An internet-based tool-kit for the initial investigation of cases of cryptic malaria

Produced by the HPA Centre for Infections, Colindale.

Reviewed 2 August 2006

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Purpose and rationale

This document aims to assist health protection professionals with the initial investigation and classification of cases of malaria in the United Kingdom (UK) where the route of transmission is unclear or unusual, ie 'cryptic malaria'. It defines various classes of cryptic malaria, outlines a protocol with a questionnaire tool for initial investigation, and discusses inter-organisation communication issues and responsibilities around such cases.

Definition of cryptic malaria

The aetiological agents of malaria are plasmodium parasites of which there are four different species (P. vivax, P. falciparum, P. ovale, and P. malariae). The lifecycle of Plasmodium is complex and involves both mosquito and human hosts (click here for a diagram of the life cycle of a malaria parasite). The standard mode of transmission for malaria is via the bite of an infected female Anopheles mosquito. Both the lifecycle of the parasite and the distribution of the mosquito vector are temperature dependent which explains the largely tropical distribution of the disease. The different species of parasite have slightly different global distributions (global map of malaria, WHO). They also vary in their incubation periods and clinical effects (click here for clinical features of malaria ). The fevers are the result of infection and destruction of red blood cells. The most serious illness, and the vast majority of fatalities, are produced by Plasmodium falciparum as a result of infected cells becoming stuck in the small blood vessels to the brain.

The overwhelming majority of cases of malaria diagnosed in the UK occur in people who have been infected abroad. Occasionally however, cases of malaria occur in the UK where the route of acquisition is not immediately apparent from an explanatory travel history. These cases are here termed 'cryptic' for convenience.

Technical definitions

  • Relapse: If fever (and parasites) returns after a gap of weeks or more after an intial attack of malaria
  • Recurrence: Malaria relapse due to activation of liver stages.
  • Recrudescence: Malaria relapse due to the persisence of red blood stages.
  • Indigenous malaria: Malaria contracted by a person in the UK from the bite of a mosquito which also became infected in the UK.
  • Introduced malaria: The first generation of malaria, where the mosquito was infected from an imported case.
  • Induced malaria: Malaria that has been contracted from parenteral inoculation other than by a mosquito bite, eg from a blood transfusion.

Cryptic malaria cases may be classified according to the following scheme:

  1. Acute infection acquired in an endemic area, but where the initial travel history has been inadequate.
  2. Late detection of an infection acquired in endemic area.
  3. Importation of an infected mosquito to the UK.
  4. Person to person transmission in the UK by direct contact with infected blood/tissues.
  5. Unexplained by any of 1 to 4.

Acute infection acquired in an endemic area

A careful detailed travel history may reveal an association with recent travel where none was initially determined. For example, so called 'runway malaria' may occur where a person has not purposely travelled to a malarious area but has been in transit at an airport in a malarious region en route and has been bitten by an infected mosquito there. They may not have even left the plane for this to occur if the doors of the aircraft were opened, eg for a refuel or catering stop (1). In addition to this, some travellers may inadvertently, or in a few cases deliberately, fail to mention that they have recently been in an endemic area. Travellers may not be aware that malaria is endemic in certain countries and so it is very important to take a detailed travel history.

Late detection of an infection acquired in an endemic area

A person may not have travelled recently but may have become infected with malaria some time ago in an endemic area. The infection may even be detected incidentally in the course of a blood examination taken for some other indication. The incubation period of the less severe types of malaria may be very prolonged. In addition, P. vivax and P. ovale have latent liver phases and so recurrence may occur some time after an initial clinical infection, which may have been missed or unreported. Around 8% of both vivax and ovale malaria cases present more than a year after returning to the UK. Sub-clinical infection or recrudescence may also occur with Plasmodium species that do not have a latent liver form, eg in people who have spent considerable time in endemic areas and may have developed partial immunity. About 0.8% of falciparum malaria cases present later than six months after the stated date of arrival in the UK, and 0.3% later than one year after arrival (2). There is ethnic variation in this proportion as those of caucasian origin present earlier (only 0.3% later than six months after arrival) than those of African or South Asian origin (over 1.3% present after six months and around half of these after more than one year).

Haemoglobinopathies are generally believed to be protective against clinical malaria (3). Not enough, however, is known about the degree of protection afforded and it is possible that chronic, sub-clinical infections may also occur in this group, especially in individuals with haemoglobinopathy trait rather than the actual disorder. Where such infections occur, relapse to produce active disease may occur in circumstances of relative immuno-suppression, including pregnancy.

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Importation of infected mosquito to the UK

There is ample evidence that mosquitoes can be transported from one part of the world to another and that malaria can occur where an infected mosquito is imported and then bites an individual in a non-endemic country (4). This may occur in an airport (5) or, where climatic conditions allow, in the area around an airport (6). This is termed 'airport malaria'. In addition, mosquitoes may survive in hand baggage stored in overhead lockers (7), or even in baggage/containers in the hold (8). This can give rise to 'baggage malaria' where an imported mosquito can infect an individual when released from the baggage, possibly at some distance from the airport and possibly affecting someone other than the person who has travelled with the baggage, eg another household member. Aircraft may often be disinsected prior to arrival in the UK from a malarious region but the effectiveness of insecticide sprays when used in isolation is limited. The World Health Organization recommends rigorous methods for disinsectation (4) but their recommendations are not always adhered to.

Person-to-person transmission in the UK by direct contact with infected blood or tissues

Although person-to-person transmission is considered rare, malaria can be directly transmitted without the intervention of a mosquito, by transfusion of infected blood (9), implantation of other infected human tissues (10), or by mother to child transmission during pregnancy. It can also be transmitted by injecting drug users sharing needles (11). By analogy with other blood borne infections, sharing of other personal equipment such as razors/toothbrushes may also pose a theoretical risk though cases of transmission in this way have not been documented (12). The same applies to invasive procedures such as tattooing, body piercing or acupuncture.

Although transmission has not been documented as a result of infected healthcare workers performing exposure prone procedures on patients, this has been thought to be the most likely, though unproven, explanation in at least one incident (13). Transmission to a healthcare worker has, however, been documented by a needlestick injury from an infected patient (14). Nosocomial transmission can also occur via cross contamination of materials/fluids used invasively (15).

Unexplained

Cases that cannot otherwise be categorised, raise the possibility of ' indigenous transmission', ie the transmission of imported malaria by local mosquito vectors. The temperate climate is cited to be the main reason why malaria does not occur naturally in the UK; the parasites requiring significantly warmer temperatures than normally occur in the UK for the insect stage of their life-cycle (particularly for P. falciparum). While P. falciparum transmission occurred in southern Europe until successful eradication campaigns after World War II, natural transmission of P. falciparum hardly ever occurred in northern Europe because of the temperature. The climate is not, however, the only important factor. Natural transmission of P. vivax malaria did occur in south-eastern coastal areas of England until the early part of the twentieth century when a change in agricultural practices largely destroyed the mosquito vector’s habitat. Species of Anopheles mosquitoes that can carry malaria (including some strains of P. falciparum) do occur in the UK (16). The last two recorded cases of natural malaria transmission in the UK were of P.vivax in 1953 in Stockwell, central London (17). There has only been one previous case of presumed natural P. falciparum transmission reported in the UK. This occurred in the autumn of 1920 and is postulated to have been the result of acquisition of the parasite by local mosquitoes from infected soldiers returning from the Mediterranean after World War I (18). It is, however, by no means certain that this was indeed the route of transmission. Although it is considered unlikely that malaria would become endemic in the UK again, climate change could facilitate a re-emergence of natural transmission of malaria in the UK, and may lead to localised outbreaks (19).

Public health significance

Cryptic malaria cases require investigation primarily to explore possible routes of transmission that may have public health significance within the UK. For example, person-to-person transmission in a health care setting would require public health investigation and intervention. Although considered to be very unlikely in current climatic conditions, the possibility of indigenous transmission of malaria within the UK would also have public health implications.

Epidemiology

The vast majority of malaria seen in the UK is imported (20). Cryptic malaria occurs very infrequently. In 2002, for example, only three cases of malaria caused by P. falciparum were identified that had no explanatory travel history. On investigation, one of these was classified as a probable airport malaria, one a nosocomial transmission and the third remained unexplained (14).

Identification of cases of cryptic malaria

Surveillance of malaria in the UK relies on two main sources of information: notifications and laboratory reports.

Malaria is a statutorily notifiable disease and clinicians diagnosing it have a legal duty to report cases to the local authority proper officer (usually the local consultant in communicable disease control (CCDC). All notifications of malaria are centrally collated at the Centre for Infections (CfI). It is known, however, that notifications of malaria considerably underestimate the true numbers of cases occurring.

Malaria is diagnosed in haematology laboratories by examination of blood films. When parasites are seen, samples may be sent to the HPA Malaria Reference Laboratory (MRL) for confirmation. The MRL then requests further information from the reporting laboratory and maintains a database of cases, which also includes other reports received from clinicians and the notifications. This is a more complete source of epidemiological information but still does not capture all cases since some cases are not reported by any route. It is helpful if CCDCs encourage reporting clinicians to complete the MRL malaria reporting form icon: pdf (52KB), which includes a travel history on each malaria case in the UK.

Cryptic cases are primarily identified when the clinician taking the medical history recognises that there is no explanatory travel history. There are two main ways in which this information may come to the attention of public health authorities: either through notification to the CCDC or through the MRL.

The standard notification form allows the clinician to state whether the disease was acquired abroad and in which country. A CCDC receiving a notification may therefore suspect a cryptic case on the grounds that geographical details of countries visited has been omitted. In order to help identify cases of cryptic malaria CCDCs are encouraged to check that all notification forms for malaria have the travel history section completed.

It is recommended that where the interval between leaving a malarious area and the detection of malaria parasites exceeds six months for caucasian people with P. falciparum, 12 months for people of other ethnic groups with P. falciparum (as they may be semi-immune), and 18 months for all people with other types of malaria, the case should be treated as a cryptic case.

The MRL may detect a possibly cryptic case when a form is returned to them with a history of no recent travel or a history of some other likely transmission route, eg a transfusion.

Action to take on identifying a possible case of cryptic malaria

  • Many possible cases of cryptic malaria can be excluded as such by enquiry of the reporting clinician, who may have omitted a relevant travel history from the report. Addressing this question to the reporting clinician is therefore the first stage in the investigation. This should be done by whoever has identified the potentially cryptic case - either the MRL or the CCDC.
  • If a case cannot be excluded as being cryptic by this means, then the case should be reported to the Travel and Migrant Health Section (TMHS) at CfI (Tel: 020 8200 4400 or email: tmhs@hpa.org.uk). If information on a case is not available to the MRL, it is possible that the CCDC may have or be able to access that information, and vice versa. TMHS will liaise between the two to determine whether this is the case.
  • If, after this process, a case still cannot be excluded as being cryptic, then further investigation will be required. Local CCDCs have statutory responsibility for local communicable disease control (21). The statutory responsibility for the investigation of cases of cryptic malaria lies with the CCDC who covers the area in which the patient is resident, not the area in which transmission may have occurred. However, close liaison may be required between local teams, eg if it is suspected that a patient acquired malaria in a UK hospital outside their area of residence. In such circumstances local agreement would be required as to who would lead the investigation. Any investigation would be supported by both TMHS and MRL.
  • A questionnaire has been devised to assist in initial investigation of cases (click here to download PDF ).
  • If further information is required directly from the patient it is to be agreed between the CCDC, TMHS and MRL who will undertake to obtain this. In most cases it is likely to be the CCDC but support can be offered where necessary for this task.
  • Once completed the questionnaire should be returned to the TMHS at CfI and the MRL.
  • Close liaison should be maintained between the local team, TMHS and MRL throughout.
  • In some cases, a satisfactory explanation for the case may be revealed through the use of the questionnaire and the investigation may terminate at this point. For example, if the case can be satisfactorily assigned to class 1, 2, or 3 of the classification scheme, eg probable airport malaria. (Note that it is very unlikely that importation of an infected mosquito will be able to be proven definitively, but there may be circumstantial evidence to support this conclusion).

Further investigations

Where the case is suspected to be in class 4 or 5 further investigation may be necessary. For example, a class 4 case (person-to-person transmission in the UK by direct contact with infected blood/tissues), may require a formal incident control team to be convened to decide upon further action. If all possibilities have been explored and the case can still not be explained then further investigations may be required. These may include entomological investigation at the patients residence. This would be decided by close liaison between the CCDC, TMHS and MRL.

Media and other communication issues

Possible cases of cryptic malaria may attract media interest. Close liaison should be maintained between the communications officers at HPA, the local Health Protection team and the London School of Hygiene and Tropical Medicine (representing MRL). The most appropriate organisation to lead on media issues will vary depending on the circumstances of the case, and should be decided by agreement between the local Health Protection Team, TMHS and MRL.

Local CCDCs are encouraged to inform their Regional Epidemiologist as well as their Director of Public Health. TMHS will ensure that, where appropriate, the Department of Health is notified.

Records of cryptic malaria cases and feedback

MRL and TMHS hold records of all cryptic malaria cases. Reports on cryptic cases are produced annually in combination with standard reports of malaria epidemiology in the UK.

References

  1. Csillag C. Mosquitoes stow away on aircraft. Lancet 1996; 348: 880
  2. Malaria. In: Health Protection Agency. Illness in England, Wales, and Northern Ireland associated with foreign travel - a baseline report to 2002. London: HPA; 2004. Available at http://www.hpa.org.uk/infections/topics_az/travel/baseline.htm.
  3. Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 1998; 11 (1): 1-51.
  4. Gratz N, Steffen R, Cocksedge W. Why aircraft disinsection? Bull WHO 2000; 78 (8): 995-1004.
  5. Isaacson M. Airport malaria: a review. Bull WHO, 1989, 67: 737-43
  6. Whitfield D et al. Two cases of falciparum malaria acquired in Britain. BMJ 1984; 289: 1607-09.
  7. Castelli F et al. Baggage malaria in Italy: cryptic malaria explained? Trans R Soc Trop Med Hyg 1993; 87: 3947.
  8. Mayers P. Recent introduction of Aedes aegypti in Bermuda. Mosquito News 1983; 43 (3): 361-2.
  9. Mingai M, Tegtmeier G, Chamberland M, Parise M. Transfusion-transmitted malaria in the United States from 1963 through 1999. N Eng J Med 2001; 344 (26): 1973-89.
  10. Fischer L, Sterneck M, Claus M, Costrad Jackle A et al. Transmission of malaria tertiana by multi-organ donation. Clinical Transplantation 1999; 13 (6): 491-510.
  11. Bastos FJ, Barcellos C, Loundes CH, Friedman SR. Co-infection with malaria and HIV in injecting drug users in Brazil: a new challenge to public health? Addiction 1999; 94 (8): 1165-74.
  12. Medline search 1993-2002.
  13. CDSC. Cryptic Malaria cases in England, 2002. Commun Dise Rep CDR Wkly 2003; 13 (10). Available at http://www.hpa.org.uk/cdr/archives/2003/cdr1003.pdf.
  14. CDSC. Needlestick malaria with tragic consequences. Commun Dis Rep CDR Wkly 1997; 7 (28). Available at http://www.hpa.org.uk/cdr/archives/CDR97/cdr2897.pdf.
  15. CDSC. Hospital acquired malaria in Nottingham. Commun Dis Rep CDR Wkly 1999; 9 (14). Available at http://www.hpa.org.uk/cdr/archives/CDR99/cdr1499.pdf.
  16. Bradley DJ. Current trends in malaria in Britain. Journal of the Royal Society of Medicine 1989; 82 (Suppl 17): 8-13.
  17. Crockett G, Simpson K. Malaria in neighbouring Londoners. BMJ 1953; ii: 1141.
  18. Blacklock B. Notes on a case of indigenous infection with P. falciparum. Ann Trop Med Parasitol 1921; 15: 59.
  19. Lindsay S, Thomas C. Global warming and risk of vivax malaria in Great Britain. Global Change and Human Health 2001; 2(1): 80-4.
  20. CDSC. Who is at risk of imported malaria? Commun Dis Rep CDR Wkly 2002; 12 (6).
  21. Chief Medical Officer. Getting ahead of the curve - A strategy for Infectious Diseases (including other aspects of health protection) London: Department of Health; 2002. See also; HSG (93) 56; EL(95) 31; EL(97) 13.

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