Tsutsugamushi disease is transmitted through a mite bite. During the inoculation period, which typically lasts for 6 to 20 days, the patient usually remains asymptomatic. Approximately at the tenth day following the initial infection, high fever, headaches, myalgia and fatigue emerge. The non-specificity of the symptoms constitutes a diagnostic obstacle at the early disease phase. During this initial period, a papule begins to form at the region of the mite bite, gradually progressing to form a necrotic localized spot, referred to as an eschar.

Despite the diagnostic challenge due to the non-specificity of the symptoms, the existence of an eschar is pathognomonic of tsutsugamushi disease; it is observed in half of the patients with a primary infection and is well-defined by the time that an individual develops fever [1] [2] [3]. Other symptoms associated with tsutsugamushi disease are lymphadenopathy, regional or generalized, ocular pain, a productive cough and infected conjunctiva [4] [5]. A characteristic symptom is also the centrifugal macular rash that appears after approximately a week following the infection. The erythema develops on the torso, may gradually assume papular characteristics and may not be observed due to its transient nature [6].

As the disease progresses, pneumonia, encephalitis, delirium and splenomegaly may be added to the clinical picture.

• Splenomegaly

  As the disease progresses, pneumonia, encephalitis, delirium and splenomegaly may be added to the clinical picture. [symptoma.com]

  As the eschar heals, there is a sudden onset of headache, malaise, anorexia, weakness, and fever, followed by pneumonia, a macular rash (on the trunk before the limbs), lymphadenopathy, hepato-splenomegaly, and conjunctivitis. [histopathology-india.net]

  Splenomegaly may be present, and interstitial myocarditis is more common than in other rickettsial diseases. In untreated patients, high fever may persist 2 week, then falls gradually over several days. [merckmanuals.com]

  Morbilliform rash, eschar, splenomegaly, and lymphadenopathies are typical signs. Leukopenia and abnormal liver function tests are commonly seen in the early phase of the illness. [en.wikipedia.org]

  Plasma fibrinogen was normal at 312 mg/dL (normal 160–380) and fibrinogen degradation products were slightly elevated at 11.4 μg/mL ( 7 cells (normal Computed tomography revealed mild splenomegaly and small pleural effusion bilaterally, but no significant [tandfonline.com]

• Generalized Lymphadenopathy

  All five children had fever, vomiting and generalized lymphadenopathy, but none had eschar or rash. One was cured with doxycycline, remaining four patients treated with azithromycin and one died despite treatment. [ncbi.nlm.nih.gov]

  After an incubation period of 6 to 21 days (mean 10 to 12 days), symptoms of scrub typhus start suddenly and include fever, chills, headache, and generalized lymphadenopathy. [merckmanuals.com]

  The bacteria multiply at the inoculation site, and a papule forms that ulcerates and becomes necrotic, evolving into an eschar, with regional lymphadenopathy that may progress to generalized lymphadenopathy within a few days. [emedicine.medscape.com]

• Fever

  […] or leptospirosis infection; the latter is known to often coexist with scrub fever. [symptoma.com]

  […] patients given doxycycline monotherapy (fever clearance time 52 h). [ncbi.nlm.nih.gov]

  The disease was also a problem for US troops stationed in Japan after WWII, and was variously known as "Shichitō fever" (by troops stationed in the Izu Seven Islands) or "Hatsuka fever" (Chiba prefecture). [en.wikipedia.org]

• Lymphadenopathy

  It presents with fever, headache, a macular rash, lymphadenopathy and eschar at the region of the mite bite. Tsutsugamushi disease is transmitted through a mite bite. [symptoma.com]

  All five children had fever, vomiting and generalized lymphadenopathy, but none had eschar or rash. One was cured with doxycycline, remaining four patients treated with azithromycin and one died despite treatment. [ncbi.nlm.nih.gov]

  Symptoms are fever, a primary lesion, a macular rash, and lymphadenopathy. Scrub typhus is related to rickettsial diseases. [merckmanuals.com]

  Other finding werecardiomegaly (10 patients), pleural effusion (6 patients), mediastinal lymphadenopathy(3 patients). [synapse.koreamed.org]

• High Fever

  Tsutsugamushi disease is characterized by the early appearance of a black crust at the bitten area and the subsequent development of macular or macropapular rush on the whole body with high fever. [ncbi.nlm.nih.gov]

  Approximately at the tenth day following the initial infection, high fever, headaches, myalgia and fatigue emerge. The non-specificity of the symptoms constitutes a diagnostic obstacle at the early disease phase. [symptoma.com]

  It features headache, high fever and a rash. [medical-dictionary.thefreedictionary.com]

• Chills

  Case report of a 60-year-old woman who complained of fever, chills, headache, lymphadenopathy, and blurred vision in the right eye following an insect bite to the lower right forehead. [ncbi.nlm.nih.gov]

  After an incubation period of 6 to 21 days (mean 10 to 12 days), symptoms of scrub typhus start suddenly and include fever, chills, headache, and generalized lymphadenopathy. [merckmanuals.com]

  A reddish or pinkish lesion appears at the site of the mite bite, and the person begins to experience headache, fever, chills, and general pains, along with swollen lymph glands. [britannica.com]

  Patient 2 In January 2016, a 40-year-old construction worker had sudden onset of high fever, chills, night sweats, headaches, myalgia, retro-orbital pain, and photophobia. [dx.doi.org]

• Malaise

  As the eschar heals, there is a sudden onset of headache, malaise, anorexia, weakness, and fever, followed by pneumonia, a macular rash (on the trunk before the limbs), lymphadenopathy, hepato-splenomegaly, and conjunctivitis. [histopathology-india.net]

  She also complained of malaise, loss of appetite, and dyspnea. Central nervous system symptoms such as headache and confusion were not observed. [tandfonline.com]

  Signs and symptoms include sudden headache, generalized muscle pain, malaise, and macular skin lesions. The infection may affect the central nervous system causing encephalitis. [fpnotebook.com]

  Increasing malaise and confusion led to hospitalization; at presentation, she was febrile (body temperature, 40.0 C) and apathetic. [dx.doi.org]

• Cough

  Other symptoms associated with tsutsugamushi disease are lymphadenopathy, regional or generalized, ocular pain, a productive cough and infected conjunctiva. [symptoma.com]

  The second patient was a 30-year-old rice and corn farmer who presented with fever that had lasted for 10 days accompanied by cough, hearing loss, lymphadenopathy, and conjunctival suffusion. [doi.org]

  Cough is present during the 1st week of fever, and pneumonitis may develop during the 2nd week. In severe cases, pulse rate increases; BP drops; and delirium, stupor, and muscular twitching develop. [merckmanuals.com]

  Signs and symptoms include fever, headache, muscle pain, cough, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation. [en.wikipedia.org]

• Pneumonia

  As the eschar heals, there is a sudden onset of headache, malaise, anorexia, weakness, and fever, followed by pneumonia, a macular rash (on the trunk before the limbs), lymphadenopathy, hepato-splenomegaly, and conjunctivitis. [histopathology-india.net]

  As the disease progresses, pneumonia, encephalitis, delirium and splenomegaly may be added to the clinical picture. [symptoma.com]

  Treatment for suspected malignancy and Pneumocystis carinii pneumonia was commenced. [jstage.jst.go.jp]

  Pneumonia is a well-documented complication of rickettsial diseases, but ARDS is rare (6 cases) [3, –7]. [academic.oup.com]

  Death either occurs as a direct result of the disease, or from secondary effects, such as bacterial pneumonia, encephalitis, or circulatory failure. If death occurs, it is usually by the end of the second week of infection. [montana.edu]

• Sore Throat

  Other signs and symptoms include: rash, lymphadenopathy, hepatosplenomegaly, cough, sore throat, abdominal pain, and central nervous system involvement. [kjim.org]

• Painful Cough

  Signs and symptoms include fever, headache, muscle pain, cough, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation. [en.wikipedia.org]

• Severe Clinical Course

  The precise mechanism underlying the more severe clinical course of JSF is not fully understood. [ncbi.nlm.nih.gov]

• Vomiting

  All five children had fever, vomiting and generalized lymphadenopathy, but none had eschar or rash. One was cured with doxycycline, remaining four patients treated with azithromycin and one died despite treatment. [ncbi.nlm.nih.gov]

  The most common gastrointestinal symptoms of scrub typhus patients included vomiting, nausea, diarrhea and hametamesis or melena. Gastrointestinal signs included hepatomegaly, jaundice and abdominal pain. [histopathology-india.net]

  Most patients who developed nausea and/or vomiting after treatment had a history of nausea or vomiting prior to admission. [doi.org]

  The most frequent presenting complaints were fever (100%), headache (91.3%), nausea and vomiting (73.9%), altered sensorium and seizures. Cases of scrub typhus that presented with altered sensorium were 14 (60.8%). [amhsr.org]

• Nausea

  The most common gastrointestinal symptoms of scrub typhus patients included vomiting, nausea, diarrhea and hametamesis or melena. Gastrointestinal signs included hepatomegaly, jaundice and abdominal pain. [histopathology-india.net]

  Most patients who developed nausea and/or vomiting after treatment had a history of nausea or vomiting prior to admission. [doi.org]

  The most frequent presenting complaints were fever (100%), headache (91.3%), nausea and vomiting (73.9%), altered sensorium and seizures. Cases of scrub typhus that presented with altered sensorium were 14 (60.8%). [amhsr.org]

  Its symptoms resemble those of dengue and include fever, headache, muscle pain, nausea, and vomiting 1, 2. It can cause multi-organ failure, haemoptysis, and pneumonitis and is fatal in 1.4–6% of cases 2, 3. [nature.com]

• Abdominal Pain

  Gastrointestinal signs included hepatomegaly, jaundice and abdominal pain. Since multiple serotypes exist and cross-immunity is transient, recurrent infections are common. [histopathology-india.net]

  Haug Browse recently published Learning/CME Learning/CME View all learning/CME CME Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis Case 4-2019: An 18-Year-Old Man with Abdominal Pain and Hematochezia Bridging the Gap Challenge Yourself [nejm.org]

  An episode of transient abdominal pain accompanied by vaginal bleeding occurred on the third hospital day. [doi.org]

  Other signs and symptoms include: rash, lymphadenopathy, hepatosplenomegaly, cough, sore throat, abdominal pain, and central nervous system involvement. [kjim.org]

  The common symptoms noted were fever (68/68, 100%), myalgia (20/68, 29.41%), vomiting (8/68, 11.76%), abdominal pain (10/68, 14.71%), chills (11/68, 16.17%), rigors, and headache (9/68, 13.23%) cases. [ijpmonline.org]

• Jaundice

  Gastrointestinal signs included hepatomegaly, jaundice and abdominal pain. Since multiple serotypes exist and cross-immunity is transient, recurrent infections are common. [histopathology-india.net]

  Clinical presentations of these infections vary widely, from acute flu-like syndrome, with or without signs of organ dysfunction, such as jaundice or renal insufficiency, to multiorgan dysfunction mimicking severe sepsis syndrome ( 10 ). [doi.org]

  […] thrombocytopenia (6/68, 8.82%), lymphadenopathy (4/68, 5.88%), eschar formation (8/68, 11.76%), diabetic ketoacidosis (1/68, 1.47%), hepatosplenomegaly (1/68, 1.47%), acute appendicitis (5/68, 7.35%), diabetes mellitus (5/68, 7.35%), ARDS (2/68, 2.94%), and jaundice [ijpmonline.org]

  Symptoms Number of patients (%) Fever 7 days 9 7-10 days 7 2 weeks 7 Myalgia 19 (82.6) Jaundice 6 (26.0) Breathlessness 7 (30.4) Cough 8 (34.7) Headache 21 (91.3) Nausea/vomiting 17 (73.9) Seizures 6 (26.0) Clinical signs Altered sensorium 14 (60.8) Pedal [amhsr.org]

• Blurred Vision

  Case report of a 60-year-old woman who complained of fever, chills, headache, lymphadenopathy, and blurred vision in the right eye following an insect bite to the lower right forehead. [ncbi.nlm.nih.gov]

• Retinal Hemorrhage

  To report branch retinal vein occlusion and retinal hemorrhages associated with tsutsugamushi disease. [ncbi.nlm.nih.gov]

• Otalgia

  Otalgia and eschar in the external auditory canal in scrub typhus complicated by acute respiratory distress syndrome and multiple organ failure. BMC Infect Dis. 2011 Mar 30. 11:79. [Medline]. [Full Text]. Edwards MS, Feigen RD. [emedicine.medscape.com]

• Exanthema

  ‘The tsutsugamushi disease is contracted by high temperature, exanthema and adenopathy following the cold-like symptoms.’ [en.oxforddictionaries.com]

  Patient 1 In January 2015, a 38-year-old homemaker was hospitalized with fever and generalized exanthema. [dx.doi.org]

• Pruritic Rash

  Two weeks earlier, she had noticed a transient pruritic rash on her abdomen, which had appeared after she had been collecting firewood in a local forest clearing. [dx.doi.org]

• Night Sweats

  Patient 2 In January 2016, a 40-year-old construction worker had sudden onset of high fever, chills, night sweats, headaches, myalgia, retro-orbital pain, and photophobia. [dx.doi.org]

• Myalgia

  Approximately at the tenth day following the initial infection, high fever, headaches, myalgia and fatigue emerge. The non-specificity of the symptoms constitutes a diagnostic obstacle at the early disease phase. [symptoma.com]

  Fever was the most common symptom in our group of patients which is similar to a previous report. [20] Narvencar et al. [2] in 2012 reported fever with myalgia as the predominant symptom in 80% of the patients, but in the present study, myalgia was observed [ijpmonline.org]

  Clinical manifestations of Tsutsugamushi disease include maculopapular skin rashes, fever, and myalgia. This is followed by disseminated systemic vasculitis affecting the lung, liver, and kidney within days or weeks [ 1 ]. [kjim.org]

  The clinical picture of scrub typhus typically associates fever, an exanthematous rash, myalgia, and diffuse lymphadenopathy. [academic.oup.com]

  Patient 2 In January 2016, a 40-year-old construction worker had sudden onset of high fever, chills, night sweats, headaches, myalgia, retro-orbital pain, and photophobia. [dx.doi.org]

• Arthralgia

  He reported that his initial symptoms were high fever, chills, night sweats, intense headaches, myalgia, and arthralgia that had started 3 weeks earlier, but his fever and systemic symptoms had resolved spontaneously after 1 week. [dx.doi.org]

• Headache

  It presents with fever, headache, a macular rash, lymphadenopathy and eschar at the region of the mite bite. Tsutsugamushi disease is transmitted through a mite bite. [symptoma.com]

  Case report of a 60-year-old woman who complained of fever, chills, headache, lymphadenopathy, and blurred vision in the right eye following an insect bite to the lower right forehead. [ncbi.nlm.nih.gov]

  After an incubation period of 6 to 21 days (mean 10 to 12 days), symptoms of scrub typhus start suddenly and include fever, chills, headache, and generalized lymphadenopathy. [merckmanuals.com]

  Tsutsugamushi disease: A mite-borne infectious disease caused by a microorganism, Rickettsia tsutsugamushi, characteristically with fever, headache, a raised (macular) rash, swollen glands (lymphadenopathy) and a dark crusted ulcer (called an eschar or [medicinenet.com]

  It features headache, high fever and a rash. [medical-dictionary.thefreedictionary.com]

The complete workup for scrub typhus encompasses a multitude of tests and procedures, including routine blood tests, serology, and PCR.

More specifically, laboratory blood tests including a complete blood count and biochemical studies usually yield the following results:

• Lymphopenia, early in the course of the disease
• Lymphocytosis, during the progressed stage
• Decreased CD4:CD8 ratio
• Thrombocytopenia [7]
• Augmented SGOT/SGPT levels in up to 95% of the patients
• Hypoalbuminemia, in 50% of the patients

The aforementioned findings may also suggest a potential dengue fever or leptospirosis infection; the latter is known to often coexist with scrub fever [8].

Serologic tests are further carried out, as they constitute the primary diagnostic procedures. A direct immunoperoxidase test and an immunofluorescent assay are used to establish the diagnosis and are expected to yield a result displaying a 4-fold augmentation of antibody titers between acute and convalescent serum specimens [9]. All potential O. tsutsugamushi subtypes should be considered as a possibility and should, therefore, be separately investigated serologically. A dot immunoassay can also be employed in order to diagnose tsutsugamushi disease, whereas the immunochromatographic test, aimed at the detection of immunoglobulin (Ig) M and IgG antibodies exhibit a considerably greater sensitivity for an early diagnosis when compared to the standard immunofluorescence assay.

The polymerase chain reaction tests (PCR) has proven a valuable diagnostic tool, on eschar samples, early in the course of the disease. In third world countries, the method of choice is the Weil-Felix OX-K strain agglutination reaction; when more advanced medical facilities are available, this test is not opted for due to its decreased sensitivity.

• Pericardial Effusion

  Pericardial effusion in Tsutsugamushi Disease is not a common manifestation, although a high rate of effusion was reported in autopsy in those who had died of the disease. [ncbi.nlm.nih.gov]

• Rickettsia Orientalis

  Tsutsugamushi, which is caused by Rickettsia nipponica (Rickettsia orientalis, Rickettsia tsutsugamushi), is widely distributed over an area which includes Japan, Malaya, French Indo-China, Sumatra, the Philippines, other islands of the Pacific and northern [jamanetwork.com]

  The cross-protection test with mice for identification and differentiation of several strains of Rickettsia orientalis newly isolated in Japan. Jpn J Med Sci Biol 1959;12:391–404. [synapse.koreamed.org]

  Strain variation of Rickettsia orientalis in the complement fixation test. Jpn J Med Sci Biol. 1964;17:59–72. View Article PubMed Google Scholar Nakayama K, Yamashita A, Kurokawa K, Morimoto T, Ogawa M, Fukuhara M. [bmcinfectdis.biomedcentral.com]

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3. Berman SJ, Kundim WD. Scrub Typhus in South Vietnam: A Study of 87 Cases. Annals Internal Med. July 1973. 79:26-30.
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9. Phetsouvanh R, Blacksell SD, Jenjaroen K, Day NP, Newton PN. Comparison of indirect immunofluorescence assays for diagnosis of scrub typhus and murine typhus using venous blood and finger prick filter paper blood spots.