Clinical, Laboratory and Radiological features, and Outcome of Acute Fat Embolism Syndrome in Sickle Cell Disease

Clinical, Laboratory and Radiological features, and Outcome of Acute Fat Embolism Syndrome in Sickle Cell Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical, Laboratory and Radiological features, and Outcome of Acute Fat Embolism Syndrome in Sickle Cell Disease Salam Alkindi, Sameer Raniga, Eiman Al-Ajmi, Khalil Al-Farsi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5040224/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 8 You are reading this latest preprint version Abstract Non-traumatic fat embolism syndrome (FES) affecting brain, lung and hematopoietic system is a rare, but a serious complication of sickle cell disease (SCD), resulting from bone marrow necrosis. SCD-related FES is rare, with the spectrum of clinical, laboratory, radiological manifestations and patient outcome is not fully understood. After medical research & ethics committee approval, retrospectively, SCD-FES patients at our centre, were reviewed between January 2006 to December 2023. 27 patients (17 males, 10 females) with a median age of 24 years and length of hospital stay of 24 (16–38) days were enrolled. They had fever, chest/back pain, cough and crepitation in 100%, 96%, 56% and 100% respectively, with neurological manifestations in 96%. Abnormal chest X-rays and CT scans were observed in 96%, and 100% respectively. Patients had significant anemia, reticulocytopenia, and thrombocytopenia, with raised WBC (p < 0.05). There was a significant rise in LDH, ALP, Ferritin and C-reactive protein levels. All patients received antibiotics, and exchange transfusions, whereas 24%, 76% required non-invasive ventilation (NIV) and mechanical ventilation respectively, with 18.5% mortality. FES is a rapidly progressive respiratory and neurological syndrome, characterized by hypoxia, and cytopenia, with raised inflammatory markers, raised LDH and ALP, with distinctive multiple cerebral microbleeds. Health sciences/Health care Health sciences/Medical research Health sciences/Pathogenesis Health sciences/Signs and symptoms Sickle Cell Disease Fat Embolism Syndrome Bone Marrow Necrosis Parvovirus B19 Exchange Transfusion Figures Figure 1 Figure 2 Figure 3 Introduction Fat embolism syndrome (FES) is a rare, but one of the most devastating acute complications of sickle-cell disease (SCD) 1 . It usually occurs following a vaso-occlusive crisis (VOC) that leads to bone marrow necrosis (BMN). The subsequent release of fat globules into the venous pulmonary microcirculatory system, causes acute chest syndrome. If BMN is more extensive, large amounts of fat droplets enters the systemic circulation, leading to the classical FES with characteristic multiorgan dysfunction. 2 Clinically, it is characterized by a triad of rapidly progressive respiratory failure, neurological manifestations, and thrombocytopenia. Involvement of various other organs leads to a multiorgan failure. The peripheral blood smear shows a leukoerythroblastic picture, whereas other laboratory investigations show extremely high levels of serum ferritin and lactic dehydrogenase (LDH) 3 . Further, FES is often associated with human parvovirus (HPV) B19 and reported to be seen more frequently in heterozygous SCD patients 4 – 5 . The diagnosis of FES is usually empiric, but based on multi-organ involvement associated with fat and/or necrotic marrow emboli leading to acute respiratory distress, neurological manifestations and multiorgan failure 6 . Evidence of BMN is suggested by histopathological evidence, although bone marrow biopsy cannot exclude BMN, since it depends on the timing of the biopsy 7 . Although, BMN results in the release of fat globules, circulating phospholipids are metabolised to arachidonic acid under the influence of secretory phospholipase A2, leading to the production and release of numerous inflammatory cytokines 6 . The historical classifications proposed for the diagnosis of FES namely, Gurd’s and Schonfeld’s are essentially in the context of traumatic FES, and not applicable to FES in SCD patients 8 – 9 . Therefore, an acute drop in haemoglobin and platelets, with significantly increased serum ferritin and lactate dehydrogenase (LDH), are the most frequently reported abnormal laboratory findings in the setting of an acute VOC crisis. Currently, there are no specific treatment protocols for FES, and patients are generally treated with multiple red blood cell (RBC) transfusions or exchange transfusions within hours of the presentation as it has been shown to hasten neurologic recovery 10 – 11 . Although the first case of FES in SCD was reported in 1941 12 , followed by several case reports 13 – 15 and few cohort studies too 16 , 17 , no prospective studies have been reported. Here, we report the largest single centre experience with FES in SCD patients, highlighting the clinical, laboratory and radiological features, emphasizing the importance of the high index of suspicion of FES (as suggested by Bailey, K. et al), along with rapid institution of treatment and supportive measures that are very important in improving the outcome in FES in SCD patients. Materials and Methods In this retrospective study, 27 SCD patients, who developed FES between 2006 and 2023 at the Sultan Qaboos University Hospital in Oman were enrolled, after a written approval from the institutional medical research ethics committee (MREC # 1858), college of medicine & health sciences. The inclusion criteria included SCD patients, who were admitted with a VOC and developed FES according to the current diagnostic criteria 19 . The data was obtained from the electronic patient record system and in accordance with relevant local guidelines and regulations. Following MREC approval (MREC #1858), and since this is a retrospective study, individual patient consent was not required / mandated by the MREC. The data collected included demographic, clinical, haematological, biochemical, and radiological parameters, as well as the therapeutic interventions given. Clinical evaluations Clinical symptoms consisted of documented fever, along with respiratory and neurological symptoms. O 2 saturation was obtained by pulse oximetry. Further, important variables like the use of prior disease modifying therapies like hydroxyurea, baseline hematological laboratory parameters and previous histories of VOC frequencies, history of ACS etc. were also noted in all these patients. Other details of SCD therapeutic management protocols like non-invasive ventilatory support, antibiotics, blood transfusion and blood exchanges were also recorded. Laboratory parameters Complete blood counts including haemoglobin (Hb), reticulocytes and platelet counts were obtained at baseline and nadir, whereas white blood cell count (WBC) was recorded at baseline and at their maximum, including baseline HbF. Biochemical parameters included CRP, Liver function tests, and renal function. Serum ferritin, and LDH were collected on arrival and their maximum values were noted during the admission. Radiological evaluation Several radiological studies were performed for patients as required and analysed. These studies including chest radiographs, chest computerized tomography (CT) scan, ultrasound of the abdomen, and magnetic resonance imaging (MRI) of the brain. Statistical Analysis . The statistical package for social science (IBM SPSS, USA ver.23, Armonk, NY) was used to analyse the collected data. Normally distributed data was characterized as mean with standard deviation, whereas data that was not normally distributed was characterized as median with interquartile range (IQR) for continuous variables and percentage and frequency for categorical variables. Wilcoxon Signed Ranks test was used to study the significance of differences in the laboratory parameters at baseline and during clinical deterioration with FES. Chi Square test was used to study the differences in proportions and ANOVA was used to compare multiple means. Logistic and multivariate analyses were also performed to see the effect of various parameters affecting mortality. An alpha of < 0.05 was considered to be the statistically significant p value. Results 27 patients (17 males, 10 females) who were enrolled in the study had a median age (IQR) of 24 (21–33) years but ranged between 15 to 55 years (Table 1 ). The median length of hospital stay was 24 days with IQR between 16 to 38 days with a range between 5 to 270 days. SCD genotyping revealed that two patients had SD Punjab, six patients had HbS β + Thal, while the majority (n = 19) had HbSS. Table 1 Demographic, and Clinical parameters in FES cohort (n = 27) Parameters Cases P value Demography Median age in years (IQR)[Range] 24(21–33) [15–55] Gender, Total cases, n, M: F 27(17:10) Median age in years, males (IQR) 26(22-30.5) P = 0.56 Median age in years, females (IQR) 24(19-48.25) Median length of Hospital Stay, days (IQR)[Range] 24(16–38) [5-270] SCD Disease severity n (%) Grade1 17(63) Grade 2 9(33) Grade 3 1(4) SCD Genotype SS, n (%) [Dead] 19(70) [3] P = 0.18 SCD Genotype SB + Thal, n (%) [Dead] 6(22) [2] Symptoms & Signs Chest/Back Pain, n (%) 26(96) Fever, n (%) 27(100) Respiratory symptoms Crepitations, n (%) 27(100) Reduced O 2 Saturation, n (%) 24(89) Reduced O 2 Saturation, median (IQR) 86(78–89) Cough, n (%), 9 (33) Tachypnoea, n (%) 6(22) Wheeze, n (%) [n = 19] 2(11) Neurological symptoms, n (%) Confusion & altered sensorium, n (%) 13(50) Memory deficit, n (%) 5(19) Coma, n (%) 5(19) Seizures, n (%) 4(15) Others n (%) 6(23) Cardiovascular symptoms Tachycardia, n (%) 25(93) Hypotension, n (%) 11(41) Radiological findings Abnormal Ultrasound, n (%) [n = 17] 7(41) Abdominal CT scan n % [n = 7] 7(100) Abnormal Chest X-Rays, n (%) 26(96) Atelectasis-Consolidation, n (%) 26(96) Splenic atrophy, n (%) 13(48) Splenomegaly, n (%) 10(37) Key: # Wilcoxon Signed Ranks Test; IQR- Interquartile Range; NS – Not significant Clinical manifestations At presentation, patients had cough, chest/back pain, fever and crepitation in 33%, 96%, 100%, and 100% respectively, with reduced O 2 saturation in 89%. Neurological symptoms seen in the majority of patients (96%) including confusion & altered sensorium, memory, deficit, coma, seizures, and others in 50%, 19%, 19%,15%, and 23% others respectively. The median O 2 saturation was 86% with the IQR ranging between 78 to 89%. Tachycardia, hypotension and tachypnoea were seen in 93%, 41% and 22% respectively. Radiological evaluations Twenty-five cases had chest radiographs, that were available for analysis, whereas 14 had a chest CT scan done as seen in Table 1 .& Fig. 1 Chest radiograph and CT scan of chest both showed varying degrees of manifestations. (Fig. 1 ; Supplemental Table 1b) MRI brain was available for analysis on 23 (85%) patients from the total cohort, with 96% having neurological syndrome, and nineteen patients had MR findings in keeping with cerebral fat embolism. 19 The classical starfield pattern was observed in seven patients with multiple foci of diffusion restriction in the white matter and deep grey matter, whereas fifteen had scattered microbleeds (Table 1 , Fig. 1 ). Laboratory parameters Amongst the haematology parameters, there was a significant drop in the median Hb and platelet counts from baseline, with a significant rise in the median WBC count (Table 2 ; p < 0.05, Wilcoxon Signed Ranks test). The median basal Hb g/dl dropped significantly to 6.9 from baseline levels of 10.8. There was reticulocytopenia with mean reticulocytes of 2.1%, with a range from (0.3–6.2%) and a median of 1.6%. The median basal white blood cell count (X10 9 /L) increased significantly to 14.3 from the baseline level of 8.5 (Fig. 2 ; p < 0.05, Wilcoxon Signed Ranks test) (Panel A-B). The median platelet count (X10 9 /L) dropped significantly to 29 from the baseline level of 272 (Fig. 2 ; p < 0.05, Wilcoxon Signed Ranks test). Table 2 Laboratory parameters & medical interventions in FES cohort (n = 27) Parameters Cases P value Laboratory Features Median hemoglobin basal, g/L(IQR) 10.8(9.5–11.3) 2.01851X10 − 10# Median hemoglobin nadir, g/L(IQR) 6.9(6.3–7.7) Median WBC counts basal,10 9 /L(IQR) 8.5(6.1–11) 1.8562X10 − 05# Median WBC counts Max, 10 9 /L(IQR) 14.3(11.6–20.7) Median platelet counts basal, X10 9 /L(IQR) 272(188–450) 1.1696X10 − 09# Median platelet counts nadir,10 9 /L(IQR) 29(15–54) Median Retic Count, nadir, %(IQR) 1.6(0.6–2.9) Median HbF, %(IQR) 7.8(5.6-10.85) Median S. Ferritin, ng/ml (IQR) 2760(1446–26589) Median S.LDH at admission, u/L(IQR) 633(403–1938) 0.00241054 # Median S.LDH max, u/L(IQR) 3166(1446–5623) Median CRP at admission (IQR) 83(14.75–180) 4.69469X10 − 06# Median CRP max (IQR) 370(236-418.5) Median AST, u/L(IQR) 209(87–481) Median ALT, u/L(IQR) 96(62–349) Median ALP, u/L (IQR) 471(395–686) Median S. bilirubin, mg/dl(IQR) 64(40–131) Abnormal Serum Creatinine, n (%) 14(52) ANA positive, n (%) 9(33) Parvo B19 positive, n (%) 6(22) Blood Culture positive, n (%) 15(56) Interventions Antibiotics, n (%) 27(100) Simple blood transfusions, n (%) 27(100) Exchange blood transfusions, n (%) 27(100) NIV alone, n (%) 6 (22) NIV + Ventilation, n (%) 10 (37) Ventilation alone, n (%) 9 (33) Key: # Wilcoxon Signed Ranks Test; IQR- Interquartile Range; NS – Not significant The biochemical parameters showed a significant rise in the median serum LDH and median CRP levels Fig. 2 ; (p < 0.05, Wilcoxon Signed Ranks test). The median CRP levels (mg/L) increased significantly from 83 at arrival to hospital, to the median CRP max value of 370 (Fig. 2 ; p < 0.05, Wilcoxon Signed Ranks test). Similarly, the median serum LDH levels (U/L) also significantly increased from 633 at admission to 3166 (Fig. 2 ; p < 0.05, Wilcoxon Signed Ranks test) (Panel C-E). In this cohort, 18 (66.6%) patients had culture-proven sepsis with 9 (50%) amongst these patients showing multiple microorganisms. Of the 21 microbial organisms isolated, 12 (57%) and 10 (48%) were bacterial, and fungal isolates respectively. Specifically, the bacterial isolates included MDR Acinetobacter baumannii (4), MDR Klebsiella (2), E. coli (2), Pantoa agglomerans (1), Salmonella spp. (1), Staph. Epidermidis (1) and Coagulase-negative Staphylococcus (1). Most fungal isolates were Candida spp. (7), while Candida krusei, Candida tropicalis, and Candida dubliniensis were isolated from 1 patient each. Additionally, EBV, CMV and Parvo B19 PCR positivity was seen in 1, 2 and 6 (22.2%) patients respectively. Further 9(33%) patients also showed ANA positivity. Predictors of mortality Table 3 shows the correlation of the clinical and laboratory parameters with mortality in the FES cohort. Mortality was seen in younger adults with respiratory distress highlighted by significantly increased of respiratory symptoms and signs namely cough, wheezing and tachypnoea (p < 0.05, Chi-Square test). Multivariate analysis did not show the predictive effects of independent variables on mortality. Logistic regression also did not show any significant effect of the predictors on mortality. Further, all had abnormal CT scans and significantly abnormal liver function namely, S. Bilirubin and AST. All patients succumbed despite maximal respiratory support with NIV and ventilation. Table 3 Correlation of Laboratory parameters with mortality in FES cohort (n = 27) Parameters Alive(n = 22) Dead (n = 5) P value Demography Median age in years (IQR)[Range] 25.5(21.75–33.75) [15–55] 23(17.5–35.5) [16–47] 0.59* Gender, Total cases, n, M: F 22(14:8) 5(3:2) 0.66** Median length of Hospital Stay, days (IQR)[Range] 24.5(17.5–33.5) [7-270] 22(7–51) [5–57] 0.62* SCD Genotype SS, n (%) 16(72) 3(60) 0.8** SCD Genotype SB + Thal, n (%) 4(18) 2(40) 0.42** Symptoms & Signs Chest/Back Pain, n (%) [n = 26] 21(95) 5(100) 0.75** Fever, n (%) [n = 27] 22(100) 5(100) 0.76** Cough, n (%) [n = 16] 2(12.5) 4(80) 0.04** Crepitations, n (%) [n = 27] 22(100) 5(100) 0.76** Wheeze, n (%) [n = 19] 1(5.2) 3(60) 0.02** Neurological manifestations, n (%) 21(95) 5(100) 0.65** Tachycardia, n (%) 20(91) 5(100) 0.82** Hypotension, n (%) [n = 19] 7(37) 4(80) 0.33** Tachypnoea, n (%) [n = 20] 2(10) 4(80) 0.02** Reduced O2 Saturation, n (%) 19(86) 5(100) 0.83 Reduced O2 Saturation, median (IQR) 85.5(78–89) 88(78–88) 0.98* Abnormal Chest X-Rays, n (%) 21(95) 5(100) 0.77** Atelectasis-Consolidation, n (%) 21(95) 5(100) 0.77** Pleural Effusion, n (%) [n = 17] 8(47) 1(20) 0.45** Abnormal CT scans, n (%) [n = 7] 2(29) 5(100) 0.01** Abdominal Ultrasound, n % [n = 17] 13(76) 4(80) 0.74** Normal Spleen, n (%) 4(18) 0 0.26 # Splenomegaly, n (%) 9(41) 1(20) Splenic atrophy, n (%) 9(41) 4(80) Laboratory Features Median hemoglobin basal, g/L(IQR) 10.7(9.5–11.3) 9.2(8-10.6) 0.06* Median hemoglobin nadir, g/L(IQR) 6.8(6.3–7.7) 7.3(5.1–7.7) 0.81* Median WBC counts basal,10 9 /L(IQR) 8.2(5.8–11) 9.9(6.7–11.3) 0.71* Median WBC counts Max, 10 9 /L(IQR) 13.8(10.6–19.2) 19.4(16.4–29.3 0.27* Median platelet counts basal, X10 9 /L(IQR) 272(182–416) 450(289–518) 0.11* Median platelet counts nadir,10 9 /L(IQR) 29(15–55) 39(23–98) 0.72* Median HbF, %(IQR) 8.1(5.9-12.05) 5.5(1.8–9.2) 0.21* Median S. Ferritin, ng/ml (IQR) 2760(1315–12960) 32166(1752-125995) 0.10* Median S.LDH at admission, u/L(IQR) 735(366–1732) 1937(836–3427) 0.06* Median S.LDH max, u/L(IQR) 3271(1390–5297) 1987(1457–11238) 0.19* Median CRP at admission (IQR) 62(14.5–142) 134(34–239) 0.55* Median CRP max (IQR) 325(265–424) 282(127–410) 0.21* Median AST, u/L(IQR) 192(91–349) 1278(79-8845) 0.006* Median ALT, u/L(IQR) 88.5(58.5–289) 258(68-2825) 0.06* Median S. bilirubin, mg/dl(IQR) 62.5(40.5–109) 312(34.5–493) 0.005* Abnormal Serum Creatinine, n (%) 10(45) 4(80) 0.46** ANA positive, n (%) [n = 19] 7(37) 2(40) 0.69** Parvo B19 positive, n (%) [n = 20] 5(25) 1(20) 0.85** Blood Culture positive, n (%) 11(50) 4(80) 0.53** Interventions Antibiotics, n (%) 22(100) 5(100) 0.97** Simple blood transfusions, n (%) 22(100) 5(100) 0.97** Exchange blood transfusions, n (%) 22(100) 5(100) 0.97** NIV alone, n (%) 6(30) 0 P = 0.004 # NIV + Ventilation, n (%) 5(25) 5(100) Ventilation alone, n (%) 9(45) 0 Key: ** Chi Square Test; IQR- Interquartile Range;* Students T test; # Anova Management All patients (100%) received antibiotics, along with simple as well as exchange blood transfusions, whereas 24%, 76% respectively required non-invasive ventilation (NIV), and invasive mechanical ventilation. Mortality was seen in 5 (18.5%) patients, whereas the remaining 22 (81.5%) showed varying degrees of recovery. Amongst the 5 deaths, 3 patients had HbSS genotype, whereas two patients had HbS β + Thal genotype. Discussion Although the survival of SCD patients has improved, patients are still dying prematurely, especially, following complications like sepsis and acute chest syndrome (ACS) 20 . Further, VOCs are associated with bone infarcts and BMN and FES ensuing in this setting can lead to a rapid downward clinical course with fatal outcomes 6 . Data from this FES cohort, suggest that it can occur at any age in SCD patients (range 15–55) presenting with uncomplicated VOCs, although the median age of 24 years indicates that young adults are at an increased risk. Our previous data on ACS showed a similar median age group with a male preponderance. 21 Historically, FES has been exclusively reported in patients with predominantly HbSC and Sβ + Thal 6 , 10 , 11 , 22 . In 2019, Tsitsikas DA et al reported that only 20.6%(n = 12) had homozygous disease, whereas, 43.1% (n = 25) had HbSC and another 27.6%(n = 16) had HbSβ + Thal. 23 It has been postulated that the higher haematocrit in HbSC compared to HbSS patients, results in a higher blood viscosity. 23 – 24 In our cohort, the majority of cases with FES had HbSS genotype (70%), while HbSβThal genotype was seen in 22%. Further, in this cohort, 63% had mild disease, similar to what is seen in the literature with reports of about 30% presenting with this SCD-related complication for the first time. 6 Interestingly, the median length of stay in this group was much longer than the average VOC hospital stay, reflecting the severity of this complication. 25 Patients with FES in this cohort, presented with fever, respiratory symptoms, painful episodes (the chest and back predominantly) and neurological syndrome in 100%, 100%, 96% and 96% respectively as indicated in Table 1 and Table 1 b. These symptoms are comparable to those reported by Tsitsikas DA et al in the case series previously published. (Fig. 3 ) 11 Respiratory manifestations include lung crepitations, drop in saturation, cough, tachypnoea, and wheezing seen in 100%, 89%,33%, 22% and 11% respectively. This significant respiratory involvement seen in the initial phases of its development, is contributed to by the release of fat droplets from the infarcted bone marrow, leading to occlusion of microvascular structures. These circulating phospholipids are hydrolysed under the influence of secretary phospholipase A2 (sPLA2), leading to many cytokines that are released causing the damage usually seen in both lungs and brain. 26 – 27 Another distinguishing feature of these patients is the presence of neurological syndrome, which was seen in 96% of all patients in this cohort with varied manifestations including acute hallucinations, seizures, impaired cognitive function, tremor, cerebellar signs, altered sensorium, confusion, disorientation, incoherent speech, impaired memory and coma. It is not clear how fat emboli get into systemic circulation, but a few of our patients had evidence of a right-to-left intracardiac or pulmonary shunt (through pulmonary capillaries) to enter into the systemic circulation into the brain or kidneys. 28 – 29 Other major organ involvement was also noted including renal, hepatic and cardiac involvement seen in 52, 33 and 15% respectively. These findings are similar to those seen with other studies (Fig. 3 ). 22 , 29 It is postulated that this may be due to disseminated cytokines, fat embolization or as a consequence of other infections present at the same time, but it is not clear. 29 However, since the presentation is not different from thrombotic thrombocytopenic purpura, it warrants a high index of suspicion by the clinician who should be alerted to the possibility of FES. 14 , 22 Several investigators have reported a possible association of FES to an underlying HPV B19 infection 6 , 30 – 33 . The premise here is that HPV B19 induced endothelial inflammation results in the increased vascular adhesion and infarction of bone marrow especially in patients with high baseline Hb 32 . This endothelial cell infection may also explain other complications of HPV infection including myocarditis, skin manifestation and also placental involvement. Tsitsikas et al 11 found that 24% of FES cases were associated with HPV 19 infections and suggested that it played a significant role in its pathogenesis. In our cohort, 22% had Parvo B 19 positivity, and this virus may be relevant in the search for a unifying trigger for reticulocytopenia. Infection with HPV contributes to the development of HPV-related complications in SCD, including triggering painful episodes, ACS, splenic sequestration, and transient red cell aplasia. 33 It is interesting to note that a recent autopsy report suggested that the presence of HPV was associated with higher mortality (63% vs 32%, in non-HPV infected). 33 FES diagnosis is based on the presence of respiratory failure, neurological syndrome, classical radiological findings, with striking laboratory findings. In our cohort, patients experienced a sudden drop in O 2 saturation associated with a rapidly progressive respiratory failure, and neurological manifestations. There is a significant rapid drop in Hb and platelets from baseline as indicated in Table 2 , with a rise in WBC associated and a significant reticulocytopenia. Also, patients showed statistically significantly rise in CRP, LDH, ALP and ferritin, with involvement of various other organs including raised creatinine in 52%, hyperbilirubinemia with raised liver enzymes in almost all of them, complicated by a multiorgan failure. 33% of cases had a positive ANA, but none of them was confirmed to progress to an autoimmune disease although our earlier data showed a higher prevalence of ANA positivity among patient with SCD. 35 Blood culture was positive in 66.6% of the cases, and the growth included bacterial, fungal as well as viral isolates. Although infection may be a triggering factor for this syndrome, many of these patients stayed in the hospital for a considerable length of time, (median length of hospital stays of 24) leading to hospital-acquired infections, considering their primary immune-compromised status (splenectomy in 48% of cases),. Moreover, other studies in patients with severe ACS who got admitted to ICU, showed that in around 50% of these cases, microbiological documentation of infective agent could be demonstrated. 36 Looking at radiological findings, it indicates a severe chest syndrome with variable and manifestations, reflecting the heterogeneity within this syndrome as indicated in Table 1 and Fig. 1 (A-B). Our findings indicate a wide range of chest manifestations in SCD patients with FES, highlighting the need for high clinical suspicion for accurate diagnosis. CT chest is superior in assessing lung parenchyma compared to radiography, and it is recommended to confirm the diagnosis, and to also investigate alternative causes of respiratory distress. Understanding the diverse patterns of thoracic involvement, was instrumental in suspecting FES in these SCD patients with respiratory distress and was crucial for early diagnosis and timely management. Similarly, some patients had distinctive neuroimaging patterns pathognomonic for this syndrome as indicated in Fig. 1 (C-E). Since this is a progressive illness, rapid attention needed be given to supportive therapy. Unfortunately, there is currently no specific treatment protocol for FES. Our data clearly emphasizes that rapid diagnosis with early supportive measures including antibiotics (given to 100% of patients), ventilatory support (including NIV and mechanical ventilation) as well as simple blood /exchange transfusions was essential for optimal outcomes. Most importantly, the sudden drop in the O 2 saturation with respiratory distress, followed by neurologic symptoms and signs of profound thrombocytopenia in the setting of a VOC crisis, warrants immediate institution of red cell simple and exchange transfusions. Overall mortality was highest in those who had no blood transfusions although 91% and 61% patients had top-up transfusions, while 29% received exchange transfusions. 11 Immediate red cell exchange transfusions can be lifesaving and should be instituted as soon as the syndrome is suspected 6 . However, to improve the outcome it is suggested to increase the use of red cell exchange, with pre-emptive transfusion to be immediately considered for high-risk patients. 6 It is believed that RBC exchange transfusion reduces the inflammatory markers and the percentage of hemoglobin S, which improves pulmonary vascular circulation by lowering the viscosity. 16 Improvement in the neurological symptoms has been seen to occur within hours of the institution of RBC transfusions or exchange transfusions. 15 Clearly exchange transfusion is the best approach, and there is also emerging data on the use of plasma exchange (done in one of our cohort) to address the inflammatory environment and potentially improve outcomes in these patients. 37 Few of our patients who were extremely sick received steroids as part of anti-inflammatory measures. Although, this was previously used in traumatic FES, it has not been used in SCD-related FES. 9 Although bone marrow biopsy can be helpful in the diagnosis of FES, delaying the care until it is done without instituting appropriate management can worsen the outcomes. Lastly, although multiple studies have observed sudden or unexplained deaths in SCD patients of up to 40% during VOCs; autopsy study has shown evidence for pulmonary fat emboli in only one-third of such cases 38 – 40 . Likewise, it has also been postulated that cases of multiorgan failure syndrome with a seemingly uncomplicated painful crisis and rapid deterioration may actually represent cases of FES 41 . There were five deaths among the cohort, three of whom had HbSS (60%), whereas two had HbSβ + Thal genotype (40%). These five patients died despite optimal support with antibiotics, blood exchange blood transfusions, NIV and ventilatory support. Two patients who died were comatose and one was in a vegetative state prior to their demise. Although the median length of hospital stay was similar, the length of stay was shorter in the mortality group with range between 5 to 57 days of hospital stay, as opposed to between 7 to 270 days in the survivor cohort. Further, the mortality cohort also had significantly more intense cardiorespiratory manifestations (cough 80% Vs 12.5%, wheezing 60% vs 5.2%, tachypnoea 80% Vs 10%, with abnormal CT scan in 100% Vs 29%) as compared to the survivors in the cohort. These patients showed grossly deranged liver function abnormalities and significantly raised LDH indicative of a severely intense inflammatory response (Table 3 ). This is a relatively small size cohort of FES, and although two-thirds of cases had the HbSS genotype, the mortality was in similar proportion to that seen in HbS β + Thal genotype, and this has not been observed in previous literature reports. In summary, FES is a rapidly progressive respiratory and neurological syndrome seen in all genotypes of SCD, presenting with fever, and pain. Its characterized by hypoxia, cytopenia, including anemia and thrombocytopenia with raised inflammatory markers (CRP, ferritin) and significant rise in LDH and ALP, as well as distinctive radiological findings. The outcome has significant improved following the use of exchange transfusions with a mortality of 18.5% in this current cohort. Declarations Acknowledgements : We wish to thank the hospital administration for the use of hospital material in this study. Funding : No funding was requested or obtained from any agency to perform this study. Author contributions : SAK and AVP were fully involved in the conception and design of the study, recruitment & care of patients, acquisition of data, analysis and interpretation of data and was instrumental in the drafting the article and critical appraisal before submission. EAA, and SRA analysed the radiological data and contributed towards manuscript preparation, KAF, HKH, KUN, MAB, FAA, AGU, AAA, ALM, and NRA, contributed in patient care. All authors have seen, and approved the final version of manuscript. Disclosure of Conflict of Interests : The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Data Availability The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. References Mellor, A. & Soni, N. Fat embolism. Anaesthesia (2001). 56,145 – 54. Ataga, K. I. & Orringer, E. P. Bone marrow necrosis in sickle cell disease: A description of three cases and a review of the literature. Am. J. Med. Sci. 320 , 342–347 (2000). Paydas, S. et al. Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am. J. Hematol. 70 , 300–305 (2002). Adamski, J. et al. Multiorgan failure and bone marrow necrosis in three adults with sickle cell-β+-thalassemia. Am. J. Hematol. 87 , 621–624 (2012). Tsitsikas, D. A. et al. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection. Blood Rev. 28 , 23–30 (2014). Tsitsikas, D. A., Vize, J. & Abukar, J. Fat Embolism Syndrome in Sickle Cell Disease. J. Clin. Med. 9 , 3601 (2020). Sangani, V. et al. Fat Embolism Syndrome in Sickle Cell β-Thalassemia Patient with Osteonecrosis: An Uncommon Presentation in a Young Adult. J. Investig Med. High. Impact Case Rep. 9 , 23247096211012266 (2021). Gurd, A. R. Fat embolism: An aid to diagnosis. J. Bone Jt. Surg. Br. 52 , 732–737 (1970). Schonfeld, S. A. et al. Fat embolism prophylaxis with corticosteroids. A prospective study in high-risk patients. Ann. Intern. Med. 99 , 438–443 (1983). Gangaraju, R., Reddy, V. V. & Marques, M. B. Fat embolism syndrome secondary to bone marrow necrosis in patients with hemoglobinopathies. South. Med. J. 109 , 549–553 (2016). Liem, R. I., O’Gorman, M. R. & Brown, D. L. Effect of red cell exchange transfusion on plasma levels of inflammatory mediators in sickle cell patients with acute chest syndrome. Am. J. Hematol. 76 , 19–25 (2004). Wade, L. J. & Stevenson, L. D. Necrosis of the bone marrow with fat embolism in sickle cell anemia. Am. J. Pathol. 17 , 47–54 (1941). Hutchinson, R. M., Merrick, M. V. & White, J. M. Fat embolism in sickle cell disease. J. clin. Path . 26 , 620–622 (1973). Akhtar, S. Fat embolism. Anesthesiol Clin. 10.1016/j.anclin.2009.07.018 (2019). Medina, F. J., Marquez, J. C. & Castillo, M. Cerebral fat embolism detection with susceptibility-weighted images in sickle cell disease. Neuroradiol. J. 25 , 411–414 (2012). Dang, N. C. et al. Bone marrow embolism in sickle cell disease: a review, Am. J. Hematol. 79, 61 – 7 (2005). Baker, P. L., Pazell, J. A. & Peltier, L. F. Free fatty acids, catecholamines, and arterial hypoxia in patients with fat embolism. J. Trauma. 11 , 1026–1030 (1971). Bailey, K., Wesley, J., Adeyinka, A. & Pierre, L. Integrating Fat Embolism Syndrome Scoring Indices in Sickle Cell Disease: A Practice Management Review. J. Intensive Care Med. 34 , 797–804 (2019). Al-Ajmi, E., Raniga, S. & Alkindi, S. M. R. Imaging Patterns of Cerebral Fat Embolism in Sickle Cell Disease. Pict. Rev. Neurographics . 15 (1), 1–8. doi.org/10.3174/ng.2300063 (2025). Alkindi, S. Al. multi-center study on mortality in children, and adults with sickle cell anemia-risk factors and causes of death. Sci. Rep. 14 , 8584 (2024). Alkindi, S. et al. Predictors of impending acute chest syndrome in patients with sickle cell anaemia. Sci. Rep. 10 , 2470 (2020). Kammeyer, R., Devnani, R. & Mehta, R. Cerebral fat embolism syndrome mimicking thrombotic thrombocytopenic purpura in a patient with hemoglobin SC disease. Am. J. Hematol. 91 , 539–542 (2016). Tsitsikas, D. A. et al. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection. Blood Rev. 28 , 23–30 (2014). Gibbs, W. N., Opatowsky, M. J. & Burton, E. C. AIRP best cases in radiologic-pathologic correlation: cerebral fat embolism syndrome in sickle cell beta-thalassemia. Radiographics 32 , 1301–1306 (2012). Esham, K. S. Assessment of health-related quality of life among adults hospitalized with sickle cell disease vaso-occlusive crisis. Blood Adv. 4 , 19–27 (2020). Styles, L. A., Aarsman, A. J., Vichinsky, E. P. & Kuypers, F. A. Secretory phospholipase A(2) predicts impending acute chest syndrome in sickle cell disease. Blood 96 , 3276–3278 (2000). Vichinsky, E. et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood 83 , 3107–3112 (1994). Dowling, M. M. et al. Increased prevalence of potential right-to-left shunting in children with sickle cell anaemia and stroke. Br. J. Haematol. 176 , 300–308 (2017). Hassell, K. L., Eckman, J. R. & Lane, P. A. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am. J. Med. 96 , 155–162 (1994). Kurtzman, G. J. et al. Chronic bone marrow failure due to persistent B19 parvovirus infection. N Engl. J. Med. 317 , 287–294 (1987). Flunker, G., Peters, A., Wiersbitzky, S., Modrow, S. & Seidel, W. Persistent parvovirus B19 infections in immunocompromised children. Med. Microbiol. Immunol. 186 , 189–194 (1998). Smith-Whitley, K. et al. Epidemiology of human parvovirus B19 in children with sickle cell disease. Blood 103 , 422–427 (2004). Lowenthal, E. A., Wells, A., Emanuel, P. D., Player, R. & Prchal, J. T. Sickle cell acute chest syndrome associated with parvovirus B19 infection: case series and review. Am. J. Hematol. 51 , 207–213 (1996). Samaee, S. Mortality Rates and autopsy findings in fat embolism syndrome complicating sickle cell disease. J. Clin. Pathol. 76 , 497–500 (2023). Alkindi, S., Al-Maini, M. & Pathare, A. Clinical and laboratory characteristics of patients with sickle-cell and autoimmune/connective tissue diseases. Rheumatol. Int. 32 , 373–378 (2012). Lopinto, J., Elabbadi, A., Gibelin, A., Voiriot, G. & Fartoukh, M. Infectious aetiologies of severe acute chest syndrome in sickle-cell adult patients, combining conventional microbiological tests and respiratory multiplex PCR. Sci. Rep. 11 , 4837 (2021). Tsitsikas, D. A. et. Al. Addition of plasma exchange to red cell exchange improves outcomes of fat embolism syndrome in sickle cell disease. Br. J. Haematol. 200 , e50–e52 (2023). Manci, E. A. et al. Causes of death in sickle cell disease: an autopsy study. Br. J. Haematol. 123 , 359–365 (2023). Darbari, D. S. et al. Circumstances of death in adult sickle cell disease patients. Am. J. Hematol. 81 , 858–863 (2006). Platt, O. S. et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl. J. Med. 330 , 1639–1644 (1994). Graham, J. K., Mosunjac, M., Hanzlick, R. L. & Mosunjac, M. Sickle cell lung disease and sudden death: a retrospective/prospective study of 21 autopsy cases and literature review. Am J. Forensic Med. Pathol (2007). 28,168 – 72. Additional Declarations No competing interests reported. Supplementary Files Table1chestradiographandCTscanfindingsinPulmonaryFESsupplemental.docx Cite Share Download PDF Status: Published Journal Publication published 28 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Accepted 14 Jul, 2025 Reviews received at journal 13 Jul, 2025 Reviews received at journal 02 Jul, 2025 Reviewers agreed at journal 01 Jul, 2025 Reviewers agreed at journal 28 Jun, 2025 Reviewers invited by journal 26 Jun, 2025 Submission checks completed at journal 18 Jun, 2025 First submitted to journal 30 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5040224","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":485119181,"identity":"7c3ff81a-a95f-4708-a0e1-41d092f93986","order_by":0,"name":"Salam 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Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nandagopal","middleName":"","lastName":"Ramachandiran","suffix":""},{"id":485119197,"identity":"e5ce7c89-ac6a-4ba8-9025-14e1d49a8b67","order_by":12,"name":"Anil V Pathare","email":"","orcid":"","institution":"Sultan Qaboos University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anil","middleName":"V","lastName":"Pathare","suffix":""}],"badges":[],"createdAt":"2024-09-05 19:41:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5040224/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5040224/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-11983-y","type":"published","date":"2025-07-28T16:20:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86783250,"identity":"7245db23-0202-44a7-ad3a-4cd3d51c08e0","added_by":"auto","created_at":"2025-07-15 13:51:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":98116,"visible":true,"origin":"","legend":"\u003cp\u003eChest and neuroimaging findings in a patient with fat embolism syndrome.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eA\u003c/strong\u003e) A chest radiograph on presentation shows bilateral perihilar and lower lung predominant opacities. An endotracheal tube, central venous line, and nasogastric tube are seen in situ.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eB\u003c/strong\u003e) Axial CT chest in lung window done on the same day reveals bilaterally dependent subpleural lower lung predominant consolidative and ground-glass opacities.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eC, D\u003c/strong\u003e) Axial diffusion-weighted images from an MRI that was performed 24 hours after presentation show bilateral scattered foci of diffusion restriction in the white matter and deep gray matter (ADC map is not shown).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eE\u003c/strong\u003e) A susceptibility-weighted image from an MRI done one week after the initial presentation demonstrates extensive microbleeds in the white matter, including the corpus callosum and deep gray matter.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5040224/v1/6f6e9cc21d58c8d3dcd01bac.jpg"},{"id":86783252,"identity":"8458890f-b103-482a-8ada-c6a432952b62","added_by":"auto","created_at":"2025-07-15 13:51:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":70292,"visible":true,"origin":"","legend":"\u003cp\u003eThe Box-Whisker plot with interquartile ranges showing the statistically significant differences in the haematological and biochemical parameters.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel A\u003c/strong\u003eshows the haemoglobin levels at admission and nadir,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel B\u003c/strong\u003e shows the WBC levels at admission and maximal,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel C\u003c/strong\u003e shows the Platelet counts at admission and nadir,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel D\u003c/strong\u003eshows the Serum LDH levels at admission and Maximum whereas,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel E\u003c/strong\u003e shows the Serum CRP levels at admission and maximum.\u003c/p\u003e\n\u003cp\u003eStatistical significance was demonstrated using the non-parametric Wilcoxon Signed Ranks test.\u003c/p\u003e","description":"","filename":"RevisedFigure2FES1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5040224/v1/94f86522181e04d1afcdc0ee.jpg"},{"id":86784737,"identity":"e91311b6-4b69-415c-8049-2f8bb1810359","added_by":"auto","created_at":"2025-07-15 13:59:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":334167,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of reported clinical and laboratory features (%) between the largest reported study and the present single institution study\u003c/p\u003e","description":"","filename":"RevisedFigure3FES21.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5040224/v1/dc5c25765dc0dc3616a8f720.jpg"},{"id":88268159,"identity":"22f23c91-a285-4330-aee3-01d5e886c84e","added_by":"auto","created_at":"2025-08-04 16:49:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1658909,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5040224/v1/55a9c4bf-afef-4a32-a199-748ee2f2e59c.pdf"},{"id":86783255,"identity":"f9c0baf7-38cd-474f-9c79-254f326a26a5","added_by":"auto","created_at":"2025-07-15 13:51:52","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":13180,"visible":true,"origin":"","legend":"","description":"","filename":"Table1chestradiographandCTscanfindingsinPulmonaryFESsupplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-5040224/v1/6cb2af305ab6847fb5c2e7b7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical, Laboratory and Radiological features, and Outcome of Acute Fat Embolism Syndrome in Sickle Cell Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFat embolism syndrome (FES) is a rare, but one of the most devastating acute complications of sickle-cell disease (SCD)\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. It usually occurs following a vaso-occlusive crisis (VOC) that leads to bone marrow necrosis (BMN). The subsequent release of fat globules into the venous pulmonary microcirculatory system, causes acute chest syndrome. If BMN is more extensive, large amounts of fat droplets enters the systemic circulation, leading to the classical FES with characteristic multiorgan dysfunction.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eClinically, it is characterized by a triad of rapidly progressive respiratory failure, neurological manifestations, and thrombocytopenia. Involvement of various other organs leads to a multiorgan failure. The peripheral blood smear shows a leukoerythroblastic picture, whereas other laboratory investigations show extremely high levels of serum ferritin and lactic dehydrogenase (LDH)\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Further, FES is often associated with human parvovirus (HPV) B19 and reported to be seen more frequently in heterozygous SCD patients\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. The diagnosis of FES is usually empiric, but based on multi-organ involvement associated with fat and/or necrotic marrow emboli leading to acute respiratory distress, neurological manifestations and multiorgan failure\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Evidence of BMN is suggested by histopathological evidence, although bone marrow biopsy cannot exclude BMN, since it depends on the timing of the biopsy\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Although, BMN results in the release of fat globules, circulating phospholipids are metabolised to arachidonic acid under the influence of secretory phospholipase A2, leading to the production and release of numerous inflammatory cytokines\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe historical classifications proposed for the diagnosis of FES namely, Gurd\u0026rsquo;s and Schonfeld\u0026rsquo;s are essentially in the context of traumatic FES, and not applicable to FES in SCD patients\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Therefore, an acute drop in haemoglobin and platelets, with significantly increased serum ferritin and lactate dehydrogenase (LDH), are the most frequently reported abnormal laboratory findings in the setting of an acute VOC crisis. Currently, there are no specific treatment protocols for FES, and patients are generally treated with multiple red blood cell (RBC) transfusions or exchange transfusions within hours of the presentation as it has been shown to hasten neurologic recovery\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Although the first case of FES in SCD was reported in 1941\u003csup\u003e12\u003c/sup\u003e, followed by several case reports \u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and few cohort studies too \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, no prospective studies have been reported.\u003c/p\u003e \u003cp\u003eHere, we report the largest single centre experience with FES in SCD patients, highlighting the clinical, laboratory and radiological features, emphasizing the importance of the high index of suspicion of FES (as suggested by Bailey, K. et al), along with rapid institution of treatment and supportive measures that are very important in improving the outcome in FES in SCD patients.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eIn this retrospective study, 27 SCD patients, who developed FES between 2006 and 2023 at the Sultan Qaboos University Hospital in Oman were enrolled, after a written approval from the institutional medical research ethics committee (MREC # 1858), college of medicine \u0026amp; health sciences. The inclusion criteria included SCD patients, who were admitted with a VOC and developed FES according to the current diagnostic criteria \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. The data was obtained from the electronic patient record system and in accordance with relevant local guidelines and regulations. Following MREC approval (MREC #1858), and since this is a retrospective study, individual patient consent was not required / mandated by the MREC. The data collected included demographic, clinical, haematological, biochemical, and radiological parameters, as well as the therapeutic interventions given.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical evaluations\u003c/h2\u003e \u003cp\u003eClinical symptoms consisted of documented fever, along with respiratory and neurological symptoms. O\u003csub\u003e2\u003c/sub\u003e saturation was obtained by pulse oximetry. Further, important variables like the use of prior disease modifying therapies like hydroxyurea, baseline hematological laboratory parameters and previous histories of VOC frequencies, history of ACS etc. were also noted in all these patients. Other details of SCD therapeutic management protocols like non-invasive ventilatory support, antibiotics, blood transfusion and blood exchanges were also recorded.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLaboratory parameters\u003c/h3\u003e\n\u003cp\u003eComplete blood counts including haemoglobin (Hb), reticulocytes and platelet counts were obtained at baseline and nadir, whereas white blood cell count (WBC) was recorded at baseline and at their maximum, including baseline HbF. Biochemical parameters included CRP, Liver function tests, and renal function. Serum ferritin, and LDH were collected on arrival and their maximum values were noted during the admission.\u003c/p\u003e\n\u003ch3\u003eRadiological evaluation\u003c/h3\u003e\n\u003cp\u003eSeveral radiological studies were performed for patients as required and analysed. These studies including chest radiographs, chest computerized tomography (CT) scan, ultrasound of the abdomen, and magnetic resonance imaging (MRI) of the brain.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analysis\u003c/b\u003e. The statistical package for social science (IBM SPSS, USA ver.23, Armonk, NY) was used to analyse the collected data. Normally distributed data was characterized as mean with standard deviation, whereas data that was not normally distributed was characterized as median with interquartile range (IQR) for continuous variables and percentage and frequency for categorical variables. Wilcoxon Signed Ranks test was used to study the significance of differences in the laboratory parameters at baseline and during clinical deterioration with FES. Chi Square test was used to study the differences in proportions and ANOVA was used to compare multiple means. Logistic and multivariate analyses were also performed to see the effect of various parameters affecting mortality. An alpha of \u0026lt;\u0026thinsp;0.05 was considered to be the statistically significant p value.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e27 patients (17 males, 10 females) who were enrolled in the study had a median age (IQR) of 24 (21\u0026ndash;33) years but ranged between 15 to 55 years (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median length of hospital stay was 24 days with IQR between 16 to 38 days with a range between 5 to 270 days. SCD genotyping revealed that two patients had SD Punjab, six patients had HbS\u003cb\u003eβ\u003c/b\u003e\u003csup\u003e\u003cb\u003e+\u003c/b\u003e\u003c/sup\u003eThal, while the majority (n\u0026thinsp;=\u0026thinsp;19) had HbSS.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, and Clinical parameters in FES cohort (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDemography\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age in years (IQR)[Range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24(21\u0026ndash;33) [15\u0026ndash;55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, Total cases, n, M: F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(17:10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age in years, males (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(22-30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age in years, females (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24(19-48.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian length of Hospital Stay, days (IQR)[Range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24(16\u0026ndash;38) [5-270]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCD Disease severity n (%) Grade1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCD Genotype SS, n (%) [Dead]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19(70) [3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCD Genotype SB\u003csup\u003e+\u003c/sup\u003eThal, n (%) [Dead]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(22) [2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptoms \u0026amp; Signs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest/Back Pain, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRespiratory symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrepitations, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced O\u003csub\u003e2\u003c/sub\u003e Saturation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24(89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced O\u003csub\u003e2\u003c/sub\u003e Saturation, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86(78\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough, n (%),\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachypnoea, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWheeze, n (%) [n\u0026thinsp;=\u0026thinsp;19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeurological symptoms, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConfusion \u0026amp; altered sensorium, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMemory deficit, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComa, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizures, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCardiovascular symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachycardia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotension, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRadiological findings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal Ultrasound, n (%) [n\u0026thinsp;=\u0026thinsp;17]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal CT scan n % [n\u0026thinsp;=\u0026thinsp;7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal Chest X-Rays, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtelectasis-Consolidation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenic atrophy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13(48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenomegaly, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eKey: # Wilcoxon Signed Ranks Test; IQR- Interquartile Range; NS \u0026ndash; Not significant\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eClinical manifestations\u003c/h3\u003e\n\u003cp\u003eAt presentation, patients had cough, chest/back pain, fever and crepitation in 33%, 96%, 100%, and 100% respectively, with reduced O\u003csub\u003e2\u003c/sub\u003e saturation in 89%. Neurological symptoms seen in the majority of patients (96%) including confusion \u0026amp; altered sensorium, memory, deficit, coma, seizures, and others in 50%, 19%, 19%,15%, and 23% others respectively. The median O\u003csub\u003e2\u003c/sub\u003e saturation was 86% with the IQR ranging between 78 to 89%. Tachycardia, hypotension and tachypnoea were seen in 93%, 41% and 22% respectively.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRadiological evaluations\u003c/h2\u003e \u003cp\u003eTwenty-five cases had chest radiographs, that were available for analysis, whereas 14 had a chest CT scan done as seen in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u0026amp; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e Chest radiograph and CT scan of chest both showed varying degrees of manifestations. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Supplemental Table\u0026nbsp;1b)\u003c/p\u003e \u003cp\u003eMRI brain was available for analysis on 23 (85%) patients from the total cohort, with 96% having neurological syndrome, and nineteen patients had MR findings in keeping with cerebral fat embolism.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The classical starfield pattern was observed in seven patients with multiple foci of diffusion restriction in the white matter and deep grey matter, whereas fifteen had scattered microbleeds (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLaboratory parameters\u003c/h3\u003e\n\u003cp\u003eAmongst the haematology parameters, there was a significant drop in the median Hb and platelet counts from baseline, with a significant rise in the median WBC count (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Wilcoxon Signed Ranks test). The median basal Hb g/dl dropped significantly to 6.9 from baseline levels of 10.8. There was reticulocytopenia with mean reticulocytes of 2.1%, with a range from (0.3\u0026ndash;6.2%) and a median of 1.6%. The median basal white blood cell count (X10\u003csup\u003e9\u003c/sup\u003e/L) increased significantly to 14.3 from the baseline level of 8.5 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Wilcoxon Signed Ranks test) (Panel A-B). The median platelet count (X10\u003csup\u003e9\u003c/sup\u003e/L) dropped significantly to 29 from the baseline level of 272 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Wilcoxon Signed Ranks test).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory parameters \u0026amp; medical interventions in FES cohort (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory Features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian hemoglobin basal, g/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.8(9.5\u0026ndash;11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2.01851X10\u003csup\u003e\u0026minus;\u0026thinsp;10#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian hemoglobin nadir, g/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.9(6.3\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian WBC counts basal,10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5(6.1\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.8562X10\u003csup\u003e\u0026minus;\u0026thinsp;05#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian WBC counts Max, 10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.3(11.6\u0026ndash;20.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian platelet counts basal, X10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e272(188\u0026ndash;450)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.1696X10\u003csup\u003e\u0026minus;\u0026thinsp;09#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian platelet counts nadir,10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29(15\u0026ndash;54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Retic Count, nadir, %(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6(0.6\u0026ndash;2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian HbF, %(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.8(5.6-10.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S. Ferritin, ng/ml (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2760(1446\u0026ndash;26589)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S.LDH at admission, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e633(403\u0026ndash;1938)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.00241054\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S.LDH max, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3166(1446\u0026ndash;5623)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian CRP at admission (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83(14.75\u0026ndash;180)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4.69469X10\u003csup\u003e\u0026minus;\u0026thinsp;06#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian CRP max (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e370(236-418.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian AST, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e209(87\u0026ndash;481)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian ALT, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96(62\u0026ndash;349)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian ALP, u/L (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e471(395\u0026ndash;686)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S. bilirubin, mg/dl(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64(40\u0026ndash;131)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal Serum Creatinine, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANA positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParvo B19 positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood Culture positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInterventions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimple blood transfusions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExchange blood transfusions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIV alone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIV\u0026thinsp;+\u0026thinsp;Ventilation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVentilation alone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eKey: # Wilcoxon Signed Ranks Test; IQR- Interquartile Range; NS \u0026ndash; Not significant\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe biochemical parameters showed a significant rise in the median serum LDH and median CRP levels Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Wilcoxon Signed Ranks test). The median CRP levels (mg/L) increased significantly from 83 at arrival to hospital, to the median CRP max value of 370 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Wilcoxon Signed Ranks test). Similarly, the median serum LDH levels (U/L) also significantly increased from 633 at admission to 3166 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Wilcoxon Signed Ranks test) (Panel C-E).\u003c/p\u003e \u003cp\u003eIn this cohort, 18 (66.6%) patients had culture-proven sepsis with 9 (50%) amongst these patients showing multiple microorganisms. Of the 21 microbial organisms isolated, 12 (57%) and 10 (48%) were bacterial, and fungal isolates respectively. Specifically, the bacterial isolates included MDR Acinetobacter baumannii (4), MDR Klebsiella (2), E. coli (2), Pantoa agglomerans (1), Salmonella spp. (1), Staph. Epidermidis (1) and Coagulase-negative Staphylococcus (1). Most fungal isolates were Candida spp. (7), while Candida krusei, Candida tropicalis, and Candida dubliniensis were isolated from 1 patient each. Additionally, EBV, CMV and Parvo B19 PCR positivity was seen in 1, 2 and 6 (22.2%) patients respectively. Further 9(33%) patients also showed ANA positivity.\u003c/p\u003e\n\u003ch3\u003ePredictors of mortality\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the correlation of the clinical and laboratory parameters with mortality in the FES cohort. Mortality was seen in younger adults with respiratory distress highlighted by significantly increased of respiratory symptoms and signs namely cough, wheezing and tachypnoea (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Chi-Square test). Multivariate analysis did not show the predictive effects of independent variables on mortality. Logistic regression also did not show any significant effect of the predictors on mortality. Further, all had abnormal CT scans and significantly abnormal liver function namely, S. Bilirubin and AST. All patients succumbed despite maximal respiratory support with NIV and ventilation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation of Laboratory parameters with mortality in FES cohort (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlive(n\u0026thinsp;=\u0026thinsp;22)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDead (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDemography\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age in years (IQR)[Range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.5(21.75\u0026ndash;33.75) [15\u0026ndash;55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23(17.5\u0026ndash;35.5) [16\u0026ndash;47]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, Total cases, n, M: F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(14:8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(3:2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian length of Hospital Stay, days (IQR)[Range]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.5(17.5\u0026ndash;33.5)\u003c/p\u003e \u003cp\u003e[7-270]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(7\u0026ndash;51) [5\u0026ndash;57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCD Genotype SS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCD Genotype SB\u003csup\u003e+\u003c/sup\u003eThal, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.42**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptoms \u0026amp; Signs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest/Back Pain, n (%) [n\u0026thinsp;=\u0026thinsp;26]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever, n (%) [n\u0026thinsp;=\u0026thinsp;27]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough, n (%) [n\u0026thinsp;=\u0026thinsp;16]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrepitations, n (%) [n\u0026thinsp;=\u0026thinsp;27]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWheeze, n (%) [n\u0026thinsp;=\u0026thinsp;19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological manifestations, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.65**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachycardia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.82**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotension, n (%) [n\u0026thinsp;=\u0026thinsp;19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachypnoea, n (%) [n\u0026thinsp;=\u0026thinsp;20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced O2 Saturation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19(86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced O2 Saturation, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85.5(78\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88(78\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal Chest X-Rays, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtelectasis-Consolidation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleural Effusion, n (%) [n\u0026thinsp;=\u0026thinsp;17]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal CT scans, n (%) [n\u0026thinsp;=\u0026thinsp;7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal Ultrasound, n % [n\u0026thinsp;=\u0026thinsp;17]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13(76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.74**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal Spleen, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.26\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenomegaly, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenic atrophy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory Features\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian hemoglobin basal, g/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.7(9.5\u0026ndash;11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.2(8-10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian hemoglobin nadir, g/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.8(6.3\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.3(5.1\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian WBC counts basal,10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.2(5.8\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.9(6.7\u0026ndash;11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.71*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian WBC counts Max, 10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.8(10.6\u0026ndash;19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.4(16.4\u0026ndash;29.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.27*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian platelet counts basal, X10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e272(182\u0026ndash;416)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e450(289\u0026ndash;518)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian platelet counts nadir,10\u003csup\u003e9\u003c/sup\u003e/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29(15\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39(23\u0026ndash;98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian HbF, %(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.1(5.9-12.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5(1.8\u0026ndash;9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S. Ferritin, ng/ml (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2760(1315\u0026ndash;12960)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32166(1752-125995)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S.LDH at admission, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e735(366\u0026ndash;1732)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1937(836\u0026ndash;3427)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S.LDH max, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3271(1390\u0026ndash;5297)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1987(1457\u0026ndash;11238)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian CRP at admission (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62(14.5\u0026ndash;142)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e134(34\u0026ndash;239)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian CRP max (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e325(265\u0026ndash;424)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e282(127\u0026ndash;410)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian AST, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e192(91\u0026ndash;349)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1278(79-8845)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian ALT, u/L(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88.5(58.5\u0026ndash;289)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e258(68-2825)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian S. bilirubin, mg/dl(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.5(40.5\u0026ndash;109)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e312(34.5\u0026ndash;493)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.005*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal Serum Creatinine, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.46**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANA positive, n (%) [n\u0026thinsp;=\u0026thinsp;19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.69**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParvo B19 positive, n (%) [n\u0026thinsp;=\u0026thinsp;20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.85**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood Culture positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInterventions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimple blood transfusions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExchange blood transfusions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIV alone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.004\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIV\u0026thinsp;+\u0026thinsp;Ventilation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVentilation alone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eKey: ** Chi Square Test; IQR- Interquartile Range;* Students T test; \u003csup\u003e#\u003c/sup\u003e Anova\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eManagement\u003c/h2\u003e \u003cp\u003eAll patients (100%) received antibiotics, along with simple as well as exchange blood transfusions, whereas 24%, 76% respectively required non-invasive ventilation (NIV), and invasive mechanical ventilation. Mortality was seen in 5 (18.5%) patients, whereas the remaining 22 (81.5%) showed varying degrees of recovery. Amongst the 5 deaths, 3 patients had HbSS genotype, whereas two patients had HbS\u003cb\u003eβ\u003c/b\u003e\u003csup\u003e\u003cb\u003e+\u003c/b\u003e\u003c/sup\u003eThal genotype.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough the survival of SCD patients has improved, patients are still dying prematurely, especially, following complications like sepsis and acute chest syndrome (ACS)\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Further, VOCs are associated with bone infarcts and BMN and FES ensuing in this setting can lead to a rapid downward clinical course with fatal outcomes\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Data from this FES cohort, suggest that it can occur at any age in SCD patients (range 15\u0026ndash;55) presenting with uncomplicated VOCs, although the median age of 24 years indicates that young adults are at an increased risk.\u003c/p\u003e \u003cp\u003eOur previous data on ACS showed a similar median age group with a male preponderance.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Historically, FES has been exclusively reported in patients with predominantly HbSC and Sβ\u0026thinsp;+\u0026thinsp;Thal \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In 2019, Tsitsikas DA et al reported that only 20.6%(n\u0026thinsp;=\u0026thinsp;12) had homozygous disease, whereas, 43.1% (n\u0026thinsp;=\u0026thinsp;25) had HbSC and another 27.6%(n\u0026thinsp;=\u0026thinsp;16) had HbSβ\u0026thinsp;+\u0026thinsp;Thal. \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e It has been postulated that the higher haematocrit in HbSC compared to HbSS patients, results in a higher blood viscosity.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003eIn our cohort, the majority of cases with FES had HbSS genotype (70%), while HbSβThal genotype was seen in 22%. Further, in this cohort, 63% had mild disease, similar to what is seen in the literature with reports of about 30% presenting with this SCD-related complication for the first time.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Interestingly, the median length of stay in this group was much longer than the average VOC hospital stay, reflecting the severity of this complication.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePatients with FES in this cohort, presented with fever, respiratory symptoms, painful episodes (the chest and back predominantly) and neurological syndrome in 100%, 100%, 96% and 96% respectively as indicated in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb. These symptoms are comparable to those reported by Tsitsikas DA et al in the case series previously published. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Respiratory manifestations include lung crepitations, drop in saturation, cough, tachypnoea, and wheezing seen in 100%, 89%,33%, 22% and 11% respectively. This significant respiratory involvement seen in the initial phases of its development, is contributed to by the release of fat droplets from the infarcted bone marrow, leading to occlusion of microvascular structures. These circulating phospholipids are hydrolysed under the influence of secretary phospholipase A2 (sPLA2), leading to many cytokines that are released causing the damage usually seen in both lungs and brain.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Another distinguishing feature of these patients is the presence of neurological syndrome, which was seen in 96% of all patients in this cohort with varied manifestations including acute hallucinations, seizures, impaired cognitive function, tremor, cerebellar signs, altered sensorium, confusion, disorientation, incoherent speech, impaired memory and coma. It is not clear how fat emboli get into systemic circulation, but a few of our patients had evidence of a right-to-left intracardiac or pulmonary shunt (through pulmonary capillaries) to enter into the systemic circulation into the brain or kidneys. \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e Other major organ involvement was also noted including renal, hepatic and cardiac involvement seen in 52, 33 and 15% respectively. These findings are similar to those seen with other studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e It is postulated that this may be due to disseminated cytokines, fat embolization or as a consequence of other infections present at the same time, but it is not clear.\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003eHowever, since the presentation is not different from thrombotic thrombocytopenic purpura, it warrants a high index of suspicion by the clinician who should be alerted to the possibility of FES.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cb\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral investigators have reported a possible association of FES to an underlying HPV B19 infection\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. The premise here is that HPV B19 induced endothelial inflammation results in the increased vascular adhesion and infarction of bone marrow especially in patients with high baseline Hb \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. This endothelial cell infection may also explain other complications of HPV infection including myocarditis, skin manifestation and also placental involvement. Tsitsikas et al\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e found that 24% of FES cases were associated with HPV 19 infections and suggested that it played a significant role in its pathogenesis. In our cohort, 22% had Parvo B 19 positivity, and this virus may be relevant in the search for a unifying trigger for reticulocytopenia. Infection with HPV contributes to the development of HPV-related complications in SCD, including triggering painful episodes, ACS, splenic sequestration, and transient red cell aplasia.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003eIt is interesting to note that a recent autopsy report suggested that the presence of HPV was associated with higher mortality (63% vs 32%, in non-HPV infected).\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFES diagnosis is based on the presence of respiratory failure, neurological syndrome, classical radiological findings, with striking laboratory findings. In our cohort, patients experienced a sudden drop in O\u003csub\u003e2\u003c/sub\u003e saturation associated with a rapidly progressive respiratory failure, and neurological manifestations. There is a significant rapid drop in Hb and platelets from baseline as indicated in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, with a rise in WBC associated and a significant reticulocytopenia. Also, patients showed statistically significantly rise in CRP, LDH, ALP and ferritin, with involvement of various other organs including raised creatinine in 52%, hyperbilirubinemia with raised liver enzymes in almost all of them, complicated by a multiorgan failure. 33% of cases had a positive ANA, but none of them was confirmed to progress to an autoimmune disease although our earlier data showed a higher prevalence of ANA positivity among patient with SCD.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBlood culture was positive in 66.6% of the cases, and the growth included bacterial, fungal as well as viral isolates. Although infection may be a triggering factor for this syndrome, many of these patients stayed in the hospital for a considerable length of time, (median length of hospital stays of 24) leading to hospital-acquired infections, considering their primary immune-compromised status (splenectomy in 48% of cases),. Moreover, other studies in patients with severe ACS who got admitted to ICU, showed that in around 50% of these cases, microbiological documentation of infective agent could be demonstrated.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLooking at radiological findings, it indicates a severe chest syndrome with variable and manifestations, reflecting the heterogeneity within this syndrome as indicated in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (A-B). Our findings indicate a wide range of chest manifestations in SCD patients with FES, highlighting the need for high clinical suspicion for accurate diagnosis. CT chest is superior in assessing lung parenchyma compared to radiography, and it is recommended to confirm the diagnosis, and to also investigate alternative causes of respiratory distress. Understanding the diverse patterns of thoracic involvement, was instrumental in suspecting FES in these SCD patients with respiratory distress and was crucial for early diagnosis and timely management. Similarly, some patients had distinctive neuroimaging patterns pathognomonic for this syndrome as indicated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (C-E).\u003c/p\u003e \u003cp\u003eSince this is a progressive illness, rapid attention needed be given to supportive therapy. Unfortunately, there is currently no specific treatment protocol for FES. Our data clearly emphasizes that rapid diagnosis with early supportive measures including antibiotics (given to 100% of patients), ventilatory support (including NIV and mechanical ventilation) as well as simple blood /exchange transfusions was essential for optimal outcomes. Most importantly, the sudden drop in the O\u003csub\u003e2\u003c/sub\u003e saturation with respiratory distress, followed by neurologic symptoms and signs of profound thrombocytopenia in the setting of a VOC crisis, warrants immediate institution of red cell simple and exchange transfusions. Overall mortality was highest in those who had no blood transfusions although 91% and 61% patients had top-up transfusions, while 29% received exchange transfusions.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Immediate red cell exchange transfusions can be lifesaving and should be instituted as soon as the syndrome is suspected \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, to improve the outcome it is suggested to increase the use of red cell exchange, with pre-emptive transfusion to be immediately considered for high-risk patients.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e It is believed that RBC exchange transfusion reduces the inflammatory markers and the percentage of hemoglobin S, which improves pulmonary vascular circulation by lowering the viscosity.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Improvement in the neurological symptoms has been seen to occur within hours of the institution of RBC transfusions or exchange transfusions.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Clearly exchange transfusion is the best approach, and there is also emerging data on the use of plasma exchange (done in one of our cohort) to address the inflammatory environment and potentially improve outcomes in these patients.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e Few of our patients who were extremely sick received steroids as part of anti-inflammatory measures. Although, this was previously used in traumatic FES, it has not been used in SCD-related FES.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Although bone marrow biopsy can be helpful in the diagnosis of FES, delaying the care until it is done without instituting appropriate management can worsen the outcomes. Lastly, although multiple studies have observed sudden or unexplained deaths in SCD patients of up to 40% during VOCs; autopsy study has shown evidence for pulmonary fat emboli in only one-third of such cases \u003csup\u003e\u003cb\u003e\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. Likewise, it has also been postulated that cases of multiorgan failure syndrome with a seemingly uncomplicated painful crisis and rapid deterioration may actually represent cases of FES \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere were five deaths among the cohort, three of whom had HbSS (60%), whereas two had HbSβ\u0026thinsp;+\u0026thinsp;Thal genotype (40%). These five patients died despite optimal support with antibiotics, blood exchange blood transfusions, NIV and ventilatory support. Two patients who died were comatose and one was in a vegetative state prior to their demise. Although the median length of hospital stay was similar, the length of stay was shorter in the mortality group with range between 5 to 57 days of hospital stay, as opposed to between 7 to 270 days in the survivor cohort. Further, the mortality cohort also had significantly more intense cardiorespiratory manifestations (cough 80% Vs 12.5%, wheezing 60% vs 5.2%, tachypnoea 80% Vs 10%, with abnormal CT scan in 100% Vs 29%) as compared to the survivors in the cohort. These patients showed grossly deranged liver function abnormalities and significantly raised LDH indicative of a severely intense inflammatory response (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis is a relatively small size cohort of FES, and although two-thirds of cases had the HbSS genotype, the mortality was in similar proportion to that seen in HbS\u003cb\u003eβ\u003c/b\u003e\u003csup\u003e\u003cb\u003e+\u003c/b\u003e\u003c/sup\u003eThal genotype, and this has not been observed in previous literature reports.\u003c/p\u003e \u003cp\u003eIn summary, FES is a rapidly progressive respiratory and neurological syndrome seen in all genotypes of SCD, presenting with fever, and pain. Its characterized by hypoxia, cytopenia, including anemia and thrombocytopenia with raised inflammatory markers (CRP, ferritin) and significant rise in LDH and ALP, as well as distinctive radiological findings. The outcome has significant improved following the use of exchange transfusions with a mortality of 18.5% in this current cohort.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eWe wish to thank the hospital administration for the use of hospital material in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eNo funding was requested or obtained from any agency to perform this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eSAK and AVP were fully involved in the conception and design of the study, recruitment \u0026amp; care of patients, acquisition of data, analysis and interpretation of data and was instrumental in the drafting the article and critical appraisal before submission. EAA, and SRA analysed the radiological data and contributed towards manuscript preparation, KAF, HKH, KUN, MAB, FAA, AGU, AAA, ALM, and NRA, contributed in patient care. All authors have seen, and approved the final version of manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of Conflict of Interests\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMellor, A. \u0026amp; Soni, N. 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Life expectancy and risk factors for early death. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e330\u003c/b\u003e, 1639\u0026ndash;1644 (1994).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraham, J. K., Mosunjac, M., Hanzlick, R. L. \u0026amp; Mosunjac, M. Sickle cell lung disease and sudden death: a retrospective/prospective study of 21 autopsy cases and literature review. \u003cem\u003eAm J. Forensic Med. Pathol\u003c/em\u003e (2007). 28,168\u0026thinsp;\u0026ndash;\u0026thinsp;72.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sickle Cell Disease, Fat Embolism Syndrome, Bone Marrow Necrosis, Parvovirus B19, Exchange Transfusion","lastPublishedDoi":"10.21203/rs.3.rs-5040224/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5040224/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNon-traumatic fat embolism syndrome (FES) affecting brain, lung and hematopoietic system is a rare, but a serious complication of sickle cell disease (SCD), resulting from bone marrow necrosis. SCD-related FES is rare, with the spectrum of clinical, laboratory, radiological manifestations and patient outcome is not fully understood. After medical research \u0026amp; ethics committee approval, retrospectively, SCD-FES patients at our centre, were reviewed between January 2006 to December 2023. 27 patients (17 males, 10 females) with a median age of 24 years and length of hospital stay of 24 (16\u0026ndash;38) days were enrolled. They had fever, chest/back pain, cough and crepitation in 100%, 96%, 56% and 100% respectively, with neurological manifestations in 96%. Abnormal chest X-rays and CT scans were observed in 96%, and 100% respectively. Patients had significant anemia, reticulocytopenia, and thrombocytopenia, with raised WBC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was a significant rise in LDH, ALP, Ferritin and C-reactive protein levels. All patients received antibiotics, and exchange transfusions, whereas 24%, 76% required non-invasive ventilation (NIV) and mechanical ventilation respectively, with 18.5% mortality. FES is a rapidly progressive respiratory and neurological syndrome, characterized by hypoxia, and cytopenia, with raised inflammatory markers, raised LDH and ALP, with distinctive multiple cerebral microbleeds.\u003c/p\u003e","manuscriptTitle":"Clinical, Laboratory and Radiological features, and Outcome of Acute Fat Embolism Syndrome in Sickle Cell Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-15 13:51:48","doi":"10.21203/rs.3.rs-5040224/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-07-14T11:36:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-13T15:51:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-02T15:48:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161701614870742882959130433856244390327","date":"2025-07-01T09:22:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74331073485733448644940997567707530756","date":"2025-06-28T14:52:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-26T11:28:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-18T05:16:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-05-30T08:42:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b104c0d2-6d3a-414d-a271-1ec8140c84d1","owner":[],"postedDate":"July 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51496900,"name":"Health sciences/Health care"},{"id":51496901,"name":"Health sciences/Medical research"},{"id":51496902,"name":"Health sciences/Pathogenesis"},{"id":51496903,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-08-04T16:40:07+00:00","versionOfRecord":{"articleIdentity":"rs-5040224","link":"https://doi.org/10.1038/s41598-025-11983-y","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-28 16:20:58","publishedOnDateReadable":"July 28th, 2025"},"versionCreatedAt":"2025-07-15 13:51:48","video":"","vorDoi":"10.1038/s41598-025-11983-y","vorDoiUrl":"https://doi.org/10.1038/s41598-025-11983-y","workflowStages":[]},"version":"v1","identity":"rs-5040224","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5040224","identity":"rs-5040224","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}