1.3 Infection, immune response and laboratory diagnosis of measles

Measles virus is highly infectious to humans, causing a self-limiting febrile illness characterized by a maculopapular rash. The H protein of wild-type measles virus binds to the cellular receptor, the signalling lymphocyte activation molecule (SLAM, also known as CD150). Studies in animal models indicate that the initial target cells are alveolar macrophages and dendritic cells which are infected via this receptor [4]. The virus is transported to draining lymphoid tissues, seeding a systemic infection with preferential tropism to B and T-lymphocytes. The incubation period is estimated to last 10 to 14 days, and is associated with leukopenia.

Viral shedding begins in the prodromal phase prior to rash onset. Following viremia mediated by infected lymphocytes, the respiratory epithelium is infected basolaterally via a second receptor, nectin 4, producing a large amount of progeny viruses in the respiratory tract [4]. Transmission of virus occurs through respiratory secretions. Rash is generally observed from 3 to 5 days following onset of fever. Individuals are considered to be infectious from approximately four days before rash to four days after rash onset. Total uncomplicated disease course is 17-21 days from first sign of fever.

Infection of the respiratory tract can give rise to croup, bronchiolitis and pneumonia. Generalised damage to the respiratory tract causes the loss of cilia and predisposes to secondary bacterial infections, such as pneumonia and otitis media. Immune reactions to the virus in the endothelial cells of dermal capillaries cause the measles rash and the measles enanthem (Koplik spots), while interaction between virus-infected cells and local cellular immune factors is thought to be involved in measles encephalitis.

Both IgM and IgG antibodies are produced during the primary immune response and measles-specific IgM can be detected in the serum as early as the first day of rash onset, while IgG is usually detectable a few days after the IgM appears. Refer to Figure 1.3, Immune response in acute measles infection.

Using sensitive EIAs to detect IgM, 90% of measles cases can be expected to have positive results for measles-specific IgM at ≥3 days post rash onset [10]. The IgM antibody levels peak about 7–10 days after the onset of rash and then decline rapidly. IgM may be undetectable after 6–8 weeks. Production of IgG antibody gradually increases, with levels peaking within about 4 weeks following rash onset and persisting long after infection. Serum IgA and secretory IgA antibodies are also produced.

When immune individuals are re-exposed to measles virus, circulating measles-specific antibodies generally provide protection from clinical disease and a rise in neutralizing antibody concentration may be measured if pre-exposure blood is available. It is sometimes possible to detect virus-specific IgM in post-exposure serum specimens among individuals that remain asymptomatic [11,12]. Cellular immunity, consisting of cytotoxic T-cells and possibly natural killer cells, plays a prominent role in immunity and recovery from acute infection. However, a fully symptomatic reinfection with measles has been demonstrated by the presence of high avidity measles IgG antibody among laboratory-confirmed measles cases [13,14]. The serologic confirmation of measles reinfections can be challenging. Symptoms may be mild, and/or the clinical progression may differ from that seen among primary cases of measles. Health-care workers may be particularly at risk of reinfection, due to a high force of infection when measles cases present in a hospital or clinical setting [14,15]. A more detailed discussion of measles reinfection cases and the approaches for laboratory confirmation for suspected reinfection cases are provided in chapter 8.

Detection of measles-specific IgM antibody from serum or oral fluid specimens containing gingival crevicular fluid, (chapter 4) and the detection of measles RNA by RT-PCR (chapter 6) are standard methods that are used among laboratories in the Global Measles and Rubella Laboratory Network (GMRLN) to confirm suspected acute cases of measles [16]. However, as measles vaccine also elicits IgM production, recent vaccine history must be considered when evaluating suspected cases by these standard methods for case confirmation. In addition, low prevalence of measles in a population greatly reduces the positive predictive value of IgM detected by EIA [17].