Abstract
In Scrunb Typhus, hepatotoxicity is an important, yet understudied, manifestation. We reviewed studies on scrub typhus, published in the last five years (2014–2019), which evaluated its clinico-epidemiological factors in India, and concentrated on its hepatic involvement. Nine studies were found, and no Indian study exclusively evaluated hepatic dysfunction. Thus, comments from a few international studies were also included. We conclude that liver dysfunction in the form of elevated serum transaminase levels is a common manifestation of scrub typhus, which may herald progress to fulminant hepatic failure.
Introduction
Scrub typhus is an important cause of acute febrile illness in tropical areas. The renowned Tsutsugamushi triangle, which spans from Japan in the east to Afghanistan/Pakistan in the west and Australia in the south, denotes the hot bed of case burden. Sporadic cases have been observed in the Middle East, Congo, Tanzania, Djibouti, Kenya and Cameroon in Africa and Chile in South America. 1 Caused by Orientia tsutsugamushi, a rickettsia, scrub typhus is a vector-borne infection spread by the bite of trombiculide mites. They thrive on small rodents, mostly wild rats. 2 The salivary glands of mites contain a large load of infective Orientia. 3 Mites in their chigger phase bite humans when they encroach an area of mite infestation, primarily, but not restricted to marshy lands, rice fields or sea shores. Being an obligate intracellular organism, Orientia tsutsugamushi invade and multiply in phagocytes, thus evading the immune system. 4 On escaping from the phagocytes, the organisms proliferate on the endothelium of the small blood vessels causing release of cytokines. Systemic manifestations of scrub typhus are the result of this inflammatory response which damage endothelial integrity, causing fluid leakage, platelet aggregation, polymorphs and monocyte proliferation, leading to focal occlusive end-angiitis causing microinfarcts. This process especially affects skeletal muscles, skin, lungs, kidneys, brain and cardiac muscles. 5 It is estimated that at least one million infections occur each year in Asia. 6
Scrub typhus is a multisystem disease and an important differential diagnosis of pyrexia of unknown origin.
Common laboratory findings include elevated serum transaminase levels, as well as thrombocytopenia, and leucocytosis. Multiorgan dysfunction syndrome may be seen in up to 34% of patients in whom 63.7% had evidence of hepatic dysfunction. 7
Methods
As no study specifically investigated liver dysfunction in scrub typhus, we gathered data from Indian case reports and case series published between 2014 and 2019. Liver dysfunction was defined as elevation of serum aspartate transaminase (AST) and/or alanine transaminase (ALT) more than twice the upper normal limit, taken as 40 IU/L. As most studies used elevation of only serum transaminases, and AST/ALT being a fairly reliable predictor of hepatocellular injury, other parameters were not used. Studies which noted causes of hepatitis other than scrub typhus were excluded, as were studies involving co-infection of scrub typhus with other hepatotoxic organisms.
Results
Studies showing hepatic dysfunction in scrub typhus.
Discussion
Liver dysfunction is therefore an important well-known manifestation in scrub typhus and is thus imperative to investigate its existence and severity. It has been suggested that elevated levels of interferon-gamma (IFN-γ) cause activation of a cell-mediated immune reaction in scrub typhus. 19 However, elevated plasma concentrations of granzymes A and B, IFN-γ-inducible protein 10 and monokine induced by IFN-γ found suggest that activation of cytotoxic lymphocytes is part of the early host response. 20 It seems that, prior to treatment, the microscopic appearance of hepatocytes showed swelling with intact architecture, the presence of Kupffer cell hyperplasia and creeping fibrosis from the portal area. A few acidophilic cells and positive Rickettsiae in the hepatocyte cytoplasm were clearly visualised with Pinkerton’s stain, appearing as tiny bright-red organisms. After commencement of treatment, ballooning degeneration of hepatocytes was noted, with mononuclear cell infiltration in portal tracts and in small clusters within hepatic lobules. Kupffer cell hyperplasia was seen as in pre-treatment liver biopsies. Post-tetracycline treatment, Rickettsiae could not be visualised in the hepatocytes by Pinkerton’s stain. 21 In a study on a case of acute hepatitis in scrub typhus, features of portal inflammation, degeneration of individual hepatocytes, mild ballooning changes with lobular disarray and small clusters of mononuclear cell infiltration were identified in the hepatic lobules. There was no sign of cholestasis or apoptosis of hepatocytes. Immunohistochemical staining for Orientia tsutsugamushi showed scattered positive immunoreactions in the hepatic cytoplasm. 22
The abdominal CT findings in cases presenting with hepatic dysfunction in scrub typhus showed intra-abdominal lymphadenopathy, non-homogenous enlargement of the liver, ascites, low attenuation of portal areas, splenomegaly and gall bladder wall thickness. 23
Limited Indian case reports and case series mentioned hepatic failure as the initial presenting manifestation of scrub typhus.24,25 Five fatal cases described that all had elevated transaminase levels (AST > ALT), with multiorgan failure as the cause of death. 26
Doxycycline, at a dose of 100 mg bd for 10–14 days, remains the first line treatment. Other antibiotics which may be used include tetracycline, azithromycin and rifampicin, the last of which is normally reserved for anti-tubercular treatment. Where doxycycline is contraindicated, azithromycin is the best alternative, especially for children under eight years of age, or during pregnancy.
Conclusion
Hepatotoxicity is an important clinical feature of scrub typhus and is largely under-studied in Indian population. Multicentre population-based studies are required to assess the actual prevalence of hepatic dysfunction among these patients but is certain to be significantly high.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
