Tropical Phagedenic Ulcer

Raveenthiran Srinidhi [1], Venkatachalam Raveenthiran [2]

[1] Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram 608002, Tamilnadu, India

[2] Department of Pediatric Surgery, Government Cuddalore Medical College, Chidambaram 608002, India.

Introduction

Tropical ulcer (phagedenic ulcer) is a rapid-onset, slow-to-heal, skin ulcer caused by the synergistic infection of Fusobacterium ulcerans (FU) and spirochetes.(1-3) It is characterized by “an acute-looking ulcer of long duration”.(4) Although no age is immune, it is common in older children and younger adults.(1,2) Mortality is extremely rare in modern days; yet, morbidity is immense and crippling. It is truly a neglected tropical disease (NTD) that the Western scientific world has completely ignored.(5,6) Even the World Health Organization (WHO) failed to recognize it as a distinct entity.(7) A PubMed-based bibliometry of tropical ulcers reveals a peak of research activities between 1925 and 1975, followed by a steep decline.(Fig.1) The peak corresponds to the World Wars I and II when the British and American troops returned with these ulcers.(8) The sharp decline in the research output of tropical ulcers may be attributed to its decreasing incidence as a result of better living conditions, good nutrition, easy access to health care, availability of better antimicrobials and modern diagnostic facilities, or it is attributable to a pure apathy of the scientific world. In the last 25 years, there are only fewer than 8 publications on the ‘tropical ulcer’!(6,8-15) Possibly, many of them might have been mislabeled as ‘simple non-healing ulcers’ and treated at non-academic centers without special research consideration. Negligible mortality and morbidity might have also resulted in poor funding chances of research.      

Fig 1: PubMed-based bibliometry of tropical phagedenic ulcer

HISTORY

Paleopathological evidences suggest that Copper-age (circa 3000 BCE) people in the basin of the Tanaro River in Northern Italy might have suffered a disease resembling tropical ulcer.(15) Tropical phagedenic ulcer (TPU) is well known at least for the last 3 centuries. According to Jadassohn’s Handbook of skin and venereal diseases, the credit of the first description of Ulcus Tropicum in 1792 is attributed to Hunter of Jamaica.(16,17) According to Harper’s Textbook of pediatric dermatology,  Vinson of Mozambique was the first to describe TPU in 1857 among the slaves of merchant ships.(8,18) However, a recent research revealed that the disease was first described by Adriaan Van Brakel in 1774.(19) 

Van Brakel was the ‘First-Surgeon’ of the Dutch East-India vessel Ouwerkerk that carried 366 crews to Java. Among them, 63 developed a peculiar leg ulcer which they acquired either while camping at the Cape of Good Hope or while crossing the Indonesian sea and 22% of them died. This unusually high mortality on board prompted the prosecution of Van Brakel for negligence of care. In the era when microbes were not known and antibiotics had not been discovered, what else a naval surgeon could have done, other than dressing the ulcers thrice daily and applying tinctures? In his journal, Van Brakel had accurately recorded the morphology of the ulcers and he noted them as “alkaline, scorbutic and of malignant humour”. Thanks to this meticulous description, he was finally acquitted. The juries observed, “Van Brakel's treatment was quite correct, dutiful, and beyond reproach”. Interestingly, Van Brakel named them as Ulcus tropicum phagedaenicum, (translated into English as Tropical Phagedenic Ulcer) - a term which is still in use. This appears to be the first known detailed description of this pathology. Van Brakel also astutely observed the link between TPU and nutritional by noting that many of those who died were ‘scorbutic’.(19)

Although the pathogenic role of fusiform bacteria and spirochetes had been well known for more than a century, it was in 1987 Beverley Adriaans established TPU as a legitimate disease entity by discovering a new species of bacteria specific to TPU.(1,2,20-25) He named the new organism as Fusobacterium ulcerans (FU).(20,22,25) He was also the first to conduct multicentric studies and electron microscopic studies on TPU.

Etymology and Nomenclature

The term ‘tropical ulcer’ has been inconsistently used in the literature with two different connotations.(26)  In a generic sense, it is used to mean any chronic ulcer seen in the tropics. This includes cutaneous Leishmaniasis, Buruli ulcer, yaws, ecthyma, cutaneous diphtheria and several other venereal diseases.(6,27-30) On the other hand, in a specific sense, it is used to mean a peculiar ulcer of the legs caused by the synergistic infection of FU. Still worse is that the term has also been confused with ‘trophic ulcers’ (with a misspelling ‘tropic ulcers’).(31) Therefore, to avoid confusion, the term ‘phagedena’ is preferred by some authors.(32) It is a combination of two Latin words, ‘Phage’ (to eat) and ‘daena’ (avidily) - ‘Phagedenic ulcer’ means ‘a devouring ulcer’. Unfortunately, this term has also been misused to mean any rapidly spreading neoplastic or venereal ulcers.(33,34) Other varieties of hospital-acquired necrotizing fasciitis such as Fournier’s gangrene, Cullen’s ulcer and Meleney’s ulcers have also been referred to as phagedena.(35) Adding to the confusion, this pathology is also known by a variety of geographic and local names that are shared with other pathologies.(1-3,19,36,37) (Box 1) For example the term Delhi sore is applied to both TPU and cutaneous Leishmaniasis.

Interestingly, in pre-independent India, TPU was also known as Aurengzebie, with reference to the Mogul emperor Bahadur Alamgir Aurangzeb (1618–1707 CE).(38) The etymology of this word is ascribed to the sufferer, which is variously cited as the emperor himself, the British army stationed at Delhi cantonment and the citizens of Delhi.(39) It may also be a contemptuous expression maligning the tyrannical emperor. On retrospective analysis, Aurengzebie appears to be a mixed lesion of TPU and cutaneous Leishmaniasis.

From the foregoing it is evident that one has to be extremely wary of the confused terminologies used in the published literature.(3) Imprecise terminology and overlapping clinical features of TPU with several other pathologies prompted Clement to comment that tropical ulcers were the “diagnostic garbage heaps of tropical medicine”.(3) The descriptive term tropical phagedenic ulcer (TPU) coined by Le Dantec in 1900 appears to be less confusing and hence is preferable.(26,40,41)    

Etiopathogenesis

Several etiopathogenic theories of TPU have been proposed. Many of them are anecdotal without proper research evidence. It is now established that TPU is essentially an infectious disease. What predisposes to the infection is extensively debated in the literature. Marsh and Wilson succinctly summarized the etiopathogenesis of TPU as “Filth (Flies), Food, Friction and Fusospirillosis”.(42)

Nutritional Deficiency Theory

Dietary deficiency is the oldest pathogenic theory of TPU known since 1774. Van Brakel considered it to be a consequence of vitamin C deficiency.(19) During the Child’s War (1686–1690), the British troops sieging Delhi did not develop TPU thanks to the availability of good food, while inhabitants of the inner city including the emperor Aurangzeb were said to have developed the disease owing to a short supply of nutritious food.(30,39) Approximately 30% of TPU patients are malnourished.(43) McCulloch called TPU a ‘dietetic ulcer’ because adding fish to the diet reduced its incidence.(44) Deficiencies of vitamin B-complex(48,49) (especially riboflavin), calcium(3,44-46), zinc(47), vitamin A,(48) and animal protein(44) have been implicated in the pathogenesis of TPU.

Nutritional deficiency theory is supported by the high incidence of TPU during drought seasons and during rainy seasons when fishing activities are abandoned. The rich people in cities are rarely affected as compared to the rural poor. However, several authors disputed and disproved this theory.(2,41,42,47,50-53) Interestingly, the ulcers healed  faster in patients treated with topical cod-liver oil dressings than in those who were given the fish oil orally.(48) Irrespective of its role in primary TPU, nutritional deficiencies certainly increase the risk of recurrent ulcers.(48)   

Vector-born infection theory

James observed that TPU is very common in areas endemic to malaria.(54) He proposed that TPU could be a vector-born disease.(48,55) Nevertheless, Loewenthal observed that malaria was common in both rich and poor, while TPU was exclusively seen in the poor.(44) Abrasions caused by scratching of insect-bite sites probably serve as the entry point of the infective agents.(55)  Mosquitoes, flies and leeches may act as mechanical vectors of pathogenic microbes. (56,57)

Traumatic Theory

It is generally accepted that tiny abrasions and minor injuries facilitate the entry of pathogens. The injury may be trivial enough to be easily forgotten by the patients. They may be thorn pricks, scratches, insect bites, scabies or sports injuries. Nearly 24-94% of patients had a history of injury.(2,52) Apostolides reported a nurse who developed TPU of finger after accidental pricking with a contaminated scalpel.(58) The traumatic theory is supported by the fact that TPU is common in the legs of boys who play outdoor games without wearing protective full trousers. The high incidence of TPU in agricultural farms and in barefoot walkers is also linked to trivial injuries. Interestingly, the sole of the foot is never involved even in barefoot walkers, perhaps due to thick epidermis.

Vascular Insufficiency Theory

The high frequency of TPU in the lower leg raised a suspicion if it could be a form of vascular insufficiency.(3,59) Jackson suggested that the ulcers may be caused by interrupted dermal blood supply as a result of obstructed perforator vessels as they pierce through the deep fascia.(2,60) Findings that support the vascular theory are presence of intravascular thrombosis near the ulcer, thickening of the vessel wall by endothelial hyperplasia, perivascular infiltration of inflammatory cells, septic emboli within the vessels and degeneration of vessel walls in the granulation tissue. However, Adriaans found no evidence of vasculitis in histopathology and electron microscopy.(2,21) He attributed the vascular changes to the effect of healing and inflammation.

Synergistic Infection Theory

Bacterial synergy is the widely accepted theory of TPU pathogenesis.(24,25) It was first proposed in 1899 by Le Dantec, Plaut and Vincent.(2) Although the association of fusiform bacteria with TPU was well known for several decades, in 1986 Adriaans discovered that the isolated species is unique to this pathology and named it as Fusobacterium ulcerans.(20,22,23,25) In addition to FU, Bacteroides, coliforms or Treponema vincentii (a spirochete) are also frequently isolated from the ulcers. Pure isolates of these organisms did not cause ulcers when injected into guinea pigs or rabbits;(2,53) but when injected together, they caused typical TPU in animals and human volunteers, thus satisfying the Koch’s postulates of infectivity.(1,2,53) These experiments indicate that these organisms are less virulent to cause disease by themselves and when inoculated together act synergistically. The low virulence and host immunity could be the reason for the spontaneous halting of ulcer size after the initial phagedenic phase. The presence of FU as a commensal in the oral cavity and intestine in 25% of TPU patients has lead to the hypothesis that they may be spreading by auto-inoculation from eating with the hand, by public spitting of saliva, or by the topical application of native medications prepared by mixing saliva or cow dung.(3,58) 

Cytotoxic Enzyme Theory

Although FU is isolated from TPU, the exact pathogenic mechanism is not known. A hypothesis of bacterial metabolic by-products causing cellular damage has been proposed.(60) FU produces a high amount of butyric acid which is proven to be directly cytotoxic to Vero cell lines in vitro at a concentration as low as 0.005M.(23) Heparinase synthesized by Bacteroides causes intravascular clotting thereby interrupting blood supply to the ulcer area.(60) The resultant anaerobic environment favors the growth of FU, thus establishing a synergy.

Apart from the bacterial exotoxins and endotoxins, dying host cells also liberate several autodigestive enzymes such as extracellular protease, collagenase, elastase, lecithinase, hemolysin and lipo-polysaccharides. These enzymes may play a major role in the pathogenesis of TPU. Platelet-activating factor (PAF) when combined with bacterial lipo-polysaccharide can cause extensive tissue necrosis.(61) Biosynthesis of PAF by host immune cells is stimulated by bacterial endotoxins and hypoxia. PAF recruits more cellular elements which in turn synthesize more PAF. As surgical excision of the ulcer removes the source of toxic enzymes, TPU are found to heal faster with this treatment than with antimicrobial therapy.(60) 

Recently, proteolytic enzymes such as matrix metalloproteinase-9 (MMP-9) released by FU are shown to inhibit wound healing. They cause destruction of extracellular matrix and inactivation of epithelial growth factors.(62) Interestingly, MMP-9 is a calcium-dependant and zinc-containing endopeptidase, thus reviving the interest in nutritional theory of TPU. 

Comorbidity Theory

TPU is known to occur as a superadded lesion to an already existing leg ulcer such as that of sickle cell disease, Leishmaniasis, Buruli ulcer or yaws.  The frequent association of TPU and hepatitis in Kiribati and Gambia suggests that both the diseases could have been acquired through a common mechanism, namely trauma.(63,64) As FU is a commensal in oral cavity, gingivitis is proposed to be a risk factor for TPU.(43) James believed that Malaria is a predisposing factor of TPU.(54) The postulated pathogenic mechanisms include hemolysis liberating iron needed for bacterial growth, immunosuppressive effect of splenomegaly, toxins released by plasmodium, mosquitoes acting as a mechanical vector, protein catabolism of malarial fever reducing the host immunity and the introduction of infection by scratching the mosquito-bite site(54) However, Adriaans did not find any significant pathogenic association of TPU with comorbidities.(2)

Genetic Theory

Coloured races (Africans and Indians) and Chinese are more commonly affected by TPU than the White races. It is more common among the Nuba tribe of Sudan than in Arabs.(48) Among Kenyans, Kikuyuns are more prone to TPU than the Maasai tribes. Similarly, Rwandans are more affected than the Baganda tribes of Uganda.(48) In Assam, it is common in the Uriah caste.(57) These differences may not be due to genetic susceptibility; but rather to cultural variations in dietary habits, exposure to causative organisms and lack of protective footwear. This is attested by the fact that the British and American troops, deputed to tropical terrains during the two World Wars, developed TPU.

Demography

Geographic Distribution

TPU is mainly reported from the tropics and subtropics.(1) It is endemic in Gambia,(47) Zambia, Central Africa,(2) Uganda,(65) Zimbabwe,(66) South Africa,(18) Mozambique, Nigeria,(67,68) Ethiopia,(69) Kenya, Sudan, Libya, Southern India,(70) Eastern India,(56,57) South China, Indonesian archipelago, Vietnam, Caribbean islands,(71) Fiji,(14) Australia,(3) Gold coast, Papua New Guinea,(72) Bolivia, Brazil and Argentina.(2) (Fig 2) It is more common in the rural areas of Gambia than in the urban centers.(44) Well-documented outbreaks(12,73-75) (Box 2) and travel-acquired TPU have been reported from other parts of the world including temperate countries.(6,14,36) Although TPU is nicknamed as desert sore, it is rare in the Arabian Peninsula. It appears that a hot humid climate rather than a dry torrid environment is essential for the pathogenesis of TPU. For this reason, it is common in the cold highlands of Somalia and in Assam with the highest rainfall in India.(1,2)

Incidence and Prevalence

The exact incidence of TPU is not known. Several of these patients might have been treated by native healers without a diagnostic label of TPU. In Madurai (Tamilnadu), 10 new cases were seen daily at a smaller clinic located on the banks of the Vaigai River, while there were none at a nearby big teaching hospital that had a footfall of 3,000 new patients per day.(41) This illustrates the case selection attitude of hospitals in the same geographic location. TPU was endemic in the tea estates of Assam, they were never seen at the Tata Tea Estate of Munnar, although the work environment

Fig 2: World-wide distribution of Tropical Phagedenic Ulcer (Compiled by analyzing 100 years of literature, 1924 - 2024)

of both places were identical.(41) Tumwine from Zimbabwe reported the largest series of 1,680 patients collected over 14 months.(66) Among the 36,000 children admitted to a Nigerian hospital over 10 years, there were 126 cases (0.35%) of TPU.(76) Prevalence at a refugee camp was 6.9% and at a primary school was 8.2%.(41) In a community survey, TPU forms 7.4% of all skin infections in Ethiopia(66) and 0.4% of all chronic leg ulcers in the tropics.(77) About 3-7% of hospital admissions in Sudan(48) and about 95% of skin ulcers in Nigeria are due to TPU.(1) It is found to occur in 1% of the vulnerable population in Uganda.(65) Very high incidence to the tune of 33-50% of hospital out-patients has been reported from Nigeria and Uganda.(44) There are some indications that the annual incidence of TPU is progressively falling in the last 4 decades.(2) 

Age Distribution

Although TPU can occur at any age, it is common between 5 and 15 years (mean 9 years).(1,2) It is extremely rare below 5 years and above 45 years of age.(1,2,41,78) As young infants are carried by mothers, they are unlikely to contract infection from environmental injuries. The youngest patient reported was a 3-years old infant.(79) The reason for the high prevalence in older boys is attributed to outdoor gaming activities without protective full-length trousers or footwear. James reported 2% of TPU occurring in infants below 2 years of age.(54) In India 41% occurred in age less than 15 years, 35% in 16-30 years, 21% in 31-45 years and 2% in above 45 years of age.(57)

Sex Distribution

The sex distribution of TPU is variously reported as equal ratio,(1,2) a female preponderance,(44) or a male predominance. A moderately high male ratio of 2:l is reported from India and Trinidad;(45,51) while others (52) found a male predominance in the cities and an equal sex ratio in the rural areas. A very high male ratio of 14:1 has been reported from India.(2,41)  The  93% male frequency reported by Buchanan is exceptional.(80) The variations in sex incidence are attributed to the nature of occupation exposure to injuries. For example, men who do fishing from boats are less prone to TPU than women who do agricultural activities in marshlands.(2) 

Seasonal Variations

In Aden, Sumatra, Gambia, Zambia and West Indies, TPU is common in the wet rainy seasons. However in Libya, it is common in dry hot draught seasons.(2) Seasonal scarcity of certain foodstuffs and nutrients could be the reason behind this variations. It is suggested that TPU is common in warm humid periods of the year due to excessive sweating, skin maceration and itching-scratching injuries that leads to inoculation of pathogens.(52) Fresh lesions erupt after a brisk shower followed by bright sunshine.(2) Therefore, a warm humid atmosphere appears to be essential for the proliferation of causative organisms in the environment. Few authors from India and Papua New Guinea have denied any seasonal variations in the incidence of TPU. (45,50)

Contagiousness

Loewenthal (44) and Adriaans(2) have proved that person-to-person spread is rare. Epidemics of TPU appear to have been due to direct inoculation from environmental rather than from human contacts. Overcrowding is not a risk factor, as TPU does not occur in several members of the same family.(44)

Pathology

The histopathological features of TPU are non-specific.(2) They vary according to the stage of the disease, the effect of treatments and the zone of ulcer that is biopsied.

At the early stages, a coagulum containing necrotic tissues, exudates and bacteria forms a pseudomembrane resembling that of diphtheria.  Underneath the pseudomembrane, bacteria are arranged in a palisade fashion. Histopathological features of the acute phase include spongiosis (intercellular edema of the epidermis), elongation of the rete ridges, polymorphonuclear leukocytic infiltration, destruction of melanocytes, edema of the dermis, disorganized collagen strands, dilated capillaries, hemorrhagic foci and micro-abscesses at the adjacent soft tissues. Acanthosis (thickening of the stratum spinosum) at the peripheries of the TPU causes raised pigmented edges.(1,2)  

In the chronic phase, progressive fibrosis of the ulcer base, peripheral hyperkeratosis (thickening of the stratum corneum), pseudoepitheliomatous hyperplasia, foreign-body giant cells reaction and lymphocytic infiltration are seen. Arteries show marked hyperplasia of smooth muscles and endothelium resulting in narrowing of lumen.(2) Some authors consider these vascular changes as the primary pathology rather than the effect of inflammation.(2) Adriaans has conclusive excluded vasculitis in the pathology of TPU.(2) Nerves are not affected.

Electron microscopy (EM) confirmed the features of conventional histology.(21,81) Direct bacterial cell lysis seen in EM may explain the rapid necrosis of tissues in the acute phase. EM demonstrated an equal proportion of helper and suppressor T cell infiltrations, but only a few B cells.(21)

Microbiology

The microbiology of TPU is faced with several challenges: (i) Anaerobic culture facilities to grow FU are not universally available. (ii) Culturing of Treponema is extremely difficult. (iii) Dark field microscopy which is essential to visualize spirochetes is not available in many low-middle income centers. (iii) Secondary invaders and surface contaminants often mask the original pathogens. Costa asserted that contaminants are usually superficial while actual pathogens are located in deeper layers.(36) However, this is not scientifically proven. (iv) Isolates differ according to the site of sampling and pathogenic phase.(Box 3) Contaminants are more at the center of the ulcer while true pathogens are at the advancing peripheries. Cultures were positive in 36% within 6 weeks of onset, while only in 1% after that.(2) (v) Several anaerobic pathogens die during the transport of samples thus accounting for a high percentage of negative cultures.

The primary pathogen of TPU is FU. They are non-sporing pleomorphic Gram-negative obligate anaerobic rods that produce large amounts of butyric acid. Among the 15 varieties of Fusobacteria, different species are etiologically associated with different diseases.(82) For example, noma is caused by F.necrophorum, gastric ulcer by F. gastrosuis and ulcerative colitis by F. nucleatum and F. varium. Similarly, F. ulcerans (20,22) and F. nucleatum (81) are identified to be specific of TPU.

Two distinct morphological variants of FU have been described. Group-1 FU (NCTC 12111) is coccoid, forming huge dome-shaped creamy or yellowish smooth colonies. They have pointed ends and are capable of growing in selective medium with bile. Group-2 FU (NCTC 12112) is irregularly stained, long rod-shaped or filamentous, forming tiny flat colonies. They have bulbous swelling in the center of the rod.(20)  Both variants are commensals in the oral cavity and colon.(83) The Group-1 FU resembles F. varium, while the Group-2 FU resembles F. moriferum. However, they differ in their fermenting characters.

Pre-reduced anaerobically sterilized, peptone yeast extract (PRAS-PYG) agar and broth dispensed into Hungate tubes are the ideal transport medium for FU.(25) It allows successful culturing as late as 6 weeks of sampling.(2,25) Eh indicator in the medium will reveal any break in the anaerobic seal. Brain heart infusion (BHI) broth or agar is the recommended regular culture medium for FU.

Pathogenic source of FU is variously described as saliva, mud, thorny bushes and marshland.(41) A minimum inoculum size of 1012 Fusobacteria was needed to cause the lesion.(2,20,24) FU is never seen in histological sections probably because of small numbers.(50)

Classification

TPU may be primary (de novo) or secondary. It may occur as a superadded infection of guinea worms, scabies, cutaneous Leishmaniasis or dog bites.(45) Secondary TPU has often led to much confusion in the literature. From epidemiological point of view, TPU may be classified as sporadic, endemic or epidemic.

Staging

Based on the evolutionary characteristics of the ulcers, TPU is variously staged by several authors. Innes(4) classified them into acute, sub-acute and chronic types; Pattanaik(84) into early, sloughing, indolent and healing stages; Blaine(5) into acute, chronic-on-acute and chronic indolent ulcers; and Robinson into phases 1 (pre-ulcerative papule), 2a (acute ulcer), 2b (chronic ulcer) and 3 (healed ulcer).(2,41) In 1938, James(54) classified TPU into Stage 1 (active progressive ulcers), Stage 2 (sub-acute ulcers with cessation of progression), Stage 3 (clean, chronic or healing ulcers). In the same paper, he also provided another detailed staging system which is modified and adopted in this review. (Table 1)

Clinical Features

Clinical features of TPU vary according to the stage of the disease.

Stage 1 (Prodromal or Pre-Ulcerative Stage)

Pre-ulcer stage lasts for a few days. A small papule of a few millimeters size develops at the site of inoculation and it soon becomes a vesicle and pustule.(78) It is highly painful and may ooze sero-sanguinous fluid. Only 3% of patients present at this stage.(41,78) These lesions are usually seen by physicians in the form of a satellite lesion that erupts near the existing ulcers. Within a few days black discolouration occurs around the papule. Rarely, the vesicle may transform into a hemorrhagic bulla. At the end of one week, the central area necroses, leaving behind a tiny ulcer. 

Approximately 80% of the lesions occur between the knee and the ankle.(1,2,57,78) The dorsum of the foot, thighs and toes are also frequently involved. The sole of the foot is never affected.(57) (Fig 3) Rarely, it may occur in shoulders, arms,  trunk, neck, and scalp.(2,50)  

Stage 2 (Acute Phagedena)

It lasts between 1 to 6 weeks of onset. About 65% of TPU patients are seen within a month of onset.(41) At this stage, the ulcer rapidly spreads in all directions. It is highly painful and is covered by a thick tenacious, gray-green or ash-white, fetid slough resembling that of diphtheric pseudomembrane. Copious discharge attracts flies. The floor of the ulcer is filled with crimson-red, friable granulation tissue that bleeds easily on touch. It is graphically described as putrid magma-like.(36) (Fig 4) The ulcers are oval, circular or of a regular geometric pattern with undermined edges, raised borders and black discolouration of peripheries. There may be mild edema around the ulcer; however adjacent tissues are mostly unaffected.

Fig 3. Anatomical distribution of Tropical Phagedenic Ulcers (Drawn using Pikaso AI tool; retouched by Srinidhi) Data source: Adriaans (2)

The ulcers are usually single (75-80%)(52) or occasionally multiple (25%). (1,2) As many as 8 ulcers have been reported in a single patient.(57) Kissing and satellite ulcers may coalesce into a single large ulcer. The size of the ulcer is usually 2 to 6 cm; but ulcers as large as 15 cm in diameter have also been reported in 6% of patients.(1,2,41) Exceptionally, Kolawole reported an ulcer of 40 cm diameter that encircled the limb.(67) The depth of the ulcer is usually less than 2 cm(41) and is inversely proportional to the extent of ulcer.(85) During the phagedenic phase, the infection may involve the underlying muscles, tendons and bone. The ulcer heal slowly over 2-6 months.(44) 

Systemic symptoms are either absent or minimal. However, during the first two stages, mild fever and malaise occur especially in young children. Lymphangitis, erysipelas and regional lymphadenopathy are seen in 25% of TPU.(5,86) Acute lymphangitis may cause massive edema of the lower limb resembling elephantiasis.(5) 

Stage 3 (Chronic Indolent Ulcer)

This stage lasts from 6 weeks to several months (range 2-6 months). Rarely, they defy healing and persist for several years. MacDonald cited an unusual case of ulcer that persisted for 18 years!(6) A peculiar mucoid secretion gives a glazed appearance to the ulcer. Ulcers at this stage are stabilized in size and are painless; but rarely, nocturnal pain may be experienced.(36) Secretions are minimal and non-foul smelling. The base of the ulcer is indurated and hard that it resembles a cartilage on palpation. A gritty sensation of the base is appreciated when a needle is pierced through it while injecting local anesthesia for biopsy. The edges are more prominent, sclerotic and elevated resembling a bund. This soft tissue thickening is the hall-mark of TPU. The floor is relatively clean with a pale-pink granulation which is less friable and does not bleed readily on palpation. Rarely, the chronic ulcers exhibit periodic exacerbation with further expansion of the ulcer size.(60) Jackson believed that TPU do not involve deep fascia and such involvements are almost always due to superadded infections.(60) With secondary infection adjacent tissue may become erythematous for a considerable distance.

Stage 4 (Chronic Erosive Ulcer)

TPU is predominantly a disease of the skin and soft tissues.(44) However, it may also erode into the underlying tendons, muscles and bone.(Vide infra) This stage may last from 6 months to 10 years.(5)

Fig 4. Clinical appearance of Tropical Phagedenic Ulcer. (A) Acute phagedenic stage; (B) Chronic non-healing stage of the same patient. (Public domain figures from Public Health Image Library ID No. 12174 and 12178 respectively)

Stage 5 (Healing & Cicatrization)

At this stage, healing starts by flattening of the edges. The resultant scar resembles the shape of the original ulcer. The scar is thin and pale-white resembling a parchment paper. (Fig. 5)  The mean duration of healing is 20 weeks (range 1-52 weeks). However, indolent ulcers may persist for 12-15 years.(5,8) As the scars are atrophic, they are liable for repeated breakdown and recurrent ulcers. The causative organism is said to lurk in the scar with periodic reactivation.

Diagnosis

Diagnosis of TPU is mainly based on the clinical characteristics of the ulcer. Flora Innes(4) defined 3 diagnostic criteria as follows:

1.   Acute-looking ulcer of long duration. (Punched out edges, undermined margins, glary mucoid foul smelling discharge, free bleeding and pearly islets projecting through the base)

2.   Extreme pain in the acute and sub-acute stages

3.   Demonstration of Fusobacterium with Spirochetae in the ulcer

Dark field microscopy, anaerobic culturing and radiographs of underlying bones are helpful in the diagnosis. Neutrophilic leukocytosis, elevated C-reactive protein and other inflammatory markers may be present; but are non-specific.

Fig 5. Characteristic parchment-paper-like thin depigmented scar of healed Tropical Phagedenic Ulcer (From MD thesis of Beverley Adriaans submitted to the University of Cape Town, South Africa, 1988).

Differential Diagnosis

Several tropical diseases clinically mimic the skin lesion of TPU. (Table 2; Fig. 6) Radiographic differential diagnoses of bone involvement in TPU include Brodie’s abscess, osteomyelitis, Ewing’s sarcoma and osteosarcoma.(59,67) The absence of a penumbra sign in the bone MRI is said to differentiate TPU changes from osteomyelitis.(11) 

Fig 6. Characteristic leg ulcer of Yaws mimicking Tropical Phagedenic Ulcer. (Reproduced from Mitja O et.al, PLOS Neglected Tropical Diseases 2017; DOI:10.1371/journal.pntd.0005136 under Creative Commons Attribution License)

Treatment

Blaine(5) summarized the principles of treatment by the acronym ACEER: Arrest of the spread of ulceration, Clearing of infection, Early and adequate separation of pseudomembrane, Encouragement of granulation tissue formation and promotion of Re-epithelization.

Marsh and Wilson (42) recommended a “lock-up treatment” wherein the affected limb is immobilized it in a plaster-of-Paris cast. Advantages of immobilization and closed dressing include protection of growing capillaries of granulation tissue and delicate epithelium from mechanical damage, prevention of tissue desiccation, reduction of pain, avoidance of further auto-inoculation,  prevention of environmental contamination and promotion of lymphatic stagnation that helps in halting the systemic spread of infection.(42) Marsh and Wilson claimed that 59 of the 85 cases treated with lock-up therapy completely healed within 2 weeks. But, Yesudian and Thambiah (40) disapproved any form of closed dressing because it creates a warm moist anaerobic environment that is conducive to the growth of pathogens.  It is to be noted the Marsh and Wilson used topical antimicrobials in conjunction with ‘lock-up’.

Several topical and systemic agents have been used in the treatment of TPU. (Box 4 &5) Some of them are obviously dangerous, while others are of doubtful use. For example, mercuric perchlorate, tar, hydrochloric acid and formalin can no longer be considered as ethical treatments. Some agents are useful selectively in specific cases. Fish oil dressing is shown to remove malodor and to promote epithelization in chronic ulcers but not in acute ulcers.(48) In fact, oily dressings may worsen acute infections. Therefore, the treatment of TPU should be tailored to the stage of disease and to the patients’ condition.

Acute Phase Management

In early stages, systemic antibiotics and frequent washing of wounds are indicated. The antibiotics should cover gram positives, gram negatives and anaerobes. Ideally, a combination treatment with third-generation cephalosporin, penicillin, erythro mycin, streptomycin, co-amoxiclav, metronidazole and aminoglycosides is recommended. Although clindamycin has a good anaerobic coverage, it should be avoided because FU are genetically resistant to it. In multidrug resistant cases, rifamycin or oral tetracycline may be used in older children with due precaution. Systemic antibiotics are useful only in acute stage, but not in chronic stages.(87)

The best topical treatment is perhaps, frequent washing of the wound with soap and running water. Hydrogen peroxide, boric acid, povidone-iodine and potassium permanganate are also useful. Hydrogen peroxide and digestive enzymes (e.g. chymotrypsin) may be useful in the separation of the pseudomembrane. Epithelial irritants (e.g. metronidazole), oil-based applications (e.g. Vaseline) and agents that can provoke bleeding (e.g. streptokinase) are better avoided in the acute phase.

Topical antibiotics (e.g. gentamicin, penicillin) are not recommended as they facilitate the emergence of resistant strains. As the offending bacteria are deep inside the wound, topical applications are mainly useful in controlling the secondary pathogens rather than the FU. Hyaluronidase is claimed to improve the penetration of topical agents.(5) Silver sulphadiazine and silver nitrate are ideal topical agents.  

Chronic Phase Management

In the chronic stage, when infection is no longer a threat, protection of growing epithelium by oil-based dressings or ‘lock-up’ therapy is preferable. Topical and systemic antibiotics are of limited use in indolent ulcers. Management of complications and rehabilitation of crippling limb deformities are inherent components of long-term care. When the underlying tendons and bones are damaged, through surgical debridement is essential for healing.  

Role of Surgery

Surgical debridement is best avoided in the acute phagedenic phase as it may precipitate septicemia. However, periodic gentle debridement is indicated in the case of extensively deep ulcers.

The importance of surgical excision in the healing of chronic ulcers was appreciated as early as in 1930s.(54,65) It is hypothesized that excision of the ulcer removes the source of cytotoxic chemicals that inhibit natural healing.

Surgical intervention may be (i) curettage of ulcer bed with or without skin grafting, (ii) tangential excision of ulcer with immediate or delayed skin grafting, (iii) excision of ulcer with primary suturing of flaps and (iv) allograft or xenograft used as temporary dressing materials. The senior author (VR) has used collagen dressing with good results.

Autologous graft may be Thiersch partial thickness sheet-graft or Reverdin’s pinch graft (also known as seed or punch graft). Seed grafts give better results than sheet grafts and are implementable by trained paramedical workers in remote African villages.(65,72) Graft failure is recorded in 2-30% especially when applied over the tibia.(54,65) In such cases cortical drilling is recommended to encourage sprouting of granulation tissue from the medulla.

Newer Treatments

Smith suggested a ‘cocktail therapy’ that includes antimicrobials (antifungal if necessary), platelet-activating-factor (PAF) antagonists and hyperoxygenating agents (e.g. hydrogen peroxide).(61) H202 not only kills microbes by liberating nascent oxygen but also deactivates PAF by oxidation. It is to be noted that this ‘cocktail therapy’ does not appear to have been tested in clinical patients.

Recently, herbs used by the Apsokok nomadic tribe of Papua New Guinea have been found to be useful in healing TPU.(9) In vitro, they inhibited Staphylococcus, but not FU. The active ingredient of Homalium foetidum (known locally as Malas) extract that exhibits antibacterial property has been identified as coumaroylquinic acids. Extracts of Alstonia scholaris (Rambaka) and Pangium edule (Kali) were found to stimulate collagen synthesis by the fibroblasts and inhibit MMP-9, a proteolytic enzyme that destroys growth factors and extracellular matrix. Burnt ashes of these plants are applied to the TPU. Possibly, it acts as an activated charcoal dressing, that absorbs toxins and promotes wound healing.(9)  

Complications

Several complications of TPU have been docu-mented in the literature, all of which are rare in modern days. Early medical intervention and the availability of better antimicrobials may be the reason for this change.

Squamous Cell Carcinoma

Malignant transformation occurred in 2-9% of TPU after a mean lapse of 3 years.(2,71) Fortunately, malignant cells do not metastasize thanks to dense fibrosis and poor vascularity of the underlying soft tissues. This is similar to Marjolin’s ulcers.(59)

Osteitis

The tibia, due to subcutaneous location, is vulnerable to secondary changes in TPU.(59,67) Bone just beneath the ulcer is usually involved; however, remote bones are rarely affected. The pathogenic sequence of bony lesions(59,67) can be summarized as follows:

1.   Lifting of the periosteum due to inflammatory edema leads to periosteal reaction and new bone formation. This causes a fusiform or ‘sun-burst’ appearance in radiographs.

2.   The involucrum blends with the existing cortex resulting in an ‘ivary-osetoma like’ cortical sclerosis. This is seen as periosteal heaping or thickening in radiographs. Rarely an onion-peel appearance is resulted. The new bone may be as thick as 2 cm(59) and is called as ‘ulcer osteoma’.(67) Two different types of ulcer osetomas are known to occur. The cancellous variety is common in the fibula while the sclerotic type is common in the tibia.(67) Sclerotic osteomas are reversible by early intervention while the cancellous osteomas almost invariably require surgical excision.(67)

3.   Irregular new bone formation causes undulations in the bone cortex.

4.   The fragile involucrum disintegrates leaving behind a sequestrum.

5.   Separation of the sequestrum leaves behind a saucer-shaped crater (cortical ulcer), thus weakening the bone cortex

6.   The weakened bone, together with inflammatory epiphyseal fusion and fibrosis of adjacent soft-tissues causes bending of limbs with a convexity towards the ulcer site.(59) Bowing of the tibia, valgus deformity of the ankle and drawing together of the tibia and fibula are well known.

7.   Two types of medullary bone changes occur in TPU: (i) Osteoporosis-like change occurs distal to the ulcer site due to disuse atrophy; (ii) Osteomyelitis-like change occurs at the ulcer site due to inflammation effect.

8.   Deformed, osteoporotic bones are prone for pathological fractures

In addition to bony changes adjoining tendons and muscles may also be involved in necrosis and fibrosis, thus adding to deformity and disability.

Hepatitis-B

About 26% of TPU patients were found to have associated hepatitis B in Kiribati and Gambia.(63,64). The ulcer exudates were positive for Hepatitis virus. Thus, open TPU are a source of great public health concern.

Rare Complications  

Gas gangrene,(68) tetanus,(68) thrombophlebitis, toxemia and death are now not seen. Psychological depression due to non-healing ulcers has not been adequately studied.(54)

Prognosis

The mean healing time of ulcers is 4-6 months.  Recurrent ulcers are not unknown in TPU. They occur at the same site in 25% and at a different site in 65% cases.(2,59) The morbidity of bone involvement and scar contractures are not well studied. Amputations were common in the pre-antibiotic era.(58) In 1972, out of the 230 cases of TPU, 11 patients required amputation of a limb, among whom 7 had squamous cell carcinoma.(71) There were no deaths reported in the last 70 years!

Prevention

The importance of good nutrition, a clean environment and personal hygiene cannot be overemphasized. Protective trousers and footwear, applying oil to legs during outdoor playing and files control measures are recommended to prevent the spread of infection. Daily bathing by applying soap is perhaps, the single most important preventive strategy of TPU.

Epilogue

More than 80% of the literature on TPU is at least 4 decades old. Almost all of them are descriptive observational studies. Randomized controlled trials and meta-analysis are almost nonexistent. Hence recommendations made in this review are of level-4 evidence. This review calls for more robust scientific studies on TPU.

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