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□ CASE REPORT □

The Rapid Effectiveness of Minocycline againstScrub Typhus Meningoencephalitis

Tameto Naoi 1,2, Haruo Shimazaki 2 and Mikio Sawada 2

Abstract

Scrub typhus is associated with various clinical symptoms. However, the pathogenesis of scrub typhus in-

fection remains to be elucidated. A 73-year-old man was admitted to our hospital with consciousness distur-

bance and suspected meningoencephalitis. The patient’s laboratory data showed deterioration and were in-

dicative of hemophagocytic lymphohistiocytosis (HLH). A whole body examination to detect the trigger dis-

ease revealed an eschar, which is a characteristic of scrub typhus, on his back. His symptoms showed dra-

matic improvement after the administration of minocycline (MINO). This case report highlights that the clini-

cal course of a case of scrub typhus meningoencephalitis that was cured with MINO.

Key words: scrub typhus, Orientia tsutsugamushi, hemophagocytosis, hemophagocytic lymphohistiocytosis,

minocycline, tumor necrosis factor α

(Intern Med 55: 805-809, 2016)(DOI: 10.2169/internalmedicine.55.5304)

Introduction

Scrub typhus is a mite-borne bacterial infection, which is

characterized by the triad of fever, skin rash, and eschar.

Scrub typhus can sometimes lead to meningoencephali-

tis (1). Although various clinical and laboratory findings

have been observed in scrub typhus patients, the patho-

genesis of the infection is yet to be elucidated. Recently,

scrub typhus-associated hemophagocytic lymphohistiocytosis

(HLH), has been reported (2-6). HLH, the fatal condition in-

volves the overproduction of cytokine and is mainly trig-

gered by malignant lymphoma, viral, bacterial infection and

collagen disease (7, 8). These case reports (2-6) suggest that

hypercytokinemia may play a main role in the development

of scrub typhus. Indeed, cytokine overproduction has been

observed in scrub typhus patients (9, 10). Although severe

scrub typhus is potentially fatal, it may be successfully

treated with minocycline (MINO). We herein present the dy-

namics of the clinical symptoms and the laboratory data in a

patient with meningoencephalitis-associated scrub typhus.

Case Report

A healthy 73-year-old man, who lived in the Tochigi pre-

fecture spent time in the mountains in mid-March. He expe-

rienced headache and fever starting from late-March (day 1).

These symptoms did not subside and he was admitted to a

hospital on day 7. A bacterial infection was suspected and

he was treated with cefoperazone/sulbactam. His symptoms

did not improve and his consciousness level deteriorated. He

was transferred to our hospital on day 14. A physical exami-

nation on admission revealed the following: body tempera-

ture, 38.6℃; blood pressure, 136/76 mmHg; pulse rate, 114

bpm; and respiratory rate, 36 breaths/min with shallow

breathing. No skin rash was observed. The laboratory data

on admission are shown in Table 1. Electroencephalogram

(EEG) showed a diffuse slow wave pattern (data not

shown). Body computed tomography (CT) showed pleural

effusion (Fig. 1A) and intestinal edema (Fig. 1B); however,

hepatosplenomegaly was not observed (Fig. 1C). The patient

was on a ventilator for respiratory failure. Bacterial menin-

goencephalitis or herpes encephalitis was strongly suspected

and the patient was treated with empirical therapy, which in-

１Division of Neurology, Department of Internal Medicine, Shin-Oyama City Hospital, Japan and ２Division of Neurology, Department of Internal

Medicine, Jichi Medical University, Japan

Received for publication March 9, 2015; Accepted for publication June 30, 2015

Correspondence to Dr. Tameto Naoi, sph89vz9@coda.ocn.ne.jp

Intern Med 55: 805-809, 2016 DOI: 10.2169/internalmedicine.55.5304

806

Figure　1.　A) Chest computed tomography (CT) of the patient on admission showing bilateral pleu-ral effusions. B) Abdominal CT of the patient on admission showing edemas of the small intestine (arrows). C) There is no evidence of hepatosplenomegaly.

Table　1.　Laboratory Data on Admission.

hematology arterial blood gaswhite blood cell 14,100 /μL K 5.2 mEq pH 7.451 neutrophil 12,300 /μL T Bil 1.72 mg/dL PaO2 60.9 mmHg atypical lymphcyte 1% D Bil 0.16 mg/dL PaCO2 45 mmHghemoglobin 14.3 g/dL AST 83 U/L HCO3- 20.6 mmol/Lplatelet 20.3 × 104/ μL ALT 91 U/L cerebrospinal fluid

coagulation LDH 408 U/L lymphcyte 36 /mm³fibriniogen 241 mg/dL triglyceride 126 mg/dL neutrophil 10 /mm³

FDP 22.5 μg/mL ferritin 1,096 ng/mL protein 285 mg/dLPT-INR 1.18 albumin 2.9 g/dL glucose 48 mg/dL

AT III activity 77.70% C-reactive protein 6.15 mg/dLbiochemistory glucose 120 mg/dL BUN 28 mg/dL serum sIL-2R 3,140 U/mL

creatinine 1.02 mg/dL serum TNF- 4.2 pg/mLNa 124 mEq (normal range:0.6 - 2.8 pg/mL)

FDP: fibrin degradation products, AT III activity: antithrombin III activity, T Bil: total bilirubin, D Bil: direct bilirubin,AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase,sIL2-R: soluble interleukin-2 receptor, TNF- umor necrosis factor-

cluded ceftriaxone, ampicillin sodium, vancomycin, and aci-

clovir from day 14 (Fig. 2). sIL2-R levels of 3,140 U/mL

can be indicative of central nervous system lymphoma.

However, brain MRI showed no abnormalities on day 15.

The patient’s laboratory data showed a gradual deterioration

and were suggestive of HLH, although the HLH diagnostic

criteria were not completely fulfilled (Table 2). Bone mar-

row aspiration to detect hemophagocytosis was not per-

formed because of concerns about bleeding. Gabexate mesi-

late and albumin were used for preventing the progression to

disseminated intravascular coagulopathy (DIC) and hypoal-

buminemia from day 18. The patient’s whole body was

thoroughly searched and an eschar was found on the right

side of his back on day 21 (Fig. 3). Scrub typhus was clini-

cally diagnosed and MINO treatment was immediately initi-

ated. The patient’s fever dramatically subsided and his level

of consciousness improved from the next day (Fig. 4). His

laboratory data also improved and he was weaned off the

ventilator on day 26. A serological analysis on day 22 was

positive for IgM (1:160) and IgG (1:320) antibodies against

Orientia tsutsugamushi, Karp strain. The patient was dis-

charged 2 months later.

Discussion

This case report highlights two clinically important issues.

First, the patient showed prompt defervescence and recovery

of consciousness after the administration of MINO, which is

known to have cytokine modulating functions (11). Second,

it is preferable to treat scrub typhus before progression to

HLH, although the diagnosis of scrub typhus is sometimes

challenging.

The present case showed rapid defervescence and recov-

ery of consciousness after the administration of MINO.

Prompt defervescence is well known in scrub typhus pa-

tients who are treated with MINO or doxycycline. However,

the rapid clinical improvement is difficult to explain by the

antibacterial action of MINO, because MINO has bacte-

riostatic actions, namely the inhibition of bacterial prolifera-

tion. O. tsutsugamushi DNA is still detected in the periph-

eral blood during the recovery phase of scrub typhus pa-

tients (12). MINO modulates the level of TNF-α and has

anti-inflammatory effects (11). TNF-α is the cytokine re-

sponsible for the development of HLH (13) and the patient’s

serum and CSF levels of TNF-α levels were elevated. This

Intern Med 55: 805-809, 2016 DOI: 10.2169/internalmedicine.55.5304

807

Figure　2.　The treatment regimen of the patient. The patient was treated with cefoperazone/sulbac-tam from day 7 to 14. On admission to our hospital, bacterial meningitis was suspected and he was treated with ceftriaxone, vancomycin, and ampicillin sodium from day 14 to 26. Aciclovir was used due to the suspicion of herpes encephalitis from day 14 to 16. The patient was on a ventilator for re-spiratory failure from day 14 to 26. Gabexate mesilate was administered from day 18 for 5 days to prevent DIC. Albumin was supplemented from day 18 for 3 days. Minocycline was administered for 2 weeks from day 21. The patient was not treated with steroids or immunoglobulins.

Figure　3.　An eschar, which was characteristic of scrub ty-phus, was found on the right side of the patient’s back.

Table　2.　HLH-2004 Diagnostic Criteria (7).

the diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled1.A molecular diagnosis consistent with HLH is made2. Diagnostic criteria for HLH are fulfilled (5 of 8 criteria below):* Fever Splenomegaly Cytopenias (affecting 2 of 3 lineages in the peripheral blood) hemoglobin < 90 g/L (in infants < 4 weeks; hemoglobin < 100 g/L) platelets < 100 × 109/ L neutrophil < 1.0 × 109/ L Hypertriglyceridemia and/or hypofibrinogenemia:fasting Hypertriglyceridemia 3.0 mmol/L (ie, 265 mg/dL), fibrinogen 1.5 g/L Hemophagocytosis in bone marrow, spleen, or lymph nodes No evidence of malignancy Low or absent NK-cell activity (according to local laboratory reference) Ferritin 500 μg/L Soluble CD25 (ie, sIL2r) 2,400 U/mL*Supportive criteria include neurologic symptoms, cerebrospinal fluid pleocytosis, conjugated hyperbilirubinemia and transaminitis, hypoalbuminemia, hyponatremia, elevated D-dimers, and lactate dehydrogenase. The absence of hemophagocytosisin the bone marrow does not exclude a diagnosis of HLH.

anti-inflammatory function of MINO might have been re-

sponsible for the rapid defervescence and the recovery of

consciousness that were observed in the present case. How-

ever, it is controversial that TNF-α may be the sole cause of

HLH, because the serum and CSF levels of TNF-α increase

in bacterial meningitis and other diseases without progres-

sion to HLH (14, 15). Thus, the role of the cytokines in

scrub typhus remains to be elucidated.

In the present case, the laboratory data also improved

with the administration of MINO (Fig. 4). MINO improved

pancytopenia, coagulopathy, renal dysfunction, hypoalbumi-

nemia, and the CSF findings. We are not able to answer

whether these results were also dependent on the cytokine

modulatory function of MINO. The administration of ga-

bexate mesilate was partially effective for treating the pa-

tient’s coagulopathy because his platelet, fibrinogen, and AT

III activity showed a slight improvement before the initia-

tion of MINO treatment. The PT-INR and FDP levels did

not show any remarkable changes over the clinical course

(data not shown). We cannot clearly explain the dynamics of

the changes in the T-bil and AST/ALT levels. MINO and

other antibiotics might cause the elevation of AST/ALT lev-

Intern Med 55: 805-809, 2016 DOI: 10.2169/internalmedicine.55.5304

808

Figure　4.　The dynamics of the clinical and laboratory findings of the patient. MINO treatment was initiated on day 21 (shown as a red bar). Defervescence was observed after the start of MINO treat-ment. The level of consciousness was scored by GCS and the verbal score was scored as 1 while the patient was on the ventilator. The patient’s consciousness also showed rapid improvement after the start of MINO treatment. The hematological, biochemical, and CSF findings improved after the MINO treatment. The most deteriorated data of each finding is as follows: hemoglobin level, 9.9 g/dL (day 23); platelet count, 5.9×109/L (day 20); fibrinogen level, 132 mg/dL (day 20); AT III activity level, 48.9% (day 20), albumin level, 1.7 mg/dL (day 17): T-Bil level, 1.72 mg/dL (day 14), AST/ALT levels, 246/479 IU/mL (day 26); creatinine level, 1.3 mg/dL (day 21); CSF lymphocyte count, 50/mm3 (day 21), CSF neutrophil count 4/mm3 (day 21); and CSF protein level, 285 mg/dL (day 21). The pa-tient’s fibrinogen, AT III activity, and creatinine levels rapidly normalized in response to MINO treatment, although it is likely that the administration of gabexate mesilate also had an effect on im-proving the patient’s coagulopathy. The elevation of the AST/ALT levels may have occurred due to the metabolism of MINO or other antibiotics. The CSF cytology showed mononuclear pleocytosis before treatment. The level of CSF TNF-α was 10.8 pg/mL on day 3, and decreased to undetectable levels on day 49.

els as side effect. The dynamics of the laboratory data helps

to know that the disease triggers HLH or not.

The diagnosis of scrub typhus is sometimes challenging.

In this case, we were not able to obtain accurate information

from the patient because of his consciousness disturbance.

Furthermore, it was difficult to locate the eschar on his back

because he was on a ventilator. Eschars are often found in

places that are difficult to see (16). The patient did not have

a skin rash, which is one of the triad symptoms of scrub ty-

phus. Meninigoencephalitis is rare form of scrub typhus, be-

sides, is not prevalent in Tochigi prefecture. According to

the data from the Tochigi public health center, the annual in-

cidence of scrub typhus in the prefecture is less than 10 pa-

tients per year.

Intern Med 55: 805-809, 2016 DOI: 10.2169/internalmedicine.55.5304

809

In conclusion, it is preferable to diagnose and treat scrub

typhus before the condition progresses to HLH, although it

is also essential to establish the criteria which is specific to

adult HLH (8, 17). Fortunately, severe scrub typhus, even

complicated HLH, can be treated with MINO or doxycy-

cline (2-5). The clinical and laboratory findings are not spe-

cific, however, they are good indicators of the progression to

HLH.

The authors state that they have no Conflict of Interest (COI).

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