Influenza is one of the most common infectious diseases in travellers, especially in those returning from subtropical and tropical regions. In late June 2018 an influenza A(H1N1)pdm09 virus infection was diagnosed in a 36-years-old man, returned from a travel in Shanghai and hospitalized at the Ospedale Policlinico San Martino, Genoa, Italy, with a diagnosis of fever and an uncommon clinical presentation characterised by a persistent leukopenia. Phylogenetic analysis revealed a closeness with influenza A(H1N1)pdm09 strains circulating in the US in May-June 2018. Prompt recognition of influenza infection led to a proper case management, demonstrating the crucial role of the continuous influenza surveillance programme

Barisione, G.

Bruzzone, B.

Butera, F.

Grammatico, F.

Guarona, G.

Murdaca, G.

Orsi, A.

Schenone, S.

Setti, M.

Tisa, V.

English

Butera F.

Schenone S.

Grammatico F.

Tisa V.

Barisione G.

Guarona G.

Bruzzone B.

Murdaca G.

Setti M.

Orsi A.

Archivio istituzionale della ricerca - Università di Genova

J PREV MED HYG 2019; 60: E1-E4E1Influenza is one of the most common infectious diseases in travellers, especially in those returning from subtropical and tropical regions.In late June 2018 an influenza A(H1N1)pdm09 virus infection was diagnosed in a 36-years-old man, returned from a travel in Shang-hai and hospitalized at the Ospedale Policlinico San Martino, Genoa, Italy, with a diagnosis of fever and an uncommon clinical presentation characterised by a persistent leukopenia. Phyloge-netic analysis revealed a closeness with influenza A(H1N1)pdm09 strains circulating in the US in May-June 2018.Prompt recognition of influenza infection led to a proper case management, demonstrating the crucial role of the continuous influenza surveillance programme.C ASE REPORTDetection of influenza A(H1N1)pdm09 virus in a patient travelling from Shanghai to Italy in July 2018:  an uncommon clinical presentation  in a non-seasonal periodF. BUTERA1, S. SCHENONE1, F. GRAMMATICO1, V. TISA1, G. BARISIONE1, G. GUARONA1, B. BRUZZONE2, G. MURDACA3, M. SETTI3, A. ORSI1,21 Department of Health Sciences, University of Genoa, Italy; 2 Hygiene Unit, Ospedale Policlinico San Martino, Genoa, Italy; 3 Clinical Immunology Unit, Department of Internal Medicine, University of Genoa and Ospedale Policlinico San Martino, Genoa, ItalyKeywordsInfluenza • Surveillance • Travellers’ infectious disease • LeukopeniaSummaryhttps://doi.org/10.15167/2421-4248/jpmh2019.60.1.1214IntroductionTravels are associated with an increased risk of infec-tious diseases, and influenza is one of the most frequent acquired infectious diseases in travellers [1].Influenza is characterized by a seasonal pattern only in temperate climates, with a virus circulation usually observed during the cold season, coinciding with a pe-riod that lasts from November to March in the Northern Hemisphere, and from April to October in the Southern Hemisphere. In tropical areas, however, influenza virus circulates at low levels all the year round [2]. Trips by air, ship or train facilitate the viral spread, depending of the length of the trip (0-1 infections could occur dur-ing a 5 hours flight, 1-3 during an 11 hours flight and 2-5 during a 17 hours flight) and the number of passen-gers [3, 4]. The short incubation period and the high in-fectivity of influenza (basic reproduction number - R0 around 1.5) are the key reasons for the high frequency of influenza among travel-related diseases [1].Fifty million people are estimated to travel to the trop-ics each year and approximately half of these presents a travel-related health problem [5-8]. The proportion of influenza in travellers returning from subtropical and tropical regions ranges between 5% and 15% as reported by different studies [3, 9-11].Case reportA 36-years-old man, returned four days earlier from a travel in Shanghai lasted 2 weeks, accessed to the Emer-gency Department (ED) of Ospedale Policlinico San Martino, Genoa, Italy, on 28th June 2018 with a diagno-sis of fever. The main clinical manifestation at the ED access was a hyperpyrexia started two days earlier (max-imum body temperature: 39.5°C) responsive to paracet-amol; associated symptoms were arthralgia, nausea and vomiting. The physical examination revealed a pharynx hyperaemia without tonsillar hypertrophy; no skin rash, headache or signs of nuchal rigidity were observed. His past medical history wasn’t characterized by any disease of note. In the ED a symptomatic therapy with paraceta-mol (1 g/100 mL) was started.In Table I the laboratory tests performed during patient’s hospitalization are reported. The tests performed at the ED revealed leukopenia (White Blood Cell count: 3 x 109/L) and a modest increase in the levels of C-re-active protein (13.6 mg/L), creatinine (1.2 mg/dL), and a low decrease of potassium (3.3 mEq/L) and alkaline phosphatase (ALP, 36 IU/L). Detection of malaria an-tigens, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) serology, blood culture and urine culture were performed and revealed only a previous EBV infection and a Escherichia coli count in the urine of 106 CFU/F. BUTERA ET AL.E2mL. The latter wasn’t treated because asymptomatic. No alterations were visible on the chest X-ray performed on 28th June.Upon admission at Clinical Immunology Unit, Depart-ment of Internal Medicine of Ospedale Policlinico San Martino, the patient was substantially asymptomatic ex-cept for a mild non-productive cough. In fact the fever, after the peak at 38.5°C on 28th June at ED, slowly de-creased. Leukopenia was still present (from 28th June to the discharge at 10th July) and characterized by low lev-els of neutrophil granulocytes (0.67 x 109/L at the nadir on 2nd July) and also a reduced reticulocyte count was observed from 3rd July (0.3%). Only on-demand therapy with paracetamol and metoclopramide was introduced.A series of laboratory tests were performed during hos-pitalization: blood cultures, sputum cultures, detection of Streptococcus pneumoniae and Legionella antigens in urine, parasites tests, detection of malaria antigens in blood samples, serological markers of infection by hepatitis A (HAV), B (HBV) and C (HCV), human immunodeficiency virus (HIV), Zika virus, Parvovi-rus, Salmonella typhi and paratyphi, Brucella, Proteus, Tab. I. Laboratory tests performed during patient’s hospitalization (Emergency Department and Clinical Immunology Unit, Ospedale Policlinico San Martino).Variable Reference range Day 1(ED)Day 2 (ED) Day 5 Day 6 Day 7 Day 8 Day 12WBCs 4.50-9.80 x 109/L 3 2.72 1.76 1.76 2.35 3.16 4.4RBCs 4.5-5.9 x 1012/L 5.2 5 4.9 4.6 4.5 4.5 4.9Hemoglobin 135-175 g/L 144 141 139 130 124 131 143Hematocrit 39-51% 44 43.1 41.3 38.2 37.2 37.7 42.1MCV 80-100 fL 85.3 85.9 83.6 82.9 83.3 83 85.4MCH 26-32 pg 27.9 28.1 28.1 28.3 27.8 28.9 29MCHC 320-360 g/L 327 327 337 341 334 348 340RDW 11.5-14.5% 12.8 12.8 12.2 11.8 11.9 11.8 12.6Platelet 130-430 x 109/L 143 148 113 114 131 157 278Neutrophils 1,80-7,80 x 109/L 2 1.7 0.67 0.74 1.22 1.63 2.7Neutrophils 40,0-70,0% 62 37.9 41.9 51.8 51.7 61.8Lymphocytes 1,10-4,80 x 109/L 0.7 0.88 0.82 0.93 1.22 1.4Lymphocytes 19,0-48,0% 24.4 49.9 46.9 39.7 38.5 32.2Monocytes 0,20-0,96 x 109/L 0.4 0.07 0.07 0.08 0.09 0.2Monocytes 3,4-12,0% 13.2 4 3.8 3.2 2.8 4.5Eosinophils 0,00-0,50 x 109/L 0 0.02 0.03 0.06 0.12 0.1Eosinophils 0,0-8,0% 0.1 0.9 1.9 2.7 3.8 1.3Basophils 0,00-0,20 x 109/L 0 0.02 0.03 0.02 0.02 0Basophils 0,0-1,5% 0.3 1.1 1.6 0.7 0.7 0.2LUC 0,0-4,0% 6.2 3.9 1.9 2.4Reticulocytes 0,7-1,7 x 100 RBCs 0.3 0.5 0.6Creatinine 0,67-1,17 mg/dL 1.2 1.2 1 1Prothrombin time % (10-13 sec) 73 82 101 101Prothrombin time INR 0.80-1.20 1.24 1.15 0.99 0.99Activated partial thromboplastin time 28,0-40,0 sec 34.8 33.7 33.2 31.9Total bilirubin 0.20-1.20 mg/dL 0.46 0.35 0.30 0.27Sodium 135-150 mmol/L 136 137 141Potassium 3,5-5 mmol/L 3.3 3.5 4Chloride 90-120 mEq/L 99 102Calcium 8,5-11,0 mg/dL 8.4 9.1Phosphorus 2.5-4.5 mg/dL 3.7 3.8Magnesium 1.9-2.5 mg/dL 2.1 2.1Glucose 65-110 mg/dL 97 96Albumin 34-50 g/L 36.4 40.3C-Reactive Protein 0-5 mg/L 13.6 9.6 3.2 3.2ALP 50-116 U/L 36 38 30 28ALT 0-40 U/L 26 23 18 16gGT 11-50 U/L 13 19 16WBCs: White Blood Cells count. RBCs: Red Blood Cells count. MCV: Mean Corpuscular Volume. MCH: Mean Cell Hemoglobin. MCHC: Mean Corpuscular Hemoglobin Concentration. RDW: Red cell Distribution Width. LUC: Large Unsustained Cells. ALP: ALkaline Phosphatase. ALT: ALanine aminoTranspherase. gGT: gamma GlutamylTranspherase. INR: International Normalized Ratio.Values out of range are in bold and underlined.INFLUENZA A(H1N1)pdm09 INFECTION DURING ITALIAN SUMMERE3Schistosoma and Leishmania. Nasopharyngeal swab for respiratory viruses and bacteria was performed for the first time on 2nd July and resulted positive on 4th July, re-vealing the presence of influenza A(H1N1)pdm09 virus and Haemophilus influenzae.Antiviral therapy with oseltamivir (150 mg/day) was started on 4th July and the patient was concurrently iso-lated. The general outcome was good and the patient was discharged at the end of antiviral therapy on 10th July, with a diagnosis of influenza A(H1N1)pdm09 infection and transient neutropenia probably due to infection. The patient received the recommendation to limit contact with people at greater risk (cardiopathic, pneumopathic, el-derly in general, immunocompromised people, pregnant women, infants) and to wear the mask until the result of the nasopharyngeal swab performed at the discharge. This last resulted negative three days later, on July 13th.Phylogenetic analysis of the virus strain were performed as previously described  [12] between July and August 2018 and revealed a similarity with viruses isolated in the US in May and June 2018 and characterized by T120A mutation (Fig. 1).Fig. 1. Phylogenetic analysis of the hemagglutinin (HA) nucleotide sequences from influenza A(H1N1)pdm09 viruses. The phylogeny tree was generated by the neighbor-joining method with 1000 bootstrap replicates. Ligurian strains (underlined), WHO recommended candidate vaccine for 2017/2018 and 2018/2019 Northern Hemisphere influenza season (bold, underlined) and reference strains (bold).F. BUTERA ET AL.E4DiscussionWorldwide, in the period June-July 2018 seasonal influ-enza type A viruses accounted for the majority of detec-tions. A(H1N1)pdm09 prevailed over A(H3N2) viruses. In temperate zone influenza activity was at inter-seasonal levels, whereas in tropical countries of Central America, South America, African region and Asia influenza activ-ity remained low in the same period. In particular viro-logical surveillance in China from week 18 to week 31 of 2018 revealed that influenza subtype A(H1N1)pdm09 virus was the most frequent detected  [2]. However, no influenza virus isolation has been notified in Shanghai in the same period [13].Influenza infection must be taken into account in differ-ential diagnosis in every season and in any patients with acute respiratory disease coming from an intercontinen-tal travel, even though with an atypical clinical presen-tation. In our case, the diagnosis of influenza infection settled diagnostic doubts, therefore providing the better patient management. Continuous virological surveillance allows constant monitoring of circulating influenza viruses, representing a key tool for characterization and selection of influenza strains to be included in vaccine composition, as well as for potential detection of new viral strains, including those carrying a pandemic risk.AcknowledgementsFunding sources: this research did not receive any spe-cific grant from funding agencies in the public, commer-cial, or not-for-profit sectors. Conflict of interest statementNone declared.Authors’ contributionsFB analysed data, wrote, drafted and revised the manu-script. SS, FG and VT advised on analysis, wrote, draft-ed and revised the manuscript. GB and GG performed virus detection and genotyping and revised the manu-script. BB coordinated laboratory activities. GM and MS coordinated clinical activities and revised the manu-script. AO supervised virological analysis and revised the manuscript. All the authors reviewed and approved the final manuscript.References[1] Belderok SM, Rimmelzwaan GF, van den Hoek A, Sonder GJ. Effect of travel on influenza epidemiology. Emerg Infect Dis 2013;19(6):925-31. doi:10.3201/eid1906.111864.[2] World Health Organization. Influenza Laboratory Surveillance Information by the Global Influenza Surveillance and Response System (GISRS). Available at: https://www.who.int/influenza/gisrs_laboratory/flunet/charts/en/. Accessed on 19/02/2019.[3] Askling HH, Rombo L. Influenza in travellers. 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Incidence of respiratory viruses among travelers with a febrile syndrome returning from tropical and subtropical areas. J Med Virol 2008;80(4):711-5. doi:10.1002/jmv.21086.[11] Askling HH, Lesko B, Vene S, Berndtson A, Björkman P, Bläck-berg J, Bronner U, Follin P, Hellgren U, Palmerus M, Ekdahl K, Tegnell A, Struwe J. Serologic analysis of returned travelers with fever, Sweden. Emerg Infect Dis 2009;15(11):1805-8. doi: 10.3201/eid1511.091157.[12] Trucchi C, Alicino C, Orsi A, Paganino C, Barberis I, Gram-matico F, Canepa P, Rappazzo E, Bruzzone B, Sticchi L, Ansaldi F. Fifteen years of epidemiologic, virologic and syn-dromic influenza surveillance: A focus on type B virus and the effects of vaccine mismatch in Liguria region, Italy. Hum Vaccin Immunother 2017;13(2):456-463. doi:10.1080/21645515.2017.1264779.[13] Flu in China. Available at: http://map.flu.org.cn/MapBrowser.aspx?reportId=192. Accessed on 19/02/2019.n Received on Janaury 19, 2019. Accepted February 12, 2019.n Correspondence: Andrea Orsi, Department of Health Sciences, University of Genoa, and Hygiene Unit, Ospedale Policlinico San Martino, Genoa, Italy - Tel. +39 010 5552996 - Fax +39 010 5556745 - E-mail: andrea.orsi@unige.it 

Detection of influenza A(H1N1)pdm09 virus in a patient travelling from Shanghai to Italy in July 2018: An uncommon clinical presentation in a non-seasonal period

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Detection of influenza A(H1N1)pdm09 virus in a patient travelling from Shanghai to Italy in July 2018: An uncommon clinical presentation in a non-seasonal period

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