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\begin{document}

\title{The importance of exposures in Culture-negative endocarditis in an IV
drugs abuser}



\author[1]{Sara Ghaderkhani}%
\author[2]{Bahar Haghdoost}%
\author[2]{Amirhossein Eghbal}%
\author[3]{Saber Esmaeili}%
\author[1]{Mahsa Azadbakhsh Kanafgorabi}%
\author[2]{Saharnaz Sazgarnejad}%
\author[2]{Arash Seifi}%
\author[1]{Ensiyeh Rahimi}%
\affil[1]{Imam Khomeini Hospital Complex}%
\affil[2]{Tehran University of Medical Sciences}%
\affil[3]{Pasteur Institute of Iran}%


\vspace{-1em}



  
  \date{June 12, 2024}


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\textbf{Introduction}

Infective endocarditis (IE) is a severe and life-threatening disease
worldwide (1). However, because of non-specific clinical presentations,
confirmation and prescription of effective treatment are sometimes not
simple tasks. History may help significantly in the diagnosis of IE; for
example, it is more common among drug addicts, particularly Intravenous
drug users (2, 3).

Approximately 5\% of IE cases have negative blood cultures (4, 5), and
its risk factors are exposure to slow-growing bacteria such as
Bartonella species, fastidious nonbacterial organisms, previous
antibiotic use, underlying valvular heart disease, and intracardiac or
vascular device or other foreign bodies in contact with the blood (6).

Most patients have nonspecific symptoms such as fever, fatigue, and
weight loss. In a case series comprising 348 blood culture-negative
endocarditis cases from France, almost all the patients had a fever as a
presenting symptom. In contrast, about 50 to 70\% had symptoms of heart
failure, such as exertional dyspnea, and about 50\% had insidious weight
loss(9).

Bartonella spp. is a small, intracellular, gram-negative, and very
fastidious rod mainly transmitted by vectors; they are the second most
common cause of culture-negative endocarditis. Among the cases of
Bartonella endocarditis, two species predominantly implicated in causing
culture-negative endocarditis are B. henselae and B. quintana(7).

These bacteria have been isolated from many mammalian species, including
cats and dogs. It can cause mild infection to severe and
life-threatening endocarditis in humans and dogs. In dogs, several
Bartonella species have been identified; one of the most common ones is
B. henselae.

It should be mentioned that in recent years, more cases of
culture-negative endocarditis have been reported from developing
countries(8).

This report presents a case of a patient with culture-negative B.
henselae endocarditis from Iran, diagnosed using a combined diagnostic
approach that included clinical evaluation, imaging, epidemiology,
serology, echocardiography, and transthoracic echocardiography (TTE).

Patient Information

The patient was a 38 years old male, single and unemployed with a
history of addiction, who had received care from a treatment camp for
six months. He was discharged when he was on methadone maintenance
therapy just before his first hospital admission. He was an IV drug
abuser with a history of regularly using amphetamine, cocaine, and
heroin. He also smoked cigarettes for 20 years. He also exposed that he
had unsafe sex and lost contact with dogs and cats.

Clinical Findings Timeline

The symptoms onset was 20 days before admission when he had fever and
chills besides shortness of breath in the camp. The patient was
hospitalized in another care center for five days as a suspected
COVID-19 case and he was treated with Remdesivir, but his nasopharyngeal
and oropharyngeal COVID-PCR tests were negative. Having been discharged
from the hospital, he started using amphetamine again, which
deteriorated his condition.

This time he was admitted to our center, as a referral center, with
severe dyspnea, high fever (40), chills, chest pain, myalgia, and
hemoptysis. The patient was ill and, on physical examination, he had
tachycardia (Heart rate=107) and tachypnea (Respiratory rate=28), with
low blood pressure (90/60), fluctuated oxygen saturation which was less
than 92\%, normal heart auscultation, no clubbing, no splenomegaly, and
no lymphadenopathy. Table 1 summarizes the lab results.

Table 1: the results of main lab tests at the admission time\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
WBC & 18,100 (normal range between 4,500-11,000)\tabularnewline
Procalcitonin & More than 30 (normal range between 0.5-5)\tabularnewline
Covid PCR test & Negative\tabularnewline
CRP & 174 (normal range: Less than 10 mg/L)\tabularnewline
Creatinine & 1.1\tabularnewline
Troponin & Negative\tabularnewline
D-dimer & 25.14 (normal range: less than 0.50)\tabularnewline
Blood culture (3 times) & Negative\tabularnewline
HCV Ab & Positive\tabularnewline
HCV PCR & Negative\tabularnewline
\bottomrule
\end{longtable}

Diagnostic Assessment \& Therapeutic Intervention

Due to fever, dyspnea, and an SPO2 below 90\%, a Computed Tomography
(CT) was performed. The chest CT showed moderate pleural effusion and
bilateral emphysema in the apex of the lungs and cardiomegaly. Pelvic
and abdominal ultrasounds were normal. Because of dyspnea, tachycardia
elevated D-dimer, and SpO2 of less than 90\%, we decided to take CT
angiography for pulmonary thromboembolism (PTE). CT angiography showed
PTE, moderate pleural effusion in the right lung compatible with
empyema, and a blurred wedge in the left upper lobe (LUL). We put the
patient under anticoagulation therapy with warfarin, after PTE was
diagnosed, and based on the~loculated~pleural fluid~in the CT scan,
empyema pattern, and the patient's fever, the effusion was tapped, and a
chest tube was placed. The patient's pleural fluid was analyzed, which
was exudative with Alb=900, Pro=2400, LDH=1184, RBC=50, WBC=3400,
Glucose=80, and negative culture.

The lung field was found to have a septic embolism pattern, which led to
an echocardiogram. Upon echocardiography, small vegetation was detected;
therefore, a transthoracic echocardiogram (TTE) was conducted to
confirm. TTE showed severe tricuspid valve damage, 8 millimeter
vegetation in place, increased pulmonary artery pressure (PAP= 40), and
ejection fraction(EF)=45\%, confirming the vegetation on the atrial side
of the tricuspid valve.

According to the findings, the first diagnosis was right-side
endocarditis, which led to septic embolism, so we started empiric
antibiotic therapy with vancomycin plus ceftriaxone. After two weeks of
constant fever despite broad-spectrum antibiotic therapy and pleural
effusion drainage, we changed the antibiotic regimen to vancomycin plus
meropenem, and, re-evaluated our diagnosis by taking a detailed history,
re-sending blood cultures, which were negative 3 times, performing
abdominal ultrasound and investigating the possible causes of
culture-negative endocarditis including Q fever, bartonella, and
brucellosis, according to the history of staying in the camp. The
serology and blood PCRs were sent to the laboratory of the Pasteur
Institute of Iran. The PCR and serology for Q-fever were negative.
serology wright and 2-ME test for brucellosis were negative, but a
serology test confirmed for Bartonella henselae with a 1: 2048
titer.11the kit used was Bartonella IFA IgG.

In the meantime, we changed the patient's drug regimen to doxycycline
(100 mg twice daily), instead of aminoglycosides, plus rifampin (300mg
twice daily), due to the high level of creatinine (3-3.3 mg/dL), and
warfarin was switched to enoxaparin due to rifampin and warfarin drug
interactions and patient noncompliance.

After 72 hours he responded to this drug combination significantly;
fever, tachycardia, and dyspnea improved, creatinine levels decreased
and the pleural fluid test result was negative for Bartonella. After two
weeks, rifampin was discontinued, but he received an extended course of
doxycycline monotherapy. Also, due to severe tricuspid valve
insufficiency, he underwent medical treatment, but because of his
addiction, the cardiac surgery service did not recommend him for
valvoplasty. A summary of the clinical practice of the patient is shown
in Figure 1.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Fig 1. Timeline of symptoms onset \& interventions.

Follow-up and Outcomes

After two weeks of treatment with doxycycline plus rifampin, clinically,
the patient recovered with no difficulty in breathing and no chest pain.
The results of the follow-up serology for B. henselae IgG were 1:512.
The patient was discharged from the hospital approximately four weeks
after admission, with a recommendation to visit a cardiologist, stop his
IV drug abuse, and continue doxycycline and enoxaparin. A controlled
chest X-ray showed improvement, and the chest tube was discontinued. The
patient left the hospital in good general condition, without fever, with
a normal heart rate and acceptable SpO2 (\textgreater{}94\%).

\textbf{Discussion:}

Blood culture-negative IE has a high variation in prevalence among
countries; the reports vary from 2.5- 70\% of all infective endocarditis
based on zoonotic agent exposure, antibiotic prescription pattern, and
diagnostic tools (10).

Bartonella species are among the main microorganisms in culture-negative
endocarditis. Meanwhile, among all 45 known Bartonella species, B.
henselae is the second most common cause of culture-negative
endocarditis(11). While cats and cat-scratch are considered the main
reservoir of B. henselae, dogs could also transmit infection as
accidental hosts(12).

Moreover, although Bartonella endocarditis is a worldwide issue and
there are case reports from all parts of the world, most reported cases
are from European countries and the Americas(11).

In this article, we are reporting a case of Bartonella endocarditis in
Iran; it is notable that since Bartonella endocarditis is not common in
Iran, usually physician does not put this agent on the list of their
differential diagnosis, which causes several challenges to achieving a
timely diagnosis and treatment of Bartonella endocarditis. Besides, the
final diagnosis is even more challenging due to non-specific symptoms,
which are the same as other subacute endocarditis or infective
syndromes.

Moreover, the diagnosis is more challenging during the COVID-19 pandemic
and the similarity between the typical symptoms of SARS-CoV-2 and
endocarditis (13). Nevertheless, several diagnostic tools are available;
despite their limitations, such as low specificity and cross-reactions,
serology is still considered valuable in diagnosing Bartonella
endocarditis(14). Also, PCR testing on whole blood or plasma specimen,
with approximate sensitivity of 58\% and specificity of 100\%, is an
effective diagnostic tool(15).

In this case, the patient had a history of contact with dogs, but based
on previous studies, connection with cats is more common in most B.
henselae endocarditis cases.

Moreover, in the current case, one of the first complaints of the
patient was exertional dyspnea, and heart failure manifestations are
considered an acute coronary syndrome. At the same time, based on the
study conducted by Okaro et al., approximately 50 to 70\% of Bartonella
endocarditis presents symptoms of heart failure, including exertional
dyspnea(11).

Low socioeconomic status is one of the underlying determinants of
developing B. quintana endocarditis. While in our patient, who was
diagnosed with B. henselae, the patient's social history regarding
IV-drug abuse and low socioeconomic status were the most important
considerations (11). Also, prognosis and treatment must consider
epidemiological exposure and alternate diagnoses for culture-negative
endocarditis in individuals who don't respond to therapy.

The authors of the article include: Sara Gaderkhani, Bahar Haghdoost,
Amirhossein Eghbal, Mahsa Azadbakhsh Kanafgorabi, Saharnaz Sazgarnejad,
Saber Esmaeili, Arash Seifi, Ensiyeh Rahimi.

S.Ghaderkhani, A.Seifi and E.Rahimi contributed to the conception and
design of this report. The case was diagnosed and followed up by S.
Sazgarnejad and S.Esmaeili. B.Haghdoost, A.Eghbal, M.Azaadbakhsh and
S.Sazgarnejad participated in data collection. B.Haghdoost, A.Eghbal and
M.Azaadbakhsh wrote the article. All authors contributed to data
interpretation, critically reviewed the article and approved the final
draft for submission.

This manuscript is original, is not published, in press, or submitted
elsewhere in English or any other language and is not currently being
considered for publication elsewhere.

All authors have seen and approved the content of the manuscript and
have contributed significantly to the work.

This study has been approved by the ethics committee of Tehran
University of Medical. Sciences, adheres to the Declaration of Helsinki
and informed consent was taken.

The patient has given a written informed consent for the publication.

The authors confirm that written consent has been obtained from the
patient for submission and publication.

All the patient's data and materials are provided in the manuscript.

The authors declare that they have no competing interests.

Funding do not applicable in this manuscript.

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Epidemiologic aspects of infective endocarditis in an urban population.
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3. Murdoch DR, Corey GR, Hoen B, Mir\selectlanguage{ngerman}ó JM, Fowler VG, Bayer AS, et al.
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13. Arbune M, Iancu AV, Lupasteanu G, Vasile MC, Stefanescu V. A
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14. Barka NE, Hadfield T, Patnaik M, Schwartzman WA, Peter JB. EIA for
detection of Rochalimaea henselae-reactive IgG, IgM, and IgA antibodies
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1993;167(6):1503-4.

15. Sanogo YO, Zeaiter Z, Caruso G, Merola F, Shpynov S, Brouqui P, et
al. Bartonella henselae in Ixodes ricinus ticks (Acari: Ixodida) removed
from humans, Belluno province, Italy. Emerg Infect Dis.
2003;9(3):329-32.\selectlanguage{english}
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