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Q
Fever Endocarditis in Queensland
H. G. WILSON, M.D., F.R.A.C.P., G. H. NEILSON, M.D., F.R.A.C.P., E. G. GALEA, M.D.,
G. STAFFORD, M.D., F.R.A.C.S., AND M. F. O'BRIEN, M.D., F.R.A.CS.
F.R.A.C.P.,
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SUMMARY Thirteen patients with proven Q fever endocarditis
and three additional patients with probable endocarditis are reviewed.
The most helpful diagnostic test is the demonstration of a high complement fixing antibody titre to Phase I antigen of Coxiella burneti.
The macroscopic pathology of the aortic valve is described and includes aneurysmal pockets in the aortic wall and valve annulus which
are demonstrable angiographically.
Evidence is presented that the infection may be controlled by
prolonged tetracycline therapy and that this is accompanied by a falling antibody titre to Phase 1 antigen. Valve replacement is undertaken only for symptomatic and hemodynamic indications. The combined tetracycline therapy and valve replacement have produced a fall
in titres with eradication of infection and palliation of the cardiac disability in all patients followed for long periods.
Q FEVER was originally described by Derrick in 1937.1 The
diagnosis is made by an increasing complement fixing antibody titre to the antigens of Coxiella burneti (C. burneti).
These antibody titres are measured against Phase I and
Phase 2 antigens. During the acute infection the rising antibody titre is to the Phase 2 antigen, whereas elevated antibody titre to Phase 1 antigen suggests past persistent infection;2 high titres are found in chronic infections, including Q
fever endocarditis.3
The ultimate diagnosis of Q fever endocarditis is based on
identification of the organism in the affected valve tissue
removed at autopsy or operation. Laboratory animals inoculated with such tissue demonstrate a rising antibody titre
and C. burneti is present in their tissues.
Cases of Q fever must be reported to the Health Department in Queensland. All diagnostic blood tests are performed in the State Health Laboratory so that it is possible
to follow all proven cases. This communication surveys Q
fever endocarditis in Queensland from 1959 to 1974.
fever, rigors, malaise, splenomegaly, painful emboli in hands
and feet, and heart failure one year earlier. Three months
before admission he had a transient left hemiparesis.
Although a meat worker for 14 years, he had no definite
history of Q fever. On examination he had aortic stenosis
and incompetence (AS, Al) and a mycotic aneurysm of the
right posterior tibial artery (fig. 1).
His hemoglobin was 11.4 g/100 ml, C. reactive protein
positive, serum protein 8.1 g/100 ml with 3.27 g/100 ml gamma globulin and complement fixing antibody titres greater
than 1:512 to Phase 1 antigen.
He was given a prolonged course of tetracycline. On
March 4, 1969 the aortic valve was removed and a calf
heterograft valve was inserted. The fused bicuspid valve was
disrupted around the whole of the attachment of the noncoronary leaflet and the adjacent anterior commissure, the
valve tissue being like a bowstring across the aortic orifice.
Some necrotic tissue was present with a large anterior commissure aneurysm (3.5 X 2.5 cm) projecting into the ventricular septum. C. burneti was not found in the smears, but
grew in inoculated mice. Repeat angiogram ten days postoperatively showed the posterior tibial aneurysm had disappeared (fig. 2).
The heterograft valve later developed moderate incompetence and was replaced by a ring-supported fascia lata
autograft in 1971. At reoperation no macroscopic or microscopic evidence of persisting Q fever infection was present.
Incompetence was due to a tear in one of the heterograft
valve cusps. The aneurysm had completely healed. The
patient is now asymptomatic and the valve remains competent. It is considered that this man has been cured of Q fever
endocarditis.
Figure 3 shows the changing C.F. antibody titre to Phase
I antigen.
Clinical History
Twenty-one patients with Q fever and cardiac murmurs
were reviewed. Thirteen patients had proven Q fever endocarditis, the organism being identified in the laboratory.
Three additional patients had probable endocarditis with
symptoms and signs of infective endocarditis, negative blood
cultures, and high or rising titres to Phase 1 antigen. Of
these, one patient was considered to have been cured prior to
his death from uremia (case 10) and one died but no autopsy
was done (case 5). The third (case 6) had five years of
tetracycline therapy with apparent clinical cure prior to
operation for residual valve damage. Only the sixteen
patients with Q fever endocarditis are reported in this paper.
The clinical features of these sixteen patients are summarized in table 1, while the important laboratory data are
shown in table 2. Brief accounts of the operative findings
and the clinical course of these patients are presented in
table 3. Two illustrative case histories follow in more detail.
Case 10
W.K., 64 years old, originally a butcher in Scotland, was
first seen in 1963. He was admitted because of pain and
swelling of the right calf and was found to have finger clubbing, anemia and Al.
The hemoglobin was 8.7 g/100 ml, erythrocyte sedimentation rate (ESR) 82 mm/hr, urine showed occasional red
cells and gamma globulin was increased. The C.F. antibody
titre to Phase 1 antigen was 1:1024.
He was treated with pyrrolidino-methyl-tetracycline
(Reverin) 275 mg b.d. and steroids for 52 days and improved. By 1965 the C.F. antibody titre to Phase 1 antigen
Case 3
a
J.D., 44 years old, a meat worker, presented in 1969 with
five year history of a heart murmur. He had developed
From the Cardiac Unit, The Prince Charles Hospital and Princess
Alexandra Hospital, Brisbane, Australia.
Address for reprints: G. H. Neilson, M.D., The Prince Charles Hospital,
Rode Road, Chermside, 4032, Brisbane, Australia.
Received June 5, 1975; revision accepted for publication November 18,
1975.
680
Q FEVER ENDOCARDITIS/Wilson et al.
681
TABLE 1. Stn marcp of Clnical J)ata
No
Occopation
1.
Meat worker
Age af,
rese rii a t 1l(1
.31
Valve
lesICion
AS) AI
5.
Farmier
A-leat woikeri
Flar han(
Farmier'
70
AS, Al
AS. Al
Al
AS, Al
6.
Stdes mnaiager
27
Al. Ml
2.
3.
4.
59
44
t)
Undferrling etiology
Important cliniea!
feat
J)iration of Q fcevi to
ires
crldocarditis
Cotgellit al
bicitspid valve
Fever,, aniginia, (dy spia,
Uiikitowit
Il-hennaltic
Congeiital
Iliennmatic
RLhIenIrnatic
Fever', angina, dy(spnlea
FeveI, spleinomegaly
Fatigue, dysplea
Arrh-llythmia, dyspaet,
Uniknlowin
2 yr
1 yr
11heuLmniatic
Palpitatiolns,ldtyspea
IUtikniowii. Bacterial
finiger clul)bing
14 yr
enidoc arditsisresumed
AS
MS
Conigeniital
lRheumatie
Ilemiparesis, dy,sIpnea
Fever, tiredness,
Salesmani
8
Al
UIiknownt
lIt (her
64
Al
? Conigenital
dyspiea
Fever, tiredness,
hepatosplenomegaly
Veniotis thrombosis leg,
Mltxtte
Meat inlspecto-r}
9.
10.
pr'eVioLnly
years
;)
50
40
7.
S.
8 yr
7 vy
11 yr
Unknown
finiger clubbinig
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l.
Gardenier
Rheumatic
Stable hand
58
20
AS, Al
12.
Al
1Rheumatic
13.
R ailway porter
47
Al
Congenital
14.
Farmer
15.
16.
Farmer
(hriazier
49
49
48
AS Al
Al
AI
Congenital
Congenital
C(ongenital
1)yspnea
Unkrnown
Uinknown
Clubbing, subungual
hemorrhages, dyspiiea
l)yspnea, clubbing
1)yspnea, hemiparesis
Acutte polmonary edemiia,
15 yr
Dyspnea, increasinig
cardiormegaly
Uniknowni
Uniknowrwn
2(0 yr
splenoomegaly
had fallen to 1:64 and to 1:32 by 1966 (see fig. 3). In 1965 he
developed heart failure and in 1966 died from uremia.
At autopsy he was found to have venous thrombi in the
legs and thromboembolism and infarction in the lungs. The
aortic valve cusps showed thickening of the free edges and
the right coronary and noncoronary cusps were roughened
and fused for about 5 mm. There was an aneurysm running
behind this fused area with a blind passage about 20 mm
deep. A full thickness posterior myocardial infarction was
also present. No C. burneti was found at autopsy or grown
in mice. A clinical diagnosis of healed Q fever endocarditis
was made, based on the change in the C.F. antibody titre
during therapy and the autopsy macroscopic appearance.
Death was caused by renal and cardiac failure with
pulmonary thromboembolism. It seems that the initial Q
fever endocarditis may be regarded as having been sterilized.
Discussion
We have now investigated 21 patients who have had Q
fever associated with an organic cardiac murmur. Of the
total, 16 have developed Q fever endocarditis. It is apparent
that such patients should be followed carefully for a long
time.
T ABLiE 2. Important Laboratory Data
ESR
No
1.
2.
3.
4.
,.
6.
7.
8.
9.
10.
11.
FIGURE 1. Angiogram of case 3, showing
the posterior libial artery.
a
sacular
aneurysm
of
12.
13.
14.
15.
16.
(mm/hr)
2
40-60
2
3-23
10
3-75
7-16
29
13
82
47
18
57
23
4
110
Abbreviation: ESR
Urine
(RBC)
No
No
No
No
No
No
No
Occas.
Yes
Occas.
No
No
Occas.
Yes
No
No
Gamma
globulin
3.0 gr
3.27 gb
2.0g 'Ye
3.3 g %I
1.2 5gc
-
Increased
2.01 g %c
1 .9 g 670
Pliase I
titre
(reciprocal)
128
512
512
512
256
512+
512
512
512
1024
512+
512+
512±
512+
1.32 g
%7o
erythrocy te sedimentation rate.
128
128
682
CIRCULATION
VOL. 53, No. 4, APRIL 1976
TABLE 3. Follow-up Data
Follow-up
Operation
Autopsy
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1.
Died of myocardial infarction
2. Aortic valve replacement
(heterograft), valve
annulus aneurysms
extending into septum
3. Aortic valve replacement
(heterograft), annular
aneurysm exteniding into
septum
4. Aortic valve replacement
(heterograft),
no aneurysm
5.6. Aortic valve replacement
(disc valve), no
aneurysms
7. Aortic valve replacement
(fascia lata), annular
aneurysm and thrombus
8.
Developed mitral valve incompetence,
valve competent and well until 412
years postop, died from myocardial
infarctioni
Two years postop AI required
reoperation (fascia lata), no evidence
of Q endocarditis, valve still
competent at 4 yr
Not performed
Valve competent, then died 2 years
postop from dislocated neck after
heavy drinking
Not performed
Sudden death in cardiac failure
Well, no symptoms, competent valve
Bicuspid aortic valve,
friable red vegetations
Not performed
3 years postop, asymptomatic, valve
Died after three months in cardiac
failure
9.
Died of heart failure and uremia
10.
11. Aortic valve replacement, 3 years postop, valve competent,
calcified necrotic leaflets, no cardiac problems
C. burineti on
mouse inoculation
C. burneti on
mouse inoculation
C. burneti On
mouse inoculation
C. burneti
microscopy
Guinea pig developed positive titre
competent
Followed for 7 years, suicide by
shotgun
Bacteriological data
Severe mitral valve stenosis, Vegetations with
irregular- vegetations over
C. burneti on
mitral valve
microscopy
Destroyed anterior leaflet of Microscopic
aortic valve, vegetations
examination of
and aneurysms of annulus
valve showed
C. burneti
posteriorly
Aortic valve congenitally
No C. burneti
bicuspid and fused, annular
2 cm deep aneurysm
anteriorly, large posterior
myocardial infarction
Positive mouse
inoculation
endothelial lined healed
annular aneurysm
12. Aortic valve replacement No evidence of Q endocarditis at
reoperations which were due to
(fascia lata), reoperated
tissue valve failure, died after 4 yr
twice with mounted
homograft & finally
from pneumonia & heart failure
prosthetic valve
13. Aortic valve replacement 1 year postop, asymptomatic, trivial
AI, diastolic murmur
(homograft), calcified
valve, healed aneurysm
14.
15. Aortic valve replacement
Autopsy permission refused
Positive evidence of
C. burneti on
microscopy
Mouse inoculated,
Coccoid organisms
consistent with
C. burneti
Calcified aortic valve stenosis, C. burneti on
Bitten by pig, 2 weeks later cardiac
thrombus & subannular
failure, died of Klebsiella
microscopy
septicemia from infected intravenous aneurysm, tricuspid valve
thrombus showed C.
site
burneti organisms
1 year, asymptomatic, valve
Positive mouse
competent
inoculation
(ball valve), thrombi
and annular aneurysm
16. Aortic valve replacement 1 year, asymptomatic, valve
(disc), calcified, bicuspid, competent
perforated valve with
annular aneurysm
The longest "proven" interval between the original attack
of Q fever and the clinical onset of Q fever endocarditis was
seven years. This patient lived for a further eight years (and
died by suicide) and his cardiac signs were not worsening at
the time of his death (case 8).
It is probable that others had their initial Q fever 20 years
(case 16), 14 years (case 2), 15 years (case 13), and 11 years
(case 9) prior to their clinical presentation with Q fever
C. burneti grown
endocarditis, but these times are based only on histories
given by the patients.
Several of the other patients gave brief histories, but in
some the initial history of "Q fever" was clearly the symptomatic onset of their Q fever endocarditis. However, both
the initial attack of Q fever and the onset of Q fever endocarditis evidently may occur many years before clinically
serious valve damage from the endocarditis occurs; hence, it
Q FEVER ENDOCARDITIS/Wilson et al.
'..
683
.--.:!C
2 56
4
i
K>
R~~~~~~~~~~~e-ol,
v
'.0
Died
Cdase 10
'~~~~
*<
\
~~~~~d
years of lollow ,Ip
FiGURE 3. Diagram showing the changing titres of complement
fixing antibody to Phase 1 antigen in cases 3 and 10.
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FIGURE 2. Angiogram from the same patient as in figure I ten
days after valve replacement and the commencement of tetracycline
therapy.
is
of the most indolent forms of infective endocarditis.
Diagnostic features often quoted for Q fever endocarditis
include: male patients with aortic valve disease4 usually with
anemia and a raised ESR5 and typically with a rise in the
gamma globulin level. Grist5 also states that the white cell
one
count may be low or normal and that albuminuria may often
be present without red cells in the urine. Robson and Shimmin6 state that there may be no anemia, leukocytosis, embolic phenomena, or red cells in the urine.
In our own 16 patients, 15 had some form of aortic valve
disease, two had associated aortic and mitral lesions and
only one had isolated mitral stenosis. One patient (case 14)
had tricuspid as well as aortic valve involvement. All were
males, and 11 were meat industry workers or farmers. Ten
had a raised ESR at some time in their illness, but contrary
to Grist's findings, only one ever had hemoglobin less than
11 g/100 ml and this patient died of uremia and pulmonary
thromboembolism.
Gamma globulin was increased in eight of the nine
patients in whom it was measured. The white cell count in
the blood was over 10,000/mm3 in only two patients. Fever
was rarely present and only three of our patients had emboli
from their valves. The patient who developed a mycotic
aneurysm (shown radiographically and disappearing after
treatment) had the first such lesion to be described in Q fever
endocarditis (case 3).
In this series, as in that of Robson and Shimmin,6 anemia,
leukocytosis, hematuria and emboli were uncommon. The
most useful laboratory finding would appear to be increased
gamma globulin, present in most cases tested for it in our experience. Other tests were of little diagnostic value except
for the C.F. antibody titre.
Elevated C.F. antibody titre for the Phase 1 antigen of Q
fever suggests a past persistent infection. It is the usual
laboratory clue that confirms the suspicion of Q fever endocarditis. In our laboratory all but one patient who have ever
shown a Phase I titre of 1:256 or greater have eventually
been shown to have Q fever endocarditis. The one exception
is still being followed. In the symptomatic stage only four
patients with Q fever endocarditis had a Phase I antibody
titre of less than 1:512 (one was 1:256 and three were 1:128).
In our laboratory, therefore, Phase I antibody titres of 1: 128
and above suggest the diagnosis. All patients with these
levels are followed up carefully. Readings of 1:512 or greater
are virtually diagnostic of the presence of Q fever endocarditis.
At least one of our patients had a known valvular lesion
before his initial attack of Q fever and, in three others, the
valvular lesion was known to be present long before the
overt symptoms of Q fever endocarditis appeared. In seven
patients the aortic valve was bicuspid, indicating a congenitally abnormal valve prior to the onset of the Q fever
endocarditis. Four patients gave a history of recurrent
rheumatic fever and in two others valve thickening, cusp fusion and valve calcification were compatible with rheumatic
valve damage prior to the onset of Q fever endocarditis.
While in some patients it was impossible to ascertain
whether the valve was normal or abnormal prior to the onset
of rickettsial endocarditis, in most patients it would appear
that the infections occurred on a valve already damaged by
rheumatic fever or on one which was congenitally abnormal.
In our experience, the appearance of the affected valve is
typical. The valves are often calcified with small areas of
necrotic, thrombotic vegetations. Ten of the 14 aortic valves
with endocarditis, either operated on or seen at autopsy,
showed aneurysms of the aortic wall at the base of the
leaflet. Such aneurysms were particularly striking in case 9
and in the patient whose infection we considered to have
been cured by therapy (case 10). These aneurysms are
demonstrable angiographically and are helpful in establishing the diagnosis of Q fever endocarditis (fig. 4).
The most useful drug in the treatment of Q fever endocarditis is tetracycline,7 and we have used 500 mg four times
daily for some months, then 250 mg four times daily for a
year or more. If oral therapy should cause side effects,
parenteral pyrrolidino-methyl-tetracycline should be used,
as in case 10. It seems probable that this patient's Q fever
endocarditis was sterilized by tetracycline therapy. Clinical
features for the diagnosis were present. Following therapy
684
CI RCU LATION
VOL. 53, No. 4, APRIL 1976
FIGURE 5. Photomicrograph X 1000 of aortic valve tissue from
patient 13, showing the presence of numerous coccoid organisms,
the appearance of which is consistent with Coxiella burneti.
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FIGURE 4. Aortogram showing aneurysm of the aortic
valve incompetence outlining the left ventricular cavity.
root
and
the antibody titres to Phase 1 antigen fell (fig. 3), and when
he died three years later an aneurysm similar to those often
seen with Q fever endocarditis was found but no C. burneti
was isolated.
Trimethroprim with sulphamethoxazole has been suggested as an alternative treatment8 but we have no personal
experience with its use.
An index of the success in controlling the Q fever infection
is the behavior of the C.F. antibody to Phase I antigen. The
falling titre following surgery and tetracycline therapy is illustrated by case 3 (fig. 3) at the time when macroscopic and
microscopic examination for Q fever infection was negative
at the second operation.
Valve replacement is undertaken when, despite medical
treatment, increasing symptoms and worsening hemodynamics occur. Ten such patients were submitted to surgery. In case 2, clinical mitral incompetence and increasing
heart size were noted one year after the aortic valve replacement. The aortic valve replacement remained competent
throughout. Whether the mitral valve lesion was related to Q
fever endocarditis, or to dilatation of the left ventricle
associated with coronary artery disease is not clear. Falling
antibody titres to both Phase I and Phase 2 antigen suggests
that the Q fever infection was controlled.
In case 12 the aortic valve was replaced but the presence
of Q fever endocarditis was not recognized at first. Aortic incompetence developed due to technical factors, but after a
course of tetracycline, at reoperation three months later no
macroscopic or microscopic evidence of continuing Q fever
infection was present. As in this case, in our experience, no
prosthetic valve replacing a Q fever infected valve has been
damaged by continuing Q fever infection, all patients of
course being treated postoperatively with tetracycline.
Acknowledgment
The authors wish to acknowledge the assistance given by the Laboratory of
Microbiology and Pathology, Queensland Health Department and the
Queensland Institute of Medical Research.
References
I. Derrick EH: Q fever, a new fever entity: Clinical features, diagnosis and
laboratory investigation. Med J Aust 2: 281, 1937
2. Powell OW, Stallman ND: The incidence and significance of phase I
complement-fixing antibody in Q fever. J Hyg Camb 60: 359, 1962
3. Marmion BP, Higgins FE, Bridges JB, Edwards AT: A case of subacute
rickettsial endocarditis with a survey of cardiac patients for this infection.
Br Med J 2: 1264, 1960
4. Kristinsson A, Bentall HH: Medical and surgical treatment of Q fever
endocarditis. Lancet 2: 693, 1967
5. Grist NR: Annotation. Am Heart J 75: 846, 1968
6. Robson AO, Shimmin CDGL: Chronic Q fever: Clinical aspects of a
patient with endocarditis. Br Med J 2: 980, 1959
7. Powell OW, Kennedy KP, Mc Iver M, Silverstone H: Tetracycline in the
treatment of Q fever. Australasian Ann Med 11: 184, 1962
8. Freeman R, Hodson ME: Q fever endocarditis treated with Trimethoprim
and Sulphamethoxazole. Br Med J 1: 419, 1972
Q fever endocarditis in Queensland.
H G Wilson, G H Neilson, E G Galea, G Stafford and M F O'Brien
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Circulation. 1976;53:680-684
doi: 10.1161/01.CIR.53.4.680
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1976 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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