Scrub typhus
Encyclopedia
Scrub typhus or Bush typhus is a form of typhus
caused by Orientia tsutsugamushi
first isolated and identified in 1930 in Japan.
Although it is similar in presentation to other forms of typhus
, it is caused by an agent in a different genus
, and is frequently classified separately from the other typhi.
", particularly Leptotrombidium deliense
), which are found in areas of heavy scrub vegetation. The bite of this mite leaves a characteristic black eschar
that is useful to the doctor for making the diagnosis.
Scrub typhus is endemic to a part of the world known as the "tsutsugamushi triangle" (after the name "Orientia tsutsugamushi" (formerly "Rickettsia tsutsugamushi"), the obligate intracellular gram-negative bacterium causing same), which extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea
into northern Australia in the south, and to Pakistan and Afghanistan in the west.
The precise incidence of the disease is unknown, as diagnostic facilities are not available in much of its large native range which spans vast regions of equatorial jungle to the sub-tropics. In rural Thailand and in Laos, murine and scrub typhus accounts for around a quarter of all adults presenting to hospital with fever and negative blood cultures
It affects females more than males in Korea
, but not in Japan
, and this is conjectured to be because sex-differentiated cultural roles have women tending garden plots more often, thus being exposed to plant tissues inhabited by chiggers.
, headache
, muscle pain, cough
, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation.
Acute scrub typhus appears to improve viral loads in patients with HIV
. This interaction is refused by an in vitro study.
.
The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test test is the Weil-Felix test
, but this is notoriously unreliable. The gold standard is indirect immunofluorescence, but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic. Indirect immunoperoxidase (IIP) is a modification of the standard IFA method that can be used with a light microscope, and the results of these tests are comparable to those from IFA. Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests are severely limited by their cost. Serological methods are most reliable when a fourfold-rise in antibody titre is looked for. If the patient is from a non-endemic area, then diagnosis can be made from a single acute serum sample. In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals.
Other methods include culture and PCR
, but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods have been summarised.
The drug most commonly used is doxycycline
; but chloramphenicol
is an alternative. Strains that are resistant to doxycycline and to chloramphenicol are common in northern Thailand. Rifampin and azithromycin
are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline-resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage.
Combination therapy with doxycycline and rifampicin
is not recommended due to possible antagonism.
Other drugs that may be effective are clarithromycin
, roxithromycin
, and the fluoroquinolones, but there is no clinical evidence on which to recommend their use. Azithromycin
or chloramphenicol is useful for infection in children or pregnant women.
An early attempt to create a scrub typhus vaccine
occurred in the United Kingdom
in 1937 (with the Wellcome Foundation infecting around 300,000 cotton rat
s in a classified project called "Operation Tyburn"), but the vaccine was not used. The first known batch of scrub typhus vaccine actually used to inoculate human subjects was despatched to India for use by Allied Land Forces, South-East Asia Command (A.L.F.S.E.A.) in June, 1945. By December, 1945, 268,000 cc. had been despatched. The vaccine was produced at Wellcomes laboratory at Ely Grange, Frant, Sussex. An attempt to verify the efficacy of the vaccine by using a placebo group for comparison was vetoed by the military commanders, who objected to the experiment.
It is now known that there is enormous antigenic variation in Orientia tsutsugamushi strains, and immunity to one strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, in order to give an acceptable level of protection. A vaccine developed for one locality may not be protective in another locality, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine.
Severe epidemics of the disease occurred among troops in Burma and Ceylon during World War II
(WWII). Several members of the U.S. Army's 5307th Composite Unit (Merrill's Marauders
) died of the disease; and before 1944, there were no effective antibiotics or vaccines available.
World war II provides some indicators that the disease is endemic to undeveloped areas in all of Oceania
in the Pacific Theater, although war records frequently lack assured diagnoses to desired by Epidemiological statics—and many records of "high fever" evacuations were also likely to be other tropical illnesses. In the chapter entitled "The Green War", General MacArthur's biographer William Manchester
identifies that the disease was one of a number debilitating afflictions affecting both sides on New Guinea
in the running bloody Kokoda battles
over unbelievably harsh terrains under incredible hardships— fought during a six month span all along the Kokoda Track
in 1942-43, and mentions that to be hospital evacuated, Allied soldiers (who cycled forces) had to run a fever of 102°F—and that sickness casualties outnumbered weapons inflicted casualties 5:1. Similarly, the illness was a casualty producer in all the jungle fighting of the land battles of New Guinea campaign
and Guadalcanal campaign
. Where the allies had bases, they could remove and cut back vegetation or use DDT as a prophylaxis area barrier treatment, so tick induced sickness rates in forces off the front lines was diminished.
The disease was also a problem for US troops stationed in Japan after WWII, and was variously known as "Shichitō fever" (by troops stationed in the Izu Seven Islands
) or "Hatsuka fever" (Chiba prefecture).
Typhus
Epidemic typhus is a form of typhus so named because the disease often causes epidemics following wars and natural disasters...
caused by Orientia tsutsugamushi
Orientia tsutsugamushi
Orientia tsutsugamushi is the causative organism of scrub typhus, and the natural vector and reservoir is probably trombiculid mites ....
first isolated and identified in 1930 in Japan.
Although it is similar in presentation to other forms of typhus
Typhus
Epidemic typhus is a form of typhus so named because the disease often causes epidemics following wars and natural disasters...
, it is caused by an agent in a different genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
, and is frequently classified separately from the other typhi.
Causes and geographical distribution
Scrub typhus is transmitted by some species of trombiculid mites ("chiggersHarvest mite
Trombicula is a genus of harvest mites in the Trombiculidae family. In their larval stage, they attach to various animals, including humans, and feed on skin, often causing itching...
", particularly Leptotrombidium deliense
Leptotrombidium deliense
Leptotrombidium deliense is a species of mite.It is a vector of scrub typhus....
), which are found in areas of heavy scrub vegetation. The bite of this mite leaves a characteristic black eschar
Eschar
An eschar is a slough or piece of dead tissue that is cast off from the surface of the skin, particularly after a burn injury, but also seen in gangrene, ulcer, fungal infections, necrotizing spider bite wounds, and exposure to cutaneous anthrax....
that is useful to the doctor for making the diagnosis.
Scrub typhus is endemic to a part of the world known as the "tsutsugamushi triangle" (after the name "Orientia tsutsugamushi" (formerly "Rickettsia tsutsugamushi"), the obligate intracellular gram-negative bacterium causing same), which extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea
Solomon Sea
The Solomon Sea is a sea located within the Pacific Ocean. It lies between Papua New Guinea and the Solomon Islands. Many major battles were fought there during World War II.-Extent:...
into northern Australia in the south, and to Pakistan and Afghanistan in the west.
The precise incidence of the disease is unknown, as diagnostic facilities are not available in much of its large native range which spans vast regions of equatorial jungle to the sub-tropics. In rural Thailand and in Laos, murine and scrub typhus accounts for around a quarter of all adults presenting to hospital with fever and negative blood cultures
It affects females more than males in Korea
Korea
Korea ) is an East Asian geographic region that is currently divided into two separate sovereign states — North Korea and South Korea. Located on the Korean Peninsula, Korea is bordered by the People's Republic of China to the northwest, Russia to the northeast, and is separated from Japan to the...
, but not in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, and this is conjectured to be because sex-differentiated cultural roles have women tending garden plots more often, thus being exposed to plant tissues inhabited by chiggers.
Symptoms and signs
Symptoms include feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, muscle pain, cough
Cough
A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...
, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation.
- Signs
- Maculopapular rash, escharEscharAn eschar is a slough or piece of dead tissue that is cast off from the surface of the skin, particularly after a burn injury, but also seen in gangrene, ulcer, fungal infections, necrotizing spider bite wounds, and exposure to cutaneous anthrax....
, splenomegalySplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
and lymphadenopathiesLymphadenopathyLymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
are typical signs.
- Laboratory findings
- LeukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
and abnormal liver function tests are commonly seen in the early phase of the illness.
- Complications
- PneumonitisPneumonitisPneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue.Pneumonia is pneumonitis combined with consolidation and exudation...
, encephalitisEncephalitisEncephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
, and myocarditisMyocarditisMyocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...
occur in the late phase of illness.
Acute scrub typhus appears to improve viral loads in patients with HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
. This interaction is refused by an in vitro study.
Diagnosis
In endemic areas, diagnosis is generally made on clinical grounds alone. Where there is doubt, the diagnosis may be confirmed by a laboratory test such as serologySerology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
.
The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test test is the Weil-Felix test
Weil-Felix test
The Weil-Felix test is an agglutination test for the diagnosis of rickettsial infections. It was first described in 1916. By virtue of its long history and of its simplicity, it has been one of the most widely employed tests for rickettsia on a global scale, despite being superseded in many...
, but this is notoriously unreliable. The gold standard is indirect immunofluorescence, but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic. Indirect immunoperoxidase (IIP) is a modification of the standard IFA method that can be used with a light microscope, and the results of these tests are comparable to those from IFA. Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests are severely limited by their cost. Serological methods are most reliable when a fourfold-rise in antibody titre is looked for. If the patient is from a non-endemic area, then diagnosis can be made from a single acute serum sample. In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals.
Other methods include culture and PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
, but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods have been summarised.
Treatment
Without treatment, the disease is often fatal. Since the use of antibiotics, case fatalities have decreased from 4%–40% to less than 2%.The drug most commonly used is doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
; but chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
is an alternative. Strains that are resistant to doxycycline and to chloramphenicol are common in northern Thailand. Rifampin and azithromycin
Azithromycin
Azithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics...
are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline-resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage.
Combination therapy with doxycycline and rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
is not recommended due to possible antagonism.
Other drugs that may be effective are clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, roxithromycin
Roxithromycin
Roxithromycin is a semi-synthetic macrolide antibiotic. It is used to treat respiratory tract, urinary and soft tissue infections. Roxithromycin is derived from erythromycin, containing the same 14-membered lactone ring. However, an N-oxime side chain is attached to the lactone ring...
, and the fluoroquinolones, but there is no clinical evidence on which to recommend their use. Azithromycin
Azithromycin
Azithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics...
or chloramphenicol is useful for infection in children or pregnant women.
Vaccine
There are currently no licensed vaccines available.An early attempt to create a scrub typhus vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
occurred in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
in 1937 (with the Wellcome Foundation infecting around 300,000 cotton rat
Cotton rat
A cotton rat is any member of the rodent genus Sigmodon. They are called cotton rats because they build their nests out of cotton, and can damage cotton crops. Cotton rats have small ears and dark coats, and are found in North and South America....
s in a classified project called "Operation Tyburn"), but the vaccine was not used. The first known batch of scrub typhus vaccine actually used to inoculate human subjects was despatched to India for use by Allied Land Forces, South-East Asia Command (A.L.F.S.E.A.) in June, 1945. By December, 1945, 268,000 cc. had been despatched. The vaccine was produced at Wellcomes laboratory at Ely Grange, Frant, Sussex. An attempt to verify the efficacy of the vaccine by using a placebo group for comparison was vetoed by the military commanders, who objected to the experiment.
It is now known that there is enormous antigenic variation in Orientia tsutsugamushi strains, and immunity to one strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, in order to give an acceptable level of protection. A vaccine developed for one locality may not be protective in another locality, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine.
History
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
(WWII). Several members of the U.S. Army's 5307th Composite Unit (Merrill's Marauders
Merrill's Marauders
Merrill’s Marauders or Unit Galahad, officially named the 5307th Composite Unit , was a United States Army long range penetration special operations unit in the South-East Asian Theater of World War II which fought in the China-Burma-India Theater of Operations, or CBI...
) died of the disease; and before 1944, there were no effective antibiotics or vaccines available.
World war II provides some indicators that the disease is endemic to undeveloped areas in all of Oceania
Oceania
Oceania is a region centered on the islands of the tropical Pacific Ocean. Conceptions of what constitutes Oceania range from the coral atolls and volcanic islands of the South Pacific to the entire insular region between Asia and the Americas, including Australasia and the Malay Archipelago...
in the Pacific Theater, although war records frequently lack assured diagnoses to desired by Epidemiological statics—and many records of "high fever" evacuations were also likely to be other tropical illnesses. In the chapter entitled "The Green War", General MacArthur's biographer William Manchester
William Manchester
William Raymond Manchester was an American author, biographer, and historian from Springfield, Massachusetts, USA, notable as the bestselling author of 18 books that have been translated into over 20 languages...
identifies that the disease was one of a number debilitating afflictions affecting both sides on New Guinea
New Guinea
New Guinea is the world's second largest island, after Greenland, covering a land area of 786,000 km2. Located in the southwest Pacific Ocean, it lies geographically to the east of the Malay Archipelago, with which it is sometimes included as part of a greater Indo-Australian Archipelago...
in the running bloody Kokoda battles
Kokoda Track campaign
The Kokoda Track campaign or Kokoda Trail campaign was part of the Pacific War of World War II. The campaign consisted of a series of battles fought between July and November 1942 between Japanese and Allied—primarily Australian—forces in what was then the Australian territory of Papua...
over unbelievably harsh terrains under incredible hardships— fought during a six month span all along the Kokoda Track
Kokoda Track
The Kokoda Trail or Track is a single-file foot thoroughfare that runs overland — in a straight line — through the Owen Stanley Range in Papua New Guinea...
in 1942-43, and mentions that to be hospital evacuated, Allied soldiers (who cycled forces) had to run a fever of 102°F—and that sickness casualties outnumbered weapons inflicted casualties 5:1. Similarly, the illness was a casualty producer in all the jungle fighting of the land battles of New Guinea campaign
New Guinea campaign
The New Guinea campaign was one of the major military campaigns of World War II.Before the war, the island of New Guinea was split between:...
and Guadalcanal campaign
Guadalcanal campaign
The Guadalcanal Campaign, also known as the Battle of Guadalcanal and codenamed Operation Watchtower by Allied forces, was a military campaign fought between August 7, 1942 and February 9, 1943 on and around the island of Guadalcanal in the Pacific theatre of World War II...
. Where the allies had bases, they could remove and cut back vegetation or use DDT as a prophylaxis area barrier treatment, so tick induced sickness rates in forces off the front lines was diminished.
The disease was also a problem for US troops stationed in Japan after WWII, and was variously known as "Shichitō fever" (by troops stationed in the Izu Seven Islands
Izu Islands
The are a group of volcanic islands stretching south and east from the Izu Peninsula of Honshū, Japan. Administratively, they form two towns and six villages; all part of Tokyo. The largest is Izu Ōshima, usually called simply Ōshima....
) or "Hatsuka fever" (Chiba prefecture).