<div>Blood culture- negative Infective endocarditis presenting with atypical
dermatologic manifestation: a rare case report and review of the
literature</div><div><sup>1</sup>Maedeh Najafizadeh , <sup>2</sup>Fatemeh
Dashti , <sup>3</sup>Hamed Pahlevani , <sup>2</sup>Farzad
Kamalizad , <sup>2,*</sup>Seyed Mohammad Ali Mirazimi</div><div><sup>1</sup> Assistant professor of infectious diseases,
department of infectious diseases, Kashan school of medicine,Kashan
university of medical sciences,Kashan,Iran</div><div><sup>2</sup> Department of infectious diseases,Kashan school of
medicine , Kashan university of medical sciences,Kashan, Iran</div><div>3 Department of anesthesiology,Kashan school of medicine, Kashan
university of medical sciences, Kashan,Iran.</div><div>*Correspond author:</div><div>Seyed Mohammad Ali Mirazimi, department of infectious diseases, Kashan
school of medicine, Kashan university of medical sciences, Kashan,Iran.
Telephone:+989136431885 , E-mail: m.azim1371@gmail.com</div><div>Introduction</div><div>Infective endocarditis (IE) is characterized by inflammation of the
endocardium, including the endocardial wall and heart valves (1). Blood
culture-negative endocarditis (BCNE) is marked by probable or definite
endocarditis where three or more blood cultures sampled over 48 hours
are negative despite adequate incubation(&gt; I week). It
accounts for 2.5% to 31% of all cases of IE(2) . Major causes of BCNE
include: 1) Antibiotic administration prior to sampling (often due to
infection with prevalent causative organisms, such as<i>streptococci</i> , <i>staphylococci</i> , or <i>enterococci</i> ), 2)
presence of fastidious organisms, which are hard to culture. These
include <i>Propionibacterium acnes</i> , <i>HACEK</i> bacteria,
defective <i>streptococci - Gemella</i> , <i>Abiotrophia</i> sp.,<i>Granulicatella</i> and <i>Candida</i> . 3) the “true” BCNE due to
infection with intra-cellular organisms that may not be typically
cultured using conventional techniques ( usually due to infection with<i>Bartonella</i> or <i>Coxiella burnetti</i> ) (3).</div><div>IE occurs most commonly in susceptible patients with prosthetic heart
valves, unrepaired cyanotic congenital heart diseases, rheumatic fever,
intracardiac devices , previous IE and history of intravenous drug use.
Nonetheless, approximately half of the affected patients have no
associated risk factor (4).</div><div>IE often presents with symptoms of multi-organ involvement. Dermatologic
manifestations of IE include Osler’s nodes, Janeway lesions, cutaneous
infarcts and petechiae, which usually manifests later in the disease
course. Although skin manifestations are important in evaluating
patients with infective endocarditis, few studies in the literature
evaluated their importance in the disease manifestation and the
diagnostic dilemma associated with atypical presenting symptoms.</div><div>This paper presents a case of IE with atypical skin manifestations and
reviews the major skin findings in the affected patients.</div><div>Case presentation</div><div>The patient is a 58-year-old man with a medical history of type 2
diabetes mellitus and ischemic heart disease with recent acute
myocardial infarction and primary cutaneous intervention (PCI) who
presented to the emergency department with abrupt onset of shaking
chills associated with fever and drenching sweats. The day prior to
admission, the patient had similar symptoms, for which he received
intravenous anti-pyretics in a primary urgent care centre. In addition,
he complained of an erythematous papular rash starting 10 days prior to
admission, which had initiated from the right arm and forearm and
further progressed to involve the bilateral upper extremities, anterior
aspect of the left knee and fingers of the both hands. After 7 days,
these lesions had progressed into painful ulcers with crusted and
necrotic center without associated purulent discharge, especially in the
arms and fingers. The patient did not seek any medical care for these
skin lesions. In addition, he also suffered from an episodic,
retrosternal chest discomfort for one week. Social history was
significant for exposure with poultry. The patient was a life-time
non-smoker and did not use illicit or recreational drugs.</div><div>Upon arrival, the patient was alert, oriented and toxic-appearing with
blood pressure of 103/56 mmHg, temperature of 38.5°C, heart rate of 78
beats/min and respiratory rate of 17/min. Physical examination of the
skin revealed numerous erythematous papules and plaques of 1*1to 2*2 cm
mainly located on the extensor aspect of the right forearm, anterior
aspect of the left knee and first finger of the left hand. These lesions
had an erythematous rim and central, necrotic crusts in association with
a mild purulent area surrounding the crusted zone. There were no
purulent discharges and the lesions were extremely tender to minimal
palpation. Since the patient was initially admitted in the emergency
department, no picture of the initial lesion is present. His cardiac
examination showed a regular rhythm and rate with no murmurs. The
remainder of the physical examination was normal.</div><div>Laboratory evaluation demonstrated no significant leukocytosis but an
elevated ESR (erythrocyte sedimentation rate) and CRP(C-reactive
protein). The results of the complete metabolic panel were within the
normal ranges. Serial troponin and Ekg monitoring were normal. Chest
X-ray revealed no abnormality. Blood cultures acquired initially were
negative. Infectious disease consultation was obtained and intravenous
antibiotics (levofloxacin+imipenem) were administered to treat the
probable pseudomonal –related sepsis due to probable ecthyma
gangrenosum. Fever was subsided and skin rash was improved following
administration of antibiotics. During the course of hospitalization,
three separate sets of blood cultures were obtained and turned negative.</div><div>Dermatology consultation was performed and smears of the lesions were
obtained and cultured to evaluate cutaneous leishmaniasis, gram positive
organisms including <i>Streptococci</i> , <i>Bacillus anthracis</i> and
fungal infections. Since the patient was from an endemic region for
malaria and leishmania infection, the peripheral blood smear was
evaluated for malaria and leishmania parasites. Intravenous levofloxacin
was exchanged for oral levofloxacin. The gram smear of the lesion
demonstrated gram-positive cocci with polymorphonuclear cells with no
fungi, bacillus or leishmania bodies. Culture of the lesion turned
negative after adequate incubation. On the 7<sup>th</sup> day of
admission,the fever relapsed. Covid-19 PCR was obtained and turned
positive. As a result, early treatment with remdesivir was initiated,
levofloxacin was discontinued and intravenous vancomycin was instilled.
The patient developed new erosive oral enanthems and smaller lesions
similar to the primary manifestation, most commonly on the fingers and
the left knee (Figure 1). Considering this and the recently-diagnosed
Covid-19 infection, the cutaneous lesion of knee was biopsied.
Subsequently, the patient complained of intermittent, short-lasting,
squeezing chest discomfort accompanied by mild dyspnea. Serial Ekg
monitoring and blood troponin levels were normal .Cardiology consult was
re-evaluated and TTE (transthoracic echocardiography) demonstrated
normal LV (left ventricular) systolic function, mild LV diastolic
dysfunction , 1+ tricuspid valve regurgitation , mild mitral
regurgitation and vegetation-like lesions on the surface of mitral valve
leaflets(Figure2) . Meanwhile, repeated blood cultures turned negative .
A previous TTE from 3 months earlier revealed no abnormality, despite
mild LV diastolic dysfunction following acute myocardial infarction. The
result of the skin biopsy revealed perivascular inflammatory
infiltrates, predominantly polymorphonuclear cells and lymphocytes in
combination with extravasated red blood cells and fragmented nuclear
debris, consistent with cutaneous leukocytoclastic vasculitis (Figure3).</div><div>The patient was subsequently diagnosed with possible subacute bacterial
endocarditis based on the modified Duke criteria for infective
endocarditis; as having endocardial involvement as the major clinical
criteria and fever, vascular phenomena as the minor criteria. The skin
lesions were likely due to septic embolization and deposition of
circulating immune complexes with the resultant leukocytoclastic
vasculitis. Antibiotic therapy was continued and the patient’s symptoms
improved remarkably and he was finally discharged home with stable vital
signs.</div><div>Discussion</div><div>Infective endocarditis (IE) may lead to life-threatening complications.
The incidence of IE has changed widely in the last decade, with a
significant rise particularly in the developing countries (5).Symptoms
of IE are caused by a variety of mechanisms: a) direct local destruction
of the involved endocardial surfaces, b) hematogenous dissemination to
other tissues, c) metastatic embolization of fragments to other organs,
and d) formation of immune complexes and precipitation in the distant
sites. IE is currently diagnosed based on the modified Duke criteria,
with a sensitivity of 80% and specificity of 99%,however its diagnosis
may be delayed due to the wide range of non-specific symptoms (6). In
the developed countries, <i>Staphylococci</i> has become gradually as
the most frequent pathogenic organism isolated in infective
endocarditis, possibly due to increased rate of intravenous drug use or
advanced hemodialysis ,whereas <i>Streptococci</i> accounts for the
majority of cases in the developing countries(7, 8). Rate of positive
blood cultures in patients with infective endocarditis ranges between 83
to 96% in developed countries (9).Extensive administration of
antibiotics prior to sampling may contribute to the low rate of
microbiological detection in BCNE, particularly due to gram-positive
cocci. Installation of specific PCR (polymerase chain reaction) tests
depending on the geographic distribution pattern of most common
causative organisms, may yield a higher detection rate (10).Likewise,
our patient had negative blood cultures on serial sampling, possibly due
to consumption of antibiotics prior to referral to our hospital.</div><div>Infective endocarditis may present with skin lesions in approximately
5% to 25% of affected patients. The most commonly reported cutaneous
lesions include purpura, followed by Osler nodes and Janeway lesions in
decreasing order of frequency. Purpura are more commonly found on the
lower extremities(11).The incidence of Osler nodes and Janeway lesions
have reduced significantly in the recent years, changing from 10–23%
in the 1980s to &lt;10% for Osler nodes and ranging between
1.6% -4.7% for Janeway lesions(12). This decline is likely due to
earlier diagnosis of IE and installation of treatment, which does not
allow the formation of skin lesions (11). Based on the modified Duke
criteria, Osler nodes and Janeway lesions are considered immunologic
phenomena and vascular phenomena; respectively, however, both these
lesions have similar pathogenesis, with septic microemboli lodging in
vessels, leading to the activation of pro-inflammatory cytokines. In
addition, immune-mediated vasculitis has been also found in the
pathogenesis of Osler nodes. Histopathologic examination of both lesions
demonstrates septic microemboli with necrotic dermal micro-abscesses
(13).Osler nodes are characterized clinically as tender, subcutaneous ,
violaceous nodules most frequently located on the toes and fingers and
to a lesser degree on the lateral digits, thenar and hypothenar region.
On the other hand, Janeway lesions are marked by irregular, non-tender,
erythematous or hemorrhagic nodules or macules, often found on the palms
(12).</div><div>Cutaneous leukocytoclastic vasculitis is characterized by vasculitis of
small-sized, dermal capillaries and venules. It may occur as a result of
autoimmune disorders, drug reactions, malignancy and infections.
Clinically, it manifests as erythematous, palpable purpura on the
dependent lower extrimities. Most common infectious causes of
leukocytoclastic vasculitis include <i>streptococci</i> and<i>staphylococci</i> (14). Cutaneous leukocytoclastic vasculitis as the
the presentation of infective endocarditis has been reported well in the
literature. It is likely due to the deposition of circulating immune
complexes and emboli on the vascular endothelial surface(15) .Moreover,
cutaneous leukocytoclastic vasculitis may be associated with deposition
of IgA in various organs, specifically the kidneys , resulting in
varying degree of proteinuria, hematuria or renal failure and IgA
glomerulonephritis in the renal biopsy(16).In our patient, although the
lesions were not typical of leukocytoclastic vasculitis, the histologic
examination was consistent with cutaneous leukocytoclastic vasculitis ,
and the gram smear of the lesion showed gram-positive cocci , excluding
other non-infectious causes, highlighting an underlying infectious
disorder as the culprit of his skin finding , which in association with
his other clinical symptoms (dyspnea, chest pain) raised suspicion for
infective endocarditis. Of note, skin manifestations carry poor
prognosis in infective endocarditis, as they are associated with an
embolic process (11).</div><div>Complex percutaneous coronary intervention (PCI) requires installation
of numerous devices into the arterial circulation, which increases the
likelihood of bacteremia or septicemia. In a study of Ramsdale et al.,
17.7% of patients undergoing complex PCI developed bacteremia
immediately following PCI, with the <i>coagulase-negative
staphylococci</i> being the most commonly isolated organism and 12%
developed positive blood cultures within 12 hours post-PCI.
Interestingly, no clinical sequelae developed (17). Our patient had a
recent history of PCI 4 weeks prior to admission. This hint in
association with gram-positive cocci in the gram smear of lesions and
resolution of lesions following administration of vancomycin ,
implicates c<i>oagulase-negative staphylococci</i> as the causative
organism.</div><div>Our case displays the cutaneous manifestations of IE as the presenting
symptoms in the absence of other more common features. Hence, clinicians
must carefully assess for skin manifestations in borderline scenarios,
as skin involvement often conveys worse outcomes.</div><div>Conclusion</div><div>Our case depicts atypical presentations of IE that may complicate the
initial diagnosis.It is noteworthy for physicians to investigate for the
skin lesions of IE, particularly when the diagnosis is not definite.Skin
manifestations implicate an increased risk of embolic complications,
thus delayed diagnosis may be life-threatening.This further necessitates
the importance of thorough physical examination for physicians.</div><div>Keywords: Infective endocarditis, skin, cutaneous leukocytoclastic
vasculitis , PCI</div><div>Availability of data and materials</div><div>The datasets during the current study are available from the
corresponding author on reasonable request.</div><div>Ethics approval and consent to participate</div><div>Informed written consent was obtained from the patient for publication
of this report and any accompanying images.</div><div>Funding Source</div><div>No funding or sponsorship was received for this study or publication of
this article.</div><div>Competing interests</div><div>No competing interests .</div><div>Conflict of Interest</div><div>All co-authors contributed significantly to this study.MM, JA,MS
collected images . Design of the study was conceptualized by MM,JA. The
initial draft of the manuscript was written by FD,SMM. Final version of
the manuscript was edited by MM,FD. This manuscript has not been
submitted to, nor is under review at, another journal or other
publishing venue. The authors have no affiliation with any organization
with a direct or indirect financial interest in the subject matter
discussed in the manuscript.</div><div>Consent for publication</div><div>Not applicable.</div><div>Acknowledgements</div><div>Not applicable.</div><div>Refrences:</div><div>1. Bumm CV, Folwaczny M. Infective endocarditis and oral health-a
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invasive cardiology. 2004;16(11):632-4.</div><div>Legends of descriptive:</div><div>Figure 1</div><div>Round, well-circumscribed ulcers with erythematous border and necrotic
central zone.</div><div>Figure 2</div><div>Small, vegetation-like particles are evident on the surface of mitral
valve leaflet.</div><div>Figure 3</div><div>Skin biopsy of the knee lesions. Perivascular inflammatory infiltrates ,
mainly composed of neutrophils and lymphocytes in association with
extravasated red blood cells and fragments of the nuclear debris.</div>