Encephalitis, Fever, and Doxycycline
August 1, 2018
By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN
Dr. Fischer reports no financial relationships relevant to this field of study.
SYNOPSIS: Scrub typhus is a significant cause of acute encephalitis in north India and other parts of Asia and Africa. Doxycycline is a safe and effective treatment option.
SOURCE: Mittal M, Bondre V, Murhekar M, et al. Acute encephalitis syndrome in Gorakhpur, Uttar Pradesh, 2016: Clinical and laboratory findings. Pediatr Infect Dis J 2018;37: doi: 10.1097/INF.0000000000002099. [Epub ahead of print].
Outbreaks of acute encephalitis occur seasonally in northern India, with about 10,000 cases per year and with case fatality rates of approximately 25%. Japanese encephalitis virus accounted for the majority of cases in the past, but the incidence of disease due to that agent has decreased with use of vaccines. Nonetheless, outbreaks of encephalitis continue. Investigations earlier this decade suggested that scrub typhus was common in northern India and might be responsible for some encephalitis cases. Mittal and colleagues prospectively evaluated patients presenting with acute encephalitis to determine current causes.
Patients of any age were included if they had acute fever with altered mental status and/or new onset of seizures during three months in 2016 (August-October). Of 1,242 patients at a single center meeting the clinical case definition, 1,037 had cerebrospinal fluid evaluation showing at least five cells per cubic milliliter; 407 of the patients with acute encephalitis and spinal fluid pleocytosis were selected randomly for study inclusion. Researchers tested serum samples for IgM antibodies to the agents of scrub typhus (Orientia tsutsugamushi), Japanese encephalitis, and dengue fever. The investigators also tested spinal fluid for IgM antibodies against Japanese encephalitis virus and O. tsutsugamushi. They performed polymerase chain reaction testing on whole blood and on spinal fluid for O. tsutsugamushi and for the spotted fever group of Rickettsia.
All patients were from rural areas. About half were 5 to 10 years of age. Of the 407 studied patients, 65% had scrub typhus, 10% had Japanese encephalitis, and 8% had dengue fever. Less than 1% (four patients) had evidence of infection with the spotted fever group of Rickettsia. Of the 266 patients with scrub typhus, 36 had coinfection: 23 with dengue, 10 with Japanese encephalitis virus, two with spotted fever group Rickettsia, and one with triple infection (scrub typhus, dengue, and Japanese encephalitis).
For patients with scrub typhus, symptoms of fever, altered sensorium, and seizures were characteristic. About half had vomiting, and 15% had abdominal pain; 5% had diarrhea. Headache was reported by 14%. Patients had been sick with fever for a median of six days between the onset of fever and the development of central nervous system findings. Hepatomegaly was seen in 44%, splenomegaly in 10%, and periorbital edema in 33%. Eschar was not seen. About three-fourths of patients were hyperreflexic. Peripheral white blood cell counts were elevated mildly, and platelet counts were diminished mildly. Spinal fluid white cell counts were elevated mildly (median 24 per cubic milliliter). In this study, patients with acute encephalitis were treated routinely with intravenous azithromycin. Sadly, 15% of patients did not survive the scrub typhus infection.
The researchers compared their results to those of other studies of etiologies that account for acute encephalitis in India. In other studies in which O. tsutsugamushi infection was not sought, the majority of patients had no identified causal microbe.
COMMENTARY
A couple of years ago, I performed teaching rounds with a pediatric team in the capital city of the Himalayan mountain kingdom of Bhutan. We saw a child with acute encephalitis who had come from the southern part of Bhutan, at low elevation near the border with India. I thought through a differential diagnosis for this febrile child who presented semi-comatose and seizing with spinal fluid pleocytosis. Bacterial testing was negative, as was a test for Japanese encephalitis. I wondered about herpes infection and arboviral diseases. Fortunately, even the Bhutanese trainees had a broader differential diagnosis than I did, and they thought to start doxycycline for possible scrub typhus. As exemplified by the other Indian studies reviewed by Mittal and colleagues, those who don’t seek scrub typhus fail to find it, and those who don’t think of scrub typhus fail to treat for it.
Obviously, the geographic epidemiology of febrile illnesses, including encephalitis, varies. Scrub typhus is borne by mites and is common in eastern and southern Asia, on western Pacific islands, and on the islands of the Indian Ocean. More than 1 million new cases are thought to occur each year.1 The epidemiology also varies over time. Even as my senior colleagues and I remember frequently seeing patients with bacterial meningitis due to Haemophilus influenzae and Streptococcus pneumoniae, those diseases are markedly rare in our current era of improved vaccination. Similarly, the likelihood of Japanese encephalitis causing illness in countries like India has dropped with more widespread Japanese encephalitis virus vaccine use.
In a study reported last year from Tanzania, researchers evaluated 57 potential causes of fever in 1,007 febrile patients.2 Plasmodium was the most common etiology identified, but Leptospira was found in 3% and Rickettsia in 1%; scrub typhus was not included in the testing for this study. However, as malaria becomes less common in Africa, other infections become relatively more common. In a recent study in Kenya, researchers looked specifically at other treatable causes of fever in children; during 13 months spanning 2011-2012, researchers evaluated 370 febrile children.3 They identified spotted fever group Rickettsia in 22% of the children, typhus group Rickettsia in 1%, and scrub typhus in 4%. In Asia and Africa, patients with fever and patients with acute febrile encephalitis should be cared for by professionals who are aware of the possibility of scrub typhus.
Patients with rickettsial diseases and patients with scrub typhus do not respond favorably to common antibacterial agents. Doxycycline usually is considered the treatment of choice, but there have been concerns about the safety of doxycycline use in children because of the concern about staining of teeth. However, a recent systematic review gives reassurance about the use of doxycycline.4 Although tetracycline has potential side effects, there is no correlation between the use of doxycycline and either staining of children’s teeth or teratogenicity when the medication is used during pregnancy.4
Mittal and colleagues chose to treat scrub typhus with azithromycin. Researchers conducted a comparison study of azithromycin and doxycycline for complicated scrub typhus using retrospective propensity score matching.1 Outcomes were similarly favorable between the two groups, suggesting that intravenous azithromycin is a valid alternative to doxycycline for treatment of patients with scrub typhus.
Thus, scrub typhus is a significant cause of acute encephalitis in parts of Asia, Oceania, and, increasingly, Africa. Patients with acute encephalitis in or from these parts of the world should be tested and/or presumptively treated with doxycycline or intravenous azithromycin to cover the possibility of scrub typhus.
REFERENCES
- Jang MO, Jang HC, Kim UJ, et al. Outcome of intravenous azithromycin therapy in patients with complicated scrub typhus compared with that of doxycycline therapy using propensity-matched analysis. Antimicrob Agents Chemother 2014;58:1488-1493.
- Hercik C, Cosmas L, Mogeni OD, et al. A diagnostic and epidemiologic investigation of acute febrile illness (AFI) in Kilombero, Tanzania. PLoS One 2017;12:e0189712.
- Maina AN, Farris CM, Odhiambo A, et al. Q fever, scrub typhus, and rickettsial diseases in children, Kenya, 2011-2012. Emerg Infect Dis 2016;22:883-886.
- Cross R, Ling C, Day NP, et al. Revisiting doxycycline in pregnancy and early childhood — time to rebuild its reputation? Expert Opin Drug Saf 2016;15:367-382.
Scrub typhus is a significant cause of acute encephalitis in north India and other parts of Asia and Africa. Doxycycline is a safe and effective treatment option.
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