Malaria complicated by gangrene: a case presentation and review

Malaria complicated by gangrene: a case presentation and review

 

Faraj Omar Alkizim^1,&, Duncan Matheka¹, Otieno Walter Mwanda^1,2

 

¹School of Medicine, University of Nairobi, PO Box 30197-00100, Nairobi, Kenya, ²Department of Human Pathology, University of Nairobi, PO Box 30197-00100, Nairobi, Kenya

 

 

^&Corresponding author
Faraj Omar Alkizim, School of Medicine, University of Nairobi, PO Box 30197-00100, Nairobi, Kenya

 

 

Symmetrical peripheral gangrene (SPG) was first described in 1891 [1]. It is now a well-documented, yet rare, disorder characterized by distal ischemic gangrene of two or more sites in the absence of large vessel obstruction or vasculitis [2]. Its pathogenesis is not well understood, and it has been linked to a wide variety of infective and non-infective etiological factors [3].

 

Malaria is one of the leading causes of morbidity and mortality worldwide. It is reported that 300 – 500 million people are infected by the parasite annually, leading to a death toll of 1.1-2.7 million [4]. It has been reported as one of causes of SPG [3], although extremely rare. Despite the millions of malaria cases annually, there has only been 23 cases, over the years, to the best of our knowledge, reported to have complicated with SPG (Table 1). We hereby describe the first (1^st) such case in Kenya, third (3^rd) in Africa, and twenty fourth (24^th) worldwide.

 

 

A 54 years old male Ugandan presented to Kenyatta National Hospital, a major referral tertiary hospital, in Kenya. He had initially reported with headache and joint pain to a local health facility in Uganda and was diagnosed to have severe Plasmodium falciparum malaria infection, and thereafter treatment with intravenous quinine commenced.

 

Treatment at the facility had been responsive; however two days after the onset, the patient started experiencing episodes of headache, pain, numbness, coldness, and swelling of the extremities. This was followed by darkening of the digits of his toes and hands, which gradually progressed proximally.

 

On presentation at out institution, he was conscious, alert, oriented, but lethargic and unable to walk. He was a non-smoker and non-alcoholic, and had no history of diabetes, hypertension or any angiopathies. He however had a history of numerous episodes of malaria bouts and a family history of hypertension with his father having succumbed to a stroke.

 

On physical examination, apart from fever, abdominal, cardiovascular, respiratory, and neurological systems were normal. Jaundice, pallor and cyanosis were absent. A right low paramedian scar was noted secondary to appendicectomy conducted in the year 1995. On local examination, the overlying skin cold, dry, wrinkled, and was darkened with a clear line of proximal demarcation (Figure 1). Pain was present in the regions proximal to the discolouration, and absent in the distal regions.

 

Investigations tested negative for HIV, HBV, HCV, and VDRL on ELISA. Urea, Electrolyte and creatinine tests were normal. Clotting profile showed a prolonged Prothrombin time of 19sec, Prothrombin time index of 74%, and an INR of 1.36. A haemogram showed macrocytic normochromic anaemia (Hb 9.03 g/dL, MCV 89.9fL, MCH 29.5pg, MCHC 27.2g/dL), Hct 33.2%, RBC 3.69x10¹²/L. WBC 4.39x10⁹, Neutrophils 2.11x10⁹ (48.2%), Lymphocytes 1.73x10⁹ (39.5%), Monocytes 0.314x10⁹ (7.16%), Eosinophils 0.193x10⁹ (4.4%), Basophils 0.035x10⁹ (0.796%).

 

An echocardiogram was normal except for type 1 left ventricular dysfunction and mild tricuspid regurgitation. The Dorsalis pedis pulses showed absence of blood flow, and a diagnosis of Symmetrical peripheral gangrene was made. Management was initiated with clopidogrel, Acetylsalicylic Acid, and Atorvastatin, and quad-amputation recommended. Time was allowed for marginalization of the gangrene, which was noted two months later. Meanwhile fresh frozen plasma was regularly administered to counter suspected thrombophilia.

 

Following satisfactory marginalization of the gangrene, the patient underwent surgical excision of the necrotic tissue. This involved trans-metatarsal amputation of both feet and ray amputation of the hands. The wounds healed well thereafter facilitated by vacuum dressing at -7.5mmHg over one month. He was then referred to plastic surgeons for prosthesis.

 

 

Malaria remains a major cause of morbidity and mortality, worldwide [5]. It is an endemic in 42 out of the 46 African countries, and more than 90% of its 1.1 – 2.7million worldwide deaths occur within the continent [5].

 

Of the four causative species, Plasmodium falciparum causes 95% of all the cases, and is responsible for most cases of complicated malaria [6]. World Health Organization defines complicated malaria as those accompanied with one or more of the following clinical or laboratory findings i.e. an impaired level of consciousness (Glasgow Coma Scale score <9), respiratory distress and pulmonary edema, multiple convulsions, circulatory collapse with hypotension refractory to treatment, abnormal bleeding, and jaundice [7]. Relevant laboratory findings include severe anemia, hypoglycemia, acidosis, hyperlactatemia, hyperparasitemia (of more than 5%), and renal impairment [7]. This type of malaria has a mortality of more than 10% [8].

 

Most of the cases reported in table 1, as well as the current case, observed the signs of tissue necrosis within a few days, some as early as two days, following effective anti-malarial therapy. This immediate onset of the ischemia, following initiation of management, and its rapid progression to necrosis, is the striking feature that makes prevention and management of the gangrene difficult. This rapid pattern, furthermore, raises query on the etiology of the gangrene.

 

It is thought that the cytoadhesive properties of parasite infected erythrocytes that causes the vascular occlusion resulting in cerebral malaria, is the same mechanism of SPG pathogenesis [9].The exact mechanism is however not well understood and only hypotheses have been made as follows.

 

Heavy parasitemia is thought to cause activation of the compliment system [10], hence triggering the coagulation pathway to cause thrombosis [11]. The parasite is also thought to cause infected erythrocytes to sequestrate within microcirculation by molecular interactions with endothelial receptors mainly intercellular cell adhesion molecule -1 (ICAM-1) [12], endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule –1 (VCAM-1), thrombospondin (TSP) and histidine rich protein (HRP) [13]. This cyto-adherence may then lead to microcirculatory obstruction. Rosetting of uninfected erythrocytes around the infected ones also occurs exacerbating the vascular obstruction caused by the above sequestration [14]. Furthermore, changes in membrane that occur in Plasmodium falciparum infected erythrocytes causes activation of the blood coagulation cascade to cause thrombosis [10,15-17]. During haemolysis, which occurs in malaria infected erythrocytes, negatively charged phosphatidylserines are exposed from the inner leaflet of the erythrocyte membrane bilayer, which trigger the formation of prothrombinase [18]. Furthermore, inflammatory cytokines, especially TNF-a and interleukin-6 [19,20], increase tissue factor expression on mononuclear cells, leading to thrombus formation.

 

Finally, the life cycle of the Plasmodium has been shown to have an effect on the membrane of infected erythrocyte. As merozoites mature to trophozoite and schizont, the erythrocyte membrane composition changes, leading to appearance of knobs on their surfaces [9]. This alteration of the erythrocyte surface mediates both their adherence to endothelial cells and adhesion to noninfected and other infected erythrocytes. This results in sequestered erythrocytes within the microcirculation, and ultimately vascular obstruction [9].

 

All these mechanisms may have contributed to the thrombosis, and consequent vascular occlusion, that resulted in the gangrene of our patient. We however question the involvement of the anti-malarial therapy, keeping in mind the acute pattern of onset, following its initiation.

 

The management of severe malaria is well established [7]. However, the management of specifically patients with malaria and micro-vascular thrombosis is limited [21] to the use of antimalarial chemotherapy, and occasional use of anticoagulants upon symptomatology of ischemia. Quinine is a commonly used antimalarial, especially used in severe malaria [22]. Resistance to the drug is however prevalent within Sub-Saharan Africa, a region which has the highest rates of infection worldwide [23]. Most of the cases on table one, as well as the current case, report the use of quinine, prior to the gangrene, raising question on its involvement in the development and progression of malaria induced gangrene.

 

Keeping in mind the severity of this complication, its management will therefore require eradication of the parasite with concurrent treatment of the gangrene. The challenge comes in identifying this rare, rapidly progressing complication, before onset of ischemia, as anticoagulants are not usually included in the treatment regime of common malaria. Heparin has commonly been used to counter the thrombosis. The clinical course of Plasmodium falciparum malaria is however not positively influenced by its use [19] justifying the use of clopidogrel on our patient. Furthermore, it is contraindicated in patients with severe thrombocytopenia due to the high risk of hemorrhage.

 

Blood transfusions has also been explored in the management of some of the patients in table 1. Its benefit, however, remains controversial [24].

 

The criticality of time cannot be over emphasized considering the extremely short period to onset and rapid progression of tissue necrosis. It has been noted that with timely and correct intervention, the ischemia may resolve before progressing to gangrene. If allowed to progress surgical techniques would be inevitable, the scope of which would depend on the extent and severity of tissue necrosis ranging from debridement to amputation (table 1). Our patient presented with gangrene having already developed, hence missing the opportunity for an early intervention.

 

 

Plasmodium falciparum malaria, a very common disease, predisposes a patient to vascular occlusive diseases such as symmetrical peripheral gangrene (SPG). This complication is extremely rare hence almost never anticipated during management of a malaria patient. Furthermore, when it occurs, it progresses extremely rapidly leading to irreversible gangrene, thereby necessitating amputation. Physicians managing malaria patients should therefore be vigilant and on the look-out for SPG in order to intervene promptly and arrest its progression.

 

 

A written informed consent for publication was obtained from the patient. We are grateful for his cooperation.

 

 

The authors declare that they have no competing interests.

 

 

Prof. Mwanda was actively involved in the care of the patient and revision of the final document. Faraj and Duncan were responsible for the literature review and writing of the manuscript.

 

 

Table 1: A review of all the 23 past similar cases of gangrene complicated severe malaria

Figure 1: Image showing lower and upper limbs gangrene of the patient prior to surgery

 

 

1. Hutchison J. Severe symmetrical gangrene of the extremities. Br Med J. 1891; 2:8-9. This article on PubMed


2. McGouran RC, Emmerson GA. Symmetrical peripheral gangrene. Br Heart J. 1977; 39:569-572. This article on PubMed


3. Ghosh SK, Bandyopadhyay D. Symmetrical peripheral gangrene. Indian J Dermatol Venereol Leprol. 2011; 77:244-248. This article on PubMed


4. The millennium project. http://www.unmillenniumproject.org/documents/GlobalBurdenofMalaria.pdf. Accessed 23 August 2011


5. World Health Organization. Facts about health in the African Region of WHO. Available at http://www.who.int/mediacentre/factsheets/fs314/en/index.html. Accessed 15 May 2011


6. Ghafoor SZ, MacRae EA, Harding KG, Patel GK. Symmetrical peripheral digital gangrene following severe Plasmodium falciparum malaria-induced disseminated intravascular coagulopathy. Int Wound J. 2010 Oct;7(5):418-22. This article on PubMed


7. World Health Organization. Communicable Diseases Cluster: Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000 Apr;94 Suppl 1:S1-90. This article on PubMed


8. Bruneel F, Hocqueloux L, Alberti C, Wolff M, Chevret S, Bédos JP, Durand R, Le Bras J, Régnier B, Vachon F. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med. 2003 Mar 1;167(5):684-9. This article on PubMed


9. MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria - A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985 Jun;119(3):385-401


10. Clemens R, Pramoolsinsap C, Lorenz R, Pukrittayakamee S, Bock HL, White NJ. Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway. Br J Haematol. 1994 May;87(1):100-5. This article on PubMed


11. Philips RE, Looaresuwan S, Warrell DA, Karbwang J, Warrell MJ, White NJ, Swasdichai C, Weatherall DJ. The importance of anaemia in cerebral and uncomplicated falciparum malaria: role of complications, dyserythropoesis, and iron sequestration. Quart J Med. 1986; 58: 305-323. This article on PubMed


12. Rojanasthien S, Surakamolleart V, Boonpucknavig S, Isarangkura P. Haematological and coagulation in malaria. J Med Assoc Thai. 1992 Jan;75 Suppl 1:190-4. This article on PubMed


13. White N J, Malaria. In Gordon Cook eds. Manson’s tropical disease. Hospital for tropical disease. University of London. 1996; 1087-1164


14. Bradley D, Newbold C, Warrel DA, Malaria. In Weatherall DJ. Ledinghan JGG, Warren DA, ed. Oxford textbook of medicine, Oxford University press. 1996; 835-863


15. Mohanty D, Marwaha N, Ghosh K, Chauhan AP, Shah S, Sharma S, Das KC. Vascular occlusion and disseminated intravascular coagulation in falciparum malaria. Br Med J (Clin Res Ed). 1985 Jan 12;290(6462):115-6. This article on PubMed


16. Schwartz RS, Olson JA, Raventos-Suarez C, Yee M, Heath RH, Lubin B, Nagel RL. Altered plasma membrane phospholipid organization in Plasmodium falciparum-infected human erythrocytes. Blood. 1987 Feb;69(2):401-7. This article on PubMed


17. Maguire PA, Prudhomme J, Sherman IW. Alterations in erythrocyte membrane phospholipid organization due to the intracellular growth of the human malaria parasite, Plasmodium falciparum. Parasitology. 1991 Apr;102 Pt 2:179-86


18. Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood. 1997 Feb 15;89(4):1121-32. This article on PubMed


19. Hemmer CJ, Kern P, Holst FG, Radtke KP, Egbring R, Bierhaus A, Nawroth PP, Dietrich M. Activation of the host response in human Plasmodium falciparum malaria: relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels. Am J Med. 1991 Jul;91(1):37-44. This article on PubMed


20. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999 Aug 19;341(8):586-92. This article on PubMed


21. Losert H, Schmid K, Wilfing A, Winkler S, Staudinger T, Kletzmayr J, Burgmann H. Experiences with severe P falciparum malaria in the intensive care unit. Intensive Care Med. 2000 Feb;26(2):195-201. This article on PubMed


22. World health organization. Guidelines for the treatment of malaria - 2nd edition. Geneva: WHO press. 2010


23. World Health Organization. World malaria report 2008. Available at http://apps.who.int/malaria/wmr2008/malaria2008.pdf. Accessed 23 August 11


24. Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis. 2002 May 1;34(9):1192-8. This article on PubMed


25. Anuradha S, Prabhash K, Shome DK, Gaiha M, Singh NP, Agarwal SK, Mandal AK, Jain S, Chaturvedi KU, Sawlani KK. Symmetric peripheral gangrene and falciparum malaria—an interesting association. J Assoc Physicians India. 1999 Jul;47(7):733-5. This article on PubMed


26. Edwards IR. Malaria with disseminated intravascular coagulation and peripheral tissue necrosis successfully treated with streptokinase. Br Med J. 1980 May 24;280(6226):1252-3. This article on PubMed


27. Kochar SDK, Kumawat B, Kochar SK. A patient with falciparum malaria and bilateral gangrene of the feet who developed arrhythmia/ventricular fibrillation after quinine therapy. QJM. 1998 Mar;91(3):246. This article on PubMed


28. Chittichai P, Chierakul N, Davis TM. Peripheral gangrene in nonfatal pediatric cerebral malaria: a report of two cases. Southeast Asian J Trop Med Public Health. 1991 Jun;22(2):190-4. This article on PubMed


29. Jain D, Srivastave S, Singhal SS. A rare presentation of falciparum malaria. J Assoc Physicians India. 1995; 43:582. This article on PubMed


30. Sharma SN. Cutaneous gangrene in falciparum malaria: an unreported manifestation. J Assoc Physicians India. 1987 Feb;35(2):150-2. This article on PubMed


31. Liechti ME, Zumsteg V, Hatz CFR, Herren T. Plasmodium falciparum Cerebral Malaria Complicated by Disseminated Intravascular Coagulation and Symmetrical Peripheral Gangrene: Case Report and Review. Eur J Clin Microbiol Infect Dis. 2003 Sep;22(9):551-4. This article on PubMed


32. Sharma BD, Gupta B. Peripheral gangrene in a case of complicated falciparum malaria. J Indian Acad Clin Med. 2002; 3:297-299


33. Tamhankar P, Tullu MS, Lahiri KR, Deshmukh CT. An unusual complication of Plasmodium falciparum malaria. Indian J Med Sci. 2008; 62:70-73. This article on PubMed


34. Agrawal A, Rastogi A, Tiwari D. Symetric peripheral gangrene with mixed malaria. Indian J Pediatr. 2007 Jun;74(6):587-8. This article on PubMed


35. Pramod S, Narendra PC, Sharma KK. Gangrene in a Child with Plasmodium falciparum Malaria. Journal of Tropical Pediatrics. 2005; 51(4):252-253. This article on PubMed


36. Vipa T, Srivicha K, Polrat W, Weerapong P, Udomsak S, Sornchai L. Peripheral gangrene in patients with severe falciparum malaria: report of 3 cases. Korean J Parasitol. 2006; 44(2): 139-143. This article on PubMed


37. Kakati S, Doley B, Barman B, Anjana D. Symmetric Peripheral Gangrene and Falciparum Malaria. J Assoc Physicians India. 2004 Jun;52:498-9. This article on PubMed


38. Raimund H, Peter L, Erich S. Severe Plasmodium falciparum malaria with peripheral gangrene. Lancet Infect Dis. 2008; 8: 400. This article on PubMed


39. Rajoo T, Apurba G, Debkrishna M, Biswajit B. Symmetrical peripheral gangrene in childhood falciparum malaria. Int J Dermatol. 2010 Mar;49(3):303-5. This article on PubMed


40. Bhattacharyya PC, Jagdish PA, Sharma M. Symmetric peripheral gangrene of the lower limbs in a case of complicated falciparum malaria. Southeast Asian J Trop Med Public Health. 2008 Jul;39(4):589-92. This article on PubMed