About Author: Dr.Ravindra Kembhavi, Asso. Professor PSM Department,
KEM hospital, Parel, Mumbai
Dr.Mahesh Ghadage, M.Sc pharmaceutical 2nd year student,
KEM hospital, Parel, Mumbai
Reference ID: PHARMATUTOR-ART-1057
Abstract
Severe or complicated P. vivax malaria seldom results in pulmonary damage, and pulmonary complications are exceedingly rare while acute renal failure, disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), hypoglycemia, coma, or epileptic seizures this are manifestations of severe or complicated P. falciparum malaria.
Introduction
Malaria, a disease of uniqueness, has proved to be a formidable deterrent to the cultural and socioeconomic progress of man in the tropical, sub-tropical and monsoon prone zones of the world.1 It is a major public health problem and more than 300 million cases are recorded every year around the globe. One to two million deaths are estimated every year, especially in Africa from where 90% of cases are reported.2 Malaria is widely rampant in India. According to the World Health Organization (WHO), an estimated 10.6 million malaria cases were reported in 2006 that accounted for approximately 60% of cases in the WHO South-East Asia Region. In India, the overall mortality has been reported to be 5.3 per 1000 cases in children aged less than 5 years age and 1.9 per 1000 cases of all ages.3 Various authors have described factors predicting mortality in severe malaria. Studies have shown that delayed diagnosis was one of the important factors associated with death and hence early identification of these risk factors may help in limiting the morbidity and mortality due to malaria5. Also it is know that, there may be major difference in the clinical manifestations of malaria at different ages and under different levels of endemicity and the WHO guidelines which are drawn from African experience which might not reflect the picture in our setup.
Malaria is a common disease of the tropical World caused by the parasite Plasmodium.The disease is transmitted from man to man by the infective bites of female mosquitoes belonging to genus Anopheles, as the mouth parts of male mosquitoes are not developed for biting and cannot pierce the skin.
There are 4 species of malaria parasites, of which 3 species are found in India. These are:
• Plasmodium Vivax that may cause relapsing malaria but seldom death (50-55% of total reported cases)
• P. falciparum that causes malignant malaria and may lead to death (48-52% of total cases) and
• P. malariae that may cause severe malaria (small numbers found in foothills in Orissa)
• P. ovale (not found in India)6
The disease manifests with sudden onset of high fever with rigors and sensation of extreme cold followed by feeling of burning heat, leading to profuse sweating and remission of fever by crisis thereafter. The febrile paroxysms occur every alternate day. Headache, bodyache, nausea, etc. may be associated features. However in atypical cases, classical presentation may not manifest.
Malaria transmission occurs in almost all areas of India except areas above 1800 meters sea level. Country's 95% population lives in malaria risk areas. Malaria in India is unevenly distributed. In most parts of the country about 90% malaria is unstable with relatively low incidence but with a risk of increase in cases in epidemic form every 7 to 10 or more years.
This depends on the immune status of the population and the breeding potential of the mosquitoes, rainfall being the leading cause of malaria epidemics as it creates high mosquito population. In North-Eastern States efficient malaria transmission is maintained during most months of the year. Intermediate level of stability of malaria transmission is maintained in the plains of India in the forests and forest fringes, predominantly tribal settlements in eight states (Andhra Pradesh, Jharkhand, Gujarat, Madhya Pradesh, Chhatisgarh, Maharashtra, Orissa and Rajasthan.8
Plasmodium falciparum this is the only parasite that causes malignant malaria. It causes the most severe symptoms and results in the most fatalities. It is responsible for highest morbidity and mortality in the world. Plasmodium vivax is geographically the most widely distributed cause of malaria in people, with up to 2•5 billion people at risk and an estimated 80 million to 300 million clinical cases every year—including severe disease and death.17In India about 50% of malaria cases which were reported are found to be caused by p. vivax. Malaria caused by p. vivax was considered to be benign because of less severity but in addition to 11 previously reported ARDS cases with vivax 3 most recent cases of ARDS having vivax infection have been reported in India in Kolkatta. So it is now no longer benign inspite of standard treatment with chloroquine and primaquine it is also presenting with severe life threatening complications.15 It has been neglected under the burden of malaria caused by p.falciparum but today mortality due to vivax is becoming a big health issue. So there is need of comparative study to identify magnitude of problem to reduce the mortality due to vivax and p. falciparum by finding standard protocol for management of p.vivax and p.falciparum rate due to both species.
Case definition of malaria is as follows:
“Clinical case description:- Any patient with fever with any of the following: Chills,sweating, jaundice or splenomegaly. Convulsions, coma, shock, pulmonary edema and death may be associated in severe cases”8
Malaria statistics:
Infection resulting from malaria accounts for >1 million child deaths globally every year at rate of 1 death every 30 seconds. Data from the 1990s suggested that as many as 90% of all malarial cases and 90% of deaths take place in sub-Saharan Africa, where levels of endemicity are high, and severe disease and mortality occur primarily during infancy and India is one of the major contributors to malarial morbidity and mortality in this part of the world.9
Standard Treatment of p. vivax:
1. Chloroquine: 25 mg/kg body weight divided over three days i.e. 10mg/kg on day
1. 10mg/kg on day 2 and 5mg/kg on day 3.
2. Primaquine: 0.25 mg/kg body weight daily for 14 days. Primaquine is contraindicated in infants, pregnant women and individuals with G6PD deficiency. 14 day regimen of Primaquine should be given under supervision.16
Treatment of uncomplicated P.falciparum cases:
Artemisinin based Combination Therapy (ACT)*
Artesunate 4 mg/kg body weight daily for 3 days Plus Sulfadoxine (25 mg/kg body weight) ñ Pyrimethamine (1.25 mg/kg body weight) on first day
*ACT is not to be given in 1st trimester of pregnancy.
Treatment of uncomplicated P.falciparum cases in pregnancy:
1st Trimester: Quinine salt 10mg/kg 3 times daily for 7 days.
Note: Quinine may induce hypoglycemia; pregnant women should not start taking quinine on an empty stomach and should eat regularly, while on quinine treatment. 2nd and 3rd trimester: ACT as per dosage given above.16
Treatment of severe malaria cases:
Severe malaria is an emergency and treatment should be given as per severity and
associated complications which can best be decided by the treating physician. The
guidelines for specific antimalarial therapy is as follows:
Artesunate: 2.4 mg/kg body weight IV or IM given on admission (time = 0h); then at 12 h and 24 h and then once a day.
(or)
Artemether: 3.2 mg/kg body weight IM given on admission and then 1.6 mg/kg body weight per day.
(or)
Arteether: 150 mg IM daily for 3 days in adults only (not recommended for children).
(or)
Quinine: 20 mg/kg* body weight on admission (IV infusion or divided IM injection) followed by maintenance dose of 10 mg/kg body weight 8 hourly.
The infusion rate should not exceed 5 mg salt/kg body weight per hour.
(*loading dose of Quinine i.e. 20mg /kg body weight on admission may not be given if the patient has already received quinine or if the clinician feels inappropriate).
Note:
The parenteral treatment in severe malaria cases should be given for minimum of 24 hours once started (irrespective of the patients ability to tolerate oral medication earlier than 24 hours).
After parenteral artemisinin therapy, patients will receive a full course of oral ACT for 3 days. Those patients who received parenteral Quinine therapy should receive:
Oral Quinine 10 mg/kg body weight three times a day for 7 days (including the days when parenteral Quinine was administered) plus Doxycycline 3 mg/kg body weight once a day or Clindamycin 10 mg/kg body weight 12-hourly for 7 days (Doxycycline is contraindicated in pregnant women and children under 8 years of age). (or) ACT as described.16
Methodology:
Previous studies shows that p.falciparum is associated with life threatening complications and high fatality rate and therefore it was labeled as malignant malaria but now a days recent studies show that that p. vivax showing virulent cases . Following are some of case studies showing virulent form p. vivax and p. falciparum.
1) In 2003 a research article was published by Clinique de Réanimation des Maladies Infectieuses et Tropicales, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France on clinical spectrum of severe imported 188 falciparum malaria cases admitted in intensive care unit showing mortality was 11% in severe malaria group with p. falciparum
2) In 2004 a retrospective study was published by the University Hospital of Montpellier,France on 32 cases having age more than 15 years of severe falciparum malaria and it was found that Severe imported falciparum malaria remains associated with a bad outcome. Improving chemoprophylaxis and an earlier diagnosis may reduce significantly this mortality.
3) In 2004 a prospective study evaluating mefloquin resistance and increased plasmodium falciparum multidrug resistance gene copy number in plasmodium falciparum over a period of 12 years was published on lancet and it was found that increased copy number of plasmodium falciparum multidrug resistance gene is responsible for the mefloquine resistance in p.falciparum.
4) In 2009 at Department of Haematology, St. Stephen's Hospital, Delhi, India a retrospective study was conducted in 265 patients to determine the incidence of various complications of Plasmodium vivax malaria based on review of case records and it was found that p.vivax which is known as benign one is also responsible for producing severe and life threatening complications.
5) In 2009 a research article was published by Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta 10430, Indonesia on resistance to therapies for infection by vivax which showed that neglection of p.vivax has resulted in production of resistance species of p.vivax and more severe complications.
6) A research article was published in 2009 by Barcelona Centre for International Health Research, CRESIB, CIBERESP, Hospital Clinic, Barcelona, Spain describing a retrospective study of 20 cases with severe falciparum malaria admitted in ICU showed that mortality by severe malaria remains high despite high quality management, which highlights the importance of chemoprophylaxis and early diagnosis and treatment and which was 25%.
7) In 2010 a study was published by Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, Oxford, UK on The international limits and population at risk of Plasmodium vivax transmission in 2009 and it was found that after more than a century of development and control, P. vivax remains more widely distributed than P.falciparum and is a potential cause of morbidity and mortality amongst the 2.85 billion people living at risk of infection, the majority of whom are in the tropical belt of CSE Asia.
8) In 2010 a research article was published by Fundacao de Medicina Tropical do Amazonas, Manaus, Brazil which showed that after treating a case series of 17 patients hospitalized in Manaus (western Brazilian Amazon) with PCR-confirmed Plasmodium vivax infection with chloroquine and primaquine still major complications jaundice and severe anemia have occurred with no in vivo chloroquine resistance showing severe form of p.vivax.
9) In 2010 a research article was published by Department of Chest Medicine, N.R.S. Medical College, Kolkata-700 014, India which showed 3 cases of p.vivax associated with ARDS requiring required immediate (within hour of onset of dyspnea) institution of mechanical ventilation with high positive end expiratory pressure showing severe form of p. vivax.
10) In2010 a cohort study was performed on 400 severe cases of imported plasmodium malaria by Service de Reanimation, Centre Hospitalier de Versailles, Le Chesnay, France and it was found that in a large population of adults treated in a non-endemic industrialized country, severe malaria still has a high mortality rate.
Conclusion:
Research made towards the eradication of malaria have so far been unsuccessful. Owing to the confinement of malaria associated to the stage of disease, understanding of host-Plasmodium interactions at this stage is essential to design new intervention strategies of treatment against severe malaria.
In this context, a challenge for the future is the development of strategies to analyze on a population level the parasite malaria, with knowing treatment, morbity, mortality and causality analysis.
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