Rocky Mountain Spotted Fever (Clinical)

Overview

Definition

Rocky Mountain spotted 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 ( RMSF RMSF 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) is an infectious disease caused by the 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 Rickettsia rickettsii Rickettsia rickettsii A species of gram-negative, aerobic bacteria that is the etiologic agent of rocky mountain spotted fever. Its cells are slightly smaller and more uniform in size than those of rickettsia prowazekii. Rickettsia, which is usually transmitted by ticks Ticks Blood-sucking acarid parasites of the order ixodida comprising two families: the softbacked ticks (argasidae) and hardbacked ticks (ixodidae). Ticks are larger than their relatives, the mites. They penetrate the skin of their host by means of highly specialized, hooked mouth parts and feed on its blood. Ticks attack all groups of terrestrial vertebrates. In humans they are responsible for many tick-borne diseases, including the transmission of rocky mountain spotted fever; tularemia; babesiosis; african swine fever; and relapsing fever. Coxiella/Q Fever.

Epidemiology^[6,9,10]

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: has risen from 495 cases in 2000 to about 5,200 cases in 2019
• Affects all ages, but most common in those 40–64 years of age
• Most common rickettsial infection in the United States
• Occurs throughout the United States, but most prevalent in the southeastern and south-central states:
  • Arkansas, Missouri, North Carolina, Tennessee, and Virginia account for > 50% of cases.
  • More cases have been reported in Arizona in the past several years.
• Outside the United States:
  • Canada
  • Mexico
  • South America (Brazil, Bolivia, Argentina, and Colombia)
• Distribution is dependent on the location of the tick vector.
• Risk factors:
  • Season:
    • More common in spring and summer
    • > 90% of cases are from April to September when adult Dermacentor Dermacentor A widely distributed genus of ticks, in the family ixodidae, including a number that infest humans and other mammals. Several are vectors of diseases such as tularemia; rocky mountain spotted fever; colorado tick fever; and anaplasmosis. Rickettsia ticks Ticks Blood-sucking acarid parasites of the order ixodida comprising two families: the softbacked ticks (argasidae) and hardbacked ticks (ixodidae). Ticks are larger than their relatives, the mites. They penetrate the skin of their host by means of highly specialized, hooked mouth parts and feed on its blood. Ticks attack all groups of terrestrial vertebrates. In humans they are responsible for many tick-borne diseases, including the transmission of rocky mountain spotted fever; tularemia; babesiosis; african swine fever; and relapsing fever. Coxiella/Q Fever are most active.
  • Increased tick burden: residency near wooded areas or areas with high grass

Etiology^[2,6]

• Causative agent is R. rickettsii:
  • Weakly gram-negative (poor Gram staining Gram staining Bacteriology)
  • Obligate intracellular bacterium
• Route of transmission: tick bite
• Hosts and vectors:
  • Most common in the United States:
    • American dog tick American Dog Tick Rocky Mountain Spotted Fever ( Dermacentor variabilis Dermacentor Variabilis Rocky Mountain Spotted Fever, D. similis)
    • Rocky Mountain wood tick Rocky Mountain Wood Tick Rocky Mountain Spotted Fever ( Dermacentor andersoni Dermacentor Andersoni Rocky Mountain Spotted Fever)
    • Brown dog tick ( Rhipicephalus sanguineus Rhipicephalus sanguineus A species of tick (ticks) in the family ixodidae, distributed throughout the world but abundant in southern europe. It will feed on a wide variety of mammals, but dogs are its preferred host. It transmits a large number of diseases including babesiosis; theileriosis; ehrlichiosis; and mediterranean spotted fever. Rocky Mountain Spotted Fever): Arizona
  • Central and South America:
    • Brown dog tick ( Rhipicephalus sanguineus Rhipicephalus sanguineus A species of tick (ticks) in the family ixodidae, distributed throughout the world but abundant in southern europe. It will feed on a wide variety of mammals, but dogs are its preferred host. It transmits a large number of diseases including babesiosis; theileriosis; ehrlichiosis; and mediterranean spotted fever. Rocky Mountain Spotted Fever): Mexico
    • Cayenne tick ( Amblyomma cajennense Amblyomma Cajennense Rocky Mountain Spotted Fever): Central and South America
    • Yellow dog tick ( Amblyomma Amblyomma A genus of hardbacked ticks, in the family Ixodidae. It includes the lone star tick, Amblyomma americanum, and the Gulf Coast tick, Amblyomma maculatum, in the Americas. Amblyomma americanum is the primary vector of Ehrlichia chaffeensis and Ehrlichia ewingii which cause Ehrlichiosis. Other Amblyomma-associated diseases include tularemia and rickettsiosis. Rickettsia aureolatum): Brazil

Pathophysiology

• R. rickettsii are transmitted to human hosts through the bite of an infected tick.^[4,5]
• During feeding, 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 are released from tick salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands: Anatomy.
• 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 have a tropism for endothelial cells and adhere to the cells via membrane lipopolysaccharides Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: lipid a, core polysaccharide, and o-specific chains (o antigens). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal b-cell mitogens commonly used in laboratory immunology. Diarrheagenic E. coli (LPS) and rickettsial outer membrane proteins Rickettsial Outer Membrane Proteins Rocky Mountain Spotted Fever ( rOmps Romps Rocky Mountain Spotted Fever).
• 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 are then endocytosed into host cells and cause host cell lysis via:
  • Phospholipase A
  • Protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS
  • Free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles–induced lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-Induced Liver Injury
• 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 are then able to spread hematogenously through the blood and also via lymphatics:
  • Continued replication within vessels causes vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus.
  • Widespread vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus can result in microhemorrhages and disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation ( DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation).
  • Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus → ↑ vascular permeability, which can lead to:
    • 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 (peripheral, cerebral, and pulmonary)
    • 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 and 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 → ↓ organ perfusion and dysfunction

Clinical Presentation

Symptoms usually occur within 2–14 days of exposure to an infected tick bite. Initial symptoms may be vague and non-specific ( 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, generalized malaise Malaise Tick-borne Encephalitis Virus). Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may not be aware of tick exposure.

Classic triad^[5,6]

All 3 components of the “classic triad” are seen in only 44% of cases.^[7]

• 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 (> 38.9°C (102.0°F))
• Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess (less common in children)^[13]
• Rash Rash Rocky Mountain Spotted Fever: 
  • Appears 3–5 days after onset of symptoms in about 90% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship; < 50% have a rash Rash Rocky Mountain Spotted Fever within the 1st 72 hours
  • Appearance:
    • Early: maculopapular Maculopapular Dermatologic Examination (spots are 1–5 mm)
    • Later: can become petechial (considered a sign of severe disease)
  • Distribution:
    • Usually starts on the wrists and ankles, then generalizes
    • Involves the palms and soles (but not always)^[11]
  • Nonpruritic
  • Note: About 10% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will not develop a rash Rash Rocky Mountain Spotted Fever (“spotless” RMSF RMSF 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).

Other possible clinical signs and symptoms^[5‒7,13]

• Arthralgias
• Myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus
• Abdominal pain Abdominal Pain Acute Abdomen (common in children)
• Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and/or vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
• Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus (more frequently noted in children)
• 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 (around eyes and extremities)
• Neurologic:
  • Confusion
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • Stupor
• Ocular involvement:^[8]
  • 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
  • Retinal hemorrhages
  • Papilledema Papilledema Swelling of the optic disk, usually in association with increased intracranial pressure, characterized by hyperemia, blurring of the disk margins, microhemorrhages, blind spot enlargement, and engorgement of retinal veins. Chronic papilledema may cause optic atrophy and visual loss. Idiopathic Intracranial Hypertension

Complications^[2,5,6]

Complications of untreated infection may include:

• 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
• Myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis/arrhythmia
• Pneumonitis Pneumonitis Human Herpesvirus 6 and 7
• 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
• Adult respiratory distress syndrome
• Arrhythmias
• Coagulopathy (including DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation; rare)
• 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
• Multiple organ dysfunction syndrome (MODS)
• Skin necrosis Skin Necrosis Rocky Mountain Spotted Fever and gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction (in very severe cases)

Diagnosis

The diagnostic workup for RMSF RMSF 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 may depend on practice location. The following information is based on US and European guidelines. See your local guidelines for additional guidance.

History^[6,7]

• Recent travel to areas with high prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency
• Possible tick exposure

Physical exam^[2,7,13]

• Rash Rash Rocky Mountain Spotted Fever
• Evidence of tick bite (rare):^[12]
  • Inoculation eschar
  • Local 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
• Pedal edema Pedal Edema Rocky Mountain Spotted Fever (especially in children)
• Conjunctival erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion
• Meningismus Meningismus Subarachnoid Hemorrhage (in cases of central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification involvement)
• Late/severe manifestations:
  • Change in mental status
  • 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
  • Gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction of digits and ears

General laboratory studies^[2,6,12,13]

• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will have normal laboratory findings initially, including normal WBC count (but often immature myeloid cells Myeloid Cells The classes of bone marrow-derived blood cells in the monocytic series (monocytes and their precursors) and granulocytic series (granulocytes and their precursors). White Myeloid Cells: Histology).
• Later abnormalities include:
  • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia (30%–50% of cases)
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (30%)
  • Leukopenia
  • Prolonged partial thromboplastin time Partial thromboplastin time The time required for the appearance of fibrin strands following the mixing of plasma with phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides). It is a test of the intrinsic pathway (factors VIII, IX, XI, and XII) and the common pathway (fibrinogen, prothrombin, factors V and X) of blood coagulation. Hemostasis (PTT) and prothrombin time Prothrombin time Clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen; prothrombin; factor V; factor VII; and factor X. Hemostasis (PT) due to consumption of clotting factors
  • Increased serum liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and muscle 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 ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests, ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests, LDH LDH Osteosarcoma, CK)
  • Hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice
  • Azotemia Azotemia A biochemical abnormality referring to an elevation of blood urea nitrogen and creatinine. Azotemia can be produced by kidney diseases or other extrarenal disorders. When azotemia becomes associated with a constellation of clinical signs, it is termed uremia. Acute Kidney Injury
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia

Confirmatory tests^[6,11‒13]

• Serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus:
  • Indirect immunofluorescence assay (IFA): most widely available and utilized
  • Perform both acute and convalescent serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus testing to compare levels:^[6]
    • 1st sample: within 1st 2 weeks
    • 2nd sample: 2‒4 weeks later
  • Seroconversion Seroconversion The appearance of antibodies against causative agents in the blood of individuals during the course of an infection or following immunization. HIV Infection and AIDS: 4x increase in IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis antibody levels
  • Immunoglobulin M ( IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions) and IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions generally appear 7–10 days after illness onset.^[13]
  • Note: Acute serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus is often negative and not helpful in the first 5 days. Treatment should be based on clinical manifestations and not delayed.
• Polymerase chain reaction Polymerase chain reaction 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) ( 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)) on a blood sample: low sensitivity:
  • May also be performed on biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of rash Rash Rocky Mountain Spotted Fever lesion
• Skin biopsy Skin Biopsy Secondary Skin Lesions:
  • Direct immunofluorescence testing or immunoperoxidase staining 
  • Not readily available across the United States
  • 70% sensitive, 100% specific
• Culture:
  • Difficult to perform
  • Reserved for research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest purposes

Management

Management of RMSF RMSF 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 may vary depending on practice location. The following information is based on US-based guidelines. Please see your local guidelines for more guidance.

Antibiotics^[6,13]

• Should be started empirically if there is high clinical suspicion
• Preferably within 5 days of symptom onset
• 1st line: doxycycline (oral or intravenous)
  • Treatment of choice, even in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Dosing:
    • Adults: 100 mg every 12 hours for 5–14 days 
    • Children: < 45.4 kg: 2.2 mg/kg twice daily; maximum: 100 mg/dose
  • Duration:
    • Treat for ≥ 3 days after the 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 subsides and clinical improvement
    • Minimum: 5–7 days
    • Severe disease may require a longer treatment period.
• If doxycycline cannot be used (e.g., severe allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction) or if the patient is pregnant → consult infectious disease specialist
• Alternative: 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 (less effective)
  • May be difficult to acquire
  • Potential risks:
    • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
    • Gray baby syndrome Gray Baby Syndrome Chloramphenicol
  • Note: Use of any antibiotics besides doxycycline (including 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) may increase the risk of death.

Additional care considerations^[14]

Deciding care setting:

• Individuals at higher risk for hospitalization Hospitalization The confinement of a patient in a hospital. Delirium:
  • Immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis individuals, such as those:
    • Undergoing cancer treatment
    • With advanced HIV HIV Anti-HIV Drugs infection
    • With prior organ transplants
  • Individuals with glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway ( G6PD G6PD Pentose Phosphate Pathway) deficiency
• Indications for hospitalization Hospitalization The confinement of a patient in a hospital. Delirium (those with severe, or the potential for severe, disease):
  • Organ dysfunction
  • Severe thrombocytopenia Severe Thrombocytopenia Thrombocytopenia
  • Mental status changes
  • 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 and 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
  • Inability to tolerate oral doxycycline
  • Social factors that may prohibit outpatient therapy and follow-up
  • Comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus (e.g., immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis state, G6PD G6PD Pentose Phosphate Pathway deficiency)

Outpatient care:

• Appropriate for those who:
  • Have mild, early disease
  • Can tolerate oral doxycycline
• Requires close follow-up care → keep in contact with patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship to ensure response to therapy
  • 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 generally subsides within 24‒48 hours. 
  • May need to consider an alternative diagnosis or coinfection if 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 persists
• In cases where the diagnosis is uncertain, a 24-hour “watch-and-wait” approach to antibiotic initiation may be considered:
  • Ideal candidates:
    • Appear well (may have 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)
    • No obvious tick bite
    • Normal physical examination
    • Laboratory values within normal range
  • Requires close monitoring owing to the potential for rapid clinical decline

Hospital care:

• Specialist consultations (if available):
  • Critical care
  • Infectious disease
• Monitor for:
  • Treatment response: clinical improvement may take > 48 hours in severe disease
  • Intracranial hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • 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
  • ARDS
  • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
• In addition to antibiotics (e.g., IV doxycycline), therapies may include (depending on the clinical course):
  • IV fluid and electrolyte replacement
  • Mechanical ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing
  • Vasopressors Vasopressors Sepsis in Children
  • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis
  • Blood and/or platelet transfusions
  • Anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs medications

Reporting^[14]

In the US, RMSF RMSF 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 is a reportable disease under a new category (since 2010) called spotted 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 rickettsiosis (SFR). Notify the local health department of potential cases.

Prevention

• Prevention of tick bites
• Detection and removal of attached ticks Ticks Blood-sucking acarid parasites of the order ixodida comprising two families: the softbacked ticks (argasidae) and hardbacked ticks (ixodidae). Ticks are larger than their relatives, the mites. They penetrate the skin of their host by means of highly specialized, hooked mouth parts and feed on its blood. Ticks attack all groups of terrestrial vertebrates. In humans they are responsible for many tick-borne diseases, including the transmission of rocky mountain spotted fever; tularemia; babesiosis; african swine fever; and relapsing fever. Coxiella/Q Fever
• Surveillance Surveillance Developmental Milestones and Normal Growth of symptoms following known tick bites
• No commercially available vaccines

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Pre-antibiotic era: 20%–25% mortality Mortality All deaths reported in a given population. Measures of Health Status (range: 20%–80%)
• Current mortality Mortality All deaths reported in a given population. Measures of Health Status is 3%–5%, mostly due to delayed diagnosis and treatment. 
• Factors associated with increased severity/lethality:
  • Male gender Gender Gender Dysphoria
  • Increasing age
  • Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway deficiency
  • Chronic alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder

Differential Diagnosis

• Meningococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis: a meningeal infection with Neisseria meningitidis Neisseria meningitidis A species of gram-negative, aerobic bacteria. It is a commensal and pathogen only of humans, and can be carried asymptomatically in the nasopharynx. When found in cerebrospinal fluid it is the causative agent of cerebrospinal meningitis. It is also found in venereal discharges and blood. There are at least 13 serogroups based on antigenic differences in the capsular polysaccharides; the ones causing most meningitis infections being a, b, c, y, and w-135. Each serogroup can be further classified by serotype, serosubtype, and immunotype. Neisseria. 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 Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, and rash Rash Rocky Mountain Spotted Fever are commonly noted in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with meningococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis. However, there is usually no history of tick exposure and symptoms do not improve with doxycycline. Diagnosis is established with lumbar puncture Lumbar Puncture Febrile Infant. Treatment is usually with ceftriaxone Ceftriaxone A broad-spectrum cephalosporin antibiotic and cefotaxime derivative with a very long half-life and high penetrability to meninges, eyes and inner ears. Cephalosporins or penicillin Penicillin Rheumatic Fever.
• Infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis: a viral infection caused by the Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus. Initial clinical symptoms of RMSF RMSF 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 and infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis are very similar to any viral infection, with malaise Malaise Tick-borne Encephalitis Virus and low-grade fever Low-Grade Fever Erythema Infectiosum. Mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as “the kissing disease,” is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis can present with a rash Rash Rocky Mountain Spotted Fever but usually spares the palms and soles. Diagnosed with a monospot test. Treatment is largely supportive.
• Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura ( TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura): a life-threatening condition caused by defects of von Willebrand factor von Willebrand factor A high-molecular-weight plasma protein, produced by endothelial cells and megakaryocytes, that is part of the factor VIII/von Willebrand factor complex. The von Willebrand factor has receptors for collagen, platelets, and ristocetin activity as well as the immunologically distinct antigenic determinants. It functions in adhesion of platelets to collagen and hemostatic plug formation. The prolonged bleeding time in von Willebrand diseases is due to the deficiency of this factor. Hemostasis. Complications of RMSF RMSF 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 include thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia and disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation ( DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation), which can cause a purpuric rash Rash Rocky Mountain Spotted Fever and be mistaken for TTP TTP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of adamts-13, a metalloproteinase that cleaves multimers of von Willebrand factor (vWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura.  Diagnosis is established with blood work. Treatment involves plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome and steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors.
• Measles Measles Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. It is highly contagious and spreads by respiratory droplets or direct-contact transmission from an infected person. Typically a disease of childhood, measles classically starts with cough, coryza, and conjunctivitis, followed by a maculopapular rash. Measles Virus: a viral infection associated with 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 maculopapular Maculopapular Dermatologic Examination rash Rash Rocky Mountain Spotted Fever. The rash Rash Rocky Mountain Spotted Fever usually starts on the face and then progresses to the trunk and extremities, sparing the palms and soles. Diagnosis is made clinically and confirmed by serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus, and treatment is largely supportive.