Overview of extrapulmonary tuberculosis in adults and children

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Overview of extrapulmonary tuberculosis in adults and children Helmuth Reuter, Robin Wood, H Simon Schaaf, and Peter R Donald

INTRODUCTION Tuberculosis is an ancient disease with evidence of spinal TB described in Neolithic man with clear evidence of TB bone lesions in mummified remains from Egypt. However, initial infection is usually respiratory following inhalation of an inoculum of organisms within tiny aerosol droplets, predominantly produced by adults with cavitary TB. Extrapulmonary TB, like pulmonary TB, is the result of infection with organisms of the Mycobacterium tuberculosis complex, which include M. tuberculosis, Mycobacterium bovis or Mycobacterium africanum. Extrapulmonary TB is defined as disease involving structures other than lung parenchyma and is less common than pulmonary TB. Extrapulmonary tuberculous disease occurs as result of contiguous spread of tubercle organisms to adjoining structures, such as pleura or pericardium, or by lymphohaematogenous spread during primary or chronic infection. Mucosal spread may occur by transfer of infected secretions, particularly by coughing and swallowing of infected respiratory secretions associated with cavitary pulmonary lesions entering the upper gastrointestinal tract. Cervical and gastrointestinal TB may also result from ingestion of M. bovis-infected milk products particularly in rural areas where pasteurization may not be readily available. The symptoms of extrapulmonary TB are protean and determined largely by local immune responses and resultant tissue injury within affected organs. The diagnosis of extrapulmonary TB may be elusive, particularly in the elderly and human immunodeficiency virus (HIV)-infected in whom the immune response may be blunted. Extrapulmonary TB is closely associated with weakened cellular immunity and is seen mainly in children younger than 3 years of age due to a greater frequency of lymphohaematogenous spread and immaturity of their immune system, the elderly whose immunodeficiency may be augmented by malnourishment and HIV-infected individuals whose CD4þ T-lymphocytes are selectively diminished. According to the World Health Organization (WHO) patients who are sputum smear-positive and also present with extrapulmonary tuberculous disease manifestations are categorized as pulmonary TB.1 According to current terminology, tuberculous intrathoracic lymphadenopathy (hilar or mediastinal), tuberculous pericarditis and pleural TB without radiographic abnormalities of the lung parenchyma constitute extrapulmonary TB. With the advent of computed tomographic imaging in association with postmortem studies,2 it is, however, clear that tuberculous pleural effusion, tuberculous pericarditis and thoracic lymph node TB are frequently associated with lung parenchymal lesions,2–4 warranting a change

in classification from pulmonary and extrapulmonary TB to intrathoracic and extrathoracic TB, respectively. In TB-endemic countries, TB control programmes focus on management of sputum smear-positive TB in an attempt to control the epidemic; extrapulmonary TB receives little public health emphasis as it tends to be paucibacillary. In endemic areas, extrapulmonary TB contributes significantly to disease burden and causes significant morbidity and mortality, especially in countries with a high HIV prevalence, where its significance has increased progressively over the past 20 years.5–8 The proportion of TB cases classified in the USA as extrapulmonary was 16% in 1991 and remained stable at approximately 20% of all TB notifications between 2001 and 2003.9 In developing countries the proportion of notifications classified as extrapulmonary disease has increased significantly in the wake of the HIV epidemic;1,5–7 however, the reported prevalence varies widely from 5% to more than 35% (Table 34.1).1 The uneven distribution of extrapulmonary TB may reflect a true difference in regional disease distribution due to factors such as race,10 gender,11 variable exposure to M. bovis and non-tuberculous mycobacteria (NTM) and differing HIV prevalence rates.12 High HIV prevalence leads to an increased TB case burden,13,14 and HIV-associated immunosuppression modifies the clinical presentation of TB with more frequent dissemination of infection and subsequent development of extrapulmonary manifestations.15 The profound differences in notification rates probably also reflect ascertainment biases in identifying extrapulmonary TB because it is generally more difficult to diagnose than pulmonary TB. Clinical case definitions of extrapulmonary disease may also differ from surveillance definitions. Individuals with extrapulmonary disease together with pulmonary infection are classified in WHO surveillance reporting as pulmonary TB.1 A confirmed diagnosis of extrapulmonary TB requires a combination of mycobacterial culture, histological examination and strong clinical evidence of active disease. However, the availability and quality of diagnostic laboratory services vary markedly.1 Extrapulmonary involvement may also be commoner than reported; once M. tuberculosis is identified in a sputum specimen, infection involving other sites is not pursued because it will not influence the initiation of chemotherapy. Recent reports suggest an increased risk for active TB, including miliary, lymphatic and peritoneal TB, in association with tumour necrosis factor (TNF)-a antagonist use.16 Although increased TB risk appears to be a drug class effect associated with TNF-a blockade, it varies between specific antagonists, which may be related to the different ways in which TNF-a is neutralized.17

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Table 34.1 The proportion of adult tuberculosis cases classified as extrapulmonary tuberculosis Study

Country

Period

Proportion classified as extrapulmonary TB (%)

CDC, 2004 CDC, 2004 WHO report, 2006 WHO report, 2006 WHO report, 2006 WHO report, 2006

USA USA Nigeria, Gambia

1991 2001–2003 2004

16 20 5

Uganda, Senegal, Ghana Zambia, South Africa, Kenya Tanzania, Malawi, Cote d’Ivoire, Congo Burundi, Algeria, Ethiopia

2004

5–10

2004

10–20

2004

20–30

2004

>30

WHO report, 2006

Adapted from American Thoracic Society, Centers for Disease Control (CDC)9 and World Health Organization (WHO).1

PATHOGENESIS OF EXTRAPULMONARY TUBERCULOSIS Extrapulmonary TB arises from organ seeding with M. tuberculosis following mucosal or lymphohaematogenous spread. Mucosal spread usually arises in those pulmonary TB patients with high bacillary loads, typically in long-standing, untreated cavitary disease, as the result of highly infectious respiratory secretions that bathe the upper respiratory mucosa and gastrointestinal tract, leading to laryngeal or gastrointestinal TB, respectively. Tuberculous pleurisy is the result of a delayed hypersensitivity response to M. tuberculosis organisms that gain access to the pleural space after rupture of a subpleural caseous focus and accompanying discharge of tubercle bacilli into the pleural cavity.2,18 For most forms of extrathoracic TB, spread occurs through blood and lymphatics from an established primary or chronic focus. Laryngeal disease is uncommon in HIV-infected persons, in whom extrapulmonary disease arising from haematogenous and lymphatic dissemination is the rule. Presumably, the basis for the high frequency of extrapulmonary TB among HIV-infected patients and young children is the failure of the immune response to contain M. tuberculosis, thereby enabling lymphohaematogenous spread to single or multiple extrathoracic sites where it is not controlled.

HIV AND EXTRAPULMONARY TUBERCULOSIS HIV infection has transformed TB from an endemic disease into a global epidemic. HIV infection increases the frequency of reactivation of latent M. tuberculosis infection, of rapid progression after initial infection with M. tuberculosis and dissemination of TB organisms to tissues other than lung parenchyma.15 The frequency of extrapulmonary TB in HIV-infected individuals is related to many factors including the degree of immunosuppression and the background prevalence of TB in the community. In industrialized countries where TB prevalence is low, the predominant HIV-associated

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disseminated mycobacterial infection is due to Mycobacterium avium complex (MAC). Disseminated MAC infection was rare prior to the HIV epidemic and its association with profound HIV immune suppression was recognized in the earliest phase of the US epidemic, allowing incorporation of the diagnosis into the earliest acquired immunodeficiency syndrome (AIDS) case definitions.19,20 In contrast, TB was endemic prior to the HIV epidemic and, although there is a similar strong positive association with CD4 cell depletion, the HIV attributable fraction of TB (both pulmonary and extrapulmonary) is lower than that for MAC. The relationship between pulmonary and extrapulmonary TB and HIV infection is further complicated by increasing difficulty in separating these diagnoses when profound immune suppression is present. Immune restoration disease (IRD) following initiation of antiretroviral therapy (ART) may frequently unmask previously unapparent extrapulmonary foci, especially in those with low nadir CD4 cell counts. In a review of reported IRD associated with M. tuberculosis, 12 of 13 cases classified as pulmonary disease prior to starting ART developed extrapulmonary manifestations as part of their IRD.21 The combination of a variable attributable fraction of TB to HIV together with diagnostic imprecision have been reflected by an uncertain role of TB in both AIDS surveillance and case definitions. In 1987 extrapulmonary TB, regardless of concurrent pulmonary disease, was added to the Centers for Disease Control (CDC) AIDS surveillance definition,22 and later that year was incorporated into the WHO surveillance definition of AIDS. In 1989 non-cavitary pulmonary TB was added to AIDS case definition for surveillance by the Pan American Health Organization, its diagnosis given equal scoring with extrapulmonary TB.23 In 1993, pulmonary TB was added to expanded CDC surveillance AIDS case definition;24 the next year it was added to the WHO AIDS surveillance definition.25 While pulmonary and extrapulmonary TB now have equal status in AIDS surveillance definitions, WHO clinical case definitions used for patient management continue to classify pulmonary disease as a WHO stage 3, a pre-AIDS diagnosis and extrapulmonary TB as an AIDS defining condition. HIV infection increases TB dissemination particularly as the CD4 cell count declines below 200 cells/mL. Extrapulmonary involvement has been reported in more than 50% of those patients with concurrent AIDS and TB.15 The clinical manifestations of extrapulmonary TB are also modified by late-stage HIV infection, resulting in increased involvement of multiple foci, frequent concurrent pulmonary and extrapulmonary disease, rapid progression of haematogenous disease and frequent development of abscesses of the liver, spleen and other intra-abdominal organs.15 Although there is a marked antibody response to M. tuberculosis infection, cellular immunity is the predominant mechanism for host defence and T-lymphocytes are central for control of M. tuberculosis infection.26 CD4þ T cells with ab T-cell receptors recognize mycobacterial antigens processed and presented by macrophages in conjunction with major histocompatibility complex (MHC) II molecules, leading to T-cell transformation and further clonal expansion of activated T cells.27 Expansion of transformed CD4þ T cells together with macrophage activation and cytokine secretion leads to inhibition of intracellular growth and development of tissue hypersensitivity. CD8þ T-lymphocytes and CD4þ Tgd-lymphocytes also play a role in tissue hypersensitivity and cellular immunity to M. tuberculosis. The pathological features of M. tuberculosis infection are determined by the interaction between tissue hypersensitivity and local mycobacterial antigen load. Where tissue hypersensitivity is high and antigen load sparse, well-formed granulomata represent a successful immunological containment of infection. The morphology of a

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Overview of extrapulmonary tuberculosis in adults and children

well-formed granuloma is characterized by a central necrotic core surrounded by concentric layers of macrophages, epithelioid cells, multinucleated Langhans giant cells and lymphocytes.28 The cellular wall and outer fibrosis restricts M. tuberculosis to the site of infection and prevents dissemination. Where both antigen load and hypersensitivity are high, the granuloma is less well organized and caseating necrosis may be present. With low hypersensitivity the tissue reaction may be non-specific with large numbers of organisms and scanty lymphocytes and macrophages.29 Quantitative and qualitative deficiencies of components of the TB immune response result in decreased containment of M. tuberculosis and increased dissemination. Tuberculous bacteraemia confirmed by positive blood culture has been documented in HIV-infected patients but is extremely rare in HIV-seronegative patients.30 The extent of mycobacterial dissemination is often unsuspected, as shown by West African autopsy data.31 Because of the high frequency of extrapulmonary TB among HIV-infected patients, diagnostic specimens from any suspected site of disease should be examined for mycobacteria. Moreover, cultures of urine, blood and bone marrow may reveal M. tuberculosis in patients without an obvious localized site of disease but who are febrile.

TREATMENT OF EXTRAPULMONARY TUBERCULOSIS IN ADULTS There have been fewer treatment studies evaluating duration and treatment response of extrapulmonary TB than of pulmonary TB. Treatment response is also frequently assessed by indirect clinical and radiological response because follow-up biopsy specimens, necessary to show bacterial treatment response, may be lacking. However, extrapulmonary foci with the exception of bone, joint and central nervous system (CNS) infections generally appear to respond to standard 6- to 9-month regimens including isoniazid (INH) and rifampicin (RMP), in a fashion similar to that of pulmonary TB.32–40 Therefore among patients with extrapulmonary TB a regimen of 2 months of INH, RMP, pyrazinamide (PZA) and ethambutol (EMB) followed by 4–7 months of INH and RMP is recommended as initial therapy unless the organisms are strongly suspected of being resistant to first-line drugs.40 The duration of therapy for extrapulmonary TB caused by drug-resistant organisms is not known. In the treatment of bone and joint TB, some studies have shown that 6- to 9-month RMP-containing regimens are as effective as 18-month non-RMP-containing regimens.39 However, because of the difficulties in assessing response to therapy some experts favour a 9-month or longer duration of treatment.40 Tuberculous meningitis has a particularly high morbidity and mortality even with prompt and adequate chemotherapy.41–43 There is a lack of randomized controlled trial data to guide optimal duration of chemotherapy for tuberculous meningitis; however, present recommendations based on expert opinion are for 2 months of four-drug therapy followed by 7–10 months of INH and RMP.40 Some recommendations suggest prolonged therapy for up to 2 years.42,43 Monitoring of cell, glucose and protein concentrations by repeat lumbar punctures is recommended to establish initial response to chemotherapy; however, these parameters may be difficult to interpret as cell count and protein may remain abnormal in patients chronically infected with HIV. A number of studies have explored the role of adjunctive corticosteroid therapy.44–46 Several smaller studies showed improvement in survival and decreased neurological sequelae with corticosteroid therapy with the greatest benefit for those with decreased level of consciousness but not coma.42,45 A large prospective

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randomized placebo-controlled study of corticosteroid adjunctive therapy performed in Vietnamese adults demonstrated improved survival but not a decreased incidence of severe disability.46 Dexamethasone is presently recommended for all patients with tuberculous meningitis, particularly those with decreased level of consciousness.40 Expert opinion recommends adjunctive corticosteroid therapy also for patients with tuberculous respiratory failure associated with disseminated or miliary TB.40 The role of adjunctive corticosteroid therapy in the management of tuberculous pericarditis is unclear.33,47 Clinical benefit, including decreased mortality and need for pericardiectomy, has been reported in HIV-seronegative patients in South Africa,34 and in HIV-infected tuberculous pericarditis patients in Zimbabwe,35 respectively, but was not observed in other studies.33,47

TREATMENT OF EXTRAPULMONARY TUBERCULOSIS IN CHILDREN Sputum smear-negative disease is usually paucibacillary and therefore the risk of acquired drug resistance is low. Drug penetration into the anatomical sites involved is good and the success of three drugs (INH, RMP, PZA) during the 2-month intensive phase and two drugs (INH, RMP) during the 4-month continuation phase is well established.48 Disseminated tuberculous disease is frequently associated with CNS involvement.48 It is therefore essential to consider the cerebrospinal fluid (CSF) penetration of drugs used in the treatment of disseminated disease. INH and PZA penetrate the CSF well.49 RMP and streptomycin (SM) penetrate the CSF poorly, but may achieve therapeutic levels in the presence of meningeal inflammation.49 The value of streptomycin is limited by poor CSF penetration and intramuscular administration. EMB hardly penetrates the CSF, even in the presence of meningeal inflammation and has no demonstrated efficacy in the treatment of tuberculous meningitis.48,49 The recommended treatment for lymph node, pleural and pericardial TB in children is 6 months of directly observed therapy (DOT); 2 months of three drugs (INH, RMP, PZA) followed by 4 months of two drugs (INH,RMP).40,50 The cellular immune response assists with organism containment and eradication. Because immunocompromised children lack this important immune contribution, they are at increased risk of disease relapse following standard short-course therapy.51 It seems prudent to prolong treatment in immunocompromised children, although this has not been verified in randomized controlled trials. In the absence of sufficient evidence current recommendations are to consider prolonging treatment to 9 months.40,48

PARADOXICAL REACTIONS AND IMMUNE RESTORATION DISEASE Clinical or radiological deterioration of TB after commencing effective anti-TB therapy is reported to occur in 2–23% of HIV-seronegative individuals.52 These paradoxical reactions may manifest mildly as exacerbation of systemic symptoms or more significantly as respiratory failure or neurological deterioration. Extrapulmonary TB, especially involvement of the CNS, is a strong risk factor for paradoxical reactions.52 Paradoxical reactions following initiation of effective chemotherapy have been associated with conversion of cutaneous response to purified protein derivative from anergy to a positive response,53 and with a rise in serum concentration of TNF-a, which may result from release of mycobacterial wall antigens liberated by mycobacterial killing.54

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Immune restoration disease in those HIV-infected patients is an adverse consequence of restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral therapy (HAART). IRD, also known as immune reconstitution inflammatory syndrome (IRIS), occurs in 29–36% of TB/HIV coinfected patients receiving newly commenced anti-TB therapy and HAART.55 A temporal association between HAART commencement and worsening existing symptoms, or new clinical findings, is a strong clue to the diagnosis of IRD. A positive response to HAART, manifested by a decrease in plasma viral load, is a necessary component for the diagnosis of IRD. However, although a brisk rise in blood CD4 lymphocyte count is frequent, it is not essential for the diagnosis of IRD. There is a strong association between IRD and extrapulmonary TB; a review of 27 papers described 86 cases of M. tuberculosisassociated IRD, 82 of which reported extrapulmonary manifestations.55 Progressive HIV-associated immunodeficiency results in impaired granuloma formation and decreased immune-mediated tissue damage. Thus patients with advanced HIV infection have a propensity to develop extrapulmonary TB with very high bacterial burdens, but without specific organ-related symptoms. IRD frequently results in worsening of existing symptoms but also in new manifestations of previously unrecognized extrapulmonary TB. The unrecognized dissemination of TB in advanced HIV disease was illustrated by the development of a new extrapulmonary manifestation of IRD in 18 of 19 reported cases where the pre-ART site of involvement was pulmonary.55 The commonest reported site for extrapulmonary IRD was lymphadenopathy, which occurred in 71% of patients; 80% was extrathoracic and 20% intrathoracic.55 Other organ involvement included hepatosplenomegaly, psoas abscess, splenic abscess, other intra-abdominal abscesses, ileocaecal disease and skin lesions. Although some manifestations of M. tuberculosis-associated IRD were life-threatening, such as respiratory failure, perforated bowel, splenic rupture and expanding intracranial lesions, no deaths were reported, but this may reflect a reporting bias. Immune reconstitution is also seen in children with TB and may follow nutritional supplementation, anti-TB therapy or initiation of HAART. In a recent prospective survey of 152 Thai children with low CD4 percentages (< 15%), IRD was documented in 14 (19%), usually within 4 weeks of HAART initiation.56 The majority of IRD cases (n ¼ 9) were due to atypical mycobacteria; three were due to M. tuberculosis and due to 2 M. bovis Bacillus Calmette–Gue´rin (BCG). HAART is now increasingly accessible in resource-poor regions where TB is prevalent. In sub-Saharan Africa individuals accessing HAART with advanced immune suppression, many of whom would have previously died without a pre-mortem diagnosis of disseminated TB being made, are developing extrapulmonary IRD after initiating HAART.21 The burden of investigating and treating large numbers of patients with TB who present with pulmonary and extrapulmonary symptoms soon after initiating HAART is a major constraint on further rapid ART rollout.57

EXTRAPULMONARY MANIFESTATIONS OF TUBERCULOSIS TUBERCULOUS LYMPHADENITIS Tuberculous lymphadenitis is the most common manifestation of extrapulmonary TB with cervical nodes most commonly involved, although inguinal, mesenteric, and mediastinal nodes may also be involved.58,59 Tuberculous lymphadenitis often

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affects HIV-seronegative children and young adults,60,61 but in countries with high HIV prevalence is most commonly seen in HIV-infected patients, and is characterized by rapidly enlarging nodes, tenderness or marked asymmetry, features inconsistent with a diagnosis of persistent generalized lymphadenopathy. The differential diagnosis includes NTM infection, Kaposi’s sarcoma and lymphoma. NTM lymphadenitis is relatively common in children and HIV-infected adults,62 but is rare in HIV-seronegative adults. The disease generally remains localized to the cervical region and usually unaccompanied by constitutional symptoms.59 NTM lymphadenitis generally remains localized to the cervical region and can be managed by excision biopsy; if left untreated, the nodes often progress to softening, rupture, sinus formation, healing with fibrosis and calcification.62 In children cervical lymphadenitis is the most common extrathoracic manifestation of TB. Disease pathology within the lymph node is similar to that in other organs, with initial tubercle formation and lymphoid hyperplasia that may progress to caseation and necrosis. Isolated involvement of a single node is rare and nodes are usually matted due to considerable periadenitis.61 A cold abscess results when caseous material liquefies and leads to a soft fluctuant node with discoloration of the overlying skin; spontaneous drainage and sinus formation may follow. Untreated, the natural course of TB lymphadenitis in an immune competent host follows a prolonged and relapsing course, often interrupted by transient lymph node enlargement, fluctuation and/or sinus formation.61 In adults tuberculous lymphadenitis is characteristically indolent and usually presents as a unilateral painless mass along the upper border of the sternocleidomastoid muscle, although more than one site may be involved in up to 35% of cases.63 Constitutional symptoms are usually mild or absent,59,60 and tuberculin skin tests (TST) positive in 75–100% of HIV-uninfected individuals.58,59,63,64 Fine needle aspiration (FNA) is the diagnostic procedure of choice with a reported diagnostic yield varying from 42% to 83%.58–61,64 In some cases an excision biopsy is required, and may result in higher yields, especially if both histology and mycobacterial culture are obtained.59,64 Excision may also be a treatment option, particularly in NTM disease where the therapeutic response to chemotherapy is frequently suboptimal.60 Incisional biopsy should be avoided because it tends to result in sinus formation, a complication not seen with FNA.61 The prevalence of associated chest radiographic abnormalities varies considerably between reported series, probably reflecting differing age distributions. Patients with mediastinal lymphadenopathy may present with cough and dysphagia.65 The diagnosis is usually confirmed by CT scan, and as CT becomes more widely available more cases of intrathoracic and intra-abdominal lymphadenopathy will probably be reported. Involvement of intrathoracic lymph nodes (perihilar and/or paratracheal) is considered the radiological hallmark of primary infection.48,50 Both anteroposterior (AP) and lateral views are required for optimal lymph node visualization. Transient hilar adenopathy is not uncommon following recent primary infection and particular care should be exercised when interpreting results of very sensitive tests such as high-resolution CT (HRCT) of the lung, in the absence of clinical data.48,50 Upper abdominal and mediastinal lymph node TB rarely causes thoracic duct obstruction and chylothorax, chylous ascites or chyluria.66 Swollen glands in the porta hepatis may compress the bile duct and result in obstructive jaundice.67

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Overview of extrapulmonary tuberculosis in adults and children

TUBERCULOUS PLEURAL EFFUSION Tuberculous pleurisy is categorized as extrapulmonary TB despite an intimate anatomic relationship between the pleural membranes and lungs.18 Pleural effusion is a common form of extrapulmonary TB, exceeding 20% of all extrapulmonary TB cases in adults.68,69 Tubercle bacilli enter the pleural space where a delayed hypersensitivity immune response is induced. High interferon-gamma (IFN-g) levels in the pleural fluid are in keeping with a Th1-type response. Tuberculous effusions can follow postprimary, chronic pulmonary and disseminated tuberculous disease. Postprimary effusions frequently develop in young adults due to rupture of subpleural collections of mycobacteria into the pleural space, and pleural fluid typically obliterates 30–60% of the affected hemithorax, although massive effusions may occur. Postprimary effusions frequently resolve spontaneously. However, in the prechemotherapy era more than 60% relapsed within 5 years.70 Effusions complicating chronic pulmonary TB occur in older individuals and may be associated with complicating cardiac or liver disease. Rupture of caseous material from a pulmonary cavity or an adjacent parenchymal focus via a bronchopleural fistula can lead to tuberculous empyema, which is much less common than tuberculous pleurisy with effusion and is associated with a large number of organisms spilling into the pleural space and multiplying there.71 Tuberculous empyema is usually accompanied by radiographic evidence of pulmonary parenchymal disease and air may be seen in the pleural space. The pleural effusion may be loculated and the aspirate is usually thick and resembles pus. Acid-fast smears and mycobacterial cultures are usually positive, making pleural biopsy unnecessary. Tuberculous empyema may burrow through soft tissues and drain spontaneously through the chest wall. Pleural effusions frequently complicate miliary TB (10–30%) where they may be bilateral and associated with pericardial and or peritoneal effusions.72,73 Pleural effusions were radiographically diagnosed in 21% of 150 HIV/TB coinfected individuals presenting sequentially to a South African HIV clinic.74 Tuberculous effusions were less strongly associated with low CD4 cell counts than disseminated or miliary TB.75 Two-year survival of those with effusions was 63%, which was also intermediate between typical pulmonary TB and other WHO stage 4 conditions.75 Clinical presentation may be acute or subacute with the main symptoms being non-productive cough, pleuritic chest pain, fever and dyspnoea, a symptom complex easily confused with bacterial pneumonia. If the effusion is large enough, dyspnoea may occur, although effusions generally are small and rarely bilateral. Chest radiography usually demonstrates a small to moderate unilateral effusion of which 20% are associated with pulmonary lesions.76 CT scan is more sensitive than chest radiograph and evidence of parenchymal infiltrates, cavitation and pleural thickening is more frequently demonstrated.3 In patients with tuberculous pleurisy the pleural fluid is an exudate with a protein content > 30 g/L, pH < 7.3 and lactate dehyrogenase (LDH) > 200 U/L. Lymphocytosis is typical, but a minority of patients have a predominantly polymorphonuclear cellular infiltrate. Direct examination of pleural fluid by Ziehl–Neelsen staining requires a bacillary density of 10,000/mL, and in the absence of empyema has low sensitivity. Pleural fluid mycobacterial culture is positive in 25–30% of cases.76 Granulomata can be identified in 80% of needle biopsies and culture of biopsy material increases the yield by a further 12%.76 Polymerase chain reaction (PCR) of pleural

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biopsy has sensitivity of 90% and specificity of 100%, similar to combined histology and mycobacterial culture; however, a definitive diagnosis can be achieved more rapidly.77 Biochemical markers such as adenosine deaminase activity (ADA), IFN-g, immunosuppressive acidic protein and soluble interleukin-2 receptor (sIL-2R) have been used to distinguish between tuberculous and non-tuberculous aetiologies. In a direct comparison, receiver operating characteristic (ROC) analysis demonstrated that pleural fluid IFN-g was the best indicator among these four biological markers. In high-TB-prevalence settings an ADA > 47 U/L is reported in 99% of tuberculous effusions and in low-prevalence settings a normal ADA has a high negative predictive value and can be used to exclude a tuberculous aetiology.76 Tuberculous pleural effusion responds well to medical therapy with resorption of pleural fluid in 6–12 weeks. Although early postprimary pleural effusions may resolve spontaneously, chemotherapy prevents recurrent disease elsewhere, which occurs in approximately 60% of untreated cases.70 In children, especially those younger than 3 years of age, small effusions often constitute part of the primary complex forming adjacent to the primary focus. Isolated larger pleural effusions are unusual in young children, occur typically in adolescence and tend to develop soon (within the first 3–9 months) after primary infection.78 The pleural fluid typically obliterates 30–60% of the affected hemithorax, although massive fluid collections may cause mediastinal shift and cardiovascular compromise.79 The pleural fluid is characteristically lymphocyte-rich, straw-coloured and represents a cell-mediated hypersensitivity response. Loculated fluid collections may indicate TB empyema that arises when bacilli actively multiply within the pleural space. This is not common, but immune compromised children may be at increased risk.

TUBERCULOUS PERICARDITIS Tuberculosis was the cause of acute pericarditis in 4% of patients in industrialized countries,80 and in 60–80% of patients in resourcepoor settings.8,34 Pericardial effusion is a frequent clinical finding in HIV-infected patients coinfected with TB.8,35 However, asymptomatic pericardial effusions are also frequently found in HIVinfected individuals and may be due to a variety of neoplastic and infective aetiologies including TB.81 While small effusions are a frequent but not considered relevant finding, moderate to severe effusions were found in 13% of 181 consecutive patients presenting to a university HIV clinic in Portugal.81 These effusions were more frequent in patients at more advanced stages of HIV infection. Tuberculous pericarditis occurs most commonly in the third to fifth decades of life although HIV infection is associated with a lower age at presentation.8,81 Tuberculous pericarditis most commonly results from direct extension from contiguous mediastinal and hilar lymph nodes or by lymphohaematogenous spread. The clinical presentation of tuberculous pericarditis is variable and includes acute pericarditis with or without effusion, cardiac tamponade, silent large pericardial effusion with a relapsing course, toxic symptoms with persistent fever, acute constrictive pericarditis, subacute constriction, effusive–constrictive or chronic constrictive pericarditis.80,82 The predominant clinical features of tuberculous pericarditis include dyspnoea, cough, chest pain, night sweats, orthopnoea, weight loss, ankle oedema, cardiomegaly, hepatomegaly, fever and tachycardia. Other findings include pericardial rub, pulsus paradoxus, distended neck veins, pleural effusion and soft heart sounds.33,82 Tuberculous pericarditis with HIV infection presents more frequently with

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fever, generalized lymphadenopathy and concomitant pulmonary infiltrates.82 Chest radiography demonstrates cardiomegaly; echocardiography or chest CT (Fig. 34.1) confirms pericardial effusion as the cause. Constrictive pericarditis may clinically resemble cirrhosis, as the associated ascites may be disproportionately large compared with the peripheral oedema present (ascites praecox). Rarely, patients may present with clinical features suggestive of constriction in the presence of pericardial effusion, a condition referred to as effusive–constrictive pericarditis. The echocardiographic visualization of fibrinous strands in pericardial fluid is suggestive of tuberculous aetiology,82 but pericardiocentesis or pericardiectomy may nevertheless be required to establish a definitive diagnosis. Concomitant pleural effusion may be present in 39–50% of cases and frequently provides an alternative source of diagnostic material.34,82,83 Tuberculous pericardial fluid shares many characteristics of tuberculous pleural fluid with low sensitivity of Ziehl–Neelsen staining and moderate sensitivity of mycobacterial culture.34,35,82 Pericardial biopsy may have a better diagnostic yield than pericardial fluid culture, but is invasive, requires surgical expertise and has a mortality risk. Typical granulomata cannot always be demonstrated and pericardial biopsy may show non-specific findings, even when M. tuberculosis is found in the pericardial fluid.4,34,84 ADA and IFN-g levels are elevated and the cellular component is predominantly lymphocytic in effusions from both HIV-infected and -uninfected individuals.82,85,86 Whereas CD4þ lymphocytes predominate in HIV-seronegative cases, CD8þ cells predominate in HIV-infected cases.86 The tuberculin skin test is usually positive in immunocompetent patients with pericardial TB.34,82 The goal of therapy for tuberculous pericarditis is to treat the acute symptoms of cardiac compression and prevent progression from the effusive to the constrictive stage, in which a fibrotic and

Fig. 34.1 Chest CT demonstrating tuberculous pericarditis. A 48-year-old man known to have tuberculous pericarditis presented with progressively worsening abdominal distension and ankle oedema following closed pericardiocentesis and 6 weeks of antituberculous therapy with adjunctive oral prednisone. Echocardiography and chest CT demonstrated large pericardial effusion with prominent pericardial thickening. In addition, echocardiography demonstrated septal ‘knocking’ and transvalvular flow patterns suggestive of effusive–constrictive pericarditis.

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calcified pericardium entraps the heart.33,87 The mortality rate in untreated acute effusive tuberculous pericarditis approaches 85%.80 Standard management of pericardial effusion includes pericardiocentesis by either echocardiographically guided closed pericardiocentesis33,87 or surgical fenestration.34,35 The open procedure has the advantage that pericardial tissue is obtained for mycobacterial culture and histopathological diagnosis, but it has the disadvantage of anaesthesia and potential surgical mortality.34,87 Recommended antituberculous chemotherapy of pericardial TB is the same as for pulmonary TB.33,84 In a large randomized, doubleblind, placebo-controlled trial, adjunctive corticosteroid therapy (prednisone) for the first 11 weeks of chemotherapy resulted in significant clinical benefit;34 significant survival benefit was maintained in those randomized to corticosteroid therapy over 10 years of follow-up.88 The same benefits have not been demonstrated elsewhere and there is currently no convincing evidence for routine corticosteroid administration in patients who have undergone successful pericardiocentesis.33,47,87 In children pericardial effusion usually develops when a subcarinal lymph node erupts into the pericardial space.78 On chest radiography the heart shadow may be enlarged with a suggestive globular appearance, but cardiac ultrasound is the most sensitive test to confirm or exclude a pericardial effusion. Long-term sequelae include constrictive pericarditis; therefore in children pericardial effusion is an indication for the use of corticosteroids together with antituberculous treatment.79

ABDOMINAL TUBERCULOSIS The term abdominal TB encompasses tuberculous involvement of any of the intra-abdominal organs including any part of the gastrointestinal tract from mouth to anus, omentum, peritoneum, mesentery and its nodes and other solid intra-abdominal organs such as liver, spleen and pancreas. Infection is primarily due to either swallowing of infected material from pulmonary disease or haematogenous spread to abdominal organs with subsequent involvement of contiguous structures. The clinical presentations are protean and mimic many other diseases. The most frequent presenting symptoms are abdominal distension and/or pain, fever and weight loss but may vary with the site of tuberculous involvement.89–92 The oropharynx may be affected with chronic ulceration. Oesophageal involvement may present with stricture or tracheo- or broncho-oesophageal fistula, as a result of erosion of mediastinal caseating nodes into the oesophagus. Gastric and duodenal disease may cause ulceration or obstruction. Fistulae, perforation or malabsorption may result from small bowel involvement. The ileocaecum and jejunoileum are the most frequent sites of involvement. Complications include a palpable mass, obstruction, perforation and fistula formation. Massive rectal bleeding can complicate colonic involvement and rectal lesions present as fissures, fistulas and perirectal abscesses.93 Solid organ involvement occurs in approximately 20% of cases of abdominal TB.92 Hepatic involvement may present with abdominal distension, right hypochondrial pain and jaundice,94 and splenic disease with moderate splenomegaly; pancreatic TB may mimic pancreatitis or carcinoma. Tuberculous hepatitis, rarely with jaundice, is usually seen in patients with disseminated disease and should be suspected if liver enzymes are elevated. Abdominal ultrasonography is indicated to look for intra-abdominal lymphadenopathy and detect hepatic enlargement, a granular infiltrate suggesting granulomatous inflammation and to exclude tuberculous abscesses. The histological abnormalities may

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Overview of extrapulmonary tuberculosis in adults and children

vary from non-specific inflammatory changes to very specific granulomatous lesions and the presence of M. tuberculosis. The diagnostic yield may improve by mycobacterial culture of biopsy specimens. The biliary ducts and the pancreas are rarely involved, although this has been described as part of miliary TB in immunocompromised patients.95 The clinical manifestations depend on the site and extent of disease and may include anorexia, malaise, lowgrade fever, weight loss, night sweats, abdominal pain, bloody stools, obstructive jaundice and acute or chronic pancreatitis.96,97 Pancreatic TB may mimic malignancy and present as a pancreatic mass or abscess.95,96 The spleen is commonly involved in patients with disseminated TB, but isolated splenic TB presenting with splenomegaly, hypersplenism, solitary splenic lesions or splenic abscesses is rare.98 Tuberculous peritonitis usually presents with pain and abdominal distension accompanied by fever, weight loss and anorexia.91 Confirmation of abdominal involvement requires a combination of endoscopic, microbiological, histological and molecular techniques. Tuberculous ascites has biochemical characteristics similar to those of tuberculous pleural and pericardial exudates. Cellular content is predominantly lymphocytic, ADA levels are elevated and the acidfast bacilli and mycobacterial culture yields are low. Isolation of M. tuberculosis is enhanced by centrifugation of large samples of peritoneal fluid, bedside inoculation of peritoneal fluid into liquid culture media and when peritoneal biopsy material can be examined and cultured. The difficulty of making a diagnosis of abdominal TB is illustrated by many autopsy-proven cases unsuspected during life94,99 and considerable diagnostic delay even in well-resourced settings.99 A strong association between untreated cavitary lung disease and gastrointestinal involvement, consistent with prolonged exposure to swallowed infected secretions, was demonstrated in autopsies performed in the prechemotherapy era. In Los Angeles, California, gastrointestinal lesions were present in 25% of 6,085 autopsies in which TB was identified,100 and more recently a continued relationship between smear-positive cavitary lung and gastrointestinal disease has been demonstrated in a South African hospital cohort, in whom the prevalence of proven gastrointestinal TB was 28%.101 The lesions were predominantly superficial mucosal lesions of the caecum, which appeared to be related to the severity of pulmonary disease.101 Conversely, pulmonary TB has been recognized in between 1% and 64% of reported series of abdominal TB in HIV-seronegative populations.90–92,102 This wide variability in the association between abdominal and pulmonary involvement may be due to selection biases due to variable sensitivities of the diagnostic modalities for defining pulmonary and abdominal involvement, the type and chronicity of abdominal involvement at presentation and the variable access of each population to diagnosis and effective chemotherapy of early pulmonary TB. Abdominal TB occurs more frequently in HIV-infected than in HIV-seronegative individuals, due to both an overall increased incidence of TB together with an increased propensity for dissemination as the CD4 cell count declines.103,104 M. tuberculosis infection in AIDS patients more frequently involves the solid abdominal organs in keeping with lymphohaematogenous spread. The liver, spleen and pancreas as well as the peritoneum and gastrointestinal tract are frequently involved. Fistulae are more frequent in AIDS and may occur from any segment of bowel. Conventional short-course chemotherapy, as for pulmonary TB, appears to be effective, although surgery is occasionally required for complications.

34

GENITOURINARY TUBERCULOSIS Genitourinary TB results from seeding of the genital organs or kidney at the time of initial tuberculous infection and bacteraemia. Genitourinary symptoms, including dysuria, haematuria and flank pain, are more frequent than constitutional symptoms in patients with renal TB. Many individuals are asymptomatic and finding sterile pyuria, with or without accompanying haematuria or albuminuria, is the clinical trigger for investigation of possible renal TB, especially in those with evidence of prior TB or other active organ involvement.105–107 Diagnosis is usually established by culture of repeated early morning urine collections.105,106 Three early morning cultures are sufficient to confirm the diagnosis in 80–90% of cases. Intravenous pyelograms are usually abnormal. Supportive clinical findings include papillary necrosis, ureteral strictures with or without hydronephrosis and focal calcification. Approximately 40–75% of patients have chest radiographic abnormalities suggesting previous or current pulmonary TB.105,106 Asymptomatic renal involvement, manifested by positive urinary mycobacterial culture in the absence of renal signs or symptoms, is present in 5% of HIVseronegative cases with active pulmonary TB and 21% of those with extrapulmonary TB.108 The frequency of renal involvement is even higher in those with TB/HIV coinfection. Urine mycobacterial culture was positive in 15% of HIV-infected pulmonary TB cases and in 29–77% of those HIV-infected known to have extrapulmonary TB.109–111 Histological evidence of renal TB was found in 23% of a series of autopsies of AIDS patients in Brazil.112 Standard antituberculous chemotherapy is indicated for renal TB, although some prefer prolonged therapy.113 If left untreated, renal TB may result in obstructive nephropathy, renal stone disease, recurrent bacterial infections and ultimately renal failure. Ureteric obstruction may also develop during chemotherapy and repeated imaging may be required to exclude development of hydronephrosis.

Male genitourinary tuberculosis Male genital TB is strongly associated with concomitant renal TB and may involve prostate, seminal vesicles, epididymis and testes with decreasing incidence.105,106 The diagnosis is usually entertained in those presenting with a scrotal mass and confirmed by biopsy. Prostate TB is rare but has been increasingly reported in AIDS and may be associated with only mild urinary symptoms.114 A substantial number of patients with any form of genitourinary TB are asymptomatic and are detected because of an evaluation for an abnormal routine urinalysis. In more than 90% of patients with renal or genital TB, urinalyses are abnormal, the main finding being pyuria and/or haematuria with no organisms isolated from routine urine culture.105,106 Diagnosis of isolated genital lesions usually requires biopsy, because the differential diagnosis often includes neoplasia or other chronic infectious processes. Female genitourinary tuberculosis Symptomatic female genital tract TB accounts for less than 2% of TB and usually presents with abnormal vaginal bleeding, menstrual irregularities, abdominal pain and constitutional symptoms.107 The primary focus is the endosalpinx from which spread takes place to the endometrium, ovaries, cervix and more rarely to the vagina. The clinical presentation of disease involving the ovaries and endosalpinx may suggest pelvic inflammatory disease or mass unresponsive to antimicrobial therapy. Involvement of the cervix may mimic a neoplasm and vaginal lesions present as indolent ulceration. The diagnosis may be made as a result of investigations for

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infertility and return to fertility after treatment is not encouraging. Involvement of the endosalpinx predisposes to both subsequent ectopic pregnancies and infertility.115 Diagnosis is by culture and histology of surgical specimens such as endometrial scrapings, ulcerative lesions and cervical biopsy. Drug treatment follows standard TB regimens, although criteria for assessing treatment efficacy are lacking. Surgery is usually reserved for large residual tubo-ovarian abscesses.

TUBERCULOSIS OF THE CENTRAL NERVOUS SYSTEM Tuberculous meningitis is the most common form of CNS TB, being responsible for between 70% and 80% of cases followed in decreasing incidence by intracranial tuberculomata and spinal arachnoiditis. Neurological TB is invariably secondary to TB elsewhere in the body. Meningitis results from intense inflammation initiated by the rupture of a subependymal tubercle (Rich focus) rather than from direct haematogenous seeding, but whether the subependymal tubercle develops during primary haematogenous dissemination or secondary spread from extracranial TB is not clear.116,117 In children, tuberculous meningitis is an early postprimary event; however, subependymal foci may remain quiescent for prolonged periods, resulting in delayed presentation. Tuberculous meningitis is the most severe manifestation of childhood TB. BCG vaccination provides some degree of protection against severe forms of TB (disseminated TB and tuberculous meningitis), but despite universal BCG vaccination severe disease manifestations still occur, mainly affecting very young (immune immature) and/ or immunocompromised children in endemic areas. In tuberculous meningitis meningeal involvement is most pronounced at the base of the brain where ensuing arachnoiditis encases cranial nerves and penetrating vessels with associated cranial nerve palsies. Cerebral vasculitis may lead to thrombosis and focal infarction of the basal ganglia and pons, resulting in movement disorders or lacunar infarcts. Associated cerebral oedema or hydrocephalus (Fig. 34.2) causes decreased level of consciousness, seizures and raised intracranial pressure. A prodrome of malaise, low-grade fever, apathy, anorexia and behaviour changes lasting for 2–3 weeks is followed by protracted headache, progressive meningism, vomiting, increasing drowsiness and focal neurological signs.116 The initial clinical spectrum is broad, ranging from subtle mental status changes to rapid progression mimicking pyogenic meningitis and consequences of acute hydrocephalus as demonstrable by CT scan (Fig. 34.2). Without early treatment, stupor and coma inevitably ensue and death follows in 5–8 weeks.116 Focal or generalized seizures and cranial nerve palsies are frequent,117 and evidence of concomitant extrapulmonary TB, including miliary shadowing on chest radiograph, is present in 75% of cases.116 A high index of clinical suspicion for the early diagnosis and prompt initiation of treatment for tuberculous meningitis should be maintained, as the long-term prognosis is influenced by the duration and level of neurological impairment at commencement of therapy. Diagnosis is largely based on an index of suspicion and examination of the CSF, which is characterized by increased opening pressure, a raised protein, a preponderate mononuclear cellular response and hypoglycorrhachia. CSF leucocyte counts vary from 100 to 1,000 leukocytes/L with lymphocytes predominating in 65–75% of patients.46 Atypical findings are common, including predominance of polymorphonuclear cells and a normal glucose. On repeated testing there is usually an evolution to the

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Fig. 34.2 Tuberculous meningitis causing acute hydrocephalus. An 11-year-old boy presented with a 1-week history of headaches and daily vomiting. His aunt had died of pulmonary TB during the previous year. A brain CT scan demonstrated acute hydrocephalus (black arrows) and basal enhancement (white arrows). He had a sudden neurological deterioration and was treated with mannitol, emergency insertion of ventriculoperitoneal (VP) shunt, four-drug antituberculous chemotherapy and adjunctive dexamethasone.

more typical picture. In adults, the yield of acid-fast bacilli on direct smear of CSF is 10–20%, but is improved when a large quantity of CSF is centrifuged and there is an incremental yield with repeat investigations. The yield of CSF culture is similarly volume dependent and is typically positive in 45–90% of cases but culture takes up to 4 weeks. CSF PCR for M. tuberculosis has been explored in order to expedite the diagnosis but lacks sensitivity and cannot be used to exclude the diagnosis of tuberculous meningitis.118 A substantial number of patients will have M. tuberculosis isolated from other sources, and, in the presence of compatible CSF findings, such isolation is sufficient to diagnose tuberculous meningitis. Given the severity of tuberculous meningitis, a presumptive diagnosis justifies empiric treatment. The combination of a suggestive clinical presentation, including a history of household contact with an infectious pulmonary TB case, and compatible laboratory and imaging findings is frequently used to initiate chemotherapy before a definitive diagnosis is made. The demonstration of basal inflammation on CT and magnetic resonance imaging (MRI) supports the diagnosis (Fig. 34.2). HIV infection increases the incidence of tuberculous meningitis several-fold but does not fundamentally alter the clinical and laboratory manifestations.119,120 The mononuclear cell preponderance and raised protein in the CSF of those with chronic HIV infection may, however, mimic the diagnosis of tuberculous meningitis. There should be a low threshold for initiation of empiric antiTB therapy and treatment is with a standard course of INH,

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Overview of extrapulmonary tuberculosis in adults and children

RMP, PZA and SM or ethionamide continued for 9–12 months together with adjunctive corticosteroids.40,44–46

INTRACRANIAL TUBERCULOMATA Tuberculomata are space-occupying lesions that may manifest with seizures. They vary in size from a few millimetres up to 3–4 cm in diameter and appear on imaging studies usually as solitary avascular structures with considerable surrounding cerebral oedema. Although definitive diagnosis is dependent on biopsy this is frequently impracticable in resource-poor settings where these lesions are more common. Treatment is with corticosteroids to reduce the oedema and symptoms, and chemotherapy results in slow resolution of the tuberculoma. In HIV-infected individuals tuberculomata occur more frequently and may become apparent as part of IRD. The main differential diagnoses include neurocysticercosis and cerebral lymphoma. In resource-poor settings where neurosurgical facilities are limited, empiric therapy for both toxoplasmosis and tuberculomata may need to be initiated for ring-enhancing intracranial lesions.

TUBERCULOUS SPINAL MENINGITIS Rarely, spinal meningitis or an intramedullary tuberculoma occurs without intracranial involvement. Symptoms result from cord or nerve root compression and are determined by the level of cord involvement but include a level of loss of sensory sensation, root pain, bladder and sphincter weakness or paralysis.

BONE AND JOINT TUBERCULOSIS Skeletal TB is predominantly caused by haematogenous spread, although spread from contiguous structures may infrequently occur. The spine is most commonly involved, followed by tuberculous arthritis of the weight-bearing joints and less commonly tuberculous osteomyelitis.121–123 Usually only one bone or joint is involved, but occasionally the process is multifocal.124,125 Evidence of either previous or current pulmonary TB is found in approximately 50% of reported patients, and other extrathoracic sites may also be involved.

SPINAL TUBERCULOSIS Archaeological skeletal evidence shows spinal TB has been with humans for millennia. However, Percival Pott (1714–1788), an eminent surgeon, has given his name to the spinal pathology and accompanying deformity; he was the first to show that it caused paraplegia and was responsive to surgery. The incidence of osteoarticular TB increases with age and is equally frequent among men and women, overall making up approximately 9% of cases of extrapulmonary TB.126 Most skeletal TB results from endogenous reactivation of foci of infection seeded during the initial bacteraemia, although spread from paravertebral lymph nodes has been postulated to account for the common localization of spinal TB to the lower thoracic and upper lumbar vertebrae.127 Spinal TB less frequently involves middle thoracic or cervical vertebrae. Usually two adjacent vertebrae are involved, although skip lesions may occur.128 The infection begins in the anterior inferior or anterior superior aspect of the vertebrae, leading to bony collapse and the classical radiological appearance of anterior wedging of two vertebrae with intervening disc destruction. The early changes of spinal

34

TB are difficult to detect by standard films, and CT scans or MRI may be needed to visualize disease process. Bone is replaced by granulomatous tissue with or without caseation necrosis and mycobacteria are scanty. While a disease of children and young adults in endemic regions it is a disease of the elderly in developed countries.129 The presentation may be cryptic with local back pain accompanied by few systemic symptoms leading to delayed diagnosis which may eventually be precipitated by signs of advancing bony destruction, deformity and neurological weakness or paraplegia secondary to spinal compression. Pus at high pressure due to confinement within tight ligaments follows the path of least resistance along fascial planes and can present with abscesses and sinuses distant from the original bony lesion before or after the initiation of chemotherapy. Involved anatomical regions may range from retropharyngeal abscess in the neck to psoas abscess presenting with a femoral triangle mass in the groin. Weakness and paralysis is the most serious complication, occurring in 30–50% of cases and can present or worsen after initiation of therapy.129 Long spinal tracts may be affected by a combination of local pressure, vasculitis and arachnoiditis.129 Treatment is predominantly medical although surgery may be indicated for those with instability of the spine at risk of progressive deformity.130,131 Medical treatment consists of standard TB chemotherapy, but is usually prolonged.40

PERIPHERAL OSTEOARTICULAR TUBERCULOSIS Tuberculous arthritis usually presents as a slowly progressive monarthritis affecting predominantly, although not exclusively, the major weight-bearing joints such as knee and hip. Systemic symptoms are frequently absent or mild and the main signs and symptoms are joint swelling, pain and diminished range of movement. Evidence of prior pulmonary TB on chest radiograph is present in approximately 50% of cases.121 Radiological findings vary with the chronicity of infection and range from soft-tissue swelling, juxta-articular osteopenia, joint-space narrowing with subchondral erosions to joint destruction.122 The diagnosis may be delayed or more difficult when TB infects joints previously damaged by other arthritic processes. The diagnosis is confirmed by demonstration of histological changes compatible with TB on synovial or bone biopsy and/or positive mycobacterial culture of synovial fluid or periarticular abscess.122,123 Acid-fast stains of joint fluid are usually negative, and culture for M. tuberculosis positive in approximately 60–80% of patients with osteoarticular TB.132 Treatment is with chemotherapy with surgical joint fusion reserved for serious joint instability present after failed prolonged medical therapy.40 Tuberculous osteomyelitis presents as a cold abscess with swelling and/or sinus formation overlying the involved bone. Lesions may be single or multiple, involving ribs, skull, pelvis or the long bones.124 Diagnosis is confirmed by bone biopsy and mycobacterial culture. Treatment is medical with adjunctive surgical debridement if necessary.121,122,124

DISSEMINATED TUBERCULOSIS The term disseminated TB refers to TB that involves two or more non-contiguous sites. It can occur during primary TB infection, after reactivation of latent infection or after reinfection, depending on the efficacy of the cellular immune response to contain the disease. Dissemination occurs when tubercle bacilli enter the blood

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circulation via the lymphatics and spread to visceral sites that have a rich vascular supply such as the liver, spleen, brain and the bone marrow. Miliary TB is a pathological name describing miliary (millet seed)-sized granulomata in various organs affected by haematogenous dissemination of tubercle bacilli. While miliary TB can be recognized in histological specimens from tissues other than the lung,133 the majority (86–91%) of published clinical papers rely on recognition of miliary shadows on chest radiograph (Fig. 34.3). In order to clarify the difference between clinical and pathological diagnoses, it has been proposed that the term miliary TB should be restricted to disseminated TB with miliary shadows on chest radiograph and those cases not showing miliary shadows on chest radiograph be called disseminated TB.134 Disseminated TB is a life-threatening disease resulting from haematogenous spread of M. tuberculosis to a variety of tissues and may lead to a wide range of manifestations, from an acute fulminant illness to a prolonged cryptic illness with subtle clinical findings. The presenting symptoms and signs are generally non-specific and are dominated by systemic effects, particularly fever, weight loss, anorexia and weakness.73 Other symptoms depend on the relative severity of disease in the organs involved. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy and splenomegaly occur in descending order of frequency. Physical findings may include choroidal tubercles, with granulomata located in the choroid of the retina, and cutis miliaris disseminata, a rare cutaneous manifestation of miliary TB.135,136 In HIV-seronegative patients with disseminated TB underlying predisposing conditions such as diabetes mellitus, organ failure and autoimmune conditions are present in 41–47% of cases.73,136,137 The disease is characterized by high mortality, reported to be 18–30%. Mortality is strongly associated with age, mycobacterial burden, delayed chemotherapy and laboratory markers indicative of severity of disease such as lymphopenia, thrombocytopenia, hypoalbuminaemia and elevated hepatic transaminases.73,133,134 Diagnosis can be made by isolation of M. tuberculosis from sputum and gastric washings but is frequently missed and more invasive investigations are required. In retrospective series the diagnostic yield of bronchoscopy, bone marrow biopsy and liver biopsy were high.73,133,134 Identification of typical granulomata and/or acid-fast

bacilli in histological specimens allows for rapid diagnosis of disseminated TB; however, mycobacterial culture, while enabling a definitive diagnosis to be made, results in increased delay in confirming the diagnosis. Adult respiratory distress syndrome (ARDS) is a serious complication of miliary TB, occurring in approximately 1% of cases. ARDS is increased in those with the same disease risk factors associated with increased mortality.137 The incidence of disseminated TB is increased in patients coinfected with HIV with miliary shadowing identified in up to 38% of AIDS patients with extrapulmonary TB.24 Constitutional symptoms predominate and the disease is characterized by a high mycobacterial burden, diffusely spread throughout multiple organs in individuals with anergic or poor immunological reactivity. Complications such as ARDS, skin lesions and abscess formation occur more frequently in those who are HIV-infected. IRD is frequent in those with disseminated TB commencing antiretroviral therapy.55 Diagnosis can be confirmed by histological examination of organ and lymph node biopsies, and culture of respiratory secretions, CSF, urine and blood. In children dissemination represents as a condition of infinite gradation. Occult dissemination is common following primary infection; however, it rarely progresses to disseminated disease except in very young (< 3 years of age) and immunocompromised children.48,78 Typical radiological signs include the presence of even-sized miliary lesions (< 2 mm) distributed bilaterally into the very periphery of the lung.79 Diagnostic confusion often exists in HIV-infected children in whom lymphocytic interstitial pneumonitis, malignancies and opportunistic infections such as Pneumocystis jiroveci pneumonia may present with a similar radiological picture.138 In these instances, response to treatment and/or bacteriological confirmation may be the only way to establish a definitive diagnosis and treatment should not be delayed while awaiting diagnostic confirmation.

CUTANEOUS TUBERCULOSIS Cutaneous responses to M. tuberculosis infection are highly varied and reflect diverse pathological responses to mycobacterial organisms and antigens. Tuberculids are the commonest skin

Fig. 34.3 Disseminated (miliary) TB. A 15-month-old HIV-infected, underweight infant presented with intermittent fever and coughing. His chest radiograph (A) and CT scan (B) demonstrated diffuse granular shadowing suggestive of disseminated (miliary) TB.

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Overview of extrapulmonary tuberculosis in adults and children

manifestations of tuberculous infection although mycobacteria are not isolated from the lesions. Erythema induratum was the commonest tuberculid (93%) followed by papulonecrotic tuberculid and together they constituted 85% of cutaneous TB cases seen over a 10-year period in Hong Kong.139 Erythema nodosum is not a form of cutaneous TB, but a hypersensitivity reaction attributed to primary TB, many other infections and some drugs. True cutaneous TB includes lupus vulgaris, scrofuloderma and verrucosa cutis and are characterized by the presence of granulomata with caseating necrosis and a relative paucity of mycobacterial organisms. Lupus vulgaris is seen mainly on the extremities; cervical and axillary regions are the commonest sites for scrofuloderma and verrucosa cutis occurs predominantly on the sole and foot.140 The diagnosis of cutaneous TB can be confirmed by demonstration of epithelioid cell granulomata and caseation necrosis on cytology or biopsy.141 In a series of fine needle aspirations from cutaneous TB lesions, acid-fast bacilli were identified in 79% of scrofulodermatous lesions and 22% of lupus vulgaris lesions.141 There is a good response to anti-TB chemotherapy with a resolution of lesions within 6 months in 92% of patients receiving RMP-containing combination chemotherapy.139 Cutis miliaris disseminate, previously recognized as a rare complication of miliary TB, is now more frequently recognized in patients with advanced HIV infection together with dissemination of M. tuberculosis organisms and is manifested by the presence of miliary tubercles within the dermis.142

OCULAR TUBERCULOSIS Besides cranial nerve involvement TB may affect all parts of the eye, most commonly the choroids.143 In children papulonecrotic TB and phlyctenular conjunctivitis are hypersensitivity reactions due to primary TB disease. Tuberculous uveitis may present as panuveitis or as chronic granulomatous iridocyclitis.143 Patients with miliary TB may present with choroidal tubercles, which can be single or multiple and vary in size.143 Rarely, lupus vulgaris may affect the eyelids.

TUBERCULOSIS OF LARYNX, PHARYNX, ORAL CAVITY AND SALIVARY GLANDS Before the advent of anti-TB treatment patients often developed laryngeal TB, which is a highly infectious form of extrapulmonary TB. Although now rare, laryngeal TB still occurs in areas with high prevalence of pulmonary TB. The clinical manifestations of laryngeal TB have changed and are different from those of classic reports.144 It can occur without pulmonary TB, and the characteristics of lesions can be granulomatous, ulcerative, polypoid or nonspecific. The main presenting symptoms are hoarseness and pain, which may radiate to one or both ears and may lead to odynophagia. Active pulmonary disease is present in approximately half of cases and inactive pulmonary TB in a third. Depending on the presentation, tuberculous laryngitis may resemble acute viral laryngitis or carcinoma of the larynx. Clinical features of these conditions may overlap and the granulomatous and ulcerative lesions may resemble laryngeal carcinoma.144 Laryngeal TB responds readily to standard TB chemotherapy. Tuberculous involvement of the tonsils, pharynx and oral cavity is uncommon. The presenting features may include ulceration of the tonsil or oropharyngeal wall, granulomatous inflammation of the nasopharynx or cervical abscess.144 Infection in the oral cavity

34

is usually acquired through infected sputum coughed out by a patient with pulmonary TB or by haematogenous spread. The tongue is the most common site of involvement and accounts for nearly half the cases. Other sites of involvement include floor of mouth, soft palate, anterior pillars and uvula.145,146 Tuberculous sialitis is usually secondary to TB of the oral cavity or pulmonary TB.146 The parotid glands are most commonly involved and clinical presentation can be acute or chronic. Acute presentation may resemble acute bacterial sialitis and clinical differentiation may be difficult. In other situations, the clinical presentation may resemble that of a salivary gland tumour.146 Unsuspected tuberculous parotid abscess may be mistaken for a pyogenic abscess and inappropriately drained, leading to formation of a persistent sinus.145

TUBERCULOSIS OF THE EAR, PARANASAL SINUSES, NOSE AND NASOPHARYNX Tuberculosis of the ear rarely involves the external ear and usually develops when the tubercle bacilli invade the Eustachian tube or by haematogenous spread to the mastoid process.137 Tuberculous otitis media may present as painless otorrhoea. Otoscopy may reveal pale granulation tissue in the middle ear with dilatation of vessels in the anterior part of the tympanic membrane. Multiple perforations of the tympanic membrane may occur as a result of caseating necrosis. Facial nerve palsy may sometimes develop.145 Tuberculous involvement of the ear appears to be particularly common in HIV-infected children. Tuberculosis of the nose, paranasal sinuses and nasopharynx is uncommon. Tuberculosis of the nasal mucosa may present with nasal discharge, mild pain and partial nasal obstruction and may be complicated by septal perforation, atrophic rhinitis and scarring of the nasal vestibule.145 Tuberculous involvement of the nasal mucosa may present with granulomatous lesions resembling Wegener’s granulomatosis.147

TUBERCULOSIS OF THE BREAST Tuberculous mastitis can occur as primary disease or can be secondary to TB elsewhere in the body. Secondary involvement of the breast is more common than primary involvement and tubercle bacilli may reach the breast through lymphatic or haematogenous routes, or by contiguous spread from the ribs or pleural space. Lymphatic spread by retrograde extension from the axillary lymph nodes is considered to be the most common mode of spread though spread from cervical and mediastinal lymph nodes has been occasionally reported.145 Primary TB mastitis is extremely rare and is thought to occur due to direct inoculation of the breast by M. tuberculosis through skin abrasions or duct openings in the nipple.145 Clinical presentation is atypical and histopathological evidence suggests the diagnosis.

MISCELLANEOUS CONDITIONS Extrapulmonary TB may involve almost any body organ system and like syphilis is a great mimic of many other diseases (Tables 34.2 and 34.3). This is mostly the result of disease progression that occurs at sites where the TB bacillus was deposited during the initial phase of occult dissemination.145,148 In some individuals a few mycobacteria may provoke intense immunological responses with local tissue injury, while in contrast there may be a non-reactive

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Table 34.2 The distribution of tuberculosis cases by anatomical site comparing HIV-seronegative with HIV-infected patients

Pulmonary TB only Extrapulmonary TB only Both pulmonary and extrapulmonary TB Pleural TB Lymph node TB Genitourinary TB Disseminated TB TB meningitis Abdominal TB Other TB

HIV-seronegative (%)

HIV-infected (%)

75 15 5

30 20 50

20 35 9 8 5 3 10

20 35

45

Adapted from Sharma and Mohan.145

pattern of response to a widespread organism burden in anergic individuals. Tuberculosis is capable of producing rare and unusual presentations, such as tuberculous adrenal involvement presenting as an Addisonian crisis or tuberculous infection of the craniovertebral junction presenting as torticollis.149 Newborn babies may acquire congenital TB via the placenta, if the mother develops active TB and haematogenous dissemination, in which case the primary (Ghon) focus is usually located in the liver. Cases of congenital TB are on the rise in countries where TB/HIV coinfection rates among expectant mothers are high. The incidence and prevalence of extrapulmonary TB varies profoundly and is closely linked to global resource inequalities. Consequently in industrialized settings where extrapulmonary TB is less common, a high index of clinical suspicion for a possible tuberculous aetiology needs to be maintained. In contrast, in resourcepoor settings where the prevalence of TB is high together with its recognized ability to produce protean manifestations many patients receive prolonged empiric courses of anti-TB treatment for non-tuberculous conditions.

REFERENCES 1. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO/ HTM/TB/2006.362. Geneva: World Health Organization, 2006. 2. Stead WW, Eichenholz A, Strauss HK. Operative and pathologic findings in twenty-four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous. Am Rev Respir Dis 1955;30:473–502. 3. Yilmmaz MU, Kumcuoglu Z, Utkaner G, et al. Computed tomography findings of tuberculous pleurisy. Int J Tuberc Lung Dis 1998;2:164–167. 4. Cherian G. Diagnosis of tuberculous aetiology in pericardial effusions. Postgrad Med J 2004;80: 262–266. 5. Elliott AM, Luo N, Tembo G, et al. Impact of HIV on tuberculosis in Zambia: a cross sectional study. BMJ 1990;301:412–415.

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Table 34.3 Disease spectrum documented in a prospective community-based survey of all children < 13 years of age, treated for tuberculosis in a highly endemic area TB manifestation

Total (%) n ¼ 439

Not TB

85 (19.4)

Intrathoracic TB Ghon focus Uncomplicated Complicated Lymph node disease Uncomplicated Complicated Compression Consolidation Pleurisy Pericarditis Miliary disease Adult-type disease

307 (69.9)

Extrathoracic TB Peripheral lymphadenitis Cervical Other Central nervous system TB Meningitis Tuberculoma Abdominal TB Osteoarticular TB Spinal TB Other Skin

72 (16.4)

[Intra þ Extrathoracic TB]

[25 (5.7)]

16/307 (5.2) 3/307 (1.0) 147/307 (47.9) 25/307 (8.1) 62/307 (20.6) 24/307 (7.8) 1/307 (0.3) 15/307 (4.9) 14/307 (4.6)

35/72 (48.6) 1/72 (1.4) 14/72 (19.4) 2/72 (2.8) 1/72 (1.4) 4/72 (5.6) 7/72 (9.7) 8/72 (11.1)

Not TB, chest radiograph not suggestive of TB (confirmed by two independent child TB experts), no bacteriological or histological proof and no extrathoracic TB recorded. [Intra þ extrathoracic TB], children with intra- and extrathoracic TB who were included in both groups; therefore this number should be deducted to add up to a total of 439 or 100%. Adapted from Marais et al.148

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