to antibiotic treatment and mechanical removal. Finally, infection with Burkholderia cepacia supervenes in many patients (6.18). Colonization with B. cepacia is associated with a poor prognosis. Necrotizing pneumonia and sepsis may occur, and treatment is made difficult by the innate resistance of this organism to many antibiotics. Some strains

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of B. cepacia are highly transmissible, and cause outbreaks among patients with cystic fibrosis. Less commonly, infections may occur with Mycobacteria such as M. avium, M. malmoense, M. intracellulare, M. chelonae, M. abscessus and, rarely, M. tuberculosis. Fungal infections, including infections with Aspergillus species, have been reported but are very rare. A macroscopic photograph of an explanted lung from a patient with cystic fibrosis is shown in 6.19. Even at low power, crowding and thickening of the bronchi can be seen consistent with the presence of bronchiectasis, with scarring of the airway walls and the surrounding lung parenchyma due to recurrent infection. Therapy Treatment depends on the severity of the exacerbation and the pathogens normally identified with the sensitivity patterns. To minimize hospitalization, intravenous therapy can be delivered at home but severe exacerbations with haemoptysis or respiratory failure should be managed in hospital. For infections due to Pseudomonas aeruginosa, two intravenous agents are normally used for 14 days and the choice is based on sensitivity patterns, e.g. i.v. ceftazidime and tobramycin. Chest physiotherapy is an important adjunct and should be used twice daily. In addition, careful attention is given to the maintenance of hydration and adequate nutrition. Care is taken to try to keep diabetes well controlled if there is pancreatic insufficiency. Oxygen and NIV can be considered in patients with respiratory failure. In the management of infections with MOTT in patients with cystic fibrosis, full identification of the mycobacterial species and susceptibility testing against an extended range of appropriate antimicrobial agents are essential. Repeated isolation of potentially pathogenic species such as M. avium, M. intracellulare, M. kansasii, and M. malmoense should be treated with three or more agents shown to be effective in laboratory tests. Prolonged treatment, with periodic monitoring by culture and susceptibility testing, is essential. Treatment should continue for 6 months after cultures have become negative. Colonization with the rapidly growing mycobacterial species such as M. chelonae, M. fortuitum, and M. abscessus often does not seem to cause disease progression. Colonization with the rapidly growing mycobacterial species may preclude lung transplantation, since they may cause invasive disease in the posttransplantation period. These organisms show variable antibiotic resistance patterns, and often develop further resistance if treatment is attempted.

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6.18 Culture of Burkholderia cepacia. (Courtesy of Prof. J.Govan, University of Edinburgh, Scotland.)

6.19 Macroscopic picture of an explanted lung from a patient with cystic fibrosis, showing bronchiectasis, with scarring of the airway walls and the surrounding lung parenchyma due to recurrent infection (one area is arrowed). Conclusions • Bronchiectasis is a chronic progressive condition presenting with recurrent chest infections. • The diagnosis is currently established by high resolution CT scan of the chest. • A multidisciplinary approach is recommended for the management of bronchiectasis.

Further reading Angrill J, Agusti C, Torres A (2001). Bronchiectasis. Current Opinions in Infectious Disease 14(2):193–197. Stockley RA (2000). Bronchiectasis. In: Oxford Text of Medicine. JGG Ledingham, DA Warrell (eds). Oxford University Press, Oxford, pp. 402–410.

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Chapter 7 Miscellaneous Respiratory Infections Introduction The diseases described in the previous chapters of this atlas are all prevalent throughout the world, although their incidence may vary somewhat between different regions. However, some infections which affect the respiratory system have a much more restricted geographical prevalence. While physicians practising in an area where such a disease is endemic may quickly recognize its manifestations, the diagnosis may be easily missed when the patient presents in a country where the disease is rarely encountered. There are many of these ‘exotic’ and rare diseases, but some are of sufficient importance to warrant their inclusion in this atlas. These include hydatid disease, histoplasmosis, coccidiomycosis, and tropical pulmonary eosinophilia. Also included are two diseases, actinomycosis and nocardiosis, which, although rare, are indigenous to most countries. This chapter starts with the investigation, diagnosis, and management of aspiration pneumonia which is not rare and is seen in both hospital and community practice.

Aspiration pnemonia There are many causes of aspiration pneumonia, but some of the common risk factors include: • General anaesthesia. • Cerebrovascular disease. • Impaired consciousness, e.g. epilepsy. • Neurological disease, e.g. Parkinson’s. • Oesophageal pathology, e.g. benign or malignant stricture or oesophageal web. • Self poisoning, e.g. opiate overdose. Aetiology Aspiration pneumonia is caused by organisms that are normal commensals of the oropharynx, or by gastro-intestinal or environmental organisms that have replaced the normal flora of the oropharynx because of antibiotic therapy, intubation, or concurrent debilitating illness. In patients who have not been recently in acute hospital care, organisms that are responsible may include anaerobic cocci, anaerobic Gram-negative bacilli, such as Bacteroides spp. and fusiforms, oral streptococci such as those of the Streptococcus milleri group, coliform organisms such as Klebsiella or Enterobacter spp., and Staphylococcus aureus.

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In hospitalized patients, more resistant organisms may be involved, including antibiotic-resistant coliforms, Pseudomonas aeruginosa, Acinetobacter spp., methicillinresistant Staphylococcus aureus (MRSA) and yeasts such as Candida albicans. Often, more than one organism may be involved. Investigations The following investigations are standard: • Chest radiograph. • Sputum Gram stain, culture (including anaerobic), and sensitivity testing if samples are available. • Blood cultures. • If the patient is ventilated, tracheal aspirates or, if indicated, bronchoalveolar lavage. • Blood tests including full blood count, inflammatory markers such as erythrocyte sedimentation rate and C reac-tive protein, urea and electrolytes, and liver function tests.

7.1A, B A: Chest radiograph showing extensive bilateral pneumonia, from a patient with a pharyngeal pouch containing an air fluid level (arrow). B:

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Barium swallow from the patient in A, confirming the presence of a pharyngeal pouch (arrow).

7.2 Macroscopic picture of a lung showing an area of consolidation with abscess formation secondary to aspiration pneumonia (arrow). Illustrative cases A chest radiograph is presented in 7.1A, showing extensive bilateral pneumonia due to a pharyngeal pouch. Note the air/fluid level in the neck. The barium swallow (7.1B) confirms there is a pharyngeal pouch. Figure 7.2 is a macroscopic picture of a lung showing an area of consolidation with abscess formation secondary to aspiration pneumonia. The abscess is cavitated and has a thickened fibrous wall. Macroscopically the appearance is similar to that which may be seen with any other cause of chronic abscess formation. Histologically, aspiration pneumonia may show a wide range of appearances depending on the nature of the aspirated material. Foreign material, such as vegetable matter and lipid, may be seen if food material is aspirated. If gastric acid is aspirated then the pattern may be nonspecific and resemble acute interstitial pneumonitis with fibrin leak into airspaces. The photomicrograph from a case of aspiration pneumonia (7.3) shows a prominent foreign body giant cell reaction to lipid. The lipid has been lost from the section and is represented by the cleft-like spaces in the giant cells. Therapy Treatment for aspiration pneumonia is often empirical. Oxygen is given if the PaO2 on air is <7.3 kPa. Fluids are recommended to maintain hydration. In patients with nonresistant

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organisms, a recommended first-line antibiotic treatment is co-amoxiclav or a combination treatment with cephalosporins, such as cefuroxime, cefotaxime, or ceftriaxone and metronidazole. In patients in whom there is concern of more resistant organisms, a more intensive regimen is given. Ideally, this should be based on culture and sensitivity results. If none are available a regimen including vancomycin and meropenem is often used.

7.3 Photomicrograph of a lung section, showing a prominent foreign body giant cell reaction to lipid, due to aspiration pneumonia. Histoplasmosis Histoplasmosis is a chronic airborne fungal infection which often presents with clinical and radiological features closely resembling TB. Aetiology Histoplasmosis is caused by the inhalation of the spores of a fungus which has yeast-like morphology when it infects mammals. This form of the fungus is known as Histoplasma capsulatum. The mycelial form of the fungus, which produces the infective spores, is widely distributed as point sources associated with bat and avian excrement in many tropical and temperate areas, particularly in south-central USA. Spores become airborne readily, and are of such a size as to reach the small bronchioles and alveoli easily when inhaled. They are ingested by macrophages, and a wide spectrum of reaction may ensue. In most cases, there is an asymptomatic and successful immune response, but in a few patients proliferation of the ingested spores and foci of macrophage infiltration, leading to caseation and necrosis, may occur in the lungs, mediastinum, and other parts of the reticuloendothelial system (disseminated histoplasmosis). The clinical outcome depends

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on the amount of spores inhaled and the immune status of the patient. The yeast may lie dormant for long periods in the lung, and reactivates to produce lesions resembling TB (chronic pulmonary histoplasmosis). These foci of reactivation are often related to centrilobular or bullous airspaces in emphysema. Illustrative cases and investigations The chest radiograph shown in 7.4 is from a patient with emphysema who presented with fibrocavitatory disease (particularly in the upper lobes) due to histoplasmosis. There can be different chest radiograph findings in histoplasmosis. There may be a single small or large lung focus with or without associated hilar lymphadenopathy, it can present with a diffuse miliary pattern usually with associated hilar lymphadenopathy, and it can present with fibrocavitatory disease similar to TB. Calcification can subsequently be seen following healing. Tissue samples from lesions of disseminated histo-plasmosis and sputum (or bronchoalveolar lavage) in chronic pulmonary histoplasmosis may be cultured on mycological culture media. Culture is often negative, since organisms may be scanty. Growth is slow (2–4 weeks). Microscopy of Giemsa-stained preparations of bronchoalveolar lavage, or preparations of tissue biopsies stained with periodic acid Schiff (PAS) or methenamine silver may provide rapid diagnosis, but require expertise. Histologically the appearance of histoplasmosis in the lung is very similar to that of fibrocaseous TB. Differentiation of the two conditions histologically relies on the use of PAS and ZiehlNeelsen stains, although in some cases no organisms may been seen and further microbiological investigation will be required. Figure 7.5 is a photomicrograph of a lung section from a case of histoplasmosis, stained with PAS which stains the capsules of the spores red. High antibody titres (complement fixation) may support the diagnosis, especially in nonendemic areas. Titration of blood or urine antigen levels using radioimmunoassay may be of value in monitoring therapy in AIDS patients. Skin testing is of value in epidemiological studies, but is not so useful in clinical diagnosis. Therapy Most cases of acute histoplasmosis resolve without specific therapy. All cases of disseminated histoplasmosis or chronic pulmonary histoplasmosis need specific antifungal therapy. Treatment is started with amphotericin B, and may be continued with oral itraconazole for 6–12 months. Treatment is continued for life in patients with AIDS.

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7.4 Chest radiograph from a patient with emphysema who presented with fibrocavitatory disease (particularly in the upper lobes) due to histoplasmosis.

7.5 Photomicrograph of a section of lung from a patient with histoplasmosis, stained with PAS

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which stains the capsules of the spores red (arrow).

7.6A Chest radiograph showing a prominent right hilum and distal consolidation (arrow) due to coccidiomycosis.

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7.6B Lateral chest radiograph showing an area of homogenous increased density within the apical segment of the right lower lobe (arrow) due to coccidiomycosis. Coccidiomycosis Coccidiomycosis is a chronic lung infection caused by inhalation of fungal spores. Most infections are mild or asymptomatic, the area of focal pneumonitis healing spontaneously to leave a coin-like scar (coccidioma) or a single, small, thin-walled cavity. In a few cases, symptomatic consolidation occurs with fever, malaise, cough, and chest pain, and may progress to chronic fibronodular disease of the lung or hilar lymph nodes. Dissemination beyond the lung or hilar nodes occurs rarely. Disseminated disease is more likely in immunocompromised patients, and carries a poor prognosis. The CNS, musculoskeletal system, and skin are particularly involved. Aetiology Coccidiomycosis is caused by inhalation of the wind-borne spores (spherules) of a soil fungus, Coccidioides imitis, found in the desert regions of south-western USA, Mexico, and central and South America. Person-to-person transmission does not occur.

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Illustrative cases and investigations A 68-year-old man presented with a lower respiratory tract illness following his return from Arizona. The chest radiograph (7.6A) shows a prominent right hilum with distal consolidation. The lateral film (7.6B) reveals an area of homogenous increased density within the apical segment of the right lower lobe. In the CT scan (lung window setting; 7.6C) a dense mass is seen in the right lower lobe, suspicious of a bronchial neoplasm. A percutaneous CT-guided biopsy confirmed necrotizing granulomatous inflammation with associated fungal spores consistent with Coccidiomycosis. Coccidiomycosis mainly presents as focal or multifocal airspace disease predominantly in the lower lobes. There may be associated mediastinal lymphadenopathy. Other presentations include fibrocavitatory disease similar to TB and histoplasmosis, widespread miliary pattern, or progres-sive airspace disease. Sputum, pus, or bronchoalveolar lavage or biopsy material are examined for characteristic endosporing spherules by microscopy, using wet microscopy, methenamine silver stain, and eosin-methylene blue stain. Hyphal forms may be seen in cavitating lesions. Figure 7.7 is a photomicrograph of a lung section from a patient who had lived in Arizona who presented with cavitating lung lesions. The section is silver stained (Grocott) and shows rounded spores and also small nonbranching hyphae, the appearances of which would be consistent with Coccidiomycosis. Cultures grow easily (optimally at 30°C) on blood agar, mycology media, or other ordinary nonselective agars into mycelial forms which are highly infectious. In disseminated disease, blood cultures or urine cultures may be positive. Therapy Symptomatic primary pulmonary disease detected early is treated with amphotericin B or itraconazole for 4–6 weeks. Disseminated infection requires prolonged or lifelong treatment, initially with amphotericin B and then with itraconazole or fluconazole.

7.6C Chest CT scan (lung window setting) revealing a dense mass in the

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right lower lobe (arrow). The patient was later diagnosed with Coccidiomycosis.

7.7 Photomicrograph of a lung section, showing rounded spores (arrow) and also small nonbranching hyphae (arrowhead) on silver staining (Grocott), the appearances of which would be consistent with coccidiomycosis. Hydatid cysts Hydatid disease is due to localized tissue cysts containing the larval form of the dog tapeworm. Aetiology Hydatid disease in humans is due to the accidental ingestion of the eggs of the dog tapeworm, Echinococcus granulosus. The eggs develop into larval stages which penetrate the mesenteric blood vessels and are carried to various tissues including the lung, where they form enlarging cysts within which further larval forms (scolices) are generated. Although hydatid cysts are often multiple and commonly affect the liver, solitary cysts may occur in the lung. Many cysts are asymptomatic, but enlarging cysts may cause pressure effects. In nature, the larval stage takes place in sheep or cattle, and the life cycle of the worm is completed by farm dogs ingesting beef or lamb. The disease is seen in

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most sheep- and cattle-raising areas of the world. It is particularly common in Greece and Lebanon. Investigations Diagnostic suspicion of hydatid cysts is raised by radiological features, peripheral blood eosinophilia, and a history of association with cattle or sheep farming. Diagnosis is confirmed by a positive serological test for antibodies to hydatid antigen, but in many cases of stable, nonenlarging hydatid cyst in the lung, there is no release of antigen and hence no detectable antibody in the blood. Diagnostic aspiration of cyst fluid is usually not attempted, since leakages of fluid into tissues may lead to dissemination of infective larvae or anaphylactic reactions. Hydatid cysts can be single or multiple. The cysts are usually spherical or oval in shape, of soft tissue density and can be up to 20 cm in size. The lesions commonly occur in the lower lobes and more commonly affect the right lung. These simple cysts can become complicated cysts, usually when the cyst develops a communication with the bronchial tree. In the early stages there is a thin periphery of air surrounding the cyst, referred to as the crescent sign. This can progress to the cyst rupturing, with the contents of the cyst emptying into the airways producing an air/fluid level. Sometimes the collapsed cyst wall is seen floating within the fluid level, known as the water lily sign. If the parasite survives, daughter cysts can develop. Occasionally the cysts can cause pneumothorax, empyema, or a lung abscess. Illustrative cases The chest radiograph in 7.8A reveals a solitary right-sided hydatid cyst with a right pleural effusion. 7.8B is a chest radiograph from a patient with multiple bilateral pulmonary hydatid cysts; the water lily sign is demonstrated in the right-sided hydatid cyst.

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7.8A Chest radiograph showing a right-sided hydatid cyst (arrow) with a right pleural effusion.

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7.8B Chest radiograph showing multiple bilateral pulmonary hydatid cysts and the water lily sign in the right-sided cyst (arrow). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland, UK.) An abdominal radiograph is presented in 7.9, showing a hepatic hydatid cyst with calcification of the wall. This is a feature often seen in hepatic cysts but is very rarely seen with pulmonary cysts. Figure 7.10 shows a photomicrograph of a thick-walled cyst composed of dense collagen, with identifiable Echinococcus organisms within the cyst. The high power photomicrograph (7.11) shows the appearance of a single scolex of Echinococcus species. The surface hooks of the organism can be identified centrally. Therapy Enlarging or symptomatic cysts are best treated by surgical resection. Antihelminthic drugs, such as albendazole or praziquantel, are useful as adjuncts to surgery, or as medical management in inoperable cases. Microscopic examination of the resected cyst is essential to confirm the diagnosis.

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7.9 Abdominal radiograph showing a hepatic hydatid cyst with calcification of the wall (arrow). (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary, Edinburgh, Scotland, UK.)

7.10 Photomicrograph of a thickwalled cyst composed of dense collagen, with identifiable Echinococcus organisms within the cyst (one example is arrowed).

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7.11 High power photomicrograph of a single scolex of Echinococcus species, showing the surface hooks of the organism centrally (arrow). Actinomycosis Actinomycosis is a chronic locally invasive infection often originating in the cervicofacial region. Aetiology Actinomycosis is caused by filamentous, branching, slowgrowing. Gram-positive anaerobic bacteria. By far the commonest species causing human infections is Actinomyces israelii. Other organisms, such as anaerobes and streptococci of the milleri group, are often found in association with this organism and may contribute to the pathogenesis. The organism is commonly found in the human mouth and pharynx, particularly when oral hygiene is poor. Most infections are derived from this endogenous source, and person-to-person transmission is rare. Infection usually presents as a slowly expanding, suppurating lump in the cervicofacial region (lumpy jaw). If untreated this often leads to sinus formation with drainage of pus containing particulate accretions (sulphur granules) which are composed of compacted bacterial filaments and debris from the host inflammatory response. Infection of intrathoracic structures is uncommon, and may result from aspiration, lymphatic extension from the oropharynx, or passage across a damaged oesophageal wall. It may involve the lung, pleura, chest wall, mediastinum, or pericardium. Figure 7.12 is a photograph of a patient with a chest wall abscess due to actinomycosis. The infection involved the lung, pleura, and chest wall, demonstrating the tendency of actinomycotic lesions to spread easily across natural tissue planes. Blood-borne metastatic spread to other organs, particularly the liver or CNS may occur, but is rare. Illustrative cases and investigations The diagnosis of actinomycosis infection of the lung may be very difficult and radiologically the appearance may mimic malignancy or TB, precipitating resection of the affected lobe or lung. The patient in 7.13A, B presented with both a left lung abscess and a left empyema. This was subsequently confirmed as actinomycosis from analysis of the pleural fluid. Actinomycosis is typically characterized by fibrosis, the formation of abscesses, and sinus tracts. This patient responded to medical treatment with antibiotic therapy for 3 months and drainage of the empyema with an intercostal chest drain.

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7.12 Photograph of a patient with a large abscess (arrow) on the lateral chest wall below the axilla (arrowhead) due to actinomycosis.

7.13A Chest radiograph (PA) showing a left lung abscess and a left empyema, due to actinomycosis. (Courtesy of Dr C.Selby, Consultant Physician, Queen Margaret Hospital, Fife, Scotland.)

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7.13B Chest radiograph (lateral) showing a left lung abscess and a left empyema, due to actinomycosis. (Courtesy of Dr C.Selby, Consultant Physician, Queen Margaret Hospital, Fife, Scotland.) Pus, aspirates, or tissue biopsies are required for definitive diagnosis. A macroscopic picture of a slice of lung from a case of pulmonary actinomycosis is shown in 7.14A. A yellow area of consolidation is seen in the lung, with shrinkage and distortion of the lung due to associated fibrosis. Histological assessment of these cases shows widespread inflammation in the lung with destruction of the lung architecture and associated fibrosis. Colonies of the organism are identified within small micro-abscesses admixed with this. Multiple tissue sections may need to be examined before any organsims are found. Gram stain microscopy shows characteristic filamentous, branching Gram-positive bacilli in samples of pus or tissues (particularly crushed sulphur granules). Acid-fast stains are negative. Specific stains using flourescein-labelled anti-bodies may distinguish Actinomyces israelii from other commensal bacteria with similar morphology. A photomicrograph from the patient in 7.14A is shown in 7.14B, demonstrating a colony of Actinomyces growing within a micro-abscess. Figure 7.15 presents a photomicrograph of a colony of Actinomyces within a micro-abscess, showing the typical appearance of a socalled ‘sulphur granule’. Actinomyces israelii grows on blood agar incubated anaerobically with additional CO2. Growth may take several days to appear. Sputum or bronchial lavage samples are usually not useful for diagnosing localized pulmonary lesions of actinomycosis because

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of low sensitivity and the possibility of false-positive findings due to contamination with oropharyngeal commensal actinomycetes. Therapy Surgical excision or drainage is required as necessary for pleural, chest wall, or mediastinal lesions. Intra-pulmonary lesions are often correctly diagnosed only after resection for suspected malignancy. Antibiotic treatment is essential, and should continue for 3–4 weeks after clinical resolution. Amoxicillin 500 mg every 6 hours, given orally, is adequate for most cases. Alternatives include cephalosporins, tetracyclines, erythromycin, or clindamycin. In vitro, the organism may be sensitive to rifampicin, isoniazid, and streptomycin.

7.14A Macroscopic picture of a slice of lung from a case of pulmonary actinomycosis, with a yellow area of consolidation (arrow), shrinkage and distortion of the lung due to associated fibrosis.

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7.14B Photomicrograph from the patient in A, demonstrating a colony of Actinomyces growing within a microabscess (arrow).

7.15 Photomicrograph of a colony of Actinomyces within a microabscess, showing the typical appearance of a so-called ‘sulphur granule’ (arrow). Nocardiosis Nocardiosis is a rare, often systemic infection which mainly affects patients with preexisting debilitating illness.

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Aetiology Nocardia are filamentous, Gram-positive, weakly acid-fast aerobic bacilli, the commonest species causing human disease being Nocardia asteroides. The organism is a soil saprophyte of widespread geographical distribution. The filamentous forms break up into smaller coccobacillary units which become airborne when the soil is disturbed. There is no person-toperson transmission of infection. Cases are usually sporadic, but clusters of infection may occur, and this should raise suspicion of an environmental point source, such as building work. The common primary site of infection is the lung, from where blood-borne dissemination may occur, particularly to the CNS, liver, kidneys, or skin. Dissemination is more likely in patients with deficient cell-mediated immunity, particularly HIV infection, organ transplantation, or long-term corticosteroid treatment. Lung lesions range from relatively acute focal lesions which may heal spontaneously, to chronic lesions resembl-ing TB or malignancy. There is often pronounced loss of weight, cachexia, fever, and peripheral blood leucocytosis. Spontaneous remissions and relapses are not uncommon. Investigations The clinical picture and radiology often resemble lung abscess, TB, or malignancy. Gram stain and microscopy of pus, tissue, sputum, or bronchoalveolar lavage reveals filamentous, branching, Gram-positive bacilli which may break up into coccobacillary forms. Nocardia asteroides is [usually acid-fast when stained by the auramine-phenol technique or by the modified Ziehl-Neelsen technique using weak (1%) acid. Figure 7.16 presents a Gram stain of pus from a lung abscess, showing filamentous, branching, Grampositive bacilli of Nocardia asteroides. Nocardia are weakly acid-fast, and grow well in aerobic cultures. Actinomyces species have a similar Gram-stain morphology in direct Gram stained preparations, but are not acid-fast and grow well only in anaerobic cultures. Nocardia grow aerobically on most nonselective culture media, and on media used for mycobacterial culture. Growth may take several days to appear. Blood cultures may be positive in disseminated infection, particularly in the severely immunocompromised, such as patients with AIDS, or with organ transplantation. Since it is not uncommon in the environment, Nocardia species may contaminate samples, especially sputum samples, and a positive culture should be interpreted with caution. Serological tests (gel precipitation, enzyme-linked assays) are not highly specific for N. asteroides, and so are of little value in primary diagnosis. They may be of value in monitoring effectiveness of therapy in immunocompromised patients with disseminated disease. Therapy High-dose cotrimoxazole or sulphonamides are recom-mended, and should be continued for several months to reduce the possibility of relapses. Other antibiotics such as amoxicillin, tetracyclines, amikacin, ciprofloxacin, or imipenem may be effective, but adequate controlled studies have not been performed.

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Tropical pulmonary eosinophilia Tropical pulmonary eosinophilia refers to a syndrome of marked (>1.0×109/l) peripheral blood eosinophilia, accom-panied by pulmonary infiltrations and airways obstruction. Fever and haemoptysis may occasionally be present. Aetiology The syndrome is endemic to the Indian subcontinent and some countries in South-east Asia, Africa, and South America. The cause is believed to be an allergic response to parasitic worm (helminth) infections. A wide variety of helminth species are implicated, including hookworms (Ascaris spp., Strongyloides spp., Ancylostoma spp., and Necator spp.) and filarial worms (Brugia spp. and Wuchereria spp.). In some cases the primary hosts for these helminths are domestic and wild mammals, and when they infect man the larval stages are arrested in tissues such as the skin and the lung (larva migrans). Illustrative cases and investigations Wet microscopy of the stool may reveal ova or larvae (7.17, 7.18). Figure 7.17 is a wet preparation of stool sample from a 12-year-old male with tropical pulmonary eosinophilia, showing an ovum of a hookworm (Necator sp.). The stool sample preparation in 7.18 is from a 48-year-old male who presented with fever, eosinophilia, cutaneous larva migrans, bronchospasm, and bilateral basal infiltrates on chest radiography. The larvae are probably Strongyloides stercoralis.

7.16 Gram stain of a sample of pus from an abscess, showing filamentous, branching Gram-positive bacilli of Nocardia asteroides.

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7.17 Wet preparation of stool sample from a patient with tropical pulmonary eosinophilia, showing an ovum of a hookworm (Necator sp.) (arrow).

7.18 Wet preparation of stool sample from a patient, showing probable Strongyloides stercoralis (arrow).

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7.19 Photograph of the skin of the patient in 7.18, showing cutaneous larva migrans over the upper thigh (arrow). Figure 7.19 is a photograph of the skin of the patient in 7.18, showing cutaneous larva migrans over the upper thigh. Antibodies to filarial larvae may be detected in serum samples. Treatment with diethyl carbamazine for 1 week usually results in resolution of symptoms.

Pulmonary eosinophilia There are many causes of pulmonary eosinophilia, including: • Allergic bronchopulmonary aspergillosis. • Bronchocentric granulomatosis. • Eosinophilic pneumonia. • Vasculitides such as Churg-Strauss syndrome and polyarteritis nodosa. • Hypereosinophilic syndrome. • Drug and chemical reactions. • Parasitic infections.

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Illustrative cases A chest radiograph from a 60-year-old female with pulmonary eosinophilia secondary to sulphasalazine is presented (7.20). In pulmonary eosinophilia there is normally nonsegmental radiographic shadowing in a peripheral distribution, usually most prominent in the upper lobes and termed ‘reversed bat’s wing’. Figure 7.21 is a chest radiograph from a 58-year-old female with confirmed eosinophilic pneumonia. Note the diffuse interstitial shadowing. Following treatment with oral corticosteroids, the chest radiograph returned to normal. Eosinophilic pneumonia due to filariasis is shown in 7.22. There was increased interstitial shadowing, particularly in the lower zones, and there was an associated right-sided pleural effusion.

7.20 Chest radiograph showing nonsegmental shadowing in a peripheral distribution, mainly in the upper lobes (reversed bat’s wing) (arrow) in keeping with pulmonary eosinophilia. (Courtesy of Dr. A.Wightman, Consultant Radiologist, Royal Infirmary Edinburgh, Scotland.)

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7.21 Chest radiograph from a patient with confirmed eosinophilic pneumonia, showing diffuse interstitial shadowing.

7.22 Chest radiograph from a patient with eosinophilic pneumonia due to filariasis, showing interstitial

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shadowing and a rightsided pleural effusion. Conclusion • Easy international travel and mass migration make it ncreasingly likely that patients with ‘exotic’ diseases may present to physicians who rarely encounter these diseases. • Although the diseases may be exotic, their manifestations are often easily mistaken for those of common lung diseases. • Good history taking and informed use of laboratory investigations are key to accurate diagnosis.

Further reading Deepe JS (2000). Histoplasma capsulatum. In: Principles and Practice of Infectious Diseases, 5th edn. GL Mandell, JC Bennett, R Dolin (eds). Churchill Livingstone, Philadelphia. Chapter 254, pp. 2718–2733. Lane DJ (1996). Pulmonary eosinophilia. In: Concise Oxford Textbook of Medicine. JGG Leadingham, DA Warrell, DJ Weatherill (eds). Oxford University Press, Oxford, pp. 435–436. Russo TA (2000). Agents of actinomycosis. In: Principles and Practice of Infectious Diseases, 5th edn. GL Mandell, JC Bennett, R Dolin (eds). Churchill Livingstone, Philadelphia. Chapter 245, pp. 2645–2654. Travis WD, Colby TV, Koss MN, Rosado-de-Chritenson ML, Muller NL, King TE (2001). Lung infections. In: Non-Neoplastic Disorders of the Lower Respiratory Tract. Armed Forces Institute of Pathology, Washington. Chapter 12, pp. 539–703.

Index Note: page numbers in bold type refer to illustrations; those in italic type to tables and boxes abdominal aortic aneurysm repair 42, 43 abscess chest wall 128 lung, see lung abscess acid-fast bacilli (AFB) staining 79–80, 81 acidosis 25, 102 Acinetobacter spp. 44, 117 Actinomyces israelii 128, 130 actinomycosis 128–31 adult respiratory distress syndrome 42, 43 adverse reactions, drug 134, 135 AIDS patient 50, 120 air bronchogram 12, 13 albendazole 126 albumin, serum 11, 83 alginate, extracellular 108, 109 allergic bronchopulmonary aspergillosis 109–12 α1-antitrypsin deficiency 97, 100 alveolar spaces, P. carinii 55 alveolar structure, loss 48, 49, 59, 99, 100 American Thoracic Society 10, 25, 26 amikacin 87, 132 aminoglycosides 26, 40 aminosalicylate sodium 87 amoxicillin 13, 25, 100, 130, 132 amphotericin B 61, 120, 123 ampicillin 26 anaemia of chronic disease 83 normocytic 11 Ancyclostoma spp. 132 anthelminthic drugs 126 antibiotic resistance 40, 44, 63, 87 antibiotic therapy actinomycosis 130 antibiotic therapy (continued) aspiration pneumonia 119 bronchiectasis 109 community-acquired pneumonia 25, 26 COPD exacerbation 100 cystic fibrosis 114

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hospital-acquired pneumonia 42, 44 intravenous 25, 42, 44 nebulized 109 nocardiosis 132 tuberculosis 84, 87 anticholinergic drugs 100 antidiuretic hormone, syndrome of inappropriate secretion 11 antifungal therapy aspergillosis 61, 112 coccidiomycosis 123 histoplasmosis 120 antimycobacterial therapy 82, 84 atypical mycobacteria 82, 88 failure of 84–7 antipseudomonal drugs 26 antiretroviral agents 54 Ascaris spp. 132 aspergilloma, post-tuberculous 76, 92–4 aspergillosis, allergic bronchopulmonary 109–12 Aspergillus spp. 58, 59, 94, 114 Aspergillus fumigatus 109, 111 culture and identification 60 infection post-tuberculosis 92–4 serum antibody test 94, 95 Aspergillus pneumonia investigations 56–61 presentation 56 specific diagnosis 60 treatment 61 aspiration pneumonia 40, 41, 117–19 asthma 109, 110, 111 atelectasis 110, 111 atovaquone 54 auramine-phenol technique 79–80, 81, 132 azithromycin 26, 82 Bacillus Calmette-Guérin (BCG) vaccination 82, 83 Bacteroides spp. 25, 117 barium swallow 118 BCG vaccination, see Bacillus Calmette-Guérin (BCG) vaccination benzylpenicillin 26 β-lactam antibiotics 26 β2-agonists 100 biopsy pleural 78, 79 transbronchial 54, 55 blood gases, arterial 47 blood tests aspiration pneumonia 117 CMV pneumonitis 47 community-acquired pneumonia 11

Index tuberculosis 83 British Thoracic Society 10, 25, 26 bronchiectasis aetiology 103 allergic bronchopulmonary aspergillosis 109–12 cystic 103, 106–7 cystic fibrosis 112, 113, 114, 115 distribution 103 investigation 104, 105–8, 109 pathogenic organisms 103 post-tuberculosis 76, 94, 95 presentation 103, 104 tubular 105, 106 bronchoalveolar lavage 54 aspergilloma 94 Aspergillus pneumonia 58, 59 community-acquired pneumonia 22, 23 bronchodilators 100, 109 bronchogram air 12, 13 bronchiectasis diagnosis 104 broncholith 90 bronchopneumonia community-acquired 10, 14, 15, 27 due to tuberculosis 72 sputum analysis 20 therapy 26 Brugia spp. 132 buffy coat, peripheral blood 50 bulging fissure sign 16, 17 Burkholderia cepacia 114, 115 butanol 87 C-reactive protein 11, 47 calcification hilar glands 64, 65, 76, 77 pleura 76, 77 post-tuberculosis 64, 65, 85, 90, 91 Candida albicans 36, 61, 117 Candida tropicalis 61 capreomycin 87 carbol fuchsin stain 79, 80 caspofungin 61 cavitation coccidiomycosis 123, 124 differential diagnoses 30 pneumonia 10, 13, 30, 31 tuberculosis 70, 71–2, 74 cefepime 26 cefotaxime 26, 30, 119 ceftazidime 42, 44, 114

177

Index ceftriaxone 26, 30, 119 cefuroxime 26, 119 cephalosporins 119, 130 CFT, see complement fixation test (CFT) Charcot Leyden crystals 109 chest drainage 128 empyema 30, 32, 36, 37 chest physiotherapy 109, 114 chest wall abscess 128 chickenpox 16, 18 Chlamydia pneumoniae 9, 10, 16, 24 Chlamydia psittaci 9, 24 ‘chocolate’ agar 20 chronic obstructive pulmonary disease (COPD) 21 aetiology of exacerbations 97–100 investigations 100, 101 morbidity and mortality 97 noninfective 97, 98 therapy 101–2 cidofovir 50 ciprofloxacin 88, 132 clarithromycin 13, 25, 26, 82, 88, 100 clindamycin 54, 130 clofazimine 87 coliform organisms 36, 44, 103, 117 colomycin 109 community-acquired pneumonia aetiology 9 complications 25–37 incidence and mortality 9 investigations 10–24 presentation and severity assessment 9–10 therapy 25, 26 complement fixation test (CFT) 24 complications community-acquired pneumonia 25–37 surgical 36 tuberculosis 66 computed tomography (CT) scans allergic bronchopulmonary aspergillosis 111 Aspergillus pneumonia 56, 57–8 bronchiectasis 105–6 CMV pneumonitis 47, 48 coccidiomycosis 123 community-acquired pneumonia 11 COPD 97, 98, 99 cystic fibrosis 112, 113 empyema 35 lung abscess 26, 27, 28, 29 P. carinii pneumonia 50, 52 tuberculosis 79 consolidation, lung

178

Index

179

actinomycosis 130 aspiration pneumonia 118 CMV pneumonitis 48 coccidiomycosis 122 pneumonia 10–12, 13, 14, 15, 28, 43 tuberculosis 70, 71, 73–4 COPD, see chronic obstructive pulmonary disease (COPD) corticosteroids 54, 84, 100, 112 inhaled 109 cotrimoxazole 40, 54, 82, 132 Coxiella burnetti 9, 24 crescent sign 56, 124 cross-infection 44 CT scans, see computed tomography (CT) scans Curschmann’s spirals 109 cutaneous larva migrans 132, 134 cycloserine 87 cystic fibrosis 109, 112–15 cystic lesions, bronchiectasis 106–7 cysts hydatid 124–7 Pneumocystis carinii pneumonia 52, 53 cytomegalovirus (CMV) pneumonitis 45 investigation 47–50 prevention 50 treatment 50 dapsone 54 diagnostic guidelines, pneumonia 10 diethyl carbamazine 134 disc sensitivity tests 82 diuretics 100 doxapram 100 doxycycline 26 drainage, chest 30, 32, 36, 37 drug reactions 134, 135 ‘E’-test 82 early secretory antigenic target (ESAT-6) 83 Echinococcus granulosus 124, 126, 127 electron micrographs 108, 109 emboli, septic 30, 31 emphysema 121 centri-acinar 97, 99 centrilobular 97, 98 pan-acinar 97, 99, 100, 101 empyema actinomycosis 128, 129 community-acquired pneumonia 30, 32–6, 37 as surgical complication 36 treatment 36, 37

Index

180

endocarditis 25, 30, 31 endotracheal aspirate 24 Enterobacter spp. 36, 117 eosin-methylene blue stain 123 eosinophilia pulmonary 134, 135–6 tropical pulmonary 132–4 erythrocyte sedimentation rate 11, 47, 83 erythromycin 25, 26, 130 ESAT-6, see early secretory antigenic target (ESAT-6) Escherichia coli 36 ethambutol 82, 84, 87, 88 ethionamide 87 exercise testing 53 ‘exotic’ diseases 117, 136 coccidiomycosis 122, 123, 124 histoplasmosis 120–1 hydatid disease 124–7 tropical pulmonary eosinophilia 132–4 fibrinolysis, intrapleural 35, 36 fibrocavitatory disease 120, 121, 123 fibrosis, lung 76, 77, 130 fibrous scarring 107 filariasis 132, 134, 136 FiO2, see inspired oxygen concentration (FiO2) flucloxacillin 30 fluconazole 61, 123 fluorescent microscopy 22–4, 54, 55 fluoroquinolone 26 foreign body giant cell reaction 119 foscarnet 50 fucidin 40 full blood count 11, 47 fungal balls 56, 57–8, 90, 92 fungal hyphae 58, 59, 94, 111 fungal infections aspergilloma 92–4 Aspergillus pneumonia 56–61 coccidiomycosis 122, 123, 124 histoplasmosis 120–1 fusiforms 117 ganciclovir 50 gastric acid, aspiration 119 genetic disorders 112 gentamicin 109 Ghon focus 64, 65 Giemsa staining 54, 55, 120 glucose, pleural fluid 30 Gram-negative bacilli 20, 39, 40, 41, 97, 101, 108, 117

Index Gram-negative cocci 21, 100, 101 Gram-positive bacilli 130, 132, 133 Gram-positive cocci 19, 22, 23, 101 granulomatous inflammation 68, 89 Grocott stain 54, 55, 59, 124 ‘ground glass’ changes 47, 48, 50, 52, 56, 57–8 growth factors 61 Haemophilus influenzae 9, 97, 100, 101, 103, 114 culture and identification 20 haemoptysis 90 halo sign 56, 57–8 Heaf test 82–3 helminth infections 124–7, 132–4 hemidiaphragms, flattening 97, 98 heparin 100 hepatic hydatid cysts 126 high dependency unit 25 hilar glands calcification 4, 65, 76, 77 lymphadenopathy 64, 72, 75, 120 hilar prominence 75, 122, 123 Histoplasma capsulatum 120 histoplasmosis 120–1 HIV infection 45 Pneumocystis carinii pneumonia 50–3 tuberculosis 68, 70, 72, 73, 78 home treatment, COPD 102 hookworms 132–4 hospital-acquired pneumonia aetiology and bacteriology 39, 44 incidence 39 investigation 40, 41–2 Legionella pneumophila 22, 23–4 presentation 40 treatment 42, 44 ventilator-associated 42–4 hydatid cysts 124–7 hypercapnia, community-acquired pneumonia 25 hyphae, fungal 58, 59, 94 hypoalbuminaemia 11, 83 hyponatraemia 11, 83 hypoxaemia 47 hypoxia, community-acquired pneumonia 25 IFNγ assay, see interferon gamma (IFNγ) assay imipenem 26, 132 immunocompromised patient aetiology of pneumonia 45 Aspergillus pneumonia 56–61 CMV pneumonitis 47–50

181

Index investigations for suspected pneumonia 46 Pneumocystis carinii pneumonia 50–4, 55 presentation 45 yeast infections 61 immunodeficiency classification and causes 45 therapeutically-induced 45, 46 immunofluorescence staining, direct 22–4, 54, 55 immunoglobulin M (IgM) 50 immunoglobulin therapy 50 immunohistochemistry 48, 49 inflammation, granulomatous 68, 89 inflammatory markers 11, 47 influenza A infection 22–4 inspired oxygen concentration (FiO2) 10 intensive care unit 25 interferon gamma (IFNγ) assay 83 intermittent positive pressure ventilation 102 intravenous antibiotics 44 isoniazid 82, 84, 88, 130 itraconazole 112, 120, 123 kanamycin 87 Kerley B lines 50 Klebsiella spp. 117 Klebsiella pneumoniae 16, 17, 25, 36, 40, 42, 103 culture 42 mucoid colonies 42 lactate dehydrogenase (LDH) 30, 53 lactophenol-blue stain 60 Langhan’s-type giant cells 68, 69 larva migrans 132, 134 LDH, see lactate dehydrogenase (LDH) left ventricular failure 50 Legionella infections 19, 44 Legionella pneumophila 9, 16, 22, 23–4 levofloxacin 26 linezolid 40 lingula abscess 29 active tuberculosis 66, 68 liver, hydatid cyst 126 liver function tests 11, 47, 83 Lowenstein-Jensen medium 80, 81, 88, 89 ‘lumpy jaw’ 128 lung abscess actinomycosis 128, 129 aspiration pneumonia 118, 119 community-acquired pneumonia 13, 25–30 nocardiosis 132, 133

182

Index

183

lung biopsy 54, 55 lung fields, hyperinflation 97, 98 lung function tests 53 lung transplantation 114 lymphadenopathy hilar 64, 72, 75, 120 paratracheal 72, 75 lymphopaenia 11 McConkey agar 40, 42 macrolide antibiotics 26, 40 macroscopic lung pictures actinomycosis 130 aspergilloma 93–4 aspiration pneumonia 118 bronchiectasis 114, 115 community-acquired pneumonia 13 COPD exacerbation/emphysema 99, 101 cystic fibrosis 114, 115 empyema 36, 37 lung abscess 28, 31, 118 tuberculosis 65, 66, 67 malt agar 60, 61 mancomycin 44 Mantoux test 82–3 mediastinal lymph node, tuberculosis 72, 75, 79 meropenum 26, 42, 44, 119 methenamine silver stain 120, 123, 124 methicillin-resistant Staphylococcus aureus (MRSA) 30, 36, 40, 117 methylene blue staining 80 metronidazole 30, 119 micro-abscesses 130, 131 microbiological tests actinomycosis 130, 131 aspiration pneumonia 117 bronchiectasis 108 coccidiomycosis 123 community-acquired pneumonia 19–24 histoplasmosis 120 hospital-acquired pneumonia 40, 41 mycobacteria 79–80, 81 nocardiosis 132, 133 microscopy fluorescent 22–4, 54, 55 see also photomicrographs molecular investigations 82 monoclonal antibodies 22–4, 50, 54 Moraxella catarrhalis 9, 97, 100, 101, 103 Moraxella catarrhalis (continued) culture 21 moxifloxacin 87

Index

184

MRSA, see methicillin-resistant Staphylococcus aureus (MRSA) mucoid bacterial strains 41, 42, 103, 108, 109, 114 mycobacteria atypical/MOTT 79, 82, 87–8, 114 culture and identification 79–83 heat-shock protein gene 82 Mycobacterium abscessus 82, 87, 114 Mycobacterium avium 82, 87, 88, 114 Mycobacterium avium intracellulare 88, 89 Mycobacterium bovis 83 Mycobacterium chelonae 82, 87, 88, 114 Mycobacterium flavescens 83 Mycobacterium fortuitum 82, 87, 114 Mycobacterium gordonae 87 Mycobacterium intracellulare 82, 87, 114 Mycobacterium kansasii 82, 83, 87–8, 89, 114 Mycobacterium malmoense 82, 87–8, 89, 114 Mycobacterium marinum 82, 83 Mycobacterium simiae 87 Mycobacterium szulgai 83, 87 Mycobacterium tuberculosis 114 Mycobacterium xenopi 87, 88 Mycoplasma pneumoniae 9, 16 Necator sp. 132, 133 necrosis, caseous 68, 69 neutropenia 40, 45, 61 NIV, see noninvasive ventilation (NIV) Nocardia asteroides 132, 133 nocardiosis 132, 133 noninvasive ventilation (NIV) 102 nucleic acid amplification tests 82 nucleic acid probes 50, 88 oral hygiene 128 osteomyelitis 25, 30, 31 ‘owl’s eye’ nuclear inclusions 48, 49 oxygen saturation (SaO2) 10, 53 oxygen therapy 100, 119 parapneumonic effusion 30–5 partial pressure of arterial oxygen (PaO2) COPD 102 pneumonia 10, 25, 100, 119 PAS (aminosalicylate) sodium 87 PAS stain, see periodic acid Schiff (PAS) stain PCR, see polymerase chain reaction (PCR) pentamidine isethionate 54 perihilar predominance 50, 51–2, 53 periodic acid Schiff (PAS) stain 120, 121 pharyngeal pouch 118, 119

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photomicrographs actinomycosis 130, 131 Aspergillus pneumonia 58, 59 bronchiectasis 107 CMV pneumonitis 48, 49 community-acquired pneumonia 14, 15 hydatid cysts 126, 127 miliary tuberculosis 66, 67 pleural tuberculosis 78, 79 post-primary tuberculosis 68, 69 physiotherapy, chest 109, 114 piperacillin 26 pleura calcification 76, 77 tuberculosis 68, 72, 74–5, 78–9 pleural biopsy 78, 79 pleural effusion 26, 27, 30–5 pleural fluid, analysis 30, 78 plombage 84, 85 pneumatoceles 50 Pneumocystis carinii pneumonia 45 investigations 50–4, 55 presentation 50 treatment 54 pneumocysts 54, 55 pneumonectomy 84–7 pneumonia aspiration 40, 41, 117–19 ‘atypical’ causes 9, 16, 24 eosinophilic 134, 135 lobar 10–14 necrotizing 48, 49, 59, 114 Pneumocystis carinii 45, 50–4, 55 see also community-acquired pneumonia; hospital acquired pneumonia pneumonitis, cytomegalovirus 45, 47–50 pneumothorax 53 polymerase chain reaction (PCR) 50, 82 polymorphonuclear cells 40, 41, 100, 101 praziquantel 126 prednisolone 54 primaquine 54 protein, pleural fluid 30 prothionamide 87 Pseudomonas spp. 44 Pseudomonas aeruginosa 26, 36, 40, 117 bronchiectasis 103, 108, 109, 114 culture 41 cystic fibrosis 114 mucoid strains 41, 103, 108, 109, 114 pyrazinamide 82, 84, 87 pyridoxine 84

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quinolones 26, 40, 100 radiographs, chest actinomycosis 128, 129 active tuberculosis 64–6, 67, 70–6, 77 Aspergillus infections 55–6, 56, 57, 90, 91–2 bronchiectasis 106–7, 112 bronchopneumonia 10, 14, 15 CMV pneumonitis 47 coccidomycosis 122, 123 community-acquired pneumonia 10, 11, 16, 17–18 cystic fibrosis 112 empyema 32–5 histoplasmosis 120, 121–2 hospital-acquired pneumonia 42, 43 hydatid disease 124–6 lung abscess 27–9 parapneumonic effusion 32–5 Pneumocystis carinii pneumonia 50–3 pulmonary eosinophilia 134, 135–6 tuberculosis 64, 65, 70–6, 77 therapy 84, 85 renal failure 11 respiratory distress, adult syndrome 42, 43 respiratory failure, type 1 47 ‘reversed bat’s wing’ 134, 135 ribs flattened 97, 98 resection 36, 37 rifabutin 87 rifampicin 26, 30, 40, 82, 84, 87, 88, 130 urine changes 87 SaO2, see oxygen saturation (SaO2) scarring, lungs 76, 77, 107, 114, 115 sellotape-on-glass slide 60 sensitivity testing, mycobacteria 82 septal thickening, interlobular 47, 48 septicaemia, staphylococcal 30, 31 severity assessment, community-acquired pneumonia 9–10 shadowing diffuse interstitial 16, 18, 43, 47, 134, 135–6 nodular 16, 18 perihilar 51–2 ‘reversed bat’s wing’ 134, 135 signet ring sign 105–6 signs bulging fissure 16, 17 crescent 56, 124 halo 56, 57–8

Index signet ring 105–6 split pleural 35 water lily 124, 125 silver stain (Grocott) 54, 55, 59, 124 skin lesions 132, 134 smokers 97 sodium, plasma 11, 83 split pleural sign 35 sputum analyses aspergillosis 111 bronchiectasis 103, 104, 108, 111 community-acquired pneumonia 19–21, 23 COPD 100, 101 hospital-acquired pneumonia 40, 41–2 mycobacteria 79–80, 81 Staphylococcus aureus 9, 13, 44, 103, 114, 117 culture from sputum 22, 23 lung abscess 25 methicillin-resistant (MRSA) 30, 36, 40, 117 septic emboli 30, 31 stool microscopy 132, 133 Streptococcus milleri group 25, 36, 117, 128 Streptococcus pneumoniae 9, 10, 11, 97, 101, 103 culture and identification 19 Streptococcus pyogenes 9, 22 streptokinase, intrapleural 35, 36 streptomycin 87, 130 Strongyloides stercoralis 132–4 sulbactam 26 sulphasalazine reaction 134, 135 sulphonamides 132 sulphur granule 128, 130, 131 surgical complications, empyema 36 surgical treatments empyema 36, 37 tuberculosis 84–7, 88 sweat test 112 T-lymphocyte deficiencies 45 tapeworm, dog 124, 126, 127 tazobactam 26 teicoplanin 30, 40 tetracyclines 40, 82, 130, 132 thiacetazone 87 thoracoplasty 84, 85 thoracotomy 36 thrush 61 tobramycin 109 Torulosis glabrata 61 trimethoprim 54 trimethoprim-sulfamethoxazole 54

187

Index

188

tropical pulmonary eosinophilia 132–4 tuberculin skin testing 78, 82–3 ‘tuberculoma’ 64, 66 tuberculosis aetiology 63 blood tests 83 complications of primary disease 66 extrapulmonary 68 fibrocaseous 68, 69, 120 inactive 65, 76, 77, 90, 91 laboratory investigations 78–9 long-term sequelae 76, 90–5 mediastinal lymph node 72, 75, 79 microbiological investigations 79–82 miliary 66, 67 multi-drug resistant 63, 87 pleural 68, 72, 74–5, 78–9 post-primary 68, 69 prevalence 63 primary 64–7, 68 radiology 64, 65, 70–6, 77 risk factors for development 63 treatment 84–9 treatment failure 84–7 ultrasonography 32, 35 urea and electrolytes 11 urine, rifampicin treatment 87 urokinase 36 vancomycin 30, 40, 42, 119 varicella pneumonia 16, 18 ventilation, assisted 102 community-acquired pneumonia 102 COPD exacerbation 25 ventilator-associated pneumonia 39, 42–4 viral infections 9, 22–4 see also cytomegalovirus (CMV) infection; HIV infection voriconazole 61 Wade Fite stain 88 water lily sign 124, 125 white cell count 11 World Health Organization (WHO) 63 Wuchereria spp. 132 yeast infections 117 empyema 36 histoplasmosis 120, 121–2 immunocompromised patients 61

Index

Ziehl-Neelsen staining 66, 68, 69, 79, 81, 88, 120 modified 132

189