Infectious Diseases Conference

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Infectious Diseases Conference

• Charles de Comarmond MD
• June 9th 2003

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History of present illness

• 62 yr old transferred to BMC on 5/30/03 with
  altered mental state
• Was in her usual state of health until 2 weeks
  PTA when she developed fever of 103F, nausea,
  vomiting and whole body rash.
• Was admitted to OSH 5/27/03. CXR demonstrated
  cardiomegaly and normal lungs. Abdominal imaging
  demonstrated hepatomegaly and kidney cysts.

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History of present illness

• Started empirically on Cefotaxime
• Continued to have fever and Erythromycin was
  added
• Continued to have fever and Metronidazole was
  added
• Continued to deteriorate with progression of
  rash, persistent fevers, shortness of breath and
  worsening mental status

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Hospital course

• Transferred to BMC 5/30/03
• CT head unremarkable
• Lumbar puncture performed
• Started on acyclovir, ampicillin, ceftriaxone,
  vancomycin and doxycycline

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Hospital course

• Develops hypoxia
• Continued worsening mental status
• CXR and MRI head ordered

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Hospital course

• MRI of head done

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Past medical history

• DM
• HTN
• Seizure disorder
• IBS
• Diverticulitis
• GERD
• PUD
• COPD
• DJD

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family social history

• Patient is retired
• No recent travel outside of North Carolina
• Smoker
• Family history, ROS otherwise unremarkable

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Physical examination
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Physical examination

• APPEARANCE Obtunded
• HEENT Marked nuchal rigidity
• CHEST Clear
• CVS S1S2 normal, tachycardic
• ABDOMEN Soft, hepatomegaly
• EXTREMITIES No edema
• NEURO Obtunded, no obvious focal deficits

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Physical examination

• SKIN Diffuse maculopapular exanthem
  involving palm and soles. No mucosal
  involvement.

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Labs
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Labs
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LABS

• HSV CX (LIP BLISTER) HSV1
• ENTEROVIRAL PCR NEG
• RPR NEG
• HIV SEROLOGY NEG
• ARBOVIRAL PANEL PENDING
• MENINGOENCEPHALITIS PANEL PENDING

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Labs

• RMSF LATEX 512

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Rocky mountain spotted fever
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Introduction

• RMSF was first described in 1896 by Woods in
  Idaho.
• Ricketts established the infectious nature of the
  illness and demonstrated the role of ticks as the
  vector in western Montana in 1906.
• Wolbach in 1919 clearly identified the etiologic
  rickettsiae within endothelial cells.

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Pathogen
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Pathogen

• Rickettsiae are obligately intracellular bacteria
  that reside in the cytosol and less often in the
  nucleus of their host cells. The rickettsiae
  measure approximately 0.3 by 1 µm.
• They have one of the smallest bacterial genomes,
  ranging between 1.1 and 1.6 MB.
• The cell wall has the ultrastructural appearance
  of a gram-negative bacterium and contains
  peptidoglycan and lipopolysaccharide

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Pathogen

• Rickettsiae are difficult to stain with ordinary
  bacterial stains but stain by the Gimenez method
  or with acridine orange.
• They have not been cultivated in cell-free medium
• Growth requires living host cells such as the
  yolk sac of embryonated eggs, experimental
  animals, or cell culture (Vero cells and L
  cells).
• Rickettsiae are not a defective or degenerate
  life form but rather are highly adapted for
  intracellular survival with effective transport
  systems and metabolic enzymes

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Gimenez stain of Rickettsia in endolymph cells
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Pathogen

• The major protein antigens of R. rickettsii are
  two surface proteins
• Outer membrane proteins A OmpA, 190 kD and B
  OmpB, 135 kD) contain heat-labile epitopes
• Some are species-specific, forming the antigenic
  basis for serotyping, and others are shared among
  varied numbers of the members of the group

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Vectors

• The seasonal distribution of RMSF parallels tick
  activity.
• The tick is both the vector and the main
  reservoir.

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Vectors

• Dermacentor variabilis, the American dog tick, is
  the prevalent vector in the eastern two thirds of
  the United States and the Far West

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Vectors

• Dermacentor andersoni, the Rocky Mountain wood
  tick, in the western states

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Vectors

• Rhipicephalus sanguineus, in Mexico
• Amblyomma cajennense, in Central and South
  America

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Vectors

• Causes of the variation in infection rates among
  populations of ticks are not clear
• humidity
• climatic variations,
• human activities altering the vegetation and
  fauna
• use of insecticides

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Vector

• Rickettsia rickettsii is transmitted
  trans-stadially (stage to stage) and
  transovarially in ticks, thus maintaining the
  agent in nature
• The likelihood of low-level attrition of the
  infected ticks due to injury by pathogenic
  rickettsiae most likely explains the very low
  prevalence of these rickettsiae in ticks
• In most mammals rickettsemia is of very short
  duration and low titer and allows infection of
  only a small proportion of ticks

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Epidemiology

• Many rickettsiae of unknown pathogenicity have
  been isolated and characterized in the United
  States
• Rickettsia bellii,
• Rickettsia montana,
• Rickettsia rhipicephali,
• Rickettsia parkeri
• These and the uncultivated Rickettsia peacockii
  may compete for the ecologic niche by an
  interference mechanism that inhibits the
  establishment of infection of ticks with R.
  rickettsii

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Epidemiology

• The tick transmits the disease to humans during a
  prolonged period of feeding that may last for 1
  to 2 weeks.
• The bite is painless and frequently unnoticed.
• After the attached tick has fed for 6 to 10
  hours, rickettsiae begin to be injected from the
  salivary glands.
• Humans may also be infected by exposure to
  infective tick hemolymph during the removal of
  ticks from persons or domestic animals,
  especially when the tick is crushed between the
  fingers.

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Epidemiology

• The considerable fluctuation in the annual number
  of patients with RMSF in the United States may
  reflect cyclic changes in the ecology of the
  tick-rickettsia relationship.

CDC. Rocky Mountain spotted fever and human
ehrlichiosis--United States, 1989. MMWR Morb
Mortal Wkly Rep. 199039281-284.
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Epidemiology

• The increase in the infection rate that occurred
  between 1969 and 1977 may have several hypothetic
  explanations an increase in the infected tick
  population or tick contact with humans, an
  increase in the interest of physicians in the
  disease, and the development of more sensitive,
  specific serologic tools.
• The fall in incidence in 1949 followed the
  introduction of effective antibiotics
• The increased incidence in the 1970s coincided
  with a decline in the use of tetracycline as a
  first-choice antibiotic for many other
  infections.
• These correlations imply a substantial occurrence
  of undiagnosed cases aborted by early treatment.

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Epidemiology

• The local prevalence in highly endemic areas such
  as North Carolina has been as high 14.59 per
  100,000
• Moreover, although the incidence of infection may
  be decreasing in one area, it may be increasing
  simultaneously in another region
• Most cases are diagnosed during late spring and
  summer with 92occuring between April-September
  and 43 between May-June
• In the southern states, a few cases also occur
  during the winter

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RMSF distribution 1994-1998
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Distribution, rates 1993-1996
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Epidemiology

• In the southern states, the incidence is highest
  among children and persons who are known to be
  exposed more often to ticks than are matched
  controls
• In the western states, owing to transmission by
  the wood tick D. andersoni, a higher proportion
  of men contract the disease because of
  occupational factors.
• The case-fatality rates are significantly higher
  for nonwhites than for whites, for males than for
  females, and for patients older than 30 years
  than for persons younger than 30.

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Epidemiology
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Epidemiology
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Pathogenesis

• Rickettsia attach to and induce their
  phagocytosis by their target cells, the vascular
  endothelium, to establish numerous disseminated
  foci of infection
• After entry by induced phagocytosis, the
  rickettsiae escape rapidly from the phagosome
  into the cytosol and less frequently invade the
  nucleus.
• Rickettsiae proliferate intracellularly by binary
  fission and are released from the infected cells
  via long thin cell projections either
  extracellularly or into the adjoining cell.

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Pathogenesis

• The movement of spotted fever rickettsiae in the
  cytoplasm and into these projections from which
  they are released is caused by propulsion by the
  host cell's actin filaments.
• The consequence of cell-to-cell spread in the
  body is a focal network of hundreds of contiguous
  infected endothelial cells corresponding to the
  lesions

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Pathogenesis

• High quantities of rickettsiae infecting the
  pulmonary microcirculation increase the vascular
  permeability and cause noncardiogenic pulmonary
  edema.
• Vascular injury and the subsequent host
  lymphohistiocytic response correspond to the
  distribution of rickettsiae and include
  interstitial pneumonia, interstitial myocarditis,
  perivascular glial nodules of the central nervous
  system, and similar vascular lesions in the skin,
  gastrointestinal tract, pancreas, liver, skeletal
  muscles, and kidneys

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Pathogenesis
Endothelial injury
Vasculitis in spinal tissue
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Pathogenesis

• However, even severe vascular injury rarely leads
  to clinically significant hemorrhage
• Platelets are consumed locally in numerous foci
  of infection
• Thrombocytopenia is observed in 32 to 52 of
  patients
• DIC occurs only rarely, and occlusive vascular
  thrombosis is not the basic pathophysiologic
  event

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Clinical Manifestations

• The incubation period of RMSF ranges from 2 to 14
  days, with a median of 7 days
• Variation in the incubation time may be related
  in part to the inoculum size.
• The disease usually begins with fever, myalgia,
  and headache, most likely the effects of
  proinflammatory cytokines

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Clinical Manifestations

• The temperature is greater than 102F in 63 of
  patients during the first 3 days and in 90
  later.
• Other signs and symptoms are frequently prominent
  early in the course before the onset of rash
• Gastrointestinal involvement with nausea,
  vomiting, abdominal pain, diarrhea, and abdominal
  tenderness occurs in substantial portions of
  patients and may suggest gastroenteritis or an
  acute surgical abdomen.

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Skin

• The rash, the major diagnostic sign, appears in a
  small fraction of patients on the first day of
  the disease and in only 49 during the first 3
  days
• Usually appears 3 to 5 days after the onset of
  fever and occurring in 84 to 91, of patients
  overall

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Skin

• Rocky Mountain "spotless" fever occurs more often
  in older patients and in black patients
• The rash typically begins around the wrists and
  ankles but may start on the trunk or be diffuse
  at the onset.
• The rash is usually macular and blanching at the
  onset and only becoming petechial later

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Skin

• Involvement of the palms and soles is considered
  characteristic yet occurs in only 36 to 82 of
  patients
• Skin necrosis or gangrene develops in only 4 of
  patients as a result of rickettsial damage to the
  microcirculation
• Gangrene affects the digits or limbs and
  occasionally necessitates amputation.
• A careful examination seldom reveals an eschar at
  the site of the tick bite in RMSF

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Early blanching macules
Early blanching macules
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Necrotic star shaped necrotic papules
Purpura fulminans-like lesions
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Neurologic

• Headache is usually quite severe
• Focal neurologic deficits, transient deafness,
  meningismus, and photophobia may suggest
  meningitis or meningoencephalitis.
• Lymphocytic or polymorphonuclear pleocytosis and
  elevation of CSF protein is seen in one third of
  cases
• Low CSF glucose concentration is seen in only 8
  of patients

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Ophthalmologic

• On funduscopic examination, retinal vein
  engorgement, arterial occlusion, flame
  hemorrhages, and papilledema without increased
  cerebrospinal fluid pressure have been noted
• These changes may reflect retinal vasculitis with
  increased permeability and focal thrombosis.

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Renal

• Renal failure is an important problem in severe
  RMSF
• Prerenal azotemia related to hypovolemia responds
  to intravenous hydration
• Acute tubular necrosis may require hemodialysis.

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Pulmonary

• Pulmonary involvement is suggested by cough and
  radiologic evidence of changes including alveolar
  infiltrates, interstitial pneumonia, and pleural
  effusion
• Pulmonary edema with impairment of pulmonary
  function or adult respiratory distress syndrome
  may require oxygen therapy and ventilatory
  assistance

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Cardiac

• Echocardiographic studies reveal minimal
  myocardial dysfunction
• Normal pulmonary capillary wedge pressure
  measurements document the noncardiogenic nature
  of the pulmonary edema

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Clinical Manifestations

• In classic RMSF, death occurs 8 to 15 days after
  the onset of symptoms when appropriate therapy is
  not given in a timely manner
• In fulminant RMSF, death occurs within the first
  5 days
• Several features account for the extreme
  difficulty in the diagnosis of fulminant RMSF
• the course is rapid
• the rash develops shortly before death if at all
• antibodies to R. rickettsii do not have time to
  develop
• pathologic lesions even appear different,
  containing more thrombi and lacking the
  characteristic lymphohistiocytic component

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Clinical Manifestations

• Characteristic laboratory data may support the
  clinical diagnosis of classic RMSF but are
  relatively nonspecific
• The white blood cell count is generally normal,
  but increased quantities of immature myeloid
  cells occur frequently
• Anemia is observed in 5 to 30
• Thrombocytopenia is seen in 32 to 52 of patients
  
• Coagulopathy with prolonged coagulation times and
  decreased concentrations of fibrinogen and other
  clotting factors occurs infrequently

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Clinical Manifestations

• The prognosis in RMSF is largely related to the
  timeliness of initiation of appropriate therapy
• The intervals between the onset of disease and
  the appearance of the rash, clinical diagnosis,
  and effective antibiotic treatment are
  significantly longer in patients dying than in
  patients surviving

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Diagnosis

• The diagnosis of RMSF before the onset of the
  rash is clinical and epidemiologic.
• The differential diagnosis at the first
  consultation includes
• typhoid fever
• measles
• rubella
• respiratory tract infection
• gastroenteritis
• acute surgical abdomen
• enteroviral infection
• meningococcemia
• disseminated gonococcal infection
• secondary syphilis
• leptospirosis
• immune complex vasculitis
• idiopathic thrombocytopenic purpura
• thrombotic thrombocytopenic purpura
• infectious mononucleosis
• drug reaction
• rickettsial diseases.

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Diagnosis

• R. rickettsii can demonstrated in cutaneous
  biopsy specimens by immunohisto-chemical
  analysis.
• Sensitivity 70-90, specificity 100

Rickettsia stained red by immunoperoxidase stain
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IFA stain for Rickettsia
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Diagnosis

• Serologic examination is retrospective, serum
  antibodies becoming detectable during
  convalescence
• Seroconversion occurs approximately 7-10 days
  after onset of symptoms
• Serologic examination does not allow
  discrimination of the particular causative SFG
  rickettsia unless cross-absorption with selected
  antigens is performed

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Diagnosis

• Antibodies to specific rickettsial antigens are
  detected by indirect immunofluorescence, latex
  agglutination, and enzyme immunoassay.
• The diagnostic titer is 164 for indirect
  immunofluorescence and latex agglutination.
• IFA has a sensitivity of 94

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Diagnosis
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Treatment

• Since the introduction of chloramphenicol and the
  tetracyclines, including doxycycline, the
  lethality of the disease has decreased
  dramatically, but mortality remains significant
  at 5
• In vitro and in ovo, R. rickettsii is susceptible
  not only to chloramphenicol and tetracycline, but
  also to rifampin

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Treatment

• Some new quinolone compounds such as
  ciprofloxacin and the clarithromycin have
  antirickettsial effects in vitro
• Erythromycin has a minimal inhibitory
  concentration of 3 to 8 mug/ml and is not
  effective
• Doxycycline, 100 mg every 12 hours is the drug of
  choice

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Treatment

• Treatment should be given intravenously in
  patients with nausea and vomiting and in those
  seriously ill
• Chloramphenicol is preferred during pregnancy
  because of the effects of tetracycline on fetal
  bones and teeth
• It is recommended that doxycycline be used for
  suspected RMSF in children of all ages because of
  the life-threatening nature of RMSF and the
  unlikelihood that a single course of doxycycline
  would stain the teeth.

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Prevention and Control

• Limiting exposure to ticks is the most effective
  way to reduce the likelihood of Rocky Mountain
  spotted fever infection.
• In persons exposed to tick-infested habitats,
  prompt careful inspection and removal of crawling
  or attached ticks is an important method of
  preventing disease.

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Prevention and Control

• Light-colored clothing should be worn to allow
  ticks that are crawling on clothing to be seen.
• Pants legs should be tucked into socks so that
  ticks cannot crawl up the inside of pants legs.
• Apply repellants to discourage tick attachment.
  Repellents containing permethrin can be sprayed
  on boots and clothing, and will last for several
  days.

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Prevention and Control

• Repellents containing DEET can be applied to the
  skin, but will last only a few hours before
  reapplication is necessary.
• Conduct a body check upon return from potentially
  tick-infested areas by searching the entire body
  for ticks.
• Parents should check their children for ticks,
  especially in the hair, when returning from
  potentially tick-infested areas. 
• Ticks may be carried into the household on
  clothing and pets.  Both should be examined
  carefully.

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Prevention and Control

• To remove attached ticks, use the following
  procedure
• Use fine-tipped tweezers or shield your fingers
  with a tissue, paper towel, or rubber gloves,
  removing ticks with bare hands should be
  avoided. 
• Grasp the tick as close to the skin surface as
  possible and pull upward with steady, even
  pressure
• Do not twist or jerk the tick this may cause the
  mouthparts to break off and remain in the skin. 

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Prevention and Control

• Do not squeeze, crush, or puncture the body of
  the tick because its fluids (saliva, body fluids,
  gut contents) may contain infectious organisms.
• After removing the tick, thoroughly disinfect the
  bite site and wash your hands with soap and
  water.
• Save the tick for identification in case you
  become ill. Place the tick in a plastic bag and
  put it in your freezer. Write the date of the
  bite on a piece of paper with a pencil and place
  it in the bag.

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Summary pitfalls

• Waiting for a petechial rash on the palms and
  soles before making a diagnosis
• Patients usually present on day 2 or 3, the rash
  usually appears on day 3 or 4.
• The rash generally begins as a macular or
  maculopapular eruption on the wrists or ankles
  that only later involves the palms and soles and
  becomes petechial. Some patients have no rash or
  a very subtle or focal rash

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Summary pitfalls

• Misdiagnosing gastroenteritis
• Nausea and vomiting early in the illness occur in
  more than 50 of patients with RMSF
• Gastrointestinal symptoms can also be a prominent
  early feature of other tick-vectored illnesses,
  such as the ehrlichioses

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Summary pitfalls

• No history of a tick bite
• Approximately 40 of patients with RMSF do not
  report an antecedent tick bite.
• In this context, absence of tick bite should
  never dissuade a clinician from considering RMSF.
  

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Summary pitfalls

• Geographic exclusion
• Rocky Mountain spotted fever has been reported in
  46 states
• It is more common in the lower midwestern and
  southeastern states, but it does occur elsewhere
  and should be considered endemic in the
  contiguous United States

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Summary pitfalls

• Seasonal exclusion
• Although 90 of cases occur during April through
  September, one needs to have an index of
  suspicion all year
• Confirmed cases have been reported during every
  calendar month
• Wintertime cases are more likely to occur in the
  southern states

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Summary pitfalls

• Failure to treat early on clinical suspicion
• Dependent on the patient's age, untreated RMSF
  has a 10 to 25 case-fatality ratio
• Delayed treatment after day 5 is associated with
  a significantly higher morbidity and mortality
• Fifty percent of all deaths occur on or before
  day 8

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Summary pitfalls

• Failure to elicit appropriate history
• The nonspecific signs and symptoms of early RMSF,
  coupled with a general lack of awareness of this
  disease, conspire to make RMSF an elusive initial
  diagnosis
• A good history that elicits exposure to ticks or
  tick-infested habitats or concurrent illness in
  household pets or in similarly exposed family
  members can be extremely helpful to establish a
  presumptive diagnosis.

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Summary pitfalls

• Failure to treat children with doxycycline
• Doxycycline therapy is recommended by the
  American Academy of Pediatrics and by CDC as the
  treatment of choice for all rickettsial diseases,
  including RMSF and the ehrlichioses, in children
  of all ages
• It has the best outcome, and the risk of
  cosmetically perceptible tooth staining appears
  to be insignificant for a single course of
  treatment.