Rickettsia

Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. The most clinically relevant pathogens are R. rickettsii, which causes 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; R. prowazekii, which causes epidemic (louse-borne) typhus; R. typhi, which causes endemic typhus; and R. akari, which causes rickettsialpox. All of these diseases are a form of inflammatory vasculitis and commonly present with fever, headache, and rash. Treatment is with doxycycline.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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General Characteristics

General characteristics

  • Obligate intracellular organisms
  • Pleomorphic (cocci, bacilli, threads)
  • Weakly gram negative (poor Gram staining)
  • Can be visualized with special stains such as Giemsa and by direct fluorescent antibody staining techniques
  • Lack enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes for amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids, sugar, lipid, and nucleotide metabolism
  • Depend on the host cells for nutritional needs
  • Have the ability to acquire host ATP (adenosine triphosphate)
  • Have a tropism for vascular endothelial cells:
    • Cause direct vascular injury
    • Also produce prostaglandins and activate clotting factors, which can lead to systemic clinical manifestations
  • Clinically relevant species:
    • Spotted fever group:
      • R. rickettsii (Western hemisphere)
      • R. akari (United States, Russia, Korea, South Africa)
      • Multiple other species (primarily in Asia and Africa)
    • Typhus group:
      • R. prowazekii
      • R. typhi

Transmission and geography

  • Transmitted by arthropod vectors
  • A summary of the major clinically relevant species is outlined in the table below.
Table: Summary of major clinically relevant species
R. rickettsii R. prowazekii R. typhi R. akari
Vector Hard ticks (Ixodidae family): Dermacentor (dog tick), Amblyoma (wood tick) Human lice (Pediculus humanus corporis):
  • Defecate on 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
  • Host scratches area.
  • Bacteria enter 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.
Eastern flying squirrels along with their lice and fleas maintain a zoonotic cycle.
Rat and cat flea bites Mites from mice
Disease 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 (the most serious rickettsial disease) Epidemic (louse-borne) typhus Endemic typhus Rickettsialpox (the least serious rickettsial disease)
Geographic variations
  • North America (in the United States, especially south-central, south-eastern states)
  • South and Central America
  • Rare nowadays
  • In some areas of Africa, Asia, and South America, especially where there are ongoing wars/disasters/refugee camps, etc.
  • Worldwide
  • Southeastern states/Gulf of Mexico
  • United States (often, New York City)
  • Russia
  • Korea
  • South Africa

Related videos

Clinical Relevance (R. rickettsii)

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

Epidemiology: 

  • More common in rural and suburban settings
  • Risk factors include living near the woods, walking in high grass, or through exposure to dogs
  • Seasonal variation: highest incidence in spring and early summer
  • Highest incidence in people 40–64 years of age
  • Higher incidence in Native Americans
  • Increased severity/lethality:
    • Male gender
    • Increasing age
    • Glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency
    • Chronic alcohol abuse
    • African American origin

Pathophysiology:

  • Virulence:
    • Factors are not well understood.
    • Dose of inoculum plays a role.
  • Inoculation from a feeding tick
  • Lipopolysaccharides, rickettsial outer membrane proteins (rOmps), and surface-exposed proteins (SEPs) act as adhesins for endothelial cells.
  • Bacteria get inside the cells via endocytosis.
  • Once in the cytosol, express proteins that lead to polymerization of actin filaments
  • This process allows passage into neighboring cells via filopodia derived from the host membrane.
  • Subsequent spread via bloodstream and lymphatics
  • Endothelial cell damage/necrosis
  • Accumulation of macrophages/ lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes → lymphocytic vasculitis

Clinical presentation:

  • Incubation period: 2–14 days
  • Prodromal symptoms:
    • 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, myalgia/arthralgia: mimics a viral infection
    • Nausea/vomiting
    • 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 common in children
  • Rash: variably present
    • Appears on days 3–5 in 50% of cases, and may never appear in about 10% of patients
    • Typically starts at wrists/ankles and spreads centrally; rash does not spare palms and soles, but often never develops in these areas (18%–64% of cases)
    • Blanching erythematous macular rash that becomes petechial over time
  • Complications:
    • Encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
    • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
    • Acute respiratory distress syndrome Acute Respiratory Distress Syndrome Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome
    • Cardiac arrhythmias
    • Coagulopathy
    • Gastrointestinal bleeding Gastrointestinal bleeding Gastrointestinal bleeding (GIB) is a symptom of multiple diseases within the gastrointestinal (GI) tract. Gastrointestinal bleeding is designated as upper or lower based on the etiology's location to the ligament of Treitz. Depending on the location of the bleeding, the patient may present with hematemesis (vomiting blood), melena (black, tarry stool), or hematochezia (fresh blood in stools). Gastrointestinal Bleeding
    • Skin necrosis
  • Preferred treatment is doxycycline.

Prognosis: 

  • Pre-antibiotic era: 20%–25% mortality (range: 20%–80%)
  • Currently 3%–5%, mostly due to delayed diagnosis and treatment

Identification:

  • Skin biopsy (3-mm punch): immunofluorescence testing/immunoperoxidase staining (70% sensitive, 100% specific)
  • Culture is difficult, dangerous, and reserved mostly for research purposes.
  • Serology: not useful for diagnosis, as it establishes diagnosis only post-factum
  • Polymerase chain reaction (PCR) tests of blood specimens not useful (low sensitivity)
Characteristic spotted rash of rocky mountain spotted fever

Characteristic spotted rash of 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: hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand and wrist of an affected child

Image: “ 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 PHIL 1962 lores” by CDC. License: Public Domain

Clinical Relevance (R. prowazekii, R. typhi, R. acari)

Epidemic (louse-borne) typhus (R. prowazekii)

Epidemic (louse-borne) typhus is now a rare disease.

Pathogenesis:

  • Direct injury to endothelial cells followed by immune response
  • Results in vascular permeability, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, activation of coagulation and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Lymphocytic vasculitis, thrombosis, microscopic hemorrhage

Clinical presentation:

  • 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, cough, headache, malaise, nausea, myalgias
  • Can be confused with typhoid fever Typhoid Fever Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) in tropical zones
  • Rash:
    • Macular or maculopapular, petechial, and confluent without treatment; starts on trunk and spreads to the extremities
    • Starts several days after the onset of symptoms; often not present
  • Neurologic symptoms (confusion, 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, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures) are common.
  • Pulmonary involvement in 35% of patients (interstitial pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, pleural effusions)

Brill-Zinsser disease:

  • Recurrence of typhus symptoms years after initial infection
  • Usually mild illness associated with fever, headache, malaise, and rash
  • Diagnosis: 
    • Skin biopsy (3-mm punch): immunohistochemical stain
    • Can also test louse found on patient 
  • Treatment: doxycycline
  • Prognosis: Untreated disease is fatal in 7%–40% of cases.
  • Prevention:
    • Control body lice by washing clothes and bedding in hot water or dry-cleaning clothes.
    • Use permethrin or other insecticides as needed.
Rash in a patient with epidemic typhus

Rash in a patient with epidemic typhus Epidemic Typhus Epidemic typhus is a febrile illness caused by the obligate intracellular gram-negative bacterium, Rickettsia prowazekii. Epidemic typhus is also known as louse-borne typhus or jail fever, and its symptoms include high fever, headache, myalgias, dry cough, delirium, stupor, and rash. 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

Endemic (murine) typhus (R. typhi)

  • Worldwide distribution
  • More frequent in areas with rat accumulations
  • In temperate regions, more common in late summer and early fall
  • Inflammatory vasculitis
  • Symptoms are usually mild, fatality is low
  • 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, and rash
  • In severe cases, may present with neurologic, renal, cardiac, pulmonary, or hepatic dysfunction
  • Treatment: doxycycline
  • Prognosis: severe disease associated with old age, comorbidities; case-fatality rate is 1%

Rickettsialpox (R. acari)

  • Mice serve as natural reservoirs.
  • Mice mites rarely bite humans, unless the mouse population is reduced.
  • Incubation period: 10–14 days
  • Initial lesion: a small papule that vesiculates and then forms an eschar
  • Constitutional symptoms: fever, malaise, and headache
  • Rash
    • Generalized
    • Maculopapular that becomes papulovesicular, followed by eschar crust
    • Lesions scab (crust) and fall off without scarring.
  • Diagnosis: clinical symptoms and signs, epidemiologic data, and convalescent sera
  • Treatment and prognosis: doxycycline; without treatment, fever lasts 6–10 days
Painless black, crusted eschar of rickettsialpox

Painless, black, crusted eschar of rickettsialpox, which develops as the last stage of the typical rash (macules → papules → vesicles → crusts/eschars that heal without scarring).

Image: “Rickettsialpox lesion” by Krusell A, Comer JA, Sexton DJ. License: Public Domain

References

  1. Sexton D.J., McClain M.T. (2020). Biology of Rickettsia rickettsii infection. Retrieved January 6, 2021, from https://www.uptodate.com/contents/biology-of-rickettsia-rickettsii-infection
  2. Sexton D.J., McClain M.T. (2020). Clinical manifestations and diagnosis of Rocky Mountain spotted fever. Retrieved January 6, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-rocky-mountain-spotted-fever
  3.  Sexton D.J., McClain M.T. (2019). Epidemic typhus. Retrieved January 6, 2021, from https://www.uptodate.com/contents/epidemic-typhus
  4. Sexton D.J., McClain M.T. (2020). Murine typhus. Retrieved January 6,  2021, from https://www.uptodate.com/contents/murine-typhus
  5. Sexton D.J., McClain M.T. (2020). Rickettsialpox. Retrieved January 6, 2021, from https://www.uptodate.com/contents/rickettsialpox
  6. Petri, W.A. (2020). Overview of rickettsial and related infections. Merck Manuals Professional Edition. Retrieved January 17, 2021, from https://www.merckmanuals.com/professional/infectious-diseases/rickettsiae-and-related-organisms/overview-of-rickettsial-and-related-infections
  7. Riedel, S., Hobden, J.A. (2019). Rickettsia and Related Gener. In Riedel, S, Morse, S.A., Mietzner, T., Miller, S. (Eds.), Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed, pp. 357-363).
  8. CDC. Rocky Mountain spotted fever (RMSF) | tick-borne diseases | ticks | cdc. (2020, October 1). Retrieved on Jan. 18, 2021, from https://www.cdc.gov/ticks/tickbornediseases/rmsf.html
  9. Walker, D.H., Dumler, J.S., Blanton, L.S., Marrie, T. (2018). Diseases Caused by Rickettsiae, Mycoplasmas, and Chlamydia. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 1, pp. 1303–1309).

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