*2.2.2 Other related El Tor hemolysin of Vibrio species*

Several studies have reported that other *Vibrio* species such as *V. mimicus*, *V. vulnificus*, and *V. fluvialis* also produce hemolysin that shares some common structural features with HlyA [100–102].

*V. mimicus,* a species closely related to *V. cholerae*, is a causative agent of human gastroenteritis [103]. Pathogenic strains of *V. mimicus* exhibit various clinical symptoms from watery to dysentery-like diarrhea [104]. This pathogen produces many kinds of virulence factors such as CT-like enterotoxin and heat-stable enterotoxin [105–108], with Vm-TDH as a causative factor in some clinical strains. However, most clinical strains lack the ability to produce any of these toxins. The heat-labile hemolysin/cytolysin (*V. mimicus* hemolysin; VMH) is thought to be the most common virulent enteropathogenic factor [109, 110]. In fact, VMH induces FA in a ligated rabbit ileal loop in dose-dependent manner, and the antibody against VMH apparently reduces enterotoxicity by *V. mimicus* in the living cells [100, 111]. These findings indicate that VMH is potently related to pathogenesis of this pathogen. The enterotoxic activity of VMH might be due to intestinal Cl− secretion caused by the activation of both Ca2+-dependent and cyclic AMP-dependent Cl− secretion systems [111, 112]. Similar to HlyA, it has been indicated that VMH is also a pore-forming toxin. This toxin can disrupt various mammalian erythrocytes including bovine, rabbit, sheep, human, and mouse in colloid osmotic manner, and it shows the highest sensitivity for the horse erythrocytes [100].

VMH encoded by *vmhA* gene is predicted to be of 83 kDa with 82% similarity with *V. cholerae* HlyA. VMH is also secreted as 80 kDa precursor known as pro-VMH [113], which is then converted to 66 kDa mature toxin through the removal of N-terminal propeptide by trypsin-like protease of *V. mimicus* between the amino acid residues Arg151 and Ser152 [114, 115]. It has been assumed that VMH might be processed in a two-step reaction just like HlyA and pro-toxin can be activated by various proteases such as trypsin, chymotrypsin, and metalloprotease [115, 116]. Similar to 50 kDa variant of HlyA, mature VMH can be converted to 51 kDa of VMH (designated VMH51) through the removal of 15 kDa from C-terminal end by metalloprotease of *V. mimicus*. VMH51 almost showed no lytic activity toward horse erythrocytes because it lost the binding affinity toward erythrocyte membrane [116]. However, the VMH51 can associate with sheep erythrocyte membranes though the affinity is reduced as compared with intact VMH, suggesting that the truncated toxin interacts with other components in sheep erythrocyte membrane. It might be concluded that the 15 kDa C-terminal domain of VMH is functionally similar to β-prism lectin domain of HlyA.

*V. fluvialis* is one of the foodborne pathogens which can cause clinical symptoms similar to *V. cholerae* [117–119]. *V. fluvialis* secrets El Tor-like hemolysin, designed as *V. fluvialis* hemolysin (VFH), which can elicit lysis of erythrocytes from various animal. In addition to hemolytic activity, VFH can also trigger cytotoxicity toward Chinese hamster ovary (CHO) cells and induction of fluid accumulation in suckling mouse [102]. The purified VFH has molecular weight of 63 kDa, whose N-terminal amino acid sequence shares homology to HlyA from *V. cholerae* and VMH from *V. mimicus* [102]. It is suspected that VFH might play an important role in *V. fluvialis* pathogenicity.

*V. vulnificus* was first isolated from a leg ulcer, and it was wrongly reported as *V. parahaemolyticus* [120]. Later, it was found that some characters were different from *V. parahaemolyticus* such as positive lactose fermentation, so subsequently it was termed as *V. vulnificus* [20]. *V. vulnificus* can cause two types of illness, the primary septicemia and the wound infection [24]. The former is remarkable for its high fatality rate (over 50%). The primary septicemia is caused by the consumption of raw seafood, especially shellfish such as oyster contaminated by *V. vulnificus*, and it is reported that 95% of all seafood-related deaths are caused by *V. vulnificus* in the United States [121, 122]. Because most septicemia patients have an underlying disease such as hepatic cirrhosis, hepatitis, or diabetes, the septicemia by *V. vulnificus* is considered as an opportunistic infection [24]. Wound infections characterized clinical symptoms are edema, erythema, or necrosis and occurred after exposure to contaminated seawater or marine products. However, gastrointestinal symptom like diarrhea is very rare due to *V. vulnificus* infection [25, 26]. *V. vulnificus* produces various extracellular virulence factors such as hemolysin or protease [123, 124]. Hemolysin secreted by *V. vulnificus* called as *V. vulnificus* hemolysin (VVH) is also a toxin that can form pore on the target membranes of various mammalian cells. Purified VVH exhibits lytic activity against erythrocytes of various mammals and cultured cells such as CHO, mast, and pulmonary endothelial cells [101, 125–127]. In addition, it is reported that the sublytic doses of hemolysin can trigger apoptotic signaling pathway in human vascular endothelial cell line, ECV304 cells [128], and oligomerization of VVH is essential for the apoptotic activity in CHO cells [129].

VVH (VvhA) precursor has molecular weight of 51 kDa encoded by the structure gene *vvhA*, which constitutes an operon with *vvhB* gene. The *vvhB* gene is present upstream of *vvhA* and encodes 18 kDa protein VvhB. The VvhA precursor is composed of a signal peptide (20 amino acid residues) and cytolysin domain (Gln1 to Arg318) including a putative pre-stem and β-trefoil lectin-like domain (His319 to Leu451) (**Figure 1**); the pro-region and β-prism lectin domain are absent as compared with HlyA precursor [78, 130]. Although the function of VvhB is unknown, it might act as a chaperon in the absence of the pro-region like HlyA. This speculation is supported by the fact that even though VvhA is expressed in the absence of *vvhB* in vitro, the hemolytic activity cannot be detected [131]. Although VVH lacks β-prism lectin domain, the β-trefoil lectin domain has displayed binding capability for glycerol, N-acetyl-D-galactosamine, and N-acetyl-D-lactosamine unlike HlyA [92, 130]. In fact, VVH exhibits decreased ability to bind CHO cells when preincubated with methyl-beta-cyclodextrin, an oligosaccharide, and, thus, inhibition of its cytotoxic effect [132]. Similar to HlyA, it is believed that the VVH monomer binds to the cell membrane and forms oligomers [101, 133, 134] and the crystal structure of β-trefoil lectin domain of VVH reveals a heptameric ring arrangement [130]. It is strongly suggested that cholesterol is the receptor for VVH and facilitates conversion of monomer to oligomer [133, 135]. In addition, it is reported that Thr438 in the β-trefoil lectin domain is responsible for binding to cholesterol [131]. On the other hand, Phe334 in cytolysin domain that is located near the joint of two domains is essential for oligomerization of toxin monomer [136]. Moreover, it is shown that the mutation of Leu451 causes inhibition of hemolytic activity without reducing the membrane binding ability; this suggests that the Leu451 is essential for the oligomer formation [137]. Recently, a study showed that properties such as polarity and indole ring of amino acid Trp246 are essential for the binding of toxin to the target membrane [138]. It is assumed that hemolytic process of VVH is almost similar to HlyA though there are some differences in the function and structure of VVH.

It has been reported that a heat-labile hemolysin purified from *V. tubiashii*, a pathogen of juvenile bivalve, is similar to VVH [139]. Like VVH, this toxin has showed competitive inhibition by cholesterol and can lyse erythrocytes. In addition, the toxin exhibits cytotoxicity to CHO, Caco-2, and Atlantic menhaden liver cells in tissue culture.

*V. damsela* has been reported to cause wound infection by handling of fish, exposure to seawater and marine animals, and ingestion of raw seafood [21, 140–143]. It has been considered that there is not any other hemolysin in this bacterium, except of a hemolysin with phospholipase D activity known as damselysin [144].

**95**

*Hemolysin of* Vibrio *Species*

like domain (**Figure 1**) [145].

**3. Conclusion**

with these pathogens.

**Acknowledgements**

Development (AMED).

*DOI: http://dx.doi.org/10.5772/intechopen.88920*

Recently, it is reported that this bacterium possesses HlyA-like hemolysin encoded within a new virulence plasmid pPHDD1. The characteristics of this new HlyA-like hemolysin from *V. damsela* are not yet identified, but the predicted amino acid sequences show 69% similarity with HlyA of *V. cholerae*, missing the β-prism lectin-

This chapter is focused on the hemolysins produced by *Vibrio* species, especially the human pathogens. Hemolysins are classified into two groups, namely, thermostable direct hemolysin (TDH) and El Tor hemolysin (HlyA). This chapter pays attention to Vp-TDH (*V. parahaemolyticus*), HlyA (*V. cholerae*), VMH (*V. mimicus*), and VVH (*V. vulnificus*) because these are well studied in terms of the toxin structure and their relation with the pathogenesis. The mechanism of action by HlyA and the essential amino acid residues have been clarified through the crystal structure of HlyA pro-toxin and the transmembrane heptameric oligomer over the past decade. Although the crystal structure has revealed the structural information about Vp-TDH and VVH, the exact mechanism of pore formation in the target membrane is yet to be studied. Several studies have indicated the involvement of novel virulence factors in pathogenesis like T3SS, but still Vp-TDH and Vp-TRH are considered to be the major virulence factors of *V. parahaemolyticus*, one of the important food poisoning bacteria in Japan and other eastern and Southeast Asian countries. HlyA is thought to be a major factor in CT-negative strains (e.g., *V. cholerae* non-O1/ non-O139) that can cause diarrhea because it can induce enterotoxicity as well as apoptosis. *V. mimicus* hemolysin, VMH, is just one of the many enterotoxic factors. Even though there is detailed information about structural composition and mode of action of some of the hemolysin such as Vp-TDH and HlyA, still there is a lack of information about other hemolysins. Therefore, it is necessary to further enhance our knowledge regarding these toxins in order to thoroughly understand the mechanism of pathogenesis for the prevention of endemic infectious diseases associated

This investigation was supported by a grant from the Program of the Japan

Technology in Japan (MEXT), and from the Japan Agency for Medical Research and

Initiative for Global Research Network on Infectious Diseases (J-GRID), JP19fm0108002, from Ministry of Education, Culture, Sport, Science and

### *Hemolysin of* Vibrio *Species DOI: http://dx.doi.org/10.5772/intechopen.88920*

Recently, it is reported that this bacterium possesses HlyA-like hemolysin encoded within a new virulence plasmid pPHDD1. The characteristics of this new HlyA-like hemolysin from *V. damsela* are not yet identified, but the predicted amino acid sequences show 69% similarity with HlyA of *V. cholerae*, missing the β-prism lectinlike domain (**Figure 1**) [145].


**2.1 Freezing in mechanical freezers**

Passive cooling uses insulation to moderate the cooling rate of samples that have been equilibrated with low concentrations of cryoprotectant and then placed inside traditional electromechanical refrigerators at -20 °C, -40 °C, -80 °C or even at lower temperatures. The cells are dessicated slowly during the cooling process. This method can be used for most robust cells but even under the best circumstances the post-thaw recovery rates may not be ideal. In addition, in most cases no instrumentation monitoring or recording of the process is provided. The variation of temperature within mechanical refrigerators is well known with one study reporting values of -43.5 °C to -90 °C in upright freezers (Su et. al., 1996). Since there is no active control during the process, it follows that the poor repeatability of the process can affect the cooling rate and hence the efficiency of the whole procedure. Variability might be improved if the local environment were more stable and protected from instantaneous variation due to external factors such as door openings etc. It is generally preferable to use a liquid nitrogen gas phase freezer for this approach since the internal temperature variation is small and the environment disturbed less frequently.

This approach to cooling and freezing is increasingly being used for material provision in pharmaceutical drug screening programmes as they move from supply by continuous culture towards a "cells-as-reagents" concept. In this approach, the cells are insulated in polystyrene containers as they are cooled initially to -80 °C and then transferred for cryogenic storage into liquid or vapour phase nitrogen. The need for rapid use of the cells for drug assays following cryopreservation, places an increased importance on the postthaw quality of the cells. In recent work carried out at LGC (Teddington,UK) this has been shown to be compromised by this type of freezing where the cooling rates are not actively controlled but rely on the passive characteristics of the system. In particular, temperature fluctuations within the polystyrene container and the storage time at -80 °C can significantly impact the post-thaw recovery of the cells and their biological function.

Precision in Cryopreservation – Equipment and Control 515

samples with very small volumes, ideally those with very high surface area-to-volume ratios; for example cryogenic straws can fit this description. It is important to be aware of the Leidenfrost effect where a sheath of vapour will surround a warm sample when plunged into liquid cryogen, essentially insulating the sample for a short period of time. For many vitrification protocols however, even this short additional time period before the sample is vitrified has proven fatal to the cells due to increased toxic exposure to the CPA and decreased cooling rates. In conventional vitrification, very high cooling rates are achieved by exposing small samples directly to the liquid nitrogen. The sample is surrounded with as little physical material as possible to achieve the maximum cooling

Although vitrification is normally associated with cooling rates in the tens of thousands of degrees Celsius per minute, slower techniques have been reported such as the S3 vitrification technique for blastocysts (Stachecki & Chen, 2008); this uses rates <200 °C/minute. But in fact vitrification does not necessarily require rapid cooling at all. It all depends on the dependence of the critical cooling rate required to prevent freezing on the concentration of the cryoprotectant. (Sutton, 1991). As the following section describes.

It is usual to thaw cryopreserved or vitrified samples rapidly – typically by plunging them in a 37 °C water bath. The warming rate does have an effect on the recovery of living cells but this is not as great an influence as cooling rate is during cooling. In fact, optimum cooling rates have usually been determined using rapid warming so it is hardly surprising that rapid warming then gives the highest recovery! However, there are circumstances when the warming rate is of importance in its own right. The first is when the sample has been vitrified but is nucleated without a significant amount of ice being present. This is an unstable situation and in such circumstances the warming must be rapid to avoid intracellular freezing during warming. This consideration argues for rapid warming. The other situation occurs when the frozen material contains a significant amount of vitrified material, as is always the case in conventional cryopreservation. Glasses are brittle and the hazard here is that rapid warming will generate thermal stresses and cause the vitreous material to fracture. This will not matter greatly with cell suspensions where a fracture running through the sample is unlikely to traverse many cells but it is very important when the extracellular matrix must be intact – as it must, for example, in grafted blood vessels and heart valves. The solution here is to warm through the vitreous zone, that is from -196 °C to -123 °C, relatively slowly: once above the Tg there is no hazard from fractures and the sample can be warmed as rapidly as you like. A convenient way to do this is to allow the sample to warm slowly in a -80 °C refrigerator or packed in solid CO2 until its temperature is at above -100 °C. Alternatively the sample can be surrounded by a layer of insulation during the initial stage of warming in room air. A warming rate of around 50 °C/minute up to -100 °C was 'slow' enough to prevent fractures in

The controlled-rate freezing process achieves its results by preventing the formation of intracellular ice. In some samples, however, even extracellular ice can be severely damaging.

rates. With large samples, however, such high cooling rates are impracticable.

vitrification can be produced at really low cooling rates.

cryopreserved rabbit carotid arteries (Pegg et al., 1997).

**2.5 Liquidus tracking – A new method**

**2.4 Warming and thawing**


**Author details**

Unai Hernandez-Jayo\* , Aboobeker Sidhik Koyamparambil Mammu and Idoia De-la-Iglesia

\*Address all correspondence to<EMAIL_ADDRESS>
Deusto Institute of Technology, DeustoTech Mobility, Bilbao Bizkaia, Spain


**6. VBAC and the number of repeat cesarean section**

Clinical decision-making for women following multiple prior cesarean deliveries is influenced by limited evidence and the expectations of the mother. Vaginal birth after multiple cesarean deliveries can be an option if women are eligible. In order to provide the currently best available evidence, we extracted and regrouped information from four trials (**Table 3**).

A meta-analysis of 20 studies compared the success rate—and the associated adverse maternal and fetal outcomes of vaginal birth—after one and two cesarean sections (VBAC-1/VBAC-2) with a further repeat multiple cesarean section [30]. Women requesting a trial of labor following two cesarean sections should be informed of a success rate for vaginal delivery of 71.7%, a uterine rupture rate of 1.36%, and of a similar maternal morbidity in both groups. Maternal morbidity of VBAC-2 is comparable to that of multiple cesarean sections. The neonatal morbidity data were too limited to draw valid conclusions [30].

Another trial pointed out that women with three or more prior cesareans who attempt VBAC have similar success rates and maternal morbidity as those with only one prior cesarean, as well as those delivered by elective repeat cesarean [31].

There are also two systematic Cochrane reviews showing no statistically significant differences between a planned repeat cesarean birth and a planned vaginal birth after a cesarean section [32, 33].

#### **Table 3.**

*Maternal outcome of vaginal birth following multiple cesarean section for VBAC versus a setting of increasing higher multiple repeat cesarean sections.*

In conclusion, there was no difference in the maternal morbidity of women with multiple prior cesareans for the mode of delivery in these studies. A history of multiple cesarean deliveries is not associated with an increased rate of uterine rupture in women attempting vaginal birth compared with those with a single prior operation (**Table 3**). However, when looking at uterine rupture alone, the risks increase with each cesarean section (>2 CS: 3.71% and >3 CS: 4.34%).

In conclusion, vaginal birth after multiple cesarean deliveries remains an option for eligible women.

#### **7. Timing of elective repeat cesarean section**

In clinical practice obstetricians have to decide when best to perform an elective repeat cesarean delivery. For the decision-making, it is interesting to have knowledge on the gestation with the best neonatal and maternal outcomes. We found five studies in total to be analyzed.

Three retrospective studies with a total of 48,757 women were identified comparing the neonatal risks at repeat cesarean delivery before and after 39 weeks of gestation [34–36]. In general elective repeat cesarean sections between 37 and 39 weeks are associated with a higher neonatal morbidity. Especially the rates of adverse respiratory outcomes and mechanical ventilation were increased. Neonates born before 39 weeks of gestation have significant more respiratory distress syndromes. Additionally the risks of newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization are also higher in the group with a repeat cesarean section before 39 weeks [36].

**45**

*Maternal and Fetal Risks in Higher Multiple Cesarean Deliveries*

essary increased risk of respiratory distress syndromes.

yielding both the best neonatal and maternal outcome.

Another study demonstrated increased costs through increasing adverse neonatal outcomes because of elective repeat cesarean deliveries at 37 or 38 weeks [37]. On the opposite side, the elective cesarean delivery at 39 weeks seems to be associated with better neonatal outcome in comparison to a later timing of delivery [34]. Altogether our findings suggest that from the neonatal point of view, there are benefits to waiting until 39 weeks of gestation to perform an elective repeat cesar-

To achieve the prolongation of the pregnancy until 39 weeks for the neonatal benefit, it is important to know if an elective repeat cesarean section at this time is also of benefit for the maternal outcome. The results of three studies with a total of 37.938 women show that an elective repeat cesarean delivery at 37 or 38 weeks is not associated with decreased maternal morbidity [34, 35, 38]. In comparison to the group of elective delivery at 39 weeks, there was no significant difference in uterine scar rupture, estimated blood loss, hysterectomy, or other maternal complications. Additionally one study pointed out that elective cesarean delivery at 37 weeks had

significantly higher risks of a prolonged (>5 days) maternal hospitalization [38]. Although a cesarean section before 39 weeks has a similar rate of risks for women with multiple repeated cesarean sections as the delivery after 39 weeks, the elective repeat cesarean section at 37 or 38 weeks exposes the neonate to an unnec-

In conclusion, if there are no other medical indications for an earlier delivery, 39 weeks of gestation is apparently the optimal timing for repeat cesarean delivery

• The risks of rare but potentially serious maternal morbidities such as visceral injury, hemorrhage, abnormal placentation, hysterectomy, or severe adhesions importantly increased with the number of multiple repeat cesarean sections.

• Adverse neonatal outcome depends more on the mode and the timing of

• There is no clear absolute threshold for a safe number of previous cesarean sections, but a total of four or more cesarean deliveries was identified as the critical level for most of the major complications to be substantially increased.

• Repeat cesarean delivery is done best at 39 weeks yielding the best outcome for

• Vaginal birth after multiple cesarean deliveries remains an option for eligible

delivery than on the numbers of repeat cesarean sections.

*DOI: http://dx.doi.org/10.5772/intechopen.86334*

ean delivery.

**8. Summary**

both the mother and baby.

women.

Another study demonstrated increased costs through increasing adverse neonatal outcomes because of elective repeat cesarean deliveries at 37 or 38 weeks [37].

On the opposite side, the elective cesarean delivery at 39 weeks seems to be associated with better neonatal outcome in comparison to a later timing of delivery [34].

Altogether our findings suggest that from the neonatal point of view, there are benefits to waiting until 39 weeks of gestation to perform an elective repeat cesarean delivery.

To achieve the prolongation of the pregnancy until 39 weeks for the neonatal benefit, it is important to know if an elective repeat cesarean section at this time is also of benefit for the maternal outcome. The results of three studies with a total of 37.938 women show that an elective repeat cesarean delivery at 37 or 38 weeks is not associated with decreased maternal morbidity [34, 35, 38]. In comparison to the group of elective delivery at 39 weeks, there was no significant difference in uterine scar rupture, estimated blood loss, hysterectomy, or other maternal complications.

Additionally one study pointed out that elective cesarean delivery at 37 weeks had significantly higher risks of a prolonged (>5 days) maternal hospitalization [38].

Although a cesarean section before 39 weeks has a similar rate of risks for women with multiple repeated cesarean sections as the delivery after 39 weeks, the elective repeat cesarean section at 37 or 38 weeks exposes the neonate to an unnecessary increased risk of respiratory distress syndromes.

In conclusion, if there are no other medical indications for an earlier delivery, 39 weeks of gestation is apparently the optimal timing for repeat cesarean delivery yielding both the best neonatal and maternal outcome.

## **8. Summary**

*Recent Advances in Cesarean Delivery*

VBAC 1 76.50%

VBAC 2 71.70%

VBAC > 2 79.77%

*higher multiple repeat cesarean sections.*

Second CS

n = 38,814/50,685 [30]

n = 4064/5666 [30]

Third CS – 3.71%

n = 71/89 [31]

≥4 CS – 4.34%

*VBAC1/VBAC2 = vaginal birth after one/two cesarean sections; CS = cesarean section*

In conclusion, there was no difference in the maternal morbidity of women with

*Maternal outcome of vaginal birth following multiple cesarean section for VBAC versus a setting of increasing*

**Delivery VBAC successes Uterine rupture Hysterectomy Transfusion**

0.72% n = 372/50,685 [30]

> n = 52/8542 [3, 8, 12]

> 1.36% n = 74/5421 [30]

n = 29/782 [3, 8]

0.00% n = 0/89 [31]

n = 41/945 [3, 4, 8, 13]

– 0.61%

0.19% n = 42/50,685 [30]

0.43% n = 75/17,378 [3, 8, 10, 11]

0.56% n = 14/2512 [30]

0.91% n = 65/7106 [3, 8, 10, 11]

2.49% n = 66/2652 [3, 8, 10, 11, 13]

1.21% n = 358/50,685 [30]

1.58% n = 273/17,280 [3, 5, 10, 11]

2.01% n = 39/5666 [30]

2.23% n = 157/7050 [3, 5, 10, 11]

> n = 2/89 [31]

5.35% n = 142/2652 [3, 5, 10, 11, 13, 14]

n.k. 2.20%

multiple prior cesareans for the mode of delivery in these studies. A history of multiple cesarean deliveries is not associated with an increased rate of uterine rupture in women attempting vaginal birth compared with those with a

single prior operation (**Table 3**). However, when looking at uterine rupture alone, the risks increase with each cesarean section (>2 CS: 3.71% and >3 CS: 4.34%).

In conclusion, vaginal birth after multiple cesarean deliveries remains an option

In clinical practice obstetricians have to decide when best to perform an elective repeat cesarean delivery. For the decision-making, it is interesting to have knowledge on the gestation with the best neonatal and maternal outcomes. We found five

Three retrospective studies with a total of 48,757 women were identified comparing the neonatal risks at repeat cesarean delivery before and after 39 weeks of gestation [34–36]. In general elective repeat cesarean sections between 37 and 39 weeks are associated with a higher neonatal morbidity. Especially the rates of adverse respiratory outcomes and mechanical ventilation were increased. Neonates born before 39 weeks of gestation have significant more respiratory distress syndromes. Additionally the risks of newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization are also higher in the group with a repeat cesarean

**44**

for eligible women.

**Table 3.**

studies in total to be analyzed.

section before 39 weeks [36].

**7. Timing of elective repeat cesarean section**

*Recent Advances in Cesarean Delivery*


*Article* **Effect of the COVID-19 Outbreak on Pediatric Patients' Admissions to the Emergency Department in an Italian Orthopedic Trauma Hub**

**Fabio Verdoni 1 , Martina Ricci 2 , Cristina Di Grigoli 2 , Nicolò Rossi 2 , Michele Davide Maria Lombardo 2 , Domenico Curci 1 , Riccardo Accetta 1 , Marco Viganò 1 , Giuseppe Maria Peretti 1,3 and Laura Mangiavini 1,3,\***

**Abstract:** Background: The rapid diffusion of Coronavirus disease (COVID-19) in Northern Italy led the Italian government to dictate a national lockdown from 12 March 2020 to 5 May 2020. The aim of this observational cohort study is to analyze the differences in the number of pediatric patients' admission to the Emergency Room (ER) and in the type and causes of injury. Methods: The pediatric population during the pandemic was compared to a similar group of patients admitted to the ER in 2019. Sex, age, triage color-code at admission, cause of trauma and presence of symptoms related to COVID-19 infection, discharge diagnosis and discharge modes were investigated. Results: The lockdown period led to a reduction of 87.0% in ER admissions with a particular decrease in patients older than 12 years old. Moreover, a trend towards more severe codes and an increase in home-related injuries were observed during the pandemic, whereas the diagnosis of fracture was less frequent in the pre-pandemic group (*p* < 0.0001). Conclusions: A significant decrease in the ER attendances was reported during the lockdown. A shift in the cause and type of injury was observed; only the most serious traumas sought medical care with a higher percentage of severe triage codes and fractures.

**Keywords:** COVID-19; pediatric trauma HUB; outbreak; ER admissions; pediatric fractures; pediatric injuries

### **1. Introduction**

Coronavirus disease (COVID-19) is a worldwide public health challenge, declared a pandemic by the World Health Organization on 12 March 2020 [1]. Northern Italy was the most affected area within the whole country and has been struggling with COVID-19 since the end of February 2020 [2]. The government dictated measures of national lockdown; in Italy, from 12 March 2020 to 5 May 2020, people could leave their homes only for proved necessity, no recreational activities or sport were allowed and schools were closed. Hospitals were overwhelmed with COVID-19 patients and most of the wards were converted into ICU or infectious diseases care units, while deferrable surgeries and outpatient visits were suspended. Two regional referral centers specialized in traumas and orthopedics emergencies were identified in Milan, Italy, as the hubs for minor traumas or non-deferrable elective orthopedic surgeries [3].

Indeed, during the COVID-19 crisis, the necessity to reduce the risk of virus exposure and transmission and the need to maintain the quality of care provided to critical patients forced the healthcare system to discourage unnecessary admissions to the Emergency Room (ER) related to minor traumas and other ailments. Therefore, a reduction in patient flow to

**Citation:** Verdoni, F.; Ricci, M.; Di Grigoli, C.; Rossi, N.; Lombardo, M.D.M.; Curci, D.; Accetta, R.; Viganò, M.; Peretti, G.M.; Mangiavini, L. Effect of the COVID-19 Outbreak on Pediatric Patients' Admissions to the Emergency Department in an Italian Orthopedic Trauma Hub. *Children* **2021**, *8*, 645. https://doi.org/ 10.3390/children8080645

Academic Editor: Johannes Mayr

Received: 9 July 2021 Accepted: 26 July 2021 Published: 27 July 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the ER during the pandemic period was noticed, especially in the pediatric population. We performed an observational cohort study on the ER admission of pediatric population (<16) before and after lockdown. The aim of this study was to analyze the number of pediatric patients' admission to the ER, the type and the possible causes of injury.

#### **2. Materials and Methods**

We conducted a retrospective study of prospectively collected data. Data collection has been performed on two groups, according to the STROBE guidelines [4]. The Pandemic Group (Pandemic Group—PG) was composed of consecutive patients, aged 0–16 years, admitted to the ER of our Orthopaedic Trauma Hub Centre between 12 March and 5 May 2020, the lockdown period. The Non-Pandemic Group (NG) was composed of all the ER pediatric admissions between 12 March and 5 May 2019. The investigated variables were sex, age, triage color-code at admission, declared cause of trauma and presence of symptoms related to COVID-19 infection, discharge diagnosis and discharge modes.

During ER admission, after checking for symptoms related to COVID-19 disease, the PG patients were assigned to a triage category by a nurse:

Pediatric patients were defined as age ≤16 years old.

After triage, patients were evaluated by the attending orthopedic surgeon that provided the appropriate treatment and the most adequate ER discharge mode.

The place where the trauma has occurred was also analyzed based on the clinical history:

Our Institutional Board did not require any ethical approval for this kind of study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

#### *Statistical Analysis*

The analyses were performed using Graphpad Prism v5.0 (GraphPad Software, San Diego, CA, USA). Numerical data are presented as median and interquartile range; categorical variables are reported as absolute frequency and percentage. Distribution of continuous variables was assessed by Shapiro–Wilk test. In accordance with the results of this test, the difference between the groups were assessed by Student *t* test or Mann–Whitney test for normally and non-normally distributed variables, respectively; Fisher's exact test was applied to categorical variables. Chi-square test for trends have been applied for ordinal categorical variables with more than 2 categories. A *p*-value < 0.05 was considered statistically significant.

#### **3. Results**

Our main finding was the decrease in the number of pediatric patients admitted to ER during the pandemic period: the NG counts for 790 cases, whereas the PG includes 103 patients, showing a reduction of 87.0% in the admissions. Data are reported in Table 1; a statistically significant difference between the two groups was found in the mean age of patients, that decreased from 11.4 ± 3.4 (NG) to 8.6 ± 4.6 years (PG) (*p* < 0.0001); in particular, the decrease relates to the percentage of patients older than 12 years in 2020, from 41.8% in NG to 22.3% in PG (*p* < 0.0001; OR 0.40, CI 95%: 0.25–0.65) (Table 2).

**Table 1.** Demographic differences between NG and PG.

\* = statistically significant difference, *p* < 0.0001. particular, the decrease relates to the percentage of patients older than 12 years in 2020, from 41.8% in NG to 22.3% in PG (*p* < 0.0001; OR 0.40, CI 95%: 0.25–0.65) (Table 2).

*Children* **2021**, *8*, x FOR PEER REVIEW 3 of 7

**Table 2.** Patients divided by age groups admitted to ER: differences between NG and PG. **Table 1.** Demographic differences between NG and PG.

Regarding the triage code assigned at admittance, a trend toward more severe codes (green and yellow) in the PG compared to NG was recorded (*p* = 0.039) (Figure 1); the diagnosis of fracture was less frequent in NG (*p* < 0.0001) with an Odds Ratio of 2.78 (CI 95%: 1.75–4.09), while the percentage of contusions changed from 19.1% in NG to 13.6% in PG, though no significant difference was detected (*p* = 0.22; OR= 0.67 CI95%: 0.37–1.20). Additionally, a change in the most common diagnoses was noticed: in the NG prevailed ankle sprains (14.2%), forearm fractures (9.4%) and sprains of the interphalangeal joints (8.0%), whereas in PG, forearm fracture was the most frequent trauma (26.2%), followed by elbow contusions (7.2%) and fingers fractures (6.8%). Complete data are reported in Figure 2. **Table 2.** Patients divided by age groups admitted to ER: differences between NG and PG. **Age (Years) 0–2 2–6 6–12 >12 Mean Age SD Median Age**  NG (2019) 2.3% 6.5% 49.5% 41.8% 11.4 3.4 12 PG (2020) 14.6% 15.5% 47.6% 22.3% 8.6 4.6 9 Regarding the triage code assigned at admittance, a trend toward more severe codes (green and yellow) in the PG compared to NG was recorded (*p* = 0.039) (Figure 1); the diagnosis of fracture was less frequent in NG (*p* < 0.0001) with an Odds Ratio of 2.78 (CI 95%: 1.75–4.09), while the percentage of contusions changed from 19.1% in NG to 13.6% in PG, though no significant difference was detected (*p* = 0.22; OR= 0.67 CI95%: 0.37–1.20). Additionally, a change in the most common diagnoses was noticed: in the NG prevailed ankle sprains (14.2%), forearm fractures (9.4%) and sprains of the interphalangeal joints (8.0%), whereas in PG, forearm fracture was the most frequent trauma (26.2%), followed by elbow contusions (7.2%) and fingers fractures (6.8%). Complete data are reported in Figure 2.

**Figure 1.** Triage code at ER admission: differences between NG and PG. Legend: NG: Non-**Figure 1.** pandemic Group PG: Pandemic Group. Triage code at ER admission: differences between NG and PG. Legend: NG: Non-pandemic Group PG: Pandemic Group. *Children* **2021**, *8*, x FOR PEER REVIEW 4 of 7

*\* = statistically significant difference. Legend: NG: Non-pandemic Group PG: Pandemic Group.*  **Figure 2.** Most frequent diagnosis: differences between NG and PG. **Figure 2.** Most frequent diagnosis: differences between NG and PG. \* = statistically significant difference. Legend: NG: Non-pandemic Group PG: Pandemic Group.

As far as the location of injuries, data were available for 474 patients out of 790 (60%)

pandemic period injuries at home were far more frequent (34.8% compared to 6.8% in NG), whereas in 2019, traumas mostly occurred during sport activities or at playgrounds (68.4%), followed by injuries at school (18.8%); all these differences are highly statistically

*\* = statistically significant difference, p < 0.0001. Legend: NG: Non-pandemic Group PG: Pandemic Group.*

**Figure 3.** Place of traumas, differences between NG and PG

significant (*p* < 0.0001). Detailed results are shown in Figure 3.

As far as the location of injuries, data were available for 474 patients out of 790 (60%) for the NG and for 69 patients out of 103 (67%) for the PG. As expected, during the pandemic period injuries at home were far more frequent (34.8% compared to 6.8% in NG), whereas in 2019, traumas mostly occurred during sport activities or at playgrounds (68.4%), followed by injuries at school (18.8%); all these differences are highly statistically significant (*p* < 0.0001). Detailed results are shown in Figure 3. *\* = statistically significant difference. Legend: NG: Non-pandemic Group PG: Pandemic Group.*  **Figure 2.** Most frequent diagnosis: differences between NG and PG. As far as the location of injuries, data were available for 474 patients out of 790 (60%) for the NG and for 69 patients out of 103 (67%) for the PG. As expected, during the pandemic period injuries at home were far more frequent (34.8% compared to 6.8% in NG), whereas in 2019, traumas mostly occurred during sport activities or at playgrounds (68.4%), followed by injuries at school (18.8%); all these differences are highly statistically significant (*p* < 0.0001). Detailed results are shown in Figure 3.

*\* = statistically significant difference, p < 0.0001. Legend: NG: Non-pandemic Group PG: Pandemic Group.*

*Children* **2021**, *8*, x FOR PEER REVIEW 4 of 7

**Figure 3.** Place of traumas, differences between NG and PG **Figure 3.** Place of traumas, differences between NG and PG. \* = statistically significant difference, *p* < 0.0001. Legend: NG: Non-pandemic Group PG: Pandemic Group.

Surprisingly, no cases of suspected or confirmed COVID-19 infection were recorded in the PG at the investigated Emergency Room.

#### **4. Discussion**

Over the last few decades, ERs have known an important growth in patient flow. Thus, "Observatoire Regionale des Urgences Champagne—Ardennes" organization reported an increase in the number of admissions to the ERs in the Champagne-Ardennes state of France of 6.43% per year from 2008 to 2013 [5].

During the outbreak of COVID-19, patients were forced to postpone regular check-ups and non-urgent clinical or surgical procedures to avoid risks of COVID-19 transmission due to the overcrowding of the ERs and of the departments. At the same time, the government imposed a total lockdown in Italy and obligated people to stay at home except for proved necessities. Schools of any grade were closed and sport activities were prohibited. Our findings demonstrate that the lockdown led to 87% reduction in the overall ER pediatric patient flow of our Regional Trauma Hub. In normal conditions, unnecessary admissions contribute to the ER congestion with a long length of stay. Nevertheless, these issues resolved spontaneously during the pandemic. A similar decrease in ER patient's flow was reported in Canada, Taiwan and Hong Kong during the SARS epidemic (2003–2004), and this may be attributed to people's perception of the ER as a possible source of infection. As reported by Huang et al. [6], at the peak of the SARS epidemic, the reduction in daily ER visits reached 51.6% of pre-epidemic numbers (*p* < 0.01). In pediatric patients, the maximum mean decreases in number of visits were 80.0% (*p* < 0.01), 57.6% (*p* < 0.01) and 40.8% (*p* < 0.01), respectively. Moreover, this reduction persisted 3 months after the end of the epidemic. Man et al. [7] displayed a significant drop in the overall ER attendance following the outbreak of SARS; in particular, the trauma rate was significantly lower in 2003 than in 2002 (*p* = 0.03) due to the fear of virus exposure. In addition, during the SARS spread, as well as during the COVID-19 outbreak, most people preferred to avoid crowded areas; thus, recreational or sporting activities may have been less popular then before. Consequently, a change in community behavior may also explain the drop in ER admission reported in the present study.

Moreover, Bhuvaneswari et al. [8] reported that the most common age group injured at home included patients younger than 12 years and toddlers. Similarly, our study demonstrates an important reduction of patients' age during the lockdown. As a matter of fact, we found an important reduction of patients older than 12 years old who visited the Emergency Department during the COVID-19 outbreak (41.8% in 2019 vs. 22.3% in 2020) (Table 2). This finding may be related to several elements. First, younger children are less aware of the risks of injury and they probably have a similar behavior during outdoor or indoor activities. Thus, they are exposed to traumas even in a domestic context. Furthermore, the closure of schools and play areas constricted at home many older children. Therefore, older children radically changed their behaviors, becoming more focused on board games, computer games and videogames, as they were not allowed to meet with their friends and play outdoors. This clearly represents a difference in the risk of injuries since all these indoor recreational activities did not expose them to traumas. Lastly, older children are more keen on competitive sports activities and contact sports that were prohibited during the national lockdown, and this clearly can explain the reduction of ER admissions of these subset of pediatric patients.

Farrell et al. [9] reported that during the SARS outbreak in 2003, ER visits declined by 21% (95% CI, 18–24%) over the 4-week study period. Conversely to what the present study shows, those authors found the greatest reduction involves both infant and toddler visits (69%; 95% CI, 58–79%) and these data did not recover the following year. This difference might be explained by the fact that our data are relative only to pediatric admissions in a Trauma Hub center specialized only in Orthopaedic surgery. Indeed, COVID-19 disease in neonates, infants and children has been reported to be significantly milder than their adult counterparts. Similarly, all the reported neonatal cases have been mild [10]. Concerning admissions to ER in our Center, no cases of COVID-19 were registered in children, whereas many adult patients diagnosed with COVID-19 were hospitalized at our institute.

During the COVID-19 pandemic, a spike in the purchase of home play equipment and trampolines has been registered. Consequently, the lockdown per se did not prevent all injuries [9]. Regarding the place and causes of trauma, Prakash et al. [11] reported that up to 63.9% children attending ER in ordinary times sustained injuries at home, followed by road accidents (26.2%), whereas school and play areas accounted only for 8.8% of traumas. Conversely, Sephton et al. reported a change in mechanism of injuries during the pandemic period. Indeed, authors showed that the proportion of sports-related injuries during the lockdown period fell from 6.2% to 3.6% [12]. Similarly, the present study demonstrated a big shift from non-domestic traumas (including both scholastic, sport and play areas injuries) to injuries occurred at home in the NG in comparison with the PG (respectively 6.8% and 34.8%). More specifically, our study showed 0% of scholastic traumas during the period of lockdown and only 10% of play area injuries, whereas in 2019 they counted for 18.8% and 68.4% of traumas, respectively. This shift is obviously due to the banning of both outdoor activities and sports performed in gyms and swimming pools. These measures led to a drop of patients presenting for non-urgent chronic reasons, sports-related injuries (sprains, contusions, dislocations) and minor road accidents. Therefore, fewer minor traumas such as sprains of knee reached our ER, as expected, and this finding explains the decreased percentages of non-urgent codes and a statistically significant tendency towards more serious triage codes in the PG. Moreover, we found that the fracture diagnosis was more frequent in the PG in comparison with the NG, confirming that only the most severe injured patients sought medical attention during the pandemic period. In addition, forearm fractures and elbow contusions were the most frequent traumas in the PG, consistently with the younger age of ER admissions as these type of injuries are more frequent in this subset of pediatric patients [13].

A recent study also reported an increase in domestic violence and child abuse, particularly in dysfunctional families during the pandemic period. This event might be related to

restrictions, isolation, higher level of anxiety and stress with a relevant impact on risks of developmental delay and behavioral problems [14]. Nevertheless, our study did not show any increase in domestic violence and child abuse rate, probably because our institution is mainly an Orthopedic Trauma Hub and it lacks a psychological or psychiatric support for children and adolescents; thus, suspected child abuses were not recorded. A more extensive analysis involving other hospitals with a pediatric psychiatric service may confirm the results shown by Boo et al. [14].

The conclusions drawn from this study rely on data about an Orthopedic Trauma Hub that includes also a Pediatric Orthopedics service and may be different from the flow in other hospitals. Thus, we cannot comment on the pediatric patients' flow in the ER due to ailments other than traumas. Nevertheless, this is the first study revealing the epidemiologic effects that COVID-19 pandemic and lockdown measures had on pediatric patients' flow in an emergency department.

Moreover, our study indirectly demonstrated that the vast majority of ER admissions in normal conditions is due to non-urgent or deferrable conditions. Thus, this evidencebased analysis is fundamental to improving the strategies of care of the National Health System, to better employ the available resources and to reduce overcrowding in the ER that usually leads to long waiting time for patients and the risk of a lower standard of care.

#### **5. Conclusions**

A significant drop in the overall ER attendances in a Trauma Hub center was reported after the outbreak of COVID-19 pandemic. The fear of virus exposure in hospital undoubtedly acted as a significant deterrent. However, it is likely that the community precautions adopted during the lockdown, namely school closures and decreased sport activities, resulted in fewer injuries; thus, only the most serious traumas sought medical care, resulting in a higher percentage of severe triage codes and fractures.

**Author Contributions:** Conceptualization, F.V., G.M.P. and L.M.; methodology, M.R., C.D.G., N.R., D.C. and M.D.M.L.; software, M.V.; validation, F.V., G.M.P. and L.M.; formal analysis, M.V.; investigation, F.V., M.R., C.D.G., N.R., D.C., R.A. and M.D.M.L.; resources, F.V. and R.A.; data curation, M.R., C.D.G., N.R., M.V. and M.D.M.L.; writing—original draft preparation, F.V., M.R., C.D.G. and N.R.; writing—review and editing, G.M.P. and L.M.; visualization, M.R., C.D.G., N.R., D.C. and M.D.M.L.; supervision, F.V., G.M.P. and L.M.; project administration, F.V. and L.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived for this study, due to the retrospective nature of the analysis.

**Informed Consent Statement:** Patient consent was waived due to due to the retrospective nature of the analysis.

**Data Availability Statement:** Data supporting reported results can be found at this link: https: //osf.io/k2wh5/?view\_only=e59648fbba854840b32ca3988736da6a (accessed on 26 July 2021).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


2.1. "Paddy field" as a farmland with rice and flooded water

The words of "paddy field" are usually and widely used for the farmland, where rice is cultivated, and they generally imply the area flooded, like the definitions of Cambridge Dictionary as "a field planted with rice growing in water" [5], Collins English Dictionary as "a flooded piece of land used for growing rice" [6], and The Free Dictionary as "a field, often flooded with water, in which rice is grown" [7]. The definition of "paddy field," however, is intricate slightly. Fundamentally "paddy" means "rice" especially in the husk. Consequently, a "paddy field" means a field planted with rice. Some dictionaries describe that only "paddy" could mean "paddy field," without any word for indicates the space, like the definition of the Oxford Living Dictionary as "A field where rice is grown" [8], and of Merriam-Webster as "wet land in which rice is grown" [9], while it also show the meaning as "Rice before threshing or in the husk."

Since rice is usually grown in level basin flooded with water throughout most of the growing season, "paddy field" generally means "a field flooded with water for growing rice," and the definitions of "paddy field" in most of the current dictionaries include words of "rice" and "water" or "flood," as introduced above.

In Japan, the English words "paddy field" is translated to the Japanese word "suiden," while there this word "suiden" is used for flooded farm land, which distinguishes "flooded field" from "upland field" or "hatake" in Japanese. The upland field is not flooded and cultivated for normal crops like vegetables and flowers. Accordingly, in Japan, it is expressed that some aquatic crops like lotus and tatami are cultivated in "paddy fields." This Japanese case is recognized as an exceptional case. In this chapter, "paddy field" is to be used basically as "a field planted with rice."

As mentioned below, actually, in considerable area in the world, rice is produced in fields without flooding. Then, some parts of paddy fields of the world are not identified as the "wetland" with water submergence.


*3.3. Experiment Procedure*

On arriving for the experiment, the participant was seated in a regular office in front of a 24 computer monitor that displayed the experiment environment. The monitor was equipped with a Gazepoint GP3 HD eye tracker (https://www.gazept.com/product/gp3 hd/) (accessed on 6 March 2022). The participant was asked to read the informed consent form and given the opportunity to ask questions about the experiment and study before signing it. The participant was then asked to respond to a survey with demographic questions and asked to take a seat in front of the monitor. The eye tracker was calibrated using the manufacturer's built-in calibration sequence with nine points [45]. The calibration was considered successful when the control software deemed all nine points valid. In cases where the eye tracker could not be successfully calibrated, eye-tracking data were disregarded for that participant. This happened for three participants.

The participant was then reminded of Jenny's persona and asked to classify the email in Jenny's inbox. The participant was instructed to delete all phishing emails and keep all legitimate emails. The participant was asked to think aloud during the experiment, especially about how decisions to delete emails were made. The participant was also told that at least one of the emails was phishing and that a score was to be calculated based on the participants' performance. The intent was to make the participant as aware

of phishing as possible. The rationale was that mere inclusion in the experiment would increase the participant's awareness level, and by priming all participants to high awareness would make the awareness levels of the participants comparable. Consequently, the gathered data reflects the participants' best ability to delete phishing rather than the ability they can be assumed to have during their daily work. Gazepoint analysis UX Edition (https://www.gazept.com/product/gazepoint-analysis-ux-edition-software/) (accessed on 6 March 2022) was used to monitor the participant's performance in real time on an adjacent screen and for post-experiment analysis of the collected eye-tracking data. Following the experiment, the participants in the game group were asked if they had played the game before the experiment as instructed. The experiment process, from the participant's point of view, is visualized in Figure 4.

**Figure 4.** Visualization of experiment procedure. Dashed boxes only applied to some groups.


**4. Discussion**

Sardinia Region has a middle-size population with mean age and rate of elderly lower than the Italian average. It has at its disposal resources in line with the national average and its screening campaign covers only one province; the incidence of the disease is lower than the national average, its emigration index is low and the refund of health expenditure is in line

> **GDP/ capita index**

**Incidence colorectal cancer**

41,07

35,98

35,98

35,93

45,33

69,64

Campania Region has a large-size population with mean age and rate of elderly lower than the Italian average. It has at its disposal fewer resources than the national average and its screening campaign covers only some provinces; the incidence of the disease is lower than the national average; its emigration index is intermediate and the refund of health expendi‐

Puglia Region has a large population with mean age and rate of elderly lower than the Ital‐ ian average. It has at is disposal fewer resources than the national average and it has no screening campaign; the incidence of the disease is lower than the national average and its emigration index is intermediate. The refund of health expenditure is in line with the nation‐

Basilicata has a small-sized population with mean age and rate of elderly higher than the Italian average. It has at its disposal fewer resources than the national average and the screening campaign was discontinued in 2007, the incidence of the disease is lower than the national average, its emigration index is high and the refund of health expenditure is in line

**Screening plans Migration**

Global regional plan STOP 2007

L.D. 138 2004 art. 2 bis Sof > 50 years

**Index**

4 plans 7,55 0,89

4 plans 14,82 1

24,01 1

**DRG Index**

with the national average.

**Table 3.** Macro-area: Southern Italy

al average.

with the national average.

**Population (pop)**

80 Colonoscopy and Colorectal Cancer Screening - Future Directions

**Mean age**

Campania 5.812.962 39,0 15,4 0,64 60,09

Puglia 4.079.702 40,7 17,4 0,66 68,89

Basilicata 590.601 42,1 20,0 0,70 104,31

Calabria 2.008.709 41,1 18,4 0,65 83,08

Sicily 5.037,799 40,7 18,0 0,66 71,15

ITALY 60.387.000 42,8 19,9 1 107,8

ture is slightly lower than the national average.

**% pop ≥ 65 years**

> The average cost of colo-rectal cancer treatments in Italy has been estimated to be approxi‐ mately € 9.149,00 per patient per year including chemotherapy [27]. Some authors estimate that for the city of Ferrara the overall cost related to the introduction of a CCS programme was approximately € 1.400.000,00 (from October 2005 until March 2007 with more than 99.000 individuals invited) with a large proportion of these costs related to the implementa‐ tion and management of the programme [28]. FOBT plus COL, increase cost relative to cheapest strategy. As a consequence of screening, some individuals with low risk receive a recommendation for a follow-up COL. However follow-up colonoscopies will increase the cost consequences of introducing screening, but not the expected colorectal cancer treatment costs. The Italian Observatory on screening Practices has been collecting data on CCS since 2004 [29]. In 2007 there were 71 CRC screening programmes in Italy, covering 46,6% of the total eligible population, with a higher coverage in the North (71,6%), and in the Centre (52,1%) than in the South (7%). The majority of programmes (65) used the guaiac FOBT (gFOBT) as first-line test. Only seven programmes used the flexible sigmoidoscopy (FS), of which three used a combination of FS and gFOBT. The quality and efficacy of the screening programmes are evaluated using ad hoc indicators developed by the Italian Group for Col‐ orectal Screening (GISCoR) [28]. In 2007, on average 79,1% of the eligible population was in‐ vited for FOBT screening, with only Lombardy, Umbria, and most of the programmes in Emilia Romagna reaching the 90% target. Among the invited individuals, 46,3% underwent FOBT with significant variations across (from 26,5% in Lazio to 65% in Veneto) and within regions (from 11 to 80%). Among the people invited for the first time, the average percent‐ age of individuals with a positive test was 5,6%, while among people who were recalled it was 4%. The probability of having a positive result was higher for men than for women and increased with age. Among people with a positive test, only 78,7% underwent a COL [2]. The South and Centre had a lower rate of COL attendance than the North. Men were slight‐ ly more likely to undertake a COL after a positive FOBT than women, mainly because of the uncomfortable feeling and concern of women having a male physician performing the tests. The risk of bowel perforation and bleeding during COL was negligible. For FS, on average 66,5% of the eligible population was invited with large variations across programmes. Only 27,7% of those invited underwent FS with a slightly higher proportion among men than

women. The response rate was higher whenever FS was combined with FOBT [30]. The per‐ centage of FS successfully completed was 88%, with again a higher level among men than women; 14,3% of men and 7,6% of women were sent for a COL for further analysis and 90% of these attended the test. In 2007 overall FOBT and FS detected 20.796 adenoma of which, 2.449 were carcinomas. An additional 295 carcinomas were diagnosed in individuals who underwent further follow-up tests. Most of the adenomas identified were in Stage I, (54.5%), followed by increased widely Stages III and IV (24,9%), and then in Stage II (20,7%). The crit‐ ical points are: complications of COL (40 programs) with average perforation rate of 0,08% (2,5% operative COL) and average bleeding rate of 0,55%; low coverage and delay in South‐ ern Italy; low compliance; overload on endoscopy facilities.

staff, confirmation procedure (selection of population at risk to reduce costs); second assess‐ ment of efficacy: sensitivity, specificity, productive value; third non-invasive method: it is addressed to probably healthy subjects; latter possibility of intervention: the disease or con‐

The Future of Colonoscopy: The Use of Data Envelopment Analysis (DEA) for Colorectal Cancer Screening...

http://dx.doi.org/10.5772/52310

83

In the first years 2000 the Italian Government, in view of the severe unbalanced offer of screening plans, established to allocate further financial resources (52 million euro between 2004 and 2006) for interventions promoting the re-balancing of the offer and the quality of the screening plan of cervix and breast cancers and the diffusion of the screening of colorec‐ tal cancer [33]. Even though in year 2008 in oncology the plans of screening of colorectal can‐ cers had a significant increase exceeding the threshold of 50%, unfortunately they are not always able to achieve acceptable levels of efficacy. According to "The screening plans in Italy 2009", the screening campaigns for colorectal cancers carried out in the last years, showed some critical aspects: we observed a progressive increase in the compliance of the first years versus a progressive stabilization or decrease in the compliance afterwards [20]. There are extremely strong differences between Northern, Central and Southern Italy. How‐ ever, the rate of detection of cancers by using faecal occult blood and endoscopy has always

In fact, many differences are reported in relation with the ratio between regional and per capita income resulting into a three-speed Italy. This is mirrored also by the incidence of col‐ orectal cancer, which exhibits a different distribution where the highest rate is in the North‐ ern Italy and the minimum rate in the Southern Italy. According to the data of the National Screening Observatory, they are spread not uniformly throughout the territory. According to "The screening plans in Italy 2009", the real extension of colorectal screening plans (faecal occult blood plus endoscopy) for the macro-areas evidenced some critical aspects [20]. We passed from 5% in 2004 to 12% in 2005, then to 30% in 2006, which stabilized at 37% in 2007/2008 as global Italian data. Even though there were significant differences with a posi‐ tive presence in the Northern Italy versus a delay in the Central Italy and an insufficient presence in the Southern Italy, these data showed a similar annual tendency for each macroarea. However, the rate of identification of cancers by using faecal occult blood and endos‐ copy has always been lower than the acceptable minimum. After an initial enthusiasm, we observed a progressive decrease in the percentage of compliance with the plan in both mac‐ ro-areas. Regarding the emigration index, there are notable differences within the three mac‐ ro-areas, which influence the general index. The value shows that the regions of Northern Italy have more attraction power versus the regions of Southern Italy, whereas the regions

This latter parameter: the DRG index shows clear imbalances within all regions and there‐

The lack of homogeneity on the territory, moreover, is still marked with evident consequen‐ ces on mortality and morbidity [38]. The implementation of federalism poses a question: if these large differences already exist, will the situation be improved or will the disparity be‐ come even stronger? On April 29, 2010, the agreement between Government, Regions and Autonomous Provinces of Trento and Bolzano was undersigned. According to this agree‐

dition to be diagnosed should be susceptible of therapy.

been lower than the acceptable minimum.

of Central Italy have not particularly high emigration indices.

fore it is not a useful element to discriminate the different macro-areas.

The role of screening is an extremely topical question even though in the past it was already subject of discussion and until few years ago it was considered to fall within the competence of the central government [31]. Only in the last years we have observed a different interest especially in Italy due to the changed political conditions. Does a convergence really exist between federalism, screening and standard cost? The process which links the federal struc‐ ture of the nation with the screening is a thin red line which began with the promulgation of the Constitution and over the years it has been fully implemented with Act No. 42 of year 2009 with enforcement of Article 119 of the Constitution which guarantees autonomy of rev‐ enues and expenditure of municipalities, provinces, towns and regions and assure princi‐ ples of support and social cohesion [32]. In particular, it assures the funding of the essential levels of health care (which includes the practice of screening) referring to a benchmark of cost and requirements [32]. In year 2001 an agreement was made between Government and Regions for the guidelines about prevention, diagnosis and assistance in oncology, including indications for the screenings, and the promulgation of Decree of the President of the Coun‐ cil of Ministry No. 26 of November 29th 2001, which defines the Essential Levels of Care (LEA) including the plans of screening for the early diagnosis of colorectal, breast, cervix cancers [33]. Within the 2001 financial budget (law N. 388, 2000) it was decided that target population screening was free of charge [34]. In 2004 the Health Minister redistributed over‐ all € 7.000.000, a minimum of € 50.000 per region, for reducing the gaps in cancer screenings and activating the CCS programme (€ 1.750.000 specifically for CCS). This agreement made these plans to be a right for women and men. The debate about the allocation of resources in regimen of federalism is very lively, in particular regarding the costs of Health Care System. We remind that the allocation of the funds to the Health Care System for the prevention of diseases remained constant at 5% for some years [35]. The criterion of the historical expendi‐ ture will be replaced by the standard cost. The standard cost is the tool to assure the LEA funding and consists of the expenditure for the following items: staff, equipment, consuma‐ bles and general costs of the health performances of the production unit [36]. Moreover, a "direct" cost of production is predicted, i.e. a percentage to cover the general functioning costs of the equipment of the production unit [37]. The characteristics of the colorectal can‐ cers show a strong geographical variability: chronic trend, increase in the incidence and a still too high mortality rate. The increase in the prevalence should be allotted partially to the ageing of the population, but mostly to the diffusion and implementation of screening plans. The cost of the screening campaign is defined by the following factors: first costs of tests, staff, confirmation procedure (selection of population at risk to reduce costs); second assess‐ ment of efficacy: sensitivity, specificity, productive value; third non-invasive method: it is addressed to probably healthy subjects; latter possibility of intervention: the disease or con‐ dition to be diagnosed should be susceptible of therapy.

women. The response rate was higher whenever FS was combined with FOBT [30]. The per‐ centage of FS successfully completed was 88%, with again a higher level among men than women; 14,3% of men and 7,6% of women were sent for a COL for further analysis and 90% of these attended the test. In 2007 overall FOBT and FS detected 20.796 adenoma of which, 2.449 were carcinomas. An additional 295 carcinomas were diagnosed in individuals who underwent further follow-up tests. Most of the adenomas identified were in Stage I, (54.5%), followed by increased widely Stages III and IV (24,9%), and then in Stage II (20,7%). The crit‐ ical points are: complications of COL (40 programs) with average perforation rate of 0,08% (2,5% operative COL) and average bleeding rate of 0,55%; low coverage and delay in South‐

The role of screening is an extremely topical question even though in the past it was already subject of discussion and until few years ago it was considered to fall within the competence of the central government [31]. Only in the last years we have observed a different interest especially in Italy due to the changed political conditions. Does a convergence really exist between federalism, screening and standard cost? The process which links the federal struc‐ ture of the nation with the screening is a thin red line which began with the promulgation of the Constitution and over the years it has been fully implemented with Act No. 42 of year 2009 with enforcement of Article 119 of the Constitution which guarantees autonomy of rev‐ enues and expenditure of municipalities, provinces, towns and regions and assure princi‐ ples of support and social cohesion [32]. In particular, it assures the funding of the essential levels of health care (which includes the practice of screening) referring to a benchmark of cost and requirements [32]. In year 2001 an agreement was made between Government and Regions for the guidelines about prevention, diagnosis and assistance in oncology, including indications for the screenings, and the promulgation of Decree of the President of the Coun‐ cil of Ministry No. 26 of November 29th 2001, which defines the Essential Levels of Care (LEA) including the plans of screening for the early diagnosis of colorectal, breast, cervix cancers [33]. Within the 2001 financial budget (law N. 388, 2000) it was decided that target population screening was free of charge [34]. In 2004 the Health Minister redistributed over‐ all € 7.000.000, a minimum of € 50.000 per region, for reducing the gaps in cancer screenings and activating the CCS programme (€ 1.750.000 specifically for CCS). This agreement made these plans to be a right for women and men. The debate about the allocation of resources in regimen of federalism is very lively, in particular regarding the costs of Health Care System. We remind that the allocation of the funds to the Health Care System for the prevention of diseases remained constant at 5% for some years [35]. The criterion of the historical expendi‐ ture will be replaced by the standard cost. The standard cost is the tool to assure the LEA funding and consists of the expenditure for the following items: staff, equipment, consuma‐ bles and general costs of the health performances of the production unit [36]. Moreover, a "direct" cost of production is predicted, i.e. a percentage to cover the general functioning costs of the equipment of the production unit [37]. The characteristics of the colorectal can‐ cers show a strong geographical variability: chronic trend, increase in the incidence and a still too high mortality rate. The increase in the prevalence should be allotted partially to the ageing of the population, but mostly to the diffusion and implementation of screening plans. The cost of the screening campaign is defined by the following factors: first costs of tests,

ern Italy; low compliance; overload on endoscopy facilities.

82 Colonoscopy and Colorectal Cancer Screening - Future Directions

In the first years 2000 the Italian Government, in view of the severe unbalanced offer of screening plans, established to allocate further financial resources (52 million euro between 2004 and 2006) for interventions promoting the re-balancing of the offer and the quality of the screening plan of cervix and breast cancers and the diffusion of the screening of colorec‐ tal cancer [33]. Even though in year 2008 in oncology the plans of screening of colorectal can‐ cers had a significant increase exceeding the threshold of 50%, unfortunately they are not always able to achieve acceptable levels of efficacy. According to "The screening plans in Italy 2009", the screening campaigns for colorectal cancers carried out in the last years, showed some critical aspects: we observed a progressive increase in the compliance of the first years versus a progressive stabilization or decrease in the compliance afterwards [20]. There are extremely strong differences between Northern, Central and Southern Italy. How‐ ever, the rate of detection of cancers by using faecal occult blood and endoscopy has always been lower than the acceptable minimum.

In fact, many differences are reported in relation with the ratio between regional and per capita income resulting into a three-speed Italy. This is mirrored also by the incidence of col‐ orectal cancer, which exhibits a different distribution where the highest rate is in the North‐ ern Italy and the minimum rate in the Southern Italy. According to the data of the National Screening Observatory, they are spread not uniformly throughout the territory. According to "The screening plans in Italy 2009", the real extension of colorectal screening plans (faecal occult blood plus endoscopy) for the macro-areas evidenced some critical aspects [20]. We passed from 5% in 2004 to 12% in 2005, then to 30% in 2006, which stabilized at 37% in 2007/2008 as global Italian data. Even though there were significant differences with a posi‐ tive presence in the Northern Italy versus a delay in the Central Italy and an insufficient presence in the Southern Italy, these data showed a similar annual tendency for each macroarea. However, the rate of identification of cancers by using faecal occult blood and endos‐ copy has always been lower than the acceptable minimum. After an initial enthusiasm, we observed a progressive decrease in the percentage of compliance with the plan in both mac‐ ro-areas. Regarding the emigration index, there are notable differences within the three mac‐ ro-areas, which influence the general index. The value shows that the regions of Northern Italy have more attraction power versus the regions of Southern Italy, whereas the regions of Central Italy have not particularly high emigration indices.

This latter parameter: the DRG index shows clear imbalances within all regions and there‐ fore it is not a useful element to discriminate the different macro-areas.

The lack of homogeneity on the territory, moreover, is still marked with evident consequen‐ ces on mortality and morbidity [38]. The implementation of federalism poses a question: if these large differences already exist, will the situation be improved or will the disparity be‐ come even stronger? On April 29, 2010, the agreement between Government, Regions and Autonomous Provinces of Trento and Bolzano was undersigned. According to this agree‐ ment the regions are committed to implement by September 2010, the Regional Plan of Pre‐ vention to carry out the interventions established by the National Plan of Prevention: among the macro-areas of interventions there are oncologic screening programs [39]. The critical points are: complications of COL (40 programmes) with average perforation rate of 0.08% (2,5% operative COL) and average bleeding rate of 0,55%; low coverage and delay in South‐ ern Italy; low compliance; overload on endoscopy facilities.

the prices [53]. In this sense the results of non-parametric methods are objective, because they do not require prior specifications. On the other hand, however, their disadvantage is that they do not admit errors being deterministic methods; the results could be therefore in‐ fluenced. The relative efficiency of the responsibility centres is determined according to the

The Future of Colonoscopy: The Use of Data Envelopment Analysis (DEA) for Colorectal Cancer Screening...

http://dx.doi.org/10.5772/52310

85

Now the system of weights adopted strongly influences the efficiency, therefore through an algorithm of Charnes, Cooper and Rhodes (CCR), we try to find the optimal system of weights (among the proposed ones) in order to maximize the efficiency of the respon‐ sibility centre and the comparable ideal responsibility centre [54]. This suggests that the standard cost can be calculated in two ways: maximizing the numerator and fixing the denominator (output-oriented method – screening) or, vice versa, keeping the numerator and minimizing the denominator (input-oriented method – prevention budget) [55]. The difference is important since it determines the form of efficiency that we are assessing. Output-effective means there is no other unit that develops a larger screening with the

A productive unit is called input-effective if there is no other unit able to obtain the same

This methodology assesses the efficiency as the ratio between quality of the screening and available budget. Some weights are obviously introduced to include demographic and health characteristics of the Region. Now for each unit we can obtain the optimal budget to be allocated to the Region for the screening campaign. In this way by adding the sum of ev‐ ery single regional budget, the necessary budget of national expenditure can be obtained to

In view of the above mentioned results, we can assume an equivalent model (Table 4).

The following example of three Regions (large, middle, and small) illustrate how DEA

Each Region has exactly 10 COL (the only input), and we are be able to measure a Region CCR programme based on two outputs: number of patients subject to screening, and num‐

Region "large": 100 COL, 1000 number of recruited patients, 20 number of found cancers;

Region "medium": 100 COL, 400 number of recruited patients, 50 number of found cancers;

Now, the key to DEA is to determine whether we can create a virtual Region that is better than one or more of the real Regions. Any such dominated Region will be an inefficient Re‐ gion. Consider trying to create a virtual Region that is better than Region "large". Such a Re‐ gion would use no more inputs than a Region "large", and produce at least as much output. Clearly, no combination of Regions "medium" and "small" can possibly do that. Region

Region "small": 100 COL, 200 number of recruited patients, 150 number of found cancers.

following formula:

(*u*, *v*)=∑ *r*

*ur yr*<sup>0</sup> / <sup>∑</sup> *vixi*<sup>0</sup>

same budget for the prevention [56].

screening using a lower budget (DMUs).

carry out an effective and really sustainable screening campaign.

ber of found cancers. The data for these Regions is as follows:

**max** *u*,*v h* 0

works.

The critical limit to implement the screening campaigns of colorectal cancers is the allocation of own resources to Regions and local bodies and the overcoming of the dichotomy between legislative and administrative (on the territory) competences and derived finance (transfer from Government to territory) [40]. Up to now the Government has been engaged in fund‐ ing screening campaigns, from now on the Regions will be in charge of it [41]. Unfortunately since there is not yet an assessment of the costs of this procedure, the "promotion cam‐ paign", so far implemented, is risking to be reduced [42].

The concept of standard cost versus the historical cost is playing a crucial role in the fiscal federalism. The standard cost will contribute, in fact, to establish the "official" needs of each local body and therefore the contingent equalizing transfer to which it will have the right to in case of insufficient fiscal capacity [43].

Which approach should be used to calculate the standard costs of the federal finance?

There are two models among those currently used: micro-analytical (standard cost of each supplied performance) and macro-analytical (standard cost of easily measurable variables: demographic structure, epidemiological and social characteristics). The first approach is not very consistent with the purposes of the federalist reform (valid only as control mean) while the second model establishes a budget of expenditure resulting from merely political choices and not from the real needs of the population. What is the solution? To calculate the neces‐ sary resources the fundamental element to refer to is the efficiency [44-46]. The efficiency measures the economical employment of resources in the productive process. It is defined as the ratio between performances (screening) and resources (budget) according to the formu‐ la: efficiency= output/input [47,48].

A better approach, but for some aspects much more complex, could be the one of DEA [49]. Farrell (1957) in his preliminary work "The measurement of productive efficiency" intro‐ duced not only the well-known allocation between technique and price or allocative efficien‐ cy, but he also proposed a key to measure the comparative efficiency of the productive units which use various inputs to produce different outputs [50]. The efficiency of each unit would be equal to the ratio between real and potential output [51]. More than two decades after Charnes, Cooper and Rhodes (CCR), the idea of Farrell was developed and it was dem‐ onstrated that a linear mathematical program could be used to choose the most effective productive unit. The method, known as Data Envelopment Analysis, has been extensively used to measure the efficiency in many economical areas [52].

The analyses are non-parametric and its characteristic is that it can evaluate the relative effi‐ ciency of decisional units, and the like, through linear programming techniques without specifying whether the relative importance of the different factors of production or that of the prices [53]. In this sense the results of non-parametric methods are objective, because they do not require prior specifications. On the other hand, however, their disadvantage is that they do not admit errors being deterministic methods; the results could be therefore in‐ fluenced. The relative efficiency of the responsibility centres is determined according to the following formula:

**max** *u*,*v h* 0 (*u*, *v*)=∑ *r ur yr*<sup>0</sup> / <sup>∑</sup> *vixi*<sup>0</sup>

ment the regions are committed to implement by September 2010, the Regional Plan of Pre‐ vention to carry out the interventions established by the National Plan of Prevention: among the macro-areas of interventions there are oncologic screening programs [39]. The critical points are: complications of COL (40 programmes) with average perforation rate of 0.08% (2,5% operative COL) and average bleeding rate of 0,55%; low coverage and delay in South‐

The critical limit to implement the screening campaigns of colorectal cancers is the allocation of own resources to Regions and local bodies and the overcoming of the dichotomy between legislative and administrative (on the territory) competences and derived finance (transfer from Government to territory) [40]. Up to now the Government has been engaged in fund‐ ing screening campaigns, from now on the Regions will be in charge of it [41]. Unfortunately since there is not yet an assessment of the costs of this procedure, the "promotion cam‐

The concept of standard cost versus the historical cost is playing a crucial role in the fiscal federalism. The standard cost will contribute, in fact, to establish the "official" needs of each local body and therefore the contingent equalizing transfer to which it will have the right to

There are two models among those currently used: micro-analytical (standard cost of each supplied performance) and macro-analytical (standard cost of easily measurable variables: demographic structure, epidemiological and social characteristics). The first approach is not very consistent with the purposes of the federalist reform (valid only as control mean) while the second model establishes a budget of expenditure resulting from merely political choices and not from the real needs of the population. What is the solution? To calculate the neces‐ sary resources the fundamental element to refer to is the efficiency [44-46]. The efficiency measures the economical employment of resources in the productive process. It is defined as the ratio between performances (screening) and resources (budget) according to the formu‐

A better approach, but for some aspects much more complex, could be the one of DEA [49]. Farrell (1957) in his preliminary work "The measurement of productive efficiency" intro‐ duced not only the well-known allocation between technique and price or allocative efficien‐ cy, but he also proposed a key to measure the comparative efficiency of the productive units which use various inputs to produce different outputs [50]. The efficiency of each unit would be equal to the ratio between real and potential output [51]. More than two decades after Charnes, Cooper and Rhodes (CCR), the idea of Farrell was developed and it was dem‐ onstrated that a linear mathematical program could be used to choose the most effective productive unit. The method, known as Data Envelopment Analysis, has been extensively

The analyses are non-parametric and its characteristic is that it can evaluate the relative effi‐ ciency of decisional units, and the like, through linear programming techniques without specifying whether the relative importance of the different factors of production or that of

Which approach should be used to calculate the standard costs of the federal finance?

ern Italy; low compliance; overload on endoscopy facilities.

84 Colonoscopy and Colorectal Cancer Screening - Future Directions

paign", so far implemented, is risking to be reduced [42].

used to measure the efficiency in many economical areas [52].

in case of insufficient fiscal capacity [43].

la: efficiency= output/input [47,48].

Now the system of weights adopted strongly influences the efficiency, therefore through an algorithm of Charnes, Cooper and Rhodes (CCR), we try to find the optimal system of weights (among the proposed ones) in order to maximize the efficiency of the respon‐ sibility centre and the comparable ideal responsibility centre [54]. This suggests that the standard cost can be calculated in two ways: maximizing the numerator and fixing the denominator (output-oriented method – screening) or, vice versa, keeping the numerator and minimizing the denominator (input-oriented method – prevention budget) [55]. The difference is important since it determines the form of efficiency that we are assessing. Output-effective means there is no other unit that develops a larger screening with the same budget for the prevention [56].

A productive unit is called input-effective if there is no other unit able to obtain the same screening using a lower budget (DMUs).

This methodology assesses the efficiency as the ratio between quality of the screening and available budget. Some weights are obviously introduced to include demographic and health characteristics of the Region. Now for each unit we can obtain the optimal budget to be allocated to the Region for the screening campaign. In this way by adding the sum of ev‐ ery single regional budget, the necessary budget of national expenditure can be obtained to carry out an effective and really sustainable screening campaign.

In view of the above mentioned results, we can assume an equivalent model (Table 4).

The following example of three Regions (large, middle, and small) illustrate how DEA works.

Each Region has exactly 10 COL (the only input), and we are be able to measure a Region CCR programme based on two outputs: number of patients subject to screening, and num‐ ber of found cancers. The data for these Regions is as follows:

Region "large": 100 COL, 1000 number of recruited patients, 20 number of found cancers;

Region "medium": 100 COL, 400 number of recruited patients, 50 number of found cancers;

Region "small": 100 COL, 200 number of recruited patients, 150 number of found cancers.

Now, the key to DEA is to determine whether we can create a virtual Region that is better than one or more of the real Regions. Any such dominated Region will be an inefficient Re‐ gion. Consider trying to create a virtual Region that is better than Region "large". Such a Re‐ gion would use no more inputs than a Region "large", and produce at least as much output. Clearly, no combination of Regions "medium" and "small" can possibly do that. Region "large" is therefore deemed to be efficient. Region "small" is in the same situation. Howev‐ er, consider Region "medium". If we take half of Region "large" and combine it with half of Region "small", then we create a Region that processes different outputs (600 number of re‐ cruited patients, 85 number of found cancers) with just input (100 COL). This dominates "medium" (we would much rather have the virtual Region we created than Region "medi‐ um"). Region "medium" is therefore inefficient. Another way to see this is that we can scale down the inputs to "medium" (number of COL) and still have at least as much output. If we assume (and we do), that inputs are linearly scalable, then we estimate that we can get by with 63 COL. We do that by taking 0.34 times Region "small" plus 0.29 times Region "medi‐ um". The result uses 63 COL and produces at least as much as Region "medium" does. We say that Region "medium"'s efficiency rating is 0.63. Regions "small" and "large" have an efficiency rating of 1.

After the definition of the population size and the observed input and output to assess the screening unit (DMUs), it is possible to calculate the index of efficiency by using the abovementioned formula. This index can be referred to the single Regions or to the system Italy as

The Future of Colonoscopy: The Use of Data Envelopment Analysis (DEA) for Colorectal Cancer Screening...

http://dx.doi.org/10.5772/52310

87

In many states, a larger question may be whether the overwhelming use of COL as the

Determination of the appropriateness of an indication for COL has been advanced as a means to help rationalize the use of endoscopic resources. Current guidelines regarding the appropriateness of COL are relatively inefficient in excluding a clinically meaningful CRC risk for patients, in whom COL is generally not indicated, raising serious concerns about

A tailored navigation approach, which determines the particular concerns and barriers of an eligible individual and matches them with the strengths and weaknesses of each strategy to find the one most suitable, may be the optimal way to maximize the number of people who

Nowadays the Italian National Health Service is distributed on extremely diversified region‐ al realities. Needs and inefficiencies of production are inseparably correlated in the health expenditure of the Regions. In the future the issues that are now more critical will have to be adjusted: to implement screening plans, supply the Regions with the objectives related to common LEAs in view of the regional differences. According to the "National Centre for the Prevention and Control of the Diseases" (institution of coordination between Ministry of Health and Regions for the activities of surveillance, prevention and prompt response to the emergencies), it is necessary to "design the interventions of secondary prevention not as performances but rather as "paths" (profiles of care) offered to the citizen within various or‐ ganizing activities on the territory aiming at the efficiency in the practice". Only in this way the efficiencies can be optimized and the necessary budget minimized for each Region for the screening campaigns. In order to avoid the funding of squandering, a formula of analyti‐ cal calculation of the needs will be necessary [58]. A further problem in the future will be to make homogeneous the different kinds of screening currently in use on the territory to as‐ sure a higher allocative efficiency and COL will clearly has a future, which will expand even if the technology stands still. For a screening programme to be successful, multiple events have to occur, beginning with awareness and recommendation from the primary-care physi‐ cian, patient acceptance, financial coverage, risk stratification, screening test, timely diagno‐ sis, timely treatment, and appropriate follow-up. If any one of these steps is faulty or is not of high quality, the screening will fail. In this scenario we had to consider the COL as a means than an aim. In this regard DEA, which is an innovative methodology easy to be ap‐

In the end, a test can only provide benefit if it is actually done [57].

a whole.

screening method is the appropriate choice.

their applicability to clinical practice.

can benefit from COL.

**5. Conclusions**

**Table 4.** Example of sustainable screening campaign.

After the definition of the population size and the observed input and output to assess the screening unit (DMUs), it is possible to calculate the index of efficiency by using the abovementioned formula. This index can be referred to the single Regions or to the system Italy as a whole.

In many states, a larger question may be whether the overwhelming use of COL as the screening method is the appropriate choice.

Determination of the appropriateness of an indication for COL has been advanced as a means to help rationalize the use of endoscopic resources. Current guidelines regarding the appropriateness of COL are relatively inefficient in excluding a clinically meaningful CRC risk for patients, in whom COL is generally not indicated, raising serious concerns about their applicability to clinical practice.

A tailored navigation approach, which determines the particular concerns and barriers of an eligible individual and matches them with the strengths and weaknesses of each strategy to find the one most suitable, may be the optimal way to maximize the number of people who can benefit from COL.

In the end, a test can only provide benefit if it is actually done [57].