1. Dept. Infection Disease
Pediatrics
FEVER and RASH
Yinghu Chen
Dept. Infection Disease

2. Rash and infections
Rashes are a common manifestation of many infections.
Skin lesions provide important clues to the diagnosis
Macular or Maculopapular Rash
Diffuse Erythroderma
Urticarial Rash
Vesicular, Bullous, Pustular
Petechial-Purpuric
Erythema Nodosum

3. Differential Diagnosis of Fever and Rash
Macular or Maculopapular Rash -- virus
Measles
Rubella
Roseola (HHV-6 or HHV-7)
Varicella-Zoster virus (VZV)

4. Differential Diagnosis of Fever and Rash
Macular or Maculopapular Rash--bacteria
Scarlet fever (group A streptococcus)
Others: Secondary syphilis, Leptospirosis, 
Pseudomonas, Meningococcal infection (early), Salmonella typhi (typhoid fever), Lyme disease (erythema migrans), Mycoplasma pneumoniae

5. Measles

6. Outline Etiology Epidemiology Pathogenesis Clinical manifestations
Lab findings
Treatment
Complications
Preventions

7. Introduction Historically widespread but now very rare
Characterized by fever, coryza, cough, Koplik’s spots, and maculopapular rash

8. Etiology
Measles virus, a single-stranded RNA paramyxovirus with one serum type. Humans are the only natural host
Found in nasopharyngeal secretions, blood and urine, during the prodromal period and for a short time after the rash appears
Remain active for 1-2 days at room temperature

9. Epidemiology Spread throughout the world, vaccine-preventable disease
For susceptible persons, 90% of the exposed acquire disease
Infection sources: patients and person with latent infection
Contagious period: 5 days before and after the rash appearance, accompanied with pneumonia, prolonging to 10th day
Transmission: airborne and contact
Season: spring, Age: 5-10yr
New trends: measles appears in <8m infants and elders, due to inadequate vaccination as well as vaccine failure

10. Pathogenesis Process of virus in the body (two times of viremia)
Invade airway endothelial cells, portal lymph node, and multiply (warthin-Finkeldey giant cell)
Some invade to blood
Captured by Monocyte - macrophage system, and replicates greatly,
Invade blood second time, cause disseminated lesions, some target T cells
The host immunity decrease, induce secondary bacterial infection and TB reactivation
Endothelial cells
Dendritic cell
T cells

11. Pathogenesis Process of virus in the body Clinical stage
Virus inhalation
Incubation
Local proliferation
First viremia
Proliferation in endoreticular system
Second viremia
Prodromal
All parts of the body
Eruption
Clearance of virus
Convalescence

12. Clinical manifestaions
Persons with typical symptoms
immunocompetent children who didn’t receive measles vaccine, or vaccine failure, and didn’t receive immunoglobulin
Four stages
Incubation stage: 6-12d, may transmit virus by 9-10th day
Prodromal stage: 3-5d, fever, cough, coryza, Koplik spots
Rash stage: rash erupts for 2-3d , and fades
Recovery stage

13. Prodromal stage
Last 3-5d, low-grade to moderate fever, dry cough, coryza, and conjunctivitis, photophobia, Koplik spots.

14. Koplik spots and Stimson line
Koplik spots: 1-2d before rash, grayish white dots, as small as grains, opposite the lower molars, may spread over the buccal mucosa, last 12-24hr

15. Rash stage
Temperature rises abruptly as the rash appears and often reaches 40℃ or higher
The rash appears and fade downward sequence: stars (faint macules) on the upper lateral part of neck, behind the ears, along the hairline, cheek, spreads to entire face (maculopapular), neck, upper arms, chest back, abdomen, entire arm, thighs, and finally reach feet on the 2nd-3rd day
In uncomplicated cases, as the rash appears on the legs and feet, the patients may appear desperately ill, but the symptoms subside within 2d
Branny desquamation within 7-10d

16. Black measles Hemorrhagic type of measles Rash is confluent, petechiae
Bleeding may occur from mouth, nose, or bowel, thrombocytopenia
Occurs in immunocompromised or secondly infection patients
Rash is confluent, petechiae
Often accompanied with pneumonia, heart failure, disseminated intravascular coagulation (DIC), high mortality

17. Mild measles Mild cases
Occurs in person with partial protection against measles, such as vaccine, immuoglobulin

18. Atypical measles Partial protection against measles, such as vaccine.
Fever 2-3 days, appearance of the rash.
The eruption order: the distal limbs, trunk and face.
Mild case.

19. Laboratory findings Cytopathic change Antigen: in nasal mucosa PCR
Warthin-Finkeldey cells: consist of multinucleated giant cells with intranuclear inclusions
Antigen: in nasal mucosa
PCR
Virus isolation
Antibodies
IgM and IgG become detectable when the rash appears
Leucocytopenia with a relative lymphocytosis

20. Chest radiograph
May show interstitial or perihilar infiltrates, but do not distinguish measles pneumonia and bacterial superinfection.

21. Diagnosis Contact history Characteristic clinical picture
Laboratory confirmation is rarely needed

22. Differential diagnosis
All kind of fever with red rashes
Such as: Rubella, roseola, scarlet fever, meningococcemia, drug fever, Kawasaki disease, serum sickness, infectious mononucleosis, toxoplasmosis, etc

23. Differential diagnosis
Enteroviral and adenoviral infections, rubella: The rashes are less striking without desquamation
Roseola infantum: the rash appears as fever disappears
Serum illness and drug fever: The absence of administration of a drug history

24. Red rash in bacterium infection
Acute meningococcemia
The rash is petechial, and purpuric without cough and conjunctivitis
Streptococcal scarlet fever
The diffuse, finely papular rash has a “goose flesh” texture, “sandpaper” texture, strawberry tongue, red pharynx. Perioral and periorbital area, palm, and soles have no rash. Rash desquamates after 7-14d
Staphylococcal scarlet fever
Resembles streptococcal scarlet fever
Except strawberry tongue, pharynx, and focal infection usually presents

25. Treatment No specific antiviral therapy
Supportive treatment: antipyratic, bed rest, fluid intake, avoiding exposure to strong lights
Vitamin A: 7-12m infant: 100,000IU, ≥1y: 200,000IU, reduce the morbidity and mortality
Complications such as encephalitis, giant cell pneumonia, DIC must be assessed individually
Secondary infection requires antimicrobial therapy
Immune globulin and corticosteroids has limited value

26. Vitamin A and measles: evidence
Hyporetinemia is present in over 90% of measles cases in Africa and 22-70% in USA.
There is an apparent inverse correlation between retinol concentration and the severity of measles.
Oral Vitamin A supplement reduces the morbidity and mortality of severe cases.

27. Indication for Vit A supplement (American Academy of Pediatrics)
Hospitalized children 6mo~2yr of ages
Children >6mo with
immunodeficiency
ophthalmologic evidence of Vit A deficiency
impaired intestinal absorption
moderate to severe malnutrition
recent immigration from areas with a high mortality from measles

28. Complication Pneumonia Reactivation of TB infection, and anergy to PPD
Interstitial pneumonia: may be caused by measles virus (giant cell pneumonia), measles pneumonia in HIV-infected patients is often fatal.
However, bacterial superinfection and bronchopneumonia is more frequent
Reactivation of TB infection, and anergy to PPD
Myocarditis
An infrequent serious complication, varies from transient electrocardiographic changes to heart failure, and cardiogenic shock

29. Complication in nervous system
Eary encephalitis
1-2/1000 cases, occur from prodromal period to final stage
Late encephalitis
Demyelinization, probably an immunopathologic phenomenon.
Subacute sclerosing panencephalitis (SSPE)
A chronic encephalitis caused by persistant measles virus infection of the central nervous system, occur 8-10yr after measles
Insidiously onset, subtle changes in behavior, and deterioration of schoolwork, and finally dementia.
1/1,000,000 measle

30. Prognosis
Deaths: bronchopneumonia or encephalitis(15%), with malignancy or HIV infection
SSPE

31. Prevent Attenuate live measle vaccine Contraindications:
Two times(8m, 4-6yr), not booster, but intensive immunization
Contraindications:
Immunocompromised states, pregnancy or recent administration of IVIg

32. Postexposure prophylaxis
Vaccine within 72 hr (produce antibody within 7-12d)
Immune globulin within 6d

33. Typical temperature curve of measles and the effectiveness of passive immunization

34. Take home points Koplik spots Feature of measles maculopapular rash
Differential diagnosis of red rash
Complications
Post exposure prophylaxis

35. Rubella

36. Rubella also known as German measles and 3-day measles;
congenital rubella syndrome (infection in utero )

37. Etiology and epidemiology
a single-stranded, positive-sense RNA virus, togavirus family, one serum type.
Humans as the only host
Spread either by oral droplet or transplacentally to fetus causing congenital infection
Contagious period: 5 days before until 7 days after onset of the rash.
Peak incidence in children 1~5 yr of age

38. Clinical manifestations
Incubation stage (14 to 21 d)
Prodromal stage (1-2d)
Mild catarrhal symptoms with shorter period
Low-grade fever (1~3d) with mild systemic symptoms.
About 2/3 are subclinical.
Eruption stage

39. Eruption stage The most characteristic sign：
Enlarged post-occipital, retroauricular and posterior cervical lymph nodes accompanied by a maculopapular, discrete rash.
The rash begins after 1-2d of fever, on the face and spreads to the body in 1d and lasts for 3 days.

41. Congenital rubella (syndrome)
Affects virtually all organ systems
The common manifestation is: intrauterine growth retardation
Never system: microcephaly, deafness
Eye: microphthalmia, cataracts, glaucoma, chorioretinitis
Blood system: anemia, thrombocytopenia, leukopenia,
Skin and others: blueberry muffin rash, hepatosplenomegaly, jaundice, PDA
B cell and T cell deficiency infant may be asymptomatic at birth.

42. Diagnosis Apparent diagnosis based on clinical symptoms and signs
Laboratory findings non-specific and generally do not aid in diagnosis
Confirmed by serology or virus culture
Congenital rubella: serum IgM or virus culture
Prenatal diagnosis: cord blood IgM or virus culture from amniotic fluid

43. Treatment and prognosis
There is no specific antiviral therapy
Entirely supportive, and antipyretics
The prognosis is excellent, but congenital rubella syndrome may have sequalae such as intrauterine growth retardation, cataracts, deafness, and PDA.

44. Prevention
Live rubella vaccine recommended as MMR for children( initial at 12-15m and second 4-6y)
It is important for girls to have immunity before they reach childbearing age.

45. Roseola infantum

46. Etiology Human herpesvirus (HHV) type 6 (HHV-6), HHV-7.
Large, enveloped double-stranded DNA viruses, members of the herpesvirus family.
Infect mature mononuclear cells and cause a relatively prolonged (3 to 5 days) viremia during primary infection.
Be detected in the saliva of healthy adults, which suggests, the development of lifelong latent infection and intermittent shedding of virus.

47. Epidemiology
Transplacental antibody protects most infants until 6 months of age.
Primary HHV-6 infection occurs early in life with peak acquisition from 6-15 months of age.
By 12 months of age, approximately 60% to 90% of children have antibodies to HHV-6, and essentially all children are seropositive by 2 to 3 years of age.
The virus is likely acquired from asymptomatic adults who periodically shed these viruses..
HHV-6 and HHV-7 can cause encephalitis in immunocompromised persons.
HHV-6 can be transmitted in utero.

48. Cinical manifestations
Incubation period: 5-10d
Prodromal period:
Usually asymptomatic
Mild URT signs
Mild cervical lymphadenopathy

49. Cinical manifestations
Clinical illness heralded by high fever
37.9~40.0 with an average of 39℃
Persists for 3-5 days and then resolves rather abruptly. Occasionally fever diminish over 24-36h gradually.
May be irritable and anorexia but most behave normally
Seizures in 5~10%. Roseola is associated with approximately one third of febrile seizures.
Infrequent : rhinorrhea, sore throat, abdominal pain, vomiting and diarrhea.

50. Cinical manifestations
Eruption and fever
A rash appears within 12~24 hours of fever resolution
Eruption during defervescence or within a few hours of fever resolution

51. Cinical manifestations
Characteristic rash
Rose colored rash ( discrete, small (2~5mm),slightly raised pink lesions)
appears trunk , neck, behind ears, face and proximal extremities
No pruritic, no vesicles
Fade in 1~3 days
Reactivation of HHV-6 may cause bone marrow suppression after bone marrow transplantation

53. Treatment and prevention
There is no specific therapy
HHV-6 is inhibited by ganciclovir but the benign nature preclude consideration of antiviral therapy.
Excellent prognosis in majority
no guidelines for prevention of roseola.

54. Varicella

55. Etiology
Varicella-zoster virus (VZV): an enveloped, double-stranded DNA virus that is a member of the herpesvirus family.
Humans are the only natural host.
Chickenpox (varicella) is the manifestation of primary infection of varicella-zoster virus (VZV).
Zoster (shingles) is the manifestation of reactivated latent infection of endogenous VZV.

56. Epidemiology Spread throughout the world, vaccine-preventable disease
For susceptible persons, 90% of the exposed acquire disease
Infection sources: patients and person with latent infection
Contagious period: 2 days before to 7 days after the onset of the rash
Transmission: droplet, air, direct contact.
Incidence of Zost:
Approximately 10% to 20% of chickenpox
Only 5% of cases of zoster occur in children <15 years old
75% of cases occurring after 45 years of age.
The incidence of zoster is increased among immunocompromised persons.

57. Pathogenesis Process of virus in the body (two times of viremia)
VZV infects individuals via the conjunctivae or respiratory tract and replicates in the nasopharynx and upper respiratory tract.
It disseminates by a primary viremia and infects regional lymph nodes, the liver, the spleen, and other organs.
A secondary viremia follows, resulting in a cutaneous infection with the typical vesicular rash.
After resolution of chickenpox, the virus persists in latent infection in the dorsal root ganglia cells.

58. Clinical manifestation
Incubation period: 10~21d
Subclinical varicella is rare
Prodromal symptoms
Usually moderate fever
malaise, headache, anorexia and occasionally mild abdominal pain
precede the rash by 24~48h

60. Clinical manifestation
The characteristic rash
initially as small red papules
rapidly progress to nonumbilicated, oval, "teardrop" vesicles on an erythematous base.
The fluid progresses from clear to cloudy, and the vesicles ulcerate, crust, and heal.
New crops appear for 3 to 4 days, usually beginning on the trunk followed by the head, the face, and, less commonly, the extremities.

61. Clinical manifestation
Pruritus, mucous membrane lesions, lymphadenopathy
Hypopigmentation or hyperpigmentation persists for days to weeks in some
Scarring unusual unless secondarily infected

62. Clinical manifestation
Progressive varicella
usually in immunocompromised children, complicated with pneumonia, hemorrhagic, DIC.
Neonatal chickenpox
Delivery within 1 week before or after the onset of maternal varicella frequently results in severe hemorrhagic varicella in neonates at 5~10 days old, accompanied by fever, often involving the lung and liver, the mortality rate is as high as 30%.
Congenital varicella
when pregnant women (especially between 8-20 weeks) contract chickenpox, 2% of the fetuses may become infected. accompanied with cicatrix, limb hypoplasia, eye abnormalities, central nervous system damage, low birth weight.

63. Complication Complications are common
Secondary infection of skin lesions.
Thrombocytopenia and hemorrhagic lesions or bleeding.
Pneumonia , myocarditis, pericarditis, orchitis, hepatitis, ulcerative gastritis, glomerulonephritis, and arthritis , Reye syndrome.
Nervous system damage: encephalitis, cerebellar ataxia, nystagmus, and tremor.

64. Therapy Symptomatic therapy
Antivirals (acyclovir, famciclovir, or valacyclovir ) are effective in preventing severe complications
the routine oral administration of acyclovir is not recommended in healthy children because of the marginal therapeutic benefit, the lack of difference in complications, and the cost of acyclovir treatment.

65. Prevention Vaccine post exposure prophylaxis
a live attenuated varicella vaccine is recommended as a single dose for children at age 12 to 15 months, and repeated at 4-6years old.
post exposure prophylaxis
immune suppression, perinatal neonate whose mother suffering from chicken pox
passive immunity: Immune globulin, within 10 day of exposure.

66. 浙江大学医学院附属儿童医院
感染病科
滨江院区
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