Share this article on:

Cytomegalovirus immune reconstitution inflammatory syndrome manifesting as sialadenitis in an HIV-infected patient

Sheikh, Virginiaa; Caplan, Margaretb; Wilson, Eleanor M.P.a; Papadi, Bhaveshc; Rosenberg, Avi Z.c; Higgins, Jeannetteb; Driscoll, Briand; Filie, Armando C.c; Sereti, Irinia

doi: 10.1097/QAD.0b013e328362d8b0

aLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda

bScience Applications International Corporation-Frederick, Frederick National Laboratory, Frederick

cLaboratory of Pathology, National Cancer Institute, National Institutes of Health

dHead and Neck Surgery Branch, National Institute on Deafness and Communications Disorders, National Institutes of Health, Bethesda, Maryland, USA.

Correspondence to Virginia Sheikh, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, CRC, Rm. 8C408, Bethesda, MD 20892, USA. Tel: +1 301 435 1939; fax: +1 301 402 1137; e-mail:

Received 18 April, 2013

Accepted 2 May, 2013

Advances in antiviral medications effective in treating both cytomegalovirus (CMV) and HIV have resulted in decreased morbidity and mortality related to CMV end-organ-disease (EOD) among severely immunosuppressed HIV/AIDS patients [1], but rapid immune reconstitution with antiretroviral therapy (ART) may also result in the immune reconstitution inflammatory syndrome (IRIS). In patients with HIV/AIDS, CMV EOD typically manifests with colitis, retinitis, polyradiculopathy or, after ART with CMV IRIS, in the form of retinitis or inflammatory uveitis [2]. We present an unusual case of CMV-IRIS which occurred in a severely CD4+ depleted HIV-infected and resembled acute CMV in an immunocompetent individual.

Several months after being diagnosed with HIV/AIDS in the context of cryptococcal meningitis, the patient consented for enrollment in an Institutional Review Board-approved, prospective observational study of HIV-1 infected patients with CD4 cell count below 100 T cells/μl in Bethesda, Maryland (NCT #00286767). At study screening, he reported only mild fatigue and physical exam and routine laboratory investigations were unremarkable. CMV IgG was positive, CMV IgM was negative and blood CMV PCR was positive at 2150 copies/ml. Ophthalmologic exam demonstrated no evidence of CMV retinitis. At ART initiation, his CMV PCR was 3350 copies/ml, his CD4 cell count was 5 cells/μl, and his plasma HIV-RNA was 626 036 copies/ml.

Two weeks after starting ART, his physical exam remained unremarkable and his laboratory studies revealed an excellent virologic response to ART (plasma HIV-RNA 207 copies/ml) with a concomitant rise in his CMV PCR levels to 22 500 copies/ml (Fig. 1a). Two weeks later, the patient presented with 2 days of fever and acute onset left neck swelling and pain. Physical exam revealed hard, nontender swelling in the submandibular region, predominantly on the left. He denied gastrointestinal or ocular symptoms and his labs were notable only for a CD4 cell count of 13 cells/μl, HIV-RNA less than 40 copies/ml, and CMV PCR 11 350 copies/ml. A computed tomography scan of the neck demonstrated plump, dense-appearing submandibular glands (Fig. 1b) without mass or lymph node enlargement. Over the next 2 weeks, he continued to experience fever, malaise, and fatigue and reported increased submandibular swelling. On follow-up exam, his submandibular swelling was more prominent and tender (3 × 3 cm on right and 2 × 2 cm on the left), and he was referred to Otolaryngology. Eight weeks after starting ART, fine needle aspirate (FNA) was performed for the right submandibular gland.

Fig. 1

Fig. 1

Gram stain, wet mount, and AFB smear were negative. Papanicolaou and Diff-Quick stained smears revealed scattered considerably enlarged cytomegalic cells with enlarged nuclei, single large intranuclear inclusions surrounded by a clear halos, thickened nuclear membranes and intracytoplasmic rounded inclusions, cytologic features characteristic of CMV-infected cells, as well as lymphocytic infiltrate with no acinar cells identified, consistent with significant immune-mediated inflammation (Fig. 1c). Laser capture microdissection was performed using an Arcturus XT (Life Technologies, Carlsbad, California, USA). The cytomegalic cells were identified by morphology, captured from a Papanicolaou-stained smear preparation using a near-infrared laser pulse and transferred onto a cap (Capsure Macro LCM Caps, Life Technologies, catalog number LCM0211). The DNA was extracted from the cap after overnight incubation with proteinase K buffer at 56°C, using the QIAamp DNA micro kit (Qiagen, Valencia, California, USA, catalog number 56304). Following proteinase K digestion, the buffer was incubated at 90°C for 1 h and DNA was isolated and eluted in 20 μl of buffer following the kit manufacturer's instructions. PCR of DNA derived from laser micro-dissected cytomegalic cells was positive for CMV genomic DNA. On the same day, his serum CMV PCR was less than 250 copies/ml, for the first time since starting ART. Flow cytometric analysis of peripheral blood performed at timepoints before, during and after the event demonstrated an increase of both CD8+ and CD4+ T-cells immediately following the initial presentation (Fig. 1d). The patient was monitored clinically and, by week 12, his symptoms had completely resolved.

Although the salivary glands are a known site of acute CMV infection and probably latency, CMV-attributed submandibular swelling and fever have been described only rarely in HIV-infected patients [3–6]. In our case, the cytopathology FNA sample clearly demonstrated CMV cytopathic features that, after laser microdissection, were positive for CMV by PCR. The cytopathologic finding of lymphocytic infiltrate and the absence of acinar cells support our hypothesis that part of this patient's symptomatology was immune-mediated. We conclude that this presentation, which is atypical in HIV/AIDS but typical for immunocompetent individuals, occurred as a result of an abrupt and aberrant recovery of the immune response following ART known as IRIS.

Back to Top | Article Outline


V.S., B.D. and J.C. provided clinical care for the patient. A.R., B.P. and A.F. provided pathological diagnosis and performed laser microdissection. V.S., E.W. and I.S. wrote the article. J.H. performed flow cytometry analysis. The authors would like to thank Dr Susan Robilotto for assistance in clinical management, Mr Jeffrey Hanson for technical support with LCM and Mr Gary Fahle for performing PCR studies.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Funding: This work was supported in part by the Intramural Research Programs of National Institute of Allergy and Infectious Diseases (NIAID) and National Cancer Institute (NCI), and with federal funds from the NCI, NIH under Contract No. HHSN261200800001E. The views expressed in this article are those of the authors and views or policies do not necessarily reflect those of the of Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Back to Top | Article Outline


1. Yust I, Fox Z, Burke M, Johnson A, Turner D, Mocroft A, et al. Retinal and extraocular cytomegalovirus end-organ disease in HIV-infected patients in Europe: a EuroSIDA study, 1994–2001. Eur J Clin Microbiol Infect Dis 2004; 23:550–559.
2. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18:1615–1627.
3. Pialoux G, Ravisse P, Trotot P, Dupont B. Cytomegalovirus infection of the submandibular gland in a patient with AIDS. Rev Infect Dis 1991; 13:338.
4. Smith NA, Leen EJ, Derias NW, Nicholson F, Bingham JS. Massive salivary gland swelling due to primary cytomegalovirus infection in an AIDS patient. Int J STD AIDS 1997; 8:528–529.
5. Gisserot O, de Jaureguiberry JP, Carloz E, Marlier S, Jaubert D. Cytomegalovirus infection of the submandibular gland in a patient with HIV infection. Rev Med Interne 2000; 21:200–201.
6. Schellenberg DM, Desmond NM, Murphy SM, Tanner AG. AIDS-associated cytomegalovirus infection of the submandibular gland mimicking a tumour. J R Soc Med 1994; 87:483–484.
© 2013 Lippincott Williams & Wilkins, Inc.