(BQ) Part 1 book Textbook of respiratory and critical care infections has contents: Genetic predisposition for respiratory infections, upper respiratory tract infections, community acquired pneumonia, atypical pneumonias, healthcare associated pneumonia,... and other contents.
Textbook of Respiratory and Critical Care Infections PRELIMS.indd 8/19/2014 4:19:14 PM PRELIMS.indd 8/19/2014 4:19:15 PM Textbook of Respiratory and Critical Care Infections Francesco Blasi MD PhD Professor of Respiratory Medicine Department of Pathophysiology and Transplantation University of Milan, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico Milan, Italy George Dimopoulos MD PhD FCCP Associate Professor Department of Critical Care Medicine, University Hospital Attikon Medical School Univeristy of Athens Athens, Greece The Health Sciences Publishers New Delhi | London | Philadelphia | Panama PRELIMS.indd 8/19/2014 4:19:16 PM Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: jaypee@jaypeebrothers.com Overseas Offices J.P Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 Email: info@jpmedpub.com Jaypee-Highlights Medical Publishers Inc City of Knowledge, Bld 237, Clayton Panama City, Panama Phone: +1 507-301-0496 Fax: +1 507-301-0499 Email: cservice@jphmedical.com Jaypee Medical Inc The Bourse 17/1-B Babar Road, Block-B, Shaymali 111 South Independence Mall East Suite 835, Philadelphia, PA 19106, USA Phone: +1 267-519-9789 Email: jpmed.us@gmail.com Jaypee Brothers Medical Publishers (P) Ltd Mohammadpur, Dhaka-1207 Bangladesh Mobile: +08801912003485 Email: jaypeedhaka@gmail.com Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu, Nepal Phone: +977-9741283608 Email: kathmandu@jaypeebrothers.com Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2015, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and not necessarily represent those of editor(s) of the book All rights reserved No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book Medical knowledge and practice change constantly This book is designed to provide accurate, authoritative information about the subject matter in question However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications It is the responsibility of the practitioner to take all appropriate safety precautions Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book This book is sold on the understanding that the publisher is not engaged in providing professional medical services If such advice or services are required, the services of a competent medical professional should be sought Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity Inquiries for bulk sales may be solicited at: jaypee@jaypeebrothers.com Textbook of Respiratory and Critical Care Infections First Edition: 2015 ISBN: 978-93-5090-298-1 Printed at PRELIMS.indd 8/19/2014 4:19:17 PM Dedications To my beloved wife Brunella from the bottom of my heart for supporting me each and every day with love and patience Francesco Blasi To Deppy and Efi, my family, who endured the many long hours her husband and daddy spent at home uncommunicative, with stoic patience George Dimopoulos PRELIMS.indd 8/19/2014 4:19:17 PM PRELIMS.indd 8/19/2014 4:19:17 PM Contents Contributors ix Preface xiii Chapter 1 Genetic Predisposition for Respiratory Infections 1 Natalie J Slowik, Om P Sharma Chapter 2 Upper Respiratory Tract Infections 16 Tatjana Peroš-Golubičić, Jasna Tekavec-Trkanjec Chapter 3 Community Acquired Pneumonia 29 Adamantia Liapikou, Antoni Torres Chapter 4 Atypical Pneumonias 45 Francesco Blasi, Maria Pappalettera, Federico Piffer, Paolo Tarsia Chapter 5 Healthcare-associated Pneumonia 61 Muthiah P Muthiah, M Jawad Habib, Ali E Solh Chapter 6 Community-acquired Methicillin-resistant Staphylococcus aureus Pneumonia 70 Irene D Karampela, Garyphallia Poulakou, Despoina Koulenti, George Dimopoulos Chapter 7 Acute Exacerbations of Chronic Bronchitis and Chronic Obstructive Pulmonary Disease 86 Zinka Matkovic, Marc Miravitlles Chapter 8 Viral Respiratory Infections 102 Ioannis Mastoris, Sotirios Tsiodras Chapter 9 Respiratory Infections in Specific Populations: HIV Patients 139 Charles Feldman, Ronald Anderson Chapter 10 Respiratory Infections in Specific Populations: Transplant Patients 159 Robert P Baughman, Lisa A Haglund, Gautham Mogilishetty Chapter 11 Respiratory Infections in Specific Populations: Lung Cancer Patients 174 Eleftherios Zervas, Athanasios Thomopoulos, Angelos Pefanis, Theoplasti Grigoratou, Ilias Athanasiadis, Mina Gaga Chapter 12 Respiratory Infections In Specific Populations: Drug Users 185 Georgios Kouliatsis, Vasileios Papaioannou, Ioannis Pneumatikos Chapter 13 Tuberculosis 198 Giovanni Sotgiu, Giovanni B Migliori Chapter 14 Invasive Fungal Infections in Critically Ill Patients 214 Stijn I Blot, Koenraad Vandewoude Chapter 15 Adjunctive Therapies for Respiratory Infections 231 Evangelos J Giamarellos-Bourboulis Chapter 16 Parapneumonic Pleural Effusions 242 Stavros Anevlavis, Demosthenes Bouros PRELIMS.indd 8/19/2014 4:19:17 PM Chapter 17 Intensive Care Unit-associated Infections: Pathogenesis, Diagnosis, Management, and Prevention 258 Timothy L Wiemken, Ruth Carrico, Paula Peyrani, Julio A Ramirez Chapter 18 Ventilator-associated Pneumonia 270 Alejandra López-Giraldo, Rosanel Amaro, Gianluigi L Bassi, Miquel Ferrer, Antoni Torres Chapter 19 Diagnosis and Management of Hospital-acquired Pneumonia Due to Methicillinresistant Staphylococcus aureus 288 Carolina de La Cuesta, Juan M del Rio, Daniel H Kett Chapter 20 Management of Multidrug-resistant Pathogens 305 Helen Giamarellou Chapter 21 Using PK/PD Properties of Antibiotics in the Treatment of Respiratory Infections 323 Francesco Scaglione Chapter 22 Scores for the Assessment of Pneumonia Severity and Outcome 333 Textbook of Respiratory and Critical Care Infections Benjamin Klapdor, Santiago Ewig Chapter 23 Biomarkers in the Diagnosis and Treatment of Respiratory Infections 348 Dimitrios K Matthaiou, Irene D Karampela, Apostolos D Armaganidis, George Dimopoulos Chapter 24 Vaccine-preventable Respiratory Infections 360 Gernot GU Rohde Chapter 25 Pulmonary Endothelium in Sepsis and Infections 367 Ioanna Nikitopoulou, Nikolaos A Maniatis, Anastasia Kotanidou, Stylianos E Orfanos Chapter 26 Bioterrorism and Respiratory Infections 379 Petros Kopterides, Nikitas Nikitas, Dimitrios K Matthaiou, Apostolos D Armaganidis, George Dimopoulos Chapter 27 The Role of the Nurse in the Treatment of Respiratory Infections 400 Sonia O Labeau, Stijn I Blot Chapter 28 Lung Infections in Cystic Fibrosis 411 Baroukh M Assael Index 427 viii PRELIMS.indd 8/19/2014 4:19:18 PM Contributors EDITORS Francesco Blasi MD PhD Professor of Respiratory Medicine Department of Pathophysiology and Transplantation University of Milan, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico Milan, Italy George Dimopoulos MD PhD FCCP Associate Professor Department of Critical Care Medicine University Hospital Attikon Medical School Univeristy of Athens Athens, Greece CONTRIBUTING AUTHORS Rosanel Amaro MD Ilias Athanasiadis MD Ronald Anderson PhD Gianluigi L Bassi MD PhD Department of Pulmonary and Critical Care Medicine Hospital Clinic of Barcelona Barcelona, Spain Research Professor Department of Medical Immunology Faculty of Health Sciences, University of Pretoria Pretoria, South Africa Stavros Anevlavis MD PhD Senior Lecturer of Pneumonology Democritus University of Thrace University Hospital of Alexandroupolis Alexandroupolis, Greece Apostolos D Armaganidis MD PhD Consultant Mitera Hospital Athens, Greece Division of Animal Experimentation Department of Pulmonary and Critical Care Medicine Hospital Clinic of Barcelona, Barcelona Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias Mallorca, Spain Robert P Baughman MD Professor Department of Medicine, University of Cincinnati Cincinnati, Ohio, USA Professor Department of Critical Care Medicine University Hospital Attikon Medical School Univeristy of Athens Athens, Greece Stijn I Blot MNSc PhD Baroukh M Assael MD PhD Professor of Pneumonology Democritus University of Thrace and University Hospital of Alexandroupolis Alexandroupolis, Greece Cystic Fibrosis Center Azienda Ospedaliera-Universitaria di Veron Verona, Italy PRELIMS.indd Department of Internal Medicine Faculty of Medicine and Health Sciences, Ghent University Hospital Ghent, Belgium Demosthenes Bouros MD PhD FCCP 8/19/2014 4:19:18 PM PATHOGENESIS Tuberculosis does not represent the more frequent outcome following the interaction between the human host and the M tuberculosis strains Environmental, mycobacterial, and host variables can play major/minor roles in the transition from a healthy condition to one or more of the subsequent conditions: latent tuberculosis infection, pulmonary and/or extra-pulmonary disease, Chapter_13.indd 199 and death An additive and/or synergistic effect between the above-mentioned factors can increase or decrease the probability of the transition from one status to another.4,11,12 Tuberculosis is mainly an airborne disease; mycobacteria are transmitted from contagious to susceptible individuals by inhalation of droplet nuclei, which are aerosolized particles produced when an infectious human being coughs, sings, sneezes, or talks Other routes of transmission have been described but their impact on the incidence of tuberculosis are negligible; they include foodborne transmission (through the ingestion of unpasteurized milk, contaminated by M. bovis and collected from cow with tuberculous mastitis), sexual transmission, and direct transmission (mucous or cutaneous unintentional inoculation of mycobacteria in laboratory workers and pathologists).4,11 Usually, a prolonged and/or recurrent exposure, like a close contact with a pulmonary source (i.e., a patient with a pulmonary disease who transmits mycobacteria in the environment) is crucial to significantly increase the probability of infection; staying in a small environment with an inadequate ventilation can further augment that risk.4,11 The number of prevalent contagious individuals in a specific geographical area, related to the number of incident tuberculosis cases and on the duration of their infectiousness, represents one of the main variables contributing to the probability of exposure.11 It is relevant to highlight that the duration of infectiousness is significantly influenced by the ability of the local health system to early diagnose and cure a tuberculosis patient.11,12 Following the bacteriological identification of the responsible mycobacterial strains and their phenotypic characterization in terms of sensitivity to anti-tuberculosis drugs, a tailored therapy based on a combination of antibiotics should be immediately administered.13 Nonadherence to a correct medical prescription, following the long duration of anti-tuberculosis treatment and/ or its adverse effects, or inadequate dosages, incorrect drug combinations, and treatment durations can reduce the probability of treatment success and then, can favor the persistence of contagiousness Early diagnosis and treatment can significantly reduce the incidence of infected subjects, who can subsequently develop tuberculosis disease; typically out of (~40%) of the close contacts of a highly contagious patient is infected at the time of the case detection.11,14,15 Patients adequately treated are not infectious after 2–3 weeks; nevertheless, not all patients are similarly contagious, considering a correlation between the number of mycobacteria in an mL of sputum and the efficiency of transmission At Tuberculosis on the surface can be detected, functional to interact with host cell receptors (for instance, toll-like receptors (TLRs), intercellular adhesion molecule-3, macrophage mannose receptor) and to help mycobacteria to fight the environmental stress.7,8 In particular, it is worthwhile to mention the role of mannose-capped lipoarabinomannan, lipomannan, arabinomannan, mannan, mannoglycoproteins, and phosphatidyl-myoinositol mannosides in the mycobacterial physiology, whose location is quantitatively variable.7 Numerous lipids embedding the envelope (e.g., phthiocerol dimycocerosate) are relevant virulence factors.9,10 Their contribution to the dry weight of the mycobacterium is consistent, being approximately, 40% On the other side, the sulpholipids seems to play a role in the growth pathways.9 Glycolipids containing mycolic acid, a high weight fatty acid, can interfere with the immune system of the host and can confer resistance to anti-tuberculosis drugs owing to their hydrophobic content.9 The genome is characterised by 4.4 × 106 bp, with almost 4,000 genes.6 Numerous genes (more than 200) are involved in the codification of enzymes included in the metabolism of the fatty acids, particularly in the β-oxidation process This feature can explain the relevant mycobacterial ability to survive in the host, that is using lipids as the main energetic source Another important aspect of M tuberculosis genome is the relative weight of genes encoding the prolineglutamic acid and the proline-proline-glutamic acid families of acidic, glycine-rich proteins (4%): they are 172 genes (104 and 68 genes of the proline-glutamic acid and the proline-proline-glutamic acid family, respectively).6 The activity of their products is not well known, even if several experimental models proved their virulence and their role in the antigenic changeability during the infection in host tissues Its duplication time is about one day (i.e., 18–24 hours), slower than other Gram-positive and -negative bacteria, probably due to the complexity of its structure and metabolism.5 199 8/19/2014 3:33:39 PM Textbook of Respiratory and Critical Care Infections 200 least 5,000 mycobacteria in mL of sputum should be present in a sputum sample to obtain a positive smear microbiological examination Sputum smear positive patients are significantly more contagious than those who are sputum smear negative and culture positive Furthermore, the latter are not greatly more infectious than tuberculosis patients who have a negative smear and culture examination.11,12 Moreover, the human density (urban vs rural areas, household crowding) and the climatic conditions (cold vs warm geographical areas) can affect the quality and the quantity of human relationships and consequently, the probability of close contacts Social variables related to the age (elderly patients are more frequently diagnosed in high income countries vs young adults in low income countries), gender, and customs can modify the risk of interaction with a contagious patient.11 Following the exposure to a contagious patient, the size of the droplet nuclei containing mycobacterial strains represents a relevant pathogenetic feature influencing the risk of infection: it should range between and 5 µm to be inhaled in the respiratory airways and retained in the pulmonary alveoli; a droplet nucleus sized above 5 µm can be entrapped by the nasal vibrissae and by the mucociliary system, whereas if the diameter is less than 1 µm it can reach the alveoli but is not retained Physical factors like humidity and temperature, can modify the size of the particles, as well as the ventilation can decrease its density and the probability of exposure with susceptible individuals.4,11 In particular, natural, mixedmode, or mechanical ventilation can be important in a household or nosocomial setting to reduce the chance of being infected Natural ventilation may be enhanced by increasing the size of windows and positioning them on opposite walls but can be hindered by outdoor cold conditions and low air quality (i.e., pollution).11,16 Fans can improve the airflow direction from a contagious case to an air exhaust area when natural ventilation is not satisfactory The World Health Organization (WHO) recommends more than 11 air changes/hour for an isolation room of 24 m3 This environmental intervention should be supported by preventive measures like education on cough etiquette and respiratory hygiene and personal protective equipment; in particular, high-efficiency particulate airfilter respirators have to be worn in critical situations They should be able to filter out droplet nuclei whose size range from to µm, that is meeting or exceeding the N95 standards set by the US Centers for Disease Control and Prevention (CDC)/National Institute for Occupational Safety and Health (NIOSH) or the Conformité Européenne (CE) certified free flight phase (FFP2) standards They Chapter_13.indd 200 should be worn by susceptible individuals (healthcare workers or visitors in a nosocomial setting), while surgical masks should be worn by patients Health education on the importance of respirators in communities at risk should be carried out in order to avoid stigma; in addition, continuous training of healthcare providers on the correct use (fit testing) and indications of respirators should be organized.16 If droplet nuclei can bypass the upper airways and lodge in the alveoli spaces, alveolar macrophages engulf M tuberculosis strains and start a chronic inflammatory process It includes the enrolment of other mononuclear and non-mononuclear cells, following the release of pro-inflammatory cytokines like interleukin (IL)-12, IL-1β, and tumor necrosis factor (TNF) by infected macrophages.4,5,17 Interactions between mycobacterial antigens and host cells involve several molecules like TLRs, nucleotide-binding oligomerization domain (NOD)-like receptors and C-type lectins;3 in the majority of cases, M tuberculosis-host cell receptor contact starts an intracellular signaling cascade oriented to trigger inflammatory events Dendritic cells transfer to pulmonary lymph nodes, where mycobacterial antigens are presented to naïve T and B lymphocytes, which are primed and migrate to the original infectious focus in the lung parenchyma This early inflammatory response, characterized by the pulmonary recruitment of neutrophils, macrophages, dendritic cells, and lymphocytes lasts 12–30 days and culminates in the development of caseous granuloma, acknowledged as the histological feature of the mycobacterial infection and so labeled owing to the gross cheese-like look of its centre.1,3,10,17-20 Different macrophage phenotypes form the granuloma: they can have anti-mycobacterial activity, can secrete pro- and anti-inflammatory cytokines as well as proteins useful to rebuild the damaged tissues Only those macrophages activated by T-helper (Th) lymphocytes with IL-12 and TNF (classically activated macrophages) can kill mycobacteria and can recruit T lymphocytes, whereas those macrophages responding to Th2 lymphocyte signals, like IL-4 and -10, decrease the intensity of the inflammation process (alternatively activated macrophages).5,17 The prevalence of macrophages infected by mycobacteria (i.e., not growing in the extracellular environment) is indirectly linked to their ability of containing M tuberculosis replication The granuloma sized between mm and cm cannot eliminate the mycobacterial strains but contain their replication Some physical and chemical environmental characteristics of the granuloma (i.e., low pH, hypoxia, increased concentration of carbon monoxide, and nitric oxide) favor the induction of M tuberculosis 8/19/2014 3:33:39 PM EPIDEMIOLOGY The WHO annually evaluates the impact of tuberculosis in developing and developed countries worldwide.2 Epidemiological indicators are commonly used to compare the temporal and spatial trends of the disease as well as to analyze the efficacy of the adopted public health interventions; in particular, indicators are regularly estimated: annual incidence of the disease (i.e., number of new tuberculosis cases/100,000 population), annual prevalence of the disease (i.e., number of tuberculosis cases/100,000 population), and annual mortality among tuberculosis cases (i.e., number of deaths/100,000 population) The number of new tuberculosis cases estimated in 2010 globally, was 8.8 million (range: 8.5–9.2 million), equivalent to 128 patients/100,000 population The proportional spatial distribution of the incident cases was unequal, with Asia and Africa characterized by the higher estimates (59% and 26%, respectively) The most affected countries were India (range: 2.0–2.5 million), China (range: 900,000–1.2 million), South-Africa Chapter_13.indd 201 (range: 400,000–590,000), Indonesia (range: 370,000– 540,000), and Pakistan (range: 330,000–480,000) An estimated 1.1 million (range: 1.0–1.2 million)/8.8 million (12–14%) incident cases were HIV-positive, mainly living in the WHO African Region, where 82% of the tuberculosis/HIV co-infected patients has been diagnosed Annual tuberculosis incidence rate is decreasing worldwide, with different regional declining rates (from 90%) Furthermore, they are worse in XDR-tuberculosis compared with MDRtuberculosis.22,37-40 The prevalent cases of MDR-tuberculosis estimated in 2010 were 650,000, whereas the incident cases were 290,000 (range: 210,000–380,000).2 Twenty-seven countries were defined “high MDR-tuberculosis burden countries” by the WHO, almost half belonging to the former Soviet Union Belarus and Moldova recorded the highest prevalence among new and previously treated patients (26% and 65%, respectively) The estimates on MDR-tuberculosis are not representative of the true figures in some countries, particularly those located in the African Region The drug susceptibility testing is carried out only in less than 2% and 6% among new and previously treated tuberculosis patients worldwide, respectively Additionally, treatment accounting drug susceptibility testing results was performed in 16% of the 290,000 incident MDRtuberculosis patients in 2010 CLINICAL FEATURES 202 Tuberculosis disease development is favored by a qualitative and/or quantitative impairment of the immune system.4,11,12,17 It can follow the status “infection” and its probability of occurrence varies, being highest in the first 1–2 years after the mycobacterial entry (5%) and lower as time passes by (lifetime risk: 5–10%).4,11,12 The cumulative risk of developing tuberculosis is directly correlated with the age of the primary infection: it is highest in younger subjects (35–50% in children who are in close contact of a contagious patient).11,12 Chapter_13.indd 202 Several medical conditions are acknowledged as relevant risk factors for tuberculosis development One of the most significant factor, from a clinical and public health perspective, is the HIV/AIDS HIV impairs the innate and the adaptive immune responses, particularly decreasing the CD4+ cells, which play a crucial role in the response to mycobacteria.4,11,12,41-43 The estimated annual risk of tuberculosis is 5–15% in tuberculosis/HIV co-infected when M tuberculosis infection precedes HIV infection; it could be significantly higher if the mycobacterial infection develops in a severely immunocompromised patients Prospective studies showed that HIV-positive patients have a statistically significant highest relative risk (RR) of developing tuberculosis if compared with HIVnegative patients; nevertheless, quantitative differences were demonstrated on the basis of the impact of HIV epidemic in the population The estimated RR is 36.7 in low HIV/AIDS prevalence areas, 26.7 in areas with concentrated epidemics, and 20.6 in areas with a generalized epidemic.4,11,12,41-44 Diabetes mellitus, one of the most frequent chronic diseases worldwide, can affect native and acquired immunity, particularly decreasing the chemotaxis, the oxidative killing ability of neutrophils, and the production of IFN-γ and IL-12.45-47 The global prevalence of diabetes in people aged 20–79 years was 6.4% in 2010, equivalent to 285 million individuals; it is expected to rise to 7.7% in 2030 (equivalent to 439 million patients), particularly in low-income than in high-income countries (69% vs 20%, respectively).48 The risk of developing tuberculosis in diabetic patients is 2–9 times lower than HIV/AIDS, but the global prevalence of diabetes is significantly higher The probability of tuberculosis in diabetic patients is 1.5–8 higher than in healthy people.43,45,47,49-53 Chronic renal failure and the hemodialytic therapy increase the probability of tuberculosis if compared with the risk of tuberculosis among the healthy subjects (6.9–52.5 times higher than the baseline risk) owing to immunodepression (i.e., declined production of IFN-γ and IL-12), malnutrition (decreased vitamin D intake), and hyperparathyroidism.11,54,55 Exposure to crystalline silica dust, associated to a reduced function of macrophages, favors the probability of developing tuberculosis; in particular, silicosis increases the probability of pulmonary and extra-pulmonary tuberculosis of 2.8–39 and 3.7 times, respectively.4,11,43,56-58 It has been shown that the risk of disease is significantly increased in HIV-positive patients Several occupational activities are associated to a different likelihood; in particular, drilling seems one of the most hazardous activities.11,56-58 8/19/2014 3:33:40 PM Chapter_13.indd 203 or without pleural effusion Hemoptysis is an infrequent and late clinical sign of progressive illness, following the damage of a pulmonary artery by a tuberculosis cavity (Rasmussen’s aneurysm) Physical examination does not reveal specific findings and is frequently negative; only in a few patients, rales, dullness, and signs of consolidation can be detected.4,65 Extra-pulmonary tuberculosis, which accounts for 15–20% of all tuberculosis cases in HIV-negative population, is classified in groups on the basis of the pathogenesis: mucosal forms (dissemination of infectious secretions in the gastrointestinal or respiratory tracts), lymphohematogenous forms, and contiguous forms to a primary focus The most frequently detected conditions are: miliary tuberculosis, tuberculous meningitis, tuberculous pleurisy, skeletal tuberculosis, genitourinary tuberculosis, and tuberculous lymphadenitis.4,66 Military tuberculosis could be classified in acute, chronic (or cryptic), and non-reactive Acute (or usual) miliary tuberculosis is more prevalent in older individuals with co-morbidities or young patients with severe immunodepression and is characterized by non-specific, systemic symptoms like fever, anorexia, weakness, and weight loss Chronic miliary tuberculosis is diagnosed in elderly patients and is habitually asymptomatic (postmortem examination often allows to diagnose it) Patients with non-reactive miliary tuberculosis show a severe sepsis with splenomegaly and scattered necrotic tissues.4,67,68 Meningitis is usually the consequence of the rupture of a subependymal tubercle into the subarachnoid space The more frequently detected clinical signs and symptoms are: headache, fever, meningismus, vomiting, confusion, and sometimes, focal neurological signs.4,68-71 Tuberculous pleurisy typically occurs in several forms of tuberculosis and is characterised by high-grade fever, chest pain, and cough 4,72,73 Skeletal tuberculosis is in more than 30% of the skeletal cases located in the spine (tuberculous spondylitis or Pott’s disease) The inflammation process involves more vertebral bodies and intervertebral discs It is often asymptomatic in the early stages and then, patients complain of back pain or stiffness It occurs in the elderly and in young individuals in high- and low-income countries, respectively.4,74,75 Genitourinary tuberculosis usually starts from the kidney and then, can involve testicles, endometrium, or ovaries.4,68,76 Tuberculous lymphadenitis (scrofula) frequently involves cervical lymph nodes and is clinically characterized by a red and painless mass It is multilateral in HIV-positive patients and associated with systemic Tuberculosis Less scientific evidence for tuberculosis risk has been obtained for other chronic conditions like neoplasias (for instance, lymphoma, lung, head/neck cancers), gastrectomy, and jejunoileal by-pass.11,43 Exposure to toxic substances or drugs can modify the baseline risk of developing tuberculosis after mycobacterial infection Anti-TNF-α therapies with monoclonal antibodies (adalimumab, certolizumab pegol, golimumab, and infliximab), prescribed for chronic diseases like rheumatoid arthritis, psoriasis, ankylosing spondylitis, and inflammatory bowel disease rise the probability of tuberculosis from 1.6 to 25.1 times and a preventive chemotherapy is usually prescribed before treating patients with those immunosuppressive drugs.59,60 Tobacco smoking is proved to have a role in the susceptibility to latent tuberculosis infection and tuberculosis, damaging the mucociliary system, alveolar macrophages, and CD4+ lymphocytes The risk of disease is increased from 2.3 to 2.7 times and is directly associated to the daily number of smoked cigarettes However, it is complicated to separate the effect of smoking from that of other confounding socio-economic factors (for instance, alcohol consumption, intra-venous drug abuse etc.).4,11,43,61,62 In the majority of cases, patients develop a pulmonary form; only in a few cases, particularly in those severely immunocompromised (for instance, AIDS patients with less than 100 CD4+ cell counts/µL), an extra-pulmonary tuberculosis may occur, with or without pulmonary involvement.4 From a clinical perspective, it can be identified a primary tuberculosis, following the entry of the mycobacteria in the lower respiratory airways and a post-primary tuberculosis, following a latent tuberculosis infection Generally, primary tuberculosis occurs without clinical signs and symptoms in adults whereas several age-related clinical syndromes can be described in the pediatric population In children aged less than years, a regional lymphadenitis may be the cause of cough due to the mechanical compression of main or lobar bronchi; occasionally, a lymphohematogenous spread can cause a systemic disease (the so called miliary tuberculosis from its pathological lesions similar to millet seeds) or a meningoencephalitis.4,63,64 Post-primary tuberculosis is characterized by systemic symptoms like low-grade fever, anorexia or inappetence followed by weight loss, asthenia, and night sweats A persistent mucopurulent cough, lasting more than 21 days, may represent a typical clinical feature Chest pain can be the consequence of a pleuritic process with 203 8/19/2014 3:33:40 PM symptoms Lymphadenitis can involve even mediastinal or mesenteric lymph nodes.4,77 Textbook of Respiratory and Critical Care Infections DIAGNOSIS 204 Pulmonary tuberculosis disease should be suspected in individuals with a persistent, chronic cough, which lasts for more than 14–21 days.33,78,79 At least sputum specimens should be submitted for a microscopic examination in a quality-assured laboratory; at least sample should be obtained in early morning.4,33,78,79 The first specimen is positive in 85.8% of the sputum smear positive individuals; the average incremental yield of the second specimen is 11.1%.14,78,79 Mycobacteria are defined as acid-fast bacilli because of the characteristic reaction of their membrane to the Ziehl-Neelsen staining The smear is covered with carbol-fuchsin, then heated, rinsed, and decolorized with acid-alcohol and counterstained with methylene blue More than 5,000–10,000/mL bacilli should be located in the sample in order to obtain a positive result In the last decades, several laboratories have used a fluorochrome stain with auramine-rhodamine It was recently proved that fluorescence microscopy has a 10% higher sensitivity than conventional microscopy, whose sensitivity is 50–60% when compared with culture A 10–20% higher sensitivity was shown after centrifugation and/or sedimentation, although specificity is comparable to conventional light microscopy both for the fluorescence microscopy and after treatment of the sample (i.e., centrifugation and/or sedimentation).78,79 Samples can be evaluated directly or after sedimentation by centrifugation.4 Instead of sputum, gastric aspiration material can be collected for children who are unable to expectorate.4,33,63,78,79 Samples are then cultured in solid and/or liquid media; they should be initially liquefied or decontaminated using N-acetyl-L-cysteine in 1% sodium hydroxide solution After centrifugation, the sediment is inoculated onto solid culture agar-based (for instance, Middlebrook 7H11) or egg-based (for instance, Lowenstein-Jensen) media in 5–10% carbon dioxide Another option is represented by a liquid culture system (BACTEC) that detects mycobacterial growth through the identification of carbon dioxide from radioactive palmitic acid Its sensitivity is higher than the sensitivity of the solid media and identifies mycobacteria rapidly (in 70 kg OD • 500 mg for BW 50 kg OD 1,000 mg for BW >70 kg OD • 600 mg for BW 70 kg OD • • • • • • • Para-aminosalicylic acid Thiacetazone g for BW 70 kg OD • 150 mg OD • • • • • Linezolid 600 mg OD • • • Clofazimine 100–300 mg OD • • • Amoxicillin-clavulanic Clarithromycin 206 Arthralgia Gastrointestinal intolerance Hepatitis Hyperuricemia Allergy Auditory and vestibular nerve damage Nausea Neuromuscular blockade Renal failure Skin rash CNS toxicity GI intolerance Hypersensitivity Dizziness Elevation of liver enzymes Gastrointestinal intolerance Hallucinations Headache QT prolongation CNS toxicity Gastrointestinal intolerance Hepatitis CNS toxicity Dizziness Psychosis CNS toxicity Dizziness Psychosis Gastrointestinal intolerance Hypersensitivity Gastrointestinal intolerance Hepatitis Hypersensitivity Vertigo Anaemia Neuropathy Thrombocytopenia Discoloration of the skin Gastrointestinal intolerance Ichthyosis 875/125 mg BID or 500/250 mg TID • 500 mg BID Gastrointestinal intolerance • Gastrointestinal intolerance Rash OD, once a day; BID, twice a day; TID, thrice a day; BW, body weight; CNS, central nervous system Chapter_13.indd 206 8/19/2014 3:33:41 PM Chapter_13.indd 207 studies is poor, particularly for selection bias due to the exclusion of individuals with severe tuberculosis.101 Tuberculosis cases have to be treated to avoid further transmission and new infections, but unfortunately, WHO estimates that almost one third of the global population is infected and new cases of tuberculosis will continuously to emerge from this group.2,102 There is a scientific consensus on the individuals who have to be screened to ascertain a mycobacterial infection They are children and adults having close contact with a contagious tuberculosis patient, HIV-positives, and patients with autoimmune disorders who have to start an immunosuppressive therapy with anti-TNF-α drugs On the other hand, a case-by-case evaluation, performed by experts in the public health field, is necessary in order to better understand when to screen and treat some potentially at-risk groups (for instance, migrants from high incidence countries) It is widely accepted that screening has to be performed only in those individuals who want to be treated in case of latent tuberculosis infection diagnosis.82 It was proved that treatment of infected individuals with isoniazid for 6–12 months, prescribed at a daily dosage of mg/Kg, reduces the risk of tuberculosis by 60% in a time period longer than years; no differences were found between and 12 months but a higher frequency of hepatic adverse events was recorded with a longer duration.82 The effectiveness of this drug for the elimination of mycobacteria, when it is prescribed for 6, 9, or 12 months, is hindered by treatment completion rates ranging from 30 to 64%.103,104 Another alternative therapy is a 3-month regimen of isoniazid and rifampicin, whose efficacy and safety profile is comparable to isoniazid prescribed for months.82 A recent multi-centre study showed that a weekly combination of rifapentine (900 mg) and isoniazid (900 mg) for months has the same efficacy of isoniazid prescribed for months, but with higher adherence rates.103 It is unknown how to manage the contacts of MDRtuberculosis patients There is no evidence for a therapy but the only accepted alternative is the active surveillance in the initial years following the close contact.82 Tuberculosis combination with pyrazinamide reduces the length of treatment to months Ethambutol is combined when the probability of resistance to one drug is elevated or when the mycobacterial load is elevated For new tuberculosis patients the duration of therapy is months, combining isoniazid, rifampicin, ethambutol, and pyrazinamide for months, followed by isoniazid and rifampicin for months.91-95 Fixed-dose combinations are strongly suggested because they improve the patient’s adherence, reduce the pill burden, and prescription errors.91 Treatment duration in HIV-infected patients is equal to that described for the HIV-negatives.91 It is recommended to start anti-tuberculosis treatment before anti-retroviral therapy There is no clear evidence on the timing of the anti-retroviral therapy; a clear advantage of an early administration of anti-retroviral drugs is the reduction of mortality, particularly high in the first months On the opposite side, the disadvantages are represented by the pharmacological interactions (particularly, with the protease inhibitors and the nonnucleoside reverse transcriptase inhibitors), the higher risk of adverse events and of immune reconstitution inflammatory syndrome (IRIS), and the pill burden.96-98 However, the anti-retroviral therapy has to be administered as soon as possible, irrespective of the CD4 cell counts Previously-treated patients (i.e., individuals treated for more than month with anti-tuberculosis drugs) should submit a specimen for the drug sensitivity testing, who are being at higher risk of infection with drugresistant mycobacterial strains; a standard regimen can be recommended before obtaining the drug sensitivity testing results (for instance, HRZES/1 HRZE/5 HRE).91 Second-line drugs should be prescribed in case of MDR-tuberculosis, although they are more expensive, more toxic, and less efficacious, with the consequence of increasing the probability of non-adherence Drug combinations should contain more than second-line drugs, with an injectable administered for months Treatment duration should be of at least 20 months.24,99 Strict supervision by skilled healthcare workers should be performed in order to monitor patient’s adherence and the potential occurrence of adverse events Recently, community surveillance activities have been successfully implemented in low-income countries.100 Surgery has been performed for the treatment of tuberculosis, particularly in the past; in the last decade, the evidence of poor efficacy of drug combination regimens against some MDR/XDR-tuberculosis forms raised the attention on surgical interventions Findings related to high success rates and tolerable morbidity suggested their role as adjunctive therapy, even if the quality of the PREVENTION Epidemiologic indicators of tuberculosis in high-income countries started to improve following the availability of the anti-tuberculosis drugs after the 1950s’ and the implementation of the national tuberculosis programs, along with the social and economic progress.4,11,12,28,29 207 8/19/2014 3:33:41 PM Textbook of Respiratory and Critical Care Infections 208 The HIV/AIDS epidemic, the significant migration flows from high-incidence countries, as well as the wrong feeling of a definitive success on infectious diseases owing to the antibiotic therapy were recognized as the main factors responsible for the increase of prevalence and incidence of tuberculosis in developed countries after the 1980s’.4,11,12,28,29,105,106 Following a dramatic increase of tuberculosis in highand low-income countries, United Nations declared tuberculosis a public health emergency in 1993 and included the fight against tuberculosis, malaria, and HIV/AIDS among the Millennium Development Goals (MDGs) The WHO has made tremendous efforts to improve the epidemiological situation of tuberculosid in the last few decades, worldwide In 1996, it issued the first global public health strategy called directlt observed treatment short course (DOTS) strategy; after its successful implementation, that strategy was included in another, more comprehensive public health approach 10 years later-the Stop Tuberculosis Strategy, which accounts for the new epidemiological scenario and the emerging public health issues Both of them were created after interactive discussions among the main governmental and non-governmental stakeholders.12,13,28,107-112 The DOTS strategy was focused on the management of the infectious cases in order to interrupt the epidemiological chain of the transmission It was mainly aimed to diagnose 70% of the sputum smear-positive patients nationwide and to successfully treat 85% of them by 2005 If adequately implemented and scaled-up, it could reduce the tuberculosis notification from to 8% It is characterized by elements: • Government dedication to tuberculosis control • Bacteriological diagnosis through smear microscopy, mostly focused on subjects complaining of tuberculosis symptoms • Short-course anti-tuberculosis therapy, which has to be standardized and supervised, particularly in the early phase • Uninterrupted supply of high-quality drugs • Implementation of a standardized recording and reporting system for the evaluation of treatment outcomes The Stop Tuberculosis strategy is characterized by further elements to meet the 2015 MDG targets, that is to halve the prevalence and the mortality due to tuberculosis compared to the figures recorded in 1990 (Table 2) It is focused on the expansion and the national improvement of high-quality DOTS, the issue of tuberculosis/HIV co-infection, MDR-tuberculosis, the improvement of the Chapter_13.indd 208 TABLE The World Health Organization Stop Tuberculosis Strategy109 • • • • • • Pursue high-quality DOTS expansion and enhancement – Secure political commitment toward tuberculosis, with adequate and continuous financing – Ensure early case detection and diagnosis through quality-assured bacteriology – Provide standardized treatment with supervision and patient support – Ensure effective drug supply and management – Monitor and evaluate performance and impact Address tuberculosis/HIV co-infection, MDR-tuberculosis, and the needs of poor and vulnerable populations – Scale up collaborative tuberculosis/HIV activities – Scale up prevention and management of MDR tuberculosis – Address the needs of tuberculosis contacts and poor and vulnerable populations Contribute to health system strengthening – Help improve health policies, human resource development, financing, supplies, service delivery, and information – Strengthen infection control in healthcare services, other congregate settings, and households – Upgrade laboratory networks and implement the Practical Approach to Lung Health – Adapt successful approaches from other fields and sectors and foster action on the social determinants of health Engage all care providers – Involve all public, voluntary, corporate, and private careproviders through Public-Private Mix approaches – Promote use of the ISTC Empower people with tuberculosis, and communities through partnership – Pursue advocacy, communication, and social mobilization – Foster community participation in tuberculosis care – Promote use of the Patients’ Charter for tuberculosis Care Enable and promote research – Conduct program-based operational research and introduce new tools into practice – Advocate for and participate in research to develop new diagnostics, drugs, and vaccines DOTS, directly observed treatment, short-course; HIV, human immunodeficiency virus; MDR, multidrug resistant; ISTC, International Standards for Tubuerculosis care healthcare systems, the engagement of the care providers, the empowerment of individuals with tuberculosis and of their communities, and promotion of the scientific research All its elements represent an intentional response to issues and shortcomings detected during the implementation and scale-up of the DOTS strategyemergence and spread of MDR-tuberculosis, increased incidence of tuberculosis/HIV co-infection, weaknesses 8/19/2014 3:33:42 PM CONCLUSION Tuberculosis represents a relevant clinical and public health issue worldwide However, where the evidence- Chapter_13.indd 209 based WHO public health strategies (i.e., DOTS and Stop Tuberculosis) were implemented and scaled-up, the epidemiological scenario dramatically changed Unfortunately, numerous geographical areas, particularly in the sub-Saharan Africa, should improve the sustainability of their healthcare systems in order to hinder the spread of tuberculosis, MDR-tuberculosis , and HIV/ AIDS The improvement of the funding system for lowincome countries, the sustained political commitment against tuberculosis and HIV/AIDS, the introduction of new healthcare models, as well as the discovery of innovative preventive, therapeutic, and diagnostic means might help in addressing the target of less than new sputum smear-positive case/1 million inhabitants, that is the elimination of tuberculosis It can be obtained by reducing the incidence and the prevalence of individuals with latent tuberculosis infection, that is the potential source of new tuberculosis cases.29 Only a plural, multi-sectorial strategy, adequately funded and supported by the political parties, can eliminate tuberculosis in the near future, following the correct tactics implemented by several countries worldwide.107,119,120 REFERENCES Huynh KK, Joshi SA, Brown EJ A delicate dance: host response to mycobacteria Curr Opin Immunol 2011;23: 464-72 World Health Organization Global tuberculosis control 2011 Geneva: WHO Available from: http://whqlibdoc who.int/publications/2011/9789241564380_eng.pdf Ahmad S Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection Clin Dev Immunol 2011: 2011;814943 Fitzgerald D, Haas DW Mycobacterium tuberculosis In: Mandell GL, Bennett JE, Dolin R, eds Principles and practice of infectious diseases, 6th ed Philadelphia: Churchill Livingstone; 2005 p 2852-86 Flynn JL, Chan J, Lin PL Macrophages and control of granulomatous inflammation in tuberculosis Mucosal Immunol 2011;4:271-8 Smith I Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence Clin Microbiol Rev 2003;16:463-96 Torrelles JB, Schlesinger LS Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host Tuberculosis (Edinb) 2010;90:84-93 Mishra AK, Driessen NN, Appelmelk BJ, Besra GS Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role in Mycobacterium tuberculosis physiology and host-pathogen interaction FEMS Microbiol Rev 2011;35:1126-57 Karakousis PC, Bishai WR, Dorman SE Mycobacterium tuberculosis cell envelope lipids and the host immune response Cell Microbiol 2004;6:105-16 Tuberculosis of the healthcare systems, exclusion of private healthcare systems, unidirectional management of the patients, and few efforts on research on new diagnostics, drugs, and vaccines The Stop Tuberculosis strategy is supported by the Global Plan to Stop Tuberculosis (2011–2015), prepared by the Stop Tuberculosis partnership; it was developed in order to discover financial needs, and new political and public health approaches.112 Another relevant clinical and public health tool is prepared by the WHO together with numerous stakeholders is the International Standards of Tuberculosis Care (ISTC) It summarizes the standards of care that should be followed by the public and private careproviders while managing suspected or confirmed tuberculosis patients, in order to ensure a high-quality care In particular, it is focused on early bacteriological diagnosis, accurate prescription of anti-tuberculosis drugs, management of vulnerable groups (for instance, HIV-positives), and recording and reporting of treatment outcomes.78,79 Recently, the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC) prepared the European standards to complement the ISTC, that is to adapt them to the epidemiological scenario of the European Union/European economic areas, oriented to the elimination of tuberculosis.110 The primary prevention of tuberculosis has not been successful with BCG vaccination After its introduction in the clinical practice in 1921, several clinical trials evaluated its efficacy It consists of a live attenuated strain of M bovis and represents the only registered vaccine for the prevention of tuberculosis It was proved that it is efficacious in preventing tuberculous meningitis and miliary tuberculosis in children in areas of the world where the disease is endemic It confers a variable protection against pulmonary tuberculosis, particularly in adolescents and adults.113-115 Several concerns were raised on its safety in immunocompromised patients, primarily in HIVpositives.116,117 It was given billion times until now and is currently prescribed to newborns in high-risk areas as component of the WHO Expanded Program on Immunization.115,117,118 Elimination of tuberculosis by 2050 seems unlikely It is equivalent to an incidence of new sputum smearpositive patients below 1/1 million population 209 8/19/2014 3:33:42 PM Textbook of Respiratory and Critical Care Infections 210 10 Kaufmann SH, Cole ST, Mizrahi V, Rubin E, Nathan C Mycobacterium tuberculosis and the host response J Exp Med 2005;201:1693-7 11 Rieder H Epidemiologic basis of tuberculosis control Paris IUATaLD, 1999 12 Styblo RMT, public health aspects Encyclopedia of Human Biology, second edition, volume Academic Press, 1997 pp 537-558 13 Raviglione MC The 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Mendelian Chapter _1. indd 12 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 susceptibility to mycobacterial diseases Ann N Y Acad Sci 2 011 ;12 46:92 -10 1 Abel L, Casanova JL Human genetics of tuberculosis... with Mycobacterium tuberculosis Beijing genotype strains is 8 /19 /2 014 3:00:32 PM 95 96 97 98 10 0 10 1 10 2 10 3 10 4 10 5 10 6 10 7 10 8 10 9 11 0 factor is associated with mortality in cerebral malaria patients