Rickettsia

General Characteristics

General characteristics

• Obligate intracellular organisms
• Pleomorphic Pleomorphic Bacteroides ( cocci Cocci Bacteriology, bacilli Bacilli Shigella, threads)
• Weakly gram negative Gram negative Bacteria which lose crystal violet stain but are stained pink when treated by gram’s method. Yersinia spp./Yersiniosis (poor Gram staining Gram staining Bacteriology)
• Can be visualized with special stains such as Giemsa and by direct fluorescent antibody Direct Fluorescent Antibody A form of fluorescent antibody technique utilizing a fluorochrome conjugated to an antibody, which is added directly to a tissue or cell suspension for the detection of a specific antigen. Congenital TORCH Infections 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 Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate)
• Have a tropism for vascular endothelial cells:
  • Cause direct vascular injury
  • Also produce prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids and activate clotting factors, which can lead to systemic clinical manifestations
• Clinically relevant species:
  • 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 group:
    • R. rickettsii (Western hemisphere)
    • R. akari (United States, Russia, Korea, South Africa)
    • Multiple other species (primarily in Asia ASIA Spinal Cord Injuries 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.

Clinical Relevance (R. rickettsii)

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

Epidemiology: 

• More common in rural and suburban settings
• Risk factors include living near the woods, walking in high grass, or through exposure Exposure ABCDE Assessment to dogs
• Seasonal variation: highest 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 in spring and early summer
• Highest 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 in people 40–64 years of age
• Higher 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 in Native Americans
• Increased severity/lethality:
  • Male gender Gender Gender Dysphoria
  • Increasing age
  • Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway deficiency
  • Chronic alcohol abuse
  • African American origin

Pathophysiology:

• Virulence Virulence The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenic capacity of an organism is determined by its virulence factors. Proteus:
  • Factors are not well understood.
  • Dose of inoculum plays a role.
• Inoculation from a feeding tick
• 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, rickettsial outer membrane proteins Rickettsial Outer Membrane Proteins Rocky Mountain Spotted Fever ( rOmps Romps Rocky Mountain Spotted Fever), and surface-exposed proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (SEPs) act as adhesins Adhesins Cell-surface components or appendages of bacteria that facilitate adhesion (bacterial adhesion) to other cells or to inanimate surfaces. Most fimbriae of gram-negative bacteria function as adhesins, but in many cases it is a minor subunit protein at the tip of the fimbriae that is the actual adhesin. In gram-positive bacteria, a protein or polysaccharide surface layer serves as the specific adhesin. What is sometimes called polymeric adhesin (biofilms) is distinct from protein adhesin. Diarrheagenic E. coli for endothelial cells.
• 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 get inside the cells via endocytosis Endocytosis Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. The Cell: Cell Membrane.
• Once in the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton, express proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis that lead to polymerization of actin filaments Actin filaments Fibers composed of microfilament proteins, which are predominately actin. They are the smallest of the cytoskeletal filaments. The Cell: Cytosol and Cytoskeleton
• This process allows passage into neighboring cells via filopodia derived from the host membrane.
• Subsequent spread via bloodstream and lymphatics
• Endothelial cell damage/ necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
• Accumulation of macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation/ 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: Histology → lymphocytic 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

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor:

• Incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus 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 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, myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy/ arthralgia Arthralgia Pain in the joint. Rheumatic Fever: mimics a viral infection
  • 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/ vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Abdominal pain Abdominal Pain Acute Abdomen common in children
• Rash Rash Rocky Mountain Spotted Fever: variably present
  • Appears on days 3–5 in 50% of cases, and may never appear in 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
  • Typically starts at wrists/ankles and spreads centrally; rash Rash Rocky Mountain Spotted Fever does not spare palms and soles, but often never develops in these areas (18%–64% of cases)
  • Blanching Blanching Dermatologic Examination erythematous macular rash Rash Rocky Mountain Spotted Fever 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 (ARDS)
  • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) 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 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. Skin: Structure and Functions necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
• Preferred treatment is doxycycline.

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%)
• Currently 3%–5%, mostly due to delayed diagnosis and treatment

Identification Identification Defense Mechanisms:

• 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. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (3-mm punch): immunofluorescence testing/immunoperoxidase staining (70% sensitive, 100% specific)
• Culture is difficult, dangerous, and reserved mostly 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.
• Serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus: not useful for diagnosis, as it establishes diagnosis only post-factum
• 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)) tests of blood specimens not useful (low sensitivity Sensitivity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Blotting Techniques)

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

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 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, thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus, microscopic hemorrhage

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor:

• 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 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, malaise Malaise Tick-borne Encephalitis Virus, 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, myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus
• Can be confused with typhoid Typhoid 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) 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 in tropical zones
• Rash Rash Rocky Mountain Spotted Fever:
  • Macular or maculopapular Maculopapular Dermatologic Examination, 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 Pulmonary involvement Coccidioides/Coccidioidomycosis in 35% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship (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 Brill-Zinsser Disease Epidemic Typhus:

• Recurrence of typhus symptoms years after initial infection
• Usually mild illness 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, 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, malaise Malaise Tick-borne Encephalitis Virus, and rash Rash Rocky Mountain Spotted Fever
• Diagnosis: 
  • 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. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (3-mm punch): immunohistochemical stain
  • Can also test louse found on patient 
• Treatment: doxycycline
• 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: 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 Permethrin A pyrethroid insecticide commonly used in the treatment of lice infestations and scabies. Scabies or other insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease 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 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
• 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 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, myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus, and rash Rash Rocky Mountain Spotted Fever
• In severe cases, may present with neurologic, renal, cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR), pulmonary, or hepatic dysfunction
• Treatment: doxycycline
• 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: severe disease associated with old age, 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; case-fatality rate is 1%

Rickettsialpox (R. akari)

• Mice serve as natural reservoirs.
• Mice mites Mites Any arthropod of the subclass acari except the ticks. They are minute animals related to the spiders, usually having transparent or semitransparent bodies. They may be parasitic on humans and domestic animals, producing various irritations of the skin (mite infestations). Many mite species are important to human and veterinary medicine as both parasite and vector. Mites also infest plants. Scabies rarely bite humans, unless the mouse population is reduced.
• Incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus period: 10–14 days
• Initial lesion: a small papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes that vesiculates and then forms an eschar
• Constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: 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, malaise Malaise Tick-borne Encephalitis Virus, and 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
• Rash Rash Rocky Mountain Spotted Fever: 
  • Generalized
  • Maculopapular Maculopapular Dermatologic Examination that becomes papulovesicular, followed by eschar crust Crust Dried exudate of body fluids (blood, pus, or sebum) on an area of damaged skin Secondary Skin Lesions
  • Lesions scab ( crust Crust Dried exudate of body fluids (blood, pus, or sebum) on an area of damaged skin Secondary Skin Lesions) and fall off without scarring Scarring Inflammation.
• Diagnosis: clinical symptoms and signs, epidemiologic data, and convalescent sera
• Treatment and 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: doxycycline; without treatment, 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 lasts 6–10 days