Epidemic Typhus

Epidemic typhus is a febrile illness caused by the obligate intracellular gram-negative bacterium, Rickettsia Rickettsia Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. Rickettsia prowazekii. Epidemic typhus is also known as louse-borne typhus or jail fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and its symptoms include high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, myalgias, dry cough, delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium, stupor, and rash. Untreated epidemic typhus can lead to hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock, and death. R. prowazekii can be transmitted by the bites of infected mites, fleas, or lice. Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries, chronic illness, crowding, and poor hygiene are factors leading to the spread of epidemic typhus. Improvement in nutrition and hygiene can help prevent spread, thereby decreasing the risk of typhus infections. The primary method of treatment is using the antibiotic doxycycline.

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Overview

Definition

Epidemic typhus is a potentially lethal, febrile illness caused by the obligate intracellular gram-negative bacterium, Rickettsia Rickettsia Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. Rickettsia prowazekii.

Epidemiology

Transmission:

  • Typhus is transmitted by infected lice.
  • Infections occur in winter or spring.

Risk factors:

  • Overcrowded conditions:
    • Reported in army camps, refugee camps, prisons, and homeless shelters
    • Sometimes called “jail fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Poor hygiene: 
    • Civil strife
    • War zones
  • Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries:
    • Famine
    • Extreme poverty

Geography:

  • In the US:
    • Rare
    • Cases often associated with exposure to flying squirrels
  • Epidemic typhus outbreaks have been reported in the following countries:
    • Africa:
      • Ethiopia
      • Nigeria
      • Rwanda
      • Burundi
    • Mexico
    • Central America
    • South America
    • Eastern Europe
    • Afghanistan
    • Russia
    • Northern India
    • China

Etiology and Pathophysiology

Etiology

  • Causative agent: R. prowazekii is the most pathogenic member of the Rickettsia Rickettsia Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. Rickettsia genus.
  • Vector:
    • Human body louse, Pediculus humanus corporis
    • Human head louse, P. humanus capitis
  • Reservoir:
    • Humans
    • Flying squirrels
  • Transmission:
    • Infected lice pass infectious feces when they feed.
    • The feces and not the bite of the louse spread illness in humans.
    • Transmitted when the infectious feces of lice or crushed, infected body lice are rubbed into small cuts or abrasions on the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
    • The disease may also be spread when: 
      • A person breathes in dust containing infected dried feces of lice
      • Mucous membranes, such as the conjunctiva of the eye, are exposed to infectious feces

Pathophysiology

  • After entering the body, Rickettsia Rickettsia Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. Rickettsia infect and multiply in the endothelial cells of the small venous, arterial, and capillary vessels.
  • Infected endothelial cells enlarge due to microbial proliferation.
  • Multiorgan vasculitis develops.
  • Vasculitis can lead to: 
    • Thrombosis of the supplying blood vessels: gangrene of the distal parts of the extremities, nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose, ear lobes, and genitalia
    • Deposition of leukocytes, macrophages, and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets results in the formation of small nodules.
    • Increased vascular permeability:
      • Loss of intravascular colloid with subsequent hypovolemia
      • Loss of electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes 
      • Decreased tissue perfusion → organ failure

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Clinical Presentation

  • Incubation period: usually < 14 days
  • Clinical manifestations:
    • General:
      • Fever
      • Severe headache
      • Rash (a pink macular rash that spares the palms and soles)
      • Chills
      • Myalgias
      • Arthralgias
      • Anorexia
      • Nonproductive cough
    • GI:
      • Nausea
      • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Vomiting
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Severe epidemic typhus can lead to:
    • Hypotension
    • Gangrene
    • Loss of digits, limbs, or other appendages
    • CNS dysfunction (ranging from decreased mentation to coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma)
    • Multiorgan system failure
    • Death
  • Brill-Zinsser disease:
    • Recrudescence of epidemic typhus following an initial attack
    • Patients can have a prolonged, asymptomatic R. prowazekii infection for years.
    • A relapse that occurs months or years following the 1st illness, when the immune system is weakened due to certain medications, advanced age, or illness
    • Symptoms are similar to the original infection, but usually milder.

Diagnosis and Management

Diagnosis

  • Epidemic typhus is diagnosed by its clinical features in the setting of a louse infection.
  • Confirmatory laboratory tests:
    • Biopsy of rash using fluorescent antibody staining to determine the causative microbe
    • Acute and convalescent serologic testing
    • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR)
Rash in a patient with epidemic typhus

Rash in a patient with epidemic typhus

Image: “Epidemic typhus Burundi” by D. Raoult, V. Roux, J.B. Ndihokubwayo, G. Bise, D. Baudon, G. Martet, and R. Birtles. License: Public Domain

Management

Antibiotics:

  • Primary treatment: doxycycline (4 mg/kg/day)
  • Alternative treatments:
    • Tetracycline (25–50 mg/kg/day)
    • Chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol 500 mg orally or IV 4 times daily for 7 days 

Prevention:

  • Louse control:
    • Lice may be eliminated by dusting infested individuals with malathion or lindane.
    • Washing of clothing in hot water 
    • Sweeping off dust particles, as they contain excreta of infected lice
  • Immunization is highly effective for prevention; however, typhus vaccines are no longer available in the US.
  • Antibiotic prophylaxis with doxycycline (once weekly) for individuals traveling to high-risk areas

Prognosis:

  • Mortality rate of untreated epidemic typhus:
    • 20% in otherwise healthy individuals 
    • 60% in the elderly or in debilitated individuals
  • When treated with appropriate antibiotics, the mortality rate can decrease to approximately 3%–4%.

Differential Diagnosis

  • Rocky Mountain spotted fever Rocky Mountain Spotted Fever Rocky Mountain spotted fever (RMSF) is a bacterial infection caused by the obligate intracellular parasite Rickettsia rickettsii. Transmission occurs through an arthropod vector, most commonly the American dog tick (Dermacentor variabilis). Early signs and symptoms of RMSF are nonspecific and include a high fever, severe headache, and rash. Rocky Mountain Spotted Fever (RMSF): a disease caused by R. rickettsii and transmitted by ixodid ticks. The incidence is highest in children < 15 years and in individuals who frequent tick-infested areas for work or recreation. Rocky Mountain spotted fever Rocky Mountain Spotted Fever Rocky Mountain spotted fever (RMSF) is a bacterial infection caused by the obligate intracellular parasite Rickettsia rickettsii. Transmission occurs through an arthropod vector, most commonly the American dog tick (Dermacentor variabilis). Early signs and symptoms of RMSF are nonspecific and include a high fever, severe headache, and rash. Rocky Mountain Spotted Fever presents with abrupt headaches, chills, prostration, muscular pains, and centripetal rash, and is diagnosed based on clinical features, serology, and PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR). Treatment is using doxycycline.
  • Kawasaki disease Kawasaki disease Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome or infantile polyarteritis, is a medium-sized necrotizing febrile vasculitis that affects children < 5 years of age. Multiple systems are involved but the most serious is the predilection of the coronary arteries. Kawasaki Disease: an acute febrile illness of early childhood of unknown cause. Kawasaki disease Kawasaki disease Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome or infantile polyarteritis, is a medium-sized necrotizing febrile vasculitis that affects children < 5 years of age. Multiple systems are involved but the most serious is the predilection of the coronary arteries. Kawasaki Disease is the leading cause of acquired coronary artery disease in developed nations and is characterized by vasculitis of the medium-sized arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries, especially coronary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries. Other features of Kawasaki disease Kawasaki disease Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome or infantile polyarteritis, is a medium-sized necrotizing febrile vasculitis that affects children < 5 years of age. Multiple systems are involved but the most serious is the predilection of the coronary arteries. Kawasaki Disease include rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes on the extremities, oropharyngeal rash, and bulbar conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis, as well as acute, unilateral, nonpurulent cervical lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. The diagnosis is made on clinical grounds and the diagnostic test of choice is echocardiography. The mainstays of treatment are aspirin and IV Igs. 
  • Anthrax Anthrax Anthrax is an infection caused by the bacterium Bacillus anthracis, which usually targets the skin, lungs, or intestines. Anthrax is a zoonotic disease and is usually transmitted to humans from animals or through animal products. Symptoms depend on which organ system is affected. Anthrax: a disease caused by the gram-positive microbe Bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus anthracis. Anthrax Anthrax Anthrax is an infection caused by the bacterium Bacillus anthracis, which usually targets the skin, lungs, or intestines. Anthrax is a zoonotic disease and is usually transmitted to humans from animals or through animal products. Symptoms depend on which organ system is affected. Anthrax is transmitted to humans when they come in contact with infected animals or their products. Cutaneous anthrax begins as a painless, pruritic, red-brown papule 1–10 days after exposure to infective spores. The papule can enlarge, become necrotic, and form a black eschar. The diagnosis is made through clinical findings and is based on occupational and exposure history. Confirmatory laboratory tests include Gram staining and culture, direct fluorescent antibody test, and PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR). Empiric treatment is using ciprofloxacin, levofloxacin, moxifloxacin, or doxycycline. 

References

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  3. Boostrom, A., et al. (2002). Geographic association of Rickettsia felis-infected opossums with human murine typhus, Texas. Emerg Infect Dis. 8(6), 549–54. https://pubmed.ncbi.nlm.nih.gov/12023908/
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