Chronic thromboembolic pulmonary hypertension in Saudi Arabia: preliminary results from the SAUDIPH registry.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive vascular disease with poor prognosis if left untreated. This study aims to assess the patient characteristics, treatment approach and clinical and survival outcomes for CTEPH patients enrolled in the Systematic Prospective Follow Up for Better Understanding of Clinical Characteristics of Patients with Pulmonary Hypertension Disease (SAUDIPH) registry. METHODS: This study presents a subanalysis of CTEPH patients enrolled in the SAUDIPH registry. This registry enrolled patients with pulmonary hypertension, established through right heart catheterisation, under clinical management at a specialised tertiary care centre. Patients received standard care during the period of the registry. RESULTS: At the time of this analysis, 64 CTEPH patients were enrolled in the registry. Mean age at diagnosis was 39.7 years and there was a female predominance (67.6%). At baseline, most patients were in World Health Organization functional classes III or IV (70.1%). At the last follow-up visit, most patients (63.2%) had undergone endarterectomy, showing significant improvement in disease severity from baseline. Patients who underwent endarterectomy showed numerically higher (p=0.126) probability of survival at 1 year (97.5%) versus those who did not undergo endarterectomy (94.4%). CONCLUSION: Patients were diagnosed at relatively young age, but still showed high disease severity, suggesting delay in diagnosis. Patients who underwent surgical treatment showed substantial improvements in clinical and haemodynamic parameters, while the remaining patients tended to show disease progression. The 96.6% 1-year cumulative probability of survival was high compared to previous studies.

Incidence and impact of chronic lung allograft dysfunction after lung transplantation - single-center 14-year experience.

Objectives. Lung transplantation remains the only available treatment option for many end-stage lung diseases. We evaluated our long-term lung transplantation results and the impact of chronic lung allograft dysfunction (CLAD). Design. Adult de novo lung transplants (2003-2015, n=175) in a nationwide single transplant center were retrospectively analyzed. Kaplan-Meier survival and Cox regression analysis were used to evaluate the effect of CLAD. Results. Recipient and graft 1-, 5- and 10-year survival estimates were 94%, 79% and 64%, and 93%, 75% and 59%, respectively. CLAD affected 43% of patients at a median of 2.3 years after transplantation, and impaired recipient (p = .03) and graft survival (p = .001) with the most advanced CLAD stage, and restrictive CLAD phenotype, resulting in worst graft survival. CLAD was the primary cause of death in 54% of all patients, and in 80% of patients with an established CLAD diagnosis. CLAD, high-risk cytomegalovirus serostatus, and recipient preoperative sensitization increased graft loss hazard ratio. CLAD was the only significant investigated risk factor for graft loss in multivariate regression analysis. Conclusions. Although very favourable lung transplant patient long-term survival was achieved, CLAD significantly impaired recipient and graft survival. Identification of risk factors and therapeutic options for CLAD may further improve lung transplantation results.

Effect of Donor Age on Outcome of Lung Transplantation Stratified by Recipient Diagnosis: A Nordic Multicenter Study.

BACKGROUND: Organs from older donors are increasingly used in lung transplantation, and studies have demonstrated that this could be safe in selected recipients. However, which recipient groups that have the largest benefit of older organs are unclear. This multicenter study reviews all bilateral lung transplantations (BLTx) from donors 55 years or older stratified by recipient diagnosis and compares outcomes with transplantations from younger donors. METHODS: All BLTx recipients (excluding retransplantation) at 5 Scandiatransplant centers between 2000 and 2013 were included (n = 913). Recipients were stratified to diagnosis groups including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and "other." Intensive care unit (ICU) length of stay (LOS) and survival were assessed. RESULTS: Overall, there was no difference in survival among patients transplanted from donors 55 years or older compared with younger donors. However, in CF recipients, donor age 55 years or older was associated with inferior survival (P = 0.014), and this remained significant in a multivariate model (hazard ratio, 5.0; 95% confidence interval, 1.8-14.1; P = 0.002). There was no significant effect of donor age on survival in recipients with COPD, ILD, or in the "other" group in multivariate models. Utilization of older donors was associated with increased ICU LOS for recipients with CF and ILD, but not in the COPD or "other" group. CONCLUSIONS: The BLTx recipients with CF had inferior survival and longer ICU LOS when receiving organs from donors 55 years or older. Recipients with COPD, ILD, or in the "other" group did not have inferior survival in multivariate models.

Urgent lung allocation system in the Scandiatransplant countries.

BACKGROUND: Throughout the world, the scarcity of donor organs makes optimal allocation systems necessary. In the Scandiatransplant countries, organs for lung transplantation are allocated nationally. To ensure shorter wait time for critically ill patients, the Scandiatransplant urgent lung allocation system (ScULAS) was introduced in 2009, giving supranational priority to patients considered urgent. There were no pre-defined criteria for listing a patient as urgent, but each center was granted only 3 urgent calls per year. This study aims to explore the characteristics and outcome of patients listed as urgent, assess changes associated with the implementation of ScULAS, and describe how the system was utilized by the member centers. METHODS: All patients listed for lung transplantation at the 5 Scandiatransplant centers 5 years before and after implementation of ScULAS were included. RESULTS: After implementation, 8.3% of all listed patients received urgent status, of whom 81% were transplanted within 4 weeks. Patients listed as urgent were younger, more commonly had suppurative lung disease, and were more often on life support compared with patients without urgent status. For patients listed as urgent, post-transplant graft survival was inferior at 30 and 90 days. Although there were no pre-defined criteria for urgent listing, the system was not utilized at its maximum. CONCLUSIONS: ScULAS rapidly allocated organs to patients considered urgent. These patients were younger and more often had suppurative lung disease. Patients with urgent status had inferior short-term outcome, plausibly due to the higher proportion on life support before transplantation.

Low-dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti-thymocyte globulin.

BACKGROUND: Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. OBJECTIVE: We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. METHODS: Hundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900 mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450 mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis. RESULTS: All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P = .001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients. CONCLUSIONS: The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis.

Lung transplantation after allogeneic stem cell transplantation: a pan-European experience.

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT.SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed.Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p<0.001) the leading risk factor. No SCT-specific risk factors were identified. Recurring malignancy occurred in four patients (4%). Lung transplantation <2 years post-SCT increased all-cause 1-year mortality (HR 7.5, 95% CI 2.3-23.8; p=0.001).Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.

Effects of Perioperative Fluid Replacement Therapy in Lung Transplant Patients.

OBJECTIVES: Approximately 10 to 25 lung transplant procedures are performed annually in Finland, and 1-year survival has been 95% over the last 10 years. Our aim was to find associations between perioperative fluid replacement therapies and postoperative patient outcomes, with special emphasis on the use of colloids and blood products. MATERIALS AND METHODS: We retrospectively evaluated data from 100 patients who underwent lung transplant with cardiopulmonary bypass support in Finland from 2007 to 2013. Outcomes of interest were length of intensive care unit and hospital stays, time in ventilator, use of extracorporeal membrane oxygenation postoperatively, postoperative renal replacement therapy, postoperative graft failure, and 1-year mortality. RESULTS: Of 100 patients, 12 were on extracorporeal membrane oxygenation preoperatively. The 1-year mortality was 5/100 (5%), and the 3-year mortality was 7/100 (7%). Intraoperative fluid balance was positive (4762 a 3018 mL) but fell significantly postoperatively (below +1000 mL on postoperative day 1). During postoperative days 2 to 7, net fluid balance continued decreasing and stayed negative. Intraoperative use of hydroxyethyl starch and fresh frozen plasma were significantly higher in patients who died during follow-up versus those who survived (P < .05). Intraoperative use of fresh frozen plasma, but not red blood cells or platelets, correlated with graft failure (P = .012). Postoperative use of colloids or blood products did not correlate with mortality or graft failure. Patients who were on extracorporeal membrane oxygenation preoperatively stayed longer on ventilators and had longer intensive care unit and hospital stays (P < .001). Eight patients needed postoperative renal replacement therapy. CONCLUSIONS: Intraoperative use of fresh frozen plasma and hydroxyethyl starch is associated with increased mortality and graft failure. Postoperative use of colloids and red blood cells did not correlate with patient outcome. Use of extracorporeal membrane oxygenation preoperatively resulted in prolonged length of hospital stay.

Decreased maximum clot firmness in rotational thromboelastometry (ROTEM®) is associated with bleeding during extracorporeal mechanical circulatory support.

BACKGROUND:: We aimed to characterize the coagulation disturbances which may increase the risk of bleeding, thrombosis or death shortly after implantation of an extracorporeal membrane oxygenation (ECMO) or ventricular assist (VAD) device. METHODS:: Antithrombotic treatment was started in 23 VAD and 24 ECMO patients according to the hospital protocol. Additionally, conventional laboratory testing, rotational thromboelastometry (ROTEM®) and platelet function analysis (Multiplate®) were performed at predetermined intervals. RESULTS:: Four out of twenty-four (16.7%) of ECMO patients and 6/23 (26.1%) of VAD patients had severe bleeding after the procedure. When all the patients were analyzed together, low maximum clot firmness (MCF) in ExTEM and FibTEM analyses was associated with severe bleeding (p<0.05) and low MCF in FibTEM with 30-day mortality. Low platelet count and hematocrit levels were also associated with severe bleeding. When VAD and ECMO patients were separated into different groups, the association between ROTEM® parameters, bleeding and survival was found only in limited time points. Four patients with VAD had cerebral ischemia indicative of thromboembolism. However, this had no significant correlation with ROTEM® or Multiplate® parameters. CONCLUSION:: Hypocoagulation shown by ROTEM® was associated with bleeding complications in patients with mechanical circulatory support. In contrast, hypercoagulation did not correlate with clinical thrombosis.

Pulmonary retransplantation in the Nordic countries.

BACKGROUND: The increasing demand for pulmonary retransplantation (re-LTx) raises ethical issues on the correct allocation of the scarce donor pool. Thus, we performed a thorough review of the current results for re-LTx in the Nordic countries. METHODS: Seventy-five patients with a median age of 50 years (range, 22 to 64 years) underwent re-LTx from 1992 until June 2013, of which 53 had single re-LTx, 21 had double re-LTx, and 1 patient underwent a heart-lung retransplantation. Primary graft dysfunction (PGD) was the primary indication in 9 cases, bronchiolitis obliterans syndrome (BOS) in 62 cases, and airway complications in 4 cases. RESULTS: Patients who underwent re-LTx in the period 1992 to 1999 (n = 16) had a 1-year survival of 37.5% (95% confidence interval [CI], 19.9 to 70.6), whereas patients who underwent re-LTx in the period 2000 to 2013 (n = 64) had a 1-year survival of 81.0% (95% CI, 71.5 to 91.8). Corresponding 5-year survival was 25.0% (95% CI, 10.7 to 58.4) in the early era group (1992 to 1999) and 57.2% (95% CI, 44.3 to 73.7) in the more recent era group (2000 to 2013; p = 0.0151). Patients with BOS who underwent re-LTx in the period 1992 to 1999 (n = 13) had a 1-year survival of 38.5% (95% CI, 19.3 to 76.5), whereas patients with BOS who underwent re-LTx in the period 2000 to 2013 (n = 49) had a 1-year survival of 85.4% (95% CI, 75.9 to 96.0). Corresponding 5-year survival was 23.1% (95% CI, 8.6 to 62.3) in the early era group (1992 to 1999) and 56.1% (95% CI, 41.9 to 75.2) in the more recent era group (2000 to 2013; p = 0.0199). The cumulative incidence among patients who underwent re-LTx because of BOS and developed BOS again after re-LTX was analyzed. The cumulative incidence curves for time periods 1992 to 1999 and 2000 to 2013 are not statistically different for repeat BOS (p = 0.5087), but they are highly significant for time periods among patients who died (p = 0.02381). CONCLUSIONS: Results for re-LTx have improved over time, especially when BOS is the primary indication. The cumulative incidence among patients who underwent re-LTx because of BOS and developed repeat BOS after re-LTX showed equal risk between 1992 to 1999 and 2000 to 2013 in the aspect of developing repeat BOS, but in the later era the patients had a significantly higher chance of surviving.

Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass.

BACKGROUND: Bone marrow mononuclear cell (BMMC) transplantation for heart failure has shown inconsistent therapeutic efficacy. METHODS: We enrolled 104 ischemic heart failure patients scheduled for coronary artery bypass surgery (CABG). After 4- to 12-week pharmacotherapy optimization, 39 patients with left ventricular ejection fraction (LVEF) of ≤45% received injections of BMMC or vehicle intra-operatively into the myocardial infarction border area in a randomized, double-blind manner. RESULTS: The median number of cells injected was 8.4 × 10(8) (interquartile range [IQR]: 5.2 × 10(8) to 13.5 × 10(8)). We measured LV function and myocardial scar size by magnetic resonance imaging (MRI), and viability by positron emission tomography (PET) and single-photon emission computed tomography (SPECT), pre-operatively and after 1-year follow-up. LVEF, the pre-defined primary end-point measure, improved by a median of 5.6% in the control group (IQR 0.2 to 10.1) and by 4.8% in the BMMC group (IQR -0.5 to 8.2) (p = 0.59). Wall thickening in injected segments rose by a median of 4.5% among controls (IQR -18.1 to 23.9) and by 5.5% in the BMMC group (IQR -6.6 to 26.5) (p = 0.68). Changes in viability by PET and SPECT did not differ between groups. Myocardial scar size by MRI in injected segments rose by a median of 5.1% among controls (IQR -3.3 to 10.8), but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (p = 0.0002). CONCLUSIONS: BMMC therapy combined with CABG failed to improve LV systolic function, or viability, despite reducing myocardial scar size.

[Mechanical support for the heart and circulation in adults]. / Sydämen ja verenkierron mekaaninen tuki aikuisilla.

In severe, acute or chronic heart failure, the heart and the circulation can be mechanically supported, if the patient's life is in danger despite maximal drug therapy, and other cardiologic or heart surgery treatment options or a suitable heart transplant are not available. Long-term prognosis of those treated with mechanical support has improved in the 2000's. This is based on technically advanced equipment, improved treatment practices, properly targeted patient selection and more accurate timing of therapy.

[Application of extracorporeal membrane oxygenation therapy (ECMO) in the treatment of severe adult respiratory distress syndrome]. / ECMO eli kehonulkoinen happeuttaminen aikuisten vaikeassa hengitysvajauksessa.

Extracorporeal oxygenator is used in severe respiratory and/or circulatory failure that is intractable to other therapies. In ECMO therapy, poorly oxygenated blood is pumped through an extracorporeal oxygenator and directed back to the patient's circulation. The therapy can be utilized to maintain the homeostasis of the organ system during circulatory or respiratory failure resulting from a disease. Due to risk of complications, ECMO should be used with caution on carefully selected patients. For a severely ill patient ECMO can be life-saving when started early.

Usefulness of extracorporeal membrane oxygenation as a bridge to lung transplantation: a descriptive study.

BACKGROUND: This retrospective study investigated early outcome in patients with end-stage pulmonary disease bridged with extracorporeal membrane oxygenation (ECMO) with the intention of lung transplantation (LTx) in 2 Scandinavian transplant centers. METHODS: ECMO was used as a bridge to LTx in 16 patients between 2005 and 2009 at Sahlgrenska and Helsinki University Hospitals. Most patients were late referrals for LTx, and all failed to stabilize on mechanical ventilation. Thirteen patients (7 men) who were a mean age of 41 ± 8 years (range, 25-51 years) underwent LTx after a mean ECMO support of 17 days (range, 1-59 days). Mean follow-up at 25 ± 19 months was 100% complete. RESULTS: Three patients died on ECMO while waiting for a donor, and 1 patient died 82 days after LTx; thus, by intention-to-treat, the success for bridging is 81% and 1-year survival is 75%. All other patients survived, and 1-year survival for transplant recipients was 92% ± 7%. Mean intensive care unit stay after LTx was 28 ± 18 days (range, 3-53 days). All patients were doing well at follow-up; however, 2 patients underwent retransplantation due to bronchiolitis obliterans syndrome at 13 and 21 months after the initial ECMO bridge to LTx procedure. Lung function was evaluated at follow-up, and mean forced expiratory volume in 1 second was 2.0 ± 0.7 l (62% ± 23% of predicted) and forced vital capacity was 3.1 ± 0.6 l (74% ± 21% of predicted). CONCLUSION: ECMO used as a bridge to LTx results in excellent short-term survival in selected patients with end-stage pulmonary disease.

Association between gastrointestinal symptoms and health-related quality of life after heart transplantation.

BACKGROUND: Heart transplantation (HTx) ameliorates the self-perceived health-related quality of life (HRQoL) of patients with terminal heart disease; gastrointestinal (GI) symptoms, due to obligatory immunosuppression, may contribute to impaired HRQoL post-HTx. METHODS: In this cross-sectional, exploratory study we aimed to investigate association between GI symptoms and HRQoL. The study consisted of 167 patients who had undergone HTx between 1985 and 2006 in Finland. Short-Form 36 (SF-36) Quality of Life and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires were sent to the patients at the end of 2006 for capturing data on the HRQoL of HTx recipients. RESULTS: Higher or equal SF-36 scores describing the HRQoL dimensions compared with the Finnish age- and gender-matched reference population were as follows: physical functioning, 60.5%; role-physical, 67.5%; bodily pain, 62.6%; general health, 64.0%; vitality, 68.1%; social functioning, 68.1%; role-emotional, 70.0%; and mental health, 70.4%. The prevalence of troublesome GI symptoms (GSRS score >1) per GSRS dimension was 53.9% for diarrhea, 91.0% for indigestion, 60.6% for constipation, 73.4% for abdominal pain, 46.4% for reflux and 95.8% for any GI symptom. Diabetes contributed to the presence of diarrhea (odds ratio [OR]: 3.00; 95% confidence interval [CI]: 1.12 to 8.00), use of prednisolone to indigestion (OR: 3.21; 95% CI: 1.05 to 9.79) and increased age to constipation (OR: 1.04; 95% CI: 1.02 to 1.07). CONCLUSIONS: HRQoL after HTx is relatively good and comparable to the age- and gender-matched reference population. HRQoL is vulnerable to side-effects caused by the obligatory post-HTx immunosuppressive regimen, where GI symptoms play a major but clearly an underestimated role.

Natural course and risk factors for impaired renal function during the first year after heart transplantation.

BACKGROUND: Post-operative renal failure is a common and potentially hazardous complication after heart transplantation (HTx). In this study we characterized pre- and post-operative risk factors for acute renal failure requiring renal replacement therapy (RRT). METHODS: Ninety-three patients underwent orthotopic HTx between 2000 and 2007. The risk factors for RRT during the early post-operative period and predictors contributing to impaired renal function within the first post-transplant year were analyzed by regression analysis. The impact of pre-operative renal failure and early post-operative RRT on renal function within 1 year were studied. RESULTS: Before HTx, 55% of patients (51 of 93) had normal renal function or mild renal failure (glomerular filtration rate [GFR] >60 ml/min/1.73 m(2)). Before discharge from the hospital, 25% (23 of 93) developed acute renal failure and required RRT. Of these, 16% (8 of 51) had pre-operatively normal renal function or mild renal failure, and 36% (15 of 42) had moderate or severe renal failure (GFR <60 ml/min/1.73 m(2); p = 0.02). The prognosticators for early RRT were prolonged graft dysfunction, re-admission to the operating room due to post-operative bleeding, poor diuresis during surgery (<1,000 ml), pre-operative pacemaker implantation, intubation time >24 hours, pre-operative GFR <60 ml/min/1.73 m(2), post-operative troponin T >6 microg/liter and pre-operative use of angiotensin receptor blocker. CONCLUSIONS: Pre-operative renal failure is a significant risk factor for RRT during the immediate post-operative period and requires aggressive treatment. Patients with pre-operative renal failure secondary to severe heart failure and acute post-operative renal failure requiring RRT tend to recover within the first year post-HTx.

Serum cystatin C in elderly cardiac surgery patients.

BACKGROUND: Elderly cardiac surgery patients are more prone to develop postoperative acute kidney injury (AKI). The common clinical glomerular filtration marker, plasma creatinine, is considered to be inadequate to discover AKI in its early stage. The aim of this study was to determine if serum cystatin C can detect mild renal failure earlier than plasma creatinine. METHODS: From 110 cardiac surgery patients aged 70 or greater years, serum cystatin C and plasma creatinine samples were collected preoperatively and on postoperative days 1 to 5. Their urine output, creatinine, and estimated glomerular filtration rate were calculated and AKI was determined by the risk-injury-failure-loss-end-stage kidney disease criteria (RIFLE). The correlation of plasma creatinine and serum cystatin C to AKI was calculated. RESULTS: After cardiac surgery, 62 of the 110 patients (56.4%) developed AKI according to the RIFLE classification. In this group, both serum cystatin C and plasma creatinine peaked on postoperative day 3. Cystatin C and creatinine correlated equally with AKI at different time points calculated with receiver operating characteristic curves. On postoperative day 1 the area under the curve (AUC) for creatinine was 0.66 (0.55 to 0.76) and for cystatin C 0.71 (0.61 to 0.81); Delta AUC 0.05 (0.01 to 0.12), p = 0.11. On postoperative day 2 the AUC for creatinine was 0.74 (0.64 to 0.83) and for cystatin was C 0.77 (0.68 to 0.86); Delta AUC -0.03 (-0.09 to 0.03), p = 0.32. CONCLUSIONS: Elderly cardiac surgery patients have a high incidence of AKI, as defined by the RIFLE criteria. After cardiac surgery serum cystatin C and plasma creatinine detected AKI similarly.

Levosimendan reversing low output syndrome after heart transplantation.

After heart transplantation primary graft failure is a major cause of early mortality. Treatment options include inotropes and mechanical assist devices. Developing better methods would impact on patients' short- and long-term survival. We present a case of primary graft failure manifested as cardiogenic shock unresponsive to catecholamines and a phosphodiesterase inhibitor. Reversal of low output syndrome was achieved with a new type of inotropic agent, levosimendan, leading to the later complete recovery.