System configuration for energy harvesting circuit.
\r\n\tApplied and basic studies - Field studies and lab assays of fungicides can be discussed. We also look for examples of application methods, which may include timing of application, tools for application, fungicide compatibility, phytotoxicity, etc. Field trials have to have at least two years of data;
\r\n\tAdaptation of Integrated Plant Disease Management - How the IPM practice has been adapted in the field. Application of disease risk models, or use of fungicide application aids, which can be hardware or software. The introduction of a new tool for growers can also be included;
\r\n\tNovel fungicides - In addition to the traditional chemical approach, alternative materials (enzymes, oils, extracts, etc.), biological control agents, or plant defense activators can be discussed;
\r\n\tAdaptation of new technologies - Examples will be the use of unmanned vehicles, sensor technologies, advanced sprayers, or disease forecast systems for precision agriculture;
\r\n\tFungicide resistance - Unfortunately, we cannot ignore the fact that fungicide-resistant strains are widespread. Documentation of fungicide-resistant strains, the introduction of new technologies and methods can be discussed.
Supercapacitors have started to gain attention and are widely used for energy storage in recent years especially in the renewable energy sector. The advantages such as fast charging time, unlimited life cycle, low equivalent series resistance (ESR) and robust and high power density make it attractive and have been used to replace battery in a number of applications [1]. However, supercapacitors are greatly affected by temperature as an increase in temperature will produce negative effects to the electrolyte in the supercapacitor, thus reducing the lifespan. Charge balancing of supercapacitors has always been an issue, and it is important to minimize it in order to improve the performance and reliability. Analysis of few existing charge balancing circuits along with their pros and cons have been taken into consideration. By placing passive resistors across each capacitor, there is a high power loss from the resistors, which causes the circuit to be inefficient. Another concept of using DC/DC converters across two supercapacitors, on the other hand, results in high efficiency as no other losses occur besides from the converters itself. However, this circuit requires a large amount of components which adds to the cost.
Liyan Qu, Wei Qiao (2011) proposed a novel two-layer constant power control (CPC) scheme for a wind farm equipped with doubly fed induction generator (DFIG) wind turbines [3], where each wind turbine generator (WTG) is equipped with a supercapacitor energy storage system (ESS). The ESS serves as either a source or a sink of active power to control the generated active power of the DFIG wind turbine. Results have shown that the proposed CPC scheme enabled the wind farm to effectively participate in unit commitment and active power and frequency regulations of the grid [2, 3, 4]. The proposed system and control scheme provide a solution to help achieve high levels of penetration of wind power into electric power grids. Output power of wind turbine fluctuates constantly, which may cause grid frequency variations, and imposes a high risk on system stability. In order to smoothen power output of wind turbine, the proposed system was used. By using a supercapacitor-based energy storage, the effects of frequency fluctuation and deviation on system during fault condition were minimized. This was one of the early examples of using supercapacitors in wind turbine. However, our research deals with off-grid wind energy harvesting; therefore, Lian Qu’s model cannot be used. Moreover, our research aims to charge a DC battery, whereas Lian Qu worked with three-phase grid connection.
Battery and supercapacitors are used together to form a hybrid system. As discussed earlier, battery and supercapacitor have their own advantages and disadvantages. Supercapacitors have high-power density but low energy density, whereas batteries have low power density and high energy density. Besides, battery also has higher ESR which results in high internal loss, thus less efficient compared to supercapacitors. Therefore, both devices are often integrated so that they can complement each other. This system known as hybrid energy storage system (HESS), which is widely used now in order to prolong the lifespan of each device and improve stand-alone systems [5]. For example, Babazadeh et al. [6] implemented an HESS system into a PMSG wind turbine with a large variable wind speed between 6 and 21 m/s. The HESS system helps to smoothen and regulate the output caused by peaks generated due to variation in the wind speed by using a control system to disconnect the battery from wind turbine. This successfully proved that the battery life is able to last longer as the battery experiences lesser stress. The average urban driving patterns that require rapid discharging of battery banks when accelerating and charging of banks when decelerating will reduce the battery banks’ lifespan; thus, supercapacitors are beneficial in this case. Since supercapacitors are able to charge and discharge at a fast rate, it is able to provide a boost of power during acceleration and absorbs power during regenerative braking [7, 8].
One of the problems of establishing the hybrid storage system is the different voltage level of the supercapacitor and battery bank. The most common way of coupling the two storage devices is to connect them in parallel. Although this way of harvesting energy maintains the same voltage in both storage banks, yet it restricts the power delivered by the supercapacitor. The role of an electronic control unit in a ‘battery supercapacitor hybrid energy storage system’ under different load conditions with the aid of various sensors have been previously studied [9, 10]. Here, the DC/DC converter permits the supercapacitor to supply extra power required by the load. However, in low wind speed, it will not be possible for the turbine to charge a hybrid storage system where both the supercapacitors and battery are connected in parallel. Because at low wind speed the turbine rotates at a very low RPM resulting in a low output voltage at the generator terminal, which is not sufficient to charge the hybrid storage in parallel configuration.
Also areas with low wind do not require a system that includes a generator of mega watt range. Coming back to the energy harvesting circuit, this investigation discovers a novel hybrid circuit with a combination of a battery and supercapacitor bank. In 2010, Worthington proposed a novel circuit that combines the synchronous switched harvesting technique, which was connected to a load capacitor directly to harvest energy [11]. This allowed the capacitor to act as a reservoir that would be disconnected when fully charged and then would discharge to a load. The circuit was connected with a charge pump tire circuit [11]. Experiment results showed that this idea was capable of harvesting three times more the amount of energy compared to the usual bridge rectifier circuit. However, this idea has not yet been implemented into the off-grid wind energy sector. Although Lee [12] implemented a hybrid energy harvesting storage in 2008 for wind power application, it was meant for grid connection and again was of high power range. Hence, it was impossible for the energy storage system to be implemented for the off-grid system. This study brings the supercapacitor-based hybrid energy harvesting for first time into the off-grid low wind power application. A supercapacitor bank is used in this experiment that charges up from the turbine and discharges through the battery with the use of power electronics.
Batteries have relatively high energy density compared to supercapacitors; however, they do not have the characteristics of supercapacitors, that is, instantaneous charging and discharging [13, 14]. Even though batteries can store more energy, it requires longer time to discharge and recharge. Moreover, batteries require constant voltage for charging. If the current exceeds battery rating, it may get heated up and voltage fluctuation reduces life span of the battery. In order to give a constant voltage from the generator, a DC/DC converter has to be used. However, the internal voltage drops in DC/DC converter together with low voltage at generator output does not make a vertical axis wind turbine worthy of charging a battery in low wind speed. Therefore, this research proposes a balancing circuit which introduces the supercapacitor to act as a buffer between the turbine and a battery. The supercapacitor would get charged up from the turbine and discharge through the battery in two separate processes by using MOSFET control switching system. In this research, the proposed hybrid supercapacitor-based battery charging circuit has been implemented into a vertical axis wind turbine in low wind speed and compared with direct charging of battery from the turbine with or without a DC/DC converter. Finally, the proposed system has also been compared with current existing systems of rural Malaysia in terms of cost-effectiveness.
The novel idea we introduce in this research does not include the conventional DC/DC converter between turbine supercapacitor. Therefore, the converter voltage loss is removed. What had been done is, just after the supercapacitor gets fully charged by the turbine directly, the supercapacitor gets disconnected from the turbine by smart MOSFET switching using Arduino. Then, the fully charged supercapacitor gets connected with the battery by the MOSFET switch, which will charge the battery through a DC/DC converter by self-discharging and the process go on. In this method, voltage as small as 3–4 V can charge up a 6 V/12 V battery.
For harvesting energy from the wind, MagLEV VAWT with PMSG is used, and its specifications are as follows.
From Table 1, it can be seen that for low wind speed configuration, voltage ranges from 3.5 to 8 V. As the whole configuration is in low voltage, the battery choice we have is either 6 or 12 V. In low voltage settings, stepping up low input voltage as low as 3–12 V will result in stepping down current by even a smaller amount. Considering the facts stated, 6 V battery was chosen, which was to be charged by the turbine. Between the turbine and battery, a supercapacitor bank is placed which will be charged up by the turbine at first. Then subsequently it will be discharged through the battery. Since a constant voltage is needed for battery to be charged up properly, a DC/DC boost converter is needed between supercapacitor and the battery which will ensure constant stepped-up voltage to the battery when supercapacitor discharges. The field testing was done in the laboratory.
VAWT | Wind speed | 5 m/s |
Height | 60 cm | |
Radius | 14.5 cm | |
Number of blades | 9 | |
PMSG | Phase | 3-Phase |
Rated power | 200 W | |
Rated voltage | 12 V | |
Diameter | 16 cm | |
Weight | 12.5 kg | |
Open circuit voltage |
|
System configuration for energy harvesting circuit.
Figure 1 is the schematic diagram of the system architecture. As seen in Figure 1, few LED lights along with a 434 Ohm resistor were inserted as loads to discharge the battery.
Schematic diagram of system architecture of energy harvesting system.
Initially, supercapacitors are used to store the charges as a part of the hybrid energy harvesting. In this chapter, to construct a supercapacitor bank, four supercapacitors rated 35 F–2.7 V each by Cooper Bussmann are used, which were connected in series. Therefore, a supercapacitor bank rated 8.75 F–10.8 V is formed. Battery choice is a tough one as there are many variations and specifications. For example, for rechargeable or nonrechargeable, different types such as lithium-ion, lead-acid, nickel-metal hybrid, and so on exist, which ultimately lead to confusion. In the research laboratory, there were few good quality batteries but they were rejected due to cost effectiveness and maintenance issues. For instance, Li-ion batteries are omitted because it needs extra circuitry for protection even though it has high efficiency and life cycle. Therefore, considering all these facts lead-acid battery was chosen to be fit for the research for having the optimum characteristics. For this project, a three-cell lead-acid battery manufactured by Yokohama rated 6 V (3.2 AH/20HR) was chosen.
A DC/DC boost converter was used to give a constant voltage of 7.5 V to the 6 V battery as per the schematic diagram of the hardware architecture. As the setup environment is for small-scale and low voltage system, the “LT1303” micropower step-up high-efficiency DC/DC converter was selected. There is another version of LT1303, that is, LT13035, which has added features like it can supply output voltage up to 25 V and also it is adjustable.
To smartly control the charging and discharging of the supercapacitor bank and the battery, two N-channel MOSFETs were used as a switch, which are controlled by Arduino.
Transducers or also known as electrical sensors are a vital part of the system which constantly monitors the physical quantities of the system. The current and voltage transducers used in the system are as follows.
A rotary encoder was used to measure the rotational speed of the wind turbine. It was mounted at the base of the turbine. It senses the rotation of the turbine and sends the signal directly to LabView through data acquisition (DAQ). In this case, a simple binary system is used where and whenever the turbine blade cuts through the encoder that sends logic high or otherwise logic low. Counter was used in LabView where it counts the number of logic high sent by the encoder per minute.
To measure wind speed, an anemometer was used as shown in Figure 2. The device gives measurements in miles per hour (mph); therefore, conversion to m/s was required.
Anemometer.
To display power and most importantly the current flow through the load in real time, a ‘16 × 2 LCD’ was used as shown in Figure 3. LCD screen was controlled by Arduino.
LCD screen of energy harvesting circuit.
Switching circuit is the crucial part of this energy harvesting system. Arduino UNO microcontroller is used in this circuit where it controls two N-type MOSFETs namely P36NF06L. For testing, LED was placed in parallel to the gate-source pin of the MOSFET. The system will continue to charge and discharge until the battery reaches up to 6 V. In the stripboard of the energy harvesting circuit, MOSFETs are placed as shown in Figure 4. Aligned with the bias voltage, two LEDs are placed to indicate the status of the circuit. When the MOSFET is turned on, the LED will glow and vice versa.
MOSFET configurations in energy harvesting circuit.
The algorithm of the decision-making switching algorithm is illustrated in Figure 5. Here MOSFET 3 is usually turned off all the time. However, it is significant to declare that although the MOSFET does not have any role worthy of mention in the system, it is placed there if in case the battery has to be discharged manually. Therefore, unless stated otherwise, this MOSFET will be turned off all the time.
Flowchart of EHC control structure.
As it is seen in Figure 5, the control system has mainly two conditions. First one is the supercapacitor charging circuit which occurs when Vsupercap is less than 4 V. Under this condition, MOSFET 1 is turned on; thus, it will charge the supercapacitor bank. In the meantime, MOSFET 2 whose job is to charge the battery from supercapacitor is turned off. When Vsupercap is greater than or equal to 7.5 V, the second condition triggers which will turn off the MOSFET 1 and turn on MOSFET 2. Thus, overcharging does not occur from the wind turbine. In this time, the rechargeable battery will be charged up to rated voltage 6 V. When the supercapacitors’ voltage dropped to 4 V, MOSFET 1 was switched on again. The switching circuit coding in Arduino is given in Figure 6.
Arduino control coding.
The basic working principle of this part of the code is very simple. A signal “LOW” corresponding to 0 V was sent to the Arduino digital pin assigned to “MOSFET 1.” As soon as the voltage across the supercapacitor bank exceeded 7.5 V, MOSFET 1 was switched off to prevent overcharging. A signal “HIGH” which equals to 5 V was sent to Arduino digital pin “MOSFET 2” at the same time, and the rechargeable battery then was charged by the supercapacitor bank. Now, a signal “HIGH” was sent to one of the Arduino digital pins assigned “MOSFET 1” as soon as the voltage across supercapacitor bank was lesser than 4 V. A signal “LOW” equivalent to 0 V was sent to Arduino digital pin assigned to “MOSFET 2” at the same time. This charging and discharging of supercapacitor bank algorithm repeated simultaneously until battery was fully charged.
With NI-6212 device, data acquisition was implemented. A graphical user interface (GUI) was developed using LabVIEW. This GUI enables the user to easily monitor and analyze data. The LabVIEW interface is shown in Figure 7. This GUI displays supercapacitor and battery’s voltage, charging current of the supercapacitor, charging current of the battery when supercapacitor discharges and finally the rotational speed of the turbine. The data gathered here can also be easily exported to the spreadsheet software (Figure 8). Therefore, this enables the user to keep track of the system in real time of the system 9.
Developed GUI panel of Labview.
Data exported to excel spreadsheet from LabVIEW.
The energy harvesting circuit built and the experimental setup are shown in Figure 9. The field testing was done in the Research Building, Block N, University of Nottingham Malaysia Campus.
Experimental setup for the integrated system.
This section gives a performance analysis of a Supercap (supercapacitor)-based energy harvesting battery charging device operated by the Maglev VAWT adopted to a 200 W PMSG as per the configuration discussed previously which was sent for fabrication. Upon arrival of the turbine, the system was set up in the laboratory, and field testing was performed to tabulate the data.
This subchapter has two parts. First part includes one of the three cases in detail which has been compared for performance analysis. “Case A” showed a battery of 6 V, 3.2 AH, which was charged from 4.2 to 5 V through a DC/DC converter followed by a series of four supercapacitors (2.7 V, 35 F). “Case B” and “Case C” demonstrated the direct charging of the battery where “Case B” was experimented with the converter and “Case C” was without converter. All the three cases were experimented in low wind speed that ranges between 6 and 3 m/s. To keep it short, only results from wind speed 4 m/s will be discussed in detail. The remaining results have been given in a tabularized form to compare and find out the efficiency of the EHC.
The same procedure from the earlier section was followed, and results were graphically plotted for analysis. Following figures are the details of the charging process. It is noteworthy mentioning that both the Supercap discharge voltage and discharge current were the same as the previous value. This is because while Supercap bank discharged its charge to the battery, the turbine system was isolated through the MOSFET switch. Therefore, wind speed cannot make any impact on the discharging half cycle. Consequently, in all the three cases, the discharge voltage and current amount with respect to time were the same. Here, Figures 10 and 11 show the charging voltage and current graph with respect to time. For the discharging details, Section 4.5.1 may be reviewed as in both of the cases, the data will be the same.
“Supercap charging voltage” vs. “time” at wind speed 4 m/s.
“Supercap charging current” vs. “time” at wind speed 4 m/s.
At this point, 35 min were required to charge up the Supercap bank. Adding the discharging cycle time which was 2 min, the complete cycle duration was then 37 min. The starting current was 145 mA which took a rapid fall in the next second, bringing the current down to 22 mA. As for the inertia of the turbine, understandably, the charging current at first was very high but that could not be misinterpreted as the actual current. The real current started from 22 mA followed by a gradual decrease that ended up at 2.5 mA. Therefore, the pick current could be considered as 22 mA. Figure 12 displays the complete cycle process, which basically was the charging and discharging cycle of 37 min.
Supercap charging and discharging voltage with respect to time at wind speed 4 m/s.
Again 18 cycles were needed to charge up the Supercap bank from 4.8 to 5 V, but in this time, one cycle consisted of 37 min which in total made the system take 10.4 h of charging time. Figure 13 represents the battery voltage charging up to 5 V in 10.4 h.
Battery charging voltage with respect to time for 4 m/s wind speed.
According to Figure 14, it took 18.75 h to reach its maximum value of 4.54 V. After that the increase of the voltage was so less with respect to time, the value was not taken into consideration. Therefore, this charging system was incapable to charge up the device at 4 m/s.
Battery charging voltage with respect to time for 4 m/s wind speed (with converter).
“Case C” took 15 h to finish the task. Figure 15 shows the battery charging voltage with respect to time.
Battery charging voltage with respect to time for 4 m/s wind speed (without converter).
Table 2 recapitulates the result of this section in brief.
Supercap charging cycle: | |
Supercap discharging cycle: | 2 min |
Number of complete cycle: | 18 |
Maximum Supercap charging current: | 22 mA |
Maximum Supercap discharging current: | 18.5 mA |
Time duration: | 10.4 h |
Battery charging voltage (4.2–5 V) | Efficiency (%) | Reference point: |
Case A (Energy harvesting): | 31 | |
Case B (Charging with converter): | Incompetent |
Charging battery (from 4.2 to 5 V) through Supercap at 4 m/s wind speed.
Table 3 recapitulates the result of this section in brief.
Supercap charging cycle: | |
Supercap discharging cycle: | 1 min |
Number of complete cycle: | 25 |
Maximum Supercap charging current: | 18 mA |
Maximum Supercap discharging current: | 18.5 mA |
Time duration: | 38.4 h |
Battery charging voltage (4.2–5 V) | Efficiency (%) | Reference point: |
Case A (Energy harvesting): | 28 | |
Case B (Charging with converter): | Incompetent |
Charging battery (from 4.2 to 5 V) through Supercap at 3 m/s wind speed.
Table 4 recapitulates the result of this section in brief.
Supercap charging cycle: | 25 min |
Supercap discharging cycle: | 2 min |
Number of complete cycles: | 18 |
Maximum Supercap charging current: | 30 mA |
Maximum Supercap discharging current: | 18.5 mA |
Time duration: | 8.1 h |
Battery charging voltage (4.2–5 V) | Efficiency (%) | Reference point: |
Case A (Energy harvesting): | 19% | |
Case B (Charging with converter): | Incompetent |
Charging battery (from 4.2 to 5 V) through Supercap at 5 m/s wind speed.
As shown in Table 5, the energy harvesting circuit data show excellent values for all the results with very good performance overall. Change in the wind speed from 5 to 4 m/s produces better efficiency as it goes to 31% from 19%. For a low speed of 3 m/s, where direct charging displays a poor performance, the energy harvesting circuit, even though it took a long time of 38.4 h to charge up the battery, still maintains its productivity by producing 28% efficiency. Here, the highest amount of efficiency drawn from the system was 31%. Comparing to Worthington’s work of pulling off 300% more efficiency with hybrid energy harvesting, it is drastically low. However, his storage system was implemented to a pump tire circuit, whereas our circuit was designed for a low wind application. As an off-grid stand-alone low voltage energy harvesting system, the EHC was able to provide, noteworthy, better efficiency in all three low wind speeds.
Wind speed (m/s) | Battery charging via Supercap (h) | Direct battery charging time (h) | Efficiency (%) |
---|---|---|---|
5 | 8.1 | 10 | 19 |
4 | 10.4 | 15 | 31 |
3 | 38.4 | 53 | 28 |
Summary of energy harvesting circuit result for charging a 6 V lead acid battery from 4.2 to 5 V.
An important observation had been made in this experiment. At low wind speed, the turbine tends to slow down and stop if there is a heavy load. This is because a permanent magnet synchronous generator has an output frequency, which is proportional to its armature speed. The required torque to rotate the PMSG is proportional to the electrical load. Therefore, at low wind speed, with the increase of the electric load, there is always a tendency to slow down while the mechanical input coming from the VAWT restores it. However, if the load is too much to handle, the mechanical speed from the turbine becomes very slow and eventually the turbine stops.
The peak voltage of Supercap bank cycle = 10.8 V,
However, the boost converter cannot step up voltage less than 4 V. Therefore, usable energy in the supercapacitor bank is
Battery rating, 6 V, 3.2 AH which is equivalent to 19.2 Wh [A 6 V 1 AH can store 12 Wh].
Here, 19.2 Wh ~ (19.2 × 3600 J) ~ 69,120 J.
From one cycle of supercapacitor bank, battery can store energy up to 440 J.
Again, 440 J is stored into a 6 V 3.2 AH battery in one cycle.
Therefore, 69,120 J can be stored into a 6 V 3.2 AH battery in (69,120/440) or 157 cycles.
It takes 8.1 h to charge 1 V of the battery [from the previous result section]. Moreover, after 5 V, it takes 18.8 h to charge another 0.5 V.
The voltage drops in boost converter and MOSFET switch are the main reasons for difference in theoretical and experimental values.
The battery takes 15 h to charge 1 V from the turbine until 5 V. After 5 V, it takes 24.2 h to charge 0.5 V.
As a conclusion to this research, the achievements are reviewed in terms of research objectives. This consequently facilitates the system, and results are to be analyzed in terms of the percentage and degree of the research objectives that were achieved. Three cases had been compared for performance analysis. “Case A” showed a battery of 6 V, 3.2 AH, being charged from 4.2 to 5 V through a DC/DC converter followed by a series of four Supercaps. “Case B” and “Case C” demonstrated the direct charging of the battery, where “Case B” was experimented with the converter and “Case C” was without converter. Investigation was carried for 3, 4 and 5 m/s wind speed. “Case C” was taken as a reference. For a wind speed of 5 m/s, the result showed an increase of 19% of the charging time for Case A while charging through the Supercap. It took only 8.1 h whereas direct charging without converter took 10 h. Supercap-based charging was also found to be 133% more efficient than direct battery charging with a converter. Keeping in mind, direct charging might not be the appropriate way of charging a device since fluctuation of wind would result in damaging the battery. As far as wind speed of 4 m/s was concerned, the energy harvesting circuit, taking only 10.4 h to charge up the battery, again showed an excellent performance of 31% efficiency comparing with direct charging that took a straight 15 h lap. For 3 m/s, the energy harvesting circuit still held the top position handsomely with 28% efficiency in comparison with direct charging.
To recapitulate, this research provides an excellent novel idea of a stand-alone Maglev-based VAWT system connected to a PMSG that can harvest energy via Supercap-based battery charging circuit in low wind areas of rural areas. Research contribution is original, and it gives an outstanding foundation for future study in energy harvesting for low wind rural areas.
The entire research had not been absolutely smooth all throughout and naturally it faced few ups and downs.
The limitations of the developed system and technique are listed below:
Firstly, turbine blade design was not taken into consideration in the simulation. As there was no proper mathematical model that relates turbine blade number to output torque or power, the simulation therefore did not account for blade design although it could give better performance if blade number was included in the design. It was not possible to apply finite element analysis (FEA) on turbine blades due to lack of time. Moreover, the position of blade, cut-in angle and vibration analysis of the turbine could be done with FEA. Surely it could have given a wider research scope area on modeling, and blade material could have been brought into the optimization process for a better configuration.
Moreover, DC/DC boost converter used in this research did not perform well according to the data sheet in its minimum range. As it was stated in the data sheet, the converter can step up voltage from as low as 2.5 V, practically it could not step up voltage less than 4 V. Therefore, the Supercap charging range was made from 4 to 7.5 V, which should have been 3–7.5 V. This had a direct effect on system efficiency.
Conventional DC/DC boost converter is to be replaced with the efficient one, which is specifically designed to work with voltage as low as 2–3 V. This will help Supercap to discharge even more and will play a vital role while dealing with low wind. All these changes will improve the system and should make it capable of performing at 2 m/s. Since most of the electronic devices operate at 12 V, a second DC/DC converter may be placed to charge a 12 V battery from the current 6 V-led acid battery.
Laptop should be replaced with wireless system in the future. A real-time wireless monitoring interface could be made available. Embedded solutions providing wireless end point connectivity to devices like XBEE modules can be of use in cases like this.
LCH is a rare disease with a variety of presentations and outcomes. Indeed, for most of its history, it was thought to be several different entities until sufficient cases were described that made the spectrum of this disease clearer.
The descriptive approach in medicine in the early 20th century and the extremely heterogeneous clinical presentation of LCH led to the fact that different manifestations of the disease were described as separate syndromes. Thus, the history of the disease began with the description of the Hand-Schüller-Christian syndrome, [1, 2, 3], the Letterer-Siwe disease, [4, 5] and the eosinophilic granuloma [6].
In 1953, Dr. L. Lichtenstein in a critical review of the literature introduced a unifying concept, stating that the conditions previously designated eosinophilic granuloma of bone, Letterer-Siwe disease and Hand-Schüller-Christian disease, are interrelated manifestations of a single disease [7]. The name “histiocytosis X” was suggested to underscore the unknown origin of the disease.
In 1973, Dr. Christian Nezelof, a French pediatric pathologist, proposed the Langerhans cells as the origin of histiocytosis X [8]. His hypothesis was based on morphologic similarities (e.g. Birbeck granule, a cytoplasmic pentalaminar structure with a tennis racket shape) between normal Langerhans cells and the abnormal cells in histiocytosis X. Since then the disease is referred to as Langerhans cell histiocytosis.
The estimated incidence of LCH is 4–9 children younger than 15 years per million [9, 10, 11, 12]. The peak incidence of childhood LCH is between 0 and 4 years [13]. There is a relation between age at manifestation and disease extent, younger children have more disseminated disease [14]. All large epidemiologic studies report a male predominance in the range of 1.2–1.5 [9, 10, 11, 12]. The causes and risk factors for developing LCH are unclear [15]. However, the unique patterns of presentation, ranging from localized bone lesions with spontaneous regression to disseminated forms with involvement of multiple organs, suggest a complex pathogenesis. Familial clustering, particularly the observation of increased incidence in monozygotic twins, have suggested the presence of a germline predisposition at least for a proportion of cases [16, 17]. In addition, population-based studies have shown differences in the incidence of disseminated LCH by race and ethnic group; a higher incidence has been reported for Hispanics and a lower incidence for blacks [18]. Studies have also shown a correlation with maternal and neonatal infections, [15, 19, 20] lack of childhood vaccinations, [15, 20] family history of thyroid disease, [15] in vitro fertilization, [21] and feeding problems and transfusions during infancy [19]. Finally, lower socioeconomic conditions have been associated with an increased incidence of disseminated LCH [18].
The clinical presentations of LCH range from incidentally detected asymptomatic bone lesions to severe multisystem disease manifesting with disseminated rash, fever, failure to thrive, enlarged liver and spleen and transfusion-dependent cytopenia (Figure 1). The disease can present with insidious nonspecific manifestations such as fever, impaired appetite, anxiety, and sleep disturbances, particularly in infants. Virtually all organ systems can be affected either individually (single system LCH; SS-LCH) or in different combinations (multisystem LCH; MS-LCH). Hence, LCH can mimic a large spectrum of diseases (Table 1). Frequent, though unspecific manifestations are: bone pain, soft tissue swelling (“bumps”) in the head and neck area, persistent polymorphic skin eruptions, mucous membrane ulcerations, respiratory symptoms (cough, shortness of breath, chest pain), enlargement of the liver, spleen and lymph nodes, growth failure, polyuria with polydipsia or, rarely, neurological symptoms.
Spectrum of clinical manifestations. Bone lesions in the skull (A) with irregular punched out appearance, vertebra (B) with partial collapse of the vertebral body, and the tibia (C) with periosteal reaction and bone deformity; Cutaneous manifestations: purpuric rash with erythema and maceration of the inguinal folds resembling diaper dermatitis (D), characteristic confluent maculopapular rash with purpuric appearance and crusting on the trunk (E), and papulonodular reddish-brown rash in a newborn (F); Right-sided proptosis caused by a lesion of the orbital bones (G); Jawbone lesion presenting as a massive soft-tissue swelling (H) and the respective MRI findings (I); J - Thickening of the pituitary infundibulum, manifesting as central diabetes insipidus; Characteristic non-granulomatous lesions of the cerebellum (K) and the basal ganglia (L); Massive hepatosplenomegaly and skin rash in severe multisystem LCH (M); Pulmonary LCH with bullae visible on radiography (N) and combination of nodules and cysts on CT scan (O).
Affected organ | Manifestation/finding | Differentials |
---|---|---|
Skin | Vesicles and bullae (most common in early infancy) | Erythema toxicum Herpes simplex Varicella |
Dermatitis (most frequently scalp, diaper area, or axilla) Nodules (“blueberry muffin” like) Petechia Pruritic rash | Seborrheic dermatitis Mastocytosis Juvenile xanthogranuloma Neuroblastoma Infant leukemia Intrauterine infections Scabies | |
Bone | Vertebral lesions (vertebra plana) | Chronic relapsing multifocal osteomyelitis (CRMO) Leukemia/Lymphoma Aneurysmal bone cyst Erdheim-Chester disease Ewing sarcoma Osteosarcoma Metabolic bone diseases |
Temporal bone | Chronic otitis media Mastoiditis Cholesteatoma Soft tissue sarcoma | |
Orbit | Acute infection (preseptal cellulitis) Dermoid cyst Erdheim–Chester disease Pseudoinflammatory tumor Rhabdomyosarcoma Neuroblastoma | |
Lytic lesions of the long bones | Septic osteomyelitis CRMO Aneurysmal bone cyst Bone angiomatosis (Gorham disease) Fibrous dysplasia Giant cell tumor of bone Atypical mycobacterial infection Osteogenic sarcoma Ewing’s sarcoma | |
Lung | Respiratory symptoms, reticular lesions (nodules and cysts) | Mycobacterial or other pulmonary infections Sarcoidosis |
Liver | Hepatomegaly, jaundice with direct hyperbilirubinemia Hypoalbuminemia | Chronic destructive cholangitis Metabolic diseases Hepatitis Diseases obstructing biliary tract Inherited diseases of bilirubin conjugation Toxic (Reye syndrome) Neonatal hemochromatosis Chronic inflammatory bowel disease |
Endocrine glands (pituitary, thyroid) | Polyuria/polydipsia, growth failure, hypothyroidism, hypogonadism | Renal diabetes insipidus Head trauma Germ cell tumors of CNS Lymphatic hypophysitis Non-LCH histiocytoses |
Common differential diagnoses of LCH.
The organs mostly affected are bone (80%), skin (33%) and pituitary (25%). The hematopoietic system, spleen, liver and lungs are affected in up to 15%, lymph nodes in 5–10% and the central nervous system without the pituitary in 2–4% of the patients [22].
Flat bones and particularly the cranial bones are most commonly affected. Other common locations in decreasing order are the long bones of the extremities, the vertebral bodies and the pelvic bones. The proximal bones of the extremities are more frequently involved than the distal ones. The bones of the hands and feet are usually sparred. The lesions are characteristically located in the diaphysis or metaphysis, but the epiphysis can be affected as well.
Vertebral lesions typically localize in the vertebral body, vertebral arch, transverse or spinous process and present with pain, kyphoscoliosis, or neurological deficits due to compression of the spinal cord [23]. While vertebra plana in LCH are rare, LCH is the leading cause of vertebra plana in children.
Unilateral or bilateral lesions in the temporal bone range from unspecific opacification of the mastoid cells with minimal bone destruction, to extensive osseous destruction and intracranial soft tissue infiltration. The most common symptoms are recurrent or persistent otitis, mucopurulent otorrhea, swelling of the mastoid, and eczema or polyps of the ear canal. In rare cases of inner ear involvement, hearing loss, dizziness or paralysis of the facial nerve also occur.
Lesions of the orbital bones in LCH are mostly unilateral and have exclusively extraconal location, typically affecting the roof and the lateral wall [24]. They manifest with lid swelling (with or without inflammatory appearance), palpable mass, or proptosis. The differentials of orbital involvement include acute infections, inflammatory pseudotumor, hemangioma, rhabdomyosarcoma, retinoblastoma, metastatic neuroblastoma, lymphoma, and optic glioma. However, other histiocytic disorders, such as juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease can present with orbital involvement as well.
Jaw involvement can present with gingival hyperplasia or ulceration, extensive dissolution of the jawbone structure with tooth loosening (“floating teeth”) or loss.
Skin is the second most frequently involved organ system after the skeleton overall. In patients younger than two years, it is even the most frequently involved organ. Cutaneous involvement is typically representative of multisystem disease, as 87–93% also have systemic involvement. Cutaneous lesions may be either circumscribed (nodular) or spread and confluent (rash).
They typically present as pinpoint erythematous or skin-colored papules or pustules. The morphology can mimic a seborrheic dermatitis-like or an eczematous erythematous, skin-colored, or brown petechial rash with or without scale, scabbing, crusting, and/or purpura. In infants, a seborrheic dermatitis-like rash on the scalp often causes LCH to be misdiagnosed as seborrheic dermatitis, while groin involvement can mimic treatment-resistant, recurring diaper dermatitis [25].
Nail involvement is rare, but can present as subungual pustules, hemorrhage, or hyperkeratosis, purpuric striae, purulent discharge, longitudinal grooving, onycholysis, paronychia, and pitting [25].
Enlarged lymph nodes are rarely the only manifestation of a single system LCH. The lymphadenopathy encountered in the setting of multisystem disease is usually mild to moderate.
Peripheral blood cytopenia in LCH patients, often referred to as “hematologic dysfunction”, is a sign of severe disease and heralds unfavorable prognosis. For decades, the terms “hematopoietic dysfunction” and “bone marrow involvement” were interchangeably used in the literature [26]. Bone marrow studies in LCH patients using immunochemical staining for CD1a or molecular markers (BRAFV600E), have found increased proportion of histiocytes compared to controls, but their numbers did not correlate well with disease extent and severity [26, 27]. Strikingly, the phagocytosis in the bone marrow, which better correlates to disease severity, is carried out by CD1a-negative macrophages. Although the exact mechanisms leading to peripheral cytopenia remain uncovered, it is clear that it is not due to marrow infiltration in most cases, and is probably due to increased phagocytosis or inflammatory marrow suppression.
Enlargement of the spleen in LCH occurs exclusively in the setting of MS-LCH. It occurs in 15–30% of the patients mostly coinciding with hematopoietic and liver involvement.
Liver involvement occurs exclusively in children with MS-LCH. Patients may present with hepatomegaly only or with functional impairment (elevated liver enzymes, hypoproteinemia and hypoalbuminemia) and/or jaundice.
Two patterns of liver dysfunction can been seen in children: one with predominant hypoproteinemia/hypoalbuminemia ± mild elevation of transaminases and bilirubin; and a less common cholestatic one, due to progressive sclerosing cholangitis [28]. The former is usually combined with prominent constitutional symptoms, and is characteristically observed in the setting of active LCH, while the latter is usually seen as a disease consequence and often without concomitant activity of LCH elsewhere.
Isolated pulmonary LCH (also known as primary pulmonary LCH) is extremely rare in children, accounting for less than 1% of all pediatric LCH cases. However, pulmonary involvement in the setting of MS-LCH presents at diagnosis in about 25% of cases [29]. The most common clinical symptoms are tachypnea, cyanosis, chest pain and chronic or persistent cough. Characteristic imaging findings are symmetric bilateral reticulo-nodular opacities ± bullae on radiography and combination of nodules and cysts on CT. Histopathological verification of lung involvement in children with confirmed LCH is required only in case of uncharacteristic or inconsistent imaging findings. Symptom severity and time course can vary. In rare cases, excessive tissue destruction and cyst formation can result in (recurring) life-threatening pneumothorax. Honeycombing with end-stage lung disease is a rare permanent sequela of pediatric LCH.
Gastrointestinal involvement in LCH (GI-LCH) is infrequent, accounting for about 2–3% of the pediatric series. It usually occurs in the setting of a multisystem LCH, and depending of the affected gut segment, clinically presents with vomiting, abdominal pain, protein-losing enteropathy, bloody and non-bloody diarrhea, malabsorption, and failure to thrive. The prognostic value of gut involvement remains controversial but currently published paper suggests unfavorable impact on survival [30].
Involvement of the hypothalamic–pituitary axis and the resulting central diabetes insipidus (CDI) and dysfunction of the anterior pituitary are a hallmark of LCH. Characteristic findings on MRI are hypothalamic mass, infundibular thickening, and lacking posterior bright spot. CDI manifests with polyuria and polydipsia, and can be the inaugural manifestation of LCH or develop later during disease course. Its prevalence in children with multisystem LCH is between 20 and 35%. Loss of the hormones of the anterior pituitary is less common than CDI. In order of decreasing frequency, pituitary LCH can cause growth hormone (growth failure), thyroid-stimulating hormone (hypothyroidism), adrenocorticotropic hormone (hypocortisolism), luteinizing and follicle-stimulating hormone (hypogonadism) loss. Thyroid involvement is rare, with only 75 cases reported in the literature [25]. It can manifest with gland enlargement due to diffuse or nodular lesions, but the function is mostly preserved.
Thymus involvement is a rare event with estimated frequency of 1–2% and mostly seen in young children with MS-LCH [31]. Typical imaging findings are enlargement of the gland, cysts and calcifications. Sonography allows for a reliable non-invasive evaluation of the thymus [31].
LCH can affect brain in different ways and result in a variety of manifestations and clinical problems. With respect to risk factors, clinical presentation, imaging findings and the classification of CNS-LCH, the interested readers are referred to two dedicated review papers [32, 33]. For the purposes of clinical management LCH of the brain is divided into granulomatous (tumorous) and non-granulomatous (neurodegenerative) CNS-LCH.
Granulomatous (tumorous) lesions of the CNS are defined as space-occupying lesions involving brain structures. Any of the following brain regions may be involved either by isolated lesions or in the context of multisystem disease: hypothalamic–pituitary region (HPR), pineal gland, meninges or choroid plexus [32, 33].
Non-granulomatous (neurodegenerative) lesions encompass two subtypes [32, 33]:
Radiological neurodegeneration or LCH-associated abnormal CNS imaging (LACI). This term refers to typical signal changes on two consecutive MRI scans performed within an interval of at least 3 months without related clinical manifestations.
Clinical neurodegeneration or LCH-associated abnormal CNS symptoms (LACS). This clinical syndrome is defined as the presence of overt neurological or neuropsychological deficits in the context of consistent radiological findings.
The broad spectrum of clinical manifestations and the variability of disease course and outcome makes prediction of prognosis quite challenging. Attempts to split the disease into categories with distinct prognosis led to elaboration of a number of staging and scoring systems [34, 35, 36, 37]. Established prognostic factors in pediatric LCH are disease extent (SS-LCH vs. MC-LCH), involvement of organs crucial for survival (risk organs, e.g. hematopoiesis, liver, spleen) and early response to systemic treatment [38].
SS-LCH has an excellent prognosis, with a survival rate of nearly 100% and a 5-year recurrence rate of less than 20% [39]. Relapses are usually limited to skeleton and posterior pituitary (diabetes insipidus) and therefore do not affect survival [39, 40].
MS-LCH is a broad category encompassing patients with involvement of two to more than seven organ systems. In 1975, E. Lahey introduced the definition of organ dysfunction [41]. Lahey’s definition has been in use for treatment stratification for many decades, and in the 1990s, it was replaced by the definition of “risk organ involvement” [34, 35, 37, 42].
Response to an initial 6-week course of systemic therapy has proved to be an additional independent prognostic factor [37, 43, 44, 45]. Risk organ involvement at diagnosis and lack of response to 6-weeks of systemic treatment define a subgroup of MS-LCH patients with survival of only 20–40% [46].
The French LCH Working Group has developed a disease activity score, which is suitable, for longitudinal objective assessment of disease burden and treatment success [47].
The experience from institutional cohorts, registries and clinical trials has unequivocally proven that treatment of LCH has to be tailored to disease extent and severity and to take into account mortality risk. For this purpose, standardized clinical evaluation of each patient at initial diagnosis and relapse is mandatory [22, 48, 49]. The mandatory set of laboratory tests and imaging is presented in Table 2. Further investigations to be performed upon specific indications are listed in Table 3. Based on the results of the initial evaluation the patients are attributed to one of the disease extent categories of the clinical classification of LCH (Table 4). The empirical clinical classification of LCH was developed for the purposes of treatment stratification. The definitions of risk organ involvement are summarized in Table 5.
Test | Description |
---|---|
Blood counts |
|
Erythrocyte sedimentation rate | |
Blood chemistry |
|
Coagulation studies |
|
Urinalysis |
|
Imaging: | |
Abdominal ultrasound | Size and structure of liver and spleen? |
Chest radiography | Reticulo-nodular opacifications, bullae? |
Skeletal survey (radiography, PET/CT, whole-body MRI*) | * Marrow signal alterations detected by MRI need confirmation. Only bone lesions confirmed by x-ray, CT, PET/CT, or biopsy count for stratification. |
Mandatory baseline evaluation upon initial diagnosis, progression or relapse.
Indication | Test |
---|---|
Risk organ involvement |
|
Bi- or pancytopenia, or persistent unexplained single cytopenia |
|
Liver dysfunction |
|
Lung involvement (abnormal radiography or symptoms/signs suggestive for lung involvement) |
|
Abnormal lung CT AND findings not characteristic for LCH or suspicion for atypical infection* |
|
Suspected craniofacial bone lesions including maxilla (mandible excluded) |
|
Suspected vertebral lesions |
|
Visual or neurological abnormalities |
|
Suspected endocrine abnormality (i.e. short stature, growth failure, polyuria, polydipsia, hypothalamic syndromes, precocious or delayed puberty) and/or imaging abnormality of hypothalamus/ pituitary |
|
Aural discharge or suspected hearing impairment/mastoid involvement |
|
Unexplained chronic diarrhea, failure to thrive or evidence of malabsorption |
|
Laboratory investigations and imaging recommended upon specific indications.
In case of verified LCH in other organs, biopsy is indicated ONLY if the pulmonary findings on CT are inconsistent with LCH or atypical infection is suspected.
Disease category | Definition |
---|---|
Single system LCH (SS-LCH) | One organ/system involved (uni- or multifocal):
|
Multisystem LCH (MS-LCH) | Two or more organs/systems involved:
|
Clinical classification of LCH.
Risk organ | Involvement criteria |
---|---|
Hematopoiesis (with or without bone marrow infiltration*) | At least 2 of the following:
|
Spleen |
|
Liver |
|
Definition of risk organ involvement.
Bone marrow infiltration is defined as presence of CD1a positive cells on marrow slides. The clinical significance of marrow CD1a positivity is still unclear. In cases of severe progressive disease, prominent hemophagocytosis, as well as hypocellularity, myelodysplasia or myelofibrosis may be found.
Enlargement in cm below the costal margin as assessed by palpation or sonography.
Patients with single skeletal lesions usually do not need systemic treatment, except for large symptomatic lesions or lesions in weight-bearing bones, which are not easily accessible for surgical treatment. Treatment of isolated cutaneous LCH is controversial, but if topical treatments fail, systemic treatment needs consideration in infants.
Multifocal skeletal disease and MS-LCH indicate systemic treatment.
Randomized prospective trials for the treatment of localized LCH are not available. Therefore, current treatment recommendations for localized LCH based on experience gained from retrospective cohorts and non-randomized controlled trials [39, 50].
According to existing clinical experience, the majority of patients with localized LCH (mostly confined to skeleton) do not need systemic treatment. Established treatment options range from expectant attitude, through surgery or topical drug application, to systemic therapy in selected cases. Decisive for the treatment choice in unifocal skeletal LCH is the location (weight-bearing bones or imminent compression of adjacent structures), the size, the surgical accessibility, the presence of considerable adjacent soft-tissue mass, pain or functional impairment, and the risk of permanent consequences.
A best practice based treatment approach to SS-LCH is depicted on Figure 2.
Treatment approach to single system LCH.
A “wait and see” approach is justified in small asymptomatic osseous or cutaneous lesions in view of the high likelihood for spontaneous healing.
Surgical procedures such as biopsy, curettage, or resection are used to treat solitary bone lesions, solitary affected lymph nodes, or solitary circumscribed nodular skin lesions. A biopsy is necessary to confirm the diagnosis and at the same time represents a healing stimulus. Clinical experience showed that radical surgery is not necessary and usually not useful in localized LCH [22, 51]. Wide surgical resection is particularly harmful in skull vault, jawbone lesions, as it impedes bone remodeling, and causes permanent defects, which are unlikely in non-resected lesions.
An intralesional application of crystalline methylprednisolone (100-150 mg) in symptomatic bone lesion can quickly bring about a reduction in symptoms and facilitated cure [52, 53].
Because of its potential to induce secondary malignancies, radiotherapy at a low dose (6–10 Gy) is nowadays limited to specific indications (for example, imminent compression of vital structures (e.g. the spinal cord or the optic nerve).
In case of large, symptomatic lesions, which are not easily accessible and bear high likelihood for pathologic fractures and permanent consequences, mild systemic treatment of short duration (3–6 months) using the same regimen as in disseminated LCH, may be the preferable option for local disease control.
Multifocal skeletal and multisystem LCH (earlier unified under the term disseminated LCH) have been traditionally considered an indication for systemic treatment. While there is a general agreement on the indication of systemic therapy for patients with MS-LCH, the value of systemic therapy for multifocal skeletal SS-LCH is less well documented and still needs evaluation in controlled prospective trials [46, 50, 54, 55]. A number of individual drugs, drug combinations and regimens have been tested in LCH since the 1960s. Most trials before the era of international cooperation have pooled patients with varying clinical presentation, course, and prognosis to gain meaningful numbers [56]. Methodological weaknesses and inappropriate sample size lead to contradicting results, and most of the early trials are of historic importance only.
The current standard of care foots on evidence of the consecutive clinical trials of the Histiocyte Society [42, 44, 57]. The cumulative evidence of the empirical trials LCH I-III can be summarized as follows:
The standard front-line therapy for patients with MS-LCH treated outside of controlled clinical trials should consist of a 6–12 weeks of initial therapy (oral steroids and weekly vinblastine injections), followed by pulses of prednisolone/vinblastine every 3 weeks, for a total treatment duration of 12 months.
Patients with risk organ involvement (particularly those with bi-, pancytopenia and liver dysfunction), who do not respond to 6 weeks of standard treatment have particularly dismal prognosis (survival less than 50%). This small subgroup categorized as “very high risk” deserves treatment intensification. To date only few options have shown promising results in the treatment of severe progressive LCH in small series and pilot trials [58, 59, 60, 61, 62, 63]. Their applicability is limited by either high toxicity (cladribine + cytarabine), limited availability of matched donors (hematopoietic stem cell transplantation), or the high relapse rate (MAPK inhibitors when used as single drugs).
A standard of care for patients who fail front-line therapy (suboptimal response, disease progression or relapse) but the disease is not life-threatening (low risk LCH), remains to be established. Controlled prospective trials with appropriate endpoints (prevention of subsequent relapses and permanent consequences, as well as, improvement of quality of life) are still lacking.
The same is true for some specific or rare clinical scenarios, i.e. isolated destructive pulmonary LCH, sclerosing cholangitis, LCH reactivation presenting with isolated diabetes insipidus, CNS-LCH of neurodegenerative type.
A currently ongoing international trial of the Histiocyte Society (LCH-IV International Collaborative Treatment Protocol for Children and Adolescents with Langerhans Cell Histiocytosis; NCT02205762) with a complex design (5 interventional and 2 observational strata) is looking for improvement of relapse-free survival and quality of life by targeting still unsolved clinical issues [56, 64].
The combination of prednisolone plus vinblastine is the most extensively studied first-line therapy in pediatric-onset LCH [42, 57, 65, 66, 67, 68]. The major advantages are its extensively documented activity, its favorable toxicity profile and good tolerability in children, and its moderate costs, which make this treatment applicable even in countries with limited health-care resources [56]. In ‘high-risk’ patients of the LCH-III trial, the prednisolone plus vinblastine combination has induced response in risk organs in 70% of the patients after 6–12 weeks of treatment, and resulted in an overall 5-year survival of 84%, and a reactivation-free survival of 73% [57].
This regimen is the current standard frontline therapy for pediatric patients with multifocal and multisystem LCH treated outside of clinical trials (Figure 3A and B). It consists of 6–12 weeks of initial therapy (oral steroids and weekly vinblastine injections), followed by a continuation therapy given to total treatment duration of 12 months. The continuation therapy consists of prednisolone (day 1–5)/vinblastine (day 1) pulses given every 3 weeks.
Standard treatment of disseminated LCH.
The role of systemic treatment and the most appropriate drugs and regimens for patients with non-risk LCH who fail frontline therapy, is less clear. In the majority of those cases, LCH is confined to skeleton, skin and pituitary, and does not influence survival [40, 69, 70]. Similarly, most relapses of LCH are confined to non-risk organs and are not life-threatening. Relapses of LCH, however, are associated with an increased risk of permanent consequences [40, 69, 70]. The belief that control of the disease will prevent subsequent relapses and, thus, related permanent consequences, prompts physicians to use systemic chemotherapy for ‘low-risk’ multisystem LCH.
Temporary disease control in patients with low-risk disease, particularly in those, who have a relapse after complete disease resolution, is achievable both by repetition of the front-line regimen, or by application of a number of other single drugs or drug combinations [40, 50, 64, 69, 70, 71]. Remarkably, none of the available options can prevent further relapses and permanent consequences in all patients. Therefore, second-line treatment of non-risk LCH should be preferably offered within controlled trials. Future trials seeking effective treatment for ‘low-risk’ LCH should focus on appropriate end-points such as quality of life, risk for and severity of permanent consequences, instead on control of active lesions or remission rates [38]. Such trials are only possible within the frame of a large-scale cooperation and require implementation of innovative study designs and appropriate statistical methods.
For treatment outside of clinical trials, the following drugs and regimens seem to be reasonable choices, based on existing evidence for activity in LCH or experience from the clinical practice, as well as, justifiable toxicity:
Patients with relapse months or years after stopping prednisone and vinblastine can benefit from re-induction of the first-line regimen [39].
An alternative treatment regimen employs vincristine, prednisone, and cytosine arabinoside [72]. This regimen, modified for prednisolone duration, is being prospectively tested in the LCH-IV trial.
Cytosine-arabinoside 100 mg/m2/das for 5 days every 28 days has been used with success both in patients with extracranial non-risk LCH and in CNS-LCH [51, 73].
2-Cholorodeoxyadenosine (2-CdA, Cladribine®, Leustatin®) at 5 mg/m2/day for 5 days per course has also been shown to be effective therapy for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH) with acceptable toxicity [71]. Use of 2-CdA should be limited to a maximum of six cycles to avoid cumulative toxicity and potentially long-lasting or irreversible cytopenias.
Clofarabine is a proven effective therapy for patients with multiple relapses of low-risk or high-risk organs [51, 62]. In LCH, it is usually applied at a dose of 25 mg/m2/day for 5 days every 28 days for six cycles. Depending on hematopoietic toxicity or the need for longer treatment, (further) cycles at the same daily dose, but reduced to 3 days can be given.
Bisphosphonate therapy has reported effects in treating recurrent skeletal LCH [74, 75, 76, 77]. The regimen most commonly used in children consist of six doses of pamidronate at 1 mg/kg, given at 4-week intervals. Other bisphosphonates, such as zoledronate and oral alendronate, have also been successful in treating skeletal LCH in adults.
The choice of an individual drug or regimen requires consideration of comorbidities, previous treatments, cumulative toxicities and known individual intolerances and side effects. The decision remains on discretion of the treating physician, as the level of published evidence is not sufficient for a clear recommendation of a particular regimen or for a ranked list of preference.
Two prospective trials have confirmed the curative potential of the combination of 2-CdA and Ara-C in patients with severe refractory to front-line systemic therapy MS-LCH [58, 59]. Unfortunately, this regimen is highly myelotoxic and associated with treatment-related mortality even if applied in experienced centers [59].
Allogeneic hematopoietic stem cell transplantation is another treatment option for very high-risk multisystem LCH with curative rate comparable to those achieved with the combination of 2-CdA and Ara-C [63, 78]. However, the most optimal conditioning regimen remains to be defined [78].
The mitogen-activated protein kinase (MAPK) signalling pathway plays a key role in the regulation of gene expression, cellular growth and survival. A number of activating mutations affecting this pathway result in overactive downstream extracellular-signal-regulated kinase (ERK), which proves to be the ultimate driving event in LCH. Both specific inhibition of the mutated RAF and MEK kinases, as well as, downstream ERK inhibition (Figure 4) are undoubtedly appealing treatment options [49, 60, 61, 79].
MAPK pathway and relevant inhibition options.
The clinical experience available to date confirmed at least two essential expectations to BRAF inhibitors, namely in vivo activity and rapid clinical effect [80, 81, 82, 83]. In patients with severe life-threatening LCH rapid clinical response is of particular importance. Currently published pediatric series show impressive rapid response to vemurafenib and prove that BRAF inhibitors can induce remission in patients with the most severe form of the disease [60, 61, 84, 85]. The clinical remission is sustainable as far as the treatment is given. However, most patients experience disease relapse shortly after treatment discontinuation. Hence, it is currently unclear whether treatment with a single inhibitor can eradicate the disease.
The European experience with vemurafenib in children with severe MS-LCH has shown that a daily dose of 20 mg/kg (2 x 10 mg/kg) is both well tolerated and clinically effective [60].
The major tasks to be addressed in controlled prospective trials are therefore: finding the most effective and least toxic specific inhibitors, establishing downstream inhibition for patients without known mutations, defining appropriate pediatric dosages, and establishing optimal treatment duration and drug combination for a definitive cure.
Treatment of the disease form referred to as a “non-granulomatous” or “neurodegenerative” CNS-LCH remains frustrating. The two currently recommended treatment options, monthly cytarabine pulses and/or monthly intravenous immunoglobulins have limited effect on disease course, mostly slowing down the process and achieving some improvement in anecdotal cases [33, 86, 87, 88]. A pilot study testing retinoic acid could achieve stabilization of the neurologic manifestations only [89].
A recently published paper has shed light on the underlying mechanism of the neurodegenerative CNS-LCH with possible therapeutic implications [90]. The authors could reproduce “neurodegenerative” LCH in a mouse model, by introducing the BRAFV600E mutation in the early erythro-myeloid progenitors, which give rise to the microglia. Moreover, in that model the neurodegeneration was preventable by BRAF inhibition. Human data are still limited and indicate that treatment with MAPK inhibitors can be effective if started in advance of irreversible brain damage [61, 91].
Apart of organ transplantation, effective treatments are still not available for the most severe disease-related complications of LCH, such as sclerosing cholangitis, and end-stage lung disease (honeycombing).
The current standard of care for pediatric onset LCH has been developed through laborious empirical trials over four decades. Future optimization of the treatment approach to MS-LCH and development of targeted drugs should be guided by biology insights. In the absence of this knowledge, the clinical needs have to be met by optimization of available treatments. The ongoing LCH –IV trial (ClinicalTrials.gov Identifier: NCT02205762) is designed to address the still remaining problems and unmet patient needs [46, 50]. The most urgent need is eliminating mortality (15–20%) among patients with risk MS-LCH. A two-step stratification based on risk organ involvement at diagnosis and lack of response to standard initial treatment (e.g. at week 6) allows for an early identification of patients who are at risk to die [50]. The combination of 2-CdA and Ara-C has proved to be curative, albeit too toxic. On the other hand, BRAF inhibitors provide rapid control of organ dysfunction, but alone are obviously unable to eradicate the mutated clone. A combination of the empiric and the targeted treatment options may be able to achieve ultimate cure, as this has been the case in other malignancies (e.g. Ph + acute lymphoblastic leukemia).
With all regimens used to date high relapse rates remain another unsolved problem in MS-LCH. Historical controls and preliminary data of the LCH-III trial have shown that treatment duration of 12 months significantly reduces relapse rates compared to 6 months of treatment [46, 57]. The question whether further prolongation of the total treatment duration will result in further reduction of the relapse risk is under investigation in the ongoing LCH-IV trial. A “2x2” factorial design will allow for additional evaluation of the role of oral 6-MP in the continuation treatment of MS-LCH.
There is an urgent need to address optimal treatment of some special disease presentations (i.e. new-onset central diabetes insipidus and non-granulomatous CNS-LCH. The potential of BRAF and MEK inhibitors is still insufficiently explored for these particular indications, but a mouse model delivers a rationale and awakes expectations [90].
Whatever new drugs and regimens appear appropriate testing in LCH, the design of the future prospective studies has to take into account the extreme clinical diversity and unpredictable natural course of MS-LCH, in order to avoid wrong conclusions and therapeutic strays [50, 56].
The authors are indebted to the medical student Martina Minkov for her assistance in the preparation of the figures.
Sigmund Freud University, Vienna, Austria provided financial support for the publication fees.
The authors declare no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
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\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
\\n\\nFrede Blaabjerg 2015-18
\\n\\nGang Chen 2016-18
\\n\\nJunhong Chen 2017, 2018
\\n\\nZhigang Chen 2016, 2018
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\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
\\n"}]'},components:[{type:"htmlEditorComponent",content:'New for 2018 (alphabetically by surname).
\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
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\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPrevious years (alphabetically by surname)
\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). 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In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. 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It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment"},{id:"5",title:"Parasitic Infectious Diseases",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:287,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRqB9QAK/Profile_Picture_1626163237970",institutionString:null,institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/274426",hash:"",query:{},params:{id:"274426"},fullPath:"/profiles/274426",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()