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Internal Medicine

Rickettsioses

Zoonotic diseases with worldwide distribution in foci of endemicity, with sporadic and often seasonal outbreaks.

Zoonotic diseases with worldwide distribution in foci of endemicity, with sporadic and often seasonal outbreaks.


Epidemiology

Rickettsial organisms have been found on all continents except Antarctica. Most rickettsial species are region-locked due to climatic conditions and vector and natural host constraints.

Major rickettsioses described by causative agent, clinical syndrome, and vector by region. | Abdad, M. Y., Abou Abdallah, R., Fournier, P.-E., Stenos, J., & Vasoo, S. (2018). A Concise Review of the Epidemiology and Diagnostics of Rickettsioses: <span class=”named-content genus-species” id=”named-content-1″>Rickettsia</span> and <span class=”named-content genus-species” id=”named-content-2″>Orientia</span> spp. Journal of Clinical Microbiology, 56(8), e01728-17. https://doi.org/10.1128/JCM.01728-17

Vector lifecycle:

Rickettsiae require a vector for host transmission; however, infection is acquired by different routes depending on the vector type and rickettsial species. Most SFG rickettsiae are harbored by ixodid ticks and are transmitted by their bites during feeding (saliva). This is also true for most other rickettsiae that are harbored by mites. Flea- and louse-borne rickettsiae are known to cause infection via entry of fecal material in bite sites and cuts on the host’s skin. TG rickettsiae can cause infection via inhalation through the aerosolization or contamination of dust particles floating in the air. An uncommon route of infection is via the conjunctivae, through exposure of contaminated tick hemolymph on fingers from crushed ticks.
Developmental cycle and host range of Rickettsia-infected ticks: Ticks are the main vectors and constitute a threat of rickettsial infection regardless of their development stage (larvae, nymphs, or adults). Many factors play a role in the epidemiology of tick-borne rickettsioses, including the prevalence and species diversity of rickettsiae in mammals and the dispersion of infected ticks by migratory birds. | Sekeyová, Z., Danchenko, M., Filipčík, P., & Fournier, P. E. (2019). Rickettsial infections of the central nervous system. PLoS neglected tropical diseases, 13(8), e0007469. https://doi.org/10.1371/journal.pntd.0007469

Microbiology

Rickettsiae:

Strictly intracellular bacteria that are vectored by various arthropods. To date, 18 species are recognized human pathogens, 12 of which cause CNS R
  • Weakly gram positive
  • Obligate intracellular
  • Non-motile
Phylogenetic tree of Rickettsia species inferred from the comparison of concatenated sequences from the gltA and sca4 genes. | Rickettsia species are distributed into 4 groups: SFG, TRG, TG, and AG. SFG rickettsiae are mostly associated with ticks; TG rickettsiae with human body lice (R. prowazekii) and rat fleas (R. typhi); TRG rickettsiae with ticks, cat fleas, or mites; and AG rickettsiae with ticks. Asterisks mark pathogenic species, and bold letters indicate species causing CNS infections. | AG, ancestral group; CNS, central nervous system; SFG, spotted fever group; TG, typhus group; TRG, transitional group. | Sekeyová, Z., Danchenko, M., Filipčík, P., & Fournier, P. E. (2019). Rickettsial infections of the central nervous system. PLoS neglected tropical diseases, 13(8), e0007469. https://doi.org/10.1371/journal.pntd.0007469

Classification:

Classification into the two groups was historically based on their physiological characteristics of intracellular localization, optimal growth temperature, and cross-reaction of serum from an infected patient with somatic antigens of three strains of Proteus. The classification of new members of Rickettsia today is done through genomic sequence comparison with information for well-published strains.
The classification of the rickettsial diseases | Greer, F. R. (1998). <em>Intrauterine Growth as Estimated From Liveborn Birth-Weight Data at 24 to 42 Weeks of Gestation</em>, by Lula O. Lubchenco et al,<em>Pediatrics</em>, 1963;32:793–800. Pediatrics, 102(Supplement 1), 237 LP – 239. Retrieved from http://pediatrics.aappublications.org/content/102/Supplement_1/237.abstract

Spotted fever group (SFG) rickettsioses:

  • Rocky Mountain spotted fever (RMSF)| R. rickettsii
  • Mediterranean spotted fever (MSF) | R. conorii
  • Japanese spotted fever (JSF) | R. japonica
  • Tick-borne lymphadenopathy (TIBOLA)/Dermacentor-borne necrosis erythema and lymphadenopathy (DEBONEL)/Scalp eschar and neck lymphadenopathy after tick bite (SENLAT) | R. slovaca and R. raoultii
  • African tick bite fever (ATBF) | R. africae
  • R. helvetica infection

Typhus group (TG) rickettsiae:

  • Epidemic typhus | R. prowazekii
  • Murine/endemic typhus | R. typhi

Transitional group rickettsiae:

  • Rickettsial pox | R. akari transmitted by the mite, Liponyssoides sanguineus
  • Queensland tick typhus (QTT) | R. australis transmitted by Ixodes ticks
  • Flea-borne spotted fever | R. felis transmitted by fleas, Ctenocephalides felis

Scrub typhus

  • Orientia (O. tsutsugamushi and O. chuto)

Pathophysiology

Rickettsia and Orientia species are transmitted by the bite of infected ticks or mites or by the feces of infected lice or fleas. From the portal of entry in the skin, rickettsiae spread via the bloodstream to infect the endothelium and sometimes the vascular smooth muscle cells. Rickettsia species enter their target cells, multiply by binary fission in the cytosol, and damage heavily parasitized cells directly.

Lymphohistiocytic vasculitis:

Damage to small blood vessels lead to extravasastion of fluid leading into interstitial space
  • Oedema, hypovolemia, hypotension, hypoalbuminemia
  • Complications: Encephalitis (CNS), myocarditis (heart), pulmonary oedema

Procoagulant state:

Due to activation of platelets & fibrinolytic system
  • Thrombi

Rickettsial neuroinvasion:

Occurs during the systemic phase of the disease and typically follows bacterial dissemination via the bloodstream via a transcellular approach
Mechanisms of bacterial penetration through the blood–brain barrier: (A) Intercellular or paracellular, described in extracellular pathogens. The physical barrier formed by endothelial tight junctions is disturbed by bacterial penetration. (B) Transcellular, passing through cells, e.g., direct invasion of endothelial cells. In this scenario, blood-borne bacteria directly invade CNS endothelial cells. (C) By leukocytes, within infected macrophages, named “Trojan horse” mechanism. Infected leukocytes adhere to endothelial cells, allowing the spread of bacteria or, alternatively, leukocytes can transmigrate and deliver bacteria to the CNS parenchyma. | CNS, central nervous system. | Sekeyová, Z., Danchenko, M., Filipčík, P., & Fournier, P. E. (2019). Rickettsial infections of the central nervous system. PLoS neglected tropical diseases, 13(8), e0007469. https://doi.org/10.1371/journal.pntd.0007469

Presentation

Rickettsia species cause Rocky Mountain spotted fever, rickettsial pox, other spotted fevers, epidemic typhus, and murine typhus. Orientia (formerly Rickettsia) tsutsugamushi causes scrub typhus. Patients present with febrile exanthems and visceral involvement; symptoms may include nausea, vomiting, abdominal pain, encephalitis, hypotension, acute renal failure, and respiratory distress.

Clinical manifestations of rickettsial disease range from a mild, self-limiting illness to life-threatening multi-organ failure.

Spotted fever group (SFG) rickettsioses:

  • Clinical triad: Fever, inoculation eschar(s), and generalized cutaneous rash
  • Other faetures: Nonspecific flu-like symptoms, isolated fever, myalgia, cough, generalized lymphadenopathy, abdominal pain
A–Macular petechial rash of the palms in a patient with SFG infection, B–Digital ischemia in a patient with SFG infection; this patient later required digital amputation, C–CXR demonstrating bilateral patchy non-confluent alveolar opacification in a patient with scrub typhus, D–CXR demonstrating right middle and lower lobe pneumonia and early left lower lobe consolidation in a patient with severe SFG infection in ICU. | SFG: Spotty fever group | Stewart, A., Smith, S., Binotto, E., McBride, W., & Hanson, J. (2019). The epidemiology and clinical features of rickettsial diseases in North Queensland, Australia: Implications for patient identification and management. PLoS neglected tropical diseases, 13(7), e0007583. https://doi.org/10.1371/journal.pntd.0007583

TG ricket:

  • Red maculopapulat rash (HALLMARK feature, which starts at trunk and spreades to extremities sparing hands, feet and head)
  • Complication: Brill-Zinsser disease

Diagnosis

The diagnosis of a rickettsial infection is usually achieved through the gathering of a complete clinical history indicating exposure to a potential source of rickettsial disease alongside laboratory testing. The submission of arthropods collected at the bite site or eschar for rickettsial detection is also recommended if available.

Illustration summarizing samples that can be obtained from patients and invertebrates and the testing that can be conducted with respect to sample type. | Abdad, M. Y., Abou Abdallah, R., Fournier, P.-E., Stenos, J., & Vasoo, S. (2018). A Concise Review of the Epidemiology and Diagnostics of Rickettsioses: <span class=”named-content genus-species” id=”named-content-1″>Rickettsia</span> and <span class=”named-content genus-species” id=”named-content-2″>Orientia</span> spp. Journal of Clinical Microbiology, 56(8), e01728-17. https://doi.org/10.1128/JCM.01728-17

Laboratory findings:

  • Thrombocytopenia
  • ↑ PT & aPTT
  • Transaminitis
  • Hyponatremia

Tissue biopsy:

Indirect immunofluorescence (IFA)
Immunohistochemical analysis shows the presence of spotted fever group rickettsiae (brown) in vessels of brain of a patient with fatal Rocky Mountain spotted fever (magnification ×400). | Hidalgo, M., Orejuela, L., Fuya, P., Carrillo, P., Hernandez, J., Parra, E., Keng, C., Small, M., Olano, J. P., Bouyer, D., Castaneda, E., Walker, D., & Valbuena, G. (2007). Rocky Mountain spotted fever, Colombia. Emerging infectious diseases, 13(7), 1058–1060. https://doi.org/10.3201/eid1307.060537

Management

It is important to recognise rickettsial infections early in their disease course as they can lead to life-threatening multi-organ failure if specific anti-rickettsial antimicrobial therapy is not prescribed promptly.

Antibiotic therapy:

M/efficient antibiotics to cure rickettsioses are tetracycline derivatives, primarily doxycycline
  • Doxycycline 200 mg (for 7 days or until 2 days after apyrexia is obtained)
  • Severe forms: IV doxycycline
  • Alternative: Chloramphenicol and macrolides (azithromycin, clarithromycin, and roxytromycin)

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