AJR 2000; 175:387-390
© American Roentgen Ray Society
Imaging of Mycobacterium avium-intracellulare Infection in AIDS Patients on Highly Active Antiretroviral Therapy
Reversal Syndrome
Kenneth M. Nalaboff1,
Anna Rozenshtein2 and
Mark H. Kaplan3
1
Department of Radiology, North Shore University Hospital, 300 Community Dr.,
Manhasset, NY 11030.
2
Department of Radiology, St. Luke's Roosevelt Hospital Center, St. Luke's
Division, 1111 Amsterdam Ave., New York, NY 10025.
3
Department of Infectious Diseases, North Shore University Hospital, Manhasset,
NY 11030.
Received October 5, 1999;
accepted after revision January 17, 2000.
Presented at the annual meeting of the American Roentgen Ray Society, New
Orleans, May 1999.
Address correspondence to K. M. Nalaboff.
Abstract
OBJECTIVE. We recently encountered six patients with AIDS and an
unusual complication of disseminated infection with Mycobacterium
avium-intracellulare, which developed after the initiation of highly
active antiretroviral therapy, including protease inhibitors and two new
nucleoside analogues. Each patient had a febrile illness after the initiation
of therapy and then developed mass lesions containing mycobacterial organisms
in various organ systems, including bone, skin, and mesenteric and mediastinal
nodes. All these patients suddenly experienced improvement in immunologic
status as evidenced by decreasing viral loads and increasing CD4 cell counts.
We chose to call this reaction "M. avium-intracellulare
reversal syndrome." We describe the radiologic appearance of this
unusual manifestation of infection with M. avium-intracellulare in
patients with AIDS.
CONCLUSION. New or enlarging lymphadenopathy or unusual
musculoskeletal and cutaneous infections in patients with AIDS who are
receiving highly active antiretroviral therapy may represent a response of the
recovering immune system to a new or previously subclinical infection with
M. avium-intracellulare.
Introduction
The clinical and radiologic features of infection with Mycobacterium
avium-intracellulare in patients with AIDS have been extensively
described
[1,2,3,4,5,6,7].
The manifestations of infection with M. avium-intracellulare in
patients with AIDS significantly differ from those in nonimmunocompromised
hosts [7]. The use of highly
active antiretroviral therapy has changed the natural course of infection with
M. avium-intracellulare in patients with AIDS
[8]. Two recent articles have
described the clinical aspects of focal mycobacterial lymphadenitis after the
initiation of highly active antiretroviral therapy
[9,
10]; however, to the best of
our knowledge, no published reports describe the radiographic manifestations
of this phenomenon, which we call "M. avium-intracellulare
reversal syndrome." We present the clinical and radiographic findings of
six patients with advanced AIDS who developed unusual manifestations of
disseminated infection with M. avium-intracellulare after improvement
in their immunologic status while on highly active antiretroviral therapy,
including large necrotic lymphadenopathy and musculoskeletal infections.
Subjects and Methods
Six patients with AIDS who had recently undergone a new antiretroviral
treatment protocol known as highly active antiretroviral therapy and who then
developed unusual inflammatory lesions of various organ systems were
retrospectively identified from the AIDS clinics at two institutions. Each
patient was clinically identified as suffering from M.
avium-intracellulare reversal syndrome. Imaging was performed on five of
the patients. All the patients underwent diagnostic biopsy.
The patients (five women and one man; age range, 28-50 years; mean age, 38
years) were severely immunocompromised when they started the new treatment
protocol. Before therapy, the patients' CD4 cell counts ranged from 11 to 60
cells per microliter (mean CD4 count, 30 cells per microliter) and initial
viral loads ranged from 290,000 to 2,700,000 RNA copies per milliliter (mean
viral load, 1,081,500 RNA copies per milliliter).
All patients had a known history of HIV infection and four had
long-standing systemic infection with M. avium-intracellulare. Each
patient was started on highly active antiretroviral therapy that included at
least one protease inhibitor (indinavir, saquinavir, crixivan, viracept, or
sustiva) and two of the new nucleoside analogues (zidovudine, lamivudine, or
stavudine). Patients became symptomatic between 2 weeks and 4 months after the
initiation of treatment, once their CD4 cell counts had increased and viral
loads had decreased. At the time they became symptomatic, the patients' CD4
cell counts ranged from 64 to 189 cells per microliter (mean CD4 count, 107
cells per microliter) and viral loads ranged from fewer than 90,000 RNA copies
per milliliter to undetectable amounts.
All patients became febrile after starting antiretroviral therapy and three
patients continued to have fever at the time they presented with mass lesions.
Individual symptoms included cutaneous nodules in two patients, abdominal pain
caused by mesenteric lymphadenopathy in two patients, arthralgias caused by
osteomyelitis in one patient, neck swelling caused by bilateral cervical
lymphadenopathy in one patient, and asymptomatic hilar lymphadenopathy in one
patient.
Of five patients who underwent diagnostic imaging, all underwent
radiography and four underwent subsequent CT scanning on a helical scanner
(HiSpeed CT/I; General Electric Medical Systems, Milwaukee, WI). A fifth
patient underwent MR imaging on a 1.5-T superconducting magnet (Signa; General
Electric Medical Systems) before undergoing CT-guided percutaneous biopsy of a
paraspinal mass. All images were retrospectively reviewed with particular
attention to the morphologic features of the mass lesions caused by infection
with M. avium-intracellulare and any associated findings.
Additionally, one patient also underwent a sonographically guided percutaneous
biopsy of a retroperitoneal mass. A laparoscopic biopsy was originally planned
to obtain a large enough tissue sample because lymphoma was suspected.
However, given the lesion's radiographic appearance and the patient's recent
treatment history and improved immune status, we suggested the possibility of
infection with M. avium-intracellulare. We then recommended a
percutaneous biopsy because less tissue would be required to confirm this
diagnosis as opposed to lymphoma, and percutaneous biopsy would save the
patient a formal surgical procedure. A percutaneous biopsy using an HDI
Ultramark 9 (Advanced Technology Laboratories, Bothell, WA) sonography system
with a circular 4-2-MHz transducer was then performed and was well tolerated
by the patient. To our knowledge, this is the first instance in which the
radiographic recognition of the M. avium-intracellulare reversal
syndrome has led to a change in patient treatment.
Results
In four (67%) of six patients, CT scans revealed lymphadenopathy. The
enlarged lymph nodes were located in the cervical
(Fig. 1), retroperitoneal
(Fig. 2), mesenteric, and right
hilar (Fig. 3) regions. Three
of these patients (75%) had massive lymphadenopathy with central low
attenuation consistent with necrosis identified at biopsy. The enlarged hilar
nodes in the fourth patient were less prominent and revealed diffuse
soft-tissue density. Two (33%) of six patients developed subcutaneous nodules.
One of these patients also developed osteomyelitis of T7 and of the
right-sided fifth metatarsal. An MR image of the thoracic spine revealed a
paraspinal mass with collapse of T7 and associated spinal cord compression
(Fig. 4); a CT scan at the same
level revealed a destructive lytic lesion on the T7 vertebral body.
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Fig. 1. —31-year-old man with AIDS wh developed sudden massive cervica
lymphadenopathy 3 weeks after beginnin highly active antiretroviral therapy. C
scan shows large bilateral low-densit cervical nodes (arrowheads)
consisten with necrosis.
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Fig. 2. —28-year-old woman with AIDS and history of infection with
Mycobacterium avim-intracellulare who developed severe abdominal pain
1 month after beginning highly active antiretroviral therapy. CT scan of
abdomen reveals extensive necrotic mesenteric lymphadenopathy
(arrowheads).
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Fig. 4. —50-year-old woman with AIDS who developed fever, arthralgias,
cutaneous nodules, and osteomyelitis of right foot and thoracic spine after
starting highly active antiretroviral therapy. T1-weighted MR image of
thoracic spine shows paraspinal mass (arrow). Note collapse of T7
from Mycobacterium avium-intracellulare osteomyelitis.
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Although these lesions were initially thought to include lymphoma, sarcoma,
tuberculosis, or worsening of other HIV-related infections, diagnosis of
infection with M. avium-intracellulare was confirmed with biopsy and
culture in five patients. Biopsy of a mass lesion in a sixth patient, who had
a known history of infection with M. avium-intracellulare, revealed
granulomatous inflammation consistent with infection with M.
avium-intracellulare; however, the patient's cultures revealed negative
findings.
Therapy included steroids and indomethacin in two patients and continued
highly active antiretroviral therapy with the addition of antimycobacterial
medications in four patients. This treatment resulted in slow clinical
resolution (up to 2 years) in all patients.
Discussion
Infection with M. avium-intracellulare inevitably develops in
10-30% of patients with AIDS, representing more than 95% of all nontuberculous
mycobacterial infections in this population. The disease is most common in
patients with a CD4 cell count of fewer than 100 cells per microliter
[1]. A cellular inflammatory
response, granulomatous or not, is frequently absent. Before the advent of
highly active antiretroviral therapy, the average survival after diagnosis of
disseminated infection was between 4 and 10 months
[1,
7].
M. avium-intracellulare is known to be widely distributed in the
environment [7]. It has been
suggested that the main entry site for infection is the gastrointestinal tract
[1]. In patients with AIDS,
infection with M. avium-intracellulare frequently causes enteritis
and abdominal and mediastinal lymphadenopathy
[1] compared with infection
with M. avium-intracellulare in immunocompetent patients, who usually
develop pulmonary disease without dissemination
[7]. Cervical lymphadenitis in
immunocompetent children and infrequent skin lesions and musculoskeletal
infections in both immunosuppressed and immunocompetent populations have also
been described
[5,6,7].
The disseminated form of infection with M. avium-intracellulare in
patients with AIDS commonly involves other organs such as the liver, bone
marrow, and nodal chains outside the abdomen and thorax.
The disseminated infection with M. avium-intracellulare in our
patients generally developed when their CD4 cell counts surpassed 100 cells
per microliter. Fever and mediastinal or abdominal lymphadenopathy, the most
common findings in our patients, parallels those of infection with M.
avium-intracellulare in patients with AIDS not being treated with highly
active antiretroviral therapy. However, we noted other findings including
scrofula, osteomyelitis, and skin and soft-tissue granulomatous abscesses, all
of which are extremely unusual manifestations of infection with M.
avium-intracellulare in patients with AIDS. Moreover, the dissemination
of infection and acute illnesses coincided with dramatic increases in CD4 cell
counts and decreases in viral loads after receiving highly active
antiretroviral therapy, a combination of protease inhibitors and two new
nucleoside analogues, which is now in widespread clinical use and resulting in
prolonged patient survival.
We believe that this appearance represents a reversal syndrome, reflecting
the patient's new ability to mount a response to a new or previously
unrecognized infection with M. avium-intracellulare after improvement
in immunologic status. A review of current literature revealed two similar
case series [9,
10]; we may begin to see this
entity more commonly now, because of the widespread use of highly active
antiretroviral therapy. Additionally, other reports suggest reversal syndromes
involving other opportunistic infections afflicting patients with AIDS,
including disseminated tuberculosis
[11] and Cytomegalovirus
retinitis [12].
Two of our patients required immunosuppressive therapy such as steroids in
addition to antimycobacterial medications to achieve symptomatic improvement.
Until recently, it would be unusual to treat a patient with AIDS with steroids
or other immunosuppressants. It would also be expected that an improvement in
disease status would result in both clinical and radiologic improvement with
the resolution of lymphadenopathy. We observed the opposite situation. Once an
improvement in immune status was achieved, our patients developed new
lymphadenopathy, musculoskeletal infections, and cutaneous lesions that
resolved only with the addition of antimycobacterial medications and
perseverance with highly active antiretroviral therapy. Most important, our
patients did not succumb to either the infection or resultant inflammatory
reactions.
Another aspect of M. avium-intracellulare reversal syndrome that
may distinguish it from other causes of new enlarging lymphadenopathy in
patients with AIDS, such as lymphoma or Kaposi's sarcoma, is the presence of
central low attenuation in the nodes, which suggests necrosis. Reports by
Nyberg et al. [3] and Radin
[4] revealed that
low-attenuation necrotic lymphadenopathy in patients with AIDS caused by
disseminated infection with M. avium-intracellulare is far less
frequent a presentation than diffuse soft-tissue density nodes. Three of four
patients in our series who presented with new lymphadenopathy had central
low-attenuation nodes. This finding suggests that lymphadenopathy caused by
disseminated infection with M. avium-intracellulare in the context of
reversal syndrome is more likely necrotic than lymphadenopathy of infection
with M. avium-intracellulare in other patients with AIDS.
Our sample is too small to establish the radiologic manifestations specific
to the M. avium-intracellulare reversal syndrome; however, both
worsening symptoms and radiographic appearances can be expected when this
entity is encountered. This lack of specificity makes it more important to
obtain a proper clinical and therapeutic history to put the radiographic
manifestations in the proper context. Further study of a much larger group is
necessary.
In conclusion, the M. avium-intracellulare reversal syndrome may
represent a response of the recovering immune system to a new or previously
subclinical infection with M. avium-intracellulare. It is important
for radiologists to recognize that new or enlarging lymphadenopathy or unusual
musculoskeletal and cutaneous infections in patients with AIDS who are
receiving highly active antiretroviral therapy may not represent a worsening
of HIV-related infections or lymphoma but an actual improvement in their
immune status.
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Abstract
Introduction
