Tuberculosis and Mycobacterial Pneumonia

Tuberculosis and mycobacterial pneumonia

I. What every physician needs to know.

Globally, the most common and contagious mycobacterial pneumonia is pulmonary tuberculosis (TB), which continues to kill 2 million people annually. Most deaths occur in high-burden countries with limited access to diagnostic tests and effective antitubercular therapy, but preventable deaths due to TB occur in the United States each year. This is an infectious disease spread through droplets and thus poses a major threat to public health worldwide.

The classic symptoms include cough, hemoptysis, fatigue, weight loss, and night sweats, though atypical presentations are common. Tuberculosis also tends to present as a chronic, indolent disease of the lung or extrapulmonary sites, and patients may present with acute complaints or have active TB without symptoms.

In the United States, TB is rare and rates have been declining with better public health measures. Diagnosis is a challenge and requires thinking of TB in the differential diagnosis when appropriate. The most important risk factor in the United States is birth in or travel to high burden countries in Africa, Asia, Latin America, Eastern Europe and the Middle East. Sixty-six percent of the TB cases reported in the United States are among foreign-born persons and annual rates are 11-fold higher among foreign-born than US born residents. Among the US- born, children of foreign-born parents and elderly US born adults are at an increased risk of TB. Individuals with known contact with infectious TB, substance abuse, homelessness, and incarceration are also at increased risk for TB.

While TB rates are declining in the United States, the frequency of lung diseases due to nontuberculous mycobacteria (NTM), most often Mycobacterium avium complex (MAC), has been on the rise. MAC typically causes chronic pneumonias often with cavitation and bronchiectasis, but can also cause an acute hypersensitivity pneumonitis.

Other mycobacteria, including Mycobacteria kansasii, can also cause chronic pneumonia in humans with underlying lung disease but will not be discussed here.

II. Diagnostic Confirmation: Are you sure your patient has Tuberculosis/Mycobacterial Pneumonia?

An early presumptive diagnosis of TB is made based on:

Symptoms + radiographic findings + acid-fast bacilli (AFB) smear results +/- histology in a high risk patient.

Sputum culture is the gold standard for diagnosis, but generally takes 2 to 6 weeks, and 20% of TB cases are culture-negative. AFB smears are helpful, but keep in mind that up to 50% of patients with culture positive pulmonary TB have negative smears and extrapulmonary TB is rarely smear positive. The tuberculin skin test (TST) or interferon gamma release assay (IGRA – a tuberculosis blood test) can be helpful only for determining a person’s risk for infection, but are negative in 15-30% patients with active TB.

This is a difficult diagnosis because: typical symptoms can be absent, chest X-ray (CXR) appearance may be atypical, and AFB smear may be negative. The most important factors in making the decision to treat should be the patient’s risk of progressive illness and the risk of transmission to others.

The diagnosis of NTM pneumonia is based on:

Pulmonary symptoms + radiographic appearance + acid-fast bacilli smear positivity (+ nucleic acid amplification) in a patient who is not high risk for TB. Sputum culture is the gold standard for diagnosis.

A. History Part I: Pattern Recognition:

Most common symptoms of patients with TB presenting in the inpatient setting are: cough, hemoptysis, chest pain (pleurisy), shortness of breath, fever, fatigue, weight loss.

None of the above are common, with cough present in about 20% of patients.

One-third of patients diagnosed with tuberculosis in the hospital DO NOT present with pulmonary symptoms and are evaluated for other complaints prior to an incidental diagnosis of pulmonary tuberculosis.

Elderly patients (age>60) with more comorbid conditions exhibit less fever, sweats, and hemoptysis, making diagnosis of pulmonary tuberculosis in this population more challenging. They also tend to have less cavitation on CXR and more negative PPDs in the setting of active infection.

There is further suggestion that “atypical” presentations of pulmonary tuberculosis are perhaps more common than typical ones, and that “classic symptoms” of prolonged fever and cough are insensitive predictors of tuberculosis. This may be race-dependent with Asians, in general, having less typical presentations.

The hospitalized patient with pulmonary tuberculosis is often hospitalized for nonpulmonary complaints and tuberculosis becomes a consideration either because of significant risk for this disease or because of a suggestive radiographic study. For example, a trauma patient from sub-Saharan Africa had a chest CT showing cavitation and a history of treatment for TB as a child.

Patients with MAC often have symptoms of chronic pneumonia in the setting of underlying lung disease. “Hot tub lung” due to MAC presents with acute hypoxia, dyspnea, cough and fever in the setting of hot tub exposure.

B. History Part 2: Prevalence:

Tuberculosis is a major problem worldwide. One-third of the world’s population (2 billion people) is estimated to be infected with tuberculosis.

The rate of infection in the United States is low: 3 per 100,000 people in 2014.

Because tuberculosis in the United States is rare, presenting symptoms are often atypical and diagnosis can be challenging; the most important key to diagnosing tuberculosis is knowing who is at risk. If you are able to identify those at risk, your ability to make this diagnosis will improve.

A majority of the TB cases in the United States occur in foreign-born persons.

Most of these cases are due to reactivation and occur most commonly within 5 years of immigration. See Figure 1.

Figure 1.

The countries of origin that account for most of the TB in the United States are: Mexico, Phillipines, Vietnam, India, China, the Dominican Republic, and Haiti.

A 2011 NEJM paper by Horsburgh at al. discussed the relative risks of various factors on developing reactivated tuberculosis:

• AIDS (relative ratio of almost 10)

• close contact with person with infectious TB

• radiographic evidence of old, healed TB (untreated)

• immunosuppressive therapy (prednisone 15mg daily or equivalent for > 1 month)

• chronic renal disease

• treatment with TNF-alpha inhibitor

• poorly controlled diabetes

• underweight (>10% under ideal body weight)

• smoking

• gastrectomy (also, in current scope of practice, gastric bypass)

See Figure 2.

Figure 2.

Other risk factors reported in the literature:

• malignancy (head and neck and hematologic cancers)

• celiac disease (may be associated with malnutrition)

• alcohol use (>40g/day)

• illicit drug use (homelessness and incarceration often associated with intravenous drug use (IVDU) may contribute to high prevalence)

History of exposure is also important, particularly previous treatment for TB, which raises the suspicion for multi-drug resistant TB (MDR TB).

Thus, the typical patient with pulmonary TB in the United States, is foreign-born or travelled to an endemic area +/- HIV/immunocompromise, with a history of homelessness or incarceration.

Meanwhile, with increased sensitization to NTM, MAC may be the most common mycobacteria causing lung disease in North America.

C. History Part 3: Competing diagnoses that can mimic Tuberculosis and Mycobacterial Pneumonia.

Based on presentation and findings on CXR, TB can mimic a variety of pneumonias: typical, atypical, aspiration. It can classically be distinguished from these based on a longer duration of symptoms and more systemic symptoms such as weight loss, and night sweats.

Oftentimes, TB and NTM pneumonia have similar clinical presentations, with cavitation, and positive AFB smears and are hard to distinguish from each other. PCR-based nucleic acid amplification tests (NAAT) can help distinguish the two but cultures are needed for a definitive diagnosis.

D. Physical Examination Findings.

These are varied and not sensitive. Patients may have an abnormal lung exam, or other manifestations of disease such as lymphadenopathy or signs of extrapulmonary disease.

E. What diagnostic tests should be performed?

The diagnosis of mycobacterial pneumonia can be difficult to confirm because of:

• frequent atypical symptoms (high index of suspicion is most important)

• atypical radiographic appearance

• potential low mycobacterial burden (AFB smears not sensitive)

• slow rate of growth for this bacterium (confirmation can take 2 months)

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

If pulmonary TB is suspected based on risk factors, presenting symptoms, and/or CXR (see below), obtain the following:

• Three sputum samples for acid-fast bacilli stain (AFB), induce if necessary, one should be early morning.

• Send one AFB stain for nucleic acid amplification (NAA).

• Send all AFB smears for culture and susceptibility testing (communicate with lab to keep samples 2 months).

• Interferon-gamma release assays (Quantiferon-TB Gold test) can be used to aid in the diagnosis (a positive test increases the suspicion for active TB), but is only 60% sensitive and should not be used to rule out active TB.

Gold standard for diagnosis is culture. Up to 20% pulmonary TB cases are culture-negative (culture can detect 10 bacteria/mL). Depending on bacterial burden, culture may take months to result.

Interpretation:

• AFB+/NAA+ –> TB

• AFB-/NAA+ –> likely TB –> treat likely TB while awaiting cultures

• AFB+/NAA- –> likely nontuberculous mycobacteria

Pitfall: AFB smears will be negative if there are <5,000 bacilli/mL –> this DOES NOT rule out disease. Sensitivity 45-80%. PPV 50-80%.

Remember: The decision to treat may come before confirmatory data is available, especially if the patient is critically ill. The most important factor is your suspicion is for TB.

If extrapulmonary TB is suspected, obtain AFB smear and culture of those sites as well. Suspected pleural or peritoneal TB (in setting of effusion or ascites) should prompt a biopsy since fluid samples have a low sensitivity.

Based on prevalence alone, a US-born patient with a cavitary lesion with positive AFB and low risk for tuberculosis likely has NTM.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest radiography is a step in the diagnostic approach after risk factors and symptoms cause suspicion for mycobacterial pneumonia. Alternatively, CXR may be your initial clue about tuberculosis. Classic presentation for reactivation tuberculosis:

• infiltrate in the upper lobes (apical/posterior)

• infiltrate in lower lobes (superior segments)

• cavitation

Some cases do not have this typical appearance. Infiltrates can be bilateral or miliary. Cavitation is a sign of advanced disease. Persons with HIV can present with intrathoracic adenopathy.

Beware that active pulmonary TB cannot be distinguished from inactive disease based on radiography alone (CXR readings that say “fibrosis” or “scarring” do not mean the patient does NOT have active disease).

Computed tomography (CT) chest does not usually add much to the diagnosis of TB, however, it may help to further characterize NTM pneumonia. MAC pneumonia often has the following features on HRCT:

• nodular opacities

• cavitary lesions

• multifocal bronchiectasis

• nodular opacities/bronchiectasis in lingula or right middle lobe (Lady Windermere syndrome)

The diagnostic criteria for MAC pneumonia depend on symptoms, characteristic radiographic findings, and exclusion of other diagnoses, as well as confirmation by microbiology. See Table in Figure 3.

Figure 3.

See Figure 4, Figure 5 and Figure 6.

Figure 4.

Figure 5.

Figure 6.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Purified protein derivative (PPD) skin test (also known as tuberculin skin test) may not be very useful in the diagnosis of active TB, although it may help determine risk. It is:

• not sensitive (patients with immunocompromise may not mount a response)

• not specific (may be positive due to BCG immunization/past infection and not indicative of active disease)

• cannot distinguish between TB and NTM sensitization

The interferon-gamma release assays (IGRAs), are more specific for TB but still not sensitive enough to rule out this diagnosis. IGRAs (like PPD) are not a test for active tuberculosis. They are most commonly used in the outpatient setting to screen high-risk individuals for latent TB infection. That said, if a patient is known to be IGRA- or PPD-positive and a CXR is consistent with parenchymal fibrotic lesions, that patient likely deserves an evaluation with AFB sputum stains and cultures, even if asymptomatic.

III. Default Management.

The first step is to determine whether the diagnosis is consistent with pulmonary tuberculosis. You will not have all diagnostic data available at this point.

If TB:

• Isolate in negative pressure ventilation.

• Collect sputum and other specimens as appropriate for AFB smears and cultures.

• Report to public health department (even if the case is not yet confirmed).

• Initiate multidrug regimen (not emergent unless patient critically ill), ideally with the assistance of infectious disease specialist.

• If the patient has a history of prior TB treatment and is foreign-born, the likelihood of MDR TB is 10% and therapy decisions should be made in consultation with a TB expert.

If NTB:

• Treatment is rarely urgent and generally can await confirmation of diagnosis. Initiate multidrug regimen ideally with the assistance of a pulmonologist or infectious disease specialist.

A. Immediate management.

Immediate management in the setting of suspicion for pulmonary tuberculosis is isolation in a negative pressure room in order to prevent transmission.

Tuberculosis is a reportable disease. It is your responsibility to report this case to the Public Health Department in your area. Report suspected TB even if AFB smears are negative when the patient is at significant risk.

Initiating antitubercular therapy is not an emergent matter, unless the patient is critically ill. It is important to avoid fluoroquinolones in a patient in whom TB is considered and who is simultaneously being treated for pneumonia. Fluoroquinolones have tremendous activity against TB and can cause temporary symptomatic, radiographic, and microbiologic improvements, resulting in delays in diagnosis.

For pulmonary tuberculosis, initial phase of therapy includes four antitubercular agents to prevent induction of resistance. The initial regimen is based on the knowledge of likely drug susceptibility. Commonly, this includes isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). If multidrug resistant TB is suspected, this regimen will change. If there is an infectious disease specialist at your facility, it would be wise to include them in the case before beginning therapy.

See Figure 7 for drug treatment table.

Figure 7.

MAC pneumonia is not infectious and patients do not need to be isolated. Treatment varies based on radiographic appearance of disease and previous history of disease and includes a macrolide, a rifamycin, ethambutol +/- aminoglycoside.

See Figure 8.

Figure 8.

B. Physical Examination Tips to Guide Management.

It is important to look for evidence of adverse reactions, which would cause drug discontinuation or revision of therapy:

• Signs of hepatotoxicity – jaundice, abdominal pain, loss of appetite, pruritis (INH, RIF, PZA).

• Rash – generalized or petechial.

• Drug fever – other causes of fever first have to be ruled out.

• Ocular toxicity – blurred vision or scotoma can occur with EMB.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

At the initiation of therapy for TB, obtain:

• AFB and sputum cutlure with sensitivities*

• Liver function tests (LFTs)*

• HCV/HBV tests in high risk populations*

• Creatinine

• HIV antibody

*Also useful in NTB

Sputum AFB with culture should be obtained monthly until two consecutive samples are negative.

No routine LFT follow-up is necessary for patients with baseline normal liver function. Monthly questioning for signs and symptoms of hepatotoxicity is recommended.

Monthly hepatic enzyme monitoring is necessary for patients with:

• baseline abnormal results

• a drug reaction is suspected

• underlying liver disease or alcohol abuse

• pregnancy and up to 3 months postpartum

• therapy including PZA in continuation phase

D. Long-term management.

For TB, this part of the management will not take place in the hospital and the decisions surrounding treatment should be made in conjunction with the local public health department and a knowledgeable infectious diseases or pulmonary specialist.

After the initial phase of therapy, the continuation phase will begin. This phase lasts 4-7 months and is typically based on INH and RIF. Duration of treatment depends on clearance of respiratory cultures, interruptions of therapy, presence of cavitation on presenting CXR, and whether or not the patient was able to tolerate all components of the initial phase.

In order to maximize adherence to treatment, the WHO strategy for elimination of tuberculosis lies in directly observed therapy (DOT), during which patients are observed as they take their medications.

NTB is even more difficult to treat than pulmonary TB. Treatment duration is 12 months beyond the time that cultures convert to a negative.

E. Common Pitfalls and Side-Effects of Management.

Medications for pulmonary TB (weight based regimens are based on lean body weight):

See Figure 9 for adverse effects of TB medication.

Figure 9.

First-line agents:

Isoniazid (INH)* – 5 mg/kg/day, 300 mg daily

Rifampin (RIF) – 10 mg/kg/day, 600 mg daily, adjust with HIV meds

Rifabutin – 5 mg/kg/day, 300 mg daily

Rifapentine 600 mg weekly (only in the continuation phase)

Pyrazinamide (PZA) – 1 g/kg for 40-55 kg, 1.5 g/kg for 56-75 kg, 2 g/kg for 76-90 kg

Ethambutol (EMB) – 0.8 g/kg for 40-55 kg, 1.2 g/kg for 56-75 kg, 1.6 g/kg for 76-90 kg

Second-line agents:

Amikacin – 15mg/kg/day, 10mg/kg/day for age>59

Capreomycin – 15 mg/kg/day, 10 mg/kg/day for age>59

Cycloserine* – 10-15 mg/kg/day, 250 mg twice daily (renal failure 250 daily)

Ethionamide* – 15-20 mg/kg/day, usually 500-750 mg per day

Kanamycin – 15 mg/kg/day, 10 mg/kg/day for age>59

Levofloxacin – 500-1000 mg daily

Moxifloxacin – 400 mg daily

Para-aminosalicylate (PAS) – 8-12 g daily divided in 2-3 doses

Other agents rarely used that have shown in-vitro activity against TB: amoxicillin/clavulanate, clofazimine, imipenem/cilastatin, linezolid, ofloxacin

* require co-treatment with B6

Medications for MAC pneumonia:

Clarithromycin – 100 mg thrice weekly (100 mg daily for cavitary/advanced disease)

Azithromycin – 500 mg thrice weekly (300 mg daily for cavitary/advanced disease)

Ethambutol – 25 mg/kg thrice weekly (15mg/kg daily for cavitary/advanced disease)

Rifampin – 600 mg thrice weekly (600 mg daily for cavitary/advanced disease)

Streptomycin – 15 mg/kg IV/IM daily (for cavitary/advanced disease only)

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

For CrCl<30:

1. Doses should be reduced to 2-3 weekly: PZA, EMB, amikacin, capreomycin, kanamycin, levofloxacin

2. Halve dose: rifabutin 150 mg daily, cycloserine 250 mg daily

B. Liver Insufficiency.

Generally, there are no changes in dosing. However, since multiple medications (INH, RIF, PZA) are hepatotoxic, patient with underlying liver insufficiency should get monthly liver function profile. Other patients should be questioned monthly about symptoms of hepatitis.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management, though it should be noted that patients with diabetes often have longer-persisting culture positivity.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

This is a complex issue, and full discussion is beyond the scope of this chapter. HIV-infected individuals with pulmonary tuberculosis should be managed by an expert in HIV, if available.

The WHO recommends that all patients with HIV who also have TB be started on antiretroviral therapy (ART), regardless of CD4 count.

There are multiple drug-drug interactions between various ART and antitubercular regimens. Both rifampin and rifabutin induce the CYP3A4 enzymes and accelerate the metabolism of protease inhibitors (PI) and some non-nucleaoside reverse transcriptase inhibitors (NNRTI). Rifampin is a much more potent inducer, thus rifabutin-based regimens are preferred.

Pyridoxine is required for patients with HIV taking INH to prevent peripheral neuropathy.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

No specific considerations. Caretakers should wear a fitted duckbill mask while evaluating the patient if patient has TB.

B. Anticipated Length of Stay.

Length of stay often depends on the social situation of the patient. Diagnostic evaluation and treatment of TB can be done in the outpatient setting if circumstances are right. The main concern is infectiousness. Most patients can be told to remain at home without visitors and without contact with young children. If there is a risk to public health, public health personnel should evaluate the situation while the patient is hospitalized in negative pressure isolation.

C. When is the Patient Ready for Discharge.

A patient with TB is ready for discharge if they meet all the following criteria:

• They can isolate themselves at home without a threat to public health (if this is impossible, keep hospitalized in negative pressure room until AFB’s are negative)

• Public health department is aware of patient so directly observed therapy can continue, and follow-up is set up

NTB patients can be discharged if they have an established treatment plan, follow-up plan, and can ambulate.

D. Arranging for Clinic Follow-up.

The Public Health Department will be essential in follow up of patients with pulmonary TB.

1. When should clinic follow up be arranged and with whom.

Public Health Department should be alerted when patient is being discharged.

Follow up with primary care or preferably an infectious disease specialist should be scheduled within a month if possible for both TB and NTB.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Make sure sputum has been sent for culture and susceptibility. All baseline tests listed above.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

• Sputum for AFB and culture at 1 month

• Liver function tests if underlying liver disease, alcohol use, or baseline abnormal LFT’s, creatinine if baseline CKD

E. Placement Considerations.

Placement is usually not a consideration.

F. Prognosis and Patient Counseling.

Tuberculosis is a treatable disease. Cure and prevention of resistance depends on adherence and DOT increases rates of completion of treatment from 61% unsupervised to 90%. Relapse can happen.

Patients should be counseled to avoid contact with others, stay at home, and to avoid visits with small children. At all costs, patients should be aware that missing doses can cause resistance and lack of cure. Proper nutrition should be stressed.

MAC pneumonia is also a curable disease, but significantly harder to treat than pulmonary TB. Seventy percent of patients with noncavitary disease may achieve cure. Cure rates for cavitary disease may only be 20-50%. Medication adherence is key again due to high rates of resistance.

“Hot tub lung” has a great prognosis with stopping hot tub use.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None per JCAHO. Public health charge is to cure disease and prevent transmission.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission

If patient has history of IVDU/HIV but no evidence of viral hepatitis, hepatitis A and hepatitis B vaccines are appropriate.

VII. What's the evidence?

Barnes, PF. “Chest roentgenogram in pulmonary tuberculosis. New data on an old test”. . vol. 94. 1988. pp. 316-20.

Blumberg, HM. “Update on the treatment of tuberculosis and latent tuberculosis infection”. . vol. 293. 2005. pp. 2776-84.

Horsburgh, CR. “Latent Tuberculosis Infection in the United States”. . vol. 364. 2011. pp. 1441-8.

Horsburgh, CR. “Priorities for the treatment of latent tuberculosis infection in the United States”. . vol. 350. 2004. pp. 2060-7.

Kasperbauer, SH, Daley, CL. “Diagnosis and treatment of infections due to Mycobacterium avium complex”. . vol. 29. 2008. pp. 569-76.

Miller, LG. “A population-based survey of tuberculosis symptoms: how atypical are atypical presentations”. . vol. 30. 2000. pp. 293-9.

Alimuddin, Zumla, Mario, Raviglione, Richard, Hafner, Fordham von Reyn, C.. N Engl J Med. vol. 368. 2013. pp. 745-755.

Robert Horsburgh, C., Barry, Clifton E, Christoph, Lange. N Engl J Med. vol. 373. 2015. pp. 2149-2160.

Dewan, PK. “Low Sensitivity of a whole-blood Interferon Gamma Release assay for Detection of Active Tuberculosis”. Clin. Infect. Dis. vol. 44. 2007. pp. 69-73. (This article addresses the usefulness and lack thereof of using quantiferon test for hospitalized patients at risk for TB.)

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