Clinical Profile and Influences on Outcomes in Patients Hospitalized

DOI: 10.1161/CIRCULATIONAHA.114.010376

1

Clinical Profile and Influences on Outcomes in Patients Hospitalized for

Acute Pericarditis

Running title: Kytö et al.; Clinical Profile and Acute Pericarditis

Ville Kytö, MD, PhD, MsocSc1; Jussi Sipilä, MD2; Päivi Rautava, MD, PhD3

1Heart Center, Clinical Neurosciences; 2Neurology; 3Clinical Research Center,

Turku University Hospital, Turku, Finland

Address for Correspondence:

Ville Kytö, MD, PhD

Heart Center

Turku University Hospital

POB 52, FI-20521 Turku, Finland

Tel: +358405383511

Fax: +35823137206

E-mail: [email protected]

Journal Subject Codes: Hypertension:[114] Pericardial disease, Etiology:[8] Epidemiology

Ville Kytö, MD, PhD, MsocSc1; Jussi Sipilä, MD2; Päivi Rautava, MD,D,D, PPPhDhDhD333

11HeHeHeara t CeCeCennter, Clinical Neurosciences;;; 22NeNN urology; 3Clinicalall RRRese earch Center,

TuTuTurkrkrkuu u UnUnUnivivi eersiiitytyty HHHosspipipittal,,, TTTururrkukuku, , FFiFinlnllanand d d

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

http://circ.ahajournals.org/


2

Abstract

Background—The clinical profile with regard to gender and the influences on outcomes in

patients who have been hospitalized for acute pericarditis are largely uncharacterized.

Methods and Results—We studied all patients aged 16 years admitted to hospital due to acute

pericarditis (post-pericardiotomy and myocardial infarction associated pericarditis were

excluded). Data were collected from a Finnish national registry including data on all

cardiovascular admissions (670,409) during 9.5 years in 29 hospitals nationwide. During the

study period there were 1,361 admissions for acute pericarditis. Pericarditis patients were more

likely to be male (64.9% of patients) than female (35.1%) with age-adjusted likelihood ratio of

1.85 (95% confidence interval (CI) 1.65-2.06, p<0.0001) for male sex. Standardized incidence

rate of hospitalizations for acute pericarditis was 3.32 per 100.000 person-years. Men aged 16-

65 were at higher risk for pericarditis (relative risk (RR) 2.02; CI 1.81-2.26; p<0.0001) than

women in general admitted population with highest risk-difference among young adults. Acute

pericarditis caused 0.20% (CI 0.19-0.22%) of all cardiovascular admissions. Proportion of

caused admissions declined by estimated 51% per 10-year increase in age. In-hospital mortality

rate for acute pericarditis was 1.1% (CI 0.6-1.8%). Mortality increased with age (HR 3.26; CI

1.78-5.95; per 10-year increase in age; p=0.0001) and severe co-infection (pneumonia or

septicemia) (HR 13.46; CI 2.26-80.01; p<0.005) but was not associated with sex in multivariate

analysis.

Conclusions—Patients hospitalized for acute pericarditis are more commonly men. Increasing

age and severe co-infection are associated with greater in-hospital mortality in hospitalized acute

pericarditis patients.

Key words: pericardial disease, pericarditis, sex, aging, epidemiology

ate of hospitalizations for acute pericarditis was 3.32 per 100.000 person years. MMenen aageg dd 1616

65 were at higher risk for pericarditis (rela tive risk (RR) 2.02; CI 1.81-2.26; p<00...000000 11)1) tthahhannn

women in general admitted population with highest risk-difference among young adults. Acute

pericaarditis ccaua sesed d 0.20% (CI 0.19-0.22%) of alll cara diovascular admissssioions. Proportion of Proportion of

cacaausuuseeded admdmisisi sionons s dedeclclinineded by y esestit mamatet d d 5151% % peperr r 110- yeyearar iincreeaasasee inn aagege. Inn-hhosospipitaal momortallitity

aateee ffor acute ppererricccarrdidditiiss wawaass 11.1%1%% ((CCCI 00.6--1..8%))). MMorororttatalilittyty iincnccreeasededd wwwitith h h aagage e (H(H(HR R R 333.262626; CICICI

1.1.787878-5-5- .9.95;; pppererer 11000-yyeyeararr inncncreeaasa e e e inin aaagegge; ; ; pp=p=0.0.000000101 (p(ppneneeumumonononia orr r )) aannd d seeeveverrere cco-o--innnfefectctioionn

eptpticiceemiaia)) (H(HR R 133 4.46;6; CCI I 2.2626 8-80.0 01;; p<p<0.0 00005)5) but wwasas nonot t asa soociciatateded wwiti h h sesex x ini mmulu titivavaririatte e

analysy is.



ownloaded from



3

Acute pericarditis is an inflammatory disease of pericardium triggered commonly by viral

infections in developed countries, while tuberculosis is the most common cause in developing

countries 1, 2. Experimental studies have found males to be at higher risk for acute viral heart

disease 3, 4, but clinical studies have reported conflicting results on sex distribution of acute

pericarditis patients 5-7. It is commonly thought that there is no specific sex predisposition to

pericarditis 8. Murine studies have also found the susceptibility for viral heart disease to be

significantly age-dependent with highest sensitivity at adolescence or young adulthood 9. Mean

age of acute pericarditis patients in clinical series has ranged from 41 to 60 years 5, 10-12, but sex

associated differences in age have not been reported. Prognosis of viral/idiopathic pericarditis is

good 12, but purulent and tuberculosis pericarditis have high mortality 13. Female sex has been

associated with complications after acute pericarditis14, but this little is known about the effect of

age. We studied the associations of age- and sex- with occurrence of acute pericarditis in all-

comer adult patients using a multihospital, nationwide setting.

Methods

Study patients and data collection

Patients aged 16 years admitted to hospital due to acute pericarditis during a 9.5 year period

were studied. Postpericardiotomy syndromes and post infarction pericarditis were excluded. Data

of all cardiovascular hospital admissions (n=670,409) between May 1st, 2000 and October 31st,

2009 in 29 hospitals were retrospectively collected from the Finnish Hospital Discharge Register

(FHDR), a nationwide maintained by the Finnish National Institute for Health and Welfare

database containing hospital discharge data of all hospital admissions in Finland. Patients aged

16 years with acute pericarditis as the primary cause of admission (ICD-10 codes I01.0 and I30)

good 12, but purulent and tuberculosis pericarditis have high mortality 13. Femalee sexexx hhhasasas bbbeeeeeenn

associated with complications after acute pericarditis14, but this little is known about the effect ofkk

agge.e.e. WeWeWe ssstututudidd eddd ttthhehe associations of age- and sex-x-x- wwwith occurrencecee of f acacacuutute pericarditis in all-

coommemer adult paatiitienenentss uuusisingngng aa mmmulultitiihohohosspppittaal, nnnatttionnwwiidee sseettttinini gg.g.

Methods



ownloaded from



4

were identified. Co-morbidities and potential etiologies were detected from hospital discharge

diagnoses. Study population was mainly Caucasians. Differences in incidence rate were

estimated using age- and sex-matched population data of Finland from the study period

(39,523,746 person-years) obtained from Statistics Finland.

Hospital organization in Finland consists of three main levels: 5 university

hospitals represent the highest level of hierarchy, followed by 16 central hospitals with coronary

angiolaboratory and intensive care units, and smaller regional hospitals. Treatment of acute

cardiovascular patients occurs mainly in university and central hospitals. This study included

data from all university and central hospitals and 8 large regional hospitals located across the

country. The study was conducted according to the National Institute for Health and Welfare

permission (THL/1576/5.05.00/2010).

Statistical analysis

Data was analyzed with Poisson regression models. In the Poisson model of incidence rate, the

logarithm of population was used as an offset and in the model for the proportion of

cardiovascular admissions, the logarithm of total cardiovascular admissions was used as an

offset. Sex-differences in dichotomous variables were estimated by modified Poisson regression

with robust error variances15. In-hospital mortality during admission for acute pericarditis was

studied using Cox-regression model stratified by study year with exact method for failure time

ties. Multivariate mortality model included patient characteristics associated with mortality at the

level of p<0.1 in univariate analysis. Variables displayed in Table 1 in addition to gender and

age were considered as potential predictors of in-hospital mortality. Scale variables are presented

as mean±standard deviation or median with interquartile range (IQR) as appropriate. Total

incidence rates were standardized with US 2000 standard population by using a direct method.

country. The study was conducted according to the National Institute for Health h aaand dd WeWeWelflflfararareee

permission (THL/1576/5.05.00/2010).

Sttatatatisisistititicacaalll anananalysysysiisis

DDattata was analylyzzeeddd wiwiithth PPPoioioisssssoonon rrregegegreressssiion momodells. Innn tththee PoPooisisssosonn momoodeeel l ofofof iiincncidididenenncecee rrataate,e, thhhe

oogagagariririthththm m ofofof ppopoppulullatatioioon n wawas ususu ededed aaasss anann oooffffffsssetet f aaandndnd iinnn ththhe e momomodededel ll ffofor rr thththee prrropopoorortititiononn ooofff

cardiovascullararar aaadmdmmisisi sisis onoo s,s,, ttheheh lllogogogararariti hmhmhm ooof f f totootatata ll cacacardrdr iooovavavascscsculululararar aadmdmdmisisissisis onononsss wawawas s s usususededd as an



ownloaded from



5

Categorical variables are presented as counts, percentages or relative risks (RR) with 95%

confidence intervals (CI) as appropriate. Confidence intervals were calculated using Poisson

distribution. P-values <.05 were considered statistically significant. The SAS system version 9.3

(SAS Institute Inc, Cary, NC, USA) was used for statistical analyses.

Results

Frequency

The study period included 1361 hospital admissions with acute pericarditis as primary diagnosis.

Pericarditis patient was more likely to be male (64.9% of patients; CI 60.7-69.3%) than female

(35.1%; CI 32.0-38.4%) with age-adjusted likelihood ratio of 1.85 (CI 1.65-2.06, p<0.0001) for

male sex. Prevalence of potential etiological co-morbidities was similar between men and

women, but previous acute pericarditis was more common among women (Table 1). In addition,

bacterial etiology was confirmed more commonly in women. Acute pericarditis patient was

most commonly aged 50-59 years with median age of 52 years (range 16-93, IQR 35-63 years)

(Figure 1A). Male patients were significantly younger than female patients (mean 45.9±18.3 vs.

56.2±17.3 years, p<0.0001). Age distribution varied significantly by sex, as proportion of male

patients was notably higher in patients aged 16-65 years (Figure 1B). Median duration of

admission for acute pericarditis was 5 days (IQR 3-8). Women were treated longer than men

(7.5±6.9 vs. 6.1±5.1 days, age-adjusted p<0.0001). Admission lengthened by estimated 10% per

10-year increase in age (RR 1.10; CI 1.09-1.12, p<0.0001).

Acute pericarditis as cause of hospital admission

Acute pericarditis caused 4 % of all cardiovascular admissions among adults aged 16-20 years,

but the proportion decreased by estimated 51% (RR 0.49; 95% 0.48-0.51, p<0.0001) per 10-year

35.1%; CI 32.0-38.4%) with age-adjusted likelihood ratio of 1.85 (CI 1.65-2.06,6,, p<0<0< .0.0.00000001)1)1) fforo

male sex. Prevalence of potential etiological co-morbidities was similar between men and

wowomememenn,n, bbbututut ppprevivivioouous acute pericarditis was morrre ee cooommon amonggg womommeenen (Table 1). In addition,

bbaactcttere ial etioloogygyy wwwasas conononfififirmrmrmeded mmmoororeee cccommmmooonlyyy iinn wowowomemeen.. AAccuutute e pepeerriicacardrdrdiititisis pppatattieieiennnt wwwasass

momooststst cccomomo momomonlnly y y agggeded 500-0-595 yyyeaaarsrsrs wwwitithh h mememeddidianann agagge e ofoff 55222 yeyeyeararrsss (r(r(rananngegeg 166-6-93933, , , IQIQIQRR R 33535-6663 yeyeaaars)s)s)

Figure 1A).). MMMalaleee papapatitit enee tstss wwwererre e e sisis gngng iffficici ananantltltly y y yoyoyoununungegeger thththananan fffemememalaa e e e papapatitiienenentststs (m(mmeaeaean n n 454545.9±18.3 vs..



ownloaded from



6

increase in age to 0.02 % in patients aged 85 years or older (Figure 2). Overall, 0.20% (CI 0.19-

0.22%) of cardiovascular admissions were caused by acute pericarditis. In men, pericarditis

caused 0.24% (CI 0.22-0.25%) of admissions while this proportion was 0.16% (CI 0.15-0.18%)

in women. Men aged 16-35 were more likely to have acute pericarditis as the cause of admission

than women, while opposite was true for patients aged 46-75 (Figure 2B).

Incidence rate

Overall incidence rate of acute pericarditis was similar in population aged 16-49 years, but

increased in older population (Figure 3A). Incidence rate among men was 4.52 (CI 4.22-4.83)

per 100,00 person-years, with declining trend between 16-45 years followed by re-increase in

older population segments (Figure 3B). Among women, standardized incidence rate of acute

pericarditis was 2.11 (CI 1.91-2.32) per 100,000. Incidence was lowest among young women,

followed by gradual increase with age with peak in population aged 65-74 years. Young (16-35

year old) men had highest incidence of acute pericarditis compared to young women (incidence

rate ratio 4.65; CI 3.52-6.14, p<0.0001). Sex-difference in incidence rate was reduced with

increasing age, and in population aged 66 years rate for acute pericarditis was similar in both

sexes (Figure 4). Total standardized incidence rate of acute pericarditis was 3.32 (CI 3.14-3.50) /

100,000 person-years. Incidence rate of acute pericarditis was 2.02 (CI 1.81-2.26; p<0.0001)

times higher among men compared to women in total population (Figure 4).

In-hospital mortality

In-hospital mortality rate for acute pericarditis was 1.10% (CI 0.61-1.82). Female sex was

associated with increased mortality in univariate analysis, but was not an independent predictor

of death in multivariate model (Table 2). Mortality increased significantly with age in both

univariate and multivariate analysis (Table 2). Strongest predictor of in-hospital mortality in

older population segments (Figure 3B). Among women, standardized incidencee rrratatte ee ofofof aaacucucutetete

pericarditis was 2.11 (CI 1.91-2.32) per 100,000. Incidence was lowest among young women,

foolllllowowowededed bbby y y gggradadduauaual l increase with age with peak k k inin population agggedee 665-5-5-77474 years. Young (16-35

yyearrar old) men n hahahad hiiighghg eesesttt ininincicicidedencncnceee ooff aaacuttee pppericacaardiittisiss ccomomompapareredd toto yyoououngngng wwomommenenn (((inini cicicideedencncce

aatetete rrratatatioio 444.6.6.655;5; CCCI 3.3.52522-666.1.14, ppp<<<000.00000001011).). SSSexexex-dddififi fefeferereenccce ininin iiincnccididi eeencncce e e raraateee wwaasas rrrededucucuceded wwititi h h

ncreasing agegege,, ananand d d inini pppopopulululatatatiooon n n agaggedede 666666 yyyeaeaearsrss rrratatate e fofofor rr acacacututute e e pepp ririricacacardrdrditititisiss wwasasas sssimimimilili ara in both



ownloaded from



7

acute pericarditis was severe co-infection (pneumonia or septicemia). Co-morbidities listed in

Table 1, but not in Table 2 were not associated with in-hospital mortality in univariate analysis.

Discussion

This nationwide multi-hospital study describes age- and sex- associated occurrence of acute

pericarditis at the population level. Previous studies have reported conflicting results on effect of

sex on risk of pericarditis 5-7. Recent randomized trial of 240 acute pericarditis patients found

60% of patients to be male6, while previous studies have reported higher male prominence7, but

also female prominence5. We found 65% of 1361 patients to be male and the age-adjusted

likelihood of acute pericarditis patient to be a male was 1.9. Furthermore, the incidence rate of

acute pericarditis in general adult population was two-fold among men compared to women.

Etiology of acute pericarditis is idiopathic in majority of cases but with an immune-

mediated process probably triggered by a viral infection in many cases 16, 17. Reasons of sex-

differences in pericardial inflammation are unknown, but experimental viral studies of

myocardial inflammation have suggested that although genetic differences have some effect, sex

hormones are major contributors for sex predisposition 3, 18. Testosterone appears to play a

major role in development of myocarditis, as exogenous testosterone increases viral replication

and inflammation in the heart and gonadectomy inhibits cardiac inflammation in experimental

viral myocarditis 19, 20. Mechanisms of testosterone action include inhibition of anti-

inflammatory cells 19, commitment to Th1 type immune response 21, and increasing viral binding

to myocytes 20. In accordance with testosterone-effect, we found the risk for pericarditis to be

significantly higher among young men compared to women. Although occurrence of acute

pericarditis in men declined with age after teenage years, there was a re-increase in occurrence

ikelihood of acute pericarditis patient to be a male was 1.9. Furthermore, the inccidiidenee cecee rrratatateee ofof

acute pericarditis in general adult population was two-fold among men compared to women.

EtEtEtioioiololologyy ooofff aacute pericarditis is idiopathihiicc c innn majority of cccasaa ess bbbuutut with an immune-f

mmeddidiated procecessss ppproobabab blblbly y trtrrigigiggegerrered d d bbyy a viirraal infffeecctiononon iin n mmamanynyy cccasasesess 166, 177. RReReasassononnss ofofo sssexex--

didifffffferererenenencecesss ininin ppeericccarardddiaalal iinfnfflalal mmmmmmatatatioionnn ararareee unununknknk owowown,n, bbututut eeexpxpxperere imimmenenentatalll vviviraralll ststtududu ieieiesss offf

myocardial iinfnfnflalaammmmmmatattioioion hahahavevv sssugugu gegegestttededed ttthahahatt t alala ththhouououghghg gggeneneneteteticicc dddifi fefeferererencncnceseses hhhavavveee sososomemem effect, sexxx



ownloaded from



8

after 45 years of age. This may suggest that interaction of testosterone with susceptibility to

pericarditis may not be linear or that unrecognized etiology of pericarditis varies by age.

Female sex hormones also affect the risk for cardiac inflammation. Progesterone

aggravates cardiac inflammation 22 while oestrogen has inhibitory effects by favouring inhibiting

pro-inflammatory T-cells 23, stimulating inhibitory T cells 24 and favouring Th2 type immune

response 21. Accordingly, we found the incidence of pericarditis in women to be highest at

postmenopausal period when estrogenic levels are low. In addition to viral infections, systemic

connective tissue diseases are potential causes of acute pericarditis 25. In line with previous

studies 6, 7, connective tissue disease was diagnosed in 2 % of our patients. Women have a

general higher tendency for connective tissue diseases associated with pericarditis, e.g, systemic

lupus erythematosus and rheumatoid arthritis 26, but we found no sex difference in prevalence

among acute pericarditis patients. Systemic autoimmune diseases are however a diagnostic

challenge 27 and autoimmune processes begin earlier than classical clinical symptoms are

diagnosed 28.

Few studies have reported on epidemiology of pericarditis. Pericarditis is found in 4.4 %

of emergency room chest-pain patients 29 and in 1.7% of patients with ST-segment elevation 30 of

whom myocardial infarction is ruled out. We found acute pericarditis to be a significant cause of

cardiovascular admissions among young adults, but with increasing general morbidity the

proportion deceased logarithmically with aging. Pericarditis was a more likely cause of

admission to men at younger age-groups, but to women at ages of 46-75. Overall, pericarditis

caused 0.2% of hospital admissions, which compares to previous estimate of acute pericarditis

causing 0.1% of all hospital admissions 1. Swedish registry study found incidence rate of 18.0

per 100,000 for pericarditis in general population 31 while clinical study conducted in Italian

general higher tendency for connective tissue diseases associated with pericardititiiss, eee.ggg,, sysysystststememe ic

upus erythematosus and rheumatoid arthritis 26, but we found no sex difference in prevalence

ammononongg g acacutututee ppeririicacacardr itis patients. Systemic autoooiimimmmune diseases s ara e hohohowwwever a diagnostic

hchhalalllel nge 277 andndd auuutoioiimmmmmununneee pprprococcesesssesees bbeggiinn earrllieeer thhhaanan ccclaaassssiciccaall ccliliininn ccacal l sysysympmptototommsms aareree

didiagagagnononosesedd 28288.

Few ststtudududieiees s s hahahaveveve rrepepeporoo teteed d d ononon eepipipidededemimimiololologogogy yy ofofo pepepeririicacacardrdditititisisi . PePePeririricacacardrdrdititisss iiisss fofofoununu d in 4.4 %%



ownloaded from



9

urban metropoly area reported incidence rate of 27.7 per 100,000 11. In retired US military

personnel, the incidence rate of pericarditis is 7.4 / 100,000 32. We found an incidence rate of 3.3.

per 100,000, reflecting the fact that we included only patients with acute pericarditis admitted to

hospital and excluded pericardiotomy and myocardial infarction caused disease. Since

overdiagnosis of pericarditis is common14, we maximized the accuracy of real-life diagnosis by

including patients that had been examined and diagnosed at the hospital ward. This, in addition

to the fact that our data collection did not cover all of the smallest regional hospitals that treat

cardiac patients, may result in underestimation of the absolute incidence rate of acute

pericarditis.

Presentation of pericarditis varies from chest pain to classical symptoms of cardiac

tamponade. Prodromal syndrome of fever, myalgia, and malaise is common33. Main findings

include ST-level changes in ECG, elevation of circulating inflammatory markers, friction rub in

cardiac ausculation, fever, and pericardial effusion in echocardiography2, 33, 34. In clinical

practice, and in the current study, diagnosis is based on combination of these findings, exclusion

of acute coronary syndromes when appropriate, and clinical judgment. Diagnosis of even life

threatening pericarditis is however a challenging task as demonstrated by study on unrecognized

causes of death in intensive care unit 35.

This study has some limitations. Major limitation is the retrospective nature of

observational registry data. Thus, diagnoses were made by treating physicians, which may have

affected the included patient population and accuracy of co-morbidity data. In addition, as we

included only hospitalized patients our results may underrepresent patients with low-risk features

that may be treated without admissions 14. Although we report on potential etiological co-

morbidities, the nature of our data does not allow describing on detailed etiological studies. Also,

Presentation of pericarditis varies from chest pain to classical symptoms ooof f cacc rdrdrdiaiaiacc c

amponade. Prodromal syndrome of fever, myalgia, and malaise is common33. Main findings

nnclclludududeee STSTST-l-l-leeevelel ccchahah nges in ECG, elevation of cicicircrcuulating inflammmamm tooryryry mmarkers, friction rub in

caardddiai c auscullatatioii nnn, fffeeeveerer, ananand dd peperirir ccacarrddiiaal efefffuuusioonn iin ececechohoccacardrdioiooggrrapaphyhyh 22,, 33,, 343434.. InIn ccclililininiicacac l ll

prpracacactititicecec ,, , anannd d d inin ttthehee ccuruurrereentnt stututudydydy, dididiagagnononosisisis s s iss babab ssseddd oonon cccomomombibibinananatitiononon ooff ththhesesse ee fififindnddininingsgs,,, exxxclcluuusiioon

of acute corononnarararyyy sysysyndnddroror mememes s s whwhhenene aaappppprororoprprpriaiaiatetete, , ananand d clc ininnicicicalalal jjjudududgmgmgmenenent.t.t DDDiaiaiagngng osososisisis ooof f f eve en life



ownloaded from



10

since prevalence of tuberculosis in Northern Europe is very low, our results may not be

applicable world-wide.

Prognosis of acute pericarditis is usually good. Although mortality in idiopathic / viral

pericarditis is low, purulent pericarditis is always fatal if untreated and carries a mortality of c.a.

40 % even when treated13, 36. Purulent pericarditis is commonly a complication of intra-thoracic

infection or a consequence of haematological bacterial spread13. Accordingly, we found

pneumonia and septicaemia to be strong predictors of in-hospital mortality. Female sex has been

associated with complications in acute pericarditis14. We found female sex to be associated with

mortality in univariate analysis, but not in multivariate analysis. Increasing age was however an

independent predictor of death.

In conclusion, men have a two-fold incidence rate of acute pericarditis compared to

women with highest difference among young adults. Increasing age and severe co-infection

predict in-hospital mortality in acute pericarditis, but sex does not appear to be an independent

risk factor for death.

Funding Sources: This study was funded by the Clinical Research Foundation of Turku

University Hospital.

Conflict of Interest Disclosures: None.

References: 1. Lange RA and Hillis LD. Clinical practice. Acute pericarditis. N Engl J Med. 2004;351:2195-2202.

2. Imazio M, Spodick DH, Brucato A, Trinchero R and Adler Y. Controversial issues in the management of pericardial diseases. Circulation. 2010;121:916-928. 3. Huber SA, Job LP and Auld KR. Influence of sex hormones on Coxsackie B-3 virus infection

ndependent predictor of death.

In conclusion, men have a two-fold incidence rate of acute pericarditis compared to

wowomememennn wiwiwiththth hhhigghehehestst difference among young addduuulttss. Increasing aagegg aandndnd ssevere co-infection

predddici t in-hosspipiittatall momoorrtalalalititity y ininin aacucuutetee ppererricarrrdiiitis, buuut sssexexx ddoeoeoes s nnoott apppepeeaarr ttooo bebbe aan nn ininndededepeeendndndenenentt r

iisksksk fffacacactotorr fofoforr dedeeatatth.h.



ownloaded from



11

in Balb/c mice. Cell Immunol. 1982;67:173-179.

4. Li Z, Yue Y and Xiong S. Distinct Th17 inductions contribute to the gender bias in CVB3-induced myocarditis. Cardiovasc Pathol. 2013;22:373-382.

5. Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, Moratti M, Gaschino G, Giammaria M, Ghisio A, Belli R and Trinchero R. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 2005;112:2012-2016. 6. Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D, Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH, Adler Y and Investigators I. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369:1522-1528. 7. Zayas R, Anguita M, Torres F, Gimenez D, Bergillos F, Ruiz M, Ciudad M, Gallardo A and Valles F. Incidence of specific etiology and role of methods for specific etiologic diagnosis of primary acute pericarditis. Am J Cardiol. 1995;75:378-382.

8. Imazio M and Brucato A. Management of pericarditis in women. Womens Health (Lond Engl). 2012;8:341-348. 9. Lyden D, Olszewski J and Huber S. Variation in susceptibility of Balb/c mice to coxsackievirus group B type 3-induced myocarditis with age. Cell Immunol. 1987;105:332-339. 10. Permanyer-Miralda G, Sagrista-Sauleda J and Soler-Soler J. Primary acute pericardial disease: a prospective series of 231 consecutive patients. Am J Cardiol. 1985;56:623-630. 11. Imazio M, Cecchi E, Demichelis B, Chinaglia A, Ierna S, Demarie D, Ghisio A, Pomari F, Belli R and Trinchero R. Myopericarditis versus viral or idiopathic acute pericarditis. Heart. 2008;94:498-501.

12. Imazio M, Brucato A, Barbieri A, Ferroni F, Maestroni S, Ligabue G, Chinaglia A, Cumetti D, Della Casa G, Bonomi F, Mantovani F, Di Corato P, Lugli R, Faletti R, Leuzzi S, Bonamini R, Modena MG and Belli R. Good prognosis for pericarditis with and without myocardial involvement: results from a multicenter, prospective cohort study. Circulation. 2013;128:42-49. 13. Pankuweit S, Ristic AD, Seferovic PM and Maisch B. Bacterial pericarditis: diagnosis and management. Am J Cardiovasc Drugs. 2005;5:103-112.

14. Imazio M, Cecchi E, Demichelis B, Ierna S, Demarie D, Ghisio A, Pomari F, Coda L, Belli R and Trinchero R. Indicators of poor prognosis of acute pericarditis. Circulation. 2007;115:2739-2744. 15. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159:702-706.

8. Imazio M and Brucato A. Management of pericarditis in women. Womens Heaeaaltth hh (L(L(Lononnd d d EnEEnglgl))2012;8:341-348.

9. Lydyden D,, OlO szewski J and Huber S. Variation in susceptibility of Balb/c mice to cooxsxsxsacacckikikieveveviririruuus gggrororoupu B type 3-induced myocardididittisss with age. Ceellllll Immmmmuununol. 1987;105:332-339.

1100. PPermanyer-r-MiMiM raraldldlda G,GG, SSSagagagririststta-a-a SaSaaululledaa J anddd SSSoleeer-r--SoSoleler r J.J PPririmamaryry aacucucutetete ppererericiccarardidid alalal dididiseeeasa e: a prorospeeectttivee seeerieess s oofof 223131 cccoonnsssecuuttivvve ppattieientntnts.s.s. AmAmAm J CCCaarrdiolll. 191988585;5;56:6626233-3-6663000.

11. ImImazioio MM, , CeC cccchihi E, DeD mimichchelelisi B, ChChininagaglilia A, IIerernana SS, , DeDemamaririee D, GGhihisisio o A, PPommararii F, Belli R and TrTrrinininchchherereroo R.RR MMMyoyoyopepeeririricacaardrditititisiss vvvererersusususs vvviriri alala oorr r ididdioioiopapapathththiccc aaacucucutetete ppperere icccararardididititit s.s.s Heart. 20200808;9;94:4:494988-505011



ownloaded from



12

16. Pankuweit S, Stein A, Karatolios K, Richter A, Ruppert V and Maisch B. Viral genomes in the pericardial fluid and in peri- and epicardial biopsies from a German cohort of patients with large to moderate pericardial effusions. Heart Fail Rev. 2013;18:329-336. 17. Imazio M, Brucato A, Maestroni S, Cumetti D, Belli R, Trinchero R and Adler Y. Risk of constrictive pericarditis after acute pericarditis. Circulation. 2011;124:1270-1275. 18. Fairweather D, Cooper LT, Jr. and Blauwet LA. Sex and gender differences in myocarditis and dilated cardiomyopathy. Curr Probl Cardiol. 2013;38:7-46. 19. Frisancho-Kiss S, Coronado MJ, Frisancho JA, Lau VM, Rose NR, Klein SL and Fairweather D. Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun. 2009;23:649-657. 20. Lyden DC, Olszewski J, Feran M, Job LP and Huber SA. Coxsackievirus B-3-induced myocarditis. Effect of sex steroids on viremia and infectivity of cardiocytes. Am J Pathol. 1987;126:432-438. 21. Huber SA and Pfaeffle B. Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3. J Virol. 1994;68:5126-5132. 22. Lyden DC and Huber SA. Aggravation of coxsackievirus, group B, type 3-induced myocarditis and increase in cellular immunity to myocyte antigens in pregnant Balb/c mice and animals treated with progesterone. Cell Immunol. 1984;87:462-472. 23. Li Z, Yue Y and Xiong S. Distinct Th17 inductions contribute to the gender bias in CVB3-induced myocarditis. Cardiovasc Pathol. 2013;22:373-382. 24. McCarthy RE, 3rd, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM and Baughman KL. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med. 2000;342:690-695. 25. Imazio M. Pericardial involvement in systemic inflammatory diseases. Heart. 2011;97:1882-1892.

26. Tedeschi SK, Bermas B and Costenbader KH. Sexual disparities in the incidence and course of SLE and RA. Clin Immunol. 2013;149:211-218.

27. Schirmer M, Duftner C and Dejaco C. Challenges in the diagnosis of chronic immune-mediated rheumatic diseases. Discov Med. 2013;15:160-165.

28. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA and Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. NEngl J Med. 2003;349:1526-1533.

1987;126:432-438.

21. Huber SA and Pfaeffle B. Differential Th1 and Th2 cell responses in male andndd fffemememalalaleee BALB/c mice infected with coxsackievirus group B type 3. J Virol. 1994;68:5126-5132.

222. . LyLyLydededennn DCDCDC aandndnd HHuber SA. Aggravation of coooxsxx aackievirus, grouououp B,B,B tttyype 3-induced mymymyooocarditiis aaand d ininincrcreaeaaseses iiin n n cecelllllululularara iimmmmununitity y y toto mymym ocytytyteee anana tigegegensnsn iin n prprpregee nanantntt BBBalalb/b/c c mimim cecee aaandn annimmmals treateed d wiwiw thth ppproroogegegesststerereronone.e.e. CeCeC lll IImmmmunnol. 11998444;8;8;87:7:4646462-2-447472.2.

2333. LiLiLi ZZZ,, , YuYuYueee Y Y annnd d XXXioonongg SS.S. DDDisisistititinncnct t ThThTh171717 indndnduucctitiiononns cococonnntririibubub tete ttto o o ththhe e gegeg nndnderere bbbiaiaiass innn CCCVBVBB33--nduducecedd mymyoccarardititis.s. CCardrdioovavascsc PPatholl. . 20201313;2;22:2 3773-3-38382.2.

2424 McMcCaCartrthyhy RREE 33rdrd BoBoehehmemerr JPJP HrHrububanan RRHH HuHutctchihinsns GGMM KKasaspeperr EKEK HaHarere JJMM anandd



ownloaded from



13

29. Launbjerg J, Fruergaard P, Hesse B, Jorgensen F, Elsborg L and Petri A. Long-term risk of death, cardiac events and recurrent chest pain in patients with acute chest pain of different origin. Cardiology. 1996;87:60-66. 30. Brady WJ, Perron AD, Martin ML, Beagle C and Aufderheide TP. Cause of ST segment abnormality in ED chest pain patients. Am J Emerg Med. 2001;19:25-28. 31. Elfstrom P, Hamsten A, Montgomery SM, Ekbom A and Ludvigsson JF. Cardiomyopathy, pericarditis and myocarditis in a population-based cohort of inpatients with coeliac disease. JIntern Med. 2007;262:545-554. 32. Lin AH, Phan HA, Barthel RV, Maisel AS, Crum-Cianflone NF, Maves RC and Nayak KR. Myopericarditis and pericarditis in the deployed military member: a retrospective series. MilMed. 2013;178:18-20. 33. Maisch B, Seferovic PM, Ristic AD, Erbel R, Rienmuller R, Adler Y, Tomkowski WZ, Thiene G, Yacoub MH, Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. Guidelines on the diagnosis and management of pericardial diseases executive summary; The Task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Eur Heart J. 2004;25:587-610. 34. Seferovic PM, Ristic AD, Maksimovic R, Simeunovic DS, Milinkovic I, Seferovic Mitrovic JP, Kanjuh V, Pankuweit S and Maisch B. Pericardial syndromes: an update after the ESC guidelines 2004. Heart Fail Rev. 2013;18:255-266. 35. Combes A, Mokhtari M, Couvelard A, Trouillet JL, Baudot J, Henin D, Gibert C and Chastre J. Clinical and autopsy diagnoses in the intensive care unit: a prospective study. Arch Intern Med. 2004;164:389-392. 36. Sagrista-Sauleda J, Barrabes JA, Permanyer-Miralda G and Soler-Soler J. Purulent pericarditis: review of a 20-year experience in a general hospital. J Am Coll Cardiol. 1993;22:1661-1665.

he European Society of Cardiology. Guidelines on the diagnosis and managemennt t ofofof ppperericicarardidialdiseases executive summary; The Task force on the diagnosis and management oofof ppperericiccararardididialaal diseases of the European society of cardiology. Eur Heart J. 2004;25:587-610. JJ

34. SeS ferovic PM,, Ristic AD, Maksimovic R, Simeunovic DS, Milinkovic I, Seferovic MitrovicJPP,, KaKaKanjnjnjuhuhuh VVV, PaPaanknknkuuweit S and Maisch B. Pericacacardrdiial syndromes:s:: an upupupdddate after the ESC guguuididdelelini es 2200004.4. HeHeH arartt t FaFaailili RRevevv.. 20202 1313;1;1; 8:8:25255-5-26266.6.

35355. CCoC mbess AA, MoMoMokhtttarrri MM, CCCouvu elellarardd AA, TTTroouilllleett JLJLL, BaBaBaududdot JJ, Henninn n DD,, GGGibiberttt CCC aaanddd ChhhaasstreJ.. CCCliliinininicacall ananandd auauutooopspsyyy ddidiaagnononoseseesss ininin ththhee ininintetetensnssivivive e caaareree uunininit:t:t: aa ppproroospsppecece titiiveee sstututudydydy.. ArArArccch IIInttterernnnMeedd. 20200404;1; 644:3: 899-3-3992.

3636 SaSagrgrisistata S-Sauauleledada JJ BaBarrrrababeses JJAA PPerermamanynyeerr-MiMiraraldldaa GG anandd SoSolelerr-SoSolelerr JJ PPururululenentt



ownloaded from



14

Table 1. Patient characteristics and sex-differences.

Prevalence (%) (95%CI) Women vs. Men

Co-diagnosis Total (n=1361)

Women (n=478)

Men (n=883)

RR (95%CI) P

Previous acute pericarditis* 21.9 (19.5-24.5)

28.2 (23.7-33.4)

18.5 (15.7-21.5)

1.53 (1.25-1.87) <0.0001

Hypertension 6.54 (5.25-8.05)

8.58 (6.16-11.64)

5.44 (4.01-7.21)

1.58 (1.06-2.36) 0.03

Diabetes 3.75 (2.79-4.93)

3.14 (1.75-5.18)

3.96 (2.76-5.51)

0.79 (0.44-1.43) 0.44

Heart failure or cardiomyopathy

3.09 (2.22-4.17)

3.56 (2.07-5.69)

2.83 (1.83-4.18)

1.26 (0.69-2.30) 0.46

Atrial fibrillation 3.75 (2.79-4.93)

5.44 (3.55-7.97)

2.83 (1.83-4.18)

1.92 (1.12-3.29) 0.02

Connective tissue disease 2.13 (1.43-3.06)

2.93 (1.60-4.91)

1.70 (0.95-2.80)

1.72 (0.84-3.54) 0.14

Malignancy 1.54 (0.96-2.36)

2.09 (1.00-3.85)

1.25 (0.62-2.23)

1.68 (0.72-3.93) 0.23

Previous cardiac surgery 1.25 (0.73-2.00)

1.05 (0.34-2.44)

1.36 (0.70-2.37)

0.77 (0.27-2.17) 0.62

Chronic pulmonary disease 1.03 (0.56-1.73)

1.26 (0.46-2.73)

0.91 (0.39-1.79)

1.39 (0.48-3.97) 0.54

Inflammatory bowel disease 0.73 (0.35-1.35)

0.21 (0.01-1.17)

1.02 (0.47-1.93)

0.21 (0.03-1.62) 0.13

Renal insufficiency 0.44 (0.16-0.96)

0.21 (0.01-1.17)

0.57 (0.18-1.32)

0.37 (0.04-3.15) 0.36

Pneumonia or septicemia 4.04 (3.04-5.26)

5.23 (3.38-7.72)

3.40 (2.29-4.85)

1.54 (0.92-2.59) 0.10

Rheumatic fever 1.91 (1.24-2.80)

2.72 (1.45-4.65)

1.47 (0.78-2.52)

1.85 (0.86-3.95) 0.11

Tuberculosis 0.59 (0.25-1.16)

1.05 (0.34-2.44)

0.34 (0.07-0.99)

3.08 (0.74-12.83) 0.12

Confirmed bacterial etiology† 1.69 (1.07-2.54)

2.93 (1.60-4.91)

1.02 (0.47-1.93)

2.87 (1.25-6.59) 0.01

* Previous admission caused by acute pericarditis during the study period. †Excluding mycobacterium.

(1.43-3.06) (1.60-4.91) (0.95-2.80) (0.84-3.3..54545 ) )

Malignancy 1.54 (0.96-2.36)

2.09 (1.00-3.85)

1.25 (0.62-2.23)

1.1.686868 (0.72-2-333.99393) )) 0.0.0 23232

Previous cardiac surgery 1.25 (0.73-2.00)

1.05 (00.34-2.44)

1.36 (0.70-2.3737)))

0.77 (0.27-2.17) 0.62

ChChhroooninic c puulmlmlmonnarary y did seseasase e 1.03 (0(0(0.5.5. 6-6-6 1.1.1 73733)))

11.26 (0( ..466-2.2.737373)))

0.0.0 91 (0(00 33.39-9-9-1.1.1 797979)))

1.39 (0(0(0.4.4.48-8-8-3.3.3 97977))) 0.0 545

nnnfllaaammatoryry bowowowel dddisseasesee 0.0 7373 (0( .3.335-5--1..35))

000.2111 (0( ..011-1.1..171717))

1..0202 (0.44777-1.993)))

0.0 22121 (000.003-11.66262)) 000.113

Renanalll iininsusufffficcieiency y 0.0 444444 (0(0(0 1.1.16-6-6 00.0.969696)))

00.0.212121 (0(0(0 0.0.01-1-1 11.1.171717)))

00.0.575757 (0(0(0 1.1.18-8-8 11.1.323232)))

0.0.0.373737 (0(0(0 0.0.04-4-4 33.3.151515))) 00.0.363636

PnPneueumomoniniaa oror ssepeptiticecemimiaa 44.4 040404 555.2232 3.3 404040 11.1 545454 00 1010



ownloaded from



15

Table 2. Predictors of in-hospital mortality. Results of both univariate and multivariate Cox-analysis. See methods for details.

Univariate analysis Multivariate analysis HR (95%CI) p HR (95%CI) p

Female sex 3.66 (1.11 - 12.05) 0.03 1.23

(0.32 - 4.74) 0.76

Age / 10-year increase 3.61 (1.94 - 6.72) <0.0001 3.26

(1.78 - 5.95) 0.0001

Septicemia or pneumonia 8.53 (2.27 - 32.06) 0.0008 13.46

(2.26 – 80.01) 0.003

Heart failure or cardiomyopathy 4.54 (0.88 - 23.15) 0.07 1.54

(0.22 - 10.61) 0.66

Figure Legends:

Figure 1. Frequency of acute pericarditis. Age-distribution of all pericarditis patients (A) and by

sex (from total number of patients) (B). Error bars represent upper limits of 95% confidence

intervals. *** p<0.0005

Figure 2. Cardiovascular admissions caused by acute pericarditis. Proportion of all

cardiovascular admissions (A) and by sex (B). Error bars represent upper limits of 95%

confidence intervals. *** p<0.0005, ** p<0.005, *p<0.05. Please note logarithmic y-axis.

Figure 3. Incidence rate of acute pericarditis in general population. Total (A) and sex-specific

(B) incidence rates (per 100,000 person-years) by age. Error bars represent upper limits of 95%

confidence intervals. *** p<0.0005, ** p<0.005.

Figure 4. Sex-associated incidence rate ratio of acute pericarditis by age in general population.

Ratio is calculated as men vs. women and adjusted for study year. Error bars represent 95%

confidence intervals.

Figure 1. Frequency of acute pericarditis. Age-distribution of all pericarditis pattiei tnts (A(A)) andd bby

ex x (f(frorom m tootatal nunuumbmbm er of patients) (B). Error baarsrs rrrepresent upper limmititits s s of 95% confidence

nnnteterrvrvals. ****** ppp<0<0<0.0.0000000555

FiFigugureree 222. CCaCardrdioioi vavascscullularar aadmmisisissisisionons caausususededed bbby y acac tututee pepee iriricaca drdrditisis.. PPrPropoporortitionon ooof ff alall l

cacardrdioiovavascsculullarar aadmdmd isiissisiononss (A(A(A)) aandndd bbby y sesexx (B(B).)). EEErrrroror bbbararss rereprpresesenentt upuppeperr lilimimitstts ooff f 959595%%



ownloaded from


Figure 1



ownloaded from


Figure 2



ownloaded from


Figure 3



ownloaded from


Figure 4



ownloaded from


Ville Kytö, Jussi Sipilä and Päivi RautavaClinical Profile and Influences on Outcomes in Patients Hospitalized for Acute Pericarditis

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2014 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online September 9, 2014;Circulation.

http://circ.ahajournals.org/content/early/2014/09/09/CIRCULATIONAHA.114.010376World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer available in the

Permissions in the middle column of the Web page under Services. Further information about this process isOnce the online version of the published article for which permission is being requested is located, click Request

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Circulation Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



ownloaded from

http://circ.ahajournals.org/content/early/2014/09/09/CIRCULATIONAHA.114.010376

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circ.ahajournals.org//subscriptions/


Documents

Clinical Profile and Influences on Outcomes in Patients Hospitalized