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\begin{document}

\title{Co-infection of Dengue, Scrub typhus and Typhoid during Dengue outbreak
in Nepal, 2022: A case report}



\author[1]{Bibek Raj Bhattarai}%
\author[2]{Rajshree Bhujel}%
\author[1]{Sushant Pokhrel}%
\author[3]{Abhishek Mishra}%
\author[4]{Anamika Priyadarshinee}%
\affil[1]{Manmohan Memorial Institute of Health Sciences}%
\affil[2]{Tribhuvan University Central Department of Microbiology}%
\affil[3]{Tribhuvan University Teaching Hospital}%
\affil[4]{KISTMCTH}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
In midst of recent dengue outbreak in Nepal, 2022, the risk of
co-infection increases and may lead to fatal outcomes if the diagnosis
of multiple infections is delayed. Thus, all available diagnostic
approaches must be taken to decrease the burden of illness and lessen
mortality.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Dengue is a tropical disease which is primarily caused by \emph{Aedes
aegypti and Aedes albopictus} . It is particularly prevalent in tropical
and subtropical regions, and has been expanding into new geographic
areas throughout time \textsuperscript{1}. Scrub typhus, which is caused
by the bacteria \emph{Orientia tsutsugamushi} , is another disease to be
concerned aboutdue to its endemicity in Nepal. The lack of distinct
clinical symptoms and diagnostic resources, scrub typhus is frequently
under-diagnosed\textsuperscript{2}. Another endemic febrile sickness in
Nepal is typhoid fever; causative agent\emph{Salmonella typhi,} and
causes multi-systemic illness when contaminated food and water is
consumed\textsuperscript{3}.

Monsoon and post-monsoon is a high risk season for spreading of typhoid,
dengue, and scrub-typhus\textsuperscript{4}. Even though, the
co-infections among the organisms are rare due to multiple etiological
agents and/or vector involved, the probability cannot be neglected.
Here, we present a case of 58 years old female from Dang, a district
with sub-tropical climate, having co-infection of dengue, typhoid fever,
and scrub typhus during dengue outbreak in Nepal.

\textbf{Case Report:}

A 58-year-old woman presented with a continuous fever that persisted for
16 days. The patient stated that 16 days prior, she was in good health.
Then she had a moderate grade fever of 103\selectlanguage{ngerman}°F that wasn't accompanied by
chills or rigor. She also reported experiencing 2 weeks of progressively
worsening epigastric discomfort accompanied by a feeling of abdominal
fullness. There was no history of rashes, chest pain, coughing, loose
stools, nausea/vomiting. Additionally, the patient also stated that she
had no prior history of thyroid disease, pulmonary TB, diabetes
mellitus, or hypertension. She said that she does not smoke, although
she does consume 200 ml of alcohol twice daily. The most recent intake
was about two weeks ago.

On examination, the patient was presented as conscious, pale, icterus,
had a low grade fever of 100.5\textsuperscript{o}C along with bilateral
pitting edema, oral ulcer, and abdominal tenderness in epigastric
region. Vital checkup of patient presented hypotension (BP = 80/60
mmHg), Tachycardia (PR= 116 beats per minute), Respiratory rate of 20
beats per minute, low level SPO\textsubscript{2} i.e. 89\% in room
atmosphere.

Considering the recent dengue outbreak in Nepal, 2022 and based on the
patient's presenting symptoms, test for dengue (NS1 and IgG/IgM),
and\emph{Salmonella typhi} IgG/IgM was requested along with
hematological and biochemical parameters. Furthermore, urine culture and
routine examination as well as blood culture was also requested. Blood
tests revealed Dengue Anti- IgM positivity along with thrombocytopenia,
both of which are consistent with dengue infection. Moreover, bilirubin
and liver enzymes were increased with subsequent hypoalbuminemia. The
results of the \emph{S. typhi} IgM test were positive, indicating
possible concurrent \emph{Salmonella typhi} and dengue infection.
Hydration therapy with crystalloid fluid was initiated instantaneously.
Additionally, 100mg hydrocortisone was also injected immediately. The
patient received three doses of a 1000mg paracetamol tablet each day and
two daily injections of the ceftriaxone, 1000mg. Domperidone 10 mg \&
Ondansetron 4 mg were given to the patient to treat the nausea and
vomiting that accompanied the indigestion. Tables 1 and 2 documents the
serological testing and subsequent hematological as well as biochemical
profile respectively following patient hospitalization.

Three to four days following hospitalization, the blood parameters were
initially checked. With the exception of normal platelets and a total
WBC count, the aberrant blood values were concerning. Urine and blood
cultures test requested during admission came out negative despite
routine examination reported increase in pus and epithelial cells. No
clinical improvements were noticed. Consequently, the follow-up tests
for Dengue IgG/IgM and \emph{S. typhi} IgG/IgM as well as several tests
for tropical fever panel (Scrub typhus IgG/IgM,
\emph{Leptospira}IgG/IgM, tests for \emph{Brucella} Ab, K-39 total Ab
test for Leishmaniosis, and smear for malarial parasite) were required.
Acute infection of Scrub typhus with IgM positivity was reported despite
having no physical signs of eschar as seen in patients with scrub typhus
infection. Additionally, positive IgG Ab for \emph{Leptospira} , Dengue
and \emph{S. typhi} was also recorded. Leishmanial (K-39) Ab came back
negative, but the test for \emph{Brucella} Ab agglutination came back
positive implying exposure of the patient to the bacteria but did not
establish acute or previous infection. For the treatment, 100mg
Doxycycline was immediately initiated. Follow up I serological testing
and subsequent hematological as well as biochemical profile is
documented in Table 1 and 2.

Regular follow-up and no adjustments to the prescription were made.
Subsequent follow-up showed no improvement in the liver enzyme levels \selectlanguage{english}-
ALP value of \textgreater{}1600 U/L; bilirubin levels had dropped from
the first follow-up but had~remained clinically higher. Low hemoglobin
level, low hematocrit \%, low RBC indices, lymphocytosis, neutropenia,
increase in bilirubin, and liver enzymes were seen throughout the
follow- up course. Platelets level fluctuated during the course but
eventually returned to normal. Patient was discharged when she was
hemo-dynamically stable and symptomatically better. All the follow-up
laboratory investigations performed until discharge was represented in
Table 2.

The patient was informed upon discharge of any potential warning
indications. It was advised to stay hydrated and to use insect repellant
and/or mosquito nets. The patient was given a full explanation of how to
take the prescribed prescriptions on a regular basis.

\textbf{Discussion}

The case illustrates the acute multi-bacterial infection
of\emph{Salmonella typhi} and \emph{Orientia tsutsugamushi} in patient
with Dengue fever. All the diagnosis was made on the basis of rapid
serology test kit. Rapid serology kits can be questioned for their
accuracy, but due to lack of resources in the settings and deteriorating
condition of patient, the need for quick diagnostic approach was needed.
Clinical laboratory parameters also played a vital role for taking the
medical decision in addition to rapid serological tests. Other tests
such as ELISA and/or polymerase chain reaction would lead to more
confirmatory identification but were not accessible.

Dengue infection was diagnosed based on IgM positivity. Manufacturer (SD
Bioline\selectlanguage{english} Dengue Duo, Abbott, Santa Clara, USA) reported sensitivity of
94.2\% and specificity of 96.4\% for diagnosis of acute IgM dengue
infection.~\emph{Salmonella typhi} IgG/IgM (Bioline Diagnostics LLP,
Delhi, India) was also identified based on IgM positivity with
sensitivity and specificity of 91\% and 99.3\% respectively. Suspecting
the possible cross-reactivity of Rapid \emph{Salmonella typhi} IgM in
dengue fever, which is also concluded with the study performed by Bhatti
et al, follow-up test was requested\textsuperscript{5}. Three to four
days following the initial test, a follow-up test showed that both the
IgG/IgM tests for \emph{S. typhi} and dengue were IgG positive. The
study performed by Bhatti et al concluded cross-reactivity based on
positive \emph{S. typhi} IgM but negative IgG on dengue patients using
rapid kits but our test showed positive IgM-Ab on initial test and
subsequent IgG positivity on follow-up\textsuperscript{5}. ImmuneMed
Scrub Typhus Rapid test kit was used for qualitative detection of
IgM/IgG Ab specific to \emph{Orientia tsutsugamushi.} The sensitivity
and specificity was 97.3\% and 99.7\% respectively.

Our patient works primarily in agricultural fields in Dang district of
Nepal. Her work may have had her be exposed to ticks and mites.
Furthermore, climatic condition as well as seasonal factors also played
a role in co-infection\textsuperscript{4}. Various studies and case
reports have been documented regarding co-infection of Dengue virus and
scrub typhus \textsuperscript{6}, scrub typhus and enteric
fever\textsuperscript{7} as well as dengue and enteric fever
\textsuperscript{8} in Nepal. Few cases of all three i.e. dengue, scrub
typhus and \emph{S. typhi} co-infection was reported in
India\textsuperscript{9}. A study conducted by Murdoch DR et aldid not
observe any eschar in patient with scrub typhus-typhoid co-infection
which is also consistent with our non-finding of
eschar\textsuperscript{7}. Thrombocytopenia, transaminitis,
hyperbilirubinemia along with subsequent hypoalbuminemia was seen in our
patient which is also consistent with dengue-scrub infection as
conducted by Basheer A et al\textsuperscript{10}. Another study in
scrub- typhoid and dengue- typhoid co-infection revealed low hemoglobin
level, thrombocytopenia, and increase in transaminases
level\textsuperscript{11,12}.

\textbf{Conclusion}

Multiple co-infections may result in a febrile sickness with overlapping
spectrum of symptoms that can be difficult to detect and treat. Nepal is
prevalent to numerous endemic diseases such as dengue, scrub typhus and
typhoid fever. Rapid diagnostic tests as well as subsequent correlation
with other laboratory parameters can be useful in early treatment of
patient and subsequently decrease the burden of co-infection and
mortality.

\textbf{Author's contribution}

BRB, AP and SP contributed in data collection. BRB, RB and AM
contributed to the writing of the manuscript. BRB and RB helped editing
of the manuscript and critical reviewing. All authors have read and
approved the final version of the manuscript.

\textbf{Funding}

The author(s) received no financial support for the research,
authorship, and/or publication of this article.

\textbf{Acknowledgments}

The author acknowledges patient and her son's willingness to share
medical history for educational, research, and publication purposes.

\textbf{Declaration of conflicting interests}

The author(s) declared no potential conflicts of interest.

\textbf{Ethics approval}

Our institution does not require ethical approval for reporting
individual cases.

\textbf{Informed consent}

Written informed consent was obtained from the patient for publication
of this case report and accompanying medical data.

\textbf{References}

1. Kyle JL, Harris E. Global spread and persistence of dengue.
\emph{Annual review of microbiology} . 2008;62:71-92.
doi:10.1146/annurev.micro.62.081307.163005

2. Pokhrel A, Rayamajhee B, Khadka S. Seroprevalence and Clinical
Features of Scrub Typhus among Febrile Patients Attending a Referral
Hospital in Kathmandu, Nepal. May 13
2021;6(2)doi:10.3390/tropicalmed6020078

3. Bhandari J, Thada PK, DeVos E. Typhoid Fever. \emph{StatPearls} .
StatPearls Publishing

Copyright (c) 2022, StatPearls Publishing LLC.; 2022.

4. Monsoon Preparedness and Response Plan, 2077 (The Government of
Nepal) (2077 B.S).

5. Bhatti AB, Ali F, Satti SA. Cross-Reactivity of Rapid Salmonella
Typhi IgM Immunoassay in Dengue Fever Without Co-Existing Infection.
\emph{Cureus} . Dec 4 2015;7(12):e396. doi:10.7759/cureus.396

6. Sapkota S, Bhandari S. Dengue and Scrub Typhus Coinfection in a
Patient Presenting with Febrile Illness. 2017;2017:6214083.
doi:10.1155/2017/6214083

7. MURDOCH DR, WOODS CW, ZIMMERMAN MD, et al. THE ETIOLOGY OF FEBRILE
ILLNESS IN ADULTS PRESENTING TO PATAN HOSPITAL IN KATHMANDU, NEPAL.
\emph{The American Journal of Tropical Medicine and Hygiene Am J Trop
Med Hyg} . 01 Jun. 2004 2004;70(6):670-675.
doi:10.4269/ajtmh.2004.70.670

8. Mahato AK, Shrestha N, Gharti SB, Shah M. Typhoid Fever among
Patients Diagnosed with Dengue in a Tertiary Care Centre: A Descriptive
Cross-sectional Study. \emph{JNMA: Journal of the Nepal Medical
Association} . Aug 2022;60(252):714-7. doi:10.31729/jnma.7624

9. Singh R, Singh S, Ahmad N. A study of etiological pattern in an
epidemic of acute febrile illness during monsoon in a tertiary health
care institute of Uttarakhand, India.\emph{Journal of Clinical and
Diagnostic Research: JCDR} . 2014;8(6):MC01.

10. Basheer A, Iqbal N, Mookkappan S, et al. Clinical and Laboratory
Characteristics of Dengue-Orientia tsutsugamushi co-Infection from a
Tertiary Care Center in South India.\emph{Mediterranean journal of
hematology and infectious diseases} . 2016;8(1):e2016028.
doi:10.4084/mjhid.2016.028

11. Amin S, Noor M, Rahim F, Yasir Khan M, Ullah R. Co-infection With
Dengue Virus and Extensively Drug-Resistant Salmonella typhi.
\emph{Cureus} . Nov 2021;13(11):e19653. doi:10.7759/cureus.19653

12. Seow CW, Logarajah V, Tan NWH. Typhoid and Scrub Typhus Coinfection
in a Returned Traveler.\emph{Global pediatric health} .
2017;4:2333794x17726941. doi:10.1177/2333794x17726941

\textbf{Table legend}

\textbf{Table 1:} Serological tests of patient demonstrating infection
with multiple micro-organisms

\textbf{Table 2:} Hematological, Biochemical and Urine analysis of
patient during admission and subsequent follow-up until discharge.

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