**1. Introduction**

Malaria is one of the oldest parasitic tropical diseases, and it takes a huge toll on human lives. It also causes great economic loss. Almost half of the population in the world is under the threat of malaria mostly in the tropical and sub-tropical countries. About 90% of the total malaria burden occurs in sub-Saharan African countries. Efforts to eradicate/or eliminate malaria began after the discovery of the role of mosquitoes in malaria transmission by Ronald Ross in 1897. In the beginning of the 20th century, most of the mosquito control operations were aimed at larval control using larvicidal oil, larvivorous fish and environmental management. These efforts made significant impacts on malaria control. Everything changed with the introduction of dichloro diphenyl trichloroethane (DDT) in the mid-1940s. Many European countries and the USA successfully eradicated malaria with the application of DDT and vector sanitation strategies, and improving general living standard [1].

Malaria eradication program in India haves had mixed success. After successful results from pilot studies on DDT, the National Malaria Eradication Program (NMEP) was launched in 1958 from the National Malaria Control Program (NMCP) in 1953. There was a huge success that resulted in almost complete malaria eradication in

the mid-1960s with 0.1 million cases and no deaths. A kind of complacency led to a slow rise in malaria cases, and a total of 6.4 million cases were reported in 1976. This was due to the development of resistance to DDT by vector species, especially by *Anopheles culicifacies* s.l. and chloroquine resistance by *P. falciparum* malaria [2].

A Modified Plan of Operation (MPO) was launched aiming to treat each fever case suspected to be malarial infection with a presumptive dose of anti-malarial drug especially chloroquine. This provided some respite but the malaria cases remained at a static level with occasional regional outbreaks. In 1995, a revised guideline named Modified Action Plan (MAP) gave some lead which renamed as National Malaria Eradication Program (NMEP) in 1999. Subsequently this program was more disease centric and named as National Vector Borne Disease Control Program (NVBDCP) in 2002 [3].

In 2017, 0.84 million malaria cases with 174 related deaths were reported from India, while WHO estimated 9.6 million cases with 16,723 malaria-related deaths. This may be due to different methods of case estimation. From this state of current situation in India, malaria elimination has been envisaged with an aim to achieve it by 2030 [1, 4].

### **2. Malaria elimination initiatives**

The global malaria elimination framework was launched in 2007, and a detailed Global Technical Strategy (GTS) was released in May 2015 aiming to eliminate malaria by 2030. The three recommendations to achieve this goal strongly emphasize strengthening of smart surveillance; prompt diagnosis and treatment; and enhance elimination process. The GTS thus focuses on 35 countries in which to eliminate malaria by 2030, and India is one of them [4].

India is one of the countries that have signed the National Framework for Malaria Elimination (NFME). The WHO estimated 219 million malaria cases with 435,000 related deaths in the world in 2017. This was higher than the previous years. The WHO Director-General has called an aggressive new approach `High Burden to High Impact' [1]. Of the 11 high malaria burden countries 10 are from Africa, but India is also under this category. Nearly half of the global malaria occurred in Nigeria (25%), the Democratic Republic of the Congo (11%), Mozambique (5%) and 4% each by India and Uganda. This means India needs a special attention. The NFME has been designed to ease the burden in most high burden Indian states especially Odisha, Madhya Pradesh, Chhattisgarh and Jharkhand. The major attention should be on strengthening the surveillance which is still poor in many states [1, 3].

### **3. Strengthening of ongoing surveillance**

Surveillance is the main pillar in the malaria elimination process. In most situations, ongoing surveillance is not consistent with the national guidelines resulting in poor estimates of malaria burden. This needs to be converted into smart surveillance. In the digital era, all surveillance systems should follow the concept of the 'test–treat–track' strategy [5]. Android-based mobile apps can be applied for quick dispensation of surveillance data from the field to the local administrator for immediate action. This system at district-level management is implemented in many African countries. In this way, the time lag between diagnosis and treatment can be minimized [6]. Tracking the patient for completion and follow-up of the treatment has wider effects on the local cycle of malaria [1]. WHO has developed surveillance and data analysis dashboards

**39**

*New Ways to Tackle Malaria*

*DOI: http://dx.doi.org/10.5772/intechopen.89467*

using district health information software 2 (DHIS 2) [4]. Such digital-based data

Strategy to change in surveillance is also an important step to accelerate the malaria elimination process. China adopted the '1-3-7' strategy that promoted the elimination process with zero indigenous malaria cases in 2017. This strategy envisions the strategic action from diagnosis to treatment within 3 days and public health responses to vector management within day 7 of the case detection. This also makes an easy platform for establishment of personal communication in the community [7]. Indonesia also adopted the '1-2-5' strategy for surveillance and response protocol in malaria elimination; on day 1 case management and notification; on day 2 case classification and foci investigation; and by day 5 foci response and elimination [8]. In southwestern coastal Mangaluru city, Karnataka state, India, malaria has been endemic over two decades. The local authority has implemented indigenously developed digital handheld tablets (TABs) for smart surveillance. These TABs have been allotted to each health worker after proper training. Now no manual data collection is used in the city. The link of the software was also provided to the local hospitals and diagnostic labs. The data can be accessed to the local administrators for taking action on the feedback received. Here the '1-3-7-14' strategy has been adopted where positive case is registered with start of treatment on day 1; completion of treatment by day 3; on day 7 vector control activities with follow-up smear check, and on day 14 follow-up smear check and completion of radical treatment for *P. vivax* cases with primaquine. In this way, the initial response of the antimalarial drugs can be assessed. The best part of this system is that all the data can be retrieved, and the program can be monitored at all levels, assessing the opening and closing of each case. This system creates a great scope of community awareness through person-to-person communication [9]. In the dashboard of this system, algorithms of specific data can be incorporated for possible prediction of malaria outbreaks. Thus, the concept of 'predict–perform–protect' can be established using

A recent study in Bangladesh has found that the movement of people can be tracked from the mobile phone network which can help prediction of outbreaks of diseases such as malaria. This enables the health authorities to take preventive

Malaria microscopy is still the best method and gold standard for malaria diagnosis. A microscopist normally examines 60 blood smears per day. This includes staining and data maintaining. Now expert microscopist can detect 20 to 50 parasites/μl blood that means a 0.001 to 0.005% level of parasitemia. This is not the cases with regular microscopists where the sensitivity is low. Routine in-house training on the line of continued medical education program can improve the

Recent deployment of Rapid Detection Tests (RDTs) have changed the malaria

diagnosis at large, but it has failed to detect when the level is <100 parasites/ μl blood. This has become a nagging problem in detecting very low numbers of infected red blood cells and sub-microscopic parasites especially gametocytes in *P. falciparum* cases. This necessitated an alternate system of diagnosis. An indigenously developed handheld real-time micro-PCR based PDA (personal digital assistant) device that can detect parasites as low as 1.3/μl blood has been used successfully. This is a point-of-care device that performs tests onsite within 40 minutes. About 80 cases can be performed per day. The result of the cases can be shared

systems will make the surveillance system smart and efficient.

artificial intelligence (AI) and machine learning.

**4. Quick, efficient and point-of-care diagnosis**

measures in time [10].

efficiency of the microscopists [11].

#### *New Ways to Tackle Malaria DOI: http://dx.doi.org/10.5772/intechopen.89467*

*Vector-Borne Diseases - Recent Developments in Epidemiology and Control*

Program (NVBDCP) in 2002 [3].

**2. Malaria elimination initiatives**

is still poor in many states [1, 3].

**3. Strengthening of ongoing surveillance**

eliminate malaria by 2030, and India is one of them [4].

by 2030 [1, 4].

the mid-1960s with 0.1 million cases and no deaths. A kind of complacency led to a slow rise in malaria cases, and a total of 6.4 million cases were reported in 1976. This was due to the development of resistance to DDT by vector species, especially by *Anopheles culicifacies* s.l. and chloroquine resistance by *P. falciparum* malaria [2]. A Modified Plan of Operation (MPO) was launched aiming to treat each fever case suspected to be malarial infection with a presumptive dose of anti-malarial drug especially chloroquine. This provided some respite but the malaria cases remained at a static level with occasional regional outbreaks. In 1995, a revised guideline named Modified Action Plan (MAP) gave some lead which renamed as National Malaria Eradication Program (NMEP) in 1999. Subsequently this program was more disease centric and named as National Vector Borne Disease Control

In 2017, 0.84 million malaria cases with 174 related deaths were reported from India, while WHO estimated 9.6 million cases with 16,723 malaria-related deaths. This may be due to different methods of case estimation. From this state of current situation in India, malaria elimination has been envisaged with an aim to achieve it

The global malaria elimination framework was launched in 2007, and a detailed

Global Technical Strategy (GTS) was released in May 2015 aiming to eliminate malaria by 2030. The three recommendations to achieve this goal strongly emphasize strengthening of smart surveillance; prompt diagnosis and treatment; and enhance elimination process. The GTS thus focuses on 35 countries in which to

India is one of the countries that have signed the National Framework for Malaria Elimination (NFME). The WHO estimated 219 million malaria cases with 435,000 related deaths in the world in 2017. This was higher than the previous years. The WHO Director-General has called an aggressive new approach `High Burden to High Impact' [1]. Of the 11 high malaria burden countries 10 are from Africa, but India is also under this category. Nearly half of the global malaria occurred in Nigeria (25%), the Democratic Republic of the Congo (11%), Mozambique (5%) and 4% each by India and Uganda. This means India needs a special attention. The NFME has been designed to ease the burden in most high burden Indian states especially Odisha, Madhya Pradesh, Chhattisgarh and Jharkhand. The major attention should be on strengthening the surveillance which

Surveillance is the main pillar in the malaria elimination process. In most situations, ongoing surveillance is not consistent with the national guidelines resulting in poor estimates of malaria burden. This needs to be converted into smart surveillance. In the digital era, all surveillance systems should follow the concept of the 'test–treat–track' strategy [5]. Android-based mobile apps can be applied for quick dispensation of surveillance data from the field to the local administrator for immediate action. This system at district-level management is implemented in many African countries. In this way, the time lag between diagnosis and treatment can be minimized [6]. Tracking the patient for completion and follow-up of the treatment has wider effects on the local cycle of malaria [1]. WHO has developed surveillance and data analysis dashboards

**38**

using district health information software 2 (DHIS 2) [4]. Such digital-based data systems will make the surveillance system smart and efficient.

Strategy to change in surveillance is also an important step to accelerate the malaria elimination process. China adopted the '1-3-7' strategy that promoted the elimination process with zero indigenous malaria cases in 2017. This strategy envisions the strategic action from diagnosis to treatment within 3 days and public health responses to vector management within day 7 of the case detection. This also makes an easy platform for establishment of personal communication in the community [7]. Indonesia also adopted the '1-2-5' strategy for surveillance and response protocol in malaria elimination; on day 1 case management and notification; on day 2 case classification and foci investigation; and by day 5 foci response and elimination [8].

In southwestern coastal Mangaluru city, Karnataka state, India, malaria has been endemic over two decades. The local authority has implemented indigenously developed digital handheld tablets (TABs) for smart surveillance. These TABs have been allotted to each health worker after proper training. Now no manual data collection is used in the city. The link of the software was also provided to the local hospitals and diagnostic labs. The data can be accessed to the local administrators for taking action on the feedback received. Here the '1-3-7-14' strategy has been adopted where positive case is registered with start of treatment on day 1; completion of treatment by day 3; on day 7 vector control activities with follow-up smear check, and on day 14 follow-up smear check and completion of radical treatment for *P. vivax* cases with primaquine. In this way, the initial response of the antimalarial drugs can be assessed. The best part of this system is that all the data can be retrieved, and the program can be monitored at all levels, assessing the opening and closing of each case. This system creates a great scope of community awareness through person-to-person communication [9]. In the dashboard of this system, algorithms of specific data can be incorporated for possible prediction of malaria outbreaks. Thus, the concept of 'predict–perform–protect' can be established using artificial intelligence (AI) and machine learning.

A recent study in Bangladesh has found that the movement of people can be tracked from the mobile phone network which can help prediction of outbreaks of diseases such as malaria. This enables the health authorities to take preventive measures in time [10].

## **4. Quick, efficient and point-of-care diagnosis**

Malaria microscopy is still the best method and gold standard for malaria diagnosis. A microscopist normally examines 60 blood smears per day. This includes staining and data maintaining. Now expert microscopist can detect 20 to 50 parasites/μl blood that means a 0.001 to 0.005% level of parasitemia. This is not the cases with regular microscopists where the sensitivity is low. Routine in-house training on the line of continued medical education program can improve the efficiency of the microscopists [11].

Recent deployment of Rapid Detection Tests (RDTs) have changed the malaria diagnosis at large, but it has failed to detect when the level is <100 parasites/ μl blood. This has become a nagging problem in detecting very low numbers of infected red blood cells and sub-microscopic parasites especially gametocytes in *P. falciparum* cases. This necessitated an alternate system of diagnosis. An indigenously developed handheld real-time micro-PCR based PDA (personal digital assistant) device that can detect parasites as low as 1.3/μl blood has been used successfully. This is a point-of-care device that performs tests onsite within 40 minutes. About 80 cases can be performed per day. The result of the cases can be shared through an internet system. Thus, case management becomes more efficient and effective [12]. Recently, a genome mining based identical multi-repeat sequences (IMRS) qPCR assay has been developed for diagnosis of malaria infection. This diagnostic method can detect very low level of parasitemia that cannot be detected by the routine 18S rRNA-based diagnostic system [13].

#### **5. Tackling sub-microscopic and asymptomatic cases**

In recent years, asymptomatic and sub-microscopic cases are reported from many endemic countries. In fact, these two aspects are non-synonymous. Submicroscopic malaria cases present very low levels of parasitemia which generally missed in the routine microscopic examinations. Such cases may be symptomatic, and in most situations, these are asymptomatic cases. It has also been observed that in most high endemic areas asymptomatic cases with detectable levels of parasites do not show symptoms. This is because of a high immune status of the individual patients. It is suggested that such cases may be monitored under hospital supervision and clinical algorithms can be drawn to know more specific symptoms. Possibly such patients may show some kind of symptoms and may be on alternate days which are indicative of chronic malaria cases. Differential diagnosis of such cases becomes very difficult since they normally do not show any routine symptoms. However, experience clinicians can diagnose and successfully treat them with scheduled anti-malarials.

On the other hand, asymptomatic cases do not show presentable routine symptoms. Once proper diagnosis is confirmed treatment becomes very easy. In our experience, patients having malaria-like symptoms who could not be diagnosed with routine tests even with RDTs, had been treated for other diseases, mostly with antibiotics, but also with anti-tubercular therapy (ATT) for a long time even months. It has been observed that most antibiotics with quinoline molecules and ATT with rifampicin have anti-malarial properties. But these therapies cannot completely eliminate malarial parasites rather reduces the cure rate [14]. Such cases show sub-microscopic level of parasites. Normally these parasites do not show normal morphological features under microscopy. Only expert microscopists can identify such drug-affected parasites. In such cases, it may deem necessary first to stop all medicines and wait for the fever or fever-like symptoms to appear, then treat them with effective anti-malarials after expert microscopy. All these exercises should be done under medical supervision. The post response and relief from agony of such patients are remarkable.

Generally an important question is raised by most public health experts whether asymptomatic cases may cause potential risk of source of malaria transmission in endemic areas. In most endemic areas with high *P. falciparum* cases, residual load of gametocytes remain active in the blood circulation for a considerable period even after successful treatment, either with artemisinin-based combination therapy (ACT) or radical treatment with primaquine [1]. This can be solved with a simple *ex vivo* tests for detecting the presence of exflagellation. If this happens, it will indicate the potency of the gametocytes. This can be further extended to artificial membrane or direct feeding on patients (after obtaining human ethical approval) to *Anopheles stephensi* which will be kept at temperature of 28°C and 70–75% relative humidity (RH) in a controlled chamber for 7–8 days. Gut dissection on day 7 postfeeding will confirm the presence of oocysts. The presence of oocysts will indicate the potential threat of such gametocytes and their role in active transmission. It would be better to know the male and female gametocyte ratio before the experiment is performed. Generally 1 male to 3–5 female gametocytes sex ratio is found

**41**

*New Ways to Tackle Malaria*

*DOI: http://dx.doi.org/10.5772/intechopen.89467*

**6. Treatment of malaria cases**

tance in most malaria-endemic settings.

**7. Change in vector control strategy**

**6.1 Primaquine and tefenoquine for radical treatment**

in *P. falciparum* [15]. Post-treatment gametocytemia is commonly detected by a quantitative nucleic acid sequence-based amplification (QT-NASBA) method [16]. It is better to kill all the fed mosquitoes on day 8 post-feeding so that there will be no threat of accidental release of infected mosquitoes for possible malaria infections.

Chloroquine the cheapest anti-malarial drug is no longer prescribed for the treatment of *P. falciparum* malaria cases. Even monotherapy with artemisinin is also not recommended. Currently different ACTs are prescribed for treatment of *P. falciparum* malaria including some *P. vivax* cases. The partner drugs are sulfadoxine-pyrimethamine, piperaquine, lumefantrine, pyrrolidine, etc. In India, chloroquine is still efficacious against *P. vivax* even in the presence of *Pvcrt-0* and *Pvmdr-1* mutations [17]. On the other hand, the presence of *kelch 13* (*k13*) mutations in *P. falciparum* is linked to artemisinin resistance. Recent report from eastern India indicated the presence of two mutations G625R and R539T in 5/72 *P. falciparum* cases treated with artemisinin that linked to its presence of resistance [18]. In Africa, where *P. falciparum* is predominant there is no sign of artemisinin resistance even with more than 200 non-synonymous *k13* mutations recorded. A recent report suggested that artemisinin resistance in a patient can be addressed by changing the partner drugs which is responding to the local parasites [19]. Such combination should be selected for *P. falciparum* treatment. Several studies indicated the absence of S769 N mutation in *Pf*ATPase6 gene responsible for artemisinin resistance [20]. Possibly this marker would be the better one for monitoring of artemisinin resis-

Primaquine – an 8-aminoquinoline is used for radical cure. In case of *P. vivax* 15 mg per day for 14 days and for *P. falciparum* a single dose of 45 mg is administered for eliminating hypnozoites for the former and gametocytes for the later, respectively. Recently tefenoquine, another 8-aminoquioline, has been recommended. But both of these drugs may cause possible hemolysis in G6PD-deficient patients [21]. Attempts are being made to find newer molecules to address this issue. In this regard, Medicines for Malaria Venture (MMV) is playing a primary role [22].

There are 465 *Anopheles* mosquitoes in the world, of which many members have sibling species complexes. Approximately 70 of them are capable for human malaria transmission [23]. Application of public health insecticides is the main strategy for vector control. DDT is the main insecticide and is partially responsible for most malaria elimination in Europe and Americas along with general improvement of living standards, and an effective detection and treatment program. Other countries missed out this opportunity to achieve this feat. Prolongation of its use lead to the development of resistance in the mid-1970s and also recorded the highest number of malaria cases. Other insecticides namely malathion (organophosphorous) and subsequently synthetic pyrethroids (deltamethrin, alphacypermethrin, lambdacyhalothrin, cyfluthrin, etc.) are used in the program. In some endemic areas, triple resistance has been recorded against the main rural vector *An. culicifacies*. Currently long lasting insecticidal nets (LLINs) impregnated with synthetic

*Vector-Borne Diseases - Recent Developments in Epidemiology and Control*

by the routine 18S rRNA-based diagnostic system [13].

scheduled anti-malarials.

of such patients are remarkable.

**5. Tackling sub-microscopic and asymptomatic cases**

through an internet system. Thus, case management becomes more efficient and effective [12]. Recently, a genome mining based identical multi-repeat sequences (IMRS) qPCR assay has been developed for diagnosis of malaria infection. This diagnostic method can detect very low level of parasitemia that cannot be detected

In recent years, asymptomatic and sub-microscopic cases are reported from many endemic countries. In fact, these two aspects are non-synonymous. Submicroscopic malaria cases present very low levels of parasitemia which generally missed in the routine microscopic examinations. Such cases may be symptomatic, and in most situations, these are asymptomatic cases. It has also been observed that in most high endemic areas asymptomatic cases with detectable levels of parasites do not show symptoms. This is because of a high immune status of the individual patients. It is suggested that such cases may be monitored under hospital supervision and clinical algorithms can be drawn to know more specific symptoms. Possibly such patients may show some kind of symptoms and may be on alternate days which are indicative of chronic malaria cases. Differential diagnosis of such cases becomes very difficult since they normally do not show any routine symptoms. However, experience clinicians can diagnose and successfully treat them with

On the other hand, asymptomatic cases do not show presentable routine symptoms. Once proper diagnosis is confirmed treatment becomes very easy. In our experience, patients having malaria-like symptoms who could not be diagnosed with routine tests even with RDTs, had been treated for other diseases, mostly with antibiotics, but also with anti-tubercular therapy (ATT) for a long time even months. It has been observed that most antibiotics with quinoline molecules and ATT with rifampicin have anti-malarial properties. But these therapies cannot completely eliminate malarial parasites rather reduces the cure rate [14]. Such cases show sub-microscopic level of parasites. Normally these parasites do not show normal morphological features under microscopy. Only expert microscopists can identify such drug-affected parasites. In such cases, it may deem necessary first to stop all medicines and wait for the fever or fever-like symptoms to appear, then treat them with effective anti-malarials after expert microscopy. All these exercises should be done under medical supervision. The post response and relief from agony

Generally an important question is raised by most public health experts whether asymptomatic cases may cause potential risk of source of malaria transmission in endemic areas. In most endemic areas with high *P. falciparum* cases, residual load of gametocytes remain active in the blood circulation for a considerable period even after successful treatment, either with artemisinin-based combination therapy (ACT) or radical treatment with primaquine [1]. This can be solved with a simple *ex vivo* tests for detecting the presence of exflagellation. If this happens, it will indicate the potency of the gametocytes. This can be further extended to artificial membrane or direct feeding on patients (after obtaining human ethical approval) to *Anopheles stephensi* which will be kept at temperature of 28°C and 70–75% relative humidity (RH) in a controlled chamber for 7–8 days. Gut dissection on day 7 postfeeding will confirm the presence of oocysts. The presence of oocysts will indicate the potential threat of such gametocytes and their role in active transmission. It would be better to know the male and female gametocyte ratio before the experiment is performed. Generally 1 male to 3–5 female gametocytes sex ratio is found

**40**

in *P. falciparum* [15]. Post-treatment gametocytemia is commonly detected by a quantitative nucleic acid sequence-based amplification (QT-NASBA) method [16]. It is better to kill all the fed mosquitoes on day 8 post-feeding so that there will be no threat of accidental release of infected mosquitoes for possible malaria infections.
