CONTENTS

• Clinical presentation
• Measles rash & its differential diagnosis
• General laboratory and radiologic findings
• Laboratory testing for measles
• Epidemiology & high-risk features
• Post-exposure prophylaxis
• Management
  • Vitamin A & ribavirin
  • Pulmonary complications
  • Neurologic complications
  • Other management issues

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clinical presentation

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[phase #1] incubation

• Usually ~10-14 days.
• Ranges from 7-23 days. (35093206)

[phase #2] prodrome (usually 2-4 days)

• Fever, malaise.
• At least one of the three C's:
  • Cough.
  • Coryza (rhinitis).
  • Conjunctivitis (sometimes with lacrimation or photophobia). (31184814)
• The prodromal phase may reflect direct damage from viral replication within epithelial cells. (35093206)

Koplik spots (overlaps with phases #2-3)

• Koplik spots usually appear 1-2 days before the skin rash, but disappear within two days after the skin rash appears. (31184814, 32877891)
• These are 1-3 mm white/grey/blue plaques on an erythematous base (sometimes described as “grains of salt on a red background”).
• They are typically seen on the buccal mucosa opposite the molar teeth, but may be more widespread (including the hard and soft palate).
• Koplik spots occur in roughly half of patients. If encountered, these are considered pathognomonic of measles.

[phase #3] exanthematous phase

• Measles rash (described in further detail in the section below).
• Fever.
  • Fever generally resolves within 3-4 days after rash appearance.  Prolonged fever beyond this timepoint may suggest a superinfection.
  • One series of adults admitted with measles found fever >38.5 C in all 93 patients. (32877891)
• Other symptoms:
  • Conjunctivitis.
  • Pharyngitis.
  • Dry cough.
• Lymphadenopathy (rarely, generalized lymphadenopathy with splenomegaly may occur).

[phase #4] recovery phase

• Rash heals, often with fine desquamation of the uppermost skin layer.
• Cough often persists.
• Fever should not be seen (if present, fever at this stage suggests an infectious complication). (32241708)

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measles rash & its differential diagnosis

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features of the measles rash

characteristics of the measles rash

• Early lesions are blotchy and blanching, but later lesions aren't blanching.
• During resolution, fine desquamation of the upper skin layer may occur.
• Petechiae can occur but aren't typical. In severe cases, the rash can look hemorrhagic.

distribution & progression of measles rash

• The rash typically begins on the face (especially forehead) and behind the ears.
• It spreads downwards and outwards to the extremities.
• Finally, it may involve the palms and soles.
• The rash lasts for ~3-4 days, then fades in the order that it appeared. (32241708)

important features from the H&P to assist diagnosis:

• Features suggestive of measles:
  • [1] Incomplete vaccination & exposure history (but this is also seen in Rubella).
  • [2] Prodromal symptoms preceding the rash:
    • (i) Presence of either cough, rhinitis, and/or conjunctivitis.
    • (ii) Rash usually occurs ~3-5 days after fever onset.
  • [3] Koplik spots (extremely useful, if seen).
• Cough, if present, may argue against a primary dermatological entity (e.g., drug rash).
• Recent drug exposure may support a diagnosis of drug rash, SJS/TEN, or mononucleosis (amoxicillin rash).
• Potential tick exposure may raise the possibility of Rocky Mountain Spotted Fever.
• Sexual or IV drug use history may support the possibility of acute HIV seroconversion.
• Marked hemodynamic instability suggests a more sinister diagnosis (e.g., toxic shock syndrome, meningococcemia).

relationship of rash to immunological status

• Rash is associated with an immune response to measles.
• The rash may be absent in patients with impaired cell-mediated immunity (e.g., HIV, transplantation). (23982057)
• Modified measles: People with some degree of immunity may display modified measles, with an atypical rash appearance. Such patients aren't highly contagious and usually have milder disease.

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differential diagnosis and distinguishing characteristics 

The following differential diagnosis isn't exhaustive, but it merely highlights some more prominent considerations in adult patients.  

viral infections

• Rubella (“German measles”):
  • Perhaps the closest mimic of measles.
  • Prodrome is often absent.
  • Maculopapular rash may start in the face and spread to the rest of the body.
  • Rash usually lasts only 1-3 days and quickly fades (shorter than measles).
  • The rash is often less intense than in measles and doesn't coalesce.
• Infectious mononucleosis:
  • Pharyngitis, fever, and lymphadenopathy are characteristic.
  • A maculopapular rash can occur, most often after treatment with amoxicillin.
  • Rash often predominantly involves the trunk (similar to other drug reactions).
• Primary HIV infection:
  • Fever, pharyngitis, lymphadenopathy, and mucocutaneous ulceration are often seen.
  • A maculopapular rash on the trunk or face can occur.

bacterial infections

• Toxic shock syndrome: 📖 May present with pharyngitis and a diffuse erythematous blanching rash.
• Mycoplasma may cause a mild erythematous maculopapular or vesicular rash.
• Rocky Mountain Spotted Fever 📖: maculopapular rash typically begins in the extremities and spreads inwards to the trunk. It starts as blanching pink macules, which later become maculopapular and then petechial.
• Meningococcemia: A petechial rash may be present, but is generally not prominent.

autoimmune/noninfectious

• Adult-onset Still disease: An evanescent, salmon pink maculopapular rash may occur. The rash mainly involves the trunk and extremities (but can also affect the palms, soles, and occasionally the face).
• Acute cutaneous lupus erythematosus: Widespread eruption may occur, especially over extensor surfaces of the hands and arms exposed to sunlight.
• Drug rash, including DRESS syndrome 📖:
  • May be suggested by exposure history and/or eosinophilia (DRESS syndrome).
  • Often lacks prodromal symptoms.
  • Often starts on the trunk and spreads towards the extremities.
• Stevens-Johnson Syndrome/toxic epidermal necrolysis: May be suggested by blistering, desquamation, and prominent mucosal involvement.
• (Kawasaki disease): Rare in adults. It may cause conjunctivitis, strawberry tongue, involvement of palms and soles.

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laboratory and radiological findings

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laboratory abnormalities may include

• Blood count:
  • Thrombocytopenia is common, but usually mild.
  • Leukopenia is frequently seen in critically unwell patients. (23982057) Lower lymphocyte counts may correlate with greater risk of viral pneumonia (e.g., median absolute lymphocyte count of 490 vs. 740 for patients with and without pneumonia, respectively). (32877891)
• Liver function test abnormalities:
  • Elevated transaminase levels are more common and might reflect direct viral cytopathic effect.
  • Cholestasis may occur later, possibly reflecting a host-mediated immune response to the virus. (31573732)
• Creatine kinase elevation (sometimes with rhabdomyolysis). (23982057)
• CRP elevation.

chest imaging features of measles pneumonitis

• Typical features:
  • Micronodular opacities are common, often in a centrilobular or peribronchial configuration. (31573732)
  • Thickening of the interlobar septa may be seen.
  • The overall distribution is generally symmetric, and sometimes central.
• Other features which may be seen:
  • Hilar lymphadenopathy.
  • Pleural effusion.
  • In extremely severe cases, micronodules and ground-glass opacities may progress to confluence, yielding consolidation (the final common pathway of any severe parenchymal lung injury).

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laboratory testing for measles

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A combination of both PCR and IgM levels is recommended: (32241708) 

PCR

• Respiratory specimens are preferred (e.g., throat swab, nasopharyngeal swab, bronchoalveolar lavage). (Red book 33e) Other potential sources include blood and urine.
• Sampling >1 site may increase sensitivity. (Red book 33e)
• Sensitivity:
  • PCR has high performance for acute presentations (sensitivity of 94%, specificity of 99%).
  • PCR positivity may not be seen among patients with late presentation from complications (such patients would, however, have a positive IgM serology – as discussed below). Viral RNA is usually detectable for about three days after rash onset (which roughly coincides with the period of disease transmission).
• PCR turns positive before seroconversion. (31184814) 

serology (IgM anti-measles antibody)

• Sensitivity should be excellent for unvaccinated, immunocompetent patients tested >3 days after rash onset. Causes of false-negative IgM levels include:
  • [1] Within three days of rash onset, IgM is absent in ~20% of patients. IgM is almost always present after 4 days of rash.
  • [2] Prior vaccination may cause an absence of IgM production (the initial response may be IgG). (35093206)
• Specificity of ~95-99%. (31184814)
  • IgM remains detectable for ~1-2 months, so it implies recent infection. (35093206)
  • False-positive results can result from rheumatoid factor or antibodies against other pathogens. (35093206)

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epidemiology & high-risk factors

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spread 

• Measles is the most highly infectious pathogen known to medicine. Its R-0 is 12-18, meaning that each patient infects an average of 12-18 other people (within an unvaccinated population).
• Measles is spread via airborne transmission. This occurs between ~4 days before and ~4 days after the onset of rash. However, immunocompromised patients may have prolonged shedding of virus. (35093206, Red Book 33e)
• In temperate climates, peak transmission occurs during late winter and spring. (Red Book 33e) Epidemics seem to burn out in the summer. A French ICU study found that over several years, nearly all patients were admitted between December and June. (23982057)

individuals at higher risk of complications

• [1] Adults >20 years old.
• [2] Pregnancy.
• [3] Malnutrition (especially vitamin A deficiency).
• [4] Immunosuppression (especially cell-mediated immunity):
  • Including:
    • Malignancy (especially certain leukemias and lymphomas). (37692196)
    • HIV. (31184814)
    • T-cell suppressive therapies (e.g., transplantation).
  • Unusual presentations may occur:
    • Lack of characteristic rash.
    • Inclusion-body encephalitis.

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post-exposure prophylaxis

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preferred: measles vaccine (MMR vaccine)

• MMR vaccination should be given within 72 hours of exposure for people who:
  • [1] Aren't fully vaccinated (i.e., have received 0-1 doses of the MMR vaccine).
  • [2] Are vaccine-eligible (the life-attenuated vaccine is contraindicated in some patients with severe immune deficiency).
• This is highly effective and provides durable protection against measles.

alternative: IVIG (intravenous immune globulin)

• IVIG is highly effective and may be given up to 6 days after exposure.
• IVIG should be considered for people at increased risk of morbidity or mortality, including:
  • Pregnancy without evidence of measles immunity (e.g., unvaccinated).
  • Severely immunocompromised persons regardless of vaccination status, e.g.:
    • Bone marrow transplant recipients.
    • Solid organ transplantation.
    • HIV with CD4+ count <200/mm3.
    • Acute leukemia. (Red Book 33e)
• Recommended dose: 0.4 grams/kg.
• Immunity is short-lived, so follow-up vaccination is still required. However, the antibody will interfere with vaccine efficacy, so vaccination must be delayed for >8 months. (31184814)
• For immunodeficient patients already receiving scheduled IVIG, 0.4 grams/kg should be sufficient if the patient received this within the prior three weeks. (Red Book 33e)
• ⚠️ IVIG cannot be given along with the MMR vaccine, since immunoglobulin will neutralize the virus and prevent the vaccine from working. IVIG is only intended for people who are not candidates for vaccine post-exposure prophylaxis. (37692196)

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management of adults hospitalized with measles

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general treatment considerations

vitamin A

• Lower levels of vitamin A correlate with more severe disease and ocular complications. High-dose vitamin A has been shown to reduce mortality and complications among young children hospitalized with measles in resource-limited countries. (31184814, 16235283)
• It is unknown whether vitamin A supplementation benefits well-nourished adults with measles. Some evidence supports the presence of vitamin A deficiency in adult measles patients within developed countries. (22932125) 
• Available guidance:
  • The American Academy of Pediatrics recommends vitamin A administration to all children requiring hospitalization. The dose for children >12 years old is 200,000 IU PO given once daily for two days (immediately upon diagnosis and then repeated the next day). (31184814, Red Book 33e)
  • The WHO recommendation: “All children or adults with measles should receive two doses of vitamin A supplements, given 24 hours apart. This restores low vitamin A levels that occur even in well-nourished children. It can help prevent eye damage and blindness. Vitamin A supplements may also reduce the number of measles deaths.” 📄
• Overall, providing hospitalized adults with 200,000 IU of vitamin A PO daily for two doses seems reasonable and consistent with available guidelines. (32241708)
• ⚠️ High cumulative doses of vitamin A can be toxic since vitamin A is a fat-soluble vitamin that will accumulate over time. Therefore:
  • [1] The cumulative dose should probably be capped at 400,000 IU.
  • [2] For patients who have already been taking high doses of vitamin A or vitamin A-containing products (e.g., cod liver oil), additional vitamin A administration should be omitted.

ribavirin

• Ribavirin has demonstrated antiviral efficacy against measles in vitro. However, there is no high-quality data showing that it is clinically beneficial.
• Potential complications of ribavirin include hemolytic anemia, renal failure, hemodynamic instability, psychiatric side effects, teratogenicity, and cytopenias.
• Ribavirin might theoretically play a more significant role among profoundly immunocompromised patients (who may have difficulty clearing the virus). It's dubious whether ribavirin would be beneficial among immunocompetent patients. In modern case series, ribavirin has rarely been utilized.

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pulmonary complications

pathophysiology of acute hypoxemic respiratory failure in measles

• Respiratory failure may be caused by viral pneumonia and/or bacterial superinfection. Historically, it was believed that pneumonia generally reflected bacterial superinfection. However, modern imaging techniques suggest that a majority of early respiratory failure is due to viral pneumonia. (23982057)
• Giant Cell Pneumonia (aka Hecht's pneumonia) is another name for viral pneumonia due to measles (the viral cytopathic effect causes giant cell formation). (35093206)

differentiating measles pneumonia vs. bacterial superinfection

• Clear differentiation is frequently impossible.
• Features that suggest superinfection may include:
  • Asymmetric radiographic opacities (especially lobar consolidation).
  • Longer time delay between rash onset and respiratory deterioration (e.g., >>5 days).
  • Purulent sputum production. (31573732)

management should reflect standard ICU practices

• Respiratory support:
  • Noninvasive and invasive support should be based on standard practices.
  • Most patients admitted to ICU for hypoxemic respiratory failure will meet the definition of ARDS.
  • Pneumothorax and pneumomediastinum seem to be common in this population. (23982057)
• Antimicrobial therapy may often be reasonable, due to difficulties in excluding bacterial superinfection.
• Steroids:
  • There is no high-quality evidence regarding the use of steroids for respiratory failure in measles pneumonia (available data is confounded by indication). However, the very sparse available data suggests that steroids are safe. (37820949)
  • ATS and SCCM guidelines recommend steroids for the treatment of ARDS. (38032683, 38240492)
  • Steroid therapy would seem to be rational for patients with substantial hypoxemia without underlying immunosuppression.

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acute neurological complications

ADEM (acute disseminated encephalomyelitis) aka PIE (postinfectious encephalomyelitis)

• Basics: Most patients with encephalitis or encephalomyelitis within a few weeks of the measles rash appear to have a virus-induced autoimmune demyelinating process that fits within the paradigm of ADEM (acute disseminated encephalomyelitis).
• Epidemiology: Occurs in ~1/1000 patients. (32034528)  
• Timing: this usually occurs within about two weeks of the rash.
• Clinical features may include:
  • Encephalitis (e.g., headache, seizures, somnolence, multifocal neurological signs).
  • Myelitis (e.g., paraplegia, sensory loss, loss of bowel/bladder control, back pain).
  • Optic neuritis.
• CSF often reveals:
  • Pleocytosis is usually lymphocytic. However, some patients have a neutrophilic pleocytosis (possibly analogous to a more severe, acute form of ADEM known as acute hemorrhagic leukoencephalitis 📖). (34436997)
  • Elevated protein levels.
  • Glucose is generally normal.
• MRI findings:
  • Multifocal, disseminated lesions may be seen with T2 hyperintensity within the brain and spinal cord (predominantly within the white matter).
  • Measles post-infectious encephalitis may initially present with a splenial lesion reminiscent of MERS 📖 (mild encephalopathy with reversible splenial lesion), which subsequently transitions into imaging more consistent with ADEM. (33456033)
• Management:
  • There is no high-quality data regarding treatment due to the rarity of this entity.
  • Treatment based on the therapy for ADEM is sensible. High-dose pulse steroids is a front-line therapy, with IVIG or plasma exchange being potential second-line treatments for refractory disease. Case reports describe favorable responses to immunomodulatory therapy. (discussed further here: 📖) (33456033, 34436997, 33229483)

aseptic meningitis

• Less commonly, measles may cause aseptic meningitis.
• Clinical features may include headache, photophobia, phonophobia, and nuchal rigidity.
• This appears to be a benign process that shouldn't be confused with ADEM/PIE.

(acute measles encephalitis probably doesn't exist)

• Some articles describe an entity of “acute measles encephalitis” as being caused by direct viral neuroinvasion. However, this doesn't appear to exist. More recent pathological studies have not detected viral antigens or neuron cytopathic effects within brain samples of patients with encephalitis in the context of measles. (32034528, 6204579) Some reports have found that CSF samples are positive for measles via PCR, but this could easily represent contamination from blood or airborne droplets (air surrounding measles patients can be PCR-positive). (26386428) Thus, most patients historically labeled as having “viral encephalitis” likely had an inflammatory process representing a form of ADEM (as discussed above).
• A PubMed and Google Scholar search for “acute measles encephalitis” does not reveal any convincing case reports of this entity (in contrast, there are numerous, well-documented reports of measles-induced ADEM).
• Many recent articles don't mention primary measles encephalitis at all (but rather solely discuss ADEM/PIE). (32523912, 35093206, 23982057) 
• Direct neuroinvasion from measles can occur, but this appears to be a subacute or chronic phenomenon (see the discussion below on inclusion body encephalitis).

(inclusion body encephalitis)

• Inclusion body encephalitis may develop subacutely, usually between 5 weeks and 6 months of the onset of measles. (23982057)
• Inclusion body encephalitis may reflect persistent, slow viral replication within the CNS. Affected patients have substantial immunosuppression.
• Clinical features may include:
  • Normal CSF analysis.
  • Seizures.
  • Clinical improvement after holding immunosuppression. (23982057)

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other management issues

diarrhea

• Treatment is supportive.
• IV fluid may be indicated.

hepatitis

• In addition to elevated liver function tests, patients may have clinical features of hepatitis (e.g., right upper quadrant tenderness).
• Frank hepatic failure does not appear to be a feature of measles.
• Treatment is supportive. (32066574)

rhabdomyolysis

• Rhabdomyolysis may occur, especially among critically ill measles patients. (23982057)
• Treatment of rhabdomyolysis is discussed further here: 📖

otitis media

• This is more common in children.
• It may merit antibiotic therapy.

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questions & discussion

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