Fifty years after the eradication of Malaria in Italy. The long pathway toward this great goal and the current health risks of imported malaria

ABSTRACT

Fifty years ago, Italy was declared a malaria-free country by the World Health Organization (WHO). In remembering this important anniversary, the authors of this paper describe the long journey that led to this goal. In the century following the unification of Italy, malaria was one of the main public health problems. At the end of the 19th century, malaria cases amounted to 2 million, with 15,000–20,000 deaths per year. This manuscript examines the state of public and social health in Italy from the end of the 19th century to the beginning of the 20th century, with particular regard to the government’s measures for the prevention, prophylaxis and treatment of malaria. The authors describe the main findings of Italian malariologists during the period under review, from the identification of Plasmodium as a malaria pathogen and the recognition of the Anopheles mosquito as its vector. They also make some considerations regarding the current situation and the importation of malaria by travelers and migrants from countries where the disease is still endemic.

Introduction and some considerations on the current situation

Malaria is an infectious disease caused by a parasitic protozoon called Plasmodium spp, which lives and reproduces, in different phases, in human blood and in various species of mosquitoes belonging to the genus Anopheles [1]. Known and described since antiquity, malaria takes its name from the belief, which was widely held until the late 19th century, that the disease was caused by foul emanations (mal’aria meaning ‘bad air’) from swampsFigure 1–5.

Figure 1.

Imported malaria cases reported in 1976–1989

Source: Italian National Institute of Health.

Figure 2.

Malaria cases in Italy in the period 2013–2017

Source: Italian National Institute of Health.

Figure 3.

Deaths from malaria in Italy between 1887 and 1899

Figure 4.

Deaths from malaria in Italy between 1900 and 1920

Figure 5.

Deaths from malaria in Italy between 1900 and 1920 (× 1,000,000 inhabitants)

In 1880, however, the etiological agent of the disease was discovered by the French army doctor Charles Louis Alphonse Laveran, who first identified the parasite in the blood of a patient in Constantine, Algeria [2]. Characterized by intermittent, putrid, malignant fevers, ‘mal’aria’ has constituted a major social and health problem since ancient times [3,4].

Fifty years ago, in 1970, Italy was officially declared malaria-free by the World Health Organization (WHO). Today, many high- and middle-income countries are free from the disease. Nevertheless, it must be remembered that, according to the data published in the 2020 World Malaria Report, an estimated 229 million cases of malaria still occurred worldwide in 2019, compared with 251 million in 2010 and 228 million in 2018 [5]. Most of these cases occurred in the WHO African Region (215 million: 94% of cases), followed by the WHO South-East Asia Region (about 6.3 million) and the WHO Eastern Mediterranean Region (about 5 million) [5,6].

Despite the appreciable decline revealed by these figures, the death toll remains unacceptably high. Indeed, malaria is estimated to have caused more than 409,000 deaths worldwide in 2019, compared with 405,000 in 2018, and 585,000 in 2010 [5]. Children under 5 years of age are the most vulnerable subjects, accounting for 67% of all malaria deaths worldwide in 2019 [5].

The epidemiology of malaria in endemic countries, combined with population movements and international travel, also explains the proportion of cases of imported malaria in European countries, where malaria has been eradicated since the 1970s [7], which constitutes a threat to individual and public health. Soon after the eradication of malaria in Europe, 2,812 cases of imported malaria per year were detected in Europe (1971–1975), becoming 6762 a year in 1986–1987. In Italy, cases of imported malaria rose from 102 in 1976 to 479 in 1989 [8–10].

The latest data provided by the Italian surveillance system, and national case records of imported malaria between 2013 and 2017, indicate the need to include malaria in national plans for the surveillance of vector-borne diseases [11].

The analysis of provisional 2013–2017 data showed 3,805 imported cases (677–888/year), 17% of which among Italians, while the most significant group was represented by settled immigrants. Twelve cases were autochthonous, 4 induced and 8 cryptic, with a peak of 7 cases that occurred in summer 2017 creating a great concern for public health. [12]

Indeed, in Italy, as in other European countries, society is undergoing changes (increased international travel, climatic and environmental change, migratory flows), though these have been drastically reduced by the COVID-19 pandemic. In order to cope with these changes, the utmost attention must be paid to the continuous surveillance of both competent vectors and cases of imported malaria.

Mosquitoes of the genus Anopheles, which are potential vectors of malaria, particularly those belonging to the maculipennis complex, continue to be present in Italy [13]. Specifically, Anopheles labranchiae, which was historically the principal vector of Plasmodium in Italy, is still widespread in coastal areas of the central-southern regions and islands.

In Italy, malaria is a notifiable disease, and the Ministry of Health and the Italian National Institute of Health are responsible for maintaining a national surveillance system that carries out annual assessments of the epidemiological situation of imported cases and which enables intervention to be promptly undertaken in the case of suspected autochthonous events [14]. Moreover, preventing the reestablishment of malaria in all countries declared disease-free is among the goals of the Global Technical Strategy (GTS) for Malaria 2016–2030 [15].

In addition, the current COVID-19 pandemic is a health emergency that must all the more prompt the international community to support all the efforts necessary to prevent, detect and treat malaria. Indeed, ‘during the COVID-19 pandemic, the malaria community must remain committed to supporting the prevention of malaria infection, illness and death through preventive and case-management services, while maintaining a safe environment for patients, clients and staff. Deaths due to malaria and its comorbidities (anemia, undernutrition, etc.) must continue to be prevented’ [16].

These recommendations are even more important when we think of the extraordinary commitment that Italy had to make in order to be defined a malaria-free country in 1970 [17]. This result, however, was achieved only after a long struggle involving the implementation of numerous social and public health measures, beginning in the second half of the 19th century [18].

In the fight against malaria, the most striking achievements were the result of the initiatives undertaken between the 1930s and the 1950s: swampland was reclaimed; in 1944–1945, an efficacious insecticide derived from arsenic (dubbed “Paris Green”) [19] was sprayed from airplanes; and from 1946 to 1947, vast malarial zones were treated with DDT (dichloro-diphenyl-trichloroethane) [20,21]. Nevertheless, we should also remember the progress made through the State quinine campaigns at the beginning of the century. In this period, Italy had not long been unified, malaria was endemic and the first legislation, in the early 1900s, was passed in the wake of the discovery of Plasmodium and the advances in malariology.

Malaria: the ‘Italian national disease’

In 1882, the senator Luigi Torelli, who presided over a specific Commission of the Senate of the Kingdom, wrote in his report accompanying the Map of Malaria in Italy: ‘Italy, with its 28 million inhabitants, is physically ill; it is ill with malaria’ [22]. In the northern regions of the country, excluding the coastal areas of Veneto, a mild form of the disease prevailed, while in the southern regions and the islands, an extremely severe form raged. The Kingdom’s first public health statistics, published in 1887, revealed that malaria was endemic in about one-third of the national territory, with a mortality rate of 710 per million inhabitants [21]. The total number of cases was estimated to be about 2 million, on a total population of about 30 million, while annual deaths exceeded 20,000, mostly among children [23].

In a speech in Parliament prior to the passage of Law 460 of 1901 (the law on malaria control) [24], a Deputy, Raffaele Perla, described the trend in mortality at the end of the 19th century: ‘In 1887, deaths due to malarial fever and palustral cachexia numbered 21,033; in the following years, up to 1896 (except for 1891, when the number rose to 18,229), mortality due to the above-mentioned causes oscillated between 15,000 and 14,000; in the last two years, it has declined markedly, reaching 11,947 in 1897 and 11,378 in 1898’ [25]. These figures indicate that malaria was one of the most serious public health problems in Italy at the time.

The discovery of the parasite and of the relationship between cause and clinical picture

In this very worrying public health context, it was hoped that aid might come from the important scientific discoveries of the time.

The belief that emanations from swamps caused intermittent fevers persisted until the middle of the 19th century. However, back in 1717, Giovanni Maria Lancisi, in his work De noxiis paludum effluviis eorumque remediis, had already attributed the cause of malaria to palustral exhalations, which he regarded as living beings (effluvia animata), and to mosquitoes [26]. Indeed, he hypothesized that these harmful emanations were inoculated into humans by mosquitoes, a conviction which prompted him to study blood under the microscope in a search for ‘worms or winged insects’.

However, it was not until 1880, that the French doctor Alphonse Laveran managed to detect the protozoon responsible for malaria in the blood of individuals affected by the disease, a discovery which earned him the Nobel Prize for medicine in 1907.

In 1885, a few years after Laveran’s discovery, Camillo Golgi demonstrated the association between the periodicity of malarial fevers and the life-cycle of the parasite that caused the disease; he discerned the link between the onset of the fever and the division (which he called ‘segmentation’) of plasmodia [27]. Indeed, tertian and quartan fevers are caused by two distinct species of Plasmodium: Plasmodium vivax, responsible for benign tertian malaria, which causes febrile attacks every 3 days, and Plasmodium malariae, responsible for quartan malaria, which is characterized by febrile attacks occurring every 4 days.

Subsequently, in 1889 in Rome, a group of researchers, among whom Ettore Marchiafava, Angelo Celli and Pietro Canalis, demonstrated the existence of Plasmodium falciparum, the species responsible for pernicious tertian malaria, or summer–autumn fevers, which caused thousands of deaths in the Lazio Region and in Southern Italy and the islands [28,29].

In 1894, Patrick Manson, who is regarded as the founder of tropical medicine, hypothesized that mosquitoes played a fundamental role in transmitting malaria, and asked his colleague Ronald Ross to examine this hypothesis. Thus, in 1897–1898, while Ross was in India, he ascertained that an avian Plasmodium was transmitted by mosquitoes. He was, however, unable to demonstrate that malaria was transmitted by the bite of the mosquito, nor to establish that only one genus of mosquitoes, Anopheles, could act as a vector of the human malarial parasite. ‘These two fundamental facts were demonstrated experimentally in 1898, during work with a patient at S. Spirito Hospital in Sassia, by Amico Bignami, Giuseppe Bastianelli and Giovanni Battista Grassi, who also described, in humans and mosquitoes, the developmental cycle of the three species of malarial parasites present in Italy’ [23]. Grassi’s fundamental contribution stemmed from his ample biogeographical studies; by mapping all the species of mosquito in Italy’s malarial and non-malarial areas, he was able to correlate the presence of malaria with a specific genius of mosquito. In 1898–1899, he identified the Anopheles mosquito as the sole vector of malaria [21].

In his volume Studi di uno zoologo sulla malaria, published in 1900 by the R. Accademia dei Lincei, Grassi summarized all the procedures and conclusions of his years of study of the Anopheles mosquito and Plasmodium.

The question gave rise to lively controversy between Grassi and Ross, who was awarded the 1902 Nobel Prize for medicine ‘for his work on malaria’ [30,31]. Indeed, Ross had shown how malaria entered the organism, thereby laying the foundations for fruitful research into this disease and the methods for combating it, as stated by the committee of the Karolinska Institutet in Stockholm on assigning the Nobel prize. The dispute was also echoed by Italian scholars, who split into two opposing camps, and was exacerbated with regard to the strategies that should be adopted in the fight against malaria.

Consequently, two distinct schools of thought emerged:

- on one side stood those who focused exclusively on treating the disease with quinine and on the prophylactic use of this drug, according to the indications provided by the bacteriologist Robert Koch;

- on the other, malariologists who especially advocated taking action against the vector of the disease and sanitizing the territory [23].

Initially, the former approach prevailed, given the firm conviction that the first step in the struggle against malaria should be to treat the sick. Very soon, however, owing to the various difficulties encountered in administering the drug, it was realized that quinine treatment would have to be supported by ‘mechanical prophylaxis’, as proposed by Giovanni Battista Grassi and Angelo Celli. The indications of these two scientists brought the question of mechanical barriers (mosquito nets) into legislation on malaria prevention. In the early decades of the 20th century, governments of various political colors returned to the issue several times, beginning with Law 460 of 2 November 1901, which provided financial incentives up to 1000 lire for those who installed mechanical barriers against mosquitoes in their homes. Unfortunately, however, as the implementation of such prophylaxis was mainly delegated to landowners, it was frequently disregarded.

However, a dispute arose between these two researchers as to who had first demonstrated and practiced mechanical prophylaxis; this culminated in the ‘question of the efficacy of the quinine preparations produced by the State in comparison with a private industrial preparation: Esanofele, produced by the company Felice Bisleri & C.’ [23].

While Celli advocated implementation of the Law of 23 December 1900, which established that the State should produce and distribute various quinine-based formulation – and a fundamental role in this was played by the State Quinine Factory in Turin – Grassi was conducting experimentation on Esanofele in Ostia in 1901. Essentially, Esanofele was the ‘Baccelli mixture’ that this Roman clinician had invented in 1869 to treat chronic malaria; it was composed of ‘quinine sulphate, ferric potassium tartrate, pure arsenous acid and distilled water’ in fixed proportions [23].

Italian antimalarial legislation

Leaving aside these polemics, it was precisely the presence of doctors and scientists in the Chamber of Deputies that led Parliament to pass some laws in the first few years of the 20th century. Drawn up mainly by the malariologist Angelo Celli, these helped to change the destiny of so many regions afflicted by the disease [23]. Law 505 of 1900, dubbed the ‘State Quinine Law’ [32], authorized the Minister of Finance to purchase quinine directly from the producers and to sell it to the public at a controlled low price. However, quinine therapy was not proposed only to treat malaria, but also as a means of preventing the disease. Indeed, in an address to the Senate, Carlo Bizzozero asserted that, ‘Now, quinine is no longer only a means of treatment; it is also a highly efficacious means of preventing the disease’ [33].

On the initiative of Angelo Celli and Giustino Fortunato, Law 460 of 1901 was then passed, which imposed obligatory prophylaxis for those workers who were most exposed to malaria [24]. Article 3 of the law established, in a highly innovative manner, that malaria contracted in the workplace was to be considered, from the juridical standpoint, to be on a par with injury in the workplace. Public works contractors were therefore obliged to distribute quinine free of charge to their workers.

A further step forward was taken in 1902, with the passage of Law 224, which established that quinine was to be distributed free of charge to malaria sufferers who were poor. This provision was subsequently underscored by Law 209 of 1904, article 2 of which stated that this was applicable, “For the entire duration of preventive therapy and treatment of malarial infection” to tenant-farmers and workers “engaged permanently or temporarily in any work with fixed or piece-rate remuneration” [34]. The norms contained in these laws were subsequently reiterated, in systematic order, in Subsection IV of Section V of the Consolidated Text of health laws, approved by Royal Decree on 1 August 1907, which extended the range of action to a framework of social intervention [35].

In the meantime, while Celli, with the support of some Members of Parliament and of the Italian Society for the Study of Malaria, was managing to focus the efforts of the government on the distribution of quinine for both the prophylaxis and treatment of malaria, Grassi was increasingly being contested and sidelined, so much so that he abandoned his studies on malaria.

However, despite the passage of an important set of norms, the scientific community was not united in recognizing the efficacy of quinine prophylaxis, and on several occasions political discussion was shifted to the issues of land reclamation and the large agricultural estates of Southern Italy. Thus, the problem of malaria had not only public health implications but also economic and social repercussions. Under the pressure of these opposing positions, in addition to the above-mentioned disputes among the scientists, Italian malariology formally split in 1909. The Italian Society for the Study of Malaria, which had been founded in 1898, was joined by the National League Against Malaria, which operated in Milan under the presidency of Golgi and with the endorsement of Baccelli and Grassi [23].

At the same time, in 1909 the Badaloni Report was presented to the Superior Council of Health; the report constituted a veritable attack on Celli’s theories concerning quinine, casting doubt on its ability to reduce malaria mortality and on the alleged harmlessness of its prophylactic administration. Nevertheless, the Badaloni Commission itself did acknowledge that ‘everywhere, the treatment of malaria patients has progressed to a degree that is incomparable with the past […] and current legislation has implemented good social prophylaxis, as it has provided the means of treating malaria patients’ [36]. The conclusions of the Badaloni Report reveal the difficulties of the young Italian nation and its public health structures in tackling the problem of malaria, which manifested itself as the Italian national disease [37].

The fight against malaria

Over the period of time examined, appreciable results were clearly achieved in terms of the reduction in mortality due to malaria – a slow and steady reduction consolidated by the first laws to be passed on this issue, and interrupted only during wartime.

Indeed, while 20,000 deaths occurred in 1887 (710 per million inhabitants), the number declined to 15,865 (490 per million inhabitants) in 1900, and fell still further to 2045 (57 per million) in 1914 [25]. This reduction in the mortality rate can largely be ascribed to the widespread use of quinine, for the purposes of both prevention and treatment. In 1887, the malaria mortality rate was higher in Central Italy (Maremma in the Tuscany Region, Agro Romano), in the South and the islands, with malignant tertian malaria (falciparum malaria) accounting for 20–30% of cases [21].

The North was affected almost exclusively by benign tertian and quartan malaria (vivax and malariae malaria, respectively). In Europe, malaria was particularly present in countries of the Mediterranean basin and Eastern regions, including European Russia [18].

As mentioned above, the use of quinine was one of the main means of malaria control in Italy. The dosages of this drug varied; in general, adults took 0.40 g/day, corresponding to two tablets, while in children the dose was halved. At the time, dosages of quinine ranging from 0.20 to 0.60 g/day were considered sufficient to kill and/or to arrest the development of the schizonts.

It should, however, be borne in mind that it was very difficult to assess the real impact of quinine treatment, as the population, which was often poor and ignorant, did not look favorably upon this treatment. Indeed, it was popularly believed that quinine caused miscarriages in pregnant women, that it was contraindicated in persons with mental problems, and that it should not be administered for a long time in children.

Moreover, the diffidence of country folk toward any new product was compounded by the fact that the distribution of quinine was often intermittent and handled by third persons; consequently, doctors were rarely able to supervise administration of the drug. We can therefore suppose that, while large amounts of quinine were distributed, much of it was not actually taken, except in more controlled settings, such as military barracks and among railway workers and other State workers [38]. In addition, members of the general public almost always took quinine only when they had febrile attacks.

In order to tackle the problems connected with the cultural context of most of the population that was afflicted by malaria, some hygienists proposed that educational interventions be implemented in order to promote the quinine campaigns, or even simply the use of mosquito nets: one of these was Achille Sclavo [39]. As he routinely dealt with epidemic diseases, he realized that such diseases could, in many cases, be avoided by following simple rules of hygiene that could reduce contagion and the spread of infections [40]. The propagation of good hygiene practices therefore became the centerpiece of his activities as an educator and characterized the antimalarial campaigns conducted in Sardinia in 1910 and 1911. Angelo Celli and his wife Anna Fraentzel were also convinced that education could promote the prevention of both malaria and other infectious diseases. They therefore helped to found the ‘Scuole per contadini’, which, in 1904, began to provide elementary education in the rural areas of the Agro Romano, while at the same time spreading information on the prevention of malaria. This was made possible by their collaboration with the Italian Red Cross. In 1917, there were 90 such schools; by 1924, they numbered almost 2000 throughout central Italy.

Moreover, in 1918, moreover, a School of Rural Hygiene and Malaria Prophylaxis was established in Nettuno (near Rome) in order to train the Public Health Staff in charge of malaria control. The School was under the authority of the Public Health Laboratories, national structures of the Public Health Directorate General of the Ministry of Interior of Italy [18].

The advent of fascism, however, put an end to these schools, as their functions were transferred to the Opera Nazionale Balilla and, subsequently, to the Gioventù Italiana del Littorio.

Last steps of malaria eradication

While the administration of quinine yielded important results in terms of reducing mortality due to malaria and improving the health of those affected, the use of this drug could not, on its own, put an end to the epidemic of malaria in Italy in the period considered. Indeed, as already asserted by senator Torelli in 1882, ‘No epidemic disease is more closely related to the conditions of the physical environment than malaria is, since the cause of this disease is stagnant water, the nature of the terrain and the mixture of brackish water with fresh water’ [22].

At the same time, however, the important interventions of the drainage of swampland and the reclamation of farmland often remained detached from the activities of malaria prophylaxis and treatment. In the first decade following the unification of Italy, several laws were passed with the aim of reclaiming swampland, starting with the Consolidated Text ‘on the reclamation of swamps and marshland’. Published in 1900, this identified some 19 districts for intervention throughout the country; the law issued in 1902 raised this number to 28. Nevertheless, a coordinated program of interventions that acted on both malaria patients and the environment was lacking.

Thus, it seems that the government was seeking an immediate and specific solution to the problem of malaria, and, while some good results were achieved, more complex and definitive interventions were not implemented. This is demonstrated by the fact that, when Italy entered the First World War on 24 May 1915, the positive trend in the fight against malaria was arrested.

At the end of the First World War, the direct and indirect consequences of the conflict had led to a serious upsurge of the disease [18]. Indeed, deaths due to malaria rose from 57 per million inhabitants in 1914 to 105 per million in 1915, to 237 in 1917, and to 325 in 1918. A total of 2050 people died of malaria in 1914, while in 1918 the figure was 11,500.

Although these numbers again declined in the postwar years (6800 in 1919 and 4250 in 1920), the prewar values were only reached in 1932. Only when new massive interventions were undertaken – from the total land reclamation programs conducted by the fascist regime to the spraying of “Paris Green” and DDT (dichloro-diphenyl-trichloroethane) – would a definitive solution be achieved in Italy, which was finally declared malaria-free in 1970 [37,41].

After the discovery of the insecticidal action of ‘Paris Green’ against the larvae of the Anopheles mosquito, in 1923 the League of Nations promoted an investigation on malaria endemicity in Europe and the use of quinine. Thus, the Rockefeller Foundation in New York launched a program of cooperation in Italy under the direction of Lewis Wendell Hackett, a public health doctor with previous experience in ancylostomiasis control in Central America. Collaboration with Alberto Missiroli led to the foundation of the Stazione Sperimentale per la Lotta Antimalarica (The Experimental Station for Malaria Control) in Italy, which played a major role in staff training and updating on the most advanced techniques of malariology. In 1925, Paris Green was tested as an anti-larval agent in several malarial zones in central and southern Italy, with good results in small urban centers.

Meanwhile, the fascist regime was beginning to carry out extensive operations of total land reclamation. In 1934, the Istituto di Sanità Pubblica (the Institute of Public Health) was inaugurated; this absorbed the previous bodies responsible for the fight against malaria. In 1941, the Institute of Public Health became the Istituto Superiore di Sanità (ISS), and expanded the activities of clinical, laboratory and field research in malaria and other public health subjects.

All these actions led to a progressive improvement in the situation. However, Italy’s entry into the war in 1940 determined a major upsurge in the transmission of malaria, owing to the interruption of prophylactic interventions and, toward the end of the war, the systematic destruction of reclamation works by the Germans. Thus, in 1944, the number of cases of malaria in Italy rose to 133,842, albeit with ‘only’ 421 deaths.

In the same year, DDT (Dichlorodiphenyltrichloroethane) for the control of malaria was first tested in Italy. Sprayed on the walls of houses and stables, it proved effective in reducing mosquito populations and the level of transmission of the disease.

In January 1946, Missiroli announced a five-year plan of action designed to eradicate malaria from Italy. […] The campaign for the eradication of malaria from the whole national territory began in 1947 and ended virtually in 1948, with the total interruption of transmission of falciparum malaria. [18]

In 1947, the Sardinian Project was launched with the aim of eradicating malaria from the island by directly eliminating the vector of the disease, Anopheles labranchiae. The project was managed by the ‘Ente Regionale per la Lotta Anti-anofelica in Sardegna’ (ERLAAS) with the financial contribution and under the technical direction of the Rockefeller Foundation.

The result was that, on the close of operation in 1950, malaria transmission had been eliminated, but An. labranchiae still existed. The Sardinian Project was a failure: the result was just the interruption of malaria transmission, at a considerably higher cost than in other parts of Italy and with considerable environmental pollution. [18]

In 1965, the last case of transmission of Plasmodium malariae by a local mosquito was recorded, and on 17 November 1970, the World Health Organization officially declared Italy malaria-free. However, vigilance must not be allowed to wane, as malaria continues to be endemic in many countries, especially in Africa. Immigrants arriving in Europe and travelers returning to Italy or other malaria-free countries from endemic zones constitute a potential source of disease and must be kept under strict health control [42–44].

Moreover, malaria continues to pose a health risk to travelers [45]. Nonimmune patients and people visiting friends and relatives (VFR), especially children, have a higher risk of severe malaria. Prevention should be promoted by increasing risk awareness and improving access to well-tolerated prophylactic drugs. Surveillance of travel-related malaria infections is fundamental to safeguarding travelers’ health, as well as to avoiding reintroduction of the disease in countries like Italy, where competent vectors are still present [46,47].

Disclosure statement

No potential conflict of interest was reported by the authors.