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Murine Typhus Outbreak Presenting as Multisystem Inflammatory Syndrome in Children During SARS-CoV-2 Pandemic

Alamarat, Zain MD; Pérez, Norma DO; Wootton, Susan MD; Kamdar, Ankur MD; Smith, Keely MD; Heresi, Gloria P. MD; Chang, Michael MD

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The Pediatric Infectious Disease Journal: December 2020 - Volume 39 - Issue 12 - p e447-e449
doi: 10.1097/INF.0000000000002947


In April 2020, global attention was directed to a new clinical entity that was named pediatric inflammatory, multisystem syndrome-temporally associated with SARS-CoV-2 (PIMS-TS) or multisystem inflammatory syndrome in children (MIS-C). This uncommon syndrome affecting children and few young adults share common features with other pediatric inflammatory conditions including Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes. First described in the United Kingdom, increasing cases in the United States and other parts of the world1,2 lead the US Centers for Disease Control and Prevention (CDC) to develop an MIS-C case definition.3 In this context, during the second week of May 2020, while cases of confirmed SARS-CoV-2 remained low in our region, several patients presented to our pediatric tertiary referral hospital in Houston, TX, with signs and symptoms suggestive of MIS-C. After Pediatric Infectious Diseases consultation with thorough history taking, consideration of the clinical scenario, and directed investigation, an alternative and underappreciated diagnosis was identified.

Six previously healthy children with no sick contacts and no confirmed SARS-CoV-2 exposure presented with clinical and laboratory signs of systemic inflammation summarized in Table 1. Fortunately, all had normal cardiac enzymes and normal echocardiograms (Table, Supplemental Digital Content 1, All patients had negative SARS-CoV-2 nasopharyngeal polymerase chain reaction testing and negative serum IgG (Table 1) inconsistent with the CDC case definition for MIS-C. Multiple pediatric specialties were consulted including pediatric rheumatology. Further history taking by Pediatric Infectious Diseases team members revealed all patients had exposure to dogs, some with flea infestations. Despite not fulfilling the CDC MIS-C case definition at the time of presentation, 5 of 6 patients received intravenous immunoglobulin as therapy for MIS-C. With the additional history of dog and flea exposure, 4 of 6 patients received doxycycline for presumed murine typhus. All had complete resolution of symptoms and improvement in inflammatory markers, including 1 patient that received no therapeutic interventions. Serologies obtained before administration of intravenous immunoglobulin, but reported days later, demonstrated that all had elevated IgM and either negative or low IgG titers specific for Rickettsia typhi, consistent with early infection. Convalescent sera obtained in the Pediatric Infectious Diseases clinic were available for 4 patients (1, 3, 5, and 6), all of whom showed increased titers of anti-R. typhi IgM and IgG consistent with the diagnosis of acute murine typhus (Table 1). Positive convalescent serologies in 4 of 6 patients reinforced the diagnosis of acute murine typhus, which significantly increased our index of suspicion for acute murine typhus for the remaining 2 patients. Furthermore, the relative paucity of pediatric SARS-CoV-2 cases per capita in this region both preceding and at the times of presentation further points toward non-SARS-CoV-2 associated causes.

TABLE 1. - Selected Outcomes
Characteristic 1 2 3 4 5 6
Age (yr) 9 11 13 13 11 14
 Fever (d) 10 7 7 6 10 8
 Myalgia + + + + +
 Cough + + + + +
 Abdominal pain + + + + +
 Sore throat + + + +
 Vomiting + + + +
 Diarrhea +
 Fatigue +
 Tachycardia + + + + + +
 Tachypnea + + + + + +
 Macular + + + +
 Papular + + +
Distribution Diffuse Generalized Right side Extremities Lower limb Extremities
 Dog + + + + + +
 Obvious fleas + +
 Doxycycline + + + +
 IVIG + + + + +
 WBC 4.0 4.9 5.4 6.8 10.8 4.4
 Neutrophils 81% 76% 63% 71% 63% 68%
 Lymphocytes 13% 18% 30% 22% 26% 27%
 Platelets 82 156 157 120 459 88
 ALT 198 98 74 149 158 59
 AST 305 108 84 187 87 56
 LDH 1482 534 490 765 534 287
 Procalcitonin 1.3 4.1 0.4 4.5 1.3 2.1
 Triglycerides 264 370 240 265 141 176
 D-dimer 3.5 3.1 2.0 >20 0.60 2.36
 CRP 96 233 143 151 14 108
 IL-6 63 34 78 17 19 NA
 Ferritin 786 1312 373 1686 338 400
R. typhi IgG
 Acute 1:128 1:64 1:64 1:64 1:128 <1:64
 Convalescent >1:256 NA 1:256 NA >1:256 >1:256
R. typhi IgM
 Acute 1:512 1:128 1:64 1:256 1:256 1:128
 Convalescent 1:256 NA 1:256 NA >1:256 >1:256
Bolded outcomes are outside of the range for health individuals.
+, positive; −, negative; IVIG, intravenous immunoglobulin; WBC, white blood cells, 103/mL; neutrophils and lymphocytes are % of WBC; platelets, 103/ml; ALT, alanine transferase, unit/L; ALK, aspartate transaminase, unit/L; LDH, lactate dehydrogenase, unit/L; procalcitonin, ng/mL; triglycerides, mg/dL; D-dimer, µg/mL; CRP, C-reactive protein, mg/L; IL-6, interleukin-6, pg/mL; ferritin, ng/ml; immunoglobulin measurements, qualitative or titer; PCR, polymerase chain reaction.

Given the potential for serious sequelae of PIMS-TS/MIS-C,4 significant attention within the scientific and healthcare community and the media and general public has been appropriately focused on awareness of MIS-C. However, frequent symptom overlap with other infectious and inflammatory diseases delivers a significant diagnostic challenge to all clinicians during the pandemic. The fear of failure to recognize a new diagnostic entity with potentially serious negative outcomes may lead to premature closure of diagnosis and diagnostic error.

The fundamental causes of premature closure of diagnoses and diagnostic error remain unclear, although clinical reasoning appears to follow a dual processing model incorporating both type 1 reasoning (intuitive) and type 2 reasoning (analytical). One form of type 1 error is availability bias, where diagnoses that come readily to mind are more representative than is actually the case.5 External factors can influence availability bias. As an example, according to Kinetiq media intelligence measurement (iQ media) provided for May, there were 1902 media mentions of murine typhus compared with 6149 mentions of MIS-C across online, TV, and radio sources.

On the other hand, knowledge deficits may lead to type 2 analytical errors.6 Caused by R. typhi, murine typhus is considered “a rare disease” by the CDC.7 However, most cases in the United States are reported from southern Texas, the southeastern Gulf Coast, and southern California. In fact, murine typhus is endemic in Texas from spring to fall. Transmission is commonly associated with fleas, with exposure in 85% of pediatric patients in 1 series.8 The infection can vary from asymptomatic to fulminant with multiorgan involvement requiring intensive care.8,9 Cardiac involvement has been rarely described.10 As demonstrated (Table 1), the constellation of symptoms and laboratory evidence of multisystem inflammation described in pediatric patients with murine typhus overlaps with those described for MIS-C, although typhus cases lack the significant cardiac involvement described in MIS-C. From our experience, availability bias may have led to overdiagnosis of MIS-C, while an analytic error also occurred likely due to limited clinician knowledge of the epidemiology and clinical presentation of murine typhus in pediatric patients in Texas.

During the SARS-CoV-2 pandemic, while providers should be attentive to the possibility of PIMS-TS/MIS-C, we hope our experience with a murine typhus outbreak in the mid of the pandemic reminds clinicians of the risk of type 1 cognitive biases and type 2 analytic errors that may contribute to underdiagnosis of antibiotic treatable infections while leading to unnecessary administration of other medications. Diagnostic dilemmas during times of great uncertainty highlight the importance of multidisciplinary collaboration when evaluating patients to avoid biased early closure of diagnoses toward diseases that are dominating the conversation.


1. Chiotos K, Bassiri H, Behrens EM, et al. Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series. J Pediatric Infect Dis Soc. 2020;9:393–398.
2. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395:1771–1778.
3. CDCHAN-00432, May 14, 2020. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). Available at: Accessed June 24, 2020.
4. Riphagen S, Gomez X, Gonzales-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395:1607–1608.
5. Klein Jill G. Five pitfalls in decisions about diagnosis and prescribing. BMJ. 2005;330:781.
6. Norman GR, Monteiro SD, Sherbino J, et al. The causes of errors in clinical reasoning: cognitive biases, knowledge deficits, and dual process thinking. Acad Med. 2017;92:23–30.
7. Centers for Disease Control and Prevention. Flea-borne (murine) typhus.Available at Accessed June 24, 2020.
8. Whiteford SF, Taylor JP, Dumler JS. Clinical, laboratory, and epidemiologic features of murine typhus in 97 Texas children. Arch Pediatr Adolesc Med. 2001;155:396–400.
9. Afzal Z, Kallumadanda S, Wang F, et al. Acute febrile illness and complications due to murine typhus, Texas, USA1,2. Emerg Infect Dis. 2017;23:1268–1273.
10. Buchs AE, Zimlichman R, Sikuler E, et al. Murine typhus endocarditis. South Med J. 1992;85:751–753.

murine typhus; MIS-C; SARS-CoV-2; children

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