Scrub typhus meningitis in a renal transplant recipient

Introduction

Scrub typhus is caused by Orientia tsutsugamushi of Rickettsiaceae family, an obligate intracellular bacterium. It is transmitted by trombiculid mite bite while field rodents act as reservoirs.[1] The infection usually presents as acute febrile illness accompanied by headache, myalgia, vomiting, diarrhea, or cough on 3–4 days and rash/lymphadenopathy at the end of the 1^st week after bite. During the 2^nd week of illness, serious complications[2] such as pneumonitis, myocarditis, acute kidney injury (AKI), acute respiratory distress syndrome, and multiorgan dysfunction syndrome can occur. Central nervous system (CNS) manifestations of scrub typhus range from aseptic meningitis to frank meningoencephalitis.[3] We report here a renal transplant recipient with scrub typhus meningitis who improved after intravenous (IV) azithromycin.

Case Report

A 45-year-old woman, renal transplant recipient, presented to us with fever with chills, myalgia, severe headache, and persistent vomiting of 6 days duration. She had undergone deceased donor renal transplant 4 years ago, and did not have any rejection or major infections. She was on triple immunosuppression (tacrolimus – 3 mg/day, mycophenolate mofetil – 1500 mg/day, and prednisolone – 7.5 mg/day) and was maintaining normal graft function. There was no pallor, icterus, lymphadenopathy, rash, or edema. Physical examination revealed pulse rate of 102/min, respiratory rate of 16/min, temperature of 103°F, blood pressure of 120/80 mm Hg, and a circumscribed eschar on the back just below left scapula [Figure 1]. Examination of cardiovascular, respiratory system, and abdomen was normal. Neurological examination revealed neck stiffness, mild irritability with normal mentation, and optic fundus. She was started on oral doxycycline of 100 mg twice daily after clinical diagnosis of scrub typhus meningitis was made. Laboratory investigations revealed urine analysis: Trace proteinuria; total blood count: 6500 cells/mm³ with a polymorphonuclear predominance; hemoglobin: 11 g/dl, platelet count 100,000 cells/mm³; normal peripheral smear; blood urea 60 mg/dl; serum creatinine 1.6 mg/dl; bilirubin 0.8 mg/dl; alanine aminotransferase (ALT) 53 IU/L; aspartate aminotransferase 48 IU/L; alkaline phosphatase 86 IU/L; total protein 6.8 g/dl; and albumin 3.8 g/dl. IgM antibodies against O. tsutsugamushi by enzyme-linked immunosorbent assay (ELISA) were positive. Blood and urine cultures were negative. Quantitative buffy coat for malaria, microscopic agglutination tests, and IgM and IgG antibodies for leptospirosis and dengue were negative. Blood polymerase chain reaction (PCR) for cytomegalovirus was negative. Chest X-ray and electrocardiogram were normal. Abdominal ultrasound showed no organomegaly and normal allograft kidney. Computerized tomography of the brain was normal. Cerebrospinal fluid (CSF) analysis showed mild pleocytosis (6–7 cells) mainly lymphocytes, high protein (203 mg/dl), normal sugar (77 mg/dl), normal adenosine deaminase (6 U/L), and negative for tuberculosis and herpes simplex virus by PCR. The patient had persistent fever and headache even after 5 days of oral doxycycline therapy. She was started on IV azithromycin 500 mg/day. She became afebrile within 24 h, her general condition improved dramatically and discharged with normal creatinine. She received totally 1 week of IV azithromycin followed by oral dose for 1 week.

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Figure 1

Clinical photography showing eschar on the back

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Discussion

Scrub typhus infection usually occurs during the rainy months of June to November. In recent years, there is increasing occurrence of scrub typhus in India, especially in southern parts.[4] The name “typhus” is derived from the Greek word, typhos that means stupor. O. tsutsugamushi spreads by blood and lymphatics and induces generalized vasculitis. Clinical findings include such as fever, maculopapular rash, generalized lymphadenopathy, liver dysfunction, pneumonitis, meningitis/meningoencephalitis, AKI, and septic shock.[5] Eschar, which is the pathognomonic sign of scrub typhus, is nonitchy and nonpainful ulcer surrounded by red areolae and covered by dark scabs. It is present in 40–50% of patients and is often present in areas such as groin, gluteal folds, breast folds, and external genitals.[6]

The diagnosis of scrub typhus is usually made by either a single indirect immunofluorescent antibody (IFA) titer against O. tsutsugamushi of 1/400 or a 4-fold or greater rise in IFA titer. IgM ELISA, based on the detection of 56 Da antigen is a dot blot test which has high specificity (~90%) and sensitivity (~90%) when compared to IFA. A standard PCR targeting the 56-kDa outer membrane protein will be useful but not widely available.[7]

In a study of 30 children with scrub typhus in Thailand, only one patient had meningitis.[8] A case series of scrub typhus from India reported meningitis as a common CNS complication. Other complications include seizures, delirium, and hearing loss. Focal CNS damage, cerebellitis, myelitis, and cerebral hemorrhage were reported rarely.[9] Pai et al. identified O. tsutsugamushi DNA using nested PCR in the CSF in 6/25 patients with scrub typhus. They reported mild pleocytosis with lymphocyte dominance and protein levels >45 mg/dl in the CSF in 48% of patients.[10] A study showed association of pneumonitis was with the occurrence of scrub typhus meningitis and meningoencephalitis.

In a study of 20 consecutive patients with acute encephalitis, 30% were due to scrub typhus.[11] Eschar was seen in 50% and renal involvement in 100% of patients. Magnetic resonance imaging brain revealed cerebral edema, bright lesions in the putamen, and the thalamus. All patients responded well to oral doxycycline. The overall mortality rate with scrub typhus meningitis was 25%.

Risk factors for scrub typhus infection are living in rural areas, sleeping outdoors, rapid urbanization, aging populations, and recent rainfall. Our patient was from the rural area and sleeping outdoors in rainy season would have been the risk factor. She had fever, headache, and eschar which was typical presentation of scrub typhus but had meningitis and nonresponsiveness to oral doxycycline which was rare. The causes of meningitis after renal transplantation include bacterial (Listeria monocytogenes, Streptococcus pneumonia, Neisseria meningitis, Escherichia coli, etc.), viral (cytomegalovirus, herpes simplex), tuberculosis, fungal (Cryptococcus neoformans, Histoplasma capsulatum), and parasitic (invasive strongyloidiasis).

The CSF findings in scrub typhus resemble those in viral meningoencephalitis, leptospirosis, and tuberculous meningitis.[12] We excluded all these causes in our patient. CSF lymphocyte predominance and elevated serum ALT levels may be helpful in differentiating from bacterial meningitis.[13] The transmission of tropical infections in transplant recipients occurs through three routes: donor-Derived infections, reactivation or recrudescence of latent infections, or de novo transmission after transplantation. The increasing emphasis on tropical infections in transplant recipients recently is due to include increasing travel of transplanted patients to the tropics, increasing numbers of transplantation, and transplant tourism in tropical countries.[14] Apart from tuberculosis, infections such as leprosy, malaria, leishmaniasis, dengue, yellow fever, measles, and leptospirosis have been reported in transplant recipients.

Doxycycline 200 mg/day for 7 days is the treatment of choice. Our patient did not respond to oral doxycycline. Possible explanations for the therapeutic failure of doxycycline include bacteriostatic action, lower penetration into CSF (only 15–30%), and resistance to the drug. Intravenous doxycycline or a higher oral dose may be helpful in achieving higher CSF levels. Chloramphenicol 500 mg, qid or rifampicin 900 mg/day for a week can be used patients who do not respond to conventional therapy. Azithromycin (10 mg/kg/day) has been proven to be more effective in both doxycycline-susceptible and resistant scrub typhus.[15] Our patient responded well to IV azithromycin.

Conclusions

Renal transplant recipients are prone to opportunistic infections. Rare causes such as scrub typhus should also be considered in the case of mononuclear meningitis, especially in endemic areas. Thorough clinical examination and high index of suspicion are needed for early diagnosis and favorable outcome.