TUBERCULOSIS
Globally, tuberculosis (TB) remains an immense cause of morbidity and mortality. Approximately one-third of the population, more than 2 billion persons, harbor latent infection with Mycobacterium tuberculosis, and 9 million new cases develop annually. Because of delayed diagnosis, lack of access to medications, or nonadherence to prescribed regimens, approximately 1.5 million people die annually of TB.
The progressive appearance of drug-resistant forms of
TB has been ominous. Circa 1990, cases of “multi drug resistant tuberculosis”
(MDR-TB) were recognized in New York City and Miami, Florida. Strains of TB
resistant to the two major drugs, isoniazid (INH) and rifampin (RIF), were
associated with hospital-based outbreaks, primarily among persons with AIDS. Similar,
highly lethal outbreaks were subsequently recognized around the globe, and by
2007, the World Health Organization estimated that nearly 500,000 new cases of
MDR-TB were occurring yearly. More ominously, in 2005 in South Africa, an even
more resistant epidemic was noted, extensive drug-resistant TB (XDR- TB). These
strains had evolved from MDR-TB and entailed resistance not only to INH and RIF
but also to two other major classes of anti-TB drugs, the fluoroquinolones and
the second-line injectables such as amikacin, kanamycin, and capreomycin. Cases
of XDR-TB have now been reported from 47 nations on all of the continents.
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| DISSEMINATION OF TUBERCULOSIS |
HIV/AIDS has profoundly accelerated case rates and
deaths over the past quarter century. The coincidence of TB and AIDS has been
most pronounced in sub-Saharan Africa but is increasingly problematic in China,
India, Russia, and the former Soviet Republics.
Failure of the TB vaccine, bacillus Calmette-Guérin
(BCG), has been a major element of the ongoing epidemic. Although BCG given in
infancy does protect against some of the severe forms of childhood TB (meningeal, spinal, or disseminated
disease), the vaccine has not curtailed adult pulmonary TB, the vector of
ongoing airborne transmission.
In the United States, TB case rates have declined
mostly because of the widening use of directly observed therapy (DOT). This
practice has increased treatment completion, reduced transmission, and
dramatically reduced acquired drug resistance. In 1992 in the United States,
when DOT was used in less than 20% of cases, there were nearly 27,000 cases for a rate of 10.4 per
100,000 population, and there were more than 400 MDR-TB cases. By 2007, there
were fewer than 14,000 cases, and the rate had fallen to 4.4 per 100K. Notably,
58% of these cases were among foreign-born individuals, the majority of whom
brought this infection from their country of origin. Fewer than 100 MDR-TB
cases were seen in 2007, mainly among foreign-born individuals who arrived with
preformed drug resistance.
TB is primarily spread by patients with sputum
smear–positive pulmonary disease. Coughing produces small particles, which float
in the air and undergo dehydration, forming “droplet nuclei” in the range of 1
m size. These can reach the alveoli and avoid clearance by the mucociliary
escalator of the airways. Transmission occurs exclusively indoors, where these
particles are concentrated and protected against ultraviolet irradiation (see
Plate 4-93).
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| EVOLUTION OF TUBERCLE |
After they have been taken up by naïve alveolar
macrophages, the bacilli replicate and before inhibitory cellular immunity can
limit their growth, there is wide-spread dissemination (see Plates 4-93 and
4-94). In most instances, host defenses prevail. The infected loci involute,
and the only detectable manifestation of the encounter is a reactive tuberculin
skin test result. However, in various sites, viable tubercle bacilli may
persist for years or decades with the potential to cause “reactivation” TB,
either in the lungs or extrapulmonary tissue. Among those with compromised
immunity (e.g., very young individuals, people with AIDS, patients on
immunosuppressive therapy), however, there may be progressive disseminated
disease appearing within a few months of exposure.
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| INITIAL (PRIMARY) TUBERCULOUS COMPLEX |
Pulmonary disease is the commonest presentation of TB
(see Plates 4-95 to 4-98). Among newly infected infants and children, there is
a distinctive pattern referred to as primary TB. These young patients
commonly react to the new infection with exuberant lymphadenopathy in the
peribronchial, hilar, or paratracheal nodes, draining the region of the lung
where the new infection occurred. The original parenchymal focus may be very
small or not visible on routine chest radio- graphs by this time. Over months
or years, this primary lesion may calcify, leaving a “Ghon lesion.” Cavitation
rarely occurs, and there are very limited numbers of tubercle bacilli in respiratory
secretions. Among such patients, many of whom cannot cooperate with sputum
collection, gastric aspirates or bronchoscopy may be required to isolate the TB
organisms.
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| PROGRESSIVE PATHOLOGY |
The histopathology of tuberculous lesions classically
involves granulomas with central caseous (“cheeselike”) necrosis. Bacilli, if
seen, are typically at the margins of the lymphocyte-macrophage palisades and
the necrotic debris. As the
disease advances, the lesions erode into the airways, allowing expulsion of the
bacilli into the environment. However, the critical component of transmission
is the formation of cavities. In the environment of the cavity wall, tubercle
bacilli undergo logarithmic extracellular replication. Patients with cavitary
disease 6 to 108 bacilli per milliliter of um.
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| EXTENSIVE CAVITARY DISEASE |
Another aspect of the large population of rapidly
multiplying organisms in cavities is the likelihood of spawning drug-resistant
mutants. Therapeutically, this places a great premium on the initial intensive
phase of treatment (see below).
Pleuritis may occur if the primary parenchymal lesion
is close enough to the visceral pleura to induce inflammation of the mesothelial
surface. In some cases, there is typical sharp chest pain, but in others, an
asymptomatic effusion is observed. The pleural effusion may be accessed by
aspiration; classically, it is a lymphocyte-rich exudate. Acid-fast bacilli are
rarely seen on stain, and culture results are positive in fewer than half of
the cases. Biopsy is the most useful study.
Miliary TB is manifested in the lungs by bilateral fine
nodular opacities, predominantly in the dependent zones, where the bacilli have
been deposited hematogenously (see Plate 4-98). Disseminated TB is seen among
patients with impaired immunity, including those at the extremes of age.
MILIARY TUBERCULOSIS
TUBERCULIN SKIN TESTING AND INTERFERON RELEASE ASSAYS
Historically, reactivity to intradermally injected tuberculoprotein has been used in the diagnosis of TB (see Plate 4-99). “Old tuberculin,” originally prepared by Koch, was supplanted by purified protein derivative (PPD). The test results were measured by the amount of induration at 48 to 96 hours after placement. However, the tuberculin skin test (TST) was limited by insensitivity and nonspecificity; 15% to 25% of “normal hosts” with TB did not have a significant response to PPD, and prior BCG vaccination or nontuberculous mycobacterial infections may induce significant reactions to PPD.
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| TUBERCULIN TESTING |
The primary role of the TST has been identifying latent TB infection (LTBI). Because it has been the only test that defines LTBI, its sensitivity is unknown. However, the lack of specificity has clearly been problematic, particularly among high-risk immigrants who have received BCG.
Recent studies have identified two antigens that are
nearly specific to M. tuberculosis: culture filtrate protein- 10 (CFP-10)
and early secretory antigen-6 (ESAT-6). Two new commercial tests have been
developed that measure ex vivo production by whole blood of interferon-(IFN-) on exposure to
CFP-10 and ESAT-6 (Quantiferon or T. Spot-TB). Overall, these IFN-release
assays (IGRAs) appear to be slightly more sensitive and significantly more
specific than the TST. Other advantages are that they require only a single
encounter, are more objective in interpretation, and do not “boost” reactivity
as do serial TSTs. Conversely, the IGRAs are substantially more expensive,
technically demanding, and
require proximity to a laboratory.
The routine chest radiograph, posteroanterior (PA) and
lateral (LAT) views, has been the traditional test for pulmonary, pleural, and
miliary TB. The most common sites for disease area the posterior aspects of the
upper lobes and the superior segments of the lower lobes. Common findings
include fibronodular stranding extending up from the hilum, retraction cephalad
of the pulmonary artery, thickening of the apical pleural cap and (with
advanced disease) cavitation. Among HIV- negative “normal” hosts, roughly
two-thirds have these typical findings.
Among immunocompromised patients (people with AIDS,
those who have undergone organ transplantation, those with renal failure, and
recipients of tumor necrosis factor– [TNF-] inhibitors), the radiographic
presentation may be quite atypical, including lower zone pneumonic infiltrates,
prominent lymphadenopathy, huge pleural effusions, and diffuse opacities that
begin as tiny, discrete (“millet seed”) shadows but may progress to a confluent
airspace filling process or acute respiratory distress syndrome.
Computed tomography (CT) scans may reveal important
diagnostic findings, including cavities obscured by osseous or soft tissue
structures in the apices, grossly enlarged lymphadenopathy with hypodense
centers typical of AIDS-TB, or early miliary shadowing not visible on routine
chest radiography.
Pleural effusions were typically assessed by
performing lateral decubitus views that led the effusions to collect in the
dependent zones. Although decubitus views are still popular, ultrasound studies
allow for more thorough characterization of the pleural process and increase
the yield of aspiration, biopsy, and drainage procedures.
SPUTUM STUDIES
Sputum studies include nucleic acid amplification (NAA) and culture (see Plates 4-100 and 4-101). In much of the world, unprocessed sputum is smeared on a glass slide, stained with the Ziehl-Neelsen or Kinyoun technique, and examined by a technician at high-power magnification under a light microscope. This system is insensitive, identifying fewer than 50% of patients whose sputum would be culture positive in more sophisticated laboratories. This system has been justified by identifying the cases most likely to transmit TB. However, it is diminishingly acceptable given its insensitivity and incapacity for drug susceptibility testing.
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| SPUTUM EXAMINATION |
In modern laboratories, sputum undergoes
decontamination (so the media are not overgrown by microorganisms other than
mycobacteria), digestion (to release the mycobacteria from the proteinaceous
matrix of the mucus), and concentration (in
a centrifuge that is refrigerated so that the heat generated by high-speed
centrifugation does not kill too many of the mycobacteria). At the end of this
three-step process, the supernatant is decanted, and the pellet is subjected
to microscopy, NAA, and culture. Fluorescent microscopy using auramine-O stains
the mycobacteria bright yellow on a black background, which allows the reading
at 40 magnification.
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| SPUTUM CULTURE |
NAA may be performed on uncultivated bacilli to
establish the species as M. tuberculosis. This is particularly valuable
in communities with a significant prevalence of pulmonary disease because of
nontuberculous mycobacteria (NTM; see below). Early species identification
allows optimal selection of the drug regimen (TB or NTM), efficient use of
isolation facilities, and appropriate initiation of contact investigation (see
below).
Culture remains the central element in the diagnosis
of TB. Because microscopy results are positive in only 40% to 60% of cases
ultimately proven to be pulmonary TB, culture enhances the sensitivity of
sputum study and confirms the species and facilitates drug susceptibility
testing.
Solid media such as Löwenstein-Jensen remain in use in
many parts of the world. However, such techniques are slow in yielding results,
typically requiring 4 to 6 weeks. Liquid media have replaced or supplemented
the solid media in many industrialized nations, offering culture results,
speciation, and preliminary susceptibility results in 1 to 2 weeks (see below).
Drug susceptibility testing (DST) has become a
critical need in the era of epidemic drug resistance. There are a number of
variables in DST. Historically, it was common to perform the culture, and when
growth was observed and the species confirmed, to take a subculture and perform DST. This
“indirect” method required 6 to 8 weeks on average.
DST in the latter 20th century generally used the
“proportionality” method. Equal aliquots were put on drug-free clear agar, and
“control,” and others were placed on agar with various concentrations of the
drugs. Then the number of colonies on the drug-containing media was compared
with the control count.
More recently, techniques using liquid media
containing different quantities of the relevant drugs determined the minimum
inhibitory concentration (MIC) of the drugs. MIC techniques have either used
the cut points derived from the proportionality method (see above) or have
calculated presumed efficacy by comparing the maximum concentration (Cmax)
derived from pharmacokinetic studies with the MIC of a given drug.
However,
clinical and public health issues have created pressure to identify MDR-TB (or
XDR) in a much shorter period because of high rates of mortality among patients
with AIDS and continued nosocomial transmission to health care workers and
other patients on hospital units.
Two methods have been used to facilitate early
recognition of resistance: accelerated microbiologic methods and molecular
probes for chromosomal markers of resistance. The microscopic observation of
drug susceptibility (MODS) technique uses multiple wells of control and
drug-containing media. The wells are examined regularly for the presence of
corded bacilli. This technique has been reported to yield results in as little
as 7 to 10 days for multiple drugs.
By contrast, techniques to probe for chromosomal
mutations known to be associated with resistance appear to be faster and
simpler. Although the mutations related to resistance for many TB drugs are
known, the one most reliable and clinically meaningful is that for rifamycin
resistance, the RIF polymerase B (rpoB) mutation. Because resistance to
the rifamycins is the keystone to MDR- or XDR-TB, using this mutation to triage
patients appears very attractive.
TREATMENT OF TUBERCULOSIS
Modern regimens use four drugs: RIF, INH, pyrazinamide
(PZA), and ethambutol (EMB). The current standard duration is 6 months. The
RIF, INH, PZA, and EMB are given for the first 2 months, and the RIF and INH are
given for the last 4 months. Current guidelines, however, indicate that if the
sputum culture taken after the first 2 months is positive, the RIF and INH
should be extended to a total of 9 months to lessen the risk of relapse.
Because nonadherence or noncompliance with the
prescribed regimen was shown to be associated with delayed conversion to sputum
negativity, higher rates of failure or relapse and—most importantly acquired drug resistance, directly observed
therapy (DOT) has become the normative practice in the United States.
Under the typical DOT program, at the time of
diagnosis, patients are served notice that they must make themselves regularly
available for supervised treatment or will face confinement. Patients cannot be
compelled to take medications, but if they are recalcitrant, they can be placed
under enforced isolation.
To facilitate supervised therapy, intermittent (less
than daily) regimens may be used. One model, based on studies from Hong Kong,
used thrice-weekly treatment throughout. Another, first used in Denver, begins
with 2 weeks of four drugs daily, switches to 6 weeks of four drugs twice
weekly, and concludes with 18 weeks of RIF-INH twice weekly. Of note, the
twice-weekly schedule has been found inadequate in the setting of AIDS; either thrice-weekly or daily
(five times per week) is
indicated.
MDR-TB or XDR-TB
As already noted, MDR (resistance at least to RIF and
INH) and XDR [(resistance at least to RIF, INH, one of fluoroquinolone agents,
and one of the second-line injectables [amikacin, kanamycin, or capreomycin])
are threatening global TB control.
TB drug resistance is based on chromosomal mutations,
not transferable resistance factors. The mutations are not induced by therapy;
rather, failure to take an adequate number of drugs in correct dosages allows
the resistant mutation to escape and by selection become the dominant strain.
Drug-resistant epidemics are amplified by making drugs available without the
infra- structure to ensure reliable therapy. After “primary” resistance is
established in a patient, he or she can transmit the resistant strain to others
(i.e., “transmitted” or “secondary” resistance).
Treatment of patients with highly resistant TB is
challenging because the second-line drugs (SLDs) are less efficacious, more
toxic, and more expensive than the first-line drugs. Plus the duration of
therapy required to cure increases from 6 months to 24 months. Historically,
drug-resistant TB was observed to be less readily transmissible and less
virulent (likely to progress to active disease) among contacts. However, over
the past 20 years, Beijing strains have tended to replace the older European
strains, and these organisms have been shown to be readily transmissible and
highly virulent.
Optimal management of drug-resistant cases entails
access to in vitro susceptibility testing, including SLDs, experience with the
clinical nuances of SLDs and ideally access to resectional surgery. Among the agents used
are the injectables (streptomycin, amikacin, kanamycin, or capreomycin), the
fluoroquinolones (cipro-, levo-, or moxifloxacin), cycloserine, ethionamide,
paraaminosalicylic acid (PAS), clofazimine, linezolid, clarithromycin, and
amoxicillin/clavulanate. Comprehensive discussions of the treatment of highly
resistant TB are beyond the scope of this chapter.
Treatment of Latent Tuberculosis Infection
As noted above, reactivation of latent foci or
infection typically acquired months, years, or even decades earlier is the commonest pathway in
the pathogenesis of TB. Recognizing this pattern, the United States Public
Health Service conducted a series of trials to determine whether giving INH to
those with latent TB would reduce their risk of developing active disease.
Briefly, these placebo-controlled trials, which involved roughly 72,000 diverse
subjects, showed approximately 60% to 70% protection. In the group followed
longest,
Alaskan villagers, the protection extended over 19
years. Because BCG vaccination would substantially confound the utility of the
TST, the sole means of identifying latent infection, vaccination has not been
used in the United States.
In the United States, treatment of latent TB infection
(TLTI) focuses on identifying individuals or groups historically at high risk
for TB and, based on reactivity to the TST or IGRA, administering “preventive
therapy”: (1) contacts to cases of communicable TB who may be presumed to have
been recently infected; (2) those with
HIV infection or AIDS; (3) health care workers with recent conversion of their
TST or IGRA; (4) immigrants
from high-risk regions; (5) individuals with radiographic abnormalities
consistent with healed TB; and (6) other immunocompromised subjects, including
those with chronic renal failure, organ trans- plantation, recipients of tumor
necrosis factor inhibitors, or other agents (including high-dose steroids or
cytotoxic agents).
The current guidelines from the American Thoracic
Society (ATS) and Centers for Disease Control and Prevention (CDC) offer three
TLTI regimens: (1) INH for 9 months (first choice), (2) INH for 6 months
(acceptable), or (c) RIF for 4 months. The 9-month INH regimen is rated highest
by evidence-based analysis; 6 months of treatment is deemed acceptable. The 4
months of RIF option is a reflection of the efficacy of RIF in accelerated
sterilization in the treatment of active disease and its superior activity in
the murine model. TLTI with INH or RIF substantially lessens the number of
viable bacilli in those with latent infection and thereby prevents (or delays)
reactivation.
The side effects and toxicity of INH include rare but
serious hepatitis. Roughly 10% to 20% of those started on INH will have modest,
asymptomatic elevations in their hepatic transaminase values, more common with
increased age. A total of 1% to 3% of those receiving INH may develop
symptomatic hepatitis, which requires discontinuation. Lethal liver failure
occurs with continued use of INH in the setting of worsening liver chemistries and symptoms.
Current ATS and CDC guidelines indicate that symptom surveillance is generally
sufficient to prevent serious liver damage.
RIF is less likely to cause serious hepatitis and does
not have the central nervous system effects (e.g., lethargy, decreased
concentration) experienced by some patients taking INH. The major issue with
RIF is the potential for drug interactions with a variety of agents, including
antiretroviral (ARV) agents, oral contraceptives, warfarin, and a variety of other meds
(see the Physicians’ Desk Reference). It should not be used in people
with HIV/AIDS because of the risk of acquired monoresistance.
For contacts with MDR-TB cases, there is no unanimity
for TLTI. A 6-month course of a fluoroquinolone (levofloxacin or moxifloxacin) may
be appropriate. There are in practical options for TLTI in contacts with XDR-TB.
Treating Tuberculosis in Persons with AIDS
There are four unique aspects of managing TB in
persons with AIDS:
1. The clinical presentation may be atypical, including
chest radiography. In the absence of cavitation (rare in AIDS), sputum smears
are less readily smear positive. Diagnosis may be established by unusual
modalities such as blood culture, lymph node biopsy, and culture or bone marrow
biopsy and culture.
2. In persons with AIDS with advanced malnutrition and
infectious enteritis, there may be suboptimal TB drug absorption;
pharmacokinetic studies may be helpful.
3. There may be significant drug interaction between the
rifamycins and the ARV agents. In general, RIF has such a profound effect in
accelerating the elimination of the ARVs that they cannot be used together.
Instead, rifabutin, which has about 30% of the effect on the cytochrome P450
system, should be used. (See the CDC’s website for updates on TB therapy and
ARVs.)
4. When ARV therapy is begun and the CD4 lymphocyte population
increases, there may be an amplified immune response to the TB. This immune reconstitution
inflammatory syndrome (IRIS) may result in organ-specific flares or exaggerated constitutional
symptoms. Recent experience indicates that despite this risk, ARV be begun within
2 to 3 weeks of commencing TB therapy. If serious problems arise, corticosteroids
may ameliorate the IRIS.
PREVENTING NOSOCOMIAL TRANSMISSION OF TUBERCULOSIS
The MDR-TB epidemic was highly instructive regarding
institutional safety. In retrospect, health care authorities had confused the
early bactericidal effects of modern regimens with adequate infection control
measures. With drug-susceptible TB, the number of viable bacilli in the sputum
falls by two to three logs in
the first week of treatment; additionally, the
patients’ cough frequency decreases abruptly. By contrast, with MDR-TB, the
bacillary population and cough do not diminish under standard therapy. In the
New York City MDR-TB outbreak in the early 1990s, molecular epidemiology showed
that 80% of the cases were nosocomially transmitted.
This recognition led to several protective measures: (1) placing all suspected cases in negative-pressure isolation rooms, (2) establishing
six or more air changes per hour in these rooms, (3) having all health care
workers potentially exposed to wear fit-tested N95 respirators, and (4) using
ultraviolet germicidal irradiation in patient rooms.
These measures appear to have significantly reduced the
risk of nosocomial transmission. Nonetheless, health care workers are still
required to have annual testing, either
TSTs or IGRAs.
