Travel Medicine and Infectious Disease 52 (2023) 102542

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Travel Medicine and Infectious Disease

journal homepage: www.elsevier.com/locate/tmaid

Clinical manifestations of Rickettsia rickettsii in a familial outbreak

in Panama
Carlos A. Daza T a, Dora Estripeaut b, c, Melissa Santana Morales d, Abdiel Rodríguez Sánchez e,
Aurelio González f, Michelle Hernández g, Yamitzel Zaldívar g, Ámbar Poveda g,
Mabel Martínez-Monter g, Erin Guenther h, Nathan Gundacker h, i, *, Jose Antonio Suarez c, g, **
a
Hospital Materno Infantil José Domingo De Obaldía. David, Panama
b
Hospital del Niños. Ciudad de Panamá, Panama
c
SIN Senacyt Instituto Gorgas Panamá, Panama
d
Médica Forense del Instituto de Medicina Legal y Ciencias Forenses. Bocas del Toro, Panama
e
Epidemiologist, District of Bocas del Toro, Panama
f
Hospital “Dr. Raúl Dávila Mena” Caja del Seguro Social. Bocas del Toro, Panama
g
Gorgas Memorial Institute for Health Research, Panama City, Panama
h
Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
i
Zablocki VA Medical Center, Milwaukee, WI, USA

A R T I C L E I N F O A B S T R A C T

Keywords: We report an isolated outbreak of Rickettsia rickettsii in the Ngäbe-Buglé indigenous region, located 750 m
Outbreak (tropical wet) above sea level, in a jungle and mountainous area of Western Panama. Seven members of a family
Rickettsia rickettsii were infected simultaneously, resulting in four deaths. Family outbreaks have been previously described and are
Rocky mountain spotted fever
responsible for 4–8% of the cases described [1–4]. The simultaneous onset of symptoms in the affected popu­
lation group is extremely unusual [1,5], but it should not dissuade the clinician from considering the possibility
of Rickettsia rickettsii infection.

1. Introduction
Rickettsia rickettsii is a gram-negative, obligate-intracellular cocco­
bacillus which causes the disease Rocky Mountain Spotted Fever
(RMSF), which is severe if not recognized and treated early [6]. The
primary lesion is the endothelium of the small caliber vessels, through a
generalized vasculitis with altered permeability, microbleeds, and
platelet consumption [7]. It is a zoonosis where humans are accidently
included in its chain of transmission between tick vectors. Panama has
the three tick vectors of RMSF: Dermacentor andersonii, Dermacentor
variabilis, Rhipicephalus sanguineus. These species are widely distributed
in Panama, in both rural and urban areas. The natural hosts are mainly
rodents, horses, dogs, and opossums [8].
RMSF is often sporadic, with reports of familial outbreaks and foci of
disease in hyperendemic areas. The reporting of these outbreaks is
important for public health in the control and treatment of the disease.
In Panama, the first case of infection by R. rickettsii was reported in 1950
[9]. Five cases were reported between 1950 and 1953, resulting in two
deaths. Fifty years later, there were 10 reported cases from 2004 to
2017, resulting in nine deaths [8,10].
In this report, we present a familial outbreak that simultaneously
affected seven members of the same family in the Piedra Roja neigh­
borhood of Kankintú district, located in the Ngäbe-Buglé region of
western Panama.
2. Methods
A descriptive retrospective study was carried out, to facilitate and
standardize the collection of data from medical records. The study was
approved by the Bioethics Committee of the Hospital del Niño “Dr. José
Renán Esquivel”.
Confirmed cases were defined by two criteria: 1) fever with or
without rash 2) seroconversion or a four-fold increase in antibody titer
for R. rickettsii or molecular detection through polymerase chain

* Corresponding author. Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
** Corresponding author. Gorgas Memorial Institute for Health Research. Panama City, Panama.
E-mail addresses: carlosadazat@gmail.com (C.A. Daza T), ngundacker@mcw.edu (N. Gundacker), jsuarez@gorgas.gob.pa (J.A. Suarez).

https://doi.org/10.1016/j.tmaid.2023.102542
Received 14 July 2022; Received in revised form 22 December 2022; Accepted 5 January 2023
Available online 13 January 2023
1477-8939/© 2023 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
C.A. Daza T et al. Travel Medicine and Infectious Disease 52 (2023) 102542

reaction (PCR) specific for R. rickettsii in different types of samples
(blood, biopsies, skin, cerebrospinal fluid, exudates, scrapings of bed­
sores and ticks). The most commonly analyzed genes were the gltA gene,
encoding the enzyme citrate synthetase which is present in all Rickettsia,
and genes encoding two outer membrane proteins, including OmpA
(present in all species of the spotted fever group) and OmpB (present in
all species except R. bellii). PCR tests utilized the primers Rr190.70p and
Rr190.602n, which amplified a fragment of ≈532 bp of the outer
membrane protein gene (ompA) suggesting R. Rickettsii [11].
3. Outbreak
On February 20, 2019, seven patients from the same family entered
the emergency room of Hospital “Dr. Raúl Dávila Mena” in Changuinola
City with a history of fever and headache. None of the patients reported
a history of insect bites. The family lived in the rural forested area of
Western Panama. Table 1 shows the clinical characteristics, date of
symptoms, and diagnostic tests performed.
The 14-year-old male developed fever and headache on February 11,
2019, On February 13, he developed vomiting and diarrhea, accompa­
nied by a generalized rash. In the initial blood sample, the IgG-IgM in­
direct immunofluorescence test (IFA) was negative for R. rickettsia with
repeat testing positive 12 days later. Initially, Leptospirosis was the
leading diagnosis, and penicillin was initiated, but, PCR from blood on
day 10 of symptoms was positive for R. rickettsii and doxycycline was
initiated. CBC showed platelet count of 45,000 (normal range
150,000–450,000); electrolytes and renal function were normal. Liver
Function Tests revealed Aspartate Aminotransferase (AST) of 99U/L
(normal range 15–40 U/L) and Alanine Aminotransferase (ALT) of 44U/
L (normal range 10–45 U/L). Due to his hemodynamic instability, he
was transferred to the Pediatric Intensive Care Unit (PICU) at the Hos­
pital del Niño “Dr. José Renan Esquivel” Panama City on day 10, where
ciprofloxacin was added. However, he proceeded to developed adult
respiratory distress syndrome, requiring ventilatory and inotrope sup­
port. On day 11 of illness a 14 day course of doxycycline was initiated.
Echocardiogram showed and ejection fraction of 40%, biventricular
dysfunction with dilatation of the mitral and tricuspid annulus, and
secondary atrioventricular failure. He was discharged after 27 days of
hospitalization.
A 23-year-old female patient presented with fever, vomiting, and
headache on February 11, 2019. Penicillin was started on February 20.
Labs on February 20 revealed thrombocytopenia of 95,000 (normal
range 150,000–450,000). No other laboratory data was available. An­
tibiotics were changed to cefepime, azithromycin, and piperacillin-
tazobactam on February 21. She improved after initiation of doxycy­
cline on February 26. She was discharged from the hospital after 18 days
of hospitalization.
An 8-year-old male developed fever, vomiting, headache, and diar­
rhea on February 13, 2019. He was initiated on penicillin and was
transferred to the Hospital del Niño “José Renán Esquivel” in Panama
City on February 21. Penicillin was continued and cefotaxime was
added. The patient arrived with hemodynamic instability and died in the
emergency room.
A 20-year-old female developed fever, headache, vomiting, and
diarrhea on February 13, 2019. She received penicillin on February 20;
doxycycline was added on February 21. She arrived in unstable condi­
tion and died on February 21. The autopsy reported macroscopic find­
ings of cerebral and pulmonary edema, hepatomegaly, and congestive
splenomegaly. No blood count or blood chemistry results were found.
A 17-year-old female developed fever and headache on February 13,
2019. She then developed altered mental status on February 19 and died
on February 20. No antibiotics were given. No blood count or blood
chemistry results were found.
A 9-year-old female developed fever, vomiting, and headache on
February 15, 2019. On February 18, she developed abdominal pain and
generalized skin rash. On February 19, she developed altered mental
status. She did not receive antibiotics. She died on February 20 in the
emergency room of Hospital “Dr. Raúl Dávila Mena” in Changuinola
City. The autopsy reported macroscopic findings of cerebral edema,
hepatomegaly, and congestive splenomegaly. No blood count or blood
chemistry results were found.
A 3-year-old male developed fever, vomiting, and headache on
February 15, 2019. On February 16, he developed edema of the eyelids
and lower limbs. On February 23, he developed generalized petechiae,

Table 1
Summary of Clinical Course in 2019 familial outbreak of Rickettsia ricketsii.
Age, Symptom onset date – Signs or symptoms IFA serum Rickettsia. PCR in Antibiotic Result and Days of
Sex Hospital Admission blood Start date hospitalization
1st 2nd sample
sample

14, M 11 Feb – 20 Feb Fever and headache-11 Feb. Negative Positive Positive Penicillin-20 Feb. Alive
Vomiting, diarrhea and rash-13 22 Feb. IgM/IgG 22 Feb Doxycycline-22 Feb to 5 Mar 27 days
Feb. 25 Feb.
23, F 11 Feb − 20 Feb Fever, vomiting headache and N/A N/A N/A Penicillin-20 Feb Alive
diarrhea-11 Feb. Cefepime+azithromycin+ 18 days
piperacillin/tazobactam-21 Feb
Doxycycline-26 Feb to 01 Mar
8, M 13 Feb-20 Feb Fever, vomiting headache and Negative N/A Positive Penicillin+cefotaxime-20 Feb Death
diarrhea-13 Feb. 21 Feb. 21 Feb 1 day
Altered mental status-17 Feb.
Rash-20 Feb.
20, F 13 Feb-20 Feb Fever, headache, vomiting and Negative N/A Positive Penicillin-20 Feb. Death
diarrhea-13 Feb 20 Feb. 21 Feb Doxycycline-21 Feb. 1 day
Altered alertness-19 Feb
17, F 13 Feb-20 Feb Fever and headache-13 Feb. Negative N/A Positive None Death
Altered alertness-19 Feb. 20 Feb. 20 Feb <1 day
Vomiting/diarrhea and status
epilepticus-20 Feb.
9, F 15 Feb-20 Feb Fever, vomiting headache and Negative N/A Positive None Death
diarrhea-15 Feb. 20 Feb. 20 Feb <1 day.
Rash-18 Feb
Altered alert status-19 Feb.
3, M 15 Feb-20 Feb Fever, vomiting headache and Negative N/A Positive Penicillin-20 Feb. Alive
diarrhea-15 Feb. 20 Feb. Doxycycline-23 Feb. 31 days
Rash-15 Feb.

AbbreviationsF: Female, M: Male, IFA: Immunofluorescence.

2
C.A. Daza T et al.
at which time he was referred to the Hospital del Niño “José Renán
Esquivel” in Panama City. He received penicillin and azithromycin on
February 20. He was admitted to the intensive care unit for monitoring
from February 23 to 26. Antibiotics were transitioned to doxycycline,
which he received from February 23 to March 3. Laboratories revealed
WBC of 3400 (normal range 5000–14,500) with absolute neutrophils of
2040 and platelets of 50,000 (normal range 150,000–450,000), which
normalized on day 5 of doxycycline therapy. AST was slightly elevated
at 117 U/L (normal range 15–40 U/L). ALT was normal at 35 U/L
(normal range 10–45 U/L). Electrolytes and renal function were normal.
He was discharged from the hospital on March 22.
4. Discussion
Rocky Mountain Spotted Fever, caused by R. rickettsii, remains a
diagnostic challenge both in its early and advanced presentations, with a
wide differential diagnosis in tropical areas due to the low specificity of
symptoms. This disease can be confused with dengue, chikungunya,
Zika, infectious hepatitis, leptospirosis, meningococcus, and other viral
exanthems [12], including SARS CoV-2 [13]. In addition, the epidemi­
ology of R. rickettsii in Central America is poorly understood. Cases in
Costa Rica were first identified in 1977 with sporadic high mortality
outbreaks [14]. Cases have been reported in the bordering South
American country of Colombia in the 1930s and then two patients were
diagnosed posthumously in 2003–2004, concurrent serologic surveys
found 4.7–21.9% positivity for spotted fever group rickettsiae in febrile
patients, however this serology has high cross reactivity among
R. parkeri, R. akari and R. felis making the actual incidence of disease
unclear [15]. In Panama, cases were initially identified in the 1950s with
no cases reported until 20044.
Fever, headache, vomiting, and diarrhea were present in all seven
patients; rash was present in four of seven patients; altered alertness was
present in four of seven patients; and seizure occurred in one of seven
patients (Table 1). None of the patients reported a history of contact
with ticks or other insect bites. This coincides with what has been pre­
viously described, with a history of fever and rash but no reported his­
tory of contact with ticks [12]. At the time of the consultation, the
patients who presented with altered mental status and rash died in the
first 24 h of care (image 2); as these are clinical signs of advanced disease
and poor prognosis [12].
The high mortality in this cohort is due to delayed presentation after
symptom onset and delayed recognition of diagnosis. As a result, four of
seven patients died, including all of those who presented more than 5
days after symptom onset. Because R. ricketsii is a rare cause of disease in
Panama, other more common differentials that cause outbreaks (lepto­
spirosis, dengue, Zika) were considered, resulting in delay in initiation
of empiric therapy with doxycycline, which was not started until after
PCR test returned positive. The delay in therapy led to longer hospital
stays (18 days, 27 days, and 31 days) for the three surviving patients.
The mortality of R. Ricketsii infection continues to be high due to late
initiation of doxycycline, 57% in this outbreak and 68% Panama overall.
This is much higher compared to the USA (1%) [16] and Mexico
(30–80%) [17].
The simultaneous infection of this group of patients is puzzling for
several reasons. First, only 1–3% of ticks are typically infected with
R. rickettsii, and none of the patients reported tick bites despite the ticks
needing to attach for two to 10 h [12,18]. Second, R. rickettsii has not
been reported in this geographical area and vector studies that have
been carried out in Panama do not identify it as an endemic area [8].
This suggests that this outbreak may utilize a different vector than
standard tick bites. One hypothesis is that a family member removed
several ticks by hand and subsequently contaminated other family
members through minor wounds in the skin. There have been multiple
cases of individuals being infected with R. rickettsii, but their only
exposure was removal of a tick from the dog [19]. A second hypothesis
involves the difference in disease transmission between fed and unfed
3
Travel Medicine and Infectious Disease 52 (2023) 102542
ticks. Unfed-ticks need a prolonged period of time (>10 h) to transmit
R. rickettsii while fed-ticks only require approximately 10 min to trans­
mit disease. It is possible that several ticks fed on some members of the
family and then proceeded to attach for short period of time to other
members, successfully transmitting disease [20].
The simultaneous onset of symptoms in the affected population
group is unusual, but it should not dissuade the clinician from consid­
ering the possibility of R. rickettsii infection.
5. Conclusion
Primary care clinicians and referral hospitals in Panama continue to
have a low diagnostic suspicion of R. rickettsii infection, even in its
advanced presentation. This allows the progression of the disease,
resulting in a high mortality rate of 57% in this case series (four of seven
patients). Clinicians rightfully have a wide differential diagnosis of in­
fectious etiologies in patients in tropical areas. This case series high­
lights that RMSF should be considered and doxycycline initiated in
febrile patients with symptoms consistent with RMSF, especially if
standard infectious disease diagnostic tests are negative.
Conflict of interest
The authors have no competing interests to declare.
CRediT authorship contribution statement
Carlos A. Daza T: Conceptualization, Visualization, Investigation,
Methodology, Writing – original draft. Dora Estripeaut: Investigation,
Data curation. Melissa Santana Morales: Investigation, Data curation.
Abdiel Rodríguez Sánchez: Investigation, Data curation. Aurelio
González: Investigation, Data curation. Michelle Hernández: Investi­
gation, Data curation. Yamitzel Zaldívar: Investigation, Data curation.
Ámbar Poveda: Investigation, Data curation. Mabel Martínez-Monter:
Investigation, Data curation. Erin Guenther: Writing – original draft.
Nathan Gundacker: Writing – original draft, Writing – review & edit­
ing. Jose Antonio Suarez: Project administration, Writing – original
draft, Writing – review & editing.
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