Case Report: A Fatal Case of Scrub Typhus Complicated by Heatstroke

INTRODUCTION

Scrub typhus, otherwise called Tsutsugamushi disease, is a mite-borne infectious disease caused by the organism Orientia tsutsugamushi.¹ In Japan, the four species of mite vectors (Leptotrombidium akamushi, Leptotrombidium pallidum, Leptotrombidium scutellare, and Leptotrombidium palpale) transmit O. tsutsugamushi, and six serotypes are known (Kato, Karp, Gilliam, Irie/Kawasaki, Hirano/Kuroki, and Shimokoshi).^2,3 Scrub typhus secondary to serotype Hirano/Kuroki that is transmitted by L. scutellare has relatively mild murine virulence⁴ and known non-severe clinical manifestations.⁵ On the other hand, serotypes Karp and Kato are considered as highly virulent strains in animal studies,⁶ and historical and clinical experiences.⁷ The clinical course can be impacted by comorbidities. However, extrinsic risk factors including environmental factors such as ambient temperature during its clinical course are uncertain.

CASE REPORT

In late October 2017, a 76-year-old man went to his field in the suburb of Koriyama city, Fukushima prefecture, which is known as an endemic area of scrub typhus in the northern part of Honshu, Japan. One or two weeks later, he went to bathe in a local hot spring. According to the patient’s wife, he felt mild fatigue from that morning. After more than 30 minutes, the patient did not exit the bath, so the staff went to check on him and found him unresponsive in the bath but with his head above the water. He was immediately removed from the bath and brought to the hospital. The patient had a history of type 2 diabetes mellitus, hypertension, dyslipidemia, cerebral infarction without residual symptoms, left renal tumor, and abdominal aortic aneurysm and was a heavy smoker (more than 100 pack-year history of smoking until a few years before admission). The detailed history of exposure in the endemic area of rickettsial diseases was unknown even in his family.

On admission, the patient was critically ill with the following vital signs: blood pressure 60/40 mmHg, heart rate 135 beats/minute, respiratory rate 35 breaths/minute, pulse oximetry 98% (10 L FiO₂ via face mask), body temperature 39.5°C (core temperature via an indwelling urinary catheter 40.3°C), and Glasgow Coma Scale 3/15. On a physical examination, his medial upper right arm revealed an eschar surrounded by erythema (Figure 1) and his trunk had several 1 × 1-cm circular cherry red lesions on a background of generalized erythema (Figure 2). Laboratory results are presented in Table 1. Whole body computed tomography revealed no obvious intracranial hemorrhage, slight bilateral pleural effusion without pulmonary infiltration, and left renal tumor suggestive of renal cell carcinoma.

View Full Size

Eschar surrounded by erythema.

Citation: The American Journal of Tropical Medicine and Hygiene 103, 6; 10.4269/ajtmh.20-0577

• Download Figure
• Download figure as PowerPoint slide

View Full Size

Red skin eruptions on the trunk.

Citation: The American Journal of Tropical Medicine and Hygiene 103, 6; 10.4269/ajtmh.20-0577

• Download Figure
• Download figure as PowerPoint slide

In the emergency room, endotracheal intubation and fluid resuscitation were performed. Septic shock due to scrub typhus complicated by heatstroke was strongly suspected based on the characteristic eschar and hyperthermia. Minocycline, meropenem, and vancomycin were administered to treat the sepsis, and a cooling blanket was applied for the heatstroke. Despite intensive treatment and management in the intensive care unit, multiple organ dysfunction rapidly progressed. In particular, disseminated intravascular coagulation (DIC) was not controlled, despite massive transfusion of fresh frozen plasma and platelet concentrates along with deteriorated thrombocytopenia and coagulopathy. Lumbar puncture was deferred because of bleeding tendency during rapidly worsening clinical course. The patient died 14 hours after admission. The result of the indirect fluorescent antibody: serologic test was not elevated during the acutely ill phase. However, PCR performed on the eschar tissue confirmed O. tsutsugamushi: M63380 Kuroki, using genotyping via DNA sequencing of 56-kDa type-specific antigen gene.

DISCUSSION

Scrub typhus is caused by the organism O. tsutsugamushi. In Japan, L. akamushi, L. pallidum, L. scutellare, and L. palpale are believed to transmit serotypes Kato, Karp and Gilliam, Irie/Kawasaki and Hirano/Kuroki, and Shimokoshi, respectively.^3,8 In the period from 1999 to 2016, 34 fatal cases were found over total 7,888 reported cases, and the fatality rate was 0.4% in Japan.⁹ Generally, serotype Hirano/Kuroki transmitted by L. scutellare has a relatively mild clinical course.¹⁰ From a previous report, it was shown that the virulence of strains is classified into three types: a highly virulent strain, such as Kato and Karp, which are capable of killing mice with only a few organisms; a low virulent strain, such as Irie/Kawasaki and Hirano/Kuroki, which are not capable of infecting mice even with relatively large doses of organisms; and a intermediately virulent strain, such as Gilliam, which readily kills susceptible mice.⁶

The present case suffered multiple-organ failure and death secondary to scrub typhus complicated with heatstroke. In terms of antigenic phenotypic diversity under clinical manifestations, there have been no fatal case reports of Irie/Kawasaki or Hirano/Kuroki besides the fatal case reports of other strains.¹¹ From the viewpoint of local endemicity in Fukushima prefecture, seasonal distribution depending on the vector chigger mites has been reported.¹² The L. pallidum–mediated serotype Karp is regarded as “the summer type “(otherwise from spring to autumn) of scrub typhus which is the fatal serotype.¹³ Conversely, Irie/Kawasaki or Hirano/Kuroki, the L. scutellare–mediated serotypes, is “the autumn type” of scrub typhus, which produces the so-called “November fever.”¹⁴ To our knowledge, this is the first fatality report of the scrub typhus serotype Hirano/Kuroki. It is assumed that the combination of sepsis and heatstroke superimposed on several host comorbid factors led to the patient’s rapid decline.

The presented case had been affected not only by extrinsic factors of the environment but also by comorbidities, diabetes, and underlying malignancy which enhanced the pathophysiology of both sepsis and heatstroke. It is also assumed that the patient’s systemic cytokine production was dysregulated by a synergistic effect of sepsis and heatstroke, and host factors enhanced the aforementioned synergistic effect. Consequently, an auto-destructive systemic inflammation occurred, which is also known as “cytokine storm” as well as vasculitis phenomena of scrub typhus and DIC. Of note, generalized erythema due to high body temperature from heat stroke might have made typical irregular-shaped macular lesions of scrub typhus unremarkable, besides the highlighted circular cherry red lesions. In terms of biochemical profiles, we had no chance to send for the paired serological test, because of death, and cytokine assays such as interleukin-6 or others to evaluate its severity, despite definitive genetic diagnosis of scrub typhus caused by the Kuroki strain.

The scrub typhus serotype Hirano/Kuroki usually has a relatively mild clinical course. However, the synergistic effect of heatstroke superimposed on multiple underlying risk factors likely led to a fatal cytokine storm. Despite the serotype Hirano/Kuroki being regarded as a relatively non-virulent strain, it needs to be treated with attention when there are comorbidities and extrinsic or environmental risk factors.