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)

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.

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