tuberculosis

tuberculosis (TB), a multisystemic disease with myriad presentations and manifestations, is the most common cause of infectious disease–related mortality worldwide. Although TB rates are decreasing in the United States, the disease is becoming more common in many parts of the world. In addition, the prevalence of drug-resistant TB is increasing worldwide.

Essential update: CDC reports increased prevalence of resistance to pyrazinamide

A recent CDC analysis of the prevalence, trends, and risk factors for initial resistance to pyrazinamide among Mycobacterium tuberculosis complex (MTBC) cases in the U.S. between 1999 and 2009 showed that such resistance increased from 2.0% in 1999 to 3.3% in 2009

Among 79,321 cases with drug susceptibility testing results, 2,167 (2.7%) had initial resistance to pyrazinamide. More than a third of multidrug-resistant TB cases (38.0%) were resistant to pyrazinamide, compared with 2.2% of non—multidrug-resistant cases. The increased prevalence of pyrazinamide resistance from 2.0% in 1999 to 3.3% in 2009 reflected a doubling in pyrazinamide monoresistance from 1.2% in 1999 to 2.5% in 2009

Pyrazinamide monoresistance was associated with younger age, Hispanic ethnicity, HIV infection, extrapulmonary disease, and normal chest radiograph and inversely associated with Asian and Black race, substance use, homelessness, and residence in a correctional facility. Pyrazinamide polyresistance was associated with Hispanic ethnicity, Asian race, previous TB diagnosis, and normal chest x-ray and inversely associated with age 45 years and older. Pyrazinamide resistance in multidrug-resistant cases was associated with female sex and previous TB diagnosis.

Bacterial lineage, rather than host characteristics, was the primary predictor of pyrazinamide resistance among M tuberculosis cases

Signs and symptoms

Classic clinical features associated with active pulmonary TB are as follows (elderly individuals with TB may not display typical signs and symptoms):

• Cough
• Weight loss/anorexia
• Fever
• Night sweats
• Hemoptysis
• Chest pain (can also result from tuberculous 
• Fatigue

• Headache that has been either intermittent or persistent for 2-3 weeks
• Subtle mental status changes that may progress to coma over a period of days to weeks
• Low-grade or absent fever

Symptoms of skeletal TB may include the following:

• Back pain or stiffness
• Lower-extremity paralysis, in as many as half of patients 
• Tuberculous arthritis, usually involving only 1 joint (most often the hip or knee, followed by the ankle, elbow, wrist, and shoulder)

Symptoms of genitourinary TB may include the following:

• Flank pain
• Dysuria
• Frequent urination
• In men, a painful scrotal mass, prostatitis, orchitis,

Symptoms of gastrointestinal TB are referable to the infected site and may include the following:

• Nonhealing ulcers of the mouth or anus
• Difficulty swallowing (with esophageal disease)
• Abdominal pain mimicking peptic ulcer disease (with gastric or duodenal infection)
• Malabsorption (with infection of the small intestine)
• Pain, diarrhea, or hematochezia (with infection of the colon)

Physical examination findings associated with TB depend on the organs involved. Patients with pulmonary TB may have the following:

• Abnormal breath sounds, especially over the upper lobes or involved areas
• Rales or bronchial breath signs, indicating lung consolidation

Signs of extrapulmonary TB differ according to the tissues involved and may include the following:

• Confusion
• Coma
• Neurologic deficit
• cholerectis
• Lymphadenopathy
• Cutaneous lesions

The absence of any significant physical findings does not exclude active TB. Classic symptoms are often absent in high-risk patients, particularly those who are immunocompromised or elderly.

Diagnosis

Screening methods for TB include the following:

• moutex tuberculin skin test
• In vitro blood test based on interferon gamma release assay (IGRA) with antigens specific for Mycobacterium tuberculosis for latent infection

Obtain the following laboratory tests for patients with suspected TB:

• Acid-fast bacilli (AFB) smear and culture using sputum obtained from the patient: Absence of a positive smear result does not exclude active TB infection; AFB culture is the most specific test for TB
• HIV serology in all patients with TB and unknown HIV status: Individuals infected with HIV are at increased risk for TB

Other diagnostic testing may warrant consideration, including the following:

• Specific enzyme-linked immunospot (ELISpot)
• Nucleic acid amplification tests
• Blood culture

Positive cultures should be followed by drug susceptibility testing; symptoms and radiographic findings do not differentiate multidrug-resistant TB (MDR-TB) from fully susceptible TB. Such testing may include the following:

• Direct DNA sequencing analysis
• Automated molecular testing
• Microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays
• Additional rapid tests (eg, BACTEC-460, ligase chain reaction, luciferase reporter assays, FASTPlaque TB-RIF)

Obtain a chest radiograph to evaluate for possible associated pulmonary findings. The following patterns may be seen:

• Cavity formation: Indicates advanced infection; associated with a high bacterial load
• Noncalcified round infiltrates: May be confused with lung carcinoma
• Homogeneously calcified nodules (usually 5-20 mm): Tuberculomas, representing old infection
• Primary TB: Typically, pneumonialike picture of infiltrative process in middle or lower lung regions
• Reactivation TB: Pulmonary lesions in posterior segment of right upper lobe, apicoposterior segment of left upper lobe, and apical segments of lower lobes
• TB associated with HIV disease: Frequently atypical lesions or normal chest radiographic findings
• Healed and latent TB: Dense pulmonary nodules in hilar or upper lobes; smaller nodules in upper lobes
• Miliary TB: Numerous small, nodular lesions that resemble millet seeds
• Pleural TB: Empyema may be present, with associated pleural effusions

Workup considerations for extrapulmonary TB include the following:

• Biopsy of bone marrow, liver, or blood cultures
• If tuberculous meningitis or tuberculoma is suspected, perform lumbar puncture
• If vertebral or brain involvement is suspected, CT or MRI is necessary
• If genitourinary complaints are reported, urinalysis and urine cultures can be obtained

Management

Physical measures (if possible or practical) include the following:

• Isolate patients with possible TB in a private room with negative pressure
• Have medical staff wear high-efficiency disposable masks sufficient to filter the bacillus
• Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after approximately 2-4 weeks of treatment)

Initial empiric pharmacologic therapy consists of the following 4-drug regimens:

• Isoniazid
• Rifampin
• Pyrazinamide
• Either ethambutol or streptomycin

Special considerations for drug therapy in pregnant women include the following:

• In the United States, pyrazinamide is reserved for women with suspected MDR-TB
• Streptomycin should not be used
• Preventive treatment is recommended during pregnancy
• Pregnant women are at increased risk for isoniazid-induced hepatotoxicity
• Breastfeeding can be continued during preventive therapy

Special considerations for drug therapy in children include the following:

• Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible.
• For postnatal TB, the treatment duration may be increased to 9 or 12 months
• Ethambutol is often avoided in young children

Special considerations for drug therapy in HIV-infected patients include the following:

• Dose adjustments may be necessary
• Rifampin must be avoided in patients receiving protease inhibitors; rifabutin may be substituted
• Considerations in patients receiving antiretroviral therapy include the following:
• Patients with HIV and TB may develop a paradoxical response when starting antiretroviral therapy
• Starting antiretroviral therapy early (eg, < 4 weeks after the start of TB treatment) may reduce progression to AIDS and death
• In patients with higher CD4+ T-cell counts, it may be reasonable to defer antiretroviral therapy until the continuation phase of TB treatment

Multidrug-resistant TB

When MDR-TB is suspected, start treatment empirically before culture results become available, then modify the regimen as necessary. Never add a single new drug to a failing regimen. Administer at least 3 (preferably 4-5) of the following medications, according to drug susceptibilities:

• An aminoglycoside: Streptomycin, amikacin, capreomycin, kanamycin
• A fluoroquinolone: Levofloxacin (best suited over the long term), ciprofloxacin, ofloxacin
• A thioamide: Ethionamide, prothionamide
• Pyrazinamide
• Ethambutol
• Cycloserine
• Terizidone
• Para-aminosalicylic acid
• Rifabutin as a substitute for rifampin

Surgical resection is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Procedures include the following:

• Segmentectomy (rarely used)
• Lobectomy
• Pneumonectomy
• Pleurectomy for thick pleural peel (rarely indicated)

Latent TB

Recommended regimens for isoniazid and rifampin for latent TB have been published by the US Centers for Disease Control and Prevention (CDC) : An alternative regimen for latent TB is isoniazid plus rifapentine ; it is not recommended for children under 2 years, pregnant women or women planning to become pregnant, HIV-infected persons taking antiretrovirals, or patients with TB infection presumed to result from exposure to a person with TB that is resistant to 1 of the 2 drugs.