OVERVIEW: What every practitioner needs to know

When do you suspect tuberculosis? What should you expect to find?

In non-endemic areas of the world such as the US, tuberculosis (TB) should be suspected in the setting of a recent close contact with a person with infectious TB or other risk factors for developing TB (see below). Clinical findings depend on the organ system(s) involved. Constitutional symptoms for all forms of TB include fever, night sweats, failure to thrive (children) or weight loss (adults). Pulmonary TB is the most common form with patients presenting with productive cough (>2 weeks) and often hemoptysis, that does not respond to standard anti-bacterial treatment. Other manifestations of TB include non-painful, often matted adenopathy with or without sinus formation, meningitis, pleural/pericardial effusion, non-painful joint swelling, erythema nodosum, and phlyctenular conjunctivitis.

How did the patient develop tuberculosis? What was the primary source from which the infection spread?

Mycobacterium tuberculosis, the causative organism for TB, is spread via aerosolized nuclei from individuals with TB disease (pulmonary or rarely upper airway, e.g. laryngeal TB). Close contact with such individuals, especially in a closed, crowded space without good air circulation is the primary source of infection. Infrequently, bovine TB (M. bovis) may also be acquired by drinking raw or poorly pasteurized milk from infected cattle.

Which individuals are of greater risk of developing tuberculosis?

  • Close and recent (generally within the last 12 months) contact with an individual with infectious TB. Individuals (especially children) may be diagnosed as part of a contact investigation, or may be sentinels for close contact with infectious TB.

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  • Born (or spent significant time – months to years) in a country with a high prevalence of TB (most of the world except North America, Western Europe and Australia). Individuals (or close contact of individuals) with high risk of TB such as homeless, users of illicit drugs, incarcerated persons, or migrant farm workers.

  • Young children or the elderly. Adolescents also have a higher risk of developing TB than other age groups.

  • Patients with HIV, immunosuppressive therapy (corticosteroids, TNF alpha inhibitors), patients with chronic illness such as lymphoma, Hodgkin’s disease, chronic renal failure, diabetes, etc.

Worldwide (2014), there were an estimated 9.6 million new cases of TB, and 1.5 million individuals died of TB. Children account for up to 10% of total TB burden globally.

In the US:

  • TB incidence is 2.96 per 100,000 people (2014), for a total of 9421 reported cases. 1.3% of all culture positive cases were multi-drug resistant (MDR).

  • Incidence of TB is highest in Asians > Native Hawaiian and other pacific islanders > Black / African American > Hispanic / Latino, American Indians / Alaska Natives >> Whites.

  • Two third of the new TB cases occurred in foreign-born individuals.

  • Certain geographical pockets have high incidence of TB and the risk should be evaluated based on local health data.

Beware: there are other diseases that can mimic tuberculosis:

Because TB can affect multiple organs and does not have pathognomonic clinical signs, many chronic infectious and non-infectious diseases can mimic TB. Notable amongst them is sarcoidosis, which presents with noncaseating granulomas in affected organ tissues (TB presents with caseating granulomas). Similarly, malignancies such as lymphomas and autoimmune diseases affecting the lungs can mimic TB.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Positive tuberculin skin test (TST) is supportive. TST should be placed and interpreted by an experienced person. Size of induration (rather than redness) should be recorded in mm (rather than positive or negative). Interpretation of the TST is dependent on the risk of infection and developing active TB. A cut-off of greater than or equal to 5mm induration is used for individuals with immunosuppression (HIV infected, systemic corticosteroids, etc.), recent close contacts of individuals with infectious TB or those with abnormal chest X-ray consistent with prior TB. Induration of greater than 10mm is used for recent immigrants from high-prevalence countries, injection drug users or high-prevalence populations based on local epidemiology. Though routine testing is not recommended for low risk individuals, a cut off of greater than and equal to 15mm is used for those individuals. A positive TST indicates that the patient has been exposed to TB, but does not distinguish between latent and active TB disease. A negative TST does not rule out TB (especially in young children, immunosuppressed individuals, and those with disseminated TB). False positives can also occur due to atypical mycobacterial infections (NTM) and prior BCG vaccination. Note that the effect of prior BCG vaccination wanes quickly (within a few years after vaccination) and current recommendations (based on expert opinion and limited published data) are to ignore prior BCG vaccination while interpreting TST.

  • Positive interferon-gamma release assays (QuantiferonTM or T-Spot-TBTM) are in vitro surrogates for the TST. Like TST, they also cannot distinguish between latent TB infection and active TB. However, in contrast to TST, these tests are more sensitive, especially in immunosuppressed patients, and more specific – less affected by NTM and prior BCG vaccination (at least in studies performed in non TB endemic settings).

  • Chest X-ray (see below)

  • Acid-fast bacilli (AFB) staining and culture (see below)

  • For suspected meningitis, lumbar puncture and head imaging (see below) should be performed in addition to the tests listed above. Cell count is elevated (median 50-450 cells per microliter) with lymphocytic (>50%) predominance, and elevated protein (0.5-3 g/L) with low glucose (CSF/plasma <0.5). CSF findings are similar in HIV co-infected patients versus patients without HIV. Atypical CSF findings including normal cell count, neutrophil predominance, normal protein and glucose have also been reported in patients with TB meningitis. CSF findings that favor TB versus bacterial meningitis include clear appearance of the CSF, cell count greater than 900-1000 per microliter, neutrophil less than 30-75%, and a protein concentration greater than 1g/L. Increasing the volume and number of CSF examinations, and meticulous microscopy (at least 30 minutes) can increase the sensitivity of both AFB microscopy and culture. The cerebrospinal fluid (CSF) should be sent for AFB stains and culture. Though nucleic acid amplification tests are highly specific, they are not necessarily more sensitive than culture methods.

  • Similarly, depending on organ involvement, analysis of other fluids (e.g. pleural, peritoneal, pericardial, synovial) can be helpful.

Results that confirm the diagnosis

  • AFB stains are helpful and have a sensitivity of 50-60%, though this can be as low as 10-15% for children. Although AFB staining is rapid, it needs to be performed in conjunction with culture (or other methods such as rapid nucleic acid tests) to confirm M. tuberculosis versus NTM. In addition, AFB stains do not provide any information on drug susceptibilities. Culture of relevant clinical specimen(s), e.g. sputum, gastric aspirate/induced sputa in children, CSF, tissue specimen, bone marrow, etc. remains the gold standard for diagnosing TB. Sputum (adolescent and adults) and early morning gastric aspirate or induced sputa (from young children) is the most common clinical sample used to diagnose TB, but other clinically relevant samples should also be sent for similar tests. Sending three consecutive specimens increases the yield. Sensitivity of culture is greater than 90% from respiratory samples, though it can be as low as 30-50% for TB meningitis, and 30-40% in young children. It generally takes several weeks, though automated systems such as BACTEC, MGIT can provide results in a few days to weeks. Drug-susceptibility testing should be performed on all positive M. tuberculosis isolates.

  • Several rapid nucleic acid amplification tests with high specificity are available. They are generally used to confirm M. tuberculosis versus NTM from smear positive specimens. Some of the available tests can also provide information on drug-susceptibility by probing for known drug-resistance mutations. In adults, these tests have a sensitivity of 90–100% for smear positive and 60–70% for smear negative, culture positive sputum samples. An automated, cartridge-based nucleic acid amplification system (GeneXpert® MTB/RIF) has been recently introduced. This system can detect M. tuberculosis and identify resistance to rifampicin within 2 hours directly from sputa. This test has a sensitivity of 98% smear positive and 72% for smear negative, culture positive sputum samples.

  • Demonstration of typical pathology e.g. caseating granulomas from tissue samples can also be considered diagnostic in the correct clinical setting.

  • Serological tests for TB are unreliable and should NOT be used.

What imaging studies will be helpful in making or excluding active tuberculosis?

  • Chest X-ray ($) is quite helpful for diagnosing pulmonary TB. Intrathoracic adenopathy (e.g. hilar adenopathy), cavitary lesion(s), and miliary shadowing are suspicious for TB. In addition, patterns consistent with various forms of pneumonia can also be seen. Calcification is suggestive of a long standing process or likely latent TB infection. Chest radiograph should also be performed in patients with extra-pulmonary TB. For example, abnormalities suggestive of TB are seen in 30-50% of children with TB meningitis. When available and depending on organ involvement, ultrasound ($) and computed tomography (CT) with contrast ($$$) may also be performed.

  • Central nervous system (CNS) TB: Head CT or magnetic resonance imaging (MRI) should be performed as part of the assessment for TB meningitis. Imaging studies may be normal in some patients with TB meningitis though MRI ($$$-$$$$) is more sensitive than CT. Hydrocephalus is observed in 80% of children and is typically less frequently seen in adults or adolescents. Basal meningeal enhancement is detected in 75-89% of patients with TB meningitis. Other findings include tuberculomas (8-31%) and infarcts (8-44%). Interestingly, tuberculoma may develop in over 75% of patients during treatment, most of which are asymptomatic. The combination of hydrocephalus, basal meningeal enhancement and infarcts was found to be 100% specific for TB meningitis in one study. Similarly, another study demonstrated the presence of a pre-contrast hyperdensity in the basal cisterns to be 100% specific for TB meningitis in children. Patients with HIV co-infection are reported to have less hydrocephalus and basal meningeal enhancement, but higher frequency of infarcts and mass lesions.

($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has tuberculosis, what therapies should you initiate immediately?

Infectious diseases should be consulted to evaluate all patients with suspected TB. Since TB treatment is complex and requires several months of therapy, confirmation of the diagnosis is essential and should be sought aggressively. When suspicion for active TB is low, the patient is not seriously ill and initial tests such as AFB stains are negative, treatment can be deferred until culture results are available. This is possible in most clinical settings. Consideration should also be made about the infectiousness of the patient and their close contacts. Infectious diseases (when available) or other physician with TB experience should be consulted. Local health authorities may also be consulted.

Since the incidence of isoniazid resistance is high, treatment involves an intensive phase with four drugs (rifampin – R, isoniazid – H, pyrazinamide – Z, and ethambutol – E or RHZE) for 2 months followed by treatment with two drugs (rifampin and isoniazid – RH) during a continuation phase of 4 months. The first-line TB drugs and their common side effects are listed in Table I. Several regimens with intermittent therapies are available. For example, one regimen utilizes 2 weeks of daily therapy with RHZE, followed by twice weekly RHZE (twice weekly dosing different from daily therapy) for another 6 weeks and then a continuation phase with twice weekly RH (twice weekly dosing different from daily therapy) for 18 weeks.

Table I.
Drug Dosage Side effects/Comments
Isoniazid children 10-15 mg/kg; adults 5 mg/kg; maximum 300 mg Hepatotoxic, though this is less frequent in children. Patients may develop asymptomatic elevation of liver enzymes or signs/symptoms that resemble viral hepatitis. Elevated liver enzymes may resolve, even with continued therapy. Peripheral neuropathy can occur with INH, presenting with parasthesias that start in the feet and climb to the hands and arms. This phenomenon is dose dependent and is seen in 0.2-1.2% of patients. Risks for neuropathy include increasing age, slow acetylator status, malnutrition, diabetes, renal failure, alcoholism, pregnancy, and breastfeeding. Symptoms are reversible with withdrawal of medication, and pyridoxine supplementation with INH can prevent occurrence.
Rifampin children 10-20 mg/kg; adults 10 mg/kg; maximum 600 mg Studies of monotherapy with rifampin in various populations have shown adverse rates (hepatic, dermatology, immunologic, hematologic, and gastrointestinal effects) of 22-26%, resulting in discontinuation in 1-14% of cases. Hepatitis is a well described side effect. In addition, rifampin increases the hepatic metabolism of several drugs including oral anticoagulants, oral contraceptive pills, antiretrovirals, etc. Cutaneous reactions (flushing of the face and neck, pruritis or rash) occur in 5-10% of patients. There have been reports of generalized hypersensitivity reactions with rash, fever, lymphadenopathy, hepatosplenomegaly, and elevated transaminases. The “flu-like syndrome” generally occurs with intermittent dosing of rifampin, in patients with poor adherence to daily rifampin therapy, and when daily rifampin is resumed after a drug-free period. Thrombocytopenia is the most common hematologic adverse effect and may occur in up to 1% of patients. Rifampin turns most bodily fluids orange and can stain contact lenses, clothes, etc. This should be explained to all patients before starting rifampin.
Pyrazinamide 15-30 mg/kg; maximum 2000 mg Pyrazinamide can often cause gastrointestinal symptoms – nausea (1-5%). Elevated transaminases have also been reported. It can also cause elevations in uric acid with the drug. Other effects include sideroblastic anemia, lupus, photodermatitis, aseptic meningitis, and leukopenia.
Ethambutol 15-20 mg/kg; maximum 1000 mg The main adverse effect is ocular toxicity – a noninflammatory process affecting the central fibers of the optic nerve, causing decreased visual acuity and loss of green vision. These reactions are dose dependent and reversible. However, ocular toxicity in children receiving ethambutol at standard doses is rare, and therefore the WHO recommends that children of all ages can be given ethambutol in daily doses of 20 mg/kg (range 15–25 mg/kg) and three times weekly intermittent doses of 30 mg/kg body weight without concerns.

Since compliance with medications is critical, several health programs utilize directly observed treatment (DOT) which is generally administered intermittently (twice weekly), but under direct supervision. If drug susceptibility results are known at the time of treatment initiation, and the organism is fully susceptible, ethambutol may be omitted in the intensive phase. Pyridoxine may be given to avoid the side effects of isoniazid therapy. The continuation phase is prolonged to 7 months in patients with cavitary pulmonary TB with positive 2 month sputum culture. Longer treatments are also recommended for CNS and bone TB. If patient’s isolate is not available, it is generally accepted to guide treatment based on the susceptibility of the organism from the source (close contact). Expert opinion is essential when drug-resistant TB is suspected or confirmed.

There is a strong recommendation for using adjunctive dexamethasone during the initial 6 weeks for treating TB meningitis in HIV negative individuals. Dexamethasone at an initial dose of 8 mg/day for children weighing less than 25kg and 12mg/day for those over 25kg is administered for 3 weeks and then decreased gradually during the following 3 weeks. A prednisolone regimen at 4mg/kg/day of for initial 4-weeks and then tapered over the next 2 weeks has also been used. Adjunctive dexamethasone should also be considered in certain other forms of TB (pleuritis, pericarditis).

Recommendations for TB treatment in the HIV co-infected are generally the same as those for HIV-uninfected. Corticosteroids are also likely to be beneficial in HIV-positive patients with TB meningitis. Acquired rifampin resistance has been noted in patients with advanced immunosuppression treated with intermittent rifampin/rifabutin-based regimens. Management of HIV co-infection requires special expertise, and experts in the treatment of HIV and TB should be consulted. Rifamycins interact with antiretroviral agents. TB or HIV treatment can also lead to paradoxical worsening often referred to as immune reconstitution syndrome, which is a consequence of effective antiretroviral therapy.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

A 2-week trial with anti-bacterial drugs for community acquired pneumonia is often recommended when suspicion for active TB is low and initial tests such as AFB stains are negative. TB treatment in these situations is often deferred until culture or other results are available.

What complications could arise as a consequence of tuberculosis?

What should you tell the family about the patient’s prognosis?

Outcome is determined by the organ involved and the stage at which treatment is initiated. Cavitation on the initial chest X-ray with positive 2-month sputum cultures leads to higher treatment failures or relapse. TB with drug-resistant strains also has a higher failure rate, relapse and development of resistance to other TB drugs.

Compliance with TB treatment is of utmost importance. Therefore, several health programs utilize DOT which is generally administered intermittently (twice weekly) but under direct supervision.

Tuberculosis meningitis

Outcome of this disease, both in the form of mortality and sequelae, is determined by the neurologic stage at which treatment is initiated. Stage one disease (without any neurological deficits) typically has a lower mortality and morbidity if therapy is initiated, whereas stage three disease can carry a 50% mortality rate. In studies among adult patients, 28% of patients had neurologic deficits at the time of discharge and 13% continued to have neurologic sequelae at the end of 6 months. Cranial nerve palsy, hemiplegia, and paraparesis were the most frequent neurological deficits. Hearing loss in tuberculous meningitis has been reported in several case reports; however, it does not appear to be as common as found in other types of bacterial meningitis.

Note that approximately 10% of patients with TB meningitis (and sometimes other forms of TB) may develop paradoxical worsening of their symptoms several weeks to months after initiation of TB treatment. This does not represent treatment failure. Addition of corticosteroids is likely to be beneficial.

What other additional laboratory findings may be ordered?

Though non-specific, markers of inflammation (e.g. erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) are elevated in the majority of patients with active TB. CRP therefore has a high negative predictive value.

CSF interferon-gamma release assays may be useful for diagnosing CNS TB, but large studies are required to determine their efficacy. Adenosine deaminase (ADA) activity in CSF, pleural fluid, etc. may also be supportive, but cannot reliably distinguish TB versus bacterial infections.

All patients with TB should be tested for HIV. For known HIV positive patients, CD4 count should also be obtained. For adults, baseline measurements of liver function tests and serum creatinine and platelet count should be obtained. Testing of visual acuity and red-green color discrimination should be obtained when ethambutol is being used.

How can tuberculosis be prevented?

  • Prevention of TB remains a major public health concern both in the US and worldwide. Major interventions include early diagnosis of active TB patients to limit its spread to other persons. Patients with suspected TB should be considered infectious if they are suspected to have TB of the lungs, airway or larynx. These individuals should be placed in a private room with airborne infection isolation room, previously known an as negative-pressure isolation room.

  • It is estimated that one third of the world population are infected with M. tuberculosis and have latent TB infection. Immunocompetent persons with latent TB have a lifetime risk of 10% of developing reactivation TB disease while this risk is increased to 5-10% per year for those infected with HIV. Therefore, identifying people with latent TB infection and providing chemoprophylaxis is a major public health intervention that if taken appropriately can reduce the risk of developing active TB substantially. Individuals with latent TB infection will have a positive TST or interferon-gamma release assay without any evidence (sign/symptoms) of active TB, and a normal chest X-ray. In countries with low incidence of TB, chemoprophylaxis is recommended for all people with untreated latent TB infection. Recently, the WHO also recommended that TB chemoprophylaxis should also be offered to all HIV-infected individuals with latent TB infection in resource-constrained settings. Some common chemoprophylaxis regimens for latent TB are listed in Table II. Expert opinion should be sought for individuals suspected with latent TB infection with drug-resistant strains.

  • Live attenuated BCG, developed in 1908, is the only vaccine licensed to prevent TB. Its efficacy has been inconsistent with efficacy against pulmonary TB, ranging from 0-80%. However, BCG does protect against disseminated TB and TB meningitis in infancy. Therefore, the WHO currently recommends administering the BCG vaccine intradermally after birth to all infants in areas where TB is endemic.

Table II.
Chemoprophylaxis regimen Duration Interval
Isoniazid# 9 months DailyTwice weekly*
Isoniazid and Rifapentine 3 months Once weekly*
Rifampin 4 months Daily

Preferred regimen for children younger than 12 years old and for pregnant women (add pyridoxine);

DOT

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

“TB Fact Sheet”.

“Treatment of Tuberculosis”. MMWR Recommendations and Reports. vol. 52. 2003. pp. 1-77.

Wilson, M. “Recent Advances in the Laboratory Detection of Mycobacterium tuberculosis Complex and Drug resistance”. Clinical Infectious Disease. vol. 52. 2011. pp. 1350-1355.

Peto, HM, Pratt, RH, Harrington, TA. “Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006”. CID. vol. 49. 2009. pp. 1350-1357.

Marais, S, Thwaites, G, Schowman, JF. “Tuberculous meningitis: a uniform case definition for use in clinical research”. The Lancet. vol. 10. 2010. pp. 803-812.

Jain, SK, Kwon, P, Moss, WJ. “Management and outcomes of intracranial tuberculomas developing during antituberculous therapy: case report and review”. Clin Pediatr (Phila). vol. 44. 2005. pp. 443-50.

Curless, R, Mitchell, C. “Central nervous system tuberculosis in children”. Pediatric Neurology. vol. 7. 1991. pp. 270-274.

Saukonnen, JJ, Cohn, DL, Jasmer, RM. “An official ATS statement: hepatotoxicity of antituberculosis therapy”. American Journal of Respiratory and Critical Care Medicine. vol. 174. 2006. pp. 935-952.

Forget, EJ, Menzies, D. “Adverse reactions to first line antituberculosis drugs”. Expert Opin. Drug Safe. vol. 5. 2006. pp. 231-252.

Be, NA, Kim, KS, Bishai, WR, Jain, SK. “Pathogenesis of central nervous system tuberculosis”. Curr Mol Med. vol. 9. 2009. pp. 94-9.

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