Fever and Rash Fred A. Lopez, MD, FACP Richard Vial Professor and Vice Chair

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Fever and RashFred A. Lopez, MD, FACPRichard
Vial Professor and Vice Chair
Department of Medicine in New Orleans
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He who knows syphilis, knows medicine.--Sir
William Osler, MD

• He/she who knows fever and rash, knows medicine.

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Objectives

• Provide a basic overview of the approach to fever
  and rash
• Review associations between compromised host
  defenses and infectious agents that can cause
  fever and rash
• Highlight several fever and rash emergencies
  (including management) in a case-based format

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Fever and Rash The Basics-Talk the Talk
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FEVER

• One oral recording exceeding 38.3ºC or a
  temperature gt 38 ºC (100.4 ºF) for at least 1 hour

Clin Infect Dis 2002 34730-751.
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Macule Flat, circumscribed, nonpalpable lesion
lt0.5--1 cm diameter
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Papule Raised, circumscribed, palpable lesion
lt0.5--1 cm diameter
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Purpura Macular or papular nonblanching lesion
formed by extravasation of RBCs

• Petechiae--punctate purpuric lesions lt 1 mm in
  diameter
• Ecchymoses--larger purpuric lesions usually
  several centimeters in diameter

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Nodule Deep-seated, roundish lesion lt1.5 cm in
diameter that can involve dermis or subcutaneous
tissue
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Plaque Raised, palpable lesion gt1 cm diameter
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Vesicle Skin blister lt0.5--1 cm in diameter
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Bullae Vesicle gt0.5--1 cm in diameter
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Pustule Pus-filled vesicle
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Ulcer Depressed skin lesion due to loss of
epidermis and upper dermis
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Desquamation Shedding of a layer of skin
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Fever and Rash The Basics

• Features of the rash
• Characteristics of the lesions
• Distribution and progression of the rash
• Timing of the onset in relation to fever

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RMSF Clinical Manifestations

• Incubation period averages 1 week
• ABRUPT onset of flu-like symptoms
• Rash (approx. 5 days after sx begin) gt 90
• Initially maculopapular then petechial
• Begins on ankles/wrists/palms/soles and then
  spreads to trunk
• Abdominal pain (gt50)
• Aseptic meningitis (approx. 30)

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RMSF Treatment

• DOXYCYCLINE unless
• Pregnancy
• Children lt9 yrs of age
• Alternative gt Chloramphenicol
• Treat for 7 days or at least 2 days beyond
  defervescence
• Untreated gt Mortality rate 22

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Fever and Rash Physical Exam/Diagnostic Work-up

• Physical Exam
• Arthritis?
• Desquamation?
• Lymphadenopathy?
• Lung abnormalities?
• Meningeal signs?
• Conjunctival, mucosal, or genital lesions?
• Lab/Work-up
• Glomerular disease? Liver involvement?
• Bone marrow involvement?
• Abnormal CXR?

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Fever, Rash, and Arthritis

• Acute meningococcal infection
• DGI
• Erythema marginatum
• Hepatitis
• Lyme disease

• Parvovirus B19
• Rocky Mountain spotted fever
• Roseola
• Rubella
• Noninfectious diseases

Hurst JW, ed. 3rd edition. 1992274.
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Clinical Vignette

• 80 yo woman admitted with nonspecific complaints
  including weakness, arthralgias
• PE
• Hypertensive
• Skin changes

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Significant Labs

• AST/ALT and serum creatinine mildly elevated
• Urine with 1 gram protein/24 hrs
• RBC casts noted in urine
• Complement levels low
• Cryoglobulins levels present
• Underlying systemic dz ????

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Nephritic disease gt Hematuria, HTN, Proteinuria

• Decreased complement
• SLE
• SBE
• Post-infectious GN (not always Group A strep)
• Membranoproliferative glomerulonephritis
• Cryoglobulinemia
• Immunoglobulins that precipitate in cold
• Clinical triad gt Weakness, arthralgias, palpable
  purpura

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Type II Essential Mixed Cryoglobulinemia

• 87-- 95 of patents with Type II essential mixed
  cryoglobulinemia infected with hepatitis C
• Much less frequently associated with
• Hepatitis B, HIV and Epstein-Barr infections
• Prevalence of cryoglobulinemia gt approximately
  50 percent among patients with chronic hepatitis
  C infection

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Fever and Rash The Basics

• Age of the patient?
• Immunizations and history of childhood illnesses?
• Season of the year?
• Geography/travel history?
• Medications?

Lopez FA, Sanders CV. UpToDate 2011.
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Severe Cutaneous Drug Reactions
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Severe Cutaneous Drug ReactionsStevens-Johnson
Syndrome and Toxic Epidermal Necrolysis

• At least two mucous membranes involved
• Stevens-Johnson syndrome lt10 detachment of
  epidermis
• Toxic epidermal necrolysis gt30 of epidermis
  involved
• Drugs frequently associated (usually 1-3 weeks
  after initiating)
• Sulfonamides/Amoxicillin/Ampicillin
• Non-antibiotics include anticonvulsants NSAIDs
  allopurinol

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Severe Cutaneous Drug ReactionsStevens-Johnson
Syndrome and Toxic Epidermal Necrolysis

• Therapy
• Stop drug
• No well-controlled trials supporting or refuting
  benefits of steroids, IV IgG, cyclophosphamide,
  cyclosporine, hyperbaric oxygen, plasmapheresis,
  GCSF, N-acetylcysteine

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Fever and Rash The Basics

• Exposures including insects, animals, and ill
  contacts?
• Sexual history?
• Predisposition to endocarditis?
• Immune status of the host?
• Cellular immune deficiency
• Neutrophil immune deficiency
• Humoral immune deficiency

Lopez FA, Sanders CV. UpToDate 2003.
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Abnormalities in Cellular- Immunity

• HIV infection
• Hodgkins lymphoma
• Organ transplantation
• Sarcoidosis

• Drugs (corticosteroids, cyclosporine, tacrolimus)
• Last trimester of pregnancy

Adapted from Lopez FA, Sanders CV. Infect Dis
Clin North Am 15(2) 671-702, 2001.
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Abnormalities in Cellular Immunity Pathogens

• Bacteria
• Mycobacteria
• Nocardia
• Salmonella
• Listeria
• Legionella
• Bartonella
• Herpes viruses

• Fungi
• Histoplasma
• Coccidioides
• Blastomyces
• Penicillium
• Cryptococcus
• Aspergillus
• Candida
• Parasites

Adapted from Lopez FA, Sanders CV. Infect Dis
Clin North Am 15(2) 671-702, 2001.
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Clinical Case

• 40 yo man with AIDS gt subjective fever and
  facial skin lesion
• Not taking antiretrovirals, OI prophylaxis
• Lafayette-area no recent travel 7 cats at home

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Workup

• Initial w/u notable for anemia, slightly elevated
  LFTs
• Routine blood cultures No growth
• Skin biopsy obtained

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Histoplasmosis

• Dimorphic fungi
• Bird roosts caves
• Infection results in pulmonary and/or progressive
  disseminated histoplasmosis (PDH)
• PDH seen with cellular immune deficiency and
  extremes of age

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PDH HIV Infection

• Risk factors CD4 lt 150--200 cells/ul exposure
  to chicken coops
• Estimated incidence of 5 in endemic areas
• Fever, malaise, weight loss
• Hepatosplenomegaly, lymphadenopathy, lung
  crackles
• Skin lesions in up to 25 of cases

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HIV Disseminated Histoplasmosis

• Diagnosis
• Clinical suspicion
• Pancytopenia elevated LFTs reticulonodular
  pattern on CXR
• Peripheral blood smear
• Urine (90) serum (70) Histoplasma antigen
• Tissue biopsy
• Fungal blood cultures (gt50)

• Treatment
• If hospitalized, induction with amphotericin B
  followed by itraconazole
• If mild disease, itraconazole

Mortality without treatment 80-100 lt25 with
treatment
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Neutropenia or Neutrophil Dysfunction

• Cytotoxic chemotherapy
• Myeloproliferative/ myelodysplastic syndromes
• Drugs

• Chronic granulomatous disease
• Jobs syndrome
• Connective tissue disorders

Adapted from Lopez FA, Sanders CV. Infect Dis
Clin North Am 15(2) 671-702, 2001.
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Neutropenia or Neutrophil Dysfunction Pathogens

• Bacteria
• Gram-negative bacilli
• Viridans streptococci
• Staphylococci
• Corynebacteria jeikeium
• Clostridium spp
• Bacteroides

• Fungi
• Aspergillus spp
• Candida spp
• Fusarium spp
• Zygomycetes

Adapted from Lopez FA, Sanders CV. Infect Dis
Clin North Am 15(2) 671-702, 2001.
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Ecthyma Gangrenosum

• 2 to 28 of patients with pseudomonal bacteremia
  develop EG
• Macular, nodular, vesiculobullous gt ulcer with
  central necrosis
• Located on perineum, axilla
• Disseminated gtgt Primary
• Can be due to other gram (-) bacilli, fungi

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Ecthyma Gangrenosum

• Diagnosis
• Grams stain, culture of skin biopsy
• Blood culture

• Treatment
• Antimicrobial
• Cytokine
• Surgery

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Abnormalities in Humoral Immunity

• Asplenia
• Nephrotic syndrome
• Non-Hodgkins lymphoma

• Paraproteinemias
• CLL
• Hypogamma-globulinemia

Adapted from Lopez FA, Sanders CV. Infect Dis
Clin North Am 15(2) 671-702, 2001
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Abnormalities in Humoral Immunity Pathogens

• Bacteria
• Streptococcus pneumoniae
• Neisseria meningitidis
• Haemophilus influenzae
• Encapsulated gram(-) bacilli

• Virus
• Enteroviruses
• Parasites
• Giardia lamblia

Adapted from Lopez FA, Sanders CV. Infect Dis
Clin North Am 15(2) 671-702, 2001
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History of Present Illness

• 56 y.o. healthy woman presents with
• Severe headache 4 hours following ingestion of
  boiled crabs beer
• History of MVA with splenectomy 30 yrs earlier

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Immunologic Abnormalities

• Asplenism/Hyposplenism
• Defect in early IgM production
• Defect in opsonin production
• Lower concentration of complement particularly C3
  and factor B
• Decreased ability to clear damaged red cells and
  intraerythrocytic inclusion bodies

Sumaraju V, et al. Infect Dis Clin North Am
152001.
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Initial Evaluation

• Normal physical exam
• CBC
• WBC 9,500 with 65 PMN
• Lumbar puncture CSF
• No abnormalities noted
• U/A (-)
• CXR
• No abnormalities noted

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Hospital Course

• DIC
• ARDS
• Acute renal failure
• Shock liver
• Refractory hypotension

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Impaired Splenic Function

• Splenectomy
• Sickle cell disease
• Hemoglobin SC

• SLE
• RA
• Alcohol-associated liver disease

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Overwhelming Postsplenectomy Infection (OPSI)

• Fulminant infection involving the blood stream,
  lungs, and/or meninges
• Overall incidence gt 0.1--8.5
• gt 50 within two years postsplenectomy
• 50-90 due to S. pneumoniae
• Mortality rates of 45--70

Lynch AM et al. Infect Dis Clin North Am, 1996.
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OPSI

• Diagnosis
• Clinical suspicion
• Peripheral blood/buffy coat smears
• Gram-stain / culture of skin lesions
• Blood cultures
• CSF

• Treatment
• Early initiation of antimicrobials
• Supportive care
• Other modalities
• Recombinant Activated Protein C

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OPSI Prevention

• Education
• Antibiotic prophylaxis?
• Immunization
• S. pneumoniae
• N. meningitidis
• H. influenzae B

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CDC. MMWR. 2010Vol 59 No. 34 1102-1106.
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Overwhelming Post-Splenectomy Infection (OPSI)

• Passive surveillance data on 77 cases of OPSI in
  England from 1994-1998
• Overall mortality gt 50
• 90 due to S. pneumoniae
• 24 received chemoprophylaxis
• 31 received prior pneumococcal vaccination

Waghorn DJ. J Clin Pathol 2001 54214-218.
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Diabetes Mellitus Immune Dysfunction

• Humoral immune system appears normal
• Cell-mediated immune defects
• Decreased lymphocyte responses to antigens
  including Staphylococcus aureus
• Polymorphonuclear leukocyte function abnormal
• Chemotaxis, phagocytosis, intracellular killing

Calvet HM et al. Infect Dis Clin North Am, 15
(2) 2001.
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Immunologic Abnormalities

• Cirrhosis
• Impaired reticuloendothelial system
• Complement Defects
• Neutrophil Defects
• T and B lymphocyte defects
• Immunoglobulin defects
• Macrophage defects

Johnson DH, Cunha BA. Infect Dis Clin North Am
15363, 2001.
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CASE

• 43 yo man with PMHx of cirrhosis secondary to
  chronic hepatitis B and C/ethanol
• Chief complaint of left lower extremity pain,
  redness around ankle, fever and chills
• No history of recent trauma, insect bites, or
  wading in water
• Had been given oral cephalosporin for skin
  infection earlier that day
• BP 99/45 P 100 T 37.4º C
• Labs Leukocytosis with bandemia ? platelets

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Vibrio vulnificus
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Primary Septicemia

• Almost 90 males
• Associated with food-borne illness 24 to 96 hrs
  after ingestion
• Undercooked shellfish particularly oysters
• Sudden onset of fever and chills (90)
• Abdominal pain, nausea/vomiting (70)
• Skin lesions--cellulitis, bullae, ecchymoses
  (75)
• Hypotension (35) portends poor prognosis
• Bacteremia 100 Mortality rate gt50

Koenig KL et al. West J Med 991.
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Diagnosis

• Clinical suspicion important
• Shellfish ingestion?
• Water exposure?
• Host risk factors particularly liver failure
• Organism isolated from skin lesions gt 20-50 of
  cases
• Blood cultures
• Almost always () in septicemia

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Treatment

• Aggressive wound care and surgery
• Tetracycline aminoglycoside or 3rd generation
  cephalosporin
• Quinolones effective in vitro

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Summary Fever and Rash

• Be systematic
• Understanding associations between compromised
  host defenses and certain infectious agents is
  important in the diagnostic and therapeutic
  approach to the patient
• Be aggressive in obtaining additional clues as
  clinical course evolves