Localized Mycobacterium avium complex infection of vertebral and paravertebral structures in an HIV patient on highly active antiretroviral therapy.

Key Words: HIV, immune reconstitution syndrome (IRS), Mycobacterium avium complex (MAC), vertebral osteomyelitis, paravertebral abscess.

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Before the introduction of highly active antiretroviral therapy (HAART) Mycobacterium avium complex (MAC) disease was the most common bacterial infection in patients with acquired immune deficiency syndrome (AIDS) in developed countries. (1) Effective antiviral therapy against HIV has allowed for control of viral replication, improvement in immune function, and a significant decrease in opportunistic infections (OIs). (2) However, atypical presentations of these infections have been increasingly described in patients a few weeks after the initiation of HAART. This clinical worsening despite decrease in HIV viral load and increase in CD4+ lymphocyte cell count is called immune reconstitution syndrome (IRS). (3) We report a case of localized vertebral and paravertebral MAC infection in an HIV-infected patient with high CD4+ lymphocyte counts, more than one year after starting antiretroviral therapy.

Case Report

A 35-year-old Latin male diagnosed with HIV infection in 1999 developed Pneumocystis carinii pneumonia (PCP) in February, 2001. His CD4+ lymphocyte count was 24 cells/[mm.sup.3] and he had a negative PPD at the time. There was no information on MAC prophylaxis during that period. In April 2001 the patient was started on lamivudine/zidovudine, indinavir and efavirenz. A few months later, zidovudine was discontinued due to peripheral neuropathy, and he continued on indinavir, efavirenz and lamivudine.

In April 2002, the patient reported low back pain radiating to both flanks. His symptoms were attributed to indinavir-induced nephrolithiasis, and this was replaced by tenofovir. Despite the change and the use of ibuprofen, his pain persisted. Two weeks before admission, after slipping in the bathtub, his low back pain increased with radiation to both thighs, weakness of the lower extremities, and subjective fever. Two days before admission in December 2002, the patient started experiencing intermittent numbness and tingling in both legs.

Physical examination revealed tenderness to palpation over the lumbar spine and spasm of paraspinal muscles. There was musculer wasting of the lower extremities with 4/5 proximal muscle strength in the left lower extremity and 2/5 on the right. Reflexes were brisk and symmetrical. Sensation was intact and rectal sphincter tone was normal.

Laboratory values were remarkable for an erythrocyte sedimentation rate of 52 mm/h and an alkaline phosphatase of 159 mg/dL. Blood cultures were negative. The CD4+ lymphocyte count was 320 cells/[mm.sup.3] and the PPD was now positive at 12 mm induration. Magnetic resonance imaging showed spondylitis and diskitis of L1 through L3, causing compression of both cauda equina and conus, as well as bilateral psoas abscesses. Purulent material was removed by CT-guided drainage and the smear showed large numbers of acid-fast bacilli.

The patient was started on isoniazid, rifampin, ethambutol and pyrazinamide for presumed tuberculosis although PCR assay for Mycobacterium tuberculosis was negative. After two weeks, his symptoms and radiologic appearance remained unchanged and cultures grew Mycobacterium avium complex. Rifampin was changed to rifabutin and clarithromycin was added, and due to poor of clinical response, IV steroids (dexamethasone, 6 mg IV every 6 h) were started for suspected IRS. Four days later his motor function improved significantly, and after two weeks the patient was ambulating with a walker. Two months later, when seen in clinic, he was walking unassisted and had a CD4+ lymphocyte count of 429 cells/[mm.sup.3] and an undetectable viral load.

Discussion

Mycobacterium avium complex is widely found in the environment with transmission to humans occurring after colonization of the respiratory or gastrointestinal tract. In patients with AIDS, clinical disease usually presents as a disseminated infection with fever, anorexia, weight loss, anemia, leukopenia, hepatosplenomegaly, and lympadenopathy. (4) Since the widespread use of HAART, the disseminated form of MAC has become less common. (2) Antiretroviral therapy has reduced the incidence of Ols, although unusual presentations of such infections have been described after HAART is started and CD4+ lymphocyte counts recover, a condition known as immune reconstitution syndrome (IRS). (3) Most commonly, IRS associated with MAC presents as focal lymphadenitis, and fever about 1 to 12 weeks after the initiation of HAART. (3) More unusual and delayed presentations have also been described, including cutaneous lesions, endobronchial masses, focal brain lesions, ileitis, and bone and soft tissue infections. (3) Only a few cases of later and more localized MAC presentations involving vertebral and/or paravertebral tissues after initiation of HAART have been reported (5-8) (Table). Our patient presented with a unique combination of spinal osteomyelitis with diskitis, epidural and bilateral psoas abscesses due to MAC infection a combination not previously described in the setting of IRS.

Of the seven cases listed in Table 1, nadir CD4+ lymphocyte counts (reported for six cases) were below fifty cells/mm, and CD4+ lymphocyte counts at presentation of IRS were well above 100 cells/[mm.sup.3] (in two cases above 400) for the 5 patients with these data available. All patients were receiving HAART at the time of IRS, with time from starting HAART to the beginning of symptoms ranging from two to thirty months. The duration between beginning of symptoms to the diagnosis of infection ranged from less than one month to five months. Pain was the main symptom in the two cases of unilateral psoas abscesses. (5) In three of the five cases with vertebral compromise, neurologic symptoms were prominent and included paresthesia, weakness and sensory levels. (6) Interestingly, fever is described in only two cases. (7)

[FIGURE 1 OMITTED]

None of the seven cases we found were receiving prophylaxis for MAC at the time of diagnosis. It was not possible to obtain information about MAC prophylaxis between AIDS diagnosis and presentation to our hospital for our patient. In three of the other six cases, there is no reference about history of MAC prophylaxis. (5,7,8) Two patients had prophylaxis stopped at three and sixteen months before presentation, after their CD4 counts rose to above 100/[mm.sup.3] (6) in accordance with US Public Health Service/Infectious Diseases Society of America recommendations. (9) Another patient had a history of disseminated MAC infection while on HARRT with low CD4 count (23/[mm.sup.3]) and after treatment for that infection and improvement in CD4 counts, developed a psoas abscess four months after therapy for MAC was stopped. (5)

Recommendations for stopping MAC therapy after HAART-induced immune reconstitution are less clear. One study evaluated 48 subjects (median CD4+ lymphocyte count of 240 cells/[mm.sup.3]) on HAART for whom therapy for DMAC infection was stopped after a year of macrolide-based therapy. After a median follow-up of 77 weeks, only one patient developed MAC osteomyelitis. (10) At this point, there is no reliable tool to identify at-risk patients who may benefit from continuation of prophylactic or suppressive therapies after immune restoration has occurred.

Paradoxical reactions after HAART were initially reported in tuberculous patients starting antiretroviral and antituberculous therapy, where worsening of symptoms is sometimes noted. Such paradoxical responses were often associated with conversion of PPD skin tests to positive. (11) Restoration of delayed type hypersensitivity for Mycobacterium avium is also reported in patients with localized MAC disease on HAART. (12) In our patient, the restoration of the PPD test may reflect improving immunity (13) and possible cross-reaction with Mycobacterium avium antigens as has previously been described. (4,14) We hypothesize that these presentations are secondary to the restoration of immune function, unmasking previous subclinical tissue infection acquired during nadir CD4+ cell counts with or without clinical DMAC at that time.

Although comparative trials are lacking, steroids have been used with success for the treatment of Mycobacterium tuberculosis (MTB) and Mycobacterium avium infections after HAART. (11,15) We used steroids since our patient's symptoms failed to improve with specific antituberculous treatment, and had an excellent clinical outcome.

Relatively high CD4+ lymphocyte count, insidious onset and unspecific symptoms lead to diagnostic difficulties in most cases. In our patient and in one described by Aberg et al, (6) initial treatment for presumed Mycobacterium tuberculosis was given under the assumption that MTB is most frequently involved in vertebral and paravertebral infections. Interestingly, we found that in most reports of OIs in the setting of IRS, MAC largely surpasses Mycobacterium tuberculosis in the incidence of mycobacterial infections. (12) However, as access to HAART improves in the developing world where tuberculosis is endemic, IRS-associated tuberculosis may become a common clinical scenario.

Conclusion

This is one of the few reports of localized MAC infection involving vertebral and paravertebral structures after treatment with HAART. We suggest that our patient had subclinical MAC disease that manifested as a localized infection after beginning HAART. In patients with AIDS, the CD4+ lymphocyte count is the only recommended marker to evaluate the degree of immune function, but T-cells are a quantitative measure that may not, as in this case, identify those who remain at risk of developing opportunistic infections.

Diagnosis of mycobacterial infections represents a challenge for the clinician, since final results of cultures often take weeks. We emphasize the importance of considering localized atypical mycobacterial infection in HIV-infected patients on HAART with relatively high CD4+ lymphocyte counts for purposes of adequate and timely treatment.

References

1. Jones JL, Hanson DL, Chu SY, et al. Surveillance of AIDS defining conditions in the United States. AIDS 1994;8:1489-1493.

2. Kapkan JE. Hanson D, Dworkin MS, et al. Epidemiology of Human Immunodeficiency Virus-Associated Opportunistic Infections in the United States in the Era of Highly Active Antiretroviral Therapy. Clin Infect Dis 2000;30:S5-14.

3. Shelburne SA III, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67-79.

4. Cabie A, Abel S. Brebion A. et al. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 1998;17:812-813.

5. Boyd AE. Brettle RP. Mycobacterium avium intracellulare psoas abscess in patients with AIDS after antiretroviral therapy. AIDS 1999;13:2185-2186.

6. Aberg JA, Chin-Hong PV, McCutchan A, et al. Localized osteomyelitis due to Mycobacterium avium complex in patients with human immunodeficiency virus receiving highly active antiretroviral therapy. Clin Infect Dis 2002;35:e8-13.

7. Nalaboff KM, Rozenshtein A, Kaplan MH. Imaging of Mycobacterium avium-intracellulare infection in AIDS patients on highly active antiretroviral therapy: Reversal syndrome. AJR 2000;175:387-390.

8. Erard P. Robert-Grandpierre F, Kaeser P. Vertebral osteomyelitis caused by Mycobacterium avium intracellulare in a patient with AIDS. Clin Microbiol Infect 1999;5:643-644.

9. Currier JS, Williams PL, Koletar SL, et al., for the AIDS Clinical Trials Group 362 Study Team: Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. Ann Intern Med 2000;133:493-503.

10. Aberg JA, Williams PL, Liu T, et al. A study of discontinuing maintenance therapy in human immunodeficiency virus-infected subjects with disseminated Mycobacterium avium complex: AIDS Clinical Trial Group 393 Study Team. J Infect Dis 2003;187:1046-1052.

11. Narita M. Ashkin D. Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157-161.

12. French MA. Lenzo N, John M. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Medicine 2000;1:107-115.

13. Michelet C, Arvieux C, Francois C, et al. Opportunistic infections occurring during highly active antiretroviral treatment. AIDS 1998;12:1815-1822.

14. Hassell M, French MA. Mycobacterium avium infection and immune restoration disease after highly active antiretroviral therapy in a patient with HIV and normal CD4+ counts. Eur J Clin Microbiol Infect Dis 2001;20:889-891.

15. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1 infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 2000;133:447-454.</p> <pre> Life can be pulled by goals just as surely as it can be pushed by drives. --Viktor E. Frankl </pre> <p>Vicente Corrales-Medina, MD, Stephen Symes, MD, Martin Valdivia-Arenas, MD, and Catherine Boulanger, MD

From Infections Diseases, University of Miami, Miami, FL.

Reprint requests to Catherine Boulanger, MD, University of Miami, Infectious Diseases, PO Box 016960 (D90-A), Miami, FL 33136. Email: [e-mail]

Accepted October 10, 2005.

RELATED ARTICLE: Key Points

* Opportunistic infections (OIs) may have unusual presentations in HIV-infected patients on highly active antiretroviral therapy with relatively high CD4+ lymphocyte counts.

* Initially described as presenting one to twelve weeks after initiation of HAART, immune reconstitution syndrome (IRS) may be seen many months after starting treatment of HAART.

* Localized MAC infections in the setting of IRS involving body structures other than lymph nodes have been well described.

* Delay in recognizing these entities may lead to important sequelae especially when involving vertebral and paravertebral structures.

Table. Characteristics of reported cases of localized MAC infection
involving vertebral and paravertebral structures in the setting of
immune reconstitution syndrome

Report               Sex  Age  Involvement

Boyd, et al (5)      M    52   Right psoas, paraspinal and iliacus
                                 muscle
Boyd, et al (5)      F    25   Left psoas abscess
Aberg, et al (6)     M    49   T9-T10 osteomyelitis, diskitis, epidural
                                 abscess
Aberg, et al (6)     M    49   T6-T7 osteomyelitis, paraspinal mass
Nabaloff, et al (7)  F    50   T7 osteomyelitis and paraspinal mass
Erard, et al (8)     F    36   T8-T9, T9-T10 osteomyelitis and diskitis
Corrales, et al      M    35   L1-L3 osteomyelitis, diskitis, epidural
                                 and bilateral psoas abscesses

Report               CD4 count nadir  CD4 count at presentation

Boyd, et al (5)            <20                243
Boyd, et al (5)             23                NR
Aberg, et al (6)            16                465
Aberg, et al (6)            23                118
Nabaloff, et al (7)         NR                NR
Erard, et al (8)            44                423
Corrales, et al             24                300

MAC, Mycobacterium avium complex; IRS, immune reconstitution syndrome;
CD4, CD+ lymphocyte; HAART, highly active antiretroviral therapy; NR,
not reported; M, male; F, female.