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REVIEW

URRENT
C
OPINION

Complications of tuberculosis
Maunank Shah a and Caitlin Reed b,c

Purpose of review
Diagnosis and management of tuberculosis (TB) remains challenging and complex because of the
heterogeneity of disease presentations. Despite effective treatment, TB disease can lead to significant shortand long-term health consequences. We review potential acute and chronic complications of TB disease
and current management approaches.
Recent findings
Acute and subacute complications of TB disease are attributable to structural damage or vascular
compromise caused by Mycobacterium tuberculosis, as well as metabolic abnormalities and host
inflammatory responses. TB-related sepsis is a life-threatening acute complication for which current
diagnostic and management approaches are likely inadequate. Therapeutic intensification and usage of
immunomodulators are areas of ongoing research. Paradoxical reaction or symptom worsening during TB
treatment may benefit from corticosteroids. Despite successful cure of TB, chronic complications can arise
from anatomic alterations at disease sites. Examples include mycetomas developing within residual TB
cavities, impaired pulmonary function, or focal neurologic deficits from tuberculomas.
Summary
Effective management of TB requires attention to potential structural, metabolic, vascular, and infectious
complications. In some instances, individualizing treatment regimens may be necessary. Imunosuppression
and other host factors predispose to complications; others occur despite adequate treatment. Public health TB
programs and health systems require additional resources to provide comprehensive TB and post-TB care.
Keywords
corticosteroids, hypercalcemia, mycetoma, sepsis, tuberculosis

INTRODUCTION

ACUTE AND SUBACUTE COMPLICATIONS

Despite recent progress, the global burden of tuberculosis (TB) remains high, particularly in communities with high HIV prevalence [1]. In sub-Saharan
Africa, TB is the leading cause of death among HIVinfected patients and 43% of TB patients are HIV
coinfected [13]. Globally, in 2012, an estimated 8.6
million people developed active TB. Despite the
availability of effective treatment, mortality is high,
with nearly 1.3 million annual TB deaths.
TB also results in morbidity from acute and
chronic complications. TB remains in the top 20
causes of morbidity as measured by disabilityadjusted life years [4,5]. These complications result
from systemic, metabolic, infectious, or structural
derangements as a consequence of current or prior
TB disease. Comorbid conditions, including HIV,
diabetes, and organ transplantation, further complicate TB treatment. In this article, we discuss
several common and uncommon complications
that TB clinicians and public health practitioners
should consider when providing TB or post-TB care.
Adverse events related to TB drugs are common, but
are reviewed elsewhere [69].

Several acute and subacute complications may occur


during the course of TB disease which may impact
patient care and TB disease management.

Tuberculosis sepsis and acute respiratory


failure
Although TB disease often presents subacutely, it can
also manifest as sepsis or septic shock. In some instances, TB sepsis is accompanied by acute lung injury or
acute respiratory distress syndrome, with high rates
of morbidity and mortality [1013,14 ,15].
&

Johns Hopkins University School of Medicine, Baltimore, Maryland,


Inpatient Tuberculosis Unit, Olive View-UCLA Medical Center, Sylmar
and cDavid Geffen School of Medicine at University of California Los
Angeles, Los Angeles, California, USA
b

Correspondence to Maunank Shah, MD, Johns Hopkins University,


School of Medicine, 725 N. Wolfe St. PCTB building-224, Baltimore,
MD 21205, USA. Tel: +1 443 287 0401; fax: +1 410 955 0740; e-mail:
mshah28@jhmi.edu
Curr Opin Infect Dis 2014, 27:403410
DOI:10.1097/QCO.0000000000000090

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Tropical and travel-associated diseases

KEY POINTS
 TB-associated sepsis or acute respiratory failure has
high mortality rates despite appropriate therapy in both
developed and developing settings.

Even with rapid diagnosis, TB-sepsis management remains difficult. Current treatment recommendations do not differ between inpatient and
outpatient settings, or by disease severity [26]. However, because mortality of TB sepsis and respiratory
failure exceeds 50% [1113,14 ,15] adjunctive management strategies might be considered.
New data suggest that therapeutic intensification with higher doses of rifamycins results in
improved early bactericidal activity against Mycobacterium tuberculosis, with faster reductions in bacterial burden [27,28]. The maximum tolerated dose
of rifampin remains unclear, with small studies
suggesting that doses as high as 35 mg/kg may be
well tolerated [29]. A randomized controlled trial
demonstrated 58% reduction in mortality among
patients with TB meningitis who received i.v. rifampin at higher doses (13 mg/kg) compared with those
receiving a standard oral dosage of 10 mg/kg [30 ].
Fluoroquinolone usage is also being evaluated in
new TB regimens. Data suggest that substitution
of moxifloxacin for isoniazid or ethambutol may
lead to improved outcomes, including reductions in
time to sputum culture conversion [29,3134].
Whether using higher doses of rifamycins or adding
fluoroquinolones could reduce early mortality in
the setting of TB sepsis is unknown.
&

 The maximum tolerated dose of rifampin remains


unclear, with emerging evidence that increased
rifamycin dosing may have mortality benefit in cases of
severe TB disease, including TB meningitis.
 Therapeutic drug monitoring is a valuable tool for TB
care, particularly in evaluating TB treatment failure and
for managing drugdrug interactions.
 TB treatment in patients with comorbidities, including
diabetes mellitus or coinfection with HIV or hepatitis C,
requires individualized considerations and close
monitoring for complications.
 Both pulmonary and extrapulmonary TB may lead to
site-specific chronic sequelae because of structural or
vascular alterations despite successful TB treatment.

Poor outcomes related to TB sepsis are found


worldwide. A recent multinational retrospective
review of adults presenting with TB septic shock at
28 institutions found an in-hospital mortality
approaching 80% [14 ]. Survival was only 5% among
individuals in whom TB therapy was delayed. TB is a
particularly important cause of sepsis in patients with
immunosuppression. Recent data from endemic settings suggest that TB bacteremia is the underlying
cause for sepsis in a high proportion of HIV-infected
individuals. In Uganda, for example, 23% of HIV
patients with sepsis were mycobacteremic, with
mortality exceeding 50% [16 ].
Rapid diagnosis of TB sepsis is critical but
difficult. Presentations may be indistinguishable
from bacterial sepsis, and the current TB detection
methods are insensitive (e.g., AFB smear-microscopy)
or slow (e.g., mycobacterial culture). Xpert MTB/RIF
and other nucleic acid amplifications tests are more
rapid and are now FDA approved and WHO endorsed,
but are less sensitive than mycobacterial culture
[17 ,18,19 ]. The role of other emerging technologies for rapid diagnosis remains unclear. For
example, the product Determine TB-LAM (Alere
Inc.,Waltham, Massachusetts, USA) is a point-of-care
lateral-flow urine antigen test that detects lipoarabinomannan, a component of the mycobacterial cell
wall [2022]. The test is low cost and provides results
in 30 min. Test sensitivity is suboptimal (2080%),
but may be highest in HIV patients with advanced
immunosuppression and/or mycobacteremia [20,21,
2325]; additional data are needed to explore its role
in diagnosis of TB-sepsis syndromes.

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Paradoxical reaction in tuberculosis sepsis


and other forms of tuberculosis
Alternatively, management of the inflammatory
response during TB-sepsis syndromes may be considered. In all forms of TB, paradoxical reaction, or
immune-mediated worsening of symptoms during
treatment, has been described [35,36]. Disease
exacerbation is likely mediated by an exaggerated
response to the release of mycobacterial antigen from
dying organisms [37]. Corticosteroids have been
recommended in other forms of TB in which reducing inflammation is a priority, including TB meningitis and pericarditis [26,38,39 ]. Steroids have
potential short-term benefits for pulmonary TB
patients, but their impact on reducing mortality
remains unclear [39 ,40,41]. A recent small retrospective study found that steroids were associated
with decreased death in TB patients with respiratory
failure [15]. No prospective trials to date have evaluated the role, optimal dosage, or duration of adjunctive steroids or other immunomodulators in the
management of TB sepsis or other disease presentations.
&&

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Complications associated with comorbidities


Although TB incidence is declining in some settings,
the complexity of TB cases is increasing. In the
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Complications of tuberculosis Shah and Reed

United States, the majority of TB cases occur among


individuals born in endemic countries [42], with
reactivation often occurring decades later because
of immunosuppression. TB patients often have
co-morbidities, including organ transplantation,
rheumatologic disease, diabetes, hemodialysis, and
malignancy. In our experience, achieving successful
outcomes requires an individualized approach that
may not conform to standardized treatment algorithms. Tailored drug regimens may require dosing
adjustments, or use of second-line drugs.
Suboptimal drug absorption is a potential complication of comorbid conditions. For example, a
patient with prior gastrectomy and small bowel
surgery presented to our care with refractory TB
disease. Therapeutic drug monitoring (TDM)
revealed nearly undetectable drug concentrations
because of inadequate oral absorption of first-line
TB drugs [43]; oral doses three to four times higher
than standard were required to achieve adequate
absorption of rifampin and isoniazid.
Diabetes mellitus has become recognized as a
specific risk factor for slower treatment response,
increased morbidity, and poor TB drug absorption
[4446]. One recent study demonstrated that in
patients with slow treatment response, over half
had rifampin levels below the expected range; diabetics had increased risk for low rifampin levels
(AOR 5.7) [44]. Future TB guidelines may suggest
routine screening for diabetes mellitus, or incorporating TDM as part of standard TB care to optimize
patient outcomes. In our practice, TDM is a valuable
tool for evaluating TB treatment failure and managing drugdrug interactions.
Hepatic or renal disease may complicate treatment. We recently encountered a patient with a
history of liver transplant and hepatitis C who developed pleural TB while on tacrolimus and prednisone.
Standard TB therapy led to hepatotoxicity. We substituted a liver-sparing treatment regimen that
included moxifloxacin instead of isoniazid [29,
3134], and discontinued rifamycins because of
drugdrug interactions with the immunosuppressive
regimen and new hepatitis C drugs sofosbuvir and
simeprevir [47]. Patients unable to tolerate first-line
TB drugs often require alternate regimens usually
reserved for multidrug resistant TB (MDR-TB).
Drug intolerance is functionally similar to
drug resistance because both require alternative TB
regimens. After several decades of stagnation in
TB drug development, bedaquiline (an ATP synthase
inhibitor) has now been approved by the FDA for
usage in some cases of MDR-TB [48 ]; delamanid
(a nitro-dihydro-imidazooxazole antibiotic) has
similarly been approved by the European Medicines
Agency for the treatment of MDR-TB [49,50]. Clinical
&&

experience with these drugs remains limited. We


have also occasionally incorporated linezolid into
alternative TB regimens. Linezolid is an oxazolidinone with antituberculous activity and efficacy
as part of drug-resistant TB treatment regimens
[51 ,52,53].
&&

Massive hemoptysis
A rare but serious complication of TB disease is the
development of massive hemoptysis. In the United
States, 716% of all massive hemoptysis cases are
due to complications of TB and require prompt
action [54]. Pulmonary TB causes hemoptysis by
erosion into the bronchial or pulmonary circulation,
or by formation of pseudoaneuryms (Rasmussens
aneurysm), leading to potentially life-threatening
impairment of gas exchange or hemodynamic collapse. Pseudoaneurysms have been described in up to
4% of TB autopsy series [55]. The treatment of choice
for massive hemoptysis is selective embolization of
the bleeding arteries, but surgical interventions can
also be considered [5456].

Extrapulmonary tuberculosis complications


TB disease presents with extraordinary heteterogeneity (Table 1). As a result, clinicians must pay
special attention to identifying site-specific extrapulmonary complications. In the United States,
extrapulmonary tuberculosis (EPTB) now represents
over 20% of all cases, an increase from only 15% in
1993 [57]. Diagnosis of EPTB is particularly challenging because of reduced sensitivity of conventional
diagnostics. Recently, WHO recommended the
adjunctive usage of molecular assays such as Xpert
MTB/RIF to aid in the detection of TB from CSF,
lymph nodes, and pleura [58]. Empiric TB therapy is
often warranted while TB diagnostic evaluation is
ongoing. TB of the central nervous system (CNS)
and pericardial TB offer examples of potentially
serious EPTB complications.
Central nervous system tuberculosis
CNS TB disease, including TB meningitis and CNS
tuberculomas, is associated with high rates of early
mortality. Recent studies show that optimization of
the chemotherapeutic regimen for TB meningitis
with i.v. rifampin at higher doses may reduce mortality [30 ,59].
Other major complications with long-term morbidity include hydrocephalus, stroke, and mass
effect of tuberculomas.
Hydrocephalus is common and occurs more frequently in children than in adults. The presentation
can include loss of consciousness and increased
intracranial pressure. No consensus strategies have

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Tropical and travel-associated diseases


Table 1. Selected acute and chronic TB related
complications, by site
Anatomic site

Complication

Lung parenchyma

 Tuberculoma
 Residual cavitation
 Aspergilloma
 Scarring or fibrosis
 Obstructive or restrictive
ventilatory deficits

Airways

 Bronchiectasis
 Tracheobronchial stenosis
 Broncholithiasis

Vascular

 Pulmonary or bronchial
arteritis or thrombosis
 Rasmussen pseudoaneurysm

Mediastinal or cardiac

 Lymph node calcification


 Esophagobronchial fistula
 Cardiac tamponade
 Constrictive pericarditis

Pleural

 Chronic empyema
 Bronchopleural fistula
 Pneumothorax

Central nervous system

 Tuberculomasfocal neurologic
deficits or seizures
 Vasculitis or stroke
 Hydrocephalus

Eye

 Posterior or anterior uveitis


 Choroiditis
 Optic neuropathy

Genitourinary

 Renal TB
 Ureteral stenosis
 Hydronephrosis
 Prostatic abscess

Endocrine or metabolic

 Paradoxical worsening of lymphadenitis


 Lymphocutaneous fistulas

Abdomen

 Tuberculous ascites
 Peritoneal implants
 Granulomatous colitis (may be
mistaken for Crohns disease)
 Pelvic abscess

Bone

Tuberculosis pericarditis
Tuberculous pericarditis develops from contiguous
spread from mediastinal nodes or hematogenous
seeding during dissemination with mycobacteremia.
In endemic countries, TB is among the most common
causes of pericardial disease, and poses diagnostic
challenges; mortality occurs in 1740% of cases,
often due to acute cardiac tamponade [61]. Chronic
pericardial inflammation may progress into constrictive pericarditis, in which the calcified, stiff pericardium impairs diastolic filling and causes symptoms of
heart failure. Tuberculous pericardial effusions are
typically bloody and exudative, with an elevated
leukocyte count, predominately lymphocytes. In
addition to TB medications, management of TB pericarditis may require pericardiocentesis for effusions
and tamponade, pericardectomy for constriction,
or adjuvant corticosteroids, although evidence for
steroid usage is limited to small trials [62].

 Adrenal insufficiency
 Hypercalcemia

Lymph nodes

TB meningitis can lead to particularly poor outcomes because of inflammation and thrombosis of
cerebral vasculature causing stroke, or from cerebral
vasospasm. These effects can lead to ischemic brain
damage, including basilar infarcts and hemiplegia.
In our experience, TB vasculitis or stroke can occur
as either early or late complications with devastating
consequences.
Finally, CNS tuberculomas can be silent, and
may even develop or enlarge during therapy [59].
One study conducting serial MRIs on CNS TB
patients found that nearly 80% of adults with TB
meningitis had evidence of CNS tuberculomas
despite effective TB therapy, including steroids
[60]. Tuberculomas can exert mass effect and cause
focal neurologic deficits or seizures.

 Focal osteomyelitis
 Spinal diskitis and osteomyelitis
(Potts disease)

Complications at other anatomic sites


TB can affect any organ system, each with particular
potential complications: TB uveitis may lead to
residual blindness, spinal TB may result in loss of
structural integrity, peritoneal disease can cause
intestinal obstruction, genitourinary TB can lead
to ureteral strictures, and hydronephrosis, adrenal
infiltration may cause hemorrhage and adrenal
insufficiency, and TB lymphadenitis may result in
lymphocutaneous fistulas, among many others
(Table 1).

 Pathologic fractures

Metabolic complications
been developed for the management of TB hydrocephalus; interventions may include medical treatment, such as acetazolamide, or management of
intracranial pressure through ventriculoperitoneal
shunting [59].
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Hypercalcemia is a well known complication of


granulomatous diseases. Activated macrophages in
granulomas contain alpha-1 hydroxylase, which
converts precursor 25-hydroxy vitamin D into the
active form of 1,25-dihydroxy vitamin D. The active
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Complications of tuberculosis Shah and Reed

form of vitamin D mediates a rise in serum calcium


by increasing absorption in the gut and mobilizing
calcium from bone.
Hypercalcemia symptoms include nephrolithiasis, acute kidney injury, osteoporosis, constipation, and neuropsychiatric manifestations. In
TB-related hypercalcemia, parathyroid hormone
levels are appropriately suppressed [63]. Depending
on severity, management can include aggressive
normal saline hydration, loop diuretics, calcitonin,
steroids, or bisphosphonates.
Vitamin D deficiency has been associated with
progression from latent infection to active TB disease on a population level. However, studies of
vitamin D supplementation for treatment of active
TB disease have produced conflicting results [64,65].
Patients with granulomatous disease are more sensitive to vitamin D by the mechanism above. In our
experience, hypercalcemia can occur in TB patients
treated with even modest doses of vitamin D, and
there have been similar case reports [66]. A comprehensive review recommended targeting a lower
25-hydroxy vitamin D goal level of 2030 ng/ml
when treating vitamin D deficiency in patients with
granulomatous disease [67].

Complications of human immunodeficiency


virus associated tuberculosis
The general principles of TB treatment in HIVinfected individuals are similar to those in HIVuninfected patients, and a comprehensive summary
is beyond the scope of this review. However, several
recent developments are worth mention.
New evidence-based guidance recommends
early initiation of antiretroviral therapy (ART) within
2 weeks of starting TB therapy in patients with CD4
counts less than 50 cells/ml, and within 812 weeks in
individuals with higher CD4 counts [6870,71 ].
Early ART initiation confers mortality benefit, but
also increases development of immune reconstitution inflammatory syndromes (IRIS). TB-IRIS
increases complexity of care, occurs in 1520% of
patients starting ART, and is a clinical diagnosis
[72,73]. TB-IRIS mortality is estimated at 3%; particular caution is warranted with CNS or pericardial TB
[72]. Corticosteroids are often utilized for TB-IRIS
management, but clinical trial data are limited
[74]. Clinicians must monitor for HIV treatment
failure and TB-HIV drug interactions [71 ]. Recommendations on rifabutin dosing, when used in conjunction with protease inhibitors, have recently
changed; rifabutin should be given at 150 mg daily,
rather than 150 mg every other day [71 ]. In our
experience, liver function should be monitored
because of possible additive hepatoxicity. Note that
&&

&&

&&

rifampin is currently contraindicated with etravirine,


rilpivirine, or elvitegravir/cobiscistat, whereas usage
with integrase inhibitors may require dose adjustment [71 ,75].
&&

CHRONIC COMPLICATIONS
In addition to complications during TB disease and
TB treatment, longer term sequelae of TB may occur.
Clinicians and public health practitioners should
consider continued follow-up after successful TB
therapy to monitor for chronic structural and
infectious complications.

Architectural compromise of lung


parenchyma or airways
Pulmonary TB causes damage to airways and lung
parenchyma and may result in long-lasting complications despite effective TB therapy [76]. The extent
of chronic damage ranges from minimal scarring to
extensive bronchiectasis and impressive fibrocavitary destruction [77] (Fig. 1). TB disease can lead to
chronic restrictive or obstructive decline in pulmonary function [7780]. In environments in which
patients are frequently reinfected, pulmonary
impairment progressively worsens with each TB episode [81].
When advanced, parenchymal damage can lead
to destruction of a lobe or an entire lung [82,83]
(Fig. 1). In such cases of tuberculous lung destruction,
chronic symptoms may mimic those of postpneumonectomy syndrome, with mediastinal shift, traction on the heart and great vessels, or bronchial
compression [84,85]. A retrospective review of
patients with tuberculous-destroyed lung found that
degree of destruction was an independent predictor
of shorter survival; overall mortality was 28%, with
median survival 39 months [86]. Added complications include bacterial pneumonia, cor pulmonale,
pneumothorax, and acute respiratory failure [86].
Pulmonary airways may also be compromised
after TB disease. Calcified mediastinal nodes can
erode into airways, causing broncholithiasis. Alternatively, fibrostenosis may result from healing
endobronchial tuberculosis. Excess granulation tissue can be removed with laser or microwave ablation, electrocautery, or cryotherapy. Management
of stenosis may require surgical or interventional
radiologic approaches, including balloon dilatation
and stent placement [87].

Infectious complications mycetoma


Residual TB cavitary lesions may become colonized
by aspergillus and other fungi. Fungal balls, or
mycetomas, may develop within these cavities

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Tropical and travel-associated diseases

Panel A

Panel B

FIGURE 1. A 52 year old man with severe pulmonary tuberculosis causing total fibrocavitary destruction of the left lung. Panel
A. Chest radiograph demonstrating lucencies and large cavities replacing the entire left lung parenchyma, along with
scattered nodular infiltrates of active tuberculosis in the right lung. Panel B. CT scan of the chest demonstrating correlated
findings.

and can cause chronic hemoptysis from erosions of


capillaries in the adjacent parenchyma. Mycetoma
occurs in 1117% of patients with tuberculous
cavities [88]. For patients with hemoptysis, surgical
lobar resection offers definitive treatment [89]. In
our experience, many patients with mycetoma have
chronic pulmonary symptoms; these patients often
undergo repeated admissions for evaluation of
possible recurrent TB, adding substantial morbidity
for patients and cost for health systems.

Acknowledgements
This project was funded with Federal funds from
the National Institute of Allergy and Infectious
Diseases, National Institutes of Health, under grant #
K23AI089259 [MS].
Conflicts of interest
The authors declare that they have no conflicts of
interest.

CONCLUSION

REFERENCES AND RECOMMENDED


READING

Although effective therapies exist for the treatment


of active TB disease, comprehensive TB management is challenging. TB disease can lead to lifealtering acute and chronic health consequences
from structural damage, vascular compromise,
metabolic derangements, and infectious complications. Comorbidities complicate TB therapy
because of impaired drug absorption, drugdrug
interactions, and additive therapeutic toxicities.
These complications may occur even in the face
of appropriate antituberculous drug treatment,
and are often overlooked. These elements of TB care
are not well accounted for in health policy, research,
or costeffectiveness studies. Additional resources
and funding are needed for TB programs to manage
the myriad complications arising from TB disease,
even after the bacilli have been eradicated from the
patient. Although standardized approaches to TB
care are useful, TB disease heterogeneity requires
individualized considerations to improve TB outcomes and reduce short and long-term TB complications.

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