Académique Documents
Professionnel Documents
Culture Documents
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
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].
www.co-infectiousdiseases.com
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
&
&&
&
&
&
404
&&
www.co-infectiousdiseases.com
&&
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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].
&&
www.co-infectiousdiseases.com
405
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
Pleural
Chronic empyema
Bronchopleural fistula
Pneumothorax
Tuberculomasfocal neurologic
deficits or seizures
Vasculitis or stroke
Hydrocephalus
Eye
Genitourinary
Renal TB
Ureteral stenosis
Hydronephrosis
Prostatic abscess
Endocrine or metabolic
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)
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].
406
www.co-infectiousdiseases.com
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
&&
&&
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.
www.co-infectiousdiseases.com
407
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
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
408
www.co-infectiousdiseases.com
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
35. Carvalho AC, De Iaco G, Saleri N, et al. Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients. Clin Infect Dis 2006; 42:893
895.
36. Hawkey CR, Yap T, Pereira J, et al. Characterization and management of
paradoxical upgrading reactions in HIV-uninfected patients with lymph node
tuberculosis. Clin Infect Dis 2005; 40:13681371.
37. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab
in tuberculosis to control severe paradoxical reaction of the brain and lymph
nodes. Clin Infect Dis 2008; 47:e83e85.
38. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;
351:17411751.
39. Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of
&&
mortality in people with tuberculosis: a systematic review and meta-analysis.
Lancet Infect Dis 2013; 13:223237.
This systematic review and meta-analysis is among the most comprehensive
evaluating the role of steroids as adjunctive treatment to improve TB patient
outcomes. This analysis includes patients with all forms of TB, including pulmonary
and extrapulmonary disease.
40. Bilaceroglu S, Perim K, Buyuksirin M, Celikten E. Prednisolone: a beneficial
and safe adjunct to antituberculosis treatment? A randomized controlled trial.
Int J Tuberc Lung Dis 1999; 3:4754.
41. Smego RA, Ahmed N. A systematic review of the adjunctive use of systemic
corticosteroids for pulmonary tuberculosis. Int J Tuberc Lung Dis 2003;
7:208213.
42. Alami NN, Yuen CM, Miramontes R, et al., Centers for Disease Control and
Prevention (CDC). Trends in tuberculosis United States, 2013. MMWR
Morb Mortal Wkly Rep 2014; 63:229233.
43. Peloquin C. Use of therapeutic drug monitoring in tuberculosis patients.
Chest 2004; 126:17221724.
44. Heysell SK, Moore JL, Keller SJ, Houpt ER. Therapeutic drug monitoring for
slow response to tuberculosis treatment in a state control program, Virginia,
USA. Emerg Infect Dis 2010; 16:15461553.
45. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of
two epidemics. Lancet Infect Dis 2009; 9:737746.
46. Dooley KE, Tang T, Golub JE, et al. Impact of diabetes mellitus on treatment
outcomes of patients with active tuberculosis. Am J Trop Med Hyg 2009;
80:634639.
47. Williamson B, Dooley KE, Zhang Y, et al. Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin,
rifabutin, and rifapentine. Antimicrob Agents Chemother 2013; 57:6366
6369.
48. Centers for Disease Control and Prevention. Provisional CDC guidelines for
&&
the use and safety monitoring of bedaquiline fumarate (Sirturo) for the
treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep 2013;
62:112.
Bedaquiline is the first new drug for TB to be approved by the FDA in decades. This
document outlines provisional guidance for use in treatment of drug-resistant TB in
the United States, and contains important data on indications for usage, drug
toxicities, and need for close monitoring.
49. EMA. European Medicines Agency: Positive opinion on the marketing authorisation for Deltyba1 (delamanid). http://www.ema.europa.eu/docs/en_GB/
document_library/Medicine_QA/human/002552/WC500155462.pdf. [Accessed March 2014]
50. TB-Online. Otsuka wins European marketing authorization for Deltyba. 2014.
http://www.tbonline.info/posts/2014/4/30/otsuka-wins-european-marketing-authorization-delty/. [Accessed 16 May 2014]
51. Lee M, Lee J, Carroll MW, et al. Linezolid for treatment of chronic extensively
&&
drug-resistant tuberculosis. N Engl J Med 2012; 367:15081518.
This study is among the first to demonstrate the efficacy of linezolid for the
treatment of XDR-TB in a controlled clinical trial. The study has implications for
the treatment of drug-resistant TB, and for patients who are unable to tolerate first
line TB drugs.
52. Sotgiu G, Centis R, DAmbrosio L, et al. Efficacy, safety and tolerability of
linezolid containing regimens in treating MDR-TB and XDR-TB: systematic
review and meta-analysis. Eur Respir J 2012; 40:14301442.
53. Schecter GF, Scott C, True L, et al. Linezolid in the treatment of multidrugresistant tuberculosis. Clin Infect Dis 2010; 50:4955.
54. Jayet PY, Denys A, Zellweger JP, et al. Successful embolization of Rasmussens
aneurysm for severe haemoptysis. Swiss Med Wkly 2004; 134:705706.
55. Santelli ED, Katz DS, Goldschmidt AM, Thomas HA. Embolization of multiple
Rasmussen aneurysms as a treatment of hemoptysis. Radiology 1994;
193:396398.
56. Ramakantan R, Bandekar VG, Gandhi MS, et al. Massive hemoptysis due to
pulmonary tuberculosis: control with bronchial artery embolization. Radiology
1996; 200:691694.
57. Peto HM, Pratt RH, Harrington TA, et al. Epidemiology of extrapulmonary
tuberculosis in the United States, 19932006. Clin Infect Dis 2009;
49:13501357.
58. WHO. The use of the xpert mtb/rif assay for the detection of pulmonary and
extrapulmonary tuberculosis and rifampicin resistance in adults and children
Expert Group Meeting Report. http://www.stoptb.org/wg/gli/assets/docu
ments/Xpert%20Meeting%20Report%2024102013%20%20Pre%20publi
cation%20FINAL.pdf. [Accessed March 2014]
www.co-infectiousdiseases.com
409
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
410
www.co-infectiousdiseases.com
74. Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebocontrolled trial of prednisone for paradoxical tuberculosis-associated
immune reconstitution inflammatory syndrome. AIDS 2010; 24:2381
2390.
75. Wenning LA, Hanley WD, Brainard DM, et al. Effect of rifampin, a potent
inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir.
Antimicrob Agents Chemother 2009; 53:28522856.
76. Dheda K, Booth H, Huggett JF, et al. Lung remodeling in pulmonary tuberculosis. J Infect Dis 2005; 192:12011209.
77. Vecino M, Pasipanodya JG, Slocum P, et al. Evidence for chronic lung
impairment in patients treated for pulmonary tuberculosis. J Infect Public
Health 2011; 4:244252.
78. Skoogh BE. Lung mechanics in pulmonary tuberculosis. 3. Bronchial reactivity. Scand J Respir Dis 1973; 54:379387.
79. Lopez-Majano V. Ventilation and transfer of gases in pulmonary tuberculosis.
Respiration 1973; 30:4863.
80. Willcox PA, Ferguson AD. Chronic obstructive airways disease following
treated pulmonary tuberculosis. Respir Med 1989; 83:195198.
81. Hnizdo E, Singh T, Churchyard G. Chronic pulmonary function impairment
caused by initial and recurrent pulmonary tuberculosis following treatment.
Thorax 2000; 55:3238.
82. Massard G, Olland A, Santelmo N, Falcoz PE. Surgery for the sequelae of
postprimary tuberculosis. Thorac Surg Clin 2012; 22:287300.
83. Bobrowitz ID, Rodescu D, Marcus H, Abeles H. The destroyed tuberculous
lung. Scand J Respir Dis 1974; 55:8288.
84. Kam JC, Dieguez J, Doraiswamy V, et al. Postpneumonectomy-like syndrome
presenting in a patient with treated pulmonary tuberculosis: a case report. J
Med Case Rep 2013; 7:40.
85. Lee Y, Kim HK, Lee S, et al. Surgical correction of postpneumonectomy-like
syndrome in a patient with a tuberculosis-destroyed lung. J Thorac Cardiovasc
Surg 2008; 136:780781.
86. Ryu YJ, Lee JH, Chun EM, et al. Clinical outcomes and prognostic factors in
patients with tuberculous destroyed lung. Int J Tuberc Lung Dis 2011;
15:246250; i.
87. Xue Q, Wang N, Xue X, Wang J. Endobronchial tuberculosis: an overview. Eur
J Clin Microbiol Infect Dis 2011; 30:10391044.
88. B.T.T.A. British Thoracic and TB Association. Aspergilloma and residual
tuberculous cavities the results of a resurvey. Tubercle 1970; 51:227
245.
89. Glimp RA, Bayer AS. Pulmonary aspergilloma. Diagnostic and therapeutic
considerations. Arch Intern Med 1983; 143:303308.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.