\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Hemophagocytic Lympho-Histiocytosis Secondary to Rickettsial Infection:
A Case Report}



\author[1]{Shriya Sharma}%
\author[2]{Aakriti Adhikari}%
\author[3]{Nirmal Ghimire}%
\author[1]{Gaurab Mainali}%
\author[4]{Sumit Yadav}%
\author[2]{Prasamsa  Pudasaini}%
\author[2]{Shashank Neupane}%
\affil[1]{Nepalese Army Institute of Health Sciences College of Medicine}%
\affil[2]{Nepalese Army Institute of Health Sciences}%
\affil[3]{Nepal Police Hospital}%
\affil[4]{Birendra Sainik Aspatal}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Hemophagocytic Lympho-histiocytosis (HLH) is a rare life-threatening
condition characterized by widespread activation of the immune system
leading to tissue damage all over the body.%
\end{abstract}%



\sloppy


\textbf{Hemophagocytic Lympho-Histiocytosis Secondary to Rickettsial
Infection: A Case Report}

Shriya Sharma\textsuperscript{1}, Aakriti Adhikari\textsuperscript{1},
Nirmal Ghimire\textsuperscript{2}, Gaurab Mainali\textsuperscript{1},
Sumit Kumar Yadav\textsuperscript{3}, Prasamsa
Pudasaini\textsuperscript{1}, Shashank Neupane\textsuperscript{1}

\textsuperscript{1}Nepalese Army Institute of Health Sciences,
Kathmandu, Nepal

\textsuperscript{2}Department of Internal Medicine, Nepal Police
Hospital, Kathmandu, Nepal

\textsuperscript{3}Department of Internal Medicine, Shree Birendra
Hospital, Kathmandu, Nepal

\textbf{Corresponding author}

Shriya Sharma

Nepalese Army Institute of Health Sciences, Kathmandu, Nepal

Email:shriya.sharma@naihs.edu.np

\textbf{Abstract}

Hemophagocytic Lympho-histiocytosis (HLH) is a rare life-threatening
condition characterized by widespread activation of the immune system
leading to tissue damage all over the body. It is divided into Primary
HLH due to inborn error in lymphocytes, T cells, and macrophages and
Secondary HLH which is mostly due to infections, systemic connective
tissue diseases, and lymphoid malignancies. Here we report, a
34-year-old man with a history of high-grade fever, chills, and rigor,
eschar, splenomegaly with the laboratory findings of thrombocytopenia,
hypochromic RBCs with anisocytosis and basophilic stippling, elevated
transaminases, and a positive Weil Felix test along with positive PCR
results for Orientia tsutsugamushi and the presence of IgG and IgM
antibodies. A detailed workup was done to rule out other etiology for
fever. Diagnosis of HLH secondary to Rickettsia infection was made with
a thorough history, clinical evaluation, and a variety of
investigations. The patient was treated with Doxycycline, Ciprofloxacin,
Etoposide, and Dexamethasone but unfortunately, the patient expired
during treatment due to multiorgan failure. Patients with scrub typhus
typically respond well to therapy, therefore early detection and
antibiotic treatment can help avoid serious complications. Scrub typhus
with the hemophagocytic syndrome can result in DIC and multiorgan
failure. Despite its rarity, scrub typhus may be lethal; as a result,
practitioners must be aware of the necessity of detecting and treating
suspected cases as soon as possible. We learned that a systematic
diagnostic approach, use of diagnostic criteria, and prompt treatment
are very crucial in this disease.

Keywords : scrub typhus, \emph{Orientia tsutsugamushi} ,
hemophagocytosis, hemophagocytic lymphohistiocytosis

\textbf{1 \textbar{} Introduction}

Hemophagocytic lymphohistiocytosis is an aggressive and life-threatening
condition with excessive activation of cytotoxic T lymphocytes, natural
killer (NK) cells, and macrophages resulting in hypercytokinemia and
immune-mediated damage to multiple organ systems. Primary (driven via
underlying genetic mutations or secondary (driven from a malignant,
infectious, or autoimmune stimulus without an identifiable underlying
genetic trigger).(1) Progress has been made regarding the
pathophysiology of HLH over the past decade. However, diagnosis of HLH
remains with many dilemmas because of the heterogeneous nature of the
disease.(2)

The guidelines for hemophagocytic lymphohistiocytosis describe the
various symptoms that can be considered for a clinical diagnosis. If
five of the following eight symptoms are present, then a clinical
diagnosis can be made. These eight symptoms are fever; an abnormally
large spleen (splenomegaly); low red cell, white cell, or platelet
levels (cytopenias); abnormally high levels of a type of fat called a
triglyceride in the blood (hypertriglyceridemia) or low levels of a
specific blood-clotting protein (hypofibrinogenemia); destruction of
blood cells by macrophages (hemophagocytosis) in the bone marrow; low or
absent natural killer cell activity; abnormally high levels in the blood
of a protein that binds to iron (ferritinemia); and elevated soluble
interleukin-2 receptor (sCD25), a specialized protein that builds up in
the blood when the immune system is stimulated.

Excessive monocyte activation in HLH could be caused by high amounts of
activating cytokines. High levels of interferon (IFN), soluble
interleukin-2 receptor, tumor necrosis factor (TNF), interleukin-1, and
interleukin-6 have been found, implying that T-helper cells are
elaborating activating cytokines or that poorly regulated or
inappropriate Th1 responses to intracellular pathogens are to blame.
Although the details of immunological protective mechanisms against
rickettsial infections, such as cytokine activation, are unknown,
macrophages and T-cells are thought to play a key role in rickettsial
infection protection and the emergence of HLH. HLH is caused by a
variety of viruses, including CMV, Epstein-Barr virus (EBV), and human
herpesvirus-6, as well as collagen-vascular disorders and malignancies,
including T-cell lymphomas.(3)

\textbf{2 \textbar{} Case report}

A 34 years old male presented to the emergency department with a history
of high-grade intermittent fever, associated with chills and rigor along
with a frontal headache with no rash or bleeding diathesis. There is no
history of cough, sore throat, pain abdomen, burning micturition,
earache/discharge, nausea, vomiting. There was the presence of two
similar dark scab-like lesions with erythematous bases around 1 cm in
diameter on the abdomen (Figure 1). He was later admitted for further
evaluation and a definitive diagnosis. In view of thrombocytopenia
(platelet count -- 97600/cmm, raised transaminases (AST -- 164 IU/dl and
ALT -- 156 IU/L), LDH (i.e2780 IU/L), CRP (i.e1474 mg/L) with no other
localizing signs, and a positive Weil Felix Test he was treated as a
case of Rickettsia fever with Doxycycline and Ciprofloxacin tablets. He
was hemodynamically stable but continued to have fever(101-102\selectlanguage{ngerman}°F) with
chills and rigors which was intermittent. The patient was receiving
supportive care, including IV fluids and paracetamol for fever. The
fever began to fade during his stay, but it was predicted to last for
around a month, according to the infectious diseases specialist.

He was evaluated in the line of infective, inflammatory, autoimmune,
neoplastic possibilities for the fever. To rule out infectious processes
as a cause for fever; PPD tests and malarial blood smear were done for
Tuberculosis and Malaria which were negative. Similarly, workup was done
to rule out EBV, CMV, Hepatitis A, Hepatitis B, Hepatitis C, HIV 1 and
2, Dengue fever, Salmonella, and Brucella infections which were
negative.

Then, a Peripheral blood smear was done where Hypochromic RBC with
Anisocytosis and basophilic stippling along with-it Leukopenia and giant
platelets were seen. For further evaluation, a Bone marrow biopsy was
done which showed Dys-erythropoietic features with erythrophagocytic
cells (Figure 2). In the line of investigation to rule out malignancy; a
CT scan of the Chest, Abdomen, and pelvis was done. An Abdomen CT scan
showed a spleen with an upper limit size measuring 14 cm. Whole Body FDG
PET/CT was done which showed mildly enlarged spleen measuring up to 13
cm in length, demonstrating mild diffuse hypermetabolism of liver
activity. The remaining low-attenuation splenic lesions were not
appreciated with certainty on the current unenhanced CT, without focal
abnormal FDG uptake. However, few small upper abdominal lymph nodes are
seen demonstrating faint FDG uptake just above background liver
activity, including at the gastrohepatic ligament, periportal, and right
superior diaphragmatic regions, such as a 12 x 8 mm gastrohepatic
ligament lymph node. There is normal FDG activity throughout the
remainder of the abdomen and pelvis.

After this extensive Work-up, a diagnosis of Hemophagocytic
lymphohistiocytosis secondary to Rickettsial infection was made with the
following findings:Triglyceride: 267 mg/dl, Ferritin: \textgreater{}2000
mcg/dl, Fibrinogen: 98mg/dl, Bone marrow aspiration and biopsy:
Hyperactive macrophages with erythrophagocytosis, LDH: 2780 U/L,
Bi-cytopenia: Hb:10.9g/dl TLC: 3800/microliter

He was started on dexamethasone 10 mg/m\textsuperscript{2} after which
the patient started getting better. Further treatment were dexamethasone
10 mg/m\textsuperscript{2} once daily for 2 weeks followed by tapering
to 4-5 mg/ m\textsuperscript{2}, Etoposide 150
mg/m\textsuperscript{2}twice weekly for 6 weeks followed by once weekly
and reassessment accordingly. The patient then developed abdominal pain
in the right and left upper quadrant along with petechial spots in the
abdomen. He also developed a high-grade fever of 103 F along with
features suggestive of septic shock. He was shifted to ICU due to his
deteriorating condition and deranged hematological panel. During his
stay in ICU the patient died because of MODS.

\textbf{3 \textbar{} Discussion}

O.~tsutsugamushi~being a mite-borne~bacterium poses the risk of a
serious disease called Scrub Typhus. Rodents function as animal
reservoirs for O.~tsutsugamushi, however, the microorganism also can be
maintained among mite colonies through~ transovarial~transmission.(4)
Studies show scrub typhus is an evolving public health problem with
numerous outbreaks since 2015 in Nepal. Scrub typhus is a neglected
tropical disease, is one of the important causes of undifferentiated
treatable fever in Asia.(5)

Scrub typhus is associated with the eschar, which is a pathognomonic
lesion. It's the first lesion that appears after being bitten by a
chigger (Leptotrombidium mite). Because eschar is where O. tsutsugamushi
is multiplying and a huge number of organisms are found there, it has
been demonstrated to be a superior sample for PCR test than blood.(6)
Scrub typhus is defined by small vessel vasculitis, which affects the
lungs, heart, brain, and kidneys in particular. Scrub typhus has
non-specific clinical signs, and patients frequently report to the
physician with a generalized fever of uncertain etiology. Severe
symptoms of MOF, ARDS, shock, and DIC, on the other hand, may
develop.(7)

Primary HLH occurs due to hereditary immune conditions, while on the
contrary secondary HLH occurs in settings such as infection, malignancy,
autoimmune disease, post-allogeneic hematopoietic stem cell
transplantation, and drug hypersensitivity.(5) Interconnection between
HLH and infection is vital as both familial and sporadic cases are
commonly provoked by infectious diseases. HLH imitates infectious
diseases concealing the identification of a causative agent leading to
serious health problems.(8)

Patients with HLH die because of bleeding in visceral organs,
opportunistic infection secondary to neutropenia, or Multiple organ
failure within 2 months which accounts for more than 10\% of cases.(4)

With an increasing number of cases documented in the last ten years, HLH
is a potentially serious consequence of scrub typhus. However, the
majority of instances recorded thus far have been single cases or case
series with limited sample size. As a result, the clinical symptoms and
prognosis of individuals with HLH linked with scrub typhus are mostly
unknown.(2)

In the present case, the patient had a high-grade intermittent fever
with eschar which was not responding to broad-spectrum antibiotics.
During the initial work, the patient was diagnosed with a case of Scrub
typhus not responding to Doxycycline and Ciprofloxacin. For this reason,
an extensive workup was carried out to rule out other etiologies of
fever which failed to establish the cause. Bi-cytopenia and Hyperactive
macrophages with erythrophagocytosis in bone marrow biopsy suggested the
possibility of HLH. Similarly, in line with HLH, biochemical parameters
met the criteria for diagnosis of HLH. The patient initially responded
well to the treatment but eventually, his condition deteriorated due to
multi-organ failure leading to death.

\textbf{4 \textbar{} Conclusion}

Hemophagocytic Lympho-histiocytosis (HLH) is a rare life-threatening
condition. Scrub typhus with the hemophagocytic syndrome can result in
DIC and multiorgan failure. Despite its rarity, scrub typhus may be
lethal; as a result, practitioners must be aware of the necessity of
detecting and treating suspected cases as soon as possible

\textbf{CONFLICT OF INTEREST:}

The authors declare that they have no competing interest

\textbf{ACKNOWLEDGMENTS:}

None

\textbf{AUTHOR CONTRIBUTIONS:}

All the authors were involved in the drafting and/or revision of the
article and approved the final version to be published.

\textbf{CONSENT:}

The authors confirm that the patient has provided written informed
consent to the submission of this case report, in accordance with the
journal's patient consent policy.

\textbf{DATA AVAILABILITY STATEMENT:}

Data available on request from the authors The data that support the
findings of this study are available from the corresponding author upon
reasonable request

\textbf{References}

1. Al-Samkari H, Berliner N. Hemophagocytic Lymphohistiocytosis. Annu
Rev Pathol. 2018 Jan;13:27--49.

Crossref Pubmed

2. Naoi T, Morita M, Kawakami T, Fujimoto S. Hemophagocytic
Lymphohistiocytosis Associated with Scrub Typhus: Systematic Review and
Comparison between Pediatric and Adult Cases. Trop Med Infect Dis
{[}Internet{]}. 2018 Feb 14;3(1):19. Available from:
https://pubmed.ncbi.nlm.nih.gov/30274417

Crossref Pubmed

3. Valsalan R, Kosaraju K, Sohanlal T, Prem Kumar P. Hemophagocytosis in
scrub typhus. J Postgrad Med {[}Internet{]}. 2010 Oct 1;56(4):301--2.
Available from: https://www.jpgmonline.com/article.asp?issn=0022-3859

Crossref

4. Salje J. Orientia tsutsugamushi: A neglected but fascinating obligate
intracellular bacterial pathogen. PLoS Pathog. 2017;13(12):1--6.

Crossref Pubmed

5. Dhimal M, Dumre SP, Sharma GN, Khanal P, Ranabhat K, Shah LP, et al.
An outbreak investigation of scrub typhus in Nepal: confirmation of
local transmission. BMC Infect Dis {[}Internet{]}. 2021;21(1):193.
Available from: https://doi.org/10.1186/s12879-021-05866-6

Crossref Pubmed

6. Biswal M, Zaman K, Suri V, Rao H, Kumar A, Kapur G, et al. Use of
eschar for the molecular diagnosis and genotypic characterisation of
Orientia tsutsugamushi causing scrub typhus. Indian J Med Microbiol.
2018;36(3):422--5.

Crossref Pubmed

7. Jin Y, Huang L, Fan H, Lu G, Xu Y, Wu Z. Scrub typhus associated with
hemophagocytic lymphohistiocytosis: A report of six pediatric patients.
Exp Ther Med {[}Internet{]}. 2016/09/06. 2016 Oct;12(4):2729--34.
Available from: https://pubmed.ncbi.nlm.nih.gov/27698778

Crossref Pubmed

8. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis.
2000;6(6):601--8.

Crossref Pubmed

\selectlanguage{english}
\FloatBarrier
\end{document}

