A Case Report of Scrub Typhus: Secondary Acute Arrest of Hemopoiesis with Multiple Organ Dysfunction Syndromes

Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi (O. tsutsugamushi) in which humans are accidental hosts. Acute arrest of hemopoiesis (AAH) always manifests in pancytopenia and with supportive treatment or inducement removal, the AAH patients would show significant im-provement in blood routine for about a week. As a rapidly progressive and potentially life-threatening organ function disorder syndrome, multiple organ dysfunction syndrome (MODS) is often induced by many factors including infection, illness and injury. We received a rare case of scrub typhus rapidly presenting with AAH and MODS 2 weeks ago. The clinical data of a 32-year-old female with O. tsutsugamushi-induced AAH and MODS was summarized retrospectively and analyzed with a literature review. In this case, we selected tigecycline and moxifloxacin as treatment regimens for scrub typhus. When the potential infection was controlled, her pancytopenia and hepatic function rapidly improved in a few days.


Introduction
Scrub typhus, also known as tsutsugamushi disease, is a natural focal disease caused by infection with O. tsutsugamushi, with rodents as the main source of infection and Chigger mite larvae as the vector. Orientia tsutsugamushi (from Japanese tsutsuga meaning "illness", and mushi meaning "insect") is a mite-borne bacterium belonging to the family Rickettsiaceae and is responsible for a disease How to cite this paper: Song, G.C., Song, Y., Zhang, Y.F., Huang, X. and Deng, J.C. called scrub typhus in humans [1]. Patients mostly have a history of field work, and an incubation period of 5 -20 days. They are characterized by complex and diverse clinical manifestations, and numerous complications, often leading to multiple organ damage, and a high rate of early misdiagnosis [2]. In some cases, the pathogens form eschar-like inflammatory lesions when they enter the body site. Various antibiotics, such as chloramphenicol, tetracycline, doxycycline, macrolides, quinolones, and rifampicin, have been used to treat scrub typhus [3]. The failure of two or more vital organ systems is termed multi-organ dysfunction syndrome (MODS) and resembles a very critical condition associated with high morbidity and mortality [4]. Scrub typhus is a serious disease that can result in multiple organ dysfunctions in some individuals, with a maximum mortality rate of 30% if left untreated [2]. Nevertheless, cases of aplastic crisis due to scrub typhus have been rarely reported. A case of acute arrest of hemopoiesis with multiple organ dysfunction syndrome secondary to scrub typhus was admitted to the Department of Hematology, the Second Affiliated Hospital of Chongqing Medical University, which was diagnosed promptly and successfully cured with tigecycline, was presented here for analysis and review of the literature.

Case Presentation
A 32-year-old female was admitted to our hospital with recurrent fever for 2 weeks and abnormal hemogram for 2 days. Two weeks before, she had fever of unknown origin at the highest temperature of 40.0˚C with fatigue, dizziness and muscle soreness. The first blood routine in the local hospital showed: hemoglobin, 141 g/L; white blood cell count, 3.74 × 10 9 /L and platelet count, 72 × 10 9 /L. Thirteen days after this examination, she rechecked the blood routine and other imaging examinations: hemoglobin, 45 g/L; white blood cell count, 2.50 × 10 9 /L; platelet count, 18 × 10 9 /L; chest computed tomography (CT) suggested a fibrous cord lesion in the middle lobe of the right lung, a small amount of effusion in bilateral pleura and pericardium; abdominal CT showed a significantly enlarged spleen. At this time, pancytopenia appeared on her body and she was treated with andrographolide, dexamethasone and blood component transfusion without any response. There were still many symptoms on her body: fever at a highest temperature of 40.3˚C, chills, cough, expectoration, tired out of breath, polypnea, dizziness, headache and leg muscle soreness. Therefore, she was brought to emergency department of our hospital and rapidly screened by professional doctors to send to the hematology department.
On physical examination, the temperature was 40.3˚C, the pulse rate was 125 beats/min, the respiratory rate was 35 breaths/min, and the blood pressure was 99/62mmHg. The patient presented an acutely ill face with mild yellow staining of the bilateral scleral icterus, pale palpebral conjunctiva, slightly swollen left submaxillary lymph nodes touched soft without pain, coarse breath sounds in both lungs with little moist rales, soft abdomen that pressed mild pain and spleen could be touched 2 cm below the ribs, mild pitting edema in both lower limbs.
Laboratory testing and imaging examinations showed the following (Table 1)  pain. The circumstance of edema worsened and the limbs started to become cold. A signature eschar was observed in the sacrococcygeal region ( Figure 1).
The results of emergency examinations showed the following (Table 1) Empirical intravenous administration of tigecycline and moxifloxacin was initiated immediately. Human immunoglobulin 20 g per day was given for 4 consecutive days to enhance immunity and resist potential virus infection. Human serum albumin (HSA) and plasma were infused for edema remission and coagulation factors complement. Glutathione was administered for liver protection.
In addition, quantity fluid resuscitation, oxygen inhalation and other support treatments were added to the regimen. On day 5 of hospitalization, after 3 days of treatment with tigecycline and moxifloxacin, the clinical manifestations, liver function, coagulation function and aplastic crisis improved greatly ( of hospitalization, we reexamined some indicators: blood biochemical indexes basically recovered (Table 1); bone marrow smear and biopsy showed the hyperplasia of hematopoietic cells; CT of chest and abdomen suggested that the pulmonary infection and chest cavity fluid were obviously fade away, meanwhile, the size of spleen reduced. She spent 12 days during hospitalization, and she was discharged with basic recovery. After discharge, she was continued with a course of oral minocycline. During nearly 9 months of follow-up, she was left with sequelae of lung infection that she felt out of breath after moderate-intensity physical activity. Beyond that, she didn't feel any discomfort.

Discussion
Scrub typhus is a zoonosis caused by the pathogen O. tsutsugamushi which is classified as a separate genus in the Rickettsiaceae family. It is described as an acute febrile illness and is confined to a definite geographic region. The "tsutsugamushi triangle" extends from northern Japan and far eastern Russia in the north, to northern Australia in the south, and to Pakistan and Afghanistan in the west [5]. Scrub typhus is a serious public health problem in the Asia-Pacific area.
There is an estimated one million new scrub typhus infections each year, and over one billion people around the world are at risk. Without appropriate treatment, the case fatality rate of scrub typhus can reach 30% or even higher [6]. Based on previous studies, rickettsiae are located in endothelial cells in all the organs evaluated, namely heart, lung, brain, kidney, pancreas, appendix, and skin, and within cardiac muscle cells and in macrophages located in lymph node, liver and spleen [7] [8]. The manifestation of disease varies from mild to severe, some just have fever and some cases get fatal syndromes like MODS. According to previous studies, liver dysfunction accounted for 89%, lung involvement accounted for 65%, splenomegaly accounted for 47%, gastro-intestinal haemorrhage accounted for 25% and there were variant reports on the injury of other organ systems [9]. Typical symptoms include eschar, fever, gastrointestinal disturbance, malaise, cough, myalgia, and headache. Diagnosis is often missed in the early stage of the disease, as it presented as an acute febrile illness which is similar to other tropical febrile infections. However, the characteristic eschar-like rash, endemic area, and history of mite bites can assist doctors in rapid diagnosis. In most cases, the timely administration of antibiotics brought out a good outcome [2] [10]. Splenomegaly is a common hematological manifestation in typhus, seen in up to 47% of patients [9], furthermore, disseminated intravascular coagulopathy (DIC) [11] [12], hemophagocytic lymphohistiocytosis (HLH) [13] [14], thrombopenia [15], monoclonal gamma-globulinemia [16] and thrombosis [17], all of which have been reported in some cases. AAH, also known as aplastic crisis, is a sharp decline in hematopoietic function of bone marrow under the interaction of infection, drugs, immune disorders and other inducement, manifested as erythropenia, hyperplasia of bone marrow and erythroid hematopoietic cells differentiation disorder. Scrub typhus can be secondary to various infectious diseases containing virus infection, which is the most common, especially the B19 virus infection. Specifically, hemoglobin of this case progressive declined in the short term and the bone marrow suggested hypoplasia of erythroid hematopoietic cells. During the hospitalization, after treatment of anti-infection and symptomatic treatment, her symptoms, signs, blood parameters and hypoplasia of erythroid hematopoietic cells recovered rapidly. After case analysis, we considered AAH in scrub typhus was secondary to infection and immune disorders.
As previous articles indicated, there are many literatures summarizing the manifestations of scrub typhus secondary multiple organs involvement. It usually presents as an acute febrile illness, with high fever, malaise, headache and cough. The most characteristic clinical feature of scrub typhus is the presence of an eschar at the site of the bite of the mite [9]. In this case, the transaminase level increased 5 times over than standard values which showed the liver dysfunction. Besides, the level of WBC and PLT decreased sharply and weak erythroid hematopoiesis in bone marrow reflected the further impairment of hematologic system. This specific case, scrub typhus involving AAH and MODS progressed promptly. With medical history details and typical eschar found, correctly diagnosis was given by our experienced doctors. Thanks to timely therapy, this patient rapidly recovered and the expected treatment outcome was achieved.

Conclusion
Scrub typhus involving AAH and MODS is not frequently seen in clinical. Apart from careful medical history questioning, witness of eschar is the critical evidence. As shown in our case, people with common febrile illnesses in the tsutsugamushi triangle must be carefully evaluated by the screening of eschar and after treatment of antibiotics, the symptoms and laboratory indicators improved promptly.