Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycaemia in mice: implications for malarial pathology.

The origin of illness and pathology in malaria is now largely attributed to high levels of circulating tumour necrosis factor (TNF), released from cells of macrophage lineage after triggering by the products of malarial schizogony. The role of lymphocytes and their products in malarial pathology is not yet known. This paper reports the presence of a related cytokine, lymphotoxin, which is produced only by lymphocytes, in the serum of malarial patients. This is the first report of raised serum levels of lymphotoxin in a systemic disease state. When injected into mice, recombinant human lymphotoxin induced hypoglycaemia and increased serum levels of interleukin-6. These changes, which are seen in severe experimental and human malaria, were also provoked by TNF. Both of these cytokines acted synergistically with interleukin-1, which has also been reported to be raised in malaria, to produce these alterations. These observations imply that lymphotoxin, as well as TNF, may contribute to the hypoglycaemia and raised serum interleukin-6 observed in malaria. This reduces the likelihood of effectively blocking the pathology of this disease by the use of neutralizing antibody directed against just one member of this family of functionally overlapping mediators.     

Roles of tumour necrosis factor in the illness and pathology of malaria

Evidence is accumulating that the illness and pathology observed in malaria are not caused directly by parasite products, but by normal components of the immune response, mainly monokines such as tumor necrosis factor (TNF), produced in excess. These mediators are released from the host's monocytes and macrophages, apparently in response to stimulation by parasite products. Recombinant TNF, if injected into a range of animal species or into tumour patients, is demonstrably toxic, giving rise to changes typical of acute malaria, and several groups have detected circulating TNF in serum from patients acutely ill with malaria. The short serum clearance time of TNF and TNF tolerance have to be considered when interpreting such data. Current studies indicate that some malarial antigens, in the absence of lipopolysaccharide, can trigger release of TNF. This and other monokines could contribute to cerebral malaria in at least 2 ways: by increasing thrombospondin secretion, and hence favouring local sequestration of knob-bearing parasitized red cells, and, as has been demonstrated in clinical trials in tumour patients, by causing neurological symptoms directly. In addition, it seems that TNF does not act alone, but as part of an interdependent synergizing network of polypeptide mediators. These evidently act together to induce secretion of other cell products, such as platelet-activating factor, prostaglandins, reactive oxygen species and procoagulant activity, that actually cause illness, biochemical change and tissue damage. Understanding these processes should lead to a range of new therapeutic interventions.     

Illness after travel not always due to exotic disease

It is extremely important to look for tropical and other exotic diseases in travellers who return with illness or become ill after travelling. Especially tropical diseases and exotic infectious diseases have to be excluded because of their possible fatal outcome. On the other hand, many travellers return with 'common' not-exotic illnesses not related to their journey. When in such cases attention is only given to exotic causes of their illness, diagnosis can be delayed which may be harmful. This was the case in 5 patients: a woman aged 44 years who suffered for months from bloody diarrhoea since her return from Brasil, due to a rectal adenocarcinoma, a 61-year-old man with diarrhoea upon returning from Egypt, who had hairy-cell leukaemia, a 17-year-old boy who developed a ketoacidotic diabetic crisis whilst on a journey in Uganda, but in whose case the first thoughts went to malaria, a 50-year-old man who suffered from throat pain since a journey through East Africa, during which he contracted a flu-like disease, and in whom Kahler's disease was diagnosed, and 69-year-old man suffering from recurrent fever and cough, in whom a radiological lesion was observed in the thorax which proved to be part of Wegener's disease.     

A perspective on malaria vaccines

The data obtained with adjuvant—antigen vaccines against asexual malaria parasites in different host—parasite systems are reviewed. From these data the problems associated with antimalarial vaccine development and testing are considered. The requirement for an adjuvant to induce immunity and the type of adjuvant required depends primarily on the host. Since the immune response of man to malaria vaccines is unknown, it is impossible to predict which animal infection is most likely to be a faithful model of malaria in man although it is generally assumed that the monkey is the most appropriate analogue. Therefore careful studies of the immune response of monkeys to purified malarial antigens are needed to develop vaccines for testing in man.     

Detection of Ehrlichia spp. and Anaplasma phagocytophilum in whole blood specimens using a duplex real-time PCR assay on the ARIES instrument

Cases of tick-borne diseases are increasing in the United States, and new tick-borne pathogen species causing human illness are being discovered. The specific etiology is generally difficult to diagnose based on clinical signs and symptoms alone, because of their generalized nature and often lack of a known tick bite. For some infections, such as Lyme disease and spotted fever group rickettsioses, serology remains the most appropriate laboratory diagnostic tool, but for others such as anaplasmosis, ehrlichiosis, and babesiosis, direct detection in the blood is preferred for rapid diagnosis. In Kentucky, USA, the area served by our laboratory, the most commonly reported tick-borne illnesses include spotted fever group rickettsiosis, ehrlichiosis and Lyme disease, but of these three diseases, only ehrlichiosis is well-suited for direct detection using PCR methods during the acute stage of illness. We report here the validation of a duplex real-time PCR assay using whole blood specimens on the Luminex ARIES® instrument, combining DNA extraction, amplification and detection into a one-step process. This method allows for rapid and sensitive detection of acute infections with Ehrlichia spp. and Anaplasma phagocytophilum using whole blood specimens. We included A. phagocytophilum to monitor emergence of this pathogen in Kentucky, since surrounding states have reported many more cases than Kentucky.     

Studies on various aspects of the indirect haemagglutination test for malaria

This paper gives the results of studies on various technical aspects of the indirect haemagglutination (IHA) test for malaria, on the similarity of the results obtained in the IHA test and in the indirect fluorescent antibody test, on the use of various plasmodial extracts as sensitizing antigens in the IHA test, and on the influence of heterophile antibodies on the titres obtained in the IHA test. Some longitudinal observations on induced malaria infections of man and monkey showed that the infection can induce the production of heterophile antibodies: their appearance, however, remains unpredictable. In some infections agglutinins against host erythrocyte components are also produced. Absorption of sera with tanned sheep cells sensitized with noninfected host red blood cell antigens is advocated as a control on the IHA titre for specific agglutinins.     

Unstable malaria in Sudan: the influence of the dry season. Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission.

Studies of infection and immunity to malaria often take little account of the fact that the amount of infectious challenge individuals receive is very variable. Classic studies in areas of holoendemic transmission showed that clinical immunity develops quite rapidly during childhood, although the processes through which increasing levels of resistance to infection are acquired are still not understood. However, holoendemic transmission is one end of the spectrum of malaria epidemiology and the development of clinical immunity is also affected by factors such as the infection rate and the local parasite species composition. An exceptionally simple type of malaria transmission occurs during the short, autumnal malaria outbreaks of the Sudanese sahel-savannah belt, where a sparse 200-500 mm of rain falls in 2-3 summer months, Plasmodium falciparum causes > 95% of malaria cases in most areas, and the entomological inoculation rate (EIR) is very low by African standards; thus the population dynamics of malaria parasites are less affected by super-infection. A comparison of certain features of parasite genetic diversity, particularly the average number of parasite clones present in infections in the Sudanese sahel and in malaria study sites with different levels of transmission, is presented. It is proposed that increasing EIRs are associated with progressively smaller increases in the average number of malaria parasite clones per host and the implications of this relationship for studies on malaria infection and immunity are discussed.     

The changing response of Plasmodium falciparum to antimalarial drugs in east Africa

For the past 20 years, chloroquine chemotherapy has been the single most effective malaria control measure in East Africa. The advent of chloroquine-resistant Plasmodium falciparum has reduced the clinical effectiveness of chloroquine and this trend is likely to continue. Combinations of antifol drugs are at present effective inhibitors of most P. falciparum infections in the region, in spite of widespread resistance to pyrimethamine. The development of (i) sensitive methods for monitoring changes in sensitivity to antifol combinations, (ii) more effective and less costly alternatives to commercially available combinations, and (iii) investigation of host and parasite factors leading to drug treatment failure in P. falciparum infections has been the primary goal of the Wellcome Trust Research Laboratories in Kenya (directed by Dr W.M. Watkins) within the malaria programme of the Kenya Medical Research Institute, and collaborating laboratories at the School of Tropical Medicine and the University of Liverpool.     

Possible autochthonous malaria from Marseille to Minneapolis

We report 2 cases of Plasmodium falciparum malaria in southern France in a French woman and an American man of Togolese origin who reported no recent travel to malaria-endemic countries. Both infections occurred after a stay near Marseille, which raises the possibility of autochthonous transmission. Entomologic and genotypic investigations are described.     

Late relapse of Plasmodium ovale malaria--Philadelphia, Pennsylvania, November 2004

Approximately 1,300 cases of malaria are reported each year in the United States; nearly all of these cases occur in travelers, many of whom fail to receive or adhere to prescribed chemoprophylaxis or do not follow recommendations for prevention of mosquito bites. Malaria can persist if not treated or if treated incorrectly (e.g., with an ineffective drug or an incorrect dosage of an effective drug). Early treatment is required to avoid severe illness or death. Although malaria typically becomes clinically apparent within 1 month of infection, cases can occur years after the last presumed exposure. In November 2004, CDC received a report of a late relapse of malaria in a Nigerian man aged 23 years in Philadelphia, Pennsylvania. His malaria was determined to have been caused by Plasmodium ovale, one of the four species of Plasmodium parasite that are transmitted by mosquitoes and cause malaria. The patient had been treated for malaria in Nigeria on multiple occasions, most recently 6 years before onset of his illness in the United States. This report describes the Philadelphia case, which underscores the importance of taking a detailed travel and immigration history when evaluating unexplained fever and considering malaria in the differential diagnosis.     

Investigations leading to the identification of members of the Anopheles umbrosus group as the probable vectors of mouse deer malaria

Although mosquitos of the Anopheles umbrosus group have long been recognized as important vectors of human malaria in Malaya, there have been doubts about the origin of some of the malaria infections found, especially in A. umbrosus and A. letifer. Investigations have accordingly been carried out in the Malayan swamp-forest, in conjunction with laboratory studies, into the nature of malaria infections in wild-caught mosquitos, the biting behaviour of anophelines and the presence of malaria infection in man and animals. The authors conclude from the results reported in this paper that A. umbrosus is a vector of mouse deer malaria and rarely, if ever, transmits primate malaria; that A. letifer transmits both human and mouse deer malaria; and that A. baezai and A. roperi are probably vectors of mouse deer malaria.     

Asymptomatic malaria infection prevailing risks for human health and malaria elimination

There has been a consistent rise in malaria cases in the last few years. The existing malaria control measures are challenged by insecticide resistance in the mosquito vector, drug résistance in parasite populations, and asymptomatic malaria (ASM) in healthy individuals.The absence of apparent malaria symptoms and the presence of low parasitemia makes ASM a hidden reservoir for malaria transmission and an impediment in malaria elimination efforts.This review focuses on ASM in malaria-endemic countries and the past and present research trends from those geographical locations. The harmful impacts of asymptomatic malaria on human health and its contribution to disease transmission are highlighted. We discuss certain crucial genetic changes in the parasite and host immune response necessary for maintaining low parasitemia leading to long-term parasite survival in the host. Since the chronic health effects and the potential roles for disease transmission of ASM remain mostly unknown to significant populations, we offer proposals for developing general awareness. We also suggest advanced technology-based diagnostic methods, and treatment strategies to eliminate ASM.     

Implications of malaria on iron deficiency control strategies

The populations in greatest need of iron supplementation are also those at greatest risk of malaria: pregnant women and young children. Iron supplementation has been shown to increase malaria risk in these groups in numerous studies, although this effect is likely diminished by factors such as host immunity, host iron status, and effective malaria surveillance and control. Conversely, the risk of anemia is increased by malaria infections and preventive measures against malaria decrease anemia prevalence in susceptible populations without iron supplementation. Studies have shown that subjects with malaria experience diminished absorption of orally administered iron, so that as a consequence, iron supplementation may have generally reduced efficacy in malarious populations. A possible mechanistic link between malaria, poor absorption of iron, and anemia is provided by recent research on hepcidin, the human iron control hormone. Our improved understanding of iron metabolism may contribute to the control of malaria and the treatment of anemia. Malaria surveillance and control are necessary components of programs to control iron deficiency and may enhance the efficacy of iron supplementation.     

Open questions in the case management of sick children

Despite much progress in the specific treatment of diseases in children, some basic management questions remain controversial. Examples for this are fluid management of children with infectious diseases and the control of fever in children. Fluid restriction in children with meningitis has been recommended by several authorities in the field; the basis for these recommendations is reviewed, and reasons are outlined why these recommendations may not be appropriate. Similarly, there are few data on which to base recommendations for fluid management in severe pneumonia and cerebral malaria. Some activities supported by WHO are presented. In the management of fever, opinions vary whether fever is a useful protective factor in combating infections, or whether fever might be harmful and should be lowered. Results of a recent survey of experts on this topic are presented, and the research agenda in the field of supportive management of childhood infections is outlined.     

Why is malaria in Vietnam under control, but Africa is threatened with a malaria disaster?

In Africa malaria parasites are increasingly developing resistance to the 3 affordable and tolerable drugs: chloroquine, amodiaquine and sulfadoxine-pyrimethamine. Alternative products are much more expensive and more toxic. A malaria disaster is looming. On the contrary, in Vietnam a disaster appears to have been averted. Data on malaria epidemiology, on the mosquito, the parasite and the host, man, give insight into the differences and the possibilities of control. Artemisinin derivatives can play an important role in malaria control, also in Africa. Without improvement of care which will require considerable investment and attention, the prospects are bleak.     

Unstable malaria in Sudan: the influence of the dry season. Malaria in areas of unstable and seasonal transmission. Lessons from Daraweesh.

Most studies of the natural history of Plasmodium falciparum infection have been performed in areas of stable malaria transmission and the acquisition of immunity to malaria in individuals who live in such areas is well documented. For the past 10 years, we have monitored host-parasite relationships in an area characterized by unstable and seasonal malaria of low transmission intensity. The work was performed in the village Daraweesh located in north-eastern Sudan 16 km from Gedaref town. The climate of the region is characterized by well-defined wet and dry periods with a short rainy season followed by a long dry season. In some years the rains fail and there is little precipitation even during the wet season. Malaria cases are rare in the dry season and during droughts. In years with rains, falciparum malaria sweeps through Daraweesh during the wet season and 20-40% of the entire population suffer at least 1 attack of malaria. All age-groups are affected, but the risk of getting a clinical attack is about twice as high in the age-group from 5 to 20 years as in adults aged above 30 years. Serological data and evidence obtained by polymerase chain reaction indicate that only about half of new blood-stage infections cause clinical disease. Together these findings suggest that many new infections are controlled immunologically and that individuals aged over 30 years are more successful in controlling infections than are teenagers. Parasite strains collected in Daraweesh are genotypically diverse and it is likely that the outcome of new P. falciparum infections depends on the preparedness of the host immune system to mount an attack against polymorphic or variable antigens expressed by the infecting parasite.     

Chlamydiae as agents of human and animal diseases

A brief review is given of the properties, occurrence, and public health significance of chlamydiae in man and animals and of the diagnosis and control of chlamydial infections. Chlamydiae occur naturally in a large number of avian and mammalian species. Man is the primary host of chlamydiae causing trachoma, inclusion conjunctivitis, genito-urinary tract infection, and lymphogranuloma venereum. In animals chlamydial infections have been recognized as a cause of pneumonia, encephalitis, abortion, arthritis, diarrhoea, and conjunctivitis. Chlamydial infections have been recognized in a wide range of avian hosts. Sporadic psittacosis/ornithosis in man is associated with close exposure to birds and may occur as an occupational disease. Transmission studies suggest that mammalian chlamydial strains are not very host-specific and that diseases and even chains of infection may develop in secondary hosts. There are a few well-documented cases of human infection with chlamydiae of mammalian origin. Although various chlamydial isolates have specific antigenic components, no routine test for identifying different serotypes has been generally accepted. Further investigation of the host range of chlamydiae and of their antigenic properties is essential for a more accurate assessment of the potential danger of chlamydia-infected animals to human health. The frequent occurrence of inapparent or latent infections makes it imperative to establish adequate laboratory facilities for the effective surveillance and control of chlamydial infections.     

Prevention and future control of hospital-associated infections commonly caused by gram-negative bacteria

Nosocomial infections are a distinct reality for many hospitalized patients. However, it is possible with presently available measures to substantially reduce the threat of such infection for patients in whom some physical barrier of normal immunity has been bypassed. For these patients, conscientious attention by health care personnel to such things as careful insertion and aseptic care of urinary catheters and intravenous cannulae, and cleanliness of ventilatory equipment and other mechanical devices used in intensive care units is needed. In contrast, the potential risk of actual hospital-acquired infection in patients with impaired cellular or humoral immunity is very great. No easy solutions to prevention and effective treatment of infection in these immunosuppressed patients are available. The general approach of protection from harmful bacteria, judicious use of antibiotics when infection occurs, and immunologic reconstitution of the deficient host with specific antibodies and competent phagocytic cells seems encouraging.     

Concurrent dengue and malaria due to Plasmodium falciparum and P. vivax

Concurrent infections of dengue and malaria are rare. We report a case of dengue fever with acute malaria due to Plasmodium falciparum and P. vivax in which the presence of mixed infection with P. vivax was overlooked and confirmed later on during recurrence of the fever that had initially responded to conventional antimalarial treatment and symptomatic treatment for dengue fever. We suggest that in concurrent infections of dengue and malaria, possibility of mixed infection with various Plasmodium species should be excluded to ensure a better treatment outcome.