Expulmonary tuberculosis Extrapulmonary Tuberculosis (TB) is TB which occurs in any other part of the body outside the lungs. Many people do not realise it but TB can infect almost any place in the body: the inner organs, the bone, the brain, the spine etc. In fact, the only place that TB cannot infect is our hair or nails. One in five TB patients are infected with extrapulmonary TB and these strains are often much more difficult to diagnose.

Extrapulmonary TB is especially prevalent in countries with a low prevalence of TB and, as a consequence, it is often overlooked as doctors will not immediately think that TB is the problem when diagnosing illnesses outside of the lungs.

Risk factors for extrapulmonary tuberculosis. To control for potential confounders, we used a series of logistic regression models. All models included sex, age, and race/ethnicity; other variables were added individually. After adjustment, sex, race/ethnicity, and HIV status remained strongly associated with extrapulmonary tuberculosis (table 2). Patients with extrapulmonary tuberculosis were more likely to be female, non-Hispanic black, and HIV-positive, whereas excessive alcohol use appeared to be negatively associated with extrapulmonary tuberculosis. Although other variables, such as homelessness, residence in a long-term care facility, and noninjection drug use, appeared to have a significant association with extrapulmonary disease using univariate analysis, these factors did not show a statistically significant association with extrapulmonary disease after controlling for potential confounders using multivariate logistic regression analysis. Because of the small size of the subpopulation of patients identified as American Indians and Asian/Pacific Islanders, these 2 groups were combined into a single group, designated as “other,” for analysis; this group showed an increased risk for extrapulmonary tuberculosis, compared with non-Hispanic whites.

SIGNS AND SYMPTOMSExtrapulmonary tuberculosis (TB) In some cases, TB can occur outside the lungs, which is known as extrapulmonary TB. Extrapulmonary TB is more common in people with a weakened immune system, particularly people with an HIV infection. You are also more likely to develop extrapulmonary TB if you have previously been infected with TB but haven't had any symptoms (a latent TB infection).

A TB infection can affect the:-lymph nodes (lymph node TB)-bones and joints (skeletal TB)-the digestive system (gastrointestinal TB)-the bladder and reproductive system (genitourinary TB)-the nervous system (central nervous system TB)

These types of extrapulmonary TB can cause additional symptoms, which are described below.

Lymph node TB

Lymph nodes are small glands that are part of the immune system. They remove unwanted bacteria and particles from the body. Symptoms of lymph node TB include:persistent, painless swelling of the lymph nodes, which usually affects nodes in the neck, but swelling can occur in nodes throughout your body over time, the swollen nodes can release fluid through the skin

Skeletal TBSymptoms of skeletal TB include:-bone pain-curving of the affected bone or joint-loss of movement or feeling in the affected bone or joint-weakened bone that may fracture easily

Gastrointestinal TBSymptoms of gastrointestinal TB include:-abdominal pain-diarrhoea -rectal bleeding

Genitourinary TB Symptoms of genitourinary TB include:-a burning sensation when you urinate-blood in your urine -a frequent urge to pass urine during the night-groin pain

Central nervous system TBYour central nervous system consists of your brain and spinal cord. Symptoms of central nervous system TB include:-headaches-being sick -stiff neck-changes in your mental state, such as confusion-blurred vision-fits (seizures)

DIAGNOSTIC APPROACH

Step-by-step diagnostic approach

Many forms of extrapulmonary TB (EPTB) are paucibacillary, and the diagnosis of EPTB is therefore challenging. Acid-fast bacilli (AFB) smear of biological specimens is often negative. Tuberculin skin testing (TST) and interferon-gamma release assays (IGRA) are adjunctive diagnostic tools, at best. Constitutional symptoms associated

with EPTB, (such as fever, weakness, and weight loss) may be infrequent and non-specific. In addition, EPTB is less common than pulmonary tuberculosis (PTB) and may be less familiar to clinicians.

A high level of suspicion is important in evaluating a patient with presence of risk factors (for full details please refer to risk factor section). The firm diagnosis of TB requires culturing of Mycobacterium tuberculosis and is important for drug-susceptibility testing. Appropriate specimens are obtained and tested microbiologically and histologically. Although culture remains the diagnostic standard, it can take up to 8 to 10 weeks using a solid media, and in 10% to 15% of patients the diagnosis of TB is based on clinical grounds. Delays in diagnosis and initiation of therapy are associated with increased mortality.

Tests for all suspected EPTB

As the lungs may be involved in patients with EPTB, sputum for AFB smear and culture is indicated for all suspected patients. Culture-positive sputum becomes useful when the specimens from extrapulmonary sites are culture-negative, and it may also add further information on the infectiousness of the patient. Chest x-ray should be part of the basic initial work-up and may show evidence of active or old TB. Tuberculin skin test (TST) is also done in all patients with suspected EPTB, although the sensitivity may range from 30% to 90% depending on the site of disease. A positive TST is helpful for diagnosis, but a negative TST does not rule out active disease. An FBC should be sent and may show abnormalities.

If the suspicion of TB is high or the patient is very ill, consideration can be given to starting antituberculous medicines as soon as diagnostic specimens are obtained.

Interferon-gamma release assay (IGRA) is an in vitro test, which the Centers for Disease Control and Prevention (CDC) recommends can be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programmes for infection control (e.g., those for healthcare workers). The sensitivity of IGRA to diagnose EPTB is suboptimal.

Several molecular diagnostic methods (nucleic acid amplification tests) are available. They are based on amplification of mycobacterial nucleic acid. These methods enable the laboratory to provide the results to clinicians within a day, with higher specificity and sensitivity than AFB smear.

It is recommended that all patients with TB have an HIV test within 2 months of diagnosis. In 2008, 6% of patients with TB were known to be HIV-positive.

HIV infection and its treatment may alter the treatment of TB; treatment of HIV may be crucial to the morbidity of HIV-infected TB patients.

TB lymphadenitis

Patients most commonly present with enlarged lymph nodes in the cervical or supraclavicular areas that may be unilateral or bilateral.

If a patient with superficial lymphadenitis is suspected of having TB, the first diagnostic test is FNA, especially if the lymph node is fluctuant. If the diagnosis remains in question, then a surgical consultation is obtained for lymph node excision (not incisional biopsy, due to the risk of sinus tract formation).

If the patient has inaccessible lymphadenitis (e.g., mediastinal), excisional biopsy is obtained with mediastinoscopy or thoracoscopy.

Pleural TB

Pleural TB usually presents with symptoms such as pleurisy, pleuritic chest pain, cough, and fever, and a chest x-ray showing a unilateral effusion. The effusion is commonly small to moderate in size; bilateral TB effusions are rare and associated with disseminated disease.

In addition to a chest x-ray, sputum cultures, and TSTs, a thoracentesis is done. Chest x-ray may show no obvious parenchymal disease in 50% of patients with pleural TB; sputum cultures are positive in 20% to 30% of those without definite parenchymal involvement. False-negative TSTs are also common.

Pleural fluid analysis is performed on the sample obtained from thoracentesis. Pleural fluid is sent for AFB smear and culture, cell count with differential, protein, LDH, glucose, and pH. AFB smear is rarely positive. Pleural fluid analysis usually shows an exudative effusion that is lymphocyte-predominant and often has low glucose level. The adenosine deaminase (ADA) level may be measured because it is often elevated in pleural TB (sensitivity and specificity approximately 90%).

Although results of pleural fluid analysis may be helpful, they will seldom confirm a diagnosis of pleural TB. Because a malignancy may also cause a lymphocyte-predominant exudative effusion, the diagnosis of pleural TB is based on microbiology, pathology (granulomas), and negative cytology. It is important to obtain a TB isolate for susceptibility testing. Therefore pleural biopsy is indicated when the patient has a lymphocyte-dominant exudative effusion, or even at the same time as thoracentesis if clinical suspicion for TB is very high. The combination of AFB culture and histology from pleural biopsy is the most sensitive to diagnose

pleural TB. If results of biopsy are non-diagnostic, thoracoscopy or thoracotomy may be indicated.

Skeletal TB

About 70% percent to 90% of patients may have a positive TST. One half of cases will have abnormalities on chest x-ray consistent with TB.

Pain of the involved area is the most common complaint in skeletal TB; constitutional symptoms are usually absent. Diagnosis is based on tissue biopsy. Onset of pain is gradual (over weeks to months) and diagnosis is frequently delayed. Local swelling and limitation of movement may be present. Cold abscesses (non-tender) with sinus tracts may form.

If skeletal TB is suspected, MRI (especially in spinal involvement) or CT is obtained. Microbiological confirmation of TB is also essential. AFB smears are unlikely to be positive due to low bacillary loads. Cold abscesses, if present, may be aspirated for AFB smear and culture. CT-guided biopsy in vertebral TB will have positive microbiological or histological yields in 65% to 90% of patients.

Synovial biopsy should be done to diagnose TB arthritis. Biopsy may yield culture positive in 90% to 95% and can be performed if the diagnosis of TB arthritis remains in question. In joint involvement, evaluation of synovial fluid is usually not diagnostic; WBC counts in TB arthritis are usually 10,000 to 20,000/mL, but can be much higher. AFB smear is positive in <20% but culture may be positive in up to 80%.

CNS TB

CNS TB may present with meningitis or intracranial tuberculomas. Diagnosis of TB meningitis is dependent upon CSF examination, and its rapid diagnosis is essential for improved outcomes.

Signs and symptoms of meningeal TB include headache, neck stiffness, altered mental status, and cranial nerve abnormalities. Only 38% of children with TB meningitis have fever and 9% report photophobia. Seizures are common in children and the elderly.

In the presence of meningeal signs, the patient undergoes lumbar puncture and the CSF is submitted for cell count with differential, glucose, protein, AFB smear and culture, Gram stain, and bacterial culture. The usual results of analysis include a lymphocyte predominance, elevated protein, and reduced glucose. Although smears of spinal fluid are frequently negative, the diagnostic yield is dependent on the volume of CSF submitted and the quality of examination.

In order to maximise the sensitivity of TB diagnosis by spinal fluid analysis, some experts suggest increased CSF volume (at least 6 mL of spinal fluid for AFB) and repeated sampling (up to 3 lumber punctures on different days).

AFB culture is the definitive standard for diagnosis but treatment must not wait until culture results are available. Treatment is initiated presumptively based on clinical suspicion, risk factors, and CSF results.

Head CT or MRI may show oedema, hydrocephalus, basilar meningeal thickening, or tuberculomas. Tuberculomas present as a slowly growing focal lesion, or, rarely, with signs and symptoms consistent with increased intracranial pressure. CSF analysis is usually normal and diagnosis is based on CT or MRI findings.

Up to 50% of patients have chest x-ray abnormalities consistent with pulmonary TB.

Abdominal TB

TST may be positive in 70% and chest x-ray may show evidence of old TB.

Abdominal TB includes TB peritonitis and TB of the GI tract. Definitive diagnosis is based on culture growth of M tuberculosis from ascitic fluid or a biopsy of the lesion. Patients may have disease for months before the diagnosis is made. Peritoneal disease is the more common presentation. The presenting symptoms include abdominal swelling, abdominal pain, fever, and change in bowel habits. In TB enteritis (TB of the GI tract), the ileocaecum is the most commonly involved area, followed by the ileum, caecum, and ascending colon. Chronic abdominal pain is the most common symptom in addition to changes in bowel habits and haem-positive stool. Patients may develop small bowel obstruction or a RLQ mass.

CT scan of the abdomen, ascitic fluid analysis, and peritoneal biopsy are done initially.

CT scan may show ascites, bowel-wall thickening, or abdominal lymphadenopathy.

Ascitic fluid analysis is non-specific and rarely AFB smear-positive. Although the sensitivity of culture from peritoneal fluid is high (92%), results require up to 8 weeks and delay in initiating treatment is associated with higher mortality.

Peritoneal biopsy (laparoscopy or laparotomy) is the most effective means for diagnosis. Direct inspection may reveal miliary nodules over the peritoneum and allow a presumptive diagnosis in 80% to 95%. Biopsy demonstrates caseating granulomas (up to 100%) and the presence of AFBs on examination in 67% of samples.

Colonoscopy and biopsy are carried out to diagnose TB enteritis. Colonoscopy will reveal ulcers, pseudopolyps, or nodules. Definitive diagnosis is based on biopsy, which usually shows granulomas and culture positive for TB.

Genitourinary TB

Chest x-ray is abnormal in 40% to 75% of patients. TST is positive in up to 90% of patients.

Diagnosis relies on culturing TB from morning urine samples (3 are recommended) or biopsy of the lesion. The common symptoms are dysuria, haematuria, and urinary frequency. Symptoms may be absent in 20% to 30% of patients. Genital TB in men may present as a scrotal mass and in women may be asymptomatic or cause pelvic pain. Constitutional symptoms are rare. Extensive renal destruction may have occurred by the time GU TB is diagnosed.

Urinalysis is done initially. Results commonly show pyuria, haematuria, or proteinuria, although they may be normal. Urine culture for TB may be positive in 80% of patients; 3 samples for culture improve sensitivity. The classic finding of sterile pyuria is neither sensitive nor specific. Definitive diagnosis of genital TB is based on tissue biopsy.

Pericardial TB

Chest x-ray shows cardiomegaly (in 70% to 95% of cases) and pleural effusion (in about 50%). ECG is low voltage (in about 25%) and shows T-wave inversion (in about 90%). Echocadiography, CT, or MRI shows pericardial effusion and thickness across the pericardial space. Diagnosis of pericardial TB requires aspiration of pericardial fluid or, usually, pericardial biopsy. Pericardial fluid is exudative with increased leukocytes, predominantly lymphocytes. Haemorrhagic effusion is often seen. AFB smear of the fluid is commonly negative and cultures are positive in 50% to 60% of cases. Pericardial biopsy offers a higher diagnostic yield.

Disseminated TB

The diagnosis of disseminated TB concentrates on the organs most likely to be involved. The most commonly involved organs (in order) are lungs, liver, spleen, kidneys, and bone marrow. Patients with disseminated TB will typically have constitutional symptoms including fever (90%), anorexia (78%), and sweats (76%).

If disseminated TB is suspected, chest x-ray (if non-diagnostic, consider a chest CT), sputum for AFB smear and culture, blood culture for mycobacteria, and first-morning-void urine for AFB are obtained; lumber puncture and biopsy of superficial lymph nodes are also done if applicable. Sputum smear will be positive in one-third of

patients with culture positive in about 60%. TST is positive in only 45% of patients with disseminated disease.

As delays in treatment are associated with increased mortality, a rapid diagnostic test (i.e., faster than culture results) is frequently needed. If sputum smears are negative and chest x-ray is abnormal, bronchoscopy with transbronchial biopsies are indicated. If results are non-diagnostic, bone marrow or liver biopsy is also done. Both have similar sensitivities, but bone marrow biopsy may be preferred because of its lower procedure risk. If thrombocytopenia or leukopenia are present, the sensitivity of bone marrow biopsy is increased.

TREATMENT APPROACH

The basic principles of treatment for extrapulmonary tuberculosis (EPTB) are the same as pulmonary tuberculosis (PTB) with a few exceptions. The goals of treatment of TB are to cure the patient clinically and minimise the chance of relapse, and to prevent further transmission of TB to others. Therapy for EPTB requires a minimum of 6 months of treatment.

The treating physician acts in a public health role and is responsible for ensuring that the patient successfully completes treatment. Therefore, many physicians share that responsibility with a local public health department. Patients can receive treatment through direct observation of therapy (DOT) whereby the patient is provided with the tablets and is observed swallowing them. This is often done in conjunction with a local public health department.

Treatment consists of an initial intensive phase and subsequent continuation phase.

The decision on the use of directly observed therapy as opposed to self-administered daily therapy depends on the resources available to local public health, collaboration with community partners, and prioritisation of cases. The high priority should generally be given to situations such as treatment failure, drug resistance, relapse, HIV co-infection, current or prior substance abuse, psychiatric illnesses, memory impairment, and cases in children/adolescents.

Treatment of drug-resistant TB, especially multidrug-resistant (MDR) TB, should be attempted only with expert advice. Although there are many TB patients co-infected with HIV globally, expert advice should be sought if the clinician is not familiar with management of TB patients co-infected with HIV.

Initial phase Microbiological confirmation of EPTB can take several weeks and this delay in treatment initiation may increase mortality in some forms (CNS, disseminated, peritoneal). Therefore, antituberculous therapy is initiated based on clinical suspicion after optimal diagnostic samplings.

Initial intensive-phase treatment involves the first-line drugs of isoniazid, rifampicin, pyrazinamide, and ethambutol, with drug-susceptibility testing for those agents.

Initial phase for multidrug resistance MDR may be suspected on the basis of historical or epidemiological information. MDR isolates are resistant to at least both isoniazid and rifampicin. In this case, consultation with an expert in treatment of MDR TB is necessary to determine the most appropriate antituberculous therapy.

Continuation phase If the Mycobacterium tuberculosis isolate is sensitive to isoniazid, rifampicin, and pyrazinamide, then isoniazid and rifampicin are given for 4 months in the continuation phase (i.e., 6 months of total treatment).

Total therapy for 9 months is considered for patients with extensive skeletal TB, especially when large joints are involved with slow clinical response. Patients with CNS TB receive 7 to 10 months of continuation phase (9 to 12 months total). Patients with MDR should have their final regimen based on the results of drug-susceptibility testing, in consultation with an expert.

Administration of therapy on an intermittent basis, as opposed to daily dosing, facilitates DOT, thereby improving the outcome in patients suitable for this regime.

CNS or pericardial TB Patients who have CNS or pericardial TB receive adjunctive corticosteroid treatment.

Pyrazinamide-unsuitable patients Pyrazinamide is not recommended for patients experiencing acute gout or for pregnant women because of little safety information. Those patients who do not receive pyrazinamide during the intensive phase should receive 7 months of continuation phase (9 months total).

Liver injury Several TB medicines (e.g., isoniazid, rifampicin, and pyrazinamide) are metabolised by the liver and may potentially cause or exacerbate hepatic injury. Mild hepatitis may require only closer monitoring without changes in the standard regimen. However, severe hepatitis while on TB treatment may make it necessary to hold medicines and use an alternate liver-sparing regimen.

If drug-induced liver injury (DILI) occurs, potentially hepatotoxic drugs are stopped and alcohol is avoided.

An asymptomatic, mild increase in AST occurs in 20% of patients; if this is <5x upper limit of normal (ULN) with no symptoms, or <3x ULN with symptoms, TB medicines can be continued but liver function tests (LFTs) and symptoms are monitored closely.

While LFTs are normalising and symptoms are improving, at least 3 drugs without hepatotoxic effects (e.g., ethambutol, fluoroquinolone, and an injectable) may be given, especially if the burden of TB disease is more than minimal. When AST becomes <2x ULN, first-line drugs are

serially reintroduced one by one, waiting 4 to 7 days before adding next drug. Before introducing each new drug LFTs are checked. If an increase in AST occurs, the most recently introduced drug is likely responsible for hepatitis. Expert opinion should be sought.

Renal insufficiency This complicates treatment as some medicines and their metabolites (e.g., ethambutol, streptomycin, pyrazinamide) are cleared by the kidneys. Dosing changes are needed.

HIV-positive Intermittent twice-weekly administration not recommended for HIV-positive patients with CD4+ count <100 cells/mL. Instead, either a daily or thrice-weekly regimen is recommended.

Seriously ill Not seriously ill TB meningitis Disseminated TB TB pericarditis TB peritonitis & gastrointestinal TB Bilateral or extensive pleurisy Spinal TB with Neurological

complications GUT TB

Lymph node TB Pleural effusion Bone excluding spine Peripheral joints

Category of treatment Type of patient RegimenCategory 1 New sputum smear-

positive PTBSeriously ill** new sputum smear- negative PTBSeriously ill** new EPTB

2H3R3Z3+4H3R3

Category 2 Sputum smear- positive relapseSputum smear- positive FailureSputum smear- positive Treatment after default, others ***

2S3H3R3Z3E3+1H3R3Z3E3+5H3R3E3

Category 3 New sputum smear- negative PTBNew EPTB, not seriously ill

2H3R3Z3+4H3R3

No. before the letters refers to the mos. Of treatment; the subscript after the letters refer to the no. of doses per week

PATIENT MANAGEMENT

Respiratory hygiene/cough etiquette comprises of: -covering the nose/mouth with a tissue when coughing or sneezing; -using tissues to contain respiratory secretions; -spitting into a tissue if spitting is necessary; -disposing of tissues into the nearest rubbish bin after use; and -performing hand hygiene after contact with respiratory secretions and contaminated objects/materials e.g. tissue

Patient Accommodation -Single room with ensuite facilities -Door to remain closed -Airborne precautions sign to be placed prominently on entrance to room -Negative pressure air-conditioning to be used (if available) -Do not use a positive pressure air conditioning system. If this type of system is installed it must be turned off during the patient's isolation -If no negative pressure is available and there is no possibility of air currents resulting in TB transmission, the window may be opened (consult with TB or Infection Control Coordinator); and -Do not cohort TB patients in multi-bedded rooms, due to the possibility of multi-drug resistant TB (MDR-TB)

Hand hygiene -Hand hygiene to be performed as per the 5 Moments for Hand hygiene -Hand hygiene to be performed on leaving the room and after removal of PPE using an antiseptic hand wash solution or alcohol based hand rub or gel

Masks -A particulate filter personal respiratory protection device or P2/N95 mask, is a close fitting mask worn for Airborne Precautions, which is capable of filtering 0.3μm particles -A P2/N95 mask must comply with AS/NZS 1716 -A mask must be discarded once it has been worn, or becomes visibly soiled or moist, and must not be used again. When the mask becomes moist from the wearer, or from contamination, the barrier has been breached and the mask is no longer effective -A mask must be removed by touching the strings/ties or loops only -The P2/N95 mask (for airborne precautions) should be removed outside the room, after the door has been closed

Patients -Patients must wear a fluid resistant surgical mask when leaving the room for any reason -Patients on oxygen therapy must be changed to nasal prongs and wear a fluid resistant surgical mask over the top of the nasal prongs if condition allows -Must be provided with instructions for donning and removal of mask; and

Patients are not required to wear a mask when the staff or visitors are entering their room

Health Care Workers -Particulate mask (P2 or N95) to be worn by all HCWs entering the room of patients diagnosed or with a provisional diagnosis of TB and removed after leaving the room -Perform hand hygiene after removing and discarding mask

Visitors/Family -Visitors must wear a particulate mask (P2 or N95) on entering the room and removed after leaving the room Perform hand hygiene after removing and discarding mask