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Human herpesvirus 8 and Kaposi's sarcoma in the Amsterdam cohort studies.
Disease association, transmission and natural history
Renwick, N.M.
Publication date
2001
Link to publication
Citation for published version (APA):
Renwick, N. M. (2001). Human herpesvirus 8 and Kaposi's sarcoma in the Amsterdam cohort
studies. Disease association, transmission and natural history.
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Clinicall symptoms related to primary
humann herpesvirus 8 infection in homosexual
menn with or at risk for HIV-1 infection
NeilNeil Renwick, Nicole H. Dukers, Peter Reiss, Gerritjan Weverling,
ThomasThomas F. Schulp Koel A. Coutinho, jaap Goudsmit
Abstract t
Thee incidence of H H V 8 infection is high among homosexual men, however data on clinical symptoms associated with pri-maryy H H V 8 infection are scarce due to the limited number of prospective studies including clinical documentation. We have previouslyy identified 215 homosexual men with primary H H V 8 infection between 1984 and 1996 and recorded clinical symp-tomss during each quarterly or half yearly visit. Seroconversion rates of HHV8 showed no seasonal distribution. Incidence ratess of symptoms during HHV8 seroconversion were compared with rates before and after seroconversion; sore throat, coughh and muscle ache were elevated during HHV8 seroconversion in HIV-1 uninfected participants. Our findings indicate thatt primary HHV8 infection produces a flu-like illness in HIV-1 uninfected adults, consistent with HHV8 being a respiratory infection.. N o symptoms associated with primary HHV8 infection were detected in HIV-1 infected individuals, possibly due too high background symptomatology.
Introduction n
H u m a nn H e r p e s v i r u s 8 ( H H V 8 ) , also k n o w n as K a p o s i ' s sar-c o m a - a s s o sar-c i a t e dd h e r p e s v i r u s ( K S H V ) , is a rhadinovirus that iss phylogenetically related t o R h e s u s Rhadinovirus (RRV), H e r p e s v i r u ss Saimiri (HVS) a n d m u r i n e herpesvirus 68 ( M H V 6 8 )) ( l ) . T h e closest relative o f H H V 8 to infect hu-m a n ss is E p s t e i n - B a r r virus ( E B V ) , a l y hu-m p h o c r v p t o v i r u s t h a tt is associated w i t h Burkitt's l y m p h o m a , H o d g k i n ' s D i s -ease,, n a s o p h a r y n g e a l c a r c i n o m a and several l y m p h o p r o l i f e r a t i v ee diseases (2). Persistent H H V 8 infec-tionn p r o d u c e s a similar pathological repertoire, namely K a p o s i ' ss s a r c o m a , P r i m a r y Effusion L y m p h o m a and C a s t l e m a n ' ss D i s e a s e (3).
Clinicall s y n d r o m e s h a v e b e e n r e p o r t e d to a p p e a r in the m o n t h ss following p r i m a r y H H V 8 infection in i m m u n o c o m p r o m i s e dd individuals; an H I V 1 infected h o -m o s e x u a ll -m a n d e v e l o p e d fever, arthralgia, cervical l y m p h a d e n o p a t h y ,, s p l e n o m e g a l y and pancytopenia and a t r a n s p l a n tt recipient, w h o s e kidney was harvested from a n H H V 88 seropositive cadaveric d o n o r , d e v e l o p e d fever, s p l e n o m e g a l y ,, p a n c y t o p e n i a a n d m a r r o w failure (4,5).
T oo date, there has been a single prospective case study on thee clinical s y m p t o m s associated with primary H H V 8 infec-tionn in five i m m u n o c o m p e t e n t individuals (6). In this study, primaryy infection p r o d u c e d transient cervical and submentall l y m p h a d e n o p a t h y , fatigue, diarrhea and rash lo-calizedd to either the face o r the ankle. T h e s e s y m p t o m s , in conjunctionn with an increase in s e r u m H H V 8 antibody titer, appearancee o f H H V 8 D N A in b l o o d m o n o n u c l e a r cells and a n t i - H H V 88 C D 8+ T-cell r e s p o n s e s indicate that primary
H H V 88 infection has distinct clinical, virological and i m m u -nologicall c o m p o n e n t s .
W ee have previously identified 215 h o m o s e x u a l m e n w h o seroconvertedd for H H V 8 d u r i n g their participation in the Amsterdamm C o h o r t Studies (1984-1996) and d e m o n s t r a t e d thatt the majority of these s e r o c o n v e r s i o n events w e r e pri-maryy H H V 8 infections (7,8). H e r e we describe the symp-tomss associated with primary' H H V 8 infection in these HIV-11 infected and uninfected h o m o s e x u a l m e n .
Methods s
Participantss and study design
Twoo hundred and fifteen HIV-1 infected and uninfected homosexuall men seroconverted for HHV8 during their participationn in the Amsterdam Cohort Studies on HIV-1 infectionn and AIDS (1984-1996) (7,8). HIV-1 seropositive andd HIV-1 seronegative participants returned for follow-up att 3 and 6 monthly intervals respectively. At each visit, trainedd nurses collected blood samples and administered a standardisedd questionnaire on symptoms experienced since thee previous visit.The following symptoms were investi-gated;; muscle ache, sore throat, cough, fever (<38°C), diar-rhoea,, headache, fatigue, lymph node swelling and rash. Dataa on symptoms were available for 195 (90.7%) and un-availablee for 13 (6.0%) homosexual men. An additional sevenn (3.3%) participants were excluded from the analysis becausee the seroconversion interval was longer than 1 year. Antibodiess to HHV8 lytic phase capsid (ORF65) and/or la-tentt phase nuclear (ORF73) antigens were detected using an Enzymee Immunoassay (EIA) system (7,8). HIV-1 antibod-iess were detected using one of two commercially available assaysassays (Abbott Laboratories, North Chicago, Illinois; Vironostika,, Organon Teknika, The Netherlands) and posi-tivee results were confirmed by Western blot analyses. Seroconversionn for HIV-1 and HHV8 was defined as a changee from a seronegative to a seropositive result in a se-riall collection of serum samples. The seroconversion inter-vall was defined as the period from the last seronegative visit too the first seropositive visit with the midpoint being re-gardedd as the moment of seroconversion. The mean length
off the seroconversion interval was 0.75 year (standard devi-ationn (sd): 0.29) for HIV-1 seronegative participants and 0.555 year (sd: 0.63) for HIV-1 seropositive individuals.
Statisticall methods
Symptomm incidence rates during the HHV8 seroconversion intervall were calculated using data at the first HHV8 sero-positivee visit and at the last HHV8 seronegative visit, as symptomss may be experienced prior to the detection of HHV88 antibodies; we have previously shown that the mo-lecularr incubation period between viral DNAemia and the detectionn of HHV8 antibodies was rarely longer than three monthss (8).
Incidencee rates in the HHV8 seroconversion interval were comparedd with those during the biannual interval prior to thee last HHV8 seronegative test and during consecutive bi-annuall intervals after the first HHV8 seropositive test. Inci-dencee rates for specific symptoms represent the number of episodess divided by the total number of person-years of ob-servationn for the evaluated time periods. We evaluated dif-ferencess in incidence rates, thereby controlling for repeated measurementss per person, using generalized estimating equationss assuming a poisson distribution and a compound symmetryy covariance matrix (9). Analyses were performed usingg a model that included an interaction term between timee and H I V 4 status and using this model, incidence rates weree calculated separately for HIV-1 seronegative and sero-positivee individuals as primary HIV-1 infection is character-isedd by several symptoms (10).
Results s
Generall characteristics at HHV8 seroconversion Presence and type of symptoms associated
withh HHV8 seroconversion
Onee hundred and ninety-five HHV8 seroconverters were includedd in this study. The average age at seroconversion wass 37.9 years (sd: 8.4) and the majority (93.8'/.») were pre-dominantlyy of Western European nationality. One hundred andd three (52.8%) seroconverters were HIV-1 seronegative andd 80 (41.0%) were HIV-1 seropositive throughout the periodd of observation from 2 years prior to the HHV8 seroconversionn interval to 4 years after this interval. Twelve menn (6.2%)) seroconverted for HIV-1 during the period of observation;; eight seroconverted prior to the HHY8 seroconversionn interval and four seroconverted during the HHV88 seroconversion interval.
Seasonall distribution of HHV8 seroconversion
Off the 103 HIV-1 seronegative men 23.1%, 22.1%, 24.0% andd 30.8% seroconverted for HHV8 in winter, spring, sum-merr and fall respectively; for the 92 HIV-1 seropositive men thesee figures were 27.5%, 24.2%, 18.7% and 29.7% for the respectivee seasons. Although there was slight variation, the seasonall seroconversion distribution did not defer from uniformity-- (p value for HIV-1 negatives: 0.59, for HIV-1 positives:: 0.48).
Duringg the HHV8 seroconversion interval, 39 (37.9%) of 1033 HIV-1 seronegative men and 27 (29.3%) of 92 HIV-1 seropositivee men did not report am of the symptoms under investigation.. Symptom incidence rates in the HHV8 seroconversionn interval were compared to those in the peri-odss before and atter HHV8 seroconversion (Table 1). Sta-tisticallyy significantly higher incidences of cough, sore throatt and muscle ache were noted during the HHV8 seroconversionn interval in HIV-1 seronegative participants. Thee incidences of sore throat and cough decreased after the seroconversionn interval whereas the incidence of muscle achee remained elevated. Non-significant increases in the in-cidencee of fever, diarrhoea, fatigue, lymph node swelling andd rash were also seen during the HHV8 seroconversion interval.. Despite incidence rates being higher in HIV-1 se-ropositivee participants, no statistically significant increase in incidencee rate of any symptom was seen during the HHV8 seroconversionn interval. When season was entered in the multivariatee model, no change was observed in either the incidencee rates or risks for each symptom (data not shown).
Tablee 1 : Incidence rates and relative risks of symptoms reported by HIV-1 seronegative and seropositive participants during the HHV8
seroconversionn interval relative to intervals prior to and after this interval, Amsterdam Cohort Study among homosexual men (1984-1996). . Symptom m Musclee ache Soree throat Cough h Fever r Diarrhoea a Headache e Fatigue e
Lymphh node swelling
Rash h Timee relative to seroconversionn period 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after 0-22 years before Seroconversion n 0-22 years after 2-44 years after
HIV-11 positive men Incidencee * (episodes/100(episodes/100 PY) 31.64 4 12.06 6 36.03 3 48.12 2 63.08 8 41.05 5 42.02 2 40.34 4 74.21 1 68.60 0 78.16 6 72.63 3 44.57 7 44.68 8 51.63 3 45.46 6 37.28 8 33.87 7 34.50 0 42.02 2 32.97 7 20.59 9 35.30 0 41.81 1 26.83 3 29.79 9 35.43 3 55.72 2 42.60 0 31.97 7 36.52 2 20.14 4 4.75 5 12.12 2 12.37 7 14.80 0 Incidencee * (episodes/100 0 8.59 9 21.05 5 18.86 6 17.76 6 14.60 0 33.93 3 19.44 4 24.30 0 30.41 1 45.77 7 33.06 6 26.21 1 30.18 8 37.13 3 31.14 4 24.46 6 14.97 7 19.75 5 17.83 3 8.46 6 22.18 8 19.56 6 18.05 5 26.34 4 22.53 3 24.12 2 25.81 1 13.38 8 9.95 5 11.48 8 7.41 1 8.48 8 1.45 5 2.60 0 2.00 0 5.69 9
HIV-11 negative men Relativee risk * PY)) (95% CI) 1 1 2.12(1.15-3.91) ) 2.02(1.07-3.83) ) 2.13(1.17-3.89) ) 1 1 2.32(1.24-4.37) ) 1.33(0.77-2.30) ) 1.73(0.89-3.12) ) 1 1 1.511 (1.00-2.27) 1.09(0.75-1.58) ) 0.86(0.55-1.35) ) 1 1 1.23(0.78-1.94) ) 1.03(0.69-1.54) ) 0.81(0.47-1.39) ) 1 1 1.32(0.63-2.78) ) 1.19(0.65-2.19) ) 0.57(0.26-1.22) ) 1 1 0.88(0.44-1.77) ) 0.811 (0.48-1.38) 1.19(0.65-2.17) ) 1 1 1.07(0.53-2.16) ) 1.15(0.67-1.96) ) 0.59(0.24-1.48) ) 1 1 1.15(0.62-2.14) ) 0.74(0.37-1.51) ) 0.85(0.38-1.93) ) 1 1 1.79(0.43-7.42) ) 1.38(0.20-9.33) ) 3.93(0.81-19.22) ) P P valuee * 0.0161 1 0.0314 4 0.0133 0.0133 0.0088 8 0.3049 9 0.1115 5 0.0502 2 0.6601 1 0.5152 2 0.3750 0 0.8782 2 0.4473 0.4473 0.4654 4 0.5721 1 0.1448 8 0.7244 4 0.4433 0.4433 0.5766 6 0.8493 3 0.6197 7 0.2625 5 0.6505 5 0.4149 9 0.7011 1 0.4201 1 0.7396 6 0.0906 6
Discussion n
Wee have investigated the seasonal distribution, presence andd type of symptoms associated with primary HHV8 in-fectionn in a large prospective cohort of HIV-1 infected and uninfectedd homosexual men in the Netherlands. Primary H H V 88 infection showed no substantial seasonal variation. Duringg primary HHV8 infection approximately two thirds off HIV-1 seronegative and HIV-1 seropositive men re-portedd any of the nine symptoms under investigation in this study.. Higher incidence rates of cough, sore throat and musclee ache were observed among HIV-1 seronegative par-ticipantss during primary HHV8 infection. Symptom inci-dencee rates were generally higher in HIV-1 coinfected indi-viduals,, however no increase in incidence of any symptom wass seen when these acquired primary HHV8 infection. Of thee HIV-1 seronegative men, 34% reported either cough, soree throat, muscle ache or a combination of these symp-tomss during the seroconversion interval; this proportion wass 3 8 % for HIV-1 seropositive men.
Thee large number of participants increases the power of our studyy and allows us to provide a more comprehensive view off primary H H V 8 infection than the five symptomatic pa-tientss presented by Wang et al. (6). We defined primary HHV88 infection as the appearance of IgG antibodies to ORF655 a n d / o r ORF73 in a serial collection of serum sam-pless and the HHV8 seroconversion interval in this study is synonymouss to primary HHV8 infection (8). Although cur-rentt HHV8 serological assays are limited by suboptimal sensitivityy and specificity, it is unclear what effect, if any, an assayy with improved characteristics will have on the mo-mentt of seroconversion and the degree of association with thee symptoms.
Higherr incidences of sore throat, cough and muscle ache weree reported during primary HHV8 infection in HIV-1 seronegativee individuals. The incidences of fever, diarrhoea, fatigue,, lymph node swelling and rash were also elevated butt the results were not statistically significant. The symp-tomss that we found to be significantly related to primary HHV88 infection differ from those reported by Wang et al. butt are well supported by studies on the gammaherpesvirus familyy (6). Sore throat as a symptom is consistent with the mucosall shedding of HHV8 from the oro-pharynx and oro-genitall transmission of HHV8 (11,12). Cough may re-sultt from HHV8 replication in the lung; MHV-68 replicates inn alveolar epithelial and mononuclear cells after intranasal inoculationn and HHV8 has been detected in lung biopsies fromm HIV-1 infected patients with otherwise unexplained interstitiall pneumonitis (13,14). Myalgia may be part of the hostt inflammatory response or be indicative of persistent virall replication in muscle and was the only symptom to re-mainn more common in HIV-1 negative HHV8 seroconverterss for up to four years after primary HHV8 in-fection.. Although HIV-1 seropositive individuals were moree likely than HIV-1 seronegative individuals to report symptoms,, incidence rates were not raised during primary HHV88 infection. Higher incidence rates may reflect anxiety aboutt HIV-1 infection or be an accurate representation of thee symptoms of primary HIV-1 infection. HIV-1 and HHV88 seroconversion occurred simultaneously in four participantss however, due to the small number of events, wee were unable to show whether this altered the clinical ex-pressionn of primary HIV-1 infection.
Preliminaryy studies on the symptoms associated with pri-maryy HHV8 infection are limited by the practical difficul-tiess of excluding other infectious and non-infectious
cessess that produce the same symptoms.(6) Nonetheless, thee temporal association between HHV8 seroconversion andd symptoms in our study and that by Wang et al. indicates thatt primary HHV8 infection is a distinct clinical entity that producess a flu-like illness. Sudden onset of unexplained soree throat, cough and/or muscle ache in an HIV-1 seronegativee homosexual man should alert the research cli-niciann to include primary HH V8 infection as part of the
dif-ferentiall diagnosis. However, it should be noted that a rela-tivelyy small part of the seroconverters expressed the symp-tomss associated with seroconversion. Further studies are requiredd to determine the full spectrum of clinical symp-tomss associated with primary HHV8 infection.
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