Drainage can be achieved by: \200 Bronchoscopy: \200 \200 Further reading Davis B, Systrom DM. Lung abscess: pathogenesis, diagnosis and Debate about role. Value limited by the risk of spillage of abscess contents into the unaff ected bronchial tree. treatment. Curr Clin Top Infect Dis 1998; 18: 252 \200\223273. Hirshberg B, Sklair-Levi M, Nir-Paz R et al. Factors predicting mor- tality of patients wit h lung abscess. Chest 1999; 115: 746 \200\223750. External percutaneous drainage: \200 Preferred option, surgery frequently avoided (84%), marked improvement in sepsis indicators within 48 hours of drainage. Variety of imaging techniques reported ( \202 uoroscopy, ult rasound and CT scanning). Ultrasound provides more precise spatial localization, real-time images and no radiation dose. CT scanning is frequently used, provides better visualization of intrathoracic structures and is familiar with operators. Complication rate low (broncho pleural fistula, hemorrhage, empyema). Mansharamani N, Balachandran D, Delaney D et al. Lung abscess in adults: clinical compariso n of immunocompromised to non- immunocompromised patients. Resp Med 2002; 96: 178 \200\2231 85. Mwandumba HC, Beeching NJ. Pyogenic lung infections: factors for predicting clinical outcom e of lung abscess and thoracic empyema. Curr Opin Pulm Med 2000; 6: 234 \200\223239. Wang J-L, Chen K-y, Fang C-T et al. Changing bacteriology of adult community-acquired lung abscess in Taiwan: Klebsiella pneumo- niae vs anaerobes. Clin Infect Dis 2005; 40: 915 \200 \22322. Wiedemann HP, Rice TW. Lung abscess and empyema. Sem Thor Card Surg 1995; 7: 119 \200\223128. Surgery Surgery is now seldom required in the management of lung abscess (<10%). A MALIN 182 8.5 Nocardia and actinomycosis Nocardia Nocardia species are aerobic actinomycetes, branching beaded \201 lamentous bact eria which usually stain weakly acid fast. Nocardiosis results from opportunistic infection due to a variety of Nocardia spp. Infection is limited to the skin (subcutaneous or lympho cutaneous) in about 20% of cases. More invasive disease occurs in 80%, predominantly pulmon ary infection (40%), but also systemic disease with frequent cerebral abscess formation. Investigations Imaging Plain and CT chest imaging of pulmonary nocardiosis is protean and m ay show: \200 Mild subtle in \201 ltrates. \200 Reticular nodular shadowing \200\223 patchy or diffuse. \200 Lobar or multilobar consolidation. \200 Diffuse alveolar in \201 ltrates, especially in severe immuno- compromise (HIV with CD4 <200). Abscess formatio n. Irregular nodules. Cavitary disease. Effusions and empyema. Pulmonary TB-like appearance with calci \201 ed lesions. \200 \200 \200 \200 Fig. 8.5.1 Smear preparation of Nocardia asteroides. (See Plate 5.) Epidemiology Nocardia spp. are ubiquitous bacteria found in soil, water and vegetable matte r. Infection usually occurs by inhalation, aspiration into the lung, direct inoculation of the skin or possibly from contaminated food via gastrointestinal tract. Hospital transmissi on has occurred in transplant and oncology units. Globaly, the N. asteroides complex accoun ts for up to 90% of pulmonary and disseminated infections. N. brasiliensis is a common caus e of skin mycetomas. N. farcinica, linked to hand transmission by anaethestists, has been a ssociated with sternotomy wound infection. Incidence has been estimated as 500 \200\2231000 cases a year in the USA with a steady increase due to the increased number of immunocompro mised individuals. Signi \201 cant under-report- ing is likely. Infection is three times m ore common in men. Fig. 8.5.2 CXR showing overwhelming pulmonary nocardiosis. Microbiology Sputum, BAL or other samples should be sent for pro- longed culture. Speci \201 c molecular tests can be employed to distinguish species, particularly N. farcinia, a species associated with disseminated disease which may be resist- ant to co-trimoxazole. Pathology Biopsy material is usually suppurative with numerous poly- morphonucleocytes, but can be granulomatous with an absence of epithelioid cells but multinucleate giant cells ca n be found. History and examination Clinical presentation varies widely and depends both on the site of infection and host response. Pulmonary nocar- diosis may present as an acute pyogenic infe ction mimick- ing pneumonia or as a chronic insidious disease mimicking pulmonary tuberculo sis, lung cancer or more rarely, aspergillosis and actinomycosis. Systemic infection and CN S involvement occur more frequently in those with severe immunocompromise. Infection also o ccurs in those with intact immunity and is usually focal such as following an inoculation i njury of the skin. Management Patient \200\231s management must be individualized and take into account clinic al presentation and in vitro antibiotic sensitivi- ties. Empirical treatment prior to labor atory results should include trimethoprim-sulphamethoxazole (with a second agent in those w ith signi \201 cant immunocompromise or sys- temic/ CNS involvement). Other agents include : carbapen- ems, amikacin, minocycline, cephalosporins or linezolid. AUTHOR \200\231S TIP Consider nocardiosis if unexplained in \201 ltrates/infec- tion in: \200 \200 \200 \200 Prognosis Outcome is determined by the site of infection and coex- istent co-morbidity. Cut aneous infection is the most benign. Even uncomplicated pulmonary nocardiosis has a mortali ty of 10%. Patients with advanced immunocompromise have a worse outcome. HIV infection. Solid organ transplant recipients. Lymphoreticular malignancy. Other causes of immunocompromise \200\223 high dose cor- ticosteroid use, alcoholism and diabetes. Alve olar proteinosis. CHAPTER 8.5 Nocardia and actinomycosis 183 Key points \200 Other investigations \200 Leukocytosis. \200 Culture from sputum, bronchial washings or biopsy material (needs anaerobic culture). Histology from lung biopsy or resected lung. Consider nocardiosis if spread to CNS or contiguous structures with soft tissue swellings o r \201 stulas. Culture samples require prolonged incubation \200\223 alert laboratory if nocardiosis possible. Species identi \201 cation in a Reference Laboratory will assist an tibiotic choice. Pathology \200 \200 \200 Actinomyces israelii commonest cause. See chronic in \202 ammatory and granulation tissue. Occasional multinucleate giant cells containing sulfur granules. Untreated disease may pro gress to: \200 \200 Actinomycosis De \201 nition An uncommon chronic suppurative infection caused by the genus , Actinomyces. These are slow-growing branching Gram-positive bacteria which form mycelia ( mass of branching, thread-like hyphae) similar to fungi. Unlike Nocardia spp., they are not acid fast. Characteristically they invade locally, forming external sinuses which discharg e sulfur granules. Multiple abscesses. Draining sinuses. Management \200 Penicillin is the treatment of choice but can also use ceftriaxone or a carbapenem. Treatme nt duration of 10 days with recent infections but need longer if \201 brosis present. Con sider co-infection. Epidemiology Actinomyces are common non-virulent oral saprophytes frequently found in assoc iation with dental infection. Spread may occur by local invasion through damaged mucosa or following surgery or trauma. Sites of infection include: 55% Cervicofacial (direct invasion ) 15% Thorax (aspiration) Abdomen (ingestion) 20% Other organs \200\223 bone, brain, skin 10% Key points \200 Despite forming mycelia, not a fungus and treated with penicillin. May mimic lung cancer or any abscess-forming organism. May co-exist with lung cancer or any abscess-forming organis m. May see sinus formation with purulent discharge of sulfur granules. Thoracic actinomycosis History and examination \200 \200 Common \200\223 cough, fever, and chest pain. Less frequently \200\223 breathlessness, ha emoptysis, weight loss, and night sweats. Further reading Beaman BL and Beaman L. Nocardia species: host-parasite relation- ships. Clin Microbiol Rev. 1994; 7: 213 \200\223264. Imaging \200 CDC Division of Bacterial and Mycotic Diseases. Nocardiosis www. cdc.gov/NCIDOD/DBMD/diseas einfo/nocardiosis_ t.htm Diagnostic triad (1) Effusion and pleural thickening. (2) Adjacent lung involvement. (3) Pe riosteal rib involvement. Solid or patchy consolidation. Lower lobe predominance \200\223 perhaps due to aspiration. Mediastinum may be involved. May mimic lung cancer with either s ingle lesions or bilateral ill-de \201 ned pulmonary opacities indistinguishable from lung neoplasia. Menendez R, Cordero PJ, Santos M. Pulmonary infection with Nocardia species: a report of 10 cases and review. Eur Respir J 1997; 10: 1542 \200\2231546. \200 \200 \200 Menendez R, Cordero PJ, Santos M, et al. Differentiating Thoracic Actinomycosis From Lung C ancer. Infect Med 2000; 17: 695-698. Hsieh MJ, Liu HP, Chang JP, Chang CH. Thoracic actinom ycosis. Chest 1993; 104: 366 \200\223370. Kwong JS, Muller NL, Godwin JD, et al. Thoracic actinomycosis: CT \201 ndings in eight patients. Radiology 1992; 183: 189 \200\223192. M PAREEK & I STEPHENSON 184 8.6 Viral infections of the respiratory tract Variation in speci \201 c at-risk groups Although all respiratory viruses have the potenti al to cause illness there are speci \201 c features among at-risk popula- tions. Despite medical advances in the control of most infectious diseases in the developed world, acute respiratory tract infections continue to impose substantial morbidity and mortality among the elderly and those with underlying chronic medical conditions. Children \200 Etiology and epidemiology Over 200 viruses are known to infect the respiratory tract, altho ugh many are recognized for their systemic manifesta- tions, e.g. measles. \200 Respiratory syncytial virus (RSV) is a common cause of broncholitis in infants and may be a ssociated with devel- opment of asthma. Most children are infected before the age of 3 year s, but immunity is incomplete and re-infection can occur later in life. Peak attack rates o ccur in infants aged below 6 months. In \202 uenza is increasingly recognized as a signi \201 cant cause of hospitalisations and attendances particularly in those aged under 12 mon ths, whereas rhinovirus infections are frequent throughout childhood. Parain \202 uenza (P IV) is more associated with croup and laryngitis than other viruses. \200\230Respiratory virus \200\231 typically refers to a pathogen whose major manifestatio ns are respiratory in nature (Table 8.6.1). The number and diversity of viruses capable of infecting or re-infecting the respiratory tract explains the high incidence of community-ac quired respiratory infection in all populations. The frequency of viral respiratory illness in populations varies by age; with highest incidence in children under 4 years of age, par ents exposed to children, and the elderly. This age-related pattern re \202 ects the cruci al role that children play in virus transmission by acquisition of infection at school or n urseries and subsequent intro- duction into their homes. Elderly \200 As 30% of elderly people suffer from at least one respi- ratory infection per winter, even low rates of morbidity have signi \201 cant impact. Limitations in physiological reserves, age-related decline in immune responses and chronic underlying medical conditions are asso ciated with increased morbidity in the elderly. Residential or nursing homes facilitate tra nsmission of respiratory viruses and outbreaks can be severe with high attack rates and fat ality rates. Although in \202 uenza is responsible for considerable mor- bidity and mortal ity, RSV, PIV, and rhinoviruses are increasingly understood as causes of serious lower resp i- ratory tract illness in aging populations. Table 8.6.1 Viruses causing respiratory syndromes Family Species and subtype RNA viruses Picornaviridae Rhinovirus (>120 serotypes) Enteroviruses Coronaviruses 229E, OC43 SARS coronavirus In \202 uenza A and B Parain \202 uenza (PIV) 1 \200\2234 Respiratory syncytial virus A&B Hum an metapneumovirus Sin nombre Coronaviridae Orthomyxoviridae Paramyxoviridae Metapneumoviridae Chronic pulmonary disease \200 Acute respiratory infection is a leading cause of hospi- talisation in those with underlyin g chronic medical conditions. Exacerbations of chronic airways disease have been linked to respiratory virus infections, with studies suggesting an association with up to two-thirds of exacerbations. Bunyaviridae DNA viruses Adenoviridae Herpesviridae Adenovirus HSV, CMV, VZV Immunocompromised patients \200 Assessing the specific causes of acute respiratory infections is important to determine pri orities for control. However, diagnosis is challenged by \200 Patients with myelosuppression, and bone marrow or solid organ transplant recipients are at risk of severe dis- ease due to community or hospital-acquired respiratory viruses Disease may result from reactivation of latent adenovi- rus infection Dual pathogens are frequentl y identi \201 ed. Pneumonia and death may complicate up to 80% and 50% of infections respe ctively, with greater morbidity for RSV and PIV than other viruses. Diversity of virus pathogens giving spectrum of clinically indistinguishable illness. Frequ ency of co-circulating pathogens. Difficulties in culturing certain rhinoviruses and corona viruses. Relatively insensitive antigen detection assays and complement \201 xation tests used in serological diagnosis. Poor quality of diagnostic nasal samples and variable virus shedding reduces diagnostic yields. \200 \200 Seasonality of respiratory viruses \200 Respiratory viruses exhibit seasonal patterns, but noso- comial outbreaks can occur year-ro und. In temperate areas, enveloped viruses including in \202 uenza and RSV circulate durin g winter, whereas rhinoviruses predominate in spring and summer. Advances in molecular diagnostics permit rapid, speci \201 c and sensitive detection of re spiratory viruses although these tests remain mainly a research tool. CHAPTER 8.6 Viral infections of the respiratory tract 185 Reduced ventilation, indoor crowding, and improved survival of aerosolised virus at lower t emperature and higher humidity have been suggested as factors that con- tribute to seasonal ity of winter outbreaks. In a study of rhinovirus-infected elderly patients attend- ing day care in the US, the majo rity had evidence of lower tract involvement including sputum (58%), crack- les (48%) and d yspnoea (36%). In \202 uenza A and B \200 Transmission of respiratory viruses \200 In \202 uenza A is characterized by an unproductive cough, nasal discharge, stuf \201 nes s and sore throat. Fever is prom- inent peaking at the time of systemic features and lastin g for 1 \200\2235 days. Up to 80% of infected patients develop systemic features including myalgia, chills, headache, and malaise. Influenza B predominates every 3 \200\2235 years, t ypically produces a milder infection than H3N2 but may impose a signi \201 cant burden on school-age children. Transmission to a susceptible individual can occur as a result of virus-laden large droplet s or small particle aer- osols generated by an infected person during sneezing and coughing . Nosocomial transmission is often due to direct contact with the virus itself either by ha nd-to-hand contact, or transfer from contaminated fomites. Pathogenesis of respiratory virus infection The extent of virus shedding generally correlat es with dis- ease severity, although in the immunocompromised and children, prolonged shedd ing may continue after recovery. \200 Generally, infection begins in the upper tracheobro nchial respiratory tract then spreads down the airways. Viral replication destroys the epit helium and induces cytokine release that contributes to clinical symptoms, in addition to a iding viral clearance. Typically, rhinovirus and coronavirus are limited to upper airways, whereas in \202 uenza, RSV, PIV and adenovirus are capable of lower respiratory tract infe ction. SARS targets pneumocytes causing extensive and diffuse alveolar damage in the lower airways. Virus infection of the respiratory tract may alter bacte- rial \202 ora, increas e bacterial adherence to epithelial cells and disrupt mucociliary clearance leading to seco ndary bacterial invasion. The spread of highly pathogenic avian in \202 uenza H5N1 in poul try has been associated with >380 human cases worldwide. The determinants that confer virul ence of highly pathogenic in \202 uenza viruses are unclear, but the ease with which the H 5 haemagglutinin is cleaved is a major factor. Induction of excessive inflammatory response s (so called cytokine storm) exacerbates and sustains tissue injury. RSV \200 RSV is a well known cause of lower respiratory tract disease among children in early life. As bronchiolitis progresses, tachypnoea, intercostal recession and cough are prominent feat ures. In adults, fever is generally lower than seen in in \202 uenza but RSV is more frequ ently accompanied by wheeze and crackles on examination. RSV and PIV display the greatest m orbidity in the immuno-compromised, partic- ularly among bone marrow transplant recipients, and are associated with high fever, cough and lower respiratory symptoms. Adenovirus \200 In young military recruits, adenoviruses have been identi \201 ed as dominant pathogens af fecting up to 80% of new recruits within months of residence in camps. Adenovirus infection is more frequently associated with fever and conjunctivitis, than other pathogens. Avian in \202 uenza \200 Human H5N1 infections generally occur in younger adults or children exposed to infected pou ltry. Unlike human in \202 uenza viruses which bind predomi- nantly to upper airway epithe lial cells, avian in \202 uenza viruses are capable of binding to cells that are present d eep in the lung tissue. Case-fatality rates in H5N1 infection exceed 60%. Infection is asso ciated with high fever, bilateral lung in \201 ltrates and rapid progression to respirator y failure. Gastrointestinal symptoms are prominent. Lymphopenia and thrombocytopenia are po or prognostic indicators. Clinical features of respiratory virus infection In \202 uenza has been associated with th e most severe illness, but as diagnostic techniques improve, other viruses have been shown to cause clinically indistinguishable disease. Respiratory virus infections may be subclini cal or cause symptoms ranging from mild upper respiratory illness to life-threatening pneum onia. Infections cause overlapping syndromes that correspond to the site of infection. \200 \200 \200 SARS \200 Severe multilobar pneumonia is frequent with 25% of symptomatic patients, particularly olde r persons, requiring ICU support. Diarrhea and vomiting are prominent features. Clinical fi ndings are non-specific including wheeze, crackles, and bronchial breath sounds over the in volved lungs. Prolonged virus shedding and high infectivity of secre- tions after presentat ion require good infection control to prevent extensive nosocomial transmission. Upper respiratory tract: low-grade fever, nasal conges- tion and discharge, otitis media an d sinusitis. Laryngopharyngitis: sore throat and hoarseness. Tracheobronchitis: wheeze, cou gh, dyspnoea, substernal chest pain and sputum production. Lower respiratory tract: exacerb ations of airways disease, pleuritic chest pain, productive cough and crack- les on auscult ation. \200 \200 Clinical characteristics of common respiratory viruses Rhinovirus and coronavirus \200 Pulmonary complications of respiratory viruses A chest radiograph should be obtained in all patients with suspected pneumonia for evidence of cavitations, effusion Prominent symptoms of the \200\230common cold \200\231 syndrome in healthy adults include sore throat, stuffy nose, sneezing and malaise. M PAREEK & I STEPHENSON 186 and consolidation. The presence of unilateral, bilateral or multilobe changes may be helpfu l in clinical management although radiological appearance does not allow differen- tiation between pathogens. \200 patients where RSV, PIV, rhinovirus, and adenovirus have been detected. Secondary bacterial pneumonia \200 Some in \202 uenza patients in 1918 seemed to develop pul- monary bacterial complications after apparent resolu- tion of the in \202 uenza illness. In these \200\230delayed \200 \231 cases of pneumonia, a marked exudative broncho-pneumonia is the prominent post-mortem feature. Studies during pandemics indicate that one or more bac- terial pathogens including pneumococci, haemolytic streptococci, Haemophilus in \202 uenzae, and staphylococci are r ecovered from blood or respiratory secretions. Overall, Staphylococcus aureus has been iden ti \201 ed in the majority of bacterial pneumonias complicating proven in \202 uenza infe ctions. Staphyloccocus aureus, Streptococcus pneumoniae and Haemophilus in \202 uenzae hav e been frequently cultured in blood or sputum from hospitalized elderly patients with in \202 uenza and rhinovirus infection. Nursing home outbreaks of parain \202 uenza 1 have be en associated with pneumococcal pneumonia and bacter- aemia in up to 20% patients. A review of in \202 uenza-related pediatric deaths in the US during 2003/04 identi \201 ed 153 fa tal cases. The median age was 3 years and the majority of children were previously healthy. Around 30% deaths occurred within 3 days of onset of symptoms. Methicillin-susceptible and resistant Staphylococcus aureus were identi \201 ed in 24% of the cases. Host factors in \202 uencing the incidence and outcome of respiratory virus-associated pne umonia include age, pre- infection immunity, and presence of chronic medical conditions as well as properties of the infecting virus. The interval between onset of symptoms and signs of pneumonia is variable. Two major patterns of pneumonia are recognized: primary viral an d secondary bacterial pneumonia. Pneumonia is usually accompanied by fever, cough, dyspnoea , substernal and pleuritic chest pain. Viral pneumonia is generally considered to be radiol ogi- cally and clinically indistinguishable from bacterial infections. 3000 n o i t a l u p o p 2500 1918 pandemic 1916 epidemic 2000 0 0 0 0 0 1 1500 r e p Control of respiratory viruses Speci \201 c vaccination The diversity of respiratory virus es and frequency of anti- genic drift makes vaccine preparation for respiratory viruses cha llenging. \200 e t a r 1000 y t i l a t r o M 500 Inactivated in \202 uenza vaccines contain haemagglutinin from two A (H1N1 and H3N2) subty pes and one B strain. Protective ef \201 cacy of 70 \200\22395% in healthy adults is obtai ned when there is a good match between the vaccine and circulating strains. Vaccine ef \201 cacy is reduced in the elderly, but is still associated with 19 \200\22363% reduc- tio ns in hospitalization for pneumonia and in \202 uenza, and 17 \200\22339% reductions for a ll respiratory conditions As outbreaks of in \202 uenza occur in well immunized eld- erly subjects, enhanced vaccine effectiveness by adjuvan- tation, improved formulation or altern ative routes of delivery are under evaluation. Several inactivated RSV vaccine candidates c ontaining subunit proteins or peptide fragments, and chimeric proteins are in stages of cli nical development. Live attenuated virus vaccines delivered intransally may offer potential advantages over injectable preparations. Mucosal IgA may give broader immunological protec tion at the site of entry and reduce the peak and duration of virus shedding. However, as i ndividuals acquire partial immunity throughout life by frequent exposure to respi- ratory v iruses, replication of live attenuated virus vac- cines in adults may be limited reducing i nduction of desired local and humoral immune responses. Live attenuated parain \202 uenza virus vaccines are immu- nogenic in seronegative children, but induce limited responses amo ng seropositive recipients. Highly ef \201 cacious live attenuated adenovirus vaccines use d in military camps virtually eliminated outbreaks; however withdrawal of vaccine due to co mmercial 0 70 80 90 10 20 30 40 50 60 Age (years) Fig. 8.6.1 Age-speci \201 c pneumonia and in \202 uenza mortality, 1916 and 1918. Viral pneumonia \200 During the 1918 Spanish H1N1 pandemic, the incidence of pneumonia and mortality was unusual ly high in those aged 20 \200\22340 years compared to earlier in \202 uenza epi- demic yea rs (Fig. 8.6.1). Clinical and post-mortem descriptions of in \202 uenza virus pneumonia ha ve followed pandemic outbreaks. In the 1918 in \202 uenza pandemic, pneumonia was frequent ly reported in patients at onset of, or within 1 \200\2232 days of symptoms. In these patie nts, post-mortem \201 ndings were consistent with viral pneumonia with no lung consolida- tion and histological evidence of tracheitis, bronchitis, bronchiolitis, and intra-alveola r hemorrhage. During the 1957 Asian H2N2 pandemic, the onset of ill- ness in fatal cases wa s also typically abrupt, often with rapid deterioration in younger patients. In \202 uenza could be cultured from post-mortem lung tissue in 75% cases. Respiratory virus outbreaks a mong bone marrow trans- plant recipients are associated with extremely high mor- tality. Hi stological changes in bronchial biopsies at post-mortem are consistent with viral pneumonia in CHAPTER 8.6 Viral infections of the respiratory tract 187 reasons resulted in re-emergence of the virus in this high-risk population. 12 Speci \201 c antiviral therapy \200 10 Two classes of drug are available for in \202 uenza: M2 inhibi- tors (amantadine) and neur aminidase inhibitors, (zanamivir and oseltamivir). Amantadine use is limited by inactivity against in \202 uenza B, adverse effects and rapid emergence of drug resistance. In acute in \202 uenza in children and adults, treatment with neuraminidase inhibitors shortens the duration of symp- toms and the time to return to normal daily activities by 1.5 days (30%) and reduces antibiotic use when compared with placebo. Meta-analysis of placebo-controlled trials of oseltamivir for acute community-acquired in \202 uenza in adults shows signi \201 cant reductions in lower respiratory tract compli- cations and hospitalisations includ ing among those aged >65 years (Fig. 8.6.2). Ribavirin inhibits RSV replication by blocking transcrip- tion. Prompt therapy with inhaled ribavirin in RSV-infected bone marrow transpl ant recipients may reduce progres- sion to pneumonia and improve outcome, however, its ef \201 cacy in established RSV disease is questionable. Passive immunization against RSV can be achieved with polyclonal or monoclonal antibodies. Palivizumab is a humanized mouse mono clonal IgG, directed against the virus F surface protein, that blocks virus-induced cell fu sion and has neutralizing activity against RSV A and B. Monthly palivizumab infusions dur- ing the winter seasons are effective in the prevention of severe RSV disease in high-risk c hildren. RSV fusion and replication inhibitors are under develop- ment to reduce progressio n to lower respiratory disease in children Picornavirus capsid binders have broad in vitro antirhino- viral activity by blocking virus attachment and uncoating. However clinical tria ls produced only modest improve- ments in symptom relief. 8 Placebo Oseltamivir ) % ( s t n e i t a P 6 4 2 0 s n o i t a s i l a t i p s o H s n o i t a s i l a t i p s o H s n o i t a c i l s t c e b u s l l a s r y 5 6 > T R L j p m o c Fig. 8.6.2 Impact of oseltamivir on lower respiratory tract (LRT) complications and hospita lisations in in \202 uenza Further reading Bhat N et al. In \202 uenza-associated deaths among children in the United States, 2003 \200\2232004. NEJM 2005; 353: 2559 \200\2232567. Falsey AR et al. The \200\230common cold \200\231 in frail older persons: impact of rhinov irus and coronavirus in a senior daycare center. J Am Ger Soc 1997; 45: 706 \200\223711. Human In \202 uenza. In: Textbook of In \202 uenza KG Nicholson (ed.), Oxford: Blackwell, 1998. Johnston SL, Papadopoulos NG (eds) Respiratory Infections in Allergy and Asthma, Marcel Dekker, 2003. Kaiser L et al. Impact of oseltamivir treatment on in \202 uenza-related lower respiratory tract complications and hospitalizations Arch Intern Med 2003: 163: 1667 \200\2231674. Nicholson KG et al. Acute viral infections of upper respiratory tract in elderly people liv ing in the community. BMJ 1997; 315: 1060 \200\2231064. AUTHOR \200\231S TIP Antibiotic therapy Bacterial complications of influenza and respiratory viruses include bro nchopneumonia, bacteraemia and sepsis. Antibiotic selection should include anti-staphyloc- cocal and pneumococcal activity P ORMEROD 188 8.7 Respiratory tuberculosis Epidemiology World-wide there are approximately 9 million new clinical cases of tuberculosi s (TB), with1.8 million deaths each year, and 32% of the world population is infected with TB as judged by a positive tuberculin test. HIV co-infection is increasingly linked to TB, particularly in sub-Saharan Africa but now also with rising frequency in South Asia and Chi na. In developed countries TB increasingly is a disease of the overseas born. In England an d Wales in 2007, of the 8417 cases seen, less than 22% were in the white ethnic group, wher eas over 72% were in persons born abroad, with the majority of cases being in those of Sout h-Asian, Black- African, or Chinese ethnic origins. The rate for those UK- born (including ethnic minority groups) was 4.4/100000pa, for those born abroad 103.3/100000pa. The rate in the Black-African population born abroad at 309/100000pa, was ten times higher that that f or the UK-born Black- African, and the rates is the South-Asian group were 6 times higher i n the non-UK born. Only a minority of cases occur within 1 \200\2232 years of initial entry , when the high- est rates are found. Second and third generation immi- grants still have h igher rates than native born white persons. In the white population, over half the cases ar e in the over 55s representing reactivation of disease acquired earlier in life. Rates rang e from 1/100,000pa at age 0 \200\22315 to >15/100,000 in the over 80 \200\231s with males h aving higher rates in the white population. In older white persons it is thought that the s ubstant ial majority of cases are due to reactiva- tion of disease acquired in childhood or adolescence when TB was much commoner in the UK. Tuberculin testing should be performed for suspected TB pleural effusion and isolated media stinal lymphaden- opathy. Chest radiography No X-ray pattern is absolutely diagnostic of TB, but some patterns are ve ry suggestive, but still can be mimicked by other diseases. There is a strong predeliction for the upper zones, particularly the posterior segments. Disease in the lower lobes is usu ally in the apical segments. The shadowing initially is an in \201 ltrate, which can then become con \202 uent with cavitation and loss of volume developing. In association with HI V-infection the pattern becomes increasing less typi- cal as immunosuppression progresses. Clinical approach Suspicion of respiratory TB is a synthesis of 3 elements: a) the clinical setting (for which a knowledge of the above epidemiology is important), b) symptoms, and c ) CXR appearances (see later). Of the common respiratory symptoms, cough, weight loss, feve r, night sweats, breath- lessness and haemoptysis, only fever and night sweats are statisti cally more associated with TB than other respiratory conditions. Fig. 8.7.1 CXR: in \201 ltration and cavitation left upper lobe 5 \200\2238% of respirator y TB presents as a pleural effusion. This is associated with a strongly positive tuberculin test and the \202 uid is a lymphoc yte rich exudate. It is usually within 3 \200\22312 months of primary infection. Pleural bi opsy gives gran- ulomas in 50 \200\22360% of cases and 50 \200\22360% are culture positive. Examination \200 Unless there is extensive lung involvement, or a signi \201 - cant pleural effusion there are seldom signs in the lung. General examination may show evidence of TB at other sites, p articularly cervical lymphadenopathy. Investigation \200 CXR de \201 nes extent and the clinical pattern raises suspi- cion (see later). Bacteriolo gy is crucial both to con \201 rm the diagnosis and to obtain drug susceptibility testing. Three early morning sputums should be sent for TB microscopy and culture if the patient is expectorating. If no spontaneous sputum is produced consider induced sputum, or preferably bronchoscopy with washings tar- geted to the areas of X-ray abnormality (with appropriate infection control measures). Blood tests may be normal and only give non-speci \201 c abno rmalities. Tuberculin testing is usually unhelpful in pulmonary TB as it does not different iate between disease and infec- tion, and may be falsely negative due to illness or co- mor bidities e.g. HIV co-infection. Fig. 8.7.2 CXR: right pleural effusion. 5 \200\2238% of respiratory TB presents as isolated mediastinal lym- phadenopathy, associat ed with a strongly positive tuberculin test. CT scan may show lymphadenopathy with central CHAPTER 8.7 Respiratory tuberculosis 189 Commencing treatment \200 hypodensity (caseation). Mediastinoscopy is only needed if either the tuberculin test is we ak or negative (to exclude lym- phoma or sarcoidosis) or if there is not some reduction in gland size after 2 months standard treatment. If sputum or respiratory secretions are microscopy posi- tive, or the probablility of TB is high after samples have been sent, TB treatment should be commenced. Treatment should be w ith rifampicin, isoniazid, pyrazina- mide and ethambutol as Rifater plus ethambutol 15mg / kg (to the nearest 100mg), unless there is signi \201 cant renal impairment. Pyridoxine (10mg) is not routinely required unless there are risk factors for peripheral neuropathy \200\223 e.g. diabetes, alcoholism, malnutrition or HIV-positivity. U&Es and LFTs should be checked pre-treatment, to con \201 rm normal renal function and give a base-line for LFTs Visual acuity using Snellen chart should be checked, full ophthalmolgical assessment is no t necessary. Patients starting on TB treatment should be noti \201 ed to the Consultant in Communicable Disease Control. Consideration should be given to named HIV-testing to \201 nd/exclude co-existent HIV infection. Material sent to the lab should be screened by auram ine stain and cultured using rapid liquid culture. An assessment of likely adherence with t reatment should be made before starting treatment and consideration given to Directly Obser ved Treatment (DOT) with a three times weekly regimen. Isoniazid 15mg/kg, rifampicin 600 \200\223900mg, pyrazinamide 2.0 \200\2232.5gm, and ethambutol 30mg/kg should be given thric e weekly, most conveniently Monday, Wednesday and Friday under direct observation if this i s used. A risk assessment for drug resistance should be made, particularly if there is any prior treatment history, and a rifampicin resistance probe requested on any micros- copy or culture-positive material if concern exists. Adherence to medication should be monitored a t least monthly with pill counts and random urine tests for rifampicin. If a large contact tracing exercise is likely e.g. in a school or a hospital or care facility con \201 rm tha t the organisms seen/isolated is M.tuberculosis by appropriate gene probe before embarking on the contact tracing (with attendant publicity). Fig. 8.7.3 CXR: right paratracheal lymphadenopathy. Classical miliary TB occurs in a few % of cases. The full X-ray picture is easy to spot, wi th homogenous micro-nodules of 1 \200\2232mm spread throughout all lung zones. The early st ages are more subtle and are best seen on HRCT scans. The diag- nosis is usually easily con \201 rmed with positive cultures, and often scanty-positive microscopy positive bronchial washings \200 A lumbar puncture and CT scan should be carried out in classical miliary T B even in the absence of symptoms. 30% of such cases will have either LP or CT abnormali- t ies, showing CNS involvement. Such CNS involvement then needs a 12-month regimen and cortic osteroid treatment (see Chapter 8.8). Treatment in special situations \200 \200 Diabetes \200\223 standard treatment plus pyridoxine. Pregnancy \200\223 standard treatme nt, only streptomycin and prothionamide to be avoided. Liver disease \200\223 standard tre atment but regular LFTs \200\223 weekly \201 rst 2 weeks, then 2-weekly. Renal disease \200\223 rifampicin, isoniazid and pyrazinamide in standard dosages. Reduced dosages of eth ambutol or streptomycin. Moxi \202 oxacin 400mg od is an acceptable alternative. HIV-posit ive. TB takes precedence. Standard treat ment, adjust HAART if necessary to avoid rifampici n interac- tions. Fig. 8.7.4 CXR: classical miliary TB. AUTHOR \200\231S TIPS \200 Infection control \200 In ethnic minority groups, pleural effusion or isolated mediastinal glands with a positive tuberculin test, should be treated as TB until proved otherwise. Cavititation is active TB is highly (>0.00001) correlated with sputum microscopy positivity for AFB. If 3 sponta- neo us sputum tests are negative for AFB, the diagnosis of TB should be reconsidered. Suspected respiratory TB if admitted should be to a single side ward until results of 3 spu tums known. Sputum microscopy cases remain infectious until 2 weeks standard treatment. Mas ks are only needed for suspected or proven MDR-TB cases. P ORMEROD 190 resistance is M.bovis. Pyrazinamide should stopped and treatment should be with 2 months ri fampicin, isoniazid and ethmabutol, followed by a continuation phase of rifampicin and ison iazisd for 7 months. Ethambutol: ethambutol mono-resistance is very uncom- mon. It does not affect the ef \201 cacy of standard 6-months short course chemotherapy which should be co ntinued. Rifampicin: Isolated rifampicin resistance is uncommon, accounting for only 5 \200 \22310% of rifampicin resistance. The \201 nding of rifampicin resistance, particularly o n a gene- probe, SHOULD BE TREATED AS MDR-TB, with the patient isolated as for, and treated for MDR-TB until proved otherwise. If rifampicin monoresistance is con \201 rmed on full suscep- tibility tests then a regimen of 18 months isoniazid and ethambutol, supplemented b y an initial 2 months pyrazi- namide should be used. Suspected or proven MDR-TB should be in a negative pressure room if in hospital. NICE Guide lines and JTC 2000 guidance give criteria for cessation of respiratory isolation. During treatment \200 