Pulmonary Tuberculosis in AIDS

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Patients: Transient Chest Radiographic

Worsening After Initiation of
Antiretroviral Therapy
Joel E. Fishman 1 OBJECTIVE. Immune function and inflammatory responses often increase in AIDS patients
Efrat Saraf-Lavi 1 who receive antiretroviral therapy. We evaluated the occurrence and nature of transient worsening on
Masahiro Narita 2 chest radiographs in AIDS patients with tuberculosis after initiation of antiretroviral therapy and com-
Elena S. Hollender 2 pared these findings with chest radiographs of patients undergoing antituberculous therapy alone.
MATERIALS AND METHODS. A retrospective review of sequential chest radiographs
Rajeev Ramsinghani 1
was performed of 87 patients undergoing therapy for pulmonary tuberculosis: AIDS patients
David Ashkin 2
receiving antiretroviral therapy (n = 31), HIV-positive patients not receiving antiretroviral
therapy (n = 26), and HIV-negative patients (n = 30). Pulmonary consolidations, thoracic lym-
phadenopathy, and pleural effusions were evaluated for worsening, stability, or improvement.
Patients with concurrent pulmonary infections were excluded.
RESULTS. Transient worsening on radiography was observed in 14 (45%) of 31 AIDS pa-
tients receiving antiretroviral therapy, including seven patients (23%) who showed severe
worsening. Of 56 patients in the other two groups, 11 (20%) showed worsening ( p = 0.023),
two of whom showed severe worsening ( p = 0.009). Worsening was first noted between 1 and
5 weeks after initiation of antiretroviral therapy, with improvement occurring between 2
weeks and 3 months later. Four patients with severe worsening converted their tuberculin pu-
rified protein derivative responses from anergic to positive after antiretroviral treatment.
CONCLUSION. Transient worsening is frequently seen on chest radiography in AIDS
patients with tuberculosis who subsequently undergo antiretroviral therapy. This phenomenon
may be related to improved immune function.

M ost patients with pulmonary tuber-

Received October 19, 1998; accepted after revision
June 11, 1999.
1
Department of Radiology, University of Miami School of
Medicine, Jackson Memorial Hospital, West Wing 279,
1611 N.W. l2th Ave., Miami, FL 33136. Address
correspondence to J. E. Fishman.
2
A. G. Holley State Tuberculosis Hospital,
1199 W. Lantana Rd., Lantana, FL 33462.
AJR 2000;174:4349
0361803X/00/174143
American Roentgen Ray Society
culosis (TB) will show clinical,
microbiologic, and radiographic im-
provement within weeks to a few months after
beginning therapy [1]. A transient worsening in
either symptoms or signs of tuberculosis has
been described in small numbers of patients, usu-
ally occurring within 1 month after therapy is be-
gun. New or worsened lymphadenopathy, fever,
cerebral tuberculomas, and pleural effusions
have been noted and termed paradoxical re-
sponses by some authors [28]. Although not
completely understood, these transient findings
may be inflammatory responses caused by im-
proved host immunity as a result of antitubercu-
lous therapy [9]. We have observed episodes of
transient clinical worsening on chest radiographs
in AIDS patients undergoing antituberculous
therapy who subsequently begin antiretroviral
therapy. In these patients, worsening appears to
be temporally related to starting antiretroviral
therapy, in contrast to the paradoxical responses
of HIV-negative patients related to initiation of
antituberculous therapy. We hypothesized that
rapid improvements in immune function would
cause patients with AIDS and TB who are started
on antiretroviral therapy to show radiographic
worsening more frequently than would patients
on TB therapy alone. To evaluate this hypothesis,
we performed a blinded retrospective review of
sequential chest radiographs in patients on com-
bined antiretroviral and antituberculous therapy
and compared the chest radiographic changes
with those of TB patients not receiving antiretro-
viral therapy.
Materials and Methods
The target population consisted of all patients ad-
mitted to an inpatient state referral center for active cul-
tureproven tuberculosis during the 12-month period
from February 1996 through January 1997. A
description of the clinical findings in these patients has
been published [10]. Conditions for referrals of patients
to this facility included noncompliance with antituber-
culous medication; concurrent diseases, such as AIDS,
that complicate antituberculous therapy; side effects to

AJR:174, January 2000 43

 antituberculous medications that had been previously
documented; and known drug-resistant tuberculosis.
Antituberculous therapy consisted of multidrug
regimens according to the recommendations of the
Centers for Disease Control and the American Tho-
racic Society [11, 12]. All patients were tested for HIV
status at admission. For HIV-positive patients, CD4+
cell count was measured at the time of diagnosis, the
day before antiretroviral therapy was begun, at subse-
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Of 98 patientsFishman
admitted toet
theal.
hospital during the
study period (February 1996 through January 1997),
three patients were omitted because their admissions
were too short to generate a series of radiographs for
review. Of the remaining patients, 40 had AIDS and 55
were HIV-negative. Seven of the AIDS patients were
excluded because of nontolerance or refusal of antiret-
roviral therapy or because antiretroviral therapy was
given before admission. The remaining 33 AIDS pa-
sessment was made whether the findings were se-
verely worsened, mildly to moderately worsened,
unchanged, or improved. Severe worsening was de-
fined as either the unequivocal appearance of new dis-
ease in a previously normal region of the chest or a
doubling of the previous extent of disease (either in
amount of opacified lung or in the size of enlarged
nodes or pleural effusions). Mild to moderate worsen-
ing was defined as a visible increase in disease but

quent 2-month intervals, and when worsening of signs
or symptoms was observed. In most patients, multi-
drug antiretroviral therapy consisted of zidovudine
(AZT), lamivudine (3TC), and either zalcitabine or
didanosine. HIV-positive patients who were not re-
ceiving rifampin as part of antituberculous therapy re-
ceived AZT, 3TC, and saquinavir (a protease inhibitor).
All patients were known to have TB and had received
some antituberculous therapy before admission. Be-
cause of the complexity of multidrug regimens for
both TB and HIV, antiretroviral therapy was not
started until patients had received at least 2 weeks
(generally longer) of inpatient antituberculous therapy.
Tuberculin purified protein derivative (PPD) (Con-
naught Laboratories, Swiftwater, PA) testing and an-
ergy skin testing were performed on all patients at
admission; if anergic, tests were performed every sub-
sequent 2 weeks during hospitalization or until PPD
conversion. Posteroanterior and lateral chest radio-
graphs were obtained at admission and subsequent
posteroanterior and lateral or anteroposterior radio-
graphs were obtained at monthly intervals for the du-
ration of the patients hospitalization. Some patients
exhibited clinical worsening during treatment, which
was defined as new fever equal to or exceeding 101.5 F
of at least a 1-week duration, or as worsened or new
respiratory symptoms, cervical adenopathy, cutaneous
tuberculous lesions, or ascites. Worsening prompted
physical examination; cultures of sputum, blood, and
urine; and additional examinations on chest radiogra-
phy. Bronchoscopy, biopsy, or both were routinely
performed if there were localized findings and physi-
cal examination and cultures did not explain worsen-
ing. Drug sensitivity was evaluated by performing
monthly testing in patients who continued to produce
sputum that was culture-positive for TB.
tients were termed group 1. Of the HIV-negative pa-
tients admitted during the study period, 31 were
randomly selected from medical record numbers to
obtain an approximately equal number of HIV-positive
and HIV-negative patients for comparison; the HIV-
negative patients were termed group 2. In designing
the study, we sought to evaluate the possibility that
worsening seen on chest radiographs might be caused
by HIV positivity rather than antiretroviral therapy.
Consequently, we formed a historical control group of
all HIV-positive patients treated for TB at the hospital
between January 1986 and December 1987 (n = 26).
Because these patients were treated during the time pe-
riod before the development of antiretroviral therapy,
they comprised a control group of HIV-positive pa-
tients who had TB but did not receive antiretroviral
therapy, and these patients were termed group 3. Sex
and gender distribution in the three groups was as fol-
lows: group 1 (n = 33), 17 men and 16 women with a
mean age of 39.9 years; group 2 (n = 31), 26 men
and five women with a mean age of 43.3 years; and
group 3 (n = 26), 19 men and seven women with a
mean age of 34.6 years.
All chest radiographs obtained of patients in groups
1, 2, and 3 were collected. The radiographs were or-
dered chronologically and reviewed by agreement be-
tween two radiologists who were unaware of each
patients group affiliation. The radiographs were re-
viewed sequentially (i.e., time-lapse) without prior or
simultaneous viewing of the whole series and without
knowledge of the time interval between radiographs.
The admission radiographs were evaluated for three
categories of findings: pulmonary parenchymal opaci-
ties, intrathoracic adenopathy, and pleural effusions.
Each subsequent radiograph was then compared with
the previous one; in each of the three categories an as-
qualitatively less than doubling. After all radiographs
were reviewed, cases were categorized as to whether
the series of radiographs showed: sequentially improv-
ing or unchanged findings; one or more occurrences of
mild to moderate worsening; or one or more occur-
rences of severe worsening. For all occurrences of se-
vere radiographic worsening, the clinical record was
then consulted to determine whether there was concur-
rent clinical worsening as defined previously and
whether a specific reason for radiographic or clinical
worsening (or both) had been established. Alternate di-
agnoses to explain worsening were identified in two
group 1 patients (pneumocystis pneumonia and bacte-
rial sepsis) and one group 2 patient (nephrotic syn-
drome with pleural effusions); these three patients
were excluded from subsequent analysis, leaving 31
patients in group 1 and 30 patients in group 2.
Statistical analysis was performed using the
Fishers exact test to compare the frequency of ra-
diographic worsening among the groups. Among
group 1 patients, CD4 + counts of patients who
showed severe worsening and those who did not
were compared using the Mann-Whitney test.
Results
The occurrence of radiographic worsening
during TB treatment is shown in Table 1. The
difference in the overall frequency of worsen-
ing in group 1 versus groups 2 and 3 was sig-
nificant (45% versus 20%, p = 0.023). Of
patients in group 1, seven patients (23%)
showed at least one occurrence of severe ra-
diographic worsening during therapy, whereas
two (4%) of the patients in groups 2 and 3 did

TABLE 2 Radiographic Findings at Presentation and Manifestations of Worsening

Parenchymal Thoracic
Sequential Radiographic Pleural Effusion Normal
Patient Group Disease Adenopathy
Changes in Patients
TABLE 1
Undergoing Antituberculous No. % No. % No. % No. %
Therapy
Group 1 (n = 31)
Group 1 Group 2 Group 3 At admission 15 48 8 26 3 10 13 42
Sequential (n = 31) (n = 30) (n = 26)
Evaluation Worsening or 10 32 6 19 7 23
No. % No. % No. % development of
All images showed 17 55 23 77 22 85 Group 2 (n = 30)
Improvement or At admission 25 83 1 3 1 3 5 17
no change Worsening or 6 20 1 3 0 0
One or more development of
episodes of: Group 3 (n = 26)
Mild to moderate 7 23 6 20 3 12 At admission 19 73 5 19 8 31 2 8
worsening Worsening or 4 15 1 4 2 8
Severe worsening 7 23 1 3 1 4 development of
Note.Dash () indicates not applicable.

44 AJR:174, January 2000

 Radiography of Pulmonary Tuberculosis in AIDS Patients
Characteristics of Severe Radiographic Worsening After Antiretroviral
TABLE 3
Therapy
Radiographic Worsening
Patient No. Initial Findings
Severe
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1 Right LAD and Right LAD and right
right consolidation consolidation
2 Normal Right consolidation
3 Mild interstitial Miliary disease
opacities
4 Normal Right LAD
5 Normal Right LAD (cervical
and intrathoracic)
6 Left effusion Right effusion
7 Left consolidation Left consolidation
Note.LAD = intrathoracic lymphadenopathy; dash () indicates no findings.
a Chest radiographs available only up to 35 days after worsening.
b Next radiograph available after 81 days, at which time there had been no improvement.
so ( p = 0.009). Table 2 shows the types of ra-
diographic abnormalities at admission as well
as the characteristics of worsening in the three
groups. Worsening most frequently manifested
as pulmonary parenchymal disease in all three
groups, but 19% of the group 1 patients
showed new or worsened effusion and 23%
showed new or worsened lymphadenopathy.
Among patients in group 2 (HIV-negative),
worsening almost exclusively occurred as pa-
renchymal disease; patients in group 3 had oc-
casional episodes of worsened effusion (4%)
and lymphadenopathy (8%). No significant
differences were seen in the frequency of mild
to moderate worsening among the groups.
Radiographic findings in the seven group 1
patients with severe worsening are listed in Ta-
ble 3. Severely worsened pulmonary parenchy-
mal disease was observed in four patients (Figs.
1 and 2), hilar or mediastinal adenopathy in
two patients (Fig. 3), and pleural effusion in
one patient. In four of the seven patients,
the focus of radiographic worsening was in a
previously normal region on the admission ra-
diograph. Of the seven patients, five showed si-
multaneous mild to moderate worsening in a
second category of findings. Radiographic
worsening was observed between 2 and 32
days after initiation of antiretroviral therapy,
whereas these seven patients had started inpa-
tient TB therapy between 5 and 19 weeks be-
fore worsening (mean, 12 weeks). In six of the
seven patients, worsening on the chest radio-
graph was concurrent with fever (n = 5), cervi-
cal lymphadenopathy (n = 2), ascites (n = 1),
AJR:174, January 2000
Time from
Antiretroviral
Mild to Worsening to
Therapy to
Moderate Improvement
Worsening
15 days 45 days
Right LAD 32 days 52 days
Right LAD 12 days 33 days
Left effusion 16 days Not availablea
2 days 7 months b
Right 5 days 11 days
consolidation
Left effusion 5 days 59 days
and cutaneous tuberculosis (n = 1). Baseline
CD4+ cell counts before initiation of antiret-
roviral therapy were 47 33 cells/mm3
(0.047 0.033 10 9/l) in patients who subse-
quently showed severe radiographic worsen-
ing and 145 196 cells/mm3 (0.145 0.196
10 9/l) in other group 1 patients (differences
not significant). There was no difference in the
absolute increase in CD4+ count after treat-
ment, with a mean CD4+ count increase of 38
cells/mm3 among worsening patients and 43
cells/mm3 among nonworsening ones. Four of
the seven patients had PPD skin testing before
beginning antiretroviral therapy; all were ini-
tially anergic. All four patients showed conver-
sion of findings from the PPD skin test to
positive between 4 and 20 weeks after antiret-
roviral therapy was started.
Among all group 1 patients with radio-
graphic worsening (any degree), the mean
time from beginning of worsening to begin-
ning improvement was 7 weeks for pulmonary
disease, 13 weeks for adenopathy, and 4 weeks
for effusion. The times to improvement in pa-
tients in groups 2 and 3 were not significantly
different. Of the seven group 1 patients with
severe radiographic worsening, six patients
showed radiographic improvement and one
patient did not show radiographic improve-
ment, although radiographs were only avail-
able for this patient up to 5 weeks after
worsening was first identified (Table 3). All six
patients in whom radiographic worsening was
accompanied by clinical worsening showed
clinical improvement, including the patient
who failed to show radiographic improvement.
In six of the seven patients with severe worsen-
ing, no changes were made to antituberculous
therapy or antiretroviral therapy after clinical
evaluation failed to show another reason for
worsening. In one patient with severe worsen-
ing (Fig. 1), the possibility of drug reaction
was considered and both antituberculous ther-
apy and antiretroviral therapy were discontin-
ued after superimposed infection had been
excluded, after which radiographic and clinical
improvement were seen. When this patient
was subsequently restarted on antituberculous
therapy and antiretroviral therapy, transient
clinical worsening ensued but no radiographic
worsening was noted.
Discussion
Transient clinical and radiographic worsen-
ing in patients undergoing antituberculous ther-
apy was first described more than four decades
ago. In the years since, this phenomenon, which
is also called paradoxical response, has been
identified in numerous reports involving TB and
various organ systems. It has been hypothesized
that these paradoxical responses are largely
caused by improvements in cell-mediated im-
mune function including strengthened delayed
hypersensitivity responses and decreased sup-
pressor mechanisms [9]. Patients infected with
AIDS have also been noted to show paradoxical
responses in the first weeks after antitubercu-
lous therapy has begun [5]. In this report, we de-
scribe a similar phenomenon after introduction
of antiretroviral therapy to AIDS patients being
treated for TB. Radiographically, transient
worsening manifested as new or increased pul-
monary parenchymal disease, lymphadenopa-
thy, or pleural effusion alone or in combination.
Severe worsening occurred in patients with
low initial CD4+ counts, all of which were
less than 100 cells/mm3 (0.1 10 9/l). Three
of the seven patients with severe worsening
initially had normal findings on radiographs,
which is not uncommon in markedly immu-
nosuppressed AIDS patients with TB [13].
Worsening was related to commencement of
antiretroviral therapy and was associated
with fever or other clinical signs and restora-
tion of PPD reactivity in several patients.
A diagnosis of paradoxical response should
not be made until noncompliance with therapy,
drug resistance, superimposed disease processes,
and drug reaction have been excluded as
causes of apparent worsening. In our patients,
noncompliance was not a consideration because
all patients were hospitalized throughout the
45
 Fishman et al.
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A B

C D

Fig. 1.Worsened pulmonary parenchymal disease in 41-year-old woman with AIDS who underwent antiretroviral therapy.
A, Chest radiograph obtained at admission shows mild diffuse reticulonodular opacities.
B, Chest radiograph obtained after 1 month of antituberculous therapy shows resolution of opacities. Patient subsequently underwent antiretroviral therapy.
C, Chest radiograph obtained after 1 month of antiretroviral therapy shows diffuse miliary disease. Patient also manifested fever and cervical lymphadenopathy (not
shown). Both antituberculous therapy and antiretroviral therapy were discontinued.
D, Chest radiograph obtained 2 months after C shows improvement in miliary opacities. Fever and lymphadenopathy had also resolved. Combination therapy was begun
46
again without subsequent radiographic worsening. AJR:174, January 2000
 Radiography of Pulmonary Tuberculosis in AIDS Patients
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A B

Fig. 2.Worsening pulmonary consolidation in 33-year-old woman with AIDS who under-
went antiretroviral therapy.
A, Chest radiograph obtained after 1 month of antituberculous therapy shows mild left up-
per and lower lobe opacities (arrows). Mild left hilar enlargement is possible.
B, Chest radiograph obtained shortly after beginning antiretroviral therapy shows wors-
ened left lower lobe consolidation. Patient also developed fever and ascites. Cultures
failed to detect superimposed infection, and combined therapy was continued.
C, Follow-up chest radiograph 2 months after B shows interval clearing of consolidation.
AJR:174, January 2000 47
C
 Fishman et al.
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A B
Fig. 3.Development of lymphadenopathy in 36-year-old woman with AIDS who underwent antiretroviral therapy.
A, Chest radiograph obtained at admission shows no adenopathy.
B, Chest radiograph obtained within 1 week after commencement of antiretroviral therapy shows right paratracheal adenopathy (arrowheads) and right cervical and supra-
clavicular adenopathy (asterisk). Patient also developed fever. Biopsy of the cervical node showed noncaseating granuloma. Combination therapy was continued, and steroids
were added to reduce symptoms from extensive adenopathy. Findings on chest radiograph obtained at conclusion of antituberculous therapy (not shown) were normal.

course of therapy. Resistance testing was per-
formed monthly, and no patient developed drug
resistance during this study. It is unlikely that mi-
nor variations in TB drug combinations among
patients caused the differences among patient
groups because treatment guidelines have not
changed significantly over time [11, 12] and be-
cause worsening was more temporally related to
antiretroviral therapy than to TB therapy. All pa-
tients with worsening were examined for the
possibility of superimposed disease processes,
which were identified in three patients. Finally,
drug reaction may cause clinical and radio-
graphic worsening in immunocompromised pa-
tients but was considered unlikely in our patients
because the worsening resolved without changes
or interruption of therapy for six of the seven pa-
tients; in the patient whose medications were
discontinued (Fig. 1), the diffuse miliary pattern
on the radiograph was not characteristic of drug
reaction [14].
Clinical restoration of cell-mediated im-
munity after antiretroviral therapy in AIDS
patients was first described by French et al.
in 1992 [15]. In that study, 27 (42%) of 64
patients who had been anergic to tuberculin
before AZT therapy subsequently developed
a positive skin test response. Five patients
also manifested an acute illness consisting of
localized Mycobacterium aviumcomplex
infection, lymphadenopathy, or fever
(alone or in combination) after 12 weeks
of therapy. In a more recent report, five late-
stage HIV-infected patients (CD4+ count,
<50 cells/mm3 [0.05 109/l]) who were
started on antiretroviral therapy with the pro-
tease inhibitor indinavir developed fever, leu-
kocytosis, and generalized lymphadenopathy
within 3 weeks of commencing therapy [16].
Nodal biopsy results revealed granulomatous
inflammation with M. aviumcomplex infec-
tion. The authors hypothesized that these pa-
tients had untreated subclinical M. avium
complex infection that was unmasked by the
immunorestorative effects of antiretroviral
therapy, resulting in an inflammatory lym-
phadenitis. Evidence for immune restoration
included increases in CD4+ count, the pres-
ence of granulomatous features on biopsy
specimens, and the vast preponderance of the
memory CD4+ phenotype after treatment,
suggesting an expansion of the CD4+ subset
that had T-cell receptors to mycobacterial an-
tigens resulting from the (previously subclin-

48 AJR:174, January 2000

 Radiography of Pulmonary Tuberculosis in AIDS Patients
ical) infection. All patients improved after
initiation of antimycobacterial therapy. In
our study, PPD reactivity was restored in pa-
tients with less than 200 CD4+ cells/mm3
(0.2 109/l), below which level most HIV
patients remain anergic. This finding also
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suggests a selective restoration of immune
function of the memory type. It has been
shown in vitro that antiretroviral therapy se-
lectively restores some but not all CD4+ T-
cell surface marker phenotypes [17], which
may help explain the lack of a large rise in
the overall CD4+ count among our patients.
We recognize several limitations to our
study. There were some differences in age and
gender distribution among the three groups.
This study occurred at a dedicated TB treat-
ment facility at which most patients had been
noncompliant with outpatient therapy, necessi-
tating hospitalization. Thus, patients had re-
ceived at least some antituberculous treatment
at the time of admission, albeit suboptimal or
intermittent. The fact that many of the patients
(23%) had normal findings on chest radio-
graphs at the time of admission could be re-
lated to prior therapy. Because of the high rate
of noncompliance, antiretroviral therapy had
generally not been started before admission as
a result of concerns about development of HIV
resistance. Patients who have not received
prior antiretroviral therapy may be particularly
at risk for paradoxical responses. Furthermore,
most of our patients did not receive a protease
inhibitor, which is the most highly active anti-
retroviral therapy; such combination therapies
are becoming more frequently used, which
may affect the frequency of paradoxical re-
sponses. Our use of a historical control group
is limited by possible differences in the relative
degree of immunosuppression in the two
groups of AIDS patients (which could affect
the relative incidence of paradoxical response)
as well as in the degree of virulence of the TB
organism. However, use of an HIV control
group not receiving antiretroviral therapy is
not feasible in the current era of AIDS therapy.
Two aspects of radiographic evaluation in
these patients also deserve mention. First, the
differentiation between mild to moderate and
severe worsening was qualitative; agree-
AJR:174, January 2000
ment between two radiologists was required
but no prestudy training sessions were per-
formed. On the other hand, there is not a com-
monly used or agreed on rating scale for chest
radiographs of patients with TB, and our goal
was to identify radiographic changes and not
to quantitatively assess the amount of disease.
Second, paradoxical responses did not always
manifest as severe radiographic worsening.
Five patients showed clinical signs or symp-
toms of paradoxical response, three of whom
showed no radiographic worsening and two of
whom showed only mild to moderate worsen-
ing. All five improved with continued therapy.
In conclusion, transient and occasionally se-
vere chest radiographic worsening may be
seen in AIDS patients undergoing antitubercu-
lous therapy subsequent to the introduction of
antiretroviral therapy. Worsening may mani-
fest as an increase in preexisting consolidation,
lymphadenopathy, or effusion or may occur as
new findings in previously normal areas.
These episodes are similar in characteristics
and timing to previously reported paradoxical
responses in patients who begin antitubercu-
lous therapy. These phenomena may be a re-
sult of improving immunologic function, as
suggested by the restoration of PPD reactivity
in all previously anergic patients who showed
severe worsening. After excluding superim-
posed infections, noncompliance with ther-
apy, drug reaction, and drug resistance,
patients exhibiting paradoxical responses
should be maintained on combined therapy
with consideration given to the addition of ste-
roids to control local symptoms [10, 18].
Acknowledgment
We thank Arthur Pitchenik for valuable
assistance with this project.
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