Scrub Typhus

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Scrub typhus is one of the tropical rickettsial infections which if left untreated, can have fatal consequences. It is caused by Orientia tsutsugamushi and transmitted by the bite of the mite larvae or chiggers. It is a systemic illness and can present as a vasculitis-like infection. This activity focuses on the role of the interprofessional team in prompt diagnosis and early treatment of scrub typhus.

Objectives:

  • Identify the etiology of scrub typhus.
  • Describe clinical manifestations of scrub typhus.
  • Review the treatment options for scrub typhus.
  • Explain the importance of improving care coordination among the interprofessional team to improve outcomes for patients with scrub typhus.

Introduction

Scrub typhus is an infectious disease caused by the rickettsial bacterium Orientia tsutsugamushi. The causative organism displays high levels of antigenic variation.[1] It is a serious public health problem in the Asia-Pacific region including but not limited to the region known as the “tsutsugamushi triangle”. One billion people globally covering more than 8 million kilometers from Pakistan in the west, Australia in the south, and Japan in the east are threatened by this infection which can be fatal at times.[2] 

A systemic review on the burden of scrub typhus in India which is in the “tsutsugamushi triangle” revealed that that scrub typhus accounts for at least 25.3% among individuals with acute undifferentiated febrile illness (AUFI).[3] Despite being one of the commonest pathogens of the cause of such commonly encountered illness, it remains a neglected disease in terms of research and formulation of health care policies.

It is transmitted to humans by the bite of the larva of trombiculid mites. Later it causes disseminated vasculitis and perivascular inflammation ultimately leading to significant vascular leakage leading to end-organ injury. The disease can affect people of all ages and travelers across the globe who have visited regions of endemicity.

Clinical features usually arise after an incubation period of 6-21 days and manifest as fever, headache, myalgia, and gastrointestinal symptoms. An eschar which usually begins as a primary papular lesion later crusts to form a black ulcer with central necrosis is a distinct feature of scrub typhus although its presence varies in different regions.

The decision to initiate treatment should be based on clinical suspicion and later confirmed by serological tests.

Etiology

Scrub typhus in its region of endemicity is one of the causes of acute febrile illness which usually is underdiagnosed. It can affect multiple organ systems principally by its vasculitis and perivascular inflammation. Mite larvae or chiggers which carry the pathogenic gram-negative bacteria act as a vector to humans and they transmit the organism through their bite. The infection is maintained in nature as the organism follows transovarial transmission in the vector and sometimes in small mammals as a reservoir.[4]

The Orientia genome is considered to be the most highly repetitive bacterial genome sequenced. This is attributed to a result of high numbers of intragenomic deletions and duplications that occur in the genome. There are also rearrangements with transposable and conjugative elements within the genome that contribute to this phenomenon. Of the various structural proteins of Orientia tsutsugamushi, the 56-kDa type-specific antigen (TSA) is an outer membrane protein unique to O. tsutsugamushi.

Based on the serological characterization from this particular outer membrane protein which displays variable regions several new subtypes have been identified in different geographical regions as a result of its high genomic plasticity apart from the previously known prototype strains namely Karp, Kato, and Gilliam.[5]

The 56-kDa type-specific antigen is also described as a primary immunogen that can elicit neutralizing antibodies at the time of infection.[6] Due to these divergent strains of O.tsutsugamushi that are present in different endemic regions/countries the process of developing an effective vaccine has been hindered.

Epidemiology

The available data on the epidemiology of scrub typhus is currently very limited. Fever studies that have been done prospectively in Asia show that scrub typhus is a major cause of non-malarial febrile illnesses. Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%–27.9% and its incidence appears to be increasing.[2] Several hypotheses have been proposed for the increasing trend of scrub typhus infection in endemic regions. The population explosion in the last few decades and increased urbanization trend which resulted in a change in land use are major contributing factors. Also, the availability of specific tests for the diagnosis is leading to increased case detection. There have also been changes in antimicrobial prescription practices. In the early 1990s, there was a trend for use of chloramphenicol and tetracyclines for empiric treatment of enteric fever and other acute undifferentiated fevers. These antimicrobials also act against Orientia tsutsugamushi but in the late 1990s use of fluoroquinolones and second and third-generation cephalosporins predominated, and have been ineffective against the same. Another possible reason is that the chigger thrives in hot and humid conditions and with the recent trend of global warming and high humidity during the rainy season posing more to the infection. Changes in human behavior like spending more leisure hours participating in activities such as trekking or camping increase the risk of exposure of the vector in its natural habitat and thus an increased risk of infection.[7] There are no licensed vaccines for scrub typhus available to date, and at the same time, no systematic vector control efforts have been in place as of yet.[2] Orientia tsutsugamushi infections are seen in all age groups and there is no gender or race predilection.[8]

Pathophysiology

The pathophysiology of O. tsutsugamushi consists of vasculitis as a result of infection of endothelial cells and subsequently perivascular infiltration of T cells and monocytes/macrophages. This is followed by a wide range of inflammatory responses resulting in the endothelial and non-endothelial cells producing several cytokines which can be both beneficial (i.e., anti-microbial) and also cause tissue destruction to the infected host. This nature of the immune response can result in severe complications like hepatitis, renal failure, meningoencephalitis, and respiratory failure in the form of acute respiratory distress syndrome (ARDS), and sometimes myocarditis.

History and Physical

In humans, the incubation period of scrub typhus can range between 10 to 12 days, although it can vary between 6 and 21 days.[9] After the bite of the infected Leptotrombidium mite, patients can present with nonspecific flu-like symptoms that include fever and rash.

Patients may also present with an eschar at the site of the bite, which usually produces no pain or itch at the time of the bite (Fig 1).

  • The bite mark ‘eschar’ is a pathognomonic clinical feature of scrub typhus that occurs at the site of the chigger feeding. It appears as an ulcer that enlarges and undergoes central necrosis to finally turn into a black crust. This particular skin lesion may appear similar to a skin burn from a cigarette.[9]
  • Common sites of eschar include the neck, axillary, and infraaxillary regions. In both sexes, it is usually seen below the umbilicus in the front of the body, while in women, the prominent sites were the mammary and inframammary regions.[10]

There can be nonspecific symptoms in the form of headaches and fever, which are the most common features. Infected individuals may also develop generalized lymphadenopathy, nausea, and vomiting, along with abdominal pain and myalgia.

Towards the beginning of the second week, especially those individuals with untreated disease, systemic manifestations of the disease may start to develop. This can range from the central nervous system manifestations such as acute diffuse encephalomyelitis, encephalopathy, meningitis, and sometimes hearing loss, cranial nerve palsies, and several ocular manifestations.[11][12][13] Scrub typhus meningitis, defined as the presence of headache or nuchal rigidity with either altered sensorium or focal neurological deficits on history or examination is a common nervous system manifestation of scrub typhus. Meningoencephalitis is the more severe form, seen in a subset of patients, and characterized by altered sensorium and seizures and has been observed in the setting of multiorgan dysfunction syndrome (MODS) with an increased case-fatality if not treated promptly.

Cardiovascular manifestations may range from non-fatal rhythm abnormalities to features of congestive heart failure.[9][14] The renal system may also be affected which might result in acute renal failure. Interstitial pneumonia and acute respiratory distress syndrome may herald the involvement of respiratory system involvement. There may also be involvement of the gastrointestinal system, which can manifest as pancreatitis, alteration in liver functions, and diarrhea.[15][16][17]

Evaluation

Early diagnosis of acute scrub typhus infection is important for appropriate patient management as it is paramount in guidance for appropriate therapy, and its timely prevention of complications. In areas where scrub typhus is endemic, rapid, sensitive, and affordable diagnostics tools are usually unavailable hence clinicians have to begin empirical treatment based on suspicion. This may often lead to misdiagnosis and, as a result, patient mismanagement.

Diagnosis of scrub typhus via serological methods is the mainstay. A significant IgM antibody titer appears by the end of the first week in primary scrub typhus infection, whereas IgG antibodies usually take around two weeks to appear at significant levels. In cases of reinfection, IgG titers can be detected as early as the sixth day of infection, and the levels of IgM antibody titers in such cases may be variable.[1]

Weil–Felix Testing: This is the oldest test still in use today and is neither sensitive nor a specific diagnostic test for scrub typhus. This test relies on the use of cross-reacting proteus OXK strain for the serodiagnosis, but it provides little help in timely diagnosis as it has low sensitivity.[18]

The Indirect Immunofluorescent Antibody (IFA): This test is considered the gold standard for the diagnosis of scrub typhus. The test is based on the principle of fluorescence-labeled anti-human immunoglobulin, and it detects antibodies in the serum of the infected patient. The test is positive when the fluorescence-labeled anti-human immunoglobulin binds to the immobilized bacterial antigen that has been placed on a slide. This method has several limitations as it requires repeat testing to demonstrate the difference of a fourfold increase in antibody titers while in the acute and subsequently in the convalescent phase of serum samples. Thus it is a retrospective diagnosis and is of little importance to guide initial management in settings of acute infection. If prior studies have not been performed in the population of the locality for baseline seroprevalence levels, a single high antibody titer cannot be considered diagnostic.[19]

Indirect Immunoperoxidase (IIP): This test came into use to overcome the above shortcoming after modifying the IFA methods. Diagnosis can be made without a fluorescent microscope, as this method uses peroxidase-labeled antibodies instead of fluorescein. IIP methods have shown results that are equivalent to IFA. However, the sensitivity of this test is influenced by the various strains (as in IFA). Although there is no use of a fluorescent microscope, the need for technical expertise remains the same.

Enzyme-linked Immunoabsorbent Assays (ELISA): Currently, it is the preferred method of choice for serological diagnosis in acute scrub typhus infection as the resources for conducting IFA are not routinely available in common laboratories, and since there is the low sensitivity of Weil–Felix testing. It uses a recombinant p56-kDa type-specific antigen of O. tsutsugamushi strains that combine with IgM antibodies produced against the strains of Karp, Kato, Gilliam, and TA716 in acute infections for its detection. IgM ELISA is a sensitive test to indicate a recent infection with O. tsutsugamushi.[20]

Immunochromatographic Tests (ICT): This is a rapid diagnostic point-of-care test. The rapid diagnostic tests used for scrub typhus use the same basic principles as employed in other serologic tests. Since it uses the same recombinant 56-kDa TSA of only the common subgroups (Karp, Kato, and Gilliam) it results in a wide range of sensitivities and specificities. ICTs in the detection of IgM have sensitivities that range from 74% to 90% and specificities from 86% to 99%.[21]

Polymerase Chain Reaction (PCR) Techniques: They have a major advantage as they can detect the disease before antibodies have become detectable by serological methods and thus allows the infection to be diagnosed earlier. There are concerns that direct detection of the organism can be affected by antibiotics. However, cultures of eschar tissues have yielded positive results even up to 7 days after the use of antibiotics.[1] Though PCR is highly sensitive and specific in detecting very low numbers of copies, the cost factor prevents its use in routine diagnosis in areas of endemicity.

Bacterial Culture: It is a long and tedious process as O. tsutsugamushi is an obligate intracellular pathogen. It also requires biosafety level 3 containment and requires significant technical expertise. Samples are taken from the buffy coat of whole blood samples, and skin biopsies from experimental mammals. However, due to these tedious processes, culture can hardly be used as a diagnostic tool in a clinical setting. Hence, this endeavor remains only for research purposes in reference laboratories.

Cerebrospinal Fluid (CSF) Evaluation: For patients with signs of central nervous system involvement, a CSF evaluation may be helpful. Lymphocytic pleocytosis can be observed in scrub meningitis. CSF findings can mimic tuberculous meningitis (CSF lymphocytic pleocytosis with increased proteins) and viral meningoencephalitis.

Chest Radiographs: For patients with respiratory symptoms, a chest radiograph may be obtained. Pleural effusions may be seen scrub typhus along with pneumonia as para-pneumonic effusions. Acute respiratory distress syndrome (ARDS) characterized by bilateral heterogeneous diffuse infiltrates is a relatively uncommon but severe complication of scrub typhus.

Therefore, in summary, the diagnosis of scrub typhus is highly dependent on maintaining a higher degree of clinical suspicion and judicious use of limited diagnostic tests, especially in the areas of high endemicity.

Treatment / Management

Tetracycline, azithromycin, doxycycline, and rifampicin are effective antimicrobials for scrub typhus. Several studies particularly in doxycycline and azithromycin have used different dosing regimens including a loading dose of both agents followed by maintenance doses with an average duration of treatment with doxycycline for 7 days and 3 days in the case of azithromycin.[2] Tetracycline and rifampicin are also effective antimicrobials for scrub typhus.

Doxycycline

It has been the mainstay of treatment for most rickettsial diseases, including scrub typhus given at a dose of 100 mg IV or orally twice daily for 7 to 14 days. However, several reports have indicated suspected doxycycline resistance.

Azithromycin

It is an excellent alternative, particularly when resistance to doxycycline is suspected.[22] It has a long tissue half-life and long-lasting post-antibiotic effects and hence may be given for a shorter duration without the risks of relapses. Also, it efficiently penetrates polymorphonuclear leukocytes and macrophages, which are target cells for O. tsutsugamushi.[23]

Rifampicin

It is another option. However, the risk of inducing resistant tuberculosis must be weighted in undiagnosed patients, and hence clinicians should not regard this agent as a first-line treatment option but should consider it as a second-line treatment option after exclusion of active tuberculosis.[24]

Chemoprophylaxis

It can be given with a weekly dose of 200 mg of doxycycline. This is, however, controversial as there are limited studies favoring it, but this may be suggested for those with a high occupational risk such as agricultural laborers.[25] 

Despite these measures, patients may present with multi-organ dysfunction syndrome, a life-threatening complication of scrub typhus, and require an interprofessional approach and management involving ICU care. Patients in the ICU frequently require IV fluids and patients with ARDS may need mechanical ventilation. However, timely symptomatic treatment and antibiotic therapy can lead to patient recovery without end-organ deficits.

Differential Diagnosis

Scrub typhus is one of the most underdiagnosed causes of tropical fevers. It can present as a fever of unknown origin and as with other rickettsioses can cause diagnostic confusion. Scrub typhus presenting with encephalitis can be difficult to distinguish from other common causes of viral or bacterial encephalitis. It can sometimes present without eschar with only flu-like symptoms, thus can be confused with other causes of acute febrile illness. Although the incidence of eschar in acute scrub typhus can range from 10% to 90%, these may be easily overlooked.

Since it can affect almost every organ system in the body, even with a high index of clinical suspicion and the best clinical knowledge, diagnosis remains difficult, and the timely initiation of appropriate therapy is sometimes delayed.

The following diseases should be kept in differentials:

  • Malaria
  • Dengue
  • Leptospirosis
  • Typhoid fever

Prognosis

Various studies for risk factors for severe scrub typhus have revealed that deranged laboratory parameters such as leukocytosis, thrombocytopenia, elevated transaminases, abnormal chest X-ray, and serum creatinine levels are associated with a worse prognosis. Patients who presented with these features along with septic shock with concomitant hypothermia carry a higher risk factor for organ dysfunction and, ultimately, death compared to those who presented with fever alone. Severe pulmonary involvement, as in acute respiratory distress syndrome, is associated with higher mortality rates. Renal failure associated with patients with severe scrub typhus may be life-threatening, and a serum creatinine level of more than 1.4 mg has been proposed to be an independent predictor of fatality in scrub typhus.

Lee et al., while conducting a retrospective epidemiological study, proposed that those who are managed in ICU who presented without an eschar along with a higher APACHE II score are independent risk factors associated with high mortality.[26] Also, Sonthayanon et al., in their study, have demonstrated that initial high loads of DNA of scrub typhus at the time of admission are positively correlated with higher mortality and a longer duration of illness.[27] However, due to the high-cost factor, it is of little practical value in resource-limited setups. In conclusion, prognostic indicators for severe scrub typhus infection cannot be established with the currently available evidence due to limited studies performed and their conflicting results. Multiple organ dysfunction syndrome (MODS) in the form of ARDS, myocarditis, liver failure, acute renal failure, encephalitis in various combinations, and shock from vasculitis are common presentations of severe scrub typhus infection in which a delay in treatment poses a high mortality index sometimes as high as 30%.

Complications

Pulmonary

Scrub typhus is associated with the development of respiratory complications such as ARDS and the presence of pneumonitis has been suggested to be a marker of severe disease.[13] Radiological abnormalities are relatively common and include bilateral reticular opacities and pleural effusion, in addition to cardiac abnormalities such as that of congestive heart failure.[28][29][28] Pleural effusions are seen in scrub typhus and could be transudative or exudative in nature. These are more likely to occur with older age, in patients with cardiac involvement, or in patients with a reduced serum albumin level.[13] 

Cardiac

The exact pathogenesis of cardiac involvement in scrub typhus and its contribution to the final outcome is unclear. However, reversible cardiomegaly is seen in chest radiography in more than 80% of patients in one autopsy series.[30] Various electrocardiogram (ECG) changes have also been reported and can range from sinus tachycardia to relative bradycardia (more common in scrub typhus). There can also be atrial flutter or fibrillation, atrial standstill, heart block, PR-interval prolongation, ST-T changes, prominent U-waves, and sometimes ventricular premature beats and Q-T prolongation.[31] Despite these varied manifestations in ECG, there is no conclusive evidence that suggests a greater severity or a worse outcome in the majority of the patients. In fact, ECG changes could simply be due to electrolyte imbalance or acidosis rather than a primary effect of scrub typhus infection. Also, myocarditis, which is a rare but severe manifestation of complicated scrub typhus, can present with a wide range of clinical manifestations, from nonspecific symptoms such as fever, myalgia, palpitations, and exertional dyspnea to cardiogenic shock or sudden cardiac death.[14]

Neurological

The pathophysiology of nervous system involvement in scrub typhus infections may be multifactorial, although the main mechanism appears to be due to vasculitis and perivasculitis in the endothelial cells where the proliferation of O. tsutsugamushi occurs. Scrub typhus meningitis, as in other forms, can present with headache or nuchal rigidity along with an altered sensorium or focal neurological deficits. Examination of the cerebrospinal fluid (CSF) may show pleocytosis, and sometimes results can mimic tuberculous meningitis, which can show lymphocytic pleocytosis with increased proteins.[11][32] Meningoencephalitis, which is the more severe form of CNS involvement, is characterized by presentation with altered sensorium and seizures.[32][33] These features had been observed in the setting of multiorgan dysfunction syndrome, and case fatalities may be a resultant outcome of other systemic involvement. Rarely there may be unilateral or bilateral sixth nerve palsy. Generally, central nervous system involvement has a fair outcome with good treatment. In another spectrum, scrub typhus may also present with transient Parkinsonism, myoclonus, opsoclonus, trigeminal neuralgia, and visual hallucinations.

Gastrointestinal

Gastrointestinal symptoms usually develop 3 to 7 days after the initiation of fever. Scrub typhus can present as an acute abdomen without an underlying surgical cause, and features like diarrhea, pancreatitis, gastrointestinal bleeding, and liver dysfunction manifested in the form of raised transaminases and bilirubin are not uncommon. Abdominal pain, abdominal tenderness, indigestion, nausea, and vomiting, along with splenomegaly, also happen frequently with scrub typhus.[17] The mechanism of these varied GI manifestations is not exactly known. However, as in other organ systems, vasculitis and perivasculitis of the small blood vessels by the causative organism have been implicated.[15] Hepatic dysfunction, as manifested by raised liver enzymes, is particularly common in patients without eschar.[16]

Renal

Acute kidney injury (AKI) is an under-recognized complication of scrub typhus, and numerous factors contribute to its development. It is a predictor of mortality, and possible mechanisms include pre-renal failure due to septic shock, vasculitis of the renal vessels, rhabdomyolysis, and direct renal invasion.[34] However, the prevalence of comorbidities was the significant predictor in patients who developed AKI, and prompt treatment with anti-rickettsial drug therapy and proper supportive care is very much essential to avert adverse outcomes.

Others

Rarely, scrub typhus may also manifest as disseminated intravascular coagulopathy and “hemophagocytic syndrome,” which is a rare but serious complication of scrub typhus infection. Patients may also develop papilledema, which is a very common ocular manifestation that occurs during the second to the third week may persist till convalescence. In pregnant women, those affected with scrub typhus were reported to have preterm deliveries; there can be miscarriages and delivery of small for gestational age babies. In a more severe outcome, neonatal deaths also have been reported.

Consultations

A primary clinician can diagnose and treat the majority of cases, however, complicated scrub typhus cases need input from an infectious disease physician especially for handling drug-resistant cases.

Deterrence and Patient Education

The symptoms of scrub typhus infection are similar to many other diseases. Since it is endemic in certain parts of the world, travel history should be communicated to the health care provider if signs and symptoms of it develop after a visit to such areas. Patients in endemic regions should be made aware that eschar formation with a fever requires a medical evaluation. The importance of timely management should be emphasized as it is a disease that can be cured without complications. Travelers to endemic areas should be educated regarding the prevention of mite bites. This can be done by covering exposed skin, particularly during farmhouse or field visits. As discussed above, chemoprophylaxis can be provided to high-risk groups with 200 mg doxycycline weekly, but this remains controversial. There is no vaccine to prevent Orientia tsutsugamushi infection.

Enhancing Healthcare Team Outcomes

The diagnosis and management of scrub typhus are complex, and this is best managed by an interprofessional team that includes an infectious disease expert, emergency department clinicians, primary clinicians, nurses, and pharmacists. When lab testing is available, skilled laboratory technicians are also an important part of this team. Patients with severe illness will require an intensive. The care is supportive including IV fluids, acetaminophen for fever, and antibiotics including doxycycline or azithromycin. A confirmed diagnosis is established by antigen detection, polymerase chain reaction, or serologic testing. No laboratory tests can predict the progression to severe disease. The prognosis for untreated scrub typhus is abysmal, but with proper care, most patients can survive, albeit sometimes with residual multisystem organ damage.


(Click Image to Enlarge)
Fig 1: Eschar over the right chest produced after the bite of a chigger in a farmer
Fig 1: Eschar over the right chest produced after the bite of a chigger in a farmer
Contributed by PK Panda, MD
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