Enlarged Parotid Glands -- DILS

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Disease Management

Diagnosis of Diffuse CD8+ Lymphocytosis Syndrome in HIV-Infected Patients

Franco-Paredes, MD, ina Rebolledo, MD, Folch, MD, Isabel , MD, del Rio, MD AIDS Read 12(9):408-413, 2002. © 2002 Cliggott Publishing, Division of SCP Communications

Posted 11/01/2002

Abstract and Introduction

Abstract

The diffuse infiltrative lymphocytosis syndrome (DILS) in HIV-infected persons is characterized by a persistent circulating CD8+ lymphocytosis. Certain HIV-infected persons appear to respond to their infection by developing an oligoclonal expansion of CD8+ lymphocytes. These cells infiltrate multiple organs, but the salivary glands and the lung constitute the major sites involved in this process. This infiltrative process resembles in many aspects a Sjögren-like syndrome, owing to the visceral lymphocytic infiltration. Unilateral parotid gland enlargement in a patient with HIV infection should prompt clinicians to suspect DILS. In addition, clinicians should be aware that the pulmonary process associated with DILS may mimic clinically and radiographically the pneumonic process caused by Pneumocystis carinii. Other manifestations of DILS to consider include a severe form of peripheral neuropathy; lymphocytic infiltration of the liver, evident as hepatitis; myositis; and lymphocytic interstitial nephritis.

Introduction

During the first 20 years of the HIV pandemic, significant advances have been made in the understanding of the immunopathogenesis of the disease.[1] One such advance is the recognition that HIV infection is not simply an immune deficiency disease but also a disease characterized by immune dysregulation that sometimes is associated with autoimmune-like phenomena.[2]

HIV infection shares many similarities with a variety of autoimmune conditions. From one perspective, there is an increased incidence of antinuclear antibodies and polyclonal B-cell activation with production of anticardiolipin antibodies in HIV-infected persons.[2] The one condition that may occur with increased frequency in patients with HIV infection is a variant of primary Sjögren syndrome. Certain HIV-infected persons respond to their infection by developing a syndrome characterized by a persistent circulating CD8+ lymphocytosis with visceral lymphocytic infiltration, mostly of the salivary glands.[3, 4] This syndrome, defined as the diffuse infiltrative lymphocytosis syndrome (DILS), is associated with lymphocytic infiltrates of the salivary gland and lung and causes parotid gland enlargement, dry eyes, and dry mouth.

However, in contrast to a classic Sjögren syndrome, in which these infiltrates are composed predominantly of CD4+ cells, DILS in patients with HIV infection is characterized by infiltrates that predominantly comprise CD8+ lymphocytes.[3, 4] Pulmonary involvement, which consists of lymphocytic infiltrates that manifest clinically as dyspnea with diffuse bilateral pulmonary infiltrates, is frequent and can cause confusion among clinicians because of its ability to mimic Pneumocystis carinii pneumonia (Figure 1).

Figure 1. Chest radiograph from a 35-year-old man with HIV/AIDS who presented to the hospital with bilateral parotid gland enlargement and xerostomia. His CD4+ cell count was 233/µL, and his total CD8+ cell count was 1873/µL. The diagnosis of Pneumocystis carinii pneumonia was entertained on admission to the hospital, but cultures from his bronchoalveolar lavage were negative for fungi, bacteria, and viruses. Nevertheless, a diagnosis of diffuse infiltrative lymphocytosis syndrome was made based on the association of a significantly elevated total CD8+ lymphocyte count, a salivary gland biopsy showing a lymphocytic infiltrate, and the presence of diffuse pulmonary infiltrates.

A severe peripheral neuropathy subsequently has been recognized as another important manifestation of DILS5 and is associated with massive HIV proviral load in peripheral nerves and oligoclonal infiltration of CD8+ lymphocytes. The lymphocytic infiltrations seen with DILS may also cause myositis,[3] hepatitis,[6, 7] and interstitial nephritis.[8]

DILS was first described by Solal-Celigny and colleagues[9] in 1985; they described 3 patients who had marked lymph node hyperplasia, 1 with bilateral parotid gland enlargement. In 1987, Couderc and colleagues[10] reported 5 more patients, of whom 4 had parotid gland enlargement with lymphocytic infiltration of the salivary gland along with extraglandular sites, such as lung, liver, kidney, and bone marrow.

Two years later, Tunkel and colleagues[11] demonstrated the presence of benign lymphoepithelial infiltration of the parotid tissue with cystic degeneration when parotidectomies were performed in 3 HIV-infected patients with bilateral parotid gland enlargement. The term "diffuse infiltrative lymphocytosis syndrome" was proposed in 1989 in a case series in which 11 of 12 patients were African American and 10 expressed the major histocompatibility class (MHC) II HLA-DR5.[3, 12] The same group of researchers demonstrated the association of DILS with a particular cell lineage expansion, CD8+CD29+ lymphocytes.[13] In addition, Itescu and colleagues[14] detected certain HLA class I antigens, such as HLA-B45 and -B49, that conferred increased risk of developing DILS.

Epidemiology

DILS has been reported to occur predominantly in HIV-infected African American middle-aged men,[3, 4, 15] and male-to-male transmission of HIV infection has been consistently reported as a risk factor for the development of DILS.[3, 16] In one of the largest series of patients, Kazi and colleagues[3] reported that the average age of patients with DILS at the time of diagnosis was 36.9 years.

Although the incidence of DILS remains elusive, estimates range from 0.8% to 7.8% in HIV-infected persons.[3, 4] A study from West Africa showed that the prevalence of DILS may be as high as 48% when assessed histologically.[7] DILS is most frequently reported in the pediatric literature, and many series have noted its occurrence at an early stage of HIV disease, before the development of AIDS. For example, in the series reported by Kazi's group,[3] the average CD4+ T-lymphocyte count was 342/µL, while the average CD8+ T-lymphocyte count was 1639/µL.[4] Of recent interest are observations suggesting that this syndrome appears to be less prevalent as a result of the widespread use of HAART; this may be explained by the effect of antiretroviral therapy in decreasing the number of circulating CD8+ lymphocytes.[3, 17, 18]

Immunopathogenesis

DILS is a clinical and molecular phenotypic mimic of Sjögren syndrome, which includes salivary gland enlargement, extraglandular involvement, and symptoms of the sicca syndrome.[3, 4, 15] However, there are important demographic and immunophenotypic differences between DILS and Sjögren syndrome, which are summarized in Table 1.

The ability of T-cell lymphocytes to respond to antigen such as HIV arises from the wide array of and T-cell receptors that recognize diverse foreign peptides presented by MHC molecules.[19] Molecular analysis of T-cell receptor structure provides a convenient method for the study of the clonal lineage of mature T cells.[18-20]

Structure analysis of CD8+ lymphocytes infiltrating the salivary glands of patients who have DILS provides evidence that DILS represents an MHC-restricted, antigen-driven oligoclonal selection of CD8+CD29+ lymphocytes that express selective homing receptors, such as CD29 (very late activation antigen-4), the integrin CD11a/CD18 (lymphocyte function-associated antigen-1 [LFA-1]), and CD57. These receptors allow this particular cell lineage to become sequestered and infiltrate the salivary glands, lung, and other organs. Specifically, there is strong expression of CD54 (intracellular adhesion molecule-1 [iCAM-1]) molecules on postcapillary venule endothelium within lymphoid aggregates.

Therefore, the entry of lymphocytes into tissues involves interactions between specific cell adhesion molecules and their ligands, such as between LFA-1 and ICAM-1.[20] These studies have suggested that both the circulating and the infiltrative CD8+ lymphocytes in HIV-infected persons with DILS represent an antigenically driven and immunogenetically determined host response to HIV infection. The cellular and molecular responses described here and the presence of HIV-encoded proteins in salivary gland macrophages localized in close proximity to lymphoid aggregates suggest that the systemic response to HIV infection, in certain immunogenetically predisposed persons, gives rise to a specific oligoclonal CD8+ T-cell response that infiltrates certain tissues, such as the salivary glands.[20]

Of particular interest is that the marked CD8+ lymphocytosis that is observed during primary simian immunodeficiency virus infection in rhesus and cynomolgus macaques invokes a mechanism whereby virus-induced cytokine production in mucosal sites initiates the transient migration of the preexisting CD8+ population from compartments such as the lung into the bloodstream. These findings suggest that the magnitude of the lymphocytosis may depend primarily on the level of viral replication in mucosal sites.[21]

Diagnosis

The clinical features of DILS may be similar to those of a classic Sjögren syndrome and include sicca symptoms (xerostomia and xerophthalmia).[3, 4, 15] The parotid glands, and occasionally the submandibular gland, may show unilateral, but most commonly bilateral, enlargement. In a series of 35 patients with DILS, bilateral parotid gland enlargement was present in all cases.[3] The glands are firm and occasionally tender.[3, 4, 22] The extraglandular manifestations occasionally may become symptomatic. Severe dyspnea may be present in patients with significant lung involvement in the form of a lymphocytic interstitial pneumonia. Occasionally, muscular involvement manifested as a debilitating myositis may develop.[3]

The diagnostic criteria developed by Itescu and Winchester[23] require that the subject be HIV-seropositive, have bilateral salivary gland enlargement or xerostomia for more than 6 months, and have histologic confirmation of salivary or lacrimal gland lymphocytic infiltration in the absence of granulomatous or neoplastic involvement.

Pathologically, under light microscopy, DILS resembles the focal sialadenitis seen with Sjögren syndrome, although it tends to be less destructive of the glandular architecture than in Sjögren syndrome. Most of the inflammatory infiltrate is composed of CD8+ lymphocytes. Lymphoepithelial cysts are frequently observed in the parotid glands of patients with DILS. These cysts are characterized by follicular hyperplasia, cystic dilatation of the ducts lined by pseudostratified squamous epithelium, and CD8+ lymphocytic infiltrates.[3, 4, 7, 15]

Peripheral nervous system involvement has been reported in association with DILS. Both a symmetric sensorimotor neuropathy and an asymmetric neuropathy have been described.[5, 24, 25] These polyneuropathies might be confused with the very common distal sensory polyneuropathy of late HIV infection or with a toxic polyneuropathy related to antiretroviral nucleoside analogue drugs.

Both of the neuropathies associated with DILS may present with predominating distal sensory symptoms and (less commonly) with either mononeuritis multiplex or a demyelinating polyneuropathy. Some authors have shown that the angiocentric infiltration of peripheral nerves by CD8+ lymphocytes in this disorder parallels the histopathologic changes seen in the peripheral neuropathy associated with T-cell lymphomas in patients with HIV infection.[5, 24, 25] A seventh nerve palsy has also been reported and is apparently due to compression of the parotid gland.[15]

The diagnosis of DILS can be made from a labial salivary gland biopsy by demonstrating a CD8+-predominant focal lymphocytic infiltrate, in contrast to the CD4+-predominant infiltrate in Sjögren syndrome.[15, 23] MRI and CT scans are useful in the diagnosis and may also reveal benign lymphoepithelial cysts, which can be a feature of DILS. Scintigraphy with gallium citrate Ga 67 has been shown to be extremely useful as a substitute for salivary gland biopsy in 2 different studies in which a classic, intense uptake of tracer occurred, provided that the patient has persistent bilateral parotid gland enlargement.[3, 4] The intense gallium activity in DILS patients reveals the extensive lymphocytic infiltration of the salivary glands.[26]

The differential diagnosis of enlargement of the parotid glands is quite involved and includes diverse conditions, ranging from neoplasms to autoimmune diseases (Table 2).[22] There should be a high index of suspicion in HIV-infected patients with parotid gland enlargement. (Interestingly, parotid lipomatosis recently has been reported as a complication associated with the use of HAART in patients with HIV infection.[27] In these cases, gallium scans should be the diagnostic modality of choice to distinguish between DILS and parotid lipomatosis.[15]) In addition, clinicians should keep DILS in mind when confronted with diffuse interstitial infiltrates that may mimic P carinii pneumonia.

A Word on Treatment

Therapy for DILS centers on the use of prednisone and antiretroviral drugs.[15] Corticosteroids in moderate to high doses tend to elicit a good response, but their use is recommended only for patients with significant symptoms.[8, 15, 28] The lymphocytic interstitial pneumonitis associated with DILS requires higher doses of corticosteroids (up to 60 mg/d), as suggested by Reveille.[15] Reports of low-dose radiotherapy suggest good short-term efficacy in reducing parotid gland enlargement in DILS patients but with frequent relapses occurring in patients with less favorable initial responses.[28, 29]

The prevalence of DILS seems to be decreasing since the advent of HAART.[3, 15] This supposition is based on the results of T-cell receptor analyses that show oligoclonally expanded CD8+ T cells to be significantly diminished during HAART,[17] with the entire CD8+ T-cell repertoire decreasing after 8 weeks.[30] These results suggest that with HAART, there may be an interruption of chronic antigenic stimulation and that persistently replicating viral populations are required to maintain elevated levels of HIV-1-specific CD8+ lymphocytes.[17, 31]

The response of CD8+ lymphocytes to antiretroviral therapy was seen even in the "old days" of antiretroviral therapy, when monotherapy with zidovudine was used for HIV-related Kaposi sarcoma.[32] In addition, many reports have shown significant improvement in CD8+ lymphocytosis and reversal of visceral infiltration with the institution of antiretroviral therapy.[3, 6, 15, 33] Others have shown that HAART is also effective in resolving parotid epithelial cysts.[34] The initiation of HAART seems to be the best modality for treating DILS in patients with HIV infection.

Tables

Table 1. Differences Between the Diffuse Infiltrative Lymphocytosis Syndrome (DILS) and Sjögren Syndrome

DILS

Sjögren syndrome

Predominant infiltrating cell lineage

CD8+

CD4+

Class I alleles

HLA-B45, HLA-B49, HLA-B50

HLA-B8

Class II alleles

HLA-DR5, HLA-DR6

HLA-DR2, HLA-DR3

Autoantibodies

Negative antibodies

Anti-Ro/SSA and Anti-La/SSB

Extraglandular manifestations

Very common

Uncommon (one third of the patients)

Predominant population

Middle-aged African American men

Middle-aged women

Table 2. Differential Diagnosis of Parotid Gland Enlargement

Neoplasia Pleomorphic adenoma Adenolipoma (Warthin tumor) Acinic cell adenocarcinomaAutoimmune disorder Sjögren syndrome SarcoidosisDrug-related Propylthiouracil useViral infection Mumps sackie virus A infection Acute HIV infection syndrome Epstein-Barr virus infection Cytomegalovirus infection

Bacterial infection Pyogenic infection (such as with Staphylococcus aureus) Mycobacterium tuberculosis infectionHIV infection-related Diffuse infiltrative CD8+ lymphocytosis syndromeEndocrine disorder Acromegaly Gonadal hypofunctionMiscellaneous Amyloidosis

References

Fauci A. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996;124:654-663. Schattner A, Bentwich Z. Autoimmunity in human immunodeficiency virus infection. Clin Aspects Autoimmunol. 1993;5:19-27. Kazi S, Cohen PR, F, et al. The diffuse infiltrative lymphocytosis syndrome: clinical and immunogenetic features in 35 patients. AIDS. 1996;10: 385-391. FM, Cohen PR, Jumshyd J, Reveille JD. Prevalence of the diffuse infiltrative lymphocytosis syndrome among human immunodeficiency virus type-1 positive outpatients. Arthritis Rheum. 1998; 41:863-868. Gherardi R, Chretien F, Delfau-Larue M, et al. Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma. Neurology. 1998;50:1041-1044. Sancho JM, Ribera JM, Vaquero M, et al. Diffuse infiltrative CD8 lymphocytosis syndrome in a patient with HIV-1 infection. Med Clin (Barc). 2000;115:399. McArthur C, Subtil-DeOliveira A, Palmer D, et al. Characteristics of salivary diffuse infiltrative lymphocytosis syndrome in West Africa. Arch Pathol Lab Med. 2000;124:1773-1779. Lesprit P, Fornairon S, Michaut P, et al. Renal involvement in the diffuse infiltrative CD8 lymphocytosis syndrome. AIDS. 1997;11:262-263. Solal-Celigny P, Couderc LJ, Herman D, et al. Lymphoid interstitial pneumonitis in acquired immunodeficiency syndrome-related complex. Am Rev Respir Dis. 1985;131:956-960. Couderc LJ, D'Agay MF, Danon F, et al. Sicca complex and infection with human immunodeficiency virus. Arch Intern Med. 1987;147:898-901. Tunkel DE, Loury MC, Fox CH, et al. Bilateral parotid enlargement in HIV-seropositive patients. Laryngoscope. 1989;99:590-595. Itescu S, Brancato IJ, Winchester R. A sicca syndrome in HIV infection: association with HLA-DR5 and CD8 lymphocytosis. Lancet. 1989;2:466-468. Itescu S, Brancato IJ, Buxbaum J, et al. A diffuse infiltrative lymphocytosis syndrome in human immunodeficiency virus (HIV) infection: a host immune response associated with HLA-DR5. Ann Intern Med. 1994;112:3-10. Itescu S, Rose S, Dwyer E, Winchester R. Grouping HLA-B locus serologic specificities according to shared structural motifs suggests that different peptide-anchoring pockets may have contrasting influences on the course of HIV-1 infection. Hum Immunol. 1995;42:81-89. Reveille JD. The changing spectrum of rheumatic disease in human immunodeficiency virus infection. Semin Arthritis Rheum. 2000;30:147-166. Guillon JM, Fouret P, Mayaud C, et al. Extensive T8-positive lymphocytic visceral infiltration in a homosexual man. Am J Med. 1987;82:655-661. Gray C, Lawrence J, Schapiro J, et al. Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART). J Immunol. 1999;162:1780-1788. P, Cavenagh J, Milne T, et al. Benign monoclonal expansion of CD8+ lymphocytes in HIV infection. J Clin Pathol. 2000;53:177-181. Dwyer E, Itescu S, Winchester R. Characterization of the primary structure of T cell receptor beta chains in cells infiltrating the salivary gland in the sicca syndrome of HIV-1 infection: evidence of antigen-driven clonal selection suggested by restricted combinations of V beta J beta gene segment usage and shared somatically encoded amino acid res-idues. J Clin Invest. 1993;92:495-502. Itescu S, Dalton J, Zhang HZ, et al. Tissue infiltration in a CD8 lymphocytosis syndrome associated with human immunodeficiency virus-1 infection has the phenotypic appearance of antigenically driven response. J Clin Invest. 1993;91:2216-2225. Rosenberg Y, Cafaro A, Brennan T, et al. Characteristics of the CD8+ lymphocytosis during primary simian immunodeficiency virus infections. AIDS. 1997;11:959-968. Schrot R, Adelman H, Linden C, et al. Cystic parotid gland enlargement in HIV disease: the diffuse infiltrative lymphocytosis syndrome. JAMA. 1997;278:166-167. Itescu S, Winchester R. Diffuse infiltrative lymphocytosis syndrome: a disorder occurring in human immunodeficiency virus-1 infection that may present as a sicca syndrome. Rheum Dis Clin North Am. 1992;18:683-697. Price R. Neuropathy complicating diffuse infiltrative lymphocytosis. Lancet. 1998;352:592-594. Berger JR, Simpson DM. The pathogenesis of diffuse infiltrative lymphocytosis syndrome: an AIDS-related peripheral neuropathy. Neurology. 1998;50:855-857. Rosenberg Z, Joffe S, Itescu S. Spectrum of salivary gland disease in HIV-infected patients: characterization with Ga-67 citrate imaging. Radiology. 1992;184:761-764. Olive A, Salavert A, Manriquez M, et al. Parotid lipomatosis in HIV positive patients: a new clinical disorder associated with protease inhibitors. Ann Rheum Dis. 1998;57:749. Kooper DP, Leemans CR, Hulshof MC, et al. Management of benign lymphoepithelial lesions of the parotid gland in HIV-positive patients. Eur Arch Otorhinolaryngol. 1998;255:427-429. Beitler JJ, Vikram B, Silver CE, et al. Low-dose radiotherapy for multicystic benign lymphoepithelial lesions of the parotid gland in HIV-positive patients: long-term results. Head Neck. 1995;17:31-35. Gray CM, Schapiro JM, Winters MA, Merigan TC. Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience. AIDS Res Hum Retroviruses. 1998;14:561-564. Murali-Krishna K, Altman JD, Suresh M, et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity. 1998;8:177-187. Kovacs J, Deyton L, Davey R, et al. Combined zidovudine and interferon-alpha therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1989;111: 280-287. Bachmeyer C, Dhote R, Blanche P, et al. Diffuse infiltrative CD8 lymphocytosis syndrome with predominant neurologic manifestations in two HIV-infected patients responding to zidovudine. AIDS. 1995;9:1101-1102. Craven DE, Duncan RA, Stram JR, et al. Response of lymphoepithelial parotid cysts to antiretroviral treatment in HIV-infected adults. Ann Intern Med. 1998;128:455-459.

Editorial Comment: CD8+ Lymphocytosis and DILS -- A Tale of Split Personality

CD8+ lymphocyte responses in HIV infection are part of the initial reaction to viral infection because there is a progressive decline in the number of CD4+ lymphocytes. This response is an important mechanism of antiviral immunity that contributes in part to the control of viral load, and its persistence may bring beneficial factors to the host's fight against HIV infection. Dr Franco-Paredes and colleagues[1] review an interesting clinical problem in the group of disorders associated with dysregulation of the immune system in HIV infection, in which the persistence of CD8+ lymphocytosis crosses the line between host defense and a pathogenic immune response. The particularity of the diffuse infiltrative lymphocytosis syndrome (DILS), a disorder in which an increased number of CD8+ lymphocytes infiltrate glands, lungs, the peripheral nervous system, and other organs, is defined by several characteristics: a polyclonal expansion of T lymphocytes rather than a neoplastic reaction, an antigen-driven response that correlates with the viral load, an association with specific major histocompatibility complex (MHC) class II alleles, and a responsiveness to HAART.

The presence of a marked increase in the number of CD8+ lymphocytes that produce pathogenic effects in selected tissues of the HIV-infected host as seen in DILS raises several important issues about the various roles of CD8+ lymphocytes in the immune response to HIV infection. What are the factors that maintain a persistent CD8+ lymphocytosis? There are some partial answers to this question. There is an inverse relationship between the viral load and the number of specific CD8+ lymphocytes or cytotoxic T lymphocytes.[2] HIV-infected long-term nonprogressors maintain an active CD8+ lymphocyte response, and many patients with persistent CD8+ lymphocytosis have better control of viral replication and a relatively benign clinical evolution compared with other patients with low levels of CD8+ lymphocyte activity;[3] this finding is, perhaps, a good demonstration that CD8+ lymphocytes actively help control HIV infection and may protect patients against further development of HIV-related complications. What is more interesting is that both viral and host factors may be key determinants in the perpetuation of CD8+ lymphocyte responses during HIV infection.[4, 5]

But the question now is why in subsets of patients with CD8+ lymphocytosis does the reaction cross the line from protective to pathogenic? What are the mechanisms that modulate the pathologic infiltration by CD8+ lymphocytes into different tissues? Unfortunately, there are not too many answers to this question. Previous studies have shown that host genetic factors, such as certain MHC class II alleles, HLA-DR5 and HLA-DR6, are associated with persistent CD8+ lymphocyte activity and eventually with the presence of DILS. However, it is possible that other host and tissue factors, such as genotypic variation in chemokines and chemokine receptors, may be responsible for the abnormal stage of tissue lymphocyte infiltration. Subsets of chemokine receptors not only play roles as viral receptors but also determine such cellular immune responses as T-lymphocyte trafficking into tissues. This is still an unexplored issue in DILS. Is the abnormal trafficking of lymphocytes into tissues, such as glands, lungs, and peripheral nerves, associated with the magnitude of HIV infection of such tissues? Studies in cases of peripheral neuropathy associated with DILS have suggested that the magnitude of viral load is a contributing factor.[6] However, despite the pathogenic effect of CD8+ lymphocyte infiltration in different tissues, such as occurs in DILS, many patients with DILS appear to have less advanced stages of HIV disease.

So, can we take advantage of these T-lymphocyte reactions in HIV infection? New knowledge of the CD8+ lymphocyte biology in HIV infection has provided clues in the development of new therapeutic approaches. The potential use of anti-HIV vaccines that use CD8+ lymphocyte responses is now a promising area of research.[5, 7] The challenge would be to control the CD8+ lymphocyte reaction and avoid the complications seen in DILS. Finally, as is well described by Franco-Paredes and colleagues, the issue in the clinical management of this complication is to correctly identify patients with DILS and to establish the proper antiretroviral treatment before further complications, such as pneumonitis and peripheral neuropathy, develop.

A. Pardo, MDAssistant Professor of Neurology and PathologyHIV Neuroscience Groups Hopkins University School of Medicine, Baltimore

References

Franco-Paredes C, Rebolledo P, Folch E, et al. Diagnosis of diffuse CD8+ lymphocytosis syndrome in HIV-infected patients. AIDS Reader. 2002;12:408-413. Ogg GS, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science. 1998;279:2103-2106. Valdez H, Carlson NL, Post AB, et al. HIV long-term non-progressors maintain brisk CD8 T cell responses to other viral antigens. AIDS. 2002;16:1113-1118. Currier JR, deSouza M, Chanbancherd P, et al. Comprehensive screening for human immunodeficiency virus type 1 subtype-specific CD8 cytotoxic T lymphocytes and definition of degenerate epitopes restricted by HLA-A0207 and -C(W)0304 alleles. J Virol. 2002;76:4971-4986. Appay V, Papagno L, Spina CA, et al. Dynamics of T cell responses in HIV infection. J Immunol. 2002;168:3660-3666. Gherardi RK, Chretien F, Delfau-Larue MH, et al. Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma. Neurology. 1998;50:1041-1044. HL. New hope for an AIDS vaccine. Nat Rev Immunol. 2002;2:239-250.

Funding Information

This work was supported in part by an NIH/AIDS International Training and Research Program of Emory University (D43 TW01042-01) (CFP, EF, IH, PR).

Dr Franco-Paredes is chief medical resident and infectious disease fellow; Drs Rebolledo, Folch, and are part of the AIDS Training and Research Program; and Dr del Rio is chief of the medical service in the department of medicine, division of infectious diseases, Emory University School of Medicine, Atlanta.