Case Report: Co-infection with SARS-CoV-2 and influenza H1N1 in a patient with acute respiratory distress syndrome and a pulmonary sarcoidosis

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been a global public health concern. We report coinfection of SARS-CoV-2 and 2009 H1N1 Influenza strain in a French patient with pneumonia leading to acute respiratory distress syndrome. The patient also had a medical history of pulmonary sarcoidosis with a restrictive ventilatory syndrome and obesity, which would be a supplementary risk to develop a poor outcomes. This case highlights the possible coinfection of two severe SARS-CoV-2 and influenza H1N1 viruses in comorbid patient, which presents a higher risk to extend the care duration. The overlapping clinical features of the two respiratory syndromes is a challenge, and awareness is required to recommend an early differential diagnosis and it’s necessary to adopt the vigilant preventive measures and therapeutic strategies to prevent a deleterious impacts in patients with comorbid factors.


Introduction
Coinfections involving SARS-CoV-2 and respiratory viruses influenza viruses (A or B) have been rarely reported [1][2][3][4][5][6][7][8][9] . One recent meta-analysis indicated that overall 1.2% of COVID-19 patients had influenza co-infection 10 . However, there was no more evaluation of the infection effect in clinical outcomes and less in patients with other comorbidity factors. Our patient presented concurrent COVID-19 and Influenza infections with a history of pulmonary sarcoidosis.

Case report
A 41-year-old man presented to the hospital's emergency unit with fever and cough that has been progressing for several days. The SARS-CoV-2 RT-PCR test carried on the 3 targets genes RdRp, N, E was positive on March 22 nd 2020, wheares the cough and fever had already been evolving for three to four days before. On March 24 th 2020, the patient had developed a dyspnea aggravation and was taken care of by a medical unity at home. He has a medical history of pulmonary sarcoidosis with a restrictive ventilatory syndrome, which was being treated with Methotrexate (15mg per week) and folinic acid (0,4mg one tablet per day). He also had malaria in 2004 from a trip to Central Africa.
Physical examination on the 24 th March revealed a respiratory rate of 41 breaths/minute (normal range (NR) 12-20 breaths/ minute) and oxygen saturation SpO2 of 75% (reference range (R-R) 95-100%) on ambient air. The SpO2 became at 96% when given mask flow oxygen at a rate of 12l/minute. The patient was transferred to the emergency room with 97% SpO2, body temperature 37.2°C, and respiratory rate of 30 breaths per minute. The patient presented with superficial polypnea, dyspnea with little effort, difficulty in speaking and bilateral "crackles". Neurological and cardiovascular examinations were normal.
Other parameters showed decreased values such as red cells, hemoglobins, hematocrits and mean corpuscular hemoglobin content ( Table 1). The number of leukocytes and neutrophils underwent fluctuations with high rates between April 7 th and 10 th ( Figure 1). In this period, bacteriological examination culture revealed infection by additional pathogens, with the presence of yeasts (Candidate albicans) and bacteria (Klebsiella pneumoniae) in bronchial sampling, probably with nosocomial origin. Indeed, Klebsiella pneumoniae was isolated on the deep bronchial sample of March 28 th , 2020, five days after his admission and mechanical ventilation. On the 14 th day of admission (April 4 th 2020), Klebsiella pneumoniae was found once again at 10 6 in a bronchoalveolar lavage which means the failure of treatment with imipenem, meropenem is then introduced. Also, Candidas albicans was found in the same bronchoalveolar lavage at 10 4 .
The patient stayed at ICU for 26 days from March 24 th to April 19 th with orotracheal intubation and using Etomidate (40 mg intravenous dose) for sedation and 120mg of Celocurine for curarization. Enoxaparin (40mg /day) was administered by subcutaneous injection as a preventive anticoagulation up to April 1 st and increased to 80 mg/day according to the patient being overweight (Body Mass Index 33.8) and to evolution of biological criteria (D-Dimers 1890ng/l, Fibrinogen 10.82g/l, platelets 528x10e9/l). Unfractionated heparin was used as relay according to the high probability of pulmonary embolism. Mechanical ventilation was used with several sessions of prone position and then oxygen therapy on April 19 th . He was treated with hydroxychloroquine for 10 days (Plaquenil, 200mg every eight hours), and by Oseltamivir (4 days, oral suspension 6mg/ml: 75mg twice/day) for influenza H1N1 infection. Klebsiella pneumoniae infection was treated using Meropenem (intravenous 1 g every four hours) from 6 th to 15 th April and Enterococcus faecalis infection was treated using Clamoxyl (intravenous 2 g every eight hours). Venous echodoppler performed on April 14 th found no thrombosis and no pulmonary embolism.
On April 19 th , the patient was transferred to the pulmonology department where he has a good respiratory evolution allowing oxygen weaning on April 23 rd . He was discharged on April 28 th , receiving kinesitherapy treatment, and taking

REVISED Amendments from Version 1
In the second version, we have taken into account the interesting remarks of the reviewers. We had added some molecular, clinical, and therapeutic details during the patient's hospitalization. But the most important remark is the fact that the co-infection occurred in a patient with a history of pulmonary sarcoidosis, it seems more original and deserves more emphasis in the discussion and in the title. Also, it is very important to note that it is necessary to adopt the vigilant preventive measure and therapeutic strategies to prevent a deleterious impact on infected and comorbid patients. We have added Dr. Toufik Kamel in the author list.
Any further responses from the reviewers can be found at the end of the article Table 1. Laboratory findings in the patient with coinfection of SARS-CoV-2 and influenza H1N1. NA: data non available.

May, 06
Leukocytes (4-10x10e9/l)  a preventive anticoagulant therapy (Enoxaparine 4000 IU /0.4ml once daily by SC injection) for three weeks. The CT scan control on April 30 th 2020 revealed reduction of affection to less than 25% with appearance of more or less symmetrical, predominantly peripheral, bilateral pulmonary ground glass areas. The patient was integrated into the post COVID-19 rehabilitation program.

Discussion
We report a case of coinfection with SARS-CoV-2 and seasonal influenza H1N1 in a French comorbid patient. The prolonged intensive care and detection of SARS-CoV-2 viral RNA on the bronchoalveolar sample for at least three weeks might be explained by the immunosuppression caused by lung polyinfection (viral, bacterial and fungal) and also by his medical history of pulmonary sarcoidosis with a restrictive ventilatory syndrome and obesity. Indeed patients who had influenza co-infection was 1.2%. One other meta-analysis study revealed that co-infection with SARS-CoV-2 and influenza showed a high heterogeneity for overall mortality 13 . However, the relationship with the severity of COVID19 disease in the case of co-infection associated with one or more comorbidity factors such as diabetes, cardiovascular diseases, hypertension, malignancies, chronic obstructive pulmonary disease, and other comorbidities has been largely reported and could induce a life-threatening situation [14][15][16] . For example, the risk for ICU admissions in COVID-19 individuals with diabetic comorbidity is 14.2% higher than individuals without diabetes 15 . Cuadrado-Payán et al. 5 reported that all COVID-19 patients studied with medical history of hypertension, end-stage kidney disease, or type 2 diabetes attended the emergency unit 5 .
The co-detection of SARS-CoV-2 and Influenza H1N1 in our case with comorbidity factor the pulmonary sarcoidosis and obesity demonstrates the challenge to screen in the onset of the respiratory illness for a panel of viruses, which have overlapping clinical patterns and might exacerbate clinical symptoms, increase morbidity and prolong ICU stay. Hence, this case highlights the higher risk and poor outcomes caused by co-infection and the importance to achieve a differential diagnosis of respiratory distress syndromes speciallly in comorbid patients, to recommend seasonal influenza vaccination in addition of SARS-CoV-2 vaccine. It's necessary to adopt the vigilant preventive measure and therapeutic strategies to prevent a deleterious impact and health service demand on infected and comorbid individuals.

Consent
Written informed consent was obtained from the patient for the publication of this article and any associated images.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.

Open Peer Review
The most important physical examination and diagnostic tests are reported in the case report. The methodology followed is well reported. However, data concerning the genetic investigations for both viruses is missed. It is recommended to discuss it, taking into consideration the specific phenotype observed in this case.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes   The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com