Tài liệu PULMONARY TUBERCULOSIS IN ADULTS doc

SECTION 5 CLINICAL PRESENTATIONS OF TUBERCULOSIS CHAPTER 29 Pulmonary tuberculosis in adults Christopher J Hoffmann and Gavin J Churchyard BACKGROUND The World Health Organization (WHO) defines pulmonary tuber culosis (TB) as tuberculous disease that involves the lung paren chyma. Tuberculosis involving the trachea is often also included in the definition. Extrapulmonary TB is disease involving any part of the body other than lung parenchyma including other structures within the thorax such as the pleura, pericardium and perihilar lymph nodes. This distinction is most important from a public health per spective because patients with untreated pulmonary TB pose an infectious risk to the rest of the community, whereas the risk to the community from extrapulmonary TB is minimal. Thus patients with pulmonary TB who also have extrapulmonary involvement are clas sified as cases of pulmonary TB by the WHO. In addition to classification by location, TB has traditionally been classified as primary or postprimary disease. Primary infection includes the symptoms and complications arising from the first con tact between host and the bacillus and is most clearly defined by conversion from a negative to a positive tuberculin skin test (TST). In the minority, the primary complex results in local progression or distant disease; in the majority, the complex resolves. Postprimary TB disease usually follows the primary infection by years, occurring through reactivation or reinfection. Other nearly synonymous terms with postprimary TB include reactivation TB, recrudescent TB, endogenous reinfection and adult type progressive TB. In years past, primary TB was considered a disease of children and post primary TB a disease of adults. In the era of human immunodefi ciency virus (HIV) distinctions between primary and postprimary TB have become increasingly blurred as primary TB is often seen in HIV infected adults. This chapter focuses on the clinical presentation of pulmonary TB and its complications. The classic presentation of primary and postprimary pulmonary TB among HIV uninfected adults and the atypical presentations of pulmonary TB associated with HIV and other immunosuppressive diseases and drugs are described along with the differential diagnoses. The impact of active TB case finding on clinical presentation and its public health impor tance is also included. EPIDEMIOLOGY A basic understanding of the epidemiology of pulmonary TB is useful for estimating a patient’s or a population’s risk for pulmonary TB. This is especially important when determining the most likely aetiologies in building a differential diagnosis. In 2004, an estimated 9 million people had new TB diseases and 2 million deaths were attributable to TB (see Chapter 3). Most new diseases and deaths occurred in Asia and Africa, where 80% of all cases of TB occur. 1 Of the 9 million new cases, three quarters were pulmonary TB. 2 Multiple factors have contributed to the surge in TB that began during the late 1980s and 1990s; immunosuppression from HIV is the most dramatic. However, the impact of HIV on pulmonary TB epidemiology is complex. HIV contributes to pulmonary TB epidemiolog y in fou r impor tant ways. Firstly, HIV associated immunosuppression increases the risk of tuberculous disease, either from reactivation or from progression of primary infection. Approximately 3–5% of adults with intact immune systems develop TB disease w ithin a year of initial infec tion; subsequent lifetime risk of reactivation is 3–5%. 3 Among HIV inf ected individuals, nearly two thirds develop symptomatic TB disease within the first few months of infection. 4 As a result, a disproportionate number of HIV infected individuals are diagnosed with pulmonary TB. 1 Secondly, individuals with HIV are at higher risk than HIV uninfected individuals for recurrence of pulmonary TB from exog enous infection. 5 Thus, regions with both high HIV prevalence and pulmonary TB incidence have a high proportion of the popu lation highly susceptible to recurrence. Thirdly, HIV coinfection accelerates progression of pulmonary TB. As a result, HIV infected individuals typically progress to death or diagnosis in a shorter time after developing pulmonary TB than HIV uninfected individuals. Several recent studies have estimated time to diagnosis by comparing incident pulmonary TB cases identified in clinics with prevalent pulmonary TB identified through community wide symptom and sputum screens. The esti mated duration of pulmonary TB before development of signifi cant symptoms ranges from 6 to 51 weeks among HIV infected individuals and from 38 to 60 weeks among HIV uninfected indi viduals. 6–8 Fourthly, HIV coinfection diminishes the infectiousness of pul monary TB. Although HIV leads to more rapid progression of pulmonary TB, the burden of TB bacilli in the lungs is lower among HIV infected individu als, leading to a lower rate of sputum smear positivity. 9,10 Among acquired immunodeficiency syndrome (AIDS) patients with pulmonary TB, approximately 30–40% have smear negative disease compared with 20% smear negative pulmona ry TB among th ose uninfe cted with H IV. 11 Smear negative pulmonary TB is 10 fold less transmissible than 332 ELSEVIER smear positive disease. Possibly as a result, contacts of HIV infected people with pulmon ary T B are slightly less likely to become infected with TB. 12–16 Understanding these differences is important from clinical and public health standpoints. The implication of a much longer period of contagiousness of an HIV uninfected person with pulmonary TB than an HIV infected individual is increased opportunity for the HIV uninfected individual to transmit infection. Other conditions that increase the risk of pulmonary TB include silicosis, diabetes, haemodialysis, malnutrition, smoking, underlying lung disease, diseases affecting the immune system and immuno suppressive medications. 17,18 Silicosis increases pulmonary TB risk three to fivefold. 19 Diabetes mellitus, especially insulin dependent diabetes, increases the risk of TB approximately two to three fold. 20 Immunosuppression increases risk based on the therapy and the dose. Tumour necrosis factor alpha (TNF a) antagonists such as infliximab and etanercept are most strongly associated with TB disease. The principal mechanism of active disease among patients receiving these medications is believed to be from reactiva tion of latent foci. Because of this risk, TST is recommended prior to initiation of anti TNF a therapy. Crowded conditions such as those found in dormitories, nursing homes, prisons, naval vessels and healthcare centres also increase transmission risk. 21 PATHOPH YSIOLOGY In order to understand the differences in clinical presentation of primary and postprimary TB a brief outline of the pathophysiology of TB infection and disease is required. Tuberculosis bacilli are aerosolized during coughing, sneezing and singing. Once bacilli laden nuclei are aerosolized they can remain suspended for hours, presenting an infection risk long after a person with TB has left an indoor space. Bacilli degrade rapidly in outdoor environments because ultraviolet light from sunlight destroys the bacilli. When inhaled, small droplet nuclei, ranging from 1 to 5 mm in diameter and containing 1–10 bacilli, enter the lung, avoid being trapped in the lining of the upper respiratory tract and travel to distal alveoli. The well aerated regions close to the pleura in the lower lung fields are the most common place for the bacilli containing droplets to settle. 22 After lodging in the alveoli, non activated alve olar macrophages ingest the bacilli in an attempt to destroy them. It is believed that at least 5–200 bacilli are necessary to overcome the macrophage response and cause infection. These bacilli then multi ply within macrophages and establish a focus of primary TB. This occurs in approximately one third of individuals with robust immune systems. As the quantity of bacilli increases, inflammation develops, forming a collection of bacilli, macrophages, lympho cytes and debris known as the Ghon focus. During early mycobac terial replication, the burden of bacilli in the Ghon focus is insufficient to trigger a systemic immune response. As the burden of bacilli grows, additional activated alveolar macrophages and T lymphocytes are recruited to this site and a systemic response is activated. Bacilli are also trafficked from the Ghon focus to the mediastinal and perihilar lymph nodes either within macrophages or along lymphatic channels and may become haematogenously distributed, developing foci of replication in regions with high oxygen tension: the meninges, epiphyses of long bones, kidneys, vertebral bones, lymph nodes and apicoposterior areas of the lungs. At the time that activated macrophages and lymphocytes are recruited, symptoms may become pronounced and conversion to a positive TST occurs. For most individuals the systemic immune response is sufficient to control further growth of bacilli. The orig inal Ghon focus and associated perihilar lymph node infection (known as the Ranke complex) are often eradicated within months of infection, whereas disseminated foci become walled off by gran ulomatous inflammation, which occasionally harbour viable bacilli. When the disseminated focus is in the lung apex, the site is known as Simon’s focus. Simon’s focus is usually the nidus of reactivation in postprimary pulmonary TB. SYMPTOMS AND SIGNS PRIMARY PULMONARY TUBE RCULOSIS Primary TB infection may be asymptomatic, cause fevers and pleuritic pain o r, rarely, progress to life threaten ing disease. Dur ing the primary pulmonary infection, symptoms may occur as the burden o f bacilli increases and the host mounts a systemic immune response. Fever is the most common symptom. A study conducted prior to the HIV pandemic reported fever among 70% of individuals with p rimary TB, often several weeks after expo sure, that lasted a median of 2–3 weeks, but much longer among some patients. 23 The fever onset is usually gradual and is not usu ally accompa nied by other symptoms, although some patients develop pleuritic or retrosternal pain. Cough, arthralgias and fatigue occur rarely. While haematogenous seeding of dist ant sites is common, rarely does it cause symptomatic disease among indi viduals with intact immune systems. The most common extrapul monary manifestations, when they occur, are lymphadenitis and meningitis. On examination, a patient with primary pulmonary TB may have erythema nodosum, bluish red tender subcutaneous nodules several millimetres to several centimetres in diameter appearing on the legs, and phlyctenular conjunctivitis, hard raised red 1 to 3 mm nodules accompanied by a zone of hyperaemia located near the limbus on the bulbar conjunctiva of the eye. Both conditions are an immune phenomenon seen in primary TB and other infectious and non infectious diseases and do not contain bacilli. After the initial inflammation, 90% of individuals with intact immunity control further replication of the bacilli. The remaining individuals either develop TB pneumonia with expansion of infil trates at the site of the initial seeding or near the hilum (Fig. 29.1) and hilar lymphadenopathy or develop disease at more distant sites, most commonly cervical lymph nodes, meninges, pericardium or miliary dissemination. Among individuals with weakened immune response, including advanced age, HIV, kidney failure and poorly controlled diabetes mellitus, progression to disseminated or local disease occurs more frequently. POSTPRIMARY PULMONARY TUBERCULOSIS Postprimary pulmonary TB refers to all pulmonary TB resulting from reactivation of controlled (latent) infection, late progression of primary infection or exogenous reinfection. The contribution of any one of these mechanisms to the total number of postprimary TB cases depends on the local prevalence and the susceptibility of the individuals in the community to TB. In the past it was believed that 90% of TB among adults was a result of reactivation. 24 More recent studies have suggested large population dependent varia tions in the ratio of reinfection to reactivation. 25 333 CHAPTER 29Pulmonary tuberculosis in adults ELSEVIER Classic presentation of postprimary pulmonary tuberculosis The classic presentation of postprimary pulmonary TB is character ized by weeks to months of chronic cough (chronic usually refer ring to either > 2 or 3 weeks), weight loss, fatigue, fevers, night sweats and haemoptysis. 26 Fever in postprimary TB is classically diurnal with an afebrile period early in the morning and a gradually rising temperature throughout the day, and a fever peak in the late afternoon or evening. Nighttime defervescence is often accompa nied by diaphoresis leading to drenching night sweats. Both fever and night sweats are more common among patients with advanced pulmonary TB, often with significant parenchymal disease and cav itary lesions. Interestingly, the fraction of individua ls with pulmonary TB presenting for healthcare with these symptoms has remained remarkably consistent over multiple decades, continents and clin ical settings: cough occurs among 70–90%, weight loss among 43–75%, haemoptysis in 21–29%, fatigue or malaise among 58% and fever among 15–52%. 27–31 However, no single symptom or constellation of s ymptoms clea rly distinguishes patients who have pulmonaryTBfromthosewhodonot. Cough may be absent or subtle early in the disease course. A mild non productive cough commonly occurs initially in the morning and may be confused with a ‘smoker’s cough’ by a clini cian and ignored by the patient. The morning cough is a result of accumulation of secretions during the sleeping hours (a similar mech anism to the smoker’s cough). During disease progression, cough often becomes more continuous throughout the day and may become productive of yellow or yellow–green and occasionally blood streaked sputum. Nocturnal coughing is associated with advanced pulmonary disease, often with cavitations. Pleuritic pain may occur with coughing. Hoarseness of voice suggests laryngeal involvement (see below). Anorexia, wasting and malaise are common features of advanced disease and may be the only presenting features in some patients, especially among patients with extrapulmonary TB. The most salient clinical feature of TB is the chronic nature the disease can assume. Pulmonary TB may remain undiagnosed and infectious for 2–3 years, or even longer due to its indolent nature with symptoms only developing later in the course of the disease. 7 However, as symptoms correlate with extent of disease in patients with normal immune systems, symptomatic individuals are more likely to have smear positive sputum. 32 Given the potentially indo lent nature of the disease, patients with persistent or recurrent respiratory complaints over months to years should be aggressively evaluated for pulmonary TB, even if they describe resolution between episodes of illness, lack classic symptoms and have an unremarkable physical examination. Even after preliminary nega tive evaluations, repeat investigation for pulmonary TB is war ranted if no other diagnosis has been made. PHYSICAL EXAMINATION Physical examination of an individual with pulmonary TB is usu ally non specific. Classic findings are pallor, cachexia, tachycardia and post tussive crackles over affected lung. Because of the latter examination finding, it is useful to ask the patient to cough before auscultation of the lung fields. An additional pulmonary finding in advanced cases is a cavernous or ‘amphoric’ sound on lung auscul tation, so named because of a resemblance to the sound made when blowing across a Greek jug. ATYPICAL PRESENTATIONS Culture-negative pulmonary tuberculosis Some patients present with classic symptoms of pulmonary TB with chronic and progressive fever, cough and weight loss along with radiographic findings but do not have Mycobacterium tuberculo sis identified by sputum direct microscopy or culture. This may be a result of low mycobacterial burden, suboptimal sputum quality or improper sputum processing. Among a percentage of such patients, after extensive evaluation, often including fibreoptic bronchoscopy with lavage and biopsy and computed tomography of the chest and abdomen, no aetiology is identified. In some TB treatment pro grammes over 10% of patients fit this category. 33 These patients often are preliminarily diagnosed with culture negative TB and started on standard four drug TB treatment. Failure to respond clinically after 2 months of treatment places the diagnosis in question and should prompt a re evaluation of diagnosis and management; improvement in symptoms helps to confirm the diag nosis of culture negative TB. Patients with improvement in symp toms should have treatment completion per local TB guidelines. HIV Immunosuppression with advancing AIDS alters the presenting symptoms of pulmonary TB. Patients with advanced HIV are more likely to have progression of primary infection to persistent and often disseminated (miliary) disease and less likely to have typical symptoms. Fever may be more common among HIV coinfected patients while cough is less common. 34 Along with a lower pro portion with cough, more HIV infected individuals are sputum smear negative. In addition to fever, other non specific symptoms such as wasting and malaise are more common among individuals coinfected with HIV and pulmonary TB. AIDS patients with pul monary TB are more likely to also have extrapulmonary infection: 60% have extrapulmonary sites of infection compared with 28% of pulmonary TB patients without AIDS. 35 Fig. 29.1 Chest radiograph showing right hilar adenopathy from primary pulmonary TB. From Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005: Figure 31.16. 334 SECTION 5 CLINICAL PRESENTATIONS OF TUBERCULOSIS ELSEVIER Advanced age The presentation of infectious diseases is often atypical in older individuals, pulmonary TB included. Most notably older indivi duals (> 65 years old) are less likely to present with fevers, night sweats or haemoptysis and are more likely to present with the non specific findings of dyspnoea and fatigue. Because chronic lung dis ease is common in older populations, the diagnosis of pulmonary TB can easily be overlooked in a patient with chronic obstructive pulmonary disease (COPD) presenting with worsening dyspnoea and malaise. Furthermore, cavitary disease is less common and mul tilobar and lower lobe involvement more common. 36 Thus the presentation of pulmonary TB in the elderly can be similar to that of COPD or pyogenic bacterial pneumonia. However, the incidence of pulmonary TB is two to three times higher among the elderly, especially those in institutions such as old age homes, and the risk of death considerably higher. 37 Laryngeal tuberculosis Before the advent of effective chemotherapy for TB, laryngeal TB was considered a terminal event during the progression of pulmo nary TB, developing soon before death, and possibly occurring in over 50% of patients. In the era of effective chemotherapy, laryn geal TB has become rare (< 1% of TB cases). It can occur in iso lation or in association with pulmonary TB or extrapulmonary TB. The true vocal cords, epiglottis and false vocal cords are the most common sites of involvement. Symptoms almost always include dys phonia, which is often accompanied by cough, dysphagia, odyno phagia, stridor and haemoptysis. 38 Findings on laryngoscopy may be areas of hyperaemia, nodules, ulcerations or exophytic masses. Recurrent pulmonary tuberculosis Pulmonary TB should be more strongly suspected among patients who have been previously treated for TB disease as both relapse and new infection are more frequent. The specific frequency of recurrence depends on local disease prevalence and the effective ness of local TB treatment programmes. 25,39,40 HIV, other immu nodeficiency states and cavitary pulmonary disease further increase the risk of recurrent pulmonary TB, commonly due to reinfec tion. 25,41 Recurrent pulmonary TB may present with classic pul monary TB symptoms of fever, night sweats, weight loss, malaise and worsening chronic cough or atypical symptoms. However, the proportion of patients with recurrent pulmonary TB presenting with classic versus atypical symptoms has not been well described. Diagnosis is often complicated because pulmonary fibrosis and cav itary lesions from previous disease can obscure new infiltrates and complicate interpretation of chest radiographs. DIFFERENTIAL DIAGNOSIS Differential diagnoses for pulmonary TB are listed in Table 29.1. INVESTIGATIONS A major reason for misdiagnosis of pulmonary TB is the absence of typical symptoms or radiographic features. 42,43 Many patients with pulmonary TB lack fever, night sweats, chronic cough and wasting or have only one of these symptoms. Thus, in the right clinical and epidemiological setting, the absence of classic symptoms should not diminish the vigilance and aggressiveness of evaluation for pul monary TB. This problem is illustrated by a community wide cross sectional pulmonary TB prevalence study using sputum culture and clinical interviews, conducted in an area with very high TB prevalence. 44 Two or more of cough, night sweats, weight loss and anorexia were present among only 25% of previously Table 29.1 Differential diagnoses of tuberculosis Disease Characteristics Mycobacterium kansasii Mycobacterium kansasii disease may have a presentation similar to that of TB, especially among individuals with advanced AIDS (CD4 < 100 mm 3 ). A distinction is that M. kansasii is more likely to cause cavitary pulmonary disease when the CD4 count is very low. M. kansasii disease is uncommon with higher CD4 counts. Chest radiography may be similar and culture is often needed to distinguish between the two conditions. 75 Lung tumour Upper lobe tumours and pulmonary TB both can be associated with chronic cough, malaise and weight loss and can be radiographically indistinguishable. Biopsy may be needed to confirm a diagnosis. Pneumocystis jiroveci pneumonia (PCP) Opportunistic infection, which is very common among HIV-infected individuals with CD4 count < 200 mm 3 . Usually presents with hazy bilateral infiltrates, more rarely with nodules or small cavities. Nocardia spp. Opportunistic infection of compromised hosts including people with AIDS, immunosuppressive therapy and pulmonary alveolar proteinosis. Can present with chronic cough, fevers and night sweats. May be associated with central nervous system abscesses. Rhodococcus equi Opportunistic infection seen in advanced AIDS. May present with infiltrates, hilar lymphadenopathy or cavitary lesions or chest radiography. Patients most likely to acquire Rhodococcus infection have CD4 counts < 50 mm 3 . Kaposi’s sarcoma Common malignancy with advanced AIDS. Cutaneous lesions are often present when pulmonary disease develops. Radiographic findings are usually bilateral infiltrates spreading from hilum. Cryptococcus In advanced AIDS (CD4 < 100 mm 3 ) this is a common cause of meningitis. It can cause pulmonary infiltrates, nodules or cavitary disease, especially with advanced AIDS or immunosuppression from glucocorticoids or cancer chemotherapy. The serum cryptococcal antigen may be negative with localized pulmonary disease. 76 Salmonella Non-typhi species of Salmonella are common causes of bacteraemia with advanced AIDS (CD4 < 100 mm 3 ). In rare cases salmonella pneumonia develops, presenting with infiltrates or cavitary lung lesions. 77 Bacterial pneumonia Bacterial pneumonia can appear on chest radiography similar to pulmonary TB, especially if perihilar infiltrates or apical cavities are present. Evolution of disease over hours to days is more suggestive of a bacterial pneumonia caused by Streptococcus pneumoniae, Panton Valentine leucocidin-producing Staphylococcus aureus, Pseudomonas aeruginosa or Klebsiella pneumoniae. 335 CHAPTER 29Pulmonary tuberculosis in adults ELSEVIER undiagnosed pulmonary TB (prevalence cases). However, two or more of these symptoms were present among 22% of the population without pulmonary TB. Thus, in that study population, classic symptoms for pulmonary TB lacked both sensitivity and specificity. Another African study reported similar findings: 20% of individuals with pulmonary TB detected on a community survey were asymptomatic. 45 SPUTUM SMEAR AND CULTURE The diagnosis of pulmonary TB (especially postprimary disease) is usually based on sputum examination and, optimally, culture. Thus quality assurance of collection, handling and processing of sputum is essential. The first sputum sample should be collected at the time of evaluation when the diagnosis of TB is considered with, ideally, at least one more specimen collected early in the morning on subsequent days. See Chapter 18 for details on sputum smear and culture. LABORATORY INVESTIGATIONS Some patients with pulmonary TB are anaemic and have leucocy tosis. Normochromic, normocytic anaemia occurs most com monly. Tuberculosis also can cause a leukaemoid reaction with markedly elevated leucocyte counts (>50,000 cells/mm 3 ). How ever, normal or low leucocyte counts are also consistent with the diagnosis of pulmonary TB. Mild monocytosis or eosinophilia may also be observed. The erythrocyte sedimentation rate may be normal or increased. The platelet count, alkaline phosphatase, lactate dehydrogenase and ferritin may also be increased; however, these findings are not sensitive or specific for the diagnosis of pul monary TB. 28 TUBERCULIN SKIN TESTING The TST is a test of delayed type, cell mediated hypersensitivity to purified protein derivative. TST has substantial limitations that diminish its value in diagnosing pulmonary TB. The TST lacks sensitivity and specificity. Prior to the emergence of HIV, false negative TSTs among patients with pulmonary TB were well recognized and reported to occur in over 2% of patients. 46 Among patients with immunosuppression (HIV, renal dialysis, malignancy, immunosuppressive medications), false negative TSTs are much more common. 47 A positive TST may represent latent TB infec tion unrelated to illness being evaluated. In addition, exposure to environmental Mycobacteria spp. and Bacillus Calmette–Gue ´ rin vac cination can result in a false positive TST. CHEST RADIOGRAPHY In primary pulmonary TB, chest radiography is often normal. When present, typical pathological findings of primary pulmonary TB are hilar enlargement with or without perihilar infiltrate and pleural effusions (Figs 29.2 and 29.3). 48 In primary pulmonary TB 85% of infiltrates are in the mid to lower lung fields. In postprimary pulmonary TB most patients have abnormalities on chest radiography, even in the absence of respiratory symp toms. 27,49 Conversely the chest radiograph may be normal in a small fraction of symptomatic individuals, especially in the setting of HIV coinfection. Classic findings in postprimary pulmonary TB are alveolar infiltrates, interstitial infiltrates or cavitary lesions in the lung apex or upper zones of the lower lobes (Figs 29.4 and 29.5; Table 29.2). Effusions, lymphadenopathy, lower lung zone infiltrates and a miliary pattern (diffuse 2 to 3 mm nodules evenly distributed throughout the lung fields) are atypical (Fig. 29.6). Underlying lung diseases such as chronic obstructive pulmonary disease, silicosis and tumours of the lung can increase the risk for TB while making radiographic interpretation more difficult. Immunosuppression further complicates interpreting radiographs, especially when it is more profound. With HIV, at high CD4 counts, typical findings, including apical cavitary lesions, are common. HIV infected patients with more advanced immunodefi ciency (CD4 < 200 cells/mm 3 ) very rarely develop cavitary lesions from pulmonary TB and are much more likely to have the atypical findings of lymphadenopathy, effusions or mid and lower zone infiltrates. 50 When a patient with profound immunodeficiency Fig. 29.2 Chest radiograph showing a Ghon focus with hilar adenopathy and bilateral infiltrates. From Marx J, Hockberger R, Walls R (eds). Rosen’s Emergency Medicine: Concepts and Clinical Practice, 6th edn. St Louis: Mosby, 2006: Figure 133.3. Fig. 29.3 Primary TB effusion in a 26-year-old adult. Grainger RG, Allison DJ, Dixon AK (eds). Grainger amd Allison’s Diagnostic Radiology: A Textbook of Medical Imaging, 4th edn. Edinburgh: Churchill Livingstone, 2001: Figure 18.21. 336 SECTION 5 CLINICAL PRESENTATIONS OF TUBERCULOSIS ELSEVIER develops a cavitary lesion, the differential diagnosis should be broadened to include additional causative pathogens such as M. kansasii and Nocardia (Table 29.1). The limited accuracy of chest radiography is illustrated in a recent study from Kenya in which sputum culture results were compared with an experienced radiologist ’s interpretation of a chest radiograph. In that study, 13% of chest radiographs with no abnormal findings and 27% with findings not considered consistent with TB were from subjects with positive sputum culture. Of note, approximately half of subjects in that study who were tested were HIV infected. 51 TRIAL OF ANTIBIOTICS The administration of empiric antibiotics was previously used in situations when the sputum smear is negative and a chest radiograph either is equivocal or cannot be obtained to aid in differentiating pulmonary TB from bacterial pneumonia and was widely used in resource constrained settings. With this approach, symptomatic Fig. 29.4 Left hilar infiltrate in postprimary pulmonary TB. Cohen J, Powderly W (eds). Cohen & Powderly: Infectious Diseases, 2nd edn. St Louis: Mosby, 2003: Figure 31.16. Fig. 29.5 Upper lobe cavitary lesion typical of postprimary pulmonary TB. Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005: Figure 33.17. Fig. 29.6 Postprimary TB: miliary TB. Diffuse nodulation is present in all zones. Nodules are approximately 1 mm in diameter and well defined. Grainger RG, Allison DJ, Dixon AK (eds). Grainger and Allison’s Diagnostic Radiology: A Textbook of Medical Imaging, 4th edn. Edinburgh: Churchill Livingstone, 2001: Image 18. Table 29.2 Chest radiograph findings for patients with symptomatic pulmonary tuberculosis and approximate percentage of cases with a given finding based on HIV status or other immunodeficiency HIV( ) (%) HIV(þ) CD4 > 200 mm 3 (%) HIV(þ) CD4 < 200 mm 3 (%) HIV( ) immuno- compromised (%) Typical Upper lobe infiltrates 60 >50 20 10 30 Cavitation 30 66 30 10 20 Atypical Reticulonodular 2 5 5 10 10 30 Effusion 5 20 10 20 10 30 30 Adenopathy 2 15 5 15 20 30 15 Miliary 2 10 15 18 Normal 0 5 15 From studies of symptomatic patients presenting for healthcare. 31 50 51 78–80 337 CHAPTER 29Pulmonary tuberculosis in adults ELSEVIER patients with a negative sputum smear received a 5 to 10 day course of antibiotics for bacterial pneumonia (e.g. amoxicillin). Lack of response to antibiotics suggests a process other than pyogenic bacterial pneumonia, possibly pulmonary TB. However, response to antibiotics does not eliminate the possibility of pulmonary TB for two reasons: 1. symptoms of pulmonary TB may wax and wane; and 2. both bacterial pneumonia and pulmonary TB may be present at the same time. 52 Because of the frequency of coinfection with community acquired bacterial pathogens and M. tuberculosis, patients should be re evalu ated for pulmonary TB with repeat sputum examinations and culture even if they recover while taking empiric antibiotics. Although a clinical evaluation conducted in Guinea supported using empiric antibiotics, 53 as 8% of patients who responded to amoxicillin had pulmonary TB, and 94% of patients who did not respond either had a positive culture for mycobacterium or responded to TB ther apy despite a negative sputum culture. This approach is no longer advised by the WHO. Fluoroquinolones should not be used to treat presumptive bacterial pneumonia where TB is common because they have activity against M. tuberculosis and some other mycobacte rial species, potentially confounding the diagnosis of pulmonary TB and promoting fluoroquinolone resistant TB. 54,55 ACTIVE CASE FINDING AND SCREENING ALGORITHMS The WHO directly observed treatment, short course (DOTS) strategy is reliant on symptomatic individuals self presenting for healthcare, which is how most cases of pulmonary TB are currently diagnosed. However, the new Global Plan to Stop TB recom mends adding active case finding for TB in order to find cases ear lier and reduce transmission and morbidity and mortality from TB. 56 Active case finding involves symptom screens and, in some settings, chest radiography, sputum smear and culture as part of annual physical examinations, workplace screening, antenatal clinics and HIV care clinics, and at prison intake and release, school evaluations, HIV voluntary counselling and testing centres (VCT) and community TB surveillance programmes. However, pulmonary TB identified during active case finding activities is more likely to be asymptomatic or mildly symptomatic, below the threshold for seeking medical care, and more likely to have limited radiological disease and to be smear negative. This is true for both HIV infected and uninfected individuals. 6 Identification of these cases is also vital to controlling the spread of the disease. PATHOLOGY Gross pathology of pulmonary TB ischaracterized byareas ofcaseation with surrounding fibrosis. As areas of caseation enlarge and empty into patent bronchi, cavities may form (Fig. 29.7). A smear of contents of a cavity is typically laden with acid fast M. tuberculosis bacilli. MANAGEMENT CHEMOTHERAPY Three components of management need to be considered when pulmonary TB is diagnosed: 1. which anti TB chemotherapy regimen is appropriate; 2. how to assure adherence; and 3. how to monitor treatment success. Please refer to Chapter 62 for details on chemotherapy for TB. PROGNOSIS Patients with pulmonary TB who are adherent to therapy to which the bacilli are sensitive have an excellent chance of cure. Even patients with other underlying illnesses, such as AIDS, have equal rates of cure to HIV uninfected individuals. 57 However, such indi viduals cured of pulmonary TB are at higher risk for recurrence. In addition, permanent lung injury may occur, leading to decreased pulmonary function and risk for chronic lung disease. 58 COMPLICATIONS HAEMOPTYSIS Haemoptysis usually only occurs with advanced cavitary pulmo nary disease and is usually mild. The typical presentation is blood streaked sputum. Massive, sometimes fatal, haemorrhage is rare. When it occurs it is a result of erosion into a bronchial artery or rupture of an aneurysm (Rasmussen aneurysm) within the TB cavity. 59 Haemoptysis may also occur after completion of TB treat ment due to bronchiectasis, a mycetoma invading and colonizing a healed cavity or recurrence of TB disease itself. Medical manage ment is appropriate, even for major or massive haemoptysis, except in the cases of impending exsanguination which require immediate surgical care. Initial care includes bed rest, postural management, volume replacement, cough suppression and intravenous vasopres sin. When medical management fails (25–50% of patients after 24 hours), options include surgical ligation of arteries, resection of a lung lobe, endobronchial tamponade and bronchial artery emboli zation. Both ligation and embolization can be complex because of the frequent presence of multiple feeder arteries often connecting systemic with bronchial circulation. 60–62 Careful identification and ligation or embolization of feeder arteries is required to reduce the chance of recurrent haemoptysis. Fig. 29.7 Gross pathology showing lungs with postprimary pulmonary TB. The upper parts of both lungs are riddled with grey white areas of caseation and multiple areas of softening and cavitation. Kumar V, Abbas AK, Fausto N (eds). Robbins and Cotran: Pathologic Basis of Disease, 7th edn. Philadelphia: WB Saunders, 2004: Figure 8.32. 338 SECTION 5 CLINICAL PRESENTATIONS OF TUBERCULOSIS ELSEVIER PNEUMOTHORAX Pneumothorax is a rare complication of pulmonary TB in the era of TB therapy. A case series from Turkey reported pneu mothoraces in 1.5% of cases of pulmonary TB. 31 However, in set tings with high TB prevalence, pulmonary TB is a leading cause of secondary pneumothorax. 63 The pneumothorax can be associated with active or inactive pulmonary TB. RIGHT MIDDLE LOBE SYNDROME The rare occurrence of atelectasis of the right middle lobe occurs when bulky perihilar lymphadenopathy compresses the middle lobe bronchus, leading to collapse of its feeding lung. Initial management should focus on therapy for TB. Persistence of lymphadenopathy or failure of the middle lobe to re expand should lead to consideration of other or additional diagnoses. MYCETOMA Healed pulmonary cavitary lesions can become colonized by Asper gillus spp., resulting in formation of a mycetoma (aspergilloma). These are usually asymptomatic and are often incidental findings on chest radiography, appearing as an ‘air crescent’ sign in a cavitary lesion (Fig. 29.8). However, scant haemoptysis may be a harbinger of massive haemoptysis; thus surgical intervention should be considered if feasible, when cardiopulmonary function allows. 64 There is little evidence that anti fungal therapies improve prognosis, although they are often administered peri operatively when surgical management is pursued. Resection is the only known effective cure; however, bronchial artery embolization can be used to treat haemoptysis. 65 IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME After initiation of antiretroviral therapy for patients with AIDS, serum HIV RNA levels decline and CD4 counts rise. As immune function is restored, antigens from ongoing or past infections can provoke an inflammatory response, leading to a syndrome known as immune reconstitution inflammatory syndrome (IRIS). Mycobacterial disease has been reported to cause at least one third of IRIS cases. 66 The frac tion attributable to TB is likely much higher in regions with high TB prevalence. Symptoms of mycobacterium associated IRIS usually present 4–12 weeks after highly active antiretroviral therapy (HAART) initiation in patients who have experienced a significant rise in CD4 count from a low nadir (often <100 cells/mm 3 ) and sup pression of HIV replication 67,68 Symptoms are often systemic, but may include prominent pulmonary symptoms including pneumonitis and acute respiratory distress syndrome. 66 In addition to treating TB disease, corticosteroids may relieve symptoms. PARADOXICAL REACTION After weeks or months of clinical and radiological improvement, some individuals experience a dramatic worsening in clinical status. When this occurs during treatment of susceptible disease it is known as a ‘paradoxical reaction’ or ‘paradoxical response’. A paradoxical reaction involves clinical or radiographic worsening of symptoms that is sometimes accompanied by fever. It is probably a immunologi cal phenomenon and is usually characterized by increased cell mediated response to tuberculin antigens (increased induration with TST) and may share some immunological similarities with the HIV associated IRIS. However, the biological mechanisms of the reaction have not been elucidated. A recent study identified paradoxical reaction among 16% of 104 patients treated for any TB and 7% of patients treated for exclusively pulmonary TB. Patients with HIV have an increased rate of paradoxical reaction. 69 The most common finding among patients with pulmonary TB is a new or worsening pleural effusion and the median time to development of the paradoxical reaction is 56 days, ranging from 20 to 109 days. 70 Before the diag nosis of paradoxical reaction can be made, other potential causes of decline, including emergence of drug resistance, should be ruled out. PREVENTION The foundation of TB control is identifying individuals with pul monary TB, ideally through community wide active case finding, and completing TB therapy so they are no longer infectious. Thus identifying individuals at highest risk for transmitting TB – sputum smear positive with chronic cough – is the first priority of TB con trol programmes. However, smear negative individuals account for a fifth of transmission. 71 In addition, the large fraction of asymp tomatic or subclinical disease adds to delays in diagnosis with half of individuals asymptomatic at the time of screening in some cross sectional prevalence surveys. 6 Patients with chronic cough (and suspected pulmonary TB) should be identified and, ideally, isolated. Once patients are diag nosed and started on treatment, they should avoid crowded places, ideally staying in their place of residence, until they become spu tum smear negative. Although patients have a significant initial reduction in bacilli, 90% by 2 weeks, they may remain sputum Fig. 29.8 Chest radiograph showing a fungus ball (mycetoma or aspergilloma) in a preexisting tuberculous cavity. Note the characteristic crescent of air (arrowheads) over the superior margin of the fungus ball. Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005: Figure 33.15. 339 CHAPTER 29Pulmonary tuberculosis in adults ELSEVIER smear positive for 4–6 weeks. 72,73 Furthermore, patients with drug resistant TB or who are non adherent to therapy may remain potentially contagious for a longer duration. There is no evidence that a family member being treated for TB places family members at high risk for infection. 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