Cases & Commentaries

Missed TB

Commentary By J. Mark FitzGerald, MB; Dick Menzies, MD

The Case

A 38-year-old white female with no past medical
history presented to the hospital with fevers, respiratory failure,
and bilateral pulmonary infiltrates. She was treated empirically
with broad-spectrum antibiotics, which were continued even after
her initial blood and sputum cultures returned negative. Fevers
persisted and she soon developed acute respiratory distress
syndrome (ARDS). The treating physicians considered bronchoscopy,
but felt the patient was too ill to tolerate the procedure. An HIV
test was sent and was negative. On hospital day 21, her providers
considered the possibility of tuberculosis, and sent sputum for
acid-fast bacilli (AFB) smear and culture. The AFB smears were
negative. The patient continued to deteriorate, with progressive
respiratory failure, and died shortly afterward. Several days
later, the AFB cultures began growing Mycobacterium

The Commentary

This case represents an unfortunate failure to
identify tuberculosis (TB) in a young woman. Although TB is a
common pathogen worldwide, it affects very few people in North
America.(1) However,
rates of TB are relatively high among the foreign born.

TB is a relatively infrequent cause of
respiratory failure. In a population-based study in Manitoba over a
10-year period, Penner and colleagues identified only 13 patients
with pulmonary TB requiring mechanical ventilation, compared with
722 cases of pulmonary TB and 37 cases of miliary TB during the
same period.(2) The
mortality rate of 69% was higher than the mortality for respiratory
failure due to bacterial pneumonia (36%; p3) Because
TB does not cause respiratory failure very often, it is an unlikely
infectious cause of ARDS. In a prospective study of severe
community acquired pneumonia (CAP) requiring mechanical
ventilation, only 1 of 144 patients had pneumonia due to M.

The diagnosis of TB is often delayed. In one
study of 429 hospitalized patients with newly diagnosed pulmonary
TB (5), 127 (30%)
had not received antituberculous chemotherapy during their first
week in the hospital. The risk of delayed treatment was
particularly high in hospitals that rarely saw patients with the
disease (ie, fewer than 3.3 cases of TB per 10,000 admissions).
These delays are harmful: patients with delayed diagnosis and
therapy have higher rates of potentially preventable intensive care
unit admissions and death. The difficulty of making an early
diagnosis of TB is further compounded by the increasingly frequent
use of respiratory quinolones as first-line therapy in community
acquired pneumonia, since they may partly treat the active
pulmonary TB and lead clinicians to be falsely reassured by a
clinical response.(6)

Thus, the clinician is challenged by the
relatively infrequent occurrence of TB as a cause of respiratory
failure, along with the dire consequences of delayed or missed
diagnoses. Clearly, it is critical to consider TB as a possible
diagnosis in patients with infectious respiratory failure.
Unfortunately, no signs or symptoms are sufficiently sensitive or
specific to help guide decision-making. For example, the presence
of cough for longer than 2 weeks (a "classic" symptom of TB) is
only seen in half of patients with pulmonary TB.(7)

A pragmatic approach would be to suspect TB in
all cases of severe community acquired pneumonia who fail to show a
response to treatment within the first 48 hours. Clinicians should
be especially vigilant in patients who are prescribed quinolones
initially, and those from groups at high risk of TB. Such groups
include immigrants from high prevalence TB countries, persons known
to be infected with or at risk of HIV infection, or persons with a
documented history of contact with an active case of TB or a
positive TB skin test.

More broadly, clinicians need to recognize that
"pneumonia" that does not respond to empiric antibiotic therapy has
a differential diagnosis, which includes other infections,
resistant organisms, as well as non-infectious conditions
(Table). Like TB,
each of these entities is relatively rare; however, as a group,
they occur commonly enough that clinicians need to have a
structured approach to evaluating "non-resolving pneumonia." In
this case, the error was not so much that the clinicians failed to
consider TB until hospital day 21, but that they did not consider
any alternative diagnoses or complications that might explain the
patient's non-resolving pneumonia in a timely fashion.


It is important to understand that only 50% of
persons will have positive sputum smears for AFB. Thus, patients
who don't respond to regular antibiotics and have a radiographic
pattern suggestive of TB should receive empiric treatment for TB.
Induced sputum has a greater yield than bronchoscopy; it should be
considered in patients who cannot provide a sputum
sample.(8,9,10) In
patients who do not respond to broad-spectrum antibiotics, an
additional consideration is the use of CT scan imaging, which may
show radiological features such as cavitation, apical nodular
disease, or a "tree and bud" pattern, which may not be apparent on
a plain radiograph.(11,12) Newer
nucleic acid amplification based diagnostic tests have a similar
yield as culture from bronchial secretions and should be considered
in all patients with severe CAP who fail to respond to

Take-Home Points

  • "Non-resolving pneumonia" has a broad
    differential diagnosis of infectious and non-infectious etiologies
    that clinicians need to address in a systematic and timely
  • Since the prognosis for missed TB in a
    patient presenting with severe CAP or respiratory failure is poor,
    TB is particularly important to consider in the approach to
    patients who do not respond to initial antibiotic therapy for
    presumed pneumonia. Most cases of missed TB can be traced to the
    fact that clinicians failed to consider the possibility rather than
    difficulties with diagnostic testing.
  • Because a delay in diagnosis is
    associated with higher mortality, a high index of suspicion is
    needed. If there is any suspicion, early initiation of empiric
    (multidrug) anti-TB treatment is warranted. There should be a low
    threshold to initiate such treatment in patients who fail to
    respond to broad-spectrum antibiotics.
  • Induced sputum or bronchial secretions
    should be submitted as soon as there is any clinical suspicion.
    Computerized tomography of the chest and nucleic acid
    amplification-based diagnostics may be helpful to confirm the
  • Once TB is entertained, respiratory
    isolation should continue until bronchial secretions have been
    screened negative for AFB and the patient is responding clinically
    and radiologically to antibiotic treatment (or to treatment for a
    plausible alternative diagnosis).

J. Mark FitzGerald,
Professor of Medicine
Director, Centre for Clinical Epidemiology and Evaluation
University of British Columbia

Dick Menzies, MD
Associate Professor of Medicine, Epidemiology, and
McGill University


1. Idemarco MF, Castro KG. Epidemiology of
tuberculosis. Semin Respir Infect. 2003;18:225-40.[ go to PubMed ]

2. Penner C, Roberts D, Kunimoto D, Manfreda J,
Long R. Tuberculosis as a primary cause of respiratory failure
requiring mechanical ventilation. Am J Respir Crit Care Med.
1995;151:867-72.[ go to PubMed ]

3. Lee PL, Jerng JS, Chang YL, et al. Patient
mortality of active pulmonary tuberculosis requiring mechanical
ventilation. Eur Respir J. 2003;22:141-7.[ go to PubMed ]

4. Pascual FE, Mathay MA, Bachetti P, Wachter RM.
Assessment of prognosis in patients with community-acquired
pneumonia who required mechanical ventilation. Chest.
2000;117:503-12.[ go to PubMed ]

5. Greenaway C, Menzies D, Fanning A, et al.
Delay in diagnosis among hospitalized patients with active
tuberculosis-predictors and outcomes. Am J Respir Crit Care Med.
2002;165:927-33.[ go to PubMed ]

6. Dooley KE, Golub J, Goes FS, Merz WG, Sterling
TR. Empiric treatment of community-acquired pneumonia with
fluoroquinolones, and delays in the treatment of tuberculosis. Clin
Infect Dis. 2002;34:1607-12.[ go to PubMed ]

7. Miller LG, Asch SM, Yu EM, Knowles L, Gelberg
L, Davidson P. A population-based survey of tuberculosis symptoms:
how atypical are atypical presentations? Clin Infect Dis.
2000;30:293-9.[ go to PubMed ]

8. Anderson C, Inhaber N, Menzies R. Comparison
of sputum induction with fiber-optic bronchoscopy in the diagnosis
of tuberculosis. Am J Respir Crit Care Med. 1995;152:1570-4.[ go to PubMed ]

9. Al Zahrani K, Al Jahdali H, Poirier L,
René P, Menzies D. Yield of smear, culture and amplification
tests from repeated sputum induction for the diagnosis of pulmonary
tuberculosis. Int J Tuberc Lung Dis. 2001;5:855-60.[ go to PubMed ]

10. McWilliams T, Wells AU, Harrison AC,
Lindstrom S, Cameron RJ, Foskin E. Induced sputum and bronchoscopy
in the diagnosis of pulmonary tuberculosis. Thorax.
2002;57:1010-4.[ go to PubMed ]

11. Choi D, Lee KS, Suh GY, et al. Pulmonary
tuberculosis presenting as acute respiratory failure: radiologic
findings. J Comput Assist Tomogr. 1999;23:107-13.[ go to PubMed ]

12. Akira M, Sakatani M. Clinical and
high-resolution computed tomographic findings in five patients with
pulmonary tuberculosis who developed respiratory failure following
chemotherapy. Clin Radiol. 2001;56:550-5.[ go to PubMed ]


Table. Causes to Consider When Pneumonia Does
Not Respond to Several Days of Empiric Antibiotic Therapy

Lung Infections Requiring More Than
Just Antibiotics

Infections Not Covered by Initial
Antibiotic Choices

Non-Infectious Conditions


Legionella, Mycoplasma, Chlamydia
(depending on initial antibiotic choice)

Pulmonary hemorrhage

Post-obstructive pneumonia

Resistant organisms (eg, Streptococcus
pneumonia with high-level beta-lactam resistance)


Empyema (if pneumonia is accompanied by
an effusion)


Congestive Heart Failure


TB, fungi, Nocardia, Actinomyces

Inflammatory conditions (eg, BOOP
[Bronchiolitis obliterans with organizing pneumonia], Wegner's



Drug-induced lung injury