C a r d i o p u l m o n a r y I m a g i n g C l i n i c a l Pe r s p e c t i ve

Rozenshtein et al.
Radiographic Appearance of Pulmonary Tuberculosis

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Cardiopulmonary Imaging
Clinical Perspective

Radiographic Appearance
of Pulmonary Tuberculosis:
DogmaDisproved
Anna Rozenshtein1
Frank Hao1
Michael T. Starc2
Gregory D. N. Pearson1
Rozenshtein A, Hao F, Starc MT, Pearson GDN

OBJECTIVE. The purpose of this article is to review the origins of the classic teaching
on pulmonary tuberculosis, its evolution in the modern literature, and the evidence that led
to its demise.
CONCLUSION. Use of molecular epidemiologic techniques that entail DNA fingerprinting has led to the discovery that the radiographic appearance of pulmonary tuberculosis
does not depend on the time since infection. It has been confirmed that the upper lobe cavitary disease typical in adults is the disease of the immunocompetent host, whereas lower lung
zone disease, adenopathy, and effusions, which are uncommon in adults, are the hallmarks of
tuberculosis in an immunocompromised host.

Keywords: cavitary lesion, epidemiology, molecular

epidemiology, primary pulmonary tuberculosis,
radiography, reactivation pulmonary tuberculosis,
tuberculosis
DOI:10.2214/AJR.14.13483
Received July 8, 2014; accepted after revision
October22, 2014.
1
Department of Radiology, Columbia University Medical
Center, 622 W 168th St, PH-1 317, New York, NY 10032.
Address correspondence to F. Hao (frh9020@nyp.org).
2
Department of Radiology, St Lukes Roosevelt Hospital
Center, New York, NY.

This article is available for credit.

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0361803X/15/2045974
American Roentgen Ray Society

974

enerations of physicians have

been taught that pulmonary reactivation tuberculosis can be differentiated from the primary
lung infection on the basis of radiographic
appearance. According to the classic teaching, upper lobe cavitary disease was believed
to be the hallmark of reactivation of latent infection, whereas lower lung zone disease, adenopathy, and effusions were believed to indicate recent infection [14]. Compelling
evidence has accumulated against the classic
teaching, but like all dogma it is proving resistant to change. Of the 11 popular radiology
textbooks [515] for sale at the 2012 annual
meeting of the Society of Thoracic Radiology, only two [5, 6] clearly stated that there is
no difference in the radiographic appearances of reactivation and primary tuberculosis.
In this article we review the origins of the
classic teaching, the evolution of the classic
teaching in the modern literature, and the evidence that led to the demise of this teaching. Our purposes are to promote new understanding of the radiographic appearance of
tuberculosis and to place the classic teaching
in the pantheon of grand old theories of interest primarily to medical historians.
Classic Teaching Meets the
AIDSEpidemic
By convention, tuberculosis is classified as
primary if the onset of clinical disease falls
within 1 year of the initial infection and as re-

activation if the disease onset is more than 1

year after the initial exposure. Because the
prevalence of tuberculosis was high throughout much of history, and thus most individuals were exposed and presumably infected in
childhood, the classic teaching held that children commonly presented with primary disease but that adults usually presented with reactivation of a latent infection. Because lower
lobe disease, adenopathy, and pleural effusions
(Fig. 1), which are common in children, are unusual in adults, this pattern became known as
atypical disease [3, 4]. On the other hand, the
upper lobe disease observed in most adults [1,
2] became known as typical reactivation tuberculosis (Fig. 2). This observation was explained by the linear pathogenesis model,
whereby a droplet laden with bacilli inhaled
into the alveoli entered the lymphatic system
and remained dormant. Later, at some point
in time dependent on the hosts immunologic state, reactivation of the dormant infection
was thought to occur preferentially in the upper
lung zones as the result of decreased lymphatic drainage and increased partial oxygen pressures [16, 17]. As late as 2008 this model provided support for the classic teaching [1822].
With the advent of molecular epidemiology in the 1990s, the classic view was increasingly questioned. In 1997 Jones and
colleagues [23] proposed and in 2005 Geng
and colleagues [24] confirmed that the radiographic appearance of tuberculosis is independent of the time since infection. Instead,

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Radiographic Appearance of Pulmonary Tuberculosis

Fig. 137-year-old man with atypical pulmonary

tuberculosis.
A, Posteroanterior chest radiograph shows right
paratracheal, aortopulmonary window, and hilar
enlargement.
B, Contrast-enhanced CT image shows subcarinal
and bilateral hilar adenopathy.

cavitary upper lobe disease is usually seen in

an infected immunocompetent host, whereas
immunocompromised patients usually present with lower lung zone disease, adenopathy, and effusions. This change in understanding resulted from research on HIV.
The AIDS epidemic of the 1980s and
1990s coincided with a dramatic increase
in cases of active tuberculosis in the United
States. In 1989 Selwyn and colleagues [25]
reported that in the general population, latent infection with tuberculosis carried a 10%
lifetime risk of reactivation, whereas in patients with concomitant untreated HIV infection, the risk of reactivation was 10% per year.
However, patients with HIV infection more
often than not had atypical manifestations of
tuberculosis, that is, lower lung zone disease
and adenopathy [26, 27]. The high rate of active tuberculosis has been linked to the loss
of -interferon, an important cytokine that is
normally produced by CD4+ T cells depleted

by HIV [28]. Therefore, the atypical presentation of tuberculosis in patients with HIV infection was initially believed to be due to the
increased susceptibility and more rapid progression of primary tuberculosis in this population [29, 30].
In the 1990s, however, a growing body of
evidence suggested that tuberculosis manifests itself differently in an immunosuppressed host irrespective of the time since the
initial infection. In 1993, Jones and colleagues
[31] reported that the radiographic pattern of
tuberculosis in HIV-positive patients correlated with the stage of HIV infection. For example, patients with CD4 counts greater than
354 cells/L usually had upper lobe disease.
As CD4 counts declined, cavitation occurred
less frequently. Pleural effusions were seen
at CD4 counts greater than 200 cells/L, but
mediastinal adenopathy was most frequently
seen at CD4 counts less than 200 cells/L.
Two years later, Post et al. [32] found that the

radiographic appearance of tuberculosis could

be used as a predictor of CD4 count. The positive predictive value (PPV) of apical disease
for CD4 counts greater than 200 cells/L was
78%, the PPV of lower lung zone disease for
CD4 counts less than 200 cells/L was 84%,
and the PPV of adenopathy for CD4 counts
less than 200 cells/L was 89%.

Molecular Epidemiology and

Radiographic Appearance
The newly discovered association between pulmonary tuberculosis and the immune status of the host called into question
the accepted relation between radiographic
appearance and time since infection. At the
same time, advances in molecular epidemiologyDNA fingerprinting with restriction
fragment length polymorphismsprovided
a powerful new epidemiologic tool [3335]
as an alternative to seroconversion. The technique involves extraction of the Mycobacte-

Fig. 242-year-old man with typical pulmonary tuberculosis.

A, Posteroanterior radiograph shows cavitary consolidation in right upper lobe with smaller opacity in periphery of left upper lobe.
B, CT image through apices shows upper lobe cavitary consolidation.
C, CT image through upper lobes shows bilateral tree-in-bud opacities due to bronchial spread of tuberculosis with foci of airspace consolidations.

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Rozenshtein et al.
rium tuberculosis DNA, digestion with the
restriction enzyme PvuII, electrophoresis,
and hybridization by Southern blotting, allowing generation of a so-called DNA fingerprint. Tuberculosis strains were classified as clustered when genetically identical
strains were recovered from two or more
patients and as unique if found in only one
person. Clustered cases were observed in
miniepidemics and correlated with primary
disease; unique cases correlated with reactivation of latent infections [36]. A single molecular strain isolated from two or more people, who also happened to be related in space
and time, could be accurately characterized as primary disease. On the other hand,
unique molecular isolates were more likely
to be cases of reactivation tuberculosis [36].
DNA fingerprinting was used to study the
epidemiology of tuberculosis in several large
urban areas. In June 1994, the New England
Journal of Medicine published the results of
two studies on the transmission of tuberculosis. Alland et al. [37] examined 104 adult
patients in New York City and found 35 clustered strains. Small et al. [38] examined 473
patients in San Francisco and found 191 clustered strains. Contrary to previous teaching,
in both urban centers only approximately
one third of newly diagnosed adult cases of
tuberculosis were due to primary disease;
the others were due to reactivation [37, 38].
The classic teaching had come into question. In 1997 Jones and colleagues [23] examined a group of 103 patients with tuberculosis. They used molecular epidemiologic
techniques to look for correlations with radiographic findings in patients with primary and
reactivation disease and found no difference.
A review of their results is instructive. In the
HIV-negative group 24 of 28 (86%) patients
with reactivation disease (unique isolates) and
24 of 30 (80%) patients with primary tuberculosis (clustered cases) presented with upper
lung zone disease. Only two had the classic
pattern of primary infection. In the HIV-positive group the opposite was true: 10 of 16
(63%) patients with primary disease and 10
of 16 (63%) patients with reactivation had the
atypical pattern of primary disease. The authors concluded that the radiographic appearance of tuberculosis was not determined by
the time since infection but by the state of the
immune system. These results were supported
by findings of a follow-up study published in
2005 by Geng and colleagues [24], who used
similar techniques to examine 456 patients,
54% with HIV infection, who presented with

976

tuberculosis in New York City between 1990

and 1999. Their study was powered at 95% to
detect a 15% difference between study populations. Although there was overlap in radiographic appearance in the two groups,
presumably related to differences in patient
disease susceptibility and the virulence of
the different M. tuberculosis strains, the investigators found that cluster status, which allowed them to differentiate recently acquired
from remotely acquired tuberculosis, was not
a significant predictor of radiographic appearance [24]. Although the virulent properties of
the tuberculous strains seen in the 1960s and
the disease patterns in the affected host could
theoretically be different from those seen 50
years later, Geng and colleagues proved that
time since infection is not predictive of the radiographic appearance of tuberculosis in either patients with or patients without symptoms of HIV infection.
The newer studies had limitations. There
was overlap in radiographic appearance between the groups with and without HIV, at
least in part related to patient immune status
and the virulence of the individual strain. Molecular fingerprinting has limitations. Some
unique isolates could represent recent infection
from an unknown and possibly distant source.
In each cluster, one case could represent reactivation, and others could represent infections
that occurred before the 1-year window of primary tuberculosis. There are also issues of interpretation. When in a minority of cases DNA
isolates had similar but not identical patterns,
reactivation could not be definitively differentiated from primary tuberculosis because genetic divergence could happen in the process of
disease transmission [39]. The limitations notwithstanding, by 2005 there was compelling
evidence that radiographic appearance cannot
be used to differentiate primary from reactivation tuberculosis.
Origins of the Classic Teaching
When new data are incompatible with a
generally held notion taught to generations
of physicians, it is instructive to examine the
origins of the original belief. We started by
looking at reference textbooks in search of
source articles. Many texts offered no citations, as if this truth were self-evident, and
others commonly quoted four articles from
the 1960s through the 1980s [13, 40]. Each
of these works used a different definition of
primary and reactivation disease, and none
provided strong evidence in support of the
classic teaching. For example, in the 1983

case series of patients with primary tuberculosis described by Choyke and colleagues [1],
only 64% of patients had documented recent
seroconversion. The others were so classified
on the basis of radiographic features (lymphadenopathy and pleural effusions) or clinical
manifestations. This method had been popularized earlier by Stead and colleagues [40],
who in 1968 reported a series of 37 cases of
primary tuberculosis in which eight (22%)
were included solely on the basis of lymphadenopathy and parenchymal disease in the
lower lung zones. Moreover, their definition
of primary tuberculosis was elastic: only 30%
of their patients with documented tuberculin
conversion became ill within 1 year of infection, 40% within 2 years, and 65% within 9
years. This means that one third of their patients with documented seroconversion did
not have disease close enough to the time of
infection to meet the consensus definition of
primary disease. Furthermore, the authors admitted to excluding any patient if the disease
involved the apical or posterior segment of
the upper lobe because these are segments so
commonly involved in the postprimary stage
of infection. Woodring et al. [2] referenced
Choyke et al. [1] in discussing the radiographic manifestations of tuberculosis and presented data of their own showing considerable
overlap between primary and reactivation disease, grouping adults with children. Weber et
al. [3] reported on the findings of primary tuberculosis in childhood, and thus their findings are of limited value to our discussion.
Stead and colleagues [40] explained their
reliance on radiographic appearance to differentiate primary disease from reactivation because several authors had reported mid and
lower lung zone disease with adenopathy or
pleural effusions as common in primary tuberculosis and rare in postprimary (so-called
reinfection-type) tuberculosis. Analysis of
those publications identified three Englishlanguage articles [4143] relevant to the radiographic appearance of tuberculosis. In
1944 Frostad [41] published data on a population of 3336 Norwegian students who underwent periodic testing with tuberculin over 10
years in the 1930s. In his introduction, Frostad referred to a body of German language literature by Assmann, Redeker and Walter,
Fraeuning, Lyditin, Ickert, Kayser-Petersen, Ulruci, and others that showed that tuberculosis originating in the apex of the lung
was an infrequent occurrence. We reviewed
Frostads raw data in a yellowed foldoutthe
1940s equivalent of a 21st century computer

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Radiographic Appearance of Pulmonary Tuberculosis

spreadsheet. Of 48 adult patients with proven active pulmonary tuberculosis within 12
months of the last negative tuberculin skin
test result, 25 (52%) were noted to have upper
lung zone disease and 23 (48%) to have lower
lung zone disease. These findings are incompatible with the assertion that apical disease is
infrequent in primary infection. The distribution in the pediatric population was even less
supportive: of the 28 children (younger than
14 years) who had active tuberculosis within
12 months since infection 23 (82%) had upper
lobe disease and six (18%) had lower lobe disease. The rates of adenopathy and pleural effusion were not reported.
Three years after Frostads publication,
Poulsen [42] published his account of a 1945
epidemic of tuberculosis in an isolated community on the Faroe Islands. Owing to frequent outbreaks of tuberculosis in this fishing community, mandatory examination for
tuberculosis was begun in 1939. Six years
later a documented cluster of seroconversions followed by clinical illness in 17 patients was traced to a single source. In this
group 13 (76%) had right hilar enlargement,
three (18%) had a pleural effusion, three
(18%) had a basilar or perihilar infiltrate,
and one (6%) had right upper lobe disease.
Poulsens data were difficult to generalize to
the general population, however, because of
the small sample size and the unique characteristics of the cohort. Many of the patients
were related, and the infection was unusually
virulent: three (18%) patients had meningitis, an uncommon complication of tuberculous infection.
The most convincing work to support the
classic teaching was published in 1952 by
Gedde-Dahl [43], who reported results of
universal tuberculin testing of a population
of 6500 in the district of Kinn, Norway. Between 1937 and 1944, active tuberculosis developed in 130 persons (2% of the population) after documented seroconversion; 95
(73%) of the cases of tuberculosis presented with adenitis. Careful review of the paper,
however, puts the validity of the tuberculin
conversion data in question: Gedde-Dahl reported repeated disruptions of the annual tuberculin testing program due to World War
II, with frequent multiyear gaps. Moreover,
the rural coastal population in question was
highly impoverished and malnourished, subsisting on a meager diet of fish, potatoes,
and cereals lacking in meat, milk, fruit,
and vegetables [43]. Last, 42 (32%) of the
patients were children 014 years old.

It is noteworthy that U.S. data on the radiographic appearance of confirmed primary

tuberculosis were available when Stead et al.
[40] were writing their work. In 1965 Alpert and Levison [44] published an account
of an epidemic of tuberculosis in a medical
school. Of their 25 patients, all with primary disease, eight (32%) had cavitary lesions
thought then to be the hallmark of reactivation disease, and nine had pleural effusions.
They did not comment on lobar distribution or adenopathy. In 1968, the same year
Stead et al. published their results, Hardy
and Schmidek [45] reported on an epidemic of tuberculosis aboard a U.S. Navy heavy
cruiser. Among the 25 previously healthy
young men with active tuberculosis documented with sputum smears, sputum cultures, or pleural biopsy, 16 patients had pulmonary involvement. Of these, 13 (81%) had
upper lobe disease, one (6%) had lower lobe
disease, and two (13%) had pleural effusions.
Epilogue
Review of the seminal work on the radiographic appearance of tuberculosis shows
that the classic teaching was not based on
strong epidemiologic data in large representative populations. Although authors have
frequently divided patients into those having typical and those having atypical patterns, the definitions varied, and when patient findings have been available for review,
it becomes clear that there is often considerable overlap in individual patients. It appears that Frostad [41] was wrongly handed paternity of the dogma, which appears to
have been based on the works of other authors publishing primarily in the German literature. Gedde-Dahl [43] made his observations in an impoverished population in which
high rates of tuberculosis were attributed to
malnutrition, a well-known cause of immunocompromise [4648]. Poulsen [42] reported an outbreak of tuberculosis caused
by a single strain in a small genetically homogeneous group. Although at the time of
Poulsens publication, variation in virulence
among M. tuberculosis strain may not have
been widely known, it was accepted that genetic susceptibility plays an important part in
the development of active tuberculosis [49].
It is intriguing that despite the presence of
contradictory data on U.S. adults, the dogma
was accepted wholesale. We speculate that the
ability to differentiate primary and reactivation
tuberculosis was critical to clinical management. Reactivation disease requires that close

contacts of the index patient undergo screening for conversion. If no cases of conversion are
found, treatment of the index patient prevents
further spread. Discovery of a case of primary tuberculosis, on the other hand, necessitates
a search for the source of infection: treatment
of the index patient is insufficient to contain
an epidemic because the person who infected
the index patient may still be infecting others.
In the years after World War II, tuberculosis
posed a major public health threat to rebuilding
communities with limited medical resources.
Using readily available and relatively inexpensive chest radiography to attempt to differentiate a possible epidemic from an isolated case
of infection was attractive. This may be why
all evidence that did not fit the classic teaching
was ignored, and the dogma survived into the
21st century.
The physicist Max Planck [50] wrote, A
new scientific truth does not triumph by convincing its opponents and making them see
the light, but rather because its opponents
eventually die, and a new generation grows
up that is familiar with it. It has been 20
years since the first papers disproving the
classic tuberculosis dogma were published.
It is time to put it to rest.
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