key: cord-279570-lgbqpfh5
authors: Fragkou, Paraskevi C.; Thomas, Konstantinos; Sympardi, Styliani; Liatsos, George D.; Pirounaki, Maria; Sambatakou, Helen; Marantos, Theodoros; Karofylakis, Emmanouil; Dourakis, Spyridon P.; Tsiodras, Sotirios; Kavvatha, Dimitra
title: Clinical characteristics and outcomes of measles outbreak in adults: a multicenter retrospective observational study of 93 hospitalized adults in Greece
date: 2020-08-26
journal: J Clin Virol
DOI: 10.1016/j.jcv.2020.104608
sha: 
doc_id: 279570
cord_uid: lgbqpfh5

OBJECTIVES: Measles outbreaks are increasingly reported among countries that were close-to-eliminate measles infection. There are few reports of clinical characteristics of adult measles in the contemporary literature. In this study we aim to describe the clinical characteristics and complications of measles infection in hospitalized adults during the recent epidemic in Greece. METHODS: A multicentre observational retrospective study was conducted in three tertiary hospitals in Greece. All adult hospitalized patients (≥18 years old) with serologically confirmed and/or clinical features compatible with measles were included. Pediatric patients and patients with missing data were excluded. RESULTS: In total, 93 patients, 40 males (43%) and 53 females (57%), mostly young patients were included. Most of them (87%) had no past medical history. Among women, 4 were pregnant. 56 (60.2%) and 25 (26.9%) patients reported either unknown or incomplete vaccination for measles. Ribavirin was administered in 8 (8.6%) patients. Pneumonitis and hepatic involvement were the most common complications, occurring in 43 (46.2%) and 75 (80.6%) patients respectively. Pneumonitis was significantly associated with male sex, older age, lower lymphocyte counts and higher C-reactive protein (CRP) on admission. One pregnant woman suffered spontaneous fetal miscarriage and one patient died due to acute respiratory distress syndrome (ARDS) and high-risk pulmonary embolism. CONCLUSION: Considerable proportions of incompletely vaccinated or unvaccinated adults have led to the re-emergence of measles in countries with reported close-to-elimination rates. Pneumonitis is a major complication among adults with measles. More studies are imperative in order to explore the role of immune paresis in measles.

Measles infection is a highly contagious, air-borne, acute febrile illness caused by a paramyxovirus of the Morbillivirus genus [1] and still remains an unresolved global issue with considerable mortality and morbidity rates [2] . The World Health Organization (WHO) has recently reported an upsurge of measles cases in the Eastern Mediterranean, the European and the Americas Regions, in areas with reported closeto-elimination or elimination of measles [2] [3] [4] . The re-emergence of measles infection possibly signifies the gap in previous vaccination strategies. According to latest WHO-UNICEF report only five European countries reported >95% vaccination coverage with both doses of measles-containing vaccine; the respective rates in Greece for the first and second dose were 97-99% and 77-83% between 2008-2018 [5] . Although the epidemic was contained in Greece during 2019, there was a substantial upsurge in other European countries during the same year with a total of 13,460 cases [6] . Similarly, an outbreak with 1,282 cases (of whom 29% adults) was reported in the United States of America (USA) during 2019, a country that declared measles elimination in 2000 [7] .

The natural course of the infection has only been scantly defined in adults, making management challenging even for experienced clinicians. In this study, we describe our experience from the recent outbreak of measles in adult hospitalized patients in Greece [8] . 

This study was approved by the Research Ethics Committee of each participating institution (protocol numbers: AUH: 1821A/22-9-16, TGH: 433/18-12-19, HGH: 2613/18-2-2020) and was conducted according to the Outbreak Reports and Intervention studies Of Nosocomial infection (ORION) reporting guidelines [9] .

Patients' data were collected and analyzed under strict anonymity in agreement with the Declaration of Helsinki. Since this was a retrospective study, no informed consent was obtained.

All patients were classified either as probable or as confirmed cases according to the case classification by the European Centers for Disease Control and prevention J o u r n a l P r e -p r o o f 8 (ECDC) ( Table 1) . Definitions of pneumonitis and hepatic involvement are provided in Table 1 .

Probable case of measles infection [10] Any person meeting the clinical criteria with an epidemiological link.

Clinical Criteria: Fever AND Maculo-papular rash AND at least one of:

Cough, Coryza, Conjunctivitis. 

Εlevation of ALΤ above the ULNon admission (according to each centre's reference range)

The severity was divided into 2 Grades; 

In total 93 patients, 40 males (43%) and 53 females (57%) aged between 18

and 62 years old, were included ( Table 2) . Laboratory results are summarized in Table S1 .

In total, 43 (46.2%) patients (24 men) fulfilled the definition of pneumonitis. Age-CRP interaction was also included in the final model, however it was non-significant. ALT: alanine aminotransferase, FiO 2 : fraction of inspired oxygen, IQR: interquartile range, L: liter, n: number of patients, PaO 2 : arterial partial pressure of oxygen, SD: standard deviation, U: units. Table 5 . Characteristics and outcomes of ribarivin group in patients with pneumonitis and hepatic involvement.

Hepatic involvement was found in 77 (82.8%) patients. Among them, 47

(50.5%) and 28 (30.2%) patients had Grade I and Grade II hepatic involvement respectively. When patients divided into those without or with Grade I liver injury and those with Grade II hepatic involvement, no statistically significant differences J o u r n a l P r e -p r o o f regarding baseline characteristics and presenting symptoms or signs were noted apart from the gastrointestinal (GI) symptoms that were more frequent in those without or with Grade I liver involvement (Table S2) . A similar comparison between those with normal alanine aminotransferase (ALT) and those with any degree of hepatic involvement did not reveal any statistically significant difference.

A patient with confirmed measles was presented with a generalized vasculitic eruption instead of the typical rash, while another two males developed haematuria with dysmorphic red blood cells in urine sediment, suggestive of acute glomerulonephritis. In one of them, further work-up with C3, C4, rheumatoid factor and immunoglobulin levels disclosed normal values. Furthermore, 1 out of the 4 pregnant women suffered spontaneous fetal miscarriage during her hospital stay at the 8 th week of gestation. No neurological complications were reported in this cohort.

All but one patient, were discharged alive from hospital after a median hospitalization of 6 days (IQR= 4-7). Pneumonitis was not correlated with the length of hospital stay (Table 3) . One obese female patient with a Grade II hepatic involvement and pneumonitis that progressed rapidly into acute respiratory distress syndrome (ARDS) requiring mechanical ventilation, died within 6 days of her admission due to high-risk pulmonary embolism (PE) despite being treated with ribavirin.

In this study we describe the clinical features and outcomes of mostly healthy and young adult hospitalized patients with measles. Our data show that the most prevalent symptoms and signs are high-grade fever, cough and generalized maculopapular rash in concordance with previous reports in adults [11, 12] . Hepatic involvement and pneumonitis frequencies were as high as 80.6% and 46.2%

respectively. When compared to other recent studies including adults, our cohort was quite similar in terms of mean age, sex distribution, presenting symptoms and baseline laboratory findings [13] . Despite the high prevalence of pneumonitis in this study, Genotype B3 was the most common [8] . Prior to this, a major outbreak occurred during 2005-2006 where genotypes D4 and D6 co-circulated [14] and a less severe one followed in 2010.

Pneumonitis is probably the most serious complication of measles. The prevalence of pneumonitis in our study (46.2%) was slightly higher than the one recently reported in Israel (30.5%), in Serbia (26.8%) and China (33%), although the latter two studies included pediatric and adolescent cases that could have affected the pooled results [13, 15, 16] . Here, we show that male sex, older age, higher CRP and low lymphocyte counts are significantly associated with the presence of pneumonitis.

To our knowledge, only one recent study has focused on identifying risk factors for pneumonitis. Tu et al reported that measles-associated pneumonia was associated with younger age, longer fever duration, higher white blood cell (WBC) counts and normal ALT [16] . Again, we believe that the inclusion of all age groups in this analysis may have a significant impact on the outcomes, making the extrapolation of the results in adults less sounding. Indeed, children<8 months old had significantly higher rates of pneumonitis; moreover, normal lymphocytosis of childhood may have attenuated the impact of lymphopenia as an independent associated factor for pneumonitis.

Another interesting finding is the low proportion of patients with Koplik spots seen in our cohort (30.4%). This could be possibly attributed to the long median time from symptom onset to hospital admission (4 days), given that Koplik spots appear 1-2 days prior to skin rash and usually disappear within the second day of rash eruption.

Measles-induced lymphocytopenia as well as its grade, possibly has a role either as a disease severity biomarker or by predisposing to short-and long-term infectious complications. There is growing evidence that measles infection induces immunosuppression; a recent study in measles-infected children found significantly higher rates of hospitalization (during the first month), non-measles infections and antibiotics prescription up to 5 years post-measles [17] . Mina et al showed that measles infection, but not MMR vaccination, reduces the humoral immune memory against numerous viruses in children [18] . Another study demonstrated that measles compromises the protection acquired by vaccinations or previous infections by altering the memory B-lymphocyte diversity and leads to incomplete naïve B-cell reconstitution, characterized by a narrower post-infection B-cell receptor repertoire [19] .

Although it is generally believed that CRP is not increased in patients with viral infections in the absence of pneumonitis, several studies have shown modest increases of CRP in patients with influenza and other viruses even in the context of non-severe disease sparing the lower respiratory tract [20] [21] [22] . As for measles, Griffin et al have reported in an older study including children 4-to 5-fold increases in CRP even in uncomplicated cases. In concordance with the above, we do not consider the increased CRP in our patients with and without pneumonitis unusual [23] .

Diagnosis of pneumonitis was followed by antibiotic prescription in 72% of patients, though we had no proven superinfections in this cohort. In contrast, an older study by Loukides et al reported a bacterial pneumonia rate of 26% in measlesinfected young males during an epidemic in the Greek army, with Streptococcus pneumoniae and Klebsiella pneumonia being the most commonly isolated pathogens [24] .

In our cohort, only 8 patients received ribavirin. Due to the small number of treated patients and the heterogeneity in its use among the participating centers, our study could not reach to any specific conclusions regarding its exact role in the management of patients with measles. Ribavirin use in this setting is mainly supported by case reports or small case series [25, 26] .

Only one death was seen among 93 patients. This case was a 36-year old previously healthy female who developed measles-induced ARDS and PE with hemodynamic compromise. The interplay between viruses and pro-coagulant state has been previously reported; influenza has been associated with acute coronary syndromes [27] and possibly de novo PE in the absence of deep venous thrombosis [28] , while similar cases have also been reported with other viral infections [29] .

Apart from obesity, our patient did not have any other risk factors for PE, in agreement with a recently reported pediatric case [30] . This potentially fatal complication could be attributed to direct endothelial damage caused by the measles virus, given that endothelial dysfunction has already been reported in children with fatal measles encephalitis [31] . This particular complication in acutely ill patients with respiratory viral infections has become even more relevant in light of the COVID-19 pandemic, where venous thromboembolism (VTE) is increasingly reported, even in the presence of prophylaxis [32] . Moreover, some evidence supports a survival benefit with VTE treatment in critically ill patients with COVID-19 (but not in those with non-COVID-19 illness) and increased D-dimers [33] . Current guidelines show significant divergence ranging between more conservative [34] and more liberal approaches [35] . Regarding measles infection, we suggest that hospitalized patients with measles should be treated according to the existing VTE prophylaxis guidelines in patients with acute medical illness.

Another finding of great interest is the disease pattern in pregnant women with measles. In our cohort, 4 women (7.5% of female patients) were pregnant and we recorded one miscarriage among them (25%). Pregnant women are more likely to be hospitalized, develop pneumonia and die when compared to non-pregnant women and, although not regularly associated with a higher miscarriage rate, measles has been correlated with preterm labor, low birth weight and higher rates of admission in neonatal ICU [36] . Our study also has some limitations. The retrospective design could attribute to several biases and missing data, although the medical files were thoroughly reviewed and the percentage of missing data was quite low for almost all variables.

Moreover, treatment patterns across participating centers were not aligned, as it was depicted in the heterogeneity of ribavirin administration. This is not surprising, given the absence-to our knowledge-of guidelines establishing the role of ribavirin or other antivirals in immunocompetent adult patients with measles. Finally, the inclusion of hospitalized patients may not precisely reflect the physical history of measlesassociated pneumonitis in general population, since a proportion of patients with a more indolent lung involvement might not require hospitalization.

In summary, in this study we presented the clinical characteristics of measles infection during the recent epidemic in hospitalized adults in Greece. We further Conflict of interest: None of the authors has any conflicts to declare.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The data that support the findings of this study are available from the corresponding author [PCF: evita.fragou@gmail.com] upon request.

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