Scrub typhus involving central nervous system, India, 2004-2006.
Article Type: Report
Subject: Scrub typhus (Diagnosis)
Scrub typhus (Care and treatment)
Scrub typhus (Research)
Scrub typhus (Causes of)
Authors: Mahajan, Sanjay K.
Rolain, Jean-Marc
Kanga, Anil
Raoult, Didier
Pub Date: 10/01/2010
Publication: Name: Emerging Infectious Diseases Publisher: U.S. National Center for Infectious Diseases Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 U.S. National Center for Infectious Diseases ISSN: 1080-6040
Issue: Date: Oct, 2010 Source Volume: 16 Source Issue: 10
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: India Geographic Code: 9INDI India
Accession Number: 238895958
Full Text: To the Editor: Scrub typhus, caused by Orientia tsutsugamushi, is one of the most common infectious diseases of rural southern Asia, southeastern Asia, and the western Pacific. The disease is transmitted to humans by the bite of larvae of trombiculid mites harboring the pathogen. The disease often appears as a nonspecific febrile illness. The clinical picture of scrub typhus is typically associated with fever, rash, myalgia, and diffuse lymphadenopathy (1). Immunofluorescence assay (IFA) is the test of choice for serodiagnosis of rickettsial diseases (2). Scrub typhus has been reported from northern, eastern, and southern India, and its presence has been documented in at least 11 Indian states (3-7).

Our study's goal was to retrospectively analyze data of patients with scrub typhus involving the central nervous system. Scrub typhus was suspected on the basis of clinical signs such as febrile illness or fever with rash or eschar. The fever workup profile (Widal agglutination test, peripheral smear, blood, and urine culture) was noncontributory. Blood samples were obtained after patients gave informed consent. All patients with clinically suspected scrub typhus received antirickettsial drugs (doxycycline and/ or azithromycin) empirically. IFA and PCR of blood samples were performed to confirm scrub typhus following standard protocol (3). DNA was extracted from the blood sample (buffy coat) by using QIAamp DNA Mini Kit (QIAGEN GmbH, Hilden, Germany) according to the manufacturer's instructions. A standard PCR specific for the 56-kDa protein with forward and reverse primers (OtsuF: 5'AATTGCTAGTGCAATGTCTG-3' and OtsuR: 5'-GGCATTATAGTAGGC TGAG-3') was performed (3). PCR products were purified by using the QIAquick PCR Purification Kit (QIAGEN) according to the manufacturer's instructions. Sequencing reactions were done by using a DNA sequencing kit, dRhodamine Terminator Cycle Sequencing Ready Reaction Mix (Applied Biosystems, Foster City, CA, USA). Sequencing was performed on an ABI PRISM 310 DNA Sequencer (Applied Biosystems). The obtained sequences were identified by comparison with sequences available in GenBank by using the BLAST software (http://blast.ncbi.nlm.nih.gov) (3).

During 2004-2006, scrub typhus was confirmed in 27 patients; 4 had features of central nervous system involvement. All 4 had fever with altered sensorium and meningeal signs; 2 had seizures. No neurologic focal deficit was noted, but all showed cerebrospinal fluid abnormalities. One patient had an eschar, but none had a rash. Serum of 2 patients was subjected to IFA; both samples showed high titers (Table), and PCR for blood was positive for O. tsutsugamushi for all patients. Serum was not subjected to examination for leptospirosis. Patients were treated mainly on the basis of clinical grounds because results of serology were not available immediately. Some clinical features of scrub typhus and leptospirosis are similar, and dual infections have been reported (8); therefore, antimicrobial drugs active against both leptospirosis and scrub typhus were included in treatment regimens. One patient received doxycycline and azithromycin, and the remaining 3 received ceftriaxone in addition to doxycycline. Two patients improved, 1 died, and 1 left hospital against medical advice. The clinical and laboratory details, treatments, and outcomes of all patients are given in the Table.

O. tsutsugamushi is an obligate intracellular parasite of professional and nonprofessional phagocytes that invades the central nervous system as part of systemic infection and is found in endothelial cells of blood vessels and in circulating phagocytes. A severe headache occurs almost invariably and has been used as a key clinical criterion for identifying suspected cases. Severe features of central nervous system involvement, such as neck stiffness, neurologic weakness, seizures, delirium, and coma, have been reported. Meningismus or meningitis has been found in 5.7%-13.5% of patients (9). The greatest degree of central nervous system involvement in rickettsial diseases occurs in Rocky Mountain spotted fever and epidemic typhus, followed closely by scrub typhus. The meninges are more commonly involved by O. tsutsugamushi than by other rickettsial infections, and the overall histologic picture in the central nervous system is best described as a meningoencephalitis (9). An exhaustive study of 200 cases of scrub typhus showed central nervous system involvement in most patients. However, focal central nervous system damage was rare, and during the encephalitis stage, few objective neurologic signs were apparent, other than those suggesting more generalized cerebral involvement, such as confusion, tremor, and restlessness (10).

Now that it is established that O. tsutsugamushi does invade cerebrospinal fluid, scrub typhus should be considered a cause of mononuclear meningitis in areas in which it is endemic. In our study 1 patient died despite treatment with doxycycline and azithromycin, suggesting the possibility of resistance to these antimicrobial drugs as recently posited in a study conducted in southern India (6). Scrub typhus in these regions should be further investigated in prospective studies, and clinical isolates should be obtained to evaluate susceptibility to antimicrobial drugs.

DOI: 10.3201/eid1610.100456

Sanjay K. Mahajan, Jean-Marc Rolain, Anil Kanga, and Didier Raoult

Author affiliations: Indira Gandhi Medical College, Shimla, India (S.K. Mahajan, A. Kanga); and Universite de la Mediterranee, Marseille, France (J.-M. Rolain, D. Raoult)

References

(1.) Raoult D. Scrub typhus. In: Mandell GL, Bennet JE, Dolin R, editors. Principles and practice of infectious diseases. 6th ed. Philadelphia: Churchill Livingstone; 2004. p. 230-10.

(2.) Blacksell SD, Bryant NJ, Paris DH, Doust AJ, Sakoda Y, Day NPJ. Scrub typhus serologic testing with indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to lot of confusion. Clin Infect Dis. 2007;44:391 401. DOI: 10.1086/510585

(3.) Mahajan SK, Rolain JM, Kashyap R, Bakshi D, Sharma V, Prasher BS, et al. Scrub typhus in Himalayas. Emerg Infect Dis. 2006;12:1590-2.

(4.) Mahajan SK, Kashyap R, Kanga A, Sharma V, Prasher BS, Pal LS. Relevance of Weil-Felix test in diagnosis of scrub typhus in India. J Assoc Physicians India. 2006;54:619-21.

(5.) Chaudhry D, Garg A, Singh I, Tandon C, Saini R. Rickettsial diseases in Haryana: not an uncommon entity. J Assoc Physicians India. 2009;57:334-7.

(6.) Mathai E, Rolain JM, Verghese GM, Abraham OC, Mathai D, Mathai M, et al. Outbreak of scrub typhus in southern India during the cooler months. Ann N Y Acad Sci. 2003;990:359-64.

(7.) Prabagaravarthanan R, Harish BN, Parija SC. Typhus fever in Pondicherry. J Commun Dis. 2008;40:159-60.

(8.) Lee CH, Liu JW. Coinfection with leptospirosis and scrub typhus in Taiwanese patients. Am J Trop Med Hyg. 2007;77:525-7.

(9.) Drevets DA, Leenen PJM, Greenfield RA. Invasion of central nervous system by intracellular bacteria. Clin Microbiol Rev. 2004;17:323-47. DOI: 10.1128/ CMR.17.2.323-347.2004

(10.) Kim DE, Lee SH, Park KI, Chang KH, Roh KH. Scrub typhus encephalomyelitis with prominent neurological signs. Arch Neurol. 2000;57:1770-2. DOI: 10.1001/ archneur.57.12.1770

Address for correspondence: Sanjay K. Mahajan, 25/3, US Club, Shimla, Himachal Pradesh, India 171001; email: sanjay_mahajan64@rediffmail. com
Table. Clinical features and laboratory investigations of patients who
had scrub typhus with central nervous system involvement, India,
2004-2006 *

                                                      Results

Clinical and laboratory features                     Patient 1

Age, y/sex                                              52/M
Date of hospital admission                          2004 Aug 22
Fever duration before admission, d ([dagger])            12

Chills                                                   +
Rigors                                                   +
Headache                                                 +
Myalgia                                                  +
Abdominal pain                                           +
Seizure                                                  -
Altered sensorium                                        +
Conjunctival suffusion                                   +
Jaundice                                                 +
Eschar                                                + Axilla
Lymphadenopathy                                    + Generalized
Meningeal signs                                          +

Urea, mg/dL                                             104
Creatinine, mg/dL                                       3.9

Bilirubin, mg/dL
  Total                                                 3.5
  Conjugated                                            1.0

Aspartate aminotransferase, IU                          167
Alanine aminotransferase, IU                            139
Alkaline phosphatase, IU                                 80
Proteinuria, mg/dL                                       +

CSF cytology                                        Lymphocytes,
                                                54 cells/[mm.sup.3]

Protein, mg/dL                                          125
Glucose, mg/dL                                           34

IFA titers ([double dagger])
  IgG                                                   512
  IgM                                                   <64

Drug treatment                                     Azithromycin,
                                                    doxycycline
Outcome                                                 Died

                                                      Results

Clinical and laboratory features                     Patient 2

Age, y/sex                                              50/F
Date of hospital admission                          2004 Aug 30
Fever duration before admission, d ([dagger])            12

Chills                                                   +
Rigors                                                   +
Headache                                                 +
Myalgia                                                  +
Abdominal pain                                           +
Seizure                                                  +
Altered sensorium                                        +
Conjunctival suffusion                                   -
Jaundice                                                 +
Eschar                                                   -
Lymphadenopathy                                      + Cervical
Meningeal signs                                          +

Urea, mg/dL                                              96
Creatinine, mg/dL                                       1.5

Bilirubin, mg/dL
  Total                                                 2.7
  Conjugated                                            1.7

Aspartate aminotransferase, IU                          160
Alanine aminotransferase, IU                            198
Alkaline phosphatase, IU                               1,000
Proteinuria, mg/dL                                       -

CSF cytology                                        Lymphocytes,
                                                14 cells/[mm.sup.3]

Protein, mg/dL                                           69
Glucose, mg/dL                                           44

IFA titers ([double dagger])
  IgG                                                   512
  IgM                                                   <64

Drug treatment                                      Ceftriaxone,
                                                    doxycycline
Outcome                                               Improved

                                                      Results

Clinical and laboratory features                     Patient 3

Age, y/sex                                              30/F
Date of hospital admission                           2005 Sep 9
Fever duration before admission, d ([dagger])            9

Chills                                                   +
Rigors                                                   +
Headache                                                 +
Myalgia                                                  +
Abdominal pain                                           -
Seizure                                                  +
Altered sensorium                                        +
Conjunctival suffusion                                   +
Jaundice                                                 +
Eschar                                                   -
Lymphadenopathy                                      + Cervical
Meningeal signs                                          +

Urea, mg/dL                                              84
Creatinine, mg/dL                                       1.6

Bilirubin, mg/dL
  Total                                                 4.6
  Conjugated                                            3.6

Aspartate aminotransferase, IU                          166
Alanine aminotransferase, IU                            185
Alkaline phosphatase, IU                               1,000
Proteinuria, mg/dL                                       +

CSF cytology                                        Lymphocytes,
                                                60 cells/[mm.sup.3]

Protein, mg/dL                                           34
Glucose, mg/dL                                           33

IFA titers ([double dagger])
  IgG                                                 Not done
  IgM

Drug treatment                                      Ceftriaxone,
                                                    doxycycline
Outcome                                               Improved

                                                      Results

Clinical and laboratory features                     Patient 4

Age, y/sex                                              47/F
Date of hospital admission                          2005 Sep 15
Fever duration before admission, d ([dagger])            16

Chills                                                   -
Rigors                                                   -
Headache                                                 -
Myalgia                                                  +
Abdominal pain                                           -
Seizure                                                  -
Altered sensorium                                        +
Conjunctival suffusion                                   +
Jaundice                                                 +
Eschar                                                   -
Lymphadenopathy                                          -
Meningeal signs                                          +

Urea, mg/dL                                             143
Creatinine, mg/dL                                       2.7

Bilirubin, mg/dL
  Total                                                 3.0
  Conjugated                                            2.6

Aspartate aminotransferase, IU                           30
Alanine aminotransferase, IU                             38
Alkaline phosphatase, IU                                782
Proteinuria, mg/dL                                       +

CSF cytology                                        Neutrophils,
                                                38 cells/[mm.sup.3]

Protein, mg/dL                                          118
Glucose, mg/dL                                           48

IFA titers ([double dagger])
  IgG                                                 Not done
  IgM

Drug treatment                                      Ceftriaxone,
                                                    doxycycline
Outcome                                            Left hospital
                                                   against advice

* CSF, cerebrospinal fluid; IFA, immunofluorescence assay; Ig,
immunoglobulin.

([dagger]) Fever defined as AM temperature >98.9[degrees] F or PM
temperature >99.9[degrees] F.

([double dagger]) IFA significant titers: IgG [greater than or equal
to] 128; IgM [greater than or equal to] 64. The single serum samples,
obtained at admission to hospital, were subjected to IFA by using a
panel of 11 rickettsial antigens comprising spotted fever group
rickettsiae (Rickettsia japonica, R. helvetica, R. slovaca, R. conorii
subsp. indica, R. honei, R. heilongjangensis, and R. felis), R. typhi,
and Orientia tsutsugamushi (Gilliam, Kato, and Kawasaki strains).
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