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PubMed1998

A diagnostic score to predict the difficulty of a laparoscopic cholecystectomy from preoperative variables.

BACKGROUND: Modified logistic regression analysis of 24 variables in 300 patients undergoing laparoscopic cholecystectomy found the following parameters independently predictive for a difficult operation: right upper quadrant pain (p < 0.01), rigidity in right upper abdomen (p < 0.01), previous upper abdominal surgery (p < 0.01), biliary colic within the last 3 weeks (p < 0.05), white blood cell count > 10 x 10(9)/l (p < 0.05), thickening of the gallbladder wall (p < 0.05), hydroptic gallbladder (p < 0.05), pericholecystic fluid (p < 0.01), shrunken gallbladder (p < 0.01), and no filling of the gallbladder in preoperative intravenous cholangiography (p < 0.05). METHODS: Based on these variables a diagnostic model was developed to predict the difficulty of a laparoscopic cholecystectomy, with scores ranging from 0 (ideal case) to IV (conversion to open cholecystectomy expected) prior to surgery. RESULTS: When the reliability of our model was examined in a second study in 340 consecutive patients undergoing laparoscopic cholecystectomy 80% of the patients were predicted correctly. CONCLUSIONS: Our model should help to select patients for either laparoscopic or open cholecystectomy based on the expected difficulties and the experience of the surgeon.

Acute Disease↗
PubMed1998

Bile duct injury after laparoscopic cholecystectomy. The United States experience.

BACKGROUND: Forty series reporting experience with laparoscopic cholecystectomy in the United States from 1989 to 1995 were reviewed. A total of 114,005 cases were analyzed and 561 major bile duct injuries (0.50%) and 401 bile leaks from the cystic duct or liver bed (0.38%) were recorded. Intraoperative cholangiography (IOC) was attempted in 41.5% of the laparoscopic cholecystectomies and was successful in 82.7%. In major bile duct injuries, the common bile duct/common hepatic duct were the most frequently injured (61.1%) and only 1.4% of the patients had complete transection. METHODS: When reported, most of the bile duct injuries were managed surgically with a biliary-enteric anastomosis (41.8%) or via laparotomy and t-tube or stent placement (27.5%). The long-term success rate could not be determined because of the small number of series reporting this information. The management for bile leaks usually consisted of a drainage procedure (55.3%) performed endoscopically percutaneously, or operatively. RESULTS: The morbidity for laparoscopic cholecystectomy, excluding bile duct injuries or leaks, was 5.4% and the overall mortality was 0.06%. It was also noted that the conversion rate to an open procedure was 2.16%. CONCLUSIONS: It is concluded based on this review of laparoscopic cholecystectomies that the morbidity and mortality rates are similar to open surgery. In addition, the rate of bile duct injuries and leaks is higher than in open cholecystectomy. Furthermore, bile duct injuries can be minimized by lateral retraction of the gallbladder neck and careful dissection of Calot's triangle, the cystic duct-gallbladder junction, and the cystic duct-common bile duct junction.

Bile Ducts↗
PubMed2001

Open versus laparoscopic cholecystectomy for gallbladder carcinoma.

Laparoscopic surgery has replaced conventional open cholecystectomy for benign gallbladder disease. A major concern is how to handle gallbladder cancer in the laparoscopic era, since there are numerous case reports of port site metastases from gallbladder cancer after laparoscopic cholecystectomy. There are also many experimental studies favoring the opinion that the laparoscopic technique implies a higher risk of spreading malignant disease. This opinion has gained wide acceptance despite little previous clinical effort to determine the risk of tumor dissemination and the lack of comparisons between open and laparoscopic surgery. This report is a short summary of our own studies and present knowledge with special respect to the clinical aspects of the development and incidence of abdominal wall metastases. Among 270 patients with verified gallbladder carcinoma in whom 210 had open surgery and 60 a laparoscopic cholecystectomy, 12 patients (6.5%) in the open cholecystectomy group and 9 (15%) in the laparoscopic group developed incisional metastases. Although the sparse clinical documentation does not unavoidably mean that laparoscopic cholecystectomy has an increased risk of disseminating tumor cells, we recommend open surgery in cases of known or suspected gallbladder carcinoma.

Abdominal Neoplasms↗
PubMedDate not supplied

Laparoscopic cholecystectomy during pregnancy is safe for both mother and fetus.

The use of laparoscopic cholecystectomy in pregnant women has been slow to gain wide acceptance for two reasons: one is the potential for mechanical problems related to the pregnant uterus and the other is fear of fetal injury resulting from instrumentation or the pneumoperitoneum. To assess the effects of laparoscopic cholecystectomy on both the mother and the unborn fetus, we reviewed our surgical experience over a 5-year period analyzing indications for the procedure along with complications and outcome. During this 5-year period, 22 patients ranging in age from 17 to 31 years underwent laparoscopic cholecystectomy during pregnancy. Gestational ages ranged from 5 to 31 weeks with two patients being in the first trimester, 16 in the second, and four in the third. The primary indications for surgical intervention were persistent nausea, vomiting, pain, and inability to eat in 17 patients, acute cholecystitis in three, and choledocholithiasis in two. In all patients a pneumoperitoneum was established by means of a closed technique starting in the right upper quadrant of the abdomen. Two of the 22 patients also underwent successful transcystic common bile duct exploration with removal of common duct stones. All 22 patients survived the surgical procedure without complications, and there were no fetal deaths or premature births related to the procedure. Based on the preceding results, it would appear that laparoscopic cholecystectomy during pregnancy is safe for both the mother and the unborn fetus. Indications for this procedure should include stringent criteria such as unrelenting biliary tract symptoms or the complications of cholelithiasis. If at all possible, when laparoscopic cholecystectomy is indicated, it should be performed either in the second trimester or early in the third.

Acute Disease↗
PubMed1978

Incidental cholecystectomy during major abdominal surgery in the elderly.

Forty-four elderly patients with an average age of seventy-eight years were found to have cholelithiasis during unrelated major abdominal surgery. Thirty-nine of them underwent incidental cholecystectomy, one had cholecystostomy, and four had no surgical treatment of their gallbladder disease. Of the thirty-nine patients with an incidental cholecystectomy, none died and only sixteen had nonfatal complications. Of these complications, only one was clearly related to the cholecystectomy and resolved spontaneously. The results compare favorably with other reports of similar procedures in elderly patients. Incidental cholecystectomy does not seem to significantly alter the mortality and morbidity of elderly patients undergoing major abdominal surgery. We advocate incidental cholecystectomy for cholelithiasis in elderly patients as long as the gallbladder is easily accessible and the condition of the patient warrants the additional procedure.

Abdomen↗
PubMed1984

Parenteral nutrition-induced gallbladder disease: a reason for early cholecystectomy.

Patients who receive long-term parenteral nutrition have an increased incidence of both calculous and acalculous cholecystitis. In an attempt to establish guidelines for the clinical management of patients with TPN-induced gallbladder disease, we have reviewed the records of 35 patients who have undergone cholecystectomy for this problem since 1976 at the UCLA Medical Center. The mean age of the 23 adult and 12 children who had cholecystectomy was 29.1 years. Forty percent of these patients required emergency cholecystectomy. The overall operative morbidity was 54 percent, and the hospital mortality was 11 percent. Significant factors contributing to this high rate of complications included a delay in diagnosis, especially in the young children, and increased operative difficulty due to extensive adhesions and intraoperative hemorrhage. Our analysis suggests that patients receiving long-term TPN should have a program of ultrasound surveillance for gallstone formation, elective cholecystectomy when stones first appear, and consideration of cholecystectomy at the time of laparotomy performed for other reasons. Whether TPN-induced gallstones can be prevented through daily stimulated gallbladder emptying awaits the results of future studies.

Adult↗
PubMed1991

Traditional versus laparoscopic cholecystectomy.

Laparoscopic cholecystectomy is a minimally invasive procedure whereby the gallbladder is removed using laparoscopic techniques. The indications are similar to those for elective traditional cholecystectomy, but selection of patients is important for success. Contraindications are currently evolving. Patients with advanced cholecystitis, abdominal sepsis, ileus, bleeding disorders, pregnancy, and morbid obesity should not undergo this procedure. The procedure requires good traditional surgical skills, as well as additional laparoscopic (and laser) skills. Operative time is slightly longer than for traditional cholecystectomy, but decreases with experience. Morbidity is low, but there is a concern about bile duct injuries. Mortality is very low (0%) and is comparable to traditional cholecystectomy (0.4%). The major advantages of laparoscopic cholecystectomy are the short hospital stay (average: 2 days) and early return to normal activity (7 days). This results in a reduction in hospital costs. Adequate training and credentialing are important processes to foster good patient outcomes.

Cholecystectomy↗
PubMed1991

Laparoscopic cholecystectomy.

With more than 500,000 cholecystectomies performed per year, great interest has developed in laparoscopic cholecystectomy. The procedure offers the patient reduced hospital stay, faster return to work, less pain, and improved cosmetic results. In September 1988, we developed a technique of performing laparoscopic cholecystectomy that we have now performed in more than 800 cases with good results. The technique allows the surgeon to fully evaluate the common duct via operative cholangiography and has allowed us to use a laparoscopic approach in all patients who were candidates for cholecystectomy. The technique offers a minimally invasive alternative to open cholecystectomy.

Cautery↗
PubMed1991

Elective laparoscopic cholecystectomy for "all-comers".

Laparoscopic cholecystectomy is a safe and effective procedure in specialist centres, but its wider application will depend on the ability of general surgeons to become skilled in this technique. 180 patients underwent elective laparoscopic cholecystectomy during a nine-month period at a single district general hospital. All patients who would have been eligible for elective open cholecystectomy were offered the laparoscopic alternative. Laparoscopic cholecystectomy was abandoned in favour of an open procedure in 10 (6%) patients. Median operating time was 55 min. 2 patients had serious morbidity (right hepatic duct injury and a duodenal fistula) and there were no deaths. 3 patients required subsequent treatment for retained common duct stones. 90% of patients were discharged within 48 h of the operation and the median time to resume full activity after discharge was 12 days. Laparoscopic cholecystectomy is a safe and cost-effective technique in a district general hospital.

Adult↗
PubMed1993

Risk of extrahepatic bileduct cancer after cholecystectomy.

The aetiology of cancer of the extrahepatic bile duct is unknown. Gallstones have been proposed to be a risk factor on the basis of ecological and epidemiological evidence. As gallstones are formed in the gallbladder, the occurrence of extrahepatic bileduct cancer in patients after cholecystectomy is of interest. All patients (62,734) who had had a cholecystectomy during 1965-1983 within the Uppsala Health Care Region, Sweden, were followed up to the end of 1987. Excluding the first year of follow-up, 23 cancers of the extrahepatic bileduct occurred vs 26.3 expected for a standardised incidence ratio (SIR) of 0.88 (95% confidence interval [CI] 0.56-1.31). 10 years or more after operation there was a greater reduction of risk (SIR = 0.27; 95% CI 0.06-0.80). Similar patterns were observed for men and women, and among patients who had undergone cholecystectomy only compared with those who had had their common bileducts explored. To assess surveillance bias the incidence of primary liver cancer was also analysed: SIR = 1.15; 95% CI 0.91-1.44 overall, and 10 years or more after cholecystectomy SIR = 0.98; 95% CI 0.66-1.40. This study shows a reduced risk of extrahepatic bileduct cancer 10 or more years after cholecystectomy, indicating that gallstones may be a cause of this cancer.

Bias↗
PubMed1994

The impact of laparoscopic cholecystectomy in Canada and Australia.

The introduction of laparoscopic cholecystectomy in Canada and Australia has been associated in each country with an increase in the rates of all cholecystectomies following a period where these had remained constant. Estimated costs of cholecystectomies to health programs declined by about 13% in Canada after the laparoscopic procedure became widely available, and about 2% in Australia. Days lost to patients because of surgery, and associated costs to them, decreased in each country. Neither country is realising the potential savings through use of laparoscopic cholecystectomy because of the increase in the number of procedures. The utility of these additional operations remains unclear. These trends associated with the advent of laparoscopic cholecystectomy suggest the need for caution in the introduction and application of other minimal-access surgery techniques.

Australia↗
PubMed2005

[Bile duct injuries at laparoscopic cholecystectomy: early repair results].

STUDY AIM: To compare the early repair results in bile duct injuries at laparoscopic cholecystectomy to a later repair and so the early reconstruction by an end-to-end anastomosis to a Roux-en-Y bypass. PATIENTS AND METHOD: From 1990 to 2003, twelve patients were treated for bile duct injury, not diagnosed at the time of cholecystectomy and had an early repair within 30 days after the cholecystectomy. They had either a duct to duct anastomosis or a Roux-en-Y bypass at the time of the reconstruction. RESULTS: The level of the injury was Bismuth II (N=7), III (N=1), IV (N=2) and V (N=1) referral to Bismuth classification and one isolated right sectoral duct injury. Four patients had an duct to duct anastomosis and eight an hepaticojejunostomy at a median of 15.3 days after cholecystectomy. With one patient lost to follow up, the overall success rate in this series was 81.8% after reconstruction with a mean 40 months follow up. The reconstruction by an end to end anastomosis was successful in 100% of patients (with a mean 31.2 months follow up) and in 71.4% of patients after a Roux-en-Y biliary reconstruction (with a mean 45 months follow up). CONCLUSION: Good results may be performed, by an early repair in bile duct injuries at laparoscopic cholecystectomy, either by an duct to duct anastomosis or a Roux-en-Y bypass.

Adult↗
PubMed2004

Pre-operative endoscopic ultrasonography can optimise the management of patients undergoing laparoscopic cholecystectomy with abnormal liver function tests as the sole risk factor for choledocholithiasis: a prospective study.

BACKGROUND: Pre-operative endosonography has been proposed as a cost-effective procedure in the management of patients who undergo laparoscopic cholecystectomy having an intermediate risk of common bile duct stones. We prospectively evaluated the impact of pre-operative endosonography on the management of patients facing laparoscopic cholecystectomy with abnormal liver function tests as the sole risk factor for choledocolithiasis. METHODS: Among 587 consecutive patients scheduled for laparoscopic cholecystectomy, 47 (8%) patients having one or more abnormal liver function tests but a normal appearance of common bile duct at abdominal ultrasound, underwent pre-operative endosonography. In patients with endosonography-detected common bile duct stones, a pre-operative endoscopic retrograde cholangiography was performed, or an intra-operative endoscopic retrograde cholangiography was scheduled. In all endosonography-negative patients, an intra-operative trans-cystic cholangiography was performed. RESULTS: Endosonography detected common bile duct stones in nine patients (19%) but only in five of them stones were radiologically confirmed (PPV 0.55). Endosonography-detected stones were confirmed in four of four (100%) patients in whom cholangiography was performed within 1 week, but only in one of five (20%) patients in whom radiology was further delayed (P < 0.05). In three of four cases (75%), stones detected at endosonography but not confirmed at X-rays, were smaller than 2.0 mm. Among 38 patients with negative endosonography, common bile duct stones were found in two patients (NPV 0.95), whereas unplanned endoscopic stone extraction was needed only in one patient (NPV 0.97). CONCLUSIONS: Pre-operative endosonography can spare unnecessary pre-operative endoscopic retrograde cholangiography as well as inappropriate scheduling of intra-operative endoscopic retrograde cholangiography in patients undergoing laparoscopic cholecystectomy with abnormal liver function tests. To maximise the impact of endosonography on the management of these patients, the procedure should be performed immediately before laparoscopic cholecystectomy.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed2007

Third-generation cholecystectomy by natural orifices: transgastric and transvesical combined approach (with video).

BACKGROUND: An isolated transgastric port has some limitations in performing transluminal endoscopic cholecystectomy. However, transvesical access to the peritoneal cavity has recently been reported to be feasible and safe. OBJECTIVE: To assess the feasibility and the technical benefits of transgastric and transvesical combined approach to overcome the limitations of isolated transgastric ports. DESIGN: We created a transgastric and transvesical combined approach to perform cholecystectomy in 7 consecutive anesthetized female pigs. The transgastric access was achieved after perforation and dilation of the gastric wall with a needle knife and with a balloon, respectively. Under cystoscopic control, an ureteral catheter, a guidewire, and a dilator of the ureteral sheath were used to place a transvesical 5-mm overtube into the peritoneal cavity. By using a gastroscope positioned transgastrically and a ureteroscope positioned transvesically, we carried out cholecystectomy in all animals. RESULTS: Establishment of transvesical and transgastric accesses took place without complications. Under a carbon dioxide pneumoperitoneum controlled by the transvesical port, gallbladder identification, cystic duct, and artery exposure were easily achieved in all cases. Transvesical gallbladder grasping and manipulation proved to be particularly valuable to enhance gastroscope-guided dissection. With the exclusion of 2 cases where mild liver-surface hemorrhage and bile leak secondary to the sliding of cystic clips occurred, all remaining cholecystectomies were carried out without incidents. LIMITATIONS: Once closure of the gastric hole proved to be unreliable when using endoclips, the animals were euthanized; necropsy was performed immediately after the surgical procedure. CONCLUSIONS: A transgastric and transvesical combined approach is feasible, and it was particularly useful to perform a cholecystectomy through exclusive natural orifices.

Animals↗
PubMed2006

Risk factors for perioperative complications in patients undergoing laparoscopic cholecystectomy: analysis of 22,953 consecutive cases from the Swiss Association of Laparoscopic and Thoracoscopic Surgery database.

BACKGROUND: Reliable risk factors for perioperative complications in patients undergoing laparoscopic cholecystectomy would be extremely useful to optimize the clinical management. This study aimed to determine risk factors that can be used for predicting perioperative complications. STUDY DESIGN: Possible risk factors for perioperative complications in patients undergoing laparoscopic cholecystectomy for acute and chronic cholecystitis were analyzed by a stepwise logistic regression model using data from the Swiss Association of Laparoscopic and Thoracoscopic Surgery (SALTS) database. RESULTS: A total of 22,953 patients with a mean (+/-SD) age of 54.5+/-16.1 years (range 17 to 89 years) and a male-to-female ratio of 1:2, underwent elective (85%) and emergency (15%) laparoscopic cholecystectomy. Multivariable analysis showed that male gender (odds ratio [OR]=1.16; p<0.0001), duration of intervention (OR=1.68 per 30 minutes; p<0.0001), body weight (>90 kg versus<60 kg; OR=1.34; p<0.0001), and the surgeon's own experience (>100 versus 11 to 100 interventions; OR=1.36; p<0.0002) were independently associated with an increased intraoperative local complication rate. In addition, male gender (OR=1.21; p<0.02), age (OR=1.12 per 10 years; p<0.0001), intraoperative complications (OR=2.1; p<0.0001), conversion to open surgery (OR=1.25; p<0.01), American Society of Anesthesiologists risk score (ASA score III/IV versus I/II: OR=1.28; p<0.0005), body weight (<60 kg versus>90 kg; OR=1.53; p<0.007), emergency surgery (OR=1.36; p<0.003), and duration of surgery (OR=1.28 per 30 minutes; p<0.0001) were found to be associated with a higher incidence of postoperative local complications. Higher postoperative systemic complications were encountered with conversion (OR=1.5; p<0.0002), ASA score (III/IV versus I/II: OR=1.54; p<0.0001), emergency surgery (OR=1.41; p<0.001), and a prolonged intervention time (OR=1.16 per 30 minutes; p<0.0001). CONCLUSIONS: For patients undergoing laparoscopic cholecystectomy (LC), the risk of possible perioperative complications can be estimated based on patient characteristics (gender, age, ASA score, body weight), clinical findings (acute versus chronic cholecystitis), and the surgeon's own clinical practice with LC. So in the likelihood of a case being a "difficult cholecystectomy," an experienced surgeon should be involved both in the decision-making process and during the operation. If LC lasts longer than 2 hours, the cumulative risk for perioperative complications is four times higher compared with an intervention that lasts between 30 and 60 minutes, independent of the surgeon's personal skills with LC.

Adolescent↗
PubMed2005

Biliary dyskinesia: the most common indication for cholecystectomy in children.

BACKGROUND: The purpose of this study is to examine the current indications for cholecystectomy in children and to evaluate the results after such surgery. METHODS: Retrospective analysis of 107 consecutive cholecystectomies performed in children at the Children's Hospital of Illinois between October 1998 and September 2003. Hospital medical charts and outpatient clinic charts were reviewed. Patients' families were contacted by telephone to obtain longer-term follow-up. Results were analyzed with SPSS 12.0 for Windows (SPSS Inc, Chicago, Ill). RESULTS: Biliary dyskinesia (BD) was the indication for surgery for 62 (58%) of the 107 children who underwent cholecystectomy during the study period. Gallbladder calculus (GC) disease was the next most common indication with 29 (27%) children. The duration of symptoms was longer for BD. The most common presenting symptom in both groups was abdominal pain. Food intolerance was reported by 45% of patients with BD, significantly higher than patients with GC. Mean length of stay after cholecystectomy was 17 hours and 45 hours for BD and GC, respectively. Short-term follow-up showed relief or improvement of symptoms in 85% of children with BD and in 97% with GC. There were no deaths. Two (1.9%) children of the total of 107 developed complications; both had intra-abdominal abscesses. Most patients had complete or considerable long-term improvement in symptoms. CONCLUSIONS: Biliary dyskinesia was the most common indication for cholecystectomy in children in our study. More than half of the surgeries were performed on an outpatient basis. Morbidity was minimal and mortality was zero. We had satisfactory short- and long-term symptom resolution with long-term patient satisfaction reaching 95%.

Abdominal Abscess↗
PubMed2001

A risk score for conversion from laparoscopic to open cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy has become the standard operative procedure for cholelithiasis, but there are still some patients requiring conversion to open cholecystectomy mainly because of technical difficulty. Our aim was to develop a risk score for prediction of conversion from laparoscopic to open cholecystectomy. METHODS: Preoperative clinical, laboratory, and radiologic parameters of 1,000 patients who underwent laparoscopic cholecystectomy were analyzed for their effect on conversion rates. Six parameters (male sex, abdominal tenderness, previous upper abdominal operation, sonographically thickened gallbladder wall, age over 60 years, preoperative diagnosis of acute cholecystitis) were found to have significant effect in multivariate analysis. A constant and coefficients for these variables were calculated and formed the risk score. RESULTS: Overall 48 patients required conversion to open cholecystectomy (4.8%). These patients had significantly higher scores (mean 6.9 versus -7.2, P <0.001). Increasing scores resulted with significant increases in conversion rates and probabilities (P <0.001). Ideal cut-off point for this score was -3; conversion rate was 1.6% under -3, but 11.4% over this value (P <0.001). CONCLUSIONS: Conversion risk can be predicted easily by this score. Patients having high risk may be informed and scheduled appropriately. An experienced surgeon has to operate on these patients, and he or she has to make an early decision to convert in case of difficulty.

Adolescent↗
PubMed1994

Altered antroduodenal motility after cholecystectomy.

BACKGROUND: Persistent nonspecific symptoms such as epigastric pain, bloating, nausea, and bilious vomiting are common following cholecystectomy. The etiology of these symptoms is unknown, but abnormal antroduodenal motility associated with duodenogastric reflux (DGR) is a possible cause. PATIENTS AND METHODS: Sixteen postcholecystectomy patients and 19 healthy volunteers ("normals") were studied. Ten of the patients were asymptomatic and 6 were symptomatic. The study consisted of a 4-hour 99mTc-DISIDA (diisopropyl imidodiacetic acid) infusion and gastric aspiration, 24-hour intragastric pH monitoring, and 24-hour ambulatory antroduodenal manometry. RESULTS: The postcholecystectomy patients showed increased DGR of the infused 99mTc-DISIDA. The data are given as coulter counts x 10(6)/min. The increase was more marked in symptomatic postcholecystectomy patients (2.54 +/- 0.15) compared to asymptomatic patients (1.21 +/- 0.46) or normals (0.26 +/- 0.15). Postcholecystectomy patients had increased percentage of time with intragastric pH > 3. In the supine period in particular, the pH was > 3 in symptomatic patients 25.4% +/- 7.7% of the time versus 8.1% +/- 4.3% for asymptomatic patients (P < 0.01). The antral phase III frequency after cholecystectomy was 2.5 +/- 0.09 cycles/min compared to 3.2 +/- 0.08 cycles/min in normals (P < 0.0001). Furthermore, propagation of the phase III front in the duodenum was significantly slowed to 0.14 +/- 0.02 cm/s after cholecystectomy compared to 0.27 +/- 0.02 cm/s in normals (P < 0.001). The duration of phase III in the proximal duodenum after cholecystectomy was also decreased to 4.3 +/- 0.27 min compared to 5.9 +/- 0.35 min in normals (P < 0.005). CONCLUSIONS: Fasting antroduodenal motility is altered after cholecystectomy. The abnormality is associated with increased DGR, which is more marked in symptomatic patients.

Adult↗