Last February, amid concerns that the dominant seasonal H3N2 virus had drifted away from last winter’s vaccine (see CDC HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus), we began to hear of cases of Unusual Presentation Of Parotitis With Seasonal Influenza.
The classic cause of parotid swelling is the mumps virus, but other viruses (EBV & HIV), along with acute bacterial parotitis or Extrapulmonary Tuberculosis can cause inflammation of these glands, as well as some autoimmune diseases. And sometimes, the etiology is unknown.
In January, the Chicago Department of Public Health issued an alert to local doctors to test for both influenza, and mumps, when diagnosing parotitis, as several unusual influenza-related cases had surfaced.
The following month, the CDC published an overview of the 2014-15 flu season, with the following comment on these parotitis cases.
Is there any unusual disease activity going on this season?
Since December 2014, multiple states have notified CDC of laboratory-confirmed influenza infections in persons who have swelling of their salivary glands (a condition called ‘parotitis’). Of the cases of influenza infection with parotitis that have been reported to CDC, the majority have occurred in children with influenza A (H3) infection, and have resulted in mild illness. No deaths have been reported. CDC is currently investigating the situation in order to understand the characteristics of patients and the occurrence of parotitis.
Parotitis is not a common symptom of influenza infection, although cases of parotitis with influenza infection have been reported in the past. Parotitis is much more commonly seen following infection with other pathogens such as the mumps virus. Symptoms of influenza infection include fever, chills, cough, sore throat, runny or stuffy nose, muscle or body aches, headache, fatigue (tiredness), and sometimes vomiting and diarrhea (more common in children than adults).
Fast forward to today, and we have a report in today’s Eurosurveillance Journal of A/H3N2 detected last winter in children being tested for mumps in the England.
Eurosurveillance, Volume 20, Issue 31, 06 August 2015
Influenza A(H3N2) virus was detected in oral fluid from 16/107 children (aged 2 to 12 years) with a clinical diagnosis of mumps, who were sampled between December 2014 and February 2015 in England, during the peak of the 2014/15 influenza season. Sequence analysis of an A(H3N2) virus from a child with suspected mumps showed the virus was similar to other circulating A(H3N2) viruses detected in winter 2014/15, which were antigenically drifted from the A(H3N2) vaccine strain.
During winter 2014/15, clinical parotitis in children with confirmed influenza A(H3) infection was reported in North America . In contrast, however, neither clinical nor virological surveillance for influenza-like illness (ILI) through sentinel general practitioners (GPs) in England detected an association between parotitis and influenza virus infection in the 2014/15 winter. In light of the observations from North America, gingival crevicular fluid (oral fluids) submitted for mumps surveillance in England were examined for influenza virus. Analysis of samples from 107 children (aged 2 to 12 years) with a clinical diagnosis of mumps but negative for mumps virus, sampled between December 2014 and February 2015, during the peak of the 2014/15 influenza season, showed that 16 (15%) were infected with influenza A(H3N2) virus.
Influenza virus as an atypical cause of acute viral parotitis should be considered especially during epidemic seasons with drifted A(H3N2) strains, such as in 2014/15, or when zoonotic exposure has occurred.
Influenza A(H3N2) viruses from the 3C.2a clade that have predominantly circulated in the UK during winter 2014/15 show reduced agglutination of red blood cells used in laboratory tests suggestive of a change in binding specificity or avidity for sialic acid receptors . Both mumps and influenza viruses bind sialic acid receptors on cells in the upper respiratory tract . The unusual clinical presentation of parotitis during the 2014/15 season in conjunction with a change in virus receptor binding properties warrants further investigation.
The idea that a sufficiently `drifted’ or zoonotic H3N2 virus might cause an atypical presentation like parotitis isn’t without precedent. While rare, it has been documented before, as in this April of 2009 edition of the Journal of Clinical Microbiology.
Swine H3N2 influenza virus designated A/Ontario/1252/2007 was isolated from a child with parotitis. Diagnosis was confirmed by viral isolation and serological assays. A/Ontario/1252/2007 was related to H3N2 triple reassortants that emerged in swine in the United States in 1998. Three of five tested household members were also seropositive for A/Ontario/1252/2007.
Going even further back in the literature, in 1977 the NEJM reported on Acute Parotitis Associated with Influenza Type a — A Report of Twelve Cases, which occurred during the last year that A/H3N2 ruled the influenza court alone (H1N1 reemerged in May of 1977 after a 20 year absence).
Although there is always a degree of diversity in the flu strains circulating around the globe, the most recent ECDC Influenza Virus Characterization Report describes an increasingly complex H3N2 viral field.
Since 2009, seven genetic groups based on the HA gene have been defined for A(H3N2) viruses.
The HA genes fall within genetic group 3C. This group has three subdivisions: 3C.1 (to which the recommended vaccine virus for the 2014–15 northern hemisphere season, A/Texas/50/2012, belongs), 3C.2 and 3C.3. Viruses in these three subdivisions have been antigenically similar.
However, in 2014 three new genetic subgroups emerged, one in subdivision 3C.2, 3C.2a, and two in 3C.3, 3C.3a and 3C.3b (Figure 2). While viruses in genetic subgroups 3C.2a and 3C.3a are antigenic drift variants, those in 3C.3b have remained antigenically similar to previously circulating viruses in the 3C.3 subdivision. Amino acid substitutions that define these subdivisions and subgroups compared with A/Texas/50/2012 are:
- (3C.2) N145S and V186G5 in HA1, and D160N in HA2, e.g. A/Hong Kong/146/2013
- (3C.2a) Those in 3C.2 plus L3I, N144S (resulting in the loss of a potential glycosylation site), F159Y, K160T (in the majority of viruses, resulting in the gain of a potential glycosylation site), N225D and Q311H in HA1, e.g. A/Hong Kong/5738/2014
- (3C.3) T128A (resulting in the loss of a potential glycosylation site), R142G, N145S and V186G in HA1, e.g. A/Samara/73/2013
- (3C.3a) those in 3C.3 plus A138S, F159S and N225D in HA1, many with K326R, e.g. A/Switzerland/9715293/2013
- (3C.3b) those in 3C.3 plus E62K, K83R, N122D (resulting in the loss of a potential glycosylation site), L157S and R261Q in HA1 with M18K in HA2, e.g. A/Newcastle/22/2014.
Whether this growing diversity portends more atypical flu presentations is far from certain. It does, however, make selecting the right vaccine strain for future flu seasons a lot more complicated.
The authors of today’s Eurosurveillance Journal report conclude by saying:
The specific detection of influenza A(H3N2), and not influenza B or A(H1N1)pdm09 in this sample set, in combination with the clinical syndrome reporting from North America, suggests that influenza should be considered as part of the differential diagnosis for parotitis at the time when influenza virus is circulating, but this conclusion requires evaluation with different circulating influenza virus strains.
The question of whether 3C.2a A(H3N2) influenza virus strains have an unusual tissue distribution compared with other A(H3N2) viruses or whether a subset of children infected with any influenza strain experience parotitis remains to be determined. Our conclusions would be strengthened by evaluation of further studies during future influenza seasons where oral fluids are taken in parallel with nasal swabs from children with influenza, with and without parotitis.
Nevertheless, greater awareness of influenza virus as a potential cause of parotitis especially during epidemic periods associated with a drifted A(H3N2) strain is an important clinical and public health message.