Chest Reseach Chin Pace 12020) 205-209 Contents lists available at ScienceDirect Obesity Research & Clinical Practice journal homepage: www.elsevier.com/locatelorop Original Article Obesity prolongs the hospital stay in patients affected by COVID-19, ® and may impact on SARS-COV-2 shedding soa ie Diego Moriconi’, Stefano Masi’, Eleni Rebelos, Agostino Virdis®, Maria Laura Manca®, Salvatore De Marco”, Stefano Taddei*, Monica Nannipieri*” « peperent of lial an xperimenal Medicine, Unies Psa. aly "tend pele Universtara Ma ADU. Pay ARTICLE INFO ABSTRACT ‘le hit “neaduction:On the last three months the new SARS-COV.2 coronavirus has created a pandemic. apidly Received 23 May 2020 spreading al around the world The aim ofthe study is toinvestigate whether obesity impacts on COVID- ‘Accept 29 2020 19 morbidity _Methods: One hundred consecutive patients with COVID-19 pneumonia admitted in our Meslcal Unit yw tere evant. Anthropometric parameters nd ss mes soy were eer Nasophanynge oes Sab samples an biochem ans were obtained at mission and rng spa a om Rest atten ait (O82) and wot ay N-O8.7 were sian age, gender and cmon cr ties, with the exeeption of hypertension thar was more frequent in OB group. At admission, inflammatory a markers were higher OB than 8 group. Ob group showed worse pulmonary cline itr wh lowes Pa02 (57 15.68 dmv p= D082) and S402 (88 © us 82 2 Sep = 0089) at aission Consequty rearing higher umes of oxygen (0238 1545 29+ 10% p = DOA?) naa longer period vo chew oygen weaning (10-1615 days p= 003) OB group aso had pov sabe forlonger ie 19 283.27 ym p= ODD ond req ings onptal sty (2128 13 = 84s p = 0.0008) Paral lest square regresion nai showed that BM age and CR 3 admission ‘tereeatedtolonger enh of hospital sta, atime for negative swab On the conta, hs cbor, hei ld not pred her moray Cencton Subst with abst seed by COVID-19 require longer hospitalization more intensive Sndlonger oxygen ucstment and they may hae longer SAVS-COV-2 shedding {© 2020 sl Oceania Asolton for the ty of Obst Published by Eee LA igs reseed Introduction Js known tobe higher in patients with obesity than in the general Obesity is an increasingly important mortality risk factor, par- tially because it increase the risk of several non-communicable diseases [1~4], Pathogenetic mechanisms underlying these dis- ‘eases appear to be related, atleast in part, to a chronic, low-level inflammatory exposure which often accompanies adipose tissue accurnulation and promotes the development of metabolic and car= ‘diovascular complications. Furthermore, the thromboembolic tisk * Govesponding author a: Department of China and Experimental Medicine Univers of isa Vi a 10, 56126 Psa, faly maladies: mrionioo- penton (0. Movicon)sefana.masiOunipist(S. Masi eleniebelosogmaitcom (E Rebees), 2gostinawiisunput (A Vids), Lnancaé ned uniplc(MLL Manca ‘Edemarcodao isa scanai(& De Maro}, stefan taddeiOunp (Tadd), ‘nies nannplern. nit (M, Nannie). poor] 40 1016,» 202005 09 1871-403X) population (5) ‘Although increased body mass index (BMI) has been associ- ated with a higher susceptibility to and more severe presentation, of infections 5] (such as HINI influenza virus), data remain con- ficting. Indeed, several reports have suggested that patients with obesity might have alower mortality rate during severe sepsis than ‘normal-weight patients [7-12]. This phenomenon seems to be in Iine with some studies reporting a paradoxical association between, overweight and class | obesity and reduced mortality in patients with chronic heart failure [13,14] On the last three months, the new SARS-COV-2 infection has rapidly spread around the world, Even though the outbreak started inChina, the pandemic quickly moved to Europe and America, lead- ing toa crisis of several National Health Systems. ‘Compared to China, in these westernized societies the popu- lation is older, and there is a much higher prevalence of obesity. 320 Asia Oceanis Asotin forthe Study of Obesity, Published by Elsevier Ld Al ight ceserve,205 Atco et aj Obst Research Cine Practice 14 (2020) 205-209, ‘These features might aggravate the severity of the disease, given the greater frailty of the population and the well-established mechanical restrictive pattern imposed by high body weight 10 the respiratory system dynamic. Furthermore, in obese patients there isan increased prevalence of respiratory diseases, including, chronic obstructive pulmonary disease (COPD) and sleep apnea. ‘These factors might explain the greater severity, hospitalization and mortality from HIN1 virus infection observed in obese com- pared to non-obese patients [15] Recent studies have suggested that BMI represents a risk factor for severe complications in patients with COVID-19 [16,17], Epidemiological data of the italian Health institute (Epicentro) have shown that in people died with positive SARS-COV-2 swab the prevalence of obesity was 11% 18]. This data reflects the prevalence (of obesity in italian popolation reported by the Italian Barometer Diabetes Observatory Foundation in the 2019 [ 19}. Inthe present study, we wished to investigate whether in our ‘cohort of COVID-19 subjects, obesity Was predicting a worse out- come, in terms of mortality. or of other factors that could be related toa worse clinical picture. ‘Methods and material ‘Study design and patients Consecutive patients admitted tothe COVID-19 uni of Cisanelo Hospital, atthe “Azienda Ospedaliero Universitaria Pisana-AOUP. (Pisa, Italy), between March 16th and April 15th, 2020 were enrolled in this single-centre, retrospective, observational cohort study, This retrospective observational study was based on med- ical records, in strict agreement with local Ethical statement of ‘AOUP. Patient confidentiality was protected by assigning an anony- ‘mous identification code, and the electronic data were stored in a locked, password-protected computer. All patients were diagnosed with COVID-19 pneumonia according to World Health Organiza- tion interim guidance [20] with SARS symptoms characterized by ‘dyspnea, increased respiratory frequency, decreased blood oxy gen saturation, and! need for oxygen support therapy. Two nose and pharyngeal swab samples were obtained from all patients at admission and, at different times depending on the clinical evo lution of the disease, during the hospital stay. The presence of the SARS-COV-2 genome was detected using real-time reverse transcriptase-polymerase chain reaction assays [21], Demographic, anthropometric and clinical parameters, including sex, age, body mass index (BMD, blood pressure, heart and respitatory rate, ‘oxygen saturation, body temperature, oxygen requirements were Fecorded at the admission Vital signs were regularly collected dut~ ing hospitalization to monitor clinical conditions. Arterial blood 'g35ses and venous blood samples (for standard biochemistry and circulating levels of inflammatory markers) were collected at the admission and, depending on the patient clinical conditions, dur~ ing the hospita stay. Cytokines were measured by Quantikine ELISA assay kits (RD system), Detailed medical history was recorded from all patients, with a specific focus on the following diseases: hypertension, cardiovas- cular disease, diabetes, dyslipidemia, chronic respiratory disease, chronic obstructive pulmonary disease (COPD). Statistical analysis Quantitative data were expressed as mean + SD or median, [interquartile range), for variables with normal or skewed distribu- tion, respectively. Continuous variables with a normal distribution were compared by the Student t test, while the variables with a Table “Mai anthropometric and biochemical features of study parteipans at admission, a(n = 25) Now= 7 ‘Age yeas) sis war os BMI kg) soa 246225 “20001 Gender MF) nna “ont ts Smoking habit 5am) nase) ts Hypertension Hust) ne Type 2aberes isa) as caro sam 9c) ts Chronichcart faite 71258) 219%) te [oratory parameters Rac 10%/mm) a2 [407-478] 430 [400-43] ns WaC 10%) 752|599-1302] | 671[533-985) ns Hb (si) Hoss BAST ons Netrophis(10 mm?) 66 [41-114] 53/3670] ws Iympnoeres Iolma?) 10 [088-142] 1.1 1068-1.58) as Monoeyes (IO!) 058 [034-082] O51 [038-083] as Platelets (102mm?) 8156-305] 212]153-208) as Creatinine (ma) ineas, los04 ts Fastinglucose(mgidt) 139-56 12678 os ‘Albumin 37/3340) $6 [27-39] ns Asti 3220-50) 25 [20-36] as Array) 216-48] 20|ts-32] as ser) Sr26-74) 24 [18-46] as ton) 347 [255-408] 273(211-340) as Geatnekiase wy 474-275), as-tas) ts Myoslbin (ug) TY38-132] 4827-111) as herroponin(ngiml) 270 [115-857] 190 (101-342) ae Gholneserase(Uiml) —_52[43-66) 5914-68) as skewed distribution by the Mann Whitney U test. Categorical data, expressed as percentage, were analysed with X2 test. In order to identity the variables, at admission, maximally con- tributing tothe duration for obtaining a negative oropharyngeal or nasal swab, and the length of hospital stay. respectively, two par= tial least square (PLS) regressions [22] were generated. Variables with Variable Importance in Projection (VIP, expressing a mea- sure of a variable’s relevance in the model) greater than 1,50 were considered significant for association with the dependent variable (duration for a negative swab, or length of hospital stay).The same ‘method has been used in order to identify the variables maximally contributing to group separation of subjects between survisors and dead, ‘Apvalue <0.05 was considered tobe significant; whennecessary correction for multiple testing was applied. Statistical analysis was performed by R and IBM-SPSS packages for Mac Os X. Results (Characteristics ofthe study participants at hospital admission by ‘BMI groups A total of 100 consecutive patients admitted in our Covid- ‘Medical Unit were enrolled in the present study. Patients were grouped by BMII (>30 kg/m? or <30 kg/m") as patients with obesity (08, 29) and patients without obesity (N-O8,71).The OB group was ‘mainly constituted by class I obesity subjects, with only 4 patients ‘with BMI ranging between 35 and 40 kgjm-. ‘The anthropometric and biochemical characteristics of the study participants at admission are shown in Table 1. Age and sex distri- Dution were similar between the two groups, as well asthe main ‘comorbidities, except for hypertension that was mote frequent in the OB group (OB vs. N-OB: 69% vs. 46%, p= 0.04). ‘There were no differences in total blood count, fasting plasma slucose, indexes of cytolysis, renal and liver function between the {wo groups. Among inflammatory markers, feritin, C-reactive pro- tein (CRP) and tumor necrosis factor alpha (TNF-a) levels were higher in the OB group than N-O8 subjects (Table 2). No differencesTable? Acute phase protein ad etokines tthe hospital admission, 7 Pale Feuto(eial) 7opascrma) eaajas-ssn) cota Finngen(nglt) States] tala = Getjomien) —ass|ass a7] ws earns Ssisereal,) elena) Om veri adfoa-o4s) —Gr1foue-oz3) os ead) Lantoat = testa) detrrceaa) 5 Tweed) ttolas203] —Sewseiasl! Goa = p-o00 3 ie e nos 08 B. p= 0008 a> z £., 2 Noe oe ig. 1. obese subjects had ange lenght of hospital say (A), and longer length {ar having negative aropharygeal andor oat swabs (B) nthe box plas the op fd botam ofthe box epresent the 75th and 25th percent respectively. The top and bottom brs ("whiskers") represent the entice spread ofthe data ois for length of hospital stay or ime pre for having a negative swab) apd each group. ‘xcing extreme pons, whch aeneated witless, The ine nee theboxplt show the median vals. ‘were found in any other cytokine parameters, OB patients tended to have a worse blood gas analysis compared to the N-OB subjects, ‘with a lower value of arterial oxygen pressure (57 + 15 vs.68 + 14 mg, p = 0.042) and worse oxygen saturation (88 +6 Vs, 92 +5, ‘% P= 0.049), consequently requiring higher oxygen support (Fi02, via Venturi Mask 38 + 15 vs, 29 + 19%, p= 0.047). ie. i & z e & ee coe Sere ° ear 0 eo ee (C-Reactve protein (matt) 40) 032, p= 00007 0 6 DB MD % ‘C-Reactve protein (mgt) ig. inlineae egression nals Reactive poten a admission correlated po tively wath the length of hospital stay (A) and wit lenght for having negative ‘oropharyngeal andlor asa swabs (8) Obesity and COVID-19 outcomes PLS detected the following variables strictly related (VIP> 1,50), to length of hospital stay: age, BMH, lymphocytes, hemoglobin and (CRP at admission. Regarding the dependent variable "length of hos- pital stay”, the method identify: age, BMI and CRP at admission According to these results, patients with obesity shoved a longer duration for obtaining a negative oropharyngeal or nasal swab (19 £8 s, 13 £7, days, p = 0.002), required a longer period to achieve oxygen weaning (@8 + 64 vs. 152 + 7.1, days, p = 0.03) which resuits ina longer length of hospital stay (21 + 8 vs, 13+ 8 days, p = 0.0008) (Fig. 1AB). In any case, at discharge, no difference was found in CRP lev- els (0.8 [05-27] vs. 07 [0.13.5], OB Vs. N-OB respectively, p = 1s), while ferritin tended to remain higher in OB group (1379 [343-1712] vs, 624 [323-981], OB vs N-OB respectively, p= 0.06). ‘The CRP at admission was associated with a longer length of hospital stay and time for negative swab (Fi, 2) In this relatively small sample size, we did not find any ditfer~ cence in the mortality rates between the two groups (16% vs. 19%, (08 vs. N-OB, respectively, p = ns). Moreover, PLS regression aimed to detect the variables at admission related to "survivor/dead” provided the following results: age (67 + 17 vs. 80 +7 yrs) lym- phocytes (1304 + 1034 vs. 784 4 412, mm?) and creatinine (1.0 = OAs, 1-4 0.5, mgidl) but not BMI and CRP.208 (Morn ot a. / Obesity Resurch Cine! Paice 14 (2020) 205-200 Discussion Our study shows that obesity is associated with a severer respiratory presentation of COVID-19 and severer elevation of inflammatory markers, likely leading to higher oxygen demands at admission, prolonged oxygen requirement during hospitalization, elayed vital clearance and extended hospital stay. These charac: teristis, however, did not translate into a higher risk of mortality in subjects with obesity compared tothe patients without obesity Ina retrospective study on 112 COVID-19 patients with car~ diovascular disease admitted to the intensive care unit (ICU) in ‘Wuhan, BMI has been reported to be associated with higher mor- tality [17.23] Furthermore, Lighter eal. [16] found tha inpatients aged <6 years, class Il obesity was associated with a doubled risk DOF ICU access, wheteas in patents aged =60 years, body weight did not appear to bea predictive factor fr hospital admission or access tou. In another recent paper {24] it has also been deseribed that of 124 patients admitted to ICU for COVID-19, almost half of them ‘were affected by obesity, and a higher BMI was associated with an inereased risk of mechanical ventilation. Nearly 90% subjects requiring invasive mechanical ventilation had clas It or Il obesity In out cohort of patients, the prevalence of obesity (28%) in CCOVID-19 patients Is higher compared to that (11%) reported by Healian Health Institute (Epicentro) [18] This difference could nave multiple explanations: frst ofall, our cohort is relatively smal; moreover, out patients were older and represented a selected population, with greater clinical impairment and need for hospi- {alization compared to the total SARS-COV-2 confirmed cases if realy Ina preliminary report of 52 subjects, we have previously reported that obesity was associated with a longer length of hospital tay [25], We now confirm this nding. expanding the pop- lation included nour cohort and providing potential explanations for these results. We now did not find any significant eifference concerning previous comorbidities between OB and N-O8 group. Farthermore, in PS egressionanalsisag, BMI and CRP a admis- sion were related tothe duration ofthe hospitalization. ven though the prevalence of COPD was not higher in the OB compared to the N-O8 group, obesity initse might impair the res- piratory system dynamic, reducing lung compliance and increasing respiratory muscle reactivity, ultimately leading toan impaired gas ‘exchangealsoin apparently healthy individuals [25} Itisknow that Subjects with obesity pet se have an inereased pro-iflammarory patter [27] For this reason, beyond the potential impact on the lung mechanics, obesity might influence the clinical presentation and evolution of SARS-COV-2 infection through exacerbation of the immune-inflammatory esponse related tothe disease as con- firmed by the increased levels of several inflammatory markers ‘detected in the peripheral blood of patients with obesity in our population. Particularly the abnormal secretion of adipokines and ‘oytokines like TNF-alpha by the adipose tissue can sustain and amplify the inflammatory response to the SARS-COV.2 infection, ‘with potential consequences not only on the lung but also on the cardiovascular system [7,8], Of note, Yende et al have already docu- mented that elevated pre-infection levels ofsystericinflammatory markers predict a higher risk of hospitalization in patients with ccommunity-acquired pneumonia [28] Collectively. these consid erations might explain the later recavery, delayed weaning from (02 therapy and prolonged relapse from viral clearance of patients ‘with obesity compared to the N-OB group observed in our stu. ‘Thishypothesisisinkeeping with previous results showing ahigher, risk invasive mechanical ventilation in subjects with higher BMI independently of other comorbidities [19] as wellasthe prolonged Viral shedding observed in people with'>30 kgim? BMI during influenza A infection [29}. Ie should be highlighted, however, that the estimated duration, (of the vial shedding calculated in our report might be inaccurate, Indeed, the days of viral shedding were counted starting from the date of the frst positive swab performed upon admission to the Emergency Department, Information regarding the exact onset of the clinical symptoms was not systematically recorded. Another limitation of the present study is represented by the small nun ber of patients included in our cohort, associated with a lack of a better characterization of adiposity. While in a routine clinical ‘setting the most commonly used definition of obesity is based on. the presence of a BMI »30 kg/m2, itis well established that other ‘measures stich a5 waist-to-hip ratio might provide better infor ‘ation on the amount of visceral vs, subcutaneous adipose tissu thus they might better reflect the presence of a pro-inflammatory environment related to fat accumulation, However, in the setting ‘of an acute medical ward, with the huge burden of patients faced uring phase 1 ofthe pandemic, collection of these measures was practically impossible. Finally, we did not have information on. the severity of insulin resistance associated with obesity, which is known to have an impact on the risk of cardiac dysfunction and CvD-related mortality [30]. Phase 2 of the pandemic might rep resent an excellent opportunity for deepening our knowledge and acquiring further information regarding the potential influence of ‘waist-to-hip ratio and the levels of insulin resistance on the asso- ciation between obesity and severity of the SARS-CoV-2 infection, Inconclusion, our data show that subjects with obesity affected, by COVID-19 required extended hospitalization and more inten- sive and prolonged oxygen treatment. Stil, they did not have an. increased risk of mortality as compared to the subjects without ‘obesity. Ourdata also suggest that people affected by abesity might require more time to clear from SARS-COV-2 shedding, 1f future studies will confirm this finding clinical guidelines for the isolation period upon infection from SARS-COV-2 should be personalized in case of individuals with obesity. Finally, subjects with obe- sity affected by COVID-19 have higher CRP and TNF-a levels, and future studies should clarify whether the pro-inflammatory state that is commonly observed in obesity could provide a mechanistic background for their severer clinical presentation and evolution in course of SARS-COV-2 infection Author contributions statement Diego Moricont has made substantial contributions to cancep- tion, collection and interpretation of data and he hasbeen involved, in drafting the manuscript. Stefano Masi, lent Rebelos, Salvatore De Marco have made substantial contributions to data collection and they have been involved in drafting the manuscript. ‘Maria Laura Manca, has been involved in statistical analysis, ‘Agostino Virds, Stefano Taddet have been involved in revising it critically for important intellectual content. Monica Nannipieri has made substantial contributions to con~ ception and design of the study, data interpretation, and she has been involved in writing of the manuscript Conflict of interest ‘The authors received no funding and declare no conflict of inter- est Ethical statement Al retrospective data involving human participants were in accordance with the ethical standards and with the 1954 Helsinki Declaration and its later amendments or compatable ethical stan- dards, Ethical approval was obtained by the Local Ethics Committee,‘Arcot aj Obesty Research Cnc! Mate 142020) 205-209, 2 | have read and have abided by the statement of ethical stan- {dards for manuscripts submitted to the Obesity Research & Clinical Practice. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https:|/doi.org/10.1016)}.orep.2020.05 009, References 11] Khan SS, Ning H. Wks JT Allen N Carmethon Mt. Bert, ea. 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