Is human herpesvirus 6 linked to Kikuchi-Fujimoto disease? The importance of consistent molecular and serologic analysis. (Original Article).

Background: Kikuchi-Fujimoto disease, also called histiocytic necrotizing lymphadenitis, is a self-limiting lymphadenopathy of unknown cause. The patient often presents with fever, malaise, and lymphadenopathy primarily involving the cervical lymph nodes. Laboratory findings are nonspecific, and the diagnosis is established by identifying characteristic pathologic features from lymph node biopsy. The etiologic agent has been proposed to be of viral origin; specifically, human herpesvirus 6 (HHV-6) has been implicated.

Methods: The clinical, histologic, serologic, and molecular data from 471 cases of Kikuchi-Fujimoto disease reported between 1982 and 2001 and their relationship to HHV-6 were reviewed.

Results: Thirty-two of the 471 patients in this review were tested for HHV-6 serology; all 32 had elevated titers for HHV-6. One hundred twelve patients with lymphadenopathies, including histiocytic necrotizing lymphadenitis, tested positive for HHV-6 by polymerase chain reaction. In situ hybridization results were positive in 41 cases.

Conclusion: This review illustrates the necessity for consistent molecular and serologic analysis.

**********

Kikuchi-Fujimoto disease (KFD) was independently described in 1972 by Japanese pathologists Kikuchi (1) and Fujimoto et al. (2) Since then, it has been reported worldwide with increasing frequency. (3-7) Kikuchi-Fujimoto disease, also termed histiocytic necrotizing lymphadenitis (HNL), is a self-limiting lymphadenopathy of uncertain orgin, (3,4,8) although recent collected data presuppose the existence of viral denVation. (7,9-12) Our intent was to examine the possible viral relationship between human herpesvirus 6 (HHV-6) and HNL, and we present three cases depicting such a relationship. Histiocytic necrotizing lymphadenitis is seen predominantly in young women. Patients present with cervical lymphadenopathy in association with fever or flu-like symptoms, malaise, elevated erythrocyte sedimentation rate (ESR), neutropenia, and lymphocytosis with reactive lymphocytes, suggesting a viral origin of the condition. (3,9,13) Laboratory tests are often nonspecific, and the diagnosis of KED is established by identif ying characteristic histologic features in the lymph node. (5,9,14,15) No sequelne have been reported, antimicrobial therapy is not required, and the patient's condition resolves spontaneously within 1 to 4 months. (3,4,7) Although uncommon, relapse of HNL has been described, (2,5,16) and we present our own illustrative cases. Relapse may be because of viral latency. (17-21) We present a review of the serologic and molecular results that could link HHV-6 to the development of KFD.

Patients and Methods

Patient 1

A 33-year-old Hispanic woman presented with a 3-week history of a solitary lymph node mass in the anterior cervical lymph node chain, associated with fever, fatigue, and anorexia. On examination, she had a temperature of 37.8[degrees]C and a solitary, nonmatted lymph node in the left anterior cervical chain. Physical examination was otherwise unremarkable. All laboratory studies, including leukocyte count (7.9 X [10.sup.9]/L) and tests for antinuclear antibodies, Brucella and Toxoplasma organisms, and human cytomegalovirus (CMV), were normal. An elevated ESR (21 mm/h) and positive HHV-6 serology were reported. Elevated titers of anti-HHV-6 immunoglobulin (IG) M (1:40) and anti-HHV-6 IgG (1:320) were detected by indirect immunofluorescence (Specialty Laboratories, Santa Monica, CA). The lymph node biopsy specimen had characteristics consistent with HNL, lacking polymorphonuclear cells. The patient recovered without complications and was symptom-free for 6 years, until she presented again with a solitary lymph node in the anterior cervical chain that, on biopsy, was again consistent with KFD. No therapy was given, and on follow-up she had complete resolution of her symptoms.

Patient 2

A 43-year-old Asian woman presented with several weeks' history of low-grade fever, night sweats, headaches, and pain in the suprapubic area. Physical examination revealed a temperature of 38.6[degrees]C, with generalized lymphadenopathy in the cervical chain, axillae, and groin. The lymph nodes were nontender and nonmatted. Laboratory evaluations for lupus (antinuclear antibodies), Brucella and Toxoplasma organisms, and human CMV serologies (immunfluorescence and latex agglutination, respectively) were all negative. A leukocyte count of 8.9 X 1 [10.sup.9]/L and an increased ESR (23 mm/h) were noted. Bone marrow aspiration and biopsy were negative for malignancy and infection. Serology for HHV-6 revealed positive titers for anti-HHV-6 IgM (1:40) and anti-HHV-6 IgG (1:160; Specialty Laboratories). Cervical lymph node biopsy was consistent with HNL (Fig. 1). Because of persistent high fever, the patient was treated with low-dose steroids, which resulted in a good clinical response. Follow-up 1 year later revea led no evidence of recurrent lymphadenopathy.

Patient 3

A 53-year-old woman with a history of non-insulin-dependent diabetes mellitus presented with a 4-week history of a large lymph node in the left cervical chain, associated with low-grade fevers and night sweats. Physical examination revealed a temperature of 37.8[degrees]C, with a single, nonmatted lymph node in the posterior cervical chain. A leukocyte count of 5.6 X [10.sup.9]/L was reported, along with an ESR of 23 mm/h. Cervical lymph node biopsy was consistent with HNL. Serologic results were negative, with the exception of positive titers for anti-HiHV-6 IgM (1:40) and anti-HHV-6 IgG (1:320) (Specialty Laboratories). Adenopathy and fever resolved over a period of 6 months. One year later, she presented with a large submandibular lymph node which, on biopsy examination, was shown to be consistent not with KFD but with nonspecific adenitis. She was managed conservatively without any residual sequelae.

Methods

The clinical, histologic, serologic, and molecular data from 471 cases of KFD reported between 1982 and 2001 and their relationship to HHV-6 were reviewed.

Results

Our Cases

The three patients we describe were women with a mean age of 43 years. All three patients presented with fever and enlarged cervical lymph nodes. Laboratory values were nonspecific, except for increased ESR and positive HHV-6 serology. Elevated titers for anti-HHV-6 IgM and anti-HHV-6 IgG were found in all three patients (Table 1). Serology was performed by indirect immunofluorescence. Detection of active HHV-6 can be made by IgM antibody detection of the early antigen of HHV-6, or by seroconversion or a sudden increase in HHV-6 -specific IgG. Reference ranges for HHV-6 performed by Specialty Laboratories were as follows: not detected, <1:10; indeterminate, 1:10 to 1:20; and positive, >1:20. Lymph node biopsy results were consistent with HNL (Fig. 1). All three patients recovered without complications; however, one patient later relapsed. The clinical outcome was benign for all three patients.

Literature Review

Clinical Features. Literature review was conducted on the basis of clinical cases of KFD correlating with molecular and/or serologic diagnosis of HHV-6 infection. Between 1982 and 2001, there were 471 documented cases of KFD, including our own three. The age distribution among those patients ranged from 10 to 53 years (mean, 31 years). Three hundred thirty-one (70%) of the patients were female patients and 140 (30%) were male patients, with a female-to-male ratio of 2.4:1. Sixty percent of the reported adenopathies were localized in the neck, primarily in the cervical area (Table 2). (3-9, 13, 15, 22-40) Affected lymph nodes were of moderate size, usually <3 cm. Fifty percent of the patients presented with fever of unknown origin (37.4[degrees]-40[degrees]C). Laboratory values were nonspecific, with the most common manifestations being elevated ESR, leukopenia (1.2-3.8 X [10.sup.9]/L), and lymphocytosis with reactive lymphocytes. The clinical outcome appeared to be benign, although a minority of patients had a recurrence (including the patient in our own illustrative case). The clinical features of HNL are summarized in Table 3.

Histology

The most common histologic findings included necrotic foci, typically confined to the paracortex, with abundant karyorrhectic nuclear debris. The paracortex adjacent to the karyorrhectic foci was often found to be hyperplastic. A population of cells consisting of histiocytes, immunoblasts (predominantly of T-cell origin), and reactive lymphocytes was found within and around the necrotic area, with interspersed apoptotic bodies. It was also noted that, when necrosis was overt, eosinophilic fibrinoid material was present. A characteristic feature of the lesion is the absence of plasma cells and polymorphonuclear leukocytes. The degree of necrosis within individual nodes can vary greatly, and histologic features may be confused with those of malignant lymphoma. The histologic features associated with HNL are summarized in Table 4.

Serologic and Molecular Association with HHV-6

Elevated titers of IgM and/or IgG were documented for 42 cases of HNL, 11 of which, including our own, showed elevated titers for both anti-HHV-6 IgM and anti-HHV-6 IgG (Table 5). One hundred twelve patients with reactive lymphadenitis, including HNL, had positive serology for HHV-6 by polymerase chain reaction (PCR). Forty-one patients had positive results by in situ hybridization (Table 6).

Discussion

Kikuchi-Fujimoto disease, or HLN, typically presents with the acute onset of fever, myalgia, and generalized lymph-adenopathy. The lymph nodes are usually tender and involve the cervical area. In our review, patient age varied widely, from 10 to 53 years (mean age, 31 yr). (3,14,36) Female patients are slightly more likely to test positive for HHV than male patients, and spontaneous resolution of the adenopathy within months and without sequelae is the rule. Fever occurred in more than 50% of the patients, and an upper respiratory prodrome was occasionally present. (7,13,29,33) Other clinical features less commonly seen included weight loss, rash, nausea, vomiting, night sweats, and hepatomegaly. (4,33) Laboratory test results may be normal or nonspecific. Elevated ESR was reported in 70% of the patients. (8,14,25) Leukopenia, with a white blood cell count less than 4,000 X [10.sup.9]/L, was observed in 40% of patients. (13,25) Lymphocytosis (absolute or relative values not specified) with reactive lymphocyt es was documented in half of the patients. Elevated lactate dehydrogenase and the transaminase levels were reported in some patients. (26) Serologic studies varied for a wide variety of conditions, including influenza, Q fever, adenovirus infection, and infection by Mycoplasma organisms. Positive serologic results for Epstein-Barr virus and human CMV have not been common. Elevated titers for toxoplasmosis and Yersinia enterocolitica were occasionally reported but were not consistently demonstrated. (7,10,51)

Association with HHV-6

Antibody to HHV-6 is typically found in titers of 1:160 and greater in patients with acquired immunodeficiency syndrome, chronic fatigue syndrome, exanthem subitum, and some lymphoproliferative disorders. Previous serologic studies and tissue-based investigations implicate HHV-6 as a possible etiologic agent of KFD. (31,41,50) Kruger et al (40) demonstrated an HHV-6 infection rate of 87.5% in KFD cases and pointed out that patients with KFD tend to be infected only by HIHV-6. (31) All of these studies provide evidence of HHV-6 infection in patients with cervical and mesenteric lymphadenitis, including HNL and lymphoproliferative lesions. (37,41,46,47,49) In our three illustrative cases, we have documented positive seroconversion for HHV-6, with titers of 1:160 and greater, and presuppose HHV-6 to play a role as the contributory agent for HNL. Despite this evidence, a supportive or causative role for HHV-6 in HNL remains unclear. Direct identification of HHV-6 in blood cells, tissues, or body fluids is the mo st reliable method for diagnosis of postprimary HHV-6 infection. DNA hybridization and PCR are useful, although they do not indicate whether the virus is active. Recently, in an effort to elucidate the possible association of HHV-6 with HNL and/or lymphoproliferative disorders, a number of studies have used molecular techniques, which are more sensitive and specific. (35,48,50,52,53) Results from these studies remain controversial. The majority of these investigations fail to support a specific role for HHV-6 in the pathogenesis of HNL and/or lymphoproliferative disorders, whereas others provide evidence of a link between well-defined lymphoproliferative lesions and HHV-6. (35,52)

In this review, we note that several studies were performed on formalin-fixed (archival) specimens. It is important to point out that selection of tissue specimens is crucial when using molecular techniques, because autolyzed or inadequately fixed tissues may lead to degraded or low molecular DNA. The amount of DNA recovered decreases with increased fixation time, and DNA cannot be recovered from fixatives containing picric acid (eg, Bouin's) or mercuric chloride (eg, Zenker's and B5). (42,54) In addition, fixation time varies from a few hours to 5 days, depending on the pathology laboratory. Furthermore, detection of HHV-6 genomes depends on the type of amplification method used and the amount and source of sample. The HHV-6 genome has been detected in HNL and different lymphoproliferative disorders by the PCR and in situ hybridization techniques; however, Southern blot analysis often fails to detect the virus, probably because of the low number of viruses in the samples. (42,45,50,55) One concern about mol ecular methodology is the lack of standardization. Polymerase chain reaction is an extremely sensitive technique, in which even minute changes in the reagents and/or temperature may dramatically affect the efficiency of the technique. For example, in these studies, different primers were used and the parameters of PCR protocol varied greatly. In instances where equivalent methodology was used, conflicting results were obtained. (35,45,53) One important factor to consider in KFD is the significant amount of necrotic tissue present in lesions, which could lead to inaccurate results. It is also important to point out that, even though HHV-6 is divergent from HHV-7, there is substantial homology between these two viruses. A caveat of molecular diagnosis for HHV-7, as stated by Berneman et al, (43) is the potential presence of both HHV-6 and HHV-7 when these viruses are propagated in peripheral blood mononuclear cells.

In our review of the literature, it was determined that results of PCR or in situ hybridization tests for HHV-6 were positive for 70% (112 of 158) of the lymphadenitis and KFD patients tested by molecular methods. Considering the problems associated with current molecular approaches and the potential for false-positive and false-negative results, it appears that 70% of the cases that tested positive for HHV-6 cannot be discounted as clinically insignificant. Notwithstanding this consideration, it is difficult to assess the role of HHV-6 in HNL.

It has been determined that there are two variants of HHV-6, variant A (U1102) and variant B (Z29), which have been recognized as distinct species. (44,45,56,57) The epidemiology of these two HHV-6 variants in the normal population is still unclear, and their association to disease (with the exception of exanthem subitum) is still very controversial. It is interesting to note that although Di Luca et al (58) reported a 75% prevalence of HHV-6B and only a 25% prevalence of HHV-6A in a normal population, in this review we found that all of the cases testing positive by molecular methods appear to be related to HHV-6A, on the basis of the probes and cell lines used (Table 6). Because the majority of the authors do not state whether their results relate to HHV-6A, HHV-6B, or both viruses, an accurate interpretation of the literature is complex and problematic. To add to the caveat, many of the antisera and DNA probes (pZVH14) that were initially used for the detection of HHV-6 were later found to cross-react wit h HHV-7 (G. Krueger, personal communication); thus, early HHV-6 data need to be evaluated with care.

Serologic analysis of HHV-6 was performed in 42 of 471 cases, including our own. All 42 cases had positive serologic results; however, only 11 tests were conclusive for HHV-6 (positive for IgM and IgG) association with HNL. Although DNA homologies between HHV-6 and other herpesviruses have been described, cross-reactions do not occur, thus decreasing the possibility of serologic false-positive results. (47,59) It is important to highlight that only those cases in which tests for both anti-HHV-6 IgM and anti-HHV-6 IgG were positive demonstrated an association with HNL (Table 5). This is only 2% (11 of 471) of all of the cases reviewed. Because of this association, we suggest that further serologic studies include both anti-HFIV-6 IgM and anti-HV-6 IgG so that association can be verified. Although these serologic results are not considered a standard, they are suggestive of a recent or past infection with HHV-6. It is important to keep in mind, however, that IgM serology is frequently negative in reactivated in fections, and in these cases other tests, such as antigencapture enzyme-linked immunosorbent assay and nested PCR, will add value to the diagnosis of HHV-6 infection. (60) More than 90% of the population is seropositive by age 5 years for HHV-6. Clinical serologic determination of HHV-6 does not differentiate between the two strains. Investigations have shown that these variants are approximately 88% identical at the nucleotide level and are differently distributed in the healthy population, with HHV-6B emerging as the predominant strain. Taking into account the high seroprevalence of HHV-6, it is possible that the etiologic agent of HNL is not HHV-6, and that the true etiologic agent for HNL merely acts as a catalyst for HHV-6, or vice versa. The challenge that remains is to ascertain if indeed HiHV-6 infection is responsible for producing the clinical syndrome of KFD, because it cannot be discounted.

Histopathology 

The histopathology of HNL appears to suggest a viral cause (lymphocytosis and neutropenia). Using electron microscopy, Imamura et al (11) detected tubuloreticular structures in activated lymphocytes and vascular endothelial cells in affected foci. These structures are thought to be associated with the production of interferon-alfa, again suggesting a viral cause. Furthermore, the activity of the enzyme 2',5'-oli goadenylate synthetase, which is induced by interferon-alfa, has been found to be elevated in the acute stage of HNL and decreased to normal levels in the convalescent stage. (59) All of these results suggest the possibility of a viral cause.

The obliteration of the normal lymph node structure and the increased number of polymorphous cells observed in KFD may be mistaken for malignant lymphoma. The histologic differential diagnosis includes infectious mononucleosis, infection by Yersinia organisms, cat-scratch disease, toxoplasmosis, early human immunodeficiency virus infection, and systemic lupus erythematosus (SLE) lymphadenitis.

The lack of polymorphonuclear leukocytes or granulomas distinguishes KFD from most types of infectious lymphadenitis. Systemic lupus erythematosus lymphadenitis appears to be very similar to HNL; however, numerous plasma cells and characteristic clinical features distinguish SLE from HNL. (5,14,38,59)

Conclusion

Kikuchi-Fujimoto disease is an uncommon disease process, in which patients present with fever, malaise, and non-specific lymphadenopathy. The diagnosis is made by identifying characteristic pathologic features from lymph node biopsy. The precise etiologic agent for KFD is still unknown, and the search for it must be very carefully controlled and executed. The association between HHV-6 and KED is intriguing. Further research, including both serologic studies (IgG) and molecular techniques, might elucidate the role of HiHV-6 in this disease.

Table 1

Reported cases of human herpes virus 6 serology (a)

                    Reciprocal  Reciprocal
Patient             titer IgM   titer IgG

General population     <40         <80
Case 1                  40         320
Case 2                  40         160
Case 3                  40         320

(a)IgM, immunoglobulin M; IgG. immunoglobulin G.

Table 2

Summary of reported Kikuchi's disease cases from 1982 to 2001 (a)

                              No.            Mean
                              of              Age
Series (ref. no.)            Cases    F/M    (yr)   Adenopathy Site

Piled et at, 1982 (4)         27     20/7     27    15 cervical
                                                    7 axillary
                                                    4 supraclavicular
                                                    1 other
Turner et al, 1983 (7)        30     27/3     28    28 cervical
                                                    4 axillary
                                                    2 supraclavicular
Evans et al, 1985 (22)         3      3/0     36    3 cervical
Gteeson et al, 1985 (23)       1      1/0     20    1 cervical
Chan and Saw, 1986 (24)        9      4/5     23    7 cervical
                                                    2 generalized
Rivano et al, 1987 (25)        8      8/0     28    7 cervical
Unger et at, 1987 (26)         4      3/1     28    3 cervical
                                                    1 parotid
                                                    supraclavicular
Ohta et al, 1988 (27)          3      2/1           3 cervical
                                                    1 axillar
                                                    1 inguinal
Dorfman and Berry, l988 (3)   108    85/23    30    Cervical, majority
Chan et al, 1989 (23)          1      0/1     38    Generalized
Kapadia et al, l989 (9)        1      1/0     40    Supraclavicular
Pearl and Strauchen,           1      0/1     45    Mediastinal
1989 (29)
Chamulak et al, 1990 (30)     10      8/2     30    7 cervical
                                                    3 supractavicular
                                                    3 other
Hoyt et al, l990 (33)          1      1/0     46    1 cervical
Kutty et al, l99l (31)         5      3/2     30    1 cervical
                                                    1 mandibular
                                                    3 supraclavicular
Dylewski et al, 1991 (32)      1      1/0     35    1 cervical
Piccirillo et at, 1991 (8)     2      2/0     26    1 cervical
                                                    supraclavicular
Litwin et al, l992 (34)        1      0/1     19    1 cervical
Sumiyoshi et al, l993 (35)    27     16/11    24    20 cervical
Garcia et al, 1993 (36)        1      1/0     21    1 supraclavicular
Tsang et al, 1994 (15)        75     55/20    26    68 cervical
                                                    2 submandibular
                                                    2 intra-abdominal
                                                    1 supraclavicular
                                                    1 axillary
                                                    1 laguinal
Hollingsworth et al,          20     17/3     27    14 cervical
l994 (37)                                           2 axillary
                                                    1 supraclavicular
                                                    1 submental
                                                    2 not specified
Kuo, l995 (5)                 79     41/38    27    Cervical,
                                                    almost all
Norris et al, l996 (13)        6      2/4     43    4 cervical
                                                    2 axillary
                                                    supraclavicular
Nikanne et al, 1997 (6)        3      3/0     28    1 supraclavicular
                                                    1 cervical
                                                    1 submandibular
Al Salloum, 1998 (38)          1      0/1     10    1 cervical
Huh et al, l998 (39)          26     16/10    27    24 cervical
Krueger et al, 2001 (40)      14      8/6    16-43
Dominguez et al, 2003          3      3/0     43    2 axilla
(present study)                                     2 cervical
                                                    1 generalized
Totals                        471   331/140

(a)Aggregate female-to-male patient ratio 2.36:1; aggregated mean
patient age, 31 yr.

Table 3

Clinical features of Kikuchi-Fujimoto disease


Acute Onset
Female predominance
Median age 30.7 years
Lymphadenopathy with cervical predominance
Fever (>37.4[degrees]C)
Myalgia
Elevated erythrocyte sedimentation rate
Leukopenia
Benign and self-limiting
Rare recurrence

Data derived from Dorfman and Berry, 1988 (2); Pileri et al, 1982 (4);
Turner et al, 1983 (7); Piccirillo et al, 1991 (8); Norris et al, 1996
(13); Recco, 1998 (14); Garcia et al, 1993 (36); Pearl and Strauchen,
1989 (29); and Hoyt and Fisher, 1990. (33)

Table 4

Histologic features associated with histiocytic necrotizing
lymphadenitis


Predominantly intact lymph node capsule
Paracortical foci of necrosis
  Abundant karyorrhectic nuclear debris
  Aggregates of large lymphoid cells
  Hyperplasia with "starry sky" pattern
  Plasmacytoid monocyte clusters
Well circumscribed and surrounded by
   zone of immunoblasts and macrophages
  Macrophage with distinct C-shaped nuclei
   (crescentic histiocytes)
  Foamy histiocytes
Scant polymorphonuclear leukocytes and plasma cells
Presence of eosinophilic fibrinoid material
Necrotic zone demonstrates preponderance of CD8 T cells
Xanthoma in late lesions

Data derived from Kikuchi, 1972 (1); Fujimoto et al, 1972 (2), Pileri et
al, 1982 (4); Nikanne et al, 1997 (6); Piccirillo et al, 1991 (8);
Feller et al, 1983 (10); Luppi et al, 1998 (18); Niederman et al, 1988
(41); Sumiyoshi et al, 1993 (42); Berneman et al, 1992 (43);
Campadelli-Fuiume et al, 1999 (44); and Secchiero et al, 1995. (45)

Table 5

Human herpes virus 6 serology in histiocytic necrotizing lymphadenitis
and lymphoproliferative disorders (a)


                             No. of
Series (ref. no.)           patients         Clinical Diagnosis

Kirchesch et al, 1988 (46)     1      Mononucleosis-like disease
Niederman et al, 1988 (41)     3      Lymphadenopathy


Borisch, l989 (49)                    Reactive, virally induced lesion
Borisch et al, 1991 (48)       3      Viral-induced lymphadenopathy or
                                       high-grade B-cell lymphoma
                                      High-grade B-cell lymphoma
Rodriguez et al, 1996 (47)     1      HNL

Krueger et al, 2001 (40)      14      HNL

Dominguez et al, 2003          3      NL
 (present study)



                                             Reciprocal titer

Series (ref. no.)           Site                  IgM

Kirchesch et al, 1988 (46)  Cervical          1,024-1,064
Niederman et al, 1988 (41)  Cervical               10
                            Cervical               <2
                            Cervical               10
Borisch, l989 (49)          Mesenteric      32-128 (IgM/IgG)
Borisch et al, 1991 (48)    Cervical          64 (IgM/IgG)

                            Cervical          32 (IgM/IgG)
Rodriguez et al, 1996 (47)  All palpable           20
                            sites
Krueger et al, 2001 (40)

Dominguez et al, 2003       Cervical               40
 (present study)            Cervical,              40
                            axillae, groin
                            Cervical               40

                             Reciprocal
                                titer

Series (ref. no.)               IgG

Kirchesch et al, 1988 (46)  2,048-4,096
Niederman et al, 1988 (41)     2,560
                                160
                                160
Borisch, l989 (49)
Borisch et al, 1991 (48)


Rodriguez et al, 1996 (47)      80

Krueger et al, 2001 (40)        160
                               1,280
Dominguez et al, 2003           320
 (present study)                160

                                320

(a)Serology studied by immunofluorescence. Eleven cases were positive
for both IgM/IgG, and 14 cases involved IgG only. IgM, immunoglobulin M;
IgG, immunoglobulin G; HNL, histiocytic necrotizing lymphadenitis.

Table 6

Human herpes virus 6 genomes in histiocytic necrotizing lymphadenitis
and lymphoproliferative disorders (a)


                                 No. of
Series (ref. no.)               patients        Clinical diagnosis

Borisch et al, 1991 (48)            5     Lymph node swelling
 (cord blood cells)
Sumiyoshi et al, 1993 (35)        140     Hodgkin's (14)
 (cord blood cells)                       B-cell lymphoma (29)
                                          T-cell lymphoma (41)
                                          Lymphadenitis (56)
Sumiyoshi et al, 1993 (42)         56     HNL (27)
 (cord blood cells)                       Nonspecific lymphadenitis (10)
                                          Tuberculous lymphadenitis (9)
                                          Reactive paracortical
                                           hyperplasia (10)
Hollingsworth et al, 1994 (37)     20     HNL




Hallas et al, 1996 (50)           243     Non-Hodgkin's (113)
 (HSB-2 cell line)                        Hodgkin's (23)
                                          Lymphadenitis (42)
                                          Other (65)
Krueger et al, 2001 (40)           14     HNL (KFD) (14)

                                                         HHV-6
                                                       Detection
                                                        Method

Series (ref. no.)                      Site              PCR

Borisch et al, 1991 (48)        Cervical (4)         4+ (U1102)
 (cord blood cells)             Abdominal (1)
Sumiyoshi et al, 1993 (35)                            9+ (U1102
 (cord blood cells)                                      18+
                                                         24+
                                                         55+
Sumiyoshi et al, 1993 (42)                           IN (U1102)
 (cord blood cells)                                      IN
                                                         IN
                                                         IN

Hollingsworth et al, 1994 (37)  Cervical (14)        0 (pZVH14)
                                Axillary (2)
                                Submental (1)
                                Supraclavicular (1)
                                Nonspecified (2)
Hallas et al, 1996 (50)                              44+ (U1102)
 (HSB-2 cell line)                                       12+
                                                         27+
                                                         26+
Krueger et al, 2001 (40)

                                 HHV-6 Detection Method

                                              Southern
Series (ref. no.)                   ISH         blot

Borisch et al, 1991 (48)        5+ (pZVH14)      NP
 (cord blood cells)
Sumiyoshi et al, 1993 (35)           NP          0
 (cord blood cells)                  NP          0
                                     NP          0
                                     NP          0
Sumiyoshi et al, 1993 (42)          10+          0
 (cord blood cells)                  6+
                                     2+
                                     6+

Hollingsworth et al, 1994 (37)       0           NP




Hallas et al, 1996 (50)              NP          NP
 (HSB-2 cell line)                   NP          NP
                                     NP          NP

Krueger et al, 2001 (40)        12+ (pZVH14)

(a)PCR, polymerase chain reaction; ISH, in situ hybridization; IN,
indeterminate; NP, not performed; KFD, Kikuchi-Fujimoto disease.

Accepted December 14, 2001.

References

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(4.) Pileri S, Kikuchi M, Helbron D, Lennert K. Histiocytic necrotizing lymphadenitis without granulocytic infiltration. Virchows Arch A Pathol Anat Histol 1982;395:257-271.

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RELATED ARTICLE: Key Points

* Human herpesvirus 6 tends to be consistently associated with Kikuchi-Fujimoto disease (KFD).

* KFD is an uncommon lymphadenopathy of unknown cause.

* Both molecular and immunologic studies should be used to determine the association of human herpesvirus 6 and KFD.

From the Clinical Laboratory Science Program, University of Texas at El Paso, and U.S. Oncology, El Paso, TX.

Reprint requests to Delfina C. Dominguez, PhD, College of Health Sciences, University of Texas at El Paso, 1101 N. Campbell, El Paso, TX 79902. Email: [e-mail]

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