Infectious Diseases Flashcards
To what family and genus do the rabies viruses belong?
Rabies appears to be caused by a number of different species of neurotropic viruses in the Rhabdoviridae Family, genus Lyssavirus.
Which tissue does rabies have a predilection for? How does it cause disease in this tissue?
Lyssaviruses have a predilection for neural tissue and spread via peripheral nerves to the central nervous system (CNS). The mechanism by which rabies causes severe CNS disease is unclear. Lyssaviruses may produce neuronal dysfunction, such as autonomic instability, rather than neuronal death. Oxidative stress caused by dysfunction of mitochondria in neurons and other cells of the CNS may also be a pathway leading to the abnormalities observed.
How does the rabies virus get to its target system in the body?
Viruses amplify near the site of inoculation in muscle cells and subsequently enter local motor and sensory nerves. Viruses then migrate centrally in a retrograde direction within the axoplasm of peripheral nerves at approximately 50 to 100 mm per day until reaching the dorsal root ganglia of the spinal cord. Rabies viruses then ascend rapidly up the spinal cord to the brain, initially infecting the diencephalon, hippocampus, and brainstem.
Where does productive viral replication and shedding take place?
In highly innervated areas, such as the salivary glands.
What is a pathognomonic histological finding in rabies infection?
Dense, ovoid, intracytoplasmic inclusions, (ie, Negri bodies).
Which factors determine the host’s susceptibility to infection with rabies?
Factors that may increase host susceptibility to infection include:
- A bite with prominent salivary contamination
- The virus variant
- The size of the viral inoculum
- The degree of innervation at the site of the bite
- Host immunity and genetics
What is the geographical distribution of rabies?
Worldwide with some exceptions, including Antarctica, New Zealand, Japan, Sweden, Norway, Spain and some Caribbean Islands.
What is the incidence of rabies?
Around 30 000 - 70 000 worldwide.
How is rabies transmitted?
Most rabies is acquired through exposure to saliva from an animal bite. In rare cases, rabies results from a non-bite exposure (eg, aerosolized virus in bat caves or in laboratories handling the virus), or transplantation of tissue or organs from a donor with unrecognized rabies.
Which animal reservoirs account for the most rabies infections?
In developing countries, rabid dogs account for 90 percent or more of reported cases of rabies transmitted to humans. Rabies surveillance in the United States has identified the four major animal reservoirs as bats, raccoons, skunks, and foxes.
What is the typical incubation period for rabies?
The average incubation period of rabies is one to three months, but can range from several days to many years after an exposure.
Under which conditions can the incubation period be different?
The incubation period is shorter in patients with an exposure that occurs in richly innervated areas (eg, the face versus the extremities). Longer incubation periods may also be related to inadequate rabies prophylaxis, or an unknown new exposure.
How can the clinical manifestations of rabies be classified?
Prodromal phase and then clinical rabies.
What are the three main groups of manifestations of clinical rabies?
Encephalitic (furious) rabies (80%), paralytic (dumb) rabies (20%) and atypical rabies.
What are the features of the rabies prodrome?
Rabies is usually unsuspected during the prodromal phase, which starts with non-specific symptoms, such as low-grade fever, chills, malaise, myalgias, weakness, fatigue, anorexia, sore throat, nausea, vomiting, headache, and occasionally photophobia.
Paresthesias radiating proximally from the site of a known wound would be suggestive of rabies infection. The patient may describe a variety of symptoms including pain, tenderness, tingling, itching, burning, abnormal localized temperature sensation, or numbness at the site. In addition, percussion myoedema (mounding of the muscle at the percussion site) may be present during the prodrome and throughout the illness.
How long does the rabies prodrome last?
This stage lasts from a few days to approximately one week.
Outline the classic features of encephalitic rabies.
The classic presentation of encephalitic rabies includes fever, hydrophobia, pharyngeal spasms, and hyperactivity subsiding to paralysis, coma and death.
Describe the features of encephalitic rabies.
●Hydrophobia is the most characteristic clinical feature of rabies, occurring in 33 to 50 percent of patients. After some preliminary feeling of discomfort in the throat or dysphagia, the patient suddenly develops an overwhelming terror of water based on involuntary pharyngeal muscle spasms during attempts to drink. Later in the disease, even the sight or mention of water may trigger these involuntary spasms.
●Aerophobia is also pathognomonic of rabies although it occurs less often than hydrophobia (approximately 9 percent in one series). Pharyngeal spasms are triggered upon feeling a draft of air and can last approximately 5 to 15 seconds. Painful inspiratory spasms of the diaphragm and accessory inspiratory muscles can lead to aspiration, coughing, choking, vomiting and hiccups; when severe, these spasms can lead to asphyxiation and respiratory arrest.
●The facial muscles may contract leading to a grimace and the neck and back can become hyperextended with muscle spasticity (referred to as opisthotonos).
●Autonomic instability is observed in approximately 25 percent of patients.
●Patients may exhibit dysarthria, dysphagia or may complain of diplopia or vertigo. Dysphagia was reported in approximately half of all cases in one retrospective series.
●Agitation and combativeness are also commonly seen (approximately 50 percent of patients), along with auditory and visual hallucinations.
What additional features of clinical rabies may be found on examination?
The physical examination is notable for mental status changes, increased muscular tone and tendon reflexes with extensor plantar responses and fasciculations. Nuchal rigidity may be present. Once the patient develops coma, flaccid paralysis with generalized areflexia is usually noted.
Describe the clinical features of paralytic rabies.
Fewer than 20 percent of rabies patients present with an ascending paralysis, which can mimic Guillain-Barré syndrome. These patients have little evidence of cerebral involvement until late in their course of disease.
After the prodromal symptoms described above, the patient develops a flaccid paralysis. Paralysis is usually most prominent in the bitten limb, and then spreads symmetrically or asymmetrically. The physical examination is notable for fasciculations; deep tendon and plantar reflexes are lost.
The patient may complain of headache and pain in the affected muscles with mild sensory disturbance. Nuchal rigidity and cranial nerve palsies are occasionally seen, while hydrophobia is unusual.
As the paralysis ascends, there is onset of dense paraplegia with loss of sphincter tone and subsequent paralysis of the muscles of deglutition and respiration, leading to death.
How soon after the onset of coma do most patients die? What do they die from?
Most patients with rabies die within two weeks after the onset of coma, although longer courses have been described with intensive care support.
Patients often die of complications, such as asphyxiation and respiratory arrest secondary to muscular spasms or uncontrolled generalized seizures in encephalitic rabies or respiratory paralysis in paralytic rabies.
Besides the CNS, which other organ is affected by rabies and how does this manifest clinically?
The heart.
Supraventricular arrhythmias, atrioventricular block, sinus bradycardia and sinus arrest with non-specific ST segment and T-wave changes have all been reported. Myocarditis has been found at necropsy with evidence of viral invasion and lymphocytic infiltration.
What lab findings are associated with rabies?
Routine laboratory tests are non-specific. A peripheral leukocytosis is often noted. When a constellation of clinical features suggestive of meningitis or encephalitis is present, a lumbar puncture may demonstrate a lymphocytic pleocytosis (mean 60 cells/uL). CSF protein is characteristically elevated, but typically less than 100 mg/dL, with a normal glucose concentration. A hemorrhagic CSF is not characteristically seen with rabies.
What radiographic findings are associated with rabies?
CT scans are usually normal in the early phase of the illness. In later stages, cerebral edema may be seen. MR imaging may show areas of increased T2 signaling in the hippocampus, hypothalamus and brainstem.
How can an antemortem diagnosis of rabies be made?
Before death, the diagnosis can be made by virus-specific immunofluorescent staining of skin biopsy specimens, isolation of virus from the saliva, or detection of anti-rabies antibodies in serum or cerebrospinal fluid (CSF). Important to utilize all modalities.
How do you interpret the presence of rabies antibodies in the serum?
If no vaccine or rabies immune globulin has been given, the presence of antibody to rabies virus in serum is diagnostic of infection. A patient who has been immunized will have rabies antibodies in serum. Thus, in the immunized patient, a second specimen should be obtained a few days later to see if antibody titers are rising, which would be indicative of infection.
How do you interpret the presence of rabies antibodies in the CSF?
Antibody to virus in a CSF specimen, regardless of immunization history, suggests infection.
What is the differential diagnosis of encephalitic rabies?
In patients with a constellation of symptoms and signs of encephalitis, other more common infections (eg, herpes simplex virus, West Nile virus) and other noninfectious disorders (eg, central nervous system vasculitis, toxic or metabolic encephalopathy ) should be ruled out. Other causes of muscular rigidity that can be seen with rabies include tetanus, phenothiazine dystonia, and strychnine poisoning.
What is the differential diagnosis of paralytic rabies?
Paralytic rabies may be confused with Guillain-Barré syndrome, poliomyelitis, West Nile virus and acute transverse myelitis.
What is the approach to the treatment of rabies?
There is no proven effective therapy for rabies. Thus, preventing human rabies infection through the use of either pre-exposure prophylaxis (for high-risk groups) or post-exposure prophylaxis remains the cornerstone of management.
For patients with symptomatic rabies, treatment is mostly supportive. However, in rare situations, the use of an aggressive treatment protocol may provide some benefit.
What supportive care should be given to patients infected with rabies?
For most patients, the management of symptomatic rabies is palliative. Palliative therapy should focus on comfort care, pain control, and sedation.
Are glucocorticoids indicated as adjunctive therapy in rabies?
Corticosteroid therapy is not recommended for rabies since glucocorticoids have been found to increase mortality and decrease the incubation period in experimental rodent models.
What are the roles of rabies immune globulin and vaccine in the treatment of patients with clinical rabies?
There is no role for rabies vaccine or immune globulin in patients with symptomatic infection.
What is the Milwaukee protocol?
An aggressive treatment approach designed to protect the brain from injury while waiting for the host immune response to clear the virus.
For which patients is the Milwaukee protocol indicated?
In light of experience thus far, we agree with most experts and do not use this protocol for the routine treatment of patients with rabies.
However, this protocol may be reasonable for patients who present at an early stage of disease, had the rabies vaccine administered before the onset of clinical rabies, and/or are otherwise healthy. Another favorable prognostic factor is the presence of rabies antibodies at presentation in the absence of viral antigen or viral RNA.
What are the components of therapy of the Milwaukee protocol?
●Induction of therapeutic coma to reduce putative excitotoxicity (the proposed pathologic actions of viral-induced excessive excitatory amino acids or neurotransmitters upon neural cells), brain metabolism, and autonomic reactivity, which can be severe and life-threatening. One suggested therapeutic agent is ketamine, a dissociative anesthetic agent and a noncompetitive antagonist of the N-methyl-D-aspartate receptor; at high concentrations, ketamine may also inhibit rabies virus replication in vitro or in animal models. Benzodiazepines and barbiturates have also been used in this protocol.
●Intensive supportive care
●Use of drugs with potential antiviral activity (eg, ribavirin, amantadine)
●Therapeutic blockade of cerebral artery spasm
●Avoidance of passive or active immunization with rabies vaccine or rabies immunoglobulin because of theoretical concerns regarding interference with the native immune response and uncertainty about penetration into the central nervous system
What are the outcomes when using the Milwaukee protocol?
Dismal.
Which antiviral medication has been proven useful in the management of clinical rabies?
None.
Which infection control measures should be applied in the care of rabies patients?
●Consistent standard precautions should be utilized by HCP and family members (for example, HCP should wear gowns, masks, gloves, and eye/face protection).
●Individuals who have a percutaneous, mucous membrane, or nonintact skin exposure to the body fluids or tissues of a patient with rabies should receive proper wound care and post-exposure prophylaxis as soon as possible. Saliva, respiratory secretions, spinal fluid, and nervous tissue are most likely to transmit infection; however, all specimens collected from patients with rabies should be considered infectious.
Comment on the appropriate timing of rabies PEP.
Rabies postexposure prophylaxis is an urgent medical intervention and should begin as soon as possible after the presumed exposure.
When should each of either rabies vaccine or immune globulin be given? When should they both be given?
Rabies immunoglobulin is referred to as “passive immunization”; rabies vaccine is referred to as “active immunization”.
●Vaccine alone is given for preexposure prophylaxis
●Postexposure rabies prophylaxis, in previously unimmunized persons, should always include both passive and active immunization.
●Vaccine alone is indicated in exposed persons who have had preexposure prophylaxis with a cell culture vaccine series or who had been vaccinated with other types of rabies vaccine with a documented neutralizing antibody response.
How should a potential rabies wound be treated?
One of the most important initial steps to prevent rabies is wound care. Thorough washing of bite wounds, scratches, and non-bite exposures with soap and water is recommended, if feasible. When available, a virucidal agent such as povidone-iodine should also be used. In animal studies of rabies, wound cleansing alone reduced the likelihood of rabies up to 90 percent. Tetanus prophylaxis, as well as antibiotics, should also be considered depending on the type of wound.
How does rabies immune globulin work?
The administration of RIG provides immediate virus-neutralizing antibodies until protective antibodies are generated in response to vaccine. HRIG has a half-life of approximately three weeks.
How does the rabies vaccine work?
Rabies vaccine induces the production of protective virus-neutralizing antibodies within approximately 7 to 10 days that persist for several years.
Is post-exposure prophylaxis with RIG and rabies vaccine effective?
The effectiveness of cell culture rabies vaccine plus RIG in preventing death and eliciting neutralizing antibodies after rabies exposure has been demonstrated in several studies.
Is the rabies vaccine effective for pre-exposure prophylaxis?
Multiple studies in humans demonstrate that vaccination with HDCV or PCECV results in significant titers of neutralizing antibodies by day 14.
What are the side-effects of RIG?
HRIG is associated with local reactions including pain and tenderness, erythema, and induration. Headache is the most commonly reported systemic side effect.Only one patient developed anaphylaxis associated with ERIG administration.
What are the side-effects of the rabies vaccine?
Local reactions, including pain at the injection site, redness, swelling, and induration. Systemic reactions are less common and include mild fever, headache, dizziness, and gastrointestinal symptoms. Systemic hypersensitivity reactions have been reported in up to 6 percent of persons receiving a booster vaccination with HDCV following primary rabies prophylaxis.
What is the dose of RIG and how is it given?
The recommended dose of HRIG in all age groups is 20 IU/kg while the recommended dose of ERIG (including F(ab”)2 products) is 40 IU/kg body weight. RIG can partially suppress antibody production, so no more than the single recommended dose should be administered.
RIG should always be given in a different syringe from the vaccine, and at a different intramuscular site, such as the deltoid muscle opposite the vaccine dose or the anterior thigh.
As much of the RIG dose as is anatomically feasible should be infiltrated in the area around and in the wounds. Any remaining dose should be given intramuscularly. If there is no obvious wound (eg, suspected bat exposure), the large volume of RIG is best administered into the gluteal muscle. When this area is used for injection, RIG should be administered carefully in the upper outer quadrant of the gluteus to avoid possible damage to the sciatic nerve.
How should the rabies vaccine be given in previously unimmunized persons?
1mL IM according to the relevant schedule. Check the package insert/ local guidelines (there are 5-dose schedules and 4-dose schedules; immunocompromised patients should receive the 5-dose one).
How should the rabies vaccine be given in immunized persons?
A previously vaccinated person who has had a potential rabies exposure should receive two intramuscular doses of vaccine; the first dose should be given on day 0, as soon after exposure as possible, and the other three days later.
Where should the rabies vaccine never be given?
Vaccine should never be administered in the gluteal area, because this may result in lower antibody titers. The deltoid is the only acceptable site of administration in adults.
Is post-vaccination serological testing required?
Rabies vaccine induces protective neutralizing antibodies in the vast majority of patients; thus, no postvaccination serologic testing is necessary. However, serologic testing may be considered in the immunosuppressed host or in any patient who has had significant deviations from the recommended vaccine schedule.
What does one do if rabies PEP cannot be given immediately and is delayed?
However, no vaccine failures have been reported in the United States, despite an average delay to vaccination of approximately five days. Furthermore, since latency periods between exposure and onset of disease as long as one to eight years have been reported, postexposure prophylaxis should be given following a rabies exposure, regardless of the length of the delay. Postexposure prophylaxis is never too early and is only too late when signs of clinical rabies are developing.
What if a patient misses a rabies injection after having started a schedule?
Most deviations from the immunization schedule do not require complete reinitiation of vaccination. If a patient misses an injection, the immunization series should be continued until all doses have been administered. Vaccine should be administered according to the regular intervals (eg, if day 7 vaccine is given on day 10, the next dose should be on day 17, 7 days later, etc.). If there is any concern regarding efficacy, antibody testing can be conducted at or after 14 days and 7 to 14 days after the final dose is given.
Although the vaccine formulations are essentially equivalent in immunogenicity, and theoretically can be substituted for one another, there are scant data on this approach. Thus, when feasible, use of the same vaccine formulation is recommended during the entire immunization series.
Is the rabies vaccine safe in pregnancy?
Yes.
Should the general population receive pre-exposure prophylaxis?
Nope.
What is brucellosis?
Brucellosis is a zoonotic infection transmitted to humans by contact with fluids from infected animals (sheep, cattle, goats, pigs, or other animals) or derived food products such as unpasteurized milk and cheese.
Whch Brucella species cause disease in humans and which one is the major cause worldwide?
B. melitensis (small ruminants), B. abortus (cattle), B. suis (swine), and B. canis (dogs) are known to cause human disease. The majority of human cases worldwide are attributed to B. melitensis.
What does Brucella look like under the microscope?
Brucellae are small, nonmotile, facultative intracellular aerobic rods. Gram staining demonstrates single tiny, gram-negative coccobacilli.
What is the incidence of Brucella infection and what is its geographical distribution?
It is estimated that the number of Brucella-infected individuals may be up to 26 times higher than the 500,000 cases reported annually. (Most common zoonosis worldwide) Major endemic areas include countries of the Mediterranean basin, Persian Gulf, the Indian subcontinent, and parts of Mexico and Central and South America.
What does the prevalence of Brucellosis depend on?
The prevalence of Brucella infection in humans depends upon several factors, including geography, husbandry practices, slaughtering, food preparation techniques, and trade.
How do humans become infected with Brucellosis?
Humans acquire the infection through the consumption of products from infected animals, such as unpasteurized milk, cheese, and insufficiently cooked or raw meat. Infection may also result from the entry of the bacteria from infected animals or their secretions through skin lesions, conjunctiva, or from inhalation of contaminated dust or aerosols.
Human-to-human transmission is unusual. Rare cases due to blood transfusion, tissue transplantation, breastfeeding, sexual contact, congenital, laboratory, and nosocomial infection have been reported.
Laboratory workers handling Brucella cultures are at a high risk of acquiring brucellosis through accidents, aerosolization, and/or inadequate laboratory precautions (table 1). Laboratory-associated infections represent 2 percent of reported cases.
Should contacts of Brucellosis sufferers be traced?
screening household members of an index case detects additional unrecognized cases, allowing early diagnosis and prevention of complications.
What is the pathogenesis of Brucellosis?
Brucellae are readily ingested by polymorphonuclear cells and macrophages, which then pass to local lymph nodes. Organisms replicate intracellularly, and bacteria from lysed cells can infect other cells or disseminate systemically. Some Brucellae are destroyed within the lysosomes of phagocytic cells, while others are capable of preventing phagosome-lysosome fusion and avoiding intracellular killing in lysosomes to reach an endoplasmic reticulum-derived vacuole.Once inside the endoplasmic reticulum, Brucella replicates extensively without restricting basic cellular functions or generating obvious cell damage. Brucella establish long-lasting infection within host cells.
How does Brucella evade the host immune response once inside a host cell?
During the intracellular stage, Brucellae display a range of survival strategies to suppress host immune response and avoid immediate destruction; they circumvent strong activation of the innate immune system, withstand the direct action of complement and other bactericidal substances, and evade the action of polymorphonuclear cells and macrophages.
Does Brucella exhibit classic virulence factors? If yes, which ones; if no, then how does it go about virulence?
No classical virulence factors.
The smooth LPS and proteins involved in signaling, gene regulation, and transmembrane transportation are suspected to be involved in virulence. The LPS does not trigger a strong innate immune response, and, thus, the synthesis of inflammatory cytokines is low during the early stages of infection, which prevents a timely triggering of Th1 responses. Moreover, LPS has a role in cell entry and immune evasion of the infected cell and is essential for intracellular survival.
Comment on the immune response to Brucellosis. Mention whether it is predominantly humoral- or cell-mediated.
Cell-mediated immunity appears to be the principal mechanism of recovery as well as the mechanism for partial resistance to subsequent reinfection. Antibody response in brucellosis plays a limited part in the overall host response.
the immune response in brucellosis can be classified into three mechanisms. First, IFN-gamma activates the bactericidal function in macrophages to hamper the intracellular survival of Brucella. Then, cytotoxicity of CD8+ and gamma delta T cells destroys the infected macrophages. Finally, Th1-type antibodies opsonize the pathogen to facilitate phagocytosis.
What is the typical histology in Brucellosis?
In humans, Brucella spp infection results in the formation of noncaseating sarcoidosis-like granulomas, consisting of epithelioid cells, polymorphonuclear leukocytes, lymphocytes, and some giant cell.
What is the incubation period of Brucellosis?
The incubation period is usually one to four weeks; occasionally, it may be as long as several months
What is the clinical spectrum of Brucellosis infection?
Brucellosis is a systemic infection with a broad clinical spectrum, ranging from asymptomatic disease to severe and/or fatal illness.
What are the two main presentations of Brucellosis?
The main presentations are acute febrile illness, with or without signs of localization, and chronic infection.
What symptoms can patients with acute brucellosis present with?
Acute illness usually consists of the insidious onset of fever, night sweats (with a strong, peculiar, moldy odor), arthralgias, myalgias, low back pain, and weight loss as well as weakness, fatigue, malaise, headache, dizziness, depression, and anorexia. A significant percentage of patients may have dyspepsia, abdominal pain, and cough.
What signs can patients with acute brucellosis present with?
Physical findings are variable and nonspecific. Hepatomegaly, splenomegaly, and/or lymphadenopathy may be observed. The fever in untreated acute brucellosis can be high or slightly elevated and usually lasts for days to weeks. Irregular undulation has been described. Brucellosis can be a cause of fever of unknown origin.
How common is localized infection in brucellosis?
Focal infection occurs in about 30 percent of cases.
Which organ systems can be affected by brucellosis?
Any organ system.
Which is the organ system most commonly affected by focal brucellosis and how disease manifest there?
Osteoarticular involvement is the most common presentation. The sacroiliac joints and large joints of the lower limbs are most frequently involved. Spondylitis is a serious complication of brucellosis. The lumbar vertebrae are involved more frequently than the thoracic and cervical vertebrae. Paravertebral, epidural, and psoas abscess can occur in the setting of brucellar spondylitis.
Which is the second most commonly affected organ system by focal brucellosis and how does disease manifest there?
Genitourinary involvement occurs in 2 to 20 percent of cases; orchitis and/or epididymitis are the most common manifestations. Less common manifestations include prostatitis, cystitis, interstitial nephritis, glomerulonephritis, and renal, testicular, or tuboovarian abscess.
Briefly outline pulmonary brucellosis.
Pulmonary involvement occurs in up to 7 percent of patients with brucellosis. Bronchitis, interstitial pneumonitis, lobar pneumonia, lung nodules, pleural effusion, hilar lymphadenopathy, empyema, or abscesses may be observed.
