Are You Confident of the Diagnosis?
What you should be alert for in the history?
The prodromal phase of measles is highly symptomatic. A history of high fever (up to 105° F), pronounced catarrh (profusely running nose), harsh, dry cough (sometimes leading to croup) and an intense, nonpurulent conjunctivitis (often with photophobia), followed by appearance of skin rash in a child should, prompt the clinician to consider a diagnosis of measles. Enquire about a history of contact with a case of measles in school or in the family.
Characteristic findings on physical examination
During the prodromal phase, the conjunctival involvement starts as marked linear erythema along the eyelid margins, which is quite characteristic, and gradually becomes diffuse. It is accompanied or followed by the pathognomonic enanthem “Koplik’s spots”; these are transient , grayish, pin-point dots (simulating table salt crystals), surrounded by an erythematous halo, present in the buccal mucosa, opposite to the lower molar teeth (Figure 1).
Koplik’s spots are rarely appreciable and fade away by 2 days, leaving behind a speckled, reddish discoloration of the buccal mucosa. The skin lesions of measles are nondescript, but its evolution is characteristic. A dusky-red, maculopapular rash appears along the ear, hairline, forehead, and upper lateral parts of the neck (Figure 2) and progresses cephalocaudally over the next 3-4 days to involve trunk and extremities (Figure 3). Initial lesions are discrete and thereafter become confluent and blanchable. It subsides in the same sequence of appearance leaving behind a brownish, branny desquamation. The fever continues till 2-4 days of the eruptive phase of the disease and ends abruptly. Epistaxis, posterior cervical lymphadenopathy, and splenomegaly may be present.
Expected results of diagnostic studies
In children, classical measles may be diagnosed clinically with a fair degree of accuracy. The diagnosis of measles in adults may be difficult because of lack of suspicion. Leucopenia with a relative lymphocytosis is observed. Thrombocytopenia is a feature of measles infection and may be quite severe. In absence of bacterial infections, erythrocite sedimentation rate (ESR) and C-reactive protein are normal.
If diagnostic confirmation is required, demonstration of anti-measles IgM antibodies is the simplest way to do this. It is detectable from 3 days after the onset of the rash and persists up to 1 month. The hemagglutination-inhibiting antibody assay technique done at the onset of the rash and again at 4 weeks when the titer is at its peak is the most sensitive method for detection of antibodies. Confirmation of diagnosis is done by demonstrating a fourfold (or more) rise in the IgM antibody titer in paired sera. The virus can be cultivated in tissue culture (human embryonic cell or Rhesus monkey kidney cells).
The specimens for viral culture include various body fluids like nasopharyngeal and conjunctival secretions, blood and urine, collected during late prodromal phase of the illness. Chances of virus isolation decreases following appearance of the skin rash. Histopathologic examination of the involved organs reveals pericapillary infiltration of mononuclear cells with or without pathognomonic, multinucleated, Warthin-Finkeldey giant cells. In skin, the inflammatory infiltrate is particularly located around the hair follicles and sebaceous glands.
Other febrile illnesses with a maculopapular skin rash must be differentiated from measles. In rubella, a milder, pink-colored rash is observed with prominent suboccipital lymphadenopathy. In parvovirus B-19 infection, the skin rash appears when the fever subsides and the child appears apparently well. Infectious mononucleosis, human herpes virus-6 infection (roseola infantum), Coxsackie virus and Enteroviral infections may simulate measles but lack the intense catarrh and conjunctivitis seen during prodromal phase.
The morbilliform rash, fever and conjunctivitis of Kawasaki disease may be difficult to distinguish clinically from measles but cheilitis, strawberry tongue and the characteristic desquamation during subsidence of the rash in the former are the differentiating features. Maculopapular drug eruptions and the early stage of Stevens-Johnson syndrome may also simulate measles.
Who is at Risk for Developing this Disease?
Measles is a ubiquitous viral illness, with frequent outbreaks occurring in almost all countries. The usual season of occurrence is spring. Preschool children are the common sufferers but older children and adults may be affected. Measles is extremely rare before 3-4 months of age because of protective maternal immunity.
Immunocompromised and malnourished children are at special risk of developing prolonged and severe clinical features of the disease. Measles is highly contagious with a secondary attack rate of about 90%. The source of infection is a case of measles. Transmission is through respiratory droplets. The period of infectivity spans from the prodromal phase to the early phase of appearance of the rash (approximately 4 days before and 5 days after the appearance of the rash). The portal of entry is mostly the respiratory mucosa and probably intact conjunctiva. The incubation period of measles is around 10-12 days.
One attack of measles confers life-long immunity and second attacks are rare except in severely immunocompromised children. Newborns acquire immunity to measles transplacentally from the mothers who were immunized or had natural infection. This immunity provides complete protection up to 4-6 months during infancy and thereafter gradually wanes off by 1 year. Natural infection confers better immunity than acquired infection by vaccination; infants born of vaccinated mothers experience early waning of maternal antibodies.
In resource-limited countries, measles-associated mortality rate may be as high as 25%.
What is the Cause of the Disease?
Measles is caused by a single-stranded RNA virus, genus Morbillivirus, family Paramyxoviridae.
Initial localization of the virus is in the epithelia of nasopharynx and conjunctiva, from where it is spread to the regional lymph nodes. After 2-3 days, viremia ensues and the virus is carried to other reticuloendothelial organs. There is hyperplasia of the lymphoreticular tissue, particularly involving spleen, appendix, and posterior cervical and mesenteric lymph nodes. A secondary intense viremia occurs after 5-7 days, followed by onset of prodromal phase. Secondary viremia leads to involvement of other organs, most importantly skin, respiratory tract and conjunctiva. Viral replication continues in these organs, with a peak tissue viral load by 14th day ; thereafter the level falls rapidly by next 2-3 days, along with appearance of antimeasles antibody – this coincides with the appearance of skin rash.
During the viremic stage, there is marked depression of the cell-mediated immunity, as evidenced by low CD4+ T cell count and low level of interleukin-12. This persists up to 1 month in the postmeasles period, with gradual recovery thereafter and explains the propensity to infectious episodes during this time. Activation of CD8+ T cells facilitates viral clearance from the system and activation of type 2 CD4+ T cells facilitates antimeasles antibody production.
Systemic Implications and Complications
Multiorgan complications are common in measles. Frequent serious complications are myocarditis and pneumonia. Secondary bacterial pneumonia is more common than the interstitial pneumonia (Hecht’s giant cell pneumonia) caused by the measles virus itself. Hecht’s pneumonia is more common in immunocompromised patients. Respiratory tract involvement like laryngitis, tracheitis, bronchitis, and otitis media may be caused by measles virus or superimposed bacterial infection. Persistent fever beyond 1-2 days of the onset of skin rash is likely to be an indicator of secondary bacterial infection. Acute abdominal pain may result from appendicitis (obstruction of appendicular lumen due to lymphoid hyperplasia) or mesenteric lymphadenitis.
In developed countries, the most common complication associated with measles is otitis media, followed by pneumonia and diarrhea. In developing countries, measles associated complications are severe, leading to a high mortality rate. Pneumonia and diarrhea are the most common complications in these children, which are enhanced in the background of a preexisting malnourished state. Staphylococcal pneumonia is life threatening. Pneumonia is the most common cause of death in children with measles. Preexisting low vitamin A reserve in the body makes these children prone to developing blindness.
Rare complications are purpura fulminans with or without digital gangrene, encephalitis, Guillain-Barre syndrome, cerebral thrombophlebitis, hemiplegia, and retrobulbar neuritis.
Subacute sclerosing panencephalitis (SSPE) is a very rare complication of measles infection (1/100,000 cases). It results from persistent infection by defective measles virus. It is common among children who had measles before 1 year of age. Clinical manifestations start at around 9 years of age, approximately 7-13 years after the childhood measles infection. There is progressive mental and motor deterioration, personality changes and myoclonic seizures. Coma and death is the ultimate end of the children suffering from SSPE.
There is a persistent high titer of antimeasles antibody over several years in children with SSPE. A higher cerebrospinal fluid antimeasles antibody titer compared to seum may be helpful in diagnosis. If facilities with immunofluorescence and electron microscopy are available, a brain biopsy and histopathologic examination is diagnostic.
Treatment options for measles are summarized in Table I.
|Treatment of acute episode||
Photophobia: protection from bright light
Laryngitis: humidification of room environment
Febrile convulsion: anticonvulsants
|Specific therapy||—–||Effective antiviral drug not available|
|Supportive therapy during acute episode||High dose vitamin A(WHO recommended dose):Children >/= 1 year:200.000 IU daily orally X2 days;Infants between 6-11 months: 100,000 IU daily orally X 2 days; Infants< 6 months: 50,000 IU daily orally X 2 days||Measles infection itself reduces serum retinol level increasing the subclinical cases of vitamin A deficiency.|
|Prophylactic therapy to combat secondary bacterial pneumonia||—–||Role of prophylactic antibiotics is controversial.|
|Preventive therapy; active immunization||Active immunization: Live attenuated vaccine (Measles, Mumps, Rubella [MMR] vaccine, Edmonston Zagreb vaccine); subcutaneous injection (0.5ml) at age between 9-15 months.||Most common side effect is measles-like maculopapular skin rash. Increased risk of febrile seizures (5%-7%). Should be used cautiously in children with thrombocytopenia.|
|Post-exposure prophylaxis(PEP)||Passive immunization:Human immunoglobulin (0.25ml /kg in immunocompetent children and 0.5ml in the immunocompromised, maximum up to 15ml), to be administered at the earliest, within 5 days of contact.||Vaccination should be postponed for 3-11 months after immunoglobulin administration|
Optimal Therapeutic Approach for this Disease
Treatment of the acute attack of measles is mostly symptomatic. Allowing the patient to rest in a dim-lighted, humidified room and addition of antipyretics for high fever are the mainstay of management. Complications are to be taken care of; anticonvulsant medications are to be administered for seizures (febrile / encephalitis-associated). Secondary bacterial infections must be identified early, and specific antibacterial therapy is indicated in such cases. In presence of secondary bacterial pneumonia, antistaphylococcal antibiotics dicloxacillin or linezolid) may be started empirically while awaiting the culture sensitivity report. The role of prophylactic antibiotics is controversial. However, in developing countries, such treatment protocols have been found to reduce the morbidity and mortality associated with measles.
A high dose of vitamin A is administered, especially for children in a resource-poor environment. Both the World Health Organization (WHO) and the American Academy of Pediatrics (AAP) recommend mandatory administration of vitamin A during acute illness to minimize the morbidity and mortality associated with measles. During an outbreak, vitamin A should also be administered to all immunosuppressed children with measles, children with overt clinical features of vitamin A deficiency, and to those who migrated from endemic areas of measles with high mortality rate. There is no antiviral drug with proven efficacy to treat measles.
Live attenuated measles vaccine is administered as a preventive measure all over the world. The internationally accepted protocol for administration of measles vaccine is at 9-15 months of age. However, it may be administered at 6 months of age for postexposure and for outbreak prophylaxis. A second dose of MMR (Measles – Mumps – Rubella) vaccine may be given during school entry (4-6 years) or at 12-14 years of age. Pregnant women and immunocompromised individuals should not be vaccinated with live measles vaccine. HIV-infected children, unless severely immunocompromised, should receive measles vaccination to prevent infection by the wild virus. Active immunization is avoided if there is history of hypersensitivity to neomycin or gelatin (vaccine components). Vaccination is not contraindicated in children with history of seizure disorder.
The MMR vaccine is a combination of three live attenuated viruses.
Postexposure prophylaxis (PEP) is performed with human immunoglobulin. Non-immunized household contacts of a measles case aged 6-12 months, pregnant women, and immunocompromised individuals are the targets. Immunocompromised individuals should receive PEP irrespective of their earlier immunization status. Infants less than 6 months of age, born to mothers nonimmune to measles should also receive PEP if they are in contact with a case. Unvaccinated children may not have full protection following immunoglobulin administration. Ideally , whenever feasible, vaccination should precede administration of immunoglobulin by at least 2 weeks.
Close monitoring of the children is required after an attack of measles. Disease-associated depression of cell-mediated immunity continues for approximately 1 month after the acute infection. Children from developing countries are particularly at risk of developing acute gastroenteritis during this period. Weight loss is common. There may be unmasking of a subclinical malnourished state and vitamin A deficiency. The latter is an important cause of postmeasles blindness. Reactivation of pulmonary tuberculosis may occur.
During the convalescence period of measles, prevention of secondary infection and ensuring adequate nutrition is important to reduce morbidity and mortality. Parents of children with seizure disorder should be counseled that there may be a slightly increased risk of convulsions following active immunization.
Unusual Clinical Scenarios to Consider in Patient Management
There are variations in the classical clinical picture of measles in various situations.
Black measles: Children from developing countries may develop severe course of the disease. The skin rash in these children is intense and often hemorrhagic. Bleeding may occur from mouth, nose, and gastrointestinal tract. The rash subsides with marked desquamation.
Measles infection in the immunocompromised host: In this background measles is prolonged, severe and may end with fatal outcome. The classical skin rash may be absent or the children may not develop the skin rash at all. The course of the disease is frequently complicated with systemic manifestations like acute progressive encephalitis and Hecht’s pneumonia (giant cell pneumonia). Impaired cell-mediated immunity may be contributory to the severity of the infection.
Atypical measles: Recipients of killed measles vaccine may develop an atypical clinical picture when encountered with the wild virus. The prodrome consists of high fever, headache, abdominal pain, myalgia and cough. The skin lesions appear after 2-3 days; morphology and the chronological order of appearance being totally different from the classical disease. Petechial or vesicular skin lesions, often associated with edema and pruritus, first appear on the palms, soles and distal extremities, and thereafter progress centripetally to the trunk. Systemic involvements include pneumonitis with pleural effusion and very high level of hepatic enzymes. Though there is severe involvement, fatality is rare.
Individuals with atypical measles demonstrate extremely high level of antimeasles antibody. Exposure to the wild virus leads to anamnestic production of nonprotective, complement-fixing antibodies, resulting in immune complex formation. These patients are usually noncontagious and protected from further infection.
Killed measles vaccine was in use in the US up to 1967; since the introduction of live vaccine, it is no longer recommended worldwide, because it provides short-lasting immunity and confers the risk of atypical measles. Withdrawal of killed measles vaccine from the vaccination schedules in various countries has made “atypical measles” an obsolete disease.
Inapparent measles: This is a subclinical form of measles occurring in infants having passively acquired maternal antibody or in children who have received blood products. The skin rash is brief and indistinct or entirely absent. It is a noninfectious illness.
Severe measles in immunocompromised individuals has been treated with various agents. such as ribavirin (intravenous / aerosol preparation), interferon, thymic humoral factor, thymostimulin, levamisole, and immunoglobulin. These drugs may be useful in treating Hecht’s pneumonia or encephalitis. Prevention of atypical measles may be achieved by the exclusive administration of live attenuated measles vaccine.
What is the Evidence?
Strebel, PM, Papania, MJ, Dayan, GH, Halsay, NA, Plotkin, S, Orenstein, W. Measles vaccine. 2008. pp. 353-98. (This chapter provides an excellent review on virology, immunology, and practical aspects on use of measles vaccine. Other management aspects like utility of vitamin A in measles are discussed in detail.)
Mason, WH, Kliegman, RM, Behrman, RE, Jenson, HB, Stanton, BS. “Measles”. Nelson textbook of pediatrics. 2007. pp. 1331-36. (Tthis chapter provides an in-depth discussion on the systemic involvement and complications of measles. Differential diagnostic points are discussed. Clinical features and pathogenesis of SSPE are highlighted in detail.)
Isaacs, D, Mulholland, K, McIntosh, N, Helms, P, Smyth, R, Logan, S. “Infections”. Forfar & Arneil's textbook of pediatrics. 2008. pp. 1177-1384. (In this chapter, readers will get a quick glimpse on the important clinical features of measles.)
Park, K, Park, K. “Epidemiology of communicable diseases”. Park's textbook of preventive and social medicine. 2009. pp. 135-38. (There is a concise discussion on the epidemiological aspects of measles.)
Gagneur, A, Pinquier, D. “Early warning of maternal measles antibodies: why immunization programs should be adapted over time?”. Expert Rev Anti Infect Ther. vol. 8. 2010. pp. 1339-43. (This article discusses the need for modification in the existing measles vaccination schedule in childhood. Vaccinated mothers have lower antimeasles antibody compared to the mothers who had natural measles infection. The transplacental immunity conferred to the child by the vaccinated mothers is shorter lasting compared to the mothers who had natural measles infection. The immunization schedule for measles may be modified accordingly, introducing earlier immunization to combat the unprotected period between waning off of maternal immunity and vaccination.)
van den Berg, JP, Westerbeek, EA, van der Klis, FR, Berbers, GA, van Elburg, RM. “Transplacental transport of IgG antibodies to preterm infants: a review of the literature”. Early Hum Dev. 2010 Nov 29. (This article highlights the special risk of preterm infants acquiring vaccine preventable neonatal infectious diseases, as transplacental transport of immunoglobulin G is lower in them compared to term infants. Moreover, IgG antibody titer in preterm infants decreases to below protective level earlier than term infants. This risk is in addition to the risk preterm infants already face because of an immature immune system.)
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