Differential diagnosis of fever and rash cases negative for measles and rubella to complement surveillance activities

Abstract

In the quest to eliminate measles virus (MV) and rubella virus (Ruv), every suspected case must be properly identified and diagnosed. Since 2017, in Milan (Italy), a total of 978 measles and rubella suspected cases (fever and rash) were investigated and 310 were not laboratory confirmed (discarded cases). To improve surveillance activities, we investigated the presence in discarded cases of 8 other viral pathogens commonly associated with rash: human herpesvirus 6 (HHV‐6) and 7 (HHV‐7), parvovirus B19 (B19V), enterovirus (EV), Epstein−Barr virus (EBV), human adenovirus (HAdV), cytomegalovirus (HCMV), and SARS‐CoV‐2. Differential diagnosis was carried out on 289 discarded cases by multiplex real‐time PCR assays. At least one pathogen was detected in 188 cases (65.1%) with HHV‐7 being the most frequently detected virus. No difference in the number of detected infections overtime was observed and infections were identified in all age groups. As expected, most HHV‐6, EV, HAdV, and HCMV‐positive cases were found in children aged 0−4 years and HHV‐7 was most frequent in the 15−39 age group. In light of the World Health Organization measles elimination goal, the introduction of laboratory methods for differential diagnosis is required for the final classification of clinically compatible cases. The used screening panel allowed us to increase the percentage of virus‐positive cases to 87.5%, allowing us to clarify viral involvement and epidemiology, improve diagnosis, and strengthen surveillance activities. As all investigated pathogens were detected, this diagnostic panel was a suitable tool to complement MV and RuV surveillance activities.

Increased reports of measles in the Metropolitan City of Milan, northern Italy, September 2023 to March 2024

“…In the aftermath, a provision of the Italian regional health authorities raised the attention on measles surveillance, investigating all cases with fever and rash (Regional regulation n. G1.2024.0004194, 6 February 2024). Overall, we observed five different genotype D8 DSIds from Asia and from two other Italian regions, suggesting multiple introductions of MeV; however, in contrast to outbreaks that occurred between 2017 and 2019 [10,11], no onward transmission was observed so far. This could be due to the major effort of the competent authorities to improve vaccination coverage and recommend vaccination in fragile populations, travellers and healthcare workers (Regional regulation n. G1.2024.0004194, 6 February 2024).…”

“…Prior to the COVID-19 pandemic period, we observed three epidemic peaks in the Metropolitan City of Milan and surrounding areas: March-June 2017, April-June 2018 and January-July 2019 [10]. Since August 2019, we noticed a significant drop in measles cases with only four confirmed cases of 86 suspected as of August 2023, none of which was autochthonous.…”

Measles and Rubella Diagnostic and Classification Challenges in Near- and Post-Elimination Countries

“…False–positive results can also be obtained due to antibody interference (e.g., rheumatoid factor) or other factors [ 13 ]. There are also many other potential viral causes of a febrile exanthem that can present clinically as a measles-like illness, including adenovirus, enterovirus, Epstein–Barr virus, and cytomegalovirus, although antibody cross-reactivity has not been routinely demonstrated for these pathogens [ 14 , 15 ].…”